Pyrrolo[2,3-b]pyridine PGDH inhibitors and methods of making and using them

Abstract

Disclosed herein are 15-hydroxyprostaglandin dehydrogenase inhibitor compounds that contain pyrrolopyrimidine mutations. Such compounds can be administered to subjects that may benefit from modulation of prostaglandin levels.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 226,670, filed July 28, 2021, which is incorporated by reference in its entirety. [Background technology]

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

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

[0004] In one aspect, provided herein is a compound having the structure of formula (IV) or a pharma- ceutically acceptable salt, or solvate:

[0005] [ka] In the formula, ring Q is a C6 aryl or a 5-10 membered heteroaryl; W is -CR 6 R 6 -, -O-, -S-, -NR 5 -, -S(O)2-, or -C(O)-; R 1 and R 2 are each independently H, halogen, -CN, or -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 , -C(O)NR 8 R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; R 3 are H, halogen, -CN, and -NR 8 R 9 , -OR 10 , CN, -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 , -OC(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5-10 membered heteroaryl; R 5 is H, C1-C6 alkyl, or -C(O)R 10 and R 6 are each independently H, halogen, CN, or -NR 8 R 9, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO2R 11 , substituted or unsubstituted C1-C6 alkyl; Or, two R's 6 can join together with the atoms to which they are attached to form a C3-C6 cycloalkyl or a C3-C8 heterocycloalkyl ring; R 7 are each independently H, halogen, -CN, or -NR 10 R 10 , -OR 10 , -C(O)R 10 , -C(O)OR 10 or substituted or unsubstituted C1-C6 alkyl; R 8 and R 9 are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C6 10 independently selected at each occurrence from cycloalkyl; R 10 are H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 aryl, and 5-10 membered heteroaryl; R 11 are respectively C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 aryl, and 5-10 membered heteroaryl; R 12 are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; n and m are each independently 0, 1, 2, or 3; q is 0, 1, 2, or 3, and p is 1, 2, 3, or 4.

[0006] In some embodiments, the compound has the structure of Formula (V):

[0007] [ka] During the ceremony, X 2 is N, NR 3A , or CR 3A and X 3 is N or CR 3B and X 4 is N, NR 3C , or CR 3C and R 3A , R 3B and R 3C are each independently H, halogen, -CN, or -NR 8 R 9 , -OR 10 , CN, -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 , -OC(O)NR 8 R 9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5-10 membered heteroaryl; R 3A and R 3B together with the atom to which they are attached form a substituted or unsubstituted 5-6 membered aryl or heteroaryl; or R 3B and R 3C together with the atom to which they are attached form a substituted or unsubstituted 5- to 6-membered aryl or heteroaryl; Here, CR 3A , C.R. 3B , and C.R. 3C are not all H at the same time.

[0008] In some embodiments, the compound has the structure of Formula (Va):

[0009] [ka] During the ceremony, X 2 is N or CR 3A and X 4 is N or CR 3C and R 3A , R 3B and R 3C are each independently H, halogen, -CN, or -NR 8 R 9 , -OR 10 , CN, -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 , -NR12 C(O)NR 8 R 9 , -OC(O)NR 8 R 9 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5-10 membered heteroaryl; R 3A , R 3B and R 3C are not H.

[0010] In some embodiments, X 2 is N and X 4 is CR 3C In some embodiments, R 3B is H and R 3C is -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , a substituted or unsubstituted C-C heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3C is H and R 3B is -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , a substituted or unsubstituted C-C heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl. 2 is C3A, and X 4 is N. In some embodiments, X 2 is CR 3A and X 4 is CR 3C In some embodiments, R 3A is H and R 3Bis -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , a substituted or unsubstituted C-C heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3B is H and R 3A is -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)R 10 , a substituted or unsubstituted C-C heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl. 2 is CR 3A Also, X 4 is CR 3C In some embodiments, R 3A and R 3B are H and R 3C is -C(O)R 10 , -NR 12 C(O)R 10 , a substituted or unsubstituted C-C heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3A and R 3C are H and R 3B is -C(O)R 10 , -NR 12 C(O)R 10 , a substituted or unsubstituted C-C heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3B and R 3C are H and R 3A is -C(O)R 10 , -NR 12 C(O)R 10 , a substituted or unsubstituted C3-C8 heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl.

[0011] In some embodiments, R 3A , R 3B , or R 3C is a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, the 5-membered heteroaryl is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.

[0012] In some embodiments, the compound has the structure of Formula (VIIa) or Formula (VIIb):

[0013] [ka] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, Y 1 is O, S, or NR 3D and Y 2 is N or CR 3A and Y 3 and Y 4 are each independently N or CR 3B and R 3A and R 3B are H, halogen, and -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl; R 3D is H or C1-C6 alkyl.

[0014] In some embodiments, the compound has the structure of formula (VIII):

[0015] [ka] During the ceremony, Ring A is a 5-membered heteroaryl optionally containing 1 or 2 N atoms; X 6 is C or N, R 15 is H, halogen, -NR 8 R 9 , -substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl;

[0016] In another aspect, provided herein is a compound having the structure of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof:

[0017] [ka] During the ceremony, Ring Q is a C6 aryl or a 5-10 membered heteroaryl; L is -CR 13A R 13B -, -C(O)-, -S-, -S(O)-, or -S(O)-; R 1 and R 2 are each independently H, halogen, -CN, or -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 , -C(O)NR 8 R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; R 3 are H, halogen, -CN, and -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 , -OC(O)NR 8 R 9 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5-10 membered heteroaryl; R 4 is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, or a substituted or unsubstituted C1-C8 heteroalkyl; or R 4 teeth,

[0018] [ka] where: W is -CR 6 R 6 -, -O-, -S-, -NR 5 -, -S(O)2-, or -C(O)-; R 5is H, or substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R 6 are each independently H, halogen, CN, or -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO2R 11 , substituted or unsubstituted C1-C6 alkyl; Or, two R's 6 can join together with the atoms to which they are attached to form a C3-C6 cycloalkyl or a C3-C8 heterocycloalkyl ring; n and m are each independently 0, 1, 2, or 3; q is 0, 1, 2, 3, 4, 5, or 6; R 7 is H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 or substituted or unsubstituted C1C6 alkyl; R 8 and R 9 are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C6 10 independently selected at each occurrence from cycloalkyl; R 10 are H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 aryl, and 5-10 membered heteroaryl; R 11 are respectively C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C10 aryl, and 5-10 membered heteroaryl; R 12 are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; R 13A and R 13B are each independently H, CF3, halogen, or C1-C6 alkyl; and p is 1, 2, 3 or 4.

[0019] In some embodiments, the compound has the structure of formula (II):

[0020] [ka] During the ceremony, X 2 is N or CR 3A and R 3A , R 3B and R 3C is H, halogen, -CN, -NR 8 R 9 , -OR 10 , CN, -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 , -OC(O)NR 8 R 9, independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, and substituted or unsubstituted 5-10 membered heteroaryl; However, R 3A , R 3B , and R 3C are not all H at the same time.

[0021] In some embodiments, the compound has the structure of formula (IIIa):

[0022] [ka] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, Y 1 is O, S, or NR 3D and Y 2 is N or CR 3A and Y 3 and Y 4 are each independently N or CR 3B and R 3A and R 3B are H, halogen, and -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl; R 3D is H or C1-C6 alkyl.

[0023] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient.

[0024] In another aspect, provided herein is a method of promoting and / or stimulating skin pigmentation, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0025] In another aspect, provided herein is a method of inhibiting hair loss, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0026] In another aspect, provided herein is a method of preventing and / or treating skin inflammation and / or damage, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0027] In another aspect, provided herein is a method for preventing and / or treating vascular insufficiency, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0028] In another aspect, provided herein is a method of preventing, treating, minimizing and / or reversing congestive heart failure, cardiomyopathy, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0029] In another aspect, provided herein is a method of reducing cardiac ejection fraction, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0030] In another aspect, provided herein is a method of preventing and / or treating a gastrointestinal disorder, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0031] In another aspect, provided herein is a method for preventing and / or treating renal dysfunction, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0032] In another aspect, provided herein are methods for stimulating bone resorption and formation, the methods comprising administering one or more compositions described herein to a subject in need thereof.

[0033] In another aspect, provided herein is a method of stimulating tissue regeneration by stimulation, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0034] In another aspect, provided herein is a method of modulating cervical ripening, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0035] In another aspect, provided herein is a method of promoting neuroprotection and / or stimulating neuroregeneration, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0036] In another aspect, provided herein is a method of treating and / or preventing a neurological disorder, a neuropsychiatric disorder, a nerve injury, a neurotoxic disorder, neuropathic pain, or a neurodegenerative disorder, comprising administering to a subject in need thereof one or more compositions described herein.

[0037] In another aspect, provided herein is a method of treating and / or preventing a fibrotic or adhesive disease, disorder or condition, comprising administering to a subject in need thereof one or more compositions described herein.

[0038] In another aspect, provided herein is a method of reducing and / or preventing scar formation, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0039] In another aspect, provided herein is a method of treating and / or preventing muscle disorders, muscle damage and / or muscle atrophy, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0040] In another aspect, provided herein is a method of treating and / or preventing fibrosis, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0041] In another aspect, provided herein is a method of treating and / or preventing idiopathic pulmonary fibrosis, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0042] In another aspect, provided herein is a method of treating and / or preventing renal fibrosis, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0043] In another aspect, provided herein is a method of stimulating muscle regeneration, the method comprising administering to a subject in need thereof one or more of the compositions described herein.

[0044] In another aspect, provided herein is a method of promoting organ compatibility, the method comprising administering one or more compositions described herein to a subject in need thereof.

[0045] In another aspect, provided herein is a method of promoting wound healing, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0046] In another aspect, provided herein is a method of treating acute kidney injury, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0047] In another aspect, provided herein is a method of treating sarcopenia, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0048] In another aspect, provided herein is a method of treating a neuromuscular disease, the method comprising administering to a subject in need thereof one or more of the above claimed compositions.

[0049] INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or take precedence over such conflicting material. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] definition While various embodiments of the present 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. Numerous modifications, changes, and substitutions may be apparent to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be utilized.

[0051] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference.

[0052] Unless the context otherwise requires, throughout this specification and the claims that follow, the term "comprise" and variations thereof (such as "comprises" and "comprising") are to be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Moreover, the headings provided herein are for convenience only and do not interpret the scope or meaning of the subject invention.

[0053] References throughout this specification to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, appearances of the phrases ("in one embodiment") or ("in an embodiment") throughout this specification are not necessarily all referring to the same embodiment. Moreover, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Similarly, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

[0054] The following terms, as used herein, have the following meanings unless otherwise indicated:

[0055] "Oxo" refers to =O.

[0056] "Carboxyl" refers to --COOH.

[0057] "Cyano" refers to -CN.

[0058] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, more preferably from 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, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Wherever it appears in this specification, "C1-C6 alkyl" or "C 1-6 Numeric ranges such as "alkyl" mean that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the definition also includes instances where the term "alkyl" appears without a numerical range being specified. In some embodiments, alkyl is C 1-10 In some embodiments, alkyl is C 1-6 In some embodiments, alkyl is C 1-5 In some embodiments, alkyl is C 1-4 In some embodiments, alkyl is C 1-3 Unless otherwise specified in the specification, the alkyl group may be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.

[0059] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever appearing herein, "C2-C6 alkenyl" or "C 2-6 Numerical ranges such as "alkenyl" mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the definition also includes the appearance of the term "alkenyl" when no numerical range is specified. Unless otherwise specified in the specification, an alkenyl group may be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.

[0060] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever appearing in this specification, "C2-C6 alkynyl" or "C 2-6Numerical ranges such as "alkynyl" mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the definition also includes the appearance of the term "alkynyl" when no numerical range is specified. Unless otherwise specified in the specification, alkynyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.

[0061] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, an alkylene group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.

[0062] "Alkoxy" is a group of formula -OR a where R a is an alkyl radical as defined. Unless otherwise specified in the specification, an alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.

[0063] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic polycyclic hydrocarbon ring system can contain only hydrogen and carbon, as well as carbon from 5 to 18 carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to the Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-10 membered aryl. In some embodiments, the aryl is a 6 membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, (phenanthrylene), anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. Unless otherwise specified herein, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2.

[0064] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles may include 3-10 membered monocyclic rings, 6-12 membered bicyclic rings, and 6-12 membered bridged rings. The rings of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings, respectively. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle, as long as valences permit. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless otherwise specified herein, a carbocycle may be optionally substituted.

[0065] "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 attached through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, cycloalkyls are fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms (e.g., C3-C4, C5-C6, C7-C8, C9-C10, C11-C12, C13-C14, C15-C16, C17-C18, C19-C20, C21-C22, C22-C30, C23-C31, C24-C25, C25-C32, C26-C33, C27-C34, C28-C29-C35, C29-C36, C28-C37, C29-C38, C39-C40, C39-C41, C39-C42, C39-C43, C39-C44, C39-C45, C39-C46, C39-C47, C39-C48, C39-C49, C41-C41, C42-C43, C43-C44, C44-C45, C45-C46, C45-C47, C45-C48, C46-C49, C47-C48, C47-C48, C48-C49, C49-C49, C49-C50, C49-C51, C49-C52, C49-C53, C49-C54, C49-C55, C49-C56, C49-C57, C49 15 Fully saturated cycloalkyl or C3-C 15 cycloalkenyl), 3 to 10 carbon atoms (e.g., C3-C 10 Fully saturated cycloalkyl or C3-C 10cycloalkenyl), 3 to 8 carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 to 10 membered fully saturated cycloalkyl or a 3 to 10 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 to 10 membered fully saturated cycloalkyl or a 3 to 10 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 to 6 membered fully saturated cycloalkyl or a 3 to 6 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 to 6 membered fully saturated cycloalkyl or a 5 to 6 membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise in the specification, cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.

[0066] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, preferably having 3-12 carbon atoms, including fused or bridged ring systems containing at least one double bond. In certain embodiments, cycloalkenyls contain 3-10 carbon atoms. In other embodiments, cycloalkenyls contain 5-7 carbon atoms. Cycloalkenyls can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0067] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0068] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl radical, as defined above, that 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 is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and trihalomethanes (e.g., trichloromethane, 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 an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with one or more halogen radicals, each halogen may be independently selected, for example, from 1-chloro, 2-fluoroethane.

[0069] "Fluoroalkyl" refers to an alkyl group as defined above that is substituted with one or more fluoro radicals, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0070] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0071] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0072] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed of 1-6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH)-CHCHNHCH, or -CHCHN(CH). Unless otherwise specified herein, a heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0073] "Heterocycloalkyl" refers to a 3-24 membered partially or fully saturated ring radical group containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1-3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise specified in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom), spiro, or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocyclic rings having 2 to 15 carbon atoms (e.g., C2-C 15 Fully saturated heterocycloalkyl, or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (e.g., C2-C 10 Fully saturated heterocycloalkyl or C2-C 10heterocycloalkenyl), 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or 2 to 4 carbon atoms (e.g., C2-C4 heterocycloalkyl or C Examples of such heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having a C4 heterocycloalkenyl group, such as aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, and the like. The term "heterocycloalkyl" includes heterocycloalkyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. Also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, a heterocycloalkyl has 2-10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is noted that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, a heterocycloalkyl is a 3-8 membered fully saturated heterocycloalkyl.In some embodiments, the heterocycloalkyl is a 3-7 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-6 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-6 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-6 membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkenyl. Unless otherwise specified in the specification, the heterocycloalkyl can be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyl can be optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.

[0074] "Heteroaryl" or "aromatic heterocycle" refers to a radical derived from a heteroaromatic ring radical containing 1-11 carbon atoms and at least one heteroatom, where each heteroatom may be selected from N, O, and S. As used herein, a heteroaryl ring may be selected from monocyclic or bicyclic, and fused or bridged ring systems, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to the Hückel theory. Heteroatoms in a heteroaryl may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl may be bonded to the remainder of the molecule through any atom of the heteroaryl, where valence allows, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, futhirane, thiophene, benzothiazole, and indazopyridine. "X-membered heteroaryl" refers to the number of endosilyl atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 ring atoms, e.g., triazole, oxazole, thiophene, etc. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogens. In some embodiments, the heteroaryl contains 1 or 2 nitrogens. In some embodiments, the heteroaryl contains 1 nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is joined by an aromatic ring atom) ring system, or bridged ring system, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl.In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5 membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienylbenzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, iso including indolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetraazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified in the specification, heteroaryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.

[0075] The term "optionally" or "optionally" means that the event or circumstance described below may or may not occur, and that the description includes examples in which the event or circumstance occurs and examples in which it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0076] The term "substituted" refers to a moiety having a substituent replacing one or more carbon or substitutable heteroatoms, e.g., a hydrogen of NH, of its structure. It is understood that "substituted" or "substituted" such substitution is subject to the permissible valences of the substituted atoms and substituents, as well as the implicit proviso that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo change by rearrangement, cyclization, elimination, and the like. In certain embodiments, substitution refers to a moiety having a substituent replacing two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0077] The term "one or more" when referring to any substituent 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.

[0078] In some embodiments, a substituent may be any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazino (=N-NH2), -R b -OR a , -Rb -OC(O), -R a , -R b -OC(O), -OR a , R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -0-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O), R a (wherein t is 1 or 2); R b -S(O) t R a (t is 1 or 2), -R b -S(O) t 0R a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocycle, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , R b -OC(O)-0R a R b -OC(O)-N(Ra )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -0-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O), R a (t is 1 or 2), -R b -S(O), R a (t is 1 or 2), -R b -S(O) t 0R a (t is 1 or 2) and -R b -S(O) t N(R a )2 (t is 1 or 2); a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, and heterocycle; a is, where valence allows, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=N-OH), hydrazine (=N-)NH2, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-0R a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a, -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -0-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , R b -N(R a )S(O), R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t 0R a (t is 1 or 2) and -R b -S(O) t N(R a )2 (t is 1 or 2); b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain; c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0079] It is understood by those skilled in the art that the substituents themselves can be substituted, where appropriate.Unless specifically stated as "unsubstituted", references to chemical moieties herein are understood to include substituted variants.For example, references to "heteroaryl" groups or moieties include both substituted and unsubstituted variants.

[0080] Where substituents are specified by their conventional formula and written from left to right, they equally encompass the chemically identical substituents that result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0081] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, and that the description includes examples of when the event or circumstance occurs and examples of when it does not occur. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and that the description includes both substituted aryl groups and aryl groups that have no substitution.

[0082] The compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharma- ceutically acceptable salts, and active metabolites of these compounds, having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0083] The compounds disclosed herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that found predominantly in nature. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the scope of the disclosure. For example, hydrogen is: 1 H (protium), 2 H (deuterium), and 3 It has three naturally occurring isotopes, designated H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enrichment with deuterium may provide certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or provide a compound useful for investigating in vivo pathways of drug excretion and metabolism. Isotopically enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0084] "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture when appropriate. "Diastereomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. A compound whose absolute configuration is unknown can be designated (+) or (-) by the direction (dextro or levolo) it rotates plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or (S)-. The subject chemical entities, pharmaceutical compositions, and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound may be analyzed via appropriate methods, including, but not limited to, chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other may be determined.

[0085] Chemical entities having carbon-carbon or carbon-nitrogen double bonds can exist in Z- or E-forms (or cis- or trans-forms). Additionally, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E-, and tautomeric forms as well.

[0086] Isolation and purification of the chemical entities and intermediates described herein can be carried out, as necessary, by any suitable separation or purification procedure, such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.

[0087] When stereochemistry is not specified, certain small molecules described herein include, but are not limited to, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, if possible, to the extent that they can be prepared by those skilled in the art through routine experimentation. In these circumstances, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemate or diastereomer mixture. Resolution of the racemate or diastereomer mixture, if possible, can be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two enantiomers can be purified to provide a more optically enriched form of the major enantiomer by recrystallization and / or trituration. Additionally, such specific small molecules include the Z and E forms (or cis and trans forms) of specific small molecules that have a carbon-carbon or carbon-nitrogen double bond. Where a specific small molecule described herein exists in various tautomeric forms, the term "specific small molecule" is intended to include all tautomeric forms of the specific small molecule.

[0088] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, substituted amines including basic ion exchange resins, and the like, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharma-ceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0089] The phrase "pharmacologically acceptable excipient" or "pharmacologically acceptable carrier" as used herein means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of substances that can function as pharma- ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and the like. (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffers; and (21) other non-toxic compatible substances utilized in pharmaceutical formulations. .

[0090] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein sufficient to affect the intended use, including, but not limited to, the treatment of diseases as defined below. The therapeutically effective amount may vary depending on the intended treatment use (in vivo), or the subject and disease state being treated, such as the subject's weight and age, the severity of the disease state, the method of administration, etc., which can be readily determined by one of ordinary skill in the art. The term also applies to a dose that induces a particular response in a target cell, such as a reduction in platelet adhesion and / or cell migration. A particular dose may vary depending on the particular compound selected, the dosing regimen followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system in which it is delivered.

[0091] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may include, for example, eradication or amelioration of the underlying disorder being treated. Similarly, a therapeutic benefit may include, for example, eradication or amelioration of one or more physiological symptoms associated with an underlying disorder, such that an improvement in the subject is observed, even though the subject may still be affected by the underlying disorder. In certain embodiments, with respect to a prophylactic benefit, the composition is administered to a subject at risk of developing a particular disease, or to a subject reporting one or more physiological symptoms of the disease, even if a diagnosis of the disease has not been made.

[0092] A "therapeutic benefit," as that term is used herein, encompasses therapeutic benefits and / or prophylactic benefits as described above. A prophylactic benefit includes slowing or eliminating the appearance of a disease or condition, slowing or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0093] As used herein, "co-administration," "administered in combination with," and their grammatical equivalents encompass the administration of two or more agents to an animal, including a human, whereby both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0094] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds that have the ability to inhibit the biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein or enzyme. Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Preferred antagonists herein specifically interact (e.g., bind) with the target, but also specifically included within this definition are compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway in which the target protein is a member. Preferred biological activities inhibited by antagonists are related to tumor progression, growth, or spread.

[0095] Whenever a protein is referred to herein, it is understood that a single protein may be referred to by different names. For example, "15-PGDH," "PGDH," and "hPGDH" all refer to the same protein, 15-hydroxyprostaglandin dehydrogenase.

[0096] compound Provided herein are compounds and methods for inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH).

[0097] In one aspect, provided herein is a compound having the structure of formula (Ia):

[0098] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, Ring Q is C6-C 10 aryl or 5-10 membered heteroaryl; L is -CR 5 R 5 -, -C(O)-, -S-, -S(O)-, or -S(O)-; R 1 and R 2 are each independently H, halogen, -CN, or -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 , -C(O)NR 8 R 9 , -NR 10 C(O)R 10 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R 3 are H, halogen, -CN, and -NR 8 R 9 , -OR 10 , CN, -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 , -OC(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-10 membered heteroaryl, wherein each or which is one, two, or three R 14 substituted or unsubstituted with R 4 is a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C1-C8 heteroalkyl, or a substituted or unsubstituted C1-C8 heteroalkyl, each of which is selected from one, two, or three R 14 substituted or unsubstituted with Or, R 4 teeth,

[0099] [ka] where: W is -CR 6 R 6 -, -C(O)R 10 -, -O-, -S-, -NR 5 -, -S(O)2-, or -C(O); R 5 is H or substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R 6 are each independently H, halogen, CN, or -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO2R 11 , -NR 8 C(O)R 9 , -SR 8, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; Or, two R's 6 can join together with the atoms to which they are attached to form a C3-C6 cycloalkyl or a C3-C8 heterocycloalkyl ring; n and m are each independently 0, 1, 2, or 3; q is 0, 1, 2, 3, 4, 5, or 6; R 7 are each independently H, halogen, -CN, or -NR 10 R 10 , -OR 10 , -C(O)R 10 , -C(O)OR 10 or substituted or unsubstituted C1-C6 alkyl; R 8 and R 9 are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C6 10 independently selected at each occurrence from cycloalkyl; R 10 are H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 aryl, and 5-10 membered heteroaryl; R 11 are respectively C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 aryl, and 5-10 membered heteroaryl; R 12 are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; R 14 are halogen, -CN, and -NR 8 R 9, -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, or C3-C 10 heterocycloalkyl, and p is 1, 2, 3 or 4.

[0100] In some embodiments, ring Q is aryl or heteroaryl. In some embodiments, ring Q is aryl. In some embodiments, ring Q is bicyclic or monocyclic heteroaryl. In some embodiments, ring Q is bicyclic heteroaryl. In some embodiments, ring Q is monocyclic heteroaryl. In some embodiments, ring Q is 5-6 membered heteroaryl.

[0101] In some embodiments, ring Q is a C6 aryl. In some embodiments, ring Q is a 6-membered monocyclic heteroaryl. In some embodiments, ring Q is a phenyl or a 6-membered monocyclic heteroaryl. In some embodiments, ring Q is a phenyl, pyridinyl, pyrazinyl, pyrimidinyl, or pyridazinyl. In some embodiments, ring Q is a phenyl or pyridinyl. In some embodiments, ring Q is a phenyl. In some embodiments, ring Q is a pyridinyl. In some embodiments, ring Q is a pyrazinyl. In some embodiments, ring Q is a pyrimidinyl. In some embodiments, ring Q is a pyridazinyl.

[0102] In some embodiments, ring Q is

[0103] [ka] and During the ceremony, X 1 , X 2 , X 3 , X 4 and X 5 are each independently N or CR 3 and And X 1 ~X 5 At least two of the following are CR 3 It is.

[0104] In some embodiments, X 2 is N, and X 1 , X 3 , X 4 , and X 5 are CR 3 In some embodiments, X 3 is N, and X 1 , X 2 , X 4 and X 5 are CR 3 In some embodiments, X 1 is N, and X 2 , X 3 , X 4 , and X 5 are CR 3 In some embodiments, X 2 and X 4 are n, and X 1 , X 3 , and X 5 are CR 3 In some embodiments, X 2 and X 3 are n, and X 1 , X 4 and X 5 are CR 3 In some embodiments, X 1 and X 4 are n, and X 2 , X 3 , and X 5 are CR 3In some embodiments, X 1 , X 2 and X 4 is N, and X 3 and X 5 are CR 3 It is.

[0105] In some embodiments, ring Q is

[0106] [ka] and During the ceremony, X 1 and X 5 are each independently N or CH; X 2 is N or CR 3A and X 3 is N or CR 3B and X 4 is N, NR 3C , or CR 3C and R 3A , R 3B and R 3C are H, halogen, -CN, and -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , -OC(O)NR 8 R 9 , -OC(O)NR 8 R 9, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, and substituted or unsubstituted 5-membered heteroaryl.

[0107] In some embodiments, the compound has the structure of formula (II):

[0108] [ka] During the ceremony, X 2 is N or CR 3A and R 3A , R 3B , and R 3C are H, halogen, -CN, and -NR 8 R 9 , -OR 10 , CN, -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)OR 10 , -NR 12 C(O)NR 8 R 9 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 , -OC(O)NR 8 R 9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5-10 membered heteroaryl; However, R 3A , R 3B , and R 3C is not all H at the same time.

[0109] In some embodiments, X 2 is N. In some embodiments, X 2 is CR 3A It is.

[0110] In some embodiments, X 2 is N, and R 3B and R 3C are H, halogen, -CN, and -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , -substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl.

[0111] In some embodiments, R 3B is H or a halogen, and R 3C is a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3B is H, Br, Cl, or F, and R 3C is a substituted or unsubstituted 5-membered heteroaryl.

[0112] In some embodiments, ring Q is a 5-membered heteroaryl. In some embodiments, ring Q is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. In some embodiments, ring Q is imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. In some embodiments, ring Q is imidazolyl or pyrazolyl. In some embodiments, ring Q is imidazolyl. In some embodiments, ring Q is pyrazolyl. In some embodiments, ring Q is thiophenyl or thiazolyl. In some embodiments, ring Q is thiophenyl. In some embodiments, ring Q is thiazolyl.

[0113] In some embodiments, ring Q is

[0114] [ka] and During the ceremony, Y 1 is O, S, or NR 3D and Y 2 is N or CR 3A and Y 3 and Y 4 are each independently N or CR 3B and R 3A and R 3B are H, halogen, and -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9, -substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl, and R 3D is H or C1-C6 alkyl.

[0115] In some embodiments, Y 1 is O or S, and Y 2 CR 3A and Y 3 and Y 4 are each independently N or CR 3B In some embodiments, Y 1 is O and Y 2 CR 3A and Y 3 and Y 4 are each independently N or CR 3B In some embodiments, Y 1 is S and Y 2 CR 3A and Y 3 and Y 4 are each independently N or CR 3B It is.

[0116] In some embodiments, Y 1 is O or S, and Y 2 is N, and Y 3 and Y 4 are each independently N or CR 3B In some embodiments, Y 1 is O and Y 2 is N, and Y 3 and Y 4 are each independently N or CR 3B In some embodiments, Y 1 is S and Y 2 is N, and Y 3 and Y 4are each independently N or CR 3B It is.

[0117] In some embodiments, R 3A , R 3B , and R 3C are H, halogen, and -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3A , R 3B , and R 3C are -NR, respectively. 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 In some embodiments, R 3A , R 3B , and R 3C are each independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, and substituted or unsubstituted C3-C8 heterocycloalkyl. 3A , R 3B , and R 3C are each independently selected from substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3A , R 3B , and R 3C are each independently selected from H or a halogen.

[0118] In some embodiments, R3D is H. In some embodiments, R 3D is C1-C6 alkyl.

[0119] In some embodiments, the compound has the structure of Formula (IIIa) or Formula (IIIb):

[0120] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0121] In some embodiments, the compound has the structure of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of formula (IIIb), or a pharma- ceutically acceptable salt or solvate thereof.

[0122] In some embodiments, ring Q is a bicyclic heteroaryl. In some embodiments, ring Q is a bicyclic heteroaryl containing 1-3 heteroatoms selected from N, O, and S atoms. In some embodiments, ring Q is a bicyclic heteroaryl containing 1, 2, or 3 N atoms. In some embodiments, ring Q is a [1,2,4]triazolo[1,5-a]pyridine.

[0123] In some embodiments, ring Q is

[0124] [ka] and During the ceremony, Ring A is a 5-membered heteroaryl optionally containing 1 or 2 N atoms; X 6 is C or N, and R 15 is H, halogen, -NR 8 R 9, -substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl.

[0125] In some embodiments, ring A is imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. In some embodiments, ring Q is pyrazolyl. In some embodiments, ring Q is imidazolyl. In some embodiments, ring Q is triazolyl.

[0126] In some embodiments, X 6 is C. In some embodiments, X 6 is N.

[0127] In some embodiments, R 3 are H, halogen, -CN, and -NR 8 R 9 , -OR 10 , CN, -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)NR 8 R 9 , -NR 12 C(O)OR 10 , -NR 12 SO2R 10 , -NR 12 SO2NR 8 R 9 , -OC(O)NR 8 R 9, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C2-C8 alkenyl, or C2-C8 substituted or unsubstituted alkynyl. In some embodiments, R 3 are H, halogen, and -NR 8 R 9 , -OR 10 , CN, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5-membered heteroaryl.

[0128] In some embodiments, R 3 Each is independently selected from H, Cl, F, a substituted or unsubstituted C3-C8 heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl.

[0129] In some embodiments, R 3 are each independently selected from substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl, and are substituted or unsubstituted with one or two -NH2, CF3, C1-C6 alkyl, or C3-C8 cycloalkyl. In some embodiments, R 3 Each independently is a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3are each independently triazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl, each of which is substituted or unsubstituted with one or two halogen, -NH2, CF3, C1-C6 alkyl, or C3-C8 cycloalkyl.

[0130] In some embodiments, R 3 are respectively

[0131] [ka] is selected from the group consisting of:

[0132] In some embodiments, R 3 are respectively

[0133] [ka] is selected from the group consisting of:

[0134] In some embodiments, R 3 are each independently -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , or -NR 12 C(O)OR 10 In some embodiments, R 3 are each independently -C(O)R 10 , -C(O)NR 8 R 9 , or -NR 12 C(O)OR 10 In some embodiments, R 3 are each independently -C(O)R 10 In some embodiments, R 3 are each independently -C(O)OR 10 In some embodiments, R3 are each independently -C(O)NR 8 R 9 In some embodiments, R 3 are each independently -NR 12 C(O)OR 10 It is.

[0135] In some embodiments, R 3 are respectively

[0136] [ka] are independently selected from

[0137] In some embodiments, L is -S-, -S(O)-, or -S(O)2-. In some embodiments, L is -S-. In some embodiments, L is -S(O)-. In some embodiments, L is -S(O)2-. In some embodiments, L is -C(O)-. In some embodiments, L is -O-. In some embodiments, L is -CR 6 R 6 In some embodiments, L is -C(O)R 10 -It is.

[0138] In some embodiments, L is -S-, -S(O)-, or -S(O)-, and R 4 is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 heteroalkyl.

[0139] In some embodiments, L is -S-, -S(O)-, or -S(O)-, and R 4 is a substituted or unsubstituted C1-C6 alkyl.

[0140] In some embodiments, R 4is substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C1-C8 heteroalkyl. In some embodiments, R 4 is substituted or unsubstituted C1-C8 alkyl. In some embodiments, R 4 is a substituted or unsubstituted C2-C8 alkenyl. In some embodiments, R 4 is a substituted or unsubstituted C1-C8 heteroalkyl.

[0141] In some embodiments, L is C(O), and R 4 teeth

[0142] [ka] It is.

[0143] In another aspect, provided herein is a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof:

[0144] [ka] During the ceremony, Ring Q is a C6 aryl or a 5-10 membered heteroaryl; W is -CR 6 R 6 -, -O-, -S-, -NR 5 -, -S(O)2-, or -C(O)-; R 1 and R 2 are each independently H, halogen, -CN, or -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 , -C(O)NR 8 R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl; R3 are H, halogen, -CN, and -NR 8 R 9 , -OR 10 , CN, -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 , -OC(O)NR 8 R 9 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5-10 membered heteroaryl; R 5 is H or C1-C6 alkyl; R 6 are each independently H, halogen, CN, or -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -SOR 11 , -SO2R 11 , substituted or unsubstituted C1-C6 alkyl; Or, two R's 6 can join together with the atoms to which they are attached to form a C3-C6 cycloalkyl or a C3-C8 heterocycloalkyl ring; R 7 is H, halogen, -CN, -NR 10 R 10 , -OR 10 , -C(O)R 10 , -C(O)OR 10 or substituted or unsubstituted C1-C6 alkyl; R 8 and R 9 are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C6 10 independently selected at each occurrence from cycloalkyl; R 10 are H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 aryl, and 5-10 membered heteroaryl; R 11 are respectively C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 aryl, and 5-10 membered heteroaryl; R 12 are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; n and m are each independently 0, 1, 2, or 3; q is 0, 1, 2, or 3; and p is 1, 2, 3 or 4.

[0145] In some embodiments, the compound has the structure of formula (V-1):

[0146] [ka] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, X 2 is CH, X 3 is N or CR 3B and X 4 is N or CR 3C and X 5 is N or CR 3F However, X 2 -X 5 One of the must be N, R 3B , R 3C and R 3F are each independently H, halogen, -CN, or -NR 8 R 9 , -OR 10 , CN, -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 , -OC(O)NR 8 R 9 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5-10 membered heteroaryl.

[0147] In some embodiments, X 2 and X 5 are N and X, respectively.3 is CR 3B and X 4 is CR 3C In some embodiments, X 2 and X 4 are N and X, respectively. 3 is CR 3B and X 5 is CH. In some embodiments, X 2 is N and X 3 CR 3B and X 4 CR 3C and X 5 is CH. In some embodiments, X 2 and X 5 are CH and X 3 is N, and X 4 is CR 3C It is.

[0148] In some embodiments, the compound has the structure of formula (V):

[0149] [ka] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, X 2 is N, NR 3A , or CR 3A and X 3 is N or CR 3B and X 4 is N, NR 3C , or CR 3C and R 3A , R 3B and R 3C are each independently H, halogen, -CN, or -NR 8 R 9 , -OR 10 , CN, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R9 , -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 , -OC(O)NR 8 R 9 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5-10 membered heteroaryl; R 3A and R 3B together with the atom to which they are attached form a substituted or unsubstituted 5- to 6-membered aryl or heteroaryl; or R 3B and R 3C together with the atom to which they are attached form a substituted or unsubstituted 5-6 membered aryl or heteroaryl; Here, R 3A , R 3B , and R 3C are not all H at the same time.

[0150] In some embodiments, X 2 is N or CR 3A and X 3 is N or CR 3B and X 4 is N or CR 3C It is.

[0151] In some embodiments, X 2 , X 3 , or X 4is N. In some embodiments, X 2 , X 3 , or X 4 Two of them are N.

[0152] In some embodiments, X 2 is N and X 3 is CR 3B and X 4 is CR 3C In some embodiments, X 2 is CR 3A and X 4 is N and X 3 is CR 3B In some embodiments, X 2 is CR 3A and X 3 is CR 3B and X 4 is N.

[0153] In some embodiments, R 3A and R 3B together with the atom to which they are attached form a substituted or unsubstituted 5-6 membered aryl or heteroaryl optionally containing 1, 2, or 3 heteroatoms selected from O, S, and N. In some embodiments, R 3A and R 3B together with the atom to which they are attached form a substituted or unsubstituted 5-membered aryl or heteroaryl containing 1, 2, or 3 heteroatoms selected from N.

[0154] In some embodiments, R 3B and R 3C together with the atom to which they are attached form a substituted or unsubstituted 5-6 membered aryl or heteroaryl optionally containing 1, 2, or 3 heteroatoms selected from O, S, and N. In some embodiments, R 3B and R 3Ctogether with the atom to which they are attached form a substituted or unsubstituted 5-membered aryl or heteroaryl containing 1, 2, or 3 heteroatoms selected from N.

[0155] In some embodiments, the compound has the structure of Formula (Va):

[0156] [ka] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, X 2 is N or CR 3A and X 4 is N, or CR 3C and R 3A , R 3B and R 3C are each independently H, halogen, -CN, or -NR 8 R 9 , -OR 10 , CN, -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 , -OC(O)NR 8 R 9 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5-10 membered heteroaryl; R 3A , R 3B and R 3C are not H.

[0157] In some embodiments, X 2 is N, and X 4 is CR 3C In some embodiments, R 3B is H and R 3C is -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 , a substituted or unsubstituted C-C heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3C is H and R 3B is -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 , a substituted or unsubstituted C3-C8 heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl.

[0158] In some embodiments, X 2 is C3A, and X 4 is N. In some embodiments, R 3A is H and R 3B is -(O)R 10 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , a substituted or unsubstituted C-C heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3B is H and R 3A is -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)R10 , -NR 12 C(O)OR 10 , a substituted or unsubstituted C3-C8 heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl.

[0159] In some embodiments, X 2 is CR 3A and X 4 is CR 3C In some embodiments, R 3A and R 3B are H and R 3C is -C(O)R 10 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , a substituted or unsubstituted C-C heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3A and R 3C are H and R 3B is -C(O)R 10 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , a substituted or unsubstituted C-C heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, R 3B and R 3C are H and R 3A is -C(O)R 10 , -NR 12 C(O)R 10 , -NR 12 C(O)OR 10 , a substituted or unsubstituted C3-C8 heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl.

[0160] In some embodiments, the compound has the structure of formula (Vb):

[0161] [ka] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, X 2 is N, R 3B is H or a halogen, and R 3C is -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 , a substituted or unsubstituted C3-C8 heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl; or R 3C is H or a halogen, and R 3B is -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 , a substituted or unsubstituted C3-C8 heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl.

[0162] In some embodiments, R 3A is H and R 3B is a substituted or unsubstituted C3-C8 heterocycloalkyl, or a substituted or unsubstituted 5-10 membered heteroaryl. In some embodiments, R 3A is a substituted or unsubstituted C3-C8 heterocycloalkyl or a substituted or unsubstituted 5-10 membered heteroaryl; R 3B is H.

[0163] In some embodiments, R 3A , R 3B , or R 3C is a substituted or unsubstituted 5-membered heteroaryl. In some embodiments, the 5-membered heteroaryl is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.

[0164] In some embodiments, R 3A , R 3B , or R 3C One of the

[0165] [ka] is represented by the part During the ceremony, Y 5 is NR 15A , S, or O; Y 6 , Y 7 and Y 8 are each independently N or CR 15 and R 15 is H, halogen, -NR 8 R 9 , -C1-C6 alkyl, C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl; R 15A is H or C1-C6 alkyl.

[0166] In some embodiments, R 3A , R 3B , or R 3C One of the

[0167] [ka] is represented by the part

[0168] [ka] is R 3A , R 3B , or R 3C Represents a connection point to

[0169] In some embodiments, the compound has the structure of Formula (VI), or a pharma- ceutically acceptable salt, or solvate thereof.

[0170] [ka]

[0171] In some embodiments, the compound has the structure of Formula (VIa) or Formula (VIb):

[0172] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0173] In some embodiments, the compound has the structure of Formula (VIc) or Formula (VId):

[0174] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0175] In some embodiments, the compound has the structure of Formula (VIa), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of Formula (VIb), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of Formula (VIc), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the compound has the structure of Formula (VId), or a pharma- ceutically acceptable salt or solvate thereof.

[0176] In some embodiments, Y 5 is S, or O. In some embodiments, Y 5 is NR 15A In some embodiments, Y 5 is NH. In some embodiments, Y 5 is NCH3.

[0177] In some embodiments, Y 7 and Y 8 are each N. In some embodiments, Y 6 is N. In some embodiments, Y 6 is CR 15 In some embodiments, Y 7 is N. In some embodiments, Y 7 is CR 15 In some embodiments, Y 8 is N. In some embodiments, Y 8 is CR 15 It is.

[0178] In some embodiments, the compound has the structure of formula (VIIa):

[0179] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0180] In some embodiments, the compound has the structure of formula (VIIb):

[0181] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0182] In some embodiments, the compound has the structure of formula (VIII):

[0183] [ka] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, Ring A is a 5-membered heteroaryl optionally containing 1 or 2 N atoms; R 15 is H, halogen, -NR 8 R 9 , -substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl.

[0184] In some embodiments, R 15 is H, halogen, -NR 8 R 9 , -C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 15 is H. In some embodiments, R 15 Ha-NR 8 R 9 In some embodiments, R 15 is -NH, -NHCH, or -N(CH). In some embodiments, R 15 is -C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 15 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, or CHF2.

[0185] In some embodiments, R 15 is a substituted or unsubstituted C-C cycloalkyl. In some embodiments, R 15 is a substituted or unsubstituted C-C heterocycloalkyl. In some embodiments, R 15 teeth,

[0186] [ka] It is.

[0187] In some embodiments, the compound has the structure of formula (IX):

[0188] [ka] or a pharma- ceutically acceptable salt or solvate thereof; During the ceremony, R 3A , R 3B , R 3C and R 3 Each E is independently H, halogen, or -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , -NR 12 C(O)NR 8 R 9 , a substituted or unsubstituted C3-C8 heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl; However, R 3A , R 3B , R 3C , or R 3D One of them is not H.

[0189] In some embodiments, R 3A , R 3B , R 3C , and R 3 Each E is independently H, halogen, or -C(O)R 10 , -C(O)NR 8 R 9 , -NR 12 C(O)OR 10 , a substituted or unsubstituted C3-C8 heterocycloalkyl, or a substituted or unsubstituted 5-membered heteroaryl.

[0190] In some embodiments, W is -CR 6 R 6 -, -O-, -S-, -NR 5In some embodiments, W is -O-, -S-, or -S(O)2. In some embodiments, W is -O-. In some embodiments, W is -S-. In some embodiments, W is -NR 5 In some embodiments, W is -S(O)-.

[0191] In some embodiments, W is -CR 6 R 6 In some embodiments, W is -CH2-. In some embodiments, W is -CF2-. In some embodiments, W is -CHF-.

[0192] In some embodiments, R 6 are each independently H, halogen, CN, or -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 11 --SOR 11 , -SO2R 11 , -SR 11 , substituted or unsubstituted C1-C6 alkyl, or C3-C8 cycloalkyl.

[0193] In some embodiments, R 6 are each independently H, halogen, CN, or -NR 8 R 9 , -OR 10 , -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 6 are each halogens.

[0194] In some embodiments, R 6are each independently F, -NH2, -OH, -OCH3, or -CH3. In some embodiments, R 6 are each independently F. In some embodiments, R 6 are each independently -CH3.

[0195] In some embodiments, two R 6 can be joined together with the atom to which they are attached to form a C-C cycloalkyl ring. In some embodiments, two R 6 can be joined together to form a cycloalkyl ring. In some embodiments, two R on different carbon atoms can be joined together to form a cycloalkyl ring. 6 can be joined together to form a cycloalkyl ring. In some embodiments, the ring is a spirocycle. In some embodiments, two R 6 can be joined together to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, two R 6 can be joined together to form a cyclopropyl.

[0196] In some embodiments, R 7 is H, halogen, -OR 10 , -C(O)R 10 , -C(O)OR 10 or substituted or unsubstituted C1-C6 alkyl. In some embodiments, R 7 is H.

[0197] In some embodiments,

[0198] [ka] teeth,

[0199] [ka] In some embodiments,

[0200] [ka] teeth,

[0201] [ka] It is.

[0202] In some embodiments,

[0203] [ka] teeth,

[0204] [ka] It is.

[0205] In some embodiments,

[0206] [ka] teeth,

[0207] [ka] It is.

[0208] In some embodiments,

[0209] [ka] teeth,

[0210] [ka] In some embodiments,

[0211] [ka] teeth,

[0212] [ka] In some embodiments,

[0213] [ka] teeth,

[0214] [ka] In some embodiments,

[0215] [ka] teeth,

[0216] [ka] In some embodiments,

[0217] [ka] teeth,

[0218] [ka] It is.

[0219] In some embodiments,

[0220] [ka] teeth,

[0221] [ka] It is.

[0222] In some embodiments,

[0223] [ka] teeth,

[0224] [ka] It is.

[0225] In some embodiments,

[0226] [ka] teeth,

[0227] [ka] isn't it.

[0228] In some embodiments, R 1 and R 2 are each independently H, halogen, -CN, or -OR 10 , -C(O)R 10 , -C(O)OR 10 , -NR 8 R 9 , -C(O)NR 8 R 9 , substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl. In some embodiments, R 1 and R 2 are each independently H, halogen, -CN, or -OR 10 , or -NR 8 R 9 In some embodiments, R 1 and R 2 are each independently -C(O)R 10 , -C(O)OR10 or -C(O)NR 8 R 9 In some embodiments, R 1 and R 2 are each independently substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C3-C8 cycloalkyl.

[0229] In some embodiments, R 1 is H, and R 2 is H.

[0230] In some embodiments, R 8 and R 9 are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and C3-C6 10 In some embodiments, R 8 and R 9 is independently selected at each occurrence from H, or C1-C6 alkyl. 8 and R 9 is independently selected for each occurrence from H. In some embodiments, R 8 and R 9 is independently selected at each occurrence from C1-C6 alkyl.

[0231] In some embodiments, R 10 are H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 aryl, and 5-10 membered heteroaryl. In some embodiments, R 10 are each independently selected from H or C1-C6 alkyl. 10 are each independently selected from C1-C6 haloalkyl. 10are each independently selected from C-C cycloalkyl. 10 are C6-C 10 aryl, and 5-10 membered heteroaryl. In some embodiments, R 10 are each independently a 5-membered heteroaryl.

[0232] In some embodiments, R 11 are respectively C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 aryl, and 5-10 membered heteroaryl. In some embodiments, R 11 are each independently selected from C1-C6 alkyl. 11 are each selected from C1-C6 haloalkyl. In some embodiments, R 11 are each selected from C-C cycloalkyl. 11 are C6-C 10 aryl, and 5-10 membered heteroaryl.

[0233] In some embodiments, R 12 are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl. 12 are each independently selected from H or C1-C6 alkyl. 12 are each independently selected from C1-C6 haloalkyl. 12 are each independently selected from C3-C8 cycloalkyl.

[0234] In some embodiments, R 14 are -CN and -NR, respectively. 8 R 9 , -OR 10, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 8 R 9 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkyl, or C3-C 10 In some embodiments, R 14 are -NR, respectively. 8 R 9 -OR 10 In some embodiments, R 14 are -C(O)R, respectively. 10 , -C(O)OR 10 or -C(O)NR 8 R 9 In some embodiments, R 14 is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl. 14 are C3-C 10 Cycloalkyl, or C3-C 10 heterocycloalkyl.

[0235] In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. In some embodiments, p is 3. In some embodiments, p is 5. In some embodiments, p is 4. In some embodiments, p is 3. In some embodiments, p is 2. In some embodiments, p is 1.

[0236] In some embodiments, q is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, q is 1 or 2. In some embodiments, q is 6. In some embodiments, q is 5. In some embodiments, q is 4. In some embodiments, q is 3. In some embodiments, q is 2. In some embodiments, q is 1. In some embodiments, q is 0.

[0237] In some embodiments, n and m are independently 0, 1, or 2. In some embodiments, n and m are independently 0. In some embodiments, n and m are independently 1. In some embodiments, n and m are independently 2. In some embodiments, n is 0, 1, or 2 and m is 1 or 2. In some embodiments, n is 0 and m is 1 or 2. In some embodiments, n is 1 and m is 1 or 2. In some embodiments, n is 2 and m is 1 or 2.

[0238] In some embodiments, the PDGH inhibitor is a compound represented in Table 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0239] [Table 1-1]

[0240] [Table 1-2]

[0241] [Table 1-3]

[0242] [Table 1-4]

[0243]

Table 1-5

[0244]

Table 1-6

[0245]

Table 1-7

[0246]

Table 1-8

[0247]

Table 1-9

[0248]

Table 1-10

[0249]

Table 1-11

[0250]

Table 1-12

[0251]

Table 1-13

[0252]

Table 1-14

[0253]

Table 1-15

[0254]

Table 1-16

[0255]

Table 1-17

[0256]

Table 1-18

[0257]

Table 1-19

[0258]

Table 1-20

[0259]

Table 1-21

[0260]

Table 1-22

[0261]

Table 1-23

[0262]

Table 1-24

[0263]

Table 1-25

[0264] In some embodiments, the PGDH inhibitor is a compound as provided in Table 2, or a pharma- ceutically acceptable salt or solvate thereof.

[0265] [Table 2-1]

[0266] [Table 2-2]

[0267] [Table 2-3]

[0268] How to use In one aspect, provided herein are methods for treating various disorders in a subject in need thereof, comprising administering to the subject a compound as described herein. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to prevent or treat diseases or disorders associated with reduced levels of hydroxyprostaglandin dehydrogenase (such as 15-PGDH) and / or prostaglandins. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to prevent or treat diseases or disorders in which it is desirable to increase prostaglandin levels in a subject with a disease or disorder.

[0269] In some embodiments, the method of treating a disorder comprises administering to the subject a 15-PGDH inhibitor. In some embodiments, the compound described herein is a 15-PGDH inhibitor (e.g., a compound of formula (IV) or a pharma- ceutically acceptable salt or solvate thereof). In some embodiments, the method comprises administering a therapeutically effective amount of a compound described herein. In some embodiments, the method comprises administering a therapeutically effective amount of a compound described herein or a pharma- ceutically acceptable salt or solvate thereof (e.g., a compound of formula (IV) or a pharma- ceutically acceptable salt or solvate thereof). In some embodiments, the compound described herein is a 15-PGDH inhibitor (e.g., a compound of formula (IV) or a pharma- ceutically acceptable salt or solvate thereof). In some embodiments, the administering step is performed in vitro. In some embodiments, the administering step is performed in vivo.

[0270] As used herein, the therapeutically effective amount of 15-PGDH inhibitor refers to an amount sufficient to achieve the intended use, including but not limited to disease treatment as defined herein.Furthermore, the subject method also contemplates the use of sub-therapeutic doses of 15-PGDH inhibitor to treat the intended disease state.

[0271] The therapeutically effective amount of 15-PGDH inhibitor to be administered may vary depending on the intended use (in vitro or in vivo), or the subject and disease condition being treated, e.g., the subject's weight and age, the severity of the disease condition, the method of administration, etc., and can be readily determined by one of ordinary skill in the art.

[0272] Measuring the inhibition of the biological effect of 15-PGDH can include carrying out an assay on a biological sample, such as a sample 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 samples, bronchoalveolar lavage fluid, saliva samples, urine samples, and tissue samples.

[0273] The subject treated with a 15-PGDH inhibitor may be monitored to determine the effectiveness of the treatment, and the treatment regimen may be adjusted based on the subject's physiological response to the treatment. For example, if the inhibition of the biological effect of 15-PGDH is above or below a threshold, the dosage or frequency may be decreased or increased, respectively. The method may further include continuing the treatment if the treatment is determined to be effective. The method may include maintaining, tapering, decreasing, or stopping the dosage of the compound in the treatment if the treatment is determined to be effective. The method may include increasing the dosage of the compound in the treatment if it is determined to be ineffective. Alternatively, the method may include stopping the treatment if it is determined to be ineffective. In some embodiments, if the inhibition of the biological effect is above or below a threshold, such as lack of response or adverse reaction, the treatment with the 15-PGDH inhibitor is discontinued. The biological effect may be a change in any of a variety of physiological indicators.

[0274] In general, a 15-PGDH inhibitor is a compound that inhibits one or more biological effects of 15-PGDH, which may be inhibited by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

[0275] In some other embodiments, the method is useful for treating disease conditions associated with 15-PGDH. Any disease condition that results directly or indirectly from abnormal activity or expression levels of 15-PGDH may be a disease condition of interest.

[0276] In one aspect, provided herein is a method for promoting and / or stimulating skin pigmentation, comprising administering one or more of the compositions described herein to a subject in need thereof. Inhibitors of 15-PGDH are known to promote skin pigmentation (Markowitz et.al., WO2015 / 065716). The hydroxyprostaglandin dehydrogenase inhibitors described herein can be used as agents for promoting and / or inducing and / or stimulating pigmentation of skin and / or skin appendages, and / or for preventing and / or limiting depigmentation and / or whitening of skin and / or skin appendages, in particular for preventing and / or limiting canism. In some embodiments, the 15-PGDH inhibitors provided herein can be applied to the skin of a subject, for example, topically, to promote and / or stimulate skin pigmentation and / or hair growth, inhibit hair loss, and / or treat skin damage or inflammation, for example, skin damage caused by physical or chemical irritants and / or UV exposure.

[0277] In another aspect, the present disclosure provides a method for inhibiting hair loss, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins are known to play an important role in hair growth. Prostaglandins such as prostaglandins A1, F2a, and E2 are stored in hair follicles or adjacent skin environments and have been shown to be essential for maintaining and increasing hair density (Colombe L et.al., 2007, Exp. Dermatol, 16(9), 762-9). 15-PGDH, which is involved in the degradation of prostaglandins, is present in hair follocle dermal papillae and has been reported to inactivate prostaglandins, particularly PGF2a and PGE2, causing scalp damage and alopecia (Michelet JF et.al., 2008, Exp. Dermatol, 17(10), 821-8). Therefore, the hydroxyprostaglandin dehydrogenase inhibitors described herein that 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 preventing alopecia and promoting hair growth.

[0278] In another aspect, provided herein is a method of preventing and / or treating dermatitis and / or skin damage, the method comprising administering to a subject in need thereof one or more compositions described herein.

[0279] In another aspect, the present invention provides a method for preventing and / or treating vascular insufficiency, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins, including prostaglandin homologues produced in the body, are known to maintain the proper function of vascular walls, particularly contributing to vasodilation of blood flow, preventing platelet aggregation, and regulating the proliferation of smooth muscle surrounding vascular walls (Yan.Cheng et.al.,2006,J.Clin.,Invest). In addition, inhibition of prostaglandin production or loss of their activity causes endothelial degeneration in vascular walls, dysfunction of cellular mechanisms in platelet aggregation and smooth muscle. In particular, it has been shown that the production of prostaglandins in blood vessels is reduced in hypertensive patients, including pulmonary arterial hypertension. The 15-PGDH inhibitors described herein can be used in pharmaceutical compositions for preventing or treating cardiovascular disease and / or diseases of vascular insufficiency, such as Raynaud's disease, Berger's disease, diabetic neuropathy, and pulmonary arterial hypertension.

[0280] In another aspect, provided herein is a method for preventing, treating, minimizing, and / or reversing congestive heart failure, cardiomyopathy, comprising administering one or more compositions described herein to a subject in need thereof. In another aspect, provided herein is a method for reducing cardiac ejection fraction, comprising administering one or more compositions described herein to a subject in need thereof. It has been shown that administration of 15-PGDH inhibitors can be used to treat, prevent, minimize, and / or reverse congestive heart failure, cardiomyopathy, and / or reduced cardiac ejection fraction (Markowitz et.al., WO2018 / 187810). Thus, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be administered to a subject in need of treating, preventing, minimizing, and / or reversing congestive heart failure, cardiomyopathy, reduced cardiac ejection fraction.

[0281] In another aspect, the present invention provides a method for preventing and / or treating gastrointestinal disease, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins are essential for maintaining the mechanism for protecting and defending 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 inhibitors of hydroxyprostaglandin dehydrogenase described herein exhibit suppressive or inhibitory activity against 15-PGDH, which degrades prostaglandins that protect the gastric mucosa. Thus, hydroxyprostaglandin dehydrogenase inhibitors can be effective in preventing or treating gastrointestinal disease, particularly gastritis and gastric ulcer. In addition, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to prevent and / or treat radiation and / or chemotherapy toxicity, as well as other forms of intestinal damage, including chemotherapy-induced mucositis.

[0282] Furthermore, it has been shown that administering 15-PGDH inhibitors alone or in combination with corticosteroids and / or TNF inhibitors can treat intestinal, gastrointestinal, or intestinal disorders, such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease (Markowitz et.al., WO2018 / 102552).Thus, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat and / or prevent intestinal, gastrointestinal, or intestinal disorders, such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease.

[0283] In another aspect, the present invention 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 thereof.In the kidney, prostaglandins can play a role in regulating renal blood flow and regulating urine formation through both renal vascular and tubular effects.In clinical studies, inhibitors of prostaglandins have been used to improve creatinine clearance in patients with chronic kidney disease, to prevent graft rejection and cyclosporine toxicity in renal transplant patients, and to reduce urinary albumin excretion rate and N-acetyl-β-D-glucosaminidase levels in patients with diabetic nephropathy (Porter, Am., 1989, J.Cardiol., 64:22E-26E).In addition, prostaglandins act as vasodilators in the kidney, and therefore, it has been reported that inhibition of prostaglandin production in the kidney leads to renal dysfunction (Hao.CM, 2008, Annu Rev 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 renal diseases associated with renal dysfunction.

[0284] In another aspect, the present disclosure 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 thereof.Prostaglandins have been shown to stimulate bone resorption and bone formation to increase bone volume and strength (H. Kawaguchi et.al., Clinical Orthop.Rel.,313,1995; J. Keller et.al., Eur.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). Considering that 15-PGDH inhibits the activity of prostaglandins as described above, inhibition of 15-PGDH activity can lead to promotion of bone resorption and bone formation inhibited by 15-PGDH. Thus, the inhibitors of hydroxyprostaglandin dehydrogenase described herein can be effective in promoting bone resorption and bone formation by inhibiting 15-PGDH activity.The hydroxyprostaglandin dehydrogenase inhibitors provided herein can further be used to increase bone density, treat osteoporosis, promote healing of fractures, promote healing after bone surgery or joint replacement, and / or promote healing of bone to bone implants, bone to artificial implants, dental implants, and bone grafts.

[0285] In another aspect, the present disclosure provides a method for stimulating tissue regeneration by stimulating, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandin PGE2 supports the proliferation of several types of tissue stem cells. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin degrading enzyme, enhances tissue regeneration in multiple organs. Research shows that inhibition of 15-PGDH increases prostaglandin PGE2 levels in bone marrow and other tissues, accelerates hematopoietic recovery after bone marrow transplantation, and promotes tissue regeneration in colon and liver injury (Zhang, Y. et.al. Science 2015,348(6240)). Hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used for tissue regeneration by supporting the proliferation of tissue stem cells.

[0286] In another aspect, provided herein is a method of regulating cervical ripening, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandin E2 (PGE2) is a known cervical ripening agent that mediates the EP2 receptor-signaling pathway in human cervical stromal cells, targets its own synthesis by increasing COX-2 and PTGES expression, and reduces its metabolism by the loss of its degrading enzyme 15-PGDH (Word et.AL, W02019010482). Downregulation of 15-PGDH has also been found to be important for PGE2-induced cervical ripening and preterm labor. Modulation of 15-PDGH activity can be used to regulate cervical ripening and induce or prevent preterm labor. Hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used alone or in combination with another labor-inducing agent to induce cervical ripening and labor.

[0287] In another aspect, provided herein is a method for promoting neuroprotection and / or stimulating neuroregeneration, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins have various physiological functions in the central nervous system through their specific G protein-coupled receptors. Prostaglandin E2 (PGE2), the major prostaglandin, can activate receptor types EP1, 2, 3, and 4. Activation of EP2 and EP4 receptors can regulate adenylate cyclase and the production of 3,5'-cyclic adenosine monophosphate (cAMP), while activity of EP1 and EP3 receptors can regulate Ca2+ signaling. Research shows that EP1 and EP2 receptors are expressed in neurons and microglia, as well as neurons in the cerebral cortex, striatum, and hippocampus. Furthermore, activation of EP2 receptors by PGE2 is involved in long-term synaptic plasticity and cognitive function (Chemtob et al. Semin Perinatol. 1994 Feb;18(1):23-9; Yang et al., J Neurochem. 2009 Jan;108(1):295-304). Studies further indicate that, following activation, different PGE2 receptors may contribute to or protect against N-methyl-D-aspartate (NMDA) neurotoxicity and ischemic stroke (Ahmad et al., Exp TR ansl Stroke Med.2010 Jul 8;2(1):12). Other studies have shown that activation of the EP2 receptor protected neurons from amyloid β-peptide neurotoxicity in vitro (Echeverria et al.,Eur J Neurosci.2005 Nov;22(9):2199-206). Several studies have suggested that the mechanism by which PGE2 confers neuroprotection is via the EP2 or EP4 receptors, as both increase cAMP, which then follows a protein kinase A (PKA)-dependent pathway (Echeverria et al.Eur J Neurosci.2005 Nov;22(9):2199-206;McCullough et al.,J Neurosci.2004 Jan 7;24(1):257-68). Stimulation of these receptors with PGE2 by administration of compounds that inhibit, reduce, and / or antagonize 15-PGDH activity, such as the hydroxyprostaglandin dehydrogenase inhibitors capable of inhibiting 15-PGDH described herein, can promote neuroprotection in a subject from axonal degeneration, neuronal cell death, and / or glial cell damage following injury, enhance neural signaling underlying learning and memory, stimulate neural regeneration following injury, and / or treat diseases, disorders, and / or conditions of the nervous system.

[0288] In another aspect, provided herein is 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 described herein to a subject in need thereof.In some embodiments, the nervous system disease, disorder, and / or condition that can be treated with the hydroxyprostaglandin dehydrogenase inhibitors provided herein can include at least one of neurological disorders, neuropsychiatric disorders, nerve damage, neurotoxic disorders, neuropathic pain, or neurodegenerative disorders.For example, neurological disorders can include at least one of traumatic or toxic damage to peripheral or cranial nerves, spinal cord, or brain, such as traumatic brain injury, stroke, cerebral aneurysm, and spinal cord injury. The neurological disorder can further include at least one of Alzheimer's disease, dementia associated with Alzheimer's disease, Parkinson's disease, diffuse Lewy body disease, senile dementia, Huntington's disease, Gilles de la Tourette syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Jakob-Creutzfield disease.

[0289] In some embodiments, the nerve damage may be caused by or associated with at least one of epilepsy, cerebrovascular diseases, autoimmune diseases, sleep disorders, autonomic nerve disorders, bladder disorders, abnormal metabolic conditions, disorders of the muscular system, infectious and parasitic diseases, tumors, endocrine diseases, nutritional and metabolic diseases, immune diseases, diseases of the blood and blood-forming organs, psychiatric disorders, neurological diseases, diseases of the sensory organs, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the genitourinary system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, congenital abnormalities, or diseases of perinatal origin.

[0290] In some embodiments, hydroxyprostaglandin dehydrogenase inhibitors can be administered to subjects or to the neurons of subjects to promote the survival, growth, development, and / or function of neurons, particularly central nervous system (CNS), brain, cerebrum, and hippocampus neurons.In some embodiments, hydroxyprostaglandin dehydrogenase inhibitors can be used to stimulate hippocampal neurogenesis to treat neuropsychiatric and neurodegenerative diseases, including (but not limited to) schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down's syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of neuroactive drugs such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine.

[0291] In another aspect, the present invention provides a method for treating and / or preventing fibrotic or adhesive diseases, disorders, or conditions, comprising administering one or more of the compositions described herein to a subject in need thereof.It has been shown that an inhibitor of short-chain dehydrogenase activity, such as a 15-PGDH inhibitor, can be administered to a subject in need thereof to reduce fibrotic symptoms such as collagen deposition, collagen accumulation, collagen fiber formation, inflammatory cytokine expression, and inflammatory cell infiltration, and can treat and / or prevent a variety of fibrotic diseases, disorders, and conditions characterized in whole or in part by the overproduction of fibrous material, including the overproduction of fibrous material in the extracellular matrix, or the replacement of normal tissue elements with abnormal, non-functional, and / or excessive accumulation of matrix-associated components.(Markowitz et.al.,WO2016 / 144958).

[0292] Fibrotic diseases, disorders, and conditions that are characterized in whole or in part by the overproduction of fibrotic material include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma (including localized scleroderma, systemic mottled scleroderma, or fibrotic scleroderma), scleroderma graft-versus-host disease, renal fibrosis (including glomerulosclerosis, tubulointerstitial fibrosis, progressive renal disease, or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulmonary fibrosis (e.g., pulmonary fibrosis, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease ... The fibrotic diseases, disorders, and conditions that may be present in the body may include, but are not limited to, pulmonary fibrosis, interstitial fibrotic lung disease, chemotherapy / radiation-induced pulmonary fibrosis, oral fibrosis, endomyocardial fibrosis, delta fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fasciitis, eosinophilic fasciitis, systemic fibrosis syndromes characterized by the replacement of normal muscle tissue with varying degrees of fibrotic tissue, retroperitoneal fibrosis, liver fibrosis, liver cirrhosis, chronic renal failure, myelofibrosis (myelofibrosis), drug-induced ergotism, myelodysplastic syndromes, myeloproliferative syndromes, collagenous colitis, acute fibrosis, organ-specific fibrosis, etc. Hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent fibrotic diseases, disorders, or conditions.

[0293] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent renal fibrosis, including renal fibrosis resulting from dialysis following renal failure, catheter placement, nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute kidney injury, end stage renal disease or renal failure, or a combination thereof.

[0294] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent liver fibrosis, including liver fibrosis due to chronic liver disease, viral-induced cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis obesity, diabetes, protein malnutrition, coronary artery disease, autoimmune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reactions and exposure to toxins, or a combination thereof.

[0295] Hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent cardiac fibrosis, such as cardiac fibrosis, endomyocardial fibrosis, idiopathic pulmonary fibrosis, and renal fibrosis.

[0296] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent systemic sclerosis.

[0297] Hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent fibrotic diseases, disorders or conditions caused by post-surgical adhesion formation.

[0298] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce the intensity, severity or frequency of and / or delay the onset of one or more symptoms or characteristics of a fibrotic disease, disorder or condition, or other related disease, disorder or condition.

[0299] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce collagen secretion, or collagen deposition, or collagen fiber accumulation, or a combination thereof, in tissues or organs such as the lung, liver, intestine, colon, skin or heart.

[0300] Studies have shown that 15-PGDH inhibition improves inflammatory pathology and fibrosis in pulmonary fibrosis (Smith et.al., bioRxiv 2019.12.16.878215; Barnthaler et.al., J. Allergy Clin. Immunol. 2019,145(3),818-833). In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be used to treat or prevent pulmonary fibrosis, including pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal workers' pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of mineral dusts, pulmonary fibrosis caused by infectious agents, pulmonary fibrosis caused by inhalation of toxic gases, aerosols, chemical dusts, fumes or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.

[0301] In another aspect, the present disclosure provides a method for reducing and / or preventing scar formation, comprising administering one or more of the compositions described herein to a subject in need thereof.The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce or prevent scar formation in a subject.The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce or prevent scar formation or scleroderma on the skin.

[0302] In another aspect, provided herein is a method for treating and / or preventing muscle disorders, muscle damage and / or muscle atrophy, comprising administering one or more of the compositions described herein to a subject in need thereof. Studies have shown that inhibition of PGE2 degrading enzymes, such as 15-PGDH, allows muscle regeneration and repair after injury (Ho et al., PNAS 2017; Dong et al., Stem cell reseaR c h and theR a py 2020). The inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat muscle disorders, muscle damage and / or muscle atrophy in a subject. In some cases, the subject suffering from muscle disorders, muscle damage and / or muscle atrophy is a patient suffering from Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FHMD), amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), genetic muscle disease, myotonic muscular dystrophy, or other conditions. The patient may have myotonia congenita, 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.

[0303] In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat sarcopenia. In another embodiment, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat diaphragm atrophy or limb muscle atrophy due to the use of mechanical ventilation. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat genetic disorders or neuromuscular disorders such as spinal muscular atrophy (SMA). In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat ptosis, rotator cuff muscle atrophy, immobilization-related muscle atrophy, surgery-related muscle atrophy, sarcopenia, or a combination thereof.

[0304] Pharmaceutical Compositions The inhibitors of hydroxyprostaglandin dehydrogenase can be formulated into pharmaceutical compositions to treat the diseases and disorders described herein. In some embodiments, the pharmaceutical compositions can include a therapeutically effective amount of one or more inhibitors of hydroxyprostaglandin dehydrogenase provided herein.

[0305] The pharmaceutical compositions described herein may be administered in oral dosage forms such as tablets, capsules (each of which includes sustained release or extended release formulations), pills, powders, micronized compositions, granules, elixirs, tinctures, suspensions, ointments, vapors, liposomal particles, nanoparticles, syrups, and emulsions. In some embodiments, the pharmaceutical compositions may also be administered in intravenous (bolus or infusion), subcutaneous injection, suppository, intraperitoneal, topical (e.g., dermal, epidermal, transdermal), ophthalmic such as eye drops, intranasal, subcutaneous, inhalation, intramuscular, or transdermal (e.g., patch) forms, all using forms well known to those skilled in the pharmaceutical arts.

[0306] In some embodiments, the compounds provided herein may be administered as part of a treatment regimen that includes administering one or more second agents (e.g., one, two, three, four, five, or more second agents) simultaneously or sequentially with the compounds provided herein. When administered sequentially, the compounds provided herein may be administered before or after the one or more second agents. When administered simultaneously, the compounds provided herein and the one or more second agents may be administered by the same route (e.g., injection into the same location, tablets taken orally at the same time), by different routes (e.g., tablets taken orally while receiving an intravenous infusion), or as part of the same combination (e.g., a solution containing the compounds provided herein and one or more second agents).

[0307] The combination therapy according to the present disclosure may be effective over a wide range of doses. For example, in the treatment of adult humans, doses of 0.01-1000 mg per day, 0.5-100 mg, 1-50 mg, and 5-40 mg per day are examples of doses that may be used. The exact dose will depend on the agent selected, the route of administration, the form in which the compound is administered, the subject being treated, the weight of the subject being treated, and the preferences and experience of the attending physician. EXAMPLES

[0308] Compound synthesis and characterization In another aspect, the present specification provides a method for producing the inhibitor described herein.In some cases, the inhibitor is isolated or extracted from one or more plants.In some cases, the inhibitor derived from one or more plants can be further modified.In some cases, the inhibitor is further purified after isolation from one or more plants.

[0309] Exemplary synthetic schemes for inhibitors having a phenyl core described herein include the following:

[0310] [ka]

[0311] In some cases, the synthetic scheme may be a total synthetic scheme for producing the inhibitors provided herein. In other cases, the synthetic scheme may be a partial scheme for producing the inhibitors provided herein.

[0312] Described herein are exemplary synthetic schemes that can be used to synthesize the inhibitors described herein. The following abbreviations are used:

[0313] [Table 3]

[0314] Example 1. Synthesis of B-3, B-4, B-5, B-6, B-7 and B-8

[0315] [ka]

[0316] General procedure for acid-amine coupling using HATU (Step 1): To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (SM-1) (1.0 eq.) in DMF (10V) at 0° C., HATU (1.2 eq.), amine (1.2 eq.) were added. N,N′-diisopropylethylamine (3.0 eq.) was added to the stirred solution at 0° C. and then stirring was continued for 16 h at room temperature. The reaction progress was monitored by TLC and LCMS. After the starting material was consumed, the mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 50% EtOAc / heptane to give Int-1a-d.

[0317] Int-1a: Yield = 66.22% MS: m / z = 244.1 [M+H] +.

[0318] Int-1b: Yield=66.23% MS: m / z=244.2[M+H] + .

[0319] Int-1c: Yield=99.21% MS: m / z=230.1[M+H] + .

[0320] Int-Id: Yield = 43% MS: m / z = 234.1 [M+H] + .

[0321] General procedure for Ullman coupling (step 2): To a stirred solution of amide (Int-1a-e) (1 eq.) in dioxane (10 mmol), 4-bromobenzoate (1.2 eq.), K3PO4 (1 eq.) were added in a sealed tube under inert atmosphere. Argon gas was purged for 15 min, then CuI (0.2 eq.) and trans-dimethylcyclohexane-1,2-diamine (0.2 eq.) were added at room temperature, and the resulting sealed reaction mixture was heated to 100° C. for 16 h. The reaction was monitored by crude LCMS / TLC, and after completion of the reaction, the mixture was quenched with saturated NH4Cl, filtered through a bed of celite, and washed with EtOAc (2×). The EtOAc extract was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude compound was purified by silica gel column chromatography to give Int-2a / Int-2b as well as the enantiomeric mixture Int-2c-f. The racemic product (Int-2c-f) was separated by chiral preparative HPLC purification (prep-HPLC) to give both enantiomers separately. Stereochemistry assignment is arbitrary.

[0322] Int-2a: Yield=45.16% MS: m / z=378.2[M+H] +

[0323] Int-2b: Yield=61.29% MS: m / z=378.2[M+H] +

[0324] Int-2c: Yield = 99.21% MS: m / z = 364.1 [M+H] +

[0325] Int-2d: Yield=15.5% MS: m / z=368.1[M+H] +

[0326] Int-2e: Yield=99.71% MS: m / z=364.1[M+H] +

[0327] Int-2f: Yield=11.5% MS: m / z=368.1[M+H] +

[0328] General procedure for ester hydrolysis with LiOH (Step 3): To a stirred solution of ester (Int-2a-f) (1.0 equiv.) in THF / water (1:1), LiOH (3.0 equiv.) was added at room temperature and the resulting reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC and upon completion, the reaction mixture was concentrated and neutralized with 1N HCl. The resulting solid was filtered, washed with Et2O and dried in vacuum to give B-3, B-4, B-5, B-6, B-7 and B-8.

[0329] B-3: Yield=45.16% MS:m / z=364.1[M+H] +

[0330] B-4: Yield=61.29% MS:m / z=364.1[M+H] +

[0331] B-5: Yield=78% MS: m / z=350.1[M+H] +

[0332] B-6: Yield=80.1% MS:m / z=354.2[M+H] +

[0333] B-7: Yield=84.5% MS:m / z=350.2[M+H] +

[0334] B-8: Yield=88.54% MS:m / z=354.2[M+H] +

[0335] Example 2. Synthesis of (R)-4-(5-(3-methylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile, (B-9), and synthesis of (R)-4-(5-(3-methylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile, (B-10)

[0336] [ka]

[0337] Step 1: Synthesis of Int-1a and Int-1b: Using the general procedure for acid-amine coupling with HATU, SM-1 was converted to Int-1a (yield = 39.79%, MS: m / z = 244.1 [M+H] + ) and Int-1b (yield = 66.37%, MS: m / z = 244.2 [M + H] + ) was converted to

[0338] Step 2: Synthesis of B-9 and B-10: Using the general procedure for Ullman coupling, Int-1a / Int-1b was converted to B-9 (yield = 23.23%, MS: m / z = 345.2 [M+H] + ) and B-10 (yield = 35.57%, MS: m / z = 345.1 [M + H] + ) was converted to

[0339] Example 3. General synthesis of B-2, B-13, and B-30

[0340] [ka]

[0341] Step 1: Synthesis of Int-1: To a stirred solution of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (SM-1) (1.0 eq.) in DMF (10V) at 0°C, HATU (1.2 eq.), amine (1.2 eq.) were added. To this stirred solution, N,N'-diisopropylethylamine (3 eq.) was added at 0°C and then stirring was continued at room temperature for 16 h. The reaction progress was monitored by TUC and UCMS. After the starting material was consumed, the mixture was diluted with ice-cold water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 50% EtOAc / heptane to give Int-1a (yield = 53.1% MS: m / z = 266.1 [M+H] + ) and Int-1b (yield = 53.50%, MS: m / z = 244.1 [M + H] + ) was obtained.

[0342] Step 2: Synthesis of Int-2 using the general procedure for Ullman coupling: To a stirred solution of amine (Int-1a-e) (1 eq.) in dioxane (10 mmol), 4-bromobenzoate (1.2 eq.), K3PO4 (1 eq.) were added in a sealed tube under inert atmosphere. Argon gas was purged for 15 min, then CuI (0.2 eq.) and trans-dimethylcyclohexane-1,2-diamine (0.2 eq.) were added at room temperature, and the resulting sealed reaction mixture was heated to 100° C. for 16 h. The reaction was monitored by crude LCMS / TLC, and after completion of the reaction, the mixture was quenched with saturated NH4Cl, filtered through a bed of celite, and washed with EtOAc (2×). The EtOAc extract was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude was purified by Combi-Flash column chromatography using 50% EtOAc / heptane to give Int-2a (yield=56% MS: m / z=427.1 [M+H] + ) and Int-2b (yield = 88%, MS: m / z = 447.1 [M + H] + ) was obtained.

[0343] Step 3: Synthesis of B-2, B-13, B-30: Using the general procedure for Ullman coupling, Int-2a was converted to B-2 and B-13, and Int-2b was converted to B-30. The crude was purified by preparative HPLC purification to give B-2 (yield = 33% MS: m / z = 427.1 [M+H] + ), B-13 (yield=15.3% MS:m / z=767.1[M+H] + ) as an off-white solid and combi-flash column chromatography using 50% EtOAc / heptane gave B-30 (48 mg, 88%) as an off-white solid.

[0344] Example 4. Synthesis of B-12 and B-29

[0345] [ka]

[0346] Step 1: Synthesis of Int-1a / Ib: The general procedure for acid-amine coupling using HATU was used to convert SM-1 to Int-1a (yield = 68%, MS: m / z = 266.1 [M+H] + ) and Int-1b (yield = 53.50%, MS: m / z = 244.1 [M + H] + ) was converted to

[0347] Step 2: Synthesis of B-12 and B-29: Using the general procedure for the Ullman reaction, Int-1a / Int-1b was converted to B-12 (yield = 26.70%, MS: m / z = 398.1 [M+H] + ) and B-29 (yield = 5.7%, MS: m / z = 376.2 [M + H] + ) was converted to

[0348] Example 5. Synthesis of B-28

[0349] [ka]

[0350] Step 1: Int-1 is described above in the synthesis of B-12.

[0351] Step 22: Using the general procedure for the Ullman reaction, Int-1 was converted to Int-2. (Yield=30.20% MS: m / z=346.2 [M+H] + ).

[0352] Step 3: Synthesis of (S)-5-(5-(3-methylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinimide hydrazide: To a stirred solution of (S)-5-(5-(3-methylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile, Int-2 (250 mg, 0.724 mmol, 1.0 equiv.) in ethanol (3 mL), hydrazine monohydrate (6 mL) was added. The mixture was stirred at 60° C. for 1 h. The progress of the reaction was monitored by TLC. The resulting solid was filtered, dried, and triturated with Et2O to give (S)-5-(5-(3-methylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinimide hydrazide, Int-3 (220 mg) as a yellow solid. (MS: m / z=378.2 [M+H] + ). The crude material obtained was used directly in the next step without purification.

[0353] Step 4: Synthesis of B-28: Int-3 (200 mg, 0.529 mmol) was converted to B-28 (12.20%, 25 mg) using the general procedure for 1,3,4-triazole formation using hydrazine acetate as described above for B-28.

[0354] Example 6. Synthesis of (4,4-difluoropiperidin-1-yl)(1-(5-(2-methyl-1H-imidazol-4-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-15), and (4,4-difluoropiperidin-1-yl)(1-(5-(1-(4-methoxybenzyl)-2-methyl-1H-imidazol-4-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-23)

[0355] [ka]

[0356] Int-1 is described above in the synthesis of B-12.

[0357] Step 1: (4,4-Difluoropiperidin-1-yl)(1-(5-iodopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, Int-2: Using the general procedure for Ullmann coupling, Int-1 was coupled with 3-bromo-5-iodopyridine to give Int-2 (84.4%) as an off-white solid. TLC: 50% EtOAc / heptane (Rf: 0.40) MS: m / z=469.05 [M+H] + .

[0358] Step 2A: (4,4-difluoropiperidin-1-yl)(1-(5-(1-(4-methoxybenzyl)-2-methyl-1H-imidazol-4-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, synthesis of B-23, general procedure for Suzuki coupling: (4,4-dithiolopiperidin-1-yl)(1-(5-iodopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine- To a stirred solution of (1-(4-methoxybenzyl)-2-methyl-1H-imidazol-4-yl)methanone, int-2 (210 mg, 0.448 mmol, 1 equiv.) and (1-(4-methoxybenzyl)-2-methyl-1H-imidazol-4-yl)boronic acid (165 mg, 0.672 mmol, 1.5 equiv.) in 1,4-dioxane:water (3:1, 10 mL), Na2CO3 (118 mg, 1.120 mmol, 2.5 equiv.) was added and the mixture was then purged with argon for 15 min. To this solution was added PdCL2(dppf).DCM (36 mg, 0.044 mmol, 0.1 equiv.) under argon. The resulting reaction mixture was stirred at 100° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was diluted with ethyl acetate (2×10 mL), washed with brine (10 mL), and the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give (4,4-difluoropiperidin-1-yl)(l-(5-(l-(4-methoxybenzyl)-2-methyl-1H-imidazol-4-yl)pyridin-3-yl)-lH-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-23 (13.63 mg, 5.6%) as an off-white solid. TLC: 10% MeOH / DCM; MS: m / z=543.2 [M+H] + .

[0359] Step 2B: Synthesis of (5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-2-yl)boronic acid, Int-3. General procedure for boronic acid formation: To a stirred solution of (4,4-difluoropiperidin-1-yl)(1-(5-iodopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, Int-2 (310 mg, 0.662 mol, 1 equiv.) and bis(pinacolato)diboron (252 mg, 0.993 mol, 1.5 equiv.) in 1,4-dioxane (10 mL), KOAc (129.9 mg, 1.324 mmol, 2 equiv.) was added and purged with argon for 15 min. To this solution was added (PdCl2(dppf)).DCM (5.40 mg, 0.06 mmol, 0.1 equiv.) and purged with argon for another 10 min. The resulting reaction mixture was stirred at 100° C. for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through Celite and evaporated to dryness. The crude was triturated with n-pentane and dried in vacuum to give (5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-2-yl)boronic acid, Int-3 (210 mg, 82.14%) as a brown liquid. TLC: 10% MeOH / DCM; MS: m / z=235.2 [M+H] + .

[0360] Step 3: Synthesis of (4,4-difluoropiperidin-1-yl)(1-(6-(2-methyl-1H-imidazol-4-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone B-15: (5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-2-yl)boronic acid, Int-3, was converted to B-15 (4.7%) using the general procedure for Suzuki coupling. TLC: 10% MeOH / DCM; MS: m / z=423.25 [M+H] + .

[0361] Step A: Synthesis of 4-bromo-1-(4-methoxybenzyl)-2-methyl-1H-imidazole (Int-A): To a stirred solution of 4-bromo-2-methyl-1H-imidazole (1 g, 6.21 mmol, 1 equiv.) in DMF (15 mL), NaH (60% in mineral oil) (0.298 mg, 7.45 mmol, 1.2 equiv.) was added at 0° C. to room temperature for 1 h. To this, a stirred suspension of PMBCl (1.46 g, 9.32 mmol, 1.5 equiv.) was added. The resulting reaction mixture was then stirred for 4 h. The reaction was monitored by crude LCMS / TLC and after complete consumption of starting material, the reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (20 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give 4-bromo-1-(4-methoxybenzyl)-2-methyl-1H-imidazole, Int-A (800 mg). The crude was used in the next step without further purification. TLC: 10% MeOH / DCM MS: m / z=281.1 [M+H] + .

[0362] Step B: Synthesis of (1-(4-methoxybenzyl)-2-methyl-1H-imidazol-4-yl)boronic acid (IntB): To a stirred solution of 4-bromo-1-(4-methoxybenzyl)-2-methyl-1H-imidazole, Int-A (800 mg, 2.85 mmol, 1 equiv.) in THF (10 mL) was added triisopropyl borate (1.97 mL, 8.54 mmol). The reaction mixture was cooled to -78°C and n-BuLi (1.6 M, 2.67 mL, 4.27 mmol, 1.5 mmol) was added over 45 min. The reaction mixture was stirred at the same temperature for 30 min and further stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with 2N HCl (1 ml) and stirred at room temperature for 3 h. The solvent was removed in vacuo. The resulting crude was dissolved in ethyl acetate (20 ml), washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give (1-(4-methoxybenzyl)-2-methyl-1H-imidazol-4-yl)boronic acid, Int-B (500 mg) as a brown liquid. TLC: 10% MeOH / DCM; MS: m / z = 247.04 [M+H] + .

[0363] Example 7. Synthesis of (4,4-difluoropiperidin-1-yl)(1-(6-(2-methyl-1H-imidazol-4-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-16), and (4,4-difluoropiperidin-1-yl)(1-(6-(1-(4-methoxybenzyl)-2-methyl-1H-imidazol-4-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-24)

[0364] [ka]

[0365] Int-1 is described above in the synthesis of B-12.

[0366] Step 1: Synthesis of (4,4-difluoropiperidin-1-yl)(1-(6-iodopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, Int-2: Using the general procedure for Ullmann coupling, Int-1 was converted to (4,4-difluoropiperidin-1-yl)(1-(6-iodopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, Int-2 (80%) as an off-white solid. TLC: 50% EtOAc / heptane (Rf: 0.40); MS: m / z=469.05 [M+H] + .

[0367] Step 2A: Synthesis of (4,4-difluoropiperidin-1-yl)((1-(6-(1-(4-methoxybenzyl)-2-methyl-1H-imidazol-4-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-24: Using the general procedure for Suzuki coupling, (4,4-difluoropiperidin-1-yl)(1-(6-iodopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, Int-2, was converted to B-24 using Int-B (described above for the synthesis of B-23). ​​The crude was purified by silica gel column chromatography using 5% MeOH:DCM followed by preparative HPLC purification to give B-24 (41.36 mg, 19.29%) as an off-white solid.

[0368] Step 2B: Synthesis of (5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-2-yl)boronic acid, Int-3: Using the general procedure for boronic acid formation, (4,4-difluoropiperidin-1-yl)(1-(6-iodopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, Int-2 was converted to (5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-2-yl)boronic acid, Int-3. The crude was used in the next step without further purification. TLC: 5% MeOH / DCM; MS: m / z = 387.1 [M+H] + .

[0369] Step 3: Synthesis of (4,4-difluoropiperidin-1-yl)(1-(6-(2-methyl-1H-imidazol-4-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-16: Using the general Suzuki coupling procedure, (5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-2-yl)boronic acid was converted to (4,4-difluoropiperidin-1-yl)(1-(6-(2-methyl-1H-imidazol-4-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-16, which was purified by preparative HPLC to give an off-white solid. TLC:5% MeOH / DCM;MS:m / z =423.15 [M+H] + .

[0370] Example 8. Synthesis of (4,4-difluoropiperidin-1-yl)(1-(5-(4-methyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-18), and (4,4-difluoropiperidin-1-yl(1-(6-(5-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-19)

[0371] [ka]

[0372] Int-1 is described above in the synthesis of B-12.

[0373] Step 1: Synthesis of Int-2: Using the general procedure for Ullmann coupling, (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, Int-1 (previously described in the synthesis of B-12, 1 g, 3.77 mmol, 1 equiv.) was converted to 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinaldehyde, Int-2a (400 mg, 28.7%), TLC: 100% EtOAc / heptane, MS: m / z=369.1. [MH]-, and 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinaldehyde, Int-2b (420 mg, 30.2%) TLC: 100% EtOAc / heptane, MS: m / z=371.1 [M+H] + .370.36 was isolated as a yellow gummy liquid.

[0374] Step 2: Synthesis of (4,4-difluoropiperidin-1-yl)(1-(5-(4-methyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-18 (General procedure for 1,2,3-triazole formation): Prepare 5-(5-(4,4-difluoropiperidine-1-carbonyl)- 1H-Pyrrolo[2,3-b]pyridin-1-yl)nicotinaldehyde, Int-2a (400 mg, 1.08 mmol, 1 equiv.), nitroethane (0.1 mL, 1.62 mmol, 1.5 equiv.), NaN3 (77 mg, 1.1 mmol, 1.1 equiv.), and AlCl3 (20 mg, 0.129 mmol, 0.12 equiv.) were stirred in 8 mL of DMSO at 80° C. for 16 h. The reaction was monitored by crude LCMS / TLC, and after complete consumption of starting material, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was evaporated in vacuum. The crude was purified by CombiFlash column chromatography using 70% EtOAc / heptane to give (4,4-difluoropiperidin-1-yl)(1-(5-(4-methyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-18 (85 mg, 18.5%) as an off-white solid. TLC: 100% EtOAc / heptane, MS: m / z=424.5 [M+H] + .

[0375] Step 2: Synthesis of (4,4-difluoropiperidin-1-yl)(1-(6-(5-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-19: Using the general procedure for 1,2,3-triazole formation, Int-2b (420 mg, 1.13 mmol, 1 equiv.) was converted to (4,4-difluoropiperidin-1-yl)(1-(6-(5-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-19, as an off-white solid. TLC: 100% EtOAc / heptane, MS: m / z=424.1 [M+H] + .

[0376] Example 9. Synthesis of (4,4-difluoropiperidin-1-yl)(1-(6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (B-21), (4,4-difluoropiperidin-1-yl)(1-(5-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (B-22), and (1-(5-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone (B-1)

[0377] [ka]

[0378] Int-1 is described above in the synthesis of B-12.

[0379] Step 1: Synthesis of Int-2a / Int-2b: Using the general procedure for Ullmann coupling, (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, Int-1 (5 g, 18.55 mmol, 1 equiv.) was converted to 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile, Int-2a (2 g, 30%), TLC: 100% EtOAc / heptane, MS: m / z=366.1 [MH]-, and 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile, Int-2b (3.5 g, 51%) TLC: 100% EtOAc / heptane, MS: m / z=366.1 [MH] - .Converted to .

[0380] Step 2A: Synthesis of (4,4-difluoropiperidin-1-yl)(1-(6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-21), and (4,4-difluoropiperidin-1-yl)(1-(5-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-22) ( General procedure for triazole formation: To a stirred solution of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile, Int-2a (200 mg, 0.544 mmol, 1 equiv.) in DMSO (5 mL) was added acetamidine hydrochloride (77 mg, 0.816 mmol, 1.5 equiv.), Cs2CO3 (531 mg, 1.63 mmol, 3 equiv.), CuBr (12 mg, 0.054 mmol, 0.1 equiv.). The reaction mixture was stirred at 120° C. for 14 h. The reaction was monitored by TLC and after complete consumption of the starting material, the reaction mixture was quenched with a solution of saturated NaHCO3 (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude. The crude was purified by combi-flash column chromatography using 5% MeOH:DCM to give (4,4-difluoropiperidin-1-yl)(1-(6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-21 (70 mg, 30%) as an off-white solid. TLC: 100% EtOAc / heptane MS: m / z =424.2 [M+H] +5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile, Int-2b (700 mg, 1.91 mmol, 1 equiv.) was converted to (4,4-difluoropiperidin-1-yl)(1-(5-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-22 using a similar protocol as above to give (4,4-difluoropiperidin-1-yl)(1-(5-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-22 (100 mg, 12%). TLC: 100% EtOAc / heptane MS: m / z=424.2[M+H] + .

[0381] Step 2B: Synthesis of (1-(5-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, (B-1): Using the general procedure for triazole formation, 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile, Int-2b (100 mg, 1.91 mmol, 1 equiv.) was converted to (1-(5-(5-cyclopropyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, (B-1) Pyr-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone to give crude material, which was purified by preparative HPLC to give (1-(5-(5-cyclopropyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, B-1 (10 mg, 8.19%) as an off-white solid. TLC: 10% MeOH:DCM(R f :0.23) MS:m / z=450.1 [M+H] + .

[0382] Example 10. Synthesis of (4,4-difluoropiperidin-1-yl)(1-(6-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-25), and (4,4-difluoropiperidin-1-yl)(1-(6-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-31)

[0383] [ka]

[0384] (4,4-difluoropiperidin-1-yl)(1-(6-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-21 (50 mg, 0.118 mmol, 1 equiv) in DMF (10 mL) was cooled to 0° C. and NaH (60% in mineral oil) (163 mg, 0.200 mmol, 1.7 equiv) was added. After stirring at 0° C. for 20 min, methyl iodide (25 mg, 0.177 mmol, 1.5 equiv) was added at 0° C. and allowed to warm to room temperature with stirring for 6 h. The reaction was monitored by crude LCMS / TLC and after consumption of starting material, the reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC to give (4,4-difluoropiperidin-1-yl)(1-(6-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, B-25 (23 mg, 46%) (TLC: 10% MeOH:DCM(R f : 0.43); MS: m / z = 438.2 [MH] +) and (4,4-difluoropiperidin-1-yl)(1-(6-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone as a yellow solid, B-31 (11 mg, 21.20%) (TLC: 10% MeOH:DCM(R f :0.43). MS:m / z=438.20 [MH] + ) and obtained.

[0385] Example 11. Synthesis of (1-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, (B-26)

[0386] [ka]

[0387] Int-1 is described above in the synthesis of B-12.

[0388] Step 1: Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile, Int-2: Using the general procedure for Ullmann coupling, (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, Int-1 (310 mg, 1.16 mmol, 1 equiv.) was converted to 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile, Int-2 (215 mg, 50.2%). TLC: 50% EtOAc / heptane (R f : 0.45), MS: m / z = 367.1 [M + H] +

[0389] Step 2: Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide, (Int-3): To a stirred solution of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile, Int-2 (185 mg, 0.50 mmol, 1 equiv.) in DMSO (3 mL) was added K2CO3 (70 mg, 0.50 mmol, 1.0 equiv.) followed by H2O2 (30%, 0.17 mL, 1.51 mmol, 3.0 equiv.) at 0 °C. The reaction mixture was then allowed to warm to room temperature and stirred at 60 °C for 2 h. The progress of the reaction was monitored by TLC. The resulting solid was filtered, dried and triturated with diethyl ether to give 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide, Int-3 (160 mg, crude) as a yellow solid. The crude material obtained was used in the next step without further purification. TLC: 80% EtOAc:heptane (R f :0.35) MS:m / z=385.1 [M+H] + .

[0390] Step 3: Synthesis of (E)-4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((dimethylamino)methylene)benzamide, (Int-4): A solution of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide, Int-3 (151 mg, 0.392 mmol, 1 equiv) in N,N-dimethylformamide dimethyl acetal (10 mL) was heated at 100° C. for 1 h under nitrogen atmosphere. The reaction progress was monitored by TLC. The reaction mixture was evaporated to dryness under reduced pressure and the crude obtained was triturated with EtO to give (E)-4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N((dimethylamino)methylene)benzamide, Int-4 (180 mg, crude) as a pale yellow solid. The crude obtained was used in the next step without further purification. TLC: 100% EA / heptane (R f :0.40) MS:m / z=440.2 [M+H] + .

[0391] Step 4: Synthesis of (1-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, (B-26): To a stirred solution of (E)-4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N(((dimethylamino)methylene)benzamide (Int-4) (80 mg, 0.184 mmol, 1.0 equiv.) in acetic acid (0.5 mL) was added hydrazine acetate (83 mg, 0.910 mmol, 5.0 equiv.) at room temperature. The resulting reaction mixture was stirred at 95 °C for 1 h. Stirred for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified using Combiflash chromatography (using a gradient method of 5% MeOH in DCM) to give (1-(4-(1H-1,2,4-triazol-5-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, B-26 (15 mg, 20.23%) as an off-white solid. TLC: 100% EA / heptane (R f :0.40) MS:m / z=409.2 [M+H] + .

[0392] Example 12. Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-fluorobenzoic acid, (B-27)

[0393] [ka]

[0394] Int-1 is described above in the synthesis of B-12.

[0395] Step 1: Synthesis of methyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-fluorobenzoate, Int-2: Using the general procedure for Ullmann coupling, (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, Int-1 (500 mg, 1.89 mmol, 1 equiv.) was converted to methyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-fluorobenzoate, Int-2 (350 mg, 44%). TLC: 50% EtOAc / heptane (R f : 0.35), MS: m / z = 418.1 [M + H] +

[0396] Step 2: Synthesis of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-fluorobenzoic acid, (B-27): Using the general procedure for ester hydrolysis with LiOH, methyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-fluorobenzoate, Int-2( 200 mg, 0.740 mmol, 1 equiv) was converted to 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-fluorobenzoic acid to give 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-fluorobenzoic acid, B-27 (80 mg, 41.4%) as an off-white solid. MS: m / z=404.2 [M+H] + .

[0397] Example 13. Synthesis of (1-(5-(5-amino-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone (B-11) and (1-(5-(5-(tert-butylamino)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, (B-20)

[0398] [ka]

[0399] Int-1 is described above in the synthesis of B-12.

[0400] Step 1: Synthesis of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile: Using the general procedure for the Ullman coupling reaction, Int-1 (1.5 g, 5.65 mmol, 1 equiv.) was converted to 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile, Int-2 (1.3 g, 62.50%). TLC: 70% EtOAc (R f : 0.45). MS: m / z = 368.02 [M + H] + .

[0401] Step 2: Synthesis of (Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N'-hydroxynicotinimidamide, (Int-3): To a stirred solution of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile, Int-2 (500 mg, 1.36 mmol, 1 equiv.) in EtOH (5 mL) was added NH2OH.HCl (190 mg, 2.72 mmol, 2 equiv.) at room temperature, followed by Et3N (0.206 mL, 1.5 mmol, 1.1 equiv.). The resulting mixture was heated to 80° C. for 2 h. The reaction was monitored by LCMS / TLC and after complete consumption of starting material, the reaction mixture was evaporated to dryness to remove ethanol and extracted with EtOAc (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude. The crude was triturated with EtO and dried in vacuo to give (Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N′-hydroxynicotinimidamide, Int-3 (450 mg) as an off-white solid. TLC: 70% EtOAc (R f :0.25). MS:m / z=401.01 [M+H] + .

[0402] Step 3: Synthesis of (1-(5-(5-(tert-butylamino)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, (B-20): (Z)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl A stirred solution of )-N'-hydroxynicotinimidamide (500 mg, 1.25 mmol, 1 equiv.), tert-butyl isocyanide (0.212 mL, 1.88 mmol, 1.5 equiv.), Pd(PPh3)4 (72 mg, 0.063 mmol, 5.0 mol%), K2CO3 (518 mg, 3.75 mmol, 3.0 equiv.) in 10 mL of toluene was stirred under air atmosphere for 8 h. The reaction was monitored by LCMS / TLC and after completion of the starting material, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered. The solvent was removed in vacuum. The crude was purified by combi-flash column chromatography using 10% MeOH:CH2Cl2 to give (1-(5-(5-(tert-butylamino)-1,2,4-oxodiazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, B-20 (30 mg, 4.99%) as an off-white solid. TLC: 10% MeOH:CH2Cl2(R f :0.35) MS:m / z=482.2 [M+H] + .

[0403] Step 4: Synthesis of (1-(5-(5-amino-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, (B-11): (1-(5-(5-(tert-butylamino)-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, B-20 (15 mg, 0.031 mmol, equiv.) was dissolved in 2 mL of neat trifluoroacetic acid and heated at reflux for 2 h. The reaction was monitored by LCMS / TLC and after completion of starting material, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered. The solvent was removed in vacuo. The crude was purified by combi-flash column chromatography using 10% MeOH:CH2Cl2 to give (1-(5-(5-amino-1,2,4-oxadiazol-3-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, B-11 (5.13 mg, 38.70%) as an off-white solid. TLC: 10% MeOH:CH2Cl2(R f :0.35) MS:m / z=426.1 [M+H] + .

[0404] Example 14. Synthesis of B-38, B-39, B-40, B-41, B-42, B-43, and B-44

[0405] [ka]

[0406] Step 1: Synthesis of ethyl 1-(6-cyanopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, (Int-1): Using the general procedure of Ullmann coupling with 5-bromopicolinonitrile (3.4 g, 18.8 mmol, 1.2 equiv.), ethyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate, SM-1 (3.0 g, 15.7 mmol, 1.0 equiv.) was converted to ethyl 1-(6-cyanopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, Int-1 to give Int-1 (2.1 g, 46% yield) as an off-white solid. MS: m / z=293.2 [M+1] + .

[0407] Step 2: Synthesis of ethyl 1-(6-carbamoylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, Int-2: From Int-1 (2.1 g, 7.19 mmol, 1.0 equiv.) by the general procedure for oxidation of nitriles using K2CO3 (1.48 g, 10.78 mmol, 1.5 equiv.) and H2O2 (0.73 g, 21.57 mmol, 3.0 equiv.) in DMSO (5 v). Synthesis of ethyl 1-(6-carbamoylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, Int-2 to obtain ethyl 1-(6-carbamoylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, Int-2 (2.0 g, 90% yield) as an off-white solid. MS: m / z=311.1 [M+1] + ).

[0408] Step 3: Synthesis of ethyl (E)-1-(6-(((dimethylamino)methylene)carbamoyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, (Int-3): Using the general enaminone generation reaction procedure with DMF-DMA, ethyl 1-(6-carbamoylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, Int-2 (2.0 g, 6.45 mmol, 1.0 equiv.) was converted to (E)-1-(6-(((dimethylamino)methylene)carbamoyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate to give Int-3 (2.0 g, 92% yield). MS: m / z=366.2 [M+1] + ).

[0409] Step 4: Synthesis of ethyl 1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, Int-4: Using the general procedure for triazole synthesis with hydrazine acetate and acetic acid, Int-3 (2.0 g, 5.46 mmol, 1.0 equiv.) was converted to ethyl 1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, Int-4 to give Int-4 (1.8 g, 98% yield). MS: m / z=335.2 [M+1] + ).

[0410] Step 5: Synthesis of 1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid, (Int-5): Using the general procedure for hydrolysis, ethyl 1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate, Int-4 (1.8 g, 5.38 mmol) was converted to 1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid, Int-5, with LiOH (3.0 equiv., 16.16 mmol) to give Int-5 (1.3 g, 79.2% yield) as an off-white solid. MS: m / z=305.2 [M-1] - ).

[0411] Step 6: Synthesis of B-38, B-39, B-40, B-41, B-42, B-43, and B-44: Using the general procedure of acid-amine coupling using HATU, DIPEA, 1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid, Int-5, was converted to B-38, B-39, B-40, B-41, B-42, B-43, and B-44 to give B-38 (25.5% yield, MS: m / z=402.1 [M+1]), B-39 (7.8% yield, MS: m / z=390.1 [M+1]), and B-44. + ),B-40(53.8% yield, MS:m / z=404.2 [M+1] + ),B-41(4.96%,MS:m / z=374.1 [M+1] + ), B-42 (31.7% yield, MS: m / z=388.40 [M+1] + ),B-43(1.75% yield, MS:m / z=375.1 [M+1] + ), and B-44 (35% yield, MS: m / z=389.2 [M+1] + ) was obtained.

[0412] Example 15. (S)-(1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(3-methylpiperidin-1-yl)methanone (B-33) / (1-(5-(1H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone (B-34) / (S)-(1-(5-(4H-1,2,4-triazol-3-yl)pyridin-2-yl) Synthesis of -1H-pyrrolo[2,3-b]pyridin-5-yl)(3-methylpiperidin-1-yl)methanone (B-35) / (1-(3-(1H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone (B-36) / (S)-(1-(3-(1H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(3-methylpiperidin-1-yl)methanone (B-37)

[0413] [ka]

[0414] Int-1 is described above in the synthesis of B-12 and B-29.

[0415] Step 1: Synthesis of (S)-(3-methylpiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-1a) / (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-1b): Using the general procedure for acid-amine coupling using HATU and (S)-3-methylpiperidine (1.2 equiv.) / 4,4-difluoropiperidine hydrochloride (1.2 equiv.), pyrrolo[2,3-b]pyridine-5-carboxylic acid, SM-1 (1.0 equiv.) was converted to (S)-(3-methylpiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (Int-1a) / (4,4-difluoropiperidine hydrochloride), to give (S)-(3-methylpiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-1a) (1.5 g, 66%) / (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-1b) (3 g, 96%).

[0416] Step 2: Synthesis of (Int-2a) / (Int-2b): Using general Ullmann coupling of (S)-(3-methylpiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-1a) / (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-1b), respectively, with bromobenzonitrile (1.2 eq.) was used to synthesize Int-1a / Int-1b (1.0 eq.), giving Int-2a / Int-2b as off-white solids. (Int-2a) (4th position 32.8%, m / z=345.5 [M+1] + )(3rd place 40%,m / z=345.5 [M+1] + ) / (Int-2b)(3rd place 87%,m / z=367.1 [M+1] + )

[0417] Step 3: Synthesis of (Int-3a) / (Int-3b): Int-3a / Int-3b were synthesized from Int-2a / Int-2b using general oxidation conditions by using K2CO3 (2.0 equiv.) and H2O2 (5.0 equiv.) in DMSO (10 v), giving Int-3a / Int-3b as off-white solids. Int-3a (4th position 74%, m / z=363.25 [M+1] + )(3rd place 51%, m / z=363.25 [M+1] + ) / Int-3b(3rd place 90%, m / z=385.2 [M+1] + ).

[0418] Step 4: Synthesis of (Int-4a) / (Int-4b): Int-3a / Int-3b (1.0 equiv.) was taken up in DMF DMA (10v) and heated to 90° C. for 1 h. The reaction progress was monitored by TLC. The solvent was evaporated under reduced pressure and triturated with ether to give Int-4a / Int-4b as off-white solids. The crude was used in the next step without further purification. Int-4a (4th position 62%, m / z=418.01 [M+1] + )(3rd place 66%, m / z=418.22 [M+1] + ) / Int-4b(3rd place 78%, m / z=440.1 [M+1] + ).

[0419] Example 16. Synthesis of B-34 and B-35

[0420] [ka]

[0421] Int-1 is described above in the synthesis of B-12 and B-29.

[0422] Step 1: Synthesis of (S)(3-methylpiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-1a) / (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-1b): Pyrrolo[2,3-b]pyridine-5-carboxylic acid, SM-1 (1.0 equiv.) was reacted with HATU and (S)-3-methylpiperidine (1.2 equiv.) / (4,4-difluoropiperidine hydrochloride (1.2 equiv.) using the general procedure for acid-amine coupling. (S)-(3-methylpiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (Int-1a) (1.5 g, 66%) / (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (Int-1b) (3 g, 96%) was obtained.

[0423] Step 2: Synthesis of (Int-2a) / (Int-2b): Int-1a / Int-1b (1.0 equiv.) was synthesized by using general Ullmann coupling of (Int-1a) / (Int-1b) with 4-bromobenzonitrile (1.2 equiv.) to give Int-2a / Int-2b as off-white solids. (Int-2a) (4th position 41%, m / z=346.16 [M+1] + ) / (Int-2b)(4th place 73%,m / z=368.1 [M+1] + ).

[0424] Step 3: Synthesis of (Int-3a) / (Int-3b): Int-3a / Int-3b were synthesized from Int-2a / Int-2b using general oxidation conditions by using K2CO3 (2.0 equiv.) and H2O2 (5.0 equiv.) in DMSO (10v), and Int-3a / Int-3b were obtained as off-white solids. Int-3a (4th position 70%, m / z=364.2 [M+1]+ ) / Int-3b(4th place 82%, m / z=386.2 [M+1] + ).

[0425] Step 4: Synthesis of (Int-4a) / (Int-4b): Int-3a / Int-3b (1.0 equiv.) was taken up in DMF DMA (10v) and heated to 90° C. for 1 h. The reaction progress was monitored by TLC. The solvent was evaporated under reduced pressure and triturated with ether to give Int-4a / Int-4b as off-white solids. The crude was used in the next step without further purification. Int-4a (4th position 58%, m / z=419.01 [M+1]+) / Int-4b (4th position 72%, m / z=441.1 [M+1]+).

[0426] Step 5: (S)-(1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(3-methylpiperidin-1-yl)methanone (B-33) / (1-(5-(1H-1,2,4-triazol-3-yl))pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone (B-34) / (S)-(1-(5-(4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(3-methylpiperidin-1-yl)methanone (B-35) / (1-(5-(4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(3-methylpiperidin-1-yl)methanone (B-36) / (1-(5-(4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(3-methylpiperidin-1-yl)methanone (B-37) / (1-(5-(4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(3-methylpiperidin-1-yl)methanone (B-38) Synthesis of (S)-(1-(3-(1H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone (B-36) / (S)-(1-(3-(1H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(3-methylpiperidin-1-yl)methanone (B-37): To a stirred solution of Int-5 (1.0 equiv.) in acetic acid (10v), hydrazine acetate (5.0 equiv.) was added and heated to 80° C. for 1 h. The progress of the reaction was monitored by TLC and LCMS. The acetic acid was evaporated, diluted with EtOAc, and washed with NaHCO3 solution, water, and brine solution. The combined extracts were dried over sodium sulfate, filtered, and concentrated.

[0427] Example 17. Synthesis of (1-(2-(1H-1,2,4-triazol-5-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, (B-45)

[0428] [ka]

[0429] Int-1 is described above in the synthesis of B-12.

[0430] Step 1: Synthesis of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidine-2-carbonitrile, (Int-1): Using the general procedure for Ullman coupling, (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (SM-1) (500 mg, 1.88 mmol, 1.0 equiv.) was converted to 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidine-2-carbonitrile (Int-1) (0.48 g, yield=69.1%, MS: m / z=369.00 [M+H]). + ).

[0431] Step 2: Synthesis of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidine-2-carboxamide, (Int-2): Using the general procedure for benzamide formation with HO, 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d][1,2,3]triazol-1-yl)benzonitrile (Int-1) (280 mg) was obtained. , 0.76 mmol, 1.0 equiv) was converted to 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-benzo[d][1,2,3]triazol-1-yl)benzamide to give 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidine-2-carboxamide, (Int-2) (200 mg, yield=68.25%, Ms: m / z=387.1 [M+1] + ) as a pale yellow solid.

[0432] Step 3: Synthesis of (E)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((dimethylamino)methylene)pyrimidine-2-carboxamide, (Int-3): Using the general procedure for enamine formation, 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[ 2,3-b]pyridin-1-yl)pyrimidine-2-carboxamide, (Int-2) (200 mg, 0.51 mmol, 1.0 equiv.) was converted to (E)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((dimethylamino)methylene)pyrimidine-2-carboxamide (Int-3). The resulting crude product was triturated with EtO to give (E)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)-N-((dimethylamino)methylene)pyrimidine-2-carboxamide, (Int-3) (180 mg, yield=78.94%, Ms: m / z=442.00 [M+1] + ) as an off-white solid.

[0433] Step 4: Synthesis of (1-(2-(1H-1,2,4-triazol-5-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, (B-45): Using the general procedure for triazole formation with hydrazine acetate, (E)-5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2 (1-(2-(1H-1,2,4-triazol-5-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, B-45. The crude was purified by combi-flash column chromatography using 5% MeOH:DCM to give (1-(2-(1H-1,2,4-triazol-5-yl)pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, B-45 (110 mg, yield=65.86%, Ms: m / z=411.2 [M+H] + ) as an off-white solid. TLC: 5% MeOH / CH2Cl2(R f :0.25).

[0434] Example 18. Synthesis of ethyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate, (B-32):

[0435] [ka]

[0436] Int-1 is described above in the synthesis of B-12.

[0437] Using the general procedure for Ullman coupling, (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (SM-1) (75 mg, 0.19 mmol, 1.0 equiv.) was converted to ethyl 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzoate, B-32 (44.6 mg, yield=55.4%, MS: m / z=414.20 [M+H]). + .

[0438] Example 19. (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(2-methylmorpholino)methanone (B-46) / (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl(2,6-dimethylmorpholino)methanone (B -47) / Synthesis of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinimide hydrazide (B-48) and (1-(6-(3-amino-1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(2-methylmorpholino)methanone (B-49)

[0439] [ka]

[0440] Step 1: Synthesis of (2-methylmorpholino)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, Int-1a, and (2,6-dimethylmorpholino)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, Int-1b: Using the general procedure of HATU acid-amine coupling, 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid, SM-1, was converted to Int-1a and Int-1b to give Int-1a (60% yield, m / z=246.1 [M+H]) as an off-white solid. +) and Int-1b (68% yield, m / z=260.1 [M+H] + ) was obtained. Int-1 was synthesized as previously described.

[0441] Step 2: Synthesis of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile, Int-2 / 5-(5-(2-methylmorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile, Int-2a, and 5-(5-(2,6-dimethylmorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinonitrile, Int-2b: The general procedure for Ullmann coupling with 5-bromopicolinonitrile was used to convert Int-1, Int-1a, and Int-1b to Int-2, Int-2a, and Int-2b to give Int-2 (43.50% yield, m / z=368.2 [M+H]). + ), Int-2a (44.3% yield, m / z=348.1 [M+H] + ), and Int-2b (32% yield, m / z=362.2 [M+H] + ) was isolated as an off-white solid.

[0442] Step 3: Synthesis of 5-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinimide hydrazide and 5-(5-(2-methylmorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinimide hydrazide, Int-3a: Synthesis of Int-2 / Int-2a was prepared using the general procedure for imide hydrazide formation with hydrazine, respectively, to prepare B-48 (41% yield, m / z=400.1 [M+H] + ) and Int-3a (100% crude, m / z=380.02 [M+H] + ) was converted to

[0443] Step 4: Synthesis of (1-(6-(3-amino-1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(2-methylmorpholino)methanone, B-49: To a stirred solution of (Int-3a) (1.0 equiv.) in 1,4-dioxane (10 vol.), was added triethyl orthoformate (5.0 equiv.) and p-toluenesulfonic acid monohydrate (0.2 equiv.). The resulting reaction mixture was stirred at 100° C. for 16 h. The progress of the reaction was monitored by TLC / LCMS and upon completion, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by Combi-Flash column chromatography using 5% MeOH:DCM to give (1-(6-(3-amino-1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(2-methylmorpholino)methanone, B-49 (15.33 mg, 7.1%) as an off-white solid. MS: m / z=405.1 [M+H] + .

[0444] Step 5: Synthesis of 5-(5-(2-methylmorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinamide, Int-4a / (5-(5-(2,6-dimethylmorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinamide, Int-4b: Using the general procedure for amide formation with K2CO3 and H2O2, Int-2a / Int-2b were converted to Int-4a / Int-4b, respectively, to give Int-4a (77% yield, m / z=366.1 [M+H]). + ) and Int-4b (79% yield, m / z=380.1 [M+H] + ) as an off-white solid.

[0445] Step 6: Synthesis of (E)-N-((dimethylamino)methylene)-5-(5-(2-methylmorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinamide, Int-5a / (E)-N-((dimethylamino)methylene)-5-(5-((2,6-dimethylmorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)picolinamide, Int-5b: Int-4a / Int-4b (1 equiv.) in DMF-DMA (10V) was heated to 80° C. for 2 h. The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure and washed with heptane to give Int-5a (77% yield, m / z=421.2 [M+H] + ) and Int-5b (77% yield, m / z=435.2 [M+H] + ) as an off-white solid.

[0446] Step 7: Synthesis of (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(2-methylmorpholino)methanone, B-46 / (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(2,6-dimethylmorpholino)methanone, B-47: To Int-5a, Int-5b (1 eq.) in acetic acid (10v), hydrazine acetate (5 eq.) was added and stirred at 90° C. for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and basified with saturated NaHCO3. The resulting solid was filtered and dried to give (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(2-methylmorpholino)methanone, B-46 (55% yield, m / z=390.1 [M+H] + ) / (1-(6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl(2,6-dimethylmorpholino)methanone, B-47 (81% yield, m / z=390.1 [M+H] + ) was obtained.

[0447] Example 20. Synthesis of (R)-(1-(3-(4H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(2-methylmorpholino)methanone, (B-189)

[0448] [ka]

[0449] Step 1: Synthesis of compound 2: To a mixture of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (500 mg, 3.08 mmol, 1.00 equiv), (R)-2-methylmorpholine (374 mg, 3.70 mmol, 1.20 equiv), EDCI (1.18 g, 6.17 mmol, 2.00 equiv), HOBt (833 mg, 6.17 mmol, 2.00 equiv) in DMF (5 mL), DIEA (1.20 g, 9.25 mmol, 1.61 mL, 3.00 equiv) was added and the mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with H2O (25 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions) to afford (R)-(2-methylmorpholino)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (590 mg, 2.26 mmol, 73% yield, 94% purity) as a yellow oil.

[0450] 1 H NMR (400 MHz, chloroform-d) δ = 10.46 (br s, 1H), 8.46 (d, J = 1.2 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.50-7.39 (m, 1H), 6.59 (dd, J = 1.6, 3.2 Hz, 1H), 5.01-4.28 (m, 1H), 4.01-3.53 (m, 4H), 3.40-2.76 (m, 2H), 1.31-1.07 (m, 3H).

[0451] Step 2: Synthesis of compound 3: A mixture of (R)-(2-methylmorpholino)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (300 mg, 1.22 mmol, 1.00 equiv), 3-iodobenzonitrile (336 mg, 1.47 mmol, 1.20 equiv), CuI (46.6 mg, 245 μmol, 0.20 equiv), KPO (519 mg, 2.45 mmol, 2.00 equiv), and dimethylcyclohexane-1,2-diamine (34.8 mg, 245 μmol, 0.20 equiv) in DMA (3 mL) was degassed and purged with N three times, then the mixture was stirred at 120 °C under N atmosphere (15 psi) for 2 h. The reaction mixture was diluted with H2O (30ml) and EtOAc (30ml), then filtered, and the filtrate was extracted with EtOAc (20mL x 3). The combined organic layers were washed with brine (20mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 1 / 3) to give (R)-3-(5-(2-methylmorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (390mg, 1.09mmol, 89% yield, 97% purity) as a yellow oil.

[0452] 1 H NMR(400MHz,chloroform-d) δ=8.46(d,J=1.6Hz,1H),8.21(s,1H),8.12(d,J=1.6Hz,1H),8.08(td,J=2.4,6.8Hz,1H),7.71~7.63(m,2H),7.61(d,J=4.0H z,1H),6.77(d,J=3.6Hz,1H),4.90~4.25(m,1H),4.07~3.86(m,1H),3.83~3.46(m,3H),3.42~2.72(m,2H),1.26~1.03(m,3H).

[0453] Step 3: Synthesis of compound 4: To a solution of (R)-3-(5-(2-methylmorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (340 mg, 982 μmol, 1.00 equiv.) in DMSO (3.5 mL) was added K2CO3 (203 mg, 1.47 mmol, 1.50 equiv.), the mixture was stirred at 0 °C, then H2O2 (2.01 g, 17.7 mmol, 1.7 mL, 30% purity, 18.0 equiv.) was added slowly at 0 °C, stirred at 0 °C for 1 h, then the mixture was stirred at 20 °C for another 4 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (20 mL×2), dried over Na2SO4, filtered and concentrated under reduced pressure to give (R)-3-(5-(2-methylmorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1yl)benzamide (300 mg, crude) as a white solid.

[0454] LCM (ESI, M+1): m / z=365.1

[0455] Step 4: (R)-(1-(3-(4H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(2-methylmorpholino)methanone. A solution of (R)-3-(5-(2-methylmorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (300 mg, 823 μmol, 1.00 equiv) in DMFDMA (3 mL) was stirred at 80° C. for 1.5 h, and then the reaction mixture was concentrated under reduced pressure to give a residue. To the residue was added AcOH (6 mL), NH2NH2.H2O (4.22 g, 84.3 mmol, 4.1 mL, 102 equiv) at 0° C., and the mixture was stirred at 0° C. for 0.25 h. The mixture was then stirred at 80° C. for 0.75 h. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 x 25 mm x 10 um; mobile phase: [water (FA)-ACN]; B%: 21%-51%, 10 min) to give (R)-(1-(3-(4H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(2-methylmorpholino)methanone (102 mg, 262 μmol, 32% yield, 99% purity) as a white solid. LCMS (ESI, M+1): m / z=389.1. 1 H NMR(400MHz,DMSO-d6) δ=14.65~14.01(m,1H),8.55(s,2H),8.41(d,J=1.6Hz,1H),8.19(d,J=2.0Hz,1H),8.11(d,J=3.6Hz,1H),8.02(d,J=8.0Hz,1H),7.92(br d,J=7.6Hz,1H),7.73~7.63(m,1H),6.84(d,J=3.6Hz,1H),4.53~4.13(m,1H),4.08~3.68(m,2H),3.67~3.38(m,4H),1.20~0.94(m,3H)

[0456] Example 21. Synthesis of (R)-(5-(5-(3-ethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)carbamate, (B-69), and methyl (S)-(5-(5-(3-ethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)carbamate, (B-70)

[0457] [ka]

[0458] Step 1: Synthesis of compound B: 3-ethylpyridine (100 g, 933 mmol, 105 mL, 1.00 equiv.) in AcOH (2000 mL) was added to PtO2 (20.0 g, 88.1 mmol, 9.44 e -2 Equivalents) were added. The mixture was degassed and purged with H2 three times, then the mixture was stirred under an atmosphere of H2 (50 psi) at 25 °C for 48 h. The reaction mixture was filtered, HCl (12 M, 100 mL) was added, and then concentrated under reduced pressure to give a residue. The crude product was triturated with MeCN (100 mL) and filtered to give 3-ethylpiperidine (60.0 g, 401 mmol, 43% yield, HCl) as a white solid.

[0459] 1 H NMR(400MHz,DMSO-d6) δ=9.12(br s,1H),3.20~3.08(m,2H),2.70(dt,J=3.2,12.4Hz,1H),2.44(br t,J=12.0Hz,1H),1.83~1.69(m,2H),1.68~1.56(m,2H),1.32~1.13(m,2H),1.12~1.00(m,1H),0.85(t,J=7.6Hz,3H).

[0460] Step 2: Synthesis of compound 2: To a mixture of 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (27.0 g, 166 mmol, 1.00 equiv.) in DMF (300 mL), 3-ethylpiperidine (27.4 g, 183 mmol, 1.10 equiv., HCl), EDCI (63.8 g, 333 mmol, 2.00 equiv.), HOBt (45.0 g, 333 mmol, 2.00 equiv.) was added DIEA (108 g, 833 mmol, 145 mL, 5.00 equiv.), and the mixture was stirred at 20° C. for 1.5 h. The reaction mixture was diluted with H2O (1500 mL) and extracted with EtOAc (500 mL×3). The combined organic layer was washed with brine (1000 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (100 ml) and filtered to give (3-ethylpiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (31.0 g, 112 mmol, 67% yield, 93% purity) as a yellow solid. 1 H NMR(400MHz,DMSO-d6) δ=11.86(br s,1H),8.23(d,J=1.6Hz,1H),7.98(s,1H),7.55(t,J=2.4Hz,1H),6.51(br d,J=1.6Hz,1H),4.70-4.09(m,1H),3.64(br s,1H),3.18-2.83(m,1H),2.81-2.55(m,1H),1.92-1.76(m,1H),1.63(br s,1H),1.40(br d,J=3.6Hz,2H),1.30-1.01(m,3H),0.83(br d,J=1.2Hz,3H).

[0461] Step 3: Synthesis of compound 3: A mixture of (3-ethylpiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (31.0 g, 120 mmol, 1.00 equiv), tert-butyl (5-bromopyridin-3-yl)carbamate (49.3 g, 181 mmol, 1.50 equiv), KPO (51.1 g, 241 mmol, 2.00 equiv), CuI (11.5 g, 60.2 mmol, 0.50 equiv) and dimethylcyclohexane-1,2-diamine (17.1 g, 120 mmol, 1.00 equiv) in DMA (300 mL) was degassed and purged with N three times, then the mixture was stirred at 110 °C under N atmosphere (15 psi) for 5 h. The reaction mixture was diluted with H2O (2000 mL) and EtOAc (1000 mL), and the mixture was added with NH3.H2O (200 mL, 25% purity), then filtered to obtain the filtrate and extracted with EtOAc (1000 mL x 3). The combined organic layers were washed with brine (2000 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA=3 / 1~1 / 2) to obtain tert-butyl (5-(5-(3-ethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)carbamate (47.0 g, 96.2 mmol, 80% yield, 92% purity) as a yellow solid.

[0462] 1H NMR(400MHz,DMSO-d6) δ=9.85(s,1H),8.68(d,J=2.4Hz,1H),8.61(d,J=1.6Hz,1H),8.49(t,J=2.0Hz,1H),8.35(d,J=2.0Hz,1H),8.14(d,J=2. 0Hz,1H),8.04(d,J=3.6Hz,1H),6.84(d,J=3.6Hz,1H),4.54~4.16(m,1H),3.87~3.40(m,1H),3.03~2.66(m,2H),1.84(br dd,J=4.4,9.2Hz,1H),1.77~1.55(m,1H),1.50(s,9H),1.45~1.35(m,2H),1.32~1.20(m,1H),1.17~1.03(m,2H),0.91~0.74(m,3H).

[0463] Step 4: Synthesis of MF-642 (R)-(5-(5-(3-ethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)carbamate, (B-69), and methyl (S)-(5-(5-(3-ethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)carbamate, (B-70). To a solution of tert-butyl (5-(5-(3-ethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)carbamate (35.0 g, 77.9 mmol, 1.00 equiv) in MeOH (200 mL) was added HCl·dioxane (4 M, 200 mL, 10.3 equiv) at 0 °C and stirred at 25 °C for 5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H2O (300 ml) and EtOAc (300 ml), then NaHCO3 was added to adjust the pH to 8, and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The products were further separated by SFC (column: REGIS(s,s)WHELK-O1 (250 mm x 50 mm, 10 um); mobile phase: [MeOH-ACN]; B%: 32%-32%, 7.0 min),

[0464] and (R)-(1-(5-aminopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(3-ethylpiperidin-1-yl)methanone (9.70 g, 27.2 mmol, 35% yield, 98% purity) as a yellow solid (LCMS (ESI, M+1): m / z = 350.1).

[0465] (S)-(1-(5-aminopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(3-ethylpiperidin-1-yl)methanone (9.00 g, 25.6 mmol, 33% yield, 99% purity) as a yellow solid (LCMS (ESI, M+1): m / z = 350.2). obtained. 1 H NMR(400MHz,DMSO-d6) δ=8.33(d,J=2.0Hz,1H),8.17(d,J=2.0Hz,1H),8.12(d,J=2.0Hz,1H),7.99(d,J= 3.6Hz,1H),7.93(d,J=2.4Hz,1H),7.50(t,J=2.4Hz,1H),6.79(d,J=3.6Hz,1H),5. 65(s,1H),4.51~4.21(m,1H),3.85~3.46(m,1H),3.08~2.77(m,1H),1.93~1.79(m ,1H),1.74~1.55(m,1H),1.51~1.35(m,2H),1.33~1.02(m,3H),0.92~0.73(m,3H).

[0466] Compound B-69, (R)-(5-(5-(3-ethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)carbamate: To a mixture of (R)-(1-(5-aminopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(3-ethylpiperidin-1-yl)methanone (5.00 g, 14.3 mmol, 1.00 equiv.), pyridine (3.40 g, 42.9 mmol, 3.46 mL, 3.00 equiv.) in THF (50 mL) was added methyl carbonochloridate (3.60 g, 38.1 mmol, 2.95 mL, 2.66 equiv.) at 0° C. and stirred at 20° C. for 2 hours. The reaction mixture was diluted with EtOAc (200 mL), quenched with saturated aqueous NaHCO3 at 0 °C to adjust pH to neutral, and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 0 / 1). The crude product was then triturated with MeCN (30 mL) to give (R)-(5-(5-(3-ethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)carbamate (3.51 g, 8.57 mmol, 60% yield, 99% purity) as a white solid.

[0467] LCMS(ESI,M+1):m / z=408.2.

[0468] 1H NMR(400MHz,DMSO-d6) δ=10.15(s,1H),8.71(d,J=2.0Hz,1H),8.63(d,J=2.0Hz,1H),8.53(s,1H),8.35(d,J=2.0Hz,1H),8.15(d,J=2.0Hz,1H),8.07(d,J=3.6Hz,1H),6.85(d,J=3.6Hz,1H),4.54~4.14(m,1H),3.72(s,3H),3.68~3.45(m,1H),3.15~2.60(m,2H),1.92~1.79(m,1H),1.77~1.54(m,1H),1.42(ddd,J=3.6,6.8,10.0Hz,2H),1.34~1.01(m,3H),1.00~0.73(m,3H).

[0469] Compound B-70, methyl (S)-(5-(5-(3-ethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)carbamate: To a mixture of (S)-(1-(5-aminopyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(3-ethylpiperidin-1-yl)methanone (5.00 g, 14.3 mmol, 1.00 equiv.), pyridine (3.40 g, 42.9 mmol, 3.46 mL, 3.00 equiv.) in THF (50 mL) was added methyl carbonochloridate (4.16 g, 44.0 mmol, 3.41 mL, 3.08 equiv.) at 0° C. and stirred at 20° C. for 2 h. The reaction mixture was diluted with EtOAc (200 mL), quenched with saturated aqueous NaHCO3 at 0 °C to adjust pH to neutral, and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 0 / 3). The crude product was then triturated with MeCN (30 mL) to give (S)-(5-(5-(3-ethylpiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyridin-3-yl)carbamate (3.54 g, 8.66 mmol, 61% yield, 99% purity) as a white solid. LCMS(ESI,M+1):m / z=408.2.1H NMR(400MHz,DMSO-d6) δ=10.14(br s,1H),8.72(s,1H),8.63(s,1H),8.53(br s,1H),8.35(s,1H),8.15(s,1H),8.06(br s,1H),6.85(br s,1H),4.35(br s,1H),3.72(s,3H),3.60(br s,1H),3.12~2.57(m,2H),1.85(br d,J=12.4Hz,1H),1.77~1.54(m,1H),1.43(br s,2H),1.34~1.03(m,3H),0.77~0.73(m,3H).

[0470] Example 22. Synthesis of (4,4-difluoropiperidin-1-yl)(1-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-97)

[0471] [ka]

[0472] Step 1: To a solution of 6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (5.00 g, 23.5 mmol, 1.00 equiv.) in MeCN (100 mL) was added isopentyl nitrite (8.25 g, 70.4 mmol, 9.48 mL, 3.00 equiv.) and CuCl2 (9.47 g, 70.4 mmol, 3.00 equiv.). The mixture was stirred at 70° C. for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 3 / 1). The desired fraction was concentrated to obtain compound 6-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (3.6 g, 15.5 mmol, 66% yield) as a white solid. LCMS [ESI,M+1]:233.8

[0473] Step 2: A solution of 6-bromo-2-chloro-[1,2,4]triazolo[1,5a]pyridine (3.00 g, 12.9 mmol, 1.00 equiv) in morpholine (10.0 mL) was stirred at 100° C. for 12 h. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with water (300 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=5 / 1 to 2 / 1). The desired fractions were concentrated to give compound 4-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)morpholine (3.0 g, 10.6 mmol, 82% yield) as a white solid. LCMS [ESI,M+1]:283.0. 1H NMR(400MHz,DMSO-d6) δ=9.06(dd,J=0.8,2.0Hz,1H),7.64(dd,J=2.0,9.2Hz,1H),7.45(dd,J=0.8,9.2Hz,1H),3.73~3.66(m,4H),3.48~3.42(m,4H).

[0474] Step 3: (4,4-Difluoro-1-piperidyl)-(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (2.20 g, 8.29 mmol, 1.00 equiv.), 4-(6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)morpholine (2.58 g, 9.12 mmol, 1.10 equiv.), CuI in DMAC (40 mL). A mixture of KPO (316 mg, 1.66 mmol, 0.20 equiv), KPO (3.52 g, 16.6 mmol, 2.00 equiv), and N1,N2-dimethylcyclohexane-1,2-diamine (1.18 g, 8.29 mmol, 1.00 equiv) was degassed and purged with N3 three times, then the mixture was stirred at 90 °C under N2 atmosphere (15 psi) for 3 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (400 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to 1 / 4). The desired fractions were concentrated to give the compound (4,4-difluoro-1-piperidyl)-[1-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrrolo[2,3-b]pyridin-5-yl]methanone (2.78 g, 5.90 mmol, 71% yield, 99.5% purity) as a white solid. LCMS [ESI,M+1]: 468.1.

[0475] 1H NMR(400MHz,DMSO-d6) δ=9.33(s,1H),8.44(s,1H),8.24(s,1H),8.08(d,J=3.6Hz,1H),8.06~8.01(m ,1H),7.66(d,J=9.2Hz,1H),6.84(d,J=3.6Hz,1H),3.82~3.71(m,4H),3.66(br d,J=4.0Hz,4H),3.52~3.45(m,4H),2.08(br s,4H).

[0476] Example 23. Synthesis of (4,4-difluoropiperidin-1-yl)(1-(2-(pyrrolidin-1-ylmethyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-152)

[0477] [ka]

[0478] Step 1: Synthesis of compound 2: To a solution of 4-bromopicolinaldehyde (1.50 g, 8.06 mmol, 1.00 equiv), pyrrolidine (1.15 g, 16.1 mmol, 1.35 mL, 2.0 q) in MeOH (20.0 mL) was added AcOH (242 mg, 4.03 mmol, 231 μL, 0.50 equiv), followed by NaBH3CN (1.01 g, 16.1 mmol, 2.00 equiv). The mixture was stirred at 20 °C for 4 h. The reaction mixture was quenched with water (10.0 mL) at 0 °C and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% NH3·H2O) and the mixture was lyophilized to give 4-bromo-2-(pyrrolidin-1-ylmethyl)pyridine (980 mg, 3.98 mmol, 49% yield, 98% purity) as a yellow oil. LCMS [ESI,M+1]: 243.1.

[0479] Step 2: A mixture of 4-bromo-2-(pyrrolidin-1-ylmethyl)pyridine (200 mg, 829 μmol, 1.00 equiv), (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (264 mg, 995 μmol, 1.20 equiv), KPO (352 mg, 1.66 mmol, 2.00 equiv), CuI (31.6 mg, 166 mol, 0.20 equiv), and dimethylcyclohexane-1,2-diamine (23.6 mg, 166 μmol, 0.20 equiv) in DMAC (2 mL) was degassed and purged with N three times, then the mixture was stirred at 90 °C under N atmosphere (15 psi) for 3 h. The mixture was diluted with HO (40 mL) and extracted with EA (30 mL×3), and the organic layer was washed with saturated salt solution (30 mL×3), dried over NaSO, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO, ethyl acetate / methanol=10 / 1 to 8 / 1) to give (4,4-difluoropiperidin-1-yl)(1-(2-(pyrrolidin-1-ylmethyl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (189 mg, 440 μmol, 53% yield, 99.3% purity) as a pale yellow solid. LCMS(ESI,M+1):m / z=426.2. 1H NMR(400MHz,DMSO-d6) δ=8.60(br d,J=5.2Hz,1H),8.49(d,J=2.0Hz,1H),8.27~8.26(m,1H),8.25~8.24(m,1H),8.20(s,1H),8.02(br d,J=3.6Hz,1H),6.89(d,J=4.0Hz,1H),3.80(s,2H),3.78~3.44(m,4H),2.56(br s,4H),2.09(br d,J=5.2Hz,4H),1.73(br s,4H).

[0480] Example 24. Synthesis of (1-(2-(1H-pyrazol-4-yl)pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, (B-194)

[0481] [ka]

[0482] Step 1: Synthesis of compound 2: -Bromo-2-iodo-pyridine (450 mg, 1.59 mmol, 1.00 equiv), 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (485 mg, 1.74 mmol, 1.10 equiv), Pd(dppf)Cl (115 mg, 158 μmol, 0.10 equiv), KCO (262 mg, 1.90 mmol, 1.20 equiv) in dioxane (10.0 mL) and HO (2.00 mL) was degassed and purged with N three times, then the mixture was stirred at 50 °C under N atmosphere (15 psi) for 1 h. The reaction mixture was diluted with H2O (30 ml) and EtOAc (30 ml), then filtered, and the filtrate was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 3 / 1) to give 4-bromo-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyridine (225 mg, 657 μmol, 41% yield, 90% purity) as a white oil. LCMS (ESI, M+3): m / z = 310.1.

[0483] Step 2: A mixture of 4-bromo-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)pyridine (225 mg, 730 μmol, 1.20 equiv.), (4,4-difluoro-1-piperidyl)-(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (161 mg, 608 μmol, 1.00 equiv.), CuI (23.1 mg, 121 μmol, 0.20 equiv.), KPO (258 mg, 1.22 mmol, 2.00 equiv.), and (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (17.3 mg, 121 μmol, 0.20 equiv.) in DMAC (5.00 mL) was degassed and purged with N three times, and then the mixture was stirred at 110 °C under N atmosphere for 12 h. The reaction mixture was diluted with H2O (30 ml) and EtOAc (30 ml), then filtered, and the resulting filtrate was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 0 / 1) to give (4,4-difluoro-1-piperidyl)-[1-[2-(1-tetrahydropyran-2-ylpyrazol-4-yl)-4-pyridyl]pyrrolo[2,3-b]pyridin-5-yl]methanone (120 mg, 241 μmol, 40% yield, 99% purity) as a yellow oil. LCMS (ESI, M+1): m / z = 493.3.

[0484] Step 3: To a solution of (4,4-difluoro-1-piperidyl)-[1-[2-(1-tetrahydropyran-2-ylpyrazol-4-yl)-4-pyridyl]pyrrolo[2,3-b]pyridin-5-yl]methanone (120 mg, 243 μmol, 1.00 equiv) in MeOH (0.50 mL) was added HCl / MeOH (4.00 M, 2.00 mL) at 0° C. The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Phenomenex Synergi C18 150×25mm×10um; mobile phase: [water (FA)-ACN]; B%: 11%-41%, 10min) to give (4,4-difluoro-1-piperidyl)-[1-[2-(1H-pyrazol-4-yl)-4-pyridyl]pyrrolo[2,3-b]pyridin-5-yl]methanone (70.0mg, 169μmol, 70% yield, 99% purity) as a white solid. LCM(ESI, m / z1):m / z=501.2.1H NMR(400MHz,DMSO-d6) δ=13.50~12.74(m,1H),8.63(d,J=5.6Hz,1H),8.52(d,J=2.0Hz,1H),8.37(d,J=3.6Hz,1H),8. 29~8.26(m,4H),8.15(dd,J=2.0,5.6Hz,1H),6.93(d,J=3.6Hz,1H),3.90~3.48(m,4H),2.09(br s,4H).

[0485] Example 25. Synthesis of (1-(4-(5-amino-4H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, (B-78)

[0486] [ka]

[0487] To a stirred solution of (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (2 g, 7.57 mmol, 1.0 equiv.) and 4-bromobenzonitrile (2.1 g, 11.36 mmol, 1.5 equiv.) in 1,4-dioxane (10 mL), copper iodide (0.28 g, 1.5 mmol, 0.2 equiv.), DMCD (0.2 g, 1.51 mmol, 0.2 equiv.), and potassium phosphate (3.9 g, 18.7 mmol, 2.5 equiv.) were added under argon gas at room temperature. The reaction mixture was stirred at 80° C. for 16 hours under argon atmosphere. After completion of the reaction, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuum to give the crude compound (4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile 2. It was then purified by column chromatography (100-200 silica mesh) in 20% ethyl acetate-hexane to give the desired compound 2 (1.3 g, 47.3%) as a white solid. ESI-MS (m / z) C 20 H 16 Calculated value for F2N4O: 366.37, Measured value: 367.2 (M+H) + .

[0488] To a stirred solution of 2 (200 mg, 0.54 mmol, 1.0 equiv) in dimethyl sulfoxide at room temperature was added guanidine hydrochloride (62.2 mg, 0.65 mmol, 1.2 equiv), cesium carbonate (266 mg, 0.65 mmol, 1.2 equiv), and copper bromide (3.9 mg, 0.027 mmol, 0.05 equiv). The reaction mixture was stirred at 120° C. for 16 h. After completion of the reaction, it was quenched with water. It was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness in vacuum to give the crude product, which was then purified by column chromatography (100-200 silica mesh) in 60% ethyl acetate-hexane to give the desired compound (1-(4-(5-amino-4H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone (12 mg, 2.8%) as a white solid. ESI-MS (m / z) C 21 H 19 Calculated value for F2N7O: 423.43, Measured value: 424.1 (M+H) + ;HPLC purity:97.23%; 1 H NMR(300MHz,DMSO-d6):δ / ppm 12.11(s,1H),8.44~8.43(d,J=1.8Hz,1H),8.23~8.22(d,J=3.6Hz,1H),8.11~8.10(d,J=3.6H z,1H),8.06~7.95(m,4H),6.84~6.82(d,J=3.9Hz,1H),6.13(s,2H),3.65(s,4H),2.08(s,4H).

[0489] Example 26. Synthesis of (4,4-difluoropiperidin-1-yl)(1-(4-(5-morpholino-4H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone, (B-67)

[0490] [ka]

[0491] Morpholine (0.875 g, 10 mmol, 1 equiv.) was added to a stirred solution of 1H-pyrazole-1-carboxamidine hydrochloride (1.46 g, 10 mmol, 1 equiv.) and DIPEA (1.7 mL, 11 mmol, 1.1 equiv.) in DMF (5 mL). The reaction mixture was stirred at ambient temperature for 3 h. The resulting precipitate was filtered, washed with Et2O (10 mL x 2) and dried in open air to give morpholine-1-carboximidamide (0.7 g, 54%, white solid). ESI-MS (m / z) CH 11 Calculated C for N3O: 129.16; Found: 130.1 [M+H] + NMR (300MHz, DMSO-d6): δ / ppm 7.64 (s, 1H), 3.64~3.63 (m, 1H), 3.42~3.36 (m, 1H).

[0492] To a stirred solution of 4-bromobenzonitrile (0.76 g, 4.15 mmol, 1.1 equiv.) and (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (1.0 g, 3.7 mmol, 1.0 equiv.) in 1,4-dioxane (25 mL), copper iodide (145 mg, 0.75 mmol, 0.2 equiv.), DMCD (108 mg, 0.75 mmol, 0.2 equiv.), and potassium phosphate (1.6 g, 7.54 mmol, 2 equiv.) were added at room temperature under argon gas. The reaction mixture was stirred at 110° C. for 16 hours under argon atmosphere. After completion of the reaction, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuum to give the crude intermediate, which was then purified by column chromatography (100-200 mesh) in 5% ethyl acetate-hexane to give the desired compound 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (915 mg, 60% yield, white solid). ESI-MS (m / z) C 20 H 16 Calculated value for F2N4O: 366.37, found value: 367.0. [M+H] +NMR (300MHz, DMSO-d6): δ / ppm 8.47(s,1H),8.27(m,2H),8.24(m,2H),8.06~8.03(m,2H),6.90~6.89(m,1H),3.64(bs,4H),2.12~2.03(m,4H).

[0493] Morpholine-1-carboximidamide (250 mg, 1.93 mmol, 1.1 equiv.) was added to a stirred solution of 4-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (644 mg, 1.76 mmol, 1 equiv.), cesium carbonate (2.3 g, 7.0 mmol, 3.6 equiv.), and copper(I) bromide (250 mg, 1.76 mmol, 1 equiv.) in DMSO (10 mL) and refluxed in air for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature and the contents were poured onto crushed ice (100 g). The resulting solid was filtered, washed well with cold water, and dried in air. The crude thus obtained was purified by column chromatography on silica gel (100-200 mesh) using ethyl acetate:hexane (12:88) as eluent to obtain the desired compound (4,4-difluoropiperidin-1-yl)(1-(4-(5-morpholino-4H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methanone. The obtained compound was purified by preparative HPLC. (Yield: 45.97 mg, 6%) as a white solid. ESI-MS (m / z) C 25 H 25 Calculated value of F2N7O2: 493.52, measured value: 492.1 [MH] + . HPLC purity: 86.9%; 1 H NMR(300MHz,DMSO-d6):δ / ppm 12.81(s,1H),8.44(s,1H),8.23(s,1H),8.15~8.14(m,1H),8.09~8.07(m,3H,),7.98 ~7.95(m,2H),6.84~6.82(m,1H),3.73~3.71(m,8H),3.39(m,4H),2.07~2.03(m,4H).

[0494] Example 27. Synthesis of (1-(3-(4H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone, (B-36)

[0495] [ka]

[0496] To a solution of (4,4-difluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (282 mg, 1.06 mmol, 1.00 equiv.), 3-iodobenzonitrile (292 mg, 1.28 mmol, 1.20 equiv.) in DMA (3 mL) was added CuI (40.5 mg, 213 μmol, 0.20 equiv.), dimethylcyclohexane-1,2-diamine (30.2 mg, 213 μmol, 0.20 equiv.), and K3PO4 (451 mg, 2.13 mmol, 2.00 equiv.). The mixture was stirred at 120° C. for 3 h. The mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give 3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (220 mg, 558 μmol, 52.5% yield, 93.5% purity) as a yellow solid. LCMS (ESI, M+1): m / z=367.2.

[0497] To a solution of 3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzonitrile (200 mg, 546 μmol, 1.00 equiv) in DMSO (2 mL) was added K2CO3 (113 mg, 819 μmol, 1.50 equiv) and H2O2 (9.63 g, 85.0 mmol, 8.16 mL, 30% purity, 156 equiv). The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with saturated Na2SO3 and extracted with EA (5 mL × 3). The combined organic layers were washed with brine (20 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (200 mg, crude) as a yellow solid. LCMS (ESI, M+1): m / z = 385.1.

[0498] A stirred solution of 3-(5-(4,4-difluoropiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)benzamide (200 mg, 520 μmol, 1.00 equiv) in DMF-DMA (1.79 g, 15.1 mmol, 2 mL, 28.9 equiv) was stirred at 80 °C for 1.5 h. Volatiles were removed and AcOH (4.20 g, 69.9 mmol, 4 mL, 134 equiv) was added to the reaction mixture, followed by dropwise addition of NH2NH2·H2O (0.65 g, 13.0 mmol, 631 μL, 25.0 equiv). The resulting mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with saturated Na2SO3 and extracted with EA (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give (1-(3-(4H-1,2,4-triazol-3-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)(4,4-difluoropiperidin-1-yl)methanone (104 mg, 250 μmol, 50.9% yield, 98% purity) as a white solid. LCMS (ESI, M+1): m / z=409.2. 1H NMR(400MHz,DMSO-d6) δ=14.39~14.13(m,1H),8.73~8.48(m,2H),8.45(d,J=2.0Hz,1H),8.24(d,J=2.0 Hz,1H),8.12(d,J=3.6Hz,1H),8.03(d,J=7.6Hz,1H),7.96~7.87(m,1H),7.68(br t,J=8.0Hz,1H),6.85(d,J=3.6Hz,1H),3.79~3.48(m,4H),2.15~2.01(m,4H)

[0499] Representative procedure for the synthesis of sulfides

[0500] Example 28. Synthesis of 5-(cyclopropylmethylsulfinyl)-1-[4-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridine, (B-259)

[0501] [ka]

[0502] Step 1: Synthesis of compound 2: To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (6.00 g, 30.4 mmol, 1.00 equiv) in THF (100 mL) was added NaH (2.44 g, 60.9 mmol, 60% purity, 2.00 equiv) and SEM-Cl (10.1 g, 60.9 mmol, 10.7 mL, 2.00 equiv). The mixture was stirred at 0 °C for 1 h. The mixture was poured into NH4Cl (100 mL) and extracted with EA (200 mLX3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and the mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, PE / EA=50 / 1-10 / 1) to obtain the compound 2-[(5-bromopyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (8.80 g, 26.6 mmol, yield 87%, purity 99%) as an off-white oil.

[0503] LCMS(ESI,M+3):m / z=329.1.

[0504] Step 2: Synthesis of compound 3: A solution of 2-[(5-bromopyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (8.80 g, 26.8 mmol, 1.00 equiv.), methyl 3-sulfanylpropanoate (4.85 g, 40.3 mmol, 4.37 mL, 1.50 equiv.), Pd2(dba)3 (1.55 g, 2.69 mmol, 0.10 equiv.), Xantphos (3.11 g, 5.38 mmol, 0.20 equiv.), and DIEA (6.95 g, 53.7 mmol, 9.37 mL, 2.00 equiv.) in dioxane (140 mL) was degassed and purged with N2 three times, then the mixture was stirred at 90 °C under N2 atmosphere (15 psi) for 3 h. The reaction was diluted with EA (200 mL) and quenched with H2O (100 mL). The mixture was extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with saturated H2O (3 x 100 mL) and brine (200 mL), then dried over Na2SO4. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 3 / 1) to give the compound methyl 3-[1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-5-yl]sulfanylpropanoate (4.80 g, 12.9 mmol, yield 48%, purity 99%) as an off-white oil.

[0505] LCMS(ESI,M+1):m / z=367.2.

[0506] Step 3: Synthesis of compound 4: To a solution of methyl 3-[1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-5-yl]sulfanylpropanoate (4.75 g, 12.9 mmol, 1.00 equiv) in MeOH (50.0 mL) was added NaOMe (2.10 g, 38.8 mmol, 3.00 equiv). The mixture was stirred at 20° C. for 2 h. The mixture was poured into NaHCO3 (60 mL) and extracted with EA (100 ml×3). The combined organic layers were washed with brine (100 mL) and dried over Na2SO4, then the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, PE / EA=50 / 1-5 / 1) to obtain the compound 1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-thiol (2.00 g, 6.63 mmol, yield 51%, purity 93%) as a white oil.

[0507] LCMS(ESI,M+1):m / z=281.1.

[0508] 1 H NMR(400MHz,DMSO-d6) δ=8.21(d,J=2.4Hz,1H),7.97(d,J=2.0Hz,1H),7.63(d,J=3.6Hz,1H),6.46(d,J=3.2Hz,1 H),5.58(s,2H),5.31(s,1H),3.51~3.46(m,2H),0.82~0.77(m,2H),-0.11~-0.13(m,9H).

[0509] Step 4: Synthesis of compound 5: To a solution of 1-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridine-5-thiol (500 mg, 1.78 mmol, 1.00 equiv) and bromomethylcyclopropane (481 mg, 3.57 mmol, 341 μL, 2.00 equiv) in DMSO (10.0 mL), K2CO3 (492 mg, 3.57 mmol, 2.00 equiv) was added. The mixture was stirred at 20 °C for 2 h. The mixture was poured into H2O (40 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4, then the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, PE / EA=50 / 1-5 / 1) to give 2-[[5-(cyclopropylmethylsulfanyl)pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 1.48 mmol, yield 83%, purity 99%) as a yellow oil.

[0510] LCMS(ESI,M+1):m / z=335.2.

[0511] 1 H NMR(400MHz,DMSO-d6) δ=8.33(d,J=2.0Hz,1H),8.12(d,J=2.4Hz,1H),7.66(d,J=3.6Hz,1H),6.51(dd,J=1.6,3.6Hz,1H),5.61(s,2H),3 .49(t,J=7.6Hz,2H),2.84(d,J=6.8Hz,2H),0.98~0.88(m,1H),0.80(t,J=8.4Hz,2H),0.50~0.39(m,2H),0.13(br d,J=4.8Hz,2H),-0.12(d,J=1.6Hz,9H).

[0512] Step 5: Synthesis of compound 6: To a solution of 2-[[5-(cyclopropylmethylsulfanyl)pyrrolo[2,3-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 1.49 mmol, 1.00 equiv) in DCM (1.00 mL) was added TFA (1.28 g, 11.2 mmol, 833 μL, 7.53 equiv). The mixture was stirred at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give [5-(cyclopropylmethylsulfanyl)pyrrolo[2,3-b]pyridin-1-yl]methanol (350 mg, crude) as a yellow oil.

[0513] LCMS(ESI,M+1):m / z=235.0.

[0514] Step 6: Synthesis of compound 7: To a solution of [5-(cyclopropylmethylsulfanyl)pyrrolo[2,3-b]pyridin-1-yl]methanol (350 mg, crude) in MeOH (3.00 mL) was added NH3·H2O (3.98 g, 28.4 mmol, 4.37 mL, 25% purity, 19.0 equiv). The mixture was stirred at 20 °C for 2 h. After cooling to room temperature, the mixture was concentrated. The residue was diluted with EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3 × 10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, PE / EA=20 / 1-2 / 1) to give 5-(cyclopropylmethylsulfanyl)-1H-pyrrolo[2,3-b]pyridine (280 mg, 1.23 mmol, yield 82%, purity 90%) as a white solid.

[0515] LCMS(ESI,M+1):m / z=205.0.

[0516] Step 7: Synthesis of compound 8: To a solution of 5-(cyclopropylmethylsulfanyl)-1H-pyrrolo[2,3-b]pyridine (280 mg, 1.37 mmol, 1.00 equiv) in DCM (10.0 mL) was added m-CPBA (278 mg, 1.37 mmol, 85% purity, 1.00 equiv). The mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with DCM (30 mL) and saturated Na2SO3 (10 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with saturated brine (10 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EA=10 / 1 to 1 / 1) to obtain 5-(cyclopropylmethylsulfinyl)-1H-pyrrolo[2,3-b]pyridine (280 mg, 1.19 mmol, yield 87%, purity 94%) as a white solid.

[0517] LCMS(ESI,M+1):m / z=221.0.

[0518] Step 8: Synthesis of compound 9: A mixture of 5-(cyclopropylmethylsulfinyl)-1H-pyrrolo[2,3-b]pyridine (140 mg, 635 μmol, 1.00 equiv.), 3-(4-iodophenyl)-4-tetrahydropyran-2-yl-1,2,4-triazole (270 mg, 762 μmol, 1.20 equiv.), CuI (24.2 mg, 127 μmol, 0.20 equiv.), KPO (134 mg, 635 μmol, 1.00 equiv.), and (1R,2R)-N,N-dimethylcyclohexane-1,2-diamine (90.4 mg, 635 μmol, 1.00 equiv.) in DMAC (5.00 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 90 °C for 12 h (15 psi). The mixture was poured into H2O (20 mL) and extracted with EA (40 mLX3). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4, then the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, PE / EA=10 / 1 to 0 / 1) to give 5-(cyclopropylmethylsulfinyl)-1-[4-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridine (260 mg, 540 μmol, yield 85%, purity 93%) as a white solid.

[0519] LCMS(ESI,M+1):m / z=448.2.

[0520] Step 9: Synthesis of 5-(cyclopropylmethylsulfinyl)-1-[4-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridine, (B-259): To a solution of 5-(cyclopropylmethylsulfinyl)-1-[4-(4-tetrahydropyran-2-yl-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridine (210 mg, 469 μmol, 1.00 equiv.) in MeOH (21.0 mL) was added TsOH (121 mg, 703 μmol, 1.50 equiv.). The mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the mixture was concentrated. The residue was diluted with EtOAc (10 mL) and water (10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150×40 mm×15 um; mobile phase: [water (FA)-ACN]; B%: 24%-54%, 10 min) to give 5-(cyclopropylmethylsulfinyl)-1-[4-(4H-1,2,4-triazol-3-yl)phenyl]pyrrolo[2,3-b]pyridine (110 mg, 299 μmol, yield 64%, purity 99%) as a white gum.

[0521] LCMS(ESI,M+1):m / z=364.0.

[0522] 1 H NMR(400MHz,DMSO-d6) δ=14.71~13.65(m,1H),8.59(d,J=2.0Hz,2H),8.45(d,J=2.0Hz,1H),8.23~8.16(m,3H),8.07(br s,2H),6.91(d,J=3.6Hz,1H),3.04~2.89(m,2H),0.97~0.87(m,1H),0.54(br dd,J=1.6,8.0Hz,2H),0.29(br t,J=6.0Hz,2H).

[0523] Further representative compounds of the disclosure are made by the routes and schemes of Examples 1-28.

[0524] Analytical data for the compounds described herein can be found in Table 3.

[0525] [Table 4-1]

[0526] [Table 4-2]

[0527] [Table 4-3]

[0528] [Table 4-4]

[0529] [Table 4-5]

[0530] [Table 4-6]

[0531] [Table 4-7]

[0532] [Table 4-8]

[0533] [Table 4-9]

[0534] [Table 4-10]

[0535]

Table 4-11

[0536]

Table 4-12

[0537]

Table 4-13

[0538]

Table 4-14

[0539]

Table 4-15

[0540]

Table 4-16

[0541]

Table 4-17

[0542]

Table 4-18

[0543]

Table 4-19

[0544]

Table 4-20

[0545] [Table 4-21]

[0546] [Table 4-22]

[0547] [Table 4-23]

[0548] [Table 4-24]

[0549] [Table 4-25]

[0550] [Table 4-26]

[0551] [Table 4-27]

[0552] Biological Examples Example B-1: Example B-1 hPGDH inhibitor screening biochemical assay

[0553] Hydroxyprostaglandin dehydrogenase inhibitor screening biochemical assays can be carried out to evaluate the inhibitors synthesized herein. Provided herein are exemplary biochemical assays for screening hPGDH inhibitors.

[0554] In vitro biochemical assays can be performed in white 384-well plates in a total reaction volume of 20 μl consisting of 10 nM 15-PGDH / HPGD (R&D System#5660-DH), 15 mM prostaglandin E2 (Sigma, Cat. No. P5640-10MG) and 0.25 mM b-nicotinamide adenine dinucleotide sodium salt (Sigma, Cat. No. N0632-5G) in a 10-point dose-response curve of test / tool ​​compound made in reaction buffer (50 mM Tris-HCl, pH 7.5, 0.01% Tween 20). Briefly, 5 μl (4×) of compound solution and 5 μl (final concentration, 10 nM) of enzyme solution are added to a white 384-well plate and incubated at 37° C. for 10 min. 5 mL (4x) of prostaglandin E2 and 5 mL (4x) of b-nicotinamide adenine dinucleotide sodium salt are added to the wells and incubated for 10 min at room temperature. Fluorescence is recorded at ex / em = 340 nm / 485 nm. The percentage (%) of inhibition of enzyme activity was determined against a positive control (1% DMSO) and IC50 was calculated using GraphPad Prism software (4 parameters - variable slope equation). Exemplary data are shown in Table 4.

[0555] [Table 5-1]

[0556] [Table 5-2]

[0557] Example B-2: Further biochemical assays

[0558] Cell-Based Assays: 15-PGDH is highly expressed in quiescent human lung adenocarcinoma cells (A549) (Tong et al., 2006), and this cell line was used to evaluate 15-PGDH inhibition by MF-300Na in vitro.

[0559] In this assay, A549 cells are treated with interleukin (IF) 1β, which induces the expression of cycloxygenase-2 and the synthesis of PGE2 (Tong et al., 2006). In studies evaluating test articles, 30,000 A549 cells were seeded in 100 μL of F12K complete medium and incubated at 37 °C with 5% CO2 for 24 h, followed by serum starvation for 24 h. On the day of the experiment, the buffer was replaced with complete medium, and the cells were incubated with compound for 30 min, followed by addition of IF-1β (final concentration 0.1–0.25 ng / mF) overnight at 37 °C with 5% CO2. Each concentration was run in triplicate. In this assay, tool compounds increased PGE2 in the supernatant, and the half-maximal effective concentration (EC50) was calculated for each compound. PGE2 was detected in the supernatant and quantified using Cisbio HTRF technology (homogeneous time-resolved fluorescence) kit (62P2APEG-62P2APEH) according to the manufacturer's recommendations to quantify the fold induction of PGE2 in cells treated with IF-1β test articles versus treatment with IF-1β alone.

[0560] Representative data are shown in Table 5.

[0561] [Table 6]

[0562] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are within the spirit and scope of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

Claims

Compound having the structure of formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein: 【Chemical 1】 In the formula: X₂ is N, NR₃A, or CR₃A; X₃ is N or CR₃B; X₄ is N, NR₃C, or CR₃C; R₃A, R₃B, and R₃C are each independently H, halogen, -CN, -NR₈R₉, -OR₁₀, CN, -C(O)R₁₀, -C(O)OR₁₀, -C(O)NR₈R₉, -SOR₁₁, -SO₂R₁₁, -SO₂NR₈R₉, -NR₁₂C(O)R₁₀, -NR₁₂C(O)OR₁₀, -NR₁₂C(O)NR₈R₉, -NR₁₂SO₂R₁₀, -NR₁₂SO₂NR₈R₉, -OC(O)NR₈R₉, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆ haloalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ heterocycloalkyl, substituted or unsubstituted C₆ aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl; Or R₃A and R₃B together with the atoms to which they are attached form a substituted or unsubstituted 5- to 6-membered heteroaryl; Or R₃B and R₃C together with the atoms to which they are attached form a substituted or unsubstituted 5- to 6-membered heteroaryl; R₃A, R₃B, and R₃C are not all H at the same time; Compound, or a pharmaceutically acceptable salt or solvate thereof. Compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein one of X₂, X₃, or X₄ is N. Compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein X₂ is N, X₃ is CR₃B, and X₄ is CR₃C; or X₂ is CR₃A, X₄ is N, and X₃ is CR₃B; or X₂ is CR₃A, X₃ is CR₃B, and X₄ is N. **Claim 4**: The R3A, R3B, and R3C are each independently H, halogen, -CN, -C(O)R10, -C(O)OR10, -C(O)NR8R9, -NR12C(O)R10, -NR12C(O)OR10, -NR12C(O)NR8R9, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C6 aryl, or substituted or unsubstituted 5- to 10-membered heteroaryl, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof. **Claim 5**: The R3A and R3B, together with the atoms to which they are attached, optionally form a substituted or unsubstituted 5- to 6-membered aryl or heteroaryl optionally containing one, two or three heteroatoms selected from O, S, and N, or the R3B and R3C, together with the atoms to which they are attached, optionally form a substituted or unsubstituted 5- to 6-membered aryl or heteroaryl optionally containing one, two or three heteroatoms selected from O, S, and N, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof. **Claim 6**: The X2 is N, the R3B is H, and the R3C is -C(O)R10, -C(O)OR10, -C(O)NR8R9, -NR12C(O)OR10, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl, or the R3B is -C(O)R10, -C(O)OR10, -C(O)NR8R9, -NR12C(O)OR10, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl, and the R3C is H, the compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof. **Claim 7**: The X4 is N, R3A is H, and R3B is -C(O)R10, -NR12C(O)OR10, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl, or R3B is H, and R3A is -C(O)R10, -C(O)OR10, -C(O)NR8R9, -NR12C(O)OR10, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl, the compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof.

8. R3A and R3B are each H, and R3C is -C(O)R10, -NR12C(O)OR10, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl, or R3A and R3C are each H, and R3B is -C(O)R10, -NR12C(O)OR10, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl, or R3B and R3C are each H, and R3A is -C(O)R10, -NR12C(O)OR10, substituted or unsubstituted C3-C8 heterocycloalkyl, or substituted or unsubstituted 5-membered heteroaryl, the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

9. One of R3A, R3B, or R3C is substituted or unsubstituted 5-membered heteroaryl, and the 5-membered heteroaryl is triazinyl, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl, the compound according to claim 5, or a pharmaceutically acceptable salt or solvate thereof.

10. One of R3A, R3B, or R3C is [Chemical Formula 2] represented by the moiety of wherein Y5 is NR15A, S, or O. Y6, Y7, and Y8 are each independently N or CR15, R15 is H, halogen, -NR8R9, -C1-C6 alkyl, C1-C6 haloalkyl, substituted or unsubstituted C3-C8 cycloalkyl, or substituted or unsubstituted C3-C8 heterocycloalkyl, The compound according to claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R15A is H or C1-C6 alkyl.

11. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein W is -CR6R6-.

12. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein each R6 is independently H, halogen, -NR8R9, -OR10, -C(O)R10, -C(O)OR10, -C(O)NR8R9, or substituted or unsubstituted C1-C6 alkyl, and q is 1 or 2.

13. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2, and m is 0 or 1.

14. 【Fig. 3】 is 【Chemical 4】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

15. R1 is H, or substituted or unsubstituted C1-C6 alkyl, R2 is H, or substituted or unsubstituted C1-C6 alkyl, The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is H.

16. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

17. Use of the compound according to claim 1 in the manufacture of a medicament for inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need of inhibition of 15-PGDH.

18. Use of the compound according to claim 1 in the manufacture of a medicament for use in a method of treating and / or preventing myopathy, muscle injury and / or muscle atrophy in a subject in need of treatment and / or prevention of myopathy, muscle injury and / or muscle atrophy.

19. The muscle disorder is Duchenne muscular dystrophy, Becker muscular dystrophy, Fukuyama congenital muscular dystrophy, limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, amyotrophic lateral sclerosis, distal muscular dystrophy, hereditary muscle disease, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, Emery-Dreifuss muscular dystrophy, congenital myotonia, mitochondrial myopathy, myotubular myopathy, myasthenia gravis, periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, stress-induced urinary incontinence, urethral sphincter deficiency, or sarcopenia, the use according to Claim 18.

20. Use of the compound according to Claim 1 in the manufacture of a medicament for use in treating and / or preventing a fibrotic disease or disorder in a subject in need of treatment and / or prevention of a fibrotic disease or disorder, wherein the fibrotic disease or disorder is pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitis, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by an infectious agent, pulmonary fibrosis caused by inhalation of a toxic gas, aerosol, chemical dust, smoke or vapor, drug-induced interstitial lung disease, or pulmonary hypertension.

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