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WO2025068951A1 - Inhibiteurs du facteur b du complément et leurs utilisations - Google Patents

Inhibiteurs du facteur b du complément et leurs utilisations Download PDF

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Publication number
WO2025068951A1
WO2025068951A1 PCT/IB2024/059431 IB2024059431W WO2025068951A1 WO 2025068951 A1 WO2025068951 A1 WO 2025068951A1 IB 2024059431 W IB2024059431 W IB 2024059431W WO 2025068951 A1 WO2025068951 A1 WO 2025068951A1
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Prior art keywords
oxy
indol
dimethyl
alkyl
benzoic acid
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Inventor
Lara C. CZABANIUK
Nina Gommermann
Konstanze Hurth
Sébastien Jacquier
Nancy LABBE-GIGUERE
Kaila Ashley MARGREY
Adeline SCHOEN
Martin Sendzik
Anna Vulpetti
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Novartis AG
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Novartis AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the disclosure relates to the inhibition of the complement alternative pathway, and particularly to inhibition of factor B. It also relates to treatment of patients suffering from conditions and diseases associated with complement alternative pathway activation.
  • the complement system is a crucial component of the innate immunity system and comprises a group of proteins that are normally present in an inactive state. These proteins are organized in three activation pathways: the classical, the lectin, and the alternative pathways (V. M. Holers, In Clinical Immunology: Principles and Practice, ed. R.R. Rich, Mosby Press; 1996, 363-391). Molecules from microorganisms, antibodies or cellular components can activate these pathways resulting in the formation of protease complexes known as the C3-convertase and the C5-convertase.
  • the classical pathway is a calcium/magnesium-dependent cascade, which is normally activated by the formation of antigen-antibody complexes.
  • the alternative pathway is a magnesiumdependent cascade that is activated by deposition and activation of C3 on certain susceptible surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).
  • Factor B is a suitable target for the inhibition of this amplification of the complement pathways because its plasma concentration in humans is typically about 200 pg/mL (or about 2 pM), and it has been shown to be a critical enzyme for activation of the alternative complement pathway (P.H. Lesavre and H.J. Muller-Eberhard. J. Exp. Med., 1978; 148: 1498-1510; J.E. Volanakis et al., New Eng. J. Med., 1985; 312:395-401).
  • the present disclosure provides compounds that modulate, and/or inhibit, activation of the alternative complement pathway.
  • the present disclosure provides compounds that modulate, and/or inhibit, factor B activity and/or factor B mediated complement pathway activation.
  • 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.
  • the compounds of the present disclosure inhibit or suppress the amplification of the complement system caused by C3 activation irrespective of the initial mechanism of activation (including for example activation of the classical, lectin or alternative pathways).
  • the disclosure also relates to compounds effective as factor B modulators, pharmaceutically acceptable salts thereof, compositions thereof, and their use in therapies for the conditions and purposes detailed herein.
  • the disclosure provides, in a first aspect, a compound of Formula (I) or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein the variables are defined herein.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, and a pharmaceutically acceptable carrier or excipient.
  • a method of treating or preventing a disease ordisorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • a method of modulating the complement alternative pathway activity in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • a method of treating a disease or disorder mediated by complement activation, in particular mediated by activation of the complement alternative pathway, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • a method of treating a disease or disorder that is affected by the modulation of complement alternative pathway comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • a method of treating a disease or disorder associated with dysregulation of the complement alternative pathway comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • a method of inhibiting the expression or activity of complement factor B comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • a method of treating age-related macular degeneration comprising administering to a subject in need thereof an effective amount of a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof in the manufacture of a medicament for the treatment of a disease or disorder mediated by complement activation or activation of the complement alternative pathway.
  • a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof for the treatment of a disease or disorder mediated by complement activation or activation of the complement alternative pathway.
  • Macular degeneration is a clinical term that is used to describe a family of diseases that are characterized by a progressive loss of central vision associated with abnormalities of Bruch’s membrane, the choroid, the neural retina and/or the retinal pigment epithelium.
  • the macula lutea which is about 1 to % cm in diameter.
  • the macula provides detailed vision, particularly in the center (the fovea), because the cones are higher in density and because of the high ratio of ganglion cells to photoreceptor cells. Blood vessels, ganglion cells, inner nuclear layer and cells, and the plexiform layers are all displaced to the side (rather than resting above the photoreceptor cells), thereby allowing light a more direct path to the cones.
  • the choroid Under the retina is the choroid, a part of the uveal tract, and the retinal pigmented epithelium (RPE), which is between the neural retina and the choroid.
  • the choroidal blood vessels provide nutrition to the retina and its visual
  • Age-related macular degeneration is associated with progressive loss of visual acuity in the central portion of the visual field, changes in color vision, and abnormal dark adaptation and sensitivity.
  • Two principal clinical manifestations of AMD have been described as the dry, or atrophic, form and the neovascular, or exudative, form.
  • the dry form is associated with atrophic cell death of the central retina or macula, which is required for fine vision used for activities such as reading, driving or recognizing faces.
  • About 10-20% of these AMD patients progress to the second form of AMD, known as neovascular AMD (also referred to as wet AMD).
  • Neovascular AMD is characterized by the abnormal growth of blood vessels under the macula and vascular leakage, resulting in displacement of the retina, hemorrhage and scarring. This results in a deterioration of sight over a period of weeks to years.
  • Neovascular AMD cases originate from Intermediate or advanced dry AMD. The neovascular form accounts for 85% of legal blindness due to AMD. In neovascular AMD, as the abnormal blood vessels leak fluid and blood, scar tissue is formed that destroys the central retina.
  • CNV choroidal neovascularizaton
  • the present disclosure provides compounds that modulate factor B activation and/or factor B-mediated signal transduction of the complement system. Such compounds may be used in vitro or in vivo to modulate factor B activity in a variety of contexts.
  • the compounds disclosed herein are effective as factor B modulators and/or inhibitors.
  • the compounds provided herein are useful for the treatment of disorders associated with factor B.
  • the terms “compounds of the present disclosure,” “compounds of the disclosure,” “compound of the disclosure,” “or compounds provided herein” refer to compounds of the formulae disclosed herein, exemplified compounds, salts thereof, particularly pharmaceutically acceptable salts thereof, hydrates, solvates, as well as all stereoisomers (including diastereoisomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitutions), as well as inherently formed moieties.
  • the groups, radicals, or moieties defined below the number of carbon atoms is often specified preceding the group, for example, Ci-Cwalkyl means an alkyl group or radical having 1 to 10 carbon atoms.
  • substituted means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions.
  • an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.
  • Ci-Cealkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Ci-C 3 alkyl and Ci-C 4 alkyl are to be construed accordingly.
  • Ci-C 6 alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, 1 -methylethyl (/so-propyl), n-butyl, 1 -methylpropyl (sec-butyl), 2-methylpropyl (/so-butyl), 1 ,1 -dimethylethyl (te/Y-butyl), n-pentyl and n-hexyl.
  • alkenyl employed alone or in combination with other terms, refers to a straightchain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds.
  • An alkenyl group formally corresponds to an alkene with one C H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound.
  • C n.m alkenyl refers to an alkenyl group having n to m carbons.
  • the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl and the like.
  • Ci-C 6 alkoxy refers to a radical of the formula -OR a where R a is a Ci.C 6 alkyl radical as generally defined above.
  • Examples of Ci-C 6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, /so-propoxy, butoxy, /so-butoxy, tert- butoxy, sec-butoxy, pentoxy, and hexoxy.
  • amino employed alone or in combination with other terms, refers to a group of formula -NH 2 , wherein the hydrogen atoms may be substituted with a substituent described herein.
  • alkylamino can refer to -NH(alkyl) and - N(alkyl) 2 .
  • cyano or “nitrile” refers to a group of formula -CEN, which also may be written as -CN.
  • halogen or “halo” means fluorine, chlorine, bromine or iodine.
  • hydroxy refers to an alcohol group of formula -OH.
  • cycloalkyl or “carbocycle” means a monocyclic or polycyclic saturated or partially unsaturated carbon ring containing 3-18 carbon atoms wherein there are no delocalized pi electrons (aromaticity) shared among the ring carbons.
  • C 3 -C 5 cycloalkyl is to be construed accordingly.
  • polycyclic encompasses bridged (e.g., norbornane), fused (e.g., decalin) and spirocyclic cycloalkyl.
  • cycloalkyl e.g., C 3 -C 5 cycloalkyl, is a monocyclic hydrocarbon group of 3 to 5 carbon atoms.
  • cycloalkyl groups include, without limitations, cyclopropenyl, cyclopropyl cyclobutyl, cyclobutenyl, cyclopentyl, bicyclo[1 .1 ,1]pentanyl and derivatives thereof.
  • C 3 -C5cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, and cyclo pentyl.
  • Heterocyclyl means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen, and sulfur (O, N, and S) and wherein there are no delocalized pi electrons (aromaticity) shared among the ring carbons or heteroatoms.
  • the term “4- to 6-membered heterocyclyl” is to be construed accordingly.
  • the heterocyclyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted.
  • the heterocyclyl may be bonded via a carbon atom or heteroatom.
  • polycyclic encompasses bridged, fused and spirocyclic heterocyclyl.
  • heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, 1 ,4-dioxanyl, dihydrofuranyl, 1 ,3-dioxolanyl, imidazolidinyl, di
  • 4- to 6-membered heterocyclyl examples include, without limitations, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, dihydroisoxazolinyl, tetrahydropyranyl, morpholinyl, dihydropyranyl (e.g., 3,6-dihydro-2/7-pyranyl) and oxaspiroheptanyl (e.g., 2-oxaspiro[3.3]heptan-6-yl).
  • heteroaryl is intended to include monocyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S).
  • Representative examples are pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isooxazolyl, triazolyl, (e.g., 1 ,2,4-triazolyl), oxadiazolyl, (e.g., 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl), thiadiazolyl (e.g., 1 ,2,3- thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazol
  • Heteroaryl is also intended to include bicyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S).
  • Representative examples are indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzopyranyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, cinnolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, oxazolopyridinyl, isooxazolopyridinyl, pyrrolopyridinyl, furopyridinyl, thienopyr
  • Heteroaryl is also intended to include polycyclic heterocyclic aromatic rings containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S).
  • Representative examples are carbazolyl, phenoxazinyl, phenazinyl, acridinyl, phenothiazinyl, carbolinyl, phenanthrolinyl, and the like.
  • the heteroaryl ring structure may be substituted by one or more substituents.
  • the substituents can themselves be optionally substituted.
  • the heteroaryl ring may be bonded via a carbon atom or heteroatom.
  • Examples of 5 or 6 membered heteroaryl include, but are not limited to, furan, indolyl, pyridinyl, pyrimidinyl, pyridinonyl, pyridazinyl, triazolyl, (e.g., 1 ,2,4-triazolyl), pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, pyrrolyl, oxadiazolyl, (e.g., 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5- oxadiazolyl, 1 ,3,4-oxadiazolyl), imidazolyl, thiophenyl, thiadiazolyl (e.g., 1 ,2,3-thiadiazolyl, 1 ,2,4- thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl
  • modulator means, for example, a compound of the disclosure that modulates, decreases, or reduces the levels of a specific protein (e.g., complement factor B).
  • the amount of a specific protein (e.g., complement factor B) modulated can be measured by comparing the amount of the specific protein (e.g., complement factor B) remaining after treatment with a compound of the disclosure as compared to the initial amount or level of the specific protein (e.g., complement factor B) present as measured prior to treatment with a compound of the disclosure.
  • inhibitor means, for example, a compound of the disclosure, that inhibits or reduces the activity of at least one component of the complement pathway, e.g., the compound inhibits binding of one component to another component of the pathway.
  • the complement pathway is the alternative complement pathway.
  • the component of the complement pathway is complement factor B.
  • the term “inhibit,” “inhibition,” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • an effective amount of the compounds described herein refers to that amount of a therapeutic compound necessary or sufficient to perform its intended function within a mammal.
  • An effective amount of the therapeutic compound can vary according to factors such as the amount of the causative agent already present in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compounds of the present disclosure to treat the conditions wherein complement factor B plays a role.
  • a therapeutically effective amount of a compound of the disclosure refers to an amount of the compound of the disclosure that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount refers to the amount of the compound of the disclosure that, when administered to a subject, is effective to (1) at least partially alleviate, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by complement factor B, or (ii) associated with complement factor B activity, or (iii) characterized by activity (normal or abnormal) of complement factor B: (2) reduce or inhibit the activity of complement factor B; or (3) reduce or inhibit the expression of complement factor B.
  • a therapeutically effective amount refers to the amount of the compound of the disclosure that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of complement factor B; or at least partially reducing or inhibiting the expression of complement factor B.
  • the term “subject” or “patient” refers to human and non-human mammals, including but, not limited to, primates, rabbits, pigs, horses, dogs, cats, sheep, and cows.
  • a subject or patient is a human.
  • the term “patient” or “subject” refers to a human being who is diseased with the condition (/.e., disease or disorder) described herein and who would benefit from the treatment.
  • a subject is “in need of’ a treatment if such subject (patient) would benefit biologically, medically or in quality of life from such treatment.
  • the subject is an adult human at least about 18 years of age.
  • the subject is an adult human from about 18 to about 75 years of age.
  • the subject is a human child up to about 18 years of age.
  • treating refers to inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., arresting further development of the pathology and/or symptomology) or ameliorating the disease; for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and/or symptomology) such as decreasing the severity of the disease.
  • prevent comprises the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented.
  • a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the term “about” refers to a range of values +/- 10% of a specified value.
  • the term “pharmaceutically acceptable carrier” refers to a substance useful in the preparation or use of a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffering agents, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring agents, dyes, and combinations thereof, as would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1 - 19 and in Stahl et al., Handbook of
  • the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein the variables are defined herein.
  • Embodiment 1 provides a compound of Formula (I) or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:
  • W is O, C(R 6 ) 2 , or NR 7 ;
  • R is hydrogen, halogen, Ci-C 4 alkyl, haloCi-C 4 alkyl, or hydroxyCi-C 4 alkyl;
  • R 1 is hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy, haloCi-C 6 alkyl, haloC 3 -C 6 cycloalkyl, haloCi-C 6 alkoxy, hydroxyCi-C 6 alkyl, hydroxyC 3 - C 6 cycloalkyl, aminoCi-C 6 alkyl, Ci-C 6 alkoxyCi-C 6 alkyl, Ci-C 6 alkoxyCi-C 6 alkoxy, or C 3 - C 6 cycloalkylCi-C 6 alkoxy;
  • R 2 is Ci-C 3 alkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-C 6 alkyl, or halogen, wherein the Ci-C 3 alkyl, C 3 cycloalkyl, or Ci-C 3 alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;
  • R 3 is hydrogen, halogen, or cyano
  • R 4 is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 7 is hydrogen, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 - C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkyl, Ci-C 6 alkoxyCi- C 6 alkyl, haloCi-C 6 alkoxyCi-C 6 alkyl, -COR 7a , aryl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O) q , or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein Ci-Cealkyl is unsubstituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently
  • R 9 is H, D, or T; m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3; provided that both m and n are not 0; and p is 0, 1 , 2, or 3.
  • Embodiment 2 provides the compound of Formula (I) of embodiment 1 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:
  • W is C(R 6 ) 2 , or NR 7 ;
  • R is hydrogen
  • R 1 is hydrogen, halogen, hydroxy, C1-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C1-C 6 alkoxy, haloCi-C 6 alkyl, hydroxyC1-C 6 alkyl, or aminoC1-C 6 alkyl;
  • R 2 is Ci-Csalkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-Cealkyl, or halogen, wherein the Ci-C 3 alkyl, C 3 cycloalkyl, or Ci-C 3 alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;
  • R 3 is hydrogen, halogen, or cyano
  • R 4 is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 -C 6 cycloalkyl, Cr C 6 alkoxyCi-C 6 alkyl, -CH 2 CO 2 R 5b , cyano, hydroxy, halogen, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R 5a ; each R 5a is independently selected from fluoro, hydroxyl, and Ci-C 6 alkyl that is unsubstituted or substituted with -CO 2 H;
  • R 5b is selected from hydrogen and Ci-C 5 alkyl; each R 6 is independently selected from hydrogen, halogen, hydroxy, C 3 -C 6 cycloalkylCi- C 4 alkylamino, haloC 3 -C 6 cycloalkylCi-C 4 alkylamino, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyCr Cealkyl, Ci-Cealkoxy, haloC1-C6alkoxy, C3-C6cycloalkoxy, haloC3-C6cycloalkoxy, and 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, and wherein the Ci-C 6 alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein each 4- to 6-membered heterocyclyl is independently unsubstituted or substituted with 1 , 2, or
  • R 7 is hydrogen, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, haloC 3 -C 6 cycloalkylCi- C 3 alkyl, haloC 3 -C 6 cycloalkyl, haloCi-C 6 alkoxyCi-C 6 alkyl, -COR 7a , C 3 -C 6 cycloalkyl, 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N or O, or 5- to 6- membered heteroaryl having 1 heteroatom selected from O, wherein the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are unsubstituted;
  • R 7a is Ci-C 6 alkyl; each R 8 is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C 4 alkylamino, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyCi-C 6 alkyl, cyanoCi-C 6 alkyl, Cr C 6 alkoxy, and haloCi-C 6 alkoxy;
  • R 9 is H, D, or T; m is 1 , 2, or 3; n is 1 , 2, or 3; and p is 0, 1 , or 2.
  • Embodiment 3 provides the compound of Formula (I) of embodiment 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:
  • W is C(R 6 ) 2 , or NR 7 ;
  • R is hydrogen
  • R 1 is hydrogen, halogen, hydroxy, Ci-Cealkyl, Cs-Cecycloalkyl, Ci-Cealkoxy, or haloCi- C 6 alkyl;
  • R 2 is Ci-C 3 alkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-C 6 alkyl, or halogen;
  • R 3 is hydrogen
  • R 4 is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-Cealkyl, hydroxyCs-Cecycloalkyl, -CH 2 CO 2 R 5b , cyano, hydroxy, halogen, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, and O, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R 5a ; each R 5a is independently selected from fluoro, hydroxyl, and Ci-C 6 alkyl that is unsubstituted or substituted with -CO 2 H; each R 5b is selected from hydrogen and Ci-C 5 alkyl; each R 6 is independently selected from hydrogen, halogen, hydroxy, C 3 -C 6 cycloalkylCi- C 4 alkylamino, haloC 3 -C 6 cycloalkylCi-C 4 alkylamino, Ci-
  • R 7 is hydrogen, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, haloC 3 -C 6 cycloalkylCi- C 3 alkyl, haloC 3 -C 6 cycloalkyl, haloCi-C 6 alkoxyCi-C 6 alkyl, -COR 7a , C 3 -C 6 cycloalkyl, 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N or O, or 5- to 6- membered heteroaryl having 1 heteroatom selected from O, wherein the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are unsubstituted;
  • R 7a is Ci-C 6 alkyl; each R 8 is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C 4 alkylamino, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyCi-C 6 alkyl, cyanoCi-C 6 alkyl, Cr C 6 alkoxy, and haloCi-C 6 alkoxy;
  • R 9 is H; m is 1 , or 2; n is 1 , 2, or 3; and p is 0.
  • Embodiment 4 provides the compound of Formula (I) of any of embodiments 1 to 3, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the compound of Formula (I) is a compound of Formula (1-1):
  • Embodiment 5 provides the compound of Formula (I) of any of embodiments 1 to 3, wherein the compound of Formula (I) is a compound of Formula (I-2):
  • Embodiment 6 provides the compound of Formula (I) in any of embodiments 1 to 5, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:
  • W is C(R 6 ) 2 ;
  • R is hydrogen
  • R 1 is hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy, haloCi-C 6 alkyl, hydroxyCi-C 6 alkyl, or aminoCi-C 6 alkyl;
  • R 2 is Ci-C 3 alkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-C 6 alkyl, or halogen, wherein the Ci-C 3 alkyl, C 3 cycloalkyl, or Ci-C 3 alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;
  • R 3 is hydrogen, halogen, or cyano
  • R 4 is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 -C 6 cycloalkyl, Cr CealkoxyCi-Cealkyl, -CH 2 CO 2 R 5b , cyano, hydroxy, halogen, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R 5a ; each R 5a is independently selected from fluoro, hydroxyl, and Ci-Cealkyl that is unsubstituted or substituted with -CO 2 H; each R 5b is selected from hydrogen and Ci-C 5 alkyl; each R 6 is independently selected from hydrogen, halogen, hydroxy, C 3 -C 6 cycloalkylCi- C 4 alkylamino, haloC 3 -C 6
  • R 9 is H, D, or T; m is 1 , 2, or 3; n is 1 , 2, or 3; and p is 0, 1 , or 2.
  • Embodiment 7 provides the compound of Formula (I) of any of embodiments 1 to 5, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein
  • W is NR 7 ;
  • R is hydrogen
  • R 1 is hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy, haloCi-C 6 alkyl, hydroxyCi-C 6 alkyl, or aminoCi-C 6 alkyl;
  • R 2 is Ci-C 3 alkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-C 6 alkyl, or halogen, wherein the Ci-C 3 alkyl, C 3 cycloalkyl, or Ci-C 3 alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;
  • R 3 is hydrogen, halogen, or cyano
  • R 4 is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 -C 6 cycloalkyl, Cr C 6 alkoxyCi-C 6 alkyl, -CH 2 CO 2 R 5b , cyano, hydroxy, halogen, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R 5a ; each R 5a is independently selected from fluoro, hydroxyl, and Ci-C 6 alkyl that is unsubstituted or substituted with -CO 2 H; each R 5b is selected from hydrogen and Ci-C 5 alkyl;
  • R 7 is hydrogen, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, haloC 3 -C 6 cycloalkylCi- C 3 alkyl, haloC 3 -C 6 cycloalkyl, haloCi-C 6 alkoxyCi-C 6 alkyl, -COR 7a , C 3 -C 6 cycloalkyl, 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N or O, or 5- to 6- membered heteroaryl having 1 heteroatom selected from O, wherein the 4- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are unsubstituted;
  • R 7a is Ci-C 6 alkyl
  • each R 8 is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C 4 alkylamino, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyCi-C 6 alkyl, cyanoCi-C 6 alkyl, Cr C 6 alkoxy, and haloCi-C 6 alkoxy
  • R 9 is H, D, or T
  • m is 1 , 2, or 3
  • n is 1 , 2, or 3
  • p is 0, 1 , or 2.
  • Embodiment 8 provides the compounf of Formula (I) of any of embodiments 1-6, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein
  • W is C(R 6 ) 2 ;
  • R is hydrogen
  • R 1 is hydrogen, halogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, or haloCi-C 6 alkyl;
  • R 2 is Ci-C 3 alkyl, or halogen, wherein the Ci-C 3 alkyl is unsubstituted or substituted with 1 , 2, or 3 halogen substituents;
  • R 3 is hydrogen
  • R 4 is phenyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 -C 6 cycloalkyl, -CH 2 CO 2 R 5b , cyano, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R 5a ; each R 5a is independently selected from hydroxy and Ci-C 6 alkyl; each R 5b is independently selected from hydrogen and Ci-C 3 alkyl; each R 6 is independently selected from hydrogen, halogen, hydroxy, C 3 -C 6 cycloalkylCi- C 4 alkylamino, haloC 3 -C 6 cycloalkylCi-C 4 alkylamino, Ci-C 6 alkyl, haloCi-C 6 alkyl, Ci-C 6 alkoxy, halo
  • R 9 is H; m is 1 or 2; n is 1 , 2, or 3; and p is 0, 1 , or 2.
  • Embodiment 9 provides the compound of Formula (I) of any of embodiments 1 -5 and 7, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein
  • W is NR 7 ;
  • R is hydrogen
  • R 1 is hydrogen, halogen, Ci-Cealkyl, Cs-Cecycloalkyl, or haloCi-Cealkyl;
  • R 2 is Ci-C 3 alkyl, or halogen, wherein the Ci-C 3 alkyl is unsubstituted or substituted with 1 , 2, or 3 halogen substituents;
  • R 3 is hydrogen
  • R 4 is phenyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 -C 6 cycloalkyl, -CH 2 CO 2 R 5b , cyano, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R 5a ; each R 5a is independently selected from hydroxy and Ci-C 6 alkyl; each R 5b is independently selected from hydrogen and Ci-C 3 alkyl;
  • R 7 is Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, haloC 3 -C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkyl, haloCi-C 6 alkoxyCi-C 6 alkyl, -COR 7a , 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N or O, or 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, ;
  • R 7a is Ci-C 6 alkyl; each R 8 is independently selected from hydrogen and Ci-C 6 alkyl;
  • Embodiment 10 provides the compound of Formula (I) of any of embodiments 1 -6 and 8, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein
  • W is C(R 6 ) 2 ;
  • R is hydrogen
  • R 1 is hydrogen, halogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, haloCi-C 6 alkyl;
  • R 2 is Ci-C 3 alkyl, or halogen, wherein the Ci-C 3 alkyl is unsubstituted or substituted with 1 , 2, or 3 halogen substituents;
  • R 3 is hydrogen
  • R 4 is phenyl, or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-Cealkyl, hydroxyCs-Cecycloalkyl, -CH 2 CO 2 R 5b , cyano, hydroxy, halogen, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R 5a ; each R 5a is independently selected from hydroxyl, and Ci-C 6 alkyl; each R 5b is independently selected from hydrogen; each R 6 is independently selected from hydrogen, halogen, hydroxy, C 3 -C 6 cycloalkylCi- C 4 alkylamino, haloC 3 -C 6 cycloalkylCi-C 4 alkylamino, Ci-C 6 alkyl, haloCi-C 6 alkyl, Ci-C 6 alkoxy,
  • R 9 is H or D; m is 1 or 2; n is 1 , 2, or 3; and p is 0.
  • Embodiment 11 provides the compound of Formula (I) of any of embodiments 1-5, 7 and 9, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein W is NR 7 ;
  • R is hydrogen
  • R 1 is hydrogen, halogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, haloCi-C 6 alkyl;
  • R 2 is Ci-C 3 alkyl, or halogen, wherein the Ci-C 3 alkyl is unsubstituted or substituted with 1 , 2, or 3 halogen substituents;
  • R 3 is hydrogen
  • R 4 is phenyl, or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from hydrogen, -CC>2R 5b , Ci-Cealkyl, hydroxyCs-Cecycloalkyl, -CH2CC>2R 5b , cyano, hydroxy, halogen, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R 5a ; each R 5a is independently selected from hydroxyl, and Ci-C 6 alkyl; each R 5b is independently selected from hydrogen;
  • R 7 is Ci-Cealkyl, haloCi-Cealkyl, hydroxyC2-Cealkyl, haloC 3 -C6cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkyl, haloCi-C 6 alkoxyCi-C 6 alkyl, -COR 7a , 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N or O, or 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S; each R 8 is independently selected from hydrogen, halogen; R 9 is H or D; m is 1 or 2; n is 1 , 2, or 3; and p is 0.
  • Embodiment 12 provides the compound of Formula (I) of any of applicable embodiments 1 to 11 , wherein the compound of Formula (I) is a compound of Formula (l-AC), or (l-AN): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 13 provides the compound of Formula (I) of any of embodiments 1 to 12, wherein the compound of Formula (I) is a compound of Formula (l-AO), (I-A1) or (I-A2): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 14 provides the compound of Formula (I) of embodiment 13, wherein the compound of Formula (I) is a compound of Formula (l-A), Formula (I-A11) or Formula (I-A12): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 15 provides the compound of Formula (I) of any of embodiments 1 to 13, wherein the compound of Formula (I) is a compound of Formula or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 16 provides the compound of Formula (I) of embodiment 15, wherein the compound of Formula (I) is a compound of Formulas (l-D’), (l-D’1) or (l-D’2):
  • Embodiment 17 provides the compound of Formula (I) of embodiment 13, wherein the compound of Formula (I) is a compound of Formula (l-H), (I-H1), or (l-H2): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 18 provides the compound of Formula (I) of embodiment 17, wherein the compound of Formula (I) is a compound of Formula (l-B), (I-EB1 ) or (I-B2): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 19 provides the compound of Formula (I) of embodiment 13, wherein the compound of Formula (I) is a compound of Formula (l-E), (I-E1), or (I-E2): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 20 provides the compound of Formula (I) of embodiment 13, wherein the or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 21 provides the compound of Formula (I) of embodiment 13, wherein the compound of Formula (I) is a compound of Formula (l-G), (I-G1), or (l-G2): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 22 provides the compound of Formula (I) of embodiment 13, wherein the compound of Formula (I) is a compound of Formula (l-J), (I-J1) or (l-J2):
  • Embodiment 23 provides the compound of Formula (I) of embodiment 13, wherein the compound of Formula (I) is a compound of Formula (l-CO): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 24 provides the compound of Formula (I) of embodiment 23, wherein the compound of Formula (I) is a compound of Formula (I-C01), (I-C02), (I-C03) or (l-C04): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 25 provides the compound of Formula (I) of embodiment 24, wherein the compound of Formula (I) is a compound of Formula (l-C):
  • Embodiment 26 provides the compound of Formula (I) of embodiment 25, wherein the compound of Formula (I) is a compound of Formula (I-C1), (I-C2), (I-C3) or (l-C4): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 27 provides the compound of Formula (I) of embodiment 23, wherein the compound of Formula (I) is a compound of Formula (l-l):
  • Embodiment 28 provides the compound of Formula (I) of embodiment 27, wherein the compound of Formula (I) is a compound of Formula (1-11), (I-I2), (I-I3) or (I-I4): or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 29 provides the compound of Formula (I) of embodiment 28, wherein the compound of Formula (I) is a compound of Formula (l-J): (I-J) or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 30 provides the compound of Formula (I) of embodiment 29, wherein the compound of F or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • Embodiment 31 provides the compound of Formula (I) of any of embodiments 1 to 30, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 1 is hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy, haloCi-C 6 alkyl, haloC 3 -C 6 cycloalkyl, haloCi-C 6 alkoxy, hydroxyCi-C 6 alkyl, hydroxyC 3 - C 6 cycloalkyl, aminoCi-C 6 alkyl, Ci-C 6 alkoxyCi-C 6 alkyl, Ci-C 6 alkoxyCi-C 6 alkoxy, or C 3 - CecycloalkylCi-Cealkoxy.
  • Embodiment 32 provides the compound of Formula (I) of any of embodiments 1 to 31 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 1 is hydrogen, halogen, Ci-Cealkyl, Cs-Cecycloalkyl, haloCi-Cealkyl, haloC 3 - C 6 cycloalkyl, haloCi-C 6 alkoxy, hydroxyCi-C 6 alkyl, or hydroxyC 3 -C 6 cycloalkyl.
  • Embodiment 33 provides the compound of Formula (I) of any of embodiments 1 to 32, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 1 is hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, or haloCi-C 6 alkyl.
  • Embodiment 34 provides the compound of Formula (I) of any of embodiments 1 to 33, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 1 is hydrogen, halogen, Ci-Cealkyl, Cs-Cecycloalkyl, or haloCi-Cealkyl.
  • Embodiment 35 provides the compound of Formula (I) of any of embodiments 1 to 34, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 2 is Ci-C 3 alkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-C 6 alkyl, or halogen, wherein the Ci-C 3 alkyl, C 3 cycloalkyl, or Ci-C 3 alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents.
  • Embodiment 36 provides the compound of Formula (I) of any of embodiments 1 to 35, or a pharmaceutically acceptable salt or a stereoisomer or an isoto pica lly labeled compound thereof, wherein R 2 is Ci-C 3 alkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-C 6 alkyl, or halogen, wherein the Ci-C 3 alkyl, C 3 cycloalkyl, or Ci-C 3 alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents.
  • Embodiment 37 provides the compound of Formula (I) of any of embodiments 1 to 36, or a pharmaceutically acceptable salt or a stereoisomer or an isoto pica lly labeled compound thereof, wherein R 2 is Ci-C 3 alkyl, or halogen, wherein the Ci-C 3 alkyl is unsubstituted or substituted with 1 , 2, or 3 halogen substituents.
  • Embodiment 38 provides the compound of Formula (I) of any of embodiments 1 to 37, or a pharmaceutically acceptable salt or a stereoisomer or an isoto pica lly labeled compound thereof, wherein R 2 is Ci-C 3 alkyl, or halogen.
  • Embodiment 39 provides the compound of Formula (I) of any of applicable embodiments 1 to 38, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein where applicable R 3 is hydrogen, halogen, or cyano.
  • Embodiment 40 provides the compound of Formula (I) of any of applicable embodiments 1 to 39, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein where applicable R 3 is hydrogen.
  • Embodiment 41 provides the compound of Formula (I) of any of applicable embodiments 1 to 40, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 4 is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 .
  • Embodiment 42 provides the compound of Formula (I) of any of applicable embodiments 1 to 41 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 4 is phenyl, or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 .
  • Embodiment 43 provides the compound of Formula (I) of any of applicable embodiments 1 to 42, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 4 is phenyl, or 5- to 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 .
  • Embodiment 44 provides the compound of Formula (I) of any of applicable embodiments 1 to 43, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 4 is 5- to 6-membered heteroaryl having 1 or 2 ring heteroatoms selected from N, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 .
  • Embodiment 45 provides the compound of Formula (I) of any of applicable embodiments 1 to 44, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 4 is phenyl, wherein the phenyl is unsubstituted or substituted with R 5 .
  • Embodiment 46 provides the compound of Formula (I) of any of applicable embodiments 1 to 45, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 4 is pyridinyl, or pyrazolyl, wherein the pyridinyl, or pyrazolyl is unsubstituted or substituted with R 5 .
  • Embodiment 47 provides the compound of Formula (I) of any of applicable embodiments 1 to 46, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 5 is selected from hydrogen, -CC>2R 5b , Ci-Cealkyl, hydroxyC 3 - Cecycloalkyl, Ci-C 6 alkoxyCi-C 6 alkyl, -CH 2 CO 2 R 5b , -C(O)NHSO 2 Ci-C 4 alkyl, -SO 2 NHC(O)CI- C 4 alkyl, -SO 2 Ci-C 4 alkyl, cyano, hydroxy, halogen, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R 5a .
  • R 5 is selected from hydrogen,
  • Embodiment 48 provides the compound of Formula (I) of any of applicable embodiments 1 to 47, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 5 is selected from hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 - C 6 cycloalkyl, -CH 2 CO 2 R 5b , cyano, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R 5a .
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 - C 6 cycloalkyl, -CH 2 CO 2 R 5b , cyano, -C(O)N(R 5b ) 2 and 5- to 6-membered hetero
  • Embodiment 49 provides the compound of Formula (I) of any of applicable embodiments 1 to 48, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 5 is selected from hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 - C 6 cycloalkyl, -CH 2 CO 2 R 5b , cyano, -C(O)N(R 5b ) 2 and 5-membered heteroaryl having 1-4 heteroatoms independently selected from N, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R 5a .
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 - C 6 cycloalkyl, -CH 2 CO 2 R 5b , cyano, -C(O)N(R 5b ) 2 and 5-membered heteroaryl having 1-4 heteroatoms independently selected from N, where
  • Embodiment 50 provides the compound of Formula (I) of any of applicable embodiments 1 to 49, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 5 is selected from hydrogen, -CO 2 R 5b , Ci-Cealkyl, hydroxyC 3 - C 6 cycloalkyl, -CH 2 CO 2 R 5b , cyano, -C(O)N(R 5b ) 2 and 5-membered heteroaryl having 1-3 heteroatoms independently selected from N, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R 5a .
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-Cealkyl, hydroxyC 3 - C 6 cycloalkyl, -CH 2 CO 2 R 5b , cyano, -C(O)N(R 5b ) 2 and 5-membered heteroaryl having 1-3 heteroatoms independently selected from N, where
  • Embodiment 51 provides the compound of Formula (I) of any of applicable embodiments 1 to 50, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein where applicable each R 5a is independently selected from fluoro, hydroxyl, and Ci-C 6 alkyl that is unsubstituted or substituted with -CO 2 H.
  • Embodiment 52 provides the compound of Formula (I) of any of applicable embodiments 1 to 51 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein where applicable each R 5a is hydroxyl.
  • Embodiment 53 provides the compound of Formula (I) of any of applicable embodiments 1 to 52, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein where applicable each R 5b is independently selected from hydrogen and Ci-C 5 alkyl.
  • Embodiment 54 provides the compound of Formula (I) of any of applicable embodiments 1 to 53, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein where applicable each R 5b is independently selected from hydrogen.
  • Embodiment 55 provides the compound of Formula (I) of any of applicable embodiments 1 to 54, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 5 is selected from hydrogen, -CO 2 H, Ci-C 6 alkyl, hydroxyC 3 - Cecycloalkyl, hydroxyC 3 -Cealkyl, cyano, -CONH 2 , pyrazolyl, triazolyl, and tetrazolyl, wherein the pyrazolyl, triazolyl, and tetrazolyl are unsubstituted or substituted with 1 Ci-C 6 alkyl.
  • Embodiment 56 provides the compound of Formula (I) of any of applicable embodiments 1 to 55, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein each R 6 is independently selected from hydrogen, halogen, hydroxy, C 3 -C 6 cycloalkylCi-C 4 alkylamino, haloC 3 -C 6 cycloalkylCi-C 4 alkylamino, Ci-C 6 alkyl, haloCi-C 6 alkyl, Ci-C 6 alkoxy, haloCi-C 6 alkoxy, C 3 -C 6 cycloalkoxy, haloC 3 -C 6 cycloalkoxy, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein the Ci-C 6 alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, where
  • Embodiment 57 provides the compound of Formula (I) of any of applicable embodiments 1 to 56, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein each R 6 is independently selected from Ci-C 6 alkyl, C 3 -C 6 cycloalkylCi- C 4 alkylamino, haloC 3 -C 6 cycloalkylCi-C 4 alkylamino, haloCi-C 6 alkyl, C 3 -C 6 cycloalkoxy, haloC 3 - C 6 cycloalkoxy, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein the Ci-Cealkyl is unsubsituted or substituted with 4- to 6- membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or
  • Embodiment 58 the compound of Formula (I) of any of applicable embodiments 1 to 57, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein each R 6 is independently selected from hydrogen, halogen, hydroxy, C 3 - C 6 cycloalkylCi-C 4 alkylamino, haloC 3 -C 6 cycloalkylCi-C 4 alkylamino, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyCi-C 6 alkyl, Ci-C 6 alkoxy, haloCi-C 6 alkoxy, C 3 -C 6 cycloalkoxy, haloC 3 -C 6 cycloalkoxy, and 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, and wherein the Ci-C 6 alkyl is unsubsituted or substituted with 4- to 6-membered heterocyclyl having
  • Embodiment 59 provides the compound of Formula (I) of any of applicable embodiments 1 to 58, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein each R 6 is independently selected from hydrogen, halogen, hydroxy, Ci-C 6 alkyl, haloCi-C 6 alkyl, Ci-C 6 alkoxy, and haloCi-C 6 alkoxy.
  • Embodiment 60 provides the compound of Formula (I) of any of applicable embodiments 1 to 59, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R 6 in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C 6 alkyl, and Cr C 6 alkoxy.
  • Embodiment 61 provides the compound of Formula (I) of any of applicable embodiments 1 to 60, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R 6 in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 4 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen.
  • Embodiment 62 provides the compound of Formula (I) of any of applicable embodiments 1 to 61 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R 6 in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N, O, and S(O) q , wherein the spirocyclic heterocycle is unsubstituted or substituted with 1 or 2 halogen, Ci-C 6 alkyl, haloCi-C 6 alkyl, C 3 -C 6 cycloalkyl, or haloC 3 -C 6 cycloalkyl; wherein q is 0, 1 , or 2.
  • Embodiment 63 provides the compound of Formula (I) of any of applicable embodiments 1 to 62, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R 6 in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O.
  • Embodiment 64 provides the compound of Formula (I) of any of applicable embodiments 1 to 63, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R 6 in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O, wherein the spirocyclic heterocycle has 3 to 6 ring atoms.
  • Embodiment 65 provides the compound of Formula (I) of any of applicable embodiments 1 to 64, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R 6 in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 ring heteroatom selected from O.
  • Embodiment 66 provides the compound of Formula (I) of any of applicable embodiments 1 to 65, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein two R 6 in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 ring heteroatom selected from O, wherein the spirocyclic heterocycle has 5 ring atoms.
  • Embodiment 67 provides the compound of Formula (I) of any of applicable applicable embodiments 1 to 66, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 7 is Ci-Cealkyl, haloCi-Cealkyl, hydroxyC 2 -C6alkyl, C 3 - C 6 cycloalkyl, C 3 -C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkyl, Cr C 6 alkoxyCi-C 6 alkyl, haloCi-C 6 alkoxyCi-C 6 alkyl, -COR 7a , aryl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O) q , or 5- to 6-membered heteroaryl having
  • Embodiment 68 provides the compound of Formula (I) of any of applicable applicable embodiments 1 to 67, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 7 is Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, C 3 - C 6 cycloalkyl, C 3 -C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkyl, haloCi-C 6 alkoxyCi-C 6 alkyl, -COR 7a , 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N and O, or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein the 4- to 6-membered heterocyclyl is
  • Embodiment 69 provides the compound of Formula (I) of any of applicable embodiments 1 to 68, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 7 is Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, haloC 3 - CecycloalkylCi-Csalkyl, haloCs-Cecycloalkyl, haloCi-CealkoxyCi-Cealkyl, -COR 7a , 4- to 6- membered heterocyclyl having 1 heteroatoms selected from O, or 5- to 6-membered heteroaryl having 1 heteroatoms independently selected from O, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with 1 , 2, or 3 halogen, further wherein the heteroaryl is unsubstituted or substituted with halo, Ci-C 6 alkyl
  • Embodiment 70 provides the compound of Formula (I) of any of applicable embodiments 1 to 69, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 7 is Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, haloC 3 - C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkyl, haloCi-C 6 alkoxyCi-C 6 alkyl, -COR 7a , 4- to 6- membered heterocyclyl having 1 heteroatoms selected from O, or 5-membered heteroaryl having 1 heteroatom selected from O.
  • Embodiment 71 provides the compound of Formula (I) of any of applicable embodiments 1 to 70, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 7a is Ci-C 6 alkyl.
  • Embodiment 72 provides the compound of Formula (I) of any of applicable embodiments 1 to 71 , or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein p is 0.
  • Embodiment 73 provides the compound of Formula (I) of any of applicable embodiments 1 to 72, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein R 9 is H.
  • Embodiment 74 provides the compound of Formula (I) of any of applicable embodiments 1 to 73, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein m is 1 , or 2.
  • Embodiment 75 provides the compound of Formula (I) of any of applicable embodiments 1 to 74, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein n is 1 , 2, or 3.
  • Embodiment 76 provides the compound of Formula (I) of any of applicable embodiments 1 to 75, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:
  • W is C(R 6 ) 2 , or NR 7 ;
  • R 1 is hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy, haloCi-C 6 alkyl, haloC 3 -C 6 cycloalkyl, haloCi-C 6 alkoxy, hydroxyCi-C 6 alkyl, hydroxyC 3 - C 6 cycloalkyl, aminoCi-C 6 alkyl, Ci-C 6 alkoxyCi-C 6 alkyl, Ci-C 6 alkoxyCi-C 6 alkoxy, or C 3 - C 6 cycloalkylCi-C 6 alkoxy;
  • R 3 is hydrogen, halogen, or cyano
  • R 4 is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 -C 6 cycloalkyl, Ci- C 6 alkoxyCi-C 6 alkyl, -CH 2 CO 2 R 5b , -C(O)NHSO 2 Ci-C 4 alkyl, -SO 2 NHC(O)Ci-C 4 alkyl, -SO 2 Ci- C 4 alkyl, cyano, hydroxy, halogen, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substitute
  • R 7 is hydrogen, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 - C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkyl, Ci-C 6 alkoxyCi- C 6 alkyl, haloCi-C 6 alkoxyCi-C 6 alkyl, -COR 7a , aryl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O) q , or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein Ci-C 6 alkyl is unsubstituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently
  • R 9 is H; m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3; p is 0.
  • Embodiment 77 provides the compound of Formula (I) of any of applicable embodiments 1 to 76, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:
  • W is NR 7 ;
  • R is hydrogen ;or hydroxyC 3 -C 6 cycloalkyl
  • R 1 is hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, haloCi-C 6 alkyl, haloC 3 - C 6 cycloalkyl, haloCi-C 6 alkoxy, hydroxyCi-C 6 alkyl, hydroxyC 3 -C 6 cycloalkyl; preferably hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, haloCi-C 6 alkyl; more preferably hydrogen, halogen, hydroxy, Ci-Cealkyl, Cs-Cecycloalkyl, or haloCi- C 6 alkyl; more preferably hydrogen, halogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, or haloCi-C 6 alkyl;
  • R 3 is hydrogen
  • R 4 is phenyl, or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ; preferably phenyl, or 5- to 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ; more preferably phenyl, or 5- to 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from N, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 -C 6 cycloalkyl, -CH 2 CO 2 R 5b , cyano, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R 5a ; preferably hydrogen, -CO 2 R 5b , Ci-Cealkyl, hydroxyCs-Cecycloalkyl, -CH 2 CO 2 R 5b , cyano, - C(O)N(R 5b ) 2 and 5-membered heteroaryl having 1-4 heteroatoms independently selected from N, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R 5a ; more preferably hydrogen, -CO 2 R 5b , Ci-Cealky
  • R 5 is preferably selected from hydrogen, -CO 2 H, Ci-C 6 alkyl, hydroxyC 3 -C 6 cycloalkyl, hydroxyC 3 -C 6 alkyl, cyano, -CONH 2 , pyrazolyl, triazolyl, and tetrazolyl, wherein the pyrazolyl, triazolyl, and tetrazolyl are unsubstituted or substituted with 1 Ci-C 6 alkyl;
  • R 7 is hygrogen, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 - C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkyl, Ci-C 6 alkoxyCi- C 6 alkyl, haloCi-C 6 alkoxyCi-C 6 alkyl, -COR 7a , aryl, 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O) q , or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein Ci-C 6 alkyl is unsubstituted or substituted with 4- to 6-membered heterocyclyl having 1-2
  • R 7a is Ci-C 6 alkyl; each R 8 is independently selected from hydrogen and halogen;
  • R 9 is H, or D; preferably H; m is 1 , 2, or 3; preferably 1 or 2; n is 1 , 2, or 3; and p is 0, 1 , 2, or 3; preferably 0.
  • Embodiment 78 provides the compound of Formula (I) of any of applicable embodiments 1 to 77, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, wherein:
  • W is C(R 6 ) 2 ;
  • R is hydrogen;
  • R 1 is hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, haloCi-C 6 alkyl, haloC 3 - C 6 cycloalkyl, haloCi-C 6 alkoxy, hydroxyCi-C 6 alkyl, hydroxyC 3 -C 6 cycloalkyl; preferably hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, haloCi-C 6 alkyl; more preferably hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, and haloCr C 6 alkyl; more preferably hydrogen, halogen, Ci-C 6 alkyl, C 3 -C 6 cycloalkyl;
  • R 2 is Ci-C 3 alkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-C 6 alkyl, or halogen, wherein the Ci-C 3 alkyl, C 3 cycloalkyl, or Ci-C 3 alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents; preferably Ci-C 3 alkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-Cealkyl, or halogen; more preferably Ci-C 3 alkyl, or halogen;
  • R 3 is hydrogen
  • R 4 is phenyl, or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ; preferably phenyl, or 5- to 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from N, and O, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ; more preferably phenyl, or 5- to 6-membered heteroaryl having 1 or 2 ring heteroatoms independently selected from N, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 -C 6 cycloalkyl, -CH 2 CO 2 R 5b , cyano, -C(O)N(R 5b ) 2 and 5- to 6-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R 5a ; preferably hydrogen, -CO 2 R 5b , Ci-C 6 alkyl, hydroxyC 3 -C 6 cycloalkyl, -CH 2 CO 2 R 5b , cyano, - C(O)N(R 5b ) 2 and 5-membered heteroaryl having 1-4 heteroatoms independently selected from N, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 R 5a ; more preferably hydrogen, -CO 2 R 5b , Ci-C 6
  • R 5 is preferably selected from hydrogen, -CO 2 H, Ci-Cealkyl, hydroxyCs-Cecycloalkyl, hydroxyC 3 -C 6 alkyl, cyano, -CONH 2 , pyrazolyl, triazolyl, and tetrazolyl, wherein the pyrazolyl, triazolyl, and tetrazolyl are unsubstituted or substituted with 1 Ci-C 6 alkyl; each R 6 is independently selected from hydrogen, halogen, hydroxy, C 3 -C 6 cycloalkylCi- C 4 alkylamino, haloC 3 -C 6 cycloalkylCi-C4alkylamino, Ci-C 6 alkyl, haloCi-C 6 alkyl, Ci-C 6 alkoxy, haloCi-C 6 alkoxy, C 3 -C 6 cycloalkoxy, haloC 3 -C 6 cycloalkoxy
  • R 9 is H, or D; preferably H; m is 1 , 2, or 3; preferably 1 or 2; n is 1 , 2, or 3; and p is 0, 1 , 2, or 3; preferably 0.
  • the invention provides the compound of Formula (I) selected from the compounds in Table 1.
  • the invention provides the compound of Formula (I) selected from the compounds in Table 2.
  • the compound of Formula (I) is selected from the group consisting of: 4-(4-((5,7-dimethyl-1/7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid;
  • the compound of Formula (I) is selected from the group consisting of: 4-(2-((5,7-dimethyl-1 /7-indol-4-yl)oxy)-5-methoxycyclohexyl)benzoic acid;
  • the compound of Formula (I) is selected from the group consisting of
  • the compound of Formula (I) is selected from the group consisting of:
  • the invention provides a tautomer, a diastereomer, or an enantiomer of the compound of Formula (I) of any of the embodiments herein described.
  • W is O, C(R 6 ) 2 , or NR 7 ;
  • R is hydrogen, halogen, Ci-C 4 alkyl, haloCi-C 4 alkyl, or hydroxyCi-C 4 alkyl;
  • R 1 is hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy, haloCi-C 6 alkyl, haloC 3 -C 6 cycloalkyl, haloCi-C 6 alkoxy, hydroxyCi-C 6 alkyl, hydroxyC 3 - C 6 cycloalkyl, aminoCi-C 6 alkyl, Ci-C 6 alkoxyCi-C 6 alkyl, Ci-C 6 alkoxyCi-C 6 alkoxy, or C 3 - C 6 cycloalkylCi-C 6 alkoxy;
  • R 2 is Ci-C 3 alkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-C 6 alkyl, or halogen, wherein the Ci-C 3 alkyl, C 3 cycloalkyl, or Ci-C 3 alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;
  • R 3 is hydrogen, halogen, or cyano
  • R 4 is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 7 is hydrogen, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 - C6cycloalkylC1-C3alkyl, haloC3-C6cycloalkyl, C1-C6alkoxyC1-C6alkyl, haloC1-C6alkoxyC1-C6alkyl, - COR 7a , aryl, 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N, O, and S(O) q , or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein Ci-Cealkyl is unsubstituted or substituted with 4- to 6-membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S(O) q , wherein the 4- to 6-membered hetero
  • R 9 is H, D, or T; m is 0, 1 , 2, or 3; n is 0, 1 , 2, or 3; provided that both m and n are not 0; and p is 0, 1 , 2, or 3.
  • W is C(R 6 ) 2 or NR 7 ;
  • R is hydrogen
  • R 1 is halogen, hydroxy, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy, haloCr C 6 alkyl, hydroxyCi-C 6 alkyl, or aminoCi-C 6 alkyl;
  • R 2 is Ci-C 3 alkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-Cealkyl, or halogen;
  • R 3 is hydrogen, halogen, or cyano
  • R 4 is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from -CO 2 R 5b , Ci-C 6 alkyl, Ci-C 6 alkoxyCi-C 6 alkyl, - cyano, hydroxy, halogen, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R 5a ; each R 5a is independently selected from fluoro, hydroxyl, and Ci-C 6 alkyl that is unsubstituted or substituted with -CO 2 H;
  • R 5b is selected from hydrogen and Ci-C 5 alkyl; each R 6 is independently selected from hydrogen, halogen, hydroxy, Ci-Cealkyl, haloCi- C 6 alkyl, hydroxyCi-C 6 alkyl, Ci-C 6 alkoxy, and haloCi-C 6 alkoxy; or two R 6 in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C 6 alkyl, and Ci-C 6 alkoxy; or two R 6 in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;
  • R 7 is hydrogen, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, -COR 7a , or C 3 -C 6 cycloalkyl;
  • R 7a is Ci-C 6 alkyl; each R 8 is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C 4 alkylamino, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyCi-C 6 alkyl, cyanoCi-C 6 alkyl, Cr C 6 alkoxy, and haloCi-C 6 alkoxy;
  • R 9 is H, D, or T; m is 1 , 2, or 3; n is 1 , 2, or 3; and p is 0, 1 , or 2.
  • W is C(R 6 ) 2 or NR 7 ;
  • R is hydrogen
  • R 1 is halogen, Ci-C 6 alkyl, or C 3 -C 6 cycloalkyl
  • R 2 is Ci-C 3 alkyl
  • R 3 is hydrogen
  • R 4 is phenyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from -CO 2 R 5b , Ci-Cealkyl, cyano, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with R 5a ;
  • R 5a is hydroxy or Ci-C 6 alkyl
  • R 5b is hydrogen or Ci-C 3 alkyl
  • each R 6 is independently selected at each occurrence from hydrogen and Ci-C 6 alkoxy
  • two R 6 in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;
  • R 7 is C1-C 6 alkyl -COR 7a , or haloCi-C 6 alkyl;
  • R 7a is C1-C 6 alkyl; each R 8 is independently selected from hydrogen and Ci-C 6 alkyl;
  • R 9 is H; m is 1 or 2; n is 1 , 2, or 3; and p is 0, 1 , or 2.
  • W is O, C(R 6 ) 2 , or NR 7 ;
  • R is hydrogen, halogen, Ci-C 4 alkyl, haloCi-C 4 alkyl, or hydroxyCi-C 4 alkyl;
  • R 1 is hydrogen, halogen, hydroxy, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, Ci-C 6 alkoxy, haloCi-Cealkyl, haloC3-C6cycloalkyl, haloCi-Cealkoxy, hydroxyCi-Cealkyl, hydroxyC 3 - C 6 cycloalkyl, aminoC1-C 6 alkyl, C1-C 6 alkoxyCi-C 6 alkyl, Ci-C 6 alkoxyCi-C 6 alkoxy, or C 3 - C 6 cycloalkylCi-C 6 alkoxy;
  • R 2 is Ci-C 3 alkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-C 6 alkyl, or halogen, wherein the Ci-C 3 alkyl, C 3 cycloalkyl, or Ci-C 3 alkoxy are unsubstituted or substituted with 1 , 2, or 3 halogen substituents;
  • R 3 is hydrogen, halogen, or cyano
  • R 4 is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 7 is hydrogen, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 - C 6 cycloalkylCi-C 3 alkyl, haloC 3 -C 6 cycloalkyl, Ci-C 6 alkoxyCi-C 6 alkyl, haloCi-C 6 alkoxyCi-C 6 alkyl, aryl, 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N, O, and S(O) q , or 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein Ci-C 6 alkyl is unsubstituted or substituted with 4- to 6-membered heterocyclyl having 1 -2 heteroatoms independently selected from N, O, and S(O) q , wherein the 4- to 6- membered heterocyclyl is un
  • W is C(R 6 ) 2 or NR 7 ;
  • R is hydrogen
  • R 1 is halogen, hydroxy, Ci-Cealkyl, C 2 -Cealkenyl, Cs-Cecycloalkyl, Ci-Cealkoxy, haloCi- C 6 alkyl, hydroxyCi-C 6 alkyl, or aminoCi-C 6 alkyl;
  • R 2 is Ci-C 3 alkyl, C 3 cycloalkyl, Ci-C 3 alkoxy, hydroxyCi-C 6 alkyl, or halogen;
  • R 3 is hydrogen, halogen, or cyano
  • R 4 is phenyl, naphthyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from -CO 2 R 5b , Ci-Cealkyl, Ci-CealkoxyCi-Cealkyl, - cyano, hydroxy, halogen, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with 1 , 2, or 3 R 5a ; each R 5a is independently selected from fluoro, hydroxyl, and Ci-Cealkyl that is unsubstituted or substituted with -CO 2 H;
  • R 5b is selected from hydrogen and Ci-C 5 alkyl; each R 6 is independently selected from hydrogen, halogen, hydroxy, Ci-C 6 alkyl, haloCr C 6 alkyl, hydroxyCi-C 6 alkyl, Ci-C 6 alkoxy, and haloCi-C 6 alkoxy; or two R 6 in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms, wherein the spirocyclic carbocycle is unsubstituted or substituted with 1 or 2 substituents selected from halogen, Ci-C 6 alkyl, and Ci-C 6 alkoxy; or two R 6 in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;
  • R 7 is hydrogen, Ci-C 6 alkyl, haloCi-C 6 alkyl, hydroxyC 2 -C 6 alkyl, or C 3 -C 6 cycloalkyl; each R 8 is independently selected from hydrogen, halogen, hydroxy, amino, mono- and di- Ci-C4alkylamino, Ci-Cealkyl, haloCi-Cealkyl, hydroxyCi-Cealkyl, cyanoCi-Cealkyl, Ci- C 6 alkoxy, and haloCi-C 6 alkoxy;
  • R 9 is H; m is 1 , 2, or 3; n is 1 , 2, or 3; and p is 0, 1 , or 2.
  • W is C(R 6 ) 2 or NR 7 ;
  • R 1 is halogen, Ci-C 6 alkyl, or C 3 -C 6 cycloalkyl
  • R 2 is Ci-C 3 alkyl
  • R 3 is hydrogen
  • R 4 is phenyl or 5- to 10-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 ;
  • R 5 is selected from -CO 2 R 5b , C1-C6alkyl, cyano, and 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S, wherein alkyl and heteroaryl are unsubstituted or substituted with R 5a ;
  • R 5a is hydroxy or Ci-C 6 alkyl
  • R 5b is hydrogen or Ci-C 3 alkyl; each R 6 is independently selected at each occurrence from hydrogen and Ci-C 6 alkoxy; or two R 6 in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O;
  • R 9 is H; m is 1 or 2; n is 1 , 2, or 3; and p is 0, 1 , or 2.
  • W is NR 7 .
  • W is C(R 6 ) 2 .
  • R is hydrogen
  • R 1 is halogen, Ci-C 3 alkyl, or C 3 cycloalkyl. In still another embodiment, R 1 is halogen. In another embodiment, R 1 is Ci-C 3 alkyl. In another embodiment, R 1 is C 3 cycloalkyl.
  • R 2 is methyl
  • R 3 is hydrogen
  • R 4 is phenyl or 5-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 .
  • R 4 is phenyl, wherein phenyl or heteroaryl is unsubstituted or substituted with R 5 .
  • R 4 is 5-membered heteroaryl having 1 , 2 or 3 ring heteroatoms independently selected from N, O, and S, wherein heteroaryl is unsubstituted or substituted with R 5 .
  • R 4 is phenyl or pyrazolyl, wherein phenyl or pyrazolyl is unsubstituted or substituted with R 5 .
  • R 5 is selected from -CO 2 H, Ci-C 6 alkyl, cyano, and 5-membered heteroaryl having 1 -4 heteroatoms independently selected from N, O, and S, wherein alkyl is unsubstituted or substituted with hydroxy.
  • R 5 is -CO 2 H.
  • R 5 is cyano.
  • R 5 is 5-membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S.
  • R 5 is Ci-C 6 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy.
  • each R 6 is independently selected from of hydrogen and Cr C 3 alkoxy. In yet another embodiment, each R 6 is hydrogen. In still another embodiment, each R 6 is independently selected from Ci-C 3 alkoxy.
  • two R 6 in combination with the carbon atom to which they are attached form a spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O.
  • two R 6 in combination with the carbon atom to which they are attached form a 4-6 membered spirocyclic heterocycle having 1 or 2 ring heteroatoms independently selected from N and O.
  • two R 6 in combination with the carbon atom to which they are attached form a spirocyclic carbocycle having 3 to 6 ring atoms.
  • R 7 is methyl, -COR 7a , or haloCi-C 3 alkyl. In an embodiment, R 7 is methyl or haloCi-C 3 alkyl. In another embodiment, R 7 is methyl. In yet another embodiment, R 7 is haloCi-C 3 alkyl. In still another embodiment, R 7 is -C(O)Ci-C 3 alkyl.
  • each R 8 is independently selected from hydrogen and Ci-C 6 alkyl. In another embodiment, each R 8 is hydrogen.
  • R 9 is H.
  • composition comprising a therapeutically effective amount of a compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • provided herein is a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • provided herein is a method of modulating the complement alternative pathway activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • provided herein is a method of treating a disease or disorder mediated by complement activation, in particular mediated by activation of the complement alternative pathway, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • provided herein is a method of treating a disease or disorder that is affected by the modulation of complement alternative pathway comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • provided herein is a method of treating a disease or disorder associated with dysregulation of the complement alternative pathway comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • provided herein is a method of inhibiting the expression or activity of complement factor B, the method comprising administering to the subject a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • the diseases or disorders is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy/Malattia leventinese, Sorsby fundus dystrophy, Late onset retinal macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammation, neurological disorders such as multiple sclerosis including primary progressive multiple sclerosis (PPMS), secondary progressive multiple progressive multiple sclerosis (
  • provided herein is a method of treating age-related macular degeneration comprising administering to a subject in need thereof an effective amount of a composition comprising a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • provided herein is a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.
  • provided herein is a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use in inhibiting the expression or activity of complement factor B, in a subject in need thereof.
  • provided herein is a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use in treating a disease or disorder associated with dysregulation of the complement alternative pathway.
  • provided herein is the use of a compound a provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, in the manufacture of a medicament for the treatment of a disease or disorder mediated by complement activation or activation of the complement alternative pathway.
  • a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof in the manufacture of a medicament for the treatment of a disease or disorder.
  • provided herein is the use of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for the treatment of a disease or disorder mediated by complement activation or activation of the complement alternative pathway.
  • provided herein is the use of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for the treatment of a disease or disorder that is affected by the modulation of complement alternative pathway.
  • provided herein is the use of a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for the treatment of a disease or disorder.
  • provided herein is the use of a provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for the treatment of age-related macular degeneration.
  • a pharmaceutical combination comprising a compound provided herein, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, and one or more additional therapeutic agent(s).
  • the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereomeric mixtures, depending on the number of asymmetric centres.
  • the disclosure is meant to include all such possible isomers, including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures and optically pure forms.
  • Optically active (/?)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a disubstituted or trisubstituted cycloalkyl, the cycloalkyl substituent(s) may have a c/s- or frans-configuration.
  • the disclosure includes cis and trans configurations of substituted cycloalkyl groups, e.g., cyclobutyl group, as well as mixtures thereof. All tautomeric forms are also intended to be included.
  • heteroaryl ring containing N as a ring atom is 2- pyridone
  • tautomers where the carbonyl is depicted as a hydroxy are included.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure 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 CI, 123 l, 124 I, 125
  • the disclosure includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H and 14 C, orthose into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 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 in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-labeled compounds of formula (I), orsub-formulae thereof can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and General Schemes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. Further, substitution with heavier isotopes, particularly deuterium (/.e., 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I), or any of the sub-formulae thereof.
  • the concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this disclosure is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D 2 O, cfe-acetone, cfe- DMSO.
  • co-crystals may be capable of forming co-crystals with suitable co-crystal formers.
  • co-crystals may be prepared from compounds of formula (I), or sub-formulae thereof, by known co-crystal forming procedures. Such procedures include grinding, heating, cosubliming, co-melting, or contacting in solution compounds provided herein, with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • Suitable cocrystal formers include those described in WO 2004/078163.
  • any asymmetric center (e.g., carbon or the like) of the compound(s) of the disclosure can be present in racemic or enantiomerically enriched, for example the (/?)-, (S)- or (R,S)- configuration.
  • each asymmetric center is present in at least 10% enantiomeric excess, at least 20% enantiomeric excess, at least 30% enantiomeric excess, at least 40% enantiomeric excess, at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • each asymmetric center is present in at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • compounds of the disclosure can be present in a racemic mixture or in enantiomerically enriched form or in an enantiopure form or as a mixture of diastereoisomers.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof present in at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof present in at least 90% diastereomeric excess, at least 95% diastereomeric excess, or at least 99% diastereomeric excess.
  • the term “ on a C-sp 3 indicates the absolute stereochemistry, either (/?) or (S).
  • the term “ on a C-sp 3 indicates the absolute stereochemistry, either (/?) or (S).
  • the term “ on a C-sp 3 represents a covalent bond wherein the stereochemistry of the bond is not defined. This means that the term “ on a C-sp 3 comprises an (S) configuration or an (/?) configuration of the respective chiral centre.
  • mixtures may also be present. Therefore, mixtures of stereoisomers, e.g., mixtures of enantiomers, such as racemates, and/or mixtures of diastereoisomers are encompassed by the present disclosure.
  • a compound of the disclosure can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers, racemates or mixtures thereof.
  • Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • Any resulting racemates of compounds of the disclosure or of intermediates can be resolved into the optical isomers (enantiomers) by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the disclosure into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor- 10-sulfonic acid.
  • Racemic compounds of the disclosure or racemic intermediates can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • the compounds of the disclosure can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds of the disclosure may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the disclosure embrace both solvated and unsolvated forms.
  • solvate refers to a molecular complex of a compound of the disclosure (including pharmaceutically acceptable salts thereof) with one or more solvent molecules.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • the presence of solvates can be identified by a person of skill in the art with tools such as NMR.
  • the compounds of the disclosure including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of described herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the composition comprises at least one or two pharmaceutically acceptable carriers, such as those described herein.
  • solvates and hydrates are generally considered compositions.
  • compositions comprising a compounds of Formula (I), or subformulae thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, topical administration, parenteral administration, and rectal administration, etc.
  • the pharmaceutical compositions of the disclosure can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, gels, suspensions or emulsions).
  • the pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
  • the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with one or more of: a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose, mann
  • the pharmaceutical compositions are capsules comprising the active ingredient only.
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions provided herein can be formulated for ophthalmic, ocular, topical, and transdermal administration.
  • the pharmaceutical compositions provided herein are suitable for ocular administration.
  • the active ingredient may be mixed with one or more pharmaceutically acceptable carriers) according to conventional pharmaceutical compounding techniques.
  • the carrier(s) may take a wide variety of forms depending on the form of preparation desired for administration.
  • compositions for oral administration include an effective amount of a compound of the disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs, solutions or solid dispersion.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.
  • compositions for transdermal application include an effective amount of a compound of the disclosure with a suitable carrier.
  • Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like.
  • topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
  • Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
  • the pharmaceutical compositions provided herein are formulated as solutions, suspensions, gels, creams, ointments, liposomes, ocular inserts or other pharmaceutical compositions suitable, in particular embodiments, for topical administration to the ocular surface, the cornea, the eyelid, margins of the eye, eyelashes and/or eye lid margin in order to deliver the composition to the eye.
  • liquid (aqueous or non- aqeuous) solutions may be used.
  • the pharmaceutical compositions are formulated as eye drops for topical administration to the ocular surface, the cornea, the eyelid, eye lid margins, eyelashes and/or margins of the eye in order to deliver the composition to the eye.
  • compositions may be performed with an applicator, such as the subject’s finger, a Weck-Cel®, Q-tip®, or other device capable of delivering a formulation to the eyelid, eyelashes and/or eyelid margin in order to deliver the formulation to the eye.
  • an applicator such as the subject’s finger, a Weck-Cel®, Q-tip®, or other device capable of delivering a formulation to the eyelid, eyelashes and/or eyelid margin in order to deliver the formulation to the eye.
  • the pharmaceutical compositions provided herein may be viscous or semi-viscous; liquid, solid, or semi-solid; aqueous or non-aqueous, depending on the site of application, dose, solubility of drug, and a variety of other factors that are considered by those of skill in the art.
  • the pharmaceutically acceptable carrier is a non-aqueous carrier (e.g., oil, or oil mixture) having a viscosity in a range from about 50 cps to about 1000 cps, about 50 cps to about 500 cps, about 50 cps to about 200 cps, or about 60 cps to about 120 cps.
  • the non-aqueous carrier comprises an oil, e.g., vegetable oils, silicone oils, mineral oil or any combination thereof.
  • the carrier may be liquid paraffin, white petrolatum, purified lanolin, gelation hydrocarbon, polyethylene glycol, hydrophilic ointment base, white ointment base, absorptive ointment base, Macrogol ointment base, simple ointment base, and the like.
  • the pharmaceutical composition may include a monomeric polyol such as, glycerol, propylene glycol, and ethylene glycol, polymeric polyols such as polyethylene glycol, cellulose esters such hydroxypropylmethyl cellulose, carboxy methylcellulose sodium and hydroxy propylcellulose; dextrans such as dextran 70; water soluble proteins such as gelatin, polymers such as polyvinyl alcohol, polyvinylpyrrolidone, and povidone; carbomers, such as carbomer 934P. carbomer 941 , carbomer 940 and carbomer 974P; and gums such as HP- guar.
  • a monomeric polyol such as, glycerol, propylene glycol, and ethylene glycol
  • polymeric polyols such as polyethylene glycol, cellulose esters such hydroxypropylmethyl cellulose, carboxy methylcellulose sodium and hydroxy propylcellulose
  • dextrans such as dextran 70
  • water soluble proteins such as gelatin
  • Additional excipients may optionally be included in the pharmaceutical compositions provided herein.
  • additional excipients include, for example, tonicity enhancers, preservatives, solubilizers, non-toxic excipients, demulcents, sequestering agents, pH adjusting agents, co-solvents, viscosity building agents, and combinations thereof.
  • the pharmaceutical composition of the disclosure may be in the form of an aqueous suspension or an aqueous solution. In one embodiment, the aqueous pharmaceutical composition of the disclosure is in the form of an aqueous suspension.
  • Aqueous pharmaceutical compositions according to the disclosure can be prepared using standard procedures that are familiar to the person skilled in the art, e.g., by admixture of the various components, suitably at ambient temperature and atmospheric pressure.
  • the aqueous pharmaceutical compositions of the disclosure are suitable for ocular administration.
  • the pharmaceutical composition of the disclosure is in the form of eye ointment, eye gel, eye cream, or eye drops.
  • the pharmaceutical composition of the disclsoure is administered to the subject topically in the eyes.
  • pharmacological properties e.g., complement factor B modulating properties e.g., as indicated in the in vitro tests as provided in the examples, and are therefore indicated for therapy or for use as research chemicals, e.g., as tool compounds.
  • Additional properties of the disclosed compounds include having good potency in the biological assays described herein, favorable safety profile, and possess favorable pharmacokinetic properties.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use in therapy.
  • the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use in the treatment of a disease or disorder for which complement factor B is indicated.
  • the disease or disorder is affected by the inhibition of complement factor B activity.
  • Compounds of formula (I) and their pharmaceutically acceptable salts or stereoisomers or diastereomers have complement factor B modulating and/or inhibitory activity and are believed to be of potential use for the treatment or prophylaxis of certain diseases or disorders.
  • the diseases or disorders is selected from age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet’s uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino- chorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, ocular pemphigus, nonartertic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, glaucoma, Doyne honeycomb retinal dystrophy/Malattia leventinese, Sorsby fundus dystrophy, Late onset retinal macular dystrophy, North Carolina macular dystrophy, Stargardt disease, corneal inflammation, neurological disorders such as multiple sclerosis including primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SP
  • compounds of formula (I) and sub-formulae thereof, in free or pharmaceutically acceptable salt form are useful in the treatment of conditions which may be treated by inhibition of complement factor B activity.
  • the disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a diastereomer thereof.
  • the disclosure provides a method of modulating the complement alternative pathway activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a diastereomer thereof.
  • the disclosure provides a method of treating a disease or disorder mediated by complement activation, in particular mediated by activation of the complement alternative pathway, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isoto pica lly labeled compound thereof.
  • the disclosure provides a method of treating a disease or disorder that is affected by the modulation of complement alternative pathway comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isoto pica lly labeled compound thereof.
  • the disclosure provides a method of treating a disease or disorder associated with dysregulation of the complement alternative pathway comprising administering to the subject a therapeutically effective amount of a compound of formula (I) orsub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • the disclosure provides a method of inhibiting the expression or activity of complement factor B, the method comprising administering to the subject a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof.
  • the disclosure provides a method of treating disease or disorder.
  • methods are provided for the treatment of diseases associated with increased activity of the C3 amplification loop of the complement pathway.
  • methods of treating or preventing compelment mediated diseases are provided in which the complement activation is induced by antibody-antigen interactions, by a component of an autoimmune disease, or by ischemic damage.
  • the present disclosure provides a method of treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of the compound of Formula (I) of the disclosure.
  • AMD age-related macular degeneration
  • patients who are currently asymptomatic but are at risk of developing a symptomatic macular degeneration related disorder are suitable for administration with a compound of the disclosure.
  • the methods of treating or preventing AMD include, but are not limited to, methods of treating or preventing one or more symptoms or aspects of AMD selected from formation of ocular drusen, inflammation of the eye or eye tissue, loss of photoreceptor cells, loss of vision (including loss of visual acuity or visual field), neovascularization (including CNV), retinal detachment, photoreceptor degeneration, RPE degeneration, retinal degeneration, chorioretinal degeneration, cone degeneration, retinal dysfunction, retinal damage in response to light exposure, damage of the Bruch’s membrane, and/ or loss of RPE function.
  • the compound of Formula (I) ofthe disclosure can be used, inter alia, to prevent the onset of AMD, to prevent the progression of early AMD to advanced forms of AMD including neovascular AMD or geographic atrophy, to slow and/or prevent progression of geographic atrophy, to treat or prevent macular edema from AMD or other conditions (such as diabetic retinopathy, uveitis, or post surgical or non-surgical trauma), to prevent or reduce the loss of vision from AMD, and to improve vision lost due to pre-existing early or advanced AMD. It can also be used in combination with anti-VEGF therapies for the treatment of neovascular AMD patients or for the prevention of neovascular AMD.
  • All the aforementioned embodiments relating to the methods of treatment of the aforementioned diseases are equally applicable to: a compound of formula (I) or sub-formula thereof or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for use in the teatment of the aforementioned diseases according to the present disclosure; use of a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, in the manufacture of a medicament for the teatment ofthe aforementioned diseases according to the present disclosure; use of a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotopically labeled compound thereof, for the treatment of the aforementioned diseases according to the present disclosure; and a pharmaceutical composition comprising a compound of formula (I) or sub-formula thereof, or a pharmaceutically acceptable salt or a stereoisomer or an isotop
  • the compounds of the disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
  • R, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , W, m, n, and p are defined according to enumerated Embodiment 1 .
  • 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 enumerated Embodiments 1 to 23.
  • PG refers to protecting groups. Suitable protecting groups are known to one skilled in the art and the same or different protecting groups may be used in any Scheme. Additional definitions are provided as applicable in the General Schemes below.
  • Alcohol intermediates S1-4 can be prepared as outlined in General Scheme 1.
  • Arylation of ketone S1-2 with aryl bromide S1-1 can be performed utilizing Buchwald coupling conditions.
  • Ketone reduction of S1 -3 can be accomplished with a hydride reducing agent such as sodium borohydride or lithium tri-sec-butylborohydride.
  • alcohol intermediates S2-4 can be prepared as outlined in General Scheme 2. Reaction of aryl magnesium bromide S2-1 with epoxide S2-2 provides alcohol S2-3 with trans relative configuration at the vicinal stereocenters. Inversion to c/s-configured S2-4 is achieved through Mitsunobu reaction with a carboxylic acid such as 4-nitro benzoic acid followed by basepromoted hydrolysis.
  • a carboxylic acid such as 4-nitro benzoic acid followed by basepromoted hydrolysis.
  • Piperidinol intemediates S3-5 can be prepared as outlined in General Scheme 3. Boronic acid or ester S3-1 and pyridyl halide S3-2 are coupled to provide biaryl S3-3 using Suzuki crosscoupling conditions. Nitrogen protection with a reagent like CbzCI followed by treatment with a reducing agent such as sodium borohydride provides enone S3-4. Further reduction to the alcohol S3-5 is achieved through metal-catalyzed hydrogenation with a catalyst such as platinum oxide.
  • a catalyst such as platinum oxide.
  • the disclosure provides a process for the preparation of a compound of formula (I), in free form or in pharmaceutically acceptable salt form, comprising the step as described above.
  • Suitable protecting groups include hydroxy, phenol, amino and carboxylic acid.
  • Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., tert- butyldimethylsilyl, te/Y-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, and the like.
  • Suitable protecting groups for amino, amidino and guanidino include f-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.
  • Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein.
  • the use of protecting groups is described in detail in J. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, “Greene's Protective Groups in Organic Synthesis”, Fourth Edition, Wiley, New York 2007; P. J. Kocienski, “Protecting Groups”, Third Edition, Georg Thieme Verlag, Stuttgart and New York 2005; and in Methoden der orgamschen Chemie (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974.
  • the protecting group may also be a polymer resin, such as a Wang resin or a 2-ch Io rotrity I- chloride resin.
  • reaction Examples illustrate methods to make compounds of this disclosure. It is understood that one skilled in the art would be able to make these compounds by similar methods or by methods known to one skilled in the art.
  • starting components and reagents may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, Strem, other commercial vendors, or synthesized according to sources known to those skilled in the art, or prepared as described in this disclosure.
  • Mass spectra were collected using a Waters System (Acquity UPLC and a Micromass ZQ mass spectrometer) or Agilent-1260 Infinity (6120 Quadrupole); all masses reported are the m/z of the protonated parent ions unless recorded otherwise.
  • the sample was dissolved in a suitable solvent such as MeCN, DMSO, or MeOH and was injected directly into the column using an automated sample handler.
  • a suitable solvent such as MeCN, DMSO, or MeOH
  • THF tetrahydrofuran Ts tosyl Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene wt% weight percent
  • the resulting residue was dissolved in THF (1 mL) and MeOH (1 mL), and aq NaOH soln (4M, 1 .4 mL, 5.6 mmol) was added.
  • the RM was stirred at RT for 15 min.
  • the RM was partially concentrated under reduced pressure, and the pH was adjusted to 7 with 6M aq HCI.
  • the mixture was extracted with DCM (3x).
  • the combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • the resulting residue was purified over silica gel (eluent: 0 to 50% EtOAc in heptane) to provide 5,7- dimethyl-1 -tosyl-1 /7-indol-4-ol as a grey solid (296 mg).
  • the RM was partitioned between sat. aq NaHCO 3 soln and DCM.
  • the separated org phase was dried through an Isolute® phase separator and concentrated under reduced pressure.
  • the resulting residue was dissolved in THF (3 mL) and MeOH (3 mL), and aq NaOH soln (4M, 3.46 mL, 13.85 mmol) was added.
  • the RM was stirred at RT for 15 min.
  • the mixture was partially concentrated, and the pH was adjusted to 4 with 6M aq HCI.
  • the mixture was extracted with DCM (3x).
  • the combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • Step 1 4-bromo-5-chloro-7-methyl-1H-indole (Intermediate 1-4-1 )
  • Step 2 tert-butyl 4-bromo-5-chloro-7-methyl-1H-indole-1 -carboxylate (Intermediate I-4-2)
  • Step 3 tert-butyl 5-chloro-7-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H- indole-1 -carboxylate (Intermediate I-4-3) tert-Butyl 4-bromo-5-chloro-7-methyl-1 /7-indole-1 -carboxylate (Intermediate I-4-2, 300 mg, 0.87 mmol), bis(pinacolato)diboron (332 mg, 1.3 mmol), KOAc (256 mg, 2.6 mmol), and PdCI 2 (dppf) (71 mg, 0.09 mmol) were combined in a vial.
  • the vial was purged and filled with N 2 .
  • Dioxane (5 mL) was added, and the RM was stirred at 90 °C for 16 h.
  • the RM was filtered through Celite®, and the solids were washed with DCM.
  • Step 4 tert-butyl 5-chloro-4-hydroxy-7-methyl-1H-indole-1 -carboxylate
  • the RM was allowed to cool to RT, and H 2 O 2 (30 wt% in H 2 O, 0.72 mL, 7.0 mmol) was added slowly. The RM was stirred at RT for 18 h. The RM was diluted with EtOAc and H 2 O and filtered through a pad of Celite®. The phases were separated, and the aq phase was extracted with EtOAc (2x). The combined org phases were washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure.
  • the RM was filtered through Celite®, and the solids were washed with EtOAc. The combined filtrates were concentrated under reduced pressure. The resulting residue was dissolved in THF (20 mL) and H 2 O (10 mL). Sodium perborate 1 -hydrate (3.48 g, 34.8 mmol) was added, and the RM was stirred at RT overnight. The RM was diluted with EtOAc, and the separated aq phase was extracted with EtOAc. The combined org phases were dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Step 1 4-methoxy-3-(1-methyl-1H-pyrazol-4-yl)pyridine (Intermediate K-4-1)
  • the RM was filtered through Celite®, and the solids were washed with THF (100 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with H 2 O and extracted with EtOAc (2x 100 mL). The combined org layers were washed with brine (50 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified over silica gel (40 g; eluent: O to 100% EtOAc in hexane) to provide 4-methoxy-3-(1-methyl-1 /7-pyrazol- 4-yl)pyridine as a yellow semi-solid (1 1 g).
  • the RM was allowed to cool to RT, filtered to remove solids, and the filtrate was partitioned between EtOAc and H 2 O. The separated aq layer was extracted with EtOAc (3x). The combined org phases were dried over MgSO 4 , filtered, and concentrated under reduced pressure.
  • Methyl 4-bromobenzoate (433 mg, 2.01 mmol), Cs 2 CO 3 (1.51 g, 4.63 mmol), Pd 2 dba 3 (22 mg, 24 pmol), and SPhos (CAS# 657408-07-6 , 41 mg, 0.099 mmol) were combined in a vial.
  • the vial was purged with N 2 , then toluene (2.5 mL) and 1-oxaspiro[4.5]decan-8-one (379 mg, 2.46 mmol) were added.
  • the RM was purged with N 2 and then stirred at 95 °C for 24 h. The RM was allowed to cool to RT and filtered to remove solids.
  • Methyl 4-bromobenzoate 400 mg, 1 .86 mmol
  • 4,4-difluorocyclohexan-1 -one (349 mg, 2.6 mmol)
  • K3PO4 908 mg, 4.28 mmol
  • Xantphos 47.4 mg, 81 pmol
  • Pd 2 dba 3 34.1 mg, 37.1 pmol
  • toluene 5 mL
  • Methyl 4-bromobenzoate (2.0 g, 9.3 mmol), 1 ,4-dioxaspiro[4.5]decan-8-one (2.03 g, 13.0 mmol), K 3 PO 4 (4.5 g, 21 .4 mmol), Xantphos (236.8 mg, 0.41 mmol), Pd 2 dba 3 (170.3 mg, 0.19 mol), and toluene (24 mL) were split between two vials. The mixtures were purged with N 2 and stirred at 90 °C for 18 h. The mixtures were allowed to cool to RT, combined, and diluted with DCM and H 2 O. The separated org phase was concentrated under reduced pressure.
  • Step 1 a tert-Butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxopiperidine-1 -carboxylate (Intermediate K-1 , 4.19 g, 12.6 mmol) was dissolved in THF (45 mL) and cooled to 0 °C. Potassium tri-sec- butylborohydride soln (1 M in THF, 20 mL, 20 mmol) was added in a dropwise manner, and the RM was stirred at 0 °C for 1 h. Additional potassium tri-sec-butylborohydride soln (1 M in THF, 5 mL, 5 mmol) was added in a dropwise manner.
  • the RM was stirred at 0 °C for 30 min. The RM was allowed to warm to RT and then stirred for an additional 20 min. The RM was cooled to 0 °C and quenched with sat. aq NH 4 CI soln. The mixture was extracted with DCM (3x), and the combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • Step 1 b Chiral separation and analytics according to Method SFC-1 : 2.3 g provided Intermediate A-3 (peak 1): 1 .22 g, white solid.
  • Analytical chiral HPLC: Rt 1.67 min; 100% ee.
  • Step 1 a To a soln of methyl 4-bromobenzoate (8.0 g, 37.2 mmol) in toluene (80 mL) was added tert-butyl 4-oxoazepane-1 -carboxylate (9.52 g, 44.6 mmol), followed by K 3 PO 4 (15.7 g, 74.4 mmol). The RM was degassed with argon for 15 min at RT, and then Xantphos (1.07 g, 1.86 mmol) and Pd 2 (dba) 3 (681.2 mg, 0.74 mmol) were added. The RM was stirred at 100 °C for 12 h.
  • the RM was allowed to cool to RT, filtered through Celite®, and the solids were washed with THF (200 mL). The combined filtrates were concentrated under reduced pressure, and the resulting residue was diluted with H 2 O and extracted with EtOAc (2x 100 mL). The combined org layers were washed with brine (50 mL), dried over Na 2 SO 4] and concentrated under reduced pressure.
  • Step 1 a To a stirred soln of fert-butyl 4-(4-(methoxycarbonyl)phenyl)-5-oxoazepane-1- carboxylate) and fert-butyl 3-(4-(methoxycarbonyl)phenyl)-4-oxoazepane-1 -carboxylate (4.0 g, 11 .5 mmol) in THF (80 mL) was added lithium tri-sec-butylborohydride soln (1 M in THF, 13.8 mL,
  • Step 1 c Chiral separation according to Method SFC-2: 2.7 g provided a mixture of fert-butyl (4S,5S)-4-hydroxy-5-(4-(methoxycarbonyl)phenyl)azepane-1-carboxylate and racemic fert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)azepane-1-carboxylate (peak 1 , 1.6 g).
  • Step 1 racemic tert-butyl (3S*,4R*)-3-hydroxy-4-phenylpyrrolidine-1 -carboxylate (Intermediate rac-A-6-1 ) Boc tert-Butyl 6-oxa-3-azabicyclo[3.1 ,0]hexane-3-carboxylate (881 mg, 4.76 mmol) and copper(l) iodide (90 mg, 0.47 mmol) were combined in a dry flask, and THF (9 mL) was added. The mixture was cooled to 0 °C, and a phenylmagnesium chloride soln (2M in THF, 5.0 mL, 10 mmol) was added in a dropwise manner.
  • a phenylmagnesium chloride soln (2M in THF, 5.0 mL, 10 mmol
  • Step 2 racemic tert-butyl (3R*,4R*)-3-((4-nitrobenzoyl)oxy)-4-phenylpyrrolidine-1- carboxylate (Intermediate rac-A-6-2)
  • Racemic tert-butyl (3S*,4R*)-3-hydroxy-4-phenylpyrrolidine-1 -carboxylate (Intermediate rac- - 6-1 , 530 mg, 2.01 mmol), 4-nitrobenzoic acid (673 mg, 4.03 mmol), and PPh 3 (1 .06 g, 4.03 mmol) were dissolved in toluene (6 mL) and cooled to 0 °C. DIAD (0.78 mL, 4.03 mmol) was added, the RM was stirred at 0 °C for 15 min, and then the RM was allowed to warm to RT. The RM was stirred at RT for 4 h. Sat.
  • Step 3 racemic tert-butyl (3R*,4R*)-3-hydroxy-4-phenylpyrrolidine-1 -carboxylate (Intermediate rac-A-5)
  • Racemic tert-butyl (3/?*, 4R*)-3-((4-nitrobenzoyl)oxy)-4-phenylpyrrolidine-1 -carboxylate (Intermediate rac-A-6-2, 1 .03 g, 2.50 mmol) was dissolved in MeOH (10 mL), and K 2 CO 3 (1.39 g, 10 mmol) was added. The RM was stirred at RT for 90 min, and then concentrated under reduced pressue. The residue was partitioned between DCM and sat. aq NH 4 CI soln. The aq layer was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • Step 1 a Prepared as described for Intermediate A-4 using tert-butyl 3-(4-cyanophenyl)-4- oxopiperidine-1 -carboxylate (Intermediate K-2,1 .0 g, 3.32 mmol) at 0 °C to provide racemic tertbuty (3R*,4S*)-3-(4-cyanophenyl)-4-hydroxypiperidine-1 -carboxylate as an off-white solid (300 mg).
  • Step 1 b Chiral separation and analytics according to Method SFC-4: 1 .5 g from multiple batches of racemic tert-butyl (3/?*, 4S*)-3-(4-cyanophenyl)-4-hydroxypiperidine-1 -carboxylate provided Intermediate A-7: 700 mg, off-white solid.
  • Analytical chiral HPLC: Rt 6.34 min; 96% ee.
  • 1 H NMR (400 MHz, CD 3 OD) 6 [ppm] 7.71 - 7.64, (m, 2H), 7.50 (d, J 8.2 Hz, 2H).
  • Step 1 a To a stirred soln of benzyl 5-(1-methyl-1 /7-pyrazol-4-yl)-4-oxo-3,4-dihydropyridine-1 (2/7)- carboxylate (Intermediate K-4, 4.9 g, 15.7 mmol) in EtOH (50 mL) was added PtO 2 (4.9 g) at room temperature. The RM was stirred at RT for 16 h under H 2 atmosphere (balloon). The RM was filtered through Celite®, and the solids were washed with DCM. The combined filtrates were concentrated under reduced pressure.
  • the crude material was purified by preparatory HPLC (Waters XBridge C18 19 x 250 mm; 5 pm ; eluent: 0 to 60% ACN in H 2 O with 0.02% NH 4 OH) to provide racemic benzyl (3R*,4S*)-4-hydroxy-3-(1-methyl-1 /-/-pyrazol-4-yl)piperidine-1- carboxylate and racemic benzyl (3R*,4R*)-4-hydroxy-3-(1-methyl-1 /-/-pyrazol-4-yl)piperidine-1- carboxylate as a mixture of diastereomers (1 .6 g).
  • Step 1 b Separation and analytics according to Method SFC-5: 1.6 g provided Intermediate A-9 (peak 2): 367 mg.
  • Analytical chiral HPLC: Rt 4.77 min; 98.8% ee.
  • Racemic methyl 4-((1 R*,5R*)-5-methoxy-2-oxocyclohexyl)benzoate (Intermediate rac-K-5, 817 mg, 3.12 mmol) was combined with MeOH (3 mL) and THF (3 mL). The soln was cooled to 0 °C, and NaBH 4 (118 mg, 3.12 mmol) was added. The RM was allowed to warm to RT and stirred for 1 h. The RM was quenched with H 2 O and partially concentrated under reduced pressure. The mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • Intermediate rac-A-12 and Intermediate rac-A-13 were prepared as described for Intermediate rac-A-10 and Intermediate rac-A-11 using racemic methyl 4-((1 S*,5R*)-5-methoxy-2- oxocyclohexyl)benzoate (Intermediate rac-K-6, 217 mg, 0.83 mmol) to provide racemic methyl 4-((1 S*,2S*,5R*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac-A-12, first peak eluting, 45 mg) and racemic methyl 4-((1 S*,2R*,5R*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac-A-13, second peak eluting, 137 mg).
  • Racemic methyl 4-((5S*,7S*)-8-oxo-1 -oxaspiro[4.5]decan-7-yl)benzoate (Intermediate rac-K- 7,128 mg, 0.44 mmol) was combined with MeOH (2 mL) and THF (0.5 mL). NaBH 4 (50 mg, 1.3 mmol) was added, and the RM was stirred at RT for 1 h. The RM was quenched with H2O and partially concentrated under reduced pressure. The mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • the RM was quenched with H 2 O, and the mixture was extracted with DCM (3x).
  • the combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • the residue was purified over silica gel (24 g; eluent: 15 to 50 % EtOAc in heptane) to provide racemic fert-butyl (3R*,4S*)-3-(6-(1 /-/-pyrazol-1-yl)pyridin- 3-yl)-4-hydroxypiperidine-1-carboxylate as a colorless oil (82 mg).
  • Intermediate rac-A-16 was prepared as described for Intermediate rac-A-15 using te/Y-butyl 3- (4-(1 /7-1 ,2,3-triazol-1-yl)phenyl)-4-oxopiperidine-1 -carboxylate (Intemediate K-9, 500 mg, 1.46 mmol) to provide racemic te/Y-butyl (3R*,4S*)-3-(4-(1 /7-1 ,2,3-triazol-1-yl)phenyl)-4- hydroxypiperidine-1 -carboxylate as white solid (72 mg).
  • Methyl 4-(5,5-difluoro-2-oxocyclohexyl)benzoate (Intermediate K-16, 100 mg, 0.37 mmol) was dissolved in MeOH (2.5 mL). The soln was cooled to 0 °C, and NaBH 4 (32.4 mg, 0.86 mmol) was added. The RM was stirred for 1 h. The RM was quenched with sat NH 4 CI soln and EtOAc and allowed to warm to RT. The aq phase was extracted with EtOAc (2x). The combined org phases were washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure.
  • Intermediate rac-A-24 was prepared as described for Intermediate rac-A-23 using racemic methyl 4-((1 S*5S*)-5-((te/Y-butyldimethylsilyl)oxy)-2-oxocyclohexyl)benzoate (Intermediate rac- K-17, 235 mg, 0.64 mmol) and lithium tri-sec-butylborohydride soln (1 M in THF, 0.84 mL, 0.84 mmol) to provide racemic methyl 4-((1 S*,2S*,5S*)-5-((te/Y-butyldimethylsilyl)oxy)-2- hydroxycyclohexyl)benzoate as colorless semi-solid (73 mg).
  • Step 1 a Racemic methyl 4-((1 S*,5R*)-5-methyl-2-oxocyclohexyl)benzoate (Intermediate K-18, 6.5 g, 26.4 mmol) was dissolved in MeOH (65 mL) and cooled to 0 °C. NaBH 4 (2.0 mg, 52.8 mmol) was added, and the RM was stirred for 30 min. The RM was diluted with H 2 O and EtOAc and allowed to warm to RT.
  • the separated org phase was dried over Na 2 SO 4 , concentrated under reduced pressure, and purified over silica gel (80 g; eluent: 0 to 30% EtOAc in heptane) to provide racemic methyl 4-((1 S*,2S*,5R*)-2-hydroxy-5-methylcyclohexyl)benzoate (first peak eluting) as an off-white solid (1 .0 g).
  • Step 1 b Chiral separation and analytics according to Method SFC-18: 2.67 g provided Intermediate A-25 (peak 1): 1.17 g, white solid.
  • Analytical chiral HPLC: Rt 2.87 min; 99.7% ee.
  • Methyl 4-(8-oxo-1 ,4-dioxaspiro[4.5]decan-7-yl)benzoate (Intermediate K-23, 1.50 g, 5.17 mmol) was combined with THF (50 mL). The soln was cooled to -78 °C, and a lithium tri-sec- butylborohydride soln (1 M in THF, 8.7 mL, 8.7 mmol) was added in a dropwise manner. The RM was stirred for 1 h. Additional lithium tri-sec-butylborohydride soln (1 M in THF, 3.1 mL, 3.1 mmol) was added in a dropwise manner, and the RM was stirred for 1 h.
  • the RM was diluted with MeOH. sat. aq NH 4 CI soln, and MeOH, and allowed to warm to RT. The separated aq phase was extracted with EtOAc. The combined org phases were washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure.
  • Column chromatography over silica gel 120 g; eluent: 0 to 30% EtOAc in cyclohexane) provided racemic methyl 4-((7S*,8S*)-8-hydroxy-1 ,4- dioxaspiro[4.5]decan-7-yl)benzoate as a white solid (960 mg).
  • Racemic fert-butyl (3R*,4S*)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate (Intermediate rac-A-1 , 150 mg, 0.45 mmol), PPh 3 (160 mg, 0.61 mmol), and fert-butyl 4-hydroxy- 5, 7-dimethyl-1 /-/-indole-1 -carboxylate (Intermediate 1-1 , 93 mg, 0.36 mmol) were dissolved in THF (1 .25 mL). DIAD (115 pL, 0.59 mmol) was added, and the RM was stirred at RT overnight.
  • DIAD 115 pL, 0.59 mmol
  • the RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 30% EtOAc in heptane) to provide racemic fert-butyl 4-(((3R,4/?)-1-(fert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 /-/-indole-1 -carboxylate as a colorless foam (48 mg).
  • the RM was concentrated under reduced pressure and purified over silica gel (eluent: 0 to 100% EtOAc in heptane) to provide racemic tert-butyl (3/?*,4S*)-4-((5,7-dimethyl-1-tosyl-1 /7-indol-4- yl)oxy)-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate as a light yellow oil (87.3 mg).
  • a DEAD soln (40 wt% in toluene, 0.26 mL, 0.57 mmol) was further diluted with toluene (0.3 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 1 h.
  • the RM was stirred at RT for 18 h.
  • RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 20% EtOAc in heptane) to provide tert-butyl 4-(((3R,4R)-1-(tert-butoxycarbonyl)-3-(4- (methoxycarbonyl)phenyl)azepan-4-yl)oxy)-5,7-dimethyl-1 /-/-indole-1 -carboxylate as a colorless oil (45.7 mg).
  • Racemic tert-butyl (3R*,4R*)-3-hydroxy-4-phenylpyrrolidine-1-carboxylate (Intermediate rac-A- 6, 100 mg, 0.38 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 /-/-indole-1 -carboxylate (Intermediate 1-1 , 89 mg, 0.34 mmol), and PPh 3 (149 mg, 0.57 mmol) were dissolved in toluene (0.4 mL) and the soln was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.26 mL, 0.57 mmol) was added in a dropwise manner over approximately 20 min.
  • the RM was stirred at 0 °C for 30 min, and then it was allowed to gradually warm to RT. The RM was stirred at RT for 3 days.
  • Column chromatography over silica gel (12 g; eluent: 0 to 15% EtOAc in heptane) provided encriched racemic tert-butyl 4-(((3S*,4R ⁇ -1-(tert-butoxycarbonyl)-4-phenylpyrrolidin-3-yl)oxy)-5,7-dimethyl- 1 /-/-indole-1 -carboxylate (124 mg).
  • a DEAD soln (40 wt% in toluene, 0.24 mL, 0.53 mmol) was further diluted with toluene (0.25 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 45 min.
  • the RM was allowed to gradually warm to RT, and the RM was stirred at RT overnight.
  • Racemic tert-butyl (3R*,4S*)-3-(4-(1/-/-pyrazol-1-yl)phenyl)-4-hydroxypiperidine-1 -carboxylate (Intermediate rac-A-8, 81 mg, 0.24 mmol) was dissolved in toluene (0.4 mL), and PPh 3 (92 mg, 0.35 mmol) was added followed by tert-butyl 4-hydroxy-5,7-dimethyl-1 /-/-indole-1 -carboxylate (Intermediate 1-1 , 61 mg, 0.24 mmol). The mixture was sonicated and then cooled to 0 °C.
  • a DEAD soln (40 wt% in toluene, 0.16 mL, 0.35 mmol) was further diluted with toluene (0.25 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 30 min.
  • the RM was stirred at 0 °C for approximately 30 min and then allowed to gradually warm to RT.
  • a DEAD soln (40 wt% in toluene, 89 pL, 0.20 mmol) was further diluted with toluene (0.25 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 45 min. The RM was allowed to warm to RT and stirred overnight.
  • Racemic methyl 4-((1 S*,2S*,5S*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac- A-10, 56 mg, 0.21 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 /-/-indole-1 -carboxylate (Intermediate 1-1 , 55 mg, 0.21 mmol), and PPh 3 (83 mg, 0.32 mmol) were dissolved in toluene (0.3 mL). The mixture was sonicated 1 min and then cooled to 0 °C.
  • a DEAD soln (40 wt% in toluene, 0.15 mL, 0.32 mmol) was further diluted with toluene (0.3 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 20 to 30 min.
  • the RM was stirred at 0 °C for 20 min and then allowed gradually warm to RT.
  • the RM was stirred for 2 days at RT.
  • the RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 20% EtOAc in heptane) to provide racemic tert-butyl 4-(((1 R*,2S*,4S*)-4-methoxy-2-(4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 /-/-indole-1 -carboxylate (84 mg).
  • Racemic methyl 4-((1 S*,2S*,5R ⁇ -2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac- A-12, 45 mg, 0.17 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 /-/-indole-1 -carboxylate (Intermediate 1-1 , 44 mg, 0.17 mmol), and PPh 3 (66 mg, 0.25 mmol) were dissolved in toluene (0.4 mL). The mixture was sonicated for 1 min and then was cooled to 0 °C.
  • a DEAD soln (40 wt% in toluene, 0.12 mL, 0.25 mmol) was further diluted with toluene (0.3 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over approximately 25 min.
  • the RM was stirred at 0 °C for 20 min and then allowed to gradually warm to RT.
  • the RM was stirred for 2 days at RT.
  • the RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 20% EtOAc in heptane) to provide racemic tert-butyl 4-(((1 R*,2S*,4/? ⁇ -4-methoxy-2- (4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5,7-dimethyl-1 /-/-indole-1 -carboxylate (8.7 mg).
  • Racemic methyl 4-((1 S*,2S*,5R*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac- A-11 , 60.7 mg, 0.23 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 /7-indole-1 -carboxylate (Intermediate 1-1 , 60.0 mg, 0.23 mmol), and PPh 3 (90.3 mg, 0.34 mmol) were dissolved in toluene (0.5 mL), and the mixture was cooled to 0 °C.
  • a DEAD soln (40 wt% in toluene, 0.16 mL, 0.34 mmol) was further diluted with toluene (0.3 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 20 min.
  • the RM was stirred at 0 °C for 20 min and then allowed to gradually warm to RT.
  • the RM was stirred for 3 days at RT.
  • the RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 20% EtOAc in heptane) to provide racemic tert-butyl 4-(((1 S*,2S*,4S*)-4-methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)- 5, 7-dimethyl-1 /-/-indole-1 -carboxylate (36 mg).
  • a DEAD soln (40 wt% in toluene, 0.16 mL, 0.34 mmol) was further diluted with toluene (0.3 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 20 min.
  • the RM was stirred at 0 °C for 20 min and then allowed to gradually warm to RT. The RM was stirred overnight at RT.
  • the RM was concentrated under reduced pressure and purified over silica gel (12 g; eluent: 0 to 20% EtOAc in heptane) to provide racemic tert-buty I 4-(((1 S*,2S*,4R*)-4-methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)- 5, 7-dimethyl-1 /-/-indole-1 -carboxylate as a colorless oil (36 mg).
  • Racemic methyl 4-((5S*,7S*,8S*)-8-hydroxy-1-oxaspiro[4.5]decan-7-yl)benzoate (Intermediate rac-A-12, 20 mg, 70 pmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 /-/-indole-1 -carboxylate (Intermediate 1-1 , 18 mg, 70 pmol), and PPh 3 (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 RM was stirred overnight at RT and then purified over silica gel (12 g; eluent: 0 to 25% EtOAc in heptane) to provide racemic tert-butyl 4- (((7S*,8R*)-7-(4-(methoxycarbonyl)phenyl)-1-oxaspiro[4.5]decan-8-yl)oxy)-5,7-dimethyl-1 /-/- indole-1 -carboxylate as a colorless oil (37 mg).
  • Racemic tert-butyl (3R*,4S*)-3-(6-(1 /-/-pyrazol-1 -y I) py rid in-3-y l)-4- hyd roxy p ipe rid in e- 1 - carboxylate (Intermediate rac-A-15, 59 mg, 0.17 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 /7- indole-1 -carboxylate (Intermediate 1-1 , 44.7 mg, 0.17 mmol), and PPh 3 (67 mg, 0.26 mmol) were dissolved in toluene (0.5 mL). The mixture was cooled to 0 °C.
  • a DEAD soln (40 wt% in toluene, 0.12 mL, 0.26 mmol) was further diluted with toluene (0.25 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 30 min.
  • the RM was stirred at 0 °C for 15 min and then allowed to warm to RT. The RM was stirred overnight at RT.
  • Racemic tert-butyl (3R*,4S*)-3-(4-(1 /7-1 , 2 , 3-triazol- 1 -yl)phenyl)-4-hydroxypiperidine-1 - carboxylate (Intermediate rac-A-16, 72 mg, 0.21 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 /7- indole-1 -carboxylate (Intermediate 1-1 , 54.6 mg, 0.21 mmol), and PPh 3 (82.3 mg, 0.31 mmol) were dissolved in toluene (0.2 mL) and THF (1 mL). The mixture was cooled to 0 °C.
  • a DEAD soln (40 wt% in toluene, 0.14 mL, 0.31 mmol) was further diluted with toluene (0.5 mL), and the DEAD soln was added to the cooled soln in a dropwise manner over 30 min.
  • the RM was stirred at 0 °C for 15 min and then allowed to warm to RT. The RM was stirred overnight at RT.
  • Racemic methyl 4-((1 S*,2S*,5S*)-2-hydroxy-5-methoxycyclohexyl)benzoate (Intermediate rac- A-10, 100 mg, 0.38 mmol), tert-butyl 4-hydroxy-5-cyclopropyl-7-methyl-1 /-/-indole-1 -carboxylate (Intermediate I-3, 108.7 mg, 0.38 mmol), and PPh 3 (148.8 mg, 0.57 mmol) were dissolved in toluene (0.4 mL). The mixture was cooled to 0 °C.
  • a DEAD soln (40 wt% in toluene, 0.26 mL, 0.57 mmol) was further diluted with toluene (0.5 mL), and the DEAD soln was added to the cooled soln in a dropwise manner.
  • the RM was stirred at 0 °C for 20 min and then allowed to warm to RT.
  • the RM was stirred overnight at RT and then purified over silica gel (12 g; eluent: 0 to 15% EtOAc in heptane) to provide racemic tert-butyl 5-cyclopropyl-4-(((1 R*,2S*,4S*)-4-methoxy-2-(4- (methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 /-/-indole-1 -carboxylate as a colorless oil (130 mg).
  • the RM was stirred at RT for 4 h.
  • the RM was quenched with H 2 O and extracted with EtOAc (2x).
  • the combined org phases were washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure.
  • the residue was purified Ill over silica gel (10 g; eluent: 0 to 15% EtOAc in heptane) to provide tert-butyl 5-fluoro-4- (((1 /?,2S,4S)-4-methoxy-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-7-methyl-1 /-/-indo le- 1 - carboxylate as a yellow solid (163 mg).
  • Racemic methyl 4-((1 S*,2S*)-2-hydroxycyclohexyl)benzoate (Intermediate rac-A-22, 264 mg, 1.13 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 /7-indole-1 -carboxylate (Intermediate 1-1 , 323.9 mg, 1.24 mmol), and PPh 3 (591.1 mg, 2.25 mmol) were dissolved in toluene (6 mL). The mixture was cooled to 0 °C. A DEAD soln (40 wt% in toluene, 0.88 mL, 2.25 mmol) was added to the cooled soln.
  • BTMG (66 pL, 0.32 mmol) was added, and the sealed vial was removed from the glovebox.
  • the vial was placed in a Penn photoreactor and irradiated at 450 nm, 100% LED, 6800 rpm, and cooling fan at full intensity for 80 h.
  • the RM was diluted with DCM and H 2 O and filtered through an Isolute® phase separator.
  • Racemic methyl 4-((1 S*,2S*,5S ⁇ -5-((tert-butyldimethylsilyl)oxy)-2-hydroxycyclohexyl)benzoate (Intermediate rac-A-24, 105 mg, 0.29 mmol) and tert-butyl 4-hydroxy-5-cyclopropyl-7-methyl- 1 /-/-indole-1 -carboxylate (Intermediate I-3, 91 .0 mg, 0.32 mmol) were dissolved in toluene (2 mL). PPh 3 (90.7 mg, 0.35 mmol) was added, and then DIAD (84 L, 0.43 mmol) was added in a dropwise manner.
  • the RM was stirred overnight at RT.
  • the RM was diluted with DCM and H 2 O and filtered through an Isolute® phase separator. The filtrate was concentrated under reduced pressure.
  • Column chromatography over silica gel (24 g; eluent: 0 to 20% EtOAc in cyclohexane) provided enriched material which was purified by preparatory HPLC (Waters XBridge C18 50 x 100 mm, 5 pm; eluent: 35 to 100% ACN in H 2 O with 0.2% FA) to provide racemic tert-butyl 4-(((1 R*,2S*,4S*)- 4-((tert-butyldimethylsilyl)oxy)-2-(4-(methoxycarbonyl)phenyl)cyclohexyl)oxy)-5-cyclopropyl-7- methyl-1 /-/-indole-1 -carboxylate (30.5 mg).
  • Racemic methyl 4-((5S*,6S*)-6-hydroxyspiro[2.5]octan-5-yl)benzoate (Intermediate rac-A-26, 344.0 mg, 1.24 mmol), tert-butyl 4-hydroxy-5,7-dimethyl-1 /-/-indole-1 -carboxylate (Intermediate 1-1 , 324.6 mg, 1.24 mmol), and PPh 3 (488.7 mg, 1.86 mmol) were dissolved in toluene (1 mL). The mixture was cooled to 0 °C. DIAD (0.39 mL, 1 .86 mmol) was added in a dropwise manner. The RM allowed to gradually warm to RT and stirred overnight.
  • the RM was concentrated under reduced pressure and purified over silica gel (40 g; eluent: 0 to 9% EtOAc in heptane) to provide racemic tert-butyl 4-(((5S*,6R*)-5-(4-(methoxycarbonyl)phenyl)spiro[2.5]octan-6-yl)oxy)-5,7- dimethyl-1 /-/-indole-1 -carboxylate as a white foam (195 mg).
  • Racemic methyl 4-((7S*,8S*)-8-hydroxy-1 ,4-dioxaspiro[4.5]decan-7-yl)benzoate (Intermediate rac-A-31 , 960 mg, 3.28 mmol) and tert-butyl 4-hydroxy-5-cyclopropyl-7-methyl-1 H-indole-1 - carboxylate (Intermediate I-3, 1 .04 g, 4.93 mmol) were dissolved in toluene (8 mL). PPh 3 (1 .03 g, 3.94 mmol) was added, and then DIAD (0.96 mL, 4.93 mmol) was added in a dropwise manner. The RM was stirred overnight at RT.
  • the RM was diluted with DCM and H 2 O and filtered through an Isolute® phase separator. The filtrate was concentrated under reduced pressure.
  • Column chromatography over silica gel 120 g; eluent: 0 to 30% EtOAc in cyclohexane) provided enriched material which was purified by preparatory HPLC (Waters XBridge C18 50 x 100 mm, 5 pm; eluent: 30 to 100% ACN in H 2 O with 0.2% FA) to provide racemic tert-butyl 5-cyclopropyl-4- (((7S*,8R*)-7-(4-(methoxycarbonyl)phenyl)-1 ,4-dioxaspiro[4.5]decan-8-yl)oxy)-7-methyl-1 /7- indole-1 -carboxylate as a light orange powder (570 mg).
  • Step 1 a Racemic fert-butyl 4-(((3R,4/?)-1 -(tert-butoxycarbonyl)-3-(4-
  • Step 1 b The residue was dissolved in ACN (1.5 mL). NEt 3 (30 pL, 0.22 mmol) and 2,2,2- trifluoroethyl trifluoromethanesulfonate (15.68 pL, 0.11 mmol) were added sequentially, and the RM was stirred at RT overnight. Sat. aq NaHCO 3 soln was added, and the mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • Step 1 b The residue was dissolved in DCM (1 mL), and acetaldehyde (10 pL, 0.19 mmol) was added followed by Na(OAc) 3 BH (30 mg, 0.14 mmol). The RM was stirred at RT overnight. The RM was neutralized with sat. aq NaHCO 3 soln, and the mixture was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • Step 1 a tert-Butyl (3/?,4S)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate
  • Step 1 b The material was dissolved in MeOH (2 mL). HCI soln (4M in dioxane, 0.59 mL, 2.35 mmol) was added, and the RM was stirred for 3.5 h. The pH was adjusted to 6 with NaOH, and the mixture was partitioned between EtOAc and H 2 O. The aq phase was extracted with EtOAc (2x). The combined org phases were dried over Mg 2 SO 4 and concentrated under reduced pressure.
  • HCI soln 4M in dioxane, 0.59 mL, 2.35 mmol
  • Step 1 racemic tert-butyl 4-(((3R*,4R*)-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)- 5,7-dimethyl-1H-indole-1 -carboxylate (Intermediate rac-B-13-1 )
  • Racemic tert-butyl (3/?*, 4S*)-4-hydroxy-3-(4-(methoxycarbonyl)phenyl)piperidine-1 -carboxylate (Intermediate rac-A-1 , 983.1 mg, 1.84 mmol), PPh 3 (722.7 mg, 2.76 mmol) and tert-butyl 4- hydroxy-5,7-dimethyl-1 /-/-indole-1 -carboxylate (Intermediate 1-1 , 500 mg, 1.84 mmol) were dissolved in THF (15 mL), and the mixture was cooled to 0 °C. DIAD (0.55 mL, 2.76 mmol) was added in a dropwise manner.
  • the RM was allowed to warm to RT and stirred overnight. Additional PPh 3 (481 .2 mg, 1 .84 mmol) and DIAD (0.55 mL, 2.76 mmol) were added, and the RM was stirred at RT for 5h. The RM was diluted with EtOAc, and the mixture was washed with H 2 O and brine. The org phase was dried through an Isolute® phase separator and concentrated under reduced pressure.
  • HCI soln (4M in dioxane, 3.12 mL, 12.5 mmol) was added, and RM was stirred for 1.5 h. The RM was quenched with sat. aq NaHCO3 soln, and the mixture was extracted with DCM (2x). The combined org phases were dried through and Isolute® phase separator and concentrated under reduced pressure.
  • Step 2 methyl 4-((3/?,4/?)-1-(3,3-difluoropropyl)-4-((5,7-dimethyl-1H-indol-4- yl)oxy)piperidin-3-yl)benzoate (Intermediate B-13)
  • Step 2a Racemic te/Y-butyl 4-(((3/?*,4/? ⁇ -3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 /-/-indole-1 -carboxylate (Intermediate rac-B-13-1 , 130 mg, 0.24 mmol) and 3-bromo- 1 ,1-difluoropropane (42.8 mg, 0.27 mmol) were combined in ACN (2 mL), and DIPEA (0.15 mL, 0.86 mmol) was added. The RM was stirred at 50 °C for 5 h.
  • the RM was allowed to cool to RT, diluted with EtOAc, and the mixture was washed with H 2 O.
  • the aq phase was extracted with EtOAc (2x).
  • the combined org phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure.
  • Step 2b The residue was dissolved in MeOH (2 mL), and HCI soln (4M in dioxane, 1 .22 mL, 4.89 mmoL) was added. The RM was stirred at RT overnight. The RM was diluted with DCM and neutralized with sat. aq NaHCO 3 soln. The phases were separated and the aq phase was extracted with DCM (2x). The combined org phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure.
  • HCI soln 4M in dioxane, 1 .22 mL, 4.89 mmoL
  • Step 2c Chiral separation and analytics according to Method SFC-21 : 59.1 mg provided Intermediate B-13 (peak 2): 19.8 mg, white solid.
  • Analytical chiral HPLC: Rt 1.92 min; 99.9% ee.
  • Step 1 a Racemic tert-buty I 4-(((3R,4R)-1 -(terf-butoxycarbonyl)-3-(4-
  • Step 1 b The residue was dissolved in MeOH (2 mL), and HCI soln (4M in dioxane, 1 .22 mL, 4.89 mmoL) was added. The RM was stirred at RT overnight. The RM was diluted with DCM and neutralized with sat. aq NaHCO 3 soln. The phases were separated and the aq phase was extracted with DCM (2x). The combined org phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure.
  • HCI soln 4M in dioxane, 1 .22 mL, 4.89 mmoL
  • Step 1 c Chiral separation and analytics according to Method SFC-22: 235.2 mg provided Intermediate B-14 (peak 2): 14.3 mg, white solid.
  • Analytical chiral HPLC: Rt 1.30 min; 99.9% ee.
  • Step 1 b The residue was dissolved in MeOH (1.5 mL), and HCI soln (4M in dioxane, 0.45 mL, 1.80 mmoL) was added. The RM was stirred at RT overnight. The RM was diluted with DCM and neutralized with sat. aq NaHCO 3 soln. The phases were separated and the aq phase was extracted with DCM (2x). The combined org phases were washed with brine, dried through an Isolute® phase separator, and concentrated under reduced pressure.
  • HCI soln 4M in dioxane, 0.45 mL, 1.80 mmoL
  • Step 1c Chiral separation and analytics according to Method SFC-23: 26.6 mg provided Intermediate B-15 (peak 2): 9.9 mg, colorless oil.
  • Analytical chiral HPLC: Rt 1 .24 min; 99.5% ee.
  • Step 1a racemic tert-buty 14-(((5S*,6R*)-5-(4-(methoxycarbonyl)phenyl)spiro[2.5]octan-6-yl)oxy)- 5, 7-dimethyl-1 /-/-indole-1 -carboxylate (Intermediate rac-M-35, 221 mg, 0.44 mmol) was dissolved in DCM (6 mL), and TFA (2 mL) was added. The RM was stirred at RT for 40 min. The RM was poured into a mixture of 10 wt% aq Na 2 CO 3 and MBTE. The phases were separated, and the aq phase was extracted with MBTE.
  • the org phase was washed with brine.
  • the combined org phases were dried over MgSO 4 and concentrated under reduced pressure.
  • the residue was purified using preparatory HPLC (Waters XBridge C18 50 x 100 mm; 5 pm; eluent: 40 to 90% ACN in H 2 O with 0.1 % NH 4 OH) to provide racemic methyl 4-((5S*,6R*)-6-((5,7- dimethyl-1 /7-indol-4-yl)oxy)spiro[2.5]octan-5-yl)benzoate as a white foam (65.5 mg).
  • Step 1 b Chiral separation and analytics according to Method SFC-25: 65 mg provided Intermediate B-33 (peak 2): 30.3 mg, white solid.
  • Analytical chiral HPLC: Rt 1.44 min; 99.5% ee.
  • the vial was purged with N 2 , and toluene (0.3 mL) and H 2 O (10 pL) were added.
  • the RM was stirred at 100 °C overnight.
  • the RM was concentrated under reducd pressure, and column chromatography over silica gel (12 g; eluent 0 to 100% EtOAc in heptane) provided enriched tert-butyl 5-cyclopropyl-4-(((3R,4/?)-1-(2,2-difluoroethyl)-3-(4- (methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-7-methyl-1 /-/-indole-1 -carboxylate (16 mg).
  • Racemic tert-butyl 5-cyclopropyl-4-(((7S*,8/?*)-7-(4-(methoxycarbonyl)phenyl)-1 ,4- dioxaspiro[4.5]decan-8-yl)oxy)-7-methyl-1 /-/-indole-1 -carboxylate (492.0 mg, 0.88 mmol) was dissolved in acetone (20 mL), and Amberlyst® 15 (2.75 g, 8.76 mmol) was added. The RM was stirred at RT for 4 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure.
  • Racemic tert-buty I 5-cyclopropyl-4-(((1 /?*,2S*)-2-(4-(methoxycarbonyl)phenyl)-4- oxocyclohexyl)oxy)-7-methyl-1/7-indole-1 -carboxylate (Intermediate rac-B-40, 41.3 mg, 80 pmol) was dissoved in THF (1 mL) and cooled to 0 °C. A methyl magnesium bromide soln (3.4M in THF, 28 pL, 96 pmol) was added, and the RM was stirred for 30 min. The RM was quenched with sat aq NH 4 CI soln and allowed to warm to RT.
  • Racemic tert-buty I 5-cyclopropyl-4-(((1 R*,2S*,4S*)-4-hydroxy-2-(4-(methoxycarbonyl)phenyl)-4- methylcyclohexyl)oxy)-7-methyl-1 /-/-indole-1 -carboxylate (Intermediate rac-B-41 , 22.4 mg, 42 pmol) was dissolved in MeOH (0.5 mL) and THF (1 mL). Aq NaOH soln (1 M, 0.21 mL, 0.21 mmol) was added, and the RM was stirred at 50 °C for 18 h.
  • the RM was quenched with FA (16 pL) and purified by preparatory HPLC (Waters XBridge C18 OBD 30 x 100 mm; 5 pm; eluent: 15 to 100% ACN in H 2 O with 0.2% FA) to provide racemic 4-((1 S*,2R*,5S*)-2-((5-cyclopropyl-7-methyl- 1 /7-indol-4-yl)oxy)-5-hydroxy-5-methylcyclohexyl)benzoic acid as a white solid (12.5 mg).
  • the RM was quenched with FA (5 pL) and purified by preparatory HPLC (Waters XBridge C18 OBD 30 x 100 mm; 5 pm; eluent: 15 to 100% ACN in H 2 O with 0.2% FA) to provide racemic 4-((1 S*, 2R*, 5R*)-2-((5-cyclopropyl-7-methyl-1 /-/- indol-4-yl)oxy)-5-hydroxy-5-methylcyclohexyl)benzoic acid as a white solid (12.5 mg).
  • Example Ex-1 and Example Ex -2 4-((3R,4/?)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 - methylpiperidin-3-yl)benzoic acid and 4-((3S,4S -4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 - methylpiperidin-3-yl)benzoic acid
  • Step 1 a Racemic te/Y-butyl 4-(((3/?* 4/?*)-3-(4-(methoxycarbonyl)phenyl)-1-methylpiperidin-4- yl)oxy)-5,7-dimethyl-1 /7-indole-1 -carboxylate (Intermediate rac-B-1 , 42 mg, 85 pmol) was dissolved in MeOH (2 mL), and K 2 CO 3 (50 mg, 0.36 mmol) was added. The RM was stirred at 45 °C overnight. Aq NaOH soln (1 M, 85 pL, 85 pmol) was added, and the RM was stirred at 60 °C for 90 min.
  • Example Ex-3 and Example Ex-4 4-((3R,4S)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 - methylpiperidin-3-yl)benzoic acid and 4-((3S,4R)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1- methylpiperidin-3-yl)benzoic acid
  • Step 1 a A vial was charged with racemic methyl 4-((3R*,4S*)-4-((5,7-dimethyl-1-tosyl-1 /-/-indol- 4-yl)oxy)-1-methylpiperidin-3-yl)benzoate (Intermediate rac-B-5, 38 mg, 70 pmol), EtOH (0.50 mL), and aq NaOH soln (4M, 0.52 mL 2.1 mmol). The vial was sealed, and the mixture was stirred at 85 °C overnight.
  • the mixture was purified using RP chromatography (50 g C18 column; eluent: 5% to 60% ACN in H 2 O, each with 0.1 % NH 4 OH) to provide racemic 4-((3/?*,4S*)-4-((5,7- dimethyl-1 /7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid as a white solid (21 mg).
  • Step 1 b Chiral separation and analytics according to Method SFC-7: 21 mg provided Example Ex-3 (peak 1): 6.0 mg, white solid.
  • Analytical chiral HPLC: Rt 1 .86 min; 100% ee.
  • Example Ex-5 4-((3R,4R)-4-((5-cyclopropyl-7-methyl-1H-indol-4-yl)oxy)-1-methylpiperidin- 3-yl)benzoic acid te/Y-Butyl 5-cyclopropyl-4-(((3/?,4/?)-3-(4-(methoxycarbonyl)phenyl)-1 -methylpiperidin-4-yl)oxy)- 7-methyl-1 /-/-indole-1 -carboxylate (Intermediate B-6, 50 mg, 96 pmol) was dissolved in EtOH (0.5 mL), and aq NaOH soln (4M, 0.24 mL, 096 mmol) was added.
  • the RM was stirred at RT overnight and then stirred at 50 °C for 2 h.
  • the mixture was purified by RP chromatography (50 g C18 column; eluent: 5 to 50% ACN in H 2 O, each with 0.1 % NH4OH) to provide 4-((3R,4R)-4- ((5-cyclopropyl-7-methyl-1 /7-indol-4-yl)oxy)-1-methylpiperidin-3-yl)benzoic acid as a white solid (22 mg).
  • Example Ex-6 4-((3R,4/?)-4-((5-chloro-7-methyl-1 H-indol-4-yl)oxy)-1 -methylpiperidin-3- yl)benzoic acid te/Y-Butyl 5-chloro-4-(((3/?,4/?)-3-(4-(methoxycarbonyl)phenyl)-1 -methylpiperidin-4-yl)oxy)-7- methyl-1 /-/-indole-1 -carboxylate (Intermediate B-7, 22 mg, 43 pmol) was dissolved in EtOH (0.3 mL), and aq NaOH soln (4M, 0.21 mL, 0.86 mmol) was added.
  • the mixture was gently heated until a clear soln was formed, and the RM was stirred at RT overnight.
  • the mixture was purified by RP chromatography (50 g C18 column; eluent: 5 to 50% ACN in H 2 O, each with 0.1 % NH 4 OH) to provide 4-((3R,4/?)-4-((5-chloro-7-methyl-1 /7-indol-4-yl)oxy)-1 -methylpiperidin-3-yl)benzoic acid as a white solid (16.4 mg).
  • Example Ex-7 and Example Ex-8 4-((3R,4/?)-4-((5,7-dimethyl-1H-indol-4-yl)oxy)-1 -(2,2,2- trifluoroethyl)piperidin-3-yl)benzoic acid and 4-((3S,4S)-4-((5,7-dimethyl-1H-indol-4- yl)oxy)-1 -(2,2,2-trifluoroethyl)piperidin-3-yl)benzoic acid
  • Step 1 a Racemic te/Y-butyl 4-(((3/?*,4/?)-3-(4-(methoxycarbonyl)phenyl)-1 -(2,2,2- trifluoroethyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 H-' ⁇ ndo le- 1 -carboxylate (Intermediate rac-B-2, 31 mg, 55 pmol) was dissolved in MeOH (2.5 mL), and K 2 CO 3 (35 mg, 0.25 mmol) was added. The RM was stirred at 65 °C for 2 h, and then at 75 °C for 75 min.
  • Step 1 b Chiral and analytics according to Method SFC-8: 12 mg provided Example Ex-7 (peak
  • Example Ex -9 4-((3R,4/?)-4-((5,7-dimethyl-1 H-indol-4-yl)oxy)-1 -ethylpiperidin-3-yl)benzoic acid te/Y-Butyl 4-(((3/?,4/?)-1 -ethyl-3-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)oxy)-5,7-dimethyl-1 /7- indole-1 -carboxylate (Intermediate B-3, 47 mg, 0.93 mmol) was dissolved in IPA (1.5 mL) and aq NaOH soln (1 M, 0.46 mL, 0.46 mmol) was added.
  • the RM was stirred at 60 °C for 2 days.
  • the RM was allowed to cool to RT, concentrated under reduced pressure, and purified by preparatory HPLC (Waters XBridge C18 OBD 30 x 50 mm; 5 pm; eluent: 5 to 20% ACN in H 2 O with 0.1 % NH4OH). Pure fractions were combined, and enriched fractions were repurified under the above conditions. Fractions were pooled and lyophilized to provide 4-((3R,4/?)-4-((5,7-dimethyl-1 /7- indol-4-yl)oxy)-1 -ethylpiperidin-3-yl)benzoic acid as a white solid (5.3 mg).
  • Example Ex-10 4-((4S,5R)-5-((5-cyclopropyl-7-methyl-1 H-indol-4-yl)oxy)-1-methylazepan- 4-yl)benzoic acid
  • Step 1 a te/Y-Butyl 4-(((4/?,5S)-1-(te/Y-butoxycarbonyl)-5-(4-(methoxycarbonyl)phenyl)azepan-4- yl)oxy)-5-cyclopropyl-7-methyl-1 /7-indole-1 -carboxylate (Intermediate M-6, 7 mg, 1 1 pmol) was dissolved in MeOH (1 mL), and HCI soln (4M in dioxane, 1 mL, 4.0 mmol) was added.
  • the RM was stirred at RT for 2 h and concentrated under reduced pressure. The residue was partitioned between DCM and sat. aq NaHCO 3 soln. The aq phase was extracted with DCM (2x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • Step 1 b The residue was dissolved in MeOH (1 mL). Aq formaldehyde solution (37 wt%, 0.5 mL, 6.7 mmol) and Na(OAc) 3 BH (15 mg, 71 mmol) were added. The RM was stirred at RT for 18 h. The RM was partitioned between DCM and sat. aq NaHCO 3 soln. The aq phase was extracted with DCM (2x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • Step 1 c The residue was dissolved in MeOH (3 mL), and aq NaOH soln (1 M, 150 pL, 150 pmol) was added. The RM was stirred at 70 °C for 6 h, allowed to cool to RT, and then stirred at RT for 3 days. Additional aq NaOH soln (1 M, 0.1 mL, 0.1 mmol) was added, and the RM was stirred at 65 °C for 2 h.
  • Step 1 b The residue was dissolved in MeOH (1 .5 mL). Aq formaldehyde (37 wt%, 0.5 mL, 6.7 mmol) and Na(OAc) 3 BH (50 mg, 0.23 mmol) were added. The RM was stirred at RT for 30 min. The RM was partitioned between DCM and sat. aq NaHCO 3 soln. The aq phase was extracted with DCM (2x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • Step 1 c The residue was dissolved in IPA (1 mL), and aq NaOH soln (1 M, 0.5 mL, 0.5 mmol) was added. The RM was stirred at 55 °C for 2 h and then stirred at 50 °C for 18 h. The RM was stirred at 70 °C for 2 h, and then additional aq NaOH soln (1 M, 0.15 mL, 0.15 mmol) was added.
  • the RM was stirred at 65 °C for 6 h, allowed to cool to RT, concentrated under reduced pressure, and purified by preparatory HPLC (Waters XBridge C18 OBD 30 x 50 mm; 5 pm; eluent: 10 to 30% ACN in H 2 O with 0.1 % NH 4 OH) to provide 4-((3R,4R)-4-((5,7-dimethyl-1 //-indol-4-yl)oxy)-1- methylazepan-3-yl)benzoic acid as a white solid (5.3 mg).
  • Racemic te/Y-butyl 5,7-dimethyl-4-(((3S*,4R*)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)oxy)- 1 /-/-indole-1 -carboxylate (Intermediate rac-B-8, 71 mg, 0.15 mmol) was dissolved in MeOH (2 mL). THF (0.5 mL) and aq NaOH soln (1 M, 0.6 mL, 0.6 mmol) was added. The RM was stirred at 60 °C for 3 h, allowed to cool to RT, and then stirred at RT overnight. The mixture was extracted with DCM (3x).
  • Step 1 a te/Y-Butyl 4-(((3R,4R)-1-(te/Y-butoxycarbonyl)-3-(4-cyanophenyl)piperidin-4-yl)oxy)-5,7- dimethyl-1 /-/-indole-1 -carboxylate (Intermediate M-9, 77 mg, 0.14 mmol) was dissolved in MeOH (2.5 mL), and HCI soln (4M in dioxane, 0.2 mL, 0.8 mmol) was added. The RM was stirred at RT for 90 min and concentrated under reduced pressure. The residue was partitioned between DCM and sat. aq NaHC0 3 soln. The aq phase was extracted with DCM (2x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure.
  • Step 1 b The residue was dissolved in MeOH (2.5 mL). Aq formaldehyde soln (37 wt%, 1 mL, 13 mmol) and Na(OAc) 3 BH (92 mg, 0.43 mmol) were added. The RM was stirred at RT for 1 h. The RM was partitioned between DCM and sat. aq NaHCO 3 soln. The aq phase was extracted with DCM (3x). The combined org phases were dried through an Isolute® phase separator and concentrated under reduced pressure. The residue was purified over silica gel (4 g; eluent: 0 to 100% 3:1 EtOAc/EtOH in heptane with 2% NH 4 OH).

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Abstract

L'invention concerne des composés de formule (I) et des compositions pharmaceutiques permettant de traiter des maladies ou des troubles médiés par le facteur B du complément.
PCT/IB2024/059431 2023-09-29 2024-09-26 Inhibiteurs du facteur b du complément et leurs utilisations Pending WO2025068951A1 (fr)

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Citations (3)

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WO2004078163A2 (fr) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Compositions pharmaceutiques a base d'un co-cristal
WO2015009616A1 (fr) 2013-07-15 2015-01-22 Novartis Ag Dérivés de pipéridinyl-indole et leur utilisation en tant qu'inhibiteurs du facteur b du complément
WO2024149261A1 (fr) * 2023-01-09 2024-07-18 南京正大天晴制药有限公司 Inhibiteur du facteur b du complément

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078163A2 (fr) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Compositions pharmaceutiques a base d'un co-cristal
WO2015009616A1 (fr) 2013-07-15 2015-01-22 Novartis Ag Dérivés de pipéridinyl-indole et leur utilisation en tant qu'inhibiteurs du facteur b du complément
WO2024149261A1 (fr) * 2023-01-09 2024-07-18 南京正大天晴制药有限公司 Inhibiteur du facteur b du complément

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MAINOLFI NELLO ET AL: "Discovery of 4-((2 S ,4 S )-4-Ethoxy-1-((5-methoxy-7-methyl-1 H -indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement Mediated Diseases", JOURNAL OF MEDICINAL CHEMISTRY, vol. 63, no. 11, 19 February 2020 (2020-02-19), US, pages 5697 - 5722, XP055791648, ISSN: 0022-2623, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.9b01870> DOI: 10.1021/acs.jmedchem.9b01870 *
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