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 / 097819, filed June 6, 2024, and PCT Application No. PCT / CN2025 / 099108, 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: XisRxis C1-C6alkyl; R1is –CN, halo, –ORo1, –C(O)NRn1Rn2, RA, –ORB, –NRn1RB, or –NRn1C(O)RB; RAis 3-6 membered cycloalkyl, phenyl, 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a; RBis 3-6 membered cycloalkyl, phenyl, 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b; R2is phenyl, naphthyl, or 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-5 instances of R2a; R3is C1-C6alkyl or 3-4 membered cycloalkyl;R4is H or C1-C6alkyl; R5is C1-C6alkyl, C1-C6haloalkyl, 5-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a; each R1ais independently oxo, halo, –(CH2)0-1CN, –OH, –O-(C1-C6alkyl), –O-(C1-C6haloalkyl), –(CH2)0-1C(O)NH2, –(CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1bis independently oxo, halo, –(CH2)0-1CN, –OH, –O-(C1-C6alkyl), –O-(C1-C6haloalkyl), –(CH2)0-1C(O)NH2, –(CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur each R2ais independently halo, –ORo2, –SRs1, –S(O)2Rs2, –NRn1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl optionally substituted with 1-5 instances of R2b, C1-C6heteroalkyl optionally substituted with 1-5 instances of R2b, or 3-6 membered cycloalkyl optionally substituted with 1-5 instances of R2b, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-7 membered heterocyclyl optionally substituted with 1-4 instances of halo; each R2bis independently oxo, halo, –ORo3, –NRn2, or –CN, or two instances of R2battached to the same atom, together with the atom to which they are attached, form cyclopropyl; each R5ais independently C1-C6alkyl or –OH; Ro1is C1-C6alkyl; each of Ro2and Ro3is independently H, C1-C6alkyl, C1-C6haloalkyl, or 3-6 membered cycloalkyl; each of Rs1, Rs2, Rn1, and Rn2is independently H or C1-C6alkyl; and Rn3is 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[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 use of 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 approximationsthat 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 may be 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 stale 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. Unlessexplicitly 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 spacial configuration (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 acomposition 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 are oriented 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 the swapping 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 disclosedherein 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-formingsubstituents 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-C4alkyl”). 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 (“C1alkyl”). 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 to12 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-C4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-C3alkenyl”). In some embodiments, 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 iswhile 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 grouphas 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 is , while 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, asdefined 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 optionally quaternized. 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 someembodiments, 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 some embodiments, 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, a heteroaryl 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 is, while 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 heteroatomis 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 ring system. 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. Eachinstance 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.

[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:wherein: XisRxis C1-C6alkyl; R1is –CN, halo, –ORo1, –C(O)NRn1Rn2, RA, –ORB, –NRn1RB, or –NRn1C(O)RB; RAis 3-6 membered cycloalkyl, phenyl, 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a; RBis 3-6 membered cycloalkyl, phenyl, 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b; R2is phenyl, naphthyl, or 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-5 instances of R2a; R3is C1-C6alkyl or 3-4 membered cycloalkyl; R4is H or C1-C6alkyl;R5is C1-C6alkyl, C1-C6haloalkyl, 5-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a; each R1ais independently oxo, halo, –(CH2)0-1CN, –OH, –O-(C1-C6alkyl), –O-(C1-C6haloalkyl), –(CH2)0-1C(O)NH2, –(CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1bis independently oxo, halo, –(CH2)0-1CN, –OH, –O-(C1-C6alkyl), –O-(C1-C6haloalkyl), –(CH2)0-1C(O)NH2, –(CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur each R2ais independently halo, –ORo2, –SRs1, –S(O)2Rs2, –NRn1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl optionally substituted with 1-5 instances of R2b, C1-C6heteroalkyl optionally substituted with 1-5 instances of R2b, or 3-6 membered cycloalkyl optionally substituted with 1-5 instances of R2b, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-7 membered heterocyclyl optionally substituted with 1-4 instances of halo; each R2bis independently oxo, halo, –ORo3, –NRn2, or –CN, or two instances of R2battached to the same atom, together with the atom to which they are attached, form cyclopropyl; each R5ais independently C1-C6alkyl or –OH; Ro1is C1-C6alkyl; each of Ro2and Ro3is independently H, C1-C6alkyl, C1-C6haloalkyl, or 3-6 membered cycloalkyl; each of Rs1, Rs2, Rn1, and Rn2is independently H or C1-C6alkyl; and Rn3is 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0078] In some embodiments, the compound is of Formula I-1, Formula I-2, Formula I-3, or Formula I-4:or a pharmaceutically acceptable salt thereof.

[0079] 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. In some embodiments, R3is –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 3-4 membered cycloalkyl. In some embodiments, R3is cyclopropyl. In some embodiments, R4is C1-C6alkyl.

[0083] In some embodiments, R4is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or – hexyl. In some embodiments, R4is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In someembodiments, R4is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, R4is H or –Me. In some embodiments, R4is H.

[0084] In some embodiments, the compound is of Formula I-b:or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, R5is C1-C6alkyl, wherein R5is optionally substituted with 1-2 instances of R5a.

[0086] In some embodiments, R5is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or – hexyl, wherein R5is optionally substituted with 1-2 instances of R5a. In some embodiments, R5is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu, wherein R5is optionally substituted with 1- 2 instances of R5a. In some embodiments, R5is5In some embodiments, R is C1-C6haloalkyl, wherein R5is optionally substituted with 1-2 instances of R5a. In some embodiments, R5is –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, or –CF2CF3, wherein R5is optionally substituted with 1-2 instances of R5a.

[0087] In some embodiments, R5is –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, or –CF2CH2OH. In some embodiments, R5is –CF3,–CF(CH3)2, or –CF2CH2OH. In some embodiments, R5is –CF3. In some embodiments, R5is –CF2CH3. In some embodiments, R5is –CF2CH2OH.

[0088] In some embodiments, R5is 5-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a. In some embodiments, R5is 5 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a.

[0089] In some embodiments, R5is

[0090] In some embodiments, R5is 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a. In some embodiments, R5is 5 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a.

[0091] In some embodiments, R5is

[0092] In some embodiments, R5is, –CF3, –CF(CH3)2, –CF2CH2OH,

[0093] In some embodiments, X is

[0094] In some embodiments, X is

[0095] In some embodiments, X is

[0096] In some embodiments, X is

[0097] In some embodiments, Rxis –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or – hexyl. In some embodiments, Rxis –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, Rxis –Me.

[0098] In some embodiments, X is

[0099] T In some embodiments, X is

[0100] In some embodiments, X is

[0101] In some embodiments, X is is

[0102] In some embodiments, X is

[0103] In some embodiments, X is

[0104] In some embodiments, X is

[0105] In some embodiments, X is

[0106] In some embodiments, the compound is of Formula I-c:or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the compound is of Formula I-c-1, Formula I-c-2, Formula I- c-3, or Formula I-c-4:or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the compound is of Formula I-d:or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the compound is of Formula I-d-1, Formula I-d-2, Formula I-d-3, or Formula I-d-4:or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the compound is of Formula I-e:or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the compound is of Formula I-e-1, Formula I-e-2, Formula I- e-3, or Formula I-e-4:or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the compound is of Formula I-f:or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the compound is of Formula I-f-1, Formula I-f-2, Formula I- f-3, or Formula I-f-4:or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the compound is of Formula I-g:or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the compound is of Formula I-g-1, Formula I-g-2, Formula I-g- 3, or Formula I-g-4:or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the compound is of Formula I-h:or a pharmaceutically acceptable salt thereof.

[0117] In some embodiments, the compound is of Formula I-h-1, Formula I-h-2, Formula I-h-3, or Formula I-h-4:or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, the compound is of Formula I-i:or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the compound is of Formula I-i-1, Formula I-i-2, Formula I- i-3, or Formula I-i-4:or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the compound is of Formula I-j:or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the compound is of Formula I-j-1, Formula I-j-2, Formula I- j-3, or Formula I-j-4:or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, Rn3is 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rn3is In son3me embodiments, R is

[0123] In some embodiments, each R1ais independently oxo, halo, –(CH2)0-1CN, –OH, –O- (C1-C6alkyl), –O-(C1-C6haloalkyl), –(CH2)0-1C(O)NH2, –(CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 memberedheterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R1ais independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe, – OEt, –OCF3,, , –C(O)NH2, –CH2C(O)NH2, –C(O)NHCH3, – CH2C(O)NHCH3, –C(O)N(CH3)CH2Rn3, –Me, –Et, –nPr, –iPr, –CF3, –CHF2, –CH2F,, In some embodiments, each R1ais independently oxo, –F, –Cl, –CN, – CH2CN, –OH, –OMe, –OEt, –OCF3,, , –C(O)NH2, –CH2C(O)NH2, – C(O)NHCH3, –CH2C(O)NHCH3, –C(O)N(CH3)CH2Rn3, –Me, –Et, –nPr, –iPr, –CF3, –CHF2, –CH2F, –CH(CF3)2,

[0124] In some embodiments, each R1bis independently oxo, halo, –(CH2)0-1CN, –OH, –O- (C1-C6alkyl), –O-(C1-C6haloalkyl), –(CH2)0-1C(O)NH2, –(CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R1bis independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe, – OEt, –OCF3,–C(O)NH2, –CH2C(O)NH2, –C(O)NHCH3, – CH2C(O)NHCH3, –C(O)N(CH3)CH2Rn3, –Me, –Et, –nPr, –iPr, –CF3, –CHF2, –CH2F,

[0125] In some embodiments, each R1bis independently oxo, –F, –Cl, –CN, –CH2CN, –OH, – OMe, –OEt, –OCF3,–C(O)NH2, –CH2C(O)NH2, –C(O)NHCH3, – CH2C(O)NHCH3, –C(O)N(CH3)CH2Rn3, –Me, –Et, –nPr, –iPr, –CF3, –CHF2, –CH2F, – CH(CF3)2,1bIn some embodiments, each R is independentlyoxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe,,–C(O)NH2, –CH2C(O)NH2, – C(O)NHCH3,–Me, –Et, –CF3,In some embodiments, each R1bis independently oxo or –Me.

[0126] In some embodiments, RAis 3-6 membered cycloalkyl, wherein RAis optionally substituted with 1-5 instances of R1a. In some embodiments, RAis 3-4 membered cycloalkyl, wherein RAis optionally substituted with 1-5 instances of R1a. In some embodiments, RAis cyclopropyl, wherein RAis optionally substituted with 1-5 instances of R1a. In some embodiments, RAis

[0127] In some embodiments, RAis phenyl, wherein RAis optionally substituted with 1-5 instances of R1a. In some embodiments, RAisAIn some embodiments, R is

[0128] In some embodiments, RAis 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a. In some embodiments, RAis 5-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a. In some embodiments, RAis pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, or dihydropyridinyl, wherein RAisoptionally substituted with 1-5 instances of R1a. In some embodiments, RAis,

[0129] In some embodiments, RAis 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a. In some embodiments, RAis 7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a. In some embodiments, RAis

[0130] In some embodiments, RAis 5-6 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a. In some embodiments, RAis 5-6 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a. In some embodiments, RAis imidazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, or thiadiazolyl, wherein RAis optionally substituted with 1-5 instances of R1a. In some embodiments, RAis,, , , ,

[0131] In some embodiments, RAis, , , ,

[0132] In some embodiments, RBis 3-6 membered cycloalkyl, wherein RBis optionally substituted with 1-5 instances of R1b. In some embodiments, RBis 3-4 membered cycloalkyl, wherein RBis optionally substituted with 1-5 instances of R1b. In some embodiments, RBis cyclopropyl, wherein RBis optionally substituted with 1-5 instances of R1b. In some embodiments, RBis

[0133] In some embodiments, RBis phenyl, wherein RBis optionally substituted with 1-5 instances of R1b. In some embodiments, RBis, , ,

[0134] In some embodiments, RBis 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b. In some embodiments, RBis 5-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b. In some embodiments, RBis pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, or dihydropyridinyl, wherein RBis optionally substituted with 1-5 instances of R1b. In some embodiments, RBis,

[0135] In some embodiments, RBis 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b. In some embodiments, RBis 7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b. In some embodiments, RBis

[0136] In some embodiments, RAis 5-6 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b. In some embodiments, RBis 5-6 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b. In some embodiments, RBis imidazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, or thiadiazolyl, wherein RBis optionally substituted with 1-5 instances of R1b. In some embodiments, RBis

[0137] In some embodiments, RBis, , , ,

[0138] 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.

[0139] 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.

[0140] In some embodiments, Ro1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. In some embodiments, Ro1is –Me. In some embodiments, R1is –CN, –F, –Cl, –OMe, –C(O)NH2, RA, –ORB, –NHRB, or –NHC(O)RB.

[0141] In some embodiments, R1is –CN, –F, –Cl, –OMe, –C(O)NH2,.

[0142] In some embodiments, R1is –CN.

[0143] In some embodiments, X is

[0144] In some embodiments, Ro2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, – CHF2, –CH2F, cyclopropyl, or cyclobutyl.

[0145] In some embodiments, Ro3is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, – CHF2, –CH2F, cyclopropyl, or cyclobutyl.

[0146] In some embodiments, Rs1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

[0147] In some embodiments, Rs2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

[0148] In some embodiments, each R2bis independently oxo, –F, –Cl, –OH, –OMe, –NH2, – NHCH3, –N(CH3)2, or –CN, or two instances of R2battached to the same atom, together with the atom to which they are attached, form cyclopropyl.

[0149] In some embodiments, each R2ais independently halo, –ORo2, –SRs1, –S(O)2Rs2, –NRn1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl optionally substituted with 1-5 instances of R2b, or 3-6 membered cycloalkyl optionally substituted with 1-5 instances of R2b, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo.

[0150] In some embodiments, each R2ais independently halo, –ORo2, –SRs1, –S(O)2Rs2, –NRn1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl optionally substituted with 1-5 instances of R2b, or 3-6 membered cycloalkyl optionally substituted with 1-5 instances of R2b, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo.

[0151] In some embodiments, each R2ais independently –F, –Cl, –Br, –OH, –OMe, –OEt, – OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –O-pentyl, –O-hexyl, –O-cyclopropyl, –O- cyclobutyl, –SH, –SMe, –SEt, –S(O)2Me, –S(O)2Et, –NH2, –NHCH3, –N(CH3)2, – C(CH3)=CH2, –C≡CH, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, –hexyl, – CCN(CH3)2, –CF3, –CHF2, –CH2F, –OCF3, –OCHF2, –OCH2F, –SMe, –SEt, cyclopropyl, or cyclobutyl, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo.

[0152] In some embodiments, each R2ais independently –F, –Cl, –Br, –OH, –OMe, –OEt, –O- cyclopropyl, –SH, –SMe, –S(O)2Me, –C(CH3)=CH2, –C≡CH, –Me, –Et, –CCN(CH3)2, –CF3, –CHF2, –CH2F, –OCF3, –OCHF2, –OCH2F, –SMe, –SEt, or cyclopropyl, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo.

[0153] In some embodiments, each R2ais independently –F, –Cl, –C(CH3)=CH2, –C≡CH, – Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CCN(CH3)2, –CF3, –CHF2, –CH2F, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –OCF3, –OCHF2, –OCH2F, –SMe, –SEt, cyclopropyl, or cyclobutyl, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo.

[0154] In some embodiments, each instance of R2ais independently –F, –Cl, –C(CH3)=CH2, – C≡CH, –Me, –CCN(CH3)2, –CF3, –CHF2, –OMe, –OEt, –OiPr, –OCF3, –OCHF2, –SMe, or cyclopropyl, or two R2agroups attached to two adjacent carbon atoms, together with the carbonatoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo.

[0155] In some embodiments, two ortho R2agroups, together with the carbon atoms to which each is attached to, form 5 membered heterocyclyl optionally substituted with 1-4 instances of halo.

[0156] In some embodiments, R2is phenyl or naphthyl, wherein R2is optionally substituted with 1-3 instances of R2a. In some embodiments, R2is phenyl, wherein R2is optionally substituted with 1-3 instances of R2a. In some embodiments, R2is napthyl, wherein R2is optionally substituted with 1-3 instances of R2a.

[0157] In some embodiments, R2is

[0158] In some embodiments, R2is

[0159] In some embodiments, R2is 5 membered heteroaryl 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 5 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionallysubstituted with 1-2 instances of R2a. In some embodiments, R2is pyrazolyl or thiazolyl. In some embodiments, R2is

[0160] In some embodiments, R2is 6 membered heteroaryl 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 6 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 pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl, wherein R2is optionally substituted with 1-3 instances of R2a. In some embodiments, R2is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, wherein R2is optionally substituted with 1-3 instances of R2a. In some embodiments,

[0161] In some embodiments, R2 is

[0162] In some embodiments, R2is

[0163] In some embodiments, the compound is of Formula II:or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the compound is of Formula IIa:or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the compound is of Formula IIb:or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the compound is of Formula IIc:or a pharmaceutically acceptable salt thereof.

[0167] In some embodiments, the compound is of Formula IId:or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the compound is of Formula IIe:or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the compound is of Formula IIf:or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the compound is of Formula IIg:or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the compound is of Formula IIh:or a pharmaceutically acceptable salt thereof.

[0172] Disclosed herein, in some embodiments, is a compound shown in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof

[0173] Disclosed herein, in some embodiments, is a compound shown in Table 1, or a pharmaceutically acceptable salt thereof.

[0174] Disclosed herein, in some embodiments, is a compound shown in Table 2, or a pharmaceutically acceptable salt thereof.Table 1. Exemplary compounds of the disclosure51Table 2. Exemplary compounds of the disclosure

[0175] In chemical structures in Table 1 and Table 2, above, and the Examples, below, stereogenic centers are described according to the Enhanced Stereo Representation format (MDL / Biovia, e.g. using labels “R”, “S”, “abs”, “or1”, “or2”, “&1”, “&2”).

[0176] Disclosed herein, in some embodiments, is a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0177] Disclosed herein, in some embodiments, is a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0178] 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.

[0179] 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 Table 2, 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 Table 2, or a pharmaceutically acceptable salt thereof).

[0180] In some embodiments, the glucocorticoid receptor-mediated disease or disorder is an autoimmune disease or an inflammatory disease.

[0181] In some embodiments, the disease or disorder is arthritis, asthma, bursitis, Crohn’s disease, hepatitis, lupus, rhinitis, tendonitis, or ulcerative colitis.

[0182] 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 Table 2, 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 Table 2, or a pharmaceutically acceptable salt thereof). Pharmaceutical Compositions

[0183] Compounds disclosed herein (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) areadministered alone or as pharmaceutical compositions comprising the compounds disclosed herein and one or more pharmaceutically acceptable excipients.

[0184] 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 Table 2, or a pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipients (i.e., one or more pharmaceutically acceptable excipients).

[0185] 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.

[0186] 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 Table 2, and pharmaceutically acceptable salts thereof) are useful for treating a disease, or symptoms thereof, described herein, such as autoimmune diseases or inflammatory diseases.

[0187] The dosage of the compounds disclosed herein (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1 and Table 2, 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 thecompounds disclosed here (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1 and Table 2, 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.

[0188] 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 Table 2, and pharmaceutically acceptable salts thereof) and package inserts with instructions to perform any of the methods described herein.

[0189] 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 Table 2, or a pharmaceutically acceptable salts thereof).Methods of Use and Treatment

[0190] Compounds disclosed herein (e.g. , compounds of Formula I and subformulas thereof, compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof) are useful for treating diseases. Compounds disclosed herein (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1 and Table 2, 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 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).

[0191] 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 Table 2, 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 Ior a subformula thereof or a compound of Table 1 or Table 2, or a pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable excipient. In some embodiments, the compounds are useful for treating autoimmune diseases or inflammatory diseases or cancer.

[0192] 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 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 Table 2, 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 Table 2, 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.

[0193] 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 Table 2, 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 Table 2, 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, hi some embodiments, the glucocorticoid receptor-mediated disease is a cancer.

[0194] 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 Table 2, 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 thatmodulates 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 Table 2, 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 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.

[0195] 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 Table 2, 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 Table 2, 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.

[0196] The compounds disclosed herein (e.g., compounds of Formula I and subformulas thereof, compounds of Table 1 and Table 2, 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.

[0197] 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 diseaseor disorder is arthritis, asthma, bursitis, Crohn’s disease, hepatitis, lupus, rhinitis, tendonitis, or ulcerative colitis.

[0198] 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.

[0199] 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 EmbodimentsEmbodiment 1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:X isRxis C1-C6alkyl; R1is –CN, halo, –ORo1, –C(O)NRn1Rn2, RA, –ORB, –NRn1RB, or –NRn1C(O)RB; RAis 3-6 membered cycloalkyl, phenyl, 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a; RBis 3-6 membered cycloalkyl, phenyl, 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b; R2is phenyl, naphthyl, or 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-5 instances of R2a; R3is C1-C6alkyl or 3-4 membered cycloalkyl; R4is H or C1-C6alkyl; R5is C1-C6alkyl, C1-C6haloalkyl, 5-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a; each R1ais independently oxo, halo, –(CH2)0-1CN, –OH, –O-(C1-C6alkyl), –O-(C1-C6haloalkyl), –(CH2)0-1C(O)NH2, –(CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1bis independently oxo, halo, –(CH2)0-1CN, –OH, –O-(C1-C6alkyl), –O-(C1-C6haloalkyl), –(CH2)0-1C(O)NH2, –(CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur each R2ais independently halo, –ORo2, –SRs1, –S(O)2Rs2, –NRn1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl optionally substituted with 1-5 instances of R2b, C1-C6heteroalkyl optionally substituted with 1-5 instances of R2b, or 3-6 membered cycloalkyl optionally substituted with 1-5 instances of R2b, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-7 membered heterocyclyl optionally substituted with 1-4 instances of halo; each R2bis independently oxo, halo, –ORo3, –NRn2, or –CN, or two instances of R2battached to the same atom, together with the atom to which they are attached, form cyclopropyl; each R5ais independently C1-C6alkyl or –OH; Ro1is C1-C6alkyl; each of Ro2and Ro3is independently H, C1-C6alkyl, C1-C6haloalkyl, or 3-6 membered cycloalkyl; each of Rs1, Rs2, Rn1, and Rn2is independently H or C1-C6alkyl; and Rn3is 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Embodiment 2. The compound of embodiment 1, wherein the compound is of Formula I-1, Formula I-2, Formula I-3, or Formula I-4:or a pharmaceutically acceptable salt thereof. Embodiment 3. The compound of embodiment 1 or 2, wherein R3is C1-C6alkyl. Embodiment 4. The compound of any one of embodiments 1 to 3, wherein R3is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. Embodiment 5. The compound of any one of embodiments 1 to 4, wherein R3is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 6. The compound of any one of embodiments 1 to 5, wherein R3is –Me. Embodiment 7. The compound of any one of embodiments 1 to 6, wherein the compound is of Formula I-a:or a pharmaceutically acceptable salt thereof Embodiment 8. The compound of any one of embodiments 1 to 7, wherein the compound is of Formula I-a-1 or Formula I-a-2:or a pharmaceutically acceptable salt thereof.Embodiment 9. The compound of embodiment 1 or 2, wherein R3is 3-4 membered cycloalkyl. Embodiment 10. The compound of any one of embodiments 1, 2, and 9, wherein R3is cyclopropyl. Embodiment 11. The compound of any one of embodiments 1 to 10, wherein R4is C1-C6alkyl. Embodiment 12. The compound of any one of embodiments 1 to 11, wherein R4is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. Embodiment 13. The compound of any one of embodiments 1 to 12, wherein R4is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 14. The compound of any one of embodiments 1 to 11, wherein R4is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 15. The compound of any one of embodiments 1 to 11, wherein R4is H or –Me. Embodiment 16. The compound of any one of embodiments 1 to 11, wherein R4is H. Embodiment 17. The compound of any one of embodiments 1 to 16, wherein the compound is of Formula I-b:or a pharmaceutically acceptable salt thereof. Embodiment 18. The compound of any one of embodiments 1 to 17, R5ais –OH Embodiment 19. The compound of any one of embodiments 1 to 17, R5ais C1-C6alkyl.Embodiment 20. The compound of any one of embodiments 1 to 19, wherein R5is C1-C6alkyl, wherein R5is optionally substituted with 1-2 instances of R5a. Embodiment 21. The compound of any one of embodiments 1 to 20, wherein R5is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl, wherein R5is optionally substituted with 1-2 instances of R5a. Embodiment 22. The compound of any one of embodiments 1 to 20, wherein R5is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu, wherein R5is optionally substituted with 1- 2 instances of R5a. Embodiment 23. The compound of any one of embodiments 1 to 21, wherein R5isEmbodiment 24. The compound of any one of embodiments 1 to 17, wherein R5is C1-C6haloalkyl, wherein R5is optionally substituted with 1-2 instances of R5a. Embodiment 25. The compound of any one of embodiments 1 to 19 and 24, wherein R5is –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, or –CF2CF3, wherein R5is optionally substituted with 1-2 instances of R5a. Embodiment 26. The compound of any one of embodiments 1 to 19, 24, and 25, wherein R5is –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, or –CF2CH2OH. Embodiment 27. The compound of any one of embodiments 1 to 19 and 24 to 26, wherein R5is –CF3,–CF(CH3)2, or –CF2CH2OH. Embodiment 28. The compound of any one of embodiments 1 to 19 and 24 to 26, wherein R5is –CF3. Embodiment 29. The compound of any one of embodiments 1 to 19 and 24 to 26, wherein R5is –CF2CH3. Embodiment 30. The compound of any one of embodiments 1 to 19 and 24 to 26, wherein R5is –CF2CH2OH.Embodiment 31. The compound of any one of embodiments 1 to 19, wherein R5is 5-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a. Embodiment 32. The compound of any one of embodiments 1 to 19 and 31, wherein R5is 5 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a. Embodiment 33. The compound of any one of embodiments 1 to 19, 31, and 32, wherein R5isEmbodiment 34. The compound of any one of embodiments 1 to 19, wherein R5is 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a. Embodiment 35. The compound of any one of embodiments 1 to 19 and 34, wherein R5is 5 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a. Embodiment 36. The compound of any one of embodiments 1 to 19, 34, and 35, wherein R5isEmbodiment 37. The compound of any one of embodiments 1 to 19, wherein R5is–CF3, –CF(CH3)2, –CF2CH2OH,Embodiment 38. The compound of any one of embodiments 1 to 37, wherein X isEmbodiment 39. The compound of any one of embodiments 1 to 38, wherein X isEmbodiment 40. The compound of any one of embodiments 1 to 39, wherein X isEmbodiment 41. The compound of any one of embodiments 1 to 39, wherein X isEmbodiment 42. The compound of any one of embodiments 1 to 41, wherein Rxis –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl. Embodiment 43. The compound of any one of embodiments 1 to 42, wherein Rxis –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 44. The compound of any one of embodiments 1 to 43, wherein Rxis –Me.Embodiment 45. The compound of any one of embodiments 1 to 44, wherein X isEmbodiment 46. T The compound of any one of embodiments 1 to 44, wherein X isEmbodiment 47. The compound of any one of embodiments 1 to 38, wherein X isEmbodiment 48. The compound of any one of embodiments 1 to 38 and 47, wherein X is isEmbodiment 49. The compound of any one of embodiments 1 to 38 and 47, wherein X isEmbodiment 50. The compound of any one of embodiments 1 to 38 and 47, wherein X isEmbodiment 51. The compound of any one of embodiments 1 to 38 and 47, wherein X isEmbodiment 52. The compound of any one of embodiments 1 to 38 and 47, wherein X isEmbodiment 53. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-c:or a pharmaceutically acceptable salt thereof. Embodiment 54. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-c-1, Formula I-c-2, Formula I-c-3, or Formula I-c-4:or a pharmaceutically acceptable salt thereof.Embodiment 55. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-d:or a pharmaceutically acceptable salt thereof. Embodiment 56. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-d-1, Formula I-d-2, Formula I-d-3, or Formula I-d-4:or a pharmaceutically acceptable salt thereof. Embodiment 57. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-e:or a pharmaceutically acceptable salt thereof.Embodiment 58. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-e-1, Formula I-e-2, Formula I-e-3, or Formula I-e-4:or a pharmaceutically acceptable salt thereof. Embodiment 59. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-f:or a pharmaceutically acceptable salt thereof. Embodiment 60. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-f-1, Formula I-f-2, Formula I-f-3, or Formula I-f-4:or a pharmaceutically acceptable salt thereof. Embodiment 61. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-g:or a pharmaceutically acceptable salt thereof. Embodiment 62. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-g-1, Formula I-g-2, Formula I-g-3, or Formula I-g-4:or a pharmaceutically acceptable salt thereof.Embodiment 63. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-h:or a pharmaceutically acceptable salt thereof. Embodiment 64. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-h-1, Formula I-h-2, Formula I-h-3, or Formula I-h-4:or a pharmaceutically acceptable salt thereof. Embodiment 65. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-i:or a pharmaceutically acceptable salt thereof.Embodiment 66. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-i-1, Formula I-i-2, Formula I-i-3, or Formula I-i-4:or a pharmaceutically acceptable salt thereof. Embodiment 67. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-j:or a pharmaceutically acceptable salt thereof. Embodiment 68. The compound of any one of embodiments 1 to 37, wherein the compound is of Formula I-j-1, Formula I-j-2, Formula I-j-3, or Formula I-j-4:or a pharmaceutically acceptable salt thereof. Embodiment 69. The compound of any one of embodiments 1 to 68, wherein Rn3is 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Embodiment 70. The compound of any one of embodiments 1 to 68 and 69, wherein Rn3isEmbodiment 71. The compound of any one of embodiments 1 to 68, 69, and 70, wherein Rn3isEmbodiment 72. The compound of any one of embodiments 1 to 71, wherein each R1ais independently oxo, halo, –(CH2)0-1CN, –OH, –O-(C1-C6alkyl), –O-(C1-C6haloalkyl), – (CH2)0-1C(O)NH2, –(CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Embodiment 73. The compound of any one of embodiments 1 to 72, wherein each R1ais independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe, –OEt, –OCF3,–C(O)NH2, –CH2C(O)NH2, –C(O)NHCH3, –CH2Cn3(O)NHCH3, –C(O)N(CH3)CH2R , –Me, –Et, –nPr, –iPr, –CF3, –CHF2, –CH2F,Embodiment 74. The compound of any one of embodiments 1 to 73, wherein each R1ais independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe, –OEt, –OCF3,, –C(O)NH , –CH C(O)NH , –n32 2 2C(O)NHCH3, –CH2C(O)NHCH3, –C(O)N(CH3)CH2R , –Me, –Et, –nPr, –iPr, –CF3, –CHF2, –CH2F, –CH(CF3)2,, , Embodiment 75. The compound of any one of embodiments 1 to 74 wherein each R1ais independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe,–C(O)NH2, – CH2C(O)NH2, –C(O)NHCH3,–Me, –Et, –CF3,orEmbodiment 76. The compound of any one of embodiments 1 to 75, wherein each R1bis independently oxo, halo, –(CH2)0-1CN, –OH, –O-(C1-C6alkyl), –O-(C1-C6haloalkyl), – (CH2)0-1C(O)NH2, –(CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Embodiment 77. The compound of any one of embodiments 1 to 76, wherein each R1bis independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe, –OEt, –OCF3,–C(O)NH2, –CH2C(O)NH2, –C(O)NHCH3, –CH2C(O)NHCH3, –C(O)N(CH3)CH2Rn3,–Me, –Et, –nPr, –iPr, –CF3, –CHF2, –CH2F,Embodiment 78. The compound of any one of embodiments 1 to 77, wherein each R1bis independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe, –OEt, –OCF3,–C(O)NH2, –CH2C(O)NH2, –C(O)NHCH3, –CH2C(O)NHCH3, –C(O)N(CH3)CH2Rn3, –Me, –Et, –nPr, –iPr, –CF3, –CHF2, –CH2F, –CH(CF3)2,, , Embodiment 79. The compound of any one of embodiments 1 to 78, wherein each R1bis independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe,,–C(O)NH2, – CH2C(O)NH2, –C(O)NHCH3,–Me, –Et, –CF3,orEmbodiment 80. The compound of any one of embodiments 1 to 79, wherein each R1bis independently oxo or –Me. Embodiment 81. The compound of any one of embodiments 1 to 80, wherein RAis 3-6 membered cycloalkyl, wherein RAis optionally substituted with 1-5 instances of R1a. Embodiment 82. The compound of any one of embodiments 1 to 80 and 81, wherein RAis 3-4 membered cycloalkyl, wherein RAis optionally substituted with 1-5 instances of R1a. Embodiment 83. The compound of any one of embodiments 1 to 80, 81, and 82, wherein RAis cyclopropyl, wherein RAis optionally substituted with 1-5 instances of R1a. Embodiment 84. The compound of any one of embodiments 1 to 80 and 81 to 83, wherein RAisEmbodiment 85. The compound of any one of embodiments 1 to 80, wherein RAis phenyl, wherein RAis optionally substituted with 1-5 instances of R1a.Embodiment 86. The compound of any one of embodiments 1 to 80 and 85, wherein RAis, , , Embodiment 87. The compound of any one of embodiments 1 to 80, 85, and 86, wherein RAis, , , ,Embodiment 88. The compound of any one of embodiments 1 to 80, wherein RAis 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a. Embodiment 89. The compound of any one of embodiments 1 to 80 and 88, wherein RAis 5-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a. Embodiment 90. The compound of any one of embodiments 1 to 80, 88, and 89, wherein RAis pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, or dihydropyridinyl, wherein RAis optionally substituted with 1-5 instances of R1a. Embodiment 91. The compound of any one of embodiments 1 to 80 and 88 to 90, wherein RAis. Embodiment 92. The compound of any one of embodiments 1 to 80, wherein RAis 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a. Embodiment 93. The compound of any one of embodiments 1 to 80 and 92, wherein RAis 7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a. Embodiment 94. The compound of any one of embodiments 1 to 80, 92, and 93, wherein RAisEmbodiment 95. The compound of any one of embodiments 1 to 80, wherein RAis 5-6 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a. Embodiment 96. The compound of any one of embodiments 1 to 80 and 95, wherein RAis 5-6 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a. Embodiment 97. The compound of any one of embodiments 1 to 80, 95, and 96, wherein RAis imidazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, or thiadiazolyl, wherein RAis optionally substituted with 1-5 instances of R1a.Embodiment 98. The compound of any one of embodiments 1 to 80 and 95 to 97, wherein RAis, , , , , , ,Embodiment 99. The compound of any one of embodiments 1 to 80, wherein RAisEmbodiment 100. The compound of any one of embodiments 1 to 99, wherein RBis 3-6 membered cycloalkyl, wherein RBis optionally substituted with 1-5 instances of R1b. Embodiment 101. The compound of any one of embodiments 1 to 99 and 100, wherein RBis 3-4 membered cycloalkyl, wherein RBis optionally substituted with 1-5 instances of R1b. Embodiment 102. The compound of any one of embodiments 1 to 99, 100, and 101, wherein RBis cyclopropyl, wherein RBis optionally substituted with 1-5 instances of R1b. Embodiment 103. The compound of any one of embodiments 1 to 99 and 100 to 102, wherein RBisEmbodiment 104. The compound of any one of embodiments 1 to 99, wherein RBis phenyl, wherein RBis optionally substituted with 1-5 instances of R1b. Embodiment 105. The compound of any one of embodiments 1 to 99 and 104, wherein RBisEmbodiment 106. The compound of any one of embodiments 1 to 99, 104, and 105, wherein RBis. Embodiment 107. The compound of any one of embodiments 1 to 99, wherein RBis 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b. Embodiment 108. The compound of any one of embodiments 1 to 99 and 107, wherein RBis 5-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b. Embodiment 109. The compound of any one of embodiments 1 to 99, 107, and 108, wherein RBis pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, or dihydropyridinyl, wherein RBis optionally substituted with 1-5 instances of R1b. Embodiment 110. The compound of any one of embodiments 1 to 99 and 107 to 109, wherein RBisEmbodiment 111. The compound of any one of embodiments 1 to 99, wherein RBis 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b.Embodiment 112. The compound of any one of embodiments 1 to 99 and 111, wherein RBis 7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b. Embodiment 113. The compound of any one of embodiments 1 to 99, 111, and 112, wherein RBisEmbodiment 114. The compound of any one of embodiments 1 to 99, wherein RAis 5-6 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b. Embodiment 115. The compound of any one of embodiments 1 to 99 and 114, wherein RBis 5-6 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b. Embodiment 116. The compound of any one of embodiments 1 to 99, 114, and 115, wherein RBis imidazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, or thiadiazolyl, wherein RBis optionally substituted with 1-5 instances of R1b. Embodiment 117. The compound of any one of embodiments 1 to 99 and 114 to 116, wherein RBisEmbodiment 118. The compound of any one of embodiments 1 to 99, wherein RBisEmbodiment 119. The compound of any one of embodiments 1 to 99, wherein RBisEmbodiment 120. The compound of any one of embodiments 1 to 119, wherein Rn1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.Embodiment 121. The compound of any one of embodiments 1 to 120, wherein Rn1is H or –Me. Embodiment 122. The compound of any one of embodiments 1 to 121, wherein Rn1is H. Embodiment 123. The compound of any one of embodiments 1 to 121, wherein Rn1is –Me. Embodiment 124. The compound of any one of embodiments 1 to 123, wherein Rn2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 125. The compound of any one of embodiments 1 to 124, wherein Rn2is H or –Me. Embodiment 126. The compound of any one of embodiments 1 to 125, wherein Rn2is H. Embodiment 127. The compound of any one of embodiments 1 to 125, wherein Rn2is –Me. Embodiment 128. The compound of any one of embodiments 1 to 127, wherein Ro1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 129. The compound of any one of embodiments 1 to 128, wherein Ro1is –Me. Embodiment 130. The compound of any one of embodiments 1 to 129, wherein R1is –CN, –F, –Cl, –OMe, –C(O)NH2, RA, –ORB, –NHRB, or –NHC(O)RB. Embodiment 131. The compound of any one of embodiments 1 to 130, wherein R1is –CN, –F, –Cl, –OMe, –C(O)NH2,Embodiment 132. The compound of any one of embodiments 1 to 131, wherein R1is –CN. Embodiment 133. The compound of any one of embodiments 1 to 37, wherein X isEmbodiment 134. The compound of any one of embodiments 1 to 133, wherein Ro2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, cyclopropyl, or cyclobutyl. Embodiment 135. The compound of any one of embodiments 1 to 134, wherein Ro3is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, cyclopropyl, or cyclobutyl. Embodiment 136. The compound of any one of embodiments 1 to 135, wherein Rs1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 137. The compound of any one of embodiments 1 to 136, wherein Rs2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu. Embodiment 138. The compound of any one of embodiments 1 to 137, wherein each R2bis independently oxo, –F, –Cl, –OH, –OMe, –NH2, –NHCH3, –N(CH3)2, or –CN, or two instances of R2battached to the same atom, together with the atom to which they are attached, form cyclopropyl. Embodiment 139. The compound of any one of embodiments 1 to 138, wherein each R2ais independently halo, –ORo2, –SRs1, –S(O)2Rs2, –NRn1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl optionally substituted with 1-5 instances of R2b, or 3-6 membered cycloalkyl optionally substituted with 1-5 instances of R2b, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo. Embodiment 140. The compound of any one of embodiments 1 to 139, wherein each R2ais independently halo, –ORo2, –SRs1, –S(O)2Rs2, –NRn1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl optionally substituted with 1-5 instances of R2b, or 3-6 membered cycloalkyl optionally substituted with 1-5 instances of R2b, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo. Embodiment 141. The compound of any one of embodiments 1 to 140, wherein each R2ais independently –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, – OsBu, –OtBu, –O-pentyl, –O-hexyl, –O-cyclopropyl, –O-cyclobutyl, –SH, –SMe, –SEt, –S(O)2Me, –S(O)2Et, –NH2, –NHCH3, –N(CH3)2, –C(CH3)=CH2, –C≡CH, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, –hexyl, –CCN(CH3)2, –CF3, –CHF2, –CH2F, –OCF3, –OCHF2, –OCH2F, –SMe, –SEt, cyclopropyl, or cyclobutyl, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo. Embodiment 142. The compound of any one of embodiments 1 to 141, wherein each R2ais independently –F, –Cl, –Br, –OH, –OMe, –OEt, –O-cyclopropyl, –SH, –SMe, – S(O)2Me, –C(CH3)=CH2, –C≡CH, –Me, –Et, –CCN(CH3)2, –CF3, –CHF2, –CH2F, –OCF3, – OCHF2, –OCH2F, –SMe, –SEt, or cyclopropyl, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo. Embodiment 143. The compound of any one of embodiments 1 to 140, wherein each R2ais independently –F, –Cl, –C(CH3)=CH2, –C≡CH, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CCN(CH3)2, –CF3, –CHF2, –CH2F, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, – OsBu, –OtBu, –OCF3, –OCHF2, –OCH2F, –SMe, –SEt, cyclopropyl, or cyclobutyl, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo. Embodiment 144. The compound of any one of embodiments 1 to 143, wherein each instance of R2ais independently –F, –Cl, –C(CH3)=CH2, –C≡CH, –Me, –CCN(CH3)2, – CF3, –CHF2, –OMe, –OEt, –OiPr, –OCF3, –OCHF2, –SMe, or cyclopropyl, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo. Embodiment 145. The compound of any one of embodiments 1 to 144, wherein two ortho R2agroups, together with the carbon atoms to which each is attached to, form 5 membered heterocyclyl optionally substituted with 1-4 instances of halo. Embodiment 146. The compound of any one of embodiments 1 to 145, wherein R2is phenyl or naphthyl, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 147. The compound of any one of embodiments 1 to 146, wherein R2is phenyl, wherein R2is optionally substituted with 1-3 instances of R2a.Embodiment 148. The compound of any one of embodiments 1 to 146, wherein R2is napthyl, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 149. The compound of any one of embodiments 1 to 147, wherein R2Embodiment 150. The compound of any one of embodiments 1 to 146 and 148,wherein R2 isEmbodiment 151. The compound of any one of embodiments 1 to 145, wherein R2is 5 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 152. The compound of any one of embodiments 1 to 145 and 151, wherein R2is 5 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-2 instances of R2a. Embodiment 153. The compound of any one of embodiments 1 to 145, 151, and 152, wherein R2is pyrazolyl or thiazolyl.Embodiment 154. The compound of any one of embodiments 1 to 145 and 151 to 153, wherein R2isEmbodiment 155. The compound of any one of embodiments 1 to 145, wherein R2is 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 156. The compound of any one of embodiments 1 to 145 and 155, 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 157. The compound of any one of embodiments 1 to 145, 155, and 156, wherein R2is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, or 1,3,5- triazinyl, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 158. The compound of any one of embodiments 1 to 145 and 155 to 157, wherein R2is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, wherein R2is optionally substituted with 1-3 instances of R2a. Embodiment 159. The compound of any one of embodiments 1 to 145 and 155 to 158, wherein R2isEmbodiment 160. The compound of any one of embodiments 1 to 145, wherein R2isEmbodiment 161. The compound of embodiment 1, wherein the compound is of Formula II:or a pharmaceutically acceptable salt thereof. Embodiment 162. The compound of embodiment 1, wherein the compound is of Formula IIa:or a pharmaceutically acceptable salt thereof. Embodiment 163. The compound of embodiment 1, wherein the compound is of Formula IIb:or a pharmaceutically acceptable salt thereof. Embodiment 164. The compound of embodiment 1, wherein the compound is of Formula IIc:or a pharmaceutically acceptable salt thereof. Embodiment 165. The compound of embodiment 1, wherein the compound is of Formula IId:or a pharmaceutically acceptable salt thereof. Embodiment 166. The compound of embodiment 1, wherein the compound is of Formula IIe:or a pharmaceutically acceptable salt thereof. Embodiment 167. The compound of embodiment 1, wherein the compound is of Formula IIf:or a pharmaceutically acceptable salt thereof. Embodiment 168. The compound of embodiment 1, wherein the compound is of Formula IIg:or a pharmaceutically acceptable salt thereof. Embodiment 169. The compound of embodiment 1, wherein the compound is of Formula IIh:or a pharmaceutically acceptable salt thereof. Embodiment 170. A compound of Table 1, or a pharmaceutically acceptable salt thereof. Embodiment 171. A compound of Table 2, or a pharmaceutically acceptable salt thereof. Embodiment 172. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 171, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof. Embodiment 173. 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 171, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition of embodiment 172. Embodiment 174. The method of embodiment 173, wherein the glucocorticoid receptor-mediated disease or disorder is an autoimmune disease or an inflammatory disease. Embodiment 175. The method of embodiment 173 or 174, wherein the disease or disorder is arthritis, asthma, bursitis, Crohn’s disease, hepatitis, lupus, rhinitis, tendonitis, or ulcerative colitis. Embodiment 176. 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 171, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition of embodiment 172.EXAMPLES

[0200] 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.

[0201] 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 may be synthesized using the synthetic procedures described below (e.g., in combination with other starting materials or reagents). All reactions were conducted under nitrogen atmosphere, unless otherwise specified.

[0202] 1H NMR spectra were recorded on a Bruker instrument operating at 400 MHz or 500 MHz.1HNMR spectra were obtained using CDCl3, CD2Cl2, CD3OD, D2O, DMSO-d6, d6- acetone or (CD3)2CO as solvent and tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; DMSO-d6: 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).

[0203] LC-MS experiments were performed using Agilent 1200 spectrometer, Detector: MWD(190-400nm); Mass detector: 6110 SQ. LC was run in three set ups: 1) Column: SunFireC18(4.6x50 mm, 3.5um), Mobile phase: A: water + 0.01% TFA, B: acetonitrile + 0.01% TFA, Flow: 2 mL / min; 2) Column: XBridge C18(4.6x50 mm, 3.5um), Mobile phase: A: water(10 mM NH4HCO3), B: acetonitrile, Flow: 1.8 mL / min; 3) Column: Xbridge C18(4.6x50 mm, 3.5um), Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile, Flow: 1.7 mL / min.

[0204] Preparative HPLC was performed on Boston Prep C18 (250 x 21.2 mm ID, 10 pm) or Xtimate Prep C18 (150 x 30 mm ID, 5 pm) at RT with UV detection at 214 nm or 254 nm.Eluent set ups: water (10mM NH4HCO3) / acetonitrile, or water (0.2%FA) / acetonitrile were applied.

[0205] In the Examples, below, stereogenic centers are described according to the Enhanced Stereo Representation format (MDL / Biovia, e.g., using labels “abs”, “or1”, “or2”, “or3”, “&1”, “&2”, “&3”). Additionally, in the Examples, below, “rac-” nomenclature refers to a racemic mixture. The configurations of stereocenters in enantiopure compounds set by stereospecific routes starting from the chiral pool are noted as absolute. The stereocenters of enantiopure compounds that were obtained via chiral chromatographic separation of racemates are denoted as relative (“rel-”). AbbreviationsExample 1. Synthesis of Intermediates Intermediate 1: 3-methyl-1H-indazole-5-carbonitrile

[0206] To a solution of 5-bromo-3-methyl-1H-indazole (1.0 g, 4.74 mmol) in N,N- dimethylformamide (10 mL) was added zinc cyanide (1.1 g, 9.48 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.43 g, 0.47 mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.27 g, 0.47 mmol). The mixture was stirred at 150 ºC for 1 h under microwave. The reaction mixture was quenched with water 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 column chromatography (Biotage, 40 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 3-methyl-1H-indazole-5-carbonitrile (0.9 g, 98 %). LC-MS: m / z [M+H]+158.1. Intermediate 2: 5-cyclopropyl-1H-indazoleStep 1: 5-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0207] A mixture of 5-bromo-1H-indazole (5.0 g, 25.5 mmol), sodium hydride (1.3 g, 60% in mineral oil, 30.6 mmol) in N,N-dimethylformamide (50 mL) was stirred at 0 ºC for 1 h. Thenfollowed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride (4.7 g, 28.0 mmol). The mixture was stirred for another 16 h. The mixture was poured into crushed ice, extracted with ethyl acetate (150 mL × 2). The combined organic phase was concentrated. The crude product was purified by column chromatography (Biotage, 80 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-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (5.3 g, 63.5%) as a grey oil. LC-MS: m / z [M+H]+327.0 / 329.0. Step 2: 5-Cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0208] A mixture of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.63 g, 5.0 mmol), cyclopropylboronic acid (516 mg, 6.0 mmol), palladium acetate (113 mg, 0.5 mmol), tricyclohexylphosphane (280 mg, 1.0 mmol) and potassium phosphate (2.12 g, 10.0 mmol) in toluene (50 mL) and H2O (6 mL) was stirred at 100 ºC under nitrogen for 16 h. The mixture was poured into water, extracted with ethyl acetate (100 mL × 2). The combined organic phase was concentrated. The crude product was purified by column chromatography (Biotage, 40 g SiO2-column; eluent petroleum ether: ethyl acetate 100:0 to 85:15). Product containing fractions were combined and the solvent was removed by evaporation to give 5-cyclopropyl- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.1 g, 76%) as a grey oil. LC-MS: m / z [M+H]+289.1. Step 3: 5-cyclopropyl-1H-indazole

[0209] A mixture of 5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.0 g, 3.4 mmol), tetramethylammonium fluoride (3.1 g, 34.0 mmol) and N,N-dimethylformamide (20 mL) was stirred at 80 ºC for 16 h and then at 100 ºC for 4 h. The mixture was poured into water, extracted with ethyl acetate (100 mL × 2). The combined organic phase was concentrated. The crude product was purified by column chromatography (Biotage, 40 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 5-cyclopropyl-1H- indazole (200 mg, 25.2%) as a grey solid. LC-MS: m / z [M+H]+159.1.

[0210] Compounds in the table below were prepared via procedures analogous to that described for intermediate 2.Intermediate 3: 3-isopropyl-1H-indazole-5-carbonitrileStep 1: 4-Fluoro-3-isobutyrylbenzonitrile

[0211] 4-Fluorobenzonitrile (2.3 g, 19 mmol) and N-methoxy-2-methyl-Nmethylpropanamide (3 g, 22.8 mmol) were dissolved in tetrahydrofuran (100 mL). The mixture was cooled to -78°C and lithium diisopropylamide (2 M in tetrahydrofuran / heptane / ethylbenzene, 21 mL, 41.8 mmol) was added dropwise. The reaction was stirred at -78°C for 2 h and quenched by the addition of water. The reaction was extracted with EA, the organic layers combined and dried over magnesium sulfate. Solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel; 0-25% EA in PE). Product containing fractions were combined and the solvent was removed by evaporation to afford 4- fluoro-3-isobutyrylbenzonitrile (1.5 g, 7.85 mmol, 41%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 8.28 (dd, J = 6.6, 2.1 Hz, 1H), 8.15 (ddd, J = 8.6, 4.6, 2.2 Hz, 1H), 7.61 (dd, J = 10.5, 8.7 Hz, 1H), 3.46 – 3.35 (m, 1H), 1.10 (d, J = 6.8 Hz, 6H). Step 2: 3-Isopropyl-1H-indazole-5-carbonitrile

[0212] 4-Fluoro-3-isobutyrylbenzonitrile (1.7 g, 8.9 mmol) was dissolved in toluene (10 mL) and hydrazine hydrate (0.89 g, 17.8 mmol) was added. The reaction mixture was heated in the microwave reactor at 110°C for 30 min. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel; 0-10% EA in PE). Product containing fractions were combined and the solvent was removed by evaporation to provide 3- isopropyl-1H-indazole-5-carbonitrile (1.6 g, 8.6 mmol, 97%) as white solid.1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.47 (s, 1H), 7.63 (s, 2H), 3.42 (dt, J = 13.9, 6.9 Hz, 1H), 1.37 (d, J = 6.9 Hz, 6H). LC-MS: m / z [M+H]+186.1. Intermediate 4: (6-chloropyridin-3-yl)magnesium bromide

[0213] To a suspension of 5-chloro-2-iodopyrimidine (6 g, 25 mmol) in tetrahydrofuran (30 mL) was added isopropylmagnesium bromide (1M solution in tetrahydrofuran, 25 mL, 25 mmol) at -78°C under nitrogen protection. The resulting solution was stirred for 10 min at - 78°C. The reaction solution does not need further treatment and can be directly used for the next reaction. Intermediate 5: 6-cyclopropoxynicotinaldehydeStep 1: 6-cyclopropoxynicotinonitrile

[0214] To a mixture of NaH (1.04 g, 43.3 mmol) in THF (50 mL) was added cyclopropanol (2.52 g, 43.3 mmol) slowly at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30 min. 6- chloronicotinonitrile (5.00 g, 36.1 mmol) was added into the mixture at 0 ℃ slowly. The reaction was stirred at RT for 4 h. The mixture was poured into saturated aq. NH4Cl and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-10%, EA in PE) to give 6-cyclopropoxynicotinonitrile (4.80 g, 83.0%) as a white solid. LC-MS: m / z [M+H]+161.2. Step 2: 6-cyclopropoxynicotinaldehyde

[0215] To a mixture of 6-cyclopropoxynicotinonitrile (4.50 g, 28.1 mmol) in AcOH (30.0 mL) and pyridine (15.0 mL) was added sodium phosphinate (12.1 g, 140 mmol) and Raney nickel (0.931 g, 4.26 mmol). The reaction was stirred at 80 ℃ for 1 h. The mixture was filtered, poured into H2O and extracted with EA. The combined organic phase was washed with saturated aq. citric acid, saturated aq. NaHCO3and brine, dried over anhydrous Na2SO4, filtered and concentrated to give 6-cyclopropoxynicotinaldehyde (4.00 g, 87.3%) as a yellow oil. LC-MS: m / z [M+H]+164.2. Intermediate 6: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1- yl)cyclopropane-1-carbonitrileStep 1: 2-(4-iodo-1H-pyrazol-1-yl)acetonitrile

[0216] To a mixture of NaH (0.410 g, 17.0 mmol) in THF (30 mL) was added 4-iodo-1H- pyrazole (3.00 g, 15.5 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 10 min. 3- bromopropanenitrile (2.07 g, 15.5 mmol) was added into the mixture at 0 ℃. The reaction wasstirred at RT for 16 h. The mixture was poured into saturated aq. NH4Cl and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. Then the residue was purified by flash chromatography (silica gel, 0-10%, EA in PE) to give (4-iodopyrazol-1-yl)acetonitrile (3.48 g, 96.6%) as a white solid. LC-MS: m / z [M+H]+234.1. Step 2: 1-(4-iodo-1H-pyrazol-1-yl)cyclopropane-1-carbonitrile

[0217] A mixture of NaH (0.620 g, 25.8 mmol) in DMSO (30 mL) was stirred at 0 ℃ for 10 min. 2-(4-iodo-1H-pyrazol-1-yl)acetonitrile (1.50 g, 6.44 mmol) and 1,2-dibromoethane (1.67 mL, 19.3 mmol) was added into the mixture at 0 ℃. The reaction was stirred at RT for 16 h. The mixture was poured into saturated aq. NH4Cl and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. Then the residue was purified by flash chromatography (silica gel, 0-20% EA in PE) to give 1- (4-iodopyrazol-1-yl)cyclopropane-1-carbonitrile (666 mg, 39.9%) as a white solid. LC-MS: m / z [M+H]+260.1. Step 3: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclopropane-1- carbonitrile

[0218] To a mixture of 1-(4-iodo-1H-pyrazol-1-yl)cyclopropane-1-carbonitrile (50.0 mg, 0.193 mmol) in DMF (1.0 mL) was added bis(pinacolato)diboron (98.0 mg, 0.386 mmol), Pd(dppf)Cl2(20.0 mg, 0.0270 mmol) and KOAc (56.8 mg, 0.579 mmol). The reaction mixture was stirred at 100 ℃ for 16 h. The mixture was filtered, poured into H2O and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)cyclopropane-1-carbonitrile (49 mg, 99%) as a black oil. LC-MS: m / z [M+H]+260.1. Intermediate 7: 1-(5-formylpyridin-2-yl)cyclopropane-1-carbonitrileStep 1: 1-(5-bromopyridin-2-yl)cyclopropane-1-carbonitrile

[0219] To a mixture of 2-(5-bromopyridin-2-yl)acetonitrile (3.90 g, 19.8 mmol) in ACN (40 mL) was added 1,2-dibromoethane (1.89 mL, 21.8 mmol), NaOH (16.5 mL, 12 M) and TBAB (0.640 g, 1.98 mmol). The reaction mixture was stirred at RT for 16 h. The mixture was poured into H2O and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. Then the residue was purified by flash chromatography (silica gel, 0-30%, EA in PE) to give 1-(5-bromopyridin-2-yl)cyclopropane- 1-carbonitrile (4.10 g, 92.9 %) as a white solid. LC-MS: m / z [M+H]+223.1 / 225.1. Step 2: 1-(5-vinylpyridin-2-yl)cyclopropane-1-carbonitrile

[0220] To a mixture of 1-(5-bromopyridin-2-yl)cyclopropane-1-carbonitrile (4.00 g, 17.9 mmol) in dioxane (70 mL) and H2O (10 mL) was added potassium trifluoro(vinyl)borate (4.81 g, 35.9 mmol), Pd(dppf)Cl2(1.31 g, 1.79 mmol) and K2CO3(2.48 g, 17.9 mmol) under nitrogen atmosphere. The reaction was stirred at 100 ℃ for 16 h. The mixture was filtered and concentrated. Then the residue was purified by flash chromatography (silica gel, 0-20%, EA in PE) to give 1-(5-vinylpyridin-2-yl)cyclopropane-1-carbonitrile (2.80 g, 91.8%) as a white solid. LC-MS: m / z [M+H]+171.2. Step 3: 1-(5-formylpyridin-2-yl)cyclopropane-1-carbonitrile

[0221] To a mixture of 1-(5-vinylpyridin-2-yl)cyclopropane-1-carbonitrile (2.70 g, 15.9 mmol) in THF (42.0 mL) and H2O (14.0 mL) was added K2OsO4-2H2O (100 mg, 0.272 mmol) and NaIO4(13.6 g, 63.4 mmol) under nitrogen atmosphere. The reaction was stirred at RT for 16 h. The mixture was filtered and concentrated. The mixture was poured into H2O and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 1-(5-formylpyridin-2-yl)cyclopropane-1-carbonitrile (2.50 g, 81.9%) as a white solid. LC-MS: m / z [M+H]+173.2. Intermediate 8: 6-methoxy-5-(trifluoromethyl) nicotinaldehyde

[0222] To a solution of 5-bromo-2-methoxy-3-(trifluoromethyl) pyridine (3.00 g, 11.7 mmol) in THF (30 mL) was added n-BuLi (1.6M, 11.0 mL, 17.6 mmol) at -78 ℃ under nitrogen atmosphere.The reaction mixture was stirred at -78 ℃ for 30 minutes. DMF (4.72 mL, 58.6 mmol) was added into the mixture at -78 ℃. The reaction mixture was stirred at -78 ℃ for 1 h. The reaction mixture was quenched with saturated aq. NH4Cl and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-50% EA in PE) to give 6-methoxy-5-(trifluoromethyl) nicotinaldehyde (890 mg, 37.1%) as a yellow solid. LC- MS: m / z [M+H]+206.1. Intermediate 9: tert-butyl (1H-indazol-5-yl)carbamate

[0223] To a mixture of 1H-indazol-5-amine (5.00 g, 37.5 mmol) in DMF (50 mL) were added Boc2O (9.00 g, 41.3 mmol) and DIEA (7.28 g, 56.3 mmol). The reaction was stirred at RT for 16 h. The mixture was poured into H2O and filtered. The filter cake was concentrated to givetert-butyl (1H-indazol-5-yl) carbamate (9.70 g, 110%) as a black solid. LC-MS: m / z [M+H]+234.3. Intermediate 10: 6-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)nicotinaldehydeStep 1: 2-(5-bromopyridin-2-yl)propan-2-ol

[0224] To a solution of 1-(5-bromopyridin-2-yl)ethan-1-one (5.01 g, 25.0 mmol) in THF (50 mL) was added methylmagnesium bromide (3.0 M, 15.0 mL) at 0 ºC. The mixture was stirred at RT for 16 h. The mixture was quenched with saturated aq. NaHCO3and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-100% EA in PE) to give 2-(5-bromopyridin-2-yl)propan-2-ol (3.1 g, 57.4%) as a yellow oil. LC-MS: m / z [M+H]+216.1 / 218.2. Step 2: 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyridine

[0225] To a solution of 2-(5-bromopyridin-2-yl)propan-2-ol (2.51 g, 11.6 mmol) and 2,6- dimethylpyridine (2.69 mL, 23.1 mmol) in DCM (25 mL) was added TBSOTf (4.58 g, 17.4 mmol). The mixture was stirred at RT for 2 h. The mixture was poured into water and extracted with DCM. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-50% EA in PE) to give 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyridine (3.1 g, 81%) as a yellow oil. LC-MS: m / z [M+H]+330.3 / 332.4. Step 3: 6-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)nicotinaldehyde

[0226] To a solution of 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)pyridine (2.61 g, 7.87 mmol) in THF (25 mL) was added n-BuLi (1.6 M, 9.84 mL) at -78 ºC. The mixture was stirred at -78 ºC for 30 minutes. DMF (3.2 mL, 39 mmol) was added in the mixture and stirred at -78ºC for 1 h. The reaction mixture was quenched with saturated aq. NH4Cl and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-100% EA in PE) to give 6-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)nicotinaldehyde (1.3 g, 59.1%) as a yellow oil. LC-MS: m / z [M+H]+280.4. Intermediate 11: 1-(6-formylpyridin-3-yl)cyclopropane-1-carbonitrileStep 1: 1-(6-chloropyridin-3-yl)cyclopropane-1-carbonitrile

[0227] To a solution of 2-(6-chloropyridin-3-yl)acetonitrile (5.01 g, 32.8 mmol) and NaOH (25.0 g, 625 mmol) in H2O (25 mL) was added 1,2-dibromoethane (3.07 mL, 35.4 mmol). The mixture was stirred at 50 ºC for 16 h. The mixture was poured into water and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-50%, EA in PE) to give 1-(6-chloropyridin-3-yl)cyclopropane-1-carbonitrile (3.42 g, 58.5%) as a white solid. LC-MS: m / z [M+H]+179.6. Step 2: 1-(6-vinylpyridin-3-yl)cyclopropane-1-carbonitrile

[0228] To a solution of 1-(6-chloropyridin-3-yl)cyclopropane-1-carbonitrile (3.42 g, 19.2 mmol), K2CO3(7.95 g, 57.507 mmol) and Potassium vinyltrifluoroborate (5.14 g, 38.3 mmol)in dioxane (36 mL) and H2O (12 mL) was added Pd(dppf)Cl2(1.01 g, 1.37 mmol). The mixture was stirred at 80 ºC for 16 h under nitrogen atmosphere. The mixture was poured into water and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-50%, EA in PE) to give 1-(6-vinylpyridin-3-yl)cyclopropane-1- carbonitrile (3.10 g, 95.1%) as a yellow solid. LC-MS: m / z [M+H]+171.2. Step 3: 1-(6-formylpyridin-3-yl)cyclopropane-1-carbonitrile

[0229] To a solution of 1-(6-vinylpyridin-3-yl)cyclopropane-1-carbonitrile (3.10 g, 18.2 mmol) and sodium periodate (15.6 g, 72.8 mmol) in THF (48 mL) and H2O (16 mL) was added K2OsO4-2H2O (99 mg, 0.27 mmol). The mixture was stirred at RT for 16 h. The mixture was filtered. The filtrate was extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give 1-(6-formylpyridin-3- yl)cyclopropane-1-carbonitrile (2.9 g, 92.5%) as a yellow solid. LC-MS: m / z [M+H]+173.2. Intermediate 12: 4-(2-(methylsulfonyl)propan-2-yl)benzaldehydeStep 1: 1-bromo-4-(2-(methylsulfonyl)propan-2-yl)benzene

[0230] To a mixture of 1-bromo-4-((methylsulfonyl)methyl)benzene (3.00 g, 12.0 mmol) in DMF (30 mL) was added NaH (870 mg, 36.1 mmol) at 0 ℃. The reaction was stirred at 0 ℃ for 10 minutes. Iodomethane (1.96 mL, 24.1 mmol) was added into the mixture at 0 ℃. The reaction was stirred at RT for 1 h. The mixture was poured into saturated aq. NH4Cl and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-40% EA in PE) to give 1-bromo-4-(2-(methylsulfonyl)propan-2-yl)benzene (3.41 g,100%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.59 (dd, J = 26.4, 8.6 Hz, 1H), 2.73 (s, 1H), 1.75 (s, 1H). Step 2: 4-(2-(methylsulfonyl)propan-2-yl)benzaldehyde

[0231] To a mixture of 1-bromo-4-(2-(methylsulfonyl)propan-2-yl)benzene (450 mg, 1.62 mmol) in THF (4.0 mL) was added n-BuLi (1.6M, 1.51 mL, 2.43 mmol) at -78 ℃. The reaction was stirred at -78 ℃ for 30 minutes. DMF (0.52 mL, 6.4 mmol) was added into the mixture at -78 ℃. The reaction mixture was stirred at -78 ℃ for 1 h. The mixture was poured into saturated aq. NH4Cl and extracted with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-40% EA in PE) to give 4-(2-(methylsulfonyl)propan-2- yl)benzaldehyde (140 mg, 38.1%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 7.95 (dd, J = 8.4, 8.3 Hz, 4H), 2.80 (s, 3H), 1.86 (s, 6H). Intermediate 13: 4-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)benzaldehydeStep 1: 1-(4-bromobenzyl)cyclopropan-1-ol

[0232] To a stirred solution of ethyl (p-bromophenyl)acetate (5 g, 20.6 mmol)and titanium tetraisopropanolate (666 mg, 0.3 eq., 6.17 mmol) in tetrahydrofuran (20 mL, 246 mmol) was added ethylmagnesium bromide (8.22 g, 3 eq., 61.7 mmol, 3 M in diethyl ether, 20.6 mL) at 0 °C over a period of 30 mins. This reaction was stirred at 0 °C for 1h. The reaction mixture was added 1M sulfuric acid at 0 °C to quench the reaction and extracted the aqueous phase with Et2O (3× 50 mL). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 1-[(p- bromophenyl)methyl]cyclopropanol (5.4 g, 23.8 mmol,60% purity) as a yellow oil which is used for next step without further purification.1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.3Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 2.83 (s, 2H), 0.82 (t, J = 5.9 Hz, 2H), 0.63 (t, J = 6.0 Hz, 2H). Step 2: (1-(4-bromobenzyl)cyclopropoxy)(tert-butyl)dimethylsilane

[0233] To the mixture of 1-[(p-bromophenyl)methyl]cyclopropanol (5.4 g, 23.8 mmol), imidazole (3.24 g, 2 eq., 47.6 mmol) and N,N-dimethyl-4-pyridylamine (2.9 g, 23.8 mmol) in dimethylformamide (50 mL, 646 mmol) was added (tert-butyl)(chloro)bis(methyl)silane (7.17 g, 2 eq., 47.6 mmol). The reaction was stirred at 80°C for 16h. The reaction was diluted with water (50 mL) and the reaction was extracted with ethyl acetate (50 mL x 3). The combined organic part was washed with brine (100 mL x 3), dried over Na2SO4and evaporated under vacuum. The crude was purified on flash chromatograohy using Bitage 40 g silica column (eluting with PE:EA = PE to 3% EA) to give {1-[(p-bromophenyl)methyl]cyclopropoxy}(tert- butyl)bis(methyl)silane (6 g, 17.6 mmol) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 2.83 (s, 2H), 0.78 (s, 9H), 0.74 (t, J = 6.0 Hz, 2H), 0.48 (d, J = 5.7 Hz, 2H), -0.00 (s, 6H). Step 3: 4-((1-((tert-butyldimethylsilyl)oxy)cyclopropyl)methyl)benzaldehyde

[0234] To solution of {1-[(p-bromophenyl)methyl]cyclopropoxy}(tert- butyl)bis(methyl)silane (3 g, 7.03 mmol) in tetrahydrofuran (30 mL, 369 mmol) was added lithium 1-butanide (540 mg, 1.2 eq., 8.44 mmol) at -78 °C. The resulting reaction was stirred at -78 °C for 30 min. To above reaction was added N,N-dimethylformamide (2.72 mL, 5 eq., 35.2 mmol). And the reaction was allowed to warm to RT for 1 h. The reaction was then quenched with 1 M citric acid and extracted with EtOAc. The extracts were washed with water and brine, dried over MgSO4, and evaporated and the residue was purified by silica gel chromatography eluting with EtOAc in PE from 0 to 2% to give 4-((1-((tert- butyldimethylsilyl)oxy)cyclopropyl)methyl)benzaldehyde (670 mg, 2.31 mmol) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H),2.95 (s, 2H), 0.81 (d, J = 5.0 Hz, 2H), 0.77 (s, 9H), 0.58 – 0.52 (m, 2H), -0.00 (d, J = 3.5 Hz, 6H).

[0235] Compounds in below table were prepared via procedures analogous to that described for intermediate 13.Intermediate 14: 6-ethynylnicotinaldehydeStep 1: 6-((trimethylsilyl)ethynyl)nicotinaldehyde

[0236] To a solution of 6-bromonicotinaldehyde (3.00 g, 16.1 mmol) in THF (15 mL) and TEA (15 mL) was added Pd(PPh3)4 (559 mg, 0.484 mmol) and CuI (153 mg, 0.806 mmol) at RT under nitrogen atmosphere. The reaction mixture was stirred at RT for 5 minutes. Ethynyltrimethylsilane (3.17 g, 32.2 mmol) was added into the mixture. The reaction mixture was stirred at RT for 18 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel (40 g), 0-50%, EA in PE) to give 6- ((trimethylsilyl)ethynyl)nicotinaldehyde (2.40 g, 73.2%) as a yellow solid. MS m / z [M+H]+204.3. Step 2: 6-ethynylnicotinaldehyde

[0237] A solution of 6-((trimethylsilyl)ethynyl)nicotinaldehyde (3.3 g, 16.2 mmol) and potassium carbonate (4.49 g, 2 eq., 32.5 mmol) in MeOH (50 mL, 1.23 mol) was stirred at RT for 1.5 h. The reaction mixture was diluted with water and extracted with DCM. The organic part was washed with brine and dried over sodium sulfate then concentrated under vacuum. The resulting residue was purified by column chromatography (15-30%, PE in EA) to afford 6-ethynylnicotinaldehyde.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.06 (d, J = 1.4 Hz, 1H), 8.26 (dd, J = 8.0, 2.1 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 4.69 (s, 1H). ESI MS m / z 132.0 [M+H]+ Intermediate 15: 5-((tert-butyldimethylsilyl)oxy)-1H-indazole

[0238] To a solution of 1H-indazol-5-ol (3.01 g, 22.4 mmol) and imidazole (2.28 g, 33.5 mmol) in DMF (30 mL) was added TBSCl (5.07 g, 33.5 mmol) at 0 ºC. The mixture was stirred at 60 ºC for 3 h. The mixture was poured into water and extracted with EA (100 mL *3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel (40 g), 0-100%, EA in PE) to give 5-((tert-butyldimethylsilyl)oxy)-1H-indazole (5.1 g, 91%) as a white solid. MS m / z [M+H]+249.4. Intermediate 16: 5-bromo-3-cyclopropyl-1H-indazoleStep 1: (5-bromo-2-fluorophenyl)(cyclopropyl)methanone

[0239] To a solution of 5-bromo-2-fluorobenzonitrile (3.0 g, 15.0 mmol) in THF (30 mL) was added cyclopropylmagnesium bromide (1.0 M in THF, 37.5 mL, 37.5 mmol) at -78 ºC. Themixture was stirred at -78 ºC for 2 h. HCl (3.0 M, 5.0 mL) was added in the mixture and stirred at RT for 10 min. The mixture was quenched with water and extracted with EA (50 mL *3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel (40 g), 0-100%, EA in PE) to give (5-bromo-2-fluorophenyl)(cyclopropyl)methanone (1.70 g, 46.6%) as a yellow oil. MS m / z [M+H]+243.1 / 245.0. Step 2: 5-bromo-3-cyclopropyl-1H-indazole

[0240] To a solution of (5-bromo-2-fluorophenyl)(cyclopropyl)methanone (1.70 g, 6.99 mmol) in DME (15 mL) was added hydrazinium hydroxide solution (5.0 mL). The mixture was stirred at 90 ºC for 2 h. The mixture was poured into water and extracted with EA (50 mL*3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel (20 g), 0-100%, EA in PE) to give 5-bromo-3-cyclopropyl-1H-indazole (1.20 g, 72.4%) as a white solid. MS m / z [M+H]+237.1 / 239.0. Intermediate 17: 4-(1H-indazol-5-yl)morpholineStep 1: 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)morpholine

[0241] To a solution of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (2.4 g, 7.33 mmol) in THF (20 mL) was added morpholine (962 µL, 1.5 eq., 11 mmol), BINAP (1.1 g, 0.24 eq., 1.76 mmol), Pd2(dba)3 (671 mg, 0.1 eq., 733 µmol), and NaOt-Bu (2.11 g, 3 eq., 22 mmol).The resulting deep purple solution was stirred at 55 ℃ for 18 h under nitrogen atmosphere. The reaction was diluted with EA and filtered through Celite, washing with EA. The filtrate was concentrated to give the crude. The pure title compound (2.1 g, 82%, colorlessoil) was obtained by flash column chromatography on silica gel (10-20%, EA in PE).1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.21 (dd, J = 9.1, 2.1 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 5.69 (s, 2H), 3.93 – 3.88 (m, 4H), 3.56 – 3.49 (m, 2H), 3.17 – 3.12 (m, 4H), 0.90 – 0.85 (m, 2H), -0.08 (s, 9H). MS m / z [M+H]+334.2. Step 2: 4-(1H-indazol-5-yl)morpholine

[0242] To a solution of 4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)morpholine (2.1 g, 6.3 mmol) in DMF(60 mL) was added TBAF (4.94 g, 3 eq., 18.9 mmol) and 1,2- ethanediamine (2.53 mL, 6 eq., 37.8 mmol) at RT. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was partitioned between EA and water. The organic layer was washed with water and brine, dried by anhydrous sodium sulfate, and concentrated in vacuo. The pure title compound (720 mg, 56%, colorless oil) was obtained by flash column chromatography on silica gel (30-40%, EA in PE).1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.99 (s, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.20 (dd, J = 9.0, 2.2 Hz, 1H), 7.15 (d, J = 1.7 Hz, 1H), 3.93 – 3.89 (m, 4H), 3.17 – 3.12 (m, 4H). MS m / z [M+H]+204.1. Intermediate 18: ((2-(4-bromophenyl)propan-2-yl)oxy)(tert-butyl)dimethylsilane

[0243] To a stirred solution of 2-(p-bromophenyl)-2-propanol (23 g, 107 mmol), imidazole (10.9 g, 1.5 eq., 160 mmol) in DMF (343 mL) was added (tert-butyl)(chloro)bis(methyl)silane (24.2 g, 1.5 eq., 160 mmol) and N,N-dimethyl-4-pyridylamine (13.1 g, 107 mmol). The reaction was stirred at 80 °C for 72 h. The reaction was diluted with water and extracted with EA. The combined extracts were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the pure title compound (23 g, 65%, colorless oil) was obtained from the residue by flash column chromatography on silica gel (petroleum ether).1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 1.58 – 1.52 (m, 6H), 0.97 – 0.90 (m, 11H), 0.10 – 0.04 (m, 6H). Intermediate 19: 1-(4-((trimethylsilyl)ethynyl)phenyl)propan-2-one

[0244] To the solution of 1-(p-bromophenyl)-2-propanone (3.61 mL, 23.5 mmol), dichloro- palladamethane—triphenylphosphine (1 / 2) (329 mg, 0.02 eq., 469 µmol), CuI (14.9 mg, 0.01 eq., 235 µmol) was added Et3N (0.1 L) and followed by ethynyltris(methyl)silane (4.97 mL, 1.5 eq., 35.2 mmol) under nitrogen atmosphere. The mixture was stirred at 65 ℃ for 16 h. The reaction was diluted with water and extracted with EA. The combined extracts were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the pure title compound (4.3 g, 79%, yellow oil) was obtained from the residue by flash column chromatography on silica gel (0-2%, EA in PE).1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.3 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 3.69 (s, 1H), 2.15 (s, 1H), 0.26 (s, 9H). Intermediate 20: 1-(4-(methylsulfonyl)phenyl)propan-2-one

[0245] To a solution of potassium peroxymonosulfate sulfate (17.9 g, 1.5 eq., 29.1 mmol) in water (23 mL) was added 1-(4-(methylthio)phenyl)propan-2-one (3.5 g, 1 eq., 19.4 mmol, preparation analogous to example 3, step 1) in MeOH-THF (30 mL-30 mL) at 0 °C. The solution was then allowed to warm to RT and was stirred for 24 h before being extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in a minimal amount of DCM followed by adding cold PE. The precipitated solid was filtered off, and dried to provide the title compound as a white solid (2.93 g, 71%).1H NMR (400 MHz, CDCl3) δ 7.94 – 7.89 (m, 2H), 7.42 – 7.37 (m, 2H), 3.84 (s, 2H), 3.06 (s, 3H), 2.24 (s, 3H). Intermediate 21: 1-cyclopropyl-2-(2-cyclopropylpyrimidin-5-yl)ethan-1-one

[0246] A mixture of 5-bromo-2-cyclopropylpyrimidine (0.3 g, 1.51 mmol), 1-cyclopropyl-1- ethanone (190 mg, 1.5 eq., 2.26 mmol), Pd2(dba)3 (270 mg, 0.4 eq., 603 µmol), BINAP (751 mg, 0.8 eq., 1.21 mmol), sodium t-butoxide (1.3 g, 9 eq., 13.6 mmol) in 1,4-dioxane (10 mL,117 mmol) was stirred at 70oC for 16 h. The crude was diluted with water and extracted with DCM. The organic phase was dried over with anhydrous Na2SO4 and concentrated. The resulting crude was purified on flash chromatograohy using silica-gel column (eluting with EA:PE = PE to 30% EA) to give 1-cyclopropyl-2-(2-cyclopropylpyrimidin-5-yl)ethan-1-one (160 mg, 791 µmol) as yellow oil. 1HNMR:(CDCl3) δ 8.41 (s, 2H), 3.80 (s, 1H), 2.23 (ddd, J = 13.0, 8.1, 4.8 Hz, 1H), 2.04 – 1.96 (m, 1H), 1.14 – 1.03 (m, 6H), 0.99 – 0.93 (m, 2H). Intermediate 22: synthesis of 1-(5-formylpyridin-2-yl)cyclobutane-1-carbonitrileStep 1: 1-(5-bromopyridin-2-yl)cyclobutane-1-carbonitrile

[0247] To a mixture of (5-bromo-2-pyridyl)acetonitrile (10 g, 50.8 mmol) in acetonitrile (120 mL) was added 1,3-dibromopropane (11.3 g, 1.1 eq., 55.8 mmol), sodium hydroxide (10.1 g, 5 eq., 254 mmol) and tetrabutylammonium bromide (1.64 g, 0.1 eq., 5.08 mmol) The reaction mixture was stirred at RT for 16 h. The reaction was diluted with water (150 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine (15 mL), dried over with dried over Na2SO4and evaporated under vacuo. The residue was purified by column chromatography on silica gel (10-25% EA in PE) to afford the title compound as a red solid (8.2 g, 65%).1H NMR (400 MHz, CDCl3) δ 6.77 (d, J = 1.3 Hz, 1H), 6.71 (d, J = 9.9 Hz, 1H), 6.60 (dd, J = 9.9, 1.6 Hz, 1H), 3.67 – 3.56 (m, 2H), 2.37 (t, J = 6.2 Hz, 2H), 1.95 – 1.83 (m, 2H). MS m / z [M+H]+237.0. Step 2: synthesis of 1-(5-formylpyridin-2-yl)cyclobutane-1-carbonitrile

[0248] To a mixture of sodium carbonate (1.88 g, 1.5 eq., 17.7 mmol), palladium—acetic acid (1 / 2) (107 mg, 0.04 eq., 472 µmol), N-formylsaccharin (3.74 g, 1.5 eq., 17.7 mmol), 1,3- bis(diphenylphosphino)propane (390 mg, 0.08 eq., 945 µmol) in 56 mL DMF was added 1-(5- bromo-2-pyridyl)cyclobutanecarbonitrile (2.8 g, 11.8 mmol)and triethylsilane (1.79 g, 1.3 eq., 15.4 mmol). The mixture was stirred for 10 min at RT, which is critical for the selectivity of the reaction. The reaction mixture was then stirred at 60 °C for 16 h, diluted with water (50 mL) and extracted with EA (50 mL x 3). The combined organic layer was washed with brine (45 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Thetitle compound (900 mg, 39%, red solid) was obtained from the residue by flash column chromatography on silica gel (10-25% EA in PE).1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 7.24 (s, 1H), 7.05 (d, J = 9.7 Hz, 1H), 6.81 (d, J = 9.7 Hz, 1H), 3.83 – 3.77 (m, 2H), 2.44 (t, J = 6.3 Hz, 2H), 2.00 (dd, J = 11.6, 5.9 Hz, 2H). MS m / z [M+H]+187.1. Intermediate 23: 2-(5-formylpyridin-2-yl)-2-methylpropanenitrileStep 1: synthesis of 2-methyl-2-(5-vinylpyridin-2-yl)propanenitrile

[0249] A solution of 2-(5-bromo-2-pyridyl)-2-methylpropiononitrile (9 g, 40 mmol), potassium vinyltrifluoroborate (10.7 g, 2 eq., 80 mmol), potassium carbonate (16.6 g, 3 eq., 120 mmol) and Pd(dppf)Cl2·CH2Cl2(1.31 g, 0.04 eq., 1.6 mmol) in 1,4-dioxane (0.1 L) and water (10 mL) was stirred at 100 °C for 2 h. It was then diluted with water (100 mL) and the resulting mixture was extracted with EA (200 mL x 3). The combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound (6 g, 83%, oil) was obtained from the residue by flash column chromatography on silica gel (0-10% EA in PE).1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.76 (dd, J = 8.2, 1.6 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 6.71 (dd, J = 17.6, 11.0 Hz, 1H), 5.84 (d, J = 17.7 Hz, 1H), 5.41 (d, J = 11.0 Hz, 1H), 1.76 (s, 6H). MS m / z [M+H]+173.1. Step 2: synthesis of 2-(5-formylpyridin-2-yl)-2-methylpropanenitrile

[0250] To a solution of 2-methyl-2-(5-vinyl-2-pyridyl)propiononitrile (6 g, 34.8 mmol) and potassium osmate(VI) dihydrate (642 mg, 0.05 eq., 1.74 mmol) in THF (60 mL) and water (20 mL, 1.11 mol) was added sodium tetraoxidoiodate (14.9 g, 2 eq., 69.7 mmol). The reaction mixture was stirred at rt for 1h, and then diluted with water (150 mL). The mixture was extracted with EA (200 mL x 3), and the combined organic layer was washed with brine (150 mL), dried over anhydrous sodium sulfate, and concentrated. under reduced pressure. The title compound (4 g, 63%, oil) was obtained from the residue by flash column chromatography on silica gel (0-12% EA in PE).1H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 9.06 (d, J = 1.4 Hz, 1H), 8.23 (dd, J = 8.2, 2.2 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 1.80 (s, 6H). MS m / z [M+H]+175.1.Example 2. Synthesis of Synthesis of 2,2-difluoro-N-((1R,2S)-1-(5-fluoro-1H-indazol- 1-yl)-1-(4-methoxyphenyl)propan-2-yl)propanamide (compound I-182)Step 1: tert-butyl (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate

[0251] To a solution of (tert-butoxycarbonyl)-L-alanine (20 g, 106 mmol) in DCM (250 mL) was added 1,1’-carbonyldiimidazole (25 g, 154 mmol) in portions at RT. The reaction mixture was stirred for 1.25 h. Then N,O-dimethylhydroxylamine hydrochloride (27 g, 278 mmol) was added and the reaction mixture was stirred at RT for 16 h. It was then diluted with water (500 mL), and extracted with DCM (500 mL × 2). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was adsorbed onto Isolute and purified by normal phase chromatography (Biotage, 80 g Silica gel-column; eluent 0-20% EA in PE). Product-containing fractions were combined and the solvent was removed by evaporation to give tert-butyl (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2- yl)carbamate (22 g, 89.6%) as white solid. MS m / z [M-55]+177.3. Step 2: tert-butyl (S)-(1-(4-methoxyphenyl)-1-oxopropan-2-yl)carbamate

[0252] To a solution of (4-methoxyphenyl)magnesium bromide (1 M solution in THF, 220 mL, 220 mmoL) in THF (20 mL) was added tert-butyl (S)-(1-(methoxy(methyl)amino)-1- oxopropan-2-yl)carbamate (22 g, 94.8 mmol) at -50o °C slowly. After the addition, the reaction mixture was stirred at RT for 16 h. It was diluted with NH4Cl(sat.) (500 mL), and extracted with EA (500 mL × 2). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was adsorbed onto Isolute and purified by normal phase chromatography (Biotage, 80 g Silica gel-column; eluent 0-10% EA in PE). Product-containing fractions were combined and the solvent was removed by evaporation to give tert-butyl (S)-(1-(4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (23 g, 87%) as white solid. MS m / z [M–55]+224.3. Step 3: tert-butyl ((1R,2S)-1-hydroxy-1-(4-methoxyphenyl)propan-2-yl)carbamate

[0253] To a solution of tert-butyl (S)-(1-(4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (23 g, 82.4 mmoL) in toluene (280 mL) and IPA (140 mL) was added triisopropoxyaluminum (54 g, 265 mmol) in portions. After the addition, the reaction mixture was stirred at 50 °C for 16 h. It was then diluted with NH4Cl(sat.) (800 mL) and filtered. The filtrate was extracted with EA (800 mL × 2). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was adsorbed onto Isolute and purified by normal phase chromatography (Silica gel, 0-15% EA in PE). Product-containing fractions were combined and the solvent was removed by evaporation to give tert-butyl ((1R,2S)-1-hydroxy- 1-(4-methoxyphenyl)propan-2-yl)carbamate (14 g, 60%) as white solid. MS m / z [M-55-18]+208.3. Step 4: (1R,2S)-2-amino-1-(4-methoxyphenyl)propan-1-ol

[0254] To a solution of tert-butyl ((1R,2S)-1-hydroxy-1-(4-methoxyphenyl)propan-2- yl)carbamate (14 g, 49.8 mmol) in 1,4-dioxane (70 mL) was added HCl in 1,4-dioxane (4M , 70 mL, 280 mmol). After the addition, the reaction mixture was stirred at RT for 3 h, and then concentrated. The residue was slurried in EA / PE (5%) and filtered. The collected off-white solid was dried to afford (1R,2S)-2-amino-1-(4-methoxyphenyl)propan-1-ol (6.6 g, 93%) as a white solid. MS m / z [M+H]+182.3. Step 5: (2S,3S)-2-(4-Methoxyphenyl)-3-methyl-1-((4-nitrophenyl)sulfonyl)aziridine

[0255] (1R,2S)-2-Amino-1-(4-methoxyphenyl)propan-1-ol (3.7 g, 17 mmol) was mixed with DCM (120 mL) at 20 °C.4-Nitrobenzenesulfonyl chloride (3.77 g, 17 mmol) was then added over 5 min. Afterward, the mixture was cooled to -27 °C. Triethylamine (8.6 g, 85 mmol) was slowly added while maintaining the temperature at -18 °C. The reaction mixture was cooled to -30 °C, and methanesulfonyl chloride (3.9 g, 34 mmol) was added slowly while maintaining the temperature at -25 °C. The reaction mixture was then stirred at 0 °C for 16 h. Water (120 mL) was subsequently added at 20 °C, and the resulting layers were separated. The organic layer was washed with water (80 mL) and concentrated. The crude product was purified by normal phase chromatography (Silica gel, 0-40% EA in PE). Product-containing fractions were combined and the solvent was removed by evaporation to give crude (2S,3S)-2-(4- methoxyphenyl)-3-methyl-1-((4-nitrophenyl)sulfonyl)aziridine (2.8 g, 8.05 mmol, 47.2% yield) as light yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 4.90 (d, J = 6.9 Hz, 1H), 3.72 (s, 1H), 3.69 (s, 3H), 1.11 (d, J = 6.6 Hz, 3H). MS m / z [M+H]+349.0. Step 6: N-((1R,2S)-1-(5-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)-4- nitrobenzenesulfonamide

[0256] A mixture of (2S,3S)-2-(4-methoxyphenyl)-3-methyl-1-((4- nitrophenyl)sulfonyl)aziridine (0.25 g, 0.72 mmol), 5-fluoro-1H-indazole (110 mg, 0.81 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in ACN (8 mL) was stirred at 50 °C for 16 h. The reaction mixture was concentrated. The residue was diluted with water (30 mL), and extracted with EA (30 mL × 2). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to afford N- ((1R,2S)-1-(5-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)-4- nitrobenzenesulfonamide (120 mg, 34%) and N-((1R,2S)-1-(5-fluoro-2H-indazol-2-yl)-1-(4- methoxyphenyl)propan-2-yl)-4-nitrobenzenesulfonamide (80 mg, 23%) in sequence as white solid.

[0257] N-((1R,2S)-1-(5-fluoro-2H-indazol-2-yl)-1-(4-methoxyphenyl)propan-2-yl)-4- nitrobenzenesulfonamide (P1):1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.36 (s, 1H), 8.19 (d, J = 8.9 Hz, 2H), 7.81 – 7.62 (m, 3H), 7.40 – 7.29 (m, 3H), 7.13 (td, J = 9.3, 2.4 Hz, 1H), 6.57 (d, J = 8.7 Hz, 2H), 5.38 (d, J = 10.6 Hz, 1H), 4.48 (dd, J = 10.2, 6.4 Hz, 1H), 3.61 (s, 3H), 0.85 (d, J = 6.3 Hz, 3H). LC-MS-2: MS m / z [M+H]+485.1.

[0258] N-((1R,2S)-1-(5-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)-4- nitrobenzenesulfonamide (P2):1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.24 – 8.11 (m, 3H), 7.68 (d, J = 8.9 Hz, 3H), 7.52 (dd, J = 9.0, 2.3 Hz, 1H), 7.32 – 7.17 (m, 3H), 6.53 (d, J = 8.7 Hz, 2H), 5.40 (d, J = 10.2 Hz, 1H), 4.43 (dd, J = 10.2, 6.4 Hz, 1H), 3.59 (s, 3H), 0.93 (d, J = 6.3 Hz, 3H). MS m / z [M+H]+485.1. Step 7: (1R,2S)-1-(5-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-amine

[0259] To a solution of N-((1R,2S)-1-(5-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan- 2-yl)-4-nitrobenzenesulfonamide (120 mg, 0.25 mmol) in 1,4-dioxane (4 mL) was addedsodium methoxide (30% in methanol, 4 mL) and the mixture was stirred at 50 °C for 3 h. It was then concentrated and the residue was diluted with water and extracted with. The combined organic phase was dried over sodium sulfate, filtered and concentrated to afford (1R,2S)-1-(5- fluoro-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-amine (70 mg, 93%) as yellow solid. MS m / z [M+H]+300.3. Step 8: 2,2-difluoro-N-((1R,2S)-1-(5-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2- yl)propanamide

[0260] To a solution of (1R,2S)-1-(5-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2- amine (70 mg, 0.23 mmol) and 2,2-difluoropropanoic acid (90 mg, 0.82 mmol) in THF (4 mL) was added 1-hydroxybenzotriazole (60 mg, 0.44 mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), followed by N,N-diisopropylethylamine (70 mg, 0.54 mmol), and the mixture was stirred at RT for 16 h. It was diluted with water and extracted with EA. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to afford 2,2- difluoro-N-((1R,2S)-1-(5-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2- yl)propanamide (33.3 mg, 37%) as white solid.1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 9.3 Hz, 1H), 8.19 (s, 1H), 7.66 (dd, J = 9.1, 4.1 Hz, 1H), 7.56 (dd, J = 9.0, 2.4 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.34 (td, J = 9.1, 2.5 Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H), 5.72 (d, J = 10.5 Hz, 1H), 5.08 (td, J = 9.9, 6.6 Hz, 1H), 3.67 (s, 3H), 1.38 (t, J = 19.5 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). MS m / z [M+H]+392.2. ee%=100%.

[0261] The following compounds in were synthesized according to the synthetic procedures described the example above. Table 3Example 3. Synthesis of rel-N-(1-(5-cyano-1H-indazol-1-yl)-1-(2-methoxypyrimidin-5- yl)propan-2-yl)-2,2-difluoropropanamide (compound I-134)Step 1: Synthesis of 2-methoxy-5-(2-nitroprop-1-en-1-yl)pyrimidine

[0262] 2-methoxy-5-pyrimidinecarbaldehyde (25 g, 181 mmol), nitroethane (0.1 L, 7.7 eq., 1.4 mol) and ammonium acetate (6.98 g, 0.5 eq., 90.5 mmol) were added in a 250mL round bottom flask. The mixture was stirred at 110 ℃ for 2 h. Upon completion the mixture was filtered, and the filtrate was evaporated under vacuum. The resulting residue was purified by column chromatography (Silica gel, 30-60% EA in PE) to obtain the target compound 2-methoxy-5- (2-nitroprop-1-en-1-yl)pyrimidine (13.3g, 37.6%).1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 8.07 (s, 1H), 3.99 (s, 3H), 2.42 (s, 3H). MS m / z [M+H]+196.1. Step 2: Synthesis of 1-(1-(2-methoxypyrimidin-5-yl)-2-nitropropyl)-1H-indazole-5- carbonitrile

[0263] To a solution of 2-methoxy-5-(2-nitroprop-1-en-1-yl)pyrimidine (1 g, 5.12 mmol) and 1H-indazole-5-carbonitrile (733 mg, 5.12 mmol) in ACN (10 mL, 191 mmol) was added DBU (1.53 mL, 2 eq., 10.2 mmol) at -40 ℃. The mixture was stirred at -40 ℃ until the reaction completed, and was then concentrated under vacuum. The residue was purified by column chromatography (Silica gel-40 g, 30~70% EA in PE) to afford 1-(1-(2-methoxypyrimidin-5- yl)-2-nitropropyl)-1H-indazole-5-carbonitrile (710 mg, 31.4%).1H NMR (400 MHz, DMSO- d6) δ 9.00 (s, 2H), 8.40 (d, J = 2.9 Hz, 2H), 8.16 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 10.7 Hz, 1H), 6.19 (dq, J = 13.3, 6.5 Hz, 1H), 3.88 (s, 3H), 1.53 (d, J = 6.7 Hz, 3H). MS m / z [M+H]+339.1.Step 3: Synthesis of 1-(2-amino-1-(2-methoxypyrimidin-5-yl)propyl)-1H-indazole-5- carbonitrile

[0264] To a reaction vial charged with 1-(1-(2-methoxypyrimidin-5-yl)-2-nitropropyl)-1H- indazole-5-carbonitrile (190 mg, 315 µmol), iron (630 mg, 7 eq., 11.3 mmol) and ammonium chloride (603 mg, 7 eq., 11.3 mmol) was added EtOH (11.7 mL, 0.2 mol) and water (2.34 mL, 130 mmol). The resulting mixture was stirred at 80°C for 1h, and then filtered through a Celite pad. The filtrate was concentrated and purified by column chromatography (Silica gel, 0~10% MeOH(1% NH3·H2O) in DCM) to afford 1-(2-amino-1-(2-methoxypyrimidin-5-yl)propyl)- 1H-indazole-5-carbonitrile (710 mg, 31.4%).1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 2H), 8.41 (s, 2H), 8.08 (d, J = 3.5 Hz, 1H), 7.78 (dd, J = 3.8, 1.4 Hz, 1H), 5.62 (d, J = 2.3 Hz, 1H), 3.98 – 3.89 (m, 1H), 3.86 (s, 3H), 0.99 (d, J = 6.4 Hz, 3H). MS m / z [M+H]+309.2. Step 4: Synthesis of N-(1-(5-cyano-1H-indazol-1-yl)-1-(2-methoxypyrimidin-5-yl)propan-2- yl)-2,2-difluoropropanamide

[0265] 2,2-difluoropropionyl chloride was prepared as 0.3M DCM solution by mixing 2,2- difluoropropionic acid (5 g, 45.4 mmol), oxalyl dichloride (3.88 mL, 0.1 eq., 45.4mmol) and N,N-dimethylformamide (332mg, 0.1 eq., 4.54mmol) in DCM (150 ml) at 0 ℃ for 1h, and was used as such for next step.

[0266] 1-[2-amino-1-(2-methoxy-5-pyrimidinyl)propyl]-1H-indazole-5-carbonitrile (560 mg, 1.82 mmol) and triethylamine (1.26 mL, 5 eq., 9.08 mmol) were dissolved in DCM, before 2,2- difluoropropionyl chloride (467 mg, 2 eq., 3.63 mmol) was added into the mixture slowly at 0 ℃. When the reaction was complete, the reaction mixture was washed successively with 10% citric acid, 10% sodium bicarbonate (aq.) and water, then dried over sodium sulfate and concentrated under vacuo. The resulting residue was purified by flash chromatography (C18- 80g, 20%~24% ACN in H2O), followed by chiral chromatography separation (Agilent 1260 HPLC; Column: CHIRALPAK® IC column (5.0 μm, 10 mm I.D.×250mmL); Flow rate: 2.5 mL / min; Mobile Phase: n-hexane:EtOH=40:60; Column temperature: RT) to afford rel-N- ((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(2-methoxypyrimidin-5-yl)propan-2-yl)-2,2- difluoropropanamide (7.1 mg, 17.7 µmol).1H NMR (400 MHz, CD3OD) δ 8.82 (s, 2H), 8.36 (s, 1H), 8.31 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 5.75 (d, J = 10.3 Hz, 1H), 5.17 (dq, J = 13.1, 6.6 Hz, 1H), 3.96 (s, 3H), 1.53 (t, J = 19.2 Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H). Chiral analysis condition: CHIRALCEL IC column 5.0 µm, 10 mm I.D.x250mmL;Flow rate: 0.6 mL / min; Mobile Phase: n-hexane:EtOH=60:40; Column temperature: 40 ⁰C. detection wavelength: 220 nm; Retention time: 9.88 minutes; purity: 100%.

[0267] The following compounds were synthesized according to the general synthetic procedures described in the example above. Table 4Example 4. Synthesis of rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(3- methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide (compound I-174)Step 1: 1-(3-methoxyphenyl)propan-2-one

[0268] To a solution of 3-iodoanisole (2.54 mL, 1 eq., 21.4 mmol) and 2,4-pentanedione (6.58 mL, 3 eq., 64.1 mmol) in DMSO (30 mL) was added copper iodide (814 mg, 0.2 eq., 4.27 mmol), and tripotassium phosphate trihydrate (17.1 g, 3 eq., 64.1 mmol). The resulting solution was stirred at 80 °C under nitrogen atmosphere. After 20 h, the solution was cooled, diluted with hydrochloric acid (50 mL, 2 M), and then extracted with EA (3 × 75 mL). The combined organic layers were dried over anhydrous sodium sulfate. The pure title compound (2.07 g, 59%, colorless oil) was obtained by flash column chromatography on silica gel (2-10%, EA in PE).1H NMR (500 MHz, CDCl3) δ 7.26 (m, 1H), 6.81 (dd, J = 14.8, 5.1 Hz, 2H), 6.75 (s, 1H), 3.80 (s, 3H), 3.66 (s, 2H), 2.15 (s, 3H). Step 2: 1-bromo-1-(3-methoxyphenyl)propan-2-one

[0269] To a solution of 1-(3-methoxyphenyl)propan-2-one (4.5 g, 1 eq., 27.4 mmol) in carbon tetrachloride (120 mL) was added NBS (5.37 g, 1.1 eq., 30.1 mmol) and AIBN (450 mg, 0.1 eq., 2.74 mmol). The resulting reaction mixture was degassed under nitrogen atmosphere and then heated to reflux for 1.5 h. The reaction mixture was cooled to RT and filtered. The filtrate was washed with NaHCO3(sat.), and then concentrated under reduced pressure. The pure title compound (5.6 g, 84%, off-white solid) was afforded by silica gel column chromatography (2- 10%, EA in PE).1H NMR (400 MHz, CDCl3) δ 7.33 – 7.22 (m, 1H), 7.03 – 6.95 (m, 2H), 6.89 (ddd, J = 8.3, 2.5, 0.8 Hz, 1H), 5.41 (s, 1H), 3.81 (s, 3H), 2.29 (s, 3H). Step 3: 1-(1-(3-methoxyphenyl)-2-oxopropyl)-1H-indazole-5-carbonitrile

[0270] To a solution of 1H-indazole-5-carbonitrile (2.36 g, 1 eq., 16.5 mmol) in MeCN (50 mL) was added potassium carbonate (4.55 g, 2 eq., 32.9 mmol). The resulting reaction mixture was stirred at 50 °C for 10 min, and then a solution of 1-bromo-1-(3-methoxyphenyl)propan- 2-one (4 g, 1 eq., 16.5 mmol) in MeCN (30 mL) was added. The reaction mixture was then heated to 80 °C. After being stirred for 3 h, the reaction mixture was cooled to RT, diluted with water, and extracted with EA. The combined organic layer was dried by anhydrous sodium sulfate, and solvent was removed under reduced pressure. The pure title compound (3.4 g, 67%, white solid) was obtained by flash column chromatography on silica gel (10-30%, EA in PE).1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 0.8 Hz, 1H), 8.12 (dd, J = 1.4, 0.8 Hz, 1H), 7.50 (dd, J = 8.8, 1.4 Hz, 1H), 7.34 – 7.28 (m, 2H), 6.97 – 6.88 (m, 3H), 6.33 (s, 1H), 3.77 (s, 3H), 2.28 (s, 3H). MS m / z [M+H]+306.1. Step 4: 1-(2-amino-1-(3-methoxyphenyl)propyl)-1H-indazole-5-carbonitrile

[0271] To a stirred solution of 1-(1-(3-methoxyphenyl)-2-oxopropyl)-1H-indazole-5- carbonitrile (1 g, 1 eq., 3.28 mmol) in MeOH (25 mL) was added ammonium acetate (2.52 g, 10 eq., 32.8 mmol) followed by several drops of acetic acid. After 10 min, sodium cyanoborohydride (412 mg, 2 eq., 6.55 mmol) was added and the resulting solution was stirred at 50 °C overnight. After cooling to RT, the reaction mixture was concentrated under vacuum, and the residue was diluted with water (25 mL) before extraction with EA. The combined organic layers were dried by anhydrous sodium sulfate and solvent was removed under reduced pressure. The title compound (900 mg, 89%, oil) was obtained by flash column chromatography on silica gel (2-20%, MeOH in DCM). MS m / z [M+H]+307.2. Step 5: rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(3-methoxyphenyl)propan-2-yl)-2,2- difluoropropanamide

[0272] To a solution of 2,2-difluoropropionic acid (485 mg, 1.5 eq., 4.41 mmol) in DCM (16 mL) was added oxalyl chloride (373 µL, 1.5 eq., 4.41 mmol) followed by two drops of DMF at 0 °C. The resulting solution was stirred at RT for 1 h before being added to a solution of 1- (2-amino-1-(3-methoxyphenyl)propyl)-1H-indazole-5-carbonitrile (900 mg, 1 eq., 2.94 mmol) and Et3N (1.63 mL, 4 eq., 11.8 mmol) in DCM (13 mL). After 1 h, NH4Cl (sat.) was added. The resulting mixture was extracted with DCM, and the combined organic layers were dried by anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting crude product was further purified by flash chromatography using C18 reversed phase column (50-65%, MeCN in H2O with 0.1% formic acid). Product-containing fractions were combined and lyophilized to afford rac-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(3- methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide (425 mg, white solid), which was further purified by chiral chromatography separation (CHIRALPAK AS-H column (5.0 μm, 10 mmI.D.×250mmL); Column temperature: RT; Mobile phase: n-hexane+0.1%DEA:EtOH=83:17; Flow rate: 3.0 mL / min) to afford rel-N-((1R,2S)-1-(5-cyano- 1H-indazol-1-yl)-1-(3-methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide.

[0273] 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 8.12 (s, 1H), 7.51 (dd, J = 8.8, 1.4 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.23 (t, J = 8.2 Hz, 1H), 6.96 (dd, J = 4.3, 2.4 Hz, 2H), 6.88 – 6.79 (m, 1H), 6.72 (d, J = 8.5 Hz, 1H), 5.86 (d, J = 7.9 Hz, 1H), 5.06 (m, J = 15.2, 7.7 Hz, 1H), 3.76 (s, 3H), 1.56 (t, J = 19.2 Hz, 3H), 1.34 (d, J = 6.8 Hz, 3H).

[0274] MS m / z [M+H]+399.2.

[0275] Chiral analysis condition: CHIRALPAK AS-H column (5.0 μm, 4.6 mmI.D.×250mmL); Column temperature: 40 °C; Mobile phase: n-hexane+0.1%DEA: EtOH=70:30; Flow rate: 0.8 mL / min; Detection wavelength: 254 nm; Retention time: 9.30 minutes and a purity of 97%.

[0276] The following compounds were synthesized according to the general synthetic procedures described in the example above. The indazole used in step 3 can be obtained commercially, or, if not, can be generated from corresponding haloindazole. Table 5Example 5. Synthesis of N-((1R,2S)-1-(5-cyano-2H-indazol-2-yl)-1-phenylpropan-2- yl)-2,2-difluoropropanamide (compound I-200)Step 1: methyl (S)-2-(2,5-dimethyl-1H-pyrrol-1-yl)propanoate

[0277] To a solution of methyl L-alaninate (10.0 g, 96.97 mmol) and hexane-2,5-dione (11.6 g, 101.82 mmol) in MeOH (250 mL) was added triethylamine (19.6 g, 193.95 mmol). The mixture was stirred at RT for 3 h, and then concentrated under reduced pressure. The crude product was adsorbed onto Isolute and purified by normal phase chromatography (Biotage, 80 g Silica gel-column; 0-5% EA in PE). Product-containing fractions were combined and the solvent was removed by evaporation to give methyl (S)-2-(2,5-dimethyl-1H-pyrrol-1- yl)propanoate (12 g, 68%). MS m / z [M+H]+182.1. Step 2: (S)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-N-methoxy-N-methylpropanamide

[0278] To a solution of methyl (S)-2-(2,5-dimethyl-1H-pyrrol-1-yl)propanoate (12.0 g, 66.21 mmol) and N,O-dimethylhydroxylamine Hydrochloride (7.7 g, 79.45 mmol) in THF (150 mL) was added isopropylmagnesium chloride (2M, 83 mL, 165.53 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with NH4Cl(sat.) and extracted with EA(250 mL × 3). The organic phase was washed with brine (250 mL), dried over sodium sulfate, filtered and concentrated to give 12 g crude product, which was used to the next step without further purification. MS m / z [M+H]+211.1. Step 3: (S)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-1-phenylpropan-1-one

[0279] To a solution of phenylmagnesium bromide (2.8M, 51 mL, 142.67 mmol) in THF (100 mL) was added (S)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-N-methoxy-N-methylpropanamide (12.0 g, 57.07 mmol) at 0 °C. The mixture was stirred at RT for 16 h, before NH4Cl(sat.) was added. The resulting mixture was extracted with EA (250 mL × 3). The organic phase was washed with brine (250 mL), dried over sodium sulfate, filtered and concentrated. The crude product was adsorbed onto Isolute and purified by normal phase chromatography (Biotage, 80 g Silica gel-column; 0-5% EA in PE). Product-containing fractions were combined, and the solvent was removed by evaporation to give (S)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-1-phenylpropan-1- one (12.7 g, 98%). MS m / z [M+H]+228.1. Step 4: (1S,2S)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-1-phenylpropan-1-ol

[0280] To a solution of (S)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-1-phenylpropan-1-one (10.0 g, 43.99 mmol) in THF (200 ml) was added L-selectride (88 mL, 87.99 mmol, 1 M in THF) at 0 °C. The mixture was stirred at RT for 6 h, before NH4Cl(sat.) was added, and the resulting mixture was extracted with EA (250 mL × 3). The combined organic phase was washed with brine (250 mL), dried over sodium sulfate, filtered and concentrated. The crude product was adsorbed onto Isolute and purified by normal phase chromatography (Biotage, 120 g Silica gel- column, 0-10% EA in PE). Product-containing fractions were combined and the solvent was removed by evaporation to give (1S,2S)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-1-phenylpropan-1-ol (6.7 g, 67 %). MS m / z [M+H]+230.1. Step 5: (1S,2S)-2-amino-1-phenylpropan-1-ol

[0281] To a solution of (1S,2S)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-1-phenylpropan-1-ol (1.7 g, 7.41 mmol) in IPA (60 mL) and water (10 mL) was added triethylamine (7.5 g, 74.13 mmol) and hydroxylamine hydrochloride (7.7 g, 111.20 mmol). The mixture was stirred at 100 °C for 16 h. It was then concentrated under reduced pressure and the crude product was used in the next step without further purification. MS m / z [M+H]+152.1. Step 6: tert-butyl ((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)carbamate

[0282] To a solution of (1S,2S)-2-amino-1-phenylpropan-1-ol (1.0 g, 6.61 mmol) in THF (60 mL) was added triethylamine (1.3 g, 13.23 mmol) and di-tert-butyl dicarbonate (1.5 g, 6.94 mmol). The mixture was stirred at RT for 16 h, before it was diluted with water and extracted with EA (100 mL × 3). The organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The crude product was adsorbed onto Isolute and purified by normal phase chromatography (Biotage, 40 g Silica gel-column, 0-15% EA in PE). Product- containing fractions were combined and the solvent was removed by evaporation to give tert- butyl ((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)carbamate (1.6 g, 96%). MS m / z [M-55-18]+178.1. Step 7: tert-butyl (4S,5S)-4-methyl-5-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide

[0283] To a solution of tert-butyl ((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)carbamate (500 mg, 1.99 mmol) and triethylamine (604 mg, 5.97 mmol) in DCM (20 mL) was added thionyl chloride (280 mg, 2.35 mmol) in DCM (5 mL) under -40 °C. The mixture was stirred at -40 °C for 1.5 h, and then diluted with water and extracted with DCM (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give 560 mg crude product, which was directly used in the next step without further purification. MS m / z [M+18]+315.1.Step 8: tert-butyl (4S,5S)-4-methyl-5-phenyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide

[0284] To a solution of tert-butyl (4S,5S)-4-methyl-5-phenyl-1,2,3-oxathiazolidine-3- carboxylate 2-oxide (500 mg, 1.68 mmol) in DCM (5 mL), ACN (10 mL) and water (10 mL) was added ruthenium(III) chloride hydrate(1:x) (4 mg, 0.02 mmol) and sodium periodate (540 mg, 2.52 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h and then stirred at RT for another h. Water was added and the resulting mixture was extracted with DCM (50 mL × 3). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give 570 mg crude product, which was directly used in the next step without further purification. MS m / z [M+H]+331.0. Step 9: tert-butyl ((1R,2S)-1-(5-cyano-2H-indazol-2-yl)-1-phenylpropan-2-yl)carbamate

[0285] To a solution of tert-butyl (4S,5S)-4-methyl-5-phenyl-1,2,3-oxathiazolidine-3- carboxylate 2,2-dioxide (570 mg, 1.82 mmol) in ACN (30 mL) was added 1H-indazole-5- carbonitrile (286 mg, 2.00 mmol) and cesium carbonate (1.18 g, 3.64 mmol). The mixture was stirred at 50 °C for 16 h, diluted with water, and extracted with EA (50 mL × 3). The organic phase was washed with saturated brine solution (50 mL), dried over sodium sulfate, filtered and concentrated to give 800 mg crude product, which was directly used in the next step without further purification. MS m / z [M+H]+377.1. Step 10: 2-((1R,2S)-2-amino-1-phenylpropyl)-2H-indazole-5-carbonitrile

[0286] To a solution of tert-butyl ((1R,2S)-1-(5-cyano-2H-indazol-2-yl)-1-phenylpropan-2- yl)carbamate (800 mg, 2.13 mmol) in DCM (30 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at RT for 2 h, and then concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-((1R,2S)-2-amino-1-phenylpropyl)-2H- indazole-5-carbonitrile (124 mg, 21%).1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.41 (s, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.65 (d, J = 7.2 Hz, 2H), 7.46 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 7.5 Hz, 2H), 7.33 (d, J = 7.2 Hz, 1H), 5.42 (d, J = 9.2 Hz, 1H), 4.03 – 3.92 (m, 1H), 1.85 – 1.26 (m, 2H), 0.84 (d, J = 6.2 Hz, 3H). MS m / z [M+H]+277.1. Step 11: N-((1R,2S)-1-(5-cyano-2H-indazol-2-yl)-1-phenylpropan-2-yl)-2,2- difluoropropanamide

[0287] To a solution of 2-((1R,2S)-2-amino-1-phenylpropyl)-2H-indazole-5-carbonitrile (60 mg, 0.22 mmol) and 2,2-difluoropropanoic acid (29 mg, 0.26 mmol) in THF (10 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (83 mg, 0.43 mmol), 1-hydroxybenzotriazole (59 mg, 0.43 mmol) and triethylamine (66 mg, 0.65 mmol). The mixture was stirred at RT for 16 h, diluted with water, and extracted with EA (50 mL × 3). The organic phase was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give N-((1R,2S)-1-(5-cyano- 2H-indazol-2-yl)-1-phenylpropan-2-yl)-2,2-difluoropropanamide (24.0 mg, 30 %) as white solid.1H NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.83 (d, J = 9.4 Hz, 1H), 8.41 (s, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 6.9 Hz, 2H), 7.49 (dd, J = 9.0, 1.4 Hz, 1H), 7.34 – 7.25 (m, 3H), 5.80 (d, J = 10.8 Hz, 1H), 5.19 (m, J = 10.0, 6.6 Hz, 1H), 1.33 (t, J = 19.4 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H). MS m / z [M+H]+369.3. ee%=93%.Example 6. Synthesis of N-(1-((1R,2S)-2-(2,2-Difluoropropanamido)-1-(4- methoxyphenyl)propyl)-1H-indazol-5-yl)-1H-imidazole-2-carboxamide (compound I- 131)Step 1: N-((1R,2S)-1-(5-Amino-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)-2,2- difluoropropanamide

[0288] To a solution of 2,2-difluoro-N-((1R,2S)-1-(4-methoxyphenyl)-1-(5-nitro-1H-indazol- 1-yl)propan-2-yl)propanamide (60 mg, 0.15 mol, synthesized analogously to example 1) in MeOH (4 mL) was added Pd / C(10%, 20 mg, 0.1 mmol) and the mixture was stirred at RT for 2 h under hydrogen. The catalyst was filtered off, and the filtrate was concentrated to afford N- ((1R,2S)-1-(5-amino-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)-2,2- difluoropropanamide (50 mg, 0.13 mmol, yield: 86%) as yellow solid. MS m / z [M+H]+389.0. Step 2: N-(1-((1R,2S)-2-(2,2-Difluoropropanamido)-1-(4-methoxyphenyl)propyl)-1H-indazol- 5-yl)-1H-imidazole-2-carboxamide

[0289] To a solution of N-((1R,2S)-1-(5-amino-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide (20 mg, 0.05 mol) and 2,2- difluoropropanoic acid (20 mg, 0.17 mmol) in THF (2 mL) was added 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg, 0.11 mol), 1- hydroxybenzotrizole (15 mg, 0.11 mmol), followed by N,N-diisopropylethylamine (20 mg,0.15 mmol) and the mixture was stirred at RT for 16 h. After dilution with water / EA (10 mL / 10 mL), the resulting mixture was extracted with EA (10 mL X 2). The combined organic phase was washed with brine, dried and concentrated. The residue was purified by preparative HPLC to afford N-(1-((1R,2S)-2-(2,2-difluoropropanamido)-1-(4-methoxyphenyl)propyl)-1H- indazol-5-yl)-1H-imidazole-2-carboxamide (0.8 mg, 0.0016 mmol, 3.2%) as white solid.1H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 10.42 (s, 1H), 8.71 (d, J = 9.3 Hz, 1H), 8.26 (d, J = 1.5 Hz, 1H), 8.18 (s, 1H), 7.80 (dd, J = 9.1, 1.9 Hz, 1H), 7.60 (d, J = 9.1 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.37 (s, 1H), 7.14 (s, 1H), 6.82 (d, J = 8.8 Hz, 2H), 5.69 (d, J = 10.5 Hz, 1H), 5.10 (m, J = 13.6 Hz, 1H), 3.67 (s, 3H), 1.38 (t, J = 19.5 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H). MS m / z [M+H]+483.2.

[0290] N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(3-methoxyphenyl)propan-2-yl)-2,2- difluoropropanamide (compound I-130) was also synthesized according to the general synthetic procedures described in the example above.

[0291] 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 10.30 (s, 1H), 8.75 (d, J = 9.7Hz, 1H), 8.61 (s, 1H), 8.24(s, 1H), 7.62 (d, J = 3.2Hz, 2H), 7.50 (d, J = 8.7Hz, 2H), 7.36 (s, 1H), 7.14 (s, 1H), 6.86 (d, J = 8.7Hz,2H), 5.60 (d, J = 10.8Hz, 1H), 5.12 (m, J = 9.7Hz, 1H), 3.69 (s, 3H), 1.38 (t, J = 19.4Hz, 3H), 0.94 (d, J = 6.5Hz, 3H). m / z [M+H]+483.2. Example 7. Synthesis of N-((1R,2S)-1-(5-Cyano-1H-indazol-1-yl)-1-(6- cyclopropylpyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide (compound I-114)Step 1: N-((1R,2S)-1-(5-Cyano-1H-indazol-1-yl)-1-(6-cyclopropylpyridin-3-yl)propan-2-yl)- 4-nitrobenzenesulfonamide

[0292] To a suspension of N-((1R,2S)-1-(6-chloropyridin-3-yl)-1-(5-cyano-1H-indazol-1- yl)propan-2-yl)-4-nitrobenzenesulfonamide (200 mg, 0.4 mmol, synthesized analogously to example 1) in 1,4-dioxane (5 mL) and water (0.5 mL) was added cyclopropylboronic acid (68 mg, 0.8 mmol), tricyclohexyl phosphine (22 mg, 0.08 mmol), potassium phosphate tribasic (254 mg, 1.2 mmol) and tris(dibenzylideneacetone)dipalladium (36 mg, 0.04 mmol) at RT under nitrogen protection. The resulting solution was stirred for 3 min at 110 °C. It was then partitioned between EA (30 mL) and water (50 mL). The aqueous layer was extracted with EA, the combined organic layers were then washed with brine, dried over sodium sulfate and evaporated. The crude product was purified by column chromatography (Silica gel, 0-50% [DCM:MeOH 5:1] in hexane). Product-containing fractions were combined and the solvent was removed by evaporation to give N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(6- cyclopropylpyridin-3-yl)propan-2-yl)-4-nitrobenzenesulfonamide (55 mg, 0.11 mmol, 27.4%). MS m / z [M+H]+503.2. Step 2: 1-((1R,2S)-2-Amino-1-(6-cyclopropylpyridin-3-yl)propyl)-1H-indazole-5-carbonitrile

[0293] To a suspension of N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(6-cyclopropylpyridin- 3-yl)propan-2-yl)-4-nitrobenzenesulfonamide (55 mg, 0.11 mmol) in 1,4-dioxane (5 mL) was added sodium methoxide (1 mL, 30% in methanol) at RT. The resulting solution was stirred for 16 h at 50°C. The solution was then partitioned between EA (30 mL) and water (50 mL). The aqueous layer was extracted with EA, the combined organic layers were then washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (Silica gel, 0-50% [DCM:MeOH 5:1] in hexane). Product-containing fractions were combined and the solvent was removed by evaporation to give the 1-((1R,2S)- 2-amino-1-(6-cyclopropylpyridin-3-yl)propyl)-1H-indazole-5-carbonitrile (40 mg, quant.). MS m / z [M+H]+318.2.Step 3: N-((1R,2S)-1-(5-Cyano-1H-indazol-1-yl)-1-(6-cyclopropylpyridin-3-yl)propan-2-yl)- 2,2-difluoropropanamide

[0294] To a suspension of 1-((1R,2S)-2-amino-1-(6-cyclopropylpyridin-3-yl)propyl)-1H- indazole-5-carbonitrile (40 mg, 0.12 mmol) and 2,2-difluoropropanoic acid (46 mg, 0.42 mmol) in DCM (3 mL) was added 1-hydroxybenzotriazole (16.2 mg, 0.12), 1-ethyl[3- (dimethylamino)propyl]carbodiimide (23 mg, 0.12 mmol) and triethylamine (24 mg, 0.24 mmol) at RT. The resulting solution was stirred for 3 h at RT. The solution was then partitioned between DCM (30 mL) and water (50 mL). The aqueous layer was extracted with DCM, the combined organic layers were then washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC to give N-((1R,2S)-1-(5- cyano-1H-indazol-1-yl)-1-(6-cyclopropylpyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide (4.9 mg, 0.012 mmol, 10%).

[0295] 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 9.2 Hz, 1H), 8.54 (s, 1H), 8.45 (d, J = 2.8 Hz, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.85 – 7.72 (m, 2H), 7.20 (d, J = 8.2 Hz, 1H), 5.82 (d, J = 10.3 Hz, 1H), 5.08 (m, J = 5.6 Hz, 1H), 2.00 (d, J = 4.7 Hz, 1H), 1.37 (t, J = 19.5 Hz, 3H), 0.95 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.7 Hz, 2H), 0.81 (s, 2H).

[0296] MS m / z [M+H]+410.2.

[0297] Rel-N-[(1S,2S)-2-(5-cyano-1H-indazol-1-yl)-2-(5-cyclopropyl-2-pyrimidinyl)-1- methylethyl]2,2-difluoropropionamide (I-27) was synthesized according to the general synthetic procedures described in the example above.

[0298] 1H NMR: (500 MHz, CDCl3) δ 8.36 (s, 2H), 8.28 – 8.16 (m, 3H), 7.57 (dd, J = 8.8, 1.4 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.00 (d, J = 4.6 Hz, 1H), 5.32 (d, J = 6.9 Hz, 1H), 1.85 – 1.77 (m, 1H), 1.59 (t, 3H), 1.35 (d, J = 6.9 Hz, 3H), 1.09 – 1.03 (m, 2H), 0.72 (dt, J = 7.9, 3.3 Hz, 2H).

[0299] LC-MS: m / z [M+H]+411.1.

[0300] Chiral analysis condition: Column Name: AS-H 4.6*100mm 5um; Flow rate: 3.0 mL / min; Mobile phase: CO2:EtOH [1%NH3(7M in MeOH)]=90:10; Column temperature: 40 °C; Detection wavelength: 214 nm; Retention time: 4.64 minutes; Purity: 100%. Example 8. Synthesis of rac-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(6- cyclopropoxypyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide (compound I-86)Step 1: Rac-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(6-cyclopropoxypyridin-3-yl)propan- 2-yl)-2,2-difluoropropanamide

[0301] To a mixture of rac-N-((1R,2S)-1-(5-bromo-1H-indazol-1-yl)-1-(6- cyclopropoxypyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide (50 mg, 0.13 mmol, synthesized analogously to example 2) in DMA (3.0 mL) was added Zn(CN)2(30 mg, 0.26 mmol), RuPhos Pd G3(11 mg, 0.013 mmol). The reaction mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere, poured into H2O and extracted with EA (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel (4 g), 0-100%, EA in PE) to give crude product, which was purified further by preparative HPLC (C18, 10-95%, MeCN in H2O with 0.1% HCOOH) to give rac-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(6- cyclopropoxypyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide (2.5 mg, 4.55%) as a white solid.

[0302] 1H NMR (400 MHz, DMSO-d6) δ 8.79 (d, J = 9.6 Hz, 1H), 8.45 (s, 1H), 8.44 (s, 1H), 8.36 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.87 (dd, J = 8.6, 2.4 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.83 (d, J = 10.4 Hz, 1H), 5.14 – 5.01 (m, 1H), 4.18 – 4.07 (m, 1H), 1.41 (t, J = 19.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.73 – 0.66 (m, 2H), 0.60 – 0.53 (m, 2H).

[0303] MS m / z [M+H]+426.4.

[0304] The following compounds were synthesized according to the general synthetic procedures described in the example above.Table 6201Example 9. Synthesis of (R)-N-(1-((1S*,2S*)-2-(2,2-difluoropropanamido)-1-(4- methoxyphenyl)propyl)-1H-indazol-5-yl)pyrrolidine-2-carboxamide (compound II-27) and (R)-N-(1-((1R*,2R*)-2-(2,2-difluoropropanamido)-1-(4-methoxyphenyl)propyl)-1H- indazol-5-yl)pyrrolidine-2-carboxamide (diastereomer 1 of compound II-27)Step 1: rac-N-((1R,2R)-1-(5-amino-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)-2,2- difluoropropanamide

[0305] To a solution of rac-tert-butyl (1-((1R,2R)-2-(2,2-difluoropropanamido)-1-(4- methoxyphenyl)propyl)-1H-indazol-5-yl)carbamate (180 mg, 0.368 mmol, synthesized analogously to example 2) in DCM (2.0 mL) was added HCl (4.0 M in dioxane, 2.0 mL). The reaction mixture was stirred at RT for 5 h, and then concentrated to give rac-N-((1R,2R)-1-(5- amino-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide (140 mg, 97.8%) as a yellow solid. MS m / z [M+H]+389.4. Step 2: tert-butyl (R)-2-((1-((1RS,2RS)-2-(2,2-difluoropropanamido)-1-(4- methoxyphenyl)propyl)-1H-indazol-5-yl)carbamoyl)pyrrolidine-1-carboxylate

[0306] To a solution of rac-N-((1R,2R)-1-(5-amino-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide (144 mg, 0.669 mmol) in DMF (8 mL), HATU (191 mg, 0.502 mmol) and DIEA (216 mg, 1.67 mmol) were added, followed by rac- N-((1R,2R)-1-(5-amino-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)-2,2- difluoropropanamide (130 mg, 0.335 mmol). The reaction mixture was stirred at RT for 5 h. It was then diluted with saturated NaHCO3(aq.) and the resulting mixture was extracted with DCM (40 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography(silica gel (10 g), 0-100% EA in PE) to give tert-butyl (R)-2-((1-((1RS,2RS)-2-(2,2- difluoropropanamido)-1-(4-methoxyphenyl)propyl)-1H-indazol-5-yl)carbamoyl)pyrrolidine- 1-carboxylate (170 mg, 86.7%) as a yellow solid. MS m / z [M+H]+586.6. Step 3: (R)-N-(1-((1S*,2S*)-2-(2,2-difluoropropanamido)-1-(4-methoxyphenyl)propyl)-1H- indazol-5-yl)pyrrolidine-2-carboxamide and (R)-N-(1-((1R*,2R*)-2-(2,2- difluoropropanamido)-1-(4-methoxyphenyl)propyl)-1H-indazol-5-yl)pyrrolidine-2- carboxamide

[0307] To a solution of tert-butyl (R)-2-((1-((1RS,2RS)-2-(2,2-difluoropropanamido)-1-(4- methoxyphenyl)propyl)-1H-indazol-5-yl)carbamoyl)pyrrolidine-1-carboxylate (160 mg, 0.273 mmol) in DCM (2 mL) was added HCl (4.0 M in dioxane, 2.0 mL). The reaction mixture was stirred at RT for 2 h, and then concentrated. The residue was purified by preparative HPLC (C18, 10-95%, MeCN in H2O with 0.1% HCOOH), followed by purification on SFC to give (R)-N-(1-((1S*,2S*)-2-(2,2-difluoropropanamido)-1-(4-methoxyphenyl)propyl)-1H-indazol- 5-yl)pyrrolidine-2-carboxamide (17 mg, 21%) and (R)-N-(1-((1R*,2R*)-2-(2,2- difluoropropanamido)-1-(4-methoxyphenyl)propyl)-1H-indazol-5-yl)pyrrolidine-2- carboxamide (6.2 mg, 8%) as a white solid. (R)-N-(1-((1S*,2S*)-2-(2,2-difluoropropanamido)-1-(4-methoxyphenyl)propyl)-1H-indazol- 5-yl)pyrrolidine-2-carboxamide

[0308] 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.60 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 11.2 Hz, 2H), 7.65 (d, J = 9.1 Hz, 1H), 7.49 (dd, J = 9.0, 1.9 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 5.84 (d, J = 9.0 Hz, 1H), 4.94 – 4.87 (m, 1H), 3.81 (dd, J = 8.6, 6.0 Hz, 1H), 3.69 (s, 3H), 2.98 – 2.89 (m, 3H), 2.13 – 2.06 (m, 1H), 1.83 – 1.68 (m, 3H), 1.29 (t, J = 19.5, 3H), 1.05 (d, J = 6.7 Hz, 3H.

[0309] MS m / z [M+H]+486.5. (R)-N-(1-((1R*,2R*)-2-(2,2-difluoropropanamido)-1-(4-methoxyphenyl)propyl)-1H-indazol- 5-yl)pyrrolidine-2-carboxamide

[0310] 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.61 (d, J = 8.9 Hz, 1H), 8.08 (d, J = 20.8 Hz, 2H), 7.63 (d, J = 9.1 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.84 (d, J = 8.9 Hz, 1H), 4.94 – 4.87 (m, 1H), 3.69 (s, 3H), 3.68 – 3.65 (m, 1H), 2.88 (t, J = 6.6 Hz, 2H), 2.06 – 1.99 (m, 1H), 1.79 – 1.62 (m, 3H), 1.28 (t, J = 19.5, 3H), 1.05 (d, J = 6.7 Hz, 3H.

[0311] MS m / z [M+H]+486.5. Example 10. Synthesis of rac-N-((1R,2S)-1-(6-cyclopropoxypyridin-3-yl)-1-(5-(4- fluorophenoxy)-1H-indazol-1-yl)propan-2-yl)-2,2-difluoropropanamide (compound I- 75)Step 1: Rac-N-((1R,2S)-1-(6-cyclopropoxypyridin-3-yl)-1-(5-hydroxy-1H-indazol-1- yl)propan-2-yl)-2,2-difluoropropanamide

[0312] To a solution of rac-N-((1R,2S)-1-(5-((tert-butyldimethylsilyl)oxy)-1H-indazol-1-yl)- 1-(6-cyclopropoxypyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide (180 mg, 0.339 mmol, synthesized analogously to example 2) in THF (2.0 mL) was added TBAF (1.0 M in THF, 0.51 mL). The mixture was stirred at 50 °C for 6 h, diluted with NH4Cl (sat.), and then extracted with EA (50 mLx3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel (10 g), 0-100%, EA in PE) to give rac-N-((1R,2S)-1-(6- cyclopropoxypyridin-3-yl)-1-(5-hydroxy-1H-indazol-1-yl)propan-2-yl)-2,2- difluoropropanamide (150 mg, 95.6%) as a yellow oil. MS m / z [M+H]+417.4. Step 2: Rac-N-((1R,2S)-1-(6-cyclopropoxypyridin-3-yl)-1-(5-(4-fluorophenoxy)-1H-indazol- 1-yl)propan-2-yl)-2,2-difluoropropanamide

[0313] To a solution of rac-N-((1R,2S)-1-(6-cyclopropoxypyridin-3-yl)-1-(5-hydroxy-1H- indazol-1-yl)propan-2-yl)-2,2-difluoropropanamide (25 mg, 0.060 mmol), (4- fluorophenyl)boranediol (25 mg, 0.18 mmol) and 4Å Molecular Sieves (250 mg) in DCE (3.0 mL) and pyridine (0.5 mL) was added Cu(OAc)2(36 mg, 0.18 mmol). The mixture was stirred at 80 °C for 16 h under a balloon of oxygen. The mixture was then filtered and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel (10 g), 0-100%, EA in PE) to give crude product. The crude product was further purified by preparative HPLC (C18, 10-95%, MeCN in H2O with 0.1% HCOOH) to give rac-N-((1R,2S)-1-(6-cyclopropoxypyridin-3-yl)-1-(5-(4-fluorophenoxy)-1H-indazol-1-yl)propan-2-yl)-2,2- difluoropropanamide (2.2 mg, 7.2%) as a white solid.

[0314] 1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 9.5 Hz, 1H), 8.33 (d, J = 2.3 Hz, 1H), 8.17 (s, 1H), 7.86 (dd, J = 8.6, 2.5 Hz, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.34 (d, J = 2.1 Hz, 1H), 7.27 – 7.16 (m, 3H), 7.06 – 6.99 (m, 2H), 6.78 (d, J = 8.6 Hz, 1H), 5.74 (d, J = 10.5 Hz, 1H), 5.17 – 4.98 (m, 1H), 4.19 – 4.06 (m, 1H), 1.40 (t, J = 19.5 Hz, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.75 – 0.67 (m, 2H), 0.61 – 0.54 (m, 2H).

[0315] MS m / z [M+H]+511.5. Example 11. Synthesis of (R*)-N-(1-((1SR,2RS)-2-(2,2-difluoropropanamido)-1-(4- methoxyphenyl)propyl)-1H-indazol-5-yl)pyrrolidine-2-carboxamide (compound I-117)

[0316] To a solution of rac-2,2-difluoro-N-((1R,2S)-1-(5-iodo-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)propanamide (150 mg, 0.300 mmol) in Pyridine (6 mL) was added tetrahydropyrrole-2-carboxamide hydrochloride (181 mg, 1.20 mmol), K2CO3(249 mg, 1.80 mmol), CuI (343 mg, 1.80 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 120 ℃ for 18 h. The mixture was filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-10%, MeOH in DCM) to give crude product. The crude product was purified by Prep-HPLC (C18, 10-95%, MeCN in H2O with 0.1% HCOOH) to give tile compound (8.0 mg, 5.5%) as a white solid.

[0317] 1H NMR (400 MHz, DMSO) δ 10.01 (s, 1H), 8.67 (d, J = 10.1 Hz, 1H), 8.13 (s, 2H), 7.56 (s, 2H), 7.42 (d, J = 7.1 Hz, 2H), 6.82 (d, J = 7.1 Hz, 2H), 5.68 (d, J = 10.7 Hz, 1H), 5.12 – 5.01 (m, 1H), 3.76 – 3.71 (m, 1H), 3.67 (d, J = 2.6 Hz, 3H), 2.91 (t, J = 6.2 Hz, 2H), 2.14 – 1.95 (m, 2H), 1.82 – 1.75 (m, 1H), 1.70 – 1.62 (m, 2H), 1.38 (t, J = 19.5 Hz, 3H), 0.93 (d, J = 6.3 Hz, 3H).

[0318] MS m / z [M+H]+486.5.

[0319] Rel-1-(1-((1R,2S)-2-(2,2-difluoropropanamido)-1-(4-(trifluoromethyl)phenyl)propyl)- 1H-indazol-5-yl)-1H-imidazole-2-carboxamide (Compound I-7) was also synthesized according to the general synthetic procedures described in the example above.

[0320] 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.73 (d, J = 1.0 Hz, 1H), 7.58 – 7.49 (m, 4H), 7.39 – 7.30 (m, J = 20.5, 5.2 Hz, 2H), 7.25 (s, 1H), 7.18 (s, 1H), 7.14 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.78 (d, J = 8.3 Hz, 1H), 5.34 (s, 1H), 5.18 – 4.94 (m, J = 15.2, 8.0 Hz, 1H), 1.53 (t, J = 19.3 Hz, 3H), 1.21 (d, J = 6.7 Hz, 3H).

[0321] MS m / z [M+H]+521.1.

[0322] Chiral analysis condition: CHIRALPAK IC (5.0 µm, 4.6 mmI.D.x250mmL); Flow rate: 1.0 mL / min; Mobile phase: n-hexane:EtOH = 70:30; Column temperature: 40 °C; Detection wavelength: 254 nm; Retention: 5.31 minutes; Purity: 99%. Example 12. Synthesis of rac-N-((1R,2S)-1-(6-cyclopropoxypyridin-3-yl)-1-(5-(pyrazin- 2-yl)-1H-indazol-1-yl)propan-2-yl)-2,2-difluoropropanamide (compound II-25)

[0323] To a solution of rac-N-((1R,2S)-1-(5-bromo-1H-indazol-1-yl)-1-(6- cyclopropoxypyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide (50 mg, 0.104 mmol, synthesized analogously to example 2) and 2-(tributyl-λ4-stannanyl)pyrazine (77 mg, 0.20 mmol) in dioxane (1.0 mL) was added Pd(PPh3)4(20 mg, 0.017 mmol). The mixture was stirred at 110 °C for 3 h under a nitrogen atmosphere, and then filtered. The filtrate was concentrated, and the resulting residue was purified by flash chromatography (silica gel (10 g), 0-100%, EA in PE) to give crude product. The crude product was purified by preparativeHPLC (C18, 10-95%, MeCN in H2O with 0.1% HCOOH) to give rac-N-((1R,2S)-1-(6- cyclopropoxypyridin-3-yl)-1-(5-(pyrazin-2-yl)-1H-indazol-1-yl)propan-2-yl)-2,2- difluoropropanamide (7.7 mg, 15%) as a white solid.

[0324] 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.80 (d, J = 9.5 Hz, 1H), 8.71 (s, 1H), 8.62 – 8.56 (m, 2H), 8.37 (s, 2H), 8.27 (d, J = 8.8 Hz, 1H), 7.95 – 7.84 (m, 2H), 6.79 (d, J = 8.7 Hz, 1H), 5.83 (d, J = 10.6 Hz, 1H), 5.18 – 5.05 (m, 1H), 4.19 – 4.04 (m, 1H), 1.42 (t, J = 19.5 Hz, 3H), 0.99 (d, J = 6.5 Hz, 3H), 0.74 – 0.67 (m, 2H), 0.60 – 0.54 (m, 2H). MS m / z [M+H]+479.5.

[0325] The following compounds were synthesized according to the general synthetic procedures described in the example above. Table 7Example 13. Synthesis of rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(4- cyclopropylphenyl)propan-2-yl)-2,2-difluoropropanamide (compound I-165)Step 1: 1-(1-(4-cyclopropylphenyl)-2-oxopropyl)-1H-indazole-5-carbonitrile

[0326] To a reaction vial charged with 1-(1-(4-bromophenyl)-2-oxopropyl)-1H-indazole-5- carbonitrile (0.3 g, 1 eq., 847 µmol; synthesized analogously to example 3), cyclopropylboronic acid (109 mg, 1.5 eq., 1.27 mmol), palladium acetate (19 mg, 0.1 eq., 84.7 µmol), tricyclohexyl phosphine (23.8 mg, 0.1 eq., 84.7 µmol) and tripotassium phosphate (719 mg, 4 eq., 3.39 mmol) was added toluene (8 mL) and water (0.4 mL). The reaction vial was capped and degassed under a nitrogen atmosphere, and the reaction mixture was stirred at 105 °C for 15 h. After cooling to RT, the mixture was diluted with ethyl acetate, and then washed with water. The organic layer was separated, and the aqueous layer was extracted with two additional portions of EA. The combined organic layers were dried by anhydrous sodium sulfate, and solvent was removed under reduced pressure. The pure title compound (150 mg, 56%, yellow oil) was obtained by flash column chromatography on silica gel (10-20%, EA in PE).

[0327] 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 0.7 Hz, 1H), 8.12 (s, 1H), 7.50 (dd, J = 8.8, 1.4 Hz, 1H), 7.28 – 7.22 (m, 3H), 7.10 (d, J = 8.2 Hz, 2H), 6.31 (s, 1H), 2.26 (s, 3H), 1.89 (td, J = 8.4, 4.2 Hz, 1H), 1.02 – 0.96 (m, 2H), 0.73 – 0.67 (m, 2H).MS m / z [M+H]+316.2.

[0328] Following the fourth and fifth steps of Example 4, title compound rel-N-((1R,2S)-1-(5- cyano-1H-indazol-1-yl)-1-(4-cyclopropylphenyl)propan-2-yl)-2,2-difluoropropanamide (compound I-165) was isolated as a white solid.

[0329] Chiral separation condition: CHIRALPAK IC column (5.0 μm, 10 mmI.D.x250mmL); Column temperature: 40 °C; Mobile phase: n-hexane+0.1%DEA:EtOH=82:18; Flow rate: 1.0 mL / min.

[0330] 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.15 – 8.09 (m, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.54 (dd, J = 8.0, 1.2 Hz, 1H), 5.84 (d, J = 8.0 Hz, 1H), 5.00-4.94 (m, 1H), 1.88 – 1.80 (m, 1H), 1.52-1.33 (t, 3H), 1.34 (d, J = 8.0 Hz, 3H), 0.98 – 0.90 (m, 2H), 0.64-0.63 (m, 2H).

[0331] MS m / z [M+H]+408.2.

[0332] Chiral analysis condition: CHIRALPAK IC column (5.0 μm, 4.6 mmI.D.×250mmL); Column temperature: 40 °C; Mobile Phase: n-hexane+0.1%DEA: EtOH=70:30; Flow rate: 1.0 mL / min; Detection wavelength:254 nm. Retention time: 5.31 minutes and a purity of 100%.

[0333] The following compounds were synthesized according to the general synthetic procedures described in the example above. Table 8Example 14. Synthesis of rel-2,2-difluoro-N-((1R,2S)-1-(4-methoxyphenyl)-1-(5-(4- methoxyphenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)propan-2-yl)propanamide (compound I-127)Step 1: 1-(4-methoxyphenyl)-1-(5-(6-methoxypyridin-3-yl)-1H-indazol-1-yl)propan-2-one

[0334] To a solution of 1-(5-bromo-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-one (310 mg, 1 eq., 863 µmol, synthesized analogously to example 3) in 9 mL toluene was added (6-methoxypyridin-3-yl)boronic acid (396 mg, 3 eq., 2.59 mmol), Pd(OAc)2(38.7 mg, 0.2 eq., 173 µmol), tricyclohexyl phosphine (96.8 mg, 0.4 eq., 345 µmol) and K3PO4(550 mg, 3 eq., 2.59 mmol), followed by 3 mL of water under a nitrogen atmosphere. The reaction solution was stirred at 100 °C overnight. After cooling to RT, water was added, and the mixture was extracted with two portions of EA. The combined organic layers were dried by anhydrous sodium sulfate, and solvent was removed under reduced pressure. The pure title compound (238 mg, 70%, yellow oil) was obtained by flash column chromatography on silica gel (0-20%, EA in PE).

[0335] 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.4 Hz, 1H), 8.22 (s, 1H), 8.06 – 8.02 (m, 2H), 7.80 (d, J = 8.9 Hz, 1H), 7.71 (dd, J = 8.8, 1.6 Hz, 1H), 7.33 (d, J = 8.7 Hz, 2H), 6.92 (dd, J = 8.9, 2.4 Hz, 3H), 6.87 (s, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 2.11 (s, 3H).

[0336] MS m / z [M+H]+388.2.

[0337] Following the fourth and fifth step of Example 4, title compound rel-2,2-difluoro-N- ((1R,2S)-1-(4-methoxyphenyl)-1-(5-(4-methoxyphenyl)-1H-pyrazolo[4,3-b]pyridin-1- yl)propan-2-yl)propanamide (compound I-127) was obtained as a white solid.

[0338] Chiral separation condition: CHIRALPAK IC column (5.0 μm, 10 mmI.D.×250mmL); Column temperature: RT; Mobile Phase: n-hexane:EtOH=60:40; Flow rate: 2.0 mL / min; Chiral analysis condition: CHIRALPAK IC (5.0 μm, 4.6 mmI.D.×250mmL); Column temperature: RT. Mobile Phase: n-hexane:EtOH=70:30; Flow rate: 1.0 mL / min; detection wavelength: 254 nm; Retention time: 7.39 minutes and a purity of 100%.

[0339] 1H NMR (400 MHz, CD3OD) δ 8.37 (d, J = 2.4 Hz, 1H), 8.15 (s, 1H), 7.96 (dd, J = 8.6, 2.5 Hz, 1H), 7.92 (s, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.63 (dd, J = 8.8, 1.4 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.6 Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H), 5.67 (d, J = 10.5 Hz, 1H), 5.28 (dq, J = 13.0, 6.5 Hz, 1H), 3.94 (s, 3H), 3.72 (s, 3H), 1.39 (t, J = 19.1 Hz, 3H), 1.11 (d, J = 6.5 Hz, 3H).

[0340] MS m / z [M+H]+481.3.Example 15. Synthesis of rel-2,2-difluoro-N-((1R,2S)-1-(4-methoxyphenyl)-1-(5- (pyrazin-2-yl)-1H-indazol-1-yl)propan-2-yl)propanamide (compound I-113)Step 1: 1-(4-methoxyphenyl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol- 1-yl)propan-2-one

[0341] To a stirred solution of 1-(5-bromo-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2- one (0.1 g, 1 eq., 278 µmol; synthesized analogously to example 3) in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (106 mg, 1.5 eq., 418 µmol) , potassium acetate (82 mg, 3 eq., 835 µmol) and Pd(dppf)Cl2·CH2Cl2(22.6 mg, 0.1 eq., 27.8 µmol). The reaction mixture was stirred under a nitrogen atmosphere at 100 °C for 16 h. After cooling to RT, the mixture was diluted with EA and washed with water. The layers were separated, and the aqueous layer was extracted with two additional portions of EA. The combined organic layers were dried by anhydrous sodium sulfate, and solvent was removed under reduced pressure. The pure title compound (60 mg, 48%, yellow oil) was obtained by flash column chromatography on silica gel (0-10%, EA in PE).

[0342] 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.11 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.30 – 7.27 (m, 1H), 7.26 – 7.21 (m, 2H), 6.89 (d, J = 8.6 Hz, 2H), 6.22 (s, 1H), 3.79 (s, 3H), 2.19 (s, 3H), 1.35 (s, 12H).

[0343] MS m / z [M+H]+407.3. Step 2: 1-(4-methoxyphenyl)-1-(5-(pyrazin-2-yl)-1H-indazol-1-yl)propan-2-one

[0344] A microwave tube was charged with 1-(4-methoxyphenyl)-1-(5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)propan-2-one (700 mg, 1 eq., 1.72 mmol), 2- bromopyrazine (274 mg, 1.72 mmol), PdCl2(dppf) (189 mg, 0.15 eq., 258 µmol) and dipotassium carbonate (714 mg, 3 eq., 5.17 mmol) in 1,4-dioxane (11.5 mL) and water (2.3 mL). The tube was sealed and the reaction mixture was stirred for 1.5 h at 100 °C assisted by microwave. After cooling to RT, water was added, the two layers were separated, and the aqueous layer was extracted with two additional portions of EA. The combined organic layers were dried by anhydrous sodium sulfate, and solvent was removed under reduced pressure. The title compound (500 mg, 72%, yellow oil) was obtained by flash column chromatography on silica gel (10-20%, EA in PE).

[0345] 1H NMR (400 MHz, CDCl3) δ 9.06 (d, J = 1.3 Hz, 1H), 8.65 – 8.60 (m, 1H), 8.49 (d, J = 2.4 Hz, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 8.03 (dd, J = 8.9, 1.5 Hz, 1H), 7.33 (dd, J = 8.4, 6.1 Hz, 3H), 6.93 (d, J = 8.7 Hz, 2H), 6.29 (s, 1H), 3.81 (s, 3H), 2.25 (s, 3H).

[0346] MS m / z [M+H]+359.2.

[0347] Following the fourth and fifth steps of Example 4, title compound rel-2,2-difluoro-N- ((1R,2S)-1-(4-methoxyphenyl)-1-(5-(pyrazin-2-yl)-1H-indazol-1-yl)propan-2-yl)propanamide (compound I-113) was obtained as a white solid.

[0348] Chiral separation condition： CHIRALCEL IC column (5.0 μm, 10 mmI.D.×250mmL); Column temperature: RT; Mobile Phase: n-hexane+0.1%DEA:EtOH=70:30; Flow rate: 2.5 mL / min; Chiral analysis condition：CHIRALCEL IC column (5.0 μm, 4.6 mmI.D.×250mmL); Column temperature: 40 °C; Mobile phase: n-hexane:EtOH=70:30; Flow rate: 1.0 mL / min; Detection wavelength: 254 nm; Retention time: 9.80 minutes and a purity of 100%.

[0349] 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.62 (s, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.40 (s, 1H), 8.20 (s, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 6.64 (d, J = 7.8 Hz, 1H), 5.83 (d, J = 7.4 Hz, 1H), 5.07 – 4.94 (m, 1H), 3.77 (s, 3H), 1.59 (t, J = 19.2 Hz, 3H), 1.36 (d, J = 6.8 Hz, 3H).

[0350] MS m / z [M+H]+452.3. Example 16. Synthesis of rel-2,2-difluoro-N-((1R,2S)-1-(4-methoxyphenyl)-1-(5-(6- methoxypyridin-3-yl)-2H-indazol-2-yl)propan-2-yl)propanamide (compound I-129)Step 1: 1-(4-methoxyphenyl)-1-(5-(6-methoxypyridin-3-yl)-2H-indazol-2-yl)propan-2-one

[0351] To a solution of 5-(6-methoxypyridin-3-yl)-1H-indazole (711 mg, 1 eq., 3.16 mmol, synthesized analogously to intermediate 2) and dipotassium carbonate (1.31 g, 3 eq., 9.47 mmol) in DMF (10 mL) was added 1-bromo-1-(4-methoxyphenyl)propan-2-one (1.15 g, 1.5 eq., 4.73 mmol, synthesized analogously to example 3). The mixture was stirred at 80 °C for 3 h, cooled to RT, and diluted with EA and water. The layers were separated, and the aqueous layer was then extracted with EA. The combined organic layers were dried by anhydrous sodium sulfate, and solvent was removed under reduced pressure. The pure title compound (878 mg, 47%, yellow oil) was obtained by flash column chromatography on silica gel (20-50%, EA in PE). MS m / z [M+H]+388.2.

[0352] Following the fourth and fifth steps of Example 4, title compound rel-2,2-difluoro-N- ((1R,2S)-1-(4-methoxyphenyl)-1-(5-(6-methoxypyridin-3-yl)-2H-indazol-2-yl)propan-2- yl)propanamide (compound I-129) was isolated as a white solid.

[0353] Chiral separation condition: CHIRALPAK IC column (5.0 μm, 10 mmI.D.×250mmL); Column temperature: RT; Mobile Phase: n-hexane:EtOH=85:15; Flow rate: 3.0 mL / min; Chiral analysis condition: CHIRALPAK IC (5.0 μm, 4.6 mmI.D.×250mmL); Column temperature: RT; Flow rate: 1.0 mL / min; Mobile Phase: n-hexane:EtOH=70:30; Flow rate: 1.0 mL / min; Detection wavelength: 254 nm; Retention time: 5.51 minutes and a purity of 100%.

[0354] 1H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 8.38 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 8.6, 2.5 Hz, 1H), 7.86 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.55 (dd, J = 11.4, 5.1 Hz, 3H), 6.88 (dd, J = 8.9, 2.3 Hz, 3H), 5.59 (d, J = 10.9 Hz, 1H), 5.25 (m, J = 12.9, 6.4 Hz, 1H), 3.94 (s, 3H), 3.74 (s, 3H), 1.40 (t, J = 19.1 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H).

[0355] MS m / z [M+H]+481.3.

[0356] The following compounds were synthesized according to the general synthetic procedures described in the example above. Table 9Example 17. Synthesis of rel-2,2-difluoro-N-((1R,2S)-1-(4-methoxyphenyl)-1-(5- morpholino-1H-indazol-1-yl)propan-2-yl)propanamide (compound I-135)

[0357] To a vial was added cesium carbonate (432 mg, 3 eq., 1.33 mmol) and RuPhos-Pd-G3 (37 mg, 0.1 eq., 44.2 µmol). The mixture was degassed, and then a mixture of N-(1-(5-bromo- 1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide (0.2 g, 1 eq., 442 µmol; synthesized analogously to example 3) and morpholine (77.4 µL, 2 eq., 884 µmol)in 1,4-dioxane (8 mL) was added. The resulting solution was stirred at 100 °C for 2 h under a nitrogen atmosphere assisted by microwave. The reaction mixture was cooled to RT, diluted with EA and filtered through Celite. The filtrate was concentrated, and the residue was purified by flash chromatography using C18 reversed phase column (60-70%, MeCN in H2O with 0.1% formic acid). Product-containing fractions were combined and lyophilized to afford rac-2,2- difluoro-N-((1R,2S)-1-(4-methoxyphenyl)-1-(5-morpholino-1H-indazol-1-yl)propan-2- yl)propenamide (90 mg, white solid) and rac-2,2-difluoro-N-((1S,2S)-1-(4-methoxyphenyl)-1- (5-morpholino-1H-indazol-1-yl)propan-2-yl)propenamide (12 mg, white solid).

[0358] Rac-2,2-difluoro-N-((1R,2S)-1-(4-methoxyphenyl)-1-(5-morpholino-1H-indazol-1- yl)propan-2-yl)propenamide:1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.70 (s, 1H), 7.38 (dd, J = 9.1, 1.9 Hz, 1H), 7.33 – 7.29 (m, 2H), 7.27 (s, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 8.3 Hz, 1H), 5.78 (d, J = 7.5 Hz, 1H), 4.97 (dd, J = 15.2, 7.4 Hz, 1H), 4.09 – 4.05 (m, 4H), 3.77 (s, 3H), 3.44 – 3.40 (m, 4H), 1.62 (d, J = 19.2 Hz, 3H), 1.34 (d, J = 6.8 Hz, 3H). MS m / z [M+H]+459.3.

[0359] Rac-2,2-difluoro-N-((1S,2S)-1-(4-methoxyphenyl)-1-(5-morpholino-1H-indazol-1- yl)propan-2-yl)propenamide:1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 9.2 Hz, 1H), 8.18 (s, 1H), 7.70 (s, 1H), 7.40 (d, J = 9.3 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 5.73 (d, J = 4.3 Hz, 1H), 4.95 (s, 1H), 4.09 – 4.03 (m, 4H), 3.74 (s, 3H), 3.45 – 3.39 (m, 4H), 1.56 (t, J = 19.1 Hz, 3H), 1.23 (d, J = 6.8 Hz, 3H). MS m / z [M+H]+459.3.

[0360] Rac-2,2-difluoro-N-((1R,2S)-1-(4-methoxyphenyl)-1-(5-morpholino-1H-indazol-1- yl)propan-2-yl)propenamide was separated into its enantiomers by chiral preparative liquid chromatography (CHIRALPAK IC column (5.0 μm, 10 mmI.D.×250mmL); Column temperature: RT; Mobile phase: n-hexane:EtOH=70:30; Flow rate: 2.5 mL / min.) to obtain 26 mg of rel-2,2-difluoro-N-((1R,2S)-1-(4-methoxyphenyl)-1-(5-morpholino-1H-indazol-1- yl)propan-2-yl)propenamide (compound I-135) was a white solid.

[0361] 1H NMR (400 MHz, CD3OD) δ 7.88 (s, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.16 (dd, J = 9.2, 2.1 Hz, 1H), 7.09 (d, J = 1.7 Hz, 1H), 6.71 (d, J = 8.7 Hz, 2H), 5.49 (d, J = 10.6 Hz, 1H), 5.14-5.10 (m, 6.5 Hz, 1H), 3.84 – 3.69 (m, 4H), 3.62 (s, 3H), 3.07 – 2.93 (m, 4H), 1.28 (t, J = 19.1 Hz, 3H), 0.98 (d, J = 6.5 Hz, 3H).. MS m / z [M+H]+459.3. Chiral analysis condition: CHIRALPAK AS-H column (5.0 μm, 4.6 mmI.D.×250mmL); Column temperature: RT; Mobile phase: n-hexane:EtOH=70:30; Flow rate: 1.0 mL / min; Detection wavelength: 254 nm; Retention time:10.66 minutes and a purity of 100%.

[0362] The following compounds were synthesized according to the general synthetic procedures described in the example above.Table 10Example 18. Synthesis of rel-N-((1R,2S)-1-(5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide (compound I-120 and I-121)

[0363] To a mixture of N-(1-(5-bromo-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)- 2,2-difluoropropanamide (372 mg, 822 µmol; synthesized analogously to example 3), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (319 mg, 2 eq., 1.64 mmol), cesium carbonate (536 mg, 2 eq., 1.64 mmol) in DMF / water (45 mL / 5 mL) was added Pd(PPh3)4(190 mg, 0.2 eq., 164 µmol) under a nitrogen atmosphere. The reaction solution was stirred at 100 °C overnight. After cooling to RT, the mixture was diluted with EA and washed with water. The layers were separated, and the aqueous layer was extracted with two additional portions of EA. The combined organic layers were dried by anhydrous sodium sulfate, and solvent was removed under reduced pressure. The crude product was further purified by flash chromatography using C18 reversed phase column (0-40%, MeCN in H2O). Product- containing fractions were combined and lyophilized to afford Rac-N-((1R,2S)-1-(5-(1H- pyrazol-4-yl)-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide(153 mg, white solid) and Rac-N-((1S,2S)-1-(5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide (27 mg, white solid).

[0364] Rac-N-((1R,2S)-1-(5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide,1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 8.06 (s, 2H), 7.94 (s, 1H), 7.68 – 7.60 (m, 2H), 7.48 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 5.65 (d, J = 10.5 Hz, 1H), 5.27 (dq, J = 13.1, 6.5 Hz, 1H), 3.70 (s, 3H), 1.39 (t, J = 19.1 Hz, 3H), 1.10 (d, J = 6.5 Hz, 3H). MS m / z [M+H]+440.3.

[0365] Rac-N-((1S,2S)-1-(5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide,1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.96 (d, J = 20.7 Hz, 3H), 7.64 (dd, J = 8.8, 1.5 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.86 (d, J = 7.5 Hz, 1H), 5.01 (p, J = 6.8 Hz, 1H), 3.74 (s, 3H), 1.32 (t, J = 19.1 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H). MS m / z [M+H]+440.3.

[0366] Rac-N-((1R,2S)-1-(5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide was separated by chiral preparative liquid chromatography (CHIRALPAK IG column (5.0 μm, 10 mmI.D.×250mmL); Column temperature: RT; Mobile phase: n-hexane:EtOH=60:40; Flow rate: 3.5 mL / min.) to obtain of rel-N-((1R,2S)-1-(5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)- 2,2-difluoropropanamide (compound I-121) as a white solid (8 mg) and rel-N-((1S,2R)-1-(5- (1H-pyrazol-4-yl)-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)-2,2- difluoropropanamide (compound I-120) as a white solid (43 mg).

[0367] Rel-N-((1R,2S)-1-(5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide (compound I-121):1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 8.02-7.94 (m, 3H), 7.63 (q, J = 8.8 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 5.65 (d, J = 10.5 Hz, 1H), 5.27 (dq, J = 12.9, 6.4 Hz, 1H), 3.70 (s, 3H), 1.39 (t, J = 19.1 Hz, 3H), 1.10 (d, J = 6.5 Hz, 3H). MS m / z [M+H]+440.3. Chiral analysis condition: CHIRALPAK OJ-H column (5.0 μm, 4.6 mmI.D.×250mmL); Column temperature: RT; Mobile phase: n-hexane:EtOH=70:30; Flow rate: 0.8 mL / min; Detection wavelength: 254 nm. Retention time: 13.60 minutes and a purity of 100%.

[0368] rel-N-((1S,2R)-1-(5-(1H-pyrazol-4-yl)-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan- 2-yl)-2,2-difluoropropanamide (compound I-120) was a white solid [1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 8.02-7.94 (m, 3H), 7.63 (q, J = 8.7 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 5.65 (d, J = 10.5 Hz, 1H), 5.26 (td, J = 13.2, 6.6 Hz, 1H), 3.71 (s, 3H),1.39 (t, J = 19.1 Hz, 3H), 1.10 (d, J = 6.5 Hz, 3H). MS m / z [M+H]+440.3; Chiral analysis condition: CHIRALPAK OJ-H column (5.0 μm, 4.6 mmI.D.×250mmL); Column temperature: RT; Mobile phase: n-hexane:EtOH=70:30; Flow rate: 0.8 mL / min; Detection wavelength: 254 nm; Retention time: 20.35 minutes and a purity of 100%].

[0369] The following compounds were synthesized according to the general synthetic procedures described in the example above. Table 11Example 19. Synthesis of rel-2,2-difluoro-N-((1R,2S)-1-(5-(5-fluoropyrimidin-2-yl)-1H- indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)propenamide (compound I-118)Step 1: 2,2-difluoro-N-(1-(4-methoxyphenyl)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-indazol-1-yl)propan-2-yl)propanamide

[0370] To a stirred solution of N-(1-(5-bromo-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan- 2-yl)-2,2-difluoropropanamide (260 mg, 575 µmol; synthesized analogously to example 3) in 1,4-dioxane (10 mL) were added bis(pinacolato)diboron (438 mg, 3 eq., 1.72 mmol), potassium acetate (169 mg, 3 eq., 1.72 mmol) and PdCl2(dppf) (42.1 mg, 0.1 eq., 57.5 µmol). The reaction mixture was stirred under a nitrogen atmosphere at 90 °C for 16 h. After cooling to RT, the mixture was diluted with EA and filtered through Celite, and the filtrate was concentrated to give the crude product. The pure title compound (200 mg, 69%, yellow oil) was obtained by flash column chromatography on silica gel (2-10%, EA in PE). MS m / z [M+H]+500.3. Step 2: Rel-2,2-difluoro-N-((1R,2S)-1-(5-(5-fluoropyrimidin-2-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)propanamide

[0371] A solution of 2,2-difluoro-N-(1-(4-methoxyphenyl)-1-(5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazol-1-yl)propan-2-yl)propanamide (0.2 g, 401 µmol), 2-bromo-5- fluoropyrimidine (106 mg, 1.5 eq., 601 µmol), PdCl2(dppf) (29.3 mg, 0.1 eq., 40.1 µmol) and potassium carbonate (166 mg, 3 eq., 1.2 mmol) in 1,4-dioxane / water (5 mL / 0.5 mL) was stirred at 25 °C for 10 minutes and then heated to 90 °C assisted by microwave for 1 h under a nitrogen atmosphere. After cooling to RT, the mixture was diluted with EA and washed with water. The layers were separated, and the aqueous layer was extracted with two additional portions of EA. The combined organic layers were dried by anhydrous sodium sulfate, and solvent was removed under reduced pressure. The crude product was further purified by flash chromatography using C18 reversed phase column (0-40%, MeCN in H2O). Product- containing fractions were combined and lyophilized to afford rac-2,2-difluoro-N-((1R,2S)-1- (5-(5-fluoropyrimidin-2-yl)-1H-indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)propanamide (90 mg, white solid) and rac-2,2-difluoro-N-((1S,2S)-1-(5-(5-fluoropyrimidin-2-yl)-1H- indazol-1-yl)-1-(4-methoxyphenyl)propan-2-yl)propanamide (20 mg, white solid).

[0372] Rac-2,2-difluoro-N-((1R,2S)-1-(5-(5-fluoropyrimidin-2-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)propenamide:1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.64 (s, 2H), 8.38 (dd, J = 8.9, 1.4 Hz, 1H), 8.19 (s, 1H), 7.34 (dd, J = 8.9, 2.3 Hz, 3H), 6.85 (d, J = 8.7Hz, 2H), 6.60 (d, J = 7.7 Hz, 1H), 5.82 (d, J = 7.4 Hz, 1H), 5.00 (dd, J = 15.3, 7.4 Hz, 1H), 3.77 (s, 3H), 1.61 (d, J = 19.2 Hz, 2H), 1.53 (s, 1H), 1.35 (d, J = 6.8 Hz, 3H). MS m / z [M+H]+470.3.

[0373] Rac-2,2-difluoro-N-((1S,2S)-1-(5-(5-fluoropyrimidin-2-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)propenamide:1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.65 (s, 2H), 8.46 (dd, J = 8.9, 1.5 Hz, 2H), 8.26 (s, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 5.79 (d, J = 4.2 Hz, 1H), 4.98 (s, 1H), 3.74 (s, 3H), 1.60 (s, 1H), 1.55 (s, 1H), 1.51 (s, 1H), 1.23 (d, J = 6.8 Hz, 3H). MS m / z [M+H]+470.3.

[0374] Rac-2,2-difluoro-N-((1R,2S)-1-(5-(5-fluoropyrimidin-2-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)propanamide was separated by chiral preparative liquid chromatography (CHIRALPAK IC column (5.0 μm, 20 mmI.D.×250mmL); Column temperature: RT; Mobile phase: n-hexane:EtOH=80:20; Flow rate: 2.5 mL / min.) to obtain rel- 2,2-difluoro-N-((1R,2S)-1-(5-(5-fluoropyrimidin-2-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)propenamide (compound I-119) as a white solid (27 mg) and rel- 2,2-difluoro-N-((1S,2R)-1-(5-(5-fluoropyrimidin-2-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)propanamide (compound I-118) as a white solid (19 mg).

[0375] Rel-2,2-difluoro-N-((1R,2S)-1-(5-(5-fluoropyrimidin-2-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)propenamide (compound I-119):1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.63 (s, 2H), 8.38 (d, J = 8.9 Hz, 1H), 8.19 (s, 1H), 7.35 (d, J = 8.3 Hz, 3H), 6.85 (d, J = 8.5 Hz, 2H), 6.64 (d, J = 7.9 Hz, 1H), 5.82 (d, J = 7.5 Hz, 1H), 5.07 – 4.96 (m, 1H), 3.76 (s, 3H), 1.56 (d, J = 19.2 Hz, 3H), 1.35 (d, J = 6.8 Hz, 3H). MS m / z [M+H]+470.3. Chiral analysis condition: CHIRALPAK IC column (5.0 μm, 4.6 mmI.D.×250mmL); Column temperature: 40 °C; Mobile phase: n-hexane:EtOH=70:30; Flow rate: 0.8 mL / min; Detection wavelength: 254 nm; Retention time: 4.76 minutes and a purity of 100%.

[0376] Rel-2,2-difluoro-N-((1S,2R)-1-(5-(5-fluoropyrimidin-2-yl)-1H-indazol-1-yl)-1-(4- methoxyphenyl)propan-2-yl)propanamide (compound I-118):1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 8.63 (s, 2H), 8.38 (d, J = 8.9 Hz, 1H), 8.19 (s, 1H), 7.35 (d, J = 7.1 Hz, 3H), 6.85 (d, J = 8.6 Hz, 2H), 6.65 (d, J = 7.9 Hz, 1H), 5.82 (d, J = 7.5 Hz, 1H), 5.02 (dd, J = 14.7, 7.4 Hz, 1H), 3.76 (s, 3H), 1.65 (d, J = 15.7 Hz, 2H), 1.53 (s, 1H), 1.34 (d, J = 6.8 Hz, 3H). MS m / z [M+H]+470.3. Chiral analysis condition: CHIRALPAK IC column (5.0 μm, 4.6 mmI.D.×250mmL); Column temperature: 40 °C; Mobile phase: n-hexane:EtOH=70:30; Flowrate: 0.8 mL / min; Detection wavelength: 254 nm; Retention time: 6.17 minutes and a purity of 100%.

[0377] The following compounds were synthesized according to the general synthetic procedures described in the example above.Table 12Example 20. Synthesis of rel-2,2-difluoro-N-((1R,2S)-1-(5-(4-fluorophenyl)-2H-indazol- 2-yl)-1-(4-methoxyphenyl)propan-2-yl)propanamide (compound I-122)

[0378] To a round bottom flask was added N-(1-(5-bromo-2H-indazol-2-yl)-1-(4- methoxyphenyl)propan-2-yl)-2,2-difluoropropanamide (117 mg, 1 eq., 259 µmol, synthesized analogously to example 15), 4-fluorobenzeneboronic acid (72.4 mg, 2 eq., 517 µmol), Pd(OAc)2(5.81 mg, 0.1 eq., 25.9 µmol), tricyclohexyl phosphine (14.5 mg, 0.2 eq., 51.7 µmol) and K3PO4(165 mg, 3 eq., 776 µmol). A nitrogen atmosphere was established, and toluene (3 mL) and water (1 mL) were added. The reaction mixture was stirred at 100 °C overnight, cooled to RT, diluted with EA, and washed with water. The layers were separated and the aqueous layer was extracted with EA. The combined organic layer was dried over anhydrous sodium sulfate, and solvents were removed under reduced pressure. A mixture of diastereomers (95 mg, 78%) was obtained by flash column chromatography on silica gel (10-30%, EA in PE). The diastereomers were then separated by flash chromatography using a C18 reversed phase column (40-60%, MeCN in H2O). Product-containing fractions were combined and lyophilized to afford rac-N-((1R,2S)-1-(5-((1H-pyrazol-4-yl)oxy)-1H-indazol-1-yl)-1-(2- methoxypyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (66 mg, white solid) and rac-N-((1S,2S)-1-(5-((1H-pyrazol-4-yl)oxy)-1H-indazol-1-yl)-1-(2-methoxypyrimidin-5- yl)propan-2-yl)-2,2-difluoropropanamide (6 mg, white solid).

[0379] Rac-N-((1R,2S)-1-(5-((1H-pyrazol-4-yl)oxy)-1H-indazol-1-yl)-1-(2- methoxypyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide:1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 7.84 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.66 – 7.60 (m, 2H), 7.59 – 7.52 (m, 3H), 7.15 (t, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.58 (d, J = 10.9 Hz, 1H), 5.24 (dq, J = 13.0, 6.5 Hz, 1H), 3.74 (s, 3H), 1.40 (t, J = 19.1 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H). MS m / z [M+H]+468.2.

[0380] Rac-N-((1S,2S)-1-(5-((1H-pyrazol-4-yl)oxy)-1H-indazol-1-yl)-1-(2- methoxypyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (compound II-36):1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 7.84 (s, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.66 – 7.60 (m, 2H), 7.55 (dd, J = 9.1, 1.5 Hz, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 5.71 (d, J = 8.9 Hz, 1H), 5.11 – 5.02 (m, 1H), 4.61 (s, 1H), 3.77 (s, 3H), 1.35 (d, J = 19.1 Hz, 3H), 1.17 (d, J = 6.7 Hz, 3H). MS m / z [M+H]+468.2.

[0381] Rac-N-((1R,2S)-1-(5-((1H-pyrazol-4-yl)oxy)-1H-indazol-1-yl)-1-(2- methoxypyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide was separated by chiral preparative liquid chromatography (CHIRALPAK IC column (5.0 μm, 10 mmI.D.×250mmL); Column temperature: RT; Mobile phase: n-hexane:EtOH=60:40; Flow rate: 2.0 mL / min.) to obtain rel-N-((1R,2S)-1-(5-((1H-pyrazol-4-yl)oxy)-1H-indazol-1-yl)-1-(2-methoxypyrimidin- 5-yl)propan-2-yl)-2,2-difluoropropanamide (compound I-122).

[0382] Chiral analysis condition: CHIRALPAK IC column (5.0 μm, 4.6 mmI.D.×250mmL); Column temperature: RT; Mobile phase: n-hexane:EtOH=70:30; Flow rate: 1.0 mL / min; Detection wavelength: 254 nm. Retention time: 13.60 minutes and a purity of 100%.

[0383] 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 7.82 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.61 (dd, J = 8.5, 5.4 Hz, 2H), 7.55 (t, J = 9.5 Hz, 3H), 7.14 (t, J = 8.7 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.59 (d, J = 10.8 Hz, 1H), 5.25 (dq, J = 12.8, 6.4 Hz, 1H), 3.73 (s, 3H), 1.41 (t, J = 19.1 Hz, 3H), 1.08 (d, J = 6.5 Hz, 3H).

[0384] MS m / z [M+H]+468.2. Example 21. Synthesis of rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(4- ethynylphenyl)propan-2-yl)-2,2-difluoropropanamide (compound I-155)Step 1: 1-(2-amino-1-(4-ethynylphenyl)propyl)-1H-indazole-5-carbonitrile

[0385] A solution of 1-(2-amino-1-(4-((trimethylsilyl)ethynyl)phenyl)propyl)-1H-indazole-5- carbonitrile (230 mg, 617 µmol; synthesized analogously to example 3), potassium carbonate (42.7 mg, 0.5 eq., 309 µmol) in methanol (5.75 mL) was stirred at RT for 1 h. It was then poured into water and extracted with DCM. The combined organic layer was dried by anhydrous sodium sulfate. Solvents were removed under reduced pressure, and the pure product (160 mg, 86%, yellow oil) was obtained by flash column chromatography on silica gel (0-2%, MeOH in DCM). MS m / z [M+H]+300.9.

[0386] Following the fifth step of Example 4, title compound rel-N-((1R,2S)-1-(5-cyano-1H- indazol-1-yl)-1-(4-ethynylphenyl)propan-2-yl)-2,2-difluoropropanamide was obtained as a white solid.

[0387] Chiral separation condition: CHIRALPAK AS-H column (5.0 μm, 10 mmI.D.×250mmL); Column temperature: RT; Mobile Phase: n-hexane+0.1%DEA:IPA=70:30; Column temperature: RT; Flow rate: 2.5 mL / min; Chiral analysis condition: CHIRALCEL OD-H column (5.0 μm, 4.6 mmI.D.×250mmL); Column temperature: 40 °C; Mobile Phase: n- hexane:EtOH=70:30; Flow rate: 0.8 mL / min; Detection wavelength: 254 nm; Retention time: 5.26 minutes, purity: 100%.

[0388] 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.15 (s, 1H), 7.53 (dd, J = 8.8, 1.3 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.38 – 7.32 (m, 3H), 6.50 (d, J = 6.5 Hz, 1H), 5.93 (d, J = 7.5 Hz, 1H), 5.03 – 4.90 (m, 1H), 3.08 (s, 1H), 1.64 – 1.51 (m, 3H), 1.36 (d, J = 6.8 Hz, 3H).

[0389] MS m / z [M+H]+393.2. Example 22. Synthesis of rac-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(4-(prop-1-en- 2-yl)phenyl)propan-2-yl)-2,2-difluoropropanamide (compound I-143)

[0390] To a solution of N-(1-(4-(2-((tert-butyldimethylsilyl)oxy)propan-2-yl)phenyl)-1-(5- cyano-1H-indazol-1-yl)propan-2-yl)-2,2-difluoropropanamide (315 mg, 1 eq., 583 µmol, synthesized analogously to example 3) in THF (12 mL) was added tetrabutylammonium fluoride (3.29 g, 22 eq., 12.6 mmol). The solution was stirred at 50 °C for 2 h, before it was diluted with water. The two phases were separated and the aqueous layer was extracted by ethyl acetate. The organic layers were combined, dried by anhydrous sodium sulfate, and concentrated under reduced pressure. The pure compound rac-N-((1R,2S)-1-(5-cyano-1H- indazol-1-yl)-1-(4-(prop-1-en-2-yl)phenyl)propan-2-yl)-2,2-difluoropropanamide (4 mg, white solid) was obtained from the residue by preparative HPLC.

[0391] 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.14 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.2 Hz, 2H), 7.34 (dd, J = 16.4, 8.5 Hz, 3H), 6.55 (s, 1H), 5.91 (d, J = 7.3 Hz, 1H), 5.34 (s, 1H), 5.08 (s, 1H), 5.00 (dd, J = 14.5, 6.9 Hz, 1H), 2.10 (s, 3H), 1.62-1.52 (m, 3H), 1.37 (d, J = 6.8 Hz, 3H).

[0392] MS m / z [M+H]+409.2. Example 23. Synthesis of rac-1-((1R,2S)-1-(2-cyclopropylpyrimidin-5-yl)-2-(2,2- difluoropropanamido)propyl)-1H-indazole-5-carboxamide (compound I-137)

[0393] To a solution of rac-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(2- cyclopropylpyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (20 mg, 1 eq., 48.7 µmol, synthesized analogously to example 3) and potassium carbonate (33.7 mg, 5 eq., 244 µmol) in DMSO (1 mL) was added hydrogen peroxide (55.2 mg, 10 eq., 487 µmol) dropwise. The solution was stirred at RT for 2 h, and then it was diluted with DCM / MeOH (10:1, 50 mL), washed with water and sodium sulfite (sat.), and dried over anhydrous sodium sulfate. Volatiles were removed under reduced pressure, and the crude product was purified by flash chromatography using C18 reversed phase column (30-40%, MeCN in H2O with 0.1% formic acid). Product-containing fractions were combined and lyophilized to afford rac-1-((1R,2S)-1- (2-cyclopropylpyrimidin-5-yl)-2-(2,2-difluoropropanamido)propyl)-1H-indazole-5- carboxamide (13 mg, 62%).

[0394] 1H NMR (400 MHz, DMSO-d6) δ 8.90 (d, J = 9.5 Hz, 1H), 8.79 (s, 2H), 8.38 (d, J = 10.8 Hz, 2H), 8.07 – 7.92 (m, 2H), 7.79 (d, J = 8.9 Hz, 1H), 7.34 (s, 1H), 5.80 (d, J = 10.4 Hz, 1H), 5.13 – 4.95(m, 1H), 2.19 – 2.06 (m, 1H), 1.44 (t, J = 19.5 Hz, 3H), 1.03 – 0.97 (m, 2H), 0.94 (d, J = 6.5 Hz, 3H), 0.92 – 0.84 (m, 2H).

[0395] MS m / z [M+H]+429.2. Example 24. Synthesis of rac-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(6-(2- hydroxypropan-2-yl)pyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide (compound I- 46)

[0396] To a solution of rac-N-((1R,2S)-1-(6-(2-((tert-butyldimethylsilyl)oxy)propan-2- yl)pyridin-3-yl)-1-(5-cyano-1H-indazol-1-yl)propan-2-yl)-2,2-difluoropropanamide (45 mg,0.083 mmol, synthesized analogously to example 7) in THF (2.0 mL) was added TBAF (1.0 M, 0.20 mL). The mixture was stirred at RT for 16 h, and then diluted with with NH4Cl (sat.). The mixture was extracted with EA (50 mL*3), and the combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified first by flash chromatography (silica gel, 0-100%, EA in PE) and then by preparative HPLC (C18, 10-95%, MeCN in H2O with 0.1% HCOOH) to give rac-N-((1R,2S)-1-(5-cyano-1H-indazol- 1-yl)-1-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide (9.5 mg, 26%) as a white solid.

[0397] 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 9.4 Hz, 1H), 8.65 (d, J = 1.8 Hz, 1H), 8.51 – 8.42 (m, 2H), 7.96 – 7.88 (m, 2H), 7.81 (dd, J = 8.8, 1.4 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 5.86 (d, J = 10.5 Hz, 1H), 5.18 – 5.07 (m, 2H), 1.34 (s, 6H), 1.27 (t, J = 19.5 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H).

[0398] MS m / z [M+H]+428.5.

[0399] The following compounds were synthesized according to the synthetic procedures described in the example above. Table 13Example 25. Synthesis of rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(2- isopropylpyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (compound I-41)

[0400] To a solution of N-(1-(2-chloropyrimidin-5-yl)-1-(5-cyano-1H-indazol-1-yl)propan-2- yl)-2,2-difluoropropanamide (0.2 g, 494 µmol, synthesized analogously to example 2) was added NiCl2(PPh3)2(97 mg, 0.3 eq., 148 µmol) and isopropylmagnesium bromide (291 mg, 4 eq., 1.98 mmol) in THF (2 mL) at 0 °C for 16 h. The reaction was diluted with water and extracted with EA. The organic layer was washed with brine, dried over with dried over Na2SO4and concentrated under vacuum. The crude product was purified by preparative HPLC, and then separated into its enantiomers by chiral chromatography (CHIRALPAK IC column (5.0um,20 mmI.D*250mml; Mobile Phase n-hexane:EtOH; Flow rate:16mL / min; Gradient: n- hexane / EtOH=70 / 30% in 20 min; 220 nm). The eluate corresponding to the first peak was concentrated to obtain rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(2-isopropylpyrimidin- 5-yl)propan-2-yl)-2,2-difluoropropanamide (1.3 mg).

[0401] 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 2H), 8.25 (s, 1H), 8.16 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 6.34 (s, 1H), 5.96 (d, J = 8.0 Hz, 1H), 4.91 (dd, J = 14.5, 7.3 Hz, 1H), 3.21 (dd, J = 13.5, 6.8 Hz, 1H), 1.35-1.25 (m, 9H).

[0402] MS m / z [M+H]+413.1.

[0403] Under chiral analysis condition: CHIRALCEL IC column (5.0 μm, 10 mmI.D.×250mmL); Flow rate: 1.0 mL / min; Mobile Phase: n-hexane:EtOH=70:30; Column temperature: 40 ℃; Detection wavelength: 254 nm; Retention time: 5.37 minutes and purity: 99%. Example 26. Synthesis of rel-N-((1R,2S)-1-(5-((1H-pyrazol-4-yl)oxy)-1H-indazol-1-yl)- 1-(2-methoxypyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (compound I-16)

[0404] A solution of rel-N-((1R,2S)-1-(5-bromo-1H-indazol-1-yl)-1-(2-methoxypyrimidin-5- yl)propan-2-yl)-2,2-difluoropropanamide (10 mg, 22 µmol, synthesized analogously to example 2), tert-butyl 4-hydroxy-1H-pyrazole-1-carboxylate (3.7 mg, 2 eq., 44 µmol), copper iodide (210 µg, 0.05 eq., 1.1 µmol), 1,2-bis(methylamino)cyclohexane (3.13 mg, 0.1 eq., 22 µmol), K3PO4(9.35 mg, 2 eq., 44 µmol) and then DMSO (1 mL was added. The resulting solution was stirred at 90 ℃ for 2 h. The reaction was diluted with water and extracted with EA. The combined organic layer was washed with brine, dried over Na2SO4and concentrated under vacuum. The resulting residue containing rel-tert-butyl 4-((1-((1R,2S)-2-(2,2- difluoropropanamido)-1-(2-methoxypyrimidin-5-yl)propyl)-1H-indazol-5-yl)oxy)-1H- pyrazole-1-carboxylate was redissolved in 1,4-dioxane and cooled to 0 ℃, followed by addition of HCl (4 M 1,4-dioxane solution, 20 eq.). The reaction mixture was stirred at 0 ℃ for 2 h, then concentrated under vacuum. The residue was subjected to column chromatography (silica gel, 1-10%, MeOH in DCM) to afford rel-N-((1R,2S)-1-(5-((1H-pyrazol-4-yl)oxy)-1H- indazol-1-yl)-1-(2-methoxypyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (8.7 mg, 19 µmol) as white solid.

[0405] Chiral Analysis Condition: CHIRALCEL IC column (5.0 μm, 10 mmI.D.×250mmL); Flow rate: 1.0 mL / min; Mobile Phase: n-hexane:EtOH=70:30; Column temperature: 40 °C; Detection wavelength: 254 nm; Retention time: 8.20 minutes; Purity: 98%.

[0406] 1H NMR (400 MHz, DMSO-d6) δ 8.93 – 8.85 (m, 2H), 8.79 (s, 2H), 8.29 (s, 1H), 8.05 (s, 1H), 7.94 (d, J = 4.0 Hz, 2H), 7.84 (d, J = 9.2 Hz, 1H), 7.34 (s, 1H), 5.80 (d, J = 10.5 Hz, 1H), 5.03 (d, J = 6.5 Hz, 1H), 3.85 (s, 3H), 1.48 (t, J = 19.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H).

[0407] MS m / z [M+H]+458.1. Example 27. Synthesis of rac-N-((1R,2R)-1-(5-cyano-1H-indazol-1-yl)-1-(2- (methylamino)pyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (compound I-62) and rac-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(2-(methylamino)pyrimidin-5- yl)propan-2-yl)-2,2-difluoropropanamide (compound I-61)

[0408] A mixture of N-(1-(2-chloropyrimidin-5-yl)-1-(5-cyano-1H-indazol-1-yl)propan-2-yl)- 2,2-difluoropropanamide (30 mg, 74.1 µmol, synthesized analogously to Example 3), methylamine hydrogen chloride (7.51 mg, 1.5 eq., 111 µmol) , and N,N-diisopropylethylamine (38.7 µL, 3 eq., 222 µmol) in acetonitrile (3 mL, 57.4 mmol) was heated for 16 h. The reaction was partitioned between EA and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate concentrated under vacuum. The resulting crude was purified by column chromatography (silica gel, 30-70%, EA in PE) to afford rac-N-((1R,2R)-1-(5-cyano- 1H-indazol-1-yl)-1-(2-(methylamino)pyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (1 mg, 2.5 µmol) and rac-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(2- (methylamino)pyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (9.6 mg, 24 µmol)

[0409] Rac-N-((1R,2R)-1-(5-cyano-1H-indazol-1-yl)-1-(2-(methylamino)pyrimidin-5- yl)propan-2-yl)-2,2-difluoropropanamide:1H NMR (400 MHz, CD3OD) δ 8.40 (s, 2H), 8.18 (s, 2H), 7.75 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 5.72 (d, J = 8.6 Hz, 1H), 5.10 (s, 1H), 2.79 (s, 3H), 1.20 (s, 3H), 1.13 (d, J = 6.8 Hz, 3H), MS m / z [M+H]+399.8, purity: 100%.

[0410] Rac-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(2-(methylamino)pyrimidin-5- yl)propan-2-yl)-2,2-difluoropropanamide (9.6 mg, 24 µmol):1H NMR (400 MHz, CD3OD) δ 8.41 (s, 2H), 8.23 (s, 1H), 8.20 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 5.49 (d, J = 10.4 Hz, 1H), 5.05 (dd, J = 10.3, 6.6 Hz, 1H), 2.75 (s, 3H), 1.44 (t, J = 19.1 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), MS m / z [M+H]+399.9, purity: 96%. Example 28. Synthesis of rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(2- ethynylpyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (compound I-74, compound II-23)Step 1: N-(1-(5-cyano-1H-indazol-1-yl)-1-(2-((trimethylsilyl)ethynyl)pyrimidin-5-yl)propan- 2-yl)-2,2-difluoropropanamide

[0411] To a solution of N-(1-(2-chloropyrimidin-5-yl)-1-(5-cyano-1H-indazol-1-yl)propan-2- yl)-2,2-difluoropropanamide (0.1 g, 247 µmol, synthesized analogously to example 2), PdCl2(PPh3)2(17.3 mg, 0.1 eq., 24.7 µmol), ethynyltrimethylsilane (52.4 µL, 1.5 eq., 371 µmol) and copper iodide (9.3 mg, 0.2 eq., 49.4 µmol) in DMF (1 mL)) was stirred at 55 ℃ for 4 h. The reaction was diluted with water and extracted with EA. The combined organic layer was washed with brine, dried over Na2SO4and concentrated under vacuum. The crude product was purified by column chromatography (silica gel, 0-50%, EA in PE) to give N-(1-(5-cyano-1H- indazol-1-yl)-1-(2-((trimethylsilyl)ethynyl)pyrimidin-5-yl)propan-2-yl)-2,2- difluoropropanamide (50 mg, 96.4 µmol) as yellow oil.

[0412] 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 2H), 8.33 (s, 1H), 8.22 (s, 1H), 7.67 – 7.65 (m, 1H), 7.55 (d, J = 3.6 Hz, 1H), 6.06 (d, J = 8.8 Hz, 1H), 4.95 (d, J = 6.2 Hz, 1H), 1.60 (d, J = 3.6 Hz, 3H), 1.29 (s, 3H), 0.27 (s, 9H). MS m / z [M+H]+467.2.Step 2: Rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(2-ethynylpyrimidin-5-yl)propan-2- yl)-2,2-difluoropropanamide

[0413] A solution of N-(1-(5-cyano-1H-indazol-1-yl)-1-(2-((trimethylsilyl)ethynyl)pyrimidin- 5-yl)propan-2-yl)-2,2-difluoropropanamide (0.2 g, 429 µmol) and K2CO3(29.6 mg, 0.5 eq., 214 µmol) in methanol (6.67 mL, 165 mmol) was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with EA. The combined organic layer was washed with brine, dried over with dried over Na2SO4and concentrated under vacuum. The resulting crude product was purified by preparative HPLC, followed by chiral chromatographic separation (CHIRALPAK IC column (5 µm, 20 mmI.D.x250 mmL); Flow rate: 16.0mL / min; Mobile phase: n-hexane:EtOH=70:30; Column temperature: 40 °C;) to afford rel-N-((1R,2S)-1-(5- cyano-1H-indazol-1-yl)-1-(2-ethynylpyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (5.2 mg, 13.2 µmol). Chiral Analysis Condition: CHIRALCEL IC column (5.0 μm, 10 mmI.D.×250mmL); Flow rate: 1.0 mL / min; Mobile Phase: n-hexane:EtOH=70:30; Column temperature: 40 ℃; Detection wavelength: 254 nm; Retention time: 8.53 minutes; Purity: 98%.

[0414] 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 2H), 8.27 (s, 1H), 8.17 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 6.40 – 6.30 (m, 1H), 6.06 (d, J = 8.0 Hz, 1H), 4.93 – 4.79 (m, 1H), 3.16 (s, 1H), 1.64 (d, J = 19.2 Hz, 3H), 1.34 (d, J = 8.0 Hz, 3H). MS m / z [M+H]+394.8.

[0415] Rel- N-[(1R,2R)-2-(5-cyano-1H-indazol-1-yl)-2-(2-ethynyl-5-pyrimidinyl)-1- methylethyl]2,2-difluoropropionamide (compound I-74, compound II-23) was also prepared according to the general synthetic procedures described in the example above.

[0416] 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 2H), 8.35 (s, 1H), 8.23 (s, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 5.87 (d, J = 4.4 Hz, 1H), 4.92 (s, 1H), 3.15 (s, 1H), 1.64 (d, J = 19.2 Hz, 3H), 1.26 (d, J = 6.8 Hz, 3H).

[0417] Chiral separation condition: CHIRALPAK IC column (5 µm, 20 mmI.D.x250 mmL); Flow rate: 16.0 mL / min; Mobile phase: n-hexane:EtOH=70:30; Column temperature: 40 °C; Chiral analysis condition: CHIRALCEL IC (5.0 µm, 4.6 mmI.D.x250mmL); Flow rate: 0.8 mL / min; Mobile phase: n-hexane:EtOH=70:30; Column temperature: 40 °C; Detection wavelength: 220 nm; Retention time: 8.53 minutes; Purity: 97%. Example 29. Synthesis of rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(4- hydroxyphenyl)propan-2-yl)-2,2-difluoropropanamide (compound I-112)Step 1: rac-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)propan-2-yl)-2,2-difluoropropanamide

[0418] To a stirred solution of rac-N-((1R,2S)-1-(4-bromophenyl)-1-(5-cyano-1H-indazol-1- yl)propan-2-yl)-2,2-difluoropropanamide (50 mg, 112 µmol, synthesized analogously to example 1) in 1,4-dioxane (2.53 mL, 29.6 mmol) were added 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (85.2 mg, 3 eq., 335 µmol), Pd(dppf)Cl2(8.18 mg, 0.1 eq., 11.2 µmol), potassium acetate (32.9 mg, 3 eq., 335 µmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction was diluted with water and extracted with EA. The combined organic layer was washed with brine, dried over with Na2SO4, and concentrated under vacuum. The resulting residue was subjected to column chromatography (silica gel, 15%~20% EA in PE) to afford rac-N-((1R,2S)-1-(5-cyano-1H- indazol-1-yl)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)-2,2- difluoropropanamide as a yellow oil (45 mg, 81.9 µmol).1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.13 (s, 1H), 7.76 (d, J = 7.7 Hz, 2H), 7.48 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 8.9 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 5.95 (d, J = 6.9 Hz, 1H), 5.03 – 4.91 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H), 1.31 (s, 12H). MS m / z [M+H]+495.3. Step 2: Rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(4-hydroxyphenyl)propan-2-yl)-2,2- difluoropropanamide

[0419] To a solution of rac-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)-2,2-difluoropropanamide (20 mg, 52 µmol) in THF (3 mL, 36.9 mmol) was added hydrogen peroxide (6.19 mg, 3 eq., 182 µmol, 9.79 M in H2O). The mixture was stirred at RT for 30 min. The reaction mixture was then diluted with H2O and extracted with DCM. The combined organic layer was washed with brine, dried over with Na2SO4, and concentrated under vacuum. The resulting residue was subjected to column chromatography (silica gel, 15%~12% EA in PE), followed by chiral separation (CHIRALPAK IG column 5.0 μm, 20 mmI.D.×250 mmL; Flow rate：3.5 mL / min; Mobile Phase: n-hexane+0.1%DEA:EtOH=70:30; Column temperature: RT) to afford rel-N-((1R,2S)- 1-(5-cyano-1H-indazol-1-yl)-1-(4-hydroxyphenyl)propan-2-yl)-2,2-difluoropropanamide (20 mg, 52 µmol). Chiral analysis condition: CHIRALCEL IG column 5.0 µm, 4.6 mm I.D.x250mmL; Flow rate: 0.8 mL / min; Mobile Phase: n-hexane:EtOH=70:30; Column temperature: 40 °C; Detection wavelength: 220 nm; Retention time: 5.05 minutes; purity: 100%.

[0420] 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 8.13 (s, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.28 (s, 2H), 6.78 (d, J = 7.9 Hz, 2H), 6.52 (d, J = 8.1 Hz, 1H), 5.80 (d, J = 7.6 Hz, 1H), 5.04 (s, 1H), 5.02 – 4.93 (m, 1H), 1.59 (t, J = 19.1 Hz, 3H), 1.32 (d, J = 6.7 Hz, 3H).

[0421] MS m / z [M+H]+385.2. Example 30. Synthesis of rac-1-(4-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-2-(2,2- difluoropropanamido)propyl)benzyl)cyclopropyl 2,2-difluoropropanoate (compound I- 89)

[0422] To a stirred solution of 1-(2-amino-1-(4-((1- hydroxycyclopropyl)methyl)phenyl)propyl)-1H-indazole-5-carbonitrile (0.3 g, 866 µmol), 2,2-difluoropropionic acid (143 mg, 1.5 eq., 1.3 mmol) and N-ethylbis(isopropyl)amine (336mg, 3 eq., 2.6 mmol) in DCM (10 mL, 156 mmol) was added HATU (659 mg, 2 eq., 1.73 mmol). The reaction mixture was stirred at RT for 0.5 h. It was then diluted water and extracted with DCM. The combined organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was subjected to reversed phase column chromatography (C18, 0-50% ACN in H2O) to afford rac-1-(4-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-2-(2,2- difluoropropanamido)propyl)benzyl)cyclopropyl 2,2-difluoropropanoate (60 mg, 113 µmol).

[0423] 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.7 Hz, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.74 (dd, J = 8.8, 1.4 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 5.95 (d, J = 9.7 Hz, 1H), 4.98 (dd, J = 15.7, 8.9 Hz, 1H), 3.10 – 3.01 (m, 2H), 1.57 (t, J = 19.6 Hz, 3H), 1.24 (s, 3H), 1.05 (d, J = 6.7 Hz, 3H), 0.93 (s, 4H).

[0424] MS m / z [M+H]+553.3. Example 31. Synthesis of rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(6- isopropylpyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide (compound I-28)

[0425] A solution of N-((2S)-1-(5-cyano-1H-indazol-1-yl)-1-(6-(prop-1-en-2-yl)pyridin-3- yl)propan-2-yl)-2,2-difluoropropanamide (45 mg, 1 eq., 0.11 mmol; synthesized analogously to example 1) in ethyl acetate (5 mL) was hydrogenated with Pd / C(10%, 40 mg) using a H2balloon at RT for 3 h. The catalyst was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC (C1810μm 21.2×250 mm, 48% acetonitrile in B in water (10 mM NH4HCO3)) to afford rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(6- isopropylpyridin-3-yl)propan-2-yl)-2,2-difluoropropanamide (7.4 mg，0.018 mmol, 16.4%) as white solid.

[0426] Chiral analysis condition: OD-H column 4.6*100mm 5um; Flow rate: 3.0 mL / min; Mobile phase: CO2:MeOH[0.2%NH3(7M in MeOH)]=90:10; Column temperature: 40 °C; Detection wavelength: 214 nm; Retention time: 1.75 minutes; Purity: 97%.

[0427] 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J = 9.2 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.45 (s, 2H), 7.93 (d, J = 8.9 Hz, 1H), 7.85 (dd, J = 8.2, 2.3 Hz, 1H), 7.81 (dd, J = 8.8, 1.4 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 5.85 (d, J = 10.4 Hz, 1H), 5.12 (dd, J = 16.3, 10.0 Hz, 1H), 2.93 (dt, J = 13.7, 6.8 Hz, 1H), 1.30 (t, J = 19.4 Hz, 3H), 1.13 (d, J = 6.9 Hz, 6H), 0.96 (d, J = 6.5 Hz, 3H).

[0428] MS m / z [M+H]+412.2. Example 32. Synthesis of rel-N-(1-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2- methoxypyrimidin-5-yl)propyl)-1H-indazol-5-yl)-1H-imidazole-2-carboxamide (compound I-11)Step 1: Rel-N-((1R,2S)-1-(5-((diphenylmethylene)amino)-1H-indazol-1-yl)-1-(2- methoxypyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide

[0429] A mixture of rel-N-[(1S,2R)-2-(5-bromo-1H-indazol-1-yl)-2-(2-methoxy-5- pyrimidinyl)-1-methylethyl]2,2-difluoropropionamide (0.2 g, 440 µmol, synthesized analogously to example 2), diphenylmethanimine (160 mg, 2 eq., 881 µmol), Sodium tert- butoxide (84.6 mg, 2 eq., 881 µmol) and RuPhos Pd G3 (36.9 mg, 0.1 eq., 44 µmol) in 1,4- dioxane (1 mL, 11.7 mmol) at 90 °C for 3 h. The solution was diluted with water and extracted with EA. The combined organic layer was washed with brine, dried over with Na2SO4, and concentrated under vacuo. The pure product was obtained by column chromatography (silica gel, 15%~50% EA in PE) to afford rel-N-((1R,2S)-1-(5-((diphenylmethylene)amino)-1H-indazol-1-yl)-1-(2-methoxypyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (0.2 g, 343 µmol) as a white solid.

[0430] 1H NMR (400 MHz, CDCl3) δ 8.69 – 8.64 (m, 2H), 7.93 (s, 1H), 7.74 (d, J = 7.2 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.4 Hz, 2H), 7.22 (dd, J = 11.2, 5.1 Hz, 3H), 7.16 – 7.09 (m, 3H), 7.04 (s, 1H), 6.87 (dd, J = 8.8, 1.6 Hz, 1H), 6.40 (d, J = 7.7 Hz, 1H), 5.77 (d, J = 7.7 Hz, 1H), 4.82 (dd, J = 14.7, 7.4 Hz, 1H), 3.98 (d, J = 3.4 Hz, 3H), 1.54 (d, J = 19.3 Hz, 3H), 1.30 (d, J = 6.9 Hz, 3H).

[0431] MS m / z [M+H]+555.2. Step 2: Rel-N-((1R,2S)-1-(5-amino-1H-indazol-1-yl)-1-(2-methoxypyrimidin-5-yl)propan-2- yl)-2,2-difluoropropanamide

[0432] To a solution of rel-N-((1R,2S)-1-(5-((diphenylmethylene)amino)-1H-indazol-1-yl)-1- (2-methoxypyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (0.2 g, 361 µmol) in tetrahydrofuran (1 mL, 12.3 mmol) was added hydrogen chloride (131 mg, 10 eq., 3.61 mmol), the reaction was stirred at RT for 1 h. The solution was quenched with NaHCO3(Sat.) and extracted with DCM. The combined organic layer was washed with brine, dried over with Na2SO4, and concentrated under vacuo to give rel-N-((1R,2S)-1-(5-amino-1H-indazol-1-yl)-1- (2-methoxypyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (0.1 g, 205 µmol)as a yellow solid. MS m / z [M+H]+391.1. Step 3: Rel-N-(1-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2-methoxypyrimidin-5-yl)propyl)- 1H-indazol-5-yl)-1H-imidazole-2-carboxamide

[0433] To a solution of 2-imidazolecarboxylic acid (79 mg, 2.8 eq., 705 µmol) in DCM (0.5 mL, 7.81 mmol) at 0 ℃ was added oxalyl dichloride (59.6 µL, 2.8 eq., 704 µmol) dropwise, followed by addition of N,N-dimethylformamide (1.87 mg, 0.1 eq., 25.6 µmol).The mixture was warmed to RT then added dropwise to a solution of rel-N-((1R,2S)-1-(5-amino-1H-indazol-1-yl)-1-(2-methoxypyrimidin-5-yl)propan-2-yl)-2,2-difluoropropanamide (0.1 g, 256 µmol) and triethylamine (178 µL, 5 eq., 1.28 mmol) in DMF (0.5 mL, 6.46 mmol) at 0 ⁰C. The reaction mixture was stirred for another 1 h, then was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over with dried over Na2SO4and concentrated under vacuo. The resulting residue was purified on flash chromatography (silica gel, 0%~10% MeOH in DCM), followed by preparative HPLC afford rel-N-(1-((1R,2S)- 2-(2,2-difluoropropanamido)-1-(2-methoxypyrimidin-5-yl)propyl)-1H-indazol-5-yl)-1H- imidazole-2-carboxamide (7.9 mg, 16.3 µmol) as a white solid.

[0434] 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 10.47 (s, 1H), 8.91 (d, J = 9.7 Hz, 1H), 8.76 (s, 2H), 8.30 (s, 1H), 8.26 (s, 1H), 7.86 (d, J = 9.1 Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.37 (s, 1H), 7.15 (s, 1H), 5.74 (d, J = 10.4 Hz, 1H), 5.12 – 4.99 (m, 1H), 3.85 (s, 3H), 1.48 (t, J = 19.5 Hz, 3H), 0.97 (d, J = 6.5 Hz, 3H).

[0435] MS m / z [M+H]+485.1.

[0436] Chiral analysis condition: IC column 4.6*100mm 5µm; Flow rate: 3.0 mL / min; Mobile phase: CO2:MeOH[0.2%NH3(7M in MeOH)]=70:30; Column temperature: 40 °C; Detection wavelength: 254 nm; Retention time: 9.38 minutes; Purity: 99%.

[0437] Rel-N-(1-((1R,2S)-2-(2,2-difluoropropanamido)-1-(4-(trifluoromethyl)phenyl)propyl)- 1H-indazol-5-yl)-1H-imidazole-2-carboxamide (Compound I-4) was also synthesized according to the general synthetic procedures described in the example above.

[0438] 1H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 10.45 (s, 1H), 8.82 (d, J = 9.4 Hz, 1H), 8.27 (d, J = 14.3 Hz, 2H), 7.83 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.70 – 7.61 (m, 3H), 7.37 (s, 1H), 7.14 (s, 1H), 5.83 (d, J = 10.5 Hz, 1H), 5.23 – 5.10 (m,1H), 1.35 (t, J = 19.5 Hz, 3H), 1.03 (d, J = 6.4 Hz, 3H).

[0439] MS m / z [M+H]+521.1.

[0440] Chiral analysis condition: CHIRALPAK IC (5.0 µm, 4.6 mmI.D.x250mmL); Flow rate：1.0 mL / min; Mobile phase: n-hexane:EtOH=70:30; Column temperature: 40 ⁰C; Detection wavelength: 254 nm; Retention: 3.65 minutes; Purity: 98%.Example 33. Synthesis of rel-2,2-difluoro-N-((1R,2S)-1-(2-methoxypyrimidin-5-yl)-1- (5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl)propan-2-yl)propenamide (compound I-10)Step 1: Rel-2,2-difluoro-N-((1R,2S)-1-(5-((Z)-N’-hydroxycarbamimidoyl)-1H-indazol-1-yl)-1- (2-methoxypyrimidin-5-yl)propan-2-yl)propenamide

[0441] A mixture of rel-N-((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(2-methoxypyrimidin-5- yl)propan-2-yl)-2,2-difluoropropanamide (180 mg, 450 µmol), hydrogen chloride— hydroxylamine (1 / 1) (46.9 mg, 1.5 eq., 674 µmol) and triethylamine (125 µL, 2 eq., 899 µmol) in ethanol (3.8 mL, 65.1 mmol) was stirred at 60 ℃ for 6 h. After cooling to RT, the mixture was concentrated under reduced pressure and then dried in vacuo to afford crude product which was used for next step without further purification. MS m / z [M+H]+434.1. Step 2: Rel-2,2-difluoro-N-((1R,2S)-1-(2-methoxypyrimidin-5-yl)-1-(5-(5-methyl-1,2,4- oxadiazol-3-yl)-1H-indazol-1-yl)propan-2-yl)propenamide

[0442] To a stirred solution of rel-2,2-difluoro-N-((1R,2S)-1-(5-((Z)-N’- hydroxycarbamimidoyl)-1H-indazol-1-yl)-1-(2-methoxypyrimidin-5-yl)propan-2- yl)propenamide (0.2 g, 369 µmol), tripotassium phosphate (235 mg, 3 eq., 1.11 mmol) in DMF (2.02 mL, 26.1 mmol) was added acetyl chloride (105 µL, 4 eq., 1.48 mmol) at 0 °C. This reaction solution was stirred at RT for 0.5 h and then heated to 100 °C and stirred for another 4 h. The combined organic layers were dried by anhydrous sodium sulfate, and solvent wasremoved under reduced pressure. The pure title compound rel-2,2-difluoro-N-((1R,2S)-1-(2- methoxypyrimidin-5-yl)-1-(5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl)propan-2- yl)propenamide (17 mg, 10%, white solid) was obtained by flash column chromatography on silica gel (0-10%, MeOH in DCM).

[0443] 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 2H), 8.50 (s, 1H), 8.20 (s, 1H), 8.11 (dd, J = 8.8, 1.4 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 6.42 (d, J = 7.0 Hz, 1H), 5.90 (d, J = 8.0 Hz, 1H), 4.91 (dd, J = 14.9, 7.4 Hz, 1H), 3.99 (s, 3H), 2.67 (s, 3H), 1.63 (d, J = 19.3 Hz, 3H), 1.34 (d, J = 6.8 Hz, 3H);

[0444] MS m / z [M+H]+458.1.

[0445] Chiral analysis condition: CHIRALPAK IC (5.0 µm, 4.6 mmI.D.x250mmL); Flow rate: 1.0 mL / min; Mobile phase: n-hexane:EtOH=70:30; Column temperature: 40 °C; Detection wavelength: 254 nm; Retention: 9.83 minutes; Purity: 98%. Example 34. Synthesis of rel-3-(((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(6- cyclopropylpyridin-3-yl)propan-2-yl)amino)-2,2-difluoropropanoic acid (compound I- 220)

[0446] To a solution of 1-(2-amino-1-(6-cyclopropylpyridin-3-yl)propyl)-1H-indazole-5- carbonitrile (0.2 g, 630 µmol, synthesized analogously to example 2) and ethyl 3-bromo-2,2- difluoropropionate (410 mg, 3 eq., 1.89 mmol) in dimethylformamide (10 mL, 129 mmol) was added sodium iodide (283 mg, 3 eq., 1.89 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (480 mg, 5 eq., 3.15 mmol) at rt. The reaction was stirred at 100 °C for 16 h. The reaction was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine (50 mL), dried over with dried over Na2SO4and evaporated under vacuo. The pure product was obtained by column chromatography (Silica gel, 2%~10% MeOH in DCM) to afford rac-3-(((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(6-cyclopropylpyridin-3- yl)propan-2-yl)amino)-2,2-difluoropropanoic acid (50 mg, 0.12 mmol) as a yellow solid, which was further purified by chiral chromatography separation (CHIRALPAK® IC column (5um,4.6x250mm)), Column temperature: RT; Mobile phase: n-hexane+0.1%DEA:EtOH=70:30; Flow rate: 1.0 mL / min) to afford rel-3-(((1R,2S)-1-(5-cyano-1H-indazol-1-yl)-1-(6- cyclopropylpyridin-3-yl)propan-2-yl)amino)-2,2-difluoropropanoic acid (8.9 mg, 0.02mmol). 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 1.9 Hz, 1H), 8.21 (s, 1H), 8.14 (s, 1H), 7.70 (dd, J = 8.3, 2.3 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 5.79 (d, J = 8.0 Hz, 1H), 5.05 (dd, J = 15.0, 7.9 Hz, 1H), 3.89 – 3.76 (m, 2H), 1.99 (t, J = 6.3 Hz, 1H), 1.33 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 7.9 Hz, 4H). MS m / z [M+H]+426.3. Chiral analysis condition: CHIRALPAK AS-H column (5.0 μm, 4.6 mm I.D.×250mmL); Column temperature: 40 °C; Mobile phase: n-hexane+0.1%DEA: EtOH=70:30; Flow rate: 1 mL / min; Detection wavelength: 254 nm; Retention time: 9.46 minutes and a purity of 100%.

[0447] The following compounds were synthesized according to the general synthetic procedures described in Example 34. Table 14Example 35. A20 Luciferase Assay for BEAS-2B

[0448] 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 fireflyluciferase gene and transcription is initiated. The resulting firefly luciferase activity is measured through a bioluminescent reaction catalyzed by firefly luciferases (change in luminescent signal).

[0449] 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).

[0450] 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

[0451] where Min data=data of DSMO group, and Max data= data of dexamethasone group

[0452] 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)

[0453] Where A=min Y, B=max Y, C=log EC50 and D= Hill Slope

[0454] 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 15. EC50(nM) of Exemplary CompoundsExample 36. A20 Antagonist Assay for BEAS-2B

[0455] A pGL3P-TNFAIP3 firefly luciferase reporter cell line (Beas-2B A20-luc) was established as described previously. The assay allows for the identification of compounds showing GR-mediated A20 antagonist activity at the human glucocorticoid receptor (GR) via inhibition of luciferase gene expression under the cooperative NF-kB and GR activation. Ligand-occupied GRs competed with dexamethasone-activated GR binds to Glucocorticoid Response Element (GRE) in the enhancer of the firefly luciferase gene and inhibited transcription activity. The resulting firefly luciferase activity is measured through a bioluminescent reaction catalyzed by firefly luciferases (change in luminescent signal).

[0456] 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. A final concentration of 20 ng / ml TNF-alpha and 2 nM dexamethasone was to the cells, and 2 μL compound was added at different concentrations to the cells and incubated for 8 hours, Mifepristone was used as reference molecules. 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).

[0457] The relative inhibition (% Inhibition) of a compound is calculated based on the full antagonistic effect of Mifepristone. The equation: % Inhibition = 100-(Sample data – Min data) / (Max data – Min data) *100

[0458] Where Min data=data of DSMO group, and Max data= data of 2nM dexamethasone with TNF-alpha group

[0459] 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)

[0460] Where A=min Y, B=max Y, C=log EC50and D= Hill Slope

[0461] The % inhibition at 100 nM, 300 nM, and 1000 nM using the assay is summarized in the table below. In the table below, “+” indicates % inhibition of less than 25% (< 25%); “++” indicates % inhibition range from 25% to 50% (25% ≤ % inhibition < 50%); “+++” indicates an inhibition range from 50% to 75% (50% ≤ % inhibition < 75%); “++++” % inhibition greater than or equal to 75% (≥ 75%). Table 16. A20 Antagonist Inhibition of Exemplary CompoundsINCORPORATION BY REFERENCE

[0462] 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 and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.EQUIVALENTS

[0463] 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.

[0464] 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:Rxis C1-C6alkyl; R1is –CN, halo, –ORo1, –C(O)NRn1Rn2, RA, –ORB, –NRn1RB, or –NRn1C(O)RB; RAis 3-6 membered cycloalkyl, phenyl, 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a; RBis 3-6 membered cycloalkyl, phenyl, 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b;R2is phenyl, naphthyl, or 5-10 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-5 instances of R2a; R3is C1-C6alkyl or 3-4 membered cycloalkyl; R4is H or C1-C6alkyl; R5is C1-C6alkyl, C1-C6haloalkyl, 5-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a; each R1ais independently oxo, halo, –(CH2)0-1CN, –OH, –O-(C1-C6alkyl), –O-(C1-C6haloalkyl), –(CH2)0-1C(O)NH2, –(CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R1bis independently oxo, halo, –(CH2)0-1CN, –OH, –O-(C1-C6alkyl), –O-(C1-C6haloalkyl), –(CH2)0-1C(O)NH2, –(CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur each R2ais independently halo, –ORo2, –SRs1, –S(O)2Rs2, –NRn1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl optionally substituted with 1-5 instances of R2b, C1-C6heteroalkyl optionally substituted with 1-5 instances of R2b, or 3-6 membered cycloalkyl optionally substituted with 1-5 instances of R2b, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-7 membered heterocyclyl optionally substituted with 1-4 instances of halo; each R2bis independently oxo, halo, –ORo3, –NRn2, or –CN, or two instances of R2battached to the same atom, together with the atom to which they are attached, form cyclopropyl; each R5ais independently C1-C6alkyl or –OH; Ro1is C1-C6alkyl; each of Ro2and Ro3is independently H, C1-C6alkyl, C1-C6haloalkyl, or 3-6 membered cycloalkyl; each of Rs1, Rs2, Rn1, and Rn2is independently H or C1-C6alkyl; andRn3is 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

2. The compound of claim 1, wherein the compound is of Formula I-1, Formula I-2, Formula I-3, or Formula I-4:or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, wherein R3is C1-C6alkyl.

4. The compound of any one of claims 1 to 3, wherein R3is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

5. The compound of any one of claims 1 to 4, wherein R3is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

6. The compound of any one of claims 1 to 5, wherein R3is –Me.

7. The compound of any one of claims 1 to 6, wherein the compound is of Formula I-a:or a pharmaceutically acceptable salt thereof8. The compound of any one of claims 1 to 7, wherein the compound is of Formula I-a-1 or Formula I-a-2:or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 or 2, wherein R3is 3-4 membered cycloalkyl.

10. The compound of any one of claims 1, 2, and 9, wherein R3is cyclopropyl.

11. The compound of any one of claims 1 to 10, wherein R4is C1-C6alkyl.

12. The compound of any one of claims 1 to 11, wherein R4is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

13. The compound of any one of claims 1 to 12, wherein R4is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

14. The compound of any one of claims 1 to 11, wherein R4is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

15. The compound of any one of claims 1 to 11, wherein R4is H or –Me.

16. The compound of any one of claims 1 to 11, wherein R4is H.

17. The compound of any one of claims 1 to 16, wherein the compound is of Formula I-b:or a pharmaceutically acceptable salt thereof.

18. The compound of any one of claims 1 to 17, R5ais –OH19. The compound of any one of claims 1 to 17, R5ais C1-C6alkyl.

20. The compound of any one of claims 1 to 19, wherein R5is C1-C6alkyl, wherein R5is optionally substituted with 1-2 instances of R5a.

21. The compound of any one of claims 1 to 20, wherein R5is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl, wherein R5is optionally substituted with 1-2 instances of R5a.

22. The compound of any one of claims 1 to 21, wherein R5is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu, wherein R5is optionally substituted with 1-2 instances of R5a.

23. The compound of any one of claims 1 to 22, wherein R5is24. The compound of any one of claims 1 to 17, wherein R5is C1-C6haloalkyl, wherein R5is optionally substituted with 1-2 instances of R5a.

25. The compound of any one of claims 1 to 19 and 24, wherein R5is –CF3, –CHF2, –CH2F, –CF2CH3, –CF(CH3)2, or –CF2CF3, wherein R5is optionally substituted with 1-2 instances of R5a.

26. The compound of any one of claims 1 to 19, 24, and 25, wherein R5is –CF3, – CHF2, –CH2F, –CF2CH3, –CF(CH3)2, –CF2CF3, or –CF2CH2OH.

27. The compound of any one of claims 1 to 19 and 24 to 26, wherein R5is –CF3,– CF(CH3)2, or –CF2CH2OH.

28. The compound of any one of claims 1 to 19 and 24 to 26, wherein R5is –CF3.

29. The compound of any one of claims 1 to 19 and 24 to 26, wherein R5is – CF2CH3.

30. The compound of any one of claims 1 to 19 and 24 to 26, wherein R5is – CF2CH2OH.

31. The compound of any one of claims 1 to 19, wherein R5is 5-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a.

32. The compound of any one of claims 1 to 19 and 31, wherein R5is 5 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a.

33. The compound of any one of claims 1 to 19, 31, and 32, wherein R5is,34. The compound of any one of claims 1 to 19, wherein R5is 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a.

35. The compound of any one of claims 1 to 19 and 34, wherein R5is 5 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R5is optionally substituted with 1-2 instances of R5a.

36. The compound of any one of claims 1 to 19, 34, and 35, wherein R5is.

37. The compound of any one of claims 1 to 19, wherein R5is–CF3, – CF(CH3)2, –CF2CH2OH,38. The compound of any one of claims 1 to 37, wherein X is,, , , , , 39. The compound of any one of claims 1 to 38, wherein X is40. The compound of any one of claims 1 to 39, wherein X is41. The compound of any one of claims 1 to 39, wherein X is.

42. The compound of any one of claims 1 to 41, wherein Rxis –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –pentyl, or –hexyl.

43. The compound of any one of claims 1 to 42, wherein Rxis –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

44. The compound of any one of claims 1 to 43, wherein Rxis –Me.

45. The compound of any one of claims 1 to 44, wherein X is46. T The compound of any one of claims 1 to 44, wherein X is47. The compound of any one of claims 1 to 38, wherein X is48. The compound of any one of claims 1 to 38 and 47, wherein X is is49. The compound of any one of claims 1 to 38 and 47, wherein X is50. The compound of any one of claims 1 to 38 and 47, wherein X is 51. The compound of any one of claims 1 to 38 and 47, wherein X is52. The compound of any one of claims 1 to 38 and 47, wherein X is53. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-c:or a pharmaceutically acceptable salt thereof.

54. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-c-1, Formula I-c-2, Formula I-c-3, or Formula I-c-4:or a pharmaceutically acceptable salt thereof.

55. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-d:or a pharmaceutically acceptable salt thereof.

56. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-d-1, Formula I-d-2, Formula I-d-3, or Formula I-d-4:or a pharmaceutically acceptable salt thereof.

57. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-e:or a pharmaceutically acceptable salt thereof.

58. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-e-1, Formula I-e-2, Formula I-e-3, or Formula I-e-4:or a pharmaceutically acceptable salt thereof.

59. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-f:or a pharmaceutically acceptable salt thereof.

60. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-f-1, Formula I-f-2, Formula I-f-3, or Formula I-f-4:or a pharmaceutically acceptable salt thereof.

61. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-g:or a pharmaceutically acceptable salt thereof.

62. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-g-1, Formula I-g-2, Formula I-g-3, or Formula I-g-4:or a pharmaceutically acceptable salt thereof.

63. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-h:or a pharmaceutically acceptable salt thereof.

64. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-h-1, Formula I-h-2, Formula I-h-3, or Formula I-h-4:or a pharmaceutically acceptable salt thereof.

65. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-i:or a pharmaceutically acceptable salt thereof.

66. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-i-1, Formula I-i-2, Formula I-i-3, or Formula I-i-4:or a pharmaceutically acceptable salt thereof.

67. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-j:or a pharmaceutically acceptable salt thereof.

68. The compound of any one of claims 1 to 37, wherein the compound is of Formula I-j-1, Formula I-j-2, Formula I-j-3, or Formula I-j-4:or a pharmaceutically acceptable salt thereof.

69. The compound of any one of claims 1 to 68, wherein Rn3is 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

70. The compound of any one of claims 1 to 68 and 69, wherein Rn3is.

71. The compound of any one of claims 1 to 68, 69, and 70, wherein Rn3is.

72. The compound of any one of claims 1 to 71, wherein each R1ais independently oxo, halo, –(CH2)0-1CN, –OH, –O-(C1-C6alkyl), –O-(C1-C6haloalkyl), –(CH2)0-1C(O)NH2, – (CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

73. The compound of any one of claims 1 to 72, wherein each R1ais independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe, –OEt, –OCF3,–C(O)NH2, – CH2C(O)NH2, –C(O)NHCH3, –CH2C(O)NHCH3, –C(O)N(CH3)CH2Rn3, –Me, –Et, –nPr, –iPr, –CF3, –CHF2, –CH2F,74. The compound of any one of claims 1 to 73, wherein each R1ais independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe, –OEt, –OCF3,–C(O)NH2, – CH2C(O)NH2, –C(O)NHCH3, –CH2C(O)NHCH3, –C(O)N(CH3)CH2Rn3, –Me, –Et, –nPr, –iPr, –CF3, –CHF2, –CH2F, –CH(CF3)2,75. The compound of any one of claims 1 to 74 wherein each R1ais independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe,,–C(O)NH2, –CH2C(O)NH2, – C(O)NHCH3,–Me, –Et, –CF3,76. The compound of any one of claims 1 to 75, wherein each R1bis independently oxo, halo, –(CH2)0-1CN, –OH, –O-(C1-C6alkyl), –O-(C1-C6haloalkyl), –(CH2)0-1C(O)NH2, – (CH2)0-1C(O)NHCH3, –(CH2)0-1C(O)N(CH3)2, –(CH2)0-1C(O)NHCH2R1b, –(CH2)0-1C(O)N(CH3)CH2Rn3, C1-C6alkyl, C1-C6haloalkyl, 3-4 membered cycloalkyl that is optionally substituted with –CN, or 5 membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

77. The compound of any one of claims 1 to 76, wherein each R1bis independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe, –OEt, –OCF3,–C(O)NH2, – CH2C(O)NH2, –C(O)NHCH3, –CH2C(O)NHCH3, –C(O)N(CH3)CH2Rn3, –Me, –Et, –nPr, –iPr, –CF3, –CHF2, –CH2F,78. The compound of any one of claims 1 to 77, wherein each R1bis independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe, –OEt, –OCF3,, , –C(O)NH2, – CH2C(O)NH2, –C(O)NHCH3, –CH2C(O)NHCH3, –C(O)N(CH3)CH2Rn3, –Me, –Et, –nPr, –iPr, –CF3, –CHF2, –CH2F, –CH(CF3)2,79. The compound of any one of claims 1 to 78, wherein each R1bis independently oxo, –F, –Cl, –CN, –CH2CN, –OH, –OMe,–C(O)NH2, –CH2C(O)NH2, – C(O)NHCH3,–Me, –Et, –CF3,80. The compound of any one of claims 1 to 79, wherein each R1bis independently oxo or –Me.

81. The compound of any one of claims 1 to 80, wherein RAis 3-6 membered cycloalkyl, wherein RAis optionally substituted with 1-5 instances of R1a.

82. The compound of any one of claims 1 to 80 and 81, wherein RAis 3-4 membered cycloalkyl, wherein RAis optionally substituted with 1-5 instances of R1a.

83. The compound of any one of claims 1 to 80, 81, and 82, wherein RAis cyclopropyl, wherein RAis optionally substituted with 1-5 instances of R1a.

84. The compound of any one of claims 1 to 80 and 81 to 83, wherein RAis.

85. The compound of any one of claims 1 to 80, wherein RAis phenyl, wherein RAis optionally substituted with 1-5 instances of R1a.

86. The compound of any one of claims 1 to 80 and 85, wherein RAis,87. The compound of any one of claims 1 to 80, 85, and 86, wherein RAis88. The compound of any one of claims 1 to 80, wherein RAis 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a.

89. The compound of any one of claims 1 to 80 and 88, wherein RAis 5-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a.

90. The compound of any one of claims 1 to 80, 88, and 89, wherein RAis pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, or dihydropyridinyl, wherein RAis optionally substituted with 1-5 instances of R1a.

91. The compound of any one of claims 1 to 80 and 88 to 90, wherein RAis ,92. The compound of any one of claims 1 to 80, wherein RAis 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a.

93. The compound of any one of claims 1 to 80 and 92, wherein RAis 7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a.

94. The compound of any one of claims 1 to 80, 92, and 93, wherein RAis.

95. The compound of any one of claims 1 to 80, wherein RAis 5-6 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a.

96. The compound of any one of claims 1 to 80 and 95, wherein RAis 5-6 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RAis optionally substituted with 1-5 instances of R1a.

97. The compound of any one of claims 1 to 80, 95, and 96, wherein RAis imidazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, or thiadiazolyl, wherein RAis optionally substituted with 1-5 instances of R1a.

98. The compound of any one of claims 1 to 80 and 95 to 97, wherein RAis99. The compound of any one of claims 1 to 80, wherein RAis100. The compound of any one of claims 1 to 99, wherein RBis 3-6 membered cycloalkyl, wherein RBis optionally substituted with 1-5 instances of R1b.

101. The compound of any one of claims 1 to 99 and 100, wherein RBis 3-4 membered cycloalkyl, wherein RBis optionally substituted with 1-5 instances of R1b.

102. The compound of any one of claims 1 to 99, 100, and 101, wherein RBis cyclopropyl, wherein RBis optionally substituted with 1-5 instances of R1b.

103. The compound of any one of claims 1 to 99 and 100 to 102, wherein RBis.

104. The compound of any one of claims 1 to 99, wherein RBis phenyl, wherein RBis optionally substituted with 1-5 instances of R1b.

105. The compound of any one of claims 1 to 99 and 104, wherein RBis,106. The compound of any one of claims 1 to 99, 104, and 105, wherein RBis107. The compound of any one of claims 1 to 99, wherein RBis 3-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b.

108. The compound of any one of claims 1 to 99 and 107, wherein RBis 5-6 membered monocyclic heterocyclyl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b.

109. The compound of any one of claims 1 to 99, 107, and 108, wherein RBis pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, or dihydropyridinyl, wherein RBis optionally substituted with 1-5 instances of R1b.

110. The compound of any one of claims 1 to 99 and 107 to 109, wherein RBis111. The compound of any one of claims 1 to 99, wherein RBis 6-7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b.

112. The compound of any one of claims 1 to 99 and 111, wherein RBis 7 membered spirocyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b.

113. The compound of any one of claims 1 to 99, 111, and 112, wherein RBis.

114. The compound of any one of claims 1 to 99, wherein RAis 5-6 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b.

115. The compound of any one of claims 1 to 99 and 114, wherein RBis 5-6 membered heteroaryl having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein RBis optionally substituted with 1-5 instances of R1b.

116. The compound of any one of claims 1 to 99, 114, and 115, wherein RBis imidazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, pyrazinyl, pyridinyl, pyrimidinyl, or thiadiazolyl, wherein RBis optionally substituted with 1-5 instances of R1b.

117. The compound of any one of claims 1 to 99 and 114 to 116, wherein RBis, , , ,118. The compound of any one of claims 1 to 99, wherein RBis119. The compound of any one of claims 1 to 99, wherein RBis,120. The compound of any one of claims 1 to 119, wherein Rn1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

121. The compound of any one of claims 1 to 120, wherein Rn1is H or –Me.

122. The compound of any one of claims 1 to 121, wherein Rn1is H.

123. The compound of any one of claims 1 to 121, wherein Rn1is –Me.

124. The compound of any one of claims 1 to 123, wherein Rn2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

125. The compound of any one of claims 1 to 124, wherein Rn2is H or –Me.

126. The compound of any one of claims 1 to 125, wherein Rn2is H.

127. The compound of any one of claims 1 to 125, wherein Rn2is –Me.

128. The compound of any one of claims 1 to 127, wherein Ro1is –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

129. The compound of any one of claims 1 to 128, wherein Ro1is –Me.

130. The compound of any one of claims 1 to 129, wherein R1is –CN, –F, –Cl, – OMe, –C(O)NH2, RA, –ORB, –NHRB, or –NHC(O)RB.

131. The compound of any one of claims 1 to 130, wherein R1is –CN, –F, –Cl, – OMe, –C(O)NH2,132. The compound of any one of claims 1 to 131, wherein R1is -CN.

133. The compound of any one of claims 1 to 37, wherein X is134. The compound of any one of claims 1 to 133, wherein Ro2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, cyclopropyl, or cyclobutyl.

135. The compound of any one of claims 1 to 134, wherein Ro3is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CF3, –CHF2, –CH2F, cyclopropyl, or cyclobutyl.

136. The compound of any one of claims 1 to 135, wherein Rs1is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

137. The compound of any one of claims 1 to 136, wherein Rs2is H, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, or –tBu.

138. The compound of any one of claims 1 to 137, wherein each R2bis independently oxo, –F, –Cl, –OH, –OMe, –NH2, –NHCH3, –N(CH3)2, or –CN, or two instances of R2battached to the same atom, together with the atom to which they are attached, form cyclopropyl.

139. The compound of any one of claims 1 to 138, wherein each R2ais independently halo, –ORo2, –SRs1, –S(O)2Rs2, –NRn1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl optionally substituted with 1-5 instances of R2b, or 3-6 membered cycloalkyl optionally substituted with 1-5 instances of R2b, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo.

140. The compound of any one of claims 1 to 139, wherein each R2ais independently halo, –ORo2, –SRs1, –S(O)2Rs2, –NRn1, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl optionally substituted with 1-5 instances of R2b, or 3-6 membered cycloalkyl optionally substituted with 1-5 instances of R2b, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo.

141. The compound of any one of claims 1 to 140, wherein each R2ais independently –F, –Cl, –Br, –OH, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –O-pentyl, – O-hexyl, –O-cyclopropyl, –O-cyclobutyl, –SH, –SMe, –SEt, –S(O)2Me, –S(O)2Et, –NH2, – NHCH3, –N(CH3)2, –C(CH3)=CH2, –C≡CH, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, – pentyl, –hexyl, –CCN(CH3)2, –CF3, –CHF2, –CH2F, –OCF3, –OCHF2, –OCH2F, –SMe, –SEt, cyclopropyl, or cyclobutyl, or two R2agroups attached to two adjacent carbon atoms, togetherwith the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo.

142. The compound of any one of claims 1 to 141, wherein each R2ais independently –F, –Cl, –Br, –OH, –OMe, –OEt, –O-cyclopropyl, –SH, –SMe, –S(O)2Me, –C(CH3)=CH2, – C≡CH, –Me, –Et, –CCN(CH3)2, –CF3, –CHF2, –CH2F, –OCF3, –OCHF2, –OCH2F, –SMe, – SEt, or cyclopropyl, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo.

143. The compound of any one of claims 1 to 140, wherein each R2ais independently –F, –Cl, –C(CH3)=CH2, –C≡CH, –Me, –Et, –nPr, –iPr, –nBu, –iBu, –sBu, –tBu, –CCN(CH3)2, –CF3, –CHF2, –CH2F, –OMe, –OEt, –OnPr, –OiPr, –OnBu, –OiBu, –OsBu, –OtBu, –OCF3, – OCHF2, –OCH2F, –SMe, –SEt, cyclopropyl, or cyclobutyl, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo.

144. The compound of any one of claims 1 to 143, wherein each instance of R2ais independently –F, –Cl, –C(CH3)=CH2, –C≡CH, –Me, –CCN(CH3)2, –CF3, –CHF2, –OMe, – OEt, –OiPr, –OCF3, –OCHF2, –SMe, or cyclopropyl, or two R2agroups attached to two adjacent carbon atoms, together with the carbon atoms to which each is attached to, form 5-6 membered heterocyclyl optionally substituted with 1-4 instances of halo.

145. The compound of any one of claims 1 to 144, wherein two ortho R2agroups, together with the carbon atoms to which each is attached to, form 5 membered heterocyclyl optionally substituted with 1-4 instances of halo.

146. The compound of any one of claims 1 to 145, wherein R2is phenyl or naphthyl, wherein R2is optionally substituted with 1-3 instances of R2a.

147. The compound of any one of claims 1 to 146, wherein R2is phenyl, wherein R2is optionally substituted with 1-3 instances of R2a.

148. The compound of any one of claims 1 to 146, wherein R2is napthyl, wherein R2is optionally substituted with 1-3 instances of R2a.

149. The compound of any one of claims 1 to 147, wherein R2is,150. The compound of any one of claims 1 to 146 and 148, wherein R2is,151. The compound of any one of claims 1 to 145, wherein R2is 5 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

152. The compound of any one of claims 1 to 145 and 151, wherein R2is 5 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-2 instances of R2a.

153. The compound of any one of claims 1 to 145, 151, and 152, wherein R2is pyrazolyl or thiazolyl.

154. The compound of any one of claims 1 to 145 and 151 to 153, wherein R2is155. The compound of any one of claims 1 to 145, wherein R2is 6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R2is optionally substituted with 1-3 instances of R2a.

156. The compound of any one of claims 1 to 145 and 155, 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.

157. The compound of any one of claims 1 to 145, 155, and 156, wherein R2is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl, wherein R2is optionally substituted with 1-3 instances of R2a.

158. The compound of any one of claims 1 to 145 and 155 to 157, wherein R2is pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, wherein R2is optionally substituted with 1-3 instances of R2a.

159. The compound of any one of claims 1 to 145 and 155 to 158, wherein R2is160. The compound of any one of claims 1 to 145, wherein R2is,161. The compound of claim 1, wherein the compound is of Formula II:or a pharmaceutically acceptable salt thereof.

162. The compound of claim 1, wherein the compound is of Formula IIa:or a pharmaceutically acceptable salt thereof.

163. The compound of claim 1, wherein the compound is of Formula IIb:or a pharmaceutically acceptable salt thereof.

164. The compound of claim 1, wherein the compound is of Formula IIc:or a pharmaceutically acceptable salt thereof.

165. The compound of claim 1, wherein the compound is of Formula IId:or a pharmaceutically acceptable salt thereof.

166. The compound of claim 1, wherein the compound is of Formula IIe:or a pharmaceutically acceptable salt thereof.

167. The compound of claim 1, wherein the compound is of Formula IIf:or a pharmaceutically acceptable salt thereof.

168. The compound of claim 1, wherein the compound is of Formula IIg:or a pharmaceutically acceptable salt thereof.

169. The compound of claim 1, wherein the compound is of Formula IIh:or a pharmaceutically acceptable salt thereof.

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

171. A compound of Table 2, or a pharmaceutically acceptable salt thereof.

172. A pharmaceutical composition comprising a compound of any one of claims 1 to 171, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient thereof.

173. 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 171, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition of claim 172.

174. The method of claim 173, wherein the glucocorticoid receptor-mediated disease or disorder is an autoimmune disease or an inflammatory disease.

175. The method of claim 173 or 174, wherein the disease or disorder is arthritis, asthma, bursitis, Crohn’s disease, hepatitis, lupus, rhinitis, tendonitis, or ulcerative colitis.

176. 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 171, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition of claim 172.

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