Compounds and uses thereof

Abstract

The present disclosure relates to compounds, compositions, and methods useful for modulating a glucocorticoid receptor (GR) and for treating diseases and disorders (e.g., autoimmune diseases and inflammatory diseases).

Description

COMPOUNDS AND USES THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to PCT Application No. PCT / CN2024 / 097821, filed June 6, 2024, and PCT Application No. PCT / CN2025 / 099113, filed June 4, 2025, each of which is incorporated herein by reference in its entirety.FIELD

[0002] The present disclosure relates to compounds that act as agonists or modulators of glucocorticoid receptor (GR). The disclosure also relates to compositions comprising said compounds and the use of said compounds for the treatment or prevention of diseases or disorders (e.g., autoimmune diseases or inflammatory diseases).BACKGROUND

[0003] The glucocorticoid receptor (GR) is a nuclear receptor and a ligand-activated transcription factor that mediates the effects of glucocorticoids. Upon binding to glucocorticoids, this steroid hormone receptor interacts with transcription factors, co-regulators and DNA to regulate transcription thereby exerting biologic effects. Several factors modulate GR activity, including small molecule agonists or modulators.

[0004] Synthetic glucocorticoid receptor agonists are a class of compounds (e.g., prednisolone) used in the treatment of diseases, such as autoimmune diseases or inflammatory diseases. However, the utility of synthetic glucocorticoid receptor agonists in the treatment of diseases is limited by their unwanted or harmful side effects (e.g., indigestion, osteopenia, insomnia, weakness, weight gain, mood changes, hyperglycemia, and restlessness). Accordingly, there is a need to develop glucocorticoid receptor agonists or modulators with enhanced efficacy and minimal unwanted or harmful side effects.SUMMARY

[0005] The present disclosure features compounds, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1, and pharmaceutically acceptable salts thereof), and methods useful for treating diseases or disorders (e.g., autoimmune diseases or inflammatory diseases). The disclosure also features compositions comprising compounds useful for the treatment of diseases or disorders (e.g., autoimmune diseases or inflammatory diseases).

[0006] Disclosed herein, in some embodiments, is a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: R1is C1-C6alkyl; R2is 3-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10 membered bicyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a; each instance of R2ais independently halogen, –ORo1, –NRn1Rn2, C1-C6alkyl optionally substituted with 1-4 instances of R2b, C1-C6haloalkyl,wherein m is 0, 1, 2, or 3; X is –O– or –NR2e–; each R2bis independently halogen, –ORo2, or –NRn3Rn4; each R2cis independently halogen, –ORo2, or –NRn3Rn4; each of R2d, R2e, Ro1, Ro2, Rn1, Rn2, Rn3, and Rn4is independently H or C1-C6alkyl; and R3is H or C1-6alkyl.

[0007] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0008] Disclosed herein, in some embodiments, is a process for providing a compound disclosed herein or an effective amount of a pharmaceutical composition disclosed herein.

[0009] Disclosed herein, in some embodiments, is a method of treating a disease (e.g., a glucocorticoid receptor-mediated disease) in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or an effective amount of a pharmaceutical composition disclosed herein.

[0010] Disclosed herein, in some embodiments, is a compound disclosed herein or a composition disclosed herein, in the manufacture of a medicament for the treatment of a disease (e.g., glucocorticoid receptor-mediated disease).

[0011] Still other aspects and embodiments will become apparent to those of skill in the art from the disclosure herein, which is simply illustrative and not restrictive. Thus, other embodiments will be recognized by one of skill in the art without departing from the spirit and scope of the disclosureDETAILED DESCRIPTION

[0012] As generally described herein, the present disclosure features compounds, or pharmaceutically acceptable salts thereof (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1, and pharmaceutically acceptable salts thereof), and methods useful for treating diseases or disorders (e.g. , autoimmune diseases or inflammatory diseases). The disclosure also features compositions comprising compounds useful for the treatment of diseases or disorders (e.g., autoimmune diseases or inflammatory diseases).Definitions

[0013] The following definitions apply to the terms as used to describe the present disclosure, unless otherwise indicated or apparent from context. Unless explicitly indicated otherwise, or apparent from context, the terms below do not exclude the meaning that the term has acquired in the art to which it pertains. The definitions below are provided to facilitate the description of the disclosure, but they are not intended to limit the scope of the disclosure.

[0014] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure

[0015] The terms “a, ,'” “an,” and “the” refer to one or to more than one, unless context indicates otherwise. Similarly, the term “or” is intended to include “and”, unless context indicates otherwise.

[0016] As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 mg” indicates a range of from 4.5 mg to 5.5 mg.

[0017] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0018] As used herein, the term “effective amount” of a compound refers to an amount sufficient to elicit a beneficial or desired biological response (e.g., clinical results such as treating autoimmune diseases or inflammatory diseases). As such, the effective amount may be sufficient, e.g., to reduce or ameliorate the severity or duration of a disease, or symptoms thereof, related to autoimmune diseases or inflammatory diseases; or to prevent the advancement of symptoms related to diseases related to autoimmune diseases or inflammatory diseases. An effective amount also includes the amount of a compound that avoids or substantially attenuates undesirable side effects. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound disclosed herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0019] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or symptoms thereof, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition, or symptoms thereof. A therapeutically effective amount of a compound means an amount of the compound which provides a therapeutic benefit in the treatment of the disease, disorder, or condition, or symptoms thereof. The term “therapeutically effective amount” can encompass an amount that improves overall therapy or an amount that reduces or avoids symptoms or causes of disease or condition.

[0020] As used herein, the term “glucocorticoid receptor” or “GR” refers to a receptor that binds to a glucocorticoid (e.g., cortisol or a cortisol analogue, such as dexamethasone). The term includes isoforms of GR, recombinant GR, and mutated GR.

[0021] As used herein, the term “glucocorticoid receptor-mediated disease” or “GR-mediated disorder” refers to a disease or disorder in which glucocorticoid receptor (GR) signaling plays a causal or therapeutic role (e.g., a disease or disorder that is characterized by abnormal glucocorticoid receptor signaling or whose symptoms can be suppressed or increased by glucocorticoid receptor signaling). A glucocorticoid receptor-mediated disease or disorder maybe completely or partially mediated by modulating activity of a glucocorticoid receptor. In particular, a glucocorticoid receptor-mediated disease or disorder is one in which modulation of glucocorticoid receptor results in some effect on the underlying disease or disorder (e.g., administration of a glucocorticoid receptor modulator, e.g., a glucocorticoid receptor agonist, results in improvement in the disease or disorder, or symptoms thereof).

[0022] As used herein, the term “glucocorticoid receptor modulator” (e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof) is a compound that affects the response of a glucocorticoid receptor towards a glucocorticoid.

[0023] As used herein, the term “modulate” or “modulating” or “modulation of” a glucocorticoid receptor refers to adjusting response of a glucocorticoid receptor towards a glucocorticoid (e.g., interfering with and effecting glucocorticoid receptor GR activity). For example, a glucocorticoid receptor modulator is an agent (e.g., a compound) that reduces the occurrence of glucocorticoid receptor binding to glucocorticoid (e.g., a glucocorticoid receptor antagonist) or an agent (e.g., a compound) that activates a glucocorticoid receptor (e.g., glucocorticoid receptor agonist). Further examples of a glucocorticoid receptor modulator include a partial agonist of a glucocorticoid receptor and a selective glucocorticoid receptor agonist (SEGRA).

[0024] As used herein, the term “pharmaceutical composition” refers to a formulation (e.g., medicinal formulation) that contains at least one active ingredient (e.g., a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salt thereof) as well as one or more excipients or diluents to enable the active ingredient suitable for the method of administration. The pharmaceutical composition of the present disclosure includes pharmaceutically acceptable components that are compatible with a compound disclosed herein (e.g., a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salt thereof).

[0025] As used herein, the term “pharmaceutically acceptable” refers to compounds, compositions, dosage forms, or materials which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive allergic response, irritation, toxicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In some embodiments, the term “pharmaceutically acceptable”means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0026] As used herein, the term “pharmaceutically acceptable excipient” refers to a substance or material other than the compounds disclosed herein (e.g., compounds of Formula A, Formula B, or Formula C, or any subformula thereof, compounds of Table 1 or Table 2, and compounds described in the Examples, and a pharmaceutically acceptable salt thereof) that is included in the compositions disclosed herein. Excipients are generally nontoxic to the subject and compatible with the other ingredients of the composition. Excipients include, but are not limited to, adjusting agents, adjuvants, antiadherents, antimicrobial agents, antioxidants, binders, buffers, carriers, coatings, compression aids, diluents, disintegrants, dispersing agents, dyes, emollients, emulsifiers, encapsulating materials, fillers, flavors, fragrances, glidants, lubricants, preservatives, salts, solvents, sorbents, stabilizers, surfactants, suspending agents, and sweeteners. For example, a pharmaceutically acceptable excipient may be a vehicle capable of suspending or dissolving a compound disclosed herein. Exemplary excipients are found, e.g., in Remington’s Pharmaceutical Sciences, 15thEd., Mack Publ. Co., Easton, PA (1975).

[0027] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive allergic response, irritation, toxicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The term "pharmaceutically acceptable salt” is meant to include salts of the compounds disclosed herein that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds. When compounds contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. When compounds contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Certain compounds contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Exemplary pharmaceutically acceptable salts are found, e.g., in Berge, et al. (J. Pharm. Sci. 1977, 66(1), 1; and Gould, P.L., Int. J. Pharmaceutics 1986, 33, 201-217, each of which is hereby incorporated by reference in its entirety.

[0028] As used herein, the term “subject” refers to a human (i.e., a male or female of any age group) or non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, turkey, goat, fish, monkey, chicken, rat, mouse, or sheep. In some embodiments, the subject is human. In some embodiments, the subject is non-human. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0029] As used herein, the term “treat” or “treating” a disease or disorder refers to alleviating, ameliorating, delaying, inhibiting, preventing, reversing, slowing down, or stopping the aggravation, deterioration, onset, or progression of the disease or disorder, or a condition or symptom associated with the disease or disorder. In some embodiments, treatment slows the progression of the disease (e.g., autoimmune disease or inflammatory disease), improves the subject's outcome, or eliminates the disease, or symptoms thereof. In some embodiments, treatment of a disease (e.g., autoimmune disease or inflammatory disease) in a subject alleviates or ameliorates one or more symptoms or conditions associated with the disease (e.g., autoimmune disease or inflammatory disease). In some embodiments, treatment of a disease (e.g., autoimmune disease or inflammatory disease) in a subject diminishes the extent of the disease. In some embodiments, treatment of a disease (e.g., autoimmune disease or inflammatory disease) in a subject stabilizes (i.e., not worsening) the state of the disease (e.g., autoimmune disease or inflammatory disease). In some embodiments, treatment of a disease (e.g., autoimmune disease or inflammatory disease) in a subject prevents the spread of the disease (e.g., autoimmune disease or inflammatory disease). In some embodiments, treatment of a disease (e.g., autoimmune disease or inflammatory disease) in a subject delays or slows the progress of the disease (e.g., autoimmune disease or inflammatory disease), as compared to the state or the condition of the disease (e.g., autoimmune disease or inflammatory disease) in the absence of the treatment. Chemical Definitions

[0030] The following chemical definitions apply to the abbreviations and terms as used to describe the present disclosure, unless otherwise indicated or apparent from context. Unless explicitly indicated otherwise, or apparent from context, the terms below do not exclude the meaning that the term has acquired in the chemical arts. The definitions below are provided to facilitate the description of the disclosure, but they are not intended to limit the scope of the disclosure.

[0031] The abbreviations and terms used herein have their conventional meaning within the chemical arts. The structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0032] Definitions of select chemical terms and functional groups are described in more detail below. The chemical elements are identified in accordance with the 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 therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. Compound Configuration

[0033] Those skilled in the art will appreciate that compounds described herein can exist in one or more different isomeric (e.g., constitutional isomers, geometric isomers, stereoisomers, and tautomer) or isotopic (e.g., one or more hydrogen substituted with deuterium) forms. Unless otherwise indicated, a depicted structure can be understood to represent any such isomeric or isotopic forms, individually or in combination.

[0034] As used herein, the term “chiral” is used to describe a structure or a functional group of a structure (e.g., an sp3 carbon center) that has a non-superimposable mirror image. As used herein, the term “achiral” is used to describe a structure or a functional group of a structure (e.g., an sp3 carbon center) that has a superimposable mirror image.

[0035] As used herein, the term “isomer” refers to and includes a compound or structure with identical chemical formula but different atom connectivity (e.g., constitutional (structural) isomer) or spacial configuration (e.g., stereoisomer). Generally, isomers exhibit different physical properties, such as optical rotation.

[0036] As used herein, the term “constitutional isomer” or “structural isomer” refers to and includes a compound or structure with identical chemical formula but different atom connectivity.

[0037] As used herein, the term “stereoisomer” refers to and includes a compound or structure with identical chemical formula and identical atom connectivity but different spacialconfiguration (i.e., differ in positioning or arrangement of the atoms in space). Stereoisomers may be atropisomers, diastereomers, enantiomers, or geometric (or conformational) isomers. The term “stereoisomerically pure” or “pure stereoisomer” (e.g., atropisomerically pure or pure atropisomer; diastereomerically pure of pure diastereomer; or enantiomerically pure or pure enantiomer) denotes that the compound comprises more than 75% by weight or by mole fraction, more than 80% by weight or by mole fraction, more than 85% by weight or by mole fraction, more than 90% by weigh or by mole fraction, more than 91% by weight or by mole fraction, more than 92% by weight, more than 93% by weight or by mole fraction, more than 94% by weight or by mole fraction, more than 95% by weight or by mole fraction, more than 96% by weight or by mole fraction, more than 97% by weight or by mole fraction, more than 98% by weight or by mole fraction, more than 98.5% by weight, more than 99% by weight or by mole fraction, more than 99.2% by weight or by mole fraction, more than 99.5% by weight or by mole fraction, more than 99.6% by weight or by mole fraction, more than 99.7% by weight or by mole fraction, more than 99.8% by weight or by mole fraction, or more than 99.9% by weight or by mole fraction, of the stereoisomer. In some embodiments, the weights are based upon total weight of all stereoisomers of the compound.

[0038] As used herein, the term “diastereomer” refers to a stereoisomer of a structure that is not the mirror image of the structure and that is not superimposable on the structure. Diastereomers generally contain more than one of a chiral moiety (e.g., a chiral center or a chiral axis).

[0039] As used herein, the term “enantiomer” refers to the mirror image of a structure that is not superimposable on the structure. A pair of enantiomers may contain a chiral center (e.g., an asymmetrically substituted sp3 carbon atom) or a chiral axis. A composition comprising a pure enantiomeric compound is substantially free of the other enantiomer or stereoisomers of the compound (i.e., a composition comprising a compound in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is in enantiomeric excess of the “R” form. “Racemate" or "racemic mixture" refers to a composition comprising both enantiomers of a compound, wherein such composition exhibits no optical activity (i.e., the composition does not rotate the plane of polarized light).

[0040] As used herein, the term “geometric isomer” refers to an isomer that differs in the arrangement or orientation of atoms with respect to a double bond, ring, or other rigid structural system. For example, atoms on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents areoriented on the same side) configuration. Many geometric isomers of, e.g., olefins and C=N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[0041] All stereoisomers of the compounds disclosed herein, including atropisomeric forms, diastereomeric forms, enantiomeric forms, and geometric (or conformational) isomeric forms, are contemplated within the scope of this disclosure. For example, the compounds described herein can be in the form of an individual atropisomer, diastereomer, enantiomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including a racemic mixture and a mixture that is enriched in one or more stereoisomer. Unless otherwise stated, single stereoisomers, as well as mixtures of atropisomeric isomers, diastereomeric isomers, enantiomeric isomers, or geometric isomeric isomers of the compounds described herein are within the scope of the disclosure. A composition may comprise a compound described herein as an individual isomer (e.g. , stereoisomer) that is substantially free of other isomers (e.g. , other stereoisomers). Alternatively, a composition may comprise a compound described herein as a mixture of one or more isomers e.g., stereoisomers). Unless otherwise indicated, the absolute stereochemistry of a chiral center (or asymmetric center) or a chiral axis is as depicted.

[0042] When a disclosed compound is named or depicted by structure without indicating the relative or absolute stereochemistry of the chiral moiety (e.g., chiral center or chiral axis), it is to be understood that the name or structure includes one isomer free of all other isomers; more than one isomer free of all other isomers; mixtures of isomers where all isomers are present in about the same amount by weight or by mole fraction; mixtures of isomers where one isomer is enriched relative to the other isomer(s); and mixtures of isomers where more than one isomer is enriched relative to the other isomer(s). All forms are contemplated within the scope of this disclosure.

[0043] As used herein, the term “tautomer” refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It is understood that tautomers encompass valence tautomers and proton tautomers (also known as prototrophic tautomers). Valence tautomerism includes interconversion via redistribution of electrons between isomeric forms. Proton tautomerism includes interconversion via migration of a proton (i.e., an isomeric protonation state having the same empirical formula and total charge as a reference form). In some embodiments, tautomeric forms result from theswapping of a single bond with an adjacent double bond and the concomitant migration of a proton. Examples of moieties with prototrophic tautomeric forms are amide / imidic acid pairs, enamine / imine pairs, ketone / enol pairs, lactam / lactim pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H-imidazole and 3H- imidazole; 1H-1,2,4-triazole, 2H-1,2,4-triazole, and 4H-1,2,4-triazole; 1H- isoindole and 2H- isoindole; and 1H- pyrazole and 2H-pyrazole. Unless otherwise stated, all tautomers of the compounds disclosed herein are within the scope of the disclosure. In some embodiments, tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In some embodiments, tautomeric forms result from acetal interconversion. In some embodiments, one or more compounds disclosed herein may exist in different tautomeric forms. As will be clear from context, unless explicitly excluded, reference to such compounds encompasses all tautomeric forms.

[0044] Unless otherwise stated, structures that differ only in the presence of one or more isotopically enriched atoms are contemplated within the scope of the disclosure. The term “isotope” refers to an atom having the same atomic number but different mass number, resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium (i.e.,3H) and deuterium (i.e.,2H or D). Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I, and125I. Isotopically labeled compounds can generally be prepared by following procedures analogous to those described herein for the presently disclosed compounds, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.

[0045] In some embodiments, compounds disclosed herein comprise one or more asymmetric centers or one or more chiral axes, and thus can exist in various isomeric forms, e.g., atropisomers, enantiomers, and / or diastereomers. For example, the compounds disclosed herein can be in the form of an individual stereoisomer, e.g., atropisomer, enantiomer, or diastereomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. The present disclosure contemplates compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.Select Functional Groups

[0046] For any of the following terms, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be understood, other atoms, such as hydrogen atoms or substituent groups as described herein, may be present to satisfy the valences of the atoms. For example, an unsubstituted C2alkyl group has the formula –CH2CH3.

[0047] For compounds in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different functional groups or moieties selected from the Markush group defined for R.

[0048] It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, a “substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.

[0049] Herein a phrase of the form “optionally substituted X” (e.g., optionally substituted alkyl) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) per se is optional.

[0050] Two or more substituents may optionally be joined to form aryl, heteroaryl, carbocyclyl, or heterocyclyl groups. Such ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In some embodiments, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring- forming substituents are attached to non-adjacent members of the base structure.

[0051] As used herein, the term “alkyl” refers to a saturated hydrocarbon monovalent radical having a straight chain or branched chain of 1 to 24 carbon atoms (“C1-C24alkyl”). In some embodiments, an alkyl group has 1 to 20 carbon atoms (“C1-C20alkyl”). In some embodiments, an alkyl group has 1 to 16 carbon atoms (“C1-C16alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-C12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-C10alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-C8alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-C6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-C5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-C4) alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-C3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-C2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). Examples of alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4)), tert–butyl (C4)), sec–butyl (C4)), iso–butyl (C4)), n–pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2– butanyl (C5), tertiary amyl (C5), n–hexyl (C6), n–heptyl (C7), and n–octyl (C8). Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., from 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent). In some embodiments, the alkyl group is unsubstituted alkyl. In some embodiments, the alkyl group is substituted alkyl.

[0052] As used herein, the term “alkylene” refers to a divalent alkyl group. An exemplary C2alkyl group is –CH2CH3, while an exemplary C2alkylene group is –CH2CH2–.

[0053] As used herein, the term “alkenyl” refers to an unsaturated hydrocarbon monovalent radical having a straight chain or branched chain of 2 to 24 carbon atoms (“C2-C24”), one or more carbon–carbon double bonds, and no triple bonds. In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C2-C20alkenyl”). In some embodiments, an alkenyl group has 2 to 16 carbon atoms (“C2-C16alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C2-C12alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-C8alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-C6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-C5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-C4) alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-C3alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon– carbon double bonds can be internal (e.g., as the carbon–carbon double bond in 2–butenyl) or terminal (e.g., as the carbon–carbon double bond in 1–butenyl). Examples of alkenyl groups include, but are not limited to, ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1–butenyl (C4), 2–butenyl (C4)), butadienyl (C4)), pentenyl (C5), pentadienyl (C5), hexenyl (C6), heptenyl (C7), octenyl (C8), and octatrienyl (C8). Each instance of an alkenyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents (e.g., from 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent). In some embodiments, the alkenyl group is unsubstituted alkenyl. In some embodiments, the alkenyl group is substituted alkenyl.

[0054] As used herein, the term “alkenylene” refers to a divalent alkenyl group. An exemplary C2alkenyl group is –CHCH2, while an exemplary C2alkenylene group is –CHCH–.

[0055] As used herein, the term “alkynyl” refers to an unsaturated hydrocarbon monovalent radical having a straight chain or branched chain of 2 to 24 carbon atoms (“C2-C24alkynyl”) and one or more carbon–carbon triple bonds. In some embodiments, an alkynyl group has 2 to 20 carbon atoms (“C2-C20alkynyl”). In some embodiments, an alkynyl group has 2 to 16 carbon atoms (“C2-C16alkynyl”). In some embodiments, an alkynyl group has 2 to 12 carbon atoms (“C2-C12alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-C10alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-C8alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-C6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-C5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-C4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-C3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1–propynyl (C3), 2– propynyl (C3), 1–butynyl (C4)), and 2–butynyl (C4)). Each instance of an alkynyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents (e.g., from 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent). In some embodiments, the alkynyl group is unsubstituted alkynyl. In some embodiments, the alkynyl group is substituted alkynyl.

[0056] As used herein, the term “alkynylene” refers to a divalent alkynyl group. An exemplary C2alkynyl group is –C≡CH, while an exemplary C2alkynylene group is –C≡C–.

[0057] As used herein, the terms “alkoxyl” or “alkoxy” refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, and tert-butoxy.

[0058] As used herein, “aryl” refers to a monovalent radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system of 6–14 ring carbon atoms (“C6-C14aryl”) having at least one aromatic ring and no heteroatoms in the ring system. In some embodiments, the aryl group is completely aromatic (i.e., the entire ring system is aromatic). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1–naphthyl and 2– naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents (e.g., from 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent). In some embodiments, the aryl group is unsubstituted aryl. In some embodiments, the aryl group is substituted aryl.

[0059] As used herein, the term “arylene” refers to a divalent aryl group. An exemplary C6aryl group is while an exemplary C6arylene group is

[0060] As used herein, the term “carbocyclyl” refers to a monovalent radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system of 3-14 ring carbon atoms (“C3-C14carbocyclyl”) having no heteroatoms in the ring system, wherein no ring in the ring system is aromatic. In some embodiments, a carbocyclyl group has 3-10 ring carbon atoms (“C3-C10carbocyclyl” or “3-10 membered carbocyclyl”). In some embodiments, a carbocyclyl group has 3-8 ring carbon atoms (“C3-C8carbocyclyl”). In some embodiments, a carbocyclyl group has 3-6 ring carbon atoms (“C3-C6carbocyclyl”). In some embodiments, a carbocyclyl group has 5-10 ring carbon atoms (“C5-C10carbocyclyl”). In some embodiments, a carbocyclyl group is a saturated ring system (“cycloalkyl”; e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, or adamantyl). In some embodiments, a carbocyclyl group is an unsaturated ring systems (“cycloalkenyl” or “cycloalkynyl”; e.g., cyclohexenyl or cyclooctynyl). In some embodiments, a carbocyclyl group comprises a spirocyclic ring system.In some embodiments, a carbocyclyl group comprises a bridged ring system. In some embodiments, a carbocyclyl group comprises a fused ring system. Exemplary carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro–1H– indenyl (C9), decahydronaphthalenyl (C10), and spiro[4.5]decanyl (C10). Each instance of a carbocyclyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents (e.g., from 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent). In some embodiments, the carbocyclyl group is unsubstituted carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted carbocyclyl.

[0061] As used herein, the term “carbocyclylene” refers to a divalent carbocyclyl group. An exemplary C6carbocyclyl group iswhile an exemplary C6carbocyclylene group is.

[0062] As used herein, the term “cyano” refers to the radical –CN.

[0063] As used herein, the term “halo” or “halogen,” independently or as part of another functional group or substituent, refer to a fluorine (fluoro; F), chlorine (chloro; Cl), bromine (bromo; Br), or iodine (iodo; I) radical (i.e., –F, –Cl, –Br, or –I).

[0064] As used herein, the term “haloalkyl” refers to alkyl, as defined above, substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halo groups. For example, “fluoroalkyl” refers to alkyl, as defined above, substituted with one or more fluoro groups. Examples of haloalkyl groups include, but are not limited to, –CH2F, –CHF2, –CF3, –CH2CF3, –CH2CH2CF3, and –CH(CF3)2.

[0065] As used herein, the term “heteroalkyl” refers to an alkyl group, as defined herein, in which one or more carbon atoms (e.g., 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, 1 to 2 carbon atoms, or 1 carbon atom) have been replaced by heteroatoms, wherein each heteroatom is independently selected from the group consisting of O, N, P, Si, and S, wherein the N, P, or S atoms are optionally be oxidized, and wherein the N atom is optionallyquaternized. Each heteroatom (i.e., O, N, P, Si, and S) may be located at any position of the heteroalkyl group. In some embodiments, the heteroalkyl group comprises two or more consecutive heteroatoms (e.g., as found in –CH2NHOCH3and –CH2OSi(CH3)3). Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups (e.g., –OR or – NRR'), it will be understood that the terms heteroalkyl and –OR or –NRR' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as –OR or –NRR'.

[0066] As used herein, the term “heteroalkylene” refers to a divalent heteroalkyl group. An exemplary C2heteroalkyl group is –OCH3, while an exemplary C2heteroalkylene group is – OCH2–.

[0067] As used herein, the term “heteroaryl” refers to a monovalent radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system of 5-14 atoms (“5-14–membered heteroaryl”) having at least one aromatic ring comprising one or more carbon atoms (e.g., 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, 1 to 2 carbon atoms, or 1 carbon atom) and one or more heteroatoms (e.g., 1 to 6 heteroatoms, 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom), wherein each heteroatom is independently selected from O, N, P, Si, and S, and wherein the N, P, or S atoms are optionally be oxidized. In some embodiments, the heteroaryl group is completely aromatic (i.e., the entire ring system is aromatic). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon atom or nitrogen atom, as valency permits. In some embodiments, a heteroaryl group has five ring atoms (“5–membered heteroaryl”; e.g., pyrrolyl, imidazolyl, triazolyl, or tetrazolyl). In some embodiments, a heteroaryl group has six ring atoms (“6–membered heteroaryl”; e.g., pyridinyl, pyrimidinyl, or pyridinonyl). In some embodiments, a heteroaryl group has nine ring atoms (“9–membered heteroaryl”; e.g.,. In some embodiments, a heteroaryl group has ten ring atoms (“10–membered heteroaryl”; e.g., In someembodiments, a heteroaryl group is a 5-10–membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, aheteroaryl group is a 5-8–membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl group is a 5-6–membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6–membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6–membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6–membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents (e.g., from 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent). In some embodiments, the heteroaryl group is unsubstituted heteroaryl. In some embodiments, the heteroaryl group is substituted heteroaryl.

[0068] As used herein, the term “heteroarylene” refers to a divalent heteroaryl group. An exemplary 6–membered heteroaryl group iswhile an exemplary 6–membered heteroarylene group is

[0069] As used herein, the term “heterocyclyl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring system of 3-14 ring atoms (“3-14–membered heterocyclyl”) having one or more heteroatoms (e.g., 1 to 6 heteroatoms, 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom), wherein each heteroatom is independently selected from O, N, P, Si, and S, and wherein the N, P, or S atoms are optionally be oxidized, and wherein no ring in the ring system is aromatic. In heterocyclyl groups comprising one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. In some embodiments, a heterocyclyl group is a saturated ring system (“heterocycloalkyl”; e.g., aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl). In some embodiments, a heterocyclyl group is an unsaturated ring system (“heterocycloalkenyl” or “heterocycloalkynyl”; e.g., dihydropyranyl). In some embodiments, a heterocyclyl group comprises a spirocyclic ring system. In some embodiments, a heterocyclyl group comprises a bridged ring system. In some embodiments, a heterocyclyl group comprises a fused ringsystem. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. In some embodiments, a heterocyclyl group has five ring atoms (“5–membered heterocyclyl”; e.g., pyrrolinyl). In some embodiments, a heterocyclyl group has six ring atoms (“6–membered heterocyclyl”; e.g., piperidinyl or piperazinyl). In some embodiments, a heterocyclyl group has seven ring atoms (“7–membered heterocyclyl”; e.g., azepanyl). In some embodiments, a heterocyclyl group has eight ring atoms (“8–membered heterocyclyl”; e.g., azocanyl). In some embodiments, a heterocyclyl group has nine ring atoms (“9–membered heterocyclyl”; e.g.,In some embodiments, a heterocyclyl group has ten ring atoms (“10–membered heterocyclyl”; e.g.,In some embodiments, a heterocyclyl group is a 5-10–membered ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclyl group is a 5-8–membered ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclyl group is a 5-6– membered ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6–membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6–membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6– membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heterocyclyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents (e.g., from 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, or 1 substituent). In some embodiments, the heterocyclyl group is unsubstituted heterocyclyl. In some embodiments, the heterocyclyl group is substituted heterocyclyl.

[0070] As used herein, the term “heterocyclylene” refers to a divalent heterocyclyl group. An exemplary 6–membered heterocyclyl group iswhile an exemplary 6–membered heterocyclylene group is

[0071] As used herein, the term “hydroxy” refers to the radical –OH.

[0072] As used herein, the term “hydroxyalkyl” refers to refers to alkyl, as defined above, substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) hydroxy groups. Exemplary hydroxyalkyl groups include, but are not limited to, –CH2OH, –CH2CH2OH, and –C(CH3)2OH.

[0073] As used herein, the term “hydroxycycloalkyl” refers to refers to cycloalkyl, as defined above, substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) hydroxy groups. Exemplary hydroxyalkyl groups include, but are not limited to, –CH2OH, –CH2CH2OH, and –C(CH3)2OH.

[0074] As used herein, the term “nitro” refers to –NO2.

[0075] As used herein, the term “oxo” refers to, in which both bonds from the oxygen are connected to the same atom. For example, a carbon atom substituted with oxo forms a carbonyl group (–C(O)–). Compounds

[0076] Compounds of the present disclosure include those described generally herein, and are further illustrated by the formulas, subformulas, and species disclosed herein (e.g., a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salt thereof).

[0077] Disclosed herein, in some embodiments, is a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: R1is C1-C6alkyl; R2is 3-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10 membered bicyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a; each instance of R2ais independently halogen, –ORo1, –NRn1Rn2, C1-C6alkyl optionally substituted with 1-4 instances of R2b, C1-C6haloalkyl,wherein m is 0, 1, 2, or 3; X is –O– or –NR2e–; each R2bis independently halogen, –ORo2, or –NRn3Rn4; each R2cis independently halogen, –ORo2, or –NRn3Rn4; each of R2d, R2e, Ro1, Ro2, Rn1, Rn2, Rn3, and Rn4is independently H or C1-C6alkyl; and R3is H or C1-6alkyl.

[0078] In some embodiments, R1is C1-C6alkyl.

[0079] In some embodiments, R1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or – hexyl. In some embodiments, R1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, R1is –Me.

[0080] In some embodiments, the compound is of Formula I-a:or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the compound is of Formula I-a-1 or Formula I-a-2:or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, R3is C1-C6alkyl. In some embodiments, R3is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, R3is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

[0083] In some embodiments, R3is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, R3is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, R3is H or –Me. In some embodiments, R3is H. In some embodiments, R3is –Me.

[0084] In some embodiments, R2is 3-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. In some embodiments, R2is 3-4 membered monocyclic heterocyclyl having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

[0085] In some embodiments, R2is 3 membered monocyclic heterocyclyl having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. In some embodiments, R2is 4 membered monocyclic heterocyclyl having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

[0086] In some embodiments, R2is, wherein R2is optionally substituted with 1-3 instances of R2a. n some embodiments, R2is2wherein R is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is, wherein R2is unsubstituted. In some embodiments, R2is

[0087] In some embodiments, R2is, wherein R2is optionally substituted with 1-3 instances of R2a. n some embodiments, R2is, wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is, wherein R2is unsubstituted. In some embodiments, R2is

[0088] In some embodiments, R2is 8-10 membered bicyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. In some embodiments, R2is 8-10 membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

[0089] In some embodiments, R2is, wherein R2is optionally substituted with 1-3 instances of R2a. In some embodiments, R2is, wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is, wherein R2is unsubstituted. In some embodiments, R2is

[0090] n some embodiments, R2is, wherein R2is optionally substituted with 1- 3 instances of R2a. In some embodiments, R2is2wherein R is optionallysubstituted with 1-2 instances of R2a. In some embodiments, R2is, wherein R2is unsubstituted. In some embodiments, R2is

[0091] In some embodiments, R2is 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

[0092] In some embodiments, R2is 5 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. In some embodiments, R2is 6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

[0093] In some embodiments, R2is 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

[0094] In some embodiments, R2is 5 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. In some embodiments, R2is 6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

[0095] In some embodiments, R2is oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

[0096] In some embodiments, R2is oxadiazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is triazolyl optionally substituted with 1-2 instances of R2a. In some embodiments, R2is tetrazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is thiadiazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is imidazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is pyrazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is oxazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

[0097] In some embodiments, R2is 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1,3,4- thiadazolyl, 1,2,3-thiadazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2H-tetrazolyl, 1,3,4-thiadazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

[0098] In some embodiments, R2is oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1 instance of R2a.

[0099] In some embodiments, R2is oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is unsubstituted.

[0100] In some embodiments, R2is 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1,3,4- thiadazolyl, 1,2,3-thiadazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1 instance of R2a.

[0101] In some embodiments, R2is 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1,3,4- thiadazolyl, 1,2,3-thiadazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is unsubstituted.

[0102] In some embodiments, R2is 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2H- tetrazolyl, 1,3,4-thiadazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1 instance of R2a.

[0103] In some embodiments, R2is 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2H- tetrazolyl, 1,3,4-thiadazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is unsubstituted.

[0104] In some embodiments, R2is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4- triazinyl, or 1,3,5-triazinyl, wherein R2is optionally substituted with 1-2 instances of R2a.

[0105] In some embodiments, R2is pyridinyl, wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is pyrimidinyl, wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is pyrazinyl, wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is pyridazinyl, wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is 1,2,4-triazinyl,wherein R2is optionally substituted with 1-2 instances of R2a. In some embodiments, R2is 1,3,5-triazinyl, wherein R2is optionally substituted with 1-2 instances of R2a.

[0106] In some embodiments, R2is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4- triazinyl, or 1,3,5-triazinyl, wherein R2is optionally substituted with 1 instance of R2a.

[0107] In some embodiments, R2is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4- triazinyl, or 1,3,5-triazinyl, wherein R2is unsubstituted.

[0108] In some embodiments, R2is pyrimidinyl, pyrazinyl, or pyridazinyl, wherein R2is optionally substituted with 1-2 instances of R2a.

[0109] In some embodiments, R2is pyrimidinyl, pyrazinyl, or pyridazinyl, wherein R2is optionally substituted with 1 instance of R2a.

[0110] In some embodiments, R2is pyrimidinyl, pyrazinyl, or pyridazinyl, wherein R2is unsubstituted.

[0111] In some embodiments, Ro1is C1-C6alkyl. In some embodiments, Ro1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, Ro1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

[0112] In some embodiments, Ro1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, Ro1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, Ro1is H, –Me, or –Et. In some embodiments, Ro1is H or –Me. In some embodiments, Ro1is H. In some embodiments, Ro1is –Me.

[0113] In some embodiments, Rn1is C1-C6alkyl. In some embodiments, Rn1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, Rn1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

[0114] In some embodiments, Rn1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, Rn1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, Rn1is H or –Me. In some embodiments, Rn1is H. In some embodiments, Rn1is –Me.

[0115] In some embodiments, Rn2is C1-C6alkyl. In some embodiments, Rn2is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, Rn2is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

[0116] In some embodiments, Rn2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, Rn2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, Rn2is H or –Me. In some embodiments, Rn2is H. In some embodiments, Rn2is –Me.

[0117] In some embodiments, Ro2is C1-C6alkyl. In some embodiments, Ro2is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, Ro2is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

[0118] In some embodiments, Ro2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, Ro2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, Ro2is H, –Me, or –Et. In some embodiments, Ro2is H or –Me. In some embodiments, Ro2is H. In some embodiments, Ro2is –Me.

[0119] In some embodiments, Rn3is C1-C6alkyl. In some embodiments, Rn3is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, Rn3is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

[0120] In some embodiments, Rn3is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, Rn3is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, Rn3is H or –Me. In some embodiments, Rn3is H. In some embodiments, Rn3is –Me.

[0121] In some embodiments, Rn4is C1-C6alkyl. In some embodiments, Rn4is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, Rn4is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

[0122] In some embodiments, Rn4is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, Rn4is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, Rn4is H or –Me. In some embodiments, Rn4is H. In some embodiments, Rn4is –Me.

[0123] In some embodiments, each R2bis independently –F, –Cl, –Br, –OH, –OMe, –OEt, – OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –O-pentyl, –O-hexyl, –NH2, –NHMe, or –NMe2. In some embodiments, each R2bis independently –F, –Cl, –OH, –OMe, –OEt, –OnPr, –OiPr, – OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, or –NMe2. In some embodiments, each R2bis independently –F, –Cl, –OH, –OMe, –NH2, –NHMe, or –NMe2. In some embodiments, each R2bis independently –F, –OH, –OMe, –NH2, –NHMe, or –NMe2.

[0124] In some embodiments, each R2cis independently –F, –Cl, –Br, –OH, –OMe, –OEt, – OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –O-pentyl, –O-hexyl, –NH2, –NHMe, or –NMe2. In some embodiments, each R2cis independently –F, –Cl, –OH, –OMe, –OEt, –OnPr, –OiPr, – OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, or –NMe2. In some embodiments, each R2cis independently –F, –Cl, –OH, –OMe, –NH2, –NHMe, or –NMe2. In some embodiments, each R2cis independently –F, –OH, –OMe, –NH2, –NHMe, or –NMe2.

[0125] In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1.

[0126] In some embodiments, X is –NR2e–.

[0127] In some embodiments, R2eis C1-C6alkyl. In some embodiments, R2eis –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, R2eis –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

[0128] In some embodiments, R2eis H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. In some embodiments, R2eis H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, R2eis H or –Me. In some embodiments, R2eis H. In some embodiments, R2eis –Me.

[0129] In some embodiments, each instance of R2ais independently –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –O-pentyl, –O-hexyl, –NH2, –NHMe, – NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, –hexyl, –CF3, –CHF2, –CH2F, – CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH,– CH2NH2, –CH2NHCH3, –CH2N(CH3)2,

[0130] In some embodiments, each instance of R2ais independently –F, –Cl, –OH, –OMe, – OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3,–CH2OH,–CH2NHCH3, –CH2N(CH3)2,

[0131] In some embodiments, each instance of R2ais independently –F, –Cl, –OH, –OMe, – NH2, –NHMe, –NMe2, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CH2CF3, – CH2OH,–CH2NHCH3, –CH2N(CH3)2,

[0132] In some embodiments, each instance of R2ais independently –F, –OH, –OMe, –NH2, – NHMe, –NMe2, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CH2OH,–CH2NHCH3, –CH2N(CH3)2,

[0133] In some embodiments, R2 is

[0134] In some embodiments, R2is

[0135] In some embodiments, R2is

[0136] In some embodiments, the compound is of Formula I-b-1 or Formula I-b-2:or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0137] In some embodiments, the compound is of Formula I-b-1:or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the compound is of Formula I-b-2:or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the compound is of Formula I-c-1 or Formula I-c-2:or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0140] In some embodiments, the compound is of Formula I-c-1:or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments, the compound is of Formula I-c-2:or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the compound is of Formula I-d-1 or Formula I-d-2:or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0143] In some embodiments, the compound is of Formula I-d-1:or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, the compound is of Formula I-d-2:or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the compound is of Formula I-e-1 or Formula I-e-2:or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0146] In some embodiments, the compound is of Formula I-e-1:or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the compound is of Formula I-e-2:or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the compound is of Formula I-e-3 or Formula I-e-4:or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0149] In some embodiments, the compound is of Formula I-e-3:or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the compound is of Formula I-e-4:or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the compound is of Formula I-e-5 or Formula I-e-6:or a pharmaceutically acceptable salt thereof, or a combination thereof.

[0152] In some embodiments, the compound is of Formula I-e-5:or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the compound is of Formula I-e-6:or a pharmaceutically acceptable salt thereof.

[0154] Disclosed herein, in some embodiments, is a compound shown in Table 1, or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds of the disclosure

[0155] In chemical structures in Table 1, above, and the Examples, below, stereogenic centers are described according to the Enhanced Stereo Representation format (MDL / Biovia, e.g. using labels “or1”, “or2”, “abs”, “&1”).

[0156] Disclosed herein, in some embodiments, is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0157] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

[0158] A method of treating a glucocorticoid receptor-mediated disease or disorder in a subject thereof, comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salt thereof).

[0159] In some embodiments, the glucocorticoid receptor-mediated disease or disorder is an autoimmune disease or an inflammatory disease.

[0160] In some embodiments, the disease or disorder is arthritis, asthma, bursitis, Crohn’s disease, hepatitis, lupus, rhinitis, tendonitis, or ulcerative colitis.

[0161] Disclosed herein, in some embodiments, is a method of modulating a glucocorticoid receptor (GR), comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salt thereof). Pharmaceutical Compositions

[0162] Compounds disclosed herein (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1, and pharmaceutically acceptable salts thereof) are administered alone or as pharmaceutical compositions comprising the compounds disclosed herein and one or more pharmaceutically acceptable excipients.

[0163] Disclosed herein, in some embodiments, is a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipients (i.e., one or more pharmaceutically acceptable excipients).

[0164] The compounds disclosed herein are used in free base forms, salt forms, or solvate forms, or as prodrugs. All forms are within the compositions (e.g., pharmaceutical compositions) described herein. The disclosed compounds, or salts, solvates, or prodrugs thereof, are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The pharmaceutical compositions disclosed herein are be specially formulated for administration in solid or liquid form, including those adapted for the following routes of administration: oral, parenteral, buccal, intramuscular, intraperitoneal, intrapulmonary, intrarectal, intrathecal, intratumoral, intravaginal, intravenous, nasal, ocular, subcutaneous, sublingual, transdermal, transepithelial, or transmucosal.

[0165] Pharmaceutical compositions described herein are preferably formulated for administration to a subject (e.g., a human) in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions comprising compounds disclosed herein (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1, and pharmaceutically acceptable salts thereof) are useful for treating a disease, or symptoms thereof, described herein, such as autoimmune diseases or inflammatory diseases.

[0166] The dosage of the compounds disclosed herein (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1, and pharmaceutically acceptable salts thereof) in the pharmaceutical compositions, as well as the amount of the pharmaceutical composition administered to a subject, can vary depending on factors such characteristics of the subject (e.g., age, health, weight, and gender); the nature and extent of the symptoms; the frequency of treatment; the mode of administration of the pharmaceutical compositions; the solubility of the compounds in the pharmaceutical compositions; the potency and activity of the compounds; and the pharmacodynamic properties of the compound. The dosage of the compounds disclosed here (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1, and pharmaceutically acceptable salts thereof) or compositions comprising compounds disclosed herein are varied to achieve a desired therapeutic response for a particular subject, composition, or mode of administration, without being toxic to the subject.

[0167] The present disclosure also provides kits including pharmaceutical compositions comprising compounds disclosed herein (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1, and pharmaceutically acceptable salts thereof) and package inserts with instructions to perform any of the methods described herein.

[0168] Disclosed herein, in some embodiments, is a process for providing a pharmaceutical composition comprising a compound disclosed herein (e.g., e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof). Methods of Use and Treatment

[0169] Compounds disclosed herein (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1, and pharmaceutically acceptable salts thereof) are useful for treating diseases or disorders. Compounds disclosed herein (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1, and pharmaceutically acceptable salts thereof) are useful for modulating glucocorticoid receptors (e.g., reduces the occurrence of glucocorticoid receptor binding to glucocorticoid (e.g., a glucocorticoid receptor antagonist) or activates a glucocorticoid receptor (e.g., glucocorticoid receptor agonist)). In some embodiments, the compounds are useful for treating glucocorticoid receptor-mediated diseases, such as autoimmune diseases, inflammatory diseases, or cancers.

[0170] Disclosed herein, in some embodiments, is a method of modulating a glucocorticoid receptor (GR), comprising administering to the subject an effective amount of a compound disclosed herein (e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof) or a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipient. In some embodiments, the compound is a glucocorticoid receptor agonist. In some embodiments, the compound is useful for treating a disease or disorder (e.g., an autoimmune disease, an inflammatory disease, or a cancer).

[0171] Disclosed herein, in some embodiments, is a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of acompound disclosed herein (e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof) or a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipient. In some embodiments, the compounds are useful for treating autoimmune diseases, inflammatory diseases, or cancers.

[0172] Disclosed herein, in some embodiments, is a method of treating a glucocorticoid receptor-mediated disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein (e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof) or a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipient. In some embodiments, the glucocorticoid receptor-mediated disease is an autoimmune disease, an inflammatory disease, or a cancer. In some embodiments, the glucocorticoid receptor- mediated disease is an autoimmune disease. In some embodiments, the glucocorticoid receptor- mediated disease is an inflammatory disease. In some embodiments, the glucocorticoid receptor-mediated disease is a cancer.

[0173] Disclosed herein, in some embodiments, is a compound disclosed herein (e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof) or a composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipient), in the manufacture of a medicament for the treatment of a disease or disorder. In some embodiments, the glucocorticoid receptor- mediated disease or disorder is an autoimmune disease, an inflammatory disease, or a cancer. In some embodiments, the glucocorticoid receptor-mediated disease or disorder is anautoimmune disease. In some embodiments, the glucocorticoid receptor-mediated disease or disorder is an inflammatory disease. In some embodiments, the glucocorticoid receptor- mediated disease or disorder is a cancer.

[0174] Disclosed herein, in some embodiments, is a compound disclosed herein (e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof) or a composition disclosed herein (e.g., a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound that modulates a glucocorticoid receptor, e.g., a compound described herein such as a compound of Formula I or a subformula thereof or a compound of Table 1, or a pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipient), in the manufacture of a medicament for the treatment of a glucocorticoid receptor-mediated disease. In some embodiments, the glucocorticoid receptor-mediated disease or disorder is an autoimmune disease, an inflammatory disease, or a cancer. In some embodiments, the glucocorticoid receptor-mediated disease or disorder is an autoimmune disease. In some embodiments, the glucocorticoid receptor-mediated disease or disorder is an inflammatory disease. In some embodiments, the glucocorticoid receptor-mediated disease or disorder is a cancer.

[0175] The compounds disclosed herein (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1, and pharmaceutically acceptable salts thereof) may be used in the form of free bases, salts, solvates, or prodrugs. All forms are within the methods described herein.

[0176] In some embodiments, the disease or disorder is acute lung injury, allergic bronchopulmonary aspergillosis, arthritis, asthma, bronchitis, bursitis, chronic obstructive pulmonary disease, Crohn’s disease, Cushing’s syndrome, eczema, haploinsuffiency of A20, hepatitis, lupus, myositis, muscular dystrophy, pneumonia, rhinitis, sarcoidosis, Sjogren’s syndrome, sinusitis, tendonitis, ulcerative colitis, or uveitis. In some embodiments, the disease or disorder is arthritis, asthma, bursitis, Crohn’s disease, hepatitis, lupus, rhinitis, tendonitis, or ulcerative colitis.

[0177] In some embodiments, the autoimmune disease or inflammatory disease is acute lung injury, allergic bronchopulmonary aspergillosis, arthritis, asthma, bronchitis, bursitis, chronic obstructive pulmonary disease, Crohn’s disease, Cushing’s syndrome, eczema,haploinsuffiency of A20, hepatitis, lupus, myositis, muscular dystrophy, pneumonia, rhinitis, sarcoidosis, Sjogren’s syndrome, sinusitis, tendonitis, ulcerative colitis, or uveitis.

[0178] In some embodiments, the disease or disorder is acute lung injury. In some embodiments, the disease or disorder is allergic bronchopulmonary aspergillosis. In some embodiments, the disease or disorder is arthritis. In some embodiments, the disease or disorder is asthma. In some embodiments, the disease or disorder is bronchitis. In some embodiments, the disease or disorder is bursitis. In some embodiments, the disease or disorder is chronic obstructive pulmonary disease. In some embodiments, the disease or disorder is Crohn’s disease. In some embodiments, the disease or disorder is Cushing’s syndrome. In some embodiments, the disease or disorder is eczema. In some embodiments, the disease or disorder is haploinsuffiency of A20. In some embodiments, the disease or disorder is hepatitis. In some embodiments, the disease or disorder is lupus. In some embodiments, the disease or disorder is myositis. In some embodiments, the disease or disorder is muscular dystrophy. In some embodiments, the disease or disorder is pneumonia. In some embodiments, the disease or disorder is rhinitis. In some embodiments, the disease or disorder is sarcoidosis. In some embodiments, the disease or disorder is Sjogren’s syndrome. In some embodiments, the disease or disorder is sinusitis. In some embodiments, the disease or disorder is tendonitis. In some embodiments, the disease or disorder is ulcerative colitis. In some embodiments, the disease or disorder is uveitis. Selected Embodiments Embodiment 1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: R1is C1-C6alkyl; R2is 3-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10 membered bicyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 memberedheteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a; each instance of R2ais independently halogen, –ORo1, –NRn1Rn2, C1-C6alkyl optionally substituted with 1-4 instances of R2b, C1-C6haloalkyl,wherein m is 0, 1, 2, or 3; X is –O– or –NR2e–; each R2bis independently halogen, –ORo2, or –NRn3Rn4; each R2cis independently halogen, –ORo2, or –NRn3Rn4; each of R2d, R2e, Ro1, Ro2, Rn1, Rn2, Rn3, and Rn4is independently H or C1-C6alkyl; and R3is H or C1-6alkyl. Embodiment 2. The compound of embodiment 1, wherein R1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. Embodiment 3. The compound of embodiment 1 or 2, wherein R1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 4. The compound of any one of embodiments 1 to 3, wherein R1is –Me. Embodiment 5. The compound of any one of embodiments 1 to 4, wherein the compound is of Formula I-a:or a pharmaceutically acceptable salt thereof. Embodiment 6. The compound of any one of embodiments 1 to 5, wherein the compound is of Formula I-a-1 or Formula I-a-2:or a pharmaceutically acceptable salt thereof. Embodiment 7. The compound of any one of embodiments 1 to 6, wherein R3is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. Embodiment 8. The compound of any one of embodiments 1 to 7, wherein R3is H or –Me. Embodiment 9. The compound of any one of embodiments 1 to 8, wherein R3is H. Embodiment 10. The compound of any one of embodiments 1 to 8, wherein R3is –Me. Embodiment 11. The compound of any one of embodiments 1 to 10, wherein R2is 3-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 12. The compound of any one of embodiments 1 to 11, wherein R2is 3-4 membered monocyclic heterocyclyl having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 13. The compound of any one of embodiments 1 to 12, wherein R2is 3 membered monocyclic heterocyclyl having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 14. The compound of any one of embodiments 1 to 12, wherein R2is 4 membered monocyclic heterocyclyl having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.Embodiment 15. The compound of any one of embodiments 1 to 12 and 14, wherein R2is, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 16. The compound of any one of embodiments 1 to 12, 14, and 15, wherein R2isEmbodiment 17. The compound of any one of embodiments 1 to 12 and 14 to 16, wherein R2isEmbodiment 18. The compound of any one of embodiments 1 to 11, wherein R2is 8-10 membered bicyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 19. The compound of any one of embodiments 1 to 11 and 18, wherein R2is 8-10 membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 20. The compound of any one of embodiments 1 to 11, 18, and 19, wherein R2is, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 21. The compound of any one of embodiments 1 to 11 and 18 to 20, wherein R2isEmbodiment 22. The compound of any one of embodiments 1 to 11 and 18 to 21, wherein R2isEmbodiment 23. The compound of any one of embodiments 1 to 11, wherein R2is 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.Embodiment 24. The compound of any one of embodiments 1 to 11 and 23, wherein R2is 5 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 25. The compound of any one of embodiments 1 to 11 and 23, wherein R2is 6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 26. The compound of any one of embodiments 1 to 11, 23, and 24, wherein R2is oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 27. The compound of any one of embodiments 1 to 11, 23, 24, and 26, wherein R2is oxadiazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 28. The compound of any one of embodiments 1 to 11, 23, 24, and 26, wherein R2is triazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 29. The compound of any one of embodiments 1 to 11, 23, 24, and 26, wherein R2is tetrazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 30. The compound of any one of embodiments 1 to 11, 23, 24, and 26, wherein R2is thiadiazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 31. The compound of any one of embodiments 1 to 11, 23, 24, and 26, wherein R2is imidazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 32. The compound of any one of embodiments 1 to 11, 23, 24, and 26, wherein R2is pyrazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 33. The compound of any one of embodiments 1 to 11, 23, 24, and 26, wherein R2is oxazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 34. The compound of any one of embodiments 1 to 11, 23, 24, and 26, wherein R2is 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1,3,4-thiadazolyl, 1,2,3- thiadazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.Embodiment 35. The compound of any one of embodiments 1 to 11, 23, 24, 26, and 34, wherein R2is 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2H-tetrazolyl, 1,3,4- thiadazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 36. The compound of any one of embodiments 1 to 11, 23, and 24, wherein R2is oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1 instance of R2a. Embodiment 37. The compound of any one of embodiments 1 to 11, 23, and 24, wherein R2is oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is unsubstituted. Embodiment 38. The compound of any one of embodiments 1 to 11, 23, 24, and 36, wherein R2is 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1,3,4-thiadazolyl, 1,2,3- thiadazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1 instance of R2a. Embodiment 39. The compound of any one of embodiments 1 to 11, 23, 24, and 37, wherein R2is 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1,3,4-thiadazolyl, 1,2,3- thiadazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is unsubstituted. Embodiment 40. The compound of any one of embodiments 1 to 11, 23, 24, 36, and 38, wherein R2is 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2H-tetrazolyl, 1,3,4- thiadazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1 instance of R2a. Embodiment 41. The compound of any one of embodiments 1 to 11, 23, 24, 36, and 39, wherein R2is 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2H-tetrazolyl, 1,3,4- thiadazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is unsubstituted.Embodiment 42. The compound of any one of embodiments 1 to 11, 23, and 25, wherein R2is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 43. The compound of any one of embodiments 1 to 11, 23, 25, and 42, wherein R2is pyridinyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 44. The compound of any one of embodiments 1 to 11, 23, 25, and 42, wherein R2is pyrimidinyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 45. The compound of any one of embodiments 1 to 11, 23, 25, and 42, wherein R2is pyrazinyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 46. The compound of any one of embodiments 1 to 11, 23, 25, and 42, wherein R2is pyridazinyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 47. The compound of any one of embodiments 1 to 11, 23, 25, and 42, wherein R2is 1,2,4-triazinyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 48. The compound of any one of embodiments 1 to 11, 23, 25, and 42, wherein R2is 1,3,5-triazinyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 49. The compound of any one of embodiments 1 to 11, 23, 25, and 42, wherein R2is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, or 1,3,5- triazinyl, wherein R2is optionally substituted with 1 instance of R2a. Embodiment 50. The compound of any one of embodiments 1 to 11, 23, 25, and 42, wherein R2is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, or 1,3,5- triazinyl, wherein R2is unsubstituted. Embodiment 51. The compound of any one of embodiments 1 to 11, 23, 25, and 42, wherein R2is pyrimidinyl, pyrazinyl, or pyridazinyl, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 52. The compound of any one of embodiments 1 to 11, 23, 25, and 42, wherein R2is pyrimidinyl, pyrazinyl, or pyridazinyl, wherein R2is optionally substituted with 1 instance of R2a.Embodiment 53. The compound of any one of embodiments 1 to 11, 23, 25, and 42, wherein R2is pyrimidinyl, pyrazinyl, or pyridazinyl, wherein R2is unsubstituted. Embodiment 54. The compound of any one of embodiments 1 to 53, wherein Ro1is C1-C6alkyl. Embodiment 55. The compound of any one of embodiments 1 to 54, wherein Ro1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. Embodiment 56. The compound of any one of embodiments 1 to 55, wherein Ro1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 57. The compound of any one of embodiments 1 to 53, wherein Ro1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 58. The compound of any one of embodiments 1 to 53, wherein Ro1is H, –Me, or –Et. Embodiment 59. The compound of any one of embodiments 1 to 53, wherein Ro1is H or –Me. Embodiment 60. The compound of any one of embodiments 1 to 53, wherein Ro1is H. Embodiment 61. The compound of any one of embodiments 1 to 53, wherein Ro1is –Me. Embodiment 62. The compound of any one of embodiments 1 to 61, wherein Rn1is C1-C6alkyl. Embodiment 63. The compound of any one of embodiments 1 to 62, wherein Rn1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. Embodiment 64. The compound of any one of embodiments 1 to 63, wherein Rn1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 65. The compound of any one of embodiments 1 to 61, wherein Rn1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.Embodiment 66. The compound of any one of embodiments 1 to 61, wherein Rn1is H or –Me. Embodiment 67. The compound of any one of embodiments 1 to 61, wherein Rn1is H. Embodiment 68. The compound of any one of embodiments 1 to 61, wherein Rn1is –Me. Embodiment 69. The compound of any one of embodiments 1 to 71, wherein Rn2is C1-C6alkyl. Embodiment 70. The compound of any one of embodiments 1 to 69, wherein Rn2is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. Embodiment 71. The compound of any one of embodiments 1 to 70, wherein Rn2is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 72. The compound of any one of embodiments 1 to 68, wherein Rn2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 73. The compound of any one of embodiments 1 to 68, wherein Rn2is H or –Me. Embodiment 74. The compound of any one of embodiments 1 to 68, wherein Rn2is H Embodiment 75. The compound of any one of embodiments 1 to 68, wherein Rn2is –Me. Embodiment 76. The compound of any one of embodiments 1 to 75, wherein Ro2is C1-C6alkyl. Embodiment 77. The compound of any one of embodiments 1 to 76, wherein Ro2is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. Embodiment 78. The compound of any one of embodiments 1 to 77, wherein Ro2is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.Embodiment 79. The compound of any one of embodiments 1 to 75, wherein Ro2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 80. The compound of any one of embodiments 1 to 75, wherein Ro2is H, –Me, or –Et. Embodiment 81. The compound of any one of embodiments 1 to 75, wherein Ro2is H or –Me. Embodiment 82. The compound of any one of embodiments 1 to 75, wherein Ro2is H. Embodiment 83. The compound of any one of embodiments 1 to 75, wherein Ro2is –Me. Embodiment 84. The compound of any one of embodiments 1 to 83, wherein Rn3is C1-C6alkyl. Embodiment 85. The compound of any one of embodiments 1 to 84, wherein Rn3is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. Embodiment 86. The compound of any one of embodiments 1 to 85, wherein Rn3is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 87. The compound of any one of embodiments 1 to 83, wherein Rn3is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 88. The compound of any one of embodiments 1 to 83, wherein Rn3is H or –Me. Embodiment 89. The compound of any one of embodiments 1 to 83, wherein Rn3is H. Embodiment 90. The compound of any one of embodiments 1 to 83, wherein Rn3is–Me. Embodiment 91. The compound of any one of embodiments 1 to 90, wherein Rn4is C1-C6alkyl.Embodiment 92. The compound of any one of embodiments 1 to 91, wherein Rn4is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. Embodiment 93. The compound of any one of embodiments 1 to 92, wherein Rn4is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 94. The compound of any one of embodiments 1 to 90, wherein Rn4is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 95. The compound of any one of embodiments 1 to 90, wherein Rn4is H or –Me. Embodiment 96. The compound of any one of embodiments 1 to 90, wherein Rn4is H. Embodiment 97. The compound of any one of embodiments 1 to 90, wherein Rn4is –Me. Embodiment 98. The compound of any one of embodiments 1 to 97, wherein each R2bis independently –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, – OtBu, –O-pentyl, –O-hexyl, –NH2, –NHMe, or –NMe2. Embodiment 99. The compound of any one of embodiments 1 to 98, wherein each R2bis independently –F, –Cl, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, or –NMe2. Embodiment 100. The compound of any one of embodiments 1 to 99, wherein each R2bis independently –F, –Cl, –OH, –OMe, –NH2, –NHMe, or –NMe2. Embodiment 101. The compound of any one of embodiments 1 to 100, wherein each R2bis independently –F, –OH, –OMe, –NH2, –NHMe, or –NMe2. Embodiment 102. The compound of any one of embodiments 1 to 104, wherein each R2cis independently –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, – OsBu, –OtBu, –O-pentyl, –O-hexyl, –NH2, –NHMe, or –NMe2.Embodiment 103. The compound of any one of embodiments 1 to 105, wherein each R2cis independently –F, –Cl, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, – OtBu, –NH2, –NHMe, or –NMe2. Embodiment 104. The compound of any one of embodiments 1 to 106, wherein each R2cis independently –F, –Cl, –OH, –OMe, –NH2, –NHMe, or –NMe2. Embodiment 105. The compound of any one of embodiments 1 to 107 wherein each R2cis independently –F, –OH, –OMe, –NH2, –NHMe, or –NMe2. Embodiment 106. The compound of any one of embodiments 1 to 105, wherein m is 0 or 1. Embodiment 107. The compound of any one of embodiments 1 to 106, wherein m is 1. Embodiment 108. The compound of any one of embodiments 1 to 107, wherein X is –NR2e–. Embodiment 109. The compound of any one of embodiments 1 to 108, wherein R2eis C1-C6alkyl. Embodiment 110. The compound of any one of embodiments 1 to 109, wherein R2eis –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. Embodiment 111. The compound of any one of embodiments 1 to 110, wherein R2eis –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 112. The compound of any one of embodiments 1 to 108, R2eis H, – Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 113. The compound of any one of embodiments 1 to 108, wherein R2eis H or –Me. Embodiment 114. The compound of any one of embodiments 1 to 108, wherein R2eis H. Embodiment 115. The compound of any one of embodiments 1 to 108, wherein R2eis –Me.Embodiment 116. The compound of any one of embodiments 1 to 115, wherein each instance of R2ais independently –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –O-pentyl, –O-hexyl, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, –hexyl, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH,–CH2NH2, –CH2NHCH3, –CH2N(CH3)2,Embodiment 117. The compound of any one of embodiments 1 to 116, wherein each instance of R2ais independently –F, –Cl, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH,–CH2NHCH3, –CH2N(CH3)2,Embodiment 118. The compound of any one of embodiments 1 to 117, wherein each instance of R2ais independently –F, –Cl, –OH, –OMe, –NH2, –NHMe, –NMe2, –Me, –Et, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CH2CF3, –CH2OH,–CH2NHCH3, –CH2N(CH3)2,Embodiment 119. The compound of any one of embodiments 1 to 118, wherein each instance of R2ais independently –F, –OH, –OMe, –NH2, –NHMe, –NMe2, –Me, –Et, – CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CH2OH,– CH2NHCH3, –CH2N(CH3)2,Embodiment 120. The compound of any one of embodiments 1 to 119, wherein R2isEmbodiment 121. The compound of any one of embodiments 1 to 119, wherein R2Embodiment 122. The compound of any one of embodiments 1 to 119, wherein R2isEmbodiment 123. The compound of any one of embodiments 1 to 122, wherein the compound is of Formula I-b-1 or Formula I-b-2:or a pharmaceutically acceptable salt thereof, or a combination thereof. Embodiment 124. The compound of any one of embodiments 1 to 122, wherein the compound is of Formula I-c-1 or Formula I-c-2:or a pharmaceutically acceptable salt thereof, or a combination thereof.. Embodiment 125. The compound of any one of embodiments 1 to 122, wherein the compound is of Formula I-d-1 or Formula I-d-2:or a pharmaceutically acceptable salt thereof, or a combination thereof.. Embodiment 126. The compound of any one of embodiments 1 to 122, wherein the compound is of Formula I-e-1 or Formula I-e-2:or a pharmaceutically acceptable salt thereof, or a combination thereof.. Embodiment 127. The compound of any one of embodiments 1 to 122, wherein the compound is of Formula I-e-3 or Formula I-e-4:or a pharmaceutically acceptable salt thereof, or a combination thereof.. Embodiment 128. The compound of any one of embodiments 1 to 122, wherein the compound is of Formula I-e-5 or Formula I-e-6:or a pharmaceutically acceptable salt thereof. Embodiment 129. The compound of any one of embodiments 1 to 128, wherein the compound is a compound of Table 1, or a pharmaceutically acceptable salt thereof. Embodiment 130. A compound of Table 1, or a pharmaceutically acceptable salt thereof. Embodiment 131. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 130, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof. Embodiment 132. A method of treating a glucocorticoid receptor-mediated disease or disorder in a subject thereof, comprising administering to the subject an effective amount of a compound of any one of embodiments 1 to 130, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition of embodiment 131. Embodiment 133. The method of embodiment 132, wherein the glucocorticoid receptor-mediated disease or disorder is an autoimmune disease or an inflammatory disease. Embodiment 134. The method of embodiment 132 or 133, wherein the disease or disorder is arthritis, asthma, bursitis, Crohn’s disease, hepatitis, lupus, rhinitis, tendonitis, or ulcerative colitis. Embodiment 135. A method of modulating a glucocorticoid receptor (GR), comprising administering to the subject an effective amount of a compound of any one of embodiments 1 to 130, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition of embodiment 131.EXAMPLES

[0179] The disclosure is further illustrated by the following examples, which serve as exemplary modes of making and practicing the compounds, compositions, and methods of the disclosure. The scope of the disclosure is not to be construed as limited to specific embodiments described in these examples, which are illustrative only.

[0180] In the synthetic procedures described below, it is understood that reaction conditions (e.g., atmosphere, duration, solvent or solvent systems, temperature, and workup protocols) are selected from standard conditions for that reaction, unless otherwise indicated. Some of the starting materials and reagents used in the synthetic procedures described below are commercially available or are readily prepared by standard procedures from known materials. Additional compounds not specifically exemplified below may be synthesized using the synthetic procedures described below (e.g., in combination with other starting materials or reagents).

[0181] Stereochemical assignments described herein are tentatively assigned. Abbreviations

[0182] 1H NMR spectra were recorded on a Bruker instrument operating at 400 MHz.1HNMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone or (CD3)2COas solvent and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)3CO: 2.05) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintuplet), sx (sextuplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).

[0183] LCMS-1: LC-MS spectrometer (Agilent 1200) Detector: MWD (190-400 nm), Mass detector: 6110 SQ Mobile phase: A: water with 0.01% TFA, B: acetonitrile with 0.01% TFA Column: SunFireC18, 4.6x50 mm, 3.5 um Gradient method: Flow: 2 mL / min Time (min) A (%) B (%).

[0184] LCMS-2: LC-MS spectrometer (Agilent 1200) Detector: MWD (190-400 nm), Mass detector: G6110 SQ Mobile phase: A: water with 10 mmol NH4HCO3, B: acetonitrile Column: XBridge C18, 4.6x50 mm, 3.5 um Gradient method: Flow: 1.8 mL / min Time (min) A (%) B (%)

[0185] LCMS-3: LC-MS spectrometer (Agilent 1260 Infinity II) Detector: MWD (190-400 nm), Mass detector: G6125C SQ Mobile phase: A: water with 10 mM NH4HCO3, B:acetonitrile Column: Xbridge C18, 4.6x50 mm, 3.5 um Gradient method: Flow: 1.7 mL / min Time (min) A (%) B (%)

[0186] Preparative HPLC-1 was conducted on a column (250 x 21.2 mm ID, 10 pm, Boston Prep C18) at a flow rate of 30 mL / min, A:water(10 mM NH4HCO3) B:acetonitrile injection volume 2 mL, at room temperature and UV Detection at 214 nm and 254 nm.

[0187] Preparative HPLC-2 was conducted on a column (150 x 30 mm ID, 5 pm, Xtimate Prep C18) at a flow rate of 30 mL / min, A:water(0.2%FA) B:acetonitrile injection volume 2 mL, at room temperature and UV Detection at 214 nm and 254 nm.

[0188] Unless otherwise stated, all the starting materials and reagents used in this application are commercially available.

[0189] “rac-” nomenclature refers to a racemic mixture. For example, “rac-(2R,10S,14bS)...” refers to a mixture of (2R,10S,14bS)-compound and its enantiomer (2S,10R,14bR)-compound.

[0190] The compounds described in examples 2-4 were prepared in racemic form and separated into the two enantiomers via chiral chromatography. The active enantiomers are noted here as having relative S,S,S or R,R,R configurations, such as “rel-(2S,10S,14bS)-10- methyl-2-(oxetan-3-ylamino)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8- carbonitrile.”

[0191] The compounds described in examples 1, and 5-16, and in tables 2-7 were prepared from enantiopure (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido [1,2-a]azepine-8-carbonitrile, obtained in step 13 of Example 1 via chiral chromatographic separation of the corresponding racemate. To infer the absolute configuration of the amine and all compounds derived from it, the amine and its antipode were used to prepare samples of ORG-214007-0 and its antipode (Plos One 2012, 7, 11:e48385, 2012, WO 2007 / 025938). The active enantiomer was presumed to be ORG-214007-0, andtherefore inferred to have the S,S,S configuration, as noted in the reference. Therefore, the enantiopure amine that afforded ORG-214007-0 and all compounds in the above examples and tables were tentatively assigned S,S,S absolute configurations.Example 1. Synthesis of (2S,10S,14bS)-10-methyl-2-(pyrimidin-2-ylamino)- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 1)Step 1: 5H-dibenzo[b,e]azepine-6,11-dione

[0192] A mixture of sulfuric acid (48 mL) and dichloromethane (140 mL) was cooled to 0 ºC, anthracene-9,10-dione (10.0 g, 48.0 mmol) was added thereto, then sodium azide (3.7 g, 57.0 mmol) was added in small portions over 1 hour at 0-5 ºC. The reaction mixture was stirredovernight. Two batches of the same reaction mixture were poured into water. The formed precipitate was collected by filtration, washed with saturated sodium carbonate aqueous, water and lyophilized under vacuum to afford 5H-dibenzo[b,e]azepine-6,11-dione (20.5 g, 95.7%) as grey solid. LCMS-2: MS m / z [M+H]+224.1. Step 2: 11-hydroxy-11-methyl-5,11-dihydro-6H-dibenzo[b,e]azepin-6-one

[0193] Methylmagnesium iodide (3.0 M in ethyl ether, 22.4 mL, 67.2 mmol) was added dropwise to a mixture of 5H-dibenzo[b,e]azepine-6,11-dione (5.0 g, 22.4 mmol) and toluene (150 mL) under nitrogen at room temperature. After the addition, the mixture was stirred at 100 ºC for 6 hours. Six batches of this reaction mixture were quenched with saturated ammonium chloride aqueous. The formed precipitate was collected by filtration, triturated with ethyl acetate (100 mL) and dried under vacuum to afford 11-hydroxy-11-methyl-5,11-dihydro- 6H-dibenzo[b,e]azepin-6-one (25.0 g, 77.8%) as yellow solid. LCMS-2: MS m / z [M+H]+240.1. Step 3: 11-methyl-6,11-dihydro-5H-dibenzo[b,e]azepine

[0194] 11-Hydroxy-11-methyl-5,11-dihydro-6H-dibenzo[b,e]azepin-6-one (10.0 g, 41.8 mmol) was added in portions to a suspension of lithium aluminium hydride (4.8 g, 125.4 mmol) in 1,4-dioxane (200 mL) at 100 ºC under nitrogen. After the addition, the mixture was stirred at 100 ºC for 3 hours. Two batches of the mixture were quenched with sodium sulfate decahydrate and ethyl acetate. The solid was filtered off. The filtrate was dried over sodium sulfate, filtered and concentrated. The crude product was purified by normal phase chromatography (120 g SiO2-column; eluent petroleum ether / ethyl acetate (100:0 to 80:20)). Product-containing fractions were combined and the solvent was removed by evaporation to give 11-methyl-6,11-dihydro-5H-dibenzo[b,e]azepine (13.6 g, 77.7%) as yellow solid. LCMS- 2: MS m / z [M+H]+210.2. Step 4: 2-bromo-11-methyl-6,11-dihydro-5H-dibenzo[b,e]azepine

[0195] N-Bromosuccinimide (5.8 g, 32.5 mmol) in acetone (80 mL) was added dropwise to a solution of 11-methyl-6,11-dihydro-5H-dibenzo[b,e]azepine (6.8 g, 32.5 mmol) in acetone (150 mL) at 0 ºC. After the addition, the mixture was stirred for another 2.5 hours. Two batches of this mixture were quenched with saturated sodium bicarbonate aqueous, extracted with ethyl acetate (250 mL x 2). The combined organic phase was concentrated. The crude product was purified by normal phase chromatography (120 g SiO2-column; eluent petroleum ether / ethyl acetate (100:0 to 80:20)). Product-containing fractions were combined and the solvent was removed by evaporation to give 2-bromo-11-methyl-6,11-dihydro-5H-dibenzo[b,e]azepine (18.0 g, 99.2%) as yellow solid. LCMS-2: MS m / z [M+H]+288.0 / 290.0. Step 5: 2-bromo-11-methyl-11H-dibenzo[b,e]azepine

[0196] A mixture of 2-bromo-11-methyl-6,11-dihydro-5H-dibenzo[b,e]azepine (17.0 g, 59.2 mmol), manganese dioxide (51.5 g, 592.0 mmol) and dichloromethane (400 mL) was stirred at room temperature for 16 hours. Manganese dioxide was filtered off. The filtrate was concentrated. The crude product was purified by normal phase chromatography (120 g SiO2- column; eluent petroleum ether / dichloromethane (100:0 to 50:50)). Product-containing fractions were combined and the solvent was removed by evaporation to give 2-bromo-11- methyl-11H-dibenzo[b,e]azepine (15.1 g, 89.3%) as off-white solid.

[0197] 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J = 65.2 Hz, 1H), 7.76 – 7.03 (m, 7H), 3.74 (dd, J = 150.3, 7.2 Hz, 1H), 1.81 – 1.27 (m, 3H). LCMS-2: MS m / z [M+H]+286.0 / 288.0.Step 6: 8-bromo-10-methyl-10,14b-dihydrodibenzo[c,f]pyrido[1,2-a]azepin-2(1H)-one

[0198] To a solution of 2-bromo-11-methyl-11H-dibenzo[b,e]azepine (13.0 g, 45.4 mmol) in toluene (300 mL) was added ((4-methoxybuta-1,3-dien-2-yl)oxy)trimethylsilane (27.4 g, 159.0 mmol) and ytterbium(III) trifluoromethanesulfonate hydrate (5.6 g, 9.1 mmol). The mixture was stirred at 40 ºC for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution (500 mL) and ethyl acetate (300 mL). The precipitate was filtered to as afford the crude product (16.4 g), which was used for next step reaction without further purification. LCMS-2: MS m / z [M+H]+354.1 / 356.1. Step 7: rac-(2R,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-ol

[0199] To a solution of 8-bromo-10-methyl-10,14b-dihydrodibenzo[c,f]pyrido[1,2-a]azepin- 2(1H)-one (8.1 g, 22.9 mmol) in ethanol (300 mL) was added sodium borohydride (6.5 g, 171.5 mmol) at 0 ºC. The mixture was stirred at room temperature for 16 hours. Two batches of this mixture were quenched with acetone and the mixture was concentrated under reduced pressure. The residue was treated with saturated ammonium chloride solution and extracted with ethyl acetate (500 mL×3). The organic phase was washed with brine (500 mL), dried over sodium sulfate, and concentrated to give 15.8 g crude product, which was used for the next step reaction without further purification. LCMS-2: MS m / z [M+H]+358.1 / 360.1.Step 8: rac-(2R,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl methanesulfonate

[0200] To a solution of rac-(2R,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-ol (15.6 g, 43.5 mmol) in dichloromethane (250 mL) was added triethylamine (8.8 g, 87.1 mmol) and methanesulfonyl chloride (7.5 g, 65.3 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted with dichloromethane (500 mL×3). The organic phase was washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated. The residue was slurried with petroleum ether / ethyl acetate (5 / 1) to give 14.3 g product. LCMS-2: MS m / z [M+H]+436.1 / 438.1. Step 9: rac-(2R,10S,14bS)-2-azido-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine

[0201] To a solution of rac-(2R,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl methanesulfonate (12.0 g, 27.5 mmol) in N,N- dimethylformamide (120 mL) was added sodium azide (2.7 g, 41.3 mmol). The mixture was stirred at 80 ºC for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (300 mL×3). The organic phase was washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated to give 13.5 g crude product, which was used for the next step reaction without further purification. LCMS-2: MS m / z [M+H]+383.0 / 385.0.Step 10: rac-(2R,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-amine

[0202] To a solution of rac-(2R,10S,14bS)-2-azido-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2 -a]azepine (12.0 g, 31.3 mmol) in tetrahydrofuran (200 mL) and water (7.5 mL) was added triphenylphosphine (16.4 g, 62.6 mmol). The mixture was stirred at 80 ºC for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by normal phase chromatography (120 g SiO2-column; eluent dichloromethane: methanol (100:0 to 98:2)). Product-containing fractions were combined and the solvent was removed by evaporation to give rac-(2R,10S,14bS)-8-bromo-10-methyl- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-amine (8.0 g, 72%). LCMS-1: MS m / z [M+H]+357.2 / 359.2. Step 11: rac-N-((2S,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)-2,2,2-trifluoroacetamide

[0203] To a solution of rac-(2R,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-amine (0.75 g, 2.1 mmol) in tetrahydrofuran (40 mL) was added trifluoroacetic anhydride (0.62 g, 3.2 mmol) slowly, followed by trimethylamine (0.64 g, 6.3 mmol) at room temperature. Then the reaction mixture was stirred at room temperature for 5 hours. The reaction was quenched with water (40 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by normal phase chromatography (25 g SiO2-column; eluent petroleum ether / ethyl acetate (100:0 to 70:30)). Product-containing fractions were combined and the solvent was removed by evaporation to give rac-(2R,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)-2,2,2-trifluoroacetamide (0.6 g, 63 %) as light yellow solid. LCMS-2: MS m / z [M+H]+453.1 / 455.1. Step 12: rac-N-((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido [1,2-a]azepin-2-yl)-2,2,2-trifluoroacetamide N

[0204] To a solution of rac-(2R,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)-2,2,2-trifluoroacetamide (0.6 g, 1.3 mmol) in 1-methyl-2-pyrrolidinone (8 mL) was added copper (I) cyanide (0.59 g, 6.6 mmol), then the reaction mixture was stirred at 200 °C for 3 hours under nitrogen. The reaction mixture was cooled to room temperature, then treated with ammonia aqueous solution (5 mL) and water (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3), the combined organic phase was washed with brine (20 mL), dried over sodium sulfate and concentrated to afford crude rac-N-((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2- a]azepin-2-yl)-2,2,2-trifluoroacetamide (0.5 g, 94.9%) as dark oil, which was directly used for the next step reaction without further purification. LCMS-2: MS m / z [M+H]+400.1. Step 13: (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido [1,2- a]azepine-8-carbonitrile

[0205] To a stirred solution of rac-N-((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido [1,2-a]azepin-2-yl)-2,2,2-trifluoroacetamide (0.5 g, 1.25 mmol) in ethanol (30 mL) was added sodium hydroxide (2 N aqueous solution, 6.5 mL, 12.5 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was diluted with water (20 mL), extracted with dichloromethane (20 mL × 3). The combined organic phase was washed with brine (30 mL), dried over sodiumsulfate, filtered, and concentrated. The crude product was purified by normal phase chromatography (12 g SiO2-column; eluent dichloromethane / methanol (100:0 to 90:10)). Product-containing fractions were combined and the solvent was removed by evaporation to give rac-(2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2- a]azepine-8-carbonitrile (0.25 g, 66%) as yellow solid. LCMS-2: MS m / z [M+H]+ 304.2.

[0206] The product was then separated by chiral HPLC (Instrument: SFC-150 (Waters); Column: OD 25*250mm, 10um (Daicel); Column temperature: 35 ºC; Mobile phase: CO2 / MeOH [0.2% NH3(7M in MeOH)] = 70 / 30; Flow rate: 100 mL / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 3.3 min; Sample solution: 250 mg dissolved in 15 mL Methanol; Injection volume: 4.0 mL) to afford (2S,10S,14bS)-2-amino-10-methyl- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (0.1 g, 26.4%).

[0207] 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 8.3, 1.9 Hz, 1H), 7.29 (d, J = 1.7 Hz, 1H), 7.23 (d, J = 7.4 Hz, 1H), 7.16 – 7.06 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 7.2 Hz, 1H), 4.98 (q, J = 7.1 Hz, 1H), 4.48 (d, J = 11.6 Hz, 1H), 3.70 – 3.45 (m, 2H), 3.20 (ddd, J = 11.5, 4.7, 2.3 Hz, 1H), 2.37 (t, J = 11.7 Hz, 1H), 2.09 (s, 1H), 1.82 – 1.48 (m, 7H).

[0208] 1H NMR (400 MHz, DMSO-d6) δ 7.54 (dd, J = 8.3, 1.9 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H), 7.24 – 7.19 (m, 1H), 7.15 – 7.06 (m, 3H), 6.96 – 6.86 (m, 1H), 4.89 (q, J = 7.1 Hz, 1H), 4.50 (d, J = 11.3 Hz, 1H), 3.58 (t, J = 11.1 Hz, 1H), 3.36 (s, 1H), 3.13 – 3.03 (m, 1H), 2.22 (t, J = 11.2 Hz, 1H), 1.98 – 1.58 (m, 7H), 1.50 (d, J = 12.7 Hz, 1H).

[0209] LCMS-2: MS m / z [M+H]+304.2. ee%=100%. Step 14: (2S,10S,14bS)-10-methyl-2-(pyrimidin-2-ylamino)-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile

[0210] A mixture of (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido [1,2-a]azepine-8-carbonitrile (50.0 mg, 0.17 mmol), 2- chloropyrimidine (56.0 mg, 0.5 mmol) and potassium fluoride (29.0 mg, 0.5 mmol) in dimethyl sulfoxide (5 mL) was stirred at 105 °C for 4 hours under nitrogen. The reaction mixture wascooled to room temperature and purified by PREP-HPLC-1 to afford (2S,10S,14bS)-10-methyl- 2-(pyrimidin-2-ylamino)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8- carbonitrile (17.4 mg, 26.9%) as white solid.

[0211] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 4.7 Hz, 2H), 7.69 (d, J = 6.0 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.12 (td, J = 8.3, 4.3 Hz, 4H), 6.61 (t, J = 4.8 Hz, 1H), 4.94 (d, J = 6.5 Hz, 1H), 4.49 (d, J = 11.0 Hz, 1H), 4.26 (s, 1H), 3.51 (t, J = 11.3 Hz, 1H), 3.20 (d, J = 11.3 Hz, 1H), 2.33 (dd, J = 17.3, 8.7 Hz, 1H), 2.05 (d, J = 14.0 Hz, 1H), 1.97 (d, J = 12.4 Hz, 1H), 1.82 (d, J = 12.8 Hz, 1H), 1.67 (d, J = 7.1 Hz, 3H). LC-MS-2: MS m / z [M+H]+382.3. ee%>97%.

[0212] The following compounds in the table below were synthesized with commercial available starting materials according to the synthetic procedures described in Example 1 above. Table 2.Example 2. rel-(2S,10S,14bS)-10-methyl-2-(oxetan-3-ylamino)-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 2)Step 1: rac-(2S,10S,14bS)-8-bromo-10-methyl-N-(oxetan-3-yl)-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-amine

[0213] To a solution of rac-(2S,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-amine (500 mg, 1.4 mmol, obtained by step10 inExample 1) in methanol (16 mL) was added oxetan-3-one (200 mg, 2.74 mmol) and acetic acid (0.8 mL). The mixture was stirred at room temperature for 5 hours. Then sodium cyanoborohydride (300 mg, 4.76 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (80 mL) and extracted with ethyl acetate (50 mL×3). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by normal phase chromatography (20 g SiO2-column; eluent dichloromethane / methanol (100:0 to 98:2)). Product-containing fractions were combined and the solvent was removed by evaporation to give rac-(2S,10S,14bS)-8-bromo-10-methyl-N-(oxetan-3-yl)-1,2,3,4,10,14b- hexahydrodibenzo[c,f] pyrido[1,2-a]azepin-2-amine (280 mg, 48.5%) as white solid. LCMS- 2: MS m / z [M+H]+ 413.0 / 415.0. Step 2: rel-(2S,10S,14bS)-10-methyl-2-(oxetan-3-ylamino)-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile

[0214] To a solution of rac-(2S,10S,14bS)-8-bromo-10-methyl-N-(oxetan-3-yl)- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-amine (280 mg, 0.68 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added [2'-(amino)[1,1'-biphenyl]-2-yl][bis(1,1- dimethylethyl)[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine](methanesulfonato) palladium (170 mg, 0.21 mmol) and zinc dicyanide (450 mg, 3.8 mmol). The mixture was stirred at 50 ºC in sealed tube for 2 days. The reaction mixture was diluted with water / ethyl acetate (20 mL / 20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine, dried and concentrated. The residue was purified by Preparative HPLC-1. The obtained product was then separated by chiral HPLC (Instrument: SFC-150 (Waters); Column: OJ 25*250mm, 10um (Daicel); Column temperature: 35 ºC; Mobile phase: CO2 / MeOH [0.2% NH3(7M in MeOH)]=50 / 50; Flow rate:100 mL / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 6 min; Sample solution: 80 mg dissolved in 26 mL Methanol; Injection volume: 4.9mL) to afford rel-(2S,10S,14bS)-10-methyl-2-(oxetan- 3-ylamino)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (30.5 mg, 12%) as white solid.

[0215] 1H NMR (400 MHz, DMSO-d6) δ 7.55 (dd, J = 8.3, 1.8 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1H), 7.25 – 7.18 (m, 1H), 7.17 – 7.05 (m, 3H), 6.94 (s, 1H), 4.89 (d, J = 7.1 Hz, 1H), 4.69 (dd, J = 12.8, 6.0 Hz, 2H), 4.46 (dt, J = 16.8, 8.7 Hz, 3H), 4.03 (s, 1H), 3.53 (t, J = 10.9 Hz, 1H), 3.15 – 2.95 (m, 2H), 2.83 (s, 1H), 2.18 (t, J = 11.1 Hz, 1H), 1.84 (t, J = 13.0 Hz, 1H), 1.68 (dd, J = 24.8, 10.4 Hz, 4H), 1.55 (d, J = 13.5 Hz, 1H). LCMS-2: MS m / z [M+H]+360.1. Example 3. rel-(2S,10S,14bS)-10-methyl-2-((5-methyl-1,3,4-oxadiazol-2-yl)amino)- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 3) Example 4. rel-(2R,10R,14bR)-10-methyl-2-((5-methyl-1,3,4-oxadiazol-2-yl)amino)- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 4)Step 1: rac-N-((2S,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)-5-methyl-1,3,4-oxadiazol-2-amine

[0216] A mixture of rac-(2S,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f] pyrido[1,2-a]azepin-2-amine (350 mg, 1 mmol, obtained by step 10 in Example 1) and potassium carbonate (414 mg, 3 mmol) in N,N-dimethylformamide (5 mL) was stirred at 50 oC for 16 hours. Then ethyl acetate (100 mL) and water (100 mL) were added. The organic layer was washed with water, dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by normal phase chromatography (12 g SiO2- column; eluent petroleum ether / ethyl acetate (100:0 to 50:50)). Product-containing fractions were combined and the solvent was removed by evaporation to give rac-N-((2S,10S,14bS)-8- bromo-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)-5-methyl- 1,3,4-oxadiazol-2-amine (130 mg, 29%) as brown solid. LCMS-2: MS m / z[M+H]+ 441.0 / 439.0.Step 2: rel-(2S,10S,14bS)-10-methyl-2-((5-methyl-1,3,4-oxadiazol-2-yl)amino)- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile and rel- (2R,10R,14bR)-10-methyl-2-((5-methyl-1,3,4-oxadiazol-2-yl)amino)-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile

[0217] A mixture of rac-N-((2S,10S,14bS)-8-bromo-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)-5-methyl-1,3,4-oxadiazol-2-amine (120 mg, 0.27 mmol), zinc hydride (91 mg, 1.36 mmol) and t-ButyXphos-Pd-G3 (25 mg, 0.027 mmol) in tetrahydrofuran (3 mL) and water (0.3 mL) was stirred at 40 ºC for 3 hours. Then ethyl acetate (100 mL) and water (100 mL) were added. The organic layer was washed with water, dried with magnesium sulfate, filtered, and evaporated to dryness.

[0218] The obtained product was separated by chiral HPLC (Instrument: SFC-150 (Waters) Column: OX 25*250mm, 10um (Daicel) Column temperature: 35 ºC Mobile phase: CO2 / MeOH [0.2%NH3(7M in MeOH)] = 50 / 50 Flow rate: 100 mL / min Back pressure: 100 bar Detection wavelength: 214 nm Cycle time 2.6 min Sample solution: 40 mg dissolved in 18 mL Methanol Injection volume: 3.0 mL) to afford rel-(2S,10S,14bS)-10-methyl-2-((4-methyl- 3-oxo-3,4-dihydropyrazin-2-yl)amino)-,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2- a]azepine-8-carbonitrile and rel-(2R,10R,14bR)-10-methyl-2-((5-methyl-1,3,4-oxadiazol-2- yl)amino)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile as white solid.

[0219] 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 5.1 Hz, 1H), 7.57 (dd, J = 8.3, 1.8 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.23 (d, J = 7.1 Hz, 1H), 7.16 – 7.08 (m, 3H), 7.02 (d, J = 6.8 Hz, 1H), 4.92 (d, J = 6.6 Hz, 1H), 4.36 (d, J = 11.7 Hz, 1H), 3.93 (s, 1H), 3.45 (t, J = 11.4 Hz, 1H), 3.21 (d, J = 9.7 Hz, 1H), 2.32 (d, J = 14.0 Hz, 4H), 2.10 (d, J = 13.2 Hz, 1H), 1.98 – 1.84 (m, 2H), 1.67 (d, J = 7.2 Hz, 3H). LCMS-2: MS m / z[M+H]+386.1.

[0220] 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 5.1 Hz, 1H), 7.57 (dd, J = 8.3, 1.8 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.23 (d, J = 7.0 Hz, 1H), 7.16 – 7.09 (m, 3H), 7.02 (d, J = 6.8 Hz, 1H), 4.93 (d, J = 6.8 Hz, 1H), 4.36 (d, J = 12.2 Hz, 1H), 3.94 (s, 1H), 3.45 (t, J = 11.3 Hz,1H), 3.21 (d, J = 10.3 Hz, 1H), 2.37 – 2.30 (m, 4H), 2.10 (d, J = 13.7 Hz, 1H), 1.99 – 1.83 (m, 2H), 1.67 (d, J = 7.2 Hz, 3H). LCMS-2: MS m / z[M+H]+386.1. Example 5. (2S,10S,14bS)-2-((1,3,4-oxadiazol-2-yl)amino)-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 7)Step 1: methyl 5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-1,3,4-oxadiazole-2-carboxylate (compound 10)

[0221] A mixture of (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f] pyrido[1,2-a]azepine-8-carbonitrile (150 mg, 0.49 mmol, obtained by step 13 in Example 1), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (218 mg, 0.99 mmol) and potassium fluoride (86 mg, 1.48 mmol) in dimethyl sulfoxide (5 mL) was stirred at 105 ºC for 3 hours. Then ethyl acetate (100 mL) and water (100 mL) were added. The organic layer was washed with water, dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by Preparative HPLC-1 to give methyl 5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-1,3,4-oxadiazole-2-carboxylate (180 mg, 83%) as white solid.

[0222] 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J = 5.5 Hz, 1H), 7.58 (dd, J = 8.3, 1.9 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.18 – 7.09 (m, 3H), 7.05 (d, J = 7.4 Hz, 1H), 4.93 (d, J = 6.9 Hz, 1H), 4.37 (q, J = 7.1 Hz, 3H), 4.08 (s, 1H), 3.45 (t, J = 11.2 Hz, 1H), 3.24 (d, J = 12.1 Hz, 1H), 2.39 (dd, J = 18.0, 8.1 Hz, 1H), 2.11 (d, J = 13.7 Hz, 1H), 2.03 (d, J = 13.5 Hz, 1H), 1.88 (d, J = 12.8 Hz, 1H), 1.67 (d, J = 7.2 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H); LCMS-2: MS m / z [M+H]+444.2.Step 2: 5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-1,3,4-oxadiazole-2-carboxylic acid N

[0223] A mixture of 5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-1,3,4-oxadiazole-2-carboxylate (150 mg, 0.338 mmol) and lithium hydroxide monohydrate (42.6 mg, 1.014 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at room temperature for 1 hour. The mixture was poured into water, extracted with dichloromethane (80 mL × 2). The combined organic phase was dried and concentrated. The crude product was purified by normal phase chromatography (4 g SiO2-column; eluent dichloromethane / methanol (100:0 to 90:10)). Product-containing fractions were combined and the solvent was removed by evaporation to give 5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2- a]azepin-2-yl)amino)-1,3,4-oxadiazole-2-carboxylic acid (130 mg, 92.7%) as white solid. LCMS-2: MS m / z [M+H]+416.2. Step 3: (2S,10S,14bS)-2-((1,3,4-oxadiazol-2-yl)amino)-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile

[0224] A solution of methyl 5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b-hexahy drodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-1,3,4-oxadiazole-2-carboxylate (130 mg, 0.313 mmol) in hydrochloric acid (1 mol / L, 30 mL) was stirred at room temperature for 5 min. Then ethyl acetate (100 mL) and water (100 mL) were added. The organic layer was washed with water, dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by Preparative HPLC-1 to give (2S,10S,14bS)-2-((1,3,4-oxadiazol-2-yl)amino)-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (63.4 mg, 51%) as white solid.

[0225] 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.04 (d, J = 5.2 Hz, 1H), 7.57 (dd, J = 8.3, 1.9 Hz, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.17 – 7.08 (m, 3H), 7.02 (d, J = 6.8 Hz, 1H), 4.93 (d, J = 6.7 Hz, 1H), 4.37 (d, J = 11.6 Hz, 1H), 3.99 (s, 1H), 3.46 (t, J = 11.4 Hz, 1H), 3.22 (d, J = 12.4 Hz, 1H), 2.41 – 2.30 (m, 1H), 2.14 – 1.95 (m, 2H), 1.89 (d, J = 12.2 Hz, 1H), 1.67 (d, J = 7.2 Hz, 3H). LCMS-2: MS m / z [M+H]+372.1. Example 6. (2S,10S,14bS)-10-methyl-2-(pyrimidin-4-ylamino)-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 9)

[0226] A mixture of (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (60 mg, 0.2 mmol, obtained by step 13 in Example 1), triethylamine (40 mg, 0.4 mmol), 2-chloropyrimidinehydrochloride (60 mg, 0.4 mmol) and potassium fluoride (34.8 mg, 0.6 mmol) in dimethyl sulfoxide (3 mL) was stirred at 105 ºC for 16 hours. Then ethyl acetate (100 mL) and water (100 mL) were added. The organic layer was washed with water, dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by Preparative HPLC-1 to give (2S,10S,14bS)- 10-methyl-2-(pyrimidin-4-ylamino)-1,2,3,4,10,14b-hexahydrodibenzo[c,f] pyrido[1,2-a] azepine-8-carbonitrile (32 mg, 42%) as white solid.

[0227] 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.09 (d, J = 6.0 Hz, 1H), 7.72 (d, J = 6.1 Hz, 1H), 7.58 (dd, J = 8.3, 1.9 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.17 – 7.07 (m, 3H), 6.98 (d, J = 6.6 Hz, 1H), 6.67 (d, J = 5.8 Hz, 1H), 4.94 (d, J = 6.5 Hz, 1H), 4.39 (d, J = 12.2 Hz, 2H), 3.47 (dd, J = 19.3, 7.5 Hz, 1H), 3.25 (d, J = 11.9 Hz, 1H), 2.41 – 2.29 (m, 1H), 2.00 (s, 2H), 1.77 (d, J = 13.8 Hz, 1H), 1.67 (d, J = 7.2 Hz, 3H). LCMS-2: MS m / z[M+H]+382.1. ee%=98.50%.Example 7. (2S,10S,14bS)-10-methyl-2-((5-((methylamino)methyl)-1,3,4-oxadiazol-2- yl)amino)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 34)Step 1: ethyl 5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-1,3,4-oxadiazole-2-carboxylate

[0228] A mixture of (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (80 mg, 0.26 mmol, obtained by step 13 in Example 1), ethyl 5-bromo-1,3,4-oxadiazole-2-carboxylate (115 mg, 0.52 mmol) and potassium fluoride (75 mg, 1.3 mmol) in dimethyl sulfoxide (4 mL) was stirred at 50 ºC for 4 hours. The mixture was poured into crushed ice, extracted with ethyl acetate (50 mL×2). The combined organic phase was dried and concentrated. The crude product was purified by normal phase chromatography (4 g SiO2-column; eluent petroleum ether / ethyl acetate (100:0 to 40:60)). Product-containing fractions were combined and the solvent was removed by evaporation to give ethyl 5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-1,3,4-oxadiazole-2-carboxylate (90 mg, 76.9%) as yellow solid. LCMS-2: MS m / z[M+H]+444.1.Step 2: (2S,10S,14bS)-2-((5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)amino)-10-methyl- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 23)

[0229] A mixture of ethyl 5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-1,3,4-oxadiazole-2-carboxylate (90 mg, 0.2 mmol) and sodium borohydride (152 mg, 4.0 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 3 hours. The mixture was poured into water, extracted with dichloromethane (80 mL × 2). The combined organic phase was dried and concentrated. The crude product was purified by normal phase chromatography (4 g SiO2-column; eluent dichloromethane / methanol (100:0 to 90:10)). Product-containing fractions were combined and the solvent was removed by evaporation to give (2S,10S,14bS)-2-((5-(hydroxymethyl)-1,3,4- oxadiazol-2-yl)amino)-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2- a]azepine-8-carbonitrile (60 mg, 75%) as white solid.

[0230] 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 5.1 Hz, 1H), 7.57 (d, J = 6.7 Hz, 1H), 7.42 (s, 1H), 7.23 (d, J = 7.1 Hz, 1H), 7.17 – 7.09 (m, 3H), 7.03 (d, J = 7.1 Hz, 1H), 5.67 (t, J = 5.7 Hz, 1H), 4.93 (d, J = 6.8 Hz, 1H), 4.47 (d, J = 5.4 Hz, 2H), 4.37 (d, J = 11.6 Hz, 1H), 3.97 (s, 1H), 3.45 (t, J = 11.6 Hz, 1H), 3.22 (d, J = 10.8 Hz, 1H), 2.35 (t, J = 10.8 Hz, 1H), 2.12 (d, J = 14.4 Hz, 1H), 1.98 (d, J = 12.6 Hz, 1H), 1.88 (d, J = 12.6 Hz, 1H), 1.67 (d, J = 7.1 Hz, 3H); LCMS-2: MS m / z[M+H]+402.2; ee%=99%. Step 3: (5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-1,3,4-oxadiazol-2-yl)methyl methanesulfonate

[0231] A mixture of (2S,10S,14bS)-2-((5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl)amino)-10- methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (60 mg, 0.15 mmol), triethylamine (151 mg, 1.5 mmol) and methanesulfonyl chloride (86 mg, 0.75 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. The mixture was poured into water, extracted with dichloromethane (40 mL × 2). The combined organic phase was dried and concentrated to afford (5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-1,3,4-oxadiazol-2-yl)methyl methanesulfonate (80 mg, crude) as grey solid, which was used for the next step reaction without further purification. LCMS-2: MS m / z [M+H]+485.2. Step 4: (2S,10S,14bS)-10-methyl-2-((5-((methylamino)methyl)-1,3,4-oxadiazol-2-yl)amino)- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile

[0232] A mixture of (5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-1,3,4-oxadiazol-2-yl)methyl methanesulfonate (70 mg, 0.17 mmol), methylammonium chloride (114 mg, 1.7 mmol) and potassium carbonate (469 mg, 3.4 mmol) in tetrahydrofuran (5 mL) was stirred at 70 ºC for 8 hours. The mixture was poured into water, extracted with dichloromethane (40 mL × 2). The combined organic phase was dried and concentrated. The crude product was purified by normal phase chromatography (4 g SiO2-column; eluent dichloromethane / methanol (100:0 to 85:15)). Product-containing fractions were combined and the solvent was removed by evaporation to give the crude, which was purified by Preparative HPLC-2 to afford (2S,10S,14bS)-10-methyl- 2-((5-((methylamino)methyl)-1,3,4-oxadiazol-2-yl)amino)-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (2.6 mg, 3.6%) as white solid.

[0233] 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 5.1 Hz, 1H), 7.57 (dd, J = 8.3, 1.9 Hz, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.23 (d, J = 6.9 Hz, 1H), 7.19 – 7.07 (m, 3H), 7.03 (d, J = 7.1 Hz, 1H), 4.93 (d, J = 6.6 Hz, 1H), 4.37 (d, J = 11.6 Hz, 1H), 3.96 (s, 1H), 3.70 (s, 2H), 3.45 (s, 1H), 3.21 (d, J = 10.4 Hz, 1H), 2.40 – 2.27 (m, 4H), 2.12 (d, J = 13.8 Hz, 1H), 1.98 – 1.85 (m, 2H), 1.67 (d, J = 7.2 Hz, 3H); LCMS-1: MS m / z [M+H]+415.4; ee%=96.6%.

[0234] The following compounds in the table below were synthesized with commercial available starting materials according to the synthetic procedures described in Example 7 above. Table 3.Example 8. 5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-N-methyl-1,3,4-oxadiazole-2- carboxamide (compound 24)

[0235] To a solution of ethyl 5-(((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-1,3,4-oxadiazole-2-carboxylate (80mg, 0.18 mmol, obtained by step 1 in Example 7) and methylamine hydrochloride (18 mg, 0.27 mmol) in tetrahydrofuran (5 mL) was added triethylamine (45 mg, 0.45 mol) at 0 ºC. After addition, the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water / ethyl acetate (10mL / 10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with brine, dried and concentrated. The residue was purified by Preparative HPLC-1 to afford 5-(((2S,10S,14bS)-8-cyano-10-methyl- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)amino)-N-methyl-1,3,4- oxadiazole-2-carboxamide (31 mg, 40%) as white solid.

[0236] 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 4.7 Hz, 1H), 8.58 (d, J = 5.5 Hz, 1H), 7.57 (dd, J = 8.3, 1.8 Hz, 1H), 7.43 (d, J = 1.6 Hz, 1H), 7.23 (d, J = 6.9 Hz, 1H), 7.18 – 7.08 (m, 3H), 7.05 (d, J = 7.2 Hz, 1H), 4.93 (d, J = 7.0 Hz, 1H), 4.37 (d, J = 11.5 Hz, 1H), 4.05 (s, 1H), 3.45 (t, J = 11.3 Hz, 1H), 3.24 (d, J = 10.2 Hz, 1H), 2.76 (d, J = 4.7 Hz, 3H), 2.42 – 2.30 (m, 1H), 2.12 (d, J = 13.7 Hz, 1H), 2.01 (d, J = 12.2 Hz, 1H), 1.88 (d, J = 12.5 Hz, 1H), 1.67 (d, J = 7.2 Hz, 3H); LCMS-2: MS m / z [M+H]+429.2; ee%=98.64%. Example 9. (2S,10S,14bS)-2-((5-aminopyrimidin-2-yl)amino)-10-methyl- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 44)Step 1: (2S,10S,14bS)-10-methyl-2-((5-nitropyrimidin-2-yl)amino)-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile

[0237] To a solution of (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (80 mg, 0.26 mmol, obtained by step 13 in Example 1) in dimethyl sulfoxide (3 mL) was added 2-chloro-5-nitropyrimidine (84 mg, 0.53 mmol) and potassium fluoride (30 mg, 0.53 mmol). The mixture was stirred at 100ºC for 5 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (30 mL×3). The organic phase was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated to give 100 mg crude product, which was directly used for the next step reaction without further purification. LCMS-2: MS m / z[M+H]+427.1. Step 2: (2S,10S,14bS)-2-((5-aminopyrimidin-2-yl)amino)-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile

[0238] To a solution of (2S,10S,14bS)-10-methyl-2-((5-nitropyrimidin-2-yl)amino)- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (100 mg, 0.23 mmol) in methanol (5 mL) and water (5 mL) was added iron (98 mg, 1.76 mmol) and ammonium chloride (94 mg, 1.76 mmol). The mixture was stirred at 60 ºC for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Preparative HPLC-1 to give (2S,10S,14bS)-2-((5-aminopyrimidin-2-yl)amino)-10- methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (19.6 mg, 21 %) as yellow solid.

[0239] 1H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 2H), 7.56 (dd, J = 8.3, 1.7 Hz, 1H), 7.41 (d, J = 1.5 Hz, 1H), 7.22 (d, J = 7.1 Hz, 1H), 7.13 – 7.03 (m, 4H), 6.75 (d, J = 5.8 Hz, 1H), 4.93 (d, J = 7.0 Hz, 1H), 4.45 (d, J = 11.3 Hz, 3H), 4.12 (s, 1H), 3.51 (t, J = 11.1 Hz, 1H), 3.17 (d, J = 11.5 Hz, 1H), 2.31 – 2.25 (m, 1H), 2.02 (d, J = 13.2 Hz, 1H), 1.93 (d, J = 12.6 Hz, 1H), 1.81 (d, J = 12.2 Hz, 1H), 1.66 (d, J = 7.2 Hz, 3H); LCMS-2: MS m / z [M+H]+397.3; ee%=96.5%. Example 10. (2S,10S,14bS)-2-((5-(1-Hydroxycyclopropyl)-1,3,4-oxadiazol-2-yl) amino)-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8- carbonitrile (compound 25)Step 1: 1-hydroxycyclopropane-1-carbohydrazide

[0240] To a solution of methyl 1-hydroxycyclopropane-1-carboxylate (2 g, 17.24 mmol) in methanol (15 mL) was added hydrazine hydrate (4.9 g, 86.2 mmol) and the reaction mixture was stirred at 60 °C for 16 hours. The reaction mixture was concentrated. The residue was slurried in ethyl acetate (25 mL) for 30 min. The precipitate was collected and dried to afford 1-hydroxycyclopropane-1-carbohydrazide (1.8 g, 90%) as white solid.

[0241] 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 6.09 (s, 1H), 4.22 (s, 2H), 1.00 (q, J = 4.2 Hz, 2H), 0.81 (q, J = 4.1 Hz, 2H). LCMS-1: MS m / z [M+H]+117.3. Step 2: (2S,10S,14bS)-2-isothiocyanato-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile

[0242] To a solution of (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (70 mg, 0.23 mmol, obtained by step 13 in Example 1) in dichloromethane (5 mL) and saturated aqueous sodium bicarbonate (5 mL) was added thiophosgene (53 mg, 0.46 mmol) slowly. After the addition, the reaction was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL) and extracted with dichloromethane (20 mL) twice. The combined organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford(2S,10S,14bS)-2-isothiocyanato-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2- a]azepine-8-carbonitrile (70 mg, 87.8%) as off white solid. LCMS-1: MS m / z [M+H]+346.1. Step 3: N-((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)-2-(1-hydroxycyclopropane-1- carbonyl)hydrazine-1-carbothio amide

[0243] To a solution of (2S,10S,14bS)-2-isothiocyanato-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (65 mg, 0.19 mmol) in tetrahydrofuran (10 mL) was added 1-hydroxycyclopropane-1-carbohydrazide (33 mg, 0.28 mmol). After the addition, the reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated to afford crude N-((2S,10S,14bS)-8-cyano-10-methyl- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)-2-(1-hydroxycyclopropane-1- carbonyl)hydrazine-1-carbothioamide (65 mg, 74.8%), which was directly used for the next step reaction without further purification. LCMS-2: MS m / z [M+H]+462.2. Step 4: (2S,10S,14bS)-2-((5-(1-Hydroxycyclopropyl)-1,3,4-oxadiazol-2-yl)amino)-10-methyl- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile

[0244] To a solution of N-((2S,10S,14bS)-8-cyano-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl)-2-(1-hydroxycyclopropane-1- carbonyl)hydrazine-1-carbothioamide (65 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI, 100 mg, 0.56 mmol) and triethylamine (110 mg, 1.1 mmol) and the mixture was stirred at 70 °C for 16 hours. The reaction was cooled to room temperature and filtered. The filtrate was purified byPreparative HPLC-1 to afford (2S,10S,14bS)-2-((5-(1-hydroxycyclopropyl)-1,3,4-oxadiazol-2- yl)amino)-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8- carbonitrile (49.4 mg, 81.9%) as white solid.

[0245] 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 5.1 Hz, 1H), 7.57 (dd, J = 8.3, 1.8 Hz, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.23 (d, J = 6.9 Hz, 1H), 7.18 – 7.08 (m, 3H), 7.04 (d, J = 6.9 Hz, 1H), 6.57 (s, 1H), 4.93 (d, J = 7.1 Hz, 1H), 4.37 (d, J = 11.7 Hz, 1H), 3.95 (s, 1H), 3.45 (t, J = 11.4 Hz, 1H), 3.21 (d, J = 10.4 Hz, 1H), 2.42 – 2.26 (m, 1H), 2.10 (t, J = 11.5 Hz, 1H), 2.03 – 1.80 (m, 2H), 1.67 (d, J = 7.2 Hz, 3H), 1.09 (d, J =2.4 Hz, 4H); LCMS-1: MS m / z [M+H]+428.1; ee%=100%.

[0246] The following compounds in the following table were synthesized with commercial available starting materials according to the synthetic procedures described in Example 10 above. Table 4.Example 11. (2S,10S,14bS)-10-methyl-2-((1-methyl-1H-1,2,4-triazol-3-yl)amino)- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 12)

[0247] A mixture of (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido [1,2-a]azepine-8-carbonitrile (80 mg, 0.26 mmol, obtained by step 13 in Example 1), 3-bromo-1-methyl-1H-1,2,4-triazole (51 mg, 0.32 mmol), allylpalladium(II) chloride dimer (10 mg, 0.03 mmol), t-butyl BrettPhos (26 mg, 0.05 mmol) and sodium tert-butoxide (51 mg, 0.53 mmol, dissolved in 1 mL of tetrahydrofuran) in tert-butanol (5 mL) was evacuated / backfilled with nitrogen three times and then stirred at 90 °C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL) and filtered. The filtrate was concentrated and purified by Preparative HPLC-1 to afford (2S,10S,14bS)-10-methyl-2-((1-methyl-1H-1,2,4-triazol-3-yl)amino)- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (22.5 mg, 22.5%) as white solid.

[0248] 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.56 (dd, J = 8.3, 1.8 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.22 (d, J = 7.1 Hz, 1H), 7.17 – 6.99 (m, 4H), 6.37 (d, J = 5.1 Hz, 1H), 4.93 (d, J = 6.8 Hz, 1H), 4.44 (d, J = 11.7 Hz, 1H), 3.88 (s, 1H), 3.66 (s, 3H), 3.50 (t, J = 11.2 Hz, 1H), 3.14 (d, J = 11.0 Hz, 1H), 2.27 (td, J = 13.3, 3.8 Hz, 1H), 2.12 (d, J = 13.6 Hz, 1H), 1.88 (dd, J = 22.0, 8.8 Hz, 2H), 1.66 (d, J = 7.2 Hz, 3H). LCMS-2: MS m / z [M+H]+385.1. ee%=100%.

[0249] The following compounds in the table below were synthesized with commercial available starting materials according to the synthetic procedures described in Example 11 above. Table 5.Example 12. (2S,10S,14bS)-2-((5-Methoxypyrazin-2-yl)amino)-10-methyl- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 19)

[0250] A mixture of (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido [1,2-a]azepine-8-carbonitrile (80 mg, 0.26 mmol, obtained by step 13 in Example 1), 2-chloro-5-methoxypyrazine (46 mg, 0.32 mmol), tris(dibenzylideneacetone)dipalladium (24 mg, 0.026 mmol), 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (X-Phos, 25 mg, 0.053 mmol) and sodium tert-butoxide (51 mg, 0.53 mmol) in 1,4-dioxane (10 mL) was evacuated / backfilled with nitrogen three times and then stirred at 90 °C for 16 hours under nitrogen. The reaction mixture was filtered andconcentrated. The crude product was purified by normal phase chromatography (4 g SiO2- column; eluent dichloromethane / methanol (100:0 to 95:5)). Product-containing fractions were combined and the solvent was removed by evaporation to give the crude title compound, which was further purified by Preparative HPLC-1 to afford (2S,10S,14bS)-2-((5-methoxypyrazin-2- yl)amino)-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8- carbonitrile (48.8 mg, 45%) as white solid.

[0251] 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 6.9 Hz, 2H), 7.58 (dd, J = 8.3, 1.7 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.17 – 7.06 (m, 3H), 6.95 (d, J = 6.9 Hz, 1H), 6.87 (d, J = 6.1 Hz, 1H), 4.94 (d, J = 7.0 Hz, 1H), 4.41 (d, J = 11.5 Hz, 1H), 4.18 (d, J = 16.5 Hz, 1H), 3.79 (s, 3H), 3.50 (dd, J = 15.3, 11.6 Hz, 1H), 3.22 (d, J = 12.0 Hz, 1H), 2.41 – 2.27 (m, 1H), 1.99 (s, 2H), 1.78 (d, J = 13.4 Hz, 1H), 1.67 (d, J = 7.2 Hz, 3H). LCMS-2: MS m / z [M+H]+412.1. ee%=99%.

[0252] The following compounds in the table below were synthesized with commercial available starting materials according to the synthetic procedures described in Example 12 above. Table 6.Example 13. (2S,10S,14bS)-10-methyl-2-((1-methyl-1H-imidazol-2-yl)amino)- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 45)

[0253] To a solution of (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (100 mg, 0.33 mmol, obtained by step 13 in Example 1) and 2-bromo-1-methyl-1H-imidazole (132 mg, 0.82 mmol) in tetrahydrofuran (10 mL) was added GPhos-Pd-G6 (15 mg, 0.02 mmol) and sodium trimethylsilanolate (91 mg, 0.49 mmol). The mixture was stirred at 70 ºC for 16 hours. The reaction mixture was filtered and filtrate was concentrated under reduced pressure. The residue was purified by Preparative HPLC-1 to give (2S,10S,14bS)-10-methyl-2-((1-methyl-1H- imidazol-2-yl)amino)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8- carbonitrile (7.4 mg, 6 %) as white solid.

[0254] 1H NMR (400 MHz, DMSO-d6) δ 7.56 (dd, J = 8.3, 1.8 Hz, 1H), 7.41 (s, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.11 (dd, J = 13.1, 7.8 Hz, 3H), 6.94 (s, 1H), 6.65 (d, J = 1.3 Hz, 1H), 6.44 (d, J = 1.3 Hz, 1H), 5.46 (d, J = 4.1 Hz, 1H), 4.93 (d, J = 7.1 Hz, 1H), 4.46 (d, J = 11.2 Hz, 1H), 4.04 (s, 1H), 3.56 (t, J = 11.0 Hz, 1H), 3.47 (s, 3H), 3.17 (d, J = 10.6 Hz, 1H), 2.27 (d, J = 11.7 Hz, 1H), 2.13 (d, J = 12.7 Hz, 1H), 1.93 (t, J = 11.0 Hz, 2H), 1.67 (d, J = 7.2 Hz, 3H). LCMS- 2: MS m / z [M+H]+384.2. ee%=85%. Example 14. (2S,10S,14bS)-2-((6-methoxypyridazin-3-yl)amino)-10-methyl- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 40)

[0255] A mixture of (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (60 mg, 0.2 mmol, obtained by step 13 in Example 1), 3-bromo-6-methoxypyridazine (75 mg, 0.4 mmol), t-Bu-XPhos-Pd-G3 (23 mg, 0.04 mmol) and sodium tert-butoxide (85 mg, 0.4 mmol) in 1,4-dioxane (6 mL) was stirred at 100 ºC under nitrogen for 16 hours. The mixture was poured into water, extracted with ethyl acetate (50 mL × 2). The combine organic phase was concentrated. The crude product was purified by normal phase chromatography (4 g SiO2-column; eluent petroleum ether / ethyl acetate (100:0 to 50:50)). Product-containing fractions were combined and the solvent was removed by evaporation to give 50 mg as grey oil, which was further purified by Preparative HPLC-1 to afford (2S,10S,14bS)-2-((6-methoxypyridazin-3-yl)amino)-10-methyl- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (25.3 mg, 30.5%) as white solid.

[0256] 1H NMR (400 MHz, DMSO-d6) δ 7.57 (dd, J = 8.3, 1.6 Hz, 1H), 7.43 (d, J = 1.2 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 7.17 – 7.04 (m, 4H), 6.98 – 6.91 (m, 2H), 6.81 (d, J = 5.8 Hz, 1H), 4.95 (d, J = 6.8 Hz, 1H), 4.38 (d, J = 11.4 Hz, 1H), 4.30 (s, 1H), 3.86 (s, 3H), 3.49 (t, J = 11.4 Hz, 1H), 3.24 (d, J = 11.4 Hz, 1H), 2.33 (dd, J = 17.6, 7.9 Hz, 1H), 2.09 (d, J = 13.7 Hz, 1H), 2.02 – 1.94 (m, 1H), 1.87 (d, J = 12.8 Hz, 1H), 1.68 (d, J = 7.2 Hz, 3H). LCMS-2: MS m / z [M+H]+412.1. ee%=96%. Example 15. (2S,10S,14bS)-10-Methyl-2-((5-(methylamino)pyrazin-2-yl)amino)- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 47)Step 1: 5-Bromo-N-(4-methoxybenzyl)-N-methylpyrazin-2-amine

[0257] To a solution of 2,5-dibromopyrazine (0.5 g, 2.1 mmol) in dimethyl sulfoxide (15 mL) was added 1-(4-methoxyphenyl)-N-methylmethanamine (0.32 g, 2.1 mmol), followed by cesium carbonate (1.37 g, 4.2 mmol). Then the reaction mixture was stirred at 100 °C for 2 hours under nitrogen. The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (30 mL) twice. The combined organic phase was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by normal phase chromatography (40 g SiO2-column; eluent petroleum ether / ethyl acetate (100:0 to 60:40)). Product-containing fractions were combined and the solvent was removed by evaporation to give 5-bromo-N-(4-methoxybenzyl)-N-methylpyrazin- 2-amine (0.32 g, 49.6%) as yellow solid. LCMS-2: MS m / z [M+H]+308.0 / 310.0. Step 2: (2S,10S,14bS)-2-((5-((4-Methoxybenzyl)(methyl)amino)pyrazin-2-yl)amino)-10- methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile

[0258] A mixture of 5-bromo-N-(4-methoxybenzyl)-N-methylpyrazin-2-amine (200 mg, 0.65 mmol), (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]-pyrido[1,2- a]azepine-8-carbonitrile (197 mg, 0.65 mmol, obtained by step 13 in Example 1) and cesium carbonate (0.53 g, 1.63 mmol) in 1,4-dioxane (15 mL) was evacuated / backfilled with nitrogen twice, then tris(dibenzylideneacetone)dipalladium (59.6 mg, 0.065 mmol) and 2- dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (61 mg, 0.13 mmol) were added. The reaction mixture was evacuated / backfilled with nitrogen twice and stirred at 90 °C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated. The crude product was purified by normal phase chromatography (25 g SiO2-column; eluent dichloromethane / methanol (100:0 to 90:10)). Product-containing fractions were combined and the solvent was removed by evaporation to give (2S,10S,14bS)-2-((5-((4-methoxybenzyl)(methyl)amino)pyrazin-2-yl)amino)-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8- carbonitrile (40 mg, 11.6%) as yellow solid. LCMS-2: MS m / z [M+H]+531.2. Step 3: (2S,10S,14bS)-10-methyl-2-((5-(methylamino)pyrazin-2-yl)amino)-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile

[0259] To a solution of (2S,10S,14bS)-2-((5-((4-methoxybenzyl)(methyl)amino)pyrazin-2- yl)amino)-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8- carbonitrile (30 mg, 0.057 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated. The residue was diluted with dichloromethane (10 mL), neutralized with sodium bicarbonate aqueous solution, then extracted with dichloromethane (10 mL) twice. The combined organic phase was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by Preparative HPLC-1 to afford (2S,10S,14bS)-10-methyl-2-((5- (methylamino)pyrazin-2-yl)amino)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2- a]azepine-8-carbonitrile (5.1 mg, 22%) as off-white solid.

[0260] 1H NMR (400 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.47 – 7.39 (m, 2H), 7.23 (d, J = 6.9 Hz, 1H), 7.17 – 7.06 (m, 3H), 6.93 (d, J = 6.3 Hz, 1H), 6.25 (d, J = 6.2 Hz, 1H), 5.73 (d, J = 5.3 Hz, 1H), 4.93 (s, 1H), 4.42 (d, J = 12.3 Hz, 1H), 4.10 (s, 1H), 3.51 (s, 1H), 3.21 (s, 1H), 2.71 (d, J = 5.1 Hz, 3H), 2.33 (s, 1H), 1.97 (s, 2H), 1.77 (d, J = 13.5 Hz, 1H), 1.67 (d, J = 7.2 Hz, 3H). LCMS-1: MS m / z [M+H]+411.2. ee%>95%. Example 16. (2S,10S,14bS)-2-((4-fluoro-1H-pyrazol-3-yl)amino)-10-methyl- 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (compound 48)Step 1: 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0261] A mixture of 5-methoxy-1H-pyrazole (1.0 g, 11.6 mmol) and sodium hydride (1.2 g, 60% in mineral oil, 30.0 mmol) in N,N-dimethylformamide (18 mL) was stirred at room temperature for 1 hour, followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (2.6 g, 16 mmol). The reaction mixture was stirred for another 2 hours. The mixture was poured into crushed ice, extracted with ethyl acetate (100 mL × 2). The combined organic phase was concentrated. The crude product was purified by normal phase chromatography (40 g SiO2- column; eluent petroleum ether / ethyl acetate (100:0 to 80:20)). Product-containing fractions were combined and the solvent was removed by evaporation to give 4-fluoro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.45 g, 57%) as colorless oil. LCMS-2: MS m / z [M+H]+217.0. Step 2: 5-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0262] To a mixture of 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.2 g, 5.5 mmol) in tetrahydrofuran (40 mL) at -78 ºC was added dropwise n-butyllithium (2.5 M in hexane, 2.7 mL). After the addition, the mixture was stirred at -78 ºC for 30 minutes, followedby the addition of 1,2-dibromo-1,1,2,2-tetrachloroethane (2 g, 6.1 mmol). After the addition, the mixture was stirred at -78 ºC for 4 hours. The reaction was quenched with aqueous ammonium chloride, extracted with ethyl acetate (100 mL × 2). The combined organic phase was concentrated. The crude product was purified by normal phase chromatography (40 g SiO2-column; eluent petroleum ether / ethyl acetate (100:0 to 80:20)). Product-containing fractions were combined and the solvent was removed by evaporation to give 5-bromo-4- fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.5 g, 92%) as colorless oil. LCMS- 2: MS m / z [M-55]+237.0 / 239.0. Step 3: (2S,10S,14bS)-2-((4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)amino)-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8- carbonitrile

[0263] A mixture of (2S,10S,14bS)-2-amino-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrile (150 mg, 0.5 mmol, obtained by step 13 in Example 1), 5-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (300 mg, 1.0 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'- biphenyl (50 mg, 0.1 mmol), methanesulfonato2-dicyclohexylphosphino-3,6-dimethoxy-2'-4'- 6'-tri-i-propyl-1,1'-bipheny)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (36 mg, 0.04 mmol) and sodium tert-butoxide (130 mg, 1.35 mmol) in dioxane (8 mL) was stirred at 120 ºC for 1 hour. The mixture was poured into water, extracted with dichloromethane (50 mL × 3). The combined organic phase was concentrated. The crude product was purified by normal phase chromatography (4 g SiO2-column;eluent petroleum ether / ethyl acetate (100:0 to 60:40)). Product-containing fractions were combined and the solvent was removed by evaporation to give (2S,10S,14bS)-2-((4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5- yl)amino)-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8- carbonitrile (80 mg, 31%) as yellow solid. LCMS-1: MS m / z [M+H]+518.4. Step 4: (2S,10S,14bS)-2-((4-fluoro-1H-pyrazol-3-yl)amino)-10-methyl-1,2,3,4,10,14b- hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8-carbonitrileN

[0264] A mixture of (2S,10S,14bS)-2-((4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)amino)-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8- carbonitrile (80.0 mg, 0.15 mmol, obtained by step 13 in Example 1) and 2,2,2-trifluoroacetic acid (1 mL) in dichloromethane (4 mL) was stirred at room temperature for 2 hours. The mixture was poured into water, basified with solid sodium carbonate, extracted with dichloromethane (50 mL × 3). The combined organic phase was concentrated. The resulting residual was purified by Preparative HPLC-1 to afford (2S,10S,14bS)-2-((4-fluoro-1H-pyrazol- 3-yl)amino)-10-methyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-8- carbonitrile (8.8 mg, 15%) as white solid.

[0265] 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.16 – 7.06 (m, 3H), 6.98 (d, J = 6.5 Hz, 1H), 5.36 (s, 1H), 4.93 (d, J = 6.4 Hz, 1H), 4.47 (d, J = 10.9 Hz, 1H), 3.85 (s, 1H), 3.57 (t, J = 11.6 Hz, 1H), 3.14 (d, J = 11.1 Hz, 1H), 2.26 (t, J = 10.6 Hz, 1H), 2.13 (s, 1H), 1.91 (s, 2H), 1.66 (d, J = 7.1 Hz, 3H). LCMS-2: MS m / z [M+H]+388.1.

[0266] The following compounds in the table below were synthesized with commercial available starting materials according to the synthetic procedures described in Example 16 above. Table 7.Example 17. A20 Luciferase Assay for BEAS-2B

[0001] A pGL3P-TNFAIP3 firefly luciferase reporter cell line (Beas-2B A20-luc) was established by co-transfection of human normal bronchial epithelial cell line Beas-2B with linearized pGL3P-TNFAIP3 Intron 2A firefly luciferase reporter construct and puromycin- expressing plasmid (pBABE-puro) after the selection of cell monoclone under 1 µg / mL Puromycin. The pGL3P-TNFAIP3 reporter plasmid was constructed with strong consensus GR and NF-kB binding sites for TNFAIP3I2 enhancer activity in the pGL3P-promoter vector. The generated pGL3P-TNFAIP3 Beas-B cell line allows for the identification of compounds showing GR-mediated A20 agonist activity at the human glucocorticoid receptor (GR) via induction of luciferase gene expression under the NF-kB activation by TNFa. Ligand-activated GR binds to the Glucocorticoid Response Element (GRE) in the enhancer of the firefly luciferase gene and transcription is initiated. The resulting firefly luciferase activity ismeasured through a bioluminescent reaction catalyzed by firefly luciferases (change in luminescent signal).

[0002] Beas-2B A20-luc cells were suspended in DMEM medium containing 10%FBS, 1%PS, and seeded as 25000 cells / 100 μL / well in 96-well plates and cultured at 37°C with 5 % CO2, and 95 % humidity for 24 hours. The TNF-alpha at a final concentration of 20 ng / ml and 2μl compound were added at different concentrations to the cells and incubated for 8 hours. Control wells received 2 μl 10% DMSO only and the final DMSO concentration in all wells was 0.2 %. Cells were washed once in PBS and lysed with 25 μL / well 1X Passive Lysis Buffer (PLB) for 15 min at room temperature. Transferred 5 μL of each lysate to one well of a 96-well white- bottomed assay plate, added 40 μl / well prepared Luciferase Assay Reagent II (LARII) for firefly luciferase activities. The 96-well plates were measured at a luminescent signal microplate reader (TECAN SPARK).

[0003] The relative efficacy (% Effect) of a compound is calculated based on the full agonist effect of dexamethasone. The equation: % Effect= (Sample data – Min data) / ( Max data – Min data) *100

[0004] where Min data=data of DSMO group, and Max data= data of dexamethasone group

[0005] To calculate EC50, max, min and slope factor for each compound, a concentration response curve is fitted by plotting % Effect versus compound concentration using the 4- parameter logistic equation: Y=A+(B-A) / (1+((10 C) / x) D)

[0006] Where A=min Y, B=max Y, C=log EC50 and D= Hill Slope

[0007] The EC50determined using the assay is summarized in the table below. In the table below, “A” indicates EC50of less than 5 nM (< 5 nM); “B” indicates an EC50range from 5 nM to 10 nM (5 nM ≤ EC50< 10 nM); “C” indicated an EC50range from 10 nM to 100 nM (10 nM ≤ EC50< 100 nM); “D” indicates EC50from 100 nM to 1000 nM (100 nM ≤ EC50< 1000 nM); and “E” indicates EC50of greater than or equal to 1000 nM (≥ 1000 nM).Table 8. EC50(nM) of Exemplary CompoundsINCORPORATION BY REFERENCE

[0008] All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically andindividually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.EQUIVALENTS

[0009] While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0010] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. Such equivalents are intended to be within the scope of the following claims.

Claims

CLAIMS What is claimed:

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein: R1is C1-C6alkyl; R2is 3-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 8-10 membered bicyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a; each instance of R2ais independently halogen, –ORo1, –NRn1Rn2, C1-C6alkyl optionally substituted with 1-4 instances of R2b, C1-C6haloalkyl,wherein m is 0, 1, 2, or 3; X is –O– or –NR2e–; each R2bis independently halogen, –ORo2, or –NRn3Rn4; each R2cis independently halogen, –ORo2, or –NRn3Rn4; each of R2d, R2e, Ro1, Ro2, Rn1, Rn2, Rn3, and Rn4is independently H or C1-C6alkyl; and R3is H or C1-6alkyl.

2. The compound of claim 1, wherein R1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

3. The compound of claim 1 or 2, wherein R1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

4. The compound of any one of claims 1 to 3, wherein R1is –Me.

5. The compound of any one of claims 1 to 4, wherein the compound is of Formula I-a:or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1 to 5, wherein the compound is of Formula I-a-1 or Formula I-a-2:or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1 to 6, wherein R3is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

8. The compound of any one of claims 1 to 7, wherein R3is H or –Me.

9. The compound of any one of claims 1 to 8, wherein R3is H.

10. The compound of any one of claims 1 to 8, wherein R3is –Me.

11. The compound of any one of claims 1 to 10, wherein R2is 3-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

12. The compound of any one of claims 1 to 11, wherein R2is 3-4 membered monocyclic heterocyclyl having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

13. The compound of any one of claims 1 to 12, wherein R2is 3 membered monocyclic heterocyclyl having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

14. The compound of any one of claims 1 to 12, wherein R2is 4 membered monocyclic heterocyclyl having 1 heteroatom selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

15. The compound of any one of claims 1 to 12 and 14, wherein R2is, wherein R2is optionally substituted with 1-3 instances of R2a.

16. The compound of any one of claims 1 to 12, 14, and 15, wherein R2is17. The compound of any one of claims 1 to 12 and 14 to 16, wherein R2is.

18. The compound of any one of claims 1 to 11, wherein R2is 8-10 membered bicyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

19. The compound of any one of claims 1 to 11 and 18, wherein R2is 8-10 membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

20. The compound of any one of claims 1 to 11, 18, and 19, wherein R2is, wherein R2is optionally substituted with 1-3 instances of R2a.

21. The compound of any one of claims 1 to 11 and 18 to 20, wherein R2is.

22. The compound of any one of claims 1 to 11 and 18 to 21, wherein R2is.

23. The compound of any one of claims 1 to 11, wherein R2is 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

24. The compound of any one of claims 1 to 11 and 23, wherein R2is 5 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

25. The compound of any one of claims 1 to 11 and 23, wherein R2is 6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

26. The compound of any one of claims 1 to 11, 23, and 24, wherein R2is oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

27. The compound of any one of claims 1 to 11, 23, 24, and 26, wherein R2is oxadiazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

28. The compound of any one of claims 1 to 11, 23, 24, and 26, wherein R2is triazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

29. The compound of any one of claims 1 to 11, 23, 24, and 26, wherein R2is tetrazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

30. The compound of any one of claims 1 to 11, 23, 24, and 26, wherein R2is thiadiazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

31. The compound of any one of claims 1 to 11, 23, 24, and 26, wherein R2is imidazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

32. The compound of any one of claims 1 to 11, 23, 24, and 26, wherein R2is pyrazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

33. The compound of any one of claims 1 to 11, 23, 24, and 26, wherein R2is oxazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

34. The compound of any one of claims 1 to 11, 23, 24, and 26, wherein R2is 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1,3,4-thiadazolyl, 1,2,3-thiadazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

35. The compound of any one of claims 1 to 11, 23, 24, 26, and 34, wherein R2is 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2H-tetrazolyl, 1,3,4-thiadazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1-2 instances of R2a.

36. The compound of any one of claims 1 to 11, 23, and 24, wherein R2is oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1 instance of R2a.

37. The compound of any one of claims 1 to 11, 23, and 24, wherein R2is oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is unsubstituted.

38. The compound of any one of claims 1 to 11, 23, 24, and 36, wherein R2is 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1,3,4-thiadazolyl, 1,2,3-thiadazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1 instance of R2a.

39. The compound of any one of claims 1 to 11, 23, 24, and 37, wherein R2is 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, 1,3,4-thiadazolyl, 1,2,3-thiadazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is unsubstituted.

40. The compound of any one of claims 1 to 11, 23, 24, 36, and 38, wherein R2is 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2H-tetrazolyl, 1,3,4-thiadazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is optionally substituted with 1 instance of R2a.

41. The compound of any one of claims 1 to 11, 23, 24, 36, and 39, wherein R2is 1,3,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 2H-tetrazolyl, 1,3,4-thiadazolyl, imidazolyl, pyrazolyl, or oxazolyl, wherein R2is unsubstituted.

42. The compound of any one of claims 1 to 11, 23, and 25, wherein R2is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl, wherein R2is optionally substituted with 1-2 instances of R2a.

43. The compound of any one of claims 1 to 11, 23, 25, and 42, wherein R2is pyridinyl, wherein R2is optionally substituted with 1-2 instances of R2a.

44. The compound of any one of claims 1 to 11, 23, 25, and 42, wherein R2is pyrimidinyl, wherein R2is optionally substituted with 1-2 instances of R2a.

45. The compound of any one of claims 1 to 11, 23, 25, and 42, wherein R2is pyrazinyl, wherein R2is optionally substituted with 1-2 instances of R2a.

46. The compound of any one of claims 1 to 11, 23, 25, and 42, wherein R2is pyridazinyl, wherein R2is optionally substituted with 1-2 instances of R2a.

47. The compound of any one of claims 1 to 11, 23, 25, and 42, wherein R2is 1,2,4-triazinyl, wherein R2is optionally substituted with 1-2 instances of R2a.

48. The compound of any one of claims 1 to 11, 23, 25, and 42, wherein R2is 1,3,5-triazinyl, wherein R2is optionally substituted with 1-2 instances of R2a.

49. The compound of any one of claims 1 to 11, 23, 25, and 42, wherein R2is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl, wherein R2is optionally substituted with 1 instance of R2a.

50. The compound of any one of claims 1 to 11, 23, 25, and 42, wherein R2is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl, wherein R2is unsubstituted.

51. The compound of any one of claims 1 to 11, 23, 25, and 42, wherein R2is pyrimidinyl, pyrazinyl, or pyridazinyl, wherein R2is optionally substituted with 1-2 instances of R2a.

52. The compound of any one of claims 1 to 11, 23, 25, and 42, wherein R2is pyrimidinyl, pyrazinyl, or pyridazinyl, wherein R2is optionally substituted with 1 instance of R2a.

53. The compound of any one of claims 1 to 11, 23, 25, and 42, wherein R2is pyrimidinyl, pyrazinyl, or pyridazinyl, wherein R2is unsubstituted.

54. The compound of any one of claims 1 to 53, wherein Ro1is C1-C6alkyl.

55. The compound of any one of claims 1 to 54, wherein Ro1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

56. The compound of any one of claims 1 to 55, wherein Ro1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

57. The compound of any one of claims 1 to 53, wherein Ro1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

58. The compound of any one of claims 1 to 53, wherein Ro1is H, –Me, or –Et.

59. The compound of any one of claims 1 to 53, wherein Ro1is H or –Me.

60. The compound of any one of claims 1 to 53, wherein Ro1is H.

61. The compound of any one of claims 1 to 53, wherein Ro1is –Me.

62. The compound of any one of claims 1 to 61, wherein Rn1is C1-C6alkyl.

63. The compound of any one of claims 1 to 62, wherein Rn1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

64. The compound of any one of claims 1 to 63, wherein Rn1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

65. The compound of any one of claims 1 to 61, wherein Rn1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

66. The compound of any one of claims 1 to 61, wherein Rn1is H or –Me.

67. The compound of any one of claims 1 to 61, wherein Rn1is H.

68. The compound of any one of claims 1 to 61, wherein Rn1is –Me.

69. The compound of any one of claims 1 to 68, wherein Rn2is C1-C6alkyl.

70. The compound of any one of claims 1 to 69, wherein Rn2is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

71. The compound of any one of claims 1 to 70, wherein Rn2is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

72. The compound of any one of claims 1 to 68, wherein Rn2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

73. The compound of any one of claims 1 to 68, wherein Rn2is H or –Me.

74. The compound of any one of claims 1 to 68, wherein Rn2is H 75. The compound of any one of claims 1 to 68, wherein Rn2is –Me.

76. The compound of any one of claims 1 to 75, wherein Ro2is C1-C6alkyl.

77. The compound of any one of claims 1 to 76, wherein Ro2is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

78. The compound of any one of claims 1 to 77, wherein Ro2is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

79. The compound of any one of claims 1 to 75, wherein Ro2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

80. The compound of any one of claims 1 to 75, wherein Ro2is H, –Me, or –Et.

81. The compound of any one of claims 1 to 75, wherein Ro2is H or –Me.

82. The compound of any one of claims 1 to 75, wherein Ro2is H.

83. The compound of any one of claims 1 to 75, wherein Ro2is –Me.

84. The compound of any one of claims 1 to 83, wherein Rn3is C1-C6alkyl.

85. The compound of any one of claims 1 to 84, wherein Rn3is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

86. The compound of any one of claims 1 to 85, wherein Rn3is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

87. The compound of any one of claims 1 to 83, wherein Rn3is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

88. The compound of any one of claims 1 to 83, wherein Rn3is H or –Me.

89. The compound of any one of claims 1 to 83, wherein Rn3is H.

90. The compound of any one of claims 1 to 83, wherein Rn3is–Me.

91. The compound of any one of claims 1 to 90, wherein Rn4is C1-C6alkyl.

92. The compound of any one of claims 1 to 91, wherein Rn4is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

93. The compound of any one of claims 1 to 92, wherein Rn4is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

94. The compound of any one of claims 1 to 90, wherein Rn4is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

95. The compound of any one of claims 1 to 90, wherein Rn4is H or –Me.

96. The compound of any one of claims 1 to 90, wherein Rn4is H.

97. The compound of any one of claims 1 to 90, wherein Rn4is –Me.

98. The compound of any one of claims 1 to 97, wherein each R2bis independently –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –O-pentyl, –O-hexyl, –NH2, –NHMe, or –NMe2.

99. The compound of any one of claims 1 to 98, wherein each R2bis independently –F, –Cl, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, – NH2, –NHMe, or –NMe2.

100. The compound of any one of claims 1 to 99, wherein each R2bis independently –F, –Cl, –OH, –OMe, –NH2, –NHMe, or –NMe2.

101. The compound of any one of claims 1 to 100, wherein each R2bis independently –F, –OH, –OMe, –NH2, –NHMe, or –NMe2.

102. The compound of any one of claims 1 to 101, wherein each R2cis independently –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –O-pentyl, –O-hexyl, –NH2, –NHMe, or –NMe2.

103. The compound of any one of claims 1 to 102, wherein each R2cis independently –F, –Cl, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, – NH2, –NHMe, or –NMe2.

104. The compound of any one of claims 1 to 103, wherein each R2cis independently –F, –Cl, –OH, –OMe, –NH2, –NHMe, or –NMe2.

105. The compound of any one of claims 1 to 104 wherein each R2cis independently –F, –OH, –OMe, –NH2, –NHMe, or –NMe2.

106. The compound of any one of claims 1 to 105, wherein m is 0 or 1.

107. The compound of any one of claims 1 to 106, wherein m is 1.

108. The compound of any one of claims 1 to 107, wherein X is –NR2e–.

109. The compound of any one of claims 1 to 108, wherein R2eis C1-C6alkyl.

110. The compound of any one of claims 1 to 109, wherein R2eis –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

111. The compound of any one of claims 1 to 110, wherein R2eis –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

112. The compound of any one of claims 1 to 108, R2eis H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

113. The compound of any one of claims 1 to 108, wherein R2eis H or –Me.

114. The compound of any one of claims 1 to 108, wherein R2eis H.

115. The compound of any one of claims 1 to 108, wherein R2eis –Me.

116. The compound of any one of claims 1 to 115, wherein each instance of R2ais independently –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –O-pentyl, –O-hexyl, –NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, – pentyl, –hexyl, –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH,–CH2NH2, –CH2NHCH3, –CH2N(CH3)2,117. The compound of any one of claims 1 to 116, wherein each instance of R2ais independently –F, –Cl, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, – NH2, –NHMe, –NMe2, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, – CF2CH3, –CF(CH3)2, –CF2CF3, –CH2CF3, –CH2OH,CH2NHCH3, –CH2N(CH3)2,118. The compound of any one of claims 1 to 117, wherein each instance of R2ais independently –F, –Cl, –OH, –OMe, –NH2, –NHMe, –NMe2, –Me, –Et, –CF3, –CHF2, – CH2F, –CF2CH3, –CF(CH3)2, –CH2CF3, –CH2OH,CH2NHCH3, –CH2N(CH3)2,119. The compound of any one of claims 1 to 118, wherein each instance of R2ais independently –F, –OH, –OMe, –NH2, –NHMe, –NMe2, –Me, –Et, –CF3, –CHF2, –CH2F, – CF2CH3, –CF(CH3)2, –CH2OH,–CH2NHCH3, –CH2N(CH3)2,120. The compound of any one of claims 1 to 119, wherein R2is121. The compound of any one of claims 1 to 119, wherein R2is122. The compound of any one of claims 1 to 119, wherein R2is123. The compound of any one of claims 1 to 122, wherein the compound is of Formula I-b-1 or Formula I-b-2:or a pharmaceutically acceptable salt thereof, or a combination thereof.

124. The compound of any one of claims 1 to 122, wherein the compound is of Formula I-c-1 or Formula I-c-2:or a pharmaceutically acceptable salt thereof, or a combination thereof..

125. The compound of any one of claims 1 to 122, wherein the compound is of Formula I-d-1 or Formula I-d-2:or a pharmaceutically acceptable salt thereof, or a combination thereof..

126. The compound of any one of claims 1 to 122, wherein the compound is of Formula I-e-1 or Formula I-e-2:or a pharmaceutically acceptable salt thereof, or a combination thereof..

127. The compound of any one of claims 1 to 122, wherein the compound is of Formula I-e-3 or Formula I-e-4:or a pharmaceutically acceptable salt thereof, or a combination thereof..

128. The compound of any one of claims 1 to 122, wherein the compound is of Formula I-e-5 or Formula I-e-6:or a pharmaceutically acceptable salt thereof.

129. The compound of any one of claims 1 to 128, wherein the compound is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

130. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

131. A pharmaceutical composition comprising a compound of any one of claims 1 to 130, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

132. A method of treating a glucocorticoid receptor-mediated disease or disorder in a subject thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 130, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition of claim 131.

133. The method of claim 132, wherein the glucocorticoid receptor-mediated disease or disorder is an autoimmune disease or an inflammatory disease.

134. The method of claim 132 or 133, wherein the disease or disorder is arthritis, asthma, bursitis, Crohn’s disease, hepatitis, lupus, rhinitis, tendonitis, or ulcerative colitis.

135. A method of modulating a glucocorticoid receptor (GR), comprising administering to the subject an effective amount of a compound of any one of claims 1 to 130, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition of claim 131.

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