Heterocyclic compounds that regulate NR2F6

Abstract

The present invention provides compounds capable of modulating NR2F6 activity, which may be used in methods for the prevention and / or treatment of diseases and disorders related to the regulation of NR2F6 activity. [Solution] The present invention provides a compound represented by formula (IA) or (II-A), or a pharmaceutically acceptable salt and tautomer thereof. JPEG2026090264000398.jpg45170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 981,418, filed on 25 February 2020, and U.S. Provisional Patent Application No. 63 / 139,262, filed on 19 January 2021, the contents of which these provisional applications are incorporated herein by reference in their entirety.

[0002] Disclosure technology This disclosure relates to compounds capable of modulating the activity of NR2F6. The compounds of this disclosure may be used in methods for preventing and / or treating diseases and disorders associated with the modulation of NR2F6 activity. [Background technology]

[0003] Background of Disclosure Nuclear receptor subfamily 2 group F member 6 (NR2F6), also known as nuclear receptor Ear2 and COUP-TFIII, is an orphan member of the ligand-activated receptor nuclear receptor (NR) superfamily. NRs exhibit a common modular structure and play a crucial role in homeostasis. Dysregulation of NR function has been linked to several pathological conditions, including cancer, inflammation, and metabolic syndrome.

[0004] NR2F6 regulates target gene expression through different mechanisms and competes with other NRs, such as RAR, for heterodimerization with RXR. Similar mechanisms have been reported for thyroid hormone nuclear receptors (TRs), but direct interaction between NR2F6 and TRs leads to T3-dependent activation of a reduced TR basal state. NR2F6 activity plays a crucial role as a transrepressor through direct binding to other NRs.

[0005] NR2F6 limits the activation of the immune system by suppressing the expression of inflammatory cytokines such as IL-2, TNFα, IFNγ, and IL-17. Their downregulation is mediated by a direct interaction between NR2F6 and activated T cell nuclear factor (NFAT) / AP-1. NR2F6 and NFAT compete at the same locus. Furthermore, NR interacts with NFAT, preventing it from binding to the DNA response element. NR2F6 also competes with RORγ (NR1F3) at the same locus (i.e., IL-17a). Mutagenesis studies have revealed that the activity of the NR2F6 trans-repressor depends on the integrity of both its DNA-binding and ligand-binding domains. Post-translational modifications (i.e., phosphorylation) modulate NR2F6 function.

[0006] Immunotherapy utilizes small molecule compounds, monoclonal antibodies, cell therapies, and their pharmaceutical compositions to modulate both adopted and naturally acquired immune systems. Immunotherapy has been successfully applied in various therapeutic areas, including oncological and autoimmune diseases.

[0007] NR2F6 plays a crucial role in immune-mediated cancer surveillance. NR2F6-deficient mice exhibit a favorable immune configuration for antitumor responses, for example, through the upregulation of IL-17 and other inflammatory cytokines (TNFα, IFNγ, and IL-2) in both CD4+ and CD8+ cells. Therefore, NR2F6 controls the amplitude of tumor immunity and acts as a novel, potentially promising immune checkpoint for anticancer therapy.

[0008] NR2F6 crosstalks with other immune checkpoints. For example, disruption of the NR2F6 gene leads to increased expression of PD-L1 in immune cells. Furthermore, adoptive cell therapy (ACT) that achieves acute NR2F6 knockout, in addition to embryonic NR2F6 knockout, exhibits synergistic anticancer effects when combined with the blockade of other immune checkpoints (i.e., PD-L1, CTLA-4). Both inhibition and downregulation of NR2F6 can increase the efficacy of immune checkpoint inhibitors.

[0009] Genomic studies have identified NR2F6 as a central protein regulating cell differentiation. NR2F6 plays a crucial role in maintaining clonality within the leukemia cell hierarchy. Furthermore, while NR2F6 is overexpressed in undifferentiated cancer stem cells, its disruption leads to differentiation and consequently increases the rate of apoptosis.

[0010] NR2F6 KO mice are highly susceptible to inflammatory conditions (i.e., experimental autoimmune encephalomyelitis (EAE)), and they exhibit both faster onset and generally higher clinical scores compared to wild-type mice. NR2F6 KO mice are also characterized by a greater number of CNS-infiltrating IL-17-IFNγ double-positive CD4+ effector T cells and hyperresponsive Th17 cells.

[0011] NR2F6 activity is important for gut homeostasis, in addition to regulating immunity and inflammation. NR2F6 transactivates genes that contribute to maintaining the gut barrier, such as Muc2. NR2F6 gene disruption exacerbates the condition in a colitis mouse model compared to wild-type mice, and Nr2f6- / - mice show increased susceptibility to DSS-induced colitis compared to wild-type mice, characterized by an exacerbated clinical disease phenotype and enhanced immune cell infiltration. Nr2f6- / - CD4 +T cells are not the primary cause of increased colitis and disease pathology. Rather, loss of NR2F6 in colonic epithelial cells increases intestinal permeability, which leads to idiopathic colitis in Nr2f6-deficient mice. NR2F6 directly transactivates Muc2 expression via the human colon cancer cell line LoVo and primary mouse colonic epithelial cells. Loss of NR2F6 alters intestinal permeability, resulting in idiopathic delayed-onset colitis in Nr2f6-deficient mice. Selective agonists of NR2F6 may represent a novel therapeutic strategy in the treatment of specific types of human IBD.

[0012] Therefore, NR2F6 modulation represents a novel approach to modulate adoptive and innate immunity in several diseases (including cancer) and immune-related disorders (such as autoimmune diseases), and to increase the efficacy of immune checkpoint inhibitors and adoptive cell therapies. Furthermore, NR2F6 also modulates gastrointestinal diseases. This disclosure relates, in certain embodiments, to small molecule compounds capable of modulating NR2F6 activity and methods of using the same pharmaceutical compositions, as well as methods for producing the same compounds and pharmaceutical compositions. [Overview of the Initiative]

[0013] Summary of Disclosure This disclosure relates to compounds represented by formula (IA) or (II-A): [ka] Furthermore, the present invention provides pharmaceutically acceptable salts and tautomers thereof, in which formula: each [ka] These independently represent a single bond or a double bond; X is N, NH, C, CH, or CH2; R 1 H, C 1-6 Alkyl, cycloalkyl, heterocyclyl, -C(O)R 1a, -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where R 1a is C 1-6 alkyl; and where -CH2-aryl, -CH2-heteroaryl, aryl, and heteroaryl are optionally substituted by C 1-6 alkyl or halo; A is alkyl, cycloalkyl, heterocyclyl, fused bicyclic aryl, fused bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where aryl or heteroaryl is optionally substituted by aryl, heteroaryl, -Y A -aryl, or -Y A -heteroaryl; where Y A is -O-, -C(O)-, -N(R A1 )-, S(O)-, or -S(O)2-; where R A1 is H or C 1-6 alkyl; where fused bicyclic aryl, fused bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, and each heteroaryl are optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, -CN, -N(R A )2, -OH, and -O-alkyl; where each R A is independently H or C 1-6 alkyl; L 1 is -C(O)-NR L1 -, -O-C(S)-NR L1 -, -O-C(O)-NR L1 -, -NR L1 -C(O)-, -NR L1 -C(O)-O-, -NH-C(O)-NH-, -NR L1 -C(S)-NR L1 -, -NR L1 -S(O)2-, -S(O)2-NR L1 -, -CH2-CH2-, -CH2-NR L1 -, -NR L1-CH2-, -CH2-O-, -O-CH2-, -O-, -NH-, -C(O)-azetidinyl, -CH2-NR L1 -C(O)-, -C(O)-NR L1 -CH2- or -C(O)-; where each R L1 H or C 1-6 Alkyl; and as L 2 is -C(O)-NR L2 -, -S(O)2-NR L2 -, -CH2-CH2-, -C(S)-NR L2 -, -C(O)-, or -S(O)2-; where each R L2 H or C 1-6 Alkyl; and as B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, an aryl, a heteroaryl, a cycloalkyl, a -CH2-heterocyclyl, or a heterocyclyl, where aryl, heteroaryl, cycloalkyl, or heterocyclyl is aryl, heteroaryl, -Y B -Aryl, -Y B -heteroaryl, -Y B -Optionally substituted with a heterocyclyl or cycloalkyl group; where Y B -O-, -CH2-, -C(O)-, -N(R B1 )-, -S(O)-, or -S(O)2-; where R B1 is H or C 1-6 It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, each heteroaryl, each cycloalkyl, -CH2-heterocyclyl, and each heterocyclyl are alkyl, halo, haloalkyl, -CN, -N(R) B2 ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, -O-alkyl, and oxo; where each R B2 H or C 1-6 It is alkyl; Here, the compound is of formula (IA); A is an optionally substituted phenyl or thiophenyl, and L 1 If is -C(O)-NH-, then B is [ka] Not; Here, the compound is of formula (IA); A is phenyl, and L 1 If is -C(O)-NH-, then B is [ka] Not; Here, if the compound is of formula (IA); A is a substituted phenyl and B is a substituted phenyl, then L 1 This is not -C(O)-NH-, -NH-C(O)-, -NCH3-C(O)-, or -NH-C(O)-NH; Here, the compound is given by formula (IA); L 1 -C(O)-NR L1 -CH2- and B is optionally substituted phenyl, substituted pyridyl, or [ka] If; A is a substituted phenyl, substituted pyridyl, substituted thiophenyl, substituted thiazolyl, substituted pyrazolyl, [ka] Not; Here, the compound is of formula (IA); B is an optionally substituted -CH2-aryl, and A is an optionally substituted aryl; L 1 It is not -C(O)-NH-; Here, if the compound is of formula (II-A); A is an optionally substituted phenyl, and B is an optionally substituted phenyl, then L 1 It is not -C(O)-NCH3-.

[0014] This disclosure relates to compounds represented by formula (I) or (II): [ka] The present invention also provides pharmaceutically acceptable salts and tautomers thereof, in which formula: each [ka] These independently represent single or double bonds; X is N, NH, C, CH, or CH2; R 1 H, C 1-6 Alkyl, cycloalkyl, heterocyclyl, -C(O)R 1a , -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where R 1a C1-6 alkyl; and where -CH2-aryl, -CH2-heteroaryl, aryl, and heteroaryl are C 1-6 Optionally substituted with alkyl or halo; A is an alkyl, cycloalkyl, heterocyclyl, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where aryl or heteroaryl is aryl, heteroaryl, -Y A -aryl, or -Y A -Optionally substituted by a heteroaryl; where Y A -O-, -C(O)-, -N(R A1 )-, -S(O)-, or -S(O)2-; where R A1 is H or C 1-6 It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, and each heteroaryl are alkyl, halo, -CN, -N(R) A ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R A H or C1-6 is alkyl; L 1 is -C(O)-NR L1 -, -O-C(S)-NR L1 -, -O-C(O)-NR L1 -, -NR L1 -C(O)-, -NR L1 -C(O)-O-, -NH-C(O)-NH-, -NR L1 -C(S)-NR L1 -, -NR L1 -S(O)2-, -S(O)2-NR L1 -, -CH2-CH2-, -CH2-NR L1 -, -NR L1 -CH2-, -CH2-O-, -O-CH2-, -O-, -NH-, -C(O)-azetidinyl, -CH2-NR L1 -C(O)-, or -C(O)-NR L1 -CH2-; wherein each R L1 is independently H or C 1-6 alkyl; and L 2 is -C(O)-NR L2 -, -S(O)2-NR L2 -, -CH2-CH2-, -C(S)-NR L2 -, -C(O)-, or -S(O)2-; wherein each R L2 is independently H or C 1-6 alkyl; and B is fused bicyclic aryl, fused bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, aryl, heteroaryl, cycloalkyl, or -CH2-heterocyclyl, wherein the aryl or heteroaryl is optionally substituted by aryl, heteroaryl, -Y B -aryl, or -Y B -heteroaryl; wherein Y B is -O-, -C(O)-, -N(R B1 ), -S(O)-, or -S(O)2-; wherein R B1 is H or C 1-6 alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, each heteroaryl, cycloalkyl, and -CH2-heterocyclyl are alkyl, halo, -CN, -N(R) B2 ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R B2 H or C 1-6 It is alkyl; Here, the compound is of formula (I); A is an optionally substituted phenyl or thiophenyl, and L 1 If is -C(O)-NH-, then B is [ka] Not; Here, if the compound is of formula (I); A is a substituted phenyl and B is a substituted phenyl, then L 1 This is not -C(O)-NH-, -NH-C(O)-, -NCH3-C(O)-, or -NH-C(O)-NH-; Here, the compound is of formula (I); B is an optionally substituted -CH2-aryl, and A is an optionally substituted aryl; L 1 It is not -C(O)-NH-; Here, if the compound is of formula (II); A is an optionally substituted phenyl and B is an optionally substituted phenyl, then L 1 It is not -C(O)-NCH3-.

[0015] This disclosure relates to a compound represented by formula (III): [ka] The present invention also provides pharmaceutically acceptable salts and tautomers thereof, in which formula: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, an aryl, or a heteroaryl, where the aryl or heteroaryl is optionally substituted with another aryl or heteroaryl; Here, a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, each aryl, and each heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, A is an optionally substituted phenyl or thiophenyl, and L 3 If is -C(O)-NH-; B is [ka] Not; Here, if A is a substituted phenyl and B is a substituted phenyl, then L 3 This is not -C(O)-NH-, -NH-C(O)-, -NCH3-C(O)-, or -NH-C(O)-NH-; Here, if B is an arbitrarily substituted -CH2-aryl and A is an arbitrarily substituted aryl; L 3 It is not -C(O)-NH-.

[0016] This disclosure provides pharmaceutical compositions containing compounds of formula (IA), (II-A), (I), (II), or (III), or pharmaceutically acceptable salts or tautomers thereof, and pharmaceutically acceptable excipients.

[0017] This disclosure provides compounds of formula (IA), (II-A), (I), (II), or (III), or pharmaceutically acceptable salts thereof, for use as pharmaceuticals. Another aspect of this disclosure provides pharmaceutical compositions containing compounds of formula (IA), (II-A), (I), (II), or (III), or pharmaceutically acceptable salts thereof, for use as pharmaceuticals.

[0018] This disclosure provides a method for modulating the activity of NR2F6 by exposure to NR2F6 to an effective amount of a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof. This disclosure also provides a method for treating or mitigating the effects of a disease or disorder related to NR2F6 modulation, comprising administering an effective amount of a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof.

[0019] This disclosure provides a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, for use in modulating the activity of NR2F6 by exposure to NR2F6. This disclosure provides a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, for use in treating or alleviating the effects of diseases or disorders related to NR2F6 regulation.

[0020] This disclosure provides a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, for modulating the activity of NR2F6 upon exposure to NR2F6, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof. This disclosure provides a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, for treating or mitigating the effects of diseases or disorders related to NR2F6 regulation.

[0021] This disclosure provides the use of a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a pharmaceutical for modulating the activity of NR2F6. This disclosure provides the use of a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a pharmaceutical for treating or mitigating the effects of a disease or disorder related to NR2F6 regulation.

[0022] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly understood by practitioners in the art to which this disclosure pertains. In this specification, the singular also includes the plural unless the context otherwise clearly indicates. Methods and materials similar to or equivalent to those described herein may be used in the practice and testing of this disclosure, but preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. References cited herein do not constitute an endorsement of prior art to the requested disclosure. In case of any conflict, including definitions, the specification shall prevail. In addition, these materials, methods, and examples are illustrative and not intended to be limiting.

[0023] Other features and advantages of this disclosure will become apparent from the following detailed description and claims. [Modes for carrying out the invention]

[0024] Detailed explanation of disclosure All references cited herein, including any patents or patent applications, are incorporated herein by reference. No reference is authorized to constitute prior art. Furthermore, no prior art is authorized to constitute part of the common general knowledge in the art.

[0025] As used throughout this disclosure, the following terms should be understood to have the meanings set forth below unless otherwise noted. Where a term is not found, the commonly known terms to those skilled in the art shall prevail.

[0026] As used herein, the terms “contains,” “contains,” and “contains” are used in their open, non-restrictive sense. Throughout the description and claims of this specification, the phrases “contains,” “contains,” and variations thereof, such as “contains,” and “contains,” mean “contains, but not limited to,” and do not exclude other parts, additives, components, integers, or processes. Throughout the description and claims of this specification, the singular form is inclusive of the plural form unless the context requires otherwise. In particular, where the indefinite article is used, this specification should be understood to intend both singular and plural unless the context requires otherwise.

[0027] The articles “a and an” used in this disclosure may refer to one or more (i.e., at least one) grammatical objects of the article. For example, “a certain element” may mean one or more elements.

[0028] As used in this disclosure, the terms "and / or" may mean either "and" or "or" unless otherwise specified.

[0029] To provide a more precise explanation, some of the quantitative expressions given herein are not modified by the term “about”. Whether explicitly used or not, all quantities given herein refer to the actual given value, and are understood to also refer to an approximate value of such given value that can be reasonably inferred on the basis of the ordinary art, including equivalents and approximations, which also result from the experimental and / or measurement conditions relating to such given value. Whenever a yield is given as a percentage, such yield refers to the mass of the substance to which the yield is given in relation to the maximum amount of the same substance obtained under particular stoichiometric conditions. Concentrations given as a percentage refer to a mass ratio unless otherwise noted.

[0030] As used herein, the term "alkyl" refers to a saturated linear or branched hydrocarbon chain. This hydrocarbon chain preferably consists of 1 to 8 carbon atoms (C 1-8 -alkyl), for example, 1 to 6 carbon atoms (C 1-6 -alkyl), for example, 1 to 4 carbon atoms (C 1-4 It contains C(alkyl), and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl, isohexyl, heptyl and octyl. In certain embodiments, "alkyl" is C 1-4 -Represents alkyl groups, which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, and tertiary butyl groups. The corresponding term "alkylene" refers to the corresponding biradical (-alkyl-).

[0031] As used herein, the terms "cycloalkyl" or "carbocycryl" preferably refer to a molecule with 3 to 10 carbon atoms (C 3-10 -Cycloalkyl or C 3-10 -Carbocyclyl), for example, 3 to 8 carbon atoms (C 3-8 -Cycloalkyl or C 3-10 -Carbocyclyl), preferably 3 to 6 carbon atoms (C3-6 -Cycloalkyl or C 3-10 This refers to a cyclic alkyl group containing (-carbocyclyl), and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Furthermore, the term "cycloalkyl" as used herein may also include polycyclic groups such as bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptanyl, dekalinyl, and adamantyl. The corresponding term "cycloalkylene" means the corresponding biradical (-cycloalkyl-). "Cycloalkyl" includes a cyclic system in which a cycloalkyl ring, as defined above, is condensed with one or more cycloalkyl groups, heterocyclyl groups, aryl groups, or heteroaryl groups, where the bond site is on the cycloalkyl ring. Alkyl groups and cycloalkyl groups may be optionally substituted with 1 to 4 substituents. Examples of substituents on alkyl groups include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocykyl, hydroxyl, carbamoyl, oxo, and -CN.

[0032] As used herein, the term "alkenyl" refers to a linear or branched hydrocarbon chain or cyclic hydrocarbon containing one or more double bonds, including dienes, trienes, and polyenes. Typically, an alkenyl group contains at least one double bond and 2 to 8 carbon atoms (C 2-8 -alkenyl), for example, 2 to 6 carbon atoms (C 2-6 -alkenyl), especially with 2-4 carbon atoms (C 2-4It contains (-alkenyl). Examples of alkenyl groups include ethenyl; 1- or 2-propenyl; 1-, 2- or 3-butenyl, or 1,3-butedienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or 1,3-hexedienyl, or 1,3,5-hexetrienyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-octenyl, or 1,3-octadienyl, or 1,3,5-octatrienyl, or 1,3,5,7-octatetraenyl, or cyclohexenyl. The corresponding term "alkenylene" means the corresponding biradical (-alkenyl-). The alkenyl group may be optionally substituted with 1 to 4 substituents. Examples of substituents on the alkenyl group include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocykyl, hydroxyl, carbamoyl, oxo, and -CN.

[0033] As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon chain containing one or more triple bonds, including di-ynes, tri-ynes, and poly-ynes. Typically, an alkynyl group contains at least one triple bond and 2 to 8 carbon atoms (C 2-8 -alkynyl), for example, 2 to 6 carbon atoms (C 2-6 -alkynyl), especially 2-4 carbon atoms (C 2-4It contains (-alkynyl). Examples of specific alkynyl groups include ethynyl; 1- or 2-propynyl; 1-, 2- or 3-butynyl, or 1,3-buty-diinyl; 1-, 2-, 3-, 4- or 5-hexynyl, or 1,3-hexediinyl, or 1,3,5-hexetriinyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-octinyl, or 1,3-octa-diinyl, or 1,3,5-octa-triinyl, or 1,3,5,7-octa-tetrainyl. The corresponding term "alkynylene" means the corresponding biradical (-alkynyl-). The alkynyl group may be optionally substituted with 1 to 4 substituents. Examples of substituents on the alkynyl group include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocykyl, hydroxyl, carbamoyl, oxo, and -CN.

[0034] As used herein, the terms "halo" and "halogen" refer to fluoro, chloro, bromo, or iodine. Therefore, a trihalomethyl group refers to, for example, a trifluoromethyl group or a trichloromethyl group. Preferably, the terms "halo" and "halogen" specify fluoro or chloro.

[0035] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, which is substituted one or more times with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trichloromethyl.

[0036] As used herein, the term "alkoxy" refers to an "alkyl-O-" group, as previously defined for alkyl.

[0037] As used herein, the term "oxo" refers to the "=O" group.

[0038] As used herein, the term "amine" refers to primary amines (R-NH2, R≠H), secondary amines ((R)2-NH, (R)2≠H), and tertiary amines ((R)3-N, R≠H). A substituted amine is intended to mean an amine in which at least one hydrogen atom is replaced by a substituent.

[0039] As used herein, the term "carbamoyl" refers to the "H2N(C=O)-" group.

[0040] As used herein, the term "aryl" refers to a monocyclic or polycyclic group having at least one hydrocarbon aromatic ring, wherein all ring atoms of the at least one hydrocarbon aromatic ring are carbon. When an aryl includes a polycyclic system, there are no aromatic ring heteroatoms. Aryls may include groups with a single aromatic ring (e.g., phenyl) and groups with multiple fused aromatic rings (e.g., naphthyl, anthryl). Aryls may further include groups with one or more aromatic hydrocarbon rings fused to one or more non-aromatic hydrocarbon rings (e.g., fluorenyl; 2,3-dihydro-1H-indene; 1,2,3,4-tetrahydronaphthalene). In certain embodiments, an aryl includes a group with an aromatic hydrocarbon ring fused to a non-aromatic ring, wherein the non-aromatic ring contains at least one ring heteroatom independently selected from the group consisting of N, O, and S. For example, in some embodiments, the aryl group comprises a group with a phenyl ring fused to a non-aromatic ring, where the non-aromatic ring contains at least one ring heteroatom independently selected from the group consisting of N, O, and S (e.g., chroman; thiochroman; 2,3-dihydrobenzofuran; indoline). In some embodiments, the aryl group used herein comprises 6 to 14 carbon atoms ((C6-C 14 )aryl), or 6-10 carbon atoms ((C6-C 10 The aryl group has an aryl group. If the aryl group includes a fused ring, the aryl group may be bonded to one or more substituents or parts of the formulas described herein via any atom of the fused ring that can be valenced.

[0041] Examples of specific aryl moieties include phenyl, naphthyl, indenyl, indanyl, fluorenyl, biphenyl, indenyl, naphthyl, anthracenyl, phenantrenyl, pentarenyl, azlenyl, and biphenylenyl. Examples of specific “aryl” include phenyl, naphthyl, and indanyl, and phenyl unless otherwise specified. Any aryl used may be optionally substituted. The corresponding term “arylene” means the corresponding biradical (-aryl-). The aryl group may be optionally substituted with 1 to 4 substituents. Examples of substituents on the aryl group include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocykyl, hydroxyl, and -CN.

[0042] A condensed bicyclic aryl group refers to a polycyclic group comprising two condensed rings, each having at least one hydrocarbon aromatic ring, where all ring atoms of the at least one hydrocarbon aromatic ring are carbon. In certain embodiments, the condensed bicyclic aryl group comprises two aromatic rings.

[0043] As described above, the aryl may further include a group with one or more aromatic hydrocarbon rings fused to one or more non-aromatic hydrocarbon rings (e.g., fluorenyl; 2,3-dihydro-1H-indene; 1,2,3,4-tetrahydronaphthalene). In certain embodiments, the aryl includes a group with an aromatic hydrocarbon ring fused to a non-aromatic ring, where the non-aromatic ring contains at least one ring heteroatom independently selected from the group consisting of N, O, and S. For example, in some embodiments, the aryl includes a group with a phenyl ring fused to a non-aromatic ring, where the non-aromatic ring contains at least one ring heteroatom independently selected from the group consisting of N, O, and S (e.g., chroman; thiochroman; 2,3-dihydrobenzofuran; indoline; 2,3-dihydrobenzo[b][1,4]dioxin). In certain embodiments, the fused bicyclic aryl includes an aromatic ring and a non-aromatic ring.

[0044] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic group comprising at least one aromatic ring, wherein the aromatic ring comprises at least one ring heteroatom independently selected from the group consisting of N, O, and S. A heteroaryl group may contain 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms, wherein a ring atom refers to the sum of carbon atoms and heteroatoms in one or more rings (e.g., 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered heteroaryls). In some embodiments, the heteroaryl includes a group with an aromatic ring containing at least one ring heteroatom independently selected from the group consisting of N, O, and S (e.g., pyridinyl, pyrazinyl, furanyl, thiophenyl). In certain embodiments, the heteroaryl group comprises a polycyclic group with an aromatic ring containing at least one ring heteroatom fused to a non-aromatic hydrocarbon ring (e.g., 5,6,7,8-tetrahydroquinolinyl; 4,5,6,7-tetrahydroisobenzofuranyl). In some embodiments, the heteroaryl group comprises a polycyclic group with an aromatic ring containing at least one ring heteroatom fused to an aromatic hydrocarbon ring (e.g., quinolinyl, quinoxalinyl, benzothiazolyl). In further embodiments, the heteroaryl group comprises a polycyclic group with two fused aromatic rings, each ring containing at least one ring heteroatom (e.g., naphthilidinyl). The heteroaryl group may contain 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, where each ring heteroatom is independently selected from the group consisting of N, O, and S. In one example, a heteroaryl group has 3 to 8 ring carbon atoms along with 1 to 3 ring heteroatoms independently selected from the group consisting of N, O, and S. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, benzothiazolyl, and pyrazolyl.

[0045] Examples of specific heteroaryl moieties include N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, furanyl, triazolyl, pyranyl, thiadiadinyl, benzothiophenyl, dihydro-benzo[b]thiophenyl, xanthenyl, isoindanyl, acridinyl, benzoisoxazolyl, quinolinyl, isoquinolinyl, phteridinyl, azepinyl, diazepinyl, imidazolyl, thiazolyl, carbazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, This includes benzimidazolyl, benzofuranil, cinnolinil, indazolyl, indolidinil, phthalazinil, triazinil, isoindolyl, prinil, oxadiazolyl, thiadiazolyl, flazanil, benzoflazanil, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinil, quinoxalinil, naphthilidinil, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, phlopyridinil, pyrrolopyrimidinil, azaindolyl, pyrazolinil, 1,2,4-oxadiazole-5(4H)-one, and pyrazolidinil. Non-limiting examples of partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, and 1-octaline. The corresponding term "heteroarylene" refers to the corresponding biradical (-heteroaryl-). The heteroaryl group may be optionally substituted with 1 to 4 substituents. Examples of substituents on the heteroaryl group include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocykyl, hydroxyl, and -CN.

[0046] A fused bicyclic heteroaryl refers to a polycyclic group comprising two fused rings, each containing at least one aromatic ring, wherein the aromatic ring contains at least one ring heteroatom independently selected from the group consisting of N, O, and S. In certain embodiments, the fused bicyclic heteroaryl comprises two aromatic rings.

[0047] As used herein, the term “heterocyclyl” refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system having at least one heteroatom (at least one cyclic heteroatom selected from oxygen, nitrogen, and sulfur) in the ring. A heterocyclyl includes a ring system in which a heterocycle, as defined above, is fused with one or more cycloalkyl groups, cycloalkenyl groups, heterocyclyl groups, aryl groups, or heteroaryl groups, where the bond site is located on the heterocycle, and in such cases, the number of ring members listed follows to specify the number of cyclic atoms in the heterocycle containing the bond site. Examples of heterocycles include piperidinyl (a 6-membered heterocycle with 6 cyclic atoms), azepanyl (a 7-membered heterocycle with 7 cyclic atoms), and 3-chromanil (a 6-membered heterocycle with 10 cyclic atoms). [ka] That is the case.

[0048] Examples of heterocyclyl groups include oxetane, pyrrolidinyl, pyrrolyl, 3H-pyrrolyl, oxolanil, furanil, thiolanil, thiophenyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolidinyl, 3H-pyrazolyl, 1,2-oxazolyl, 1,3-oxazolyl, 1,2-thiazolyl, 1,3-thiazolyl, 1,2,5-oxadiazolyl, piperidinyl, pyridinyl, oxanil, 2-H-pyranil, 4-H-pyranil, thianil, 2H-thiopyranil, pyridadinyl, 1,2-diadinyl, pyrimidinyl, 1,3-diadinyl, pyrazinyl, piperazinyl, 1,4 -dioxynyl, 1,4-dioxanyl, 1,3-diadinyl, 1,4-oxazinyl, morpholino, thiomorpholino, 1,4-oxathianyl, benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, chromanyl, isochromanyl, 4H-clomenyl, 1H-isoclomenyl, sinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, prinyl, naphthylidinyl, pteridinyl, indolidinyl, 1H-pyrrolidinyl, 4H-quinolidinyl, and aza-8-bicyclo[3.2.1]octane. The corresponding term "heterocyclylene" means the corresponding biradical (-heterocyclyl-). The heterocyclyl group may be optionally substituted with 1 to 4 substituents. Examples of substituents on the heterocyclyl group include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, heteroaryl, aryl, carbocyryl, hydroxyl, and -CN.

[0049] In this specification, the structural formulas of the compounds may, for convenience, represent specific isomers, but this disclosure includes all isomers, including geometric isomers, optical isomers based on chiral carbons, stereoisomers, and tautomers. Accordingly, the definition of compounds of formula (IA), (II-A), (I), (II), or (III) should be understood to include each and all individual isomers corresponding to this formula: formulas (IA), (II-A), (I), (II), or (III), including cis-trans isomers, stereoisomers, and tautomers, as well as racemic mixtures thereof and pharmaceutically acceptable salts thereof. Accordingly, the definition of compounds of formula (IA), (II-A), (I), (II), or (III) is also intended to encompass all R- and S-isomers of the chemical structure in any ratio, such as, for example, an enrichment of one isomer (i.e., enantiomeric or diastereomer enrichment) and a corresponding smaller ratio of the other isomer. In addition, crystalline polymorphisms may exist for compounds represented by formulas (IA), (II-A), (I), (II), or (III). It should be noted that any crystalline form, mixtures of crystalline forms, or their anhydrous or hydrated forms are included within the scope of this disclosure. Furthermore, so-called metabolites produced by the in vivo degradation of these compounds are also included within the scope of this disclosure.

[0050] "Isomers" refer to compounds that have the same molecular formula but differ in the arrangement of their atomic bonds or their spatial configuration. Isomers with different spatial configurations of their atoms are called "stereoisomers." Stereoiomers that are not mirror images of each other are called "diastereoisomers," while stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers" or sometimes "optical isomers." A mixture containing equal amounts of individual enantiomers with opposite chiralities is called a "racemic mixture."

[0051] A carbon atom bonded to four non-identical substituents is called a "chiral center."

[0052] A "chiral isomer" refers to a compound that has at least one chiral center. Compounds with two or more chiral centers may exist either as individual diastereomers or as a mixture of diastereomers, which is called a "diastereomixture." When one chiral center is present, the stereoisomer is characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are arranged according to the "sequence rules" of Cahn, Ingold, and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0053] Diastereoisomers, i.e., isomers with non-overlapping stereochemistry, can be separated by conventional means such as chromatography, distillation, crystallization, or sublimation. Optical isomers can be obtained by the separation of racemic mixtures according to conventional processes, for example, by the formation of salts of diastereoisomers by treatment with an optically active acid or base. Examples of suitable acids include, but are not limited to, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluyltartaric acid, and camphorsulfonic acid. Mixtures of diastereomers can be separated by crystallization, followed by the liberation of an optically active base from these salts. Another process for the separation of optical isomers involves the use of a chiral chromatography column optimally selected to maximize the separation of its enantiomeric counterparts. Yet another available method relates to the synthesis of covalently bonded diastereoisomer molecules by reacting compounds of formula (IA), (II-A), (I), (II), or (III) with an activated form of an optically pure acid or an optically pure isocyanate. These synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to obtain enantiomerically pure compounds. Optically active compounds of formulas (IA), (II-A), (I), (II), or (III) can similarly be obtained by utilizing optically active starting materials and / or by utilizing chiral catalysts. These isomers may be in the form of free acids, free bases, esters, or salts. Examples of chiral separation techniques are described in *Chiral Separation Techniques, A Practical Approach*, 2nd edition, Wiley-VCH, 2001, edited by G. Subramanian.

[0054] "Geometric isomers" refer to diastereomers whose existence is due to binding rotation around a double bond. These configurations follow the Cahn-Ingold-Prelog rule, and their names are distinguished by the prefixes cis and trans, or Z and E, indicating that the group is on the same side or opposite side of the double bond within the molecule.

[0055] Furthermore, the structures and other compounds considered in this disclosure include all of their atropisomers. “Atropisomer” is a stereoisomer in which the atoms of two isomers are arranged differently in space. Atropisomers owe their existence to restricting rotations caused by the constraint of rotation of a large group around a central bond. Such atropisomers typically exist as a mixture, however, as a result of recent advances in chromatographic techniques, it has become possible to separate a mixture of two atropisomers, if selected.

[0056] A "tautomer" is a structural isomer of two or more compounds that exist in equilibrium and can be readily converted from one isomer to the other. This conversion is the result of a formal transfer of hydrogen atoms, accompanied by the exchange of adjacent conjugated double bonds. Tautomers exist in solution as a mixture of sets of tautomers. In the solid state, one tautomer usually dominates. In a solution where tautomerization is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism.

[0057] Two of the various possible types of tautomerism are commonly observed. In keto-enol tautomerism, simultaneous shifts of electrons and hydrogen atoms occur. Cyclic-chain tautomerism, as demonstrated by glucose, arises as a result of the reaction of an aldehyde group (-CHO) within a sugar chain molecule with a single hydroxyl group (-OH) within the same molecule, and this is designated as the cyclic (ring-shaped) type.

[0058] Common tautomer pairs include ketone-enols, amide-nitriles, lactam-lactimes, and intracyclic tautomers (e.g., within nucleic acid bases such as guanine, thymine, and cytosine), such as amide-imido acids, amine-enamines, and enamine-enamines. It should be understood that the compounds of this disclosure may be described as different tautomers. Similarly, if a compound has tautomers, all tautomers are intended to be included within the scope of this disclosure, and the names of these compounds do not exclude any tautomers.

[0059] In addition, the compounds of this disclosure, such as salts of these compounds, may exist in either a hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvate, acetone solvate, etc.

[0060] A "solvate" refers to a solvation compound that contains a solvent in either a stoichiometric or non-stoichiometric amount. Some compounds tend to capture solvent molecules in a fixed molecular ratio in their crystalline solid state, resulting in the formation of solvates. When the solvent is water, the formed solvate is a hydrate; and when the solvent is an alcohol, the formed solvate is an alcoholate. Hydrates are formed by the combination of one or more water molecules with one molecule of the substance, in which the water maintains its molecular state as H2O.

[0061] As used herein, “subject” or “subject requiring it” refers to a subject having a disease or disorder related to the regulation of NR2F6. “Subject” includes mammals. Mammals can be, for example, any mammal, such as humans, primates, birds, mice, rats, poultry, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. Preferably, the mammal is a human.

[0062] This disclosure is intended to include all isotopes of the atoms that occur in the compound. Isotopes include atoms that have the same atomic number but different mass numbers. As a general example without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

[0063] compound This disclosure relates to compounds represented by formula (IA) or (II-A): [ka] Furthermore, pharmaceutically acceptable salts and tautomers thereof, wherein the formula is: each [ka] These independently represent single or double bonds; X is N, NH, C, CH, or CH2; R 1 H, C 1-6 Alkyl, cycloalkyl, heterocyclyl, -C(O)R 1a , -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where R 1a C 1-6 Alkyl; and where -CH2-aryl, -CH2-heteroaryl, aryl, and heteroaryl are C 1-6 Optionally substituted with alkyl or halo; A is an alkyl, cycloalkyl, heterocyclyl, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where aryl or heteroaryl is aryl, heteroaryl, -Y A -aryl, or -Y A -Optionally substituted by a heteroaryl; where Y A -O-, -C(O)-, -N(R A1 )-, S(O)-, or -S(O)2-; where R A1 is H or C1-6 It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, and each heteroaryl are alkyl, halo, haloalkyl, -CN, -N(R) A ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R A H or C 1-6 It is alkyl; L 1 is -C(O)-NR L1 -, -OC(S)-NR L1 -, -OC(O)-NR L1 -, -NR L1 -C(O)-, -NR L1 -C(O)-O-, -NH-C(O)-NH-, -NR L1 -C(S)-NR L1 -, -NR L1 -S(O)2-, -S(O)2-NR L1 -, -CH2-CH2-, -CH2-NR L1 -, -NR L1 -CH2-, -CH2-O-, -O-CH2-, -O-, -NH-, -C(O)-azetidinyl, -CH2-NR L1 -C(O)-, -C(O)-NR L1 -CH2- or -C(O)-; where each R L1 H or C 1-6 Alkyl; and as L 2 is -C(O)-NR L2 -, -S(O)2-NR L2 -, -CH2-CH2-, -C(S)-NR L2 -, -C(O)-, or -S(O)2-; where each R L2 H or C 1-6 Alkyl; and as B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, an aryl, a heteroaryl, a cycloalkyl, a -CH2-heterocyclyl, or a heterocyclyl, where aryl, heteroaryl, cycloalkyl, or heterocyclyl is aryl, heteroaryl, -Y B -Aryl, -Y B -heteroaryl, -Y B -Optionally substituted with a heterocyclyl or cycloalkyl group; where Y B -O-, -CH2-, -C(O)-, -N(R B1 )-, -S(O)-, or -S(O)2-; where R B1 is H or C 1-6 It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, each heteroaryl, each cycloalkyl, -CH2-heterocyclyl, and each heterocyclyl are alkyl, halo, haloalkyl, -CN, -N(R) B2 ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, -O-alkyl, and oxo; where each R B2 H or C 1-6 It is alkyl; Here, the compound is of formula (IA); A is phenyl, and L 1 If is -C(O)-NH-, then B is [ka] Not; Here, if the compound is of formula (IA); A is a substituted phenyl and B is a substituted phenyl, then L 1 This is not -C(O)-NH-, -NH-C(O)-, -NCH3-C(O)-, or -NH-C(O)-NH-; Here, the compound is given by formula (IA); L 1 -C(O)-NR L1 -CH2- and B is optionally substituted phenyl, substituted pyridyl, or [ka] If; A is a substituted phenyl, substituted pyridyl, substituted thiophenyl, substituted thiazolyl, substituted pyrazolyl, [ka] Not; Here, the compound is of formula (IA); B is an optionally substituted -CH2-aryl, and A is an optionally substituted aryl; L 1 It is not -C(O)-NH-; Here, if the compound is of formula (II-A); A is an optionally substituted phenyl, and B is an optionally substituted phenyl, then L 1 This provides a compound that is not -C(O)-NCH3-.

[0064] This disclosure relates to compounds represented by formula (I) or (II): [ka] and pharmaceutically acceptable salts and tautomers thereof, wherein the formula is: each [ka] These independently represent a single bond or a double bond; X is N, NH, C, CH, or CH2; R 1 H, C 1-6 Alkyl, cycloalkyl, heterocyclyl, -C(O)R 1a , -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where R 1a C 1-6 Alkyl; and where -CH2-aryl, -CH2-heteroaryl, aryl, and heteroaryl are C 1-6 Optionally substituted with alkyl or halo; A is an alkyl, cycloalkyl, heterocyclyl, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where aryl or heteroaryl is aryl, heteroaryl, -Y A -aryl, or -Y A -Optionally substituted by a heteroaryl; where Y A -O-, -C(O)-, -N(R A1 )-, -S(O)-, or -S(O)2-; where R A1 is H or C 1-6 It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, and each heteroaryl are alkyl, halo, -CN, -N(R) A ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R A H or C 1-6 It is alkyl; L 1 is -C(O)-NR L1 -, -OC(S)-NR L1 -, -OC(O)-NR L1 -, -NR L1 -C(O)-, -NR L1 -C(O)-O-, -NH-C(O)-NH-, -NR L1 -C(S)-NR L1 -, -NR L1 -S(O)2-, -S(O)2-NR L1 -, -CH2-CH2-, -CH2-NR L1 -, -NR L1 -CH2-, -CH2-O-, -O-CH2-, -O-, -NH-, -C(O)-azetidinyl, -CH2-NR L1 -C(O)-, or -C(O)-NR L1 -CH2-; where each R L1 H or C 1-6 Alkyl; and as L 2 is -C(O)-NRL2 -, -S(O)2-NR L2 -, -CH2-CH2-, -C(S)-NR L2 -, -C(O)-, or -S(O)2-; where each R L2 H or C 1-6 Alkyl; and as B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, an aryl, a heteroaryl, a cycloalkyl, or a -CH2-heterocyclyl, where aryl or heteroaryl is aryl, heteroaryl, or -Y B -aryl, or -Y B -Optionally substituted by a heteroaryl; where Y B -O-, -C(O)-, -N(R B1 )-, -S(O)-, or -S(O)2-; where R B1 is H or C 1-6 It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, each heteroaryl, cycloalkyl, and -CH2-heterocyclyl are alkyl, halo, -CN, N(R) B2 ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R B2 H or C 1-6 It is alkyl; Here, the compound is of formula (I); A is an optionally substituted phenyl or thiophenyl, and L 1 If is -C(O)-NH-, then B is [ka] Not; Here, if the compound is of formula (I); A is a substituted phenyl and B is a substituted phenyl, then L 1 This is not -C(O)-NH-, -NH-C(O)-, -NCH3-C(O)-, or -NH-C(O)-NH-; Here, the compound is of formula (I); B is an optionally substituted -CH2-aryl, and A is an optionally substituted aryl; L 1 It is not -C(O)-NH-; Here, if the compound is of formula (II); A is an optionally substituted phenyl and B is an optionally substituted phenyl, then L 1 This provides a compound that is not -C(O)-NCH3-.

[0065] In certain embodiments, the compound is of formula (IA) or (I), where A is a substituted phenyl, and L 1 If is -CH2-O-, then B is [ka] isn't it.

[0066] In a particular embodiment, the compound is of formula (I); A is an optionally substituted phenyl or thiophenyl, and L 1 If is -C(O)-NH-, then B is [ka] No. In certain embodiments, the compound is of formula (I); A is phenyl, and L 1 If is -C(O)-NH-, then B is [ka] No. In certain embodiments, the compound is of formula (I); L 1 -C(O)-NR L1 -CH2- and B is optionally substituted phenyl, substituted pyridyl, or [ka] If; A is a substituted phenyl, substituted pyridyl, substituted thiophenyl, substituted thiazolyl, substituted pyrazolyl, [ka] isn't it.

[0067] This disclosure relates to a compound represented by formula (III): [ka] and pharmaceutically acceptable salts and tautomers thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, an aryl, or a heteroaryl, where the aryl or heteroaryl is optionally substituted with another aryl or heteroaryl; Here, a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, each aryl, and each heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, A is an optionally substituted phenyl or thiophenyl, and L 3 If is -C(O)-NH-, then B is [ka] Not; Here, if A is a substituted phenyl and B is a substituted phenyl, then L 3 This is not -C(O)-NH-, -NH-C(O)-, -NCH3-C(O)-, or -NH-C(O)-NH-; Here, if B is an arbitrarily substituted -CH2-aryl and A is an arbitrarily substituted aryl; L 3 This provides a compound that is not -C(O)-NH-.

[0068] In a particular embodiment, the compound is of formula (III), where A is a substituted phenyl, and L 3 If is -CH2-O-, then B is [ka] isn't it.

[0069] This disclosure relates to a compound represented by formula (IV): [ka] and pharmaceutically acceptable salts and tautomers thereof, wherein the formula is: L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, an aryl, or a heteroaryl, where the aryl or heteroaryl is optionally substituted with another aryl or heteroaryl; Here, a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, each aryl, and each heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, L 3 If is -C(O)-NH-, then B is [ka] It does not provide a compound.

[0070] This disclosure relates to a compound represented by formula (V): [ka] and pharmaceutically acceptable salts and tautomers thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B1 is a condensed bicyclic aryl or condensed bicyclic heteroaryl; where the condensed bicyclic aryl and condensed bicyclic heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, A is an optionally substituted phenyl or thiophenyl, and L 3 If is -C(O)-NH-, then B is [ka] It does not provide a compound.

[0071] In a particular embodiment, the compound is of formula (V), where A is a substituted phenyl, and L 3 If is -CH2-O-, then B is [ka] isn't it.

[0072] In a particular embodiment of formula (V), B1 is a fused bicyclic aryl compound. In a particular embodiment, B1 is a fused bicyclic heteroaryl compound. In a particular embodiment, B1 is: [ka] It is selected from the group consisting of the following.

[0073] This disclosure relates to a compound represented by formula (VI): [ka] and pharmaceutically acceptable salts and tautomers thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NRL3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B2 is a monocyclic aryl or monocyclic heteroaryl; where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Y 1 It does not exist, or -O-, -C(O)-, -N(R Y )-, -S(O)-, or -S(O)2-; where R Y is H or C 1-6 Alkyl; and as B3 is a monocyclic aryl or monocyclic heteroaryl compound, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups.

[0074] In a particular embodiment of formula (VI), B2 is a monocyclic aryl. In a particular embodiment, B2 is a monocyclic heteroaryl. In a particular embodiment, B3 is a monocyclic aryl. In a particular embodiment, B3 is a monocyclic heteroaryl. In a particular embodiment, [ka] teeth, [ka] It is selected from the group consisting of the following.

[0075] This disclosure relates to a compound represented by formula (VII): [ka] and pharmaceutically acceptable salts and tautomers thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B4 is a -CH2-aryl or -CH2-heteroaryl group; where the -CH2-aryl and -CH2-heteroaryl groups are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; Here, if B4 is an arbitrarily substituted -CH2-aryl and A is an arbitrarily substituted aryl; L 3 It is not -C(O)-NH-.

[0076] In a particular embodiment of formula (VII), B4 is a -CH2-aryl compound. In a particular embodiment, B4 is a -CH2-heteroaryl compound. In a particular embodiment, B4 is [ka] It is selected from the group consisting of the following.

[0077] As mentioned above, equation (IA) or (I) is, [ka] And equation (II-A) or (II) is, [ka] In a particular embodiment, the compound is of formula (IA) or (I). In a particular embodiment, the compound is of formula (II-A) or (II).

[0078] In certain embodiments, formula (IA) or (I) has the following stereochemistry: [ka] In certain embodiments, formula (IA) or (I) has the following stereochemistry: [ka] In certain embodiments, formula (IA) or (I) has the following stereochemistry: [ka] In certain embodiments, formula (IA) or (I) has the following stereochemistry: [ka]

[0079] In a particular embodiment, [ka] teeth, [ka] In a particular embodiment, [ka] teeth, [ka] In a particular embodiment, [ka] teeth, [ka] That is the case.

[0080] In certain embodiments, X is N or NH. In certain embodiments, X is C, CH, or CH2.

[0081] As mentioned above, R 1 H, C 1-6 Alkyl, cycloalkyl, heterocyclyl, -C(O)R 1a , -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where R 1a C 1-6 Alkyl; and where -CH2-aryl, -CH2-heteroaryl, aryl, and heteroaryl are C 1-6 It is optionally substituted with alkyl or halo.

[0082] In this particular embodiment, R 1 is H. In a particular example, R 1 C 1-6 It is alkyl. In a particular embodiment, R 1 is a cycloalkyl. In a particular embodiment, R 1 is a heterocycline. In this particular embodiment, R 1 is -C(O)R 1a In a particular embodiment, R 1 is -C(O)R 1a And here R 1a C 1-6 It is alkyl. In a particular embodiment, R1 is a -CH2-aryl group. In a particular embodiment, R 1 is a -CH2-heteroaryl compound. In a particular embodiment, R 1 is an aryl. In a particular embodiment, R 1 It is a heteroaryl compound.

[0083] As stated above, A is an alkyl, cycloalkyl, heterocyclyl, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where aryl or heteroaryl is aryl, heteroaryl, -Y A -aryl, or -Y A -Optionally substituted by a heteroaryl; where Y A -O-, -C(O)-, -N(R A1 )-, -S(O)-, or -S(O)2-; where R A1 is H or C 1-6 Alkyl; where condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, and each heteroaryl are alkyl, halo, -CN, -N(R) A ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R A H or C 1-6 It is alkyl.

[0084] In certain embodiments, A is alkyl. In certain embodiments, A is cycloalkyl. In certain embodiments, A is heterocyclyl. In certain embodiments, A is a condensed bicyclic aryl. In certain embodiments, A is a condensed bicyclic heteroaryl. In certain embodiments, A is -CH2-aryl. In certain embodiments, A is -CH2-heteroaryl. In certain embodiments, A is aryl. In certain embodiments, the aryl is substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl. In certain embodiments, A is a 5- to 6-membered heteroaryl. In certain embodiments, the heteroaryl is substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

[0085] In certain embodiments, A is an aryl group. In certain embodiments, the aryl group is unsubstituted. In certain embodiments, the aryl group of ring A is an aryl group, a heteroaryl group, or a -Y group. A -aryl, or -Y A -Optionally substituted with heteroaryl, where Y A -O-, -C(O)-, -N(R A1 )-, -S(O)-, or -S(O)2-. In certain embodiments, the aryl is substituted with an aryl. In certain embodiments, the aryl is substituted with a heteroaryl. In certain embodiments, the aryl is -Y A - Replaced by an aryl. In a particular embodiment, the aryl is -Y A - Substituted with heteroaryl. In a particular embodiment, Y A is -O-. In a particular embodiment, Y A is -C(O)-. In a particular embodiment, Y A is -N(R A1 )-. In a particular embodiment, Y A is -S(O)-. In a particular embodiment, Y AIt is -S(O)2-.

[0086] In certain embodiments, A is a heteroaryl. In certain embodiments, the heteroaryl is unsubstituted. In certain embodiments, the heteroaryl of ring A is aryl, heteroaryl, -Y A -aryl, or -Y A -Optionally substituted with heteroaryl, where Y A -O-, -C(O)-, -N(R A1 )-, -S(O)-, or -S(O)2-. In certain embodiments, the heteroaryl is substituted with an aryl. In certain embodiments, the heteroaryl is substituted with another heteroaryl. In certain embodiments, the heteroaryl is -Y A - Replaced by aryl. In certain embodiments, heteroaryl is -Y A - Substituted with heteroaryl. In a particular embodiment, Y A is -O-. In a particular embodiment, Y A is -C(O)-. In a particular embodiment, Y A is -N(R A1 )-. In a particular embodiment, Y A is -S(O)-. In a particular embodiment, Y A It is -S(O)2-.

[0087] In certain embodiments, A is a monocyclic aryl or monocyclic heteroaryl; where the monocyclic aryl or monocyclic heteroaryl is substituted with an aryl or heteroaryl. For example, in certain embodiments, A is a monocyclic aryl substituted with an aryl. For example, in certain embodiments, A is a monocyclic aryl substituted with a heteroaryl. For example, in certain embodiments, A is a monocyclic heteroaryl substituted with an aryl. For example, in certain embodiments, A is a monocyclic heteroaryl substituted with a heteroaryl. In certain embodiments, the monocyclic aryl, monocyclic heteroaryl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

[0088] In certain embodiments, A is a fused bicyclic aryl group. A fused bicyclic aryl group refers to a polycyclic group comprising two fused rings having at least one hydrocarbon aromatic ring, where all ring atoms of at least one hydrocarbon aromatic ring are carbon. In certain embodiments, the fused bicyclic aryl group comprises two aromatic rings.

[0089] In certain embodiments, A is a fused bicyclic heteroaryl. A fused bicyclic heteroaryl refers to a polycyclic group comprising two fused rings, each containing at least one aromatic ring, where the aromatic ring contains at least one ring heteroatom independently selected from the group consisting of N, O, and S. In certain embodiments, the fused bicyclic heteroaryl comprises two aromatic rings.

[0090] As previously described with respect to formula (III), A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

[0091] In certain embodiments, A is an aryl group. In certain embodiments, A is a phenyl group. In certain embodiments, A is a 5- to 6-membered heteroaryl group. In certain embodiments, A is a 5-membered heteroaryl group. In certain embodiments, A is a 5-membered heteroaryl group containing S. In certain embodiments, A is a 6-membered heteroaryl group.

[0092] As previously mentioned regarding A, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, and each heteroaryl are alkyl, halo, -CN, -N(R) A ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R A H or C 1-6 It is alkyl.

[0093] As previously mentioned regarding A, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, and each heteroaryl are alkyl, halo, haloalkyl, -CN, -N(R) A ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R A H or C 1-6 It is alkyl.

[0094] As previously stated regarding equation (I), L 1 is -C(O)-NR L1 -, -OC(S)-NR L1 -, -OC(O)-NR L1 -, -NR L1 -C(O)-, -NR L1 -C(O)-O-, -NH-C(O)-NH-, -NR L1 -C(S)-NR L1 -, -NR L1 -S(O)2-, -S(O)2-NR L1 -, -CH2-CH2-, -CH2-NR L1 -, -NRL1 -CH2-, -CH2-O-, -O-CH2-, -O-, -NH-, -C(O)-azetidinyl, -CH2-NR L1 -C(O)-, or -C(O)-NR L1 -CH2-; where each R L1 H or C 1-6 It is alkyl. As previously described regarding formula (IA), L 1 is -C(O)-NR L1 -, -OC(S)-NR L1 -, -OC(O)-NR L1 -, -NR L1 -C(O)-, -NR L1 -C(O)-O-, -NH-C(O)-NH-, -NR L1 -C(S)-NR L1 -, -NR L1 -S(O)2-, -S(O)2-NR L1 -, -CH2-CH2-, -CH2-NR L1 -, -NR L1 -CH2-, -CH2-O-, -O-CH2-, -O-, -NH-, -C(O)-azetidinyl, -CH2-NR L1 -C(O)-, -C(O)-NR L1 -CH2- or -C(O)-; where each R L1 H or C 1-6 It is alkyl.

[0095] In a particular embodiment, L 1 is -C(O)-NR L1 -In a particular embodiment, L 1 is -OC(S)-NR L1 -In a particular embodiment, L 1 is -OC(O)-NR L1 -In a particular embodiment, L 1 -NR L1 -C(O)-. In a particular embodiment, L 1 -NR L1 -C(O)-O-. In a particular embodiment, L 1 -NR L1 -C(O)-NRL1 -In a particular embodiment, L 1 -NR L1 -C(S)-NR L1 -In a particular embodiment, L 1 -NR L1 It is -S(O)2-. In a particular embodiment, L 1 is -S(O)2-NR L1 -In a particular embodiment, L 1 is -CH2-CH2-. In a particular embodiment, L 1 -CH2-NR L1 -In a particular embodiment, L 1 -NR L1 -CH2-. In a particular embodiment, L 1 is -CH2-O-. In a particular embodiment, L 1 is -O-CH2-. In a particular embodiment, L 1 is -O-. In a particular embodiment, L 1 is -NH-. In a particular embodiment, L 1 is -C(O)-azetidinyl. In a particular embodiment, L 1 -CH2-NR L1 -C(O)-. In a particular embodiment, L 1 is -C(O)-NR L1 -CH2-. In a particular embodiment, L 1 It is -C(O)-.

[0096] In a particular embodiment, L 1 is -C(O)-NH-. In a particular embodiment, L 1 is -OC(S)-NH-. In a particular embodiment, L 1 is -OC(O)-NH-. In a particular embodiment, L 1 It is -NH-C(O)-. In a particular embodiment, L 1 It is -NH-C(O)-O-. In a particular embodiment, L 1 It is -NH-C(O)-NH-. In a particular embodiment, L1 is -NH-C(S)-NH-. In a particular embodiment, L 1 It is -NH-S(O)2-. In a particular embodiment, L 1 is -S(O)2-NH-. In a particular embodiment, L 1 is -CH2-CH2-. In a particular embodiment, L 1 is -CH2-NH-. In a particular embodiment, L 1 is -NH-CH2-. In a particular embodiment, L 1 is -CH2-O-. In a particular embodiment, L 1 is -O-CH2-. In a particular embodiment, L 1 is -O-. In a particular embodiment, L 1 is -NH-. In a particular embodiment, L 1 is -C(O)-azetidinyl. In a particular embodiment, L 1 is -CH2-NH-C(O)-. In a particular embodiment, L 1 It is -C(O)-NH-CH2-.

[0097] As previously stated regarding equation (II), L 2 is -C(O)-NR L2 -, -S(O)2-NR L2 -, -CH2-CH2-, -C(S)-NR L2 -, -C(O)-, or -S(O)2-; where each R L2 H or C 1-6 It is alkyl.

[0098] In a particular embodiment, L 2 is -C(O)-NR L2 -In a particular embodiment, L 2 is -S(O)2-NR L2 -In a particular embodiment, L 2 is -CH2-CH2. In a particular embodiment, L 2 is -C(S)-NR L2 -In a particular embodiment, L2 is -C(O)-. In a particular embodiment, L 2 It is -S(O)2-.

[0099] In a particular embodiment, L 2 is -C(O)-NH-. In a particular embodiment, L 2 is -S(O)2-NH-. In a particular embodiment, L 2 is -CH2-CH2. In a particular embodiment, L 2 is -C(S)-NH-. In a particular embodiment, L 2 is -C(O)-. In a particular embodiment, L 2 It is -S(O)2-.

[0100] As previously stated regarding equations (III)-(VII), L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 It is alkyl.

[0101] In a particular embodiment, L 3 is -C(O)-NR L3 -In a particular embodiment, L 3 is -OC(S)-NR L3 -In a particular embodiment, L 3 is -OC(O)-NR L3 -In a particular embodiment, L 3 -NR L3-C(O)-. In a particular embodiment, L 3 -NR L3 -C(S)-NR L3 -In a particular embodiment, L 3 -NR L3 It is -S(O)2-. In a particular embodiment, L 3 is -S(O)2-NR L3 -In a particular embodiment, L 3 is -CH2-CH2-. In a particular embodiment, L 3 -CH2-NR L3 -In a particular embodiment, L 3 -NR L3 -CH2-. In a particular embodiment, L 3 is -CH2-O-. In a particular embodiment, L 3 is -O-CH2-. In a particular embodiment, L 3 It is -O-.

[0102] In a particular embodiment, L 3 is -C(O)-NH-. In a particular embodiment, L 3 is -OC(S)-NH-. In a particular embodiment, L 3 is -OC(O)-NH-. In a particular embodiment, L 3 It is -NH-C(O)-. In a particular embodiment, L 3 is -NH-C(S)-NH-. In a particular embodiment, L 3 It is -NH-S(O)2-. In a particular embodiment, L 3 is -S(O)2-NH-. In a particular embodiment, L 3 is -CH2-CH2-. In a particular embodiment, L 3 is -CH2-NH-. In a particular embodiment, L 3 is -NH-CH2-. In a particular embodiment, L 3 is -CH2-O-. In a particular embodiment, L 3 is -O-CH2-. In a particular embodiment, L3 It is -O-.

[0103] As mentioned above, B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, aryl, heteroaryl, cycloalkyl, or -CH2-heterocyclyl, where aryl or heteroaryl is aryl, heteroaryl, -Y B -aryl, or -Y B -Optionally substituted by a heteroaryl; where Y B -O-, -C(O)-, -N(R B1 )-, -S(O)-, or -S(O)2-; where R B1 is H or C 1-6 Alkyl; where condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, each heteroaryl, cycloalkyl, and -CH2-heterocyclyl are alkyl, halo, -CN, -N(R) B2 ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R B2 H or C 1-6 It is alkyl. As previously described with respect to formula (IA), B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, aryl, heteroaryl, cycloalkyl, -CH2-heterocyclyl, or heterocyclyl, where aryl, heteroaryl, cycloalkyl, or heterocyclyl is aryl, heteroaryl, -Y B -Aryl, -Y B -heteroaryl, -Y B -Optionally substituted with a heterocyclyl or cycloalkyl group; where Y B -O-, -CH2-, -C(O)-, -N(R B1 )-, -S(O)-, or -S(O)2-; where R B1 is H or C 1-6Alkyl; where condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, each heteroaryl, each cycloalkyl, -CH2-heterocyclyl, and each heterocyclyl are alkyl, halo, haloalkyl, -CN, -N(R) B2 ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, -O-alkyl, and oxo; where each R B2 H or C 1-6 It is alkyl.

[0104] As previously stated with respect to formula (III), B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, an aryl, or a heteroaryl, where the aryl or heteroaryl is optionally substituted with an aryl or heteroaryl; where the condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, each aryl, and each heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

[0105] In certain embodiments, B is a condensed bicyclic aryl. In certain embodiments, B is a condensed bicyclic heteroaryl. In certain embodiments, B is a -CH2-aryl. In certain embodiments, B is a -CH2-heteroaryl. In certain embodiments, B is an aryl. In certain embodiments, B is a heteroaryl. In certain embodiments, B is a cycloalkyl. In certain embodiments, B is a -CH2-heterocyclyl.

[0106] In certain embodiments, B is a fused bicyclic aryl group. A fused bicyclic aryl group refers to a polycyclic group comprising two fused rings having at least one hydrocarbon aromatic ring, where all ring atoms of at least one hydrocarbon aromatic ring are carbon. In certain embodiments, the fused bicyclic aryl group comprises two aromatic rings. In certain embodiments, the fused bicyclic aryl group comprises an aromatic ring and a non-aromatic ring.

[0107] In certain embodiments, B is a fused bicyclic heteroaryl. A fused bicyclic heteroaryl refers to a polycyclic group comprising two fused rings, each containing at least one aromatic ring, where the aromatic ring contains at least one ring heteroatom independently selected from the group consisting of N, O, and S. In certain embodiments, the fused bicyclic heteroaryl comprises two aromatic rings.

[0108] In certain embodiments, B is an aryl. In certain embodiments, the aryl in ring B is an aryl, heteroaryl, or -Y B -aryl, or -Y B -Optionally substituted with heteroaryl, where Y B -O-, -C(O)-, -N(R A1 )-, -S(O)-, or -S(O)2-. In certain embodiments, the aryl is unsubstituted. In certain embodiments, the aryl is substituted with an aryl. In certain embodiments, the aryl is substituted with a heteroaryl. In certain embodiments, the aryl is -Y B - Replaced by an aryl. In certain embodiments, the aryl is -Y B - Substituted with heteroaryl. In certain embodiments, the aryl is -Y B - Substituted with heterocyclyl. In certain embodiments, aryl is substituted with cycloalkyl. In certain embodiments, Y B is -O-. In a particular embodiment, Y B is -C(O)-. In a particular embodiment, Y B is -N(R B1)-. In a particular embodiment, Y B is -S(O)-. In a particular embodiment, Y B is -S(O)2-. In a particular embodiment, Y B It is -CH2-.

[0109] In certain embodiments, B is a heteroaryl ring. In certain embodiments, the heteroaryl ring of B is aryl, heteroaryl, -Y B -aryl, or -Y B -Optionally substituted with heteroaryl, Y B -O-, -C(O)-, -N(R B1 )-, -S(O)-, or -S(O)2-. In certain embodiments, the heteroaryl is unsubstituted. In certain embodiments, the heteroaryl is substituted with an aryl. In certain embodiments, the heteroaryl is substituted with another heteroaryl. In certain embodiments, the heteroaryl is -Y B - Replaced by aryl. In certain embodiments, heteroaryl is -Y B - Substituted with a heteroaryl. In certain embodiments, the heteroaryl is -Y B - Substituted with a heterocyclyl. In certain embodiments, the heteroaryl is substituted with a cycloalkyl. In certain embodiments, Y B is -O-. In a particular embodiment, Y B is -C(O)-. In a particular embodiment, Y B is -N(R B1 )-. In a particular embodiment, Y B is -S(O)-. In a particular embodiment, Y B is -S(O)2-. In a particular embodiment, Y B It is -CH2-.

[0110] In certain embodiments, B is a monocyclic aryl or monocyclic heteroaryl; where the monocyclic aryl or monocyclic heteroaryl is substituted with an aryl or heteroaryl. For example, in certain embodiments, B is a monocyclic aryl substituted with an aryl. For example, in certain embodiments, B is a monocyclic aryl substituted with a heteroaryl. For example, in certain embodiments, B is a monocyclic heteroaryl substituted with an aryl. For example, in certain embodiments, B is a monocyclic heteroaryl substituted with a heteroaryl. In certain embodiments, the monocyclic aryl, monocyclic heteroaryl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

[0111] In certain embodiments, B is a cyclocyclyl. In certain embodiments, the cyclocyclyl of ring B is aryl, heteroaryl, -Y B -aryl, or -Y B -Optionally substituted with heteroaryl, Y B -O-, -C(O)-, -N(R B1 )-, -S(O)-, or -S(O)2-. In certain embodiments, the cyclocyclyl is unsubstituted. In certain embodiments, the cyclocyclyl is substituted with an aryl. In certain embodiments, the cyclocyclyl is substituted with a heteroaryl. In certain embodiments, the cyclocyclyl is -Y B - Substituted with aryl. In certain embodiments, cyclocyclyl is -Y B - Substituted with heteroaryl. In certain embodiments, the cycloalkyl is -Y B - Substituted by heterocyclyl. In certain embodiments, cycloalkyl is substituted by cycloalkyl. In certain embodiments, Y B is -O-. In a particular embodiment, Y B is -C(O)-. In a particular embodiment, Y B is -N(R B1)-. In a particular embodiment, Y B is -S(O)-. In a particular embodiment, Y B is -S(O)2-. In a particular embodiment, Y B It is -CH2-.

[0112] In certain embodiments, B is a heterocyclyl. In certain embodiments, the heterocyclyl of ring B is aryl, heteroaryl, -Y B -aryl, or -Y B -Optionally substituted with heteroaryl, Y B -O-, -C(O)-, -N(R B1 )-, -S(O)-, or -S(O)2-. In certain embodiments, the heterocyclyl is unsubstituted. In certain embodiments, the heterocyclyl is substituted with an aryl. In certain embodiments, the heterocyclyl is substituted with a heteroaryl. In certain embodiments, the heterocyclyl is -Y B - Replaced by aryl. In certain embodiments, heterocyclyl is -Y B - Substituted with heteroaryl. In certain embodiments, the heterocyclyl is -Y B - Substituted with a heterocyclyl. In certain embodiments, the heterocyclyl is substituted with a cycloalkyl. In certain embodiments, Y B is -O-. In a particular embodiment, Y B is -C(O)-. In a particular embodiment, Y B is -N(R B1 )-. In a particular embodiment, Y B is -S(O)-. In a particular embodiment, Y B is -S(O)2-. In a particular embodiment, Y B It is -CH2-.

[0113] As previously mentioned regarding B, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, each heteroaryl, cycloalkyl, and -CH2-heterocyclyl are alkyl, halo, -CN, -N(R) B2 ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R B2 H or C 1-6 It is alkyl.

[0114] As previously mentioned regarding B, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, each heteroaryl, each cycloalkyl, -CH2-heterocyclyl, and each heterocyclyl are alkyl, halo, haloalkyl, -CN, -N(R B2 ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, -O-alkyl, and oxo; where each R B2 These are independently H or C1-6 alkyl groups.

[0115] In a particular embodiment, B is: [ka] It is selected from the group consisting of the following.

[0116] In a particular embodiment, B is: [ka] It is selected from the group consisting of the following.

[0117] In a particular embodiment, B is: [ka] It is selected from the group consisting of the following.

[0118] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] That is the case.

[0119] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] In a particular embodiment, B is: [ka] Therefore, as stated above, B is arbitrarily substituted.

[0120] In some embodiments, the Disclosure provides compounds of formula (IA), (II-A), (I), or (II) having one, two, or three of the following features: a) A is an aryl; b) B is a condensed biringual aryl; c)L 1 is -C(O)-NR L1 -, -OC(S)-NR L1 -, -OC(O)-NR L1 -, or -NR L1 -C(S)-NR L1 - is

[0121] In some embodiments, the Disclosure provides compounds of formula (IA), (II-A), (I), or (II) having one, two, or three of the following features: a) A is an aryl; b) B is a condensed bicyclic heteroaryl; c)L 1 is -C(O)-NR L1 -, -OC(S)-NR L1 -, -OC(O)-NR L1 -, or -NR L1 -C(S)-NR L1 - is

[0122] In some embodiments, the Disclosure provides compounds of formula (IA), (II-A), (I), or (II) having one, two, or three of the following features: a) A is an aryl; b) B is an aryl substituted with an aryl or heteroaryl; c)L 1 is -C(O)-NR L1 -, -OC(S)-NR L1 -, -OC(O)-NR L1 -, or -NR L1 -C(S)-NR L1 - is

[0123] In some embodiments, the Disclosure provides compounds of formula (IA), (II-A), (I), or (II) having one, two, or three of the following features: a) A is an aryl; b) B is a heteroaryl substituted with an aryl or heteroaryl; c)L 1 is -C(O)-NR L1 -, -OC(S)-NR L1 -, -OC(O)-NR L1 -, or -NR L1 -C(S)-NR L1 - is

[0124] In some embodiments, the present disclosure provides a compound of formula (III) having one, two, or three of the following features: a) A is an aryl; b) B is a condensed biringual aryl; c)L 1 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, or -NR L3 -C(S)-NR L3 - is

[0125] In some embodiments, the present disclosure provides a compound of formula (III) having one, two, or three of the following features: a) A is an aryl; b) B is a condensed bicyclic heteroaryl; c)L 1 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, or -NR L3 -C(S)-NR L3 - is

[0126] In some embodiments, the present disclosure provides a compound of formula (III) having one, two, or three of the following features: a) A is an aryl; b) B is an aryl substituted with an aryl or heteroaryl; c)L 1 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, or -NR L3 -C(S)-NR L3 - is

[0127] In some embodiments, the present disclosure provides a compound of formula (III) having one, two, or three of the following features: a) A is an aryl; b) B is a heteroaryl substituted with an aryl or heteroaryl; c)L 1 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, or -NR L3 -C(S)-NR L3 - is

[0128] In some embodiments, the compound of formula (IA) or (I) is selected from the compounds in the table below, as well as their pharmaceutically acceptable salts and tautomers: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0129] In some embodiments, the compound of formula (IA) or (I) is a compound selected from the table below, as well as pharmaceutically acceptable salts and tautomers thereof: [Table 2-1] [Table 2-2]

[0130] In some embodiments, the compound of formula (II-A) or (II) is a compound selected from the table below, as well as its pharmaceutically acceptable salts and tautomers: [Table 3]

[0131] In some embodiments, the compound of formula (IA) or (I) is a compound selected from the table below, as well as pharmaceutically acceptable salts and tautomers thereof: [Table 4-1] [Table 4-2] [Table 4-3]

[0132] In some embodiments, the compound of formula (IA) or (I) is a compound selected from the table below, as well as pharmaceutically acceptable salts and tautomers thereof: [Table 5]

[0133] In some embodiments, the compound of formula (II-A) or (II) is a compound selected from the table below, as well as its pharmaceutically acceptable salts and tautomers: [Table 6-1] [Table 6-2]

[0134] It should be understood that such references are intended to encompass not only the general formulas mentioned above, but also each and all of the embodiments considered below. Similarly, it should be understood that such references, unless otherwise stated, also encompass isomers, mixtures of isomers, pharmaceutically acceptable salts, solvates, and prodrugs of the compounds of formulas (IA), (II-A), (I), (II), or (III).

[0135] Method for preparing compounds The compounds of this disclosure (e.g., compounds of formula (I)) can be prepared in numerous ways well known to those skilled in the art of organic synthesis. For example, the compounds of this disclosure can be synthesized using the methods described below, in conjunction with synthetic methods known in the art of synthetic organic chemistry, or variations thereof recognized by those skilled in the art. Preferred methods include, but are not limited to, those described below. The final products of the reactions described herein may be isolated by conventional techniques, such as extraction, crystallization, distillation, and chromatography.

[0136] The compounds of this disclosure can be synthesized by following the steps outlined in General Scheme 1-3. Starting materials are either commercially available or prepared by known procedures such as those described in the reported literature or as examples. Useful steps that may be used in the preparation of these compounds will be known to those skilled in the art. The following methods are given as non-limiting examples of how the compounds may be prepared. General Scheme 1. General Methods for the Preparation of Racemic Compounds [ka] General Scheme 2. General Method for the Preparation of Compounds with 3R,4S Absolute Configurations [ka] General Scheme 3. General Method for the Preparation of Compounds with 3S,4R Absolute Configuration [ka]

[0137] The enantiomers, diastereomers, and cis / trans isomer mixtures resulting from the aforementioned processes can be separated into their individual components by chiral salt techniques, normal-phase, reverse-phase, or chiral column chromatography, depending on the nature of the separation.

[0138] In the explanation and formula shown above, various groups, A ring, B ring, X, R1 , L 1 , L 2 It should be understood that, unless otherwise specified, the and other variations are those defined herein. Furthermore, with respect to the synthetic purpose, the compounds in General Schemes 1-3 are merely representative, with selected radicals, to illustrate the general synthetic methods of the disclosed compounds.

[0139] Pharmaceutical composition Compounds of formula (IA), (II-A), (I), (II), or (III) may be provided in any form suitable for the intended administration, particularly including pharmaceutically acceptable salts, solvates, and prodrugs of compounds of formula (IA), (II-A), (I), (II), or (III).

[0140] A pharmaceutically acceptable salt is a salt of a compound of formula (IA), (II-A), (I), (II), or (III) that is considered acceptable for clinical and / or veterinary use. Typical pharmaceutically acceptable salts include salts of compounds of formula (IA), (II-A), (I), (II), or (III) prepared by the reaction of such compounds with mineral or organic acids or organic or inorganic bases. Such salts are known as acid addition salts and base addition salts, respectively. In general, as long as the salt is pharmaceutically acceptable and the counterions do not contribute to undesirable properties of the salt as a whole, it will be acknowledged that the specific counterions that form part of any salt are not important properties. These salts may be prepared by methods known to those skilled in the art. Salts that are acceptable as pharmaceuticals are described and discussed, for example, in "Remington's Pharmaceutical Sciences, 17th edition, Alfonso R. Gennaro (ed.), Mack Publishing Company, Easton, PA, USA, 1985," and in more recent editions, as well as in the "Encyclopedia of Pharmaceutical Technology."

[0141] Examples of pharmaceutically acceptable addition salts include inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, hydroiodic acid, metaphosphoric acid, or phosphoric acid; and organic acids, such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, trifluoroacetic acid, malic acid, lactic acid, formic acid, propionic acid, glycolic acid, gluconic acid, camphorsulfuric acid, isothiocyanic acid, mucinic acid, gentisic acid, isonicotinic acid, sugar acids, glucuronic acid, fluoroacids, glutamic acid, ascorbic acid, anthranilic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), ethanolic acid, and ethanolic acid. Acid addition salts formed from sulfonic acids, pantothenic acid, stearic acid, sulfanilic acid, alginic acid, and galacturonic acid; and aryl sulfonic acids, such as benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid; and base addition salts formed from alkali metals and alkaline earth metals and organic bases, such as N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), lysine, and procaine; and internally formed salts. All references to pharmaceutically acceptable salts should be understood to include the solvent addition form (solvate) or crystalline form (polymorph) of the same salt as defined herein.

[0142] Compounds of formula (IA), (II-A), (I), (II), or (III), or pharmaceutically acceptable salts thereof, may be provided in soluble or insoluble form with a pharmaceutically acceptable solvent such as water or ethanol. The soluble form may also include hydrated forms, such as monohydrate, dihydrate, hemihydrate, trihydrate, and tetrahydrate.

[0143] Compounds of formula (IA), (II-A), (I), (II), or (III), or pharmaceutically acceptable salts thereof, may be provided as prodrugs. As used herein, the term “prodrug” is intended to mean a compound that, upon exposure to specific physiological conditions, releases a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt thereof, which then exhibits a desired biological effect. Typical examples are amine-substituted active carbamates.

[0144] Since prodrugs are known to enhance many desirable properties of pharmaceuticals (e.g., solubility, bioavailability, manufacture, etc.), the compounds of the Disclosure can be delivered in prodrug form. Accordingly, the Disclosure is intended to cover prodrugs of the claimed compounds, methods for delivering them, and compositions containing them. A “prodrug” is intended to include any covalent carrier that, when administered to a subject, releases the active parent drug of the Disclosure in vivo. The prodrugs of the Disclosure are prepared by modifying functional groups present in the compound in such a way that the modification is cleaved into the parent compound, either by conventional operation or in vivo. The prodrugs include the compounds of the Disclosure such that a hydroxyl group, amino group, sulfhydryl group, carboxyl group, or carbonyl group therein is cleaved in vivo and bonded to any group that can form a free hydroxyl, free amino, free sulfhydryl, free carboxyl, or free carbonyl group, respectively.

[0145] Examples of prodrugs include esters of hydroxyl functional groups (e.g., esters of acetate, dialkylaminoacetic acid, formic acid, phosphate, sulfate, and benzoic acid) and carbamates (e.g., N,N-dimethylaminocarbonyl), and esters of carboxyl functional groups (e.g., C 1-6This includes, but is not limited to, alkyl esters (e.g., methyl esters, ethyl esters, 2-propyl esters, phenyl esters, 2-aminoethyl esters, morpholinoethanol esters, etc.), N-acyl derivatives (e.g., N-acetyl), N-Mannich bases, Schiff bases, and enaminones of amino functional groups, oximes, acetals, ketals, and enol esters of ketone and aldehyde functional groups in the compounds of this disclosure. See Bundegaard, H., Design of Prodrugs, pp. 1-92, Elesevier, New York-Oxford (1985).

[0146] The compound, or pharmaceutically acceptable salts, esters, or prodrugs thereof, may be administered orally, nasally, dermatologically, pulmonaryly, by inhalation, orally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of specific routes of administration.

[0147] A drug regimen utilizing this compound is selected according to various factors, including the patient's type, race, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal and hepatic function; and the specific compound or salt thereof used. A physician or veterinarian of ordinary skill can easily determine and prescribe the effective dose of the drug necessary to prevent, reverse, or halt the progression of the condition.

[0148] The techniques relating to the formulation and administration of the compounds disclosed herein can be found in "Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995)". In embodiments, the compounds described herein and their pharmaceutically acceptable salts are used in pharmaceutical preparations in combination with pharmaceutically acceptable carriers or diluents. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents, as well as sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage within the range described herein.

[0149] In one aspect of this disclosure, a pharmaceutical composition is provided comprising, as an active component, at least one compound of formula (IA), (II-A), (I), (II), or (III) as defined herein, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients, diluents, and / or carriers. The compounds of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with a pharmaceutically acceptable carrier, diluent, or excipient, in either a single dose or a repeated dose. Suitable pharmaceutically acceptable carriers, diluents, and excipients include inert solid diluents or fillers, sterile aqueous solutions, and various organic solvents.

[0150] A "pharmaceutical composition" is a formulation containing the compound of this disclosure in a form suitable for administration to a target. The pharmaceutical composition may be formulated in accordance with customary art, such as that disclosed in "Remington: The Science and Practice of Pharmacy, 21st edition, 2000, Lippincott Williams & Wilkins," with a pharmaceutically acceptable carrier or diluent, and any other known adjuvants and excipients.

[0151] As used herein, the term "pharmaceutically acceptable" means, within the bounds of reasonable medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit-risk ratio.

[0152] "Pharmacovigilant excipients" means excipients that are generally safe, non-toxic, and not biologically or otherwise undesirable, and that are useful in the preparation of pharmaceutical compositions, and include excipients that are pharmacovigilant for veterinary and human pharmaceutical uses. As used herein and in claims, "pharmacovigilant excipients" includes both one and more such excipients.

[0153] Pharmaceutical compositions formed by combining compounds of formulas (IA), (II-A), (I), (II), or (III) as defined herein, or pharmaceutically acceptable salts thereof, with pharmaceutically acceptable carriers, diluents, or excipients can be readily administered in various dosage forms, such as tablets, powders, licks, syrups, suppositories, and injectable solutions. In powders, the carrier is a finely divided solid, such as talc or starch, mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed in a suitable proportion with a carrier having the required binding properties and compressed into a desired shape and size.

[0154] This pharmaceutical composition may be specifically prepared for administration via any preferred route, including oral and parenteral (subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes. It will be understood that the preferred route will depend on the general condition and age of the subject being treated, the nature of the condition being treated, and the selected active components.

[0155] Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, sugar-coated tablets, pills, licks, powders, and granules. Where appropriate, these may be prepared by coating, such as enteric coating, or they may be prepared to provide controlled release of the active component, such as sustained release or extended release, according to methods well known in the art.

[0156] With regard to oral administration in the form of tablets or capsules, compounds of formula (IA), (II-A), (I), (II), or (III) as defined herein, or pharmaceutically acceptable salts thereof, may preferably be combined with orally non-toxic and pharmaceutically acceptable carriers such as ethanol, glycerol, or water. Furthermore, suitable binders, lubricants, disintegrants, flavoring agents, and colorants may be appropriately added to the mixture. Suitable binders include, for example, lactose, glucose, starch, gelatin, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, and wax. Lubricants include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants include, for example, starch, methylcellulose, agar, bentonite, xanthan gum, sodium starch glycolate, crospovidone, and croscarmellose sodium. Additional excipients for capsules are macrogels or lipids.

[0157] With regard to the preparation of solid compositions such as tablets, the active compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt thereof, is mixed with one or more excipients, such as those described above, and other pharmaceutical diluents such as water, to produce a solid pre-formulation composition containing a homogeneous mixture of the compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt thereof. The term "homogeneous" is understood to mean that the compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, is evenly dispersed throughout the composition so that it can be easily divided into equally effective unit dosage forms, such as tablets or capsules.

[0158] Liquid compositions for oral or parenteral administration of compounds of formula (IA), (II-A), (I), (II), or (III), or pharmaceutically acceptable salts thereof, include, for example, aqueous solutions, syrups, elixirs, aqueous or oily suspensions, and emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil. Suitable dispersants or suspending agents for aqueous suspensions include synthetic or natural rubbers, such as tragacanth, alginate, acacia gum, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, or polyvinylpyrrolidone.

[0159] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions, or emulsions, as well as sterile powders that are reconstituted into injectable solutions or dispersions before use.

[0160] For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremofor EL® (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid enough to allow for easy passage through an injection needle. It must be stable under manufacturing and storage conditions and preserved against contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium, including, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), or a suitable mixture thereof. Adequate fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of a dispersant, and by the use of a surfactant. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it would be preferable for the composition to contain, for example, sugars, polyalcohols, isotonic agents such as mannitol, sorbitol, and sodium chloride. Extended absorption of the injectable composition can be achieved by containing absorption-delaying substances in the composition, such as aluminum monostearate and gelatin.

[0161] The preparation of all these solutions under sterile conditions can be easily achieved by standard pharmaceutical techniques well known to those skilled in the art.

[0162] For example, a sterile injection solution can be prepared by mixing the required amount of the active compound in a suitable solvent with one or a combination of the components listed above, as needed, and then sterilizing and filtering it. Generally, dispersions are prepared by mixing the active compound with a sterile vehicle containing a basic dispersion medium and other components required from those listed above. In the case of sterile powders for the preparation of sterile injection solutions, the preparation method is vacuum drying and freeze-drying, which yield a powder derived from the pre-sterilizing and filtered solution with the active component plus additional desired components. Depot injection compositions are also intended to be within the scope of this disclosure.

[0163] For parenteral administration, solutions containing compounds of formula (IA), (II-A), (I), (II), or (III), or pharmaceutically acceptable salts thereof, in sesame oil or peanut oil, aqueous propylene glycol, or sterile aqueous solutions may be used. Such aqueous solutions should be appropriately buffered if necessary, and the liquid diluent should first be isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. Oily solutions are suitable for intra-articular, intramuscular, and subcutaneous injection.

[0164] In addition to the aforementioned components, compositions of compounds of formula (IA), (II-A), (I), (II), or (III), or pharmaceutically acceptable salts thereof, may contain one or more additional components, such as diluents, buffers, flavoring agents, colorants, surfactants, thickeners, preservatives, such as methyl hydroxybenzoate (including antioxidants), and emulsifiers.

[0165] As used herein, the term “therapeutic effective dose” refers to the amount of a drug that treats, improves, or prevents a defined disease, disorder, or condition, or that exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The exact effective dose for a subject will depend on the subject's weight, size, and health; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutic effective dose for a given situation may be determined by customary experimentation, which is within the scope of the clinician’s skill and judgment. In a preferred context, the disease or disorder being treated is a disease or disorder related to the regulation of NR2F6.

[0166] For any compound, the therapeutically effective dose can first be estimated, for example, in an intracellular cell culture assay, or typically in an animal model of rat, mouse, rabbit, dog, or pig. Animal models may also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes of administration in humans. Therapeutic / prophylactic efficacy and toxicity are, for example, ED 50 (Therapeutic dose effective in 50% of the population) and LD 50 This may be determined by standard pharmaceutical procedures in cell culture or experimental animals, such as (a lethal dose for 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic coefficient, and this is the ratio LD 50 / ED 50 It can be expressed as follows. Pharmaceutical compositions exhibiting a large therapeutic coefficient are preferred. The dose may vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0167] Dosage and administration are adjusted to provide a sufficient level of the active substance(s) or to maintain the desired effect. Factors to consider include the severity of the disease state, the subject's overall health, age, weight, and sex, diet, time and frequency of administration, concomitant medications(s), sensitivity to response, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3-4 days, weekly, or every 2 weeks, depending on the half-life and clearance rate of the particular formulation.

[0168] The preferred dose of the compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt thereof, depends on the patient's age and condition, the severity of the disease being treated, and other factors well known to the practitioner. The compound may be administered orally, parenterally, or topically, according to different dosing schedules, at intervals such as daily or weekly. Generally, a single dose would be in the range of 0.01 to 500 mg / kg body weight, preferably about 0.05 to 100 mg / kg body weight, more preferably 0.1 to 50 mg / kg body weight, and most preferably 0.1 to 25 mg / kg body weight. The compound may be administered as a bolus (i.e., the entire daily dose is administered in one dose) or as two or more divided doses per day. Variations based on the aforementioned dose ranges may be made by a physician of usual skill, taking into account known considerations such as the patient's weight, age, and condition, the severity of pain, and the specific route of administration.

[0169] Compounds of formula (IA), (II-A), (I), (II), or (III), or pharmaceutically acceptable salts thereof, may also be prepared in pharmaceutical compositions containing, in single or repeated doses, one or more additional active substances, alone or in combination with pharmaceutically acceptable carriers, diluents, or excipients.

[0170] Treatment method This disclosure provides a method for modulating the activity of NR2F6 by exposing NR2F6 to an effective amount of a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof. This disclosure provides a method for treating or mitigating the effects of a disease or disorder related to NR2F6 modulation, the method comprising administering an effective amount of a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof.

[0171] This disclosure provides a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, for use in modulating NR2F6 activity by exposure to NR2F6. This disclosure provides a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, for use in treating or mitigating the effects of diseases or disorders related to NR2F6 regulation.

[0172] This disclosure provides the use of a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, for the modulation of NR2F6 activity by exposure to NR2F6. This disclosure provides the use of a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, for the treatment or mitigation of the effects of diseases or disorders related to NR2F6 modulation.

[0173] This disclosure provides the use of a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a pharmaceutical for modulating the activity of NR2F6. This disclosure provides the use of a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition containing a compound of formula (IA), (II-A), (I), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, in the manufacture of a pharmaceutical for treating or mitigating the effects of a disease or disorder related to NR2F6 regulation.

[0174] Compounds useful for regulating NR2F6 activity are disclosed. In some embodiments, the disclosed compounds are used to stimulate NR2F6 activity. In some embodiments, the disclosure provides the use of compounds to inhibit NR2F6 activation. Stimulation of NR2F6 in the context of the disclosure is particularly useful for inducing immunosuppression or stimulating cell proliferation without significantly inducing differentiation. Inhibition of NR2F6 is desirable in situations where those skilled in the art seek to enhance the immune response or induce cell differentiation. In some embodiments, inhibition of NR2F6 expression is desirable in situations where inhibition of cancer or cancer stem cells is required.

[0175] In certain embodiments, this modification includes enhancement of NR2F6 activity. In certain embodiments, this modification includes inhibition of NR2F6 activity.

[0176] Accordingly, this disclosure provides compounds that bind to the NR2F6 molecule, or to a portion of NR2F6 that is at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of NR2F6.

[0177] As used herein, the terms “agonist” or “activator” relate to compounds / substances that are known in the art and capable of fully or partially stimulating the physiological activity of a specific receptor(s). Therefore, in the context of this disclosure, an agonist can stimulate the physiological activity of a receptor, such as NR2F6, upon binding of the compound / substance to the receptor. The binding of an “agonist / activator” to a given receptor, such as NR2F6, can mimic the action of an endogenous ligand that binds to the receptor. Thus, as used herein, the term “agonist” also encompasses partial agonists or co-agonists / co-activators. In addition, in the context of this disclosure, an “agonist” or “activator” of NR2F6 can also stimulate the function of a given receptor, such as NR2F6, by inducing / enhancing the expression of a nucleic acid molecule encoding that receptor. Therefore, NR2F6 agonists / activators can lead to increased expression levels of NR2F6 (e.g., increased levels of NR2F6 mRNA and NR2F6 protein), which are reflected in increased NR2F6 activity. Accordingly, NR2F6 activators in the context of this disclosure may also include transcription activators of NR2F6 expression that are capable of enhancing NR2F6 function. The term "agonist" includes partial agonists. In the art, a partial agonist is defined as a candidate molecule that behaves like an agonist but, even at high concentrations, cannot activate NR2F6 to the same extent as a full agonist. Increased expression and / or activity of NR2F6 by NR2F6 agonists / activators leads to decreased activity (and / or expression) of components of the NR2F6-dependent signaling pathway; in particular, the activity of NF-AT and AP-1 is reduced. NF-AT / AP-1 modulates the transcription / expression of further “downstream” components of the NR2F6-dependent signaling pathway, such as IL-2, IL-17, and / or IFN-γ. A decrease in NF-AT / AP-1 activity results in reduced transcription of these “downstream” components (e.g., IL-2, IL-17, and / or IFN-γ), which in turn leads to suppression of the immune response. In summary, the NR2F6 agonists / activators described herein therefore lead to suppression of the immune response.Therefore, the use of potent agonists / activators of NR2F6 would lead to higher expression and / or activity of NR2F6.

[0178] Increased NR2F6 activity leads to decreased activity of NF-AT / AP-1 (and other components of the NR2F6-dependent signaling pathway), which in turn results in a suppressed immune response. Therefore, NR2F6 agonists / activators can be useful in the treatment of diseases in which suppression of the immune response is desired (e.g., allergies and diseases with hyperstimulated immune responses, such as multiple sclerosis).

[0179] In certain embodiments, this disorder is cancer. Inhibition of NR2F6 according to this disclosure can be used in immunotherapies to treat cancer. "To treat cancer," "to inhibit cancer," and "to reduce cancer growth" mean inhibiting or preventing the oncogenic activity of cancer cells. Oncogenic activity may include inhibiting cancer cell migration, invasion, drug resistance, cell survival, anchorage-independent growth, unresponsiveness to cell death signals, angiogenesis, or a combination thereof. The terms “cancer,” “cancer cells,” “tumor,” and “tumor cells” are used interchangeably herein and generally refer to a group of diseases characterized by uncontrolled, abnormal cell growth (e.g., neoplasm formation). In some cancer types, cancer cells can be disseminated locally or to other parts of the body through the bloodstream and lymphatic system ("metastatic cancer"). "Lymphocytes activated ex vivo," "lymphocytes with enhanced antitumor activity," and "dendritic cell cytokine-induced killers" are interchangeable terms used to refer to compositions of cells that are activated ex vivo and subsequently reintroduced within the context of this disclosure. The term "lymphocytes" is used, but this also includes xenocellular cells grown during the ex vivo culture process, including dendritic cells, NKT cells, γδT cells, and various other innate and adoptive immune cells. As used herein, "cancer" refers to all types of cancer or neoplasms or malignant tumors found in animals, including leukemia, carcinomas, and sarcomas. Examples of cancers include brain, melanoma, bladder, breast, neck, colon, head and neck, kidney, lung, non-small cell lung, mesothelioma, ovarian, prostate, sarcoma, stomach, uterus, and medulloblastoma.

[0180] The term "leukemia" refers to a widespread, progressive malignant disease of the hematopoietic organs / systems, and is generally characterized by the distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia includes, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, nonleukemia, leukocyte leukemia, basophilic leukemia, blastocyte leukemia, bovine leukemia, chronic myeloid leukemia, cutaneous leukemia, embryonic cell leukemia, eosinophilic leukemia, Gross leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemia, anaplastic cell leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, This includes histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphoid leukemia, lymphosarcomacytic leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegheri leukemia, plasmacytic leukemia, plasmacytoid leukemia, and promyelocytic leukemia.

[0181] The term "carcinoma" refers to a malignant neoplasm that develops in epithelial cells, invading surrounding tissues and / or resisting physiological and non-physiological cell death signals, and is prone to metastasis. Examples of carcinomas include, for example, lobular cell carcinoma, acinar cell carcinoma, adenocyst, adenoid cystic carcinoma, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, and basal cell carcinoma. cell) carcinoma, basal cell carcinoma, basal cell carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, encephalic carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedonal carcinoma, endometrial carcinoma, cribriform carcinoma , armor-like carcinoma, skin cancer, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, dural carcinoma, embryonic carcinoma, brain-like carcinoma, epidermoid carcinoma, epithelial adenoid carcinoma, exophytic carcinoma, ulcer carcinoma, fibrous carcinoma, gelatinous carcinoma, glue-like carcinoma, giant cell carcinoma, signet ring cell carcinoma, simple carcinoma, small tumor Cellular carcinoma, solenoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, string carcinoma, angiodetic carcinoma, dilating capillary carcinoma, transitional cell carcinoma, nodular carcinoma, nodular carcinoma, verrucous carcinoma, choriocarcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, piloma carcinoma, hematological carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, clear cell carcinoma of the kidney, infantile fetal carcinoma, carcinoma in situ This includes (in situ) intraepidermal carcinoma, carcinoma in situ, Cronpecker carcinoma, Kruchinskii cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticulare carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, black carcinoma, molluscum carcinoma, mucinous carcinoma, mucinous secretory carcinoma, mucinous cell carcinoma, mucinous epidermoid carcinoma, mucosal carcinoma, mucinous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, and scrotal carcinoma.

[0182] The term "sarcoma" generally refers to a tumor made of a substance like embryonic connective tissue and generally composed of densely packed cells embedded in a heterogeneous or homogeneous material of fibril. Sarcomas include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fasciosarcoma, fibroblastic sarcoma, giant cell sarcoma, Abemesy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, staphyloid sarcoma, green sarcoma, choriocarcinoma, embryonal sarcoma, and others. This includes Ilmus tumor sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemosarcoma, malignant mesenchymal sarcoma, paraosteal sarcoma, reticulum sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma. Examples of additional neoplasms include, for example, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small cell lung cancer, primary brain tumor, gastric cancer, colon cancer, malignant islet cell tumors of the pancreas, malignant carcinoids, skin lesions of precancerous conditions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, and adrenocortical carcinoma.

[0183] In certain embodiments, this disorder is a malignant hematological disorder. In certain cases, this malignant hematological disorder is mediated through the differentiation of hematopoietic cells.

[0184] In certain embodiments, the hematological malignancies are selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia (CML), accelerated CML, CML acute transformation phase (CML-BP), acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), Hodgkin's disease, non-Hodgkin lymphoma, follicular lymphoma, mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma, Valdenström macroglobulinemia, myelodysplastic syndrome (MDS), refractory anemia (RA), RA with ring sideroblasts, RA with supervasive blasts (RAEB), transformed RAEB, and myeloproliferative syndromes.

[0185] In certain embodiments, this disorder is cancer. Inhibition of NR2F6 according to this disclosure can be used for immunotherapy to treat cancer.

[0186] In certain embodiments, the cancer is a solid tumor selected from lung adenocarcinoma, cholangiocarcinoma, bladder cancer; bone cancer, brain tumor, glioma, undifferentiated oligodegenerative glioma, adult glioblastoma multiforme, adult undifferentiated astrocytoma; benign prostatic hyperplasia, bronchoalveolar carcinoma, breast cancer including metastatic breast cancer; cervical cancer, cholangiocarcinoma, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, squamous cell carcinoma of the head and neck, gallbladder cancer, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, melanoma; neuroendocrine cancer, metastatic neuroendocrine tumor, non-small cell lung cancer (NSCLC), small cell lung cancer, ovarian cancer, primary peritoneal cancer, pancreatic cancer, prostate cancer including androgen-dependent and androgen-independent prostate cancer, colorectal cancer, kidney cancer, metastatic renal cell carcinoma, soft tissue sarcoma, bladder cancer, and uterine cancer.

[0187] In certain embodiments, this reaction, disease, or disorder includes autoimmune diseases. Inhibition of NR2F6 according to this disclosure can be used to treat enhanced autoimmune responses. An "enhanced immune response" is characterized by a particularly strong response / reaction of the immune system to the presence of an antigen. Under normal non-pathological conditions, the immune response is regulated in a well-controlled manner. Furthermore, the immune response is self-limiting and decays with time after exposure to the antigen. However, in the case of an "enhanced immune response," the immune response can be hypersensitive, meaning that this immune response may cause damage to the organism's own cells / tissues in the presence of the antigen. Furthermore, in some cases of "enhanced immune responses," such as autoimmune diseases / disorders or transplant rejection (and similar), the immune system may fail to distinguish between self-matter and non-self-matter. Thus, the term "disease associated with an enhanced immune response" is associated with any disease / disorder in which an "enhanced immune response," as defined herein, is the etiology of, associated with, secondary to, or a result of the disorder. The enhanced immune response may be determined by directly or indirectly measuring parameters that are indicators of the magnitude of the immune response / reaction to an antigen, and by comparing the results of such measurements obtained in the subject under test with the results of the same test in a physiologically normal subject. Parameters indicating the magnitude of the immune response / reaction include, but are not limited to, the presence / amount of (specific) antibodies, the presence / amount of (specific) immune cells, the presence / amount of (specific) cytokines, and / or the presence / amount of (specific) regulatory, activating, and / or adhesive molecules. With respect to diseases associated with the enhanced immune response, the enhanced immune response may therefore be detectable prior to, during, or after the onset of the disease. In certain embodiments, the enhanced autoimmune response is an autoimmune disease. In preferred embodiments, the disease associated with the enhanced immune response is selected from the group consisting of acute or chronic transplant rejection, dermatological diseases, T-cell and B-cell-mediated inflammatory diseases, graft-versus-host diseases, and autoimmune diseases. In another preferred embodiment, the dermatological disease is psoriasis, atopic dermatitis, or contact allergy.In another preferred embodiment, the T-cell and B-cell-mediated inflammatory disease is asthma or chronic obstructive pulmonary disease (COPD). In yet another preferred embodiment, the graft-versus-host disease is acute (or fulminant) graft-versus-host disease or chronic graft-versus-host disease. In a particular embodiment, the autoimmune disease is multiple sclerosis, inflammatory bowel disease such as ulcerative colitis, or Behçet's disease; lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, myasthenia gravis, polymyositis, mixed connective tissue disease (MCTD), rheumatoid arthritis, diabetes mellitus, celiac disease, atherosclerosis, Goodpasture syndrome, Graves' disease, autoimmune hepatitis / autoimmune hepatic disease, autoimmune thrombocytopenic purpura, granulomatous disease (e.g., Morbus Wegener disease), or autoimmune hemolytic anemia. In certain embodiments, the enhanced autoimmune response is rheumatoid arthritis, systemic lupus erythema (lupus), inflammatory bowel disease, multiple sclerosis, type 1 diabetes, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, psoriasis / psoriatic arthritis, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, or vasculitis.

[0188] In certain embodiments, this disorder is a gastrointestinal disorder. Examples of gastrointestinal disorders include peptic ulcers, focal ileitis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagen-accumulating colitis, lymphocytic colitis, ischemic colitis, empty colitis, Behçet's syndrome, uncertain colitis), inflammatory bowel syndrome (IBS), and gastroprokinetic drugs. Disorders that are improved by the agent (e.g., ileus, postoperative ileus, and ileus in sepsis; gastroesophageal reflux disease (GORD, or its synonym GERD), eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerance and food allergies and other functional bowel disorders, such as non-ulcerative dyspepsia (NUD), and non-cardiac chest pain (NCCP, including costochondritis)).

[0189] This disclosure provides a method for treating conditions associated with hepatic steatosis. The accumulation of excessive triglycerides in the liver is known as hepatic steatosis (or fatty liver). This condition is associated with adverse metabolic consequences such as insulin resistance and dyslipidemia. Fatty liver is frequently observed in individuals who consume excessive amounts of alcohol and those who are obese, diabetic, or hyperlipidemia. However, non-alcoholic fatty liver disease (NAFLD) can develop even without excessive alcohol intake (>10g / day). NAFLD refers to a broad spectrum of liver diseases that can progress from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH) and to cirrhosis (irreversible, advanced scarring of the liver). All stages of NAFLD generally involve the accumulation of fat (fatty infiltration) in liver cells (hepatocytes).

[0190] The NAFLD spectrum begins and progresses from its simplest stage, known as simple fatty liver disease (steatosis). Simple fatty liver disease involves the accumulation of fat (triglycerides) in liver cells without inflammation (hepatitis) or scarring (fibrosis). The next stage and severity in the NAFLD spectrum is NASH, which involves the accumulation of fat in liver cells as well as inflammation of the liver. These inflammatory cells destroy liver cells (hepatocyte necrosis), and NASH ultimately leads to liver scarring (fibrosis), followed by irreversible progression to scarring (cirrhosis). Cirrhosis caused by NASH is the last and most severe stage in the NAFLD spectrum.

[0191] As used herein, “treating” or “treating” describes the management and care of a patient for the purpose of reversing, inhibiting, or eradicating a disease, condition, or disorder, and includes the administration of the compounds of the Disclosure (i.e., compounds of formula (IA), (II-A), (I), (II), or (III)) or pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates thereof for the purpose of reversing, eliminating, or inhibiting the process of a disease, condition, or disorder.

[0192] The compounds of the present disclosure (i.e., compounds of formula (IA), (II-A), (I), (II), or (III)), or their pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates may also be used to prevent a disease, condition, or disorder, or one or more symptoms of such a disease, condition, or disorder. As used herein, “preventing” or “preventing” refers to reducing or eliminating the onset of a symptom or complication of a disease, condition, or disorder.

[0193] The compounds of this disclosure (i.e., compounds of formula (IA), (II-A), (I), (II), or (III)), or their pharmaceutically acceptable salts, prodrugs, metabolites, polymorphs, or solvates, may also be used to alleviate one or more symptoms of such diseases, conditions, or disorders. As used herein, the term “alleviate” means to describe a process by which the severity of the signs or symptoms of the disorder is reduced. Importantly, the signs or symptoms may be alleviated without being eliminated. Preferably, the treatment is curative or ameliorative.

[0194] kit In some embodiments, the Disclosure also provides a pharmaceutical package or kit comprising one or more containers filled with at least one compound or composition of the Disclosure. Optionally attached to such container(s) is a note in the form directed by a government agency regulating the manufacture, use, or sale of a pharmaceutical or biological product, the note reflecting (a) the agency's approval for manufacture, use, or sale relating to human administration, (b) instructions for use, or both. In some embodiments, the kit comprises at least two containers, at least one of which contains at least one compound or composition of the Disclosure. In some embodiments, the kit comprises at least two containers, and each of the at least two containers contains at least one compound or composition of the Disclosure.

[0195] In some embodiments, the kit includes additional materials to facilitate the delivery of the compound and composition of interest. For example, the kit may include one or more catheters, tubes, infusion bags, syringes, etc. In some embodiments, the compound and composition are packaged in a lyophilized form, and the kit includes at least two containers: one containing the lyophilized compound or composition, and another containing an appropriate amount of water, buffer, or other liquid suitable for reconstituting the lyophilized material.

[0196] The foregoing descriptions apply to any compound, composition, method, and use described herein. Specifically, this disclosure is intended to cover the features described with respect to the various kits described in this section and any combination of such compound, composition, method, and use features (individually or in combination).

[0197] Enumerated embodiments Embodiment I-1. Compound of formula (I) or (II): [ka] Or, a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: each [ka] These independently represent a single bond or a double bond; X is N, NH, C, CH, or CH2; R 1 H, C 1-6 Alkyl, cycloalkyl, heterocyclyl, -C(O)R 1a , -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where R 1a C 1-6 Alkyl; and where -CH2-aryl, -CH2-heteroaryl, aryl, and heteroaryl are C 1-6 Optionally substituted with alkyl or halo; A is an alkyl, cycloalkyl, heterocyclyl, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where aryl or heteroaryl is aryl, heteroaryl, -Y A -aryl, or -Y A -Optionally substituted by a heteroaryl; where Y A -O-, -C(O)-, -N(R A1 )-, S(O)-, or -S(O)2-; where R A1 is H or C 1-6 It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, and each heteroaryl are alkyl, halo, haloalkyl, -CN, -N(R) A ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R A H or C 1-6 It is alkyl; L 1 is -C(O)-NR L1 -, -OC(S)-NR L1 -, -OC(O)-NR L1 -, -NR L1 -C(O)-, -NR L1 -C(O)-O-, -NH-C(O)-NH-, -NR L1 -C(S)-NR L1 -, -NR L1 -S(O)2-, -S(O)2-NR L1 -, -CH2-CH2-, -CH2-NR L1 -, -NR L1 -CH2-, -CH2-O-, -O-CH2-, -O-, -NH-, -C(O)-azetidinyl, -CH2-NR L1 -C(O)-, -C(O)-NR L1 -CH2- or -C(O)-; where each R L1 H or C 1-6 Alkyl; and as L 2is -C(O)-NR L2 -, -S(O)2-NR L2 -, -CH2-CH2-, -C(S)-NR L2 -, -C(O)-, or -S(O)2-; where each R L2 H or C 1-6 Alkyl; and as B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, an aryl, a heteroaryl, a cycloalkyl, or a -CH2-heterocyclyl, where aryl or heteroaryl is an aryl, a heteroaryl, or -Y B -aryl, or -Y B -Optionally substituted by a heteroaryl; where Y B -O-, -CH2-, -C(O)-, -N(R B1 )-, -S(O)-, or -S(O)2-; where R B1 is H or C 1-6 It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, each heteroaryl, cycloalkyl, and -CH2-heterocyclyl are alkyl, halo, -CN, -N(R) B2 ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R B2 H or C 1-6 It is alkyl; Here, the compound is of formula (I); A is an optionally substituted phenyl or thiophenyl, and L 1 If is -C(O)-NH-, then B is [ka] Not; Here, the compound is of formula (I); A is a substituted phenyl and B is a substituted phenyl; L 1 This is not -C(O)-NH-, -NH-C(O)-, -NCH3-C(O)-, or -NH-C(O)-NH-; Here, the compound is of formula (I); B is an optionally substituted -CH2-aryl, and A is an optionally substituted aryl; L 1 It is not -C(O)-NH-; Here, if the compound is of formula (II); A is an optionally substituted phenyl and B is an optionally substituted phenyl, then L 1 It is not -C(O)-NCH3-.

[0198] Embodiment I-2. Compound of formula (III): [ka] Or, a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, an aryl, or a heteroaryl, where the aryl or heteroaryl is optionally substituted with another aryl or heteroaryl; Here, a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, each aryl, and each heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, A is an optionally substituted phenyl or thiophenyl, and L 3 If is -C(O)-NH-; B is [ka] Not; Here, if A is a substituted phenyl and B is a substituted phenyl, then L 3 This is not -C(O)-NH-, -NH-C(O)-, -NCH3-C(O)-, or -NH-C(O)-NH-; Here, the compound is of formula (I); B is an optionally substituted -CH2-aryl, and A is an optionally substituted aryl; L 3 It is not -C(O)-NH-.

[0199] Embodiment I-3. Compound of formula (IV): [ka] Or, a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, an aryl, or a heteroaryl, where the aryl or heteroaryl is optionally substituted with another aryl or heteroaryl; Here, a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, each aryl, and each heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, L 3 If is -C(O)-NH-, then B is [ka] isn't it.

[0200] Embodiment I-4. Compound of formula (V): [ka] Or, a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B1 is a condensed bicyclic aryl or condensed bicyclic heteroaryl; where the condensed bicyclic aryl and condensed bicyclic heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, A is an optionally substituted phenyl or thiophenyl, and L 3 If is -C(O)-NH-, then B is [ka] isn't it.

[0201] Embodiment I-5. The compound of Embodiment I-4, or a pharmaceutically acceptable salt or tautomer thereof, where B1 is a condensed bicyclic aryl.

[0202] Embodiment I-6. The compound of Embodiment I-4, or a pharmaceutically acceptable salt or tautomer thereof, where B1 is a condensed bicyclic heteroaryl.

[0203] Embodiment I-7. The compound of Embodiment I-4, or a pharmaceutically acceptable salt or tautomer thereof, wherein B1 is: [ka] It is selected from the group consisting of the following.

[0204] Embodiment I-8. Compound of formula (VI): [ka] Or, a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NR L3-, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B2 is a monocyclic aryl or monocyclic heteroaryl; where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Y 1 It does not exist, or -O-, -C(O)-, -N(R Y )-, -S(O)-, or -S(O)2-; where R Y is H or C 1-6 Alkyl; and as B3 is a monocyclic aryl or monocyclic heteroaryl; where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

[0205] Embodiment I-9. The compound of Embodiment I-8, or a pharmaceutically acceptable salt or tautomer thereof, where B2 is a monocyclic aryl.

[0206] Embodiment I-10. The compound of Embodiment I-8, or a pharmaceutically acceptable salt or tautomer thereof, where B2 is a monocyclic heteroaryl.

[0207] Embodiment I-11. The compound of Embodiment I-8, or a pharmaceutically acceptable salt or tautomer thereof, where B3 is a monocyclic aryl compound.

[0208] Embodiment I-12. The compound of Embodiment I-8, or a pharmaceutically acceptable salt or tautomer thereof, where B3 is a monocyclic heteroaryl.

[0209] Embodiment I-13. The compound of Embodiment I-8, or a pharmaceutically acceptable salt or tautomer thereof, wherein [ka] teeth, [ka] It is selected from the group consisting of the following.

[0210] Embodiment I-14. Compound of formula (VII): [ka] Or, a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B1 is a condensed bicyclic aryl or condensed bicyclic heteroaryl; where the condensed bicyclic aryl and condensed bicyclic heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, A is an optionally substituted phenyl or thiophenyl, and L 3 If is -C(O)-NH-, then B is [ka] isn't it.

[0211] Embodiment I-15. The compound of Embodiment I-14, or a pharmaceutically acceptable salt or tautomer thereof, where B4 is a -CH2-aryl compound.

[0212] Embodiment I-16. The compound of Embodiment I-14, or a pharmaceutically acceptable salt or tautomer thereof, where B4 is a -CH2-heteroaryl compound.

[0213] Embodiment I-17. The compound of Embodiment I-14, or a pharmaceutically acceptable salt or tautomer thereof, wherein B4 is [ka] It is selected from the group consisting of the following.

[0214] Embodiment I-18. The compound of Embodiment I-1, or a pharmaceutically acceptable salt or tautomer thereof, wherein, [ka] teeth, [ka] That is the case.

[0215] Embodiment I-19. The compound of Embodiment I-1, or a pharmaceutically acceptable salt or tautomer thereof, wherein, [ka] teeth, [ka] That is the case.

[0216] Embodiment I-20. The compound of Embodiment I-1, or a pharmaceutically acceptable salt or tautomer thereof, wherein, [ka] teeth, [ka] That is the case.

[0217] Embodiment I-21. One of the compounds from Embodiments I-1 and I-18 to I-20, or a pharmaceutically acceptable salt or tautomer thereof, where X is N or NH.

[0218] Embodiment I-22. One of the compounds from Embodiments I-1 and I-18 to I-20, or a pharmaceutically acceptable salt or tautomer thereof, where X is C, CH, or CH2.

[0219] Embodiment I-23. One compound from Embodiments I-1 and I-18 to I-22, or a pharmaceutically acceptable salt or tautomer thereof, where R 1 H is H.

[0220] Embodiment I-24. One compound from Embodiments I-1 and I-18 to I-22, or a pharmaceutically acceptable salt or tautomer thereof, where R 1 C 1-6 It is alkyl.

[0221] Embodiment I-25. One compound from Embodiments I-1 and I-18 to I-22, or a pharmaceutically acceptable salt or tautomer thereof, where R 1 It is a cycloalkyl compound.

[0222] Embodiment I-26. One compound from Embodiments I-1 and I-18 to I-22, or a pharmaceutically acceptable salt or tautomer thereof, where R 1 It is a heterocycline.

[0223] Embodiment I-27. One compound from Embodiments I-1 and I-18 to I-22, or a pharmaceutically acceptable salt or tautomer thereof, where R 1 is -C(O)R 1a That is the case.

[0224] Embodiment I-28. One compound from Embodiments I-1 and I-18 to I-22, or a pharmaceutically acceptable salt or tautomer thereof, where R 1 It is a -CH2-aryl compound.

[0225] Embodiment I-29. One of the compounds from Embodiments I-1 to I-28, or a pharmaceutically acceptable salt thereof, where A is an aryl compound.

[0226] Embodiment I-30. The compound of Embodiment I-29, or a pharmaceutically acceptable salt or tautomer thereof, wherein the aryl is substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

[0227] Embodiment I-31. One of the compounds from Embodiments I-1 to I-28, or a pharmaceutically acceptable salt or tautomer thereof, where A is a 5- to 6-membered heteroaryl.

[0228] Embodiment I-32. The compound of Embodiment I-31, or a pharmaceutically acceptable salt or tautomer thereof, wherein the heteroaryl is substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

[0229] Embodiment I-33. One of the compounds from Embodiments I-1 to I-28, or a pharmaceutically acceptable salt or tautomer thereof, where A is alkyl.

[0230] Embodiment I-34. One of the compounds from Embodiments I-1 to I-28, or a pharmaceutically acceptable salt or tautomer thereof, where A is a cycloalkyl compound.

[0231] Embodiment I-35. One of the compounds from Embodiments I-1 to I-28, or a pharmaceutically acceptable salt or tautomer thereof, where A is a heterocyclyl.

[0232] Embodiment I-36. One of the compounds from Embodiments I-1 to I-28, or a pharmaceutically acceptable salt or tautomer thereof, where A is a condensed bicyclic aryl or condensed bicyclic heteroaryl.

[0233] Embodiment I-37. One of the compounds from Embodiments I-1 to I-28, or a pharmaceutically acceptable salt or tautomer thereof, where A is a -CH2-aryl or -CH2-heteroaryl compound.

[0234] Embodiment I-38. One compound from Embodiments I-1 and I-17 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 1 is -C(O)-NR L1 - is

[0235] Embodiment I-39. One compound from Embodiments I-1 and I-17 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L1 is -OC(S)-NR L1 - is

[0236] Embodiment I-40. One compound from Embodiments I-1 and I-17 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 1 is -OC(O)-NR L1 - is

[0237] Embodiment I-41. One compound from Embodiments I-1 and I-17 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 1 -NR L1 -C(S)-NR L1 - is

[0238] Embodiment I-42. One compound from Embodiments I-1 and I-17 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 1 It is -O-.

[0239] Embodiment I-43. One compound from Embodiments I-1 and I-17 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 1 -NR L1 -C(O)-, -NR L1 -C(O)-O-, -NH-C(O)-NH-, -NR L1 -S(O)2-, or -S(O)2-NR L1 - is

[0240] Embodiment I-44. One compound from Embodiments I-1 and I-17 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 1 -CH2-CH2-, -CH2-NR L1 -, -NR L1 These are -CH2-, -CH2-O-, -O-CH2-, -NH-, or -C(O)-azetidinyl.

[0241] Embodiment I-45. One compound from Embodiments I-1 and I-17 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 2 is -C(O)-NR L2 - is

[0242] Embodiment I-46. One compound from Embodiments I-1 and I-17 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 2 is -S(O)2-NR L2 - or -CH2-CH2-

[0243] Embodiment I-47. One compound from Embodiments I-2 to I-17 and I-29 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 3 is -C(O)-NR L3 - is

[0244] Embodiment I-48. One compound from Embodiments I-2 to I-17 and I-29 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 3 is -OC(S)-NR L3 - is

[0245] Embodiment I-49. One compound from Embodiments I-2 to I-17 and I-29 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 3 is -OC(O)-NR L3 - is

[0246] Embodiment I-50. One compound from Embodiments I-2 to I-17 and I-29 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 3 -NR L3 -C(S)-NR L3 - is

[0247] Embodiment I-51. One compound from Embodiments I-2 to I-17 and I-29 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 3 -NR L3 -C(O)-, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, or -NR L3 It is -CH2-.

[0248] Embodiment I-52. One compound from Embodiments I-2 to I-17 and I-29 to I-37, or a pharmaceutically acceptable salt or tautomer thereof, where L 3 These are -CH2-O-, -O-CH2-, or -O-.

[0249] Embodiment I-53. One of the compounds from Embodiments I-1 to I-3 and I-18 to I-52, or a pharmaceutically acceptable salt or tautomer thereof, where B is a condensed bicyclic aryl.

[0250] Embodiment I-54. One of the compounds from Embodiments I-1 to I-3 and I-18 to I-52, or a pharmaceutically acceptable salt or tautomer thereof, where B is a condensed bicyclic heteroaryl.

[0251] Embodiment I-55. One compound from Embodiments I-1 to I-3 and I-18 to I-52, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is [ka] It is selected from the group consisting of the following.

[0252] Embodiment I-56. One compound from Embodiments I-1 to I-3 and I-18 to I-52, or a pharmaceutically acceptable salt or tautomer thereof, where B is -CH2-aryl.

[0253] Embodiment I-57. One of the compounds from Embodiments I-1 to I-3 and I-18 to I-52, or a pharmaceutically acceptable salt or tautomer thereof, where B is a -CH2-heteroaryl compound.

[0254] Embodiment I-58. One compound from Embodiments I-1 to I-3 and I-18 to I-52, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is [ka] It is selected from the group consisting of the following.

[0255] Embodiment I-59. One of the compounds from Embodiments I-1 to I-3 and I-18 to I-51, or a pharmaceutically acceptable salt or tautomer thereof, where B is an aryl compound.

[0256] Embodiment I-60. One of the compounds from Embodiments I-1 to I-3 and I-18 to I-51, or a pharmaceutically acceptable salt or tautomer thereof, where B is an aryl or heteroaryl-substituted aryl compound.

[0257] Embodiment I-61. One of the compounds from Embodiments I-1 to I-3 and I-18 to I-51, or a pharmaceutically acceptable salt or tautomer thereof, where B is a heteroaryl compound.

[0258] Embodiment I-62. One of the compounds from Embodiments I-1 to I-3 and I-18 to I-51, or a pharmaceutically acceptable salt or tautomer thereof, where B is a heteroaryl substituted with an aryl or heteroaryl.

[0259] Embodiment I-63. One compound from Embodiments I-1 to I-3 and I-18 to I-51, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is [ka] It is selected from the group consisting of the following.

[0260] Embodiment I-64. One compound from Embodiments I-1 to I-3 and I-18 to I-51, or a pharmaceutically acceptable salt or tautomer thereof, where B is a cycloalkyl compound.

[0261] Embodiment I-65. One of the compounds from Embodiments I-1 to I-3 and I-18 to I-51, or a pharmaceutically acceptable salt or tautomer thereof, where B is a -CH2-heterocyclyl.

[0262] Embodiment I-66. A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of: [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6]

[0263] Embodiment I-67. A pharmaceutical composition comprising one of the compounds from Embodiments I-1 to I-66, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable excipient.

[0264] Embodiment I-68. A method for modifying the activity of NR2F6 by exposing NR2F6 to an effective amount of one compound from Embodiments I-1 to I-66, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment I-67.

[0265] Embodiment I-69. The method of Embodiment I-68, wherein the regulation includes enhancement of NR2F6 activity.

[0266] Embodiment I-70. The method of Embodiment I-68, wherein the regulation includes inhibition of NR2F6 activity.

[0267] Embodiment I-71. A method for treating or alleviating the effects of a disease or disorder related to NR2F6 regulation, comprising administering an effective amount of one compound from Embodiments I-1 to I-66, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment I-67.

[0268] Embodiment I-72. The method of Embodiment I-71, wherein the disease or disorder includes an enhanced autoimmune response.

[0269] Embodiment I-73. The method according to Embodiment I-72, wherein the enhanced autoimmune response is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (lupus), inflammatory bowel disease, multiple sclerosis, type 1 diabetes mellitus, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, psoriasis / psoriatic arthritis, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, and vasculitis.

[0270] Embodiment I-74. The method of Embodiment I-71, wherein the disorder is cancer.

[0271] Embodiment I-75. The method of Embodiment I-74, wherein the cancer is a solid tumor selected from the group consisting of lung adenocarcinoma, cholangiocarcinoma, bladder cancer; bone cancer, brain tumor, glioma, undifferentiated oligodendroglioma, adult glioblastoma multiforme, adult undifferentiated astrocytoma; benign prostatic hyperplasia, bronchoalveolar carcinoma, breast cancer including metastatic breast cancer; cervical cancer, cholangiocarcinoma, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, squamous cell carcinoma of the head and neck, gallbladder cancer, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, melanoma; neuroendocrine carcinoma, metastatic neuroendocrine tumor, non-small cell lung cancer (NSCLC), small cell lung cancer, ovarian cancer, primary peritoneal cancer, pancreatic cancer, prostate cancer including androgen-dependent and androgen-independent prostate cancer, colorectal cancer, kidney cancer, metastatic renal cell carcinoma, soft tissue sarcoma, bladder cancer, and uterine cancer.

[0272] Embodiment I-76. The method of Embodiment I-71, wherein the disorder is a hematological malignancy.

[0273] Embodiment I-77. The method of Embodiment I-76, wherein the hematological malignancy is selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia (CML), accelerated CML, CML acute transformation phase (CML-BP), acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), Hodgkin's disease, non-Hodgkin lymphoma, follicular lymphoma, mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma, Valdenström macroglobulinemia, myelodysplastic syndrome (MDS), refractory anemia (RA), RA with ring sideroblasts, RA with supervasive blasts (RAEB), transformed RAEB, and myeloproliferative syndromes.

[0274] Embodiment I-78. A method for treating or alleviating the effects of a gastrointestinal disorder or ailment, comprising administering an effective amount of one compound from Embodiments I-1 to I-66, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment I-67.

[0275] Embodiment I-79. The method of Embodiment I-78, wherein the gastrointestinal disease is IBD, Crohn's disease, or colitis.

[0276] Embodiment I-80. Any one compound from Embodiments I-1 to I-66, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition of Embodiment I-67, for use in modulating the activity of NR2F6 by exposure to NR2F6.

[0277] Embodiment I-81. Any one compound from Embodiments I-1 to I-66, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition of Embodiment I-67, for use in treating or alleviating the effects of a disease or disorder related to NR2F6 regulation.

[0278] Embodiment I-82. Use of any one compound from Embodiments I-1 to I-66, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment I-67, to modulate the activity of NR2F6.

[0279] Embodiment I-83. Use of any one compound from Embodiments I-1 to I-66, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment I-67, for the treatment or mitigation of the effects of a disease or disorder related to NR2F6 regulation.

[0280] Embodiment I-84. Use of any one compound from Embodiments I-1 to I-66, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment I-67, in the manufacture of a pharmaceutical for modulating the activity of NR2F6.

[0281] Embodiment I-85. Use of any one compound from Embodiments I-1 to I-66, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition of Embodiment I-67, in the manufacture of a pharmaceutical for treating or mitigating the effects of a disease or disorder related to NR2F6 regulation.

[0282] Embodiment II-1. Compound represented by formula (IA) or (II-A): [ka] or pharmaceutically acceptable salts and tautomers thereof, wherein the formula is: each [ka] These independently represent single or double bonds; X is N, NH, C, CH, or CH2; R 1 H, C 1-6 Alkyl, cycloalkyl, heterocyclyl, -C(O)R 1a , -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where R 1a C 1-6 Alkyl; and where -CH2-aryl, -CH2-heteroaryl, aryl, and heteroaryl are C 1-6 Optionally substituted with alkyl or halo; A is an alkyl, cycloalkyl, heterocyclyl, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, aryl, or heteroaryl; where aryl or heteroaryl is aryl, heteroaryl, -Y A -aryl, or -Y A -Optionally substituted by a heteroaryl; where Y A -O-, -C(O)-, -N(R A1 )-, S(O)-, or -S(O)2-; where R A1 is H or C 1-6 It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, and each heteroaryl are alkyl, halo, haloalkyl, -CN, -N(R) A ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, and -O-alkyl groups; where each R A H or C 1-6 It is alkyl; L 1 is -C(O)-NR L1 -, -OC(S)-NRL1 -, -OC(O)-NR L1 -, -NR L1 -C(O)-, -NR L1 -C(O)-O-, -NH-C(O)-NH-, -NR L1 -C(S)-NR L1 -, -NR L1 -S(O)2-, -S(O)2-NR L1 -, -CH2-CH2-, -CH2-NR L1 -, -NR L1 -CH2-, -CH2-O-, -O-CH2-, -O-, -NH-, -C(O)-azetidinyl, -CH2-NR L1 -C(O)-, -C(O)-NR L1 -CH2- or -C(O)-; where each R L1 H or C 1-6 Alkyl; and as L 2 is -C(O)-NR L2 -, -S(O)2-NR L2 -, -CH2-CH2-, -C(S)-NR L2 -, -C(O)-, or -S(O)2-; where each R L2 H or C 1-6 Alkyl; and as B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, an aryl, a heteroaryl, a cycloalkyl, a -CH2-heterocyclyl, or a heterocyclyl, where aryl, heteroaryl, cycloalkyl, or heterocyclyl is aryl, heteroaryl, -Y B -Aryl, -Y B -heteroaryl, -Y B -Optionally substituted with a heterocyclyl or cycloalkyl group; where Y B -O-, -CH2-, -C(O)-, -N(R B1 )-, -S(O)-, or -S(O)2-; where R B1 is H or C 1-6 It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH2-aryl, -CH2-heteroaryl, each aryl, each heteroaryl, each cycloalkyl, -CH2-heterocyclyl, and each heterocyclyl are alkyl, halo, haloalkyl, -CN, -N(R) B2 ) Optionally substituted with one or more substituents selected from the group consisting of 2, -OH, -O-alkyl, and oxo; where each R B2 H or C 1-6 It is alkyl; Here, the compound is of formula (IA); A is phenyl, and L 1 If is -C(O)-NH-, then B is [ka] Not; Here, if the compound is of formula (IA); A is a substituted phenyl and B is a substituted phenyl, then L 1 This is not -C(O)-NH-, -NH-C(O)-, -NCH3-C(O)-, or -NH-C(O)-NH-; Here, the compound is given by formula (IA); L 1 -C(O)-NR L1 -CH2- and B is optionally substituted phenyl, substituted pyridyl, or [ka] If; A is a substituted phenyl, substituted pyridyl, substituted thiophenyl, substituted thiazolyl, substituted pyrazolyl, [ka] Not; Here, the compound is of formula (IA); B is an optionally substituted -CH2-aryl, and A is an optionally substituted aryl; L 1 It is not -C(O)-NH-; Here, when the compound is of formula (II-A); A is optionally substituted phenyl, and B is optionally substituted phenyl, L 1 is not -C(O)-NCH3-.

[0283] Embodiment II-2. A compound of formula (I) or (II):

Chemical formula

Chemical formula

[0284] Embodiment II-3. Compound of formula (III): [ka] or a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, an aryl, or a heteroaryl, where the aryl or heteroaryl is optionally substituted with another aryl or heteroaryl; Here, a condensed bicyclic aryl, a condensed bicyclic heteroaryl, a -CH2-aryl, a -CH2-heteroaryl, each aryl, and each heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, A is an optionally substituted phenyl or thiophenyl, and L 3 If is -C(O)-NH-; B is [ka] Not; Here, if A is a substituted phenyl and B is a substituted phenyl, then L 3is not -C(O)-NH-, -NH-C(O)-, -NCH3-C(O)-, or -NH-C(O)-NH-; where the compound is of formula (I); B is optionally substituted -CH2-aryl, and A is optionally substituted aryl; L 3 is not -C(O)-NH-.

[0285] Embodiment II-4. A compound of formula (IV):

Chemical formula

Chemical formula

[0286] Embodiment II-5. Compound of formula (V): [ka] or a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B1 is a condensed bicyclic aryl or condensed bicyclic heteroaryl; where the condensed bicyclic aryl and condensed bicyclic heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, A is an optionally substituted phenyl or thiophenyl, and L 3 If is -C(O)-NH-, then B is [ka] isn't it.

[0287] Embodiment II-6. The compound of Embodiment II-5, or a pharmaceutically acceptable salt or tautomer thereof, wherein B1 is a condensed bicyclic aryl compound.

[0288] Embodiment II-7. The compound of Embodiment II-5, or a pharmaceutically acceptable salt or tautomer thereof, wherein B1 is a condensed bicyclic heteroaryl.

[0289] Embodiment II-8. B1 is, [ka] A compound of Embodiment II-5, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the above.

[0290] Embodiment II-9. Compound of formula (VI): [ka] or a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B2 is a monocyclic aryl or monocyclic heteroaryl; where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Y 1 It does not exist, or -O-, -C(O)-, -N(R Y )-, -S(O)-, or -S(O)2-; where R Y is H or C 1-6 Alkyl; and as B3 is a monocyclic aryl or monocyclic heteroaryl; where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

[0291] Embodiment II-10. The compound of Embodiment II-9, or a pharmaceutically acceptable salt or tautomer thereof, wherein B2 is a monocyclic aryl compound.

[0292] Embodiment II-11. The compound of Embodiment II-9, or a pharmaceutically acceptable salt or tautomer thereof, wherein B2 is a monocyclic heteroaryl compound.

[0293] Embodiment II-12. The compound of Embodiment II-9, or a pharmaceutically acceptable salt or tautomer thereof, wherein B3 is a monocyclic aryl compound.

[0294] Embodiment II-13. The compound of Embodiment II-9, or a pharmaceutically acceptable salt or tautomer thereof, wherein B3 is a monocyclic heteroaryl compound.

[0295] Embodiment II-14. [ka] but, [ka] A compound of Embodiment II-9, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the above.

[0296] Embodiment II-15. Compound of formula (VII): [ka] or a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; L 3 is -C(O)-NR L3 -, -OC(S)-NR L3 -, -OC(O)-NR L3 -, -NR L3 -C(O)-, -NR L3 -C(S)-NR L3 -, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, -NR L3 -CH2-, -CH2-O-, -O-CH2-, or -O-; where each R L3 These are independently hydrogen or C 1-6 Alkyl; and as B1 is a condensed bicyclic aryl or condensed bicyclic heteroaryl; where the condensed bicyclic aryl and condensed bicyclic heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, A is an optionally substituted phenyl or thiophenyl, and L 3 If is -C(O)-NH-; B is [ka] isn't it.

[0297] Embodiment II-16. The compound of Embodiment II-15, or a pharmaceutically acceptable salt or tautomer thereof, wherein B4 is -CH2-aryl.

[0298] Embodiment II-17. The compound of Embodiment II-15, or a pharmaceutically acceptable salt or tautomer thereof, wherein B4 is a -CH2-heteroaryl compound.

[0299] Embodiment II-18. B4 is, [ka] A compound of Embodiment II-15, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the above.

[0300] Embodiment II-19. [ka] but, [ka] The compound of Embodiment II-1 or II-2, or a pharmaceutically acceptable salt or tautomer thereof.

[0301] Embodiment II-20. [ka] but, [ka] The compound of Embodiment II-1 or II-2, or a pharmaceutically acceptable salt or tautomer thereof.

[0302] Embodiment II-21. [ka] but, [ka] The compound of Embodiment II-1 or II-2, or a pharmaceutically acceptable salt or tautomer thereof.

[0303] Embodiment II-22. One of the compounds from Embodiments II-1 to II-2 and II-19 to II-21, or a pharmaceutically acceptable salt or tautomer thereof, where X is N or NH.

[0304] Embodiment II-23. One compound from Embodiments II-1 to II-2 and II-19 to II-21, or a pharmaceutically acceptable salt or tautomer thereof, where X is C, CH, or CH2.

[0305] Embodiment II-24. R 1 However, one of the compounds from Embodiments II-1 to II-2 and II-19 to II-23, or a pharmaceutically acceptable salt or tautomer thereof, is H.

[0306] Embodiment II-25. R 1 However, C 1-6 A compound that is alkyl, one of the compounds from embodiments II-1 to II-2 and II-19 to II-23, or a pharmaceutically acceptable salt or tautomer thereof.

[0307] Embodiment II-26. R 1 However, one of the compounds from Embodiments II-1 to II-2 and II-19 to II-23, which is a cycloalkyl compound, or a pharmaceutically acceptable salt or tautomer thereof.

[0308] Embodiment II-27. R 1 However, the compound is a heterocycline, one of the compounds in Embodiments II-1 to II-2 and II-19 to II-23, or a pharmaceutically acceptable salt or tautomer thereof.

[0309] Embodiment II-28. R 1 However, -C(O)R 1a The compound is one of the compounds from Embodiments II-1 to II-2 and II-19 to II-23, or a pharmaceutically acceptable salt or tautomer thereof.

[0310] Embodiment II-29. R1 However, one of the compounds from Embodiments II-1 to II-2 and II-19 to II-23, which is a -CH2-aryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

[0311] Embodiment II-30. A compound from any one of Embodiments II-1 to II-29, or a pharmaceutically acceptable salt thereof, wherein A is an aryl compound.

[0312] Embodiment II-31. A compound of Embodiment II-30, or a pharmaceutically acceptable salt or tautomer thereof, wherein the aryl is substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

[0313] Embodiment II-32. A compound from any one of Embodiments II-1 to II-29, or a pharmaceutically acceptable salt or tautomer thereof, wherein A is a 5- to 6-membered heteroaryl.

[0314] Embodiment II-33. A compound of Embodiment II-32, or a pharmaceutically acceptable salt or tautomer thereof, wherein the heteroaryl is substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

[0315] Embodiment II-34. A is an alkyl compound, one of the compounds from Embodiments II-1 to II-29, or a pharmaceutically acceptable salt or tautomer thereof.

[0316] Embodiment II-35. A compound from any one of Embodiments II-1 to II-29, or a pharmaceutically acceptable salt or tautomer thereof, wherein A is a cycloalkyl compound.

[0317] Embodiment II-36. A is a heterocyclyl, one of the compounds from Embodiments II-1 to II-29, or a pharmaceutically acceptable salt or tautomer thereof.

[0318] Embodiment II-37. A compound from any one of Embodiments II-1 to II-29, or a pharmaceutically acceptable salt or tautomer thereof, wherein A is a condensed bicyclic aryl or condensed bicyclic heteroaryl.

[0319] Embodiment II-38. A compound from any one of Embodiments II-1 to II-29, or a pharmaceutically acceptable salt or tautomer thereof, wherein A is a -CH2-aryl or -CH2-heteroaryl compound.

[0320] Embodiment II-39. L 1 However, -C(O)-NR L1 -A compound from any one of embodiments II-1 to II-2 and II-18 to II-38, or a pharmaceutically acceptable salt or tautomer thereof.

[0321] Embodiment II-40. L 1 However, -OC(S)-NR L1 -A compound from any one of embodiments II-1 to II-2 and II-18 to II-38, or a pharmaceutically acceptable salt or tautomer thereof.

[0322] Embodiment II-41. L 1 However, -OC(O)-NR L1 -A compound from any one of embodiments II-1 to II-2 and II-18 to II-38, or a pharmaceutically acceptable salt or tautomer thereof.

[0323] Embodiment II-42. L 1 However, -NR L1 -C(S)-NR L1 -A compound from any one of embodiments II-1 to II-2 and II-18 to II-38, or a pharmaceutically acceptable salt or tautomer thereof.

[0324] Embodiment II-43. L 1 However, one of the compounds from Embodiments II-1 to II-2 and II-18 to II-38, which is -O-, or a pharmaceutically acceptable salt or tautomer thereof.

[0325] Embodiment II-44. L 1 However, -NR L1 -C(O)-, -NR L1 -C(O)-O-, -NH-C(O)-NH-, -NR L1 -S(O)2-, or -S(O)2-NR L1 -A compound from any one of embodiments II-1 to II-2 and II-18 to II-38, or a pharmaceutically acceptable salt or tautomer thereof.

[0326] Embodiment II-45. L 1 However, -CH2-CH2-, -CH2-NR L1 -, -NR L1 A compound from any one of Embodiments II-1 to II-2 and II-18 to II-38, which is -CH2-, -CH2-O-, -O-CH2-, -NH-, or -C(O)-azetidinyl, or a pharmaceutically acceptable salt or tautomer thereof.

[0327] Embodiment II-46. L 2 However, -C(O)-NR L2 -A compound from any one of embodiments II-1 to II-2 and II-18 to II-38, or a pharmaceutically acceptable salt or tautomer thereof.

[0328] Embodiment II-47. L 2 However, -S(O)2-NR L2 A compound from any one of Embodiments II-1 to II-2 and II-18 to II-38, which is - or -CH2-CH2-, or a pharmaceutically acceptable salt or tautomer thereof.

[0329] Embodiment II-48. L 3 However, -C(O)-NR L3 -A compound from any one of embodiments II-3 to II-18 and II-30 to II-38, or a pharmaceutically acceptable salt or tautomer thereof.

[0330] Embodiment II-49. L 3However, -OC(S)-NR L3 -A compound from any one of embodiments II-3 to II-18 and II-30 to II-38, or a pharmaceutically acceptable salt or tautomer thereof.

[0331] Embodiment II-50. L 3 However, -OC(O)-NR L3 -A compound from any one of embodiments II-3 to II-18 and II-30 to II-38, or a pharmaceutically acceptable salt or tautomer thereof.

[0332] Embodiment II-51. L 3 However, -NR L3 -C(S)-NR L3 -A compound from any one of embodiments II-3 to II-18 and II-30 to II-38, or a pharmaceutically acceptable salt or tautomer thereof.

[0333] Embodiment II-52. L 3 However, -NR L3 -C(O)-, -NR L3 -S(O)2-, -S(O)2-NR L3 -, -CH2-CH2-, -CH2-NR L3 -, or -NR L3 A compound from any one of embodiments II-3 to II-18 and II-30 to II-38, which is -CH2-, or a pharmaceutically acceptable salt or tautomer thereof.

[0334] Embodiment II-53. L 3 However, one of the compounds from Embodiments II-3 to II-18 and II-30 to II-38, which is -CH2-O-, -O-CH2-, or -O-, or a pharmaceutically acceptable salt or tautomer thereof.

[0335] Embodiment II-54. A compound from any one of Embodiments II-1 to II-4 and II-19 to II-53, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is a condensed bicyclic aryl compound.

[0336] Embodiment II-55. A compound from any one of Embodiments II-1 to II-4 and II-19 to II-53, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is a condensed bicyclic heteroaryl.

[0337] Embodiment II-56. B is, [ka] A compound selected from the group consisting of, one of embodiments II-1 to II-4 and II-19 to II-53, or a pharmaceutically acceptable salt or tautomer thereof.

[0338] Embodiment II-57. One compound from Embodiments II-1 to II-4 and II-19 to II-53, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is a -CH2-aryl compound.

[0339] Embodiment II-58. One compound from Embodiments II-1 to II-4 and II-19 to II-53, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is a -CH2-heteroaryl compound.

[0340] Embodiment II-59. B is, [ka] A compound selected from the group consisting of, one of embodiments II-1 to II-4 and II-19 to II-53, or a pharmaceutically acceptable salt or tautomer thereof.

[0341] Embodiment II-60. A compound from any one of Embodiments II-1 to II-4 and II-19 to II-52, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is an aryl compound.

[0342] Embodiment II-61. One compound from Embodiments II-1 to II-4 and II-19 to II-52, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is an aryl or heteroaryl-substituted aryl.

[0343] Embodiment II-62. A compound from any one of Embodiments II-1 to II-4 and II-19 to II-52, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is a heteroaryl compound.

[0344] Embodiment II-63. One compound from Embodiments II-1 to II-4 and II-19 to II-52, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is a heteroaryl substituted with an aryl or heteroaryl.

[0345] Embodiment II-64. B is, [ka] A compound selected from the group consisting of, one of embodiments II-1 to II-4 and II-19 to II-52, or a pharmaceutically acceptable salt or tautomer thereof.

[0346] Embodiment II-65. A compound from any one of Embodiments II-1 to II-4 and II-19 to II-52, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is a cycloalkyl compound.

[0347] Embodiment II-66. B is aryl, heteroaryl, -Y B -Aryl, -Y B -A cyclocyclyl substituted with a heteroaryl molecule, one of the compounds from Embodiments II-1 to II-4 and II-19 to II-52, or a pharmaceutically acceptable salt or tautomer thereof.

[0348] Embodiment II-67. One compound from Embodiments II-1 to II-4 and II-19 to II-52, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is a -CH2-heterocycline.

[0349] Embodiment II-68. A compound from any one of Embodiments II-1 to II-4 and II-19 to II-52, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is a heterocycline.

[0350] Embodiment II-69. One compound from Embodiments II-1 to II-4 and II-19 to II-52, or a pharmaceutically acceptable salt or tautomer thereof, wherein B is a heterocyclyl substituted with an aryl or heteroaryl.

[0351] Embodiment II-70. A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the following: [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6]

[0352] Embodiment II-71. A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the following: [Table 9-1] [Table 9-2]

[0353] Embodiment II-72. A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the following: [Table 10]

[0354] Embodiment II-73. A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the following: [Table 11-1] [Table 11-2] [Table 11-3]

[0355] Embodiment II-74. A pharmaceutical composition containing one of the compounds from Embodiments II-1 to II-73, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable excipient.

[0356] Embodiment II-75. A method for modifying the activity of NR2F6 by exposing NR2F6 to an effective amount of one compound from Embodiments II-1 to II-73, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment II-74.

[0357] Embodiment II-76. The method of Embodiment II-75, wherein the regulation includes enhancement of NR2F6 activity.

[0358] Embodiment II-77. The method of Embodiment II-75, wherein the regulation includes inhibition of NR2F6 activity.

[0359] Embodiment II-78. A method for treating or alleviating the effects of a disease or disorder related to NR2F6 regulation, comprising administering an effective amount of one compound from Embodiments II-1 to II-73, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment II-76.

[0360] Embodiment II-79. The method of Embodiment II-78, wherein the disease or disorder includes an enhanced autoimmune response.

[0361] Embodiment II-80. The method according to Embodiment II-79, wherein the enhanced autoimmune response is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus (lupus), inflammatory bowel disease, multiple sclerosis, type 1 diabetes mellitus, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, psoriasis / psoriatic arthritis, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, and vasculitis.

[0362] Embodiment II-81. The method of Embodiment II-78, wherein the disorder is cancer.

[0363] Embodiment II-82. The method of Embodiment II-81, wherein the cancer is a solid tumor selected from the group consisting of lung adenocarcinoma, cholangiocarcinoma, bladder cancer; bone cancer, brain tumor, glioma, undifferentiated oligodendroglioma, adult glioblastoma multiforme, adult undifferentiated astrocytoma; benign prostatic hyperplasia, bronchoalveolar carcinoma, breast cancer including metastatic breast cancer; cervical cancer, cholangiocarcinoma, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, squamous cell carcinoma of the head and neck, gallbladder cancer, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, melanoma; neuroendocrine carcinoma, metastatic neuroendocrine tumor, non-small cell lung cancer (NSCLC), small cell lung cancer, ovarian cancer, primary peritoneal cancer, pancreatic cancer, prostate cancer including androgen-dependent and androgen-independent prostate cancer, colorectal cancer, kidney cancer, metastatic renal cell carcinoma, soft tissue sarcoma, bladder cancer, and uterine cancer.

[0364] Embodiment II-83. The method of Embodiment II-78, wherein the disorder is a hematological malignancy.

[0365] Embodiment II-84. The method of Embodiment II-83, wherein the hematological malignancy is selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia (CML), accelerated CML, CML acute transformation phase (CML-BP), acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), Hodgkin's disease, non-Hodgkin lymphoma, follicular lymphoma, mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma, Valdenström macroglobulinemia, myelodysplastic syndrome (MDS), refractory anemia (RA), RA with ring sideroblasts, RA with supervast blasts (RAEB), transformed RAEB, and myeloproliferative syndromes.

[0366] Embodiment II-85. A method for treating or alleviating the effects of a gastrointestinal disorder or ailment, comprising administering an effective amount of one compound from Embodiments II-1 to II-73, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment II-4.

[0367] Embodiment II-86. The method of Embodiment II-85, wherein the gastrointestinal disease is IBD, Crohn's disease, or colitis.

[0368] Embodiment II-87. A method for treating a condition associated with hepatic steatohepatia, comprising administering an effective amount of one compound from Embodiments II-1 to II-73, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment II-74.

[0369] Embodiment II-88. The method of Embodiment II-87, wherein the pathological condition associated with hepatic steatosis is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0370] Embodiment II-89. Any one compound from Embodiments II-1 to II-73, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment II-74, for use in modulating the activity of NR2F6.

[0371] Embodiment II-90. Any one compound from Embodiments II-1 to II-73, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition of Embodiment II-74, for use in treating or alleviating the effects of a disease or disorder related to NR2F6 regulation.

[0372] Embodiment II-91. Use of any one compound from Embodiments II-1 to II-73, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment II-74, for the modulation of NR2F6 activity.

[0373] Embodiment II-92. Use of any one compound from Embodiments II-1 to II-73, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition of Embodiment II-74, in the manufacture of a pharmaceutical product for treating or alleviating the effects of a disease or disorder related to NR2F6 regulation.

[0374] Embodiment II-93. Use of any one compound, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment II-74, in the manufacture of a pharmaceutical for modulating the activity of NR2F6.

[0375] Embodiment II-94. Use of any one compound from Embodiments II-1 to II-73, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition of Embodiment II-4, in the manufacture of a pharmaceutical for treating or alleviating the effects of a disease or disorder related to NR2F6 regulation. [Examples]

[0376] Examples All percentages and ratios used herein are by weight unless otherwise specified. Other characteristics and advantages of this disclosure will become apparent from the various examples. The provided examples illustrate various components and methodologies useful in the practice of this disclosure. In general, this disclosure extends to any novel characteristics or any novel combination of characteristics disclosed herein (including the appended claims and drawings). The examples do not limit the claimed disclosure. Accordingly, any characteristics, integers, features, compounds or compound parts described in connection with a particular aspect, embodiment or example of this disclosure should be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. Based on this disclosure, a person skilled in the art can identify and utilize other components and methodologies useful in the practice of this disclosure. Unless further noted, any characteristic disclosed herein may be replaced by an alternative characteristic that serves the same or similar purpose.

[0377] This “Disclosure” will be explained here for illustrative purposes by simply referring to the “Examples” below:

[0378] Example Preparation of compounds General methods and materials All chemicals were purchased from Sigma-Aldrich, Alfa Aesar. Deuterated solvents were used as shown below. 1 The H NMR spectra were recorded at 200 and 400 MHz, and 13¹³C NMR spectra were recorded at 100.6 and 50.3 MHz. TLC was performed on an aluminum-backed silica plate (silica gel 60F254). All reactions were carried out under a nitrogen atmosphere using distilled solvents. All test compounds were found to have a purity >95% as determined by HPLC analysis. HPLC-grade water was obtained from a tandem Milli-Ro / Milli-Q instrument. HPLC measurements for analysis were performed on a Shimadzu LC-20A Prominence equipped with a CBM-20A communication bus module, two LC-20AD dual-piston pumps, an SPD-M20A photodiode array detector, and a Rheodyne 7725i injector with a 20 μL stainless steel loop.

[0379] The abbreviations used in the following examples and elsewhere in this specification are as follows: Ac2O Acetic anhydride Acetic acid (ACOH) AIBN Azobisisobutyronitrile ATM (Atmosphere) brs wide single line DIPEA N,N-diisopropylethylamine DCM Dichloromethane DME (Dimethoxyethane) DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) d double line dd double double line EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride ESI Ionizing Electrospray EtMgBr Ethyl Magnesium Bromide HCl ethyl acetate Et2O Diethyl ether EtOH Ethanol EtO - Na + Sodium ethoxide h (times) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate HPLC (High-Performance Liquid Chromatography) iPrOH isopropanol LCMS Liquid Chromatography-Mass Spectrometry m multiplet MeI methyl iodide MeOH methanol MHz (megahertz) min (multiple minutes) MS molecular sieve MW Microwave NBS (N-bromosuccinate) NMR nuclear magnetic resonance PET petroleum ether one part per million ppm p-TSA para-toluenesulfonic acid q quadruple line rt room temperature s Single line TLC (Thin-Layer Chromatography) THF (Tetrahydrofuran) t triple line UHPLC (Ultra-High-Performance Liquid Chromatography) v / v volume / volume

[0380] Example 1: 1-(tert-butoxycarbonyl)-4-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (1.6) [ka] Step 1: Ethyl 1-benzyl-4-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate (1,3) A solution of TFA (0.15 mL, 1.98 mmol) in CH2Cl2 (3 mL) was added dropwise to a stirred solution of intermediates 1.1 (2.0 g, 11.48 mmol) and 1.2 (8.1 mL, 31.69 mmol) in CH2Cl2 (50 mL) cooled to 0-5°C. The resulting mixture was stirred at rt for 18 hours. The reaction product was poured into H2O (100 mL) to separate the two phases. The organic phase was washed with brine (100 mL) and saturated aqueous solution of NaHCO3 (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (PET / SiO4, from 100% PET to 80:20 v / v PET / SiO4). Intermediate 1.3 (2.71 g, 8.82 mmol) was obtained in 77% yield. MS-ESI(+) m / z: 308.4 (M+H).

[0381] Step 2: 1-tert-butyl 3-ethyl 4-phenyl-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (1.5) DIPEA (1.75 mL, 10.03 mmol) and 1-chloroethyl chloroformate (2.45 mL, 22.79 mmol) were added to a stirred solution of intermediate 1.3 (2.80 g, 9.12 mmol) in CH2Cl2 (100 mL), and the resulting mixture was stirred at reflux temperature for 1 hour. After cooling to room temperature, volatile substances were removed under reduced pressure. The crude product was dissolved in MeOH (50 mL) and vigorously stirred under reflux for 1 hour. This reaction product was cooled to room temperature and concentrated under reduced pressure. The resulting oily residue (intermediate 1.4) was dissolved in CH2Cl2 (70 mL) and reacted with Boc2O (2.38 g, 10.94 mmol) and DIPEA (4.77 mL, 27.35 mmol) at rt for 3 hours. This mixture was washed with 0.5 M citric acid aqueous solution (50 mL), 10% NaHCO3 aqueous solution (50 mL), and brine (50 mL), dried on Na2SO4, and concentrated under reduced pressure. 4.2 g of intermediate 1.5 was obtained and used directly in the next step. MS-ESI(+) m / z 318.3 (M+H-100).

[0382] Step 3: 1-(tert-butoxycarbonyl)-4-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (1.6) A stirred solution of intermediate 1.5 (crude material from the previous step, 9.12 mmol) in MeOH (45 mL) was treated with 2.0 M aqueous NaOH (45.5 mL, 91.15 mmol) at rt for 1 hour. This mixture was then concentrated under reduced pressure to 1 / 3 of its original volume and diluted with 50 mL of H2O. This solution was washed with Et2O (3 × 25 mL) and then acidified to pH=1 by adding 37% HCl. The aqueous phase was extracted with SiO2 (3 × 50 mL), washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. 1.77 g of the title intermediate 1.6 was obtained as a light brown solid (yield from intermediate 1.3: 67%). MS-ESI(-) m / z 288.1 (MH).

[0383] Example 2: tert-butyl (±)-trans-3-hydroxy-4-phenylpyrrolidine-1-carboxylate (2.2) [ka] Step 1: tert-butyl (±)-trans-3-hydroxy-4-phenylpyrrolidine-1-carboxylate (2.2) A solution of intermediate 2.1 (2.36 g, 12.74 mmol) in THF (20 mL) was added dropwise to a stirred solution of 3.0 M phenylmagnesium bromide (8.5 mL, 25.48 mmol) in Et2O cooled to 0-5°C and CuI (0.12 g, 0.63 mmol) in THF (20 mL). The reaction mixture was slowly heated to rt and stirred for 3 hours. Next, the mixture was diluted with SiO (50 mL) and carefully quenched by adding brine (50 mL). The two phases were separated, and the aqueous phase was extracted with SiO (2 × 50 mL). The collected organic layer was washed with 0.5 M aqueous citric acid solution (30 mL) and brine (30 mL), dried on Na2SO4, and concentrated under reduced pressure. This crude substance was purified by flash chromatography (PET / siRNA, 85:15 to 40:60 v / v) to yield 3.17 g (23.92 mmol) (94%) of the title intermediate 2.2. MS-ESI(-) m / z 262.6 (MH).

[0384] Example 3: tert-butyl (±)-cis-3-hydroxy-4-phenylpyrrolidine-1-carboxylate (3.3) [ka] Step 1: tert-butyl (±)-cis-3-phenyl-4-{[(4-nitrophenyl)carbonyl]oxy}pyrrolidine-1-carboxylate (3.2) A solution of intermediate 2.2 (1.06 g, 4.01 mmol) and triphenylphosphine (1.26 g, 4.81 mmol) in THF (10 mL) was added dropwise to a stirred solution of DIAD (0.94 mL, 4.812 mmol) and intermediate 3.1 (0.80, 4.812 mmol) in THF (20 mL), cooled to 0-5°C under N2 air. This mixture was stirred at rt for 16 hours and then poured into a saturated aqueous solution of NaHCO3 (20 mL). The two phases were separated, and the aqueous phase was extracted with SiO2 (2 × 50 mL). The collected organic layer was washed with 0.5 M aqueous citrate (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. This crude substance was purified by flash chromatography (PET / siRNA, 90:10 to 70:30 v / v) to yield 1.64 g (3.98 mmol) (99%) of intermediate 3.2. MS-ESI(-) m / z 411.5 (MH).

[0385] Step 2: tert-butyl (±)-cis-3-hydroxy-4-phenylpyrrolidine-1-carboxylate (3.3) A stirred solution of intermediate 3.2 (1.64 g, 3.98 mmol) in MeOH (15 mL) was treated with K2CO3 (2.19 g, 15.91 mmol) at rt for 1 hour. This mixture was diluted with siRNA (50 mL), washed with H2O (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. This crude product was purified by flash chromatography (PET / siRNA, 90:10 to 60:40 v / v) to obtain 0.95 g (3.60 mmol) (89%) of the title intermediate 3.3. MS-ESI(-) m / z 262.6 (MH).

[0386] Example 4: (±)-trans-1-benzyl-4-phenylpyrrolidine-3-amine (4.3) [ka] Step 1: (±)-trans-1-benzyl-3-nitro-4-phenylpyrrolidine(4.2) Intermediate 4.2 was synthesized from intermediate 4.1 (2.00 g, 13.41 mmol), intermediate 1.2 (4.11 mL, 16.09 mmol), and TFA (0.10 mL, 1.34 mmol) in CH2Cl2 (20 mL) according to the procedure described in Step 1 of Example 1. Intermediate 4.2 (2.44 g, 8.64 mmol) was obtained after work-up and chromatographic purification (PET / SiO2, 8:2 v / v to 2:8 v / v). Yield: 64%. MS-ESI(+) m / z: 283.3 (M+H).

[0387] Step 2: (±)-trans-1-benzyl-4-phenylpyrrolidine-3-amine (4.3) 37% HCl (2.6 mL, 31.20 mmol) was added to a solution of intermediate 4.2 (400 mg, 1.42 mmol) in EtOH (5 mL). Then, zinc dust (741 mg, 11.34 mmol) was carefully added in small amounts, and the resulting mixture was stirred at rt for 16 hours. The mixture was then poured into a 28% NH3 aqueous solution (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The collected organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to yield 294 mg (1.17 mmol) of the title intermediate 4.3 in 82% yield. MS-ESI(+) m / z: 253.1 (M+H).

[0388] Example 5: tert-butyl (±)-trans-3-amino-4-phenylpyrrolidine-1-carboxylate (5.3) [ka] Step 1: tert-butyl (±)-trans-3-nitro-4-phenylpyrrolidine-1-carboxylate (5.2) Intermediate 5.1 was synthesized from intermediate 4.2 (710 mg, 2.52 mmol), DIPEA (0.48 mL, 2.77 mmol), and 1-chloroethyl chloroformate (0.68 mL, 6.29 mmol) in CH2Cl2 (30 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (10 mL). After removal of volatile substances, intermediate 5.1 was reacted with Boc2O (0.66 g, 3.02 mmol) and DIPEA (1.31 mL, 7.55 mmol) in CH2Cl2 (30 mL). After work-up and chromatographic purification (PET / siRNA, 80:20 to 50:50 v / v), intermediate 5.2 was obtained in 79% yield (582 mg, 1.99 mmol). MS-ESI(+) m / z 293.1 (M+H).

[0389] Step 2: tert-butyl (±)-trans-3-amino-4-phenylpyrrolidine-1-carboxylate (5.3) TMSCl (5.15 mL, 40.63 mmol) and Zn dust (2.81 g, 43.02 mmol) were sequentially added to a stirred solution of intermediate 5.2 (585 mg, 2.00 mmol) in MeOH (10 mL) cooled to 0°C. The resulting mixture was reacted under the same conditions for 1 hour. This mixture was filtered through a Celite pad under vacuum. The collected liquid was diluted with CH2Cl2 (50 mL), washed with saturated aqueous solution of NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to yield 400 mg of the title intermediate 5.3, which was used without purification. MS-ESI(+) m / z 263.4 (M+H).

[0390] Example 6: (±)-trans-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-3-carboxylic acid (6.5) [ka] Step 1: Ethyl (±)-trans 1-benzyl-4-phenylpyrrolidine-3-carboxylate (6.2) A solution of TFA (0.95 mL, 12.50 mmol) in toluene (10 mL) was added dropwise to a stirred solution of intermediates 6.1 (7.00 mL, 41.67 mmol) and 1.2 (11.7 mL, 45.84 mmol) in toluene (50 mL) cooled to 0-5°C. The resulting mixture was stirred at rt for 48 hours. The reaction product was poured into siRNA (50 mL) and H₂O (50 mL) to separate the two phases. The organic phase was washed with saturated aqueous solution of NaHCO₃ (60 mL) and brine (60 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by flash chromatography (PET / siRNA, PET / siRNA at 90:10 to 70:30 v / v). 7.01 g of intermediate 6.2 was obtained as a colorless oil (yield: 54%). MS-ESI(+) m / z: 310.5 (M+H).

[0391] Step 2: 1-tert-butyl 3-ethyl (±)-trans-4-phenylpyrrolidine-1,3-dicarboxylate (6.4) Intermediate 6.3 was synthesized from intermediate 6.2 (7.00 g, 22.62 mmol), DIPEA (4.33 mL, 24.89 mmol), and 1-chloroethyl chloroformate (6.17 mL, 57.24 mmol) in CH2Cl2 (100 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (100 mL). After removing volatile substances, intermediate 6.3 was reacted with Boc2O (5.43 g, 24.89 mmol) and DIPEA (11.82 mL, 7.55 mmol) in CH2Cl2 (100 mL). After workup, crude intermediate 6.4 was used without purification. MS-ESI(+) m / z 320.4 (M+H).

[0392] Step 3: (±)-trans-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-3-carboxylic acid (6.5) 4.0 M aqueous LiOH (28 mL, 0.11 mol) was added to a stirred solution of intermediate 6.4 (crude material from the previous step, 22.62 mmol) in MeOH (75 mL) and H2O (15 mL), and the reaction was vigorously stirred at rt for 4 hours. The mixture was then concentrated under reduced pressure to 1 / 4 of its original volume, H2O (30 mL) was added, and the opaque solution was washed with Et2O (3 × 50 mL). The aqueous phase was acidified to pH=1 by adding 37% HCl, and the resulting suspension was extracted with CH2Cl2 (3 × 50 mL). The collected organic layer was washed with brine (2 × 50 mL), dried over Na2SO4, and concentrated under reduced pressure. 5.95 g of the title intermediate 6.5 was obtained as a white powder (90% yield from intermediate 9.2). MS-ESI(-) m / z 290.1 ​​(MH).

[0393] Example 7: (±)-trans-1-(tert-butoxycarbonyl)-4-(thiophen-2-yl)pyrrolidine-3-carboxylic acid (7.7) [ka] Step 1: Methyl (2E)-3-(thiophen-2-yl)prop-2-enoate (7.3) Intermediate 7.2 (1.49 g, 4.46 mmol) was added to a stirred solution of intermediate 7.1 (0.33 mL, 3.57 mmol) in THF (10 mL) under N2 atmosphere, and the resulting mixture was stirred at rt for 24 hours. This mixture was concentrated under reduced pressure and purified by flash chromatography (PET / siRNA, 95:5 to 80:20 v / v PET / siRNA), yielding 561 mg (3.34 mmol) (93%) of intermediate 7.3 as white crystals. MS-ESI(-) m / z: 167.4 (MH).

[0394] Step 2: Methyl (±)-trans-1-benzyl-4-(thiophen-2-yl)pyrrolidine-3-carboxylate (7.4 ) Intermediate 7.4 was synthesized from intermediates 7.3 (548 mg, 3.26 mmol), 1.2 (1.08 mL, 4.24 mmol), and TFA (0.025 mL, 0.33 mmol) in CH2Cl2 (7.0 mL) according to the procedure described in Step 1 of Example 1. Intermediate 7.4 (740 mg, 2.46 mmol) was obtained after work-up and chromatographic purification (PET / siRNA, 8:2 v / v PET / siRNA from 100% PET). Yield: 75%. MS-ESI(+) m / z: 302.5 (M+H).

[0395] Step 3: 1-tert-butyl 3-methyl (±)-trans-4-(thiophen-2-yl)pyrrolidine-1,3-dicarboxylate (7.6) Intermediate 7.6 was synthesized from intermediate 7.4 (580 mg, 1.92 mmol), DIPEA (0.37 mL, 2.12 mmol), and 1-chloroethyl chloroformate (0.52 mL, 4.81 mmol) in CH2Cl2 (15 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (10 mL). After removal of volatile substances, intermediate 7.5 was reacted with Boc2O (630 mg, 2.87 mmol) and DIPEA (1.00 mL, 5.77 mmol) in CH2Cl2 (20 mL). After work-up and chromatographic purification (PET / siRNA, 90:10 to 70:30 v / v), intermediate 7.6 was obtained in 70% yield. MS-ESI(+) m / z 312.6 (M+H).

[0396] Step 4: (±)-trans-1-(tert-butoxycarbonyl)-4-(thiophen-2-yl)pyrrolidine-3-carboxylic acid (7.7) Intermediate 7.7 was synthesized from intermediate 7.6 (460 mg, 1.48 mmol) in MeOH (4 mL) and H2O (1 mL) and 4.0 M aqueous LiOH (1.84 mL, 7.39 mmol) according to the procedure described in Step 3 of Example 6. After workup, the title intermediate 7.7 was obtained as a white solid (440 mg, 1.48 mmol). Yield: quantitative. MS-ESI(-) m / z: 296.6 (MH).

[0397] Example 8: (±)-trans-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)pyrrolidine-3-carboxylic acid (8.6) [ka] Step 1: Methyl (2E)-3-(4-fluorophenyl)prop-2-enoate (8.2) Intermediate 8.2 was synthesized from intermediate 8.1 (0.34 mL, 3.22 mmol) and intermediate 7.2 (1.35 g, 4.03 mmol) in THF (10 mL) according to the procedure described in Step 1 of Example 7. Intermediate 8.2 (557 mg) was obtained as white crystals after chromatographic purification (PET / SiO, 95:5 to 80:20 v / v). Yield: 96%. MS-ESI(-) m / z: 179.1 (MH).

[0398] Step 2: Methyl (±)-trans-1-benzyl-4-(4-fluorophenyl)pyrrolidine-3-carboxylate (8.3) Intermediate 8.3 was synthesized from intermediate 8.2 (544 mg, 3.02 mmol), intermediate 1.2 (1.0 mL, 3.92 mmol), and TFA (0.023 mL, 0.30 mmol) in CH2Cl2 (6.5 mL) according to the procedure described in Step 1 of Example 1. Intermediate 8.3 (689 mg, 2.20 mmol) was obtained after work-up and chromatographic purification (PET / siRNA, 8:2 v / v PET / siRNA from 100% PET). Yield: 73%. MS-ESI(+) m / z: 314.5 (M+H).

[0399] Step 3: 1-tert-butyl 3-methyl (±)-trans-4-(4-fluorophenyl)pyrrolidine-1,3-dicarboxylate (8.5) Ammonium formate (410 mg, 6.51 mmol) and 10% Pd / C (68 mg) were added to a stirred solution of 8.3 (680 mg, 2.17 mmol) in MeOH (5 mL) under N2 air. The resulting mixture was stirred at 70°C for 1 hour. After cooling to rt, the mixture was filtered under vacuum through a Celite pad to obtain the methanol solution of 8.4. This solution was cooled to 0°C, and Et3N (1.51 mL, 10.85 mmol) and Boc2O (1.42 g, 6.51 mmol) were added. The resulting mixture was reacted at rt for 3 hours. Volatile substances were removed under reduced pressure, and the crude substance was poured into RINKAN (15 mL) and washed with 0.5 M citric acid aqueous solution (15 mL) and brine (15 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. After chromatographic purification (PET / siRNA, 90:10 to 70:30 v / v), intermediate 8.5 was obtained as a colorless oil (572 mg, 1.77 mmol, yield 81%). MS-ESI(+) m / z: 324.6 (M+H).

[0400] Step 4: (±)-trans-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)pyrrolidine-3-carboxylic acid (8.6) Intermediate 8.6 was synthesized from intermediate 8.5 (561 mg, 1.73 mmol) in MeOH (5 mL) and H2O (1 mL) and 4.0 M aqueous LiOH (2.5 mL, 8.67 mmol) according to the procedure described in Step 3 of Example 6. After workup, the title intermediate 8.6 was obtained as a white solid (417 mg, 1.35 mmol). Yield: 78%. MS-ESI(-) m / z: 308.5 (MH).

[0401] Example 9: (±)-trans-1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylic acid (12.7) [ka] Step 1: Methyl (2E)-3-(3-fluorophenyl)prop-2-enoate (9.2) Intermediate 9.2 was synthesized from 9.1 (0.34 mL, 3.22 mmol) and intermediate 7.2 (1.35 g, 4.03 mmol) in THF (10 mL) according to the procedure described in Step 1 of Example 7. Intermediate 9.2 (550 mg, 3.05 mmol) was obtained as white crystals after chromatographic purification (PET / siRNA, 95:5 to 70:30 v / v). Yield: 95%. MS-ESI(-) m / z: 179.2 (MH).

[0402] Step 2: Methyl (±)-trans-1-benzyl-4-(3-fluorophenyl)pyrrolidine-3-carboxylate (9.3) Intermediate 9.3 was synthesized from intermediate 9.2 (537 mg, 2.98 mmol), intermediate 1.2 (0.99 mL, 3.87 mmol), and TFA (0.023 mL, 0.30 mmol) in CH2Cl2 (6.5 mL) according to the procedure described in Step 1 of Example 1. Intermediate 9.3 (768 mg, 2.45 mmol) was obtained after work-up and chromatographic purification (PET / siRNA, 8:2 v / v PET / siRNA from 100% PET). Yield: 82%. MS-ESI(-) m / z: 314.5 (MH).

[0403] Step 3: 1-tert-butyl 3-methyl (±)-trans-4-(3-fluorophenyl)pyrrolidine-1,3-dicarboxylate (9.5) Intermediate 9.4 was synthesized from intermediate 9.3 (745 mg, 2.38 mmol), 10% Pd / C (70 mg), and ammonium formate (450 mg, 7.13 mmol) in MeOH (10 mL) according to the procedure described in Step 3 of Example 8. After filtration, the liquid containing intermediate 9.4 was treated with Et3N (1.65 mL, 11.89 mmol) and Boc2O (1.55 g, 7.13 mmol). Title intermediate 9.5 (714 mg, 2.21 mmol) was obtained after work-up and chromatographic purification (PET / siRNA, 90:10 to 70:30 v / v). Yield: 93%. MS-ESI(+) m / z: 324.6 (M+H).

[0404] Step 4: (±)-trans-1-(tert-butoxycarbonyl)-4-(3-fluorophenyl)pyrrolidine-3-carboxylic acid (9.6) Intermediate 9.6 was synthesized from intermediate 9.5 (696 mg, 2.15 mmol) in MeOH (6 mL) and H2O (1.5 mL) and 4.0 M aqueous LiOH (3.0 mL, 10.76 mmol) according to the procedure described in Step 3 of Example 6. After workup, the title intermediate 9.6 was obtained as a white solid (573 mg, 1.85 mmol). Yield: 86%. MS-ESI(-) m / z: 308.5 (MH).

[0405] Example 10: (±)-trans-1-(tert-butoxycarbonyl)-4-(2-fluorophenyl)pyrrolidine-3-carboxylic acid (10.6) [ka] Step 1: Methyl (2E)-3-(2-fluorophenyl)prop-2-enoate (10.2) Intermediate 10.2 was synthesized from intermediate 10.1 (0.25 mL, 2.42 mmol) and intermediate 7.2 (1.01 g, 3.02 mmol) in THF (8 mL) according to the procedure described in Step 1 of Example 7. Intermediate 10.2 (408 mg, 2.26 mmol) was obtained as a colorless oil after chromatographic purification (PET / SiO, 90:10 to 80:20 v / v). Yield: 94%. MS-ESI(-) m / z: 179.2 (MH).

[0406] Step 2: Methyl (±)-trans-1-benzyl-4-(2-fluorophenyl)pyrrolidine-3-carboxylate (10.3) Intermediate 10.3 was synthesized from intermediate 10.2 (394 mg, 2.19 mmol), intermediate 1.2 (0.73 mL, 2.84 mmol), and TFA (0.017 mL, 0.22 mmol) in CH2Cl2 (4.5 mL) according to the procedure described in Step 1 of Example 1. Intermediate 10.3 (491 mg, 1.57 mmol) was obtained after work-up and chromatographic purification (PET / SiO, 8:2 v / v PET / SiO from 100% PET). Yield: 72%. MS-ESI(-) m / z: 314.5 (MH).

[0407] Step 3: 1-tert-butyl 3-methyl (±)-trans-4-(2-fluorophenyl)pyrrolidine-1,3-dicarboxylate (10.5) Intermediate 10.5 was synthesized from intermediate 10.3 (495 mg, 1.58 mmol), 10% Pd / C (50 mg), and ammonium formate (299 mg, 4.74 mmol) in MeOH (10 mL) according to the procedure described in Step 3 of Example 8. After filtration, the liquid containing intermediate 10.4 was treated with Et3N (1.10 mL, 7.90 mmol) and Boc2O (1.03 g, 4.74 mmol). Intermediate 10.5 (475 mg, 1.47 mmol) was obtained after work-up and chromatographic purification (PET / SiO, 90:10 to 70:30 v / v). Yield: 93%. MS-ESI(+) m / z: 324.5 (M+H).

[0408] Step 4: (±)-trans-1-(tert-butoxycarbonyl)-4-(2-fluorophenyl)pyrrolidine-3-carboxylic acid (10.6) Intermediate 10.6 was synthesized from intermediate 10.5 (464 mg, 1.43 mmol) in MeOH (4 mL) and H2O (0.8 mL) and 4.0 M aqueous LiOH (2.0 mL, 7.17 mmol) according to the procedure described in Step 3 of Example 6. After workup, intermediate 10.6 was obtained as a white solid (477 mg, 1.43 mmol). Yield: quantitative. MS-ESI(-) m / z: 308.5 (MH).

[0409] Example 11: (±)-trans-1-(tert-butoxycarbonyl)-4-(tetrahydro-2H-pyran-4-yl)pyrrolidine-3-carboxylic acid (11.6) [ka] Step 1: Methyl (2E)-3-(tetrahydro-2H-pyran-4-yl)prop-2-enoate(11.2) Intermediate 11.2 was synthesized from intermediate 11.1 (500 mg, 4.38 mmol) and intermediate 7.2 (1.70 g, 4.88 mmol) in THF (20 mL) according to the procedure described in Step 1 of Example 7. Intermediate 11.2 (602 mg, 3.54 mmol) was obtained as a colorless oil after chromatographic purification (PET / SiO, 90:10 v / v from 100% PET). Yield: 81%. MS-ESI(-) m / z: 169.5 (MH).

[0410] Step 2: Methyl (±)-trans-1-benzyl-4-(tetrahydro-2H-pyran-4-yl)pyrrolidine-3-carboxylate (11.3) Intermediate 11.3 was synthesized from intermediate 11.2 (600 mg, 3.53 mmol), intermediate 1.2 (1.17 mL, 4.58 mmol), and TFA (0.02 mL, 0.35 mmol) in CH2Cl2 (10 mL) according to the procedure described in Step 1 of Example 1. Intermediate 11.3 (1.01 g, 3.33 mmol) was obtained after work-up and chromatographic purification (PET / SiO, 90:10 v / v from 100% PET). Yield: 94%. MS-ESI(+) m / z: 304.0 (M+H).

[0411] Step 3: 1-tert-butyl 3-methyl (±)-trans-4-(tetrahydro-2H-pyran-4-yl)pyrrolidine-1,3-dicarboxylate (11.5) Intermediate 11.5 was synthesized from intermediate 11.3 (1.00 g, 3.30 mmol), DIPEA (0.63 mL, 3.63 mmol), and 1-chloroethyl chloroformate (0.89 mL, 8.25 mmol) in CH2Cl2 (25 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (15 mL). After removal of volatile substances, intermediate 11.4 was reacted with Boc2O (1.08 g, 4.95 mmol) and DIPEA (1.72 mL, 9.90 mmol) in CH2Cl2 (25 mL). After work-up and chromatographic purification (PET / SiO2, 80:20 v / v from 100% PET), intermediate 11.5 (0.80 g, 2.55 mmol) was obtained in 78% yield. MS-ESI(+) m / z 314.5 (M+H).

[0412] Step 4: (±)-trans-1-(tert-butoxycarbonyl)-4-(tetrahydro-2H-pyran-4-yl)pyrrolidine-3-carboxylic acid (11.6) Intermediate 11.6 was synthesized from intermediate 11.5 (800 mg, 2.55 mmol) in MeOH (5 mL) and H2O (1 mL) and 4.0 M aqueous LiOH (3.6 mL, 14.4 mmol) according to the procedure described in Step 3 of Example 6. After workup, the title intermediate 11.6 was obtained as a white solid (0.65 g, 2.19 mmol). Yield: 86%. MS-ESI(-) m / z: 298.5 (MH).

[0413] Example 12: (±)-trans-1-(tert-butoxycarbonyl)-4-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (12.6) [ka] Step 1: Methyl (2E)-3-(4-methoxyphenyl)prop-2-enoate (12.2) Intermediate 12.2 was synthesized from intermediate 12.1 (0.36 mL, 2.94 mmol) and intermediate 7.2 (1.23 g, 3.67 mmol) in THF (10 mL) according to the procedure described in Step 1 of Example 7. Intermediate 12.2 (317 mg, 1.65 mmol) was obtained as white crystals after chromatographic purification (PET / SiO, 95:5 to 80:20 v / v). Yield: 68%. MS-ESI(-) m / z: 191.2 (MH).

[0414] Step 2: Methyl (±)-trans-1-benzyl-4-(4-methoxyphenyl)pyrrolidine-3-carboxylate (12.3) Intermediate 12.3 was synthesized from intermediate 12.2 (306 mg, 1.59 mmol), intermediate 1.2 (0.53 mL, 2.07 mmol), and TFA (0.012 mL, 0.16 mmol) in CH2Cl2 (3.5 mL) according to the procedure described in Step 1 of Example 1. Intermediate 12.3 (337 mg, 1.04 mmol) was obtained after work-up and chromatographic purification (PET / siRNA, 8:2 v / v PET / siRNA from 100% PET). Yield: 65%. MS-ESI(-) m / z: 326.5 (MH).

[0415] Step 3: 1-tert-butyl 3-methyl (±)-trans-4-(4-methoxyphenyl)pyrrolidine-1,3-dicarboxylate (12.5) Intermediate 12.5 was synthesized from intermediate 12.3 (330 mg, 1.01 mmol), 10% Pd / C (40 mg), and ammonium formate (183 mg, 3.04 mmol) in MeOH (10 mL) according to the procedure described in Step 3 of Example 8. After filtration, the liquid containing intermediate 12.4 was treated with Et3N (0.71 mL, 5.07 mmol) and Boc2O (664 mg, 3.04 mmol). Title intermediate 12.5 (333 mg, 0.98 mmol) was obtained after work-up and chromatographic purification (PET / siRNA, 95:5 to 80:20 v / v). Yield: 98%. MS-ESI(+) m / z 336.5 (M+H).

[0416] Step 4: (±)-trans-1-(tert-butoxycarbonyl)-4-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid (12.6) Intermediate 12.6 was synthesized from intermediate 12.5 (327 mg, 0.97 mmol) in MeOH (3 mL) and H2O (0.7 mL) and 4.0 M aqueous LiOH (1.5 mL, 4.87 mmol) according to the procedure described in Step 3 of Example 6. After workup, intermediate 12.6 was obtained as a white solid (244 mg, 0.76 mmol). Yield: 78%. MS-ESI(-) m / z: 320.4 (MH).

[0417] Example 13: (±)-trans-1-(tert-butoxycarbonyl)-4-cyclohexyl-pyrrolidine-3-carboxylic acid (13.1) [ka] Step 1: Methyl (2E)-3-cyclohexylpropa-2-enoate (13.2) Intermediate 13.2 was synthesized from intermediate 13.1 (1.08 mL, 8.92 mmol) and intermediate 7.2 (3.72 g, 11.14 mmol) in THF (15 mL) according to the procedure described in Step 1 of Example 7. Intermediate 13.2 (1.18 g, 7.01 mmol) was obtained as a colorless oil after chromatographic purification (PET / SiO2, constant composition 95:5 v / v). Yield: 78%. MS-ESI(-) m / z: 167.4 (MH).

[0418] Step 2: Methyl (±)-trans-1-benzyl-4-(cyclohexyl)pyrrolidine-3-carboxylate (13.3) Intermediate 13.3 was synthesized from intermediate 13.2 (1.15 g, 6.84 mmol), intermediate 1.2 (1.92 mL, 7.51 mmol), and TFA (0.16 mL, 2.05 mmol) in CH2Cl2 (30 mL) according to the procedure described in Step 1 of Example 1. Intermediate 13.3 (765 mg, 2.54 mmol) was obtained after work-up and chromatographic purification (PET / SiO, 90:10 v / v from 100% PET). Yield: 37%. MS-ESI(-) m / z: 300.6 (MH).

[0419] Step 3: 1-tert-butyl 3-methyl (±)-trans-4-(cyclohexyl)pyrrolidine-1,3-dicarboxylate (13.5) Intermediate 13.5 was synthesized from intermediate 13.3 (745 mg, 2.47 mmol), DIPEA (0.47 mL, 2.72 mmol), and 1-chloroethyl chloroformate (0.67 mL, 6.18 mmol) in CH2Cl2 (10 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (10 mL). After removal of volatile substances, intermediate 13.4 was reacted with Boc2O (593 mg, 2.72 mmol) and DIPEA (1.29 mL, 5.77 mmol) in CH2Cl2 (10 mL). After work-up, the crude product of intermediate 13.5 (1.0 g) was used without purification. MS-ESI(+) m / z 312.3 (M+H).

[0420] Step 4: (±)-trans-1-(tert-butoxycarbonyl)-4-(cyclohexyl)pyrrolidine-3-carboxylic acid (13.6) Intermediate 13.6 was synthesized from crude intermediate 13.5 (2.47 mmol) in MeOH (15 mL) and H2O (5 mL), and 4.0 M aqueous LiOH (3.0 mL, 12.34 mmol) according to the procedure described in Step 3 of Example 6. Yield from 11.3: 82%. MS-ESI(-) m / z: 296.4 (MH).

[0421] Example 14: (±)-trans-1-(tert-butoxycarbonyl)-4-benzyl-pyrrolidine-3-carboxylic acid (14.1) [ka] Step 1: Methyl (2E)-4-phenylbuta-2-enoate (14.2) Intermediate 14.2 was synthesized from intermediate 14.1 (0.93 mL, 8.33 mmol) and intermediate 7.2 (3.48 g, 10.41 mmol) in THF (15 mL) according to the procedure described in Step 1 of Example 7. Intermediate 14.2 (1.05 g) was obtained as a colorless oil after chromatographic purification (PET / SiO2, 95:5 to 80:20 v / v). Yield: 57%. MS-ESI(-) m / z: 175.2 (MH).

[0422] Step 2: Methyl (±)-trans-1,4-dibenzylpyrrolidine-3-carboxylate (14.3) Intermediate 14.3 was synthesized from intermediate 14.2 (1.02 g, 5.79 mmol), intermediate 1.2 (1.63 mL, 6.37 mmol), and TFA (0.13 mL, 1.74 mmol) in CH2Cl2 (20 mL) according to the procedure described in Step 1 of Example 1. Intermediate 14.3 (860 mg, 2.78 mmol) was obtained after work-up and chromatographic purification (PET / SiO2, 100% PET to 80:20 v / v). Yield: 48%. MS-ESI(-) m / z: 308.5 (MH).

[0423] Step 3: 1-tert-butyl 3-methyl (±)-trans-4-benzylpyrrolidine-1,3-dicarboxylate (14.5) Intermediate 14.5 was synthesized from intermediate 14.3 (840 mg, 2.72 mmol), DIPEA (0.52 mL, 2.99 mmol), and 1-chloroethyl chloroformate (0.73 mL, 6.79 mmol) in CH2Cl2 (10 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (10 mL). After removal of volatile substances, intermediate 14.4 was reacted with Boc2O (651 mg, 2.99 mmol) and DIPEA (1.42 mL, 8.15 mmol) in CH2Cl2 (10 mL). After workup, crude intermediate 14.5 (1.1 g) was used without purification. MS-ESI(+) m / z 320.3 (M+H).

[0424] Step 4: (±)-trans-4-benzyl-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (14.6) Intermediate 14.6 was synthesized from crude intermediate 14.5 (2.72 mmol) in MeOH (15 mL) and H2O (5 mL) and 4.0 M aqueous LiOH (3.4 mL, 13.58 mmol) according to the procedure described in Step 3 of Example 6. Yield from 2.3: 97%. MS-ESI(-) m / z: 304.8 (MH).

[0425] Example 15: (±)-trans-4-phenyl-1-(tetrahydro-2H-pyran-4-yl)pyrrolidine-3-carboxylate hydrochloride (15.3) [ka] Step 1: Ethyl (±)-trans-4-phenyl-1-(tetrahydro-2H-pyran-4-yl)pyrrolidine-3-carboxylate (15.2) In Example 6, the crude product obtained from the methanol decomposition in Step 2 was concentrated under reduced pressure. The resulting intermediate 6.3 (0.57 g, 2.26 mmol) was dissolved in CH2Cl2 (30 mL) and reacted with intermediate 15.1 (0.63 mL, 6.79 mmol) in the presence of sodium triacetoxyborohydride (1.92 g, 9.05 mmol). The resulting mixture was stirred at rt for 18 hours and then poured into a saturated aqueous solution of NaHCO3 (20 mL). The two phases were separated, and the aqueous phase was extracted with CH2Cl2 (2 × 30 mL). The collected organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. After chromatographic purification (CH2Cl2 / MeOH, 99:1 to 94:6 v / v), 630 mg (2.08 mmol) of intermediate 15.2 was obtained as a yellow oily substance (yield: 92%). MS-ESI(-) m / z 302.4 (MH).

[0426] Step 2: (±)-trans-4-phenyl-1-(tetrahydro-2H-pyran-4-yl)pyrrolidine-3-carboxylate hydrochloride (15.3) 5.0 M aqueous NaOH (2.0 mL, 10.05 mmol) was added to a solution of intermediate 15.2 (610 mg, 2.01 mmol) in MeOH (10 mL), and the mixture was stirred at rt for 16 hours. Volatile matter was removed under reduced pressure, and the crude substance was dissolved in H2O (8 mL) and acidified to pH=4.0 by adding 3.0 M HCl. This solution was washed with CH2Cl2 (3 × 5 mL) and concentrated under reduced pressure. The resulting solid was suspended in MeOH (5 mL) and filtered under vacuum. The collected liquid was concentrated under reduced pressure to yield the title intermediate 15.3 in nearly quantitative yield (548 mg, 1.99 mmol). MS-ESI(-) m / z 274.6 (MH).

[0427] Example 16: (±)-trans-1-acetyl-4-phenylpyrrolidine-3-carboxylic acid (16.2) [ka] Step 1: Ethyl (±)-trans-1-acetyl-4-phenylpyrrolidine-3-carboxylate (16.1) In Example 6, the crude product obtained from the methanol decomposition in Step 2 was concentrated under reduced pressure. The resulting intermediate 6.3 (0.57 g, 2.26 mmol) was dissolved in CH2Cl2 (30 mL) and reacted with acetic anhydride (0.32 mL, 3.39 mmol) and DIPEA (1.18 mL, 6.79 mmol) in CH2Cl2 (15 mL) for 3 hours. The mixture was washed with 0.5 M aqueous citric acid (15 mL) and brine (15 mL), dried on Na2SO4, and concentrated under reduced pressure. After chromatographic purification (CH2Cl2 / MeOH, 99:1 to 95:5 v / v), 0.59 g (2.26 mmol) of intermediate 16.1 was obtained as a yellow oily substance (quantitative yield). MS-ESI(-) m / z 260.5 (MH).

[0428] Step 2: (±)-trans-1-acetyl-4-phenylpyrrolidine-3-carboxylic acid (16.2) NaOH (488 mg, 12.21 mmol) was added to a stirred solution of intermediate 16.1 (638 mg, 2.44 mmol) in MeOH (15 mL), and the mixture was stirred at rt for 18 hours. Volatile substances were removed under reduced pressure, and the crude substance was dissolved in H2O (10 mL). The aqueous solution was acidified to pH=1 by adding 37% HCl, and then extracted with CH2Cl2 / MeOH (9:1 v / v, 3 × 15 mL). The collected organic phase was dried over Na2SO4 and concentrated under reduced pressure to yield 540 mg (2.32 mmol, yield: 95%) of the title intermediate 16.2. MS-ESI(-) m / z 232.5 (MH).

[0429] Example 17: (3S,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-3-carboxylic acid (17.6) [ka] Step 1: (4R)-4-benzyl-3-[(2E)-3-phenylpropa-2-enoyl]-1,3-oxazolidine-2-one (17.3) DCC (13.98 g, 67.79 mmol) was added to a stirred solution of trans-cinnamic acid (10.00 g, 67.79 mmol), intermediate 17.2 (9.20 g, 51.92 mmol), and DMAP (0.83 g, 6.78 mmol) in CH2Cl2 (80 mL) cooled to 0-5°C. This mixture was stirred at room temperature for 18 hours. The resulting suspension was filtered under vacuum, and the solid was washed with CH2Cl2 (30 mL). The collected liquid was washed with 10% NaHCO3 aqueous solution (50 mL) and brine (50 mL), dried on Na2SO4, and concentrated under reduced pressure. The crude substance was purified by flash chromatography (PET / Â, 95:5 to 60:40 v / v), and intermediate 17.3 (16.46 g, 53.55 mmol) was provided in 79% yield. MS-ESI(-) m / z 306.3 (MH).

[0430] Step 2: (4R)-benzyl-3-[(3S,4R)1-benzyl-4-phenyl-pyrrolidine-3-carbonyl]-oxazolidine-2-one (17.4) Intermediate 1.2 (49 mL, 0.19 mol) and TFA (3.67 mL, 47.87 mmol) were added to a stirred solution of intermediate 17.3 (49.00 g, 0.159 mol) in toluene (350 mL) cooled to 0-5°C. The resulting mixture was stirred at rt for 18 hours. 10% NaHCO3 aqueous solution (350 mL) was carefully added to separate the two phases. The organic phase was washed with brine (250 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (PET / siRNA, 90:10 to 50:50). The first eluate was diastereoisomer 17.4, isolated as a whitish solid in 51% yield (35.72 g, 81.09 mmol). MS-ESI(+) m / z 441.3 (M+H).

[0431] Step 3: tert-butyl (3S,4R)-3-[(4R)-benzyl-2-oxo-oxazolidine-3-carbonyl]-4-phenyl-pyrrolidine-1-carboxylate (17.5) DIPEA (4.35 mL, 24.97 mmol) and 1-chloroethyl chloroformate (6.12 mL, 56.75 mmol) were added to a stirred solution of intermediate 17.4 (10.00 g, 22.70 mmol) in CH2Cl2 (120 mL), and the resulting mixture was stirred and refluxed for 1 hour. The mixture was then cooled to rt, and volatile substances were removed under reduced pressure. The crude product was dissolved in MeOH (100 mL) and stirred vigorously and refluxed for 1 hour. The reaction product was cooled to rt and concentrated under reduced pressure. The resulting residue was treated with Boc2O (5.45 g, 24.97 mmol) and DIPEA (11.86 mL, 68.10 mmol) in CH2Cl2 (100 mL) for 3 hours at rt. This mixture was washed with 0.5 M citric acid aqueous solution (2 × 50 mL), 10% NaHCO3 aqueous solution (80 mL), and brine (280 mL), dried on Na2SO4, and concentrated under reduced pressure. The resulting crude intermediate 17.5 was used directly in the next step. MS-ESI(+) m / z 351.3 (M+H-100).

[0432] Step 4: (3S,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-3-carboxylic acid (17.6) 4.0 M aqueous LiOH (22.7 mL, 90.80 mmol) and 30% aqueous H2O2 (23.2 mL, 0.23 mol) were added to a stirred solution of intermediate 17.5 (crude material from the previous step, 22.70 mmol) in THF (120 mL) and H2O (20 mL), and the reaction mixture was stirred at rt for 4 hours. The mixture was concentrated under reduced pressure to 1 / 4 of its original volume, then poured into H2O (50 mL) and washed with siRNA (3 × 30 mL). The aqueous phase was acidified to pH=2.5 with 3.0 M HCl and then extracted with CH2Cl2 (3 × 50 mL). The collected organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. Intermediate 17.6 was obtained as a white powder (6.01 g, 20.63 mmol, yield: 91%). MS-ESI(-) m / z 290.1 ​​(MH).

[0433] Example 18: (3R,4S)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-3-carboxylic acid (18.3) [ka] Step 1: (4R)-benzyl-3-[(3R,4S)1-benzyl-4-phenyl-pyrrolidine-3-carbonyl]-oxazolidine-2-one (18.1) Intermediate 1.2 (49 mL, 0.19 mol) and TFA (3.67 mL, 47.87 mmol) were added to a stirred solution of intermediate 17.3 (49.00 g, 0.159 mol) in toluene (350 mL) cooled to 0-5°C. The resulting mixture was stirred at rt for 18 hours. 10% NaHCO3 aqueous solution (350 mL) was carefully added to separate the two phases. The organic phase was washed with brine (250 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (PET / siRNA, 90:10 to 50:50). The second eluate was diastereoisomer 18.1, which was isolated as a pale yellow oily substance in 46% yield (32.65 g, 74.12 mmol). MS-ESI(+) m / z 441.3 (M+H).

[0434] Step 2: tert-butyl (3R,4S)-3-[(4R)-benzyl-2-oxo-oxazolidine-3-carbonyl]-4-phenyl-pyrrolidine-1-carboxylate (18.2) To a stirred solution of intermediate 18.1 (32.60 g, 74.01 mmol) in CH2Cl2 (400 mL), DIPEA (14.20 mL, 81.41 mmol) and 1-chloroethyl chloroformate (19.96 mL, 0.19 mol) were added, and the resulting mixture was stirred and refluxed for 1 hour. The mixture was cooled to rt, and volatile substances were removed under reduced pressure. The crude product was dissolved in MeOH (400 mL) and vigorously stirred at reflux temperature for 1 hour. The reaction product was cooled to rt and concentrated under reduced pressure. The residue was pulverized with cold acetone (250 mL), and the solid was collected by filtration under vacuum. The obtained solid was treated with Boc2O (18.69 g, 81.41 mmol) and DIPEA (38.66 mL, 0.22 mol) in CH2Cl2 (350 mL), and stirred at rt for 3 hours. This mixture was washed with 0.5 M citric acid aqueous solution (2 × 200 mL), 10% NaHCO3 aqueous solution (250 mL), and brine (250 mL), dried over Na2SO4, and concentrated under reduced pressure to yield 33.20 g (73.74 mmol) of the title intermediate 18.2 (approximately quantitative yield) as a viscous, pale yellow solid. MS-ESI(+) m / z 351.3 (M+H-100).

[0435] Step 3: (3R,4S)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-3-carboxylic acid (18.3) Intermediate 18.3 was synthesized from intermediate 18.2 (33.20 g, 73.69 mmol) in THF (350 mL) and H2O (60 mL), 4.0 M aqueous LiOH (74 mL, 0.296 mol), and 30% aqueous H2O2 (75 mL, 0.74 mol) according to the procedure reported in Step 3 of Example 17. After workup, the title intermediate 18.3 was obtained as a white powder (19.52 g, 67.05 mmol, yield: 91%). MS-ESI(-) m / z 290.1 ​​(MH).

[0436] Example 19: (3R,4R)-1-(tert-butoxycarbonyl)-4-(thiophen-2-yl)pyrrolidine-3-carboxylic acid (19.5) [ka] Step 1: (4R)-4-benzyl-3-[(2E)-3-(thiophen-2-yl)prop-2-enoyl]-1,3-oxazolidine-2-one (19.2) Intermediate 19.2 was synthesized from intermediate 19.1 (1.70 g, 11.02 mmol), intermediate 17.2 (1.69 g, 9.58 mmol), DMAP (0.15 g, 1.24 mmol), and DCC (2.37 g, 11.49 mmol) in CH2Cl2 (20 mL) according to the experimental procedure of Step 1 of Example 17. After workup and chromatographic purification, 3.01 g (9.61 mmol) of intermediate 19.2 was obtained. Yield: 87%. MS-ESI(+) m / z 314.6 (M+H).

[0437] Step 2: (4R)-benzyl-3-[(3R,4R)1-benzyl-4-(thiophen-2-yl)-pyrrolidine-3-carbonyl]-oxazolidine-2-one(19.3) Diastereoisomer 19.3 was synthesized according to the experimental procedure of Step 2 in Example 17, starting from intermediate 19.2 (3.00 g, 9.13 mmol), intermediate 1.2 (2.57 mL, 10.10 mmol), and TFA (0.12 mL, 1.64 mmol) in toluene (30 mL). After work-up and chromatographic purification (PET / SiO2, 90:10 to 30:70 v / v), the second eluate was diastereoisomer 19.3 (2.00 g, 4.47 mmol). Yield: 49%. MS-ESI(+) m / z 447.4 (M+H).

[0438] Step 3: tert-butyl (3R,4R)-3-[(4R)-benzyl-2-oxo-oxazolidine-3-carbonyl]-4-(thiophen-2-yl)-pyrrolidine-1-carboxylate(19.4) Intermediate 19.4 was synthesized from intermediate 19.3 (2.00 g, 4.47 mmol), DIPEA (0.86 mL, 4.91 mmol), and 1-chloroethyl chloroformate (1.20 mL, 11.20 mmol) in CH2Cl2 (100 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (100 mL). After removing volatile substances, the crude product was pulverized in cold acetone (30 mL), and the solid was filtered under vacuum. The pure, collected debenzylated intermediate (0.94 g, 2.39 mmol) was reacted with Boc2O (0.78 g, 3.58 mmol) and DIPEA (1.25 mL, 7.17 mmol) in CH2Cl2 (25 mL). After workup, crude intermediate 19.4 (2.2 g) was used directly in the next step. MS-ESI(+) m / z 457.8 (M+H).

[0439] Step 4: (3R,4R)-1-(tert-butoxycarbonyl)-4-(thiophen-2-yl)-pyrrolidine-3-carboxylic acid (19.5) Intermediate 19.5 was synthesized from intermediate 19.4 (crude material from the previous step, 4.47 mmol) in THF (50 mL) and H2O (12 mL), 4.0 M aqueous LiOH (4.47 mL, 17.88 mol), and 30% aqueous H2O2 (4.56 mL, 44.70 mol) according to the procedure reported in Step 4 of Example 17. After workup, the title intermediate 19.5 was obtained from 9.3 in nearly quantitative yield (1.33 g, 4.47 mmol) as a white powder. MS-ESI(-) m / z 296.6 (MH).

[0440] Example 20: (3S,4S)-1-(tert-butoxycarbonyl)-4-(thiophen-2-yl)pyrrolidine-3-carboxylic acid (20.3) [ka] Step 1: (4R)-benzyl-3-[(3S,4S)1-benzyl-4-(thiophen-2-yl)-pyrrolidine-3-carbonyl]-oxazolidine-2-one(20.1) Diastereoisomer 20.1 was synthesized according to the experimental procedure of Step 2 in Example 17, starting from intermediate 19.2 (3.00 g, 9.13 mmol), intermediate 1.2 (2.57 mL, 10.10 mmol), and TFA (0.12 mL, 1.64 mmol) in toluene (30 mL). After work-up and chromatographic purification (PET / SiO, 90:10 to 70:30 v / v), the first eluate was diastereoisomer 20.1 (1.81 g, 4.05 mmol). Yield: 44%. MS-ESI(+) m / z 447.4 (M+H).

[0441] Step 2: tert-butyl (3S,4S)-3-[(4R)-benzyl-2-oxo-oxazolidine-3-carbonyl]-4-(thiophen-2-yl)-pyrrolidine-1-carboxylate (20.2) Intermediate 20.2 was synthesized from intermediate 20.1 (1.80 g, 4.03 mmol), DIPEA (0.77 mL, 4.43 mmol), and 1-chloroethyl chloroformate (1.09 mL, 10.08 mmol) in CH2Cl2 (30 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (15 mL). After removing volatile substances, the debenzylated intermediate was reacted with Boc2O (1.32 mg, 6.05 mmol) and DIPEA (2.10 mL, 12.09 mmol) in CH2Cl2 (30 mL). After work-up, the crude product was purified by flash chromatography (PET / siRNA, 90:10 to 60:40 v / v), and 1.77 g (3.88 mmol) of intermediate 20.2 was provided as a pale yellow oil. Yield: 96%. MS-ESI(+) m / z 357.3 (M+H-100).

[0442] Step 3: (3S,4S)-1-(tert-butoxycarbonyl)-4-(thiophen-2-yl)-pyrrolidine-3-carboxylic acid (20.3) Intermediate 20.3 was synthesized from intermediate 20.2 (1.75 g, 3.83 mmol) in THF (30 mL) and H2O (7.5 mL), 4.0 M aqueous LiOH (3.8 mL, 15.33 mol), and 30% aqueous H2O2 (5.8 mL, 57.50 mol) according to the procedure reported in Step 4 of Example 17. After workup, the title intermediate 20.3 was obtained as a white powder (880 mg, 2.96 mmol, yield: 77%). MS-ESI(-) m / z 296.2 (MH).

[0443] Example 21: (3R,4R)-1-(tert-butoxycarbonyl)-4-(1,3-thiazole-2-yl)pyrrolidine-3-carboxylic acid (21.7) [ka] Step 1: Methyl (2E)-3-(1,3-thiazole-2-yl)prop-2-enoate(21.2) Intermediate 21.2 was synthesized from intermediate 21.1 (0.39 mL, 4.42 mmol) and intermediate 7.2 (1.72 g, 4.95 mmol) in THF (15 mL) according to the procedure described in Step 1 of Example 7. Intermediate 21.2 (705 mg, 4.17 mmol) was obtained as white crystals after chromatographic purification (PET / SiO, 90:1 to 70:30 v / v). Yield: 94%. MS-ESI(-) m / z: 170.4 (MH).

[0444] Step 2: (2E)-3-(1,3-thiazole-2-yl)propane-2-enoic acid (21.3) 1.0 M aqueous LiOH (4.55 mL, 4.55 mmol) was added to a stirred solution of 21.2 (700 mg, 4.13 mmol) in THF (20 mL), and the mixture was stirred at rt for 3 hours. The reaction product was then poured into H2O (20 mL) and acidified to pH=1 by adding 1.0 M HCl. The aqueous phase was extracted with SiO2 (3 × 20 mL), and the collected organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. 580 mg (3.74 mmol) of intermediate 21.3 was obtained as a white powder. Yield: 72%. MS-ESI(-) m / z: 154.5 (MH).

[0445] Step 3: (4R)-4-benzyl-3-[(2E)-3-(1,3-thiazole-2-yl)prop-2-enoyl]-1,3-oxazolidine-2-one (21.4) Intermediate 21.4 was synthesized according to the experimental procedure of Step 1 of Example 17, starting with intermediate 21.3 (565 mg, 3.64 mmol), intermediate 7.2 (568 mg, 3.30 mmol), DMAP (52 mg, 0.42 mmol), and DCC (0.90 g, 4.36 mmol) in CH2Cl2 (15 mL). After workup and chromatographic purification, 1.03 g (3.28 mmol) of intermediate 21.4 was obtained. Yield: 90%. MS-ESI(+) m / z 315.5 (M+H).

[0446] Step 4: (4R)-benzyl-3-[(3R,4R)1-benzyl-4-(1,3-thiazole-2-yl)-pyrrolidine-3-carbonyl]-oxazolidine-2-one (21.5) Diastereoisomer 21.5 was synthesized according to the experimental procedure of Step 2 in Example 17, starting from intermediate 21.4 (1.00 g, 3.18 mmol), intermediate 1.2 (0.89 mL, 3.49 mmol), and TFA (0.04 mL, 0.57 mmol) in toluene (10 mL). After work-up and chromatographic purification (PET / AcOEt, 80:20 to 30:70 v / v), the second eluate was diastereoisomer 21.5 (0.74 g, 1.65 mmol). Yield: 52%. MS-ESI(+) m / z 448.6 (M+H).

[0447] Step 5: tert-butyl (3R,4R)-3-[(4R)-benzyl-2-oxo-oxazolidine-3-carbonyl]-4-(1,3-thiazole-2-yl)-pyrrolidine-1-carboxylate(21.6) Intermediate 21.6 was synthesized from intermediate 21.5 (700 mg, 1.56 mmol), DIPEA (0.29 mL, 3.91 mmol), and 1-chloroethyl chloroformate (0.41 mL, 3.91 mmol) in CH2Cl2 (30 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (30 mL). After removal of volatile substances, the debenzylated intermediate was reacted with Boc2O (510 mg, 2.34 mmol) and DIPEA (0.82 mL, 4.68 mmol) in CH2Cl2 (20 mL). After work-up, the crude product was purified by flash chromatography (PET / siRNA, 80:20 to 30:70 v / v) to obtain 444 mg (0.97 mmol) of intermediate 21.6. Yield: 62%. MS-ESI(+) m / z 458.8 (M+H).

[0448] Step 6: (3R,4R)-1-(tert-butoxycarbonyl)-4-(1,3-thiazole-2-yl)-pyrrolidine-3-carboxylic acid (21.7) Intermediate 21.7 was synthesized from intermediate 21.6 (440 mg, 0.96 mmol) in THF (30 mL) and H2O (4 mL), 4.0 M aqueous LiOH (0.96 mL, 3.84 mol), and 30% aqueous H2O2 (0.44 mL, 14.10 mol) according to the procedure reported in Step 4 of Example 17. After workup, the title intermediate 21.7 was obtained as a colorless oil (263 mg, 0.88 mmol, 92% yield). MS-ESI(-) m / z 297.6 (MH).

[0449] Example 22: (3S,4S)-1-(tert-butoxycarbonyl)-4-(1,3-thiazole-2-yl)pyrrolidine-3-carboxylic acid (22.3) [ka] Step 1: (4R)-benzyl-3-[(3S,4S)1-benzyl-4-(1,3-thiazole-2-yl)-pyrrolidine-3-carbonyl]-oxazolidine-2-one(22.1) Diastereoisomer 22.1 was synthesized according to the experimental procedure of Step 2 in Example 17, starting from intermediate 21.5 (1.00 g, 3.18 mmol), intermediate 1.2 (0.89 mL, 3.49 mmol), and TFA (0.04 mL, 0.57 mmol) in toluene (10 mL). After work-up and chromatographic purification (PET / SiO, 80:20 to 60:40 v / v), the first eluate was diastereoisomer 22.1 (0.51 g, 1.14 mmol). Yield: 36%. MS-ESI(+) m / z 448.7 (M+H).

[0450] Step 2: tert-butyl (3S,4S)-3-[(4R)-benzyl-2-oxo-oxazolidine-3-carbonyl]-4-(1,3-thiazole-2-yl)-pyrrolidine-1-carboxylate(22.2) Intermediate 22.2 was synthesized from intermediate 22.1 (0.51 g, 1.14 mmol), DIPEA (0.22 mL, 1.25 mmol), and 1-chloroethyl chloroformate (0.30 mL, 2.87 mmol) in CH2Cl2 (20 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (20 mL). After removing volatile substances, the debenzylated intermediate was reacted with Boc2O (370 mg, 1.71 mmol) and DIPEA (0.59 mL, 3.42 mmol) in CH2Cl2 (20 mL). After work-up, the crude product was purified by flash chromatography (PET / siRNA, 80:20 to 50:50 v / v), and 510 mg (1.11 mmol) of intermediate 22.2 was provided. Yield: 98%. MS-ESI(+) m / z 458.4 (M+H).

[0451] Step 3: (3S,4S)-1-(tert-butoxycarbonyl)-4-(1,3-thiazole-2-yl)-pyrrolidine-3-carboxylic acid (22.3) Intermediate 22.3 was synthesized from intermediate 22.2 (506 mg, 1.10 mmol) in THF (28 mL) and H2O (4.5 mL), 4.0 M aqueous LiOH (1.10 mL, 4.42 mol), and 30% aqueous H2O2 (0.50 mL, 16.5 mol) according to the procedure reported in Step 4 of Example 17. After workup, the title intermediate 22.3 was obtained as a white powder in nearly quantitative yield (328 mg, 1.10 mmol). MS-ESI(-) m / z 297.6 (MH).

[0452] Example 23: (3R,4S)-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)-pyrrolidine-3-carboxylic acid (23.5) [ka] Step 1: (4R)-4-benzyl-3-[(2E)-3-(4-fluorophenyl)propa-2-enoyl]-1,3-oxazolidine-2-one (23.5) Intermediate 23.2 was synthesized from intermediate 23.1 (1.50 g, 9.03 mmol), intermediate 14.2 (1.45 g, 8.18 mmol), DMAP (0.13 g, 1.07 mmol), and DCC (2.03 g, 9.84 mmol) in CH2Cl2 (15 mL) according to the experimental procedure of Step 1 of Example 17. After workup and chromatographic purification, 2.45 g (7.53 mmol) of intermediate 23.2 was obtained. Yield: 92%. MS-ESI(+) m / z 326.7 (M+H).

[0453] Step 3: (4R)-benzyl-3-[(3R,4S)1-benzyl-4-(4-fluorophenyl)-pyrrolidine-3-carbonyl]-oxazolidine-2-one (23.3) Diastereoisomer 23.3 was synthesized according to the experimental procedure of Step 2 in Example 17, starting from intermediate 23.2 (2.70 g, 8.30 mmol), intermediate 1.2 (2.76 mL, 10.79 mmol), and TFA (0.63 mL, 0.83 mmol) in toluene (15 mL). After work-up and chromatographic purification (PET / siRNA, 90:10 to 50:50 v / v), the second eluate was diastereoisomer 23.3 (1.48 g, 3.24 mmol). Yield: 39%. MS-ESI(+) m / z 459.4 (M+H).

[0454] Step 4: tert-butyl (3R,4S)-3-[(4R)-benzyl-2-oxo-oxazolidine-3-carbonyl]-4-(4-fluorophenyl)-pyrrolidine-1-carboxylate(23.4) Intermediate 23.4 was synthesized from intermediate 23.3 (1.36 g, 3.05 mmol), DIPEA (0.58 mL, 3.35 mmol), and 1-chloroethyl chloroformate (0.81 mL, 7.63 mmol) in CH2Cl2 (60 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (60 mL). After removal of volatile substances, the debenzylated intermediate was reacted with Boc2O (0.99 g, 4.57 mmol) and DIPEA (1.59 mL, 9.15 mmol) in CH2Cl2 (30 mL). After workup, the crude product was purified by flash chromatography (PET / siRNA, 90:10 to 60:40 v / v), and 1.42 g of intermediate 23.4 was provided. Yield: Quantitative. MS-ESI(+) m / z 469.4 (M+H).

[0455] Step 5: (3R,4S)-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)-pyrrolidine-3-carboxylic acid (23.5) Intermediate 23.5 was synthesized from intermediate 23.4 (1.40 g, 2.98 mmol) in THF (50 mL) and H2O (12 mL), 4.0 M aqueous LiOH (2.98 mL, 11.95 mol), and 30% aqueous H2O2 (4.56 mL, 44.70 mmol) according to the procedure reported in Step 4 of Example 17. After workup, the title intermediate 23.5 was obtained as a white powder (0.48 g, 1.55 mmol, yield 53%). MS-ESI(-) m / z 308.5 (MH).

[0456] Example 24: (3S,4R)-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)-pyrrolidine-3-carboxylic acid (24.3) [ka] Step 1: (4R)-benzyl-3-[(3S,4R)1-benzyl-4-(4-fluorophenyl)-pyrrolidine-3-carbonyl]-oxazolidine-2-one (24.1) Diastereoisomer 24.1 was synthesized according to the experimental procedure of Step 2 in Example 17, starting from intermediate 23.1 (2.70 g, 8.30 mmol), intermediate 1.2 (2.76 mL, 10.79 mmol), and TFA (0.063 mL, 0.83 mmol) in toluene (16 mL). After work-up and chromatographic purification (PET / SiO4, PET / SiO4 at 60:40 v / v from 100% PET), the first eluate was diastereoisomer 24.1 obtained as a white solid (1.59 g, 3.48 mmol). Yield: 42%. MS-ESI(+) m / z 459.4 (M+H).

[0457] Step 2: tert-butyl (3S,4R)-3-[(4R)-benzyl-2-oxo-oxazolidine-3-carbonyl]-4-(4-fluorophenyl)-pyrrolidine-1-carboxylate (24.2) Intermediate 24.2 was synthesized from intermediate 24.1 (1.58 g, 3.44 mmol), DIPEA (0.66 mL, 3.78 mmol), and 1-chloroethyl chloroformate (0.97 mL, 8.61 mmol) in CH2Cl2 (60 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (60 mL). After removal of volatile substances, the debenzylated intermediate was reacted with Boc2O (1.11 g, 5.10 mmol) and DIPEA (1.80 mL, 10.32 mmol) in CH2Cl2 (60 mL). After work-up, the crude product was purified by flash chromatography (PET / siRNA, PET / siRNA from 100% PET at 70:30 v / v), and 1.60 g (3.43 mmol) of intermediate 24.2 was provided as a pale yellow oil. Yield: 99%. MS-ESI(+) m / z 469.3 (M+H).

[0458] Step 3: (3S,4R)-1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)-pyrrolidine-3-carboxylic acid (24.3) Intermediate 24.3 was synthesized from 24.2 (1.40 g, 2.98 mmol) in THF (50 mL) and H2O (12 mL), 4.0 M aqueous LiOH (3.0 mL, 11.95 mmol), and 30% aqueous H2O2 (4.56 mL, 44.7 mmol) according to the procedure reported in Step 4 of Example 17. After workup, the title intermediate 24.3 was obtained as a white powder (0.79 g, 2.56 mmol, yield 86%). MS-ESI(-) m / z 308.6 (MH).

[0459] Example 25: (3R,4S)-1-(tert-butoxycarbonyl)-4-(4-trifluoromethylphenyl)-pyrrolidine-3-carboxylic acid (25.5) [ka] Step 1: (4R)-benzyl-3-[(3R,4S)1-benzyl-4-(4-trifluoromethylphenyl)-pyrrolidine-3-carbonyl]-oxazolidine-2-one (25.2) Intermediate 25.2 was synthesized from intermediate 25.1 (1.15 g, 5.32 mmol), intermediate 17.2 (0.94 g, 5.32 mmol), DMAP (85 mg, 0.69 mmol), and DCC (1.32 g, 6.38 mmol) in CH2Cl2 (20 mL) according to the experimental procedure of Step 1 of Example 17. After workup and chromatographic purification (PET / siRNA, 90:10 to 70:30 v / v), intermediate 25.2 was obtained in near quantitative yield (2.00 g, 5.32 mmol). MS-ESI(+) m / z 376.5 (M+H).

[0460] Step 2: (4R)-benzyl-3-[(3R,4S)1-benzyl-4-(4-trifluoromethylphenyl)-pyrrolidine-3-carbonyl]-oxazolidine-2-one (25.3) Diastereoisomer 25.3 was synthesized according to the experimental procedure of Step 2 in Example 17, starting from intermediate 25.2 (2.00 g, 5.32 mmol), intermediate 1.2 (1.63 mL, 6.38 mmol), and TFA (0.07 mL, 0.81 mmol) in toluene (20 mL). After work-up and chromatographic purification (PET / siRNA, 80:20 to 40:60 v / v), the second eluate was diastereoisomer 25.3 (0.57 g, 1.12 mmol). Yield: 21%. MS-ESI(+) m / z 509.4 (M+H).

[0461] Step 3: tert-butyl (3R,4S)-3-[(4R)-benzyl-2-oxo-oxazolidine-3-carbonyl]-4-(4-trifluoromethylphenyl)-pyrrolidine-1-carboxylate(25.4) Intermediate 25.4 was synthesized from intermediate 25.3 (700 mg, 1.59 mmol), DIPEA (0.30 mL, 1.75 mmol), and 1-chloroethyl chloroformate (0.42 mL, 3.97 mmol) in CH2Cl2 (30 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (30 mL). After removal of volatile substances, the debenzylated intermediate was reacted with Boc2O (0.52 g, 2.38 mmol) and DIPEA (0.83 mL, 4.37 mmol) in CH2Cl2 (30 mL). After workup, the crude product was purified by flash chromatography (PET / siRNA, 70:20 to 50:50 v / v) to provide intermediate 25.4 in nearly quantitative yield (820 mg, 1.58 mmol). MS-ESI(+) m / z 519.4 (M+H).

[0462] Step 4: (3R,4S)-1-(tert-butoxycarbonyl)-4-(4-trifluoromethylphenyl)-pyrrolidine-3-carboxylic acid (25.5) Intermediate 25.5 was synthesized from intermediate 25.4 (1.40 g, 2.70 mmol) in THF (50 mL) and H2O (12 mL), 4.0 M aqueous LiOH (2.7 mL, 10.79 mmol), and 30% H2O2 aqueous solution (4.13 mL, 40.50 mol) according to the procedure reported in Step 4 of Example 17. After workup, the title intermediate 25.5 was obtained as a white powder in 81% yield (0.79 g, 2.19 mmol). MS-ESI(-) m / z 358.6 (MH).

[0463] Example 26: (3S,4R)-1-(tert-butoxycarbonyl)-4-(4-trifluorophenyl)-pyrrolidine-3-carboxylic acid (26.3) [ka] Step 1: (4R)-benzyl-3-[(3S,4R)1-benzyl-4-(4-trifluoromethylphenyl)-pyrrolidine-3-carbonyl]-oxazolidine-2-one (26.1) Diastereoisomer 26.1 was synthesized according to the experimental procedure of Step 2 in Example 17, starting from intermediate 25.2 (2.00 g, 5.32 mmol), intermediate 1.2 (1.63 mL, 6.38 mmol), and TFA (0.07 mL, 0.81 mmol) in toluene (20 mL). After work-up and chromatographic purification (PET / siRNA, 80:20 to 40:60 v / v), the first eluate was diastereoisomer 26.1 (0.89 g, 1.75 mmol). Yield: 33%. MS-ESI(+) m / z 509.4 (M+H).

[0464] Step 2: tert-butyl (3S,4R)-3-[(4R)-benzyl-2-oxo-oxazolidine-3-carbonyl]-4-(4-trifluoromethylphenyl)-pyrrolidine-1-carboxylate (26.2) Intermediate 26.2 was synthesized from intermediate 26.1 (2.00 g, 3.93 mmol), DIPEA (0.75 mL, 4.32 mmol), and 1-chloroethyl chloroformate (1.06 mL, 9.83 mmol) in CH2Cl2 (40 mL) according to the procedure described in Step 2 of Example 1. The resulting crude product was treated in refluxed MeOH (30 mL). After removal of volatile substances, the debenzylated intermediate was reacted with Boc2O (1.76 g, 7.86 mmol) and DIPEA (2.05 mL, 11.796 mmol) in CH2Cl2 (40 mL). After workup, crude intermediate 26.2 was used directly in the next step. MS-ESI(+) m / z 519.4 (M+H).

[0465] Step 3: (3S,4R)-1-(tert-butoxycarbonyl)-4-(4-trifluoromethylphenyl)-pyrrolidine-3-carboxylic acid (26.3) Intermediate 26.3 was synthesized from intermediate 26.2 (crude material from the previous step, 3.93 mmol) in THF (35 mL) and H2O (6 mL), 4.0 M aqueous LiOH (3.9 mL, 15.72 mol), and 30% aqueous H2O2 (4.01 mL, 39.32 mol) according to the procedure reported in Step 4 of Example 17. After workup, the title intermediate 26.3 was obtained as a white powder (1.09 g, 3.03 mmol, 77% yield from 6.1). MS-ESI(-) m / z 358.6 (MH).

[0466] Example 27: 5-Isothiocyanateisoquinoline (27.2) [ka] 1,1′-thiocarbonyldiimidazole (3.78 g, 21.24 mmol) was added to a stirred solution of intermediate 27.1 (2.04 g) in CH2Cl2 (20 mL), and the reaction mixture was stirred at rt for 24 hours. The mixture was concentrated under reduced pressure and purified by flash chromatography (PET / siRNA, 85:15 to 60:40 v / v). 2.01 g of the title intermediate 27.2 was obtained (76%).

[0467] MS-ESI(+) m / z: 187.3 (M+H).

[0468] Example 28: 3-(2-bromo-1,3-thiazole-4-yl)pyridine (28.4) [ka] Step 1: 2-bromo-1-(pyridine-3-yl)ethanone hydrochloride (28.2) Bromine (0.51 mL, 10.01 mmol) was added to a stirred solution of intermediate 28.1 (1.10 g, 9.09 mmol) in 33% HBr (10 mL) in AcOH cooled to 0°C. The mixture was then slowly heated to 70°C and reacted for 1 hour. After cooling to rt, the resulting suspension was poured into Et2O (50 mL), and the solid was collected by filtration under vacuum, yielding 2.47 g of intermediate 28.2 (97%).

[0469] MS-ESI(+) m / z: 199.6 (M+H), 201.6 (M+H).

[0470] Step 2: 2-oxo-2-(pyridine-3-yl)thiocyanate (28.3) Et3N (1.23 mL, 8.79 mmol) was added to a stirred suspension of intermediate 28.2 (2.47 g, 8.79 mmol) in EtOH (40 mL) to produce a solution. Then potassium thiocyanate (0.94 g, 9.671 mmol) was added, and the mixture was reacted at 85°C for 1 hour. The mixture was cooled to rt, poured into H2O (50 mL) and brine (50 mL), and extracted with SiO (3 × 50 mL). The collected organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to produce 1.53 g of intermediate 28.3, which was used directly in the next step.

[0471] MS-ESI(+) m / z: 178.7 (M+H).

[0472] Step 3: 3-(2-bromo-1,3-thiazole-4-yl)pyridine (28.4) The crude substance (8.79 mmol) obtained from the previous step was dissolved in AcOH (7.5 mL) and treated with 33% HBr (15 mL) in AcOH at 50°C for 16 hours. After cooling to rt, this suspension was poured into Et2O (50 mL) and filtered under vacuum. The collected solid was dissolved in H2O (50 mL) and saturated aqueous solution of NaHCO3 was added until the pH was 8.0. This mixture was extracted with siRNA (3 × 50 mL), and the collected organic layer was washed with brine (50 mL), dried on Na2SO4, and concentrated under reduced pressure. After chromatographic purification (CH2Cl2 / MeOH, 98:2 to 93:7 v / v), 1.09 g of the title intermediate 28.4 was obtained as a pale yellow solid. Yield: 51%.

[0473] MS-ESI(+) m / z: 240.5 (M+H), 242.5 (M+H).

[0474] Example 29: 2-bromo[1,3]thiazolo[4,5-c]pyridine (29.5) [ka] Step 1: N-([1,3]thiazolo[4,5-c]pyridine-2-yl)benzamide (29.3) Intermediate 29.1 (500 mg, 3.89 mmol) was added to a stirred solution of intermediate 29.2 (0.73 mL, 5.44 mmol) in THF (15 mL) under N2 atmosphere. The resulting mixture was reacted at 50°C for 18 hours under magnetic stirring. The mixture was cooled to rt, the formed precipitate was filtered, washed with THF (3 mL), and dried under vacuum in a drying oven to obtain 898 mg (3.52 mmol) of the desired intermediate 29.3, which was used directly in the next step. Yield: 90%. MS-ESI(+) m / z: 256.0 (M+H); MS-ESI(-) m / z: 253.9 (MH).

[0475] Step 2: [1,3]thiazolo[4,5-c]pyridine-2-amine (29.4) A solution of intermediate 29.3 in 98% H2SO4 was heated at 110°C for 18 hours under magnetic stirring. The solution was then cooled to rt and slowly poured into 30 mL of 6 M NaOH aqueous solution maintained at 0°C. The resulting solid was filtered off and washed with SiO2 (3 × 10 mL) and MeOH (3 × 5 mL). These phases were separated, and the aqueous layer was extracted with SiO2 / MeOH (8:2, v / v). The combined organic matter was dried over anhydrous Na2SO4 and evaporated to dryness, yielding the desired crude intermediate 29.4, which was used directly in the next step. MS-ESI(+) m / z: 150.3 (M+H).

[0476] Step 3: 2-bromo[1,3]thiazolo[4,5-c]pyridine (29.5) NaNO2 (122 mg, 1.76 mmol) and N-bromosuccinimide (209 mg, 1.17 mmol) were added to a stirred solution of intermediate 29.4 (crude material from the previous step, 1.17 mmol) in DMF (5 mL), and this mixture was reacted at rt for 3 hours. The reaction product was poured into H2O (15 mL) and extracted with SiO2 (3 × 15 mL). The collected organic layer was washed with brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure. After chromatographic purification (CH2Cl2 / MeOH, 99:1 to 96:4 v / v), 80 mg (0.37 mmol) of the title intermediate 29.5 was obtained. Yield: 32%. MS-ESI(+) m / z: 214.9 (M+H), 217.0 (M+H).

[0477] Example 30: 4-(pyridine-3-yl)-1,3-thiazole-2-amine (30.1) [ka] Thiourea (247 mg, 3.24 mmol) and K2CO3 (814 mg, 5.90 mmol) were added to a stirred solution of intermediate 28.2 (830 mg, 2.95 mmol) in EtOH (15 mL). The resulting mixture was reacted under reflux for 5 hours. After cooling to rt, the solvent was removed under vacuum, and the residue was dissolved in saturated NaHCO3 solution (50 mL). Stirring was continued at rt for 1 hour. The aqueous mixture was extracted with siRNA (3 × 50 mL), and the organic layer was then dried over anhydrous Na2SO4 and evaporated to dryness. Intermediate 30.1 (500 mg, 2.82 mmol) was provided as a yellowish solid. Yield: 96%. MS-ESI(+) m / z: 176.6 (M+H).

[0478] Example 31: 3-(3-pyridyl)aniline (31.3) [ka] Intermediate 31.1 (2.32 g, 18.89 mmol) was dissolved in 1,4-dioxane (75 mL) and H2O (25 mL) under N2 atmosphere. Then, K2CO3 (8.02 g, 58.13 mmol), Pd(dppf)Cl2 (532 mg, 0.73 mmol), and intermediate 31.2 (5.00 g, 14.53 mmol) were added sequentially. This mixture was reacted at 80°C for 4 hours. Next, 1M aqueous NaOH (100 mL) was added, and the reaction mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with H2O (100 mL) and brine (100 mL), dried on anhydrous Na2SO4, and evaporated to dryness. After purification by flash chromatography (CH2Cl2 / MeOH, from 100% CH2Cl2 to 95:5 v / v CH2Cl2 / MeOH), the title intermediate 31.3 (2.02 g, 11.87 mmol) was obtained as a brown solid. Yield: 82%. MS-ESI(+) m / z: 171.4 (M+H).

[0479] Example 32: 3-(6-fluoropyridine-3-yl)aniline (32.3) [ka] To a stirred solution of intermediate 32.2 (0.38 mL, 3.65 mmol) in DME (15 mL), Pd(PPh3)4 (42 mg, 0.036 mmol) was added and stirred for 10 minutes. Then, intermediate 32.1 (500 mg, 3.65 mmol) and 1.0 M NaHCO3 aqueous solution (11 mL, 11.00 mmol) were added sequentially. This mixture was reacted under reflux conditions for 3 hours. After cooling, H2O (100 mL) and HCl (50 mL) were added to separate these phases, and the aqueous phase was extracted with HCl (2 × 50 mL). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried on anhydrous Na2SO4, and evaporated to dryness. After post-processing and chromatographic purification (PET / Â, 95 / 5 to 75 / 25 v / v), the title intermediate 32.3 (618 mg, 3.28 mmol) was obtained in 90% yield. MS-ESI(+) m / z: 189.4 (M+H).

[0480] Example 33: 3-Isothiocyanatothieno[2,3-c]pyridine (33.5) [ka] Step 1: Ethyl 3-aminothieno[2,3-c]pyridine-2-carboxylate (33.3) To a stirred solution of intermediate 33.1 (1.5 g, 10.83 mmol) in DMF (9 mL) cooled to 0°C, intermediate 33.2 (1.19 mL, 10.83 mmol) and tBuOK (1.21 g, 10.83 mmol) were sequentially added. The resulting solution was reacted at 0°C for 30 minutes, followed by 16 hours at rt. This mixture was slowly poured into H2O (40 mL) while continuously magnetically stirring. The resulting brownish solid was collected by filtration and used directly for further processing.

[0481] MS-ESI(+) m / z: 220.8 (M+H); MS-ESI(-) m / z: 222.9 (MH).

[0482] Step 2: Thieno[2,3-c]pyridine-3-amine (33.4) LiOH (216 mg, 9.00 mmol) was added to a stirred solution of 33.3 mg (crude material from the previous step, approximately 500 mg, 2.25 mmol) in EtOH (15 mL), and this mixture was stirred under reflux for 16 hours. This suspension was cooled to rt, and then 1N HCl aqueous solution (5.5 mL) and H2O (50 mL) were added (pH ~ 6). The resulting yellow precipitate was collected by filtration. The resulting solid was dissolved in 85% H3PO4 aqueous solution (3.6 mL) and stirred at 60°C for 16 hours. This solution was cooled to rt and slowly poured into 5M aqueous NaOH (18.6 mL) maintained at 0°C under magnetic stirring. The precipitate was filtered and washed with HCl (20 mL). These phases were separated, and the aqueous phase was extracted with HCl (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried on Na2SO4, and evaporated to dryness. Crude intermediate 33.4 was used directly in the next step.

[0483] MS-ESI(+) m / z: 150.9 (M+H); MS-ESI(-) m / z: 149.7 (MH).

[0484] Step 3: 3-Isothiocyanatothieno[2,3-c]pyridine (33.5) Intermediate 33.5 was synthesized from intermediate 33.4 (crude material from the previous step, 2.25 mmol) and TCDI (0.60 g, 3.37 mmol) in CH2Cl2 (20 mL) according to the procedure reported in Example 27. After chromatographic purification (PET / SiO), 21.5 g of the title intermediate 33.5 was obtained in a yield of 27% from 33.1.

[0485] MS-ESI(+) m / z: 193.4 (M+H).

[0486] Example 34: (2E)-3-phenyl-N-[3-(pyridine-3-yl)phenyl]prop-2-enamide (34.1) [ka] Oxalyl chloride (0.27 mL, 3.10 mmol) was added to a stirred solution of intermediate 17.1 (300 mg, 2.03 mmol) in CH2Cl2 (10 mL) cooled to 0-5°C and DMF (2 drops). This mixture was reacted at rt for 4 hours. Volatile substances were removed under reduced pressure, and the crude product was dissolved in CH2Cl2 (15 mL). Intermediate 31.3 (390 mg, 2.23 mmol) and DIPEA (0.39 mL, 2.23 mmol) were added to the resulting solution. This mixture was stirred for 16 hours, then washed with 0.5 M citric acid aqueous solution (3 × 20 mL) and brine (20 mL), dried on Na2SO4, and concentrated under reduced pressure. After chromatographic purification, the title intermediate 34.1 was obtained in 74% yield.

[0487] MS-ESI(+) m / z: 301.4 (M+H).

[0488] Example 35: N-methyl-3-(pyridine-3-yl)aniline (35.2) [ka] Step 1: 3-Bromo-N-methylaniline (35.1) KOH (179 mg, 3.20 mmol) and MeI (0.18 mL, 2.91 mmol) were sequentially added to a stirred solution of intermediate 31.1 (0.32 mL, 2.91 mmol) in DMF (3 mL), and magnetic stirring was continued at rt for 3 days. This mixture was poured into H2O (50 mL) and extracted with RINKAN (3 × 20 mL). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried on anhydrous Na2SO4, and evaporated to dryness. After purification by flash chromatography (PET / RINKAN, 8:2 v / v PET / RINKAN from 100% PET), the title intermediate 35.1 (275 mg, 1.48 mmol) was obtained. Yield: 91%. MS-ESI(+) m / z: 185.9, 187.9 (M+H).

[0489] Step 2: N-methyl-3-(pyridine-3-yl)aniline (35.2) To a degassed solution of intermediate 35.1 (270 mg, 1.45 mmol) in EtOH / toluene (1:1 v / v, 10 mL), intermediate 30.2 (193 mg, 1.57 mmol) and a solution of Na2CO3 (900 mg, 8.49 mmol) in H2O (4 mL) were sequentially added, and the mixture was reacted at 80°C for 21 hours. The mixture was extracted with SiO2 (3 × 20 mL). The combined organic layers were washed with H2O (30 mL) and brine (30 mL), dried on anhydrous Na2SO4, and evaporated to dryness. After purification by flash chromatography (PET / SiO2, PET / SiO2 from 100% PET at a ratio of 6:4 v / v), the title intermediate 35.2 (156 mg, 0.85 mmol) was obtained as a pale yellow oil. Yield: 59%. MS-ESI(+) m / z: 185.0 (M+H).

[0490] Example 36: 3-(azetidine-3-yl)pyridine (36.4) [ka] Step 1: tert-butyl 3-(pyridine-3-yl)azetidine-1-carboxylate (36.3) 1.3M in THF (9.7mL, 12.61 mmol) iPrMgCl·LiCl was added dropwise to a stirred solution of intermediate 36.2 (2.00 g, 12.61 mmol) in anhydrous THF (12 mL) under N2 air, and the resulting mixture was stirred at rt for 2 hours. Meanwhile, in a second three-necked round-bottom flask fitted with a dropping funnel, a solution of intermediate 36.1 (1.09 mL, 6.29 mmol), iron(II) chloride (80 mg, 0.63 mol), and tetramethylethylenediamine (0.09 mL, 0.63 mmol) in THF (40 mL) was prepared and cooled to 0-5°C. Then, the contents of the first flask were slowly added dropwise to the second flask while maintaining the internal temperature below 5°C. Once the addition was complete, the mixture was vigorously stirred at rt for 3 hours, then filtered through a Celite pad under vacuum, and the remaining solids were washed with RINKAN (30 mL). The collected organic liquid was washed with H2O (50 mL) and brine (50 mL), dried on Na2SO4, and concentrated under reduced pressure. After chromatographic purification (CH2Cl2 / MeOH, 98:2 to 94:6 v / v), 1.24 g of intermediate 36.3 was obtained.

[0491] Yield: 42%.

[0492] MS-ESI(+) m / z: 235.2 (M+H).

[0493] Step 2: 3-(azetidine-3-yl)pyridine (36.4) A stirred solution of intermediate 36.3 (0.50 g, 2.13 mol) in THF (20 mL) was treated with a 37% HCl aqueous solution (0.61 mL, 8.52 mmol) at 40°C for 2 hours. The resulting solution was basicized to pH=8.0 by adding a saturated aqueous solution of NaHCO3, and volatile substances were removed under reduced pressure. These crude substances were purified by reverse-phase flash chromatography (stationary phase: RP-18, elution at 80:20 to 25:75 v / v of H2O / MeOH), yielding the title intermediate 36.4 as a white powder in 77% yield.

[0494] MS-ESI(+) m / z: 176.2 (M+H+ MeCN).

[0495] Example 37: 3-(pyridine-3-yloxy)aniline (37.4) [ka] Step 1: 3-(3-nitrophenoxy)pyridine (37.3) K2CO3 (1.96 g, 14.17 mmol) and intermediate 37.2 (0.76 mL, 7.09 mmol) were sequentially added to a stirred solution of intermediate 37.1 (674 mg, 7.09 mmol) in anhydrous DMF (10 mL) maintained under N2 atmosphere, and stirring was continued at 130°C for 48 hours. This mixture was poured into H2O (150 mL) and extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were washed with H2O (80 mL) and brine (500 mL), dried on anhydrous Na2SO4, and evaporated to dryness. After purification by flash chromatography (PET / siRNA, 1:1 v / v PET / siRNA from 100% PET), the desired intermediate 37.3 (805 mg, 3.72 mmol) was obtained as a brown oily substance. Yield: 53%. MS-ESI(+) m / z: 217.0 (M+H).

[0496] Step 2: 3-(pyridine-3-yloxy)aniline (37.4) 12N HCl (3.08 mL, 37.00 mmol) and zinc (726 mg, 11.10 mmol) were sequentially added to a solution of intermediate 37.3 (800 mg, 3.70 mmol) in MeOH (30 mL), and stirring was continued at rt for 1 hour. The catalyst was filtered on a Celite pad, and the liquid was diluted with H2O (50 mL) and washed with siRNA (2 × 20 mL). The aqueous layer was treated with a saturated aqueous solution of NaHCO3 until the pH became 9, and extracted with siRNA (3 × 50 mL). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried on anhydrous Na2SO4, and evaporated to dryness. Intermediate 37.4 (579 mg, 3.11 mmol) was obtained as a yellow solid. Yield: 84%. MS-ESI(+) m / z: 187.1 (M+H).

[0497] Example 38: 3-(pyridine-3-yloxy)aniline (38.2) [ka] Intermediate 38.2 was prepared according to the procedure described in Example 100, starting with intermediate 30.1 (0.31 mL, 2.91 mmol), intermediate 38.1 (468 mg, 3.78 mmol), K2CO3 (1.60 g, 11.63 mmol), and Pd(dppf)Cl2 (106 mg, 0.15 mmol) in H2O (4 mL) and 1,4-dioxane (12 mL). Stirring was continued at 80°C for 4 hours. After work-up and purification by flash chromatography (CH2Cl2 / MeOH, 95:5 v / v CH2Cl2 / MeOH from 100% CH2Cl2), the title intermediate 38.2 (446 mg, 2.61 mmol) was obtained as a white crystalline solid. Yield: 90%. MS-ESI(+) m / z: 172.1 (M+H).

[0498] Example 39: N-methylisoquinoline-5-amine (39.1) [ka] 3.0 M EtMgBr in Et2O (1.16 mL, 3.47 mmol) was added dropwise to a solution of intermediate 27.1 (500 mg, 3.47 mmol) in THF (8 mL) maintained under N2 atmosphere. After 5 minutes, MeI (195 mL, 3.12 mmol) was added dropwise, and the resulting suspension of fine particles was reacted at rt for 3 hours. This mixture was poured into H2O (30 mL) and extracted with RINKAN (3 × 10 mL). The combined organic layers were washed with 0.5 M citric acid aqueous solution (30 mL), H2O (30 mL), and brine (30 mL), dried on anhydrous Na2SO4, and evaporated to dryness. After purification by flash chromatography (DCM / MeOH, 98:2 v / v to 94:6 v / v), the title intermediate 39.1 (265 mg, 1.66 mmol) was obtained. Yield: 48%. MS-ESI(+) m / z: 159.2 (M+H).

[0499] Example 40: 4-(pyridine-3-yl)aniline (40.2) [ka] K2CO3 (3.24 g, 23.48 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.22, 0.29 mmol) were added to a stirred solution of intermediates 40.1 (1.00 g, 5.81 mmol) and 30.2 (0.94 g, 7.64 mmol) in 1,4-dioxane (30 mL) and H2O (12 mL). The resulting mixture was reacted at 110°C for 16 hours. After cooling to rt, the reaction product was diluted with SiO2 (30 mL) and filtered under vacuum through a Celite pad. The liquid was collected, the two phases were separated, and the aqueous phase was extracted with SiO2 (2 × 15 mL). The collected organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. After chromatographic purification (CH2Cl2 / MeOH, 99:1 to 95:5), 0.70 g of the title intermediate 40.2 was obtained. Yield: 71%.

[0500] MS-ESI(+) m / z: 171.3 (M+H).

[0501] Example 41: 1-Methylisoquinoline-5-amine (41.3) [ka] Step 1: 1-Methyl-5-nitroisoquinoline (41.2) A solution of KNO3 (353 mg, 3.49 mmol) in 98% H2SO4 (2 mL) was added dropwise to a stirred solution of intermediate 41.1 (500 mg, 3.49 mmol) in 98% H2SO4 (2 mL) cooled to -15°C. This mixture was stirred at rt and reacted for 3 hours. The mixture was then poured into 5.0 M aqueous NaOH (20 mL) and extracted with CH2Cl2 (3 × 20 mL). The collected organic layer was dried over Na2SO4 and concentrated under reduced pressure, and 650 mg of intermediate 41.2 was provided as a pale yellow powder. Yield: Quantitative.

[0502] MS-ESI(+) m / z: 189.1 (M+H).

[0503] Step 2: 1-Methylisoquinoline-5-amine (41.3) A 1.5 mL aqueous Raney nickel suspension was added to a stirred solution of intermediate 41.2 (650 mg, 3.45 mmol) in 10 mL of MeOH, and the reaction mixture was warmed to 35°C. Sodium borohydride (262 mg, 6.91 mmol) was then added in small amounts. After 5 minutes, the reaction mixture was filtered under vacuum through a Celite pad, and the solid was washed with CH2Cl2 (30 mL). This liquid was concentrated under reduced pressure, the crude substance was dissolved in CH2Cl2 (20 mL), then washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to yield 505 mg of the title intermediate 41.3. Yield: 92%.

[0504] MS-ESI(+) m / z: 159.3 (M+H).

[0505] Example 42: 1-Chloroisoquinoline-5-amine (42.3) [ka] Step 1: 1-Chloro-5-nitroisoquinoline (42.2) To a stirred solution of intermediate 42.1 (500 mg, 3.06 mmol) in 98% H2SO4 (2.3 mL) cooled to 0°C, fuming HNO3 (0.44 mL, 10.70 mmol) was added, and the resulting solution was reacted at rt for 3 hours. Next, the solution was slowly poured into 6 M aqueous NaOH cooled to 0°C, and the resulting solid was collected by filtration and dried under vacuum. This product was used without further purification. MS-ESI(+) m / z: 209.4 (M+H).

[0506] Step 2: 1-Chloroisoquinoline-5-amine (42.3) To a stirred suspension of intermediate 42.2 (200 mg, 0.96 mmol) in EtOH / H2O (3:1 v / v, 6 mL), powdered iron (289 mg, 5.18 mmol) and NH4Cl (31 mg, 0.58 mmol) were sequentially added. This mixture was reacted at 80°C for 1 hour. After cooling to rt, the solvent was removed under vacuum, and the residue was chromatographically purified (CH2Cl2 / MeOH, 98:2 to 90:10 v / v) to obtain the title intermediate 42.3 (152 mg, 0.85 mmol) as a brownish solid. Yield: 89%. MS-ESI(+) m / z: 179.2 (M+H).

[0507] Example 43: 5-amino-2-methylisoquinoline-1(2H)-one (43.3) [ka] Step 1: 5-Nitroisoquinoline-1(2H)-one (43.1) A mixture of intermediate 42.2 (1.00 g, 4.79 mmol) and ammonium acetate (3.69 g, 47.94 mmol) in AcOH (10 mL) was stirred at 100 °C for 3 hours. After cooling to rt, the reaction mixture was poured into H2O / water (120 mL). The resulting yellow precipitate was filtered under vacuum, and the solid was washed with H2O (2 × 10 mL). The collected solid was azeotropically reacted with acetone under reduced pressure to produce 0.61 g of intermediate 43.1.

[0508] Yield: 67%.

[0509] MS-ESI(-) m / z: 189.1 (MHz).

[0510] Step 2: 2-Methyl-5-nitroisoquinoline-1(2H)-one (43.2) Intermediate 43.1 (500 mg, 2.63 mmol) was added to a stirred suspension of 60% NaH (420 mg, 10.517 mmol) in mineral oil in DMF (5 mL). After 5 minutes, methyl iodide (0.21 mL, 3.42 mmol) was added, and the mixture was stirred at rt for 2 hours. The resulting suspension was diluted with ELISA (50 mL), washed with 0.5 M citric acid (30 mL) and brine (50 mL), dried on Na2SO4, and concentrated under reduced pressure. After chromatographic purification (CH2Cl2 / MeOH, 98.5:1.5 to 94.6 v / v), 520 mg of intermediate 43.2 was obtained.

[0511] Yield: 97%.

[0512] MS-ESI(-) m / z: 203.3 (MH).

[0513] Step 3: 5-amino-2-methylisoquinoline-1(2H)-one (43.3) Intermediate 43.3 was synthesized from intermediate 48.2 (570 mg, 2.79 mmol), Raney-nickel aqueous suspension (2 mL), and sodium borohydride (212 mg, 5.58 mmol) according to the procedure reported in Step 2 of Example 41. After workup, 379 mg of the title intermediate 43.3 was obtained.

[0514] Yield: 78%.

[0515] MS-ESI(+) m / z: 175.2 (M+H).

[0516] Example 44: Isoquinoline-5-ylmethylmethanesulfonate (44.3) [ka] Step 1: Isoquinoline-5-ylmethanol (44.2) To a solution of intermediate 44.1 (300 mg, 1.91 mmol) in MeOH (8 mL) cooled to 0-5°C, sodium borohydride (87 mg, 2.29 mmol) was added, and the mixture was stirred for 2 hours. The reaction product was then poured into SiO2 (30 mL), washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to provide 285 mg of intermediate 44.2.

[0517] Yield: 94%.

[0518] MS-ESI(+) m / z: 160.3 (M+H).

[0519] Step 2: Isoquinoline-5-ylmethylmethanesulfonate (44.3) Mesyl chloride (0.20 mL, 2.64 mmol) and Et3N (0.74 mL, 5.28 mmol) were added to a stirred solution of intermediate 44.2 (280 mg, 1.76 mmol) in CH2Cl2 (10 mL), and the resulting mixture was stirred at rt for 16 hours. This reaction product was poured into H2O (15 mL) to separate the two phases, and the aqueous phase was extracted with CH2Cl2 (2 × 15 mL). The collected organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. After chromatographic purification (CH2Cl2 / MeOH, 99:1 to 95:5 v / v), 117 mg of the title intermediate 44.3 was obtained.

[0520] Yield: 28%.

[0521] MS-ESI(+) m / z: 178.3 (M+H-MsO+ MeCN).

[0522] Example 45: N-phenylbenzene-1,3-diamine (45.5) [ka] Step 1: 2-iodocyclohexa-2-ene-1-one (45.2) A mixture of intermediate 45.1 (1.50 mL, 15.76 mmol), iodine (6.00 g, 23.64 mmol), DMAP (1.92 g, 15.76 mmol), and K2CO3 (2.61 g, 18.91 mmol) in THF / H2O (50 mL, 1:1 v / v) was vigorously stirred at rt for 45 minutes. The resulting dark mixture was poured into siRNA (50 mL), washed with saturated aqueous solution of Na2S2O3 (2 × 50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. After chromatographic purification (PET / siRNA, 98:2 to 90:10 v / v), 0.59 g of intermediate 45.2 was obtained.

[0523] Yield: 17%.

[0524] Step 2: 3-Nitro-N-phenylaniline (45.4) pTSA (0.15 g, 0.80 mmol) was added to a stirred solution of intermediates 45.2 (0.59 g, 2.68 mmol) and 45.3 (0.37 g, 2.68 mmol) in EtOH (4 mL), and the reaction mixture was stirred at 75°C for 90 minutes. After cooling to rt, the mixture was poured into SiO (25 mL), washed with saturated aqueous solution of NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to produce 145 mg of intermediate 45.4, which was used directly in the next step.

[0525] Yield: 25%.

[0526] MS-ESI(+) m / z: 215.4 (M+H).

[0527] Step 3: N-phenylbenzene-1,3-diamine (45.5) Intermediate 45.5 was synthesized from intermediate 45.4 (491 mg, 2.29 mmol), Raney-nickel aqueous suspension (1.03 mL), and sodium borohydride (173 mg, 4.58 mmol) according to the procedure reported in Step 2 of Example 41. After work-up and purification by flash chromatography (PET / SiO, 9:1 to 1:1 v / v), the title intermediate 45.5 (350 mg, 1.90 mmol) was obtained as a yellow solid. Yield: 83%. MS-ESI(+) m / z: 185.1 (M+H).

[0528] Example 46: tert-butyl (3-aminophenyl)phenylcarbamate (46.2) [ka] Step 1: tert-butyl (3-nitrophenyl)phenylcarbamate (46.1) DMAP (16 mg, 0.13 mmol) and DIPEA (0.23 mL, 1.31 mmol) were added to a stirred solution of intermediate 45.4 (140 mg, 0.653 mmol) in CH2Cl2 (10 mL) and Boc2O (214 mg, 0.98 mmol). After 36 hours, the reaction mixture was poured into H2O (10 mL) to separate the two phases, and the aqueous phase was extracted with CH2Cl2 (2 × 5 mL). The collected organic layer was washed with 0.5 M citric acid aqueous solution (15 mL) and brine (15 mL), dried on Na2SO4, and concentrated under reduced pressure. After chromatographic purification (PET / siRNA, 90:10 to 60:40 v / v), 210 mg of intermediate 46.1 was obtained.

[0529] Yield: 99%.

[0530] MS-ESI(+) m / z: 215.3 (M+H-100).

[0531] Step 2: tert-butyl (3-aminophenyl)phenylcarbamate (46.2) Intermediate 46.2 was synthesized from intermediate 46.1 (210 mg, 0.66 mmol) in MeOH (5 mL), Raney-nickel aqueous suspension (0.3 mL), and sodium borohydride (51 mg, 1.37 mmol) according to the procedure reported in Step 2 of Example 41. After workup, 172 mg of the title intermediate 46.2 was obtained.

[0532] Yield: 91%.

[0533] MS-ESI(+) m / z: 285.3 (M+H), 185.3 (M+H-100).

[0534] Example 47: 3-(tetrahydro-2H-pyran-4-yloxy)aniline (47.4) [ka] Step 1: 4-(3-nitrophenoxy)tetrahydro-2H-pyran(47.3) A mixture of intermediates 47.1 (1.00 mL, 9.39 mmol) and 47.2 (1.16 mL, 12.20 mmol) in DMF (10 mL) was treated with 60% NaH (0.75 g, 18.78 mmol) in mineral oil at 50°C for 5 hours. After cooling to rt, the reaction mixture was poured into siRNA (30 mL), washed with H₂O (30 mL) and brine (20 mL), dried over Na₂SO₄, and concentrated under reduced pressure. After chromatographic purification (PET / siRNA, 90:10 to 65:35 v / v), 545 mg of intermediate 47.3 was obtained. Yield: 26%.

[0535] MS-ESI(-) m / z: 222.1 (MH).

[0536] Step 2: 3-(tetrahydro-2H-pyran-4-yloxy)aniline (47.4) Intermediate 47.4 was synthesized from intermediate 47.3 (540 mg, 2.42 mmol) in MeOH (7 mL), Raney-nickel aqueous suspension (0.5 mL), and sodium borohydride (184 mg, 4.84 mmol) according to the procedure reported in Step 2 of Example 41. After workup, 332 mg of the title intermediate 47.4 was obtained.

[0537] Yield: 72%.

[0538] MS-ESI(+) m / z: 285.3 (M+H).

[0539] Example 48: 3-[4-(trifluoromethyl)phenoxy]aniline (48.3 ) [ka] Intermediate 48.1 (100 mg, 0.91 mmol), intermediate 48.2 (150 mg, 0.91 mmol), and in DMSO (2 mL), t A stirring solution of BuOK (118 mg, 1.05 mmol) was stirred at 100°C for 16 hours. After cooling to rt, the reaction mixture was poured into siRNA (15 mL), washed with H₂O (2 × 10 mL) and brine (10 mL), dried over Na₂SO₄, and concentrated under reduced pressure. After chromatographic purification (PET / siRNA, 90:10 to 65:35 v / v), the title intermediate 48.3 was obtained in 77% yield as a glassy pale yellow solid.

[0540] MS-ESI(+) m / z: 254.1 (M+H).

[0541] Example 49: 3-(4-fluorophenoxy)aniline (49.2) [ka] Intermediate 48.1 (250 mg, 2.29 mmol), intermediate 49.1 (0.22 mL, 1.91 mmol), Cu(I)I (18 mg, 0.09 mmol), K3PO4 (767 mg, 3.82 mmol), and picolinic acid (24 mg, 0.19 mmol) were placed in a tube and back-filled with N2 (3 times). Then DMSO (5 mL) was added, the tube was sealed, and the resulting mixture was stirred at 80°C for 24 hours. After cooling to rt, the reaction product was poured into SiO (25 mL), washed with H2O (2 × 20 mL) and brine (20 mL), dried on Na2SO4, and concentrated under reduced pressure. After chromatographic purification (PET / siRNA, 95:5 to 70:30 v / v), the title intermediate 49.2 was obtained as a whitish solid in 77% yield.

[0542] MS-ESI(+) m / z: 244.5 (M+H+ MeCN).

[0543] Example 50: 4-(3-aminophenoxy)benzonitrile (50.2) [ka] Under N2 air, a mixture of intermediates 48.1 (1.00 g, 9.16 mmol), 50.1 (1.36 g, 9.16 mmol), and K2CO3 (1.52 g, 10.99 mmol) in toluene (7 mL) and N-methyl-2-pyrrolidinone (14 mL) was reacted under azeotropic conditions at 160 °C for 3 hours. After cooling to rt, the reaction mixture was poured into SiO (40 mL), washed with H2O (2 × 30 mL) and brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. After chromatographic purification (PET / SiO, 95:5 to 70:30 v / v), the title intermediate 50.2 was obtained as a pale yellow solid in 58% yield.

[0544] MS-ESI(+) m / z: 211.3 (M+H).

[0545] Example 51: 3-(3-methylphenoxy)aniline (51.4) [ka] Step 1: 1-Methyl-3-(3-nitrophenoxy)benzene (51.3) A mixture of intermediates 51.1 (1.00 g, 3.40 mmol) and 51.2 (0.37 g, 3.40 mmol) in pyridine (7 mL), 60% NaH in mineral oil (0.27 g, 6.80 mmol), and copper(I) bromide-dimethyl sulfide complex (0.91 g, 4.42 mmol) was stirred at 115°C for 24 hours. After cooling to rt, the reaction mixture was poured into SiO (25 mL) and 3.0 M HCl (40 mL). The two-phase mixture was filtered under vacuum through a Celite pad, and the residual solid was washed with SiO (2 × 10 mL). The two phases were separated, and the aqueous phase was extracted with SiO (3 × 15 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. After chromatographic purification (PET / siRNA, 95:5 to 80:20 v / v), 0.40 g of intermediate 51.3 was obtained.

[0546] Yield: 51%.

[0547] MS-ESI(-) m / z: 228.6 (M+H).

[0548] Step 2: 3-(3-methylphenoxy)aniline (51.4) Intermediate 51.3 was synthesized from intermediate 94.2 (0.40 g, 21.74 mmol), Raney-nickel aqueous suspension (0.5 mL), and sodium borohydride (0.13 mg, 3.49 mmol) according to the procedure reported in Step 2 of Example 41. After work-up and chromatographic purification (PET / SiO2, 90:10 to 70:30 v / v), 0.27 g of the title intermediate 51.4 was obtained as a colorless oil.

[0549] Yield: 77%.

[0550] MS-ESI(+) m / z: 200.3 (M+H).

[0551] Example 52: 3-(pyridine-4-yloxy)aniline (52.3) [ka] Step 1: 4-(3-nitrophenoxy)pyridine (52.2) A mixture of intermediate 47.1 (1.00 g, 7.09 mmol), intermediate 52.1 (0.67 g, 7.09 mmol), and K2CO3 (1.96 g, 14.17 mmol) in DMF (7 mL) was stirred at 125 °C for 18 hours. After cooling to rt, the reaction mixture was poured into SiO (40 mL), washed with H2O (2 × 30 mL) and brine (30 mL), dried on Na2SO4, and concentrated under reduced pressure. After chromatographic purification (PET / SiO, 90:10 to 50:50 v / v), intermediate 52.2 was obtained as a yellow solid in 22% yield.

[0552] MS-ESI(+) m / z: 217.3 (M+H).

[0553] Step 2: 3-(pyridine-4-yloxy)aniline (52.3) Intermediate 52.3 was synthesized from intermediate 52.2 (1.10 g, 5.09 mmol), powdered iron (1.53 g, 27.48 mmol), and NH4Cl (163 mg, 3.05 mmol) in EtOH / H2O (3:1 v / v, 25 mL) according to the procedure reported in Step 2 of Example 42. After work-up and chromatographic purification (CH2Cl2 / MeOH, 98:2 to 90:10 v / v), 635 mg (3.41 mmol) of the title intermediate 52.3 was obtained as a yellow solid. Yield: 67%.

[0554] MS-ESI(+) m / z: 187.3 (M+H).

[0555] Example 53: 3-(pyridine-2-yloxy)aniline (53.3) [ka] Step 1: 2-(3-nitrophenoxy)pyridine (53.2) A mixture of intermediate 47.1 (1.00 g, 7.09 mmol), intermediate 53.1 (0.81 g, 8.50 mmol), and K2CO3 (1.96 g, 14.17 mmol) in DMF (10 mL) was stirred at 125 °C for 24 hours. After cooling to rt, the reaction mixture was poured into SiO (40 mL), washed with H2O (40 mL) and brine (40 mL), dried on Na2SO4, and concentrated under reduced pressure. After chromatographic purification (CH2Cl2 / MeOH, 99:1 to 96:4 v / v), 1.35 g of intermediate 53.2 was obtained.

[0556] Yield: 87%.

[0557] MS-ESI(+) m / z: 217.3 (M+H).

[0558] Step 2: 3-(pyridine-2-yloxy)aniline (53.3) Intermediate 53.3 was synthesized from intermediate 53.2 (1.35 g, 6.24 mmol), powdered iron (1.89 g, 33.84 mmol), and NH4Cl (203 mg, 3.80 mmol) in EtOH / H2O (3:1 v / v, 40 mL) according to the procedure reported in Step 2 of Example 41. After work-up and chromatographic purification (CH2Cl2 / MeOH, 98:2 to 90:10 v / v), 628 mg (3.37 mmol) of the title intermediate 53.3 was obtained as a yellow solid. Yield: 54%.

[0559] MS-ESI(+) m / z: 187.3 (M+H).

[0560] Example 54: N-(pyridine-3-yl)benzene-1,3-diamine (54.3) [ka] Intermediate 54.1 (1.05 g, 5.19 mmol), Pd2(dba)3 (43 mg, 0.05 mmol), Xantphos (136 mg, 0.23 mmol), and K2CO3 (1.30 g, 9.43 mmol) were added to a flame-dried, sealed tube placed under N2 atmosphere. The flask was evacuated under vacuum and refilled with N2 three times. i A solution of intermediate 54.2 (0.44 g, 4.18 mmol) in PrOH (6 mL) was added, the tube was sealed, and the mixture was vigorously stirred at 110°C for 18 hours. After cooling to rt, bis(pinacolato)diborone (3.59 g, 14.5 mmol) and tBuOK (0.85 g, 7.55 mmol) was carefully added, the tube was sealed, and the mixture was stirred at 110°C for 2 hours. After cooling to rt, the reaction product was poured into siRNA / H₂O (50 mL, 2:1 v / v), and the two-phase mixture was filtered under vacuum through a Celite pad. The residual solid was washed with siRNA (2 × 15 mL). The liquid was collected, the two phases were separated, and the aqueous phase was extracted with siRNA (3 × 25 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. After chromatographic purification (CH₂Cl₂ / MeOH, 99:1 to 93:7 v / v), 0.34 g of the title intermediate 54.3 was obtained.

[0561] Yield: 38%.

[0562] MS-ESI(-) m / z: 186.1 (M+H).

[0563] Example 55: N-(pyridine-3-yl)benzene-1,4-diamine (55.2) [ka] Intermediate 55.2 was synthesized from intermediate 55.1 (224 mg, 1.11 mmol), intermediate 54.2 (95 mg, 1.01 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), Xantphos (29 mg, 0.05 mmol), and K2CO3 (279 mg, 2.02 mmol) according to the procedure reported in Example 54. In the second step, bis(pinacorato)diborone (1.024 g, 4.04 mmol) and tBuOK (226 mg, 2.02 mmol) were added. After work-up and chromatographic purification (CH2Cl2 / MeOH, 99:1 to 93:7 v / v), 145 mg of the title intermediate 55.2 was obtained.

[0564] Yield: 77%.

[0565] MS-ESI(-) m / z: 186.1 (M+H).

[0566] Example 56: 1-(isoquinoline-5-yl)methaneamine (56.4) [ka] Step 1: 2,2,2-trifluoro-N-(isoquinoline-5-ylmethyl)acetamide (56.3) Intermediate 56.2 (1.43 g, 10.00 mmol) was added in small amounts to a stirred solution of intermediate 56.1 (1.29 g, 10.00 mmol) in concentrated H2SO4 (50 mL) cooled to 0-5°C. Stirring was continued at 0-5°C for 15 minutes, after which the reaction mixture was warmed to rt and stirred for a further 16 hours. This mixture was carefully poured onto 200 g of stirred ice, and then 28% ammonia (130 mL) was added dropwise until a basic pH was reached. This aqueous mixture was extracted with CH2Cl2 (3 × 20 mL), and the collected organic layer was washed with brine (40 mL), dried over Na2SO4, and concentrated under reduced pressure. Chromatographic purification (PET / siRNA, 90:10 to 40:60) yielded 0.68 g of intermediate 56.3. Yield: 27%.

[0567] MS-ESI(+) m / z: 255.3 (M+H).

[0568] Step 2: 1-(isoquinoline-5-yl)methaneamine (56.4) Sodium borohydride (0.32 g, 8.40 mmol) was added in small amounts to a stirred solution of intermediate 56.3 (0.65 g, 2.50 mmol) in MeOH (25 mL). After 1 hour, volatile substances were removed under reduced pressure, and the crude substance was dissolved in CH2Cl2 (20 mL). The resulting solution was washed with brine (20 mL), dried over Na2SO4, concentrated under reduced pressure, and the title intermediate 56.4 was provided in approximately quantitative yield as a colorless oil.

[0569] MS-ESI(+) m / z: 159.3 (M+H).

[0570] Example 57: 3-[(6-methylpyridine-3-yl)oxy]aniline (57.2) [ka] Intermediate 57.2 was synthesized according to the procedure reported in Example 49, starting with intermediate 48.1 (200 mg, 1.16 mmol), intermediate 57.1 (152 mg, 1.40 mmol), Cu(I)I (11 mg, 0.06 mmol), K3PO4 (494 mg, 2.33 mmol), and picolinic acid (14 mg, 0.12 mmol) in DMSO (3 mL). After work-up and chromatographic purification (PET / SiO, 95:5 to 70:30 v / v), the title intermediate 57.2 (115 mg, 0.57 mmol) was obtained in 49% yield.

[0571] MS-ESI(+) m / z: 201.2 (M+H).

[0572] Example 58: 3-{[6-(trifluoromethyl)pyridine-3-yl]oxyaniline (58.2) [ka] A solution of intermediate 48.1 (300 mg, 2.75 mmol) in anhydrous DMF (5 mL) was degassed by evacuating the upper space and refilling with N2 (3 times). Then tBuOK (370 mg, 2.30 mmol) was added, and the resulting suspension was stirred at rt for 30 minutes. Then intermediate 58.1 (621 mg, 2.75 mmol) was added, and this mixture was reacted at 105°C for 18 hours with magnetic stirring. The mixture was poured into H2O (50 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried on anhydrous Na2SO4, and evaporated to dryness. After purification by flash chromatography (CH2Cl2 / MeOH, from 100% CH2Cl2 to 9:1 v / v CH2Cl2 / MeOH), the title intermediate 58.2 (320 mg, 1.26 mmol) was obtained as a colorless oil. Yield: 46%. MS-ESI(+) m / z: 255.5 (M+H); MS-ESI(-) m / z: 253.3 (MH).

[0573] Example 59: 4-(6-fluoropyridine-3-yl)aniline (59.3) [ka] Intermediate 59.3 was synthesized from intermediate 59.1 (500 mg, 2.28 mmol), intermediate 59.2 (386 mg, 2.73 mmol), K2CO3 (1.55 g, 11.28 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (103 mg, 0.14 mmol) in 1,4-dioxane (14 mL) and H2O (5 mL), according to the procedure reported in Example 40. After workup and chromatographic purification, 200 mg of the title intermediate 59.3 was obtained.

[0574] Yield: 38%.

[0575] MS-ESI(+) m / z: 189.6 (M+H).

[0576] Example 60: trans-3-(4-fluorophenoxy)cyclobutanamine hydrochloride (60.4) [ka] Step 1: tert-butyl [trans-3-(4-fluorophenoxy)cyclobutyl]carbamate (60.3) Diethyl azodicarboxylate (0.45 mL, 2.89 mmol) and intermediate 60.2 (325 mg, 2.89 mmol) were kept under N2 air and cooled to 0-5°C, then added to a stirred solution of intermediate 60.1 (500 mg, 2.67 mmol) and triphenylphosphine (760 mg, 2.89 mmol) in THF (20 mL). This mixture was slowly heated to 60°C and reacted for 16 hours. Volatile substances were removed under reduced pressure, the crude product was dissolved in CH2Cl2 (50 mL), washed with 2.0 M NaOH aqueous solution (2 × 10 mL) and brine (20 mL), dried on Na2SO4, and concentrated under reduced pressure. After chromatographic purification (PET / siRNA, 95:5 to 50:50 v / v), 220 mg of intermediate 60.3 was obtained as a white solid.

[0577] Yield: 29%.

[0578] MS-ESI(-) m / z: 280.4 (MHz).

[0579] Step 2: trans-3-(4-fluorophenoxy)cyclobutanamine hydrochloride (60.4) A solution of intermediate 60.3 (200 mg, 0.71 mmol) in 0.9 M HCl (3.15 mL, 2.84 mmol) in butyl was stirred at rt for 16 hours. Volatile substances were removed under reduced pressure to yield 153 mg of the title intermediate 60.4.

[0580] Yield: 99%.

[0581] MS-ESI(+) m / z: 182.3 (M+H).

[0582] Example 61: trans-3-(4-methylphenoxy)cyclobutanamine hydrochloride (61.3) [ka] Step 1: tert-butyl [trans-3-(4-methylphenoxy)cyclobutyl]carbamate (61.2) Intermediate 61.2 was synthesized from intermediate 60.1 (400 mg, 2.13 mmol), triphenylphosphine (616 mg, 2.34 mmol), DIAD (0.46 mL, 2.34 mmol), and intermediate 61.1 (253 mg, 2.34 mmol) in THF (15 mL) according to the procedure reported in Step 1 of Example 60. After work-up and chromatographic purification ( / SiO, 95:5 to 70:00 v / v), 250 mg of intermediate 61.2 was obtained.

[0583] Yield: 42%.

[0584] MS-ESI(-) m / z: 276.3 (M+H).

[0585] Step 2: trans-3-(4-methylphenoxy)cyclobutanamine hydrochloride (61.3) Intermediate 61.3 was synthesized from intermediate 61.2 (250 mg, 0.90 mmol) and 0.9 M HCl in SiO2 (4.00 mL, 6.80 mmol) according to the procedure reported in Step 2 of Example 60. 184 mg of the title intermediate 61.3 was obtained.

[0586] Yield: 96%.

[0587] MS-ESI(-) m / z: 178.3 (M+H).

[0588] Example 62: trans-3-(pyridine-3-yloxy)cyclobutanamine dihydrochloride (62.3) [ka] Step 1: tert-butyl [trans-3-(pyridine-3-yloxy)cyclobutyl]carbamate (62.2) Intermediate 62.2 was synthesized from intermediate 60.1 (350 mg, 1.87 mmol), triphenylphosphine (539 mg, 2.05 mmol), DIAD (0.40 mL, 2.05 mmol), and intermediate 62.1 (195 mg, 2.05 mmol) in THF (14 mL) according to the procedure reported in Step 1 of Example 60. After work-up and chromatographic purification (CH2Cl2 / MeOH, 99:1 to 93:7 v / v), 260 mg of intermediate 62.2 was obtained.

[0589] Yield: 52%.

[0590] MS-ESI(+) m / z: 265.3 (M+H).

[0591] Step 2: trans-3-(pyridine-3-yloxy)cyclobutanamine dihydrochloride (62.3) Intermediate 62.3 was synthesized from intermediate 62.2 (250 mg, 0.95 mmol) and 0.9 M HCl in HCl (4.22 mL, 3.80 mmol) according to the procedure reported in Step 2 of Example 60. 204 mg of the title intermediate 62.3 was obtained.

[0592] Yield: 81%.

[0593] MS-ESI(+) m / z: 165.3 (M+H).

[0594] Example 63: trans-3-[(6-methylpyridine-3-yl)oxy]cyclobutanamine dihydrochloride (63.3) [ka] Step 1: tert-butyl {trans-3-[(6-methylpyridine-3-yl)oxy]cyclobutyl}carbamate (63.2) Intermediate 63.2 was synthesized from intermediate 60.1 (350 mg, 1.87 mmol), triphenylphosphine (580 mg, 2.24 mmol), DIAD (0.44 mL, 2.24 mmol), and 63.1 (244 mg, 2.24 mmol) in THF (14 mL) according to the procedure reported in Step 1 of Example 60. After work-up and chromatographic purification (CH2Cl2 / MeOH, 99:1 to 93:7 v / v), 362 mg of intermediate 63.2 was obtained.

[0595] Yield: 69%.

[0596] MS-ESI(+) m / z: 279.4 (M+H).

[0597] Step 2: trans-3-[(6-methylpyridine-3-yl)oxy]cyclobutanamine dihydrochloride (63.3) Intermediate 63.2 (350 mg, 1.26 mmol) was treated with 0.9 M HCl in ethyl acetate (45.6 mL, 5.04 mmol) at rt for 16 hours, followed by 2 hours at 50°C. The resulting suspension was centrifuged, and the supernatant was removed. The collected white powder was washed with Et2O (2 × 5 mL), dried under vacuum, and the title intermediate 63.3 was obtained in nearly quantitative yield.

[0598] MS-ESI(+) m / z: 179.4 (M+H).

[0599] Example 64: trans-3-[(6-fluoropyridine-3-yl)oxy]cyclobutanamine dihydrochloride (64.3) [ka] Step 1: tert-butyl {trans-3-[(6-fluoropyridine-3-yl)oxy]cyclobutyl}carbamate (64.2) Intermediate 64.2 was synthesized from intermediate 60.1 (350 mg, 1.87 mmol), triphenylphosphine (539 mg, 2.05 mmol), DIAD (0.40 mL, 2.05 mmol), and intermediate 64.1 (232 mg, 2.05 mmol) in THF (15 mL) according to the procedure reported in Step 1 of Example 60. After work-up and chromatographic purification (CH2Cl2 / MeOH, 99:1 to 95:5 v / v), 600 mg of crude intermediate 64.2 was obtained and used directly in the next step.

[0600] Step 2: trans-3-[(6-fluoropyridine-3-yl)oxy]cyclobutanamine dihydrochloride (64.3) Intermediate 64.3 was synthesized according to the procedure reported in Step 2 of Example 60. After washing with Et2O and removal of residual volatile substances under vacuum, 210 mg of the title intermediate 64.3 was obtained.

[0601] Yield from intermediate 10.1: 23%.

[0602] MS-ESI(+) m / z: 182.3 (M+H).

[0603] Example of the title compound Example 64: N-(isoquinoline-5-yl)-4-phenyl-2,5-dihydro-1H-pyrrole-3-carboxamide (compound I-1) [ka] Step 1: tert-butyl 3-(isoquinoline-5-ylcarbamoyl)-4-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (64.1) DIPEA (270 μL, 1.55 mmol) and HATU (236 mg, 0.62 mmol) were added to a stirred solution of intermediate 1.6 (150 mg, 0.52 mmol) in THF (3 mL) under N2 atmosphere, and the resulting suspension of fine particles was stirred at rt for 45 minutes. In the second flask, intermediate 27.1 (112 mg, 0.78 mmol) was dissolved in THF (3 mL) under N2 atmosphere, and then 3.0 M EtMgBr (0.52 mL, 1.55 mmol) in Et2O was rapidly added dropwise. The resulting yellow-orange suspension was stirred for 15 minutes, and then the mixture from the first flask was added dropwise to this solution. The resulting mixture was vigorously stirred at rt for 4 hours. The crude substance was poured into ELISA (10 mL), washed with H2O (10 mL), 0.5 M citric acid aqueous solution (10 mL), and brine (10 mL), dried on Na2SO4, and concentrated under reduced pressure. The crude substance was purified by flash chromatography (DCM / MeOH, 99:1 to 95:5 v / v). Intermediate 64.1 (79 mg, 0.19 mmol) was obtained as a colorless oil. Yield: 24%. MS-ESI(+) m / z: 416.6 (M+H); MS-ESI(-) m / z: 414.6 (MH).

[0604] Step 2: N-(isoquinoline-5-yl)-4-phenyl-2,5-dihydro-1H-pyrrole-3-carboxamide (compound I-1) Intermediate 64.1 (79 mg, 0.19 mmol) was dissolved in 1,4-dioxane (2.5 mL) and treated with 4.0 M HCl (0.47 mL, 1.90 mmol) in 1,4-dioxane for 24 hours. Volatile substances were removed under reduced pressure, and the crude substance was then dissolved in H2O (5 mL) and washed with Et2O (2 × 5 mL). The aqueous phase was made basic by adding saturated aqueous solution of NaHCO3 and extracted with DCM / MeOH (9:1 v / v, 3 × 10 mL). The collected organic layer was washed with brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure. Title compound I-1 (36 mg, 0.11 mmol) was obtained as a pale yellow powder. Yield: 58%. 1 H-NMR (400 MHz, DMSO-d6) δ 3.20-3.55 (m, 4H), 7.30-7.50 (m, 6H), 7.69 (t, J = 9.2 Hz, 1H), 7.91-7.97 (m, 2H), 8.38 (d, J = 5.9 Hz, 1H), 9.28 (s, 1H), 10.12 (s. 1H). UHPLC purity: ≧95%. MS-ESI(+) m / z: 316.5 (M+H); MS-ESI(-) m / z: 314.5 (MH)...

Claims

1. Compounds represented by formula (I-A) or (II-A): 【Chemistry 1】 Or, a pharmaceutically acceptable salt and tautomer thereof, wherein the formula is: each 【Chemistry 2】 These independently represent a single bond or a double bond; X is N, NH, C, CH, or CH ２ And; R １ is H, C １－６ alkyl, cycloalkyl, heterocyclyl, -C(O)R １ａ , -CH ２ -aryl, -CH ２ -heteroaryl, aryl, or heteroaryl; where R １ａ is C １－６ alkyl; and where -CH ２ -aryl, -CH ２ -heteroaryl, aryl, and heteroaryl are optionally substituted by C １－６ alkyl or halo; A includes alkyl, cycloalkyl, heterocyclyl, condensed bicyclic aryl, condensed bicyclic heteroaryl, and -CH ２ -aryl, -CH ２ - is heteroaryl, aryl, or heteroaryl; where aryl or heteroaryl is aryl, heteroaryl, -Y Ａ -aryl, or -Y Ａ - Optionally substituted by heteroaryls; where Y Ａ is -O-, -C(O)-, -N(R Ａ１ )-, S(O)-, or -S(O) ２ - and; here, R Ａ１ is H or C １－６ It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH ２ -aryl, -CH ２ - Heteroaryl, each aryl, and each heteroaryl are alkyl, halo, haloalkyl, -CN, -N(R) Ａ ) ２ Optionally substituted with one or more substituents selected from the group consisting of , -OH, and -O-alkyl groups; where each R Ａ H or C １－６ It is alkyl; L １ is -C(O)-NR Ｌ１ -, -OC(S)-NR Ｌ１ -, -OC(O)-NR Ｌ１ -, -NR Ｌ１ -C(O)-, -NR Ｌ１ -C(O)-O-, -NH-C(O)-NH-, -NR Ｌ１ -C(S)-NR Ｌ１ -, -NR Ｌ１ -S(O) ２ -, -S(O) ２ -NR Ｌ１ -ien-CH ２ -CH ２ -ien-CH ２ -NR Ｌ１ -, -NR Ｌ１ -CH ２ -ien-CH ２ -O-, -O-CH ２ -, -O-, -NH-, -C(O)-azetidinyl, -CH ２ -NR Ｌ１ -C(O)-, -C(O)-NR Ｌ１ -CH ２ -, or -C(O)-; where each R Ｌ１ H or C １－６ Alkyl; and L ２ is -C(O)-NR Ｌ２ -, -S(O) ２ -NR Ｌ２ -ien-CH ２ -CH ２ -, -C(S)-NR Ｌ２ -, -C(O)-, or -S(O) ２ - and here, each R Ｌ２ H or C １－６ Alkyl; and B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, and -CH ２ -aryl, -CH ２ -heteroaryl, aryl, heteroaryl, cycloalkyl, -CH ２ -Heterocyclyl, or heterocyclyl, where aryl, heteroaryl, cycloalkyl, or heterocyclyl is aryl, heteroaryl, -Y Ｂ -Ayl, -Y Ｂ -heteroaryl, -Y Ｂ - optionally substituted with a heterocyclyl or cycloalkyl group; where Y Ｂ is -O-, -CH ２ -, -C(O)-, -N(R Ｂ１ )-, -S(O)-, or -S(O) ２ - and; here, R Ｂ１ is H or C １－６ It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH ２ -aryl, -CH ２ -heteroaryl, each aryl, each heteroaryl, each cycloalkyl, -CH ２ - Heterocyclyl, and each heterocyclyl is alkyl, halo, haloalkyl, -CN, -N(R) Ｂ２ ) ２ , optionally substituted with one or more substituents selected from the group consisting of -OH, -O-alkyl, and oxo; where each R Ｂ２ H or C １－６ It is alkyl; Here, the compound is of formula (I-A); A is phenyl, and L １ If is -C(O)-NH-; B is, 【Transformation 3】 Rather; Here, the compound is of formula (I-A); A is a substituted phenyl and B is a substituted phenyl, L １ is -C(O)-NH-, -NH-C(O)-, -NCH ３ Not -C(O)- or -NH-C(O)-NH-; Here, the compound is given by formula (I-A); L １ ga-C(O)-NR Ｌ１ -CH ２ - and B is optionally substituted phenyl, substituted pyridyl, or 【Chemistry 4】 If so, A is a substituted phenyl, substituted pyridyl, substituted thiophenyl, substituted thiazolyl, substituted pyrazolyl 【Transformation 5】 Rather; Here, the compound is of formula (I-A); B is arbitrarily substituted -CH ２ - If it is an aryl and A is an aryl which is optionally substituted; L １ It is not -C(O)-NH-; Here, when the compound is of formula (II-A); A is optionally substituted phenyl, and B is optionally substituted phenyl, L １ is a compound that is not -C(O)-NCH ３ -.

2. Compounds of formula (I) or (II): 【Transformation 6】 or a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: each 【Transformation 7】 These independently represent a single bond or a double bond; X is N, NH, C, CH, or CH ２ And; R １ is H, C １－６ alkyl, cycloalkyl, heterocyclyl, -C(O)R １ａ , -CH ２ -aryl, -CH ２ -heteroaryl, aryl, or heteroaryl; where R １ａ is C １－６ alkyl; and where, -CH ２ -aryl, -CH ２ -heteroaryl, aryl, and heteroaryl are optionally substituted by C １－６ alkyl or halo; A includes alkyl, cycloalkyl, heterocyclyl, condensed bicyclic aryl, condensed bicyclic heteroaryl, and -CH ２ -aryl, -CH ２ - is heteroaryl, aryl, or heteroaryl; where aryl or heteroaryl is aryl, heteroaryl, -Y Ａ -aryl, or -Y Ａ - Optionally substituted by heteroaryls; where Y Ａ is -O-, -C(O)-, -N(R Ａ１ )-, -S(O)-, or -S(O) ２ - and; here, R Ａ１ is H or C １－６ It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH ２ -aryl, -CH ２ - Heteroaryl, each aryl, and each heteroaryl are alkyl, halo, -CN, -N(R) Ａ ) ２ Optionally substituted with one or more substituents selected from the group consisting of , -OH, and -O-alkyl groups; where each R Ａ H or C １－６ It is alkyl; L １ is -C(O)-NR Ｌ１ -, -OC(S)-NR Ｌ１ -, -OC(O)-NR Ｌ１ -, -NR Ｌ１ -C(O)-, -NR Ｌ１ -C(O)-O-, -NH-C(O)-NH-, -NR Ｌ１ -C(S)-NR Ｌ１ -, -NR Ｌ１ -S(O) ２ -, -S(O) ２ -NR Ｌ１ -ien-CH ２ -CH ２ -ien-CH ２ -NR Ｌ１ -, -NR Ｌ１ -CH ２ -ien-CH ２ -O-, -O-CH ２ -, -O-, -NH-, -C(O)-azetidinyl, -CH ２ -NR Ｌ１ -C(O)-, or -C(O)-NR Ｌ１ -CH ２ - and here, each R Ｌ１ H or C １－６ Alkyl; and L ２ is -C(O)-NR Ｌ２ -, -S(O) ２ -NR Ｌ２ -ien-CH ２ -CH ２ -, -C(S)-NR Ｌ２ -, -C(O)-, or -S(O) ２ - and here, each R Ｌ２ H or C １－６ Alkyl; and B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, and -CH ２ -aryl, -CH ２ - Heteroaryl, aryl, heteroaryl, cycloalkyl, or - CH ２ -Heterocyclyl, where aryl or heteroaryl is aryl, heteroaryl, -Y Ｂ -aryl, or -Y Ｂ - Optionally substituted by heteroaryls; where Y Ｂ is -O-, -C(O)-, -N(R Ｂ１ )-, -S(O)-, or -S(O) ２ - and; here, R Ｂ１ is H or C １－６ It is alkyl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH ２ -aryl, -CH ２ -heteroaryl, each aryl, each heteroaryl, cycloalkyl, and -CH ２ - Heterocyclyl is alkyl, halo, -CN, N(R) Ｂ２ ) ２ Optionally substituted with one or more substituents selected from the group consisting of , -OH, and -O-alkyl groups; where each R Ｂ２ H or C １ - ６ It is alkyl; Here, the compound is of formula (I); A is an optionally substituted phenyl or thiophenyl, and L １ If is -C(O)-NH-; B is, 【Transformation 8】 Rather; Here, the compound is of formula (I); A is a substituted phenyl and B is a substituted phenyl, L １ is -C(O)-NH-, -NH-C(O)-, -NCH ３ Not -C(O)- or -NH-C(O)-NH-; Here, the compound is of formula (I); B is arbitrarily substituted -CH ２ - If it is an aryl and A is an aryl which is optionally substituted; L １ It is not -C(O)-NH-; Here, if the compound is of formula (II); A is an optionally substituted phenyl and B is an optionally substituted phenyl, then L １ is -C(O)-NCH ３ - Not a compound.

3. Compound of formula (III): 【Chemistry 9】 Or, a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; L ３ is -C(O)-NR Ｌ３ -, -OC(S)-NR Ｌ３ -, -OC(O)-NR Ｌ３ -, -NR Ｌ３ -C(O)-, -NR Ｌ３ -C(S)-NR Ｌ３ -, -NR Ｌ３ -S(O) ２ -, -S(O) ２ -NR Ｌ３ -ien-CH ２ -CH ２ -ien-CH ２ -NR Ｌ３ -, -NR Ｌ３ -CH ２ -ien-CH ２ -O-, -O-CH ２ -, or -O-; where each R Ｌ３ These are independently hydrogen or C １－６ Alkyl; and B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, and -CH ２ -aryl, -CH ２ - A heteroaryl, aryl, or heteroaryl, where the aryl or heteroaryl is optionally substituted by the aryl or heteroaryl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH ２ -aryl, -CH ２ -Heteroaryls, each aryl, and each heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; Here, A is an arbitrarily substituted phenyl or thiophenyl, and L ３ If is -C(O)-NH-; B is 【Chemistry 10】 Rather; Here, if A is a substituted phenyl and B is a substituted phenyl, then L ３ is -C(O)-NH-, -NH-C(O)-, -NCH ３ Not -C(O)- or -NH-C(O)-NH-; Here, the compound is of formula (I); B is arbitrarily substituted -CH ２ - If it is an aryl and A is an aryl which is optionally substituted; L ３ It is a compound that is not -C(O)-NH-.

4. Compound of formula (IV): 【Chemistry 11】 or a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: L ３ is -C(O)-NR Ｌ３ -, -OC(S)-NR Ｌ３ -, -OC(O)-NR Ｌ３ -, -NR Ｌ３ -C(O)-, -NR Ｌ３ -C(S)-NR Ｌ３ -, -NR Ｌ３ -S(O) ２ -, -S(O) ２ -NR Ｌ３ -ien-CH ２ -CH ２ -ien-CH ２ -NR Ｌ３ -, -NR Ｌ３ -CH ２ -ien-CH ２ -O-, -O-CH ２ -, or -O-; where each R Ｌ３ These are independently hydrogen or C １－６ Alkyl; and B is a condensed bicyclic aryl, a condensed bicyclic heteroaryl, and -CH ２ -aryl, -CH ２ - A heteroaryl, aryl, or heteroaryl, where the aryl or heteroaryl is optionally substituted by the aryl or heteroaryl; Here, condensed bicyclic aryl, condensed bicyclic heteroaryl, -CH ２ -aryl, -CH ２ -Heteroaryls, each aryl, and each heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl groups; Here, L ３ If is -C(O)-NH-; B is, 【Chemistry 12】 No, it's a compound.

5. Compound of formula (V): 【Chemistry 13】 Or, a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; L ３ is -C(O)-NR Ｌ３ -, -OC(S)-NR Ｌ３ -, -OC(O)-NR Ｌ３ -, -NR Ｌ３ -C(O)-, -NR Ｌ３ -C(S)-NR Ｌ３ -, -NR Ｌ３ -S(O) ２ -, -S(O) ２ -NR Ｌ３ -ien-CH ２ -CH ２ -ien-CH ２ -NR Ｌ３ -, -NR Ｌ３ -CH ２ -ien-CH ２ -O-, -O-CH ２ -, or -O-; where each R Ｌ３ These are independently hydrogen or C １－６ Alkyl; and B1 is a condensed bicyclic aryl or condensed bicyclic heteroaryl; where the condensed bicyclic aryl and condensed bicyclic heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, A is an arbitrarily substituted phenyl or thiophenyl, and L ３ If is -C(O)-NH-; B is, 【Chemistry 14】 No, it's a compound.

6. The compound according to claim 5, wherein B1 is a condensed bicyclic aryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

7. The compound according to claim 5, wherein B1 is a condensed bicyclic heteroaryl, or a pharmaceutically acceptable salt or tautomer thereof.

8. B1 is: 【Chemistry 15】 A compound according to claim 5, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the above.

9. Compound of formula (VI): 【Chemistry 16】 or a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; L ３ is -C(O)-NR Ｌ３ -, -OC(S)-NR Ｌ３ -, -OC(O)-NR Ｌ３ -, -NR Ｌ３ -C(O)-, -NR Ｌ３ -C(S)-NR Ｌ３ -, -NR Ｌ３ -S(O) ２ -, -S(O) ２ -NR Ｌ３ -ien-CH ２ -CH ２ -ien-CH ２ -NR Ｌ３ -, -NR Ｌ３ -CH ２ -ien-CH ２ -O-, -O-CH ２ -, or -O-; where each R Ｌ３ These are independently hydrogen or C １－６ Alkyl; and B2 is a monocyclic aryl or monocyclic heteroaryl; where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Y １ It does not exist, or -O-, -C(O)-, -N(R Ｙ )-, -S(O)-, or -S(O) ２ - and; here, R Ｙ is H or C １－６ Alkyl; and B3 is a monocyclic aryl or monocyclic heteroaryl compound, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

10. The compound according to claim 9, wherein B2 is a monocyclic aryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

11. The compound according to claim 9, wherein B2 is a monocyclic heteroaryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

12. The compound according to claim 9, wherein B3 is a monocyclic aryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

13. The compound according to claim 9, wherein B3 is a monocyclic heteroaryl compound, or a pharmaceutically acceptable salt or tautomer thereof. 【Request Item 14】 【Chemistry 17】 but, [Chemistry 18] A compound according to claim 9, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the above.

15. Compound of formula (VII): 【Chemistry 19】 or a pharmaceutically acceptable salt or tautomer thereof, wherein the formula is: A is an aryl or a 5- to 6-membered heteroaryl, where the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; L ３ is -C(O)-NR Ｌ３ -, -OC(S)-NR Ｌ３ -, -OC(O)-NR Ｌ３ -, -NR Ｌ３ -C(O)-, -NR Ｌ３ -C(S)-NR Ｌ３ -, -NR Ｌ３ -S(O) ２ -, -S(O) ２ -NR Ｌ３ -ien-CH ２ -CH ２ -ien-CH ２ -NR Ｌ３ -, -NR Ｌ３ -CH ２ -ien-CH ２ -O-, -O-CH ２ -, or -O-; where each R Ｌ３ These are independently hydrogen or C １－６ Alkyl; and B1 is a condensed bicyclic aryl or condensed bicyclic heteroaryl; where the condensed bicyclic aryl and condensed bicyclic heteroaryl are optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl; Here, A is an arbitrarily substituted phenyl or thiophenyl, and L ３ If is -C(O)-NH-; B is 【Chemistry 20】 No, it's a compound.

16. B4 is -CH ２ - The compound according to claim 15, which is an aryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

17. B4 is -CH ２ - The compound according to claim 15, which is a heteroaryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

18. B4 is 【Chemistry 21】 A compound according to claim 15, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the above. 【Request Item 19】 【Chemistry 22】 but, 【Chemistry 23】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or tautomer thereof. 【Request Item 20】 【Chemistry 24】 but, 【Chemistry 25】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or tautomer thereof. 【Request Item 21】 【Chemistry 26】 but, 【Chemistry 27】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or tautomer thereof.

22. A compound according to any one of claims 1 to 2 and 19 to 21, wherein X is N or NH, or a pharmaceutically acceptable salt or tautomer thereof.

23. X is C, CH, or CH ２ The compound according to any one of claims 1 to 2 and 19 to 21, or a pharmaceutically acceptable salt or tautomer thereof.

24. R １ A compound according to any one of claims 1 to 2 and 19 to 23, wherein H is present, or a pharmaceutically acceptable salt or tautomer thereof.

25. R １ However, C １－６ A compound according to any one of claims 1 to 2 and 19 to 23, which is alkyl, or a pharmaceutically acceptable salt or tautomer thereof.

26. R １ The compound according to any one of claims 1 to 2 and 19 to 23, which is a cycloalkyl compound, or a pharmaceutically acceptable salt or tautomer thereof.

27. R １ However, the compound according to any one of claims 1 to 2 and 19 to 23, which is a heterocycline, or a pharmaceutically acceptable salt or tautomer thereof.

28. R １ However, -C(O)R １ａ The compound according to any one of claims 1 to 2 and 19 to 23, or a pharmaceutically acceptable salt or tautomer thereof.

29. R １ However, -CH ２ - A compound according to any one of claims 1 to 2 and 19 to 23, which is an aryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

30. A compound according to any one of claims 1 to 29, wherein A is an aryl compound, or a pharmaceutically acceptable salt thereof.

31. The compound according to claim 30, or a pharmaceutically acceptable salt or tautomer thereof, wherein the aryl is substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

32. A compound according to any one of claims 1 to 29, wherein A is a 5- to 6-membered heteroaryl, or a pharmaceutically acceptable salt or tautomer thereof.

33. The compound according to claim 32, or a pharmaceutically acceptable salt or tautomer thereof, wherein the heteroaryl is substituted with one or more substituents selected from the group consisting of alkyl, halo, -OH, and -O-alkyl.

34. A is an alkyl compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or tautomer thereof.

35. A is a cycloalkyl compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or tautomer thereof.

36. A is a heterocyclyl, the compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt or tautomer thereof.

37. A is a compound according to any one of claims 1 to 29, wherein A is a condensed bicyclic aryl or a condensed bicyclic heteroaryl, or a pharmaceutically acceptable salt or tautomer thereof.

38. A is -CH ２ -aryl or -CH ２ - A compound according to any one of claims 1 to 29, which is a heteroaryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

39. L １ However, -C(O)-NR Ｌ１ - The compound according to any one of claims 1 to 2 and 18 to 38, or a pharmaceutically acceptable salt or tautomer thereof.

40. L １ However, -O-C(S)-NR Ｌ１ - The compound according to any one of claims 1 to 2 and 18 to 38, or a pharmaceutically acceptable salt or tautomer thereof.

41. L １ However, -O-C(O)-NR Ｌ１ - The compound according to any one of claims 1 to 2 and 18 to 38, or a pharmaceutically acceptable salt or tautomer thereof.

42. L １ However, -NR Ｌ１ -C(S)-NR Ｌ１ - The compound according to any one of claims 1 to 2 and 18 to 38, or a pharmaceutically acceptable salt or tautomer thereof.

43. L １ A compound according to any one of claims 1 to 2 and 18 to 38, wherein the compound is -O-, or a pharmaceutically acceptable salt or tautomer thereof.

44. L １ However, -NR Ｌ１ -C(O)-, -NR Ｌ１ -C(O)-O-, -NH-C(O)-NH-, -NR Ｌ１ -S(O) ２ -, or -S(O) ２ -NR Ｌ１ - The compound according to any one of claims 1 to 2 and 18 to 38, or a pharmaceutically acceptable salt or tautomer thereof.

45. L １ However, -CH ２ -CH ２ -ien-CH ２ -NR Ｌ１ -, -NR Ｌ１ -CH ２ -ien-CH ２ -O-, -O-CH ２ A compound according to any one of claims 1 to 2 and 18 to 38, which is -, -NH-, or -C(O)-azetidinyl, or a pharmaceutically acceptable salt or tautomer thereof.

46. L ２ However, -C(O)-NR Ｌ２ - The compound according to any one of claims 1 to 2 and 18 to 38, or a pharmaceutically acceptable salt or tautomer thereof.

47. L ２ However, -S(O) ２ -NR Ｌ２ -, or -CH ２ -CH ２ - The compound according to any one of claims 1 to 2 and 18 to 38, or a pharmaceutically acceptable salt or tautomer thereof.

48. L ３ However, -C(O)-NR Ｌ３ - The compound according to any one of claims 3 to 18 and 30 to 38, or a pharmaceutically acceptable salt or tautomer thereof.

49. L ３ However, -O-C(S)-NR Ｌ３ - The compound according to any one of claims 3 to 18 and 30 to 38, or a pharmaceutically acceptable salt or tautomer thereof.

50. L ３ However, -O-C(O)-NR Ｌ３ - The compound according to any one of claims 3 to 18 and 30 to 38, or a pharmaceutically acceptable salt or tautomer thereof.

51. L ３ However, -NR Ｌ３ -C(S)-NR Ｌ３ - The compound according to any one of claims 3 to 18 and 30 to 38, or a pharmaceutically acceptable salt or tautomer thereof.

52. L ３ However, -NR Ｌ３ -C(O)-, -NR Ｌ３ -S(O) ２ -, -S(O) ２ -NR Ｌ３ -ien-CH ２ -CH ２ -ien-CH ２ -NR Ｌ３ -, or -NR Ｌ３ -CH ２ - The compound according to any one of claims 3 to 18 and 30 to 38, or a pharmaceutically acceptable salt or tautomer thereof.

53. L ３ However, -CH ２ -O-, -O-CH ２ A compound according to any one of claims 3 to 18 and 30 to 38, which is - or -O-, or a pharmaceutically acceptable salt or tautomer thereof.

54. A compound according to any one of claims 1 to 4 and 19 to 53, wherein B is a condensed bicyclic aryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

55. A compound according to any one of claims 1 to 4 and 19 to 53, wherein B is a condensed bicyclic heteroaryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

56. B, 【Chemistry 28】 A compound according to any one of claims 1 to 4 and 19 to 53, selected from the group consisting of the above, or a pharmaceutically acceptable salt or tautomer thereof.

57. B is -CH ２ - A compound according to any one of claims 1 to 4 and 19 to 53, which is an aryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

58. B is -CH ２ - A compound according to any one of claims 1 to 4 and 19 to 53, which is a heteroaryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

59. B, 【Chemistry 29】 A compound according to any one of claims 1 to 4 and 19 to 53, selected from the group consisting of the above, or a pharmaceutically acceptable salt or tautomer thereof.

60. A compound according to any one of claims 1 to 4 and 19 to 52, wherein B is an aryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

61. A compound according to any one of claims 1 to 4 and 19 to 52, wherein B is an aryl substituted with an aryl or heteroaryl, or a pharmaceutically acceptable salt or tautomer thereof.

62. A compound according to any one of claims 1 to 4 and 19 to 52, wherein B is a heteroaryl compound, or a pharmaceutically acceptable salt or tautomer thereof.

63. A compound according to any one of claims 1 to 4 and 19 to 52, wherein B is a heteroaryl substituted with an aryl or heteroaryl, or a pharmaceutically acceptable salt or tautomer thereof.

64. B, 【Transformation 30】 A compound according to any one of claims 1 to 4 and 19 to 52, selected from the group consisting of the above, or a pharmaceutically acceptable salt or tautomer thereof.

65. A compound according to any one of claims 1 to 4 and 19 to 52, wherein B is a cycloalkyl compound, or a pharmaceutically acceptable salt or tautomer thereof.

66. B is aryl, heteroaryl, -Y Ｂ -Ayl, -Y Ｂ - A compound according to any one of claims 1 to 4 and 19 to 52, which is a cyclocyclyl substituted with a heteroaryl, or a pharmaceutically acceptable salt or tautomer thereof.

67. B is -CH ２ - A compound according to any one of claims 1 to 4 and 19 to 52, which is a heterocycline, or a pharmaceutically acceptable salt or tautomer thereof.

68. A compound according to any one of claims 1 to 4 and 19 to 52, wherein B is a heterocyclyl, or a pharmaceutically acceptable salt or tautomer thereof.

69. A compound according to any one of claims 1 to 4 and 19 to 52, wherein B is a heterocyclyl substituted with an aryl or heteroaryl, or a pharmaceutically acceptable salt or tautomer thereof.

70. A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the following: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6

71. A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the following: Table 2-1 Table 2-2

72. A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the following: Table 3

73. A compound, or a pharmaceutically acceptable salt or tautomer thereof, selected from the group consisting of the following: Table 4-1 Table 4-2 Table 4-3

74. A pharmaceutical composition comprising a compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable excipient.

75. A method for adjusting the activity of NR2F6 by exposing NR2F6 to an effective amount of a compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 74.

76. The method according to claim 75, wherein the adjustment includes enhancing NR2F6 activity.

77. The method according to claim 75, wherein the adjustment includes inhibition of NR2F6 activity.

78. A method for treating or alleviating the effects of a disease or disorder related to NR2F6 regulation, comprising administering an effective amount of a compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 76.

79. The method according to claim 78, wherein the disease or disorder includes an enhanced autoimmune response.

80. The method according to claim 79, wherein the enhanced autoimmune response is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, type 1 diabetes mellitus, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, psoriasis / psoriatic arthritis, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, and vasculitis.

81. The method according to claim 78, wherein the disorder is cancer.

82. The method according to claim 81, wherein the cancer is a solid tumor selected from the group consisting of lung adenocarcinoma, cholangiocarcinoma, bladder cancer; bone cancer, brain tumor, glioma, undifferentiated oligoglycolate, adult glioblastoma multiforme, adult undifferentiated astrocytoma; benign prostatic hyperplasia, bronchoalveolar carcinoma, breast cancer including metastatic breast cancer; cervical cancer, cholangiocarcinoma, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, squamous cell carcinoma of the head and neck, gallbladder cancer, hepatocellular carcinoma, kidney cancer, liver cancer, lung cancer, melanoma; neuroendocrine carcinoma, metastatic neuroendocrine tumor, non-small cell lung cancer (NSCLC), small cell lung cancer, ovarian cancer, primary peritoneal cancer, pancreatic cancer, prostate cancer including androgen-dependent and androgen-independent prostate cancer, colorectal cancer, kidney cancer, metastatic renal cell carcinoma, soft tissue sarcoma, bladder cancer, and uterine cancer.

83. The method according to claim 78, wherein the disorder is a hematological malignancy.

84. The method according to claim 83, wherein the hematological malignancy is selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia (CML), transitional CML, acute transformation CML (CML-BP), acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), Hodgkin's disease, non-Hodgkin lymphoma, follicular lymphoma, mantle cell lymphoma, B-cell lymphoma, T-cell lymphoma, multiple myeloma, Valdenström macroglobulinemia, myelodysplastic syndrome (MDS), refractory anemia (RA), RA with ring sideroblasts, RA with supervast blasts (RAEB), transformed RAEB, and myeloproliferative syndromes.

85. A method for treating or alleviating the effects of gastrointestinal disorders or conditions, comprising administering an effective amount of a compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 74.

86. The method according to claim 85, wherein the gastrointestinal disorder is IBD, Crohn's disease, or colitis.

87. A method for treating a condition associated with hepatic steatosis, comprising administering an effective amount of a compound according to any one of claims 1-73, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 74.

88. The method according to claim 87, wherein the condition associated with hepatic steatosis is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

89. A compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 74, for use in regulating NR2F6 activity.

90. A compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 74, for use in the treatment or mitigation of the effects of diseases or disorders related to NR2F6 regulation.

91. Use of a compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt or tautomer thereof, or the pharmaceutical composition according to claim 74, for regulating the activity of NR2F6.

92. Use of a compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 74, for treating or alleviating the effects of a disease or disorder related to NR2F6 regulation.

93. Use of a compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 74, in the manufacture of a pharmaceutical for regulating the activity of NR2F6.

94. Use of a compound according to any one of claims 1 to 73, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition according to claim 74, in the manufacture of a pharmaceutical for treating or alleviating the effects of a disease or disorder related to NR2F6 regulation.

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