Complement factor B inhibitors and uses thereof

Abstract

Provided herein are compounds having formula (I) and pharmaceutical compositions thereof useful in the treatment of diseases or disorders mediated by complement factor B. (I)

Description

Technical Field

[0001] This disclosure relates to the inhibition of the alternative complement pathway, and specifically to the inhibition of factor B. This disclosure also relates to the treatment of patients suffering from conditions and diseases associated with activation of the alternative complement pathway. Background Technology

[0002] The complement system is an important component of the innate immune system and contains a group of proteins that are normally inactive. These proteins are organized through three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway (VM Holers, In Clinical Immunology: Principles and Practice, ed. RRR Rich, Mosby Press; 1996, 363-391). Molecules, antibodies, or cellular components from microorganisms can activate these pathways, leading to the formation of protease complexes called C3-convertases and C5-convertases. The classical pathway is a calcium / magnesium-dependent cascade, which is normally activated by the formation of antigen-antibody complexes. It can also be activated in an antibody-independent manner by binding to C-reactive proteins complexed with ligands and by many pathogens, including Gram-negative bacteria. The alternative pathway is a magnesium-dependent cascade, which is activated by the deposition and activation of C3 on certain sensitive surfaces, such as cell wall polysaccharides in yeast and bacteria, and certain biopolymer materials.

[0003] Factor B is a suitable target for inhibiting this complement pathway amplification because its plasma concentration in humans is typically around 200 µg / mL (or around 2 µM), and it has been shown to be a key enzyme activating the alternative complement pathway (PH Lesavre and HJ Müller-Eberhard. J. Exp. Med., 1978; 148: 1498-1510; JE Volanakis et al., New Eng. J. Med., 1985; 312:395-401). Summary of the Invention

[0004] This disclosure provides compounds that regulate and / or inhibit activation of the complement bypass pathway. In some embodiments, this disclosure provides compounds that regulate 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.

[0005] The compounds disclosed herein inhibit or suppress complement system amplification caused by C3 activation, regardless of the original activation mechanism (including activation via, for example, the classical pathway, lectin pathway, or bypass pathway).

[0006] This disclosure also relates to compounds that are effective as factor B regulators, pharmaceutically acceptable salts thereof, compositions thereof, and their use in therapies for the conditions and purposes detailed herein.

[0007] In the first aspect, this disclosure provides compounds having formula (I).

[0008]

[0009] (I)

[0010] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein the variable is defined herein.

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

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

[0013] In another aspect, a method for modulating complement bypass pathway activity in a subject is provided, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0014] In another aspect, a method is provided for treating a disease or disorder mediated by complement activation, particularly by complement bypass pathway activation, in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0015] In another aspect, a method is provided for treating a disease or disorder affected by complement bypass pathway regulation, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

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

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

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

[0019] In another aspect, compounds having formula (I), or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, are provided for use as medicines.

[0020] In another aspect, compounds having formula (I), or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, are provided for use in subjects in need of inhibiting the expression or activity of complement factor B.

[0021] In another aspect, compounds having formula (I), or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, are provided for use in the treatment of diseases or disorders associated with dysregulation of the complement bypass pathway.

[0022] In another aspect, the use of a compound having formula (I), or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof, is provided in the manufacture of a medicament for treating diseases or disorders mediated by complement activation or complement bypass pathway activation.

[0023] In another aspect, the use of a compound having formula (I), or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof, is provided for the treatment of diseases or disorders mediated by complement activation or complement bypass pathway activation.

[0024] In another aspect, the use of a compound having formula (I), or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof, for the treatment of diseases or disorders affected by complement bypass pathway regulation is provided. Detailed Implementation

[0025] Macular degeneration is a clinical term used to describe a class of diseases characterized by progressive loss of central vision associated with abnormalities in Bruch's membrane, choroid, neuroretina, and / or retinal pigment epithelium. The macula is located in the center of the retina and has a diameter of approximately [missing information - likely related to retinal degeneration]. The macula is approximately 1 / 2 cm in diameter. It provides detailed vision, particularly in the center (fovea) due to the higher density of cone cells and the high ratio of ganglion cells to photoreceptor cells. Blood vessels, ganglion cells, the nuclear lamina and plexiform lamina are located laterally (not above the photoreceptor cells), allowing light to reach the cone cells via a more direct path. Below the retina are the choroid (part of the uveal bundle) and the retinal pigment epithelium (RPE), which lies between the neuroretina and the choroid. The choroidal vessels supply nutrients to the retina and its visual cells.

[0026] Age-related macular degeneration (AMD) is the most common form of macular degeneration, associated with progressive loss of visual acuity in the central part of the visual field, altered color vision, and abnormal dark adaptation and sensitivity. AMD has two main clinical presentations described as dry or atrophic forms and neovascular or exudative forms. The dry form is associated with atrophic cell death in the central retina or macula, which is necessary for fine vision used in activities such as reading, driving, or recognizing faces. Approximately 10-20% of these AMD patients progress to the second form, called neovascular AMD (also known as wet AMD).

[0027] Neovascular AMD is characterized by abnormal growth and leakage of blood vessels in the submacular region, leading to retinal displacement, hemorrhage, and scarring. This results in vision loss over a period ranging from weeks to years. Neovascular AMD cases originate from intermediate or late-stage dry AMD. The neovascular form accounts for 85% of legal blindness caused by AMD. In neovascular AMD, abnormal blood vessels leak fluid and blood, forming scar tissue that damages the central retina.

[0028] Neovascularization in AMD typically originates from the choroid and is termed choroidal neovascularization (CNV). The pathogenesis of CNV is poorly understood, but factors such as inflammation, ischemia, and local production of angiogenic factors are considered important. One published study showed that in a mouse laser model, CNV is induced by complement activation (Bora PS, J. Immunol. [Journal of Immunology] 2005;174; 491-497).

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

[0030] definition

[0031] Unless otherwise stated, the terms “compounds of the present disclosure” or “compounds provided herein” mean compounds having the formula disclosed herein, illustrative compounds, their salts (especially their pharmaceutically acceptable salts), hydrates, solvates, and all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers, and isotopically labeled compounds (including deuterium-substituted compounds), as well as the inherently formed moieties.

[0032] In the groups or radicals defined below, the number of carbon atoms is usually specified before the group, for example, C1-C. 10 Alkyl refers to an alkyl group having 1 to 10 carbon atoms.

[0033] Furthermore, the use of terms indicating monovalent groups where divalent groups are appropriate should be understood to indicate the corresponding divalent group, and vice versa. Unless otherwise stated, terms are assumed to correspond to conventional definitions and the valences of conventional stable atoms, and are reflected in the full formula and groups. The article “a / an” refers to one / an or more / an (e.g., at least one / an) of the grammatical object of the article. For example, “an element” means one element or more than one element.

[0034] Unless otherwise indicated, the term “and / or” means “and” or “or”.

[0035] The term "substituted" means that the specified group or portion carries one or more suitable substituents, wherein these substituents may be attached to the specified group or portion at one or more positions. For example, an aryl group substituted with a cycloalkyl group may indicate that the cycloalkyl group is attached to one atom of the aryl group by a bond or by fusion with the aryl group and sharing two or more common atoms.

[0036] As used herein, the term "C1-C6 alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without any unsaturation, having one to six carbon atoms, and attached to the rest of the molecule by a single bond. The terms C1-C3 alkyl and C1-C4 alkyl should be interpreted accordingly. Examples of C1-C6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), n-pentyl, and n-hexyl.

[0037] The term "alkenyl," used alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. Alkenyl formally corresponds to an alkene in which one CH bond is replaced by an alkenyl group attached to the remainder of the compound. The term "C..." n-m "Alkenyl" refers to an alkenyl group having n to m carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc.

[0038] As used herein, the term "C1-C6 alkoxy" refers to an alkoxy group having the formula -OR a The group, wherein R a It is a C1-C6 alkyl group as generally defined above. Examples of C1-C6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, and hexoxy.

[0039] The term "amino" as used alone or in combination with other terms refers to a group having the formula -NH2, wherein the hydrogen atom may be replaced by a substituent as described herein. For example, "alkylamino" can refer to -NH (alkyl) and -N (alkyl)2.

[0040] The term "cyano" or "nitrile" refers to a group having the formula -C≡N, which can also be written as -CN.

[0041] The term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, or iodine.

[0042] The term "hydroxyl group" refers to an alcohol group having the formula -OH.

[0043] As used herein, the terms "cycloalkyl" or "carbocyclic" refer to a monocyclic or polycyclic saturated or partially unsaturated carbocyclic ring containing 3 to 18 carbon atoms, wherein there are no shared delocalized π electrons (aromaticity) between the ring carbons. Thus, the term "C3-C5 cycloalkyl" can be interpreted. The term polycyclic encompasses bridging (e.g., norbornane), fused (e.g., decahydronaphthalene), and spirocyclic cycloalkyl. Preferably, cycloalkyl, such as C3-C5 cycloalkyl, is a monocyclic hydrocarbon group having 3 to 5 carbon atoms.

[0044] Examples of cycloalkyl groups include, but are not limited to, cyclopropenyl, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, bicyclo[1.1.1]pentyl and their derivatives.

[0045] Examples of C3-C5 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl.

[0046] "Heterocyclic group" refers to 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), wherein there are no shared delocalized π electrons (aromaticity) between the ring carbons or heteroatoms. The term "4- to 6-membered heterocyclic group" should be interpreted accordingly. The heterocyclic ring structure can be substituted by one or more substituents. The substituents themselves can be optionally substituted. Heterocyclic groups can be bonded by carbon atoms or heteroatoms. The term polycyclic encompasses bridging, fused, and spirocyclic heterocyclic groups.

[0047] Examples of heterocyclic rings include, but are not limited to, oxacyclobutane, azacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxolinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazineyl, azahexyl, oxazoxyl, diazahexyl, etc. Atrosyl, oxazolidinone, 1,4-dioxyl, dihydrofuranyl, 1,3-dioxolane, imidazolinyl, dihydroisooxazolinyl, pyrrololinyl, pyrazolinyl, oxazolidinyl, dithiopentane, homotropanyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl), oxaspiroheptyl (e.g., 2-oxaspirohept-6-yl), etc.

[0048] Examples of 4- to 6-membered heterocyclic groups include, but are not limited to, aza-butyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, dihydroisoxazolinyl, tetrahydropyranyl, morpholinyl, dihydropyranyl (e.g., 3,6-dihydro-2H-pyranyl) and oxaspiroheptyl (e.g., 2-oxaspiro[3.3]hept-6-yl).

[0049] 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 include pyrroleyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 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, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, thiadiazinyl, azazolyl, azecinyl, etc.

[0050] Heteroaryl groups are 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 include indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazole, benzopyranyl, benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, benzooxazolyl, benzoisooxazolyl, benzooxazinyl, benzotriazolyl, naphthidyl, phthalazinyl, pteridinyl, purine, quinazolinyl, cinolinyl, quinolinyl, isoquinolinyl, quinoxolinyl, oxazolopyridyl, isoxazolopyridyl, pyrrolopyridyl, furanolopyridyl, thiophenolopyridyl, imidazopyridyl, imidazopyrimidyl, pyrazololopyridyl, pyrazololopyrimidyl, pyrazololopyrimidyl, pyrazololotriazinyl, triazololopyridyl, triazololopyrimidyl, imidazothiazolyl, triazololopyrimidyl, triazololopyrimidyl, etc.

[0051] Heteroaryl groups are 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, acridinel, phenothiazinyl, carbaolinyl, phenanthrolinel, etc.

[0052] The heteroaryl ring structure can be substituted by one or more substituents. The substituents themselves can be optionally substituted. The heteroaryl ring can be bonded by carbon atoms or heteroatoms.

[0053] The term "5- or 6-membered heteroaryl" should be interpreted accordingly.

[0054] Examples of 5- or 6-membered heteroaryl groups include, but are not limited to, furan, indolyl, pyridinyl, pyrimidinyl, pyridoneyl, pyridazinyl, triazolyl (e.g., 1,2,4-triazolyl), pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrroleyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), imidazoleyl, thiophenyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), pyrazinyl, isoxazolopyridinyl, dihydropyridooxazinyl, and tetrazolyl. The term "a 5- or 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from N, O, and S" should be interpreted accordingly.

[0055] As used herein, "regulator" means, for example, a compound disclosed herein, which regulates, reduces, or lowers the level of a specific protein (e.g., complement factor B). The amount of the regulated specific protein (e.g., complement factor B) can be measured by comparing the amount of the specific protein (e.g., complement factor B) remaining after treatment with a compound disclosed herein with an initial amount or level of the specific protein (e.g., complement factor B) present before treatment with a compound disclosed herein.

[0056] As used herein, "inhibitor" means, for example, a compound disclosed herein that inhibits or reduces the activity of at least one component of the complement pathway, for example, by inhibiting the binding of one component of the pathway to another. For example, the complement pathway is a complement bypass pathway. For example, a component of this complement pathway is complement factor B.

[0057] As used herein, the terms “inhibit,” “inhibition,” or “inhibiting” refer to the reduction or suppression of a given condition, symptom, disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

[0058] The term "effective amount" for a compound used herein refers to the amount of a therapeutic compound necessary or sufficient to achieve its intended function in a mammal. The effective amount of a therapeutic compound can vary depending on factors such as the amount of pathogen present in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compound disclosed herein to treat the condition in which complement factor B functions.

[0059] Therefore, the term "therapeuticly effective amount" for compounds disclosed herein refers to the amount of the compound disclosed herein that will elicit a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, relief of condition, slowing or delaying disease progression, or prevention of disease, etc.). In one embodiment, the term "therapeuticly effective amount" refers to the amount of the compound disclosed herein that, when administered to a subject, is effective in: (1) at least partially relieving, preventing, and / or improving (i) a condition, disorder, or disease mediated by complement factor B, or (ii) associated with complement factor B activity, or (iii) characterized by (normal or abnormal) complement factor B activity; (2) reducing or inhibiting complement factor B activity; or (3) reducing or inhibiting complement factor B expression. In another embodiment, the term "therapeuticly effective amount" refers to an amount of the compound disclosed herein that, when applied to cells, tissues, non-cellular biological materials, or media, effectively at least partially reduces or inhibits the activity of complement factor B; or at least partially reduces or inhibits the expression of complement factor B.

[0060] As used herein, the terms "subject" or "patient" refer to humans and non-human mammals, including but not limited to primates, rabbits, pigs, horses, dogs, cats, sheep, and cattle. In certain embodiments, the subject or patient is a human. In some embodiments, the term "patient" or "subject" refers to a person who suffers from the condition (i.e., disease or disorder) described herein and will benefit from treatment. As used herein, a subject (patient) is "in need" of treatment if the subject (patient) will benefit biologically, medically, or in terms of quality of life from the treatment. In certain embodiments, the subject is an adult at least about 18 years of age. In certain embodiments, the subject is an adult from about 18 to about 75 years of age. In some embodiments, the subject is a child at most about 18 years of age.

[0061] As used herein, the term “treating / treatment” means suppressing a disease; for example, suppressing the disease, condition, or disorder of an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition, or disorder (i.e., preventing the further development of the pathology and / or symptoms) or improving the disease; for example, improving the disease, condition, or disorder of an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition, or disorder (i.e., reversing the pathology and / or symptoms), such as reducing the severity of the disease.

[0062] As used herein, the term "prevent / preventing / prevention" includes prevention of at least one symptom associated with, or caused by, the state, disease, or disorder to be prevented. As used herein, a subject is "in need of" treatment if the subject will benefit biologically, medically, or in terms of quality of life from the treatment.

[0063] As used in this article, the term “about” means a value that is within a range of + / - 10% of the specified value.

[0064] As used herein, the terms “a”, “the”, and similar terms used in the context of this disclosure (particularly in the context of the claims) should be interpreted as encompassing both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context.

[0065] As used herein, the term “pharmaceuticalally acceptable carrier” means 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, buffers, emulsifiers, absorption delay agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd edition, Pharmaceutical Press, 2013, pp. 1049-1070).

[0066] The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; etc. The pharmaceutically acceptable salts of the present invention comprise non-toxic salts of parent compounds formed from, for example, non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing a basic or acidic moiety. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; generally, non-aqueous media such as ethers, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition (Mack Publishing Company, Easton, 1985), p. 1418; Berge et al., J. Pharm. Sci., 1977, 66(1), 1–19; and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley, 2002). In some embodiments, the compounds described herein comprise N-oxide forms.

[0067] This document describes several enumerated embodiments of the present disclosure. It should be understood that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present disclosure.

[0068] compound

[0069] This invention provides a compound having formula (I), or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein the variables are defined herein.

[0070]

[0071] (I)

[0072] Various enumerated embodiments of the invention have been described herein. It should be understood that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.

[0073] Example 1 provides a compound having formula (I).

[0074]

[0075] (I)

[0076] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein:

[0077] W is O, C(R) 6 )2, or NR 7 ;

[0078] R is hydrogen, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, or hydroxy-C1-C4 alkyl;

[0079] R 1 It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy, hydroxyl-C1-C6 alkyl, hydroxyl-C3-C6 cycloalkyl, amino-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkoxy, or C3-C6 cycloalkyl-C1-C6 alkoxy;

[0080] R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkoxy is unsubstituted or substituted by 1, 2, or 3 halogen substituents;

[0081] R 3 It is hydrogen, halogen, or cyano;

[0082] R 4 It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0083] R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxy C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, -CH2CO2R 5b -C(O)NHSO2C1-C4 alkyl, -SO2NHC(O)C1-C4 alkyl, -SO2C1-C4 alkyl, cyano, hydroxyl, halogen, -C(O)N(R 5b)2 and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace;

[0084] Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H;

[0085] Each R 5b Independently selected from hydrogen and C1-C5 alkyl groups;

[0086] Each R 6 The heterocyclic group is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C3-C6 cycloalkylC1-C4 alkylamino, halo-C3-C6 cycloalkylC1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and 4- to 6-membered heterocyclic groups having 1 to 2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is unsubstituted or substituted by 4- to 6-membered heterocyclic groups having 1 to 2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclic group is independently unsubstituted or substituted by 1, 2 or 3 halogens;

[0087] Or two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic carbon ring having 3 to 6 ring atoms, wherein the spirocyclic carbon ring is unsubstituted or substituted by 1 or 2 substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups;

[0088] Or two Rs 6 They combine with the carbon atoms to which they are attached to form one or two independent atoms selected from N, O, and S(O). q A spirocyclic heterocycle with a cyclic heteroatom, wherein the spirocyclic heterocycle is not substituted or is substituted by one or two halogens, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C3-C6 cycloalkyl.

[0089] q is 0, 1, or 2;

[0090] R 7 It is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7aAryl group, having 1-2 independently selected from N, O, and S(O) q A 4- to 6-membered heterocyclic group with heteroatoms, or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the C1-C6 alkyl group is unsubstituted or has 1 to 2 heteroatoms independently selected from N, O, and S(O). q The heteroatom is substituted with a 4- to 6-membered heterocyclic group, wherein the 4- to 6-membered heterocyclic group is not substituted or is substituted with 1, 2 or 3 halogens, and further wherein the aryl or heteroaryl group is not substituted or is substituted with a halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C5 cycloalkyl, or halogenated C3-C5 cycloalkyl.

[0091] R 7a It is hydrogen or C1-C6 alkyl;

[0092] Each R 8 It is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy;

[0093] R 9 It is H, D, or T;

[0094] m is 0, 1, 2, or 3;

[0095] n is 0, 1, 2, or 3;

[0096] The premise is that neither m nor n is 0; and

[0097] p is 0, 1, 2, or 3.

[0098] Example 2 provides a compound having formula (I) as described in Example 1, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein:

[0099] W is C(R) 6 )2, or NR 7 ;

[0100] R is hydrogen;

[0101] R 1 It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or amino C1-C6 alkyl;

[0102] R 2It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkoxy is unsubstituted or substituted by 1, 2, or 3 halogen substituents;

[0103] R 3 It is hydrogen, halogen, or cyano;

[0104] R 4 It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0105] R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxy C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, -CH2CO2R 5b , cyano, hydroxyl, halogen, -C(O)N(R) 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace;

[0106] Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H;

[0107] R 5b Selected from hydrogen and C1-C5 alkyl groups;

[0108] Each R 6 The heterocyclic group is independently selected from hydrogen, halogen, hydroxyl, C3-C6 cycloalkyl-C1-C4 alkylamino, halo-C3-C6 cycloalkyl-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is either unsubstituted or substituted with a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclic group is either unsubstituted or substituted with 1, 2, or 3 halogens;

[0109] Or two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic carbon ring having 3 to 6 ring atoms, wherein the spirocyclic carbon ring is unsubstituted or substituted by 1 or 2 substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups;

[0110] Or two Rs 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O, wherein the spirocyclic heterocycle is not substituted;

[0111] R 7 It is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a C3-C6 cycloalkyl, a 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N or O, or a 5- to 6-membered heteroaryl group having 1 heteroatom selected from O, wherein the 4- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are not substituted;

[0112] R 7a It is a C1-C6 alkyl group;

[0113] Each R 8 It is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy;

[0114] R 9 It is H, D, or T;

[0115] m is 1, 2, or 3;

[0116] n is 1, 2, or 3; and

[0117] p is 0, 1, or 2.

[0118] Example 3 provides a compound having formula (I) as described in Example 1 or 2, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein:

[0119] W is C(R) 6 )2, or NR 7 ;

[0120] R is hydrogen;

[0121] R 1 It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or halogenated C1-C6 alkyl;

[0122] R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen;

[0123] R 3 It is hydrogen;

[0124] R 4 It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N and O, wherein the phenyl or heteroaryl group is unsubstituted or R 5 replace;

[0125] R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, hydroxyl, halogen, -C(O)N(R) 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 independent heteroatoms selected from N and O, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace;

[0126] Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H;

[0127] Each R 5b Selected from hydrogen and C1-C5 alkyl groups;

[0128] Each R 6 The heterocyclic group is independently selected from hydrogen, halogen, hydroxyl, C3-C6 cycloalkyl-C1-C4 alkylamino, halo-C3-C6 cycloalkyl-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is either unsubstituted or substituted with a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclic group is either unsubstituted or substituted with 1, 2, or 3 halogens;

[0129] Or two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic carbon ring having 3 to 6 ring atoms, wherein the spirocyclic carbon ring is unsubstituted or substituted by 1 or 2 substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups;

[0130] Or two Rs 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O, wherein the spirocyclic heterocycle is not substituted;

[0131] R 7It is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a C3-C6 cycloalkyl, a 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N or O, or a 5- to 6-membered heteroaryl group having 1 heteroatom selected from O, wherein the 4- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are not substituted;

[0132] R 7a It is a C1-C6 alkyl group;

[0133] Each R 8 It is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy;

[0134] R 9 It is H;

[0135] m is 1 or 2;

[0136] n is 1, 2, or 3; and

[0137] p is 0.

[0138] Example 4 provides a compound having formula (I) as described in any one of Examples 1 to 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound having formula (I) is a compound having formula (I-1):

[0139]

[0140] (I-1)

[0141] Or its pharmaceutically acceptable salt.

[0142] Example 5 provides a compound having formula (I) as described in any one of Examples 1 to 3, wherein the compound having formula (I) is a compound having formula (I-2):

[0143]

[0144] (I-2)

[0145] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0146] Example 6 provides a compound having formula (I) as described in any one of Examples 1 to 5, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein:

[0147] W is C(R) 6 )2;

[0148] R is hydrogen;

[0149] R 1 It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or amino C1-C6 alkyl;

[0150] R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkoxy is unsubstituted or substituted by 1, 2, or 3 halogen substituents;

[0151] R 3 It is hydrogen, halogen, or cyano;

[0152] R 4 It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0153] R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxy C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, -CH2CO2R 5b , cyano, hydroxyl, halogen, -C(O)N(R) 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace;

[0154] Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H;

[0155] Each R 5b Selected from hydrogen and C1-C5 alkyl groups;

[0156] Each R 6The heterocyclic group is independently selected from hydrogen, halogen, hydroxyl, C3-C6 cycloalkyl-C1-C4 alkylamino, halo-C3-C6 cycloalkyl-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is either unsubstituted or substituted with a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclic group is either unsubstituted or substituted with 1, 2, or 3 halogens;

[0157] Or two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic carbon ring having 3 to 6 ring atoms, wherein the spirocyclic carbon ring is unsubstituted or substituted by 1 or 2 substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups;

[0158] Or two Rs 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O, wherein the spirocyclic heterocycle is not substituted;

[0159] Each R 8 It is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy;

[0160] R 9 It is H, D, or T;

[0161] m is 1, 2, or 3;

[0162] n is 1, 2, or 3; and

[0163] p is 0, 1, or 2.

[0164] Example 7 provides a compound having formula (I) as described in any one of Examples 1 to 5, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein

[0165] W is NR 7 ;

[0166] R is hydrogen;

[0167] R 1It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, or amino C1-C6 alkyl;

[0168] R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkoxy is unsubstituted or substituted by 1, 2, or 3 halogen substituents;

[0169] R 3 It is hydrogen, halogen, or cyano;

[0170] R 4 It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0171] R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxy C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, -CH2CO2R 5b , cyano, hydroxyl, halogen, -C(O)N(R) 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace;

[0172] Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H;

[0173] Each R 5b Selected from hydrogen and C1-C5 alkyl groups;

[0174] R 7 It is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a C3-C6 cycloalkyl, a 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N or O, or a 5- to 6-membered heteroaryl group having 1 heteroatom selected from O, wherein the 4- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are not substituted;

[0175] R 7a It is a C1-C6 alkyl group;

[0176] Each R 8 It is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy;

[0177] R 9 It is H, D, or T;

[0178] m is 1, 2, or 3;

[0179] n is 1, 2, or 3; and

[0180] p is 0, 1, or 2.

[0181] Example 8 provides a compound having formula (I) as described in any one of Examples 1-6, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein...

[0182] W is C(R) 6 )2;

[0183] R is hydrogen;

[0184] R 1 It is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C1-C6 alkyl;

[0185] R 2 It is a C1-C3 alkyl or halogen, wherein the C1-C3 alkyl is unsubstituted or substituted by 1, 2 or 3 halogen substituents;

[0186] R 3 It is hydrogen;

[0187] R 4 It is a phenyl group or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0188] R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, -C(O)N(R) 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 independent heteroatoms selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or replaced by 1 R 5a replace;

[0189] Each R 5a Independently selected from hydroxyl and C1-C6 alkyl groups;

[0190] Each R 5b Independently selected from hydrogen and C1-C3 alkyl groups;

[0191] Each R 6 The heterocyclic group is independently selected from hydrogen, halogen, hydroxyl, C3-C6 cycloalkyl-C1-C4 alkylamino, halo-C3-C6 cycloalkyl-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and a 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is unsubstituted or substituted by a 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclic group is unsubstituted or substituted by 1, 2 or 3 halogens;

[0192] Or two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic carbon ring having 3 to 6 ring atoms, wherein the spirocyclic carbon ring is unsubstituted or substituted by 1 or 2 substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups;

[0193] Or two Rs 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O;

[0194] Each R 8 Independently selected from hydrogen and C1-C6 alkyl groups;

[0195] R 9 It is H;

[0196] m is 1 or 2;

[0197] n is 1, 2, or 3; and

[0198] p is 0, 1, or 2.

[0199] Example 9 provides a compound having formula (I) as described in any one of Examples 1-5 and 7, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein

[0200] W is NR 7 ;

[0201] R is hydrogen;

[0202] R 1 It is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C1-C6 alkyl;

[0203] R 2It is a C1-C3 alkyl or halogen, wherein the C1-C3 alkyl is unsubstituted or substituted by 1, 2 or 3 halogen substituents;

[0204] R 3 It is hydrogen;

[0205] R 4 It is a phenyl group or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0206] R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, -C(O)N(R) 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 independent heteroatoms selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or replaced by 1 R 5a replace;

[0207] Each R 5a Independently selected from hydroxyl and C1-C6 alkyl groups;

[0208] Each R 5b Independently selected from hydrogen and C1-C3 alkyl groups;

[0209] R 7 It is C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a , a 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N or O, or a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from N, O and S;

[0210] R 7a It is a C1-C6 alkyl group;

[0211] Each R 8 Independently selected from hydrogen and C1-C6 alkyl groups;

[0212] R 9 It is H;

[0213] m is 1 or 2;

[0214] n is 1, 2, or 3; and

[0215] p is 0, 1, or 2.

[0216] Example 10 provides a compound having formula (I) as described in any one of Examples 1-6 and 8, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein

[0217] W is C(R) 6 )2;

[0218] R is hydrogen;

[0219] R 1 It is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C1-C6 alkyl;

[0220] R 2 It is a C1-C3 alkyl or halogen, wherein the C1-C3 alkyl is unsubstituted or substituted by 1, 2 or 3 halogen substituents;

[0221] R 3 It is hydrogen;

[0222] R 4 It is a phenyl group, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N and O, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0223] R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, hydroxyl, halogen, -C(O)N(R) 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace;

[0224] Each R 5a Independently selected from hydroxyl and C1-C6 alkyl groups;

[0225] Each R 5b Independently selected from hydrogen;

[0226] Each R 6The heterocyclic group is independently selected from hydrogen, halogen, hydroxyl, C3-C6 cycloalkyl-C1-C4 alkylamino, halo-C3-C6 cycloalkyl-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is either unsubstituted or substituted with a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclic group is either unsubstituted or substituted with 1, 2, or 3 halogens;

[0227] Or two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic carbon ring having 3 to 6 ring atoms, wherein the spirocyclic carbon ring is unsubstituted or substituted by 1 or 2 substituents selected from halogens;

[0228] Or two Rs 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O;

[0229] Each R 8 Independently selected from hydrogen and halogens;

[0230] R 9 It is H or D;

[0231] m is 1 or 2;

[0232] n is 1, 2, or 3; and

[0233] p is 0.

[0234] Example 11 provides a compound having formula (I) as described in any one of Examples 1-5, 7 and 9, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein

[0235] W is NR 7 ;

[0236] R is hydrogen;

[0237] R 1 It is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C1-C6 alkyl;

[0238] R 2 It is a C1-C3 alkyl or halogen, wherein the C1-C3 alkyl is unsubstituted or substituted by 1, 2 or 3 halogen substituents;

[0239] R 3 It is hydrogen;

[0240] R4 It is a phenyl group, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N and O, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0241] R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, hydroxyl, halogen, -C(O)N(R) 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace;

[0242] Each R 5a Independently selected from hydroxyl and C1-C6 alkyl groups;

[0243] Each R 5b Independently selected from hydrogen;

[0244] R 7 It is C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a , a 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N or O, or a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from N, O and S;

[0245] Each R 8 Independently selected from hydrogen and halogens;

[0246] R 9 It is H or D;

[0247] m is 1 or 2;

[0248] n is 1, 2, or 3; and

[0249] p is 0.

[0250] Example 12 provides a compound having formula (I) as described in any one of Examples 1 to 11, wherein the compound having formula (I) is a compound having formula (I-AC) or (I-AN):

[0251] (I-AC) (I-AN)

[0252] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0253] Example 13 provides a compound having formula (I) as described in any one of Examples 1 to 12, wherein the compound having formula (I) is a compound having formula (I-A0), (I-A1), or (I-A2):

[0254] (I-A0), (I-A1) (I-A2)

[0255] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0256] Example 14 provides a compound having formula (I) as described in Example 13, wherein the compound having formula (I) is a compound having formula (IA), formula (I-A11), or formula (I-A12):

[0257] (IA) (I-A11) (I-A12)

[0258] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0259] Example 15 provides a compound having formula (I) as described in any one of Examples 1 to 13, wherein the compound having formula (I) is a compound having formula (ID), (I-D1), or (I-D2):

[0260] (ID) (I-D1) (I-D2)

[0261] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0262] Example 16 provides a compound having formula (I) as described in Example 15, wherein the compound having formula (I) is a compound having formula (I-D'), (I-D'1), or (I-D'2):

[0263] (I-D') (I-D'1) (I-D'2)

[0264] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0265] Example 17 provides a compound having formula (I) as described in Example 13, wherein the compound having formula (I) is a compound having formula (IH), (I-H1), or (I-H2):

[0266] (IH) (I-H1) (I-H2)

[0267] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0268] Example 18 provides a compound having formula (I) as described in Example 17, wherein the compound having formula (I) is a compound having formula (IB), (I-B1), or (I-B2):

[0269] (IB) (I-B1) (I-B2)

[0270] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0271] Example 19 provides a compound having formula (I) as described in Example 13, wherein the compound having formula (I) is a compound having formula (IE), (I-E1), or (I-E2):

[0272] (IE) (I-E1) (I-E2)

[0273] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0274] Example 20 provides a compound having formula (I) as described in Example 13, wherein the compound having formula (I) is a compound having formula (IF), (I-F1), or (I-F2):

[0275] (IF) (I-F1) (I-F2)

[0276] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0277] Example 21 provides a compound having formula (I) as described in Example 13, wherein the compound having formula (I) is a compound having formula (IG), (I-G1), or (I-G2):

[0278] (IG) (I-G1) (I-G2)

[0279] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0280] Example 22 provides a compound having formula (I) as described in Example 13, wherein the compound having formula (I) is a compound having formula (IJ), (I-J1), or (I-J2):

[0281] (IJ) (I-J1) (I-J2)

[0282] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0283] Example 23 provides a compound having formula (I) as described in Example 13, wherein the compound having formula (I) is a compound having formula (I-CO):

[0284]

[0285] (I-C0)

[0286] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0287] Example 24 provides a compound having formula (I) as described in Example 23, wherein the compound having formula (I) is a compound having formula (I-CO1), (I-CO2), (I-CO3), or (I-CO4):

[0288] (I-C01) (I-C02)

[0289] (I-C03) (I-C04)

[0290] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0291] Example 25 provides a compound having formula (I) as described in Example 24, wherein the compound having formula (I) is a compound having formula (IC):

[0292]

[0293] (IC)

[0294] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0295] Example 26 provides a compound having formula (I) as described in Example 25, wherein the compound having formula (I) is a compound having formula (I-C1), (I-C2), (I-C3), or (I-C4):

[0296] (I-C1) (I-C2)

[0297] (I-C3) (I-C4)

[0298] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0299] Example 27 provides a compound having formula (I) as described in Example 23, wherein the compound having formula (I) is a compound having formula (II):

[0300]

[0301] (II)

[0302] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0303] Example 28 provides a compound having formula (I) as described in Example 27, wherein the compound having formula (I) is a compound having formula (I-I1), (I-I2), (I-I3), or (I-I4):

[0304] (I-I1) (I-I2)

[0305] (I-I3) (I-I4)

[0306] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0307] Example 29 provides a compound having formula (I) as described in Example 28, wherein the compound having formula (I) is a compound having formula (IJ):

[0308]

[0309] (IJ)

[0310] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0311] Example 30 provides a compound having formula (I) as described in Example 29, wherein the compound having formula (I) is a compound having formula (I-J1), (I-J2), (I-J3), or (I-J4):

[0312] (I-J1) (I-J2)

[0313] (I-J3) (I-J4)

[0314] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0315] Example 31 provides a compound having formula (I) as described in any one of Examples 1 to 30, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 1 It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy, hydroxyl-C1-C6 alkyl, hydroxyl-C3-C6 cycloalkyl, amino-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkoxy, or C3-C6 cycloalkyl-C1-C6 alkoxy.

[0316] Example 32 provides a compound having formula (I) as described in any one of Examples 1 to 31, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 1 It is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C3-C6 cycloalkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, or hydroxy C3-C6 cycloalkyl.

[0317] Example 33 provides a compound having formula (I) as described in any one of Examples 1 to 32, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 1 It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C1-C6 alkyl.

[0318] Example 34 provides a compound having formula (I) as described in any one of Examples 1 to 33, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 1 It is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C1-C6 alkyl.

[0319] Example 35 provides a compound having formula (I) as described in any one of Examples 1 to 34, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkoxy is unsubstituted or substituted by 1, 2, or 3 halogen substituents.

[0320] Example 36 provides a compound having formula (I) as described in any one of Examples 1 to 35, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkoxy is unsubstituted or substituted by 1, 2, or 3 halogen substituents.

[0321] Example 37 provides a compound having formula (I) as described in any one of Examples 1 to 36, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 2 It is a C1-C3 alkyl or halogen, wherein the C1-C3 alkyl is unsubstituted or substituted by 1, 2 or 3 halogen substituents.

[0322] Example 38 provides a compound having formula (I) as described in any one of Examples 1 to 37, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 2 It is a C1-C3 alkyl group or a halogen.

[0323] Example 39 provides a compound having formula (I) as described in any one of Examples 1 to 38, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R, where applicable3 It is hydrogen, halogen, or cyano.

[0324] Example 40 provides a compound having formula (I) as described in any one of Examples 1 to 39, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R, where applicable 3 It is hydrogen.

[0325] Example 41 provides a compound having formula (I) as described in any one of Examples 1 to 40, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 4 It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace.

[0326] Example 42 provides a compound having formula (I) as described in any one of Examples 1 to 41, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 4 It is a phenyl group, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N and O, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace.

[0327] Example 43 provides a compound having formula (I) as described in any one of Examples 1 to 42, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 4 It is a phenyl group, or a 5- to 6-membered heteroaryl group having one or two independent cyclic heteroatoms selected from N and O, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace.

[0328] Example 44 provides a compound having formula (I) as described in any one of Examples 1 to 43, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 4 It is a 5- to 6-membered heteroaryl group having 1 or 2 cyclic heteroatoms selected from N, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace.

[0329] Example 45 provides a compound having formula (I) as described in any one of Examples 1 to 44, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 4 It is a phenyl group, wherein the phenyl group is not substituted or is R-substituted. 5 replace.

[0330] Example 46 provides a compound having formula (I) as described in any one of Examples 1 to 45, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 4 It is a pyridyl or pyrazolyl group, wherein the pyridyl or pyrazolyl group is not substituted or is R-substituted. 5 replace.

[0331] Example 47 provides a compound having formula (I) as described in any one of Examples 1 to 46, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxy C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, -CH2CO2R 5b -C(O)NHSO2C1-C4 alkyl, -SO2NHC(O)C1-C4 alkyl, -SO2C1-C4 alkyl, cyano, hydroxyl, halogen, -C(O)N(R 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace.

[0332] Example 48 provides a compound having formula (I) as described in any one of Examples 1 to 47, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, -C(O)N(R) 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace.

[0333] Example 49 provides a compound having formula (I) as described in any one of Examples 1 to 48, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, -C(O)N(R) 5b )2 and a 5-membered heteroaryl group having 1-4 independently selected heteroatoms from N, wherein the alkyl and heteroaryl groups are unsubstituted or replaced by 1 R 5a replace.

[0334] Example 50 provides a compound having formula (I) as described in any one of Examples 1 to 49, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, -C(O)N(R) 5b )2 and a 5-membered heteroaryl group having 1-3 independently selected heteroatoms from N, wherein the alkyl and heteroaryl groups are unsubstituted or replaced by 1 R 5a replace.

[0335] Example 51 provides a compound having formula (I) as described in any one of Examples 1 to 50, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, where applicable, each R 5a It is independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H.

[0336] Example 52 provides a compound having formula (I) as described in any one of Examples 1 to 51, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, where applicable, each R 5a It is a hydroxyl group.

[0337] Example 53 provides a compound having formula (I) as described in any one of Examples 1 to 52, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, where applicable, each R 5b It is independently selected from hydrogen and C1-C5 alkyl groups.

[0338] Example 54 provides a compound having formula (I) as described in any one of Examples 1 to 53, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, where applicable, each R 5b It is independently selected from hydrogen.

[0339] Example 55 provides a compound having formula (I) as described in any one of Examples 1 to 54, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 5 It is selected from hydrogen, -CO2H, C1-C6 alkyl, hydroxyC3-C6 cycloalkyl, hydroxyC3-C6 alkyl, cyano, -CONH2, pyrazolyl, triazolyl, and tetrazolyl, wherein the pyrazolyl, triazolyl, and tetrazolyl are either unsubstituted or substituted by one C1-C6 alkyl group.

[0340] Example 56 provides a compound having formula (I) as described in any one of Examples 1 to 55, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein each R 6 The heterocyclic group is independently selected from hydrogen, halogen, hydroxyl, C3-C6 cycloalkyl-C1-C4 alkylamino, halogenated C3-C6 cycloalkyl-C1-C4 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, and a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is unsubstituted or substituted by a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclic group is unsubstituted or substituted by 1, 2, or 3 halogens.

[0341] Example 57 provides a compound having formula (I) as described in any one of Examples 1 to 56, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein each R 6 The heterocyclic group is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl-C1-C4 alkylamino, halo-C3-C6 cycloalkyl-C1-C4 alkylamino, halo-C1-C6 alkyl, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is unsubstituted or substituted by a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclic group is unsubstituted or substituted by 1, 2, or 3 halogens.

[0342] Example 58 provides a compound having formula (I) as described in any one of Examples 1 to 57, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein each R 6 The heterocyclic group is independently selected from hydrogen, halogen, hydroxyl, C3-C6 cycloalkyl-C1-C4 alkylamino, halogenated C3-C6 cycloalkyl-C1-C4 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, and a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is unsubstituted or substituted by a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclic group is unsubstituted or substituted by 1, 2, or 3 halogens.

[0343] Example 59 provides a compound having formula (I) as described in any one of Examples 1 to 58, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein each R 6 It is independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, and halogenated C1-C6 alkoxy.

[0344] Example 60 provides a compound having formula (I) as described in any one of Examples 1 to 59, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein the two Rs 6 They combine with the attached carbon atoms to form a spirocyclic carbon ring having 3 to 6 ring atoms, wherein the spirocyclic carbon ring is either unsubstituted or substituted by 1 or 2 substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups.

[0345] Example 61 provides a compound having formula (I) as described in any one of Examples 1 to 60, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein the two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic carbon ring having 3 to 4 ring atoms, wherein the spirocyclic carbon ring is either unsubstituted or substituted by 1 or 2 substituents selected from halogens.

[0346] Example 62 provides a compound having formula (I) as described in any one of Examples 1 to 61, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein the two Rs 6 They combine with the carbon atoms to which they are attached to form one or two independent atoms selected from N, O, and S(O). q A spirocyclic heterocycle with cyclic heteroatoms, wherein the spirocyclic heterocycle is not substituted or is substituted by one or two halogens, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C3-C6 cycloalkyl; wherein q is 0, 1 or 2.

[0347] Example 63 provides a compound having formula (I) as described in any one of Examples 1 to 62, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein the two Rs 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles with one or two independent cyclic heteroatoms selected from N and O.

[0348] Example 64 provides a compound having formula (I) as described in any one of Examples 1 to 63, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein the two Rs 6They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O, wherein the spirocyclic heterocycle has three to six cyclic atoms.

[0349] Example 65 provides a compound having formula (I) as described in any one of Examples 1 to 64, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein the two Rs 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles with one cyclic heteroatom selected from O.

[0350] Example 66 provides a compound having formula (I) as described in any one of Examples 1 to 65, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein the two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic heterocycle having one cyclic heteroatom selected from O, wherein the spirocyclic heterocycle has 5 cyclic atoms.

[0351] Example 67 provides a compound having formula (I) as described in any one of Examples 1 to 66, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 7 It is C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a Aryl group, having 1-2 independently selected from N, O, and S(O) q A 4- to 6-membered heterocyclic group with heteroatoms, or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the C1-C6 alkyl group is unsubstituted or has 1 to 2 heteroatoms independently selected from N, O, and S(O). q The heteroatom is substituted with a 4- to 6-membered heterocyclic group, wherein the 4- to 6-membered heterocyclic group is not substituted or is substituted with 1, 2 or 3 halogens, and further wherein the aryl or heteroaryl group is not substituted or is substituted with a halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C5 cycloalkyl, or halogenated C3-C5 cycloalkyl.

[0352] Example 68 provides a compound having formula (I) as described in any one of Examples 1 to 67, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 7It is C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a A 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N and O, or a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from N, O and S, wherein the 4- to 6-membered heterocyclic group is not substituted or is substituted by 1, 2 or 3 halogens, further wherein the heteroaryl group is not substituted or is substituted by halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C5 cycloalkyl, or halogenated C3-C5 cycloalkyl.

[0353] Example 69 provides a compound having formula (I) as described in any one of Examples 1 to 68, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 7 It is C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a The heterocyclic group having a 4- to 6-membered heterocyclic group selected from O, or a 5- to 6-membered heteroaryl group having a heteroatom independently selected from O, wherein the 4- to 6-membered heterocyclic group is not substituted or is substituted by 1, 2 or 3 halogens, further wherein the heteroaryl group is not substituted or is substituted by halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C5 cycloalkyl, or halogenated C3-C5 cycloalkyl.

[0354] Example 70 provides a compound having formula (I) as described in any one of Examples 1 to 69, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 7 It is C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a A 4- to 6-membered heterocyclic group having one heteroatom selected from O, or a 5-membered heteroaryl group having one heteroatom selected from O.

[0355] Example 71 provides a compound having formula (I) as described in any one of Examples 1 to 70, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 7a It is a C1-C6 alkyl group.

[0356] Example 72 provides a compound having formula (I) as described in any one of Examples 1 to 71, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein p is 0.

[0357] Example 73 provides a compound having formula (I) as described in any one of Examples 1 to 72, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein R 9 It's H.

[0358] Example 74 provides a compound having formula (I) as described in any one of Examples 1 to 73, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein m is 1 or 2.

[0359] Example 75 provides a compound having formula (I) as described in any one of Examples 1 to 74, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein n is 1, 2, or 3.

[0360] Example 76 provides a compound having formula (I) as described in any one of Examples 1 to 75, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof, wherein:

[0361] W is C(R) 6 )2, or NR 7 ;

[0362] R is hydrogen;

[0363] R 1 It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy, hydroxyl-C1-C6 alkyl, hydroxyl-C3-C6 cycloalkyl, amino-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkoxy, or C3-C6 cycloalkyl-C1-C6 alkoxy;

[0364] R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkoxy is unsubstituted or substituted by 1, 2, or 3 halogen substituents;

[0365] R 3 It is hydrogen, halogen, or cyano;

[0366] R 4It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0367] R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxy C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, -CH2CO2R 5b -C(O)NHSO2C1-C4 alkyl, -SO2NHC(O)C1-C4 alkyl, -SO2C1-C4 alkyl, cyano, hydroxyl, halogen, -C(O)N(R 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace;

[0368] Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H;

[0369] Each R 5b Independently selected from hydrogen and C1-C5 alkyl groups;

[0370] Each R 6 Independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C3-C6 cycloalkylC1-C4 alkylamino, halo-C3-C6 cycloalkylC1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and 4- to 6-membered heterocyclic groups having 1-2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclic group is unsubstituted or substituted by 1, 2, or 3 halogens, and wherein the C1-C6 alkyl is unsubstituted or substituted by 4- to 6-membered heterocyclic groups having 1-2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclic group is independently unsubstituted or substituted by 1, 2, or 3 halogens;

[0371] Or two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic carbon ring having 3 to 6 ring atoms, wherein the spirocyclic carbon ring is unsubstituted or substituted by 1 or 2 substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups;

[0372] Or two Rs 6 They combine with the carbon atoms to which they are attached to form one or two independent atoms selected from N, O, and S(O). qA spirocyclic heterocycle with a cyclic heteroatom, wherein the spirocyclic heterocycle is not substituted or is substituted by one or two halogens, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C3-C6 cycloalkyl.

[0373] q is 0, 1, or 2;

[0374] R 7 It is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a Aryl group, having 1-2 independently selected from N, O, and S(O) q A 4- to 6-membered heterocyclic group with heteroatoms, or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the C1-C6 alkyl group is unsubstituted or has 1 to 2 heteroatoms independently selected from N, O, and S(O). q The heteroatom is substituted with a 4- to 6-membered heterocyclic group, wherein the 4- to 6-membered heterocyclic group is not substituted or is substituted with 1, 2 or 3 halogens, and further wherein the aryl or heteroaryl group is not substituted or is substituted with a halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C5 cycloalkyl, or halogenated C3-C5 cycloalkyl.

[0375] R 7a It is hydrogen or C1-C6 alkyl;

[0376] R 9 It is H;

[0377] m is 0, 1, 2, or 3;

[0378] n is 0, 1, 2, or 3;

[0379] p is 0.

[0380] Example 77 provides a compound having formula (I) as described in any one of Examples 1 to 76, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof, wherein:

[0381] W is NR 7 ;

[0382] R is hydrogen; or a hydroxyl group (C3-C6 cycloalkyl group);

[0383] R 1It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, halo-C1-C6 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy, hydroxyl-C1-C6 alkyl, hydroxyl-C3-C6 cycloalkyl;

[0384] Preferred elements include hydrogen, halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, and halogenated C1-C6 alkyl.

[0385] More preferably hydrogen, halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C1-C6 alkyl;

[0386] More preferably hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C1-C6 alkyl;

[0387] R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkoxy is unsubstituted or substituted by 1, 2, or 3 halogen substituents;

[0388] Preferably, it is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen;

[0389] More preferably, C1-C3 alkyl groups, or halogens;

[0390] R 3 It is hydrogen;

[0391] R 4 It is a phenyl group, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N and O, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0392] Preferably, it is a phenyl group, or a 5- to 6-membered heteroaryl group having one or two independent cyclic heteroatoms selected from N and O, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0393] More preferably, a phenyl group, or a 5- to 6-membered heteroaryl group having one or two independently selected N-cyclic heteroatoms, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0394] R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, -C(O)N(R) 5b)2 and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace;

[0395] Preferred hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, -C(O)N(R) 5b )2 and a 5-membered heteroaryl group having 1-4 independently selected heteroatoms from N, wherein the alkyl and heteroaryl groups are unsubstituted or replaced by 1 R 5a replace;

[0396] More preferably hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, -C(O)N(R) 5b )2 and a 5-membered heteroaryl group having 1-3 independently selected heteroatoms from N, wherein the alkyl and heteroaryl groups are unsubstituted or replaced by 1 R 5a replace;

[0397] Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl; preferably hydroxyl;

[0398] Each R 5b Independently selected from hydrogen;

[0399] R 5 Preferably selected from hydrogen, -CO2H, C1-C6 alkyl, hydroxyC3-C6 cycloalkyl, hydroxyC3-C6 alkyl, cyano, -CONH2, pyrazolyl, triazolyl, and tetrazolyl, wherein the pyrazolyl, triazolyl, and tetrazolyl are unsubstituted or substituted by one C1-C6 alkyl group;

[0400] R 7 It is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a Aryl group, having 1-2 independently selected from N, O, and S(O) q A 4- to 6-membered heterocyclic group with heteroatoms, or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the C1-C6 alkyl group is unsubstituted or has 1 to 2 heteroatoms independently selected from N, O, and S(O). qThe heteroatom is substituted with a 4- to 6-membered heterocyclic group, wherein the 4- to 6-membered heterocyclic group is not substituted or is substituted with 1, 2 or 3 halogens, and further wherein the aryl or heteroaryl group is not substituted or is substituted with a halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C5 cycloalkyl, or halogenated C3-C5 cycloalkyl.

[0401] Preferred alkyl groups include C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C2-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl, C1-C3 alkyl, halogenated C3-C6 cycloalkyl, halogenated C1-C6 alkoxy, and -COR. 7a A 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N and O, or a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from N, O and S, wherein the 4- to 6-membered heterocyclic group is not substituted or is substituted by 1, 2 or 3 halogens, further wherein the heteroaryl group is not substituted or is substituted by halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C5 cycloalkyl, or halogenated C3-C5 cycloalkyl;

[0402] More preferably, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C2-C6 alkyl, halogenated C3-C6 cycloalkyl C1-C3 alkyl, halogenated C3-C6 cycloalkyl, halogenated C1-C6 alkoxy C1-C6 alkyl, -COR 7a , or a 4- to 6-membered heterocyclic group having one heteroatom independently selected from O, or a 5- to 6-membered heteroaryl group having one heteroatom independently selected from O;

[0403] R 7a It is a C1-C6 alkyl group;

[0404] Each R 8 Independently selected from hydrogen and halogens;

[0405] R 9 It is H or D; H is preferred.

[0406] m can be 1, 2, or 3; preferably 1 or 2;

[0407] n is 1, 2, or 3; and

[0408] p can be 0, 1, 2, or 3; 0 is preferred.

[0409] Example 78 provides a compound having formula (I) as described in any one of Examples 1 to 77, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof, wherein:

[0410] W is C(R) 6 )2;

[0411] R is hydrogen;

[0412] R 1 It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, halo-C1-C6 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy, hydroxyl-C1-C6 alkyl, hydroxyl-C3-C6 cycloalkyl;

[0413] Preferred elements include hydrogen, halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, and halogenated C1-C6 alkyl.

[0414] More preferably hydrogen, halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, and halogenated C1-C6 alkyl;

[0415] More preferably, hydrogen, halogen, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0416] R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkoxy is unsubstituted or substituted by 1, 2, or 3 halogen substituents;

[0417] Preferably, it is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen;

[0418] More preferably, C1-C3 alkyl groups, or halogens;

[0419] R 3 It is hydrogen;

[0420] R 4 It is a phenyl group, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N and O, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0421] Preferably, it is a phenyl group, or a 5- to 6-membered heteroaryl group having one or two independent cyclic heteroatoms selected from N and O, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0422] More preferably, a phenyl group, or a 5- to 6-membered heteroaryl group having one or two independently selected N-cyclic heteroatoms, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0423] R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, -C(O)N(R) 5b)2 and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace;

[0424] Preferred hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, -C(O)N(R) 5b )2 and a 5-membered heteroaryl group having 1-4 independently selected heteroatoms from N, wherein the alkyl and heteroaryl groups are unsubstituted or replaced by 1 R 5a replace;

[0425] More preferably hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, -C(O)N(R) 5b )2 and a 5-membered heteroaryl group having 1-3 independently selected heteroatoms from N, wherein the alkyl and heteroaryl groups are unsubstituted or replaced by 1 R 5a replace;

[0426] Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl; preferably hydroxyl;

[0427] Each R 5b Independently selected from hydrogen;

[0428] R 5 Preferably selected from hydrogen, -CO2H, C1-C6 alkyl, hydroxyC3-C6 cycloalkyl, hydroxyC3-C6 alkyl, cyano, -CONH2, pyrazolyl, triazolyl, and tetrazolyl, wherein the pyrazolyl, triazolyl, and tetrazolyl are unsubstituted or substituted by one C1-C6 alkyl group;

[0429] Each R 6 The heterocyclic group is independently selected from hydrogen, halogen, hydroxyl, C3-C6 cycloalkyl-C1-C4 alkylamino, halo-C3-C6 cycloalkyl-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is either unsubstituted or substituted with a 4- to 6-membered heterocyclic group having 1 to 2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclic group is either unsubstituted or substituted with 1, 2, or 3 halogens;

[0430] Preferably selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl-C1-C6 alkoxy, and halo-C1-C6 alkoxy;

[0431] Preferably selected from C1-C6 alkyl, C3-C6 cycloalkyl C1-C4 alkylamino, halo-C3-C6 cycloalkyl C1-C4 alkylamino, halo-C1-C6 alkyl, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and 4- to 6-membered heterocyclic groups having 1-2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is unsubstituted or substituted by 4- to 6-membered heterocyclic groups having 1-2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclic group is independently unsubstituted or substituted by 1, 2, or 3 halogens;

[0432] Or two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic carbon ring having 3 to 6 ring atoms, preferably 3 to 4 ring atoms, wherein the spirocyclic carbon ring is unsubstituted or substituted by 1 or 2 substituents selected from halogens;

[0433] Or two Rs 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O;

[0434] Preferably, two R 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O, wherein the spirocyclic heterocycle has three to six cyclic atoms;

[0435] Preferably, two R 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles with one cyclic heteroatom selected from O;

[0436] Preferably, two R 6 They combine with the carbon atoms to which they are attached to form a spirocyclic heterocycle having one cyclic heteroatom selected from O, wherein the spirocyclic heterocycle has 5 cyclic atoms;

[0437] Each R 8 Independently selected from hydrogen and halogens;

[0438] R 9 It is H or D; H is preferred.

[0439] m can be 1, 2, or 3; preferably 1 or 2;

[0440] n is 1, 2, or 3; and

[0441] p can be 0, 1, 2, or 3; 0 is preferred.

[0442] In the embodiments, the present invention provides compounds having formula (I) selected from the compounds in Table 1.

[0443] Table 1

[0444]

[0445] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0446] In the embodiments, the present invention provides compounds having formula (I) selected from the compounds in Table 2.

[0447] Table 2

[0448]

[0449] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0450] In the embodiments, compounds having formula (I) are selected from the group consisting of:

[0451] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0452] 4-(4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0453] 4-(4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0454] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0455] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-ethylpiperidin-3-yl)benzoic acid;

[0456] 4-(5-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylazacycloheptane-4-yl)benzoic acid;

[0457] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylazacycloheptane-3-yl)benzoic acid;

[0458] 5,7-Dimethyl-4-((4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)oxy)-1H-indole;

[0459] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzylnitrile;

[0460] 4-((3-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0461] 2-(4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)prop-2-ol;

[0462] 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0463] 5,7-Dimethyl-4-((1-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-1H-indole;

[0464] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0465] 4-(1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0466] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid;

[0467] 4-(1-(3,3-difluorocyclobutyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0468] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(3-fluorocyclobutyl)piperidin-3-yl)benzoic acid;

[0469] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)benzoic acid;

[0470] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid;

[0471] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid;

[0472] 4-(4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)benzoic acid;

[0473] 4-(4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0474] 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)azacycloheptane-3-yl)benzoic acid;

[0475] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)azacycloheptane-3-yl)benzoic acid;

[0476] 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-(2-fluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0477] 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-(2,2-difluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0478] 1-(3-(4-(1H-pyrazol-1-yl)phenyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-1-yl)ethyl-1-one;

[0479] 4-((3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0480] 4-((3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0481] 1-(4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)cycloprop-1-ol;

[0482] 4-((1-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0483] 4-(4-((5-fluoro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0484] 4-(4-((7-chloro-5-methyl-1H-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)benzoic acid;

[0485] 4-(1-((2,2-difluorocyclopropyl)methyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0486] 4-(1-(4,4-difluorobutyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0487] 4-(4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)benzoic acid;

[0488] 4-(4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(3,3-difluoropropyl)piperidin-3-yl)benzoic acid;

[0489] 4-(4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid;

[0490] 4-((1-(3,3-difluoropropyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0491] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)benzoic acid;

[0492] 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpyrrolidine-3-yl)benzoic acid;

[0493] 4-(4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylazacycloheptane-3-yl)benzoic acid;

[0494] 4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid,

[0495] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0496] In the embodiments, compounds having formula (I) are selected from the group consisting of:

[0497] 4-(2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0498] 4-(8-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-oxaspiro[4.5]dec-7-yl)benzoic acid;

[0499] 4-(2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0500] 4-(2-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0501] 4-(2-((5-fluoro-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0502] 4-(5-methoxy-2-((7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid;

[0503] 4-(2-((5,7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid;

[0504] 4-(2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid;

[0505] 4-(2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid;

[0506] 4-(2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)cyclohexyl)benzoic acid;

[0507] 4-(2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid;

[0508] 4-(6-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[2.5]oct-5-yl)benzoic acid;

[0509] 4-(2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzamide;

[0510] 4-(2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid;

[0511] 4-(2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid;

[0512] 4-(5-(difluoromethoxy)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid; and

[0513] 4-(7-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[3,5]non-6-yl)benzoic acid,

[0514] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0515] In another embodiment, the compound having formula (I) is selected from the group consisting of:

[0516] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0517] 4-((3S,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0518] 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0519] 4-((3S,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0520] 4-((3R,4R)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0521] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0522] 4-((3S,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0523] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-ethylpiperidin-3-yl)benzoic acid;

[0524] 4-((4S,5R)-5-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylazacycloheptane-4-yl)benzoic acid;

[0525] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylazacycloheptane-3-yl)benzoic acid;

[0526] Racemic 5,7-dimethyl-4-(((3S) 4R )-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)oxy)-1H-indole;

[0527] 5,7-Dimethyl-4-(((3S,4R)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)oxy)-1H-indole;

[0528] 5,7-Dimethyl-4-(((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)oxy)-1H-indole;

[0529] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzylnitrile;

[0530] 4-(((3R,4R)-3-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0531] 2-(4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)prop-2-ol;

[0532] 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0533] 5,7-Dimethyl-4-(((3R,4R)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-1H-indole;

[0534] 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0535] 4-((3R,4R)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0536] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid;

[0537] 4-((3R,4R)-1-(3,3-difluorocyclobutyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0538] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-((1r,3R)-3-fluorocyclobutyl)piperidin-3-yl)benzoic acid;

[0539] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)benzoic acid;

[0540] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid;

[0541] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid;

[0542] 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)benzoic acid;

[0543] 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0544] 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)azacycloheptane-3-yl)benzoic acid;

[0545] 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)azacycloheptane-3-yl)benzoic acid;

[0546] 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(2-fluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0547] 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(2,2-difluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0548] Racemic 1-((3R) 4R )-3-(4-(1H-pyrazol-1-yl)phenyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-1-yl)ethyl-1-one;

[0549] 1-((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-1-yl)ethyl-1-one;

[0550] 1-((3S,4S)-3-(4-(1H-pyrazol-1-yl)phenyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-1-yl)ethyl-1-one;

[0551] Racemic 4-(((3R) 4R )-3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0552] 4-(((3R,4R)-3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0553] 4-(((3S,4S)-3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0554] Racemic 4-(((3R) 4R )-3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0555] 4-(((3R,4R)-3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0556] 4-(((3S,4S)-3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0557] 1-(4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)cycloprop-1-ol;

[0558] 4-(((3R,4R)-1-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0559] 4-((3R,4R)-4-((5-fluoro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid;

[0560] 4-((3R,4R)-4-((7-chloro-5-methyl-1H-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)benzoic acid;

[0561] 4-((3R,4R)-1-((2,2-difluorocyclopropyl)methyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0562] 4-((3R,4R)-1-(4,4-difluorobutyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid;

[0563] 4-((3R,4R)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)benzoic acid;

[0564] 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(3,3-difluoropropyl)piperidin-3-yl)benzoic acid;

[0565] 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid;

[0566] 4-(((3R,4R)-1-(3,3-difluoropropyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole;

[0567] 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)benzoic acid;

[0568] 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpyrrolidine-3-yl)benzoic acid;

[0569] 4-((3R,4R)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylazacycloheptane-3-yl)benzoic acid;

[0570] 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;

[0571] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0572] In another embodiment, the compound having formula (I) is selected from the group consisting of:

[0573] 4-((1S,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0574] 4-((1R,2S,5R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0575] racemic 4-((1S) ,2R 5R )-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0576] 4-((1S,2R,5R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0577] 4-((1R,2S,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0578] racemic 4-((1S) ,2S 5S )-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0579] 4-((1S,2S,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0580] 4-((1R,2R,5R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0581] racemic 4-((1S) ,2S 5R )-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0582] 4-((1S,2S,5R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0583] 4-((1R,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0584] racemic 4-((7S) ,8R )-8-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-oxaspiro[4.5]dec-7-yl)benzoic acid;

[0585] 4-((5R,7S,8R)-8-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-oxaspiro[4.5]dec-7-yl)benzoic acid;

[0586] 4-((5S,7S,8R)-8-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-oxaspiro[4.5]dec-7-yl)benzoic acid;

[0587] 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0588] 4-((1S,2R,5S)-2-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0589] 4-((1S,2R,5S)-2-((5-fluoro-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;

[0590] 4-((1S,2R,5S)-5-methoxy-2-((7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid;

[0591] racemic 4-((1S) ,2R )-2-((5,7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid;

[0592] 4-((1S,2R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid;

[0593] 4-((1R,2S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid;

[0594] 4-((1S,2R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid;

[0595] 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid;

[0596] 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)cyclohexyl)benzoic acid;

[0597] 4-((1S,2R,5R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid;

[0598] 4-((1S,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid;

[0599] 4-((5S,6R)-6-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[2.5]oct-5-yl)benzoic acid;

[0600] 4-((1S,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzamide;

[0601] 4-((1S,2R)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid;

[0602] racemic 4-((1S) ,2R 5S )-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid;

[0603] 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid;

[0604] 4-((1S,2R,5R)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid;

[0605] racemic 4-((1S) ,2R 5S )-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid;

[0606] 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid;

[0607] 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid;

[0608] 4-((6S,7R)-7-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[3,5]non-6-yl)benzoic acid,

[0609] Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

[0610] In the embodiments, the present invention provides tautomers, diastereomers, or enantiomers of compounds having formula (I) in any of the embodiments described herein.

[0611] On the one hand, this paper provides compounds having formula (I).

[0612]

[0613] (I)

[0614] Or its pharmaceutically acceptable salt;

[0615] in:

[0616] W is O, C(R) 6 )2, or NR 7 ;

[0617] R is hydrogen, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, or hydroxy-C1-C4 alkyl;

[0618] R 1 It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy, hydroxyl-C1-C6 alkyl, hydroxyl-C3-C6 cycloalkyl, amino-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkoxy, or C3-C6 cycloalkyl-C1-C6 alkoxy;

[0619] R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkoxy is unsubstituted or substituted by 1, 2, or 3 halogen substituents;

[0620] R 3 It is hydrogen, halogen, or cyano;

[0621] R 4 It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0622] R 5 Selected from -CO2R 5b C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, -CH2CO2R 5b -C(O)NHSO2C1-C4 alkyl, -SO2NHC(O)C1-C4 alkyl, -SO2C1-C4 alkyl, cyano, hydroxyl, halogen, and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms.5a replace;

[0623] Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H;

[0624] Each R 5b Independently selected from hydrogen and C1-C5 alkyl groups;

[0625] Each R 6 It is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy;

[0626] Or two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic carbon ring having 3 to 6 ring atoms, wherein the spirocyclic carbon ring is unsubstituted or substituted by 1 or 2 substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups;

[0627] Or two Rs 6 They combine with the carbon atoms to which they are attached to form one or two independent atoms selected from N, O, and S(O). q A spirocyclic heterocycle with a cyclic heteroatom, wherein the spirocyclic heterocycle is not substituted or is substituted by one or two halogens, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C3-C6 cycloalkyl.

[0628] q is 0, 1, or 2;

[0629] R 7 It is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a Aryl group, having 1-2 independently selected from N, O, and S(O) q A 4- to 6-membered heterocyclic group with heteroatoms, or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the C1-C6 alkyl group is unsubstituted or has 1 to 2 heteroatoms independently selected from N, O, and S(O). q The heteroatom is substituted with a 4- to 6-membered heterocyclic group, wherein the 4- to 6-membered heterocyclic group is not substituted or is substituted with 1, 2 or 3 halogens, and further wherein the aryl or heteroaryl group is not substituted or is substituted with a halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C5 cycloalkyl, or halogenated C3-C5 cycloalkyl.

[0630] R 7a It is hydrogen or C1-C6 alkyl;

[0631] Each R 8 It is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy;

[0632] R 9 It is H, D, or T;

[0633] m is 0, 1, 2, or 3;

[0634] n is 0, 1, 2, or 3;

[0635] The premise is that neither m nor n is 0; and

[0636] p is 0, 1, 2, or 3.

[0637] In an embodiment,

[0638] W is C(R) 6 )2 or NR 7 ;

[0639] R is hydrogen;

[0640] R 1 It is a halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, or amino C1-C6 alkyl;

[0641] R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen;

[0642] R 3 It is hydrogen, halogen, or cyano;

[0643] R 4 It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0644] R 5 Selected from -CO2R 5b C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, cyano, hydroxyl, halogen, and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5areplace;

[0645] Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H;

[0646] R 5b Selected from hydrogen and C1-C5 alkyl groups;

[0647] Each R 6 Independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy; or two R 6 They combine with the attached carbon atoms to form a spirocyclic carbide ring having 3 to 6 ring atoms, wherein the spirocyclic carbide ring is unsubstituted or substituted by one or two substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or two R groups. 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O;

[0648] R 7 It is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, -COR 7a or C3-C6 cycloalkyl;

[0649] R 7a It is a C1-C6 alkyl group;

[0650] Each R 8 It is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy;

[0651] R 9 It is H, D, or T;

[0652] m is 1, 2, or 3;

[0653] n is 1, 2, or 3; and

[0654] p is 0, 1, or 2.

[0655] In another embodiment,

[0656] W is C(R) 6 )2 or NR 7 ;

[0657] R is hydrogen;

[0658] R 1It is a halogen, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group;

[0659] R 2 It is a C1-C3 alkyl group;

[0660] R 3 It is hydrogen;

[0661] R 4 It is a phenyl group or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0662] R 5 Selected from -CO2R 5b C1-C6 alkyl, cyano, and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or R 5a replace;

[0663] R 5a It is a hydroxyl group or a C1-C6 alkyl group;

[0664] R 5b It is hydrogen or C1-C3 alkyl;

[0665] Each R 6 Each time it appears, it is independently selected from hydrogen and C1-C6 alkoxy groups; or two R groups. 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O;

[0666] R 7 It is a C1-C6 alkyl group, -COR 7a Or halogenated C1-C6 alkyl;

[0667] R 7a It is a C1-C6 alkyl group;

[0668] Each R 8 Independently selected from hydrogen and C1-C6 alkyl groups;

[0669] R 9 It is H;

[0670] m is 1 or 2;

[0671] n is 1, 2, or 3; and

[0672] p is 0, 1, or 2.

[0673] In another embodiment,

[0674] W is O, C(R) 6 )2, or NR7 ;

[0675] R is hydrogen, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, or hydroxy-C1-C4 alkyl;

[0676] R 1 It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy, hydroxyl-C1-C6 alkyl, hydroxyl-C3-C6 cycloalkyl, amino-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkoxy, or C3-C6 cycloalkyl-C1-C6 alkoxy;

[0677] R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkoxy is unsubstituted or substituted by 1, 2, or 3 halogen substituents;

[0678] R 3 It is hydrogen, halogen, or cyano;

[0679] R 4 It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0680] R 5 Selected from -CO2R 5b C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, -CH2CO2R 5b -C(O)NHSO2C1-C4 alkyl, -SO2NHC(O)C1-C4 alkyl, -SO2C1-C4 alkyl, cyano, hydroxyl, halogen, and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace;

[0681] Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H;

[0682] Each R 5b Independently selected from hydrogen and C1-C5 alkyl groups;

[0683] Each R 6Independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy; or two R 6 They combine with the attached carbon atoms to form a spirocyclic carbide ring having 3 to 6 ring atoms, wherein the spirocyclic carbide ring is unsubstituted or substituted by one or two substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or two R groups. 6 They combine with the carbon atoms to which they are attached to form one or two independent atoms selected from N, O, and S(O). q A spirocyclic heterocycle with a cyclic heteroatom, wherein the spirocyclic heterocycle is not substituted or is substituted by one or two halogens, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C3-C6 cycloalkyl.

[0684] q is 0, 1, or 2;

[0685] R 7 It is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, aryl, 4 to 6 members, independently selected from N, O and S(O). q A heterocyclic group with 1-2 heteroatoms or a 5- to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from N, O, and S, wherein the C1-C6 alkyl group is unsubstituted or 4- to 6-membered heteroaryl group with 1-4 heteroatoms independently selected from N, O, and S(O). q The heterocyclic group with 1-2 heteroatoms is substituted, wherein the 4- to 6-membered heterocyclic group is not substituted or is substituted by 1, 2 or 3 halogens, and further wherein the aryl or heteroaryl group is not substituted or is substituted by halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C5 cycloalkyl, or halogenated C3-C5 cycloalkyl.

[0686] Each R 8 It is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy;

[0687] R 9 It is H, D, or T;

[0688] m is 0, 1, 2, or 3;

[0689] n is 0, 1, 2, or 3;

[0690] The premise is that neither m nor n is 0; and

[0691] p is 0, 1, 2, or 3.

[0692] In another embodiment,

[0693] W is C(R) 6 )2 or NR 7 ;

[0694] R is hydrogen;

[0695] R 1 It is a halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, or amino C1-C6 alkyl;

[0696] R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen;

[0697] R 3 It is hydrogen, halogen, or cyano;

[0698] R 4 It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0699] R 5 Selected from -CO2R 5b C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, cyano, hydroxyl, halogen, and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace;

[0700] Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H;

[0701] R 5b Selected from hydrogen and C1-C5 alkyl groups;

[0702] Each R 6 Independently selected from hydrogen, halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy; or two R 6They combine with the attached carbon atoms to form a spirocyclic carbide ring having 3 to 6 ring atoms, wherein the spirocyclic carbide ring is unsubstituted or substituted by one or two substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; or two R groups. 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O;

[0703] R 7 It is hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C2-C6 alkyl, or C3-C6 cycloalkyl;

[0704] Each R 8 It is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy;

[0705] R 9 It is H;

[0706] m is 1, 2, or 3;

[0707] n is 1, 2, or 3; and

[0708] p is 0, 1, or 2.

[0709] In another embodiment,

[0710] W is C(R) 6 )2 or NR 7 ;

[0711] R is hydrogen;

[0712] R 1 It is a halogen, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group;

[0713] R 2 It is a C1-C3 alkyl group;

[0714] R 3 It is hydrogen;

[0715] R 4 It is a phenyl group or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace;

[0716] R 5 Selected from -CO2R 5bC1-C6 alkyl, cyano, and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or R 5a replace;

[0717] R 5a It is a hydroxyl group or a C1-C6 alkyl group;

[0718] R 5b It is hydrogen or C1-C3 alkyl;

[0719] Each R 6 Each time it appears, it is independently selected from hydrogen and C1-C6 alkoxy groups; or two R groups. 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O;

[0720] R 7 It is a C1-C6 alkyl or a halo-C1-C6 alkyl;

[0721] Each R 8 Independently selected from hydrogen and C1-C6 alkyl groups;

[0722] R 9 It is H;

[0723] m is 1 or 2;

[0724] n is 1, 2, or 3; and

[0725] p is 0, 1, or 2.

[0726] In another embodiment, W is NR 7 In another embodiment, W is C(R) 6 )2.

[0727] In another embodiment, R is hydrogen.

[0728] In another embodiment, R 1 It is a halogen, a C1-C3 alkyl group, or a C3 cycloalkyl group. In another embodiment, R 1 It is a halogen. In another embodiment, R 1 It is a C1-C3 alkyl group. In another embodiment, R 1 It is a C3 cycloalkyl group.

[0729] In another embodiment, R 2 It is a methyl group.

[0730] In another embodiment, R 3 It is hydrogen.

[0731] In another embodiment, R 4It is a phenyl group or a 5-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 Replacement. In another embodiment, R 4 It is a phenyl group, wherein the phenyl or heteroaryl group is not substituted or is R-substituted. 5 Replacement. In yet another embodiment, R 4 It is a 5-membered heteroaryl group having 1, 2, or 3 independent cyclic heteroatoms selected from N, O, and S, wherein the heteroaryl group is unsubstituted or replaced by R. 5 Replacement. In yet another embodiment, R 4 It is phenyl or pyrazolyl, wherein the phenyl or pyrazolyl group is not substituted or is R 5 replace.

[0732] In another embodiment, R 5 The group is selected from -CO2H, C1-C6 alkyl, cyano, and 5-membered heteroaryl groups having 1-4 heteroatoms independently selected from N, O, and S, wherein the alkyl group is unsubstituted or substituted with a hydroxyl group. In another embodiment, R 5 It is -CO2H. In yet another embodiment, R 5 It is cyano. In another embodiment, R 5 It is a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from N, O, and S. In the examples, R 5 It is a C1-C6 alkyl group, wherein the alkyl group is either unsubstituted or substituted with a hydroxyl group.

[0733] In another embodiment, each R 6 Independently selected from hydrogen and C1-C3 alkoxy groups. In yet another embodiment, each R 6 It is hydrogen. In another embodiment, each R 6 It is independently selected from C1-C3 alkoxy groups.

[0734] In the embodiment, two R 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O. In another embodiment, the two R... 6 They combine with the attached carbon atoms to form 4-6 membered spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O. In yet another embodiment, the two R... 6 They combine with the carbon atoms to which they are attached to form spirocyclic carbon rings with 3 to 6 ring atoms.

[0735] In another embodiment, R 7 It is methyl, -COR 7a Or halogenated C1-C3 alkyl. In the examples, R 7It is a methyl or halogenated C1-C3 alkyl group. In another embodiment, R 7 It is methyl. In yet another embodiment, R 7 It is a halogenated C1-C3 alkyl group. In yet another embodiment, R 7 It is a -C(O)C1-C3 alkyl group.

[0736] In another embodiment, each R 8 Independently selected from hydrogen and C1-C6 alkyl groups. In another embodiment, each R 8 It is hydrogen.

[0737] In another embodiment, R 9 It's H.

[0738] On the other hand, this article provides a pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of the foregoing embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0739] Treatment

[0740] In one respect, this article provides a method for treating or preventing a disease or disorder in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0741] On the other hand, this article provides a method for modulating complement bypass pathway activity in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0742] On another aspect, this article provides a method for treating a disease or disorder mediated by complement activation, particularly by complement bypass pathway activation, in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0743] On the other hand, this article provides a method for treating a disease or disorder affected by complement bypass pathway regulation, the method comprising administering to the subject a therapeutically effective amount of the compound provided herein, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0744] In one respect, this article provides a method for treating a disease or disorder associated with dysregulation of the complement bypass pathway, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0745] On the other hand, this article provides a method for inhibiting the expression or activity of complement factor B, which includes administering to the subject a compound provided herein, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0746] In embodiments of the present invention, these diseases or disorders are selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal chorioretinitis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-chorioretinitis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, non-arterial ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy / familial dominant drusen, and Sorsby fundus dystrophy. dystrophy), late-onset macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammation, neurological disorders including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRMS), stroke, Guillain-Barré 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 disorder, schizophrenia, drug-induced neurotoxicity, aquaporin-4 IgG seropositive neuromyelitis spectrum disorder (NMOSD), cerebral amyloid angiopathy, cerebral malaria, Charcot-Marie-Tooth disease, chemotherapy-induced peripheral neuropathy, chronic inflammatory demyelinating polyneuropathy, frontotemporal dementia, hereditary demyelinating neuropathy caused by CD59 p.Cys89Tyr mutation, Lewy body dementia, multiple system atrophy (MSA), myelin oligodendrocyte glial antibody-associated disease (MOGAD), oculoclonus-myoclonus syndrome (OMS), and progressive supranuclear palsy;Inappropriate or undesirable complement activation disorders, such as hemodialysis complications, hyperacute allogeneic transplant rejection, xenotransplant rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membrane proliferative 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), periodontitis, CD55 deficiency with complement overactivation, vasculopathy, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease. Diseases, neuromyelitis optica (NMO), IgA vasculitis (formerly known as allergic purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), myocarditis, post-ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis; COVID-19, immune complex disorders and autoimmune diseases. Autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergic reactions, bronchoconstriction, allergic pneumonia, parasitic diseases, Goodpasture's syndrome Syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Buerger's vasculitis, cryoglobulinemia, Kawasaki disease, aortitis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenic purpura, cold agglutinin disease, warm antibody-type autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, and Graves' disease.

[0747] On another aspect, this article provides a method for treating age-related macular degeneration, comprising administering to a subject in need an effective amount of a composition comprising the compound provided herein, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0748] On the other hand, this article provides the compounds provided herein, or their pharmaceutically acceptable salts or stereoisomers, for use as medicines.

[0749] In one respect, this article provides the compounds provided herein, or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, for use in subjects in need of inhibiting the expression or activity of complement factor B.

[0750] On the other hand, this article provides for the use of the compounds provided herein, or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, in the treatment of diseases or disorders associated with dysregulation of the complement bypass pathway.

[0751] In one respect, this article provides for the use of the compounds provided herein, or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, in the manufacture of medicaments for treating diseases or disorders mediated by complement activation or complement bypass pathway activation.

[0752] On the other hand, this article provides for the use of the compounds provided herein, or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, in the manufacture of medicaments for the treatment of diseases or disorders.

[0753] On another aspect, this article provides for the use of the compounds provided herein, or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, for the treatment of diseases or disorders mediated by complement activation or complement bypass pathway activation.

[0754] In another embodiment, this document provides the use of the compounds provided herein, or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, for the treatment of diseases or disorders affected by complement bypass pathway regulation.

[0755] In one respect, this article provides for the use of the compounds provided herein, or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, for the treatment of diseases or disorders.

[0756] On another aspect, this article provides the use of the compounds provided herein, or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, for the treatment of age-related macular degeneration.

[0757] On the other hand, this article provides a pharmaceutical combination comprising the compounds provided herein, or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, and one or more additional therapeutic agents.

[0758] Depending on the choice of starting materials and procedures, compounds may exist as one of the possible isomers or as mixtures thereof (e.g., as pure optical isomers or as mixtures of isomers, such as racemic and diastereomeric mixtures), depending on the number of asymmetric centers. This disclosure is intended to include all such possible isomers, including racemic mixtures, enantiomer-enriched mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a di- or tri-substituted cycloalkyl group, one or more cycloalkyl substituents may have cis or trans configurations. This disclosure includes cis and trans configurations of substituted cycloalkyl groups (e.g., cyclobutyl) and mixtures thereof. All tautomeric forms are also intended to be included. In particular, when the heteroaryl ring containing N as a ring atom is a 2-pyridinone, it includes, for example, tautomers in which the carbonyl group is depicted as a hydroxyl group (e.g., 2-hydroxypyridine).

[0759] The separation of cis and trans isomers can be achieved using methods known to those skilled in the art, such as chromatography using tools like HPLC (high performance liquid chromatography), thin-layer chromatography, SFC (supercritical fluid chromatography), GC (gas chromatography), or recrystallization techniques.

[0760] Isotope-labeled compounds

[0761] Any formulas given herein are intended to represent both the unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are replaced by atoms having a chosen atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 18 O、 15 N、 18 F, 17 O、 18 O、 35 S, 36 Cl、 123 I, 124 I, 125I. This disclosure includes compounds labeled with various isotopes as defined herein, such as those containing radioactive isotopes (e.g., 3 H and 14 Those compounds in (C), or those containing non-radioactive isotopes (such as...) 2 H and 13 Those compounds in C). Such isotopically labeled compounds can be used for metabolic studies (using...). 14 C) Reaction kinetic studies (e.g., using...) 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or for use in the patient's radiation therapy. In particular, 18 Compound F may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds having formula (I) or its subforms can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples and general schemes, using an appropriate isotopically labeled reagent instead of an unlabeled previously used reagent.

[0762] In addition, heavier isotopes, especially deuterium (i.e., 2 Substitution with H or D can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life, reduced dose requirement, or improved therapeutic index). It should be understood that, in this context, deuterium is considered to be a substituent in a compound having any of formula (I) or its subformulas. The concentration of such a heavier isotope (especially deuterium) can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotope abundance and the natural abundance of a particular isotope. If the substituents in the disclosed compounds indicate deuterium, then such compounds have an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping on each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0763] Pharmaceutically acceptable solvates according to this disclosure include those in which the crystallization solvent can be replaced by an isotope, such as D2O, d6-acetone, and d6-DMSO.

[0764] Compounds disclosed herein containing groups capable of acting as donors and / or acceptors of hydrogen bonds can form cocrystals with suitable cocrystal forming agents. These cocrystals can be prepared from compounds having formula (I) or its sub-formulas using known cocrystal forming procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting the compounds provided herein with a cocrystal forming agent in solution and separating the resulting cocrystal. Suitable cocrystal forming agents include those described in WO 2004 / 078163.

[0765] Unless otherwise indicated herein or otherwise obviously contradicted by the context, all methods described herein can be performed in any suitable order. The application of any and all instances or exemplary language (e.g., "such") provided herein is intended only to better illustrate this disclosure and does not limit the scope of this disclosure as otherwise claimed.

[0766] Any asymmetric center (e.g., carbon, etc.) of one or more compounds disclosed herein can exist in a racemic or enantiomerically enriched form, for example, (R)-, (S)-, or (R,S)- configuration. In some embodiments, such as as a mixture of enantiomers, each asymmetric center exists in an enantiomer excess of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. In some embodiments, for example, in an enantiomer-enriched form, each asymmetric center is present with an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. Therefore, the compounds disclosed herein may exist as racemic mixtures or enantiomer-enriched forms, or as enantiomers, or as mixtures of diastereomers.

[0767] In the embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided in an amount of at least 90% enantiomer excess, at least 95% enantiomer excess, or at least 99% enantiomer excess.

[0768] In the embodiments, compounds of formula (I) or pharmaceutically acceptable salts thereof are provided in an excess of at least 90% diastereomer, at least 95% diastereomer, or at least 99% diastereomer.

[0769] In the formula of this application, in C-sp3 The term "on" "Indicates absolute stereochemistry, (R) or (S). In the formula of this application, in C-sp..." 3 The term "on" "Indicates absolute stereochemistry, (R) or (S). In the formula of this application, in C-sp..." 3 The term "on" "" indicates a covalent bond, where the stereochemistry of the bond is not defined. This means that in C-sp 3 The term "on" "Including the (S) configuration or (R) configuration of the corresponding chiral center. In addition, mixtures may also exist. Therefore, this disclosure covers mixtures of stereoisomers, such as mixtures of enantiomers like racemates, and / or mixtures of diastereomers."

[0770] To avoid ambiguity, for any R group, when describing the structure of a compound with an undefined stereochemistry, such as by using a bond ( This indicates that the asymmetric center has an (R)- or (S)- configuration, or exists as a mixture thereof, and is thus stated.

[0771] To avoid ambiguity, in any form of this application, when R 5 When the group is shown as being connected to ring A, this means that one or more R 5 Groups can be bonded by carbon atoms or heteroatoms such as nitrogen.

[0772] To avoid any ambiguity, the compound structures shown in this article can exist in their zwitterionic form when appropriate.

[0773] Therefore, as used herein, the compounds disclosed herein may be in the form of one of the following possible stereoisomers, rotational isomers, tautomers, tautomers or mixtures thereof, for example, in the form of substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers, racemates or mixtures thereof.

[0774] Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, or racemates based on the physicochemical differences of the components, for example by chromatography and / or fractional crystallization.

[0775] Any racemic mixture of the compounds or intermediates of this disclosure can be resolved into optical isomers (enantiomers) by known methods, for example, by separating their diastereomer salts obtained with optically active acids or bases, releasing optically active acidic or basic compounds. In particular, the compounds of this disclosure can thus be resolved into their optical enantiomers using a basic moiety, for example, by fractional crystallization with salts formed from optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic compounds or racemic intermediates of this disclosure can also be resolved by chiral chromatography (e.g., high-performance liquid chromatography (HPLC) using chiral adsorbents).

[0776] Furthermore, the compounds disclosed herein (including their salts) can also be obtained as hydrates, or include other solvents used for their crystallization. The compounds disclosed herein can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, this disclosure is intended to include both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound disclosed herein (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules (e.g., water, ethanol, etc.) are those commonly used in the pharmaceutical industry and are known to be harmless to the recipient. The term "hydrate" refers to a complex in which the solvent molecule is water. Those skilled in the art can use tools such as NMR to identify the presence of solvates.

[0777] The compounds disclosed herein (including their salts, hydrates and solvates) can be inherently or by design to form polymorphs.

[0778] Pharmaceutical Composition

[0779] On the other hand, this disclosure provides pharmaceutical compositions comprising one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers.

[0780] In other embodiments, the composition comprises at least one or two pharmaceutically acceptable carriers (such as those described herein). For the purposes of this disclosure, unless otherwise specified, solvates and hydrates are generally considered to be part of the composition.

[0781] The compounds having formula (I) and its subformulas described herein can be administered alone or as active ingredients in pharmaceutical compositions. Therefore, pharmaceutical compositions comprising a compound having formula (I) or its subformulas, a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, and one or more pharmaceutically acceptable carriers are provided herein.

[0782] Methods for preparing various pharmaceutical compositions are known to those skilled in the art and can be described, for example, in the American Pharmaceutical Association's Handbook of Pharmaceutical Excipients (current edition); Marcel Dekker, Inc.'s Pharmaceutical Dosage Forms Tablets (edited by Lieberman, Lachman, and Schwartz, current edition); and Remington's Pharmaceutical Sciences (edited by Arthur Osol), 1553-1593 (current edition).

[0783] The pharmaceutical compositions can be formulated for specific routes of administration, such as oral, topical, parenteral, and rectal administration. Furthermore, the pharmaceutical compositions disclosed herein can be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including but not limited to solutions, gels, suspensions, or emulsions). Conventional pharmaceutical processes can be performed on the pharmaceutical compositions, such as sterilization, and / or they may contain conventional inert diluents, lubricants, or buffers, as well as excipients such as preservatives, stabilizers, wetting agents, emulsifiers, and buffer solutions.

[0784] Typically, a pharmaceutical composition is a tablet or gelatin capsule containing an active ingredient and one or more of the following:

[0785] a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0786] b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol;

[0787] c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone;

[0788] d) Disintegrants, such as starch, agar, alginate or its sodium salt, or effervescent mixtures; and

[0789] e) Adsorbents, colorants, flavoring agents and sweeteners.

[0790] In the examples, the pharmaceutical composition is a capsule containing only the active ingredient.

[0791] Tablets can be film-coated or enteric-coated using methods known in the art.

[0792] The administration method and pharmaceutical composition are closely related to the therapeutic amount of a compound or composition that is desired and effective for a given therapeutic application. The pharmaceutical compositions provided herein can be formulated for ophthalmic, ocular, topical, and transdermal application. In certain embodiments, the pharmaceutical compositions provided herein are suitable for ocular application. To prepare the pharmaceutical composition, the active ingredient can be mixed with one or more pharmaceutically acceptable carriers according to conventional pharmaceutical compounding techniques. The one or more carriers can be in various forms, depending on the desired formulation for application.

[0793] Suitable compositions for oral administration comprise an effective amount of the compounds disclosed herein in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs, solutions, or solid dispersions. Compositions intended for oral use are prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically refined and palatable formulation. Tablets may contain the active ingredient mixed with nontoxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period of time. For example, time-delayed materials such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0794] Some injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. These compositions may be sterile and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts and / or buffers for adjusting osmotic pressure. Additionally, they may contain other substances of therapeutic value. The compositions are prepared according to conventional mixing, granulation, or coating methods and contain about 0.1%–75%, or about 1%–50%, of the active ingredient.

[0795] Suitable compositions for transdermal applications comprise an effective amount of the disclosed compound and a suitable carrier. Carriers suitable for transdermal delivery include absorbable, pharmacologically acceptable solvents that facilitate passage through the host skin. For example, a transdermal device may be in the form of a bandage comprising a liner, a reservoir containing the compound and optionally a carrier, a rate-controlled barrier optionally delivering the compound to the host skin at a controlled and predetermined rate over an extended period of time, and an apparatus for securing the device to the skin.

[0796] Compositions suitable for topical application (e.g., application to skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations, for example, for delivery via aerosols, etc. Such topical delivery systems are particularly suitable for dermal applications, such as for the treatment of skin cancer, or for preventative use in sunscreens, lotions, sprays, etc. Therefore, they are particularly suitable for topical use, including cosmetics and formulations well known in the art. Such systems may contain solubilizers, stabilizers, tension enhancers, buffers, and preservatives.

[0797] As used herein, topical applications may also involve inhalation or intranasal application. They can be conveniently delivered, with or without a suitable propellant, by dry powder inhalers in the form of dry powder (alone, as a mixture, such as a dry blend with lactose, or mixed component particles, such as component particles mixed with phospholipids) or in the form of an aerosol spray from a pressurized container, pump, sprayer, nebulizer, or nebulizer.

[0798] In some embodiments, the pharmaceutical compositions provided herein are formulated as solutions, suspensions, gels, creams, ointments, liposomes, ocular inserts, or other pharmaceutical compositions suitable for topical application to the ocular surface, cornea, eyelids, eyelid margins, eyelashes, and / or eyelid margins in specific embodiments to deliver the composition to the eye. In some embodiments, liquid (aqueous or non-aqueous) solutions may be used. In some embodiments, the pharmaceutical compositions are formulated as eye drops for topical application to the ocular surface, cornea, eyelids, eyelid margins, eyelashes, and / or eyelid margins to deliver the composition to the eye. The application of the pharmaceutical compositions may be performed using applicators such as the subject's finger, Weck-Cel®, Q-tip®, or other devices capable of delivering the formulation to the eyelids, eyelashes, and / or eyelid margins to deliver the formulation to the eye. The pharmaceutical compositions provided herein may be viscous or semi-viscous; liquid, solid, or semi-solid; aqueous or non-aqueous, depending on the site of application, dosage, drug solubility, and a variety of other factors considered by those skilled in the art.

[0799] Any of a variety of carriers can be used in the pharmaceutical compositions provided herein. In one embodiment, a pharmaceutically acceptable carrier is a non-aqueous carrier (e.g., an oil or oil mixture) with a viscosity ranging from about 50 cps to about 1000 cps, about 50 cps to about 500 cps, about 50 cps to about 200 cps, or about 60 cps to about 120 cps. In some embodiments, the non-aqueous carrier includes oils, such as vegetable oils, silicone oils, mineral oils, or any combination thereof. In some embodiments, the carrier may be liquid paraffin, white petrolatum, purified lanolin, gelled hydrocarbons, polyethylene glycol, hydrophilic ointment bases, white ointment bases, absorbent ointment bases, polyethylene glycol (Macrogol) ointment bases, simple ointment bases, etc. In some embodiments, the pharmaceutical composition may comprise monomeric polyols such as glycerol, propylene glycol, and ethylene glycol; polymeric polyols such as polyethylene glycol; cellulose esters such as hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and hydroxypropyl cellulose; dextran, such as dextran 70; water-soluble proteins such as gelatin; polymers such as polyvinyl alcohol, polyvinylpyrrolidone, and povidone; carbomers such as carbomer 934P, carbomer 941, carbomer 940, and carbomer 974P; and gums such as HP-guar gum.

[0800] Additional excipients may optionally be included in the pharmaceutical compositions provided herein. Examples of additional excipients include, for example, tension enhancers, preservatives, solubilizers, non-toxic excipients, modifiers, chelating agents, pH adjusters, cosolvents, thickeners, and combinations thereof.

[0801] The pharmaceutical compositions disclosed herein may be in the form of an aqueous suspension or an aqueous solution. In one embodiment, the aqueous pharmaceutical composition disclosed herein is in the form of an aqueous suspension. The aqueous pharmaceutical compositions according to the present disclosure can be prepared using standard procedures familiar to those skilled in the art, for example by appropriately mixing the various components at ambient temperature and atmospheric pressure. In one embodiment, the aqueous pharmaceutical composition disclosed herein is suitable for ocular application.

[0802] In another embodiment, the pharmaceutical composition disclosed herein is in the form of an eye ointment, eye gel, eye cream, or eye drops.

[0803] In another embodiment, the pharmaceutical composition disclosed herein was applied topically to the eye of a subject.

[0804] Compounds of formula (I) that are in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, such as complement factor B regulatory properties, as indicated by in vitro tests provided in the examples, and thus indicate their use in therapeutics or as research chemicals, such as as tool compounds.

[0805] Additional properties of the disclosed compounds include good efficacy in the bioassays described herein, favorable safety profile, and favorable pharmacokinetic properties.

[0806] Diseases and disabilities and methods of use

[0807] In another aspect, this disclosure provides compounds having formula (I), or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, for use in therapeutics.

[0808] In another aspect, this disclosure provides compounds having formula (I), or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, for use in the treatment of diseases or disorders to which complement factor B is applicable. In one embodiment, the disease or disorder is affected by inhibition of complement factor B activity.

[0809] Compounds having formula (I) and their pharmaceutically acceptable salts or stereoisomers or diastereomers have complement factor B regulatory and / or inhibitory activity and are considered to have potential use for the treatment or prevention of certain diseases or disorders.

[0810] These diseases or disorders are selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, shotgun retinal choroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arterial ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doinger's honeycomb retinal dystrophy / familial dominant drusen, Sotheby's retinal dystrophy, and late-onset macular dystrophy. Good, North Carolina malnutrition, Staghorn disease, corneal inflammation, neurological disorders including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRMS), stroke, Guillain-Barré 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 disorder, schizophrenia, drug-induced neurotoxicity, aquaporin-4 IgG seropositive neuromyelitis spectrum disorder (NMOSD), cerebral amyloid angiopathy, cerebral malaria, peroneal muscular atrophy, chemotherapy-induced peripheral neuropathy, chronic inflammatory demyelinating polyneuropathy, frontotemporal dementia, caused by CD59 p.Hereditary demyelinating neuropathy caused by Cys89Tyr mutations, Lewy body dementia, multiple system atrophy (MSA), myelin oligodendrocyte glial antibody-associated disease (MOGAD), oculoclonus-myoclonus syndrome (OMS), progressive supranuclear palsy; inappropriate or undesirable complement activation disorders, such as hemodialysis complications, hyperacute allogeneic transplant rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membrane proliferative glomerulonephritis (IC-MPGN), IgA 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), periodontitis, CD55 deficiency with complement hyperactivation, vasculopathy, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as allergic purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), and myocarditis. Post-ischemia-reperfusion syndrome, myocardial infarction, post-pump syndrome after balloon angioplasty, cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis; COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease. COPD, emphysema, pulmonary embolism and infarction, pneumonia, fibrotic pneumoconiosis, pulmonary fibrosis, asthma, allergic reactions, bronchoconstriction, allergic pneumonia, parasitic diseases, Goodpassuia syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Berger's vasculitis, cryoglobulinemia, Kawasaki disease, aortitis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenic purpura, cold agglutinin disease, warm antibody-type autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, and Graves' disease.

[0811] Given their activity as modulators or inhibitors of complement factor B, compounds having formula (I) and its derivatives, in free or pharmaceutically acceptable salt form, can be used to treat conditions that can be treated by inhibiting complement factor B activity. In one aspect, this disclosure provides a method for treating or preventing a disease or disorder in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) or its derivatives, or a pharmaceutically acceptable salt or diastereomer thereof.

[0812] On the other hand, this disclosure provides a method for modulating complement bypass pathway activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) or a subformula thereof, or a pharmaceutically acceptable salt or diastereomer thereof.

[0813] On the other hand, this disclosure provides a method for treating a disease or disorder mediated by complement activation, particularly by complement bypass pathway activation, in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) or a subformula thereof, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0814] On the other hand, this disclosure provides a method for treating a disease or disorder affected by complement bypass pathway regulation, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) or a subformula thereof, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0815] On the other hand, this disclosure provides a method for treating a disease or disorder associated with dysregulation of the complement bypass pathway, the method comprising administering to the subject a therapeutically effective amount of a compound having formula (I) or a subformula thereof, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0816] On the other hand, this disclosure provides a method for inhibiting the expression or activity of complement factor B, the method comprising administering to the subject a compound having formula (I) or a subformula thereof, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof.

[0817] On the other hand, this disclosure provides a method for treating diseases or disorders.

[0818] In some aspects, methods are provided for treating diseases associated with increased activity of the C3 amplification circuit in the complement pathway. In some embodiments, methods are provided for treating or preventing complement-mediated diseases, wherein complement activation is induced by antibody-antigen interactions, components of autoimmune diseases, or ischemic injury.

[0819] In specific embodiments, this disclosure provides a method for treating or preventing age-related macular degeneration (AMD) by administering an effective amount of the disclosed compound having formula (I) to a subject in need. In some embodiments, the compound disclosed is suitable for patients who are currently asymptomatic but at risk of developing symptomatic macular degeneration-related disorders. Methods for treating or preventing AMD include, but are not limited to, methods for treating or preventing AMD selected from one or more of the following symptoms or aspects: drusen formation, inflammation of the eye or eye tissues, loss of photoreceptor cells, vision loss (including visual acuity or visual field loss), neovascularization (including CNV), retinal detachment, photoreceptor cell degeneration, RPE degeneration, retinal degeneration, choroidal-retinal degeneration, cone degeneration, retinal dysfunction, light-reactive retinal damage, Bruch's membrane damage, and / or RPE function loss.

[0820] The compounds of formula (I) disclosed herein are particularly useful for preventing the onset of AMD, preventing early AMD from progressing to late forms of AMD (including neovascular AMD or geographic atrophy), slowing and / or preventing the progression of geographic atrophy, treating or preventing macular edema caused by AMD or other conditions (such as diabetic retinopathy, uveitis, or postoperative or non-surgical trauma), preventing or reducing vision loss caused by AMD, and improving vision loss caused by pre-existing early or late AMD. It can also be used in combination with anti-VEGF therapy for the treatment of patients with neovascular AMD or for the prevention of neovascular AMD.

[0821] All of the foregoing embodiments relating to the method of treating the aforementioned diseases are equally applicable to:

[0822] A compound having formula (I) or a subformula thereof, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof, for use in the treatment of the aforementioned diseases according to this disclosure;

[0823] Use of compounds having formula (I) or its subforms, or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, in the manufacture of medicaments for treating the aforementioned diseases according to this disclosure;

[0824] The use of compounds having formula (I) or its derivatives, or pharmaceutically acceptable salts or stereoisomers or isotopically labeled compounds thereof, for the treatment of the aforementioned diseases according to this disclosure; and

[0825] A pharmaceutical composition comprising a compound having formula (I) or a subformula thereof, a pharmaceutically acceptable salt or stereoisomer or isotopically labeled thereof, and one or more pharmaceutically acceptable carriers, for use in treating the aforementioned diseases according to this disclosure.

[0826] Preparation method

[0827] The compounds disclosed herein can be prepared using many methods well known to those skilled in the art of organic synthesis. For example, the compounds disclosed herein can be synthesized using the methods described below, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof as understood by those skilled in the art.

[0828] Generally speaking, compounds having formula (I) can be prepared according to the scheme provided below.

[0829] The compounds provided in this article can be prepared according to the following examples. In the following schemes, R, R 1 R 2 R 3 R 5 R 6 R 8 W, m, n, and p are defined according to the listed embodiment 1. In the embodiment, R, R 1 R 2 R 3 R 5 R 6 R 8 W, m, n, and p are defined according to any one of the listed embodiments 1 to 23. PG refers to a protecting group. Suitable protecting groups are known to those skilled in the art, and the same or different protecting groups can be used in any scheme. Additional applicable definitions are provided in the following general scheme.

[0830] General Solution 1

[0831]

[0832] Alcohol intermediate S1-4 can be prepared as outlined in General Scheme 1. Arylation of ketone S1-2 with aryl bromide S1-1 can be carried out using Buchwald coupling conditions. Ketone reduction of S1-3 can be accomplished using hydride reducing agents such as sodium borohydride or trisec-butylborohydride.

[0833] General Solution 2

[0834]

[0835] Alternatively, the alcohol intermediate S2-4 can be prepared as outlined in General Scheme 2. The reaction of arylmagnesium bromide S2-1 with epoxide S2-2 provides an alcohol S2-3 having a trans configuration at the ortho stereocenter. The conversion to the cis configuration of S2-4 is achieved by base-promoted hydrolysis following a phototactic reaction with a carboxylic acid (such as 4-nitrobenzoic acid).

[0836] General Solution 3

[0837]

[0838] Piperidinol intermediate S3-5 can be prepared as outlined in General Scheme 3. Boric acid or ester S3-1 and pyridyl halide S3-2 are coupled using Suzuki cross-coupling conditions to provide biaryl S3-3. Nitrogen protection with a reagent (like CbzCl) followed by treatment with a reducing agent (such as sodium borohydride) provides enone S3-4. Further reduction to alcohol S3-5 is achieved by metal-catalyzed hydrogenation with a catalyst (such as platinum oxide).

[0839] General Solution 4

[0840]

[0841] The synthesis of hydroxyindole S4-2 is outlined in General Scheme 4. S4-2 can be obtained by hydrolysis of aldehyde S4-1 under alkaline aqueous conditions following Baeyer-Villiger oxidation. Alternatively, 4-bromoindole S4-3 can be boronized using Miyura conditions. Boronate S4-4 can be oxidized to S4-2 using a suitable oxidizing agent (such as sodium perborate).

[0842] General Solution 5

[0843]

[0844] The synthesis of Example S5-4 is summarized in General Scheme 5. Alcoholic intermediate S5-1 reacts with hydroxyindole S5-2 in a photo-extending reaction, wherein inversion occurs at the stereocenter of the reaction, providing S5-3. Deprotection provides the final Example S5-4. If W is N-PG, S5-3 can be selectively deprotected to give a secondary amine in which W is NH. This intermediate can be reacted with a suitable electrophile (e.g., an alkyl halide or trifluoromethanesulfonate) in the presence of a base (e.g., diisopropylethylamine). Alternatively, the NH intermediate can be reacted with a suitable aldehyde or ketone in the presence of a reducing agent (e.g., sodium triacetoxyborohydride). Deprotection provides the final Example S5-4.

[0845] In another aspect, this disclosure provides a method for preparing a compound of formula (I) in free form or in pharmaceutically acceptable salt form, the method comprising the steps described above.

[0846] It should be understood that, in the following description, such combinations are permitted only if the combination of substituents and / or variables of the described formula produces a stable compound.

[0847] Those skilled in the art will also understand that, in the methods described below, the functional groups of the intermediate compounds may require protection by suitable protecting groups. Such functional groups include hydroxyl, phenol, amino, and carboxylic acids. Suitable protecting groups for hydroxyl or phenolic compounds include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, etc. Protecting groups suitable for amino, amidine, and guanidine groups include tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for carboxylic acids include alkyl esters, aryl esters, or arylalkyl esters.

[0848] Protecting groups can be added or removed according to standard techniques well known to those skilled in the art and as described herein. The uses of protecting groups are described in detail in JFW McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; TW Greene and PGM Wuts, “Greene's Protective Groups in Organic Synthesis”, 4th edition, Wiley, New York 2007; PJ Kocienski, “Protecting Groups”, 3rd edition, Georg Thieme Verlag, Stuttgart and New York 2005; and in “Methoden derorganischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974.

[0849] The protecting group can also be a polymer resin, such as Wang resin or 2-chlorotriphenylmethyl-chloro resin.

[0850] The following reaction examples illustrate the method for preparing the compounds disclosed herein. It should be understood that those skilled in the art will be able to prepare these compounds by similar methods or by methods known to those skilled in the art. Generally, starting components and reagents can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, Fluorochem USA, Strem, and other commercial suppliers, or can be synthesized from sources known to those skilled in the art, or prepared according to the methods described in this disclosure. Example

[0851] Analytical methods, materials and instruments

[0852] Unless otherwise specified, use reagents and solvents obtained from commercial suppliers. Unless otherwise specified, obtain proton nuclear magnetic resonance (NMR) spectra on a Bruker Avance, Avance III, or Avance Neo spectrometer at 400 MHz, a Varian Oxford 400 MHz, or a Varian Mercury 300 MHz spectrometer. Spectra are given in ppm (δ), and the coupling constant J is reported in Hertz. Tetramethylsilane (TMS) is used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26), or other solvents shown in the NMR spectral data. Dissolve a small amount of the dried sample (typically 2–5 mg) in a suitable deuterated solvent (1 mL). Chemical names are generated using ChemBioDraw Ultra v19 from CambridgeSoft software.

[0853] Mass spectra were collected using a Waters system (Acquity UPLC and Micromass ZQ mass spectrometer) or an Agilent-1260 Infinity (6120 quadrupole) mass spectrometer (ESI-MS); unless otherwise specified, all reported masses are m / z of the protonated precursor ion. Samples were dissolved in a suitable solvent such as MeCN, DMSO, or MeOH and injected directly into the column using an automated sample processor.

[0854] abbreviation

[0855]

[0856]

[0857]

[0858] intermediate

[0859] Intermediate I-1: tert-butyl 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylate

[0860]

[0861] 4-Formyl-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (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 mixture was stirred in a RM for 1 h, while being warmed to RT during this time. The mixture was partitioned between a saturated aqueous NaHCO3 solution and DCM. The organic phase was dried using an Isolute® phase separator and concentrated under reduced pressure. The resulting oil was dissolved in THF (21 mL), and an aqueous NaOH solution (1 M, 21 mL, 21 mmol) was added. The RM was stirred in RT for 15 min. The mixture was neutralized with a saturated aqueous NH4Cl solution and extracted with DCM (3x). The combined organic phases were dried using an Isolute® phase separator and concentrated under reduced pressure. The resulting oil was purified by silica gel (elution buffer: 0% to 35% EtOAc in heptane) to provide tert-butyl 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylate (2.02 g) as a brown oil. LC-MS method C-1: Rt = 1.18 min; MS m / z [M+H] + = 262.2.

[0862] Intermediate I-2: 5,7-Dimethyl-1-toluenesulfonyl-1H-indole-4-ol

[0863]

[0864] 5,7-Dimethyl-1-toluenesulfonyl-1H-indole-4-carboxaldehyde (CAS# 1481633-44-6, 376 mg, 1.15 mmol) was dissolved in DCM (5 mL) and the solution was cooled to 0°C. TFA (88 µL, 1.15 mmol) and mCPBA (77 wt%, 238 mg, 1.38 mmol) were added sequentially. The mixture was stirred for 1 h and warmed to RT during this time. The RM was diluted with DCM and washed with saturated NaHCO3 aqueous solution (2x). The separated organic phase was dried using an Isolute® phase separator and concentrated under reduced pressure. The resulting residue was dissolved in THF (1 mL) and MeOH (1 mL) and NaOH aqueous solution (4 M, 1.4 mL, 5.6 mmol) was added. The RM was stirred at RT for 15 min. The RM was partially concentrated under reduced pressure, and the pH was adjusted to 7 with 6 M HCl aqueous solution. The mixture was extracted with DCM (3x). The combined organic phases were dried using an Isolute® phase separator and concentrated under reduced pressure. The resulting residue was purified by silica gel (elution: 0% to 50% EtOAc in heptane) to provide 5,7-dimethyl-1-toluenesulfonyl-1H-indole-4-ol (296 mg) as a gray solid. 1 ¹H NMR (400MHz, CDCl₃) δ [ppm] 7.70 (d, J = 3.8 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.26 - 7.17 (m, 2H), 6.81 - 6.70 (m, 2H), 2.45 (s, 3H), 2.38 (s, 3H), 2.25 (s, 3H). ¹⁶ ions were reported in ¹⁷H (OH not observed).

[0865] Intermediate I-3: tert-butyl 5-cyclopropyl-4-hydroxy-7-methyl-1H-indole-1-carboxylate

[0866]

[0867] 5-Cyclopropyl-4-formyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (CAS# 1628640-27-6, 830 mg, 2.77 mmol) was dissolved in DCM (10 mL), and the solution was cooled to 0°C. TFA (0.21 mL, 2.77 mmol) and mCPBA (77 wt%, 574 mg, 3.33 mmol) were added sequentially. The mixture was stirred for 1 h, during which time it was warmed to RT. RM was partitioned between saturated NaHCO3 aqueous solution and DCM. The separated organic phase was dried using an Isolute® phase separator and concentrated under reduced pressure. The resulting residue was dissolved in THF (3 mL) and MeOH (3 mL), and NaOH aqueous solution (4 M, 3.46 mL, 13.85 mmol) was added. RM was stirred at RT for 15 min. The mixture was partially concentrated, and the pH was adjusted to 4 with 6 M HCl aqueous solution. The mixture was extracted with DCM (3x). The combined organic phases were dried using an Isolute® phase separator and concentrated under reduced pressure. The resulting oil was purified by silica gel (elution: 0% to 50% EtOAc in heptane) to provide tert-butyl 5-cyclopropyl-4-hydroxy-7-methyl-1H-indole-1-carboxylate (585 mg) as a gray oil. LC-MS method C-1: Rt = 1.26 min; MS m / z [M-Boc+2H] + = 188.2.

[0868] Intermediate I-4: tert-butyl 5-chloro-4-hydroxy-7-methyl-1H-indole-1-carboxylate

[0869]

[0870] Step 1: 4-Bromo-5-chloro-7-methyl-1H-indole (Intermediate I-4-1)

[0871]

[0872] 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 solution of vinyl magnesium bromide (1 M, in THF, 40 mL, 40 mmol) was slowly added, and the mixture was stirred at approximately -40°C for 3.5 h. The RM was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (2x). The combined organic phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure. The resulting residue was purified by silica gel (eluent: 0% to 50% EtOAc in heptane) to provide 960 mg of 4-bromo-5-chloro-7-methyl-1H-indole as an orange solid. 1 H NMR (400 MHz, CDCl3) δ [ppm] 8.25 (s, 1H), 7.31 - 7.29 (m, 1H), 7.11 - 7.09 (m, 1H), 6.62 (dd, J = 3.3, 2.2 Hz, 1H), 2.46 (s, 3H).

[0873] Step 2: tert-butyl 4-bromo-5-chloro-7-methyl-1H-indole-1-carboxylate (intermediate I-4-2)

[0874]

[0875] 4-Bromo-5-chloro-7-methyl-1H-indole (intermediate I-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 mixture was stirred at RT for 30 min. The mixture was concentrated under reduced pressure, and the resulting oil was purified by silica gel (elution: 0% to 25% EtOAc in heptane) to provide tert-butyl 4-bromo-5-chloro-7-methyl-1H-indole-1-carboxylate (850 mg) as an orange solid. 1 H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 3.6 Hz, 1H), 7.14 - 7.05 (m, 1H), 6.55 (d, J = 3.8 Hz, 1H), 2.50 (s, 3H), 1.56 (s, 9H).

[0876] Step 3: tert-butyl 5-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-indole-1-carboxylic acid (intermediate I-4-3)

[0877]

[0878] 4-Bromo-5-chloro-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-4-2, 300 mg, 0.87 mmol), bis(pinacol)diboron (332 mg, 1.3 mmol), KOAc (256 mg, 2.6 mmol), and PdCl2(dppf) (71 mg, 0.09 mmol) were combined in a vial. The vial was purged with N2 and filled. Dioxane (5 mL) was added, and the RM was stirred at 90°C for 16 h. The RM was filtered through a Celite® filter, and the solids were washed with DCM. The combined filtrates were concentrated under reduced pressure, and the resulting residue was enriched on silica gel (elution: 0% to 30% EtOAc in heptane) to provide tert-butyl 5-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-indole-1-carboxylate (140 mg) as a colorless oil. LC-MS method C-1: Rt = 1.52 min; MS m / z [M-Boc+2H] + = 292.3.

[0879] Step 4: tert-butyl 5-chloro-4-hydroxy-7-methyl-1H-indole-1-carboxylate (intermediate I-4)

[0880] The enriched tert-butyl 5-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-indole-1-carboxylate (intermediate I-4-3, 140 mg) was dissolved in THF (0.5 mL) and H2O (0.5 mL) and cooled to 0°C. Sodium perborate 1-hydrate (39.8 mg, 0.4 mmol) was added, and the mixture was stirred at 0°C for 1 h. Additional THF (0.5 mL) and H2O (0.5 mL) were added, and stirring was continued for 3 h, during which time the mixture was warmed to RT. The mixture was diluted with H2O and extracted with DCM (3x). The combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The resulting residue was purified by silica gel (elution buffer: 0% to 30% EtOAc in heptane) to provide tert-butyl 5-chloro-4-hydroxy-7-methyl-1H-indole-1-carboxylate (30 mg) as a brown oil. LC-MS method: C₁ Rt = 1.52 min; MS m / z [M-Boc+2H] + = 182.1.

[0881] Intermediate I-5: tert-butyl 5-fluoro-4-hydroxy-7-methyl-1H-indole-1-carboxylate

[0882]

[0883] To a solution of tert-butyl 4-bromo-5-fluoro-7-methyl-1H-indole-1-carboxylate (460 mg, 1.4 mmol) and bis(pinacol)diboron (533.9 mg, 2.1 mmol) in dioxane (2 mL), PdCl2 (dppf) (102.5 mg, 0.14 mmol) and KOAc (412.7 mg, 4.2 mmol) were added. RM was stirred at 90°C for 18 h. Additional PdCl2 (dppf) (102.4 mg, 0.14 mmol) was added, and RM was stirred at 90°C for 6 h. RM was cooled to RT, and H2O2 (30 wt%, in H2O, 0.72 mL, 7.0 mmol) was slowly added. RM was stirred at RT for 18 h. RM was diluted with EtOAc and H2O and filtered through a Celite® pad. The phases were separated, and the aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by silica gel (50 g; eluent: 0% to 13% EtOAc in heptane) to provide tert-butyl 5-fluoro-4-hydroxy-7-methyl-1H-indole-1-carboxylate (220 mg) as a pink solid. LC-MS Method B-1: Rt = 1.20 min; MS m / z [MH] - = 263.9.

[0884] Intermediate I-6: tert-butyl 4-hydroxy-7-methyl-1H-indole-1-carboxylate

[0885]

[0886] 7-Methyl-1H-indole-4-ol (75 mg, 0.51 mmol) and DMAP (3.1 mg, 25 µmol) were combined in ACN (1 mL). Di-tert-butyl dicarbonate (0.35 mL, 1.5 mmol) was added, and RM was stirred at RT for 1 h. RM was concentrated under reduced pressure. The resulting residue was combined with K2CO3 (281 mg, 2.0 mmol) and MeOH (2 mL). RM was stirred at RT for 2 h. Additional K2CO3 (70 mg, 0.5 mmol) was added, and RM was stirred at RT overnight. RM was partitioned between H2O and DCM. The organic phase was concentrated under reduced pressure. The resulting residue was purified by silica gel (elution: 0% to 50% EtOAc in heptane) to provide tert-butyl 4-hydroxy-7-methyl-1H-indole-1-carboxylate (87 mg) as a colorless oil. LC-MS method C-1: Rt = 1.09 min; MS m / z [M+H] + = 248.2.

[0887] Intermediate I-7: tert-butyl 7-chloro-4-hydroxy-5-methyl-1H-indole-1-carboxylate

[0888]

[0889] 4-Bromo-7-chloro-5-methyl-1H-indole-1-carboxylic acid tert-butyl ester (5.8 g, 16.4 mmol), bis(pinacol)diboron (8.5 g, 33.7 mmol), KOAc (4.9 g, 50.5 mmol), and PdCl2(dppf)•DCM (1.37 g, 1.68 mmol) were combined in vials. Dioxane (5 mL) was added, and the mixture was stirred at 90°C for 16 h. The mixture was filtered through a Celite® filter, and the solids were washed with EtOAc. The combined filtrates were concentrated under reduced pressure. The resulting residue was dissolved in THF (20 mL) and H2O (10 mL). Sodium perborate 1-hydrate (3.48 g, 34.8 mmol) was added, and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc, and the separated aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel (24 g; 10% to 20% EtOAc in hexane) to provide tert-butyl 7-chloro-4-hydroxy-5-methyl-1H-indole-1-carboxylate (1.4 g) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ[ppm] 9.45 (s, 1H), 7.50 (d, J = 3.6 Hz, 1H), 7.07 (s, 1H), 6.88 (d, J = 3.6Hz, 1H), 2.20 (s, 3H), 1.58 (s, 9H).

[0890] Intermediate I-8: tert-butyl 5-bromo-4-hydroxy-7-methyl-1H-indole-1-carboxylate

[0891]

[0892] 5-Bromo-4-formyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (2.37 g, 7.0 mmol) was dissolved in DCM (35 mL), and the solution was cooled to 0°C. TFA (0.54 mL, 7.0 mmol) and mCPBA (77 wt%, 1.45 g, 8.41 mmol) were added sequentially. The mixture was stirred for 2.5 h, during which time it was warmed to RT. RM was partitioned between saturated NaHCO3 aqueous solution and DCM. The separated organic phases were dried using an Isolute® phase separator and concentrated under reduced pressure. The resulting residue was dissolved in THF (8 mL) and MeOH (8 mL), and NaOH aqueous solution (4 M, 8.7 mL, 35.0 mmol) was added. RM was stirred at RT for 20 min. The RM was partially concentrated, and the pH was adjusted to 4 with HCl aqueous solution (6 M). The mixture was extracted with DCM (3x). The combined organic phases were dried using an Isolute® phase separator and concentrated under reduced pressure. The resulting oil was purified by silica gel (elution: 0% to 50% EtOAc in heptane) to provide tert-butyl 5-bromo-4-hydroxy-7-methyl-1H-indole-1-carboxylate (1.74 g) as an orange solid. LC-MS method C-1: Rt = 1.15 min; MS m / z [MH] - = 324.0.

[0893] Intermediate K-1: tert-butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidin-1-carboxylate

[0894]

[0895] 4-O-piperidin-1-carboxylic acid tert-butyl ester (333.56 g, 1.67 mol), K3PO4 (454.05 g, 2.10 mol), Xantphos (21.53 g, 37.20 mmol), and Pd2(dba)3 (17.03 g, 18.60 mmol) were added to a solution of methyl 4-bromobenzoate (200 g, 930 mmol) in toluene (2 L) under N2 at 25°C. The mixture was stirred under N2 at 80°C for 16 h. The mixture was filtered, and the solids were washed with DCM (4 L). The filtrate was concentrated under reduced pressure. The enriched material was obtained by silica gel column chromatography (eluent: 3:1 PE / EtOAc), which was purified by RP chromatography (eluent: 0% to 100% ACN in H2O with 0.1 NH4OH) to provide tert-butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidin-1-carboxylate (99.2 g) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 7.92 (d, J = 8.3 Hz, 2H),7.35 (d, J = 8.3 Hz, 2H), 4.15 - 4.02 (m, 2H), 3.96 (dd, J = 5.9, 10.8 Hz,1H), 3.83 (s, 3H), 3.67 - 3.42 (m, 2H), 2.66 - 2.55 (m, 1H), 2.41 (dt, J =4.0, 14.9 Hz, 1H), 1.43 (br s, 9H).

[0896] Intermediate K-2: tert-butyl 3-(4-cyanophenyl)-4-oxopiperidin-1-carboxylate

[0897]

[0898] To a stirred solution of 4-bromobenzyl nitrile (10.0 g, 54.93 mmol) in toluene (100 mL), tert-butyl 4-oxopiperidinium-1-carboxylate (21.9 g, 109.8 mmol) was added, followed by the addition of K3PO4 (23.3 g, 109.8 mmol), and the RM was degassed with argon at RT for 15 min. Xanthphos (1.58 g, 2.74 mmol) and Pd2(dba)3 (1 g, 1.09 mmol) were added, and the RM was stirred at 100°C for 12 h. The RM was cooled to RT, filtered through a Celite® filter, and the solids were washed with THF (200 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was diluted with H2O and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel (80 g; eluent: 0% to 100% EtOAc in hexane) to provide tert-butyl 3-(4-cyanophenyl)-4-oxopiperidin-1-carboxylate (5 g) as a brown oil. LC-MS method A-1: ​​Rt = 1.75 min; MS m / z [MH] - =299.1.

[0899] Intermediate K-3: tert-butyl 3-(4-(1H-pyrazol-1-yl)phenyl)-4-oxopiperidin-1-carboxylate

[0900]

[0901] 1-(4-bromophenyl)-1H-pyrazole (339 mg, 1.52 mmol), tert-butyl 4-oxopiperidinium-1-carboxylate (363 mg, 1.82 mmol), K3PO4 (742 mg, 3.50 mmol), and XantPhos-Pd-G2 (CAS#: 1375325-77-1, 95 mg, 0.11 mmol) were combined in a vial. The vial was purged with N2 and toluene (3 mL) was added. The mixture was purged with N2 and stirred at 90°C for 24 h. The RM was cooled to RT and filtered through a Celite® filter. The solids were washed with DCM and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel (40 g; eluent: 15% to 40% EtOAc in heptane) to provide tert-butyl 3-(4-(1H-pyrazol-1-yl)phenyl)-4-oxopiperidin-1-carboxylate (180 mg) as a pale yellow solid. LC-MS method C-1: Rt = 1.00 min; MS m / z [M+H] + = 342.2.

[0902] Intermediate K-4: 5-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyridine-1(2H)-formate benzyl ester

[0903]

[0904] Step 1: 4-Methoxy-3-(1-Methyl-1H-pyrazol-4-yl)pyridine (intermediate K-4-1)

[0905]

[0906] 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1H-pyrazole (13.2 g, 63.82 mmol) was added to a stirred solution of 3-bromo-4-methoxypyridine (10.0 g, 53 mmol) in dioxane / H₂O (4:1, 100 mL), followed by the addition of K₂CO₃ (14.6 g, 106.4 mmol). The RM was degassed with argon at RT for 15 min. Pd(dppf)Cl₂•DCM (2.16 g, 2.65 mmol) was added to the mixture, and the RM was stirred at 95°C for 12 h. The RM was filtered through a Celite® filter, and the solids were washed with THF (100 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with H₂O and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by silica gel (40 g; eluent: 0% to 100% EtOAc in hexane) to provide 11 g of 4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)pyridine as a yellow semi-solid. LC-MS Method A-1: ​​Rt = 0.21 min; MS m / z [M+H] + = 190.1.

[0907] Step 2: 5-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyridine-1(2H)-formate benzyl ester (intermediate K-4)

[0908] Benzyl chloroformate (9.37 g, 54.96 mmol) was added to a stirred solution of 4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)pyridine (intermediate K-4-1, 8.0 g, 42.78 mmol) in MeOH (80 mL) at 0°C. The mixture was stirred for 10 min, and then NaBH4 (2.08 g, 54.96 mmol) was added in portions at 0°C. The mixture was warmed to RT and stirred for 2.5 h. The mixture was quenched with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel (40 g; eluent: 0% to 100% EtOAc in hexane) to provide 6.5 g of benzyl 5-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate as a yellow oil. LC-MS method A-1: ​​Rt = 1.49 min; MS m / z [M+H] + = 312.1.

[0909] Intermediates rac-K-5 and rac-K-6: racemic 4-((1S 5S methyl benzoate 5-methoxy-2-oxocyclohexyl)benzoate and racemic 4-((1S) 5R methyl 5-methoxy-2-oxocyclohexyl)benzoate

[0910]

[0911] Methyl 4-bromobenzoate (1.050 g, 4.88 mmol), 4-methoxycyclohexane-1-one (1.24 g, 9.68 mmol), K3PO4 (2.38 g, 11.2 mmol), Xantphos (113 mg, 0.195 mmol), and Pd2dba3 (67 mg, 73 µmol) were combined in vials. The vials were purged with N2 and toluene (5 mL) was added. The mixture was purged with N2 and stirred overnight at 80°C. The RM was cooled to RT, filtered to remove solids, and the filtrate was partitioned between EtOAc and H2O. The separated aqueous layer was extracted with EtOAc (3x). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was enriched with silica gel (120 g; eluent: 0% to 40% EtOAc in heptane) to provide racemic 4-((1S) 5S methyl benzoate (intermediate rac-K-5, first peak elution) and racemic 4-((1S) 5R Methyl benzoate 4-((1S)-5-methoxy-2-oxocyclohexyl)benzoate (intermediate rac-K-6, eluted by the second peak). The enriched intermediate rac-K-5 was purified by RP chromatography (50 g C18 column; eluent: 25% to 50% ACN in H2O, each with 0.1% FA) to provide a white solid racemic 4-((1S) 5S Methyl benzoate (816 mg) of 5-methoxy-2-oxocyclohexyl benzoate. 1 H NMR (400 MHz, CDCl3) δ [ppm] 8.06 - 7.97 (m, 2H), 7.24 - 7.18 (m, 2H), 4.13 - 4.02 (m, 1H), 3.91 (s, 3H), 3.80 - 3.73 (m, 1H), 3.47 (s, 3H), 2.90 -2.73 (m, 1H), 2.55 - 2.32 (m, 3H), 2.18 - 2.03 (m, 1H), 2.00 - 1.83 (m, 1H). The enriched intermediate rac-K-6 was purified by RP chromatography (50 g C18 column; eluent: 25% to 50% ACN in H2O, each containing 0.1% FA) to provide a white solid racemic 4-((1S) 5R Methyl benzoate (217 mg) of 5-methoxy-2-oxocyclohexyl benzoate. 1 H NMR (400 MHz, CDCl3) δ [ppm] 8.05 - 7.99 (m, 2H), 7.22 -7.17 (m, 2H), 3.91 (s, 3H), 3.86 - 3.75 (m, 1H), 3.74 - 3.61 (m, 1H), 3.43(s, 3H), 2.65 - 2.49 (m, 3H), 2.49 - 2.36 (m, 1H), 2.06 - 1.93 (m, 1H), 1.89- 1.75 (m, 1H).

[0912] Intermediate K-7: Methyl 4-(8-oxo-1-oxaspiro[4.5]dec-7-yl)benzoate

[0913]

[0914] Methyl 4-bromobenzoate (433 mg, 2.01 mmol), Cs₂CO₃ (1.51 g, 4.63 mmol), Pd₂dba₃ (22 mg, 24 µmol), and SPhos (CAS# 657408-07-6, 41 mg, 0.099 mmol) were combined in vials. The vials were purged with N₂ and then toluene (2.5 mL) and 1-oxaspiro[4.5]dec-8-one (379 mg, 2.46 mmol) were added. The RM was purged with N₂ and then stirred at 95°C for 24 h. The RM was cooled to RT and filtered to remove the solids. The solids were washed with DCM and the combined filtrates were concentrated under reduced pressure. The residue was enriched with silica gel (40 g; eluent: 0% to 40% EtOAc in heptane). The enriched residue eluted from the first diastereomer was purified by RP chromatography (15.5 g C18 column; eluent: 25% to 60% ACN in H2O, each with 0.1% FA) to provide methyl 4-(8-oxo-1-oxaspiro[4.5]dec-7-yl)benzoate (105 mg). LC-MS method C-1: Rt = 0.96 min; MS m / z [M+H] + = 289.0.

[0915] Intermediate K-8: tert-butyl 3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-4-oxoperidin-1-carboxylic acid

[0916]

[0917] 5-Bromo-2-(1H-pyrazol-1-yl)pyridine (318 mg, 1.4 mmol), tert-butyl 4-oxopiperidinium-1-carboxylate (339 mg, 1.7 mmol), K3PO4 (692 mg, 3.26 mmol), Xantphos (32.9 mg, 56.8 µmol), and Pd2dba3 (26 mg, 28 µmol) were combined in a vial. The vial was purged with N2 and toluene (3.5 mL) was added. The mixture was purged with N2 and stirred overnight at 80°C. The RM was cooled to RT and filtered through a Celite® filter. The solids were washed with DCM and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel (24 g; eluent: 0% to 45% EtOAc in heptane) to provide tert-butyl 3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-4-oxopiperidin-1-carboxylate (100 mg) as a colorless oil. LC-MS method C-1: Rt = 0.98 min; MS m / z [M+H] += 343.2.

[0918] Intermediate K-9: tert-butyl 3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-4-oxopiperidin-1-carboxylate

[0919]

[0920] 1-(4-bromophenyl)-1H-1,2,3-triazole (679 mg, 3.03 mmol), tert-butyl 4-oxopiperidinium-1-carboxylate (845 mg, 4.24 mmol), K3PO4 (1.48 g, 6.97 mmol), Xantphos (157.8 mg, 0.27 mmol), and Pd2dba3 (111 mg, 0.12 mmol) were combined in a vial. The vial was purged with N2 and toluene (6 mL) was added. The mixture was purged with N2 and stirred overnight at 100°C. The RM was cooled to RT and filtered through a Celite® filter. The solids were washed with DCM and the combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel (40 g; eluent: 35% to 80% EtOAc in heptane) to provide tert-butyl 3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-4-oxoperidin-1-carboxylate (500 mg). LC-MS method C-1: Rt = 0.91 min; MS m / z [M+H] + = 343.2.

[0921] Intermediate K-15: Methyl 4-(2-oxocyclohexyl)benzoate

[0922]

[0923] K3PO4 (2.3 g, 11 mmol) was added to a solution of methyl 4-bromobenzoate (1.0 g, 4.7 mmol), cyclohexanone (0.82 g, 8.4 mmol), and Xantphos (0.12 g, 0.2 mmol) in toluene (9 mL), and the vial was purged with N2. Pd2(dba)3 (85 mg, 93 µmol) was added, and the reaction mixture (RM) was stirred at 80°C for 16 h. The RM was cooled to RT and diluted with H2O and EtOAc. The organic phase was washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel (25 g; eluent: 0% to 50% EtOAc in hexane) to provide methyl 4-(2-oxocyclohexyl)benzoate (705 mg) as a pink solid. LC-MS method B-1: Rt = 0.87 min; MS m / z [M+H]+ = 233.2.

[0924] Intermediate K-16: Methyl 4-(5,5-difluoro-2-oxocyclohexyl)benzoate

[0925] Methyl 4-bromobenzoate (400 mg, 1.86 mmol), 4,4-difluorocyclohexane-1-one (349 mg, 2.6 mmol), K3PO4 (908 mg, 4.28 mmol), Xantphos (47.4 mg, 81 µmol), Pd2dba3 (34.1 mg, 37.1 µmol), and toluene (5 mL) were combined in vials. The mixture was purged with N2 and stirred at 90°C for 18 h. The RM was cooled to RT and diluted with DCM and H2O. The separated organic phase was concentrated under reduced pressure. The residue was purified by silica gel (24 g; eluent: 0% to 30% EtOAc in cyclohexane) to provide methyl 4-(5,5-difluoro-2-oxocyclohexyl)benzoate (190 mg) as a light brown oil. LC-MS method B-1: Rt = 0.84 min; MS m / z [M+H] + = 269.2.

[0926] Intermediate rac-K-17: racemic 4-((1S) 5S methyl 5-((tert-butyldimethylsilyl)oxy)-2-oxocyclohexyl)benzoate

[0927]

[0928] As described for intermediate K-16, intermediate rac-K-17 was prepared using 4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-one (743.5 mg, 3.26 mmol), providing a racemic 4-((1S)-1-one as a light brown oil. 5S Methyl benzoate 5-((tert-butyldimethylsilyl)oxy)-2-oxocyclohexyl)benzoate (190 mg). LC-MS Method B-1: Rt = 1.55 min; MS m / z [M+H2O] + = 380.3

[0929] Intermediate rac-K-18: racemic 4-((1S) 5R methyl 5-methyl-2-oxocyclohexyl)benzoate

[0930]

[0931] Methyl 4-methylcyclohexane-1-one (21.0 g, 187.2 mmol) was added to a stirred solution of methyl 4-bromobenzoate (20.1 g, 93.6 mmol) in toluene (100 mL). The mixture was purged with argon for 10 min. K3PO4 (55.6 g, 262.1 mmol), Xantphos (1.08 g, 1.87 mmol), and Pd2(dba)3 (1.71 g, 1.87 mmol) were added, and the RM was purged with argon for 10 min. The RM was stirred at 100°C for 16 h. The RM was cooled to RT and filtered through Celite®. The solids were washed with EtOAc, and the combined filtrates were washed with water. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was divided into four fractions, and each fraction was purified by silica gel (80 g; eluent: 0% to 20% EtOAc in hexane) to provide racemic 4-((1S) as a grayish-white solid. 5R Methyl 5-methyl-2-oxocyclohexyl)benzoate (total 9.0 g). LC-MS method A-1: ​​Rt = 3.05 min; MS m / z [M+H] + = 247.1.

[0932] Intermediate K-19: Methyl 4-(6-oxaspiro[2.5]oct-5-yl)benzoate

[0933]

[0934] K₃PO₄ (7.04 g, 33.2 mmol) was added to a stirred solution of methyl 4-bromobenzoate (3.1 g, 14.2 mmol), spiro[2.5]oct-6-one (2.5 g, 20.2 mmol), and Xantphos (367 mg, 0.63 mmol) in toluene (35 mL). The mixture was purged with N₂. Pd₂(dba)₃ (264 mg, 0.29 mmol) was added, and the mixture was purged with N₂. The RM was heated at 90°C for 5 h. The RM was cooled to RT and diluted with toluene and water. The mixture was filtered through Celite®. The organic phase of the filtrate was washed with NaHCO₃ and brine, dried over MgSO₄, and concentrated under reduced pressure. The material enriched by silica gel column chromatography (220 g; eluent: 5% to 34% EtOAc in hexane) was further purified by RP chromatography (86 g C18; eluent: 15% to 75% ACN in H2O with 0.1% NH4OH) to provide methyl 4-(6-oxospiro[2.5]oct-5-yl)benzoate (1.6 g) as a white solid. LC-MS method B-1: Rt = 1.05 min; MS m / z [M+H] + = 259.2.

[0935] Intermediate K-23: Methyl 4-(8-oxo-1,4-diazaspiro[4.5]dec-7-yl)benzoate

[0936]

[0937] Methyl 4-bromobenzoate (2.0 g, 9.3 mmol), 1,4-dioxaspiro[4.5]dec-8-one (2.03 g, 13.0 mmol), K3PO4 (4.5 g, 21.4 mmol), Xantphos (236.8 mg, 0.41 mmol), Pd2dba3 (170.3 mg, 0.19 mol), and toluene (24 mL) were separated between two vials. The mixture was purged with N2 and stirred at 90°C for 18 h. The mixture was cooled to RT, combined, and diluted with DCM and H2O. The separated organic phases were concentrated under reduced pressure. The residue was purified by silica gel (120 g; eluent: 0% to 30% EtOAc in cyclohexane) to provide methyl 4-(8-oxo-1,4-dioxaspiro[4.5]dec-7-yl)benzoate (1.25 g) as a light brown solid. LC-MS method B-1: Rt = 0.73 min; MS m / z [M+H] + = 291.3.

[0938] Intermediates rac-A-1 and rac-A-2: racemic (3R) 4S 4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester and racemic (3R) 4R 4-Hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

[0939]

[0940] 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidin-1-carboxylic acid tert-butyl ester (intermediate K-1, 1.09 g, 3.27 mmol) was dissolved in MeOH (25 mL) and cooled to 0°C. NaBH4 (124 mg, 3.27 mmol) was added, and RM was stirred for 30 min, while being warmed to RT during this period. RM was partially concentrated under reduced pressure and then partitioned between EtOAc and a saturated aqueous solution of NH4Cl. The separated organic phases were dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel (24 g; eluent: 0% to 100% EtOAc in heptane) to provide a racemic (3R) solid as a white solid. 4S 4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate rac-A-1, first peak elution) (299 mg) and racemic (3R) as a white solid 4R 4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate rac-A-2, eluted by the second peak) (558 mg).

[0941] intermediate rac-A-1 1 ¹H NMR (400 MHz, CDCl₃) δ [ppm] 8.09 - 8.00 (m, 2H), 7.39 - 7.33 (m, 2H), 4.18 - 4.16 (m, 1H), 4.07 (dd, J = 13.0, 4.2 Hz, 1H), 4.01 - 3.95 (m, 1H), 3.94 (s, 3H), 3.57 - 3.50 (m, 1H), 3.30 - 3.17 (m, 1H), 2.97 (ddd, J = 11.9, 4.3, 2.4 Hz, 1H), 1.94 - 1.82 (m, 2H), 1.49 (s, 9H). 24 ppm is reported in 25H (OH not observed).

[0942] intermediate rac-A-2 1 ¹H NMR (400 MHz, CDCl₃) δ [ppm] 8.10 - 7.98 (m, 2H), 7.43 - 7.31 (m, 2H), 4.34 - 4.09 (m, 2H), 3.94 - 3.87 (m, 4H), 2.94 - 2.75 (m, 2H), 2.68 (ddd, J = 11.5, 9.9, 4.2 Hz, 1H), 2.10 - 2.04 (m, 1H), 1.65 -1.55 (m, 1H), 1.48 (s, 9H). 24 ppm is reported in 25H (OH not observed).

[0943] Intermediate A-3: (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

[0944]

[0945] Step 1a: 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidin-1-carboxylic acid tert-butyl ester (intermediate K-1, 4.19 g, 12.6 mmol) was dissolved in THF (45 mL) and cooled to 0°C. A solution of tri-sec-butylborohydride (1 M, in THF, 20 mL, 20 mmol) was added dropwise, and the mixture was stirred at 0°C for 1 h. An additional solution of tri-sec-butylborohydride (1 M, in THF, 5 mL, 5 mmol) was added dropwise. The mixture was stirred at 0°C for 30 min. The mixture was warmed to RT and then stirred for another 20 min. The mixture was cooled to 0°C and quenched with a saturated aqueous NH4Cl solution. The mixture was extracted with DCM (3x), and the combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by silica gel (80 g; eluent: 0% to 70% EtOAc in heptane) to provide racemic (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (2.63 g) as a white solid. LC-MS method C-1: Rt = 0.97 min; MS m / z [M-tBu+2H] + = 280.1.

[0946] Step 1b: Chiral separation and analysis according to method SFC-1: 2.3 g of intermediate A-3 (peak 1) was provided: 1.22 g, white solid. LC-MS method C-1: Rt = 0.99 min; MS m / z [M-tBu+2H] + = 280.1. Analytical chiral HPLC: Rt = 1.67 min; 100% ee.

[0947] Intermediates A-4 and A-5: (4S,5S)-4-hydroxy-5-(4-(methoxycarbonyl)phenyl)azacycloheptane-1-carboxylic acid tert-butyl ester and (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)azacycloheptane-1-carboxylic acid tert-butyl ester

[0948]

[0949] Step 1a: To a solution of methyl 4-bromobenzoate (8.0 g, 37.2 mmol) in toluene (80 mL), tert-butyl 4-oxozycycloheptan-1-carboxylate (9.52 g, 44.6 mmol) was added, followed by the addition of K3PO4 (15.7 g, 74.4 mmol). The RM was degassed with argon at RT for 15 min, and then Xantphos (1.07 g, 1.86 mmol) and Pd2(dba)3 (681.2 mg, 0.74 mmol) were added. The RM was stirred at 100°C for 12 h. The RM was cooled to RT, filtered through a Celite® filter, and the solids were washed with THF (200 mL). The combined filtrates were concentrated under reduced pressure, and the resulting residue was diluted with H2O and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. Enriched material was obtained by silica gel column chromatography (48 g; eluent: 0% to 100% EtOAc in hexane), which was purified by RP chromatography (24 g C18 column; eluent: 0% to 100% ACN in H₂O with 0.05% NH₄OH) to provide a mixture (4.0 g) of tert-butyl 4-(4-(methoxycarbonyl)phenyl)-5-oxazacycloheptan-1-carboxylate and tert-butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxazacycloheptan-1-carboxylate as a yellow solid.

[0950] Step 1a: A solution of trisec-sec-butyllithium borohydride (1 M, 13.8 mL, 13.8 mmol) was added to a stirred solution of 4-(4-(methoxycarbonyl)phenyl)-5-oxazacycloheptan-1-carboxylate and 3-(4-(methoxycarbonyl)phenyl)-4-oxazacycloheptan-1-carboxylate (4.0 g, 11.5 mmol) in THF (80 mL). The mixture was stirred at -20°C for 10 min. The mixture was diluted with EtOAc (50 mL), quenched with a saturated aqueous solution of NH4Cl (50 mL), and warmed to RT. The aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was enriched with silica gel (24 g; eluent: 0% to 100% EtOAc in hexane) to provide a racemic (4S) solid as a grayish-white solid. 5S 4-hydroxy-5-(4-(methoxycarbonyl)phenyl)azacycloheptan-1-carboxylic acid tert-butyl ester and racemic (3R 4S A mixture of tert-butyl 4-hydroxy-3-(4-(methoxycarbonyl)phenyl)azacycloheptan-1-carboxylate (2.7 g).

[0951] Step 1c: Chiral separation according to method SFC-2: 2.7 g provides (4S,5S)-4-hydroxy-5-(4-(methoxycarbonyl)phenyl)azacycloheptan-1-carboxylic acid tert-butyl ester and racemic (3R) 4S A mixture of tert-butyl 4-hydroxy-3-(4-(methoxycarbonyl)phenyl)azacycloheptan-1-carboxylate (peak 1, 1.6 g).

[0952] Step 1d: Chiral separation and analysis according to method SFC-3: 1.6 g of peak 1 from step 1c above provides intermediate A-4 (peak 1): 375 mg, off-white solid. Analytical chiral HPLC: Rt = 4.85 min; 98.6% ee. 1¹H NMR (400 MHz, CD₃OD) δ [ppm] 7.97 - 7.88 (m, 2H), 7.43 (d, J = 7.04 Hz, 2H), 4.07-4.02 (m, 1H), 3.88 (s, 3H), 3.76 - 3.59 (m, 2H), 3.49 - 3.35 (m, 2H), 2.87-2.79 (m, 1H), 2.52 - 2.33 (m, 1H), 1.94 - 1.79 (m, 3H), 1.50 (d, J = 3.37 Hz, 9H). 26 is reported in 27H (OH not observed).

[0953] Intermediate A-5 (peak 3): 470 mg, grayish-white solid. Analytical chiral HPLC: Rt = 10.04 min, 98.9% ee. NMR (400 MHz) , CD3OD) δ [ppm] 8.00 - 7.91 (m, 2H), 7.45 - 7.40 (m, 2H), 4.10- 4.05 (m, 1H), 3.89 (s, 3H) 3.81 - 3.63 (m, 2H), 3.65 - 3.53 (m, 2H), 3.27 -3.21 (m, 1H), 3.07 - 2.97 (m, 1H), 2.19 - 2.03 (m, 2H), 1.85 - 1.74 (m, 1H), 1.73 - 1.62 (m, 1H), 1.49 - 1.40 (m, 9H).

[0954] Intermediate rac-A-6: racemic (3R) 4R 3-Hydroxy-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester

[0955]

[0956] Step 1: Racemic (3S) 4R 3-Hydroxy-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (intermediate rac-A-6-1)

[0957]

[0958] 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (881 mg, 4.76 mmol) and copper iodide (I) (90 mg, 0.47 mmol) were combined in a dry flask, and THF (9 mL) was added. The mixture was cooled to 0°C, and a solution of magnesium phenyl chloride (2 M, in THF, 5.0 mL, 10 mmol) was added dropwise. The RM was warmed to RT and stirred overnight. The RM was quenched with a saturated aqueous solution of NH4Cl, and the separated aqueous layer was extracted with DCM (3x). The combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by silica gel (40 g; eluent: 0% to 50% EtOAc in heptane) to provide a racemic (3S) colorless oil. 4R 3-Hydroxy-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (1.07 g). LC-MS method C-1: Rt = 0.95 min; MS m / z [M-Boc+2H] + = 164.2.

[0959] Step 2: Racemic (3R) 4R 3-((4-nitrobenzoyl)oxy)-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (intermediate rac-A-6-2)

[0960]

[0961] racemic (3S) 4R 3-hydroxy-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (intermediate rac-A-6-1, 530 mg, 2.01 mmol), 4-nitrobenzoic acid (673 mg, 4.03 mmol), and PPh3 (1.06 g, 4.03 mmol) were dissolved in toluene (6 mL) and cooled to 0°C. DIAD (0.78 mL, 4.03 mmol) was added, and RM was stirred at 0°C for 15 min, and then RM was warmed to RT. RM was stirred at RT for 4 h. A saturated aqueous solution of NaHCO3 was added, and the aqueous phase was extracted with DCM. The combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by silica gel (40 g; eluent: 0% to 40% EtOAc in heptane) to provide a racemic (3R) as a colorless oil. 4R 1.03 g of tert-butyl 1-((4-nitrobenzoyl)oxy)-4-phenylpyrrolidine-1-carboxylate. LC-MS method: C-1 Rt = 0.95 min; MS m / z [M-tBu+2H] + = 357.2.

[0962] Step 3: Racemic (3R) 4R 3-Hydroxy-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (intermediate rac-A-5)

[0963] racemic (3R) 4R 3-((4-nitrobenzoyl)oxy)-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (intermediate rac-A-6-2, 1.03 g, 2.50 mmol) was dissolved in MeOH (10 mL) and K2CO3 (1.39 g, 10 mmol) was added. RM was stirred at RT for 90 min and then concentrated under reduced pressure. The residue was partitioned between DCM and a saturated aqueous solution of NH4Cl. The aqueous layer was extracted with DCM (3x). The combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by silica gel (24 g; eluent: 0% to 45% EtOAc in heptane) to provide a racemic (3R) as a colorless oil. 4R 3-Hydroxy-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (548 mg). LC-MS method C-1: Rt = 0.93 min; MS m / z [M-tBu+2H] + = 208.1.

[0964] Intermediate A-7: (3R,4S)-3-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0965]

[0966] Step 1a: Prepared at 0°C using tert-butyl 3-(4-cyanophenyl)-4-oxopiperidin-1-carboxylate (intermediate K-2, 1.0 g, 3.32 mmol) as described for intermediate A-4, providing a racemic (3R) solid in the form of a grayish-white solid. 4S 3-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (300 mg).

[0967] Step 1b: Chiral separation and analysis according to method SFC-4: 1.5 g racemic (3R) samples from multiple batches. 4S Intermediate A-7, 700 mg, is a grayish-white solid, provided by tert-butyl 3-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate. Analytical chiral HPLC: Rt = 6.34 min; 96% ee. 1 H NMR (400 MHz, CD3OD) δ [ppm] 7.71 - 7.64, (m, 2H), 7.50 (d, J = 8.2 Hz, 2H). 4.13 - 4.08 (m, 1H), 3.98 - 3.83 (m, 1H), 3.86 - 3.81 (m, 1H), 3.83 - 3.76 (m, 1H), 3.63 - 3.44 (m, 1H), 3.12 - 2.98(m, 1H), 2.95 - 2.87 (m, 1H), 1.85 - 1.76 (m, 2H), 1.51 (s, 9H).

[0968] Intermediate rac-A-8: racemic (3R) 4S 3-(4-(1H-pyrazol-1-yl)phenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0969]

[0970] 3-(4-(1H-pyrazol-1-yl)phenyl)-4-oxopiperidin-1-carboxylic acid tert-butyl ester (intermediate K-3, 500 mg, 1.47 mmol) was dissolved in MeOH (3 mL) and NaBH4 (100 mg, 2.64 mmol) was added. RM was stirred at RT for 2 h. RM was quenched with H2O and the mixture was extracted with DCM (3x). The combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The enriched material from the first elution peak was provided by silica gel column chromatography (24 g; eluent: 10% to 80% EtOAc in heptane). The material was purified by RP chromatography (50 g C18 column; eluent: 25% to 50% ACN in H2O, each with 0.1% FA) to provide a racemic mixture (3R) as a colorless oil. 4S 3-(4-(1H-pyrazol-1-yl)phenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (82 mg). 1H NMR (400 MHz, CDCl3) δ[ppm] 7.91 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.68 - 7.61 (m,2H), 7.34 (d, J = 8.5 Hz, 2H), 6.49 - 6.40 (m, 1H), 4.15 - 4.08 (m, 1H), 3.98 - 3.82 (m, 1H), 3.57 - 3.41 (m, 1H), 3.30 - 3.16 (m, 1H), 2.97 - 2.85 (m,1H), 1.88 - 1.79 (m, 2H), 1.68 - 1.60 (m, 1H), 1.47 (s, 9H). 24 in 25 reported (OH not observed).

[0971] Intermediate A-8-1: (3R,4S)-3-(4-(1H-pyrazol-1-yl)phenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0972]

[0973] Chiral separation and analysis of intermediate rac-A-8 according to method SFC-11: 271 mg provided intermediate A-8-1 (peak 1): 99 mg, white solid. LC-MS method C-4: Rt = 2.11 min; MS m / z [M-tBu+2H] + = 288.6. Analytical chiral HPLC: Rt = 2.38 min; 96% ee.

[0974] Intermediate A-9: (3R,4S)-4-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylic acid benzyl ester

[0975]

[0976] Step 1a: PtO2 (4.9 g) was added to a stirred solution of 5-(1-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester (intermediate K-4, 4.9 g, 15.7 mmol) in EtOH (50 mL) at room temperature. RM was stirred at RT for 16 h under H2 atmosphere (gas bag). RM was filtered through Celite® and the solids were washed with DCM. The combined filtrates were concentrated under reduced pressure. The crude material was purified by preparative HPLC (Waters XBridge C18 19 x 250 mm; 5 µm; eluent: 0% to 60% ACN in H2O with 0.02% NH4OH) to provide a racemic mixture (3R) of diastereomers. 4S )-4-hydroxy-3-(1-methyl-1H-pyrazole-4-yl)piperidine-1-carboxylic acid benzyl ester and racemic (3R 4R 1.6 g of benzyl 4-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate.

[0977] Step 1b: Separation and analysis according to method SFC-5: 1.6 g provided intermediate A-9 (peak 2): 367 mg. Analytical chiral HPLC: Rt = 4.77 min; 98.8% ee. 1H NMR (400 MHz) , CD3OD) δ [ppm] 7.49 - 7.42 (m, 1H), 7.41 - 7.27 (m, 6H), 5.19 - 5.06 (m, 2H), 4.03 - 3.99 (m, 1H), 3.82 (s, 3H), 3.76 (dd, J = 13.20, 4.11 Hz, 1H), 3.75 - 3.63 (m, 1H), 3.58 - 3.46 (m, 2H), 2.89 (dt, J = 9.28, 3.58 Hz, 1H), 1.69 - 1.79 (m, 2H). 20 in 21H reported (OH not observed)

[0978] Intermediates rac-A-10 and rac-A-11: racemic 4-((1S ,2S 5S methyl benzoate 2-hydroxy-5-methoxycyclohexyl)benzoate and racemic 4-((1S) ,2R 5S Methyl 2-hydroxy-5-methoxycyclohexyl)benzoate

[0979]

[0980] racemic 4-((1R) 5R Methyl benzoate (intermediate rac-K-5, 817 mg, 3.12 mmol) was combined with MeOH (3 mL) and THF (3 mL). The solution was cooled to 0°C and NaBH4 (118 mg, 3.12 mmol) was added. The RM was warmed to RT and stirred for 1 h. The RM was quenched with H2O and partially concentrated under reduced pressure. The mixture was extracted with DCM (3x). The combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by silica gel (40 g; eluent: 0% to 50% EtOAc in heptane) to provide racemic 4-((1S) ,2S 5S methyl 2-hydroxy-5-methoxycyclohexyl)benzoate (intermediate rac-A-10, first peak elution, 160 mg) and racemic 4-((1S) ,2R 5S Methyl benzoate (2-hydroxy-5-methoxycyclohexyl)benzoate (intermediate rac-A-11, eluted from the second peak, 587 mg). Intermediate rac-A-10: 1 H NMR (400 MHz, CDCl3) δ [ppm] 8.04 - 7.91(m, 2H), 7.37 - 7.29 (m, 2H), 4.06 - 3.99 (m, 1H), 3.90 (s, 3H), 3.73 - 3.64(m, 1H), 3.34 (s, 3H), 3.24 - 3.15 (m, 1H), 2.29 - 2.14 (m, 1H), 2.09 - 1.95 (m, 1H), 1.95 - 1.86 (m, 1H), 1.86 - 1.69 (m, 3H), 1.43 - 1.25 (m, 1H).

[0981] Intermediate rac-A-11: 1H NMR (400 MHz, CDCl3) δ [ppm] 8.04 - 7.97 (m, 2H),7.45 - 7.30 (m, 2H), 3.91 (s, 3H), 3.82 - 3.68 (m, 1H), 3.57 - 3.51 (m, 1H),3.35 (s, 3H), 3.00 - 2.87 (m, 1H), 2.20 - 2.02 (m, 2H), 1.96 - 1.85 (m, 1H), 1.85 - 1.70 (m, 1H), 1.68 - 1.48 (m, 2H), 1.48 - 1.41 (m, 1H).

[0982] Intermediate A-10-1: Methyl 4-((1S,2S,5S)-2-hydroxy-5-methoxycyclohexyl)benzoate

[0983]

[0984] Chiral separation and analysis of intermediate rac-A-10 according to method SFC-12: 20 g provided intermediate A-10-1 (peak 1): 9.0 g, gray solid. 1 ¹H NMR (400 MHz, CDCl₃) δ [ppm] 8.02 - 7.92 (m, 2H), 7.32 (d, J = 8.4 Hz, 2H), 4.00 - 3.95 (m, 1H), 3.85 (s, 3H), 3.70 (s, 1H), 3.35 - 3.29 (m, 3H), 3.22 - 3.13 (m, 1H), 2.24 - 2.15 (m, 1H), 2.03 - 1.94 (m, 1H), 1.89 - 1.86 (m, 1H), 1.84 - 1.67 (m, 3H), 1.50 (s, 1H). Analytical chiral HPLC: Rt = 1.63 min; 99% ee.

[0985] Intermediates rac-A-12 and rac-A-13: racemic 4-((1S ,2S 5R methyl benzoate 2-hydroxy-5-methoxycyclohexyl)benzoate and racemic 4-((1S) ,2R 5R Methyl 2-hydroxy-5-methoxycyclohexyl)benzoate

[0986]

[0987] As described for intermediates rac-A-10 and rac-A-11, the use of exoracemic 4-((1S) 5R Methyl benzoate (5-methoxy-2-oxocyclohexyl)benzoate (intermediate rac-K-6, 217 mg, 0.83 mmol) was used to prepare intermediates rac-A-12 and rac-A-13, providing racemic 4-((1S) ,2S 5R methyl 2-hydroxy-5-methoxycyclohexyl)benzoate (intermediate rac-A-12, first peak elution, 45 mg) and racemic 4-((1S) ,2R 5R Methyl benzoate (2-hydroxy-5-methoxycyclohexyl)benzoate (intermediate rac-A-13, eluted from the second peak, 137 mg). Intermediate rac-A-12: 1 H NMR(400 MHz, CDCl3) δ [ppm] 8.05 - 7.98 (m, 2H), 7.38 - 7.31 (m, 2H), 4.01 -3.96 (m, 1H), 3.91 (s, 3H), 3.41 (s, 3H), 3.39 - 3.25 (m, 1H), 2.90 - 2.75(m, 1H), 2.14 - 2.00 (m, 3H), 1.99 - 1.87 (m, 1H), 1.73 - 1.61 (m, 2H), 1.59- 1.44 (m, 1H).

[0988] Intermediate rac-A-13: 1 H NMR (400 MHz, CDCl3) δ [ppm] 8.01 (d, J = 7.6 Hz,2H), 7.32 (d, J = 7.9 Hz, 2H), 3.90 (s, 3H), 3.77 - 3.64 (m, 1H), 3.35 (s,3H), 3.33 - 3.25 (m, 1H), 2.66 - 2.49 (m, 1H), 2.23 - 2.07 (m, 3H), 1.62 -1.34 (m, 4H).

[0989] Intermediate rac-A-14: racemic 4-((7S) 8S methyl 8-hydroxy-1-oxaspiro[4.5]dec-7-yl)benzoate

[0990]

[0991] racemic 4-((5S) 7S Methyl benzoate (intermediate rac-K-7, 128 mg, 0.44 mmol) was combined with MeOH (2 mL) and THF (0.5 mL). NaBH4 (50 mg, 1.3 mmol) was added, and the RM was stirred at RT for 1 h. The RM was quenched with H2O and partially concentrated under reduced pressure. The mixture was extracted with DCM (3x). The combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by silica gel (12 g; eluent: 10% to 50% EtOAc in heptane) to provide racemic 4-((7S) 8S Methyl benzoate (first eluting diastereomer, 20.9 mg). 1 ¹H NMR (400MHz, CDCl₃) δ [ppm] 8.04 - 7.95 (m, 2H), 7.38 - 7.30 (m, 2H), 4.05 - 3.97 (m, 1H), 3.91 (s, 3H), 3.88 - 3.78 (m, 2H), 3.31 - 3.20 (m, 1H), 2.21 (t, J = 13.2 Hz, 1H), 2.14 - 1.71 (m, 7H), 1.70 - 1.51 (m, 2H). ¹H 21 is reported in ¹H (OH not observed).

[0992] Intermediate rac-A-15: racemic (3R) 4S 3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0993]

[0994] 3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-4-oxopiperidin-1-carboxylic acid tert-butyl ester (intermediate K-8, 96 mg, 0.28 mmol) was dissolved in MeOH (3 mL), and NaBH4 (25 mg, 0.66 mmol) was added. RM was stirred at RT for 1 h. RM was quenched with H2O, and the mixture was extracted with DCM (3x). The combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by silica gel (24 g; eluent: 15% to 50% EtOAc in heptane) to provide a racemic (3R) as a colorless oil. 4S 3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (82 mg). 1 H NMR (400 MHz, CDCl3) δ [ppm] 8.53 (d, J = 2.6 Hz,1H), 8.30 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.74 (dd, J = 15.6,2.1 Hz, 2H), 6.50 - 6.47 (m, 1H), 4.18 - 4.14 (m, 1H), 3.98 - 3.89 (m, 1H), 3.60 - 3.50 (m, 1H), 3.37 - 3.19 (m, 1H), 2.97 - 2.90 (m\, 1H), 1.91 - 1.81(m, 2H), 1.77 - 1.68 (m, 1H), 1.47 (s, 9H). 23 is reported in 24H (OH not observed).

[0995] Intermediate rac-A-16: racemic (3R) 4S 3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester

[0996]

[0997] As described for intermediate rac-A-15, intermediate rac-A-16 was prepared using tert-butyl 3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-4-oxopiperidin-1-carboxylate (intermediate K-9, 500 mg, 1.46 mmol), providing a racemic (3R) solid as a white solid. 4S 3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (72 mg). 1 H NMR (400 MHz, CDCl3) δ [ppm] 7.99 (d, J = 1.3 Hz, 1H), 7.86 (d, J = 1.2Hz, 1H), 7.76 - 7.70 (m, 2H), 7.47 - 7.41 (m, 2H), 4.20 - 4.15 (m, 1H), 4.10- 4.04 (m, 1H), 4.00 - 3.92 (m, 1H), 3.58 - 3.48 (m, 1H), 3.28 - 3.24 (m,1H), 3.00 - 2.94 (m, 1H), 1.92 - 1.81 (m, 2H), 1.48 (s, 9H). 23 was reported in 24H (OH was not observed).

[0998] Intermediate rac-A-22: racemic 4-((1S) ,2S methyl 2-hydroxycyclohexylbenzoate

[0999]

[1000] Methyl 4-(2-oxocyclohexyl)benzoate (intermediate K-15, 705 mg, 3.03 mmol) was combined with MeOH (4 mL). The solution was cooled to 0°C and NaBH4 (264 mg, 6.98 mmol) was added. The RM was warmed to RT and stirred for 1 h. The RM was quenched with H2O and extracted with DCM (2x). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel (25 g; eluent: 0% to 30% EtOAc in heptane) to provide racemic 4-((1S) as a white solid. ,2S Methyl 2-hydroxycyclohexyl)benzoate (first peak elution, 264 mg). 1H NMR(400 MHz, DMSO-d6) δ [ppm] 7.87 - 7.84 (m, 2H), 7.41 - 7.38 (m, 2H), 4.30 -4.28 (m, 1H), 3.89 - 3.85 (m, 1H), 3.83 (s, 3H), 2.74 - 2.66 (m, 1H), 2.05 -1.96 (m, 1H), 1.79 - 1.73 (m, 2H), 1.69 - 1.63 (m, 1H), 1.59 - 1.53 (m, 1H),1.50 - 1.45 (m, 1H), 1.44 - 1.39 (m, 1H), 1.39 - 1.29 (m, 1H).

[1001] Intermediate rac-A-23: racemic 4-((1S) ,2R Methyl 5,5-difluoro-2-hydroxycyclohexyl)benzoate

[1002]

[1003] Methyl 4-(5,5-difluoro-2-oxocyclohexyl)benzoate (intermediate K-16, 100 mg, 0.37 mmol) was dissolved in MeOH (2.5 mL). The solution was cooled to 0°C and NaBH4 (32.4 mg, 0.86 mmol) was added. The RM was stirred for 1 h. The RM was quenched with saturated NH4Cl solution and EtOAc and warmed to RT. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel (12 g; eluent: 0% to 30% EtOAc in cyclohexane) to provide racemic 4-((1S) as a white solid. ,2R Methyl benzoate (82.5 mg) of 5,5-difluoro-2-hydroxycyclohexyl benzoate. 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 7.95 - 7.81(m, 2H), 7.52 - 7.35 (m, 2H), 4.66 (d, J = 6.1 Hz, 1H), 3.84 (s, 3H), 3.80 -3.69 (m, 1H), 2.81 - 2.69 (m, 1H), 2.32 - 2.14 (m, 1H), 2.12 - 1.93 (m, 4H), 1.61 - 1.48 (m, 1H).

[1004] Intermediate rac-A-24: racemic 4-((1S) ,2S 5S methyl 5-((tert-butyldimethylsilyl)oxy)-2-hydroxycyclohexyl)benzoate

[1005]

[1006] As described for intermediate rac-A-23, use exoracemic 4-((1S) 5S The intermediate rac-A-24 was prepared by reacting methyl 5-((tert-butyldimethylsilyl)oxy)-2-oxocyclohexyl)benzoate (intermediate rac-K-17, 235 mg, 0.64 mmol) with a solution of tri-sec-butyllithium borohydride (1 M, in THF, 0.84 mL, 0.84 mmol), providing a racemic 4-((1S)-2-oxocyclohexyl)benzoate as a colorless semi-solid. ,2S 5S Methyl 5-((tert-butyldimethylsilyl)oxy)-2-hydroxycyclohexyl)benzoate (73 mg). LC-MS Method B-1: Rt = 1.6 min; MS m / z [M+H] + = 365.4.

[1007] Intermediate A-25: Methyl 4-((1S,2S,5R)-2-hydroxy-5-methylcyclohexyl)benzoate

[1008]

[1009] Step 1a: Racemic 4-((1S) 5R Methyl 5-methyl-2-oxocyclohexyl)benzoate (intermediate K-18, 6.5 g, 26.4 mmol) was dissolved in MeOH (65 mL) and cooled to 0°C. NaBH4 (2.0 mg, 52.8 mmol) was added, and the mixture was stirred for 30 min. The mixture was diluted with H2O and EtOAc and warmed to RT. The separated organic phase was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel (80 g; eluent: 0% to 30% EtOAc in heptane) to provide a racemic 4-((1S) solid as a grayish-white solid. ,2S 5R Methyl 2-hydroxy-5-methylcyclohexyl)benzoate (eluted from the first peak) (1.0 g).

[1010] Step 1b: Chiral separation and analysis according to method SFC-18: 2.67 g of intermediate A-25 (peak 1) was provided: 1.17 g, white solid. LC-MS method A-1: ​​Rt = 3.27 min; MS m / z [M+H] + = 249.1. Analytical chiral HPLC: Rt= 2.87 min; 99.7% ee.

[1011] Intermediate rac-A-26: racemic 4-((5S) 6S methyl 6-hydroxyspiro[2,5]oct-5-yl)benzoate

[1012]

[1013] Methyl 4-(6-oxospiro[2.5]oct-5-yl)benzoate (intermediate K-19, 1.05 g, 4.07 mmol) was combined with THF (10.5 mL). The solution was cooled to -78°C and a solution of trisec-butylborohydride (1 M, in THF, 8.1 mL, 8.1 mmol) was added dropwise. The RM was stirred for 1 h. The RM was quenched with an aqueous solution of MeOH and HCl (2 M) and warmed to RT. EtOAc and H2O were added. The separated aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, and concentrated under reduced pressure. Recrystallization from hexane by silica gel column chromatography (40 g; eluent: 5% to 30% EtOAc in heptane) provided a racemic 4-((5S) 6S Methyl 6-hydroxyspiro[2,5]oct-5-yl)benzoate (399 mg). LC-MS method B-1: Rt = 1.15 min; MS m / z [M+H] + = 261.2.

[1014] Intermediate rac-A-28: racemic 4-((1S) ,2S Methyl 5,5-difluoro-2-hydroxycyclohexyl)benzoate

[1015]

[1016] Methyl 4-(5,5-difluoro-2-oxocyclohexyl)benzoate (intermediate K-16, 97 mg, 0.36 mmol) was combined with THF (2 mL). The solution was cooled to -78°C and a solution of trisec-butyl borohydride (1 M, in THF, 0.58 mL, 0.58 mmol) was added. The RM was stirred for 1 h. The RM was quenched with a saturated aqueous NH4Cl solution, warmed to RT, and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel (12 g; eluent: 0% to 25% EtOAc in cyclohexane) to provide racemic 4-((1S) as a white solid. ,2S Methyl benzoate (82.5 mg) of 5,5-difluoro-2-hydroxycyclohexyl benzoate. 1 H NMR (400MHz, DMSO-d6) δ [ppm] 7.93 - 7.83 (m, 2H), 7.52 - 7.34 (m, 2H), 4.74 (d, J =4.4 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.84 (s, 3H), 3.09 - 2.98 (m, 1H), 2.58 -2.40 (m, 1H), 2.24 - 2.02 (m, 1H), 2.01 - 1.73 (m, 4H).

[1017] Intermediate rac-A-31: racemic 4-((7S) 8S methyl 8-hydroxy-1,4-dioxaspiro[4.5]dec-7-yl)benzoate

[1018]

[1019] Methyl 4-(8-oxo-1,4-dioxaspiro[4.5]dec-7-yl)benzoate (intermediate K-23, 1.50 g, 5.17 mmol) was combined with THF (50 mL). The solution was cooled to -78°C, and a solution of tri-sec-butylborohydride (1 M, in THF, 8.7 mL, 8.7 mmol) was added dropwise. The RM was stirred for 1 h. An additional solution of tri-sec-butylborohydride (1 M, in THF, 3.1 mL, 3.1 mmol) was added dropwise, and the RM was stirred for 1 h. The RM was diluted with a saturated aqueous solution of MeOH and NH4Cl and then heated to RT. The separated aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purified by silica gel column chromatography (120 g; eluent: 0% to 30% EtOAc in cyclohexane), it provides a white solid racemic 4-((7S) 8S Methyl benzoate (960 mg)-8-hydroxy-1,4-dioxaspiro[4.5]dec-7-yl)benzoate. LC-MS method B-1: Rt = 0.71 min; MS m / z [M+H] + =293.1.

[1020] Intermediate rac-M-1: racemic 4-(((3R) 4R 1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1021]

[1022] racemic (3R) 4S 4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate rac-A-1, 150 mg, 0.45 mmol), PPh3 (160 mg, 0.61 mmol), and 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-1, 93 mg, 0.36 mmol) were dissolved in THF (1.25 mL). DIAD (115 µL, 0.59 mmol) was added, and RM was stirred overnight at RT. RM was concentrated under reduced pressure and purified by silica gel (12 g; eluent: 0% to 30% EtOAc in heptane) to provide racemic 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (48 mg) as a colorless foam. LC-MS method C-1: Rt = 1.57 min; MS m / z [M+H] + = 579.3.

[1023] Intermediate rac-M-2: racemic (3R) 4S 4-((5,7-dimethyl-1-toluenesulfonyl-1H-indol-4-yl)oxy)-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester

[1024]

[1025] 5,7-Dimethyl-1-toluenesulfonyl-1H-indole-4-ol (intermediate I-2, 60 mg, 0.19 mmol), racemic (3R) 4R 4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate rac-A-2, 64 mg, 0.19 mmol) and PPh3 (54.7 mg, 0.28 mmol) were dissolved in THF (0.7 mL). DIAD (55 µL, 0.26 mmol) was added dropwise, and RM was stirred overnight at RT. RM was concentrated under reduced pressure and purified by silica gel (elution: 0% to 100% EtOAc in heptane) to provide a racemic (3R) mixture as a pale yellow oil. 4S 4-((5,7-dimethyl-1-toluenesulfonyl-1H-indol-4-yl)oxy)-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (87.3 mg). LC-MS method C-1: Rt = 1.49 min; MS m / z [M-Boc+2H] + = 533.1.

[1026] Intermediate M-3: 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1027]

[1028] 5-Cyclopropyl-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-3, 50 mg, 0.17 mmol), (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate A-3, 61 mg, 0.18 mmol), and PPh3 (54.7 mg, 0.21 mmol) were dissolved in toluene (0.4 mL). A DIAD solution (55 µL, 0.26 mmol) was added dropwise to toluene (0.15 mL) over 10 min. The solution was stirred overnight at RT. RM was concentrated under reduced pressure and purified by silica gel (elution: 0% to 40% EtOAc in heptane) to provide tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylic acid (26.2 mg) as a colorless oil. LC-MS method C-1: Rt = 1.55 min; MS m / z [M+H] + =605.2.

[1029] Intermediate M-4: 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-chloro-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1030]

[1031] Intermediate M-4 was prepared as described for intermediate M-3 using tert-butyl 5-chloro-4-hydroxy-7-methyl-1H-indole-1-carboxylate (intermediate I-4, 30 mg, 0.11 mmol) and (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidin-1-carboxylate (intermediate A-3, 64.3 mg, 0.19 mmol), providing tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-chloro-7-methyl-1H-indole-1-carboxylate (39 mg) as a colorless oil. LC-MS method C-1: Rt = 1.57 min; MS m / z [M-Boc+2H] + = 499.2.

[1032] Intermediate M-5: 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1033]

[1034] (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate A-3, 152 mg, 0.45 mmol) was dissolved in toluene (4 mL) and THF (0.5 mL). PPh3 (178 mg, 0.68 mmol) and 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-1, 118 mg, 0.45 mmol) were added, and the solution was cooled to 0°C. DEAD solution (40 wt%, in toluene, 0.31 mL, 0.68 mmol) was diluted with toluene (0.25 mL), and the DEAD solution was added dropwise to the cooled solution over 30 min. RM was stirred at 0°C for 15 min, and then gradually warmed to RT and stirred overnight. 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (112 mg) was enriched as a colorless oil by silica gel column chromatography (12 g; eluent: 0% to 25% EtOAc in heptane). LC-MS method C-1: Rt = 1.55 min; MS m / z [M-Boc+2H] + = 479.3.

[1035] Intermediate M-6: 4-(((4R,5S)-1-(tert-butoxycarbonyl)-5-(4-(methoxycarbonyl)phenyl)azacycloheptane-4-yl)oxy)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1036]

[1037] (4S,5S)-4-hydroxy-5-(4-(methoxycarbonyl)phenyl)azacycloheptane-1-carboxylic acid tert-butyl ester (intermediate A-4, 80 mg, 0.23 mmol), 5-cyclopropyl-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-3, 67 mg, 0.23 mmol), and PPh3 (90 mg, 0.34 mmol) were dissolved in toluene (0.4 mL). The mixture was cooled to 0°C, and a solution of DIAD (67 µL, 0.34 mmol) in toluene (0.4 mL) was added dropwise. The RM was warmed to RT and stirred for 18 h. The mixture was purified by silica gel (12 g; eluent: 0% to 45% EtOAc in heptane) to provide tert-butyl 4-(((4R,5S)-1-(tert-butoxycarbonyl)-5-(4-(methoxycarbonyl)phenyl)azacycloheptane-4-yl)oxy)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylic acid (15 mg) as a colorless oil. LC-MS method C-1: Rt = 1.55 min; MS m / z [M-tBu+2H] + = 563.2.

[1038] Intermediate M-7: 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)azacycloheptane-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1039]

[1040] (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)azacycloheptan-1-carboxylic acid tert-butyl ester (intermediate A-5, 100 mg, 0.378 mmol), 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-1, 99 mg, 0.38 mmol), and PPh3 (149 mg, 0.57 mmol) were dissolved in a mixture of toluene (0.6 mL) and THF (0.1 mL). The solution was cooled to 0°C. The DEAD solution (40 wt%, in toluene, 0.26 mL, 0.57 mmol) was further diluted with toluene (0.3 mL), and the DEAD solution was added dropwise to the cooled solution over 1 h. The RM was stirred at RT for 18 h. RM was concentrated under reduced pressure and purified by silica gel (12 g; eluent: 0% to 20% EtOAc in heptane) to provide 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)azacycloheptan-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (45.7 mg) as a colorless oil. LC-MS method C-1: Rt = 1.57 min; MS m / z [M-Boc+2H] + = 493.3.

[1041] Intermediate rac-M-8: racemic 4-(((3S) 4R 1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-3-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1042]

[1043] racemic (3R) 4R 3-hydroxy-4-phenylpyrrolidine-1-carboxylic acid tert-butyl ester (intermediate rac-A-6, 100 mg, 0.38 mmol), 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-1, 89 mg, 0.34 mmol) and PPh3 (149 mg, 0.57 mmol) were dissolved in toluene (0.4 mL), and the solution was cooled to 0°C. DEAD solution (40 wt%, in toluene, 0.26 mL, 0.57 mmol) was added dropwise over approximately 20 min. The RM was stirred at 0°C for 30 min and then gradually warmed to RT. The RM was stirred at RT for 3 days. Enriched racemic 4-(((3S) was obtained by silica gel column chromatography (12 g; eluent: 0% to 15% EtOAc in heptane). 4R 1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-3-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (124 mg). LC-MS method C-1: Rt = 1.56 min; MS m / z [M-tBu-Boc+2H] + = 350.9.

[1044] Intermediate M-9: 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-cyanophenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1045]

[1046] (3R,4S)-3-(4-cyanophenyl)-4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (intermediate A-7, 106 mg, 0.35 mmol), 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-1, 96 mg, 0.37 mmol), and PPh3 (138 mg, 0.53 mmol) were dissolved in toluene (0.5 mL), and the solution was cooled to 0°C. DEAD solution (40 wt%, in toluene, 0.24 mL, 0.53 mmol) was further diluted with toluene (0.25 mL), and the DEAD solution was added dropwise to the cooled solution over 45 min. RM was gradually warmed to RT, and RM was stirred at RT overnight. The mixture was purified by silica gel (12 g; eluent: 0% to 20% EtOAc in heptane) to provide tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-cyanophenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylate (77 mg) as a colorless oil. LC-MS method C-1: Rt = 1.53 min; MS m / z [M-Boc+2H] + = 446.3.

[1047] Intermediate rac-M-10: racemic 4-(((3R) 4R 3-(4-(1H-pyrazol-1-yl)phenyl)-1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1048]

[1049] racemic (3R) 4S 3-(4-(1H-pyrazol-1-yl)phenyl)-4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (intermediate rac-A-8, 81 mg, 0.24 mmol) was dissolved in toluene (0.4 mL), and PPh3 (92 mg, 0.35 mmol) was added, followed by 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-1, 61 mg, 0.24 mmol). The mixture was sonicated and then cooled to 0°C. DEAD solution (40 wt%, in toluene, 0.16 mL, 0.35 mmol) was further diluted with toluene (0.25 mL), and the DEAD solution was added dropwise to the cooled solution over 30 min. RM was stirred at 0°C for approximately 30 min, and then gradually warmed to RT. RM was stirred overnight at RT and then subjected to silica gel column chromatography (12 g; eluent: 0% to 40% EtOAc in heptane) to provide enriched racemic 4-(((3R) as a colorless oil. 4R 3-(4-(1H-pyrazol-1-yl)phenyl)-1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (99 mg). LC-MS method C-1: Rt = 1.53 min; MS m / z [M+H] + = 587.2.

[1050] Intermediate M-11: 4-(((3R,4R)-1-((benzyloxy)carbonyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1051]

[1052] (3R,4S)-4-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylic acid benzyl ester (intermediate A-9, 41 mg, 0.13 mmol) was dissolved in THF (0.25 mL), and PPh3 (51 mg, 0.20 mmol) was added, followed by tert-butyl 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylic acid (intermediate I-1, 34 mg, 0.13 mmol). The RM was cooled to 0°C. The DEAD solution (40 wt%, in toluene, 89 µL, 0.20 mmol) was further diluted with toluene (0.25 mL), and the DEAD solution was added dropwise to the cooled solution over 45 min. The RM was warmed to RT and stirred overnight. 4-(((3R,4R)-1-((benzyloxy)carbonyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (86 mg) was enriched by silica gel column chromatography (12 g; eluent: 0% to 100% EtOAc in heptane). LC-MS method C-1: Rt = 1.39 min; MS m / z [M+H] + = 559.3.

[1053] Intermediate rac-M-12: racemic 4-(((1R) ,2S 4S 4-Methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1054]

[1055] racemic 4-((1S) ,2S 5S Methyl benzoate (intermediate rac-A-10, 56 mg, 0.21 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylate (intermediate I-1, 55 mg, 0.21 mmol), and PPh3 (83 mg, 0.32 mmol) were dissolved in toluene (0.3 mL). The mixture was sonicated for 1 min and then cooled to 0°C. The DEAD solution (40 wt%, in toluene, 0.15 mL, 0.32 mmol) was further diluted with toluene (0.3 mL) and added dropwise to the cooled solution over 20 to 30 min. The RM was stirred at 0°C for 20 min and then gradually warmed to RT. The RM was stirred at RT for 2 days. RM was concentrated under reduced pressure and purified by silica gel (12 g; eluent: 0% to 20% EtOAc in heptane) to provide racemic 4-(((1R) ,2S 4S 4-Methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (84 mg). LC-MS method C-1: Rt = 1.53 min; MS m / z [M-Boc+2H] + = 408.3.

[1056] Intermediate rac-M-13: racemic 4-(((1R) ,2S 4R 4-Methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1057]

[1058] racemic 4-((1S) ,2S 5R Methyl benzoate (intermediate rac-A-12, 45 mg, 0.17 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylate (intermediate I-1, 44 mg, 0.17 mmol), and PPh3 (66 mg, 0.25 mmol) were dissolved in toluene (0.4 mL). The mixture was sonicated for 1 min and then cooled to 0°C. The DEAD solution (40 wt%, in toluene, 0.12 mL, 0.25 mmol) was further diluted with toluene (0.3 mL) and added dropwise to the cooled solution over approximately 25 min. The RM was stirred at 0°C for 20 min and then gradually warmed to RT. The RM was stirred at RT for 2 days. RM was concentrated under reduced pressure and purified by silica gel (12 g; eluent: 0% to 20% EtOAc in heptane) to provide racemic 4-(((1R) ,2S 4R 4-Methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (8.7 mg). LC-MS method C-1: Rt = 1.52 min; MS m / z [M-Boc+2H] + = 408.2.

[1059] Intermediate rac-M-14: racemic 4-(((1S) ,2S 4S 4-Methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1060]

[1061] racemic 4-((1S) ,2S 5R Methyl benzoate (intermediate rac-A-11, 60.7 mg, 0.23 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylate (intermediate I-1, 60.0 mg, 0.23 mmol), and PPh3 (90.3 mg, 0.34 mmol) were dissolved in toluene (0.5 mL), and the mixture was cooled to 0°C. DEAD solution (40 wt%, in toluene, 0.16 mL, 0.34 mmol) was further diluted with toluene (0.3 mL), and the DEAD solution was added dropwise to the cooled solution over 20 min. The RM was stirred at 0°C for 20 min, and then gradually warmed to RT. The RM was stirred at RT for 3 days. RM was concentrated under reduced pressure and purified by silica gel (12 g; eluent: 0% to 20% EtOAc in heptane) to provide racemic 4-(((1S) ,2S 4S 4-Methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (36 mg). LC-MS method: C-1Rt = 1.53 min; MS m / z [M+H] + = 508.0.

[1062] Intermediate rac-M-15: racemic 4-(((1S) ,2S 4R 4-Methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1063]

[1064] racemic 4-((1S) ,2R 5R Methyl benzoate (intermediate rac-A-13, 60 mg, 0.23 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylate (intermediate I-1, 59.3 mg, 0.23 mmol), and PPh3 (90.3 mg, 0.34 mmol) were dissolved in toluene (0.3 mL), and the mixture was cooled to 0°C. DEAD solution (40 wt%, in toluene, 0.16 mL, 0.34 mmol) was further diluted with toluene (0.3 mL), and the DEAD solution was added dropwise to the cooled solution over 20 min. RM was stirred at 0°C for 20 min, and then gradually warmed to RT. RM was stirred at RT overnight. RM was concentrated under reduced pressure and purified by silica gel (12 g; eluent: 0% to 20% EtOAc in heptane) to provide a racemic 4-(((1S) as a colorless oil. ,2S 4R 4-Methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (36 mg). LC-MS method C-1: Rt = 1.53 min; MS m / z [M+H] + = 508.2.

[1065] Intermediate rac-M-16: racemic 4-(((7S) ,8R 7-(4-(methoxycarbonyl)phenyl)-1-oxaspiro[4.5]dec-8-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1066]

[1067] racemic 4-((5S) 7S 8S Methyl benzoate (intermediate rac-A-12, 20 mg, 70 µmol), tert-butyl 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylate (intermediate I-1, 18 mg, 70 µmol), and PPh3 (27 mg, 0.11 mmol) were dissolved in toluene (0.3 mL). The mixture was sonicated for 1 min and then cooled to 0°C. The DEAD solution (40 wt%, in toluene, 48 µL, 0.11 mmol) was further diluted with toluene (0.3 mL) and added dropwise to the cooled solution over 30 min. The RM was stirred at 0°C for 15 min and then gradually warmed to RT. RM was stirred overnight at RT and then purified by silica gel (12 g; eluent: 0% to 25% EtOAc in heptane) to provide a racemic 4-(((7S) as a colorless oil. ,8R 7-(4-(methoxycarbonyl)phenyl)-1-oxaspiro[4.5]dec-8-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (37 mg). LC-MS method C-1: Rt = 1.56 min; MS m / z [M-Boc+2H] + = 434.3.

[1068] Intermediate M-17: 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1069]

[1070] (3R,4S)-3-(4-(1H-pyrazol-1-yl)phenyl)-4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (intermediate A-8-1, 101.2 mg, 0.29 mmol), PPh3 (105.4 mg, 0.40 mmol), and 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-1, 70 mg, 0.27 mmol) were combined in THF (3 mL). The mixture was cooled to 0°C. A solution of DBAD (92.5 mg, 0.4 mmol) in toluene (0.5 mL) was added dropwise to the cooled solution over 10 min. The RM was gradually warmed to RT and stirred overnight. The RM was diluted with H2O, and the mixture was extracted with EtOAc (3x). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. Silica gel column chromatography (elution: 0% to 50% EtOAc in heptane) yielded an enriched white solid of tert-butyl 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid (128 mg). LC-MS method C-1: Rt = 1.54 min; MS m / z [M+H] + = 587.4.

[1071] Intermediate rac-M-18: racemic 4-(((3R) 4R 3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1072]

[1073] racemic (3R) 4S 3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (intermediate rac-A-15, 59 mg, 0.17 mmol), 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-1, 44.7 mg, 0.17 mmol), and PPh3 (67 mg, 0.26 mmol) were dissolved in toluene (0.5 mL). The mixture was cooled to 0°C. The DEAD solution (40 wt%, in toluene, 0.12 mL, 0.26 mmol) was further diluted with toluene (0.25 mL) and added dropwise to the cooled solution over 30 min. The RM was stirred at 0°C for 15 min and then warmed to RT. The RM was stirred at RT overnight. The material enriched by silica gel column chromatography (12 g; eluent: 0% to 25% EtOAc in heptane) was purified by RP chromatography (15.5 g C18; eluent: 60% to 100% ACN in H2O, each with 0.1% FA) to provide a racemic 4-(((3R) mixture as a colorless oil. 4R 3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (37.8 mg). LC-MS method C-1: Rt = 1.53 min; MS m / z [M+H] + = 588.3.

[1074] Intermediate rac-M-19: racemic 4-(((3R) 4R 3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1075]

[1076] racemic (3R) 4S 3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-4-hydroxypiperidin-1-carboxylic acid tert-butyl ester (intermediate rac-A-16, 72 mg, 0.21 mmol), 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-1, 54.6 mg, 0.21 mmol), and PPh3 (82.3 mg, 0.31 mmol) were dissolved in toluene (0.2 mL) and THF (1 mL). The mixture was cooled to 0°C. The DEAD solution (40 wt%, in toluene, 0.14 mL, 0.31 mmol) was further diluted with toluene (0.5 mL) and added dropwise to the cooled solution over 30 min. The RM was stirred at 0°C for 15 min and then warmed to RT. The RM was stirred at RT overnight. The material enriched by silica gel column chromatography (12 g; eluent: 0% to 25% EtOAc in heptane) was purified by RP chromatography (15.5 g C18; eluent: 55% to 100% ACN in H2O, each with 0.1% FA) to provide a white solid racemic 4-(((3R) 4R 3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (30.5 mg). LC-MS method C-1: Rt = 1.42 min; MS m / z [M+H] + = 588.5.

[1077] Intermediate rac-M-28: racemic 5-cyclopropyl-4-(((1R) ,2S 4S 4-Methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1078]

[1079] racemic 4-((1S) ,2S 5S Methyl benzoate (intermediate rac-A-10, 100 mg, 0.38 mmol), tert-butyl 4-hydroxy-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (intermediate I-3, 108.7 mg, 0.38 mmol), and PPh3 (148.8 mg, 0.57 mmol) were dissolved in toluene (0.4 mL). The mixture was cooled to 0°C. The DEAD solution (40 wt%, in toluene, 0.26 mL, 0.57 mmol) was further diluted with toluene (0.5 mL) and added dropwise to the cooled solution. The RM was stirred at 0°C for 20 min and then warmed to RT. RM was stirred overnight at RT and then purified by silica gel (12 g; eluent: 0% to 15% EtOAc in heptane) to provide a racemic 5-cyclopropyl-4-(((1R) as a colorless oil. ,2S 4S 4-Methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (130 mg). LC-MS method C-1: Rt = 1.52 min; MS m / z [M-Boc+2H] + = 434.3.

[1080] Intermediate rac-M-29: racemic 5-chloro-4-(((1R) ,2S 4S 4-Methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1081]

[1082] tert-butyl 5-chloro-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid (intermediate I-4, 131 mg, 0.46 mmol), racemic 4-((1S) ,2S 5S Methyl benzoate (intermediate rac-A-10, 135.2 mg, 0.51 mmol) and PPh3 (146.3 mg, 0.56 mmol) were dissolved in toluene (0.4 mL). DIAD (0.14 mL, 0.70 mmol) was added dropwise to toluene (0.1 mL) over 10 min. RM was stirred overnight at RT. RM was concentrated under reduced pressure and purified by silica gel (elution: 0% to 25% EtOAc in heptane) to provide a colorless oily racemic 5-cyclopropyl-4-(((1R) ,2S 4S 4-Methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (163 mg). LC-MS method C-2: Rt = 1.57 min; MS m / z [M-Boc] - = 426.3.

[1083] Intermediate M-30: tert-butyl 5-fluoro-4-(((1R,2S,4S)-4-methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid

[1084]

[1085] 5-Fluoro-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-5, 15 mg, 56 µmol), methyl 4-((1S,2S,5S)-2-hydroxy-5-methoxycyclohexyl)benzoate (intermediate A-10-1, 22.4 mg, 85 µmol), and PPh3 (37.1 mg, 0.14 mmol) were dissolved in THF (0.5 mL). DIAD (27 µL, 0.14 mmol) was added dropwise. RM was stirred at RT for 4 h. RM was quenched with H2O and extracted with EtOAc (2x). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel (10 g; eluent: 0% to 15% EtOAc in heptane) to provide tert-butyl 5-fluoro-4-(((1R,2S,4S)-4-methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid as a yellow solid (163 mg). LC-MS method B-1: Rt = 1.67 min; MS m / z [M+H2O]+ = 529.5.

[1086] Intermediate M-31: 4-(((1R,2S,4S)-4-methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1087]

[1088] 4-Hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-6, 45.0 mg, 0.18 mmol), 4-((1S,2S,5S)-2-hydroxy-5-methoxycyclohexyl)benzoate (intermediate A-10-1, 64.1 mg, 0.19 mmol), and PPh3 (57.3 mg, 0.21 mmol) were dissolved in toluene (0.3 mL). DIAD (53 µL, 0.70 mmol) solution was added dropwise to toluene (0.1 mL) over 10 min. The mixture was stirred overnight at RT. RM was concentrated under reduced pressure and purified by silica gel (12 g; eluent: 0% to 50% EtOAc in heptane) to provide tert-butyl 4-(((1R,2S,4S)-4-methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid as a colorless oil (14 mg). LC-MS method C-2: Rt = 1.52 min; MS m / z [M-Boc+2H]+ = 394.4.

[1089] Intermediate rac-M-32: racemic 4-(((1R) ,2S 2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1090]

[1091] racemic 4-((1S) ,2S Methyl 4-(((1R)-2-hydroxycyclohexyl)benzoate (intermediate rac-A-22, 264 mg, 1.13 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylate (intermediate I-1, 323.9 mg, 1.24 mmol), and PPh3 (591.1 mg, 2.25 mmol) were dissolved in toluene (6 mL). The mixture was cooled to 0°C. A DEAD solution (40 wt%, in toluene, 0.88 mL, 2.25 mmol) was added to the cooled solution. The RM was stirred at 0°C for 30 min and then warmed to RT. The RM was stirred at RT overnight and concentrated under reduced pressure. Silica gel column chromatography (25 g; eluent: 0% to 30% EtOAc in heptane) provided an enriched racemic 4-(((1R) as a white solid. ,2S 2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (317.8 mg). LC-MS method B-1: Rt = 1.73 min; MS m / z [M+H] + = 478.3.

[1092] Intermediate rac-M-33: racemic 4-(((1R) ,2S 4,4-Difluoro-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1093]

[1094] In the glove box, the external racemic 4-((1R) ,2S Methyl benzoate (intermediate rac-A-23, 73.5 mg, 0.27 mmol), tert-butyl 4-bromo-5,7-dimethyl-1H-indole-1-carboxylate (70.0 mg, 0.22 mmol), phthalimide (47.7 mg, 0.32 mmol), Ir[pF(Me)ppy]2(dtbbpy)PF6 (CAS#1335047-34-1, 4.2 mg, 3.4 µmol), and (4,4'-dtbbpy)NiCl2 (CAS# 1034901-50-2, 8.6 mg, 21.6 µmol) were combined in ACN (1 mL). BTMG (66 µL, 0.32 mmol) was added, and the sealed vial was removed from the glove box. The vial was placed in a Penn photoreactor and irradiated at full intensity for 80 h at 450 nm, 100% LED, 6800 rpm, and a cooling fan. The RM was diluted with DCM and H2O and filtered through an Isolute® phase separator. The filtrate was concentrated under reduced pressure and purified by preparative HPLC (Waters XBridge C18 50 x 100 mm, 5 µm; eluent: 40% to 100% ACN in H2O with 0.2% FA) to provide racemic 4-(((1R) as a white powder. ,2S 4,4-Difluoro-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (18.3 mg). LC-MS method B-1: Rt = 1.71 min; MS m / z [M+H] + = 514.4.

[1095] Intermediate rac-M-34: racemic 4-(((1R) ,2S 4S 4-((tert-butyldimethylsilyl)oxy)-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1096]

[1097] racemic 4-((1S) ,2S 5S Methyl benzoate 5-((tert-butyldimethylsilyl)oxy)-2-hydroxycyclohexyl)benzoate (intermediate rac-A-24, 105 mg, 0.29 mmol) and tert-butyl 4-hydroxy-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (intermediate I-3, 91.0 mg, 0.32 mmol) were dissolved in toluene (2 mL). PPh3 (90.7 mg, 0.35 mmol) was added, followed by dropwise addition of DIAD (84 L, 0.43 mmol). The RM was stirred overnight at RT. The RM was diluted with DCM and H2O and filtered through an Isolute® phase separator. The filtrate was concentrated under reduced pressure. Material enriched by silica gel column chromatography (24 g; eluent: 0% to 20% EtOAc in cyclohexane) was purified by preparative HPLC (Waters XBridge C18 50 x 100 mm, 5 µm; eluent: 35% to 100% ACN in H2O with 0.2% FA) to provide racemic 4-(((1R ,2S 4S 4-((tert-butyldimethylsilyl)oxy)-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (30.5 mg). 1 HNMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 3.7 Hz, 1H), 6.36 (s, 1H), 6.24 (d, J = 3.8 Hz, 1H), 4.44 - 4.32(m, 1H), 4.15 - 4.03 (m, 1H), 3.83 (s, 3H), 3.47 - 3.24 (m, 1H), 2.36 (s,3H), 2.01 - 1.81 (m, 3H), 1.79 - 1.70 (m, 1H), 1.68 - 1.58 (m, 1H), 1.55 (s,9H), 1.54 - 1.43 (m, 2H), 0.93 (s, 9H), 0.91 - 0.84 (m, 1H), 0.72 - 0.47 (m,3H), 0.06 (d, J = 2.7 Hz, 6H).

[1098] Intermediate M-35: racemic 4-(((5S) 6R 5-(4-(methoxycarbonyl)phenyl)spiro[2.5]oct-6-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1099]

[1100] racemic 4-((5S) 6S Methyl 6-hydroxyspiro[2.5]oct-5-yl)benzoate (intermediate rac-A-26, 344.0 mg, 1.24 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylate (intermediate I-1, 324.6 mg, 1.24 mmol), and PPh3 (488.7 mg, 1.86 mmol) were dissolved in toluene (1 mL). The mixture was cooled to 0°C. DIAD (0.39 mL, 1.86 mmol) was added dropwise. RM was gradually warmed to RT and stirred overnight. RM was concentrated under reduced pressure and purified by silica gel (40 g; eluent: 0% to 9% EtOAc in heptane) to provide a white foamy racemic 4-(((5S) 6R 5-(4-(methoxycarbonyl)phenyl)spiro[2.5]oct-6-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (195 mg). LC-MS method B-2: Rt = 9.29 min; MS m / z [MH] - =502.2.

[1101] Intermediate M-38: 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-fluoro-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1102]

[1103] (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate A-3, 103.7 mg, 0.29 mmol), 4-hydroxy-5-fluoro-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-5, 77.9 mg, 0.26 mmol), and PPh3 (173.3 mg, 0.66 mmol) were dissolved in THF (2 mL). DIAD (0.13 mL, 0.66 mmol) was added dropwise, and RM was stirred overnight at RT. Additional (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate A-3, 44.3 mg, 0.13 mmol), PPh3 (69.3 mg, 0.26 mmol), and DIAD (51 µL, 0.26 mmol) were added sequentially, and RM was stirred at RT for 3 h. The mixture was diluted with EtOAc and washed with H2O. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure. 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5-fluoro-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (145 mg) was enriched as an orange oil by silica gel column chromatography (elution: 0% to 40% EtOAc in cyclohexane). LC-MS Method B-1: Rt = 1.68 min; MS m / z [M+Na] + = 605.2.

[1104] Intermediate rac-M-39: racemic 5-cyclopropyl-4-(((1R) ,2S 4,4-Difluoro-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1105]

[1106] As described in step 1a for intermediate M-34, the external racemic 4-((1S) is used. ,2S The intermediate rac-M-39 was prepared by reacting methyl 5,5-difluoro-2-hydroxycyclohexyl)benzoate (intermediate rac-A-28, 87 mg, 0.32 mmol) and tert-butyl 4-hydroxy-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (intermediate I-3, 101.7 mg, 0.35 mmol) to provide racemic 5-cyclopropyl-4-(((1R) as a pale yellow powder. ,2S 4,4-Difluoro-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (35.4 mg). LC-MS method B-1: Rt = 1.71 min; MS m / z [M+H] + = 540.5.

[1107] Intermediate M-42: 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-chloro-5-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1108]

[1109] (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate A-3, 261.9 mg, 0.78 mmol), PPh3 (279.3 mg, 1.07 mmol), and 7-chloro-4-hydroxy-5-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-7, 200 mg, 0.91 mmol) were combined in toluene (5 mL). The mixture was cooled to 0°C. A solution of DBAD (245.2 mg, 1.07 mmol) in toluene (1 mL) was added dropwise to the cooled solution over 10 min. The RM was gradually warmed to RT and stirred overnight. The RM was diluted with H2O, and the mixture was extracted with EtOAc (3x). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-chloro-5-methyl-1H-indole-1-carboxylic acid tert-butyl ester (129.3 mg) was provided as a white solid by silica gel column chromatography (elution: 0% to 50% EtOAc in heptane). LC-MS method C-2: Rt = 1.52 min; MS m / z [M+H] + = 599.2.

[1110] Intermediate M-43: 5-bromo-4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1111]

[1112] (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate A-3, 501.1 mg, 1.49 mmol), PPh3 (534.3 mg, 2.03 mmol), and 5-bromo-4-hydroxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-8, 443.0 mg, 1.36 mmol) were combined in THF (5 mL). The mixture was cooled to 0°C. After 10 min, a solution of DBAD (469.1 mg, 2.04 mmol) in toluene (5 mL) was added dropwise to the cooled solution. The RM was gradually warmed to RT and stirred overnight. RM was concentrated and purified by silica gel column chromatography (elution: 0% to 50% EtOAc in heptane) to provide an enriched white solid of tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-chloro-5-methyl-1H-indole-1-carboxylic acid (tert-butyl ester, 813 mg). LC-MS method C-1: Rt = 1.57 min; MS m / z [M+H] + = 645.8.

[1113] Intermediate rac-M-44: racemic 5-cyclopropyl-4-(((7S) ,8R 7-(4-(methoxycarbonyl)phenyl)-1,4-dioxaspiro[4.5]dec-8-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1114]

[1115] racemic 4-((7S) 8S Methyl 8-hydroxy-1,4-dioxaspiro[4.5]dec-7-yl)benzoate (intermediate rac-A-31, 960 mg, 3.28 mmol) and tert-butyl 4-hydroxy-5-cyclopropyl-7-methyl-1H-indole-1-carboxylate (intermediate I-3, 1.04 g, 4.93 mmol) were dissolved in toluene (8 mL). PPh3 (1.03 g, 3.94 mmol) was added, followed by dropwise addition of DIAD (0.96 mL, 4.93 mmol). The RM was stirred overnight at RT. The RM was diluted with DCM and H2O and filtered through an Isolute® phase separator. The filtrate was concentrated under reduced pressure. The material enriched by silica gel column chromatography (120 g; eluent: 0% to 30% EtOAc in cyclohexane) was purified by preparative HPLC (Waters XBridge C18 50 x 100 mm, 5 µm; eluent: 30% to 100% ACN in H2O with 0.2% FA) to provide racemic 5-cyclopropyl-4-(((7S) ,8R 7-(4-(methoxycarbonyl)phenyl)-1,4-dioxaspiro[4.5]dec-8-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (570 mg). LC-MS method B-1: Rt = 1.65 min; MS m / z [M+H] + = 562.3.

[1116] Intermediate rac-B-1: 4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1117]

[1118] Step 1a: Racemic 4-(((3R) 4R 1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate M-1, 72 mg, 0.12 mmol) was dissolved in MeOH (1.5 mL) and HCl solution (4 M, in dioxane, 1 mL, 4.0 mmol) was added. RM was stirred at RT for 20 min and concentrated under reduced pressure. The residue was diluted with saturated NaHCO3 aqueous solution and extracted with DCM (3x). The combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure.

[1119] Step 1b: Dissolve the residue in MeOH (1 mL). Add formaldehyde aqueous solution (37 wt%, 1 mL, 13.4 mmol) and Na(OAc)3BH (79.7 mg, 0.37 mmol). Stir the RM at RT for 20 min. Partition the RM between DCM and saturated NaHCO3 aqueous solution. Extract the aqueous phase with DCM (3x). Dry the combined organic phases through an Isolute® phase separator and concentrate under reduced pressure. Purify the residue with silica gel (12 g; eluent: 0% to 100% EtOAc / EtOH with 2% NH4OH in heptane 3:1) to provide a racemic 5,7-dimethyl-4-(((3R) 4R 3-(1-Methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-1H-indole-1-carboxylic acid tert-butyl ester (42 mg). LC-MS method C-2: Rt = 1.42 min; MS m / z [M+H] + = 493.3.

[1120] Intermediate rac-B-2: racemic 4-(((3R) 4R)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1121]

[1122] Step 1a: Racemic 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-M-1, 42 mg, 73 µmol) was dissolved in MeOH (1.5 mL), and HCl solution (4 M, in dioxane, 1 mL, 4.0 mmol) was added. RM was stirred at RT for 50 min and concentrated under reduced pressure. The residue was partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with DCM (2x). The combined organic phases were dried using an Isolute® phase separator and concentrated under reduced pressure.

[1123] Step 1b: Dissolve the residue in ACN (1.5 mL). Add NEt3 (30 µL, 0.22 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (15.68 µL, 0.11 mmol) sequentially, and stir RM overnight at RT. Add saturated NaHCO3 aqueous solution, and extract the mixture with DCM (3x). Dry the combined organic phases through an Isolute® phase separator and concentrate under reduced pressure. Purify the residue with silica gel (4 g; eluent: 0% to 100% EtOAc / EtOH in heptane 3:1) to provide a racemic 4-(((3R) as a colorless oil. 31 mg of tert-butyl indole-1-carboxylic acid (4R)-3-(4-(methoxycarbonyl)phenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid. LC-MS method C-1: Rt = 1.49 min; MS m / z [M+H] + = 561.1

[1124] Intermediate B-3: 4-(((3R,4R)-1-ethyl-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1125]

[1126] Step 1a: The enriched tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid (intermediate M-5, 54 mg) was dissolved in MeOH (1.5 mL) and HCl solution (4 M, in dioxane, 0.5 mL, 2.0 mmol) was added. RM was stirred at RT for 2 h and then concentrated under reduced pressure. The residue was partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with DCM (2x). The combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure.

[1127] Step 1b: The residue was dissolved in DCM (1 mL) and acetaldehyde (10 µL, 0.19 mmol) was added, followed by Na(OAc)3BH (30 mg, 0.14 mmol). The RM was stirred overnight at RT. The RM was neutralized with a saturated aqueous solution of NaHCO3 and the mixture was extracted with DCM (3x). The combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by silica gel (4 g; eluent: 0% to 100% 3:1 EtOAc:EtOH mixture in heptane with 2% NH4OH) to provide tert-butyl 4-(((3R,4R)-1-ethyl-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid (47 mg). LC-MS method C-1: Rt = 1.08 min; MS m / z [M+H] + = 507.2.

[1128] Intermediate B-4: tert-butyl 5,7-dimethyl-4-(((3R,4R)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-1H-indole-1-carboxylic acid

[1129]

[1130] The enriched tert-butyl 5,7-dimethyl-4-(((3R,4R)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-1H-indole-1-carboxylate (intermediate M-11, 86 mg) was dissolved in MeOH (2 mL) and Pd / C (10 wt% Pd, 41 mg, 39 µmol) was added. The flask was purged with H2 (3x) and then stirred at RT for 1 h under H2 atmosphere (gas bag). RM filtration was used to remove the solid. The solid was washed with MeOH and the combined filtrates were concentrated under reduced pressure to provide tert-butyl 5,7-dimethyl-4-(((3R,4R)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-1H-indole-1-carboxylate (65 mg), which was used directly without further purification. LC-MS method C-1: Rt = 0.87 min; MS m / z [M+H] + = 425.1.

[1131] The following examples are synthesized from suitable starting materials by applying a similar method to that described in the examples above.

[1132]

[1133] Intermediate B-12: 4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester

[1134]

[1135] Step 1a: (3R,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate A-3, 353.0 mg, 1.05 mmol), 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-1, 250.0 mg, 0.96 mmol), and PPh3 (376.4 mg, 1.43 mmol) were dissolved in THF (3 mL). The mixture was cooled to 0°C. A solution of DBAD (330.4 mg, 0.51 mmol) in toluene (0.5 mL) was added dropwise to the cooled solution over 10 min. The RM was gradually heated to RT and stirred overnight. The mixture was diluted with H2O and extracted with EtOAc (3x). The combined organic phases were washed with water, dried over Mg2SO4, and concentrated under reduced pressure. 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (306 mg) was enriched by silica gel column chromatography (elution: 0% to 50% EtOAc in heptane).

[1136] Step 1b: The material was dissolved in MeOH (2 mL). HCl solution (4 M, in dioxane, 0.59 mL, 2.35 mmol) was added, and the mixture was stirred for 3.5 h. The pH was adjusted to 6 with NaOH, and the mixture was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were dried over Mg2SO4 and concentrated under reduced pressure. The residue was purified by silica gel (elution: 0% to 30% MeOH in DCM) to provide tert-butyl 4-(((3R,4R)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylate (108.3 mg). LC-MS method C-2: Rt = 1.31 min; MS m / z [M+H] + = 479.4.

[1137] Intermediate B-13: Methyl 4-((3R,4R)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoate

[1138]

[1139] Step 1: Racemic 4-(((3R) 4R 3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-B-13-1)

[1140]

[1141] racemic (3R) 4S 4-Hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate rac-A-1, 983.1 mg, 1.84 mmol), PPh3 (722.7 mg, 2.76 mmol), and 4-hydroxy-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate I-1, 500 mg, 1.84 mmol) were dissolved in THF (15 mL), and the mixture was cooled to 0°C. DIAD (0.55 mL, 2.76 mmol) was added dropwise. RM was warmed to RT and stirred overnight. Additional PPh3 (481.2 mg, 1.84 mmol) and DIAD (0.55 mL, 2.76 mmol) were added, and RM was stirred at RT for 5 h. RM was diluted with EtOAc, and the mixture was washed with H2O and brine. The organic phase was dried using an Isolute® phase separator and concentrated under reduced pressure. Enriched racemic 4-(((3R) was then obtained by silica gel column chromatography (80 g; eluent: 0% to 30% EtOAc in cyclohexane). 4R 1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester. The material (1.24 g) was dissolved in MeOH (3 mL), and the solution was cooled to 0°C. HCl solution (4 M, in dioxane, 3.12 mL, 12.5 mmol) was added, and the mixture was stirred for 1.5 h. The mixture was quenched with a saturated aqueous solution of NaHCO3, and the mixture was extracted with DCM (2x). The combined organic phases were dried using an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by silica gel (40 g; eluent: 0% to 20% MeOH in DCM) to provide a racemic mixture of 4-(((3R) in brown foam. 4R 3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (236.6 mg). LC-MS method B-1: Rt = 1.26 min; MS m / z [M+H] + = 479.4.

[1142] Step 2: Methyl 4-((3R,4R)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoate (intermediate B-13)

[1143] Step 2a: Racemic 4-(((3R) 4R 3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-B-13-1, 130 mg, 0.24 mmol) and 3-bromo-1,1-difluoropropane (42.8 mg, 0.27 mmol) were combined in ACN (2 mL) and DIPEA (0.15 mL, 0.86 mmol) was added. RM was stirred at 50°C for 5 h. RM was cooled to RT, diluted with EtOAc, and the mixture was washed with H2O. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure.

[1144] Step 2b: Dissolve the residue in MeOH (2 mL) and add HCl solution (4 M, in dioxane, 1.22 mL, 4.89 mmol). Stir the RM overnight at RT. Dilute the RM with DCM and neutralize with a saturated aqueous solution of NaHCO3. Separate the phases and extract the aqueous phase with DCM (2x). Wash the combined organic phases with brine, dry them through an Isolute® phase separator, and concentrate them under reduced pressure. Purify the residue with silica gel (12 g; eluent: 0% to 100% EtOAc in cyclohexane) to provide a racemic 4-((3R) as a colorless oil. 4R Methyl benzoate 1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoate (59.1 mg). LC-MS method B-1: Rt = 0.77 min; MS m / z [M+H] + = 457.4.

[1145] Step 2c: Chiral separation and analysis according to method SFC-21: 59.1 mg provided intermediate B-13 (peak 2): 19.8 mg, white solid. LC-MS method B-1: Rt = 0.75 min; MS m / z [M+H] + = 457.3. Analytical chiral HPLC: Rt = 1.92 min; 99.9% ee.

[1146] Intermediate B-14: Methyl 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoate

[1147]

[1148] Step 1a: Racemic 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-B-13-1, 130 mg, 0.24 mmol) and 1,1,1-trifluoro-3-iodopropane (60.2 mg, 0.27 mmol) were combined in ACN (2 mL), and DIPEA (0.15 mL, 0.86 mmol) was added. RM was stirred overnight at 50°C. An additional portion of 1,1,1-trifluoro-3-iodopropane (60.2 mg, 0.27 mmol) was added, and RM was stirred at 50°C for 2 h. RM was cooled to RT, diluted with EtOAc, and the mixture was washed with H2O. The aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure.

[1149] Step 1b: Dissolve the residue in MeOH (2 mL) and add HCl solution (4 M, in dioxane, 1.22 mL, 4.89 mmol). Stir the RM overnight at RT. Dilute the RM with DCM and neutralize with a saturated aqueous solution of NaHCO3. Separate the phases and extract the aqueous phase with DCM (2x). Wash the combined organic phases with brine, dry them through an Isolute® phase separator, and concentrate them under reduced pressure. Purify the residue with silica gel (12 g; eluent: 0% to 60% EtOAc in cyclohexane) to provide a racemic 4-((3R) as a colorless oil. 4R Methyl benzoate 3,4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoate (35.2 mg). LC-MS method B-1: Rt = 1.10 min; MS m / z [M+H] + = 475.2.

[1150] Step 1c: Chiral separation and analysis according to method SFC-22: 235.2 mg provided intermediate B-14 (peak 2): 14.3 mg, white solid. LC-MS method B-1: Rt = 1.09 min; MS m / z [M+H] + = 475.3. Analytical chiral HPLC: Rt = 1.30 min; 99.9% ee.

[1151] Intermediate B-15: Methyl 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoate

[1152]

[1153] Racemic 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-B-13-1, 92.7 mg, 0.15 mmol) and 2-bromoethyltrifluoromethyl ether (31 µL, 0.27 mmol) were combined in ACN (1.5 mL), and NEt3 (62 µL, 0.86 mmol) was added. RM was stirred at 50°C for 3 days. RM was cooled to RT and concentrated under reduced pressure.

[1154] Step 1b: Dissolve the residue in MeOH (1.5 mL) and add HCl solution (4 M, in dioxane, 0.45 mL, 1.80 mmol). Stir the RM overnight at RT. Dilute the RM with DCM and neutralize with a saturated aqueous solution of NaHCO3. Separate the phases and extract the aqueous phase with DCM (2x). Wash the combined organic phases with brine, dry them through an Isolute® phase separator, and concentrate them under reduced pressure. Purify the residue with silica gel (24 g; eluent: 0% to 100% EtOAc in cyclohexane) to provide a racemic 4-((3R) as an orange oil. 4R Methyl benzoate 4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoate (26.6 mg). LC-MS method B-1: Rt = 1.11 min; MS m / z [M+H] + = 491.3.

[1155] Step 1c: Chiral separation and analysis according to method SFC-23: 26.6 mg provided intermediate B-15 (peak 2): 9.9 mg, colorless oil. LC-MS method B-1: Rt = 1.12 min; MS m / z [M+H] + = 491.3. Analytical chiral HPLC: Rt = 1.24 min; 99.5% ee.

[1156] Intermediate rac-B-16: racemic 5-cyclopropyl-4-(((1R) ,2S 4S 4-hydroxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1157]

[1158] racemic 4-(((1R) ,2S 4S 4-((tert-butyldimethylsilyl)oxy)-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5-cyclopropyl-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-M-34, 910 mg, 1.44 mmol) was dissolved in MeOH (15 mL) and HCl solution (4 M, in dioxane, 3.59 mL, 14.36 mmol) was added. RM was stirred at RT for 1 h. RM was quenched with saturated NaHCO3 aqueous solution and the mixture was extracted with DCM (3x). The combined organic phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified by silica gel (120 g; eluent: 0% to 30% EtOAc in cyclohexane) to provide a white foamy racemic 5-cyclopropyl-4-(((1R) ,2S 4S 4-Hydroxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (641 mg). LC-MS method B-1: Rt = 1.51 min; MS m / z [M-Boc+2H] + =420.3.

[1159] The following examples are synthesized from suitable starting materials by applying a similar method to that described in the examples above.

[1160]

[1161] Intermediate rac-B-32: racemic 4-((1S) ,2R 5S )-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid

[1162]

[1163] racemic 5-cyclopropyl-4-(((1R) ,2S 4S 4-hydroxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-B-16, 43 mg, 83 µmol) was dissolved in THF (1 mL) and MeOH (0.5 mL). NaOH aqueous solution (1 M, 0.41 mL, 0.41 mmol) was added, and the mixture was stirred at 50°C for 18 h. The mixture was cooled to RT, extracted with FA (31 µL, 0.82 mmol), and diluted with ACN. The mixture was purified by preparative HPLC (Waters XBridge C18 30 x 100 mm, 5 µm; eluent: 15% to 100% ACN in H2O with 0.2% FA) to provide racemic 4-((1S) ,2R 5S 2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid (25.7 mg). LC-MS method B-1: Rt = 0.93 min; MS m / z [M+H] + = 406.2.

[1164] Intermediate B-33: Methyl 4-((5S,6R)-6-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[2,5]oct-5-yl)benzoate

[1165]

[1166] Step 1a: Racemic 4-(((5S) 6R 5-(4-(methoxycarbonyl)phenyl)spiro[2.5]oct-6-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-M-35, 221 mg, 0.44 mmol) was dissolved in DCM (6 mL) and TFA (2 mL) was added. RM was stirred at RT for 40 min. RM was poured into a mixture of 10 wt% Na2CO3 aqueous solution and MBTE. The phases were separated and the aqueous phase was extracted with MBTE. The organic phase was washed with brine. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters XBridge C18 50 x 100 mm; 5 µm; eluent: 40% to 90% ACN in H2O with 0.1% NH4OH) to provide racemic 4-((5S) as white foam. 6R Methyl benzoate (65.5 mg)-6-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[2.5]oct-5-yl)benzoate.

[1167] Step 1b: Chiral separation and analysis according to method SFC-25: 65 mg provided intermediate B-33 (peak 2): 30.3 mg, white solid. LC-MS method B-1: Rt = 1.54 min; MS m / z [M+H] + = 404.3. Analytical chiral HPLC: Rt = 1.44 min; 99.5% ee.

[1168] Intermediate B-37: tert-butyl 5-cyclopropyl-4-(((3R,4R)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid

[1169]

[1170] 5-Bromo-4-(((3R,4R)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate B-36, 23.2 mg, 38 µmol) was combined with cyclopropylboronic acid (3.9 mg, 46 µmol), tricyclohexylphosphine (1.1 mg, 4 µmol), and Pd2dba3 (2.1 mg, 2 µmol). The vial was purged with N2 and toluene (0.3 mL) and H2O (10 µL) were added. The mixture was stirred overnight at 100°C. RM was concentrated under reduced pressure and enriched with tert-butyl 5-cyclopropyl-4-(((3R,4R)-1-(2,2-difluoroethyl)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid (16 mg) by silica gel column chromatography (12 g; eluent in heptane, 0% to 100% EtOAc). LC-MS method C-1: Rt = 1.37 min; MS m / z [M+H] + = 569.5.

[1171] Intermediate rac-B-40: racemic 5-cyclopropyl-4-(((1R) ,2S 2-(4-(methoxycarbonyl)phenyl)-4-oxocyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1172]

[1173] racemic 5-cyclopropyl-4-(((7S) ,8R 7-(4-(methoxycarbonyl)phenyl)-1,4-dioxaspiro[4.5]dec-8-yl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (492.0 mg, 0.88 mmol) was dissolved in acetone (20 mL) and Amberlyst® 15 (2.75 g, 8.76 mmol) was added. RM was stirred at RT for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters XBridge C18 OBD 50 x 100 mm; 5 µm; eluent: 40% to 100% ACN in H2O with 0.2% FA) to provide racemic 5-cyclopropyl-4-(((1R ,2S 2-(4-(methoxycarbonyl)phenyl)-4-oxocyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (131 mg). LC-MS method B-1: Rt = 1.59 min; MS m / z [M-Boc+2H] + = 418.1.

[1174] Intermediates rac-B-41 and rac-B-42: racemic 5-cyclopropyl-4-(((1R) ,2S 4S 4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-methylcyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester and 5-cyclopropyl-4-(((1R) ,2S 4R 4-hydroxy-2-(4-(methoxycarbonyl)-phenyl)-4-methylcyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester

[1175]

[1176] racemic 5-cyclopropyl-4-(((1R) ,2S 2-(4-(methoxycarbonyl)phenyl)-4-oxocyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-B-40, 41.3 mg, 80 µmol) was dissolved in THF (1 mL) and cooled to 0°C. Methyl magnesium bromide solution (3.4 M, in THF, 28 µL, 96 µmol) was added, and the mixture was stirred for 30 min. The mixture was quenched with a saturated aqueous NH4Cl solution and warmed to RT. The mixture was extracted with DCM (3x). The combined organic phases were dried using an Isolute® phase separator and concentrated under reduced pressure. Racemic 5-cyclopropyl-4-(((1R) was provided by silica gel column chromatography (12 g; eluent: 0% to 20% EtOAc in cyclohexane). ,2S 4S 4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-methylcyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (first peak elution, 24.7 mg) and racemic 5-cyclopropyl-4-(((1R ,2S 4R 4-Hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-methylcyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (eluted by the second peak, 9.1 mg). Intermediate rac-B-41 LC-MS method B-1: Rt = 1.59 min; MS m / z [M+H] + = 534.2. Intermediate rac-B-42 LC-MS method B-1: Rt = 1.52 min; MS m / z [M+H] + = 534.3.

[1177] Intermediate rac-B-43: racemic 4-((1S) ,2R 5S )-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-hydroxy-5-methylcyclohexyl)benzoic acid

[1178]

[1179] racemic 5-cyclopropyl-4-(((1R) ,2S 4S 4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-methylcyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-B-41, 22.4 mg, 42 µmol) was dissolved in MeOH (0.5 mL) and THF (1 mL). NaOH aqueous solution (1 M, 0.21 mL, 0.21 mmol) was added, and RM was stirred at 50°C for 18 h. RM was quenched with FA (16 µL) and purified by preparative HPLC (Waters XBridge C18OBD 30 x 100 mm; 5 µm; eluent: 15% to 100% ACN in H2O with 0.2% FA) to provide racemic 4-((1S) ,2R 5S 2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-hydroxy-5-methylcyclohexyl)benzoic acid (12.5 mg). LC-MS method B-1: Rt = 0.99 min; MS m / z [M+H] + =420.4.

[1180] Intermediate rac-B-44: racemic 4-((1S) ,2R 5R )-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-hydroxy-5-methylcyclohexyl)benzoic acid

[1181]

[1182] racemic 5-cyclopropyl-4-(((1R) ,2S 4R 4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4-methylcyclohexyl)oxy)-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-B-42, 7.2 mg, 13 µmol) was dissolved in MeOH (0.25 mL) and THF (0.5 mL). NaOH aqueous solution (1 M, 67 µL, 67 µmol) was added, and RM was stirred at 50°C for 18 h. RM was quenched with FA (5 µL) and purified by preparative HPLC (Waters XBridge C18 OBD 30 x 100 mm; 5 µm; eluent: 15% to 100% ACN in H2O with 0.2% FA) to provide racemic 4-((1S) ,2R 5R 2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-hydroxy-5-methylcyclohexyl)benzoic acid (12.5 mg). LC-MS method B-1: Rt = 0.99 min; MS m / z [M+H] + = 420.4.

[1183] Examples Ex-1 and Ex-2: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid and 4-((3S,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid

[1184] Step 1a: Racemic 4-(((3R) 4R 3-(4-(methoxycarbonyl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole-1-carboxylic acid tert-butyl ester (intermediate rac-B-1, 42 mg, 85 µmol) was dissolved in MeOH (2 mL) and K2CO3 (50 mg, 0.36 mmol) was added. RM was stirred overnight at 45°C. NaOH aqueous solution (1 M, 85 µL, 85 µmol) was added, and RM was stirred at 60°C for 90 min. Additional NaOH aqueous solution (1 M, 85 µL, 85 µmol) was added, and RM was stirred at 60°C for 2 h. RM was cooled to RT, concentrated under reduced pressure, and purified by preparative HPLC (15.5 g C18 column; eluent: 15% to 20% ACN in H2O with 0.1% NH4OH) to provide racemic 4-((3R) as a white solid. 4R )-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid (28.6 mg).

[1185] Step 1b: Chiral separation and analysis according to method SFC-6: Example Ex-1 (peak 2): 10.1 mg, white solid. Analytical chiral HPLC: Rt = 2.64 min; 100% ee. Example Ex-2 (peak 1): 10.9 mg, white solid. Analytical chiral HPLC: Rt = 2.02 min; 95.9% ee.

[1186] Examples Ex-3 and Ex-4: 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid and 4-((3S,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid

[1187] Step 1a: Add racemic 4-((3R) to the vial 4S Methyl 4-((5,7-dimethyl-1-toluenesulfonyl-1H-indol-4-yl)oxy)-1-methylpiperid...

Claims

1. A compound having formula (I) (I) Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound, in: W is O, C(R) 6 )2, or NR 7 ; R is hydrogen, halogen, C1-C4 alkyl, halo-C1-C4 alkyl, or hydroxy-C1-C4 alkyl; R 1 It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy, hydroxyl-C1-C6 alkyl, hydroxyl-C3-C6 cycloalkyl, amino-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C6 alkoxy, or C3-C6 cycloalkyl-C1-C6 alkoxy; R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen, wherein the C1-C3 alkyl, C3 cycloalkyl, or C1-C3 alkoxy is unsubstituted or substituted by 1, 2, or 3 halogen substituents; R 3 It is hydrogen, halogen, or cyano; R 4 It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N, O, and S, wherein the phenyl or heteroaryl group is unsubstituted or R-substituted. 5 replace; R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxy C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, -CH2CO2R 5b -C(O)NHSO2C1-C4 alkyl, -SO2NHC(O)C1-C4 alkyl, -SO2C1-C4 alkyl, cyano, hydroxyl, halogen, -C(O)N(R 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace; Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H; Each R 5b Independently selected from hydrogen and C1-C5 alkyl groups; Each R 6 The heterocyclic group is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C3-C6 cycloalkylC1-C4 alkylamino, halo-C3-C6 cycloalkylC1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkoxy, halo-C3-C6 cycloalkoxy, and a 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is unsubstituted or substituted with a 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclic group is unsubstituted or substituted with 1, 2, or 3 halogens; Or two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic carbon ring having 3 to 6 ring atoms, wherein the spirocyclic carbon ring is unsubstituted or substituted by 1 or 2 substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; Or two Rs 6 They combine with the carbon atoms to which they are attached to form one or two independent atoms selected from N, O, and S(O). q Spirocyclic heterocycles with cyclic heteroatoms, wherein the spirocyclic heterocycle is not substituted or is substituted by one or two halogens, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C3-C6 cycloalkyl. q is 0, 1, or 2; R 7 It is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, C1-C6 alkoxy-C1-C6 alkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a Aryl group, having 1-2 independently selected from N, O, and S(O) q A 4- to 6-membered heterocyclic group with heteroatoms, or a 5- to 6-membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O, and S, wherein the C1-C6 alkyl group is unsubstituted or has 1 to 2 heteroatoms independently selected from N, O, and S(O). q The heteroatom is substituted with a 4- to 6-membered heterocyclic group, wherein the 4- to 6-membered heterocyclic group is not substituted or is substituted with 1, 2 or 3 halogens, and further wherein the aryl or heteroaryl group is not substituted or is substituted with halogenated, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C5 cycloalkyl, or halogenated C3-C5 cycloalkyl. R 7a It is hydrogen or C1-C6 alkyl; Each R 8 It is independently selected from hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy; R 9 It is H, D, or T; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; The premise is that neither m nor n is 0; and p is 0, 1, 2, or 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein: W is C(R) 6 )2, or NR 7 ; R is hydrogen; R 1 It is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or halogenated C1-C6 alkyl; R 2 It is a C1-C3 alkyl, C3 cycloalkyl, C1-C3 alkoxy, hydroxy C1-C6 alkyl, or halogen; R 3 It is hydrogen; R 4 It is a phenyl, naphthyl, or a 5- to 10-membered heteroaryl group having 1, 2, or 3 independently selected cyclic heteroatoms chosen from N and O, wherein the phenyl or heteroaryl group is unsubstituted or R 5 replace; R 5 Selected from hydrogen, -CO2R 5b C1-C6 alkyl, hydroxyl, C3-C6 cycloalkyl, -CH2CO2R 5b , cyano, hydroxyl, halogen, -C(O)N(R) 5b )2 and 5- to 6-membered heteroaryl groups having 1 to 4 independent heteroatoms selected from N and O, wherein the alkyl and heteroaryl groups are unsubstituted or surrounded by 1, 2, or 3 R atoms. 5a replace; Each R 5a Independently selected from fluorine, hydroxyl, and C1-C6 alkyl groups that are unsubstituted or substituted with -CO2H; R 5b Selected from hydrogen and C1-C5 alkyl groups; Each R 6 The heterocyclic group is independently selected from hydrogen, halogen, hydroxyl, C3-C6 cycloalkyl-C1-C4 alkylamino, halogenated C3-C6 cycloalkyl-C1-C4 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy, and a 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is unsubstituted or substituted with a 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclic group is unsubstituted or substituted with 1, 2, or 3 halogens; Or two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic carbon ring having 3 to 6 ring atoms, wherein the spirocyclic carbon ring is unsubstituted or substituted by 1 or 2 substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; Or two Rs 6 They combine with the carbon atoms to which they are attached to form spirocyclic heterocycles having one or two independent cyclic heteroatoms selected from N and O, wherein the spirocyclic heterocycles are not substituted; R 7 It is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-C2-C6 alkyl, halo-C3-C6 cycloalkyl-C1-C3 alkyl, halo-C3-C6 cycloalkyl, halo-C1-C6 alkoxy-C1-C6 alkyl, -COR 7a C3-C6 cycloalkyl, a 4- to 6-membered heterocyclic group having 1-2 heteroatoms independently selected from N or O, or a 5- to 6-membered heteroaryl group having 1 heteroatom selected from O, wherein the 4- to 6-membered heterocyclic group and the 5- to 6-membered heterocyclic group are not substituted; R 7a It is a C1-C6 alkyl group; Each R 8 Independently selected from hydrogen and halogens; R 9 It is H; m is 1 or 2; n is 1, 2, or 3; and p is 0.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, The compound having formula (I) is a compound having formula (I-AC) or (I-AN): (I-AC) (I-AN)。 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, The compound having formula (I) is a compound having formula (ID): (ID) Where W is C(R) 6 )2 or NR 7 .

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, The compound having formula (I) is a compound having formula (IE), (IF), (IG), or (IH): (I-E) (I-F) (I-G) (I-H)。 6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, The compound having formula (I) is a compound having formula (II): (II).

7. The compound of any one of claims 1 to 4 and 6, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, The compound having formula (I) is a compound having formula (IJ): (IJ).

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

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, R 1 It is hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated C1-C6 alkyl.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, R 2 It is a C1-C3 alkyl group or a halogen.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, R 3 It is hydrogen.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, R 4 It is phenyl, pyridyl, or pyrazolyl, wherein the phenyl, pyridyl, or pyrazolyl group is not substituted or is R-substituted. 5 replace.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, R 5 The group is selected from hydrogen, -CO2H, C1-C6 alkyl, hydroxyC3-C6 cycloalkyl, hydroxyC3-C6 alkyl, cyano, -CONH2, pyrazolyl, triazolyl, and tetrazolyl, wherein the pyrazolyl, triazolyl, and tetrazolyl are either unsubstituted or substituted by one C1-C6 alkyl group.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, Each R 6 Independently selected from hydrogen, halogen, hydroxyl, C3-C6 cycloalkyl C1-C4 alkylamino, halo-C3-C6 cycloalkyl C1-C4 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl C1-C4 alkylamino, halo-C3-C6 cycloalkyl C1-C4 alkylamino, and 4- to 6-membered heterocyclic groups having 1-2 heteroatoms independently selected from N and O, wherein the C1-C6 alkyl group is unsubstituted or substituted with 4- to 6-membered heterocyclic groups having 1-2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclic group is independently unsubstituted or substituted with 1, 2, or 3 halogens; or Two Rs 6 They combine with the attached carbon atoms to form a spirocyclic carbon ring having 3 to 4 ring atoms, wherein the spirocyclic carbon ring is unsubstituted or substituted by 1 or 2 substituents selected from halogens; or Two Rs 6 They combine with the carbon atoms to which they are attached to form a spirocyclic heterocycle having one cyclic heteroatom selected from O, wherein the spirocyclic heterocycle has five cyclic atoms.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, R 7 It is a C1-C6 alkyl, a halo-C1-C6 alkyl, a hydroxy-C2-C6 alkyl, a halo-C3-C6 cycloalkyl-C1-C3 alkyl, a halo-C3-C6 cycloalkyl, a halo-C1-C6 alkoxy-C1-C6 alkyl, a -COC1-C6 alkyl, a 4- to 6-membered heterocyclic group having one heteroatom selected from O, or a 5-membered heteroaryl group having one heteroatom selected from O.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, wherein, R 9 It's H.

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

18. The compound of claim 1, wherein the compound is selected from the group consisting of: 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-(4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-(4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-ethylpiperidin-3-yl)benzoic acid; 4-(5-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylazacycloheptane-4-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylazacycloheptane-3-yl)benzoic acid; 5,7-Dimethyl-4-((4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)oxy)-1H-indole; 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzylnitrile; 4-((3-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 2-(4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)prop-2-ol; 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 5,7-Dimethyl-4-((1-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-1H-indole; 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid; 4-(1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid; 4-(1-(3,3-difluorocyclobutyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(3-fluorocyclobutyl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid; 4-(4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)benzoic acid; 4-(4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-(1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)azacycloheptane-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)azacycloheptane-3-yl)benzoic acid; 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-(2-fluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 4-((3-(4-(1H-pyrazol-1-yl)phenyl)-1-(2,2-difluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 1-(3-(4-(1H-pyrazol-1-yl)phenyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-1-yl)ethyl-1-one; 4-((3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 4-((3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 1-(4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)cycloprop-1-ol; 4-((1-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 4-(4-((5-fluoro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-(4-((7-chloro-5-methyl-1H-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)benzoic acid; 4-(1-((2,2-difluorocyclopropyl)methyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid; 4-(1-(4,4-difluorobutyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid; 4-(4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(3,3-difluoropropyl)piperidin-3-yl)benzoic acid; 4-(4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid; 4-((1-(3,3-difluoropropyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)benzoic acid; 4-(4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpyrrolidine-3-yl)benzoic acid; 4-(4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylazacycloheptane-3-yl)benzoic acid; 4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-(2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-(8-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-oxaspiro[4.5]dec-7-yl)benzoic acid; 4-(2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-(2-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-(2-((5-fluoro-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-(5-methoxy-2-((7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid; 4-(2-((5,7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid; 4-(2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid; 4-(2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid; 4-(2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)cyclohexyl)benzoic acid; 4-(2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid; 4-(6-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[2.5]oct-5-yl)benzoic acid; 4-(2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzamide; 4-(2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid; 4-(2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid; 4-(5-(difluoromethoxy)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid; and 4-(7-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[3,5]non-6-yl)benzoic acid, Or its pharmaceutically acceptable salts or stereoisomers.

19. The compound of claim 1, wherein the compound is selected from the group consisting of: 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-((3S,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-((3S,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-((3S,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-ethylpiperidin-3-yl)benzoic acid; 4-((4S,5R)-5-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylazacycloheptane-4-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylazacycloheptane-3-yl)benzoic acid; Racemic 5,7-dimethyl-4-(((3S) 4R )-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)oxy)-1H-indole; 5,7-Dimethyl-4-(((3S,4R)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)oxy)-1H-indole; 5,7-Dimethyl-4-(((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)oxy)-1H-indole; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzylnitrile; 4-(((3R,4R)-3-(4-(1H-tetrazol-5-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 2-(4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)prop-2-ol; 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 5,7-Dimethyl-4-(((3R,4R)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-1H-indole; 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid; 4-((3R,4R)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-1-(3,3-difluorocyclobutyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-((1r,3R)-3-fluorocyclobutyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(tetrahydrofuran-3-yl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2-(trifluoromethoxy)ethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-1-(2,2-difluoroethyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)azacycloheptane-3-yl)benzoic acid; 4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)azacycloheptane-3-yl)benzoic acid; 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(2-fluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 4-(((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-1-(2,2-difluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; Racemic 1-((3R) 4R )-3-(4-(1H-pyrazol-1-yl)phenyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-1-yl)ethyl-1-one; 1-((3R,4R)-3-(4-(1H-pyrazol-1-yl)phenyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-1-yl)ethyl-1-one; 1-((3S,4S)-3-(4-(1H-pyrazol-1-yl)phenyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-1-yl)ethyl-1-one; Racemic 4-(((3R) 4R )-3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 4-(((3R,4R)-3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 4-(((3S,4S)-3-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; Racemic 4-(((3R) 4R )-3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 4-(((3R,4R)-3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 4-(((3S,4S)-3-(4-(1H-1,2,3-triazol-1-yl)phenyl)-1-methylpiperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 1-(4-((3R,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)phenyl)cycloprop-1-ol; 4-(((3R,4R)-1-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 4-((3R,4R)-4-((5-fluoro-7-methyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((7-chloro-5-methyl-1H-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-1-((2,2-difluorocyclopropyl)methyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid; 4-((3R,4R)-1-(4,4-difluorobutyl)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-(2,2-difluoroethyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(3,3-difluoropropyl)piperidin-3-yl)benzoic acid; 4-((3R,4R)-4-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-1-(3,3,3-trifluoropropyl)piperidin-3-yl)benzoic acid; 4-(((3R,4R)-1-(3,3-difluoropropyl)-3-(1-methyl-1H-pyrazol-4-yl)piperidin-4-yl)oxy)-5,7-dimethyl-1H-indole; 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-(2,2,2-trifluoroethyl)pyrrolidine-3-yl)benzoic acid; 4-((3R,4S)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-methylpyrrolidine-3-yl)benzoic acid; 4-((3R,4R)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylazacycloheptane-3-yl)benzoic acid; 4-((3R,4R)-4-((5-methoxy-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid; 4-((1S,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-((1R,2S,5R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; racemic 4-((1S) ,2R 5R )-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-((1S,2R,5R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-((1R,2S,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; racemic 4-((1S) ,2S 5S )-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-((1S,2S,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-((1R,2R,5R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; racemic 4-((1S) ,2S 5R )-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-((1S,2S,5R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-((1R,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; racemic 4-((7S) ,8R )-8-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-oxaspiro[4.5]dec-7-yl)benzoic acid; 4-((5R,7S,8R)-8-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-oxaspiro[4.5]dec-7-yl)benzoic acid; 4-((5S,7S,8R)-8-((5,7-dimethyl-1H-indol-4-yl)oxy)-1-oxaspiro[4.5]dec-7-yl)benzoic acid; 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-((1S,2R,5S)-2-((5-chloro-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-((1S,2R,5S)-2-((5-fluoro-7-methyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid; 4-((1S,2R,5S)-5-methoxy-2-((7-methyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid; racemic 4-((1S) ,2R )-2-((5,7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid; 4-((1S,2R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid; 4-((1R,2S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)cyclohexyl)benzoic acid; 4-((1S,2R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid; 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-hydroxycyclohexyl)benzoic acid; 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)cyclohexyl)benzoic acid; 4-((1S,2R,5R)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid; 4-((1S,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methylcyclohexyl)benzoic acid; 4-((5S,6R)-6-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[2.5]oct-5-yl)benzoic acid; 4-((1S,2R,5S)-2-((5,7-dimethyl-1H-indol-4-yl)oxy)-5-methoxycyclohexyl)benzamide; 4-((1S,2R)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5,5-difluorocyclohexyl)benzoic acid; racemic 4-((1S) ,2R 5S )-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid; 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid; 4-((1S,2R,5R)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid; racemic 4-((1S) ,2R 5S )-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid; 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid; 4-((1S,2R,5S)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-5-(difluoromethoxy)-5-methylcyclohexyl)benzoic acid; 4-((6S,7R)-7-((5,7-dimethyl-1H-indol-4-yl)oxy)spiro[3,5]non-6-yl)benzoic acid, Or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof.

20. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in any one of claims 1 to 19, or a pharmaceutically acceptable salt or stereoisomer or isotopically labeled compound thereof, and a pharmaceutically acceptable carrier or excipient.

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

22. The method of claim 21, wherein, The diseases or disorders mentioned are selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, intermediate uveitis, shotgun retinal choroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arterial ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, glaucoma, Doinger's celluloid retinal dystrophy / familial dominant drusen, Sotheby's retinal dystrophy, late-onset macular dystrophy, North Carolina dystrophy, Stagg's disease, corneal inflammation, and neurological disorders such as primary progressive multiple sclerosis. Multiple sclerosis including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing-remitting multiple sclerosis (RRMS), stroke, Guillain-Barré 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 disorder, schizophrenia, drug-induced neurotoxicity, aquaporin-4 IgG seropositive neuromyelitis spectrum disorder (NMOSD), cerebral amyloid angiopathy, cerebral malaria, peroneal muscular atrophy, chemotherapy-induced peripheral neuropathy, chronic inflammatory demyelinating polyneuropathy, frontotemporal dementia, and CD59p.Hereditary demyelinating neuropathy caused by Cys89Tyr mutations, Lewy body dementia, multiple system atrophy (MSA), myelin oligodendrocyte glial antibody-associated disease (MOGAD), oculoclonus-myoclonus syndrome (OMS), progressive supranuclear palsy; inappropriate or undesirable complement activation disorders, such as hemodialysis complications, hyperacute allogeneic transplant rejection, xenograft rejection, IL-2-induced toxicity during interleukin-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), immune complex membrane proliferative glomerulonephritis (IC-MPGN), IgA 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), periodontitis, CD55 deficiency with complement hyperactivation, vasculopathy, protein-losing enteropathy (CHAPLE syndrome), inflammatory or autoimmune diseases such as Crohn's disease, neuromyelitis optica (NMO), IgA vasculitis (formerly known as allergic purpura or HSP), CHAPLE syndrome, hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA), adult-onset respiratory distress syndrome (ARDS), and myocarditis. Post-ischemia-reperfusion syndrome, myocardial infarction, post-pump syndrome after balloon angioplasty, cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis; COVID-19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, spondyloarthritis, psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, myasthenia gravis, liver fibrosis, hemolytic anemia, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease. COPD, emphysema, pulmonary embolism and infarction, pneumonia, fibrotic pneumoconiosis, pulmonary fibrosis, asthma, allergic reactions, bronchoconstriction, allergic pneumonia, parasitic diseases, Goodpassuia syndrome, pulmonary vasculitis, microimmune vasculitis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Berger's vasculitis, cryoglobulinemia, Kawasaki disease, aortitis, cryoglobulinemia, immune complex-associated inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity; immune thrombocytopenic purpura, cold agglutinin disease, warm antibody-type autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurysm, and Graves' disease.

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