Novel compound as a glucocorticoid receptor modulator and its use

Abstract

The present specification describes a glucocorticoid receptor (GR) antagonist of formula (I) and a pharmaceutical composition comprising said compound. The target compound and composition are useful for the treatment of GR-related diseases or disorders.

Description

Technology Field

[0001] The present disclosure relates to novel compounds useful as glucocorticoid receptor (GR) modulators or pharmaceutically acceptable salts thereof. The present disclosure also relates to pharmaceutical compositions comprising one or more of these compounds or pharmaceutically acceptable salts thereof as active ingredients, and to the use of these compounds or pharmaceutically acceptable salts thereof in the treatment of diseases or disorders. Background Technology

[0002] Glucocorticoid receptors (GRs) are members of the nuclear receptor superfamily. GRs, mineralocorticoid receptors (MRs), progesterone receptors (PRs), androgen receptors (ARs), and estrogen receptors (ERs) are steroid hormone receptors that are subclasses of the nuclear receptor superfamily. Glucocorticoids regulate gene expression, including various cellular functions such as metabolism, inflammation, cell growth, and differentiation, by activating GRs.

[0003] According to recent studies, at least in animals, the inactivation of GR and / or restoration of MR:GR balance may be a neuropharmacological therapeutic strategy to attenuate the damaging effects of hypercortisolemia in neurodegenerative diseases.

[0004] Therefore, there is still an unmet need for novel compounds as GR regulators.

[0005] In one embodiment, the present disclosure relates to a compound of formula (I) as disclosed herein:

[0006] Chemical formula (I),

[0007] Or provides a pharmaceutically acceptable salt thereof.

[0008] In one embodiment, the present disclosure relates to a compound of formula (Ia) or formula (Ib) as disclosed herein:

[0009]

[0010] Or provides a pharmaceutically acceptable salt thereof. In one embodiment, the present disclosure provides a compound of formula (Ia-1) or formula (Ib-1) as disclosed herein:

[0011]

[0012] Or a pharmaceutically acceptable salt thereof is provided. Additionally, the present specification discloses a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ia-1), formula (Ib-1), or a compound listed in Table 1, Table 2 or Table 3), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0013] In addition, the present specification discloses a method for controlling (e.g., inhibiting) GR in a subject, comprising the step of administering to the subject a compound disclosed in the present specification (e.g., a compound of formula (I), formula (Ia), formula (Ib), formula (Ia-1), formula (Ib-1), or a compound listed in Table 1, Table 2 or Table 3), or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition disclosed in the present specification.

[0014] In addition, the present specification discloses the use of compounds disclosed in the present specification (e.g., compounds of formula (I), formula (Ia), formula (Ib), formula (Ia-1), formula (Ib-1), or compounds listed in Table 1, Table 2 or Table 3), or pharmaceutically acceptable salts or stereoisomers thereof, or pharmaceutical compositions disclosed in the present specification, in the manufacture of a drug for controlling (e.g., inhibiting) GR in a target.

[0015] In addition, the present specification discloses the use of compounds disclosed herein (e.g., compounds of formula (I), formula (Ia), formula (Ib), formula (Ia-1), formula (Ib-1), or compounds listed in Table 1, Table 2, or Table 3), or pharmaceutically acceptable salts or stereoisomers thereof, or pharmaceutical compositions disclosed herein in the manufacture of pharmaceuticals for treating or preventing diseases or disorders in subjects requiring such use. In some embodiments, the disease or disorder is a GR-related disease or disorder.

[0016] Integration by reference

[0017] All publications, patents, and patent applications mentioned in this specification are incorporated by reference into this specification to the same extent as each individual publication, patent, or patent application is specifically and individually incorporated by reference. Specific details for implementing the invention

[0018] definition

[0019] In the following description, specific details are provided to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the invention may be practiced without these details. In other cases, well-known structures have not been illustrated or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by the context, throughout the following specification and claims, the word “comprise” and variations thereof such as “comprises” and “comprising” should be interpreted in an open and inclusive sense, i.e., “comprising but not limited to.” Furthermore, headings provided in this specification are for convenience only and do not imply the scope or meaning of the claimed invention.

[0020] Throughout this specification, references to “one embodiment” or “one embodiment” mean that a specific feature, structure, or characteristic described in relation to such embodiment is included in at least one embodiment. Accordingly, the appearance of phrases “in one embodiment” or “in one embodiment” in various places throughout this specification does not necessarily refer to the same embodiment. Furthermore, a specific feature, structure, or characteristic may be combined in any appropriate manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “one (a, an)” and “the” include the plural unless the content clearly indicates otherwise. Additionally, it should be noted that the term “or” is generally used to include “and / or” unless the content clearly indicates otherwise.

[0021] The following terms as used in this specification have the following meanings unless otherwise indicated.

[0022] The definitions of specific functional groups and chemical terms are explained in more detail below. For the purposes of this disclosure, chemical elements are identified according to the CAS version of the Periodic Table of the Elements (Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover), and specific functional groups are generally defined as described herein. Additionally, specific functional moiety and reactivity, as well as the general principles of organic chemistry, are [refer to] Organic Chemistry, Thomas Sorrell, 2 nd Edition, University Science Books, Sausalito, 2006; Smith and March March's Advanced Organic Chemistry, 6 th Edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3 rd Edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4 th Edition, Cambridge University Press, Cambridge, 2004; the full contents of each of these are incorporated herein by reference.

[0023] In various places in the present disclosure, linking substituents are described. Where a structure explicitly requires a linker, the Markush variable listed for that group is understood to be the linker. For example, if a structure requires a linker and “alkyl” is listed in the Markush group definition for that variable, “alkyl” is understood to represent a linking alkylene group.

[0024] If a bond to a substituent is depicted as crossing a bond connecting two atoms within a ring, such a substituent may be bonded to any atom within the ring. If a substituent is listed without indicating the atom to which it is bonded to the remainder of the compound of a given formula, such a substituent may be bonded through any atom within that formula. Combinations of substituents and / or variables are permissible, provided that such combinations produce a stable compound.

[0025] Any variable (e.g., R i If ) occurs two or more times in the components of a compound or in the chemical formula, the definition of each occurrence is independent of the definition of all other occurrences. Therefore, for example, a certain group has 0-2 R i If indicated as being substituted with a moiety, the group is optionally up to 2 Rs i It can be replaced with a moiety, and R at each occurrence i is R i It is selected independently from the definition of. In addition, combinations of substituents and / or variables are acceptable, but only if such combinations produce a stable compound.

[0026] As used in this specification, “C i -C j” The term denotes a range of the number of carbon atoms, where i and j are integers, and the range of the number of carbon atoms includes the terminal points (i.e., i and j) and each integer point in between, where j is greater than i. For example, C1-C6 denotes a range of 1 to 6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some embodiments, “C 1-12”The term indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3, or particularly 1 to 2 carbon atoms.

[0027] “Oxo” means =O.

[0028] "Cyano" means -CN.

[0029] Whether used as part of another term or independently, “amino” refers to the radical -NR a R b Refers to, where R a and R b is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, or other suitable organic groups, each of which may be optionally substituted.

[0030] “Hydroxy” or “hydroxyl” refers to -OH, whether used as part of another term or independently.

[0031] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon radical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms, whether used as part of another term or independently. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups such as heptyl, octyl, etc. Whenever a numerical range such as “C1-C6alkyl” or “C1-6alkyl” appears in this specification, it means that the alkyl group may consist of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms, even though this definition also encompasses occurrences of the term “alkyl” where no numerical range is specified. In some embodiments, the alkyl is C1- 10It is an alkyl. In some embodiments, the alkyl is a C1-6 alkyl. In some embodiments, the alkyl is a C1-5 alkyl. In some embodiments, the alkyl is a C1-4 alkyl. In some embodiments, the alkyl is a C1-3 alkyl. Unless specifically otherwise stated in the specification, the alkyl group may be optionally substituted with one or more substituents such as, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with one or more substituents such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more substituents such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with a halogen.

[0032] “Alkenyl,” whether used as part of another term or independently, refers to a straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon double bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group may be in the cis or trans form with respect to the double bond(s), or alternatively in the E or Z form, and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever a numerical range such as “C2-C6 alkenyl” or “C2-6 alkenyl” appears in this specification, it means that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, even though this definition also encompasses occurrences of the term “alkenyl” where no numerical range is specified. Unless specifically otherwise stated in the specification, the alkenyl group may be optionally substituted with one or more substituents such as, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, etc. In some embodiments, the alkenyl is optionally substituted with one or more substituents such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more substituents such as a halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with a halogen.

[0033] “Alkynyl,” whether used as part of another term or independently, refers to a straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon triple bonds and 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethinyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever a numerical range such as “C2-C6 alkynyl” or “C2-6 alkynyl” appears in this specification, it means that the alkynyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, even though this definition also covers occurrences of the term “alkynyl” where no numerical range is specified. Unless specifically otherwise stated in the specification, the alkynyl group may be optionally substituted with one or more substituents, such as, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, etc. In some embodiments, the alkynyl is optionally substituted with one or more substituents such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more substituents such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with a halogen.

[0034] "Alkoxy" refers to the chemical formula -OR, whether used as part of another term or independently. a It refers to the radical, where R ais an alkyl radical as defined herein. Whenever a numerical range such as “C1-C6 alkoxy” or “C1-6 alkoxy” appears herein, it means that the alkyl group may consist of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms, even though this definition also encompasses occurrences of the term “alkoxy” where no numerical range is specified. In some embodiments, the alkoxy is C1- 10 It is an alkoxy. In some embodiments, the alkoxy is a C1-6 alkoxy. In some embodiments, the alkoxy is a C1-5 alkoxy. In some embodiments, the alkoxy is a C1-4 alkoxy. In some embodiments, the alkyl is a C1-3 alkoxy. In some embodiments, the alkyl is a C1-2 alkoxy. In some embodiments, the alkyl is a methoxy. Unless specifically otherwise stated in the specification, the alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, or heteroaryl. In some embodiments, the alkoxy is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with a halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with a halogen.

[0035] “Aryl,” whether used as part of another term or independently, refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic or polycyclic (including, but not limited to, 2-, 3-, or 4-cyclic) ring system. The polycyclic ring system may include a fused (e.g., an aromatic ring condensed with a cycloalkyl ring) or bridged (e.g., an aromatic ring condensed with a bridged cycloalkyl ring) ring system. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). The aryl radical includes, but is not limited to, aryl radicals derived from hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiaden, pyrene, and triphenylene. Unless specifically otherwise stated in the specification, the aryl may be optionally substituted with one or more substituents such as, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, etc. In some embodiments, the aryl is optionally substituted with one or more substituents such as halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with one or more substituents such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with a halogen.

[0036] "Cycloalkyl," whether used as part of another term or independently, refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include condensed (e.g., condensed with another cycloalkyl ring), spiro, or cross-linked ring systems. In some embodiments, the cycloalkyl is fully saturated. In some embodiments, the cycloalkyl is partially saturated. Representative cycloalkyls are cycloalkyls having 3 to 15 carbon atoms (C3-C 15 Fully saturated cycloalkyl or C3-C 15 cycloalkenyl), 3 to 10 carbon atoms (C3-C 10 Fully saturated cycloalkyl or C3-C 10cycloalkenyl), 3 to 8 carbon atoms (C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl), but not limited thereto. In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. The monocyclic cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The polycyclic cycloalkyl includes, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically otherwise stated in the specification, cycloalkyls are optionally substituted with one or more substituents such as, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, etc.In some embodiments, the cycloalkyl is optionally substituted with one or more substituents such as oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl is optionally substituted with one or more substituents such as oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with a halogen.

[0037] “Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0038] “Haloalkyl” refers to the alkyl radicals defined above substituted with one or more halo radicals, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0039] “Hydroxyalkyl” refers to an alkyl radical substituted by one or more hydroxyl radicals as defined above, such as hydroxylmethyl, 2-hydroxylethyl, 1,2-dihydroxylethyl, 1,2-dihydroxypropyl, etc.

[0040] “Heteroalkyl,” whether used as part of another term or independently, refers to an alkyl group in which one or more skeletal atoms of the alkyl group are selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the carbon atoms of the heteroalkyl group to the rest of the molecule. In some embodiments, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of one to six carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is attached to the carbon atoms of the heteroalkyl group to the rest of the molecule. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless specifically otherwise stated in the specification, the heteroalkyl group is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with a halogen.

[0041] “Heteroalkenyl,” whether used as part of another term or independently, refers to an alkenyl group in which one or more skeletal atoms of the alkenyl are selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. The heteroalkenyl is attached to the rest of the molecule at the carbon atoms of the heteroalkenyl. In some embodiments, the heteroalkenyl is a C2-C6 heteroalkenyl, wherein the heteroalkenyl consists of two to six carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof, and the heteroalkenyl is attached to the rest of the molecule at the carbon atoms of the heteroalkenyl. Examples of such heteroalkenyls are, for example, -CH=CHOCH3, -CH=CHOCH2CH2OCH3, -CH2CH2OCH=CHOCH3, -C(=CH2)OCH3, -CH=NCH3, -CH2N=CH2, -CH=CHNHCH3, or -CH=CHN(CH3)2. Unless specifically otherwise stated in the specification, heteroalkenyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkenyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkenyl is optionally substituted with an oxo, a halogen, a methyl, an ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkenyl is optionally substituted with a halogen.

[0042] “Heteroalkynyl,” whether used as part of another term or independently, refers to an alkynyl group in which one or more skeletal atoms of the alkynyl are selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. The heteroalkynyl is attached to the rest of the molecule at the carbon atoms of the heteroalkynyl. In some embodiments, the heteroalkynyl is a C2-C6 heteroalkynyl, wherein the heteroalkynyl consists of two to six carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof, and the heteroalkynyl is attached to the rest of the molecule at the carbon atoms of the heteroalkynyl. Examples of such heteroalkynyls are, e.g., -C≡COCH3, -C≡COCH2CH2OCH3, -CH2CH2OC≡COCH3, -C≡C-NHCH3, or -C≡CN(CH3)2. Unless specifically otherwise stated in the specification, the heteroalkynyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkynyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkynyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkynyl is optionally substituted with a halogen.

[0043] "Heterocyclil," whether used as part of another term or independently, refers to a 3- to 24-membered partially or fully saturated cyclic radical comprising 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur, and 2 to 23 carbon atoms. In some embodiments, the heterocyclil is fully saturated. In some embodiments, the heterocyclil is partially unsaturated. In some embodiments, the heterocyclil comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclil comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocyclil comprises 1 to 3 nitrogens. In some embodiments, the heterocyclil comprises 1 or 2 nitrogens. In some embodiments, the heterocyclyl comprises one nitrogen. In some embodiments, the heterocyclyl comprises one nitrogen and one oxygen. Unless specifically otherwise stated in the specification, the heterocyclyl radical may be a unicyclic or polycyclic (including, but not limited to, 2-ring, 3-ring, or 4-ring) ring system. The polycyclic ring system may include a condensed (e.g., a heterocyclyl ring condensed with a cycloalkyl or other heterocyclyl ring), spiro, or cross-linked ring system. The nitrogen, carbon, or sulfur atoms of the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocyclyls are heterocyclyls having 2 to 15 carbon atoms (C2-C 15 Heterocyclil), 2 to 10 carbon atoms (C2-C 10It includes, but is not limited to, heterocyclil, 2 to 8 carbon atoms (C2-C8 heterocyclil), 2 to 7 carbon atoms (C2-C7 heterocyclil), 2 to 6 carbon atoms (C2-C6 heterocyclil), 2 to 5 carbon atoms (C2-C5 heterocyclil), or 2 to 4 carbon atoms (C2-C4 heterocyclil). Examples of such heterocyclyl radicals include aziridinyl, azetidinyl, oxetanil, dioxolanil, dihydrofuryl, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolidinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperadinyl, 2-oxopiperadinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomophorinyl, thiamophorinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl and 2-oxo-1,3-dioxol-4-yl are included, but not limited thereto. The term heterocyclil also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclil has 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocyclil, it is understood that the number of carbon atoms in the heterocyclil is not the same as the total number of atoms constituting the heterocyclil (including heteroatoms, i.e., the skeletal atoms of the heterocyclil ring). In some embodiments, the heterocyclil is a 3- to 8-membered fully saturated heterocyclil. In some embodiments, the heterocyclil is a 3- to 7-membered fully saturated heterocyclil. In some embodiments, the heterocyclil is a 3- to 6-membered fully saturated heterocyclil. In some embodiments, the heterocyclil is a 4- to 6-membered fully saturated heterocyclil.In some embodiments, the heterocyclyl is a 5- to 6-membered fully saturated heterocyclyl. Unless specifically otherwise stated in the specification, the heterocyclyl may be optionally substituted with one or more substituents as described below, such as, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, etc. In some embodiments, the heterocyclyl is optionally substituted with one or more substituents such as oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclyl is optionally substituted with one or more substituents such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclyl is optionally substituted with a halogen.

[0044] “Heteroaryl,” whether used as part of another term or independently, refers to a 5- to 14-membered cyclic radical comprising 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises 1 to 3 nitrogens. In some embodiments, the heteroaryl comprises 1 or 2 nitrogens. In some embodiments, the heteroaryl comprises 1 nitrogen. The heteroaryl radical may be a unicyclic or polycyclic (e.g., 2-ring, 3-ring, or 4-ring) ring system. The polycyclic ring system may include a condensed (e.g., a heteroaryl ring condensed with a cycloalkyl, heterocyclyl, or aryl ring), a crosslinked (e.g., an aryl or heteroaryl ring condensed with a crosslinked cycloalkyl or heterocyclyl ring), or a spiro (e.g., an aryl ring condensed with a spiro heterocyclyl ring, or a heteroaryl ring condensed with a spiro cycloalkyl or spiro heterocyclyl ring) ring system. The nitrogen, carbon, or sulfur atoms of the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azefinil, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzthiazolyl, benzothiadiazollil, benzo[b][1,4]dioxephinil, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazoz[1,2-a]pyridinyl, carbazolyl, cinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, furil, isothiazollil, imidazollil, indazollil, indolyl, Isoindolyl, Indolinyl, Isoindolinyl, Isoquinolyl, Indoliginil, Isoxazolyl, Naphthiridinyl, Oxadiazolyl, 2-Oxozepinil, Oxazolyl, Oxiranil, 1-Oxidopyridinyl, 1-Oxidopyrimidinyl, 1-Oxidopyrazinyl, 1-Oxidopyridazinyl, 1-Phenyl-1H-Pyrrolyl, Fenazinyl, Fenothiazinyl, Fenoxazinyl, Phthalazinyl, Pteridinyl, Purinyl, Pyrrolyl, Pyrazolyl, Pyridinyl, Pyridyl, Pyridyl 1-Oxide, Pyrazinyl, Pyrimidinyl, Pyridazinyl, Quinazolinyl, Quinoxalinyl, Quinolyl, Quinuclidinyl, Isoquinolyl, Tetrahydroquinolyl, Thiazolyl, Includes, but is not limited to, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless specifically otherwise stated in the specification, the heteroaryl may be optionally substituted with one or more substituents, such as, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclyl, heteroaryl, etc. In some embodiments, the heteroaryl is optionally substituted with one or more substituents such as halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more substituents such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with a halogen.

[0045] The terms “partially saturated” or “partially unsaturated” refer to radicals containing at least one double or triple bond, intended to contain a ring with multiple unsaturated sites, but not intended to contain an aromatic (i.e., completely unsaturated) moiety.

[0046] The terms “optional” or “optional” mean that the event or situation described below may or may not occur, and that the description includes cases where said event or situation occurs and cases where it does not occur. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Additionally, the optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). With respect to any group comprising one or more substituents, those skilled in the art will understand that such group is not intended to introduce any substitution or substitution pattern that is stereoimpractical and / or synthetically impossible. Therefore, any substituent listed should be understood to have a maximum molecular weight of generally about 1,000 Daltons or less, more typically about 500 Daltons or less.

[0047] When referring to optional substituents, the term “one or more” means that the group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the group is optionally substituted with one, two, three, or four substituents. In some embodiments, the group is optionally substituted with one, two, or three substituents. In some embodiments, the group is optionally substituted with one or two substituents. In some embodiments, the group is optionally substituted with one substituent. In some embodiments, the group is optionally substituted with two substituents.

[0048] “Effective dose” or “therapeutic effective dose” refers to the amount of a compound effective to produce a desired therapeutic effect when administered to a mammalian subject as a single dose or as part of a series of doses.

[0049] As used herein, the terms “treat,” “treating,” or “treatment” include alleviating, reducing, or improving at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, e.g., preventing the progression of a disease or condition, alleviating a disease or condition, causing a regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping symptoms of a disease or condition.

[0050] compound

[0051] This specification describes compounds useful as GR antagonists and for the treatment of diseases or disorders, or pharmaceutically acceptable salts thereof.

[0052] In one embodiment, the present disclosure comprises a compound of formula (I):

[0053] Chemical formula (I),

[0054] or a pharmaceutically acceptable salt thereof,

[0055] Here:

[0056] Each is independently a single bond or a double bond;

[0057] X is N, C, or CH;

[0058] L 1 -C(=O)-, -C(=O)O-, -C(=O)N(R a )-, -C(R a )2-, -N(R a )-, -O-, -S-, S(=O) or -S(=O)2- and;

[0059] L 2 and L 3 Each combines independently, -N(R a )-, -C(=O)-, -C(=O)O-, -C(=O)N(R a )-, -O-, -S-, S(=O), -S(=O)2-, -S(=O)(=NR a )-, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, or oxo;

[0060] Rings A, B, and C are each independently cycloalkyl, aryl, heterocyclyl, or heteroaryl;

[0061] R 1 , R 2 and R 3 Each is independently halogen, hydroxyl, cyano, -OR b , -N(R b )2, -C(=O)R b , -C(=O)OR b , -C(=O)N(R b )2, -S(=O)R b , -S(=O)2R b, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, oxo, alkyl, alkenyl, alkynyl, haloalkyl, or hydroxyalkyl;

[0062] R 4a and R 4b Each is independently hydrogen, halogen, hydroxy, cyano, alkyl, haloalkyl, hydroxyalkyl, or alkoxy;

[0063] R 4a and R 4b They form a cycloalkyl or heterocyclyl with the carbon atom to which they are bonded, each of which is optionally substituted with one or more groups independently selected from halogen, hydroxyl, amino, or alkyl;

[0064] R a and R b Each is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, or cycloalkyl;

[0065] 2 Rs b ...forms a heterocyclyl with the nitrogen atom to which they are bonded, and is optionally substituted with one or more groups independently selected from halogen, hydroxyl, amino, or alkyl;

[0066] n is any integer from 0 to 5;

[0067] m is any integer from 0 to 5;

[0068] t is any integer from 0 to 5.

[0069] In some embodiments, L 1 is -C(=O)-.

[0070] In some embodiments, L 2 is a combination, -N(R a)- or alkyl (e.g., C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) alkyl) and L 3 -S(=O)2- or -S(=O)(=NR a )-or; L 2 is -S(=O)2- or -S(=O)(=NR a )-and, L 3 is bond, -N(R a )- or alkyl (e.g., C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) is alkyl.

[0071] In some embodiments, L 2 is a combination, -N(R a )- or alkyl (e.g., C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) alkyl) and L 3 -S(=O)2- or -S(=O)(=NR a )-am.

[0072] In some embodiments, L 2 is -S(=O)2- or -S(=O)(=NR a )-and L 3 is bond, -N(R a )- or alkyl (e.g., C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) is alkyl.

[0073] In some implementations, -L 2 -L 3 - is -S(=O)2-, -N(R a )-S(=O)2- or -S(=O)(=NR a )-am.

[0074] In some implementations, R a is hydrogen or alkyl (e.g., C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) is alkyl.

[0075] In some implementations, -L 2 -L 3 - is -S(=O)2- or -S(=O)(=NH)-.

[0076] In some embodiments, ring A is an aryl or heteroaryl.

[0077] In some embodiments, ring A is C 6-12 Aril, C 6-11 Aril, C 6-10 Aril, C 6-9 Aril, C 6-8 Aryl or C 6-7 It is Aryl. In some embodiments, ring A is C 12 Aril, C 11 Aril, C 10 It is an aryl, C9 aryl, C8 aryl, C7 aryl, or C6 aryl. In some embodiments, ring A is a unicyclic or bicyclic aryl. In some embodiments, ring A is a unicyclic aryl. In some embodiments, ring A is a bicyclic aryl.

[0078] In some embodiments, ring A is a 5- to 12-membered heteroaryl, a 5- to 11-membered heteroaryl, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, a 5- to 8-membered heteroaryl, a 5- to 7-membered heteroaryl, or a 5- to 6-membered heteroaryl. In some embodiments, ring A is a 12-membered heteroaryl, an 11-membered heteroaryl, a 10-membered heteroaryl, a 9-membered heteroaryl, an 8-membered heteroaryl, a 7-membered heteroaryl, a 6-membered heteroaryl, or a 5-membered heteroaryl. In some embodiments, ring A is a unicyclic or bicyclic heteroaryl. In some embodiments, ring A is a unicyclic heteroaryl. In some embodiments, ring A is a dicyclic heteroaryl.

[0079] In some embodiments, ring A is selected from phenyl, pyridyl, pyrazolyl, pyrimidinyl, triazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazollyl, dihydropyrrolopyrazolyl, dihydroimidazooxazinyl, or dihydropyrazolooxazinyl.

[0080] In some embodiments, ring A is selected from the group consisting of the following:

[0081]

[0082] In some implementations, each R 1 is independently halogen, cyano, -OR b , is alkyl, haloalkyl, cycloalkyl, or heterocyclic. In some embodiments, each R 1 is independently halogen, cyano, -OR b , C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) Alkyl, C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) haloalkyl, C 3-6 (e.g., C 3-5 or C 3-4 ) It is a cycloalkyl or a 3- to 6-membered (e.g., 3- to 5-membered or 3- to 4-membered) heterocyclyl. In some embodiments, the alkyl, haloalkyl, cycloalkyl, and heterocyclyl are deuterated.

[0083] In some embodiments, one or more R 1 is an alkyl. In some embodiments, one or more R 1 C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) is an alkyl. In some embodiments, the alkyl is a deuterated alkyl. In some embodiments, C1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) Alkyl is deuteriumized C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) is an alkyl. In some embodiments, one or more R 1 is -CH3. In some implementations, one or more R 1 It is -CD3.

[0084] In some implementations, each R 1 -F, -Cl, cyano, -OCH3, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, cyclopropyl or is. In some embodiments, -OCH3, -CH3, -CH2CH3, -CH2F, -CHF2, cyclopropyl and is deuteriumized. In some embodiments, -CH3 is -CD3. In some embodiments, -OCH3 is -OCD3.

[0085] In some implementations, m is 1.

[0086] In some implementations, m is 2.

[0087] In some implementations, m is 3.

[0088] In some embodiments, moiety Is , , , , , , and Selected from, where R 1A , R 1B , R 1C and R 1D Each independently hydrogen or R 1 is. In some implementations, R 1A , R 1B , R 1C and R 1DEach is independently hydrogen, alkyl (e.g., C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) alkyl), haloalkyl (e.g., C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) haloalkyl), cycloalkyl (e.g., C 3-6 (e.g., C 3-5 or C 3-4 ) is a cycloalkyl) or a heterocyclyl (e.g., a 3- to 6-membered (e.g., 3- to 5-membered or 3- to 4-membered) heterocyclyl). In some embodiments, R 1A , R 1B , R 1C and R 1D Each is independently hydrogen, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, cyclopropyl, or am.

[0089] In some embodiments, ring B is heteroaryl. In some embodiments, ring B is 5- to 12-membered heteroaryl, 5- to 11-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, or 5- to 6-membered heteroaryl. In some embodiments, ring B is 12-membered heteroaryl, 11-membered heteroaryl, 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, or 5-membered heteroaryl. In some embodiments, ring B is unicyclic or bicyclic heteroaryl. In some embodiments, ring B is a unicyclic heteroaryl. In some embodiments, ring B is a 2-cyclic heteroaryl.

[0090] In some embodiments, ring B is pyridyl, thiazoryl, pyrimidinyl, imidazoril, or oxazolyl.

[0091] In some embodiments, ring B is selected from the group consisting of the following:

[0092]

[0093] In some implementations, each R 2 is independently a halogen, alkyl, haloalkyl, or cycloalkyl. In some embodiments, each R 2 is independently a halogen, C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) Alkyl, C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) haloalkyl, or C 3-6 (e.g., C 3-5 or C 3-4 ) It is a cycloalkyl. In some embodiments, the alkyl, haloalkyl, or cycloalkyl is deuterated.

[0094] In some embodiments, one or more R 2 is an alkyl. In some embodiments, one or more R 2 is C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) is an alkyl. In some embodiments, the alkyl is a deuterated alkyl. In some embodiments, C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) Alkyl is deuteriumized C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) is an alkyl. In some embodiments, one or more R 2 is -CH3. In some implementations, one or more R 2 is -CD3.

[0095] In some implementations, each R 2 is independently -CH3, -F, -Cl, -CH2F, -CHF2, -CF3, or cyclopropyl. In some embodiments, -CH3, -CH2F, -CHF2, or cyclopropyl is deuteriumated. In some embodiments, -CH3 is -CD3.

[0096] In some implementations, n is 0.

[0097] In some implementations, n is 1.

[0098] In some embodiments, moiety Is , , , , and Selected from, where R 2A and R 2B Each independently hydrogen or R 2 am.

[0099] In some embodiments, ring C is aryl. In some embodiments, ring C is C 6-12 Aril, C 6-11 Aril, C 6-10 Aril, C 6-9 Aril, C 6-8 Aryl or C 6-7 It is an aryl. In some embodiments, ring C is C 12 Aril, C 11 Aril, C 10 It is an aryl, C9 aryl, C8 aryl, C7 aryl, or C6 aryl. In some embodiments, ring A is a unicyclic or bicyclic aryl. In some embodiments, ring A is a unicyclic aryl. In some embodiments, ring A is a bicyclic aryl.

[0100] In some embodiments, ring C is phenyl.

[0101] In some implementations, each R 3 is independently a halogen, alkyl, or haloalkyl. In some embodiments, each R 3 is independently a halogen, C 1-6 (e.g., C1-5 , C 1-4 , C 1-3 or C 1-2 ) alkyl, or C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) It is a haloalkyl. In some embodiments, the alkyl or haloalkyl is deuterated.

[0102] In some embodiments, one or more R 3 is an alkyl. In some embodiments, one or more R 3 C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) is an alkyl. In some embodiments, the alkyl is a deuterated alkyl. In some embodiments, C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) Alkyl is deuteriumized C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) is an alkyl. In some embodiments, one or more R 3 is -CH3. In some implementations, one or more R 3 It is -CD3.

[0103] In some implementations, each R 3 is -F, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments, -CH3, -CH2F, and -CHF2 are deuterides. In some embodiments, -CH3 is -CD3.

[0104] In some implementations, t is 0.

[0105] In some implementations, t is 1.

[0106] In some implementations, t is 2.

[0107] In some embodiments, moiety Is and, here R 3A , R 3B and R 3C Each independently hydrogen or R 3 am.

[0108] In some implementations, R 4a is hydrogen or alkyl. In some embodiments, R 4a is hydrogen or C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) is an alkyl. In some embodiments, R 4a is hydrogen.

[0109] In some implementations, R 4b is hydrogen or alkyl. In some embodiments, R 4b is hydrogen or C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) is an alkyl. In some embodiments, R 4b is hydrogen.

[0110] In some implementations, R 4a and R 4b Both are hydrogen.

[0111] In some implementations, R 4a and R 4b C together with the carbon atoms to which they are bonded. 3-6 (e.g., C 3-5 or C 3-4 ) forms a cycloalkyl group. In some embodiments, R 4a and R 4b together with the carbon atoms to which they are bonded, cycloalkyl (e.g., C 3-6 Cycloalkyl, C 3-5 Cycloalkyl, or C 3-4 It forms a cycloalkyl group. In some embodiments, R 4a and R 4bThey form cyclopropyl together with the carbon atoms to which they are bonded.

[0112] In some embodiments, the compound disclosed herein is a compound of formula (Ia) or formula (Ib):

[0113] Chemical formula (Ia),

[0114] Chemical formula (Ib).

[0115] In some embodiments, the compound disclosed herein is a compound of a chemical formula selected from the following:

[0116] Chemical formula (Ia-1)

[0117] Chemical formula (Ib-1).

[0118] In some embodiments of chemical formula (Ia), chemical formula (Ib), chemical formula (Ia-1), or chemical formula (Ib-1), ring A is an aryl or heteroaryl. In some embodiments, ring A is C 6-12 Aril, C 6-11 Aril, C 6-10 Aril, C 6-9 Aril, C 6-8 Aryl or C 6-7 It is Aryl. In some embodiments, ring A is C 12 Aril, C 11 Aril, C 10 It is an aryl, C9-aryl, C8-aryl, C7-aryl, or C6-aryl. In some embodiments, ring A is a 5- to 12-membered heteroaryl, a 5- to 11-membered heteroaryl, a 5- to 10-membered heteroaryl, a 5- to 9-membered heteroaryl, a 5- to 8-membered heteroaryl, a 5- to 7-membered heteroaryl, or a 5- to 6-membered heteroaryl. In some embodiments, ring A is a 12-membered heteroaryl, an 11-membered heteroaryl, a 10-membered heteroaryl, a 9-membered heteroaryl, an 8-membered heteroaryl, a 7-membered heteroaryl, a 6-membered heteroaryl, or a 5-membered heteroaryl.

[0119] In some embodiments of chemical formula (Ia), chemical formula (Ib), chemical formula (Ia-1) or chemical formula (Ib-1), ring A is phenyl, pyridyl, pyrazolyl, pyrimidinyl, triazolyl, or thiadiazolyl.

[0120] In some embodiments of chemical formula (Ia), chemical formula (Ib), chemical formula (Ia-1), or chemical formula (Ib-1), ring B is heteroaryl. In some embodiments, ring B is 5- to 12-membered heteroaryl, 5- to 11-membered heteroaryl, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, or 5- to 6-membered heteroaryl. In some embodiments, ring B is 12-membered heteroaryl, 11-membered heteroaryl, 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, or 5-membered heteroaryl.

[0121] In some embodiments of chemical formula (Ia), chemical formula (Ib), chemical formula (Ia-1) or chemical formula (Ib-1), ring B is pyridyl, pyrimidinyl, thiazolyl, or imidazolyl.

[0122] In some embodiments of chemical formula (Ia), chemical formula (Ib), chemical formula (Ia-1), or chemical formula (Ib-1), ring C is an aryl. In some embodiments, ring C is C 6-12 Aril, C 6-11 Aril, C 6-10 Aril, C 6-9 Aril, C 6-8 Aryl or C 6-7 It is an aryl. In some embodiments, ring C is C 12 Aril, C 11 Aril, C 10 It is aryl, C9aryl, C8aryl, C7aryl, or C6aryl.

[0123] In some embodiments of chemical formula (Ia), chemical formula (Ib), chemical formula (Ia-1) or chemical formula (Ib-1), ring C is phenyl.

[0124] In some embodiments of chemical formula (Ia), chemical formula (Ib), chemical formula (Ia-1) or chemical formula (Ib-1), L 2 and L 3 Each combines independently, -N(R a )- -S(=O)2- or -S(=O)(=NR a )-am.

[0125] In some embodiments of chemical formula (Ia), chemical formula (Ib), chemical formula (Ia-1) or chemical formula (Ib-1), -L 2 -L 3 - is -S(=O)2-, -N(R a )-S(=O)2- or -S(=O)(=NR a )-is. In some implementations, R a is hydrogen or alkyl (e.g., C 1-6 (e.g., C 1-5 , C 1-4 , C 1-3 or C 1-2 ) is alkyl.

[0126] In some embodiments of chemical formula (Ia), chemical formula (Ib), chemical formula (Ia-1) or chemical formula (Ib-1), -L 2 -L 3 - is -S(=O)2- or -S(=O)(=NH)-.

[0127] The present specification also provides compounds presented in Table 1, 2 or 3, or pharmaceutically acceptable salts thereof.

[0128] Table 1 Exemplary Compounds

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139] Table 2 Exemplary Compounds

[0140]

[0141]

[0142]

[0143]

[0144] Table 3 Exemplary Compounds

[0145]

[0146]

[0147]

[0148]

[0149] Additional forms of compounds disclosed in this specification

[0150] Isomers / stereoisomers

[0151] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and chuzammene (Z) isomers, as well as corresponding mixtures thereof. In some embodiments, the compounds described herein have one or more chiral centers, each center existing in an R-configuration or an S-configuration. The compounds described herein include all diastereomers, enantiomers, and epimer forms, as well as corresponding mixtures thereof. In further embodiments of the compounds and methods provided herein, a mixture of enantiomers and / or diastereomers produced from a single manufacturing step, combination, or interconversion is useful for the uses described herein. In some embodiments, the compounds described herein are prepared as each stereoisomer by reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomeric compounds, and recovering an optically pure enantiomer. In some embodiments, a dissociable complex is preferred. In some embodiments, the diastereomeric compounds have distinct physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated using these discrepancies. In some embodiments, the diastereomeric compounds are separated by chiral chromatography, or preferably by a separation / separation technique based on differences in solubility. In some embodiments, the optically pure enantiomer is recovered together with the resolving agent by any practical means that does not induce racemization.

[0152] tautomer

[0153] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by the transfer of hydrogen atoms involving the conversion of single bonds and adjacent double bonds. In bond arrangements where tautomerization is possible, chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are considered. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0154] Isotope form

[0155] Unless otherwise noted, the compounds described herein may represent their natural isotopic abundances, or one or more atoms may be artificially enriched into specific isotopes having the same atomic number but different atomic mass or mass number from that which is predominantly found in nature. All isotopic variants of the compounds of this disclosure are included within the scope of this disclosure, regardless of whether they are radioactive. For example, hydrogen 1 H (light hydrogen), 2 H (deuterium) and 3 It has three naturally occurring isotopes designated as H (tritium). Light hydrogen is the most abundant hydrogen isotope in nature. Enriching to deuterium may provide some therapeutic benefits, such as increased half-life and / or exposure in the body, or may provide compounds useful for investigating in vivo pathways of drug elimination and metabolism.

[0156] For example, the compounds described herein may be artificially enriched into one or more specific isotopes. In some embodiments, the compounds described herein may be artificially enriched into one or more isotopes that are not primarily found in nature. In some embodiments, the compounds described herein are deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 It can be artificially enriched into one or more isotopes selected from C). In some embodiments, the compounds described herein are 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125 I It is artificially enriched with one or more isotopes selected from. In some embodiments, the abundance of the enriched isotope is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% on a molar basis.

[0157] In some embodiments, the compound is deuterinated at at least one location. In some embodiments, the compound disclosed herein is 1 Some or all of the H atoms 2 It is substituted with an H atom. Unless otherwise noted, each hydrogen atom of the compounds disclosed herein is independently 1 H, 2 H (D) or 3 H (T). In some embodiments, one or more hydrogen atoms of the compounds disclosed herein are 2 It is H (deuterium, or D).

[0158] Methods for synthesizing deuterium-containing compounds are known in the art and include, by non-limiting example, the procedures described in U.S. Patents No. 5,846,514 and No. 6,334,997, and the following synthesis methods. For example, deuterium-substituted compounds may be synthesized using various methods as described below: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000 , 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989 , 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981 , 64(1-2), 9-32.

[0159] Deuterated starting materials are readily available and can be applied to the synthesis method described herein to provide for the synthesis of deuterium-containing compounds. A number of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0160] Pharmaceutically acceptable salts

[0161] In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the method disclosed herein includes a method of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the method disclosed herein includes a method of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0162] In some embodiments, the compounds described herein possess acidic or basic groups and react with any of various inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are formed during the final isolation and purification of the compounds disclosed herein. In situ It is prepared by reacting a manufactured or purified compound in its free form separately with a suitable acid or base and isolating the salt thus formed.

[0163] Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds described herein with minerals, organic acids, or inorganic bases, such salts include acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butin-1,4-dioate, camphorate, camphosulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, Hexine-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, It includes salicylates, succinates, sulfates, sulfites, succinates, suberates, sebacates, sulfonates, tartrates, thiocyanates, tosylates, undecanoates, and xylenesulfonates.

[0164] Additionally, the compounds described in this specification may be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, and inorganic acids include, but are not limited to, hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; Organic acids include acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvate, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheptonic acid, and 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid). 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid are included but not limited thereto. In some embodiments, other acids such as oxalic acid are not pharmaceutically acceptable on their own but are used in the preparation of salts useful as intermediates to obtain the compounds disclosed herein and pharmaceutically acceptable acid addition salts thereof.

[0165] In some embodiments, such compounds described herein containing a free acid group react with a suitable base, such as a hydroxide of a pharmaceutically acceptable metal cation, carbonate, bicarbonate, or sulfate, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth metal salts such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts, etc. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4, etc. are included.

[0166] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should also be understood that the compounds described herein include quaternization of any basic nitrogen-containing group they contain. In some embodiments, a water-soluble, oil-soluble, or dispersible product is obtained by such quaternization.

[0167] Treatment methods

[0168] The present specification discloses a method for modulating glucocorticoid receptors (GR) in a subject, comprising administering a therapeutically effective amount of the compound disclosed in the present specification or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0169] The present specification discloses a method for inhibiting GR in a subject, comprising administering a therapeutically effective amount of the compound disclosed in the present specification or a pharmaceutically acceptable salt thereof to a subject requiring such inhibition.

[0170] The present specification discloses a method for treating a disease or disorder in a subject, comprising administering to a subject in need of such treatment a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. In some embodiments, the disease or disorder is a GR-related disease or disorder.

[0171] In some embodiments, the disease or disorder is Cushing's syndrome, Addison's disease, osteoporosis, rheumatoid arthritis, asthma, rhinitis, adrenal function related diseases, human immunodeficiency virus, acquired immune deficiency syndrome, allergy, or wound healing.

[0172] The present specification also discloses the use of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions disclosed herein in the manufacture of agents for controlling GR in objects requiring such agents.

[0173] The present specification also discloses the use of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions disclosed herein in the manufacture of agents for inhibiting GR in objects requiring such agents.

[0174] The present specification also discloses the use of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions disclosed herein in the manufacture of a drug for treating a disease or disorder in an object requiring such a drug. In some embodiments, the disease or disorder is a GR-related disease or disorder.

[0175] In some embodiments, the disease or disorder is Cushing's syndrome, Addison's disease, osteoporosis, rheumatoid arthritis, asthma, rhinitis, adrenal function-related diseases, human immunodeficiency virus, acquired immunodeficiency syndrome, allergy, or wound healing.

[0176] administration

[0177] In some embodiments, a composition comprising the compound(s) described herein is administered for therapeutic treatment. In a specific therapeutic application, the composition is administered to a patient already suffering from the disease or condition in an amount sufficient to treat or at least partially stop at least one of the symptoms of the disease or condition. The effective dose for such use depends on the severity and course of the disease or condition, prior treatment, the patient's health status, body weight, and response to drugs, and the judgment of the attending physician. The therapeutic effective dose is arbitrarily determined by methods including, but not limited to, dose escalation and / or dose range exploration clinical trials.

[0178] In some embodiments where the patient's condition does not improve, the compound is administered chronically—that is, for an extended period including the patient's lifespan—at the discretion of the physician to improve, or otherwise control or limit, the symptoms of the patient's disease or condition.

[0179] Route of administration

[0180] Appropriate routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, penetrative, transdermal, vaginal, otological, nasal, and local administration. Additionally, by example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, and intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and nasal injections.

[0181] Pharmaceutical composition / formulation

[0182] The compounds described herein are administered to subjects in need of them, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, within a pharmaceutical composition, in accordance with standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0183] In another aspect, the present specification provides a pharmaceutical composition comprising the compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a formulation that can be pharmaceutically used. The appropriate formulation depends on the selected route of administration. A summary of the pharmaceutical compositions described herein is provided, for example, by Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which is incorporated herein by reference for such disclosure.

[0184] Examples

[0185] The following examples are included for illustrative purposes. The examples provided herein describe the synthesis of the compounds disclosed herein as well as the intermediates used to produce the compounds. However, it should be understood that these examples do not limit the disclosure and are intended only to suggest methods for carrying out the disclosure. Those skilled in the art will recognize that the described chemical reactions can be easily adapted to produce many other compounds of the disclosure, and alternative methods for producing the compounds of the disclosure are considered to be within the scope of the disclosure. For example, the synthesis of non-exemplary compounds according to the disclosure can be successfully carried out by modifications obvious to those skilled in the art, for example by appropriately protecting the hindering group, by utilizing other suitable reagents and building blocks known in the art other than those described, and / or by applying routine modifications of reaction conditions. Furthermore, those skilled in the art will also understand that the individual steps or separate batches of compounds described herein may be combined. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for producing other compounds of the disclosure. Accordingly, the following description is not intended to limit the scope of the present disclosure, but rather is defined by the claims attached to this specification.

[0186] Example 1: Synthesis of an Exemplary Compound

[0187] Example 1.1: Synthesis of Compound 1A

[0188]

[0189]

[0190]

[0191] Step 1: In anhydrous tetrahydrofuran (200 mL) Compound 1-110 M BH3·Me2S (18.2 mL, 181.82 mmol) was slowly added dropwise to a solution of (20 g, 60.61 mmol) at -10 °C. The mixture was heated at 25 °C for 3 hours. Next, 3 M NaOH (10.1 mL, 30.30 mmol) and 30% H2O2 (31.2 mL, 303.05 mmol) were slowly added dropwise to the mixture at -10 °C. The mixture was heated at 25 °C for 1 hour. The reaction mixture was quenched with saturated Na2SO3 and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography as a yellow oil Compound 1-2 (5.1 g, yield 24%) was obtained. LCMS: 349.2 [M+H] + .

[0192] 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.43 - 7.24 (m, 5H), 5.15 - 4.94 (m, 2H), 4.21 (dd, J = 12.8, 1.6 Hz, 1H), 3.91 (d, J = 12.0 Hz, 1H), 3.78 - 3.67 (m, 1H), 3.58 - 3.42 (m, 3H), 3.15 - 2.89 (m, 3H), 2.87 - 2.65 (m, 1H), 2.59 - 2.52 (m, 1H), 2.39 (d, J = 9.6 Hz, 1H), 1.84 - 1.48 (m, 3H), 1.38 - 1.19 (m, 1H).

[0193] Step 2: In dichloromethane (50 mL) Compound 1-2To a solution of (5 g, 14.37 mmol), 4A molecular sieve (5 g), NMO (2.5 g, 21.55 mmol), and TPAP (500 mg, 1.44 mmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 3 hours under an N2 atmosphere. The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography as a yellow oil Compound 1-3 (3.2 g, yield 64%) was obtained. LCMS: 347.1 [M+H] + .

[0194] 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.42 - 7.29 (m, 5H), 5.17 - 4.99 (m, 2H), 4.38 (d, J = 13.2 Hz, 1H), 3.94 (d, J = 9.6 Hz, 1H), 3.67 - 3.51 (m, 4H), 3.17 (d, J = 16.4 Hz, 1H), 3.07 - 2.77 (m, 3H), 2.61 - 2.53 (m, 1H), 2.42 - 2.33 (m, 1H), 2.30 - 2.14 (m, 2H), 1.83 - 1.70 (m, 1H).

[0195] Step 3: In anhydrous tetrahydrofuran (30 mL) Compound 1-3 KHMDS (27.7 mL, 27.75 mmol) was added to a solution of (3.2 g, 9.25 mmol) at -78 °C. The reaction mixture was stirred at this temperature for 1 hour. Subsequently, 2,2,2-trifluoroethyl formate (7.1 g, 55.49 mmol) was added. The mixture was stirred at -78 °C for 1 hour under an N2 atmosphere. The reaction mixture was quenched with 3 M HCl and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure as a red oil Compound 1-4 (3 g, yield 87%) was obtained. LCMS: 375.1 [M+H] + .

[0196] Step 4: In acetic acid (30 mL) at room temperature Compound 1-4 NaOAc (986 mg, 12.03 mmol) and 4-fluorophenylhydrazine hydrochloride (1.9 g, 12.03 mmol) were added to a solution of (3 g, 8.02 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography as a red solid Compound 1-5 (1.5 g, yield 40%) was obtained. LCMS: 465.2 [M+H] + .

[0197] 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 8.23 ​​(s, 1H), 7.83 - 7.70 (m, 2H), 7.42 - 7.19 (m, 7H), 5.09 (s, 2H), 4.34 (d, J = 13.6 Hz, 1H), 4.04 - 3.86 (m, 3H), 3.38 - 3.30 (m, 3H), 3.22 - 3.00 (m, 4H), 2.86 - 2.74 (m, 1H), 2.59 (d, J = 15.6 Hz, 1H).

[0198] Step 5: In ethyl acetate (15 mL) Compound 1-5 Pd(OH)2 (633 mg, 4.52 mmol) was added to a solution of (1.5 g, 3.23 mmol). The mixture was stirred at 25°C for 2 hours under an H2 atmosphere. The mixture was filtered. The filtrate was concentrated under reduced pressure as a yellow solid Compound 1-6 (1.15 g, crude product) was obtained. LCMS: 331.1 [M+H]+ .

[0199] Step 6: In dichloromethane (10 mL) Compound 1-6 Di-tert-butyl dicarbonate (2.1 g, 9.48 mmol) and TEA (957 mg, 9.48 mmol) were added to a solution of (1.15 g, crude product). The mixture was stirred at 25°C for 1 hour under an N2 atmosphere. The mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography as a yellow solid Compound 1-7 (0.8 g, yield 57%) was obtained. LCMS: 431.1 [M+H] + .

[0200] 1 H NMR (400 MHz, CDCl3) δ 7.54 - 7.35 (m, 3H), 7.22 - 7.06 (m, 2H), 4.43 (d, J = 12.8 Hz, 1H), 4.32 (d, J = 15.2 Hz, 1H), 4.08 - 3.89 (m, 1H), 3.79 (d, J = 15.2 Hz, 1H), 3.65 (s, 3H), 3.35 - 3.04 (m, 3H), 2.98 (d, J = 13.2 Hz, 1H), 2.72 (d, J = 9.6 Hz, 1H), 2.60 (d, J = 15.2 Hz, 1H), 1.45 (s, 9H).

[0201] Step 7: 1.6 M in a solution of 2-bromopyridine (370 mg, 3.02 mmol) in anhydrous tetrahydrofuran (15 mL) at -78 °C n -Butyllithium (1.9 mL, 3.02 mmol) was added. The reaction mixture was stirred at this temperature for 1 hour. Next, Compound 1-7(130 mg, 0.30 mmol) was added. The reaction mixture was stirred at -78 °C for 1 hour. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography as a yellow solid Compound 1-8 (75 mg, yield 52%) was obtained. LCMS: 478.2 [M+H] + .

[0202] 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.90 - 7.70 (m, 2H), 7.49 - 7.40 (m, 3H), 7.34 - 7.30 (m, 1H), 7.20 - 7.10 (m, 2H), 5.53 (s, 1H), 4.61 (d, J = 15.2 Hz, 1H), 4.48 - 4.36 (m, 1H), 4.12 (s, 1H), 4.03 - 3.85 (m, 1H), 3.55 (s, 1H), 3.32 - 3.18 (m, 1H), 3.19 - 3.01 (m, 1H), 2.89 - 2.74 (m, 2H), 1.60 - 1.59 (m, 9H).

[0203] Step 8: Compound 1-8 (75 g) was separated by SFC (Column: DAICELCHIRALCEL®IG (250*25 mm, 10 μm); Mobile phase A: Supercritical CO2; Mobile phase B: MeOH (+0.1% MeOH solution of 7.0 mol / L ammonia)) as a white solid with a retention time of 1.657 minutes. Compound 1-9A As a white solid (26 mg, yield 18%) and retention time 2.635 minutes Compound 1-9B (24 mg, yield 17%) was obtained. LCMS: 478.2 [M+H] + .

[0204] Step 9: In dichloromethane (2 mL) Compound 1-9ATFA (1 mL) was added to a solution of (20 mg, 0.04 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure as a yellow solid Compound 1-10A (14 mg, yield 89%) was obtained. LCMS: 378.1 [M+H] + .

[0205] Step 10: In dichloromethane (3 mL) Compound 1-10A DIPEA (14 mg, 0.11 mmol) and 4-(trifluoromethyl)benzenesulfonyl chloride (9.9 mg, 0.04 mmol) were added to a solution of (14 mg, 0.04 mmol). The mixture was stirred at 25°C for 30 minutes under an N2 atmosphere and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by prep-HPLC to obtain the corresponding Compound 1A (12 mg, yield 55%) was obtained. LCMS: 586.2 [M+H] + .

[0206] 1 H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 3.2 Hz, 1H), 7.80 (s, 4H), 7.71 (d, J = 8.4 Hz, 2H), 7.50 - 7.38 (m, 3H), 7.32 (s, 1H), 7.14 (t, J = 8.4 Hz, 2H), 5.41 (s, 1H), 4.68 (d, J = 14.0 Hz, 1H), 4.23 (d, J = 10.0 Hz, 1H), 3.95 (s, 1H), 3.76 (d, J = 9.2 Hz, 1H), 3.63 (s, 1H), 2.99 - 2.71 (m, 4H).

[0207] Example 1.2: Synthesis of Compound 1B

[0208]

[0209] Step 1: In dichloromethane (2 mL) Compound 1-9BTFA (1 mL) was added to a solution of (20 mg, 0.04 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure as a yellow solid Compound 1-10B (13 mg, yield 89%) was obtained. LCMS: 378.1 [M+H] + .

[0210] Step 2: In dichloromethane (2 mL) Compound 1-10B DIPEA (14 mg, 0.11 mmol) and 4-(trifluoromethyl)benzenesulfonyl chloride (9.9 mg, 0.04 mmol) were added to a solution of (13 mg, 0.04 mmol). The mixture was stirred at 25°C for 30 minutes under an N2 atmosphere and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by prep-HPLC to obtain the corresponding Compound 1B (10 mg, yield 50%) was obtained. LCMS: 586.2 [M+H] + .

[0211] 1 H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 4.4 Hz, 1H), 7.86 - 7.76 (m, 4H), 7.70 (d, J = 8.4 Hz, 2H), 7.46 - 7.41 (m, 3H), 7.32 (s, 1H), 7.14 (t, J = 8.4 Hz, 2H), 5.39 (d, J = 11.6 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.20 (d, J = 15.6 Hz, 1H), 3.91 (d, J = 14.8 Hz, 1H), 3.74 (d, J = 11.2 Hz, 1H), 3.67 - 3.54 (m, 1H), 2.91 (d, J = 11.2 Hz, 1H), 2.82 - 2.66 (m, 3H).

[0212] Example 1.3: Synthesis of Compound 5A

[0213]

[0214]

[0215]

[0216] Step 1: In diethyl ether (15 ml) Compound 1-7 LiAlH4 (92 mg, 2.42 mmol) was added to a solution of (801 mg, 1.86 mmol) at 0 °C for 10 minutes. The reaction mixture was maintained at 25 °C for 0.5 hours under an N2 atmosphere. The reaction product was diluted with water and ethyl acetate. The organic layer was separated, washed with additional brine, and concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography as a yellow oil Compound 5-1 (350 mg, 46.7% yield) was obtained. LCMS: 403.3 [M+H] + .

[0217] Step 2: In dichloromethane (10 ml) Compound 5-1 Des-martine periodinan (480 mg, 1.13 mmol) was added to a solution of (350 mg, 0.87 mmol). The reaction mixture was maintained at 25 °C for 1 hour under an N2 atmosphere. The reaction product was diluted with water and DCM. The organic layer was separated, washed with additional brine, and concentrated under reduced pressure. The obtained residue was purified by flash silica gel chromatography as a yellow oil Compound 5-2 (250 mg, 71.8% yield) was obtained. LCMS: 401.2 [M+H] + .

[0218] Step 3: In anhydrous tetrahydrofuran (15 mL) n2-(tributylstantanyl)pyrimidine (1.31 g, 3.55 mmol) in anhydrous tetrahydrofuran (2 ml) was added to a solution of -BuLi (2.22 ml, 3.55 mmol, 1.6 M) at -78 °C. After 1.5 hours, anhydrous tetrahydrofuran (2 ml) in the mixture Compound 5-2 (142 mg, 0.36 mmol) was added. The reaction mixture was stirred at -78 °C for 1.5 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography as a yellow solid Compound 5-3 (120 mg, yield 70.4%) was obtained. LCMS: 481.3 [M+H] +

[0219] Step 4: In dichloromethane (5 ml) Compound 5-3 Des-martine periodionan (106 mg, 0.25 mmol) was added to a solution of (100 mg, 0.21 mmol) at 0 °C. Subsequently, the reaction mixture was maintained at 25 °C for 12 hours under an N2 atmosphere. The reaction product was quenched with an aqueous Na2SO3 solution and extracted with ethyl acetate. The combined organic layer was washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum. The obtained residue was purified by flash silica gel chromatography as a white solid Compound 5-4 (60 mg, 35.2% yield) was obtained. LCMS: 479.3 [M+H] + .

[0220] Step 5: Compound 5-4 (60 mg) was purified with SFC (Column: DAICELCHIRALCEL®IB (250*25 mm, 10 μm); Mobile phase A: Supercritical CO2; Mobile phase B: MeOH (MeOH solution of +0.1% 7.0 mol / L ammonia)) as a white solid with a retention time of 0.896 minutes. Compound 5-5AAs a white solid (25 mg, yield 41.7%) and retention time 1.951 minutes Compound 5-5B (19 mg, yield 31.7%) was obtained.

[0221] Step 6: In dichloromethane (2 mL) Compound 5-5A TFA (1 mL) was added to a solution of (25 mg, 0.05 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure as a yellow solid Compound 5-6A (24 mg, crude product) was obtained. LCMS: 379.1 [M+H] + .

[0222] Step 7: In dichloromethane (3 mL) Compound 5-6A DIPEA (14 mg, 0.11 mmol) and 4-(trifluoromethyl)benzenesulfonyl chloride (12 mg, 0.05 mmol) were added to a solution of (24 mg, crude product). The mixture was stirred at 25°C for 30 minutes under an N2 atmosphere and filtered. The filtrate was concentrated under reduced pressure, then purified by Prep-HPLC to obtain the corresponding Compound 5A (6 mg, 20% yield) was obtained. LCMS: 587.3 [M+H] + .

[0223] 1 HNMR (400 MHz, CDCl3): δ 8.88 (d, J = 4.9 Hz, 2H), 7.87 - 7.81 (m, 2H), 7.79 - 7.74 (m, 2H), 7.47 - 7.39 (m, 3H), 7.35 (s, 1H), 7.18 - 7.10 (m, 2H), 5.04 (d, J = 11.2 Hz, 1H), 4.63 (d, J = 15.0 Hz, 1H), 4.05 - 3.85 (m, 2H), 3.63 (d, J = 10.6 Hz, 1H), 3.56 - 3.42 (m, 1H), 2.97 - 2.82 (m, 2H), 2.80 - 2.68 (m, 2H).

[0224] Example 1.4: Synthesis of Compound 5B

[0225]

[0226] Compound 5B Is Compound 5A As explained in Compound 5-5B Synthesized from. LCMS: 587.3 [M+H] + .

[0227] 1 HNMR (400 MHz, CDCl3): δ 8.89 (d, J = 4.8 Hz, 2H), 7.87 - 7.73 (m, 4H), 7.50 - 7.39 (m, 3H), 7.35 (s, 1H), 7.20 - 7.09 (m, 2H), 5.19 - 4.97 (m, 1H), 4.65 (d, J = 14.8 Hz, 1H), 4.09 - 3.85 (m, 2H), 3.65 (d, J = 9.4 Hz, 2H), 3.53 (s, 2H), 3.09 - 2.65 (m, 4H).

[0228] Example 1.5: Synthesis of Compounds 7A and 7B

[0229]

[0230]

[0231] Step 1: In a solution of 4-bromo-2-(trimethylsilyl)thiazole (546 mg, 2.32 mmol) in anhydrous tetrahydrofuran (5 mL) at -78 °C n -Butyllithium (1.5 mL, 2.32 mmol, 1.6 M) was added. The reaction mixture was stirred at this temperature for 1 hour. Next, Compound 1-7(100 mg, 0.23 mmol) was added. The reaction mixture was stirred at -78 °C for 1 hour. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the residue, which was purified by flash silica gel chromatography as a yellow solid Compound 7-1 (80 mg, yield 63%) was obtained. LCMS: 556.3 [M+H] + .

[0232] Step 2: In dichloromethane (1 mL) Compound 7-1 TFA (0.5 mL) was added to a solution of (80 mg, 0.14 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure as a yellow solid Compound 7-2 (60 mg, yield 91%) was obtained. LCMS: 456.3 [M+H] + .

[0233] Step 3: In acetonitrile (1 mL) Compound 7-2 0.1 mL of 70% pyridine hydrofluoric acid solution was added to a solution of (60 mg, 0.13 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure as a yellow solid Compound 7-3 (30 mg, yield 67%) was obtained. LCMS: 384.1 [M+H] + .

[0234] Step 4: In dichloromethane (2 mL) Compound 7-3 DIEA (40 mg, 0.31 mmol) and 4-(trifluoromethyl)benzenesulfonyl chloride (21 mg, 0.09 mmol) were added to a solution of (30 mg, 0.08 mmol). The mixture was stirred at 25°C for 30 minutes under an N2 atmosphere and filtered. The filtrate was concentrated under reduced pressure and then purified by Prep-HPLC as a white solid Compound 7-4(30 mg, 65% yield) was obtained. LCMS: 592.3 [M+H] + .

[0235] Step 5: Compound 7-4 (30 mg) was separated by SFC (Column: DAICELCHIRALCEL®AS (250*30 mm, 10μm); Mobile phase A: Supercritical CO2; Mobile phase B: MeOH (+0.1% MeOH solution of 7.0 mol / L ammonia)) with a retention time of 1.278 min Compound 7A (4 mg, yield 13%) and retention time of 2.485 minutes Compound 7B (5 mg, yield 17%) was obtained.

[0236] Compound 7A: LCMS: 592.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 2.8 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.35 (s, 1H), 7.18 - 7.09 (m, 2H), 5.28 (d, J = 11.6 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.11 (d, J = 16.4 Hz, 1H), 4.03 - 3.90 (m, 1H), 3.81 (d, J = 10.4 Hz, 1H), 3.77 - 3.61 (m, 1H), 3.04 - 2.94 (m, 1H), 2.85 - 2.65 (m, 3H).

[0237] Compound 7B: LCMS: 592.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 2.8 Hz, 1H), 7.84 (d,J = 8.4 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 3.2 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.34 (s, 1H), 7.18 - 7.07 (m, 2H), 5.26 (d, J = 11.6 Hz, 1H), 4.64 (d, J = 14.8 Hz, 1H), 4.07 (d, J = 16.0 Hz, 1H), 3.92 (d, J = 14.8 Hz, 1H), 3.79 (d, J = 10.8 Hz, 1H), 3.71 - 3.58 (m, 1H), 3.00 - 2.87 (m, 1H), 2.84 - 2.64 (m, 3H).

[0238] Example 1.6: Synthesis of Compounds 88A and 88B

[0239]

[0240]

[0241]

[0242]

[0243] Step 1: In ethanol (200 mL) Compound 88-1 Benzyl bromide (55.8 g, 326 mmol) was added to a solution of (33 g, 326 mmol) and stirred at 25 °C for 1 hour under N2. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried with sodium sulfate, and filtered. The filtrate was concentrated as a white solid Compound 88-2 (53 g, 85% yield) was obtained. LCMS: 192.2 [M+H] + .

[0244] Step 2: In DMF (200 mL) Compound 88-2Sodium 2-chloro-2,2-difluoroacetate (47.8 g, 314 mmol) and cesium carbonate (102 g, 314 mmol) were added to a solution of (30 g, 157 mmol). The reaction mixture was stirred under N2 at 70 °C for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash silica gel chromatography as a yellow oil Compound 88-3 (5.1 g, 13% yield) was obtained. LCMS: 242.1 [M+H] + .

[0245] Step 3: In acetic acid (48 mL) and water (24 mL) Compound 88-3 NCS (11.3 g, 86 mmol) was added to a solution of (5.1 g, 21 mmol). The reaction mixture was stirred under N2 at 30 °C for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated. The obtained residue was purified by flash silica gel chromatography as a yellow oil Compound 88-4 (3.1 g, 68% yield) was obtained. 1 HNMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.45 (t, J = 57.6 Hz, 1H).

[0246] Step 4: In acetonitrile (10 mL) Compound 88-4 7 M ammonia (20 mL) in methanol was added to a solution of (1.9 g, 8.73 mmol). The reaction mixture was stirred under N2 at 25 °C for 2 hours. The mixture was concentrated. The resulting residue was purified by flash silica gel chromatography as a white solid Compound 88-5 (1.0 g, 58% yield) was obtained. LCMS: 197.1 [MH] - .

[0247] Step 5: In THF (3 mL) Compound 88-5 NaH (202 mg, 5.05 mmol) was added to a solution of (500 mg, 2.52 mmol) at 0 °C and stirred for 0.5 hours. Subsequently, tert-butylchlorodimethylsilane (456 mg, 3.03 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash silica gel chromatography as a white solid Compound 88-6 (300 mg, 38% yield) was obtained. LCMS: 311.1 [MH] - .

[0248] Step 6: In 1,4-dioxane (1 mL) Compound 38-Int 1 mL of 4 M HCl in dioxane was added to a solution of (100 mg, 0.19 mmol). The reaction mixture was stirred under N2 at 25 °C for 1 hour. The mixture was quenched with saturated NaHCO3. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated as a yellow solid. Compound 88-7 (75 mg, 92% yield) was obtained. LCMS: 428.1 [M+H] + .

[0249] Step 7: 4A molecular sieve (100 mg) and in dichloromethane (4 mL) Compound 88-6 TEA (0.12 mL, 0.86 mmol) was added to a mixture of (81 mg, 0.26 mmol). The mixture was stirred at 25 °C for 10 minutes. o Dichlorotriphenylphosphorane (144 mg, 0.43 mmol) was added at C. The reaction mixture was stirred at 0 °C for 1 hour. To this reaction mixture, 0 o In C Compound 88-7(50 mg, 0.12 mmol) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with saturated NaHCO3 and extracted with ethyl acetate. The combined organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by Prep-HPLC. Compound 88-8A (15 mg, 17.3% yield) and Compound 88-8B (20 mg, 23.1% yield) was obtained. LCMS: 722.1 [M+H] + .

[0250] Step 8: In 1,4-dioxane (1 mL) Compound 88-8A 1 mL of 4 M HCl in dioxane was added to a solution of (15 mg, 0.021 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was quenched with saturated NaHCO3 and extracted with dichloromethane. The combined organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated. The obtained residue was purified by Prep-HPLC. Compound 88A (5.16 mg, 40.4% yield) was obtained. LCMS: 608.3 [M+H] + .

[0251] 1 H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.10 (s, 1H), 8.05 - 7.95 (m, 2H), 7.46 - 7.41 (m, 2H), 7.38 (t, J = 57.8 Hz, 1H), 7.35 (s, 1H), 7.20 - 7.14 (m, 2H), 6.79 (t, J = 55.4 Hz, 1H), 5.77 - 5.58 (m, 1H), 4.77 - 4.63 (m, 1H), 4.24 - 3.94 (m, 3H), 3.79 - 3.62 (m, 1H), 3.39 - 2.71 (m, 4H), 2.06 (brs, 1H).

[0252] Step 4: In 1,4-dioxane (1 mL) Compound 88-8B 1 mL of 4 M HCl in dioxane was added to a solution of (15 mg, 0.021 mmol). The reaction mixture was stirred at 25 °C for 1 hour. The mixture was quenched with saturated NaHCO3 and extracted with dichloromethane. The combined organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated. The obtained residue was purified by Prep-HPLC and Compound 88B (8.63 mg, 67.5% yield) was obtained. LCMS: 608.4 [M+H] + .

[0253] 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 8.92 (s, 1H), 8.45 (s, 1H), 8.26 (t, J = 57.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.62 - 7.54 (m, 2H), 7.42 (s, 1H), 7.38 - 7.31 (m, 2H), 7.26 (t, J = 54.8 Hz, 1H), 5.34 - 5.20 (m, 2H), 4.42 (d, J = 15.2 Hz, 1H), 4.19 (d, J = 15.2 Hz, 1H), 4.07 (d, J = 16.0 Hz, 1H), 3.78 - 3.67 (m, 1H), 3.41 - 3.35 (m, 1H), 3.02 - 2.93 (m, 1H), 2.82 - 2.70 (m, 2H), 2.69 - 2.60 (m, 1H).

[0254] The following intermediates were prepared and separated by a procedure similar to that described in Example 1.1, where * indicates a chiral center. The enantiomer separation conditions are shown in the table below, and isomer A and isomer B are the first and second eluted isomers, respectively, under the identified enantiomer separation conditions.

[0255]

[0256]

[0257]

[0258]

[0259] The following compounds were prepared by a process similar to that described in Examples 1.1-1.2.

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275] The following compounds were prepared by a process similar to that described in Example 1.6.

[0276]

[0277]

[0278]

[0279]

[0280] Example 2: Biological evaluation

[0281] In vitro GR Reporter Gene Analysis:

[0282] Cell line: HEK293T

[0283] Plasmid: pGL4.35 [luc2P / 9XGAL4 UAS / Hygro]

[0284] Culture medium: DMEM (containing phenol red) + 10% FBS

[0285] Analysis Medium: DMEM (Phenol Red Excluded) + 10% FBS

[0286] HEK293T cells are cultured in a T175 flask in culture medium under conditions of less than 90% cell density (confluence).

[0287] HEK293T cells were analyzed during the exponential growth phase.

[0288] 6*10 on a 100mm dish 6 Canine HEK293T cells were seeded.

[0289] Cells were incubated for 16 hours at 37°C under a 5% CO2 atmosphere.

[0290] The plasmid was transfected into the cells and incubated for 5-6 hours at 37°C under a 5% CO2 atmosphere.

[0291] The control and test compounds were prepared in 10 doses by serially diluting them three-fold from 1 mM in DMSO.

[0292] Using Echo655, a 75 nl diluted solution of the compound was transferred to a 384-well analysis plate.

[0293] HEK293T cells were seeded with 5 nM dexamethasone in a 384-well assay plate at 17,000 cells / well.

[0294] Cells were incubated for 18-20 hours at 37°C under a 5% CO2 atmosphere.

[0295] 25 μl of britelite plus luciferase assay reagent was added to each well of a 384-well analysis plate.

[0296] The light emission value was recorded on the Envision 2105 plate reader.

[0297] Calculate the RLU signal for each well.

[0298] The raw data was analyzed using the equation (V. Data Analysis).

[0299] The GR antagonist activity of the compounds disclosed in this specification was measured by the GR reporter gene assay and IC 50 The values ​​were determined. Table 4 shows the ICs of exemplary compounds for inhibiting GR. 50 It provides.

[0300] Table 4 IC50 of exemplary compounds for GR inhibition 50

[0301]

[0302]

[0303] IC 50 (nM): 0 < A ≤ 20 nM; 20 nM < B ≤ 100 nM; 100 nM < C ≤ 1000 nM; 1000 nM < D

[0304] Other compounds disclosed in this specification also exhibit GR antagonist activity.

Claims

Claim 1 Compound of chemical formula (I): Chemical formula (I), or a pharmaceutically acceptable salt thereof, where: each of is independently a single or double bond; X is N, C, or CH; and L 1 -C(=O)-, -C(=O)O-, -C(=O)N(R a )-, -C(R a )2-, -N(R a )-, -O-, -S-, S(=O) or -S(=O)2- and;L 2 and L 3 Each combines independently, -N(R a )-, -C(=O)-, -C(=O)O-, -C(=O)N(R a )-, -O-, -S-, S(=O), -S(=O)2-, -S(=O)(=NR a )-, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl, wherein alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, or oxo; each of ring A, ring B, and ring C is independently cycloalkyl, aryl, heterocyclyl, or heteroaryl; R 1 , R 2 and R 3 Each is independently halogen, hydroxyl, cyano, -OR b , -N(R b )2, -C(=O)R b , -C(=O)OR b , -C(=O)N(R b )2, -S(=O)R b , -S(=O)2R b , alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, oxo, alkyl, alkenyl, alkynyl, haloalkyl, or hydroxyalkyl; R 4a and R 4b Each is independently hydrogen, halogen, hydroxy, cyano, alkyl, haloalkyl, hydroxyalkyl, or alkoxy; R 4a and R 4b is formed with the carbon atoms to which they are bonded to form a cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more groups independently selected from halogen, hydroxyl, amino, or alkyl; R a and R b Each is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, or cycloalkyl; or two R b It forms a heterocyclyl with the nitrogen atom to which it is bonded, and is optionally substituted with one or more groups independently selected from halogen, hydroxyl, amino, or alkyl; n is any integer from 0 to 5; m is any integer from 0 to 5; and t is any integer from 0 to 5. Claim 2 In paragraph 1, L 1 A compound that is -C(=O)-, or a pharmaceutically acceptable salt thereof. Claim 3 In paragraph 1 or 2, L 2 A combination, -N(R a )- or alkyl and L 3 This -S(=O)2- or -S(=O)(=NR) a )-or;L 2 -S(=O)2- or -S(=O)(=NR) a )-and, L 3 This combination, -N(R a )- or alkyl, a compound, or a pharmaceutically acceptable salt thereof. Claim 4 In any one of paragraphs 1 to 3, -L 2 -L 3 -This -S(=O)2-, -N(R a )-S(=O)2- or -S(=O)(=NR a )-Phosphorus, compound, or pharmaceutically acceptable salt thereof. Claim 5 A compound, or a pharmaceutically acceptable salt thereof, wherein ring A is an aryl or heteroaryl in any one of claims 1 to 4. Claim 6 In paragraph 5, a compound in which ring A is phenyl, pyridyl, pyrazolyl, pyrimidinyl, triazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazolyl, dihydropyrrolopyrazolyl, dihydroimidazooxazinyl, or dihydropyrazolooxazinyl, or a pharmaceutically acceptable salt thereof. Claim 7 In paragraph 6, a compound in which ring A is selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof: , , , , , , , , , , , , , , , , , , , and . Claim 8 In any one of paragraphs 1 through 7, each R 1 This independently halogen, cyano, -OR b , a compound that is an alkyl, haloalkyl, cycloalkyl, or heterocyclyl, or a pharmaceutically acceptable salt thereof. Claim 9 In Paragraph 8, each R 1 This independently -F, -Cl, cyano, -OCH3, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, cyclopropyl or Phosphorus, a compound, or a pharmaceutically acceptable salt thereof. Claim 10 A compound, or a pharmaceutically acceptable salt thereof, wherein ring B is heteroaryl in any one of claims 1 to 9. Claim 11 In paragraph 9, a compound in which ring B is pyridyl, thiazolyl, pyrimidinyl, imidazolyl, or oxazolyl, or a pharmaceutically acceptable salt thereof. Claim 12 In paragraph 9, a compound in which ring B is selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof: , , , , , , , and . Claim 13 In any one of paragraphs 1 through 12, each R 2 A compound that is independently a halogen, alkyl, haloalkyl, or cycloalkyl, or a pharmaceutically acceptable salt thereof. Claim 14 In Paragraph 13, each R 2 A compound or a pharmaceutically acceptable salt thereof that is independently -CH3, -F, -Cl, -CH2F, -CHF2, -CF3, or cyclopropyl. Claim 15 In any one of claims 1 to 14, a compound in which ring C is an aryl, or a pharmaceutically acceptable salt thereof. Claim 16 In paragraph 15, a compound in which ring C is phenyl, or a pharmaceutically acceptable salt thereof. Claim 17 In any one of paragraphs 1 through 16, each R 3 A compound that is independently a halogen, alkyl, or haloalkyl, or a pharmaceutically acceptable salt thereof. Claim 18 In Paragraph 15, each R 3 A compound that is -F, -CH3, -CH2F, -CHF2, or -CF3, or a pharmaceutically acceptable salt thereof. Claim 19 In any one of paragraphs 1 through 18, R 4a A compound, or a pharmaceutically acceptable salt thereof, in which α is hydrogen or alkyl. Claim 20 In any one of paragraphs 1 through 19, R 4b A compound, or a pharmaceutically acceptable salt thereof, in which α is hydrogen or alkyl. Claim 21 In any one of paragraphs 1 through 20, R 4a and R 4b Both are hydrogen compounds, or pharmaceutically acceptable salts thereof. Claim 22 In any one of paragraphs 1 through 18, R 4a and R 4b A compound that forms cyclopropyl together with the carbon atom to which it is bonded, or a pharmaceutically acceptable salt thereof. Claim 23 In claim 1, a compound having the formula (Ia) or the formula (Ib), or a pharmaceutically acceptable salt thereof: Chemical formula (Ia), Chemical formula (Ib). Claim 24 In claim 1, a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is of a formula selected from the following formulas (Ia-1) and (Ib-1): Chemical formula (Ia-1) Chemical formula (Ib-1). Claim 25 In paragraph 24, a compound or a pharmaceutically acceptable salt thereof, wherein ring A is aryl or heteroaryl and optionally ring A is phenyl, pyridyl, pyrazolyl, pyrimidinyl, triazolyl, or thiadiazolyl. Claim 26 A compound or a pharmaceutically acceptable salt thereof, wherein ring B is heteroaryl and optionally ring B is pyridyl, pyrimidinyl, thiazolyl, or imidazolyl. Claim 27 A compound or a pharmaceutically acceptable salt thereof, wherein ring C is aryl and optionally ring C is phenyl. Claim 28 In any one of paragraphs 24 through 27, L 2 and L 3 Each combines independently, -N(R a )-, -S(=O)2- or -S(=O)(=NR a )-is, and optionally -L 2 -L 3 -This -S(=O)2-, -N(R a )-S(=O)2- or -S(=O)(=NR a )-and, optionally R a A compound, or a pharmaceutically acceptable salt thereof, in which α is hydrogen or alkyl. Claim 29 In claim 1, the compound, or a pharmaceutically acceptable salt thereof, selected from any of the compounds presented in Table 1, 2, or 3: Claim 30 A pharmaceutical composition comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Claim 31 A method for modulating glucocorticoid receptors in a subject requiring treatment, comprising the step of administering to the subject an effective amount of a compound according to any one of claims 1 to 29, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30. Claim 32 A method for treating a disease or disorder in a subject in need, comprising the step of administering to the subject an effective amount of a compound according to any one of claims 1 to 29, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30. Claim 33 In paragraph 32, a method in which a disease or disorder is Cushing's syndrome, Addison's disease, osteoporosis, rheumatoid arthritis, asthma, rhinitis, adrenal function-related diseases, human immunodeficiency virus, acquired immune deficiency syndrome, allergy, or wound healing.

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