Macrocyclic MCL-1 inhibitors

Abstract

Macrocyclic compounds containing substituted 2-(1H-indol-7-yl)-3,4-dihydropyrazino[1,2-a]indol-1(2H)-ones inhibit binding of Mcl-1 to Bcl-2 family members, and the compounds and their pharmaceutical compositions are useful for treating disorders and conditions in a subject, such as cancer cell proliferation.

Description

212657-0002-WO01MACROCYCLIC MCL-1 INHIBITORSRELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 742,207, filed January 6, 2025, which is hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0002] The present invention pertains to compounds that inhibit the activity of an anti-apoptotic Bcl-2 family member Myeloid cell leukemia- 1 (Mcl-1) protein, compositions containing the compounds, and methods of treating cancer involving over-expressed or dysregulated Mcl-1 protein.BACKGROUND

[0003] Abnormal regulation of apoptosis is now recognized to play an important role in the development of cancer. The apoptosis pathway can be initiated by various extracellular and intracellular stresses, including growth factor deprivation, DNA damage, oncogene induction, and cytotoxic drugs (Danial, N. N. and Korsmeyer, SJ. Cell (2004) 116, 205-219). The death signal leads to the oligomerization of the pro-apoptotic proteins Bax and Bak. Upon activation, they permeabilize the mitochondrial outer membrane and release apoptogenic factors into the cytoplasm. This process is tightly regulated by both pro-apoptotic (Bax, Bak, Bad, Bid, Bim, Bmf, NOXA, PUMA) and anti-apoptotic (Bcl-2, Bcl-xL, Bcl-w, Bcl2-Al, Mcl-1) members of the Bcl-2 family of proteins. Recent data suggests that the anti-apoptotic Bcl-2 proteins function to protect the cell from apoptotic insults, primarily by preventing disruption of mitochondrial outer membrane integrity by binding to the pro-apoptotic proteins as described in Adams, J. M. and Cory S. Oncogene (2007) 26, 1324-1337; Willis, S. N. et al. Science (2007) 315,856-859. Because tumor cells are under stress, alterations in their apoptotic signaling pathways are believed to be crucial for survival. Recent data implicates down-regulated apoptosis in the onset of cancer. Research has shown, for example, that anti-apoptotic proteins, are over-expressed in many cancer cell types as described in Beroukhim, R. et al. Nature (2010) 463, 899-905; Zhang J. Y., Nature Reviews Drug Discovery, (2002) 1, 101; Kirkin, V. et al. Biochimica et Biophysica Acta (2004) 1644, 229-249; and Amundson, S. A. et al. Cancer212657-0002-WO01Research (2000) 60, 6101-6110. This dysregulation results in the survival of cells that would otherwise have undergone apoptosis such as cancer cells. This suggests that neutralizing the function of anti-apoptotic Bcl-2 proteins may offer an effective strategy for the elimination of cancer cells. In addition, resistance to chemotherapy which is a major cause of treatment failure and poor prognosis in many cancers can be caused by the upregulation of anti-apoptotic Bcl-2 family proteins.

[0004] An important anti-apoptotic member of the Bcl-2 family is Myeloid cell leukemia- 1 (Mcl-1). Mcl-1 is one of the most frequently amplified anti-apoptotic genes in human cancers including prostate, lung, pancreatic, breast, ovarian, and cervical cancers, as well as melanoma, B-cell chronic lymphocytic leukemia (B-CLL), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (Beroukhim et al. Nature (2010) 463, 899-905). Moreover, its overexpression is implicated as a resistance factor for multiple therapies including widely prescribed microtubule-targeted agents for breast cancers, such as paclitaxel and vincristine as well as Gemcitabine, a first-line treatment option for pancreatic cancer (Wei et al. Cancer Chemother Pharmacol (2008) 62, 1055-1064 and Wertz et al. Nature (2011) 471, 110-114). These data suggest that Mcl-1 is an important target for a wide variety of cancers.

[0005] In many cancer cell types, the cancer cell’s survival is attributed to the dysregulation of the apoptotic pathway caused by the over-expression of one or more anti-apoptotic Bcl-2 protein family members. Because of the important role for Bcl-2 family of proteins in regulating apoptosis in both cancerous and non-cancerous cells, and the inter-cell variability of Bcl-2 family protein expression, it could be advantageous to have a small molecule inhibitor that selectively targets and preferably binds to one type or a subset of anti-apoptotic Bcl-2 protein(s). A selective compound also may confer certain advantages in the clinical setting, by providing flexibility to select a dosing regimen to reduce on-target toxic effects in normal cells.

[0006] Because Mcl-1 protein is an important Bcl-2 family member associated with a number of diseases, there is a need for compounds which bind to and inhibit the activity of Mcl-1 protein.SUMMARY

[0007] In some embodiments, the present invention provides compounds, and pharmaceutically acceptable compositions thereof, that are effective as inhibitors of Mcl-1.

[0008] In one aspect, the invention provides compounds of formula (I),212657-0002-WO01wherein:G is a 5- to 6-membered aromatic heterocyclic ring containing 1-3 nitrogen atoms, wherein X1and X2are independently carbon or nitrogen ring atoms of ring G;m is 0, 1, 2, or 3;R1, at each occurrence, is independently Ci-4alkyl, Ci-4fluoroalkyl, halogen, -Ci-4alkylene-OH, -Ci-4alkylene-OCi-4alkyl, -Ci-4alkylene-NH2, -Ci-4alkylene-NHCi-4alkyl, -Ci-4alkylene- N(Ci-4alkyl)2, -O-Ci-4alkylene-OH, -O-Ci-4alkylene-OCi-4alkyl, -O-Ci-4alkylene-NH2, -O-Ci-4alkylene-NHCi-4alkyl, -O-Ci-4alkylene-N(Ci-4alkyl)2, G1, -Ci-salkylene-G1, -OG1, or-O-Ci-salkylene-G1;G1is a Cs-ecycloalkyl, a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a 5- to 6- membered heteroaryl containing 1-3 heteroatoms, or a phenyl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, Ci- 4fluoroalkyl, oxo, OH, -OCi-4alkyl, -C(O)Ci-4alkyl, -Ci-4alkylene-OCi-4alkyl, Gla, and -Ci-3alkylene-Glaand optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G1are independently selected from the group consisting of O, N, and S;Glais a C3-6cycloalkyl or a 4- to 7-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S;L is a 4- to 8-atom divalent linker consisting of one or more members selected from the group consisting of Cialkylene, C2alkylene, Csalkylene, C4alkylene, Csalkylene, Cealkylene,212657-0002-WO01C?alkylene, Csalkylene, C2alkenylene, Czalkynylene, -0- -S-, -SO- -SO2-, -C(0)- -N(RX)-, and -Cy1-, provided that L does not comprise more than one Cy1and each occurrence of -0-, -S-, -SO-, -SO2-, or -N(RX)- is separated by C(0) or two or more carbon atoms from each other occurrence of -0-, -S-, -SO-, -SO2-, or -N(RX);Cy1is a l,l-C3-6cycloalkylene;Rxis hydrogen, Ci-4alkyl, C3-4cycloalkyl, or-Ci-3alkylene-C3-4cycloalkyl;R2is G2, -L2-Y2, Ci-4alkyl, C2-4alkenyl, CN, or H;L2is Ci-ealkylene, -CH=CH- or C3-6cycloalkylene (e.g., );Y2is -0R2a, -NR2aR2b, -C(O)OR2a, -C(O)NR2aR2b, -C(O)R2a, N3, or CN;R2ais H, Ci-4alkyl, -C2-3alkylene-Y2a, G2a, or-Ci-3alkylene-G2a;R2bis H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3-4cycloalkyl;or R2aand R2b, together with the nitrogen to which each attaches, form a 4- to 12-membered heterocyclyl containing 1-2 additional heteroatoms independently selected from the group consisting of O, N, and S, wherein the 4- to 12-membered heterocyclyl formed by R2aand R2bis optionally substituted with a first substituent selected from the group consisting of halogen, cyano, oxo, -OR20, -N(R20)2, -NR20C(O)R20, -C(O)OR20, -C(O)N(R20)2, Ci- 4alkyl, Ci-4fluoroalkyl, -Ci-4alkylene-OCi-4alkyl, -Ci-4alkylene-N(Ci-4alkyl)2, G2b, and -Ci-4alkylene-G2b, and optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen, oxo, OH, Ci-4alkyl, and Ci-4fluoroalkyl; G2is a 5-membered partially unsaturated or fully unsaturated (i.e., aromatic) heterocyclic ring that contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, is attached at a carbon ring atom of the heterocyclic ring, is optionally substituted with a first substituent selected from the group consisting of halogen, oxo, Ci-4alkyl, Ci-4fluoroalkyl, -OR21, -N(R21)2, -C(0)0R21, -C(O)N(R21)2, -Ci-3alkylene-OR21, -Ci- 3alkylene-N(R21)2, G2c, and -Ci-4alkylene-G2c, and is optionally further substituted with 1- 3 substituents independently selected from the group consisting of halogen, Ci-4alkyl, and oxo;Y2ais -OCi-4alkyl, OH, -N(Ci-4alkyl)2, -NHCi-4alkyl, or -NH2;R20and R21, at each occurrence, are independently H, Ci-4alkyl, C3-4cycloalkyl, or-Ci- 3alkylene-C3-4cycloalkyl;212657-0002-WO01G2a, G2b, and G2care independently a C3-6cycloalkyl, a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, or a phenyl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, Ci-2fluoroalkyl, -OCi-4alkyl, OH, C3-4cycloalkyl, and -Ci- 3alkylene-C3-4cycloalkyl and optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G2a, G211, and G2care independently selected from the group consisting of O, N, and S;R3is H, halogen, Ci-4alkyl, C3-4cycloalkyl, G3, or -Ci-4alkylene-N(R3a)2;R3a, at each occurrence, is independently H or Ci-4alkyl;G3is a 5-membered partially unsaturated or fully unsaturated (i.e., aromatic) heterocyclic ring that contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, is attached at a carbon ring atom of the heterocyclic ring, is optionally substituted with a first substituent selected from the group consisting of halogen, oxo, Ci-4alkyl, Ci- 4fluoroalkyl, -OR31, -N(R31)2, -C(O)OR31, -C(O)N(R31)2, -Ci-3alkylene-OCi-4alkyl, -Ci- 3alkylene-N(Ci-4alkyl)2, G3c, and -Ci-4alkylene-G3cand is optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci- 4alkyl;R31, at each occurrence, is independently H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3- 4cycloalkyl;G3Cis a C3-6cycloalkyl, a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a 5- to 6- membered heteroaryl containing 1-3 heteroatoms, or a phenyl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, C1-2fluoroalkyl, -OCi-4alkyl, OH, C3-4cycloalkyl, and -Ci-3alkylene-C3-4cycloalkyl and optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G3care independently selected from the group consisting of O, N, and S; R4ais -OCi-4alkyl, Ci-4alkyl, or H;R4bis -OR40, Ci-4alkyl, or H;R40is H, Ci-4alkyl, Ci-4haloalkyl, -C2-4alkylene-OH, -C2-4alkylene-OCi-4alkyl, -C2-4alkylene- NH2, -C2-4alkylene-NHCi-4alkyl, -C2-4alkylene-N(Ci-4alkyl)2, G4, or-Ci-3alkylene-G4;212657-0002-WO01G4is a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, a Cs-ecycloalkyl, or a phenyl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, -C(O)OCi-4alkyl, G4a, and -Ci-3alkylene-G4aand optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G4are independently selected from the group consisting of O, N, and S;G4ais a C3-6cycloalkyl or a 4- to 7-membered heterocyclyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heterocyclyl in G4acontains 1-2 heteroatoms independently selected from the group consisting of O, N, and S;R4cis H;R5is -C2-4alkylene-O-G5;G5is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl containing 1-3 heteroatoms, each being optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, Ci-4alkyl, Ci-4fluoroalkyl, -OCi-4alkyl, -OCi- 4fluoroalkyl, and C3-4cycloalkyl, wherein the heteroatoms contained in the heteroaryl of G5are independently selected from the group consisting of O, N, and S;R6, at each occurrence, is independently halogen, Ci-4alkyl, Ci-4fluoroalkyl, -OCi-4alkyl, -OCi- 4fluoroalkyl, or C3-4cycloalkyl;R7is Ci-4alkyl;o is 0, 1, 2, or 3;p is 0, 1, or 2; andq is 1 or 2.

[0009] In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0010] In another aspect, the invention provides a method for the treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.212657-0002-WO01

[0011] In another aspect, the invention provides a method for inhibiting the binding of Mcl-1 to Bcl-2 family members, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0012] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of cancer.

[0013] In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the inhibition of binding of Mcl-1 to Bcl-2 family members.

[0014] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for the treatment of cancer.

[0015] In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for the inhibition of binding of Mcl-1 to Bcl-2 family members.

[0016] In another aspect, the invention provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use.DETAILED DESCRIPTION1. Definitions

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0018] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The212657-0002-WO01present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0019] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9- 1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.

[0020] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0021] The term “alkoxy,” as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tertbutoxy.

[0022] The term “alkyl,” as used herein, means a straight or branched, saturated hydrocarbon chain. The term “lower alkyl” or “Ci-ealkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “Ci-4alkyl” means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of212657-0002-WO01alkyl include, but are not limited to, methyl, ethyl, / / -propyl, zso-propyl, / / -butyl, ec-butyl, isobutyl, tert-butyl, «-pentyl, zso-pentyl, neopentyl, / / -hexyl, 3 -methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, zz-heptyl, zz-octyl, zz-nonyl, and zz-decyl.

[0023] The term “alkenyl,” as used herein, means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond.

[0024] The term “alkylene,” as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon, for example, of 1 to 6 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2-, -CD2-, -CH2CH2-, -C(CH3)(H)-, -C(CH.3)(D)-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0025] The term “aryl,” as used herein, refers to a phenyl or a phenyl appended to the parent molecular moiety and fused to a cycloalkane group (e.g., the aryl may be indan-4-yl), fused to a 6-membered arene group (i.e., the aryl is naphthyl), or fused to a non-aromatic heterocycle (e.g., the aryl may be benzo[d][l,3]dioxol-5-yl). The term “phenyl” is used when referring to a substituent and the term 6-membered arene is used when referring to a fused ring. The 6-membered arene is monocyclic (e.g., benzene or benzo). The aryl may be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic system).

[0026] The term “cycloalkyl” or “cycloalkane,” as used herein, refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term “cycloalkyl” is used herein to refer to a cycloalkane when present as a substituent. A cycloalkyl may be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthal enyl), or a bridged cycloalkyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g.,bicyclo[2.2. l]heptanyl). Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[l.l.l]pentanyl.

[0027] The term “cycloalkenyl” or “cycloalkene,” as used herein, means a non-aromatic monocyclic or multi cyclic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring. The term “cycloalkenyl” is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl may be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic212657-0002-WO01cycloalkenyl (e.g., octahydronaphthal enyl), or a bridged cycloalkenyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0028] The term “carbocyclyl” means a “cycloalkyl” or a “cycloalkenyl.” The term “carbocycle” means a “cycloalkane” or a “cycloalkene.” The term “carbocyclyl” refers to a “carbocycle” when present as a substituent.

[0029] Terms such as cycloalkylene, arylene, phenylene, heteroarylene, heterocyclylene, etc. refer to divalent groups derived from the base ring, e.g., cycloalkane, heteroaryl, heterocycle, etc., including monocyclic or bicyclic variations of each (e.g., a spiro heterocycle such as 2,6-diazaspiro[3.3]heptane). For purposes of illustration, examples of cycloalkylene and phenyleneinclude, respectively,and. Cycloalkylene includes a 1,1-cycloalkylene (e.g.,°’3), such as 1,1 -cyclopropylene (i.e.,). The term “1,4-phenylene” refers to the following divalent group that links two portions of a molecule in a 1,4or para relationship:. The term “6-membered 1,4-heteroarylene” refers to a divalent 6-membered heterarene that links two portions of a molecule in a 1,4 or paraNrelationship on the heteroarene, e.g.,n \r=y / 1, N 'H

[0030] The term “fluoroalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a fluoro group. Representative examples of fluoroalkyl include CH2F, CHF2, CF3, and CH2CHF2.

[0031] The term “halogen” or “halo,” as used herein, means Cl, Br, I, or F.

[0032] The term “haloalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen.

[0033] The term “heteroaryl,” as used herein, refers to an aromatic monocyclic heteroatomcontaining ring (monocyclic heteroaryl) or a bicyclic ring system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). The term “heteroaryl” is used herein to refer to a heteroarene when present as a substituent. The monocyclic heteroaryl are five or six212657-0002-WO01membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g. 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). The five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds. The bicyclic heteroaryl is an 8-to 12-membered ring system and includes a fused bicyclic heteroaromatic ring system (i.e., 10π electron system) such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indol-l-yl), a monocyclic heteroaryl ring fused to a monocyclic heteroarene (e.g., naphthyridinyl), and a phenyl fused to a monocyclic heteroarene (e.g., quinolin-5-yl, indol-4-yl). A bicyclic heteroaryl / heteroarene group includes a 9-membered fused bicyclic heteroaromatic ring system having four double bonds and at least one heteroatom contributing a lone electron pair to a fully aromatic 10π electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) or a benzoxadiazolyl. A bicyclic heteroaryl also includes a fused bicyclic ring system composed of one heteroaromatic ring and one non-aromatic ring such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl), or a monocyclic heteroaryl ring fused to a monocyclic heterocycle (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). The bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom. Other representative examples of heteroaryl include, but are not limited to, indolyl (e g., indol-l-yl, indol-2-yl, indol-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[l,2-a]pyridinyl (e.g., imidazo[l,2-a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-Z>]pyridin-2-yl, and thiazolo[5,4-c / ]pyrimidin-2-yi.

[0034] The term “heterocycle” or “heterocyclic,” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The term “heterocyclyl” is used herein to refer to a heterocycle when present as a substituent. The monocyclic heterocycle is a212657-0002-WO01three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. The bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin- l-yl). Representative examples of bicyclic heterocyclyls include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzothien-2-yl, l,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-1H-indol-1-yl, isoindolin-2-yl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused212657-0002-WO01to a 6-membered arene, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2, 5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety at a non-aromatic ring atom.

[0035] The term “imino” refers to the group “=NH.”

[0036] Terms such as "alkyl," "cycloalkyl," "alkylene," etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance ( e.g., " Ci-4alkyl," " C3-6cycloalkyl," " Ci-4alkylene"). These designations are used as generally understood by those skilled in the art. For example, the representation " C" followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, " Caalkyl" is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in " Ci-4," the members of the group that follows may have any number of carbon atoms falling within the recited range. A " Ci-4alkyl," for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).

[0037] The term “substituted” refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups may include, for example, halogen, =0 (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl.

[0038] For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections212657-0002-WO01and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0039] ABBREVIATIONSAcOH = acetic acidaq. = aqueousatm. = atmosphereBoc = tert-butyl carbamate / carboxylateBoc2O = di-tert-butyl dicarbonate-BuBrettPhos = 2-(Di--butylphosphino)-2′,4′,6′- triisopropyl-3,6-dimethoxy-1,1′-biphenyl Cbz = benzyl carbamateCbz-Cl = benzyl chloroformateCDCl3= chloroform, deuteratedCDI = carbonyl diimidazoleCelite® = diatomaceous earthcone. = concentratedδ = chemical shiftd = doubletDBU = 1,8-diazabicyclo[5.4.0]undec-7-eneDCM = di chloromethaneDCE = di chloroethanedd = doublet of doubletsddd = doublet of doublet of doubletsdt = doublet of tripletsDess-Martin periodinane = 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DIAD = diisopropyl azodicarboxylateDIBAL = diisobutylaluminum hydrideDIPEA = ,-diisopropylethylamineDMAP = ,-dimethyl-4-aminopyridineDMF = A’, Af-di methyl form am ideDMSO = dimethylsulfoxideDMSO-de = DMSO, deuterated212657-0002-WO01DPPA = diphenylphosphoryl azideDt-BAD = Di--butyl azodicarboxylateEDC = l-Ethyl-3-(3-dimethylaminopropyl)carbodiimideeq = equivalentsESI = electron spray ionizationEtOAc = ethyl acetateEtOH = ethanolg = gram(s)Grubbs 1stgeneration catalyst = benzylidene-bis(tricyclohexylphosphine)dichlororuthenium Grubbs 2ndgeneration catalyst = (l,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene) dichloro(phenylmethylene)(tricyclohexylphosphine)rutheniumh or hr = hour(s)1H NMR = proton nuclear magnetic resonanceHATU = 1-[Bis(dimethylamino)methylene]-1-1,2,3-triazolo[4,5-]pyridinium 3-oxidhexafluorophosphatehex = hexanesHPLC = high pressure liquid chromatographyHz = hertz / PrOH = isopropanolJ = coupling constant (Hz)LAH = lithium aluminum hydrideLCMS = liquid chromatography / mass spectrometryLDA = lithium diisopropylamideLiOH = lithium hydroxideM = molar, molaritym = multiplet[M+H]+= the protonated mass of the free base of the compoundMeCN = acetonitrileMel = methyl iodideMeOD = methanol, deuteratedMeOH = methanol212657-0002-WO01mg = milligram(s)MHz = megahertzmin = minute(s)mL = milliliter(s)mmol = mmolMs = methanesulfonylMS = mass spectrometrymol = molesm / z = mass / charge ratioN = normalNaBH(OAc)3= sodium triacetoxyborohydrideNaOEt = sodium ethoxideNaOMe = sodium methoxideNBS = -bromosuccinamiden-BuLi = -butyllithiumNaHMDS = sodium bis-trimethylsilylamideNIS = -iodosuccinamideNMP = N-methylpyrrolidonePdCl2(dppf)•CH2Cl2= [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethanePd(OH)2 / C = palladium (II) hydroxide on carbonPd(PPh3)4= tetrakis(triphenylphosphine)palladium (0)PPh3 = triphenylphosphinePPTS = pyridinium p-toluenesulfonic acidquant. = quantitativeRT = retention time (min)rt / RT = room temperatures = singletsat. = saturatedSEM-Cl = (2-Chloromethoxyethyl)trimethylsilanesm = starting material212657-0002-WO01t = tripletBuBrettPhos = 2-(Di--butylphosphino)-2′,4′,6′- triisopropyl-3,6-dimethoxy-1,1′-biphenyl TEA = triethylamineTFA = trifluoroacetic acidTFAA = trifluoracetic anhydrideTHF = tetrahydrofuranTosic acid = para-toluene sulfonic acidTs / Tosyl = para-toluene sulfonylpmol = micromolewt. = weightZhan catalyst = Dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II)2. Compounds

[0040] In one aspect, disclosed are compounds of formula (I), wherein G, X1, X2, L, R1, R2, R3, R4a, R4b, R4C, R5, R6, R7, m, o, p, and q are as defined herein.

[0041] Throughout the embodiments and description of the compounds of the invention, all instances of haloalkyl may be fluoroalkyl (e.g., any Ci-4haloalkyl may be Ci-4fluoroalkyl).

[0042] Optionally substituted cyclic groups (i.e., unsubstituted or substituted cyclic groups), such as optionally substituted aryl, heteroaryl, etc., are composed of a ring system and the ring system's optional substitution. Accordingly, a “ring system” refers to the base molecular structure formed by the constituent ring atoms, including any hydrogens required to satisfy the valency of the ring atoms. A ring system may be defined independently of its substituents. Thus, where only the ring system of an optionally substituted cyclic group is redefined with a more specific definition, any optional substitution of the original optionally substituted cyclic group remains for the new more specifically defined ring system. For example, an optionally substituted 5- to 12-membered heteroaryl may be further defined by specifying the ring system of the optionally substituted 5- to 12-membered heteroaryl is a 5- to 6-membered heteroaryl (i.e., 5- to 6-membered heteroaryl ring system), in which case the optional substitution of the original optionally substituted 5- to 12-membered heteroaryl continues to apply to the 5- to 6-membered heteroaryl ring system, unless otherwise expressly indicated.212657-0002-WO01

[0043] Where heterocyclic and heteroaromatic ring systems are defined to "contain" or as "containing" specified heteroatoms (e.g., 1-3 heteroatoms independently selected from the group consisting of O, N, and S), any ring atoms of the heterocyclic and heteroaromatic ring systems that are not one of the specified heteroatoms are carbon atoms.

[0044] In the 4- to 8-atom linker L in formula (I), the atom count of the linker refers to the atoms linking in a straight chain and does not include atoms of any substituents or branches off the linking atoms. For example, Cy1, when present, constitutes one atom of the linking atoms,one atom / Y\i.e. l,l-C3-6cycloalkylene (''1-4).

[0045] In the following, numbered embodiments of the invention are disclosed, El, El.l, E2, E2.1, E2.2, E2.3, E2.4, etc. In the numbered embodiments, the reference to a range of preceding embodiments in multiple dependent format is a reference, in the alternative, to each embodiment sequentially listed herein in the recited range.

[0046] El. A compound of formula (I), or a pharmaceutically acceptable salt thereof,wherein:G is a 5- to 6-membered aromatic heterocyclic ring containing 1-3 nitrogen atoms, wherein X1and X2are independently carbon or nitrogen ring atoms of ring G;m is 0, 1, 2, or 3;R1, at each occurrence, is independently Ci-4alkyl, Ci-4fluoroalkyl, halogen, -Ci-4alkylene-OH, -Ci-4alkylene-OCi-4alkyl, -Ci-4alkylene-NH2, -Ci-4alkylene-NHCi-4alkyl, -Ci-4alkylene-212657-0002-WO01N(Ci-4alkyl)2, -0-Ci-4alkylene-0H, -O-Ci-4alkylene-OCi-4alkyl, -O-Ci-4alkylene-NH2, -O-Ci-4alkylene-NHCi-4alkyl, -O-Ci-4alkylene-N(Ci-4alkyl)2, G1, -Ci-salkylene-G1, -OG1, or-O-Ci-salkylene-G1;G1is a Cs-ecycloalkyl, a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a 5- to 6- membered heteroaryl containing 1-3 heteroatoms, or a phenyl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, Ci- 4fluoroalkyl, oxo, OH, -OCi-4alkyl, -C(O)Ci-4alkyl, -Ci-4alkylene-OCi-4alkyl, Gla, and -Ci-3alkylene-Glaand optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G1are independently selected from the group consisting of O, N, and S;Glais a Ca-ecycloalkyl or a 4- to 7-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S;L is a 4- to 8-atom divalent linker consisting of one or more members selected from the group consisting of Cialkylene, C2alkylene, Csalkylene, C4alkylene, Csalkylene, Cealkylene, Cvalkylene, Csalkylene, C2alkenylene, C2alkynylene, -O-, -S-, -SO-, -SO2-, -C(O)-, -N(RX)-, and -Cy1-, provided that L does not comprise more than one Cy1and each occurrence of -O-, -S-, -SO-, -SO2-, or -N(RX)- is separated by C(O) or two or more carbon atoms from each other occurrence of -O-, -S-, -SO-, -SO2-, or -N(RX);Cy1is a l,l-C3-6cycloalkylene;Rxis hydrogen, Ci-4alkyl, C3-4cycloalkyl, or-Ci-3alkylene-C3-4cycloalkyl;R2is G2, - L2- Y2, Ci-4alkyl, C2-4alkenyl, CN, or H;L2is Ci-ealkylene, -CH=CH-, or C3-6cycloalkylene (e.g., );Y2is -OR2a, -NR2aR2b, -C(O)OR2a, -C(O)NR2aR2b, -C(O)R2a, N3, or CN;R2ais H, Ci-4alkyl, -C2-3alkylene-Y2a, G2a, or-Ci-3alkylene-G2a;R2bis H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3-4cycloalkyl;or R2aand R2b, together with the nitrogen to which each attaches, form a 4- to 12-membered heterocyclyl containing 1-2 additional heteroatoms independently selected from the group consisting of O, N, and S, wherein the 4- to 12-membered heterocyclyl formed by R2aand R2bis optionally substituted with a first substituent selected from the group consisting of halogen, cyano, oxo, -OR20, -N(R20)2, -NR20C(O)R20, -C(O)OR20, -C(O)N(R20)2, Ci-212657-0002-WO014alkyl, Ci-4fluoroalkyl, -Ci-4alkylene-OCi-4alkyl, -Ci-4alkylene-N(Ci-4alkyl)2, G2b, and -Ci-4alkylene-G2b, and optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen, oxo, OH, Ci-4alkyl, and Ci-4fluoroalkyl; G2is a 5-membered partially unsaturated or fully unsaturated (i.e. aromatic) heterocyclic ring that contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, is attached at a carbon ring atom of the heterocyclic ring, is optionally substituted with a first substituent selected from the group consisting of halogen, oxo, Ci-4alkyl, Ci-4fluoroalkyl, -OR21, -N(R21)2, -C(O)OR21, -C(O)N(R21)2, -Ci-3alkylene-OR21, -Ci-3alkylene-N(R21)2, G2c, and -Ci-4alkylene-G2c, and is optionally further substituted with 1- 3 substituents independently selected from the group consisting of halogen, Ci-4alkyl, and oxo;Y2ais -OCi-4alkyl, OH, -N(Ci-4alkyl)2, -NHCi-4alkyl, or -NH2;R20and R21, at each occurrence, are independently H, Ci-4alkyl, C3-4cycloalkyl, or-Ci- 3alkylene-C3-4cycloalkyl;G2a, G2b, and G2care independently a C3-6cycloalkyl, a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, or a phenyl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, Ci-2fluoroalkyl, -OCi-4alkyl, OH, C3-4cycloalkyl, and -Ci-3alkylene-C3-4cycloalkyl and optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G2a, G2b, and G2care independently selected from the group consisting of O, N, and S;R3is H, halogen, Ci-4alkyl, C3-4cycloalkyl, G3, or -Ci-4alkylene-N(R3a)2;R3a, at each occurrence, is independently H or Ci-4alkyl;G3is a 5-membered partially unsaturated or fully unsaturated (i.e., aromatic) heterocyclic ring that contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, is attached at a carbon ring atom of the heterocyclic ring, is optionally substituted with a first substituent selected from the group consisting of halogen, oxo, Ci-4alkyl, Ci-4fluoroalkyl, -OR31, -N(R31)2, -C(O)OR31, -C(O)N(R31)2, -Ci-3alkylene-OCi-4alkyl, -Ci-3alkylene-N(Ci-4alkyl)2, G3e, and -Ci-4alkylene-G3cand is optionally further substituted212657-0002-WO01with 1-3 substituents independently selected from the group consisting of halogen and Ci- 4alkyl;R31, at each occurrence, is independently H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3- 4cycloalkyl;G3Cis a Cs-ecycloalkyl, a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a 5- to 6- membered heteroaryl containing 1-3 heteroatoms, or a phenyl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, Ci- 2fluoroalkyl, -OCi-4alkyl, OH, C3-4cycloalkyl, and -Ci-3alkylene-C3-4cycloalkyl and optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G3care independently selected from the group consisting of O, N, and S; R4ais -OCi-4alkyl, Ci-4alkyl, or H;R4bis -OR40, Ci-4alkyl, or H;R40is H, Ci-4alkyl, Ci-4haloalkyl, -C2-4alkylene-OH, -C2-4alkylene-OCi-4alkyl, -C2-4alkylene- NH2, -C2-4alkylene-NHCi-4alkyl, -C2-4alkylene-N(Ci-4alkyl)2, G4, or-Ci-3alkylene-G4; G4is a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, a C3-6cycloalkyl, or a phenyl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, -C(O)OCi-4alkyl, G4a, and -Ci-3alkylene-G4aand optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G4are independently selected from the group consisting of O, N, and S;G4ais a C3-6cycloalkyl or a 4- to 7-membered heterocyclyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heterocyclyl in G4acontains 1-2 heteroatoms independently selected from the group consisting of O, N, and S;R4cis H;R5is –C2-4alkylene–O–G5;G5is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl containing 1-3 heteroatoms, each being optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, Ci-4alkyl, Ci-4fluoroalkyl, -OCi-4alkyl, -OCi-212657-0002-WO014fluoroalkyl, and C3-4cycloalkyl, wherein the heteroatoms contained in the heteroaryl of G are independently selected from the group consisting of O, N, and S;R6, at each occurrence, is independently halogen, Ci-4alkyl, Ci-4fluoroalkyl, -OCi-4alkyl, -OCi- 4fluoroalkyl, or C3-4cycloalkyl;R7is Ci-4alkyl;o is 0, 1, 2, or 3;p is 0, 1, or 2; andq is 1 or 2.

[0047] El.1. The compound of El, or a pharmaceutically acceptable salt thereof, wherein R2and R3are not simultaneously G2and G3, respectively.

[0048] E2. The compound of El or E 1.1, or a pharmaceutically acceptable salt thereof, wherein G is a 5-membered aromatic heterocyclic ring containing 1-3 nitrogen atoms.

[0049] E2.1. The compound of any of E1-E2, or a pharmaceutically acceptable salt thereof, wherein the 5-membered aromatic ring of G is a pyrazole or pyrrole.

[0050] E2.2. The compound of E2.1, or a pharmaceutically acceptable salt thereof, wherein the 5-membered aromatic ring of G is a pyrazole.

[0051] E2.3. The compound of any of E2-E2.2, or a pharmaceutically acceptable saltG ) C1 4alkylx, X2■X1thereof, whereinJVW

[0052] E2.4. The compound of E2.3, or a pharmaceutically acceptable salt thereof, (R')mG )xX2X1wherein% / vw212657-0002-WO01

[0053] E3. The compound of any of E1-E2.2, or a pharmaceutically acceptable salt thereof, wherein R1, at each occurrence, is independently Ci-4alkyl (the alkyl may be the same or different).

[0054] E3.1. The compound of E3, or a pharmaceutically acceptable salt thereof, wherein R1, at each occurrence, is methyl.

[0055] E3.2. The compound of any of E1-E2.2 or E3-E3.1, or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0056] E3.3. The compound of any of E1-E3.1, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0057] E3.4. The compound of any of E1-E2.2 or E3-E3.1, or a pharmaceutically acceptable salt thereof, wherein m is 2.

[0058] E4. The compound of any of E1-E3.4, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-salkylene, wherein optionally 1-2 methylene units are independently replaced with -O- or -N(RX)-.

[0059] E4.1. The compound of E4, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-salkylene.

[0060] E4.2. The compound of E4, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-8alkylene, wherein 1 methylene unit is replaced with -O- or -N(RX)-.

[0061] E4.3. The compound of E4.2, or a pharmaceutically acceptable salt thereof,wherein Lis

[0062] E4.4. The compound of E4.3, or a pharmaceutically acceptable salt thereof,wherein Lis

[0063] E4.5. The compound of any of E1-E4 or E4.2, or a pharmaceutically acceptable salt thereof, wherein Rxis Ci-4alkyl.

[0064] E4.6. The compound of E4.5, or a pharmaceutically acceptable salt thereof, wherein Rxis methyl.

[0065] E4.7. The compound of any of E1-E4 or E4.2, or a pharmaceutically acceptable salt thereof, wherein Rxis H.212657-0002-WO01

[0066] E5. The compound of any of E1-E3.4 or E4.5-E4.7, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-8alkenylene containing one double bond, wherein optionally 1 methylene unit is replaced with -O- or -N(RX)-.

[0067] E6. The compound of any of E1-E5, or a pharmaceutically acceptable salt thereof, wherein R2is G2.

[0068] E6.1. The compound of any of E1-E6, or a pharmaceutically acceptable salt thereof, wherein G2is the optionally substituted fully unsaturated heterocyclic ring (i.e., optionally substituted 5-membered heteroaryl).

[0069] E6.1a. The compound of any of E1-E6.1, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted fully unsaturated heterocyclic ring at G2is pyrazolyl, triazolyl, tetrazolyl, oxazolyl, or oxadiazolyl.

[0070] E6. lb. The compound of any of E1-E6. la, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted fully unsaturated heterocyclic ring at G2is pyrazol-3-yl, pyrazol-4-yl, l,2,4-triazol-3-yl, tetrazol-5-yl, oxazol-2-yl, or 1,3,4-oxadiazol-2-yl.

[0071] E6.2. The compound of any of E6.1, E6.1a, or E6.1b, or a pharmaceuticallyp-i^alkylacceptable salt thereof, wherein G2isjC-i^alkyl212657-0002-WO01

[0072] E6.3. The compound of E6.2, or a pharmaceutically acceptable salt thereof,\ O

[0073] E6.4. The compound of any of E1-E6, or a pharmaceutically acceptable salt thereof, wherein G2is the optionally substituted partially unsaturated heterocyclic ring.

[0074] E6.5. The compound of E6.4, or a pharmaceutically acceptable salt thereof,O O HNxx, N O^Nwherein G2is or

[0075] E6.6. The compound of any of E1-E6. lb or E6.4, or a pharmaceutically acceptable salt thereof, wherein the first optional substituent of the heterocyclic ring of G2is selected from the group consisting of oxo, Ci-4alkyl, -Ci-3alkylene-OR21, -Ci-3alkylene- N(R21)2, and -Ci-4alkylene-G2c.

[0076] E6.7. The compound of E6.6, or a pharmaceutically acceptable salt thereof, wherein the first optional substituent of the heterocyclic ring of G2is selected from the group consisting of oxo, methyl, -CH2CH2-OR21, -CH2CH2-N(R21)2, and -(CH2)I-2-G2C.212657-0002-WO01

[0077] E6.8. The compound of any ofEl-E6.1b, E6.4, orE6.6-E6.7, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic ring of G2is optionally substituted with a single substituent that is the first optional substituent.

[0078] E6.9. The compound of any of E1-E6.2, E6.4, or E.6.6-E6.8, or a pharmaceutically acceptable salt thereof, wherein R21, at each occurrence, is independently Ci-4alkyl (the alkyl may be the same or different).

[0079] E6.10. The compound of E6.9, or a pharmaceutically acceptable salt thereof, wherein R21is methyl.

[0080] E6.ll. The compound of any of E1-E6.2, E6.4, or E.6.6-E6.10, or a pharmaceutically acceptable salt thereof, wherein G2cis the optionally substituted 4- to 12-membered heterocyclyl.

[0081] E6.12. The compound of any of E1-E6.2, E6.4, or E.6.6-E6.11, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl at G2cis a 4- to 7-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O and N.

[0082] E6.13. The compound of E6.12, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 7-membered heterocyclyl at G2cis oxetanyl, tetrahydropyranyl, morpholino, or piperidinyl.

[0083] E6.14. The compound of E6.13, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 7-membered heterocyclyl at G2cis oxetan-3-yl, tetrahydropyran-4-yl, morpholino, or piperidin-l-yl.

[0084] E6.15. The compound of any of E1-E6.2, E6.4, or E.6.6-E6.14, or a pharmaceutically acceptable salt thereof, wherein G2cis optionally substituted with methyl.

[0085] E6.16. The compound of E6.14, or a pharmaceutically acceptable salt thereof,

[0086] E6.17. The compound of E6.15 or E6.16, or a pharmaceutically acceptable saltthereof, wherein G2cis212657-0002-WO01

[0087] E7. The compound of any of E1-E5, or a pharmaceutically acceptable salt thereof, wherein R2is -L2-Y2.

[0088] E8. The compound of any of E1-E5 or E7, or a pharmaceutically acceptable salt thereof, wherein L2is Ci salkylene.

[0089] E8.1. The compound of E8, or a pharmaceutically acceptable salt thereof, wherein L2is -CH2-, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3)2- -CH2CH2- or -CH2CH2CH2-.

[0090] E9. The compound of any of E1-E5 or E7, or a pharmaceutically acceptable salt thereof, wherein L2is.

[0091] E10. The compound of any of El -E5 orE7, or a pharmaceutically acceptable salt thereof, wherein L2is the C3-6cycloalkylene.

[0092] E10.1. The compound of E10, or a pharmceutically acceptable salt thereof, wherein L2is.

[0093] Ell. The compound of any of E1-E5 orE7-E10.1, or a pharmaceutically acceptable salt thereof, wherein Y2is -OR2a, -NR2aR2b, -C(O)OR2a, -C(O)NR2aR2b, -C(O)R2a, or N3.

[0094] El 1.1. The compound of El 1, or a pharmaceutically acceptable salt thereof, wherein Y2is -OR2a.

[0095] El 1.2. The compound of El 1, or a pharmaceutically acceptable salt thereof, wherein Y2is -NR2aR2b.

[0096] Ell. 3. The compound ofEll, or a pharmaceutically acceptable salt thereof, wherein Y2is -C(O)OR2aor -C(O)NR2aR2b.

[0097] E12. The compound of any of E1-E5 or E7-E11.3, or a pharmaceutically acceptable salt thereof, wherein R2ais H, Ci-4alkyl, -C2-3alkylene-Y2a, G2a, or -Ci-3alkylene-G2a.

[0098] E12.1. The compound of El 2, or a pharmaceutically acceptable salt thereof, wherein R2ais H, methyl, –CH2CH2–Y2a, G2a, or –(CH2)1-2–G2a.

[0099] E12.2. The compound of any of E1-E5 or E7-E12.1, or a pharmaceutically acceptable salt thereof, wherein Y2ais -OCi-4alkyl or-N(Ci-4alkyl)2.212657-0002-WO01

[0100] El 2.3. The compound of El 2.2, or a pharmaceutically acceptable salt thereof, wherein Y2ais –OCH3or –N(CH3)2.

[0101] E12.4. The compound of any of E1-E5 or E7-E12.3, or a pharmaceutically acceptable salt thereof, wherein G2ais a C3-6cycloalkyl, a 4- to 7-membered heterocyclyl containing 1-2 heteroatoms that are O or N, or 6-membered heteroaryl containing 1-2 nitrogen atoms, each optionally substituted according to E1.

[0102] E12.5. The compound of any of E1-E5 or E7-E12.4, or a pharmaceutically acceptable salt thereof, wherein G2ais optionally substituted with 1-2 substituents independently selected from the group consisting of methyl and OH.

[0103] E12.6. The compound of E12.4, or a pharmaceutically acceptable salt thereof, G2a

[0104] E12.7. The compound of E12.5 or E12.6, or a pharmaceutically acceptable salt

[0105] E13. The compound of any of E1-E5 or E7-E12.7, or a pharmaceutically acceptable salt thereof, wherein R2bis H or Ci-4alkyl.

[0106] E13.1. The compound of any of E1-E5 or E7-E13, or a pharmaceutically acceptable salt thereof, wherein R2bis H or methyl.

[0107] E14. The compound of any of E1-E5 or E7 -El 1.3, or a pharmaceutically acceptable salt thereof, wherein R2aand R2b, together with the nitrogen to which each attaches, form the optionally substituted 4- to 12-membered heterocyclyl.

[0108] E14.1. The compound of any of E1-E5, E7-E11.3, or E14, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand R2bis azetidin-l-yl, pyrrolidin-l-yl, morpholino, piperazin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, or (S)-octahydropyrazino[2,l-c][l,4]oxazin-8-yl.212657-0002-WO01

[0109] E14.2. The compound of E14 or E14.1, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand

[0110] E14.3. The compound of any of E14-E14.2, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand

[0111] E15. The compound of any of El -E5, E7-E11.3, or E14-E14.1, or a pharmaceutically acceptable salt thereof, wherein the first optional substituent of the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand R2bis -OR20, Ci-4alkyl, or G2b.

[0112] E15.1. The compound of any of E1-E5, E7-E11.3, E14-E14.1, or E15, or a pharmaceutically acceptable salt thereof, wherein R20is C1-4alkyl.

[0113] E15.2. The compound of E15 or E15.1, or a pharmaceutically acceptable salt thereof, wherein the first optional substituent of the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand R2bis -OCH3, CH3, or G2b.

[0114] E15.3. The compound ofany of E1-E5, E7-E11.3, E14-E14.2, orE15-E15.2, ora pharmaceutically acceptable salt thereof, wherein G2bis the optionally substituted 4- to 12-membered heterocyclyl.

[0115] E15.4. The compound ofany of E1-E5, E7-E11.3, E14-E14.2, orE15-E15.3, ora pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl at G2bis morpholino, piperazin- 1-yl, or oxetan-3-yl.212657-0002-WO01

[0116] E15.5. The compound of any of E1-E5, E7-E11.3, E14-E14.2, orE15-E15.4, ora pharmaceutically acceptable salt thereof, wherein G2bis optionally substituted with one substituent that is the first optional substituent.

[0117] E15.6. The compound of any of E1-E5, E7-E11.3, E14-E14.2, orE15-E15.5, ora xC-|.4alkylpharmaceutically acceptable salt thereof, wherein G2bisor

[0118] E15.6. The compound of any of E1-E5, E7-E11.3, E14-E14.2, orE15-E15.6, orapharmaceutically acceptable salt thereof, wherein G2bis, or

[0119] E16. The compound of any of E1-E5, or a pharmaceutically acceptable salt thereof, wherein R2is Ci-4alkyl, C2-4alkenyl, CN, or H.

[0120] E16.1. The compound of E16, or a pharmaceutically acceptable salt thereof, wherein R2is methyl, ethyl, ethenyl, CN or H.

[0121] El 6.2. The compound of El 6.1, or a pharmaceutically acceptable salt thereof, wherein R2is H.

[0122] E17. The compound of any of E1-E16.2, or a pharmaceutically acceptable salt thereof, wherein R3is El.

[0123] E18. The compound of any of E1-E16.2, or a pharmaceutically acceptable salt thereof, wherein R3is G3.

[0124] E18.1. The compound of any of E1-E16.2 or E18, or a pharmaceutically acceptable salt thereof, wherein G3is the optionally substituted fully unsaturated heterocyclic ring.

[0125] E18.2. The compound of any ofEl-E16.2 orE18-E18.1, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted fully unsaturated heterocyclic ring at G is pyrazolyl.

[0126] E18.3. The compound of E18.2, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted fully unsaturated heterocyclic ring at G3is pyrazol-4-yl.212657-0002-WO01

[0127] E18.4. The compound of any ofEl-E16.2 orE18-E18.3, or a pharmaceutically acceptable salt thereof, wherein G3is optionally substituted with 1-3 Ci-4alkyl.

[0128] E18.5. The compound of any ofEl-E16.2 orE18-E18.4, or a pharmaceutically acceptable salt thereof, wherein G3is optionally substituted with 1-3 methyl.

[0129] E18.6. The compound of any ofEl-E16.2 orE18-E18.4, or a pharmaceuticallyzC-|.4alkylN-Nacceptable salt thereof, whereinG3is Y

[0130] E18.7. The compound of any ofEl-E16.2 orE18-E18.6, or a pharmaceutically N-NZacceptable salt thereof, whereinG3is Y

[0131] E19. The compound of any of E1-E18.7, or a pharmaceutically acceptable salt thereof, wherein R4ais OCH3, OCH2CH3, methyl, ethyl, or H.

[0132] E19.1. The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R4ais OCH3.

[0133] E19.2. The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R4ais methyl.

[0134] E19.3. The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R4ais H.

[0135] E20. The compound of any of E1-E19.3, or a pharmaceutically acceptable salt thereof, wherein R4bis -OR40or H.

[0136] E20.1. The compound of E20, or a pharmaceutically acceptable salt thereof, wherein R4bis -OR40.

[0137] E21. The compound of any of E1-E20.1, or a pharmaceutically acceptable salt thereof, wherein R40is H, Ci-4alkyl, -C2-4alkylene-OCi-4alkyl, -C2-4alkylene-N(Ci-4alkyl)2, G4, or -Ci-3alkylene-G4.

[0138] E21.1. The compound of E21, or a pharmaceutically acceptable salt thereof, wherein R40is Ci-4alkyl.

[0139] E21.2. The compound of E21.1, or a pharmaceutically acceptable salt thereof, wherein R40is methyl.212657-0002-WO01

[0140] E21.3. The compound of E21, or a pharmaceutically acceptable salt thereof, wherein R40is -C2-4alkylene-OCi-4alkyl or -C2-4alkylene-N(Ci-4alkyl)2.

[0141] E21.4. The compound of E21.3, or a pharmaceutically acceptable salt thereof, wherein R40is -C2-4alkylene-OCi-4alkyl.

[0142] E21.5. The compound of E21.4, or a pharmaceutically acceptable salt thereof, wherein R40is -CH2CH2OCH3.

[0143] E21.6. The compound of E21.3, or a pharmaceutically acceptable salt thereof, wherein R40is -C2-4alkylene-N(Ci-4alkyl)2.

[0144] E21.7. The compound of E21.6, or a pharmaceutically acceptable salt thereof, wherein R40is CH2CH2N(CH3)2 or CH2CH2CH2N(CH3)2.

[0145] E21.8. The compound of E21, or a pharmaceutically acceptable salt thereof, wherein R40is G4.

[0146] E21.9. The compound of E21.8, or a pharmaceutically acceptable salt thereof,

[0147] E21.10. The compound of E21.9, or a pharmaceutically acceptable salt thereof,

[0148] E21.11. The compound of E21, or a pharmaceutically acceptable salt thereof, wherein R40is -Ci-3alkylene-G4

[0149] E21.12. The compound of E21.11, or a pharmaceutically acceptable salt thereof,212657-0002-WO01G4a

[0150] E21.13. The compound of E21.12, or a pharmaceutically acceptable salt thereof,', ', *=, ', or •=

[0151] E21.14. The compound of any of E1-E21, E21.8, orE21.11-E21.12, or ai — < opharmaceutically acceptable salt thereof, wherein G4aisk'1-2.

[0152] E22. The compound of any of E1-E21.14, or a pharmaceutically acceptable salt thereof, wherein R5is -(CH2)3-O-G5.

[0153] E23. The compound of any of E1-E22, or a pharmaceutically acceptable salt thereof, wherein G5is the optionally substituted 6- to 12-membered aryl.

[0154] E23.1. The compound of any of E1-E23, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 6- to 12-membered aryl at G5is phenyl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, indan-4-yl, indan-5-yl, 5,6,7,8-tetrahydronaphthalen-l-yl, or naphthalenyl.

[0155] E23.2. The compound of any of E1-E23.1, or a pharmaceutically acceptable salt thereof, wherein the optional substitution of G3is 1-3 optional substituents independently selected from the group consisting of chloro, fluoro, methyl, OCH3, CHF2, and CF3.212657-0002-WO01

[0156] E23.3. The compound of E23.1, or a pharmaceutically acceptable salt thereof, wherein R5is C-|_2alkyl212657-0002-WO01

[0157] E23.4. The compound of E23.2 or E23.3, or a pharmaceutically acceptable salt212657-0002-WO01

[0158] E23.5. The compound of E23.4, or a pharmaceutically acceptable salt thereof,wherein R5is

[0159] E24. The compound of any of E1-E22, or a pharmaceutically acceptable salt thereof, wherein G5is the optionally substituted 5- to 12-membered heteroaryl.

[0160] E24.1. The compound of any of E1-E22 or E24, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 5- to 12-membered heteroaryl at G is phenyl fused to a 5-membered heteroarene containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S.

[0161] E24.2. The compound of E24.1, or a pharmaceutically acceptable salt thereof, wherein the 5-membered heteroarene fused to the phenyl is furan (i.e., the ring system is a benzofuran attached at the phenyl portion)

[0162] E24.3. The compound of E24.2, or a pharmaceutically acceptable salt thereof, wherein the phenyl fused to the 5-membered heteroarene is benzofuran- 5 -yl or benzofuran-6-yi-

[0163] E24.4. The compound of E24.3, or a pharmaceutically acceptable salt thereof,

[0164] E25. The compound of any of E1-E24.4, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has formula (II):212657-0002-WO01R6a, R6b, and R6care independently H, halogen, Ci-4alkyl, Ci-4fluoroalkyl, -OCi-4alkyl, -OCi-4fluoroalkyl, or C3-4cycloalkyl.

[0165] E25.1. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R6ais H.

[0166] E25.2. The compound of E25 or E25.1, or a pharmaceutically acceptable salt thereof, wherein R6bis H.

[0167] E25.3. The compound of any of E25-E25.2, or a pharmaceutically acceptable salt thereof, wherein R6cis halogen.

[0168] E25.4. The compound of E25.3, or a pharmaceutically acceptable salt thereof, wherein R6cis chloro.

[0169] E25.5. The compound of any of E25-E25.2, or a pharmaceutically acceptable salt thereof, wherein R6eis H.

[0170] E26. The compound of any of E1-E25.5, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0171] E27. The compound of any of E1-E26, or a pharmaceutically acceptable salt thereof, wherein R7is methyl.

[0172] E28. The compound of any of E1-E27, or a pharmaceutically acceptable salt thereof, wherein q is 1.212657-0002-WO01

[0173] E29. The compound of any of E25-E28, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) has formula (III):

[0174] E30. The compound of any of E25-E29, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) or (III) has formula (IV):

[0175] E31. The compound of El selected from the group consisting of a compound of Table 1:Table 1212657-0002-WO01212657-0002-WO01212657-0002-WO01212657-0002-WO01212657-0002-WO01212657-0002-WO01212657-0002-WO01212657-0002-WO01212657-0002-WO01212657-0002-WO01212657-0002-WO01212657-0002-WO01or a pharmaceutically acceptable salt thereof.

[0176] E32. A pharmaceutical composition comprising the compound of any of El-E31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0177] E33. The compound of any of E1-E31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E32, for use in the treatment of cancer.

[0178] E34. The compound of any of E1-E31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E32, for use in the inhibition of cancer cell proliferation.

[0179] E35. A method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any of E1-E31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E32.

[0180] E36. A method of inhibiting cancer cell proliferation, comprising administering to a subject in need thereof, the compound of any of E1-E31, or a pharmaceutically acceptable212657-0002-WO01salt thereof, or the pharmaceutical composition of E32, in an amount effective to inhibit the cancer cell proliferation.

[0181] E37. Use of the compound of any of E1-E31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E32, in the manufacture of a medicament for the treatment of cancer.

[0182] E38. Use of the compound of any of E1-E31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E32, in the manufacture of a medicament for the inhibition of cancer cell proliferation.

[0183] Compound names can be assigned / determined by using Struct=Name naming algorithm as part of CHEMDRAW® ULTRA. CHEMDRAW® ULTRA does not recognize axial chirality present in macrocyclic compounds; these designations are added to the CHEMDRAW® ULTRA generated name following IUPAC nomenclature conventions.

[0184] Compounds may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “A” or “5” depending on the configuration of substituents around the chiral carbon atomor or “So” depending on the configuration of substituents around an axially chiral bond. The terms “A” and “5” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. In the compounds of formula (I), when no specific configuration is indicated at a stereogenic center (e g., carbon), the compounds include all possible stereoisomers.

[0185] Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, " Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific & Technical, Essex CM20212657-0002-WO012IE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods.

[0186] It should be understood that the compound may possess tautomeric forms, as well as geometric isomers, and that these also constitute an aspect of the invention.

[0187] In the compounds of formula (I), and any subformulas, any "hydrogen" or " H," whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes1H (protium) and2H (deuterium). Accordingly, any group comprising one or more hydrogen atoms encompasses corresponding deuterium-labeled versions of the group. For example, “-CH2-”encompasses “-CD2-”;' — ' encompasses' — 'D, etc.

[0188] The present disclosure also includes an isotopically-labeled compound (e.g., deuterium labeled), where an atom in the isotopically-labeled compound is specified as a particular isotope of the atom. Examples of isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36C1, respectively.

[0189] Isotopically-enriched forms of compounds of formula (I), or any subformulas, may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-enriched reagent in place of a non-isotopically-enriched reagent. The extent of isotopic enrichment can be characterized as a percent incorporation of a particular isotope at an isotopically-labeled atom (e.g., % deuterium incorporation at a deuterium label).

[0190] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a212657-0002-WO01salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[0191] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N, N-dibenzylphenethylamine, 1 -ephenamine and TV, TV’ -dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.A. Binding to Mcl-1

[0192] In some embodiments, a provided compound has a Ki value less than about 0.011 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 0.1 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 0.2 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 0.3 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 0.4 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 0.5 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 0.6 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 0.7 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 0.8 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 0.9 pM for inhibition of Mcl-1. In some embodiments, a provided212657-0002-WO01compound has a Ki value less than about 1 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 2 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 3 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 4 pM for inhibition of Mcl-1. In some embodiments, a provided compound has a Ki value less than about 5 pM for inhibition of Mcl-1. Exemplary assays for measuring Ki value for inhibition of Mcl-1 are widely known in the art, including but not limited to those described in the examples herein.B. General Synthesis

[0193] Compounds of formula (I) may be prepared by synthetic processes or by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.

[0194] The compounds of the present disclosure can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference as to the subject matter referenced herein. Compounds of formula (I) may be also prepared by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.

[0195] The compounds of the disclosure may be prepared using the exemplary reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effective. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. One having ordinary skill in the art may adjust one or more of the conditions described herein. One skilled in the art of organic synthesis understands that the functionality present on various portions of the edict molecule must be compatible with the reagents and reactions proposed. Not all compounds of the disclosure falling into a given class may be compatible with some of the reaction conditions212657-0002-WO01required in some of the methods described. Such restrictions to the substituents, which are compatible with the reaction conditions, will be readily apparent to one skilled in the art and alternate methods can be used.Scheme 1v viVIII IX212657-0002-WO01x xi

[0196] Compounds of formula xi may be synthesized by processes illustrated in Scheme 1. Indole i may be coupled with boronic ester ii via Suzuki -Miyaura coupling (Miyaura, N.;Suzuki, A. Chem. Rev. (1995) 2457); one such exemplary procedure entails treatment with Pd(PPh3)4 and potassium carbonate. Indole iii may be alkylated using / c / 7-butyl (5)-5-methyl- l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (iv). The Boc-protecting group may be removed with trifluoracetic acid or other suitable conditions (Greene, T.; Wutz, P. Protective Groups in Organic Synthesis, (1991)), followed by treatment with a carbonate base to afford lactam vi (see, for example, Richter, H. G. F. Bioorg. Med. Chem. Lett. 2010, 5713). Cross coupling between lactam vi and indole vii under Ullmann (see Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed., (2003) 5400) or Buchwald-Hartwig (see Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed., (2008) 6338) conditions may furnish intermediate viii. Exemplary conditions for this transformation include, but are not limited to, CuI, (trans)-N1,N2-dimethylcyclohexane-1,2-diamine, K3PO4and [Pd(cinnamyl)Cl]2, t-BuBrettPhos, Cs2CO3. The benzyl ether may be removed under hydrogenolysis conditions (Greene, ibid). The resultant alcohol may be converted to a leaving group X4, including but not limited to tosylate and bromide, which may be accomplished by a number of conditions that are routine for those skilled in the art of organic synthesis. Compound x may be cyclized to form macrocycle xi using, but not limited to, Cs2CO3or NaH as a base in DMF.212657-0002-WO01Scheme 2

[0197] Compounds of formula xiv may be obtained by the processes described in Scheme 2. Treatment of indole xii with borontribromide may afford bromide xiii. Treatment of compound xiii with a suitable phenol in the presence of a carbonate base may provide compound xiv.212657-0002-WO01Scheme 3xv xvixvii xviiixix XX

[0198] Compounds of formula xix and xx may be synthesized by processes illustrated in Scheme 3. Ester xv may be saponified to acid xvi using a hydroxide base such as LiOH or NaOH. Primary amide xvii may be synthesized by activating acid xvi with an appropriate peptide coupling reagent, such as but not limited to HATU, or by generating an acyl chloride with reagents such as SOCl2or oxalyl chloride, followed by reacting with an ammonia source, such as NH4CI or NH4OH. Amide xvii may be converted to triazole xviii by treatment with212657-0002-WO01DMF / DMA then condensation with hydrazine (see Yi, L.; Lang, Jr. S. A., et al. J. Org. Chem.1979, 4180, and PCT Int. Appl. 2005105213, 10 Nov. 2005). Alkylation of xviii with an appropriate electrophile (X5= OTs, OMs, Br, I) under conditions that are routine for those skilled in the art of organic synthesis may afford either regioisomer xix or xx.Scheme 4xxi xxiixxiii xxiv xxvxxiv or xxvxxviorxix

[0199] Compounds of formula xix and xx may be synthesized by processes illustrated in Scheme 4. Indole xxi may be converted to regioisomeric triazoles xxiv and xxv in a similar212657-0002-WO01manner as described in Scheme 3. Compound xxiv or xxv may be coupled to lactam vi as previously described in Scheme 1. Intermediate xxvi may then be subjected to a sequence of benzyl deprotection, tosylation, and cyclization to furnish macrocycles xix or xx analogously to the processs described in Scheme 1.212657-0002-WO01Scheme 5xxxixxxiiixxxiv XXXV

[0200] Compounds of formula xxxv may be obtained following the processes illustrated in Scheme 5. Lactam xxvii may be debenzylated and the resultant alcohol (xxviii) may be protected, including but not limited to the THP protecting group (Greene, ibid.)', to access212657-0002-WO01compound xxix Cross coupling between lactam xxix and indole xxx as described in Scheme 1 may afford intermediate xxi. Removal of the protecting group may afford alcohol xxxii.Conversion of the alcohol xxxii to a leaving group and cyclization as described in Scheme 1 may afford macrocycle xxxiii. Hydrogenolysis of the benzyl group may afford phenol xxxiv.The phenol may be alkylated with a variety of electrophiles, (X5= OTs, OMs, Br, I) under conditions that are routine for those skilled in the art of organic synthesis. Alternatively, phenol xxxiv may also be functionalized by treatment with an appropriate alcohol (X5= OH) under Mitsunobu conditions (see Swamy, K. C. K.; Kumar, N. N. B; Balaraman, E.; Kumar, K. V. P. P. ChemRev. 2009, 2551).Scheme 6xxxviii

[0201] Compounds of formula xxxvi may be obtained following the processes illustrated in Scheme 6. Ether xxxvi may be synthesized as an appropriately substituted example described in Scheme 5, where PG is a suitable protecting group, including but not limited to Boc or Cbz. Deprotection of intermediate xxxvi under suitable conditions (Greene, ibid. may afford amine xxxvii. Reductive amination using xxxvii and a suitable aldehyde or ketone under conditions212657-0002-WO01that are routine for those skilled in the art of organic synthesis, which may include but are not limited to NaBH₃CN or NaBH(OAc)₃, may afford compounds of formula xxxviii.Scheme 7(R1)mR40a IH'N'R40bX6= Br, I, OTs,OMs

[0202] Compounds of formula 40 may be obtained following the processes illustrated in Scheme 7. Compounds of structure xxxix may also be prepared from the method described in Scheme 5 by using an appropriate difunctionalized electrophile. Compounds of structure xxxix treated with a suitable primary or secondary amine under basic conditions may afford amine xl. Scheme 8

[0203] Compounds of formula xlii and xliii may be obtained following the processes illustrated in Scheme 8. Treatment of macrocycle xli with reductive conditions, including but not limited to, Pd / C, Pd(OH)₂ / C, H₂, may provide compounds of formula xlii and / or xliii.212657-0002-WO01Scheme 9xlvi

[0204] Compounds of formula xlv and xlvi may be obtained following the processes illustrated in Scheme 9. Reduction of ester xv with a suitable reagent, including but not limited to NaBH₄, LiBH₄, or DIBAL, may afford alcohol xliv. Alternatively, treatment of ester xv with a suitable organometallic reagent where M may be, but is not limited to, Li or Mg, may afford tertiary alcohol xlv. Alcohol intermediate xliv may be alkylated with a suitable electrophile where X5may be, but is not limited to I, Br, Cl, OMs, or OTs under conditions under conditions that are routine for those skilled in the art of organic synthesis to furnish compounds of structure xlvi.212657-0002-WO01Scheme 10R2aH'N'R2b xlivxlviiR20

[0205] Compounds of formula xlix and 1 may be obtained following the processes illustrated in Scheme 10. Alcohol xliv may be oxidized under conditions that are routine for those skilled in the art of organic synthesis to furnish aldehyde xlvii. Aldehyde xlvii may be converted to compounds of formula xlviii via reductive amination using a suitable aldehyde or ketone under conditions that are routine for those skilled in the art of organic synthesis, which may include but are not limited to NaBH₃CN or NaBH(OAc)₃. Alternatively, treatment of aldehyde with a suitable organometallic reagent, as described for compound xlv, may afford compounds of formula xlix. Compounds of formula xlix may then be alkylated in a similar manner as described for compounds xlvi to afford compounds of formula 1.212657-0002-WO01Scheme 11

[0206] Compounds of formula liv may be obtained following the processes illustrated in Scheme 11 Alcohol li may be converted to a leaving group, including but not limited to, Br, OTs, or OMs under conditions that are routine for those skilled in the art of organic synthesis to give compound lii. Compound lii may then be converted to compound liii with NaN3.Reduction of azide liii with, but not limited to, PPh₃, may afford the primary amine liv.212657-0002-WO01Scheme 12Oxlvii |vj IviiR2aR6a R5Iviii

[0207] Compounds of formula Iviii may be obtained following the processes illustrated in Scheme 12. Aldehyde xlvii may be converted the alkene lvii using a suitable reagent such as, but not limited to phosphorous ylides Iv or Ivi (see Maryanoff, B. E.; Reitz, A. B. Chem. Rev.1989, 863). Treatment of the resulting alkene (Ivii) with reductive conditions, including but not limited to, Pd / C, Pd(OH)₂ / C, H₂, may provide alkane lviii.212657-0002-WO01Scheme 13lix

[0208] Compounds of formula Ixi may be obtained following the processes illustrated in Scheme 13. Unsaturated ester lix may be obtained as described in Scheme 12. Saponification of lix with a suitable hydroxide base, including but not limited to LiOH, NaOH, or KOH, may afford carboxylic acid lx. Carboxylic acid lx may then be coupled with an appropriate primary or secondary amine under conditions that are routine for those skilled in the art of organic synthesis to form amide Ixi.212657-0002-WO01Scheme 14R2ap2a H'N'R2bIxiv

[0209] Compounds of formula Ixiii or Ixv may be obtained following the processes illustrated in Scheme 14. Unsaturated ester lix may be obtained as described in Scheme 12. Unsaturated ester lix may be converted to cyclopropane Ixii by, but not limited to, treating with Corey-Chaykovsky or Simmons-Smith reagents (for Corey Chaykovsky see Sapeta, K.; Kerr, M. A. Org. Lett., 2009, 2081; Gololobov, Y. G.; Nesmeyanov A. N., et al. Tetrahedron, 1987, 2609; for Simmons-Smith see Helquist, P. in Comprehensive Organic Synthesis, 1991, pp. 951-997). Ester Ixii may be saponified and converted to amide Ixiii in a manner analogous to that described above. Alternatively, reduction of unsaturated ester Ixiv, e.g. via hydrogenation with Pd / C, may afford saturated ester Ixiv. Ester Ixiv may also be saponified and converted to the corresponding amides Ixv in a manner analogous to that described above.212657-0002-WO01

[0210] Compounds of formula Ixv, Ixvi, or Ixvii may be obtained following the processes illustrated in Scheme 15. Ester Ixiv may be reduced under conditions that are routine for those skilled in the art of organic synthesis to form alcohol Ixv. Alcohol Ixv may then be either oxidized and subjected to reductive amination (compound Ixvi) or alkylated (compound Ixvii) in processes analogous to those described in Scheme 10.212657-0002-WO01Scheme 16xvii IxviiiIxix

[0211] Compounds of formula Ixx may be obtained following the processes illustrated in Scheme 16. Primary amide xvii may be dehydrated with POCI3 or TFAA to afford nitrile Ixviii (see Borkin, D.; et al. J. Med. Chem. 2016, 892 and Pitha, J.; et al. J. Med. Chem. 1987, 612). Nitrile Ixviii may then be converted to tetrazole Ixix by treatment with NaN3(see Mendal, M.; Tomoe, C. W.; Chem. Rev. 2008, 2952 and Dhiman, N.; Kaur, K.; Jaitak, V. Bioorg. Med. Chem. 2020, 115599). Tetrazole Ixix may be alkylated to afford compound Ixx.212657-0002-WO01Scheme 17xvi IxxiiIxxi Ixxiii

[0212] Compounds of formula Ixxi and Ixxiii may be obtained following the processes illustrated in Scheme 17. Compound xvi may be converted to acyl hydrazine Ixxii via amide coupling conditions previously described. Compound Ixxii may be converted to Ixxiii via treatment with CDI (see Tong, Y.; Bouska, J. J.; et al., J. Med. Chem. 2009, 6803).Alternatively, compound xvi may be converted to oxadiazole Ixxi, e.g. via treatment with N-isocyano-1,1,1-triphenyl-λ5-phosphanimine (see Matheau-Raven D.; Boulter, E.; et al. Org. Lett. 2021, 8209).212657-0002-WO01Scheme 18OH(R1)mIxviii IxxivIxxv

[0213] Compounds of formula Ixxv may be obtained following the processes illustrated in Scheme 18. Nitrile Ixviii may be treated with NH2OH to afford intermediate Ixxiv. Compound Ixxv may be cyclized using CDI (see Tong, Y.; Bouska, J. J.; J. Med. Chem., 2009, 6803).212657-0002-WO01Scheme 19xvi IxxviIxxvii

[0214] Compounds of formula Ixxvii may be obtained following the processes illustrated in Scheme 19. Treatment of acid xvi with a suitable α-chloroketone may yield compound Ixxvi.Treatment of Ixxvi under suitable conditions, including but not limited to ammonia in acetic acid, may afford oxazole Ixxvii (see Dai, L.; Yu, S.; et al. Chem. Comm. 2021, 1376).Scheme 20lxxviii lxxix lxxx

[0215] Compounds of formula Ixxx may be obtained following processes illustrated in Scheme 20. Alkylation of the heterocyclic bromide Ixxviii may afford intermediate Ixxix.212657-0002-WO01Boronylation of intermediate Ixxix via either lithiation / quenching with boronic ester or Miyaura boronylation (see Ishiyama, T., Murata, M.; Miyaura, N., J. Org. Chem. 1995 7508) may afford boronic ester Ixxx.Scheme 21Ixxxi ixxxii IxxxiiiX3= Br, IIxxxv Ixxxvi

[0216] Compounds of formula Ixxxvi may be obtained following processes illustrated in Scheme 21. Halogenation of benzaldehyde Ixxxi may be accomplished using, but not limited to, bromine / HOAc (see Hsu, D.-S.; Hwang, T.-Y.; Eur. J. Org. Chem. 2018, 4689) or AgNO3 / ICl (see Rao, M. L. N.; Murty, V. N. Eur. J. Org. Chem. 2016, 2177). Intermediate Ixxxii may then be alkylated using routine methods for those skilled in the art of organic synthesis to afford compound Ixxxiii. Knoevenagel condensation with an azidoacetate Ixxxiv may afford intermediate Ixxxv. Heating intermediate Ixxxv either thermally or with microwave irradiation may afford indole Ixxxvi (see Gribble, G. W.; J. Chem. Soc., Perkin. Trans. 2000, 1045).212657-0002-WO01Ixxxvii Ixxxviii X3= Br, I

[0217] Compounds of formula xxi may be prepared by following the processes illustrated in Scheme 22. Treatment of the aniline Ixxxvii with NaNO2under acidic conditions, followed by treatment with SnCl2, may afford hydrazine intermediate Ixxxviii. Treatment of Ixxxviii with pyruvate Ixxxix under acidic Fischer indole synthesis conditions (see Robinson, B.; Chem. Rev.1963, 373), including, but not limited to camphorsulfonic acid, HC1, H2SO4, or TFA, may afford intermediate xxi.Scheme 23

[0218] Compounds of formula xcvi may be prepared by following the processes illustrated in Scheme 23. Indole xci may be prepared from nitrobenzene xc via the Bartoli indole synthesis (see Bartoli, G.; et al. Tetrahedron Lett. 1989, 2129 and Bartoli, G.; et al. J. Chem.212657-0002-WO01Soc. Perkin Trans. 7, 1991, 2757). Indole xci may then be protected with a suitable ortho-directing protecting group, including but not limited to Boc, to provide compound xcii (Green, ibid), ortho- Metallation followed by quenching with I2may afford iodide xciii (see Usui, S.; et al. J. Am. Chem. Soc. 2007, 15102 and Dong, J.; et al. Bioorg. Med. Chem. Lett. 2020, 12, 7601). Selective Suzuki-Miyaura cross coupling with a suitable boronic ester or acid may afford compound xcv (see Scheme 1). Deprotection of the indole nitrogen (Green, ibid) may afford compounds of structure xcvi.212657-0002-WO01Scheme 24ciii212657-0002-WO01

[0219] Compounds of formula ciii may be prepared by following the processes illustrated in Scheme 24. Diester xcvi (Burke, J. et al., J. Med. Chem., 2015, 55, 3794) may be coupled with boronic ester ii as previously described in Scheme 1. Compound xcvii may then be alkylated with compound iv and converted to compound xcviii in a manner analogous to that described in Scheme 1. Cross coupling between lactam xcviii and halide vii under Ullmann (see Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed., (2003) 5400) or Buchwald-Hartwig (see Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed., (2008) 6338) conditions may furnish intermediate xcix. Exemplary conditions for this transformation include, but are not limited to, Cui, (trans)-N1,N2-dimethylcyclohexane-1,2-diamine, K3PO4and [Pd(cinnamyl)Cl]2, LBuBrettPhos, Cs2CO3. Compound xcix may then be converted to macrocycle c following the route described in Scheme 1. Ester c may be reduced to alcohol ci using, but not limited to, lithium triethylborohydride. Alcohol ci may be converted to compounds of structure ciii by treatment with a suitable aryl alcohol under Mitsunobu conditions (see Swamy, K. C. K.; Kumar, N. N. B; Balaraman, E.; Kumar, K. V. P. P. Chem Rev. (2009) 2551). Alternatively, alcohol ci may be converted to the bromide cii using, but not limited to, CBr4and triphenyl phosphine (see Appel, R., Angew. Chem. Int. Ed., 1975, 12, 801). Displacement of the bromide of cii may be accomplished by treatment with a suitable phenol under conditions that are routine for those skilled in the art of organic synthesis to afford compounds of structure ciii.

[0220] The compounds and intermediates may be isolated and purified by methods well-known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in " Vogel's Textbook of Practical Organic Chemistry", 5th edition (1989), by Fumiss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[0221] A disclosed compound may have at least one basic nitrogen whereby the compound can be treated with an acid to form a desired salt. For example, a compound may be reacted with an acid at or above room temperature to provide the desired salt, which is deposited, and collected by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited212657-0002-WO01to tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolactic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic, carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, and the like.

[0222] Reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and substituents present in the reactants used. Specific procedures are provided in the Examples section. Reactions can be worked up in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.

[0223] Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that cannot be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.

[0224] Hydroxy protecting groups PG are well known in the art, as described in PGM Wuts and TW Greene, in Greene’s book titled Protective Groups in Organic Synthesis (4thed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. Suitable hydroxy protecting groups include, for example, trityl groups (e g., trityl, dimethoxytrityl,212657-0002-WO01methoxytrityl), acetyl, benzoyl, benzyl, p-methoxybenzyl, P-methoxyethoxymethyl (MEM), methoxymethyl (MOM), methylthiomethyl, pivaloyl, tetrahydropyranyl (THP), tetrahydrofuranyl (THF), silyl (e.g., trimethyl silyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-isopropylsilyloxymethyl (TOM), triisopropylsilyl (TIPS), methyl, and ethoxyethyl.

[0225] When an optically active form of a disclosed compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).

[0226] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

[0227] It can be appreciated that the synthetic schemes and specific examples as described are illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.C. Examples

[0228] Microwave assisted reactions are performed in a single-mode reactor: Emrys™ Optimizer microwave reactor (Personal Chemistry A. B., currently Biotage).

[0229] Hydrogenation reactions are performed using an atmospheric balloon or using a Parr hydrogenation shaker apparatus.

[0230] Normal phase flash silica gel-based column chromatography is performed using ready -to-connect cartridges from ISCO, on irregular silica gel, particle size 15-40 pm on a Combi-flash Companion chromatography system from ISCO.

[0231] Low resolution mass spectra are obtained on an Agilent 1200 series 6130 mass spectrometer. Analytical HPLC is performed on an HP1100 with UV detection at 214 and 254 nm along with ELSD detection, LC / MS (J-Sphere80-C18, 3.0 x 50 mm, 4.1 min gradient, 5%[0.05%TFA / CH3CN]:95%[0.05%TFA / H2O] to 100%[0.05%TFA / CH3CN]. Preparative RP-HPLC purification is performed using a Gilson Inc. preparative UV-based system using a212657-0002-WO01Phenomenex Gemini C18 column (50 x 30 mm I. D., 5 pm) with an acetonitrile (0.1% TFA)-water (0.1% TFA) custom gradient.

[0232] For LC-MS characterization of the compounds of the present invention, the following methods are used.

[0233] Method 1: The HPLC measurement is performed using an Agilent 1200 system comprising a binary pump with degasser, an autosampler, a column oven, a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column is split to a SQ mass spectrometer and Polymer Labs ELSD. The MS detector is configured with an ES ionization source. Nitrogen is used as the nebulizer gas. The source temperature is maintained at 350 °C. Data acquisition is performed with Agilent Chemstation software. Reversed phase HPLC is carried out on a Kinetex C18 column (2.6 pm, 2.1 x 30 pm) from Phenomenex, with a flow rate of 1.5 mL / min, at 45 °C. The gradient conditions used are: 95% A (water + 0.1% TFA), 5% B (acetonitrile), to 95% B in 2.1 minutes, returning to initial conditions at 2.11 minutes. Injection volume 1 pL. Low-resolution mass spectra (single quadruple MSD detector) are acquired in electrospray mode by scanning from 100 to 700 in 0.25 seconds, step size of 0.1 and peak width of 0.03 minutes. The capillary needle voltage is 3.0 kV and the fragmentor voltage is 100 V.

[0234] Method 2: Using method 1 instrument and column conditions. The gradient conditions used are: 50% A (water + 0.1% TFA), 50% B (acetonitrile), to 95% B in 2.0 minutes, returning to initial conditions at 2.11 minutes. Injection volume 1 pL. Low-resolution mass spectra (single quadruple MSD detector) are acquired in electrospray mode by scanning from 100 to 700 in 0.25 seconds, step size of 0.1 and peak width of 0.03 minutes. The capillary needle voltage is 3.0 kV and the fragmentor voltage is 100V.

[0235] Method 3: Using method 1 instrument and column conditions. The gradient conditions used are: 93% A (water + 0.1% TFA), 7% B (acetonitrile), to 95% B in 1.0 minutes, returning to initial conditions at 1.11 minutes. Injection volume 1 pL. Low-resolution mass spectra (single quadruple MSD detector) are acquired in electrospray mode by scanning from 100 to 700 in 0.25 seconds, step size of 0.1 and peak width of 0.03 minutes. The capillary needle voltage is 3.0 kV and the fragmentor voltage is 100V.

[0236] Method 4: The HPLC measurement is performed using an Agilent 1290 system comprising a binary pump with degasser, an autosampler, a column oven, a diode-array detector212657-0002-WO01(DAD) and a column as specified in the respective methods below. The MS detector is configured with an ES ionization source. Nitrogen is used as the nebulizer gas. The source temperature is maintained at 350 °C. Data acquisition is performed with Agilent Chemstation software. Reversed phase HPLC is carried out on a Acquity BEH C18 column (1.7 pm, 2.1 x 50 pm), with a flow rate of 1.0 mL / min, at 40 °C. The gradient conditions used are: 60% A (water + 0.1% formic acid), 40% B (acetonitrile), to 98% B in 3.9 minutes, holding at 98% B for 0.4 min, and returning to initial conditions at 4.5 minutes. Injection volume 1 pL. Low-resolution mass spectra (single quadruple MSD detector) are acquired in electrospray mode by scanning from 400 to 2000 in 0.25 seconds, step size of 0.1 and peak width of 0.03 minutes.

[0237] 1H NMR spectra are recorded either on a Bruker DPX-400 or on a Bruker AV-500 spectrometer with standard pulse sequences, operating at 400 MHz and 500 MHz respectively. Chemical shifts (5) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS), which is used as internal standard. Coupling constants (J-values) are reported in Hz.

[0238] The following Examples are offered as illustrative as a partial scope and particular embodiments of the invention and are not meant to be limiting of the scope of the invention. Abbreviations and chemical symbols have their usual and customary meanings unless otherwise indicated. Unless otherwise indicated, the compounds described herein have been prepared, isolated and characterized using the Schemes and other methods disclosed herein or may be prepared using same.IntermediatesIntermediate 1Ethyl 7-bromo-4,5-dimethoxy-LH-indole-2-carboxylate

[0239] Step A: Ethyl (Z)-3-azido-3-(5-bromo-2,3-dimethoxyphenyl)acrylate. NaOEt (36 mL, 21% wt., Ill mmol, 2.3 eq) was dissolved in EtOH (100 mL) and cooled to 0 °C. 5-Bromo-2, 3 -dimethoxybenzaldehyde (12 g, 48 mmol, 1.0 eq), ethyl azidoacetate (12.7 g, 99 mmol, 2.0 eq), and ethyl trifluoroacetate (14 g, 99 mmol, 2.0 eq) were dissolved in THF / EtOH (60 mL; 2: 1) and added to the NaOEt solution at 0 °C. The reaction was allowed to stir for 2 h212657-0002-WO01at 0 °C, and then warmed to RT for 1 h. The reaction was cooled to 0 °C, filtered and rinsed with cold EtOH to afford the desired product as a white solid. The crude reaction product was purified by flash column chromatography eluting with EtOAc in hexanes to afford the title compound (11 g, 63% yield). LCMS (ESI) Method 1: RT = 2.051 min, product mass not observed.

[0240] Step B: Ethyl 7-bromo-4,5-dimethoxy-l / / -indole-2-carboxylate. Ethyl (Z)-3-azido-3-(5-bromo-2,3-dimethoxyphenyl)acrylate (11 g, 31 mmol) was dissolved in toluene (120 mL) and portioned into five microwave vials. Each vessel was irradiated for 10 minutes in the microwave at 180 °C. The reaction vials were cooled to RT, combined, and concentrated. The crude product was purified by flash column chromatography eluting with 0 to 30% EtOAc in hexanes to afford the title compound (5.5 g, 54% yield). LCMS (ESI) Method 1: RT = 1.708 min, m / z = 327.9 [M+H]+.BrIntermediate 2Ethyl 7-bromo-5-methoxy-4-methyl-lH-indole-2-carboxylate

[0241] Step A: (2-Bromo-4-methoxy-5-methylphenyl)hydrazine. 2-Bromo-4-methoxy-5-methylaniline (9 g, 40 mmol, 1.0 eq) was cooled to 0 °C. HC1 (75 mL con. HC1: H2O in 30 mL of H2O) was added. After stirring for 10 min at 0 °C, sodium nitrite (2.9 g, 42 mmol, 1.05 eq in 10 mL H2O) was added dropwise over 30 min. The reaction was allowed to stir at 0 °C for 1 h followed by dropwise addition of SnCl2(28 g, 150 mmol, 3.7 eq, dissolved in 25 mL cone. HC1). The reaction was allowed to stir for 20 min at 0 °C then at RT for 3 h. The reaction was neutralized with NaOH (40 g in 100 mL H2O). The reaction mixture was filtered through Celite®, extracted with DCM, dried over MgSCL, filtered, and concentrated to afford the title product (8.4 g, 87% yield). ^-NMR (DMSO-de) 87.15 (s, 1H), 6.94 (s, 1H), 5.8 (s, 2H), 3.65 (s, 3H), 2.1 (s, 3H).

[0242] Step B: Ethyl 7-bromo-5-methoxy-4-methyl-lH-indole-2-carboxylate. (2-Bromo-4-methoxy-5-methylphenyl)hydrazine (9.2 g, 40 mmol, 1.0 eq) was dissolved in EtOH (100 mL). Ethyl pyruvate (5 mL, 44 mmol, 1.1 eq) was added and the reaction was heated to212657-0002-WO0170 °C for 1 h. The reaction was concentrated and the crude material was dissolved in toluene (150 mL). Camphorsulfonic acid (10.6 g, 80 mmol, 2.0 eq) was added and the reaction was heated to 120 °C for 12 h. The reaction mixture was cooled, extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 10% EtOAc in hexanes to afford the title compound (8.0 g, 64% yield). ’HAMR (DMSO-d6) 58.45 (s, 1H), 7.48 (s, 1H), 7.13 (s, 1H), 4.23 (q, 2H, J= 8 Hz), 3.75 (s, 3H), 2.26 (s, 3H), 2.13 (s, 3H), 1.25 (tr, 3H, J= 8 Hz).BrCl N OEtIntermediate 3Ethyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l / f-indole-2- carboxylate

[0243] Step A: 5-(2-(2-Bromo-3-chlorophenyl)hydrazono)-6-ethoxy-6-oxohexanoic acid. To a stirring mixture of 2-bromo-3 -chloroaniline (20 mmol) in IM HC1 (25 mL) and water (5 mL) at 0 °C was added NaNO2 (1.38 g, 20 mmol) in water (20 mL), sodium acetate (9.23 g, 112 mmol) in water (25 mL) and ethyl 2-oxocyclopentane carboxylate (3.0 mL, 20 mmol) in sequence. The reaction mixture was stirred for 15 min at 0 °C then warmed to 20 °C over 2 h and extracted with DCM, dried over MgSCL, filtered, and concentrated to afford the title compound (7.1 g, 90% yield).

[0244] Step B: Ethyl 7-bromo-6-chloro-3-(3-ethoxy-3-oxopropyl)-17 / -indole-2-carboxylate. To a solution of 5-(2-(2-bromo-3-chlorophenyl)hydrazono)-6-ethoxy-6-oxohexanoic acid (7.1 g, 18 mmol) in EtOH (30 mL) was added cone. H2SO4(7.5 mL). The reaction was refluxed for 1.5 h. The reaction was poured into ice then extracted with DCM. The combined organic layer was washed with sat. NaHCO3, water, brine, dried over MgSC>4, filtered and concentrated. The residue was purified by flash column chromatography eluting with 0 to 25% EtOAc in hexanes to give the title compound as an off-white solid (4.4 g, 11 mmol). MS (ES) 402.0 (M+H).212657-0002-WO01

[0245] Step C: Ethyl 7-bromo-6-chloro-3-(3-hydroxypropyl)-1 / 7-indole-2-carboxylate.To a solution of ethyl 7-bromo-6-chloro-3-(3-ethoxy-3-oxopropyl)-l / / -indole-2-carboxylate (1.9 g, 4.8 mmol) in THF (20 mmol) was added BH3 in THF (20 mb, 20 mmol) at 20 °C. The reaction mixture was stirred for 15 h at 20 °C and quenched by addition of MeOH then concentrated. The residue was purified by flash column chromatography eluting with 0-50% EtOAc in hexanes to afford the title compound as a white solid (1.4 g, 3.9 mmol). MS (ES) 360.1 (M+H).

[0246] Step D: Ethyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-TH-indole-2-carboxylate. To a solution of ethyl 7-bromo-6-chloro-3-(3-hydroxypropyl)-17 / -indole-2-carboxylate (101 mg, 0.28 mmol), PPh3(110 mg, 0.51 mmol) and 3,5-diMe-4-Cl-phenol (81 mg, 0.52 mmol) in THF (3.5 mL) was added D-BAD (99 mg, 0.51 mmol) at 20 °C. The reaction mixture was stirred for 15 h at 20 °C then concentrated. The residue was purified by flash column chromatography eluting with 0-10% EtOAc in hexanes to afford the title compound (105 mg, 0.21 mmol) as a colorless oil. MS (ES) 498.0 (M+H).Intermediate 43-((3-(Benzyloxy)propoxy)methyl)-l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l / / -pyrazole

[0247] Step A: 3-((3-(Benzyloxy)propoxy)methyl)-4-bromo-l-methyl-LH-pyrazole. (4-Bromo-1 -methyl- l / 7-pyrazol-3-yl)m ethanol (5.00 g, 26.2 mmol, 1.0 eq) was dissolved in DMF (32 mL). The reaction was cooled to 0 °C and NaH (1.67 g, 41.9 mmol, 1.6 eq) was added. The reaction was allowed to stir for 20 min. ((3-Bromopropoxy)methyl)benzene (7.40 mL, 41.90 mmol, 1.6 eq) was then added, and the reaction was stirred at RT for 16 h. The reaction was cooled to 0 °C, quenched with MeOH, diluted into H2O, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and then concentrated. The crude product was purified by flash column chromatography eluting with 0 to 70% EtOAc in hexanes to afford the title compound (5.78 g, 65% yield). LCMS (ESI) Method 3: RT = 1.01 min, m / z = 339.3 [M+H]+.212657-0002-WO01

[0248] Step B: 3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l / / -pyrazole. 3 -((3 -(Benzyloxy) propoxy )methyl)-4-bromo-l-m ethyl- 177-pyrazole (5.78 g, 17.1 mmol, 1.0 eq) was dissolved in anhydrous THF (85 mL) and cooled to -78 °C. 2-Isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (10.5 mL, 51.3 mmol, 3 eq) was added, followed by addition of n-BuLi (11.7 mL, 18.7 mmol, 1.1 eq) over 20 minutes. The reaction was stirred for 1 h at -78 °C, then quenched with MeOH. The reaction was extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 0 to 100 % EtOAc in hexanes to afford the title compound (6.6 g, quantitative yield). LCMS (ESI) Method 3: RT = 1.13 min, = 387.4 [M+H]+.Intermediate 5(l?)-6-(3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-LH-pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[l,2-a]indol-l(2 / / )-one

[0249] Step A: Ethyl (lf)-7-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-l / / -pyrazol-4-yl)-l-(l-((tert-butoxycarbonyl)amino)propan-2-yl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy) propyl)- l / / -indole-2-carboxylate. Intermediate 3 (5.67 g, 11.4 mmol, 1 eq), Intermediate 4 (5.94 g, 15.3 mmol, 1.35 eq), potassium carbonate (4.72 g, 34.2 mmol, 3 eq), and Pd(PPh3)4 (1.30 g, 3.4 mmol, 0.1 eq) were dissolved in dioxane (90 mL) and H2O (20 mL). The solution was sparged with argon for 5 minutes and then sealed and heated to 100 °C for 8 h. The reaction was cooled to RT, extracted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash column chromatography, eluting with 0 to 100% EtOAc in hexanes to afford the title compound (8 g, 77% yield). LCMS (ESI) Method 2: RT = 1.19 min, = 678.6 [M+H]+.212657-0002-WO01

[0250] Step B: ( / ?)-6-(3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-lA7-pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[l,2-a]indol-l(2H)-one. Ethyl (A)-7-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-l / / -pyrazol-4-yl)-l-(l-((tert-butoxycarbonyl)amino)propan-2-yl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l / / -indole-2-carboxylate (8 g, 11.8 mmol, 1 eq) was dissolved in MeCN (60 mL). -Butyl ()-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (4.19 g, 17.6 mmol, 1.5 eq.) and Cs2CO3(8.45 g, 25.9 mmol, 2.2 eq) were added, and the reaction was heated to 70 °C for 16 h. The reaction was cooled to RT, concentrated, extracted with EtOAc, washed with brine, dried over MgSC filtered, and concentrated. The product was dissolved in DCM (60 mL). Trifluoroacetic acid (9 mL) was added, and the reaction was stirred at RT for 3 h. The reaction was concentrated, and the crude residue was dissolved in ethanol (50 mL). Potassium carbonate (8.2 g, 59 mmol, 5.0 eq) was added, and the reaction was heated to 60 °C for 2 h. The reaction was concentrated, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 0 to 5% MeOH in DCM to afford the title compound (4.1 mg, 50% over yield of the 3 reactions). LCMS (ESI) Method 2: Rr = 1.06 min, m / z = 689.6 [M+H]+.Intermediate 6AEthyl (263450,l722l?„,2^1?)-2^-chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy) propyl)- H,l^-dimethoxy-2^,3'-dimethyl-2*-oxo-2*,22,2^,2^-tetrahydro-l* / f,3^ / / -5-oxa-2(2,6)- pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carboxylate

[0251] Step A: Ethyl (7?)-7-(6-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-LH-pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-l-oxo-3,4-dihydropyrazino 11.2-i / |indol-2( l / / )-yl)-4.5-diniethoxy-l / / -indole-2-carboxylale (General212657-0002-WO01Procedure A). Intermediate 5 (750 mg, 1.09 mmol, 1.0 eq), Intermediate 1 (430 mg, 1.3 mmol, 1.2 eq), and Cs2CO3(1.8 g, 5.5 mmol, 5 eq) were added to a reaction vessel followed by addition of toluene (11 mL). The vessel was capped and argon was sparged through the stirring mixture for 15 minutes. [Pd(cinnamyl)Cl]2 (14 mg, 0.03 mmol, 0.03 eq) and -butylBrettPhos (13 mg, 0.03 mmol, 0.03 eq) were added, and the reaction was sealed under argon and heated to 100 °C for 2 h. The reaction was extracted with EtOAc, washed with sat. NH4Cl, sat. NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 100% 95:5 EtOAc / MeOH in hexanes to afford the desired product (919 mg, 90% yield). LCMS (ESI) Method 2: RT = 1.929 min, = 936.0 (M+H).

[0252] Step B: Ethyl ( / ?)-7-(7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3-((3-hydroxypropoxy)methyl)-1-methyl-1-pyrazol-4-yl)-4-methyl-1-oxo-3,4-dihydropyrazino[1,2-]indol-2(1)-yl)-4,5-dimethoxy-1-indole-2-carboxylate. The product from Step A (919 mg, 0.98 mmol, 1.0 eq) was dissolved in THF / 'PrOH (2:1, 15 mL). The reaction was sparged with argon for 5 min, followed by addition of Pd / C (105 mg, 10 wt.%, 0.098 mmol, 0.1 eq) and Pd(OH)2 / C. The reaction was then sparged with H2 gas, then stirred at RT for 3 h. The reaction was filtered through a pad of Celite® and concentrated. The crude material (826 mg, quant, yield) was used in subsequent steps without further purification. LCMS (ESI) Method 2: RT = 1.528 min, 1.579 min, = 846.0 (M+H).

[0253] Step C: Ethyl (l?)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(l-methyl-3-((3-(tosyloxy)propoxy)methyl)-TH-pyrazol-4-yl)-l-oxo-3,4-diliydropyrazino[l,2-a]indol-2(LH)-yl)-4,5-diinethoxy-l / 7-indole-2-carboxylate. (General Procedure C). The product from Step B (825 mg, 0.97 mmol, 1.0 eq) was dissolved in DCM (15 mL). TEA (1.35 mL, 9.74 mmol, 10 eq) and DMAP (12 mg, 0.10 mmol, 0.10 eq) were added and the reaction was stirred for 5 min at RT. The reaction was cooled to 0 °C and p-toluenesulfonic anhydride (1.27 g, 3.9 mmol, 4 eq) was added. The reaction was allowed to stir at 0 °C for 10 minutes then warmed to room temperature for 2 h. The reaction was extracted with DCM, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 90% EtOAc in hexanes to afford the desired product (783 mg, 87% yield). LCMS (ESI) Method 2: RT = 1.843 min, = 999.9 (M+H).212657-0002-WO01

[0254] Step D: Ethyl (2634S'„.l722 / ?„.24 / ?)-27-chloro-2l 0-(3-(4-chloro-3.5-dimethylphenoxy) propyl)-l4,l^-dimethoxy-24,34-dimethyl-24-oxo- 2X,22,23,24-tetr ahydro- 1 ^H,3 l / / -5-oxa-2(2,6)-pyrazino [1,2-a] indola- 1 (7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxylate. (General Procedure D). The product from Step C (900 mg, 0.90 mmol, 1.0 eq) was dissolved in DMF (90 mL) under an atmosphere of argon. Cs2CO3(0.877 g, 2.70 mmol, 3.0 eq) was added and the reaction was heated to 60 °C and allowed to stir 16 h. The reaction was extracted with EtOAc, washed with H2O and brine, dried over MgSO4, filtered, and then concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 50% 95:5 EtOAc / MeOH in hexanes to afford the desired product (564 mg, 76% yield). LCMS (ESI) Method 2: RT = 1.843 min, = 828.0 (M+H).Intermediate 6(2^345a,l722 / ?fl,24l?)-27-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-24,3^-dimethyl-24-oxo-24,22,23,24-tetrahydro-l4ET,34Ef-5-oxa-2(2,6)- pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxylic acid

[0255] (General Procedure E). Intermediate 6A (564 mg, 0.68 mmol, 1.0 eq) was dissolved in THF (10 mL), H2O (1 mL), and MeOH (1 mL). LiOH (50 mg, 2.1 mmol, 3.0 eq) was added and the reaction was heated to 40 °C for 16 h. The reaction was acidified to pH 2-4 with IM HC1 and then extracted with EtOAc. The aqueous layer was extracted with EtOAc, washed with NH4CI and brine, dried over MgSO4, filtered, and concentrated to afford the desired product (531 mg, 97% yield). LCMS (ESI) Method 2: RT = 1.522 min, = 799.9 (M+H).212657-0002-WO01Intermediate 7(263 5fl,l722?«,2^1f)-2^-Chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15- methoxy-1,24,3 -trimethyl-2 -oxo-21,2^,2^,24-tetrahydro-l ^H,3 l / / -5-oxa-2(2,6)- pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphane-12-carboxylic acid

[0256] Step A: Ethyl (7?)-7-(6-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-LH-pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-l-oxo-3,4-dihydropyrazino [l,2-fl]indol-2(l / J)-yl)-5-methoxy-4-methyl-l / 7-indole-2-carboxylate. The title compound (3.05 g, 57% yield) was prepared following General Procedure A using Intermediate 5 (4.00 g, 5.81 mmol, 1.0 eq) and Intermediate 2 (2.17 g, 6.96 mmol, 1.2 eq). The crude residue was purified by flash column chromatography eluting with 0 to 80% EtOAc in hexanes. LCMS (ESI) Method 2: RT = 2.016 min, 2.050 min (mixture of rotamers), m / z = 921.0 (M+H)+.

[0257] Step B: Ethyl (l?)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-l / / -pyrazol-4-yl)-4-methyl-l-oxo-3,4-dihydropyrazino [l,2-«]indol-2(l / / )-yl)-5-methoxy-4-methyl-l / / -indole-2-carboxylate. The title compound (2.45 g, 89% yield) was prepared following General Procedure B using the product from Step A (3.05 mg, 3.40 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.774 min, 1.859 min (mixture of rotamers), m / z = 830.0 (M+H)+.

[0258] Step C. Ethyl (7?)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-m ethyl-6-( l-methyl-3-((3-(tosyloxy)pr opoxy )m ethyl)- LH-pyrazol-4-yl)-l-oxo-3,4-dihydropyrazino[l,2-a]indol-2(LH)-yl)-5-methoxy-4-methyl-LH-indole-2-carboxylate. The title compound (2.30 g, 95% yield) was prepared following General Procedure C using the product from Step B (2.45 g, 2.46 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.928 min, 1.999 min (mixture of rotamers), m / z = 983.9 (M+H)+.212657-0002-WO01

[0259] Step D: Ethyl (2634S'„.l722 / ?„.24 / ?)-27-chl()ro-2l0-(3-(4-chloro-3.5-dimethylphenoxy)propyl)-15-methoxy-l4,24,31-trimethyl-24-oxo- 21, 2^,2, 24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carboxylate. The title compound (1.70 g, 90% yield) was prepared following General Procedure D using the product from Step C (2.30 g, 2.34 mmol, 1.0 eq). The crude residue was purified by flash column chromatography eluting with 0 to 80% EtOAc in hexanes. LCMS (ESI) Method 2: RT = 2.054 min, / z = 811.9 (M+H)+.

[0260] Step E: (26345„,l7227?fl,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1 -methoxy-l4,24,3 -trimethyl-21-oxo- 21,2^,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carboxylic acid. The title compound (570 mg, 34% yield) was prepared following General Procedure E using the product from Step D (1.70 g, 2.10 mmol, 1.0 eq). LCMS (ESI) Method 1: RT = 1.639 min, m / z = 784.0 (M+H)+.Intermediate 8(47?)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(l-methyl-3-((3- ((tetrahydro-2 / / -pyran-2-yl)oxy)propoxy)methyl)-l / / -pyrazol-4-yl)-3,4- diliydropyraz.ino|1.2-< / |iiid()l-l(2 / / )-one

[0261] Step A: (7?)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3-((3-hydroxy propoxy)methyl)-l-methyl-LH-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[l,2-«]indol-l(2H)-one. (General Procedure B) Intermediate 5 (1.40 g, 2.03 mmol) was dissolved in THF / PrOH (40 mL, 3:1). The reaction was sparged with argon, followed by addition of Pd / C (10% wt, 450 mg, 0.45 mmol, 0.15 eq) and Pd(OH)2 / C (20% wt., 550 mg, 0.40 mmol, 0.2212657-0002-WO01eq). The vessel was evacuated and backfilled with argon (3x), followed by introduction of H2. The reaction was stirred under an atmosphere of H2 at 35 °C for 2 h. The reaction was filtered through a plug of Celite® and concentrated to afford the desired product (1.10 g, 90% yield) which was used without further purification. LCMS (ESI) Method 2: RT = 1.029 min, m / z = 599.0 [M+H],

[0262] Step B: (4 / ?)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-( 1 -met hyl-3-((3-((tet rahydro-2 / / -pyran-2-yl)oxy (propoxy (methyl)- l / / -pyrazol-4-yl)-3.4-dihydro pyrazino[l,2-<z]indol-l(2 / / )-one. The product from Step A (1.10 g, 1.84 mmol, 1.0 eq) was dissolved in DCM (100 mL). 3,4-Dihydro-2H-pyran (340 mg, 4.0 mmol, 2.2 eq) and PPTS (100 mg, 0.40 mmol, 0.2 eq) were added and the reaction was stirred at RT for 20 h. The reaction was extracted with EtOAc, washed with NaHCO3, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0 to 10% MeOH in DCM to afford the title compound (1.20 g, 95% yield). LCMS (ESI) Method 2: RT = 1.603 min, m / z = 705.0 [M+Na],OMeIIntermediate 9Ethyl 5-(benzyloxy)-7-iodo-4-methoxy-LH-indole-2-carboxylate

[0263] Step A: 3-(Benzyloxy)-2-hydroxybenzaldehyde. Sodium hydride (3 65 g, 152 mmol) was suspended in THF (100 mL) under argon at RT, then cooled to 0 °C while 2,3-dihydroxybenzaldehyde (10.0 g, 72 mmol, 1.0 eq) dissolved in DMSO (80 mL) was slowly added via addition funnel. The reaction was warmed to RT and stirred for 1 h with addition of THF (25 mL). The reaction was cooled to 0 °C and benzyl bromide (9.0 mL, 76 mmol, 1.05 eq) in DMSO (100 mL) was added dropwise via addition funnel while maintaining the reaction temperature below RT. The reaction was stirred at 0 °C for 1 h. Water (450 mL) was added and the reaction was washed with DCM (500 mL), and the organic layer was discarded. The aqueous layer was treated with 6N HC1 until the pH was between 2 and 4 (about 9 mL). The aqueous layer was then extracted with DCM, washed with IM HC1, 0.5N HC1, brine, dried over MgSO4, concentrated and dried in a vacuum oven vacuum at 45 °C overnight to afford the title212657-0002-WO01compound (12.55 g, 76% yield) as a light brown solid. LCMS (ESI) Method 1: RT = 1.570 min, m,'z = 229.1 [M+H]+.

[0264] Step B: 3-(Benzyloxy)-2-hydroxy-5-iodobenzaldehyde. To a stirred suspension of AgNCh (7.8 g, 46 mmol, 1.05 eq) dissolved in CHCh (50 mb) at 0 °C under argon was added pyridine (23 mL). The mixture was stirred until the AgNCh was dissolved to give a clear solution. The iodine monochloride (2.44 mL, 48.2 mmol, 1.05 eq), diluted in CHCh (15 mL), was added dropwise at 0 °C. The resulting slurry was stirred for 10 minutes at RT, cooled to 0 °C, and a solution of 3-(benzyloxy)-2-hydroxybenzaldehyde (9.94 g, 44 mmol, 1.0 eq) in CHCh (25 mL) was added dropwise. The reaction was warmed to RT and stirred for 2 h, then diluted with ether (100 mL) and filtered, washing the solid with 1:1 ether / CHCh (200 mL). The combined eluent was concentrated and the residue was dissolved in DCM and washed with IN HC1, aqueous saturated sodium thiosulfate, water, brine, dried over MgSO4, concentrated, and dried under vacuum at 45 °C to afford the title compound (14.61 g, 95%) as a light yellow solid. LCMS (ESI) Method 1: RT = 1.793 min, parent ion not observed.

[0265] Step C: 3-(Benzyloxy)-5-iodo-2-methoxybenzaldehyde. The crude 3 -(benzyloxy )-2-hydroxy-5-iodobenzaldehyde (14.61 g, 41.2 mmol, 1.0 eq) was stirred in DMF (150 mL). K2CO3 (11.4 g, 82.5 mmol, 2.0 eq) was added, followed by iodomethane (3.21 mL, 52 mmol, 1.25 eq) dissolved in DMF (15 mL). The reaction was stirred at 30 °C for 60 h. The reaction was extracted with EtOAc, washed with saturated NH4CI, saturated NaHCO3, water, brine, then dried over MgSO4and concentrated under vacuum at 45 °C to afford the title compound (14.87 g, 98% yield) as a light tan solid. LCMS (ESI) Method 1: RT = 1.965 min, m'z = 368.8 [M+H]+.

[0266] Step D: Ethyl (Z)-2-azido-3-(3-(benzyloxy)-5-iodo-2-methoxyphenyl)acrylate.The title compound (5.5 g, 54% yield) was prepared following General Procedure B using 3-(benzyloxy)-5-iodo-2-methoxybenzaldehyde (7.8 g, 21.3 mmol). Upon completion, the reaction was cooled to 0 °C for 15 min and the solid was filtered and washed with cold ethanol (100 mL). The solid was collected and dried in a vacuum oven to remove the excess EtOH. LCMS (ESI) Method 1: RT = 2.351 min, parent mass not observed.

[0267] Step E: Ethyl 5-(benzyloxy)-7-iodo-4-methoxy-lH-indole-2-carboxylate. The title compound (2.5 g, 48% yield) was prepared following General Procedure C using ethyl (Z)-2-azido-3-(3-(benzyloxy)-5-iodo-2-methoxyphenyl)acrylate (5.5 g, 11.5 mmol, 1.0 eq).212657-0002-WO01Following workup, the crude residue was dissolved in hot ethanol (200 mL) and was allowed to stand overnight. The flask was cooled to 0 °C for 20 min before filtering and washing the crystals with cold ethanol (70 mL). The crystals were dried in vacuum oven to afford the title compound (2.5 g, 48% yield). LCMS (ESI) Method 1: RT = 2.087 min, m / z = 451.8 [M+H]+.OMeIIntermediate 105-(Benzyloxy)-7-iodo-4-methoxy-2-(l-methyl-l / / -l,2,4-triazol-3-yl)-177-indole

[0268] Step A: 5-(Benzyloxy)-7-iodo-4-methoxy-17 / -indole-2-carboxylic acid. The title compound was prepared following General Procedure E using Intermediate 9 (6.0 g, 13.2 mmol). Yield was determined following Step B.[00269J Step B: 5-(benzyloxy)-7-iodo-4-methoxy-2-(LH-l,2,4-triazol-3-yl)-17 / -indole. The title compound (5.0 g, 84% yield over 2 steps) was prepared following General Procedure F (see Example 1) using 5-(benzyloxy)-7-iodo-4-methoxy-17 / -indole-2-carboxylic acid from Step A.

[0270] Step C: 5-(Benzyloxy)-7-iodo-4-methoxy-2-(l-methyl-l / / -l,2,4-triazol-3-yl)-l / / -indole. (General Procedure G) In a scintillation vial 5-(benzyloxy)-7-iodo-4-methoxy-2-(17 / -l,2,4-triazol-3-yl)-l / / -indole (5.0 g, 11.2 mmol, 1.0 eq) was dissolved in acetone (200 mL). Potassium carbonate (2.02 g, 14.6 mmol, 1.3 eq) and Mel (2.06 g, 14.56 mmol, 1.3 eq) were added and the reaction was allowed to stir for 48 h. The reaction was quenched with FEO, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the title compound (3.4 g, 66% yield). LCMS (ESI) Method 1: RT = 1.845 min, m / z = 460.9 [M+H]+.212657-0002-WO01Intermediate 11(2^3^. S„.1 2“ / ?„,2^ / ?)-2^-( hloro-2 ' ■'-(3-(4-chloro-3.5-dimethvlphenoxy)propyl)-l ^.1 - dimethoxy-14,31 -dimethyl-21 -oxo-21,2^,2^,2^-tetrahydro-l ^H,3 l / -5-oxa-2(2,6)- pyrazino[l,2-a]indola-l(7,l)-indoIa-3(4,3)-pyrazolacyclooctaphane-12-carbaIdehyde

[0271] Example 58 (189 mg, 0.24 mmol, 1.0 eq) was dissolved in DCM (5 mL) at RT under argon. Dess-Martin periodinane (125 mg, 0.3 mmol, 1.25 eq) and Na2COa (40 mg, 0.4 mmol, 1.7 eq) were added and the mixture was stirred for Ih. The reaction was quenched with water, extracted with EtOAc, washed with saturated NaHCO3and brine, dried over MgSO4, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 50% EtOAc / MeOH (95:5) in hexanes to afford the title compound (152 mg, 80% yield). LCMS (ESI) Method 1: RT = 2.31 min, m / z = 784 (M+H)+.ciIntermediate 11A(26345(J,l722^«,24?)-27-chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^- methoxy- 1 ^,2^,3 l-trimethyl-2 l-oxo-21,2^,2^,2^-tetr ahydr o-l ^H,3 lH-5-oxa-2(2,6)- pyrazino[l,2-a]indoIa-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphane-12-carbaldehyde212657-0002-WO01

[0272] In a reaction vessel, Example 60 (168 mg, 0.22 mmol, 1.0 eq) was stirred in DCM (4 mL) at room temperature under argon. Dess-Martin periodinane (111 mg, 0.26 mmol, 1.2 eq) was added and the mixture was stirred for 1 h, after which time the reaction was determined to be complete by LCMS. The reaction was quenched with H2O, extracted with EtOAc, washed with H2O, sat. aq. NH4CI, sat. aq. NaHCO3, brine, dried over MgSO4, filtered, and concentrated. The crude residue was used without further purification.(26345a,l722?fl,2^1?)-2^-Chloro-21(-)-(3-hydroxypropyl)-l4,l^-dimethoxy-2^,31-dimethyl- l--(l-methyl-l / / -1.2.4-tiiazol-3-yl)-2 ' ^- ’^-tetrahydro-l ' / / .3 ' / / -5-oxa-2(2,6)- pyrazino[l,2-cz]indola-l(7,l)-indola-3(4,3)-pyi’azolacydooctaphan-21-one

[0273] Step A. Ethyl 7-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-lH-pyrazol-4-yl)-6-chloro-3-(3-ethoxy-3-oxopropyl)-l / / -indole-2-carboxylate. Ethyl 7-bromo-6-chloro-3-(3-ethoxy-3 -oxopropyl)- lLf-indole-2-carboxylate (see Burke, J. et al., J. Med. Chem. 2015, 58, 3794) (40 mg, 0.10 mmol, 1 eq), Intermediate 4 (41 mg, 0.134 mmol, 1.35 eq), potassium carbonate (41 mg, 0.30 mmol, 3.0 eq), and Pd(PPh3)4 (11.5 mg, 0.01 mmol, 0.1 eq) were dissolved in dioxane (0.8 mL) and H2O (0.2 mL). The solution was sparged with argon for 5 minutes and then sealed and heated to 100 °C for 16 h. The reaction was cooled to RT, extracted with EtOAc, washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash column chromatography, eluting with 0 to 100% EtOAc in hexanes to afford the title compound (32 mg, 55% yield). LCMS (ESI) Method 4: RT = 2.41 min, m / z = 582.48 [M+H]+.

[0274] Step B. Ethyl ( / ?)-l-(l-aminopropan-2-yl)-7-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-lH-pyrazol-4-yl)-6-chloro-3-(3-ethoxy-3-oxopropyl)-LH-indole-2-carboxylate.212657-0002-WO01Ethyl 7-(3 -((3 -(benzyl oxy)propoxy)methyl)- 1 -methyl- 1 H-pyrazol -4-yl)-6-chloro-3 -(3 -ethoxy - 3 -oxopropyl)- 177-indole-2-carboxylate (32 mg, 0.05 mmol, 1 eq) was dissolved inMeCN (1 mL). / c / 7-Butyl (5)-5-methyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (20 mg, 0.084 mmol, 1.5 eq.) and Cs2CO3(39 g, 0.12 mmol, 2.2 eq) were added, and the reaction was heated to 70 °C for 16 h. The reaction was cooled to RT, concentrated, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The product was dissolved in DCM (0.35 mL). Trifluoroacetic acid (0.03 g, 5 eq) was added, and the reaction was stirred at RT for 3 h. The reaction was concentrated and the crude material used without further purification. LCMS (ESI) Method 4: RT = 3.06 min, m / z = 639.54 [M+H]+.

[0275] Step C. Ethyl (l?)-3-(6-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-LH-pyrazol- 4-yl)-7-chloro-4-methyl-l-oxo-l,2,3,4-tetrahydropyrazino[l,2-a]indol-10-yl)propanoate.Ethyl (7?)- 1 -( 1 -aminopropan-2-yl)-7-(3-((3 -(benzyl oxy )propoxy)methyl)- 1 -methyl- 1 7-pyrazol-4-yl)-6-chloro-3 -(3 -ethoxy-3 -oxopropyl)- 177-indole-2-carboxylate (23.0 g, 36 mmol, 1.0 eq) was dissolved in EtOH (230 mL). Potassium carbonate (24.8 g, 180 mmol, 5.0 eq) was added, and the reaction was heated to 60 °C for 2 h. The reaction was concentrated, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 0 to 5% MeOH in DCM to afford the title compound (11.0 g, 52% yield). LCMS (ESI) Method 4: RT = 2.16 min, m / z = 593.58 [M+H]+.

[0276] Step D. Ethyl (7?)-3-(6-(3-((3-(benzyloxy)propoxy)inethyl)-l-inethyl-177-pyrazol-4-yl)-7-chloro-2-(4,5-dimethoxy-2-(l-methyl-l / / -L2,4-triazol-3-yl)-l / / -indol-7-yl)-4-methyl-l-oxo-l,2,3,4-tetrahydropyrazino[l,2-a]indol-10-yl)propanoate. The title compound (100 mg, 70% yield) was prepared following General Procedure A using the product from Step C (100 mg, 0.17 mmol, 1.0 eq) and Intermediate 19 (85 mg, 0.25 mmol, 1.5 eq).

[0277] Step E. Ethyl (l?)-3-(7-chloro-2-(4,5-dimethoxy-2-(l-methyl-LH-l,2,4-triazol-3-yl)-l / Z-indol-7-yl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-LA / -pyrazol-4-yl)-4-methyl-l-oxo-l,2,3,4-tetrahydropyrazino[l,2-a]indol-10-yl)propanoate. The title compound (84 mg, 93% yield) was prepared following General Procedure B using the product from Step D (100 mg, 0.12 mmol, 1.0 eq). LCMS (ESI) Method 4: RT = 2.63 min, m / z = 759.57 [M+H]+.

[0278] Step F. Ethyl (7?)-3-(7-chloro-2-(4,5-dimethoxy-2-(l-methyl-lH-l,2,4-triazol-3-yl)-l / / -indol-7-yl)-4-methyl-6-(l-methyl-3-((3-(tosyloxy)propoxy)methyl)-l / / -pyrazol-4-212657-0002-WO01yl)-l-oxo-l,2,3,4-tetrahydropyrazino[l,2-a]indol-10-yl)propanoate. The title compound (50 mg, 83% yield) was prepared following General Procedure C using the product from Step E (50 mg, 0.065 mmol, 1.0 eq). LCMS (ESI) Method 4: RT = 2.20 min, m / z = 913.51 [M+H]+.

[0279] Step G. Ethyl 3-((26345a,l7227?«,24 / ?)-27-chloro-l4,l5-dimethoxy-24,31-dimethyl-l7-( 1 -methyl- 1 / / - 1.2.4-triazol-3-yl)-2 '-oxo-2',27.2-4.24-tetrahydro-l ' / / .3' / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-210-yl)propanoate. The title compound (25 mg, 62% yield) was prepared following General Procedure D using the product from Step F (50 mg, 0.055 mmol, 1.0 eq). LCMS (ESI) Method 4: RT = 2.30 min, m / z = 741.32 [M+H]+.

[0280] Step H. (2634S'„. L22 / ?„.24 / ?)-27-chloro-2l0-(3-hydroxypropyl)-l4.l5-dimethoxy-24,3 ^-dimethyl- 1 ^-(l-methyl- H- 1,2,4-triazol-3-yl)-24,2^,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan-24-one. The product from Step G (25 mg, 0.033 mmol, 1.0 eq) was dissolved in THF (0.25 mL). Lithium triethylborane (0.17 mL, 5.0 eq) was added at 0 °C and allowed to stir for 4 h. The reaction was quenched with sat. aq. NELCl, extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with EtOAc / hexanes to afford the title compound (12 mg, 51% yield). LCMS (ESI) Method 4: RT = 1.86 min, m / z = 699.36 [M+H]+.Intermediate 14Ethyl (2634$M722 / ?„.24 / ?)- -(beiizyloxy)-27-chloio-2l0-(3-(4-chloio-3.5- dimethylphenoxy)propyl)-l4-methoxy-24,34-dimethyl-24-oxo-24,2^,2^,24-tetrahydro-212657-0002-WO01l H,3*H-5 -oxa-2(2,6)-pyrazino[l,2-ff]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- l^-carboxylate

[0281] Step A: Ethyl 5-(benzyloxy)-7-((4J?)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(l-methyl-3-((3-((tetrahydro-2 / / -pyran-2-yl)oxy )propoxy )methyl)- 1 / / -pyrazol-4-yl)- l-oxo-3,4-dihydropyrazino[ l,2-a]indol-2( 1H)~ yl)-4-methoxy-l / / -indole-2-carboxylate The title compound (4.14 g, 56% yield) was prepared following General Procedure A using Intermediate 8 (5.04 g, 7.37 mmol, 1.0 eq) and Intermediate 9 (7.2 g, 16.0 mmol, 2.2 eq), palladium 7r-cinnamyl chloride dimer (400 mg, 0.77 mmol, 0.10 eq), / BuBrettPhos (400 mg, 0.825 mmol, 0.11 eq), and Cs2CO3(11.9 g, 37 mmol, 5.0 eq) and allowing the reaction to stir 30 h. The crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes. LCMS (ESI) Method 2: RT = 2.027 min, m / z = 922.0 [M+H-THP],

[0282] Step B: Ethyl (l?)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-lH-pyrazol-4-yl)-4-methyl-l-oxo-3,4-dihydropyrazino[l,2-fl]indol-2(l / / )-yl)-4-methoxy-lZ / -indole-2-carboxylate. The product from Step A (4.14 g, 4.11 mmol, 1.0 eq) was dissolved in MeOH (120 mL) and THF (30 mL) at RT. Tosic acid monohydrate (250 mg, 1.31 mmol, 0.32 eq) was added, and the reaction was stirred at RT for 2 h. The reaction was extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 10% MeOH in DCM to afford the title compound (3.84 g, quant, yield). LCMS (ESI) Method 2: RT = 1.751 min, 1.805 min, m / z = 922.0 [M+H]+.

[0283] Step C: Ethyl ( / ?)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(l-methyl-3-((3-(tosyloxy)propoxy)methyl)-l / T-pyrazol-4-yl)-l-oxo-3,4-dihydro pyrazino[l,2-fl]indol-2(LH)-yl)-4-methoxy-lZ / -indole-2-carboxylate. The title compound (1.80 g, 77% yield) was prepared following General Procedure C using the product from Step B (2.0 g, 2.17 mmol, 1.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 100% 95:5 EtOAc: MeOH in hexanes. LCMS (ESI) Method 2: RT = 1.970 min, m / z = 1075.8 [M+H]+.212657-0002-WO01

[0284] Step D: Ethyl (2634S'„.l722 / ?„.24 / ?)-l5-(benzyloxy)-27-chloro-2l0-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4-methoxy-24,34-dimethyl-24-oxo- 21,2^,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carboxylate. The title compound (1.20 g, 79% yield) was prepared following General Procedure D using the product from Step C (1.80 g, 1.67 mmol, 1.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes.LCMS (ESI) Method 2: RT = 2.069 min, m / z = 904.0 [M+H]+.Intermediate 14AEthyl (2f’34S'„.l722 / L.24 / ?)-27-c hl oro-2 '**-(3-( 4-chloro-3.5-d im ethyl ph enoxy) propyl)-!^- hydroxy- 14-m ethoxy-24, 31-dim ethyl-2 l-oxo-24,2^,2^,24-tetrahydro- 11 / 7,3 ' / / -5-oxa- 2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-P-carboxylate.

[0285] The title compound (1.05 g, 97% yield) was prepared following General Procedure B using Intermediate 14 (1.20 g, 1.32 mmol, 1.0 eq). The crude material was used without further purification. LCMS (ESI) Method 2: RT = 1.664 min, m 'z = 814.0 [M+H]+.OMeBrIntermediate 15 / / Z- Butyl 7-bromo-2-iodo-4,5-dimethoxy-l / / -indole-l-carboxylate

[0286] Step A: 7-Bromo-4,5-dimethoxy-LH-indole. In a round bottomed flask, 1-bromo- 4,5-dimethoxy-2-nitrobenzene (10 g, 38 mmol, 1.0 eq) was dissolved in THF (100 mL) and212657-0002-WO01cooled to -40 °C. Vinyl magnesium bromide (1.0 M solution in THF, 115 mL, 3.0 eq.) was added via cannula over 1 h. The reaction was then allowed to stir for 3 h at -40 °C. The reaction was quenched with aq. NH4CI, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The crude mixture was purified by flash column chromatography eluting with 0 to 30% EtOAc in hexanes to afford the title compound (1.08 g, 11% yield). LCMS (ESI) Method 1: RT = 1.452 min, m / z = 256.0 [M+H]+.

[0287] Step B: tc / 7-Butyl 7-bromo-4,5-dimethoxy-l / f-indole-l-carboxylate. 7-Bromo-4,5-dimethoxy-l / 7-indole (1.08 g, 4.2 mmol, 1.0 eq) was dissolved in DCM (20 mL). DMAP (103 mg, 0.84 mmol, 0.2 eq), BOC2O (1.84 g, 8.4 mmol, 2.0 eq), and TEA were added (1.8 mL, 12.7 mmol, 3.0 eq). The reaction was allowed to stir for 4 h. The reaction was diluted with H2O, and extracted with DCM, dried over MgSCL, filtered, and concentrated. The crude product was purified by flash column chromatography, eluting with 0 to 30% EtOAc in hexanes to afford the desired product (1.15 g, 77% yield). LCMS (ESI) Method 1: RT = 2.046 min, m / z = 300.1 [M+H-56]+.

[0288] Step C: terf-Butyl 7-bromo-2-iodo-4,5-dimethoxy-LAZ-indole-l-carboxylate. tert- Butyl 7-bromo-4,5-dimethoxy-17 / -indole-l -carboxylate (1.0 g, 2.81 mmol, 1.0 eq) was dissolved in THF (20 mL) under argon and cooled to -78 °C. LDA (1.0 M solution in THF, 5.9 mL, 2.1 eq) was added, and the reaction was allowed to stir for 30 min at -78 °C. A solution of iodine (2.85 g, 11.2 mmol, 4.0 eq) in 10 mL of THF was then added, and the reaction was stirred an additional 2 h at -78 °C. The reaction was quenched by addition of H2O, extracted with EtOAc, washed with saturated aq. NazSzOj and brine, dried over MgSO4, filtered, and then concentrated. The crude reaction product was purified by flash colum chromatography eluting with 0 to 20% EtOAc in hexanes to afford the desired product (875 mg, 65% yield). LCMS (ESI) Method 1: RT = 2.200 min, m / z = 381.9 [M+H-100]+.BrIntermediate 16Ze / / - Butyl 7-bromo-2-iodo-5-methoxy-4-methyl-Lf / -indole-l-carboxylate212657-0002-WO01

[0289] Step A: 7-Bromo-5-methoxy-4-methyl-lF7-indole. Tn a round bottomed flask, 1-bromo-5-methoxy-4-methyl-2-nitrobenzene (9.5 g, 38 mmol, 1.0 eq) was dissolved in THF (100 mL) and cooled to -40 °C. Vinyl magnesium bromide (1.0 M solution in THF, 115 mL, 3.0 eq.) was added via cannula over 1 h. The reaction was then allowed to stir for 1.5 h at -40 °C then warmed to 0 °C for 2 h. The reaction was quenched with aq. NH4Cl, diluted into EtOAc / H2O (200 mL, 1:1). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and then concentrated. The crude mixture was purified by flash column chromatography eluting with 0 to 30% EtOAc in hexanes to afford the title compound (2.93 g, 32% yield).

[0290] Step B: tert-Butyl 7-bromo-5-methoxy-4-methyl-lFT-indole -1-carboxylate. 7-Bromo-5-methoxy-4-methyl-l / / -indole (2.93 g, 12.2 mmol, 1.0 eq) was dissolved in DCM (30 mL). DMAP (75 mg, 0.61 mmol, 0.05 eq), BOC2O (4.53 g, 20.7 mmol, 1.7 eq), and DIPEA were added (3.79 g, 29.3 mmol, 2.5 eq). The reaction was stirred at RT until complete by LCMS. The crude reaction was diluted with H2O, and the aqueous layer was extracted with DCM. The combined organic fractions were dried over MgSCL, filtered, and concentrated. The crude product was purified by flash column chromatography, eluting with 0 to 30% EtOAc in hexanes to afford the desired product (3.50 g, 84% yield).

[0291] Step C: tert- Butyl 7-bromo-2-iodo-5-methoxy-4-methyl-l / / -indole-l-carboxylate. / e / 7-Butyl 7-bromo-5-methoxy-4-methyl-l / / -indole -1-carboxylate (1.8 g, 5.3 mmol, 1.0 eq) was dissolved in THF (20 mL) under argon and cooled to -78 °C. LDA (1.0 M solution in THF, 13.3 mL, 2.5 eq) was added, and the reaction was stirred for 30 min at -78 °C. A solution of iodine (5.4 g, 21 mmol, 4.0 eq) in 10 mL of THF was then added, and the reaction was allowed to stir an additional 2 h at -78 °C. The reaction was quenched by addition of H2O, extracted with EtOAc, washed with saturated aq. Na2S20s and brine, dried over MgSO4, filtered, and then concentrated. The crude reaction product was purified by flash column chromatography eluting with 0 to 20% EtOAc in hexanes to afford the desired product (1.42 g, 58% yield). LCMS (ESI) Method 1: RT = 2.328 min, m / z = 365.9 [M+H-100]+.212657-0002-WO01OMeBnOBrIntermediate 175-(benzyloxy)-7-bromo-4-methoxy-177-indole

[0292] The title compound was prepared following procedure described for Intermediate 15 Step A using 3 -benzyloxy -4-methoxy-6-nitrobromobenzene as the starting material.OMeBrIntermediate 17A / e / 7- Butyl 5-(benzyloxy)-7-bromo-2-iodo-4-methoxy-l / 7-indole-l-carboxylate

[0293] The title compound was prepared following procedure described for Intermediate 15 (Steps B-C) using Intermediate 17 as the starting material.Intermediate 18(7?)-6-(3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-lH-pyrazol-4-yl)-7-chloro-4-methyl- 10-(3-(naphthalen-l-yloxy)propyl)-3,4-dihydropyrazino[l,2-a]indol-l(2 / / )-one

[0294] Step A: Ethyl 7-bromo-3-(3-bromopropyl)-6-chloro-l£ / -indole-2-carboxylate.In a reaction vessel, Intermediate 3 (2.0 g, 4.0 mmol) was dissolved in dry DCM at 0 °C. Boron tribromide (IM, DCM, 12 mL, 12 mmol, 3.0 eq) was added dropwise to the reaction mixture which was then stirred at room temperate for 3 h. The reaction was quenched with water and extracted with DCM (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered, and then concentrated. The crude residue was purified by flash column212657-0002-WO01chromatography eluting with 0 to 30% MeOH in DCM to afford the title compound (1.0 g, 59%). 'H-NMR (CDCh) 88.83 (s, 1H), 7.65 (d, 1H, J= 8 Hz), 7.31 (d, 1H, J= 8 Hz), 4.57 (q, 2 H, J= 8Hz ), 3.30 ( tr, 2H, J= 8 Hz), 3.27 ( tr, 2H, J= 8Hz), 2.28-2.25 ( m, 2H), 1.50 (tr, 3H, J= 8 Hz).

[0295] Step B: Ethyl 7-bromo-6-chloro-3-(3-(naphthalen-l-yloxy)propyl)-TH-indole-2-carboxylate. In a reaction vessel ethyl 7-bromo-3-(3-bromopropyl)-6-chloro-l / 7-indole-2-carboxylate (0.40 g, 0.94 mmol, 1.0 eq), naphthalen-l-ol (0.40 g, 2.8 mmol, 3.0 eq), and potassium carbonate (0.52 g, 3.8 mmol, 4.0 eq) were dissolved in anhydrous DMF (10 mL). The reaction mixture was heated at 80 °C for 2 h. The reaction mixture was extracted with EtOAc, washed with H2O, dried with MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography eluting with 0 to 20% EtOAc in hexanes to afford the title compound (0.40 g, 89% yield). LCMS (ESI) Method 2: RT = 0.99 min, m z = 486.8 (M+H).

[0296] Step C: Ethyl 7-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-l / / -pyrazol-4-yl)-6-chloro-3-(3-(naphthalen-l-yloxy)propyl)-LH-indole-2-carboxylate. The title compound (0.50 g, 89% yield) was prepared following General Procedure A using ethyl 7-bromo-6-chloro-3-(3-(naphthalen-l-yloxy)propyl)-177-indole-2-carboxylate (0.45 g, 0.93 mmol, 1.0 eq) and Intermediate 2 (720 mg, 1.88 mmol, 2.0 eq) with thermal heating at 90 °C for 10 h. Upon aqueous workup, the crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes. LCMS (ESI) Method 2: RT = 1.19 min, w / z = 666.7 (M+H).

[0297] Step D: Ethyl (7f)-7-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-lH-pyrazol-4-yl)-l-(l-((ferf-butoxycarbonyl)amino)propan-2-yl)-6-chloro-3-(3-(naphthalen-l-yloxy)propyl)-l / / -indole-2-carboxylate. In a round-bottomed flask, ethyl 7-(3-((3-(benzyloxy)propoxy)methyl)-l -methyl- l / f-pyrazol-4-yl)-6-chl oro-3 -(3 -(naphthal en-1-yloxy)propyl)-l / 7-indole-2-carboxylate (500 mg, 0.75 mmol, 1 eq) was dissolved in MeCN (5 mL). tert-Butyl (S)-5-methyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (350 mg, 1.50 mmol, 2.0 eq.) and cesium carbonate (740 mg, 2.25 mmol, 3.0 eq) were added, and the reaction was heated to 70 °C for 16 h. The reaction was concentrated, extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and then concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the title compound (500 mg, 76% yield). LCMS (ESI) Method 2: RT = 1.30 min, m / z = 824.4 [M+H]+.212657-0002-WO01

[0298] Step E: ( / ?)-6-(3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-lA7-pyrazol-4-yl)-7-chloro-4-methyl-10-(3-(naphthalen-l-yloxy)propyl)-3,4-dihydropyrazino[l,2-a]indol-l(2 / / )-one The product from Step D was dissolved in DCM (10 mL). Trifluoroacetic acid (1 mL) was added, and the reaction was stirred at RT for 3 h. The reaction was concentrated and the crude residue was dissolved in EtOH (15 mL). Potassium carbonate (1.3 g, 9.35 mmol) was added, and the reaction was heated to 60 °C for 2 h. The reaction was concentrated, extracted with EtOAc, washed with brine, dried over MgSCL, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 0 to 5% MeOH in DCM to afford the title compound (300 mg, 76% yield). LCMS (ESI) Method 2: RT = 1.10 min, m z = 677.5 [M+H]+.OMeBrIntermediate 197-Bromo-4,5-dimethoxy-2-(l-methyl-l / / -l,2,4-triazol-3-yl)-l / / -indole

[0299] Step A: 7-Bromo-4,5-dimethoxy-LH-indole-2-carboxylic acid. In a reaction vessel, Intermediate 1 (6.0 g, 18.3, 1.0 eq) was dissolved in THF (40 mL), MeOH (10 ml), and H2O (10 mL). LiOH (1.3 g, 54.9 mmol, 3.0 eq) was added and the reaction was heated to 50 °C for 2 h. The reaction was partitioned between DCM and 1 M HC1, separated, and the organic layer washed with H2O, dried over MgSO4, filtered, and concentrated to afford the title compound (5.05 g, 92% yield). LCMS (ESI) Method 2: RT = 1.357 min, m / z = 300.1 [M+H]+.

[0300] Step B: 7-Bromo-4,5-dimethoxy-LH-indole-2-carboxamide. In a reaction vessel, 7-bromo-4,5-dimethoxy-1H-indole-2-carboxylic acid (3.89 g, 13.0 mmol, 1.0 eq) was dissolved in benzene (40 mL). Thionyl chloride (1.25 mL, 17.1 mmol, 1.3 eq) was added and the reaction was heated to 75 °C for 2 h. The reaction was concentrated under reduced pressure, and the crude residue was dissolved in DCM (40 mL) and cooled to 0 °C. NH4OH (2.8 mL, 71 mmol, 5.5 eq) was added and the reaction was stirred for 1 h and warmed to RT. The reaction was extracted with DCM, washed with H2O, dried over MgSO4, filtered, and concentrated to afford the title compound (3.80 g, 98% yield). The crude material was carried forward without further purification. LCMS (ESI) Method 2: RT = 1.254 min, m / z = 299.1 [M+H]+.212657-0002-WO01

[0301] Step C: 7-Bromo-4,5-dimethoxy-2-(l / 7-l,2,4-triazol-3-yl)-l / 7-indole. The title compound (4.0 g, 98% yield) was prepared following General Procedure F (see Example 1) using 7-bromo-4,5-dimethoxy-1H-indole-2-carboxamide (3.78 g, 12.6 mmol, 1.0 eq).Following isolation, the crude material was used in the next step without further purification. LCMS (ESI) Method 2: RT = 1.297 min, m / z = 323.1 [M+H]+.

[0302] Step D: 7-Bromo-4,5-dimethoxy-2-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-indole.The title compound (3.14 g, 58% yield) was prepared following General Procedure G using 7-bromo-4,5-dimethoxy-2-(1H-1,2,4-triazol-3-yl)-1H-indole (5.16 g, 16.0 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.383 min, m / z = 337.0 [M+H]+.BrIntermediate 207-Bromo-5-methoxy-4-methyl-2-(l-methyl-lH-l,2,4-triazol-3-yl)-lH-indole

[0303] Step A: 7-Bromo-5-methoxy-4-methyl-1H-indole-2-carboxylic acid. The title compound (950 mg, quant, yield) was prepared following General Procedure E using Intermediate 2 (1.05 g, 3.4 mmol, 1.0 eq). LCMS (ESI) Method 1: RT = 1.553 min, m / z = 284.1 (M+H)+.

[0304] Step B: 7-Bromo-5-methoxy-4-methyl-2-(LH-l,2,4-triazol-3-yl)-FH-indole. The title compound (300 mg, 30% yield) was prepared following General Procedure F using 7-Bromo-5-methoxy-4-methyl-l / / -indole-2-carboxylic acid (950 mg, 3.34 mmol, 1.0 eq). LCMS (ESI) Method 1: RT = 1.560 min, m / z = 307.0 (M+H)+.

[0305] Step C: 7-Bromo-5-methoxy-4-methyl-2-(l-methyl-l / / -l,2,4-triazol-3-yl)-l / / -indole. The title compound (135 mg, 43% yield) was prepared following General Procedure G using 7-bromo-5-methoxy-4-methyl-2-(lLf-l,2,4-triazol-3-yl)-l / / -indole (300 mg, 0.98 mmol, 1.0 eq). LCMS (ESI) Method 1: RT = 1.606 min, m / z = 307.0 (M+H)+.xoBrIntermediate 21212657-0002-WO017-bromo-4,5-dimethoxy-2-(l-methyl-lH-pyrazol-4-yl)-lH-indole

[0306] Step A: tert-Butyl 7-bromo-4,5-dimethoxy-2-(l-methyl-LH-pyrazol-4-yl)-l / / -indole-l-carboxylate. Intermediate 15 (1.19 g, 2.47 mmol, 1.0 eq), l-methyl-4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (630 mg, 3.03 mmol, 1.25 eq), K2CO3 (750 mg, 5.43 mmol, 2.2 eq), Pd(PPh3)4 (150 mg, 0.13 mmol, 0.05 eq) were dissolved in dioxane (15 mL) and H2O (3 mL). The reaction mixture was sparged with argon for 5 min, sealed, and then heated to 85 °C for 5 h. The reaction was extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0 to 20% EtOAc in hexanes to afford the title compound (1.04 g, 97% yield).

[0307] Step B: 7-Bromo-4,5-dimethoxy-2-(l-methyl-lH-pyrazol-4-yl)-lH-indole. tert-Butyl 7-bromo-4,5-dimethoxy-2-(l-methyl-lH-pyrazol-4-yl)-lH-indole-l-carboxylate (1.04 g, 2.38 mmol, 1.0 eq) was dissolved in DCM (30 mL). TFA (4 mL, 52 mmol, 20 eq) was added, and the reaction was allowed to stir for 2 h at RT. The reaction was concentrated, taken up in DCM, washed with aq. NaHCOs, dried over MgSO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0 to 30% EtOAc in hexanes to afford the title compound (740 mg, 92% yield). LCMS (ESI) Method 1: RT = 1.650 min, m / z = 336.0 (M+H)+.xoIntermediate 227-Bromo-4,5-dimethoxy-2-(l-methyl-LH-pyrazol-3-yl)-L / -indole

[0308] Step A: tert-butyl 7-bromo-4,5-dimethoxy-2-(l-methyl-TH-pyrazol-3-yl)-LH-indole-l-carboxylate. Intermediate 15 (875 mg, 1.81 mmol, 1.0 eq), 1 -methyl-3-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17 / -pyrazole (529 mg, 2.54 mmol, 1.4 eq), K2CO3 (500 mg, 3.63 mmol, 2.0 eq), and Pd(PPli3)4 (105 mg, 0.91 mmol, 0.05 eq) were weighed and dissolved in dioxane (5 mL) and H2O (1 mL). The reaction mixture was sparged with argon for 5 min, sealed, and heated to 80 °C overnight. The reaction was extracted with DCM, washed with H2O, dried over MgSCU, filtered, and concentrated. The crude residue was purified by212657-0002-WO01flash column chromatography eluting with 0 to 50% EtOAc in hexanes to afford the title compound (380 mg, 48% yield). LCMS (ESI) Method 1: RT = 1.973 min, m / z = 380.1 (M+H-56)+.

[0309] Step B: 7-Bromo-4,5-dimethoxy-2-(l-methyI-lH-pyrazol-3-yl)-lH-indole. tert- Butyl 7-bromo-4,5-dimethoxy-2-(l-methyl-lH-pyrazol-3-yl)-lH-indole-l -carboxylate (380 mg, 0.871 mmol, 1.0 eq) was dissolved in DCM (10 mL). TFA(1.0 mL, 13 mmol, 15 eq) was added, and the reaction was allowed to stir for 3 h. The reaction was concentrated, taken up in DCM, washed with H2O, dried over MgSC, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0 to 50% EtOAc in hexanes to afford the title compound (214 mg, 73% yield).Intermediate 237-Bromo-5-methoxy-4-methyl-2-(l-methyl-17 / -pyrazol-4-yl)-17 / -indole

[0310] Step A: rf-Butyl 7-bromo-5-methoxy-4-methyl-2-(l-methyl-lH-pyrazol-4-yl)-IH-indole-l-carboxylate. Intermediate 16 (2.48 g, 5.32 mmol, 1.0 eq), 1 -methyl-4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l / / -pyrazole (2.21 g, 10.6 mmol, 2.0 eq), K2CO3 (2.21 g, 16.0 mmol, 3.0 eq), and Pd(PPh3)4 (615 mg, 0.53 mmol, 0.1 eq) were dissolved in dioxanes (10 mL) and H2O (2 mL). The reaction was sparged with argon for 5 min, sealed, and heated to 80 °C for 3 h. The reaction was extracted with EtOAc, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the title compound (1.85 g, 83% yield). LCMS (ESI) Method 2: RT = 1.312 min, m / z = 420.1 (M+H).

[0311] Step B: 7-Bromo-5-methoxy-4-methyl-2-(l-methyl-l / 7-pyrazol-4-yl)-l / 7-indole. / erAButyl 7-bromo-5-methoxy-4-methyl-2-( 1 -methyl- l / f-pyrazol-4-yl)- l / / -indole- 1 -carboxylate (1.85 g, 4.40 mmol, 1.0 eq) was dissolved in DCM (10 mL) followed by addition of TFA (2 mL, 26 mmol, 5.9 eq). The reaction was allowed to stir at RT for 8 h. The reaction was concentrated, taken up in DCM, washed with aq. NaHCOa, washed with brine, dried over MgSCL, filtered, and concentrated. The crude material was purified by flash column212657-0002-WO01chromatography eluting with 0 to 50% EtOAc in hexanes to afford the title compound (1.25 g, 89% yield). LCMS (ESI) Method 1: RT = 1.734 min, m / z = 322.0 (M+H).Intermediate 247-Bromo-4,5-dimethoxy-l / 7-indoIe

[0312] 1 -Bromo-4,5-dimethoxy-2-nitrobenzene (10 g, 38 mmol, 1.0 eq) was dissolved in THF (100 mL) and cooled to -40 °C. Vinyl magnesium bromide (1.0 M solution in THF, 115 mL, 3.0 eq.) was added via cannula over 1 h. The reaction was then allowed to stir for 3 h at -40 °C. The reaction was quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The crude mixture was purified by flash column chromatography eluting with 0 to 30% EtOAc in hexanes to afford the title compound (1.08 g, 11% yield). LCMS (ESI) Method 1: RT = 1.452 min, m / z = 256.0 [M+H]+.Intermediate 257-Bromo-4,5-dimethoxy-3-(l-methyl-l / / -pyrazol-4-yl)-l / / -indole

[0313] Step A: 7-Bromo-3-iodo-4,5-dimethoxy-lH-indole. Intermediate 24 (300 mg, 1.17 mmol, 1.0 eq) was dissolved in THF (10 mL) under argon. The reaction was cooled to -78 °C and LDA (1.0 M in THF, 2.34 mL, 2.34 mmol, 2.0 eq) was added, and the reaction was stirred for 1 h. Iodine (1.04 g, 4.1 mmol, 3.5 eq) was dissolved in THF (5 mL), and added to the reaction. The mixture was allowed to stir at -78 °C for 2 h. The reaction was quenched by addition of aq. Na2S2C>3, extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0 to 30% EtOAc in hexanes to afford the title compound (223 mg, 49% yield). LCMS (ESI) Method 2: RT = 1.296 min, m / z = 380.8 (M+H)+.212657-0002-WO01

[0314] Step B: terf-Butyl 7-bromo-3-iodo-4,5-dimethoxy-l / / -indole-l-carboxylate. In a reaction vessel, 7-bromo-3-iodo-4,5-dimethoxy-lH-indole (223 mg, 0.117 mmol, 1.0 eq) was dissolved in DCM (10 mL). TEA (177 mg, 1.75 mmol. 3.0 eq) and DMAP (14 mg, 0.12 mmol, 0.2 eq) were added, followed by BOC2O (191 mg, 0.88 mmol, 1.5 eq). The reaction was stirred for 1 h at RT. The reaction as extracted with DCM, washed with H2O, dried over MgSCU, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the title compound (260 mg, 92% yield). LCMS (ESI) Method 2: RT = 1.794 min, m / z = 480.8 (M+H)+.

[0315] Step C: rt-Butyl 7-br()iii()-4.5-dimetlioxy-3-(l-metliyl-l / / -pyrazol-4-yl)-l / / -indole-l-carboxylate. / / 7-Butyl 7-bromo-3-iodo-4,5-dimethoxy-17 / -indole-l-carboxylate (260 mg, 0.54 mmol, 1.0 eq), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l / / -pyrazole (150 mg, 0.72 mmol, 1.35 eq), K2CO3 (150 mg, 1.09 mmol, 2.0 eq) and Pd(PPh?)4 (40 mg, 0.035 mmol, 0.06 eq) were weighed and dissolved in 1,4-di oxane (5 mL) and H2O (1 mL). The reaction was sparged with argon for 5 minutes, sealed, and heated to 80 °C overnight. The reaction was extracted with EtOAc, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0 to 50% EtOAc in hexanes to afford the title compound (210 mg, 89% yield). LCMS (ESI) Method 2: RT = 1.432 min, m / z = 436.0 (M+H)+.

[0316] Step D: 7-Bromo-4,5-dimethoxy-3-(l-methyl-LH-pyrazol-4-yl)-TH-indole. tert-Butyl 7-bromo-4,5-dimethoxy-3-(l -methyl- l / / -pyrazol-4-yl)-l / f-indole-l -carboxylate (210 mg, 0.48 mmol, 1.0 eq) was dissolved in DCM (10 mL) followed by addition of TFA (0.75 mL, 9.6 mmol, 20 eq). The reaction was stirred at RT for 3 h. The reaction was concentrated, and carried forward without further purification of the product (140 mg, 87% yield). LCMS (ESI) Method 2: RT = 0.847 min, m / z = 336.0 (M+H)+.xoIntermediate 267-Bromo-4,5-dimethoxy-2-(l-(2-methoxyethyl)-LH-pyrazol-4-yl)-l / / -indole212657-0002-WO01

[0317] Step A: l-(2-Methoxyethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole. 4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-l / / -pyrazole (300 mg, 1.55 mmol, 1.0 eq) was dissolved in THF (5 mL) and cooled 0 °C. NaH (90 wt.%, 56 mg, 2.32, 1.5 eq) was added and the reaction stirred 1 h. l-Bromo-2-methoxy ethane (430 mg, 3.09 mmol, 2.0 eq) was added and the reaction was stirred at RT for 4 h. The reaction was quenched with H2O, extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the title compound (250 mg, 65% yield). LCMS (ESI) Method 1: RT = 1.483 min, m / z = 253.2 (M+H)+.

[0318] Step B: tert- Butyl 7-bromo-4,5-dimethoxy-2-(l-(2-methoxyethyl)-LH-pyrazoI-4-yl)-TH-indole-l-carboxylate. Intermediate 15 (250 mg, 0.52 mmol, 1.0 eq), l-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l / / -pyrazole (170 mg, 0.67 mmol, 1.3 eq), K2CO3 (215 mg, 1.56 mmol, 3.0 eq), and Pd(PPh3)4 (60 mg, 0.052 mmol, 0.1 eq) were dissolved in 1,4-dioxane (5 mL) and H2O (1 mL). The reaction mixture was sparged with argon for 5 min, sealed, heated at 80 °C for 3 h, extracted with EtOAc, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 50% EtOAc in hexanes to afford the title compound (180 mg, 72% yield). LCMS (ESI) Method 2: RT = 1.472 min, m / z = 480.0 (M+H)+.

[0319] Step C: 7-Broino-4.5-dimethoxy-2-( l-(2-met hoxy el hyl)-l / / -py razol-4-yl )-! / / -indole. te / 7-Butyl 7-bromo-4,5-dimethoxy-2-(l-(2-methoxyethyl)-l / 7-pyrazol-4-yl)-l / / -indole-1 -carboxylate (180 mg, 0.375 mmol, 1.0 eq) was dissolved in DCM (5 mL). TFA (1 mL, 10 mmol, 30 eq) was added and the reaction was stirred at RT for 4 h. The reaction was concentrated, then taken up in DCM, washed with aq. NaHCOs, filtered, and concentrated. The crude material (130 mg, 91% yield) was used without further purification. LCMS (ESI) Method 1: RT = 1.998 min, m / z = 379.8 (M+H)+.BrIntermediate 27212657-0002-WO015-(Benzyloxy)-7-bromo-4-methoxy-2-(l -methyl- 1 / / -pyrazol-4-yl)-l / / -indole

[0320] Step A: tert- Butyl 5-(benzyloxy)-7-bromo-4-methoxy-2-(l-methyl-l / / -pyrazol-4-yl)-l / / -indole-l-carboxylate. Intermediate 17A (1.00 g, 1.79 mmol, 1.0 eq), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l / -pyrazole (600 mg, 2.88 mmol, 1.6 eq), K2CO3 (720 mg, 5.21 mmol, 2.9 eq), and Pd(PPh3)4 (120 mg, 0.104 mmol, 0.06 eq) were weighed and dissolved in dioxane (10 mL) and H2O (2 mL). The reaction was sparged with argon for 5 min, sealed, and then heated to 80 °C for 8 h. The reaction was extracted with EtOAc, washed with H2O, washed with brine, dried over MgSC>4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 50% EtOAc in hexanes to afford the title compound (836 mg, 107% yield). LCMS (ESI) Method 2: RT = 1.254 min, m / z = 511.9 (M+H).

[0321] Step B: 5-(Benzyloxy)-7-bromo-4-methoxy-2-(l-methyl-l / / -pyrazol-4-yl)-l / / -indole. / c / -Butyl 5-(benzyloxy)-7-bromo-4-methoxy-2-(l-methyl-l / / -pyrazol-4-yl)-127-indole-1 -carboxylate (836 mg, 1.63 mmol, 1.0 eq) was dissolved in DCM (5 mL) and TFA (1 mL, 10 mmol, 8.0 eq) was added, and the reaction was stirred at RT. The reaction was concentrated, extracted with EtOAc, washed with aq. NaHCO3, dried over MgSO4, filtered, and then concentrated. The crude material was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the title compound (638 mg, 95% yield). LCMS (ESI) Method 2: RT = 0.685 min, m / z = 412.0 (M+H).Intermediate 28(26345fl,l722^,24 / ?)-l5-(benzyloxy)-27-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4-methoxy-24,34-dimethyl-24-oxo-24,2^,2^,24-tetrahydro-212657-0002-WO01l H,3*H-5 -oxa-2(2,6)-pyrazino[l,2-ff]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- l^-carbaldehyde

[0322] Step A: (26345„,l722 / ?fl,24 / ?)-l5-(benzyloxy)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(hydroxymethyl)-l4-methoxy-24,34-dimethyl-21,2^,2^,24-tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino| l,2-a]indola-l(7,l )-indola-3(4,3)-pyrazolacyclooctaphan-21-one. Intermediate 14 (0.50 g, 0.6 mmol, 1.0 eq) was stirred in dry THF (4 mL) at RT under argon. Lithium borohydride (30 mg, 1.4 mmol, 2.3 eq) was added and the reaction was stirred at 35 °C for 48 h. The reaction was quenched by dropwise addition of MeOH. The reaction was extracted with EtOAc, washed with sat. aq. NH4CI, washed with sat. aq. NaHCO3, washed with brine, dried over MgSC>4, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 0 to 65% EtOAc / MeOH (95:5) in hexanes to afford the title compound (333 mg, 70% yield). LCMS (ESI) Method 2: RT = 1.75 min, m / z = 862 (M+H)+.

[0323] Step B: (26345fl,l722 / ?«,24 / ?)-l5-(benzyloxy)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4-methoxy-24,34-dimethyl-21-oxo- 21,22,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carbaldehyde. The product from Step A (228 mg, 0.26 mmol, 1.0 eq) was stirred in dry THF (6 mL) at RT under argon. MnCh (230 mg, 2.6 mmol, 10 eq) was added and the reaction was allowed to stir at 45 °C overnight. The reaction was filtered through Celite®, rinsed with EtOAc, and concentrated to afford the title compound (212 mg, 93% yield). The crude residue was used without further purification. LCMS (ESI) Method 2: RT = 2.20 min, m / z = 860 (M+H)+.212657-0002-WO01Exemplary Compounds of Formula (I)ciExample 1(2f'3^S„.l72" / „2^ / ?)-2^-chloro-2 '^-(3-(4-chloro-3.5-diniethylphenoxy)propyl)-.1^- dimethoxy-24,3^-dimethyl-12-(l / f-l,2,4-triazol-3-yl)-21,2^,2^,24-tetrahydro-loxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0324] (General Procedure F) Intermediate 6 (300 mg, 0.375 mmol, 1.0 eq) was dissolved in DMF (15 mL) followed by addition of DIPEA (291 mg, 2.25 mmol, 6.0 eq) and HATU (285 mg, 0.749 mmol, 2.0 eq). The reaction was allowed to stir for 5 min, followed by addition of NH4Cl (60 mg, 1.12 mmol, 3.0 eq). The reaction was stirred for 2 h at RT, extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes followed by 0 to 10% MeOH / DCM (260 mg, 87% yield). LCMS (ESI) Method 1: RT = 2.291 min, m / z = 799.2 (M+H). The resulting product (260 mg, 0.34 mmol, 1.0 eq) and 1,1-dimethoxy-A, A-dimethylmethanamine (815 pL, 6.75 mmol, 20 eq) were added to a reaction vessel and heated to 95 °C for 1 h. The 1,1 -dimethoxy -N, A-di methyl ethanamine was removed in vacuo. The crude residue was dissolved in EtOH (5 mL) and added dropwise to a solution of acetic acid (386 pL, 6.75 mmol) and hydrazine (160 pL, 5.06 mmol) in EtOH (1 mL) at 0 °C. The reaction mixture was allowed to warm to RT and then stir for 2 h. The reaction was quenched with H2O, extracted with DCM, dried over MgSO4, filtered, and concentrated. The crude product was purified by reverse phase HPLC to afford the title compound (180 mg, 65% yield). LCMS (ESI) Method 1: RT = 2.235 min, m / z = 823.2 (M+H).212657-0002-WO01Example 2(26345a,l722l?fl,2^1f)-2^-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15- methoxy-14,24,31 -trimethyl-l^-f \H- l,2,4-triazol-3-yl)-21,2^,2^,2^-tetrahydro-l ^H,3 ^H-5- oxa-2(2,6)-pyrazino[ l,2-tz]indola- 1(7,1 )-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0325] The title compound (40 mg, 41% yield) was prepared following General Procedure F starting from Intermediate 7 (100 mg, 0.128 mmol). LCMS (ESI) Method 2: RT = 1.452 min, m / z = 807.0 (M+H)+.Example 3 (2631. S„.1 2‘ / ?„,2"l / ?)-2^-( liloro-2 '^-(3-(4-clil()ro-3.5-diiiietliylphenoxy)propyl)-l^.lS- dimethoxy-24,31-dimethyl-12-(l-methyl-l / / -l,2,4-triazol-5-yI)-21,22,23,24-tetrahydro--oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 21-one

[0326] Example 1 (200 mg, 0.243 mmol, 1.0 eq) was dissolved in DMF (5 mL) followed by addition of Cs2CO3(237 mg, 0.72 mmol, 3.0 eq) and Mel (22.8 pL, 0.364 mmol, 1.5 eq). The reaction was stirred at 70 °C for 1 h. The reaction was quenched with water and extracted with212657-0002-WO01EtOAc. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated. The crude material was purified by reverse phase HPLC to afford the title compound (30 mg, 15% yield). LCMS: RT = 2.366 min, MS (ES) 837.3 (M+H). LCMS: RT = 2.366 min, MS (ES) 837.3 (M+H). 'H NMR (400 MHz, MeOH-t / i) 88.00 (s, 1H), 7.89 (s, 1H), 7.72 (d, J= 8.6 Hz, 1H), 7.27 (d, J= 8.6 Hz, 1H), 7.06 (s, 1H), 7.05(s, 1H), 6.57 (s, 2H), 4.73 -4.69 (m, 1H), 4.21 -4.15 (m, 3H), 4.07 - 4.04 (m, 1H), 4.03 (s, 3H), 4.01 (s, 3H), 3.98 (s, 3H), 3.93 - 3.86 (m, 6H), 3.63 - 3.60 (m, 2H), 3.40 - 3.34 (m, 2H), 2.84 (t, J= 9.9 Hz, 1H), 2.25 (s, 6H), 2.18 -2.11 (m, 2H), 1.61 - 1.56 (m, 1H), 1.47 - 1.42 (m, 1H), 1.41 (d, J = 6.6 Hz, 3H).Example 4(26345<J,l722?«,2^?)-2^-Chloro-2^(-).(3_(4_chloro-3,5-dimethylphenoxy)propyl)-14,l^- dimethoxy- ^, 3^-dimethyl-l^-(l-methyl- 117-1, 2, 4-triazol-3-yl)-2^, 2^,2^, ^-tetrahydro- i ^s fz-s -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 2^ -one.

[0327] The title compound (72 mg, 35% yield) was isolated from the reaction described for Example 3. LCMS (ESI) Method 1: RT = 2.341 min, m / z = 837.3 (M+H)+. 'H NMR (400 MHz, MeOH-tZr) 88.36 (s, 1H), 7.90 (s, 1H), 7.74 (d, J= 8.7 Hz, 1H), 7.29 (d, J= 8.7 Hz, 1H), 7.22 (s, 1H), 6.69 (s, 1H), 6.54 (s, 2H), 4.79 - 4.69 (m, 2H), 4.28 - 4.17 (m, 2H), 4.13 - 4.09 (m, 2H), 4.02 (s, 3H), 4.01 (s, 3H), 3.95 -3.90 (m, 5H), 3.88 - 3.85 (m, 5H), 3.70 (d, J= 10.1 Hz, 1H), 3.63 (d, J= 12.3 Hz, 1H), 3.52- 3.48 (m, 1H), 3.44 - 3.37 (m, 2H), 3.05 (t, J= 10.4 Hz, 1H), 2.20 (s, 3H), 2.19 -2.10 (m, 2H), 1.90 - 1.81 (m, 1H), 1.63 - 1.54 (m, 1H), 1.15 (d, J = 6.6 Hz, 3H).212657-0002-WO01Example 5 (26345fl,l722 / ?a,247?)-2^-Chloro-2^<-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15- methoxy-l^, 2^,3 l-trimethyl-12-(l-methyl-l / / -l, 2,4- triazol-3-yl)-2^, 2^,2^, 2^-tetrahydro- I'H^H-S -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 2^-one

[0328] Step A: (7?)-6-(3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-lH-pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(5-methoxy-4-methyl-2-(l-methyl-l / / -l,2,4-triazol-3-yl)-l / / -indol-7-yl)-4-methyl-3,4-dihydropyrazino[l,2-fl]indol-l(2Z / )-one.The title compound (140 mg, 80% yield) was prepared following General Procedure A using Intermediate 5 (130 mg, 0.189 mmol, 1.0 eq) and Intermediate 20 (90 mg, 0.283 mmol, 1.5 eq). LCMS (ESI) Method 2: RT = 1.691 min, 1.733 min (mixture of rotamers), m / z = 929.4 (M+H)+.

[0329] Step B: (l?)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3-((3-hydroxy propoxy )methyl)-l -met liyl-l / / -pyrazol-4-yl)-2-(5-methoxy-4-methyl-2-(l -methyl-l / / -l,2,4-triazol-3-yl)-l / -indol-7-yl)-4-methyl-3,4-dihydropyrazino[l,2-a]indol-l(2Z / )-one.The title compound (125 mg, 99% yield) was prepared following General Procedure B using the product from Step A (140 mg, 151 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.197 min, 1.252 min (mixture of rotamers), m / z = 839.2 (M+H)+.

[0330] Step C: (7?)-3-((4-(7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(5-methoxy-4-methyl-2-(l-methyI-l / / -l,2,4-triazol-3-yl)-l / Z-indol-7-yl)-4-methyl-l-oxo- 1.2.3.4-tet rahydropyrazino] 1.2-< / ]indol-6-yl)-l -methyl- l / / -pyr;izol-3-yl)methoxy)propyl 4-methylbenzenesulfonate. The product from Step B (125 mg, 0.149 mmol, 1.0 eq) was dissolved in DCM (1 mL). TEA (62 pL, 0.45 mmol, 3.0 eq), DMAP (4 mg, 0.03 mmol, 0.2 eq), and TsCl (68 mg, 0.36 mmol, 2.4 eq) were added and the reaction was stirred at RT for 3 h.212657-0002-WO01The reaction was extracted with DCM, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude material was purified using flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the title compound (115 mg, 78% yield). LCMS (ESI) Method 2: RT = 1.586 min, 1.645 min (mixture of rotamers), m / z = 993.3 (M+H)+.

[0331] Step D: (2634S'„.l722 / < / .24 / ?)-27-Chloro-2l0-(3-(4-chloro-3.5-dimethylphenoxy)propyl)-15-methoxy-l4,24,34-trimethyl-12-(l-methyl-l. / -l,2,4-triazol-3-yl)-2',27.2^.24-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1,2-i / |indola-l(7.1 )-indola-3(4,3)-pyrazolacyclooctaphan-24-one. The title compound (14 mg, 15% yield) was prepared following General Procedure D using the product from Step C (115 mg, 0.116 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.482 min, m / z = 821.3 (M+H)+.Example 6(26345a,l722?a,24?)-27-Chloro-2^<-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-24,3^-dimethyl-l7-(l-(oxetan-3-ylmethyl)-17f-l,2,4-triazol-3-yl)-2^,27,2^,24- tetrahydro-1' / / .3 ' / / -5-ox;i-2(2.6)-pyiaziiio| 1.2-^|indola- 1(7.1 )-indola-3(4,3)- pyrazolacyclooctaphan-21 -one

[0332] (General Procedure H) Example 1 (80 mg, 0.097 mmol, 1.0 eq) was dissolved in DMF (2 mL). NaH (60 wt.% in mineral oil, 4.7 mg, 0.12 mmol, 1.2 eq) was added at 0 °C and the reaction was stirred for 5 min. 3-(Bromomethyl)oxetane (18 mg, 0.12 mmol, 1.2 eq) was added and the reaction was heated to 50 °C for 15 h. The reaction was extracted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The crude material was212657-0002-WO01purified by reverse phase HPLC to afford the title compound (27 mg, 31% yield). LCMS (ESI) Method 1: RT = 2.209 min, m / z = 893.2 (M+H)+.

[0333] The compounds presented in Table 2 may be prepared using General Procedure H using appropriate starting materials.Table 2StartingNo. Structure Name 'H NMR and / or LCMS materialsLCMS (ESI) Method 1: RT = 2.302 (2634So,l722Ra,24 / ?)-27- mm, m / z = 921.3 (M+H)+. *H NMR Chloro-210-(3-(4-chloro-3,5- (400 MHz, MeOH-A) δ 8.45 (s, 1H), dimethylphenoxy)propyl)- 7.92 (s, 1H), 7.75 (d, J= 8.8 Hz, 1H),731 (d, J= 88 Hz, 1H), 726 (s, 1H), l4, 14-diinetli<>x\-24.31- 6.98 (s, 1H), 6.55 (s, 1H), 4.83 - 4.75 Example 1, dimethyl- P-( 1 -((tetrahydro- (m, 2H), 4.33 - 4 19 (m, 2H), 4.16 - 4-(bromo 2H-pyran-4-yl)methyl)- \H- 4.09 (m, 3H), 4.05 (s, 3H), 4.04 (s, 7 methyl) 1,2,4-triazol-3-yl)- 3H), 4.02 - 3 97 (m, 2H), 3.94 (s, tetrahydro-2H- 2 '.27.24.24-telrah\'dro- 3H), 3.93 - 3.86 (m, 4H), 376 (d, J = pyran11H,31H-5-oxa-2(2,6)- 10.0 Hz, 1H), 3.66 (d, J= 12.0 Hz, py razino [ 1,2-a] indola- 1(7,1)- 1H), 3.53 - 3.41 (m, 2H), 3.08 (t, J = indola-3(4,3)- 10.0 Hz, 1H), 2.28 - 2.26 (m, 1H), pyrazolacy clooctaphan-2 - 2 19 -2 12 (m, 2H), 1 87 - 1 80 (m, one 1H), 1.68 - 1.60 (m, 1H), 1 47 - 1.29(m, 5H), 1.18 (d, 7= 6.8 Hz, 3H) (2034S„,l7227L,24R)-27- Chloro-210-(3-(4-chloro-3,5- dimethylphenoxy )propy 1)- l4, 15-dimethoxy-24,31- dimethyl-l2-(l-((3- Example 1,methyloxetan-3-yl)methyl)- 3-(bromo LCMS (ESI) Method 1: RT = 2.245 8 l / / -l,2,4-tnazol-3-yl)- methyl)-3- min, m / z = 907.3 (M+II)+methyloxetane 21,22,2J,24-tetrahy dro- l1W,31W-5-oxa-2(2,6)- pyrazino [ 1,2-a] indola- 1(7,1)- indola-3(4,3)- pyrazolacy clooctaphan-2 - one212657-0002-WO01(2634So,l722Ro,24R)-27- LCMS (ESI) Method 1: = 2.289 Chloro-210-(3-(4-chloro-3,5- min, m / z = 881.4 (M+H)+> H NMR dimethylphenoxy)propyl)- (400 MHz, MeOH-A) S 8.42 (s, 1H), / —f7.91 (s, 1H), 7.75 (d, J= 8.8 Hz, 1H), l4,l5-dimethoxy-l2-(l-(2- 7.30 (d, J= 8.8 Hz, 1H), 7.25 (s, 1H), \ J I methoxy ethyl)- 177-1,2,4- L 6.98 (s, 1H), 6.57 (s, 2H), 4.81 - 4.76 Example 1,triazol-3-yl)-24,3 ^-dimethyl- (m, 2H), 4.36 – 4.19 (m, 4H), 4.04 (s, l-bromo-2-cl>^r’0N-^-\OMe21,22,23,24-tetrahydro- 3H), 4.03 (s, 3H), 3.97 - 3.89 (m, methoxy ethane AXj 117 / ,3177-5-oxa-2(2,6)- 6H), 3.74 (d, 7= 10.0 Hz, 1H), 3.70 - py razino [ 1,2-a] indola- 1(7,1)- 3.63 (m, 3H), 3.51 (br s, 1H), 3.28 (s, indola-3(4,3)- 3H), 3 08 (t, J= 10.4 Hz, 1H), 223 pyrazolacy clooctaphan-23- (s, 6H), 223 -2.14 (m, 2H), 1.88- one 1.81 (m, 1H), 1.65 - 1.56 (m, 1H),1.17 (d, J= 6.8 Hz, 3H) LCMS (ESI) Method 1: = 1.970 (2634Sa,1722Ra,24R)-27- min, m / z = 894.3 (M+H)+. ‘H NMR Chloro-2 ^-(3-(4-chloro-3,5- (400 MHz, MeOH-A) δ 8.45 (s, 1H), dimethylphenoxy )propyl)- 1 - 790 (s, 1H), 773 (d, J= 87 Hz, 1H), ( 1 -(2-(dimethy lamino )ethy 1)- 7.28 (d, J= 8.3 Hz, 1H), 7.23 (s, 1H),6.96 (s, 1H), 6.53 (s, 2H), 4.79 - 4.74 Example 1, 1H-1,2,4-triazol-3-yl)- 14, 15- (m, 211), 4.33 – 4.17 (m, 5H), 4.02 (s, 2-bromo-\’.\’- dimethoxy-24,3 -dimethy 1- 3H), 4.01 (s, 3H), 3.95 - 3.90 (m, dimethylethan- 2 ',22,23,24-tetrahydro- 5H), 3.73 (d,7 = 10.0 Hz, 1H), 3.63 1 -aminel177,3177-5-oxa-2(2,6)- (d, 7 = 12.1 Hz, 1H), 3.53 - 349 (m, hydrobromidepy razino [ 1,2-a] indola- 1(7,1)- 1H), 3.44 - 3.38 (m, 2H), 3.07 (t, 7 = indola-3(4,3)- 10.1 Hz, 1H), 2.78 - 2.74 (m, 2H),2.24 (s, 16H), 2.21 (s, 6H), 2.16 – pyrazolacy clooctaphan-23- 2.12 (m, 2H), 1.92 - 1.82 (m, 1H), one1.64 - 1.55 (m, 1H), 1.15 (d,7= 6.8Hz, 3H) LCMS (ESI) Method 2: = 1.569 (2°34S„,l7227?„,247?)-27- min, m / z = 877.0 (M+H)+. *H NMR Chloro-210-(3-(4-chloro-3,5- (400 MHz, CDCl3) δ 8.02 (s, 1H), dimethylphenoxy)propyl)-l3- 7.68 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), Example 2, methoxy- 14,24, 33-trimethyl- 7.30 (d, J = 8.8 Hz, 1H), 7.27 (s, 1H), 3-(bromoCIVXNONX_X 6 82 (s, 1H), 6 58 (s, 2H), 4 87 (dd, J l2-(l-(oxetan-3-ylmethyl)- methyl)oxetane = 12.8, 6.0 Hz, 1H), 481 - 4.73 (m,1H- 1,2,4-triazol-3-y 1)- 3H), 4.48 (quart. J = 5.2 Hz, 2H), 21,22.23,24-tetrahy dro- 4.42 (d, J = 7.2 Hz, 211), 4.35 - 4.24 1177,3177-5-oxa-2(2,6)- (m, 2H), 4.20 (d, J = 100 Hz, 1H), py razino [ 1,2-a] indola- 1(7,1)- 4.08 (s, 3H), 3.97 (quart., J = 6.4 Hz,212657-0002-WO01indola-3(4,3)- 2H), 3.90 (s, 3H), 3.81 (d, J = 10.0 pyrazolacy clooctaphan-2 - Hz, 1H), 3.67 - 3.60 (m, 1H), 3.50 - one 3.34 (m,4H), 3.13 (t, J= 100 Hz,1H), 2.46 (s, 3H), 2.26 (s, 6H), 2.20 (quint., J = 6.8 Hz, 2H), 1.98- 1.91 (m, 1H), 1.76 - 1.67 (m, 1H), 1.15 (d, J= 6.4 Hz, 3H) (2634So,l'22Ra,24R)-27- Chloro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-lmethoxy-l4,24,3 ^-trimethyl- 12-( 1 -(oxetan-3-y Imethyl)- Example 2, lH-l,2,4-triazol-5-yl)- LCMS (ESI) Method 2: RT = 1.618 3-(bromo2 ',22,22,24-tetrahydro- min, m / z = 876.9 (M+H)+methyl)oxetane11H,31H-5-oxa-2(2,6)- py razino [ 1,2-a] indola- 1(7,1)- indola-3(4,3)- pyrazolacy clooctaphan-2 - p A oneLCMS (ESI) Method 2: RT = 1.285 min, m / z = 918.0 (M+II)+. ’IINMR (2l’3ri„. L27?„.24 / <|-27- (400 MHz, DMSO-d6) 88.54 (s, 1H),8.03 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), Chloro-210-(3-(4-chloro-3,5- 7.30 (d, J = 8.4 Hz, 1H), 7.07 (s, 1H), dimethylphenoxy )propyl)-l 5- 6.91 (s, 1H), 6.64 (s, 2H), 4.70 (dt, J methoxy-l4,24,3 ^-trimethyl- = 13.2, 5.2 Hz, 1H), 4.54 (dd, J = Example 2, l2-(l-(2-(piperidin-l- 120, 56Hz, lH),4.30-4.19 (m, l-(2- yl)ethyl)-lH-l,2,4-triazol-3- 2H), 4.15 -4.11 (m, 2H), 4.07 (d, J = chloroethyl) 9.6 Hz, 1H), 3.97 (s, 3H), 3.92 – 3.87CL yl)-21 _2-.24.24-tetrahv dro- piperidine (m, 2H), 3.83 (s, 3H), 3.66 (d, J = hydrochloride 11H,31 / / -5-oxa-2(2,6)- 12.0 Hz, 1H), 3.60 (d,7= 9.6 Hz, py razino [ 1,2-a] indola- 1(7,1)- 1H), 3.47 - 3.39 (m, 1H), 3.26 (t,7 = indola-3(4,3)- 7.6 Hz, 2H), 2.98 (t, J = 10.0 Hz, pyrazolacy clooctaphan-2 - 1H), 2.61 (t, J = 6.4 Hz, 2H), 2.38 (s, one 3H), 2.34 - 227 (m, 4H), 2.24 (s,6H), 2.08 – 2.01 (m, 2H), 1.75 – 1.68 (m, 1H), 1.51 (m, 7H), 1.10 (d, J = 6.8 Hz, 3H)212657-0002-WO01LCMS (ESI) Method 2: RT= 1.217 min, m / z = 920.0 (M+H)+. ‘H NMR (2°34SO,1722AO,24T?)-27- (400 MHz, DMSO-d6) δ 8.11 (s, 1H), Chloro-210-(3-(4-chloro-3,5- 8.03 (s, 1H), 7.76 (d, J= 8.8 Hz, 1H), dimethy Iphenoxy )propy 1)- 1 - 7.30 (d, J= 8.8 Hz, 1H), 7.15 (s, 1H), Z-N7methoxy- 14,24,3 ' -trimethvl- 7.01 (s, 1H), 6.68 (s, 2H), 4.53 - 4.45 Example 2, l2-( l-(2-morpholinoethyl)- (m, 2H), 4.40 – 4.35 (m, 1H), 4.27 - 4-(2- lH-l,2,4-triazol-5-yl)- 4.23 (m, 1H), 4.13 -4.06 (m, 2H), bromoethyl) 4.03 (d, J = 10.0 Hz, 1H), 3.97 (s,2 ',27,2^,24-tetrahydro- morpholine 3H), 3.92 (t, J = 6.8 Hz, 2H), 3.85 (s, lrH,3rH-5-oxa-2(2,6)- hydrobromide 3H), 3.65 (d, J= 12.0 Hz, 1H), 3.53 py razino [ 1,2-a] indola- 1(7,1)- (d, J = 10.0 Hz, 1H), 3.43 – 3.28 (m, indola-3(4,3)- 7H), 3.26 (t, J = 6.4 Hz, 2H), 2.82 – pyrazolacy clooctaphan-2 - 2.72 (m, 3H), 2.39 (s, 3H), 2.34 - one 2.26 (m, 4H), 2.23 (s, 6H), 2.04(quint., J = 6.4 Hz, 2H), 1.48 (br s, 2H), 1.09 (d, J = 6.4 Hz, 3H) LCMS (ESI) Method 2: RT= 1.336 min, m / z = 918.0 (M+H)+. *H NMR (2634Sa,l722Ro,24R)-27- (400 MHz, DMSO-rfe) δ 8.10 (s, 1H), Chloro-210-(3-(4-chloro-3,5- 8.03 (s, 1H), 7.76 (d, J= 8.4 Hz, 1H), dimethylphenoxy )propyl)-l 5- 7.30 (d, J= 8.4 Hz, 1H), 7.15 (s, 1H), methoxy- 194,24,3 ' -trimelhvl- 7.01 (s, 1H), 6.68 (s, 2H), 4.52 - 4.41 Example 2, 17-( 1 -(2-(piperidm- 1 - (m, 2H), 4.37 – 4.22 (m, 2H), 4.13 - l-(2- yl)ethy 1)- IH- 1,2,4-triazol-5- 4.06 (m, 2H), 4.02 (d, J= 10.0 Hz, chloroethyl)CIV^\3N-^-A 1H), 3.97 (s, 3H), 3.92 (t, J= 6.4 Hz, yl)-21,22,2J,24-tetrahy dro- piperidine 2H), 3.85 (s, 3H), 3.66 (d, J= 12.411H,31H-5-oxa-2(2,6)- hydrochloride Hz, 1H), 3.52 (d, J= 100 Hz, 1H), pyrazino [ 1,2-a] indola- 1(7,1)- 3.29 - 3.26 (m, 2H), 2.82 (t, J = 6.8 indola-3(4,3)- Hz, 1H), 2.70 (t, J = 6.4 Hz, 2H), pyrazo lacy clooctaphan-2 - 2 39 (s, 3H), 2.36 - 2.27 (m, 2H), one 2.23 (s, 6H), 2.06 – 2.02 (m, 2H),1.47 (br s, 2H), 1 40 - 1.24 (m, 9H), 1.09 (d, J= 6.8 Hz, 3H)212657-0002-WO01(2634So,l722Ro,24R)-27- Chloro-210-(3-(4-chloro-3,5- dimethylphenoxy )propy 1)- 1methoxy- 14.24.3 ' -tnmellivl- Example 2,4-(2- l2-( l-(2-morpholinoethyl)- 1H- 1,2,4-triazol-3-yl)- LCMS (ESI) Method 2: RT = 1.258 16 bromoethyl)min, m / z = 920.0 (M+H)+morpholine 2 ',27,2^,24-tetrahydro- hydrobromide llHJlH-5-oxa-2(2,6)- pyrazino [ 1,2-a] indola- 1(7,1)- indola-3(4,3)- pyrazolacy clooctaphan-2 - oneExample 17(26347?fl,l722l?a,2^1?)-2^(-)-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-14,15-dimethoxy- 24,3^-dimethyl-12-(l-methyl-l / / -l,2,4-triazol-3-yl)-2^,2^,2^,24-tetrahydro-l^ / ,3^-5- oxa-2(2,6)-pyrazino[l,2-rz]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-2^-one

[0334] The title compound (45 mg, 35% yield) was prepared following General Procedure B using Example 4 (135 mg, 0.161 mmol, 1.0 eq) and DCM / MeOH (20 mL, 1:1) as the solvent, and allowing to stir for 24 h. The crude material was purified by reverse phase HPLC. LCMS (ESI) Method 2: RT= 1.447 min, m / z = 803.0 (M+H)+. 'H NMR (400 MHz, DMSO-tL) 58.54 (s, 1H), 7.96 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.07 (d, J = 6.8 Hz, 1H), 7.05 (s, 1H), 6.98 (s, 1H), 6.67 (s, 1H), 4.71 (dt, J= 14.0, 6.4 Hz, 1H), 4.57 (dd, J= 12.0, 6.0 Hz, 1H), 4.36 (quint., 6.0 Hz, 1H), 4.24 (t, J= 13.2 Hz, 1H), 4.06 (d, J= 9.6 Hz, 1H), 3.98 -3.93 (m, 2H), 3.94 (s, 6H), 3.88 (s, 3H), 3.85 (s, 3H), 3.66 (t, J= 13.6 Hz, 2H), 3.48 (br s, 1H),212657-0002-WO013.26 (t, J= 8.4Hz, 2H), 2.98 (t, J= 10.0 Hz, 1H), 2.21 (s, 6H), 2.09 - 2.02 (m, 2H), 1.81 - 1.74 (m, 1H), 1.60 - 1.51 (m, 1H), 1.04 (d, J= 6.8 Hz, 3H).Example 18(2634R„,l722R«,241?)-210-(3-(3,5-Dimethylphenoxy)propyl)-14,15-dimethoxy-24,31- dimethyl-12-(l-methyl-l / / -l,2,4-triazol-3-yl)-2^,22,2^,24-tetrahydro-l^ / / ,3^-5-oxa- 2(2,6)-pyrazino[l,2-£z]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan-21-one

[0335] The title compound (3 mg, 2% yield) was isolated from the reaction conditions described in Example 17. LCMS (ESI) Method 2: RT= 1.238 min, m / z = 769.1 (M+H)+.1H NMR (400 MHz, DMSO-d6) 58.55 (s, 1H), 7.96 (s, 1H), 7.74 (d, J= 7.2 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 7.07 (d, J= 6.4 Hz, 1H), 7.05 (s, 1H), 6.98 (s, 1H), 6.51 (s, 1H), 6.44 (s, 2H), 4.71 (dt, J= 13.6, 6.0 Hz, 1H), 4.57 (dd, J= 12.4, 6.0 Hz, 1H), 4.38 (quint., J = 5.6 Hz, 1H), 4.25 (t, J= 11.2 Hz, 1H), 4.06 (d, J= 9.6 Hz, 1H), 3.95 (s, 6H), 3.94 - 3.89 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.66 (t, J= 13.2 Hz, 2H), 3.48 (br s, 1H), 3.30 - 3.26 (m, 2H), 2.99 (t, J= 9.6 Hz, 1H), 2.15 (s, 6H), 2.05 (quint., J= 7.2 Hz, 2H), 1.82 - 1.75 (m, 1H), 1.60 - 1.52 (m, 1H), 1.04 (d, J = 6.4 Hz, 2H).212657-0002-WO01Example 19(26345a,l7227?a,24lf)-27-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4- methoxy-24,31-dimethyl-l7-(l-methyl-l / / -l,2,4-triazol-3-yl)-l^-(3-morpholinopropoxy)- 21,2^,2^,24-tetr ahydro- 1 ^H,3 l / / -5-oxa-2(2,6)-pyrazino [ 1,2-a] indola- 1 (7, 1 )-indola-3(4,3)- pyrazolacyclooctaphan-21 -one

[0336] Step A: (2634»S'a,l722 / ?«,24 / ?)-15-(3-Bromopropoxy)-27-chloro-21(“)-(3-(4-chlOro-3,5-dimethylphenoxy) propyl)-l4-methoxy-24,3^-dimethyl-l7-(l-methyl-l / / -l,2,4-triazol-3-yl)-2 '^-. I’ ^-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino|l,2-^|indola-l(7.1 )-indola-3(4,3)-pyrazolacyclooctaphan-21-one. Example 59 (26 mg, 0.031 mmol, 1.0 eq) was dissolved in MeCN (0.3 mL). K2CO3 (13 mg, 0.094, 3.0 eq) was added followed by 1,3-dibromopropane (19 mg, 0.094 mmol, 3.0 eq). The reaction was heated to 80 °C for 3 h. The reaction was extracted with EtOAc, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material (29 mg) was carried forward without further purification.

[0337] Step B: (26345fl,l7227?fl,24^)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4-methoxy-24,31-dimethyl-12-(l-methyl-LH-l,2,4-triazol-3-yl)-l^-(3-morpholinopropoxy)-24,22,2^,24-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1,2-fl]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The product from Step A (29 mg, 0.031 mmol, 1.0 eq) was dissolved in MeCN (0.3 mL). K2CO3 (8.5 mg, 0.061 mmol, 2.0 eq) and morpholine (4 mg, 0.046, 1.5 eq) were added. The reaction was heated to 80 °C for 1.5 h. The reaction was extracted with EtOAc, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by reverse phase HPLC to afford the title compound (8 mg, 27% yield over 2 steps). LCMS (ESI) Method 2: RT = 1.008 min, m / z = 950.4 (M+H)+.212657-0002-WO01Example 20(263^. S„.l72' / ?„.2^ / ?)-2^-( hloro-2 ^,-(3-(4-chl()ro-3.5-diiiiethylplienoxy)propyl)-l methoxy-24,3^-dimethyl-12-(l-methyl-l f-l,2,4-triazol-3-yl)-l^-((tetrahydro-2 / / -pyran-4- yl)inethoxy)-2 '.2-,2 ’,2^-tetrahydro-l ' / / .3 ' / / -5-oxa-2(2,6)-pyrazino| 1,2-^|indola-l (7.1 )- indola-3(4,3)-pyrazolacyclooctaphan-21 -one

[0338] (General Procedure I) Example 59 (110 mg, 0.133 mmol, 1.0 eq) was dissolved in DMF (1 mL). Cesium carbonate (217 mg, 0.667 mmol, 5.0 eq) and (tetrahydro-2 / 7-pyran-4-yl)methyl 4-methylbenzenesulfonate (108 mg, 0.400 mmol, 3.0 eq) were added and the reaction was heated to 55 °C for 24 h. The reaction was extracted with EtOAc, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by reverse phase HPLC to afford the title compound (60 mg, 49% yield). LCMS (ESI) Method 2: RT = 1.841 min, m / z = 921.3 (M+H)+.

[0339] The compounds presented in Table 3 may be prepared using General Procedure I using appropriate starting materials.Table 3'H NMR StartingNo. Structure Name and / or MaterialLCMS212657-0002-WO01(2634Sa,l7227?a,24T?)-27-Chloro-210-(3-(4- chloro-3, 5-dimethy Iphenoxy )propyl)-l4- LCMS (ESI) Example 59,methoxy -24, 3 ^-dimethyl- l2-( 1-methyl- \H- Method 1: RT = 4-(2-bromoethyl)1.975 min, morpholine 1,2,4-triazol-3-yl)- 1 ^-(2-morpholinoethoxy )- o\ / ~Nm / z = 936.3 hydrobromide 2^,22,2J,24-tetrahydro-1^77,3^77-5-oxa- (M+H)+2(2,6)-pyrazino [ 1,2-a] indo la- 1(7,1 )-indo la- 314, 3)-pyrazo lacy clooctaphan-21 -one / (2634S„, 17227?n,247?)-27-Chloro-210-(3-(4- rN.oz chloro-3,5-dimethylphenoxy)propyl)-l4- (D LCMS (ESI) methoxy- 1 ^-(2 -methoxyethoxy )-24, 3 - Example 59, Method 2: RT = l-bromo-2- dimethyl- 17-( 1-methyl- IH- 1,2,4-triazol-3-y 1)- 1 553 min, methoxy ethane s 2^,22,27,24-tetrahydro-1^77,3^77-5-oxa- m / z = 880.9<0 MeO2(2,6)-pyrazino [ 1,2-a] indo la- 1(7,1,-indola- (M+H)+3(4,3 )-pyrazolacy clooc taphan-2 -oneCl(2‘>34Sa,l7227?a,24^)-27-Chloro-210-(3-(4- chloro-3,5-dimethy Iphenoxy )propy 1)- 14- Example 59, LCMS (ESI) methoxy-24, 3 ^-dimethyl- P-(l-methyl-177- (sy Method 2: RT = tetrahydrofuran- 1,2,4-triazol-3-yl)- P-(((A)-tetrahydrofuran-3- 1.512 min, 3-yl-4-methyl yl)oxy)-2^,27,27,24-tetrahydro-l 'H,3 ^H-5- m / z = 892.9 benzenesulfonate oxa-2(2,6)-pyrazino[ 12-a ] indo la- 1 (7, 1)- (M+H)+indola-3(4,3)-pyrazolacyclooctaphan-2 -one / (2634Sa,l722Afl,24A)-27-Chloro-210-(3-(4- Achloro-3, 5-dimethy Iphenoxy )propyl)-l - XNfN-N J LNA) LCMS (ESI) methoxy -24, 31-dimethyl- 12-( 1 -methyl- 1W- Example 59, Method 2: RT =cixXo-d-0"63-(bromomethyl) 1,2,4-triazol-3-yl)- 1 ^-(oxetan-3-ylmethoxy)- l.537 min, oxetane 2 ' 22,27,24-tetraliydro- 1177,3 ^77-5-oxa- m,'z = 892.92(2,6)-pyrazino [ 1,2-a] indola- 1(7,1 j-indola- (M+H)+3(4,3)-pyrazolacyclooctaphan-2 -oneCl212657-0002-WO01(2634Sa,l722Ra,24R)-27-Chloro-210-(3-(4- chloro-3,5-dimetliylphenoxy)propyl)-l4- Example 59,methoxy-24,3 Ldimethyl- P-( 1-metliyl- 17 / - LCMS (ESI) (S)- l,2,4-tnazol-3-yl)-C-(((S)-tetraliydrofuran-2- Method 2: RT = ( tetrahy drofuran- 25 1.600 min, 2-yl)methyl-4- y l)methoxy)-21,27,2J,24-tetrahydro- m / z = 907.0 methylbenzene 1 ^H,3 ^ / f-5-oxa-2(2,6)-pyrazino[ 1,2-a]indola- (M+H)+sulfonate 1(7,1 )-indola-3(4,3 )-pyrazolacy clooctaphan- 2 -1 -oneExample 26(26345fl,l722l?«,24lf)-27-Chloro-2^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4- methoxy-24,31-dimethyl-12-(l-inethyl-l / / -l,2,4-triazol-5-yl)-15-(2-inorpholinoethoxy)- 21,27,2^,24-tetrahydro-l ^7 / ,3^-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21 -one

[0340] Step A: (2634S„.l722 / ?„.24 / ?)-l5-(Beiizyloxy)-27-chloro-2l0-(3-(4-cliloro-3.5-dimethylphenoxy)propyl)- l4-methoxy-24,3 -dimethyl-21 -oxo-21,2^,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l7-carboxylic acid. The title compound was prepared following General Procedure E using Intermediate 14A (335 mg, 0.370 mmol, 1.0 eq). Upon completion, the crude product was carried forward to Step B without further purification. LCMS (ESI) Method 1: RT = 1.788 min, m / z = 876.3 (M+H)+.212657-0002-WO01

[0341] Step B: (2634S„.1 22 / ?„.24 / ?)-l5-(Beiizyloxy)-27-clil()io-2l()-(3-(4-chloro-3.5-dimethylphenoxy)propyl)-l4-methoxy-24,3^-dimethyl-24-oxo- 21, 2^,23, 24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphane-l^-carboxamide. The product from Step A (320 mg, 0.364 mmol, 1.0 eq) was dissolved in benzene (3 mL). Thionyl chloride (52 mg, 0.437 mmol, 1.2 eq) was added and the reaction was heated to 80 °C for 1.5 h. The reaction was concentrated, taken up in DCM (3 mL) and ammonium hydroxide (70 mg, 2.0 mmol, 5.5 eq) was added followed by stirring for 1 h at RT. The crude material was extracted with CHCh / 'PrOH, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude material was carried forward to Step C without further purification. LCMS (ESI) Method 1: RT = 2.155 min, m / z = 875.2 (M+H)+.

[0342] Step C: (26345fl,l722T?fl,24 / ?)-l5-(Benzyloxy)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4-methoxy-24,3 -dimethyl-12-(LH-l,2,4-triazol-3-yl)-21,2^,2^,24-tetrahydro-l4H,34H-5-oxa-2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-24-one. The title compound was prepared following General Procedure F using the product from Step B (320 mg, 0.364 mmol, 1.0 eq).

[0343] Step D: (26345fl,l722 / ?„,24 / ?)-l5-(Benzyloxy)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4-methoxy-24,3^-dimethyl-12-(l-methyl-l / f-l,2,4-triazol-5-yl)-21,22,2^,24-tetrahydro-l^ / 7,3^7 / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The title compound (80 mg, 24% yield) was prepared following General Procedure G using the product from Step C (328 mg, 0.365, 1.0 eq) and allowing to stir overnight at RT. LCMS (ESI) Method 2: RT = 2.408 min, m / z = 913.3 (M+H)+.

[0344] Step E: (26345fl,l722?fl,24T?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1 -hydroxy-l4-methoxy-24,3 -dimethyl-12-(l-methyl-lH-l,2,4-triazol-5-yl)-21,22,23,24-tetrahydro-l4 / f,34F / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi’azolacyclooctaphan-24-one. The title compound (70 mg, 97% yield) was prepared following General Procedure B using the product from Step D (80 mg, 0.088 mmol, 1.0 eq) and stirring for 20 h at RT. LCMS (ESI) Method 2: RT = 1.491 min, m / z = 823.3 (M+H)+.212657-0002-WO01

[0345] Step F: (26345fl,l722 / ?fl,247?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4-methoxy-24,34-dimethyl-12-(l-methyl-l / / -l,2,4-triazol-5-yl)-l^-(2-morpholinoethoxy)-2^,22,2^,24-tetrahydro-l' / / ,3* / / -5-oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan-21-one. The title compound (15 mg, 19% yield) was prepared following General Procedure I using the product from Step E (70 mg, 0.085 mmol, 1.0 eq), 4-(2-bromoethyl)morpholine hydrobromide (80 mg, 0.291 mmol, 3.4 eq), and Cs2CO3(253 mg, 0.776 mmol, 9.1 eq). LCMS (ESI) Method 2: RT = 1.035 min, m / z = 936.0 (M+H)+.Example 27(2^345«,1^227?fl,24l?)-27-Chloro-l4,15-dimethoxy-24,3^-dimethyl-12-(l-inethyl-17 / -l,2,4- triazol-3-yl)-210-(3-(naphthalen-l-yloxy)propyl)-21,2^,2^,24-tetrahydro-l3 ^ / 7-5-oxa- 2(2,6)-pyrazino[l,2-rz]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0346] Step A: (7?)-6-(3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-17 / -pyrazol-4-yl)-7-chloro-2-(4,5-dimethoxy-2-(l-methyl-ll / -l,2,4-triazol-3-yl)-lZ / -indol-7-yl)-4-methyl-10-(3-(naphthalen-l-yloxy)propyl)-3,4-dihydropyrazino[l,2-rz]indol-l(277)-one. The title compound (110 mg, 65% yield) was prepared following General Procedure A using Intermediate 18 (120 mg, 0.18 mmol, 1.0 eq) and Intermediate 19 (140 mg, 0.41 mmol, 2.3 eq). LCMS (ESI) Method 3: RT = 1.03 min, m / z = 933.4 (M+H)+.

[0347] Step B: (7?)-7-Chloro-2-(4,5-dimethoxy-2-(l-methyl-l / / -l,2,4-triazol-3-yl)-l / / -indol-7-yl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-l / / -pyrazol-4-yl)-4-methyl-10-(3-(naphthalen-l-yloxy)propyl)-3,4-dihydropyrazino[l,2-cz]indol-l(2 / / )-one. The title compound (90 mg, 94% yield) was prepared following General Procedure B using the product212657-0002-WO01from Step A (110 mg, 0.11 mmol, 1.0 eq). LCMS (ESI) Method 3: RT = 0.78 min, m / z = 843.6 (M+H)+.

[0348] Step C: (A)-3-((4-(7-Chloro-2-(4,5-dimethoxy-2-(l-methyl-L / / -l,2,4-triazol-3-yl)-l / / -indol-7-yl)-4-methyl-10-(3-(naphthalen-l-yloxy)propyl)-l-oxo-l, 2,3,4-tetrahydropyrazino[l,2-a]indol-6-yl)-l-methyl-17 / -pyrazol-3-yl)methoxy)propyl 4-methylbenzenesulfonate. The title compound (74 mg, 70% yield) was prepared following General Procedure C using the product from Step B (90 mg, 0.11 mmol, 1.0 eq). LCMS (ESI) Method 3: RT = 0.99 min, m / z = 998.6 (M+H)+.

[0349] Step D: (2634S'„.l722 / ?„.24 / ?)-27-Chloro-l4.l -dimethoxy-24.3,-dimethyl-l2-(l- ethyl- 1 / / - 1.2.4-triazol-3-yl)-2 ^-(3-(naphthalen- 1 -yloxy)propyl)-2 '.2-.2\24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-6f]indola-l(7,l)-indoIa-3(4,3)-pyrazolacyclooctaphan-2^-one. The title compound (32 mg, 48% yield) was prepared following General Procedure D using the product from Step C (74 mg, 0.08 mmol, 1.0 eq). The crude material was purified by reverse phase HPLC. LCMS (ESI) Method 3: RT = 0.92 min, m / z = 825.5 (M+H)+. 'H-NMR (MeOH-d4) δ 8.35 (s, 1H), 7.98 (d, 1H, J= 8 Hz), 7.85 (s, 1H), 7.79-7.71 (m, 2H), 7.43-7.41 ( m, 1H), 7.33-7.30 (m, 1H), 7.26-7.23 (m, 3H), 7.20-7.17 (m, 1H), 6.93 (s, 1H), 6.66 (d, 1H, J = 8 Hz), 4.60-4.58 (m, 1H), 4.20-4.10 ( m, 2H), 4.02 (s, 3H), 4.01 (s, 3H), 3.99-3.96 (m, 2H), 3.89 (s, 2H), 3.37 (s, 3H), 3.60-3.55 (m, 2H), 3.53-3.29 (m, 2H), 2.83 (tr, 2H, J= 12 Hz), 2.37 (tr, 2H, J= 8 Hz), 1.82-1.79 (m, 2H), 1.55-1.51 (m, 2H), 0.89 (d, 3H, J= 8 Hz).Example 28(26345fl,l722?a,24?)-27-Chloro-2^-(3-(4-chloro-3-methylphenoxy)propyl)-l4,l^- dimethoxy-24,31-dimethyl-l2-(l-methyl-ll / -l,2,4-triazol-3-yl)-21,22,2J,24-tetrahydro-212657-0002-WO01I1 / , 3}H-5 -oxa-2(2.6)-pvrazino| 1.2-^| indola- 1(7.1 )-ind()la-3(4.3)-pyr;iz()lacyclooctaph;in- l^-one

[0350] (General Procedure J). Intermediate 13 (1.0 eq, 0.2 M in THF) was added to 4-chloro-3-methyl phenol (2.0 eq) followed by addition of triphenyl phosphine (3.0 eq, 0.76 M in THF). The reaction was allowed to stir at RT for 2 minutes, followed by addition of azodicarboxylic dimorpholine (2.0 eq, 1.3 M in THF). The reaction was allowed to stir at RT overnight. The reaction was concentrated and purified by reverse phase HPLC eluting with MeCN / H2O with 0.1% TFA to afford the title compound (27 mg, 82% yield). LCMS (ESI) Method 4: RT = 1.712 min, m / z = 823.0 (M+H)+.

[0351] The compounds presented in Table 4 may be prepared using General Procedure J using appropriate starting materials.Table 4p A 'll NMR StartingNo. Structure Name and / or MaterialLCMS(2O3X, 1722T?a,24T?)-27-Chloro-21°-(3- LCMS (ESI) 1 f ( 3,5 -difluorophenoxy )propy 1)- 14, 13- Method 4: dimethoxy-24,3 -dimethyl- 12-( 1 -methy 1- Intermediate 13, RT = 1.571 293,5-difluorophenol \H- 1,2,4-triazol-3-yl)-21,22,23,24- min, m / z = tetrahydro-1 ’ / 7,3 ' 77-5-oxa-2(2,6)- 811.0 pyrazino [ 1,2 -a] indola- 1(7,1 )-indola- (M+H)+3(4,3 )-pyrazolacyclooctaphan-2 -one(2°3X,1722Ro,24R)-21°-(3-(Benzofuran- 6-yloxy (propyl )-27-chloro- 14, P- LCMS (ESI)Method 4: dimethoxy-24,31-dimethyl- 12-( 1 -methy 1- Intermediate 13, RT = 1.502 30benzofuran-6-ol 177-1,2,4-triazol-3-y l)-21,22,23,24- min, m / z = tetrahydro-1 77,3 ^77-5-oxa-2(2,6)- 815.0 py razino [ 1,2 -a] indola- 1 (7, 1 )-indola- (M+H)+3(4,3 )-pyrazolacyclooctaphan-2 -one212657-0002-WO01(2634Sa,l722Ra,24R)-27-Chloro-l4,l5- dimethoxy-24,3 -dimethyl- 1 1 -methy 1- LCMS (ESI) fIntermediate 13, lH-l,2,4-triazol-3-yl)-210-(3-(3-methyl- Method 4: 3-methyl-5- 5-(trifluoromethyl)phenoxy)propyl)- RT = 1.746 (trifluoromethyl)OM®2 '.22.23.24-tetrali\dro- 1 ' 77.3 ' / / -5-o\a- min, m / z = phenol 857.22(2,6 )-py razino [ 1,2 -a] indo la- 1(7,1)- (M+H)+indola-3(4,3)-pyrazolacyclooctaphan-2 ’ - one(26345a,l722Aa,24A)-27-Chloro-210-(3- f (3,4-dichlorophenoxy)propyl)-l4,!3- LCMS (ESI)Method 4: dimethoxy-2,3 -dimethyl- 1 -( 1-methyl- Intermediate 13, RT = 1.747,4-dichlorophenol 177-1,2,4-triazol-3-yl)-21,22,23,24- min, m / z = tetrahydro-1 ^H,3 ^77-5-oxa-2(2,6)- 844.8 0 py razino [ 1,2 -a] indo la- 1 ( 7, 1 )-indola- (M+H)+3(4,3 )-pyrazolacyclooctaphan-2 -onep A (2634SO,1722Ra,24R)-27-Chloro-21°-(3-(3- lluoro-5-methylphenoxy)propyl)- 14,13- LCMS (ESI)Method 4: Intermediate 13, dimethoxy-2 4,31 -dimethyl- 1? -( 1-methyl- RT = 1.598 3-fluoro-5- lH-l,2,4-triazol-3-yl)-21,22,23,24- min, m / z = methylphenoltetrahydro-1 77,3 7i-5-oxa-2(2,6)- 807.2 pyrazino[ 1,2-a]indola- 1 (7, 1 )-indola- (M+H)+3(4,3 )-pyrazolacyclooctaphan-2 -one (2634Sa,l722Aa,24A)-27-Chloro-210-(3-(4- chloro-3- LCMS (ESI) LNfAS.Intermediate 13, (trifluoromethyl)phenoxy)propyl)-l4,l3- Method 4: 4-chloro-3- " JCO-Q-O* dimethoxy-24,3 -dimethyl- 12-( 1 -methy 1- RT = 1.757 (trifluoromethyl) \H- 1,2,4-triazol-3-yl)-21,22,23,24- min, m / z = phenol 877.0 tetrahydro-11H,31H-5-oxa-2(2,6)- (M+H)+pyrazino[ 1,2-a]indola- 1 (7, 1 )-indola- 3(4,3 )-pyrazolacyclooctaphan-2 -one212657-0002-WO01(2634Sa,l722Ra,24R)-27-Chloro-l4,l5- dimethoxy-24,31 -dimethyl- 1 1 -methyl- LCMS (ESI)Method 4: Intermediate 13, lH-l,2,4-triazol-3-yl)-210-(3-(3,4,5- Rr = 1.905 3,4,5- 1 7 -2 4 trichlorophenoxy )propyl)-2,2,2,2 - min, m,'z = trichlorophenoltetrahydro-11H,3 ' / / -5-<>xa-2l'2.6 )- 879.0 o pyrazino [ 1,2-a] indo la- 1 (7, 1 )-indola- (M+H)+3(4,3)-pyrazolacyclooctaphan-2^-one(2634S„, 1722Ra,24R)-27-Chloro-21°-(3- a((2,3-dihydrobenzofuran-6-sLCMS (ESI) r2J 5 yl)oxy)propyl)-l4, P-dimethoxy-24,3^- Method 4: Intermediate 13, Adimethyl- 12-( 1 -methy 1- \H- 1,2,4-triazol- RT = 1.842 2,3-dihydrobenzoV min, m / z = furan-6-ol 3-yl)-21,22,23,24-tetrahydro-l1 / / ,31 / / -5- 1 Oi o- 817.0 oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l )- (M+H)+indola-3(4,3)-pyrazolacyclooctaphan-2^- O K z— onep A- (263X,1722Aa,24A)-27-Chloro-21°-(3-(4- oX I chlorophenoxy )propyl)- 14,13-dimethoxy- LCMS (ESI) N-N 1 1 A.J Method 4: r~ OMe 24,31 -dimethyl- 12-( 1 -methyl- \H- 1,2,4- Intermediate 13, RT = 1.666 (Me4-chlorophenol triazol-3-yl)-21,22,2J,24-tetrahydro- min, mi'z = ^*0 11 / 7,3 l / 7-5-oxa-2(2,6)-pyrazino[l,2- 809.0 a]indola-l(7,l)-indola-3(4,3)- (M+H)+Cl pyrazolacyclooctaphan-21-one / (2634Sa,l722Aa,24A)-27-Chloro-21°-(3-(3- rN- chlorophen LCMS (ESI) XNf oxy )propy 1)- 14, 13-dimethoxy- N-N I LNASS Method 4:24,31 -dimethy l-l2-( 1 -methyl- 177- 1,2,4- Intermediate 13, CI^XLNQN-Q-0"' RT = 1.626 3-chlorophenol triazol-3-yl)-21,22,23,24-tetrahydro- min, m,'z =11 / 7,3 l / 7-5-oxa-2(2,6)-pyrazino[l,2- '~-o 809.0 a\ indola- 1(7,1 )-indola-3(4,3 )- (M+H)+tXc,pyrazolacyclooctaphan-21-one212657-0002-WO01 / (2634Sa,l722Ra,24R)-27-Chloro-210-(3- / rN.(3,4-dichloro-5-methylphenoxy)propyl)- LCMS (ESI) 14, 17-dimethoxy-24,3 -dimethyl- 12-(1 - Method 4: Intermediate 13,methyl- IH- 1,2,4-triazol-3-yl)- RT = 1.856 3,4-dichloro-5-0Memin, m / z = methylphenol 21,22,23,24-tetrahydro-l 1 / 7,3 l / f-5-oxa- '~-o 2(2,6)-pyrazino [ 1,2-a] indo la- 1(7,1)- 857.2 of l (M+H)+indola-3(4,3)-pyrazolacyclooctaphan-2^- dfc-c,nrX OZ, _. one(2634SO,1722T?O,24A)-210-(3-(3,5- n xNf \“= ots Bis(difluoromethyl)phenoxy )propyl)-2 - LCMS (ESI) Intermediate 13, n chloro- 14, 15-dimethoxy-24,31 -dimethyl- Method 4:3,5- ‘XO-O'* 12-(l -methyl- 1H- 1,2,4-triazol-3-y 1)- RT = 1.487oMebis(difluoromethyl) min, m / z =21,22,23,24-tetrahydro- 1 ' / / .? l / / -5-oxa- phenol '■'-O 875.22(2, 6 )-py razino [ 1,2-a] indo la- 1(7,1)- A,F(M+H)+indola-3(4,3)-pyrazolacyclooctaphan-2^- Fone(2°3X, 1722Ra,24R)-27-Chloro- 14, 15- dimethoxy-2 4,31 -dimethyl- 1? -( 1-methyl- LCMS (ESI)Method 4: \H- 1,2,4-triazol-3-yl)-210-(3- Intermediate 13, RT = 1.973 naphthalen-2-ol (naphthalen-2-yloxy )propyl)-2,27,2^,24- min, m / z = tetrahydro-1 ^H-5-oxa-2(2,6)- 825.0 pyrazino [ 1,2-a ] indola- 1(7,1 )-indola- (M+H)+3(4,3 )-pyrazolacyclooctaphan-2 -one / 12"3 IS’,,.1722Ra,24R )-27-Chloro-21°-(3- xNf (3,5-dichlorophenoxy )propy 1)- 14.!7’- LCMS (ESI)Method 4: dimethoxy-24,31-dimethyl- 17-( 1 -methy 1- Intermediate 13, CI^XN^N-Q-0"' RT = 1.816 3,5-dichlorophenolOMe1 / / - 1.2,4-triazol-3-y l)-21,22,23,24- min, m / z = '-0 tetrahydro-1 ^H,3 ^H-5-oxa-2(2,6)- 845.2 py razino [ 1,2 -a] indola- 1 (7, 1 )-indola- (M+H)+CL 3(4,3 )-pyrazolacyclooctaphan-2 -one212657-0002-WO01(2634Sa,l722Ra,24R)-27-Chloro-210-(3- (3,5-dichloro-4- P LCMS (ESI) methoxy phenoxy )propy 1)- 14, 13- Method 4: Intermediate 13,dimetho xy-24, 3 -dimethyl- 12-( 1 -methy 1- RT = 1.712 3,5-dichloro-4- min, mz = methoxyphenol \H- 1,2,4-triazol-3-yl)-21,22,23,24- 875.0 tetrahydro-11H,31H-5-oxa-2(2,6)- tK (M+H)+py razino [ 1,2-a] indo la- 1(7,1 )-indo la- 30, 3 )-pyrazolacyclooctaphan-23-one(2634Sa, 1722A„,24A)-27-Chloro-21°-(3- (3,5-ditluoro-4-methoxyphenoxy)propyl)- f LCMS (ESI) l4, 13-dimethoxy-24,31-dimethyl- 12-( 1 - Method 4: Intermediate 13,methyl- 1H- 1,2,4-triazol-3-y 1)- RT = 1.883 3,5-difluoro-4- min, m / z = methoxyphenol 21,22,23,24-tetrahydro- 1 P,3 P-5-oxa- 2(2,6)-pyrazino [ 1,2-a] indo la- 1(7,1)- 841.0 (M+H)+indola-3(4,3)-pyrazolacyclooctaphan-2^- one(2°3X, 107L.24P )-27-Chloro- 14, 15- LCMS (ESI) p L Y dimethoxy-2,3 -dimethyl- 1 -( 1-methyl-NAS Method 4:\H- 1,2,4-triazol-3-yl)-210-(3- Intermediate 13, CIJCO-O'0"6RT = 1.480 Phenol Up phenoxypropyl)-2 ',22.27,24-tetrahydro- min, m / z =1 P,3 P-5-oxa-2(2,6)-pyrazino[l,2- 775.0 a\ indola- 1(7,1 )-indola-3(4,3 )- (M+H)+py razolacyclooctaphan-2 -one(2°345a, 1722Ra,24R )-27-Chloro-21°-(3- LCMS (ESI) p f (3,5-dimethylphenoxy)propyl)-l4,l3- Method 4: dimethoxy-24,31-dimethyl- 12-( 1 -methy 1- Intermediate 13, X Y t RT = 1.976,5-dimethylphenol \H- 1,2,4-triazol-3-y l)-21,22,23,24- min, m / z = tetrahydro-1 P,3 H-5-oxa-2(2,6)- 803.2 py razino [ 1,2 -a] indola- 1 (7, 1 )-indo la- (M+H)+30, 3 )-pyrazolacyclooctaphan-2 -one212657-0002-WO01(26345fl,l722l?fl,2^1?)-2^-Chloro-21®-(3-(4-fluoro-3-methylphenoxy)propyl)-l^,l^- dimethoxy-24,3^-dimethyl-12-(l-methyl-l / / -l,2,4-triazol-3-yl)-21,2^,2^,2^-tetrahydro- I’ / ZA' / LS -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 21-one

[0352] (General Procedure N) Intermediate 13 (1.0 eq) in MeCN (1 mL) was added to a solution of triphenyl phosphine (2.0 eq) in MeCN (1 mL). CBr4(2.0 eq in 0.5 mL of MeCN) was added dropwise. The reaction was allowed to stir at RT overnight, followed by concentration. The crude residue was taken up in THF (0.5 mL). 4-Fluoro-3 -methyl phenol (2.0 eq) was added, followed by Cs2CO3(6.0 eq). The resultant suspension was stirred at 55 °C overnight. The reaction was concentrated, dissolved in MeOH, and purified by reverse phase HPLC eluting with MeCN / H2O with 0.1% TFA to afford the title compound (26 mg, 25% yield). LCMS (ESI) Method 4: RT = 1.592 min, m / z = 807.0 (M+H)+.

[0353] The compounds presented in Table 5 may be prepared using General Procedure N using appropriate starting materials.212657-0002-WO01Table 5‘H NMR StartingNo. Structure Name and / or Material / yieldLCMS( 2634S„, 1722Aa,24J?)-27-Chloro-210-(3- n ((2,3-dihydrobenzofuran-5- LCMS (ESI) df<- yl)oxy )propyl)- 14,13-dimethoxy-24,3 - Method 4: Intermediate 13,dimethyl- 17-( 1 -methyl- IH- 1,2,4-triazol- RT = 1.398 39 2,3-dihydrobenzomin, m / z = 817.0 oxa-2(2,6)-pyrazino[l,2-a]indola- 1(7,1 )-1i (M+H)+indola-3(4,3 )-pyrazolacyclooctaphan-2 - one(263X,l722Ra,24R)-27-Chloro-210-(3-(4- chloro-3,5-difluorophenoxy)propyl)- LCMS (ESI) 1 1=N / 14, 13-dimetlio\ v-24.31-dimethyl- 12-( 1 - Method 4: Intermediate 13,methyl- I / / -I.2.4-triazol-3-yl)- RT = 1.703 42 4-chloro-3,5- °He21,22,23,24-tetrahydro- 1 ^H,3 ^H-5-oxa- min, m / z =2(2,6)-pyrazino [ 1,2-a] indola- 1(7,1)- 8452 (M+H)+indola-3(4,3)-pyrazolacyclooctaphan-2 - one(2°3X, 1722Ra,24R)-27-Chloro-21°-(3- ((6-fluoronaphthalen- 1 -y l)oxy )propy 1)- LCMS (ESI) l4,l3-dimethoxy-24,3^-dimethyl-l2-(l- Method 4: Intermediate 13,methy 1-1 / 7- 1,2,4-triazol-3-yl)- RT = 1.724 46 6-lluoromin, m / z = 21,22,23,24-tetrahy dro- 1 ^H,3 ^H-5-oxa- 2(2,6)-pyrazino [ 1,2-a] indola- 1 (7, 1 )- 843.0 (M+H)+indola-3(4,3)-pyrazolacyclooctaphan-2 - one( 263 X, 1722Aa,24 / ?)-27-Chloro-210-(3- / ((2,3-dihydro-l / 7-inden-5- LCMS (ESI) 1 1 JL yl)oxy )propyl)- 14,13-dimethoxy-24,3 - Method 4: Intermediate 13,dimethyl- 12-( 1 -methyl- 1H- 1,2,4-triazol- RT = 1.726 48 2,3-diliydro-lH-CT V \iLjjsUf S)oMemin, m / z =3-yl)-21,22,23,24-tetrahydro-l1 / / ,31 / / -5- inden-5-ol815.2 oxa-2(2,6)-pyrazino[l,2-a]indola- 1(7,1 )- (M+H)+indola-3(4,3 )-pyrazolacyclooctaphan-2 - one212657-0002-WO01(2634Sa,l722T?a,24T?)-27-Chloro-l4,l5- dimethoxy-2 ®-(3-(4-methoxy-3,5- LCMS (ESI) Hrd dimethylphenoxy )propy l)-24,3 - Method 4: Intermediate 13,dimethyl- 12-( 1 -metliy 1- 1H- 1,2,4-triazol- RT = 1.575 2,3-diliydro-177- min, m 'z = inden-5-ol 3-yl)-21,22,23,24-tetrahydro-lO o 833.2 oxa-2(2,6)-pyrazino[ 1,2-a]indola- 1(7, 1 )- (M+H)+indola-3(4,3 )-pyrazolacyclooctaphan-2 - O z^oneA / y r (2634S„, 1 ’27?„,24 / <)-27-Chloro- 14, 15- XY cVr YSJ X dimethoxy-24,31-dimethyl- 12-( 1 -methyl- LCMS (ESI) * g o n177-1, 2, 4-triazol-3-yl)-210-(3-((5, 6,7,8- Method 4: Intermediate 13,tetrahy dronaphthalen- 1 -y l)oxy )propy 1)- RT = 1.868 5,6,7,8-tetrahydromin, m / z = 21,22,2?,24-tetrahydro- 1 ' 77,3 77-5-oxa- 829.2 2(2,6)-pyrazino [ 1,2-a]indola- 1(7,1)- (M+H)+indola-3(4,3)-pyrazolacyclooctaphan-2^- one / (2634S„, 1722T?a,24T?)-27-Chloro- 14,15- / rN- dimethoxy-24,3 -dimethyl- 12-( 1 -methyl- LCMS (ESI) Intermediate 13, l / / -l.2.4-triazol-3-\l )-2l (l-(3-(4-incth\l- Method 4: 4-methyl-3- Ci^XN^N-O'0"63 -(trifluoromethy l)phenoxy )propy 1)- RT = 1 756 (trifluoromethyl)oM® min, m / z =21,22,23,24-tetrahy dro- 1 77,3 ^77-5-oxa- phenol '-o 857.02 (2,6)-py razino [ 1,2 -a] indola- 1 (7, 1 )- A / (M+H)+\ F indola-3(4,3)-pyrazolacyclooctaphan-2^- one(26345a, 17227?a,24T?)-27-Chloro-210-(3- ((2,3-dihydro-177-inden-4- LCMS (ESI) yl)oxy )propyl)- 14,13-dimethoxy-24,3 - Method 4: Intermediate 13,dimethyl- 12-( 1 -metliy 1- 177- 1,2,4-triazol- RT = 1.757 2,3-dihydro-lH- min, m / z = inden-4-ol 3-yl)-21,22,23,24-tetrahydro-l177,3177-5- 815.2 oxa-2(2,6)-pyrazino[l,2-a]indola- 1(7,1 )- (M+H)+indola-3(4,3)-pyrazolacyclooctaphan-2 - one212657-0002-WO01Example 58(26345fl,l722l?«,241f)-2^-Chloro-2^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(hydro ymethyl)-14,l^-dimetho y-24,3^-dimethyl-2^,22,2^,24-tetrahydro-l^ / / ,3^-5-oxa- 2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan-2^-one

[0354] Intermediate 6 (100 mg, 0.12 mmol, 1.0 eq) was stirred in DCM (1.0 mL) with DIEA (0.090 mL, 0.50 mmol, 4.2 eq) at 0°C. Isobutyl chloroformate (21 mg, 0.16 mmol, 1.3 eq) was added, followed by the DMAP (1 mg, 0.01 mmol, 0.1 eq). The reaction was stirred 10 min, then warmed to RT and stirred for 1 h. The reaction showed partial conversion by LCMS, so an additional aliquot of isobutyl chloroformate (21 mg, 0.16 mmol, 1.3 eq) was added and the reaction was stirred overnight at RT. The reaction was extracted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The crude residue was dissolved in EtOH (1.3 mL) and THF (0.5 mL) at 0 °C under argon. NaBH4 (10 mg, 0.28 mmol) was added and the reaction was stirred for 1 h. The reaction was quenched by addition of IM HC1, extracted with EtOAc, washed with brine, then dried over MgSO4and concentrated. The crude residue was purified by reverse phase HPLC to afford the title compound (45 mg, 45% yield). LCMS (ESI) Method 1: RT = 2.31 min, m / z = 786.0 (M+H)+.212657-0002-WO01Example 59(26345fl,l722l?fl,2^1f)-2^-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15- hydroxy-l4-methoxy-24,31-dimethyl-12-(l-methyl-l / -l,2,4-triazol-3-yl)-2^,22,2^,24- tetrahydro-l^ / / ,3^-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21 -one

[0355] Step A: (47?)-2-(5-(Benzyloxy)-4-methoxy-2-(l-methyl-lZ / -l,2,4-triazol-3-yl)-l / -indol-7-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(l-methyl-3-((3-((tetrahydro-2 / / -pyran-2-yl)oxy)propoxy)methyl)-177-pyrazol-4-yl)-3,4-dihydropyrazino[l,2-a]indol-l(2 / / )-one. The title compound (1.25 g, 70% yield) was prepared following General Procedure A using Intermediate 8 (1.20 g, 1.76 mmol, 1.0 eq) and Intermediate 10 (1.62 g, 3.51 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.902 min, m / z = 935.8 [M+H-79]+.

[0356] Step B: ( / ?)-2-(5-(Benzyloxy)-4-methoxy-2-(l-methyl-l / / -l,2,4-triazol-3-yl)-l / / -indol-7-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-l / 7-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[l,2-ff]indol-l(2H)-one. The product from Step A (1.25 g, 1.23 mmol, 1.0 eq) was dissolved in MeOH (12 mL). Tosic acid monohydrate (25 mg, 0.123 mmol, 0.1 eq) was added, and the reaction was heated to 45 °C for 48 h. The reaction was extracted with EtOAc, washed with aq. NaHCO3, brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0 to 10% MeOH in DCM to afford the title compound (850 mg, 74% yield). LCMS (ESI) Method 2: RT = 1.606 min, 1.645 min (mixture of rotamers), m / z = 931.0 [M+H]+.212657-0002-WO01

[0357] Step C: (7?)-3-((4-(2-(5-(Benzyloxy)-4-methoxy-2-(l-methyl-l / 7-l,2,4-triazol-3-yl)-l / / -indol-7-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-l-oxo-1,2,3, 4-tetrahydropyrazino[ 1, 2-a]indol-6-yl)-l -methyl- l / 7-pyrazol-3-yl)methoxy)propyl 4-methylbenzenesulfonate. The title compound (830 mg, 84% yield) was prepared following General Procedure C using the product from Step B (850 mg, 0.912 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.835 min, 1.864 min (mixture of rotamers), m / z = 1084.9 [M+H]+.

[0358] Step D: (26345fl,l722 / ?(,,24 / ?)-l5-(Benzyloxy)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4-methoxy-24,34-dimethyl-12-(l-methyl-l / f-l,2,4-triazol-3-yl)-24,22,2^,24-tetrahydro-l4 / f,34l / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The title compound (510 mg, 67% yield) was prepared following General Procedure D using the product from Step C (800 mg, 0.736 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.801 min, m / z = 912.9 [M+H]+.

[0359] Step E: (2634&,l722T?„,24^)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15-hydroxy-l4-methoxy-24,31-dimethyl-l7-(l-methyl-lZ / -l,2,4-triazol-3-yl)-21,2^,2^,24-tetrahydro- 11 / 7,31 / 7-5 -oxa-2(2,6)-pyrazino[l,2-tz]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The title compound (400 mg, 87% yield) was prepared following General Procedure B using the product from Step D (510 mg, 0.558 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.385 min, m / z = 823.0 [M+H]LExample 60(2^345fl,l722l?a,24l?)-27-Chloro-2111-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l7- (hydroxymethyl)-l -methoxy-l4,24,31 -trimethyl-21,2^,2^,24-tetrahydro-l 1 / 7,31 / 7-5-oxa- 2(2,6)-pyrazino[l,2-cz]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one212657-0002-WO01

[0360] Step A: (26345fl,l7227?fl,24T?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15-methoxy-l4,24,31-trimethyl-21-oxo- 21, 2^,2, 24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphane-l^-carboxylic (isobutyl carbonic) anhydride. Intermediate 7 (300 mg, 0.38 mmol, 1.0 eq) was stirred in DCM (4 mL) with DIEA (0.27 mL, 1.6 mmol, 4.2 eq) at 0 °C. Isobutyl chloroformate (104 mg, 0.76 mmol, 2.0 eq) was added dropwise followed by DMAP (5 mg, 0.04 mmol, 0.1 eq). The reaction was allowed to stir for 10 min at 0 °C then warmed to RT for 48 h. The reaction was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 80% EtOAc / MeOH (95:5) in hexanes to afford the title compound (77 mg, 23% yield). LCMS (ESI) Method 2: RT = 2.43 min, m / z = 884 (M+H)+.

[0361] Step B: (2634&,l722l?«,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l7-(hydroxymethyl)-l^-methoxy-l4,24,3^-trimethyl-2 '.2-.2\2^-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyraziiio|1.2-^|indola-l(7.l )-indola-3(4.3)-pyrazolacyclooctaphan-21-one. The product from Step A (77 mg, 0.10 mmol, 1.0 eq) was stirred in THF (1 mL) at 0 °C under argon. Sodium borohydride (7 mg, 0.2 mmol, 2.0 eq) was dissolved in MeOH and added to the reaction. The reaction was allowed to stir for 45 min. The reaction was quenched by addition of IM HC1, extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 70% EtOAc / MeOH (95:5) in hexanes to afford the title comopound (25 mg, 38% yield). LCMS (ESI) Method 1: RT = 2.44 min, m / z = 770 (M+H)+.212657-0002-WO01Example 61(263 5a,l722lffl,2^1?)-2^-Chloro-2^(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,l^- dimethoxy-12-((2-methoxyethoxy)methyl)-24,3 -diinethyl-2,22,2J,24-tetrahydro- I1H, 3^-5 -oxa-2(2,6)-pyrazino[l,2-6z]indola-l(7,l)-indola-3(4,3)-pyi*azolacyclooctaphan- 2^-one

[0362] (General Procedure K) Example 58 (50 mg, 0.06 mmol, 1.0 eq) was dissolved in DMF (0.3 mL) at 0 °C. Sodium hydride (60 wt.%, 4 mg, 0.10 mmol, 1.7 eq) was added and the reaction was stirred for 15 min. 2-Bromoethyl methyl ether (0.020 mL, 0.21 mmol, 3.5 eq) was added and the reaction was warmed to RT and stirred at 35 °C for 36 h. The reaction was diluted with EtOAc and water, extracted with EtOAc, washed with H2O, sat. aq. NH4CI, sat. aq. Na2CO3, and brine, dried over MgSCU, filtered, and concentrated. The crude product was purified by reverse phase HPLC to afford the title compound (29 mg, 57% yield). LCMS (ESI) Method 1: RT = 2.44 min, m / z = 844 (M+H)+.Example 62(2^3^. S„.1 2“ / ?„,2^ / ?)-2^-( hloro-2 ' ■’-(3-(4-clil()ro-3.5-dimetliylphenoxy)propyl)-l ^.1 - dimethoxy-12-(methoxymethyl)-24,31 -dimethyl-21,2^,2^,2^-tetrahydro-l ^H,3 ^H-5-oxa- 2(2,6)-pyrazino[l,2-cz]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0363] The title compound (40 mg, 78% yield) was prepared following General Procedure K using Example 58 (50 mg, 0.06 mmol, 1.0 eq) and Mel (0.020 mL, 0.32 mmol, 5.3 eq). The crude material was purified by flash column chromatography eluting with 0 to 60% EtOAc: MeOH (95:5) in hexanes to afford the product. LCMS (ESI) Method 2: RT = 1.67 min, m / z = 800 (M+H)+.212657-0002-WO01Example 63(26345a,l722^«,24?)-2^-Chloro-2^-(3_(4-Chloro-3,5-dimethylphenoxy)propyl)-12-(2-hydroxypropan-2-yl)-14,15_(jimej|loXy_24931_(jimej|1y|_2192292^,24-tetrahydro-l^ / / ,3^-5- oxa-2(2,6)-pyrazino[l,2-6']indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan-21-one

[0364] Intermediate 6A (147 mg, 0.18 mmol, 1.0 eq) was stirred in THF (1 mL) under argon at -78 °C. Methyl lithium (1.6 M, 0.35 mL, 0.6 mmol, 3.3 eq) was added dropwise, and the reaction was allowed to stir for 2 h. The reaction was treated with ice water dropwise, then warmed to RT and diluted with EtOAc. The reaction was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The crude product was purified by reverse phase HPLC to afford the title compound (47 mg, 32% yield). LCMS (ESI) Method 2: RT = 1.67 min, m / z = 814 (M+H)+.Example 64212657-0002-WO01(2^3^. S„.1 2" / ?„,2^ / ?)-2^-( hloro-2 ' ■'-(3-(4-chloi o-3.5-[|iniethvlphenoxy)propyl)-l ^.1 - dimethoxy-2^,31 -dimethyl-12-((2-morpholinoethoxy)methyl)-21,2^,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 2^-one

[0365] The title compound (42 mg, 37% yield) was prepared following General Procedure K using Example 58 (100 mg, 0.13 mmol, 1.0 eq) and 4-(2-bromoethyl)-morpholine hydrobromide (45 mg, 0.17 mmol, 1.3 eq). After reacting for 2 h, the reaction had only reached partial conversion by LCMS. A second portion of 4-(2-bromoethyl)-morpholine hydrobromide (45 mg, 0.17 mmol, 1.3 eq) and NaH (60 wt.%, 10 mg, 0.28 mmol, 2.2 eq) were added, and the reaction was allowed to stir an additional 4 h. LCMS (ESI) Method 1: RT = 1.98 min, m / z = 899 (M+H)+.Example 65 (263^. S„.1 2‘ / ?„,2^ / ?)-2^-( hloro-2 '^-(3-(4-chloro-3,5-diiiiethylphenoxy)propyl)-l^.lS- dimethoxy-24,3^-dimethyl-l^-((pyridin-4-ylmethoxy)methyl)-2^,22,2^,24-tetrahydro--oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi*azolacyclooctaphan- 2^-one

[0366] The title compound (14 mg, 12% yield) was prepared following General Procedure K using Example 58 (100 mg, 0.13 mmol, 1.0 eq) and 4-(bromomethyl)pyridine hydrobromide (42 mg, 0.17 mmoles, 1.3 eq). After allowing to react for 2 h, the reaction failed to reach complete conversion. An additional aliquot of 4-(bromomethyl)pyridine hydrobromide (42 mg, 0.17 mmoles, 1.3 eq) and NaH (60 wt.%, 10 mg, 0.28 mmol, 2.2 eq) was added and the212657-0002-WO01reaction was allowed to stir overnight. LCMS (ESI) Method 1: RT = 2.05 min, m / z = 877 (M+H)+.Example 66 (2^3’l. S'„.l72' / ?„.2'l / ?)-27-( liloio-2 '^-(3-(4-chloro-3.5-diinethy Iphenoxy (propyl )-l --((2- (dimethylamino)ethoxy)methyl)-14,l 5-dimethoxy-24,31 -dimethyl-21,2^,2^,24-tetrahydro--oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi*azolacyclooctaphan- 21-one

[0367] The title compound (32 mg, 25% yield) was prepared following General Procedure K using Example 58 (115 mg, 0.15 mmol, 1.0 eq) and (2-bromoethyl)dimethylamine hydrobromide (70 mg, 0.30 mmol, 2.0 eq). LCMS (ESI) Method 1: RT = 1.84 min, m / z = 857 (M+H)+.Example 67(2^3^S'„.l72' / ?„.2"l / ?)-2^-( lil()io-2 'l,-(3-(4-clil()ro-3.5-dinietliylplienoxy)propyl)-l--((2- (dimethylamino)ethoxy)methyl)-13-(2-(dimethylamino)ethyl)-14,1 -dimethoxy-24,31-212657-0002-WO01dimethyl-21,2^,2^,24-tetrahydro- 11 H,31 H-5 -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)- indola-3(4,3)-pyrazoIacyclooctaphan-21 -one

[0368] The title compound (30 mg, 23% yield) was isolated from the reaction conditions described for Example 66. LCMS (ESI) Method 1: RT = 1.72 min, m / z = 928 (M+H)+.Example 68(26345a,l722 / ?a,24lf)-27-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12- (hydroxymethyl)-l4-methoxy-24, 3 l-dimethyl-1 -(2-morpholinoethoxy)-21,22,2^,24- tetrahydro-11 / 7, 31 / / -5-oxa-2(2,6)-pyrazino[l,2-rz]indola-l(7,l)-indola-3(4, 3)- pyrazolacyclooctaphan-21 -one

[0369] Step A: Ethyl ((26345fl,l7227?fl,24T?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4-methoxy-24,31-dimethyl-1 -(2-morpholinoethoxy)-21-oxo-21,22,2^,24-tetrahydro-ll / / ,31 / f-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-P-carboxylate. The title compound (430 mg, 81% yield) was prepared following General Procedure I using Intermediate 14A (467 mg, 0.573 mmol, 1.0 eq) and 4-(2-bromoethyl)morpholine hydrobromide (315 mg, 1.15 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.300 min, m. / z = 927.0 (M+H)+.

[0370] Step B: (26345fl,l722^fl,24^)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4-methoxy-24,31-dimethyl-15-(2-morpholinoethoxy)-21-oxo-21,22,2^,24-tetrahydro-ll / / ,31 / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carboxylic acid. The title compound (380 mg, 91% yield) was212657-0002-WO01prepared following General Procedure E using the product from Step A. LCMS (ESI) Method 2: RT = 1.016 min, m / z = 898.9 (M+H)+.

[0371] Step C: (26345fl,l722?fl,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(hydroxymethyl)-l4-methoxy-24,3^-dimethyl-l^-(2-niorpholinoethoxy)-2 '.2-.2 '.2^-teti ahydro-l ' / / .3 ' / / -5-oxa-2(2.6)-pyrazino|1.2-6 / |indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The product from Step B (380 mg, 0.423 mmol, 1.0 eq) was dissolved in DCM (5 mL) and DIPEA (0.3 mL, 1.69 mmol, 4.0 eq) was added at 0 °C. Isobutyl chloroformate (115 mg, 0.84 mmol, 2.0 eq) was added dropwise followed by addition of DMAP (5 mg, 0.04 mmol, 0.1 eq). The reaction was allowed to stir for 10 min at 0 °C then warmed to RT and stirred overnight. The reaction was extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude residue was taken up in THF / MeOH (5 mL / 1 mL)) and NaBH4 (35 mg, 0.92 mmol, 2.0 eq) was added. The reaction was stirred for 1 h. The reaction was quenched by addition of IM HC1, extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude material was purified by reverse phase HPLC to afford the title compound (90 mg, 24% yield).Examples 69 / 70(26345a,l722?fl,24l?)-27-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l7-((7?)-l- hydroxyethyl)- H.l -dimethoxy-2^.3 ' -dimethyl-2 ',2-.2\2^-tetrahydro- 1 ' / / .3 ' / / -5-oxa- 2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one212657-0002-WO01(2^34S„.1 2" / ?„.24 / ?)-27-( hloio-2 '('-(3-(4-chloio-3.5-[|inietliylphenoxy)piopyl)-l--((S)-l- hydroxyethyl)-l4,l -dimethoxy-24,31 -dimethyl-21,22,2^,2^-tetrahydro-l ^H,3 ^H-5-oxa- 2(2 / >)-pyrazino| 1.2-( / |indol;i-l (7.1 )-iiidol;i-3(4.3)-pyrazolacyclooctaphan-2 '-one

[0372] Intermediate 11 (75 mg, 0.10 mmol, 1.0 eq) was dissolved in THF (1 mL)) under argon at -78 °C. Methyl magnesium bromide (3.4 M in 2-MeTHF, 0.050 mL, 0.15 mmol, 1.5 eq) was added dropwise. The reaction was stirred for 15 min at -78 °C, and then stirred at 0 °C for 1 h. The reaction was diluted with EtOAc and quenched by slow addition of sat. aq.NaHCO3. The reaction was extracted with EtOAc, washed with water, brine, dried over M SO4, and concentrated. The crude product was purified by reverse phase HPLC to afford 25 mg of an earlier eluting diastereomer (Example 69) and 33 mg of a later eluting diastereomer (Example 70), without determination of the alcohol stereochemistry. Example 69: LCMS (ESI) Method 2: RT = 1.49 min, m / z = 800 (M+H)+. Example 70: LCMS (ESI) Method 2: RT = 1.50 min, m / z = 800 (M+H)+.Examples 71 / 72(2^3^. S„.1 2‘ / ?„.2^ / ?)-2^-( hloro-2 '"-(3-(4-chloro-3.5-diinethylphenoxy)propyl)-l--((5)-l- hydroxyethyl)-l4-methoxy-24,31 -dimethyl-1 ^-(2-morpholinoethoxy)-21,22,2^,24- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino|1.2-^|indola-l(7.1 )-indola-3(4,3)- pyrazolacyclooctaphan-21 -one(26345fl,l722^,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l2-(( )-l- hydroxyethyl)-l4-methoxy-24,3^-dimethyl-l^-(2-morpholinoethoxy)-21,22,2J,24-212657-0002-WO01tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyi azino|L2-( / |iiidola-l(7.1 )-indola-3(4.3)- pyrazoIacydooctaphan-21 -one

[0373] Step A: (26345„,l722 / ?fl,24 / ?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4-methoxy-24,34-dimethyl-1 -(2-morpholinoethoxy)-21-oxo-24,2^,2^,24-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino| l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carbaldehyde. Example 68 (90 mg, 0.10 mmol, 1.0 eq) was dissolved in DCM (1.5 mL) at RT under argon. In a separate vessel, Dess-Martin periodinane (60 mg, 0.14 mmol, 1.4 eq) was dissolved in DCM (1 mL) and pyridine (24 mg, 0.3 mmol, 3.0 eq) was added. The Dess-Martin periodinane solution was allowed to stir for 5 min, after which time it was added to the solution of Example 68. The reaction was stirred at RT for 2 h. The reaction was extracted with DCM, washed with H2O, dried over MgSCU, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 6% MeOH in DCM with 0.1% NH4OH additive to afford the title compound (80 mg, 89% yield). LCMS (ESI) Method 1: RT = 2.11 min, m / z = 883 (M+H)+.

[0374] Step B: (26345fl,l7227?fl,24T?)-27-ChIoro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l7-((S)-l-hydroxyethyl)-l4-methoxy-24,31-dimethyl-1 -(2-morpholinoethoxy)-21,22,2,24-tetrahydro-l / / ,31 / / -5-oxa-2(2,6)-pyrazino[l,2-o']indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one and (263450,l722l?fl,24l?)-27-Chloro-2^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l7-((7?)-l-hydroxyethyl)-l4-methoxy-24,3^-dimethyl-l -(2-m()rph()linoethoxy)-2 '^-^^-tetrahydro-l ' / / .3 / / -5-oxa-2(2.6)-pyrazino[l,2-rz]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The product from Step A (80 mg, 0.09 mmol, 1.0 eq) was stirred in THF (1 mL) under argon at -78 °C. Methyl magnesium bromide (3.4 M in 2-MeTHF, 0.040 mL, 0.14 mmol, 1.5 eq) was added dropwise. The reaction was allowed to stir for 15 min at -78 °C, and then allowed to stir at 0 °C for 1 h., after which time the reaction was determined to have reached partial conversion by LCMS. An additional aliquot of methyl magnesium bromide (3.4 M in 2-MeTHF, 0.030 mL, 0.1 mmol, 1.1 eq) was added and the reaction was allowed to stir an additional 1 h. The reaction was diluted with EtOAc and quenched by slow addition of sat. aq. NaHCCL. The212657-0002-WO01reaction was extracted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated. The crude product was purified by reverse phase HPLC to afford 24 mg of an earlier eluting diastereomer (Example 71) and 36 mg of a later eluting diastereomer (Example 72), without determination of the alcohol stereochemistry. Example 71: LCMS (ESI) Method 1: RT = 2.03 min, m / z = 899 (M+H)+. Example 72: LCMS (ESI) Method 1: RT = 2.07 min, m / z = 899 (M+H)+.Examples 73 / 74(26345a,l722l?a,2^1f)-2^-Chloro-2^(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-((l?)-l- hydroxypropyl)-l4,l^-dimethoxy-24,31-dimethyl-2^,22,2^,24-tetrahydro-l^ / f,3^77-5-oxa- 2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one(26345a,l722l?fl,24l?)-2^-Chloro-2^(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-((5)-l- hydroxypropyl)-l4,l^-dimethoxy-24,31-dimethyl-2^,22,2J,24-tetrahydro-l^ / f,3^77-5-oxa- 2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0375] Intermediate 11 (209 mg, 0.27 mmol, 1.0 eq) was stirred in THF (3 mL) under argon at -78 °C. Ethyl magnesium bromide (1.0 M in THF, 0.4 mL, 0.40 mmol, 1.5 eq) was added dropwise, and the reaction was allowed to stir at -78 °C for 15 min, followed by 0 °C for Ih. A second aliquot of ethyl magnesium bromide (1.0 M in THF, 0.4 mL, 0.40 mmol, 1.5 eq) was added and the reaction was stirred for 1 h. The reaction was extracted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated. The crude product was purified by reverse phase HPLC to afford 19 mg of an earlier eluting diastereomer (Example 73) and 39 mg of a later eluting diastereomer (Example 74), without determination of the alcohol212657-0002-WO01stereochemistry. Example 73: LCMS (ESI) Method 2: RT = 1.52 min, m / z = 814 (M+H)+. Example 74: LCMS (ESI) Method 2: RT = 1.54 min, m / z = 814 (M+H)+.Examples 75 / 76(26345fl,l722^«,247?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l5- dimethoxy-l7-((7?)-l-methoxypropyl)-24,3^-dimethyl-21,27,2^,24-tetrahydro-1^7 / ,3^7 / -5- oxa-2(2,6)-pyrazino[l,2-rz]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-2^-one(26345fl,l722?«,24l?)-27-Chloro-2^(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-l7-((6’)-l-methoxypropyl)-24,3^-dimethyl-21,27,2J,24-tetrahydro-1^77,3^7f-5- oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-2^-one

[0376] The title compounds (10 mg, 4% yield) were isolated from the same reaction conditions described for Examples 73 and 74 after being allowed to stand overnight in acidic MeOH following reverse phase HPLC purification. Example 75 (from Example 73): LCMS (ESI) Method 2: RT = 1.79 min, m / z = 828 (M+H)+. Example 76 (from Example 74): LCMS (ESI) Method 2: RT = 1.79 min, m / z = 828 (M+H)+.212657-0002-WO01Example 77(26345fl,l722?a,247?)-2^-Chloro-2^<-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15- methoxy-14,24,3l-tnmethyl-12-(morpholinomethyl)-2',22,2^,24-tetrahydro-l ' / / ,3'^-5- oxa-2(2.6)-pyrazino| 1.2-< / |indola- 1(7,1 )-iiidola-3(4.3)-py azolacyclooctaphan-2 '-one

[0377] (General Procedure L) Intermediate HA (84 mg, 0.11 mmol, 1.0 eq) and morpholine (0.020 mL, 0.22 mmol, 2.0 eq) were stirred in DCE (1.1 mL) with AcOH (13 mg, 0.22 mmol, 2.0 eq) at RT for 1 h. Sodium triacetoxyborohydride (46 mg, 0.22 mmol, 2.0 eq) was added and the reaction was allowed to stir overnight at 30 °C. The reaction was extracted with EtOAc, washed with sat. aq. NaHCO3then brine, dried over MgSO4, and concentrated. The crude product was purified by reverse phase HPLC to afford the title compound (50 mg, 54% yield). LCMS (ESI) Method 1: RT = 2.42 min, m / z = 839 (M+H)+.

[0378] The compounds presented in Table 6 may be prepared using General Procedure L using appropriate starting materials.Table 6H NMRStartingNo. Structure Name and / or MaterialLCMS212657-0002-WO01^NMe(2634S0,l7227?0,247?)-27-Chloro-210-(3-(4- \ O' *1 \N-N 1 JL chloro- 3,5 -dimethylphenoxy )propy 1)- 1 - LCMS (ESI):U'N / Intermediate 11A; methoxy- 14,24,31 -trimethyl- 12-((4- Method 1:jV-methylCLYY°Memethylpiperazin- 1 -yl)methyl)-21,22.27.24- RT = 1.94 piperazine min, m / z = ^-o tetrahydro-1 77,3 l / 7-5-oxa-2(2,6)- 852 (M+H)+pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- Cl pyrazolacyclooctaphan-2 -one (2634S<1,l722Ra,24R)-27-Chloro-210-(3-(4- 4 S\ f chloro- 3, 5-dimethy Iphenoxy )propy 1)- 1,1 - N-N I JL■■UN / LCMS (ESI) dimethoxy-24,31 -dimethyl- 12- £ \-OMe Method 1: Intermediate 11;cY^YN(morpholinomethyl)-21,22.27.24- RT = 1.94 morpholinetetrahydro-1 ^H.3 ^H-5-oxa-2(2,6)- min, m / z = ^0 pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- 854 (M+H)+pyrazolacyclooctaphan-2 -oneCl^•NMe(2634SO,17227? O,24T?)-27-Chloro-210-(3-(4- N^\ N-N 1 J \< chloro-3,5-dimcthy Iphenoxy )propyl)- 14, 1^- L.kN 7 LCMS (ESI) Intennediate 11; CIVXrNQ'-O-0Medimethoxy-24, 31-dimethyl- 12-((4- Method 1: jV-methyl methy Ipiperazm- 1 -yl)methy l)-21,22.27.24- RT = 1.84 piperazine min, m / z = ^0 tetrahxdro- 1 ' / / .3177-5-oxa-2(2,6)- 868 (M+H)+pyrazino[ 1,2-a]indola- 1(7, 1 )-indola-3(4,3 )- Cl pyrazolacy clooctaphan-2 -one\ (2634&,l7227?o,247?)-27-Chloro-210-(3-(4- N^\ O^Y \N-N 1 J< chloro- 3,5 -dimethylphenoxy )propy 1)- 1 - Y / :kN ] LCMS (ESI) Intennediate 11; ((dimethy lamino )methy 1)- 14, 1 -dimethoxy- CIXYNQN-O-0"' Method 1: JV^V- 24,31-dimethy 1-21,22,22,24-tetrahydro- RT = 1.91 dimethylamine11 / 7,3 l / / -5-oxa-2(2,6)-pyrazino[ 1,2- min, m / z = hydrochloride '*'0a]indola- 1 (7, 1 )-indola-3(4,3)- 813 (M+H)+pyrazolacy clooctaphan-21 -oneCl212657-0002-WO01(2634&,l7227?o,247?)-27-Chloro-210-(3-(4- chloro-3,5-dimethylphenoxy )propyl)- 14, 1^- LCMS (ESI) Intermediate 11; dimethoxy-24,3 -dimethyl- 1 i I - Method 1: 4-amino-l- methylpiperidin-4-yl)amiiio)methyl)- RT = 1.92 methylpiperidine min, m / z =21,22,23,24-tetrahydro- 1 ^H,3 ^H-5-oxa- 882 (M+H) 2(2,6)-pyrazino [ 1,2-a] indola- 1 (7, 1 )-indola-+3(4,3)-pyrazolacyclooctaphan-2 -one(2°34SO,1722T?I1,24T?)-27-Chloro-210-(3-(4- chloro-3,5-dimethy Iphenoxy )propyl)- 14, P- LCMS (ESI) Intermcdiatc 11; dimethoxy-24,31-dimcthyl-l2-(((pyridin-3- Method 1: 3-(aminomethyl) ylmethyl)amino)methyl)-21,22,23,24- RT = 1.96 pyridine min, m / z = tetrahydro- 1 ^77,3 ' / / -5-<>\a-2l'2.6)- 876 (M+H)+pyrazino [ 1,2-a] indo la- 1(7,1 )-indola-3(4,3 )- pyrazolacy clooctaphan-2 -one (2634Sa,l722T?a,24R)-l2-((2-Oxa-6- azaspiro [3.3]heptan-6-y l)methy 1 )-2 ' -chloro- 210-(3-(4-chloro-3,5- LCMS (ESI) Intermediate 11:dimethy Iphenoxy )propy 1 )- 14, 13-dimethoxy - Method 1: 2-oxa-6- RT = 2.02 azaspiro[3.3]- 24,31-dimethyl-21,22,23,24-tetrahydro- min, m / z = heptane 1177, 31 H- 5 -oxa-2(2,6 )-pyrazino [1,2- 867 (M+H)+a]indola- 1 (7, 1 )-indola-3(4,3)- pyrazolacyclooctaphan-2 -oneClExample 86212657-0002-WO01(2f,3^. S„.l72" / ,.2^ / ?)-2^-( hloio-2 ' ^-(3-(4-chloro-3.5-diinethylphenoxy (propyl)- 1 --(((4-hydroxy-4-methylcyclohexyl)amino)methyl)-14,l -dimethoxy-24,31 -dimethyl-21,2^,2^,2^- tetrahydro-1 ' / / .3 ' / / -5-oxa-2(2.6)-pyrazino| 1.2-< / |indol;i- 1(7.1 )-indo!a-3(4,3)- pyrazoIacyclooctaphan-21 -one

[0379] Intermediate 11 (53 mg, 0.07 mmol, 1.0 eq) and / rans-4-amino-l-methylcyclohexanol (35 mg, 0.27 mmol, 3.9 eq) were stirred in 3:1 NMP / acetic acid (0.60 mL) at 50 °C for 36 h. Sodium triacetoxyborohydride (30 mg, 0.14 mmol, 2.0 eq) was added and the reaction was allowed to stir at 30 °C for 48 h. The reaction was extracted with EtOAc, washed with sat. aq. NaHCOa and brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by reverse phase HPLC to afford the title compound (33 mg, 51% yield). LCMS (ESI) Method 1: RT = 1.97 min, m / z = 887 (M+H)+.Example 87(2634, S' / J,l722l?a,241f)-2^-Chloro-2 '('-(3-(4-clil()r()-3.5-diinethylphenoxy)propyl)-l --(((trn / rv- 4-hydroxycyclohexyl)amino)methyl)-1,15-dimethoxy-24, 3 ^-dimethyl-21,2^,2,24- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1.2-o|indola-l(7.1)-indola-3(4.3)- pyrazolacyclooctaphan-21 -one[00380J Intermediate 11 (53 mg, 0.07 mmol, 1.0 eq) and tra / ? -4-amino-l -cyclohexanol (31 mg, 0.27 mmol, 3.9 eq) were stirred in 3: 1 NMP / acetic acid (0.60 mL) at 50 °C for 36 h.Sodium triacetoxyborohydride (30 mg, 0.14 mmol, 2.0 eq) was added and the reaction was stirred at 30 °C for 48 h. The reaction was extracted with EtOAc, washed with sat. aq.NaHCOa and brine, dried over MgSO4, filtered, and concentrated. The crude residue was212657-0002-WO01purified by reverse phase HPLC to afford the title compound (34 mg, 56% yield). LCMS (ESI) Method 1: RT = 1.95 min, m / z = 883 (M+H)+.Example 88(263^. S„. L 2' / ?„.2^ / ?)-2^-( hloio-21(’-(3-(4-chl()ro-3.5-diiiiethylphenoxy)propyl)-l -- ((((lS',2 )-2-hydroxycyclopentyl)amino)methyl)-14,15-dimethoxy-24,31-dimethyl- 21,22,2,24-tetrahydro-ll / / ,3 / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21 -one

[0381] Intermediate 11 (53 mg, 0.07 mmol, 1.0 eq) and (15’,2S)-2-aminocyclopentanol hydrochloride (37 mg, 0.27 mmol, 3.9 eq), were stirred in 3:1 NMP / acetic acid (0.60 mL) at 50 °C for 36 h. Sodium triacetoxyborohydride (30 mg, 0.14 mmol, 2.0 eq) was added and the reaction was allowed to stir at 30 °C for 48 h. The reaction was extracted with EtOAc, washed with sat. aq. NaHCO3and brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by reverse phase HPLC to afford the title compound (17 mg, 29% yield). LCMS (ESI) Method 1: RT = 2.04 min, m / z = 869 (M+H)+.Examples 89 / 90212657-0002-WO01( 2634S’„.1722T?fl,24T?)-l2-(( / ?)- l-Azidoethyl)-27-chlor o-21°-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4,l -dimethoxy-24,31 -dimethyl-21,22,22,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 2^-one(2634&,l722l?«,24l?)-l2-((5)-l-AzidoethyI)-27-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4,1 -dimethoxy-24, 31 -dimethyl-2 l,22,22,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 2^-one[003821 Step A: (26345fl,l722^,24 / ?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-A,l4,l^-trimethoxy-A,24,34-trimethyl-24-oxo-21,22,2^,24-tetr ahydro- 1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino [1,2-a] indola- 1 (7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxamide. Intermediate 6 (150 mg, 0.2 mmol, 1.0 eq) was stirred in DMF (1 mL) at RT. HATU (107 mg, 0.3 mmol, 1.5 eq) and DIEA (0.070 mL, 0.4 mmol, 2.0 eq) were added, and the solution was stirred 15 min. A, O-dimethylhydroxylamine hydrochloride (22 mg, 0.22 mmol, 1.1 eq) was added and the reaction was stirred for 1 h. The reaction was extracted with EtOAc, washed with sat. aq. NEUCl, sat. aq. NaHCO3, water, brine; dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 0 to 70% EtOAc / MeOH (95:5) in hexanes to afford the title compound (126 mg, 80% yield). LCMS (ESI) Method 2: RT = 1.58 min, m / z = 843 (M+H)+.

[0383] Step B: (2634S„.l722 / ,.24 / O-l2-acetyl-27-chl()ro-2l0-(3-(4-chloro-3.5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,34-dimethyl-24,22,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan-24-one. The product from Step A (117 mg, 0.14 mmol, 1.0 eq) was stirred in THF (1.5 mL) under argon at -78 °C. Methyl magnesium bromide (3.4 M in 2-MeTHF, 0.12 mL, 0.42 mmol, 3.0 eq) was added dropwise and the reaction was allowed to stir at -78 °C for 15 min, then 0 °C for 1 h. The reaction was quenched with sat. aq. NH4CI, extracted with EtOAc, washed with brine, dried over M SO4, filtered, and concentrated. The crude residue was purified by flash212657-0002-WO01column chromatography eluting with 0 to 60% EtOAc / MeOH (95:5) in hexanes to afford the title compound (65 mg, 60% yield). LCMS (ESI) Method 2: RT = 1.73 min, m / z = 798 (M+H)+.

[0384] Step C: (26345fl,l722i?«,24 / ?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l2-(l-hydroxyethyl)-l4,l^-dimethoxy-24,34-dimethyl-24,22,2^,24-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1.2-< / |indola-l(7.1 )-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The product from Step B (172 mg, 0.22 mmol, 1.0 eq) was stirred in 3:1 EtOH / THF (4 mL) under argon at RT. Sodium borohydride (25 mg, 0.65 mmol, 3.0 eq) was added and the reaction was stirred overnight. The reaction was quenched with water, extracted with EtOAc, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude product (170 mg, 99% yield) was used without further purification. LCMS (ESI) Method 2: RT = 1.50 min, m / z = 800 (M+H)+.

[0385] Step D: (26345a,l722 / ?„,24 / ?)-l2-(( / ?)-l-Azidoethyl)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l 5-dimethoxy-24,31 -dimethyl-21,22,2J,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2 z]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-2^-one and (2^34S'„.l722 / ?„.24 / ?)-l --((. S)-l -Azidoethyl )-27-chloro-2 ' ^-(3-(4-chloro-3.5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,3^-dimethyl-21,22,2-’,24-tetrahydro-l^ / ,31 7-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-2^-one. The product from Step C (170 mg, 0.21 mmol, 1.0 eq) was stirred in THF (1 mL) and DPPA (0.070 mL, 0.32 mmol, 1.5 eq) was added dropwise at RT. The reaction was stirred 5 min, then cooled to 0 °C and DBU (0.050 mL, 0.32 mmol, 1.5 eq) was added dropwise. The reaction was stirred at 65 °C overnight, after which time the reaction showed partial conversion. A second aliquot of DPPA (0.07 mL, 0.32 mmol, 1.5 eq) and DBU (0.05 mL, 0.32 mmol, 1.5 eq) was added, and the reaction was stirred at 70 °C for 2 h. The reaction mixture was extracted with EtOAc, washed with sat. aq. NH4C1, washed with sat. aq. NaHCO3, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 50% EtOAc / MeOH (95:5) in hexanes to afford 74 mg of an later eluting diastereomer (Example 89) and 55 mg of an earleir eluting diastereomer (Example 90), without determination of the azide stereochemistry. Example 89:212657-0002-WO01LCMS (ESI) Method 2: RT = 1.85 min, m / z = 825 (M+H)+. Example 90: LCMS (ESI) Method 2: RT = 1.83 min, m / z = 825 (M+H)+.Examples 91 / 92 (2^345fl,l722l?a,24l?)-l2-((7?)-l-Aminoethyl)-27-chloro-2^-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4,l 5-dimethoxy-24,31 -dimethyl-21,22,22,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 2^-one(26345«,l7227?fl,247?)-l2-((5)-l-Aminoethyl)-27-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4,l 5-dimethoxy-24,31 -dimethyl-21,22,22,24-tetrahydro--oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 2^-one

[0386] The separated Examples 89 and 90 were each separately stirred in 3: 1 THF / H2O (2 mL). Triphenylphosphine (1.5 eq) was added to each reaction vessel and the reactions were stirred at 70 °C for 1 h. The reactions were extracted with EtOAc, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residues were purified by reverse phase HPLC. to afford the primary amine Example 91 from Example 89 and primary amine Example 92 from Example 90. Example 91: LCMS (ESI) Method 1: RT = 2.15 min, m / z = 799 (M+H)+. Example 92: LCMS (ESI) Method 1: RT = 2.10 min, m / z = 799 (M+H)+.212657-0002-WO01Example 93(2634 / ?a,l722 / ?fl24l?)-2^-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-14,15-dimethoxy- 12,14,31 -trimethyl-21,22,2^,24-tetrahydro-l1 T7-5-oxa-2(2,6)-pyrazino [1,2-#] indola- l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-2^-one[00387J In a reaction vessel, Example 58 (100 mg, 0.13 mmol, 1.0 eq) was dissolved in THF / MeOH (5 mL, 9:1). Palladium (II) chloride (40 mg, 0.22 mmol, 2.0 eq) was added, followed by addition of NaBH4 (15 mg, 0.40 mmol, 3.0 eq) over 5 min. The reaction was allowed to stir for 2 h at RT, then quenched by addition of H2O and filtered through Celite®. The filtrate was concentrated and the crude residue taken up in EtOAc, washed with water, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by reverse phase HPLC to afford the title compound (20 mg, 21% yield). LCMS (ESI) Method 2: RT = 1.61 min, m / z = 736 (M+H)+.Example 94(263 5fl,l722R«,24 / ?)-27-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,15- dimethoxy-12,24,31 -trimethyl-21,22,2J,24-tetrahydro-l ' T / ,3 / / -5-oxa-2(2,6)-pyrazino [1,2- a']indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one212657-0002-WO01

[0388] The title compound (24 mg, 35% yield) was isolated from the reaction conditions described in Example 93. LCMS (ESI) Method 2: RT = 1.76 min, m / z = 769 (M+H)+.Example 95(2^3^. S„.1 2“ / ?„,2^ / ?)-2^-( hloro-2 ' ■’-(3-(4-chloro-3.5-dimethylphen()xy)propyl)-l ^.1 - dimethoxy-2^,31 -dimethyl-l^-vinyl-21,2^,2^,24-tetrahydro-l ' / / .3 l / / -5-oxa-2(2,6)- pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan-21-one

[0389] Intermediate 11 (100 mg, 0.13 mmol, 1.0 eq) was stirred in THF (2 mL) until dissolved. In a separate flask methyltriphenylphosphonium iodide (81 mg, 0.2 mmol, 1.5 eq) was stirred in THF (1 mL) at RT under argon. To this slurry was added dropwise NaHMDS (1 M in THF, 0.20 mL, 0.20 mmol, 1.5 eq) and the resulting mixture was stirred 10 min. The solution of Intermediate 11 was added dropwise to the phosphonium mixture. The reaction was stirred for 1 h at RT. The reaction was extracted with EtOAc, washed with sat. aq. NH4Cl, washed with sat. aq. NaHCO3, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by reverse phase HPLC to afford the title compound (70 mg, 70% yield). LCMS (ESI) Method 2: RT = 1.80 min, m / z = 782 (M+H)+.Example 96212657-0002-WO01(2^’3^. Sfl,l7227?fl,2^T?)-2^-Chloro-2^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l 2-ethyl- 14,1 -dimethoxy-24,31 -dimethyl-21,2^,2^,24-tetrahydro-l ^H,3 / / -5-oxa-2(2,6)- pyrazino[l,2-a]indola-l(7,l )-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0390] Example 95 (57 mg, 0.07 mmol, 1.0 eq) was dissolved in MeOH / THF (4 mL, 3:1) at RT. Pd(OH)2 / C (20 wt.%, 10 mg, 0.012 mmol, 0.15 eq) was added and the flask was placed under vacuum and backfilled with H2. The reaction was stirred under an atm. of H2 at RT for 3 h. The reaction was filtered through a plug of Celite®. The filtrate was concentrated and purified by reverse phase HPLC to afford the title compound (40 mg, 70% yield). LCMS (ESI) Method 2: Rr = 1.81 min, m / z = 784 (M+H)+.Example 97(263^. S„.1 22 / ?„,2 / ?)-2^-( hloro-2 '^-(3-(4-clil()io-3.5-diiiietliylphenoxy)propyl)-1.1 - dimethoxy-12-((£)-2-methoxyvinyl)-24,31-dimethyl-21,22,2^,24-tetrahydro-117f,31 / / -5- oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0391] Intermediate 11 (235 mg, 0.30 mmol, 1.0 eq) was stirred in THF (4 mL) until dissolved. In a separate flask the (methoxymethyl)triphenylphosphonium chloride (154 mg, 0.45 mmol, 1.5 eq) was stirred in THF (2 mL) at -78 °C under argon. To the resultant slurry was added NaHMDS (1.0 M in THF, 0.45 mL, 0.45 mmol, 1.5 eq) and the resulting mixture was stirred 10 min at 0 °C. The solution of Intermediate 11 was added dropwise to the phosphonium mixture. The reaction was stirred at RT overnight. The reaction was extracted with EtOAc, washed with sat. aq. NH4CI, washed with sat. aq. NaHCO3, washed with brine, dried over MgSCL, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 60% EtOAc / MeOH (95:5) in hexanes. The resultant product212657-0002-WO01was then purified by reverse phase HPLC to afford the title compound (139 mg, 57% yield). LCMS (ESI) Method 2: RT = 1.74 min, m / z = 812 (M+H)+.Example 98(26345fl,l722l?a,2 1?)-2 -chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)- 1 ^-ethyl- 15- hydroxy-l4-inethoxy-24.3'-dimethyl-2 ',2-.2^.24-tetrahydro- 1 ' / / .3' / / -5-oxa-2(2.6)- pyrazino[l,2-a]indola-l(7,l)-mdola-3(4,3)-pyrazolacydooctaphan-24-one

[0392] Step A: (2634S'„.l722 / ?„.24 / ?)-l -(benzyloxy)-27-clil()i()-2l0-(3-(4-chloro-3.5-dimethylphenoxy)propyl)-l4-methoxy-24,34-dimethyl-12-vinyl-24,22,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan- 24-one. Methyltriphenylphosphonium iodide (414 mg, 1.0 mmol, 4.0 eq) was stirred in THF (2.5 mL) at RT under argon. To this slurry was added NaHMDS (1.0 M in THF, 1 mL, 1.0 mmol, 4.0 eq) and the resulting mixture was stirred 10 min. Intermediate 28 (210 mg, 0.24 mmol, 1.0 eq) dissolved in THF (2.5 mL) was then added to the reaction mixture and stirred at RT for 1 h. The reaction was extracted with EtOAc, washed with sat. aq. NH4CI, washed with sat. aq. NaHCO3, washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 0 to 40% EtOAc / MeOH (95:5) in hexanes to afford the title compound (164 mg, 78% yield). LCMS (ESI) Method 2: RT = 2.09 min, m / z = 858 (M+H)+.

[0393] Step B: (26345a,l7227?fl,24 / ?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^-ethyl-l^-hydroxy-l4-methoxy-24,34-dimethyl-24,22,2^,24-tetrahydro-l4ET,34 / ^-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-24-one. The title compound (136 mg, 94% yield) was prepared212657-0002-WO01following General Procedure B using the product from Step A (160 mg, 0.18 mmol, 1.0 eq) and stirring for 3 h at 35 °C. The product was used without further purification. LCMS (ESI) Method 2: RT = 1.80 min, m / z = 770 (M+H)+.Example 98A(2634S’„.l7227?„.24 / )-l5-(Azetidiii-3-yloxy)-27-chloro-2l0-(3-(4-chloro-3.5- dimethylphenoxy)propyl)-l2-ethyl-l4-methoxy-24,31-dimethyl-21,22,2J,24-tetrahydro- -oxa-2(2,6)-pyrazino [ 1,2-a] indola- 1(7,1 )-indola-3(4,3)-pyrazolacyclooctaphan- 2^-one

[0394] Step A: tert-butyl 3-(((2634S„.l722 / ?„.24 / ?)-27-chloro-2l0-(3-(4-chloro-3.5-dimethylphenoxy)propyl)-l2-ethyl-l4-methoxy-24,34-dimethyl-24-oxo- 24,22,23,24-tetr ahydro- 11 / / ,3 lH-5-oxa-2(2,6)-pyrazino [1,2-«] indola- 1 (7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-yl)oxy)azetidine-l-carboxylate. The title compound (110 mg, 68% yield) was prepared following General Procedure I using Example 98 (135 mg, 0.18 mmol, 1.0 eq) and tert-butyl 3-(tosyloxy)azetidine-l-carboxylate (172 mg, 0.53 mmol, 3.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 50% EtOAc / MeOH (95:5) in hexanes to afford the title compound. LCMS (ESI) Method 2: RT = 2.21 min, m / z = 925 (M+H)+.

[0395] Step B: (26345fl,l722 / ?fl,24 / ?)-l5-(Azetidin-3-yloxy)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l2-ethyl-l4-methoxy-24,31-dimethyl-21,22,23,24-tetr ahydro- 11 / 7,3 l / / -5-oxa-2(2,6)-py razino [1,2-a] indola- 1 (7, l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The product from Step A (110 mg, 0.12 mmol) was dissolved in DCM (5 mL) at RT followed by slow addition of TFA (1 mL, 10 mmol). The212657-0002-WO01reaction was stirred at RT for 1 h. The reaction was concentrated, the residue was taken up in EtOAc and washed with sat. aq. NaHCOs. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (98 mg, 99% yield). The crude material was used without further purification. LCMS (ESI) Method 1: RT = 2.33 min, m / z = 825 (M+H)+.Example 99 (263'\S'fl,l722 / ?fl,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-ethyl- 14-methoxy-24,31 -dimethyl-1 ^-((l-methylazetidin-3-yl)oxy)-21,2^,2^,2^-tetrahydro--oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan- 2^-one

[0396] Example 98A (90 mg, 0.11 mmol, 1.0 eq) was stirred in MeOH / DCM (8:2, 1.5 mL). Formaldehyde (0.100 mL, 37 wt. % in water, 1.1 mmol, 10 eq) was added, followed by AcOH (0.025 mL, 0.45 mmol, 4.0 eq). The mixture was stirred for 30 minutes, followed by addition of NaCNBH3 (34 mg, 0.54 mmol, 5.0 eq). The reaction was stirred for 1 h. The reaction was extracted with EtOAc, washed with sat. aq. NELCl, washed with sat. aq. NaHCOs, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was then purified by reverse phase HPLC to afford the title compound (31 mg, 34% yield). LCMS (ESI) Method 1: RT = 2.33 min, m / z = 839 (M+H)+.212657-0002-WO01Example 100(26345fl,l722 / ?fl,2^1?)-2^-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-ethyl- |4-methoxy-24,3'-dimethyl-l'’-(2-morpholinoethoxy)-2',22,21,24-tetrahydro-l ' / y,3' / / -5- oxa-2(2,6)-pyrazino[l,2-tz]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0397] The title compound (34 mg, 22% yield) was prepared following General Procedure I using Example 98 (137 mg, 0.18 mmol, 1.0 eq) and 4-(2-bromoethyl)morpholine hydrobromide (122 mg, 0.44 mmol, 2.5 eq). The crude residue was then purified by reverse phase HPLC to afford the title compound. LCMS (ESI) Method 1: RT = 2.35 min, m / z = 883 (M+H)+.Example 101(26345fl,l722^?«,2^?)-l^-(3-bromopropoxy)-2^-chloro-21®-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l^-ethyl-l^-methoxy-2^,3^-dimethyl-21,22,2^,2^-tetrahydro- I' / Z1 / / -? -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazoIacydooctaphan- 21-one

[0398] The title compound (134 mg, 66% yield) was prepared following General Procedure I using Example 98 (161 mg, 0.2 mmol, 1.0 eq) and 1,3 -dibromopropane (0.200 mL, 1.9 mmol, 10 eq). The crude product was purified by flash column chromatography eluting with 0 to 35%212657-0002-WO01EtOAc / MeOH (95:5) in hexanes to afford the title compound. LCMS (ESI) Method 2: RT = 2.14 min, m / z = 890 (M+H)+.ciExample 101A(2634Sa,l722?fl,24T?)-2^-Chloro-21 ®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l 2-ethyl- 14-methoxy-24,31 -dimethyl-1 ^-(3-morpholinopropoxy)-21,2^,2^,2^-tetrahydro-l ' / / ,35-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0399] Example 101 (67 mg, 0.08 mmol, 1.0 eq) was stirred in DMF (1 mL) until dissolved, then morpholine (0.040 mL, 0.45 mmol, 5.5 eq) was added. The reaction was allowed to stir at 70 °C. The reaction was extracted with EtOAc, washed with sat. aq. NELCl, washed with sat. aq. NaHCO3, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was then purified by reverse phase HPLC to afford the title compound (45 mg, 67% yield). LCMS (ESI) Method 1: RT = 2.36 min, m / z = 897 (M+H)+.Example 102( 2634S„.1 ^2~Ra,2^R)- 1 ^-(Azetidin-3-ylmethoxy)-2^-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-12-ethyl-l4-methoxy-24,3^-dimethyl-2^,22,2^,24-tetrahydro-212657-0002-WO01I1 / , 3}H-5 -oxa-2(2.6)-pvrazino| 1.2-^| indola- 1(7.1 )-ind()la-3(4.3)-pyr;iz()lacyclooctaph;in- l^-one

[0400] Step A: rt-butyl 3-((((26345fl,l722 / ?„,24 / ?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l2-ethyl-l4-methoxy-24,3 -dimethyl-21-oxo- 2X,22,23,24-tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino| l,2-a]indola-l(7,l )-indola-3(4,3)-pyrazolacyclooctaphane-15-yl)oxy)methyl)azetidine-l-carboxylate. The title compound (157 mg, 93% yield) was prepared following General Procedure I using Example 98 (138 mg, 0.18 mmol, 1.0 eq) and tert-butyl 3-((tosyloxy)methyl)azetidine-l -carboxylate (183 mg, 0.54 mmol, 3.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 60% EtOAc / MeOH (95:5) in hexanes to afford the title compound. LCMS (ESI) Method 2: RT = 2.15 min, m / z = 939 (M+H)+.

[0401] Step B: (2634&,l7227?„,24 / ?)-l5-(Azetidin-3-ylmethoxy)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l2-ethyl-l4-methoxy-24,3^-diniethyl-21,22,23,24-tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino| l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-ll-one. The product from Step A (157 mg, 0.17 mmol, 1.0 eq) was stirred in DCM (5 mL) at RT. TFA (0.64 mL, 8 mmol) was added, and the reaction was stirred for 1 h. The reaction was concentrated, the residue was taken up in EtOAc, washed with sat. aq. NaHCO3, dried over MgSO4, filtered, and concentrated to afford the title compound (113 mg, 81% yield). The reaction was used in subsequent steps without further purification.LCMS (ESI) Method 1: RT = 2.36 min, m / z = 839 (M+H)+.Example 103212657-0002-WO01(2^3^S„.r 2" / ?„.2^ / ?)-2^-( hloro-2 ’('-(3-(4-chl()ro-3. -diniethvlphenoxy)propyl)- -(3- (dimethylamino)propoxy)-12-ethyl-14-methoxy-24,3^-dimethyl-2^,22,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 2^-one

[0402] Example 101 (67 mg, 0.08 mmol, 1.0 eq) was dissolved in DMF (1.0 mL), followed by addition of K2CO3 (85 mg, 0.61 mmol, 7.5 eq) and dimethylamine: HCl salt (37 mg, 0.45 mmol, 5.5 eq). The reaction was allowed to stir at 70 °C overnight. The reaction was extracted with EtOAc, washed with sat. aq. NH4Cl, washed with sat. aq. NaHCO3, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was then purified by reverse phase HPLC to afford the title compound (33 mg, 51% yield). LCMS (ESI) Method 1: RT = 2.36 min, m / z = 855 (M+H)+.Example 104 (26345fl,l722l? / „241?)-2^-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-ethyl- 14-methoxy-24,31-dimethyl-15-((l-methylazetidin-3-yl)methoxy)-21,22,2J,24-tetrahydro--oxa-2(2,6)-pyrazino[l,2-u!]indola-l(7,l)-indola-3(4,3)-pyi*azolacyclooctaphan- 2 -one

[0403] Example 102 (100 mg, 0.12 mmol, 1.0 eq) was dissolved in MeOH / DCM (8:2, 1.2 mL). Formaldehyde (0.100 mL, 37 wt. % in water, 1.1 mmol, 10 eq) was added, followed by AcOH (0.021 mL, 0.36 mmol, 3.0 eq). The mixture was stirred for 30 min, then NaCNBH.i (37 mg, 0.60 mmol, 5.0 eq) was added. The reaction was allowed to stir for Ih. The reaction was extracted with EtOAc, washed with sat. aq. NH4CI, washed with sat. aq. NaHCOa, washed with212657-0002-WO01brine, dried over MgSO4, filtered, and concentrated. The crude residue was then purified by reverse phase HPLC to afford the title compound (40 mg, 39% yield). LCMS (ESI) Method 1: RT = 2.38 min, m / z = 853 (M+H)+.Example 105Ethyl (£)-3-((2^1?)-2^-chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2,3 -dimethyl-2 l-oxo-21,2^,2^,2^-tetr ahydro- 1 ’ H,3 ^ / / -5-oxa-2(2,6)- pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12-yl)acrylate

[0404] Intermediate 11 (1.07 g, 1.36 mmol, 1.0 eq) was dissolved in DCE (30 mb). Ethyl 2-(triphenyl-15-phosphaneylidene)acetate (950 mg, 2.73 mmol, 2.0 eq) was added and the reaction was stirred at 50 °C for 72 h. The reaction was extracted with DCM, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the title compound (1.38 g, 118% yield, contaminated with triphenylphosphine oxide). LCMS (ESI) Method 2: RT = 1.851 min, m / z = 853.9 (M+H)+.Example 105A212657-0002-WO01( / .)-3-((2f,3^S„.1 2' / ?„.2^ / ?)-2^-( hloro-2 ' ’-(3-(4-chloio-3.5-diinethylphenoxy)piopvl)- 14,1 -dimethoxy-24,31 -dimethyl-21 -oxo-21,2^,2^,2^-tetrahydro-l ^H,3 / / -5-oxa-2(2,6)- pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12-yI)acrylic acid

[0405] The title compound (13 mg, 67% yield) was prepared following General Procedure E using Example 105 (20 mg, 0.023 mmol, 1.0 eq). The crude product was purified by reverse phase HPLC to afford the product. The product was dissolved in DCM (5 mL), washed with sat. aq. NaHCO3, the layers separated, dried over MgSO4, filtered, and concentrated. LCMS (ESI) Method 2: RT = 1.421 min, m / z = 826.0 (M+H)+.Example 106Ethyl 3-((26345fl, 17?' Ra, 2^ R)-2^ -chloro-21 ®-(3-(4-chloro-3,5-dimethylphenoxy)propyI)- 14,1 -dimethoxy-24,3 l-dimethyl-2 l-oxo-21,2^,2^,24-tetrahydro- 1 ' H,3 ^H-5-oxa-2(2,6)- pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12-yl)propanoate

[0406] Example 105 (1.20 g, 1.40 mmol, 1.0 eq) was dissolved in THF (10 mL) and PrOH (10 mL) and sparged with argon. Pd / C (10 wt.%, 225 mg, 0.211 mmol, 0.15 eq) was added, and the reaction was flushed with H2. The reaction was allowed to stir under an atmosphere of H2 at 40 °C for 12 h. The crude mixture was filtered through a pad of Celite®, rinsed with DCM, and concentrated. The crude material (1.20 g, 100% yield) was used without further purification. LCMS (ESI) Method 2: RT = 1.872 min, m / z = 856.0 (M+H)+.212657-0002-WO01Example 106A3-((26345«,l722l?«,2^1?)-2^-Chloro-21Q-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,15_dimethoxy-24,31 -dimethyl-21 -oxo-21,2^,2^,24-tetrahydro-l ^H,3 ^7 / -5-oxa-2(2,6)- pyrazino[l,2-<7]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12-y|)propanoic acid

[0407] The title compound (13 mg, 67% yield) was prepared following General Procedure E using Example 106 (20 mg, 0.023 mmol, 1.0 eq). The crude product was purified by reverse phase HPLC to afford the product. LCMS (ESI) Method 1: RT = 2.396 min, m / z = 827.9 (M+H)+.JH NMR (400 MHz, CDCh) 87.57 (d, J= 8.4 Hz, 1H), 7.52 (s, 1H), 7.20 (d, J= 8.4 Hz, 1H), 6.63 (s, 1H), 6.49 (s, 2H), 6.29 (s, 1H), 4.73 (dd, J = 12.4, 6.0 Hz, 1H), 4.14 - 4.05 (m, 3H), 3.99 (s, 3H), 3.92 (s, 3H), 3.86 (t, J= 6.4 Hz, 2H), 3.82 (s, 3H), 3.68 (d, J= 10.0 Hz, 1H), 3.61 - 3.56 (m, 2H), 3.36 (d, J= 12.4 Hz, 1H), 3.26 (t, J= 6.8 Hz, 2H), 3.01 (t, J= 10.0 Hz, 1H), 2.83 -2.55 (m, 4H), 2.21 (s, 6H), 2.10 - 2.05 (m, 2H), 1.94 - 1.84 (m, 1H), 1.70 -1.60 (m, 1H), 1.03 (d, J= 6.8 Hz, 3H).Example 107212657-0002-WO01(2^3^. S„.1 2" / ?„,2^ / ?)-2^-( hloro-2 ' ■'-(3-(4-chloi o-3.5-[|iniethvlphenoxy)propyl)-l ^.1 - dimethoxy-24,3^-dimethyl-12-((E)-3-(4-methylpiperazin-l-yl)-3-oxoprop-l-en-l-yl)- 21,2^,2^.2^-1 et r ahydro- 1 ^H,3 l / -5-oxa-2(2,6)-pyrazino [1,2-a] indola- 1 (7, 1 )-indola-3(4,3)- pyrazoIacyclooctaphan-21 -one

[0408] (General Procedure M) In a reaction vessel, Example 105 A (20 mg, 0.024 mmol, 1.0 eq) was dissolved in DMF (1 mb). DIPEA (16 mg, 0.12 mmol, 5.0 eq) and HATU (14 mg, 0.036, 1.5 eq) were added and the reaction was allowed to stir for 5 min. A-Methylpiperazine (7.3 mg, 0.073 mmol, 3.0 eq) was added, and the reaction was allowed to stir for 30 min, after which time it was determined to be complete by LCMS. The reaction was extracted with EtOAc, washed with FEO, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by reverse phase HPLC afford the title compound (5 mg, 20% yield). LCMS (ESI) Method 2: RT = 1.036 min, m / z = 908.0 (M+H)+.1H NMR (400 MHz, CDCh) 87.58 (d, J= 8.8 Hz, 1H), 7.52 (t, J= 8.8 Hz, 2H), 7.21 (d, J= 8.4 Hz, 1H), 6.97 (s, 1H), 6.89 (d, J= 15.2 Hz, 1H), 6.74 (s, 1H), 6.51 (s, 2H), 4.69 (dd, J= 12.4, 5.6 Hz, 1H), 4.22 (t, J= 16.0 Hz, 1H), 4.16 -4.11 (m, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 3.87 (t, J= 6.0 Hz, 2H), 3.84 (s, 3H), 3.83 - 3.77 (m, 1H), 3.75 (m, 5H), 3.55 (dd, J= 9.6, 3.6 Hz, 1H), 3.32 (d, J= 12.4 Hz, 1H), 3.28 (t, J= 6.4 Hz, 2H), 3.04 (t, J= 10.4 Hz, 1H), 2.91 (s, 3H), 2.42 (br s, 4H), 2.23 (s, 6H), 2.07 (quint, J= 7.6 Hz, 2H), 2.00 - 1.93 (m, 1H), 1.69 - 1.63 (m, 1H), 1.03 (d, J= 6.4 Hz, 3H).

[0409] The compounds presented in Table 7 may be prepared using General Procedure L using appropriate starting materials.Table 7Starting 'HNMR and / or No. Structure NameMaterial LCMS212657-0002-WO01LCMS (ESI) Method 2: RT = 0.996 min, m / z= 910.0 (M+H)+. > HNMR (400 MHz, CDC13) 57.57 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H), 7.20 (d, J= 8.4 Hz, 1H), 664 (s, 1H), 6.50 (s, 2H), 6.31 (s, 12"3 X,.1 -22 / ?„.2'l / <|-27-Cliloro- 1H), 4.73 (dd, J = 210-(3-(4-chloro-3,5- 12.4, 5.6 Hz, 1H),4.17 -4.08 (m, 3H), dimethylphenoxy)propyl)-l4,l 5- ^ 3 99 (s, 3H), 3 92 (s, dimetho\v-24,3 ' -dimetliv]- 1 ^-(3- Example 106 A: 3H), 3.85 (t, J= 6.4 r~ (4-methylpiperazin-l-yl)-3- jV-methylCI'YZ^N / NHz, 2H), 3 83 (s, 3H), piperazine oxopropy l)-2,2^,2,24- 3.69 - 3.55 (m, 5H), tetrahydro-1 ^H,3^H-5-oxa- 3.45 (br s, 2H), 3.35 2(2,6)-pyrazino[l,2-<7]indola- (d, J= 12.4 Hz, 1H), l(7,l)-indola-3(4,3)- 3.29 - 3.22 (m, 2H), pyrazolacyclooctaphan-2 -one 3.04 -2.93 (m, 2H),2.86 -2.78 (m, 1H), 265 (br s, 2H), 243 (br s, 3H), 2.26 (s, 3H), 2.23 (s, 6H), 2.07 (quint, J= 6.8 Hz, 2H), 1.97- 1.90 (m, 1H), 1.70 - 1.62 (m, 2H), 1.03 (d, J= 6.8 Hz, 3H) (2° 34Sa, 1722Ao,24A)-27-Chloro- 210-(3-(4-chloro-3,5- dimethy Iphenoxy )propy 1)- 14, P - Example 106 A: dimethoxy-24, 3 ^-dimethyl- 1 ^-(3- LCMS (ESI) Method 4-(azetidin-3- (3-morpholinoazetidin-l -yl)-3- 2: RT = 1.057 mm, yl)morpholineoxopropyl)-2 2^ 24.2^- m / z = 9520 (M+H)- dihydrochloridetetrahydro- 1 ^11,3 Vz-5-oxa- 2(2,6)-pyrazino[l,2-a]indola- l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-2 -one212657-0002-WO01(2634SO, 1722Ra,24R )-27-Chloro- r~° 210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)- 14, 13- N-N 1 1 JL dimethoxy-24,31-dimethyl- 12-(3- Example 106 A: =N / LCMS (ESI) Method (4-(oxetan-3-yl)piperazin-l-yl)-3- l-(oxetan-3- 2: RTclY^rNQN= 1.030 min,^M'°Meyl)piperazine 'DMeoxopropy 1 )-2 '.22.23.24- m / z = 9520 (M+H)- ^0 tetrahydro- 1 ^H,3 ' / 7-5-o\a- 2(2,6)-pyrazino[l,2-a]indola- l(7,l)-indola-3(4,3)- Clpyrazolacyclooctaphan-23-one(2634So, 1 22 / ?„.24 / ?i-27-Cliloro- 210-(3-(4-chloro-3,5- O^N^J dimethylphenoxy )propyl)- 1 -(3- ((S)-hexahy dropyrazino[2, 1 - Example 106 A: \ \N-N 1 I J< c][l,4]oxazin-8(l / / )-yl)-3- LCMS (ESI) Method (S)-octahydro =NJCI^L. NQN-^Q-0'*’ zl Soxopropyl)-!, 1 -dimethoxy- 2: RT = 1.048 mm, pyrazino[2,l- °Mem / z = 9520 (M+H)* c][ 1,4] oxazine 24,31-dimethyl-21,22,23,24- '-o tetrahydro-1 ' 17,3 ' / 7-5-o\a- 2(2,6)-pyrazino[l.2-a | indo la- Cl 117.1 i-mdola-3( 4.3 ypyrazolacyclooctaphan-2 -one(2634Sa, 1722T?0,24T?)-27-Chloro- I^NMe^N, _ ) 210-(3-(4-chloro-3,5- O^NZ / dimethy Iphenoxy )propy 1)- 14, 13- Example 106 A: \ \N-N 1 1 JLl-(azetidin-3- / dimethoxy-24, 3 ^-dimethy l-l2-(3- LCMS (ESI) Method yl)-4-methyl CI^LNQN-O-0^ ( 3 -(4-methy Ipiperazin- 1 - 2: RT = 0.914 min, piperazine ^0Meyl)azetidin- 1 -yl)-3-oxopropyl)- m / z = 965 1 (M+H)* trihydrochloride '-’O 21,22,23,24-tetrahydro-l5-oxa-2(2,6)-pyrazino[l,2- Cl a\ indola- 1(7,1 )-indola- 3 (4,3 )- pyrazolacyclooctaphan-2 -one212657-0002-WO01( 2"3 Y.1722Ra,24R )-27-Chloro- 210-(3-(4-chloro-3,5- dimethylphenoxy )propyl)- d,l 5- Example 113; dimethoxy-24,31-dimethyl- 17-(2- (S)-octahydro LCMS (ESI) Method o ((S)-octahy dropyrazino [2,1- 13 A pyrazino[2,l- c][l,4]oxazine-8- 2: RT = 1.136 min, c][l,4]oxazine carbonyl)cyclopropyl)- m / z = 9640 (M+H)- dihydrochloride21,22,23,24-tetrahydro-l1H,31H- / / r or - 5-oxa-2(2,6)-pyrazino[ 1,2- 'zToy-\.,«]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-2 -one( 2"34S„, 1722T?0,24T?)-27-Chloro- O^N _ J 210-(3-(4-chloro-3,5- dimelhylphenoxy)propyl)-l4,l3- \ b*N-N 1 1Example 113; / dimethoxy-24,31-dimethyl- 12-(2- LCMS (ESI) Method 14. V-methylc|XNQ-Q0Me(4-methy Ipiperazine- 1 - 2: RT = 1.091 min, piperazine carbonyl)cyclopropyl)- m / z = 9220 (M+H)’ ^0 21,22,23,24-tetrahydro-l5-oxa-2(2,6)-pyrazino[l,2- Cl a\ indola- 1(7,1 )-indola- 3 (4,3 )- pyrazolacyclooctaphan-2 -oneClExample 113-((2634»Sfl,l722l?fl,241?)-27-Chloro-210-(3-(4-chloro-3,5-diinethylphenoxy)propyl)-14,15_dimethoxy-14,31 -dimethyl-21 -oxo-21,2^,2^,2^-tetrahydro-l ^H,3 l / 7-5-oxa-2(2,6)-212657-0002-WO01pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l7-yl)cyclopropane-l- carboxylic acid

[0410] Step A: Ethyl 2-((26345fl,l722J?fl,24l?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l -dimethoxy-24,31 -dimethyl-21 -oxo-21,2^,2^,24-tetrahydro-1 ' / / ,3' / / -5-oxa-2(2.6)-pyr;izino|l.2-^| indola- 1(7.1 )-indola-3(4.3)-pyrazolacyclooctaphane-l7-yl)cyclopropane-l-carboxylate. Trimethylsulfoxonium iodide (48 mg, 0.216 mmol, 1.5 eq) was dissolved in DMSO (2 mL) and NaH (6.2 mg, 0.144 mmol, 1.8 eq) was added. The reaction was allowed to stir for 1 h at RT. Example 105 (123 mg, 0.144 mmol, 1.0 eq) was dissolved in DMSO (2 mL) and added to the reaction vessel. The reaction was allowed to stir for 1 h at RT. The crude reaction was extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude material (120 mg, 96% crude yield) was carried forward without further purification. LCMS (ESI) Method 2: RT = 1.853 min, m / z = 868.0 (M+H)+.

[0411] Step B: 2-((26345„,l722 / ?a,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-diinethylphenoxy)propyl)-l4,l _dimethoxy-24,31 -dimethyl-21 -oxo-21,27,2^,24-letrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino|l.2-( / |indola- 1(7.1 )-indola-3(4.3)-pyrazolacyclooctaphane-l7-yl)cyclopropane-l-carboxylic acid. The title compound (96 mg, 83% crude yield) was prepared following General Procedure E using the product from Step A (120 mg, 0.138 mmol. 1.0 eq). LCMS (ESI) Method 2: RT = 1.467 min, m / z = 840.0 (M+H)+.Example 115212657-0002-WO01(26345fl,l722T?fl,2^T?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(3- hydroxypropyl)-!^,! -dimethoxy-24,31 -dimethyl-21,2^,2^,24-tetrahydro-l ^H,3 ^H-5-oxa- 2(2 / >)-pyrazino| 1.2-( / |indol;i-l (7.1 )-iiidol;i-3(4.3)-pyrazolacyclooctaphan-2 '-one

[0412] Example 106 (22 mg, 0.026 mmol, 1.0 eq) was dissolved in THF (3 mL). LiBH4 was added and the reaction was heated to 50 °C for 4 h. The reaction was quenched with H2O, extracted with DCM, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by reverse phase HPLC to afford the title compound (8 mg, 40% yield). LCMS (ESI) Method 2: RT = 1.634 min, m / z = 814.0 (M+H)+.NMR (400 MHz, CDCh) 57.57 (d, J= 8.4 Hz, 1H), 7.52 (s, 1H), 7.20 (d, J= 8.4 Hz, 1H), 6.91 (s, 1H), 6.62 (s, 1H), 6.49 (s, 2H), 6.33 (s, 1H), 4.73 (dd, J = 12.4, 6.0 Hz, 1H), 4.15 -4.09 (m, 3H), 3.99 (s, 3H), 3.92 (s, 3H), 3.87 (t, J= 6.4 Hz, 2H), 3.83 (s, 3H), 3.69 (d, J= 10.0 Hz, 1H), 3.66 - 3.56 (m, 4H), 3.37 (d, J= 12.4 Hz, 1H), 3.33 - 3.21 (m, 2H), 3.01 (t, J= 10.0 Hz, 1H), 2.66 -2.53 (m, 2H), 2.21 (s, 6H), 2.10 - 2.05 (m, 2H), 1.95 - 1.84 (m, 3H), 1.70 -1.65 (m, 1H), 1.03 (d, J= 6.8 Hz, 3H).Example 116(263 5fl,l722R«,2 / ?)-27-Chloro-21<-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,15- dimethoxy-12-(3-methoxypropyl)-24,31-dimethyI-2^,22,2^,24-tetrahydro-l^ / 7,31 / / -5-oxa- 2(2.6)-pyrazino| 1.2-< / |indola-l(7.1 )-iiidola-3(4.3)-pyraz()lacyclooctaphan-2'-one

[0413] Example 115 (50 mg, 0.061 mmol, 1.0 eq) was dissolved in DMF (2 mL) and cooled to 0 °C. Sodium hydride (2.9 mg, 0.12 mmol, 2.0 eq) was added and the reaction was allowed to stir for 30 min. Methyl iodide (35 mg, 0.25 mmol, 4.0 eq) was added and the reaction was allowed to stir for 18 h at RT. The reaction was quenched with H2O, extracted with EtOAc,212657-0002-WO01washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by reverse phase HPLC to afford the title compound (20 mg, 39% yield). LCMS (ESI) Method 2: RT = 1.825 min, m / z = 828.0 (M+H)+. ’H NMR (400 MHz, CDCI3) 8 7.57 (d, J= 8.8 Hz, 1H), 7.53 (s, 1H), 7.20 (d, J= 8.8 Hz, 1H), 6.62 (s, 1H), 6.49 (s, 1H), 6.33 (s, 2H), 4.73 (dd, J= 12.4, 5.6 Hz, 1H), 4.16 - 4.05 (m, 3H), 3.99 (s, 3H), 3.92 (s, 3H), 3.86 (t, J= 6.4 Hz, 2H), 3.83 (s, 3H), 3.69 (d, J= 10.0 Hz, 1H), 3.60 - 3.56 (m, 3H), 3.41 - 3.34 (m, 3H), 3.29 - 3.26 (m, 2H), 3.24 (s, 3H), 3.01 (t, J = 10.0 Hz, 1H), 2.66 - 2.50 (m, 2H), 2.22 (s, 6H), 2.08 (quint., J= 6.8 Hz, 2H), 1.95 - 1.88 (m, 2H), 1.71 - 1.62 (m, 1H), 1.03 (d, J= 6.8 Hz, 3H).Example 1173-((263 5fl,l722l?«,2^1?)-2^-chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-2*-oxo-2*,22,23,2^-tetrahydro-l*f / ,3* / / -5-oxa-2(2,6)- pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12-yl)propanal

[0414] Example 115 (150 mg, 0.184 mmol, 1.0 eq) was dissolved in DCM (3 mL) and pyridine was added (0.060 mL, 0.736 mmol, 4.0 eq). Dess-Martin periodinane (117 mg, 0.276 mmol, 1.5 eq) was added and the reaction was allowed to stir 18 h at RT. The reaction was extracted with DCM, washed with H2O, washed with brine, dried over MgSCL, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the title compound (114 mg, 76% yield). LCMS (ESI) Method 2: RT = 1.621 min, m / z = 811.9 (M+H)+.212657-0002-WO01Example 117A (26345fl,l722^«,247?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l5- dimethoxy-24,31 -dimethyl-l7-(3-(pyrrolidin-l-yl)propyl)-21,27,2^,24-tetrahydro--oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 2^ -one

[0415] The title compound (5 mg, 10% yield) was prepared following General Procedure L using Example 117, (38 mg, 0.047 mmol, 1.0 eq) and pyrrolidine (20 mg, 0.28 mmol, 6.0 eq). LCMS (ESI) Method 2: RT = 1.158 min, m / z = 867.0 (M+H)+.Example 118(2^34S„.1 2' / ?„,24 / ?)-27-( liloro-2 '^-(3-(4-cliloio-3.5-diiiietlivlpheiioxy)pi()pyl)-l4.l - dimethoxy-24,31 -dimethyl-12-(3-((pyridin-3-ylmethyl)amino)propyl)-21,27,2^,24- tetrahydro-ll / 7,3^-5-oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21 -one212657-0002-WO01

[0416] The title compound (5 mg, 10% yield) was prepared following General Procedure L using Example 117 (38 mg, 0.047 mmol, 1.0 eq) and pyridin-3-ylmethanamine (30 mg, 0.28 mmol, 6.0 eq). LCMS (ESI) Method 2: RT = 0.783 min, m / z = 904.0 (M+H)+Example 119(2f’3^S„.1 2' / ?„,2^ / ?)-2^-( hloro-2 '')-(3-(4-chl()io-3.5-diniethylphenoxy)propyl)-H.lS- dimetho y-24,3 l-dimethyl-12-(3-morpholinopropyI)-21,22,2^,24-tetrahydro-l 1 / 7,31 / 7-5- oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0417] The title compound (9 mg, 20% yield) was prepared following General Procedure L using Example 117 (38 mg, 0.047 mmol, 1.0 eq) and morpholine (24 mg, 0.28 mmol, 6.0 eq). LCMS (ESI) Method 2: RT = 1.086 min, m / z = 883.0 (M+H)+.Example 120(263 5a,l722lffl,2^1?)-2^-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-lz,15- dimethoxy^,31 -dimethyl- 1 ^-(l-m ethyl- l / 7-pyrazol-4-yl)-21,2^,2^,24-tetrahydro-212657-0002-WO01I1 / , 3}H-5 -oxa-2(2.6)-pyrazino| 1.2-< / |indola- 1(7.1 )-ind()la-3(4.3)-pyrazolacyclooctaphan- l^-one

[0418] Step A: (l?)-6-(3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-LH-pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(4,5-dimethoxy-2-(l-methyl-l / / -pyrazol-4-yl)-l / / -indol-7-yl)-4-methyl-3,4-dihydropyrazino[l,2-«]indol-l(2H)-one. The title compound (630 mg, 42% yield) was prepared following General Procedure A using Intermediate 5 (1.10 g, 1.59 mmol, 1.0 eq) and Intermediate 21 (740 mg, 2.2 mmol, 1.4 eq). LCMS (ESI) Method 2: RT = 1.781 min, m / z = 943.9 (M+H)+.

[0419] Step B: (l?)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(4,5-dimethoxy-2-(l-methyl-l / f-pyrazol-4-yl)-l / / -indol-7-yl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-lH-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[l,2-a]indol-l(2H)-one. The title compound was prepared in a 2-step process starting with following General Procedure B using the product from Step A (630 mg, 0.66 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.322 min, m / z = 854.0 (M+H)+. The resulting residue was converted to the title compound (533 mg, 74% yield over 2 steps) following General Procedure C. LCMS (ESI) Method 2: RT = 1.706 min, m / z = 1000.0 (M+H)+.

[0420] Step C: (26345fl,l7227?fl,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,3^-dimethyl-12-(l-inethyl-17 / -pyrazol-4-yl)-21,22,2J,24-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino|1.2 / |iiidola-l(7.l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The title compound (165 mg, 37% yield) was prepared following General Procedure D using the product from Step B (533 mg, 0.53 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.605 min, m / z = 835.9 (M+H)+.212657-0002-WO01Example 121(263 5a,l722lffl,24l?)-27-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-24,31-dimethyl-12-(l-methyl-l / / -pyrazol-3-yl)-21,22,2-’,24-tetrahydro- I1H, 3^-5 -oxa-2(2,6)-pyrazino[l,2-6z]indola-l(7,l)-indola-3(4,3)-pyi*azolacyclooctaphan- 2^-one

[0421] Step A: ( / ?)-6-(3-((3-(Benzyloxy)propoxy)inethyl)-l-methyl-lZ / -pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(4,5-dimethoxy-2-(l-methyl-l / 7-pyrazol-3-yl)-l / f-indol-7-yl)-4-methyl-3,4-dihydropyrazino[l,2-a]indol-l(2H)-one. The title compound (157 mg, 57% yield) was prepared following General Procedure A using Intermediate 5 (200 mg, 0.29 mmol, 1.0 eq) and Intermediate 22 (214 mg, 0.638 mmol, 2.2 eq). LCMS (ESI) Method 2: RT = 1.616 min, m / z = 944.3 (M+H)+.

[0422] Step B: (l?)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(4,5-dimethoxy-2-(l-methyl-l / / -pyrazol-3-yl)-l / / -indol-7-yl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-l / f-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[l,2-fl]indol-l(2H)-one. The title compound (111 mg, 78% yield) was prepared following General Procedure B using the product from Step A (157 mg, 0.166 mmol, 1.0 eq). Following isolation of the crude residue, it was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes. LCMS (ESI) Method 2: RT = 1.356 min, 1.409 min (mixture of rotamers), m / z = 854.2 (M+H)+.

[0423] (l?)-3-((4-(7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(4,5-dimethoxy-2-(l-methyl-l / f-pyrazol-3-yl)-l / / -indol-7-yl)-4-methyl-l -oxo-1, 2,3,4-tetrahydropyrazino[l,2-a]indol-6-yl)-l-methyl-lH-pyrazol-3-yl)methoxy)propyl 4-methylbenzenesulfonate. The title compound (108 mg, 82% yield) was prepared following General Procedure C using the product from Step B (111 mg, 0.13 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.638 min, 1.727 min (mixture of rotamers), m / z = 1008.3 (M+H)+.

[0424] Step D: (26345fl,l722^fl,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,3^-dimethyl-l7-(l-methyl-17 / -pyrazol-3-yl)-21,2^,2,24-tetrahydro- 11 / 7,3 / / -5-oxa-2(2,6)-py razino [1,2-a] indola- 1 (7, l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The title compound (36 mg, 40% yield) was prepared212657-0002-WO01following General Procedure D using the product from Step C (108 mg, 0.11 mmol, 1.0 eq). Following workup of the reaction, the crude product was purified by reverse phase HPLC to afford the product. LCMS (ESI) Method 2: RT = 1.577 min, m / z = 836.2 (M+H)+.Example 122 (2^3-l. S'„.l72' / ?„.2^ / ?)-2^-( hloro-2 ' ^-(3-(4-clil()ro-3.5-diiiiethylphenoxy)propyl)-lS- methoxy-14,24,31 -trimethyl-12-(l-methyl-lZ / -pyrazol-4-yl)-21,2^,2J,2^-tetrahydro--oxa-2(2,6)-pyrazino [ 1,2-a] indola- 1(7,1 )-indola-3(4,3)-pyrazolacyclooctaphan- 2^-one

[0425] Step A: (7?)-6-(3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-l / 7-pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(5-methoxy-4-methyl-2-(l-methyl-lH-pyrazol-4-yl)-lJ / -indol-7-yl)-4-inethyl-3,4-dihydropyrazino[l,2-fl]indol-l(2 / / )-one. Intermediate 5 (200 mg, 0.29 mmol, 1.0 eq), Intermediate 23 (220 mg, 0.69 mmol, 2.4 eq), Cui (28 mg, 0.145 mmol, 0.5 eq), N1,N2-dimethylcyclohexane-1,2-diamine (18 mg, 0.145 mmol, 0.5 eq), and K3PO4(185 mg, 0.87 mmol, 3.0 eq) were weighed and dissolved in toluene (0.4 mb). The reaction was sparged with argon for 5 min, sealed, and heated to 100 °C overnight. The reaction extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes followed by 0 to 10% MeOH in DCM to afford the title compound (170 mg, 63% yield). LCMS (ESI) Method 2: RT = 1.953 min, m / z = 927.9 (M+H).

[0426] Step B: (l?)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-TH-pyrazol-4-yl)-2-(5-methoxy-4-methyl-2-(l-methyl-l / / -pyrazol-4-yl)-LH-indol-7-yl)-4-methyl-3,4-dihydropyrazino[l,2-fl]indol-l(2 / / )-one.212657-0002-WO01The title compound (154 mg, quant, yield) was prepared following General Procedure B using the product from Step A (170 mg, 0.183 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.432 min, m / z = 837.9 (M+H).

[0427] Step C: (7?)-3-((4-(7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(5-methoxy-4-methyl-2-(l-methyl-LH-pyrazol-4-yl)-LH-indol-7-yl)-4-methyl-l-oxo-l, 2,3,4-tetrahydropyrazino[l,2-a]indol-6-yl)-l-methyl-l / / -pyrazol-3-yl)methoxy)propyl 4-methylbenzenesulfonate. The title compound (32 mg, 50% yield) was prepared following General Procedure C using the product from Step B (54 mg, 0.064 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.744 min, m / z = 991.8 (M+H).

[0428] Step D: (26345fl,l722^,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15-methoxy-l4,24,31-trimethyl-12-(l-methyl-LH-pyrazol-4-yl)-2'.27,2^.24-tetrahydro-l ' / / ,3' / / -5-oxa-2(2.6)-pyrazino|l,2-u|indola-l(7.1 )-indola-3(4.3)-pyrazolacyclooctaphan-2^-one. The product from Step C (20 mg, 0.02 mmol, 1.0 eq) was dissolved in DMF (0.5 mL). NaH (2.4 mg, 0.1 mmol, 5.0 eq) was added, and the reaction was stirred overnight at RT. The reaction was quenched with H2O, extracted with EtOAc, washed with H2O, washed with brine, dried over MgSCU, filtered, and concentrated. The crude product was purified by reverse phase HPLC to afford the title compound (6 mg, 40% yield). LCMS (ESI) Method 2: RT = 1.653 min, m / z = 819.9 (M+H)+.Example 123212657-0002-WO01(2634 / <„l722 / ?fl,24 / ?)-2 0-(3-(4-Chloro-3,5-dimethylphenoxy )propyl)-l4,l ^-dimethoxy- 24,31 -diniethyl-12-(l-methyl-l / / -pyrazol-4-yl)-21,2^,2^,24-tetrahydro-l^H-5-oxa- 2(2,6)-pyrazino[l,2-flf]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan-21-one

[0429] Example 120 (165 mg, 0.197 mmol, 1.0 eq) was dissolved inDCM (5 mL) and MeOH (5 mL). The reaction was sparged with argon for 5 min, and Pd / C (10 wt.%, 63 mg, 0.06 mmol, 0.3 eq) and Pd(OH)2 / C (20 wt.%, 42 mg, 0.06 mmol, 0.3 eq) were added. The reaction was sparged with H2, and then allowed to stir under an atmosphere of H2 for 48 h. The reaction was filtered through a pad of Celite®, rinsed with DCM, and concentrated. The crude product was purified by reverse phase HPLC eluting with acetonitrile in water (0.1 % of TFA) to afford the product. The product was dissolved in DCM (5 mL), neutralized with aqueous NaHCOs, and concentrated to afford the title compound (78 mg, 49% yield). LCMS (ESI) Method 2: RT = 1.489 min, m / z = 802.2 (M+H)+.Example 124(2634l?(Z,l722l?fl,24l?)-2^(-)_(3-(395_Dimethylphenoxy)propyl)-l4,15-dimethoxy-24,31- dimethyl-12-(l-methyl-l / / -pyrazol-4-yl)-2^,22,2^,24-tetrahydro-l^ / / ,3^2 / -5-oxa-2(2,6)- pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan-21-one

[0430] Example 120 (35 mg, 0.042 mmol, 1.0 eq) was dissolved in THF (4 mL) and 'PrOH (5 mL). The reaction was sparged with argon for 5 min, and Pd / C (10 wt.%, 13 mg, 0.013 mmol, 0.3 eq) and Pd(OH)2 / C (20 wt.%, 9 mg, 0.013 mmol, 0.3 eq) were added. The reaction was sparged with H2, and then allowed to stir at 50 °C under an atmosphere of H2 for 48 h. The reaction was filtered through a pad of Celite®, rinsed with DCM, and concentrated. The crude212657-0002-WO01product was purified by reverse phase HPLC to afford the title compound (78 mg, 49% yield). LCMS (ESI) Method 2: RT = 1.310 min, m / z = 768.1 (M+H)+.ACl Example 125 (2^3^S„.1 2‘ / ?„,2^ / ?)-2^-( hloio-2 '^-(3-(4-chloio-3.5-diiiiethylphenoxy)piopyl)-l^.lS- dimethoxy-2^,31-dimethyl-lJ-(l-methyl-177-pyrazol-4-yl)-2^,22,2^,24-tetrahydro--oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi*azolacyclooctaphan- 2^-one

[0431] Step A: (7?)-6-(3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-L Z-pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(4,5-dimethoxy-3-(l-methyl-l / / -pyrazol-4-yl)-l / / -ind()l-7-yl)-4-methyl-3.4-dihydropyraziiio| 1.2-u|indol- 1 (2 / / )-one. The title compound (65 mg, 40% yield) was prepared following General Procedure A using Intermediate 5 (120 mg, 0.17 mmol, 1.0 eq) and Intermediate 25 (140 mg, 0.41 mmol, 2.4 eq). LCMS (ESI) Method 2: RT = 1.746 min, m / z = 944.0 (M+H)+.

[0432] Step B: (l?)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(4,5-dimethoxy-3-(l-methyl-lH-pyrazol-4-yl)-LH-indol-7-yl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-l / J-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[l,2-ff]indol-l(2H)-one. The title compound (58 mg, 99% yield) was prepared following General Procedure B using the product from Step A (65 mg, 0.069 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.460 min, m z = 854.0 (M+H)+.

[0433] Step C: (l?)-3-((4-(7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(4,5-dimethoxy-3-(l-methyl-LH-pyrazol-4-yl)-LH-indol-7-yl)-4-methyl-l-oxo-l,2,3,4-tetraliydropyrazino[l,2-a]indol-6-yl)-l-methyl-l / / -pyrazol-3-yl)methoxy)propyl 4-212657-0002-WO01methylbenzenesulfonate. The title compound (32 mg, 47% yield) was prepared following General Procedure C using the product from Step B (58 mg, 0.068 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.739 min, m / z = 1007.8 (M+H)+.

[0434] Step D: (26345fl,l722i?«,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,34-dimethyl-l^-(l-methyl-l / 7-pyrazol-4-yl)-24,2^,2^,24-tetrahydro- 1 ' / / .3 ' H-5 -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-2*-one. The title compound (12 mg, 45% yield) was prepared following General Procedure D using the product from Step C (32 mg, 0.032 mmol, 1.0 eq). The crude material was purified by reverse phase HPLC. LCMS (ESI) Method 2: RT = 1.337 min, m / z = 837.0 (M+H)+.Example 126(2^34S„.1 2“ / ?„.24 / ?)-27-( hloro-2 ' ^-(3-(4-chl()ro-3.5-dimethylphenoxy)propyl)-l ^.1 - dimethoxy-l7-(l-(2-methoxyethyl)-17-pyrazol-4-yl)-24,3^-dimethyl-21,27,2J,24- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino|1.2-( / |indola- 1(7.1 )-indola-3(4,3)- pyrazolacyclooctaphan-21 -one

[0435] Step A: (l?)-6-(3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-l / / -pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(4,5-dimethoxy-2-(l-(2-methoxyethyl)-l / 7-pyrazol-4-yl)-l / / -indol-7-yl)-4-methyl-3,4-dihydropyrazino[l,2-«]indol-l(2J / )-one. The title compound (64 mg, 45% yield) was prepared following General Procedure A using Intermediate 5 (100 mg, 0.145 mmol, 1.0 eq) and Intermediate 26 (130 mg, 0.34 mmol,212657-0002-WO012.3 eq). The reaction was allowed to stir overnight but failed to reach complete conversion. LCMS (ESI) Method 2: RT = 2.163 min, m / z = 988.0 (M+H)+.

[0436] Step B: (l?)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(4,5-dimethoxy-2-(l-(2-methoxyethyI)-l / / -pyrazol-4-yl)-l / Z-indol-7-yI)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-LH-pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[l,2-a]indol-l(2H)-one. The title compound (55 mg, 95% yield) was prepared following General Procedure B using the product from Step A (64 mg, 0.065 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.254 min, m / z = 898.0 (M+H)+.

[0437] Step C: (7?)-3-((4-(7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2-(4,5-dimethoxy-2-(l-(2-methoxyethyl)-l / / -pyrazol-4-yl)-l / / -indol-7-yl)-4-methyl-l-oxo-l,2,3,4-tetrahydropyrazino[ l,2-a]indol-6-yl)-l-inethyl-l / / -pyrazol-3-yl)methoxy)propyl 4-methylbenzenesulfonate. The title compound (49 mg, 76% yield) was prepared following General Procedure C using the product from Step B (55 mg, 0.061 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.489 min, m / z = 1051.9 (M+H)+.

[0438] Step D: (26345fl,l722^,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)- l4. -dimethoxy-l7-( l-(2-methoxyethyl)- l / / -pyrazol-4-yl)-24,31 -dimethyl-24,2^,2^,24-tetrahydro- 1 ' / / ,3 ' / / -5 -oxa-2(2,6)-pyr azino [1,2-a] indola-l(7,l)-indoIa-3(4,3)-pyrazolacyclooctaphan-21-one. The title compound (13 mg, 32% yield) was prepared following General Procedure D using the product from Step C (49 mg, 0.047 mmol, 1.0 eq). The crude material was purified by reverse phase HPLC. LCMS (ESI) Method 2: RT = 1.489 min, m / z = 1051.9 (M+H)+.212657-0002-WO01(2^34Aa,1^227?fl,24l?)-27-Chloro-l4,l^-dimethoxy-24,34-dimethyl-l2-(l-methyl-l / 7- pyrazol-4-yl)-21<2-(3-(naphthalen-l-yloxy)propyl)-21,22,2^,24-tetrahydro-l ^H,3 ^H-5-oxa- 2(2 / >)-pyrazino| 1.2-( / |indol;i-l (7.1 )-iiidol;i-3(4.3)-pyrazolacyclooctaphan-2 '-one

[0439] Step A: (7?)-6-(3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-177-pyrazol-4-yl)-7-chloro-2-(4,5-dimethoxy-2-(l-methyl-l / f-pyrazol-4-yl)-l / / -indol-7-yl)-4-methyl-10-(3-(naphthalen-l-yloxy)propyl)-3,4-dihydropyrazino[l,2-cz]indol-l(2 / 7)-one. The title compound (400 mg, 83% yield) was prepared following General Procedure A using Intermediate 18 (350 mg, 0.51 mmol, 1.0 eq) and Intermediate 21 (260 mg, 0.77 mmol, 1.5 eq). LCMS (ESI) Method 3: Rr = 1.08 min, m / z = 932.4 (M+H)+.

[0440] Step B: ( / )-7-Chloro-2-(4,5-dimethoxy-2-(l-methyl-l / / -pyrazol-4-yl)-l / / -indol-7-yl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-17 / -pyrazol-4-yl)-4-methyl-10-(3-(naphthalen-l-yloxy)propyl)-3,4-dihydropyrazino[l,2-rz]indol-l(2 / / )-one. The title compound (360 mg, 94% yield) was prepared following General Procedure B using the product from Step A (400 mg, 0.42 mmol, 1.0 eq). LCMS (ESI) Method 3: RT = 0.87 min, m / z = 843.5 (M+H)+.

[0441] Step C: (l?)-3-((4-(7-Chloro-2-(4,5-dimethoxy-2-(l-methyl-l / / -pyrazol-4-yl)-l / / -indol-7-yl)-4-methyl-10-(3-(naphthalen-l-yloxy)propyl)-l-oxo-l, 2,3,4-tetrahydropyrazino[l,2-a]indol-6-yl)-l-methyl-177-pyrazol-3-yl)methoxy)propyl 4-methylbenzenesulfonate. The title compound (320 mg, 81% yield) was prepared following General Procedure C using the product from Step B (360 mg, 0.40 mmol, 1.0 eq). LCMS (ESI) Method 3: RT = 1.11 min, m / z = 997.5 (M+H)+.

[0442] Step D: (2634S„.l722 / C.24 / ?)-27-Cliloro-l4.l -diinethoxy-24.3l-diinethyl-l2-(l-m ethyl- 1H- pyrazol-4-yl)-240-(3-(naphthalen-l-yloxy)propyl)-24,22,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-24-one. The product from Step C (320 mg, 0.32 mmol, 1.0 eq) was dissolved in DMF (35 mL) under an atmosphere of argon. NaH (60% in mineral oil, 39 mg, 3.0 eq) was added and the reaction was heated to 60 °C for 24 h. The reaction was quenched with H2O, extracted with EtOAc, washed with H2O, washed with brine, dried over MgSCL, filtered, and concentrated. The crude material was purified by reverse phase HPLC to afford the title compound (38 mg, 23% yield). LCMS (ESI) Method 3: RT = 0.96 min, m / z = 824.6 (M+H)+.212657-0002-WO01Example 128(26345a,l722?«,2^1f)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^- hydroxy-l4-methoxy-24,34-dimethyl-l^-(l-methyl-l / / -pyrazol-4-yl)-21,2^,2^,24- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1.2-< / |indola-l (7.1 )-indola-3(4.3)- pyrazolacyclooctaphan-21-one

[0443] Step A: (47?)-2-(5-(Benzyloxy)-4-methoxy-2-(l-inethyl-l / / -pyrazol-4-yl)-LH-indol-7-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(l-methyl-3-((3-((tetrahydro-2Z / -pyran-2-yl)oxy)propoxy)methyl)- 1 / / -pyrazol-4-yl)-3.4-dihydropyrazino[l,2-a]indol-l(2Jf)-one. The title compound (688 mg, 77% yield) was prepared following General Procedure A using Intermediate 8 (600 mg, 0.878 mmol, 1.0 eq) and Intermediate 27 (638 mg, 1.55 mmol, 1.75 eq). LCMS (ESI) Method 2: RT = 1.859 min, m / z = 1013.9 (M+H).

[0444] Step B: (l?)-2-(5-(Benzyloxy)-4-methoxy-2-(l-methyl-lH-pyrazol-4-yl)-LH-indol-7-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-l / / -pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[l,2-«]indol-l(2Z / )-one. The product from Step A (688 mg, 0.702 mmol, 1.0 eq) was dissolved in MeOH (20 mL). Tosic acid monohydrate (40 mg, 0.21 mmol, 0.3 eq) was added and the reaction was heated to 50 °C for 4 h. The reaction was extracted with EtOAc, washed with aq. NaHCO3, washed with brine, dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by flash column chromatography eluting with 0 to 100% EtOAc / MeOH (95:5) in hexanes to afford the title compound (392 mg, 62% yield). LCMS (ESI) Method 2: RT = 1.486 min, m / z = 930.0 (M+H).212657-0002-WO01

[0445] Step C: (7?)-3-((4-(2-(5-(Benzyloxy)-4-methoxy-2-(l-methyl-l / / -pyrazol-4-yl)-12 / -indol-7-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-l-oxo-1,2,3, 4-tetrahydropyrazino[ 1, 2-< / | indol-6-y 1 )- 1 -methyl- 17 / -pyrazol-3-yl)methoxy)propyl 4-methylbenzenesulfonate. The title compound (454 mg, 97% yield) was prepared following General Procedure C using the product from Step B (392 mg, 0.43 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.783 min, m / z = 1083.9 (M+H).

[0446] Step D: (26345fl,l722^fl,24 / ?)-l5-(Benzyloxy)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4-methoxy-24,34-dimethyl-12-(l-methyl-l / f-pyrazol-4-yl)-2'.27,2^.24-tetrahydro-l ' / / ,3' / / -5-()xa-2(2.6)-pyraziiio|L2-< / |iiidola-l(7.1 )-indola-3(4.3)-pyrazolacyclooctaphan-21-one. The title compound (153 mg, 40% yield) was prepared following General Procedure D using the product from Step C (454 mg, 0.418 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.822 min, m / z = 912.0 (M+H).

[0447] Step E: (2634&,l7227?„,24^)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1 -hydroxy-l4-methoxy-24,34-dimethyl-12-(l-methyl-lZ / -pyrazol-4-yl)-2 '.27,2^.24-tetrahydro-l ' / / .3* / / -5 -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The title compound (138 mg, 100% yield) was prepared following General Procedure B the product from Step D (153 mg, 0.168 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.289 min, m / z = 822.0 (M+H).Example 128A212657-0002-WO01(2^3^S„.r 2" / ?„.2^ / ?)-2^-( hloro-2 ’('-(3-(4-chl()ro-3. -diniethvlphenoxy)propyl)- -(2- (dimethylamino)ethoxy)-14-methoxy-24,3^-dimethyl-12-(l-methyl-l / / -pyrazol-4-yl)- 21,2^,2^,24-tetr ahydro- 1 ^H,3 l / -5-oxa-2(2,6)-pyrazino [1,2-a] indola- 1 (7, 1 )-indola-3(4,3)- pyrazoIacyclooctaphan-21 -one

[0448] The title compound (19 mg, 25% yield) was prepared following General Procedure I using Example 128 (25 mg, 0.17 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.026 min, m / z = 893.1 (M+H).Example 129(26345fl,l722?a,24 / ?)-2 -Chloro-210-(3-(4-chloro-3,5-diniethylphenoxy)propyl)-14- methoxy-24,3^-dimethyl-12-(l-methyl-l / / -pyrazol-4-yl)-l^-(2-morpholinoethoxy)- 21,22,2,24-tetrahydro-l / / ,31. H-5-oxa-2(2,6)-pyrazino[l,2-£z]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21 -one

[0449] The title compound (27 mg, 34% yield) was prepared following General Procedure I using Example 128 (70 mg, 0.085 mmol, 1.0 eq) and 4-(2-bromoethyl)morpholine hydrobromide (47 mg, 0.17 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.035 min, m / z = 935.0 (M+H).212657-0002-WO01Example 130(26345a,l722 / ?(,,24lf)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15- methoxy-,2^,3^-trimethyl- -(l,3,4-oxadiazol-2-yl)-2*,2^,2^,2^-tetrahydro-l * / / ,3^7 / -5- oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0450] Intermediate 7 (50 mg, 0.060 mmol, 1.0 eq) was dissolved in DCM (0.5 mL). The resultant solution was added to (isocyanoimino)triphenylphosphorane (45 mg, 0.14 mmol, 2.2 eq) in DCM (0.5 mL). The reaction was allowed to stir overnight at 30 °C. The reaction was extracted with EtOAc, washed with H2O, washed with aq. NaHCO3, washed with aq. NH4CI, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by reverse phase HPLC to afford the title compound (26 mg, 50% yield).Example 131(26345«,l722?«,2^1?)-2^-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dim ethoxy-24,31 -dimethyl-21 -oxo-21,2^,2^,24-tetrahydro- 13 l / f-5-oxa-2(2,6)- pyrazino[l,2-a']indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12-carbonitrile212657-0002-WO01

[0451] Step A: (26345fl,l7227?fl,24T?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)- 14, 1 -dimethoxy-24,31 -dimethyl-21 -oxo-21,22,23,24-tetrahydro-1 ' / / .3' / / -5-ox;i-2(2.6)-pyi;izino|l.2-^| indola- 1(7.1 )-indola-3(4.3)-pyrazolacyclooctaphane-l2-carboxamide. In a reaction vessel, Intermediate 6 (420 mg, 0.525 mmol, 1.0 eq) was dissolved in DMF (20 mL). HATU (399 mg, 1.05 mmol, 2.0 eq) and DIPEA (407 mg, 3.15 mmol, 6.0 eq) were added and the reaction was allowed to stir 5 min at RT. NH4Cl (84.2 mg, 1.57 mmol, 3.0 eq) was added and the reaction was allowed to stir for 1 h. The reaction was extracted with EtOAc, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes followed by 0 to 10% MeOH in DCM to afford the title compound (284 mg, 68% yield). LCMS (ESI) Method 2: RT = 1.385 min, m / z = 799.2 (M+H)+.

[0452] Step B: (2634&,l7227?„,24^)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,34-dimethyl-24-oxo-24,22,23,24-tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino| l,2-a]indola-l(7,l )-indola-3(4,3)-pyrazolacyclooctaphane-l2-carbonitrile. The product from Step A (170 mg, 0.213 mmol, 1.0 eq) was dissolved in DCM (10 mL), followed by addition of pyridine (135 mg, 1.70 mmol, 8.0 eq) and the reaction was cooled to 0 °C. Trifluoroacetic anhydride (179 mg, 0.850 mmol, 4.0 eq) was added and the reaction was stirred for 10 min at 0 °C followed by RT for 30 min. The reaction was extracted with EtOAc, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the title compound (150 mg, 90% yield). LCMS (ESI) Method 2: RT = 1.742 min, m / z = 781.2 (M+H)+.212657-0002-WO01Example 132(26345a,l722?fl,2^1f)-2^-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15- methoxy-l4,24,3 l-trimethyl-2 l-oxo-21,27,2J,24-tetrahydro-l ^H,3 l / / -5-oxa-2(2,6)- pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carbonitrile

[0453] Step A: (26345fl,l722?fl,24T?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15-methoxy-l4,24,34-trimethyl-21-oxo-2^,2^,2^,24-tetrahydro-llH,3lH-5 -oxa-2(2,6)-pyrazino[l,2-o]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphane-12-carboxamide. The title compound (52 mg, 68% yield) was prepared following General Procedure M using Intermediate 7 (76 mg, 0.10 mmol, 1.0 eq) and NH4CI (20 mg, 0.30 mmol, 3.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 80% EtOAc / MeOH (95:5) in hexanes to afford the title compound. LCMS (ESI) Method 1: RT = 2.32 min, m / z = 783 (M+H)+.

[0454] Step B: (26345fl,l722 / ?„,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l 5-methoxy-l4,24,3 l-trimethyl-2 l-oxo-21,27,2^,24-tetrahydro-l H,3lH-5 -oxa-2(2,6)-pyrazino[l,2<z]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carbonitrile. The product from Step A (52 mg, 0.07 mmol, 1.0 eq) was dissolved in dry DCM (2 mL) under argon. Pyridine (50 mg, 0.6 mmol, 10 eq) was added, stirred 5 min, then cooled to 0 °C. TFAA (60 mg, 0.30 mmol, 4.3 eq) was added dropwise and allowed to stir for 15 min. The reaction was warmed to RT and stirred for 1 h. The reaction was extracted with EtOAc, washed with sat. aq. NH4CI, washed with sat. aq. NaHCO3, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was then purified by reverse phase212657-0002-WO01HPLC afford the title compound (40 mg, 78% yield). LCMS (ESI) Method 2: RT = 1.72 min, m / z = 765 (M+H)+.Example 133(26345„,1722 / ?«,2^T?)-2^-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l 4,1 dimethoxy-24,31-dimethyl-12-(2 / 7-tetrazol-5-yl)-2',22,2%24-tetrahydro-l ' / / ,3' / / -5-oxa- 2(2,6)-pyrazino[l,2-< ]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0455] Example 131 (150 mg, 0.192 mmol, 1.0 eq), LiCl (16 mg, 0.38 mmol, 2.0 eq), and NH4CI (62 mg, 1.15 mmol, 6.0 eq) were dissolved in DMF (6 mL) at 0 °C. Sodium azide (75 mg, 1.15 mmol, 6.0 eq) was added and the reaction was allowed to stir for 10 min, followed by warming to room temperature for 30 min. The reaction was diluted with EtOAc and IM HC1. The reaction was extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the title compound (140 mg, 89% yield). A portion (50 mg) was purified by reverse phase HPLC to afford the title compound (19 mg). LCMS (ESI) Method 1: RT = 2.297 min, m / z = 824.2 (M+H)+.212657-0002-WO01Example 134(263 5a,l722lffl,2^1?)-2^-Chloro-2^(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,l^- dimethoxy-24,31-dimethyl-12-(2-methyl-2 / / -tetrazol-5-yl)-2,22,2-’,24-tetrahydro- I1H, 3^-5 -oxa-2(2,6)-pyrazino[l,2-6z]indola-l(7,l)-indola-3(4,3)-pyi*azolacyclooctaphan- 2^-one

[0456] Example 133 (90 mg, 0.11 mmol, 1.0 eq) was dissolved in DMF (4 mL), followed by addition of Cs2CO3(110 mg, 0.33 mmol, 3.0 eq) and Mel (23 mg, 0.16 mmol, 1.5 eq). The reaction was heated to 60 °C for 1 h. The reaction was extracted with EtOAc, washed with H2O, washed with brine, dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by reverse phase HPLC to afford the title compound (38 mg, 41% yield). LCMS (ESI) Method 1: RT = 2.447 min, m / z = 838.2 (M+H)+.Example 135 (26345fl,l722l?«,2^1?)-2^-Chloro-21(-)-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,15_ dimethoxy-24,31-dimethyl-12-(l-methyl-l / / -tetrazol-5-yl)-21,22,23,24-tetrahydro--oxa-2(2,6)-pyrazino[l,2-cz]indola-l(7,l)-indola-3(4,3)-pyi*azolacyclooctaphan- 2^-one

[0457] The title compound (13 mg, 14% yield) was isolated following the procedure described in Example 134. LCMS (ESI) Method 1: RT = 2.345 min, m / z = 838.2 (M+H)+.212657-0002-WO01Example 136(26345«,l722 / ?«,24 / ?)-27-Chloro-2^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,13- dimethoxy-l^, 3 -dimethyl-12-(5-oxo-4,5-dihydro-l, 2, 4-oxadiazol-3-yl)-2tetrahydro-11 / / , 3 l / / -5-oxa-2(2,6)-pyrazino[l,2-tf]indola-l(7,l)-indola-3(4, 3)- pyrazolacyclooctaphan-21 -one

[0458] Step A: (26345fl,l722 / ?(,,24 / ?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,31-dimethyl-24-oxo- l1,!2,!3,!4-tetrahydro-l4 / / ,34 / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxamide. The title compound (136 mg, 83% yield) was prepared following General Procedure M using Intermediate 6 (163 mg, 0.20 mmol, 1.0 eq) and NH4CI (35 mg, 0.62 mmol, 3.0 eq). Following workup, the crude residue was purified by flash column chromatography eluting with 0 to 90% EtOAc / MeOH (95:5) in hexanes.

[0459] Step B: (26345fl,l722 / ?fl,24 / ?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,3^-dimethyl-2^-oxo- 21,22,23,24-tetr ahydro- 14 / / ,3 l / f-5-oxa-2(2,6)-pyrazino [1,2-a] indola- 1 (7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carbonitrile. The product from Step A (135 mg, 0.17 mmol, 1.0 eq) was stirred in dry DCM (3.4 mL) under argon. Pyridine (110 mg, 1.4 mmol, 8.2 eq) was added, stirred 5 min, then cooled to 0 °C. TFAA (140 mg, 0.70 mmol, 4.1 eq) was added and the reaction was stirred at RT for 2 h. The reaction was diluted with EtOAc and acidified with 0.5 M HC1. The reaction was extracted with EtOAc, washed with aq. HC1 (0.5 M), dried over MgSO4, filtered, and concentrated. The crude residue...

Claims

212657-0002-WO01CLAIMSWhat is claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,wherein:G is a 5- to 6-membered aromatic heterocyclic ring containing 1-3 nitrogen atoms, wherein X1and X2are independently carbon or nitrogen ring atoms of ring G;m is 0, 1, 2, or 3;R1, at each occurrence, is independently Ci-4alkyl, Ci-4fluoroalkyl, halogen, -Ci-4alkylene-OH, -Ci-4alkylene-OCi-4alkyl, -Ci-4alkylene-NH2, -Ci-4alkylene-NHCi-4alkyl, -Ci-4alkylene- N(Ci-4alkyl)2, -O-Ci-4alkylene-OH, -O-Ci-4alkylene-OCi-4alkyl, -O-Ci-4alkylene-NH2, -O-Ci-4alkylene-NHCi-4alkyl, -O-Ci-4alkylene-N(Ci-4alkyl)2, G1, -Ci-salkylene-G1, -OG1, or-O-Ci-aalkylene-G1;G1is a C3-6cycloalkyl, a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a 5- to 6- membered heteroaryl containing 1-3 heteroatoms, or a phenyl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, Ci- 4fluoroalkyl, oxo, OH, -OCi-4alkyl, -C(O)Ci-4alkyl, -Ci-4alkylene-OCi-4alkyl, Gla, and -Ci-3alkylene-Glaand optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heteroatoms212657-0002-WO01contained in the heterocyclyl and heteroaryl of G1are independently selected from the group consisting of O, N, and S;Glais a C3-6cycloalkyl or a 4- to 7-membered heterocyclyl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S;L is a 4- to 8-atom divalent linker consisting of one or more members selected from the group consisting of Cialkylene, C2alkylene, Csalkylene, C4alkylene, Csalkylene, Cealkylene, Cralkylene, Csalkylene, Cialkenylene, C2alkynylene, -O-, -S-, -SO-, -SO2-, -C(O)-, -N(RX)-, and -Cy1-, provided that L does not comprise more than one Cy1and each occurrence of -0- -S-, -SO-, -SO2-, or -N(RX)- is separated by C(O) or two or more carbon atoms from each other occurrence of –O–, –S–, –SO–, –SO2–, or –N(Rx)–;Cy1is a l,l-C3-6cycloalkylene;Rxis hydrogen, Ci-4alkyl, C3-4cycloalkyl, or-Ci-3alkylene-C3-4cycloalkyl;R2is G2, - L2- Y2, Ci-4alkyl, C2-4alkenyl, CN, or H;L2is Ci-ealkylene, -CH=CH- or C3-6cycloalkylene (e.g., );Y2is -0R2a, -NR2aR2b, -C(0)0R2a, -C(O)NR2aR2b, -C(0)R2a, N3, or CN;R2ais H, Ci-4alkyl, -C2-3alkylene-Y2a, G2a, or-Ci-3alkylene-G2a;R2bis H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3-4cycloalkyl;or R2aand R2b, together with the nitrogen to which each attaches, form a 4- to 12-membered heterocyclyl containing 1-2 additional heteroatoms independently selected from the group consisting of O, N, and S, wherein the 4- to 12-membered heterocyclyl formed by R2aand R2bis optionally substituted with a first substituent selected from the group consisting of halogen, cyano, oxo, -OR20, -N(R20)2, -NR20C(O)R20, -C(O)OR20, -C(O)N(R20)2, Ci- 4alkyl, Ci-4fluoroalkyl, -Ci-4alkylene-OCi-4alkyl, -Ci-4alkylene-N(Ci-4alkyl)2, G2b, and -Ci-4alkylene-G2b, and optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen, oxo, OH, Ci-4alkyl, and Ci-4fluoroalkyl; G2is a 5-membered partially unsaturated or fully unsaturated (i.e. aromatic) heterocyclic ring that contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, is attached at a carbon ring atom of the heterocyclic ring, is optionally substituted with a first substituent selected from the group consisting of halogen, oxo, Ci-4alkyl, Ci-4fluoroalkyl, -OR21, -N(R21)2, -C(0)0R21, -C(O)N(R21)2, -Ci-3alkylene-OR21, -Ci- 3alkylene-N(R21)2, G2c, and -Ci-4alkylene-G2c, and is optionally further substituted with 1-212657-0002-WO013 substituents independently selected from the group consisting of halogen, Ci-4alkyl, and oxo;Y2ais -OCi-4alkyl, OH, -N(Ci-4alkyl)2, -NHCi-4alkyl, or -NH2;R20and R21, at each occurrence, are independently H, Ci-4alkyl, C3-4cycloalkyl, or-Ci- 3alkylene-C3-4cycloalkyl;G2a, G2b, and G2care independently a Cs-ecycloalkyl, a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, or a phenyl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, Ci-2fluoroalkyl, -OCi-4alkyl, OH, C3-4cycloalkyl, and -Ci- 3alkylene-C3-4cycloalkyl and optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G2a, G2b, and G2care independently selected from the group consisting of O, N, and S;R3is H, halogen, Ci-4alkyl, C3-4cycloalkyl, G3, or -Ci-4alkylene-N(R3a)2;R3a, at each occurrence, is independently H or Ci-4alkyl;G3is a 5-membered partially unsaturated or fully unsaturated (i.e., aromatic) heterocyclic ring that contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, is attached at a carbon ring atom of the heterocyclic ring, is optionally substituted with a first substituent selected from the group consisting of halogen, oxo, Ci-4alkyl, Ci-4fluoroalkyl, -OR31, -N(R31)2, -C(O)OR31, -C(O)N(R31)2, -Ci-3alkylene-OCi-4alkyl, -Ci- 3alkylene-N(Ci-4alkyl)2, G3c, and -Ci-4alkylene-G3cand is optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci- 4alkyl;R31, at each occurrence, is independently H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3- 4cycloalkyl;G3Cis a C3-6cycloalkyl, a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a 5- to 6- membered heteroaryl containing 1-3 heteroatoms, or a phenyl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, Ci-2fluoroalkyl, -OCi-4alkyl, OH, C3-4Cycloalkyl, and -Ci-3alkylene-C3-4Cycloalkyl and optionally further substituted with 1-3 substituents independently selected from the group212657-0002-WO01consisting of halogen and Ci-4alkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G3care independently selected from the group consisting of O, N, and S; R4ais -OCi-4alkyl, Ci-4alkyl, or H;R4bis -OR40, Ci-4alkyl, or H;R40is H, Ci-4alkyl, Ci-4haloalkyl, -C2-4alkylene-OH, -C2-4alkylene-OCi-4alkyl, -C2-4alkylene- NH2, -C2-4alkylene-NHCi-4alkyl, -C2-4alkylene-N(Ci-4alkyl)2, G4, or –C1-3alkylene–G4; G4is a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, a C3-6cycloalkyl, or a phenyl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, -C(O)OCi-4alkyl, G4a, and -Ci-3alkylene-G4aand optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G4are independently selected from the group consisting of O, N, and S;G4ais a C3-6cycloalkyl or a 4- to 7-membered heterocyclyl, each optionally substituted with 1-4 substituents independently selected from the group consisting of halogen and Ci-4alkyl, wherein the heterocyclyl in G4acontains 1-2 heteroatoms independently selected from the group consisting of O, N, and S;R4cis H;R5is -C2-4alkylene-O-G5;G5is a 6- to 12-membered aryl or a 5- to 12-membered heteroaryl containing 1-3 heteroatoms, each being optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, Ci-4alkyl, Ci-4fluoroalkyl, -OCi-4alkyl, -OCi- 4fluoroalkyl, and C3-4cycloalkyl, wherein the heteroatoms contained in the heteroaryl of G3are independently selected from the group consisting of O, N, and S;R6, at each occurrence, is independently halogen, Ci-4alkyl, Ci-4fluoroalkyl, -OCi-4alkyl, -OCi- 4fluoroalkyl, or C3-4cycloalkyl;R7is Ci-4alkyl;0 is 0, 1, 2, or 3;p is 0, 1, or 2; andq is 1 or 2.212657-0002-WO012. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein G is a 5-membered aromatic heterocyclic ring containing 1-3 nitrogen atoms.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1, at each occurrence, is independently Ci-4alkyl (the alkyl may be the same or different).

4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-salkylene, wherein optionally 1-2 methylene units are independently replaced with -O- or -N(RX)-.

5. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-salkenylene containing one double bond, wherein optionally 1 methylene unit is replaced with -O- or -N(RX)-.

6. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R2is G2.

7. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R2is -L2-Y2.

8. The compound of any of claims 1-5 or 7, or a pharmaceutically acceptable salt thereof, wherein L2is Ci-ealkylene.

9. The compound of any of claims 1-5 or 7, or a pharmaceutically acceptable salt thereof, wherein L2is.

10. The compound of any of claims 1-5 or 7, or a pharmaceutically acceptable salt thereof, wherein L2is the Cs-ecycloalkylene.

11. The compound of any of claims 1-5 or 7-10, or a pharmaceutically acceptable salt thereof, wherein Y2is -OR2a, -NR2aR2b, -C(O)OR2a, -C(O)NR2aR2b, -C(O)R2a, or N3.

12. The compound of any of claims 1-5 or 7-11, or a pharmaceutically acceptable salt thereof, wherein R2ais H, Ci-4alkyl, -C2-3alkylene-Y2a, G2a, or -Ci-3alkylene-G2a.212657-0002-WO0113. The compound of any of claims 1-5 or 7-12, or a pharmaceutically acceptable salt thereof, wherein R2bis H or Ci-4alkyl.

14. The compound of any of claims 1-5 or 7-11, or a pharmaceutically acceptable salt thereof, wherein R2aand R2b, together with the nitrogen to which each attaches, form the optionally substituted 4- to 12-membered heterocyclyl.

15. The compound of any of claims 1-5, 7-11, or 14, or a pharmaceutically acceptable salt thereof, wherein the first optional substituent of the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand R2bis -OR20, Ci-4alkyl, or G2b.

16. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R2is Ci-4alkyl, C2-4alkenyl, CN, or H.

17. The compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R3is H.

18. The compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R3is G3.

19. The compound of any of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R4ais OCH3, OCH2CH3, methyl, ethyl, or H.

20. The compound of any of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R4bis -OR40or H.

21. The compound of any of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R40is H, Ci-4alkyl, -C2-4alkylene-OCi-4alkyl, -C2-4alkylene-N(Ci-4alkyl)2, G4, or-Ci 3alkylene-G4.

22. The compound of any of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R5is -(CH2)3-O-G5.

23. The compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein G5is the optionally substituted 6- to 12-membered aryl.212657-0002-WO0124. The compound of any of claims 1 -22, or a pharmaceutically acceptable salt thereof, wherein G5is the optionally substituted 5- to 12-membered heteroaryl.

25. The compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has formula (II):R6a, R6b, and R6care independently H, halogen, Ci-4alkyl, Ci-4fluoroalkyl, -OCi-4alkyl, -OCi-4fluoroalkyl, or C3-4cycloalkyl.

26. The compound of any of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein p is 1.

27. The compound of any of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R7is methyl.

28. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein q is 1.212657-0002-WO0129. The compound of any of claims 25-28, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) has formula (III):

30. The compound of any of claims 25-29, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (11) or (111) has formula (IV):(IV).

31. The compound of claim 1 selected from the group consisting of a compound of Table 1 in embodiment E31.212657-0002-WO0132. A pharmaceutical composition comprising the compound of any of claims 1 -31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

33. The compound of any of claims 1-31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 32, for use in the treatment of cancer.

34. The compound of any of claims 1-31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 32, for use in the inhibition of cancer cell proliferation.

35. A method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any of claims 1-31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 32.

36. A method of inhibiting cancer cell proliferation, comprising administering to a subject in need thereof, the compound of any of claims 1-31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 32, in an amount effective to inhibit the cancer cell proliferation.

37. Use of the compound of any of claims 1-31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 32, in the manufacture of a medicament for the treatment of cancer.

38. Use of the compound of any of claims 1-31, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 32, in the manufacture of a medicament for the inhibition of cancer cell proliferation.

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