Complement factor b inhibitors and uses thereof

Abstract

Provided herein are compounds of Formula (I) and pharmaceutical compositions there useful for treating diseases or disorders mediated by the complement factor B.

Description

[0001] Complement Factor B Inhibitors and Uses Thereof

[0002] Field

[0003] The disclosure relates to the inhibition of the complement alternative pathway, and particularly to inhibition of factor B. It also relates to treatment of patients suffering from conditions and diseases associated with complement alternative pathway activation.

[0004] Background

[0005] The complement system is a crucial component of the innate immunity system and comprises a group of proteins that are normally present in an inactive state. These proteins are organized in three activation pathways: the classical, the lectin, and the alternative pathways (V. M. Holers, In Clinical Immunology: Principles and Practice, ed. R.R. Rich, Mosby Press; 1996, 363-391). Molecules from microorganisms, antibodies or cellular components can activate these pathways resulting in the formation of protease complexes known as the C3-convertase and the C5-convertase. The classical pathway is a calcium / magnesium-dependent cascade, which is normally activated by the formation of antigen-antibody complexes. It can also be activated in an antibody-independent manner by the binding of C-reactive protein complexed to ligand and by many pathogens including gram-negative bacteria. The alternative pathway is a magnesiumdependent cascade that is activated by deposition and activation of C3 on certain susceptible surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).

[0006] Factor B is a suitable target for the inhibition of this amplification of the complement pathways because its plasma concentration in humans is typically about 200 pg / mL (or about 2 pM), and it has been shown to be a critical enzyme for activation of the alternative complement pathway (P.H. Lesavre and H.J. Muller-Eberhard. J. Exp. Med., 1978; 148: 1498-1510; J.E. Volanakis et al., New Eng. J. Med., 1985; 312:395-401).

[0007] Summary

[0008] The present disclosure provides compounds that modulate, and / or inhibit, activation of the alternative complement pathway. In certain embodiments, the present disclosure provides compounds that modulate, and / or inhibit, factor B activity and / or factor B mediated complement pathway activation. Such factor B modulators are preferably high affinity factor B inhibitors that inhibit the catalytic activity of complement factor B, such as primate factor B and particularly human factor B.

[0009] The compounds of the present disclosure inhibit or suppress the amplification of the complement system caused by C3 activation irrespective of the initial mechanism of activation (including for example activation of the classical, lectin or alternative pathways). The disclosure also relates to compounds effective as factor B modulators, pharmaceutically acceptable salts thereof, compositions thereof, and their use in therapies for the conditions and purposes detailed herein.

[0010] The disclosure provides, in a first aspect, a compound of Formula (I) or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein the variables are defined herein.

[0011] In a second aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, and a pharmaceutically acceptable carrier or excipient.

[0012] In a third aspect, there is provided a method of treating or preventing a disease ordisorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0013] In a further aspect, there is provided a method of modulating the complement alternative pathway activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0014] In a further aspect, there is provided a method of treating a disease or disorder mediated by complement activation, in particular mediated by activation of the complement alternative pathway, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0015] In a further aspect, there is provided a method of treating a disease or disorder that is affected by the modulation of complement alternative pathway comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0016] In a further aspect, there is provided a method of treating a disease or disorder associated with dysregulation of the complement alternative pathway comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0017] In a further aspect, there is provided a method of inhibiting the expression or activity of complement factor B, the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0018] In a further aspect, there is provided a method of treating age-related macular degeneration comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0019] In a further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use as a medicament.

[0020] In a further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use in inhibiting the expression or activity of complement factor B, in a subject in need thereof.

[0021] In a further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use in treating a disease or disorder associated with dysregulation of the complement alternative pathway.

[0022] In a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, in the manufacture of a medicament for the treatment of a disease or disorder mediated by complement activation or activation of the complement alternative pathway.

[0023] In a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for the treatment of a disease or disorder mediated by complement activation or activation of the complement alternative pathway.

[0024] In a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for the treatment of a disease or disorder that is affected by the modulation of complement alternative pathway. Detailed Description

[0025] Macular degeneration is a clinical term that is used to describe a family of diseases that are characterized by a progressive loss of central vision associated with abnormalities of Bruch’s membrane, the choroid, the neural retina and / or the retinal pigment epithelium. In the center of the retina is the macula lutea, which is about 1 to % cm in diameter. The macula provides detailed vision, particularly in the center (the fovea), because the cones are higher in density and because of the high ratio of ganglion cells to photoreceptor cells. Blood vessels, ganglion cells, inner nuclear layer and cells, and the plexiform layers are all displaced to the side (rather than resting above the photoreceptor cells), thereby allowing light a more direct path to the cones. Under the retina is the choroid, a part of the uveal tract, and the retinal pigmented epithelium (RPE), which is between the neural retina and the choroid. The choroidal blood vessels provide nutrition to the retina and its visual cells.

[0026] Age-related macular degeneration (AMD), the most prevalent form of macular degeneration, is associated with progressive loss of visual acuity in the central portion of the visual field, changes in color vision, and abnormal dark adaptation and sensitivity. Two principal clinical manifestations of AMD have been described as the dry, or atrophic, form and the neovascular, or exudative, form. The dry form is associated with atrophic cell death of the central retina or macula, which is required for fine vision used for activities such as reading, driving or recognizing faces. About 10-20% of these AMD patients progress to the second form of AMD, known as neovascular AMD (also referred to as wet AMD).

[0027] Neovascular AMD is characterized by the abnormal growth of blood vessels under the macula and vascular leakage, resulting in displacement of the retina, hemorrhage and scarring. This results in a deterioration of sight over a period of weeks to years. Neovascular AMD cases originate from Intermediate or advanced dry AMD. The neovascular form accounts for 85% of legal blindness due to AMD. In neovascular AMD, as the abnormal blood vessels leak fluid and blood, scar tissue is formed that destroys the central retina.

[0028] The new blood vessels in neovascular AMD are usually derived from the choroid and are referred to as choroidal neovascularizaton (CNV). The pathogenesis of new choroidal vessels is poorly understood, but such factors as inflammation, ischemia, and local production of angiogenic factors are thought to be important. A published study suggests that CNV is caused by complement activation in a mouse laser model (Bora P.S., J. Immunol. 2005;174; 491-497).

[0029] As noted above, the present disclosure provides compounds that modulate factor B activation and / or factor B-mediated signal transduction of the complement system. Such compounds may be used in vitro or in vivo to modulate factor B activity in a variety of contexts. The compounds disclosed herein are effective as factor B modulators and / or inhibitors. The compounds provided herein are useful for the treatment of disorders associated with factor B.

[0030] Definitions

[0031] Unless specified otherwise, the terms “compounds of the present disclosure,” “compounds of the disclosure,” “compound of the disclosure,” “or compounds provided herein” refer to compounds of the formulae disclosed herein, exemplified compounds, salts thereof, particularly pharmaceutically acceptable salts thereof, hydrates, solvates, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitutions), as well as inherently formed moieties. In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, Ci-Cwalkyl means an alkyl group or radical having 1 to 10 carbon atoms.

[0032] Furthermore, the use of a term designating a monovalent radical where a divalent radical is appropriate shall be construed to designate the respective divalent radical and vice versa. Unless otherwise specified, conventional definitions of terms control and conventional stable atom valences are presumed and achieved in all formulas and groups. The articles “a” and “an” refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0033] The term “and / or” means either “and” or “or” unless indicated otherwise.

[0034] The term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0035] As used herein the term “Ci-Cealkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. The terms Ci-C3alkyl and Ci-C4alkyl are to be construed accordingly. Examples of Ci-C6alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1 -methylethyl ( / so-propyl), n-butyl, 1 -methylpropyl (sec-butyl), 2-methylpropyl ( / so-butyl), 1 ,1 -dimethylethyl (te / Y-butyl), n-pentyl and n-hexyl.

[0036] The term “alkenyl” employed alone or in combination with other terms, refers to a straightchain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound. The term “Cn.malkenyl” refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl and the like.

[0037] As used herein, the term “Ci-C6alkoxy” refers to a radical of the formula -ORawhere Rais a Ci.C6alkyl radical as generally defined above. Examples of Ci-C6alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, / so-propoxy, butoxy, / so-butoxy, tert- butoxy, sec-butoxy, pentoxy, and hexoxy.

[0038] The term “amino,” employed alone or in combination with other terms, refers to a group of formula -NH2, wherein the hydrogen atoms may be substituted with a substituent described herein. For example, “alkylamino” can refer to -NH(alkyl) and - N(alkyl)2.

[0039] The term “cyano” or “nitrile” refers to a group of formula -CEN, which also may be written as -CN.

[0040] The term “halogen” or “halo” means fluorine, chlorine, bromine or iodine. The term ‘hydroxy” refers to an alcohol group of formula -OH.

[0041] As used herein, the term “cycloalkyl” or “carbocycle” means a monocyclic or polycyclic saturated or partially unsaturated carbon ring containing 3-18 carbon atoms wherein there are no delocalized pi electrons (aromaticity) shared among the ring carbons. The term “C3-C5cycloalkyl” is to be construed accordingly. The term polycyclic encompasses bridged (e.g., norbornane), fused (e.g., decalin) and spirocyclic cycloalkyl. Preferably, cycloalkyl, e.g., C3-C5cycloalkyl, is a monocyclic hydrocarbon group of 3 to 5 carbon atoms.

[0042] Examples of cycloalkyl groups include, without limitations, cyclopropenyl, cyclopropyl cyclobutyl, cyclobutenyl, cyclopentyl, bicyclo[1 .1 ,1]pentanyl and derivatives thereof.

[0043] Examples of C3-C5cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, and cyclo pentyl.

[0044] “Heterocyclyl” means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, and sulfur (O, N, and S) and wherein there are no delocalized pi electrons (aromaticity) shared among the ring carbons or heteroatoms. The term “4- to 6-membered heterocyclyl” is to be construed accordingly. The heterocyclyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. The heterocyclyl may be bonded via a carbon atom or heteroatom. The term polycyclic encompasses bridged, fused and spirocyclic heterocyclyl.

[0045] Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1 ,4-dioxanyl, dihydrofuranyl, 1 ,3-dioxolanyl, imidazolidinyl, dihydroisoxazolinyl, pyrrolinyl, pyrazolinyl, oxazepinyl, dithiolanyl, homotropanyl, dihydropyranyl (e.g., 3,6-dihydro-2 / 7-pyranyl), oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl) and the like.

[0046] Examples of 4- to 6-membered heterocyclyl include, without limitations, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, dihydroisoxazolinyl, tetrahydropyranyl, morpholinyl, dihydropyranyl (e.g., 3,6-dihydro-2 / 7-pyranyl) and oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl).

[0047] As used herein, the term “heteroaryl” is intended to include monocyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isooxazolyl, triazolyl, (e.g., 1 ,2,4-triazolyl), oxadiazolyl, (e.g., 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl), thiadiazolyl (e.g., 1 ,2,3- thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl), tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazinyl, thiadiazinyl, azepinyl, azecinyl, and the like. Heteroaryl is also intended to include bicyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzopyranyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, cinnolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, oxazolopyridinyl, isooxazolopyridinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, thiazolopyridinyl, thiazolopyrimidinyl, imdazothiazolyl, triazolopyridinyl, triazolopyrimidinyl, and the like.

[0048] Heteroaryl is also intended to include polycyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S). Representative examples are carbazolyl, phenoxazinyl, phenazinyl, acridinyl, phenothiazinyl, carbolinyl, phenanthrolinyl, and the like.

[0049] The heteroaryl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. The heteroaryl ring may be bonded via a carbon atom or heteroatom.

[0050] The term “5 or 6 membered heteroaryl” is to be construed accordingly.

[0051] Examples of 5 or 6 membered heteroaryl include, but are not limited to, furan, indolyl, pyridinyl, pyrimidinyl, pyridinonyl, pyridazinyl, triazolyl, (e.g., 1 ,2,4-triazolyl), pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, pyrrolyl, oxadiazolyl, (e.g., 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5- oxadiazolyl, 1 ,3,4-oxadiazolyl), imidazolyl, thiophenyl, thiadiazolyl (e.g., 1 ,2,3-thiadiazolyl, 1 ,2,4- thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl), pyrazinyl, isooxazolopyridinyl, dihydropyridooxazinyl and tetrazolyl. The term “5 or 6 membered heteroaryl ring having 1-2 heteroatoms independently selected from N, O, and S” is to be construed accordingly.

[0052] As used herein “modulator,” means, for example, a compound of the disclosure that modulates, decreases, or reduces the levels of a specific protein (e.g., complement factor B). The amount of a specific protein (e.g., complement factor B) modulated can be measured by comparing the amount of the specific protein (e.g., complement factor B) remaining after treatment with a compound of the disclosure as compared to the initial amount or level of the specific protein (e.g., complement factor B) present as measured prior to treatment with a compound of the disclosure.

[0053] As used herein, “inhibitor” means, for example, a compound of the disclosure, that inhibits or reduces the activity of at least one component of the complement pathway, e.g., the compound inhibits binding of one component to another component of the pathway. For example, the complement pathway is the alternative complement pathway. For example, the component of the complement pathway is complement factor B. As used herein, the term “inhibit,” “inhibition,” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0054] The term “effective amount” of the compounds described herein, refers to that amount of a therapeutic compound necessary or sufficient to perform its intended function within a mammal. An effective amount of the therapeutic compound can vary according to factors such as the amount of the causative agent already present in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compounds of the present disclosure to treat the conditions wherein complement factor B plays a role.

[0055] Thus, the term “a therapeutically effective amount” of a compound of the disclosure refers to an amount of the compound of the disclosure that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the disclosure that, when administered to a subject, is effective to (1) at least partially alleviate, prevent and / or ameliorate a condition, or a disorder or a disease (i) mediated by complement factor B, or (ii) associated with complement factor B activity, or (iii) characterized by activity (normal or abnormal) of complement factor B: (2) reduce or inhibit the activity of complement factor B; or (3) reduce or inhibit the expression of complement factor B. In another embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the disclosure that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of complement factor B; or at least partially reducing or inhibiting the expression of complement factor B.

[0056] As used herein, the term “subject” or “patient” refers to human and non-human mammals, including but, not limited to, primates, rabbits, pigs, horses, dogs, cats, sheep, and cows. In particular embodiments, a subject or patient is a human. In some embodiments, the term “patient” or “subject” refers to a human being who is diseased with the condition ( / .e., disease or disorder) described herein and who would benefit from the treatment. As used herein, a subject is “in need of’ a treatment if such subject (patient) would benefit biologically, medically or in quality of life from such treatment. In particular embodiments, the subject is an adult human at least about 18 years of age. In particular embodiments, the subject is an adult human from about 18 to about 75 years of age. In some embodiments, the subject is a human child up to about 18 years of age.

[0057] As used herein, the term “treating” or “treatment” refers to inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., arresting further development of the pathology and / or symptomology) or ameliorating the disease; for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomology) such as decreasing the severity of the disease.

[0058] The term “prevent,” “preventing,” or “prevention” as used herein, comprises the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented. As used herein, a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

[0059] As used herein, the term “about” refers to a range of values + / - 10% of a specified value.

[0060] As used herein, the term “a,” “an,” “the” and similar terms used in the context of the disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

[0061] As used herein, the term “pharmaceutically acceptable carrier” refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

[0062] The term “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1 - 19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N-oxide forms.

[0063] Various enumerated embodiments of the disclosure are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the disclosure. Compounds

[0064] The invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein the variables are defined herein.

[0065] Various enumerated embodiments of the invention are described herein, it will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

[0066] Embodiment 1 provides a compound of Formula (I) or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:

[0067] W is O, C(R6)2, or NR7;

[0068] R is hydrogen, halogen, Ci-C4alkyl, haloCi-C4alkyl, or hydroxyCi-C4alkyl;

[0069] R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxy, hydroxyCi-C6alkyl, hydroxyC3- C6cycloalkyl, aminoCi-C6alkyl, Ci-C6alkoxyCi-C6alkyl, Ci-C6alkoxyCi-C6alkoxy, or C3- C6cycloalkylCi-C6alkoxy;

[0070] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Ci-C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;

[0071] R3is hydrogen, halogen, or cyano; R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0072] R5is selected from hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, Ci- C6alkoxyCi-C6alkyl, -CH2CO2R5b, -C(O)NHSO2Ci-C4alkyl, -SO2NHC(O)Ci-C4alkyl, -SO2Ci- C4alkyl, cyano, hydroxy, halogen, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-C6alkyl that is unsubstituted or substituted with -CO2H; each R5bis independently selected from hydrogen and Ci-C5alkyl; each R6is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, Cs-CecycloalkylCi- alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci- C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3- C6cycloalkoxy, haloC3-C6cycloalkoxy , and 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N and O, and wherein the Ci-Cealkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclyl is independently unsubstituted or substituted with 1 , 2, or 3 halogen ; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C6alkyl, and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N, O, and S(O)q, wherein the spirocyclic heterocycle is unsubstituted or substituted with 1 or 2 halogen, Ci-Cealkyl, haloCi- C6alkyl, C3-C6cycloalkyl, or haloC3-C6cycloalkyl; q is 0, 1 , or 2;

[0073] R7is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, C3-C6cycloalkyl, C3- C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkyl, Ci-C6alkoxyCi- C6alkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, aryl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O)q, or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein Ci-Cealkyl is unsubstituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O)q, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen, further wherein the aryl or heteroaryl is unsubstituted or substituted with halo, Ci-C6alkyl, haloCi-C6alkyl, C3-C5cycloalkyl, haloC3-C5cycloalkyl; R7ais hydrogen or Ci-C6alkyl; each R8is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- C1-C4alkylamino, C1-C6alkyl, haloC1-C6alkyl, hydroxyC1-C6alkyl, cyanoC1-C6alkyl, C1 C6alkoxy, and haloCi-C6alkoxy;

[0074] R9is H, D, or T; m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3; provided that both m and n are not 0; and p is 0, 1 , 2, or 3.

[0075] Embodiment 2 provides the compound of Formula (I) of embodiment 1 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:

[0076] W is C(R6)2, or NR7;

[0077] R is hydrogen;

[0078] R1is hydrogen, halogen, hydroxy, C1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxy, haloCi-C6alkyl, hydroxyC1-C6alkyl, or aminoC1-C6alkyl;

[0079] R2is Ci-Csalkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-Cealkyl, or halogen, wherein the Ci-C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;

[0080] R3is hydrogen, halogen, or cyano;

[0081] R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0082] R5is selected from hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, Cr C6alkoxyCi-C6alkyl, -CH2CO2R5b, cyano, hydroxy, halogen, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-C6alkyl that is unsubstituted or substituted with -CO2H;

[0083] R5bis selected from hydrogen and Ci-C5alkyl; each R6is independently selected from hydrogen, halogen, hydroxy, C3-C6cycloalkylCi- C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCr Cealkyl, Ci-Cealkoxy, haloC1-C6alkoxy, C3-C6cycloalkoxy, haloC3-C6cycloalkoxy, and 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, and wherein the Ci-C6alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclyl is independently unsubstituted or substituted with 1 , 2, or 3 halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C6alkyl, and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O, wherein the spirocyclic heterocycle is unsubstituted;

[0084] R7is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, haloC3-C6cycloalkylCi- C3alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, C3-C6cycloalkyl, 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N or O, or 5- to 6- membered heteroaryl having 1 heteroatom selected from O, wherein the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are unsubstituted;

[0085] R7ais Ci-C6alkyl; each R8is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Cr C6alkoxy, and haloCi-C6alkoxy;

[0086] R9is H, D, or T; m is 1 , 2, or 3; n is 1 , 2, or 3; and p is 0, 1 , or 2.

[0087] Embodiment 3 provides the compound of Formula (I) of embodiment 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:

[0088] W is C(R6)2, or NR7;

[0089] R is hydrogen;

[0090] R1is hydrogen, halogen, hydroxy, Ci-Cealkyl, Cs-Cecycloalkyl, Ci-Cealkoxy, or haloCi- C6alkyl;

[0091] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen;

[0092] R3is hydrogen;

[0093] R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0094] R5is selected from hydrogen, -CO2R5b, Ci-Cealkyl, hydroxyCs-Cecycloalkyl, -CH2CO2R5b, cyano, hydroxy, halogen, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, and O, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-C6alkyl that is unsubstituted or substituted with -CO2H; each R5bis selected from hydrogen and Ci-C5alkyl; each R6is independently selected from hydrogen, halogen, hydroxy, C3-C6cycloalkylCi- C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCr C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkoxy, haloC3-C6cycloalkoxy, and 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, and wherein the Ci-C6alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclyl is independently unsubstituted or substituted with 1 , 2, or 3 halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-Cealkyl, and Ci-Cealkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O, wherein the spirocyclic heterocycle is unsubstituted;

[0095] R7is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, haloC3-C6cycloalkylCi- C3alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, C3-C6cycloalkyl, 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N or O, or 5- to 6- membered heteroaryl having 1 heteroatom selected from O, wherein the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are unsubstituted;

[0096] R7ais Ci-C6alkyl; each R8is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Cr C6alkoxy, and haloCi-C6alkoxy;

[0097] R9is H; m is 1 , or 2; n is 1 , 2, or 3; and p is 0.

[0098] Embodiment 4 provides the compound of Formula (I) of any of embodiments 1 to 3, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the compound of Formula (I) is a compound of Formula (1-1):

[0099] (1-1) or a pharmaceutically acceptable salt thereof. Embodiment 5 provides the compound of Formula (I) of any of embodiments 1 to 3, wherein the compound of Formula (I) is a compound of Formula (I-2):

[0100] (I-2) or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0101] Embodiment 6 provides the compound of Formula (I) in any of embodiments 1 to 5, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:

[0102] W is C(R6)2;

[0103] R is hydrogen;

[0104] R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCi-C6alkyl, hydroxyCi-C6alkyl, or aminoCi-C6alkyl;

[0105] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Ci-C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;

[0106] R3is hydrogen, halogen, or cyano;

[0107] R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0108] R5is selected from hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, Cr CealkoxyCi-Cealkyl, -CH2CO2R5b, cyano, hydroxy, halogen, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-Cealkyl that is unsubstituted or substituted with -CO2H; each R5bis selected from hydrogen and Ci-C5alkyl; each R6is independently selected from hydrogen, halogen, hydroxy, C3-C6cycloalkylCi- C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCr C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkoxy, haloC3-C6cycloalkoxy, and 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, and wherein the Ci-C6alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclyl is independently unsubstituted or substituted with 1 , 2, or 3 halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C6alkyl, and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O, wherein the spirocyclic heterocycle is unsubstituted; each R8is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, Ci-Cealkyl, haloCi-Cealkyl, hydroxyCi-Cealkyl, cyanoCi-Cealkyl, Ci- C6alkoxy, and haloCi-C6alkoxy;

[0109] R9is H, D, or T; m is 1 , 2, or 3; n is 1 , 2, or 3; and p is 0, 1 , or 2.

[0110] Embodiment 7 provides the compound of Formula (I) of any of embodiments 1 to 5, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein

[0111] W is NR7;

[0112] R is hydrogen;

[0113] R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCi-C6alkyl, hydroxyCi-C6alkyl, or aminoCi-C6alkyl;

[0114] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Ci-C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;

[0115] R3is hydrogen, halogen, or cyano;

[0116] R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0117] R5is selected from hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, Cr C6alkoxyCi-C6alkyl, -CH2CO2R5b, cyano, hydroxy, halogen, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-C6alkyl that is unsubstituted or substituted with -CO2H; each R5bis selected from hydrogen and Ci-C5alkyl;

[0118] R7is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, haloC3-C6cycloalkylCi- C3alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, C3-C6cycloalkyl, 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N or O, or 5- to 6- membered heteroaryl having 1 heteroatom selected from O, wherein the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are unsubstituted;

[0119] R7ais Ci-C6alkyl; each R8is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Cr C6alkoxy, and haloCi-C6alkoxy; R9is H, D, or T; m is 1 , 2, or 3; n is 1 , 2, or 3; and p is 0, 1 , or 2.

[0120] Embodiment 8 provides the compounf of Formula (I) of any of embodiments 1-6, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein

[0121] W is C(R6)2;

[0122] R is hydrogen;

[0123] R1is hydrogen, halogen, Ci-C6alkyl, C3-C6cycloalkyl, or haloCi-C6alkyl;

[0124] R2is Ci-C3alkyl, or halogen, wherein the Ci-C3alkyl is unsubstituted or substituted with 1 , 2, or 3 halogen substituents;

[0125] R3is hydrogen;

[0126] R4is phenyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0127] R5is selected from hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, -CH2CO2R5b, cyano, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R5a; each R5ais independently selected from hydroxy and Ci-C6alkyl; each R5bis independently selected from hydrogen and Ci-C3alkyl; each R6is independently selected from hydrogen, halogen, hydroxy, C3-C6cycloalkylCi- C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-Cealkoxy, Cs-Cecycloalkoxy, haloCs-Cecycloalkoxy, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, and wherein the Ci-C6alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C6alkyl, and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O; each R8is independently selected from hydrogen and Ci-C6alkyl;

[0128] R9is H; m is 1 or 2; n is 1 , 2, or 3; and p is 0, 1 , or 2.

[0129] Embodiment 9 provides the compound of Formula (I) of any of embodiments 1 -5 and 7, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein

[0130] W is NR7;

[0131] R is hydrogen;

[0132] R1is hydrogen, halogen, Ci-Cealkyl, Cs-Cecycloalkyl, or haloCi-Cealkyl;

[0133] R2is Ci-C3alkyl, or halogen, wherein the Ci-C3alkyl is unsubstituted or substituted with 1 , 2, or 3 halogen substituents;

[0134] R3is hydrogen;

[0135] R4is phenyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0136] R5is selected from hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, -CH2CO2R5b, cyano, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R5a; each R5ais independently selected from hydroxy and Ci-C6alkyl; each R5bis independently selected from hydrogen and Ci-C3alkyl;

[0137] R7is Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, haloC3-C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N or O, or 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, ;

[0138] R7ais Ci-C6alkyl; each R8is independently selected from hydrogen and Ci-C6alkyl;

[0139] R9is H; m is 1 or 2; n is 1 , 2, or 3; and p is 0, 1 , or 2. Embodiment 10 provides the compound of Formula (I) of any of embodiments 1 -6 and 8, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein

[0140] W is C(R6)2;

[0141] R is hydrogen;

[0142] R1is hydrogen, halogen, Ci-C6alkyl, C3-C6cycloalkyl, haloCi-C6alkyl;

[0143] R2is Ci-C3alkyl, or halogen, wherein the Ci-C3alkyl is unsubstituted or substituted with 1 , 2, or 3 halogen substituents;

[0144] R3is hydrogen;

[0145] R4is phenyl, or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0146] R5is selected from hydrogen, -CO2R5b, Ci-Cealkyl, hydroxyCs-Cecycloalkyl, -CH2CO2R5b, cyano, hydroxy, halogen, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from hydroxyl, and Ci-C6alkyl; each R5bis independently selected from hydrogen; each R6is independently selected from hydrogen, halogen, hydroxy, C3-C6cycloalkylCi- C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkoxy, haloC3-C6cycloalkoxy, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, and wherein the Ci-C6alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclyl is independently unsubstituted or substituted with 1 , 2, or 3 halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O; each R8is independently selected from hydrogen, halogen;

[0147] R9is H or D; m is 1 or 2; n is 1 , 2, or 3; and p is 0.

[0148] Embodiment 11 provides the compound of Formula (I) of any of embodiments 1-5, 7 and 9, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein W is NR7;

[0149] R is hydrogen;

[0150] R1is hydrogen, halogen, Ci-C6alkyl, C3-C6cycloalkyl, haloCi-C6alkyl;

[0151] R2is Ci-C3alkyl, or halogen, wherein the Ci-C3alkyl is unsubstituted or substituted with 1 , 2, or 3 halogen substituents;

[0152] R3is hydrogen;

[0153] R4is phenyl, or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0154] R5is selected from hydrogen, -CC>2R5b, Ci-Cealkyl, hydroxyCs-Cecycloalkyl, -CH2CC>2R5b, cyano, hydroxy, halogen, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from hydroxyl, and Ci-C6alkyl; each R5bis independently selected from hydrogen;

[0155] R7is Ci-Cealkyl, haloCi-Cealkyl, hydroxyC2-Cealkyl, haloC3-C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N or O, or 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S; each R8is independently selected from hydrogen, halogen; R9is H or D; m is 1 or 2; n is 1 , 2, or 3; and p is 0.

[0156] Embodiment 12 provides the compound of Formula (I) of any of applicable embodiments 1 to 11 , wherein the compound of Formula (I) is a compound of Formula (l-AC), or (l-AN): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0157] Embodiment 13 provides the compound of Formula (I) of any of embodiments 1 to 12, wherein the compound of Formula (I) is a compound of Formula (l-AO), (I-A1) or (I-A2): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0158] Embodiment 14 provides the compound of Formula (I) of embodiment 13, wherein the compound of Formula (I) is a compound of Formula (l-A), Formula (I-A11) or Formula (I-A12): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0159] Embodiment 15 provides the compound of Formula (I) of any of embodiments 1 to 13, wherein the compound of Formula (I) is a compound of Formula or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0160] Embodiment 16 provides the compound of Formula (I) of embodiment 15, wherein the compound of Formula (I) is a compound of Formulas (l-D’), (l-D’1) or (l-D’2):

[0161] or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0162] Embodiment 17 provides the compound of Formula (I) of embodiment 13, wherein the compound of Formula (I) is a compound of Formula (l-H), (I-H1), or (l-H2): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0163] Embodiment 18 provides the compound of Formula (I) of embodiment 17, wherein the compound of Formula (I) is a compound of Formula (l-B), (I-EB1 ) or (I-B2): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0164] Embodiment 19 provides the compound of Formula (I) of embodiment 13, wherein the compound of Formula (I) is a compound of Formula (l-E), (I-E1), or (I-E2): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0165] Embodiment 20 provides the compound of Formula (I) of embodiment 13, wherein the or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0166] Embodiment 21 provides the compound of Formula (I) of embodiment 13, wherein the compound of Formula (I) is a compound of Formula (l-G), (I-G1), or (l-G2): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0167] Embodiment 22 provides the compound of Formula (I) of embodiment 13, wherein the compound of Formula (I) is a compound of Formula (l-J), (I-J1) or (l-J2):

[0168] or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0169] Embodiment 23 provides the compound of Formula (I) of embodiment 13, wherein the compound of Formula (I) is a compound of Formula (l-CO): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0170] Embodiment 24 provides the compound of Formula (I) of embodiment 23, wherein the compound of Formula (I) is a compound of Formula (I-C01), (I-C02), (I-C03) or (l-C04): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof. Embodiment 25 provides the compound of Formula (I) of embodiment 24, wherein the compound of Formula (I) is a compound of Formula (l-C):

[0171] (l-C) or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0172] Embodiment 26 provides the compound of Formula (I) of embodiment 25, wherein the compound of Formula (I) is a compound of Formula (I-C1), (I-C2), (I-C3) or (l-C4): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0173] Embodiment 27 provides the compound of Formula (I) of embodiment 23, wherein the compound of Formula (I) is a compound of Formula (l-l):

[0174] or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0175] Embodiment 28 provides the compound of Formula (I) of embodiment 27, wherein the compound of Formula (I) is a compound of Formula (1-11), (I-I2), (I-I3) or (I-I4): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0176] Embodiment 29 provides the compound of Formula (I) of embodiment 28, wherein the compound of Formula (I) is a compound of Formula (l-J): (I-J) or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0177] Embodiment 30 provides the compound of Formula (I) of embodiment 29, wherein the compound of F or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0178] Embodiment 31 provides the compound of Formula (I) of any of embodiments 1 to 30, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxy, hydroxyCi-C6alkyl, hydroxyC3- C6cycloalkyl, aminoCi-C6alkyl, Ci-C6alkoxyCi-C6alkyl, Ci-C6alkoxyCi-C6alkoxy, or C3- CecycloalkylCi-Cealkoxy.

[0179] Embodiment 32 provides the compound of Formula (I) of any of embodiments 1 to 31 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R1is hydrogen, halogen, Ci-Cealkyl, Cs-Cecycloalkyl, haloCi-Cealkyl, haloC3- C6cycloalkyl, haloCi-C6alkoxy, hydroxyCi-C6alkyl, or hydroxyC3-C6cycloalkyl.

[0180] Embodiment 33 provides the compound of Formula (I) of any of embodiments 1 to 32, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C3-C6cycloalkyl, or haloCi-C6alkyl.

[0181] Embodiment 34 provides the compound of Formula (I) of any of embodiments 1 to 33, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R1is hydrogen, halogen, Ci-Cealkyl, Cs-Cecycloalkyl, or haloCi-Cealkyl.

[0182] Embodiment 35 provides the compound of Formula (I) of any of embodiments 1 to 34, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Ci-C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents.

[0183] Embodiment 36 provides the compound of Formula (I) of any of embodiments 1 to 35, or a pharmaceutically acceptable salt or a stereoisomer or an isoto pica lly labeled compound thereof, wherein R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Ci-C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents.

[0184] Embodiment 37 provides the compound of Formula (I) of any of embodiments 1 to 36, or a pharmaceutically acceptable salt or a stereoisomer or an isoto pica lly labeled compound thereof, wherein R2is Ci-C3alkyl, or halogen, wherein the Ci-C3alkyl is unsubstituted or substituted with 1 , 2, or 3 halogen substituents.

[0185] Embodiment 38 provides the compound of Formula (I) of any of embodiments 1 to 37, or a pharmaceutically acceptable salt or a stereoisomer or an isoto pica lly labeled compound thereof, wherein R2is Ci-C3alkyl, or halogen.

[0186] Embodiment 39 provides the compound of Formula (I) of any of applicable embodiments 1 to 38, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein where applicable R3is hydrogen, halogen, or cyano.

[0187] Embodiment 40 provides the compound of Formula (I) of any of applicable embodiments 1 to 39, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein where applicable R3is hydrogen.

[0188] Embodiment 41 provides the compound of Formula (I) of any of applicable embodiments 1 to 40, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5.

[0189] Embodiment 42 provides the compound of Formula (I) of any of applicable embodiments 1 to 41 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R4is phenyl, or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R5.

[0190] Embodiment 43 provides the compound of Formula (I) of any of applicable embodiments 1 to 42, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R4is phenyl, or 5- to 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R5.

[0191] Embodiment 44 provides the compound of Formula (I) of any of applicable embodiments 1 to 43, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R4is 5- to 6-membered heteroaryl having 1 or 2 ring heteroatoms selected from N, wherein phenyl or heteroaryl is unsubstituted or substituted with R5.

[0192] Embodiment 45 provides the compound of Formula (I) of any of applicable embodiments 1 to 44, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R4is phenyl, wherein the phenyl is unsubstituted or substituted with R5.

[0193] Embodiment 46 provides the compound of Formula (I) of any of applicable embodiments 1 to 45, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R4is pyridinyl, or pyrazolyl, wherein the pyridinyl, or pyrazolyl is unsubstituted or substituted with R5.

[0194] Embodiment 47 provides the compound of Formula (I) of any of applicable embodiments 1 to 46, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R5is selected from hydrogen, -CC>2R5b, Ci-Cealkyl, hydroxyC3- Cecycloalkyl, Ci-C6alkoxyCi-C6alkyl, -CH2CO2R5b, -C(O)NHSO2Ci-C4alkyl, -SO2NHC(O)CI- C4alkyl, -SO2Ci-C4alkyl, cyano, hydroxy, halogen, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a.

[0195] Embodiment 48 provides the compound of Formula (I) of any of applicable embodiments 1 to 47, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R5is selected from hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3- C6cycloalkyl, -CH2CO2R5b, cyano, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a.

[0196] Embodiment 49 provides the compound of Formula (I) of any of applicable embodiments 1 to 48, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R5is selected from hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3- C6cycloalkyl, -CH2CO2R5b, cyano, -C(O)N(R5b)2and 5-membered heteroaryl having 1-4 heteroatoms independently selected from N, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R5a.

[0197] Embodiment 50 provides the compound of Formula (I) of any of applicable embodiments 1 to 49, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R5is selected from hydrogen, -CO2R5b, Ci-Cealkyl, hydroxyC3- C6cycloalkyl, -CH2CO2R5b, cyano, -C(O)N(R5b)2and 5-membered heteroaryl having 1-3 heteroatoms independently selected from N, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R5a.

[0198] Embodiment 51 provides the compound of Formula (I) of any of applicable embodiments 1 to 50, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein where applicable each R5ais independently selected from fluoro, hydroxyl, and Ci-C6alkyl that is unsubstituted or substituted with -CO2H.

[0199] Embodiment 52 provides the compound of Formula (I) of any of applicable embodiments 1 to 51 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein where applicable each R5ais hydroxyl.

[0200] Embodiment 53 provides the compound of Formula (I) of any of applicable embodiments 1 to 52, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein where applicable each R5bis independently selected from hydrogen and Ci-C5alkyl.

[0201] Embodiment 54 provides the compound of Formula (I) of any of applicable embodiments 1 to 53, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein where applicable each R5bis independently selected from hydrogen.

[0202] Embodiment 55 provides the compound of Formula (I) of any of applicable embodiments 1 to 54, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R5is selected from hydrogen, -CO2H, Ci-C6alkyl, hydroxyC3- Cecycloalkyl, hydroxyC3-Cealkyl, cyano, -CONH2, pyrazolyl, triazolyl, and tetrazolyl, wherein the pyrazolyl, triazolyl, and tetrazolyl are unsubstituted or substituted with 1 Ci-C6alkyl.

[0203] Embodiment 56 provides the compound of Formula (I) of any of applicable embodiments 1 to 55, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein each R6is independently selected from hydrogen, halogen, hydroxy, C3-C6cycloalkylCi-C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkoxy, haloC3-C6cycloalkoxy, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein the Ci-C6alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen.

[0204] Embodiment 57 provides the compound of Formula (I) of any of applicable embodiments 1 to 56, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein each R6is independently selected from Ci-C6alkyl, C3-C6cycloalkylCi- C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, haloCi-C6alkyl, C3-C6cycloalkoxy, haloC3- C6cycloalkoxy, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein the Ci-Cealkyl is unsubsituted or substituted with 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen.

[0205] Embodiment 58 the compound of Formula (I) of any of applicable embodiments 1 to 57, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein each R6is independently selected from hydrogen, halogen, hydroxy, C3- C6cycloalkylCi-C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkoxy, haloC3-C6cycloalkoxy, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, and wherein the Ci-C6alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen.

[0206] Embodiment 59 provides the compound of Formula (I) of any of applicable embodiments 1 to 58, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein each R6is independently selected from hydrogen, halogen, hydroxy, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, and haloCi-C6alkoxy.

[0207] Embodiment 60 provides the compound of Formula (I) of any of applicable embodiments 1 to 59, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C6alkyl, and Cr C6alkoxy.

[0208] Embodiment 61 provides the compound of Formula (I) of any of applicable embodiments 1 to 60, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 4 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen.

[0209] Embodiment 62 provides the compound of Formula (I) of any of applicable embodiments 1 to 61 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N, O, and S(O)q, wherein the spirocyclic heterocycle is unsubstituted or substituted with 1 or 2 halogen, Ci-C6alkyl, haloCi-C6alkyl, C3-C6cycloalkyl, or haloC3-C6cycloalkyl; wherein q is 0, 1 , or 2.

[0210] Embodiment 63 provides the compound of Formula (I) of any of applicable embodiments 1 to 62, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O.

[0211] Embodiment 64 provides the compound of Formula (I) of any of applicable embodiments 1 to 63, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O, wherein the spirocyclic heterocycle has 3 to 6 ring atoms.

[0212] Embodiment 65 provides the compound of Formula (I) of any of applicable embodiments 1 to 64, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 ring heteroatom selected from O.

[0213] Embodiment 66 provides the compound of Formula (I) of any of applicable embodiments 1 to 65, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 ring heteroatom selected from O, wherein the spirocyclic heterocycle has 5 ring atoms.

[0214] Embodiment 67 provides the compound of Formula (I) of any of applicable applicable embodiments 1 to 66, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R7is Ci-Cealkyl, haloCi-Cealkyl, hydroxyC2-C6alkyl, C3- C6cycloalkyl, C3-C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkyl, Cr C6alkoxyCi-C6alkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, aryl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O)q, or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein Ci-C6alkyl is unsubstituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O)q, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen, further wherein the aryl or heteroaryl is unsubstituted or substituted with halo, Ci-C6alkyl, haloCi-C6alkyl, C3-C5cycloalkyl, haloC3- C5cycloalkyl.

[0215] Embodiment 68 provides the compound of Formula (I) of any of applicable applicable embodiments 1 to 67, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R7is Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, C3- C6cycloalkyl, C3-C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen, further wherein the heteroaryl is unsubstituted or substituted with halo, Ci-C6alkyl, haloCi-C6alkyl, C3-C5cycloalkyl, haloC3-C5cycloalkyl.

[0216] Embodiment 69 provides the compound of Formula (I) of any of applicable embodiments 1 to 68, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R7is Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, haloC3- CecycloalkylCi-Csalkyl, haloCs-Cecycloalkyl, haloCi-CealkoxyCi-Cealkyl, -COR7a, 4- to 6- membered heterocyclyl having 1 heteroatoms selected from O, or 5- to 6-membered heteroaryl having 1 heteroatoms independently selected from O, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen, further wherein the heteroaryl is unsubstituted or substituted with halo, Ci-C6alkyl, haloCi-C6alkyl, C3-C5cycloalkyl, haloC3- C5cycloalkyl. Embodiment 70 provides the compound of Formula (I) of any of applicable embodiments 1 to 69, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R7is Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, haloC3- C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, 4- to 6- membered heterocyclyl having 1 heteroatoms selected from O, or 5-membered heteroaryl having 1 heteroatom selected from O.

[0217] Embodiment 71 provides the compound of Formula (I) of any of applicable embodiments 1 to 70, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R7ais Ci-C6alkyl.

[0218] Embodiment 72 provides the compound of Formula (I) of any of applicable embodiments 1 to 71 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein p is 0.

[0219] Embodiment 73 provides the compound of Formula (I) of any of applicable embodiments 1 to 72, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R9is H.

[0220] Embodiment 74 provides the compound of Formula (I) of any of applicable embodiments 1 to 73, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein m is 1 , or 2.

[0221] Embodiment 75 provides the compound of Formula (I) of any of applicable embodiments 1 to 74, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein n is 1 , 2, or 3.

[0222] Embodiment 76 provides the compound of Formula (I) of any of applicable embodiments 1 to 75, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:

[0223] W is C(R6)2, or NR7;

[0224] R is hydrogen;

[0225] R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxy, hydroxyCi-C6alkyl, hydroxyC3- C6cycloalkyl, aminoCi-C6alkyl, Ci-C6alkoxyCi-C6alkyl, Ci-C6alkoxyCi-C6alkoxy, or C3- C6cycloalkylCi-C6alkoxy;

[0226] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Ci-C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;

[0227] R3is hydrogen, halogen, or cyano;

[0228] R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5; R5is selected from hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, Ci- C6alkoxyCi-C6alkyl, -CH2CO2R5b, -C(O)NHSO2Ci-C4alkyl, -SO2NHC(O)Ci-C4alkyl, -SO2Ci- C4alkyl, cyano, hydroxy, halogen, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-C6alkyl that is unsubstituted or substituted with -CO2H; each R5bis independently selected from hydrogen and Ci-C5alkyl; each R6is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, Cs-CecycloalkylCi- alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci- C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3- C6cycloalkoxy, haloC3-C6cycloalkoxy, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen, and wherein the Ci-C6alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclyl is independently unsubstituted or substituted with 1 , 2, or 3 halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C6alkyl, and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N, O, and S(O)q, wherein the spirocyclic heterocycle is unsubstituted or substituted with 1 or 2 halogen, Ci-C6alkyl, haloCr C6alkyl, C3-C6cycloalkyl, or haloC3-C6cycloalkyl; q is 0, 1 , or 2;

[0229] R7is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, C3-C6cycloalkyl, C3- C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkyl, Ci-C6alkoxyCi- C6alkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, aryl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O)q, or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein Ci-C6alkyl is unsubstituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O)q, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen, further wherein the aryl or heteroaryl is unsubstituted or substituted with halo, Ci-C6alkyl, haloCi-C6alkyl, C3-C5cycloalkyl, haloC3-C5cycloalkyl; R7ais hydrogen or Ci-Cealkyl;

[0230] R9is H; m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3; p is 0.

[0231] Embodiment 77 provides the compound of Formula (I) of any of applicable embodiments 1 to 76, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:

[0232] W is NR7;

[0233] R is hydrogen ;or hydroxyC3-C6cycloalkyl;

[0234] R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C3-C6cycloalkyl, haloCi-C6alkyl, haloC3- C6cycloalkyl, haloCi-C6alkoxy, hydroxyCi-C6alkyl, hydroxyC3-C6cycloalkyl; preferably hydrogen, halogen, hydroxy, Ci-C6alkyl, C3-C6cycloalkyl, haloCi-C6alkyl; more preferably hydrogen, halogen, hydroxy, Ci-Cealkyl, Cs-Cecycloalkyl, or haloCi- C6alkyl; more preferably hydrogen, halogen, Ci-C6alkyl, C3-C6cycloalkyl, or haloCi-C6alkyl;

[0235] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-Cealkyl, or halogen, wherein the Ci-C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents; preferably Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-Cealkyl, or halogen; more preferably Ci-C3alkyl, or halogen;

[0236] R3is hydrogen;

[0237] R4is phenyl, or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R5; preferably phenyl, or 5- to 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R5; more preferably phenyl, or 5- to 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from N, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0238] R5is selected from hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, -CH2CO2R5b, cyano, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; preferably hydrogen, -CO2R5b, Ci-Cealkyl, hydroxyCs-Cecycloalkyl, -CH2CO2R5b, cyano, - C(O)N(R5b)2and 5-membered heteroaryl having 1-4 heteroatoms independently selected from N, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R5a; more preferably hydrogen, -CO2R5b, Ci-Cealkyl, hydroxyCs-Cecycloalkyl, -CH2CO2R5b, cyano, -C(O)N(R5b)2and 5-membered heteroaryl having 1-3 heteroatoms independently selected from N, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-C6alkyl; preferably hydroxyl; each R5bis independently selected from hydrogen;

[0239] R5is preferably selected from hydrogen, -CO2H, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, hydroxyC3-C6alkyl, cyano, -CONH2, pyrazolyl, triazolyl, and tetrazolyl, wherein the pyrazolyl, triazolyl, and tetrazolyl are unsubstituted or substituted with 1 Ci-C6alkyl;

[0240] R7is hygrogen, Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, C3-C6cycloalkyl, C3- C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkyl, Ci-C6alkoxyCi- C6alkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, aryl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O)q, or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein Ci-C6alkyl is unsubstituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O)q, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen, further wherein the aryl or heteroaryl is unsubstituted or substituted with halo, Ci-C6alkyl, haloCi-C6alkyl, C3-C5cycloalkyl, haloC3-C5cycloalkyl; preferably Ci-Cealkyl, haloCi-Cealkyl, hydroxyC2-Cealkyl, Cs-Cecycloalkyl, C3- C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxyCi- C6alkyl, -COR7a, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, or 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen, further wherein the heteroaryl is unsubstituted or substituted with halo, Cr C6alkyl, haloCi-C6alkyl, C3-C5cycloalkyl, haloC3-C5cycloalkyl; more preferably Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, haloC3-C6cycloalkylCi- C3alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, 4- to 6-membered heterocyclyl having 1 heteroatoms independently selected from O, or 5- to 6-membered heteroaryl having 1 heteroatoms independently selected from O;

[0241] R7ais Ci-C6alkyl; each R8is independently selected from hydrogen and halogen;

[0242] R9is H, or D; preferably H; m is 1 , 2, or 3; preferably 1 or 2; n is 1 , 2, or 3; and p is 0, 1 , 2, or 3; preferably 0.

[0243] Embodiment 78 provides the compound of Formula (I) of any of applicable embodiments 1 to 77, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:

[0244] W is C(R6)2;

[0245] R is hydrogen; R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C3-C6cycloalkyl, haloCi-C6alkyl, haloC3- C6cycloalkyl, haloCi-C6alkoxy, hydroxyCi-C6alkyl, hydroxyC3-C6cycloalkyl; preferably hydrogen, halogen, hydroxy, Ci-C6alkyl, C3-C6cycloalkyl, haloCi-C6alkyl; more preferably hydrogen, halogen, hydroxy, Ci-C6alkyl, C3-C6cycloalkyl, and haloCr C6alkyl; more preferably hydrogen, halogen, Ci-C6alkyl, C3-C6cycloalkyl;

[0246] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Ci-C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents; preferably Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-Cealkyl, or halogen; more preferably Ci-C3alkyl, or halogen;

[0247] R3is hydrogen;

[0248] R4is phenyl, or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R5; preferably phenyl, or 5- to 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R5; more preferably phenyl, or 5- to 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from N, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0249] R5is selected from hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, -CH2CO2R5b, cyano, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; preferably hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, -CH2CO2R5b, cyano, - C(O)N(R5b)2and 5-membered heteroaryl having 1-4 heteroatoms independently selected from N, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R5a; more preferably hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, -CH2CO2R5b, cyano, -C(O)N(R5b)2and 5-membered heteroaryl having 1-3 heteroatoms independently selected from N, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-Cealkyl; preferably hydroxyl; each R5bis independently selected from hydrogen;

[0250] R5is preferably selected from hydrogen, -CO2H, Ci-Cealkyl, hydroxyCs-Cecycloalkyl, hydroxyC3-C6alkyl, cyano, -CONH2, pyrazolyl, triazolyl, and tetrazolyl, wherein the pyrazolyl, triazolyl, and tetrazolyl are unsubstituted or substituted with 1 Ci-C6alkyl; each R6is independently selected from hydrogen, halogen, hydroxy, C3-C6cycloalkylCi- C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkoxy, haloC3-C6cycloalkoxy, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, and wherein the Ci-C6alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclyl is independently unsubstituted or substituted with 1 , 2, or 3 halogen; preferably from hydrogen, halogen, hydroxy, Ci-C6alkyl, haloCi-C6alkyl Ci-C6alkoxy, and haloCi-C6alkoxy; preferably from Ci-Cealkyl, C3-C6cycloalkylCi-C4alkylamino, haloCs-CecycloalkylCi- C4alkylamino, haloCi-C6alkyl, C3-C6cycloalkoxy, haloC3-C6cycloalkoxy, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein the Ci-C6alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclyl is independently unsubstituted or substituted with 1 , 2, or 3 halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, preferably 3 to 4 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O; preferably two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O, wherein the spirocyclic heterocycle has 3 to 6 ring atoms; preferably two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 ring heteroatom selected from O; preferably two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 ring heteroatom selected from O, wherein the spirocyclic heterocycle has 5 ring atoms; each R8is independently selected from hydrogen and halogen;

[0251] R9is H, or D; preferably H; m is 1 , 2, or 3; preferably 1 or 2; n is 1 , 2, or 3; and p is 0, 1 , 2, or 3; preferably 0.

[0252] In an embodiment, the invention provides the compound of Formula (I) selected from the compounds in Table 1.

[0253] Table 1

[0254] or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0255] In an embodiment, the invention provides the compound of Formula (I) selected from the compounds in Table 2.

[0256] or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0257] In an embodiment, the compound of Formula (I) is selected from the group consisting of: 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0258] 4-(4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0259] 4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0260] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0261] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-ethylpiperidin-3-yl)benzoic acid; 4-(5-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylazepan-4-yl)benzoic acid;

[0262] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylazepan-3-yl)benzoic acid;

[0263] 5.7-dimethyl-4-((4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)oxy)-1 / 7-indole;

[0264] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl) benzonitrile;

[0265] 4-((3-(4-(1 / 7-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 / 7-indole; 2-(4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)propan-2-ol;

[0266] 4-((3-(4-(1 / 7-pyrazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 / 7-indole;

[0267] 5.7-dimethyl-4-((1-methyl-3-(1-methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-1 / 7-indole;

[0268] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid; 4-(1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0269] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid;

[0270] 4-(1-(3,3-difluorocyclobutyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0271] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3-fluorocyclobutyl)piperidin-3-yl)benzoic acid;

[0272] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)benzoic acid;

[0273] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid;

[0274] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid;

[0275] 4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(2, 2-difluoroethyl)piperidin-3-yl) benzoic acid;

[0276] 4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0277] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)azepan-3-yl)benzoic acid;

[0278] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)azepan-3-yl)benzoic acid;

[0279] 4-((3-(4-(1 / 7-pyrazol-1-yl)phenyl)-1-(2-fluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole;

[0280] 4-((3-(4-(1 / 7-pyrazol-1-yl)phenyl)-1-(2,2-difluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole;

[0281] 1 -(3-(4-(1 / - / -pyrazol-1 -yl)phenyl)-4-((5,7-dimethyl-1 / 7-ind ol-4-y l)oxy) pi perid in- 1 -yl)ethan- 1-one;

[0282] 4-((3-(6-(1 / - / -pyrazol-1 -yl)pyridin-3-yl)-1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole;

[0283] 4-((3-(4-(1 / 7-1 , 2 , 3-triazo I- 1 -y I) phenyl)- 1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole;

[0284] 1 -(4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)cyclopropan-1-ol;

[0285] 4-((1 -(2-fluoroethyl)-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H- indole;

[0286] 4-(4-((5-fluoro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0287] 4-(4-((7-chloro-5-methyl-1 / 7-indol-4-yl)oxy)-1 -(2, 2-difluoroethyl)piperidin-3-yl) benzoic acid;

[0288] 4-(1-((2,2-difluorocyclopropyl)methyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid;

[0289] 4-(1-(4,4-difluorobutyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0290] 4-(4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3- yl)benzoic acid;

[0291] 4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(3, 3-difluoropropyl)piperidin-3-yl) benzoic acid; 4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid;

[0292] 4-((1 -(3,3-difluoropropyl)-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl- 1 / - / -indole;

[0293] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)benzoic acid;

[0294] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpyrrolidin-3-yl)benzoic acid;

[0295] 4-(4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylazepan-3-yl)benzoic acid;

[0296] 4-(4-((5-methoxy-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0297] In an embodiment, the compound of Formula (I) is selected from the group consisting of: 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0298] 4-(8-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-oxaspiro[4.5]decan-7-yl)benzoic acid;

[0299] 4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0300] 4-(2-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0301] 4-(2-((5-fluoro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0302] 4-(5-methoxy-2-((7-methyl-1 / 7-indol-4-yl)oxy)cyclohexyl)benzoic acid;

[0303] 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl) benzoic acid;

[0304] 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid;

[0305] 4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid;

[0306] 4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-(difluoromethoxy)cyclohexyl) benzoic acid;

[0307] 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid;

[0308] 4-(6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)benzoic acid;

[0309] 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexy I) benzamide;

[0310] 4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid;

[0311] 4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-(difluoromethoxy)-5- methylcyclohexyl)benzoic acid;

[0312] 4-(5-(difluoromethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methylcyclohexy I) benzoic acid; and

[0313] 4-(7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[3.5]nonan-6-yl)benzoic acid, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0314] In another embodiment, the compound of Formula (I) is selected from the group consisting

[0315] 4-((3 / ?,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0316] 4-((3S,4S?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0317] 4-((3R,4S)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-((3S,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -methylpiperidin-3-yl)benzoic acid;

[0318] 4-((3 / ?,4R)-4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl) benzoic acid;4-((3 / ?,4R)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0319] 4-((3 / ?,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(2,2,2-trifluoroethyl)piperidin-3- yl)benzoic acid;

[0320] 4-((3S,4S)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3- yl)benzoic acid ;

[0321] 4-((3 / ?,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-ethylpiperidin-3-yl)benzoic acid;

[0322] 4-((4S,5 / ?)-5-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylazepan-4-yl) benzoic acid;

[0323] 4-((3 / ?,4R)-4-((5,7-dimethyl-1 / -indol-4-yl)oxy)-1-methylazepan-3-yl)benzoic acid; racemic 5,7-dimethyl-4-(((3S*,4 / ?^-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)oxy)- 1 / 7-indole;

[0324] 5.7-dimethyl-4-(((3S,4R)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)oxy)-1 / 7-indole;

[0325] 5.7-dimethyl-4-(((3 / ?,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)oxy)-1 / 7-indole;

[0326] 4-((3 / ?,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl) benzonitrile;

[0327] 4-(((3R,4R)-3-(4-(1 / -tetrazol-5-yl)phenyl)-1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 H- indole;

[0328] 2-(4-((3 / ?,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)propan- 2-ol;

[0329] 4-(((3R,4R)-3-(4-(1 / - / -pyrazol-1 -y I) phe ny I)- 1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 H- indole;

[0330] 5.7-dimethyl-4-(((3 / ?,4R)-1-methyl-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-1 / 7- indole;

[0331] 4-((3 / ?,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0332] 4-((3 / ?,4R)-1 -(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid;

[0333] 4-((3 / ?,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid;

[0334] 4-((3 / ?,4R)-1-(3,3-difluorocyclobutyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid;

[0335] 4-((3 / ?,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-((1 / ',3 / ?)-3-fluorocyclobutyl)piperidin-3- yl)benzoic acid;

[0336] 4-((3R,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(tetrahydrofuran-3-yl)piperidin-3- yl)benzoic acid;

[0337] 4-((3 / ?,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-hydroxy-2-methylpropyl)piperidin-3- yl)benzoic acid; 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(2-(trifluoromethoxy)ethyl)piperidin-3- yl)benzoic acid;

[0338] 4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(2,2-difluoroethyl)piperidin-3- yl)benzoic acid;

[0339] 4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(2,2,2-trifluoroethyl)piperidin-3- yl)benzoic acid;

[0340] 4-((3R,4 / ?)-1 -(2, 2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)azepan-3-yl) benzoic acid;

[0341] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)azepan-3-yl)benzoic acid;

[0342] 4-(((3R,4 / ?)-3-(4-(1 / - / -pyrazol-1 -y I) phe ny I)- 1 -(2-fluoroethyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole;

[0343] 4-(((3R,4R)-3-(4-(1 / - / -pyrazol-1 -yl)phenyl)-1 -(2, 2-difluoroethyl)piperidin-4-yl)oxy)-5, 7- dimethyl-1 / - / -indole; racemic 1 -((3R*,4 / ?*)-3-(4-(1 / - / -pyrazol-1 -yl)phenyl)-4-((5,7-dimethyl-1 H- i ndo I-4- y I) oxy) pipe rid i n- 1 -yl)ethan-1 -one;

[0344] 1 -((3R,4 / ?)-3-(4-(1 / - / -pyrazol-1 -yl)phenyl)-4-((5,7-dimethyl-1 / - i nd o l-4-yl) oxy) pi perid in- 1 - yl)ethan-1 -one;

[0345] 1 -((3S,4S)-3-(4-(1 / - / -pyrazol-1 -yl)phenyl)-4-((5,7-dimethyl-1 H- indol-4-y l)oxy) pi pe rid i n- 1 - yl)ethan-1 -one; racemic 4-(((3R*,4 / ?*)-3-(6-(1 / - / -pyrazol-1 -yl)pyridin-3-yl)-1 -methylpiperidin-4-yl)oxy)-5, 7- dimethyl-1 / - / -indole;

[0346] 4-(((3R,4 / ?)-3-(6-(1 / - / -pyrazol-1 -yl)pyridin-3-yl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl- 1 / 7-indole;

[0347] 4-(((3S,4S)-3-(6-(1 / 7-pyrazol-1-yl)pyridin-3-yl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl- 1 / 7-indole; racemic 4-(((3R*,4 / ?*)-3-(4-(1 / 7-1 ,2,3-triazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7- dimethyl-1 / 7-indole;

[0348] 4-(((3R,4 / ?)-3-(4-(1 / 7-1 ,2 , 3-triazol- 1 -yl) phe ny I)- 1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl- 1 / 7-indole;

[0349] 4-(((3S,4S)-3-(4-(1 / 7-1 ,2,3-triazol-1-yl)phenyl)-1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl- 1 / 7-indole;

[0350] 1 -(4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -methylpiperidin-3- y l)phenyl)cyclopro pan-1 -ol;

[0351] 4-(((3 / ?,4 / ?)-1-(2-fluoroethyl)-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / 7-indole;

[0352] 4-((3 / ?,4 / ?)-4-((5-fluoro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3- yl)benzoic acid; 4-((3R,4 / ?)-4-((7-chloro-5-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3- yl)benzoic acid;

[0353] 4-((3R,4 / ?)-1-((2,2-difluorocyclopropyl)methyl)-4-((5,7-dimethyl-1 / 7-indol-4- yl)oxy)piperidin-3-yl)benzoic acid;

[0354] 4-((3R,4R)-1 -(4, 4-difluorobutyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl) benzoic acid;

[0355] 4-((3 / ?,4R)-4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3- yl)benzoic acid;

[0356] 4-((3R,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(3,3-difluoropropyl)piperidin-3- yl)benzoic acid;

[0357] 4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid;

[0358] 4-(((3R,4R)-1 -(3,3-difluoropropyl)-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7- dimethyl-1 H-indole;

[0359] 4-((3 / ?,4S)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(2,2,2-trifluoroethyl)pyrrolidin-3- yl)benzoic acid;

[0360] 4-((3 / ?,4S)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpyrrolidin-3-yl)benzoic acid;

[0361] 4-((3 / ?,4 / ?)-4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylazepan-3-yl) benzoic acid;

[0362] 4-((3 / ?,4 / ?)-4-((5-methoxy-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl) benzoic acid; or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0363] In another embodiment, the compound of Formula (I) is selected from the group consisting of:

[0364] 4-((1 S,2R,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0365] 4-((1 R,2S,5R)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid ; racemic 4-((1 S*,2R*,5R*)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid;

[0366] 4-((1 S,2R,5R)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0367] 4-((1 R,2S,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; racemic 4-((1 S*,2S*,5S>2-((5,7-dimethyl-1 H-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid;

[0368] 4-((1 S,2S,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl) benzoic acid;

[0369] 4-((1 R,2 / ?,5 / ?)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl) benzoic acid; racemic 4-((1 S*,2S*,5R*)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid;

[0370] 4-((1 S,2S,5R)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl) benzoic acid; 4-((1 R,2R,5S>)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; racemic 4-((7S*,8 / ?^-8-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-oxaspiro[4.5]decan-7- yl)benzoic acid;

[0371] 4-((5 / ?,7S,8 / ?)-8-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-oxaspiro[4.5]decan-7-yl)benzoic acid;

[0372] 4-((5S,7S,8 / ?)-8-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -oxaspiro[4.5]decan-7-yl)benzoic acid;

[0373] 4-((1 S,2 / ?,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid;

[0374] 4-((1 S,2 / ?,5S)-2-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0375] 4-((1 S,2 / ?,5S)-2-((5-fluoro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0376] 4-((1 S,2R,5S)-5-methoxy-2-((7-methyl-1 / 7-indol-4-yl)oxy)cyclohexyl) benzoic acid; racemic 4-((1 S*,2R*)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl) benzoic acid;

[0377] 4-((1 S,2R)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl) benzoic acid;

[0378] 4-((1 / ?,2S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)benzoic acid;

[0379] 4-((1 S,2R)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5,5-difluorocyclohexyl) benzoic acid;

[0380] 4-((1 S,2 / ?,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5- hydroxycyclohexyl)benzoic acid;

[0381] 4-((1 S,2 / ?,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5- (difluoromethoxy)cyclohexyl)benzoic acid;

[0382] 4-((1 S,2 / ?,5 / ?)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid;

[0383] 4-((1 S,2R,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methylcyclohexyl) benzoic acid;

[0384] 4-((5S,6 / ?)-6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)benzoic acid;

[0385] 4-((1 S,2 / ?,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzamide;

[0386] 4-((1 S,2 / ?)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid; racemic 4-((1 S*,2R*,5S*)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5- (difluoromethoxy)-5-methylcyclohexyl)benzoic acid;

[0387] 4-((1 S,2 / ?,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-(difluoromethoxy)-5- methylcyclohexyl)benzoic acid;

[0388] 4-((1 S,2 / ?,5 / ?)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-(difluoromethoxy)-5- methylcyclohexyl)benzoic acid; racemic 4-((1 S*,2 / ?*,5S*)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5- (difluoromethoxy)-5-methylcyclohexyl)benzoic acid;

[0389] 4-((1 S,2 / ?,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-(difluoromethoxy)-5- methylcyclohexyl)benzoic acid; 4-((1 S,2R,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-(difluoromethoxy)-5- methylcyclohexyl)benzoic acid;

[0390] 4-((6S,7R)-7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[3.5]nonan-6-yl)benzoic acid, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0391] In an embodiment, the invention provides a tautomer, a diastereomer, or an enantiomer of the compound of Formula (I) of any of the embodiments herein described.

[0392] In an aspect, provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof; wherein:

[0393] W is O, C(R6)2, or NR7;

[0394] R is hydrogen, halogen, Ci-C4alkyl, haloCi-C4alkyl, or hydroxyCi-C4alkyl;

[0395] R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxy, hydroxyCi-C6alkyl, hydroxyC3- C6cycloalkyl, aminoCi-C6alkyl, Ci-C6alkoxyCi-C6alkyl, Ci-C6alkoxyCi-C6alkoxy, or C3- C6cycloalkylCi-C6alkoxy;

[0396] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Ci-C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;

[0397] R3is hydrogen, halogen, or cyano;

[0398] R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0399] R5is selected from -CO2R5b, Ci-C6alkyl, Ci-C6alkoxyCi-C6alkyl, -CH2CO2R5b, - C(O)NHSO2Ci-C4alkyl, -SO2NHC(O)Ci-C4alkyl, -SO2Ci-C4alkyl, cyano, hydroxy, halogen, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-Cealkyl that is unsubstituted or substituted with -CO2H; each R5bis independently selected from hydrogen and Ci-C5alkyl; each R6is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Cr C6alkoxy, and haloCi-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C6alkyl, and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N, O, and S(O)q, wherein the spirocyclic heterocycle is unsubstituted or substituted with 1 or 2 halogen, Ci-C6alkyl, haloCr Cealkyl, C3-C6cycloalkyl, or haloC3-C6cycloalkyl; q is 0, 1 , or 2;

[0400] R7is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, C3-C6cycloalkyl, C3- C6cycloalkylC1-C3alkyl, haloC3-C6cycloalkyl, C1-C6alkoxyC1-C6alkyl, haloC1-C6alkoxyC1-C6alkyl, - COR7a, aryl, 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N, O, and S(O)q, or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein Ci-Cealkyl is unsubstituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O)q, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen, further wherein the aryl or heteroaryl is unsubstituted or substituted with halo, C1-C6alkyl, haloC1-C6alkyl, C3-C5cycloalkyl, haloC3-C5cycloalkyl; R7ais hydrogen or Ci-C6alkyl; each R8is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Cr C6alkoxy, and haloCi-C6alkoxy;

[0401] R9is H, D, or T; m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3; provided that both m and n are not 0; and p is 0, 1 , 2, or 3.

[0402] In an embodiment,

[0403] W is C(R6)2or NR7;

[0404] R is hydrogen;

[0405] R1is halogen, hydroxy, Ci-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCr C6alkyl, hydroxyCi-C6alkyl, or aminoCi-C6alkyl;

[0406] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-Cealkyl, or halogen;

[0407] R3is hydrogen, halogen, or cyano; R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0408] R5is selected from -CO2R5b, Ci-C6alkyl, Ci-C6alkoxyCi-C6alkyl, - cyano, hydroxy, halogen, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-C6alkyl that is unsubstituted or substituted with -CO2H;

[0409] R5bis selected from hydrogen and Ci-C5alkyl; each R6is independently selected from hydrogen, halogen, hydroxy, Ci-Cealkyl, haloCi- C6alkyl, hydroxyCi-C6alkyl, Ci-C6alkoxy, and haloCi-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C6alkyl, and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;

[0410] R7is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, -COR7a, or C3-C6cycloalkyl;

[0411] R7ais Ci-C6alkyl; each R8is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Cr C6alkoxy, and haloCi-C6alkoxy;

[0412] R9is H, D, or T; m is 1 , 2, or 3; n is 1 , 2, or 3; and p is 0, 1 , or 2.

[0413] In another embodiment,

[0414] W is C(R6)2or NR7;

[0415] R is hydrogen;

[0416] R1is halogen, Ci-C6alkyl, or C3-C6cycloalkyl;

[0417] R2is Ci-C3alkyl;

[0418] R3is hydrogen;

[0419] R4is phenyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0420] R5is selected from -CO2R5b, Ci-Cealkyl, cyano, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with R5a;

[0421] R5ais hydroxy or Ci-C6alkyl; R5bis hydrogen or Ci-C3alkyl; each R6is independently selected at each occurrence from hydrogen and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;

[0422] R7is C1-C6alkyl -COR7a, or haloCi-C6alkyl;

[0423] R7ais C1-C6alkyl; each R8is independently selected from hydrogen and Ci-C6alkyl;

[0424] R9is H; m is 1 or 2; n is 1 , 2, or 3; and p is 0, 1 , or 2.

[0425] In another embodiment,

[0426] W is O, C(R6)2, or NR7;

[0427] R is hydrogen, halogen, Ci-C4alkyl, haloCi-C4alkyl, or hydroxyCi-C4alkyl;

[0428] R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCi-Cealkyl, haloC3-C6cycloalkyl, haloCi-Cealkoxy, hydroxyCi-Cealkyl, hydroxyC3- C6cycloalkyl, aminoC1-C6alkyl, C1-C6alkoxyCi-C6alkyl, Ci-C6alkoxyCi-C6alkoxy, or C3- C6cycloalkylCi-C6alkoxy;

[0429] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Ci-C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;

[0430] R3is hydrogen, halogen, or cyano;

[0431] R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0432] R5is selected from -CO2R5b, Ci-C6alkyl, Ci-C6alkoxyCi-C6alkyl, -CH2CO2R5b, - C(O)NHSO2Ci-C4alkyl, -SO2NHC(O)Ci-C4alkyl, -SO2Ci-C4alkyl, cyano, hydroxy, halogen, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-C6alkyl that is unsubstituted or substituted with -CO2H; each R5bis independently selected from hydrogen and Ci-Csalkyl; each R6is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, C1-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, C1 C6alkoxy, and haloCi-Cealkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Cr C6alkyl, and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N, O, and S(O)q, wherein the spirocyclic heterocycle is unsubstituted or substituted with 1 or 2 halogen, Ci-C6alkyl, haloCi-C6alkyl, C3-C6cycloalkyl, or haloC3-C6cycloalkyl; q is 0, 1 , or 2;

[0433] R7is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, C3-C6cycloalkyl, C3- C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkyl, Ci-C6alkoxyCi-C6alkyl, haloCi-C6alkoxyCi-C6alkyl, aryl, 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N, O, and S(O)q, or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein Ci-C6alkyl is unsubstituted or substituted with 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N, O, and S(O)q, wherein the 4- to 6- membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen, further wherein the aryl or heteroaryl is unsubstituted or substituted with halo, Ci-C6alkyl, haloCi-C6alkyl, C3- Cscycloalkyl, haloCs-Cscycloalkyl; each R8is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- C1-C4alkylamino, C1-C6alkyl, haloC1-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Cr C6alkoxy, and haloCi-Cealkoxy; R9is H, D, or T; m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3; provided that both m and n are not 0; and p is 0, 1 , 2, or 3.

[0434] In another embodiment,

[0435] W is C(R6)2or NR7;

[0436] R is hydrogen;

[0437] R1is halogen, hydroxy, Ci-Cealkyl, C2-Cealkenyl, Cs-Cecycloalkyl, Ci-Cealkoxy, haloCi- C6alkyl, hydroxyCi-C6alkyl, or aminoCi-C6alkyl;

[0438] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen;

[0439] R3is hydrogen, halogen, or cyano;

[0440] R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0441] R5is selected from -CO2R5b, Ci-Cealkyl, Ci-CealkoxyCi-Cealkyl, - cyano, hydroxy, halogen, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-Cealkyl that is unsubstituted or substituted with -CO2H;

[0442] R5bis selected from hydrogen and Ci-C5alkyl; each R6is independently selected from hydrogen, halogen, hydroxy, Ci-C6alkyl, haloCr C6alkyl, hydroxyCi-C6alkyl, Ci-C6alkoxy, and haloCi-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C6alkyl, and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;

[0443] R7is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, or C3-C6cycloalkyl; each R8is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, Ci-Cealkyl, haloCi-Cealkyl, hydroxyCi-Cealkyl, cyanoCi-Cealkyl, Ci- C6alkoxy, and haloCi-C6alkoxy;

[0444] R9is H; m is 1 , 2, or 3; n is 1 , 2, or 3; and p is 0, 1 , or 2.

[0445] In another embodiment,

[0446] W is C(R6)2or NR7;

[0447] R is hydrogen;

[0448] R1is halogen, Ci-C6alkyl, or C3-C6cycloalkyl;

[0449] R2is Ci-C3alkyl;

[0450] R3is hydrogen;

[0451] R4is phenyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;

[0452] R5is selected from -CO2R5b, C1-C6alkyl, cyano, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with R5a;

[0453] R5ais hydroxy or Ci-C6alkyl;

[0454] R5bis hydrogen or Ci-C3alkyl; each R6is independently selected at each occurrence from hydrogen and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;

[0455] R7is Ci-C6alkyl or haloCi-C6alkyl; each R8is independently selected from hydrogen and Ci-C6alkyl;

[0456] R9is H; m is 1 or 2; n is 1 , 2, or 3; and p is 0, 1 , or 2. In another embodiment, W is NR7. In another embodiment, W is C(R6)2.

[0457] In another embodiment, R is hydrogen.

[0458] In another embodiment, R1is halogen, Ci-C3alkyl, or C3cycloalkyl. In still another embodiment, R1is halogen. In another embodiment, R1is Ci-C3alkyl. In another embodiment, R1is C3cycloalkyl.

[0459] In another embodiment, R2is methyl.

[0460] In another embodiment, R3is hydrogen.

[0461] In another embodiment, R4is phenyl or 5-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5. In another embodiment, R4is phenyl, wherein phenyl or heteroaryl is unsubstituted or substituted with R5. In yet another embodiment, R4is 5-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein heteroaryl is unsubstituted or substituted with R5. In still another embodiment, R4is phenyl or pyrazolyl, wherein phenyl or pyrazolyl is unsubstituted or substituted with R5.

[0462] In another embodiment, R5is selected from -CO2H, Ci-C6alkyl, cyano, and 5-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, wherein alkyl is unsubstituted or substituted with hydroxy. In another embodiment, R5is -CO2H. In yet another embodiment, R5is cyano. In still another embodiment, R5is 5-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S. In an embodiment, R5is Ci-C6alkyl, wherein alkyl is unsubstituted or substituted with hydroxy.

[0463] In another embodiment, each R6is independently selected from of hydrogen and Cr C3alkoxy. In yet another embodiment, each R6is hydrogen. In still another embodiment, each R6is independently selected from Ci-C3alkoxy.

[0464] In an embodiment, two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O. In another embodiment, two R6in combination with the carbon atom to which they are attached form a 4-6 membered spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O. In yet another embodiment, two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms.

[0465] In another embodiment, R7is methyl, -COR7a, or haloCi-C3alkyl. In an embodiment, R7is methyl or haloCi-C3alkyl. In another embodiment, R7is methyl. In yet another embodiment, R7is haloCi-C3alkyl. In still another embodiment, R7is -C(O)Ci-C3alkyl.

[0466] In another embodiment, each R8is independently selected from hydrogen and Ci-C6alkyl. In another embodiment, each R8is hydrogen.

[0467] In another embodiment, R9is H.

[0468] In another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0469] Methods of Treatment

[0470] In an aspect, provided herein is a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0471] In another aspect, provided herein is a method of modulating the complement alternative pathway activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0472] In yet another aspect, provided herein is a method of treating a disease or disorder mediated by complement activation, in particular mediated by activation of the complement alternative pathway, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0473] In still another aspect, provided herein is a method of treating a disease or disorder that is affected by the modulation of complement alternative pathway comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0474] In an aspect, provided herein is a method of treating a disease or disorder associated with dysregulation of the complement alternative pathway comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0475] In another aspect, provided herein is a method of inhibiting the expression or activity of complement factor B, the method comprising administering to the subject a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0476] In an embodiment of the invention, the diseases or disorders is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, Late onset retinal macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammation, neurological disorders such as multiple sclerosis including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS), stroke, Guillain Barre Syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer’s disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington’s disease, multifocal motor neuropathy, autism spectrum disorders, schizophrenia, drug-induced neurotoxicity, Aquaporin-4 IgG seropositive neuromyelitis optica spectrum disorder (NMOSD), cerebral amyloid angiopathy, cerebral malaria, Charcot-Marie-Tooth disease, chemotherapy- induced peripheral neuropathy, chronic inflammatory demyelinating polyneuropathy, frontotemporal dementia, genetic demyelinating neuropathy due to CD59 p.Cys89Tyr mutation, Lewy bodies dementia, multiple system atrophy (MSA), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), opsoclonus myoclonus syndrome (QMS), progressive supranuclear palsy; disorders of inappropriate or undesirable complement activation such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), Hemolytic uremic syndrome, STEC- HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), peridontitis, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammation or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schbnlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis; COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, Spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, neural regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), Buerger’s vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex- associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, Cold agglutinin disease, Warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurisms, and Grave’s disease.

[0477] In yet another aspect, provided herein is a method of treating age-related macular degeneration comprising administering to a subject in need thereof an effective amount of a composition comprising a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0478] In still another aspect, provided herein is a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.

[0479] In an aspect, provided herein is a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use in inhibiting the expression or activity of complement factor B, in a subject in need thereof.

[0480] In another aspect, provided herein is a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use in treating a disease or disorder associated with dysregulation of the complement alternative pathway.

[0481] In an aspect, provided herein is the use of a compound a provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, in the manufacture of a medicament for the treatment of a disease or disorder mediated by complement activation or activation of the complement alternative pathway. In another aspect, provided herein is the use of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, in the manufacture of a medicament for the treatment of a disease or disorder.

[0482] In yet another aspect, provided herein is the use of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for the treatment of a disease or disorder mediated by complement activation or activation of the complement alternative pathway.

[0483] In still another embodiment, provided herein is the use of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for the treatment of a disease or disorder that is affected by the modulation of complement alternative pathway.

[0484] In an aspect, provided herein is the use of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for the treatment of a disease or disorder.

[0485] In yet another aspect, provided herein is the use of a provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for the treatment of age-related macular degeneration.

[0486] In still another aspect, provided herein is a pharmaceutical combination comprising a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, and one or more additional therapeutic agent(s). Depending on the choice of the starting materials and procedures, the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereomeric mixtures, depending on the number of asymmetric centres. The disclosure is meant to include all such possible isomers, including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures and optically pure forms. Optically active ( / ?)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a disubstituted or trisubstituted cycloalkyl, the cycloalkyl substituent(s) may have a c / s- or frans-configuration. The disclosure includes cis and trans configurations of substituted cycloalkyl groups, e.g., cyclobutyl group, as well as mixtures thereof. All tautomeric forms are also intended to be included. In particular, where a heteroaryl ring containing N as a ring atom is 2- pyridone, for example, tautomers where the carbonyl is depicted as a hydroxy (e.g., 2- hydroxypyridine) are included.

[0487] Separation of cis and trans isomers can be achieved according to methods known to a person of skill in the art, such as chromatographic methods, with tools such as HPLC (High Performance Liquid Chromatography), Thin Layer Chromatography, SFC (Supercritical Fluid Chromatography), GC (Gas Chromatography), or recrystallization techniques.

[0488] Isotopically Labelled Compounds

[0489] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,18O,15N,18F,17O,18O,35S,36CI,123l,124I, 125| respectively. The disclosure includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as3H and14C, orthose into which non-radioactive isotopes, such as2H and13C are present. Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F compound may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of formula (I), orsub-formulae thereof, can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and General Schemes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. Further, substitution with heavier isotopes, particularly deuterium ( / .e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I), or any of the sub-formulae thereof. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this disclosure is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0490] Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, cfe-acetone, cfe- DMSO.

[0491] Compounds of the disclosure that contain groups capable of acting as donors and / or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I), or sub-formulae thereof, by known co-crystal forming procedures. Such procedures include grinding, heating, cosubliming, co-melting, or contacting in solution compounds provided herein, with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable cocrystal formers include those described in WO 2004 / 078163.

[0492] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed.

[0493] Any asymmetric center (e.g., carbon or the like) of the compound(s) of the disclosure can be present in racemic or enantiomerically enriched, for example the ( / ?)-, (S)- or (R,S)- configuration. In certain embodiments, for example, as a mixture of enantiomers, each asymmetric center is present in at least 10% enantiomeric excess, at least 20% enantiomeric excess, at least 30% enantiomeric excess, at least 40% enantiomeric excess, at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. In certain embodiments, for example, in enantiomerically enriched form, each asymmetric center is present in at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. Thus, compounds of the disclosure can be present in a racemic mixture or in enantiomerically enriched form or in an enantiopure form or as a mixture of diastereoisomers.

[0494] In an embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, present in at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0495] In an embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, present in at least 90% diastereomeric excess, at least 95% diastereomeric excess, or at least 99% diastereomeric excess.

[0496] In the formulae of the present application the term “ “ on a C-sp3indicates the absolute stereochemistry, either ( / ?) or (S). In the formulae of the present application the term “ on a C-sp3indicates the absolute stereochemistry, either ( / ?) or (S). In the formulae of the present application the term “ “ on a C-sp3represents a covalent bond wherein the stereochemistry of the bond is not defined. This means that the term “ on a C-sp3comprises an (S) configuration or an ( / ?) configuration of the respective chiral centre. Furthermore, mixtures may also be present. Therefore, mixtures of stereoisomers, e.g., mixtures of enantiomers, such as racemates, and / or mixtures of diastereoisomers are encompassed by the present disclosure.

[0497] For the avoidance of doubt, where compound structures are drawn with undefined stereochemistry with respect to any R group, as represented by a bond this means the asymmetric center has either a ( / ?)- or (S)- configuration, or exists as a mixture thereof and stated as such.

[0498] For the avoidance of doubt, in any of formulae of the present application when the R5group is shown with attachment to ring A, this means that the R5group(s) can be bonded via a carbon atom or heteroatom, e.g., nitrogen.

[0499] For the avoidance of doubt, the compounds structures shown herein, when appropriate, may exist in their zwitterionic form.

[0500] Accordingly, as used herein a compound of the disclosure can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers, racemates or mixtures thereof.

[0501] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0502] Any resulting racemates of compounds of the disclosure or of intermediates can be resolved into the optical isomers (enantiomers) by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the disclosure into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor- 10-sulfonic acid. Racemic compounds of the disclosure or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0503] Furthermore, the compounds of the disclosure, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the disclosure may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the disclosure embrace both solvated and unsolvated forms. The term “solvate” refers to a molecular complex of a compound of the disclosure (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term “hydrate” refers to the complex where the solvent molecule is water. The presence of solvates can be identified by a person of skill in the art with tools such as NMR.

[0504] The compounds of the disclosure, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.

[0505] Pharmaceutical Compositions

[0506] In another aspect, the disclosure provides a pharmaceutical composition comprising one or more compounds of described herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0507] In a further embodiment, the composition comprises at least one or two pharmaceutically acceptable carriers, such as those described herein. For purposes of the disclosure, unless designated otherwise, solvates and hydrates are generally considered compositions.

[0508] The compounds of Formula (I), and subformulae thereof, described herein may be administered alone or as an active ingredient of a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions comprising a compounds of Formula (I), or subformulae thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, and one or more pharmaceutically acceptable carriers.

[0509] Methods of preparing various pharmaceutical compositions are known to those of skill in the art and may be described in, for example, in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition).

[0510] The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, topical administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the disclosure can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, gels, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

[0511] Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethyleneglycol; c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.

[0512] In an embodiment, the pharmaceutical compositions are capsules comprising the active ingredient only.

[0513] Tablets may be either film coated or enteric coated according to methods known in the art.

[0514] The mode of administration and pharmaceutical composition are closely related to the therapeutic amounts of the compounds or compositions which are desirable and efficacious for the given treatment application. Pharmaceutical compositions provided herein can be formulated for ophthalmic, ocular, topical, and transdermal administration. In particular embodiments, the pharmaceutical compositions provided herein are suitable for ocular administration. To prepare pharmaceutical compositions, the active ingredient may be mixed with one or more pharmaceutically acceptable carriers) according to conventional pharmaceutical compounding techniques. The carrier(s) may take a wide variety of forms depending on the form of preparation desired for administration.

[0515] Suitable compositions for oral administration include an effective amount of a compound of the disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs, solutions or solid dispersion. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0516] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and / or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.

[0517] Suitable compositions for transdermal application include an effective amount of a compound of the disclosure with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

[0518] Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. As used herein a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.

[0519] In certain embodiments, the pharmaceutical compositions provided herein are formulated as solutions, suspensions, gels, creams, ointments, liposomes, ocular inserts or other pharmaceutical compositions suitable, in particular embodiments, for topical administration to the ocular surface, the cornea, the eyelid, margins of the eye, eyelashes and / or eye lid margin in order to deliver the composition to the eye. In some embodiments, liquid (aqueous or non- aqeuous) solutions may be used. In certain embodiments the pharmaceutical compositions are formulated as eye drops for topical administration to the ocular surface, the cornea, the eyelid, eye lid margins, eyelashes and / or margins of the eye in order to deliver the composition to the eye. Application of the pharmaceutical composition may be performed with an applicator, such as the subject’s finger, a Weck-Cel®, Q-tip®, or other device capable of delivering a formulation to the eyelid, eyelashes and / or eyelid margin in order to deliver the formulation to the eye. The pharmaceutical compositions provided herein may be viscous or semi-viscous; liquid, solid, or semi-solid; aqueous or non-aqueous, depending on the site of application, dose, solubility of drug, and a variety of other factors that are considered by those of skill in the art.

[0520] Any of a variety of carriers may be used in a pharmaceutical composition provided herein. In one embodiment, the pharmaceutically acceptable carrier is a non-aqueous carrier (e.g., oil, or oil mixture) having a viscosity in a range from about 50 cps to about 1000 cps, about 50 cps to about 500 cps, about 50 cps to about 200 cps, or about 60 cps to about 120 cps. In certain embodiments, the non-aqueous carrier comprises an oil, e.g., vegetable oils, silicone oils, mineral oil or any combination thereof. In some embodiments, the carrier may be liquid paraffin, white petrolatum, purified lanolin, gelation hydrocarbon, polyethylene glycol, hydrophilic ointment base, white ointment base, absorptive ointment base, Macrogol ointment base, simple ointment base, and the like. In certain embodiments, the pharmaceutical composition may include a monomeric polyol such as, glycerol, propylene glycol, and ethylene glycol, polymeric polyols such as polyethylene glycol, cellulose esters such hydroxypropylmethyl cellulose, carboxy methylcellulose sodium and hydroxy propylcellulose; dextrans such as dextran 70; water soluble proteins such as gelatin, polymers such as polyvinyl alcohol, polyvinylpyrrolidone, and povidone; carbomers, such as carbomer 934P. carbomer 941 , carbomer 940 and carbomer 974P; and gums such as HP- guar.

[0521] Additional excipients may optionally be included in the pharmaceutical compositions provided herein. Examples of additional excipients include, for example, tonicity enhancers, preservatives, solubilizers, non-toxic excipients, demulcents, sequestering agents, pH adjusting agents, co-solvents, viscosity building agents, and combinations thereof. The pharmaceutical composition of the disclosure may be in the form of an aqueous suspension or an aqueous solution. In one embodiment, the aqueous pharmaceutical composition of the disclosure is in the form of an aqueous suspension. Aqueous pharmaceutical compositions according to the disclosure can be prepared using standard procedures that are familiar to the person skilled in the art, e.g., by admixture of the various components, suitably at ambient temperature and atmospheric pressure. In one embodiment, the aqueous pharmaceutical compositions of the disclosure are suitable for ocular administration.

[0522] In a further embodiment, the pharmaceutical composition of the disclosure is in the form of eye ointment, eye gel, eye cream, or eye drops.

[0523] In a further embodiment, the pharmaceutical composition of the disclsoure is administered to the subject topically in the eyes.

[0524] The compounds of formula (I), in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g., complement factor B modulating properties e.g., as indicated in the in vitro tests as provided in the examples, and are therefore indicated for therapy or for use as research chemicals, e.g., as tool compounds.

[0525] Additional properties of the disclosed compounds include having good potency in the biological assays described herein, favorable safety profile, and possess favorable pharmacokinetic properties.

[0526] Diseases and Disorders and Methods of Use

[0527] In a further aspect, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use in therapy.

[0528] In a further aspect, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use in the treatment of a disease or disorder for which complement factor B is indicated. In one embodiment, the disease or disorder is affected by the inhibition of complement factor B activity.

[0529] Compounds of formula (I) and their pharmaceutically acceptable salts or stereoisomers or diastereomers have complement factor B modulating and / or inhibitory activity and are believed to be of potential use for the treatment or prophylaxis of certain diseases or disorders.

[0530] The diseases or disorders is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino- chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, Late onset retinal macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammation, neurological disorders such as multiple sclerosis including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS), stroke, Guillain Barre Syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer’s disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington’s disease, multifocal motor neuropathy, autism spectrum disorders, schizophrenia, drug-induced neurotoxicity, Aquaporin-4 IgG seropositive neuromyelitis optica spectrum disorder (NMOSD), cerebral amyloid angiopathy, cerebral malaria, Charcot-Marie-Tooth disease, chemotherapy-induced peripheral neuropathy, chronic inflammatory demyelinating polyneuropathy, frontotemporal dementia, genetic demyelinating neuropathy due to CD59 p.Cys89Tyr mutation, Lewy bodies dementia, multiple system atrophy (MSA), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), opsoclonus myoclonus syndrome (QMS), progressive supranuclear palsy; disorders of inappropriate or undesirable complement activation such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC- MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), Hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), peridontitis, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammation or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schbnlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplantation- associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis; COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, Spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, neural regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), Buerger’s vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, Cold agglutinin disease, Warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurisms, and Grave’s disease.

[0531] Having regard to their activity as complement factor B modulator or inhibitors, compounds of formula (I) and sub-formulae thereof, in free or pharmaceutically acceptable salt form, are useful in the treatment of conditions which may be treated by inhibition of complement factor B activity. In one aspect, the disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a diastereomer thereof.

[0532] In another aspect, the disclosure provides a method of modulating the complement alternative pathway activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a diastereomer thereof.

[0533] In another aspect, the disclosure provides a method of treating a disease or disorder mediated by complement activation, in particular mediated by activation of the complement alternative pathway, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isoto pica lly labeled compound thereof.

[0534] In another aspect, the disclosure provides a method of treating a disease or disorder that is affected by the modulation of complement alternative pathway comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isoto pica lly labeled compound thereof.

[0535] In another aspect, the disclosure provides a method of treating a disease or disorder associated with dysregulation of the complement alternative pathway comprising administering to the subject a therapeutically effective amount of a compound of formula (I) orsub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0536] In another aspect, the disclosure provides a method of inhibiting the expression or activity of complement factor B, the method comprising administering to the subject a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0537] In another aspect, the disclosure provides a method of treating disease or disorder.

[0538] In certain aspects, methods are provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway. In certain embodiments, methods of treating or preventing compelment mediated diseases are provided in which the complement activation is induced by antibody-antigen interactions, by a component of an autoimmune disease, or by ischemic damage. In a specific embodiment, the present disclosure provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of the compound of Formula (I) of the disclosure. In certain embodiments, patients who are currently asymptomatic but are at risk of developing a symptomatic macular degeneration related disorder are suitable for administration with a compound of the disclosure. The methods of treating or preventing AMD include, but are not limited to, methods of treating or preventing one or more symptoms or aspects of AMD selected from formation of ocular drusen, inflammation of the eye or eye tissue, loss of photoreceptor cells, loss of vision (including loss of visual acuity or visual field), neovascularization (including CNV), retinal detachment, photoreceptor degeneration, RPE degeneration, retinal degeneration, chorioretinal degeneration, cone degeneration, retinal dysfunction, retinal damage in response to light exposure, damage of the Bruch’s membrane, and / or loss of RPE function.

[0539] The compound of Formula (I) ofthe disclosure can be used, inter alia, to prevent the onset of AMD, to prevent the progression of early AMD to advanced forms of AMD including neovascular AMD or geographic atrophy, to slow and / or prevent progression of geographic atrophy, to treat or prevent macular edema from AMD or other conditions (such as diabetic retinopathy, uveitis, or post surgical or non-surgical trauma), to prevent or reduce the loss of vision from AMD, and to improve vision lost due to pre-existing early or advanced AMD. It can also be used in combination with anti-VEGF therapies for the treatment of neovascular AMD patients or for the prevention of neovascular AMD.

[0540] All the aforementioned embodiments relating to the methods of treatment of the aforementioned diseases are equally applicable to: a compound of formula (I) or sub-formula thereof or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use in the teatment of the aforementioned diseases according to the present disclosure; use of a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, in the manufacture of a medicament for the teatment ofthe aforementioned diseases according to the present disclosure; use of a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for the treatment of the aforementioned diseases according to the present disclosure; and a pharmaceutical composition comprising a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, and one or more pharmaceutically acceptable carriers, for use in the treatment of the aforementioned diseases according to the present disclosure. Methods of Making

[0541] The compounds of the disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.

[0542] Generally, the compounds of formula (I) can be prepared according to the Schemes provided infra.

[0543] Compounds provided herein can be prepared according to the following Examples. In the following Schemes, R, R1, R2, R3, R5, R6, R8, W, m, n, and p are defined according to enumerated Embodiment 1 . In an embodiment, R, R1, R2, R3, R5, R6, R8, W, m, n, and p are defined according to any one of enumerated Embodiments 1 to 23. PG refers to protecting groups. Suitable protecting groups are known to one skilled in the art and the same or different protecting groups may be used in any Scheme. Additional definitions are provided as applicable in the General Schemes below.

[0544] General Scheme 1

[0545] Alcohol intermediates S1-4 can be prepared as outlined in General Scheme 1. Arylation of ketone S1-2 with aryl bromide S1-1 can be performed utilizing Buchwald coupling conditions. Ketone reduction of S1 -3 can be accomplished with a hydride reducing agent such as sodium borohydride or lithium tri-sec-butylborohydride.

[0546] General Scheme 2

[0547] Alternatively, alcohol intermediates S2-4 can be prepared as outlined in General Scheme 2. Reaction of aryl magnesium bromide S2-1 with epoxide S2-2 provides alcohol S2-3 with trans relative configuration at the vicinal stereocenters. Inversion to c / s-configured S2-4 is achieved through Mitsunobu reaction with a carboxylic acid such as 4-nitro benzoic acid followed by basepromoted hydrolysis.

[0548] General Scheme 3

[0549] Piperidinol intemediates S3-5 can be prepared as outlined in General Scheme 3. Boronic acid or ester S3-1 and pyridyl halide S3-2 are coupled to provide biaryl S3-3 using Suzuki crosscoupling conditions. Nitrogen protection with a reagent like CbzCI followed by treatment with a reducing agent such as sodium borohydride provides enone S3-4. Further reduction to the alcohol S3-5 is achieved through metal-catalyzed hydrogenation with a catalyst such as platinum oxide.

[0550] General Scheme 4

[0551] Synthesis of hydroxy indoles S4-2 is outlined in General Scheme 4. Baeyer-Villiger oxidation of aldehyde S4-1 followed by hydrolysis under basic aqueous conditions can provides S4-2. Alternatively, 4-bromo indole S4-3 can be borylated using Miyura conditions. Boronic ester S4-4 can be oxidized to S4-2 using a suitable oxidizing agent such as sodium perborate. General Scheme 5

[0552] Synthesis of examples S5-4is outlined in General Scheme 5. Alcohol intermediates S5-1 react with hydroxy indole S5-2 in a Mitsunobu reaction with inversion at the reacting stereocenter to provide S5-3. Deprotection can provide final Examples S5-4. If W is N-PG, S5-3 can be selectively deprotected to give the secondary amine where W is N-H. This intermediate can be reacted with a suitable electrophile, e. g. an alkyl halogenide or triflate, in the presence of base such as di-isopropyl ethyl amine. Alternatively, the N-H intermediate can be reacted with a suitable aldehyde or ketone in the presence of a reducing agent such as sodium triacetoxyboronhydride. Deprotection provides the final Examples S5-4.

[0553] In a further aspect, the disclosure provides a process for the preparation of a compound of formula (I), in free form or in pharmaceutically acceptable salt form, comprising the step as described above.

[0554] It is understood that in the following description, combinations of substituents and / or variables of the depicted formulae are permissible only if such combinations result in stable compounds.

[0555] It will also be appreciated by those skilled in the art that in the processes described below, the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, phenol, amino and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., tert- butyldimethylsilyl, te / Y-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, and the like. Suitable protecting groups for amino, amidino and guanidino include f-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.

[0556] Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein. The use of protecting groups is described in detail in J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, “Greene's Protective Groups in Organic Synthesis”, Fourth Edition, Wiley, New York 2007; P. J. Kocienski, “Protecting Groups”, Third Edition, Georg Thieme Verlag, Stuttgart and New York 2005; and in Methoden der orgamschen Chemie (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / 1, Georg Thieme Verlag, Stuttgart 1974.

[0557] The protecting group may also be a polymer resin, such as a Wang resin or a 2-ch Io rotrity I- chloride resin.

[0558] The following reaction Examples illustrate methods to make compounds of this disclosure. It is understood that one skilled in the art would be able to make these compounds by similar methods or by methods known to one skilled in the art. In general, starting components and reagents may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, Strem, other commercial vendors, or synthesized according to sources known to those skilled in the art, or prepared as described in this disclosure.

[0559] Examples

[0560] Analytical Methods, Materials, and Instrumentation

[0561] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker A vance, Avance III or Avance Neo spectrometer 400 MHz, Varian Oxford 400 MHz, or Varian Mercury 300 MHz spectrometer unless otherwise noted. Spectra are given in ppm (6) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (6 2.50), methanol (6 3.31), chloroform (6 7.26) or other solvent as indicated in NMR spectral data. A small amount of the dry sample (typically 2-5 mg) is dissolved in an appropriate deuterated solvent (1 mL). The chemical names were generated using ChemBioDraw Ultra v19 from CambridgeSoft.

[0562] Mass spectra (ESI-MS) were collected using a Waters System (Acquity UPLC and a Micromass ZQ mass spectrometer) or Agilent-1260 Infinity (6120 Quadrupole); all masses reported are the m / z of the protonated parent ions unless recorded otherwise. The sample was dissolved in a suitable solvent such as MeCN, DMSO, or MeOH and was injected directly into the column using an automated sample handler. Abbreviations

[0563] ACN acetonitrile

[0564] AcOH acetic acid aq aqueous

[0565] Boc te / Y-butyl carboxy br broad

[0566] BTMG te / Y-butyl tetramethy guanidine

[0567] Cbz benzyloxycarbonyl

[0568] CD3OD methanol-cL

[0569] CDC chloroform-d

[0570] CO2carbon dioxide d doublet DAD diode-array detection

[0571] DCM dichloromethane

[0572] DEAD diethyl azodicarboxylate DI AD diisopropyl azodicarboxylate DMAP / V, / V-dimethylaminopyridine DMF A / ,A / -dimethylformamide DMSO dimethylsulfoxide ee enantiomeric excess EtOAc ethyl acetate EtOH ethanol FA formic acid h hour(s)

[0573] H2hydrogen

[0574] HATU hexafluorophosphate azabenzotriazole tetramethyl uronium HCI hydrochloric acid

[0575] HPLC high performance liquid chromatography

[0576] IPA / so-propanol

[0577] K2CO3potassium carbonate

[0578] KOAc potassium acetate

[0579] K3PO4potassium phosphate, tribasic

[0580] LC-MS liquid chromatography and mass spectrometry

[0581] LED light emitting diode m multiplet m / z mass to charge ratio mCPBA mefa-chloro perbenzoic acid

[0582] MeOH methanol

[0583] Me-THF 2-methyltetrahydrofuran

[0584] MgSO4magnesium sulfate min minutes MS mass spectrometry N2nitrogen

[0585] Na(OAc)3BH sodium triacetoxy borohydride

[0586] NaBH4sodium borohydride

[0587] NaHCO3sodium bicarbonate

[0588] Na2SO4sodium sulfate

[0589] NaOH sodium hydroxide

[0590] NH4CI ammonium chloride NH4OH ammonium hydroxide NMR nuclear magnetic resonance NP normal phase org organic Pd2(dba)3tris(dibenzylideneacetone)dipalladium(0) PdCI2(dppf) 1 ,1 '-bis(diphenylphosphino)ferrocene-palladium(ll) dichloride

[0591] PE petroleum ether

[0592] PPh3triphenylphosphine

[0593] PPm parts per million

[0594] PtO2platinum oxide rac racemic

[0595] RM reaction mixture RP reversed phase Rt retention time RT room temperature s singlet sat. saturated scCO2super critical carbon dioxide sec secondary SFC supercritical fluid chromatography soln solution SPhos dicyclohexyl(2',6'-dimethoxy[1 ,1 '-biphenyl]- yl)phosphane t triplet tBu tertiary butyl tert tertiary TFA trifluoroacetic acid

[0596] THF tetrahydrofuran Ts tosyl Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene wt% weight percent

[0597] Intermediates

[0598] Intermediate 1-1 : tert-butyl 4-hydroxy-5,7-dimethyl-1 H-indole-1 -carboxylate fert-Butyl 4-formyl-5,7-dimethyl-1 / 7-indole-1 -carboxylate (CAS# 1644667-04-8, 2.7 g, 10 mmol) was dissolved in DCM (25 mL), and the mixture was cooled to 0 °C. TFA (0.77 mL, 10 mmol) and mCPBA (77 wt%, 2.69 g, 12 mmol) were added sequentially. The RM was stirred for 1 h, during which time it was allowed to warm to RT. The mixture was partitioned between sat. aq NaHCO3soln and DCM. The org phase was dried through an Isolute® phase separator and concentrated under reduced pressure. The resulting oil was dissolved in THF (21 mL), and aq NaOH soln (1 M, 21 mL, 21 mmol) was added. The RM was stirred at RT for 15 min. The mixture was neutralized with sat. aq NH4CI soln and extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The resulting oil was purified over silica gel (eluent: 0 to 35% EtOAc in heptane) to provide fert-butyl 4-hydroxy- 5, 7-dimethyl-1 / - / -indole-1 -carboxylate as a brown oil (2.02 g). LC-MS Method C-1 : Rt = 1 .18 min; MS m / z [M+H]+= 262.2.

[0599] Intermediate I-2: 5,7-dimethyl-1-tosyl-1H-indol-4-ol

[0600] 5,7-Dimethyl-1 -tosyl-1 / 7-indole-4-carbaldehyde (CAS# 1481633-44-6, 376 mg, 1.15 mmol) was dissolved in DCM (5 mL), and the soln was cooled to 0 °C. TFA (88 pL, 1 .15 mmol) and mCPBA (77 wt%, 238 mg, 1.38 mmol) were added sequentially. The mixture was stirred for 1 h, during which time it was allowed to warm to RT. The RM was diluted with DCM and washed with sat. aq NaHCO3soln (2x). The separated org phase was dried through an Isolute® phase separator and concentrated under reduced pressure. The resulting residue was dissolved in THF (1 mL) and MeOH (1 mL), and aq NaOH soln (4M, 1 .4 mL, 5.6 mmol) was added. The RM was stirred at RT for 15 min. The RM was partially concentrated under reduced pressure, and the pH was adjusted to 7 with 6M aq HCI. The mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The resulting residue was purified over silica gel (eluent: 0 to 50% EtOAc in heptane) to provide 5,7- dimethyl-1 -tosyl-1 / 7-indol-4-ol as a grey solid (296 mg).1H NMR (400 MHz, CDCh) 6 [ppm] 7.70 (d, J = 3.8 Hz, 1 H), 7.58 - 7.50 (m, 2H), 7.26 - 7.17 (m, 2H), 6.81 - 6.70 (m, 2H), 2.45 (s, 3H), 2.38 (s, 3H), 2.25 (s, 3H). 16 of 17H reported (OH not observed)

[0601] Intermediate I-3: tert-butyl 5-cyclopropyl-4-hydroxy-7-methyl-1 H-indole-1 -carboxylate fert-Butyl 5-cyclopropyl-4-formyl-7-methyl-1 / - / -indole-1 -carboxylate (CAS# 1628640-27-6, 830 mg, 2.77 mmol) was dissolved in DCM (10 mL), and the soln was cooled to 0 °C. TFA (0.21 mL, 2.77 mmol) and mCPBA (77 wt%, 574 mg, 3.33 mmol) were added sequentially. The mixture was stirred for 1 h, during which time it was allowed to warm to RT. The RM was partitioned between sat. aq NaHCO3soln and DCM. The separated org phase was dried through an Isolute® phase separator and concentrated under reduced pressure. The resulting residue was dissolved in THF (3 mL) and MeOH (3 mL), and aq NaOH soln (4M, 3.46 mL, 13.85 mmol) was added. The RM was stirred at RT for 15 min. The mixture was partially concentrated, and the pH was adjusted to 4 with 6M aq HCI. The mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The resulting oil was purified over silica gel (eluent: 0 to 50% EtOAc in heptane) to provide tert-butyl 5-cyclopropyl-4-hydroxy-7-methyl-1 / - / -indole-1 -carboxylate as a grey oil (585 mg). LC-MS Method C-1 : Rt = 1 .26 min; MS m / z [M-Boc+2H]+= 188.2.

[0602] Intermediate I-4: tert-butyl 5-chloro-4-hydroxy-7-methyl-1 H-indole-1 -carboxylate

[0603] Step 1 : 4-bromo-5-chloro-7-methyl-1H-indole (Intermediate 1-4-1 )

[0604] 1-Bromo-2-chloro-4-methyl-5-nitrobenzene (2.5 g, 10 mmol) was dissolved in THF (20 mL), and cooled to -40 °C. A vinyl magnesium bromide soln (1 M in THF, 40 mL, 40 mmol) was added slowly, and the mixture was stirred at approximately -40 °C for 3.5 h. The RM was quenched with sat. aq NH4CI soln and extracted with EtOAc (2x). The combined org phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure. The resulting residue was purified over silica gel (eluent: 0 to 50% EtOAc in heptane) to provide 4- bromo-5-chloro-7-methyl-1 / - / -indole as an orange solid (960 mg).1H NMR (400 MHz, CDCh) 6 [ppm] 8.25 (s, 1 H), 7.31 - 7.29 (m, 1 H), 7.1 1 - 7.09 (m, 1 H), 6.62 (dd, J = 3.3, 2.2 Hz, 1 H), 2.46 (s, 3H).

[0605] Step 2: tert-butyl 4-bromo-5-chloro-7-methyl-1H-indole-1 -carboxylate (Intermediate I-4-2)

[0606] 4-Bromo-5-chloro-7-methyl-1 / - / -indole (Intermediate 1-4-1 , 960 mg, 3.93 mmol) and DMAP (24 mg, 0.19 mmol) were combined in DCM (20 mL). Di-tert-butyl dicarbonate 1.08 mL, 4.7 mmol) was added, and the RM was stirred at RT for 30 min. The RM was concentrated under reduced pressure, and the resulting oil was purified over silica gel (eluent: 0 to 25% EtOAc in heptane) to provide tert-butyl 4-bromo-5-chloro-7-methyl-1 / - / -indole-1 -carboxylate as an orange solid (850 mg).1H NMR (400 MHz, CDCI3) 6 7.49 (d, J = 3.6 Hz, 1 H), 7.14 - 7.05 (m, 1 H), 6.55 (d, J = 3.8 Hz, 1 H), 2.50 (s, 3H), 1.56 (s, 9H).

[0607] Step 3: tert-butyl 5-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H- indole-1 -carboxylate (Intermediate I-4-3) tert-Butyl 4-bromo-5-chloro-7-methyl-1 / 7-indole-1 -carboxylate (Intermediate I-4-2, 300 mg, 0.87 mmol), bis(pinacolato)diboron (332 mg, 1.3 mmol), KOAc (256 mg, 2.6 mmol), and PdCI2(dppf) (71 mg, 0.09 mmol) were combined in a vial. The vial was purged and filled with N2. Dioxane (5 mL) was added, and the RM was stirred at 90 °C for 16 h. The RM was filtered through Celite®, and the solids were washed with DCM. The combined filtrates were concentrated under reduced pressure and the resulting residue was enriched over silica gel (eluent: 0 to 30% EtOAc in heptane) to provide tert-butyl 5-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 / - / -indole-1 -carboxylate as a colorless oil containing tert-butyl 5-chloro-7-methyl-1 / - / -indole-1 - carboxylate (140 mg). LC-MS Method C-1 : Rt = 1.52 min; MS m / z [M-Boc+2H]+= 292.3.

[0608] Step 4: tert-butyl 5-chloro-4-hydroxy-7-methyl-1H-indole-1 -carboxylate

[0609] (Intermediate I-4)

[0610] Enriched tert-butyl 5-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 / 7-indole- 1 -carboxylate (Intermediate I-4-3, 140 mg) was dissolved in THF (0.5 mL) and H2O (0.5 mL) and cooled to 0 °C. Sodium perborate 1-hydrate (39.8 mg, 0.4 mmol) was added, and the RM was stirred at 0 °C for 1 h. Additional THF (0.5 mL) and H2O (0.5 mL) were added, and stirring was continued for 3 h, during which time the mixture was allowed to warm to RT. The mixture was diluted with H2O and extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The resulting residue was purified over silica gel (eluent: 0 to 30% EtOAc in heptane) to provide tert-butyl 5-chloro-4- hydroxy-7-methyl-1 / - / -indole-1 -carboxylate as a brown oil (30 mg). LC-MS Method C-1 Rt = 1 .52 min; MS m / z [M-Boc+2H]+= 182.1.

[0611] Intermediate I-5: tert-butyl 5-fluoro-4-hydroxy-7-methyl-1 H-indole-1 -carboxylate

[0612] To a soln of tert-butyl 4-bromo-5-fluoro-7-methyl-1 / - / -indole-1 -carboxylate (460 mg, 1 .4 mmol) and bis(pinacolato)diboron (533.9 mg, 2.1 mmol) in dioxane (2 mL) were added PdCI2(dppf) (102.5 mg, 0.14 mmol) and KOAc (412.7 mg, 4.2 mmol). The RM was stirred at 90 °C for 18 h. Additional PdCI2(dppf) (102.4 mg, 0.14 mmol) was added, and the RM was stirred at 90 °C for 6 h. The RM was allowed to cool to RT, and H2O2(30 wt% in H2O, 0.72 mL, 7.0 mmol) was added slowly. The RM was stirred at RT for 18 h. The RM was diluted with EtOAc and H2O and filtered through a pad of Celite®. The phases were separated, and the aq phase was extracted with EtOAc (2x). The combined org phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified over silica gel (50 g; eluent: O to 13% EtOAc in heptane) to provide tert-butyl 5-fluoro-4-hydroxy-7-methyl-1 / - / -indole-1 -carboxylate as a pink solid (220 mg). LC-MS Method B-1 : Rt = 1.20 min; MS m / z [M-H] = 263.9.

[0613] Intermediate I-6: tert-butyl 4-hydroxy-7-methyl-1 H-indole-1 -carboxylate

[0614] 7-Methyl-1 / 7-indol-4-ol (75 mg, 0.51 mmol) and DMAP (3.1 mg, 25 pmol) were combined in ACN (1 mL). Di-tert-butyl dicarbonate (0.35 mL, 1 .5 mmol) was added, and the RM was stirred at RT for i h. The RM was concentrated under reduced pressure. The resulting residue was combined with K2CO3(281 mg, 2.0 mmol) and MeOH (2 mL). The RM was stirred at RT for 2 h. Additional K2CO3(70 mg, 0.5 mmol) was added, and the RM was stirred at RT overnight. The RM was partitioned between H2O and DCM. The org phase was concentrated under reduced pressure. The resulting residue was purified over silica gel (eluent: 0 to 50% EtOAc in heptane) to provide tert-butyl 4-hydroxy-7-methyl-1 / - / -indole-1 -carboxylate as a colorless oil (87 mg). LC-MS Method C-1 : Rt = 1 .09 min; MS m / z [M+H]+= 248.2.

[0615] Intermediate I-7: tert-butyl 7-chloro-4-hydroxy-5-methyl-1 H-indole-1 -carboxylate tert-Butyl 4-bromo-7-chloro-5-methyl-1 / 7-indole-1 -carboxylate (5.8 g, 16.4 mmol), bis(pinacolato)diboron (8.5 g, 33.7 mmol), KOAc (4.9 g, 50.5 mmol), and PdCI2(dppf)«DCM (1.37 g, 1 .68 mmol) were combined in a vial. Dioxane (5 mL) was added, and the RM was stirred at 90 °C for 16 h. The RM was filtered through Celite®, and the solids were washed with EtOAc. The combined filtrates were concentrated under reduced pressure. The resulting residue was dissolved in THF (20 mL) and H2O (10 mL). Sodium perborate 1 -hydrate (3.48 g, 34.8 mmol) was added, and the RM was stirred at RT overnight. The RM was diluted with EtOAc, and the separated aq phase was extracted with EtOAc. The combined org phases were dried over Na2SO4and concentrated under reduced pressure. The residue was purified over silica gel (24 g; 10 to 20% EtOAc in hexane) to provide tert-butyl 7-chloro-4-hydroxy-5-methyl-1 / - / -indole-1 - carboxylate as a light brown solid (1.4 g).1H NMR (400 MHz, DMSO-cfe) 6 [ppm] 9.45 (s, 1 H), 7.50 (d, J = 3.6 Hz, 1 H), 7.07 (s, 1 H), 6.88 (d, J = 3.6 Hz, 1 H), 2.20 (s, 3H), 1 .58 (s, 9H).

[0616] Intermediate I-8: tert-butyl 5-bromo-4-hydroxy-7-methyl-1H-indole-1 -carboxylate tert-Butyl 5-bromo-4-formyl-7-methyl-1 / - / -indole-1 -carboxylate (2.37 g, 7.0 mmol) was dissolved in DCM (35 mL), and the soln was cooled to 0 °C. TFA (0.54 mL, 7.0 mmol) and mCPBA (77 wt%, 1 .45 g, 8.41 mmol) were added sequentially. The mixture was stirred for 2.5 h, during which time it was allowed to warm to RT. The RM was partitioned between sat. aq NaHCO3soln and DCM. The separated org phase was dried through an Isolute® phase separator and concentrated under reduced pressure. The resulting residue was dissolved in THF (8 mL) and MeOH (8 mL), and aq NaOH soln (4M, 8.7 mL, 35.0 mmol) was added. The RM was stirred at RT for 20 min. The RM was partially concentrated, and the pH was adjusted to 4 with aq HCI (6M). The mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The resulting oil was purified over silica gel (eluent: 0 to 50% EtOAc in heptane) to provide fert-butyl 5-bromo-4-hydroxy-7-methyl-1 / 7-indole- 1-carboxylate as an orange solid (1.74 g). LC-MS Method C-1 : Rt = 1.15 min; MS m / z [M-H] = 324.0.

[0617] Intermediate K-1 : tert-butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1 -carboxylate

[0618] To a soln of methyl 4-bromobenzoate (200 g, 930 mmol) in toluene (2 L) was added tert-butyl 4- oxopiperidine-1 -carboxylate (333.56 g, 1 .67 mol), K3PO4(454.05 g, 2.10 mol), Xantphos (21.53 g, 37.20 mmol), and Pd2(dba)3(17.03 g, 18.60 mmol) at 25 °C under N2. The RM was stirred at 80 °C under N2for 16 h. The mixture was filtered, and the solids were washed with DCM (4 L). The filtrate was concentrated under reduced pressure. Column chromatography over silica gel (eluent: 3:1 PE / EtOAc) provided enriched material which was purified by RP chromatography (eluent: 0 to 100% ACN in H2O with 0.1 NH4OH) to provide tert-butyl 3-(4- (methoxycarbonyl)phenyl)-4-oxopiperidine-1 -carboxylate as a white solid (99.2 g)1H NMR (400 MHz, DMSO-c / e) 6 [ppm] 7.92 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 4.15 - 4.02 (m, 2H), 3.96 (dd, J = 5.9, 10.8 Hz, 1 H), 3.83 (s, 3H), 3.67 - 3.42 (m, 2H), 2.66 - 2.55 (m, 1 H), 2.41 (dt, J = 4.0, 14.9 Hz, 1 H), 1 .43 (br s, 9H).

[0619] Intermediate K-2: tert-butyl 3-(4-cyanophenyl)-4-oxopiperidine-1 -carboxylate

[0620] To a stirred soln of 4-bromobenzonitrile (10.0 g, 54.93 mmol) in toluene (100 mL) was added tertbutyl 4-oxopiperidine-1 -carboxylate (21 .9 g, 109.8 mmol), followed by K3PO4(23.3 g, 109.8 mmol) and the RM was degassed with argon for 15 min at RT. Xanthphos (1 .58 g, 2.74 mmol) and Pd2(dba)3(1 g, 1.09 mmol) were added, and the RM was stirred at 100 °C for 12 h. The RM was allowed to cool to RT, filtered through Celite®, and the solids were washed with THF (200 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was diluted with H2O and extracted with EtOAc (2x 100 mL). The combined org layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified over silica gel (80 g; eluent: 0 to 100% EtOAc in hexane) to provide tert-butyl 3-(4-cyanophenyl)-4- oxopiperidine-1 -carboxylate as a brown oil (5 g). LC-MS Method A-1 : Rt = 1.75 min; MS m / z [M- H] = 299.1 .

[0621] Intermediate K-3: tert-butyl 3-(4-(1H-pyrazol-1-yl)phenyl)-4-oxopiperidine-1 -carboxylate

[0622] 1-(4-Bromophenyl)-1 / 7-pyrazole (339 mg, 1.52 mmol), tert-butyl 4-oxopiperidine-1 -carboxylate (363 mg, 1.82 mmol), K3PO4(742 mg, 3.50 mmol), and XantPhos-Pd-G2 (CAS#: 1375325-77-1 , 95 mg, 0.11 mmol) were combined in a vial. The vial was purged with N2, and toluene (3 mL) was added. The mixture was purged with N2and stirred at 90 °C for 24 h. The RM was allowed to cool to RT and filtered through Celite®. The solids were washed with DCM, and the combined filtrates were concentrated under reduced pressure. The residue was purified over silica gel (40 g; eluent: 15 to 40% EtOAc in heptane) to provide fert-butyl 3-(4-(1 / 7-pyrazol-1-yl)phenyl)-4-oxopiperidine- 1 -carboxylate as a pale yellow solid (180 mg). LC-MS Method C-1 : Rt = 1 .00 min; MS m / z [M+H]+= 342.2.

[0623] Intermediate K-4: benzyl 5-(1-methyl-1 H-pyrazol-4-yl)-4-oxo-3,4-dihydropyridine-1(2H)- carboxylate

[0624] Step 1 : 4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)pyridine (Intermediate K-4-1)

[0625] To a stirred soln of 3-bromo-4-methoxypyridine (10.0 g, 53 mmol) in dioxane / H2C (4:1 , 100 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 / 7-pyrazole (13.2 g, 63.82 mmol), followed by K2CO3(14.6 g, 106.4 mmol). The RM was degassed with argon for 15 min at RT. Pd(dppf)CI2«DCM (2.16 g, 2.65 mmol) was added to the mixture, and the RM was stirred at 95 °C for 12 h. The RM was filtered through Celite®, and the solids were washed with THF (100 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with H2O and extracted with EtOAc (2x 100 mL). The combined org layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified over silica gel (40 g; eluent: O to 100% EtOAc in hexane) to provide 4-methoxy-3-(1-methyl-1 / 7-pyrazol- 4-yl)pyridine as a yellow semi-solid (1 1 g). LC-MS Method A-1 : Rt = 0.21 min; MS m / z [M+H]+= 190.1. Step 2: benzyl 5-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (Intermediate K-4)

[0626] To a stirred soln of 4-methoxy-3-(1 -methyl-1 / 7-pyrazol-4-yl)pyridine (Intermediate K-4-1 , 8.0 g, 42.78 mmol) in MeOH (80 mL) was added benzyl chloroformate (9.37 g, 54.96 mmol) at 0 °C. The RM was stirred for 10 min, and then NaBH4(2.08 g, 54.96 mmol) was added in portions at 0 °C. The RM was allowed to warm to RT and stirred for 2.5 h. The mixture was quenched with H2O (50 mL) and extracted with EtOAc (3x 50 mL). The combined extracts were dried over Na2SO4and concentrated under reduced pressure. The residue was purified over silica gel (40 g; eluent: 0 to 100% EtOAc in hexane) to provide benzyl 5-(1-methyl-1 / 7-pyrazol-4-yl)-4-oxo-3,4- dihydropyridine-1 (2 / - / )-carboxylate as a yellow oil (6.5 g). LC-MS Method A-1 : Rt = 1.49 min; MS m / z [M+H]+= 312.1.

[0627] Intermediate rac-K-5 and Intermediate rac-K-6: racemic methyl 4-((1S*,5S*)-5-methoxy-2- oxocyclohexyl)benzoate and racemic methyl 4-((1S*,5R*)-5-methoxy-2- oxocyclohexyl)benzoate

[0628] Methyl 4-bromobenzoate (1 .050 g, 4.88 mmol), 4-methoxycyclohexan-1 -one (1 .24 g, 9.68 mmol), K3PO4, (2.38 g, 1 1 .2 mmol), Xantphos (113 mg, 0.195 mmol), and Pd2dba3(67 mg, 73 pmol) were combined in a vial. The vial was purged with N2, and toluene (5 mL) was added. The mixture was purged with N2and was stirred at 80 °C overnight. The RM was allowed to cool to RT, filtered to remove solids, and the filtrate was partitioned between EtOAc and H2O. The separated aq layer was extracted with EtOAc (3x). The combined org phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was enriched over silica gel (120 g; eluent: 0 to 40 % EtOAc in heptane) to provide racemic methyl 4-((1 S*,5S*)-5-methoxy-2- oxocyclohexyl)benzoate (Intermediate rac-K-5, first peak eluting) and racemic methyl 4- ((1 S*,5R*)-5-methoxy-2-oxocyclohexyl)benzoate (Intermediate rac-K-6, second peak eluting). Enriched Intermediate rac-K-5 was purified by RP chromatography (50 g C18 column; eluent: 25 to 50 % AON in H2O, each with 0.1 % FA) to provide racemic methyl 4-((1 S*,5S*)-5-methoxy- 2-oxocyclohexyl)benzoate as a white solid (816 mg).1H NMR (400 MHz, CDCI3) 6 [ppm] 8.06 - 7.97 (m, 2H), 7.24 - 7.18 (m, 2H), 4.13 - 4.02 (m, 1 H), 3.91 (s, 3H), 3.80 - 3.73 (m, 1 H), 3.47 (s, 3H), 2.90 - 2.73 (m, 1 H), 2.55 - 2.32 (m, 3H), 2.18 - 2.03 (m, 1 H), 2.00 - 1 .83 (m, 1 H). Enriched Intermediate rac-K-6 waspurified by RP chromatography (50 g C18 column; eluent: 25 to 50% ACN in H2O, each with 0.1 % FA) to provide racemic methyl 4-((1 S*,5R*)-5-methoxy-2- oxocyclohexyl)benzoate as a white solid (217 mg).1H NMR (400 MHz, CDCI3) 6 [ppm] 8.05 - 7.99 (m, 2H), 7.22 - 7.17 (m, 2H), 3.91 (s, 3H), 3.86 - 3.75 (m, 1 H), 3.74 - 3.61 (m, 1 H), 3.43 (s, 3H), 2.65 - 2.49 (m, 3H), 2.49 - 2.36 (m, 1 H), 2.06 - 1 .93 (m, 1 H), 1 .89 - 1 .75 (m, 1 H). Intermediate K-7: methyl 4-(8-oxo-1 -oxaspiro[4.5]decan-7-yl)benzoate

[0629] Methyl 4-bromobenzoate (433 mg, 2.01 mmol), Cs2CO3(1.51 g, 4.63 mmol), Pd2dba3(22 mg, 24 pmol), and SPhos (CAS# 657408-07-6 , 41 mg, 0.099 mmol) were combined in a vial. The vial was purged with N2, then toluene (2.5 mL) and 1-oxaspiro[4.5]decan-8-one (379 mg, 2.46 mmol) were added. The RM was purged with N2and then stirred at 95 °C for 24 h. The RM was allowed to cool to RT and filtered to remove solids. The solids were washed with DCM, and the combined filtrates were concentrated under reduced pressure. The residue was enriched over silica gel (40 g; eluent: 0 to 40% EtOAc in heptane). The enriched residue from the first diastereomer eluting was purified by RP chromatography (15.5 g C18 column; eluent: 25 to 60 % ACN in H2O, each with 0.1 % FA) to provide methyl 4-(8-oxo-1-oxaspiro[4.5]decan-7-yl)benzoate (105 mg). LC-MS Method C-1 : Rt = 0.96 min; MS m / z [M+H]+= 289.0.

[0630] Intermediate K-8: tert-butyl 3-(6-(1 H-pyrazol-1-yl)pyridin-3-yl)-4-oxopiperidine-1- carboxylate

[0631] 5-Bromo-2-(1 / 7-pyrazol-1-yl)pyridine (318 mg, 1 .4 mmol), fert-butyl 4-oxopiperidine-1 -carboxylate (339 mg, 1 .7 mmol), K3PO4(692 mg, 3.26 mmol), Xantphos (32.9 mg, 56.8 pmol), and Pd2dba3(26 mg, 28 pmol) were combined in a vial. The vial was purged with N2, and toluene (3.5 mL) was added. The mixture was purged with N2and stirred at 80 °C overnight. The RM was allowed to cool to RT and filtered through Celite®. The solids were washed with DCM, and the combined filtrates were concentrated under reduced pressure. The residue was purified over silica gel (24 g; eluent: 0 to 45% EtOAc in heptane) to provide fert-butyl 3-(6-(1 / - / -pyrazol-1 -yl)pyridin-3-yl)-4- oxopiperidine-1 -carboxylate as a colorless oil (100 mg). LC-MS Method C-1 : Rt = 0.98 min; MS m / z [M+H]+= 343.2.

[0632] Intermediate K-9: fert-butyl 3-(4-( 1 H-1 ,2,3-triazol-1 -yl)phenyl)-4-oxopiperidine-1 - carboxylate

[0633] 1-(4-Bromophenyl)-1 / 7-1 ,2,3-triazole (679 mg, 3.03 mmol), fert-butyl 4-oxopiperidine-1 - carboxylate (845 mg, 4.24 mmol), K3PO4(1.48 g, 6.97 mmol), Xantphos (157.8 mg, 0.27 mmol) and Pd2dba3(11 1 mg, 0.12 mmol) were combined in a vial. The vial was purged with N2, and toluene (6 mL) was added. The mixture was purged with N2and stirred at 100 C overnight. The RM was allowed to cool to RT and filtered through Celite®. The solids were washed with DCM, and the combined filtrates were concentrated under reduced pressure. The residue was purified over silica gel (40 g; eluent: 35 to 80% EtOAc in heptane) to provide te / Y-butyl 3-(4-(1 / 7-1 ,2,3- triazol-1-yl)phenyl)-4-oxopiperidine-1 -carboxylate (500 mg). LC-MS Method C-1 : Rt = 0.91 min; MS m / z [M+H]+= 343.2.

[0634] Intermediate K-15: methyl 4-(2-oxocyclohexyl)benzoate

[0635] To a soln of methyl 4-bromobenzoate (1.0 g, 4.7 mmol), cyclohexanone (0.82 g, 8.4 mmol), and Xantphos (0.12 g, 0.2 mmol) in toluene (9 mL) was added K3PO4(2.3 g, 1 1 mmol), and the vial was purged with N2. Pd2(dba)3(85 mg, 93 pmol) was added, and the RM was stirred at 80 °C for 16 h. The RM was allowed to cool to RT and diluted with H2O and EtOAc. The org phase was washed with sat. aq NaHCO3soln and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified over silica gel (25 g; eluent: 0 to 50% EtOAc in hexane) to provide methyl 4-(2-oxocyclohexyl)benzoate as a pink solid (705 mg). LC-MS Method B-1 : Rt = 0.87 min; MS m / z [M+H]+= 233.2.

[0636] Intermediate K-16: methyl 4-(5,5-difluoro-2-oxocyclohexyl)benzoate

[0637] Methyl 4-bromobenzoate (400 mg, 1 .86 mmol), 4,4-difluorocyclohexan-1 -one (349 mg, 2.6 mmol), K3PO4 (908 mg, 4.28 mmol), Xantphos (47.4 mg, 81 pmol), Pd2dba3(34.1 mg, 37.1 pmol), and toluene (5 mL) were combined in a vial. The mixture was purged with N2and stirred at 90 °C for 18 h. The RM was allowed to cool to RT and diluted with DCM and H2O. The separated org phase was concentrated under reduced pressure. The residue was purified over silica gel (24 g; eluent: 0 to 30% EtOAc in cyclohexane) to provide methyl 4-(5,5-difluoro-2- oxocyclohexyl)benzoate as a light brown oil (190 mg). LC-MS Method B-1 : Rt = 0.84 min; MS m / z [M+H]+= 269.2.

[0638] Intermediate rac-K-17: racemic methyl 4-((1S*5S*)-5-((tert-butyldimethylsilyl)oxy)-2- oxocyclohexyl)benzoate Intermediate rac-K-17 was prepared as described for Intermediate K-16 using 4-((te / Y- butyldimethylsilyl)oxy)cyclohexan-1-one (743.5 mg, 3.26 mmol) to provide racemic methyl 4- ((1 S*5S*)-5-((te / Y-butyldimethylsilyl)oxy)-2-oxocyclohexyl)benzoate as a light brown oil (190 mg). LC-MS Method B-1 : Rt = 1 .55 min; MS m / z [M+H2O]+= 380.3

[0639] Intermediate rac-K-18: racemic methyl 4-((1 S*,5R*)-5-methyl-2-oxocyclohexyl)benzoate

[0640] To a stirred soln of methyl 4-bromobenzoate (20.1 g, 93.6 mmol) in toluene (100 mL) was added methyl 4-methylcyclohexan-1-one (21.0 g, 187.2 mmol). The mixture was purged with argon for 10 min. K3PO4 (55.6 g, 262.1 mmol), Xantphos (1 .08 g, 1 .87 mmol), and Pd2(dba)3 (1 .71 g, 1 .87 mmol) were added, and the RM was purged with argon for 10 min. The RM was stirred at 100 °C for 16 h. The RM was allowed to cool to RT and filtered through Celite®. The solids were washed with EtOAc, and the combined filtrates were washed with water. The org phase was dried over Na2SO4and concentrated under reduced pressure. The residue was divided into four portions and each was purified over silica gel (80 g; eluent: 0 to 20% EtOAc in hexane) to provide racemic methyl 4-((1 S*,5R*)-5-methyl-2-oxocyclohexyl)benzoate as an off-white solid (9.0 g total). LC- MS Method A-1 : Rt = 3.05 min; MS m / z [M+H]+= 247.1 .

[0641] Intermediate K-19: methyl 4-(6-oxospiro[2.5]octan-5-yl)benzoate

[0642] To a stirred soln of methyl 4-bromobenzoate (3.1 g, 14.2 mmol), spiro[2.5]octan-6-one (2.5 g,

[0643] 20.2 mmol), and Xantphos (367 mg, 0.63 mmol) in toluene (35 mL) was added K3PO4 (7.04 g,

[0644] 33.2 mmol). The mixture was purged with N2. Pd2(dba)3(264 mg, 0.29 mmol) was added, and the mixture was purged with N2. The RM was heated at 90 °C for 5 h. The RM was allowed to cool to RT and diluted with toluene and water. The mixture was filtered through Celite®. The org phase of the filtrate was washed with NaHCO3and brine, dried over MgSO4, and concentrated under reduced pressure. Column chromatography over silica gel (220 g; eluent: 5 to 34% EtOAc in hexane) provided enriched material which was then further purified by RP chromatography (86 g C18; eluent: 15 to 75% ACN in H2O with 0.1 % NH4OH) to provide methyl 4-(6- oxospiro[2.5]octan-5-yl)benzoate as a white solid (1 .6 g). LC-MS Method B-1 : Rt = 1 .05 min; MS m / z [M+H]+= 259.2.

[0645] Intermediate K-23: methyl 4-(8-oxo-1 ,4-dioxaspiro[4.5]decan-7-yl)benzoate

[0646] Methyl 4-bromobenzoate (2.0 g, 9.3 mmol), 1 ,4-dioxaspiro[4.5]decan-8-one (2.03 g, 13.0 mmol), K3PO4(4.5 g, 21 .4 mmol), Xantphos (236.8 mg, 0.41 mmol), Pd2dba3(170.3 mg, 0.19 mol), and toluene (24 mL) were split between two vials. The mixtures were purged with N2and stirred at 90 °C for 18 h. The mixtures were allowed to cool to RT, combined, and diluted with DCM and H2O. The separated org phase was concentrated under reduced pressure. The residue was purified over silica gel (120 g; eluent: 0 to 30% EtOAc in cyclohexane) to provide methyl 4-(8-oxo-1 ,4- dioxaspiro[4.5]decan-7-yl)benzoate as a light brown solid (1 .25 g). LC-MS Method B-1 : Rt = 0.73 min; MS m / z [M+H]+= 291 .3.

[0647] Intermediate rac-A-1 and Intermediate rac-A-2: racemic tert-butyl (3R* 4S*)-4-hydroxy-3-(4- (methoxycarbonyl)phenyl)piperidine-1 -carboxylate and racemic tert-butyl (3R*,4R*)-4- hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate te / Y-Butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1 -carboxylate (Intermediate K-1 , 1 .09 g, 3.27 mmol) was dissolved in MeOH (25 mL) and cooled to 0 °C. NaBH4(124 mg, 3.27 mmol) was added, and the RM was stirred for 30 min, during which time it was allowed to warm to RT. The RM was partially concentrated under reduced pressure and then partitioned between EtOAc and sat. aq NH4CI soln. The separated org phase was dried over Na2SO4, concentrated under reduced pressure, and purified over silica gel (24 g; eluent: 0 to 100% EtOAc in heptane) to provide racemic tert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1- carboxylate (Intermediate rac-A-1 , first peak eluting) as a white solid (299 mg) and racemic tert- butyl (3 / ?*, 4R*)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate (Intermediate rac-A-2, second peak eluting) as a white solid (558 mg).

[0648] Intermediate rac-A-11H NMR (400 MHz, CDCI3) 6 [ppm] 8.09 - 8.00 (m, 2H), 7.39 - 7.33 (m, 2H), 4.18 - 4.16 (m, 1 H), 4.07 (dd, J = 13.0, 4.2 Hz, 1 H), 4.01 - 3.95 (m, 1 H), 3.94 (s, 3H), 3.57 - 3.50 (m, 1 H), 3.30 - 3.17 (m, 1 H), 2.97 (ddd, J = 11 .9, 4.3, 2.4 Hz, 1 H), 1 .94 - 1 .82 (m, 2H), 1.49 (s, 9H). 24 of 25H reported (OH not observed)

[0649] Intermediate rac-A-21H NMR (400 MHz, CDCI3) 6 [ppm] 8.10 - 7.98 (m, 2H), 7.43 - 7.31 (m, 2H), 4.34 - 4.09 (m, 2H), 3.94 - 3.87 (m, 4H), 2.94 - 2.75 (m, 2H), 2.68 (ddd, J = 11 .5, 9.9, 4.2 Hz, 1 H), 2.10 - 2.04 (m, 1 H), 1.65 - 1.55 (m, 1 H), 1.48 (s, 9H). 24 of 25H reported (OH not observed) Intermediate A-3: tert-butyl (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1- carboxylate

[0650] Step 1 a: tert-Butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1 -carboxylate (Intermediate K-1 , 4.19 g, 12.6 mmol) was dissolved in THF (45 mL) and cooled to 0 °C. Potassium tri-sec- butylborohydride soln (1 M in THF, 20 mL, 20 mmol) was added in a dropwise manner, and the RM was stirred at 0 °C for 1 h. Additional potassium tri-sec-butylborohydride soln (1 M in THF, 5 mL, 5 mmol) was added in a dropwise manner. The RM was stirred at 0 °C for 30 min. The RM was allowed to warm to RT and then stirred for an additional 20 min. The RM was cooled to 0 °C and quenched with sat. aq NH4CI soln. The mixture was extracted with DCM (3x), and the combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (80 g; eluent: 0 to 70% EtOAc in heptane) to provide racemic fert-butyl (3R,4S)-4-hydroxy-3-(4- (methoxycarbonyl)phenyl)piperidine-1-carboxylate as a white solid (2.63 g). LC-MS Method C-1 : Rt = 0.97 min; MS m / z [MrtBu+2H]+= 280.1 .

[0651] Step 1 b: Chiral separation and analytics according to Method SFC-1 : 2.3 g provided Intermediate A-3 (peak 1): 1 .22 g, white solid. LC-MS Method C-1 : Rt = 0.99 min; MS m / z [M- / Bu+2H]+= 280.1 . Analytical chiral HPLC: Rt = 1.67 min; 100% ee.

[0652] Intermediate A-4 and Intermediate A-5: tert-butyl (4S,5S)-4-hydroxy-5-(4- (methoxycarbonyl)phenyl)azepane-1 -carboxylate and tert-butyl (3R,4S)-4-hydroxy-3-(4- (methoxycarbonyl)phenyl)azepane-1 -carboxylate

[0653] Step 1 a: To a soln of methyl 4-bromobenzoate (8.0 g, 37.2 mmol) in toluene (80 mL) was added tert-butyl 4-oxoazepane-1 -carboxylate (9.52 g, 44.6 mmol), followed by K3PO4(15.7 g, 74.4 mmol). The RM was degassed with argon for 15 min at RT, and then Xantphos (1.07 g, 1.86 mmol) and Pd2(dba)3(681.2 mg, 0.74 mmol) were added. The RM was stirred at 100 °C for 12 h. The RM was allowed to cool to RT, filtered through Celite®, and the solids were washed with THF (200 mL). The combined filtrates were concentrated under reduced pressure, and the resulting residue was diluted with H2O and extracted with EtOAc (2x 100 mL). The combined org layers were washed with brine (50 mL), dried over Na2SO4]and concentrated under reduced pressure. Column chromatography over silica gel (48 g; eluent: 0 to 100% EtOAc in hexane) provided enriched material which was purified using RP chromatography (24 g C18 column; eluent: 0 to 100% ACN in H2O with 0.05% NH4OH) to provide a mixture of tert-butyl 4-(4- (methoxycarbonyl)phenyl)-5-oxoazepane-1 -carboxylate and fert-butyl 3-(4-

[0654] (methoxycarbonyl)phenyl)-4-oxoazepane-1 -carboxylate as a yellow solid (4.0 g).

[0655] Step 1 a: To a stirred soln of fert-butyl 4-(4-(methoxycarbonyl)phenyl)-5-oxoazepane-1- carboxylate) and fert-butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxoazepane-1 -carboxylate (4.0 g, 11 .5 mmol) in THF (80 mL) was added lithium tri-sec-butylborohydride soln (1 M in THF, 13.8 mL,

[0656] 13.8 mmol) at -20 °C. The RM was stirred at -20 °C for 10 min. The mixture was diluted with EtOAc (50 mL), quenched with sat. aq NH4CI soln (50 mL), and allowed to warm to RT. The aq was phase was extracted with EtOAc (2x 50 mL). The combined org phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was enriched over silica gel (24 g; eluent: 0 to 100% EtOAc in hexane) to provide a mixture of racemic fert-butyl (4S*,5S*)- 4-hydroxy-5-(4-(methoxycarbonyl)phenyl)azepane-1 -carboxylate and racemic fert-butyl (3 / ?*, 4S*)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)azepane-1 -carboxylate as an off-white solid (2.7 g).

[0657] Step 1 c: Chiral separation according to Method SFC-2: 2.7 g provided a mixture of fert-butyl (4S,5S)-4-hydroxy-5-(4-(methoxycarbonyl)phenyl)azepane-1-carboxylate and racemic fert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)azepane-1-carboxylate (peak 1 , 1.6 g).

[0658] Step 1d: Chiral separation and analytics according to Method SFC-3: 1.6 g peak 1 from Step 1 c above provided Intermediate A-4 (peak 1): 375 mg, off-white solid. Analytical chiral HPLC: Rt = 4.85 min; 98.6% ee.1H NMR (400 MHz, CD3OD) 6 [ppm] 7.97 - 7.88 (m, 2H), 7.43 (d, J = 7.04 Hz, 2H), 4.07 - 4.02 (m, 1 H), 3.88 (s, 3H), 3.76 - 3.59 (m, 2H), 3.49 - 3.35 (m, 2H), 2.87 - 2.79 (m, 1 H), 2.52 - 2.33 (m, 1 H), 1 .94 - 1.79 (m, 3H), 1.50 (d, J = 3.37 Hz, 9H). 26 of 27H reported (OH not observed).

[0659] Intermediate A-5 (peak 3): 470 mg, off-white solid. Analytical chiral HPLC: Rt = 10.04 min, 98.9% ee. NMR (400 MHz, CD3OD) 6 [ppm] 8.00 - 7.91 (m, 2H), 7.45 - 7.40 (m, 2H), 4.10 - 4.05 (m, 1 H), 3.89 (s, 3H) 3.81 - 3.63 (m, 2H), 3.65 - 3.53 (m, 2H), 3.27 - 3.21 (m, 1 H), 3.07 - 2.97 (m, 1 H), 2.19 - 2.03 (m, 2H), 1 .85 - 1 .74 (m, 1 H), 1 .73 - 1.62 (m, 1 H), 1.49 - 1 .40 (m, 9 H).

[0660] Intermediate rac-A-6: racemic tert-butyl (3R*,4R*)-3-hydroxy-4-phenylpyrrolidine-1- carboxylate

[0661] Step 1 : racemic tert-butyl (3S*,4R*)-3-hydroxy-4-phenylpyrrolidine-1 -carboxylate (Intermediate rac-A-6-1 ) Boc tert-Butyl 6-oxa-3-azabicyclo[3.1 ,0]hexane-3-carboxylate (881 mg, 4.76 mmol) and copper(l) iodide (90 mg, 0.47 mmol) were combined in a dry flask, and THF (9 mL) was added. The mixture was cooled to 0 °C, and a phenylmagnesium chloride soln (2M in THF, 5.0 mL, 10 mmol) was added in a dropwise manner. The RM was allowed to warm to RT and stirred overnight. The RM was quenched with sat. aq NH4CI soln, and the separated aq layer was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (40 g; eluent: 0 to 50% EtOAc in heptane) to provide racemic tert-butyl (3S*,4R*)-3-hydroxy-4-phenylpyrrolidine-1-carboxylate as a colorless oil (1.07 g). LC-MS Method C-1 : Rt = 0.95 min; MS m / z [M-Boc+2H]+= 164.2.

[0662] Step 2: racemic tert-butyl (3R*,4R*)-3-((4-nitrobenzoyl)oxy)-4-phenylpyrrolidine-1- carboxylate (Intermediate rac-A-6-2)

[0663] Racemic tert-butyl (3S*,4R*)-3-hydroxy-4-phenylpyrrolidine-1 -carboxylate (Intermediate rac- - 6-1 , 530 mg, 2.01 mmol), 4-nitrobenzoic acid (673 mg, 4.03 mmol), and PPh3(1 .06 g, 4.03 mmol) were dissolved in toluene (6 mL) and cooled to 0 °C. DIAD (0.78 mL, 4.03 mmol) was added, the RM was stirred at 0 °C for 15 min, and then the RM was allowed to warm to RT. The RM was stirred at RT for 4 h. Sat. aq NaHCO3soln was added, and the aq phase was extracted with DCM. The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (40 g; eluent: 0 to 40% EtOAc in heptane) to provide racemic tert-butyl (3R*,4R*)-3-((4-nitrobenzoyl)oxy)-4- phenylpyrrolidine-1 -carboxylate as a colorless oil (1 .03 g). LC-MS Method C-1 Rt = 0.95 min; MS m / z [M- / Bu+2H]+= 357.2.

[0664] Step 3: racemic tert-butyl (3R*,4R*)-3-hydroxy-4-phenylpyrrolidine-1 -carboxylate (Intermediate rac-A-5)

[0665] Racemic tert-butyl (3 / ?*, 4R*)-3-((4-nitrobenzoyl)oxy)-4-phenylpyrrolidine-1 -carboxylate (Intermediate rac-A-6-2, 1 .03 g, 2.50 mmol) was dissolved in MeOH (10 mL), and K2CO3(1.39 g, 10 mmol) was added. The RM was stirred at RT for 90 min, and then concentrated under reduced pressue. The residue was partitioned between DCM and sat. aq NH4CI soln. The aq layer was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (24 g; eluent: 0 to 45% EtOAc in heptane) to provide racemic tert-butyl (3R*,4R*)-3-hydroxy-4- phenylpyrrolidine-1 -carboxylate as a colorless oil (548 mg). LC-MS Method C-1 : Rt = 0.93 min; MS m / z [MrtBu+2H]+= 208.1 .

[0666] Intermediate A-7: tert-butyl (3R,4S)-3-(4-cyanophenyl)-4-hydroxypiperidine-1 -carboxylate

[0667] Step 1 a: Prepared as described for Intermediate A-4 using tert-butyl 3-(4-cyanophenyl)-4- oxopiperidine-1 -carboxylate (Intermediate K-2,1 .0 g, 3.32 mmol) at 0 °C to provide racemic tertbuty (3R*,4S*)-3-(4-cyanophenyl)-4-hydroxypiperidine-1 -carboxylate as an off-white solid (300 mg).

[0668] Step 1 b: Chiral separation and analytics according to Method SFC-4: 1 .5 g from multiple batches of racemic tert-butyl (3 / ?*, 4S*)-3-(4-cyanophenyl)-4-hydroxypiperidine-1 -carboxylate provided Intermediate A-7: 700 mg, off-white solid. Analytical chiral HPLC: Rt = 6.34 min; 96% ee.1H NMR (400 MHz, CD3OD) 6 [ppm] 7.71 - 7.64, (m, 2H), 7.50 (d, J = 8.2 Hz, 2H). 4.13 - 4.08 (m, 1 H), 3.98 - 3.83 (m, 1 H), 3.86 - 3.81 (m, 1 H), 3.83 - 3.76 (m, 1 H), 3.63 - 3.44 (m, 1 H), 3.12 - 2.98 (m, 1 H), 2.95 - 2.87 (m, 1 H), 1 .85 - 1 .76 (m, 2H), 1 .51 (s, 9 H).

[0669] Intermediate rac-A-8: racemic tert-butyl (3R*,4S*)-3-(4-(1 H-pyrazol-1-yl)phenyl)-4- hydroxypiperidine-1 -carboxylate fert-Butyl 3-(4-(1 / 7-pyrazol-1-yl)phenyl)-4-oxopiperidine-1 -carboxylate (Intemediate K-3, 500 mg, 1 .47 mmol) was dissolved in MeOH (3 mL) and NaBH4(100 mg, 2.64 mmol) was added. The RM was stirred at RT for 2 h. The RM was quenched with H2O, and the mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. Column chromatography over silica gel (24 g; eluent: 10 to 80 % EtOAc in heptane) provided enriched material from the first peak to elute. The material was purified by RP chromatography (50 g C18 column; eluent: 25 to 50% ACN in H2O, each with with 0.1 % FA) to provide racemic fert-butyl (3R*,4S*)-3-(4-(1 / 7-pyrazol-1-yl)phenyl)-4- hydroxypiperidine-1 -carboxylate as a colorless oil (82 mg).1H NMR (400 MHz, CDCI3) 5 [ppm] 7.91 (d, J = 2.4 Hz, 1 H), 7.71 (d, J = 1 .8 Hz, 1 H), 7.68 - 7.61 (m, 2H), 7.34 (d, J = 8.5 Hz, 2H), 6.49 - 6.40 (m, 1 H), 4.15 - 4.08 (m, 1 H), 3.98 - 3.82 (m, 1 H), 3.57 - 3.41 (m, 1 H), 3.30 - 3.16 (m, 1 H), 2.97 - 2.85 (m, 1 H), 1 .88 - 1 .79 (m, 2H), 1 .68 - 1 .60 (m, 1 H), 1 .47 (s, 9H). 24 of 25 reported (OH not observed).

[0670] Intermediate A-8-1 : tert-butyl (3R,4S)-3-(4-(1H-pyrazol-1-yl)phenyl)-4-hydroxypiperidine-1- Chiral separation of Intermediate rac-A-8 and analytics according to Method SFC-1 1 : 271 mg provided Intermediate A-8-1 (peak 1): 99 mg, white solid. LC-MS Method C-4: Rt = 2.11 min; MS m / z [M- / Bu+2H]+= 288.6. Analytical chiral HPLC: Rt = 2.38 min; 96% ee.

[0671] Intermediate A-9: benzyl (3 / ?,4S)-4-hydroxy-3-(1-methyl-1 H-pyrazol-4-yl)piperidine-1- carboxylate

[0672] Step 1 a: To a stirred soln of benzyl 5-(1-methyl-1 / 7-pyrazol-4-yl)-4-oxo-3,4-dihydropyridine-1 (2 / 7)- carboxylate (Intermediate K-4, 4.9 g, 15.7 mmol) in EtOH (50 mL) was added PtO2(4.9 g) at room temperature. The RM was stirred at RT for 16 h under H2atmosphere (balloon). The RM was filtered through Celite®, and the solids were washed with DCM. The combined filtrates were concentrated under reduced pressure. The crude material was purified by preparatory HPLC (Waters XBridge C18 19 x 250 mm; 5 pm ; eluent: 0 to 60% ACN in H2O with 0.02% NH4OH) to provide racemic benzyl (3R*,4S*)-4-hydroxy-3-(1-methyl-1 / - / -pyrazol-4-yl)piperidine-1- carboxylate and racemic benzyl (3R*,4R*)-4-hydroxy-3-(1-methyl-1 / - / -pyrazol-4-yl)piperidine-1- carboxylate as a mixture of diastereomers (1 .6 g).

[0673] Step 1 b: Separation and analytics according to Method SFC-5: 1.6 g provided Intermediate A-9 (peak 2): 367 mg. Analytical chiral HPLC: Rt = 4.77 min; 98.8% ee. 1 H NMR (400 MHz, CD3OD) 6 [ppm] 7.49 - 7.42 (m, 1 H), 7.41 - 7.27 (m, 6H), 5.19 - 5.06 (m, 2H), 4.03 - 3.99 (m, 1 H), 3.82 (s, 3H), 3.76 (dd, J = 13.20, 4.11 Hz, 1 H), 3.75 - 3.63 (m, 1 H), 3.58 - 3.46 (m, 2H), 2.89 (dt, J = 9.28, 3.58 Hz, 1 H), 1 .69 - 1 .79 (m, 2H). 20 of 21 H reported (OH not observed)

[0674] Intermediate rac-A-10 and Intermediate rac-A-11 : racemic methyl 4-((1S*,2S*,5S*)-2- hydroxy-5-methoxycyclohexyl)benzoate and racemic methyl 4-((1 S*,2R*,5S*)-2-hydroxy-5- methoxycyclohexyl)benzoate

[0675] Racemic methyl 4-((1 R*,5R*)-5-methoxy-2-oxocyclohexyl)benzoate (Intermediate rac-K-5, 817 mg, 3.12 mmol) was combined with MeOH (3 mL) and THF (3 mL). The soln was cooled to 0 °C, and NaBH4(118 mg, 3.12 mmol) was added. The RM was allowed to warm to RT and stirred for 1 h. The RM was quenched with H2O and partially concentrated under reduced pressure. The mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (40 g; eluent: 0 to 50% EtOAc in heptane) to provide racemic methyl 4-((1 S*,2S*,5S*)-2- hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac-A-10, first peak eluting, 160 mg) and racemic methyl 4-((1 S*,2R*,5S*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac- A-11 , second peak eluting, 587 mg). Intermediate rac-A-10:1H NMR (400 MHz, CDCI3) 6 [ppm] 8.04 - 7.91 (m, 2H), 7.37 - 7.29 (m, 2H), 4.06 - 3.99 (m, 1 H), 3.90 (s, 3H), 3.73 - 3.64 (m, 1 H), 3.34 (s, 3H), 3.24 - 3.15 (m, 1 H), 2.29 - 2.14 (m, 1 H), 2.09 - 1.95 (m, 1 H), 1.95 - 1.86 (m, 1 H), 1 .86 - 1 .69 (m, 3H), 1 .43 - 1 .25 (m, 1 H).

[0676] Intermediate rac-A-11 :1H NMR (400 MHz, CDCI3) 6 [ppm] 8.04 - 7.97 (m, 2H), 7.45 - 7.30 (m, 2H), 3.91 (s, 3H), 3.82 - 3.68 (m, 1 H), 3.57 - 3.51 (m, 1 H), 3.35 (s, 3H), 3.00 - 2.87 (m, 1 H), 2.20 - 2.02 (m, 2H), 1 .96 - 1 .85 (m, 1 H), 1 .85 - 1 .70 (m, 1 H), 1 .68 - 1 .48 (m, 2H), 1 .48 - 1 .41 (m, 1 H).

[0677] Intermediate A-10-1 : methyl 4-((1S,2S,5S)-2-hydroxy-5-methoxycyclohexyl)benzoate

[0678] Chiral separation of Intermediate rac-A-10 and analytics according to Method SFC-12: 20 g provided Intermediate A-10-1 (peak 1): 9.0 g, gray solid.1H NMR (400 MHz, CDCI3) 6 [ppm] 8.02 - 7.92 (m, 2H), 7.32 (d, J = 8.4 Hz, 2H), 4.00 - 3.95 (m, 1 H), 3.85 (s, 3H), 3.70 (s, 1 H), 3.35 - 3.29 (m, 3H), 3.22 - 3.13 (m, 1 H), 2.24 - 2.15 (m, 1 H), 2.03 - 1 .94 (m, 1 H), 1 .89 - 1 .86 (m, 1 H), 1 .84 - 1 .67 (m, 3H), 1 .50 (s, 1 H). Analytical chiral HPLC: Rt = 1 .63 min; 99% ee.

[0679] Intermediate rac-A-12 and Intermediate rac-A-13: racemic methyl 4-((1 S*,2S*,5R*)-2- hydroxy-5-methoxycyclohexyl)benzoate and racemic methyl 4-((1S*,2R*,5R*)-2-hydroxy-5- methoxycyclohexyl)benzoate

[0680] Intermediate rac-A-12 and Intermediate rac-A-13 were prepared as described for Intermediate rac-A-10 and Intermediate rac-A-11 using racemic methyl 4-((1 S*,5R*)-5-methoxy-2- oxocyclohexyl)benzoate (Intermediate rac-K-6, 217 mg, 0.83 mmol) to provide racemic methyl 4-((1 S*,2S*,5R*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac-A-12, first peak eluting, 45 mg) and racemic methyl 4-((1 S*,2R*,5R*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac-A-13, second peak eluting, 137 mg). Intermediate rac-A-12:1H NMR (400 MHz, CDCI3) 6 [ppm] 8.05 - 7.98 (m, 2H), 7.38 - 7.31 (m, 2H), 4.01 - 3.96 (m, 1 H), 3.91 (s, 3H), 3.41 (s, 3H), 3.39 - 3.25 (m, 1 H), 2.90 - 2.75 (m, 1 H), 2.14 - 2.00 (m, 3H), 1.99 - 1.87 (m, 1 H), 1 .73 - 1 .61 (m, 2H), 1 .59 - 1 .44 (m, 1 H).

[0681] Intermediate rac-A-13:1H NMR (400 MHz, CDCI3) 6 [ppm] 8.01 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 3.90 (s, 3H), 3.77 - 3.64 (m, 1 H), 3.35 (s, 3H), 3.33 - 3.25 (m, 1 H), 2.66 - 2.49 (m, 1 H), 2.23 - 2.07 (m, 3H), 1 .62 - 1 .34 (m, 4H). Intermediate rac-A-14: racemic methyl 4-((7S ,8S*)-8-hydroxy-1-oxaspiro[4.5]decan-7- yl)benzoate

[0682] Racemic methyl 4-((5S*,7S*)-8-oxo-1 -oxaspiro[4.5]decan-7-yl)benzoate (Intermediate rac-K- 7,128 mg, 0.44 mmol) was combined with MeOH (2 mL) and THF (0.5 mL). NaBH4(50 mg, 1.3 mmol) was added, and the RM was stirred at RT for 1 h. The RM was quenched with H2O and partially concentrated under reduced pressure. The mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (12 g; eluent: 10 to 50% EtOAc in heptane) to provide racemic methyl 4-((7S*,8S*)-8-hydroxy-1-oxaspiro[4.5]decan-7-yl)benzoate (first diastereomer to elute, 20.9 mg).1H NMR (400 MHz, CDCI3) 6 [ppm] 8.04 - 7.95 (m, 2H), 7.38 - 7.30 (m, 2H), 4.05 - 3.97 (m, 1 H), 3.91 (s, 3H), 3.88 - 3.78 (m, 2H), 3.31 - 3.20 (m, 1 H), 2.21 (t, J = 13.2 Hz, 1 H), 2.14 - 1 .71 (m, 7H), 1 .70 - 1 .51 (m, 2H). 21 of 22H reported (OH not observed).

[0683] Intermediate rac-A-15: racemic tert-butyl (3R*,4S*)-3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-4- hydroxypiperidine-1 -carboxylate fert-Butyl 3-(6-(1 / 7-pyrazol-1 -yl)pyridin-3-yl)-4-oxopiperidine-1 -carboxylate (Intemediate K-8, 96 mg, 0.28 mmol) was dissolved in MeOH (3 mL), and NaBH4(25 mg, 0.66 mmol) was added. The RM was stirred at RT for 1 h. The RM was quenched with H2O, and the mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (24 g; eluent: 15 to 50 % EtOAc in heptane) to provide racemic fert-butyl (3R*,4S*)-3-(6-(1 / - / -pyrazol-1-yl)pyridin- 3-yl)-4-hydroxypiperidine-1-carboxylate as a colorless oil (82 mg).1H NMR (400 MHz, CDCI3) 6 [ppm] 8.53 (d, J = 2.6 Hz, 1 H), 8.30 (d, J = 2.3 Hz, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 7.74 (dd, J = 15.6, 2.1 Hz, 2H), 6.50 - 6.47 (m, 1 H), 4.18 - 4.14 (m, 1 H), 3.98 - 3.89 (m, 1 H), 3.60 - 3.50 (m, 1 H), 3.37 - 3.19 (m, 1 H), 2.97 - 2.90 (m\, 1 H), 1 .91 - 1.81 (m, 2H), 1 .77 - 1.68 (m, 1 H), 1 .47 (s, 9H). 23 of 24H reported (OH not observed).

[0684] Intermediate rac-A-16: racemic tert-butyl (3R*,4S*)-3-(4-(1 H-1 ,2,3-triazol-1 -yl)phenyl)-4- hydroxypiperidine-1 -carboxylate

[0685] Intermediate rac-A-16 was prepared as described for Intermediate rac-A-15 using te / Y-butyl 3- (4-(1 / 7-1 ,2,3-triazol-1-yl)phenyl)-4-oxopiperidine-1 -carboxylate (Intemediate K-9, 500 mg, 1.46 mmol) to provide racemic te / Y-butyl (3R*,4S*)-3-(4-(1 / 7-1 ,2,3-triazol-1-yl)phenyl)-4- hydroxypiperidine-1 -carboxylate as white solid (72 mg).1H NMR (400 MHz, CDCI3) 6 [ppm] 7.99 (d, J = 1.3 Hz, 1 H), 7.86 (d, J = 1 .2 Hz, 1 H), 7.76 - 7.70 (m, 2H), 7.47 - 7.41 (m, 2H), 4.20 - 4.15 (m, 1 H), 4.10 - 4.04 (m, 1 H), 4.00 - 3.92 (m, 1 H), 3.58 - 3.48 (m, 1 H), 3.28 - 3.24 (m, 1 H), 3.00 - 2.94 (m, 1 H), 1 .92 - 1 .81 (m, 2H), 1 .48 (s, 9H). 23 of 24H reported (OH not observed).

[0686] Intermediate rac-A-22: racemic methyl 4-((1 S*,2S*)-2-hydroxycyclohexyl)benzoate

[0687] Methyl 4-(2-oxocyclohexyl)benzoate (Intermediate K-15, 705 mg, 3.03 mmol) was combined with MeOH (4 mL). The soln was cooled to 0 °C, and NaBH4(264 mg, 6.98 mmol) was added. The RM was allowed to warm to RT and stirred for 1 h. The RM was quenched with H2O and extracted with DCM (2x). The combined org phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified over silica gel (25 g; eluent: 0 to 30% EtOAc in heptane) to provide racemic methyl 4-((1 S*,2S*)-2-hydroxycyclohexyl)benzoate as a white solid (first peak eluting, 264 mg).1H NMR (400 MHz, DMSO-c / 6) 5 [ppm] 7.87 - 7.84 (m, 2H), 7.41 - 7.38 (m, 2H), 4.30 - 4.28 (m, 1 H), 3.89 - 3.85 (m, 1 H), 3.83 (s, 3H), 2.74 - 2.66 (m, 1 H), 2.05 - 1 .96 (m, 1 H), 1 .79 - 1 .73 (m, 2H), 1 .69 - 1 .63 (m, 1 H), 1 .59 - 1 .53 (m, 1 H), 1 .50 - 1 .45 (m, 1 H), 1 .44 - 1 .39 (m, 1 H), 1 .39 - 1 .29 (m, 1 H).

[0688] Intermediate rac-A-23: racemic methyl 4-((1 S*,2R*)-5,5-difluoro-2- hydroxycyclohexyl)benzoate

[0689] Methyl 4-(5,5-difluoro-2-oxocyclohexyl)benzoate (Intermediate K-16, 100 mg, 0.37 mmol) was dissolved in MeOH (2.5 mL). The soln was cooled to 0 °C, and NaBH4(32.4 mg, 0.86 mmol) was added. The RM was stirred for 1 h. The RM was quenched with sat NH4CI soln and EtOAc and allowed to warm to RT. The aq phase was extracted with EtOAc (2x). The combined org phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified over silica gel (12 g; eluent: 0 to 30% EtOAc in cyclohexane) to provide racemic methyl 4-((1 S*,2R*)-5,5-difluoro-2-hydroxycyclohexyl)benzoate as a white solid (82.5 mg).1H NMR (400 MHz, DMSO-c / 6) 6 [ppm] 7.95 - 7.81 (m, 2H), 7.52 - 7.35 (m, 2H), 4.66 (d, J = 6.1 Hz, 1 H), 3.84 (s, 3H), 3.80 - 3.69 (m, 1 H), 2.81 - 2.69 (m, 1 H), 2.32 - 2.14 (m, 1 H), 2.12 - 1.93 (m, 4H), 1 .61 - 1.48 (m, 1 H).

[0690] Intermediate rac-A-24: racemic methyl 4-((1S* 2S*,5S*)-5-((tert-butyldimethylsilyl)oxy)-2- hydroxycyclohexyl)benzoate

[0691] Intermediate rac-A-24 was prepared as described for Intermediate rac-A-23 using racemic methyl 4-((1 S*5S*)-5-((te / Y-butyldimethylsilyl)oxy)-2-oxocyclohexyl)benzoate (Intermediate rac- K-17, 235 mg, 0.64 mmol) and lithium tri-sec-butylborohydride soln (1 M in THF, 0.84 mL, 0.84 mmol) to provide racemic methyl 4-((1 S*,2S*,5S*)-5-((te / Y-butyldimethylsilyl)oxy)-2- hydroxycyclohexyl)benzoate as colorless semi-solid (73 mg). LC-MS Method B-1 : Rt = 1.6 min; MS m / z [M+H]+= 365.4.

[0692] Intermediate A-25: methyl 4-((1S,2S,5R)-2-hydroxy-5-methylcyclohexyl)benzoate

[0693] Step 1 a: Racemic methyl 4-((1 S*,5R*)-5-methyl-2-oxocyclohexyl)benzoate (Intermediate K-18, 6.5 g, 26.4 mmol) was dissolved in MeOH (65 mL) and cooled to 0 °C. NaBH4(2.0 mg, 52.8 mmol) was added, and the RM was stirred for 30 min. The RM was diluted with H2O and EtOAc and allowed to warm to RT. The separated org phase was dried over Na2SO4, concentrated under reduced pressure, and purified over silica gel (80 g; eluent: 0 to 30% EtOAc in heptane) to provide racemic methyl 4-((1 S*,2S*,5R*)-2-hydroxy-5-methylcyclohexyl)benzoate (first peak eluting) as an off-white solid (1 .0 g).

[0694] Step 1 b: Chiral separation and analytics according to Method SFC-18: 2.67 g provided Intermediate A-25 (peak 1): 1.17 g, white solid. LC-MS Method A-1 : Rt = 3.27 min; MS m / z [M+H]+= 249.1 . Analytical chiral HPLC: Rt = 2.87 min; 99.7% ee.

[0695] Intermediate rac-A-26: racemic methyl 4-((5S* 6S*)-6-hydroxyspiro[2.5]octan-5-yl)benzoate Methyl 4-(6-oxospiro[2.5]octan-5-yl)benzoate (Intermediate K-19, 1.05 g, 4.07 mmol) was combined with THF (10.5 mL). The soln was cooled to -78 °C, and lithium tri-sec-butylborohydride soln (1 M in THF, 8.1 mL, 8.1 mmol) was added in a dropwise manner. The RM was stirred for 1 h. The RM was quenched with MeOH and aq HCI (2M) and allowed to warm to RT. EtOAc and H2O were added. The separated aq phase was extracted with EtOAc. The combined org phases were washed with brine, dried over MgSO4, and concentrated under reduced pressure. Column chromatography over silica gel (40 g; eluent: 5 to 30% EtOAc in heptane) followed by recrystallization from hexane provided racemic methyl 4-((5S*,6S*)-6-hydroxyspiro[2.5]octan-5- yl)benzoate as a white solid (399 mg). LC-MS Method B-1 : Rt = 1 .15 min; MS m / z [M+H]+= 261.2.

[0696] Intermediate rac-A-28: racemic methyl 4-((1S*,2S*)-5,5-difluoro-2- hydroxycyclohexyl)benzoate

[0697] Methyl 4-(5,5-difluoro-2-oxocyclohexyl)benzoate (Intermediate K-16, 97 mg, 0.36 mmol) was combined with THF (2 mL). The soln was cooled to -78 °C, and lithium tri-sec-butylborohydride soln (1 M in THF, 0.58 mL, 0.58 mmol) was added. The RM was stirred for 1 h. The RM was quenched with sat. aq NH4CI soln, allowed to warm to RT, and diluted with EtOAc. The aq phase was extracted with EtOAc (2x). The combined org phases were washed with brine, dried over Na2S04, and concentrated under reduced pressure. The residue was purified over silica gel (12 g; eluent: 0 to 25% EtOAc in cyclohexane) to provide racemic methyl 4-((1 S*,2S*)-5,5- difluoro-2-hydroxycyclohexyl)benzoate as a white solid (82.5 mg).1H NMR (400 MHz, DMSO- c / 6) 6 [ppm] 7.93 - 7.83 (m, 2H), 7.52 - 7.34 (m, 2H), 4.74 (d, J = 4.4 Hz, 1 H), 3.92 - 3.87 (m, 1 H), 3.84 (s, 3H), 3.09 - 2.98 (m, 1 H), 2.58 - 2.40 (m, 1 H), 2.24 - 2.02 (m, 1 H), 2.01 - 1 .73 (m, 4H).

[0698] Intermediate rac-A-31 : racemic methyl 4-((7S*,8S*)-8-hydroxy-1 ,4-dioxaspiro[4.5]decan-7- yl)benzoate

[0699] Methyl 4-(8-oxo-1 ,4-dioxaspiro[4.5]decan-7-yl)benzoate (Intermediate K-23, 1.50 g, 5.17 mmol) was combined with THF (50 mL). The soln was cooled to -78 °C, and a lithium tri-sec- butylborohydride soln (1 M in THF, 8.7 mL, 8.7 mmol) was added in a dropwise manner. The RM was stirred for 1 h. Additional lithium tri-sec-butylborohydride soln (1 M in THF, 3.1 mL, 3.1 mmol) was added in a dropwise manner, and the RM was stirred for 1 h. The RM was diluted with MeOH. sat. aq NH4CI soln, and MeOH, and allowed to warm to RT. The separated aq phase was extracted with EtOAc. The combined org phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Column chromatography over silica gel (120 g; eluent: 0 to 30% EtOAc in cyclohexane) provided racemic methyl 4-((7S*,8S*)-8-hydroxy-1 ,4- dioxaspiro[4.5]decan-7-yl)benzoate as a white solid (960 mg). LC-MS Method B-1 : Rt = 0.71 min; MS m / z [M+H]+= 293.1.

[0700] Intermediate rac-M-1 : racemic tert-butyl 4-(((3R* 4R*)-1-(fert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0701] Racemic fert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate (Intermediate rac-A-1 , 150 mg, 0.45 mmol), PPh3(160 mg, 0.61 mmol), and fert-butyl 4-hydroxy- 5, 7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 93 mg, 0.36 mmol) were dissolved in THF (1 .25 mL). DIAD (115 pL, 0.59 mmol) was added, and the RM was stirred at RT overnight. The RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 30% EtOAc in heptane) to provide racemic fert-butyl 4-(((3R,4 / ?)-1-(fert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate as a colorless foam (48 mg). LC-MS Method C-1 : Rt = 1 .57 min; MS m / z [M+H]+= 579.3.

[0702] Intermediate rac-M-2: racemic tert-butyl (3R* 4S*)-4-((5,7-dimethyl-1-tosyl-1H-indol-4- yl)oxy)-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate

[0703] 5,7-Dimethyl-1 -tosyl-1 / 7-indol-4-ol (Intermediate I-2, 60 mg, 0.19 mmol), racemic fert-butyl (3 / ?*, 4R*)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate (Intermediate rac- A-2, 64 mg, 0.19 mmol), and PPh3(54.7 mg, 0.28 mmol) were dissolved in THF (0.7 mL). DIAD (55 pL, 0.26 mmol) was added in a dropwise manner, and the RM was stirred at RT overnight. The RM was concentrated under reduced pressure and purified over silica gel (eluent: 0 to 100% EtOAc in heptane) to provide racemic tert-butyl (3 / ?*,4S*)-4-((5,7-dimethyl-1-tosyl-1 / 7-indol-4- yl)oxy)-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate as a light yellow oil (87.3 mg). LC-MS Method C-1 : Rt = 1 .49 min; MS m / z [M-Boc+2H]+= 533.1 .

[0704] Intermediate M-3: tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-

[0705] (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-cyclopropyl-7-methyl-1H-indole-1- carboxylate tert-Butyl 5-cyclopropyl-4-hydroxy-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-3, 50 mg, 0.17 mmol), tert-butyl (3 / ?,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate (Intermediate A-3, 61 mg, 0.18 mmol), and PPh3(54.7 mg, 0.21 mmol) were dissolved in toluene (0.4 mL). A DIAD (55 pL, 0.26 mmol) soln in toluene (0.15 mL) was added in a dropwise manner over 10 min. The RM was stirred at RT overnight. The RM was concentrated under reduced pressure and purified over silica gel (eluent: 0 to 40% EtOAc in heptane) to provide tert-butyl 4- (((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5- cyclopropyl-7-methyl-1 / - / -indole-1 -carboxylate as a colorless oil (26.2 mg). LC-MS Method C-1 : Rt = 1 .55 min; MS m / z [M+H]+= 605.2.

[0706] Intermediate M-4: tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-

[0707] (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-chloro-7-methyl-1H-indole-1 -carboxylate

[0708] Intermediate M-4 was prepared as described for Intermediate M-3 using tert-butyl 5-chloro-4- hydroxy-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-4, 30 mg, 0.11 mmol) and tert-butyl (3 / ?, 4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate (Intermediate A-3, 64.3 mg, 0.19 mmol) to provide tert-butyl 4-(((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-chloro-7-methyl-1 H-'\ ndo le- 1 -carboxylate as a colorless oil (39 mg). LC-MS Method C-1 : Rt = 1 .57 min; MS m / z [M-Boc+2H]+= 499.2.

[0709] Intermediate M-5: tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-

[0710] (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate tert-Butyl (3 / ?, 4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate

[0711] (Intermediate A-3, 152 mg, 0.45 mmol) was dissolved in toluene (4 mL) and THF (0.5 mL). PPh3(178 mg, 0.68 mmol) and tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 118 mg, 0.45 mmol) were added, and the soln was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.31 mL 0.68 mmol) was diluted with toluene (0.25 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 30 min. The RM was stirred at 0 °C for 15 min, and then it was gradually allowed to warm RT and stirred overnight. Column chromatography over silica gel (12 g; eluent: 0 to 25% EtOAc in heptane) provided enriched tert- butyl 4-(((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate as a colorless oil (112 mg). LC-MS Method C-1 : Rt = 1 .55 min; MS m / z [M-Boc+2H]+= 479.3.

[0712] Intermediate M-6: tert-butyl 4-(((4R,5S)-1-(tert-butoxycarbonyl)-5-(4-

[0713] (methoxycarbonyl)phenyl)azepan-4-yl)oxy)-5-cyclopropyl-7-methyl-1H-indole-1- carboxylate tert-Butyl (4S,5S)-4-hydroxy-5-(4-(methoxycarbonyl)phenyl)azepane-1-carboxylate

[0714] (Intermediate A-4, 80 mg, 0.23 mmol), tert-butyl 5-cyclopropyl-4-hydroxy-7-methyl-1 / - / -indole-1 - carboxylate (Intermediate I-3, 67 mg, 0.23 mmol), and PPh3(90 mg, 0.34 mmol) were dissolved in toluene (0.4 mL). The mixture was cooled to 0 °C, and a soln of DIAD (67 pL, 0.34 mmol) in toluene (0.4 mL) was added in a dropwise manner. The RM was allowed to warm to RT and stirred for 18 h. The mixture was purified over silica gel (12 g; eluent: O to 45% EtOAc in heptane) to provide tert-butyl 4-(((4 / ?,5S)-1-(tert-butoxycarbonyl)-5-(4-(methoxycarbonyl)phenyl)azepan-4- yl)oxy)-5-cyclopropyl-7-methyl-1 / - / -indole-1 -carboxylate as a colorless oil (15 mg). LC-MS Method C-1 : Rt = 1 .55 min; MS m / z [M-tBu+2H]+= 563.2.

[0715] Intermediate M-7: tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-

[0716] (methoxycarbonyl)phenyl)azepan-4-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate tert-Butyl (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)azepane-1 -carboxylate

[0717] (Intermediate A-5, 100 mg, 0.378 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 - carboxylate (Intermediate 1-1 , 99 mg, 0.38 mmol), and PPhs (149 mg, 0.57 mmol) were dissolved in a mixture of toluene (0.6 mL) and THF (0.1 mL). The soln was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.26 mL, 0.57 mmol) was further diluted with toluene (0.3 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 1 h. The RM was stirred at RT for 18 h. The RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 20% EtOAc in heptane) to provide tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)azepan-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate as a colorless oil (45.7 mg). LC-MS Method C-1 : Rt = 1 .57 min; MS m / z [M-Boc+2H]+= 493.3.

[0718] Intermediate rac-M-8: racemic tert-butyl 4-(((3S*,4R*)-1-(tert-butoxycarbonyl)-4- phenylpyrrolidin-3-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0719] Racemic tert-butyl (3R*,4R*)-3-hydroxy-4-phenylpyrrolidine-1-carboxylate (Intermediate rac-A- 6, 100 mg, 0.38 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 89 mg, 0.34 mmol), and PPh3(149 mg, 0.57 mmol) were dissolved in toluene (0.4 mL) and the soln was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.26 mL, 0.57 mmol) was added in a dropwise manner over approximately 20 min. The RM was stirred at 0 °C for 30 min, and then it was allowed to gradually warm to RT. The RM was stirred at RT for 3 days. Column chromatography over silica gel (12 g; eluent: 0 to 15% EtOAc in heptane) provided encriched racemic tert-butyl 4-(((3S*,4R^-1-(tert-butoxycarbonyl)-4-phenylpyrrolidin-3-yl)oxy)-5,7-dimethyl- 1 / - / -indole-1 -carboxylate (124 mg). LC-MS Method C-1 : Rt = 1.56 min; MS m / z [M-tBu-Boc+2H]+= 350.9.

[0720] Intermediate M-9: tert-butyl 4-(((3R,4R)-1 -(tert-butoxycarbonyl)-3-(4- cyanophenyl)pipendin-4-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate tert-Butyl (3 / ?, 4S)-3-(4-cyanophenyl)-4-hydroxypiperidine-1 -carboxylate (Intermediate A-7, 106 mg, 0.35 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 96 mg, 0.37 mmol) and PPh3(138 mg, 0.53 mmol) were dissolved in toluene (0.5 mL), and the soln was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.24 mL, 0.53 mmol) was further diluted with toluene (0.25 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 45 min. The RM was allowed to gradually warm to RT, and the RM was stirred at RT overnight. The mixture was purified over silica gel (12 g; eluent: 0 to 20% EtOAc in heptane) to provide tert-butyl 4-(((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3-(4-cyanophenyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate as a colorless oil (77 mg). LC-MS Method C-1 : Rt = 1.53 min; MS m / z [M-Boc+2H]+= 446.3.

[0721] Intermediate rac-M-10: racemic tert-butyl 4-(((3R*,4 / ?*)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(tert- butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0722] Racemic tert-butyl (3R*,4S*)-3-(4-(1 / - / -pyrazol-1-yl)phenyl)-4-hydroxypiperidine-1 -carboxylate (Intermediate rac-A-8, 81 mg, 0.24 mmol) was dissolved in toluene (0.4 mL), and PPh3(92 mg, 0.35 mmol) was added followed by tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 61 mg, 0.24 mmol). The mixture was sonicated and then cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.16 mL, 0.35 mmol) was further diluted with toluene (0.25 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 30 min. The RM was stirred at 0 °C for approximately 30 min and then allowed to gradually warm to RT. The RM was stirred overnight at RT and then column chromatography over silica gel (12 g; eluent: 0 to 40% EtOAc in heptane) provided enriched racemic tert-butyl 4-(((3R*,4 / ?*)-3-(4-(1 / - / -pyrazol-1- yl)phenyl)-1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate as a colorless oil (99 mg. LC-MS Method C-1 : Rt = 1 .53 min; MS m / z [M+H]+= 587.2.

[0723] Intermediate M-11 : tert-butyl 4-(((3R,4 / ?)-1-((benzyloxy)carbonyl)-3-(1-methyl-1H-pyrazol-4- yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0724] Benzyl (3 / ?,4S)-4-hydroxy-3-(1-methyl-1 / 7-pyrazol-4-yl)piperidine-1 -carboxylate (Intermediate A-9, 41 mg, 0.13 mmol) was dissolved in THF (0.25 mL), and PPh3(51 mg, 0.20 mmol) was added followed by tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 34 mg, 0.13 mmol). The RM was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 89 pL, 0.20 mmol) was further diluted with toluene (0.25 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 45 min. The RM was allowed to warm to RT and stirred overnight. Column chromatography over silica gel (12 g; eluent: 0 to 100 % EtOAc in heptane) provided enriched tert-butyl 4-(((3 / ?,4 / ?)-1 -((benzyloxy)carbonyl)-3-(1-methyl-1 / 7-pyrazol-4-yl)piperidin-4- yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (86 mg). LC-MS Method C-1 : Rt = 1 .39 min; MS m / z [M+H]+= 559.3.

[0725] Intermediate rac-M-12: racemic tert-butyl 4-(((1R*,2S* 4S*)-4-methoxy-2-(4-

[0726] (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0727] Racemic methyl 4-((1 S*,2S*,5S*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac- A-10, 56 mg, 0.21 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 55 mg, 0.21 mmol), and PPh3(83 mg, 0.32 mmol) were dissolved in toluene (0.3 mL). The mixture was sonicated 1 min and then cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.15 mL, 0.32 mmol) was further diluted with toluene (0.3 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 20 to 30 min. The RM was stirred at 0 °C for 20 min and then allowed gradually warm to RT. The RM was stirred for 2 days at RT. The RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 20% EtOAc in heptane) to provide racemic tert-butyl 4-(((1 R*,2S*,4S*)-4-methoxy-2-(4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (84 mg). LC-MS Method C-1 : Rt = 1 .53 min; MS m / z [M-Boc+2H]+= 408.3.

[0728] Intermediate rac-M-13: racemic tert-butyl 4-(((1 / ?* 2S* 4R*)-4-methoxy-2-(4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0729] Racemic methyl 4-((1 S*,2S*,5R^-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac- A-12, 45 mg, 0.17 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 44 mg, 0.17 mmol), and PPh3(66 mg, 0.25 mmol) were dissolved in toluene (0.4 mL). The mixture was sonicated for 1 min and then was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.12 mL, 0.25 mmol) was further diluted with toluene (0.3 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over approximately 25 min. The RM was stirred at 0 °C for 20 min and then allowed to gradually warm to RT. The RM was stirred for 2 days at RT. The RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 20% EtOAc in heptane) to provide racemic tert-butyl 4-(((1 R*,2S*,4 / ?^-4-methoxy-2- (4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (8.7 mg). LC- MS Method C-1 : Rt = 1 .52 min; MS m / z [M-Boc+2H]+= 408.2.

[0730] Intermediate rac-M-14: racemic tert-butyl 4-(((1S*,2S*,4S*)-4-methoxy-2-(4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0731] Racemic methyl 4-((1 S*,2S*,5R*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac- A-11 , 60.7 mg, 0.23 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / 7-indole-1 -carboxylate (Intermediate 1-1 , 60.0 mg, 0.23 mmol), and PPh3(90.3 mg, 0.34 mmol) were dissolved in toluene (0.5 mL), and the mixture was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.16 mL, 0.34 mmol) was further diluted with toluene (0.3 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 20 min. The RM was stirred at 0 °C for 20 min and then allowed to gradually warm to RT. The RM was stirred for 3 days at RT. The RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 20% EtOAc in heptane) to provide racemic tert-butyl 4-(((1 S*,2S*,4S*)-4-methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)- 5, 7-dimethyl-1 / - / -indole-1 -carboxylate (36 mg). LC-MS Method C-1 Rt = 1.53 min; MS m / z [M+H]+= 508.0.

[0732] Intermediate rac-M-15: racemic tert-butyl 4-(((1S*,2S*,4R*)-4-methoxy-2-(4-

[0733] (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0734] Racemic methyl 4-((1 S*,2R*,5 / ?*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac- A-13, 60 mg, 0.23 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 59.3 mg, 0.23 mmol), and PPh3(90.3 mg, 0.34 mmol) were dissolved in toluene (0.3 mL), and the mixture was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.16 mL, 0.34 mmol) was further diluted with toluene (0.3 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 20 min. The RM was stirred at 0 °C for 20 min and then allowed to gradually warm to RT. The RM was stirred overnight at RT. The RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 20% EtOAc in heptane) to provide racemic tert-buty I 4-(((1 S*,2S*,4R*)-4-methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)- 5, 7-dimethyl-1 / - / -indole-1 -carboxylate as a colorless oil (36 mg). LC-MS Method C-1 : Rt = 1.53 min; MS m / z [M+H]+= 508.2.

[0735] Intermediate rac-M-16: Racemic tert-butyl 4-(((7S* 8R*)-7-(4-(methoxycarbonyl)phenyl)-1- oxaspiro[4.5]decan-8-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0736] Racemic methyl 4-((5S*,7S*,8S*)-8-hydroxy-1-oxaspiro[4.5]decan-7-yl)benzoate (Intermediate rac-A-12, 20 mg, 70 pmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 18 mg, 70 pmol), and PPh3(27 mg, 0.11 mmol) were dissolved in toluene (0.3 mL). The mixture was sonicated for 1 min and then cooled to 0 °C. A DEAD soln (40 wt% in toluene, 48 pL, 0.11 mmol) was further diluted with toluene (0.3 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 30 min. The RM was stirred at 0 °C for 15 min and then allowed to gradually warm to RT. The RM was stirred overnight at RT and then purified over silica gel (12 g; eluent: 0 to 25% EtOAc in heptane) to provide racemic tert-butyl 4- (((7S*,8R*)-7-(4-(methoxycarbonyl)phenyl)-1-oxaspiro[4.5]decan-8-yl)oxy)-5,7-dimethyl-1 / - / - indole-1 -carboxylate as a colorless oil (37 mg). LC-MS Method C-1 : Rt = 1.56 min; MS m / z [M- Boc+2H]+= 434.3.

[0737] Intermediate M-17: tert-butyl 4-(((3R,4 / ?)-3-(4-(1H-pyrazol-1 -yl)phenyl)-1-(tert- butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate tert-Butyl (3 / ?,4S)-3-(4-(1 / -pyrazol-1 -yl)phenyl)-4-hydroxypiperidine-1 -carboxylate

[0738] (Intermediate A-8-1 , 101.2 mg, 0.29 mmol), PPhs (105.4 mg, 0.40 mmol), and tert-butyl 4- hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 70 mg, 0.27 mmol) were combined in THF (3 mL). The mixture was cooled to 0 °C. A soln of DBAD (92.5 mg, 0.4 mmol) in toluene (0.5 mL) was added to the cooled soln in a dropwise manner over 10 min. The RM was allowed to gradually warm to RT and stirred overnight. The RM was diluted with H2O, and the mixture was extracted with EtOAc (3x). The combined org phases were dried over MgSO4and concentrated under reduced pressure. Column chromatography over silica gel (eluent: 0 to 50% EtOAc in heptane) provided enriched tert-butyl 4-(((3R,4 / ?)-3-(4-(1 / 7-pyrazol-1 -yl)phenyl)-1 -(tert- butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate as a white solid (128 mg. LC-MS Method C-1 : Rt = 1 .54 min; MS m / z [M+H]+= 587.4.

[0739] Intermediate rac-M-18: racemic tert-butyl 4-(((3R*,4R*)-3-(6-(1 H-pyrazol-1-yl)pyridin-3-yl)-1- (tert-butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0740] Racemic tert-butyl (3R*,4S*)-3-(6-(1 / - / -pyrazol-1 -y I) py rid in-3-y l)-4- hyd roxy p ipe rid in e- 1 - carboxylate (Intermediate rac-A-15, 59 mg, 0.17 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / 7- indole-1 -carboxylate (Intermediate 1-1 , 44.7 mg, 0.17 mmol), and PPh3(67 mg, 0.26 mmol) were dissolved in toluene (0.5 mL). The mixture was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.12 mL, 0.26 mmol) was further diluted with toluene (0.25 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 30 min. The RM was stirred at 0 °C for 15 min and then allowed to warm to RT. The RM was stirred overnight at RT. Column chromatography over silica gel (12 g; eluent: 0 to 25% EtOAc in heptane) provided enriched material which was purified by RP chromatography (15.5 g C18; eluent: 60% to 100% ACN in H2O, each with 0.1 % FA) to provide racemic tert-butyl 4-(((3R*,4 / ?*)-3-(6-(1 / - / -pyrazol-1 -yl)pyridin-3-yl)-1-(tert- butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7-indole-1 -carboxylate as a colorless oil (37.8 mg). LC-MS Method C-1 : Rt = 1 .53 min; MS m / z [M+H]+= 588.3.

[0741] Intermediate rac-M-19: racemic tert-butyl 4-(((3R*,4R*)-3-(4-(1 H-1 ,2,3-triazol-1 -yl)phenyl)-1 - (tert-butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0742] Racemic tert-butyl (3R*,4S*)-3-(4-(1 / 7-1 , 2 , 3-triazol- 1 -yl)phenyl)-4-hydroxypiperidine-1 - carboxylate (Intermediate rac-A-16, 72 mg, 0.21 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / 7- indole-1 -carboxylate (Intermediate 1-1 , 54.6 mg, 0.21 mmol), and PPh3(82.3 mg, 0.31 mmol) were dissolved in toluene (0.2 mL) and THF (1 mL). The mixture was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.14 mL, 0.31 mmol) was further diluted with toluene (0.5 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 30 min. The RM was stirred at 0 °C for 15 min and then allowed to warm to RT. The RM was stirred overnight at RT. Column chromatography over silica gel (12 g; eluent: 0 to 25% EtOAc in heptane) provided enriched material which was purified by RP chromatography (15.5 g C18; eluent: 55% to 100% ACN in H2O, each with 0.1 % FA) to provide racemic fert-butyl 4-(((3R*,4 / ?*)-3-(4-(1 / - / -1 ,2,3-triazol-1 - yl)phenyl)-1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate as a white solid (30.5 mg). LC-MS Method C-1 : Rt = 1 .42 min; MS m / z [M+H]+= 588.5.

[0743] Intermediate rac-M-28: racemic tert-butyl 5-cyclopropyl-4-(((1 R* 2S*,4S*)-4-methoxy-2-(4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 H-indole-1 -carboxylate

[0744] Racemic methyl 4-((1 S*,2S*,5S*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac- A-10, 100 mg, 0.38 mmol), tert-butyl 4-hydroxy-5-cyclopropyl-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-3, 108.7 mg, 0.38 mmol), and PPh3(148.8 mg, 0.57 mmol) were dissolved in toluene (0.4 mL). The mixture was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.26 mL, 0.57 mmol) was further diluted with toluene (0.5 mL), and the DEAD soln was added to the cooled soln in a dropwise manner. The RM was stirred at 0 °C for 20 min and then allowed to warm to RT. The RM was stirred overnight at RT and then purified over silica gel (12 g; eluent: 0 to 15% EtOAc in heptane) to provide racemic tert-butyl 5-cyclopropyl-4-(((1 R*,2S*,4S*)-4-methoxy-2-(4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate as a colorless oil (130 mg). LC-MS Method C-1 : Rt = 1 .52 min; MS m / z [M-Boc+2H]+= 434.3.

[0745] Intermediate rac-M-29: racemic tert-butyl 5-chloro-4-(((1R*,2S* 4S*)-4-methoxy-2-(4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 H-indole-1 -carboxylate tert-Butyl 5-chloro-4-hydroxy-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-4, 131 mg, 0.46 mmol), racemic methyl 4-((1 S*,2S*,5S*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac-A-10, 135.2 mg, 0.51 mmol), and PPh3(146.3 mg, 0.56 mmol) were dissolved in toluene (0.4 mL). A DIAD (0.14 mL, 0.70 mmol) soln in toluene (0.1 mL) was added in a dropwise manner over 10 min. The RM was stirred at RT overnight. The RM was concentrated under reduced pressure and purified over silica gel (eluent: 0 to 25% EtOAc in heptane) to provide racemic tert-butyl 5-cyclopropyl-4-(((1 R*,2S*,4S*)-4-methoxy-2-(4-

[0746] (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate as a colorless oil (163 mg). LC-MS Method C-2: Rt = 1 .57 min; MS m / z [M-Boc] = 426.3.

[0747] Intermediate M-30: tert-butyl 5-fluoro-4-(((1 R,2S,4S)-4-methoxy-2-(4-

[0748] (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 H-indole-1 -carboxylate tert-Butyl 5-fluoro-4-hydroxy-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-5, 15 mg, 56 pmol), methyl 4-((1 S,2S,5S)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate A-10-1 , 22.4 mg, 85 pmol), and PPh3(37.1 mg, 0.14 mmol) were dissolved in THF (0.5 mL). DIAD (27 pL, 0.14 mmol) was added in a dropwise manner. The RM was stirred at RT for 4 h. The RM was quenched with H2O and extracted with EtOAc (2x). The combined org phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified Ill over silica gel (10 g; eluent: 0 to 15% EtOAc in heptane) to provide tert-butyl 5-fluoro-4- (((1 / ?,2S,4S)-4-methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 / - / -indo le- 1 - carboxylate as a yellow solid (163 mg). LC-MS Method B-1 : Rt = 1.67 min; MS m / z [M+H2O]+ = 529.5.

[0749] Intermediate M-31 : tert-butyl 4-((( 1 R,2S,4S)-4-methoxy-2-(4-

[0750] (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1 -carboxylate tert-Butyl 4-hydroxy-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-6, 45.0 mg, 0.18 mmol), methyl 4-((1 S,2S,5S)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate A-10-1 , 64.1 mg, 0.19 mmol), and PPh3(57.3 mg, 0.21 mmol) were dissolved in toluene (0.3 mL). A DIAD (53 pL, 0.70 mmol) soln in toluene (0.1 mL) was added in a dropwise manner over 10 min. The RM was stirred at RT overnight. The RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 50% EtOAc in heptane) to provide tert-butyl 4-(((1 R,2S,4S)-4- methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate as a colorless oil (14 mg). LC-MS Method C-2: Rt = 1.52 min; MS m / z [M-Boc+2H]+ = 394.4.

[0751] Intermediate rac-M-32: racemic tert-butyl 4-(((1R*,2S*)-2-(4-

[0752] (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0753] Racemic methyl 4-((1 S*,2S*)-2-hydroxycyclohexyl)benzoate (Intermediate rac-A-22, 264 mg, 1.13 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / 7-indole-1 -carboxylate (Intermediate 1-1 , 323.9 mg, 1.24 mmol), and PPh3(591.1 mg, 2.25 mmol) were dissolved in toluene (6 mL). The mixture was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.88 mL, 2.25 mmol) was added to the cooled soln. The RM was stirred at 0 °C for 30 min and then allowed to warm to RT. The RM was stirred overnight at RT and concentrated under reduced pressure. Column chromatography over silica gel (25 g; eluent: 0 to 30% EtOAc in heptane) provided enriched racemic tert-butyl 4- (((1 R*,2S*)-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole- 1 -carboxylate as a white solid (317.8 mg). LC-MS Method B-1 : Rt = 1 .73 min; MS m / z [M+H]+= 478.3.

[0754] Intermediate rac-M-33: racemic tert-butyl 4-(((1 R*,2S*)-4,4-difluoro-2-(4-

[0755] (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0756] In a glovebox racemic methyl 4-((1 R*,2S*)-5,5-difluoro-2-hydroxycyclohexyl)benzoate (Intermediate rac-A-23, 73.5 mg, 0.27 mmol), tert-butyl 4-bromo-5,7-dimethyl-1 / - / -indole-1 - carboxylate (70.0 mg, 0.22 mmol), phthalimide (47.7 mg, 0.32 mmol), lr[p-F(Me)ppy]2(dtbbpy)PF6(CAS# 1335047-34-1 , 4.2 mg, 3.4 pmol), and (4,4’-dtbbpy)NiCI2(CAS# 1034901-50-2, 8.6 mg, 21 .6 pmol) were combined in ACN (1 mL). BTMG (66 pL, 0.32 mmol) was added, and the sealed vial was removed from the glovebox. The vial was placed in a Penn photoreactor and irradiated at 450 nm, 100% LED, 6800 rpm, and cooling fan at full intensity for 80 h. The RM was diluted with DCM and H2O and filtered through an Isolute® phase separator. The filtrate was concentrated under reduced pressure and purified by preparatory HPLC (Waters XBridge C18 50 x 100 mm, 5 pm; eluent: 40 to 100% ACN in H2O with 0.2% FA) to provide racemic tert-butyl 4- (((1 / ?*,2S*)-4,4-difluoro-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole- 1-carboxylate as a white powder (18.3 mg). LC-MS Method B-1 : Rt = 1 .71 min; MS m / z [M+H]+= 514.4.

[0757] Intermediate rac-M-34: racemic tert-butyl 4-(((1R*,2S*,4S*)-4-((tert-butyldimethylsilyl)oxy)- 2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5-cyclopropyl-7-methyl-1 H-indole-1 - carboxylate

[0758] Racemic methyl 4-((1 S*,2S*,5S^-5-((tert-butyldimethylsilyl)oxy)-2-hydroxycyclohexyl)benzoate (Intermediate rac-A-24, 105 mg, 0.29 mmol) and tert-butyl 4-hydroxy-5-cyclopropyl-7-methyl- 1 / - / -indole-1 -carboxylate (Intermediate I-3, 91 .0 mg, 0.32 mmol) were dissolved in toluene (2 mL). PPh3(90.7 mg, 0.35 mmol) was added, and then DIAD (84 L, 0.43 mmol) was added in a dropwise manner. The RM was stirred overnight at RT. The RM was diluted with DCM and H2O and filtered through an Isolute® phase separator. The filtrate was concentrated under reduced pressure. Column chromatography over silica gel (24 g; eluent: 0 to 20% EtOAc in cyclohexane) provided enriched material which was purified by preparatory HPLC (Waters XBridge C18 50 x 100 mm, 5 pm; eluent: 35 to 100% ACN in H2O with 0.2% FA) to provide racemic tert-butyl 4-(((1 R*,2S*,4S*)- 4-((tert-butyldimethylsilyl)oxy)-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5-cyclopropyl-7- methyl-1 / - / -indole-1 -carboxylate (30.5 mg).1H NMR (400 MHz, DMSO-c / 6) 6 7.91 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 3.7 Hz, 1 H), 6.36 (s, 1 H), 6.24 (d, J = 3.8 Hz, 1 H), 4.44 - 4.32 (m, 1 H), 4.15 - 4.03 (m, 1 H), 3.83 (s, 3H), 3.47 - 3.24 (m, 1 H), 2.36 (s, 3H), 2.01 - 1.81 (m, 3H), 1 .79 - 1 .70 (m, 1 H), 1 .68 - 1 .58 (m, 1 H), 1 .55 (s, 9H), 1 .54 - 1 .43 (m, 2H), 0.93 (s, 9H), 0.91 - 0.84 (m, 1 H), 0.72 - 0.47 (m, 3H), 0.06 (d, J = 2.7 Hz, 6H).

[0759] Intermediate M-35: racemic tert-butyl 4-(((5S*,6R*)-5-(4-

[0760] (methoxycarbonyl)phenyl)spiro[2.5]octan-6-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0761] Racemic methyl 4-((5S*,6S*)-6-hydroxyspiro[2.5]octan-5-yl)benzoate (Intermediate rac-A-26, 344.0 mg, 1.24 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 324.6 mg, 1.24 mmol), and PPh3(488.7 mg, 1.86 mmol) were dissolved in toluene (1 mL). The mixture was cooled to 0 °C. DIAD (0.39 mL, 1 .86 mmol) was added in a dropwise manner. The RM allowed to gradually warm to RT and stirred overnight. The RM was concentrated under reduced pressure and purified over silica gel (40 g; eluent: 0 to 9% EtOAc in heptane) to provide racemic tert-butyl 4-(((5S*,6R*)-5-(4-(methoxycarbonyl)phenyl)spiro[2.5]octan-6-yl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate as a white foam (195 mg). LC-MS Method B-2: Rt = 9.29 min; MS m / z [M-H]- = 502.2.

[0762] Intermediate M-38: tert-butyl 4-(((3R,4R)-1 -(tert-butoxycarbonyl)-3-(4-

[0763] (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-fluoro-7-methyl-1H-indole-1 -carboxylate tert-Butyl (3 / ?, 4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate

[0764] (Intermediate A-3, 103.7 mg, 0.29 mmol), tert-butyl 4-hydroxy-5-fluoro-7-methyl-1 / - / -indole-1 - carboxylate (Intermediate I-5, 77.9 mg, 0.26 mmol), and PPh3(173.3 mg, 0.66 mmol) were dissolved in THF (2 mL). DIAD (0.13 mL, 0.66 mmol) was added in a dropwise manner, and the RM was stirred overnight at RT. Additional tert-butyl (3R,4S)-4-hydroxy-3-(4-

[0765] (methoxycarbonyl)phenyl)piperidine-1 -carboxylate (Intermediate A-3, 44.3 mg, 0.13 mmol), PPh3(69.3 mg, 0.26 mmol), and DIAD (51 pL, 0.26 mmol) were added sequentially, and the RM was stirred at RT for 3 h. The mixture was diluted with EtOAc and washed with H2O. The aq phase was extracted with EtOAc (2x). The combined org phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure. Column chromatography over silica gel (eluent: 0 to 40% EtOAc in cyclohexane) provided enriched tert- butyl 4-(((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5- fluoro-7-methyl-1 / - / -indole-1 -carboxylate as an orange oil (145 mg). LC-MS Method B-1 : Rt = 1 .68 min; MS m / z [M+Na]+= 605.2.

[0766] Intermediate rac-M-39: racemic tert-butyl 5-cyclopropyl-4-(((1R* 2S*)-4,4-difluoro-2-(4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1 -carboxylate

[0767] Intermediate rac-M-39 was prepared as described in Step 1a for Intermediate M-34 using racemic methyl 4-((1 S*,2S*)-5,5-difluoro-2-hydroxycyclohexyl)benzoate (Intermediate rac-A-28, 87 mg, 0.32 mmol) and tert-butyl 4-hydroxy-5-cyclopropyl-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-3, 101.7 mg, 0.35 mmol) to provide racemic tert-butyl 5-cyclopropyl-4- (((1R*,2S*)-4,4-difluoro-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 / - / -indole-1 - carboxylate as a light yellow powder (35.4 mg). LC-MS Method B-1 : Rt = 1.71 min; MS m / z [M+H]+= 540.5.

[0768] Intermediate M-42: tert-butyl 4-(((3R,4 / ?)-1-(tert-butoxycarbonyl)-3-(4-

[0769] (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-chloro-5-methyl-1H-indole-1 -carboxylate tert-Butyl (3 / ?, 4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate

[0770] (Intermediate A-3, 261.9 mg, 0.78 mmol), PPh3(279.3 mg, 1 .07 mmol), and tert-butyl 7-chloro- 4-hydroxy-5-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-7, 200 mg, 0.91 mmol) were combined in toluene (5 mL). The mixture was cooled to 0 °C. A soln of DBAD (245.2 mg, 1 .07 mmol) in toluene (1 mL) was added to the cooled soln in a dropwise manner over 10 min. The RM was allowed to gradually warm to RT and stirred overnight. The RM was diluted with H2O, and the mixture was extracted with EtOAc (3x). The combined org phases were dried over MgSO4and concentrated under reduced pressure. Column chromatography over silica gel (eluent: 0 to 50% EtOAc in heptane) provided tert-butyl 4-(((3R,4 / ?)-1-(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-chloro-5-methyl-1 H-'\ ndo le- 1 -carboxylate as a white solid (129.3 mg). LC-MS Method C-2: Rt = 1.52 min; MS m / z [M+H]+= 599.2.

[0771] Intermediate M-43: tert-butyl 5-bromo-4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1 -carboxylate tert-Butyl (3 / ?, 4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate

[0772] (Intermediate A-3, 501.1 mg, 1.49 mmol), PPh3(534.3 mg, 2.03 mmol), and tert-butyl 5-bromo- 4-hydroxy-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-8, 443.0 mg, 1.36 mmol) were combined in THF (5 mL). The mixture was cooled to 0 °C. A soln of DBAD (469.1 mg, 2.04 mmol) in toluene (5 mL) was added to the cooled soln in a dropwise manner over 10 min. The RM was allowed to gradually warm to RT and stirred overnight. The RM was concentrated, and column chromatography over silica gel (eluent: 0 to 50% EtOAc in heptane) provided enriched tert-butyl 4-(((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-chloro-5- methyl-1 / - / -indole-1 -carboxylate as a white solid (813 mg). LC-MS Method C-1 : Rt = 1 .57 min; MS m / z [M+H]+= 645.8. Intermediate rac-M-44: racemic tert-butyl 5-cyclopropyl-4-(((7S*,8R*)-7-(4- (methoxycarbonyl)phenyl)-1 ,4-dioxaspiro[4.5]decan-8-yl)oxy)-7-methyl-1 H-indole-1 - carboxylate

[0773] Racemic methyl 4-((7S*,8S*)-8-hydroxy-1 ,4-dioxaspiro[4.5]decan-7-yl)benzoate (Intermediate rac-A-31 , 960 mg, 3.28 mmol) and tert-butyl 4-hydroxy-5-cyclopropyl-7-methyl-1 H-indole-1 - carboxylate (Intermediate I-3, 1 .04 g, 4.93 mmol) were dissolved in toluene (8 mL). PPh3(1 .03 g, 3.94 mmol) was added, and then DIAD (0.96 mL, 4.93 mmol) was added in a dropwise manner. The RM was stirred overnight at RT. The RM was diluted with DCM and H2O and filtered through an Isolute® phase separator. The filtrate was concentrated under reduced pressure. Column chromatography over silica gel (120 g; eluent: 0 to 30% EtOAc in cyclohexane) provided enriched material which was purified by preparatory HPLC (Waters XBridge C18 50 x 100 mm, 5 pm; eluent: 30 to 100% ACN in H2O with 0.2% FA) to provide racemic tert-butyl 5-cyclopropyl-4- (((7S*,8R*)-7-(4-(methoxycarbonyl)phenyl)-1 ,4-dioxaspiro[4.5]decan-8-yl)oxy)-7-methyl-1 / 7- indole-1 -carboxylate as a light orange powder (570 mg). LC-MS Method B-1 : Rt = 1 .65 min; MS m / z [M+H]+= 562.3.

[0774] Intermediate rac-B-1 : tert-butyl 4-(((3R,4 / ?)-3-(4-(methoxycarbonyl)phenyl)-1- methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate Racemic tert- butyl 4-(((3R*,4 / ?*)-1-(fert-butoxycarbonyl)-3-(4-

[0775] (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate M-1 , 72 mg, 0.12 mmol) was dissolved in MeOH (1.5 mL), and HCI soln (4M in dioxane, 1 mL, 4.0 mmol) was added. The RM was stirred at RT for 20 min and concentrated under reduced pressure. The residue was diluted with sat. aq NaHCO3soln and extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. Step 1 b: The residue was dissolved in MeOH (1 mL). Aq formaldehyde soln (37 wt%, 1 mL, 13.4 mmol) and Na(OAc)3BH (79.7 mg, 0.37 mmol) were added. The RM was stirred at RT for 20 min. The RM was partitioned between DCM and sat. aq NaHCO3soln. The aq phase was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (12 g; eluent: 0 to 100% 3:1 EtOAc / EtOH with 2% NH4OH in heptane) to provide racemic tert-butyl 5,7-dimethyl-4-

[0776] (((3R*,4R*)-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-1 / 7-i ndo le- 1 -carboxylate as a colorless oil (42 mg). LC-MS Method C-2: Rt = 1 .42 min; MS m / z [M+H]+= 493.3.

[0777] Intermediate rac-B-2: racemic tert-butyl 4-(((3R*,4R)-3-(4-(methoxycarbonyl)phenyl)-1- (2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0778] Step 1 a: Racemic fert-butyl 4-(((3R,4 / ?)-1 -(tert-butoxycarbonyl)-3-(4-

[0779] (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate

[0780] (Intermediate rac-M-1 , 42 mg, 73 pmol) was dissolved in MeOH (1.5 mL), and HCI soln (4M in dioxane, 1 mL, 4.0 mmol) was added. The RM was stirred at RT for 50 min and concentrated under reduced pressure. The residue was partitioned between DCM and sat. aq NaHC03soln. The aq phase was extracted with DCM (2x). The combined org phases were dried though an Isolute® phase separator and concentrated under reduced pressure.

[0781] Step 1 b: The residue was dissolved in ACN (1.5 mL). NEt3(30 pL, 0.22 mmol) and 2,2,2- trifluoroethyl trifluoromethanesulfonate (15.68 pL, 0.11 mmol) were added sequentially, and the RM was stirred at RT overnight. Sat. aq NaHCO3soln was added, and the mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (4 g; eluent: 0 to 100% 3:1 EtOAc / EtOH in heptane) to provide racemic tert-butyl 4-(((3R*,4 / ?)-3-(4- (methoxycarbonyl)phenyl)-1 -(2, 2, 2-trifluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 - carboxylate as a colorless oil (31 mg). LC-MS Method C-1 : Rt = 1 .49 min; MS m / z [M+H]+= 561 .1 Intermediate B-3: tert-butyl 4-(((3R,4 / ?)-1-ethyl-3-(4-(methoxycarbonyl)phenyl)piperidin-4- yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate nriched tert-buty I 4-(((3R,4R)-1-(te / Y-butoxycarbonyl)-3-(4-

[0782] (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate

[0783] (Intermediate M-5, 54 mg) was dissolved in MeOH (1 .5 mL), and HCI soln (4M in dioxane, 0.5 mL, 2.0 mmol) was added. The RM was stirred at RT for 2 h and then concentrated under reduced pressure. The residue was partitioned between DCM and sat. aq NaHCC3soln. The aq phase was extracted with DCM (2x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.

[0784] Step 1 b: The residue was dissolved in DCM (1 mL), and acetaldehyde (10 pL, 0.19 mmol) was added followed by Na(OAc)3BH (30 mg, 0.14 mmol). The RM was stirred at RT overnight. The RM was neutralized with sat. aq NaHCO3soln, and the mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (4 g; eluent: 0 to 100% 3:1 EtOAc:EtOH mixture in heptane with 2% NH4OH) to provide tert-butyl 4-(((3R,4 / ?)-1-ethyl-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (47 mg). LC- MS Method C-1 : Rt = 1 .08 min; MS m / z [M+H]+= 507.2.

[0785] Intermediate B-4: tert-butyl 5, 7-dimethyl-4-(((3R,4 / ?)-3-(1 -methyl-1 H-pyrazol-4-yl)piperidin- 4-yl)oxy)-1 H-indole-1 -carboxylate

[0786] Enriched fert-Buty I 5,7-dimethyl-4-(((3R,4 / ?)-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-1 H- indole-1 -carboxylate (Intermediate M-11 , 86 mg) was dissolved in MeOH (2 mL) and Pd / C (10 wt% Pd, 41 mg, 39 pmol) was added. The flask was purged with H2(3x) and then stirred at RT under H2atmosphere (balloon) for 1 h. The RM was filtered to remove solids. The solids were washed with MeOH, and the combined filtrates were concentrated under reduced pressure to provide tert-buty I 5,7-dimethyl-4-(((3R,4 / ?)-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-1 H- indole-1 -carboxylate (65 mg) which was directly used without further purification. LC-MS Method C-1 : Rt = 0.87 min; MS m / z [M+H]+= 425.1 .

[0787] The following examples were synthesized from the appropriate starting materials by applying similar methods described in the examples above.

[0788] Intermediate B-12: tert-butyl 4-(((3R,4 / ?)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)- 5,7-dimethyl-1 H-indole-1 -carboxylate

[0789] Step 1 a: tert-Butyl (3 / ?,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate

[0790] (Intermediate A-3, 353.0 mg, 1 .05 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 - carboxylate (Intermediate 1-1 , 250.0 mg, 0.96 mmol), and PPhs (376.4 mg, 1.43 mmol) were dissolved in THF (3 mL). The mixture was cooled to 0 °C. A DBAD (330.4 mg, 0.51 mmol) soln in toluene (0.5 mL) was added to the cooled soln in a dropwise manner over 10 min. The RM was allowed to gradually warm to RT and stirred overnight. The mixture was diluted with H2O and extracted with EtOAc (3x). The combined org phases were washed with water, dried over Mg2SO4, and concentrated under reduced pressure. Column chromatography over silica get (eluent: 0 to 50% EtOAc in heptane) provided enriched tert-butyl 4-(((3R,4R)-1 -(tert- butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1- carboxylate (306 mg).

[0791] Step 1 b: The material was dissolved in MeOH (2 mL). HCI soln (4M in dioxane, 0.59 mL, 2.35 mmol) was added, and the RM was stirred for 3.5 h. The pH was adjusted to 6 with NaOH, and the mixture was partitioned between EtOAc and H2O. The aq phase was extracted with EtOAc (2x). The combined org phases were dried over Mg2SO4and concentrated under reduced pressure. The residue was purified over silica gel (eluent: 0 to 30% MeOH in DCM) to provide tert-butyl 4-(((3 / ?,4 / ?)-3-(4-(methoxycarbonyl)phenyl)pipendin-4-yl)oxy)-5,7-dimethyl-1 / 7-indole- 1-carboxylate (108.3 mg). LC-MS Method C-2: Rt = 1.31 min; MS m / z [M+H]+= 479.4.

[0792] Intermediate B-13: methyl 4-((3R,4R)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1 H-indol-4- yl)oxy)piperidin-3-yl)benzoate

[0793] Step 1 : racemic tert-butyl 4-(((3R*,4R*)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)- 5,7-dimethyl-1H-indole-1 -carboxylate (Intermediate rac-B-13-1 )

[0794] Racemic tert-butyl (3 / ?*, 4S*)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate (Intermediate rac-A-1 , 983.1 mg, 1.84 mmol), PPh3(722.7 mg, 2.76 mmol) and tert-butyl 4- hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 500 mg, 1.84 mmol) were dissolved in THF (15 mL), and the mixture was cooled to 0 °C. DIAD (0.55 mL, 2.76 mmol) was added in a dropwise manner. The RM was allowed to warm to RT and stirred overnight. Additional PPh3(481 .2 mg, 1 .84 mmol) and DIAD (0.55 mL, 2.76 mmol) were added, and the RM was stirred at RT for 5h. The RM was diluted with EtOAc, and the mixture was washed with H2O and brine. The org phase was dried through an Isolute® phase separator and concentrated under reduced pressure. Column chromatography over silica gel (80 g; eluent: 0 to 30% EtOAc in cyclohexane) provided enriched racemic tert-butyl 4-(((3R*,4 / ?*)-1-(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate. The material (1 .24 g) was dissolved in MeOH (3 mL), and the soln was cooled to 0 °C. HCI soln (4M in dioxane, 3.12 mL, 12.5 mmol) was added, and RM was stirred for 1.5 h. The RM was quenched with sat. aq NaHCO3 soln, and the mixture was extracted with DCM (2x). The combined org phases were dried through and Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (40 g; eluent: 0 to 20% MeOH in DCM) to provide racemic tert- butyl 4-(((3R*,4 / ?*)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 - carboxylate as a brown foam (236.6 mg). LC-MS Method B-1 : Rt = 1 .26 min; MS m / z [M+H]+=

[0795] 479.4.

[0796] Step 2: methyl 4-((3 / ?,4 / ?)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4- yl)oxy)piperidin-3-yl)benzoate (Intermediate B-13)

[0797] Step 2a: Racemic te / Y-butyl 4-(((3 / ?*,4 / ?^-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac-B-13-1 , 130 mg, 0.24 mmol) and 3-bromo- 1 ,1-difluoropropane (42.8 mg, 0.27 mmol) were combined in ACN (2 mL), and DIPEA (0.15 mL, 0.86 mmol) was added. The RM was stirred at 50 °C for 5 h. The RM was allowed to cool to RT, diluted with EtOAc, and the mixture was washed with H2O. The aq phase was extracted with EtOAc (2x). The combined org phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure.

[0798] Step 2b: The residue was dissolved in MeOH (2 mL), and HCI soln (4M in dioxane, 1 .22 mL, 4.89 mmoL) was added. The RM was stirred at RT overnight. The RM was diluted with DCM and neutralized with sat. aq NaHCO3soln. The phases were separated and the aq phase was extracted with DCM (2x). The combined org phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure. The residue was purified over silica gel (12 g; eluent: 0 to 100% EtOAc in cyclohexane) to provide racemic methyl 4- ((3R*,4R*)-1 -(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoate as a colorless oil (59.1 mg). LC-MS Method B-1 : Rt = 0.77 min; MS m / z [M+H]+= 457.4.

[0799] Step 2c: Chiral separation and analytics according to Method SFC-21 : 59.1 mg provided Intermediate B-13 (peak 2): 19.8 mg, white solid. LC-MS Method B-1 : Rt = 0.75 min; MS m / z [M+H]+= 457.3. Analytical chiral HPLC: Rt = 1.92 min; 99.9% ee.

[0800] Intermediate B-14: methyl 4-((3R,4 / ?)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)benzoate

[0801] Step 1 a: Racemic tert-buty I 4-(((3R,4R)-1 -(terf-butoxycarbonyl)-3-(4-

[0802] (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate

[0803] (Intermediate rac-B-13-1 , 130 mg, 0.24 mmol) and 1 ,1 ,1-trifluoro-3-iodopropane (60.2 mg, 0.27 mmol) were combined in ACN (2 mL), and DIPEA (0.15 mL, 0.86 mmol) was added. The RM was stirred at 50 °C overnight. An additional portion of 1 ,1 ,1 -trifluoro-3-iodopropane (60.2 mg, 0.27 mmol) was added, and the RM was stirred at 50 °C for 2 h. The RM was allowed to cool to RT, diluted with EtOAc, and the mixture was washed with H2O. The aq phase was extracted with EtOAc (2x). The combined org phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure.

[0804] Step 1 b: The residue was dissolved in MeOH (2 mL), and HCI soln (4M in dioxane, 1 .22 mL, 4.89 mmoL) was added. The RM was stirred at RT overnight. The RM was diluted with DCM and neutralized with sat. aq NaHCO3soln. The phases were separated and the aq phase was extracted with DCM (2x). The combined org phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure. The residue was purified over silica gel (12 g; eluent: 0 to 60% EtOAc in cyclohexane) to provide racemic methyl 4- ((3R*,4R*)-4-((5,7-dimethyl-1 / - / -indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoate as a colorless oil (35.2 mg). LC-MS Method B-1 : Rt = 1.10 min; MS m / z [M+H]+= 475.2.

[0805] Step 1 c: Chiral separation and analytics according to Method SFC-22: 235.2 mg provided Intermediate B-14 (peak 2): 14.3 mg, white solid. LC-MS Method B-1 : Rt = 1 .09 min; MS m / z [M+H]+= 475.3. Analytical chiral HPLC: Rt = 1.30 min; 99.9% ee.

[0806] Intermediate B-15: methyl 4-((3R,4R)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -(2-

[0807] (trifluoromethoxy)ethyl)piperidin-3-yl)benzoate

[0808] Racemic te / Y-butyl 4-(((3 / ?,4 / ?)-1-(te / Y-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin- 4-yl)oxy)-5,7-dimethyl-1 / 7-indole-1 -carboxylate (Intermediate rac-B-13-1 , 92.7 mg, 0.15 mmol) and 2-bromoethyl trifluoromethyl ether (31 pL, 0.27 mmol) were combined in ACN (1 .5 mL), and NEt3(62 pL, 0.86 mmol) was added. The RM was stirred at 50 °C for 3 days. The RM was allowed to cool to RT and concentrated under reduced pressure.

[0809] Step 1 b: The residue was dissolved in MeOH (1.5 mL), and HCI soln (4M in dioxane, 0.45 mL, 1.80 mmoL) was added. The RM was stirred at RT overnight. The RM was diluted with DCM and neutralized with sat. aq NaHCO3soln. The phases were separated and the aq phase was extracted with DCM (2x). The combined org phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure. The residue was purified over silica gel (24 g; eluent: 0 to 100% EtOAc in cyclohexane) to provide racemic methyl 4- ((3 / ?*,4 / ?^-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3- yl)benzoate as an orange oil (26.6 mg). LC-MS Method B-1 : Rt = 1.11 min; MS m / z [M+H]+=

[0810] 491.3. Step 1c: Chiral separation and analytics according to Method SFC-23: 26.6 mg provided Intermediate B-15 (peak 2): 9.9 mg, colorless oil. LC-MS Method B-1 : Rt = 1.12 min; MS m / z [M+H]+= 491 .3. Analytical chiral HPLC: Rt = 1 .24 min; 99.5% ee.

[0811] Intermediate rac-B-16: racemic tert-butyl 5-cyclopropyl-4-(((1R*,2S*4S*)-4-hydroxy-2-(4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1 -carboxylate

[0812] Racemic tert-butyl 4-(((1 R*,2S*,4S*)-4-((tert-butyldimethylsilyl)oxy)-2-(4-

[0813] (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5-cyclopropyl-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate rac-M-34, 910 mg, 1.44 mmol) was dissolved in MeOH (15 mL), and HCI soln (4M in dioxane, 3.59 mL, 14.36 mmol) was added. The RM was stirred at RT for 1 h. The RM was quenched with sat. aq NaHCO3soln, and the mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (120 g; eluent: 0 to 30% EtOAc in cyclohexane) to provide racemic tert-butyl 5-cyclopropyl-4-(((1 R*,2S*,4S*)-4-hydroxy-2-(4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate as a white foam (641 mg). LC-MS Method B-1 : Rt = 1 .51 min; MS m / z [M-Boc+2H]+= 420.3.

[0814] The following examples were synthesized from the appropriate starting materials by applying similar methods described in the examples above.

[0815] Intermediate rac-B-32: racemic 4-((1S*,2 / ?* 5S*)-2-((5-cyclopropyl-7-methyl-1 H-indol-4- yl)oxy)-5-hydroxycyclohexyl)benzoic acid Racemic te / Y-butyl 5-cyclopropyl-4-(((1 R*,2S*,4S*)-4-hydroxy-2-(4-

[0816] (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 H-'\ ndo le- 1 -carboxylate (Intermediate rac- B-16, 43 mg, 83 pmol) was dissolved in THF (1 mL) and MeOH (0.5 mL). Aq NaOH soln (1 M, 0.41 mL, 0.41 mmol) was added, and the RM was stirred at 50 °C for 18 h. The RM allowed to cool to RT, quenched with FA (31 pL, 0.82 mmol), and diluted with ACN. The mixture was purified by preparatory HPLC (Waters XBridge C18 30 x 100 mm, 5 pm; eluent: 15 to 100% ACN in H2O with 0.2% FA) to provide racemic 4-((1 S*,2R*,5S*)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)- 5-hydroxycyclohexyl)benzoic acid as a white solid (25.7 mg). LC-MS Method B-1 : Rt = 0.93 min; MS m / z [M+H]+= 406.2.

[0817] Intermediate B-33: methyl 4-((5S,6R)-6-((5,7-dimethyl-1 H-indol-4-yl)oxy)spiro[2.5]octan-5- yl)benzoate

[0818] Step 1a: racemic tert-buty 14-(((5S*,6R*)-5-(4-(methoxycarbonyl)phenyl)spiro[2.5]octan-6-yl)oxy)- 5, 7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac-M-35, 221 mg, 0.44 mmol) was dissolved in DCM (6 mL), and TFA (2 mL) was added. The RM was stirred at RT for 40 min. The RM was poured into a mixture of 10 wt% aq Na2CO3and MBTE. The phases were separated, and the aq phase was extracted with MBTE. The org phase was washed with brine. The combined org phases were dried over MgSO4and concentrated under reduced pressure. The residue was purified using preparatory HPLC (Waters XBridge C18 50 x 100 mm; 5 pm; eluent: 40 to 90% ACN in H2O with 0.1 % NH4OH) to provide racemic methyl 4-((5S*,6R*)-6-((5,7- dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)benzoate as a white foam (65.5 mg).

[0819] Step 1 b: Chiral separation and analytics according to Method SFC-25: 65 mg provided Intermediate B-33 (peak 2): 30.3 mg, white solid. LC-MS Method B-1 : Rt = 1.54 min; MS m / z [M+H]+= 404.3. Analytical chiral HPLC: Rt = 1.44 min; 99.5% ee.

[0820] Intermediate B-37: tert-butyl 5-cyclopropyl-4-(((3R,4 / ?)-1-(2,2-difluoroethyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1 -carboxylate tert-Butyl 5-bromo-4-(((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4- yl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate B-36, 23.2 mg, 38 pmol) was combined with cyclopropyl boronic acid (3.9 mg, 46 pmol), tricyclohexylphosphine (1.1 mg, 4 pmol), and Pd2dba3(2.1 mg, 2 pmol). The vial was purged with N2, and toluene (0.3 mL) and H2O (10 pL) were added. The RM was stirred at 100 °C overnight. The RM was concentrated under reducd pressure, and column chromatography over silica gel (12 g; eluent 0 to 100% EtOAc in heptane) provided enriched tert-butyl 5-cyclopropyl-4-(((3R,4 / ?)-1-(2,2-difluoroethyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate (16 mg). LC-MS Method C-1 : Rt = 1 .37 min; MS m / z [M+H]+= 569.5. Intermediate rac-B-40: racemic tert-butyl 5-cyclopropyl-4-(((1R*,2S*)-2-(4-

[0821] (methoxycarbonyl)phenyl)-4-oxocyclohexyl)oxy)-7-methyl-1H-indole-1 -carboxylate

[0822] Racemic tert-butyl 5-cyclopropyl-4-(((7S*,8 / ?*)-7-(4-(methoxycarbonyl)phenyl)-1 ,4- dioxaspiro[4.5]decan-8-yl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate (492.0 mg, 0.88 mmol) was dissolved in acetone (20 mL), and Amberlyst® 15 (2.75 g, 8.76 mmol) was added. The RM was stirred at RT for 4 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparatory HPLC (Waters XBridge C18 OBD 50 x 100 mm; 5 pm; eluent: 40 to 100% ACN in H2O with 0.2% FA) to provide racemic tert-butyl 5- cyclopropyl-4-(((1 / ?*,2S*)-2-(4-(methoxycarbonyl)phenyl)-4-oxocyclohexyl)oxy)-7-methyl-1 / - / - indole-1 -carboxylate (131 mg). LC-MS Method B-1 : Rt = 1 .59 min; MS m / z [M-Boc+2H]+= 418.1 .

[0823] Intermediate rac-B-41 and Intermediate rac-B-42: racemic tert-butyl 5-cyclopropyl-4- (((1R*,2S*,4S*)-4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-methylcyclohexyl)oxy)-7- methyl-1H-indole-1 -carboxylate and tert-butyl 5-cyclopropyl-4-(((1R*,2S*4 / ?*)-4-hydroxy-2- (4-(methoxycarbonyl)phenyl)-4-methylcyclohexyl)oxy)-7-methyl-1H-indole-1 -carboxylate

[0824] Racemic tert-buty I 5-cyclopropyl-4-(((1 / ?*,2S*)-2-(4-(methoxycarbonyl)phenyl)-4- oxocyclohexyl)oxy)-7-methyl-1 / 7-indole-1 -carboxylate (Intermediate rac-B-40, 41.3 mg, 80 pmol) was dissoved in THF (1 mL) and cooled to 0 °C. A methyl magnesium bromide soln (3.4M in THF, 28 pL, 96 pmol) was added, and the RM was stirred for 30 min. The RM was quenched with sat aq NH4CI soln and allowed to warm to RT. The mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. Column chromatography over silica gel (12 g; eluent: 0 to 20% EtOAc in cyclohexane) provided racemic tert-butyl 5-cyclopropyl-4-(((1 R*,2S*,4S*)-4-hydroxy-2-(4- (methoxycarbonyl)phenyl)-4-methylcyclohexyl)oxy)-7-methyl-1 / -indole-1 -carboxylate (first peak eluting, 24.7 mg) and racemic te / Y-butyl 5-cyclopropyl-4-(((1 R*,2S*,4 / ?*)-4-hydroxy-2-(4- (methoxycarbonyl)phenyl)-4-methylcyclohexyl)oxy)-7-methyl-1 / 7- indol e- 1 -carboxylate (second peak eluting, 9.1 mg). Intermediate rac-B-41 LC-MS Method B-1 : Rt = 1 .59 min; MS m / z [M+H]+= 534.2. Intermediate rac-B-42 LC-MS Method B-1 : Rt = 1 .52 min; MS m / z [M+H]+= 534.3.

[0825] Intermediate rac-B-43: racemic 4-((1S*,2R*,5S*)-2-((5-cyclopropyl-7-methyl-1 H-indol-4- yl)oxy)-5-hydroxy-5-methylcyclohexyl)benzoic acid

[0826] Racemic tert-buty I 5-cyclopropyl-4-(((1 R*,2S*,4S*)-4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4- methylcyclohexyl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate rac-B-41 , 22.4 mg, 42 pmol) was dissolved in MeOH (0.5 mL) and THF (1 mL). Aq NaOH soln (1 M, 0.21 mL, 0.21 mmol) was added, and the RM was stirred at 50 °C for 18 h. The RM was quenched with FA (16 pL) and purified by preparatory HPLC (Waters XBridge C18 OBD 30 x 100 mm; 5 pm; eluent: 15 to 100% ACN in H2O with 0.2% FA) to provide racemic 4-((1 S*,2R*,5S*)-2-((5-cyclopropyl-7-methyl- 1 / 7-indol-4-yl)oxy)-5-hydroxy-5-methylcyclohexyl)benzoic acid as a white solid (12.5 mg). LC- MS Method B-1 : Rt = 0.99 min; MS m / z [M+H]+= 420.4.

[0827] Intermediate rac-B-44: racemic 4-((1S* 2R* 5 / ?*)-2-((5-cyclopropyl-7-methyl-1 H-indol-4- yl)oxy)-5-hydroxy-5-methylcyclohexyl)benzoic acid

[0828] Racemic tert-buty I 5-cyclopropyl-4-(((1 R*,2S*,4 / ?*)-4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4- methylcyclohexyl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate rac-B-42, 7.2 mg, 13 pmol) was dissolved in MeOH (0.25 mL) and THF (0.5 mL). Aq NaOH soln (1 M, 67 pL, 67 pmol) was added, and the RM was stirred at 50°C for 18 h. The RM was quenched with FA (5 pL) and purified by preparatory HPLC (Waters XBridge C18 OBD 30 x 100 mm; 5 pm; eluent: 15 to 100% ACN in H2O with 0.2% FA) to provide racemic 4-((1 S*, 2R*, 5R*)-2-((5-cyclopropyl-7-methyl-1 / - / - indol-4-yl)oxy)-5-hydroxy-5-methylcyclohexyl)benzoic acid as a white solid (12.5 mg). LC-MS Method B-1 : Rt = 0.99 min; MS m / z [M+H]+= 420.4. Example Ex-1 and Example Ex -2: 4-((3R,4 / ?)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 - methylpiperidin-3-yl)benzoic acid and 4-((3S,4S -4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 - methylpiperidin-3-yl)benzoic acid

[0829] Step 1 a: Racemic te / Y-butyl 4-(((3 / ?* 4 / ?*)-3-(4-(methoxycarbonyl)phenyl)-1-methylpiperidin-4- yl)oxy)-5,7-dimethyl-1 / 7-indole-1 -carboxylate (Intermediate rac-B-1 , 42 mg, 85 pmol) was dissolved in MeOH (2 mL), and K2CO3(50 mg, 0.36 mmol) was added. The RM was stirred at 45 °C overnight. Aq NaOH soln (1 M, 85 pL, 85 pmol) was added, and the RM was stirred at 60 °C for 90 min. Additional aq NaOH soln (1 M, 85 pL, 85 pmol) was added, and the RM was stirred at 60 °C for 2 h. The RM was allowed to cool to RT, concentrated under reduced pressure, and purified using preparatory HPLC (15.5 g C18 column; eluent: 15 to 20% ACN in H2O with 0.1 % NH4OH) to provide racemic 4-((3R*,4 / ?*)-4-((5,7-dimethyl-1 / - / -indol-4-yl)oxy)-1-methylpiperidin-3- yl)benzoic acid as a white solid (28.6 mg).

[0830] Step 1 b: Chiral separation and analytics according to Method SFC-6: 28.6 mg provided Example Ex-1 (peak 2): 10.1 mg, white solid. Analytical chiral HPLC: Rt = 2.64 min; 100% ee. Example Ex-2 (peak 1): 10.9 mg, white solid. Analytical chiral HPLC: Rt = 2.02 min; 95.9% ee.

[0831] Example Ex-3 and Example Ex-4: 4-((3R,4S)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 - methylpiperidin-3-yl)benzoic acid and 4-((3S,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1- methylpiperidin-3-yl)benzoic acid

[0832] Step 1 a: A vial was charged with racemic methyl 4-((3R*,4S*)-4-((5,7-dimethyl-1-tosyl-1 / - / -indol- 4-yl)oxy)-1-methylpiperidin-3-yl)benzoate (Intermediate rac-B-5, 38 mg, 70 pmol), EtOH (0.50 mL), and aq NaOH soln (4M, 0.52 mL 2.1 mmol). The vial was sealed, and the mixture was stirred at 85 °C overnight. The mixture was purified using RP chromatography (50 g C18 column; eluent: 5% to 60% ACN in H2O, each with 0.1 % NH4OH) to provide racemic 4-((3 / ?*,4S*)-4-((5,7- dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid as a white solid (21 mg).

[0833] Step 1 b: Chiral separation and analytics according to Method SFC-7: 21 mg provided Example Ex-3 (peak 1): 6.0 mg, white solid. Analytical chiral HPLC: Rt = 1 .86 min; 100% ee.

[0834] Example Ex-4 (peak 2): 2.2 mg, white solid. Analytical chiral HPLC: Rt = 2.08 min; 100% ee.

[0835] Example Ex-5: 4-((3R,4R)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin- 3-yl)benzoic acid te / Y-Butyl 5-cyclopropyl-4-(((3 / ?,4 / ?)-3-(4-(methoxycarbonyl)phenyl)-1 -methylpiperidin-4-yl)oxy)- 7-methyl-1 / - / -indole-1 -carboxylate (Intermediate B-6, 50 mg, 96 pmol) was dissolved in EtOH (0.5 mL), and aq NaOH soln (4M, 0.24 mL, 096 mmol) was added. The RM was stirred at RT overnight and then stirred at 50 °C for 2 h. The mixture was purified by RP chromatography (50 g C18 column; eluent: 5 to 50% ACN in H2O, each with 0.1 % NH4OH) to provide 4-((3R,4R)-4- ((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid as a white solid (22 mg). Example Ex-6: 4-((3R,4 / ?)-4-((5-chloro-7-methyl-1 H-indol-4-yl)oxy)-1 -methylpiperidin-3- yl)benzoic acid te / Y-Butyl 5-chloro-4-(((3 / ?,4 / ?)-3-(4-(methoxycarbonyl)phenyl)-1 -methylpiperidin-4-yl)oxy)-7- methyl-1 / - / -indole-1 -carboxylate (Intermediate B-7, 22 mg, 43 pmol) was dissolved in EtOH (0.3 mL), and aq NaOH soln (4M, 0.21 mL, 0.86 mmol) was added. The mixture was gently heated until a clear soln was formed, and the RM was stirred at RT overnight. The mixture was purified by RP chromatography (50 g C18 column; eluent: 5 to 50% ACN in H2O, each with 0.1 % NH4OH) to provide 4-((3R,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -methylpiperidin-3-yl)benzoic acid as a white solid (16.4 mg).

[0836] Example Ex-7 and Example Ex-8: 4-((3R,4 / ?)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3S,4S)-4-((5,7-dimethyl-1H-indol-4- yl)oxy)-1 -(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid

[0837] Step 1 a: Racemic te / Y-butyl 4-(((3 / ?*,4 / ?)-3-(4-(methoxycarbonyl)phenyl)-1 -(2,2,2- trifluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-'\ ndo le- 1 -carboxylate (Intermediate rac-B-2, 31 mg, 55 pmol) was dissolved in MeOH (2.5 mL), and K2CO3(35 mg, 0.25 mmol) was added. The RM was stirred at 65 °C for 2 h, and then at 75 °C for 75 min. Aq NaOH soln (1 M, 0.11 mL, 0.1 1 mmol) and H2O (0.3 mL) were added, and the RM was stirred at 60 °C for 2 h. The RM was allowed to cool to RT and stirred overnight. Additional aq NaOH soln (1 M, 0.2 mL, 0.2 mmol) was added, and the RM was stirred for 1 h at RT. The RM as concentrated under reduced pressure and purified using preparatory HPLC (15.5 g C18 column; eluent: 15 to 20% ACN in H2O with 0.1 % NH4OH) to provide racemic 4-((3 / ?*,4 / ?*)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid as a white solid (12 mg).

[0838] Step 1 b: Chiral and analytics according to Method SFC-8: 12 mg provided Example Ex-7 (peak

[0839] 1): 5.1 mg, white solid. Analytical chiral HPLC: Rt = 2.36 min; 100% ee. Example Ex-8 (peak

[0840] 2): 4.8 mg, white solid. . Analytical chiral HPLC: Rt = 2.83 min; 100% ee.

[0841] Example Ex -9: 4-((3R,4 / ?)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -ethylpiperidin-3-yl)benzoic acid te / Y-Butyl 4-(((3 / ?,4 / ?)-1 -ethyl-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole-1 -carboxylate (Intermediate B-3, 47 mg, 0.93 mmol) was dissolved in IPA (1.5 mL) and aq NaOH soln (1 M, 0.46 mL, 0.46 mmol) was added. The RM was stirred at 60 °C for 2 days. The RM was allowed to cool to RT, concentrated under reduced pressure, and purified by preparatory HPLC (Waters XBridge C18 OBD 30 x 50 mm; 5 pm; eluent: 5 to 20% ACN in H2O with 0.1 % NH4OH). Pure fractions were combined, and enriched fractions were repurified under the above conditions. Fractions were pooled and lyophilized to provide 4-((3R,4 / ?)-4-((5,7-dimethyl-1 / 7- indol-4-yl)oxy)-1 -ethylpiperidin-3-yl)benzoic acid as a white solid (5.3 mg).

[0842] Example Ex-10: 4-((4S,5R)-5-((5-cyclopropyl-7-methyl-1 H-indol-4-yl)oxy)-1-methylazepan- 4-yl)benzoic acid Step 1 a: te / Y-Butyl 4-(((4 / ?,5S)-1-(te / Y-butoxycarbonyl)-5-(4-(methoxycarbonyl)phenyl)azepan-4- yl)oxy)-5-cyclopropyl-7-methyl-1 / 7-indole-1 -carboxylate (Intermediate M-6, 7 mg, 1 1 pmol) was dissolved in MeOH (1 mL), and HCI soln (4M in dioxane, 1 mL, 4.0 mmol) was added. The RM was stirred at RT for 2 h and concentrated under reduced pressure. The residue was partitioned between DCM and sat. aq NaHCO3soln. The aq phase was extracted with DCM (2x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.

[0843] Step 1 b: The residue was dissolved in MeOH (1 mL). Aq formaldehyde solution (37 wt%, 0.5 mL, 6.7 mmol) and Na(OAc)3BH (15 mg, 71 mmol) were added. The RM was stirred at RT for 18 h. The RM was partitioned between DCM and sat. aq NaHCO3soln. The aq phase was extracted with DCM (2x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.

[0844] Step 1 c: The residue was dissolved in MeOH (3 mL), and aq NaOH soln (1 M, 150 pL, 150 pmol) was added. The RM was stirred at 70 °C for 6 h, allowed to cool to RT, and then stirred at RT for 3 days. Additional aq NaOH soln (1 M, 0.1 mL, 0.1 mmol) was added, and the RM was stirred at 65 °C for 2 h. The mixture was concentrated under reduced pressure and purified by preparatory HPLC (Waters XBridge C18 OBD 30 x 50 mm; 5 pm; eluent: 10 to 30% ACN in H2O with 0.1 % NH4OH) to provide 4-((4S,5 / ?)-5-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylazepan-4- yl)benzoic acid as a white solid (2.0 mg).

[0845] Example Ex-11 : 4-((3 / ?,4 / ?)-4-((5, 7-d imethy 1-1 H-indol-4-yl)oxy)-1 -methylazepan-3- yl)benzoic acid

[0846] Step 1 a: terf-Butyl 4-(((3R,4R)-1-(te / Y-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)azepan-4- yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate M-7, 45.7 mg, 77 pmol) was dissolved in MeOH (1 .5 mL), and HCI soln (4M in dioxane, 1 mL, 4.0 mmol) was added. The RM was stirred at RT for 2 h and concentrated under reduced pressure. The residue was partitioned between DCM and sat. aq NaHCO3soln. The aq phase was extracted with DCM (2x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.

[0847] Step 1 b: The residue was dissolved in MeOH (1 .5 mL). Aq formaldehyde (37 wt%, 0.5 mL, 6.7 mmol) and Na(OAc)3BH (50 mg, 0.23 mmol) were added. The RM was stirred at RT for 30 min. The RM was partitioned between DCM and sat. aq NaHCO3soln. The aq phase was extracted with DCM (2x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.

[0848] Step 1 c: The residue was dissolved in IPA (1 mL), and aq NaOH soln (1 M, 0.5 mL, 0.5 mmol) was added. The RM was stirred at 55 °C for 2 h and then stirred at 50 °C for 18 h. The RM was stirred at 70 °C for 2 h, and then additional aq NaOH soln (1 M, 0.15 mL, 0.15 mmol) was added. The RM was stirred at 65 °C for 6 h, allowed to cool to RT, concentrated under reduced pressure, and purified by preparatory HPLC (Waters XBridge C18 OBD 30 x 50 mm; 5 pm; eluent: 10 to 30% ACN in H2O with 0.1 % NH4OH) to provide 4-((3R,4R)-4-((5,7-dimethyl-1 / / -indol-4-yl)oxy)-1- methylazepan-3-yl)benzoic acid as a white solid (5.3 mg).

[0849] Example Ex-12: racemic 5,7-dimethyl-4-(((3S* 4R*)-4-phenyl-1 -(2,2,2- trifluoroethyl)pyrrolidin-3-yl)oxy)-1 H-indole

[0850] Racemic te / Y-butyl 5,7-dimethyl-4-(((3S*,4R*)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)oxy)- 1 / - / -indole-1 -carboxylate (Intermediate rac-B-8, 71 mg, 0.15 mmol) was dissolved in MeOH (2 mL). THF (0.5 mL) and aq NaOH soln (1 M, 0.6 mL, 0.6 mmol) was added. The RM was stirred at 60 °C for 3 h, allowed to cool to RT, and then stirred at RT overnight. The mixture was extracted with DCM (3x). The combined org layers were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by preparatory HPLC (Waters XBridge C18 OBD 30 x 50 mm; 5 pm; eluent: 10 to 30% ACN in H2O with 0.1 % NH4OH) to provide racemic 5,7-dimethyl-4-(((3S*,4R*)-4-phenyl-1 -(2,2,2-trifluoroethyl)pyrrolidin-3-yl)oxy)-1 / - / -indole as a white solid (8.1 mg).

[0851] Example Ex-13: 4-((3R,4 / ?)-4-((5,7-dimethyl-1 / / -indol-4-yl)oxy)-1-methylpiperidin-3- yl)benzonitrile

[0852] Step 1 a: te / Y-Butyl 4-(((3R,4R)-1-(te / Y-butoxycarbonyl)-3-(4-cyanophenyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate (Intermediate M-9, 77 mg, 0.14 mmol) was dissolved in MeOH (2.5 mL), and HCI soln (4M in dioxane, 0.2 mL, 0.8 mmol) was added. The RM was stirred at RT for 90 min and concentrated under reduced pressure. The residue was partitioned between DCM and sat. aq NaHC03soln. The aq phase was extracted with DCM (2x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.

[0853] Step 1 b: The residue was dissolved in MeOH (2.5 mL). Aq formaldehyde soln (37 wt%, 1 mL, 13 mmol) and Na(OAc)3BH (92 mg, 0.43 mmol) were added. The RM was stirred at RT for 1 h. The RM was partitioned between DCM and sat. aq NaHCO3soln. The aq phase was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (4 g; eluent: 0 to 100% 3:1 EtOAc / EtOH in heptane with 2% NH4OH).

[0854] Step 1 c: The material was dissolved in MeOH (4 mL), and K2CO3(78 mg, 0.56 mmol) was added. The RM was stirred at 60 °C for 1 h, allowed to cool to RT, and then stirred at RT for 3 days. The RM was partitioned between sat. aq NaHCO3soln and DCM. The aq phase was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by preparatory HPLC (Waters XBridge C18 OBD 30 x 50 mm; 5 pm; eluent: 35 to 60% ACN in H2O with 0.1 % FA) to provide 4- ((3R,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -methylpiperidin-3-yl)benzonitrile as a white solid (18 mg).

[0855] Example Ex-14: 4-(((3R,4R)-3-(4-(1 H-tetrazol-5-yl)phenyl)-1 -methylpiperidin-4-yl)oxy)-5,7- dimethyl-1 / / -indole tert-Butyl 4-(((3 / ?,4 / ?)-3-(4-cyanophenyl)-1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 / 7-indole-1- carboxylate (Intermediate B-9, 27.7 mg, 60.3 pmol), NH4CI (14 mg, 0.26 mmol) and sodium azide (20 mg, 0.31 pmol) were charged in a vial, and then DMF (0.5 mL) was added. The RM was stirred at 100 °C for 24 h. Additional NH4CI (5.1 mg, 95 pmol) and sodium azide (21 mg, 323 pmol) were added, and the RM was stirred at 100 °C for 24 h. To the RM was added MeOH (0.5 mL) followed by aq NaOH soln (1 M, 0.3 mL, 0.30 mmol). The RM was stirred at 70 °C for 5 h and then at 60 °C for 18 h. The mixture was allowed to cool to RT, concentrated under reduced pressure, and purified by preparatory HPLC (Column: Waters XBridge C18 OBD 30 x 50 mm; 5 pm; eluent: 5 to 20% ACN in H2O with 0.1 % NH4OH) to provide the 4-(((3R,4 / ?)-3-(4-(1 / 7-tetrazol- 5-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole as an off-white solid (6.0 mg).

[0856] Example Ex-15: 2-(4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3- yl)phenyl)propan-2-ol

[0857] Step 1 a: te / Y-Butyl 4-(((3 / ?,4 / ?)-3-(4-(methoxycarbonyl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate (Intermediate B-10, 43 mg, 87 pmol) was dissolved in THF (1.0 mL), and methylmagnesium bromide soln (1 .4M in THF / toluene, 0.25 mL, 0.35 mmol) was added. The RM was stirred at RT for 80 min. Additional methylmagnesium bromide soln (0.50 mL, 0.70 mmol) was added, and the RM was stirred at RT for 2 h. A third portion of methylmagnesium bromide soln (0.75 mL, 1 .1 mmol) was added, and the RM was stirred at RT for 1 h. A final portion of methylmagnesium bromide soln (0.25 mL, 0.35 mmol) was added, and the RM was stirred at RT for 30 min. The RM was quenched with sat. aq NH4CI soln. The separated aq phase was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.

[0858] Step 1 b: The residue was dissolved in MeOH (2 mL), and K2CO3(90 mg, 0.65 mmol) was added. The RM was stirred at 65 °C for 90 min, allowed to cool to RT, and then stirred at RT overnight. The RM was diluted with H2O, and the separated aq phase was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by preparatory HPLC (Waters XBridge C18 OBD 30 x 50 mm; 5 pm; eluent: 35 to 60% ACN in H2O with 0.1 % NH4OH) to provide 2-(4-((3R,4R)-4- ((5,7...

Claims

Claims1. A compound of Formula (I)or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:W is O, C(R6)2, or NR7;R is hydrogen, halogen, Ci-C4alkyl, haloCi-C4alkyl, or hydroxyCi-C4alkyl;R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloC3-C6cycloalkyl, haloCi-C6alkoxy, hydroxyCi-C6alkyl, hydroxyC3- C6cycloalkyl, aminoCi-C6alkyl, Ci-C6alkoxyCi-C6alkyl, Ci-C6alkoxyCi-C6alkoxy, or C3- C6cycloalkylCi-C6alkoxy;R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Ci-C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;R3is hydrogen, halogen, or cyano;R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;R5is selected from hydrogen, -CO2R5b, Ci-Cealkyl, hydroxyCs-Cecycloalkyl, Ci- C6alkoxyCi-C6alkyl, -CH2CO2R5b, -C(O)NHSO2Ci-C4alkyl, -SO2NHC(O)Ci-C4alkyl, -SO2Ci- C4alkyl, cyano, hydroxy, halogen, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-C6alkyl that is unsubstituted or substituted with -CO2H; each R5bis independently selected from hydrogen and Ci-C5alkyl; each R6is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, C3-C6cycloalkylCi-C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci- C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3- C6cycloalkoxy, haloC3-C6cycloalkoxy, and 4- to 6-membered heterocyclyl having 1-2 heteroatomsindependently selected from N and O, and wherein the Ci-C6alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C6alkyl, and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N, O, and S(O)q, wherein the spirocyclic heterocycle is unsubstituted or substituted with 1 or 2 halogen, Ci-Cealkyl, haloCi- C6alkyl, C3-C6cycloalkyl, or haloC3-C6cycloalkyl; q is 0, 1 , or 2;R7is hydrogen, Ci-Cealkyl, haloCi-Cealkyl, hydroxyC2-Cealkyl, Cs-Cecycloalkyl, C3- C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkyl, Ci-C6alkoxyCi- C6alkyl, haloCi-C6alkoxyCi-C6alkyl, -COR7a, aryl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O)q, or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein Ci-C6alkyl is unsubstituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O)q, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen, further wherein the aryl or heteroaryl is unsubstituted or substituted with halo, Ci-C6alkyl, haloCi-C6alkyl, C3-C5cycloalkyl, haloC3-C5cycloalkyl; R7ais hydrogen or Ci-C6alkyl; each R8is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Cr Cealkoxy, and haloCi-Cealkoxy;R9is H, D, or T; m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3; provided that both m and n are not 0; and p is 0, 1 , 2, or 3.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:W is C(R6)2, or NR7; R is hydrogen;R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6alkoxy, or haloCr C6alkyl;R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen;R3is hydrogen;R4is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R5;R5is selected from hydrogen, -CO2R5b, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, -CH2CO2R5b, cyano, hydroxy, halogen, -C(O)N(R5b)2and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N and O, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R5a; each R5ais independently selected from fluoro, hydroxyl, and Ci-C6alkyl that is unsubstituted or substituted with -CO2H;R5bis selected from hydrogen and Ci-Csalkyl; each R6is independently selected from hydrogen, halogen, hydroxy, C3-C6cycloalkylCi- C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCr Cealkyl, Ci-Cealkoxy, haloCi-Cealkoxy, Cs-Cecycloalkoxy, haloCs-Cecycloalkoxy, and 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, and wherein the Ci-C6alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C6alkyl, and Ci-C6alkoxy; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O, wherein the spirocyclic heterocycle is unsubstituted;R7is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, haloC3-C6cycloalkylCi- C3alkyl, haloCs-Cecycloalkyl, haloCi-CealkoxyCi-Cealkyl, -COR7a, Cs-Cecycloalkyl, 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N or O, or 5- to 6- membered heteroaryl having 1 heteroatom selected from O, wherein the 4- to 6-membered heterocyclyl and the 5- to 6-membered heterocyclyl are unsubstituted;R7ais Ci-C6alkyl; each R8is independently selected from hydrogen, and halogen;R9is H; m is 1 , or 2; n is 1 , 2, or 3; and p is 0.

3. The compound of claim 1 or 2, wherein the compound of Formula (I) is a compound of Formula (l-AC), or (l-AN):or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

4. The compound of any of claims 1 to 3, wherein the compound of Formula (I) is a compound of Formula (l-D):(l-D) or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein W is C(R6)2or NR7.

5. The compound of any of claims 1 to 4, wherein the compound of Formula (I) is a compoundor a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

6. The compound of any of claims 1 to 4, wherein the compound of Formula (I) is a compound of Formula (l-l):R6RXrR3? k "'R2(l-l) or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

7. The compound of any of claims 1 to 4 and 6, wherein the compound of Formula (I) is a compound of Formula (l-J):(l-J) or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

8. The compound of any of claims 1 to 7, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R is hydrogen.

9. The compound of any of claims 1 to 8, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R1is hydrogen, halogen, Ci- C6alkyl, C3-C6cycloalkyl, or haloCi-C6alkyl.

10. The compound of any of claims 1 to 9, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R2is Ci-C3alkyl, or halogen.

11. The compound of any of claims 1 to 10, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R3is hydrogen.

12. The compound of any of claims 1 to 11 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R4is phenyl, pyridinyl, or pyrazolyl, wherein the phenyl, pyridinyl, or pyrazolyl is unsubstituted or substituted with R5.

13. The compound of any of the claims 1 to 12, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R5is selected from hydrogen, -CO2H, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, hydroxyC3-C6alkyl, cyano, -CONH2, pyrazolyl, triazolyl, and tetrazolyl, wherein the pyrazolyl, triazolyl, and tetrazolyl are unsubstituted or substituted with 1 Ci-Cealkyl.

14. The compound of any of the claims 1 to 13, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein each R6is independently selected from hydrogen, halogen, hydroxy, Cs-CecycloalkylCi- C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkylCi-C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, and wherein the Ci-Cealkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclyl is independently unsubstituted or substituted with 1 , 2, or 3 halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 4 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 ring heteroatom selected from O, wherein the spirocyclic heterocycle has 5 ring atoms.

15. The compound of any of the claims 1 to 14, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R7is Ci-C6alkyl, haloCr C6alkyl, hydroxyC2-C6alkyl, haloC3-C6cycloalkylCi-C3alkyl, haloC3-C6cycloalkyl, haloCr C6alkoxyCi-C6alkyl, -COCi-C6alkyl, 4- to 6-membered heterocyclyl having 1 heteroatoms selected from O, or 5-membered heteroaryl having 1 heteroatom selected from O.

16. The compound of any of the claims 1 to 15, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R9is H.

17. The compound of any of the claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein p is 0; m is 1 , or 2; andn is 1 , 2, or 3.

18. The compound of claim 1 , selected from the group consisting of:4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;4-(4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-ethylpiperidin-3-yl)benzoic acid;4-(5-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylazepan-4-yl)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylazepan-3-yl)benzoic acid;5.7-dimethyl-4-((4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)oxy)-1 / 7-indole;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl) benzonitrile;4-((3-(4-(1 / 7-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 / 7-indole;2-(4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)propan-2-ol;4-((3-(4-(1 / 7-pyrazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 / 7-indole;5.7-dimethyl-4-((1-methyl-3-(1-methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-1 / 7-indole;4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;4-(1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid;4-(1-(3,3-difluorocyclobutyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3-fluorocyclobutyl)piperidin-3-yl)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid;4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(2, 2-difluoroethyl)piperidin-3-yl) benzoic acid;4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)azepan-3-yl)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)azepan-3-yl)benzoic acid;4-((3-(4-(1 / 7-pyrazol-1-yl)phenyl)-1-(2-fluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole;4-((3-(4-(1 / 7-pyrazol-1-yl)phenyl)-1-(2,2-difluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole;1 -(3-(4-(1 / - / -pyrazol-1 -yl)phenyl)-4-((5,7-dimethyl-1 / 7-ind ol-4-y l)oxy) pi perid in- 1 -yl)ethan-1-one;4-((3-(6-(1 / - / -pyrazol-1 -yl)pyridin-3-yl)-1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole;4-((3-(4-(1 / 7-1 , 2 , 3-triazo I- 1 -y I) phenyl)- 1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole; 1 -(4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)cyclopropan-1-ol; 4-((1 -(2-fluoroethyl)-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H- indole;4-(4-((5-fluoro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;4-(4-((7-chloro-5-methyl-1 / 7-indol-4-yl)oxy)-1 -(2, 2-difluoroethyl)piperidin-3-yl) benzoic acid;4-(1-((2,2-difluorocyclopropyl)methyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid;4-(1-(4,4-difluorobutyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;4-(4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3- yl)benzoic acid;4-((3R,4R)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(3,3-difluoropropyl)piperidin-3- yl)benzoic acid;4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid;4-((1 -(3,3-difluoropropyl)-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl- 1 H-indole;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpyrrolidin-3-yl)benzoic acid;4-(4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylazepan-3-yl)benzoic acid; 4-(4-((5-methoxy-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;4-(8-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-oxaspiro[4.5]decan-7-yl)benzoic acid; 4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-(2-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;4-(2-((5-fluoro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;4-(5-methoxy-2-((7-methyl-1 / 7-indol-4-yl)oxy)cyclohexyl)benzoic acid;4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl) benzoic acid;4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid;4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid;4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-(difluoromethoxy)cyclohexyl) benzoic acid;4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid;4-(6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)benzoic acid;4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexy I) benzamide;4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid;4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-(difluoromethoxy)-5- methylcyclohexyl)benzoic acid;4-(5-(difluoromethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methylcyclohexy I) benzoic acid; and4-(7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[3.5]nonan-6-yl)benzoic acid, or a pharmaceutically acceptable salt or a stereoisomer thereof.

19. The compound of claim 1 , selected from the group consisting of:4-((3 / ?,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;4-((3S,4S?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;4-((3R,4S)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;4-((3S,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl) benzoic acid;4-((3 / ?,4R)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(2,2,2-trifluoroethyl)piperidin-3- yl)benzoic acid;4-((3S,4S)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3- yl)benzoic acid ;4-((3R,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-ethylpiperidin-3-yl)benzoic acid;4-((4S,5R)-5-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylazepan-4-yl) benzoic acid;4-((3R,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylazepan-3-yl)benzoic acid; racemic 5,7-dimethyl-4-(((3S*,4R*)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)oxy)- 1 / 7-indole;5.7-dimethyl-4-(((3S,4R)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)oxy)-1 / 7-indole;5.7-dimethyl-4-(((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)oxy)-1 / 7-indole;4-((3 / ?,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl) benzonitrile;4-(((3R,4R)-3-(4-(1 / 7-tetrazol-5-yl)phenyl)-1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 H- indole;2-(4-((3 / ?,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)pro pan- 2-01;4-(((3R,4R)-3-(4-(1 / - / -pyrazol-1 -y I) phe ny I)- 1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl-1 H- indole;5,7-dimethyl-4-(((3 / ?,4 / ?)-1-methyl-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-1 / 7- indole;4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;4-((3 / ?,4 / ?)-1 -(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid;4-((3 / ?,4 / ?)-1-(3,3-difluorocyclobutyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / -indol-4-yl)oxy)-1-((1 / ',3 / ?)-3-fluorocyclobutyl)piperidin-3- yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(tetrahydrofuran-3-yl)piperidin-3- yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-hydroxy-2-methylpropyl)piperidin-3- yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(2-(trifluoromethoxy)ethyl)piperidin-3- yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(2,2-difluoroethyl)piperidin-3- yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(2,2,2-trifluoroethyl)piperidin-3- yl)benzoic acid;4-((3R,4 / ?)-1 -(2, 2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)azepan-3-yl) benzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)azepan-3-yl)benzoic acid;4-(((3R,4 / ?)-3-(4-(1 / - / -pyrazol-1 -y I) phe ny I)- 1 -(2-fluoroethyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole;4-(((3R,4 / ?)-3-(4-(1 / - / -pyrazol-1 -yl)phenyl)-1 -(2, 2-difluoroethyl)piperidin-4-yl)oxy)-5, 7- dimethyl-1 / - / -indole; racemic 1 -((3R*,4 / ?*)-3-(4-(1 / - / -pyrazol-1 -yl)phenyl)-4-((5,7-dimethyl-1 H- i ndo I-4- y I) oxy) pipe rid i n- 1 -yl)ethan-1 -one;1 -((3R,4 / ?)-3-(4-(1 / - / -pyrazol-1 -yl)phenyl)-4-((5,7-dimethyl-1 / - i nd o l-4-yl) oxy) pi perid in- 1 - yl)ethan-1 -one;1 -((3S,4S)-3-(4-(1 / - / -pyrazol-1 -yl)phenyl)-4-((5,7-dimethyl-1 H- indol-4-y l)oxy) pi pe rid i n- 1 - yl)ethan-1 -one; racemic 4-(((3R*,4 / ?*)-3-(6-(1 / - / -pyrazol-1 -yl)pyridin-3-yl)-1 -methylpiperidin-4-yl)oxy)-5, 7- dimethyl-1 / - / -indole;4-(((3R,4 / ?)-3-(6-(1 / - / -pyrazol-1 -yl)pyridin-3-yl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl- 1 / 7-indole;4-(((3S,4S)-3-(6-(1 / - / -pyrazol-1 -yl)pyridin-3-yl)-1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl- 1 / 7-indole; racemic 4-(((3R*,4R*)-3-(4-(1 / - / -1 ,2,3-triazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole;4-(((3R,4R)-3-(4-(1 / 7-1 ,2 , 3-triazol- 1 -yl) phe ny I)- 1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl- 1 / 7-indole;4-(((3S,4S)-3-(4-(1 / 7-1 ,2,3-triazol-1-yl)phenyl)-1 -methylpiperidin-4-yl)oxy)-5,7-dimethyl- 1 / 7-indole;1 -(4-((3R,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -methylpiperidin-3- y l)phenyl)cyclopro pan-1 -ol;4-(((3 / ?,4 / ?)-1-(2-fluoroethyl)-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole;4-((3 / ?,4 / ?)-4-((5-fluoro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3- yl)benzoic acid;4-((3 / ?,4 / ?)-4-((7-chloro-5-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3- yl)benzoic acid;4-((3 / ?,4 / ?)-1-((2,2-difluorocyclopropyl)methyl)-4-((5,7-dimethyl-1 / 7-indol-4- yl)oxy)piperidin-3-yl)benzoic acid;4-((3R,4R)-1 -(4, 4-difluorobutyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl) benzoic acid;4-((3 / ?,4 / ?)-4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3- yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(3,3-difluoropropyl)piperidin-3- yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid;4-(((3R,4R)-1 -(3,3-difluoropropyl)-3-(1 -methyl-1 / 7-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7- dimethyl-1 H-indole;4-((3 / ?,4S)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(2,2,2-trifluoroethyl)pyrrolidin-3- yl)benzoic acid;4-((3 / ?,4S)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-methylpyrrolidin-3-yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylazepan-3-yl) benzoic acid;4-((3 / ?,4 / ?)-4-((5-methoxy-7-methyl-1 / 7-indol-4-yl)oxy)-1-methylpiperidin-3-yl) benzoic acid;4-((1 S,2R,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;4-((1 R,2S,5 / ?)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;racemic 4-((1 S*,2R*,5 / ?*)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid;4-((1 S,2R,5 / ?)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;4-((1 R,2S,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; racemic 4-((1 S^2S*,5S*)-2-((5,7-dimethyl-1 H-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid;4-((1 S,2S,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl) benzoic acid;4-((1 R,2 / ?,5 / ?)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl) benzoic acid; racemic 4-((1 S*,2S*,5R*)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid;4-((1 S,2S,5R)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl) benzoic acid;4-((1 R,2R,5S>)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; racemic 4-((7S*,8R*)-8-((5,7-dimethyl-1 / - / -indol-4-yl)oxy)-1-oxaspiro[4.5]decan-7- yl)benzoic acid;4-((5 / ?,7S,8 / ?)-8-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-oxaspiro[4.5]decan-7-yl)benzoic acid;4-((5S,7S,8 / ?)-8-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -oxaspiro[4.5]decan-7-yl)benzoic acid;4-((1 S,2 / ?,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid;4-((1 S,2 / ?,5S)-2-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;4-((1 S,2 / ?,5S)-2-((5-fluoro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;4-((1 S,2R,5S)-5-methoxy-2-((7-methyl-1 / 7-indol-4-yl)oxy)cyclohexyl) benzoic acid; racemic 4-((1 S*,2R*)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl) benzoic acid;4-((1 S,2R)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl) benzoic acid;4-((1 / ?,2S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)benzoic acid;4-((1 S,2R)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5,5-difluorocyclohexyl) benzoic acid;4-((1 S,2 / ?,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5- hydroxycyclohexyl)benzoic acid;4-((1 S,2 / ?,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5- (difluoromethoxy)cyclohexyl)benzoic acid;4-((1 S,2 / ?,5 / ?)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid;4-((1 S,2R,5S)-2-((5,7-dimethyl-1 H-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid;4-((5S,6 / ?)-6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)benzoic acid;4-((1 S,2 / ?,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzamide;4-((1 S,2R)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid; racemic 4-((1 S*,2R*,5S^-2-((5-cyclopropyl-7-methyl-1 / 7-ind ol-4-y l)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid; 4-((1 S,2R,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-(difluoromethoxy)-5- methylcyclohexyl)benzoic acid;4-((1 S,2R,5R)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-(difluoromethoxy)-5- methylcyclohexyl)benzoic acid; racemic 4-((1 S*,2R*,5S*)-2-((5-cyclopropyl-7-methyl-1 / -ind ol-4-yl)oxy)-5- (difluoromethoxy)-5-methylcyclohexyl)benzoic acid;4-((1 S,2R,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-(difluoromethoxy)-5- methylcyclohexyl)benzoic acid;4-((1 S,2R,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-(difluoromethoxy)-5- methylcyclohexyl)benzoic acid; 4-((6S,7R)-7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[3.5]nonan-6-yl)benzoic acid, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, and a pharmaceutically acceptable carrier or excipient.21 . A method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, or the pharmaceutical composition of claim 20.

22. The method of claim 21 , wherein the diseases or disorders is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / Malattia leventinese, Sorsby fundus dystrophy, Late onset retinal macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammation, neurological disorders such as multiple sclerosis including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS), stroke,Guillain Barre Syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer’s disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington’s disease, multifocal motor neuropathy, autism spectrum disorders, schizophrenia, drug-induced neurotoxicity, Aquaporin-4 IgG seropositive neuromyelitis optica spectrum disorder (NMOSD), cerebral amyloid angiopathy, cerebral malaria, Charcot-Marie-Tooth disease, chemotherapy- induced peripheral neuropathy, chronic inflammatory demyelinating polyneuropathy, frontotemporal dementia, genetic demyelinating neuropathy due to CD59 p.Cys89Tyr mutation, Lewy bodies dementia, multiple system atrophy (MSA), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), opsoclonus myoclonus syndrome (QMS), progressive supranuclear palsy; disorders of inappropriate or undesirable complement activation such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membranoproliferative glomerulonephritis (IC-MPGN), IgA nephropathy, membranous nephropathy including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome (aHUS), Hemolytic uremic syndrome, STEC- HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), peridontitis, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammation or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as Henoch-Schbnlein purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult respiratory distress syndrome (ARDS), myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis; COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, Spondyloarthropathies, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, neural regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), Buerger’s vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, cryoglobulinemia, immune complex- associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, Cold agglutinin disease, Warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurisms, and Grave’s disease.

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