Complement factor b inhibitors and uses thereof

Abstract

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

Description

[0001] PAT059793-PCT-SEC01

[0002] Complement Factor B Inhibitors and Uses Thereof

[0003] Field

[0004] 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.

[0005] Background

[0006] 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 antibodyindependent manner by the binding of C-reactive protein complexed to ligand and by many pathogens including gram-negative bacteria. The alternative pathway is a magnesium-dependent 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).

[0007] Factor B is a suitable target forthe 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).

[0008] Summary

[0009] 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.

[0010] 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). PAT059793-PCT-SEC01

[0011] 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.

[0012] 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.

[0013] 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.

[0014] In a third aspect, there is provided 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 a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0015] 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.

[0016] 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.

[0017] In a further aspect, there is provided a method oftreating a disease ordisorderthat 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. PAT059793-PCT-SEC01

[0018] 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.

[0019] 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.

[0020] 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.

[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 as a medicament.

[0022] 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.

[0023] 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.

[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, 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.

[0025] 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.

[0026] 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

[0027] 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 PAT059793-PCT-SEC01 effective as factor B modulators and / or inhibitors. The compounds provided herein are useful for the treatment of disorders associated with factor B.

[0028] Definitions

[0029] 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.

[0030] 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.

[0031] 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.

[0032] The term “and / or” means either “and” or “or” unless indicated otherwise.

[0033] 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.

[0034] As used herein the term “Ci-C6alkyl” 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.

[0035] 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-m alkenyl” 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. PAT059793-PCT-SEC01

[0036] As used herein, the term “Ci-Cealkoxy” 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, te / Y-butoxy, sec-butoxy, pentoxy, and hexoxy.

[0037] 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.

[0038] The term “cyano” or “nitrile” refers to a group of formula -CEN, which also may be written as -CN.

[0039] The term “halogen” or “halo” means fluorine, chlorine, bromine or iodine.

[0040] 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., Cs-Cscycloalkyl, 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 cyclopentyl.

[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, PAT059793-PCT-SEC01 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] The term “5 or 6 membered heteroaryl” is to be construed accordingly.

[0052] 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.

[0053] 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 PAT059793-PCT-SEC01 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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 (i.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. PAT059793-PCT-SEC01

[0059] 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.

[0060] 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.

[0061] 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.

[0062] As used herein, the term “about” refers to a range of values + / - 10% of a specified value.

[0063] As used herein, the term “a,” “an,” “the” and similarterms 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.

[0064] 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).

[0065] 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 PAT059793-PCT-SEC01 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. 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.

[0066] Compounds

[0067] 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.

[0068] 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.

[0069] Embodiment 1 provides a compound of Formula (I) or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:

[0070] W is C(R6)2, or NR7; PAT059793-PCT-SEC01

[0071] R1is hydrogen, halogen, hydroxy, Ci-Cealkyl, Cs-Cecycloalkyl, Ci-Cealkoxy, haloCi-Cealkyl, haloC3-C6cycloalkyl, or haloCi-C6alkoxy;

[0072] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Cr C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;

[0073] R3is hydrogen, or halogen;

[0074] R4is selected from hydrogen, -CO2R4a, Ci-C6alkyl, hydroxyC3-C6cycloalkyl, Ci-C6alkoxyCi- C6alkyl, -CH2CO2R4a, -C(O)NHSO2Ci-C4alkyl, -SO2NHC(O)Ci-C4alkyl, -SO2Ci-C4alkyl, cyano, hydroxy, halogen, -C(O)N(R4a)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 R4b; each R4ais independently selected from hydrogen and Ci-C5alkyl; each R4bis independently selected from fluoro, hydroxyl, Ci-Cealkyl, and haloCi-Cealkyl, wherein the Ci-C6alkyl, and haloCi-C6alkyl are unsubstituted or substituted with -CO2H; each R5is independently selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, C3-C6cycloalkyl, Cs-Cecycloalkoxy, hydroxy, Ci-Cealkoxy, haloCi-Cealkoxy, amino, Ci-Cealkylamino, and haloCi- C6alkylamino; or two R5in combination with the carbon atoms to which they are attached form a partially saturated carbocycle having 4 to 6 ring atoms, wherein the carbocycle is unsubstituted or substituted with 1 to 4 substituents selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCr C6alkoxy; or two R5in combination with the carbon atoms to which they are attached form a partially saturated 4- to 6-membered heterocycle having 1 or 2 ring heteroatoms independently selected from N, O, and S(O)q, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy; each R6is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, mono(haloCi-C4alkyl)amino, / V-haloCi-C4alkyl- / V-Ci-C4alkylamino, C3- C6cycloalkylCi-C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkoxy, haloC3- C6cycloalkoxy, Ci-C6alkoxyCi-C6alkyl, haloCi-C6alkoxyCi-C6alkyl, and 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N and O, and wherein the Cr 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; PAT059793-PCT-SEC01 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;

[0075] R7is hydrogen, Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, C3-C6cycloalkyl, C3- CecycloalkylCi-Csalkyl, haloC3-C6cycloalkylCi-C3alkyl, haloCs-Cecycloalkyl, Ci-CealkoxyCi-Cealkyl, 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, Cr Cealkyl, haloCi-Cealkyl, Cs-Cscycloalkyl, haloCs-Cscycloalkyl; R7ais hydrogen or Ci-C6alkyl; each R8is independently selected from halogen, hydroxy, amino, mono- and di- Cr C4alkylamino, Ci-Cealkyl, haloCi-Cealkyl, hydroxyCi-Cealkyl, cyanoCi-Cealkyl, Ci-Cealkoxy, and haloCi-C6alkoxy; m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3; provided that m and n are not both 0; p is 0, 1 , 2, or 3; q is 0, 1 , or 2; and x is 1 or 2.

[0076] 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:

[0077] W is C(R6)2;

[0078] R1is halogen, Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloC3-C6cycloalkyl, or haloCi-C6alkoxy; preferably R1is halogen, Ci-C6alkyl, or C3-C6cycloalkyl;

[0079] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Cr C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents; preferably R2is Ci-C3alkyl, C3cycloalkyl, or halogen, wherein the Ci-C3alkyl, and C3cycloalkyl are unsubstituted or substituted with 1 , 2, or 3 halogen substituents; more preferably R2is Ci-C3alkyl;

[0080] R3is hydrogen, or halogen; PAT059793-PCT-SEC01 preferably R3is hydrogen;

[0081] R4is selected from -CO2R4a, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R4b; preferably R4is selected from -CO2R4a;

[0082] R4ais selected from hydrogen and Ci-Csalkyl; preferably R4ais hydrogen; each R4bis independently selected from fluoro, hydroxyl, Ci-C6alkyl, and haloCi-C6alkyl, wherein the Ci-C6alkyl, and haloCi-C6alkyl are unsubstituted or substituted with -CO2H; preferably each R4bis fluoro; each R5is independently selected from halogen, Ci-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, amino, Ci-C6alkylamino, and haloCi-C6alkylamino; preferably each R5is independently selected from halogen, Ci-Cealkyl, Ci-Cealkoxy, haloCi- C6alkoxy, amino, and Ci-C6alkylamino; or two R5in combination with the carbon atoms to which they are attached form a partially saturated carbocycle having 4 to 6 ring atoms, wherein the carbocycle is unsubstituted or substituted with 1 to 4 substituents selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCr C6alkoxy; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated carbocycle having 4 to 6 ring atoms, wherein the carbocycle is unsubstituted; or two R5in combination with the carbon atoms to which they are attached form a partially saturated 4- to 6-membered heterocycle having 1 or 2 ring heteroatoms independently selected from N, and O, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 4- to 6-membered heterocycle having 1 or 2 ring heteroatoms independently selected from N, and O, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 5- to 6-membered heterocycle having 1 ring heteroatom independently selected from N, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 5- to 6-membered heterocycle having 1 ring heteroatom independently selected from N, wherein the heterocycle is unsubstituted; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 5- to 6-membered heterocycle having 1 ring heteroatom independently selected PAT059793-PCT-SEC01 from O, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 5- to 6-membered heterocycle having 1 ring heteroatom independently selected from O, wherein the heterocycle is unsubstituted or substituted with 2 substituents selected from halogen; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 5- to 6-membered heterocycle having 2 ring heteroatom independently selected from O, wherein the heterocycle is unsubstituted; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 5- to 6-membered heterocycle having 1 or 2 ring heteroatoms independently selected from N, and O, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen; each R6is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, mono(haloCi-C4alkyl)amino, / V-haloCi-C4alkyl- / V-Ci-C4alkylamino, C3- CecycloalkylCi- alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-Cealkyl, haloCi-Cealkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkoxy, haloC3- C6cycloalkoxy, Ci-C6alkoxyCi-C6alkyl, haloCi-C6alkoxyCi-C6alkyl, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, and wherein the Cr 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 each R6is independently selected from Ci-C6alkoxy, haloCi-C6alkoxy, mono(haloCi-C4alkyl)amino, and hydroxy; 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; preferably 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, 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; each R8is independently selected from halogen, hydroxy, amino, mono- and di- Cr C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Ci-C6alkoxy, and haloCi-C6alkoxy; PAT059793-PCT-SEC01 m is 0, 1 , 2, or 3; preferably m is 1 ; n is 0, 1 , 2, or 3; preferably n is 2; provided that m and n are not both 0; p is 0, 1 , 2, or 3; preferably p is 0; q is 0, 1 , or 2; preferably q is 0; and x is 1 or 2.

[0083] Embodiment s provides the compound of Formula (I) of embodiment 1 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:

[0084] W is NR7;

[0085] R1is halogen, Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloC3-C6cycloalkyl, or haloCi-C6alkoxy; preferably R1is halogen, Ci-Cealkyl, or Cs-Cecycloalkyl;

[0086] R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Cr C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents; preferably R2is Ci-C3alkyl, C3cycloalkyl, or halogen, wherein the Ci-C3alkyl, and C3cycloalkyl are unsubstituted or substituted with 1 , 2, or 3 halogen substituents; more preferably R2is Ci-C3alkyl;

[0087] R3is hydrogen, or halogen; preferably R3is hydrogen;

[0088] R4is selected from -CO2R4a, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R4b; preferably R4is selected from -CO2R4a;

[0089] R4ais selected from hydrogen and Ci-C5alkyl; preferably R4ais hydrogen; each R4bis independently selected from fluoro, hydroxyl, Ci-C6alkyl and haloCi-C6alkyl, wherein the Ci-C6alkyl, and haloCi-C6alkyl are unsubstituted or substituted with -CO2H; preferably each R4bis fluoro; each R5is independently selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, amino, Ci-C6alkylamino, and haloCr C6alkylamino; preferably R5is independently selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Cr C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, and amino; or two R5in combination with the carbon atoms to which they are attached form a partially saturated carbocycle having 4 to 6 ring atoms, wherein the carbocycle is unsubstituted or substituted PAT059793-PCT-SEC01 with 1 to 4 substituents selected from halogen, Ci-Cealkyl, haloCi-Cealkyl, Ci-Cealkoxy, haloCi- C6alkoxy; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated carbocycle having 4 to 6 ring atoms, wherein the carbocycle is unsubstituted; or two R5in combination with the carbon atoms to which they are attached form a partially saturated 4- to 6-membered heterocycle having 1 or 2 ring heteroatoms independently selected from N, and O, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 4- to 6-membered heterocycle having 1 or 2 ring heteroatoms independently selected from N, and O, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 5- to 6-membered heterocycle having 1 ring heteroatom independently selected from N, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 5- to 6-membered heterocycle having 1 ring heteroatom independently selected from N, wherein the heterocycle is unsubstituted; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 5- to 6-membered heterocycle having 1 ring heteroatom independently selected from O, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 5- to 6-membered heterocycle having 1 ring heteroatom independently selected from O, wherein the heterocycle is unsubstituted; preferably two R5in combination with the carbon atoms to which they are attached form a partially saturated 5- to 6-membered heterocycle having 1 or 2 ring heteroatoms independently selected from N, and O, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen;

[0090] 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 , PAT059793-PCT-SEC01

[0091] 2, or 3 halogen, further wherein the aryl or heteroaryl is unsubstituted or substituted with halo, Ci- C6alkyl, haloCi-C6alkyl, C3-C5cycloalkyl, haloC3-C5cycloalkyl;

[0092] R7ais hydrogen or Ci-C6alkyl; preferably R7is Ci-C6alkyl, haloCi-C6alkyl, or haloCi-C6alkoxyCi-C6alkyl; preferably R7is haloCi-C6alkyl; each R8is independently selected from halogen, hydroxy, amino, mono- and di- Ci- C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Ci-C6alkoxy, and haloCi-C6alkoxy; m is 0, 1 , 2, or 3; preferably m is 1 ; n is 0, 1 , 2, or 3; preferably n is 2; provided that m and n are not both 0; p is 0, 1 , 2, or 3; preferably p is 0; q is 0, 1 , or 2; preferably q is 0; and x is 1 or 2.

[0093] Embodiment 4 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:

[0094] W is C(R6)2; each R6is independently selected from Ci-C6alkoxy, haloCi-C6alkoxy, mono(haloCi- C4alkyl)amino; 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; preferably 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.

[0095] Embodiment 5 provides the compound of Formula (I) of embodiment 1 or 3, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:

[0096] W is NR7;

[0097] R7is Ci-C6alkyl, haloCi-C6alkyl, hydroxyC2-C6alkyl, haloC3-C6cycloalkylCi-C3alkyl, or haloCi-C6alkoxyCi-C6alkyl; preferably R7is Ci-C6alkyl, haloCi-C6alkyl, or haloCi-C6alkoxyCi-C6alkyl; preferably R7is haloCi-C6alkyl. PAT059793-PCT-SEC01

[0098] Embodiment 6 provides the compound of Formula (I) of any of applicable embodiments 1 to

[0099] 4, wherein the compound of Formula (I) is a compound of Formula (1-1), or (I-2): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0100] Embodiment 7 provides the compound of Formula (I) of any of applicable embodiments 1 to

[0101] 6, wherein the compound of Formula (I) is a compound of Formula (1-1 A), (I-1AB), (1-1 C), or (l-1 D): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0102] Embodiment 8 provides the compound of Formula (I) of any of applicable embodiments 1 to

[0103] 7, wherein the compound of Formula (I) is a compound of Formula (1-1 E): PAT059793-PCT-SEC01 or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0104] Embodiment 9 the compound of Formula (I) of any of applicable embodiments 1 to 8, wherein the compound of Formula (I) is a compound of Formula (I-E1), (I-E2), (I-E3) or (l-E4): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0105] Embodiment 10 provides the compound of Formula (I) of any of applicable embodiments 1 to 9, wherein the compound of Formula (I) is a compound of Formula (I-2A), (I-2EB) , (I-2C), or (I-2D): PAT059793-PCT-SEC01 or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0106] Embodiment 11 provides the compound of Formula (I) of any of applicable embodiments 1 to 10, wherein the compound of Formula (I) is a compound of Formula (I-2E): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0107] Embodiment 12 provides the compound of Formula (I) of any of applicable aembodiments 1 to 1 1 , wherein the compound of Formula (I) is a compound of Formula (I-2E1), (I-2E2), (I-2E3) or (I- 2E4): PAT059793-PCT-SEC01 or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0108] Embodiment 13 provides the compound of Formula (I) of any of embodiments 1 to 12, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R1is halogen, Ci-C6alkyl, or C3-C6cycloalkyl.

[0109] Embodiment 14 provides the compound of Formula (I) of any of embodiments 1 to 13, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R2is Ci-C3alkyl.

[0110] Embodiment 15 provides the compound of Formula (I) of any of embodiments 1 to 14, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R3is hydrogen.

[0111] Embodiment 16 provides the compound of Formula (I) of any of embodiments 1 to 15, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R4is selected from -CC>2R4a, and R4ais hydrogen. PAT059793-PCT-SEC01

[0112] Embodiment 17 provides the compound of Formula (I) of any of embodiments 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R5is halogen, Ci-C6alkyl, haloCi-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkoxy, hydroxy, Cr C6alkoxy, haloCi-C6alkoxy, amino, and Ci-C6alkylamino.

[0113] Embodiment 18 provides the compound of Formula (I) of any of embodiments 1 to 17, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R5in combination with the carbon atoms to which they are attached form a partially saturated 4- to 6-membered heterocycle having 1 ring heteroatoms independently selected from N, and O, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen.

[0114] Embodiment 19 provides the compound of Formula (I) of any of applicable embodiments 1 to 18, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein each R6is independently selected from hydrogen, Ci-C6alkoxy, mono(haloCi- C4alkyl)amino, / V-haloCi-C4alkyl- / V-Ci-C4alkylamino, hydroxy, and haloCi-Cealkoxy.

[0115] Embodiment 20 provides the compound of Formula (I) of any of applicable embodiments 1 to 19, 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 2 substituents selected from halogen.

[0116] Embodiment 21 provides the compound of Formula (I) of any of applicable embodiments 1 to 20, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, where two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 ring heteroatoms selected from O, wherein the spirocyclic heterocycle is unsubstituted.

[0117] Embodiment 22 provides the compound of Formula (I) of any of applicable embodiments 1 to 21 , 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, or haloCi-C6alkoxyCi-C6alkyl; preferably R7is Ci-C6alkyl, haloCi-C6alkyl, or haloCi-C6alkoxyCi- C6alkyl. PAT059793-PCT-SEC01

[0118] Embodiment 23 provides the compound of Formula (I) of any of applicable embodiments 1 to 22, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein m is 1 or 2.

[0119] Embodiment 24 provides the compound of Formula (I) of any of applicable embodiments 1 to 23, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein m is 1 .

[0120] Embodiment 25 provides the compound of Formula (I) of any of applicable embodiments 1 to 24, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein n is 2 or 3.

[0121] Embodiment 26 provides the compound of Formula (I) of any of applicable embodiments 1 to 25, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein n is 2.

[0122] Embodiment 27 provides the compound of Formula (I) of any of applicable embodiments 1 to 26, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein p is 0.

[0123] Embodiment 28 provides the compound of Formula (I) of any of applicable embodiments 1 to 27, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein x is 1 or 2.

[0124] Embodiment 29 provides the compound of Formula (I) of any of applicable embodiments 1 to 28, selected from the compounds in Table 1 :

[0125] Table 1

[0126] PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0127] Embodiment 30 provides the compound of Formula (I) of any of applicable embodiments 1 to 28, selected from the compounds in Table 2: PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0128] Embodiment 31 provides the compound of Formula (I) of any of applicable embodiments 1 to 30, selected from the group consisting of:

[0129] 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-methoxybenzoic acid;

[0130] 4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-methoxybenzoic acid;

[0131] 4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- (difluoromethoxy)benzoic acid;

[0132] 2-amino-4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0133] 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-fluorobenzoic acid;

[0134] 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-(methylamino)benzoic acid

[0135] 4-(6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-2-methoxybenzoic acid;

[0136] 4-(6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-3-methoxybenzoic acid;

[0137] 4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-2-methoxybenzoic acid;

[0138] 2-amino-4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl) benzoic acid;

[0139] 4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-fluorobenzoic acid;

[0140] 4-(2-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-methoxybenzoic acid;

[0141] 4-(2-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- (difluoromethoxy)benzoic acid;

[0142] 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-methoxybenzoic acid;

[0143] 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-fluorobenzoic acid;

[0144] 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-methylbenzoic acid;

[0145] 4-(6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-3-fluorobenzoic acid;

[0146] 4-(7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-2,2-difluorospiro[3.5]nonan-6-yl)-2-methoxybenzoic acid; PAT059793-PCT-SEC01

[0147] 4-(7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-2,2-difluorospiro[3.5]nonan-6-yl)-3-methoxybenzoic acid;

[0148] 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-(methylamino)benzoic acid; 4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-fluorobenzoic acid;

[0149] 4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-2-methoxybenzoic acid;

[0150] 4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3-methoxybenzoic acid;

[0151] 4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3-fluoro benzoic acid;

[0152] 4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- methylbenzoic acid;

[0153] 4-(5-((2,2-difluoroethyl)amino)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- methylbenzoic acid;

[0154] 4-(5-((2,2-difluoroethyl)(methyl)amino)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- methylbenzoic acid;

[0155] 3-chloro-4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid;

[0156] 3-chloro-4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl) benzoic acid;

[0157] 3-chloro-4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0158] 4-(7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[3.5]nonan-6-yl)-2-methoxybenzoic acid;

[0159] 4-(7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[3.5]nonan-6-yl)-3-methoxybenzoic acid; and 4-(7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-2-oxaspiro[3.5]nonan-6-yl)-2-methylbenzoic acid, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0160] Embodiment 32 provides the compound of Formula (I) of any of applicable embodiments 1 to 31 , selected from the group consisting of:

[0161] 4-((1 S,2R,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-methoxybenzoic acid;

[0162] 4-((1 S,2R,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- methoxybenzoic acid;

[0163] 4-((1 S,2R,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- (difluoromethoxy)benzoic acid;

[0164] 2-amino-4-((1 S,2R,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; PAT059793-PCT-SEC01

[0165] 4-((1 S,2 / ?,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-fluorobenzoic acid;

[0166] 4-((1 S,2 / ?,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- (methylamino)benzoic acid;

[0167] 4-((5S,6 / ?)-6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-2-methoxybenzoic acid;

[0168] 4-((5S,6 / ?)-6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-3-methoxybenzoic acid;

[0169] 4-((1 S,2 / ?,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-2- methoxybenzoic acid;

[0170] 2-amino-4-((1 S,2 / ?,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid;

[0171] 4-((1 S,2 / ?,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- fluorobenzoic acid;

[0172] 4-((1 S,2 / ?,5S)-2-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- methoxybenzoic acid;

[0173] 4-((1 S,2 / ?,5S)-2-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- (difluoromethoxy)benzoic acid;

[0174] 4-((1 S,2 / ?,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-methoxybenzoic acid;

[0175] 4-((1 S,2 / ?,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-fluorobenzoic acid;

[0176] 4-((1 S,2 / ?,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-methylbenzoic acid;

[0177] 4-((5S,6 / ?)-6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-3-fluorobenzoic acid;

[0178] 4-((6S,7 / ?)-7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-2,2-difluorospiro[3.5]nonan-6-yl)-2- methoxybenzoic acid;

[0179] 4-((6S,7 / ?)-7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-2,2-difluorospiro[3.5]nonan-6-yl)-3- methoxybenzoic acid;

[0180] 4-((1 S,2 / ?,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-2- methoxybenzoic acid;

[0181] 4-((1 S,2 / ?,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- methoxybenzoic acid;

[0182] 4-((1 S,2 / ?,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- fluorobenzoic acid;

[0183] 4-((1 S,2 / ?,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- methylbenzoic acid;

[0184] 4-((1 S,2 / ?,5S)-5-((2,2-difluoroethyl)amino)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- methylbenzoic acid; PAT059793-PCT-SEC01

[0185] 4-((1 S,2R,5S)-5-((2,2-difluoroethyl)(methyl)amino)-2-((5,7-dimethyl-1 / 7-indol-4- yl)oxy)cyclohexyl)-3-methylbenzoic acid;

[0186] 3-chloro-4-((1 S,2R,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid;

[0187] 3-chloro-4-((1 S,2R,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4- yl)oxy)cyclohexyl)benzoic acid;

[0188] 3-chloro-4-((1 S,2R,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0189] 4-((6S,7R)-7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[3.5]nonan-6-yl)-2-methoxybenzoic acid;

[0190] 4-((6S,7R)-7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[3.5]nonan-6-yl)-3-methoxybenzoic acid; and

[0191] 4-((6S,7R)-7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-2-oxaspiro[3.5]nonan-6-yl)-2-methylbenzoic acid, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0192] Embodiment 33 provides the compound of Formula (I) of any of applicable embodiments 1 to 32, selected from the group consisting of:

[0193] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-methoxybenzoic acid;

[0194] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-fluorobenzoic acid;

[0195] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2-fluorobenzoic acid;

[0196] 4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-2- fluorobenzoic acid;

[0197] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-methylbenzoic acid;

[0198] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2-methylbenzoic acid;

[0199] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-methylbenzoic acid;

[0200] 4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- methylbenzoic acid;

[0201] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-methoxybenzoic acid; PAT059793-PCT-SEC01

[0202] 4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- methoxybenzoic acid;

[0203] 2-chloro-4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0204] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-3-methylbenzoic acid;

[0205] 4-(1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-methylbenzoic acid;

[0206] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-fluorobenzoic acid;

[0207] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,6- dimethylbenzoic acid;

[0208] 4-(1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-methylbenzoic acid;

[0209] 2-amino-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid;

[0210] 2-amino-4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0211] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-ethoxybenzoic acid;

[0212] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-ethoxybenzoic acid;

[0213] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (difluoromethoxy)benzoic acid;

[0214] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dihydrobenzofuran-7-carboxylic acid;

[0215] 7-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dihydrobenzofuran-4-carboxylic acid;

[0216] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)indoline-7- carboxylic acid;

[0217] 7-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,2- difluorobenzo[d][1 ,3]dioxole-4-carboxylic acid;

[0218] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-fluorobenzoic acid;

[0219] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dimethylbenzoic acid; PAT059793-PCT-SEC01

[0220] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,5- dimethylbenzoic acid;

[0221] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3,5- dimethylbenzoic acid;

[0222] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- methylbenzoic acid;

[0223] 4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- (difluoromethoxy)benzoic acid;

[0224] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3-fluorobenzoic acid;

[0225] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- methoxybenzoic acid;

[0226] 4-(1-(2,2-difluoroethyl)-4-((5-fluoro-7-methyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- fluorobenzoic acid;

[0227] 4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- fluorobenzoic acid;

[0228] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2,3- dihydrobenzofuran-7-carboxylic acid;

[0229] 4-(1 -(3, 3-d ifluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-fluoro benzoic acid:

[0230] 4-(1-(2-(difluoromethoxy)ethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methylbenzoic acid;

[0231] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3- methoxybenzoic acid;

[0232] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3- fluorobenzoic acid;

[0233] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3- methylbenzoic acid;

[0234] 2-amino-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3- yl)benzoic acid;

[0235] 4-(1-(2-(difluoromethoxy)ethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methoxybenzoic acid;

[0236] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-2- methylbenzoic acid;

[0237] 7-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2,3- dihydrobenzofuran-4-carboxylic acid; PAT059793-PCT-SEC01

[0238] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (trifluoromethyl)benzoic acid;

[0239] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-propylpiperidin-3-yl)-3-(trifluoromethyl)benzoic acid;

[0240] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- (trifluoromethyl)benzoic acid;

[0241] 4-(4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- methylbenzoic acid;

[0242] 3-cyclopropyl-4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid;

[0243] 3-cyclopropyl-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-propylpiperidin-3-yl)benzoic acid;

[0244] 3-cyclopropyl-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid;

[0245] 3-chloro-4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0246] 3-chloro-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid;

[0247] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-ethylbenzoic acid;

[0248] 4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3-ethylbenzoic acid;

[0249] 3-(difluoromethoxy)-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin- 3-yl)benzoic acid;

[0250] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (difluoromethyl)benzoic acid;

[0251] 3-(difluoromethyl)-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid;

[0252] 4-(4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-3- methylbenzoic acid;

[0253] 3-cyclopropoxy-4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid; and

[0254] 3-cyclopropoxy-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0255] Embodiment 34 provides the compound of Formula (I) of any of applicable embodiments 1 to33, selected from the group consisting of: PAT059793-PCT-SEC01

[0256] 4-((3 / ?,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2- methoxybenzoic acid;

[0257] 4-((3 / ?,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2- fluorobenzoic acid;

[0258] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2- fluorobenzoic acid;

[0259] 4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-2- fluorobenzoic acid;

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

[0261] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2- methylbenzoic acid;

[0262] 4-((3 / ?,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methylbenzoic acid;

[0263] 4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- methylbenzoic acid;

[0264] 4-((3 / ?,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methoxybenzoic acid;

[0265] 4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- methoxybenzoic acid;

[0266] 2-chloro-4-((3 / ?,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid;

[0267] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-3- methylbenzoic acid;

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

[0269] 4-((3 / ?,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2- fluorobenzoic acid;

[0270] 4-((3 / ?,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,6- dimethylbenzoic acid;

[0271] 4-((3 / ?,4 / ?)-1 -(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2- methylbenzoic acid;

[0272] 2-amino-4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid;

[0273] 2-amino-4-((3 / ?,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid; PAT059793-PCT-SEC01

[0274] 4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2- ethoxybenzoic acid;

[0275] 4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- ethoxybenzoic acid;

[0276] 4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (difluoromethoxy)benzoic acid;

[0277] 4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dihydrobenzofuran-7-carboxylic acid;

[0278] 7-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dihydrobenzofuran-4-carboxylic acid;

[0279] 4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)indoline-7- carboxylic acid;

[0280] 7-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,2- difluorobenzo[d][1 ,3]dioxole-4-carboxylic acid;

[0281] 4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- fluorobenzoic acid;

[0282] 4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dimethylbenzoic acid;

[0283] 4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,5- dimethylbenzoic acid;

[0284] 4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3,5- dimethylbenzoic acid;

[0285] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- methylbenzoic acid;

[0286] 4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- (difluoromethoxy)benzoic acid;

[0287] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- fluorobenzoic acid;

[0288] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- methoxybenzoic acid;

[0289] 4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5-fluoro-7-methyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- fluorobenzoic acid;

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

[0291] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2,3- dihydrobenzofuran-7-carboxylic acid; PAT059793-PCT-SEC01

[0292] 4-((3R,4 / ?)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- fluorobenzoic acid;

[0293] 4-((3 / ?,4 / ?)-1-(2-(difluoromethoxy)ethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methylbenzoic acid;

[0294] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3- methoxybenzoic acid;

[0295] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3- fluorobenzoic acid;

[0296] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3- methylbenzoic acid;

[0297] 2-amino-4-((3R,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(2- (trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid;

[0298] 4-((3 / ?,4 / ?)-1-(2-(difluoromethoxy)ethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methoxybenzoic acid;

[0299] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-2- methylbenzoic acid;

[0300] 7-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2,3- dihydrobenzofuran-4-carboxylic acid;

[0301] 4-((3R,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (trifluoromethyl)benzoic acid;

[0302] 4-((3R,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-propylpiperidin-3-yl)-3- (trifluoromethyl)benzoic acid;

[0303] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- (trifluoromethyl)benzoic acid;

[0304] 4-((3 / ?,4R)-4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)- 3-methylbenzoic acid;

[0305] 3-cyclopropyl-4-((3 / ?,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin- 3-yl)benzoic acid;

[0306] 3-cyclopropyl-4-((3R,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-propylpiperidin-3-yl) benzoic acid;

[0307] 3-cyclopropyl-4-((3R,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid;

[0308] 3-chloro-4-((3R,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid;

[0309] 3-chloro-4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid; PAT059793-PCT-SEC01

[0310] 4-((3R,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- ethylbenzoic acid;

[0311] 4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- ethylbenzoic acid;

[0312] 3-(difluoromethoxy)-4-((3R,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid;

[0313] 4-((3R,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (difluoromethyl)benzoic acid;

[0314] 3-(difluoromethyl)-4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid;

[0315] 4-((3 / ?,4 / ?)-4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3- yl)-3-methylbenzoic acid;

[0316] 3-cyclopropoxy-4-((3 / ?,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin- 3-yl)benzoic acid; and

[0317] 3-cyclopropoxy-4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0318] Embodiment 35 provides a tautomer, an enantiomer, or a diastereomer of the compound of Formula (I) of any of the embodiments herein described.

[0319] Embodiment 36 provided a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt ora stereoisomer or an isotopically labeled compound thereof, and a pharmaceutically acceptable carrier or excipient.

[0320] Methods of Treatment or Use

[0321] 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 diastereomer or an isotopically labelled compound thereof.

[0322] 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 diastereomer or an isotopically labelled compound thereof. PAT059793-PCT-SEC01

[0323] In 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 diastereomer or an isotopically labelled compound thereof.

[0324] In 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 diastereomer or an isotopically labelled compound thereof. In another 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 diastereomer or an isotopically labelled compound thereof.

[0325] 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 diastereomer or an isotopically labelled compound thereof.

[0326] 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 PAT059793-PCT-SEC01 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.

[0327] In another aspect, provided herein is a compound provided herein, or a pharmaceutically acceptable salt or a diastereomer or an isotopically labelled compound thereof, for use as a medicament.

[0328] In another aspect, provided herein is a compound provided herein, or a pharmaceutically acceptable salt or a diastereomer or an isotopically labelled compound thereof, for use in inhibiting the expression or activity of complement factor B, in a subject in need thereof.

[0329] In another aspect, provided herein is a compound provided herein, or a pharmaceutically acceptable salt or a diastereomer or an isotopically labelled compound thereof, for use in treating a disease or disorder associated with dysregulation of the complement alternative pathway. PAT059793-PCT-SEC01

[0330] In another aspect, provided herein is the use of a compound a provided herein, or a pharmaceutically acceptable salt or a diastereomer or an isotopically labelled 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.

[0331] In another aspect, provided herein is the use of a compound provided herein, or a pharmaceutically acceptable salt or a diastereomer or an isotopically labelled compound thereof, in the manufacture of a medicament for the treatment of a disease or disorder.

[0332] In another aspect, provided herein is the use of a compound provided herein, or a pharmaceutically acceptable salt or a diastereomer or an isotopically labelled compound thereof, for the treatment of a disease or disorder mediated by complement activation or activation of the complement alternative pathway.

[0333] In another embodiment, provided herein is the use of a compound provided herein, or a pharmaceutically acceptable salt or a diastereomer or an isotopically labelled compound thereof, for the treatment of a disease or disorder that is affected by the modulation of complement alternative pathway.

[0334] In another aspect, provided herein is the use of a compound provided herein, or a pharmaceutically acceptable salt or a diastereomer or an isotopically labelled compound thereof, for the treatment of a disease or disorder.

[0335] In another aspect, provided herein is the use of a provided herein, or a pharmaceutically acceptable salt or a diastereomer or an isotopically labelled compound thereof, for the treatment of age-related macular degeneration.

[0336] In another aspect, provided herein is a pharmaceutical combination comprising a compound provided herein, or a pharmaceutically acceptable salt or a diastereomer or an isotopically labelled compound thereof, and one or more additional therapeutic agent(s).

[0337] Isotopically Labelled Compounds

[0338] 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,180,35S,36CI,123l,124l,125l respectively. The disclosure includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as3H and14C, or those 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) PAT059793-PCT-SEC01 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), or sub-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.

[0339] 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. 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.

[0340] 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.

[0341] 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.

[0342] 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.

[0343] Mixtures of stereoisomers, e.g., mixtures of enantiomers, such as racemates, and / or mixtures of diastereoisomers are encompassed by the present disclosure.

[0344] For the avoidance of doubt, in any of formulae of the present application when the R5group is shown with attachment to a phenyl ring, this means that the R5group(s) can be bonded via a carbon atom.

[0345] For the avoidance of doubt, the compounds structures shown herein, when appropriate, may exist in their zwitterionic form.

[0346] 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.

[0347] 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. PAT059793-PCT-SEC01

[0348] In another aspect, the disclosure provides a pharmaceutical composition comprising one or more the 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.

[0349] 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, 22ndEd. Pharmaceutical Press, 2013, pp. 1049-1070).

[0350] 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).

[0351] The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, topical administration, parenteral administration, and rectal administration, etc. Typically, the pharmaceutical compositions are tablets or gelatin capsules.

[0352] In one embodiment, the pharmaceutical composition is formulated for oral administration.

[0353] In one embodiment, the pharmaceutical composition is a tablet, either film coated or enteric coated. In one embodiment, the tablet comprises the 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.

[0354] In one embodiment, the pharmaceutical composition is a capsule. In one embodiment, the capsule comprises a capsule shell and only the compounds of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

[0355] In one embodiment, the pharmaceutical composition is a combination, in particular a pharmaceutical combination, comprising the compounds of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, or any one of the specifically disclosed compounds of the invention, and at least one additional therapeutically active agent.

[0356] In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the compounds of Formula (I) or subformulae thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, and at least one additional therapeutically active agent. PAT059793-PCT-SEC01

[0357] Methods of Making

[0358] 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.

[0359] Generally, the compounds of formula (I) can be prepared according to the Schemes provided / nfra.

[0360] Compounds provided herein can be prepared according to the following Examples. In the following Schemes, R1, R2, R3, R5, R6, R7, R8, W, m, n, p and x 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 herein. 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. General Scheme 1

[0361] 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.

[0362] General Scheme 2

[0363] 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.

[0364] General Scheme 3 PAT059793-PCT-SEC01

[0365] 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.

[0366] General Scheme 4 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 provide 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.

[0367] General Scheme 5 PAT059793-PCT-SEC01

[0368] Synthesis of examples S5-4 is 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. If W is C-OPg or C(OPg)2, S5-3 can selectively be deprotected to give an alcohol or ketone, respectively. This intermediate can be reacted with a suitable electrophile, e. g. an alkyl halogenide or tritiate, 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. Alternatively, the C-OH can be reacted with a suitable electrophile, e. g. an alkyl halogenide or tritiate, in the presence of base. Alternatively, the C=O intermediate can be reacted with a nucleophile such as an alkyl magnesium halide or a suitable amine in the presence of a reducing agent such as sodium triacetoxyborohydride. Deprotection provides the final Examples S5-4.

[0369] 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.

[0370] 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.

[0371] 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 t- butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.

[0372] 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 PAT059793-PCT-SEC01

[0373] 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 organischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / 1, Georg Thieme Verlag, Stuttgart 1974.

[0374] The protecting group may also be a polymer resin, such as a Wang resin or a 2-chlorotrityl- chloride resin.

[0375] 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.

[0376] Examples

[0377] Analytical Methods, Materials, and Instrumentation

[0378] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker Ultrashield Plus Avance Neo spectrometer 700 MHz or 600 MHz, Bruker Avance, 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 1-4 mg) is dissolved in an appropriate deuterated solvent (1 mL). The chemical names were generated using ChemDraw v23.1 from CambridgeSoft.

[0379] 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 ACN, DMSO, or MeOH and was injected directly into the column using an automated sample handler.

[0380] Stereocenter Configuration Assignment PAT059793-PCT-SEC01

[0381] The absolute configuration at stereocenters in compounds (I-2E1) and (1-1 E1) were assigned to the biologically more active enantiomer as shown above. For intermediates separated in steps prior to the final step, the absolute configuration was matched with the assigned absolute configuration of the final compounds (I-2E1) and (1-1 E1) as described above. Any additional stereocenters, such as in mono-R6substituted compound (1-1 E1), are assigned relative to the two stereocenters defined above (assignment by 2D NMR or in analogy to analogues that have 2D

[0382] NMR).

[0383] Abbreviations

[0384] ACN acetonitrile AcOH acetic acid aq aqueous Boc fert-butyl carboxy br broad Cbz benzyloxycarbonyl CD3OD methanol-cU CDCI3 chloroform-d CO2carbon dioxide CS2CO3 cesium carbonate d doublet DAD diode-array detection DBAD di-fe / Y-butyl azodicarboxylate DCM dichloromethane DEAD diethyl azodicarboxylate DI AD diisopropyl azodicarboxylate DMAP / V, / V-dimethylaminopyridine DMF / V, / V-dimethylformamide DMSO dimethylsulfoxide ee enantiomeric excess EtOAc ethyl acetate EtOH ethanol FA formic acid h hour(s) H2hydrogen PAT059793-PCT-SEC01

[0385] H2O water

[0386] HATU hexafluorophosphate azabenzotriazole tetramethyl uronium

[0387] HCI hydrochloric acid

[0388] HPLC high performance liquid chromatography

[0389] IPA / so-propanol

[0390] K2CO3potassium carbonate

[0391] KOAc potassium acetate

[0392] K3PO4potassium phosphate, tribasic

[0393] LC-MS liquid chromatography and mass spectrometry

[0394] LED light emitting diode m multiplet m / z mass to charge ratio mCPBA mefa-chloro perbenzoic acid

[0395] MeOH methanol

[0396] Me-THF 2-methyltetrahydrofuran

[0397] MgSO4magnesium sulfate min minutes

[0398] MS mass spectrometry N2nitrogen Na(OAc)3BH sodium triacetoxy borohydride NaBH4sodium borohydride NaHCO3sodium bicarbonate Na2SO4sodium sulfate NaOH sodium hydroxide NEt3triethylamine NH4CI ammonium chloride NH4OH ammonium hydroxide NMR nuclear magnetic resonance NP normal phase org organic

[0399] Pd2(dba)3tris(dibenzylideneacetone)dipalladium(0) PdCI2(dppf) 1 ,1 '-bis(diphenylphosphino)ferrocene-palladium(ll) dichloride

[0400] PE petroleum ether PPh3triphenylphosphine PPm parts per million PtO2platinum oxide Q quartet rac racemic 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 PAT059793-PCT-SEC01 soln solution

[0401] SPhos dicyclohexyl(2',6'-dimethoxy[1 ,1 '-biphenyl]- yl)phosphane t triplet

[0402] TBME tert-butyl methyl ether tBu tertiary butyl tert tertiary

[0403] TMG tetramethy guanidine

[0404] TFA trifluoroacetic acid

[0405] THF tetra hydrofuran

[0406] Ts tosyl

[0407] Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene wt% weight percent

[0408] Intermediates

[0409] Intermediate 1-1 : tert-butyl 4-hydroxy-5,7-dimethyl-1 H-indole-1 -carboxylate tert-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 NaHCOs soln 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 tert-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.

[0410] Intermediate I-3: tert-butyl 5-cyclopropyl-4-hydroxy-7-methyl-1H-indole-1 -carboxylate tert-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 PAT059793-PCT-SEC01 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 soln of NaOH (4M, 3.46 mL, 13.84 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 aq HCI soln (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 tert-butyl 5- cyclopropyl-4-hydroxy-7-methyl-1 / - / -indole-1 -carboxylate (585 mg) as a greyish oil. LC-MS Method C-1 : Rt = 1 .26 min; MS m / z [M-Boc+2H]+= 188.2.

[0411] Intermediate I-4: tert-butyl 5-chloro-4-hydroxy-7-methyl-1H-indole-1 -carboxylate

[0412] Step 1 : 4-bromo-5-chloro-7-methyl-1H-indole (Intermediate 1-4-1)

[0413] 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. After 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 (960 mg) as an orange solid.1H NMR (400 MHz, CDCI3) 6 [ppm] 8.25 (s, 1 H), 7.31 - 7.29 (m, 1 H), 7.11 - 7.09 (m, 1 H), 6.62 (dd, J = 3.3, 2.2 Hz, 1 H), 2.46 (s, 3H).

[0414] Step 2: tert-butyl 4-bromo-5-chloro-7-methyl-1H-indole-1 -carboxylate (Intermediate I-4-2)

[0415] 4-Bromo-5-chloro-7-methyl-1 / 7-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 PAT059793-PCT-SEC01 provide tert-butyl 4-bromo-5-chloro-7-methyl-1 / - / -indole-1 -carboxylate (850 mg) as an orange solid.1H NMR (400 MHz, CDCI3) 6 [ppm] 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).

[0416] Step 3: tert-butyl 5-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-

[0417] 1 -carboxylate (Intermediate I-4-3) tert-Butyl 4-bromo-5-chloro-7-methyl-1 / - / -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 heated 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. Column chromatography over silica gel (eluent: 0 to 30% EtOAc in heptane) provided enriched tert-butyl 5-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-'\ ndo le- 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.

[0418] Step 4: tert-butyl 5-chloro-4-hydroxy-7-methyl-1H-indole-1 -carboxylate (Intermediate I-4) Enriched tert-butyl 5-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)-1 / - / -indole-1 - carboxylate (Intermediate I-4-3, 140 mg) was dissolved in THF / H2O (1 :1 , 1 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. The mixture was diluted with THF / H2O (1 :1 , 1 mL) 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 / 7- indole-1 -carboxylate (30 mg) as a brown oil. LC-MS Method C-1 Rt = 1 .52 min; MS m / z [M- Boc+2H]+= 182.1.

[0419] Intermediate I-M1 : tert-butyl 5,7-dimethyl-4-((4-oxocyclohex-2-en-1-yl)oxy)-1H-indole-1- carboxylate PAT059793-PCT-SEC01

[0420] To a soln of 4-oxocyclohex-2-en-1-yl benzoate (CAS 274262-62-3, 2.30 g, approximate 90%, 9.57 mmol), te / Y-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 2.88 g, 11.0 mmol), and PPh3(377 mg, 1.44 mmol) in DCM (55 mL) was added Cs2CO3(6.24 g, 19.2 mmol). The mixture was purged with argon for 3 min, and allylpalladium(ll)chloride (87.6 mg, 0.239 mmol) was added. The RM was stirred at 20 °C for 30 min. The mixture was filtered over a pad of Celite®. The solids were rinsed with DCM. The filtrate was concentrated under reduced pressure. Column chromatography over silica gel (120 g; eluent: 0 to 15% EtOAc in heptane) provided enriched te / Y-butyl 5,7-dimethyl-4-((4-oxocyclohex-2-en-1-yl)oxy)-1 / - / -indole-1 -carboxylate (2.34 g) as a yellowish oil which was used in the next reaction without further purification. LC-MS Method B-1 : Rt = 1 .46 min; MS m / z [M+H]+= 356.2.

[0421] Intermediate BA1-E51 : methyl 4-bromo-3-cyclopropylbenzoate

[0422] A soln of 4-bromo-3-cyclopropylbenzoic acid (5.0 g, 20.7 mmol) in DMF (50 mL) was cooled to 0 to 5 °C. K2CO3(325 mesh, 4.3 g, 31.1 mmol) and iodomethane (3.8 g, 1 .69 mL, 27.0 mmol) were added. The cooling bath was removed, and the RM was stirred for 100 min. The mixture was poured into a well stirred emulsion of water and TBME. The layers were separated and washed with water (2x), brine and TBME. The combined org layers were dried over MgSO4, filtered and concentrated under reduced pressure at 50 °C. Purification by column chromatography over silica gel (eluent: 0 to 13% EtOAc in cyclohexane) provided methyl 4-bromo-3-cyclopropylbenzoate (5.11 g) as a colorless oil.1H NMR (600 MHz, DMSO-c / 6) 6 [ppm] 7.75 (d, J = 8.3 Hz, 1 H), 7.66 (dd, J = 8.3, 2.2 Hz, 1 H), 7.50 (d, J = 2.1 Hz, 1 H), 3.84 (s, 3H), 2.17 - 2.11 (m, 1 H), 1.11 - 1.00 (m, 2H), 0.76 - 0.67 (m, 2H).

[0423] Intermediate BA1-E69: tert-butyl 4-bromo-3-(difluoromethyl)benzoate

[0424] A soln of tert-butyl 4-bromo-3-formylbenzoate (4.77 g, 16.7 mmol) in DCM (48 mL) was cooled to 0 to 5 °C. Diethylaminosulfur trifluoride (8.84 mL, 66.9 mmol) was added in a dropwise manner. The RM was then stirred for 1 .5 h while allowing the temperature to reach RT. The mixture was poured into a well stirred mixture of TBME and sat. aq NaHCO3soln. The layers were separated and washed with sat. aq NaHCO3soln, brine and extracted with TBME. The combined org layers were dried over MgSO4, filtered and concentrated under reduced pressure at 50 °C. Purification by column chromatography over silica gel (120 g; eluent: 0 to 23% DCM in cyclohexane) provided te / Y-butyl 4-bromo-3-(difluoromethyl)benzoate (4.55 g) as a light yellowish oil.1H NMR (600 MHz, PAT059793-PCT-SEC01

[0425] DMSO-c / e) 6 [ppm] 8.08 (d, J = 2.0 Hz, 1 H), 7.95 (dd, J = 8.5, 2.0 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 1 H),

[0426] 7.21 (t, J = 54.1 Hz, 1 H), 1 .56 (s, 9H).

[0427] Intermediate K1-E116-E117: 4-(2,2-difluoroethoxy)cyclohexan-1-one oethoxy)-1 ,4-dioxaspiro[4.5]decane (Intermediate K1-E116-E117-1)

[0428] A soln of 1 ,4-dioxaspiro[4.5]decan-8-ol (CAS 22428-87-1 , 26.0 g, 164 mmol) in THF (350 mL) was brought under N2atmosphere. The soln was cooled to 2°C. Sodium hydride (60 wt% in mineral oil,

[0429] 7.89 g, 197.2 mmol) was added portion-wise over a period of 10 min. The RM was stirred in the ice bath for 10 min. A soln of 2,2-Difluoroethyl trifluoromethanesulfonate (45.8 g, 28.5 mL, 214 mmol) in THF (25 mL) was added in a dropwise manner while maintaining the temperature below 15 °C (duration: 20 min). The cooling bath was removed, and the RM was stirred for 80 min. The RM was poured on a well stirred emulsion of TBME and water. The layers were separated and washed with brine and TBME. The combined org layers were dried over MgSO4, filtered and the volatiles were removed under reduced pressure at 40 °C to give a yellow oil. Column chromatography over silica gel (eluent: 1 to 24.5% EtOAc in cyclohexane) provided 8-(2,2-difluoroethoxy)-1 ,4- dioxaspiro[4.5]decane (33.1 g) as a colorless liquid.1H NMR (600 MHz, DMSO-c / 6) 5 [ppm] 6.22 - 5.99 (m, 1 H), 3.87 - 3.81 (m, 4H), 3.69 - 3.62 (m, 2H), 3.52 - 3.47 (m, 1 H), 1 .79 - 1 .72 (m, 2H), 1.69 - 1.62 (m, 2H), 1.61 - 1.53 (m, 2H), 1.49 - 1.43 (m, 2H). 16 of 16H reported.

[0430] Step 2: 4-(2,2-difluoroethoxy)cyclohexan-1-one (Intermediate K1-E116-E117)

[0431] To a soln of 8-(2,2-difluoroethoxy)-1 ,4-dioxaspiro[4.5]decane (Intermediate K1-E116-E117-1 , 33.06 g, 149 mmol) in THF (661 mL) was added an aq soln of HCI (4M, 186 mL, 744 mmol) was added. The RM was stirred overnight. Most of the volatiles (THF) were removed under reduced pressure at 40 °C. TBME was then added to the resulting aq slurry, and the layers were separated. They were washed with water, brine and TBME. The combined org layers were dried over MgSO4and filtered, and concentrated under reduced pressure at 40

[0432] °C. Purification by column chromatography over silica gel (eluent: 5.0 to 44.7% EtOAc in cyclohexane) provided 4-(2,2-difluoroethoxy)cyclohexan-1-one (22.9 g) as a light-yellow volatile liquid.1H NMR (600 MHz, DMSO-c / 6) 6 [ppm] 6.26 - 6.05 (m, 1 H), 3.85 - 3.80 (m, 1 H), 3.80 - 3.72 (m, 2H), 2.39 - 2.32 (m, 2H), 2.25 - 2.18 (m, 2H), 2.01 - 1.94 (m, 2H), 1.94 - 1.86 (m, 2H).

[0433] Intermediate K2-E208-E209: 2,2-difluorospiro[3.5]nonan-7-one PAT059793-PCT-SEC01

[0434] Step 1 : diethyl 3,3'-(3,3-difluorocyclobutane-1 ,1-diyl)(2E,2'E)-diacrylate (Intermediate K2-

[0435] E208-E209-1)

[0436] Stepl a: A soln of DMSO (12.4 mL, 175 mmol) in DCM (700 mL) was cooled to -75 °C under N2atmosphere. Oxalyl chloride (14.5 mL,166 mmol) was added in a dropwise manner while maintaining the temperature below -70 °C, and stirring was continued for 40 min. A soln of (3,3- difluorocyclobutane-1 ,1-diyl)dimethanol (CAS 1934699-78-1 ; 10.0 g, 95 wt%, 62.4 mmol) in DCM (50 mL) and DMSO (2.50 mL) was added over 30 min in a dropwise manner while maintaining the temperature below -70 °C. The resulting milky mixture was stirred for 1 h. Triethylamine (50.6 g, 69.6 mL, 500 mmol) was added over 15 min in a dropwise manner while maintaining the temperature below -68 °C. The cooling bath was removed, and the RM was stirred for an additional 2 h at an ambient temperature.

[0437] Stepl b: The resulting mixture from Step 1 a was cannulated over a period of 25 min to a mixture of triethyl phosphonoacetate (37.2 g, 33.0 mL, 166 mmol), anhydrous lithium chloride (14.1 g, 333 mmol), and DIPEA (85.9 g, 116 mL, 664 mmol) in ACN (503 mL) under N2atmosphere. The resulting RM was stirred overnight and then most of the volatiles were removed under reduced pressure at 40 °C. The remaining slurry was diluted with water and TBME. The layers were separated, the org layer was washed with water (2x), sat. aq NaHCO3soln, and brine, and the separated aq layer was extracted with TBME. The combined org layers were dried over MgSO4, filtered, and the volatiles were removed under reduced pressure at 40 °C. The residue was purified by column chromatography over silica gel (eluent: 0 to 17% TBME in cyclohexane) to provide diethyl 3,3'-(3,3-difluorocyclobutane-1 ,1 -diyl)(2E,2'E)-diacrylate (11.4 g) as a slightly yellowish liquid. LC-MS Method B-1 : Rt = 1.10 min; MS m / z [M+NH4]+= 306.3.1H NMR (600 MHz, CDCI3) 6 [ppm] 7.05 (d, J = 15.8 Hz, 2H), 5.85 (d, J = 15.8 Hz, 2H), 4.26 - 4.20 (m, 4H), 2.84 (t, J = 12.0 Hz, 4H), 1.31 (t, J = 7.1 Hz, 6H).

[0438] Step 2: diethyl 3,3'-(3,3-difluorocyclobutane-1 ,1 -diyl)dipropionate (Intermediate K2-E208- PAT059793-PCT-SEC01

[0439] To a soln of diethyl 3,3'-(3,3-difluorocyclobutane-1 ,1-diyl)(2E,2'E)-diacrylate (11.4 g, 39.6 mmol) in EtOAc (388 mL) under N2atmosphere was added Pd / C (4.22 g, 10 wt%, 3.96 mmol). The mixture was stirred under a H2atmosphere (balloon) overnight. The RM was purged with N2and filtered through Celite®, and the solids were washed with EtOAc (3x). The volatiles of the filtrate were removed under reduced pressure at 40 °C to provide diethyl 3,3'-(3,3-difluorocyclobutane-1 ,1- diyl)dipropionate (11 .6 g) as colorless liquid which was directly used without further purification.1H NMR (600 MHz, CDCI3) 6 [ppm] 4.14 (q, J = 7.2 Hz, 4H), 2.33 (t, J = 12.6 Hz, 4H), 2.26 - 2.20 (m, 4H), 1 .89 - 1 .83 (m, 4H), 1 .27 (t, J = 7.1 Hz, 6H).

[0440] Step 3: ethyl 2,2-difluoro-7-oxospiro[3.5]nonane-6-carboxylate (Intermediate K2-E208-E209-3)

[0441] To a soln of diethyl 3,3'-(3,3-difluorocyclobutane-1 ,1-diyl)dipropionate (11.6 g, 39.8 mmol) in THF (200 mL) under N2atmosphere was slowly added a soln of potassium te / Y-butoxide (1 M in THF, 79.6 mL, 79.6 mmol). The resulting mixture was heated to reflux for 1 .5 h. The RM was cooled to 0 °C and then poured into a well stirred mixture of water, ice, and a soln of HCI (4M, 21 .9 mL, 87.5 mmol) and TBME. The layers were separated, the org layer was washed with brine, and the aq layer was extracted with TBME. The combined org layers were dried over MgSO4and filtered, and the volatiles were removed under reduced pressure at 40 °C. The residue was purified by column chromatography over silica gel (eluent: 0 to 11 .8% TBME in cyclohexane) to provide ethyl 2,2- difluoro-7-oxospiro[3.5]nonane-6-carboxylate (9.45 g) as a slightly yellowish liquid. LC-MS Method B-1 : Rt = 1 .26 min; MS m / z [M+H]+= 247.0.1H NMR (600 MHz, CDCI3) 6 [ppm] 12.24 (s, 1 H), 4.23 (q, J = 7.2 Hz, 2H), 2.40 - 2.33 (m, 8H), 1 .78 (t, J = 6.5 Hz, 2H), 1 .32 (t, J = 7.1 Hz, 3H).

[0442] Step 4: 2,2-difluorospiro[3.5]nonan-7-one (Intermediate K2-E208-E209)

[0443] To a soln of ethyl 2,2-difluoro-7-oxospiro[3.5]nonane-6-carboxylate (9.45 g, 38.4 mmol) in 1 ,4- dioxane (60.6 mL) under N2atmosphere was added a soln of potassium hydroxide (12.67 g, 85 wt%, 192 mmol) in water (100.8 mL), and the resulting mixture was stirred at 100 °C for 2 h 20 min. The RM was cooled to RT, TBME was added, and the layers were separated. The org layer was washed with water (2x) and brine, and the aq layer was extracted with TBME. The combined org layers were dried over MgSO4and filtered, and the volatiles were removed under reduced pressure at 38 °C providing crude 2,2-difluorospiro[3.5]nonan-7-one (Intermediate K2-E208-E209, 6.27 g) as a white solid which was directly used without further purification.1H NMR (600 MHz, CDCI3) 6 [ppm] 2.50 (t, J = 12.5 Hz, 4H), 2.34 (t, J = 6.7 Hz, 4H), 1 .99 (t, J = 6.7 Hz, 4H).

[0444] Intermediate K3-E212-E213: 6-bromo-2-oxaspiro[3.5]nonan-7-one PAT059793-PCT-SEC01

[0445] To a soln of 2-oxaspiro[3.5]nonan-7-one (1.00 g, 7.13 mmol) in DCM (20 mL) under argon atmosphere was added / V-bromosuccinimide (1.40 g, 7.85 mmol) and 4-methylbenzenesulfonic acid monohydrate (149 mg, 0.713 mmol). The RM was stirred at RT overnight and then diluted with DCM and a sat. aq NaHCO3soln. The phases were separated using Isolute® phase separator, and the org phase was concentrated under reduced pressure to give crude 6-bromo-2- oxaspiro[3.5]nonan-7-one (1 .75 g) of a beige oil which was directly used in the next reaction without further purification.1H NMR (400 MHz, DMSO-c / 6) 5 [ppm] 5.00 (dd, J = 11 .2, 5.8, 0.8 Hz, 1 H), 4.61 (d, J = 6.0, 1.0 Hz, 1 H), 4.47 - 4.40 (m, 2H), 4.32 (d, J = 5.9 Hz, 1 H), 2.85 (m, J = 13.4, 5.8, 2.5 Hz, 1 H), 2.51 (m, 2H), 2.30 (m, J = 13.0, 7.8, 2.5 Hz, 2H), 2.05 - 1.95 (m, 1 H).

[0446] Intermediate K-E1 : tert-butyl 3-(3-methoxy-4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1- carboxylate

[0447] To a stirred soln of methyl 4-bromo-2-methoxybenzoate (20.0 g, 81.6 mmol) in toluene (100 mL) was added fert-butyl 4-oxopiperidine-1 -carboxylate (45.5 g, 228.5 mmol), K3PO4 (28.4 g, 163.2 mmol), and Xantphos (1 .89 g, 3.26 mmol). The mixture was purged with argon for 5 min at RT. Pd2(dba)3(1 .49 g, 1 .63 mmol) was added, and the RM was stirred at 90 °C for 6 h. The RM was allowed to cool to RT, filtered through Celite®, and the solids were washed with THF. The combined filtrates were concentrated under reduced pressure. Column chromatography over silica gel (80 g; eluent: 25% EtOAc in hexane) provided enriched material which was then further purified by RP chromatography (120 g C18; eluent: 48 to 55% ACN with 0.1 % FA in H2O) to provide fert- butyl 3-(3-methoxy-4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1 -carboxylate as a white solid (14 g). LC-MS Method A-1 : Rt = 1 .83 min; MS m / z [M-Hp = 361 .9.

[0448] Intermediate K-E2: tert-butyl 3-(3-fluoro-4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1- carboxylate

[0449] To a stirred soln of methyl 4-bromo-2-fluorobenzoate (20.0 g, 85.8 mmol) in toluene (200 mL) was added tert-butyl 4-oxopiperidine-1 -carboxylate (47.9 g, 240.3 mmol), followed by K3PO4(36.4 g, 171 .6 mmol), and the mixture was purged with argon for 15 min. Xantphos (1 .99 g, 3.43 mmol) and Pd2(dba)3(1 .57 g, 1 .71 mmol) were added, and the RM was heated at 100 °C for 16 h. The RM was allowed to cool to RT, diluted with H2O, and filtered through Celite®. The org phase of the PAT059793-PCT-SEC01 filtrate was dried over Na2SC>4 and concentrated under reduced pressure. Column chromatography over silica gel (24 g; eluent: 0 to 80% EtOAc in hexane) provided enriched material which was then further purified by RP chromatography (120 g C18; eluent: 0 to 100% ACN in H2O) to provide tert- butyl 3-(3-fluoro-4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1 -carboxylate as a white solid (9.0 g). LC-MS Method A-1 : Rt = 1 .84 min; MS m / z [M-Hp = 350.0.

[0450] Intermediate K-E5: tert-butyl 3-(4-(methoxycarbonyl)-3-methylphenyl)-4-oxopiperidine-1-

[0451] To a stirred soln of methyl 4-bromo-2-methylbenzoate (20.0 g, 87.3 mmol) in toluene (200 mL) was added fert-butyl 4-oxopiperidine-1 -carboxylate (48.7 g, 244.5 mmol), followed by K3PO4(37.1 g, 174.6 mmol), and the mixture was purged with argon for 15 min at RT. Xantphos (2.02 g, 3.49 mmol) and Pd2(dba)3(1 .60 g, 1 .75 mmol) were added, and the RM was purged with argon for 5 min. The RM was heated at 100 °C for 16 h. The RM was allowed to cool to RT and filtered through Celite®. The filtrate was concentrated under reduced pressure. Column chromatography over silica gel (80 g; eluent: 25% EtOAc in hexane) provided enriched material which was and then further purified by RP chromatography (120 g C18; eluent: 48 to 55% ACN with 0.1 % FA in H2O) to provide fert-butyl 3-(4-(methoxycarbonyl)-3-methylphenyl)-4-oxopiperidine-1 -carboxylate as a pale green solid (15 g). LC-MS Method A-1 : Rt = 1 .73 min; MS m / z [M-H] = 346.1 .

[0452] Intermediate K-E7: tert-butyl 3-(4-(methoxycarbonyl)-2-methylphenyl)-4-oxopiperidine-1- carboxylate

[0453] To a stirred soln of methyl 4-bromo-3-methylbenzoate (15.2 g, 66.2 mmol) in toluene (150 mL) was added tert-butyl 4-oxopiperidine-1 -carboxylate (33.0 g, 165.6 mmol). The mixture was purged with argon for 15 min at RT. K3PO4 (39.4 g, 185.5 mmol), Xantphos (766.7 mg, 1.32 mmol), and Pd2(dba)3(1 .21 g, 1 .33 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 filtrate was partitioned between EtOAc and H2O. The org phase was dried over Na2SO4 and concentrated under reduced pressure. Column chromatography over silica gel (80 g; eluent: 0 to 40% EtOAc in hexane) provided enriched material which was then further purified by RP chromatography (120 g C18; eluent: 0 to 100% ACN with 0.01 % FA in H2O) to provide tert-butyl 3- PAT059793-PCT-SEC01

[0454] (4-(methoxycarbonyl)-2-methylphenyl)-4-oxopiperidine-1 -carboxylate as a pale yellow solid (3.0 g).

[0455] LC-MS Method A-1 : Rt = 3.09 min; MS m / z [M-H]- = 346.1 .

[0456] Intermediate K-E9: tert-butyl 3-(2-methoxy-4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-

[0457] To a vial was added tert-butyl 4-oxopiperidine-1 -carboxylate (1.53 g, 8.16 mmol), methyl 4-bromo- 3-methoxybenzoate (1.00 g, 4.08 mmol), Xantphos-Pd-G2 (CAS#: 1375325-77-1 , 77.4 mg, 81.6 pmol), and K3PO4 (1 .73 g, 8.16 mmol). The vial was purged with N2. Toluene (10 mL) was added, and the RM was stirred at 100 °C overnight. The RM was allowed to cool to RT, quenched with H2O, and the mixture was extracted with EtOAc (2x). The combined org phases were concentrated under reduced pressure. The residue was purified over silica gel (40 g; eluent: 0 to 60% EtOAc in heptane) to provide fert-butyl 3-(2-methoxy-4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1- carboxylate (859 mg) as a white solid. LC-MS Method C-1 : Rt = 1 .05 min; MS m / z [M-Boc+2H]+= 264.2.

[0458] Intermediate rac-K-E11 : tert-butyl 3-(3-chloro-4-(methoxycarbonyl)phenyl)-4-oxopiperidine- 1 -carboxylate

[0459] To a soln of methyl 2-chloro-4-iodobenzoate (1 .00 g, 3.37 mmol) in toluene (20 mL) was added fert-butyl 4-oxopiperidine-1 -carboxylate (941 mg, 4.72 mmol), K3PO4 (1 .65 g, 7.76 mmol), Xantphos (156 mg, 0.27 mmol), and Pd2(dba)3(92.7 mg, 0.10 mmol) at 25 °C under N2atmosphere. The RM was stirred at 85 °C under N2atmosphere for 16 h. The mixture was allowed to cool to RT. The solids were filtered off and washed with DCM (20 mL). The filtrate was concentrated under reduced pressure. Column chromatography over silica gel (120 g; eluent: 0 to 50% EtOAc in heptane) provided enriched rac fert-butyl 3-(3-chloro-4-(methoxycarbonyl)phenyl)-4- oxopiperidine-1 -carboxylate (1.18 g) as an orange solid. LC-MS Method C-2: Rt = 1.08 min; MS m / z [M-H]- = 366.2.

[0460] Intermediate K-E43-E44: fert-butyl 3-(4-(methoxycarbonyl)-2-(trifluoromethyl)phenyl)-4- oxopiperidine-1 -carboxylate PAT059793-PCT-SEC01

[0461] K3PO4(7.80 g, 36.7 mmol) was added to a soln of tert-butyl 4-oxopiperidine-1 -carboxylate (4.46 g, 22.4 mmol), methyl 4-bromo-3-(trifluoromethyl)benzoate (4.52 g, 16.0 mmol) and xantphos (407 mg, 703 pmol) in toluene (39.9 mL). The mixture was purged with N2. Pd2(dba)3(293 mg, 319.4 pmol) was added, and the resulting RM was stirred at 90 °C overnight under N2atmosphere. The mixture was allowed to cool to RT and then filtered through Celite®. The solids were washed with toluene, and the filtrate was concentrated under reduced pressure at 50 °C. RP chromatography (C18 360 g; eluent: 40 to 80% ACN in H2O with 0.1% NH4OH) provided enriched material which was then further purified by column chromatography over silica gel (220 g; eluent: 3 to 30% EtOAc in cyclohexane) to provide rac tert-butyl 3-(4-(methoxycarbonyl)-2-(trifluoromethyl)phenyl)-4- oxopiperidine-1 -carboxylate (3.3 g) as a colorless oil. LC-MS Method B2: Rt = 5.72 min; MS m / z [M-H]- = 400.2.

[0462] Intermediate K-E51-E52: tert-butyl 3-(2-cyclopropyl-4-(methoxycarbonyl)phenyl)-4- oxopiperidine-1 -carboxylate

[0463] K3PO4(9.76 g, 46.0 mmol) was added to a soln of tert-butyl 4-oxopiperidine-1 -carboxylate (5.6 g, 28.0 mmol), methyl 4-bromo-3-cyclopropylbenzoate (Intermediate BA1-E51 , 5.10 g, 20.0 mmol) and Xantphos (509 mg, 880 pmol) in toluene (50 mL). The mixture was purged with N2. Pd2(dba)3(366 mg, 399.8 pmol) was added, and the RM was stirred at 90 °C overnight under N2atmosphere The mixture was allowed to cool to RT and filtered through Celite®. The solids were washed with toluene, and the filtrate was concentrated under reduced pressure at 50 °. RP chromatography (C18 360 g; eluent: 40 to 70% ACN in H2O with 0.1% NH4OH) provided enriched material which was then further purified by column chromatography over silica gel (220 g; eluent: 1 .0 to 9.7% TBME in DCM) to provide fert-butyl 3-(2-cyclopropyl-4-(methoxycarbonyl)phenyl)-4-oxopiperidine- 1-carboxylate (3.4 g) as a colorless, sticky oil. LC-MS Method B1 : Rt = 1 .14 min; MS m / z [M- Boc+2H]+= 274.0.

[0464] Intermediate rac-K-E101 : rac methyl 2-methoxy-4-((1S*,5S*)-5-methoxy-2- oxocyclohexyl)benzoate PAT059793-PCT-SEC01

[0465] Methyl 4-bromo-2-methoxybenzoate (500 mg, 2.04 mmol), 4-methoxycyclohexan-1-one (292.3 mg, 3.06 mmol), K3PO4(996 mg, 4.69 mmol), Xantphos (51.9 mg, 89.7 pmol), Pd2dba3(37.4 mg, 40.8 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 (40 g; eluent: 0 to 50% EtOAc in cyclohexane) to provide rac methyl 2-methoxy-4-((1 S*,5S*)-5- methoxy-2-oxocyclohexyl)benzoate (223 mg) as a brownish oil. LC-MS Method B-1 : Rt = 0.66 min; MS m / z [M+H]+= 293.2.

[0466] Intermediate rac-K-E103: rac methyl 2-(difluoromethoxy)-4-((1 S*,5S*)-5-methoxy-2- oxocyclohexyl)benzoate

[0467] Intermediate rac-K-E S was prepared as described for Intermediate rac-K-E101 using methyl 4- bromo-2-difluoromethoxybenzoate (500 mg, 1.78 mmol) and 4-methoxycyclohexan-1-one (319 mg, 2.49 mmol) to provide rac methyl 2-(difluoromethoxy)-4-((1 S*,5S*)-5-methoxy-2- oxocyclohexyl)benzoate benzoate (146 mg) as a light yellow semi-solid. LC-MS Method B-1 : Rt = 0.83 min; MS m / z [M+H]+= 329.2.

[0468] Intermediate rac-K-E104: rac methyl 4-((1S*,5S*)-5-methoxy-2-oxocyclohexyl)-2- nitrobenzoate

[0469] Intermediate rac-K-E104 was prepared as described for Intermediate rac-K-E101 using methyl 4- bromo-2-nitrobenzoate (3.63 g, 14.0 mmol) and 4-methoxycyclohexan-1-one (2.51 g, 19.5 mmol) to provide rac methyl 4-((1 S*,5S*)-5-methoxy-2-oxocyclohexyl)-2-nitrobenzoate (980 mg) as a light red oil.1H NMR (400 MHz, CDCI3) 6 [ppm] 7.72 (d, J = 7.9 Hz, 1 H), 7.70 (d, J = 1 .7 Hz, 1 H), 7.46 - 7.43 (m, 1 H), 3.92 (s, 3H), 3.85 - 3.80 (m, 1 H), 3.80 - 3.75 (m, 1 H), 3.44 (s, 3H), 2.64 - 2.51 (m, 3H), 2.49 - 2.43 (m, 1 H), 2.04 - 1 .96 (m, 1 H), 1 .89 - 1 .80 (m, 1 H). PAT059793-PCT-SEC01

[0470] Intermediate rac-K-E105: rac methyl 2-fluoro-4-((1S*,5S*)-5-methoxy-2- oxocyclohexyl)benzoate

[0471] A mixture of methyl 4-bromo-2-fluorobenzoate (4.00 g, 17.2 mmol), 4-methoxycyclohexan-1-one (3.08 g, 24.0 mmol), K3PO4 (8.38 g, 39.5 mmol), Xantphos (437 mg, 755 pmol), and Pd2dba3(314 mg, 343 pmol) in toluene (42 mL) was purged with N2and stirred at 90 °C for 1 .5 h. The RM was allowed to cool to RT and diluted with toluene and H2O. The mixture was filtered over Celite®. The collected separated org phase was washed with sat. aq NaHCO3soln and brine, and the aq layer was extracted with toluene. The combined org phases were dried over MgSC , filtered and concentrated under reduced pressure. Enrichment was achieved by RP purification over C18 (360 g; eluent: 30 to 60% ACN in H2O). The residue was purified over silica gel (120 g; eluent: O to 35.1 % EtOAc in heptane) to provide rac methyl 2-fluoro-4-((1 S*,5S*)-5-methoxy-2- oxocyclohexyl)benzoate (1 .22 g) as a light yellow solid. LC-MS Method B-1 : Rt = 0.78 min; MS m / z [M+H]+= 281.3.

[0472] Intermediate K-E116-E117: methyl 4-(5-(2,2-difluoroethoxy)-2-oxocyclohexyl)-3- methoxybenzoate (trans / cis mixture)

[0473] To a mixture of 4-(2,2-difluoroethoxy)cyclohexan-1-one (Intermediate K1-E116-E117, 2.62 g, 14.7 mmol), methyl 4-bromo-3-methoxybenzoate (3.00 g, 12.2 mmol) and Xantphos (312 mg, 539 pmol) in toluene (30 mL) was added powdered K3PO4(5.98 g, 26.2 mmol). The mixture was brought under N2atmosphere. Pd2(dba)3(224 mg, 245 pmol) was added, and the mixture was stirred at 90 °C overnight. The RM was allowed to cool to RT and filtered over Celite®, and the solids were washed with toluene (4x). The filtrate was concentrated under reduced pressure at 50 °C.

[0474] Purification by HPLC (Teledyne Redisep® C18, 360 g; 40 to 63 pm; eluent: 30 to 60% ACN in water with 0.1% NH4OH) provided methyl 4-(5-(2,2-difluoroethoxy)-2-oxocyclohexyl)-3-methoxybenzoate (2.27 g, trans / cis = 63 / 37) as a colorless oil. LC-MS Method B-1 : Rt = 0.82 min; [M+H]+= 360.1 ; Rt = 0.87 min; [M+H]+= 360.1.

[0475] Intermediate K-E208-E209: methyl 4-(2,2-difluoro-7-oxospiro[3.5]nonan-6-yl)-2- methoxybenzoate PAT059793-PCT-SEC01

[0476] To a mixture of 2,2-difluorospiro[3.5]nonan-7-one (Intermediate K2-E208-E209.782 mg, 4.49 mmol), methyl 4-bromo-2-methoxybenzoate (1.00 g, 4.08 mmol) and Xantphos (104 mg, 180 pmol) in toluene (10 mL) was added powdered K3PO4(1 .99 g, 9.39 mmol). The mixture was brought under N2atmosphere, Pd2(dba)3(74.7 mg, 81 .6 pmol) was added, and the mixture was stirred at 90 °C for 6.5 h. The RM was allowed to cool to RT and filtered over Celite®, and the solids were washed with toluene (4x). The filtrate was concentrated under reduced pressure at 50 °C. The residue was purified by column chromatography over silica gel (eluent: 10 to 50% EtOAc in cyclohexane) to provide methyl 4-(2,2-difluoro-7-oxospiro[3.5]nonan-6-yl)-2-methoxybenzoate (459 mg) as an orange-brownish oil. LC-MS Method B-2: Rt = 4.10 min; MS m / z [M+H]+= 339.2. Intermediate K-E212-E213: methyl 2-methyl-4-(7-oxo-2-oxaspiro[3.5]nonan-6-yl)benzoate

[0477] A vial was charged with 6-bromo-2-oxaspiro[3.5]nonan-7-one (Intermediate K3-E212-E213, 1 .56 g, 7.13 mmol), (4-(methoxycarbonyl)-3-methylphenyl)boronic acid (1.38 g, 7.13 mmol), and Na2CO3(1.13 g, 10.7 mmol). The vial was purged with argon and then hexafluoro / sopropanol (23 mL) was added. The RM was stirred at 65 °C for 24 h in a sealed vial. The mixture was concentrated under reduced pressure and the residue was diluted with DCM and water. The phases were separated using Isolute® phase separator, and the org phase was concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (eluent: 0 to 30% EtOAc in DCM) to provide methyl 2-methyl-4-(7-oxo-2-oxaspiro[3.5]nonan-6-yl)benzoate (824 mg) as a colorless oil. LC-MS Method B-1 : Rt = 0.68 min; MS m / z [M-H]- = 287.0

[0478] The following compounds were synthesized from the appropriate starting materials by applying similar methods described in the examples above. PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01

[0479] Intermediate rac-A-E1 : rac tert-butyl (3R*,4S*)-4-hydroxy-3-(3-methoxy-4- (methoxycarbonyl)phenyl)piperidine-1 -carboxylate

[0480] O O' tert-Butyl 3-(3-methoxy-4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1 -carboxylate (Intermediate K-E1 , 12 g, 33.1 mmol) was combined with MeOH (100 mL). The soln was cooled to 0 °C, and NaBH4(624 mg, 16.5 mmol) was added. The RM was stirred for 10 min. The RM was quenched with H2O and allowed to warm to RT. The mixture was extracted with EtOAc (3x). The combined org phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified over silica gel (24 g; eluent: 40% EtOAc in heptane) to provide rac fert-butyl (3R*,4S*)-4-hydroxy-3-(3-methoxy-4-(methoxycarbonyl)phenyl)piperidine-1- carboxylate (3.9 g) as a brown oil.1H NMR (400 MHz, CDCI3) 6 [ppm] 7.80 (d, J = 8.00 Hz, 1 H), 6.90 - 6.87 (m, 2H), 4.24 - 4.09 (m, 2H), 3.89 - 3.86 (m, 7H), 2.88 - 2.82 (m, 2H), 2.66 - 2.60 (m, 1 H), 2.09 - 2.03 (m, 1 H), 1 .63 (m, 1 H), 1.47 (s, 9H). 26 of 27H reported. Intermediate rac-A-E2: rac tert-butyl (3R*,4S*)-3-(3-fluoro-4-(methoxycarbonyl)phenyl)-4- hydroxypiperidine-1 -carboxylate PAT059793-PCT-SEC01

[0481] Four equal batches of fert-butyl 3-(3-fluoro-4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1- carboxylate (Intermediate K-E2, 2.1 g, 23.9 mmol each) were combined with THF (20 mL each). The soln was cooled to -20 °C, and lithium tri-sec-butylborohydride soln (1 M in THF, 11 .8 mL, 11 .8 mmol each) was added. The RM was stirred for 30 min. The RM was quenched with sat. NH4CI soln and allowed to warm to RT. The combined mixtures were extracted with EtOAc (4x). The combined org phases were dried over Na2SO4and concentrated under reduced pressure. The residue was purified over silica gel (80 g; eluent: 0 to 80% EtOAc in hexane) to provide rac tertbuty (3R*,4S*)-3-(3-fluoro-4-(methoxycarbonyl)phenyl)-4-hydroxypiperidine-1 -carboxylate (2.6 g) as a yellow oil. LC-MS Method A-2: Rt = 1 .79 min; MS m / z [M+H]+= 354.4.

[0482] Intermediate rac-A-E5: rac tert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)-3- methylphenyl)piperidine-1 -carboxylate

[0483] Rac fert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)-3-methylphenyl)piperidine-1 - carboxylate was prepared as described for Intermediate rac-A-E2 starting from fert-butyl 3-(4- (methoxycarbonyl)-3-methylphenyl)-4-oxopiperidine-1 -carboxylate (Intermediate K-E5, 12 g, 34.5 mmol) to provide rac fert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)-3- methylphenyl)piperidine-1 -carboxylate (6.0 g) as a light yellow oil. LC-MS Method A-2: Rt = 1 .74 min; MS m / z [M+H]+= 350.4.

[0484] Intermediate rac-A-E7: rac tert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidine-1 -carboxylate fert-Butyl 3-(4-(methoxycarbonyl)-2-methylphenyl)-4-oxopiperidine-1 -carboxylate (Intermediate K- E7, 2.00 g, 3.6 mmol) was dissolved in THF (10 mL). The soln was cooled to 0 °C, and potassium tri-sec-butylborohydride soln (1 M in THF, 9 mL, 9 mmol) was added. The RM was stirred for 80 min. The RM was quenched with sat. NH4CI soln and allowed to warm to RT. The mixture was extracted with EtOAc (3x). The combined org phases were dried over MgSO4and concentrated PAT059793-PCT-SEC01 under reduced pressure. The residue was purified over silica gel (120 g; eluent: 0 to 40% EtOAc in hexane) to provide rac fert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidine-1 -carboxylate (2.6 g) as a yellowish oil. LC-MS Method B1 : Rt = 1.08 min;

[0485] MS m / z [M-fBu+2H]+= 294.3.

[0486] Intermediate rac-A-E9: rac tert-butyl (3R*,4S*)-4-hydroxy-3-(2-methoxy-4-

[0487] (methoxycarbonyl)phenyl)piperidine-1 -carboxylate

[0488] Rac fert-butyl (3R*,4S*)-4-hydroxy-3-(2-methoxy-4-(methoxycarbonyl)phenyl)piperidine-1 - carboxylate was prepared as described for Intermediate rac-A-E7 starting from fert-butyl 3-(2- methoxy-4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate (Intermediate K-E9, 850 mg, 2.22 mmol) to provide rac fert-butyl (3R*,4S*)-4-hydroxy-3-(2-methoxy-4-

[0489] (methoxycarbonyl)phenyl)piperidine-1-carboxylate (570 mg) as a white solid. LC-MS Method C-2: Rt = 1 .05 min; MS m / z [M-Boc+2H]+= 266.4.

[0490] Intermediate rac-A-E101 : rac methyl 4-((1S*,2S*,5S*)-2-hydroxy-5-methoxycyclohexyl)-2- methoxybenzoate

[0491] Rac methyl 2-methoxy-4-((1 S*,5S*)-5-methoxy-2-oxocyclohexyl)benzoate (Intermediate rac-K- E101 , 398 mg, 1 .36 mmol) was combined with THF (8 mL). The soln was cooled to -78 °C, and lithium tri-sec-butylborohydride soln (1 M in THF, 1 .63 mL, 1 .63 mmol) was added. The RM was stirred for 1 h. Additional lithium tri-sec-butylborohydride soln (1 M in THF, 0.34 mL, 0.34 mmol) was added, and the RM was stirred for 15 min. The RM was quenched with sat. 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 Na2SO4, and concentrated under reduced pressure. The residue was purified over silica gel (40 g; eluent: 0 to 40% EtOAc in cyclohexane) to provide rac methyl 4-((1 S*,2S*,5S*)-2-hydroxy-5-methoxycyclohexyl)-2- methoxybenzoate (258 mg) as a colorless semi-solid. LC-MS Method B-1 : Rt = 0.70 min; MS m / z [M+H]+= 295.1.

[0492] Intermediate rac-A-E103: rac methyl 2-(difluoromethoxy)-4-((1S*,2S*,5S*)-2-hydroxy-5- methoxycyclohexyl)benzoate PAT059793-PCT-SEC01

[0493] Intermediate rac-A-E103 was prepared as described for Intermediate rac-A-E101 using rac methyl 2-(difluoromethoxy)-4-((1 S*,5S*)-5-methoxy-2-oxocyclohexyl)benzoate (Intermediate rac-K-E103, 146 mg, 0.44 mmol) to provide rac methyl 2-(difluoromethoxy)-4-((1 S*,2S*,5S*)-2-hydroxy-5- methoxycyclohexyl)benzoate (82.5 mg) as a colorless oil. LC-MS Method B-1 : Rt = 0.85 min; MS m / z [M+H]+= 331.1.

[0494] Intermediate rac-A-E104: rac methyl 4-((1S*,2S*,5S*)-2-hydroxy-5-methoxycyclohexyl)-2- nitrobenzoate

[0495] Rac methyl 4-((1 S*,5S*)-5-methoxy-2-oxocyclohexyl)-2-nitrobenzoate (Intermediate rac-K-E104, 880 mg, 2.86 mmol) was combined with THF (9 mL). The soln was cooled to -78 °C, and lithium tri- sec-butylborohydride soln (1 M in THF, 6.3 mL, 6.3 mmol) was added. The RM was stirred for 45 min. The RM was quenched with MeOH and allowed to warm to RT. The mixture was partitioned between sat. NH4CI soln and TBME. The aq phase was extracted with TBME. The combined org phases were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified using RP HPLC (Waters XBridge C18 50 x 100 mm; 5 pm; eluent: 10 to 60% ACN in H2O with 0.1% TFA) to provide rac methyl 4-((1 S*,2S*,5S*)-2-hydroxy-5- methoxycyclohexyl)-2-nitrobenzoate (191.5 mg) as a yellow oil. LC-MS Method B-1 : Rt = 0.77 min; MS m / z [M+NH4]+= 327.1.

[0496] Intermediate rac-A-E11 : rac tert-butyl (3R*,4S*)-3-(3-chloro-4-(methoxycarbonyl)phenyl)-4- hydroxypiperidine-1 -carboxylate

[0497] Enriched fert-butyl 3-(3-chloro-4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1 -carboxylate (Intermediate rac-K-E11 , 1.18 g) was dissolved in THF (10 mL) and cooled to 0 °C. Potassium tri- sec-butylborohydride soln (1 M in THF, 3.63 mL, 3.63 mmol) was added in a dropwise manner, and the resulting RM was stirred at 0 °C for 20 min. The RM was carefully quenched with sat. aq NH4CI PAT059793-PCT-SEC01 soln. The mixture was extracted with EtOAc (3x), and the combined org phases were dried over MgSO4and concentrated under reduced pressure. The residue was purified over silica gel (120 g; eluent: 0 to 40% EtOAc in heptane) to provide rac tert-butyl (3R,4S)-3-(3-chloro-4- (methoxycarbonyl)phenyl)-4-hydroxypiperidine-1-carboxylate (321.9 mg) as a white solid. LC-MS Method C-2: Rt = 1 .04 min; MS m / z [M-Boc+2H]+= 270.2.

[0498] Intermediate rac-A-E105: rac methyl 2-fluoro-4-((1S*,2S*,5S*)-2-hydroxy-5- methoxycyclohexyl)benzoate

[0499] To a soln of rac methyl 2-fluoro-4-((1 S*,5S*)-5-methoxy-2-oxocyclohexyl)benzoate (Intermediate rac-K-EIOS, 1 .02 g, 3.57 mmol) in THF (15 mL) at -78 °C was added dropwise a lithium tri-sec- butylborohydride soln (1 M in THF, 5.35 mL, 5.35 mmol). The RM was stirred at -78 °C for 3 h. The RM was quenched with MeOH. The mixture was diluted with sat. NaHCO3soln, H2O, and EtOAc and was then allowed to warm to RT. The separated aq phase was extracted with EtOAc (2x). The combined org phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Enrichment over silica gel (40 g; eluent: 0 to 50% EtOAc in cyclohexane) provided rac methyl 2-fluoro-4-((1 S*,2S*,5S*)-2-hydroxy-5-methoxycyclohexyl)benzoate (647 mg) as a colorless oil. LC-MS Method B-1 : Rt = 0.79 min; MS m / z [M+H]+= 283.2.

[0500] Intermediate rac-A-E14: rac tert-butyl (3R*,4R*)-3-(2-fluoro-4-(methoxycarbonyl)phenyl)-4- hydroxypiperidine-1 -carboxylate

[0501] Enriched rac fert-butyl 3-(2-fluoro-4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1 -carboxylate (Intermediate K-E14, 1 .42 g) was dissolved in THF (8 mL) and cooled to 0 °C. Potassium tri-sec- butylborohydride soln (1 M in THF, 6.39 mL, 6.39 mmol) was added in a dropwise manner, and the resulting RM was stirred at 0 °C for 45 min. The RM was carefully diluted with sat. aq NH4CI soln. The mixture was extracted with EtOAc (3x), and the combined org phases were dried over MgSO4, filtered off and concentrated under reduced pressure. The residue was purified over silica gel (120 g; eluent: 0 to 50% EtOAc in heptane) to provide rac fert-butyl (3R*,4R*)-3-(2-fluoro-4- (methoxycarbonyl)phenyl)-4-hydroxypiperidine-1 -carboxylate (423.6 mg) as a white solid. LC-MS Method C-2: Rt = 1 .03 min; MS m / z [M-Hp = 352.3. PAT059793-PCT-SEC01

[0502] Intermediate rac-A-E25-E26-1 and Intermediate rac-A-E25-E26-2: rac tert-butyl (3R*,4S*)-4- hydroxy-3-(4-(methoxycarbonyl)-3-nitrophenyl)piperidine-1 -carboxylate and rac tert-butyl ethoxycarbonyl)-3-nitrophenyl)piperidine-1 -carboxylate

[0503] A soln of fert-butyl 3-(4-(methoxycarbonyl)-3-nitrophenyl)-4-oxopiperidine-1 -carboxylate (Intermediate K-E25-E26, 3.80 g, 10.04 mmol) in EtOH (52 mL) was cooled to 0 to 5 °C. Powdered NaBH4(228 mg, 6.03 mmol) was added in one portion. The RM was stirred in the ice bath for 20 min. The RM was diluted with TBME, and water was added. To the mixture was carefully added an aq 1 M HCI soln, and the layers were separated. They org layer was washed with brine, aq layer was extracted with TBME. The combined org layers were dried over MgSO4, filtered and concentrated under reduced pressure at 50 °C. Purification by column chromatography over silica gel (eluent: 15 to 42% EtOAc in heptane with 5% MeOH) provided rac fert-butyl (3R*,4S*)-4- hydroxy-3-(4-(methoxycarbonyl)-3-nitrophenyl)piperidine-1 -carboxylate (1.16 g; first eluting) as a pale yellow foam and rac tert-butyl (3R*,4R*)-4-hydroxy-3-(4-(methoxycarbonyl)-3- nitrophenyl)piperidine-1-carboxylate (1.59 g; second eluting) as a pale yellow foam. Intermediate rac-A-E25-E26-1 (first eluting):1H NMR: 600 MHz, DMSO-c / 66 [ppm] 7.95 (d, J = 1.6 Hz, 1 H), 7.80 (d, J = 7.9 Hz, 1 H), 7.73 (dd, J = 8.0, 1 .6 Hz, 1 H), 4.91 (d, J = 4.2 Hz, 1 H), 4.02 - 3.96 (m, 1 H), 3.84 (s, 3H), 3.82 - 3.68 (m, 2H), 3.57 - 3.34 (m, 1 H), 3.28 - 3.07 (m, 1 H), 3.02 - 2.96 (m, 1 H), 1.71 - 1 .63 (m, 2H), 1 .39 (s, 9H). LC-MS Method B-2: Rt = 4.68 min; MS m / z [M-Boc+2H]+= 281.1. Intermediate rac-A-E25-E26-2 (second eluting):1H NMR: 600 MHz, DMSO-c / 65 [ppm] 7.98 (d, J = 1 .6 Hz, 1 H), 7.82 (d, J = 7.9 Hz, 1 H), 7.74 (dd, J = 8.0, 1 .6 Hz, 1 H), 4.84 (d, J = 5.8 Hz, 1 H), 4.03 - 3.86 (m, 2H), 3.84 (s, 3H), 3.83 - 3.76 (m, 1 H), 3.12 - 2.79 (m, 2H), 2.67 - 2.60 (m, 1 H), 1.92 - 1 .86 (m, 1 H), 1.45 - 1.30 (m, 10H). LC-MS Method B-2: Rt = 4.52 min; MS m / z [M- Boc+2H]+= 281.1.

[0504] Intermediate rac-A-E43-E44: rac tert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)-2- (trifluoromethyl)phenyl)piperidine-1 -carboxylate

[0505] A mixture of lithium tri-sec-butylborohydride soln (1 M in THF, 24.9 mL, 24.9 mmol) and THF (7.0 mL) under N2atmosphere was cooled to -78 °C. A soln of rac tert-butyl 3-(4-(methoxycarbonyl)-2- (trifluoromethyl)phenyl)-4-oxopiperidine-1 -carboxylate (Intermediate K-E43-E44, 3.3 g, 8.3 mmol) PAT059793-PCT-SEC01 in THF (22 mL) was added in a dropwise manner over a period of 40 min using a syringe pump. The RM was stirred at -78 °C for 20 min. The cold RM was directly poured into a well stirred mixture of aq NH4CI soln (10 wt%) and TBME. The mixture was stirred for 5 min. The layers were then separated and washed with aq NH4CI soln (10 wt%), brine and TBME. The combined org layers were dried over MgSO4, filtered, and MeOH was added to the filtrate. The mixture was concentrated under reduced pressure at 50 °C. The residue was dissolved in MeOH, and the mixture was again concentrated under reduced pressure at 50 °C; this process was repeated twice. Column chromatography over silica gel (120 g; eluent: 0 to 19% EtOAc in DCM) provided rac fert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)-2-(trifluoromethyl)phenyl)piperidine-1- carboxylate(1 .16 g) as a white solid. LC-MS Method B2: Rt = 5.91 min; MS m / z [M-fBu+2H]+= 348.2.

[0506] Intermediate rac-A-E51-E52: rac tert-butyl (3R*,4S*)-3-(2-cyclopropyl-4- (methoxycarbonyl)phenyl)-4-hydroxypiperidine-1 -carboxylate

[0507] A mixture of lithium tri-sec-butylborohydride soln (1 M in THF, 25.5 mL, 25.5 mmol) and THF (7.2 mL) under N2atmosphere was cooled to -78 °C. A soln of fert-butyl 3-(2-cyclopropyl-4- (methoxycarbonyl)phenyl)-4-oxopiperidine-1-carboxylate (Intermediate K-E51-E52, 3.2 g, 8.5 mmol) in THF (23 mL) was added in a dropwise manner over a period of 40 min using a syringe pump. The RM was stirred at -78 °C for 50 min and then directly poured into a well stirred mixture of aq NH4CI soln (10 wt%) and TBME. The mixture was stirred for 5 min. The separated org layer was washed with aq NH4CI soln (10 wt%), brine, and TBME. The combined org layers were dried over MgSO4, filtered, and diluted with MeOH. The mixture was concentrated under reduced pressure at 50 °C. The residue was dissolved in MeOH, and the mixture was again concentrated under reduced pressure at 50 °C; this process was repeated twice. Column chromatography over silica gel (120 g; eluent: 3 to 20% TBME in DCM) provided rac fert-butyl (3R*,4S*)-3-(2- cyclopropyl-4-(methoxycarbonyl)phenyl)-4-hydroxypiperidine-1 -carboxylate (2.52 g) as a white solid. LC-MS Method B2: Rt = 5.67 min; MS m / z [M-Boc+2H]+= 276.2.

[0508] Intermediate rac-A-E116-E117-1 and Intermediate rac-A-E116-E117-2: rac methyl 4- ((1 S*,2S*,5S*)-5-(2,2-difluoroethoxy)-2-hydroxycyclohexyl)-3-methoxybenzoate and rac methyl 4-((1R*,2R*,5S*)-5-(2,2-difluoroethoxy)-2-hydroxycyclohexyl)-3-methoxybenzoate PAT059793-PCT-SEC01

[0509] To a mixture of lithium tri-sec-butylborohydride soln (1 M in THF, 19.9 mL, 19.9 mmol) and THF (5.62 mL) under N2atmosphere at -78 °C was added a soln of methyl 4-(5-(2,2-difluoroethoxy)-2- oxocyclohexyl)-3-methoxybenzoate (Intermediate K-E116-E117, 2.27 g, 6.63 mmol) in THF (17.7 mL) over a period of 40 min utilizing a syringe pump. The RM was stirred for an additional 20 min at -78 °C. The cooling bath was removed, and the RM was carefully diluted with aq 1 M HCI soln. The mixture was allowed to warm up to RT, and water and TBME were added. The layers were separated, the org layer was washed with aq 1 M HCI soln and brine, and the aq layer was extracted with TBME. The combined org layers were dried over MgSO4, filtered off, and the filtrate was diluted with MeOH and concentrated under reduced pressure at 50 °C. The residue was dissolved in MeOH, and the volatiles were removed under reduced pressure at 50 °C (3x). Purification by column chromatography over silica gel (eluent: 0 to 15% EtOAc in DCM) provided rac methyl 4-((1 S*,2S*,5S*)-5-(2,2-difluoroethoxy)-2-hydroxycyclohexyl)-3-methoxybenzoate (1.17 g; first eluting) as a white solid and enriched rac methyl 4-((1 R*,2R*,5S*)-5-(2,2-difluoroethoxy)-2- hydroxycyclohexyl)-3-methoxybenzoate (664 mg; second eluting) as a white solid. Intermediate rac-A-E116-E117-1 (first eluting):1H NMR: 600 MHz, DMSO-c / 66 [ppm] 7.52 (dd, J = 7.9, 1.6 Hz, 1 H), 7.43 (d, J = 1 .6 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 6.24 - 6.02 (m, 1 H), 4.29 (d, J = 4.5 Hz, 1 H), 3.86 (s, 1 H), 3.85 - 3.81 (m, 7H), 3.70 - 3.62 (m, 2H), 3.46 - 3.41 (m, 1 H), 2.21 - 2.14 (m, 1 H), 1 .85 - 1 .77 (m, 2H), 1 .70 - 1 .63 (m, 1 H), 1 .62 - 1 .57 (m, 1 H), 1 .56 - 1 .48 (m, 1 H). LC-MS Method B-1 : Rt = 0.97 min; MS m / z no ionization. Intermediate rac-A-E116-E117-2 (second eluting):1H NMR: 600 MHz, DMSO-c / 66 [ppm] 7.53 (dd, J = 7.9, 1 .6 Hz, 1 H), 7.44 (d, J = 1 .7 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 6.21 - 6.00 (m, 1 H), 4.32 (d, J = 4.7 Hz, 1 H), 3.84 (s, 3H), 3.84 (s, 3H), 3.81 - 3.77 (m, 1 H), 3.76 - 3.67 (m, 2H), 3.53 - 3.46 (m, 1 H), 3.10 - 3.05 (m, 1 H), 1.99 - 1 .90 (m, 1 H), 1 .82 - 1 .74 (m, 2H), 1 .74 - 1 .69 (m, 1 H), 1 .65 - 1 .49 (m, 2H). LC-MS Method B-1 : Rt = 0.92 min; MS m / z [M+H]+= 345.2

[0510] Intermediate rac-A-E120-E121 -1 and Intermediate rac-A-E120-E1121-2: rac methyl 4- nd rac methyl PAT059793-PCT-SEC01

[0511] To a mixture of lithium tri-sec-butylborohydride soln (1 M in THF, 15.3 mL, 15.3 mmol) and THF (4.3 mL) under N2atmosphere at -78 °C was added a soln of methyl 4-(5-(2,2-difluoroethoxy)-2- oxocyclohexyl)-3-methylbenzoate (Intermediate K-E120-E121 , 1 .66 g, 5.09 mmol) in THF (13.6 mL) over a period of 35 min utilizing a syringe pump. The RM was stirred for an additional 30 min at -78 °C. The cooling bath was removed, and the RM was carefully diluted with aq 1 M HCI soln. The mixture was allowed to warm up to RT, and water and TBME were added. The layers were separated, the org layer was washed with aq 1 M HCI soln and brine, and the aq layer was extracted with TBME. The combined org layers were dried over MgSO4, filtered off, and the filtrate was diluted with MeOH and concentrated under reduced pressure at 50 °C. The residue was dissolved in MeOH, and the volatiles were removed under reduced pressure at 50 °C (3x). Purification by column chromatography over silica gel (eluent: 0 to 13% EtOAc in DCM) provided rac methyl 4-((1 S*,2S*,5S*)-5-(2,2-difluoroethoxy)-2-hydroxycyclohexyl)-3-methylbenzoate (943 mg; first eluting) as a white solid and enriched rac methyl 4-((1 R*,2R*,5S*)-5-(2,2-difluoroethoxy)- 2-hydroxycyclohexyl)-3-methylbenzoate (352 mg; second eluting) as a colorless oil. Intermediate rac-A-E120-E121-1 (first eluting):1H NMR: 600 MHz, DMSO-c / 66 [ppm] 7.75 - 7.69 (m, 2H), 7.42 (d, J = 8.0 Hz, 1 H), 6.24 - 6.03 (m, 1 H), 4.42 (d, J = 4.3 Hz, 1 H), 3.82 (s, 4H), 3.80 (s, 1 H), 3.72 - 3.62 (m, 2H), 3.29 - 3.24 (m, 1 H), 2.32 (s, 3H), 2.25 - 2.19 (m, 1 H), 1 .89 - 1 .81 (m, 2H), 1 .70 - 1 .64 (m, 1 H), 1 .64 - 1 .58 (m, 1 H), 1 .58 - 1 .52 (m, 1 H). LC-MS Method B-2: Rt = 4.86 min; MS m / z [M+H]+329.2. Intermediate rac-A-E120-E121 -2 (second eluting):1H NMR: 600 MHz, DMSO-c / 66 [ppm] 7.75 - 7.70 (m, 2H), 7.40 (d, J = 8.0 Hz, 1 H), 6.21 - 6.00 (m, 1 H), 4.40 (d, J = 4.7 Hz, 1 H), 3.82 (s, 3H), 3.76 - 3.68 (m, 3H), 3.56 - 3.50 (m, 1 H), 2.95 - 2.89 (m, 1 H), 2.33 (s, 3H), 2.04 - 1 .97 (m, 1 H), 1 .82 - 1 .77 (m, 2H), 1 .75 - 1 .70 (m, 1 H), 1 .64 - 1 .58 (m, 2H). LC-MS Method B-2: Rt = 4.46 min; MS m / z [M+H]+= 329.2

[0512] Intermediate rac-A-E208-E209: rac methyl 4-((6S*,7S*)-2,2-difluoro-7- hydroxyspiro[3.5]nonan-6-yl)-2 -methoxybenzoate

[0513] To a mixture of lithium tri-sec-butylborohydride soln (1 M in THF, 4.54 mL, 4.54 mmol) and THF (1 .28 mL) under N2atmosphere at -78 °C was added a soln of methyl 4-(2,2-difluoro-7- oxospiro[3.5]nonan-6-yl)-2-methoxybenzoate (Intermediate K-E208-E209, 512 mg, 1 .51 mmol) in THF (4.00 mL) over a period of 30 min utilizing a syringe pump. The RM was stirred for an additional 30 min at -78 °C. The cooling bath was removed, and the RM was carefully diluted with aq 1 M HCI soln. The mixture was allowed to warm up to RT, and water and TBME were added. The layers were separated, the org layer was washed with aq 1 M HCI soln and brine, and the aq layer was extracted with TBME. The combined org layers were dried over MgSO4, filtered off, and PAT059793-PCT-SEC01 the filtrate was diluted with MeOH and concentrated under reduced pressure at 50 °C. The residue was dissolved in MeOH, and the volatiles were removed under reduced pressure at 50 °C (3x). Purification by column chromatography over silica gel (eluent: 0 to 15% EtOAc in DCM) provided rac methyl 4-((6S*,7S*)-2,2-difluoro-7-hydroxyspiro[3.5]nonan-6-yl)-2-methoxybenzoate (450 mg) as a colorless oil. LC-MS Method B-1 : Rt = 1 .00 min; MS m / z [M+H]+= 341 .2.

[0514] The following compounds were synthesized from the appropriate starting materials by applying similar methods to those described in the examples above. PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01

[0515] Intermediate rac-A2-E18: rac methyl 4-((3R*,4S*)-1-(2,2-difluoroethyl)-4-hydroxypiperidin-3- yl)indoline-7 -carboxylate

[0516] Rac methyl 4-((3R*,4S*)-1-(tert-butoxycarbonyl)-4-hydroxypiperidin-3-yl)-1 / 7-indole-7-carboxylate (Intermediate rac-A-E18, 1.90 g, 5.07 mmol) was combined with TFA (5.5 mL). The resulting soln was cooled to 0 °C, and triethylsilane (2.43 mL, 15.2 mmol) was added in a dropwise manner. The RM was allowed to warm to RT and stirred for 30 min. The RM was carefully diluted with sat. aq NaHCO3soln and extracted with EtOAc (2x). The combined org phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The aq phase was PAT059793-PCT-SEC01 lyophilized. The residue was triturated with MeOH, and the resulting suspension was filtrated. The filtrate was concentrated under reduced pressure and combined with the residue from the org phases above. Column chromatography over silica gel (50 g; eluent: 0 to 20% MeOH in DCM) provided a mixture of rac methyl 4-((3R*,4S*)-4-hydroxypiperidin-3-yl)indoline-7-carboxylate and rac methyl 4-((3R,4S)-4-hydroxypiperidin-3-yl)-1 H-indole-7-carboxylate (1 .38 g) as a yellowish solid. LC-MS Method-B-3: Rt = 0.75 min; MS m / z [M+H]+= 277.2. A Boc-protection of this mixture (1 .3 g) using Boc20 (1 .3 g, 6.0 mmol) and DMAP (61 mg, 0.5 mmol) in THF (5 mL) for 3 h at RT remained incomplete. The RM was diluted with water and extracted with EtOAc (2x). The separated aq. layer was lyophilized, and the residue was taken up in MeOH. The resulting suspension was filtered, and the filtrate was concentrated under reduced pressure to give the starting material (1 .4 g) that was directly used in the next step without further drying.

[0517] Step 2: rac methyl 4-((3R*,4S*)-1-(2,2-difluoroethyl)-4-hydroxypiperidin-3-yl)indoline-7- carboxylate (Intermediate rac-A2-E18)

[0518] To a soln of the mixture from Stepl (Intermediate rac-A2-E18-1 , 1 .4 g) in ACN (20 mL) was added Cs2CO3(4.99 g, 15.3 mmol) followed by 2,2-difluoroethyl trifluoromethanesulfonate (1 .09 g, 5.10 mmol). The RM was stirred for 45 min at 80 °C. The RM was diluted with ice-water and extracted with EtOAc (2x). The combined org phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Column chromatography over silica gel (50 g; eluent: 0 to 80% EtOAc in heptane) provided rac methyl 4-((3R*,4S*)-1-(2,2-difluoroethyl)-4-hydroxypiperidin- 3-yl)indoline-7-carboxylate (155 mg) as a white solid. LC-MS Method B-1 : Rt = 0.35 min; MS m / z [M+H]+= 341.1.

[0519] Isolation of chiral alcohols was achieved through chiral separations of the racemic mixtures:

[0520] Intermediate rac-A-EI (3.2 g) provided Intermediate A-E1e (peak 1 , 0.95 g) as a white solid; chiral separation and analytics according to Method SFC-A-E1 . Analytical chiral HPLC: Rt = 1 .67 min; 100% ee.

[0521] Intermediate rac-A-E2 (2.5 g) provided Intermediate A-E2e (peak 1 , 1 .05 g) as a yellowish oil; chiral separation and analytics according to Method SFC-A-E2. Analytical chiral HPLC: Rt = 1.72 min; 100% ee.

[0522] Intermediate rac-A-E5 (6.0 g) provided Intermediate A-E5e (peak 1 , 1 .0 g) as a yellowish oil; chiral separation and analytics according to Method SFC-A-E5. Analytical chiral HPLC: Rt = 2.05 min; 100% ee.

[0523] Intermediate rac-A-E7 (663 mg) provided Intermediate A-E7e (peak 1 , 297 mg) as a white solid; chiral separation and analytics according to Method SFC-A-E7. Analytical chiral HPLC: Rt = 1.55 min; 100% ee. PAT059793-PCT-SEC01

[0524] Intermediate rac-A-E9 (570 mg) provided Intermediate A-E9e (peak 1 , 277 mg) as a white solid; chiral separation and analytics according to Method SFC-A-E9. Analytical chiral HPLC: Rt = 2.45 min; 100% ee.

[0525] Intermediate rac-A-EI 1 (315.9 mg) provided Intermediate A-E11 e (peak 1 , 143 mg) as a white solid; chiral separation and analytics according to Method SFC-A-E11 . Analytical chiral HPLC: Rt = 1.46 min; 100% ee.

[0526] Intermediate rac-A-E14 (422.6 mg) provided Intermediate A-E14e (peak 1 , 201 .4 mg) as a white solid; chiral separation and analytics according to Method SFC-A-E14. Analytical chiral HPLC: Rt = 0.60 min; 100% ee. Intermediate rac-A-E15 (407.3 mg) provided Intermediate A-E15e (peak 1 , 145.1 mg) as a white solid; chiral separation and analytics according to Method SFC-A-E15. Analytical chiral HPLC: Rt = 1.52 min; 100% ee.

[0527] Intermediate / 'ac-A-E16 (651.3 mg) provided enriched Intermediate A-E16e (peak 1 , 348.6 mg) as a white solid; chiral separation and analytics according to Method SFC-A-E16. Analytical chiral HPLC: Rt = 1.03 min; 100% ee.

[0528] Intermediate rac-A-E201 (167.4 mg) provided Intermediate A-E201e (peak 1 , 40.9 mg) as a colorless oil; chiral separation and analytics according to Method SFC-A-E201 . Analytical chiral HPLC: Rt = 0.40 min; 100% ee. PAT059793-PCT-SEC01

[0529] Intermediate M-E1 : tert-butyl 4-(((3R,4 / ?)-1-(tert-butoxycarbonyl)-3-(3-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate PAT059793-PCT-SEC01 tert-Butyl (3 / ?, 4S)-4-hydroxy-3-(3-methoxy-4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate (Intermediate A-E1 e, 230.7 mg, 0.63 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 - carboxylate (Intermediate 1-1 , 150 mg, 0.57 mmol), and PPh3(225.8 mg, 0.86 mmol) were dissolved in THF (2.0 mL). The mixture was cooled to 0 °C. A soln of DBAD (198.3 mg, 0.86 mmol) in toluene (0.5 mL) was added to the cooled soln in a dropwise manner over 10 min. The RM was stirred at 0 °C for 15 min and then allowed to gradually warm to RT. The RM was stirred for 3 days at RT. The RM was diluted with H2O, and the mixture was extracted with EtOAc (3x). The combined extracts were washed with H2O, dried over Mg2SO4, and concentrated under reduced pressure. Column chromatography over silica gel (eluent: 0 to 50% EtOAc in heptane) provided enriched tert-butyl 4-(((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3-(3-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (295 mg) as a colorless oil. LC-MS Method C-1 : Rt = 1 .52 min; MS m / z [M+H]+= 609.2.

[0530] Intermediate M-E2: tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(3-fluoro-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate tert-Butyl (3 / ?,4S)-3-(3-fluoro-4-(methoxycarbonyl)phenyl)-4-hydroxypiperidine-1 -carboxylate (Intermediate A-E2e, 234.4 mg, 0.69 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 - carboxylate (Intermediate 1-1 , 150 mg, 0.57 mmol), and PPh3(225.8 mg, 0.86 mmol) were dissolved in THF (1 .5 mL). The mixture was cooled to 0 °C. A soln of DBAD (198.3 mg, 0.86 mmol) in toluene (1 .5 mL) was added to the cooled soln in a dropwise manner over 10 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. The RM was concentrated under reduced pressure. Column chromatography over silica gel (eluent: 0 to 50% EtOAc in heptane) provided enriched tert-butyl 4-(((3R,4 / ?)-1-(tert- butoxycarbonyl)-3-(3-fluoro-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole- PAT059793-PCT-SEC01

[0531] 1-carboxylate (223 mg) as a colorless oil. LC-MS Method C-2: Rt = 1.52 min; MS m / z [M-Boc+2H]+= 497.2.

[0532] Intermediate M-E4: tert-butyl 4-(((3R,4R)-1 -(tert-butoxycarbonyl)-3-(3-fluoro-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-chloro-7-methyl-1 H-indole-1 -carboxylate

[0533] Intermediate M-E4 was prepared as described for Intermediate M-E2 using fert-butyl 5-chloro-4- hydroxy-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-4, 125 mg, 0.44 mmol) and tert-butyl (3 / ?, 4S)-3-(3-fluoro-4-(methoxycarbonyl)phenyl)-4-hydroxypiperidine-1 -carboxylate (Intermediate A-E2e, 188.1 mg, 0.53 mmol) to provide enriched tert-butyl 4-(((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3- (3-fluoro-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-chloro-7-methyl-1 / - / -indole-1 -carboxylate (209 mg). LC-MS Method C-1 : Rt = 1 .57 min; MS m / z [M-Boc+2H]+= 517.2.

[0534] Intermediate M-E5: tert-butyl 4-(((3R,4 / ?)-1 -(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)-3- methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate tert-Butyl (3 / ?, 4S)-4-hydroxy-3-(4-(methoxycarbonyl)-3-methylphenyl)piperidine-1 -carboxylate (Intermediate A-E5e, 608.4 mg, 1 .74 mmol) and tert-butyl 4-hydroxy-5,7-dimethyl-1 H-indole-1 - carboxylate (Intermediate 1-1 , 350 mg, 1.34 mmol) were dissolved in THF and cooled to 0 °C. PPh3(1 .05 g, 4.02 mmol) was added, followed by DBAD (936 mg, 4.02 mmol). The RM was allowed to warm to RT and stirred for 2 h. The RM was concentrated under reduced pressure. Column chromatography over silica gel (40 g; eluent: 4 to 5% EtOAc in cyclohexane) provided enriched tert-butyl 4-(((3 / ?,4 / ?)-1 -(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)-3-methylphenyl)piperidin-4- yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate as a brown oil (250 mg. LC-MS Method A-1 : Rt = 2.43 min; MS m / z [M-Boc+2H]+= 493.2.

[0535] Intermediate M-E7: tert-butyl 4-(((3R,4 / ?)-1 -(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate PAT059793-PCT-SEC01

[0536] Intermediate M-E7 was prepared as described for Intermediate M-E1 using tert-butyl 4-hydroxy- 5, 7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 100 mg, 0.38 mmol) and tert-butyl (3R,4S)- 4-hydroxy-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidine-1 -carboxylate (Intermediate A-E7e, 147.1 mg, 0.42 mmol) in THF (3 mL) to provide enriched tert-butyl 4-(((3R,4 / ?)-1-(tert- butoxycarbonyl)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole-1 -carboxylate (184.3 mg). LC-MS Method C-1 : Rt = 1.59 min; MS m / z [M-Boc+2H]+= 493.3.

[0537] Intermediate M-E8: tert-butyl 4-(((3 / ?,4 / ?)-1 -(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidin-4-yl)oxy)-5-chloro-7-methyl-1 H-indole-1 -carboxylate

[0538] Intermediate M-E8 was prepared as described for Intermediate M-E1 using tert-butyl 5-chloro-4- hydroxy-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-4, 108 mg, 0.38 mmol) and tert-butyl (3 / ?, 4S)-4-hydroxy-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidine-1 -carboxylate (Intermediate A-E7e, 147.3 mg, 0.42 mmol) in THF (3 mL) to provide enriched tert-butyl 4-(((3R,4 / ?)-1-(tert- butoxycarbonyl)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5-chloro-7-methyl-1 / 7- indole-1 -carboxylate (170.7 mg). LC-MS Method C-1 : Rt = 1.61 min; MS m / z [M-Boc+2H]+= 513.4.

[0539] Intermediate M-E9: tert-butyl 4-(((3R,4 / ?)-1 -(tert-butoxycarbonyl)-3-(2-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate PAT059793-PCT-SEC01 tert-Butyl (3 / ?, 4S)-4-hydroxy-3-(2-methoxy-4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate (Intermediate A-E9e, 137.3 mg, 0.38 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 H-indole-1 - carboxylate (Intermediate 1-1 , 105 mg, 0.34 mmol), and PPh3(225.8 mg, 0.86 mmol) were dissolved in THF (3 mL). The mixture was cooled to 0 °C. A DBAD soln (119.3 mg, 0.51 mmol) in toluene (2 mL) was added to the cooled soln in a dropwise manner over 10 min. The RM was allowed to gradually warm to RT. The RM was stirred for 3 days at RT. The mixture was extracted with EtOAc (3x). The combined org phases were washed with H2O, dried over Mg2SO4, and concentrated under reduced pressure. Column chromatography over silica gel (eluent: 0 to 50% EtOAc in heptane) provided enriched tert-butyl 4-(((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3-(2-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (117 mg) as a colorless oil. LC-MS Method C-1 : Rt = 1 .55 min; MS m / z [M+H]+= 609.5.

[0540] Intermediate M-E10: tert-butyl 4-(((3 / ?,4 / ?)-1-ftert-butoxycarbonyl)-3-(2-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-chloro-7-methyl-1 H-indole-1 -carboxylate

[0541] Intermediate M-E10 was prepared as described for Intermediate M-E9 using tert-butyl 5-chloro-4- hydroxy-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-4, 97 mg, 0.34 mmol) and tert-butyl (3 / ?, 4S)-4-hydroxy-3-(2-methoxy-4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate (Intermediate A-E9e, 138.4 mg, 0.38 mmol), to provide enriched tert-butyl 4-(((3R,4 / ?)-1 - tert- butoxycarbonyl)-3-(2-methoxy-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-chloro-7-methyl- 1 / 7-ind ole- 1 -carboxylate (152 mg) as a colorless oil. LC-MS Method C-1 : Rt = 1 .54 min; MS m / z [M+H]+= 629.4.

[0542] Intermediate M-E11 : tert-butyl 4-(((3R,4 / ?)-1-(tert-butoxycarbonyl)-3-(3-chloro-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate PAT059793-PCT-SEC01 tert-Butyl (3 / ?,4S)-3-(3-chloro-4-(methoxycarbonyl)phenyl)-4-hydroxypiperidine-1 -carboxylate (Intermediate A-E1 1 , 140 mg, 0.38 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 - carboxylate (Intermediate 1-1 , 90 mg, 0.34 mmol), and PPh3(90 mg, 0.34 mmol) were dissolved in DCM (1 .0 mL). The mixture was cooled to 0 °C, and a soln of DBAD (1 19 mg, 0.5 mmol) in toluene (1 .0 mL) was added in a dropwise manner. The RM was allowed to warm to RT and stirred for 18 h. Column chromatography over silica gel (40 g; eluent: 0 to 40% EtOAc in heptane) provided enriched tert-butyl 4-(((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3-(3-chloro-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (60.4 mg) as a colorless oil. LC-MS Method C-2: Rt = 1 .55 min; MS m / z [M-Boc+2H]+= 513.3.

[0543] Intermediate rac-M-E27-E28: rac tert-butyl 4-(((3R*,4R*)-1 -(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0544] A soln of rac tert-butyl (3 / ?*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidine-1- carboxylate (Intermediate rac-A-E7, 0.26 g, 0.74 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / 7- indole-1 -carboxylate (Intermediate 1-1 , 214 mg, 0.82 mmol) and PPh3(263 mg, 1.0 mmol) in toluene (3.8 mL) was cooled to 0 to 5 °C. A soln of DIAD (202 pL, 5.2 mmol) in toluene (1 .9 mL) was added in a dropwise manner. The RM was stirred overnight while allowing the temperature to reach RT. The mixture was concentrated under reduced pressure at 50 °C to give. RP chromatography (Waters Xbridge 50 mm x 100 mm 5 pm; eluent: 50 to 100% ACN in H2O with 0.1 % NH4OH) provided rac tert-butyl 4-(((3 / ?*,4 / ?*)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)- 2-methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (135 mg) as a light yellowish oil. LC-MS Method B1 : Rt = 1 .73 min; MS m / z [M+NH4]+= 610.5.

[0545] Intermediate rac-M-E43-E44: rac tert-butyl 4-(((3R*,4R*)-1 -(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1- carboxylate PAT059793-PCT-SEC01

[0546] A soln of rac tert-butyl (3 / ?*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)-2- (trifluoromethyl)phenyl)piperidine-1-carboxylate (Intermediate rac-A-E43-E44, 1.16 g, 2.9 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 601 mg, 2.3 mmol) and PPh3(1 .06 g, 4.0 mmol) in toluene (19 mL) was cooled to 0 to 5 °C. A soln of DIAD (839 pL, 4.2 mmol) in toluene (15.5 mL) was added in a dropwise manner over a period of 70 min using a syringe pump. The RM was stirred overnight while allowing the temperature to slowly reach RT. The RM was concentrated under reduced pressure at 50 °C. Column chromatography over silica gel (120 g; eluent: 2 to 19% EtOAc in cyclohexane) provided rac tert-butyl 4-(((3R*,4 / ?*)-1-(tert- butoxycarbonyl)-3-(4-(methoxycarbonyl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl- 1 / - / -indole- 1 -carboxylate (472 mg) as an off-white foam. LC-MS Method B2: Rt = 8.62 min; MS m / z [M-tBu+2H]+= 591.4.

[0547] Intermediate rac-M-E49-E50: rac tert-butyl 4-(((3R*,4R*)-1 -(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5-cyclopropyl-7-methyl-1H-indole-1- carboxylate

[0548] A soln of crude rac tert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidine-1 -carboxylate (crude sample of Intermediate rac-A-E7, 1 .08 g), tert-butyl 5-cyclopropyl-4-hydroxy-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate I-3, 720 mg, 2.51 mmol) and PPh3(806 mg, 3.07 mmol) in toluene (11 .6 mL) was cooled to 0 to 5 °C. A soln of DIAD (619 pL, 3.07 mmol) in toluene (5.8 mL) was added in a dropwise manner. The RM was stirred overnight while allowing the temperature to reach RT. The RM was concentrated under reduced pressure at 50 °C. RP chromatography (Waters Xbridge 50 mm x 100 mm 5 pm; eluent: 50 to 100% ACN in H2O with 0.1 % NH4OH) provided rac tert-butyl 4-(((3R*,4 / ?*)-1-(tert-butoxycarbonyl)- 3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5-cyclopropyl-7-methyl-1 / - / -indole-1- PAT059793-PCT-SEC01 carboxylate (202.4 mg) as a brownish oil. LC-MS Method B1 : Rt = 1 .74 min; MS m / z [M+NH4]+= 636.5.

[0549] Intermediate rac-M-E51-E52: rac tert-butyl 4-(((3R*,4R*)-1-(tert-butoxycarbonyl)-3-(2- cyclopropyl-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1- carboxylate

[0550] A soln of rac tert-butyl (3 / ?*,4S*)-3-(2-cyclopropyl-4-(methoxycarbonyl)phenyl)-4- hydroxypiperidine-1-carboxylat (Intermediate A-E51-E52, 1.34 g, 3.6 mmol), fert-butyl 4-hydroxy- 5, 7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate 1-1 , 746 mg, 2.9 mmol) and PPh3(1.3 g, 5.0 mmol) in toluene (24 mL) was cooled to 0 to 5 °C. A soln of DIAD (1 .04 mL, 5.2 mmol) in toluene (19.3 mL) was added in a dropwise manner over a period of 55 min using a syringe pump. The RM was stirred overnight while allowing the temperature to reach RT. The RM was concentrated under reduced pressure at 50 °C. Column chromatography over silica gel (120 g; eluent: 0 to 23% EtOAc in cyclohexane) provided enriched material which was then further purified by RP chromatography (Waters Xbridge 50 mm x 100 mm 5 pm; eluent: 50 to 100% ACN in H2O with 0.1% NH4OH) to provide rac tert-butyl 4-(((3R*,4 / ?*)-1-(tert-butoxycarbonyl)-3-(2-cyclopropyl-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (294 mg) as an off-white solid. LC-MS Method B1 : Rt = 1 .74 min; MS m / z [M+NH4]+= 636.4.

[0551] Intermediate M-E101 : tert-butyl 4-(((1R,2S,4S)-4-methoxy-2-(3-methoxy-4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0552] Step 1a: Rac methyl 4-((1 S*,2S*,5S*)-2-hydroxy-5-methoxycyclohexyl)-2-methoxybenzoate (Intermediate rac-A-E101 , 88 mg, 0.30 mmol) and tert-butyl 4-hydroxy-5,7-dimethyl-1 / - / -indole-1 - carboxylate (Intermediate 1-1 , 85.9 mg, 0.33 mmol) were dissolved in toluene (1 .5 mL). PPh3(94.1 mg, 0.36 mmol) was added, and then DIAD (87 pL, 0.45 mmol) was added in a dropwise manner. PAT059793-PCT-SEC01

[0553] The RM was stirred overnight at RT. The RM was diluted with DCM and H2O, dried through an Isolute® phase separator, and concentrated under reduced pressure. Column chromatography over silica gel (24 g; eluent: 0 to 40% EtOAc in cyclohexane) provided enriched material which was purified by RP HPLC (Waters XBridge C18 50 x 100 mm, 5 pm; eluent: 35 to 100% ACN in H2O with 0.2% FA) to provide rac tert-butyl 4-(((1 / ?*,2S*,4S*)-4-methoxy-2-(3-methoxy-4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (62.5 mg) as a colorless solid. LC-MS Method B-1 : Rt = 1 .58 min; MS m / z [M-Boc+2H]+= 438.3.

[0554] Step 1 b: Chiral separation and analytics according to Method SFC-E101 . 62 mg provided Intermediate M-E101 (peak 2): 29.3 mg, white solid. LC-MS Method B-1 : Rt = 1 .58 min; MS m / z [M-Boc+2H]+= 438.3. Analytical chiral HPLC: Rt = 1.60 min; 100% ee.

[0555] Intermediate M-E102: tert-butyl 5-cyclopropyl-4-(((1R,2S,4S)-4-methoxy-2-(3-methoxy-4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 H-indole-1 -carboxylate

[0556] Step 1a: Rac tert-butyl 5-cyclopropyl-4-(((1 / ?*,2S*,4S*)-4-methoxy-2-(3-methoxy-4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate was prepared as described in Step 1 a for Intermediate M-E101 using rac methyl 4-((1 S*,2S*,5S*)-2-hydroxy-5- methoxycyclohexyl)-2-methoxybenzoate (Intermediate rac-A-EI OI , 32.8 mg, 95 pmol) and tertbutyl 4-hydroxy-5-cyclopropyl-7-methyl-1 / 7-indole-1 -carboxylate (Intermediate I-3, 29.9 mg, 1.04 mmol) to provide rac tert-butyl 5-cyclopropyl-4-(((1 R*,2S*,4S*)-4-methoxy-2-(3-methoxy-4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate (258 mg) as a colorless semi-solid.

[0557] Step 1 b: Chiral separation. Analytics according to Method SFC-E102. 44.5 mg provided Intermediate M-E102 (peak 1): 14.8 mg, white solid. LC-MS Method C-1 : Rt = 1 .64 min; MS m / z [M+H]+= 564.3. Analytical chiral HPLC: Rt = 1.96 min; 100% ee.

[0558] Intermediate rac-M-E103: rac tert-butyl 5-cyclopropyl-4-(((1R*,2S*,4S*)-2-(3- (difluoromethoxy)-4-(methoxycarbonyl)phenyl)-4-methoxycyclohexyl)oxy)-7-methyl-1H- indole-1 -carboxylate PAT059793-PCT-SEC01

[0559] Intermediate rac-M-E103 was prepared as described in Step 1 a for Intermediate M-E101 using rac methyl 2-(difluoromethoxy)-4-((1 S*,2S*,5S*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac-A-E103, 77 mg, 0.23 mmol) and tert-butyl 4-hydroxy-5-cyclopropyl-7-methyl-1 / 7- indole-1 -carboxylate (Intermediate I-3, 73.4 mg, 0.26 mmol) to provide rac tert-butyl 5-cyclopropyl- 4-(((1 / ?*,2S*,4S*)-2-(3-(difluoromethoxy)-4-(methoxycarbonyl)phenyl)-4-methoxycyclohexyl)oxy)-7- methyl-1 / - / -indole-1 -carboxylate (35.4 mg) as a light brownish semi-solid. LC-MS Method B-1 : Rt = 1 .69 min; MS m / z [M+H]+= 600.5.

[0560] Intermediate rac-M-E104: rac tert-butyl 4-(((1R*,2S*,4S*)-4-methoxy-2-(4-(methoxycarbonyl)- 3-nitrophenyl)cyclohexyl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0561] Intermediate rac-M-E104 was prepared as described in Step 1 a for Intermediate M-E101 using rac methyl 4-((1 S*,2S*,5S*)-2-hydroxy-5-methoxycyclohexyl)-2-nitrobenzoate (Intermediate rac-A- E104, 191.5 mg, 0.62 mmol) and tert-butyl 4-hydroxy-5,7-dimethyl-1 / 7-indole-1 -carboxylate (Intermediate 1-1 , 197.9 mg, 0.71 mmol) to provide rac tert-butyl 4-(((1 R*,2S*,4S*)-4-methoxy-2-(4- (methoxycarbonyl)-3-nitrophenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (118 mg) as a yellow solid. LC-MS Method B-1 : Rt = 1 .58 min; MS m / z [M+NH4]+= 570.3.

[0562] Intermediate rac-M-E105: rac tert-butyl 4-(((1R*,2S*,4S*)-2-(3-fluoro-4- (methoxycarbonyl)phenyl)-4-methoxycyclohexyl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate PAT059793-PCT-SEC01

[0563] To a soln of tert-butyl 4-hydroxy-5,7-dimethyl-1 / 7-indole-1 -carboxylate (Intermediate I-3, 250 mg, 0.957 mmol), enriched rac methyl 2-fluoro-4-((1 S*,2S*,5S*)-2-hydroxy-5- methoxycyclohexyl)benzoate (Intermediate rac-A-EIOS, 296.8 mg), and triphenylphosphine (627.3 mg, 2.39 mmol) in THF (8.0 mL) was added DIAD (465 pL, 2.39 mmol) in a dropwise manner. The RM was stirred at RT overnight. The RM was diluted with EtOAc and washed with H2O. The combined aq phases were 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 (40 g; eluent: 0 to 100% EtOAc in cyclohexane) provided enriched material which was purified by RP chromatography (XBridge C18 OBD 30 x100 mm, 5 pm; eluent: 5 to 100% ACN in H2O with 0.2% FA) to provide rac tert-butyl 4-(((1R*,2S*,4S*)-2-(3- fluoro-4-(methoxycarbonyl)phenyl)-4-methoxycyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1- carboxylate (157.6 mg) as a colorless oil. LC-MS Method B-1 : Rt = 1 .64 min; MS m / z [M-Boc+H]+= 426.2.

[0564] The following compounds were synthesized from the appropriate starting materials by applying similar methods to those described in the examples above. PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01

[0565] Intermediate rac-M-E17a: rac tert-butyl 4-(((3R*,4R*)-1-(tert-butoxycarbonyl)-3-(7- (methoxycarbonyl)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1- carboxylate

[0566] To a mixture of enriched fert-butyl 4-(((3R*,4 / ?*)-1-(tert-butoxycarbonyl)-3-(7-(methoxycarbonyl)- 2, 3-dihydrobenzofuran-4-yl)piperidin-4-yl)oxy)-5-chloro-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate rac-M-EI 7, approximate 31%, 1.01 g, 0.49 mmol), palladium(ll)acetate (11.0 mg, 48.8 pmol), 2-(dicyclohexylphosphanyl)-2',4',6'-tris( / sopropyl)biphenyl (46.5 mg, 97.6 pmol), K3PO4(311 mg, 1.46 mmol) in 1 ,4-dioxane / water (2.40 mL / 0.60 mL) was added a soln of 2,4,6-trimethyl- 1 ,3,5,2,4,6-trioxatriborinane (50% in THF, 209 pL, 732 pmol), and the mixture was heated in a sealed vial under argon atmosphere at 100 °C overnight. The RM was allowed to cool to RT and diluted with EtOAc and water. The separated aq layer was extracted with EtOAc (2x), and the combined org layers were washed with brine, dried through an Isolute® phase separator and concentrated under reduced pressure. Column chromatography over silica gel (40 g, eluent: 0 to 40% EtOAc in cyclohexane) provided enriched tert-butyl 4-(((3R*,4 / ?*)-1-(tert-butoxycarbonyl)-3-(7- (methoxycarbonyl)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1- carboxylate (181 mg) as an orange oil which was directly used without further purification. LC-MS Method B-1 : Rt = 1 .63 min; MS m / z [M+Na]+= 643.3.

[0567] Intermediate B-E1a: tert-butyl 4-(((3R,4 / ?)-3-(3-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0568] Enriched tert-butyl 4-(((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3-(3-methoxy-4-

[0569] (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate

[0570] M-E1 , 295.9 mg) was dissolved in MeOH (1 mL). A soln of HCI (4M in dioxane, 0.61 mL, 2.4 mmol) PAT059793-PCT-SEC01 was added, and the RM was stirred for 1 h. The pH was adjusted to 6 with aq NaOH soln (1 M), 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 (40 g; eluent: 0 to 50% MeOH in DCM) provided enriched tert-butyl 4-(((3 / ?,4 / ?)-3-(3-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (85.1 mg) as a white solid. LC-MS Method C-2: Rt = 1 .25 min; MS m / z [M+H]+= 509.2.

[0571] Intermediate B-E14a: tert-butyl 4-(((3 / ?,4 / ?)-3-(2-fluoro-4-(methoxycarbonyl)phenyl)piperidin- 4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0572] To a soln of tert- butyl 4-(((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3-(2-fluoro-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate M-E14, 250 mg) in MeOH (4.0 mL) was added a soln of HCI (4M in dioxane, 1 .89 mL, 7.56 mmol) at 0 °C. The RM was stirred at 0 °C for 10 min and at 20 °C for 3 h. The mixture was poured into a well stirred emulsion of a sat. aq NaHCO3soln and DCM. The separated aq layer was extracted with DCM. The combined org layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford crude tert-butyl 4-(((3 / ?,4 / ?)-3-(2-fluoro-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (190 mg) as a brownish oil which was directly used in the next reaction without further purification. LC-MS Method B-1 : RT = 1 .02 min; MS m / z [M+H]+= 497.1 .

[0573] Intermediate rac-B-E17a and Intermediate rac-B-E19a: rac tert-butyl 4-(((3R*,4R*)-3-(7- (methoxycarbonyl)-2,3-dihydrobenzofuran-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1- carboxylate and rac methyl 4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)-2,3- dihydrobenzofuran-7 -carboxylate PAT059793-PCT-SEC01

[0574] To a soln of enriched tert-butyl 4-(((3R*,4 / ?*)-1-(tert-butoxycarbonyl)-3-(7-(methoxycarbonyl)-2,3- dihydrobenzofuran-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac- M-E17a, 181 mg, approximate 60%) in MeOH (1.0 mL) was added a soln of HCI (4M in dioxane, 1 .31 mL, 5.24 mmol). The RM was stirred at RT for 3 h and then carefully diluted with sat. aq NaHCO3soln (gas evolution). The mixture was extracted with DCM (2x), and the combined org layers were washed with brine, dried through an Isolute® phase separator and concentrated under reduced pressure. Column chromatography of the residue over silica gel (24 g, eluent: 0 to 20% MeOH in DCM) provided enriched rac tert-butyl 4-(((3R*,4 / ?*)-3-(7-(methoxycarbonyl)-2,3- dihydrobenzofuran-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac- B-E17a, 18.9 mg) as a brown solid and enriched rac methyl 4-((3R*,4 / ?*)-4-((5,7-dimethyl-1 / 7- indol-4-yl)oxy)piperidin-3-yl)-2,3-dihydrobenzofuran-7-carboxylate (Intermediate rac-B-EI 9a, 15.0 mg) as a beige solid which were directly used without further purifications. Intermediate rac-B- E17a: LC-MS Method B-1 : Rt = 0.95 min; MS m / z [M+H]+= 521 .3. Intermediate rac-B-E19a: LC- MS Method B-1 : Rt = 0.57 min; MS m / z [M+H]+= 421 .3.

[0575] Intermediate rac-B-E27a-E28a: rac tert-butyl 4-(((3R*,4R*)-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0576] A soln of rac tert-butyl 4-(((3R*,4 / ?*)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac-M-E27- E28, 135 mg, 227.8 pmol) in MeOH (1 .9 mL) was cooled to 0 to 5 °C. A soln of HCI (4M in dioxane, 1.14 mL, 4.6 mmol) was added. The mixture was stirred for 30 min at 0 to 5 °C, then the cooling bath was removed and stirring was continued for an additional 3.5 h at ambient temperature. The mixture was poured into a well stirred mixture of sat. aq NaHCO3soln and DCM. The separated aq layer was washed with DCM. The combined org layers were dried over MgSO4and filtered. The filtrate was concentrated under reduced pressure at 50 °C to provide crude rac tert-butyl 4-(((3 / ?*,4 / ?*)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl- 1 / - / -indole-1 -carboxylate (82.4 mg) as a light brownish oil which was directly used in the next reaction without further purification. LC-MS Method B1 : Rt = 1 .05 min; MS m / z [M+H]+= 493.4.

[0577] Intermediate rac-B-E29a: rac tert-butyl 4-(((3R*,4R*)-3-(2-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate, HCI salt PAT059793-PCT-SEC01

[0578] To a soln of rac tert-butyl 4-(((3R*,4 / ?*)-1-(tert-butoxycarbonyl)-3-(2-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac-M-E29, 475 mg, 780 pmol) in dioxane (3.5 mL) was added a HCI soln (4M in dioxane, 3.90 mL, 15.6 mmol), and the RM was stirred at 25 °C for 6 h. The mixture was concentrated under reduced pressure to provide crude rac tert-butyl 4-(((3 / ?*,4 / ?*)-3-(2-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7-ind ole- 1 -carboxylate, HCI-salt (526 mg) as a dark violet solid which was used in the next step without further purification. Method B-1 : Rt = 1 .03 min; MS m / z [M+H]+= 509.3.

[0579] Intermediate rac-B-E43a-E44a: rac tert-butyl 4-(((3R*,4R*)-3-(4-(methoxycarbonyl)-2- (trifluoromethyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0580] A soln of rac tert-butyl 4-(((3 / ?*,4 / ?*)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)-2- (trifluoromethyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac- M-E43-E44, 472 mg, 730 pmol) in MeOH (4.2 mL) was cooled to 0 to 5 °C. A soln of HCI (4M in dioxane, 3.65 mL, 14.6 mmol) was added. The cooling bath was removed, and the RM was stirred for 140 min while allowing to reach RT. The mixture was poured into a well stirred mixture of sat. aq NaHCO3soln and DCM. The layers were separated, and the aq layer was washed with DCM (2x). The combined org layers were dried over MgSO4and filtered. The filtrate was concentrated under reduced pressure at 50 °C to provide crude rac tert-butyl 4-(((3R*,4 / ?*)-3-(4- (methoxycarbonyl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1- carboxylate (387 mg) as an off-white foam which was directly used in the next reaction without further purification. LC-MS Method B2: Rt = 5.56 min; MS m / z [M+H]+= 547.2.

[0581] Intermediate rac-B-E49a-E50a: rac tert-butyl 5-cyclopropyl-4-(((3R*,4R*)-3-(4- (methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-7-methyl-1 H-indole-1 -carboxylate PAT059793-PCT-SEC01

[0582] A soln of rac tert-butyl 4-(((3R*,4 / ?*)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidin-4-yl)oxy)-5-cyclopropyl-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate rac- M-E49-E50, 202.4 mg, 327.1 pmol) in MeOH (2.7 mL) was cooled to 0 to 5 °C. A soln of HCI (4M in dioxane, 1 .64 mL, 6.5 mmol) was added. The mixture was stirred for 30 min at 0 to 5 °C, then the cooling bath was removed, and stirring was continued for 5 h at ambient temperature. The mixture was poured into a well stirred mixture of sat. aq NaHCO3soln and DCM. The separated aq layer was extracted with DCM. The combined org layers were dried over MgSO4and filtered. The filtrate was concentrated under reduced pressure at 50 °C to provide crude rac tert-butyl 5- cyclopropyl-4-(((3 / ?*,4 / ?*)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-7-methyl-1 / 7- indole-1 -carboxylate (165 mg) as a brown oil which was directly used in the next reaction without further purification. LC-MS Method B2: Rt = 5.49 min; MS m / z [M+H]+= 519.4.

[0583] Intermediate rac-B-E51a-E52a: rac tert-butyl 4-(((3R*,4R*)-3-(2-cyclopropyl-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0584] A soln of rac tert-butyl 4-(((3R*,4 / ?*)-1-(tert-butoxycarbonyl)-3-(2-cyclopropyl-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate M-E51-E52, 294 mg, 475.1 pmol) in MeOH (2.7 mL) was cooled to 0 to 5 °C. A soln of HCI (4M in dioxane, 2.38 mL, 9.5 mmol) was added. The cooling bath was removed, and the RM was stirred for 2.5 h while allowing the temperature to reach RT. The mixture was poured into a well stirred mixture of sat. aq NaHCO3soln and DCM. The separated aq layer was washed with DCM (2x). The combined org layers were dried over MgSO4and filtered. The filtrate was concentrated under reduced pressure at 50 °C to provide crude rac tert-butyl 4-(((3R*,4 / ?*)-3-(2-cyclopropyl-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (243 mg) as an PAT059793-PCT-SEC01 off-white solid which was directly used in the next reaction without further purification. LC-MS Method B2: Rt = 5.55 min; MS m / z [M+H]+= 519.2.

[0585] The following compounds were synthesized from the appropriate starting materials by applying similar methods to those described in the examples above. PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01

[0586] Intermediate B-E1 : tert-butyl 4-(((3R,4 / ?)-1-(2,2-difluoroethyl)-3-(3-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0587] Enriched tert-butyl 4-(((3 / ?,4 / ?)-3-(3-methoxy-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate (Intermediate B-E1 a) was combined with DIPEA (53 pL, 0.30 mmol) in ACN (1 mL). 2,2-Diflluoroethyl trifluoromethanesulfonate (20.3 mg, 95 pmol) was added slowly, and the RM was stirred at 60 °C for 2 h. The RM was allowed to cool to RT and was concentrated under reduced pressure to provide crude tert-butyl 4-(((3R,4 / ?)-1-(2,2-difluoroethyl)- 3-(3-methoxy-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (49.3 mg) as a yellowish solid which was directly used in the next reaction. Method C-2: Rt = 1 .40 min; MS m / z [M+H]+= 573.8.

[0588] Intermediate B-E2: tert-butyl 4-(((3R,4 / ?)-1-(2,2-difluoroethyl)-3-(3-fluoro-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0589] Step 1 a: Enriched tert-butyl 4-(((3 / ?,4R)-1 -(fert-butoxycarbonyl)-3-(3-fluoro-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate (Intermediate M-E2, 223 mg) was dissolved in DCM (3 mL). A soln of HCI (4M in dioxane, 0.93 mL, 3.73 mmol) was added, and the RM was stirred for 3 h. The RM was concentrated under reduced pressure. Step 1 b: The residue was dissolved in ACN (1.25 mL). NEt3(93 pL, 0.67 mmol) and 2,2- difluoroethyl trifluoromethanesulfonate (53 pL, 0.40 mmol) were added, and the RM was stirred for 1 h. The RM was quenched with H2O, and the mixture was extracted with EtOAc. The org phase was concentrated under reduced pressure. The residue was purified over silica gel (12 g; eluent: 0 to 20% MeOH in DCM) to provide tert-butyl 4-(((3R,4 / ?)-1 -(2,2-difluoroethyl)-3-(3-fluoro-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate (81 .9 mg). LC- MS Method C-1 : Rt = 1 .37 min; MS m / z [M+H]+= 561 .5. PAT059793-PCT-SEC01

[0590] Intermediate B-E7: tert-butyl 4-(((3R,4 / ?)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate tert-Butyl 4-(((3 / ?,4 / ?)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole-1 -carboxylate (Intermediate B-E7a, 22.4 mg, 42 pmol) was combined with DIPEA (26 pL, 0.15 mmol) in ACN (1 mL). 2,2-Diflluoroethyl trifluoromethanesulfonate (10 mg, 47 pmol) was added slowly, and the RM was stirred at 50 °C for 3 h. The RM was allowed to cool to RT and was concentrated under reduced pressure to provide crude tert-butyl 4-(((3R,4 / ?)-1-(2,2-difluoroethyl)- 3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate (23.6 mg) which was directly used in the next reaction. Method C-2: Rt = 1 .51 min; MS m / z [M+H]+= 557.4.

[0591] Intermediate B-E8: tert-butyl 5-chloro-4-(((3R,4 / ?)-1-(2,2-difluoroethyl)-3-(4- (methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-7-methyl-1 H-indole-1 -carboxylate tert-Butyl 5-chloro-4-(((3 / ?,4 / ?)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-7- methyl-1 / - / -indole-1 -carboxylate (Intermediate B-E8a, 74.4 mg, 0.12 mmol) was combined with DIPEA (71 pL, 0.41 mmol) in ACN (1 mL). 2,2-Diflluoroethyl trifluoromethanesulfonate (27.4 mg, 0.13 mmol) was added slowly, and the RM was stirred at 60 °C for 3 h. The RM was allowed to cool to RT and was concentrated under reduced pressure to provide crude tert-butyl 5-chloro-4- (((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-7-methyl- 1 / - / -indole-1 -carboxylate (67.2 mg) as a yellowish solid which was directly used in the next reaction. Method C-2: Rt = 1 .55 min; MS m / z [M+H]+= 557.5.

[0592] Intermediate B-E9: tert-butyl 4-(((3R,4 / ?)-1-(2,2-difluoroethyl)-3-(2-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate PAT059793-PCT-SEC01

[0593] „ / I

[0594] Boc I tert-Butyl 4-(((3 / ?,4 / ?)-3-(2-methoxy-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl- 1 / - / -indole-1 -carboxylate (Intermediate B-E9a, 40.1 mg, 74 pmol) was combined with NEt3(31 pL, 0.21 mmol) in ACN (1 mL). 2,2-Difluoroethyl trifluoromethanesulfonate (17.3 mg, 81 pmol) was added slowly, and the RM was stirred at 60 °C for 2 h. The RM was allowed to cool to RT and was concentrated under reduced pressure to provide crude tert-butyl 4-(((3R,4 / ?)-1-(2,2-difluoroethyl)- 3-(2-methoxy-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (11 .2 mg) which was directly used in the next reaction. Method C-2: Rt = 1 .48 min; MS m / z [M+H]+= 573.2.

[0595] Intermediate B-E10: tert-butyl 5-chloro-4-(((3R,4 / ?)-1-(2,2-difluoroethyl)-3-(2-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1 -carboxylate

[0596] Step 1a: Enriched tert-butyl 4-(((3 / ?,4 / ?)-1-(tert-butoxycarbonyl)-3-(2-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-chloro-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate M-E10, 152 mg) was dissolved in MeOH (2 mL). A soln of HCI (4M in dioxane, 0.44 mL, 1 .75 mmol) was added, and the RM was stirred at RT for 3 h. The pH was adjusted to 6 with aq NaOH soln (1 M), 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.

[0597] Step 1 b: The residue was combined with NEt3(33 pL, 0.24 mmol) in ACN (1 mL). 2,2-Difluoroethyl trifluoromethanesulfonate (18.7 mg, 88 pmol) was added slowly, and the RM was stirred at 60 °C for 2 h. The RM was allowed to cool to RT and was concentrated under reduced pressure to provide crude tert-butyl 5-chloro-4-(((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-3-(2-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate (47.2 mg) as a PAT059793-PCT-SEC01 yellowish solid which was directly used in the next reaction. Method C-2: Rt = 1 .50 min; MS m / z [M+H]+= 593.4.

[0598] Intermediate B-E11 : tert-butyl 4-(((3R,4 / ?)-3-(3-chloro-4-(methoxycarbonyl)phenyl)-1-(2,2- difluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate fert-Butyl 4-(((3 / ?,4 / ?)-3-(3-chloro-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole-1 -carboxylate (Intermediate B-E11a, 9.2 mg, 14 pmol) was combined with NEt3(5.9 pL, 43 pmol) in ACN (1 mL). 2,2-Difluoroethyl trifluoromethanesulfonate (3.3 mg, 16 pmol) was added slowly, and the RM was stirred at 60 °C for 2 h. The RM was allowed to cool to RT and was concentrated under reduced pressure to provide crude fert-butyl 4-(((3R,4 / ?)-3-(3-chloro-4- (methoxycarbonyl)phenyl)-1 -(2, 2-difluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1- carboxylate (8.2 mg) as a yellowish solid which was directly used in the next reaction. Method C-2: Rt = 1 .49 min; MS m / z [M+H]+= 577.4.

[0599] Intermediate B-E12: tert-butyl 4-(((3R,4 / ?)-3-(4-(methoxycarbonyl)-2-methylphenyl)-1 -(2,2,2- trifluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate tert-Butyl 4-(((3 / ?,4 / ?)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole-1 -carboxylate (Intermediate B-E7a, 18.2 mg, 34 pmol) was combined with NEt3(14.4 pL, 0.10 mmol) in ACN (1 mL). 2,2,2-Trifluoroethyl trifluoromethanesulfonate (8.9 mg, 38 pmol) was added slowly, and the RM was stirred at 60 °C for 2 h. The RM was allowed to cool to RT and concentrated under reduced pressure to provide crude tert-butyl 4-(((3R,4 / ?)-3-(4- (methoxycarbonyl)-2-methylphenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole-1 -carboxylate (19.8 mg) as a yellowish solid which was directly used in the next reaction. Method C-2: Rt = 1 .56 min; MS m / z [M+H]+= 575.3. PAT059793-PCT-SEC01

[0600] Intermediate B-E13: tert-butyl 4-(((3R,4 / ?)-1-(3,3-difluoropropyl)-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate tert-Butyl 4-(((3 / ?,4 / ?)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole-1 -carboxylate (Intermediate B-E7a, 18.2 mg, 34 pmol) was combined with NEt3(14.4 pL, 0.10 mmol) in ACN (1 mL). 3,3-Difluoropropyl trifluoromethanesulfonate (15.7 mg, 69 pmol) was added slowly, and the RM was stirred at 60 °C for 2 h. The RM was allowed to cool to RT and concentrated under reduced pressure to provide crude fert-butyl 4-(((3R,4 / ?)-1-(3,3-difluoropropyl)- 3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (19.6 mg) as a yellowish solid which was directly used in the next reaction. Method C-2: Rt = 1.50 min; MS m / z [M+H]+= 571 .4.

[0601] Intermediate rac-B-E19-E20: rac methyl 4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1- (2, 2, 2-trifluoroethyl)piperidin-3-yl)-2,3-dihydrobenzofuran-7 -carboxylate

[0602] To a soln of enriched rac methyl 4-((3R*,4 / ?*)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dihydrobenzofuran-7-carboxylate (Intermediate rac-B-E19a, 15 mg) in ACN (0.40 mL) were added DIPEA (19.6 pL, 112.4 pmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.6 pL, 32 pmol). The RM was stirred at RT over the weekend. The mixture was diluted with EtOAc and water. The separated aq layer was extracted with EtOAc (2x). The combined org layers were washed with brine and dried through an Isolute® phase separator. Concentration under reduced pressure provided crude rac methyl 4-((3R*,4 / ?*)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(2,2,2- trifluoroethyl)piperidin-3-yl)-2,3-dihydrobenzofuran-7-carboxylate (19.4 mg) as a brownish solid which was directly used without further purification. Method B-1 : Rt = 1 .29 min; MS m / z [M+H]+= 503.3. PAT059793-PCT-SEC01

[0603] Intermediate rac-B-E21-E22: tert-butyl 4-(((3R*,4R*)-1-(3,3-difluoropropyl)-3-(2-fluoro-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0604] O

[0605] To a soln of tert- butyl 4-(((3 / ?*,4 / ?*)-3-(2-fluoro-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac-B-E21a-E22a, 46 mg, 88 pmol) in ACN (2.0 mL) were added DIPEA (19.3 mg, 150 pmol) and 3-bromo-1 ,1 -difluoropropane (15.4 mg, 96.8 pmol). The RM was stirred at 50 °C for 16 h. Additional 3-bromo-1 ,1 -difluoropropane (2.8 mg, 17.6 pmol) in ACN (0.20 mL) was added and stirring was continued at 50 °C for 24 h. The mixture was diluted with TBME and H2O. The separated org layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (12 g; eluent: 0 to 100% EtOAc in heptane) to provide rac tert-butyl 4-(((3R*,4 / ?*)-1-(3,3-difluoropropyl)-3- (2-fluoro-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (32 mg) as a brownish oil. LC-MS Method B-1 : Rt = 1 .42 min; MS m / z [M+H]+= 575.4.

[0606] Intermediate rac-B-E23-E24: rac tert-butyl 4-(((3R*,4R*)-3-(2-fluoro-4- (methoxycarbonyl)phenyl)-1 -(3,3,3-trifluoropropyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H- indole-1 -carboxylate

[0607] To a soln of tert-butyl 4-(((3 / ?*,4 / ?*)-3-(2-fluoro-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate (Intermediate / 'ac-B-E21a-E22a, 56 mg, 102 pmol) in ACN (2.0 mL) were added DIPEA (32.8 mg, 254 pmol) and 1 ,1 ,1-trifluoro-3-iodopropane (40.9 mg, 183 pmol). The RM was stirred at 70 °C for 48 h. The mixture was allowed to cool to RT and was diluted with TBME and H2O. The separated org layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified over silica gel (12 g; eluent: 0 to 100% EtOAc in heptane) to provide tert-butyl 4-(((3R*,4 / ?*)-3-(2-fluoro-4- PAT059793-PCT-SEC01

[0608] (methoxycarbonyl)phenyl)-1 -(3, 3, 3-trifluoropropyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1- carboxylate (40 mg) as a yellowish oil. LC-MS Method B-1 : Rt = 1 .67 min; MS m / z [M+H]+= 593.2.

[0609] Intermediate rac-B-E30-E31 : rac tert-butyl 4-(((3R*,4R*)-3-(2-fluoro-4- (methoxycarbonyl)phenyl)-1 -(2-(trifluoromethoxy)ethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H- indole-1 -carboxylate

[0610] To a soln of tert- butyl 4-(((3 / ?*,4 / ?*)-3-(2-fluoro-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac-B-E21a-E22a, 96 mg, 184 pmol) in ACN (2.0 mL) were added DIPEA (40.6 mg, 312 pmol) and trifluoromethanesulfonic acid 2- (trifluoromethoxy)ethyl ester (53 mg, 202 pmol). The RM was stirred at 20 °C for 30 min. The mixture was diluted with TBME and H2O. The separated org layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to provide enriched rac tert-butyl 4- (((3 / ?*,4 / ?*)-3-(2-fluoro-4-(methoxycarbonyl)phenyl)-1-(2-(trifluoromethoxy)ethyl)piperidin-4-yl)oxy)- 5, 7-dimethyl-1 / - / -indole-1 -carboxylate (116 mg) as a brownish oil which was directly used without further purification. LC-MS Method B-1 : Rt = 1 .69 min; MS m / z [M+H]+= 609.3.

[0611] Intermediate rac-B-E40: rac tert-butyl 4-(((3R*,4R*)-1-(2,2-difluoroethyl)-3-(4- (methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0612] To the soln of crude rac tert-butyl 4-(((3 / ?*,4 / ?*)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin- 4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate / 'ac-B-E27a-E28a, 82.4 mg) and DIPEA (49.5 pL, 284 pmol) in ACN (0.9 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (24.5 pL, 184 pmol), and the RM was stirred at RT for 2 h. The mixture was partitioned between TBME and water. The layers were separated and washed with brine and TBME. The combined org layers were dried over MgSO4, filtered and concentrated under reduced pressure at 50 °C to PAT059793-PCT-SEC01 provide crude rac tert-butyl 4-(((3R*,4 / ?*)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (86.9 mg) as a beige solid which was directly used in the next reaction without further purification. LC-MS Method B1 : Rt = 1 .66 min; MS m / z [M+H]+= 557.2.

[0613] Intermediate rac-B-E41 -E42: rac tert-butyl 4-(((3R*,4R*)-3-(4-(methoxycarbonyl)-2- methylphenyl)-1 -(3,3,3-trifluoropropyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 - carboxylate

[0614] To a soln of rac tert-butyl 4-(((3 / ?*,4 / ?*)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)- 5, 7-dimethyl-1 H-indole-1 -carboxylate (Intermediate rac-B-E27a-E28a, 80 mg, 162 pmol) and DIPEA (48.1 pL, 276 pmol) in ACN (0.9 mL) was added 3,3,3-trifluoropropyl trifluoromethanesulfonate (44 mg, 179 pmol), and the RM was stirred at RT for 2.5 h. The mixture was partitioned between TBME and water. The layers were separated and washed with brine and TBME. The combined org layers were dried over MgSO4, filtered and concentrated under reduced pressure at 50 °C to provide crude rac tert-butyl 4-(((3 / ?*,4 / ?*)-3-(4-(methoxycarbonyl)-2- methylphenyl)-1 -(3, 3, 3-trifluoropropyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (85.7 mg) as slightly brownish oil which was directly used in the next reaction without further purification. LC-MS Method B1 : Rt = 1 .67 min; MS m / z [M+H]+= 589.3.

[0615] Intermediate rac-B-E43-E44: rac tert-butyl 4-(((3R*,4R*)-1 -(2,2-difluoroethyl)-3-(4- (methoxycarbonyl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 - carboxylate

[0616] The soln of crude rac tert-butyl 4-(((3R*,4 / ?*)-3-(4-(methoxycarbonyl)-2- (trifluoromethyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate (Intermediate rac- B-E43a-E44a, 127 mg) and DIPEA (80.9 pL, 464.7 pmol) in ACN (1 .2 mL) was cooled to 0 to 5 °C. PAT059793-PCT-SEC01

[0617] 2,2-Difluoroethyl trifluoromethanesulfonate (37.1 pL, 279 pmol) was added to the soln, the ice bath was removed and stirring was continued for 70 min at ambient temperature. The mixture was partitioned between TBME and water. The layers were separated and washed with sat. aq NaHCO3soln, brine and TBME. The combined org layers were dried over MgSO4, filtered and concentrated under reduced pressure at 50 °C to provide crude rac fert-butyl 4-(((3R*,4 / ?*)-1-(2,2- difluoroethyl)-3-(4-(methoxycarbonyl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole-1 -carboxylate (136 mg) as an off-white solid which was directly used in the next reaction without further purification. LC-MS Method B2: Rt = 8.49 min; MS m / z [M+H]+= 611 .4.

[0618] Intermediate rac-B-E49-E50: rac tert-butyl 5-cyclopropyl-4-(((3R*,4R*)-1-(2,2-difluoroethyl)-3- (4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-7-methyl-1 H-indole-1 -carboxylate

[0619] To the soln of crude rac fert-butyl 5-cyclopropyl-4-(((3 / ?*,4 / ?*)-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidin-4-yl)oxy)-7-methyl-1 / 7-ind ole- 1 -carboxylate (Intermediate / 'ac-B-E49a-E50a, 80 mg) and DIPEA (45.7 pL, 262 pmol) in ACN (0.8 mL) was slowly added 2,2-difluoroethyl trifluoromethanesulfonate (22.6 pL, 169.7 pmol). The RM was stirred at RT for 2 h and then partitioned between TBME and water. The layers were separated and washed with brine and TBME. The combined org layers were dried over MgSC , filtered and concentrated under reduced pressure at 50 °C to provide crude rac fert-butyl 5-cyclopropyl-4-(((3R*,4 / ?*)-1-(2,2-difluoroethyl)-3- (4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate (82.6 mg) as a brownish oil which was directly used in the next reaction without further purification. LC- MS Method B1 : Rt = 1 .69 min; MS m / z [M+H]+= 583.3.

[0620] Intermediate rac-B-E51 -E52: rac fert-butyl 4-(((3R*,4R*)-3-(2-cyclopropyl-4- (methoxycarbonyl)phenyl)-1 -(2,2-difluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-indole-1 - PAT059793-PCT-SEC01

[0621] A soln of rac tert-butyl 4-(((3 / ?*,4 / ?*)-3-(2-cyclopropyl-4-(methoxycarbonyl)phenyl)piperidin-4- yl)oxy)-5,7-dimethyl-1 / 7-indole-1 -carboxylate (Intermediate B-E51a-E52a, 80.5 mg, 155.2 pmol) and DIPEA (54.1 pL, 310.4 pmol) in ACN (0.8 mL) was cooled to 0 to 5 °C. 2,2-Difluoroethyl trifluoromethanesulfonate (24.8 pL, 186.3 pmol) was added to the soln, the ice bath was removed, and the RM was stirred for an additional 1 .5 h. The mixture was partitioned between TBME and water. The layers were separated and washed with sat. aq NaHCOs soln, brine and TBME. The combined org layers were dried over MgSO4, filtered and concentrated under reduced pressure at 50 °C to provide crude rac tert-butyl 4-(((3 / ?*,4 / ?*)-3-(2-cyclopropyl-4-(methoxycarbonyl)phenyl)-1- (2, 2-difluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (86.4 mg) as an off- white solid which was directly used in the next reaction without further purification. LC-MS Method B2: Rt = 8.56 min; MS m / z [M+H]+= 583.4.

[0622] The following compounds were synthesized from the appropriate starting materials by applying similar methods to those described in the examples above. PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01

[0623] Intermediate rac-N-17: rac tert-butyl 4-(((1R*,2S*,4S*)-2-(3-amino-4- (methoxycarbonyl)phenyl)-4-methoxycyclohexyl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate Rac tert-butyl 4-(((1 / ?*,2S*,4S*)-4-methoxy-2-(4-(methoxycarbonyl)-3-nitrophenyl)cyclohexyl)oxy)- 5, 7-dimethyl-1 H-indole-1 -carboxylate (Intermediate rac-M-E104, 116 mg, 0.21 mmol) was dissolved in EtOH (3 mL) and brought under a N2atmosphere. Pd / C (10 wt%, 22.3 mg, 21 pmol) was added. The mixture was stirred at RT under H2atmosphere (balloon) for 1 h. The RM was diluted with DCM and filtered to remove solids. The solids were rinsed with DCM, and the combined filtrates were concentrated under reduced pressure. The residue was purified over silica gel (12 g; eluent: 5 to 22.6% EtOAc in heptane) to provide rac tert-butyl 4-(((1R*,2S*,4S*)-2-(3- amino-4-(methoxycarbonyl)phenyl)-4-methoxycyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1- carboxylate (110 mg). LC-MS Method B-1 : Rt = 1 .62 min; MS m / z [M+H]+= 523.3.

[0624] Intermediate N-17e: tert-butyl 4-(((1R,2S,4S)-2-(3-amino-4-(methoxycarbonyl)phenyl)-4- methoxycyclohexyl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0625] Chiral separation and analytics according to Method SFC-17: Intermediate rac-N-17 (110 mg) provided Intermediate N-17e (peak 2, 50.1 mg). LC-MS Method B-1 : Rt = 1.62 min; MS m / z [M+H]+= 523.3. Analytical chiral HPLC: Rt = 0.60 min; 100% ee. PAT059793-PCT-SEC01

[0626] The following compounds were synthesized from the appropriate starting materials by applying similar methods to those described in the example above. Intermediate rac-B-E114-E115a: rac tert-butyl 4-(((1 R*,2S*,4S*)-4-hydroxy-2-(3-methoxy-4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0627] To a soln of rac tert-butyl 4-(((1 / ?*,2S*,4S*)-4-((tert-butyldimethylsilyl)oxy)-2-(3-methoxy-4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / 7- indole- 1 -carboxylate (Intermediate rac- M-E114-E115, 350 mg, 0.55 mmol) in MeOH (5 mL) was added a soln of HCI (4M in dioxane, 1 .37 mL) at 0 °C. The RM was stirred at 0 °C for 3 h and then diluted with sat. aq NaHCOs soln. 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: 0 to 35% EtOAc in cyclohexane) to provide rac tert-butyl 4-(((1 R*,2S*,4S*)-4- hydroxy-2-(3-methoxy-4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1- carboxylate as a colorless semi-solid (277 mg, 95% purity). LC-MS Method B-1 : Rt = 1 .37 min; MS m / z [M-H]- = 522.2. PAT059793-PCT-SEC01

[0628] Intermediate rac-B-E114-E115: rac tert-butyl 4-(((1R*,2S*,4S*)-4-(2,2-difluoroethoxy)-2-(3- methoxy-4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0629] To a soln of rac tert-butyl 4-(((1 R*,2S*,4S*)-4-hydroxy-2-(3-methoxy-4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / - indole- 1 -carboxylate (Intermediate rac- B-E114-E115a, 100 mg, 0.19 mmol) in THF (2 mL) and at 0 °C was added sodium hydride (9.9 mg, 60 wt%, 0.25 mmol). The mixture was stirred at 0 °C for 10 min and 2,2-difluoroethyl trifluoromethanesulfonate (76.3 pL, 0.57 mmol) was added. The RM was allowed to warm to RT and stirring was continued for 3 h. The mixture was diluted with sat. aq NaHCO3soln and then 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 20% EtOAc in cyclohexane) to provide rac fert-butyl 4-(((1R*,2S*,4S*)-4-(2,2- difluoroethoxy)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole- 1 -carboxylate (59 mg) as colorless semi-solid. LC-MS Method B-1 : Rt = 1 .60 min; MS m / z [M- Boc+2H]+= 488.1.

[0630] Intermediate rac-B-K1 : rac tert-butyl 4-(((1R*,2S*)-2-(4-(methoxycarbonyl)-2-methylphenyl)-4- oxocyclohexyl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0631] To a soln of enriched tert-butyl 5,7-dimethyl-4-((4-oxocyclohex-2-en-1-yl)oxy)-1 H-indole-1 - carboxylate (Intermediate I-M1 , 389 mg) and (4-(methoxycarbonyl)-2-methylphenyl)boronic acid (510 mg, 2.63 mmol) in dioxane (10 mL) and water (1.0 mL) was added NEt3(133mg, 183 pL, 1.31 mmol) at 20 °C. The RM was purged with argon for 3 min. Then, chloro(1 ,5- cyclooctadiene)rhodium(l) dimer (21 .6 mg, 43.8 pmol) was added, and the RM was stirred at 20 °C for 1 h. The mixture was diluted with EtOAc and sat. aq NaHCO3soln. The separated aq layer was extracted with EtOAc (2x). The combined org layers were washed with brine, dried over MgSO4, PAT059793-PCT-SEC01 filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (40 g; eluent: 5 to 25% EtOAc in heptane) to provide rac tert-butyl 4-(((1 / ?*,2S*)-2-(4-(methoxycarbonyl)-2-methylphenyl)-4-oxocyclohexyl)oxy)-5,7-dimethyl-1H- indole-1 -carboxylate (436 mg) as a white solid. LC-MS Method B-1 : Rt = 1 .46 min; MS m / z [M- Boc+2H]+= 406.3.

[0632] Intermediate rac-B-K2: rac tert-butyl 4-(((1R*,2S*)-2-(2-chloro-4-(methoxycarbonyl)phenyl)-4- oxocyclohexyl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0633] Intermediate rac-B-K2 was prepared as described for Intermediate rac-B-K1 using (2-chloro-4- (methoxycarbonyl)phenyl)boronic acid (828 mg, 3.86 mmol) and chloro(1 ,5- cyclooctadiene)rhodium(l) dimer (27.2 mg, 55.1 pmol; additional 27.2 mg were added after 3 h) at 20 °C stirring for 5 h to provide rac fert-butyl 4-(((1 R*,2S*)-2-(2-chloro-4-(methoxycarbonyl)phenyl)- 4-oxocyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (344 mg) as a white solid. LC-MS Method B-1 : Rt = 1 .63 min; MS m / z [M-Boc+2H]+= 426.1 .

[0634] Intermediate rac-B-A3 and Intermediate rac-B-A4: rac tert-butyl 4-(((1R*,2S*,4S*)-4-hydroxy- 2 -(4-(methoxycarbonyl)-2-methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1 H-indole-1 - carboxylate and rac tert-butyl 4-(((1R*,2S*4R*)-4-hydroxy-2-(4-(methoxycarbonyl)-2- methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0635] To a soln of rac tert-butyl 4-(((1 / ?*,2S*)-2-(4-(methoxycarbonyl)-2-methylphenyl)-4- oxocyclohexyl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate (Intermediate rac-B-K1 , 315 mg) in MeOH (10 mL) was added NaBH4(44.8 mg, 1 .18 mmol) at 0 °C. The RM was stirred at 0 °C for 30 min. The mixture was carefully diluted with sat. aq NH4CI soln and further diluted with EtOAc. The separated org layer was washed with H2O, and combined aq layers were back extracted with EtOAc (2x). The combined org layers were washed with brine, dried over MgSO4, filtered and PAT059793-PCT-SEC01 concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (40 g; eluent: 5 to 80% EtOAc in heptane) to provide rac tert-butyl 4-(((1 R*,2S*,4S*)-4- hydroxy-2-(4-(methoxycarbonyl)-2-methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1- carboxylate (first eluting, 29 mg) as a white solid, LC-MS Method B-1 : Rt = 1 .50 min; MS m / z [M+H]+= 508.3, and rac tert-butyl 4-(((1 / ?*,2S*4 / ?*)-4-hydroxy-2-(4-(methoxycarbonyl)-2- methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (second eluting, 264 mg) as a white solid, LC-MS Method B-1 : Rt = 1 .48 min; MS m / z [M+H]+= 508.2.

[0636] Intermediate rac-B-A5: rac tert-butyl 4-(((1R*,2S*,4S*)-2-(2-chloro-4- (methoxycarbonyl)phenyl)-4-hydroxycyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0637] To a soln of rac tert-butyl 4-(((1 / ?*,2S*)-2-(2-chloro-4-(methoxycarbonyl)phenyl)-4- oxocyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac-B-K2, 270 mg, 503 pmol) in THF (5.0 mL) at -78 °C was added a soln of lithium tri-sec-butylborohydride soln (1 M in THF, 629 pL, 629 pmol) in THF (1 .0 mL) over a period of 10 min. The RM was stirred at -78 °C for additional 45 min. The cooling bath was removed, and the mixture was diluted slowly with sat. aq NH4CI soln. The mixture was further diluted with EtOAc and H2O and allowed to warm up to RT. The separated org layer was washed with sat. aq NH4CI soln and H2O, and the aq layer was extracted with EtOAc (2x). The combined org layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH and concentrated under reduced pressure at 50 °C; this process was repeated twice. Column chromatography over silica gel (40 g; eluent: 0 to 50% EtOAc in heptane) provided enriched material which was then further purified by column chromatography over silica gel (24 g; eluent: 0 to 5% MeOH in DCM) to provide rac tert-butyl 4-(((1 R*,2S*,4S*)-2-(2-chloro-4- (methoxycarbonyl)phenyl)-4-hydroxycyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (130 mg) as a white solid. LC-MS Method B-1 : Rt = 1 .50 min; MS m / z [M-Boc+2H]+428.3.

[0638] Intermediate rac-B-A6: rac tert-butyl 4-(((1R*,2S*,4R*)-2-(4-(methoxycarbonyl)-2- methylphenyl)-4-((methylsulfonyl)oxy)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate PAT059793-PCT-SEC01

[0639] To a soln of rac tert-butyl 4-(((1 R*,2S*4 / ?*)-4-hydroxy-2-(4-(methoxycarbonyl)-2- methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac-B-A4, 276 mg, 544 pmol) in DCM (8.0 mL) was added NEt3(165 mg, 227 pL, 1.63 mmol). The mixture was cooled to 0 °C, methanesulfonyl chloride (74.7 mg, 50.8 pL, 652 pmol) was added slowly, and the RM was stirred at 0 °C for 30 min. The mixture was diluted with MeOH (4 mL) in a dropwise manner at 0°C. The mixture was concentrated under reduced pressure. The white residue was purified by column chromatography over silica gel (24 g; eluent: 10 to 60% EtOAc in heptane) to provide rac tert-buty I 4-(((1 R*,2S*,4 / ?*)-2-(4-(methoxycarbonyl)-2-methylphenyl)-4- ((methylsulfonyl)oxy)cyclohexyl)oxy)-5,7-dimethyl-1 / 7-indole-1-carboxylate (286 mg) as a white solid. LC-MS Method B-1 : Rt = 1 .54 min; MS m / z [M-Hp = 584.3.

[0640] Intermediate rac-B-A7: rac tert-butyl 4-(((1R*,2S*,4S*)-4-azido-2-(4-(methoxycarbonyl)-2- methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1 H-indole-1 -carboxylate

[0641] To a soln of rac tert-butyl 4-(((1 R*,2S*,4 / ?*)-2-(4-(methoxycarbonyl)-2-methylphenyl)-4- ((methylsulfonyl)oxy)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac-B-A6, 275 mg, 446 pmol) in DMF (8.0 mL) was added sodium azide (87 mg, 1 .34 mmol) at RT. The RM was stirred at 70 °C for 24 h. The mixture was allowed to cool to rt and then poured into ice-water. The resulting mixture was diluted with EtOAc, and the separated aq layer was extracted with EtOAc (2x). The combined org layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified column chromatography over silica gel (24 g; eluent: 0 to 25% EtOAc in heptane) to provide rac tert-butyl 4-(((1 R*,2S*,4S*)-4- azido-2-(4-(methoxycarbonyl)-2-methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1- carboxylate (180 mg) as a white solid. LC-MS Method B-1 : Rt = 1 .71 min; MS m / z [M-H]- = 531 .2. PAT059793-PCT-SEC01

[0642] Intermediate rac-B-A8: rac tert-butyl 4-(((1R*,2S*,4S*)-4-amino-2-(4-(methoxycarbonyl)-2- methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0643] To a soln of:rac tert-butyl 4-(((1 R*,2S*,4S*)-4-azido-2-(4-(methoxycarbonyl)-2- methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1 H-'\ ndo le- 1 -carboxylate (Intermediate rac-B-M, 179.5 mg, 320 pmol) in THF (5.0 mL) and H2O (115 pL, 6.40 mmol) was slowly added a soln of trimethylphosphine (1 M in THF, 480 pL, 480 pmol). The RM was stirred at RT for 2 h. The mixture was diluted with TBME and H2O. The separated aq layer was extracted with TBME (2x). The combined org layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to provide crude rac fert-butyl 4-(((1 / ?*,2S*,4S*)-4-amino-2-(4- (methoxycarbonyl)-2-methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indo le- 1 -carboxylate (159.0 mg) as a white solid which was used directly without purification. LC-MS Method B-1 : Rt = 1 .06 min; MS m / z [M+H]+= 507.4.

[0644] Intermediate rac-E122 / 123: rac tert-butyl 4-(((1R*,2S*,4S*)-4-((2,2-difluoroethyl)amino)-2-(4- (methoxycarbonyl)-2-methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0645] To a soln of crude rac tert-butyl 4-(((1R*,2S*,4S*)-4-amino-2-(4-(methoxycarbonyl)-2- methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac-B-A8, 159 mg) in ACN (5.0 mL) were added DIPEA (67.6 mg, 91 pL, 523 pmol) and 2,2-difluoroethyl trifluoromethanesulfonate (85.6 mg, 53.2 pL, 400 pmol). The RM was stirred at 20 °C for 2 h. The mixture was diluted with TBME and washed with H2O. The separated aq layer was extracted with TBME. The combined org layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (24 g; eluent: 0 to 20% EtOAc in heptane) to afford rac tert-butyl 4-(((1 R*,2S*,4S*)-4- ((2,2-difluoroethyl)amino)-2-(4-(methoxycarbonyl)-2-methylphenyl)cyclohexyl)oxy)-5,7-dimethyl- PAT059793-PCT-SEC01

[0646] 1 / - / -indole-1 -carboxylate (140 mg) as a white solid. LC-MS Method B-1 : Rt = 1 .56 min; MS m / z [M+H]+= 571.4.

[0647] Intermediate B-E122 and Intermediate B-E123: tert-butyl 4-(((1 / ?,2S,4S)-4-((2,2- difluoroethyl)amino)-2-(4-(methoxycarbonyl)-2-methylphenyl)cyclohexyl)oxy)-5,7-dimethyl- 1H-indole-1 -carboxylate and tert-butyl 4-(((1S,2 / ?,4R)-4-((2,2-difluoroethyl)amino)-2-(4- (methoxycarbonyl)-2-methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0648] Chiral separation and analytics according to Method SFC-E122 / 123. The racemic mixture Intermediate rac-E122 / 123 (140 mg) provided Intermediate B-E122 (peak 1): 41 mg, white solid. Analytical chiral HPLC: Rt = 1 .2 min; 100% ee. LC-MS Method B-1 : Rt = 1 .54 min; MS m / z [M+H]+= 571 .4. Intermediate B-E123 (peak 2): 40 mg, white solid. Analytical chiral HPLC: Rt = 1 .6 min; 99.9% ee. LC-MS Method B-1 : Rt = 1 .56 min; MS m / z [M+H]+= 571 .4.

[0649] Intermediate B-E124: tert-butyl 4-(((1 / ?,2S,4S)-4-((2,2-difluoroethyl)(methyl)amino)-2-(4- (methoxycarbonyl)-2-methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1 -carboxylate

[0650] _ Boc1i l

[0651] To a soln of tert-butyl 4-(((1 / ?,2S,4S)-4-((2,2-difluoroethyl)amino)-2-(4-(methoxycarbonyl)-2- methylphenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate B-E122, 25 mg, 43.8 pmol) in DCE (0.5 mL) were added an aq soln of formaldehyde (7.1 mg, 6.5 pL, 37 wt%, 87.6 pmol) and AcOH (5.3 mg, 5.0 pL, 87.6 pmol). The mixture was stirred at 20 °C for 10 min, and then Na(OAc)3BH (46.4 mg, 219 pmol) was added in one portion. The RM was stirred at 20 °C for 15 min. The mixture was diluted with DCM and then poured carefully into a sat. aq NaHCO3soln. After stirring for 5 min, the layers were separated, and the separated aq layer was extracted with DCM (2x). The combined org layers were washed with H2O and brine, dried over MgSO4, filtered and concentrated under reduced pressure to provide crude te / Y-butyl 4-(((1 R,2S,4S)-4-((2,2- difluoroethyl)(methyl)amino)-2-(4-(methoxycarbonyl)-2-methylphenyl)cyclohexyl)oxy)-5,7-dimethyl- PAT059793-PCT-SEC01

[0652] 1 / - / -indole-1 -carboxylate (25 mg) as a white solid which was directly used in the next reaction without further purification. LC-MS Method B-1 : Rt = 1 .70 min; MS m / z [M+H]+= 585.4.

[0653] Example Ex-1 : 4-((3R,4R)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)piperidin-3- yl)-2-methoxybenzoic acid

[0654] The crude te / Y-butyl 4-(((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-3-(3-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7-ind ole-1 -carboxylate (Intermediate B- E1 , 49.3 mg) was dissolved in IPA (1 mL). Aq NaOH soln (1 M, 0.75 mL, 0.75 mmol) was added, and the RM was stirred at 70 °C for 2 h. Additional aq NaOH soln (1 M, 0.38 mL, 0.38 mmol) was added, and RM was stirred at 80 °C for 2 h. The mixture was allowed to cool to RT and partially concentrated under reduced pressure. The pH was adjusted to 4 with aq HCI soln (1 M), and the mixture was extracted with EtOAc (3x). The combined org phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by RP 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- ((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-methoxybenzoic acid (24.0 mg) as a white solid.

[0655] Example Ex-2: 4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)piperidin-3- yl)-2-fluorobenzoic acid te / Y-Butyl 4-(((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-3-(3-fluoro-4-(methoxycarbonyl)phenyl)piperidin-4- yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate B-E2, 81.9 mg, 0.15 mmol) was dissolved in MeOH (1.5 mL) and H2O (1.5 mL). K2CO3(60.6 mg, 0.44 mmol) was added, and the RM was stirred at RT overnight. The RM was acidified to pH of 2 with aq HCI soln (1 M). The mixture was extracted with EtOAc. The org phase was concentrated under reduced pressure. The residue was purified by RP 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-((3 / ?,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H- indol-4-yl)oxy)piperidin-3-yl)-2-fluorobenzoic acid (10.8 mg).

[0656] Example Ex-3: 4-((3 / ?,4 / ?)-4-((5,7-d imethy 1-1 H-indol-4-yl)oxy)-1 -(2,2,2-trifluoroethyl)piperidin- 3-yl)-2-fluorobenzoic acid

[0657] Example Ex-3 was prepared as described for Example Ex-2 using te / Y-butyl 4-(((3R,4R)-1 -(2,2,2- trifluoroethyl)-3-(3-fluoro-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 - carboxylate (Intermediate B-E3, 79.2 mg, 0.14 mmol) to provide 4-((3R,4 / ?)-4-((5,7-dimethyl-1 / 7- indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2-fluorobenzoic acid (12.8 mg).

[0658] Example Ex-4: 4-((3R,4 / ?)-4-((5-chloro-7-methyl-1 H-indol-4-yl)oxy)-1 -(2,2- difluoroethyl)piperidin-3-yl)-2 -fluorobenzoic acid

[0659] Example Ex-4 was prepared as described for Example Ex-2 using te / Y-butyl 5-chloro-4-(((3R,4 / ?)- 1 -(2, 2-difluoroethyl)-3-(3-fluoro-4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1 / - / -indole- PAT059793-PCT-SEC01

[0660] 1-carboxylate (Intermediate B-E4, 73.2 mg, 0.13 mmol) to provide 4-((3R,4 / ?)-4-((5-chloro-7- methyl-1 / 7-indol-4-yl)oxy)-1 -(2,2-difluoroethyl)piperidin-3-yl)-2-fluorobenzoic acid (16.7 mg). Example Ex-5: 4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)piperidin-3- yl)-2-methylbenzoic acid te / Y-Butyl 4-(((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)-3-methylphenyl)piperidin-4- yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate B-E5, 46 mg, 82 pmol) was dissolved in MeOH (1 mL) and H2O (1 mL). K2CO3(34.6 mg, 0.25 mmol) was added, and the RM was stirred at 70 °C overnight. The RM was allowed to cool to RT and concentrated under reduced pressure.

[0661] The residue was purified by RP HPLC (Waters XBridge C18 20 x 50 mm, 5 pm; eluent: 10 to 70% ACN in H2O with 0.02% NH4OH) to provide 4-((3 / ?,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H- indol-4-yl)oxy)piperidin-3-yl)-2-methylbenzoic acid (14.5 mg) as an off-white solid.

[0662] Example Ex-6: 4-((3 / ?,4 / ?)-4-((5,7-d imethy 1-1 H-indol-4-yl)oxy)-1 -(2,2,2-trifluoroethyl)piperidin- 3-yl)-2-methylbenzoic acid

[0663] Example Ex-6 was prepared as described for Example Ex-5 using te / Y-butyl 4-(((3R,4 / ?)-3-(4- (methoxycarbonyl)-3-methylphenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole-1 -carboxylate (Intermediate B-E6, 47 mg, 82 pmol) to provide 4-((3 / ?,4 / ?)-4-((5,7-dimethyl- 1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2-methylbenzoic acid (14 mg) as an off- white solid.

[0664] Example Ex-7 : 4-((3R,4R)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)piperidin-3- yl)-3-methylbenzoic acid

[0665] The crude te / Y-butyl 4-(((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate B-E7, 23.6 mg) was dissolved in EtOH (1 mL). Aq NaOH soln (1 M, 0.22 mL, 0.22 mmol) was added, and the RM was stirred at 70 °C for 2 days. The mixture was allowed to cool to RT and partially concentrated under reduced pressure. The pH was adjusted to 4 with aq HCI soln (1 M), and the mixture was extracted with EtOAc (3x). The combined org phases were dried over MgSO4and concentrated under reduced pressure. The residue was purified by RP 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- ((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-methylbenzoic acid (13.2 mg) as a white solid.

[0666] Example Ex-8: 4-((3R,4 / ?)-4-((5-chloro-7-methyl-1 H-indol-4-yl)oxy)-1 -(2,2- difluoroethyl)piperidin-3-yl)-3-methylbenzoic acid

[0667] The crude te / Y-butyl 5-chloro-4-(((3 / ?,4 / ?)-1 -(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidin-4-yl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate B-E8, 67.2 mg) was dissolved in IPA (1 mL). Aq NaOH soln (1 M, 0.58 mL, 0.58 mmol) was added, and the RM was stirred at 80 °C for 20 h. Additional aq NaOH soln (1 M, 0.58 mL, 0.58 mmol) was added, and the RM was stirred at 80 °C for 20 h. The mixture was allowed to cool to RT and partially PAT059793-PCT-SEC01 concentrated under reduced pressure. The pH was adjusted to 4 with aq HCI soln (1 M), and the mixture was extracted with EtOAc (3x). The combined org phases were dried over MgSO4and concentrated under reduced pressure. The residue was purified by RP 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-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(2,2-difluoroethyl)piperidin-3-yl)-3- methylbenzoic acid (41 .9 mg) as a white solid.

[0668] Example Ex-9: 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)piperidin-3- yl)-3-methoxybenzoic acid

[0669] The crude te / Y-butyl 4-(((3R,4R)-1-(2,2-difluoroethyl)-3-(2-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7-ind ole-1 -carboxylate (Intermediate B- E9, 11 .2 mg) was dissolved in IPA (1 mL). Aq NaOH soln (1 M, 0.11 mL, 0.11 mmol) was added, and the RM was stirred at 80 °C for 20 h. The mixture was allowed to cool to RT and partially concentrated under reduced pressure. The pH was adjusted to 4 with aq HCI soln (1 M), and the mixture was extracted with EtOAc (3x). The combined org phases were dried over MgSO4and concentrated under reduced pressure. The residue was purified by RP 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)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-methoxybenzoic acid (5.4 mg) as a white solid.

[0670] Example Ex-10: 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2- difluoroethyl)piperidin-3-yl)-3-methoxybenzoic acid

[0671] The crude te / Y-butyl 5-chloro-4-(((3R,4R)-1 -(2,2-difluoroethyl)-3-(2-methoxy-4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1 / -ind ole- 1 -carboxylate (Intermediate B- E10, 47.2 mg) was dissolved in IPA (1 mL). Aq NaOH soln (1 M, 0.40 mL, 0.40 mmol) was added, and the RM was stirred at 80 °C for 20 h. The mixture was allowed to cool to RT and partially concentrated under reduced pressure. The pH was adjusted to 4 with aq HCI soln (1 M), and the mixture was extracted with EtOAc (3x). The combined org phases were dried over MgSO4and concentrated under reduced pressure. The residue was purified by RP 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-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(2,2-difluoroethyl)piperidin-3-yl)-3- methoxybenzoic acid (10.3 mg) as a white powder.

[0672] Example Ex-11 : 2-chloro-4-((3R,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4- yl)oxy)piperidin-3-yl)benzoic acid

[0673] The crude te / Y-butyl 4-(((3R,4R)-3-(3-chloro-4-(methoxycarbonyl)phenyl)-1-(2,2- difluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7-indole-1 -carboxylate (Intermediate B-E1 1 , 8.2 mg) was dissolved in THF (1 mL). Aq NaOH soln (1 M, 0.14 mL, 0.14 mmol) was added, and the RM was stirred at 70 °C for 20 h. The mixture was allowed to cool to RT and partially concentrated under reduced pressure. The pH was adjusted to 4 with 0.5 mL of aq HCI soln (1 M), and the PAT059793-PCT-SEC01 mixture was extracted with EtOAc (3x). The combined org phases were dried over MgSC>4 and concentrated under reduced pressure. The residue was purified by RP HPLC (Waters XBridge C18 OBD 30 x 50 mm, 5 pm; eluent: 15 to 40% ACN in H2O with 0.1% NH4OH) to provide 2- chloro-4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid (4.1 mg) as a white solid.

[0674] Example Ex-12: 4-((3R,4R)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -(2,2,2- trifluoroethyl)piperidin-3-yl)-3-methylbenzoic acid

[0675] The crude te / Y-butyl 4-(((3 / ?,4 / ?)-3-(4-(methoxycarbonyl)-2-methylphenyl)-1 -(2,2,2- trifluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7-i nd o le- 1 -carboxylate (Intermediate B-E12, 19.8 mg) was dissolved in IPA (1 mL). Aq NaOH soln (2M, 0.17 mL, 0.34 mmol) was added, and the RM was stirred at 80 °C for 20 h. The mixture was allowed to cool to RT and partially concentrated under reduced pressure. The pH was adjusted to 4 with 1 .0 mL of aq HCI soln (1 M), and the mixture was extracted with EtOAc (3x). The combined org phases were dried over MgSO4and concentrated under reduced pressure. The residue was purified by RP HPLC (Waters XBridge C18 OBD 30 x 50 mm, 5 pm; eluent: 15 to 40% ACN in H2O with 0.1% NH4OH) to provide 4- ((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-3-methylbenzoic acid (14.5 mg) as a white solid.

[0676] Example Ex-13: 4-((3R,4R)-1 -(3,3-difluoropropyl)-4-((5,7-dimethyl-1 H-indol-4- yl)oxy)piperidin-3-yl)-3-methylbenzoic acid

[0677] The crude te / Y-butyl 4-(((3 / ?,4 / ?)-1-(3,3-difluoropropyl)-3-(4-(methoxycarbonyl)-2- methylphenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate B-E13, 19.6 mg) was dissolved in IPA (1 mL). Aq NaOH soln (2M, 0.17 mL, 0.34 mmol) was added, and the RM was stirred at 80 °C for 20 h. The mixture was allowed to cool to RT and partially concentrated under reduced pressure. The pH was adjusted to 4 with 1 .0 mL aq HCI soln (1 M), and the mixture was extracted with EtOAc (3x). The combined org phases were dried over MgSO4and concentrated under reduced pressure. The residue was purified by RP 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- ((3 / ?,4 / ?)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-methylbenzoic acid (12 mg) as a white solid.

[0678] Example Ex-7 / 40: rac 4-((3R*,4R*)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4- yl)oxy)piperidin-3-yl)-3-methylbenzoic acid

[0679] An aq NaOH soln (4M, 273 pL, 1 .09 mmol) was added to the soln of crude rac te / Y-butyl 4- (((3 / ?*,4 / ?*)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac-B-E40, 86.9 mg) in MeOH (1 .1 mL) and THF (0.52 mL). The RM was stirred at 50 °C for 4 h. The mixture was allowed to cool to RT overnight. The RM was diluted with aq HCI soln (4M, 273 pL, 1.09 mmol). RP chromatography of the crude product soln (Waters Xbridge 50 mm x 100 mm 5 pm; eluent: 10 to 55% ACN in H2O with 0.1% PAT059793-PCT-SEC01

[0680] NH4OH) and subsequent lyophilization provided rac 4-((3R*,4R*)-1 -(2, 2-difluoroethyl)-4-((5, 7- dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-methylbenzoic acid (55.3 mg) as a white solid. LC-MS Method B2: Rt = 5.16 min; MS m / z [M+H]+= 443.3.

[0681] Example Ex-41 / 42: rac 4-((3R*,4R*)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)-3-methylbenzoic acid

[0682] An aq NaOH soln (4M, 255 pL, 1 .02 mmol) was added to the soln of crude rac tert-butyl 4- (((3 / ?*,4 / ?*)-3-(4-(methoxycarbonyl)-2-methylphenyl)-1-(3,3,3-trifluoropropyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac-B-E41-E42, 85.7 mg) in MeOH (0.97 mL) and THF (0.49 mL). The RM was stirred at 50 °C for 4 h. The mixture was cooled to RT and diluted with aq HCI soln (4M, 255 pL, 1 .02 mmol). RP chromatography of the crude product soln (Waters Xbridge 50 mm x 100 mm 5 pm; eluent: 10 to 55% ACN in H2O with 0.1 % NH4OH) and subsequent lyophilzation provided rac 4-((3R*,4R*)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)-3-methylbenzoic acid (56.5 mg) as a white solid. LC-MS Method B2: Rt = 4.55 min; MS m / z [M+H]+= 475.3.

[0683] Example Ex-43 / 44: rac 4-((3R*,4R*)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4- yl)oxy)piperidin-3-yl)-3-(trifluoromethyl)benzoic acid

[0684] An aq NaOH soln (4M, 390 pL, 1 .56 mmol) was added to the crude soln of rac tert-butyl 4- (((3R*,4 / ?*)-1 -(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)-2-(trifluoromethyl)phenyl)piperidin-4- yl)oxy)-5,7-dimethyl-1 / - / -indole-1 -carboxylate (Intermediate rac- B-E43- E44, 136 mg) in MeOH (1.30 mL) and THF (0.20 mL). The RM was stirred at 50 °C for 2.5 h. The mixture was cooled to RT and diluted with aq HCI soln (4M, 390 pL, 1 .56 mmol). RP chromatography of the crude product soln (Waters Xbridge 30 mm x 100 mm 5 pm; eluent: 10 to 50% ACN in H2O with 0.1 % NH4OH) and subsequent lyophilization provided 4-((3R*,4R*)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-ind ol-4- yl)oxy)piperidin-3-yl)-3-(trifluoromethyl)benzoic acid (93 mg) as a white solid. LC-MS Method B2: Rt = 6.02 min; MS m / z [M+H]+= 497.2.

[0685] Example Ex-49 / 50: rac 4-((3R*,4R*)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-(2,2- difluoroethyl)piperidin-3-yl)-3-methylbenzoic acid

[0686] An aq NaOH soln (4M, 248 pL, 992 pmol) was added to the soln of crude rac tert-butyl 5- cyclopropyl-4-(((3R*,4 / ?*)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)-2-methylphenyl)piperidin-4- yl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate rac-B-E49-E50, 82.6 mg, 141.8 pmol) in MeOH (0.95 mL) and THF (0.47 mL). The RM was stirred at 50 °C for 4 h. The mixture was cooled to RT and diluted with aq HCI soln (4M, 248 pL, 992 pmol). RP chromatography of the crude product soln (Waters Xbridge 50 mm x 100 mm 5 pm; eluent: 10 to 55% ACN in H2O with 0.1 % NH4OH) and subsequent lyophilization provided rac 4-((3R*,4R*)-4-((5-cyclopropyl-7-methyl-1 H- indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3-methylbenzoic acid (45.8 mg) as a white solid. LC-MS Method B2: Rt = 5.55 min; MS m / z [M+H]+= 469.3. PAT059793-PCT-SEC01

[0687] Example Ex-51 / 52: rac 3-cyclopropyl-4-((3R*,4R*)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H- indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0688] An aq NaOH soln (4M, 260 pL, 1.04 mmol) was added to a soln of rac tert-butyl 4-(((3R*,4R*)-3-(2- cyclopropyl-4-(methoxycarbonyl)phenyl)-1 -(2,2-difluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 / 7- indole-1 -carboxylate (Intermediate B-E51-E52, 86.4 mg, 148.3 pmol) in MeOH (0.8 mL) and THF (0.25 mL). The RM was stirred at 50 °C for 2 h. The mixture was cooled to RT and diluted with aq HCI soln (4M, 260 pL, 1 .04 mmol). RP chromatography of the soln (Waters Xbridge 30 mm x 100 mm 5 pm; eluent: 15 to 50% ACN in H2O with 0.1 % NH4OH) and subsequent lyophilization provided rac 3-cyclopropyl-4-((3R*,4R*)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4- yl)oxy)piperidin-3-yl)benzoic acid (68.4 mg) as a white solid. LC-MS Method B2: Rt = 5.66 min; MS m / z [M+H]+= 469.3.

[0689] Example Ex-101 : 4-(( 1 S,2R,5S)-2-((5,7-dimethyl-1 H-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- methoxybenzoic acid

[0690] Enriched tert-butyl 4-(((1 / ?,2S,4S)-4-methoxy-2-(3-methoxy-4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 / 7- indole- 1 -carboxylate (Intermediate M- E101 , 29 mg) was dissolved in THF (1 .4 mL) and MeOH (0.7 mL). Aq NaOH soln (1 M, 1 .08 mL, 1.08 mmol) was added, and the RM was stirred at 50 °C for 18 h. The RM was concentrated under reduced pressure and purified using RP HPLC (Waters XBridge C18 30 x 100 mm, 5 pm; eluent: 10 to 60% ACN in H2O with 0.2% FA) to provide 4-((1 S,2R,5S)-2-((5,7-dimethyl-1 H-indol-4-yl)oxy)- 5-methoxycyclohexyl)-2-methoxybenzoic acid (17 mg) as a white solid.

[0691] Example Ex-102: 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5- methoxycyclohexyl)-2 -methoxybenzoic acid

[0692] Example Ex-102 was prepared as described for Example Ex-101 using fert-butyl 5-cyclopropyl-4- (((1 R,2S,4S)-4-methoxy-2-(3-methoxy-4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 / 7- indole-1 -carboxylate (Intermediate M-E102, 14.7 mg, 26 pmol) to provide 4-((1 S,2R,5S)-2-((5- cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-methoxybenzoic acid 4- ((1 S,2R,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- methoxybenzoic acid (9.5 mg) as a colorless semi-solid.

[0693] Example Ex-103 / 127: rac 4-((1S*,2R*,5S*)-2-((5-cyclopropyl-7-methyl-1 H-indol-4-yl)oxy)-5- methoxycyclohexyl)-2-(difluoromethoxy)benzoic acid

[0694] Rac tert-butyl 5-cyclopropyl-4-(((1 R*,2S*,4S*)-2-(3-(difluoromethoxy)-4-(methoxycarbonyl)phenyl)- 4-methoxycyclohexyl)oxy)-7-methyl-1 / - / -indole-1 -carboxylate (Intermediate rac-M-EI OS, 63.4 mg, 0.11 mmol) was dissolved in THF (2 mL) and MeOH (1 mL). Aq NaOH soln (1 M, 1 .05 mL, 1 .05 mmol) was added, and the RM was stirred at 50 °C for 18 h. The RM was quenched with FA (62 pL), and the mixture was purified using RP HPLC (Waters XBridge C18 30 x 100 mm, 5 pm; eluent: 15 to 100% ACN in H2O with 0.2% FA) to provide rac 4-((1 S*, 2R*, 5S*)-2-((5-cyclopropyl-7- PAT059793-PCT-SEC01 methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-(difluoromethoxy)benzoic acid (100.8 mg) as a white solid. Method B-1 : Rt = 1 .20 min; MS m / z [M+H]+= 486.4.

[0695] Example Ex-104: 2-amino-4-((1 S,2R,5S)-2-((5,7-dimethyl-1 H-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid te / Y-Butyl 4-(((1 / ?,2S,4S)-2-(3-amino-4-(methoxycarbonyl)phenyl)-4-methoxycyclohexyl)oxy)-5,7- dimethyl-1 / - / -indole-1 -carboxylate (Intermediate B-17, 50.1 mg, 96 pmol) was dissolved in MeOH (1.5 mL). Aq NaOH soln (4 M, 0.17 mL, 0.67 mmol) was added, and the RM was stirred at 50 °C for 2 days. The RM was quenched with aq soln of HCI (4M, 0.17 mL), and the mixture was purified using RP HPLC (Waters XBridge C18 30 x 100 mm, 5 pm; eluent: 10 to 35% ACN in H2O with 0.1% NH4OH) to provide 2-amino-4-((1 S,2R,5S)-2-((5,7-dimethyl-1 H-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid (36.2 mg) as a white solid.

[0696] Example Ex-105 / 128: rac 4-((1S*,2R*,5S*)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5- methoxycyclohexyl)-2 -fluorobenzoic acid

[0697] To a soln of rac te / Y-butyl 4-(((1 R*,2S*,4S*)-2-(3-fluoro-4-(methoxycarbonyl)phenyl)-4- methoxycyclohexyl)oxy)-5,7-dimethyl-1 / 7-indole-1 -carboxylate (Intermediate rac-M-46, 157.6 mg, 300 pmol) in MeOH (1.0 mL) was added an aq NaOH soln (1 M, 0.75 mL, 0.75 mmol). The RM was stirred at 50 °C for 24 h and then at RT for 48 h. The RM was quenched with aq HCI soln (1 M, 0.75 mL, 0.75 mmol), concentrated under reduced pressure, and the residue was directly purified by RP chromatography (XBridge C18 OBD 30 x 100 mm, 5 pm; eluent: 5 to 100% ACN in H2O with 0.2% FA). Fractions were treated with sat. aq NaHCO3soln and extracted with DCM (3x). The combined org layers were dried over a phase separator cartridge and concentrated under reduced pressure to provide crude rac 4-((1 S*,2R*,5S*)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- fluorobenzoic acid (109.9 mg) as a yellow solid. Method B-1 : Rt = 1 .08 min; MS m / z [M+H]+= 412.3.

[0698] Example Ex-125 and Example Ex-126: rac 3-chloro-4-((1S*,2R*,5S*)-2-((5,7-dimethyl-1H- indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid and rac 3-chloro-4-((1S*,2R*,5S*)-5-(2,2- difluoroethoxy)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid

[0699] Step 1a: To a soln of rac te / Y-butyl 4-(((1 R*,2S*,4S*)-2-(2-chloro-4-(methoxycarbonyl)phenyl)-4- hydroxycyclohexyl)oxy)-5,7-dimethyl-1 / 7-indole-1 -carboxylate (Intermediate rac-B-AS, 113 mg, 214.0 pmol) in THF (2.1 mL) at 0 to 5 °C and under N2atmosphere was added sodium hydride (60 wt% in mineral oil, 11.1 mg, 278 pmol) in one portion. The mixture was stirred for 10 min, and 2,2- difluoroethyl trifluoromethanesulfonate (85.5 pL, 642 pmol) was added. The cooling bath was removed, and the RM was stirred for 4 h. Additional sodium hydride (60 wt% in mineral oil, 11.1 mg, 278 pmol) was added and stirring was continued for 2.5 h.

[0700] Step 1 b: The mixture was diluted with MeOH (1 .0 mL) and aq NaOH soln (4M, 375 pL, 1 .50 mmol), and the RM was stirred at 50 °C for 4 h and then at RT for 16 h. To the mixture was added aq HCI soln (4M, 375 pL, 1 .50 mmol). RP chromatography of the crude product soln (Waters Xbridge 30 PAT059793-PCT-SEC01 mm x 100 mm 5 pm; eluent: 10 to 55% ACN in H2O with 0.1 % NH4OH) and subsequent lyophilization provided rac 3-chloro-4-((1 S*,2R*,5S*)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5- hydroxycyclohexyl)benzoic acid (39.5 mg; first eluting) as a white solid and rac 3-chloro-4- ((1 S*,2R*,5S*)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)benzoic acid (26.3 mg; second eluting) as a white solid.

[0701] Example Ex-129 / 130: rac 3-chloro-4-((1 S*,2R*,5S*)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid

[0702] Aq NaOH soln (4M, 384 pL, 1 .53 mmol) was added to a soln of te / Y-butyl 4-(((1 R*,2S*,4S*)-2-(4- (te / Y-butoxycarbonyl)-2-chlorophenyl)-4-methoxycyclohexyl)oxy)-5,7-dimethyl-1 / - / -indole-1 - carboxylate (Intermediate rac-M-E129-E130, 128 mg, 219 pmol) in MeOH (1.50 mL) and THF (0.50 mL). The RM was stirred at 50 °C for 4 h. The mixture was cooled to RT and treated with aq HCI soln (4M, 384 pL, 1.53 mmol). RP chromatography of the crude mixture (Waters Xbridge 30 mm x 100 mm 5 pm; eluent: 10 to 50% ACN in H2O with 0.1 % NH4OH) and subsequent lyophilization provided 3-chloro-4-((1 S*,2R*,5S*)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid (88.5 mg) as a white solid. LC-MS Method B2: Rt = 5.75 min; MS m / z [M+H]+= 428.3 / 430.3.

[0703] The following chiral Examples or racemic mixtures of Examples were prepared from the appropriate starting materials by applying similar methods described in the Examples above.

[0704] Example Ex-14: 4-((3R,4R)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)piperidin- 3-yl)-3-fluorobenzoic acid

[0705] LC-MS Method C-4: Rt = 1 .19 min; MS m / z [M+H]+= 447.5

[0706] Example Ex-15: 4-((3R,4R)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)piperidin- 3-yl)-2,3-dimethylbenzoic acid

[0707] LC-MS Method C-4: Rt = 1 .46 min; MS m / z [M+H]+= 457.3

[0708] Example Ex-16: 4-((3R,4R)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)piperidin- 3-yl)-2,6-dimethylbenzoic acid

[0709] LC-MS Method C-3: Rt = 1 .66 min; MS m / z [M+H]+= 457.3

[0710] Example Ex-17: rac 4-((3R*,4R*)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4- yl)oxy)piperidin-3-yl)-2,3-dihydrobenzofuran-7 -carboxylic acid

[0711] LC-MS Method B-2: Rt = 4.50 min; MS m / z [M+H]+= 471 .3

[0712] Example Ex-18: rac 4-((3R*,4R*)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4- yl)oxy)piperidin-3-yl)indoline-7 -carboxylic acid

[0713] LC-MS Method B-1 : Rt = 1 .00 min; MS m / z [M+H]+= 470.3

[0714] Example Ex-19 / 20: rac 4-((3R*,4R*)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -(2,2,2- trifluoroethyl)piperidin-3-yl)-2,3-dihydrobenzofuran-7 -carboxylic acid PAT059793-PCT-SEC01

[0715] LC-MS Method B-1 : Rt = 1 .17 min; MS m / z [M+H]+= 489.1

[0716] Example Ex-21 / 22: rac 4-((3R*,4R*)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4- yl)oxy)piperidin-3-yl)-3-fluorobenzoic acid

[0717] LC-MS Method B-1 : Rt = 0.64 min; MS m / z [M+H]+= 461 .4

[0718] Example Ex-23 / 24: rac 4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)-3-fluorobenzoic acid

[0719] LC-MS Method B-1 : Rt = 1 .01 min; MS m / z [M+H]+= 479.2

[0720] Example Ex-25 / 26: rac 2-amino-4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid

[0721] LC-MS Method B-2: Rt = 3.48 min; MS m / z [M+H]+= 476.2

[0722] Example Ex-27 / 28: rac 4-((3R*,4R*)-1-(2-(difluoromethoxy)ethyl)-4-((5,7-dimethyl-1H-indol-4- yl)oxy)piperidin-3-yl)-3-methylbenzoic acid

[0723] LC-MS Method B-1 : Rt = 0.63 min; MS m / z [M+H]+= 473.3

[0724] Example Ex-29: rac 4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-

[0725] (trifluoromethoxy)ethyl)piperidin-3-yl)-3-methoxybenzoic acid

[0726] LC-MS Method B-1 : Rt = 0.82 min; MS m / z [M+H]+= 507.1

[0727] Example Ex-30 / 31 : rac 4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-

[0728] (trifluoromethoxy)ethyl)piperidin-3-yl)-3-fluorobenzoic acid

[0729] LC-MS Method B-1 : Rt = 0.99 min; MS m / z [M+H]+= 495.1

[0730] Example Ex-32 / 33: rac 4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-

[0731] (trifluoromethoxy)ethyl)piperidin-3-yl)-3-methylbenzoic acid

[0732] LC-MS Method B-1 : Rt = 0.98 min; MS m / z [M+H]+= 491 .3

[0733] Example Ex-34 / 35: rac 2-amino-4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-

[0734] (trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid

[0735] LC-MS Method B-2: Rt = 3.53 min; MS m / z [M+H]+= 492.4

[0736] Example Ex-36 / 37: rac 4-((3S*,4S*)-1-(2-(difluoromethoxy)ethyl)-4-((5,7-dimethyl-1H-indol-4- yl)oxy)piperidin-3-yl)-3-methoxybenzoic acid

[0737] LC-MS Method B-1 : Rt = 0.56 min; MS m / z [M+H]+= 489.3

[0738] Example Ex-38: 4-((3R,4R)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)-2 -methylbenzoic acid

[0739] LC-MS Method B-1 : Rt = 0.91 min; MS m / z [M+H]+= 475.2

[0740] Example Ex-39: rac 7-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(2,2,2- trifluoroethyl)piperidin-3-yl)-2,3-dihydrobenzofuran-4-carboxylic acid

[0741] LC-MS Method B-2: Rt = 6.16 min; MS m / z [M+H]+= 489.4

[0742] Example Ex-45 / 46: rac 4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-propylpiperidin-3- yl)-3-(trifluoromethyl)benzoic acid

[0743] LC-MS Method B-2: Rt = 6.09 min; MS m / z [M+H]+= 475.3 PAT059793-PCT-SEC01

[0744] Example Ex-47 / 48: rac 4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)-3-(trifluoromethyl)benzoic acid

[0745] LC-MS Method B-2: Rt = 5.99 min; MS m / z [M+H]+= 529.2

[0746] Example Ex-53 / 54: rac 3-cyclopropyl-4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1- propylpiperidin-3-yl)benzoic acid

[0747] LC-MS Method B-2: Rt = 3.07 min; MS m / z [M+H]+= 447.4

[0748] Example Ex-55 / 56: rac 3-cyclopropyl-4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid

[0749] LC-MS Method B-2: Rt = 5.15 min; MS m / z [M+H]+= 501 .4

[0750] Example Ex-57 / 58: rac 3-chloro-4-((3R*,4R*)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4- yl)oxy)piperidin-3-yl)benzoic acid

[0751] LC-MS Method B-1 : Rt = 1 .16 min; MS m / z [M+H]+= 463.3

[0752] Example Ex-59 / 60: rac 3-chloro-4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid

[0753] LC-MS Method B-1 : Rt = 1 .09 min; MS m / z [M+H]+= 495.1

[0754] Example Ex-61 / 62: rac 4-((3R*,4R*)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4- yl)oxy)piperidin-3-yl)-3-ethylbenzoic acid

[0755] LC-MS Method B-2: Rt = 5.65 min; MS m / z [M+H]+= 457.3

[0756] Example Ex-63 / 64: rac 4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)-3-ethylbenzoic acid

[0757] LC-MS Method B-2: Rt = 5.19 min; MS m / z [M+H]+= 489.3

[0758] Example Ex-65 / 66: rac 4-((3R*,4R*)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4- yl)oxy)piperidin-3-yl)-3-(difluoromethoxy)benzoic acid

[0759] LC-MS Method B-2: Rt = 5.46 min; MS m / z [M+H]+= 495.3

[0760] Example Ex-67 / 68: rac 3-(difluoromethoxy)-4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-

[0761] (3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0762] LC-MS Method B-2: Rt = 5.06 min; MS m / z [M+H]+= 527.4

[0763] Example Ex-69 / 70: rac 4-((3R*,4R*)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4- yl)oxy)piperidin-3-yl)-3-(difluoromethyl)benzoic acid

[0764] LC-MS Method B-2: Rt = 5.40 min; MS m / z [M+H]+= 479.3

[0765] Example Ex-71 / 72: rac 3-(difluoromethyl)-4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-

[0766] (3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0767] LC-MS Method B-2: Rt = 5.17 min; MS m / z [M+H]+= 511 .4

[0768] Example Ex-73 / 74: rac 4-((3R*,4R*)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1 -(2,2,2- trifluoroethyl)piperidin-3-yl)-3-methylbenzoic acid

[0769] LC-MS Method B-2: Rt = 6.64 min; MS m / z [M+H]+= 487.4 PAT059793-PCT-SEC01

[0770] Example Ex-75 / 76: rac 3-cyclopropoxy-4-((3R*,4R*)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H- indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0771] LC-MS Method B-2: Rt = 5.36 min; MS m / z [M+H]+= 485.4

[0772] Example Ex-77 / 78: rac 3-cyclopropoxy-4-((3R*,4R*)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-

[0773] (3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0774] LC-MS Method B-2: Rt = 4.67 min; MS m / z [M+H]+= 517.2

[0775] Example Ex-106 / 107: rac 4-((1S*,2R*,5S*)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5- methoxycyclohexyl)-2-(methylamino)benzoic acid

[0776] LC-MS Method B-1 : Rt = 1 .14 min; MS m / z [M+H]+= 423.2

[0777] Example Ex-108 / 109: rac 4-((1S*,2R*,5S*)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5- methoxycyclohexyl)-3-fluorobenzoic acid

[0778] LC-MS Method B-1 : Rt = 1.15 min; MS m / z [M+H]+= 412.2

[0779] Example Ex-110 / 111 : rac 4-((1 S*,2R*,5S*)-2-((5,7-dimethyl-1 H-indol-4-yl)oxy)-5- methoxycyclohexyl)-3-methoxybenzoic acid

[0780] LC-MS Method B-1 : Rt = 1 .12 min; MS m / z [M+H]+= 424.2

[0781] Example Ex-112 / 113: rac 4-((1S*,2R*,5S*)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5- methoxycyclohexyl)-3-methylbenzoic acid

[0782] LC-MS Method B-2: Rt = 5.72 min; MS m / z [M+H]+= 408.3

[0783] Example Ex-114 / 115: rac 4-((1S*,2R*,5S*)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1H-indol-4- yl)oxy)cyclohexyl)-2 -methoxybenzoic acid

[0784] LC-MS Method B-1 : Rt = 1 .08 min; MS m / z [M+H]+= 474.1

[0785] Example Ex-116 / 117: rac 4-((1S*,2R*,5S*)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1H-indol-4- yl)oxy)cyclohexyl)-3-methoxybenzoic acid

[0786] LC-MS Method B-2: Rt = 5.62 min; MS m / z [M+H]+= 474.2

[0787] Example Ex-118 / 119: rac 4-((1S*,2R*,5S*)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1H-indol-4- yl)oxy)cyclohexyl)-3-fluorobenzoic acid

[0788] LC-MS Method B-2: Rt = 5.78 min; MS m / z [M+H]+= 462.1

[0789] Example Ex-120 / 121 : rac 4-((1S*,2R*,5S*)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1H-indol-4- yl)oxy)cyclohexyl)-3-methylbenzoic acid

[0790] LC-MS Method B-2: Rt = 5.93 min; MS m / z [M+H]+= 458.3

[0791] Example Ex-122: 4-(( 1 S,2R,5S)-5-((2,2-difluoroethyl)amino)-2-((5,7-dimethyl-1 H-indol-4- yl)oxy)cyclohexyl)-3-methylbenzoic acid

[0792] LC-MS Method B-1 : Rt = 0.79 min; MS m / z [M+H]+= 457.4

[0793] Example Ex-123: 4-(( 1 R,2S,5R)-5-((2,2-difluoroethyl)amino)-2-((5,7-dimethyl-1 H-indol-4- yl)oxy)cyclohexyl)-3-methylbenzoic acid

[0794] LC-MS Method B-1 : Rt = 0.79 min; MS m / z [M+H]+= 457.3 PAT059793-PCT-SEC01

[0795] Example Ex-124: 4-(( 1 S,2R,5S)-5-((2,2-difluoroethyl)(methyl)amino)-2-((5,7-dimethyl-1 H- indol-4-yl)oxy)cyclohexyl)-3-methylbenzoic acid

[0796] LC-MS Method B-1 : Rt = 1 .16 min; MS m / z [M+H]+= 471 .4

[0797] Example Ex-201 : 4-((5S,6R)-6-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-2- methoxybenzoic acid

[0798] LC-MS Method C-4: Rt = 1 .53 min; MS m / z [M+H]+= 420.4

[0799] Example Ex-202 / 203: rac 4-((5S*,6R*)-6-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[2.5]octan-5-yl)- 3-methoxybenzoic acid

[0800] LC-MS Method B-1 : Rt = 1 .36 min; MS m / z [M+H]+= 420.1

[0801] Example Ex-204 / 205: rac 4-((6S*,7R*)-7-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[3.5]nonan-6- yl)-2-methoxybenzoic acid

[0802] LC-MS Method B-2: Rt = 6.69 min; MS m / z [M+H]+= 434.2

[0803] Example Ex-206 / 207: rac 4-((6S*,7R*)-7-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[3.5]nonan-6- yl)-3-methoxybenzoic acid

[0804] LC-MS Method B-2: Rt = 7.10 min; MS m / z [M+H]+= 434.

[0805] Example Ex-208 / 209: rac 4-((6S*,7R*)-7-((5,7-dimethyl-1H-indol-4-yl)oxy)-2,2- difluorospiro[3.5]nonan-6-yl)-2 -methoxybenzoic acid

[0806] LC-MS Method B-2: Rt = 6.05 min; MS m / z [M+H]+= 470.2

[0807] Example Ex-210 / 211 : rac 4-((6S*,7R*)-7-((5,7-dimethyl-1H-indol-4-yl)oxy)-2,2- difluorospiro[3.5]nonan-6-yl)-3-methoxybenzoic acid

[0808] LC-MS Method B-2: Rt = 6.49 min; MS m / z [M+H]+= 468.3

[0809] Example Ex-212 / 213: rac 4-((6S*,7R*)-7-((5,7-dimethyl-1H-indol-4-yl)oxy)-2- oxaspiro[3.5]nonan-6-yl)-2 -methylbenzoic acid

[0810] LC-MS Method B-1 : Rt = 1 .06 min; MS m / z [M+H]+= 420.1

[0811] Isolation of the following chiral examples was achieved through chiral separation of the corresponding racemic mixtures:

[0812] Example Ex-19 and Example Ex-20: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(2,2,2- trifluoroethyl)piperidin-3-yl)-2,3-dihydrobenzofuran-7 -carboxylic acid and 4-((3S,4S)-4-((5,7- dimethyl-1H-indol-4-yl)oxy)-1 -(2,2,2-trifluoroethyl)piperidin-3-yl)-2,3-dihydrobenzofuran-7- carboxylic acid

[0813] Chiral separation and analytics according to Method SFC-E19 / 20. The racemic mixture Example Ex-19 / 20 (6.6 mg) provided Example Ex-19 (peak 2): 2.7 mg, off-white solid. Analytical chiral HPLC: Rt = 2.72 min; 99% ee. Example Ex-20 (peak 1): 3 mg, off-white solid. Analytical chiral HPLC: Rt = 1.65 min; 99% ee. PAT059793-PCT-SEC01

[0814] Example Ex-21 and Example Ex-22: 4-((3R,4R)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H- indol-4-yl)oxy)piperidin-3-yl)-3-fluorobenzoic acid and 4-((3S,4S)-1-(3,3-difluoropropyl)-4- ((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)-3-fluorobenzoic acid

[0815] Chiral separation and analytics according to Method SFC-E21 / 22. The racemic mixture Example Ex-21 / 22 (19 mg) provided Example Ex-21 (peak 1): 6.8 mg, white solid. Analytical chiral HPLC: Rt = 1 .39 min; 99.5% ee. Example Ex-22 (peak 2): 6.7 mg, white solid. Analytical chiral HPLC: Rt = 2.97 min; 99.5% ee.

[0816] Example Ex-23 and Example Ex-24: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)-3-fluorobenzoic acid and 4-((3S,4S)-4-((5,7-dimethyl-1H-indol- 4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3-fluorobenzoic acid

[0817] Chiral separation and analytics according to Method SFC-E23 / 24-1 and Method SFC-E23 / 24-2.

[0818] The racemic mixture Example Ex-23 / 24 (24 mg) provided Example Ex-23 (peak 1): 5.8 mg, white solid. Analytical chiral HPLC: Rt = 1 .80 min; 99.5% ee. Example Ex-24 (peak 2): 8.6 mg, white solid. Analytical chiral HPLC: Rt = 2.95 min; 95.0% ee.

[0819] Example Ex-25 and Example Ex-26: 2-amino-4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1- (3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 2-amino-4-((3S,4S)-4-((5,7-dimethyl-1H- indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0820] Chiral separation and analytics according to Method SFC-E25 / 26. The racemic mixture Example Ex-25 / 26 (58 mg) provided Example Ex-25 (peak 1): 26.4 mg, brownish solid. Analytical chiral HPLC: Rt = 0.92 min; 99.5% ee. Example Ex-26 (peak 2): 26.5 mg, brownish solid. Analytical chiral HPLC: Rt = 2.11 min; 99.5% ee.

[0821] Example Ex-27 and Example Ex-28: 4-((3R,4R)-1-(2-(difluoromethoxy)ethyl)-4-((5,7-dimethyl- 1H-indol-4-yl)oxy)piperidin-3-yl)-3-methylbenzoic acid and 4-((3S,4S)-1-(2- (difluoromethoxy)ethyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)-3-methylbenzoic acid

[0822] Chiral separation and analytics according to Method SFC-E27 / 28. The racemic mixture Example Ex-27 / 28 (41.9 mg) provided Example Ex-27 (peak 2): 18.6 mg, beige solid. Analytical chiral HPLC: Rt = 2.4 min; 100% ee. Example Ex-28 (peak 1): 18.3 mg, beige solid. Analytical chiral HPLC: Rt = 1.5 min; 100% ee.

[0823] Example Ex-30 and Example Ex-31 : 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2- (trifluoromethoxy)ethyl)piperidin-3-yl)-3-fluorobenzoic acid and 4-((3S,4S)-4-((5,7-dimethyl- 1 H-indol-4-yl)oxy)-1 -(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3-fluorobenzoic acid

[0824] Chiral separation and analytics according to Method SFC-E30 / 31. The racemic mixture Example Ex-30 / 31 (51 mg) provided Example Ex-30 (peak 1): 13 mg, white solid. Analytical chiral HPLC: Rt = 0.90 min; 99.5% ee. Example Ex-31 (peak 2): 13 mg, white solid. Analytical chiral HPLC: Rt = 1 .45 min; 96.0% ee. PAT059793-PCT-SEC01

[0825] Example Ex-32 and Example Ex-33: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2- (trifluoromethoxy)ethyl)piperidin-3-yl)-3-methylbenzoic acid and 4-((3S,4S)-4-((5,7-dimethyl- 1 H-indol-4-yl)oxy)-1 -(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3-methylbenzoic acid

[0826] Chiral separation and analytics according to Method SFC-E32 / 33. The racemic mixture Example Ex-32 / 33 (25.6 mg) provided Example Ex-32 (peak 1): 11 .6 mg, off-white solid. Analytical chiral HPLC: Rt = 0.9 min; 99.5% ee. Example Ex-33 (peak 2): 11 .4 mg, off-white solid. Analytical chiral HPLC: Rt = 1.9 min; 99.5% ee.

[0827] Example Ex-34 and Example Ex-35: 2-amino-4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1- (2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid and 2-amino-4-((3S,4S)-4-((5,7- dimethyl-1 H-indol-4-yl)oxy)-1 -(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid

[0828] Chiral separation and analytics according to Method SFC-E34 / 35. The racemic mixture Example Ex-34 / 35 (110 mg) provided Example Ex-34 (peak 1): 34.9 mg, brownish solid. Analytical chiral HPLC: Rt = 0.90 min; 99.5% ee. Example Ex-35 (peak 2): 26.7 mg, brownish solid. Analytical chiral HPLC: Rt = 2.45 min; 99.5% ee.

[0829] Example Ex-36 and Example Ex-37: 4-((3R,4R)-1-(2-(difluoromethoxy)ethyl)-4-((5,7-dimethyl- 1H-indol-4-yl)oxy)piperidin-3-yl)-3-methoxybenzoic acid and 4-((3S,4S)-1-(2- (difluoromethoxy)ethyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)-3-methoxybenzoic acid

[0830] Chiral separation and analytics according to Method SFC-E36 / 37. The racemic mixture Example Ex-36 / 37 (110 mg) provided Example Ex-36 (peak 2): 39 mg, pinkish solid. Analytical chiral HPLC: Rt = 1.63 min; 99% ee. Example Ex-37 (peak 1): 40 mg, pinkish solid. Analytical chiral HPLC: Rt = 1.01 min; 99% ee.

[0831] Example Ex-40: 4-((3S,4S)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)piperidin-

[0832] 3-yl)-3-methylbenzoic acid

[0833] Chiral separation and analytics according to Method SFC-E40. The racemic mixture Example Ex- 7 / 40 (55.3 mg) provided Example Ex-40 (peak 2): 24.8 mg, off-white solid. Analytical chiral HPLC: Rt = 2.50 min; 99.5% ee.

[0834] Example Ex-41 and Example Ex-42: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)-3-methylbenzoic acid and 4-((3S,4S)-4-((5,7-dimethyl-1H-indol-

[0835] 4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3-methylbenzoic acid

[0836] Chiral separation and analytics according to Method SFC-E41 / 42. The racemic mixture Example Ex-41 / 42 (53.3 mg) provided Example Ex-41 (peak 2): 23.0 mg, off-white solid. Analytical chiral HPLC: Rt = 1.3 min; 99.5% ee. Example Ex-42 (peak 1): 23.2 mg, off-white solid. Analytical chiral HPLC: Rt = 0.9 min; 99.5% ee.

[0837] Example Ex-43 and Example Ex-44: 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 H-indol- 4-yl)oxy)piperidin-3-yl)-3-(trifluoromethyl)benzoic acid and 4-((3S,4S)-1 -(2,2-difluoroethyl)-4- ((5,7-dimethyl-1 H-indol-4-yl)oxy)piperidin-3-yl)-3-(trifluoromethyl)benzoic acid PAT059793-PCT-SEC01

[0838] Chiral separation and analytics according to Method SFC-E43 / 44. The racemic mixture Example Ex-43 / 44 (92 mg) provided Example Ex-43 (peak 1): 34.3 mg, off-white solid. Analytical chiral HPLC: Rt = 1 .45 min; 99.5% ee. Example Ex-44 (peak 2): 30.3 mg, off-white solid. Analytical chiral HPLC: Rt = 1.96 min; 96.0% ee.

[0839] Example Ex-45 and Example Ex-46: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1- propylpiperidin-3-yl)-3-(trifluoromethyl)benzoic acid and 4-((3S,4S)-4-((5,7-dimethyl-1H- indol-4-yl)oxy)-1-propylpiperidin-3-yl)-3-(trifluoromethyl)benzoic acid

[0840] Chiral separation and analytics according to Method SFC-E45 / 46. The racemic mixture Example Ex-45 / 46 (88 mg) provided Example Ex-45 (peak 1): 33.7 mg, white solid. Analytical chiral HPLC: Rt = 1.3 min; 99.0% ee. Example Ex-46 (peak 2): 42.3 mg, white solid. Analytical chiral HPLC: Rt = 1 .7 min; 95.0% ee.

[0841] Example Ex-47: 4-((3R,4R)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)-3-(trifluoromethyl)benzoic acid

[0842] Step 1a: A soln of TMS-diazomethane (2.1 M in hexane, 203 pL, 426.5 pmol) was added to a soln of rac 4-((3R*,4R*)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- (trifluoromethyl)benzoic (Example Ex-47 / 48, 98.0 mg, 185 pmol) in DCM (1.0 mL) and MeOH (1.0 mL) in a dropwise manner. The slightly yellowish soln was stirred at RT for 2.7 h, and then 2 drops of AcOH were added. The mixture was diluted with DCM and concentrated under reduced pressure at 50 °C to provide rac methyl 4-((3R*,4R*)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)-3-(trifluoromethyl)benzoate (109 mg) as a yellow oil.

[0843] Step 1 b: Chiral separation and analytics according to Method SFC-E47 / 48. The racemic mixture rac methyl 4-((3R*,4R*)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- (trifluoromethyl)benzoate (109 mg) provided Intermediate E47 (peak 1): 44.6 mg, white solid.

[0844] Analytical chiral HPLC: Rt = 0.8 min; 99.5% ee. LC-MS Method B-2: Rt = 6.83 min; MS m / z [M+H]+= 543.3 and Intermediate E48 (peak 2): 44.6 mg, white solid. Analytical chiral HPLC: Rt = 1 .3 min; 99.5% ee. LC-MS Method B-2: Rt = 6.88 min; MS m / z [M+H]+= 543.2.

[0845] Step 1c: Aq soln of NaOH (4M, 103 pL, 411.0 pmol) was added to a soln of methyl 4-((3R,4R)-4- ((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3, 3, 3-trifluoropropyl)piperidin-3-yl)-3-(trifluoromethyl) benzoate (Intermediates E47, 44.6 mg, 82.2 pmol) in MeOH (0.40 mL) and THF (0.10 mL). The RM was stirred at 50 °C for 2.7 h. The mixture was allowed to cool to RT and diluted with aq soln of HCI (4M, 102.8 pL, 411 pmol). The resulting mixture was directly purified by RP-HPLC (Waters Xbridge C18 Dimensions: 30 mm x 100 mm 5 pm; eluent: 15 to 55% ACN in water with 0.1% NH4OH) to provide 4-((3R,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- (trifluoromethyl)benzoic acid (39.8 mg) as a white, fluffy solid.

[0846] Example Ex-48: 4-((3S,4S)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)-3-(trifluoromethyl)benzoic acid PAT059793-PCT-SEC01

[0847] Example Ex-48 was prepared as described for Example Ex-47 using methyl 4-((3S,4S)-4-((5,7- dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3, 3, 3-trifluoropropyl)piperidin-3-yl)-3-(trifluoromethyl) benzoate (Intermediate E48, 44.6 mg, 82.2 pmol) to provide 4-((3S,4S)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1- (3,3,3-trifluoropropyl)piperidin-3-yl)-3-(trifluoromethyl)benzoic acid (38.9 mg) as a white, fluffy solid.

[0848] Example Ex-49 and Example Ex-50: 4-((3R,4 / ?)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)- 1-(2,2-difluoroethyl)piperidin-3-yl)-3-methylbenzoic acid and 4-((3S,4S)-4-((5-cyclopropyl-7- methyl-1 H-indol-4-yl)oxy)-1 -(2,2-difluoroethyl)piperidin-3-yl)-3-methylbenzoic acid

[0849] Chiral separation and analytics according to Method SFC-E49 / 50. The racemic mixture Example Ex-49 / 50 (42.3 mg) provided Example Ex-49 (peak 2): 18.5 mg, off-white solid. Analytical chiral HPLC: Rt = 2.4 min; 99.5% ee. Example Ex-50 (peak 1): 18.5 mg, off-white solid. Analytical chiral HPLC: Rt = 1.7 min; 99.5% ee.

[0850] Example Ex-51 and Example Ex-52: 3-cyclopropyl-4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7- dimethyl-1 H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid and 3-cyclopropyl-4-((3S,4S)-1-(2,2- difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0851] Chiral separation and analytics according to Method SFC-E51 / 52. The racemic mixture Example Ex-51 / 52 (66 mg) provided Example Ex-51 (peak 2): 27.2 mg, white solid. Analytical chiral HPLC: Rt = 1.9 min; 99.5% ee. Example Ex-52 (peak 1): 28.3 mg, white solid. Analytical chiral HPLC: Rt = 1 .2 min; 99.5% ee.

[0852] Example Ex-53 and Example Ex-54: 3-cyclopropyl-4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4- yl)oxy)-1-propylpiperidin-3-yl)benzoic acid and 3-cyclopropyl-4-((3S,4S)-4-((5,7-dimethyl-1H- indol-4-yl)oxy)-1 -propylpiperidin-3-yl)benzoic acid

[0853] Chiral separation and analytics according to Method SFC-E53 / 54. The racemic mixture Example Ex-53 / 54 (63 mg) provided Example Ex-53 (peak 2): 19.4 mg, off-white solid. Analytical chiral HPLC: Rt = 3.0 min; 96.0% ee. Example Ex-54 (peak 1): 18.1 mg, off-white solid. Analytical chiral HPLC: Rt = 2.3 min; 99.5% ee.

[0854] Example Ex-55 and Example Ex-56: 3-cyclopropyl-4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4- yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 3-cyclopropyl-4-((3S,4S)-4- ((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0855] Chiral separation and analytics according to Method SFC-E55 / 56. The racemic mixture Example Ex-55 / 56 (75 mg) provided Example Ex-55 (peak 2): 31 .4 mg, white solid. Analytical chiral HPLC: Rt = 1.6 min; 99.5% ee. Example Ex-56 (peak 1): 31.7 mg, white solid. Analytical chiral HPLC: Rt = 1 .0 min; 99.5% ee.

[0856] Example Ex-57 and Example Ex-58: 3-chloro-4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl- 1 H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid and 3-chloro-4-((3S,4S)-1-(2,2-difluoroethyl)-4- ((5,7-dimethyl-1 H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0857] Chiral separation and analytics according to Method SFC-E57 / 58. The racemic mixture Example Ex-57 / 58 (16 mg) provided Example Ex-57 (peak 1): 4.3 mg, beige solid. Analytical chiral HPLC: PAT059793-PCT-SEC01

[0858] Rt = 1.9 min; 99.5% ee. Example Ex-58 (peak 2): 4.4 mg, beige solid. Analytical chiral HPLC: Rt =

[0859] 2.5 min; 99.5% ee.

[0860] Example Ex-59 and Example Ex-60: 3-chloro-4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1- (3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 3-chloro-4-((3S,4S)-4-((5,7-dimethyl-1 H- indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0861] Chiral separation and analytics according to Method SFC-E59 / 60. The racemic mixture Example Ex-59 / 60 (25 mg) provided Example Ex-59 (peak 1): 7.8 mg, beige solid. Analytical chiral HPLC: Rt = 1.2 min; 99.5% ee. Example Ex-60 (peak 2): 7.2 mg, beige solid. Analytical chiral HPLC: Rt = 1 .8 min; 99% ee.

[0862] Example Ex-61 and Example Ex-62: 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol- 4-yl)oxy)piperidin-3-yl)-3-ethylbenzoic acid and 4-((3S,4S)-1-(2,2-difluoroethyl)-4-((5,7- dimethyl-1 H-indol-4-yl)oxy)piperidin-3-yl)-3-ethylbenzoic acid

[0863] Chiral separation and analytics according to Method SFC-E61 / 62. The racemic mixture Example Ex-61 / 62 (69 mg) provided Example Ex-61 (peak 2): 26.0 mg, white solid. Analytical chiral HPLC: Rt = 1.4 min; 96.4% ee. Example Ex-62 (peak 1): 25.9 mg, white solid. Analytical chiral HPLC: Rt = 1.0 min; 100% ee.

[0864] Example Ex-63 and Example Ex-64: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)-3-ethylbenzoic acid and 4-((3S,4S)-4-((5,7-dimethyl-1 H-indol-4- yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3-ethylbenzoic acid

[0865] Chiral separation and analytics according to Method SFC-E63 / 64. The racemic mixture Example Ex-63 / 64 (69.4 mg) provided Example Ex-63 (peak 2): 28.2 mg, white solid. Analytical chiral HPLC: Rt = 2.1 min; 96.8% ee. Example Ex-64 (peak 1): 25.0 mg, white solid. Analytical chiral HPLC: Rt = 1.3 min; 100% ee.

[0866] Example Ex-65 and Example Ex-66: 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol- 4-yl)oxy)piperidin-3-yl)-3-(difluoromethoxy)benzoic acid and 4-((3S,4S)-1-(2,2-difluoroethyl)- 4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)-3-(difluoromethoxy)benzoic acid

[0867] Chiral separation and analytics according to Method SFC-E65 / 66. The racemic mixture Example Ex-65 / 66 (46 mg) provided Example Ex-65 (peak 1): 19.3 mg, white solid. Analytical chiral HPLC: Rt = 2.7 min; 99.5% ee. Example Ex-66 (peak 2): 19.7 mg, white solid. Analytical chiral HPLC: Rt =

[0868] 3.6 min; 99.5% ee.

[0869] Example Ex-67 and Example Ex-68: 3-(difluoromethoxy)-4-((3R,4R)-4-((5,7-dimethyl-1H-indol- 4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 3-(difluoromethoxy)-4- ((3S,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0870] Chiral separation and analytics according to. The racemic mixture Example Ex-67 / 68 (63 mg) provided Example Ex-67 (peak 1): 30.6 mg, white solid. Analytical chiral HPLC: Rt = 1.57 min; PAT059793-PCT-SEC01

[0871] 99.5% ee. Example Ex-68 (peak 2): 30.2 mg, white solid. Analytical chiral HPLC: Rt = 2.37 min; 99.5% ee.

[0872] Example Ex-69 and Example Ex-70: 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol- 4-yl)oxy)piperidin-3-yl)-3-(difluoromethyl)benzoic acid and 4-((3S,4S)-1 -(2,2-difluoroethyl)-4- ((5,7-dimethyl-1 H-indol-4-yl)oxy)piperidin-3-yl)-3-(difluoromethyl)benzoic acid

[0873] Example Ex-69 and Example Ex-70 were prepared as described for Example Ex-47 and Example Ex-48. Step 1a: rac 4-((3R*,4R*)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-

[0874] 3-yl)-3-(difluoromethyl)benzoic acid (Example Ex-69 / 70, 64 mg, 134 pmol) provided rac methyl 4- ((3R*,4R*)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (difluoromethyl)benzoate (68 mg, white solid). LC-MS Method B-1 : Rt = 1 .28 min; MS m / z [M+H]+= 493.1. Step 1 b: Chiral separation and analytics according to Method SFC-E69 / 70 provided methyl

[0875] 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (difluoromethyl)benzoate (peak 1 , Intermediate E69, 29.1 mg, white solid). Analytical chiral HPLC: Rt = 0.9 min; 99.5% ee. LC-MS Method B-2: Rt = 6.16 min; MS m / z [M+H]+= 493.4. Methyl 4- ((3S,4S)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (difluoromethyl)benzoate (peak 2, Intermediate E70, 29.4 mg, white solid). Analytical chiral HPLC: Rt = 1.6 min; 99.2% ee. LC-MS Method B-2: Rt = 6.18 min; MS m / z [M+H]+= 493.3. Step 1c: Intermediate E69 (peak 1) provided Example Ex-69 (25.1 mg, white solid). Intermediate E70 (peak 2) provided Example Ex-70 (20.6 mg, white solid).

[0876] Example Ex-71 and Example Ex-72: 3-(difluoromethyl)-4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4- yl)oxy)-1 -(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 3-(difluoromethyl)-4-((3S,4S)- 4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid Example Ex-71 and Example Ex-72 were prepared as described for Example Ex-47 and Example Ex-48. Step 1a: rac 3-(difluoromethyl)-4-((3R*,4R*)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid (Example Ex-71 / 72, 68 mg, 133 pmol) provided rac methyl 3-(difluoromethyl)-4-((3R*,4R*)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)benzoate (70 mg, white solid). LC-MS Method B-1 : Rt = 1 .27 min; MS m / z [M+H]+= 525.1. Step 1 b: Chiral separation and analytics according to Method SFC-E71 / 72 provided methyl 3-(difluoromethyl)-4-((3R,4R)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)benzoate (peak 1 , Intermediate E71 , 28.7 mg, white solid). Analytical chiral HPLC: Rt = 0.8 min; 99.5% ee. LC-MS Method B-2: Rt = 6.13 min; MS m / z [M+H]+= 525.1.

[0877] Methyl 3-(difluoromethyl)-4-((3S,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(3,3,3- trifluoropropyl)piperidin-3-yl)benzoate (peak 2, Intermediate E72, 29.8 mg, white solid). Analytical chiral HPLC: Rt = 1.3 min; 99.5% ee. LC-MS Method B-2: Rt = 6.13 min; MS m / z [M+H]+= 525.1. Step 1c: Intermediate E71 (peak 1) provided Example Ex-71 (19.9 mg, white solid). Intermediate E72 (peak 2) provided Example Ex-72 (26.4 mg, white solid). PAT059793-PCT-SEC01

[0878] Example Ex-73 and Example Ex-74: 4-((3R,4 / ?)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)- 1-(2,2,2-trifluoroethyl)piperidin-3-yl)-3-methylbenzoic acid and 4-((3S,4S)-4-((5-cyclopropyl- 7-methyl-1 H-indol-4-yl)oxy)-1 -(2,2,2-trifluoroethyl)piperidin-3-yl)-3-methylbenzoic acid

[0879] Chiral separation and analytics according to Method SFC-E73 / 74. The racemic mixture Example Ex-73 / 74 (38.7 mg) provided Example Ex-73 (peak 1): 18.4 mg, pale greenish solid. Analytical chiral HPLC: Rt = 1 .0 min; 99.5% ee. Further purification of peak 1 by preparative HPLC (X-Bridge C18 column, 10 to 50% ACN in water with 0.1% NH4OH) provided Example Ex-73 (9.3 mg).

[0880] Example Ex-74 (peak 2): 15.3 mg, pale greenish solid. Analytical chiral HPLC: Rt = 2.1 min; 99.5% ee.

[0881] Example Ex-75 and Example Ex-76: 3-cyclopropoxy-4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7- dimethyl-1 H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid and 3-cyclopropoxy-4-((3S,4S)-1-(2,2- difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid

[0882] Chiral separation and analytics according to Method SFC-E75 / 76. The racemic mixture Example Ex-75 / 76 (77 mg) provided Example Ex-75 (peak 2): 36.2 mg, off-white solid. Analytical chiral HPLC: Rt = 1.6 min; 99.5% ee. Example Ex-76 (peak 1): 37.9 mg, off-white solid. Analytical chiral HPLC: Rt = 0.6 min; 99.5% ee.

[0883] Example Ex-77 and Example Ex-78: 3-cyclopropoxy-4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4- yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid and 3-cyclopropoxy-4-((3S,4S)-4- ((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid

[0884] Chiral separation and analytics according to Method SFC-E77 / 78. The racemic mixture Example Ex-77 / 78 (76 mg) provided Example Ex-77 (peak 2): 35 mg, white solid. Analytical chiral HPLC: Rt = 4.3 min; 99.5% ee. Example Ex-78 (peak 1): 34 mg, white solid. Analytical chiral HPLC: Rt = 3.3 min; 99.5% ee.

[0885] Example Ex-103 and Example Ex-127: 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4- yl)oxy)-5-methoxycyclohexyl)-2-(difluoromethoxy)benzoic acid and 4-((1R,2S,5R)-2-((5- cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-(difluoromethoxy)benzoic acid

[0886] Chiral separation and analytics according to Method SFC-E103 / 127. The racemic mixture Example Ex-103 / 127 (101 mg) provided Example Ex-103 (peak 2): 9.0 mg, white solid. Analytical chiral HPLC: Rt = 1.28 min; 99.5% ee. Example Ex-127 (peak 1): 11 mg, white solid. Analytical chiral HPLC: Rt = 1.10 min; 99.5% ee.

[0887] Example Ex-105 and Example Ex-128: 4-((1S,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5- methoxycyclohexyl)-2-fluorobenzoic acid and 4-((1R,2S,5R)-2-((5,7-dimethyl-1H-indol-4- yl)oxy)-5-methoxycyclohexyl)-2 -fluorobenzoic acid

[0888] Chiral separation and analytics according to Method SFC-E105 / 128. The racemic mixture Example Ex-105 / 128 (110 mg) provided Example Ex-105 (peak 1): 47.8 mg, beige solid. Analytical chiral PAT059793-PCT-SEC01

[0889] HPLC: Rt = 1 .66 min; 99% ee. Example Ex-128 (peak 2): 45.3 mg, beige solid. Analytical chiral HPLC: Rt = 2.07 min; 99% ee.

[0890] Example Ex-106 and Example Ex-107: 4-((1S,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5- methoxycyclohexyl)-2-(methylamino)benzoic acid and 4-((1R,2S,5R)-2-((5,7-dimethyl-1H- indol-4-yl)oxy)-5-methoxycyclohexyl)-2-(methylamino)benzoic acid

[0891] Chiral separation and analytics according to Method SFC-E106 / 107. The racemic mixture Example Ex-106 / 107 (15.1 mg) provided Example Ex-106 (peak 2): 6.9 mg, white solid. Analytical chiral HPLC: Rt = 1.75 min; 99% ee. Example Ex-107 (peak 1): 6.9 mg, white solid. Analytical chiral HPLC: Rt = 1.29 min; 95.5% ee.

[0892] Example Ex-108 and Example Ex-109: 4-((1S,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5- methoxycyclohexyl)-3-fluorobenzoic acid and 4-((1R,2S,5R)-2-((5,7-dimethyl-1H-indol-4- yl)oxy)-5-methoxycyclohexyl)-3-fluorobenzoic acid

[0893] Chiral separation and analytics according to Method SFC-E108 / 109. The racemic mixture Example Ex-108 / 109 (138 mg) provided Example Ex-108 (peak 1): 59.6 mg, greyish solid. Analytical chiral HPLC: Rt = 1.4 min; 99.5% ee. Example Ex-109 (peak 2): 58.9 mg, greyish solid. Analytical chiral HPLC: Rt = 2.6 min; 99.5% ee.

[0894] Example Ex-110 and Example Ex-111 : 4-((1S,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5- methoxycyclohexyl)-3-methoxybenzoic acid and 4-((1R,2S,5R)-2-((5,7-dimethyl-1H-indol-4- yl)oxy)-5-methoxycyclohexyl)-3-methoxybenzoic acid

[0895] Chiral separation and analytics according to Method SFC-E110 / 111. The racemic mixture Example Ex-110 / 111 (60 mg) provided Example Ex-110 (peak 1): 26 mg, off-white solid. Analytical chiral HPLC: Rt = 2.0 min; 99.5% ee. Example Ex-111 (peak 2): 28 mg, off-white solid. Analytical chiral HPLC: Rt = 2.8 min; 99.5% ee.

[0896] Example Ex-112 and Example Ex-113: 4-((1S,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5- methoxycyclohexyl)-3-methylbenzoic acid and 4-((1R,2S,5R)-2-((5,7-dimethyl-1H-indol-4- yl)oxy)-5-methoxycyclohexyl)-3-methylbenzoic acid

[0897] Chiral separation and analytics according to Method SFC-E112 / 113. The racemic mixture Example Ex-112 / 113 (268 mg) provided Example Ex-112 (peak 1): 128 mg, greyish solid. Analytical chiral HPLC: Rt = 1.06 min; 99.5% ee. Example Ex-113 (peak 2): 116 mg, greyish solid. Analytical chiral HPLC: Rt = 2.14 min; 99.5% ee.

[0898] Example Ex-114 and Example Ex-115: 4-((1S,2R,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl- 1H-indol-4-yl)oxy)cyclohexyl)-2 -methoxybenzoic acid and 4-((1R,2S,5R)-5-(2,2- difluoroethoxy)-2 -((5, 7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)-2 -methoxybenzoic acid

[0899] Chiral separation and analytics according to Method SFC-E114 / 115. The racemic mixture Example Ex-114 / 115 (42 mg) provided Example Ex-114 (peak 2): 17.0 mg, white solid. Analytical chiral HPLC: Rt = 2.5 min; 99.5% ee. Example Ex-115 (peak 1): 17.1 mg, white solid. Analytical chiral HPLC: Rt = 1.8 min; 99.5% ee. PAT059793-PCT-SEC01

[0900] Example Ex-116 and Example Ex-117: 4-((1S,2 / ?,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl- 1H-indol-4-yl)oxy)cyclohexyl)-3-methoxybenzoic acid and 4-((1R,2S,5 / ?)-5-(2,2- difluoroethoxy)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)-3-methoxybenzoic acid

[0901] Chiral separation and analytics according to Method SFC-E116 / 117. The racemic mixture Example Ex-116 / 117 (116 mg) provided Example Ex-116 (peak 1): 53.3 mg, greysh solid. Analytical chiral HPLC: Rt = 1.07 min; 99.5% ee. Example Ex-117 (peak 2): 55.3 mg, greyish solid. Analytical chiral HPLC: Rt = 2.09 min; 99.5% ee.

[0902] Example Ex-118 and Example Ex-119: 4-((1S,2R,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl- 1H-indol-4-yl)oxy)cyclohexyl)-3-fluorobenzoic acid and 4-((1R,2S,5R)-5-(2,2-difluoroethoxy)- 2-((5,7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)-3-fluorobenzoic acid

[0903] Chiral separation and analytics according to Method SFC-E118 / 119. The racemic mixture Example Ex-118 / 119 (116 mg) provided Example Ex-118 (peak 1): 59.3 mg, greyish solid. Analytical chiral HPLC: Rt = 0.86 min; 99.5% ee. Example Ex-119 (peak 2): 57.9 mg, greyish solid. Analytical chiral HPLC: Rt = 2.39 min; 99.5% ee.

[0904] Example Ex-120 and Example Ex-121 : 4-((1S,2R,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl- 1H-indol-4-yl)oxy)cyclohexyl)-3-methylbenzoic acid and 4-((1R,2S,5R)-5-(2,2-difluoroethoxy)- 2-((5,7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)-3-methylbenzoic acid

[0905] Chiral separation and analytics according to Method SFC-E120 / 121 . The racemic mixture Example Ex-120 / 121 (104 mg) provided Example Ex-120 (peak 1): 49.7 mg, off-white solid. Analytical chiral HPLC: Rt = 0.90 min; 99.5% ee. Example Ex-121 (peak 2): 49.0 mg, off-white solid. Analytical chiral HPLC: Rt = 3.30 min; 99.5% ee.

[0906] Example Ex-129 and Example Ex-130: 3-chloro-4-((1S,2R,5S)-2-((5,7-dimethyl-1H-indol-4- yl)oxy)-5-methoxycyclohexyl)benzoic acid and 3-chloro-4-((1R,2S,5R)-2-((5,7-dimethyl-1H- indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid

[0907] Chiral separation and analytics according to Method SFC-E129 / 130. The racemic mixture Example Ex-129 / 130 (86 mg) provided Example Ex-129 (peak 1): 38.2 mg, white solid. Analytical chiral HPLC: Rt = 1.05 min; 99.5% ee. Example Ex-130 (peak 2): 39.3 mg, white solid. Analytical chiral HPLC: Rt = 1.89 min; 99.5% ee.

[0908] Example Ex-202 and Example Ex -203: 4-((5S,6R)-6-((5,7-dimethyl-1H-indol-4- yl)oxy)spiro[2.5]octan-5-yl)-3-methoxybenzoic acid and 4-((5R,6S)-6-((5,7-dimethyl-1H-indol- 4-yl)oxy)spiro[2.5]octan-5-yl)-3-methoxybenzoic acid

[0909] Chiral separation and analytics according to Method SFC-E202 / 203. The racemic mixture Example Ex-202 / 203 (110 mg) provided Example Ex-202 (peak 2): 47.5 mg, greyish solid. Analytical chiral HPLC: Rt = 2.3 min; 99.5% ee. Example Ex-203 (peak 1): 50.8 mg, greenish oil. Analytical chiral HPLC: Rt = 1.5 min; 99.5% ee. PAT059793-PCT-SEC01

[0910] Example Ex-204 and Example Ex -205: 4-((6S,7R)-7-((5,7-dimethyl-1H-indol-4- yl)oxy)spiro[3.5]nonan-6-yl)-2-methoxybenzoic acid and 4-((6R,7S)-7-((5,7-dimethyl-1H-indol- 4-yl)oxy)spiro[3.5]nonan-6-yl)-2-methoxybenzoic acid

[0911] Chiral separation and analytics according to Method SFC-E204 / 205. The racemic mixture Example Ex-204 / 205 (276 mg) provided Example Ex-204 (peak 2): 117.4 mg, greyish solid. Analytical chiral HPLC: Rt = 3.13 min; 98.5% ee. Example Ex-205 (peak 1): 118.8 mg, greyish solid. Analytical chiral HPLC: Rt = 2.57 min; 99.5% ee.

[0912] Example Ex-206 and Example Ex -207: 4-((6S,7R)-7-((5,7-dimethyl-1H-indol-4- yl)oxy)spiro[3.5]nonan-6-yl)-3-methoxybenzoic acid and 4-((6R,7S)-7-((5,7-dimethyl-1H-indol- 4-yl)oxy)spiro[3.5]nonan-6-yl)-3-methoxybenzoic acid

[0913] Chiral separation and analytics according to Method SFC-E206 / 207. The racemic mixture Example Ex-206 / 207 (62 mg) provided Example Ex-206 (peak 1): 27.6 mg, off-white solid. Analytical chiral HPLC: Rt = 1.54 min; 99.5% ee. Example Ex-207 (peak 2): 27.9 mg, off-white solid. Analytical chiral HPLC: Rt = 2.48 min; 99.5% ee.

[0914] Example Ex-208 and Example Ex -209: 4-((6S,7R)-7-((5,7-dimethyl-1H-indol-4-yl)oxy)-2,2- difluorospiro[3.5]nonan-6-yl)-2 -methoxybenzoic acid and 4-((6R,7S)-7-((5,7-dimethyl-1H- indol-4-yl)oxy)-2,2-difluorospiro[3.5]nonan-6-yl)-2 -methoxybenzoic acid

[0915] Chiral separation and analytics according to Method SFC-E208 / 209. The racemic mixture Example Ex-208 / 209 (238 mg) provided Example Ex-208 (peak 1): 94.0 mg, off-white solid. Analytical chiral HPLC: Rt = 1.17 min; 99.5% ee. Example Ex-209 (peak 2): 97.2 mg, off-white solid. Analytical chiral HPLC: Rt = 3.38 min; 99.5% ee.

[0916] Example Ex-210 and Example Ex-211 : 4-((6S,7R)-7-((5,7-dimethyl-1H-indol-4-yl)oxy)-2,2- difluorospiro[3.5]nonan-6-yl)-3-methoxybenzoic acid and 4-((6R,7S)-7-((5,7-dimethyl-1H- indol-4-yl)oxy)-2,2-difluorospiro[3.5]nonan-6-yl)-3-methoxybenzoic acid

[0917] Chiral separation and analytics according to Method SFC-E210 / 211 . The racemic mixture Example Ex-210 / 211 (36 mg) provided Example Ex-210 (peak 2): 14.7 mg, off-white solid. Analytical chiral HPLC: Rt = 2.56 min; 99.5% ee. Example Ex-211 (peak 1): 14.9 mg, off-white solid. Analytical chiral HPLC: Rt = 2.06 min; 99.5% ee.

[0918] Example Ex-212 and Example Ex -213: 4-((6S,7R)-7-((5,7-dimethyl-1H-indol-4-yl)oxy)-2- oxaspiro[3.5]nonan-6-yl)-2-methylbenzoic acid and 4-((6R,7S)-7-((5,7-dimethyl-1H-indol-4- yl)oxy)-2-oxaspiro[3.5]nonan-6-yl)-2 -methylbenzoic acid

[0919] Chiral separation and analytics according to Method SFC-E212 / 213. The racemic mixture Example Ex-212 / 213 (140 mg) provided Example Ex-212 (peak 2): 54 mg, greyish solid. Analytical chiral HPLC: Rt = 3.19 min; 99% ee. Example Ex-213 (peak 1): 49 mg, greyish solid. Analytical chiral HPLC: Rt = 2.03 min; 99% ee.

[0920] Analytical data from the examples described above are tabulated in the following table. PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01 PAT059793-PCT-SEC01

[0921] LC-MS Methods

[0922] LC-MS Method A-1 :

[0923] Column: Acquity UPLC BEH C18, 2.1 mm x 50 mm, 1 .7 pm

[0924] Column temperature: 40 °C

[0925] Eluents: A: H2O + 0.1% FA

[0926] B: ACN + 0.1% FA

[0927] Flow rate: 2.0 mL / min

[0928] Gradient: Time / %B: 0.1 / 5; 0.5 / 5; 1.0 / 95; 1.5 / 95; 2.0 / 5; 3.0 / 5 (3 min method)

[0929] LC-MS Method A-2:

[0930] Column: Acquity UPLC BEH C18, 2.1 mm x 50 mm, 1 .7 pm

[0931] Column temperature: 40 °C

[0932] Eluents: A: H2O + 0.1% FA

[0933] B: ACN + 0.1% FA

[0934] Flow rate: 0.8 mL / min

[0935] Gradient: Time / %B: 0.01 / 5; 0.3 / 5; 0.5 / 100; 1.8 / 100; 2.0 / 5; 3.0 / 5 (3 min method)

[0936] LC-MS Method B-1 :

[0937] Column: CORTECS C18, 2.1 mm x 50 mm, 2.7pm

[0938] Column temperature: 80 °C PAT059793-PCT-SEC01

[0939] Eluents: A: H2O + 0.05% FA + 3.75 mM ammonium acetate

[0940] B: IPA + 0.05% FA

[0941] Flow rate: 1 .0 mL / min

[0942] Gradient: initial 5% B; 5% to 50% B in 1 .40 min, 50% to 98% B in 0.30 min; 0.10 min 98% B.

[0943] LC-MS Method B-2:

[0944] Column: Acquity UPLC BEH C18, 2.1 mm x 100 mm, 1 ,7pm

[0945] Column temperature: 80 °C

[0946] Eluents: A: H2O + 0.05% FA + 3.75 mM ammonium acetate

[0947] B: IPA + 0.05% FA

[0948] Flow rate: 0.4 mL / min

[0949] Gradient: Pre-run with 5% B for 0.50 min; 5% to 60% B in 8.4 min, 60% to 98% B in 1 .00 min; 0.40 min 98% B.

[0950] LC-MS Method B-3:

[0951] Column: XBridge BEH C18, 2.1 mm x 50 mm, 2.5pm

[0952] Column temperature: 80 °C

[0953] Eluents: A: 5 mM NH4OH in H2O

[0954] B: 5 mM NH4OH in ACN

[0955] Flow rate: 1 .0 mL / min

[0956] Gradient: initial 2% B; 2% to 98% B in 1 .40 min; 0.40 min 98% B.

[0957] LC-MS Method C-1 :

[0958] Column: Acquity UPLC BEH C18, 2.1 mm x 30 mm, 1 ,7pm

[0959] Column temperature: 50 °C

[0960] Eluents: A: H2O + 0.1% FA

[0961] B: ACN + 0.1% FA

[0962] Flow rate: 1 .0 mL / min

[0963] Gradient: 2% B until 0.1 min; 2% to 98% B until 1 .5 min, 98% B until 1 .8 min.

[0964] LC-MS Method C-2:

[0965] Column: Acquity UPLC BEH C18, 2.1 mm x 30 mm, 1 ,7pm

[0966] Column temperature: 50 °C

[0967] Eluents: A: 5 mM NH4OH in H2O

[0968] B: 5 mM NH4OH in ACN

[0969] Flow rate: 1 .0 mL / min

[0970] Gradient: 2% B until 0.1 min; 2% to 98% B until 1 .5 min, 98% B until 1 .8 min.

[0971] LC-MS Method C-3:

[0972] Column: Acquity UPLC BEH C18, 2.1 mm x 30 mm, 1 .7 pm

[0973] Column temperature: 50 °C

[0974] Eluents: A: 0.1% FA in H2O

[0975] B: 0.1 % FA in ACN

[0976] Flow rate: 1 .0 mL / min

[0977] Gradient: 2% to 98% B until 4.40 min, 98% B until 5.15 min.

[0978] LC-MS Method C-4:

[0979] Column: Acquity UPLC BEH C18, 2.1 mm x 30 mm, 1 .7 pm

[0980] Column temperature: 50 °C

[0981] Eluents: A: 5 mM NH4OH in H2O

[0982] B: 5 mM NH4OH in ACN PAT059793-PCT-SEC01

[0983] Flow rate: 1 .0 mL / min Gradient: 2% to 98% B until 4.40 min, 98% B until 5.15 min.

[0984] Chiral Separtion Methods

[0985] Method SFC-A-E1 :

[0986] Preparative chiral HPLC Instrument: SFC-PICLAB Prep 175-2 Column: Chiralpak ID, 250 mm x 30 mm, 5 pm Eluent: A: 25% 1 :1 MeOH / IPA with 10 mM NH3B: 75% scCO2(isocratic)

[0987] Flow rate: 100 mL / min

[0988] Detection: 210 nm

[0989] Injection volume: 35x 0.4 mL

[0990] Oven temperature: 40 °C

[0991] Pressure: 100 bar

[0992] Analytical chiral HPLC Instrument: SFC-PIC solution Mobile phase: A: 50% 1 :1 MeOH / IPA with 10 mM NH3

[0993] B: 50% scCO2(isocratic)

[0994] Flow rate: 100 mL / min Column: Chiralpak ID, 250 mm x 30 mm, 5 pm Detection: UV 210 nm

[0995] Oven temperature: 40 °C

[0996] Pressure: 100 bar

[0997] Method SFC-A-E2:

[0998] Preparative chiral HPLC Instrument: SFC-PICLAB Prep 175-2 Column: Chiralpak ID, 250 mm x 30 mm, 5 pm Eluent: A: 30% 1 :1 MeOH / IPA

[0999] B: 70% scCO2(isocratic)

[1000] Flow rate: 80 mL / min

[1001] Detection: UV 210 nm

[1002] Injection volume: 20x 0.75 mL

[1003] Oven temperature: 40 °C

[1004] Pressure: 100 bar

[1005] Analytical chiral HPLC Instrument: SFC-PIC solution

[1006] Injection: 15 pL

[1007] Mobile phase: A: 30% 1 :1 :1 IPA / EtOH / MeOH

[1008] B: 70% scCO2(isocratic)

[1009] Flow rate: 3 mL / min Column: Chiralpak ID, 4.6 mm x 250 mm, 5 pm Detection: UV 210 nm

[1010] Oven temperature: 40 °C

[1011] Pressure: 100 bar

[1012] Method SFC-A-E5:

[1013] Preparative chiral HPLC Instrument: Agilent-1260 Infinity Column: Chiralpak IC, 21 mm x 250 mm, 5 pm Eluent: A: 25% 1 :1 MeOH / IPA

[1014] B: 75% hexane (isocratic) PAT059793-PCT-SEC01

[1015] Flow rate: 15 mL / min

[1016] Detection: UV 210 nm

[1017] Injection volume: 150x 0.3 mL

[1018] Oven temperature: 40 °C

[1019] Pressure: 100 bar

[1020] Analytical chiral HPLC

[1021] Instrument: SFC-PIC solution

[1022] Injection: 5 pL

[1023] Mobile phase: A: 30% 70:30 EtOH / MeOH with 0.1 % diethylamine

[1024] B: 70% hexane (isocratic)

[1025] Flow rate: 1 mL / min

[1026] Column: Chiralpak IC 4.6 mm x 150 mm, 5 pm

[1027] Detection: UV 214 nm

[1028] Pressure: 100 bar

[1029] Method SFC-A-E7:

[1030] Preparative chiral HPLC

[1031] Instrument: Waters 150 MGM

[1032] Column: Chiralpak AD-H 30 mm x 250 mm, 5 pm

[1033] Eluent: A: 35% 1 :1 MeOH / IPA

[1034] B: 65% scCO2(isocratic)

[1035] Flow rate: 120 g / min

[1036] Detection: UV 243 nm

[1037] Injection volume: 5x 6 mL

[1038] Oven temperature: ambient

[1039] Pressure: 125 bar

[1040] Analytical chiral HPLC

[1041] Instrument: Waters UPC2

[1042] Injection: 3 pL

[1043] Mobile phase: A: 5 to 55% 1 :1 MeOH / IPA w / 0.1 % NH3

[1044] B: scCO2

[1045] Flow rate: 2.5 mL / min

[1046] Column: Chiralpak AD-3 30 mm x 100 mm, 3 pm

[1047] Detection: UV 243 nm

[1048] Oven temperature: 40 °C

[1049] Pressure: 1500 psi

[1050] Method SFC-A-E9:

[1051] Preparative chiral HPLC

[1052] Instrument: Berger Multigram-ll

[1053] Column: ColumnTek Enanantiocel A25, 2 cm x 25 cm

[1054] Eluent: A: 30% EtOH

[1055] B: 70 scCO2(isocratic)

[1056] Flow rate: 64 mL / min

[1057] Detection: UV 220 nm

[1058] Pressure: 100 bar

[1059] Analytical chiral HPLC

[1060] Instrument: Waters SFC ACQUITY UPC2

[1061] Injection: 3 pL

[1062] Mobile phase: A: 30% EtOH

[1063] B: 70 scCO2(isocratic)

[1064] Flow rate: 3 mL / min

[1065] Column: ColumnTek Enantiocel A25, 25 cm x 0.46 cm PAT059793-PCT-SEC01

[1066] Detection: UV 220 / 254 / 280 nm

[1067] Oven temperature: 40 °C

[1068] Pressure: 1500 psi

[1069] Method SFC-A-E11 :

[1070] Preparative chiral HPLC

[1071] Instrument: Waters 150 MGM

[1072] Column: Chiralpak IG, 30 mm x 250 mm, 5 pm

[1073] Eluent: A: 50% IPA

[1074] B: 50% scCO2(isocratic)

[1075] Flow rate: 100 g / min

[1076] Detection: UV 240 nm

[1077] Injection volume: 4 mL

[1078] Oven temperature: ambient

[1079] Pressure: 100 bar

[1080] Analytical chiral HPLC

[1081] Instrument: Waters UPC2

[1082] Injection: 3 pL

[1083] Mobile phase: A: IPA with 0.1 % NH3

[1084] B: scCO2

[1085] Flow rate: 1.9 mL / min

[1086] Column: Chiralpak IG, 3 mm x 100 mm, 3 pm

[1087] Detection: UV 240 nm

[1088] Oven temperature: 40 °C

[1089] Pressure: 1500 psi

[1090] Method SFC-A-E14:

[1091] Preparative chiral HPLC

[1092] Instrument: Waters 150 MGM

[1093] Column: Chiralpak IG, 30 mm x 250 mm, 5 pm

[1094] Eluent: A: 50% 1 :1 MeOH / IPA

[1095] B: 50% scCO2(isocratic)

[1096] Flow rate: 120 g / min

[1097] Detection: UV 277 nm

[1098] Injection volume: 2 mL

[1099] Oven temperature: ambient

[1100] Pressure: 100 bar

[1101] Analytical chiral HPLC

[1102] Instrument: Shimadzu Nexera

[1103] Injection: 3 pL

[1104] Mobile phase: A: 50% 1 :1 IPA / MeOH with 0.1% NH3

[1105] B: 50% scCO2(isocratic)

[1106] Flow rate: 2.5 mL / min

[1107] Column: Chiralpak IG, 3 mm x 100 mm, 3 pm

[1108] Detection: UV 215 - 400 nm

[1109] Oven temperature: 40 °C

[1110] Pressure: 100 bar

[1111] Method SFC-A-E14:

[1112] Preparative chiral HPLC

[1113] Instrument: Waters 150 MGM

[1114] Column: Chiralpak IG, 30 mm x 250 mm, 5 pm

[1115] Eluent: A: 50% 1 :1 MeOH / IPA

[1116] B: 50% scCO2(isocratic) PAT059793-PCT-SEC01

[1117] Flow rate: 120 g / min

[1118] Detection: UV 277 nm

[1119] Injection volume: 2 mL

[1120] Oven temperature: ambient

[1121] Pressure: 100 bar

[1122] Analytical chiral HPLC

[1123] Instrument: Shimadzu Nexera

[1124] Injection: 3 pL

[1125] Mobile phase: A: 50% 1 :1 IPA / MeOH with 0.1 % NH3

[1126] B: 50% scCO2(isocratic)

[1127] Flow rate: 2.5 mL / min

[1128] Column: Chiralpak IG, 3 mm x 100 mm, 3 pm

[1129] Detection: UV 215 - 400 nm

[1130] Oven temperature: 40 °C

[1131] Pressure: 100 bar

[1132] Method SFC-A-E15:

[1133] Preparative chiral HPLC

[1134] Instrument: Waters 150 MGM

[1135] Column: Chiralpak IG, 30 mm x 250 mm, 5 pm

[1136] Eluent: A: 35% IPA

[1137] B: 65% scCO2(isocratic)

[1138] Flow rate: 125 g / min

[1139] Detection: UV 240 nm

[1140] Injection volume: 4 mL

[1141] Oven temperature: ambient

[1142] Pressure: 100 bar

[1143] Analytical chiral HPLC Instrument: Waters UPC2

[1144] Injection: 2 pL

[1145] Mobile phase: A: 5 to 65% IPA with 0.1 % NH3

[1146] B: scCO2

[1147] Flow rate: 1 .9 mL / min

[1148] Column: Chiralpak IG, 3 mm x 100 mm, 3 pm

[1149] Detection: UV 240 nm

[1150] Oven temperature: 40 °C

[1151] Pressure: 1500 psi

[1152] Method SFC-A-E16:

[1153] Preparative chiral HPLC

[1154] Instrument: Waters 150 MGM

[1155] Column: Chiralpak AD-H, 30 mm x 250 mm, 5 pm

[1156] Eluent: A: 50% MeOH

[1157] B: 50% scCO2(isocratic)

[1158] Flow rate: 100 g / min

[1159] Detection: UV 238 nm

[1160] Injection volume: 6 mL

[1161] Oven temperature: ambient

[1162] Pressure: 100 bar

[1163] Analytical chiral HPLC Instrument: Waters UPC2

[1164] Injection: 2 pL

[1165] Mobile phase: A: 5 to 65% MeOH PAT059793-PCT-SEC01

[1166] B: scCO2

[1167] Flow rate: 1 .9 mL / min

[1168] Column: Chiralpak AD, 3 mm x 100 mm, 3 pm

[1169] Detection: UV 235 nm

[1170] Oven temperature: 40 °C

[1171] Pressure: 1500 psi

[1172] Method SFC-17:

[1173] Preparative chiral HPLC

[1174] Instrument: ACCQPrep SFC

[1175] Column: Chiralpak IG, 250 mm x 30 mm, 5 pm

[1176] Eluent: A: 30% IPA with 0.05% NH3

[1177] B: 70% scCO2(isocratic)

[1178] Flow rate: 80 mL / min

[1179] Detection: UV 225 nm

[1180] Injection volume: 2x 1 mL

[1181] Oven temperature: 40 °C

[1182] Pressure: 100 bar

[1183] Analytical chiral HPLC Instrument: Waters UPC2

[1184] Injection: 5 pL

[1185] Mobile phase: A: 30% IPA with 0.05% NH3

[1186] B: 70% scCO2(isocratic)

[1187] Flow rate: 3 mL / min

[1188] Column: Chiralpak IG, 4.6 mm x 100 mm, 5 pm

[1189] Detection: DAD

[1190] Oven temperature: 40 °C

[1191] Pressure: 1800 psi

[1192] Method SFC-A-E201 :

[1193] Preparative chiral HPLC

[1194] Instrument: Waters MS100

[1195] Column: Chiralpak ID, 20 mm x 250 mm, 5 pm

[1196] Eluent: A: 50% MeOH

[1197] B: 50% scCO2(isocratic)

[1198] Flow rate: 80 g / min

[1199] Detection: UV 243 nm

[1200] Injection volume: 4 mL

[1201] Oven temperature: ambient

[1202] Pressure: 100 bar

[1203] Analytical chiral HPLC

[1204] Instrument: Waters UPC2

[1205] Injection: 2 pL

[1206] Mobile phase: A: 40% MeOH

[1207] B: 60% scCO2(isocratic)

[1208] Flow rate: 2.5 mL / min

[1209] Column: Chiralpak ID, 3 mm x 100 mm, 3 pm

[1210] Detection: UV 243 nm

[1211] Oven temperature: 40 °C

[1212] Pressure: 1500 psi

[1213] Method SFC-E19 / 20:

[1214] Preparative chiral HPLC Instrument: ABPrep SFC Prep System PAT059793-PCT-SEC01

[1215] Column: Daicel Chiralpak IM-N, 250 mm x 30 mm, 5 pm

[1216] Eluent: A: 10 to 70% MeOH + 0.05% NH3

[1217] B: scCO2(isocratic) Flow rate: 180 mL / min to 80 mL / min in 9 min total flow Detection: UV 220 nm

[1218] Injection volume: 4 mL Oven temperature: 40 °C Pressure: 100 bar

[1219] Analytical chiral HPLC

[1220] Instrument: Waters UPC2

[1221] Injection: 5 pL

[1222] Mobile phase: A: 50% MeOH with 0.05% NH3

[1223] B: 50% scCO2(isocratic)

[1224] Flow rate: 3 mL / min

[1225] Column: Chiralpak OZ, 4.6 mm x 100 mm, 5 pm

[1226] Detection: DAD

[1227] Oven temperature: 40 °C

[1228] Pressure: 1800 psi

[1229] Method SFC-E21 / 22:

[1230] Preparative chiral

[1231] Column: CHIRALPAK AD, 30 mm x 250 mm, 5 pm

[1232] Eluent: A: IPA + 0.05% NH3

[1233] B: scCO2, gradient 30 to 41 .4%

[1234] Flow rate: 80 mL / min

[1235] Detection: UV 214 / 254 nm

[1236] Oven temperature: 40 °C

[1237] Pressure: 120 bar

[1238] Analytical chiral

[1239] Instrument: Waters UPC2

[1240] Injection: 5 pL

[1241] Mobile phase: A: 30% IPA with 0.05% NH3

[1242] B: 70% scCO2(isocratic)

[1243] Flow rate: 3 mL / min

[1244] Column: Chiralpak AD, 4.6 mm x 100 mm, 5 pm

[1245] Detection: DAD

[1246] Oven temperature: 40 °C

[1247] Pressure: 1800 psi

[1248] Method SFC-E23 / 24-1 :

[1249] Preparative chiral, 1strun

[1250] Column: CHIRALPAK AD, 30 mm x 250 mm, 5 pm

[1251] Eluent: A: 25% IPA + 0.05% NH3

[1252] B: 75% scCO2, isocratic

[1253] Flow rate: 80 mL / min

[1254] Detection: UV 218 / 254 nm

[1255] Injection volume: 2 mL

[1256] Oven temperature: 40 °C

[1257] Pressure: 100 bar

[1258] Method SFC-E23 / 24-2:

[1259] Preparative chiral HPLC

[1260] Column: CHIRALPAK AD, 30 mm x 250 mm, 5 pm

[1261] Eluent: A: IPA + 0.05% NH3 PAT059793-PCT-SEC01

[1262] B: SCCO2, gradient 25 to 36 .2% Flow rate: 80 mL / min

[1263] Detection: UV 218 / 254 nm

[1264] Injection volume: 3.3 mL

[1265] Oven temperature: 40 °C

[1266] Pressure: 100 bar

[1267] Analytical chiral

[1268] Instrument: Waters UPC2

[1269] Injection: 5 pL

[1270] Mobile phase: A: 25% IPA with 0.05% NH3

[1271] B: 75% scCO2(isocratic)

[1272] Flow rate: 3 mL / min

[1273] Column: Chiralpak AD, 4.6 mm x 100 mm, 5 pm

[1274] Detection: DAD

[1275] Oven temperature: 40 °C

[1276] Pressure: 1800 p...

Claims

PAT059793-PCT-SEC01Claims1. A compound of Formula (I)or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:W is C(R6)2, or NR7;R1is hydrogen, halogen, hydroxy, Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloC3-C6cycloalkyl, or haloCi-C6alkoxy;R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Cr C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;R3is hydrogen, or halogen;R4is selected from hydrogen, -CO2R4a, Ci-Cealkyl, hydroxyCs-Cecycloalkyl, Ci-CealkoxyCi- C6alkyl, -CH2CO2R4a, -C(O)NHSO2Ci-C4alkyl, -SO2NHC(O)Ci-C4alkyl, -SO2Ci-C4alkyl, cyano, hydroxy, halogen, -C(O)N(R4a)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 R4b; each R4ais independently selected from hydrogen and Ci-C5alkyl; each R4bis independently selected from fluoro, hydroxyl, Ci-C6alkyl, and haloCi-C6alkyl, wherein the Ci-C6alkyl, and haloCi-C6alkyl are unsubstituted or substituted with -CO2H; each R5is independently selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkoxy, hydroxy, Ci-C6alkoxy, haloCi-C6alkoxy, amino, Ci-C6alkylamino, and haloCr C6alkylamino; or two R5in combination with the carbon atoms to which they are attached form a partially saturated carbocycle having 4 to 6 ring atoms, wherein the carbocycle is unsubstituted or substituted with 1 to 4 substituents selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCr C6alkoxy; or two R5in combination with the carbon atoms to which they are attached form a partially saturated 4- to 6-membered heterocycle having 1 or 2 ring heteroatoms independently selected fromPAT059793-PCT-SEC01N, O, and S(O)q, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy; each R6is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, mono(haloCi-C4alkyl)amino, / V-haloCi-C4alkyl- / V-Ci-C4alkylamino, C3- C6cycloalkylCi-C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-Cealkyl, cyanoCi-Cealkyl, Ci-Cealkoxy, haloCi-Cealkoxy, Cs-Cecycloalkoxy, haloC3- C6cycloalkoxy, Ci-C6alkoxyCi-C6alkyl, haloCi-C6alkoxyCi-C6alkyl, and 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N and O, and wherein the Cr 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;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, Cr C6alkyl, haloCi-C6alkyl, C3-C5cycloalkyl, haloC3-C5cycloalkyl; R7ais hydrogen or Ci-C6alkyl; each R8is independently selected from halogen, hydroxy, amino, mono- and di- Cr C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Ci-C6alkoxy, and haloCi-C6alkoxy; m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3; provided that m and n are not both 0; p is 0, 1 , 2, or 3; q is 0, 1 , or 2; and x is 1 or 2.PAT059793-PCT-SEC012. 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;R1is halogen, Ci-C6alkyl, C3-C6cycloalkyl, Ci-C6alkoxy, haloCi-C6alkyl, haloC3-C6cycloalkyl, or haloCi-C6alkoxy;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;R3is hydrogen, or halogen;R4is selected from -CO2R4a, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R4b;R4ais selected from hydrogen and Ci-Csalkyl; each R4bis independently selected from fluoro, hydroxyl, Ci-C6alkyl, and haloCi-C6alkyl, wherein the Ci-C6alkyl, and haloCi-C6alkyl are unsubstituted or substituted with -CO2H; each R5is independently selected from halogen, Ci-Cealkyl, Ci-Cealkoxy, haloCi-Cealkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, amino, Ci-C6alkylamino, and haloCi-C6alkylamino; or two R5in combination with the carbon atoms to which they are attached form a partially saturated carbocycle having 4 to 6 ring atoms, wherein the carbocycle is unsubstituted or substituted with 1 to 4 substituents selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCr C6alkoxy; or two R5in combination with the carbon atoms to which they are attached form a partially saturated 4- to 6-membered heterocycle having 1 or 2 ring heteroatoms independently selected from N, and O, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy; each R6is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, mono(haloCi-C4alkyl)amino, / V-haloCi-C4alkyl- / V-Ci-C4alkylamino, C3- C6cycloalkylCi-C4alkylamino, haloC3-C6cycloalkylCi-C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkoxy, haloC3- C6cycloalkoxy, Ci-C6alkoxyCi-C6alkyl, haloCi-C6alkoxyCi-C6alkyl, and 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N and O, and wherein the Cr 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 each R6is independently selected from Ci-C6alkoxy, haloCi-C6alkoxy, mono(haloCi-C4alkyl)amino, and hydroxy;PAT059793-PCT-SEC01 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; each R8is independently selected from halogen, hydroxy, amino, mono- and di- Cr C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Ci-C6alkoxy, and haloCi-Cealkoxy; m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3; provided that m and n are not both 0; p is 0, 1 , 2, or 3; q is 0, 1 , or 2; and x is 1 or 2.

3. The compound of claim 1 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:W is NR7;R1is halogen, Ci-Cealkyl, Cs-Cecycloalkyl, Ci-Cealkoxy, haloCi-Cealkyl, haloCs-Cecycloalkyl, or haloCi-C6alkoxy;R2is Ci-C3alkyl, C3cycloalkyl, Ci-C3alkoxy, hydroxyCi-C6alkyl, or halogen, wherein the Cr C3alkyl, C3cycloalkyl, or Ci-C3alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;R3is hydrogen, or halogen;R4is selected from -CO2R4a, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R4b;R4ais selected from hydrogen and Ci-C5alkyl; each R4bis independently selected from fluoro, hydroxyl, Ci-C6alkyl, and haloCi-C6alkyl, wherein the Ci-C6alkyl, and haloCi-C6alkyl are unsubstituted or substituted with -CO2H; each R5is independently selected from halogen, Ci-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy, C3-C6cycloalkyl, C3-C6cycloalkoxy, amino, Ci-C6alkylamino, and haloCi-C6alkylamino; or two R5in combination with the carbon atoms to which they are attached form a partially saturated carbocycle having 4 to 6 ring atoms, wherein the carbocycle is unsubstituted or substituted with 1 to 4 substituents selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCr C6alkoxy; or two R5in combination with the carbon atoms to which they are attached form a partially saturated 4- to 6-membered heterocycle having 1 or 2 ring heteroatoms independently selected from N, and O, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen, Ci-C6alkyl, haloCi-C6alkyl, Ci-C6alkoxy, haloCi-C6alkoxy;PAT059793-PCT-SEC01R7is 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, Cr C6alkyl, haloCi-C6alkyl, C3-C5cycloalkyl, haloC3-C5cycloalkyl;R7ais hydrogen or Ci-Cealkyl; each R8is independently selected from halogen, hydroxy, amino, mono- and di- Cr C4alkylamino, Ci-C6alkyl, haloCi-C6alkyl, hydroxyCi-C6alkyl, cyanoCi-C6alkyl, Ci-C6alkoxy, and haloCi-Cealkoxy; m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3; provided that m and n are not both 0; p is 0, 1 , 2, or 3; q is 0, 1 , or 2; and x is 1 or 2.

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

5. The compound of any of claims 1 to 4, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R1is halogen, Ci-C6alkyl, or C3- C6cycloalkyl.

6. The compound of any of claims 1 to 5, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R2is Ci-C3alkyl.PAT059793-PCT-SEC017. The compound of any of claims 1 to 6, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R3is hydrogen.

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 R4is selected from -CO2R4a, and R4ais 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:R5is halogen, Ci-Cealkyl, haloCi-Cealkyl, Ci-Cealkoxy, Cs-Cecycloalkoxy, hydroxy, Ci-Cealkoxy, haloCi-C6alkoxy, amino, or Ci-C6alkylamino; or two R5in combination with the carbon atoms to which they are attached form a partially saturated 4- to 6-membered heterocycle having 1 ring heteroatom selected from N, and O, wherein the heterocycle is unsubstituted or substituted with 1 to 2 substituents selected from halogen.

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: each R6is independently selected from hydrogen, Ci-C6alkoxy mono(haloCi-C4alkyl)amino, N- haloCi-C4alkyl-A / -Ci-C4alkylamino, hydroxy, 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 2 substituents selected from halogen; or two R6in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 heteroatom selected from O, wherein the spirocyclic heterocycle is unsubstituted.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 R7is Ci-C6alkyl, haloCi-C6alkyl, or haloCi-C6alkoxyCi-C6alkyl.

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: m is 1 ; n is 2; p is 0; and x is 1 or 2.PAT059793-PCT-SEC0113. The compound of any of claims 1 to 10 and 12, selected from the group consisting of:4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-methoxybenzoic acid;4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-methoxybenzoic acid;4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- (difluoromethoxy)benzoic acid;2-amino-4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-fluorobenzoic acid;4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-(methylamino)benzoic acid4-(6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-2-methoxybenzoic acid;4-(6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-3-methoxybenzoic acid;4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-2-methoxybenzoic acid;2-amino-4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl) benzoic acid;4-(2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-fluorobenzoic acid;4-(2-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-methoxybenzoic acid;4-(2-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- (difluoromethoxy)benzoic acid;4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-methoxybenzoic acid;4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-fluorobenzoic acid;4-(6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-3-fluorobenzoic acid;4-(7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-2,2-difluorospiro[3.5]nonan-6-yl)-2-methoxybenzoic acid; and4-(7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-2,2-difluorospiro[3.5]nonan-6-yl)-3-methoxybenzoic acid;4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-(methylamino)benzoic acid;4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-fluorobenzoic acid;4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-2-methoxybenzoic acid;4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3-methoxybenzoic acid;4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3-fluoro benzoic acid;4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- methylbenzoic acid;PAT059793-PCT-SEC014-(5-((2,2-difluoroethyl)amino)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- methylbenzoic acid;4-(5-((2,2-difluoroethyl)(methyl)amino)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- methylbenzoic acid;3-chloro-4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid;3-chloro-4-(5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl) benzoic acid;3-chloro-4-(2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;4-(7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[3.5]nonan-6-yl)-2-methoxybenzoic acid;4-(7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[3.5]nonan-6-yl)-3-methoxybenzoic acid; and 4-(7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-2-oxaspiro[3.5]nonan-6-yl)-2-methylbenzoic acid, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

14. The compound of claim 13, selected from the group consisting of:4-((1 S,2R,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-methoxybenzoic acid;4-((1 S,2R,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- methoxybenzoic acid;4-((1 S,2R,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- (difluoromethoxy)benzoic acid;2-amino-4-((1 S,2R,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;4-((1 S,2R,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2-fluorobenzoic acid;4-((1 S,2R,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- (methylamino)benzoic acid;4-((5S,6R)-6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-2-methoxybenzoic acid;4-((5S,6R)-6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-3-methoxybenzoic acid;4-((1 S,2R,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-2- methoxybenzoic acid;2-amino-4-((1 S,2R,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5- methoxycyclohexyl)benzoic acid;4-((1 S,2R,5S)-2-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- fluorobenzoic acid;4-((1 S,2R,5S)-2-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- methoxybenzoic acid;PAT059793-PCT-SEC014-((1 S,2 / ?,5S)-2-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-2- (difluoromethoxy)benzoic acid;4-((1 S,2 / ?,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-methoxybenzoic acid;4-((1 S,2 / ?,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-fluorobenzoic acid;4-((1 S,2 / ?,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)-3-methylbenzoic acid;4-((5S,6 / ?)-6-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)-3-fluorobenzoic acid;4-((6S,7 / ?)-7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-2,2-difluorospiro[3.5]nonan-6-yl)-2- methoxybenzoic acid;4-((6S,7 / ?)-7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-2,2-difluorospiro[3.5]nonan-6-yl)-3- methoxybenzoic acid;4-((1 S,2 / ?,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-2- methoxybenzoic acid;4-((1 S,2 / ?,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- methoxybenzoic acid;4-((1 S,2 / ?,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- fluorobenzoic acid;4-((1 S,2 / ?,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- methylbenzoic acid;4-((1 S,2 / ?,5S)-5-((2,2-difluoroethyl)amino)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)cyclohexyl)-3- methylbenzoic acid;4-((1 S,2 / ?,5S)-5-((2,2-difluoroethyl)(methyl)amino)-2-((5,7-dimethyl-1 / 7-indol-4- yl)oxy)cyclohexyl)-3-methylbenzoic acid;3-chloro-4-((1 S,2 / ?,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid;3-chloro-4-((1 S,2 / ?,5S)-5-(2,2-difluoroethoxy)-2-((5,7-dimethyl-1 / 7-indol-4- yl)oxy)cyclohexyl)benzoic acid;3-chloro-4-((1 S,2 / ?,5S)-2-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;4-((6S,7 / ?)-7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[3.5]nonan-6-yl)-2-methoxybenzoic acid;4-((6S,7 / ?)-7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)spiro[3.5]nonan-6-yl)-3-methoxybenzoic acid; and4-((6S,7 / ?)-7-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-2-oxaspiro[3.5]nonan-6-yl)-2-methylbenzoic acid,PAT059793-PCT-SEC01 or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

15. The compound of claim 1 , selected from the group consisting of:4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-methoxybenzoic acid;4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-fluorobenzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2-fluorobenzoic acid;4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-2- fluorobenzoic acid;4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-methylbenzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2-methylbenzoic acid;4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-methylbenzoic acid;4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- methylbenzoic acid;4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-methoxybenzoic acid;4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- methoxybenzoic acid;2-chloro-4-(1-(2,2-difluoroethyl)-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-(2,2,2-trifluoroethyl)piperidin-3-yl)-3-methylbenzoic acid;4-(1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-methylbenzoic acid;4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-fluorobenzoic acid;4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,6- dimethylbenzoic acid;4-(1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-methylbenzoic acid;PAT059793-PCT-SEC012-amino-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid;2-amino-4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;4-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2-ethoxybenzoic acid;4-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-ethoxybenzoic acid;4-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (difluoromethoxy)benzoic acid;4-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dihydrobenzofuran-7-carboxylic acid;7-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dihydrobenzofuran-4-carboxylic acid;4-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)indoline-7- carboxylic acid;7-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,2- difluorobenzo[d][1 ,3]dioxole-4-carboxylic acid;4-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-fluorobenzoic acid;4-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dimethylbenzoic acid;4-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,5- dimethylbenzoic acid;4-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3,5- dimethylbenzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- methylbenzoic acid;4-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1 -(2,2-difluoroethyl)piperidin-3-yl)-3- (difluoromethoxy)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3-fluorobenzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- methoxybenzoic acid;4-(1 -(2,2-difluoroethyl)-4-((5-fluoro-7-methyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- fluorobenzoic acid; andPAT059793-PCT-SEC014-(4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- fluorobenzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2,3- dihydrobenzofuran-7-carboxylic acid;4-(1 -(3, 3-d ifluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-fluoro benzoic acid:4-(1-(2-(difluoromethoxy)ethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methylbenzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3- methoxybenzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3- fluorobenzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3- methylbenzoic acid;2-amino-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3- yl)benzoic acid;4-(1-(2-(difluoromethoxy)ethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methoxybenzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-2- methylbenzoic acid;7-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2,3- dihydrobenzofuran-4-carboxylic acid;4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (trifluoromethyl)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-propylpiperidin-3-yl)-3-(trifluoromethyl)benzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- (trifluoromethyl)benzoic acid;4-(4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- methylbenzoic acid;3-cyclopropyl-4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid;3-cyclopropyl-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-propylpiperidin-3-yl)benzoic acid;3-cyclopropyl-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid;3-chloro-4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;PAT059793-PCT-SEC013-chloro-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid;4-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3-ethylbenzoic acid;4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3-ethylbenzoic acid;3-(difluoromethoxy)-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3-trifluoropropyl)piperidin- 3-yl)benzoic acid;4-(1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (difluoromethyl)benzoic acid;3-(difluoromethyl)-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid;4-(4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-3- methylbenzoic acid;3-cyclopropoxy-4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid; and3-cyclopropoxy-4-(4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

16. The compound of claim 15, selected from the group consisting of:4-((3R,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2- methoxybenzoic acid;4-((3R,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2- fluorobenzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2- fluorobenzoic acid;4-((3R,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-2- fluorobenzoic acid;4-((3R,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2- methylbenzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2- methylbenzoic acid;4-((3R,4 / ?)-1 -(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methylbenzoic acid;4-((3R,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- methylbenzoic acid;PAT059793-PCT-SEC014-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methoxybenzoic acid;4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- methoxybenzoic acid;2-chloro-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 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-3- methylbenzoic acid;4-((3 / ?,4 / ?)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methylbenzoic acid;4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2- fluorobenzoic acid;4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,6- dimethylbenzoic acid;4-((3 / ?,4 / ?)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2- methylbenzoic acid;2-amino-4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3- yl)benzoic acid;2-amino-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-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2- ethoxybenzoic acid;4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- ethoxybenzoic acid;4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (difluoromethoxy)benzoic acid;4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dihydrobenzofuran-7-carboxylic acid;7-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dihydrobenzofuran-4-carboxylic acid;4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)indoline-7- carboxylic acid;7-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,2- difluorobenzo[d][1 ,3]dioxole-4-carboxylic acid;4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- fluorobenzoic acid;PAT059793-PCT-SEC014-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,3- dimethylbenzoic acid;4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-2,5- dimethylbenzoic acid;4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3,5- dimethylbenzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- methylbenzoic acid;4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- (difluoromethoxy)benzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- fluorobenzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- methoxybenzoic acid;4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5-fluoro-7-methyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- fluorobenzoic acid;4-((3 / ?,4 / ?)-4-((5-chloro-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)-3- fluorobenzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2,3- dihydrobenzofuran-7-carboxylic acid;4-((3 / ?,4 / ?)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- fluorobenzoic acid;4-((3 / ?,4 / ?)-1-(2-(difluoromethoxy)ethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methylbenzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3- methoxybenzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3- fluorobenzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)-3- methylbenzoic acid;2-amino-4-((3R,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(2- (trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid;4-((3 / ?,4 / ?)-1-(2-(difluoromethoxy)ethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- methoxybenzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-2- methylbenzoic acid;PAT059793-PCT-SEC017-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2,3- dihydrobenzofuran-4-carboxylic acid;4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (trifluoromethyl)benzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-propylpiperidin-3-yl)-3-(trifluoromethyl)benzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- (trifluoromethyl)benzoic acid;4-((3 / ?,4 / ?)-4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)- 3-methylbenzoic acid;3-cyclopropyl-4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin- 3-yl)benzoic acid;3-cyclopropyl-4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-propylpiperidin-3-yl) benzoic acid;3-cyclopropyl-4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid;3-chloro-4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3- yl)benzoic acid;3-chloro-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-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- ethylbenzoic acid;4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)-3- ethylbenzoic acid;3-(difluoromethoxy)-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-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)-3- (difluoromethyl)benzoic acid;3-(difluoromethyl)-4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid;4-((3 / ?,4 / ?)-4-((5-cyclopropyl-7-methyl-1 / 7-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3- yl)-3-methylbenzoic acid;3-cyclopropoxy-4-((3 / ?,4 / ?)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)piperidin-3-yl)benzoic acid; and3-cyclopropoxy-4-((3 / ?,4 / ?)-4-((5,7-dimethyl-1 / 7-indol-4-yl)oxy)-1 -(3,3,3- trifluoropropyl)piperidin-3-yl)benzoic acid,PAT059793-PCT-SEC01 or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, and a pharmaceutically acceptable carrier or excipient.

18. A pharmaceutical composition comprises the compounds according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, and at least one additional therapeutically active agent.

19. 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 16, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, or the pharmaceutical composition according to claim 17 or 18.

20. The method of claim 19, 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, xenograftPAT059793-PCT-SEC01 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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