CROSS-REFERNCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Nos. 63/402,613, 63/402,619, 63/402,640, 63/402,646, 63/402,648, and 63/402,690, each filed August 31, 2022, the contents of which are hereby incorporated by reference in their entireties.

FIELD

[0002] Provided herein are substituted indole compounds. In certain embodiments, the compounds are inhibitors of the alternative pathway of the complement system, and in particular, complement factor B (CFB). Also provided are compositions comprising the compounds and methods of use thereof. The compounds provided are useful in the treatment, prevention or amelioration of a disease, condition, or disorder through inhibition of the complement alternative pathway.

BACKGROUND

[0003] The complement system is a key component of the innate immunity system with two main functions of host defense against microbial pathogens and clearance of apoptotic cells. Since first discovered by Jules Bordet and Paul Ehrlich in the 1890s, more than a century of research on complement has uncovered its diverse roles in immune response, surveillance, homeostasis, and metabolism (Hajishengallis, Nat Immunol 2017 18: 1288-1298; Sim, Immunobiology 2016 221(10): 1037-1045; Ricklin, Nat Immunol 2010 11(9): 785-797). The complement system comprises a large number of soluble proteins that are found in circulation and tissue as inactive zymogens that are activated upon serine protease cleavage. Activation of complement is tightly regulated by both plasma and membrane-bound regulators. Dysregulation of complement activity through genetic mutation, autoantibodies or chronic inflammation has been found to cause tissue damage in various pathological conditions, including autoimmune, inflammatory, neurodegenerative and in a broad range of renal diseases (Zipfel, Nat Rev Immunol 2009 9: 729- 749; Holers, Annu Rev Immunol 2014 32: 433-459).

[0004] There are three activation pathways: the classical pathway (CP), lectin pathway (LP), and alternative pathway (AP) (Merle, Front Immunol 2015 6: 262). The CP is activated by immunoglobulins (TgG and TgM) and immune complexes through binding of Cl q to the Fc domain (Botto, Annu Rev Immunol 2002 205:395-406). The LP is activated by a group of proteins that bind to sugars on the surface of bacteria, for example, mannose binding lectin (MBL) (Garred, Immunol Rev 2016 274(1): 74-97). In contrast to the other two pathways that require specific stimuli for activation, the AP maintains a low level of activation in plasma through a spontaneous hydrolysis process called “tickover” and can also be secondarily activated by the other two complement pathways (Lachmann, Adv Immunol 2009 104: 115-149). The AP forms a rapidly self-amplified loop unless inactivated by factor H and factor I. The three activation pathways generate protease complexes termed “C3 convertases” (C3bBb and C4b2a) to cleave C3, and form C3bBbC3b as C5 convertase. The terminal complement pathway assembles C5b with other complement proteins to form C5b-9 membrane attach complex (MAC), which mediates lysis of pathogens or apoptotic cells (Bhakdi, Immunol Today 1991 12: 318-320). Two soluble fragments of C3 and C5 cleavage products, C3a and C5a, also termed “anaphylatoxins” are potent chemoattractants that trigger pro-inflammatory responses through their receptors (Klos, Mol Immunol 2009 46(14): 2753-2766).

[0005] Complement overactivation and kidney deposition is observed in various chronic kidney diseases (CKDs) including atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), ANCA-associated vasculitis (AAV), focal segmental glomerulosclerosis (FSGS) and lupus nephritis (LN) (Harris, Semin Immunopathol 2018 40(1): 125-140; Willows, Clin Med 2020 20(2): 156-160). Pre-clinical and clinical evidence support the role of complement, especially the AP, in disease initiation and progression. Genetic defects in complement genes, such as CFH, CFI, CFHRs, CFB, C3 and MCP/CD46, have been directly linked to aHUS and C3G (Bu, J Am Soc Nephrol 2014 25(1): 55- 64; Marinozzi, J Am Soc Nephrol 2015 25: 2053-2065; Xiao, Semin Thromb Hemost 201440(4): 465-471). Complement activation by autoantibodies and immune complexes in the kidney lead to renal injury and contribute to disease progression in multiple glomerular diseases (Corvillo, Front Immunol 2019 10: 886; Marinozzi, J Am Soc Nephrol 2017 28(5): 1603-1613; Seikrit, N Engl J Med 2018 379(25): 2479-2481). Recent studies provide evidence of kidney local production and activation of complement proteins in CKDs such as IgAN and diabetic kidney disease (Miihlig, Front Immunol 2020 11: 1833; Zhou, Clin J Am Soc Nephrol 2021 16(2): 213-224; Kelly Am J Nephrol 2015 41 : 48-56). It is believed the local production of complement and the unique microenvironment in the kidney make the organ more susceptible to complement overactivation (Thurman, Clin J Am Soc Nephrol 2020 11 :1856).

[0006] Significant efforts have been directed towards the development of complement-targeted therapies. Eculizumab is a C5 monoclonal antibody that has been approved for treatment of aHUS. However, when tested in C3G, only a subset of patients who had higher level of C5b-9 (MAC) showed improvement of disease. This is likely due to the contribution of activation fragments at the C3 level upstream of the terminal pathway (Vivarelli, Semin Thromb Hemost 201440(4): 472- 477). Multiple therapeutic agents targeting different complement pathways are currently in development, each with advantages and limitations (Zipfel, Front Immunol 2019 10: 2166; Thurman, Kidney Int 2016 90(4): 746-752). Nevertheless, there remain needs for potent therapeutic compounds blocking both C3 and C5 levels of the complement system.

[0007] As the key enzyme of the AP, CFB provides a highly desirable target to block the central amplification loop and the terminal complement pathway. Knocking out CFB has been shown to be protective in rodent models of C3G (Pickering, Nat Genet 2002 31(4): 424-428), MN (Luo, Front Immunol 2018 9: 1433), ANCA-associated vasculitis (Xiao, Am J Pathol 2007 170(1): 52- 64), LN (Watanabe, J Immunol 2000 164(2): 786-794), and multiple renal injury models (Thurman, Am J Physiol Renal Physiol 2012302: F1529-F1536; Casiraghi, Am J Transplant 2017 17: 2312-2325; Morigi, Sei Rep 20166:8445). Genetic deficiency of CFB in these models resulted in reduced proteinuria, protection from renal injury, and prolonged survival. Like many complement proteins, CFB circulates in its native form at high plasma concentration of 300-400 pg/mL. Recently, a selective CFB inhibitor, iptacopan (LNP023), has been shown to bind to active CFB (Schubart Proc Natl Acad Sci U S A. 2019 116(16): 7926-7931). In a Phase II clinical trial in C3G, iptacopan demonstrated encouraging efficacy with reduced proteinuria after 12 weeks of treatment (Wong, J Am Soc Nephrol 2020 31 : 55A). However, variability in complement activity and patient response was also observed, indicating highly potent compounds with greater and more sustained complement inhibition in vivo could provide greater therapeutic benefit to patients with C3G and a broad range of CKDs.

SUMMARY

[0008] In certain embodiments, provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds are inhibitors of the complement alternative pathway. Tn certain embodiments, the compounds are inhibitors of complement factor B (CFB). In certain embodiments, the compounds provided herein will confer therapeutic benefits associated with the inhibition of the complement alternative pathway, or CFB, including treating or preventing certain autoimmune disease or disorder, inflammatory disease or disorder, metabolic disease or disorder, neurological disease or disorder, pulmonary disease, respiratory disease or disorder, ophthalmic disease, cardiovascular disease, and kidney disease. Complement-mediated kidney disease includes chronic kidney disease (CKD), diabetic nephropathy, glomerular kidney disease, complement C3 glomerulopathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), dense-deposit disease (DDD), minimal change disease (MCD), paroxysmal nocturnal hemoglobinuria (PNH), ANCA-associated vasculitis, lupus nephritis and polycystic kidney disease (PKD).

[0009] In certain embodiments, provided herein are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

Ring A is a phenyl or 5- or 6-membered heteroaryl;

R ^x is halo, hydroxyl, C _1-3 alkyl, haloC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxy or haloCi- salkoxy; membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl of -R ^v -C3- ecycloalkyl, -R ^v -4- to 6-membered heterocyclyl or -R ^v -5-to 6-membered membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ;

R ^2a is -NR ¹⁵ R ¹⁶ and R ^2b is hydrogen, deuterium, halogen, C _1-3 alkyl, deutero C _1-3 alkyl or haloC _1-3 alkyl; or

R ^2a and R ^2b , together with the carbon atom to which they are attached, form Cb-ecycloalkyl or 3- to 6-membered heterocyclyl, wherein the C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl is substituted with one, two or three groups each independently selected from R ¹¹ , R ^11a and R ^llb ;

R ³ is halo, cyano, C _1-3 alkyl, or haloC _1-3 alkyl;

R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl;

R ⁵ is -R ^w -halo, -R ^w cyano-, -R ^w -C _1-3 alkyl, -R ^w -deuteroC _1-3 alkyl, -R ^w -haloC _1-3 alkyl, -R ^w - cyanoC _1-3 alkyl, -R ^w -hydroxyC _1-3 alkyl, C _3-5 cycloalkyl, 3- to 5-membered heterocyclyl, deuteroC3- scycloalkyl, -R ^W OH, -R ^w -O- C _1-3 alkyl or -R ^w -S-C _1-3 alkyl, wherein the C _3-5 cycloalkyl, 3- to 5- membered heterocyclyl, C _1-3 alkyl of -R ^w -OC _1-3 alkyl or C _1-3 alkyl of -R ^w -S-C _1-3 alkyl, is optionally substituted with one to seven groups each independently selected from halo, deutero, cyano, C _{1 - 3} alkyl, haloC _1-3 alkyl or hydroxyl;

R ⁶ is halo, cyano, C _1-3 alkyl, C _3-5 cycloalkyl, haloC _1-3 alkyl, C _1-3 alkoxy or haloC _1-3 alkoxy;

R ⁷ is hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, -R ^u cyanoCi-6alkyl, -R ^U COOR ¹³ , -R ^u -C _{3- 6} cycloalkyl, -R ^u -3- to 6-membered heterocyclyl, -R ^u -aryl, or -R ^u -5- to 6-membered heteroaryl, wherein the C _1-6 alkyl, halo _a l _a C6kyl, C _3-6 cycloalkyl of -R ^u -C _3-6 cycloalkyl, 3- to 6-membered heterocyclyl of -R ^u -3- to 6-membered heterocyclyl, aryl of -R ^u -aryl, or 5- to 6-membered heteroaryl of -R ^u -5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; each R ⁸ is independently hydrogen, C _1-6 alkyl, or haloC _1-6 alkyl; and R ⁹ is hydrogen, -R ^u -Ci-6alkyl, -R ^u haloC _1-6 alkyl, -R ^u cyanoCi-6alkyl, -R ^U COOR ¹³ , -R ^u -C _{3- 6} cycloalkyl, -R ^u -3- to 6-membered heterocyclyl, -R ^u -6-membered aryl or -R ^u -5- to 6-membered heteroaryl, wherein the C _3-6 cycloalkyl, 3- to 6-membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl of -R“-C _3-6 cycloalkyl, -R ^u -3- to 6- membered heterocyclyl, -R ^u -6- membered aryl or -R ^u -5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; or

R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, form 3- to 12- membered heterocyclyl (e g., 3- to 6- membered heterocyclyl) or 5- to 6-membered heteroaryl wherein the 3- to 12-membered heterocyclyl or 5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ;

R ¹⁰ is -R ^u C _1-6 alkyl, -R ^u haloC _1-6 alkyl -R ^u cyanoC _1-6 alkyl, -R ^U COOR ¹³ , -R ^u -C ₃ - ₆ cycloalkyl, -R ^u -3- to 6-membered heterocyclyl, -R ^u -6-membered aryl or -R ^u -5- to 6-membered heteroaryl, wherein the Cs-ecycloalkyl, 3- to 6-membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl of -R ^u -C _3-6 cycloalkyl, -R ^u -3- to 6- membered heterocyclyl, -Remembered aryl or -R ^u -5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; each R ¹¹ , R ^lla , R ^llb and R ¹² is independently halo, cyano, oxo, hydroxyl, amino, Ci- ₃ alkyl, deuteroC _1-3 alkyl, haloC _1-3 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, hydroxyl, C _1-3 alkoxy, haloC _1-3 alkoxy, -C(O)OR ¹³ , -C(O)R ¹⁴ , Ci- salkyloxy, C _1-3 alkylthio, haloC _1-3 alkylthio, haloC _1-3 alkoxy, C _1-3 alkylsulfonyl, haloC _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl, or haloC _1-3 alkylsulfmyl; or two R ¹¹ groups or two R ¹² groups, together with the carbon atom to which they are attached, form C _3-5 cycloalkyl, 3- to 6- membered heterocyclyl or oxo, wherein the C _3-5 cycloalkyl or 3- to 6- membered heterocyclyl is optionally substituted with 1 or 2 independently selected halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl; each R ^12a is independently C _1-3 alkyl, deuteroC _1-3 alkyl, haloC _1-3 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyCioalkyl, -C(O)OR ¹³ , -C(O)R ¹⁴ , C3- 6cycloalkyl, C _1-3 alkylsulfonyl, haloC _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl, or haloC _1-3 alkylsulfinyl; each R ¹³ is independently hydrogen, C _1-6 alkyl, deuteroC _1-3 alkyl, haloC _1-6 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, C _3-6 cycloalkylCi- ₃ alkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6-membered arylC _1-3 alkyl or 5- to 6-membered heteroaryl C i -3 alky 1 ; each R ¹⁴ is independently Ci-6alkyl, deuteroC _1-3 alkyl, haloC _1-6 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, C _3-6 cycloalkylC _1-3 alkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6-membered arylC _1-3 alkyl or 5- to 6-membered heteroaryl C _{1 -3} alky 1 ;

R ¹⁵ is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl; R ¹⁶ is C _3-6 cycloalkyl optionally substituted with one, two or three groups each independently selected from R ⁿ , R ^lla and R ^llb ; each R ^u and R ^v is independently absent or a linker having the formula -(CR ^c R ^d ) _z - C(R ^a )(R ^b )-(CR ^c R ^d ) _z wherein R ^a and R ^b are each independently hydrogen, halo, amino, C _1-3 alkyl, haloC _1-3 alkyl, Cs-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6- membered heteroaryl, C _3-6 cycloalkylC _1-3 alkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6- membered arylC _1-3 alkyl or 5- to 6-membered heteroarylC _1-3 alkyl, or R ^a and R ^b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl wherein the cycloalkyl or heterocyclyl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ;

R ^c and R ^d are each independently hydrogen, C _1-3 alkyl, or haloC _1-3 alkyl;

R ^w is either absent or is methylene, ethylene, propylene, butylene, cyclopropylene, cyclobutylene, optionally substituted with one to three groups each independently selected from halo, cyano or hydroxyl; k is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; each t is independently 1 or 2; and each z is independently 0, 1 or 2.

[00010] Also provided are pharmaceutical compositions formulated for administration by an appropriate route and means containing therapeutically effective concentrations of one or more of the compounds provided herein, or pharmaceutically acceptable salts thereof, and optionally comprising at least one pharmaceutical carrier.

[00011] In another aspect, provided herein are methods of treating a disease or disorder mediated by the complement alternative pathway, and particularly by complement factor B, comprising administering to a subject having such disease or disorder, a therapeutically effective amount of one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical compositions disclosed herein. In certain embodiments, the disease or disorder is chronic kidney disease (CKD), diabetic nephropathy, glomerular kidney disease, complement C3 glomerulopathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), dense-deposit disease (DDD), minimal change disease (MCD), paroxysmal nocturnal hemoglobinuria (PNH), ANCA-associated vasculitis, lupus nephritis, polycystic kidney disease (PKD), autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), end stage renal disease (ESRD), acute kidney injury, or polycystic liver disease.

[00012] Also provided herein are combination therapies using one or more compounds or compositions provided herein, in combination with other pharmaceutical agents for the treatment of the diseases and disorders described herein. These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description and drawings.

DETAILED DESCRIPTION

A. DEFINITIONS

[00013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[00014] As used herein, when used to refer to modify a numerical value, the term “about” encompasses a range of uncertainty of the numerical value of from 0% to 10% of the numerical value.

[00015] The term “alkyl” as used herein and unless otherwise indicated, refers to a saturated hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms or otherwise having from one to ten, one to eight, one to six, one to four or one to three carbon atoms, and which is attached to the rest of the molecule by a single bond. In certain embodiments, the hydrocarbon chain is optionally deuterated. For example, C1-C3 alkyl indicates that the group may have from 1 to 3 (inclusive) carbon atoms; Ci-Ce alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms. In some embodiments, an alkyl is a C1-C3 alkyl which represents a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 3 carbon atoms. In some embodiments, an alkyl is a Ci-Ce alkyl which represents a straightchain or branched saturated monovalent hydrocarbon group having 1 to 6 carbon atoms. Examples of alkyl include without limitation methyl, ethyl, //-propyl, isopropyl, //-butyl, isobutyl, .sec-butyl, and tert-butyl. [00016] The term “alkoxy” as used herein and unless otherwise indicated, refers to a group of the formula -OR wherein R is alkyl as defined herein. Alkoxy can be, for example, methoxy, ethoxy, //-propoxy, isopropoxy, //-butoxy, iso-butoxy, .scc-butoxy, //-pentoxy, 2-pentoxy, 3 -pentoxy, or hexyloxy. Likewise, the term “alkylthio” refers to a group of formula -S-(alkyl). The terms “haloalkoxy” and “haloalkylthio” refer to -O-(haloalkyl) and -S-(haloalkyl), respectively.

[00017] The term “alkylsulfinyl” as used herein and unless otherwise indicated, refers to the group of the formula -S(O)R wherein R is alkyl as defined herein.

[00018] The term “alkylsulfonyl” as used herein and unless otherwise indicated, refers to the group of the formula -S(O)2R wherein R is alkyl as defined herein.

[00019] The term “amino” as used herein and unless otherwise indicated, refers to the group of the formula -NR’R” wherein R’ and R’ ’ are each independently hydrogen, alkyl or haloalkyl, as defined herein, or wherein R’ and R”, together with the nitrogen atom to which they are attached, form a heterocyclyl.

[00020] The term “aryl” as used herein and unless otherwise indicated, is intended to mean any stable monocyclic or bicyclic carbon ring of up to 6 members in each ring, wherein at least one ring is aromatic. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, indanyl, or biphenyl.

[00021] The term “azolyl” as used herein and unless otherwise indicated, refers to a 5-membered heteroaryl ring system containing at least one nitrogen atom. Examples of azolyl include pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, thiadiazole and oxadiazole.

[00022] The term “cycloalkyl” as used herein and unless otherwise indicated, refers to a monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon group having the indicated number of ring carbon atoms or otherwise having three to ten carbon atoms and which are fully saturated or partially unsaturated (i.e., non-aromatic). Multicyclic cycloalkyl may be fused, bridged and/or spiro-ring systems. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, bicyclo[l.l. l]pentane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, spiro[3.3]heptane, and partially unsaturated hydrocarbon rings (e.g., cycloalkenyl groups) such as cyclobutylene, cyclopentene and cyclohexene. In some embodiments, cycloalkyl is a monocyclic Cs-Cs cycloalkyl.

[00023] The term “deuterium” as used herein and unless otherwise indicated, refers to the heavy isotope of hydrogen represented by the symbol D or ² H. As used herein, when a particular position in a compound is designated as “deuterated”, as having deuterium or having the prefix “deutero- ”, it is understood that the compound is an isotopically enriched compound and the presence of deuterium at that position in the compound is substantially greater than its natural abundance of 0.0156%, for example, at least 90% deuterium in the specified position(s).

[00024] The term “deuteroalkyl” as used herein and unless otherwise indicated, refers to an alkyl group in which one or more hydrogen atoms of the alkyl are replaced with deuterium in substantially greater abundance than its natural abundance, for example, at least 90% deuterium in the specified position(s).

[00025] The term “enantiomerically pure” or “pure enantiomer” as used herein denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of a single enantiomer to the exclusion of its corresponding non-superimposable mirror image. Some embodiments described herein provide a compound that is present as a pure enantiomer. Some embodiments also provide pharmaceutical compositions comprising an enantiomerically pure compound described herein.

[00026] The term “halo”, “halogen” or “halide” as used herein and unless otherwise indicated, refers to a monovalent fluorine, chlorine, bromine or iodine group.

[00027] The term “haloalkyl” as used herein and unless otherwise indicated, refers to a monovalent alkyl group in which at least one hydrogen atom is replaced by a halogen. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5 or 6) are replaced by independently selected halogens. In these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluoro and chloro). “Haloalkyl” also includes alkyl moieties in which all hydrogens have been replaced by halogens (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl).

[00028] The term “cyano” as used herein and unless otherwise indicated, refers to a -CN group. [00029] The term “cyanoalkyl” as used herein and unless otherwise indicated, refers to an alkyl group in which one hydrogen atom of the alkyl is replaced with a cyano group, as defined herein. [00030] The term “hydroxyl” as used herein and unless otherwise indicated, refers to an -OH group.

[00031] The term “hydroxyalkyl” as used herein and unless otherwise indicated, refers to an alkyl group in which one hydrogen atom of the alkyl is replaced with a hydroxyl group, as defined herein.

[00032]

[00033] The term “heterocycle”, “heterocyclyl” or “heterocyclic” as used herein and unless otherwise indicated, represents a stable 3-, 4-, 5-, 6- or 7-membered monocyclic-, a stable 4-, 5-, 6- or 7-membered monocyclic- or a stable 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic heterocyclic saturated or partially unsaturated ring system which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms may optionally be oxidized as A-oxide, sulfoxide or sulfone, Wherein the nitrogen atom may optionally be quatemized, and wherein one or two carbon atoms can be present as oxo groups. A heterocycle can be bonded via a ring carbon atom or, if available, via a ring nitrogen atom. Bicyclic heterocyclic ring systems may be fused, bridged, and/or spiro-bicyclic ring system(s). In some embodiments, heterocyclyl is monocyclic having 4 to 7, preferably 4 to 6, ring atoms, of which 1 or 2 are heteroatoms independently selected from the group consisting of N, O and S. In some embodiments, heterocyclyl is monocyclic having 4 to 7, preferably 4 to 6, ring atoms, of which at least 1 heteroatom is N and the second heteroatom is N, O or S. In certain embodiments, the heterocyclyl is azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine. In some embodiments, a heterocyclyl group is bicyclic, and in which case, the first ring (the point of attachment to the remainder of the molecule) is saturated or partially saturated monocyclic heterocyclyl as described herein, and the second ring may be a non-aromatic ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms independently selected from the group consisting of N, O and S, or the second ring may be a “cycloalkyl”, or a “cycloalkenyl”, as defined herein. Examples of such heterocyclic groups include, but are not limited to azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline, isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine, piperidine, dihydropyridine, tetrahydropyridine, dihydropyridazine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, piperazinone, tetrahydrofuran, tetrahydropyran, thiamorpholine, tetrahydrothiophene, thiazoline, thiazolidine, thiomorpholine, thietane, thiolane, sulfolane, 1,3-dioxolane, 1,3-oxazolidine, 1,3-thiazolidine, tetrahydrothiopyran, tetrahydrotriazine, 1,3 -di oxane, 1,4-di oxane, hexahydrotriazine, tetrahydro-oxazine, tetrahydropyrimidine, perhydroazepine, perhydro- 1,4-diazepine, perhydro- 1,4-oxazepine, 7- azabicyclo[2.2.1]heptane, 3-azabicyclo[3.2.0]heptane, 7-azabicyclo[4.1.0]heptane, 2,5- diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, tropane, 2-oxa-6- azaspiro[3.3]heptane, dihydrobenzofuran, diydrobenzimidazolyl, dihydrobenzoxazole, and dihydrobenzothiazolyl, 4,7-diazaspiro[2.5]octane, 2,7-diazaspiro[3.5]nonane, 2,6- diazaspiro[3.3]heptane, azaspiro[3.3]heptane, oxa-6-azaspiro[3.3]heptane, and A-oxides or sulfones or sulfoxides thereof

[00034] The term “heteroaryl”, as used herein and unless otherwise indicated, represents a stable 5-, 6- or 7-membered monocyclic- or stable 9- or 10-membered fused bicyclic ring system which comprises at least one aromatic ring, which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S wherein the nitrogen and sulfur heteroatoms or a carbon atom of the heteroaryl may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized. In the case of a “heteroaryl” which is a bicyclic group, the first ring (the point of attachment to the remainder of the molecule) is a monocyclic heteroaryl group as described herein, and the second ring need not be aromatic and need not comprise a heteroatom. Accordingly, bicyclic “heteroaryl” includes, for example, a stable 5- or 6-membered monocyclic aromatic ring consisting of carbon atoms and from one to four, preferably up to three, heteroatoms, as defined immediately above, fused to a benzene ring, or a second monocyclic “heteroaryl”, or a “heterocyclyl”, a “cycloalkyl”, or a “cycloalkenyl”, as defined above. Examples of heteroaryl groups include, but are not limited to, benzimidazole, benzopyrazole, benzisothiazole, benzisoxazole, benzofuran, isobenzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyridinone, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, benzimidazole, benzothiadiazole, isoindole, pyrrol opyri dines, imidazopyridines such as imidazo[l,2-a]pyridine, pyrazol opyri dine, pyrrol opyrimi dine and A ^f -oxidcs thereof.

[000351 The term “oxo” refers to a carbonyl (C=O) group. When a carbon atom is indicated as being substituted with an oxo group, it is understood that two hydrogen atoms will be removed from the carbon atom and replaced with =0. Similarly, when a carbon atom is indicated as being substituted by two groups, and may be substituted with an “oxo” group, the two substituents may come together to form the oxo group.

[00036] The term “subject” as used herein and unless otherwise indicated, refers to any human or veterinary subject, including mammals such as mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans, including neonatal, infant, juvenile, adolescent, adult or geriatric patients.

[00037] The term “thiol” refers to a group having the formula -SH.

[00038] The term "therapeutically effective amount" is an amount sufficient to effect beneficial or desired clinical results. A therapeutically effective amount can be administered in one or more administrations. A therapeutically effective amount is sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.

[00039] Unless stated otherwise or specifically described, it is understood that substitutions where present can occur on any atom of the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups, valence permitting.

[00040] Unless specifically stated otherwise, where a compound may assume alternative tautomeric or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the claimed subject matter. For example, unless specifically stated otherwise, the compounds provided herein may be stereoisomerically pure (e.g., single enantiomers or diastereomers), or be mixtures of stereoisomers such as racemic or diastereomeric mixtures.

[00041] The term "treating", "treat", or "treatment" refers generally to controlling, alleviating, ameliorating, slowing the progress of and/or eliminating a named condition once the condition has been established. In addition to its customary meaning, the term "preventing", “prevent”, or “prevention” also refers to delaying the onset of, or reducing the risk of developing a named condition or of a process that can lead to the condition, and/or the recurrence of symptoms of a condition. [00042] In the description herein, if there is any discrepancy between a chemical name and chemical structure, the chemical structure controls.

B. COMPOUNDS

[00043] In certain embodiments, provided herein are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

Ring A is a phenyl or 5- or 6-membered heteroaryl;

R ^x is halo, hydroxyl, C _1-3 alkyl, haloC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxy or haloCi- salkoxy;

R ¹ is -R ^V OR ⁷ , -R' NR ^X R ⁹ , -R ^v S(O)tR ¹⁰ , -R ^V CN, -R ^V -C(O)OR ⁷ , -R ^V C(O)NR ⁸ R ⁹ , -R ^v S(O)tNR ⁸ R ⁹ , -R ^V NR ^X C(O)R ^I() , -R ^V NR ⁸ C(O)OR ^1IJ , -R ^V NR ^X C(O) NR ⁸ R ⁹ , -R ^v NR ⁸ S(O)tR ¹⁰ , -R ^v -C _3-6 cycloalkyl, -R ^v -4- to 6-membered heterocyclyl or -R ^v -5-to 6- membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl of -R ^v -C3- ecycloalkyl, -R ^v -4- to 6-membered heterocyclyl or -R ^v -5-to 6-membered membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ;

R ^2a is -NR ¹⁵ R ¹⁶ and R ^2b is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl; or

R ^2a and R ^2b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein the Cs-ecycloalkyl or 3- to 6-membered heterocyclyl is substituted with one, two or three groups each independently selected from R ¹¹ , R ^lla and R ^llb ;

R ³ is halo, cyano, C _1-3 alkyl, or haloC _1-3 alkyl;

R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl; R ⁵ is -R ^w -halo, -R ^w cyano-, -R ^w -C _1-3 alkyl, -R ^w -deuteroC _1-3 alkyl, -R ^w -haloC _1-3 alkyl, -R ^w - cyanoC _1-3 alkyl, -R ^w -hydroxyC _1-3 alkyl, Cs-scycloalkyl, 3- to 5-membered heterocyclyl, deuteroCs- scycloalkyl, -R ^W OH, -R ^w -O-C _1-3 alkyl or -R ^w -S-C _1-3 alkyl, wherein the C _3-5 cycloalkyl, 3- to 5- membered heterocyclyl, C _1-3 alkyl of -R ^w -OC _1-3 alkyl or C _1-3 alkyl of -R ^w -S-C _1-3 alkyl, is optionally substituted with one to seven groups each independently selected from halo, deutero, cyano, Ci- salkyl, haloC _1-3 alkyl or hydroxyl;

R ⁶ is halo, cyano, C _1-3 alkyl, Cs-scycloalkyl, haloC _1-3 alkyl, C _1-3 alkoxy or haloC _1-3 alkoxy;

R ⁷ is hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, -R ^u cyanoCi-6alkyl, -R ^U COOR ¹³ , -R ^u -C3- 6cycloalkyl, -R ^u -3- to 6-membered heterocyclyl, -R ^u -aryl, or -R ^u -5- to 6-membered heteroaryl, wherein the C _1-6 alkyl, haloCi -ealkyl, Cs-ecycloalkyl of -R ^u -C3-ecycloalkyl, 3- to 6-membered heterocyclyl of -R ^u -3- to 6-membered heterocyclyl, aryl of -R ^u -aryl, or 5- to 6-membered heteroaryl of -R ^u -5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; each R ⁸ is hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, or -R ^u -3- to 12-membered heterocyclyl; and R ⁹ is hydrogen, -R ^u -Ci-6alkyl, -R ^u haloC _1-6 alkyl, -R ^u cyanoCi-6alkyl, -R ^U COOR ¹³ , -R ^u -C3- locycloalkyl (e.g., -R"-C _3-6 cycloalkyl), -R"-3- to 12-membered heterocyclyl (e.g., -R ^u -3- to 6- membered heterocyclyl), -R ^u -6-membered aryl or -R ^u -5- to 6-membered heteroaryl, wherein the C3-iocycloalkyl, 3- to 12-membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl of -R ^u -C3-iocycloalkyl, -R ^u -3- to 12- membered heterocyclyl, -R ^u -6-membered aryl or -R ^u -5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; or

R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, form 3- to 12- membered heterocyclyl (e.g., 3- to 6- membered heterocyclyl) or 5- to 6-membered heteroaryl wherein the 3- to 12-membered heterocyclyl or 5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; or

R ⁸ is hydrogen, alkyl, or haloalkyl, and R ⁹ and R ^x adjacent to -C(O)NR ⁸ N ⁹ , together form a 5- to 6-membered heterocyclyl group optionally substituted with one, two or three groups each independently selected from R ¹¹ , R ^lla and R ^llb ;

R ¹⁰ is -R ^u C _1-6 alkyl, -R ^u haloC _1-6 alkyl -R ^u cyanoCi-6alkyl, -R ^U COOR ¹³ , -R ^u -C ₃ - ecycloalkyl, -R ^u -3- to 6-membered heterocyclyl, -R ^u -6-membered aryl or -R ^u -5- to 6-membered heteroaryl, wherein the C _3-6 cycloalkyl, 3- to 6-membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl of -R ^u -C _3-6 cycloalkyl, -R ^u -3- to 6- membered heterocyclyl, -R ^u -6- membered aryl or -R ^u -5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; each R ¹¹ , R ^lla , R ^llb and R ¹² is independently halo, cyano, oxo, hydroxyl, amino, Ci- salkyl, deuteroC _1-3 alkyl, haloC _1-3 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, hydroxyl, C _1-3 alkoxy, haloC _1-3 alkoxy, -C(O)OR ¹³ , -C(O)R ¹⁴ , Ci- 3alkyloxy, C _1-3 alkylthio, haloC _1-3 alkylthio, haloC _1-3 alkoxy, C _1-3 alkylsulfonyl, haloC _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl, or haloC _1-3 alkylsulfmyl; or two R ¹¹ groups or two R ¹² groups, together with the carbon atom to which they are attached, form C _3-5 cycloalkyl, 3- to 6- membered heterocyclyl or oxo, where the Cs-scycloalkyl or 3- to 6- membered heterocyclyl is optionally substituted with 1 or 2 independently selected halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl; each R ^i2a is independently C _1-3 alkyl, deuteroC _1-3 alkyl, haloC _1-3 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, -C(O)OR ¹³ , -Ci- 3alkylC(O)OR ¹³ , -C(O)R ¹⁴ , Cs-scycloalkyl, C _1-3 alkylsulfonyl, haloC _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl, haloC _1-3 alkylsulfinyl, 3- to 6- membered heterocyclyl, 6-membered aryl, or 5- to 6-membered heteroaryl, wherein the 3- to 6- membered heterocyclyl, 6-membered aryl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from halo, cyano, C _1-3 alkyl, and haloC _1-3 alkyl; each R ¹³ is independently hydrogen, C _1-6 alkyl, deuteroC _1-3 alkyl, haloC _1-6 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, C _3-6 cycloalkylCi- salkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6-membered arylC _1-3 alkyl or 5- to 6-membered heteroarylC _1-3 alkyl; each R ¹⁴ is independently C _1-6 alkyl, deuteroC _1-3 alkyl, haloC _1-6 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, Cs-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, C _3-6 cycloalkylC _1-3 alkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6-membered arylC _1-3 alkyl or 5- to 6-membered heteroaryl C i -3 alky 1 ;

R ¹⁵ is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl;

R ¹⁶ is C _3-6 cycloalkyl optionally substituted with one, two or three groups each independently selected from R ⁿ , R ^lla and R ^llb ; each R ^u and R ^v is independently absent or a linker having the formula -(CR ^c R ^d ) _z -C(R ^a )(R ^b )- (CR ^c R ^d ) _z wherein R ^a and R ^b are each independently hydrogen, halo, amino, C _1-3 alkyl, haloCi- salkyl, C _1-3 alkoxyC _1-3 alkyl, C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, C _3-6 cycloalkylC _1-3 alkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6- membered arylC _1-3 alkyl or 5- to 6-membered heteroarylC _1-3 alkyl, or R ^a and R ^b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl wherein the cycloalkyl or heterocyclyl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ;

R ^c and R ^d are each independently hydrogen, C _1-3 alkyl, or haloCi-ralkyl;

R ^w is either absent or is methylene, ethylene, propylene, butylene, cyclopropylene, cyclobutylene, optionally substituted with one to three groups each independently selected from halo, cyano or hydroxyl; k is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; each t is independently 1 or 2; and each z is independently 0, 1 or 2.

[00044] In certain embodiments, provided herein are compounds Formula (I), or a pharmaceutically acceptable salt thereof, wherein:

Ring A is a phenyl or 5- or 6-membered heteroaryl;

R ^x is halo, hydroxyl, C _1-3 alkyl, haloC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxy or haloCi- salkoxy; membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl of -R ^v -C3- ecycloalkyl, -R ^v -4- to 6-membered heterocyclyl or -R ^v -5-to 6-membered membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ;

R ^2a is -NR ¹⁵ R ¹⁶ and R ^2b is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl; or R ^2a and R ^2b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein the Cs-ecycloalkyl or 3- to 6-membered heterocyclyl is substituted with one, two or three groups each independently selected from R ¹¹ , R ^lla and R ^llb ;

R ³ is halo, cyano, C _1-3 alkyl, or haloC _1-3 alkyl;

R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl;

R ⁵ is -R ^w -halo, -R ^w cyano-, -R ^w -C _1-3 alkyl, -R ^w -deuteroC _1-3 alkyl, -R ^w -haloC _1-3 alkyl, -R ^w - cyanoC _1-3 alkyl, -R ^w -hydroxyC _1-3 alkyl, C _3-5 cycloalkyl, 3- to 5-membered heterocyclyl, deuteroC3- scycloalkyl, -R ^W OH, -R ^w -O-C _1-3 alkyl or -R ^w -S-C _1-3 alkyl, wherein the C _3-5 cycloalkyl, 3- to 5- membered heterocyclyl, C _1-3 alkyl of -R ^w -OC _1-3 alkyl or C _1-3 alkyl of -R ^w -S-C _1-3 alkyl, is optionally substituted with one to seven groups each independently selected from halo, deutero, cyano, Ci- salkyl, haloC _1-3 alkyl or hydroxyl;

R ⁶ is halo, cyano, C _1-3 alkyl, C _3-5 cycloalkyl, haloC _1-3 alkyl, C _1-3 alkoxy or haloC _1-3 alkoxy;

R ⁷ is hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, -R ^u cyanoCi-6alkyl, -R ^U COOR ¹³ , -R ^u -C3- ecycloalkyl, -R ^u -3- to 6-membered heterocyclyl, -R ^u -aryl, or -R ^u -5- to 6-membered heteroaryl, wherein the C _1-6 alkyl, haloCi -ealkyl, C _3-6 cycloalkyl of -R ^u -C3-ecycloalkyl, 3- to 6-membered heterocyclyl of -R"-3- to 6-membered heterocyclyl, aryl of -R''-aryl, or 5- to 6-membered heteroaryl of -R ^u -5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; each R ⁸ is independently hydrogen, C _1-6 alkyl, or haloC _1-6 alkyl; and R ⁹ is hydrogen, -R ^u -Ci-6alkyl, -R" haloCi-ealkyl, -R ^u cyanoCi-6alkyl, -R ^U COOR ¹³ , -R ^u -C3- ecycloalkyl, -R ^u -3- to 6-membered heterocyclyl, -R ^u -6-membered aryl or -R ^u -5- to 6-membered heteroaryl, wherein the Cs-ecycloalkyl, 3- to 6-membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl of -R ^u -C _3-6 cycloalkyl, -R ^u -3- to 6- membered heterocyclyl, -R ^u -6- membered aryl or -R ^u -5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; or

R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, form 3- to 12- membered heterocyclyl (e.g., 3- to 6- membered heterocyclyl) or 5- to 6-membered heteroaryl wherein the 3- to 12-membered heterocyclyl or 5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ;

R ¹⁰ is -R ^u C _1-6 alkyl, -R ^u haloC _1-6 alkyl -R ^u cyanoC _1-6 alkyl, -R ^U COOR ¹³ , -R ^u -C3- ecycloalkyl, -R ^u -3- to 6-membered heterocyclyl, -R ^u -6-membered aryl or -R ^u -5- to 6-membered heteroaryl, wherein the Cs-ecycloalkyl, 3- to 6-membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl of -R ^u -C _3-6 cycloalkyl, -R ^u -3- to 6- membered heterocyclyl, -R ^u -6- membered aryl or -R ^u -5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; each R ¹¹ , R ^lla , R ^llb and R ¹² is independently halo, cyano, oxo, hydroxyl, amino, Cisalkyl, deuteroC _1-3 alkyl, haloC _1-3 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, hydroxyl, C _1-3 alkoxy, haloC _1-3 alkoxy, -C(O)OR ¹³ , -C(O)R ¹⁴ , Ci- salkyloxy, C _1-3 alkylthio, haloC _1-3 alkylthio, haloC _1-3 alkoxy, C _1-3 alkylsulfonyl, haloC _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl, or haloC _1-3 alkyl sulfinyl; or two R ¹¹ groups or two R ¹² groups, together with the carbon atom to which they are attached, form Cs-scycloalkyl, 3- to 6- membered heterocyclyl or oxo, where the Cs-scycloalkyl or 3- to 6- membered heterocyclyl is optionally substituted with 1 or 2 independently selected halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl; each R ^12a is independently C _1-3 alkyl, deuteroC _1-3 alkyl, haloC _1-3 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, -C(O)OR ¹³ , -C(O)R ¹⁴ , C3- scycloalkyl, C 1-3 alkyl sulfonyl, haloCi-aalkylsulfonyl, C _1-3 alkylsulfinyl, or haloC _1-3 alkylsulfinyl; each R ¹³ is independently hydrogen, Ci-6alkyl, deuteroC _1-3 alkyl, haloC _1-6 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, Cs-ecycloalkylCi- salkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6-membered arylC _1-3 alkyl or 5- to 6-membered heteroaryl C 1 -3 alky 1 ; each R ¹⁴ is independently Ci-6alkyl, deuteroC _1-3 alkyl, haloC _1-6 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, Cs-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, C _3-6 cycloalkylC _1-3 alkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6-membered arylC _1-3 alkyl or 5- to 6-membered heteroaryl C 1 -3 alky 1 ;

R ¹⁵ is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl;

R ¹⁶ is C _3-6 cycloalkyl optionally substituted with one, two or three groups each independently selected from R ⁿ , R ^lla and R ^llb ; each R ^u and R ^v is independently absent or a linker having the formula -(CR ^c R ^d ) _z - C(R ^a )(R ^b )-(CR ^c R ^d ) _z wherein R ^a and R ^b are each independently hydrogen, halo, amino, C _1-3 alkyl, haloC _1-3 alkyl, Ca-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6- membered heteroaryl, C _3-6 cycloalkylC _1-3 alkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6- membered arylC _1-3 alkyl or 5- to 6-membered heteroarylC _1-3 alkyl, or R ^a and R ^b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl wherein the cycloalkyl or heterocyclyl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ;

R ^c and R ^d are each independently hydrogen, C _1-3 alkyl, or haloC _1-3 alkyl;

R ^w is either absent or is methylene, ethylene, propylene, butylene, cyclopropylene, cyclobutylene, optionally substituted with one to three groups each independently selected from halo, cyano or hydroxyl; k is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; each t is independently 1 or 2; and each z is independently 0, 1 or 2.

[00045] In some embodiments, when Ring A phenyl or pyridinyl, then R ¹ is not -COOH.

[00046] In some embodiments, when Ring A phenyl or pyridinyl; R ¹ is -R ^V -C(O)OR ⁷ , and

R ^z is hydrogen, then R ^v is -(CR ^c R ^d )z-C(R ^a )(R ^b )-(CR ^c R ^d ) _z -; and R ^a , R ^b , R ^c , R ^d and z are as described herein.

[00047] In some embodiments, R ^2a and R ^2b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein the C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl is substituted with one, two or three groups each independently selected from R ¹¹ , R ^lla and R ^llb ; and R ¹¹ , R ^lla and R ^llb are as described herein.

[00048] In some embodiments, R ^2a and R ^2b , together with the carbon atom to which they are attached, form C3-ecycloalkyl substituted with one, two or three groups each independently selected from R ¹¹ , R ^lla and R ^llb ; and R ¹¹ , R ^lla and R ^llb are as described herein.

[00049] In some embodiments, R ^2a is -NR ¹⁵ R ¹⁶ and R ^2b is hydrogen, deuterium, halogen, Ci- 3alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl; and R ¹⁵ and R ¹⁶ are as described herein. [00050] Some embodiments provide a compound of Formula (I’): or a pharmaceutically acceptable salt thereof, wherein Ring A, R ^x , R ¹ , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , k and n are as described herein.

[00051] Some embodiments provide a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; X ¹ , X ³ and X ⁴ are each independently N, CH or CR ^X ; and X ² is O, S, N or CR ^X , provided X ¹ , X ² , X ³ , and X ⁴ are not all N and when X ² is O, m is 0 and X ³ is N and when X ² is S, m is 0; and wherein R ^x , R ¹ , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , and k are as described herein.

[00052] Some embodiments provide a compound of Formula (IF):

or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; X ¹ , X ³ and X ⁴ are each independently N, CH or CR ^X ; and X ² is O, S, N or CR ^X , provided X ¹ , X ² , X ³ , and X ⁴ are not all N and when X ² is O, m is 0 and X ³ is N and when X ² is S, m is 0; and wherein R ^x , R ¹ , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , and k are as described herein.

[00053] In some embodiments, Ring A is azolyl.

[00054] In some embodiments, Ring A is pyridinyl, pyridinonyl, pyrimidinyl, pyrazolyl, oxazolyl, thiazolyl, tetrazolyl, oxadiazolyl, or oxadiazol onyl.

H

[00055] In some embodiments, Ring A is O N

[00056] Some embodiments provide a compound of Formula (III): or a pharmaceutically acceptable salt thereof, wherein X ¹ and X ² are each independently N, CH or CR ^X ; and wherein R ^x , R ¹ , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , and k are as described herein. [00057] Some embodiments provide a compound of Formula (TIT’): or a pharmaceutically acceptable salt thereof, wherein X ¹ and X ² are each independently N, CH or CR ^X ; and wherein R ^x , R ¹ , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , and k are as described herein.

[00058] Some embodiments provide a compound of Formula (la): or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2; q is 1, 2 or 3; and Ring A, R ^x , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , k and n are as described herein.

[00059] Some embodiments provide a compound of Formula (la’): [00060] or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2; q is 1 , 2 or 3; and Ring A, R ^x , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , k and n are as described herein.

[00061] Some embodiments provide a compound of Formula (lb): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^x , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^lla , R ^llb , k and n are as described herein.

[00062] Some embodiments provide a compound of Formula (lb’): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^x , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^lla , R ^llb , k and n are as described herein.

[00063] Some embodiments provide a compound of Formula (Tc): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^x , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , k and n are as described herein.

[00064] Some embodiments provide a compound of Formula (Ic’): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^x , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , k and n are as described herein.

[00065] Some embodiments provide a compound of Formula (Ic”): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^x , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , k and n are as described herein.

[000661 Some embodiments provide a compound of Formula (Ic” ’): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ¹ , R ⁴ , R ⁵ , R ⁶ , and R ¹¹ , are as described herein.

[00067] Some embodiments provide a compound of Formula (Id):

R ⁶ , k and n are as described herein.

[00068] Some embodiments provide a compound of Formula (Id’):

or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^x , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , k and n are as described herein.

[00069] Some embodiments provide a compound of Formula (le): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^x , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , k and n are as described herein.

[00070] Some embodiments provide a compound of Formula (le’): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^x , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , k and n are as described herein.

[00071] Some embodiments provide a compound of Formula (le”): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^x , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , k and n are as described herein.

[00072] In some embodiments, are each independently N, CH or CR ^X ; and X ² is O, S, N or CR ^X , provided X ¹ , X ² , X ³ , and X ⁴ are not all N and when X ² is O, m is 0 and X ³ is N, and when X ² is S, m is 0; and R ¹ is as described in herein.

[00073] herein.

[00074] are each independently N, CH or CR ^X ; and R ¹ is as described herein. is as described herein.

[00077] In some embodiments, independently N, CH or CR ^X ; X ² is O, S, N, provided when X ² is O, then X ³ is N; and R ¹ is as described herein.

[00078] In some embodiments, and R ^x are as described herein.

[00079] In some embodiments, herein.

[00080] In some embodiments, independently N, CH or CR ^X ; X ² is O, S, N, provided when X ² is O, then X ³ is N; and R ¹ and R ^x are as described herein.

[00081] In some embodiments, Ring A is 5- or 6-membered heteroaryl and R ¹ is -R ^V -C(O)OR ⁷ ; and R ^v and R ⁷ are as described herein. [00082] Embodiment 35: The compound of any one of embodiments 1 to 4 and 14 to 26, wherein are each independently N, CH or CR ^X ; X ² is

O, S, N, provided when X ² is O, then X ³ is N; and R ¹ and R ^x are as described herein.

[00083] In some embodiments, p is 1.

[00084] In some embodiments, R ¹ is -R ^V OR ⁷ , -R ^V NR ^S R ⁹ , -R ^V NR ⁸ C(O)R ¹⁰ , -R ^V NR ⁸ C(O)OR ¹⁰ , -R ^V NR ⁸ C(O)NR ⁸ R ⁹ , -R ^v NR ⁸ S(O)tR ¹⁰ or -R ^v S(O)tR ¹⁰ or -R ^v S(O)tNR ⁸ R ⁹ ; and R ^v , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and t are as described herein.

[00085] In some embodiments, R ¹ is -R ^V OR ⁷ ; and R ^v and R ⁷ are as described herein.

[00086] In some embodiments, R ¹ is -R ^V OR ⁷ or -R ^V C(O)NR ⁸ R ⁹ ; and R ^v , R ⁷ , R ⁸ and R ⁹ are as described herein. some embodiments, R ¹ NR ⁸ C(O)R ¹⁰ , -R ^V NR ⁸ C(O)OR ¹⁰ , -R ^V NR ⁸ C(O)NR ⁸ R ⁹ or -R ^v NR ⁸ S(O)tR ¹⁰ ; and R ^v , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and t are as described herein.

[00088] In some embodiments, R ¹ is -R ^v S(O)tR ¹⁰ or -R ^v S(O)tNR ⁸ R ⁹ ; and R ^v , R ⁸ , R ⁹ , R ¹⁰ and t are as described herein.

[00089] In some embodiments, R ¹ is -R ^V C(O)NR ⁸ R ⁹ ; and R ^v , R ⁸ and R ⁹ are as described herein.

[00090] In some embodiments, R ¹ is - R ^V CN or -R ^V -C(O)OR ⁷ ; and R ^v and R ⁷ are as described herein.

[00091] In some embodiments, R ^x is -R'-Cs-ecycloalkyl, -R ^v -4- to 6-membered heterocyclyl or -R ^v -5-to 6-membered heteroaryl; and R ^v is as described herein.

[00092] In some embodiments, R ^v is either absent, or -C(R ^a )(R ^b )-, wherein R ^a and R ^b are each independently hydrogen, C _1-3 alkyl or haloC _1-3 alkyl; or R ^a and R ^b , together with the carbon atom to which they are attached, form C3-ecycloalkyl or 3- to 6-membered heterocyclyl wherein the cycloalkyl or heterocyclyl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; and R ¹² and R ^12a are as described herein.

[00093] In some embodiments, R ^v is either absent, or -C(R ^a )(R ^b )-, wherein R ^a and R ^b are each independently hydrogen, C _1-3 alkyl or haloC _1-3 alkyl.

[00094] In some embodiments, R ^v is absent. [00095] In some embodiments, R ^u is absent or a linker having the formula -C(R ^a )(R ^b )-, wherein R ^a and R ^b are each independently hydrogen, C _1-3 alkyl or haloC _1-3 alkyl, or R ^a and R ^b , together with the carbon atom to which they are attached, form Cs-ecycloalkyl or 3- to 6-membered heterocyclyl wherein the cycloalkyl or heterocyclyl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; and R ¹² and R ^12a are as described herein.

[00096] In some embodiments, R ^u is absent or a methylene linker, or R ^a and R ^b , together with the carbon atom to which they are attached, form cyclobutyl or oxetanyl.

[00097] In some embodiments, R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl; R ⁵ is halo, C _1-3 alkyl, C _3-5 cycloalkyl, haloC _1-3 alkyl, haloC _1-3 alkoxy or C _1-3 alkoxy wherein the C3- scycloalkyl is optionally substituted with one, two or three groups each independently selected from halo, deutero, cyano, C _1-3 alkyl or hydroxyl; and R ⁶ is halo, cyano, C _1-3 alkyl, C _3-5 cycloalkyl, haloC _1-3 alkyl, C _1-3 alkoxy or haloC _1-3 alkoxy.

[00098] In some embodiments, R ⁴ is hydrogen or methyl; R ⁵ is bicyclo[l.l.l]pentanyl, cyclopropyl or methoxy and R ⁶ is methyl.

[00099] In some embodiments, R ⁴ is hydrogen or methyl; R ⁵ is cyclopropyl or methoxy and R ⁶ is methyl.

[000100] In some embodiments, R ⁴ is hydrogen; R ⁵ is methoxy and R ⁵ is methyl.

[000101] In some embodiments, R ⁴ is hydrogen; R ⁵ is bicyclo[l. l.l]pentanyl and R ⁶ is methyl.

[000102] In some embodiments, R ⁴ is hydrogen; R ⁵ is cyclopropyl and R ⁶ is methyl.

[000103] In some embodiments, each R ¹¹ , R ^lla and R ^llb is independently halo, cyano, haloCi- salkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, hydroxyl, C _1-3 alkoxy or haloC _1-3 alkoxy.

[000104] In some embodiments, ach R ¹¹ , R ^lla and R ^llb is independently halo, cyano, or haloC _1-3 alkyl or hydroxyl.

[000105] In some embodiments, each R ¹¹ , R ^lla and R ^llb is independently fluoro, cyano, oxo, hydroxyl, methyl, CHF2, CF3 or -OCHF2, or two R ¹¹ groups, together with the carbon atom to which they are attached, form cyclobutyl or oxo.

[000106] In some embodiments, each R ¹¹ , R ^lla and R ^llb is independently halo, cyano, haloCi- salkyl, haloC _1-3 alkoxy or C _1-3 alkylsulfonyl; or two R ¹¹ groups, together with the carbon atom to which they are attached, form Ca-scycloalkyl. [000107] In some embodiments, each R ¹¹ , R ^lla and R ^llb is independently fluoro, cyano, -CF3, -CHF2, -OCF3 or S(O) ₂ CH ₃ or two R ¹¹ groups, together with the carbon atom to which they are attached, form cyclopropyl.

[000108] In certain embodiments, provided herein are compounds of Formula (V):

Ring A is a phenyl or 5- or 6-membered heteroaryl;

R ^x is halo, hydroxyl, C _1-3 alkyl, haloC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxy or haloCi- salkoxy;

R ^2a is -NR ¹⁵ R ¹⁶ and R ^2b is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl; or

R ^2a and R ^2b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein the C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl is substituted with one, two or three groups each independently selected from R ¹¹ , R ^lla and R ^llb ;

R ³ is halo, cyano, C _1-3 alkyl, or haloC _1-3 alkyl;

R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl;

R ⁵ is -R ^w -halo, -R ^w cyano-, -R ^w -C _1-3 alkyl, -R ^w -deuteroC _1-3 alkyl, -R ^w -haloC _1-3 alkyl, -R ^w - cyanoC _1-3 alkyl, -R ^w -hydroxyC _1-3 alkyl, Cs-scycloalkyl, 3- to 5-membered heterocyclyl, deuteroCs- scycloalkyl, -R ^W -OH, -R ^w -O-C _1-3 alkyl or -R ^w -S-C _1-3 alkyl, wherein the C _3-5 cycloalkyl, 3- to 5- membered heterocyclyl, C _1-3 alkyl of -R ^w -OC _1-3 alkyl or C _1-3 alkyl of -R ^w -S-C _1-3 alkyl, is optionally substituted with one to seven groups each independently selected from halo, deutero, cyano, Ci- 3alkyl, haloC _1-3 alkyl or hydroxyl;

R ⁶ is halo, cyano, C _1-3 alkyl, C _3-5 cycloalkyl, haloC _1-3 alkyl, C _1-3 alkoxy or haloC _1-3 alkoxy;

R ⁸ is hydrogen, C _1-6 alkyl, haloC _1-6 alkyl, or -R ^u -3- to 12-membered heterocyclyl; R ⁹ is hydrogen, -R ^u -C _1-6 alkyl, -R ^u haloCi -ealkyl, -R ^u cyanoC _1-6 alkyl, -R ^U COOR ¹³ , -R ^u -C3- locycloalkyl, -R ^u -3- to 12-membered heterocyclyl, -R ^u -6-membered aryl or -R ^u -5- to 6-membered heteroaryl, wherein the Cs-iocycloalkyl, 3- to 12-membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl of -R ^u -C3-iocycloalkyl, -R ^u -3- to 12- membered heterocyclyl, -R ^u -6- membered aryl or -R ^u -5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; or

R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, form 3- to 12- membered heterocyclyl (e.g., 3- to 6- membered heterocyclyl) or 5- to 6-membered heteroaryl wherein the 3- to 12-membered heterocyclyl or 5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; or

R ⁸ is hydrogen, alkyl, or haloalkyl, and R ⁹ and R ^x adjacent to -C(O)NR ⁸ N ⁹ , together form a 5- to 6-membered heterocyclyl group optionally substituted with one, two or three groups each independently selected from R ⁿ , R ^iia and R ^lib ; each R ¹¹ , R ^lla , R ^llb and R ¹² is independently halo, cyano, oxo, hydroxyl, amino, C _1-3 alkyl, deuteroC _1-3 alkyl, haloC _1-3 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloCi- 3alkoxyC _1-3 alkyl, hydroxyl, C _1-3 alkoxy, haloC _1-3 alkoxy, -C(O)OR ¹³ , -C(O)R ¹⁴ , C _1-3 alkyloxy, Ci- salkylthio, haloC _1-3 alkylthio, haloC _1-3 alkoxy, C _1-3 alkylsulfonyl, haloC _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl, or haloC _1-3 alkylsulfinyl; or two R ¹¹ groups or two R ¹² groups, together with the carbon atom to which they are attached, form Cs-scycloalkyl, 3- to 6- membered heterocyclyl or oxo, wherein the C _3-5 cycloalkyl or 3- to 6- membered heterocyclyl is optionally substituted with 1 or 2 independently selected halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl; each R ^12a is independently C _1-3 alkyl, deuteroC _1-3 alkyl, haloC _1-3 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, -C(0)0R ¹³ , -Ci- 3alkylC(O)OR ¹³ , -C(0)R ¹⁴ , C _3-5 cycloalkyl, C _1-3 alkylsulfonyl, haloC _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl, haloC _1-3 alkylsulfinyl, 3- to 6- membered heterocyclyl, 6-membered aryl, or 5- to 6-membered heteroaryl, wherein the 3- to 6- membered heterocyclyl, 6-membered aryl, and 5- to 6-membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from halo, cyano, C _1-3 alkyl, and haloC _1-3 alkyl; each R ¹³ is independently hydrogen, C _1-6 alkyl, deuteroC _1-3 alkyl, haloC _1-6 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, C _3-6 cycloalkylCi- salkyl, 3- to 6-membered heterocyclyl C _1-3 alkyl, 6-membered arylC _1-3 alkyl or 5- to 6-membered heteroaryl C i -3 alky 1 ; each R ¹⁴ is independently Ci-6alkyl, deuteroC _1-3 alkyl, haloC _1-6 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, Cs-ecycloalkylC _1-3 alkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6-membered arylC _1-3 alkyl or 5- to 6-membered heteroaryl C i -3 alky 1 ;

R ¹⁵ is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl;

R ¹⁶ is C _3-6 cycloalkyl optionally substituted with one, two or three groups each independently selected from R ⁿ , R ^lla and R ^llb ; each R ^u and R ^v is independently absent or a linker having the formula -(CR ^c R ^d ) _z -C(R ^a )(R ^b )- (CR ^c R ^d ) _z wherein R ^a and R ^b are each independently hydrogen, halo, amino, C _1-3 alkyl, haloCi- salkyl, C _1-3 alkoxyC _1-3 alkyl, Cs-scycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, C _3-6 cycloalkylC _1-3 alkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6- membered arylC _1-3 alkyl or 5- to 6-membered heteroarylC _1-3 alkyl, or R ^a and R ^b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl wherein the cycloalkyl or heterocyclyl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ;

R ^c and R ^d are each independently hydrogen, C _1-3 alkyl, or haloC _1-3 alkyl;

R ^w is either absent or is methylene, ethylene, propylene, butylene, cyclopropylene, cyclobutylene, optionally substituted with one to three groups each independently selected from halo, cyano or hydroxyl; k is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and each z is independently 0, 1 or 2.

[000109] In some embodiments, provided herein are compounds of of Formula (V), wherein:

Ring A is a phenyl or 5- or 6-membered heteroaryl;

R ^x is halo, hydroxyl, C _1-3 alkyl, haloC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxy or haloCi- 3alkoxy; R ^2a is -NR ¹⁵ R ¹⁶ and R ^2b is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl; or

R ^2a and R ^2b , together with the carbon atom to which they are attached, form C3-ecycloalkyl or 3- to 6-membered heterocyclyl, wherein the C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl is substituted with one, two or three groups each independently selected from R ¹¹ , R ^lla and R ^llb ;

R ³ is halo, cyano, C _1-3 alkyl, or haloC _1-3 alkyl;

R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl;

R ⁵ is -R ^w -halo, -R ^w cyano-, -R ^w -C _1-3 alkyl, -R ^w -deuteroC _1-3 alkyl, -R ^w -haloC 1-3 alkyl, -R ^w - cyanoC _1-3 alkyl, -R ^w -hydroxyC _1-3 alkyl, C _3-5 cycloalkyl, 3- to 5-membered heterocyclyl, deuteroC3- scycloalkyl, -R ^W -OH, -R ^w -O-C _1-3 alkyl or -R ^w -S-C _1-3 alkyl, wherein the C _3-5 cycloalkyl, 3- to 5- membered heterocyclyl, C _1-3 alkyl of -R ^w -OC _1-3 alkyl or C _1-3 alkyl of -R ^w -S-C _1-3 alkyl, is optionally substituted with one to seven groups each independently selected from halo, deutero, cyano, Ci- salkyl, haloC _1-3 alkyl or hydroxyl;

R ⁶ is halo, cyano, C _1-3 alkyl, C _3-5 cycloalkyl, haloC _1-3 alkyl, C _1-3 alkoxy or haloC _1-3 alkoxy;

R ⁸ is hydrogen, C _1-6 alkyl, or haloC _1-6 alkyl; and R ⁹ is hydrogen, -R ^u -C _1-6 alkyl, -R ^u haloCi- 6alkyl, -R"cyanoCi-6alkyl, -R"COOR ¹³ , -R ^u -C _3-6 cycloalkyl, -R"-3- to 6-membered heterocyclyl, -R ^u -6-membered aryl or -R ^u -5- to 6-membered heteroaryl, wherein the C3- ecycloalkyl, 3- to 6-membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl of -R ^u -C _3-6 cycloalkyl, -R ^u -3- to 6- membered heterocyclyl, -R ^u -6-membered aryl or -R ^u -5- to 6- membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; or

R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, form 3- to 12- membered heterocyclyl or 5- to 6-membered heteroaryl wherein the 3- to 12-membered heterocyclyl or 5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; or

R ⁸ is hydrogen, alkyl, or haloalkyl, and R ⁹ and R ^x adjacent to -C(O)NR ⁸ N ⁹ , together form a heterocyclyl group optionally substituted with one, two or three groups each independently selected from R ¹¹ , R ^lla and R ^llb ; each R ¹¹ , R ^lla , R ^llb and R ¹² is independently halo, cyano, oxo, hydroxyl, amino, Ci- salkyl, deuteroC _1-3 alkyl, haloC _1-3 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, hydroxyl, C _1-3 alkoxy, haloC _1-3 alkoxy, -C(O)OR ¹³ , -C(O)R ¹⁴ , Ci- salkyloxy, C _1-3 alkylthio, haloC _1-3 alkylthio, haloC _1-3 alkoxy, C 1-3 alkyl sulfonyl, haloC _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl, or haloC _1-3 alkylsulfinyl; or two R ¹¹ groups or two R ¹² groups, together with the carbon atom to which they are attached, form C _3-5 cycloalkyl, 3- to 6- membered heterocyclyl or oxo, wherein the C _3-5 cycloalkyl or 3- to 6- membered heterocyclyl is optionally substituted with 1 or 2 independently selected halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl; each R ^12a is independently C _1-3 alkyl, deuteroC _1-3 alkyl, haloC _1-3 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, -C(O)OR ¹³ , -C(O)R ¹⁴ , C3- scycloalkyl, C _1-3 alkylsulfonyl, haloC _1-3 alkylsulfonyl, C _1-3 alkylsulfinyl, or haloC _1-3 alkylsulfinyl; each R ¹³ is independently hydrogen, Ci-6alkyl, deuteroCi -3alkyl, haloCi-6alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, C _3-6 cycloalkylCi- 3alkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6-membered arylC _1-3 alkyl or 5- to 6-membered heteroaryl C 1 -3 alky 1 ; each R ¹⁴ is independently Ci-6alkyl, deuteroC _1-3 alkyl, haloC _1-6 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, C _3-6 cycloalkylC _1-3 alkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6-membered arylC _1-3 alkyl or 5- to 6-membered heteroaryl C 1 -3 alky 1 ;

R ¹⁵ is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl;

R ¹⁶ is C _3-6 cycloalkyl optionally substituted with one, two or three groups each independently selected from R ⁿ , R ^lla and R ^llb ; each R ^u and R ^v is independently absent or a linker having the formula -(CR ^c R ^d ) _z -C(R ^a )(R ^b )- (CR ^c R ^d ) _z wherein R ^a and R ^b are each independently hydrogen, halo, amino, C _1-3 alkyl, haloCi- salkyl, C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, C _3-6 cycloalkylC _1-3 alkyl, 3- to 6-membered heterocyclylC _1-3 alkyl, 6-membered arylC _1-3 alkyl or 5- to 6-membered heteroarylC _1-3 alkyl, or R ^a and R ^b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl wherein the cycloalkyl or heterocyclyl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ;

R ^c and R ^d are each independently hydrogen, C _1-3 alkyl, or haloC _1-3 alkyl; R ^w is either absent or is methylene, ethylene, propylene, butylene, cyclopropylene, cyclobutylene, optionally substituted with one to three groups each independently selected from halo, cyano or hydroxyl; k is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and each z is independently 0, 1 or 2.

[000110] In some embodiments, R ^2a and R ^2b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein the C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl is substituted with one, two or three groups each independently selected from R ¹¹ , R ^lla and R ^llb , wherein R ¹¹ , R ^lla and R ^llb are as described herein.

[000111] In some embodiments, R ^2a is -NR ¹⁵ R ¹⁶ and R ^2b is hydrogen, deuterium, halogen, Ci- salkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl; R ¹⁵ is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl; and R ¹⁶ is C _3-6 cycloalkyl optionally substituted with one, two or three groups each independently selected from R ¹¹ , R ^lla and R ^llb , wherein R ¹¹ , R ^lla and R ^llb are as described herein.

[000112] Some embodiments provide a compound of Formula (V’): or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3 or 4; and Ring A, R ^v , R ^x , R ^2a ' R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ and k are as described herein.

[000113] Some embodiments provide a compound of Formula (Va):

or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; X ¹ , X ³ and X ⁴ are each independently N, CH or CR ^X ; and X ² is O, S, N or CR ^X , provided X ¹ , X ² , X ³ , and X ⁴ are not all N and when X ² is O, m is 0 and X ³ is N and when X ² is S, m is 0; and Ring A, R ^v , R ^x , R ^2a R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ and k are as described herein.

[000114] Some embodiments provide a compound of Formula (Va’): or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; X ¹ , X ³ and X ⁴ are each independently N, CH or CR ^X ; and X ² is O, S, N or CR ^X , provided X ¹ , X ² , X ³ , and X ⁴ are not all N and when X ² is O, m is 0 and X ³ is N and when X ² is S, m is 0; and Ring A, R ^v , R ^x , R ^2a ’ R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ and k are as described herein. [000115] Some embodiments provide a compound of Formula (Vb): or CR ^X ; and Ring A, R ^v , R ^x , R ^2a R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ and k are as described herein.

[000116] Some embodiments provide a compound of Formula (Vb’): or a pharmaceutically acceptable salt thereof, wherein X ¹ and X ² are each independently N, CH or CR ^X ; R ^v , R ^2a R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ and k are as described herein.

[000117] Some embodiments provide a compound of Formula (Vc): or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2; q is 1, 2 or 3 and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹¹ , k and n are as described herein.

[0001181 Some embodiments provide a compound of Formula (Vc’): or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2; q is 1, 2 or 3 and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹¹ , k and n are as described herein.

[000119] Some embodiments provide a compound of Formula (Vc’ ’): or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2; q is 1, 2 or 3 and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ , k and n are as described herein; and wherein ring C is 3- to 12-membered heterocyclyl or 5- to 6-membered heteroaryl each optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a . [000120] Some embodiments provide a compound of Formula (Vd): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ^lla , R ^llb , k and n are as described herein.

[000121] Some embodiments provide a compound of Formula (Vd’): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ^lla , R ^llb , k and n are as described herein.

[000122] Some embodiments provide a compound of Formula (Vd”): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ^lla , R ^llb , k and n are as described herein.

[000123] Some embodiments provide a compound of Formula (Ve): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹¹ , k and n are as described herein.

[000124] Some embodiments provide a compound of Formula (Ve’): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹¹ , k and n are as described herein.

[000125] Some embodiments provide a compound of Formula (Vf): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , k and n are as described herein.

[000126] Some embodiments provide a compound of Formula (Vf ): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , k and n are as described herein.

[000127] Some embodiments provide a compound of Formula (Vg): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , k and n are as described herein.

[0001281 Some embodiments provide a compound of Formula (Vg’): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , k and n are as described herein.

[000129] Some embodiments provide a compound of Formula (V”): or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2; and Ring A, R ^v , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , k and n are as described herein.

[000130] Some embodiments provide a compound of Formula (VI): or a pharmaceutical salt thereof, wherein Ring B is C _3-6 cycloalkyl, 3- to 6-membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and Ring A, R ^u , R ^x , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹² and k are as described herein.

[000131] Some embodiments provide a compound of Formula (VI’): or a pharmaceutically acceptable salt thereof, wherein Ring B is Cs-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and Ring A, R ^u , R ^x , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹² and k are as described herein.

[000132] Some embodiments provide a compound of Formula (Vic): or a pharmaceutically acceptable salt thereof, wherein Ring B is C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 0, 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein.

[000133] Some embodiments provide a compound of Formula (Vic’): or a pharmaceutically acceptable salt thereof, wherein Ring B is Cs-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 0, 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein. [000134] Some embodiments provide a compound of Formula (Vid): or a pharmaceutically acceptable salt thereof, wherein Ring B is Cs-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ^lla ,R ^llb , R ¹² and k are as described herein.

[000135] Some embodiments provide a compound of Formula (Vid’): or a pharmaceutically acceptable salt thereof, wherein Ring B is Cs-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1 or 2 and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ^lla ,R ^llb , R ¹² and k are as described herein. [000136] Some embodiments provide a compound of Formula (Vid”): or a pharmaceutically acceptable salt thereof, wherein Ring B is Cs-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ^lla ,R ^llb , R ¹² and k are as described herein. [000137] Some embodiments provide a compound of Formula (Vie): or a pharmaceutically acceptable salt thereof, wherein Ring B is Cs-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1 or 2 and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein. [000138] Some embodiments provide a compound of Formula (VTe’) or a pharmaceutically acceptable salt thereof, wherein Ring B is C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein.

[000139] Some embodiments provide a compound of Formula (Vie”): or a pharmaceutically acceptable salt thereof, wherein Ring B is Cs-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3, n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein. [000140] Some embodiments provide a compound of Formula (Vie”’): or a pharmaceutically acceptable salt thereof, wherein Ring B is C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein.

[000141] Some embodiments provide a compound of Formula (VIf): or a pharmaceutically acceptable salt thereof, wherein Ring B is C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein. [000142] Some embodiments provide a compound of Formula (VTf ): or a pharmaceutically acceptable salt thereof, wherein Ring B is Cs-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein. [000143] Some embodiments provide a compound of Formula (VIg): or a pharmaceutically acceptable salt thereof, wherein Ring B is Cs-ecycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4 and p is 1 or 2.

[000144] Some embodiments provide a compound of Formula (VTg’): or a pharmaceutically acceptable salt thereof, wherein Ring B is C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹² and k are as described herein.

[000145] Some embodiments provide a compound of Formula (VIg”): or a pharmaceutically acceptable salt thereof, wherein Ring B is C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹² and k are as described herein.

[000146] Some embodiments provide a compound of Formula (VIg’”): or a pharmaceutically acceptable salt thereof, wherein Ring B is C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹² and k are as described herein.

[000147] Some embodiments provide a compound of Formula (VII): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹² and k are as described herein.

[000148] Some embodiments provide a compound of Formula (VTT’): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹² and k are as described herein.

[000149] Some embodiments provide a compound of Formula (Vile): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1 or 2; q is 1, 2 or 3; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein.

[000150] Some embodiments provide a compound of Formula (VTTc’): described herein.

[000151] Some embodiments provide a compound of Formula (Vlld): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ^lla , R ^llb , R ¹² and k are as described herein.

[000152] Some embodiments provide a compound of Formula (VTTd’): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ^lla , R ^llb , R ¹² and k are as described herein.

[000153] Some embodiments provide a compound of Formula (Vlld”): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ^lla , R ^llb , R ¹² and k are as described herein.

[000154] Some embodiments provide a compound of Formula (Vile):

1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein.

[000155] Some embodiments provide a compound of Formula (Vile’): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 1 or 2 and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein.

[000156] Some embodiments provide a compound of Formula (VTTe”): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0,

1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein.

[000157] Some embodiments provide a compound of Formula (Vile’”): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0,

1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ , R ¹² and k are as described herein.

[000158] Some embodiments provide a compound of Formula (Vllf): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^12a and k are as described herein. [0001591 Some embodiments provide a compound of Formula (Vllf ): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^12a and k are as described herein.

[000160] Some embodiments provide a compound of Formula (Vllg): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^12a and k are as described herein.

[000161] Some embodiments provide a compound of Formula (VTTg’): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^12a and k are as described herein. [000162] Some embodiments provide a compound of Formula (Vllg”): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^12a and k are as described herein.

[000163] Some embodiments provide a compound of Formula (Vllg’”): or a pharmaceutically acceptable salt thereof, wherein Y is O, NH or NR ^12a ; j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^12a and k are as described herein. [000164] Some embodiments provide a compound of Formula (VIII): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^12a and k are as described herein.

[000165] Some embodiments provide a compound of Formula (VIII’): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^l2a and k are as described herein.

[000166] Some embodiments provide a compound of Formula (VlIIc):

or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹¹ , R ¹² , R ^12a and k are as described herein.

[000167] Some embodiments provide a compound of Formula (VIIIc’): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹¹ , R ¹² , R ^12a and k are as described herein.

[000168] Some embodiments provide a compound of Formula (Vllld): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1 , 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ^lla , R ^llb , R ¹² , R ^12a , and k are as described herein.

[000169] Some embodiments provide a compound of Formula (Vllld’): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2 and n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ^lla , R ^llb , R ¹² , R ^12a and k are as described herein.

[000170] Some embodiments provide a compound of Formula (Vllld”): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ^lla , R ^llb , R ¹² , R ^12a and k are as described herein.

[000171] Some embodiments provide a compound of Formula (Ville):

or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹¹ , R ¹² , R ^12a and k are as described herein.

[000172] Some embodiments provide a compound of Formula (Ville’): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹¹ , R ¹² , R ^12a and k are as described herein.

[000173] Some embodiments provide a compound of Formula (Ville”): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1 , 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹¹ , R ¹² , R ^12a and k are as described herein.

[000174] Some embodiments provide a compound of Formula (Ville’”): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹¹ , R ¹² , R ^12a and k are as described herein.

[000175] Some embodiments provide a compound of Formula (Vlllf): (Vlllf) or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^12a and k are as described herein.

[000176] Some embodiments provide a compound of Formula (Vlllf):

or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^12a and k are as described herein.

[000177] Some embodiments provide a compound of Formula (Vlllg): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ⁱ² , R ^12a and k are as described herein.

[000178] Some embodiments provide a compound of Formula (Vlllg’): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1 , 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^12a and k are as described herein.

[0001791 Some embodiments provide a compound of Formula (Vlllg”): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^12a and k are as described herein.

[000180] Some embodiments provide a compound of Formula (Vlllg’”): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ ,R ⁸ , R ¹² , R ^12a and k are as described herein.

[000181] Some embodiments provide a compound of Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; and Ring A, R ^u , R ^x , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and k are as described herein.

[000182] Some embodiments provide a compound of Formula (IX’): or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; and Ring A, R ^u , R ^x , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and k are as described herein.

[000183] Some embodiments provide a compound of Formula (IXc):

or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; p is 0, 1 or 2; q is 1, 2 or 3; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ and k are as described herein.

[000184] Some embodiments provide a compound of Formula (IXc’): or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; p is 0, 1, or 2; q is 1, 2 or 3; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ and k are as described herein.

[000185] Some embodiments provide a compound of Formula (IXd):

or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ^lla , R ^llb and k are as described herein.

[000186] Some embodiments provide a compound of Formula (IXd’): or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ^lla , R ^llb and k are as described herein.

[000187] Some embodiments provide a compound of Formula (IXd”):

or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ^lla , R ^llb and k are as described herein.

[000188] Some embodiments provide a compound of Formula (IXe): or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ and k are as described herein.

[000189] Some embodiments provide a compound of Formula (IXe’):

or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ and k are as described herein.

[000190] Some embodiments provide a compound of Formula (IXe”): or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ and k are as described herein.

[000191] Some embodiments provide a compound of Formula (IXe’”):

or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ¹¹ and k are as described herein.

[000192] Some embodiments provide a compound of Formula (IXf): or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and k are as described herein.

[000193] Some embodiments provide a compound of Formula (IXf):

or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and k are as described herein.

[000194] Some embodiments provide a compound of Formula (IXg): or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and k are as described herein.

[000195] Some embodiments provide a compound of Formula (IXg’):

or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and k are as described herein.

[000196] Some embodiments provide a compound of Formula (IXg”): or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and k are as described herein.

[000197] Some embodiments provide a compound of Formula (IXg’”):

or a pharmaceutically acceptable salt thereof, wherein Py is pyridinonyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; n is 0, 1, 2, 3 or 4; p is 1 or 2; and Ring A, R ^u , R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ and k are as described herein.

[000198] In some embodiments,

[000199] In some embodiments,

[000200] In some embodiments,

[000201] Some embodiments provide a compound of Formula (Xc): or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2, j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1 or 2; q is 1, 2 or 3; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ and R ¹² are as described herein. [000202] Some embodiments provide a compound of Formula (Xd):

or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and Ring A, k, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^lla , R ^llb and R ¹² are as described herein.

[000203] Some embodiments provide a compound of Formula (Xe): or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and Ring A, k, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ and R ¹² are as described herein.

[000204] Some embodiments provide a compound of Formula (Xe’): or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2; j is 0, 1 , 2 or 3; n is 0, 1 , 2, 3 or 4; and Ring A, k, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ and R ¹² are as described herein.

[0002051 Some embodiments provide a compound of Formula (Xe”): or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and Ring A, k, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ and R ⁱ² are as described herein.

[000206] Some embodiments provide a compound of Formula (Xe’”): or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and Ring A, k, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ and R ¹² are as described herein.

[000207] Some embodiments provide a compound of Formula (Xf):

or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and Ring A, k, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ and R ¹² are as described herein.

[000208] Some embodiments provide a compound of Formula (Xg): or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and Ring A, k, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ¹² are as described herein.

[000209] Some embodiments provide a compound of Formula (Xg’): or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2; j is 0, 1 , 2 or 3; n is 0, 1 , 2, 3 or 4; and Ring A, k, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ¹² are as described herein.

[0002101 Some embodiments provide a compound of Formula (Xg”):

4; and Ring A, k, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹² are as described herein.

[000211] Some embodiments provide a compound of Formula (Xg’”): or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2; j is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; and Ring A, k, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ¹² are as described herein.

[000212] In some embodiments, two R ¹² groups, together with the carbon atom to which they are attached, form Ca-scycloalkyl, 3- to 6- membered heterocyclyl or oxo, wherein the C3- scycloalkyl or 3- to 6- membered heterocyclyl is optionally substituted with 1 or 2 independently selected halo, cyano, C _1-3 alkyl haloC _1-3 alkyl. In some embodiments, two R ⁱ² groups, together with the carbon atom to which they are attached, form 3- to 6- membered heterocyclyl, wherein the 3- to 6- membered heterocyclyl is optionally substituted with 1 or 2 independently selected halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl. [000213] Some embodiments provide a compound of Formula (XIc): or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2; j is 0, 1, 2 or 3; j’ is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; p is 1 or 2; q is 1, 2 or 3; X’ is NH, NR ^12a , O, CH ₂ , or CHR ^12a ; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ and R ¹² are as described herein.

[000214] Some embodiments provide a compound of Formula (Xie): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1, 2 or 3; j’ is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; X ⁵ is NH, NR ^12a , O, CH ₂ , or CHR ^12a ; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ and R ¹² are as described herein.

[000215] Some embodiments provide a compound of Formula (Xie’): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1, 2 or 3; j’ is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; X ⁵ is NH, NR ^12a , O, CH ₂ , or CHR ^12a ; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁵ , R ¹¹ and R ¹² are as described herein.

[000216] Some embodiments provide a compound of Formula (Xie”): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1, 2 or 3; j’ is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; X ⁵ is NH, NR ^12a , O, CH ₂ , or CHR ^12a ; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹¹ and R ¹² are as described herein.

[000217] Some embodiments provide a compound of Formula (Xie’”):

or a pharmaceutically acceptable salt thereof, wherein j is 0, 1, 2 or 3; j’ is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; X ⁵ is NH, NR ^12a , O, CH ₂ , or CHR ^12a ; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁵ , R ¹¹ and R ¹² are as described herein.

[000218] Some embodiments provide a compound of Formula (Xlg): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1, 2 or 3; j’ is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; X ⁵ is NH, NR ^12a , O, CH ₂ , or CHR ^12a ; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ¹² are as described herein.

[000219] Some embodiments provide a compound of Formula (Xlg’):

or a pharmaceutically acceptable salt thereof, wherein j is 0, 1, 2 or 3; j’ is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; X ⁵ is NH, NR ^12a , O, CH ₂ , or CHR ^12a ; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁵ , and R ¹² are as described herein.

[000220] Some embodiments provide a compound of Formula (Xlg”): or a pharmaceutically acceptable salt thereof, wherein j is 0, 1, 2 or 3; j’ is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; X ⁵ is NH, NR ^12a , O, CH ₂ , or CHR ^12a ; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ¹² are as described herein.

[000221] Some embodiments provide a compound of Formula (Xlg’”):

or a pharmaceutically acceptable salt thereof, wherein j is 0, 1, 2 or 3; j’ is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4; X ⁵ is NH, NR ^12a , O, CH ₂ , or CHR ^12a ; and Ring A, R ^x , R ³ , R ⁴ , R ⁵ , R ⁵ , and R ¹² are as described herein.

[000222] In some embodiments, X ⁵ is NH, NR ^12a , O, or CHR ^12a . In some embodiments, X ⁵ is NH or NR ^12a . In some embodiments, X ⁵ is NR ^12a In some embodiments, X ⁵ is NR ^12a , and R ^12a is C _1-3 alkyl.

[000223] In some embodiments, R ^12a is C _1-3 alkyl, -C(O)OR ¹³ , or C _3-5 cycloalkyl.

[000224] In some embodiments, R ⁵ is C _3-5 cycloalkyl or -R ^w -O-C _1-3 alkyl. In some embodiments, R ⁵ is cyclopropyl, cyclobutyl, or methoxy. In some embodiments, R ⁵ is cyclopropyl.

[000225] In some embodiments, X ⁵ is NH, NR ^12a , O, or CHR ^12a ; R ¹¹ is halo or cyano; R ^12a is C _1-3 alkyl, -C(O)OR ¹³ , or Cs-scycloalkyl; and R ⁵ is C _3-5 cycloalkyl or -R ^w -O-C _1-3 alkyl.

[000226] In some embodiments, wherein m is 0 or 1; X ¹ , X ³ and X ⁴ are each independently N, CH or CR ^X ; and X ² is O, S, N or CR ^X , provided X ¹ , X ² , X ³ , and X ⁴ are not all N and when X ² is O, m is 0 and X ³ is N and when X ² is S, m is 0; and R ^v , R ⁸ and R ⁹ are as described herein. [000227] In some embodiments, wherein X ¹ and X ² are each independently N, CH or CR ^X ; and R ^v , R ^X ,R ⁸ and R ⁹ are as described herein.

[000228] In some embodiments,

, wherein X ¹ is CH or CR ^X and R ^v , R ⁸ and R ⁹ are as described herein.

[000229] In some embodiments, wherein Y is O, NH or NR ^i2a ; j is 0, 1 or 2; and R ⁸ , R ⁱ² and R ^i2a are as described herein.

[000230] In some embodiments,

0 or 1 and R ⁸ , R ¹² and R ^12a are as described herein.

[000231] In some embodiments, Ring A is phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionally substituted with halo, hydroxyl, C _1-3 alkyl, haloCi-aalkyl, hydroxyCi- salkyl, C _1-3 alkoxy or haloC _1-3 alkoxy.

[000232] In some embodiments, R ⁸ is hydrogen, C _1-3 alkyl or haloC _1-6 alkyl and R ⁹ is - R ^U C(O)OR ¹³ ; and R ^u and R ¹³ are as described herein.

[000233] In some embodiments, R ⁸ is hydrogen, C _1-3 alkyl or haloC _1-6 alkyl; R ⁹ is - R ^U C(O)OR ¹³ ; R ^u is a linker having the formula -C(R ^a )(R ^b )- wherein R ^a and R ^b are each independently hydrogen, halo, C _1-3 alkyl, haloC _1-3 alkyl, 3- to 6-membered cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkylC _1-3 alkyl, 3- to 6-membered heterocyclylCualkyl, 6-membered arylCisalkyl or 5- to 6- membered heteroaryl C ualkyl, or R ^a and R ^b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; and R ¹³ is hydrogen, Ciealkyl, deuteroC _1-3 alkyl, haloCiealkyl, cyanoC ualkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, C _3-6 cycloalkyl, 3- to 6- membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, C _3-6 cycloalkylC _1-3 alkyl, 3- to 6-membered heterocyclylCisalkyl, 6-membered arylCi salkyl or 5- to 6-membered heteroarylCi -alkyl; and R ¹² and R ^12a are as described herein.

[000234] In some embodiments, R ⁸ is hydrogen, Ciealkyl, haloC _1-6 alkyl, or -R ^u -3- to 12- membered heterocyclyl; R ⁹ is -R ^u -C3-iocycloalkyl, R ^u -3- to 12-membered heterocyclyl, R ^u -6- membered-aryl or R ^u -5- to 6-membered heteroaryl; wherein the Cs-iocycloalkyl, 3- to 12- membered heterocyclyl, 6-membered aryl or 5- to 6-membered heteroaryl of -R ^u -C3-iocycloalkyl, R ^u -3- to 12- membered heterocyclyl, R ^u -6-membered aryl or R ^u -5- to 6-membered heteroaryl is optionally substituted with R ¹² ; R ^u is absent or a linker having the formula (CR ^c R ^d ) _z -C(R ^a )(R ^b )- (CR ^c R ^d ) _z ; R ^a and R ^b are each independently hydrogen, halo, amino, C _1-3 alkyl or haloCiealkyl; R ^c and R ^d are each independently hydrogen, Ciealkyl, or haloCiealkyl; z is 0, 1 or 2 and R ¹² is hydroxyl, Ciealkoxy or -COOH.

[000235] In some embodiments, R ⁸ is hydrogen, Ciealkyl, haloCiealkyl, or -R"-3- to 12- membered heterocyclyl and R ⁹ is hydrogen, R ^u Ciealkyl, R ^u haloCiealkyl, R ^u -C3-iocycloalkyl, R ^u - 3- to 12-membered heterocyclyl or R ^u -6-membered aryl, wherein the Cs-iocycloalkyl, 3- to 12- membered heterocyclyl or 6-membered aryl of -R ^u -C3-iocycloalkyl, R ^u -3- to 12- membered heterocyclyl or R ^u -6-membered aryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; and R ¹² and R ^12a are as described herein.

[000236] In some embodiments, R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl (e.g., 3- to 6- membered heterocyclyl) or 5- to 6- membered heteroaryl wherein the 3- to 12-membered heterocyclyl or 5- to 6-membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a .

[000237] In some embodiments, R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocyclyl (e.g., 3- to 6- membered heterocyclyl) wherein the 3- to 12-membered heterocyclyl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a . [000238] In some embodiments, R ⁸ and R ⁹ , together with the nitrogen atom to which they are attached, form 4- to 8-membered heterocyclyl wherein the 4- to 8-membered heterocyclyl is optionally substituted with one or two groups each independently selected from R ¹² and R ^12a .

[000239] In some embodiments, R ^v is either absent, or -C(R ^a )(R ^b )-, wherein R ^a and R ^b are each independently hydrogen, C _1-3 alkyl or haloC _1-3 alkyl; or R ^a and R ^b , together with the carbon atom to which they are attached, form Cs-6cycloalkyl or 3- to 6-membered heterocyclyl wherein the cycloalkyl or heterocyclyl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; and R ¹² and R ^12a are as described herein.

[000240] In some embodiments, R ^v is either absent or -C(R ^a )(R ^b )-, wherein R ^a and R ^b are each independently hydrogen, C _1-3 alkyl or haloC _1-3 alkyl.

[000241] In some embodiments, R ^v is absent.

[000242] In some embodiments, R ^u is absent or a linker having the formula -C(R ^a )(R ^b )-, wherein R ^a and R ^b are each independently hydrogen, C _1-3 alkyl or haloC _1-3 alkyl, or R ^a and R ^b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl or 3- to 6- membered heterocyclyl wherein the cycloalkyl or heterocyclyl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^l2a ; and R ¹² and R ^12a are as described herein.

[000243] In some embodiments, R ^u is absent or a methylene linker, or R ^a and R ^b , together with the carbon atom to which they are attached, form cyclobutyl or oxetanyl.

[000244] In some embodiments, R ^w is absent.

[000245] In some embodiments, R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl; R ⁵ is halo, C _1-3 alkyl, C _3-5 cycloalkyl, haloC _1-3 alkyl, haloC _1-3 alkoxy or Cisalkoxy wherein the C3- scycloalkyl is optionally substituted with one, two or three groups each independently selected from halo, deutero, cyano, C _1-3 alkyl or hydroxyl; and R ⁶ is halo, cyano, C _1-3 alkyl, Cs-scycloalkyl, haloC _1-3 alkyl, C isalkoxy or haloC 1-3 alkoxy.

[000246] In some embodiments, R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl; R ⁵ is halo, C _1-3 alkyl, Cs-scycloalkyl, haloC _1-3 alkyl, haloC _1-3 alkoxy or Cisalkoxy, and R ⁶ is halo, cyano, C _1-3 alkyl, Cs-scycloalkyl, haloC _1-3 alkyl, C isalkoxy or haloC _1-3 alkoxy.

[000247] In some embodiments, R ⁴ is hydrogen or methyl; R ⁵ is bicyclo[l .1. l]pentanyl, cyclopropyl or methoxy and R ⁶ is methyl. [000248] In some embodiments, R ⁴ is hydrogen or methyl; R ⁵ is cyclopropyl or methoxy and R ⁶ is methyl.

[000249] In some embodiments, R ⁴ is hydrogen; R ⁵ is methoxy and R ⁶ is methyl.

[000250] In some embodiments, R ⁴ is hydrogen; R ⁵ is bicyclo[l.l.l]pentanyl and R ⁶ is methyl.

[000251] In some embodiments, R ⁴ is hydrogen; R ⁵ is cyclopropyl and R ⁶ is methyl.

[000252] In some embodiments, each R ¹¹ , R ^lla and R ^llb is independently halo, cyano, haloCwalkyl, hydroxyC _1-3 alkyl, C _1-3 alkoxyC _1-3 alkyl, haloC _1-3 alkoxyCi3alkyl, hydroxyl, Cualkoxy or haloC 1-3 alkoxy.

[000253] In some embodiments, each R ¹¹ , R ^lla and R ^llb is independently halo, cyano, or haloCwalkyl or hydroxyl.

[000254] In some embodiments, each R ⁿ , R ^iia and R ^ub is independently fluoro, cyano, oxo, hydroxyl, methyl, CHF2, CF3 or -OCHF2, or two R ¹¹ groups, together with the carbon atom to which they are attached, form cyclobutyl or oxo.

[000255] In some embodiments, each R ¹¹ , R ^lla and R ^llb is independently halo, cyano, haloC _1-3 alkyl, haloCwalkoxy or C _1-3 alkylsulfonyl; or two R ¹¹ groups, together with the carbon atom to which they are attached, form C _3-5 cycloalkyl.

[000256] In some embodiments, each R ¹¹ , R ^lla and R ^llb is independently fluoro, cyano, - CF3, -CHF2, -OCF3 or S(O) ₂ CH3 or two R ¹¹ groups, together with the carbon atom to which they are attached, form cyclopropyl

[000257] In some embodiments, the compound is selected from the group consisting of:

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((6-oxo-l,6 dihydropyridin-3-yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((6-oxo-I,6 dihydropyridin-3-yl)methyl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((6-oxo-l,6-dihydropyridin-3-yl)m ethyl)benzamide; l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan6- yl)benzamido)cyclopropane- 1 -carboxylic acid; l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan6-yl)benzamido)cyclopropane-l-carboxylic acid; l -(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)cyclopropane- 1 -carboxylic acid;

N-(azetidin-3-ylmethyl)-4-(2-cyano-7-((5-methoxy-7-methyl -lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

N-(azetidin-3-ylmethyl)-4-((2R,4s,6S)-2-cyano-7-((5-metho xy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

N-(azetidin-3-ylmethyl)-4-((2S,4r,6S)-2-cyano-7-((5-metho xy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((2-oxo-l,2-dihydropyri din-3 -yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((2-oxo-l,2-dihydropyridin-3-yl)m ethyl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((2-oxo-l,2-dihydropyridin-3-yl)m ethyl)benzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((2-oxo-l,2-dihydropyridin-4-yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((2-oxo-l,2-dihydropyridin-4-yl)m ethyl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((2-oxo-l,2-dihydropyridin-4-yl)m ethyl)benzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(pyrazin-2-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(pyrazin-2-ylmethyl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(pyrazin-2-ylmethyl)benzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(thiazol-2-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(thiazol-2-ylmethyl)benzamide; 4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7- azaspiro[3.5]nonan-6-yl)-N-(thiazol-2-ylmethyl)benzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-((l-methylazeti din-3 -yl)methyl)benzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-methylazetidin-3-yl)methyl)be nzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-methylazetidin-3-yl)methyl)be nzamide;

(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6- yl)benzoyl)glycine;(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-me thyl-lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)glycine;

(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)glycine;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((3-hydroxyoxetan-3-yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-hydroxyoxetan-3-yl)methyl)ben zamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-hydroxyoxetan-3-yl)methyl)ben zamide; tert-butyl-3-((4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-ind ol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)methyl)azetidine-l -carboxylate; tert-butyl(S)-3-((4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)methyl)azetidine-l -carboxylate; tert-butyl(R)-3-((4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)methyl)azeti dine- 1 -carboxylate;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(oxetan-3-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide; 4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7-az aspiro[3 5]nonan-6- yl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

4-(6-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-azaspir o[2.5]octan-5-yl)benzamide;

(S)-4-(6-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-aza spiro[2.5]octan-5- yl)benzamide;

(R)-4-(6-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-aza spiro[2.5]octan-5- yl)benzamide;

4-(2-cyano-7-((5,7-dimethyl-lH-indol-4-yl)methyl)-7-azasp iro[3.5]nonan-6- yl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5,7-dimethyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5,7-dimethyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)benzamide;

((4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)me thyl)-7-azaspiro[3.5]nonan- 6-yl)benzoyl)-D-proline;

((4-((S)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-D-proline;

((4-((R)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-D-proline;

(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan-6- yl)benzoyl)-L-proline;

(4-((S)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-L-proline,

(4-((R)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-L-proline;

(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan-6- yl)phenyl)(3-hydroxypyrrolidin-l-yl)m ethanone; (4-((S)-2,2-di fluoro-7-((5 -m ethoxy-7-methyl - 1 H-i ndol -4-yl )m ethyl )-7- azaspiro[3.5]nonan-6-yl)phenyl)((S)-3-hydroxypyrrolidin-l-yl )methanone;

(4-((S)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)((R)-3-hydroxypyrrolidin-l-yl )methanone;

(4-((R)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)(R)-3 -hydroxypyrrolidin- 1 -yl)methanone;

(4-((R)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)((R)-3-hydroxypyrrolidin-l-yl )methanone;

(3-cyclopropylazetidin-l-yl)(4-(2,2-difluoro-7-((5-methox y-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)phenyl)methanone;

(S)-(3-cyclopropylazetidin-l-yl)(4-(2,2-difluoro-7-((5-me thoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)phenyl)methanone;

(R)-(3-cyclopropylazetidin-l-yl)(4-(2,2-difluoro-7-((5-me thoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)phenyl)methanone;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3,3-difluorocyclobutyl)methyl)b enzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-2-fluorobenzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-2 -fluorobenzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-2 -fluorobenzamide;

2-(l-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)azetidin-3-yl)acetonitrile;

(S)-2-(l-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)azetidin-3-yl)acetonitrile;

(R)-2-(l-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)azetidin-3-yl)acetonitrile; l-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan- 6-yl)benzoyl)azetidine-3-carbonitrile; (S)-l -(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)methy l)-7- azaspiro[3.5]nonan-6-yl)benzoyl)azetidine-3-carbonitrile;

(R)-l-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)azetidine-3-carbonitrile;

(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan-6- yl)phenyl)(3-(2,2,2-trifluoroethyl)azetidin-l-yl)methanone;

(S)-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)(3-(2,2,2-trifluoroethyl)azet idin-l-yl)methanone;

(R)-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)(3-(2,2,2-trifluoroethyl)azet idin-l-yl)methanone;

(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan-6- yl)phenyl)(3-(trifluoromethyl)azetidin-l-yl)m ethanone;

(S)-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)(3-(trifluoromethyl)azetidin- l-yl)methanone;

(R)-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)(3-(trifluoromethyl)azetidin- l-yl)methanone;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-( 1,1,1 -trifluoropropan-2-yl)benzamide;

4-((S)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-( 1,1,1 -trifluoropropan-2-yl)benzamide;

4-((R)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-( 1,1,1 -trifluoropropan-2-yl)benzamide;

N-(3-cyanooxetan-3-yl)-4-(2,2-difluoro-7-((5-methoxy-7-me thyl-lH-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6-yl)benzamide;

(S)-N-(3-cyanooxetan-3-yl)-4-(2,2-difluoro-7-((5-methoxy- 7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

(R)-N-(3-cyanooxetan-3-yl)-4-(2,2-difluoro-7-((5-methoxy- 7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

N-(cyclopropylmethyl)-4-(2,2-difluoro-7-((5-methoxy-7-met hyl-lH-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6-yl)benzamide; (S)-N-(cyclopropylmethyl)-4-(2,2-difluoro-7-((5-methoxy-7-me thyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

(R)-N-(cyclopropylmethyl)-4-(2,2-difluoro-7-((5-methoxy-7 -methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-(3-(trifluoromethyl)oxetan-3-yl)benzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(3-(trifluoromethyl)oxetan-3-yl)b enzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(3-(trifluoromethyl)oxetan-3-yl)b enzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-(3-(trifluoromethyl)bicyclo[l .1. l]pentan-l-yl)benzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(3 -(trifluoromethyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)benzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(3 -(trifluoromethyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)benzamide;

N-(l-cyanocyclopropyl)-4-(2,2-difluoro-7-((5-methoxy-7-me thyl-lH-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6-yl)benzamide;

(S)-N-(l-cyanocyclopropyl)-4-(2,2-difluoro-7-((5-methoxy- 7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

(R)-N-(l-cyanocyclopropyl)-4-(2,2-difluoro-7-((5-methoxy- 7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

N-(3,3-difluoro-l-methylcyclobutyl)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl-lH-indol- 4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

(S)-N-(3,3-difluoro-l-methylcyclobutyl)-4-(2,2-difluoro-7 -((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

(R)-N-(3,3-difluoro-l-methylcyclobutyl)-4-(2,2-difluoro-7 -((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

N-(bicyclo[l. l.l]pentan-l-yl)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-i ndol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide; (S)-N-(bicyclo[l .1 ,l]pentan-l -yl)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

(R)-N-(bicyclo[l .1. l]pentan-l-yl)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-ind ol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-(oxetan-3-ylmethyl)benzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-(oxetan-3-yl)benzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-yl)benzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-yl)benzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N,N-dimethylbenzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N,N-dimethylbenzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N,N-dimethylbenzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-(3,3-difluorocyclobutyl)benzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(3,3-difluorocyclobutyl)benzamide ;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(3,3-difluorocyclobutyl)benzamide ;

N-cyclobutyl-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide; (S)-N-cyclobutyl-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-i ndol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

(R)-N-cyclobutyl-4-(2,2-difluoro-7-((5-methoxy-7-methyl-l H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

N-cyclopropyl-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-i ndol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

(S)-N-cyclopropyl-4-(2,2-difluoro-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

(R)-N-cyclopropyl-4-(2,2-difluoro-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-phenylbenzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-phenylbenzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-phenylbenzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-(2,2,2-trifluoroethyl)benzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2,2,2-trifluoroethyl)benzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2,2,2-trifluoroethyl)benzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-(3 ,3 , 3 -trifluor opropy l)b enzamide ;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(3,3,3-trifluoropropyl)benzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(3,3,3-trifluoropropyl)benzamide;

4-(2,2-difluoro-7-((5-meflioxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan-6- yl)-N-ethylbenzamide; (S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7- azaspiro[3.5]nonan-6-yl)-N-ethylbenzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-ethylbenzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)benzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-methylbenzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-methylbenzamide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-methylbenzamide;

5-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-3-fluoropicolinamide;

(S)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-3-fluoropicolinamide;

(R)-5 -(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-fluoropicolinamide;

5-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)picolinamide

(S)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)picolinamide;

(R)-5 -(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)picolinamide;

6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-2,2- difluoro-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane; (R)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)-2,2 -difluoro-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

(S)-6-(6-(3,3-difluorocyclobutoxy)-5-fluoropyridin-3-yl)- 2,2-difluoro-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

6-(6-((3,3-difluorocyclobutyl)methoxy)-5-fluoropyridin-3- yl)-2,2-difluoro-7-((5- methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane ;

(R)-6-(6-((3,3-difluorocyclobutyl)methoxy)-5-fluoropyridi n-3-yl)-2,2-difluoro-7-((5- methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane ;

(S)-6-(6-((3,3-difluorocyclobutyl)methoxy)-5-fluoropyridi n-3-yl)-2,2-difluoro-7-((5- methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane ;

2.2-difluoro-6-(5-fluoro-6-(oxetan-3-ylmethoxy)pyridin-3- yl)-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

(R)-2,2-difluoro-6-(5-fluoro-6-(oxetan-3-ylmethoxy)pyridi n-3-yl)-7-((5-methoxy-7- methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

(S)-2,2-difluoro-6-(5-fluoro-6-(oxetan-3-ylmethoxy)pyridi n-3-yl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

2.2-difluoro-6-(5-fluoro-6-(oxetan-3-yloxy)pyridin-3-yl)- 7-((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

(R)-2,2-difluoro-6-(5-fluoro-6-(oxetan-3-yloxy)pyridin-3- yl)-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

(S)-2,2-difluoro-6-(5-fluoro-6-(oxetan-3-yloxy)pyridin-3- yl)-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

6-(6-(cyclopropylmethoxy)-5-fluoropyridin-3-yl)-2,2-diflu oro-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

2.2-difluoro-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin -3-yl)-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

(R)-2,2-difluoro-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyr idin-3-yl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

(S)-2,2-difluoro-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyr idin-3-yl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane; 2-((5 -(2, 2-difluoro-7-((5 -m ethoxy-7 -m ethyl - 1 H-i ndol -4-yl)m ethyl )-7 - azaspiro[3.5]nonan-6-yl)-3-fluoropyridin-2-yl)oxy)acetic acid;

(R)-2-((5-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4 -yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-fluoropyridin-2-yl)oxy)acetic acid;

(S)-2-((5-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4 -yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-fluoropyridin-2-yl)oxy)acetic acid;

5-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- y 1 ) - 3 -fluoropyridin-2-ol ;

6-(6-(benzyloxy)-5-fluoropyridin-3-yl)-2,2-difluoro-7-((5 -methoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonane;

2,2-difluoro-6-(5-fluoro-6-methoxypyridin-3-yl)-7-((5-met hoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonane;

(R)-2,2-difluoro-6-(5-fluoro-6-methoxypyridin-3-yl)-7-((5 -methoxy-7-methyl-lH-indol- 4-yl)methyl)-7-azaspiro[3.5]nonane;

(S)-2,2-difluoro-6-(5-fluoro-6-methoxypyridin-3-yl)-7-((5 -methoxy-7-methyl-lH-indol- 4-yl)methyl)-7-azaspiro[3.5]nonane;

2-(4-(2-(2-hydroxypropan-2-yl)-7-((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)propan-2-ol;

2-(4-((2R,4s,6S)-2-(2-hydroxypropan-2-yl)-7-((5-methoxy-7 -methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)phenyl)propan-2-ol;

2-(4-((2 S,4r, 6 S)-2-(2-hy droxypropan-2-yl)-7-((5 -methoxy-7-methyl- 1 H-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)phenyl)propan-2-ol;

6-(4-(hydroxymethyl)phenyl)-7-((5-methoxy-7-methyl-lH-ind ol-4-yl)methyl)-7- azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(hydroxymethyl)phenyl)-7-((5-methoxy-7-me thyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2S,4r,bS)-6-(4-(hydroxymethyl)phenyl)-7-((5-methoxy-7-me thyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

2-(4-(6-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-azas piro[2.5]octan-5- yl)phenyl)propan-2-ol; (S)-2-(4-(6-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-aza spiro[2.5]octan-5- yl)phenyl)propan-2-ol;

(R)-2-(4-(6-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6- azaspiro[2.5]octan-5- yl)phenyl)propan-2-ol;

5-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)pyridin-2-ol;

(S)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)pyridin-2-ol;

(R)-5 -(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)pyridin-2-ol;

1-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7-azaspiro[3.5]nonan- 6-yl)phenyl)cyclopropan-l-ol;

(S)-l-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)cyclopropan-l-ol;

(R)-l-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)cyclopropan-l-ol;

2-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7-azaspiro[3.5]nonan- 6-yl)phenyl)propan-2-ol;

(S)-2-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)propan-2-ol;

(R)-2-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)propan-2-ol;

(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan-6- yl)phenyl)methanol;

(S)-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)methanol;

(R)-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5 ]nonan-6-yl)phenyl)m ethanol ;

N-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7-azaspiro[3.5]nonan- 6-yl)phenyl)benzamide; (S)-N-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)benzamide;

(R)-N-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)benzamide;

N-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7-azaspiro[3.5]nonan- 6-yl)phenyl)benzamide;

(S)-N-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)benzamide;

(R)-N-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)benzamide;

N-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7-azaspiro[3.5]nonan- 6-yl)phenyl)cyclopropanecarboxamide;

(S)-N-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)cyclopropanecarboxamide;

(R)-N-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)cyclopropanecarboxamide;

2.2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl) -6-(5- (methylsulfonyl)pyri din-2 -yl)-7-azaspiro[3.5]nonane;

4-((6-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)pyridin-3-yl)sulfonyl)morpholine;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N,N-dimethylbenzenesulfonamide;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-methylbenzenesulfonamide;

2.2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl) -6-(4- (methylsulfonyl)phenyl)-7-azaspiro[3.5]nonane;

(S)-2,2-difluoro-7 -((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-6-(4- (methylsulfonyl)phenyl)-7-azaspiro[3.5]nonane;

(R)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-6-(4- (methylsulfonyl)phenyl)-7-azaspiro[3.5]nonane; 2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6- (4- ((methylsulfonyl)methyl)phenyl)-7-azaspiro[3.5]nonane;

(S)-2,2-difluoro-7 -((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-6-(4- ((methylsulfonyl)methyl)phenyl)-7-azaspiro[3.5]nonane;

(R)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-6-(4- ((methylsulfonyl)methyl)phenyl)-7-azaspiro[3.5]nonane; l-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan- 6-yl)benzyl)-lH-pyrazole-4-carboxylic acid;

(S)-l-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzyl)-lH-pyrazole-4-carboxylic acid;

(R)-l-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzyl)-lH-pyrazole-4-carboxylic acid;

3-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7-azaspiro[3.5]nonan- 6-yl)phenyl)-l,2,4-oxadiazol-5(4H)-one;

(S)-3-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)-l,2,4-oxadiazol-5(4H)-one;

(R)-3-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)-l,2,4-oxadiazol-5(4H)-one;

6-(4-((lH-pyrazol-l-yl)methyl)phenyl)-2,2-difluoro-7-((5- methoxy-7-methyl-lH-indol- 4-yl)methyl)-7-azaspiro[3.5]nonane;

(S)-6-(4-((lH-pyrazol-l-yl)methyl)phenyl)-2,2-difluoro-7- ((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

(R)-6-(4-((lH-pyrazol-l-yl)methyl)phenyl)-2,2-difluoro-7- ((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonane;

6-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)isoquinolin-l(2H)-one;

(S)-6-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5 ]nonan-6-yl)i soquinolin- 1 (2H)-one;

(R)-6-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5 ]nonan-6-yl)i soquinolin- 1 (2H)-one; 3-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan- 6-yl)phenyl)pyridin-2(lH)-one;

(S)-3-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)pyridin-2(lH)-one;

(R)-3-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)pyridin-2(lH)-one;

6-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7-azaspiro[3.5]nonan- 6-yl)phenyl)pyridin-2(lH)-one;

(S)-6-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)pyridin-2(lH)-one; and

(R)-6-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)pyridin-2(lH)-one; or a pharmaceutically acceptable salt of any of the foregoing.

[000258] In some embodiments, the compound is selected from the group consisting of compounds in Table A, or a pharmaceutically acceptable salt of any of the foregoing:

[000259] In some embodiments, the compound is selected from the group consisting of:

2-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzamido)-2-(tetrahydro-2H-pyran-4-yl)acetic acid;

2-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)-2-(tetrahydro-2H-pyran-4- yl)acetic acid;

2-(4-((2 S,4r, 6 S)-2-cy ano-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)-2-(tetrahydro-2H-pyran-4- yl)acetic acid;

(4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)benzoyl)glycine;

(4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indo l-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)glycine;

(4-((2S,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indo l-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)glycine;

N-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzoyl)-O-methyl serine;

N-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-O-methylserine; N-(4-((2S,4r,6S)-2-cyano-7-((5-rnethoxy-7-rnethyl-lH-indol-4 -yl)rnethyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-O-methylserine; l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6- yl)benzamido)cyclobutane- 1 -carboxylic acid; l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)cyclobutane-l-carboxylic acid;

1 -(4-((2 S,4r, 6 S)-2-cy ano-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)cy cl obutane-1 -carboxylic acid;

4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-7-azaspiro[3.5]nonan-6- yl)-N-((3-hydroxyoxetan-3-yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-hydroxyoxetan-3-yl)methyl)ben zamide;

4-((2S,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-hydroxyoxetan-3-yl)methyl)ben zamide; l-(4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-7-azaspiro[3.5]nonan- 6-yl)benzamido)cyclopropane- 1 -carboxylic acid; l-(4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)cyclopropane- 1 -carboxylic acid; l-(4-((2S,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)cyclopropane- 1 -carboxylic acid;

4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-7-azaspiro[3.5]nonan-6- yl)-N-(oxetan-3-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide ;

4-((2S,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(2-(2-oxopyridin-l(2H)-yl)ethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-(2-oxopyridin-l(2H)-yl)ethyl)b enzamide; 4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-rnethyl-lH-indol-4-yl) rnethyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-(2-oxopyridin-l(2H)-yl)ethyl)b enzamide;

(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6- yl)benzoyl)-L-phenylalanine;

(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-L-phenylalanine;

(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-L-phenylalanine;

3-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzamido)oxetane-3 -carboxylic acid;

3-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)oxetane-3-carboxylic acid;

3 -(4-((2 S,4r, 6 S)-2-cy ano-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)oxetane-3-carboxylic acid;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(oxetan-3-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide;

4-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzoyl)morpholine-2-carboxylic acid;

4-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)morpholine-2-carboxylic acid;

4-(4-((2 S,4r, 6 S)-2-cy ano-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)morpholine-2-carboxylic acid;

4-(7 -((5 -chi oro-7-m ethyl- 1 H-indol-4-yl)methyl)-2-cy ano-7-azaspiro[3.5 ]nonan-6-yl)-N- (oxetan-3-ylmethyl)benzamide;

4-((2R,4s,6S)-7-((5-chloro-7-methyl-lH-indol-4-yl)methyl) -2-cyano-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide; 4-((2S,4r,6S)-7-((5-chloro-7-rnethyl-lH-indol-4-yl)rnethyl)- 2-cyano-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-methyl-N-(oxetan-3-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-methyl-N-(oxetan-3-ylmethyl)benza mide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-methyl-N-(oxetan-3-ylmethyl)benza mide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(l-(oxetan-3-yl)ethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(l-(oxetan-3-yl)ethyl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-( 1 -(oxetan-3 -yl)ethyl)benzamide;

6-(4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)phenyl)-7-( (5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl) phenyl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

(2S,4r,6S)-6-(4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl) phenyl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((l-methylazeti din-3 -yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-methylazetidin-3-yl)methyl)be nzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-methylazetidin-3-yl)methyl)be nzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(pyrimidin-2-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(pyrimidin-2-ylmethyl)benzamide;

Ill 4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-rnethyl-lH-indol-4-yl) rnethyl)-7- azaspiro[3.5]nonan-6-yl)-N-(pyrimidin-2-ylmethyl)benzamide;

(S)-2-amino-3-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)propanoic acid;

(S)-2-amino-3-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-meth yl-lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)propanoic acid;

(S)-2-amino-3-(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-meth yl-lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)propanoic acid;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((tetrahydrofuran-3-yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((tetrahydrofuran-3-yl)methyl)ben zamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((tetrahydrofuran-3-yl)methyl)ben zamide;

N-((lH-pyrazol-5-yl)methyl)-4-(2-cyano-7-((5-methoxy-7-me thyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

N-((lH-pyrazol-5-yl)methyl)-4-((2R,4s,6S)-2-cyano-7-((5-m ethoxy-7-methyl-lH-indol- 4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

N-((lH-pyrazol-5-yl)methyl)-4-((2S,4r,6S)-2-cyano-7-((5-m ethoxy-7-methyl-lH-indol- 4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(( 1 -methyl-6-oxo- 1 ,6-dihydropyri din-3 -yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-methyl-6-oxo-l,6-dihydropyrid in-3-yl)methyl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-methyl-6-oxo-l,6-dihydropyrid in-3-yl)methyl)benzamide;

4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-7-azaspiro[3.5]nonan-6- yl)-N-((2-oxo-l,2-dihydropyri din-3 -yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((2-oxo-l,2-dihydropyridin-3-yl)m ethyl)benzamide; 4-((2S,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4- yl)rnethyl)-7- azaspiro[3.5]nonan-6-yl)-N-((2-oxo-l,2-dihydropyridin-3-yl)m ethyl)benzamide; l-(4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-7-azaspiro[3.5]nonan- 6-yl)benzamido)cyclobutane-l -carboxylic acid; l-(4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)cyclobutane-l-carboxylic acid; l-(4-((2S,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)cy cl obutane-1 -carboxylic acid;

4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-7-azaspiro[3.5]nonan-6- yl)-N-((2-oxo- 1 ,2-dihydropyridin-4-yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((2-oxo-l,2-dihydropyridin-4-yl)m ethyl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((2-oxo-l,2-dihydropyridin-4-yl)m ethyl)benzamide;

3-(4-((2S,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)oxetane-3-carboxylic acid;

3-(4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)oxetane-3-carboxylic acid;

3-(4-((2S,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)oxetane-3-carboxylic acid;

4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-7-azaspiro[3.5]nonan-6- yl)-N-((6-oxo-l,6-dihydropyri din-3 -yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((6-oxo-l,6-dihydropyridin-3-yl)m ethyl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((6-oxo-l,6-dihydropyridin-3-yl)m ethyl)benzamide;

3-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzamido)propanoic acid;

3-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)propanoic acid; 3-(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)propanoic acid;

2-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzamido)-2-(oxetan-3-yl)acetic acid;

2-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)-2-(oxetan-3-yl)acetic acid;

2-(4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)-2-(oxetan-3-yl)acetic acid;

(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6- yl)benzoyl)-D-alanine;

(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-D-alanine;

(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-D-alanine;

(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6- yl)benzoyl)-L-alanine;

(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-L-alanine;

(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-L-alanine;

6-(4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)phenyl)-7-( (5-cyclopropyl-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl) phenyl)-7-((5-cyclopropyl-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

(2R,4r,6S)-6-(4-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl) phenyl)-7-((5-cyclopropyl-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

N-((3-hydroxyoxetan-3-yl)methyl)-4-(7-((5-methoxy-7-methy l-lH-indol-4-yl)methyl)-2- (trifluoromethyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

N-((3-hydroxyoxetan-3-yl)methyl)-4-((2R,4s,6S)-7-((5-meth oxy-7-methyl-lH-indol-4- yl)methyl)-2-(trifluoromethyl)-7-azaspiro[3.5]nonan-6-yl)ben zamide; N-((3-hydroxyoxetan-3-yl)methyl)-4-((2R,4r,6S)-7-((5-methoxy -7-methyl-lH-indol-4- yl)methyl)-2-(trifluoromethyl)-7-azaspiro[3.5]nonan-6-yl)ben zamide;

(4-(7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-2-(trifl uoromethyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)glycine;

(4-((2R,4s,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methy l)-2-(trifluoromethyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)glycine;

(4-((2R,4r,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methy l)-2-(trifluoromethyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)glycine;

4-(2-(difluoromethyl)-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-hydroxyoxetan-3-yl)methyl)ben zamide;

4-((2R,4s,6S)-2-(difluoromethyl)-7-((5-methoxy-7-methyl-l H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-hydroxyoxetan-3-yl)methyl)ben zamide;

4-((2R,4r,6S)-2-(difluoromethyl)-7-((5-methoxy-7-methyl-l H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-hydroxyoxetan-3-yl)methyl)ben zamide;

4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-7-azaspiro[3.5]nonan-6- yl)-N-((l-methylazeti din-3 -yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-methylazetidin-3-yl)methyl)be nzamide;

4-((2R,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-methylazetidin-3-yl)methyl)be nzamide;

4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-7-azaspiro[3.5]nonan-6- yl)-N-((R)-piperidin-3-yl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((R)-piperidin-3-yl)benzamide;

4-((2R,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((R)-piperidin-3-yl)benzamide;

N-(azetidin-3-yl)-4-(2-cyano-7-((5-cyclopropyl-7-methyl-l H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

N-(azetidin-3-yl)-4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl -7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide; N-(azetidin-3-yl)-4-((2R,4r,6S)-2-cyano-7-((5-cyclopropyl-7- methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

6-(4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-((5 -cyclopropyl-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)ph enyl)-7-((5-cyclopropyl-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

(2R,4r,6S)-6-(4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)ph enyl)-7-((5-cyclopropyl-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

N-(azetidin-3-ylmethyl)-4-(2-cyano-7-((5-cyclopropyl-7-me thyl-lH-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6-yl)benzamide;

N-(azetidin-3-ylmethyl)-4-((2R,4s,6S)-2-cyano-7-((5-cyclo propyl-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

N-(azetidin-3-ylmethyl)-4-((2R,4r,6S)-2-cyano-7-((5-cyclo propyl-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

(4-(2-(difluoromethyl)-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)glycine;

(4-((2R,4s, 6 S)-2-(difluoromethyl)-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)glycine;

(4-((2R,4r,6S)-2-(difluoromethyl)-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)glycine;

(R)-4-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)me thyl)-7-azaspiro[3.5]nonan- 6-yl)benzoyl)morpholine-2-carboxylic acid;

(R)-4-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)morpholine-2-carboxylic acid;

(R)-4-(4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)morpholine-2-carboxylic acid;

4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-7-azaspiro[3.5]nonan-6- yl)-N-(2-azaspiro[3.3]heptan-6-yl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-azaspiro[3.3]heptan-6-yl)benza mide; 4-((2R,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4- yl)rnethyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-azaspiro[3.3]heptan-6-yl)benza mide;

N-(2-(azetidin-l-yl)ethyl)-4-(2-cyano-7-((5-methoxy-7-met hyl-lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

N-(2-(azetidin-l-yl)ethyl)-4-((2R,4s,6S)-2-cyano-7-((5-me thoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

N-(2-(azetidin-l-yl)ethyl)-4-((2R,4r,6S)-2-cyano-7-((5-me thoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-7-azaspiro[3.5]nonan-6- yl)-N-(pyrrolidin-3-yl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(pyrrolidin-3-yl)benzamide;

4-((2R,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(pyrrolidin-3-yl)benzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(oxetan-3-yl)benzamide;

4-((2S,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-yl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-yl)benzamide;

7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(3-oxop iperazine-l- carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2S,4s,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(3-oxopiperazine-l- carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2S,4r,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(3-oxopiperazine-l- carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

4-(2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-7-azaspiro[3.5]nonan-6- yl)-N-((S)-piperidin-3-yl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol -4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((S)-piperidin-3-yl)benzamide; 4-((2R,4r,6S)-2-cyano-7-((5-cyclopropyl-7-methyl-lH-indol-4- yl)rnethyl)-7- azaspiro[3.5]nonan-6-yl)-N-((S)-piperidin-3-yl)benzamide;

6-(4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-((5 -methoxy-7-methyl-lH-indol-

4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)ph enyl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

(2R,4r,6S)-6-(4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)ph enyl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(2-azaspiro[3.3]heptan-6-yl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-azaspiro[3.3]heptan-6-yl)benza mide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-azaspiro[3.3]heptan-6-yl)benza mide;

(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan-6- yl)benzoyl)glycine;

(S)-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)glycine;

(R)-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)glycine;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((3-fluoroazetidin-3-yl)methyl)benzamide;

4-((2S,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-fluoroazetidin-3-yl)methyl)be nzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-fluoroazetidin-3-yl)methyl)be nzamide;

N-(2-(azetidin-3-yl)ethyl)-4-(2-cyano-7-((5-methoxy-7-met hyl-lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

N-(2-(azetidin-3-yl)ethyl)-4-((2R,4s,6S)-2-cyano-7-((5-me thoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide; N-(2-(azeti din-3-yl)ethyl)-4-((2R, 4r, 6S)-2-cy ano-7-((5-methoxy-7-rn ethyl- lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

6-(4-(2,7-diazaspiro[3.5]nonane-7-carbonyl)phenyl)-7-((5- methoxy-7-methyl-lH-indol- 4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(2,7-diazaspiro[3.5]nonane-7-carbonyl)phe nyl)-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4r,6S)-6-(4-(2,7-diazaspiro[3.5]nonane-7-carbonyl)phe nyl)-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((3-methoxyazeti din-3 -yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-methoxyazetidin-3-yl)methyl)b enzamide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-methoxyazetidin-3-yl)methyl)b enzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((3-methylazeti din-3 -yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-methylazetidin-3-yl)methyl)be nzamide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-methylazetidin-3-yl)methyl)be nzamide;

7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(morpho line-4-carbonyl)phenyl)-7- azaspiro[3.5]nonane-2-carbonitrile;

(2S,4s,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(morpholine-4- carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2S,4r,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(morpholine-4- carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((l -methyl- lH-pyrazol-5-yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-methyl-lH-pyrazol-5-yl)methyl )benzamide; 4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-methyl-lH-pyrazol-5-yl)methyl )benzamide;

N-cyclopropyl-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-i ndol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

(S)-N-cyclopropyl-4-(2,2-difluoro-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

(R)-N-cyclopropyl-4-(2,2-difluoro-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((R)- 1 -(oxetan-3 -y l)ethy l)b enzami de ;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((R)-l-(oxetan-3-yl)ethyl)benzami de;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((R)-l-(oxetan-3-yl)ethyl)benzami de;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((S)-1 -(oxetan-3 -yl)ethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((S)-l-(oxetan-3-yl)ethyl)benzami de;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((S)-l-(oxetan-3-yl)ethyl)benzami de;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(piperidin-4-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(piperidin-4-ylmethyl)benzamide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(piperidin-4-ylmethyl)benzamide;

N-(azetidin-3-ylmethyl)-4-(2-cyano-7-((5-methoxy-7-methyl -lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-ethylbenzamide;

N-(azetidin-3-ylmethyl)-4-((2R,4s,6S)-2-cyano-7-((5-metho xy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-N-ethylbenzamide; N-(azetidin-3-ylmethyl)-4-((2R,4r,6S)-2-cyano-7-((5-methoxy- 7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-N-ethylbenzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((3 -methoxy oxetan-3-yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-methoxyoxetan-3-yl)methyl)ben zamide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3-methoxyoxetan-3-yl)methyl)ben zamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)-

N-((l-cy cl opropylazeti din-3 -yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-cyclopropylazetidin-3-yl)meth yl)benzamide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-cyclopropylazetidin-3-yl)meth yl)benzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((3,3-difluorocyclobutyl)methyl)benzamide;

4-((2S,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3,3-difluorocyclobutyl)methyl)b enzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((3,3-difluorocyclobutyl)methyl)b enzamide;

6-(4-(4,7-diazaspiro[2.5]octane-7-carbonyl)phenyl)-7-((5- methoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(4,7-diazaspiro[2.5]octane-7-carbonyl)phe nyl)-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4r,6S)-6-(4-(4,7-diazaspiro[2.5]octane-7-carbonyl)phe nyl)-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

3-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- y 1)-N -methy lb enzami do)propanoi c acid ;

3-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-methylbenzamido)propanoic acid; 3 -(4-((2R,4r,6 S)-2-cy ano-7-((5 -m ethoxy-7-m ethyl - 1 H-i ndol -4-yl )m ethyl )-7- azaspiro[3.5]nonan-6-yl)-N-methylbenzamido)propanoic acid;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(2 -methyl- 1 -(pyrrolidin- 1 -yl)propan-2-yl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2 -methyl- 1 -(pyrrolidin- 1 -yl)propan-2-yl)benzamide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2 -methyl- 1 -(pyrrolidin- 1 -yl)propan-2-yl)benzamide;

4-(7-((3-chloro-5-methoxy-7-methyl-lH-indol-4-yl)methyl)- 2-cyano-7- azaspiro[3.5]nonan-6-yl)-N-((l-methylazetidin-3-yl)methyl)be nzamide;

4-((2R,4s,6S)-7-((3-chloro-5-methoxy-7-methyl-lH-indol-4- yl)methyl)-2-cyano-7- azaspiro[3.5]nonan-6-yl)-N-((l-methylazetidin-3-yl)methyl)be nzamide;

4-((2R,4r,6S)-7-((3-chloro-5-methoxy-7-methyl-lH-indol-4- yl)methyl)-2-cyano-7- azaspiro[3.5]nonan-6-yl)-N-((l-methylazetidin-3-yl)methyl)be nzamide;

7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methyl)-6-(4-(6- methyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile;

(2R,4s,6S)-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-6-(4-(6-methyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile;

(2R,4r,6S)-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-6-(4-(6-methyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile;

7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(6-(2,2 ,2-trifluoroethyl)-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile;

(2R,4s,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(6-(2,2,2-trifluoroethyl)- 2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5 ]nonane-2-carbonitrile;

(2R,4r,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(6-(2,2,2-trifluoroethyl)- 2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5 ]nonane-2-carbonitrile;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(2-(3,3-difluoroazetidin-l-yl)ethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-(3,3-difluoroazetidin-l-yl)eth yl)benzamide; 4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-(3,3-difluoroazetidin-l-yl)eth yl)benzamide;

7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(4-(2,2 ,2-trifluoroethyl)piperazine-

1-carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(4-(2,2,2- trifluoroethyl)piperazine-l-carbonyl)phenyl)-7-azaspiro[3.5] nonane-2-carbonitrile;

(2R,4r,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(4-(2,2,2- trifluoroethyl)piperazine-l-carbonyl)phenyl)-7-azaspiro[3.5] nonane-2-carbonitrile;

6-(4-(4-cyclopropylpiperazine-l-carbonyl)phenyl)-7-((5-me thoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(4-cyclopropylpiperazine-l-carbonyl)pheny l)-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4r,6S)-6-(4-(4-cyclopropylpiperazine-l-carbonyl)pheny l)-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(2-methyl-2-azaspiro[3.3]heptan-6-yl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-methyl-2-azaspiro[3.3]heptan-6 -yl)benzamide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-methyl-2-azaspiro[3.3]heptan-6 -yl)benzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)-

2-fluoro-N-(oxetan-3-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-2-fluoro-N-(oxetan-3-ylmethyl)benza mide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-2-fluoro-N-(oxetan-3-ylmethyl)benza mide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- 2-fluoro-N-(oxetan-3-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-2-fluoro-N-(oxetan-3-ylmethyl)benza mide; 4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7- azaspiro[3.5]nonan-6-yl)-2-fluoro-N-(oxetan-3-ylmethyl)benza mide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(2-(3-(trifluoromethyl)azetidin-l-yl)ethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-(3-(trifluoromethyl)azetidin-l -yl)ethyl)benzamide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-(3-(trifluoromethyl)azetidin-l -yl)ethyl)benzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((l -(2 -m ethoxy ethyl)azeti din-3 -yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-(2 -methoxy ethyl)azetidin-3-yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-(2 -methoxy ethyl)azetidin-3-yl)methyl)benzamide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-(3-methoxyazetidin-l-yl)ethyl) benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-(3-methoxyazetidin-l-yl)ethyl) benzamide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-(3-methoxyazetidin-l-yl)ethyl) benzamide;

7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(pipera zine-l-carbonyl)phenyl)-7- azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s, 6 S)-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-6-(4-(piperazine- 1 - carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4r,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(piperazine-l- carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-( 1 -methyl azeti din-3 -yl)b enzami de;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(l-methylazetidin-3-yl)benzamide; 4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7- azaspiro[3.5]nonan-6-yl)-N-(l-methylazetidin-3-yl)benzamide;

7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(4-meth yl-4,7- diazaspiro[2.5]octane-7-carbonyl)phenyl)-7-azaspiro[3.5]nona ne-2-carbonitrile;

(2R,4s,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(4-methyl-4,7- diazaspiro[2.5]octane-7-carbonyl)phenyl)-7-azaspiro[3.5]nona ne-2-carbonitrile;

(2R,4r,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(4-methyl-4,7- diazaspiro[2.5]octane-7-carbonyl)phenyl)-7-azaspiro[3.5]nona ne-2-carbonitrile;

7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(6-meth yl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile;

(2R,4s,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(6-methyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile;

(2R,4r,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(6-methyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile;

4-(2-cyano-7-((5-cyano-7-methyl-lH-indol-4-yl)methyl)-7-a zaspiro[3.5]nonan-6-yl)-N- (oxetan-3-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-cyano-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide;

4-((2R,4r,6S)-2-cyano-7-((5-cyano-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide;

7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(4-meth yl-3-oxopiperazine-l- carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(4-methyl-3- oxopiperazine-l-carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-car bonitrile;

(2R,4r,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(4-methyl-3- oxopiperazine-l-carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-car bonitrile;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-((l-(2,2,2-trifluoroethyl)azetidin-3-yl)methyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-(2,2,2-trifluoroethyl)azetidi n-3-yl)methyl)benzamide; 4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7- azaspiro[3.5]nonan-6-yl)-N-((l-(2,2,2-trifluoroethyl)azetidi n-3-yl)methyl)benzamide;

6-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzamido)spiro[3 ,3]heptane-2-carboxylic acid;

6-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)spiro[3.3]heptane-2-carbox ylic acid;

6-(4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)spiro[3.3]heptane-2-carbox ylic acid;

6-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzamido)spiro[3.3]heptane-2-carboxylic acid;

6-(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)spiro[3.3]heptane-2-carbox ylic acid;

6-(4-((2S,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)spiro[3.3]heptane-2-carbox ylic acid;

3-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzamido)-2,2-dimethylpropanoic acid;

3-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)-2,2-dimethylpropanoic acid;

3-(4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)-2,2-dimethylpropanoic acid;

2-(l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan-

6-yl)benzoyl)azeti din-3 -yl)acetic acid;

2-(l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-ind ol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)azetidin-3-yl)acetic acid;

2-(l-(4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-ind ol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)azetidin-3-yl)acetic acid; l-((4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)- 7-azaspiro[3.5]nonan-6- yl)-3-fluorobenzamido)methyl)cyclobutane-l-carboxylic acid; l-((4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-fluorobenzamido)methyl)cyclobutan e-l-carboxylic acid; l-((4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-fluorobenzamido)methyl)cy cl obutane-1 -carboxylic acid;

N-(azetidin-3-ylmethyl)-4-(2-cyano-7-((5-methoxy-7-methyl -lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)benzamide;

N-(azetidin-3-ylmethyl)-4-((2R,4s,6S)-2-cyano-7-((5-metho xy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)b enzamide;

N-(azetidin-3-ylmethyl)-4-((2R,4r,6S)-2-cyano-7-((5-metho xy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)b enzamide;

N-(azetidin-3-ylmethyl)-4-(2-cyano-7-((5-methoxy-7-methyl -lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-methylbenzamide;

N-(azetidin-3-ylmethyl)-4-((2R,4s,6S)-2-cyano-7-((5-metho xy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-N-methylbenzamide;

N-(azetidin-3-ylmethyl)-4-((2R,4r,6S)-2-cyano-7-((5-metho xy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)-N-methylbenzamide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- 3-fluoro-N-(oxetan-3-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-fluoro-N-(oxetan-3-ylmethyl)benza mide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-fluoro-N-(oxetan-3-ylmethyl)benza mide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- 3-fluoro-N-(oxetan-3-ylmethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-fluoro-N-(oxetan-3-ylmethyl)benza mide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-3-fluoro-N-(oxetan-3-ylmethyl)benza mide;

N-(2-(azetidin-3-yl)propan-2-yl)-4-(2-cyano-7-((5-methoxy -7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

N-(2-(azetidin-3-yl)propan-2-yl)-4-((2R,4s,6S)-2-cyano-7- ((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide; N-(2-(azetidin-3-yl)propan-2-yl)-4-((2R,4r,6S)-2-cyano-7-((5 -methoxy-7-rn ethyl- 1H- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide; l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6- yl)benzoyl)piperidine-4-carboxylic acid; l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)piperidine-4-carboxylic acid; l-(4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)piperidine-4-carboxylic acid;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(2-morpholinoethyl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-morpholinoethyl)benzamide;

4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-morpholinoethyl)benzamide;

N-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-4-(2-cyano- 7-((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

N-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-4-((2R,4s,6 S)-2-cyano-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benza mide;

N-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-4-((2R,4r,6 S)-2-cyano-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benza mide;

N-(l-(azetidin-l-yl)-2-methylpropan-2-yl)-4-(2-cyano-7-(( 5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

N-(l-(azetidin-l-yl)-2-methylpropan-2-yl)-4-((2R,4s,6S)-2 -cyano-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benza mide;

N-(l-(azetidin-l-yl)-2-methylpropan-2-yl)-4-((2R,4r,6S)-2 -cyano-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benza mide;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(2-(2,2,2-trifluoroethyl)-2-azaspiro[3.3]heptan-6-yl)benza mide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-(2,2,2-trifluoroethyl)-2-azasp iro[3.3]heptan-6-yl)benzamide; 4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-(2,2,2-trifluoroethyl)-2-azasp iro[3.3]heptan-6-yl)benzamide;

3-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzamido)butanoic acid;

(S)-3-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)butanoic acid;

(S)-3-(4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)butanoic acid;

7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(4-meth ylpiperazine-l- carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2S,4s,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(4-methylpiperazine-l- carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2S,4r,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(4-methylpiperazine-l- carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

6-(4-(4-isopropylpiperazine-l-carbonyl)phenyl)-7-((5-meth oxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(4-isopropylpiperazine-l-carbonyl)phenyl) -7-((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4r,6S)-6-(4-(4-isopropylpiperazine-l-carbonyl)phenyl) -7-((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

2-(l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan- 6-yl)benzoyl)pyrrolidin-2-yl)acetic acid;

2-((S)-l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH -indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidin-2-yl)acetic acid;

2-((S)-l-(4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH -indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidin-2-yl)acetic acid;

2-(l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan-

6-yl)benzoyl)pyrrolidin-2-yl)acetic acid;

2-((R)-l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH -indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidin-2-yl)acetic acid; 2-((R)-l -(4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidin-2-yl)acetic acid;

6-(4-(4-ethylpiperazine-l-carbonyl)phenyl)-7-((5-methoxy- 7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(4-ethylpiperazine-l-carbonyl)phenyl)-7-( (5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4r,6S)-6-(4-(4-ethylpiperazine-l-carbonyl)phenyl)-7-( (5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

3-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzamido)butanoic acid;

(R)-3-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)butanoic acid;

(R)-3-(4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)butanoic acid;

6-(4-(4-cyclobutylpiperazine-l-carbonyl)phenyl)-7-((5-met hoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(4-cyclobutylpiperazine-l-carbonyl)phenyl )-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4r,6S)-6-(4-(4-cyclobutylpiperazine-l-carbonyl)phenyl )-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

6-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)-7-azaspiro[3.5]nonan- 6-yl)benzamido)spiro[3.3]heptane-2-carboxylic acid;

6-(4-((S)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)spiro[3.3]heptane-2-carbox ylic acid;

6-(4-((R)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)spiro[3.3]heptane-2-carbox ylic acid;

6-(4-(2,2-difluoro-7-((5 -methoxy-7-m ethyl- 1 H-indol-4-yl)methyl)-7-azaspiro[3.5 ]nonan- 6-yl)benzamido)spiro[3.3]heptane-2-carboxylic acid;

6-(4-((S)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)spiro[3.3]heptane-2-carbox ylic acid; 6-(4-((R)-2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)spiro[3.3]heptane-2-carbox ylic acid;

6-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(oxetan-3-ylmethyl)nicotinamide;

6-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)nicotinamide;

6-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)nicotinamide;

6-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(oxetan-3-ylmethyl)nicotinamide;

6-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)nicotinamide;

6-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(oxetan-3-ylmethyl)nicotinamide;

7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(4-(l-m ethylazetidin-3- yl)piperazine-l-carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-car bonitrile;

(2R, 4s, 6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(4-(l- methylazeti din-3- yl)piperazine-l-carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-car bonitrile;

(2R,4r,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(4-(l-methylazetidin-3- yl)piperazine-l-carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-car bonitrile;

6-(4-(4-(azeti din- l-yl)piperi dine- l-carbonyl)phenyl)-7-((5-methoxy-7-methyl- IH-indol- 4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(4-(azetidin-l-yl)piperidine-l-carbonyl)p henyl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

(2R,4r,6S)-6-(4-(4-(azetidin-l-yl)piperidine-l-carbonyl)p henyl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

3-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzamido)-3 -methylbutanoic acid;

3-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)-3-methylbutanoic acid; 3 -(4-((2R,4r,6 S)-2-cy ano-7-((5 -m ethoxy-7-m ethyl - 1 H-i ndol -4-yl )m ethyl )-7- azaspiro[3.5]nonan-6-yl)benzamido)-3-methylbutanoic acid;

7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(4-(pyr i din-2 -yl)piperazine-l - carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R, 4s, 6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6-(4-(4-(py ri din-2- yl)piperazine-l-carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-car bonitrile;

(2R,4r,6S)-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6 -(4-(4-(pyri din-2- yl)piperazine-l-carbonyl)phenyl)-7-azaspiro[3.5]nonane-2-car bonitrile; l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6- yl)benzoyl)piperidine-3 -carboxylic acid;

(R)-l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)piperidine-3-carboxylic acid;

(R)-l-(4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)piperidine-3-carboxylic acid;

1-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzoyl)piperidine-3 -carboxylic acid;

(S)-l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)piperidine-3-carboxylic acid;

(S)-l-(4-((2R,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)piperidine-3-carboxylic acid;

2-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzoyl)-2-azaspiro[3.3]heptane-6-carboxylic acid;

2-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-2-azaspiro[3.3]heptane-6-ca rboxylic acid;

2-(4-((2 S,4r, 6 S)-2-cy ano-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-2-azaspiro[3.3]heptane-6-ca rboxylic acid;

(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan-6- yl)phenyl)(2,6-diazaspiro[3.3 ]heptan-2-yl)m ethanone;

(S)-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl )methyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)(2,6-diazaspiro[3.3]heptan-2- yl)methanone; (R)-(4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)me thyl)-7- azaspiro[3.5]nonan-6-yl)phenyl)(2,6-diazaspiro[3.3]heptan-2- yl)methanone;

N-(2-(azetidin-3-yl)ethyl)-4-(2,2-difluoro-7-((5-methoxy- 7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

(S)-N-(2-(azetidin-3-yl)ethyl)-4-(2,2-difluoro-7-((5-meth oxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

(R)-N-(2-(azetidin-3-yl)ethyl)-4-(2,2-difluoro-7-((5-meth oxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamide;

6-(4-(4-(azeti din- l-yl)piperi dine- l-carbonyl)phenyl)-7-((5-methoxy-7-methyl- IH-indol- 4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(4-(azetidin-l-yl)piperidine-l-carbonyl)p henyl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

(2R,4r,6S)-6-(4-(4-(azetidin-l-yl)piperidine-l-carbonyl)p henyl)-7-((5-methoxy-7- methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

6-(4-((R)-4-cyclopropyl-3-(hydroxymethyl)piperazine-l-car bonyl)phenyl)-7-((5- methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane -2-carbonitrile;

(2R,4s,6S)-6-(4-((R)-4-cyclopropyl-3-(hydroxymethyl)piper azine-l-carbonyl)phenyl)-7- ((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]no nane-2-carbonitrile;

(2R,4r,6S)-6-(4-((R)-4-cyclopropyl-3-(hydroxymethyl)piper azine-l-carbonyl)phenyl)-7- ((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]no nane-2-carbonitrile;

4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)meth yl)-7-azaspiro[3.5]nonan-6- yl)-N-(2-azaspiro[3.3]heptan-6-yl)benzamide;

(S)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-azaspiro[3.3]heptan-6-yl)benza mide;

(R)-4-(2,2-difluoro-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-azaspiro[3.3]heptan-6-yl)benza mide; l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6- yl)benzoyl)pyrrolidine-3 -carboxylic acid;

(R)-l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidine-3-carboxylic acid; (R)-l -(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-rnethyl-lH-indol-4-y l)rnethyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidine-3-carboxylic acid;

1-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzoyl)pyrrolidine-3 -carboxylic acid;

(S)-l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidine-3-carboxylic acid;

(S)-l-(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-in dol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidine-3-carboxylic acid;

2-(l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan- 6-yl)benzoyl)pyrrolidin-3-yl)acetic acid;

2-((S)-l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH -indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidin-3-yl)acetic acid;

2-((S)-l-(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH -indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidin-3 -yl)acetic acid;

2-(l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan- 6-yl)benzoyl)pyrrolidin-3-yl)acetic acid;

2-((R)-l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH -indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidin-3 -yl)acetic acid;

2-((R)-l-(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH -indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidin-3 -yl)acetic acid;

6-(4-(4-cyclopropyl-3-oxopiperazine-l-carbonyl)phenyl)-7- ((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carbonitrile;

(2R,4s,6S)-6-(4-(4-cyclopropyl-3-oxopiperazine-l-carbonyl )phenyl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

(2S,4r,6S)-6-(4-(4-cyclopropyl-3-oxopiperazine-l-carbonyl )phenyl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

6-(4-(6-cyclopropyl-2,6-diazaspiro[3.3]heptane-2-carbonyl )phenyl)-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

(2R,4s,6S)-6-(4-(6-cyclopropyl-2,6-diazaspiro[3.3]heptane -2-carbonyl)phenyl)-7-((5- methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane -2-carbonitrile; (2S,4r,6S)-6-(4-(6-cyclopropyl-2,6-diazaspiro[3.3]heptane-2- carbonyl)phenyl)-7-((5- methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane -2-carbonitrile;

6-(4-((R)-4-cyclopropyl-3-(hydroxymethyl)piperazine-l-car bonyl)phenyl)-7-((5- methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane -2-carbonitrile;

(2S,4s,6S)-6-(4-((R)-4-cyclopropyl-3-(hydroxymethyl)piper azine-l-carbonyl)phenyl)-7- ((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]no nane-2-carbonitrile;

(2S,4r,6S)-6-(4-((R)-4-cyclopropyl-3-(hydroxymethyl)piper azine-l-carbonyl)phenyl)-7- ((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]no nane-2-carbonitrile;

4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6-yl)- N-(2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)benzamide;

4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-cyclopropyl-2-azaspiro[3.3]hep tan-6-yl)benzamide;

4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)-N-(2-cyclopropyl-2-azaspiro[3.3]hep tan-6-yl)benzamide;

7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methyl)-6-(4-(6- isopropyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile;

(2R,4s,6S)-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-6-(4-(6-isopropyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile;

(2R,4r,6S)-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-6-(4-(6-isopropyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile;

6-(4-(6-cyclopropyl-2,6-diazaspiro[3.3]heptane-2-carbonyl )phenyl)-7-((5-cyclopropyl-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

(2R,4s,6S)-6-(4-(6-cyclopropyl-2,6-diazaspiro[3.3]heptane -2-carbonyl)phenyl)-7-((5- cyclopropyl-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]no nane-2-carbonitrile;

(2R,4r,6S)-6-(4-(6-cyclopropyl-2,6-diazaspiro[3.3]heptane -2-carbonyl)phenyl)-7-((5- cyclopropyl-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]no nane-2-carbonitrile;

6-(4-(6-cyano-2,6-diazaspiro[3.3]heptane-2-carbonyl)pheny l)-7-((5-cyclopropyl-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

(2S,4s,6S)-6-(4-(6-cyano-2,6-diazaspiro[3.3]heptane-2-car bonyl)phenyl)-7-((5- cyclopropyl-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]no nane-2-carbonitrile; (2S,4r,6S)-6-(4-(6-cyano-2,6-diazaspiro[3.3]heptane-2-carbon yl)phenyl)-7-((5- cyclopropyl-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]no nane-2-carbonitrile;

7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methyl)-6-(4-(6- ethyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile;

(2R,4s,6S)-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-6-(4-(6-ethyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile;

(2R,4r,6S)-7-((5-cyclopropyl-7-methyl-lH-indol-4-yl)methy l)-6-(4-(6-ethyl-2,6- diazaspiro[3.3]heptane-2-carbonyl)phenyl)-7-azaspiro[3.5]non ane-2-carbonitrile; l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7 -azaspiro[3.5]nonan-6- yl)benzoyl)-3-methylpyrrolidine-3 -carboxylic acid;

1-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-3-methylpyrrolidine-3-carbo xylic acid;

1 -(4-((2 S,4r, 6 S)-2-cy ano-7-((5 -methoxy-7-methyl- 1 H-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)-3-methylpyrrolidine-3-carbo xylic acid;

2-(l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan- 6-yl)benzoyl)pyrrolidin-3-yl)acetic acid;

2-((S)-l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH -indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidin-3 -yl)acetic acid;

2-((S)-l-(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH -indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidin-3-yl)acetic acid;

2-(l-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan- 6-yl)benzoyl)pyrrolidin-3-yl)acetic acid;

2-((R)-l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH -indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidin-3 -yl)acetic acid;

2-((R)-l-(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH -indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoyl)pyrrolidin-3 -yl)acetic acid;

4-(4-(2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl )-7-azaspiro[3.5]nonan-6- yl)benzamido)bicyclo[2.2.2]octane-l-carboxylic acid;

4-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol- 4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)bicyclo[2.2.2]octane-l-car boxylic acid; 4-(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)bicyclo[2.2.2]octane-l -carboxylic acid;

6-(4-(6-cyclobutyl-2,6-diazaspiro[3.3]heptane-2-carbonyl) phenyl)-7-((5-cyclopropyl-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonane-2-carboni trile;

(2R,4s,6S)-6-(4-(6-cyclobutyl-2,6-diazaspiro[3.3]heptane- 2-carbonyl)phenyl)-7-((5- cyclopropyl-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]no nane-2-carbonitrile;

(2S,4r,6S)-6-(4-(6-cyclobutyl-2,6-diazaspiro[3.3]heptane- 2-carbonyl)phenyl)-7-((5- cyclopropyl-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]no nane-2-carbonitrile; or a pharmaceutically acceptable salt of any of the foregoing.

[000260] In some embodiments, R ¹ is -R ^V OR ⁷ , -R'NR ^X R ⁹ , -R ^v S(O)tR ¹⁰ , -R ^V CN, -R ^V C(O)NR ⁸ R ⁹ , -R ^v S(O)tNR ⁸ R ⁹ , -R ^V NR ⁸ C(O)R ¹⁰ , -R ^v NR ⁸ C(O)OR ⁱ⁰ , -R ^V NR ⁸ C(O)NR ⁸ R ⁹ , -R ^v NR ⁸ S(O)tR ⁱ⁰ , -R ^v -C _3-6 cycloalkyl, -R ^v -4- to 6-membered heterocyclyl or -R ^v -5-to 6-membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl of -R ^v -C ₃ -6cycloalkyl, -R ^v -4- to 6-membered heterocyclyl or -R ^v -5-to 6-membered membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; and R ¹² and R ^,2a is as described herein.

[000261] In some embodiments, R ¹ is -R ^V OR ⁷ , -R ^V NR ⁸ R ⁹ , -R ^v S(O)tR ¹⁰ , -R ^V CN, -(CR^z- C(R ^a )(R ^b )-

(CR ^c R ^d ) _z -C(O)OR ⁷ , -R ^V C(O)NR ⁸ R ⁹ , -R ^v S(O)tNR ⁸ R ⁹ , -R ^V NR ⁸ C(O)R ¹⁰ , -R ^V NR ⁸ C(O)OR ¹⁰ , -R'NR ⁸ C(O)NR ⁸ R ⁹ , -R ^v NR ⁸ S(O)tR ¹⁰ , -R ^v -C ₃ -6cycloalkyl, -R ^v -4- to 6-membered heterocyclyl or -R ^v -5- to 6-membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl of -R ^v -C ₃ - ecycloalkyl, -R ^v -4- to 6-membered heterocyclyl or -R ^v -5-to 6-membered membered heteroaryl is optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a ; and R ^a , R ^b , R ^c , R ^d , R ^v , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ R ¹⁰ , R ⁵ , R ⁶ R ¹² , R ^12a , t and z are as described herein.

[000262] In certain embodiments, provided herein are compounds of Formula (Ic), (Ic’), (Ic”), (Ic’ ”), (Ve), (Ve’), (Vie), (Vie’), (Vie”), (Vie’ ”) (Vile), (Vile’), (Vile”), (Vile’”) (Ville), (Ville’), (Ville”), (Ville’ ”) (IXe), (IXe’), (IXe”), (IXe’ ”), (Xe), (Xe’), (Xe”), (Xe’ ”), (Xg), (Xg”), (Xg’”), (XIc), (Xie), (Xie”), (Xie’”), (Xlg), (Xlg”), (Xlg’”), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is independently halo, cyano, or haloC _1-3 alkyl; and the remaining variables are as described elsewhere herein for Formula (Ic), (Tc’), (Ic”), (Ic” ’), (Ve), (Ve’), (Vie), (Vie’), (Vie”), (Vie’”) (Vile), (Vile’), (Vile”), (Vile’”) (Ville), (Ville’), (Ville”), (Vine’”) (IXe), (IXe’), (IXe”), (IXe’”), (Xe), (Xe’), (Xe”), (Xe’”), (Xg), (Xg”), (Xg’”), (XIc), (Xie), (Xie”), (Xie’”), (Xlg), (Xlg”), (Xlg’”), respectively. In certain embodiments, provided herein are compounds of Formula (Ic), (Ic’), (Ic”), (Ic’”), (Ve), (Ve’), (Vie), (Vie’), (Vie”), (Vie’”) (Vile), (Vile’), (Vile”), (Vile’”) (Ville), (Ville’), (Ville”), (Ville’”) (IXe), (IXe’), (IXe”), (IXe’”), (Xe), (Xe’), (Xe”), (Xe’”), (Xg), (Xg”), (Xg’”), (XIc), (Xie), (Xie”), (Xie”’), (Xlg), (Xlg”), (Xlg’”), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is cyano or haloC _1-3 alkyl; and the remaining variables are as described elsewhere herein for Formulae (Ic), (Ic’), (Ic”), (Ic’”), (Ve), (Ve’), (Vie), (Vie’), (Vie”), (Vie’”) (Vile), (Vile’), (Vile”), (Vile’”) (Ville), (Ville’), (Ville”), (Vine’”) (IXe), (IXe’), (IXe”), (IXe’”), (Xe), (Xe’), (Xe”), (Xe’”), (Xg), (Xg”), (Xg’”), (XIc), (Xie), (Xie”), (Xie’”), (Xlg), (Xlg”), (Xlg’”), respectively. In certain embodiments, provided herein are compounds of Formula (Ic), (Ic’), (Ic”), (Ic’”), (Ve), (Ve’), (Vie), (Vie’), (Vie”), (Vie’”) (Vile), (Vile’), (Vile”), (Vile’”) (Ville), (Ville’), (Ville”), (Ville’”) (IXe), (IXe’), (IXe”), (IXe’”), (Xe), (Xe’), (Xe”), (Xe’”), (Xg), (Xg”), (Xg’”), (XIc), (Xie), (Xie”), (Xie’”), (Xlg), (Xlg”), (Xlg’”), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is cyano or fluoroC _1-3 alkyl; and the remaining variables are as described elsewhere herein for Formulae (Ic), (Ic’), (Ic”), (Ic’”), (Ve), (Ve’), (Vie), (Vie’), (Vie”), (Vie’”) (Vile), (Vile’), (Vile”), (Vile’”) (Ville), (Ville’), (Ville”), (Ville’”) (IXe), (IXe’), (IXe”), (IXe’”), (Xe), (Xe’), (Xe”), (Xe’”), (Xg), (Xg”), (Xg’”), (XIc), (Xie), (Xie”), (Xie’”), (Xlg), (Xlg”), (Xlg’”), respectively. In certain embodiments, provided herein are compounds of Formula (Ic), (Ic’), (Ic”), (Ic’”), (Ve), (Ve’), (Vie), (Vie’), (Vie”), (Vie’”) (Vile), (Vile’), (VHe”), (Vile’”) (Ville), (Ville’), (Ville”), (Ville’”) (IXe), (IXe’), (IXe”), (IXe’”), (Xe), (Xe’), (Xe”), (Xe’”), (Xg), (Xg”), (Xg’”), (XIc), (Xie), (Xie”), (Xie”’), (Xlg), (Xlg”), (Xlg’”), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is cyano, -CHF2 or -CF3; and the remaining variables are as described elsewhere herein for Formulae (Ic), (Ic’), (Ic”), (Ic”’), (Ve), (Ve’), (Vie), (Vie’), (Vie”), (Vie’”) (Vile), (Vile’), (VHe”), (Vile’”) (Ville), (Ville’), (Ville”), (Ville’”) (IXe), (IXe’), (IXe”), (IXe’”), (Xe), (Xe’), (Xe”), (Xe’”), (Xg), (Xg”), (Xg’”), (XIc), (Xie), (Xie”), (Xie’”), (Xlg), (Xlg”), (Xlg’”), respectively.

[000263] In certain embodiments, provided herein are compounds of Formula (III), (III’), (Vb) or (Vb’), or a pharmaceutically acceptable salt thereof, wherein X ¹ and X ² are each independently CH or CR ^X ; R ^x is fluoro, chloro or methyl; R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl; R ⁵ is halo, C _1-3 alkyl, C _3-5 cycloalkyl, haloC _1-3 alkyl, haloC _1-3 alkoxy or C _1-3 alkoxy; R ⁶ is halo, cyano, C _1-3 alkyl, C _3-5 cycloalkyl, haloC _1-3 alkyl, C _1-3 alkoxy or haloCi- salkoxy; R ^2a and R ^2b , together with the carbon atom to which they are attached, form C3- ecycloalkyl substituted with one, two or three groups each independently selected from R ¹¹ ; and R ¹¹ is cyano or haloC _1-3 alkyl. In certain embodiments, provided herein are compounds of Formula Formula (III), (III’), (Vb) or (Vb’), or a pharmaceutically acceptable salt thereof, wherein X ¹ and X ² are each independently CH or CR ^X ; R ^x is fluoro, chloro or methyl; R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloCi-ralkyl; R ⁵ is halo, C _1-3 alkyl, Cs-scycloalkyl, haloCi- salkyl, haloC _1-3 alkoxy or C _1-3 alkoxy; R ⁶ is halo, cyano, C _1-3 alkyl, Cs-scycloalkyl, haloC _1-3 alkyl, C _1-3 alkoxy or haloC 1-3 alkoxy; R ^2a and R ^2b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl substituted with one, two or three groups each independently selected from R ¹¹ ; and R ¹¹ is cyano or fluoroC _1-3 alkyl. In certain embodiments, provided herein are compounds of Formula (III), (III’), (Vb) or (Vb’), or a pharmaceutically acceptable salt thereof, wherein X ¹ and X ² are each independently CH or CR ^X ; R ^x is fluoro, chloro or methyl; R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloC 1-3 alkyl; R ⁵ is halo, C _1-3 alkyl, C _3-5 cycloalkyl, haloCi- salkyl, haloC _1-3 alkoxy or C _1-3 alkoxy; R ⁶ is halo, cyano, C _1-3 alkyl, Cr-scycloalkyl, haloC _1-3 alkyl, C _1-3 alkoxy or haloC 1-3 alkoxy; R ^2a and R ^2b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl substituted with one, two or three groups each independently selected from R ¹¹ ; and R ¹¹ is cyano, -CHF2 or -CF3.

[000264] In certain embodiments, provided herein are compounds of Formula (III), (III’), (Vb) or (Vb’), or a pharmaceutically acceptable salt thereof, wherein X ¹ and X ² are each independently CH or CR ^X ; R ^x is fluoro or chloro; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; R ^2a and R ^2b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl substituted with one, two or three groups each independently selected from R ¹¹ ; and R ¹¹ is cyano or haloC _1-3 alkyl. In certain embodiments, provided herein are compounds of Formula (III), (III’), (Vb) or (Vb’), or a pharmaceutically acceptable salt thereof, wherein R ^x is fluoro or chloro; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; R ^2a and R ^2b , together with the carbon atom to which they are attached, form Cs-ecycloalkyl substituted with one, two or three groups each independently selected from R ¹¹ ; and R ¹¹ is cyano or fluoroC _1-3 alkyl. In certain embodiments, provided herein are compounds of Formula (TFT), (ITT’), (Vb) or (Vb’), or a pharmaceutically acceptable salt thereof, wherein R ^x is fluoro or chloro; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; R ^2a and R ^2b , together with the carbon atom to which they are attached, form C3- ecycloalkyl substituted with one, two or three groups each independently selected from R ¹¹ ; and R ¹¹ is cyano, -CHF2 or -CF3.

[000265] In certain embodiments, provided herein are compounds of Formula (ITT), (ITT’), (Vb) or (Vb’), or a pharmaceutically acceptable salt thereof, wherein X ¹ and X ² are each independently CH or CR ^X ; R ^x is fluoro; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; R ^2a and R ^2b , together with the carbon atom to which they are attached, form Cs-ecycloalkyl substituted with one, two or three groups each independently selected from R ¹¹ ; and R ¹¹ is cyano or haloC _1-3 alkyl.

[000266] In certain embodiments, provided herein are compounds of Formula (ITT), (ITT’), (Vb) or (Vb’), or a pharmaceutically acceptable salt thereof, wherein X ¹ and X ² are each independently CH or CR ^X ; R ^x is fluoro; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; R ^2a and R ^2b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl substituted with one, two or three groups each independently selected from R ¹¹ ; and R ¹¹ is cyano or fluoroC _1-3 alkyl.

[000267] In certain embodiments, provided herein are compounds of Formula (III), (III’), (Vb) or (Vb’), or a pharmaceutically acceptable salt thereof, wherein X ¹ and X ² are each independently CH or CR ^X ; R ^x is fluoro; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; R ^2a and R ^2b , together with the carbon atom to which they are attached, form C _3-6 cycloalkyl substituted with one, two or three groups each independently selected from R ¹¹ ; and R ⁿ is cyano, -CHF2 or -CF3.

[000268] In certain embodiments, provided herein are compounds of Formula (la), (la’), (la’), (lb), (lb’), (Vc), (Vc’), (V”), (Vd), (Vd’) or (Vd”), or a pharmaceutically acceptable salt thereof, wherein are each independently N, CH or

CR ^X ; R ^x is fluoro, chloro or methyl; R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl; R ⁵ is halo, C _1-3 alkyl, Cs-scycloalkyl, haloC _1-3 alkyl, haloC _1-3 alkoxy or C _1-3 alkoxy; R ⁶ is halo, cyano, Ci- 3alkyl, C _3-5 cycloalkyl, haloC _1-3 alkyl, C _1-3 alkoxy or haloC _1-3 alkoxy; k is 0; p is 1 or 2; and R ¹¹ , R ^lla and R ^llb are each independently halo. Tn certain embodiments, provided herein are compounds of Formula (la), (la’), (la’), (lb), (lb’), (Vc), (Vc’), (Vc”), (Vd), (Vd’) or (Vd”), or a pharmaceutically acceptable salt thereof, wherein are each independently N, CH or CR ^X ; R ^x is fluoro, chloro or methyl;

R ⁴ is hydrogen, halo, cyano, C _1-3 alkyl or haloC _1-3 alkyl; R ⁵ is halo, C _1-3 alkyl, Cs-scycloalkyl, haloCi- salkyl, haloC _1-3 alkoxy or C _1-3 alkoxy; R ⁶ is halo, cyano, C _1-3 alkyl, Cs-scycloalkyl, haloC _1-3 alkyl, C _1-3 alkoxy or haloC 1-3 alkoxy; k is 0; p is 1 or 2; and R ¹¹ , R ^lla and R ^llb are each fluoro.

In certain embodiments, provided herein are compounds of Formula (la), (la’), (la’), (lb), (lb’), (Vc), (Vc’), (Vc”), (Vd), (Vd’) or (Vd”), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ , R ^lla and R ^llb is fluoro; and the remaining variables are as described elsewhere herein for Formula (la), (la’), (la’), (lb), (lb’), (Vc), (Vc’), (Vc”), (Vd), (Vd’) and (Vd”), respectively. In certain embodiments, provided herein are compounds of Formula (la), (la’), (la’), (lb), (lb’), (Vc), (Vc’), (Vc”), (Vd), (Vd’) or (Vd”), or a pharmaceutically acceptable salt thereof, wherein chloro; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; k is 0; p is 1 or 2; and R ¹¹ , R ^lla and R ^llb are each fluoro.

[000269] In certain embodiments, provided herein are compounds of Formula (la), (la’), (la’), (lb), (lb’), (Vc), (Vc’), (Vc”), (Vd), (Vd’) or (Vd”), or a pharmaceutically acceptable salt thereof, wherein

CR ^X ; R ^x is fluoro; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; k is 0; p is 1 or 2; and R ¹¹ , R ^lla and R ^llb are each fluoro.

[000270] In certain embodiments, provided herein are compounds of (la), (la’), (la’), (lb),

(lb’), (Vc), (Vc’), (Vc”), (Vd), (Vd’) or (Vd”), or a pharmaceutically acceptable salt thereof, wherein are each independently N, CH or CR ^X ; R ^x is fluoro or chloro; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; and R ¹¹ , R ^lla and R ^llb are each fluoro. In certain embodiments, provided herein are compounds of Formula (la), (la’), (la’), (lb), (lb’), (Vc), (Vc’), (Vc”), (Vd), (Vd’) or (Vd”), or a pharmaceutically acceptable salt thereof, wherein R ^x is fluoro; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; and R ¹¹ , R ^lla and R ^llb are each fluoro.

In certain embodiments, provided herein are compounds of Formula (lb), (lb’), (Vd), (Vd’), (Vd”), (Vid), (Vid’), (Vid”), (Vlld), (VIId’)(VIId”), (Vllld), (Vllld’) or (Vind”),or a pharmaceutically acceptable salt thereof, wherein R ^lla and R ^llb are each independently halo, cyano, oxo, C _1-3 alkyl, deuteroC _1-3 alkyl, haloC _1-3 alkyl, cyanoC _1-3 alkyl, hydroxyC _1-3 alkyl, Ci- 3alkoxyC _1-3 alkyl, haloC _1-3 alkoxyC _1-3 alkyl, hydroxyl, C _1-3 alkoxy, haloC _1-3 alkoxy, C _1-3 alkylthio, haloC _1-3 alkylthio, C _1-3 alkylsulfonyl, C _1-3 alkylsulfmyl, or haloC _1-3 alkylsulfinyl; or two R ¹¹ groups, together with the carbon atom to which they are attached, form C _3-5 cycloalkyl, 3- to 6- membered heterocyclyl or oxo; and the remaining variables are as described elsewhere herein for Formulae (lb), (lb’), (Vd), (Vd’), (Vd”), (Vid), (Vid’), (Vid”), (Vlld), (VIId’)(VIId”), (Vllld), (Vllld’) and (Vllld”), respectively.

[000271] In certain embodiments, provided herein are compounds of Formula (I), wherein are each independently N, CH or CR ^X ; R ^x is fluoro or chloro; R ^2a is -NR ¹⁵ R ¹⁶ and R ^2b is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; R ¹⁵ is hydrogen, C _1-3 alkyl or haloC _1-3 alkyl; R ¹⁶ is Cs-ecycloalkyl optionally substituted with one, two or three groups each independently selected from R ¹² ; each R ¹² is independently halo or haloC _1-3 alkyl; and R ¹ , R ³ , k and n are as described for Formula (I). In certain embodiments, provided herein are compounds of Formula (I), wherein Ring A is phenyl, n is 0 or 1; R ^x is fluoro; R ^2a is -NR ¹⁵ R ¹⁶ and R ^2b is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroCi. salkyl or haloC _1-3 alkyl; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; R ¹⁵ is hydrogen, C _1-3 alkyl or haloC _1-3 alkyl; R ⁹ is Cs-scycloalkyl optionally substituted with one, two or three groups each independently selected from R ¹² ; each R ¹² is independently halo or haloC _1-3 alkyl; and R ¹ , R ³ , and k are as described for Formula (I).

[0002721 In certain embodiments, provided herein are compounds of Formula (I), wherein Ring A is phenyl; n is 0 or 1; R ^x is fluoro or chloro; R ^2a is -NR ¹⁵ R ¹⁶ and R ^2b is hydrogen, deuterium, halogen, C _1-3 alkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; R ¹⁵ is hydrogen; R ¹⁶ is C _3-6 cyclobutyl, or bicyclo[l.l. l]pentan-l-yl wherein the cyclobutyl, or bicyclo[l. l.l]pentan-l-yl is optionally substituted with one, two or three groups each independently selected from R ¹² ; each R ¹² is independently fluoro or trifluoromethyl; and R ¹ , R ³ , and k are as described for Formula (I) . In certain embodiments, provided herein are compoundsof Formula (I), wherein Ring A is phenyl; n is 0 or 1; R ^x is fluoro or chloro; R ^2a is -NR ¹⁵ R ¹⁶ and R ^2b is hydrogen, deuterium, halogen, Ci- salkyl, deuteroC _1-3 alkyl or haloC _1-3 alkyl; R ⁴ is hydrogen, fluoro, chloro or methyl; R ⁵ is methoxy or cyclopropyl; R ⁶ is methyl; R ¹⁵ is hydrogen; R ¹⁶ is Cs-ecyclobutyl optionally substituted with one, two or three R ¹² ; each R ¹² is independently fluoro or trifluoromethyl; and R ¹ , R ³ , and k and are as described for Formula (I).

[000273] In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is 5- to 6-membered heteroaryl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a . In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is 5-membered heteroaryl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is 6-membered heteroaryl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a

[000274] In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is 3- to 12-membered heterocyclyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a . In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is 4-membered heterocyclyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a . In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is 5-membered heterocyclyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is 6-membered heterocyclyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a . In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is 7-membered heterocyclyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a . In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is 7- to 12-membered heterocyclyl optionally substituted with one, two or three groups each independently selected from R ¹² and R ^12a .

[000275] In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, piperazinonyl, 4,7-diazaspiro[2.5]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, azaspiro[3.3]heptanyl, and oxa-6-azaspiro[3.3]heptanyl.

In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring

[000276] In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is selected from the group consisting of

[000277] In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is selected from the group consisting [000278] In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is selected from the group consisting of

[000279] In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is selected from the group consisting

[000280] In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is selected from the group consisting of , and

[000281] In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is selected from the group consisting of

[000282] In certain embodiments, provided herein are compounds of Formula (Vc”), wherein ring C is selected from the group consisting of

[000283] In certain embodiments, provided herein are compounds of Formula (Vc”), o X N-J- wherein ring C is

[000284] In some embodiments, the compound of Formula (I) is not a compound selected from the following list of compounds: [000285] 4-(7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-2-oxa-7-azas piro[3.5]nonan-6- yl)benzoic acid;

[000286] 4-(7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-l-oxa-7-azas piro[3.5]nonan-6- yl)benzoic acid;

[000287] 4-(8-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-l-oxa-8-azas piro[4.5]decan-7- yl)benzoic acid;

[000288] 4-(9-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-l-oxa-9-azas piro[5.5]undecan-

8-yl)benzoic acid;

[000289] 4-(l,l-difluoro-6-((5-methoxy-7-methyl-lH-indol-4-yl)methyl) -6- azaspiro [2.5 ] octan- 5 -y l)b enzoi c aci d;

[000290] 4-(l-methoxy-6-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6- azaspiro [2.5 ] octan- 5 -y l)b enzoi c aci d;

[000291] 4-(l,l-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl) -7- azaspiro[3.5]nonan-6-yl)benzoic acid;

[000292] 4-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl) -7- azaspiro[3.5]nonan-6-yl)benzoic acid;

[000293] 4-(l-methoxy-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoic acid;

[000294] 4-(2-methoxy-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoic acid;

[000295] 4-(2-ethoxy-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoic acid;

[000296] 4-(l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-4-(trifluoro methyl)piperi din-2- yl)benzoic acid;

[000297] 4-(4-(difluoromethyl)-l-((5-methoxy-7-methyl-lH-indol-4-yl)m ethyl)piperi din-2- yl)benzoic acid;

[000298] 4-(4-fluoro-l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-4-m ethylpiperi din-2- yl)benzoic acid;

[000299] 4-(4-ethyl-4-fluoro-l-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)piperi din-2- yl)benzoic acid; [000300] 4-(4-fluoro-l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-4-p ropylpiperidin-2- yl)benzoic acid;

[000301] 4-((lR,3S,5S)-3-ethoxy-8-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-8- azabicyclo[3.2.1 ]octan- 1 -yl)benzoic acid;

[000302] 4-((2R,8R)-8-ethoxy-3-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-3- azabicyclo[3.2.1]octan-2-yl)benzoic acid;

[000303] 4-((lR,4R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-2- azabicyclo[2.2.2]octan-l-yl)benzoic acid;

[000304] 4-((3R,5R)-5-ethoxy-2-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-2- azabicyclo[2.2.2]octan-3-yl)benzoic acid;

[000305] 4-((2R,4R)-4-cyclopropoxy-l-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000306] 4-((2R,4R)-4-cyclobutoxy-l-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000307] 4-((2R,4R)-4-(cyclopentyloxy)-l-((5-methoxy-7-methyl-lH-indo l-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000308] 4-((2R,4R)-4-(cyclopropylmethoxy)-l-((5-methoxy-7-methyl-lH- indol-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000309] 4-((2R,4R)-4-(cyclobutylmethoxy)-l-((5-methoxy-7-methyl-lH-i ndol-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000310] 4-((2R,4R)-4-(cyclopentylmethoxy)-l-((5-methoxy-7-methyl-lH- indol-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000311] 4-((2R,4R)-4-(cyclohexylmethoxy)- 1 -((5-methoxy-7-methyl- lH-indol-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000312] 4-((2R,4R)-l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-4-(o xetan-3- ylmethoxy)piperidin-2-yl)benzoic acid;

[000313] 4-((2R,4R)-l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-4-(( tetrahydrofuran-

3-yl)methoxy)piperidin-2-yl)benzoic acid;

[000314] 4-((2R,4R)-l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-4-(o xetan-2- ylmethoxy)piperidin-2-yl)benzoic acid; [000315] 4-((2R,4R)-l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-4-(( tetrahydrofuran- 2-yl)methoxy)piperidin-2-yl)benzoic acid;

[000316] 4-((2R,4R)-l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-4-(( tetrahydro-2H- pyran-2-yl)methoxy)piperidin-2-yl)benzoic acid;

[000317] 4-((2R,4R)-l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-4-(( tetrahydro-2H- pyran-3-yl)methoxy)piperidin-2-yl)benzoic acid;

[000318] 4-((2R,4R)-l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-4-(( tetrahydro-2H- pyran-4-yl)methoxy)piperidin-2-yl)benzoic acid;

[000319] 4-((2R,4R)-l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-4-

(trifluoromethoxy)piperi din-2 -yl)benzoic acid;

[000320] 4-((2R,4R)-4-(difluoromethoxy)-l-((5-methoxy-7-methyl-lH-ind ol-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000321] 4-(3-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-3-azabicyclo [4.1 ,0]heptan-2- yl)benzoic acid;

[000322] 4-(3-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-3-azabicyclo [4.1 ,0]heptan-4- yl)benzoic acid;

[000323] 4-(6-ethoxy-3-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-3- azabicyclo[4.1 ,0]heptan-2-yl)benzoic acid;

[000324] 4-(6-ethoxy-3-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-3- azabicyclo[4.1.0]heptan-4-yl)benzoic acid;

[000325] 4-((2R,4R)-4-(2,2-difluorocyclopropoxy)-l-((5-methoxy-7-meth yl-lH-indol-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000326] 4-((2R,4R)-4-(2-fluoro-2-methylcyclopropoxy)-l-((5-methoxy-7 -methyl-lH- indol-4-yl)methyl)piperidin-2-yl)benzoic acid;

[000327] 4-((2R,4R)-4-(2,2-dimethylcyclopropoxy)-l-((5-methoxy-7-meth yl-lH-indol-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000328] 4-((2R,4R)-4-(3, 3 -difluorocyclobutoxy)- l-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000329] 4-(4-acetamido-l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)p iperidin-2- yl)benzoic acid; [000330] 4-((2R,4R)-4-((2,2-difluorocyclopropyl)methoxy)-l -((5-methoxy-7-methyl-lH- indol-4-yl)methyl)piperidin-2-yl)benzoic acid;

[000331] 4-((2R,4R)-4-((2-fluoro-2-methylcyclopropyl)methoxy)-l-((5-m ethoxy-7-methyl- lH-indol-4-yl)methyl)piperi din-2 -yl)benzoic acid;

[000332] 4-((2R,4R)-l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-4-(( 2- methylcyclopropyl)methoxy)piperidin-2-yl)benzoic acid;

[000333] 4-((2R,4R)-4-((2,2-dimethylcyclopropyl)methoxy)-l-((5-methox y-7-methyl-lH- indol-4-yl)methyl)piperidin-2-yl)benzoic acid;

[000334] 4-((2R,4R)- 1 -((5 -m ethoxy-7 -methyl- lH-indol-4-yl)methyl)-4-( 1 - methylcyclopropoxy)piperidin-2-yl)benzoic acid;

[000335] 4-(5-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)octahydrofuro [3,2-c]pyridin-4- yl)benzoic acid;

[000336] 4-((6S)-5-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)octahydr ofuro[3,2- c]pyridin-6-yl)benzoic acid;

[000337] 4-(6-(((5S)-5-methoxy-7-methyloctahydro-lH-indol-4-yl)methyl )-2H-614- pyrano[3,2-c]pyridin-5-yl)benzoic acid;

[000338] 4-(6-(((7S)-5-methoxy-7-methyloctahydro-lH-indol-4-yl)methyl )-2H-614- pyrano[3,2-c]pyridin-7-yl)benzoic acid;

[000339] 4-((lR)-2-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)- 1,2,3, 4-tetrahydro-214- isoquinolin-l-yl)benzoic acid;

[000340] (S)-4-(5-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-5-azaspi ro[2.5]octan-4- yl)benzoic acid;

[000341] 4-((2R,4R)-4-ethoxy-l-((6-fluoro-5-methoxy-7-methyl-lH-indol -4- yl)methyl)piperidin-2-yl)benzoic acid;

[000342] 4-((2R,4R)-l-((6-chloro-5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-4- ethoxypiperidin-2-yl)benzoic acid;

[000343] 4-((2R,4R)-4-ethoxy-l-((5-methoxy-6,7-dimethyl-lH-indol-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000344] 4-((2R,4R)- 1 -((7 -cyclopropyl-5 -methoxy- 1 H-indol-4-yl)methyl)-4- ethoxypiperidin-2-yl)benzoic acid; [000345] 4-((2R,4R)-l-((7-cyano-5-methoxy-lH-indol-4-yl)methyl)-4-eth oxypiperidin-2- yl)benzoic acid;

[000346] 4-((2R,4R)-4-ethoxy-l-((5-methoxy-7-(trifluoromethyl)-lH-ind ol-4- yl)methyl)piperidin-2-yl)benzoic acid;

[000347] 4-((2R,4R)-l-((7-(difluoromethyl)-5-methoxy-lH-indol-4-yl)me thyl)-4- ethoxypiperidin-2-yl)benzoic acid;

[000348] rac-4-((2R,4S)-4-(cyclopropylmethoxy)-l-((5-methoxy-7-(methy l-d3)-lH-indol-

4-yl)methyl)piperi din-2 -yl)benzoic acid;

[000349] 4-((2R,4R)-4-(cyclopropylmethoxy)-l-((3-fluoro-5-methoxy-7-m ethyl-lH-indol-

4-yl)methyl)piperi din-2 -yl)benzoic acid;

[000350] 4-((2R,4R)-4-ethoxy-l-(4-methyl-3,7,8,9-tetrahydropyrano[3,2 -e]indol-9- yl)piperidin-2-yl)benzoic acid;

[000351] 4-((2R,4R)-4-ethoxy-l-(4-methyl-6,7,8,9-tetrahydro-3H-benzo[ e]indol-9- yl)piperidin-2-yl)benzoic acid;

[000352] 4-((2R,4R)-4-ethoxy-l-(5-methyl-l,6-dihydro-2H-furo[3,2-e]in dol-l-yl)piperidin-

2-yl)benzoic acid;

[000353] 4-((2R,4R)-4-ethoxy-l-(4-methyl-3,6,7,8-tetrahydrocyclopenta [e]indol-8- yl)piperidin-2-yl)benzoic acid;

[000354] 4-((2R,4R)-4-ethoxy-l-(4-methyl-3,7,8,9-tetrahydrothiopyrano [3,2-e]indol-9- yl)piperidin-2-yl)benzoic acid;

[000355] 4-((2R,4R)-4-ethoxy-l-(4-methyl-6,6-dioxido-3,7,8,9-tetrahyd rothiopyrano[3,2- e]indol-9-yl)piperidin-2-yl)benzoic acid;

[000356] 4-((2R,4R)-4-ethoxy-l-(6-methoxy-8-methyl- 1,3,4, 5-tetrahydrobenzo[cd]indol-5- yl)piperidin-2-yl)benzoic acid;

[000357] 4-((2R,4R)-4-ethoxy-l-(6-methoxy-8-methyl-4,5-dihydro-lH-pyr ano[2,3,4- cd]indol-5-yl)piperidin-2-yl)benzoic acid;

[000358] 4-((2R,4R)-4-(cyclopropylmethoxy)-l-(4-methyl-3,7,8,9-tetrah ydropyrano[3,2- e]indol-9-yl)piperidin-2-yl)benzoic acid;

[000359] 4-((2R,4R)-4-(cyclopropylmethoxy)-l-(4-methyl-6,7,8,9-tetrah ydro-3H- benzo[e]indol-9-yl)piperidin-2-yl)benzoic acid; [000360] 4-((2R,4R)-4-(cyclopropylmethoxy)-l-(5-methyl-l,6-dihydro-2H -furo[3,2- e]indol- 1 -yl)piperidin-2-yl)benzoic acid;

[000361] 4-((2R,4R)-4-(cyclopropylmethoxy)-l-(4-methyl-3,6,7,8- tetrahydrocyclopenta[e]indol-8-yl)piperidin-2-yl)benzoic acid;

[000362] 4-((2R,4R)-4-(cy cl opropylmethoxy)-l-(4-methyl-3, 7,8,9- tetrahydrothiopyrano[3,2-e]indol-9-yl)piperidin-2-yl)benzoic acid;

[000363] 4-((2R, 4R)-4-(cy cl opropylmethoxy)-l-(4-methyl-6,6-dioxido-3, 7,8,9- tetrahydrothiopyrano[3,2-e]indol-9-yl)piperidin-2-yl)benzoic acid;

[000364] 4-((2R,4R)-4-(cyclopropylmethoxy)-l-(6-methoxy-8-methyl-l,3, 4,5- tetrahydrobenzo[cd]indol-5-yl)piperidin-2-yl)benzoic acid;

[000365] 4-((2R,4R)-4-(cyclopropylmethoxy)-l-(6-methoxy-8-methyl-4,5- dihydro-lH- pyrano[2,3,4-cd]indol-5-yl)piperidin-2-yl)benzoic acid;

[000366] 4-((2R,4R)-4-(cyclopropylmethoxy)-l-((5-methoxy-7-methyl-lH- indol-4- yl)methyl)piperidin-2-yl)- 1 -naphthoic acid;

[000367] 5-((2R,4R)-4-(cyclopropylmethoxy)-l-((5-methoxy-7-methyl-lH- indol-4- yl)methyl)piperidin-2-yl)quinoline-8-carboxylic acid;

[000368] 8-((2R,4R)-4-(cyclopropylmethoxy)-l-((5-methoxy-7-methyl-lH- indol-4- yl)methyl)piperidin-2-yl)quinoline-5-carboxylic acid;

[000369] 8-((2R,4R)-4-(cyclopropylmethoxy)-l-((5-methoxy-7-methyl-lH- indol-4- yl)methyl)piperidin-2-yl)imidazo[l,2-a]pyridine-5-carboxylic acid;

[000370] 5-((2R,4R)-4-(cyclopropylmethoxy)-l-((5-methoxy-7-methyl-lH- indol-4- yl)methyl)piperidin-2-yl)-6-oxo- 1 ,6-dihydropyridine-2-carboxylic acid;

[000371] 6-((2R,4R)-4-(cyclopropylmethoxy)-l-((5-methoxy-7-methyl-lH- indol-4- yl)methyl)piperidin-2-yl)-2-oxo-l,2-dihydropyridine-3 -carboxylic acid;

[000372] 4-((2R,4R)-4-(cyclopropylmethoxy)-l-((5-methoxy-7-methyl-lH- indol-4- yl)methyl)piperidin-2-yl)-5,6,7,8-tetrahydronaphthalene-l -carboxylic acid;

[000373] rac-7-((2R,4S)-4-(cyclopropylmethoxy)-l-((5-methoxy-7-methyl -lH-indol-4- yl)methyl)piperidin-2-yl)-2,3-dihydro-lH-indene-4-carboxylic acid;

[000374] 7-((2R,4R)-4-(cyclopropylmethoxy)-l-((5-methoxy-7-methyl-lH- indol-4- yl)methyl)piperidin-2-yl)-2,3-dihydrobenzofuran-4-carboxylic acid; [000375] (S)-3-(4-(cyclopropylmethoxy)-l -((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-

1.2.3.4-tetrahydroquinolin-7-yl)propanoic acid;

[000376] (S)-2-((4-(cyclopropylmethoxy)-l-((5-methoxy-7-methyl-lH-ind ol-4-yl)methyl)-

1.2.3.4-tetrahydroquinolin-7-yl)oxy)acetic acid;

[000377] 4-(9-((5-methoxy-7-(methyl-d3)-lH-indol-4-yl)methyl)-l-oxa-9 - azaspiro[5.5]undecan-8-yl)benzoic acid;

[000378] 4-(7-((5-methoxy-7-(methyl-d3)-lH-indol-4-yl)methyl)-l-oxa-7 - azaspiro[3.5]nonan-6-yl)benzoic acid;

[000379] 4-(8-((5-methoxy-7-(methyl-d3)-lH-indol-4-yl)methyl)-l-oxa-8 - azaspiro[4.5]decan-7-yl)benzoic acid;

[000380] (4-(l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)piperidin-2- yl)phenyl)phosphonic acid;

[000381] rac-4-((2R,4S)-4-ethoxy-l-((5-methoxy-7-(methyl-d3)-lH-indol -4- yl)methyl)piperidin-2-yl)benzoic acid;

[000382] 4-((2R,4R)-4-ethoxy-l-((5-ethyl-7-methyl-lH-indol-4-yl)methy l)piperidin-2- yl)benzoic acid;

[000383] N-hydroxy-4-(l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)pip eridin-2- yl)benzamide;

[000384] (4-(l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)piperidin-2- yl)phenyl)boronic acid;

[000385] imino(4-(l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)piperid in-2- yl)phenyl)(methyl)-16-sulfanone;

[000386] (S)-4-(4,4-difluoro-l-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)piperidin-2- yl)benzoic acid;

[000387] 4-(5-ethoxy-2-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-2- azabicyclo[4.1.0]heptan-l-yl)benzoic acid;

[000388] 4-(5-ethoxy-2-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-2- azabicyclo[4.1 ,0]heptan-3-yl)benzoic acid;

[000389] 4-(l-ethoxy-6-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-6- azaspiro [2.5 ] octan- 5 -y l)b enzoi c aci d; [000390] 4-(l -ethoxy-7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzoic acid;

[000391] methyl 4-(4-(ethylamino)-l-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)piperidin-2-yl)benzoate;

[000392] 7-(l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)piperidin-2-y l)-2,3- dihydrobenzofuran-4-carboxylic acid;

[000393] 8-(l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)piperidin-2-y l)imidazo[l,2- a]pyridine-5-carboxylic acid;

[000394] 4-((2S)-3-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-3- azabicyclo[4.1.0]heptan-2-yl)benzoic acid;

[000395] 4-(((2R,4R)-2-(4-(2H-tetrazol-5-yl)phenyl)-4-(cyclopropylmet hoxy)piperidin-l- yl)methyl)-5-methoxy-7-methyl-lH-indole;

[000396] 5-(l-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)piperidin-2-y l)-6-oxo-l,6- dihydropyridine-2-carboxylic acid;

[000397] 4-(8-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-2,2-dimethyl -l-oxa-8- azaspiro[4.5]decan-7-yl)benzoic acid;

[000398] 4-((2S)-4-(cyclopropylmethoxy)-l-((5-methoxy-7-methyl-lH-ind ol-4- yl)methyl)piperidin-2-yl)-2-fluorobenzoic acid; and

[000399] 4-[4-(ethylamino)-l-[(5-methoxy-7-methyl-lH-indol-4-yl)methy l]-2-piperidinyl]-

2-fluoro-benzoic acid; or stereoisomers and pharmaceutically acceptable salts thereof.

[000400] In some embodiments, the compound of Formula (I) is not a compound disclosed in PCT Publication No. WO2022/028527, which is incorporated by reference herein for purposes of excluding the compounds disclosed therein.

[000401] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[000402] The compounds of the present disclosure include the compounds themselves, as well as their salts. Salts for the purposes of the present disclosure are preferably pharmaceutically acceptable salts of the compounds according to the present disclosure. Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the disclosure are also included. A salt, for example, can be formed between an anion and a positively charged substituent (e g., amino) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.

[000403] As used herein, “pharmaceutically acceptable salts” refer to acid or base addition salts, including but not limited to, base addition salts formed by the compound of Formula (I) having an acidic moiety with pharmaceutically acceptable cations, for example, sodium, potassium, magnesium, calcium, aluminum, lithium, and ammonium. Lists of suitable salts may be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; S. M. Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci. 1977, 66, 1-19; and “Pharmaceutical Salts: Properties, Selection, and Use. A Handbook”; Wermuth, C. G. and Stahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8]; each of which is incorporated herein by reference in its entirety.

[000404] The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not. An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature.

[000405] Examples of isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁶ C1, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I and ¹³¹ I. Particular isotopic variants of a compound according to the present disclosure, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body. Compounds labelled with ³ H, ¹⁴ C and/or ¹⁸ F isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required. [000406] Accordingly, certain embodiments provide isotopically enriched analogs of the compounds disclosed herein, for example, deuterated analogs, to improve pharmacokinetics (PK), pharmacodynamics (PD) and toxicity profiles of the compounds.

[000407] In some embodiments, hydrogen atoms of the compounds described herein may be replaced with deuterium atoms. In certain embodiments, “deuterated” as applied to a chemical group and unless otherwise indicated, refers to a chemical group that is isotopically enriched with deuterium in an amount substantially greater than its natural abundance, for example, at least 90% deuterium in the specified position(s).

[000408] Isotopic variants of the compounds according to the present disclosure can be prepared by various, including, for example, the methods described below and in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein.

C. FORMULATION

[000409] In certain embodiments, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier .

[000410] The term “pharmaceutical composition” as used herein is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[000411] The term “pharmaceutically acceptable carrier” refers to a carrier or an adjuvant that may be administered to a patient, together with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. [000412] The amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined, and variations will necessarily occur depending on the target, the host, and the route of administration, etc. Generally, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 milligram (mg) to about 100 mg or from about 1 mg to about 1000 mg, according to the particular application. For convenience, the total daily dosage may be divided and administered in portions during the day.

[000413] Solid dosage forms of the instant pharmaceutical compositions for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[000414] Solid pharmaceutical compositions of a similar type may also be employed as fdlers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[000415] The solid dosage forms of the instant pharmaceutical compositions of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other pharmaceutical coatings. They may optionally contain opacifying agents and can also be of a formulation that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding pharmaceutical compositions which can be used include polymeric substances and waxes.

[000416] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. [000417] Liquid dosage forms of the instant pharmaceutical compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[000418] Suspensions of the instant compounds, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar, and tragacanth, and mixtures thereof.

[000419] Pharmaceutical compositions of the present disclosure for injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[000420] Besides inert diluents, these pharmaceutical compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, dispersing agents, sweetening, flavoring, and perfuming agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. The compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. Such formulations may provide more effective distribution of the compounds. [000421] The pharmaceutical compositions that are injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[000422] Dosage forms for topical administration of a compound or pharmaceutical composition of the present disclosure include powders, patches, sprays, ointments, and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants which may be required.

[000423] The compounds and compositions described herein can, for example, be administered orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously or intramuscularly), topically, rectally, nasally sublingually or buccally, with a dosage ranging from about 0.01 milligrams per kilogram (mg/kg) to about 1000 mg/kg, (e.g., from about 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg) every 4 to 120 hours, or according to the requirements of the particular drug, dosage form, and/or route of administration. Other routes of administration include enteric, intraarterial, intraperitoneal and intrathecal administration. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep. 50, 219-244 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). In certain embodiments, the compositions are administered by oral administration or by injection. The methods herein contemplate administration of a therapeutically effective amount of compound or compound composition to achieve a desired or stated effect. Typically, the pharmaceutical compositions of the present disclosure will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.

[000424] Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, and the judgment of the treating physician. [000425] Dosage forms include from about 0.001 mg to about 2,000 mg (including, from about 0.001 mg to about 1,000 mg, from about 0.001 mg to about 500 mg, from about 0.01 mg to about 250 mg) of a compound of Formula (I) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein. The dosage forms can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent.

[000426] Appropriate dosage levels may be determined by any suitable method. Preferably, the active substance is administered at a frequency of 1 to 4 times per day for topical administration, or less often if a drug delivery system is used. Nevertheless, actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve a desired therapeutic response for a particular patient, composition and mode of administration, without being intolerably toxic to the patient. In certain cases, dosages may deviate from the stated amounts, in particular as a function of age, gender, body weight, diet and general health status of the patient, route of administration, individual response to the active ingredient, nature of the preparation, and time or interval over which administration takes place. Thus, it may be satisfactory in some cases to manage with less than the aforementioned minimum amount, whereas in other cases the stated upper limit may be exceeded. It may in the event of administration of larger amounts be advisable to divide these into multiple individual doses spread over the day.

D. METHODS OF USE

[000427] Provided herein are methods of using the compounds disclosed herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment, prevention or amelioration of a disease or disorder that is mediated by or otherwise affected via complement alternative pathway. In yet certain embodiments, provided herein are methods of using the compounds disclosed herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment, prevention or amelioration of a disease or disorder that is mediated by or otherwise affected via complement factor B (CFB). In yet certain embodiments, provided herein are methods of using the compounds disclosed herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment, prevention or amelioration of a disease or disorder that is mediated by or otherwise affected via inhibition of the complement alternative pathway. In yet certain embodiments, provided herein are methods of using the compounds disclosed herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment, prevention or amelioration of a disease or disorder that is mediated by or otherwise affected via inhibition of complement factor B.

[000428] Some embodiments provide a method of treating a disease or disorder mediated by complement activation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[000429] In some embodiments, the disease or disorder is selected from the group consisting of: 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 inflammatory diseases, neurological disorders such as multiple sclerosis, stroke, Guillain Barre Syndrome, spinal cord injury, traumatic brain injury, Parkinson's disease, Alzheimer’s disease, schizophrenia, amyotrophic lateral sclerosis (ALS), Huntington’s disease, multifocal motor neuropathy, autism spectrum disorders, schizophrenia , drug-induced neurotoxicity; disorders of inappropriate or undesirable complement activation such as hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, inflammatory disorders, paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis (including dense deposit disease and C3 glomerulonephritis), IgA nephropathy, membranous nephropathy, including idiopathic membranous nephropathy, diabetic nephropathy, atypical hemolytic uremic syndrome, Hemolytic uremic syndrome, STEC-HUS (Shiga toxin-producing Escherichia coli hemolytic uremic syndrome), peridontitis, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, protein-losing enteropathy (CHAPLE syndrome), inflammation or autoimmune diseases such as Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis , renal ischemia, acute kidney injury, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis; COVID- 19, immune complex disorders and autoimmune diseases, rheumatoid arthritis, osteoarthritis, Spondyloarthropathies including psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, tissue regeneration, neural regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, pulmonary fibrosis, asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis including anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides, other vasculitides, including Henoch-Schdnlein vasculitis, Buerger’s vasculitis, cryoglobulinemia, Kawasaki disease, Takayasu arteritis, immune complex- associated inflammation, antiphospholipid syndrome, glomerulonephritis and obesity; immune thrombocytopenia, Cold agglutinin disease, Warm autoimmune hemolytic anemia (wAIHA), thrombotic thrombocytopenic purpura (TTP), abdominal aortic aneurisms, Grave’s disease, immune complex membranoproliferative glomerulonephritis (IC-MPGN), neuromyelitis optica (NMO), and hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA).

[000430] In some embodiments, the disease or disorder is selected from the group consisting of: neurological disorders, multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, disorders of inappropriate or undesirable complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during I L-2 therapy, inflammatory disorders, inflammation of autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, thermal injury including burns or frostbite, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post- pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious disease or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration and neural regeneration. In addition, other known complement related disease are lung disease and disorders such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritant gases and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn, freeze), asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, parasitic diseases, Goodpasture's Syndrome, pulmonary vasculitis, Pauci-immune vasculitis, immune complex-associated inflammation; eye diseases including age related macular degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-choroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion uveitis (including Behcet's disease and other sub-types of uveitis), and antiphospholipid syndrome.

[000431] In some embodiments, the disease or disorder is selected from the group consisting of: multiple sclerosis, stroke, Guillain Barre Syndrome, traumatic brain injury, Parkinson's disease, hyperacute allograft rejection, xenograft rejection, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion conditions, myocardial infarction, balloon angioplasty, post- pump syndrome in cardiopulmonary bypass or renal bypass, atherosclerosis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, and myasthenia gravis.

[000432] In some embodiments, the disease or disorder is selected from the group consisting of: dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, pulmonary fibrosis, organic dust diseases, asthma, hypersensitivity pneumonitis, Goodpasture's Syndrome, pulmonary vasculitis, and Pauci-immune vasculitis.

[000433] In some embodiments, the disease or disorder is selected from the group consisting of: age related macular degeneration, diabetic retinopathy, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, birdshot retino-choroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, and retinal vein occlusion uveitis (including Behcet's disease and other sub-types of uveitis), and antiphospholipid syndrome.

[0004341 In some embodiments, the disease or disorder is immune complex membranoproliferative glomerulonephritis (IC-MPGN).

[000435] In some embodiments, the disease or disorder is neuromyelitis optica (NMO).

[000436] In some embodiments, the disease or disorder is hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA).

[000437] Some embodiments provide a method of treating a kidney disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[000438] In some embodiments, the kidney disease is selected from the group consisting of: chronic kidney disease, diabetic nephropathy, glomerular kidney disease, complement C3 glomerulopathy (C3G), IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), dense- deposit disease (DDD), minimal change disease (MCD), paroxysmal nocturnal hemoglobinuria (PNH), ANCA-associated vasculitis, lupus nephritis, polycystic kidney disease (PKD), and immune complex membranoproliferative glomerulonephritis (IC-MPGN).

[000439] In some embodiments, the kidney disease is chronic kidney disease.

[000440] In some embodiments, the kidney disease is diabetic nephropathy.

[000441] In some embodiments, the kidney disease is glomerular kidney disease.

[000442] In some embodiments, the kidney disease is complement C3 glomerulopathy (C3G).

[000443] In some embodiments, the kidney disease is IgA nephropathy (IgAN).

[000444] In some embodiments, the kidney disease is membranous nephropathy (MN).

[000445] In some embodiments, the kidney disease is focal segmental glomerulosclerosis (FSGS).

[000446] In some embodiments, the kidney disease is atypical hemolytic uremic syndrome (aHUS).

[000447] In some embodiments, the kidney disease is dense-deposit disease (DDD).

[000448] In some embodiments, the kidney disease is minimal change disease (MCD). [000449] In some embodiments, the kidney disease is paroxysmal nocturnal hemoglobinuria (PNH).

[000450] In some embodiments, the kidney disease is ANCA-associated vasculitis.

[000451] In some embodiments, the kidney disease is lupus nephritis.

[000452] In some embodiments, the kidney disease is polycystic kidney disease (PKD).

[000453] In some embodiments, the kidney disease is immune complex membranoproliferative glomerulonephritis (IC-MPGN).

F. EXAMPLES

[000454] The starting materials used for the synthesis were synthesized according to known literature procedures or obtained from commercial sources, such as, but not limited to, Sigma- Aldrich, Fluka, Acros Organics, Alfa Aesar, VWR Scientific, and the like. Nuclear Magnetic Resonance (NMR) analysis was conducted using a Bruker Acuity 300 MHz or 400 MHz spectrometer with an appropriate deuterated solvent. NMR chemical shift (5) is expressed in units of parts per million (ppm). LCMS analysis was conducted using a Waters Acquity UPLC with a QDA MS detector using a Waters C18 BEH 1.7 pm, 2.1 x 50 mm column, eluting with 95:5 to 0: 100 H20:MeCN + 0.1% formic acid at a flow rate of 0.6 mL/min over 3.5 minutes. Alternatively, LCMS was conducted using a Shimadzu LCMS-2020 using a Ascentis Express C18 2.7 pm, 3.0 x 50 mm column, eluting with 95:5 to 0: 100 H2O:MeCN + 0.05% trifluoroacetic acid at a flow rate of 1.5 mL/min over 3.0 minutes. The MS detector was set up to scan under both positive and negative mode ions ranging from 100-1200 Daltons. General methods for the preparation of compounds can be modified using appropriate reagents and conditions for the introduction of the various moieties found in the structures as provided herein.

[000455] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. Various alternatives to the embodiments of the disclosure described herein may be employed in practicing the subject matter. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby. [000456] Standard abbreviations and acronyms as defined in Journal of Organic

Chemistry’s Author’s Guideline at used herein. Other abbreviations and acronyms used herein are as follows:

Table 1: Abbreviations

GENERAL SYNTHETIC SCHEMES

[000457] In some embodiments, compounds described herein can be prepared as outlined in the following general synthetic schemes. The methods below may be conducted on pure enantiomers, mixture of enantiomers, pure diastereomers or mixture of diastereomers. The diastereomers may be separated by normal, reverse or scCCh column chromatography, utilizing achiral or chiral stationary phases. The enantiomers may be separated by normal, reverse or scCCh column chromatography, utilizing chiral stationary phases.

[000458]

Method A: Alpha-Arylation of NBoc-heterocycles:

[000459] A Boc-protected cyclic amine A-1 is treated with a catalyst, such as NiCl2, ligand (dtbbpy), pyridine with TBAI as additive, followed by addition of an aryl or heteroaryl halide A- 2 with Zn and DTBP. A similar procedure is described by Hegui Gong et. al. in Angew. Chem. hit. Ed. 2022, 61, e202201662. The product can be deprotected using strong acid, such as TFA, to afford the free amine A-3. Where R1 is an acid or ester group, A-3 may then undergo the reductive amination step shown in Method D.

[000460] Alternatively, the amide can be synthesized from ester A-4, hydrolyzed to acid A- 5 and couple to amines to yield the amides A-6.

Method B: Cycloaddition Chemistry for Spiro Analogs:

[000461] The ketone compound B-l can be converted to an alkene B-2 using standard chemistry, such as a Wittig olefination. The olefin serves as a suitable partner for a cycloaddition reaction which, in the presence of a suitable reagent (e.g., carbene, ketene) can afford a spirocyclic compound B-3. The spirocycle can contain the indole moiety or be protected and converted to the final products of the claim using chemistry described in the methods within.

Method C: Reductive Amination for Amine Analogs

[000462] Ketone intermediate C-l can be reacted with an amine C-2, under standard reductive amination conditions (e.g., NaBH(OAc)3, DCE) to yield the desired product C-3. The nitrogen of the central heterocycle can be substituted with a protecting group, or it may contain the indole moiety.

Method D: Reductive Amination: deprotection

(and/or ester hydrolysis where R ¹ is -C(O)OR ⁷ ester) (and/or ether formation where R ¹ is -OR ⁷ ether)

[000463] The cyclic amine A-3, which can be obtained from any of the methods listed here, either directly, or via deprotection of an JV-protected analog (e.g. hydrogenation of a A'-Cbz protected piperidine) is treated with D-2 under reductive amination conditions to yield product D- 3. This is then followed by protecting group cleavage and, where R ¹ is -C(O)OR ⁷ ester, followed by ester hydrolysis, to yield the corresponding carboxylic acid or related targets D-4. In some embodiments, the deprotection step includes ether formation to yield the corresponding target D- 4 where R ¹ is -OR ⁷ ether.

Method E amide formation:

[000464] D-4 may be converted to amide product E-2 using chemistry described in the methods herein.

PREPARATION OF INTERMEDIATES

Inter mediate A: Preparation of (±) cis and trans-benzyl 4-((tert- butyldiphenylsilyl)oxy)-2-(4-(methoxycarbonyl)phenyl)piperid ine-l-carboxylate

[000465] Intermediate A was prepared in a similar fashion as described in J. Med.

Chem. 2020, 63, 11, 5697-5722, using methyl 4-iodobenzoate instead of 4-bromobenzonitrile.

Intermediate B: Preparation of (±1 trans-benzyl 4-((7crZ-hutyldiphenylsilyl)oxy)-2-(4-

(methoxycarbonyl)phenyl)piperidine-l-carboxylate [000466] Intermediate A was loaded a silica gel column and purified by column chromatography eluting with a 0-100% EtOAc in hexanes as a gradient to afford the title product, as the first eluting peak.

Intermediate C; Preparation of (+)-</s- benzyl 4-((7c77-butyldiphenylsilyl)oxy)-2-(4- (methoxycarbonyl)phenyl)piperidine-l-carboxylate

Intermediate A was loaded a silica gel column and purified by column chromatography eluting with a 0-100% EtOAc in hexanes as a gradient to afford the title product as the second eluting peak.

Intermediate D; Preparation of (±)-terf-butyl 4-((4-hydroxy-2-(4- (methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy-7-m ethyl- indole-l- carboxylate

Intermediate D

[000467] Step 1: Preparation of methyl 4-(4-((/c/7-butyldiphenyl silyl )oxy)piperi din-2 - yl)benzoate: To a solution of Intermediate A (1.0 equiv) in THF (0.03 M) and EtOAc (0.03 M) was added 10 wt% Pd/C (0.1 equiv). The mixture was degassed with Ni and then stirred at 20-25 °C for 16 hours under a H2 atmosphere. The reaction mixture was degassed with N2, filtered through a plug of celite to remove the Pd/C, washed with CH2CI2, and concentrated under reduced pressure to afford a residue. The mixture was purified by column chromatography through silica gel using an eluent of 0% to 10% MeOH in CH2CI2 as a gradient. The desired product containing fractions were concentrated and dried under vacuum to afford a grey oil (99% yield).

[000468] Step 2: Preparation of Zc/7-butyl 4-((4-((te/7-butyldiphenylsilyl)oxy)-2-(4- (methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy-7-m ethyl-l/7-indole-l -carboxylate: To a solution of methyl 4-(4-((tert-butyldiphenylsilyl)oxy)piperidin-2-yl)benzoate (1.0 equiv) in DCE (0.2 M) was added tert-butyl 4-formyl-5-methoxy-7-methyl-indole-l -carboxylate (1.2 equiv) and NaBH(OAc)3 (2.8 equiv). The resulting mixture was stirred at 20-25 °C for 16 hours while monitoring by LCMS and TLC analysis. The solution was quenched by addition of saturated aqueous NH4Q solution, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue. The mixture was purified by column chromatography through silica gel, using an eluent of 0% to 30% ethyl acetate in petroleum ether as a gradient. The desired product containing fractions were concentrated and dried under vacuum to afford a colorless oil (63% yield). LCMS (ESI) m/z 747 (M+l) ⁺ .

[000469] Step 3: Preparation of tert-butyl 4-((4-hydroxy-2-(4-

(methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy- 7-methyl-l//-indole-l -carboxylate: To a solution of tert-butyl 4-((4-((tert-butyldiphenylsilyl)oxy)-2-(4- (methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy-7-m ethyl-l/7-indole-l -carboxylate (1.0 equiv) in THF (0.15 M) was added TBAF (2.0 equiv) at 0 °C and the mixture was stirred at 20-25 °C for 16 hours. The reaction was monitored by LCMS and TLC analysis and stopped at completion. The reaction mixture was concentrated under reduced pressure, the resulting crude residue was diluted with H2O and extracted with EtOAc several times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a residue. The mixture was purified by column chromatography through silica gel, eluting with 0% to 10% ethyl acetate in petroleum ether as a gradient. The desired product containing fractions were concentrated and dried under vacuum to afford a colorless oil (75% yield). LCMS (ESI) m/z 509 (M+l) ⁺ .

Intermediate E; Preparation of fez7-hiityl 4-((4-hydroxy-2-(4-

(methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy- 7-methyl-lH-indole-l- carboxylate

Intermediate E was synthesized in a similar fashion as Intermediate D, using Intermediate

C as starting material instead of Intermediate A.

Intermediate F: Preparation of (±)-fert-butyl 4-(( 4-amino-2-(4-

(methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy- 7-methyl-lH-indole-l- carboxylate

[000470] Step 1: Preparation of (±)-methyl 4-((c/.s)-4-((/c77- butyldiphenylsilyl)oxy)piperidin-2-yl)benzoate: To a solution of (±)-(czs)-benzyl 4-((/erl- butyldiphenylsilyl)oxy)-2-(4-(methoxycarbonyl)phenyl)piperid ine-l -carboxylate (Intermediate C, 1.0 equiv) in MeOH (0.33 M) was added Pd/C (10 wt%, 0.12 equiv) under a nitrogen atmosphere. The suspension was degassed and purged with 112 a total of 3 times. The mixture was stirred at 20-25 °C for 7 hours under a H2 (15 psi) atmosphere. After this time, LCMS indicated the completion of the reaction. The reaction mixture was filtered through a pad of celite, and the filtrate concentrated under reduced pressure to afford (±)-methyl 4-((cz.s)-4-((Zc'/7- butyldiphenylsilyl)oxy)piperidin-2-yl)benzoate as a colorless gum. The crude product was used for the next step without further purification. LCMS (ESI) m/z 475 (M+l) ⁺ . [000471] Step 2: Preparation of (±)-tert-butyl 4-(((cz\)-4-((ter/-butyldiphenylsilyl)oxy)-2- (4-(methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy- 7-methyl-l/7-indole-l- carboxylate: (±)-Methyl 4-((c/.sj-4-((/cz7-butyldiphenylsilyl)oxy)piperidin-2-yl)ben zoate (1.0 equiv) and /cz7-butyl 4-formyl-5-methoxy-7-methyl-l//-indole-l -carboxylate (0.5 equiv) were dissolved in MeOH (0.7 M, mixture A) and stirred at 20-25 °C. In another round bottom flask, NaBHsCN (2.0 equiv) and ZnCh (1.0 equiv) were dissolved in MeOH (0.7 M, mixture B). Both mixtures were vigorous stirred under a nitrogen atmosphere at 20-25 °C. After 1.5 hours, mixture B was added to mixture A, and the final combined reaction mixture was stirred under a nitrogen atmosphere for 20 hours at 35 °C. After this time, another portion of tert-butyl 4-formyl-5- methoxy-7-methyl-l//-indole-l-carboxylate (0.5 equiv) was added to the mixture at 20-25 °C and stirring was continued at 35 °C for another 24.5 hours. The reaction mixture was evaporated under vacuum to remove the solvent and the residue was diluted with EtOAc. The suspension was then washed with H2O, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography through silica gel, eluting with 0% to 5% ethyl acetate in petroleum ether as a gradient, to yield the title product as a white solid (52% yield). 'H-NMR (400 MHz, CDCh): d 8.04 (d, J - 8.4 Hz, 2H), 7.65-7.62 (m, 4H), 7.56 (d, J = 7.2 Hz, 2H), 7.47 (d, J = 3.6 Hz, 1H), 7.42-7.39 (m, 2H), 7.37-7.33 (m, 4H), 6.64- 6.62 (m, 2H), 3.92 (s, 3H), 3.75 (s, 3H), 3.74-3.73 (m, 1H), 3.52 (d, J = 12.4 Hz, 1H), 3.13 (d, J = 12.4 Hz, 1H), 3.05 (dd, J = 11.6, 2.8 Hz, 1H), 2.74-2.69 (m, 1H), 2.57 (s, 3H), 1.91-1.88 (m, 1H), 1.84-1.78 (m, 2H), 1.64 (s, 2H), 1.62 (s, 9H), 1.01 (s, 9H). LCMS (ESI) m/z 747 (M+l) ⁺ .

[000472] Step 3: Preparation of (±)-te/7-butyl 4-(((cz.s)-4-hydroxy-2-(4- (methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy-7-m ethyl-U/-indole-l -carboxylate: To a solution of (±)-tez7-butyl 4-(((c/s)-4-((tert-butyldiphenylsilyl)oxy)-2-(4- (methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy-7-m ethyl-l//-indole-l -carboxylate (1.0 equiv) in THF (0.22 M) was added TBAF (1 M, 4.0 equiv) at 0 °C. The mixture was stirred at 20-25 °C for 4 hours. The reaction mixture was quenched by addition of saturated aqueous NH4Q solution at 20-25 °C, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography through silica gel, eluting with 0 to 67% ethyl acetate in petroleum ether as a gradient, to yield the title compound as a yellow solid (83% yield). ^X H-NMR (400 MHz, CDCh): 5 8.07 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 7.6 Hz, 2H), 7.49 (d, J = 3.6 Hz, 1H), 6.68 (s, 1H), 6.62 (d, J = 3.6 Hz, 1H), 3.93 (s, 3H), 3.80 (s, 3H), 3.77-3.71 (m, 1H), 3.60 (d, J = 12.4 Hz, 1H), 3.28-3.22 (m, 2H), 2.92-2.87 (m, 1H), 2.59 (s, 3H), 2.11-2.07 (m, 1H), 2.03-2.02 (m, 1H), 1.89-1.84 (m, 1H), 1.70-1.64 (m, 1H), 1.62 (s, 9H), 1.55- 1.45 (m, 2H). LCMS (ESI) m/z 509 (M+l) ⁺ .

[000473] Step 4: Preparation of (±)-/e/7-butyl 5-methoxy-4-(((cA)-2-(4-

(methoxycarbonyl)phenyl)-4-((methylsulfonyl)oxy)piperidin - 1 -yl)methyl)-7-methyl- LH-indole-

1 -carboxylate: To a solution of (±)-/c/7-butyl 4-(((cA)-4-hydroxy-2-(4-

(methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy- 7-methyl-l/7-indole-l -carboxylate (1.0 equiv) in CH2CI2 (0.15 M) was added EhN (2.5 equiv) followed by MsCl (1.8 equiv) at 0 °C. The mixture was then stirred at 20-25 °C for 0.5 hours. TLC analysis indicated the completion of the reaction. The reaction mixture was diluted with CH2CI2, washed with H2O, brine, dried over anhydrous Na2SOr, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography through silica gel, eluting with 0% to 20% ethyl acetate in petroleum ether as a gradient, to give the title compound as a yellow solid (87% yield). 'H-NMR (400 MHz, CDCh): 8 8.08 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 7.6 Hz, 2H), 7.49 (d, J = 3.6 Hz, 1H), 6.68 (s, 1H), 6.55 (d, J - 4.0 Hz, 1H), 4.78-4.71 (m, 1H), 3.93 (s, 3H), 3.80 (s, 3H), 3.59 (d, J = 12.0 Hz, 1H), 3.33 (dd, J = 11.6, 2.6 Hz, 1H), 3.24 (d, J = 12.4 Hz, 1H), 2.98 (s, 3H), 2.97- 2.92 (m, 1H), 2.59 (s, 3H), 2.27-2.22 (m, 1H), 2.17-2.10 (m, 1H), 2.02-2.01 (m, 1H), 1.96-1.90 (m, 1H), 1.84-1.74 (m, 1H), 1.62 (s, 9H).

[000474] Step 5: Preparation of (±)-tert-butyl 4-(((/ra/z.s)-4-azido-2-(4- (methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy-7-m ethyl-l//-indole-l -carboxylate: A mixture of (=)-/c/7-butyl 5-methoxy-4-(((c7.s)-2-(4-(methoxycarbonyl)phenyl)-4- ((methylsulfonyl)oxy)piperidin-l-yl)methyl)-7-methyl-l//-ind ole-l-carboxylate (1.0 equiv), NaNs (3.0 equiv) in DMF (0.17 M) was heated to 100 °C for 3 hours. TLC indicated completion of the reaction, and the mixture was cooled to 20-25 °C, diluted with EtOAc and quenched with saturated aqueous NaHCCh solution to pH ~9. The organic phase was then separated, washed with water, brine, dried over anhydrous Na2SOr, and then evaporated under reduced pressure to afford a residue. The residue was purified by column chromatography through silica gel, eluting with 0% to 10% EtOAc in petroleum ether as a gradient, to give the title compound a white solid (71% yield). 'H-NMR (400 MHz, CDCh): 8 8.06 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 4.0 Hz, 1H), 6.68 (s, 1H), 6.62 (d, J = 3.6 Hz, 1H), 3.98-3.94 (m, 1H), 3.93 (s, 3H), 3 81 (s, 3 H), 3.64 (d, J = 12 0 Hz, 1H), 3.54-3.51 (m, 1H), 3.31 (d, J = 12.0 Hz, 1H), 2.71 -2.67 (m, 1H), 2.59 (s, 3H), 2.41-2.34 (m, 1H), 1.91-1.82 (m, 2H), 1.80-1.70 (m, 2H), 1.62 (s, 9H).

[0004751 Step 6: Preparation of (±)-ZczZ-butyl 4-(((Zz'<:z/zsj-4-armno-2-(4- (methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy-7-m ethyl-l//-indole-l -carboxylate formic acid salt: A mixture of (±)-Zc/7-butyl 4-(((7ra//.s)-4-azido-2-(4- (methoxycarbonyl)phenyl)piperidin-l-yl)methyl)-5-methoxy-7-m ethyl-177-indole-l -carboxylate (1.0 equiv), PPhs (1.5 equiv) in THF (0.20 M) was degassed and purged with nitrogen a total of 3 times, after which the mixture was heated to 50 °C for 3 hours with stirring. An aqueous solution of NHr’HiO (12 M, 60 equiv) was added to the mixture and the mixture was stirred at 50 °C for another 16 hours. The reaction mixture was diluted with EtOAc, and the organic phase separated, washed with brine, dried over anhydrous Na2SOr, fdtered and concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography through silica gel, eluting with 100:0 to 90:10 CTEChMeOH as a gradient to afford the title compound as a formic acid salt (white solid, 69% yield). 'H-NMR (1 equiv formic acid salt, 400 MHz, CD3OD): 8 8.54 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 4.0 Hz, 1H), 6.76 (s, 1H), 6.61 (d, J - 4.0 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.76 (d, J - 12.1 Hz, 1H), 3.72 (dd, J 10.4, 3.1 Hz, 1H), 3.53-3.50 (m, 2H), 2.83-2.77 (m, 1H), 2.57-2.51 (m, 4H), 2.22-2.15 (m, 1H), 2.00-1.91 (m, 2H), 1.80 (d, J = 14.0 Hz, 1H), 1.63 (s, 9H). LCMS (ESI) m/z 508 (M+l) ⁺ .

Intermediate G: Preparation of (±)-ZcrZ-butyl 5-methoxy-4-((2-(4- (mcthoxycarbonyl)phcnyl)-4-oxopiperidin-l-yl)mcthyl)-7-methy l- indole-l- carboxylate

Intermediate G

[000476] To a solution of (COC1)2 (1.2 equiv) in CH2CI2 (0.2 M) at -78 °C was added

DMSO (2.5 equiv) and the mixture was stirred at -78 °C for 5 minutes. A solution of Zc/Z-butyl 4-((4-hydroxy-2-(4-(methoxycarbonyl)phenyl)piperidin-l -yl)methyl)-5-methoxy-7-methyl-177- indole-1 -carboxylate (Intermediate E, 1 equiv) in CH2CI2 (0.16 M) was added to the above mixture while maintaining the reaction temperature at -78 °C. Stirring at this temperature was continued for 30 minutes and was followed by addition of EtsN (5 equiv). The cooling bath was removed, and the reaction mixture was stirred for 1 hour at 20-25 °C. Analysis by TLC revealed starting material was consumed and one major new spot had formed. The solution was quenched by addition of saturated aqueous NH4CI solution at 0 °C and the mixture was extracted with EtOAc. Then the combined organic layers were washed with brine, dried over Na2SO4, fdtered, and concentrated under reduced pressure. The residue was purified by column chromatography through silica gel, eluting with 0% to 50% ethyl acetate in petroleum ether as a gradient. The desired product containing fractions were concentrated and dried under vacuum to afford a white solid (75% yield). ’H-NMR (400 MHz, CDCh) 8 8.09 (d, J = 8 Hz, 2H), 7.62 (d, J = 8 Hz, 2H), 7.52 (d, J = 4 Hz, 1H), 6.71 (s, 1H), 6.61 (d, J = 4 Hz, 1H), 3.94 (s, 3H), 3.82 (s, 3H), 3.77 (d, J = 12 Hz, 1H), 3.70 (dd, J= 12, 4 Hz, 1H), 3.41 (d, J = 12 Hz, 1H), 3. 17 - 3.09 (m, 1H), 2.78- 2.66 (m, 1H), 2.61 (s, 3H), 2.59-2.51 (m, 2H), 2.50-2.42 (m, 1H), 2.32 (dd, J = 12, 4 Hz, 1H), 1.63 (s, 9H). LCMS (ESI) m/z 525 (M+19) ⁺ .

Intermediate H: Preparation of benzyl (.S)-2-(4-(niethoxycarhonyl)plienyl)-4- oxopiperidine-l-carboxylate

The racemic ketone from Intermediate A, step 2 route was purified by chiral SFC method to obtain Intermediate H.

Intermediate I: Preparation of (±) benzyl-4-hydroxy-2-(4-

(methoxycarbonvDphenyl)pineridine-l-carboxylate [000477] To a solution of (±)-//z/u.s-benzyl 4-((ter/-butyldiphenylsilyl)oxy)-2-(4- (methoxycarbonyl)phenyl)piperidine-l -carboxylate (Intermediate B, 1.0 equiv) in THF (0.15 M) was slowly added TBAF (1.0 M, 4.0 equiv) dropwise at 0 °C. After addition, the reaction mixture was stirred at 20-25 °C for 16 hours. Analysis by TLC (petroleum etherethyl acetate = 1 :1) indicated no reactant remained and a new spot had formed. The reaction mixture was concentrated under reduced pressure, diluted with H2O, and extracted with ethyl acetate (3 x). The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by column chromatography through silica gel (eluent of 0% to 70% ethyl acetate in petroleum ether as a gradient). The desired product containing fractions were concentrated and dried under vacuum to afford a yellow oil (85% yield).

Intermediate J: Preparation of benzyl (5 ^l )-6-(4-(methoxycarbonyl)phenyl)-2-oxo-7- azaspiro[3.5]nonane-7-carboxylate

Intermediate J

[000478] Step 1: Preparation of benzyl (5)-2-(4-(methoxycarbonyl)phenyl)-4- methylenepiperidine-1 -carboxylate: To a nitrogen-purged, flame-dried flask, containing a cooled (-20 °C) suspension of methyltriphenylphosphonium bromide (1.5 equiv) in THF (0.17 M) was added a solution of lithium bis(trimethylsilyl)amide (1 M in THF, 1.5 equiv). The mixture was stirred for 2 hours at -20 °C under a nitrogen atmosphere, after which a solution of benzyl (S)-2- (4-(m ethoxy carbonyl)phenyl)-4-oxopiperi dine- 1 -carboxylate (Intermediate H,1.0 equiv) in THF (0.57 M) was added. The reaction mixture was slowly warmed to 20-25 °C and stirred for 64 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated aqueous NH4Q and diluted with EtOAc. The aqueous layer was separated and extracted three times with EtOAc. The combined organic layers were washed with brine, concentrated under reduced pressure, applied to a silica precartridge and purified by column chromatography through silica gel, eluting with a 0-100% EtOAc in hexanes as a gradient. The fractions from the major peak eluting at 35% EtOAc in hexanes were combined and concentrated under reduced pressure to afford a colourless oil (14% yield). LCMS (ESI) m/z 366 (M+l) ⁺ . [000479] Step 2: Preparation of benzyl (6S)-1 ,1 -dichloro-6-(4-(methoxycarbonyl)phenyl)-2- oxo-7-azaspiro[3.5]nonane-7-carboxylate: To a suspension of benzyl (.S')-2-(4- (methoxycarbonyl)phenyl)-4-methylenepiperidine-l carboxylate (1.0 equiv) and zinc-copper couple (14 equiv) in ether (0.18 M) under a nitrogen atmosphere was added, dropwise, a solution of 2,2, 2-tri chloroacetyl chloride (3.3 equiv) in 1 ,2-dimethoxy ethane (3.3 M). The reaction mixture was stirred at 20-25 °C for 18 hours, after which additional 2,2,2-trichloroacetyl chloride (9.75 equiv) in 1,2-dimethoxy ethane (3.3 M) was added and the reaction mixture was stirred at 20-25 °C for another 6 hours. The reaction mixture was quenched with saturated aqueous NaHCCh solution at 0 °C, filtered, and the solids were washed with EtOAc. The aqueous layer was separated and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, concentrated under reduced pressure, and purified by column chromatography, eluting with a 0-100% EtOAc in hexanes gradient. The fractions from the major peaks eluting near 80% EtOAc in hexanes were combined and concentrated under vacuum to afford an orange oil (92% yield). LCMS (ESI) m/z 476 (M+l) ⁺ .

[000480] Step 3: Preparation of benzyl (S)-6-(4-(methoxycarbonyl)phenyl)-2-oxo-7- azaspiro[3.5]nonane-7-carboxylate: To a solution of benzyl (65)-l,l-dichloro-6-(4- (methoxycarbonyl)phenyl)-2-oxo-7-azaspiro[3.5]nonane-7-carbo xylate (1.0 equiv) in saturated NH4Q in methanol (0.2 M) was added zinc powder (5.8 equiv) at 20-25 °C . The reaction mixture was stirred at 20-25 °C for 19 hours. The mixture was applied to a silica gel precartridge and purified by column chromatography through silica gel, eluting with a 0-100% EtOAc in hexanes gradient. The fractions from the major peak eluting at 78% EtOAc in hexanes were combined and concentrated under reduced pressure to afford a white solid (86% yield). LCMS (ESI) m/z 408 (M+l) ⁺ .

Intermediate K; Preparation of 6y)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-17/- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid

Intermediate K

[000481] Step 1: Preparation of benzyl (5)-2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7- azaspiro[3.5]nonane-7-carboxylate: To a solution of benzyl (5)-6-(4-(methoxycarbonyl)phenyl)- 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate J, 1.0 equiv) in CH2CI2 (0.3 M) at 0 °C was added dropwise, diethylaminosulfur trifluoride (3.0 equiv), over 1 hour using a syringe pump. The reaction mixture was stirred at 0 °C for 2 hours and at 20-25 °C for 19 hours. The reaction was cooled to 0 °C and quenched by dropwise addition of saturated aqueous saturated NaHCCh solution. The mixture was stirred at 0 °C for 1 hour, the organic layer was separated, and the aqueous layer was further extracted three times with CH2CI2. The combined organic layers were dried over anhydrous MgSCh, concentrated under reduced pressure, applied to a silica precartridge, and purified by column chromatography through silica gel, eluting with a 0-100% EtOAc in hexanes gradient. The fraction from the major peak eluting at 82% EtOAc in hexanes was concentrated under reduced pressure to afford the desired product as a white solid (53% yield). LCMS (ESI) m/z 430 (M+l) ⁺ .

[000482] Step 2: Preparation of methyl (S)-4-(2,2-difluoro-7-azaspiro[3.5]nonan-6- yl)benzoate: To a solution of benzyl (5)-2,2-difluoro-6-(4-(methoxycarbonyl)phenyl)-7- azaspiro[3.5]nonane-7-carboxylate (1.0 equiv) in methanol (0.06 M) was added palladium on carbon (10 wt%, 0.02 equiv). The flask was purged with N2, followed by purging with H2, and the mixture was stirred under a H2 atmosphere at 20-25 °C for 18 hours. Additional palladium on carbon (10 wt%, 0.02 equiv) was added and the reaction mixture was stirred at 20-25 °C for 2 hours under an atmosphere of H2. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford a colourless solid (96% yield) which was used in the next step without further purification. LCMS (ESI) m/z 296 (M+l) ⁺ . [000483] Step 3: Preparation of tert-butyl (5)-4-((2,2-difluoro-6-(4-

(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl )-5-methoxy-7-methyl-17/-indole- 1 -carboxylate: To a solution of methyl (S)-4-(2,2-difluoro-7-azaspiro[3.5]nonan-6-yl)benzoate (1.0 equiv) in DCE (0.15 M) was added tert-butyl 4-formyl-5-methoxy-7-methyl-l//-indole-l- carboxylate (1.3 equiv) and 3 A molecular sieves. The reaction mixture was stirred at 20-25 °C for 1 hour. Sodium triacetoxyborohydride (2.50 equiv) was added, and the reaction mixture was stirred for 18 hours at 20-25 °C. The reaction was quenched with a small amount of water, applied to a silica precartridge, and purified by column chromatography through silica gel, eluting with a 0- 100% EtOAc in hexanes as a gradient. The fractions from the peaks eluting at 80% EtOAc in hexanes were combined and concentrated under reduced pressure to afford a colourless oil (80% yield). LCMS (ESI) m/z 569 (M+l) ⁺ .

[000484] Step 4: Preparation of (5)-4-(2,2-difluoro-7-((5-methoxy-7-methyl-l/7-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid: To a solution of tert-butyl (5)-4-((2,2- difluoro-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan- 7-yl)methyl)-5-methoxy-7- methyl-17/-indole-l-carboxylate (1.0 equiv) in 1: 1 v/v THF/MeOH (0.09 M) was added 1 M aqueous LiOH solution (5.0 equiv). The reaction mixture was heated to 80 °C with stirring for 2 hours. The reaction mixture was acidified with dilute formic acid, applied to a C18 precartridge, and purified by reverse phase column chromatography through a Cl 8 column, eluting with a 10- 100% MeCN in water as a gradient containing 0.1% HCO2H. The fractions from the peak eluting at 46% MeCN in water were combined and lyophilized to afford a light pink powder (63% yield). 'H-NMR (400 MHz, DMSO): 8 10.82 (s, 1H), 7.97 (d, J = 7.9 Hz, 2H), 7.68 (d, J = 7.8 Hz, 2H), 7.25 (t, J = 2.9 Hz, 1H), 6.65 (s, 1H), 6.45 (s, 1H), 3.70 (s, 3H), 3.53 (d, J = 11.8 Hz, 1H), 3.23 (s, 1H), 3.16 (d, J = 1 E9 Hz, 1H), 2.67 (d, J = 12.4 Hz, 1H), 2.59 (d, J = 13.1 Hz, 1H), 2.46 (s, 1H), 2.43 (s, 3H), 2.29 (t, J = 13.3 Hz, 2H), 1.98 (s, 1H), 1.70 (d, J = 9.0 Hz, 2H), 1.53 (d, J = 9.5 Hz, 2H). LCMS (ESI) m/z 455 (M+l) ⁺ .

Intermediate L; Preparation of (S)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid

Intermediate L

[000485] Step 1: Preparation of (±) tert-butyl 2,2-difluoro-6-(6-(methoxycarbonyl)pyridin- 3-yl)-7-azaspiro[3.5]nonane-7-carboxylate. A flame dried 20 mL microwave vial, equipped with a stir bar, rubber septum and needle temperature probe, was put under an atmosphere of nitrogen, charged with tert-butyl 2,2-difluoro-7-azaspiro[3.5]nonane-7-carboxylate (1.00 eq), N,N,N',N'- tetram ethylethane- 1,2-diamine (1.30 eq), THF (20 V) and cooled to - 78 °C with a dry ice/acetone bath. sec-Butyllithium 1.4 M in cyclohexane (1.30 eq) was added dropwise, not allowing internal temperature to rise above - 70 °C and allowed to stir for 10 min. Zinc chloride anhydrous in 2- methyltetrahydrofuran 1.9 M (1.35 eq) was added dropwise, maintaining internal temperature below - 70 °C. After complete addition of the zinc chloride, the solution was allowed to mix for 5 min followed by removal of the dry ice/acetone bath, the mixture was allowed to warm to room temperature and was allowed to mix for a further 10 min once at room temperature. Methyl 5- iodopicolinate (1.40 eq) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (0.100 eq) were as a solid under a stream of nitrogen. The microwave vial was sealed, and heated at 65 °C for 3 h. The reaction mixture was then allowed to cool to room temperature and 20 volumes of a 5 % NH4OH solution was added to the reaction mixture. The reaction mixture was then extracted three times with 40 mL EtOAc. The combined organic extracts were dried over sodium sulphate, concentrated in vacuo, and purified by silica gel chromatography. Column conditions 0 to 100 %, 55 % EtOAc in Hex/EtOAc, elutes 65 %. ^X H NMR (400 MHz, CDC13) 8 8.60 (d, J = 2.3 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.66 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H), 5.48 (dd, J = 6.8, 2.9 Hz, 1H), 4.20 (dt, J = 14.0, 3.9 Hz, 1H), 3.01 (dt, J = 14.0, 7.8 Hz, 1H), 2.49 - 2.27 (m, 3H), 2.17 (dd, J = 14.1, 6.5 Hz, 1H), 1.97 (tdd, J = 13.6, 9.4, 3.4 Hz, 3H), 1.84 - 1.60 (m, 5H), 1.41 (s, 9H). LCMS (ESI) Wz 397.5 (M+l) ⁺ . [000486] Step 2: Preparation of (±) methyl 5-(2,2-difluoro-7-azaspiro[3.5]nonan-6- yl)picolinatehydrochloride. A 100 mL round bottom flask, equipped with a stir bar, was charged with (±) tert-butyl 2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-azaspiro[ 3.5]nonane-7- carboxylate (1.00 eq), hydrochloric acid 4 M in dioxane (4 eq), and allowed to stir for 1 h under nitrogen, CO2 & t-butyl-chloride gaseous effluent. Upon completion, the product crashed out and the reaction mixture solidified, complete conversion observed by LCMS. The reaction mixture was resuspended in methanol and concentrated in vacuo to dryness. Crude material carried through to next step without further purification. LCMS (ESI) m/z 297.3 (M+l) ⁺ .

Step 3: Preparation of (±) tert-butyl 4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-lH-indole -l-carboxylate. A 40 mL vial, equipped with a stir bar, was charged with (±) methyl 5-(2,2-difluoro-7-azaspiro[3.5]nonan-6- yl)picolinate hydrochloride (1.00 eq), tert-butyl 4-formyl-5-methoxy-7-methyl-indole-l- carboxylate (1.2 eq), diisopropyl ethyl amine (4.00 eq), sodium triacetoxyborohydride (2.00 eq) DCM (5 V) and heated at 60 °C overnight. The reaction was quenched with 10 volumes of water and extracted three times with 10 volumes of DCM. Combined organic extracts were dried over sodium sulphate, concentrated in vacuo and purified by silica gel column chromatography, 0 to 100 % Hex/EtOAc, elutes 50 - 60 % EtOAc in Hex. ’H NMR (400 MHz, CDCk) 1H NMR (400 MHz, CDC13) 5 8.82 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 7.1 Hz, 1H), 7.47 (d, J = 3.8 Hz, 1H), 6.64 (s, 1H), 6.54 (d, J = 3.8 Hz, 1H), 4.02 (s, 3H), 3.77 (s, 3H), 3.58 (d, J = 12.3 Hz, 1H), 3.29 - 3.19 (m, 2H), 2.85 (dt, J = 12.1, 3.4 Hz, 1H), 2.58 (s, 3H), 2.46 (q, J = 11.8 Hz, 2H), 2.29 (q, J = 12.3 Hz, 2H), 2.09 - 2.00 (m, 1H), 1.79 - 1.66 (m, 3H), 1.57 (s, 9H).

[000487] Step 4: Preparation tert-butyl (S)-4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-

3-yl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methy l-lH-indole-l -carboxylate and tertbutyl (A)-4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-a zaspiro[3.5]nonan-7- yl)methyl)-5-methoxy-7-methyl-lH-indole-l -carboxylate. (±) tert-butyl 4-((2,2-difluoro-6-(6- (methoxycarbonyl)pyridin-3-yl)-7-azaspiro[3.5]nonan-7-yl)met hyl)-5-methoxy-7-methyl-lH- indole-1 -carboxylate was separated by chiral chromatography using a ChiralPak Ad 4.6 x 150 nm column, 5 to 60 % IP A. First eluting peak was carried forward in next step. [000488] Step 5: Preparation of (5) 5-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)picolinic acid. A 5 mL vial was charged with (S) tert-butyl 4-((2,2-difluoro-6-(6-(methoxycarbonyl)pyridin-3-yl)-7-azasp iro[3.5]nonan-7-yl)methyl)-5- methoxy-7-methyl-lH-indole-l-carboxylate (1.00 eq), THF (10 V), methanol (10 V), lithium hydroxide 2M (5 eq) and Heated overnight at 65 °C. The next day the reaction was acidified with formic acid (8 eq), the volatiles were removed in vacuo and the crude mixture was redissolved to a homogeneous mixture with DMSO. The crude mixture was purified by reverse phase chromatography, 15 to 70 % MeCN/Water with 0.1 % HCO2H, elutes 40 to 45 %. ^X H NMR (400 MHz, MeOD) 8 8.78 (d, J = 1.1 Hz, 1H), 8.21 - 8.05 (m, 2H), 7.31 (d, J = 3.1 Hz, 1H), 6.71 (s, 1H), 6.38 (d, J = 3.2 Hz, 1H), 4.36 (d, J = 11.1 Hz, 1H), 4.21 (d, J = 12.6 Hz, 1H), 3.99 (d, J = 12.6 Hz, 1H), 3.72 (s, 3H), 3.45 (dt, J = 12.8, 3.3 Hz, 1H), 3.14 (td, J = 13.8, 3.0 Hz, 1H), 2.83 - 2.57 (m, 2H), 2.48 (s, 5H), 2.25 (t, J = 13.5 Hz, 1H), 2.12 - 1.96 (m, 2H), 1.94 - 1.82 (m, 1H). LCMS (ESI) m/z 455.3 (M+l) ⁺ .

Intermediate M: Preparation of (S)-5-(2,2-difluoro-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7-azaspiro [3.51 nonan-6-yl)-3-fluoropicolinic acid

Intermediate M

[000489] Intermediate M was prepared in the same way as intermediate L, replacing methyl 5 -iodopicolinate with methyl 3-fluoro-5-iodopicolinate in step one.

Intermediate N; Preparation of 4-((2/?,4.s,6,S ^T )-2-cyano-7-((5-methoxy-7-methyl- indol-4- yl)methyl)-7-azaspiro[3.51nonan-6-yl)benzoic acid or 4-((2>S'.,4r.,6 _t S')-2-cvano-7-((5-methoxy- 7-methyl- indol-4-yl)methyl)-7-azasDiro[3.5]nonan-6-yl)benzoic acid

Intermediate N

[000490] Step 1: Preparation of CS’)-benzyl 2-cyano-6-(4-(methoxycarbonyl)phenyl)-7- azaspiro[3.5]nonane-7-carboxylate : To a mixture of fS')-benzyl 6-(4-(methoxycarbonyl)phenyl)- 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate J, 1.0 equiv) in MeOH (0.01 M) was added 2,4,6-trimethylbenzenesulfonohydrazide (1 equiv). The reaction mixture was stirred at 50 °C for 2 hours. The mixture was concentrated, co-evaporated with toluene to remove most solvents then further dried under high vacuum. The resulting crude product was dissolved in dioxane (0.02 M), treated with KCN (4.0 equiv), the reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was diluted with water (1 volume) and extracted with EtOAc (3 >< 1 volume). The organic layers were concentrated under reduced pressure. The residue was purified by column chromatography through silica gel, eluting with 0-30% ethyl acetate in petroleum ether as a gradient. The product containing fractions were concentrated and dried under vacuum to give (S)- benzyl 2-cyano-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane- 7-carboxylate (52% yield) as a light-yellow liquid. LCMS (ESI) m/z 441.1 (M+23) ⁺ .

[000491] Step 2: Preparation of (5)-methyl 4-(2-cyano-7-azaspiro[3.5]nonan-6-yl)benzoate : To a solution of (A)-benzyl 2-cyano-6-(4-(methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonane- 7- carboxylate (1.0 equiv) in EtOAc (0.04 M) was added Pd/C (1.0 equiv, 10% w/w) under N2. The suspension was degassed under vacuum and purged with H23 times. The mixture was stirred under H2 (15 psi) at 25 °C for 16 hours. The reaction mixture was fdtered, and the solvent was concentrated to give CS')-m ethyl 4-(2-cyano-7-azaspiro[3.5]nonan-6-yl)benzoate (78% yield) as a white solid. LCMS (ESI) m/z 284.9 (M+23) ⁺ .

[000492] Step 3: Preparation of (S)-ter/-butyl 4-((2-cyano-6-(4-(methoxycarbonyl)phenyl)- 7-azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-17/-ind ole-l -carboxylate: To a mixture of CS')-m ethyl 4-(2-cyano-7-azaspiro[3.5]nonan-6-yl)benzoate (1.1 equiv) in MeOH (0.02 M) was added ZnCh (2.0 equiv) and Zcz'Z-butyl 4-formyl-5-mcthoxy-7-mcthyl- 17/-indolc- l -carboxylate (1.3 equiv). The mixture was stirred at 30 °C for 1 hour. NaBHaCN (3.0 equiv) was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was concentrated and diluted with H2O (1 volume) and extracted with EtOAc (3 x 1 volume). The combined layers were concentrated. The mixture was purified by column chromatography through silica gel, eluting with 0-100% ethyl acetate in petroleum ether as a gradient, the product containing fractions were concentrated to give (S)-tert-butyl 4-((2-cyano-6-(4-(methoxycarbonyl)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-U/-indole -l-carboxylate (56% yield) as a white solid. LCMS (ESI) m/z 580.1 (M+23) ⁺ .

[000493] Step 4: Preparation of zcz'Z-butyl 4-(((27?,4s,65)-2-cyano-6-(4- (methoxycarbonyl)phenyl)-7-azaspiro[3.5]nonan-7-yl)methyl)-5 -methoxy-7-methyl-l//-indole-

1 -carboxylate and Zcz'Z-butyl 4-(((25',4zy65)-2-cyano-6-(4-(methoxycarbonyl)phenyl)-7- azaspiro[3.5]nonan-7-yl)methyl)-5-methoxy-7-methyl-17/-indol e-l -carboxylate: The residue was purified by prep-SFC (column: DAICEL CHIRALCEL OD (250mm x 50mm, 10 pm); mobile phase: 5% to 40% MeOH in CO2 + 0.05% diethylamine as a gradient over 2.5 min). The fractions of first peak were concentrated and lyophilized overnight and carried out to the next step. LCMS (ESI) m/z 580.2 (M+23) ⁺ .

[000494] Step 5: Preparation of 4-((27?,4s,65)-2-cyano-7-((5-methoxy-7-methyl-117-indol- 4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid or 4-((2S,4r,65)-2-cyano-7-((5-methoxy-7- methyl-17/-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benz oic acid: To the first peak product from step 4 (1.0 equiv) was added 1 M aqueous LiOH/THF/MeOH solution (10.0 equiv LiOH, v/v/v, 1/1/1). The reaction mixture was stirred at 30 °C for 16 hours. The mixture was quenched with acetic acid to pH~5 and extracted with EtOAc (3 x 100 mL). The organic layers were concentrated under reduced pressure. The residue was purified by prep-SFC (column: DAICEL CHIRALPAK AD; mobile phase: 5% to 40% isopropanol in CO2 + 0.05% diethylamine as a gradient over 2.5 min). The desired product containing fractions were concentrated and lyophilized overnight to give 4-((27?,4s,6 _l S)-2-cyano-7-((5-methoxy-7-methyl-l//-indol-4-yl)methy l)-7- azaspiro[3.5]nonan-6-yl)benzoic acid or 4-((25',4r,65)-2-cyano-7-((5-methoxy-7-methyl-177- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (60% yield) as a white solid. ^X HNMR (400 MHz, <A-MeOD): 8 8.14 (br d, J = 8.0 Hz, 2H), 7.62 (br d, J = 8.0 Hz, 2H), 7.30 (d, J = 4.0 Hz, 1H), 6.74 (s, 1H), 6.30 (br s, 1H), 4 39 - 4.22 (m, 2H), 4.02 (br d, J = 12.0 Hz, 1H), 3 74 (s, 3H), 3.39 (br d, J = 12.0 Hz, 2H), 3.28 - 3.16 (m, 1H), 2.67 - 2.57 (m, 1H), 2.49 (s, 3H), 2.47 - 2.40 (m, 1H), 2.25 (m, 2H), 2.17 (m, 2H), 2.05 - 1.95 (m, 1H), 1.87 (m, 1H). LCMS (ESI) m/z 444.2 (M+l) ⁺ .

Intermediate O: Preparation of 4-((2R,4s.,6S)-2-cvano-7-((5-cvclopropyl-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.51nonan-6-yl)benzoic acid or 4-((2S,4r,6S)-2-cvano-7-((5- cydopropyl-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]non an-6-yl)benzoic acid

Intermediate O

[000495] Intermediate O was prepared in a similar manner as Intermediate N replacing tert-butyl 4-formyl-5-methoxy-7-methyl- 17/-indole- l -carboxylate with the tert-butyl 5- cyclopropyl-4-formyl-7-methyl-lH-indole-l-carboxylate in step 3.

PREPARATION OF EXAMPLES

Example 1: Preparation of l-(4-((2R.,4s.,6S)-2-cyano-7-((5-methoxy-7-methyl-lH- indol-4-yl)methvD-7-azaspiro[3.5]nonan-6-yl)benzamido)cvclop ropane-l-carboxylic acid or l-(4-((2S.,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4- yl)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)cyclopropane-l-carboxylic acid [000496] Step 1 : Preparation of methyl l -(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl- lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamido)cy clopropane-l -carboxylate or methyl l-(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-y l)methyl)-7- azaspiro[3.5]nonan-6-yl)benzamido)cy cl opropane-1 -carboxylate: 4-((2R,4s,6S)-2-cyano-7-((5- methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonan- 6-yl)benzoic acid or 4- ((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl)met hyl)-7-azaspiro[3.5]nonan-6- yl)benzoic acid (Intermediate N, 1.0 equiv) was mixed with HATU (1.5 equiv), N, N- diisopropylethylamine (4.0 equiv) in DMF (0.2M). After 10 minutes, methyl 1- aminocyclopropanecarboxylate (2.0 equiv) was added to the reaction mixture. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was acidified with dilute formic acid, applied to a Cl 8 precartridge, and purified by reverse phase column chromatography through a C18 column, eluting with a 10-100% MeCN in water as a gradient containing 0.1% HCO2H. The fractions from the peak eluting at 30-40% MeCN in water were combined and lyophilized to afford a white powder (20% yield). LCMS (ESI) m/z 541 (M+l) ⁺ .

[000497] Step 2: Preparation of l-(4-((2R,4s,6S)-2-cyano-7-((5-methoxy-7-methyl-lH- indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzamido)cyclo propane-l -carboxylic acid or 1- (4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7-methyl-lH-indol-4-yl) methyl)-7-azaspiro[3.5]nonan-6- yl)benzamido)cy cl opropane-1 -carboxylic acid: To a solution of methyl l-(4-((2R,4s,6S)-2-cyano- 7-((5-methoxy-7-methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5] nonan-6- yl)benzamido)cy cl opropane-1 -carboxylate or methyl l-(4-((2S,4r,6S)-2-cyano-7-((5-methoxy-7- methyl-lH-indol-4-yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benza mido)cy cl opropane-1 - carboxylate (1.0 equiv) was added a 5.6 M aqueous LiOH/THF/MeOH solution (13.0 equiv LiOH, v/v/v, 4/7/7). The mixture was stirred while heating at 60 °C for 16 hours. LCMS indicated completion of hydrolysis, after which the mixture was cooled, and the reaction quenched with formic acid to pH ~6. The mixture was purified by preparative-HPLC (column: Welch Xtimate Cl 8; mobile phase: 18% to 48% CH3CN in water + 0.225% formic acid as a gradient over 6 min). The desired product containing fractions were concentrated and lyophilized overnight to yield the title product as a white solid (27% yield). LCMS (ESI) m/z 527 (M+l) ⁺ .

[000498] The following compounds in Table 2 were prepared in a similar manner as Example 1 replacing methyl 1 -aminocyclopropanecarboxylate with the corresponding commercially available amines in the table in step 1 , followed by hydrolysis of the ester if applicable as described in step 2 above.

Table 2

Example 50: This example was prepared according to Method A as described herein.

Examples 51 - 75: These examples were prepared according to Method D as described herein.

Example 90; Preparation of (2R,4s,6S)-7-((5-cyclopropyl-7-methyl-lH-indol-4- yl)methyl)-6-(4-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbo nyl)phenyl)-7- azaspiro[3.5]nonane-2-carbonitrile or (2R,4r.,6S)-7-((5-cyclopropyl-7-methyl-lH- indol-4-yl)methyl)-6-(4-(6-methyl-2,6-diazaspiro[3.3]heptane -2-carbonyl)phenyl)-7- azaspiro[3.5]nonane-2-carbonitrile

[000499] To a solution of 4-((65)-2-cyano-7-((5-cyclopropyl-7-methyl-l/7-indol-4- yl)methyl)-7-azaspiro[3.5]nonan-6-yl)benzoic acid (1.0 equiv) and 2-methyl-2,6- diazaspiro[3.3]heptane (2.0 equiv) in DMF (0.06 M) was added EDCI (1.5 equiv), HOBt (1.5 equiv) and DIPEA (3.0 equiv). The suspension was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with H2O, dried over NazSOr, fdtered and concentrated under reduced pressure to give a residue. The crude product was purified by preparative-HPLC (column: Phenomenex Cl 8; mobile phase: 60% to 90% CH3CN in water + 0.1% NH3 H2O+NH4HCO3 as a gradient over 7 min). The desired product containing fractions were concentrated and dried under vacuum to afford a white solid (35.6 % yield). LCMS (ESI) m/z 548 (M+l) ⁺ . ^X H NMR (400 MHz, CD3OD) 5 7.61-7.66 (m, 4H), 7.17 (d, J= 3.2 Hz, 1H), 6.57 (d, J= 11.2 Hz, 1H), 6.52 (s, 1H), 4.42-4.51 (m, 2H), 4.21-4.29 (m, 2H), 3.88 (d, J = 12.0 Hz, 1H), 3.43 (s, 4H), 3.33 - 3.34 (m, 1H), 3.16 - 3.24 (m, 2H), 2.77 - 2.81 (m, 1H), 2.42 - 2.50 (m, 1H), 2.39 (s, 3H), 2 30 (s, 3H), 2.23-2.28 (m, 1H), 2.05-2.19 (m, 4H), 1.89-1.93 (m, 2H), 1.63-1.69 (m, 1H), 1.49-1.59 (m, 1H), 0.79-0.86 (m, 1H), 0.68-0.74 (m, 1H), 0.47-0.54 (m, 1H), 0.12-0.18 (m, 1H).

[000500] The following compounds in Table 3 were prepared in a similar manner as Example 90 replacing 2-methyl-2,6-diazaspiro[3.3]heptane with the corresponding commercially available amine intermediates in the table below.

Table 3

Example 234: Human C3bBb Enzyme Assay

[000501] Compounds disclosed herein were evaluated for their potency to inhibit human C3bBb in a biochemical assay. To generate active C3bBb complex in vitro, purified human C3b (Complement Technology, Al 14), CFB (Complement Technology, A135) and CFD (Complement Technology, A136) were mixed in a 1 : 1 : 1 ratio to a final concentration of 1 pM each in the C3bBb assay buffer (PBS pH 7.4, 100 pM NiCh, 0.05% (w/v) CHAPS). The reaction mix was incubated at room temperature for 30 minutes on a rotating platform. After the incubation, a sample was taken to confirm the cleavage of CFB by Western blot using a polyclonal anti-human factor B antibody (Quidel, A311), and the rest of the reaction was immediately aliquoted on ice and stored at -80 °C. On the day of the enzyme assay, a reaction mixture containing 3 nM C3bBb complex and 1 pM purified human C3 (Complement Technology, Al 13) was prepared in the C3bBb assay buffer. Compounds were serial diluted 3 -fold in 100% DMSO for a 10-point dose-response curve. A 0.5 pL aliquot of diluted compound solution was transferred to a conical bottom 96-well plate, before 49.5 pL of the reaction mix was added to each well to initiate the reaction. The plate was incubated for 1 hour at room temperature. The reaction was terminated by adding 0.5 pL of Protease Inhibitor Cocktail (Thermo Fisher, 75446) to each well. The generation of C3a from C3 by the C3bBb complex was measured using the MicroVue C3a Plus EIA ELISA kit (Quidel, A031). The concentration of C3a from each well was calculated using a standard curve. Percent inhibition values were generated using the baseline (C3 only) and the maximum control (DMSO instead of compound), and IC50 of each compound was calculated using 4-parameter logistic regression. Table 4 below (middle column) shows the IC50 values obtained for the compounds disclosed herein. IC50 values are categorized according to potency: A<25 nM, 25 nM <B<50 nM, 50 nM <C < 100 nM, 100 nM <D <200 nM, 200 nM <E and “ND.” means “not determined”.

Example 235: Human Serum MAC Formation Assay

[000502] MAC deposition assay using normal human serum was applied to evaluate compound potency under physiologically relevant conditions. Black Maxisorp plates (Thermo Fisher, 437111) were coated with preactivated zymosan (Complement Technology, B400) at 0.5 mg/mL in carbonate buffer (pH 9.5, Sigma, C3041) at room temperature overnight. Compounds were serial diluted 3 -fold in 100% DMSO for a 10-point dose-response curve. Normal human serum (Complement Technology, NHS) was diluted to 50% (v/v) with the gelatin buffer (4.2 mM HEPES pH 7.4, 0.15 mM CaCh, 141 mM NaCl, 4.5 mM MgCh, 0.1% gelatin) containing 20 mM EGTA or 20 mM EDTA. In conical bottom 96-well plates, 1 pL compound and 99 pL of serum- EGTA were mixed. Serum-EDTA was used as baseline control. The serum-compound mixture was incubated at room temperature for 15 minutes before being transferred to the washed zymosan plate for complement activation at 37 °C for 30 minutes. The reaction was terminated by decanting the reaction mixture and adding blocking buffer (Thermo Fisher, 37539) for 20 minutes. MAC formation on the ELISA plate was detected using 0.2 pg/mL mouse anti-human C9 neoepitope monoclonal antibody (Thermo Fisher, MA5-33373) diluted in phosphate-buffered saline with 0.05% Tween-20 (PBST). A goat anti-mouse IgG-HRP antibody (Thermo Fisher, A16072) was used at 1 :2000 in PBST as secondary antibody. After washing, the reaction was developed using QuantaBlu (Thermo Fisher, 15169) for 20 minutes at room temperature. The plates were read at 325 nm excitation and 420 nm emission wavelengths. Percent inhibition values were generated using the baseline (EDTA-serum) and the maximum control (EGTA-serum). An ICso for each compound was calculated using 4-parameter logistic regression. Table 4 below (last column) shows the ICso values obtained for the compounds disclosed herein. ICso values are categorized according to potency: 0<A<100 nM, 100 nM <B<200 nM, 200 nM <C <300 nM, 300 nM <D <500 nM, 500 nM <E and “N D.” means “not determined”.

Table 4:

Example 236; Additional Human Serum MAC Formation Assay

[000503] MAC deposition assay using normal human serum was applied to evaluate compound potency under physiologically relevant conditions. Black Maxisorp plates (Thermo Fisher, 437111) were coated with preactivated zymosan (Complement Technology, B400) at 0.5 mg/mL in carbonate buffer (pH 9.5, Sigma, C3041) at room temperature overnight. Compounds were serial diluted 3 -fold in 100% DMSO for a 10-point dose-response curve. Normal human serum (Complement Technology, NHS) was diluted to 50% (v/v) with the gelatin buffer (4.2 mM HEPES pH 7.4, 0.15 mM CaC12, 141 mM NaCl, 4.5 mM MgC12, 0.1% gelatin) containing 20 mM EGTA or 20 mM EDTA. In conical bottom 96-well plates, 1 pL compound and 99 pL of serum- EGTA were mixed. Serum-EDTA was used as baseline control. The serum-compound mixture was incubated at room temperature for 15 minutes before being transferred to the washed zymosan plate for complement activation at 37 °C for 25 minutes. The reaction was terminated by decanting the reaction mixture and adding blocking buffer (Thermo Fisher, 37539) for 20 minutes. MAC formation on the ELISA plate was detected using 0.2 pg/mL mouse anti-human C9 neoepitope monoclonal antibody (Thermo Fisher, MA5-33373) diluted in phosphate-buffered saline with 0.05% Tween-20 (PBST). A goat anti-mouse IgG-HRP antibody (Thermo Fisher, A16072) was used at 1 :2000 in PBST as secondary antibody. After washing, the reaction was developed using QuantaBlu (Thermo Fisher, 15169) for 20 minutes at room temperature. The plates were read at 325 nm excitation and 420 nm emission wavelengths. Percent inhibition values were generated using the baseline (EDTA-serum) and the maximum control (EGTA-serum). An IC50 for each compound was calculated using 4-parameter logistic regression. Table 5 below shows the ICso values obtained for selected compounds disclosed herein. IC50 values are categorized according to potency: 0<A<100 nM, 100 nM <B<200 nM, 200 nM <C <300 nM, 300 nM <D <500 nM, and 500 nM <E.

Table 5:

Example 237: C3bBb Enzyme Jump Dilution Assay

[000504] Compound residency time was examined in the C3bBb enzyme jump dilution assay. C3bBb was generated in house with commercially acquired human C3b (Complement Technologies, Al 14) and human FB (Complement Technologies, A135). Compounds described herein (e g., compounds of Formula I) were serially diluted in DMSO, and 1 pL of diluted compound was added to 50 pL of C3bBb (2 nM) in assay buffer consisting of PBS at pH 7.4, 100 pM NiCh, and 0.05% (w/v) CHAPS. After incubating at room temperature for 15 min, 10 pL of the compound-enzyme mixture was combined with equal volume of human C3 at 2 pM (Complement Technologies, Al 13) in assay buffer. For jump dilution, 1 pL of the compoundenzyme mixture was added to 19 pL of C3 at 1.05 pM. After incubating at room temperature for 1 h, the reaction was stopped by adding protease inhibitor cocktail. The amount of C3a generated was measured using the MicroVue C3a Plus EIA kit according to manufacturer’s protocol (Quidel, A031). The amount of C3a was calculated from the standard curve and plotted against compound concentrations to determine IC50 values.

Example 238: 50% Human Whole Blood Assay for Membrane Attack Complex (MAC) Formation Quantification

[000505] Human whole blood was collected from healthy volunteers and immediately anti coagulated using the thrombin-specific inhibitor Hirudin (Creative BioMart, #Hirudin-02) at 50 pg/mL. Gelatin Veronal Buffer (GVB) (Complement Technology Inc, #B103) containing 2 mM MgCh and 10 mM EGTA or EDTA was added to whole blood in equal volume to allow for alternative pathway-specific complement activation (EGTA), or to serve as a negative control (EDTA). The anti-coagulated 50% whole blood mixtures were then added to a 96-well plate in the presence or absence of compounds serial diluted in DMSO (1% final (v/v)) and incubated for 15 minutes at room temperature (21-25 °C, RT). The alternative pathway was initiated by the addition of pre-activated zymosan A (Complement Technology Inc, #B400) at a final concentration of 1 mg/mL, in which the reaction mixture was incubated for 70 minutes at 37 °C, followed by the immediate addition of an equal volume of 50 mM EDTA in GVB to stop the activated complement reaction. The entire stopped reaction mixture was transferred to a 96-well plate (Nunc Maxisorp) and incubated for 1 hour for C9 ELISA detection. Following aspiration of the reaction mixture after coating, the plate was immediately blocked using the StartingBlock T20 buffer (ThermoFisher, #37539) for 20 minutes at RT, proceeded by a wash step with PBS containing 0.05% (v/v) Tween-20 (PBS-T). A mouse anti-human C9 monoclonal antibody (ThermoFisher, #MA5-33373) was used as the primary antibody at 0.2 pg/mL in PBS-T and incubated for 1 hour, followed by a PBS-T wash, and the addition of a horseradish peroxidase (HRP)-conjugated goat anti-mouse IgG secondary antibody (ThermoFisher, #A16072) at 0.5 pg/mL for 45 minutes. After a final wash, the reaction was developed using QuantaBlu Fluorogenic Peroxidase Substrate Detection (ThermoFisher, #15169), and the plate was read at 325 nm excitation and 420 nm emission wavelengths using the FlexStation 3 Microplate Reader (Molecular Devices). Percentage inhibition values were calculated by baseline correcting all values with the EDTA-containing negative control and normalizing all values to the EGTA-containing compound-free positive control. ICso values were calculated using a four-parameter logistic regression dose response model.

Example 239: Wieslab Assay for Alternative Complement Pathway

[000506] The ability of the compounds described herein (e.g., compounds of Formula I) to inhibit the formation of C5b-9 in the alternative pathway is examined with the Wieslab Complement Alternative Pathway kit (Svar, COMPLAP330RUO) following the manufacturer’s protocol. In brief, human serum (Complement Technology, NHS) is diluted 1/18 with Diluent AP and added to compound serially diluted in DMSO (1% final (v/v)). After compound pre-incubation at room temperature for 15 min, samples are then transferred to the pre-coated plate and incubated for 60 min at 37 °C. The plate is washed three times with Wash Buffer and incubated with 100 pL of Conjugate for 30 min at room temperature followed by another three times of washing. The plate is then incubated with 100 pL of Substrate Solution for another 30 min at room temperature before measuring the absorbance at 405 nm on the FlexStation 3 Microplate Reader (Molecular Devices). Absorbance is normalized to DMSO control and plotted against compound concentration to determine IC50 values. Example 240: Rat LPS Challenge Model for Pharmacodynamic Assessment of Compounds [000507] Studies were performed with 9-week-old male Sprague Dawley rats (Envigo RMS LLC). Lipopolysaccharide (LPS from Salmonella typhimurium, Sigma, L6143) was dissolved in sterile 0.9% saline at 50 pg/mL and administrated by intraperitoneal (i.p.) injection at 1 mL per animal. Compounds described herein (e.g., compounds of Formula I) were formulated in water containing 0.5% (w/v) methylcellulose and 0.1% (v/v) Tween 80. Two hours after the injection of LPS to induce complement activity, compound or vehicle was administrated by oral gavage at various doses. Studies were terminated 4 hours after compound administration, for the duration of 6 hours. Negative or positive control animals were dosed with 1 mL of saline or LPS by i.p. injection respectively, with both control groups receiving vehicle by oral gavage. At the end of the studies, plasma and kidney tissue were collected for PD evaluation. Diluted plasma and kidney homogenate samples were analyzed using the Jess Simple Western system with a rat complement C3d antibody (R&D Systems, AF2655). The peak area of the C3d band from each sample was measured by the Compass software and normalized by total protein input. Percentage inhibition values were calculated using the average of negative and positive control animals.

Example 241: Rat Passive Heymann Nephritis Model of Membranous Nephropathy for Efficacy Assessment

[000508] Studies are performed with 9-week-old male Sprague Dawley rats (Envigo RMS LLC). Passive Heymann Nephritis is induced via i.v. injection of Sheep Anti-Rat FxlA Serum (Probetex, PTX- 002S) at 6 mL/kg. Compound A, a selected compound of Formula I, is formulated in water containing 0.5% (w/v) methylcellulose and 0.1% (v/v) Tween 80. Compound A and/or vehicle is administered by oral gavage at 5 mL/kg either BID (12: 12) or QD at various doses (typically 0.1-100 mg/kg), and administration is initiated either 24 hours prior to injection of Sheep Anti-Rat FxlA Serum (prophylactic) or 6 days post injection of Sheep Anti-Rat FxlA Serum (therapeutic) depending on desired dosing regimen. Negative or positive control animals are dosed with 6 mL/kg of 0.9% saline or Sheep Anti-Rat FxlA Serum via i.v. injection respectively, with both control groups receiving vehicle by oral gavage. Rats are placed into metabolic caging (Lab Products) and urine is collected over the course of 24 hours at 4, 7, 10, and 14 days post injection of Sheep Anti-Rat FxlA Serum. Diluted urine samples are analyzed using Bradford reagent (Sigma, B6916-500mL), Creatinine colorimetric kit (Caymen Chemical, 500701) and MesoScale Rat Kidney Injury Panel 1 (MSD, K15162C) to assess proteinuria, urinary creatinine, and urinary biomarkers respectively. Studies are terminated 14 days post injection of Sheep Anti-Rat FxlA Serum, and at the end of the studies, kidney tissue are collected for PD evaluation. Diluted kidney homogenate samples are analyzed using the Jess Simple Western system with a rat complement C3d antibody (R&D Systems, AF2655). Abundance of CFB activation product, Ba in the urine samples are also measured as a PD marker using the Simple Western with a polyclonal antisera to human CFB (cross-reacting with rat; Quidel, A311). The peak area of the C3d or Ba band from each sample is measured by the Compass software. Percentage inhibition values are calculated using the average of negative and positive control animals.

Example 242: Compound permeability in a CACO-2 Cell Line

[000509] Complement Factor B (CFB) inhibitors that showed good potency in the enzymatic assay were assessed for their in vitro permeability in Caco-2 cell. Caco-2 monolayers were cultured for 21-28 days on polyethylene membranes of 96-well Corning insert plate (seeding density: 100,000 cells/cm2). Test compounds were diluted to 2 pM concentration in HBSS buffer (10 mM HEPES, pH 7.4) and added to either the apical or basolateral side of the cell monolayers and incubated at 37 °C in a cell culture incubator for 2 h. At the end of the incubation time, samples were obtained from the contralateral sides and the compound levels were assessed by liquid chromatography - tandem mass spectrometry (LC-MS/MS) assay to determine the apparent permeability coefficients Papp (A— >B), Papp (B— >A) and efflux ratio (ER = Papp (B— >A) / Papp (A-B)).

Example 243: In Vitro Stability in Hepatocytes

[000510] Select compounds of Formula I were assessed for in vitro metabolic stability in cryopreserved hepatocyte suspensions using loss-of-parent approach. Test compounds at 0.3 pM final concentration were incubated with cryopreserved hepatocyte suspensions (rat or human; 0.1 x 10 ⁶ cells in 0.2 mL volume) in a 96-well plate at 37 °C for up to 2 h. During the incubation, samples were obtained at different time points and analyzed by LC-MS/MS assay for the remaining parent compound. From the percent parent remaining vs. time curve, half-life, in vitro intrinsic clearance, and scaled-up clearance values were calculated. Selected compounds of Formula I were also assessed for metabolic stability in dog and monkey hepatocyte suspensions. Example 244: CYP Inhibition Assessment of Compounds

[0005111 Compounds of Formula I are first assessed in vitro for their potential to inhibit the major cytochrome P450 (CYP) enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Human liver microsomes (150-donor, mixed gender; 0.2 mg/mL) are incubated at 37 °C for 10 min with a mixture of respective probe substrates for each of the CYP enzymes in the presence of the test compounds at 30 pM and NADPH (cofactor; 1 mM). The reaction is quenched at the end of the incubation, and metabolite formation is assessed by LC-MS/MS, to determine the IC50 (test compound concentration that produces 50% inhibition of the activity of a CYP enzyme). The probe substrate and the corresponding metabolite measured as well as the positive control inhibitor for each of the CYP enzymes are listed in the table below.

[000512] Selected compounds of Formula (I) are further assessed at different concentrations (e.g., 0.05 - 50 pM) in vitro for their potential to inhibit each of the major cytochrome P450 enzymes, such as CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, directly or in a time-dependent manner (TDI ). Compounds are followed up with kinact/KI determination for any CYP enzyme showing time-dependent inhibition (IC50 shift > 1.5). The probe substrate and the corresponding metabolite measured as well as the direct and TDI positive control inhibitor for each of the CYP enzymes are listed in the table below.

Example 245: Non-Clinical Pharmacokinetic Assessment of Compounds of Formula (I)

[000513] Selected compounds of Formula (I) were evaluated for in vivo pharmacokinetics and oral bioavailability in rats. After administration of 1 mg/kg IV and 10 mg/kg PO doses in suitable formulations to rats (e.g., 60% PEG400/40% water for IV formulation, 0.5% methocel + 0.1% tween 80 for PO formulation), plasma samples were obtained at different time points up to 24 h (e.g., 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h), and compound levels were quantified by LC-MS/MS. Pharmacokinetic parameters (e.g., CLp, Vdss, AUCO-24 h, % oral bioavailability) were estimated by non-compartmental analysis (NCA) of the time vs. plasma concentration data. In addition, trough concentration of the test compounds was measured in rat kidney tissues obtained at 24 h after PO administration to determine the kidney -to-plasma ratio (Kp, kidney). All compounds evaluated in rat pharmacokinetic studies were also assessed for plasma protein binding by using ultracentrifugation approach. Fraction unbound (Fu) values in rat plasma were then used to determine the unbound concentrations achieved in rat plasma.

[000514] Pharmacokinetic properties of selected compounds of Formula (I) were also evaluated in higher species such as beagle dogs and cynomolgus monkeys to guide human PK prediction by allometric scaling.

[000515] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials and procedures. All such equivalents are considered to be within the scope of the claimed subject matter and are encompassed by the appended claims. Since modifications will be apparent to those of skill in the art, it is intended that the claimed subject matter be limited only by the scope of the appended claims.