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

MACROCYCLIC MCL-1 INHIBITORSRELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Application No. 63 / 717,970, filed November 8, 2024, 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. CancerResearch (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),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-3alkylene-G1, -OG1, or–O–Ci-3alkylene–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- to7-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,C?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 –NR2aR2b, –OC1-6alkyl, OH, C1-6alkyl, or H;R2aisH, Ci-6alkyl, SO2R20, SO2N(R20)2, -C2-3alkylene-Y2, G2, or-Ci-3alkylene-G2;R2bis H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3-4cycloalkyl;R3is H, halogen, Ci-4alkyl, C3-4cycloalkyl, C(O)OR3a, or CH2NR3aR3b;R3ais H or Ci-ealkyl;R3bis H, Ci-ealkyl, -C2-3alkylene-Y3, G3, or-Ci-3alkylene-G3;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, -OR21, -N(R21)2, -NR22C(O)R21, C(O)R21, C(O)OR21, Ci-4alkyl, Ci- 4fluoroalkyl, -Ci-4alkylene-OR22, -Ci-4alkylene-N(R22)2, G2a, and -Ci-4alkylene-G2a, and optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen, oxo, OH, Ci-4alkyl, and Ci-4fluoroalkyl;or R3and R2b, together with the atom to which each attaches, form a 5-membered heterocycle; Y2is -OR22or-N(R22)2;G2is a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a Cs-iocarbocyclyl, a 5- to 12-membered heteroaryl containing 1-3 heteroatoms, or a 6- to 12- membered aryl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, Ci-4fluoroalkyl, -OR21, -N(R21)2, C(0)0R21, 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 G2are independently selected from the group consisting of O, N, and S;R20, at each occurrence, is independently H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3- 4cycloalkyl;R21, at each occurrence, is independently H, Ci-4alkyl, -Ci-3alkylene-OCi-4alkyl, -Ci- 3alkylene-N(Ci-4alkyl)2, G2b, or -Ci-3alkylene-G2b;R22, at each occurrence, is independently H, Ci-4alkyl, G2b, or –Ci-3alkylene–G2b;G2ais 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, G2c, and -Ci-3alkylene-G2cand 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 G2aare independently selected from the group consisting of O, N, and S;G2bis a Cs-ecycloalkyl 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 G2bcontains 1-2 heteroatoms independently selected from the group consisting of O, N, and S;G2Cis a 4- to 7-membered heterocyclyl containing 1-2 heteroatoms, a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, or a C3-6cycloalkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G2eare independently selected from the group consisting of O, N, and S;Y3is -OR30or-N(R30)2;R30, at each occurrence, is independently H, Ci-4alkyl, G3a, or -Ci-3alkylene-G3a;G3and G3aare independently a Cs-ecycloalkyl 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 G3contains 1-2 heteroatoms 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 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 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;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.

[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 atherapeutically 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. The present 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 of alkyl include, but are not limited to, methyl, ethyl, / / -propyl, Ao-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, / / -pentyl, z.vopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, / / -heptyl, / / -octyl, / / -nonyl, and / / -decyl.

[0023] The term “alkenyl,” as used herein, means a straight or branched, hydrocarbon chain of two or more carbons containing at least one carbon-carbon double bond, e.g., ethenyl, allyl.

[0024] The term “alkynyl,” as used herein, means a straight or branched, hydrocarbon chain of two or more carbons containing at least one carbon-carbon triple bond, e.g., ethynyl, propargyl.

[0025] The term “alkylene,” as used herein, refers to a divalent group derived from a straight or branched chain saturated 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(CH3)(D)-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0026] The term “alkenylene,” as used herein, refers to a divalent group derived from a straight or branched chain alkenyl. Alkenylene includes, for example, C4-8alkenylene, such as aCsalkenylene with one double bond, e.g.,. Alkenylene also includes C2alkenylene (ethenylene or vinylene)

[0027] The term “alkynylene,” as used herein, refers to a divalent group derived from a straight or branched chain alkynyl. Alkynylene includes, for example, C2alkynylene (ethynylene).

[0028] 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).

[0029] 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.

[0030] 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 bicyclic cycloalkenyl (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.

[0031] 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.

[0032] 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,Cycloalkylene includes a 1,1-cycloalkylene (e.g.,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 pararelationship on the heteroarene, e.g.,

[0033] 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.

[0034] The term “halogen” or “halo,” as used herein, means Cl, Br, I, or F.

[0035] 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.

[0036] 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 six membered 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., thi azol -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[1,2-a]pyridinyl (e.g., imidazo[1,2-a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl, and thiazolo[5,4-b]pyrimidin-2-yl.

[0037] 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 a three-, 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 abridged 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 fused to 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.

[0038] The term “imino” refers to the group “=NH.”

[0039] 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, "C3alkyl" 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).

[0040] 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.

[0041] 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 selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0042] ABBREVIATIONSAcOH = acetic acidaq. = aqueousatm. = atmosphereBoc = tert-butyl carbamate / carboxylateCbz = benzyl carbamateCbz-Cl = benzyl chloroformateCDCl3 = chloroform, deuteratedCelite® = diatomaceous earthcone. = concentratedδ = chemical shiftd = doubletDBU = 1,8-diazabicyclo[5.4.0]undec-7-eneDCM = dichloromethaneDCE = dichloroethanedd = 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)-oneDIAD = diisopropyl azodicarboxylateDIPEA = N,N-diisopropylethylamineDMAP = N,N-dimethyl-4-aminopyridineDMF = A’, Af-di methyl form am ideDMSO = dimethylsulfoxideDMSO-de = DMSO, deuteratedDi-tBAD = Di-tert-butyl azodicarboxylateEDC = 1-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]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphatehex = hexanesHPLC = high pressure liquid chromatographyHz = hertz / PrOH = isopropanolJ = coupling constant (Hz)LAH = lithium aluminum hydrideLCMS = liquid chromatography / mass spectrometryLiOH = lithium hydroxideM = molar, molaritym = multiplet[M+H]+= the protonated mass of the free base of the compoundMeCN = acetonitrileMeOD = methanol, deuteratedMeOH = methanolmg = milligram(s)MHz = megahertzmin = minute(s)mL = milliliter(s)mmol = mmolMS = mass spectrometrymol = molesm / z = mass / charge ratioN = normalNaOEt = sodium ethoxideNaOMe = sodium methoxideNBS = N-bromosuccinimiden-BuLi = n-butyllithiumNIS = N-iodosuccinimidePdC12(dppf)»CH2C12 = [l,l'-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-C1 = (2-Chloromethoxyethyl)trimethylsilanesm = starting materialt = triplet / BuBrettPhos = 2-(Di- / er / -butylphosphino)-2',4',6'- triisopropyl-3,6-dimethoxy-l,l'-biphenyl TEA = triethylamineTFA = trifluoroacetic acidTHF = tetrahydrofuranTosic acid = para-toluene sulfonic acidTosyl = para-toluene sulfonylpmol = micromolewt. = weightZhan catalyst = Dichloro[l,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5- [(dimethylamino)sulfonyl]-2-(l-methylethoxy-O)phenyl]methylene-C]ruthenium(II)2. Compounds

[0043] 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.

[0044] 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).

[0045] 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.

[0046] Where heterocyclic and heteroaromatic ring systems are defined to "contain" or as "containing" specified heteroatoms (e g., 1-3 heteroatoms independently selected from thegroup 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.

[0047] 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,onei.e. l,l-C3-6cycloalkylene (

[0048] In the following, numbered embodiments of the invention are disclosed, El, E2, E2.1, E2.2, E3, 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.

[0049] 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- 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-aalkylene-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 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- to7-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, 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 –NR2aR2b, –OC1-6alkyl, OH, C1-6alkyl, or H;R2ais H, C1-6alkyl, SO2R20, SO2N(R20)2, –C2-3alkylene–Y2, G2, or –C1-3alkylene–G2;R2bis H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3-4cycloalkyl;R3is H, halogen, Ci-4alkyl, C3-4cycloalkyl, C(O)OR3a, or -CH2NR3aR3b;R3ais H or Ci-ealkyl;R3bis H, Ci-ealkyl, -C2-3alkylene-Y3, G3, or-Ci-3alkylene-G3;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, -OR21, -N(R21)2, -NR22C(O)R21, C(O)R21, C(O)OR21, Ci-4alkyl, Ci- 4fluoroalkyl, -Ci-4alkylene-OR22, -Ci-4alkylene-N(R22)2, G2a, and -Ci-4alkylene-G2a, andoptionally further substituted with 1-3 substituents independently selected from the group consisting of halogen, oxo, OH, Ci-4alkyl, and Ci-4fluoroalkyl;or R3and R2b, together with the atom to which each attaches, form a 5-membered heterocycle; Y2is -OR22or-N(R22)2;G2is a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a Cs-iocarbocyclyl, a 5- to 12-membered heteroaryl containing 1-3 heteroatoms, or a 6- to 12- membered aryl, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, Ci-4fluoroalkyl, -OR21, -N(R21)2, C(O)OR21, 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 G2are independently selected from the group consisting of O, N, and S;R20, at each occurrence, is independently H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3- 4cycloalkyl;R21, at each occurrence, is independently H, Ci-4alkyl, -Ci-3alkylene-OCi-4alkyl, -Ci- 3alkylene-N(Ci-4alkyl)2, G2b, or -Ci-3alkylene-G2b;R22, at each occurrence, is independently H, Ci-4alkyl, G2b, or -Ci-3alkylene-G2b;G2ais 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, G2c, and -Ci-3alkylene-G2cand 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 G2aare independently selected from the group consisting of O, N, and S;G2bis 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 G2bcontains 1-2 heteroatoms independently selected from the group consisting of O, N, and S;G2cis a 4- to 7-membered heterocyclyl containing 1-2 heteroatoms, a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, or a C3-6cycloalkyl, wherein the heteroatomscontained in the heterocyclyl and heteroaryl of G2care independently selected from the group consisting of O, N, and S;Y3is -OR30or-N(R30)2;R30, at each occurrence, is independently H, Ci-4alkyl, G3a, or -Ci-3alkylene-G3a;G3and G3aare independently a Cs-ecycloalkyl 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 G3contains 1-2 heteroatoms 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;R3is -C2-4alkylene-O-G5;G5is a 6- to 12-membered aryl 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;R6, at each occurrence, is independently halogen, Ci-4alkyl, Ci-rfluoroalkyl, -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.

[0050] E2. The compound of El, or a pharmaceutically acceptable salt thereof, wherein G is a 5-membered aromatic heterocyclic ring containing 1-3 nitrogen atoms.

[0051] E2.1. The compound of El or E2, or a pharmaceutically acceptable salt thereof, wherein the 5-membered aromatic ring of G is a pyrazole or pyrrole.

[0052] E2.2. The compound of E2 or E2.1, or a pharmaceutically acceptable salt

[0053] E3. The compound of El, or a pharmaceutically acceptable salt thereof, wherein G is a 6-membered aromatic heterocyclic ring containing 1-3 nitrogen atoms.

[0054] E3.1. The compound of El, E2.1, or E3, or a pharmaceutically acceptable salt thereof, wherein the 6-membered aromatic heterocyclic ring of G is a pyridine.

[0055] E3.2. The compound of E3 or E3.1, or a pharmaceutically acceptable saltthereof, wherein

[0056] E4. The compound of any of E1-E2.1 or E3-E3.1, or a pharmaceutically acceptable salt thereof, wherein R1, at each occurrence, is independently Ci-4alkyl (the alkyl may be the same or different).

[0057] E4.1. The compound of E4, or a pharmaceutically acceptable salt thereof, wherein R1, at each occurrence, is methyl.

[0058] E4.2. The compound of any of E1-E2.1, E3-E3.1, or E4-E4.1, or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0059] E4.3. The compound of any of E1-E2.1, E3-E3.1, or E4-E4.1, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0060] E4.4. The compound of any of E1-E2.1, E3-E3.1, or E4-E4.1, or a pharmaceutically acceptable salt thereof, wherein m is 2.

[0061] E5. The compound of any of E1-E4.4, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-salkylene, wherein optionally 1-2 methylene units of the alkylene are independently replaced with -O- or -N(RX)-.

[0062] E5.1. The compound of E5, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-salkylene.

[0063] E5.2. The compound of E5.1, or a pharmaceutically acceptable salt thereof,wherein

[0064] E5.3. The compound of E5, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-salkylene, wherein 1 methylene unit of the alkylene is replaced with — O~ or -N(RX)-

[0065] E5.4. The compound of E5.3, or a pharmaceutically acceptable salt thereof,

[0066] E5.5. The compound of E5.4, or a pharmaceutically acceptable salt thereof,wherein.

[0067] E5.6. The compound of any of E1-E5 or E5.3, or a pharmaceutically acceptable salt thereof, wherein Rxis Ci-4alkyl.

[0068] E5.7. The compound of E5.6, or a pharmaceutically acceptable salt thereof, wherein Rxis methyl.

[0069] E5.8. The compound of any of E1-E5 or E5.3, or a pharmaceutically acceptable salt thereof, wherein Rxis H.

[0070] E6. The compound of any of E1-E4.4 or E5.6-E5.8, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-salkenylene containing one double bond, wherein optionally 1 methylene unit of the alkenylene is replaced with -O- or -N(RX)-.

[0071] E6.1. The compound of E6, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-salkenylene containing one double bond.

[0072] E6.2. The compound of E6.1, or a pharmaceutically acceptable salt thereof,wherein

[0073] E6.3. The compound of E6, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-salkenylene containing one double bond, wherein 1 methylene unit of the alkenylene is replaced with -O-.

[0074] E6.4. The compound of E6.3, or a pharmaceutically acceptable salt thereof,wherein

[0075] E7. The compound of any of E1-E4.4 or E5.6-E5.8, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-8alkylene, wherein optionally 1 propylene unit (i.e., three contiguous methylene units) of the alkylene is replaced with -OC(O)N(RX)-.

[0076] E7.1. The compound of E7, or a pharmaceutically acceptable salt thereof,wherein.

[0077] E8. The compound of any of E1-E7.1, or a pharmaceutically acceptable salt thereof, wherein R2is -NR2aR2b.

[0078] E9. The compound of any of E1-E8, or a pharmaceutically acceptable salt thereof, wherein:R2ais H, Ci-ealkyl, SO2R20, SO2N(R20)2, -C2-3alkylene-Y2, G2, or-Ci-salkylene-G2; and R2bis H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3-4cycloalkyl.

[0079] E9.1. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein R2ais methyl.

[0080] E9.2. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein R2ais -C2-3alkylene-Y2and R22, at each occurrence, is independently H or Ci-4alkyl.

[0081] E9.2a. The compound of E9.2, or a pharmaceutically acceptable salt thereof, wherein R2ais -CH2CH2-Y2.

[0082] E9.3. The compound of any of E1-E9, E9.2 or E9.2a, or a pharmaceutically acceptable salt thereof, wherein R22, at each occurrence, is independently H or methyl.

[0083] E9.4. The compound of any of E1-E9 or E9.2-E9.3, or a pharmaceutically acceptable salt thereof, wherein Y2is OH, OCH3, or NH2.

[0084] E9.5. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein R2ais G2.

[0085] E9.6. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein R2ais -Ci-3alkylene-G2.

[0086] E9.6a. The compound of E9.6, or a pharmaceutically acceptable salt thereof, wherein R2ais -CH2-G2.

[0087] E9.6b. The compound of E9.6, or a pharmaceutically acceptable salt thereof, wherein R2ais -CH2CH2-G2.

[0088] E9.7. The compound of any of E9 or E9.3-E9.6b, or a pharmaceutically acceptable salt thereof, wherein G2is the optionally substituted Cs-iocarbocyclyl.

[0089] E9.8. The compound of any of E1-E9 or E9.3-E9.7, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted C -iocarbocyclyl of G2is a C3-7cycloalkyl.

[0090] E9.9. The compound of E9.8, or a pharmaceutically acceptable salt theeof,

[0091] E9.10. The compound of any of E9 or E9.3-E9.6b, or a pharmaceutically acceptable salt thereof, wherein G2is the optionally substituted 4- to 12-membered heterocyclyl.

[0092] E9.ll. The compound of any ofEl-E9, E9.3-E9.6b, E9.8, orE9.10, ora pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl of G2is an oxetan-3-yl, tetrahydropyran-4-yl, piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl, or 3-azabicyclo[3.1.0]hexan-6-yl.

[0093] E9.12. The compound of any ofEl-E9, E9.3-E9.6b, E9.8, orE9.10, ora pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl of G2is a piperidin-l-yl, piperazin- 1-yl, morpholino, azetidin-1-yl, or 2-oxa-6-azaspiro[3.3]heptan-6-yl.

[0094] E9.13. The compound of E9.11, or a pharmaceutically acceptable salt theeof,

[0095] E9.14. The compound of E9.12, or a pharmaceutically acceptable salt theeof,

[0096] E9.15. The compound of any of E9 or E9.3-E9.6b, or a pharmaceutically acceptable salt thereof, wherein G2is the optionally substituted 5- to 12-membered heteroaryl.

[0097] E9.16. The compound of any ofEl-E9, E9.3-E9.6b, E9.8, E9.ll-E9.12, or E9.15, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 5- to 12-membered heterocyclyl of G2is a 6-membered heterocyclyl containing 1-2 nitrogen atoms.

[0098] E9.17. The compound of E9.16, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 6-membered heterocyclyl of G2is a pyridinyl.

[0099] E9.18. The compound of E9.17, or a pharmaceutically acceptable salt thereof,wherein

[0100] E9.19. The compound of any of E1-E9, E9.3-E9.8, E9.10-E9.12, or E9.15-E9.17, or a pharmaceutically acceptable salt thereof, wherein the optional substitution of G2is a first optional substituent selected from the group consisting of halogen, Ci-4alkyl, -OR21, -N(R21)2, and C(O)OR21, and 1-3 further optional substituents independently selected from the group consisting of halogen and Ci-4alkyl; and R21, at each occurrence, is independently H or Ci- 4alkyl.

[0101] E9.20. The compound of E9.19, or a pharmaceutically acceptable salt thereof, wherein the optional substitution of G2is a first optional substituent selected from the group consisting of fluoro, methyl, ethyl, isopropyl, OH, -OCH3, -N(CHs)2, and C(O)O-tert-butyl, and 1-3 further optional substituents independently selected from the group consisting of fluoro and methyl.

[0102] E9.21. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein R2ais SO2R20.

[0103] E9.22. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein R2ais SO2N(R20)2.

[0104] E9.23. The compound of any of E9, E9.3-E9.4, E9.7-E9.8, E9.10-E9.12, E9.15- E9.17, or E9.19-E9.22, or a pharmaceutically acceptable salt thereof, wherein R20, at each occurrence, is independently H or Ci-4alkyl.

[0105] E9.24. The compound of E9.23, or a pharmaceutically acceptable salt thereof, wherein R20, at each occurrence, is independently H or methyl.

[0106] E9.25. The compound of E9.23, or a pharmaceutically acceptable salt thereof, wherein R20is Ci-4alkyl.

[0107] E9.26. The compound of E9.24 or E9.25, or a pharmaceutically acceptable salt thereof, wherein R20is methyl.

[0108] E9.27. The compound of any of E1-E9.26, or a pharmaceutically acceptable salt thereof, wherein R2ais H, Me, SChMe, SO2NMe2, SO2NH2, -CH2CH2OH, -CH2CH2OMe,

[0109] E9.28. The compound of any of E1-E9.27, or a pharmaceutically acceptable salt thereof, wherein R2bis H.

[0110] E9.29. The compound of any of E1-E9.27, or a pharmaceutically acceptable salt thereof, wherein R2bis Ci-4alkyl.

[0111] E9.30. The compound of E9.29, or a pharmaceutically acceptable salt thereof, wherein R2bis methyl.

[0112] E10. The compound of any of E1-E8, 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.

[0113] Ell. The compound of any of E1-E8 or El 0, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand R2bis a 4- to 8-membered monocyclic heterocyclyl optionally in which two non-adjacent atoms are linked by an alkylene bridge of 1, 2, or 3 carbon atoms, a 7- to 12-membered spiro heterocyclyl, or a 7- to 12-membered fused bicyclic heterocyclyl in which two non-adjacent atoms are optionally linked by an alkylene bridge of 1, 2, or 3 carbon atoms.

[0114] E12. The compound of El 1, or a pharmaceutrically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand R2bis the 4- to 8-membered monocyclic heterocyclyl optionally in which two non-adjacent atoms are linked by an alkylene bridge of 1, 2, or 3 carbon atoms.

[0115] E12.1. The compound of E12, or a pharmaceutrically acceptable salt thereof, wherein the ring system formed by R2aand R2bis azetidin-l-yl, pyrrolidin-l-yl, piperidin-l-yl, piperazin- 1-yl, 1,4-diazepan-l-yl, 3,6-diazabicyclo[3.1.1]heptan-3-yl, 3,6-diazabicyclo[3.1. l]heptan-6-yl, or 2,5-diazabicyclo[2.2. l]heptan-2-yl.

[0116] E12.2. The compound of E12 or E12.1, or a pharmaceutrically acceptable salt thereof, wherein:the ring formed by R2aand R2bis optionally substituted with a first substituent selected from the group consisting of halogen, cyano, oxo, -OR21, -N(R21)2, -NR22C(O)R21, C(O)R21, C(O)OR21, Ci-4alkyl, Ci-4fluoroalkyl, -Ci-4alkylene-OR22, -Ci-4alkylene-N(R22)2, G2a, and -Ci-4alkylene-G2a, and optionally further substituted with a second substituent selected from the group consisting of halogen, oxo, OH, Ci-4alkyl, and Ci-4fluoroalkyl;R22, at each occurrence, is independently H, Ci-4alkyl, or G2b;G2ais a C3-6cycloalkyl, a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, or a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, each optionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, G2c, and -C 1-3 alkyl ene- G2Cand 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 G2aare independently selected from the group consisting of O, N, and S; andG2cis a 4- to 7-membered heterocyclyl containing 1-2 heteroatoms or a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G2care independently selected from the group consisting of O, N, and S.

[0117] E12.3. The compound of E12.2, or a pharmaceutically acceptable salt thereof,

[0118] El 2.4. The compound of El 2.3, or a pharmaceutically acceptable salt thereof,

[0119] E12.5. The compound of any of E1-E8 or E10-E12.3, or a pharmaceutically acceptable salt thereof, wherein G2ais the optionally substituted C3-6cycloalkyl.

[0120] E12.6. The compound of E12.5, or a pharmaceutically acceptable salt thereof,wherein

[0121] E12.7. The compound of E12.6, or a pharmaceutically acceptable salt thereof,Ywherein G2ais JWV

[0122] E12.8. The compound of any of E1-E8 or E10-E12.3, or a pharmaceutically acceptable salt thereof, wherein G2ais the optionally substituted 4- to 12-membered heterocyclyl.

[0123] El 2.9. The compound of any of El -E8, El 0-E12.3, or El 2.8, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 4- to 12-membered heterocyclyl at G2ais attached to the ring formed by R2aand R2bat a first nitrogen ring atom in the optionally substituted 4- to 12-membered heterocyclyl.

[0124] E12.10. The compound of E12.9, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 4- to 12-membered heterocyclyl at G2aoptionally contains a second ring heteroatom independently selected from the group consisting of N, O, and S.

[0125] E12.ll. The compound of any of E1-E8, E10-E12.3, or E12.8-E12.10, ora pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl at G2ais azetidin-l-yl, pyrrolidin-l-yl, piperidin-l-yl, morpholino, piperazin- 1-yl, or octahydrocyclopenta[c]pyrrol-2-yl.

[0126] E12.12. The compound of E12.9 orE12.10, or a pharmaceutically acceptable salt

[0127] El 2.13. The compound of El 2.12, or a pharmaceutically acceptable salt thereof,wherein

[0128] E12.14. The compound of any of E12.9-E12.13, or a pharmaceutically acceptablesalt thereof, wherein G2ais

[0129] E12.15. The compound of any of E1-E8, E10-E12.3, or E12.8, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl at G2ais a 4- to 7-membered heterocyclyl containing 1 oxygen atom.

[0130] E12.16. The compound of E12.15, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 7-membered heterocyclyl containing 1 oxygen atom is oxetan-3-yl or tetrahydrofuran-2-yl.

[0131] E12.17. The compound of E12.15, or a pharmaceutically acceptable salt thereof,wherein

[0132] E12.18. The compound of E12.16 or E12.17, or a pharmaceutically acceptable saltthereof, wherein

[0133] El 2.19. The compound of any of E1-E8 or E10-E12.3, or a pharmaceutically acceptable salt thereof, wherein G2ais the optionally substituted 5- to 6-membered heteroaryl.

[0134] E12.20. The compound of E12.19, or a pharmaceutically acceptable salt thereof, wherein G2ais pyridinyl.

[0135] E12.21. The compound of any of E1-E9, E9.3-E9.8, E9.10-E9.12, E9.15-E9.17, E9.19, E9.23-E9.26, E9.28-E12.3, or E12.5-E12.20, or a pharmaceutically acceptable salt thereof, wherein G2bis the optionally substituted C3-6cycloalkyl.

[0136] E12.22. The compound of E12.21, or a pharmaceutically acceptable salt thereof,wherein

[0137] E12.23. The compound of E12.22, or a pharmaceutically acceptable salt thereof,Ywherein G2bis JVUV

[0138] E12.24. The compound of any of E1-E9, E9.3-E9.8, E9.10-E9.12, E9.15-E9.17, E9.19, E9.23-E9.26, E9.28-E12.3, or E12.5-E12.20, or a pharmaceutically acceptable salt thereof, wherein G2bis the optionally substituted 4- to 7-membered heterocyclyl.

[0139] E12.25. The compound of E12.24, or a pharmaceutically acceptable salt thereof,wherein

[0140] El 2.26. The compound of El 2.25, or a pharmaceutically acceptable salt thereof,wherein

[0141] E12.27. The compound of E12.24, or a pharmaceutically acceptable salt thereof,wherein

[0142] E12.28. The compound of E12.27, or a pharmaceutically acceptable salt thereof,wherein

[0143] E12.29. The compound of any of E1-E8, E10-E12.3, E12.5, E12.8-E12.13, E12.15- E12.16, E12.19, or E12.21-E12.28, or a pharmaceutically acceptable salt thereof, wherein G2cis the optionally substituted 4- to 7-membered heterocyclyl (e.g., pyrrolidin-l-yl).

[0144] E12.30. The compound of E12.29, or a pharmaceutically acceptable salt thereof,wherein

[0145] E12.31. The compound of El 2.30, or a pharmaceutically acceptable salt thereof,wherein

[0146] E12.32. The compound of any of E1-E8, E10-E12.3, E12.5, E12.8-E12.13, E12.15-E12.16, E12.19, or E12.21-E12.28, or a pharmaceutically acceptable salt thereof, wherein G2cis the optionally substituted 5- to 6-membered heteroaryl.

[0147] E12.33. The compound of E12.32, or a pharmaceutically acceptable salt thereof, wherein G2cis pyridinyl.

[0148] E13. The compound of El 1, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand R2bis the 7- to 12-membered spiro heterocyclyl.

[0149] E13.1. The compound of E13, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 7- to 12-membered spiro heterocyclyl formed by R2aand R2bis 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,7-diazaspiro[3.5]nonan-2-yl, 5-oxa-2,8-diazaspiro[3.5]nonan-2-yl, l,7-diazaspiro[3.5]nonan-l-yl, 2,6-diazaspiro[3.4]octan-2-yl, or 2,7-diazaspiro[3.5]nonan-7-yl.

[0150] E13.2. The compound of E13 or E13.1, or a pharmaceutically acceptable salt thereof, wherein the 7- to 12-membered spiro heterocyclyl formed by R2aand R2bis optionally substituted with a first substituent selected from the group consisting of Ci-4alkyl, C(O)OCi-4alkyl, and -Ci-4alkylene-OH.

[0151] E13.3. The compound of E13.2, or a pharmaceutically acceptable salt thereof, wherein the first substituent is selected from the group consisting of methyl, ethyl, C(O)O-tert-butyl, and -CH2C(CH3)2-OH.

[0152] El 3.4. The compound of El 3.2, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand R2bis

[0153] E13.5. The compound of E13.3 or E13.4, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 7- to 12-membered spiro heterocyclyl formed by R2a

[0154] E14. The compound of El 1, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl formedby R2aand R2bis the 7- to 12-membered fused bicyclic heterocyclyl in which two non-adjacent atoms are optionally linked by an alkylene bridge of 1, 2, or 3 carbon atoms.

[0155] E14.1. The compound of E14, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 7- to 12-membered fused bicyclic heterocyclyl formed by R2aand R2bis a 3,6-diazabicyclo[3.2.0]heptan-6-yl, 3,8-diazabicyclo[4.2.0]octan-8-yl, octahydro-2H-pyrido[l,2-a]pyrazin-2-yl, octahydro-2H-6,9-methanopyrido[ 1,2-a]pyrazin-2-yl, octahydropyrazino[2, 1 -c] [ 1,4]oxazin-8-yl, octahydro-2H-pyrazinof 1,2-a]pyrazin-2-yl, octahydropyrrolo[3,4-c]pyrrol-2-yl, or octahydrocyclopenta[c]pyrrol-2-yl.

[0156] E14.2. The compound of E14 or E14.1, or a pharmaceutically acceptable salt thereof, wherein the 7- to 12-membered fused bicyclic heterocyclyl formed by R2aand R2bis optionally substituted with a first substituent selected from the group consisting of Ci-4alkyl, oxo, C(O)OCi-4alkyl, and -Ci-4alkylene-OH.

[0157] E14.3. The compound of E14.2, or a pharmaceutically acceptable salt thereof, wherein the first substituent is selected from the group consisting of methyl, ethyl, oxo, C(O)O-tert-butyl, and -CH2C(CH3)2-OH.

[0158] E14.4. The compound of E14.2, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 7- to 12-membered fused bicyclic heterocyclyl formed by

[0159] E14.5. The compound of E14.3 or E14.4, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 7- to 12-membered fused bicyclic heterocyclyl

[0160] El 5. The compound of any of El -E8, or a pharmaceutically acceptable salt thereof, wherein R3and R2b, together with the atom to which each attaches, form the 5-

[0161] E15.1. The compound of E15, or a pharmaceutically acceptable salt thereof, wherein R2ais Ci-ealkyl, -C2-3alkylene-Y2, G2, or -Ci-salkylene-G2.

[0162] E15.2. The compound of E15 or E15.1, or a pharmaceutically acceptable salt thereof, wherein -C2-3alkylene-Y2is -CH2CH2-Y2.

[0163] E15.3. The compound of any of E15-E15.2, or a pharmaceutically acceptable salt thereof, wherein Y2is -N(R22)2.

[0164] El 5.4. The compound of any of E15-E15.3, or a pharmaceutically acceptable salt thereof, wherein R22, at each occurrence, is independently Ci-4alkyl.

[0165] E15.5. The compound of E15.4, or a pharmaceutically acceptable salt thereof, wherein R22is methyl.

[0166] E15.6. The compound of any of E15-E15.5, or a pharmaceutically acceptable salt thereof, wherein G2is a 4- to 7-membered heterocyclyl containing 1 heteroatom independently selected from the group consisting of O, N, and S and optionally substituted with Ci-4alkyl.

[0167] E15.7. The compound of E15.6, or a pharmaceutically acceptable salt thereof, s / Xi -2- C N-C1-4alkylwherein G2and -Ci-3alkylene-G2are, respectively, ' '1-2and

[0168] E15.8. The compound of E15.7, or a pharmaceutically acceptable salt thereof,wherein G2and -Ci-3alkylene-G2are, respectively,andcH2CH2-N -

[0169] E16. The compound of any of E1-E15.8, or a pharmaceutically acceptable salt thereof, wherein R4ais OCH3, OCH2CH3, methyl, ethyl, or H.

[0170] E16.1. The compound of E16, or a pharmaceutically acceptable salt thereof, wherein R4ais OCH3.

[0171] E17. The compound of any of E1-E16.1, or a pharmaceutically acceptable salt thereof, wherein R4bis -OR40.

[0172] E18. The compound of any of E1-E17, or a pharmaceutically acceptable salt thereof, wherein R40is H, Ci-4alkyl, or Ci-4haloalkyl.

[0173] E18.1. The compound of El 8, or a pharmaceutically acceptable salt thereof, wherein R40is Ci-4alkyl.

[0174] E18.2. The compound ofE18.1., or a pharmaceutically acceptable salt thereof, wherein R40is methyl or ethyl.

[0175] El 8.3. The compound of El 8, or a pharmaceutically acceptable salt thereof, wherein R40is Ci-4haloalkyl.

[0176] El 8.4. The compound of El 8.3, or a pharmaceutically acceptable salt thereof, wherein R40is -CH2CH2Br or -CH2CH2CH2Br.

[0177] E19. The compound of any of E1-E17, or a pharmaceutically acceptable salt thereof, wherein R40is -C2-4alkylene-OH, -C2-4alkylene-OCi-4alkyl, -C2-4alkylene-NH2, -C2-4alkylene-NHCi-4alkyl, or -C2-4alkylene-N(Ci-4alkyl)2.

[0178] E19.1. The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R40is -C2-4alkylene-OCi-4alkyl.

[0179] E19.2. The compound of E19.1, or a pharmaceutically acceptable salt thereof, wherein R40is -CH2CH2OCH3.

[0180] E19.3. The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R40is -C2-4alkylene-N(Ci-4alkyl)2.

[0181] E19.4. The compound of E19.3, or a pharmaceutically acceptable salt thereof, wherein R40is -CH2CH2N(CH3)2or -CH2CH2CH2N(CH3)2.

[0182] E20. The compound of any of E1-E17, or a pharmaceutically acceptable salt thereof, wherein R40is G4or -Ci-3alkylene-G4

[0183] E20.1. The compound of E20, or a pharmaceutically acceptable salt thereof, wherein R40is G4.

[0184] E20.2. The compound of E20.1, or a pharmaceutically acceptable salt thereof,wherein

[0185] E20.3. The compound of E20.2, or a pharmaceutically acceptable salt thereof,

[0186] E20.4. The compound of E20, or a pharmaceutically acceptable salt thereof, wherein R40is -Ci-3alkylene-G4.

[0187] E20.5. The compound of E20.4, or a pharmaceutically acceptable salt thereof,

[0189] E20.7. The compound of any of E1-E17, E20-E20.1, E20.4-E20.5, or apharmaceutically acceptable salt thereof, wherein G4ais

[0190] E21. The compound of any of E1-E20.7, or a pharmaceutically acceptable salt thereof, wherein R5is -(CH2)3-O-G5.

[0191] E22. The compound of any of E1-E21, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 6- to 12-membered aryl at G3is phenyl, 2,3-dihydrobenzofuran-5-yl, indan-5-yl, or naphthal enyl.

[0192] E22.1. The compound of any of E1-E22, or a pharmaceutically acceptable salt thereof, wherein the optional substitution of G5is 1-3 optional substituents independently selected from the group consisting of chloro, fluoro, methyl, and CF3.

[0193] E22.2. The compound of E22.1, or a pharmaceutically acceptable salt thereof,

[0194] E22.3. The compound of E22.2, or a pharmaceutically acceptable salt thereof,

[0196] E23. The compound of any of E1-E22.4, 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.

[0197] E23.1. The compound of E23, or a pharmaceutically acceptable salt thereof, wherein R6ais H.

[0198] E23.2. The compound of E23 or E23.1, or a pharmaceutically acceptable salt thereof, wherein R6bis H.

[0199] E23.3. The compound of any of E23-E23.2, or a pharmaceutically acceptable salt thereof, wherein R6cis halogen.

[0200] E23.4. The compound of E23.3, or a pharmaceutically acceptable salt thereof, wherein R6cis chloro.

[0201] E23.5. The compound of any of E23-E23.2, or a pharmaceutically acceptable salt thereof, wherein R6cis H.

[0202] E24. The compound of any of E1-E23.5, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0203] E25. The compound of any of E1-E24, or a pharmaceutically acceptable salt thereof, wherein R7is methyl.

[0204] E26. The compound of any of E1-E25, or a pharmaceutically acceptable salt thereof, wherein q is 1.

[0205] E26.1. The compound of any of E23-E26, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) has formula (III):

[0206] E27. The compound of any of E23-E26.1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) or (III) has formula (IV):

[0207] E28. The compound of any of E1-E27, or a pharmaceutically acceptable salt thereof, wherein R3is H.

[0208] E29. The compound of El selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

[0209] E30. A pharmaceutical composition comprising the compound of any of El-E29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0210] E31. The compound of any of El -E29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E30, for use in the treatment of cancer.

[0211] E32. The compound of any of E1-E29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E30, for use in the inhibition of cancer cell proliferation.

[0212] E33. A method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any of E1-E29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E30.

[0213] E34. A method of inhibiting cancer cell proliferation, comprising administering to a subject in need thereof, the compound of any of E1-E29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E30, in an amount effective to inhibit the cancer cell proliferation.

[0214] E35. Use of the compound of any of E1-E29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E30, in the manufacture of a medicament for the treatment of cancer.

[0215] E36. Use of the compound of any of E1-E29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E30, in the manufacture of a medicament for the inhibition of cancer cell proliferation.

[0216] 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.

[0217] Compounds may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “?” or “5” depending on the configuration of substituents around the chiral carbon atom or “JU” or “Sa” depending on the configuration of substituents around an axially chiral bond. The terms “J?” and “S” 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 compoundsof formula (I), when no specific configuration is indicated at a stereogenic center (e g., carbon), the compounds include all possible stereoisomers.

[0218] 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 CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods.

[0219] 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.

[0220] In the compounds of formula (I), and any subformulas, any "hydrogen" or "H," whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes ’H (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, etc.

[0221] 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,33S,18F, and36C1, respectively.

[0222] 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).

[0223] 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 a salt. 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, thri chloroacetate, 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.

[0224] 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 N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.A. Binding to Mcl-1

[0225] 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 thanabout 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 provided compound 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

[0226] 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.

[0227] 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.

[0228] 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 target 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 conditions required 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 1

[0229] In some embodiments, compounds of Formula 13 may be synthesized by processes illustrated in Scheme 1. Indole 1 may be coupled with boronic ester 2 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 3 may then be alkylated using appropriately substituted-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (4). The Boc-protecting group may be removed with trifluoroacetic 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 6 (see, for example, Richter, H. G. F. Bioorg. Med. Chem. Lett.2010, 5713). Cross coupling between lactam 6 and halide 7 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 8.Exemplary conditions for this transformation include, but are not limited to, CuI, (trans)-N1,N2-dimethylcyclohexane-1,2-diamine, K3PO4 and [Pd(cinnamyl)Cl]2, t-BuBrettPhos, Cs2CO3. Thebenzyl ether may be removed under hydrogenolysis conditions (Green, ibid). The resultant alcohol may be converted to a leaving group X4, including but not limited 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 10 may be cyclized to form macrocycle 11 using, but not limited to, Cs2CO3 or NaH as a base in DMF. Ester 11 may be saponified to the carboxylic acid 12 using a hydroxide base such as LiOH or NaOH. Primary, secondary, and tertiary amides of formula 13 may then be synthesized using the appropriate reagent amine and a number of conditions that are routine for those skilled in the art of organic synthesis.Scheme

[0230] In some embodiments, compounds of Formula 22 may be synthesized by processes illustrated in Scheme 2. Lactam 6 may be debenzylated (14) and then the resultant alcohol protected, including but not limited to the THP protecting group (PG) (Green, ibid), to accesscompound 15. Cross coupling between lactam 15 and indole 16 as described in Scheme 1 may afford intermediate 17. Removal of the THP ether may afford alcohol 18. Conversion of the alcohol to a leaving group and cyclization may proceed as described in Scheme 1 to afford macrocycle 19. Hydrogenolysis of the benzyl group may afford phenol 20. The phenol may be alkylated with a variety of electrophiles, (X4= OTs, OMs, Br, I) under conditions that are routine for those skilled in the art of organic synthesis. Alternatively, phenol 20 may also be functionalized by treatment with an appropriate alcohol (X4= OH) under Mitsunobu conditions (see Swamy, K. C. K.; Kumar, N. N. B; Balaraman, E.; Kumar, K. V. P. P. Chem Rev. (2009) 2551). Ester 21 may be converted to the macrocyclic acid or amide (24) as described in Scheme 1.Scheme 3

[0231] In some embodiments, compounds of formula 24 and 25 may be accessed as illustrated in Scheme 3. Treatment of macrocycle 23 to reductive conditions, including but not limited to, Pd / C, Pd(OH)2 / C, H2, may provide either mono- or bis-dehalogenation to afford compounds of formula 24 and 25.Scheme 4

[0232] In some embodiments, compounds of formula 29 and 30 may be synthesized as illustrated in Scheme 4. Carboxylic acid 12 may be coupled with cyclic / acyclic diamine 26 as described in Scheme 1, where PG is a suitable protecting group, including but not limited to Boc or Cbz. Deprotection of intermediate 27 under suitable conditions (Green, ibid may afford amine 27. Treatment of 27 with 2,2-dimethyloxirane may provide alkylated amine 29. Alternatively, reductive amination using 28 and a suitable aldehyde or ketone under conditionsthat are routine for those skilled in the art of organic synthesis, which may include but are not R9limited to NaBH₃CN or NaBH(OAc)3, may afford compounds of formula 30, wherein R8represents an alkyl group.

[0233] In some embodiments, compounds of formula 39 may be synthesized as illustrated in Scheme 5. Compound 31 may be converted to lactam 32 in a manner analogous to that described in Scheme 1. Lactam 32 may then cross couple with indole 33 and converted the macrocycle 34, analogously to the route described in Scheme 1. Zc / 7-Butyl ester 34 may thenbe deprotected under acidic conditions to reveal carboxylic acid 35, which may then be coupled with an appropriate amine reagent under conditions that are routine for those skilled in the art of organic synthesis to form amide 36. The ethyl ester of compound 36 may be reduced using, but not limited to, LAH to afford alcohol 37. The alcohol may be converted to the bromide 38 using, but not limited to, CBn and triphenylphosphine. Displacement of the bromide with a suitable phenol in the presence of a carbonate base may provide ether 39.Scheme 6

[0234] In some embodiments compounds of formula 1 may be obtained by the processes shown in Scheme 6. Treatment of indole 40 with borontribromide may afford bromide 41. Treatment of compound 41 with a suitable phenol in the presence of a carbonate base may afford compound 1.Scheme 7

[0235] In some embodiments, compounds of formula 13a may be synthesized as illustrated in Scheme 7. Indole 1 may be coupled with boronic ester 42 via Suzuki-Miyaura coupling to afford intermediate 43, which may itself then be elaborated to compound 44 in a manner analogous that described in Scheme 1. Hydrogenolysis of the benzyl protecting group may afford alcohol 45. A-Alkylation of alcohol 45 with electrophile 46, where X3may include, but is not limited to, Br, I, or OTs, may be accomplished by treatment with NaH or a carbonate base to afford compound 47. Subsequent O-alkylation from the tethered electrophileemploying, but not limited to, NaH or a carbonate base, may afford macrocycle Ila Saponification and amide coupling as described in Scheme 1 may afford compounds of formula 13aScheme 8

[0236] In some embodiments, compounds of formula 53 may be synthesized as illustrated in Scheme 8. Compound 45 may be treated with electrophile 48 to afford protected amine 49. Conversion of the alcohol functionality to a leaving group may be accomplished in a mannerroutine for those skilled in the art of organic synthesis; as exemplified by treatment with CBn and triphenylphosphine to afford bromide 50. Deprotection of the Boc-protected amine (Green, ibid may afford compound 51. Treatment of 51 with basic conditions, including but not limited to carbonate bases, may afford macrocycle 52. Saponification and amide coupling as described in Scheme 1 may afford compounds of formula 53.Scheme 6

[0237] In some embodiments, compounds of formula 58 may be obtained following the processes illustrated in Scheme 9. A-Alkylation of alcohol 45 with alkene-bearing electrophiles under basic conditions, including but not limited to, NaH or carbonate bases, may afford compound 54. Subsequent O-alkylation under similar basic conditions with a second alkene-bearing electrophile may provide intermediate 55. Ring closing metathesis (see Monfette, S.; Fogg, D. E. Chem. Rev. (2009) 3783 and Grubbs, R. H. Angew. Chem. Int. Ed. (2006) 3760) may then be accomplished by using a suitable catalyst, including but not limited to Grubbs 1stgeneration catalyst (see Schwab P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem. Int. Ed. (1995) 2039), Grubbs 2ndgeneration catalyst (see Scholl M., Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. (1999) 953), or Zhan catalyst (see Zhen, Z.-Y. U. S. Pat. Appl. US20070043180A1, (2007)), to afford compound 56. Alkene 56 may then be reduced under hydrogenation conditions, routine for those skilled in the art of organic synthesis, to afford compound 57. Compound 57 may then be saponified and subjected to amide coupling as described in Scheme 1 to afford compounds of formula 58. Alternatively, compound 56 may first be saponified to alkenyl macrocyclic acid 59. Alkene 59 may then be subjected to hydrogenation to afford intermediate 60, which may then be subjected to amide coupling conditions to afford compounds of formula 58.Scheme 10

[0238] In some embodiments, compounds of formula 69 may be obtained following the processes illustrated in Scheme 10. Aldehyde 61 may be olefinated using via the Wittig or similar reaction (see Maryanoff, B. E.; Reitz, A. B. Chem. Rev. (1989) 863) to afford pyrazole 62. Compound 62 may be converted to the pinacol borane 63 using, but not limited to, Miyaura boronylation conditions (see Ishiyama, T., Murata, M.; Miyaura, N., J. Org. Chem. (1995) 7508). Suzuki-Miyaura cross coupling with compound 1 (see Scheme 1) may afford intermediate 64. Intermediate 64 may then be elaborated to lactam 65, then to intermediate 66via cross coupling with indole 7 in a manner analogous to that described in Scheme 1.Intermediate 66 may then be alkylated with an alkene-bearing electrophile in a manner analogous to Scheme 8 in order to afford intermediate 67. Intermediate 67 may be converted to macrocyclic alkene 68 using ring closing metathesis (see Scheme 8). Saponification and amide coupling as described in Scheme 1 may afford compounds of formula 69. Alternatively, macrocycle 68 may be reduced to intermediate 70 under conditions routine to those skilled in the art of organic synthesis, including but not limited to treatment with Pd / C, Pd(OH)2, and H2. Saponification and amide coupling as described in Scheme 1 may afford compounds of formula 71.Scheme 1176 77

[0239] In some embodiments, compounds of formula 77 may be obtained following the processes illustrated in Scheme 11. Indole 1 may be reacted with 6-membered boronic ester 72 (see Scheme 1). The resultant intermediate (73) may then be elaborated to lactam 74 and then to macrocycle 75 in a manner analogous to that described in Scheme 1. Saponification and amide coupling as described in Scheme 1 may afford compounds of formula 76 and 77.Scheme 12

[0240] In some embodiments, compounds of formula 86 may be obtained following the processes illustrated in Scheme 12. Compound 1 may be elaborated to lactam 78, following the same procedures described in Scheme 1. Lactam 78 may then be cross coupled via Ullmann or Buchwald-Hartwig conditions (see Scheme 1) to afford compound 79. A-Alkylation of the indole of 79 may be accomplished with electrophile 80, where X4may include, but is not limited to, Br, I, or OTs, under conditions routine to those skilled in the art of organic synthesis. Suzuki coupling (see Scheme 1) between 81 and 82 may provide intermediate 83.Deprotection of the aryl nitrogen (Green, ibid may afford compound 84. Intramolecular N-alkylation, which may be accomplished with, but not limited to, NaH, carbonate bases, or tertiary amine bases, to afford macrocycle 85. Saponification and amide coupling as described in Scheme 1 may afford compounds of formula 86.Scheme 13

[0241] In some embodiments, compounds of formula 88 and 90 may be obtained following the processes in Scheme 12. Carboxylic acid 12 may be reduced to alcohol 87 followed by oxidation to compounds of formula 88 using routine conditions for those skilled in the art of organic synthesis. As an exemplary case, the reduction to 87 may be accomplished by treatment with isobutyl chloroformate then LAH, and the oxidation to 88 with Dess-Martinperiodinane. Alternatively, the acid 12 may be converted to the Weinreb amide 89 (see Balasubramaniam, S.; Aidhen, I. S. Synthesis, (2008) 3707). Treatment of the Weinreb amide with MeMgBr may afford compounds of formula 90.Scheme 1495 96

[0242] In some embodiments, intermediates of formula 96 may be obtained following the processes in Scheme 14. Halogenation of benzaldehyde 91 may be accomplished using, but not limited to, bromine / HOAc (see Hsu, D.-S.; Hwang, T.-Y.; Eur. J. Org. Chew. (2018) 4689) or AgNO₃ / ICl (see Rao, M. L. N.; Murty, V. N. Eur. J. Org. Chem. (2016) 2177). Intermediate 92 may then be alkylated using routine methods known to those skilled in organic synthesis. Knoevenagel condensation with an azidoacetate 94 may afford intermediate 95. Heating intermediate 95 either thermally or with microwave irradiation may afford indole 96 (see Gribble, G. W.; J. Chem. Soc., Perkin. Trans. (2000) 1045).

[0243] In some embodiments, intermediates of formula 7 may be prepared by following the processes in Scheme 15. Treatment of the aniline 97 with NaNO₂ under acidic conditions, followed by treatment with SnCh, may afford hydrazine intermediate 98. Treatment of 98 with ethyl pyruvate 99 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 7.

[0244] 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 CM202FE, England.

[0245] 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 limited to 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.

[0246] 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.

[0247] 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.

[0248] 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, dimethoxy trityl, methoxytrityl), acetyl, benzoyl, benzyl, p-methoxybenzyl, P-methoxyethoxymethyl (MEM), methoxymethyl (MOM), methylthiomethyl, pivaloyl, tetrahydropyranyl (THP),tetrahydrofuranyl (THF), silyl (e.g., trimethyl silyl (TMS), tert-butyl di methyl silyl (TBDMS), tri-isopropyl silyloxy methyl (TOM), triisopropylsilyl (TIPS), methyl, and ethoxyethyl.

[0249] 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).

[0250] 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.

[0251] 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

[0252] Microwave assisted reactions are performed in a single-mode reactor: Emrys™ Optimizer microwave reactor (Personal Chemistry A. B., currently Biotage).

[0253] Hydrogenation reactions are performed using an atmospheric balloon or using a Panhydrogenation shaker apparatus.

[0254] 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.

[0255] 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 / H20] to 100%[0.05%TFA / CH3CN]. Preparative RP-HPLC purification is performed using a Gilson Inc. preparative UV-based system using a Phenomenex Gemini C18 column (50 x 30 mm ID., 5 pm) with an acetonitrile (0.1% TFA)-water (0.1% TFA) custom gradient.

[0256] For LC-MS characterization of the compounds of the present invention, the following methods are used.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 'H 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.

[0261] 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-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-TH-indole-2- carboxylate

[0262] 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 MgSCh, filtered and concentrated in vacuo to afford the title compound (7.1 g, 90% yield) as a red oil.

[0263] Step B: Ethyl 7-bromo-6-chloro-3-(3-ethoxy-3-oxopropyl)-LH-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), slowly. The reaction mixture was refluxed for 1.5 h. The reaction was quenched by pouring into ice then extracted with DCM. The combined organic layer was washed with sat. NaHCCh, water, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography eluting with 0 to 25% EtOAc in hexanes to give the title compound as an off-white solid in 4.4 g (11 mmol). MS (ES) 402.0 (M+H).

[0264] Step C: Ethyl 7-bromo-6-chloro-3-(3-hydroxypropyl)- l / / -iiidole-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 mL, 20 mmol) at 20 °C. The reaction mixture was stirred for 15 h at 20 °C and quenched by addition of MeOH then concentrated in vacuo. 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).

[0265] Step D: Ethyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l / / -indole-2-carboxylate. To a solution of ethyl 7-bromo-6-chloro-3-(3-hydroxypropyl)-l / 7-indole-2-carboxylate (101 mg, 0.28 mmol), PPha (110 mg, 0.51 mmol) and 3,5-diMe-4-Cl-phenol (81 mg, 0.52 mmol) in THF (3.5 mL) was added DAB AD (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 23-((3-(Benzyloxy)propoxy)methyl)-l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l / / -pyr azole

[0266] Step A: 3-((3-(Benzyloxy)propoxy)methyl)-4-bromo-l-methyl-lH-pyrazole. In a dry round bottom (4-bromo-l-methyl-12 / -pyrazol-3-yl)methanol (5.00 g, 26.2 mmol, 1.0 eq) was dissolved in DMF (32 mL). The reaction mixture was cooled to 0 °C and sodium hydride (1.67 g, 41.9 mmol, 1.6 eq) was added. The reaction was allowed to stir for 20 minutes. ((3-Bromopropoxy)methyl)benzene (7.40 mL, 41.90 mmol, 1.6 eq) was then added, and the reaction was allowed to stir for 16 h at RT. Upon completion, the reaction was cooled to 0 °C, quenched with MeOH (20 mL), and diluted into H2O (200 mL). The reaction was extractedwith ethyl acetate (3 x 100 mL), washed with brine, dried over MgSCh, 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, / z = 339.3 [M+H]+.

[0267] Step B: 3-((3-(Benzyloxy)propoxy)methyl)-l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l / / -pyrazole. In a dry round-bottomed flask, 3 -((3 -(benzyloxy) propoxy )methyl)-4-bromo-l -methyl- 1 7-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 w-BuLi (11.7 mL, 18.7 mmol, 1.1 eq) over 20 minutes. The reaction was allowed to stir 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, m / z = 387.4 [M+H]+.Intermediate 3(l?)-6-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-l / / -pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[l,2-a]indol-l(2Z / )-one

[0268] Step A: Ethyl (7?)-7-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-lH-pyrazol-4-yl)-l-(l-((tert-butoxycarbonyl)amino)propan-2-yl)-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy) propyl)- l / / -indole-2-car boxy late. (General Procedure A) In a heavy wall vial, Intermediate 1 (5.67 g, 11.4 mmol, 1 eq), Intermediate 2 (5.94 g, 15.3 mmol, 1.35 eq), K2CO3 (4.72 g, 34.2 mmol, 3 eq), and Pd(PPhs)4 (1.30 g, 3.4 mmol, 0.1 eq) were added and dissolved in dioxane (90 mL) and H2O (20 mL). The solution was sparged with argon for 5 min, and the reaction was then sealed and heated to 100 °C for 8 h. The reaction was thencooled to room temperature, extracted with EtOAc, dried over MgSO4 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 (8 g, 77% yield). LCMS (ESI) Method 2: RT = 1.19 min, m / z = 678.6 [M+H]+.

[0269] Step B: ( / ?)-6-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-lLT-pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[l,2-a|indol-l(2A / )-one. In a round-bottomed flask, ethyl (7?)-7-(3-((3-(benzyloxy)propoxy)methyl)- 1 -methyl- LH-pyrazol-4-yl)- 1-( 1 -((tertbutoxy carbonyl)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 mb). Ze / 7-Butyl (S)-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 after which time the reaction was determined to be complete. The reaction mixture was concentrated, extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The product was dissolved in DCM (60 mL). Trifluoroacetic acid (9 mL) was added, and the reaction was allowed to stir at room temperature 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 solvent was removed and the crude residue 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 5% MeOH in DCM to afford the title compound (4.1 mg, 50% over yield of the 3 reactions). LCMS (ESI) Method 2: RT = 1.06 min, m / 'z = 689.6 [M+H]+.Intermediate 4Ethyl 7-bromo-4,5-dimethoxy-l / / -indole-2-carboxylate

[0270] Step A: Ethyl (Z)-2-azido-3-(5-bromo-2,3-dimethoxyphenyl)acrylate. (General Procedure B) In a round bottomed flask, NaOEt (36 mL, 21% wt., Ill mmol, 2.3 eq) wascharged followed by 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 (40 mL; 1:1) and added to the NaOEt solution at 0 °C. The reaction was allowed to stir for 2 h at 0 °C, and then warmed to RT for 1 h. The reaction was cooled to 0 °C and fdtered 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.

[0271] Step B: Ethyl 7-bromo-4,5-dimethoxy-17Z-indole-2-carboxylate. (General Procedure C) Ethyl (Z)-2-azido-3-(5-bromo-2,3-dimethoxyphenyl)acrylate (11 grams, 31 mmol) was dissolved in toluene (120 mL) and irradiated for 10 minutes in a laboratory microwave at 180 °C. The reaction was concentrated, and the crude product was purified by flash column chromatography eluting with 0 to 30% EtOAc in hexanes to afford the title compound (5.5 grams, 54% yield). LCMS (ESI) Method 1: RT = 1.708 min, m / z = 327.9 [M+H]+.Intermediate 5(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-«]indol-l(2 / / )-one

[0272] Step A: Ethyl 7-bromo-3-(3-bromopropyl)-6-chloro-l / / -indole-2-carboxylate.In a reaction vessel, Intermediate 1 (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 MgSCh, fdtered, and then concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 30% MeOH in DCM to afford the title compound (1.0 g,59%). 'H-NMR (CDCI3) 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).

[0273] Step B: Ethyl 7-bromo-6-chloro-3-(3-(naphthalen-l-yloxy)propyI)-l / f-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), naphthal en-l-ol (0.40 g, 2.8 mmol, 3.0 eq), and K2CO3 (0.52 g, 3.8 mmol, 4.0 eq) were dissolved in anhydrous DMF (10 mb). The reaction mixture was heated at 80 °C for 2 h. The reaction mixture was extracted with EtOAc, 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).

[0274] Step C: Ethyl 7-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-l / 7-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)-17 / -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, m 'z = 666.7 (M+H).

[0275] Step D: (l?)-6-(3-((3-(Benzyloxy)propoxy)inethyl)-l-methyl-lH-pyrazol-4-yl)-7-chloro-4-methyl-10-(3-(naphthalen-l-yloxy)propyl)-3,4-dihydropyrazino[l,2-«]indol- l(2 / / )-one. In a round-bottomed flask, ethyl 7-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl- l / 7-pyrazol-4-yl)-6-chloro-3-(3-(naphthalen-l-yloxy)propyl)-l / 7-indole-2-carboxylate (500 mg, 0.75 mmol, 1 eq) was dissolved in MeCN (5 m ). / c' / 7-Butyl (5)-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 extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and then concentrated. The crude residue was flashed by flash column chromatography eluting with 0 to 100% EtOAc in hexanes (500 mg, 76% yield). LCMS (ESI) Method 2: RT = 1.30 min, m / z = 824.4 [M+H]+. The residue was dissolved in DCM (10 mL). Trifluoroacetic acid (1 mL) was added, and the reaction was allowed to stir at room temperature for 3 h. The reaction was concentrated and the crude residue was dissolved in EtOH (15 mL). Potassium carbonate (1.3g, 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 H2O, 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 (300 mg, 76% yield). LCMS (ESI) Method 2: RT = 1.10 min, m / z = 677.5 [M+H]+.Intermediate 6(41?)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(l-methyl-3-((3- ((tetrahydro-2J / -pyran-2-yl)oxy)propoxy)methyl)-LH-pyrazol-4-yl)-3,4-dihydropyrazino [l,2-a]indol-l(2 / / )-one

[0276] Step A: (l?)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3-((3-hydroxy propoxy)methyl)-l-methyl-lJ / -pyrazol-4-yl)-4-methyl-3,4-dihydropyrazino[l,2-fl]indol-l(2H)-one. (General Procedure D) Intermediate 3 (200 mg, 0.29 mmol) was dissolved in THF / 'PrOH (8 mL, 3:1). The reaction was sparged with argon, followed by addition of Pd / C (10% wt, 45 mg, 0.045 mmol, 0.15 eq) and Pd(OH)2 / C (20% wt., 31 mg, 0.045 mmol, 0.15 eq). The vessel was evacuated and backfilled with argon (3x), followed by introduction of H2. The reaction was allowed to stir under a balloon atmosphere of H2 at 35 °C for 2 h until no starting material was detected by LCMS. Upon completion, the reaction was filtered through a plug of Celite® and rinsed with DCM. The filtrate was concentrated to afford the desired product (170 mg, 98% yield) and used without further purification. LCMS (ESI) Method 2: RT = 1.029 min, m / z = 599.0 [M+H],

[0277] Step B: (47?)-7-Chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(l-methyl-3-((3-((tetrahydro-2 / f-pyran-2-yl)oxy)propoxy)methyl)-l / Z-pyrazol-4-yl)-3,4-dihydro pyrazino[l,2-fl]indol-l(2H)-one. In a reaction vessel, (J?)-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-a]indol-l(2 / / )-one (100 mg, 0.17 mmol, 1.0 eq) was dissolved in DCM (1 mL). 3,4-Dihydro-2H-pyran (56 mg, 0.66 mmol, 4.0 eq) and PPTS (12 mg, 0.048 mmol, 0.3 eq) were added and the reaction was allowed to stir at room temperature for 20 h. The reaction was extracted with EtOAc, washed with NaHCO.i, 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 (85 mg, 75% yield). LCMS (ESI) Method 2: RT = 1.603 min, m / z = 705.0 [M+Na].Intermediate 73-((Benzyloxy)mcthyl)-l-mcthyl-4-(4,4,5,5-tctramethyl-l,3,2-dioxaborolaii-2-yl)-l / / -pyrazolc

[0278] Step A: 3-((Benzyloxy)methyl)-4-bromo-l-methyl-l / / -pyrazole. In a round-bottomed flask (4-bromo-l-methyl-177-pyrazol-3-yl)methanol (2.0 g, 10.5 mmol, 1.0 eq) was combined and dissolved in DMF (25 ml). Sodium hydride (300 mg, 12.5 mmol, 1.2 eq) was added at RT, and the reaction was allowed to stir for 1 h. Benzyl bromide (1.7 g, 14.3 mmol, 1.4 eq) was added, and the reaction was allowed to stir for 4 h at RT, after which time the reaction was complete. The reaction was quenched with H2O (10 mL), extracted with EtOAc, washed with H2O (2 x 20 mL), brine, dried over MgSCh, 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 (2.6 g, 89% yield). LCMS (ESI) Method 1: RT = 1.506 min, m / z = 281.0 [M+H],

[0279] Step B: 3-((BenzyIoxy)methyl)-l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lET-pyrazole. In a round-bottomed flask 3-((benzyloxy)methyl)-4-bromo-1 -methyl -l / / -pyrazole (2.6 g, 9.2 mmol, 1.0 eq) and 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.4 g, 18.4 mmol, 2.0 eq) were combined and dissolved in THF (40 mL) under an atm. of argon. The reaction was cooled to -78 °C and / v-BuLi (2.5 M, 5.5 mL, 13.8 mmol, 1.5 eq) was added. The reaction was allowed to warm to RT over 2 h, followed by stirring for 1 h at RT. The reaction was quenched with H2O (10 mL), diluted into EtOAc / ELO (60 mL,1:1), and the organic layer was separated. The aqueous layer was extracted with EtOAc, 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 (0.99 g) and recovered starting material (1.3 g). LCMS (ESI) Method 1: RT = 1.781 min, m / z = 329.1 [M+H]+.Intermediate 83-((Benzyloxy)methyl)-l,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole

[0280] Step A: 3-((Benzyloxy)methyl)-4-bromo-l,5-dimethyl-LH-pyrazole. (1,5-Dimethyl-177-pyrazol-3-yl)methanol (840 mg, 6.67 mmol, 1,0 eq) was dissolved in DMF (15 mb) and cooled to 0 °C. NBS (1.4 g, 7.86 mmol, 1.15 eq) was added and the reaction was allowed to stir at RT for 1 h. The reaction was diluted into DCM (50 m ), washed with saturated aq. Na2S20s, brine, and then dried with MgSO4, filtered, and concentrated. LCMS (ESI) Method 1: RT = 0.799 min, m z = 205.0 [M+H], The crude residue was taken up in DMF (15 mL) and cooled to 0 °C. Sodium hydride (300 mg, 1.87 mmol, 1.9 eq) was added, and the reaction was allowed to stir for 15 minutes. Benzyl bromide (1.5 g, 8.8 mmol, 1.3 eq) was added, and the reaction was allowed to stir at room temperature until complete by LCMS analysis. The reaction was quenched with H2O (10 mL), extracted with DCM, washed with FEO, 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 (1.72 g, 87% yield). LCMS (ESI) Method 1: RT = 1.594 min, m / z = 295.0 [M+H],

[0281] Step B: 3-((Benzyloxy)methyl)-l,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l / / -pyrazole. 3-((Benzyloxy)methyl)-4-bromo-l,5-dimethyl-l / / -pyrazole (1.6 g, 5.4 mmol, 1.0 eq) was dissolved in THF (40 mL) under an atm. of argon. The reaction was cooled to -78 °C. / ?-BuLi (2.5 M, 2.6 mL, 6.5 mmol, 1.2 eq) was added, and the reactionwas allowed to stir for 1 h. Bis(pinacalato)diboron (1.5 g, 8.0 mmol, 1.5 eq) was added, and the reaction was allowed to stir at RT for 5 h. The reaction was concentrated, dissolved in EtOAc, filtered through a pad of Celite®, and concentrated. The crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the title compound (1.52 g, 82% yield). LCMS (ESI) Method 1: RT = 1.802 min, m / z = 343.1 [M+H]+.Intermediate 9Ethyl 7-iodo-LH-indole-2-carboxylate

[0282] Ethyl 7-bromo-l / 7-indole-2-carboxylate (1.0 g, 3.8 mmol, 1.0 eq), (trans)-N^, N^-dimethylcyclohexane-l,2-diamine (50 mg, 0.35 mmol, 0.10 eq), copper (I) iodide (70 mg, 0.36 mmol, 0.1 eq), and sodium iodide (1.7 g, 11.3 mmol, 3.0 eq) were combined and dissolved in dioxane (10 mb). The reaction was sparged with argon for 5 min, sealed, and then heated to 110 °C for 48 h. The reaction was extracted with EtOAc, washed with 10% NEUOH aq. solution, brine, dried over MgSO4, filtered, and then concentrated. The crude reaction mixture was purified by flash column chromatography eluting with 0 to 20% EtOAc in hexanes to afford the title compound (0.95 g). LCMS (ESI) Method 1: RT = 1.825 min, m / z = 315.9 [M+H]+.Intermediate 10Methyl 7-iodo-4,5-dimethoxy-lH-indole-2-carboxylate

[0283] Step A: 2-Hydroxy-5-iodo-3-methoxybenzaldehyde. 2-Hydroxy-3-methoxybenzaldehyde (10 g, 65 mmol, 1 eq) was dissolved in DCM (200 mL). Pyridine (8 mL, 1.5 eq) was added at room temperature, followed by addition of NIS (19.2 g, 85.3 mmol, 1.3 eq). The reaction was allowed to stir at room temperature for 10 h, then washed with water, saturated aq. Na2S2O3, and brine. The organic layer was dried over MgSO4, filtered, and then concentrated. The crude solid was triturated to afford the title compound (14 g, 77% yield).

[0284] Step B: 5-Iodo-2,3-dimethoxybenzaldehyde. 2-Hydroxy-5-iodo-3-methoxybenzaldehyde (14 g, 50 mmol, 1.0 eq) was dissolved in DMF (150 mL) at room temperature. K2CO3 (17.4 g, 126 mmol, 2.5 eq) was added, followed by addition of Mel (9.3 g, 65 mmol, 1.3 eq). The reaction was allowed to stir for 10 h, extracted with EtOAc, washed with H2O, washed with brine, dried over MgSC>4, filtered, and concentrated. Trituration provided the title compound (13 g, 88% yield).

[0285] Step C: Methyl (Z)-2-azido-3-(5-iodo-2,3-dimethoxyphenyl)acrylate. The title compound (9.0 g, 56% yield) was prepared following General Procedure B using 5-iodo-2,3-dimethoxybenzaldehyde (12 g, 41 mmol) and methyl 2-azidoacetate (18.6 g, 160 mmol, 4.0 eq). Following aqueous workup, the crude product was triturated with hexanes to afford the desired product.

[0286] Step D: Methyl 7-iodo-4,5-dimethoxy-LH-indole-2-carboxylate. The title compound (5.5 g, 67% yield) was prepared following General Procedure C using methyl (Z)-2-azido-3-(5-iodo-2,3-dimethoxyphenyl)acrylate (10 g, 25.8 mmol, 1 eq). The crude product was purified by flash column chromatography eluting with 0 to 50% EtOAc in hexanes.Intermediate 11

[0287] Step A: (4-Bromo-l,3-dimethyl-lH-pyrazol-5-yl)methanol. To a solution of (1,3-dimethyl-l / / -pyrazol-5-yl)methanol (5 g, 39.62 mmol, 1.0 eq) in DCM (195 mL) was added NBS (7.40 g, 41.6 mmol, 1.05 eq) at 0 °C. The reaction mixture was stirred for 2 h at RT, quenched with water (200 mL), and extracted with DCM, dried over MgSCh, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 0 to 10% MeOH in DCM to afford the title compound (7.84 g, 96 % yield).1H NMR (CDCh, 400 MHz) 8 (ppm) 4.66 (d, J= 6.0 Hz, 2H), 3.89 (s, 3H), 2.21 (s, 3H); LCMS (ESI) Method 1: RT = 0.103 min, m!z = 206.07 [M+H]+.

[0288] Step B: 5-((3-(Benzyloxy)propoxy)methyl)-4-bromo-l,3-dimethyl-l / / -pyrazole.To a solution of (4-bromo-l,3-dimethyl-H7-pyrazol-5-yl)methanol (4 g, 19.5 mmol, 1.0 eq) in DMF (65 mL) was added NaH (1.25 g, 31.21 mmol, 1.6 eq) at 0 °C. After stirring 30 min, ((3-bromopropoxy)methyl)benzene (5.51 mb, 31.21 mmol, 1.6 eq) was added. The reaction was stirred for 3 h at RT, diluted with EtOAc, and washed with H2O. The combined organic layers were dried over MgSCh, filtered, and then concentrated. The crude product was purified by flash column chromatography eluting with 0 to 50% EtOAc in hexane to afford the colorless oil title compound (3.88 g, 57 % yield).NMR (CDCh, 400 MHz) 5 (ppm) 7.36-7.27 (m, 5H), 4.48 (s, 2H), 4.47 (s, 2H), 3.80 (s, 3H), 3.54 (dd, J= 11.2, 6.4 Hz, 4H), 2.21 (s, 3H), 1.88 (dt, J = 10.0, 6.4 Hz, 2H); LCMS (ESI) Method A: RT = 1.111 min, / 7? z = 353.3 [M+Hf.

[0289] Step C: 5-((3-(Benzyloxy)propoxy)methyl)-l,3-dimethyl-4-(4,4,5,5-tetramethyl- 1.3.2-dioxaborolan-2-yl)-LH-pyrazole. To a solution of 5-((3-(benzyloxy)propoxy)methyl)-4-bromo-l,3-dimethyl-l / / -pyrazole (3.88 g, 11.02 mmol, 1.0 eq) in THF (73 m ) was added n-BuLi (8.3 mb, 13.22 mmol, 1.2 eq), followed by addition of 2-isopropoxy-4,4,5,5-tetramethyl- 1.3.2-dioxaborolane (3.15 mb, 15.43 mmol, 1.4 eq) at -78 °C. The reaction mixture was allowed to stir for 1 h at -78 °C, then quenched with sat. NH4Q (70 mb), 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 60% EtOAc in hexanes to afford the colorless oil title compound (3.60 g, 81% yield). LCMS (ESI) Method A: Rr = 1.191 min, m / z = 401.4 [M+H]+.Intermediate 12(47?)-6-(4-((3-(Benzyloxy)propoxy)methyl)pyridin-3-yl)-7-chloro-10-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-4-methyl-3,4-dihydropyrazino[ l,2-a]indol- l(2 / / )-one

[0290] Intermediate 4 (2.6 g, 7.92 mmol, 1.0 eq) was dissolved in 1,4-dioxane (7 mb). Nal (3.56 g, 23.8 mmol, 3.0 eq), Cui (75 mg, 0.4 mmol, 0.05 eq), and trans-('[R,2R)-Nl, N2-dimethylcyclohexane-l,2-diamine (113 mg, 0.79 mmol, 0.1 eq) were added, and the reaction mixture was degassed with argon. The reaction was stirred at 110 °C for 60 h. The reaction was extracted with EtOAc, washed with 30% NH4OH, washed with brine, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatographyeluting with 0 to 10% EtOAc in hexanes to afford the title compound (2.25 g, 76% yield). LCMS (ESI) Method 1: RT = 1.783 min, m / z = 375.90 [M+H]+.Intermediate 13(7?)-6-bromo-7-chloro-10-(4-(4-chloro-3,5-dimethylphenyl)butyl)-4-methyl-3,4- dihydropy razino [1,2-a] indol- 1 (2H)-one[00291J Intermediate 1 (5.0 g, 10 mmol, 1.0 eq) was dissolved in MeCN (85 mL). tert-Butyl (S)-5-methyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (3.85 g, 16.2 mmol, 1.6 eq.) and CS2CO3 (7.18 g, 22 mmol, 2.2 eq) were added, and the reaction was heated to 80 °C for 5 h. The reaction mixture was concentrated, extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The product was dissolved in DCM (40 mL). TFA (13 mL) was added, and the reaction stirred at RT for 1 h. The reaction was concentrated, and the crude residue was dissolved in methanol (150 mL). K2CO3 (15.8 g, 107 mmol, 10.0 eq) was added, and the reaction was heated to 50 °C for 2 h. The solvent was removed and the crude residue was extracted with H2O, 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 (4.68 mg, 86% yield). LCMS (ESI) Method 1: Rr = 2.405 min, m,z = 508.8 [M+H]+.Intermediate 14Ethyl ( / ?)-7-(6-bromo-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-l- oxo-3, 4-dihydropyrazino[l,2-a]indol-2(U / )-yl)-4,5-dimethoxy-l / / -indole-2-carboxylate

[0292] (General Procedure E) Intermediate 12 (1.48 g, 3.94 mmol, 1.0 eq), Intermediate 13 (470 mg, 1.3 mmol, 3 eq), K3PO4 (553 mg, 1.30 mmol, 3 eq), copper(I) iodide (49.7 mg, 261 pmol), and / ra / 7.s-(l / ^2 / \')-A'l, A'2-dimethylcyclohexane-l,2-di amine (68.6 pL, 435 pmol) were charged in a reaction vessel equipped with a stir bar and dissolved in toluene (1 mb). The reaction was sparged with argon for 10 min, followed by heating to 110 °C for 6 hr. The reaction extracted with EtOAc, washed with 30% aq. NH4OH, washed with brine, dried over MgSCL, fdtered and concentrated. The residue was purified by flash column chromatography eluting with 0 to 100 % EtOAc in hexanes to afford the desired product (780 mg, 53% yield). LCMS (ESI) Method 2: RT = 1.778 min, m / z = 757.7 (M+H).Intermediate 155-((3-(Benzyloxy)propoxy)methyl)-l,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l / / -pyrazole

[0293] Step A: (4-Bromo-l,3-dimethyl-lH-pyrazol-5-yl)methanol. To a solution of (1,3-dimethyl-l / / -pyrazol-5-yl)methanol (5 g, 39.62 mmol, 1.0 eq) in DCM (195 mL) was added NBS (7.40 g, 41.6 mmol, 1.05 eq) at 0 °C. The reaction mixture was stirred for 2 h at RT, quenched with H2O (200 mL), extracted with DCM, dried over MgSO4, filtered, and then concentrated. The crude product was purified by flash column chromatography eluting with 0 to 10% MeOH in DCM to afford the title compound (7.84 g, 96 % yield).1H NMR (CDCI3, 400 MHz) 8 (ppm) 4.66 (d, J= 6.0 Hz, 2H), 3.89 (s, 3H), 2.21 (s, 3H); LCMS (ESI) Method 1: RT = 0.103 min, m!z = 206.07 [M+H]+.

[0294] Step B: 5-((3-(Benzyloxy)propoxy)methyl)-4-bromo-l,3-dimethyl-l / Z-pyrazole.To a solution of (4-bromo-l,3-dimethyl-H / -pyrazol-5-yl)methanol (4 g, 19.5 mmol, 1.0 eq) in DMF (65 mL) was added NaH (1.25 g, 31.21 mmol, 1.6 eq) at 0 °C. After stirring 30 min at 0 °C, ((3-bromopropoxy)methyl)benzene (5.51 mL, 31.21 mmol, 1.6 eq) was added to thereaction mixture. The reaction mixture was stirred for 3 h at RT, diluted with EtOAc, washed with H2O, dried over MgSCU, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 0 to 50% EtOAc in hexane to afford the colorless oil title compound (3.88 g, 57 % yield). 'H NMR (CDCI3, 400 MHz) 8 (ppm) 7.36-7.27 (m, 5H), 4.48 (s, 2H), 4.47 (s, 2H), 3.80 (s, 3H), 3.54 (dd, J= 11.2, 6.4 Hz, 4H), 2.21 (s, 3H), 1.88 (dt, J = 10.0, 6.4 Hz, 2H); LCMS (ESI) Method 1: RT = 1.111 min, m / z = 353.3 [M+H]+.

[0295] Step C: 5-((3-(Benzyloxy)propoxy)methyl)-l,3-dimethyl-4-(4,4,5,5-tetramethyl- 1.3.2-dioxaborolan-2-yl)-lH-pyrazole. To a solution of 5-((3-(benzyloxy)propoxy)methyl)-4-bromo-l,3-dimethyl-17 / -pyrazole (3.88 g, 11.02 mmol, 1.0 eq) in THF (73 mL) was added n-BuLi (8.3 mL, 13.22 mmol, 1.2 eq), followed by addition of 2-isopropoxy-4,4,5,5-tetramethyl- 1.3.2-dioxaborolane (3.15 mL, 15.43 mmol, 1.4 eq) at -78 °C. The reaction mixture was allowed to stir for 1 h at -78 °C, then quenched with sat. NH4CI (70 mL), 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 60% EtOAc in hexanes to afford the colorless oil title compound (3.60 g, 81% yield). LCMS (ESI) Method 1: RT = 1.191 min, m / z = 401.4 [M+H]+.Intermediate 16Ethyl 5-(benzyloxy)-7-iodo-4-methoxy-LH-indole-2-carboxylate

[0296] Step A: 3-(benzyloxy)-2-hydroxybenzaldehyde. Sodium hydride (3.65 g, 152 mmol) was added to a 500 mL round-bottomed flask under argon followed by dry THF (100 mL). The suspension was stirred 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, and additional THF (25 mL) was added. 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 stirred 10 minutes then 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. The aqueous layer was then extracted with DCM, washed with IN HC1, brine, dried over MgSCh, concentrated, and dried in a vacuum oven vacuum at 45 °C overnight to afford the title compound (12.55 g, 76% yield) as a light brown solid. LCMS (ESI) Method 1: RT = 1.570 min, m / z = 229.1 [M+H]+.

[0297] Step B: 3-(Benzyloxy)-2-hydroxy-5-iodobenzaldehyde. To a stirred suspension of AgNOs (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. Then iodine monochloride (2.44 mL, 48.2 mmol, 1.05 eq), diluted in CHCh (15 mL), was added dropwise at 0 °C with constant stirring. 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 poured through filter paper, 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 (5x), aqueous saturated sodium thiosulfate (3x), water, brine (2x) dried over MgSCh and 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.

[0298] 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). Potassium carbonate (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 60 h. The reaction was extracted with EtOAc, washed with saturated NH4CI, water, saturated NaHCCh, brine, then dried over MgSC>4 and 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]+.

[0299] 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 fdtered in a Buchner funnel andwashed 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.

[0300] 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).Following 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 fdtering 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]+.Intermediate 17Ethyl 7-iodo-5-methyl-lH-indole-2-carboxylate

[0301] The title compound was prepared analogously to Intermediate 12 starting with ethyl 7-bromo-5-methyl-17 / -indole-2-carboxylate (1.72 g, 74% yield). LCMS (ESI) Method 2: RT = 1.003 min, m 'z = 329.9 (M+H).Intermediate 18Ethyl 7-iodo-4-m ethoxy- l / / -indole-2-car boxy late

[0302] The title compound was prepared analogously to Intermediate 12 starting with ethyl 4-methoxy-7-bromo-177-indole-2-carboxylate (4.96 g, 77% yield). LCMS (ESI) Method 1: RT = 1.828 min, m / z = 345.9 (M+H).Intermediate 19Ethyl 7-iodo-4-methoxy-5-methyl-lH-indole-2-carboxylate

[0303] The title compound was prepared analogously to Intermediate 16 (Steps B thru E) starting with 2-hydroxy-3-methylbenzaldehdye.Intermediate 20Ethyl 7-bromo-5-methoxy-4-methyl-l / / -indole-2-carboxylate

[0304] Step A: (2-Bromo-4-methoxy-5-methylphenyl)hydrazine. In a reaction vessel 2-bromo-4-methoxy-5-methylaniline (9 g, 40 mmol, 1.0 eq) was added and 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 dropwise added for 30 min. The reaction was stirred at 0°C for 1 h followed by dropwise addition of SnCh (28 g, 150 mmol, 3.7 eq, dissolved in 25 mL cone. HC1). The reaction was stirred 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® then rinsed with DCM. The filtrate was extracted with DCM, dried over MgSCh, filtered, and concentrated to afford the title product (8.4 g, 87% yield). 'H-NMR (DMSO-d6) 57.15 (s, 1H), 6.94 (s, 1H), 5.8 (s, 2H), 3.65 (s, 3H), 2.1 (s, 3H).

[0305] Step B: Ethyl 7-bromo-5-methoxy-4-methyl-TH-indole-2-carboxylate. In a reaction vessel (2-bromo-4-methoxy-5-methylphenyl)hydrazine (9.2 g, 40 mmol, 1.0 eq) was dissolved in anhydrous EtOH (100 mL). Ethyl pyruvate (5 mL, 44 mmol, 1.1 eq) was added and the reaction was heated to 70 °C for 1 h. The reaction was concentrated and the crude material was transferred to a heavy-walled pressure vessel and 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 MgSCh, 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). 'H-NMR (DMSO-d6) 88.45 (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).Intermediate 21Methyl 7-iodo-5-methoxy-TH-indole-2-carboxylate

[0306] The title compound was prepared analogously to Intermediate 12 using methyl 5-methoxy-7-bromo-l / / -indole-2-carboxylate.Intermediate 22Ethyl 7-bromo-4-ethoxy-5-methoxy-LH-indole-2-carboxylate

[0307] Step A: 5-Bromo-2-ethoxy-3-methoxybenzaIdehyde. In a reaction vessel 5-bromo-2-hydroxy-3 -methoxy -benzaldehyde (1.0 g, 4.33 mmol, 1.0 eq) was dissolved inDMF (22 mL). Potassium carbonate (720 mg, 5.2 mmol, 1.2 eq) and bromoethane (0.36 mb, 4.8 mmol, 1.1 eq) were added and the reaction was allowed to stir at 65 °C until complete by LCMS. The reaction was extracted with EtOAc, washed with H2O, dried over MgSC>4, filtered, and concentrated to afford the title compound (1.09 g, 97% yield). LCMS (ESI) Method 1: RT = 1.541 min, m z = 259.0 (M+H).

[0308] Step B: Ethyl (Z)-2-azido-3-(5-bromo-2-ethoxy-3-methoxyphenyl)acrylate. The title compound (560 mg, 37% yield) was prepared following General Procedure B using 5-bromo-2-ethoxy-3-methoxybenzaldehyde (1.05 g, 4.05 mmol, 1.0 eq). Upon completion, the reaction was cooled to 0 °C, filtered through Celite®, and rinsed with cold EtOH. The filtrate was concentrated to afford the title compound (560 mg, 37% yield).

[0309] Step C: Ethyl 7-bromo-4-ethoxy-5-methoxy-TH-indole-2-carboxylate. The title compound (270 mg, 52% yield) was prepared following General Procedure C using ethyl (Z)-2-azido-3-(5-bromo-2-ethoxy-3-methoxyphenyl)acrylate (560 mg, 1.51 mmol, 1.0 eq). The crude residue was purified by flash column chromatography eluting with 0 to 15% EtOAc in hexanes. LCMS (ESI) Method 1: RT = 1.828 min, nvz = 342.1 (M+H).Intermediate 23Ethyl 4,5-diethoxy-7-iodo-l / f-indole-2-carboxylate

[0310] Step A: 5-Bromo-2,3-diethoxybenzaldehyde. In a reaction vessel 5-bromo-2, 3-dihydroxybenzaldehyde (1.07 g, 4.93 mmol, 1.0 eq) was dissolved in DMF (25 mL).Potassium carbonate (2.04 g, 15 mmol, 3.0 eq) was added, followed by bromoethane (0.81 mL, 11 mmol, 2.2 eq). The reaction was heated to 65 °C for 24 h. The reaction was extracted with EtOAc, washed with H2O, dried over MgSCh, 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 (1.03 g, 76% yield). LCMS (ESI) Method 1: RT = 1.541 min, m / z' = 273.0 (M+H).

[0311] Step B: Ethyl (Z)-2-azido-3-(5-bromo-2,3-diethoxyphenyl)acrylate. The title compound (858 mg, 60% yield) was prepared following General Procedure B using 5-bromo-2,3-diethoxybenzaldehyde (1.03 g, 3.77 mmol, 1.0 eq). The crude material was purified by flash column chromatography eluting with 0 to 10% EtOAc in hexanes. LCMS (ESI) Method 1: RT = 1.908 min, m / z = 355.9 (fragment).

[0312] Step C: Ethyl 4,5-diethoxy-7-bromo-l / / -indole-2-carboxylate. The title compound (367 mg, 68% yield) was prepared following General Procedure C using ethyl (Z)-2-azido-3-(5-bromo-2,3-diethoxyphenyl)acrylate (580 mg, 1.5 mmol). Upon concentrating, the reaction was purified by flash column chromatography eluting with 0 to 10% EtOAc in hexanes to afford the title compound (367 mg, 68% yield). LCMS (ESI) Method 1: RT = 1.639 min, m z = 355.9 (M+H).

[0313] Step D: Ethyl 4,5-diethoxy-7-iodo-LH-indole-2-carboxylate. The title compound was prepared analogously to Intermediate 12 using ethyl 4,5-diethoxy-7-bromo- l / / -indole-2-carboxylate (345 mg, 85% yield, 9:1 mixture of product:sm). LCMS (ESI) Method 1: RT = 1.944min, m / 'z = 403.9 (M+H).Intermediate 24(26345«,l722l?a,2^7?)-2^-Chloro-21®-(3-hydroxypropyl)-l^,l^-dimethoxy-2^,31-dimethyl- 1 -((5)-octahydropyrazino[2,l-c] [1, 4]oxazine-8-carbonyl)-21,l^-tetrahydro- I ' / ZA1 / / -? -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 21-one

[0314] Step A: Ethyl 7-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-l / 7-pyrazol-4-yl)-6-chloro-3-(3-ethoxy-3-oxopropyl)-lfT-indole-2-carboxylate. The title compound (4.0 g, 55% yield) was prepared following General Procedure A using ethyl 7-bromo-6-chloro-3-(3-ethoxy-3 -oxopropyl)- l / Z-indole-2-carboxylate (5.0 g, 12 mmol, 1.0 eq) and Intermediate 2 (6.74 g, 17 mmol, 1.4 eq). Following aqueous workup, the crude residue was purified by flash column chromatography.

[0315] Step B: Ethyl (Z?)-3-(6-(3-((3-(beiizyloxy)propoxy)inethyl)-l-niethyl-lZZ-pyrazol-4-yl)-7-chloro-4-methyl-l-oxo-l,2,3,4-tetrahydropyrazino[l,2-a]indol-10-yl)propanoate.Ethyl 7 -(3 -((3 -(benzyl oxy)propoxy)methyl)- 1 -methyl- I ZZ-py razol -4-yl)-6-chloro-3 -(3 -ethoxy -3 -oxopropyl)- l / / -indole-2-carboxylate (24 g, 41 mmol, 1.0 eq) was dissolved in MeCN (240 mL). / tv - Butyl (S)-5-methyl-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (14.67 g, 62 mmol, 1.5 eq) and CS2CO3 (29.5 g, 91 mmol, 2.2 eq) was added and the reaction was heated to 70 °C for 16 h. Upon completion, the reaction was extracted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated. The crude residue was taken up in DCM (280 mL) and TFA (21.6 g, 189 mmol, 5.0 eq) was added and the reaction was allowed to stir for 3 h at room temperature. The reaction was poured into ice water, extracted with EtOAc, and concentrated. The resulting residue was taken up in EtOH (230 mL) and K2CO3 (24.8 g, 180 mmol, 5.0 eq) was added. The reaction was heated to 60 °C for 2 h, after which time the reaction was determined to be complete. The reaction was extracted with EtOAc, washed withH2O, dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography to afford the title compound (11 g, 52% yield).

[0316] Step C: tc / V- Butyl (l?)-7-(6-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-l / / -pyrazol-4-yl)-7-chloro-10-(3-ethoxy-3-oxopropyl)-4-methyl-l-oxo-3,4-dihydropyrazino[l,2-a]indol-2(lH)-yl)-4,5-dimethoxy-lfl-indole-2-carboxylate. Ethyl (R)- 3-(6-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-177-pyrazol-4-yl)-7-chloro-4-methyl-l-oxo-l,2,3,4-tetrahydropyrazino[l,2-rz]indol-10-yl)propanoate (2.0 g, 3 mmol, 1.0 eq), Zcz7-butyl 7-bromo-4,5-dimethoxy-l / / -indole-2-carboxylate (1.80 g, 5 mmol, 1.5 eq), and CS2CO3 (3.28 g, 10 mmol, 3 eq) were added to a reaction vessel equipped with a stir bar, followed by addition of toluene (11 mb). The vessel was capped and argon was sparged through the stirring mixture for 10 minutes. [Pd(cinnamyl)Cl]2 (175 mg, 0.3 mmol, 0.1 eq) and ZBuBrettPhos (163 mg, 0.3 mmol, 0.1 eq) were added, and the reaction was sealed under argon and heated to 100 °C for 16 h until no remaining starting material was observed by LCMS. The reaction was cooled to room temperature and diluted with 1: 1 EtOAc / EEO. The aqueous layer was separated and extracted with EtOAc (2x). The combined organic layers were washed with sat. NH4CI, sat. NaHCCh, water, and brine. The organic layer was dried over MgSCh, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to afford the desired product (1.75 g, 60% yield).

[0317] Step D: te / 7-Butyl (l?)-7-(7-chloro-10-(3-ethoxy-3-oxopropyl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-l / / -pyrazol-4-yl)-4-methyl-l-oxo-3,4-dihydr(>pyrazino| 1.2-u|indol-2( l / / )-yl)-4.5-dimethoxy-l / / -indole-2-carboxylate. The title compound was prepared following General Procedure D using Zcvz-Butyl (R)-7-(6-(3-((3-(benzyloxy)propoxy)methyl)-l -methyl- l / 7-pyrazol-4-yl)-7-chloro-10-(3-ethoxy-3-oxopropyl)- 4-methyl-l -oxo-3, 4-dihydropyrazino[l,2-rz]indol-2(l / / )-yl)-4,5-dimethoxy-l / / -indole-2-carboxylate (7.0 g, 8 mmol, 1.0 eq). The crude product was carried forward to the next step without further purification (quantitative yield).

[0318] Step E: te / 7-Butyl (l?)-7-(7-chloro-10-(3-ethoxy-3-oxopropyl)-4-methyl-6-(l-inethyl-3-((3-(tosyloxy)propoxy)methyl)-l / / -pyrazol-4-yl)-l-oxo-3,4-dihydropyrazino[l,2-ii|indol-2(l / / )-yl)-4,5-dimethoxy-l / / -indole-2-carboxylate. Zcz'Z-Butyl (?)-7-(7-chloro-10-(3-ethoxy-3-oxopropyl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-l / / -pyrazol-4-yl)-4-methyl-1 -oxo-3, 4-dihydropyrazino[l,2-rz]indol-2(l / / )-yl)-4,5-dimethoxy-l / 7-indole-2-carboxylate (6.5g, 8 mmol, 1.0 eq) was dissolved in DCM (65 mL) and cooled to 0 °C. Triethylamine (2.54 g, 25 mmol, 3.0 eq) and DMAP (100 mg, 0.08 mmol, 0.1 eq) were added, followed by p-toluenesulfonic acid (7.2 g, 42 mmol, 5.0 eq). The reaction was allowed to stir at room temperature for 16 h. The reaction was extracted with DCM, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography to afford the title compound (6.5 g, 83% yield).

[0319] StepF: m / 7-Butyl (26345a,l722l?a,24lf)-27-chloro-21®-(3-ethoxy-3-oxopropyl)-l4. -diniethoxy-24.3'-diniethyl-2 '-oxo-2'.22.23.24-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino[l,2-<z]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxylate. tert-Butyl (A)-7-(7-chloro-10-(3-ethoxy-3-oxopropyl)-4-methyl-6-(l-methyl-3-((3-(tosyloxy)propoxy)methyl)-177-pyrazol-4-yl)-l -oxo-3, 4-dihy dropyrazino[l, 2-cz]indol-2(17 )-yl)-4,5-dimethoxy-l / 7-indole-2-carboxylate (6.7 g, 7 mmol, 1.0 eq) was dissolved in DMF (1.0 L) and CS2CO3 (11.67 g, 35 mmol, 5.0 eq) was added. The reaction was heated at 55 °C and allowed to stir 16 h. The reaction was extracted with EtOAc, washed with H2O, dried over MgSCh, filtered, and concentrated. The crude residue was purified by flash column chromatography to afford the title compound (2.4 g, 44% yield).

[0320] Step G: (2634,l722^fl,24 / ?)-27-Chloro-210-(3-ethoxy-3-oxopropyl)-l4,l5-dimethoxy-24,3^-dimethyl-21-oxo-21,2^,2^,24-tetrahydro-ll / 7,31 / / -5-oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxylic acid. In a round-bottomed flask, / e / 7-butyl (2(’34a,l722Aa,24)-27-chloro-2^-(3-ethoxy-3-oxopropyl)-14, 1 -dimethoxy-24,31 -dimethyl-21 -oxo-21,22, 23,24-tetrahydro- 1 ^H,3 ^H-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclo- octaphane-l2-carboxylate (1.0 g, 1.31 mmol, 1.0 eq) was dissolved in DCM (20 ml) and cooled to 0 °C. TFA (3 mL) was added dropwise, and the reaction was allowed to stir at room temperature until complete by LCMS. The solvent was removed to afford the title compound (925 mg, quantitative yield). The crude material was used in the subsequent step without further purification. LCMS (ESI) Method 2: RT = 0.89 min, m / z = 704.5 (M+H).

[0321] Step H: Ethyl 3-((2634S'„.l722 / ?„.24 / ?)-27-chloro-l4.l5-dimethoxy-24.3l-dimethyl-l2-((5)-octahydropyrazino[2,l-c][l,4]oxazine-8-carbonyl)-21-oxo- 24,22,23,24-tetrahydro--indola-3(4.3)-pyrazolacyclooctaphane-210-yl)propanoate. 26,34Sa, 172~A'„. 2^A')-2^-('hloro-2 '(’-(3-ethoxy-3 -oxopropyl)- 1 1 -di m ethoxy-24, 31 -dimethyl-21 -oxo-2 ^,2^,2^,24-tetrahy dro- -oxa-2(2,6)-pyrazino[ 1,2-a]i ndol a- 1 (7, 1 )-indola-3 (4,3)-pyrazolacyclooctaphane- 12-carboxylic acid (0.925 g, 1.31 mmol, 1.0 eq) was dissolved in DMF (10 mL) and DIPEA (0.96 mL, 5.24 mmol, 4.0 eq) and HATU (695 mg, 1.83 mmol, 1.4 eq) was added. The reaction was allowed to stir for 5 minutes, followed by addition of (5)-octahydropyrazino[2,l-c][l,4]oxazine (420 mg, 1.95 mmol, 1.5 eq). Reagents were initially added and stirred for 30 min at 0 °C, followed by stirring at room temperature overnight. Following aqueous workup, the reaction was purified by flash column chromatography eluting with 0 to 20% MeOH in DCM to afford the title compound (0.92 g, 85% yield). LCMS (ESI) Method 2: RT = 1.02 min, m / z = 828.7 (M+H).

[0322] Step I: (26345fl,l722 / ?„,24 / ?)-27-Chloro-210-(3-hydroxypropyl)-l4,l5-dimethoxy-24,3^-dimethyl-l^-((i )-octahydropyrazino[2,l-c][l,4]oxazine-8-carbonyl)-2 '.27,2^.24-tetrahydro-l ' / / ,3' / / -5-oxa-2(2.6)-pyi azino| 1.2-i / |indola-l(7.1 )-indola-3(4.3)-pyrazolacyclooctaphan-24-one. In a round-bottomed flask, ethyl 3-((2,3V2 Ra, 24A)-27-chloro- 14, 15-dimethoxy-24,31 -dimethyl- -((5)-octahydropyrazino[2, 1 -c] [ 1,4]oxazine-8-carbonyl)-2' -oxo-2',27,2'\24-tetrahydro-l ' / / ,3 '7 / -5-oxa-2(2.6)-pyrazino[l,2-c / ]indola-l(7, l)-indola-3(4,3)-pyrazolacyclooctaphane-2^-yl) propanoate (0.92 g, 1.10 mmol, 1.0 eq) was dissolved in THF (30 mL) and cooled to 0 °C. LAH (103 mg, 2.71 mmol, 2.5 eq) was added in two portions, and the reaction was allowed to stir 15 min. LCMS shows complete conversion. The crude reaction was quenched with H2O and extracted with DCM (3 x 15 mL). The combined organic layers were dried over MgSCh, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 0 to 100% 95:5 EtOAc: MeOH in hexanes to afford the title compound (0.87 g, 75% yield). 'H NMR (400 MHz, DMSO) 57.92 (s, 1H), 7.77 (d, lH, J= 12 Hz), 7.35 (d, 1H, J= 12Hz), 7.02 (s, 1H), 4.90 (s, 2H) 4.72-4.67 (m, 1H), 4.21-4.15 (m, 3H), 4.04 (s, 3H), 4.01 (s, 3H), 3.92 (s, 3H), 3.86-3.93 (m, 2H), 3.73-3.67 (m, 4H), 3.62-3.54 (m, 5H), 3.29-3.20 (m, 4H), 3.12 (tr, 2H, J =12 Hz) ), 2.73-2.70 (m, 4H), 1.93-1.88 (m, 3H), 1.75-1.72 (m, 1H), 1.15 (d, 3H, J= 7 Hz). LCMS (ESI) Method 2: RT = 0.95 min, m / z = 786.6 (M+H).Intermediate 25Methyl 7-bromo-4,5-dimethoxy-TH-indole-2-carboxylate

[0323] Step A: Methyl (Z)-2-azido-3-(5-bromo-2,3-dimethoxyphenyl)acrylate. In a reaction vessel 5-bromo-2,3-dimethoxybenzaldehyde (1.0 g, 4.1 mmol, 1.0 eq) was dissolved in MeOH (2 mL) and THF (2 mL) at -20 °C under argon. Methyl azidoacetate (1.6 mL, 16.3 mmol, 4.0 eq) in MeOH (2 mL) was added, followed by NaOMe (881 mg, 16.3 mmol. 4.0 eq) in MeOH (12 mL) added dropwise. The reaction was warmed to 0 °C and allowed to stir overnight. The reaction was quenched with aq. NH4CI, 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 15% EtOAc in hexanes to afford the title compound (903 mg, 65%). LCMS (ESI) Method 1: RT = 2.045 min, m / z = 235.9 (fragment).

[0324] Step B: Methyl 7-bromo-4,5-dimethoxy-L T-indole-2-carboxylate. The title compound (356 mg, 74% yield) was prepared following General Procedure C using methyl (Z)-2-azido-3-(5-bromo-2,3-dimethoxyphenyl)acrylate (523 mg, 1.53 mmol). Upon completion, the crude residue was purified by flash column chromatography eluting with 0 to 10% EtOAc in hexanes. LCMS (ESI) Method 1: RT = 1.704 min, m / z = 313.9 (M+H).Example 1(26345«,l722 / ?fl,2^T?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^-dimethoxy-2^,3 -dimethyl-2 -oxo-21,2^,2^,2^-tetr ahydro- 1 ' / / ,3' / / -5-oxa-2(2,6)- pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphane-1 -carboxylic acid

[0325] 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-a]indol-2( l / / )-yl)-4,5-dimethoxy-l / / -indole-2-carboxylate. (General Procedure F). Intermediate 3 (750 mg, 1.09 mmol, 1.0 eq), Intermediate 4 (430 mg, 1.3 mmol, 1.2 eq), and CS2CO3 (1.8 g, 5.5 mmol, 5 eq) were added to a reaction vessel equipped with a stir bar, 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 LBuBrettPhos (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 diluted with 1: 1 EtOAc / FhO, extracted with EtOAc, washed with sat. NH4CI, sat. NaHCCh, water, and brine. The organic layer was dried over MgSC, 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, mz = 936.0 (M+H).

[0326] Step B: Ethyl ( / ?)-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( lZ / )-yl)-4,5-dimethoxy-U / -indole-2-carboxylate. The title compound (826 mg, quantitative yield) was prepared following General Procedure D using ethyl (7?)-7-(6-(3-((3-(benzyloxy)propoxy )methyl)-l -methyl- 17 / -pyrazol-4-yl)-7-chloro-10-(3-(4-chloro-3,5-dimethyl phenoxy )propyl)-4-methyl-l -oxo-3, 4-dihydropyrazino[ l,2-a]indol-2(17y)-yl)-4,5-dimethoxy-17 / -indole-2-carboxylate (919 mg, 90% yield). LCMS (ESI) Method 2: RT = 1.528 min, 1.579 min, m / z = 846.0 (M+H).

[0327] Step C: Ethyl (l?)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-m ethyl-6-(l -methyl-3-((3-(tosyloxy)pr opoxy)m ethyl)- 1 / / -py razol-4-y 1 )- 1 -oxo-3, 4-dihydropyrazino[ 1,2-a]indol-2( l / / )-yl)-4.5-diniethoxy-l / / -indole-2-carboxylate. (General Procedure G). Ethyl (?)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3-((3-hydroxy-propoxy)methyl)-l -methyl- 17 / -pyrazol-4-yl)-4-methyl-l -oxo-3, 4-dihydropyrazino[l,2-cz]indol-2(l / 7)-yl)-4,5-dimethoxy-l / / -indole-2-carboxylate (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 allowed to stir 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 diluted with DCM / H2O, 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, m.'z = 999.9 (M+H).

[0328] Step D: Ethyl (26345fl,l7227?fl,24 / ?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-l4,l^-dimethoxy-24,31-dimethyl-21-oxo- 2X,22,23,24-tetrahydro-l4 / / ,34 / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxylate. (General Procedure H). Ethyl (R)-7-(7-chloro-10-(3 -(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-( 1 -methyl-3 -((3 - (tosyloxy )propoxy)methyl)-l / 7-pyrazol-4-yl)-l -oxo-3, 4-dihy dropyrazino[l, 2-cz]indol-2(l / / )-yl)-4,5-dimethoxy-l / 7-indole-2-carboxylate (900 mg, 0.90 mmol, 1.0 eq) was dissolved in DMF (90 mb) 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 diluted into EtOAc / FhO, extracted with EtOAc, washed with H2O, 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, m / z = 828.0 (M+H).

[0329] Step E: (2634Sa, I722Ra,24R)-21-Chloro-210-(3-(4-chloro-3, 5-dimethylphenoxy)propyl)-l4,l3-dimethoxy-24,3^-dimethyl-24-oxo-21,22,23,24-tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1,2-a]indola-l (7,1 )-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxylic acid. (General Procedure I). Ethyl(2634Sa, 1722T?a,24T?)-27-chl oro-2 ^-(3 -(4-chl oro-3,5 -dimethylphenoxy)propyl)- 14,1^-dimethoxy-24,3 l-dimethyl-2 -oxo-2,22,23,24-tetrahydro-l / 7,3 l / / -5-oxa-2(2,6)-pyrazino[l,2-rz]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxylate (564 mg, 0.68 mmol, 1.0 eq) was added to a reaction vessel equipped with a stir bar and dissolved in THF (10 mL), H2O (1 mL), and MeOH (1 mL). Lithium hydroxide (50 mg, 2.1 mmol, 3.0 eq)was added and the reaction was heated to 40 °C for 16 h after which time no starting material was observed by LCMS. The reaction was acidified to pH 2-4 with IM HC1 and then extracted with EtOAc. The aqueous layer was separated and extracted with EtOAc (2x). The combined organic layers were washed with NH4CI, brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (531 mg, 97% yield). LCMS (ESI) Method 2: RT = 1.522 min, m / z = 799.9 (M+H).Example 2(2^3^5a,1^2^7?fl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-NJV,2^,3^-tetramethyl-2^-oxo-2^,2^,2^,2^-tetrahydro-l^H,3^H-5-oxa-2(2,6)- pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carboxamide

[0330] (General Procedure J) Example 1 (15 mg, 0.019 mmol, 1.0 eq) was dissolved in DMF (0.5 mL). DIPEA (11 pL, 0.057 mmol, 3.0 eq) was added, followed by HATU (10 mg, 0.024 mmol, 1.3 eq). The reaction was allowed to stir for 5 min, followed by addition of dimethylamine hydrochloride (6 mg, 0.075 mmol, 4.0 eq). The reaction was allowed to stir for 1 h. The reaction was diluted into EtOAc / TEO, extracted with EtOAc, washed with aq.NaHCOs, brine, dried over MgSCh, filtered, and concentrated. The crude product was purified by reverse phase HPLC using a Phenomenex Gemini column eluting with MeCN / FEO and 0.1% TFA as mobile phase. After concentration, the residue was dissolved in EtOAc and washed with sat. aq. NaHCOi. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (6 mg, 38% yield). LCMS (ESI) Method 2: RT = 1.223 min, m / z = 827.2 (M+H)+.Example 3(263 5a,l722lffl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,l^- dimethoxy-2^,3^-dimethyl-21-oxo-21,2^,2^,2^-tetrahydro-ll / 7,3^Ef-5-oxa-2(2,6)- pyrazino[l,2-<z]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carboxamide

[0331] The title compound (38 mg, 51% yield) was prepared following General Procedure J using Example 1 (75 mg, 0.094 mmol, 1.0 eq) and NH4CI (15 mg, 0.28 mmol). LCMS (ESI) Method 1: RT = 2.239 min, m / z = 798.9 (M+H).Example 4(263 5a,l722lffl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-V.2^,31-tr im ethyl-2 l-oxo-21,2^,2^,2^-tetr ahydr o-l 1 H,3 ^H-5-oxn-2(2,6)- pyrazino[l,2-<z]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carboxamide

[0332] The title compound (12 mg, 79% yield) was prepared following General Procedure J using Example 1 (15 mg, 0.019 mmol, 1.0 eq) and methylamine hydrochloride (5 mg, 0.075 mmol, 4.0 eq). LCMS (ESI) Method 2: RT = 1.424 min, m / z = 813.3 (M+H)+.Example 5(26345fl,l722^«,247?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l5- dimethoxy-24,34-dimethyl-7V-(methylsulfonyl)-24-oxo-24,2^,2^,24-tetrahydro-l4 / f,34^-5- oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12- carboxamide

[0333] In reaction vessel, Example 1 (42 mg, 0.052 mmol, 1.0 eq) was dissolved DCM (0.5 mL). EDC (25 mg, 0.131 mmol, 2.5 eq) and DMAP (16 mg, 0.131 mmol, 2.5 eq) were added and the reaction was allowed to stir at room temperature for 10 minutes. Methansulfonamide (12.5 mg, 0.131 mmol, 2.5 eq) was added and the reaction was allowed to stir for 1.5 h at 35 °C, after which time the reaction was determined to be complete by LCMS. The reaction was extracted with EtOAc, washed with aq. NaHCCh then 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 (30 mg, 59% yield).JH NMR (400 MHz, CDC13) 87.67 (d, J= 8.6 Hz, 1H), 7.63 (s, 1H), 7.31 (s, 1H), 7.25 (s, 1H), 6.99 (s, 1H), 6.59 (s, 2H), 4.78 (dd, J= 12.3, 5.7 Hz, 1H), 4.53 (dq, J= 13.2, 6.1 Hz, 1H), 4.29 - 4.18 (m, 3H), 4.17 - 4.06 (m, 4H), 4.01 (s, 3H), 3.98 - 3.87 (m, 4H), 3.76 (d, J= 10.0 Hz, 1H), 3.72 -3.64 (m, 1H), 3.43 - 3.28 (d, J= 11.0 Hz, 5H), 3.13 (t, J= 10.1 Hz, 1H), 2.32 (s, 6H), 2.27 -2.12 (m, 3H), 1.73 - 1.62 (t, = 12.2 Hz, 1H), 1.28 (t, J= 7.2 Hz, 1H), 1.13 (d, J = 6.7 Hz, 3H).e- l^-carboxamide

[0334] In a scintillation vial, Example 1 (80 mg, 0.10 mmol, 1.0 eq) was dissolved in THF (1 mL). A, A-carbonyldiimidazole (32 mg, 0.20 mmol, 2.0 eq) was added and the reaction was heated at 50 °C for 0.5 h. The reaction was cooled to room temperature andr.r-dimethylsulfamide (27 mg, 0.22 mmol, 2.2 eq) was added, followed by DBU (66 pL, 0.44 mmol, 4.4 eq). The reaction was allowed to stir at 35 °C for 40 h. The reaction was extracted with EtOAc, washed with H2O, aq. NH4CI, aq. NaHCCh, dried over MgSC, filtered, and concentrated. The crude product was purified by reverse phase HPLC using a Phenomenex Gemini column eluting with MeCN / H2O and 0.1% TFA as mobile phase to afford the desired product. After concentration, the residue was dissolved in EtOAc and washed with sat. aq. NaHCOs. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (39 mg, 43% yield). LCMS (ESI) Method 1: RT = 1.669 min, m / z = 906.5 (M+H)+.Example 7(26345«,l722?«,2^?)-2^-Chloro-2^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- d imethoxy-2^,3' -d imethyl-2' -oxo-A-s ulfamoyl-21,2^,2^,2^-tetrahydro- 1 ' / / ,3 ' / 7-5-oxa-2(2,6)-pyrazino[l,2-«]indoIa-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphane-12-carboxamide

[0335] The title compound (48 mg, 36% yield) was prepared analogously to Example 6 using Example 1 (120 mg, 0.15 mmol, 1.0 eq) and sulfamide (43 mg, 0.45 mmol, 3.0 eq). LCMS (ESI) Method 1: RT = 2.183 min, m / z = 878.2 (M+H)+.ne- l^-carboxamide

[0336] The title compound (212 mg, 62% yield) was prepared following General Procedure J using Example 1 (300 mg, 0.4 mmol) and 2-(4-morpholinyl)ethanamine (97.5 mg, 0.80 mmol, 2.0 eq). LCMS (ESI) Method 1: RT = 1.927 min, OT / Z = 914.2 (M+H)’.1HNMR (400MHz, DMSO) 88.48 (t, J= 5.8 Hz, 1H), 8.02 (s, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.29 (d, J= 8.6 Hz, 1H), 7.15 (s, 1H), 7.02 (s, 1H), 6.67 (s, 2H), 4.49 (td, J= 14.1, 12.0, 5.8 Hz, 2H), 4.07 (dt, J= 15.8, 9.7 Hz, 3H), 3.95 (d, J= 7.5 Hz, 6H), 3.93 - 3.87 (m, 2H), 3.84 (s, 3H), 3.63 - 3.43 (m, 7H), 3.41 - 3.33 (m, 1H), 3.24 (tt, J= 13.2, 6.4 Hz, 3H), 2.95 (t, J= 10.1 Hz, 1H), 2.47 -2.32 (m, 6H), 2.23 (s, 6H), 2.09 - 1.86 (m, 3H), 1.50 (q, J= 12.1 Hz, 1H), 1.06 (d, J= 6.6 Hz, 3H).Example 9(263‘\ „,l722 / ?«,24. / ?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,15-dimethoxy-Ar-(2-methoxyethyl)-2^,3^-diniethyl-2*-oxo-2^,22,2^,2^-tetrahydro-loxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12- carboxamide

[0337] The title compound (22 mg, 69% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.04 mmol) and 2-methoxyethylamine (6 mg, 0.07 mmol, 2.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 10% MeOH in DCM. LCMS (ESI) Method 1: RT = 2.413 min, m z ' = 857.0 (M+H)+.Example 10(26345fl,l722J?fl,2^1?)-2^-Chloro-2^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-Az-(2- (dimethylamino) ethyl)-l^,l^-dimethoxy-2^,3^-dimethyl-21-oxo-21,2^,2^,2^-tetrahydro-l^HS -oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-mdola-3(4,3)-pyrazolacyclooctaphane- l^-carboxamide

[0338] The title compound (20 mg, 61% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.04 mmol, 1.0 eq) and A-dimethylethylene diamine (7 mg, 0.07 mmol, 2.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 10% MeOH in DCM. LCMS (ESI) Method 1: RT = 2.038 min, m / z = 870.0 (M+H)+.imethylphenoxy)propyl)-Az-((lr,41?)- 4-hydroxycyclohexyl)-l^,l^-dimethoxy-2^,31-dimethyl-21-oxo- 21,2^,2^,2^-tetrahy dro- -oxa-2(2,6)-pyrazino[l,2-ff]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- l^-carboxamide

[0339] The title compound (28 mg, 83% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and (lr,4r)-4-aminocyclohexan-l -ol (8.6 mg, 0.075 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.608 min, m / z = 898.9 (M+H)+. ' H NMR (400 MHz, DMSO) 58.30 (d, J= 8.0 Hz, 1H), 8.02 (s, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.29 (d, J= 8.6 Hz, 1H), 7.17 (s, 1H), 7.01 (s, 1H), 6.67 (s, 2H), 4.57-4.41 (m, 3H), 4.08 (dd, J= 14.9, 8.3 Hz, 2H), 4.01 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.90 (t, J= 6.8 Hz, 2H), 3.84 (s, 3H), 3.58 (t, J = 11.0 Hz, 2H), 3.47 (s, 1H), 3.23 (d, J= 6.4 Hz, 2H), 2.94 (t, J= 10.3 Hz, 1H), 2.73 (s, 1H), 2.23 (s, 6H), 2.10 - 1.95 (m, 2H), 1.88 - 1.74 (m, 5H), 1.48 (d, J= 12.2 Hz, 1H), 1.34 (t, J = 11.1 Hz, 2H), 1.22 (t, J = 9.4 Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H).Example 12(26345fl,l722l?0,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^-(3-(2- hydroxy-2-methylpropyl)azetidine-l-carbonyl)-14,15-diniethoxy-24,31-dimethyl- 21,2^,2^,2^-tetrahydro-l ' / / .3* / / -5-oxa-2(2.6)-pyrazino| l,2-a]indola-l(7,l )-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0340] The title compound (28 mg, 49% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and l-(azeti din-3 -yl)-2-methylpropan-2-ol (20 mg, 0.16 mmol, 2.5 eq). LCMS (ESI) Method 2: RT = 1.441 min, m / z = 910.9 (M+H)+.Example 13(2^3^5fl,1^2^1?fl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-12-(4-methylpiperazine-l-carbonyl)-21,22,2^,2^-tetrahydro- I 'Z / J1 / / -? -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 21-one

[0341] The title compound (16 mg, 73% yield) was prepared following General Procedure J using Example 1 (20 mg, 0.02 mmol, 1.0 eq) and A'-m ethyl pi perazine (5 mg, 0.05 mmol, 2.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 10% MeOH in DCM. LCMS (ESI) Method 1: RT = 2.046 min, m / z = 882.0 (M+H)~.Example 14(263 5a,l722lffl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^-dimethoxy-2^,3^-dimethyl-A^-(oxetan-3-yl)-2 l-oxo-21,2^,2^,2^-tetrahydro-l ^H,3^H-5-oxa- 2(2,6)-pyrazino [l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^- carboxamide

[0342] The title compound (18 mg, 86% yield) was prepared following General Procedure J using Example 1 (20 mg, 0.02 mmol, 1.0 eq) and 3-oxetanamine (5 mg, 0.05 mmol, 2.0 eq).The crude product was purified by flash column chromatography eluting with 0 to 100% of 95:5 EtOAc / MeOH in hexanes. LCMS (ESI) Method 2: RT = 1.610 min, m / z = 854.9 (M+H)+.Example 15(26345«,l722?«,24 / ?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,1 - dimethoxy-2^,31-dimethyl-21-oxo-A (tetrahydro-2 / / -pyran-4-yl)-21,2^,2^,2^-tetrahydro- (' / / 1 / / -? -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- 1 ^-carboxamide

[0343] The title compound (28 mg, 85% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and tetrahydro-2 7-pyran-4-amine hydrochloride (10 mg, 0.075 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.760 min, m / z = 883.9 (M+H)+. 'H NMR (400 MHz, DMSO) 88.43 (d, J= 7.8 Hz, 1H), 8.02 (s, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.29 (d, J= 8.5 Hz, 1H), 7.21 (s, 1H), 7.02 (s, 1H), 6.67 (s, 2H), 4.54 -4.43 (m, 2H), 4.14 -3.98 (m, 4H), 3.96 (s, 3H), 3.95 (s, 3H), 3.91 (q, J= 6.6 Hz, 4H), 3.84 (s, 3H), 3.66 - 3.54 (m, 2H), 3.47 (s, 1H), 3.36 (d, J= 12.2 Hz, 2H), 3.23 (d, J= 4.3 Hz, 2H), 2.95 (t, J= 10.1 Hz, 1H), 2.23 (s, 6H), 2.01 (t, J= 6.9 Hz, 2H), 1.88 (s, 1H), 1.72 (d, J= 12.9 Hz, 2H), 1.55 (ddd, J = 22.8, 17.9, 12.2 Hz, 3H), 1.06 (d, J= 6.7 Hz, 3H).Example 16(26345»,l722l?«,241?)-JV-(2-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-2 -chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,34-dimethyl-21-oxo- 2X,22,23,24- tetrahydro-l4H,34L -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphane-l2-carboxamide

[0344] The title compound (51 mg, 88% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethan-l-amine (18 mg, 0.12 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.053 min, m / z = 925.9 (M+H)+. ’H NMR (400 MHz, DMSO) 58.46 (t, J= 5.8 Hz, 1H), 8.02 (s, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.29 (d, J= 8.6 Hz, 1H), 7.17 (s, 1H), 7.02 (s, 1H), 6.67 (s, 2H), 4.56 (s, 4H), 4.52 - 4.42 (m, 2H), 4.14 - 4.01 (m, 3H), 3.96 (s, 3H), 3.94 (s, 3H), 3.90 (t, J= 6.6 Hz, 2H), 3.84 (s, 3H), 3.58 (t, J = 11.7 Hz, 2H), 3.47 (s, 1H), 3.29 - 3.22 (m, 6H), 3.13 (q, J = 6.5 Hz, 2H), 2.95 (t, J = 10.2 Hz, 1H), 2.43 (s, 2H), 2.23 (s, 6H), 2.01 (t, J= 6.9 Hz, 2H), 1.90 (s, 1H), 1.48 (d, J= 12.4 Hz, 1H), 1.06 (d, J= 6.6 Hz, 3H).e- l2-carboxamide[00345J The title compound (11 mg, 33% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and l-methylpiperidin-4-amine (8.6 mg, 0.075 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.065 min, m / z = 896.0 (M+H)+.Example 18(26345«,l722l?«,24R)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,15_ dimethoxy-2,31-dimethyl-12-(4-(oxetan-3-yl)piperazine-l-carbonyl)-21, 2^,23,2 - tetrahydro-15-oxa-2(2, 6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4, 3)- pyrazolacyclooctaphan-21-one

[0346] The title compound (12 mg, 42% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.031 mmol) and l-(oxetan-3-yl)piperazine (4.4 mg, 0.031 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.050 min, m / z = 924.0 (M+H)+. 1H NMR (400 MHz, DMSO) 58.02 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.00 (s, 1H), 6.72 (s, 1H), 6.68 (s, 2H), 4.52 (td, J = 6.5, 3.1 Hz, 2H), 4.43 (p, J = 6.0 Hz, 3H), 4.09 (dd, J = 15.3, 8.3 Hz, 2H), 4.03 - 3.86 (m, 11H), 3.83 (s, 3H), 3.73 (s, 3H), 3.56 (t, J = 11.6 Hz, 4H), 3.44 (q, J = 6.7 Hz, 2H), 3.23 (dq, J = 13.2, 6.6 Hz, 2H), 2.92 (t, J = 10.2 Hz, 1H), 2.32 (d, J = 2.2 Hz, 2H), 2.23 (s, 6H), 2.07 - 1.97 (m, 2H), 1.80 (d, J = 11.0 Hz, 1H), 1.60 (d, J = 12.3 Hz, 1H), 1.06 (d, J = 6.6 Hz, 3H).Example 19tot-Butyl 3-((26345„,l722^fl,24^)-27-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4,15_(iiineti1oxy-24,34-dimethyl-24-oxo- 2X,22,23,24- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyraz.ino| 1.2-n|indola-l (7.1 )-indola-3(4,3)- pyrazolacyclooctaphane-l2-carboxamido)piperidine-l-carboxylate

[0347] The title compound (40 mg, crude mass) was prepared following General Procedure J using Example 1 (30 mg, 0.04 mmol, 1.0 eq) and 3-amino-l-A-Boc-piperidine (15 mg, 0.07 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 2.102 min, m / z = 981.9 (M+H)~.Example 19A(26345a,l722?«,24?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,1 - dimethoxy-24,3l-dimethyl-2’-oxo- / V-(piperidin-3-yl)-2*,22,23,24-tetrahydro-l’ / / ,3 / -5- oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphane-l2- carboxamide

[0348] Example 19 (37 mg, 0.04 mmol) was dissolved in DCM: TFA (10:1, 1 mL) at RT and allowed to stir overnight, after which time the reaction was complete by LCMS. The reaction was extracted with DCM, washed with NaHCCh, dried over MgSO4, filtered, and concentrated to afford the title compound (33 mg, 95% yield). LCMS (ESI) Method 1: RT = 2.043 min, m / z = 882.0 (M+H)+.Example 20(2^345a,1^227?fl,2^1?)-27-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-2^,31-dimethyl-12-(octahydro-2 T-pyrido[l,2-«]pyrazine-2-carbonyl)- 2^,2^,2^,24-tetrahydro-l^ZT, 3^H-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0349] The title compound (22 mg, 81% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.03 mmol) and octahydro-2 / / -pyrido[l,2-a]pyrazine (9 mg, 0.06 mmol, 2.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 5% MeOH in DCM with 1% NH4OH. LCMS (ESI) Method 1: RT = 2.071 min, m 'z = 922.0 (M+H)+.Example 21tert-Butyl 3-(((26345„,l722 / ?a,24 / ?)-27-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l^,l^_(jimetj1oxy-2^,3^-diinethyl-21-oxo-21,22,23,2^- tetrahydro-l4ET,34Ef-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphane-l^-carboxamido)methyl) pyrrolidine-l-carboxylate

[0350] The title compound (approx. 40 mg, crude mass) was prepared following General Procedure J using Example 1 (30 mg, 0.04 mmol, 1.0 eq) and 3 -(aminomethyl)- 1-7V-Boc-pyrrolidine (15 mg, 0.07 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.918 min, m / z = 881.9 (M+H-Boc)+.Example 21A(26345«,l722?«,2^T?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-24,31-dimethyl-21-oxo-7V-(pyirolidin-3-ylmethyl)-21,22,23,24-tetrahydro- 11 / / .31 / / -5 -oxa-2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphane- -carboxamide

[0351] Example 21 (37 mg, 0.04 mmol) was dissolved in DCM: TFA (10:1, 1 mL) at RT and allowed to stir overnight, after which time the reaction was complete by LCMS. The reaction was extracted with DCM, washed with NaHCCL, dried over MgSO4, filtered, and concentrated to afford the title compound (33 mg, 95% yield). LCMS (ESI) Method 1: RT = 2.000 min, m / z = 882.0 (M+H)+.Example 22(26345«,l722 / ffl,2 ft)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-JV-((l- ethylpyrrolidin-3-yl)methyl)-l^,l^-dimethoxy-2^,3^-dimethyl-21-oxo-21,22,2^,2^- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyiazino| 1.2-u|indola-l (7.1 )-indola-3(4,3)- pyrazolacyclooctaphane-l^-carboxamide

[0352] In a scintillation vial, Example 21 A (25 mg, 0.03 mmol, 1.0 eq) was dissolved in THF (0.3 mL) and MeOH (0.3 mL). Acetaldehyde (0.016 mL, 0.3 mmol, 10 eq) was added, followed by acetic acid (0.016 mL, 0.3 mmol, 10 eq), and the reaction was allowed to stir for 5 minutes at room temperature. Sodium cyanoborohydride (5 mg, 0.08 mmol, 3.0 eq) was added and the reaction was allowed to stir at room temperature for 1.5 h, after which time the reaction was determined to be complete by LCMS. The reaction was diluted with EtOAc and 0.2 N NaOH and then 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 10% MeOH in DCM with 1% NH4OH to afford the tile compound (12 mg, 46% yield). LCMS (ESI) Method 1: RT = 2.070 min, m / z = 910.0 (M+H)+.Example 23(26345fl,l7227?«,24?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^ ' -dimethyl- 12-((, S')-octaliydropyr:izino|2.1-c| 11.4|()x;i / .iiie-8-c:irbonyl)- 21,22,2^,2^-tetrahydro-l ' / / .3* / / -5-()x:i-2(2.6)-pyrazino| l,2-a]indola-l(7,l )-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0353] The title compound (21 mg, 72% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.03 mmol, 1.0 eq) and (5)-octahydropyrazino[2,l-c][l,4]oxazine dihydrochloride (24 mg, 0.06 mmol, 2.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 5% MeOH in DCM with 1% NH4OH. LCMS (ESI) Method 1: RT = 2.039 min, m / z = 924.0 (M+H)+.Example 24(263 s«J722l?fl,241f)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-V-(2- hydroxy ethyl)- 14, 15-dim ethoxy-24, 31-dim ethyl-2 l-oxo-24,2^, 2^,24- tetrahydro- 1 ^H,3 ^H- 5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12- carboxamide

[0354] The title compound (81 mg, 77% yield) was prepared following General Procedure J using Example 1 (100 mg, 0.12 mmol, 1.0 eq) and ethanolamine (11 mg, 0.19 mmol, 1.5 eq). The crude product was purified by flash column chromatography eluting with 0 to 5% MeOH in DCM with 1% NH4OH. LCMS (ESI) Method 1: RT = 2.249 min, m / z = 843.0 (M+H)+.Example 25(26345fl,l722?a,24?)-2^-Chloro-24^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-24,3*-dimethyl-2'-oxo-A-((tetrahydro-2 / f-pyran-4-yl)methyl)-2*,22,23,24- tetrahydro-1 l / / .3l / / -5-oxa-2(2.6)-pyrazino|1.2-u|indola-l(7.1 )-indola-3(4.3)- pyrazolacyclooctaphane-l2-carboxamide

[0355] The title compound (24 mg, 86% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.031 mmol) and (tetrahydro-2 / 7-pyran-4-yl)methanamine (7.2 mg, 0.062 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.614 min, m / z = 897.0 (M+H)+.ethylphenoxy)propyl)- -((lr,4 / ?)- 4-hydroxy-4-methylcydohexyl)-1,1 -dimethoxy-2,31-dimethyl-21-oxo- 21,22,23,24- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino|1.2-<7|indola-l(7.1 )-indola-3(4.3)- pyrazolacyclooctaphane-l2-carboxamide

[0356] The title compound (23 mg, 81% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.031 mmol) and ( l / ',4 / ')-4-amino- l-methylcyclohexan- l-ol (8.1 mg, 0.062 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.426 min, m / z = 911.0 (M+H)+.(26345fl,l722?a,2^7?)-2^-Chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2,31-dimethyl-21-oxo-7V-(2-(tetrahydro-2Z -pyran-4-yl)ethyl)-21,tetrahydro-1 l / / .3' / / -5-oxa-2(2.6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4, 3)- pyrazolacyclooctaphane-l^-carboxamide

[0357] The title compound (17 mg, 60% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.031 mmol) and 2-(tetrahydro-2 / / -pyran-4-yl)ethan-l -amine (8.1 mg, 0.062 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.713 min, m / z = 911.0 (M+H)+.Example 28(26345«,l722^?«,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^-(4- cyclopropylpiperazine-l -carbonyl)-! ‘L -dimethoxy-2‘1.31 -dimethyl-2 *.22.2- 2"l- tetrahydro-13^ H-5-oxa-2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0358] The title compound (19 mg, 67% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.031 mmol) and 1 -cyclopropylpiperazine (3.9 mg, 0.031 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.145 min, m / z = 908.0 (M+H)+. 'H NMR (400 MHz, DMSO) 88.02 (s, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.29 (d, J= 8.6 Hz, 1H), 7.00 (s, 1H), 6.69 (d, J= 13.7 Hz, 3H), 4.44 (dd, J= 12.3, 5.9 Hz, 1H), 4.14 - 3.82 (m, 16H), 3.54 (td, J= 34.1, 16.0 Hz, 8H), 3.22 (tt, J= 13.3, 7.2 Hz, 3H), 2.92 (t, J = 10.2 Hz, 1H), 2.59 - 2.56 (m, 1H), 2.23 (s, 6H), 2.01 (p, J= 7.1 Hz, 2H), 1.81 (d, J = 5.9 Hz, 1H), 1.71 - 1.53 (m, 2H), 1.06 (d, J= 6.6 Hz, 3H), 0.36 (dd, J= 39.8, 5.0 Hz, 4H).e- -carboxamide

[0359] The title compound (9 mg, 30% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.031 mmol) and 2-(piperidin-l-yl)ethan-l -amine (8.0 mg, 0.062 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.192 min, m / z = 910.0 (M+H)+.dimethylphenoxy)propyl)-7V-(4- (dimethylamino) cyclohexyl)- ld,l^-dimethoxy-2^,3 l-dimethyl-2 l-oxo-21,2^,2^,2^-tetrahy dro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12-carboxamide

[0360] The title compound (15 mg, 52% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.031 mmol) adimethylcyclohexane-l^-diamine (8.9 mg, 0.062 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.096 min, m / z = 924.0 (M+H)+.Example 31(26345«,l722 / ?fl,247?)-A^-(2-(Azetidin-l-yl)ethyl)-27-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4,15-dimethoxy-24,34-dimethyl-21-oxo- 2X,22,23,24- tetrahydro--indoIa-3(4,3)- pyrazolacyclooctaphane-l2-carboxamide

[0361] The title compound (8 mg, 30% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.031 mmol) and 2-(azetidin-l-yl)ethan-l -amine (6.3 mg, 0.062 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.161 min, m / z = 882.0 (M+H)+Example 32(26345fl,l722l?fl,24l?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2V-(3,3- difluorocyclobutyl)-l4,1 -dimethoxy-24,34-dimethyl-24-oxo-21,22,23,24-tetrahydro- H / y ' / z-s -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- l2-carboxamide

[0362] The title compound (22 mg, 79% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.031 mmol) and 3,3-difluorocyclobutyl)-l-amine hydrochloride (8.9 mg, 0.062 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.735 min, m / z = 888.9 (M+H)+.Example 33(26345«,l722l?fl,241?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-JV-(3- hydroxycyclobutyl)-1,1 -dimethoxy-24,31-dimethyl-21-oxo-21,22,2,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-tf]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- -carboxamide

[0363] The title compound (21 mg, 77% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.031 mmol) and 3-aminocyclobutan-l-ol (5.4 mg, 0.062 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.355 min, m / z = 868.9 (M+H)+.Example 34(2^3^5fl,l722l?fl,241?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^-dimethoxy-2^,3^-dimethyl-A ((lr,4^)-4-methylcyclohexyl)-21-oxo-21,22,2^,2^-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-ff]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- 1^-carboxamide

[0364] The title compound (23 mg, 82% yield) was prepared following General Procedure J using Example 1 (25 mg, 0.031 mmol) and (lr,4r)-4-methylcyclohexan-l-amine (7.1 mg, 0.062 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 2.039 min, m / z = 895.0 (M+H)’.Example 35(2634l?fl, 1122Ra^R)-210-(3-(3,5-Dimethylphenoxy)propyl)-l, 1 ^-dimethoxy-2^,31- dimethyl-l^-(octahydropyrazino[2,l-c][l,4]oxazine-8-carbonyl)-21,2^,2^,2^-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazoIacyclooctaphan- 21-one

[0365] The title compound (13 mg, 17% yield) was prepared following General Procedure D using Example 23 (85 mg, 0.09 mmol) stirring overnight at 35 °C. The crude product was purified by reverse phase HPLC using a Phenomenex Gemini column eluting with MeCN / H2O and 0.1% TFA. LCMS (ESI) Method 1: RT = 1.87 min, m / z = 856.0 (M+H)+.Example 36(2634Rfl,l722R«,2 R)-210-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-1,15_dimethoxy- 2,31-dimethyl-12-(octahydropyrazino[2,l-c][l,4]oxazine-8-carbonyl)-21, 2^,2,2 -tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1.2-u|indola-l(7.1 )-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0366] The title compound (34 mg, 41% yield) was isolated from the same reaction mixture as Example 35. LCMS (ESI) Method 1: RT = 1.985 min, m / z = 890.0 (M+H)+.Example 37(263 5fl,l722lf„,2^7?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-l^-(4-morpholinopiperidine-l-carbonyl)-21,2^,2^,2^- tetrahydro-ll / 7,3^-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0367] The title compound (25 mg, 70% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and 4-(piperidin-4-yl)morpholine (6.4 mg, 0.037 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.250 min, m / z = 952.0 (M+H)+.Example 38(26345«,l722l?«,2^?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,31-dimethyl-l^-((3al?,6a5)-5 -m ethyloctahydropyrrolo [3,4-c] pyrrole-2-carbonyl)-2^,2^,2^,2^-tetrahydro-l^JT,3^-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)- indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0368] The title compound (25 mg, 73% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and ((3a / ?,6a1S’)-2-methyloctahydropyrrolo[3,4-c]pyrrole dihydrochloride (7.5 mg, 0.037 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.204 min, m / z = 908.1 (M+H)+.Example 39(2^3^5fl,1^2^1?fl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3*-dimethyl-12-(4-methylpiperidine-l-carbonyl)-2l,22,2^,2^-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 21-one

[0369] The title compound (25 mg, 76% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and 4-methylpiperidine (3.7 mg, 0.037 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.970 min, m / z = 881.0 (M+H)+.Example 40(26345fl,l722?a,2^?)-2^-Chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-12-(4-oxopiperidine-l-carbonyl)-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

[0370] The title compound (27 mg, 82% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and piperidin-4-one hydrochloride hydrate (5.8 mg, 0.037 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.617 min, m / z = 881.0 (M+H)+.Example 41(263 5a,l722lffl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2,31-dimethyl-V-(2-(4-methylpiperazin-l-yl)ethyl)-21-oxo-21, 2^,23,24- tetrahydro-ll / / ,3^TT-5-oxa-2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphane-l^-carboxamide[00371J The title compound (25 mg, 72% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and 2-(4-methylpiperazin-l-yl)ethan-l -amine (11 mg, 0.075 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 0.940 min, m / z = 925.0 (M+H)+.Example 42(26345«,l722l?fl,241?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1 -(4- hydroxypiperidine-l-carbonyl)-l4,l^-dimethoxy-24,34-dimethyl-21,22,2^,24-tetrahydro--oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 21-one

[0372] The title compound (30 mg, 91% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and piperidin-4-ol (3.8 mg, 0.037 mmol, 1.0 eq).LCMS (ESI) Method 2: RT = 1.414 min, m / z = 883.0 (M+H)+.Example 43(263 5fl,l722l?„,24l?)-2^-Chloro-24®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-2^,3*-dimethyl- -(morpholine-4-carbonyl)-2*,22,2^,2^-tetrahydro-l* / / ,3* / / - 5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0373] The title compound (50 mg, 62% yield) was prepared following General Procedure J using Example 1 (75 mg, 0.09 mmol, 1.0 eq) and morpholine (16 mg, 0.16 mmol, 2.0 eq). LCMS (ESI) Method 1: RT = 2.360 min, m / z = 869.0 (M+H)+.Example 44(26345a,l722?a,2^?)-2^-Chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-7V,2,31-trimethyl-7V-(2-morpholinoethyl)-21-oxo-21,22,23,2 -tetrahydro- 11^31fl-5 -oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- 1^-carboxamide

[0374] The title compound (31 mg, 89% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and jV-methyl-2-morpholinoethan-l -amine (11 mg, 0.075 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.105 min, m / z = 926.0 (M+H)+.Example 45l-((26345«,l722 / ?a,24l?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-2^,3^-dimethyl-21-oxo-21,2^,2^,2^-tetrahydro-ll / / ,3^ -5-oxa-2(2,6)- pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12- carbonyl)piperidine-4-carbonitrile

[0375] The title compound (27 mg, 84% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and piperidine-4-carbonitrile (4.2 mg, 0.038 mmol, 1.0 eq). LCMS (ESI) Method 1: RT = 2.379 min, m / z = 892.0 (M+H)+.Example 46(26345fl,l722?a,2^7?)-2^-Chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2,31-dimethyl-12-(3-oxopiperazine-l-carbonyl)-21,22,2,2 -tetrahydro- I' / ZJ1 / / -? -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazoIacydooctaphan- 21-one

[0376] The title compound (24 mg, 75% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and piperazin-2-one (11 mg, 0.075 mmol, 2.0 eq).LCMS (ESI) Method 1: RT = 2.183 min, m / z = 882.0 (M+H)+.Example 47(2^3^5a,l72^7?fl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-12-(4-methyl-l,4-diazepane-l-carbonyl)-21,2^,2^,2^- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1.2-u|indola-l(7.1 )-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0377] The title compound (54 mg, 60% yield) was prepared following General Procedure J using Example 1 (80 mg, 0.10 mmol, 1.0 eq) and A'-methylhomopiperazine (23 mg, 0.20 mmol, 2.0 eq). LCMS (ESI) Method 1: RT = 2.012 min, m / z = 896.0 (M+H)+.Example 48(263 5fl,l722l?„,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,31-dimethyl-12-(( / ?)-octahydropyrazino[2,l-f][l,4]oxazine-8-carbonyl)- 2*,2^,2^,2^-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1,2-aJindola-l (7,1 )-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0378] The title compound (72 mg, 62% yield) was prepared following General Procedure J using Example 1 (100 mg, 0.12 mmol, 1.0 eq) and (7?)-octahydropyrazino[2,l-c][l,4]oxazine (36 mg, 0.25 mmol, 2.0 eq). LCMS (ESI) Method 1: RT = 2.071 min, m / z = 924.0 (M+H)+.Example 49(26345«,l7227?fl,2^ / ?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^-(4-(2- (dimethylamino)ethyl)piperazine-l-carbonyl)-l^,l^-dimethoxy-2^,31-dimethyl- 21,22,2^,2^-tetrahydro-l^ / f,31 / / -5-oxa-2(2,6)-pyrazino[l,2-aJindola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0379] The title compound (37 mg, 63% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and jV, V-dimethyl-2-(piperazin-l-yl)ethan-l -amine (9.8 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 1: RT = 1.945 min, m / z = 939.0 (M+H)+.Example 50(26345fl,l722l?fl,24J?)-12-(4-Acetylpiperazine-l-carbonyl)-27-chloro-24®-(3-(4-chloro-3,5- dimethyl phenoxy)propyl)-l4,l^-dimethoxy-24,34-dimethyl-24,2^,2^,24-tetrahydro--oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 24-one

[0380] The title compound (20 mg, 59% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol) and 1 -(piperazin- l-yl)ethan-l -one (4.8 mg, 0.037 mmol, 1.0 eq). LCMS (ESI) Method 1: Rr = 2.275 min, m / z = 910.0 (M+H)+.Example 51rt-Butyl 4-((26345fl,l722 / ?fl,24 / ?)-27-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4,15_(jimetj1oxy-24,34-dimethyl-24-oxo-24,22,2^,24-tetrahydro--indol;i-3(4.3)- pyrazolacyclooctaphane-l^-carbonyl)piperazine-l-carboxylate

[0381] The title compound (30 mg, 83% yield) was prepared following General Procedure J using Example 1 (30 mg, 0.037 mmol, 1.0 eq.) and Zc / 7-butyl piperazine- 1 -carboxylate (7.0 mg, 0.037 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.813 min, m / z = 968.0 (M+H)+.Example 51A(263 5fl,l722lf„,2^7?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^-dimethoxy-2^,3^-dimethyl-l^-(piperazine-l-carbonyl)-21,2^,2^,2^-tetrahydro-llZ / ,3^T^-5- oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0382] Example 51 (30 mg, 0.031 mmol, 1.0 eq.) was dissolved in DCM (2 m ) and TFA (1 mb, 10 mmol) was added. The resulting mixture was stirred for 1 h at RT and then concentrated. The crude product was purified by reverse phase HPLC using a Phenomenex Gemini column eluting with MeCN / H2O and 0.1% TFA as mobile phase to afford the desired product. After concentration, the residue was dissolved in EtOAc and washed with sat. aq. NaHCCh. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound. LCMS Method 1: RT = 2.033 min, m / z = 886.0 (M+H)+.Example 52(26345a,l722lffl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-12-(4-(2-methoxyethyl)piperazine-l-carbonyl)-24,31-dimethyl-21, 2^,23,24- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyraz.ino| l,2-a]indola-l (7,1 )-indola-3(4,3)- pyrazolacyclooctaphan-24-one

[0383] The title compound (38 mg, 66% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and l-(2-methoxyethyl)piperazine (9.0 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 1: Rr = 2.076 min, m / z = 926.0 (M+H)+.Example 53(263450,l722l?„,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(2,6- dimethylmorpholine-4-carbonyl)-l^,l^-dimethoxy-2^,31-dimethyl-21,22,2^,2^- tetrahydro-llH,31 / / -5-oxa-2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0384] The title compound (40 mg, 71% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 2,6-dimethylmorpholine (7.2 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.697 min, m / z = 897.0 (M+H)+.Example 54(26345a,l722l?„,24 )-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(4-isopropylpiperazine- 1 -carbonyl )-H. -diniethoxy-2^.3' -dime! hyl-2 '.22.2^.2^-tetr:ihydro- ^H^HS -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 2^-one[00385J Example 51 A (45 mg, 0.05 mmol, 1.0 eq) was dissolved in DCM (0.5 mL) and acetone (0.5 mL). Acetic acid (2 drops) was added and the reaction was allowed to stir for 30 min at RT. Sodium triacetoxyborohydride (20 mg, 0.10, 1.8 eq) was added, and the reaction was allowed to stir at RT for 1 h. The reaction was diluted with EtOAc and IN NaOH, extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude product was purified by reverse phase HPLC using a Phenomenex Gemini column eluting with MeCN / HaO and 0.1% TFA as mobile phase to afford the desired product. After concentration, the residue was dissolved in EtOAc and washed with sat. aq. NaHCOa. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound. LCMS (ESI) Method 1: RT = 2.052 min, m / z = 910.0 (M+H)+.Example 55(2634«,l722l?fl,2^1?)-27-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2,31-dimethyl-12-(4-((tetrahydrofuran-2-yl)methyl)piperazine-l-carbonyl)- 21,2^,2^,2^-tetrahydro-ll / f,31 / f-5-oxa-2(2,6)-pyrazino[l,2-aJindola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0386] The title compound (33 mg, 55% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and l-((tetrahydrofuran-2-yl)methyl)piperazine (11 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 1: RT = 2.106 min, m / z = 952.0 (M+H)+.Example 56(263 5a,l722lffl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,l^- dimethoxy-2,31-dimethyl-12-(4-(2-morpholinoethyl)piperazine-l-carbonyl)-21, 2^,23,24- tetrahydro-ll / f,3^TT-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0387] The title compound (36 mg, 59% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 4-(2-(piperazin-l-yl)ethyl)morpholine (12 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 1: RT = 1.954 min, m / z = 981.0 (M+H)+.Example 57tert-Butyl 3-((26345«,l722 / ?fl,24 / f)-27-chloro-210-(3-(4-chloro-3,5-dimethyl phenoxy)propyl)-l4,l^-dimethoxy-24,3^-dimethyl-24-oxo-24,22,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- l^-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0388] The title compound (180 mg, 97% yield) was prepared following General Procedure J using Example 1 (168 mg, 0.21 mmol, 1.0 eq) and 6-Boc-3,6-diaza-bicyclo[3.1.1]heptane (83 mg, 0.42 mmol, 2.0 eq). LCMS (ESI) Method 1: RT = 2.002 min, m / z = 979.9 (M+H)+.Example 57A(2f,3^S„.l72' / ?„.2^ / ?)-l^-(3.6-l)iazabicyclo|3.1.1 |heptane-3-carb()nyl)-2^-chloro-2***-(3-(4- chloro-3,5-dimethylphenoxy)propyl)-l4,l^_dimethoxy-24,34-dimethyl-24,2^,2^,24-tetrahydro-1 ^H, 3^H-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-ll-one

[0389] Example 57 (180 mg, 0.18 mmol) was dissolved in DCM (1.0 mL) atRT, followed by addition of HC1 (4.0 M in dioxanes, 0.5 mL, 1.8 mmol). The reaction was allowed to stir for 1.5 h, and then concentrated from DCM (3x) to afford the title compound as the HC1 salt (163 mg, 97% yield). LCMS (ESI) Method 1: RT = 2.180 min, m / z = 880.0 (M+H)+.Example 58(263 5a,l722lffl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-l^-(6-isopropyl-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)- 21,22,2^,2^-tetrahydro-ll / f,31 / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one[00390J In a scintillation vial, Example 57A (65 mg, 0.07 mmol, 1.0 eq) was dissolved in DCM (0.75 mL) and acetone (0.75 mL). Acetic acid (2 drops) was added and the reaction was allowed to stir for 0.5 h. Sodium triacetoxyborohydride (23 mg, 0.11 mmol, 1.5 eq) was added and the reaction was allowed to stir for 0.5 h at RT. The reaction was diluted with EtOAc and 2M NaOH, extracted with EtOAc, washed with H2O, dried over MgSO4, filtered, and concentrated. The crude product was purified by reverse phase HPLC using a Phenomenex Gemini column eluting with MeCN / LEO and 0.1% TFA as mobile phase to afford the desired product. LCMS (ESI) Method 1: RT = 2.236 min, m / z = 922.0 (M+H)+.Example 59(26345fl,l722l?a,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(3- hydroxyazetidine-l-carbonyl)-l^,15_(jjmetjloXy_24931-dimethyl-21,22,2^,2^-tetrahydro- I 'Z / 1 / / -? -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 21-one

[0391] The title compound (38 mg, 71% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and azetidin-3-ol hydrochloride (6.8 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.729 min, m / z = 855.0 (M+H)+.Example 60(2^345o,l722l?a,24l?)-2^-Chloro-24®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-((»y)-2,4-dimethyl piperazine-l-carbonyl)-l4,l^-dimethoxy-24,34-dimethyl-24,22,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 21-one

[0392] The title compound (33 mg, 59% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and (5)-l,3-dimethylpiperazine (7.1 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.252 min, m / z = 896.0 (M+H)+.Example 61(26345O, 1722Ra,2^R)-2^ -Chloro-21 ®-(3-(4-chloro-3,5-dimethylphenoxy)pr opyl)- -(3,3- difluoroazetidine-l-carbonyl)-14,15-dimethoxy-24,31-dimethyl-21,22,23,24-tetrahydro- I ' / ZJ1 / / -? -oxa-2(2,6)-pyrazino[l,2-tf]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 21-one

[0393] The title compound (37 mg, 68% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 3,3-difluoroazetidine hydrochloride (8.1 mg, 0.062 pmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.863 min, m z = 874.9 (M+H)+.- 2^-one

[0394] The title compound (40 mg, 74% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 3-methoxyazetidine hydrochloride (7.7 mg, 0.062mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.936 min, m / z = 868.9 (M+H)+'H NMR (400 MHz, DMSO) 88.03 (s, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.30 (d, J= 8.6 Hz, 1H), 7.05 (s, 1H), 6.95 (s, 1H), 6.68 (s, 2H), 4.46 (dd, J= 12.1, 5.8 Hz, 1H), 4.36 (s, 1H), 4.25 (s, 1H), 4.15 -4.04 (m, 3H), 3.97 (s, 3H), 3.94 (s, 3H), 3.90 (d, J= 6.6 Hz, 2H), 3.84 (s, 3H), 3.58 (t, J= 10.6 Hz, 2H), 3.47 (s, 1H), 3.30 (s, 5H), 3.24 (s, 4H), 2.95 (t, J= 10.1 Hz, 1H), 2.24 (s, 5H), 2.02 (t, J= 7.0 Hz, 2H), 1.84 (s, 1H), 1.56 (s, 1H), 1.07 (d, J= 6.7 Hz, 3H).Example 63( 2634S'„.1722l?„,2^1?)-2^-Chloro-21 ®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)- 1^-((?)- 3,4-dimethyl piperazine-l-carbonyl)-14,l^-dimethoxy-24,31-dimethyl-21,22,2^,2^- tetrahydro--indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0395] The title compound (39 mg, 70% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and ( / )- 1,2-dimethylpiperazine (7.1 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.237 min, m / z = 896.1 (M+H)+.Example 64(26345fl,l722^a,24?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^-(3- (dimethylamino) azetidine-l-carbonyl)-14,l^-dimethoxy-24,34-dimethyl-21,22,2^,24- tetrahydro-14 / / ,3^Tf-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0396] The title compound (42 mg, 76% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and jV,7V-dimethylazeti din-3 -amine dihydrochloride (11 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.600 min, m / z = 881.9 (M+H)+.JH NMR (400 MHz, DMSO) 88.03 (s, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.30 (d, J= 8.6 Hz, 1H), 7.05 (s, 1H), 6.95 (s, 1H), 6.68 (s, 2H), 4.46 (dd, J= 12.3, 5.9 Hz, 2H), 4.40 - 4.28 (m, 2H), 4.10 (dd, J= 16.2, 8.4 Hz, 3H), 3.94 - 3.72 (m, 11H), 3.58 (t, J= 10.6 Hz, 2H), 3.47 (s, 1H), 3.32 (s, 3H), 3.25 (t, J= 12 Hz, 2H), 3.18 - 3.04 (m, 2H), 2.95 (t, J= 10.2 Hz, 1H), 2.24 (s, 5H), 2.12 (s, 2H), 2.07 (s, 2H), 2.02 (t, J= 6.8 Hz, 2H), 1.91 - 1.75 (m, 1H), 1.62 - 1.47 (m, 1H), 1.07 (d, J= 6.6 Hz, 3H).Example 65(26345«,l722?«,2^?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-24,31-dimethyl-12-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-21, 2^,23,24- tetrahydro- 1 ' / / ,3 * / / -5-oxa-2(2.6)-pyrazino|l, 2-^|indola- 1(7.1 )-indola-3(4, 3)- pyrazolacyclooctaphan-21-one

[0397] The title compound (18 mg, 33% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 2-oxa-6-azaspiro[3.3]heptane hemioxalate (9.0 mg, 0.031 mmol, 0.5 eq). LCMS (ESI) Method 2: RT = 1.796 min, m / z = 880.9 (M+H)+.Example 66(26345a,l722lfa,24?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,15_ dimethoxy-24,31-dimethyI-12-(4-methyI-3-oxopiperazine-l-carbonyl)-21,tetrahydro- 1 ' / / ,3' / / -5-oxa-2(2.6)-pyrazino|l, 2-f / |indola- 1(7.1 )-indola-3(4.3)- pyrazolacyclooctaphan-21-one

[0398] The title compound (41 mg, 73% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 1 -methylpiperazin-2-one (7.1 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.601 min, m / z = 896.0 (M+H)+.Example 67(26345a,l722 / f«,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(4-(2,2- difluoroethyl) piperazine-l-carbonyl)-14,15_dimethoxy-24,31-dimethyl-21,22,23,24- tetrahydro-llf,31 T-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0399] The title compound (43 mg, 74% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and l-(2,2-difluoroethyl)piperazine (9.4 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: Rr = 1.694 min, m / z = 831.9 (M+H)+.n- 21-one

[0400] The title compound (40 mg, 75% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 3 -fluoroazetidine hydrochloride (7.0 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.958 min, m / z = 856.9 (M+H)~. 'H NMR (400 MHz, DMSO) 58.03 (s, 1H), 7.75 (d, J= 8.7 Hz, 1H), 7.30 (d, J= 8.5 Hz, 1H), 7.06 (s, 1H), 6.99 (s, 1H), 6.68 (s, 2H), 5.52 - 5.37 (m, 1H), 4.46 (dd, J= 12.4, 5.9 Hz, 2H), 4.36 (s, 1H), 4.15 - 4.00 (m, 3H), 3.94 (t, J= 12.7 Hz, 8H), 3.85 (s, 3H), 3.58 (t, J= 10.6 Hz, 2H), 3.48 (d, J = 9.0 Hz, 1H), 3.32 (s, 3H), 3.24 (t, J= 7.2 Hz, 2H), 2.95 (t, J= 10.1 Hz, 1H), 2.24 (s, 6H), 2.06 - 1.98 (m, 2H), 1.86 (s, 1H), 1.56 (s, 1H), 1.07 (d, J= 6.7 Hz, 3H).Example 69(263 5a,l722 / f(,,2^1?)-27-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-l^-(3-(pyrrolidin-l-yl)azetidine-l-carbonyl)-21,2^,2^,2^-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino|1.2- |indola-l(7.1 )-indola-3(4.3)- pyrazolacyclooctaphan-ll-one

[0401] The title compound (41 mg, 72% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and l-(azetidin-3-yl)pyrrolidine dihydrochloride (12 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.519 min, m / z = 910.0 (M+H)+.Example 70(26345«,l722?«,2^T?)-2^-Chloro-2^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^-dimethoxy-2^,3^-dimethyl-l^-(4-(2-morpholinoacetyl)piperazine-l-carbonyl)-21,2^,2^,2^- tetrahydro-ll / , 31 / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0402] The title compound (50 mg, 81% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.06 mmol, 1.0 eq) and 2-morpholino-l -(piperazin- l-yl)ethan-l -one (27 mg, 0.12 mmol, 2.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 4% DCM in MeOH with 0.1% NEUOH. LCMS (ESI) Method 1: RT = 2.335 min, m / z = 995.0 (M+H)+.Example 71(2634flJ722l?«,24 / ?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1 -(4- (dimethylglycyl) piperazine-l-carbonyl)-l^,l^-dimethoxy-2^,34-dimethyl-21,22,23,2^- tetrahydro-ll / / ,34TT-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-24-one

[0403] The title compound (44 mg, 73% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.06 mmol, 1.0 eq) and 2-(dimethylamino)-l -(piperazin- 1 -yl)ethan- 1 -one (21 mg, 0.12 mmol, 2.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 5% DCM in MeOH with 0.1% NH4OH. LCMS (ESI) Method 1: RT = 2.291 min, m / z = 953.0 (M+H)+.Example 72(26345«,l722 / ?fl,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(4-(2- hydroxy-2-methyl propyl)piperazine-l-carbonyl)-l^,l^-dimethoxy-2^,34-dimethyl- 2*,22,2^,2^-tetrahydro-l'f / ,3'ff-5’ -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0404] The title compound (45 mg, 76% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.06 mmol, 1.0 eq) and 2-methyl-l -(piperazin- l-yl)propan-2-ol (20 mg, 0.12 mmol, 2.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 5% DCM in MeOH with 0.1% NH4OH. LCMS (ESI) Method 1: RT = 2.351 min, m / z = 940.0 (M+H)+.Example 73Az-(l-((26345'fl,l722l?fl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)- 1,1 -dimethoxy-24,3 l-dimethyl-2 l-oxo-21,22,2^,24-tetrahydro- 1l / / -5-oxa-2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12-carbonyl)piperidin- 4-yl)-A^-methylacetamide

[0405] The title compound (43 mg, 73% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) andiV-methyl-2V-(piperidin-4-yl)acetamide hydrochloride (12 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.612 min, m / z = 870.9 (M+H)+.Example 74(2634> Sfl,l722lG,2 1?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-7V-((ls,4»y)-4-hydroxycyclo-hexyl)-1,1 -dimethoxy-V,2,31-trimethyl-21-oxo- 21,2^,2^,2^-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- 1^-carboxamide

[0406] The title compound (45 mg, 79% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and (lr,4r)-4-(methylamino)cyclohexan-l-ol (8.1 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.308 min, m / z = 910.9 (M+H)+.Example 75(26345«,l7227?«,2^T?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-l^-(4-methoxypiperidine-l-carbonyl)-2^,3^-dimethyl-2^,2^,2^,2^-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 21-one

[0407] The title compound (40 mg, 71% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 4-methoxypiperidine (7.2 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.920 min, m / z = 897.0 (M+H)+.Example 76(26345fl,l722?fl,2^7?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-Az-(2- hydroxy ethyl)- 1^,15-dimethoxy-V,2,3 l-trimethyl-2 l-oxo-21,2^,2^,2^-tetrahydro- 11^31fl-5 -oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- l^-carboxamide

[0408] The title compound (39 mg, 73% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 2-(methylamino)ethan-l-ol (4.7 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.743 min, m / z = 857.0 (M+H)+.Example 77(263"15«,l722?fl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^-(4-(2- (dimethylamino) ethyl)-3-oxopiperazine-l-carbonyl)-dimethyl- 21,2^,2^,2^-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino| l,2-«]indola-l(7,l )-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0409] The title compound (41 mg, 69% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and l-(2-(dimethylamino)ethyl)piperazin-2-one (11 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.861 min, m / z = 853.1 (M+H)+.Example 78L(l-(Chloro-24®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)- 1,15-dimethoxy-2,3 l-dimethyl-2 l-oxo-21,22,2^,24-tetrahy dro- 11 H,3 l / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carbonyl)piperidin- 4-yl)acetamide

[0410] The title compound (37 mg, 64% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and jV-(piperidin-4-yl)acetamide (8.9 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.713 min, m / z = 924.0 (M+H)+.ne- l^-carboxamide

[0411] The title compound (44 mg, 81% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 2-methoxy-V-methylethan-l -amine hydrochloride (7.8 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.754 min, m / z = 871.0 (M+H)+.Example 80(2^3^5fl,1^2^1?fl,2^?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2,31-dimethyl-12-(3-morpholinoazetidine-l-carbonyl)-21,22,tetrahydro-15-oxa-2(2, 6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4, 3)- pyrazolacyclooctaphan-21-one

[0412] The title compound (42 mg, 73% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 4-(azetidin-3-yl)morpholine dihydrochloride (13 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.246 min, m / z = 924.0 (M+H)+. 'H NMR (400 MHz, DMSO) 88.03 (s, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.30 (d, J= 8.6 Hz, 1H), 7.05 (s, 1H), 6.96 (s, 1H), 6.68 (s, 2H), 4.46 (dd, J= 12.2, 5.8 Hz, 2H), 4.42 - 4.28 (m, 2H), 4.15 - 4.05 (m, 3H), 4.02 (s, 1H), 3.97 (s, 3H), 3.94 (s, 5H), 3.84 (s, 3H), 3.63 -3.53 (m, 5H), 3.48 (s, 1H), 3.32 (s, 3H), 3.24 (t, J = 6.8 Hz, 2H), 3.20 - 3.12 (m, 1H), 2.95 (t, J= 10.1 Hz, 1H), 2.41 -2.28 (m, 3H), 2.24 (s, 6H), 2.02 (t, J= 7.0Hz, 2H), 1.91 - 1.78 (m, 1H), 1.60- 1.48 (m, 1H), 1.07 (d, J= 6.7 Hz, 3H).(26345'fl,l7227?fl,2^1?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l2-(4- (dimethylamino) piperidine-l-carbonyl)-l4,l=-dimethoxy-24,31-dimethyl-21,22,23,24- tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino|l.2- |indola- 1(7.1 )-indola-3(4.3)- pyrazolacyclooctaphan-21-one

[0413] The title compound (10 mg, 18% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and / V, A-dimethylpiperidiri-4-amine (16 mg, 0.12 mmol, 2.0 eq.). LCMS (ESI) Method 2: RT = 0.78 min, m / z = 910.8 (M+H)+. ‘HNMR (400 MHz, MeOD) 87.90 (s, 1H), 7.72 (d, J= 8.7 Hz, 1H), 7.28 (d, J= 8.6 Hz, 1H), 7.00 (s, 1H), 6.79 (s, 1H), 6.59 (s, 2H), 4.67 (dd, J= 12.5, 5.7 Hz, 1H), 4.19 - 4.08 (m, 2H), 4.01 (d, J = 11.0 Hz, 5H), 3.92 (s, 3H), 3.91 (s, 3H), 3.67 (d, J= 10.0 Hz, 1H), 3.59 (d, J= 12.5 Hz, 1H), 3.52 (s, 2H), 3.00 (t, J= 10.3 Hz, 1H), 2.26 (s, 7H), 2.17 -2.09 (m, 2H), 1.29 (s, 2H), 1.14 (d, J = 6.8 Hz, 3H).Example 82(2^3^5fl,l722l?fl,2^1?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l5- dimethoxy-A^,24,31-trimethyl-A (l-methylpiperidin-4-yl)-21-oxo-21,22,23,24-tetrahydro- l1Zf,31 / -5-oxa-2(2,6)-pyrazino[l,2-<z]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- l2-carboxamide

[0414] The title compound (10 mg, 18% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and A(l-dimethylpiperidin-4-amine (16 mg, 0.12 mmol, 2.0 eq.). LCMS (ESI) Method 2: RT = 0.760 min, m / z = 910.4 (M+H)+. ‘HNMR (400 MHz, MeOD) 87.90 (s, 1H), 7.72 (d, J= 8.6 Hz, 1H), 7.28 (d, J= 8.6 Hz, 1H), 6.99 (s,1H), 6.57 (s, 2H), 4.25 - 4.08 (m, 3H), 4.02 (s, 3H), 3.99 (s, 2H), 3.91 (s, 3H), 3.72 - 3.55 (m, 2H), 3.48 (p, J= 1.7 Hz, 1H), 3.13 (p, J= 1.7 Hz, 1H), 2.96 (s, 3H), 2.26 (s, 6H), 2.13 (d, J= 7 A Hz, 2H), 1.29 (s, 2H), 1.14 (d, J= 6.7 Hz, 3H), 0.98 (d, J= 6.6 Hz, OH), 0.95 - 0.83 (m, 1H).Example 83Methyl 4-((2634'ff,l722l?„,241?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)- l4,ls-dimethoxy-24,31-dimethyl-21-oxo-21,22,23,24-tetrahydro-l1f,31Z / -5-oxa-2(2,6)- pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2- carbonyl)piperazine-l-carboxylate

[0415] The title compound (10 mg, 18% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and methyl piperazine-1 -carboxylate (18 mg, 0.12 mmol, 2.0 eq.). LCMS (ESI) Method 2: RT = 1.02 min, m / z = 926.5 (M+H)+. ’H NMR (400 MHz, MeOD) 57.90 (s, 1H), 7.72 (d, J= 8.6 Hz, 1H), 7.28 (d, J= 8.6 Hz, 1H), 7.01 (s, 1H), 6.83 (s, 1H), 6.57 (s, 3H), 4.68 (dd, J= 12.3, 6.0 Hz, 1H), 4.19 -4.08 (m, 3H), 4.01 (d, J= 10.5 Hz, 7H), 3.99 - 3.86 (m, 1H), 3.91 (s, 4H), 3.67 (d, J= 12.8 Hz, 4H), 3.59 (d, J= 12.6 Hz, 2H), 3.53 (s, 4H), 3.00 (s, 1H), 2.26 (s, 7H), 2.13 (t, J= 6.8 Hz, 2H), 2.03 (d, J= 15.7 Hz, 1H), 1.89 (s, 1H), 1.73 (s, 1H), 1.31 - 1.18 (m, 3H), 1.14 (d, J = 6.7 Hz, 4H).-dimethylphenoxy)propyl)-l2-(3- (dimethylamino)-3-methylazetidine-l-carbonyl)-l^,l^-dimethoxy-2^,3' -dimethyl- 2l.2-.2^.2^-tetr hydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1.2-( / |indola-l(7,l )-indola-3(4.3)- pyrazolacyclooctaphan-21-one

[0416] The title compound (37 mg, 66% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and V,jV,3-trimethylazetidin-3 -amine dihydrochloride (12 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.051 min, m / z = 896.1 (M+H)+.Example 85(26345«,l722l?fl,241?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1 -(3- (ethyl(methyl)amino) azetidine-l-carbonyl)-l^,l^-dimethoxy-2^,31-dimethyl-21,22,2^,2^- tetrahydro-ll / T,34TT-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-24-one

[0417] The title compound (31 mg, 55% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and A-cthyl-A-mcthylazeti din-3 -amine dihydrochloride (12 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.067 min, m / z = 896.1 (M+H)+.Example 86(263 5a,l722 / f(,,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,l^- dimethoxy-2^,3^-dimethyl- -(3-methyl-3-morpholinoazetidine-l-carbonyl)-21,22,2^,2^- tetrahydro-l ' / / .31f -5-oxa-2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)- pyrazolacydooctaphan-21-one[00418J The title compound (34 mg, 58% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 4-(3-methylazetidin-3-yl)morpholine dihydrochloride (14 mg, 0.062 mmol, 1.0 eq.). LCMS Method 2: RT = 1.070 min, m / 'z = 938.1 (M+H)+.(26345fl,l722?a,2^?)-2^-Chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-21-oxo-f-(pyridin-3-yl)-21,22,2^,2^-tetrahydro-ll / / ,3^Ef-5- oxa-2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphane-12- carboxamide

[0419] The title compound (35 mg, 80% yield) was prepared following General Procedure J using Example 1 (40 mg, 0.05 mmol, 1.0 eq) and 3 -aminopyridine (9 mg, 0.10 mmol, 2.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 4% DCM in MeOH with 0.1% NH4OH. LCMS (ESI) Method 1: RT = 2.101 min, m / z = 876.0 (M+H)+.Example 88(26345a,l7227?«,2^?)-2^-Chloro-21d-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3'-dimethyl-2'-oxo- / V-(pyridin-4-yl)-2l,22,2^,2^-tetrahydro-l' / / ,3' / / -5- oxa-2(2.6)-pyrazino| 1.2-<7|indola-l (7.1 )-indola-3(4.3)-pyrazolacyclooclaphane-l carboxamide

[0420] The title compound (35 mg, 80% yield) was prepared following General Procedure J using Example 1 (40 mg, 0.05 mmol, 1.0 eq) and 4-aminopyridine (9 mg, 0.10 mmol, 2.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 3% DCM in MeOH with 0.1% NH4OH. LCMS (ESI) Method 1: RT = 2.098 min, m / z = 876.0 (M+H)+.Example 89(263 5a,l722lffl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-12-(3-(4-methylpiperazin-l-yl)azetidine-l-carbonyl)- 21,22,2^,2^-tetrahydro-ll / f, 31 / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one[00421J The title compound (376 mg, 80% yield) was prepared following General Procedure J using Example 1 (400 mg, 0.50 mmol, 1.0 eq) and l-(azeti din-3 -yl)-4-methylpiperazine trihydrochloride (210 mg, 0.79 mmol, 1.6 eq). LCMS (ESI) Method 2: RT = 1.029 min, m / z = 937.0 (M+H)+.Example 90(26.3~ $„. 1722?O, 2^7?)-2^-Chloro-2^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^-(3- (cyclopropyl(methyl) amino)azetidine-l-carbonyl)-l^,l^-dimethoxy-2^,3^-dimethyl- 21,22,23,24-tetrahydro-ll / / , 31 / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0422] The title compound (47 mg, 83% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and N-cy cl opropyl-A-m ethyl azcti din-3 -amine dihydrochloride (12 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.346 min, m / z = 908.1 (M+H)+. ’H NMR (400 MHz, DMSO) 58.03 (s, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.04 (s, 1H), 6.95 (s, 1H), 6.68 (s, 2H), 4.46 (dd, J= 12.3, 6.0 Hz, 2H), 4.40 -4.27 (m, 1H), 4.22 - 3.87 (m, 15H), 3.84 (s, 3H), 3.58 (t, J= 10.4 Hz, 3H), 3.51 - 3.42 (m, 1H), 3.24 (t, J= 6.8 Hz, 2H), 2.94 (t, J= 10.1 Hz, 1H), 2.27 (s, 1H), 2.24 (s, 6H), 2.20 (s, 1H), 2.04 (dt, J= 13.9, 7.8 Hz, 2H), 1.90 - 1.74 (m, 1H), 1.71 - 1.50 (m, 2H), 1.07 (d, J= 6.7 Hz, 3H), 0.50 - 0.29 (m, 4H).e- -carboxamide

[0423] The title compound (30 mg, 52% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 4-m ethoxy -JV-methylcy cl ohexan-1 -amine hydrochloride (11 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.814 min, m / z = 925.0 (M+H)+.Example 92(263 s„,l722R«,24R)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(3-(3,3- difluoropyrrolidin-l-yl)azetidine-l-carbonyl)-14,1 -dimethoxy-2,31-dimethyl- 21,2^,2^,2^-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino| l,2-«]indola-l(7,l )-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0424] The title compound (45 mg, 76% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and l-(azetidin-3-yl)-3,3-difluoropyrrolidine di hydrochloride (15 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.603 min, m / z = 944.1 (M+H)+.Example 93(263 5a,l722lffl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-12-(3-(methyl(oxetan-3-yl)amino)azetidine-l-carbonyl)- 21,22,2^,2^-tetrahydro-l ' / / .3' / / -5-o\a-2(2.6)-pyrazino| l,2-«]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0425] The title compound (45 mg, 78% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 7V-methyl-V-(oxetan-3-yl)azetidin-3 -amine bis(2,2,2-trifluoroacetate) (23 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.323 min, m / z = 924.0 (M+H)+.NMR (400 MHz, DMSO) 88.03 (s, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.29 (d, J= 8.6 Hz, 1H), 7.05 (s, 1H), 6.96 (s, 1H), 6.68 (s, 2H), 4.59 - 4.41 (m, 6H), 4.31 - 4.26 (m, 1H), 4.19 - 3.70 (m, 19H), 3.58 (t, J= 10.0 Hz, 2H), 3.50 - 3.44 (m, 2H), 3.24 (t, J = 7.4 Hz, 2H), 2.95 (t, J= 10.1 Hz, 1H), 2.24 (s, 7H), 2.13 (s, 1H), 2.03 (h, J = 7.7 Hz, 2H), 1.89 - 1.76 (m, 1H), 1.62 - 1.46 (m, 1H), 1.07 (d, J= 6.7 Hz, 3H).dimethylphenoxy)propyl)-12-(3- (diethylamino) azetidine-l-carbonyl)-l^,l^-dimethoxy-2^,31-dimethyl-21,2^,23,2^- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino|1.2-n|indola-l(7.1 )-indola-3(4.3)- pyrazolacyclooctaphan-21-one

[0426] The title compound (26 mg, 46% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and AGV-diethylazetidin-3-amine dihydrochloride (13 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.256 min, m / z = 910.0 (M+H)+.Example 95(26345fl,l722?a,241?)-12-(Azetidine-l-carbonyl)-2 -chIoro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,34-dimethyl-24,2^,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 21-one

[0427] The title compound (22 mg, 42% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and azetidine (3.6 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.887 min, m / z = 839.0 (M+H)+.Example 96(26345fl,l722T?„,24l?)-2^-Chloro-24®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)- -(3- (hexahydrocyclopenta[c]pyrrol-2(l / / )-yl)azetidine-l-carbonyl)-l^,l^-dimethoxy-2^,31- dimethyl-21,22,2^,2^-tetrahydro-l4 / / ,31 / / -5-oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)- indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0428] The title compound (35 mg, 59% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq) and 2-(azeti din-3 -yl)octahydrocyclopenta[c]pyrrole dihydrochloride (15 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.565 min, m / z = 948.0 (M+H)+.Example 97(263 5a,l722lffl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-12-(3-((2-methoxyethyl)(methyl)amino)azetidine-l-carbonyl)-2^,3^-dimethyl- 21,2^,2^,2^-tetrahydro-l ' / / .3' / / -5-o\a-2(2.6)-pyrazino| l,2-«]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-2^-one

[0429] The title compound (37 mg, 64% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and V-(2-methoxyethyl)-jV-methylazetidin-3-amine dihydrochloride (14 mg, 0.062 mmol, 1.0 eq ). LCMS (ESI) Method 2: RT = 0.942 min, m / z = 896.1 (M+H)+.Example 98(26345«,l722l?fl,24 )-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1 -(3- ((dimethylamino) methyl)azetidine-l-carbonyl)-l^,l^-dimethoxy-2^,34-dimethyl-2^,22,2^,24-tetrahydro-l^ZT, 3^H-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0430] The title compound (42 mg, 75% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and l-(azetidin-3-yl)-A(A'-dimethylmethanamiiie dihydrochloride (12 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.563 min, m / z = 926.0 (M+H)+.Example 99(26345fl,l722JR„,24l?)-l2-([l,3'-Biazetidine]-r-carbonyl)-27-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy) propyl)-l4,l^-dimethoxy-24,3^-dimethyl-21,22,2^,24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 2^-one

[0431] The title compound (30 mg, 54% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 1,3 '-biazetidine bis(2,2,2-trifluoroacetate) (21 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.953 min, m / z = 894.0 (M+H)+.Example 100(26345fl,l722?a,2^7?)-2^-Chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2,31-dimethyl-12-(6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)- 21,22,23,24-tetrahydro-l l / / .3l / / -5-oxa-2(2.6)-pyrazino| l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0432] The HC1 salt of Example 57 A (95 mg, 0.104 mmol, 1.0 eq) was dissolved in DMF (2 mL). Formaldehyde (0.10 mL, 37% wt. in water, 1.2 mmol) was added and the reaction was allowed to stir for 5 min at RT. Sodium triacetoxyborohydride (66 mg, 0.31 mmol, 3.0 eq) was added and the reaction was allowed to stir for 0.5 h. The reaction was diluted with EtOAc and FEO, extracted with EtOAc, washed with FEO, washed with aq. NaHCOs, dried over MgSO4, filtered, and concentrated. The crude product was purified by reverse phase HPLC using a Phenomenex Gemini column eluting with MeCN / H2O and 0.1% TFA as mobile phase to afford the desired product. After concentration, the residue was dissolved in EtOAc and washed with sat. aq. NaHCOa. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound. LCMS (ESI) Method 1: RT = 1.951 min, m / z = 894.0 (M+H)+.Example 101(26345a,l7227?«,24?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-24,31-dimethyl-12-(6-inethyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)- 2*,22,2^,2^-tetrahydro-l' / / ,3' / / -5-oxa-2(2,6)-pyrazino[l,2-«|indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0433] The title compound (40 mg, 72% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 2-methyl-2,6-diazaspiro[3.3]heptanedi hydrochloride (12 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.950 min, m / z = 894.0 (M+H)+.Example 102(26345a,l722?a,2^T?)-2^-Chloro-2^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2,31-dimethyl-12-(4-(2-morpholinoethyl)piperidine-l-carbonyl)-21, 2^,2,2 - tetrahydro- 11 / / , 31 / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0434] The title compound (38 mg, 62% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 4-(2-(piperidin-4-yl)ethyl)morpholine (12 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.984 min, m / z = 980.1 (M+H)+.Example 103(26345«,l722 / fa,2^ / ?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,31-dimethyl-21-oxo-A?-(pyridin-3-ylmethyl)-21,22,2^,2^-tetrahydro-l H,3*H-5 -oxa-2(2,6)-pyrazino[l,2-ff]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- l^-carboxamide

[0435] The title compound (45 mg, 80% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 3-(aminomethyl)pyridine (14 mg, 0.12 mmol, 2.0 eq.). The crude product was purified by flash column chromatography eluting with 0 to 6% MeOH in DCM with 0.1% NH4OH. LCMS (ESI) Method 1: RT = 1.966 min, m / z = 890.0 (M+H)+.ne- -carboxamide

[0436] The title compound (44 mg, 78% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 4-(aminomethyl)pyridine (14 mg, 0.12 mmol, 2.0 eq.). The crude product was purified by flash column chromatography eluting with 0 to 6% MeOH in DCM with 0.1% NH4OH. LCMS (ESI) Method 1: RT = 1.955 min, m / z = 890.0 (M+H)+.ne- -carboxamide

[0437] The title compound (51 mg, 91% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 2-(aminomethyl)pyridine (14 mg, 0.12 mmol, 2.0 eq.). The crude product was purified by flash column chromatography eluting with 0 to 4% MeOH in DCM with 0.1% NH4OH. LCMS (ESI) Method 1: RT = 1.998 min, m / z = 890.0 (M+H)+.Example 106(263 5«,l722lG,2 1?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,15_ dimethoxy-2^,3^-dimethyl- -(4-(2-(piperidin-l-yl)ethyl)piperidine-l-carbonyl)-2^,2^,2^,2^-tetrahydro-l^ / / ,3^H-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indoIa-3(4,3)- pyrazolacyclooctaphan-21-one

[0438] The title compound (38 mg, 62% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and l-(2-(piperidin-4-yl)ethyl)piperidine (12 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.025 min, m / z = 978.1 (M+H)+.methylphenoxy)propyl)-12-(4-(2- (dimethylamino)ethyl)piperidine-l-carbonyl)-l^,l^-dimethoxy-2^,31-dimethyl- 2'.2^.2^.2^-tetrahydro-l ^ / / .3' / / -5-oxa-2(2.6)-pyrazino| 1.2-n|indola-l(7.1)-indola-3(4.3)- pyrazolacyclooctaphan-ll-one

[0439] The title compound (39 mg, 67% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and A'-dimethyl-2-(piperidin-4-yl)ethan-l-amine (9.8 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.023 min, m / z = 938.1 (M+H)+.Example 108(26345«,l722l?fl,241?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1 -(3-cyclopropyl-3-hydroxyazetidine-l-carbonyl)-l4,l^-dimethoxy-24,34-dimethyl-24,2^,2^,24- tetrahy dro- 1 ' / / .3 ' / / -5-oxa-2( 2.6 )-py razino [ 1,2-a] indola- l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0440] The title compound (37 mg, 66% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 3-cyclopropylazetidin-3-ol hydrochloride (9.3 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.404 min, m / z = 895.0 (M+H)+.Example 109(26345«,l7227?«,2^T?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,34-dimethyl-l^-(3-(2-(4-methylpiperazin-l-yl)ethoxy)azetidine-l-carbonyl)- 21.22,2',2'l-tetraliydro-l ' / / .3l / / -5-oxa-2(2.6)-pyrazino| 1.2-( / |indola-l(7.1 )-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0441] To a solution of Example 59 (50 mg, 0.058 mmol, 1.0 eq.) in DMF (5 mL) was added sodium hydride (1.9 mg, 90% wt, 0.070 mmol, 1.2 eq) at 0 °C. After the mixture was stirred for 20 min, l-(2-bromoethyl)-4-methylpiperazine dihydrobromide (26 mg, 0.070 mmol, 1.2 eq.) was added. The reaction mixture was allowed to come to room temperature and stirred for 18 h. Excess of sodium hydride was quenched with H2O, and the mixture was then diluted with water and extracted with CHCh. The organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated. The crude product was purified by reverse phase HPLC using a Phenomenex Gemini column eluting with MeCN / H2O and 0.1% TFA as mobile phase to afford the desired product. After concentration, the residue was dissolved in EtOAc and washed withsat. aq. NaHCCh. The organic layer was dried over MgSCh, filtered, and concentrated to afford the title compound (12 mg, 21%). LCMS (ESI) Method 2: RT = 0.612 min, m / z = 981.0 (M+H)+.n- 21-one

[0442] The title compound (6 mg, 10% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and azeti din-3 -one hydrochloride (6.7 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.591 min, m / z = 852.9 (M+H)+.Example 111tert-Butyl 6-((26345„,l722^fl,24^)-27-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4,15_(iiineti1oxy-24,34-dimethyl-24-oxo- 2X,22,23,24-tetrahydro--indola-3(4,3)- pyrazolacyclooctaphane-l^-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0443] The title compound (80 mg, 93% yield) was prepared following General Procedure J using Example 1 (70 mg, 0.087 mmol) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (17 mg, 0.087 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 = 1.736 min, m / z = 979.9 (M+H)+.Example 111A(26345a,l722?fl,2^1f)-12-(3,6-Diazabicyclo[3.1.1]heptane-6-carbonyl)-2^-chloro-21®-(3-(4- chloro-3,5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-2^,31-dimethyl-21,22,2^,2^- tetrahydro-l^E,3^Ef-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0444] Example 111 (80 mg, 0.082 mmol) was dissolved in DCM (2 mL) and trifluoroacetic acid (1 mL, 0.01 mol) was added. The resulting mixture was stirred for 1 h at RT. Solvent was evaporated and the crude product was purified by reverse phase HPLC eluting with MeCN / 1 LO and 0.1% TFA as mobile phase to afford the desired product (45 mg, 63%). LCMS (ESI) Method 1: RT = 0.927 min, m / z = 880.0 (M+H)+.Example 11 IB(26345«,l722l?«,24l?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)- -(3-(2- hydroxy-2-methylpropyl)-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)-l^,l^-dimethoxy- 24, 3 l-dimethyl-21,2^,2^, 24-tetrahydro- 1l / / -5-oxa-2(2,6)-py razino [1,2-a] indola- l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0445] A solution of Example 111 A (45 mg, 0.051 mmol), l-bromo-2-methylpropan-2-ol (16 mg, 0.10 mmol, 2.0 eq.), and DIPEA (33 mg, 44 uL, 0.26 mmol, 5.0 eq.) in ethanol (2 mL) was heated at 150 °C under microwave irradiation for 1 h. The reaction was diluted with EtOAc and water, then stirred for 15 minutes. The aqueous layer was extracted with EtOAc, washed with saturated NEUCl, water, saturated NaHCCh, brine, dried over MgSO4, and concentrated. The crude product was purified by reverse phase HPLC eluting with MeCN / IEO and 0.1% TFA as mobile phase to afford the desired product. After concentration, the residue was dissolved in EtOAc and washed with sat. aq. NaHCOs. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (17 mg, 35%). LCMS (ESI) Method 2: RT = 0.679 min, m / z = 952.0 (M+H)+.Example 112(26345fl,l722?a,2^?)-2^-Chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-l^-(2-(methoxymethyl)azetidine-l-carbonyl)-2^,3^-dimethyl-21,22,2^,2^- tetrahydro-ll / / ,3^Tf-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0446] The title compound (6 mg, 10% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 2-(methoxymethyl)azetidine (6.3 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.690 min, m / z = 883.0 (M+H)+.Example 113(26345«,l722^«,2^T?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^-(3- hydroxy-3-(trifluoromethyl)azetidine-l-carbonyl)-1,1 -dimethoxy-2,3 -dimethyl- 21,22,2,24-tetrahydro-llH,31? / -5-oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0447] The title compound (40 mg, 69% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 3-(trifluoromethyl)azetidin-3-ol hydrochloride (11 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.620 min, m / z = 922.9 (M+H)+.Example 114(26345«,l722?«,2^T?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(3- hydroxy-3-methyl azetidine-l-carbonyl)-14,l^-dimethoxy-24,3^-dimethyl-21,2^,2^,24- tetrahydro-ll / 7,3^-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0448] The title compound (40 mg, 74% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 3-methylazetidin-3-ol hydrochloride (7.7 mg, 0.062 mmol, 1.0 eq ). LCMS (ESI) Method 2: RT = 1.431 min, m / z = 869.0 (M+H)+. 'H NMR (400 MHz, DMSO) 88.03 (s, 1H), 7.75 (d, J= 8.6 Hz, 1H), 7.30 (d, J= 8.6 Hz, 1H), 7.05 (s, 1H), 6.93 (s, 1H), 6.88 (s, 1H), 6.68 (s, 2H), 5.67 (s, 1H), 4.46 (dd, J= 12.0, 5.7 Hz, 1H), 4.35 (dt, J= 13.3, 7.3 Hz, 2H), 4.10 (dd, J= 17.0, 8.3 Hz, 3H), 4.00 - 3.87 (m, 10H), 3.84 (s, 4H), 3.58 (dd, J= 10.9, 8.4 Hz, 2H), 3.48 (s, 1H), 3.24 (t, J= 7.4 Hz, 2H), 2.95 (d, J= 10.7 Hz, 1H), 2.24 (s, 6H), 2.02 (t, J= 7.1 Hz, 2H), 1.56 (q, J= 12.1 Hz, 1H), 1.45 (s, 1H), 1.36 (s, 1H), 1.07 (d, J= 6.7 Hz, 3H).terf-Butyl (3a?,6a5)-5-((26,34Afl,l722 / ?«,24 / ?)-27-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy) propyl)-l4,l^-dimethoxy-24,3x-dimethyl-2x-oxo- 2X,22,23,24- tetrahydro-lXET,3XEf-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphane-l2-carbonyl) hexahydropyrrolo[3,4-c]pyrrole-2(l / / )-carboxylate

[0449] The title compound (70 mg, 80% yield) was prepared following General Procedure J using Example 1 (70 mg, 0.087 mmol) and / erCbutyl (3a / ?,6a )-hexahydropyrrolo[3,4-c]pyrrole-2(177)-carboxylate (19 mg, 0.087 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 = 1.670 min, m / z = 994.0 (M+H)+.Example 115A(26345«,l722?«,24?)-27-Chloro-2x0-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,15- dimethoxy-24,3^-dimethyl-l2-((3a7?,6a»S)-octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)- 2l.22.23.24-tetrahydro-l ' / / .3l / / -5-oxa-2(2.6)-pyrazino| 1.2-i / |indola-l(7.1 )-indola-3(4,3)- pyrazolacyclo-octaphan-2x-one

[0450] Example 115 (70 mg, 0.070 mmol) was dissolved in DCM (2 mL) and trifluoroacetic acid (1 mL, 0.01 mol) was added. The resulting mixture was stirred for 1 h at rt. The solvent was evaporated to afford the title compound. LCMS (ESI) Method 1: RT = 0.918 min, m / z = 894.0 (M+H)+.Example 115B(2634»fl,l722l?a,247?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12- ((3a / ?,6a5)-5-(2-hydroxy-2-methylpropyl)octahydropyiTolo[3,4-c|pyrrole-2-carbonyl)- H. -dimethoxy-2^.3'-diinethyl-2 '.22.2^.2^-tetrahydro- 1 l / / .3' / / -5-oxa-2(2.6)- pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacydooctaphan-21-one

[0451] A solution of Example 115A (40 mg, 0.045 mmol, 1.0 eq.), l-bromo-2-methylpropan-2-ol (14 mg, 0.09 mmol, 2.0 eq.), and DIPEA (29 mg, 39 pL, 0.22 mmol, 5.0 eq) in ethanol (2 mL) was heated at 150 °C under microwave irradiation for 1 h. The reaction was diluted with EtOAc and water, extracted with EtOAc, washed with saturated NH4CI, water, saturated NaHCCE, brine, dried over MgSC, and concentrated. The crude product was purified by reverse phase HPLC eluting with MeCN / H2O and 0.1% TFA as mobile phase to afford the desired product. After concentration, the residue was dissolved in EtOAc and washed with sat. aq. Nal ICO. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (20 mg, 46%). LCMS (ESI) Method 2: RT = 0.921 min, m z = 966.0 (M+H)+.Example 116(26345»722l?fl,241?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(6-(2- hydroxy-2-methylpropyl)-3,6-diazabicyclo[3.1.1]heptane-3-carbonyl)-14,15_dimethoxy- 24,3'-diniethyl-2 '.22,2^.24-tetrahydro-l ' / / ,3' / / -5-oxa-2(2.6)-pyi az.ino| 1,2-u|indola- l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0452] The HC1 salt of Example 57A (229 mg, 0.25 mmol, 1.0 eq) was dissolved in EtOH (1.7 mL). DIPEA (162 mg, 1.25 mmol, 5.0 eq) was added, followed by isobutylene oxide (72 mg, 1.0 mmol, 4.0 eq). The reaction vial was irradiated in a microwave at 120 °C for 1 h, after which time the reaction was determined to be complete by LCMS. The reaction was diluted with EtOAc, washed with H2O, aq. NH4CI, then aq. NaHCOa, dried over MgSCh, filtered, and then concentrated. The crude product was purified by reverse phase HPLC eluting with MeCN / HaO and 0.1% TFA as mobile phase to afford the desired product. After concentration, the residue was dissolved in EtOAc and washed with sat. aq. NaHCOa. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (66 mg, 28%).LCMS Method 1: RT = 1.883 min, m / z = 952.0 (M+H)+.Example 117(26345fl,l722^«,247?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l5- dimethoxy-24,34-dimethyl-12-(4-(pyridin-2-ylmethyl)piperazine-l-carbonyl)-24,22,2^,24- tetrahydro-l4 / f, 3' / / -5-oxa-2(2.6)-pyrazino|1.2-u|indola-l(7.1)-indola-3(4.3)- pyrazolacyclooctaphan-21-one

[0453] The title compound (31 mg, 52% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and l-(pyridin-2-ylmethyl)piperazine (11 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.863 min, m / z = 959.0 (M+H)+.Example 118(26345«,l722 / ffl,24 / ?)-17. Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,15_ dimethoxy-24,31-dimethyl-12-(4-(pyridin-4-ylmethyl)piperazine-l-carbonyl)-21,tetrahydro-11 / / , 34 / / -5-oxa-2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0454] The title compound (33 mg, 55% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and l-(pyridin-4-ylmethyl)piperazine (11 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.801 min, m z = 959.0 (M+H)+.Example 119(26345a,l722 / ?a,24 / ?)-17-Chloro-210-(3-(4-chloro-3,5-diniethylphenoxy)propyl)-14,15- dimethoxy-24,31-dimethyl-12-(4-(pyridin-3-ylmethyl)piperazine-l-carbonyl)-21, 22,23,14.tetrahydro-1 ^H, 3^ET-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-ll-one

[0455] The title compound (28 mg, 47% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and l-(pyridin-3-ylmethyl)piperazine (11 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.752 min, m / z = 959.1 (M+H)+.Example 120(26345fl,l722l?fl,241?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(3-(2- (dimethylamino) ethyl)azetidine-l-carbonyl)-l4,l^-dimethoxy-24,34-dimethyl- 21,2^,2^,24-tetrahydro-l4 / f, 31 / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one[00456J The title compound (45 mg, 79% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and 2-(azetidin-3-yl)-A(JV-dimethylethan-l -amine dihydrochloride (13 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.436 min, m / z = 910.0 (M+H)+.Example 121(26345fl,l722l? / „24l?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(6-(2- hydroxy-2-methylpropyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-14,15_dimethoxy-24,31- dimethyl-21,22,2^,24-tetrahydro-ll / ,31z / -5-oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)- indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0457] Step A: tert-Butyl 6-(2-hydroxy-2-methylpropyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate. In a microwave vial, tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemioxalate (100 mg, 0.206 mmol, 1.0 eq) and 2,2-dimethyloxirane (59 mg, 0.822 mmol, 4.0 eq) were combined and dissolved in EtOH (2 mL). The reaction was irradiated in the microwave for 1 h at 120 °C after which time the reaction was determined to be complete by LCMS. The reaction was extracted with EtOAc, washed with EbO followed by aq. NEUC1, aq. NaHCCh, and brine. The combined organic extracts were dried over MgSCh, filtered, and concentrated. The crude residue was purified by flash column chromatography to afford the title compound (80 mg, 70% yield). LCMS (ESI) Method 1: RT = 0.661 to 1.13 min (broad peak), m / z = 271.2 (M+H)+.

[0458] Step B: 2-methyl-l-(2,6-diazaspiro[3.3]heptan-2-yl)propan-2-ol trifluoroacetate salt. In a scintillation vial, tert-butyl 6-(2-hydroxy-2-methylpropyl)-2,6-diazaspiro[3.3]heptane-2- carboxylate (80 mg, 0.30 mmol, 1.0 eq) was dissolved in DCM (2 mL) and TFA was added (1 mL). The reaction mixture was allowed to stir for 1 h at room temperature, after which time starting material was consumed as determined by LCMS. The reaction was concentrated to afford the title compound. The crude material was used in subsequent reactions without further purification (79 mg, quantitative yield). LCMS (ESI) Method 1: RT = 0.233 min, m z = 171.3 (M+H)+.

[0459] Step C: (26345fl,l722 / ?„,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^-(6-(2-hydroxy-2-methylpropyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-l4,15_dimethoxy-24,34-diinethyl-21,22,23,24-tetrahydro-l4H,31H-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The title compound (6 mg, 10% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 2-methyl-l-(2,6-diazaspiro[3.3]heptan-2-yl)propan-2-oltri fluoroacetic acid salt (17 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.623 min, m / z = 952.0 (M+H)+.Example 122(263 5a,l722lffl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,l^- dimethoxy-24,31-dimethyl-12-(4-(pyrrolidin-l-yl)piperidine-l-carbonyl)-21, 22,2^,24- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyraz.ino| 1.2-<7|indola-l (7.1 )-indola-3(4.3)- pyrazolacyclooctaphan-2^-one

[0460] The title compound (46 mg, 79% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 4-(pyrrolidin-l-yl)piperidine (9.6 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: Ri = 0.681 min, m / z = 936.0 (M+H)+.Example 123(2^3^5fl,1^22l?fl,2^1?)-12-(4-(Azetidin-l-yl)piperidine-l-carbonyl)-2^-chloro-21®-(3-(4- chloro-3,5-dimethylphenoxy)propyl)-1,15-dimethoxy-2,31-dimethyl-21, 2^,23,24-tetrahydro-1 ^H, 3^H-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-mdola-3(4,3)- pyrazolacyclooctaphan-21-one

[0461] The title compound (45 mg, 78% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 4-(azetidin-l-yl)piperidine dihydrochloride (13 mg, 0.062 mmol, 1.0 eq). LCMS Method 2: RT = 0.557 min, m / z = 922.0 (M+H)+.Example 124(26345«,l7227?«,2 / ?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,1 - dimethoxy-24,31-dimethyl-12-(3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-carbonyl)- 21,22,2^,2^-tetrahydro-ll / / ,31 / / -5 -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0462] The title compound (47 mg, 84% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 3-methyl-3,6-diazabicyclo[3.1.1]heptane bis(2,2,2-trifluoroacetate) (21 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.092 min, m / z = 894.0 (M+H)+.(26345fl,l722?a,2^7?)-2^-Chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-24,31-dimethyl-l2-(7-methyl-2,7-diazaspiro[3.5]nonane-2-carbonyl)- 21,22,2^,24-tctr ahydro-1’ / / ,3 ' f / -5-oxa-2(2,6)-py razino [ 1,2-a] indola- l(7,l)-indo!a-3(4,3)- pyrazolacyclooctaphan-21-one

[0463] The title compound (45 mg, 78% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 7-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (13 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.076 min, m / z = 922.0 (M+H)+.Example 126(26345fl,l722 / ?fl,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l2-(2-(2- hydroxy-2-methylpropyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-l4,15-dimethOxy-24,31- dimethyl-21,22,2^,24-tetrahydro-l4 / / ,34L / -5-oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)- indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0464] Step A: tert- Butyl 2-(2-hydroxy-2-methylpropyl)-2-azaspiro[3.5]nonane-7-carboxylate. In a microwave vial, tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (200 mg, 0176 mmol, 1.0 eq) and 2,2-dimethyloxirane (220 mg, 3.04 mmol, 4.0 eq) were combined and dissolved in EtOH (2 mb). The reaction was irradiated in a microwave at 120 °C for 1 h, after which time the reaction was determined to be complete by LCMS. The reaction mixture was extracted with EtOAc, washed with H2O followed by aq. NH4CI, aq. NaHCOs, and brine. The combined organic extracts were dried over MgSO4, filtered, andconcentrated. The crude residue was purified by flash column chromatography to afford the title compound (220 mg, 97% yield).

[0465] Step B: 2-Methyl-l-(2,7-diazaspiro[3.5]nonan-2-yl)propan-2-ol trifluoroacetic acid. In a scintillation vial, tert-butyl 2-(2-hydroxy-2-methylpropyl)-2-azaspiro[3.5]nonane-7-carboxylate (220 mg, 0.76 mmol, 1.0 eq) was dissolved in DCM (2 mL) and TFA was added (1 mL). The reaction mixture was allowed to stir for 1 h at room temperature, after which time starting material was consumed as determined by LCMS. The reaction was concentrated to afford the title compound (228 mg, quantitative yield). LCMS (ESI) Method 1: RT = 0.204 min, m / z = 199.2 (M+H)+.

[0466] Step C: (26.34S'„. l722tffl, 24 / f)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-P-(2-(2-hydroxy-2-methylpropyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)-l4,l^-dimethoxy-24,34-dimethyl-21,22,2^,24-tetrahydro-l4 / f,34 / 7-5-oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-2^-one. The title compound (50 mg, 82% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 2-methyl-l-(2,7-diazaspiro[3.5]nonan-2-yl)propan-2-ol trifluoroacetic acid salt (18 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: Rr = 1.085 min, m / z = 980.1 (M+H)+.Example 127(26345«,l722?«,24?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,15- dimethoxy-24,31-dimethyl-12-(4-(2-(methyl(oxetan-3-yl)amino)ethyl)piperazine-l-carbonyl)-! 1, 2^,2^, 24-tetrahydro-l^JT, 3 ^ZT-5-oxa-2(2, 6)-pyrazino[l, 2-a]indola-l(7,l)- indola-3(4,3)-pyrazo!acyclooctaphan-21-one

[0467] Step A: tert-Butyl 4-(2-(methyl(oxetan-3-yl)amino)ethyl)piperazine-l-carboxylate. In a microwave vial, tert-butyl 4-(2-chloroethyl)piperazine-l -carboxylate (400 mg, 1.61 mmol, 1.0 eq), A-methyloxetan-3 -amine hemioxalate (425 mg, 1.61 mmol, 1.0 eq), and CS2CO3 (1.57 g, 4.82 mmol, 3.0 eq) were combined and then dissolved in MeCN (1 mL). The reaction mixture was irradiated in a microwave at 100 °C for 1 h, after which time the reaction was determined to be complete by LCMS. The reaction mixture was concentrated, and the crude residue was purified by flash column chromatography to afford the title compound (40 mg, 8.3% yield).

[0468] Step B: 7V-methyl-7V-(2-(piperazin-l-yl)ethyl)oxetan-3-amine. In a scintillation vial, / crt-butyl 4-(2-(methyl(oxetan-3-yl)amino)ethyl)piperazine-l -carboxylate (18 mg, 0.060 mmol, 1.0 eq) was dissolved in DCM (2 mL) and TFA (1 mL). The reaction was allowed to stir for 1 h at room temperature. The solvent was evaporated to afford the title compound (12 mg, quantitative yield).

[0469] Step C: (2634S'„.l722 / <,.24 / ?)-27-Chloro-2l0-(3-(4-chloro-3.5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,34-dimethyl-l^-(4-(2-(methyl(oxetan-3-yl)amino)ethy l)piperazine- l-carbonyl)-24,2^,23,24-tetrahy dro- 1 ^H,3477-5-oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyi"azola cyclooctaphan-2^-one. The title compound (21 mg, 34% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and A-methyl- / V-(2-(piperazin-l-yl)ethyl)oxetan-3 -amine (12 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: Ri = 0.898 min, m / z = 981.0 (M+H)+.Example 128(26345fl,l722l? / „24l?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(4-(2- (cyclopropyl(methyl)amino)ethyl)piperazine-l-carbonyl)-14,15_dimethoxy-24,31- dimethyl-21,22,2^,24-tetrahydro-ll / ,31z / -5-oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)- indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0470] Step A: tert-Butyl 4-(2-(cyclopropyl(methyl)amino)ethyl)piperazine-l-carboxylate. In a microwave vial, Zc / 7-butyl 4-(2-chloroethyl)piperazine-l -carboxylate (200 mg, 0.804 mmol, 1.0 eq), A-methylcyclopropanamine hydrochloride (87 mg, 0.804 mmol, 1.0 eq), and CS2CO3 (786 mg, 2.41 mmol, 3.0 eq) were combined and dissolved in MeCN (5 mL). The reaction mixture was irradiated in the microwave at 100 °C for 1 h, after which time it was determined to be complete by LCMS. The reaction was concentrated, and the crude residue was purified by flash column chromatography eluting with 0 to 5% MeOH in DCM to afford the title compound (150 mg, 66% yield). LCMS (ESI) Method 1: RT = 1.188 min, m / z = 284.2 (M+H)+.

[0471] Step B: 7V-Methyl-7V-(2-(piperazin-l-yl)ethyl)cyclopropanamine dihydrochloride. In a scintillation vial, / e / V-butyl 4-(2-(cyclopropyl(methyl)amino)ethyl)piperazine-l -carboxylate (150 mg, 0.529 mmol, 1.0 eq) was dissolved in DCM (2 mL) and HC1 (4.0 M in dioxane, 2 mL) was added. The reaction was allowed to stir at RT for 1 h. The reaction was concentrated to afford the title compound (136 mg, quantitative yield). LCMS (ESI) Method 1: RT = 0.216 min, m / z = 184.2 (M+H)+.

[0472] Step C: (26345fl,l722 / ?a,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-P-(4-(2-(cyclopropyl(methyl)amino)ethyl)piperazine-l-carbonyl)-l4,l^-dimethoxy-24,34-dimethyl-24,22,2^,24-tetrahydro-ll / f,34 / 7-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The title compound (44 mg, 73% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and / V-methyl- / -(2-(piperazin- l-yl)ethyl)cyclopropanamine dihydrochloride (18 mg, 0.062 mmol). LCMS (ESI) Method 2: RT = 1.092 min, m / z = 965.1 (M+H)+.Example 129to / *- Butyl (3 / ?.4x.5. S)-4-((2634. S„.l722 / ?„.24 / ?)-27-chloro-210-(3-(4-chloro-3.5- dimethylphenoxy) propyl)-l4,l^-dimethoxy-24,34-dimethyl-21-oxo- 2X,22,23,24- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino| l,2-a]indola-l (7,1 )-indola-3(4,3)- pyrazolacyclooctaphane-l2-carboxamido) piperidine-l-carboxylate

[0473] The title compound (119 mg, 99% yield) was prepared following General Procedure J using Example 1 (100 mg, 0.12 mmol, 1.0 eq) and / c / 7-butyl (17?,55’,6.s')-6-amino-3-azabicyclo[3.1.0]hexane-3 -carboxylate (31 mg, 0.16 mmol). The crude product was purified by flash column chromatography eluting with 0 to 80% EtOAc: MeOH (95:5) in hexanes. LCMS (ESI) Method 2: RT = 1.712 min, m / z = 979.9 (M+H)+.Example 129A(2634S'„,l722 / ,.24 / ?)-\-((l / ,5. S'.6s)-3-Azabicycl()|3.1.0|hexan-6-yl)-27-chloro-2l0-(3-(4- chloro-3,5-dimethyl phenoxy)propyl)-l4,l^-dimethoxy-24,31-dimethyl-21-oxo-2^,2^,2^,2^-tetrahydro-l^ / T,3^^ / -5-oxa-2(2,6)-pyrazino[ l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphane-l^-carboxamide

[0474] Example 129 (119 mg, 0.12 mmol) was dissolved in DCM (2 mL) at room temperature followed by addition of HC1 (4.0 M in dioxane, 0.3 mL, 1.2 mmol). The reaction was allowed to stir for 1 h, after which time the reaction was complete by LCMS. The reaction was concentrated from DCM / MeOH (3x) to afford the title compound (111 mg, quant, yield). LCMS (ESI) Method 1: RT = 1.935 min, m / z = 880.0 (M+H)+.Example 130(26345«,l722?«,24 / ?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,1 - dimethoxy-2,31-dimethyl-7V-((17?,5> S',6s)-3-methyl-3-azabicydo[3.1.0]hexan-6-yl)-21-oxo- 21.2-.2- 2"l-tetraliydr()-l l / / .3' / / -5-oxa-2(2.6)-pyrazino| l,2-«]indola-l(7,l )-indola-3(4,3)- pyrazolacyclooctaphane-l^-carboxamide

[0475] In a scintillation vial, the HC1 salt of Example 129A (50 mg, 0.055 mmol, 1.0 eq) was dissolved in MeOH. Formaldehyde (0.030 mL, 37% wt. in water, 0.38 mmol, 7.0 eq) was added, and the reaction was allowed to stir at room temperature for 5 minutes. Sodium cyanoborohydride (17 mg, 0.27 mmol, 5.0 eq) was added and the reaction was allowed to stir for 0.5 h at room temperature, after which time the reaction was determined to be complete by LCMS. The reaction was diluted with EtOAc and aq. NaHCCh. The reaction was extracted with EtOAc, washed with H2O, washed with NaHCOs, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography eluting with 0to 10% MeOH in DCM (with 0.1 % NH40H) to afford the title compound (31 mg, 63% yield). LCMS (ESI) Method 1: RT = 1.974 min, m / z = 894.0 (M+H)+.Example 131(26345fl,l722l?fl,24lf)-2^-Chloro-24®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-A- ((ll?,55,6s)-3-isopropyl-3-azabicyclo[3.1.0]hexan-6-yl)-l4,l^-dimethoxy-24,34-dimethyl- 2 ' -oxo-2 2^. l^ -l-tetraliydro- 1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1.2-< / |indola- 1(7.1 )-indola- 3(4,3)-pyrazolacyclooctaphane- 1 ^-carboxamide

[0476] In a reaction vessel, the HC1 salt of Example 129A (52 mg, 0.06 mmol, 1.0 eq) was dissolved in DCM (1 mL) and acetone (0.6 mL). Acetic acid (30 uL) was added, and the reaction stirred for 15 min. The reaction was treated with sodium triacetoxyborohydride (50 mg, 0.24 mmol, 4.0 eq) and allowed to stir overnight at RT, after which time it was determined to be complete by LCMS. The reaction was diluted with EtOAc and IM NaOH, extracted with EtOAc, washed with H2O, dried over MgSCh, filtered, and concentrated. The crude product was purified by flash column chromatography eluting with 0 to 10% MeOH in DCM with 1% NH4OH to afford the title compound (34 mg, 65% yield). LCMS (ESI) Method 1: RT = 2.012 min, m / z = 924.0 (M+H)+.Example 132(26345a,l722 / ?a,24?)-2^-Chloro-24®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-24,34-dimethyl-l^-(8-methyloctahydro-2 / / -pyrazino[l,2-a]pyrazine-2- carbonyl)-21,2,13,24-tetr ahydr o-l l / / ,3 -5-oxa-2(2,6)-pyrazino [1,2-«] indola-1 (7,1)- indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0477] The title compound (54 mg, 77% yield) was prepared following General Procedure J using Example 1 (60 mg, 0.07 mmol, 1.0 eq) and 2-methyloctahydro-17 / -pyrazino[l,2-a]pyrazine trihydrochloride (26 mg, 0.10 mmol, 1.30 eq.). LCMS (ESI) Method 1: RT = 1.909 min, m / z = 937.0 (M+H)+.Example 133(26345«,l722l?fl,241?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(3- ((cyclopropyl(methyl) amino)methyl)azetidine-l-carbonyl)-14,15-dimethoxy-2,31- dimethyl-21,22,2^,2^-tetrahydro-l4 / ,31 / / -5-oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)- indola-3(4,3)-pyrazolacyclooctaphan-24-one

[0478] Step A: Benzyl 3-(((methylsulfonyl)oxy)methyl)azetidine-l-carboxylate. Benzyl 3-hydroxymethylazetidine-l-carboxylate (1.0 g, 4.52 mmol, 1.0 eq) and TEA (2.5 mL, 18 mmol, 4.0 eq) were dissolved in DCM (5 mL). The reaction was cooled to 0 °C and MsCl (388 mg, 3.39 mmol, 0.75 eq) was added dropwise. The reaction was allowed to stir for 2 h. The reaction was extracted with DCM, washed with H2O, dried over MgSO4, filtered, and concentrated to afford the title compound. LCMS (ESI) Method 1: RT = 1.403 min, m / z = 300.1 (M+H)+.

[0479] Step B: Benzyl 3-((cyclopropyl(methyl)amino)methyl)azetidine-l-carboxylate.Benzyl 3-(((methylsulfonyl)oxy)methyl)azetidine-l-carboxylate (200 mg, 0.66 mmol, 1.0 eq) and A-methylcyclopropanamine hydrochloride (86 mg, 0.80 mmol, 1.2 eq) were dissolved in EtOH (2 mL). The reaction was irradiated at 120 °C for 1 h. The reaction was concentrated and the crude residue was purified by flash column chromatography to afford the title compound (55 mg, 30% yield).

[0480] Step C: 7V-(Azetidin-3-ylinethyl)-JV-methylcyclopropanamine. Benzyl 3-((cyclopropyl(methyl)amino)methyl)azetidine-l -carboxylate (55 mg, 0.20 mmol, 1.0 eq) was dissolved in DCM (2 mL) and MeOH (2 mL). The reaction was then charged with Pd / C (10% wt., 21 mg, 0.02 mmol, 0.1 eq) and Pd(OH)2 / C (20% wt., 14 mg, 0.1 eq). The reaction was flushed with argon, then H2. The reaction was stirred under at atmosphere of H2 at room temperature for 1.5 h, after which time the reaction was determined to be complete by LCMS. The reaction mixture was diluted with MeOH and filtered through a plug of Celite®, which was then rinsed with DCM / MeOH. The filtrate was concentrated to afford the title compound (25 mg, 89% yield), which was used without further purification. LCMS (ESI) Method 1: RT = 0.144 min, m / z = 141.3 (M+H)+.

[0481] Step D: (26345fl,l722 / ?fl,247?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-12-(3-((cyclopropyl(methyl)amino)methyl)azetidine-l-carbonyl)-l4,l^-dimethoxy-24,34-dimethyl-24,22,2^,24-tetrahydro-l4 / f,34 / f-5-oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-24-one. The title compound (25 mg, 43% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol) and A-(azeti din-3 -ylmethyl)-A-methylcy cl opropanamine (8.8 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.012 min, m / z =(M+H)+.Example 134(26345fl,l722?a,2^?)-2^-Chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,31-dimethyl-12-(3-(4-(pyrrolidin-l-yl)piperidin-l-yl)azetidine-l-carbonyl)- 2* ^^ J-tetrahydro-l l / / .3l / / -5-oxa-2(2.6)-pyrazino| l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0482] Step A: Benzyl 3-(4-(pyrrolidin-l-yl)piperidin-l-yl)azetidine-l-carboxylate. In a microwave vial, benzyl 3 -(tosyloxy )azetidine-l -carboxylate (200 mg, 0.55 mmol, 1.0 eq), 4-(l-pyrrolidinyl)-piperidine (85 mg, 0.55 mmol, 1.0 eq), and DIPEA (0.385 mb, 2.21 mmol, 4.0 eq) were dissolved in MeCN (2 mL). The reaction was irradiated in a microwave for 130 °C for 1 h. The reaction was concentrated and the crude residue was purified by flash column chromatography to afford the title compound (95 mg, 51% yield). LCMS (ESI) Method 1: RT = 0.980 min, m / z = 344.2 (M+H)+.

[0483] Step B: l-(azetidin-3-yl)-4-(pyrrolidin-l-yl)piperidine. In a scintillation vial, benzyl 3 -(4-(pyrrolidin-l-yl)piperi din- l-yl)azeti dine- 1 -carboxylate (95 mg, 0.28 mmol, 1.0 eq) was dissolved in DCM (2 mL) and MeOH (2 mL). The reaction was then charged with Pd / C (10% wt., 29 mg, 0.028 mmol, 0.1 eq) and Pd(OH)2 / C (20% wt., 20 mg, 0.1 eq). The reaction was flushed with argon, then H2. The reaction was stirred under an atmosphere of H2 at room temperature for 1.5 h, after which time the reaction was determined to be complete by LCMS. The reaction mixture was diluted with MeOH and filtered through a plug of Celite®. The filtrate was concentrated to afford the title compound. LCMS (ESI) Method 1: RT = 0.142 min, m z = 210.3 (M+H)+.

[0484] Step C: (26345fl,l722?fl,24T?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,15-dimethoxy-24,31-dimethyl-12-(3-(4-(pyrrolidin-l-yljpiperidin- 1-yl [azetidine- l-caibonyl)-21.22.2^.24-tetrahydro-l * / / .3' / / -5-ox;i-2(2.6)-pyrazino[l,2-a]indoIa-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The title compound (13 mg, 21% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and l-(azetidin-3-yl)-4-(pyrrolidin-l-yl)piperidine (13 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.803 min, m / z = 991.0 (M+H)+.Example 135(2^345a,l72^7?fl,24l?)-27-Chloro-24®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-24,3^-dimethyl-12-(3-(4-(pyridin-4-ylmethyl)piperazin-l-yl)azetidine-l- carbonyl)-21,22,23,24-tetrahydro-l4JT,34^ / -5-oxa-2(2,6)-pyrazino[ l,2-a]indola-l(7,l )- indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0485] Step A: Benzyl 3-(4-(pyridin-4-ylmethyl)piperazin-l-yl)azetidine-l-carboxylate.In a scintillation vial, l-Cbz-azetidin-3-one (100 mg, 0.49 mmol, 1.0 eq) and l-(pyridin-4-ylmethyl)piperazine (95 mg, 0.54 mmol, 1.1 eq) were dissolved in DCE (5 mL). The reaction was allowed to stir at RT for 4 h, followed by addition of NaBH(OAc)3 (207 mg, 0.975 mmol, 2.0 eq). The reaction was allowed to stir for 18 h at RT. The reaction was filtered through a pad of Celite® and concentrated. The crude residue was purified by flash column chromatography to afford the title compound (126 mg, 71% yield). LCMS (ESI) Method 1: RT = 0.808 min, 0.956 min, m / z = 367.2 (M+H)+.

[0486] Step B: l-(Azetidin-3-yl)-4-(pyridin-4-ylmethyl)piperazine. In a scintillation vial, benzyl 3 -(4-(pyridin-4-ylmethyl)piperazin-l-yl)azeti dine- 1 -carboxylate (126 mg, 0.37 mmol, 1.0 eq) was dissolved in DCM (2 mb) and MeOH (2 mL). The reaction was then charged with Pd / C (10% wt., 39 mg, 0.037 mmol, 0.1 eq) and Pd(OH)2 / C (20% wt., 26 mg, 0.037 mmol, 0.1 eq). The reaction was flushed with argon, then Hz. The reaction was stirred under an atmosphere of H2 at RT for 1.5 h, after which time the reaction was determined to be complete by LCMS. The reaction mixture was diluted with MeOH and filtered through a plug of Celite®, which was then rinsed with DCM / MeOH. The filtrate was concentrated to afford the title compound, which was used without further purification. LCMS (ESI) Method 1: RT = 0.139 min, m.'z = 233.2 (M+H)+.

[0487] Step C: (26345„,l722 / ?fl,24 / ?)-27-Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,34-dimethyl-l2-(3-(4-(pyridin-4-ylinethyl)piperazin-l -yl)azetidine-l-carbonyl)-2 '.22,23.24-letrahydi o-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 (42 mg, 66% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and l-(azeti din-3 -yl)-4-(pyridin-4-ylmethyl)piperazine (15 mg, 0.062 pmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.710 min, m / z = 1014.0 (M+H)+.Example 136tert-Butyl l-((2634S'„.l722 / ?„.24 / ?)-27-chloro-2l0-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,34-dimethyl-24-oxo- 2X,22,23,24- tetrahydro-1 ' / / ,3' / / -5-oxa-2(2.6)-pyrazino|L2-i / |indola-l(7.1 )-indola-3(4,3)- pyrazolacyclooctaphane-l2-carbonyl)-l,7-diazaspiro [3.5]nonane-7-carboxylate

[0488] The title compound (87 mg, 67% yield) was prepared following General Procedure J using Example 1 (100 mg, 0.12 mmol, 1.0 eq) and / c / 'Z-butyl l,7-diazaspiro[3.5]nonane-7-carboxylate (35 mg, 0.16 mmol, 1.25 eq). The crude residue was purified by flash column chromatography eluting with 0 to 100% EtOAc / MeOH (95:5) in hexanes. LCMS (ESI) Method 2: RT = 1.797 min, m.'z = 908.1 (M+H-Boc)+.Example 136A(263 5a,l722lffl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,l^- dimethoxy-2^,3^-dimethyl-12-(l,7-diazaspiro[3.5]nonane-l-carbonyl)-21,22,2^,2^- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyr:iz.ino| 1.2-i / |indola-l (7.1 )-indola-3(4,3)- pyrazolacydooctaphan-21-one

[0489] Example 136 (87 mg, 0.09 mmol) was dissolved in DCM (1.5 mL) at 0 °C followed by addition of TFA (0.2 mL, 2.6 mmol). The reaction was allowed to stir for 15 min, then warmed to RT and stirred for 3 h. The reaction was concentrated and purified by flash column chromatography eluting with 0 to 10% MeOH in DCM (1% NH4OH) to afford the title compound (70 mg, 90% yield). LCMS (ESI) Method 1: RT = 1.829 min, 1.995 min (2 amide rotamers observed), m 'z = 908.0 (M+H)+.Example 137(263 5fl,l722l?«,24l?)-27-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-2,3 -dimethyl-12-(3-((methyl(oxetan-3-yl)ainino)methyl)azetidine-l- carbonyl)-21,2^,2^,24-tetrahydro-l ' / / .3' / / -5-ox:i-2(2.6)-pyr:izino| 1.2-( / |indola-l(7.1 )- indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0490] Step A: Benzyl 3-((methyl(oxetan-3-yl)amino)methyl)azetidine-l-carboxylate.In a microwave vial, benzyl 3-(((methylsulfonyl)oxy)methyl)azetidine-l -carboxylate (200 mg, 0.67 mmol, 1.0 eq), bis(A-methyloxetan-3- amine) hemioxalate (106 mg, 0.40, 0.6 eq), and DIPEA (0.47 mL, 2.67 mmol, 4.0 eq) were dissolved in MeCN (2 mL). The reaction was irradiated in a microwave at 130 °C for 1 h. The reaction mixture was concentrated and the crude residue was purified by flash column chromatography to afford the title compound (26 mg, 13% yield). LCMS Method 1: RT = 1.063 min, m / z = 291.1 (M+H)+.

[0491] Step B: A-(Azetidin-3-ylmethyl)-7V-methyloxetan-3-amine. In a scintillation vial, benzyl 3 -((methyl(oxetan-3-yl)amino)methyl)azetidine-l -carboxylate (26 mg, 0.09 mmol, 1.0 eq) was dissolved in DCM (2 mL) and MeOH (2 mL), followed by addition of Pd / C (10% wt., 9 mg, 0.009 mmol, 0.1 eq) and Pd(OH)2 / C (20% wt., 6 mg, 0.009 mmol, 0.1 eq). The reaction was flushed with argon, then EE. The reaction was stirred under at atmosphere of H2 at RT for 1.5 h. The reaction mixture was diluted with MeOH and filtered through a plug of Celite®. The filtrate was concentrated to afford the title compound (14 mg, quantitative yield). LCMS (ESI) Method 1: RT = 0.141 min, m / z = 157.2 (M+H)+.

[0492] StepChloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,34-dimethyl-l^-(3-((methyl(oxetan-3-yl)amino)methyl)azetidine-l-carbonyl)-2,2^,2^,2^-tetrahydro-l H,3^ / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one. The title compound (51 mg, 87% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and? / -(azetidin-3-ylmethyl)-jV-methyloxetan-3-amine (9.8 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.963 min, m / z = 937.9 (M+H)+.Example 138(2^3^5a,1^2^7?fl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3 ^-dimethyl- 1 ^-(5-methyl-2, 5-diazabicyclo[2.2.1 ]heptane-2-carbonyl)- 21,2^,2^,2^-tetr ahydro-1 ^H,3 lfT-5-oxa-2(2,6)-py razino [ 1,2-a] indola- l(7,l)-indo!a-3(4,3)- pyrazolacyclooctaphan-21-one

[0493] The title compound (46 mg, 82% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and (17?,4 / ?)-2-methyl-2,5-di azabi cyclo [2.2.1] heptane dihydrochloride (12 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: Rr = 0.897 min, m / z = 894.0 (M+H)+.Example 139(26345«J722l?fl,241?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1 -(3- (cyclopropyl(methyl) amino)pyrrolidine-l-carbonyl)-l4,l3-dimethoxy-24,34-dimethyl- 21,22,23,24-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino| l,2-«]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0494] The title compound (47 mg, 82% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and V-cyclopropyl-jV-methylpyrrolidin-3-amine (8.8 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.997 min, m / z = 922.0 (M+H)+.Example 140tert-Butyl 2-((26345„,l722^fl,24 / ?)-27-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4,15-dimethoxy-24,34-dimethyl-21-oxo- 2X,22,23,24- tetrahydro-1 ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1.2-n|indola-l (7.1 )-indola-3(4.3)- pyrazolacyclooctaphane-l2-carbonyl)-2,6-diazaspiro [3.4]octane-6-carboxylate

[0495] The title compound (100 mg, 47% yield) was prepared following General Procedure J using Example 1 (170 mg, 0.21 mmol, 1.0 eq) and / c / 7-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (55 mg, 0.258 mmol, 1.2 eq). The crude residue was purified by flash column chromatography eluting with 0 to 10% MeOH in DCM. LCMS Method 2: RT = 1.13 min, m / z = 994.5 (M+H)+.Example 140A(26345«,l7227fa,24?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,15- dimethoxy-24,31-dimethyl-12-(6-methyl-2,6-diazaspiro[3.4]octane-2-carbonyl)- 21,2^,2^,2^-tetrahydro-ll / f, 31 / f-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0496] Example 140 (100 mg, 0.10 mmol) was dissolved in DCM (5 mL) and TFA (0.2 mL). The reaction was stirred until complete by LCMS, then concentrated. The residue was taken up in MeOH (2 mL), acetic acid (2 drops) was added followed by addition of formaldehyde (0.04 mL, 37% wt. in water, 5.0 eq), and the reaction was allowed to stir at RT for 5 min. Sodium cyanoborohydride (30 mg, 0.52 mmol, 5.0 eq) was added and the reaction was allowed to stir at RT for 45 min. The crude reaction was extracted with EtOAc, washed with H2O, 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 (60 mg, 70% yield). LCMS (ESI) Method 2: RT = 0.80 min, m / z = 909.4 (M+H)+.(26345fl,l722?a,2^7?)-2^-Chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2,31-dimethyl-12-(7-methyl-l,7-diazaspiro[3.5]nonane-l-carbonyl)- 21,22,23,24-tetrahydro-ll / , 31 / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0497] Example 136A (32 mg, 0.034 mmol, 1.0 eq) was dissolved in MeOH (2 mL). Acetic acid (2 drops) and formaldehyde (0.05 mL, 37% wt. in water, 0.6 mmol) were added, and the reaction was stirred at RT for 5 min. Sodium cyanoborohydride (11 mg, 0.17 mmol, 5.0 eq) was added and the reaction was stirred at RT for 45 min. The crude reaction was extracted with EtOAc, washed with H2O, dried over MgSC, filtered, and concentrated. The crude product was purified by reverse phase HPLC eluting with MeCN / H2O and 0.1% TFA as mobile phase to afford the desired product. After concentration, the residue was dissolved in EtOAc and washed with sat. aq. NaHCOa. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (20 mg, 64% yield). LCMS (ESI) Method 1: RT = 1.791 min, m / z = 922.0 (M+H)+.Example 142(26345«,l7227?«,2^T?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-24,3 -dimethyl-12-(3-morpholinopyrrolidine-l-carbonyl)-21, 22,2^,24- lelrahydro-1 ' / / .3l / / -5-oxa-2(2.6)-pyrazino|1.2-u|indola-l(7.1 )-indola-3(4.3)- pyrazolacyclooctaphan-21-one

[0498] The title compound (50 mg, 85% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 4-(pyrrolidin-3-yl)morpholinehydrochloride (12 mg, 0.062 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 0.979 min, m / z = 938.0 (M+H)+.Example 143(26345fl,l722?«,24?)-27-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4,l^- dimethoxy-24,34-dimethyl-l2-((15,45)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2- carbonyl)-2'.22.23.24-tetrahydro-l l / / .31 / / -5-oxa-2(2.6)-pyrazino| l,2-a]indola-l(7,l )- indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0499] The title compound (43 mg, 77% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and (15,4S)-2-methyl-2,5-di azabi cyclo [2.2.1] heptane dihydrobromide (17 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 0.967 min, m / z = 894.0 (M+H)+.Example 144terf-Butyl 2-((26345„,l722l?(Z,24l?)-27-chloro-210-(3-(4-chloro-3,5- dimethylphenoxy)propyl)-l4,l^-dimethoxy-24,34-dimethyl-24-oxo- 2X,22,23,24-tetrahvdro-l ' / / .3' / / -5-oxa-2(2.6)-pvrazino [l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphane-l^-carbonyl)-5-oxa-2,8-diaza- spiro[3.5]nonane-8-carboxylate

[0500] The title compound (190 mg, quant, yield) was prepared following General Procedure J using Example 1 (150 mg, 0.19 mmol, 1.0 eq) and Zc / 7-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate (64 mg, 0.28 mmol, 1.5 eq). The crude product was purified by flash column chromatography eluting with 0 to 60% EtOAc / MeOH (95:5) in hexanes. LCMS Method 2: RT = 1.709 min, m / z = 1009.9 (M+H)+.Example 144A(26345a,l722?«,2^?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,31-dimethyl-l^-(5-oxa-2,8-diazaspiro[3.5]nonane-2-carbonyl)-21,22,2^,2^- tetrahydro-ll / , 31 / / -5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0501] Example 144 (190 mg, 0.19 mmol) was dissolved in DCM (2 mL) at room temperature, followed by addition of HC1 (4.0 M in dioxane, 0.5 mL, 2.0 mmol). The reaction was allowed to stir for 2 h, followed by concentration from DCM / MeOH to afford the title compound (166 mg, 93% yield) as the HC1 salt. LCMS (ESI) Method 1: Rr = 2.034 min, m / z = 910.0 (M+H)+.Example 145(26345a,l722l?<z,24ft)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1 -(8- ethyl-5-oxa-2,8-diazaspiro[3.5]nonane-2-carbonyl)-l^,l^-dimethoxy-2^,34-dimethyl- 21,22,2^,2^-tetrahydro-ll / f,34^-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacydooctaphan-21-one

[0502] The HC1 salt of Example 145 (78 mg, 0.082 mmol, 1.0 eq) was dissolved in MeOH (1.5 mL) and acetaldehyde (0.050 mL, 0.80 mmol) was added at RT. The reaction was allowed to stir for 15 min, followed by addition of sodium cyanoborohydride (26 mg, 0.41 mmol, 5.0 eq). The reaction was allowed to stir for 30 min then extracted with EtOAc, washed with H2O, dried over MgSCh, filtered, and concentrated. The crude product was purified by reverse phase HPLC eluting with MeCN / H2O and 0.1% TFA as mobile phase to afford the desired product (45 mg, 58% yield). LCMS (ESI) Method 1: RT = 2.119 min, m z = 938.0 (M+H)+.Example 146(26345fl,l722?a,2^7?)-2^-Chloro-21^-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2,31-dimethyl-12-(8-methyl-5-oxa-2,8-diazaspiro[3.5]nonane-2-carbonyl)- 2 L22.2^.2^-tetrahydro-H / / .3 l / / -5-oxa-2(2.6)-pyiazino| l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0503] The HC1 salt of Example 145 (78 mg, 0.082 mmol, 1.0 eq) was dissolved in MeOH (1.5 mL) and formaldehyde (0.050 mL, 37% wt. in water, 0.60 mmol) was added at RT. The reaction was allowed to stir for 15 min, followed by addition of sodium cyanoborohydride (26 mg, 0.41 mmol, 5.0 eq). The reaction was allowed to stir for 30 min then extracted with EtOAc, washed with H2O, dried over MgSCh, filtered, and concentrated. The crude product was purified by reverse phase HPLC afford the desired product. After concentration, the residue was dissolved in EtOAc and washed with sat. aq. NaHCOs. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound (52 mg, 68% yield).LCMS (ESI) Method 1: RT = 2.086 min, m / z = 924.0 (M+H)+.Example 147(263^V«,l722l?«,2^1?)-27-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-l^-((5)-4-oxooctahydropyrazino[2,l-c][l,4]oxazine-8- carbonyl)-21,22,2^,2^-tetrahydro-l ' / / .3' / / -5-ox:i-2(2.6)-pyr:izino| 1.2-( / |indola-l(7.1 )- indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0504] The title compound (49 mg, 84% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and (5)-hexahydropyrazino[2,l-c][l,4]oxazin-4(3 / / )-one hydrochloride (12 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.346 min, m / z = 937.9 (M+H)+.Example 148(2^3^5a,l7227?fl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-12-((H?,6ky)-3-methyl-3,8-diazabicyclo[4.2.0]octane-8- carbonyl)-21,22,13,24-tetr ahydr o-l lj / ,3 ^ / -5-oxa-2(2,6)-pyrazino [1,2-a] indola-1 (7,1)- indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0505] The title compound (30 mg, 53% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and (l / ?,65)-3-methyl-3,8-diazabicyclo[4.2.0]octane hydrochloride (10 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.070 min, m / z = 908.1 (M+H)+Example 149(263 5„,l722l?«,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-14,l^- dimethoxy-24,31-dimethyl-l^-((15,6?)-8-methyI-3,8-diazabicyclo[4.2.0]octane-3-carbonyl)-2¹,2²,2³,2⁴-tetrahydro-1¹H,3¹H-5-oxa-2(2,6)-pyrazino[1,2-a]indola-1(7,1)-indola-3(4,3)-pyrazolacyclooctaphan-2¹-one

[0506] The title compound (36 mg, 63% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and (15,6 / )-8-methyl-3,8-diazabicyclo[4.2.0]octane hydrochloride (10 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.016 min, m / z = 908.0 (M+H)+Example 150(26345«,l722 / ?fl,2^T?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,3^-dimethyl-l^-(3-methyl-3,6-diazabicyclo[3.2.0]heptane-6-carbonyl)- 21,22,2^,2^-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6)-pyrazino| 1.2-( / |indola-l(7.1 )-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0507] The title compound (11 mg, 20% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and 3-methyl-3,6-diazabicyclo[3.2.0]heptane bis(2,2,2-trifluoroacetate) (21 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.106 min, m / z = 894.0 (M+H)+.Example 151(2^3^5a,1^2^7?fl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^,l^- dimethoxy-2^,31-dimethyl-l^-((65,91?,9a5)-octahydro-2J / -6,9-methanopyrido[l,2- ff]pyrazine-2-carbonyl)-2,2^,2^,2^-tetrahydro-l / / .3' / / -5-oxa-2(2.6)-pyiazino| 1,2- tf]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan-21-one

[0508] The title compound (51 mg, 87% yield) was prepared following General Procedure J using Example 1 (50 mg, 0.062 mmol, 1.0 eq.) and (6S,9R,9aS)-octahydro-2H-6,9-methanopyrido[1,2-a]pyrazine dihydrochloride (14 mg, 0.062 mmol, 1.0 eq.). LCMS (ESI) Method 2: RT = 1.139 min, m / z = 934.0 (M+H)+.Example 152(2f>3^. S„. l72" / ?„.2^ / ?)-2^-( hloro-2*®-(3-(4-chloro-3.5-dimethylphenoxy)piopyl)-V. H. - trimethoxy-V, 2^,31 -trimethyl-21-oxo-21,2^,2, 2 -tetrahydro- 11 / / ,3 l -5-oxa-2(2, 6)- pyrazino[l,2-a]indola-l(7,l)-indoIa-3(4,3)-pyrazolacyclooctaphane-l^-carboxamide

[0509] The title compound (126 mg, 80% yield) was prepared following General Procedure J using Example 1 (150 mg, 0.19 mmol, 1.0 eq.) and N,O-dimethylhydroxylaminehydrochloride (22 mg, 0.22 mmol, 1.2 eq ). The crude product was purified by flash column chromatography eluting with 0 to 70% EtOAc / MeOH (95:5) in hexanes. LCMS (ESI) Method 2: RT = 1.581 min, m / z = 843.0 (M+H)+.Example 153(26345a,l722?«,24 / ?)-27-Chloro-21 -(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1,1 - dimethoxy-2^,31-dimethyl-l^-(3-(2-morpholinoethoxy)azetidine-l-carbonyl)-21,2^,2^,2^- tetrahydro-ll / , 31 / / -5-oxa-2(2,6)-pyrazino[l,2-o]indola-l(7,l)-mdola-3(4,3)- pyrazolacyclooctaphan-21-one

[0510] Example 59 (50 mg, 0.058 mmol, 1.0 eq.) was dissolved in DMF (5 mL) to which was added sodium hydride (1.9 mg, 90% Wt, 0.070 mmol, 1.2 eq.) at 0 °C. After the mixture was stirred for 20 min, 4-(2-bromoethyl)morpholine hydrobromide (19 mg, 0.070 mmol, 1.2 eq.) was added. The reaction mixture stirred for 18 h at RT. The reaction was quenched with H2O, extracted with CHCh, dried over Na2SO4, filtered, and concentratred. The crude product was purified by reverse phase HPLC to afford the desired product (37 mg, 65%). LCMS (ESI) Method 2: RT = 0.947 min, m / z = 968.1 (M+H)+.Example 154Methyl (26345fl,l722J?fl,2^T?)-2^-chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^- methoxy- 1,1,3 -trimethyl-2 l-oxo-21,2^,2, l^-tetrahydr o-l l / ,3 l / 7-5-oxa-2(2, 6)- pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacydooctaphane-l2-carboxylate

[0511] Step A: Methyl ( / ?)-7-(6-(3-((3-(benzyloxy)propoxy)methyl)-l-methyl-l / T-pyrazol-4-yl)-7-chIoro-10-(3-(4-chloro-3,5-dimethyIphenoxy)propyl)-4-methyl-l-oxo-3,4-dihydropyrazino [ l,2-«]indol-2( 1 / / )-y 1 )-5-m et hoxy-4-methyl-l / / -indole-2-car boxy late. The title compound (311 mg, 80% yield) was prepared following General Procedure F using Intermediate 3 (300 mg, 0.43 mmol, 1.0 eq) and Intermediate 20 (136 mg, 0.46 mmol, 1.05 eq). The crude residue was purified by flash column chromatography eluting with 0 to 80% EtOAc in hexanes. LCMS (ESI) Method 2: RT = 1.762 min, m / z = 906.3 (M+H)+.

[0512] Step B: Methyl (l?)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-6-(3-((3-hydroxypropoxy)methyl)-l-methyl-l / 7-pyrazol-4-yl)-4-methyl-l-oxo-3,4-dihydropyrazino [l,2-«]indol-2(177)-yl)-5-methoxy-4-methyl-17 / -indole-2-carboxylate. The title compound (280 mg, quant, yield) was prepared following General Procedure D using the product from Step A (310 mg, 0.34 mmol, 1.0 eq). LCMS (ESI) Method 2: RT = 1.479 min, 1.528 min (mixture of rotamers), m / z = 816.3 (M+H)+.

[0513] Step C. Methyl (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(TH)-yl)-5-methoxy-4-methyl-l / / -indole-2-carboxylate. (General Procedure K). The product from Step B (280 mg, 0.33 mmol, 1.0 eq) was added to a reaction vessel and dissolved in DCM (10 mL). Tosyl chloride (250 mg, 1.32 mmol, 4 eq), TEA (0.290 mL, 2.01 mmol, 6 eq), and DMAP (40 mg, 0.33 mmol, 1 eq) were added, and the reaction was allowed to stir at 30 °C for 24 h. The reaction mixture extracted with DCM, washed with water, IM HC1, brine, dried over MgSO4, filtered, and concentrated. The crude reaction mixture was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes to afford the desired product (255 mg, 68% yield). LCMS Method 2: RT = 1.666 min, m / z = 970.1 (M+H)+.

[0514] Step D: Methyl (26345fl,l722 / ?fl,24 / ?)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1 -methoxy-14,24,3 -trimethyl-21-oxo- 21,22,2^,24-tetrahydro- 7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxylate. The title compound (138 mg, 75% yield) was prepared following General Procedure H using the product from Step C (225 mg, 0.23 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 = 1.768 min, m / z = 798.2 (M+H)+.Example 155(26345«,l722?a,2^7?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^- methoxy- 14,24,31-trimethyl-2 i-oxo-21,22,23,24-tetr ahydr o-l1 / / -5-oxa-2( 2.6 )- pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxylic acid

[0515] The title compound (60 mg, 48% yield) was prepared following General Procedure I using Example 154 (128 mg, 0.16 mmol, 1.0 eq). LCMS (ESI) Method 1: RT = 2.327 min, m / z = 784.2 (M+H)+.-dimethylphenoxy)propyl)-15- methoxy- 14,24,3 l-trimethyl-2 l-oxo-21,22,23,24-tetr ahydr o-l ^H,3 l / 7-5-oxa-2(2,6)- pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxamide

[0516] The title compound (60 mg, 79% yield) was prepared following General Procedure J using Example 155 (76 mg, 0.10 mmol) and NEUCl (16 mg, 0.29 mmol, 3.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 100% EtOAc / MeOH (95:5) in hexanes. LCMS (ESI) Method 1: RT = 2.320 min, m / z = 783.2 (M+H)+.Example 157ne- l^-carboxamide[00517J The title compound (45 mg, 98% yield) was prepared following General Procedure J using Example 155 (40 mg, 0.051 mmol) and 2-(4-morpholinyl)ethanamine (13 mg, 0.10 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.163 min, m / z = 898.0 (M+H)+.Example 158(26345«,l722 / ?fl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15- methoxy-1^, 2^, 31-trimethyl-12-(4-methylpiperazine-l-carbonyl)-21, 2^,2^, 2^-tetrahydro- 1 ' / / 177-5 -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan- 21-one

[0518] The title compound (65 mg, 80% yield) was prepared following General Procedure J using Example 155 (73 mg, 0.10 mmol) and A-methylpiperazine (19 mg, 0.19 mmol, 2.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 5% MeOH in DCM with 1% NH4OH. LCMS (ESI) Method 1: RT = 2.065 min, m / z = 866.0 (M+H)+.Example 159(26345fl,l722?( / ,2^?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15- methoxy-l^,2^,3^-trimethyl-l^-((5)-octahydropyrazino[2,l-c][l,4]oxazine-8-carbonyl)- 21,2^,2^,2^-tetrahydro - 11 / 7,3 l / / -5-oxa-2(2,6)-pyrazino [1,2-a] indola- 1 (7, l)-indola-3(4,3)- pyrazolacyclooctaphan-21-one

[0519] The title compound (29 mg, 63% yield) was prepared following General Procedure J using Example 155 (40 mg, 0.05 mmol, 1.0 eq) and (S)-octahydropyrazino[2,l-c][l,4]oxazine (22 mg, 0.10 mmol, 2.0 eq). The crude product was purified by flash column chromatography eluting with 0 to 5% MeOH in DCM with 1% NH4OH. LCMS (ESI) Method 1: RT = 2.082 min, m / z = 908.0 (M+H).Example 160(26345fl,l7227?fl,241?)-2 -Chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-15-methoxy-7V,2V,l,1,31 -pentamethyl-2 l-oxo-21,2^,2^,14-tetrahydro- 1 ^H,3 ^H-5-oxa-2(2,6)- pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carboxamide

[0520] The title compound (158 mg, 76% yield) was prepared following General Procedure J using Example 155 (200 mg, 0.255 mmol) and dimethylamine hydrochloride (41.6 mg, 0.510 mmol, 2.0 eq). LCMS (ESI) Method 2: RT = 1.703 min, m / z = 811.0 (M+H)+.1HNMR (400 MHz, DMSO) 88.03 (s, 1H), 7.76 (d, J= 8.6 Hz, 1H), 7.29 (d, J= 8.4 Hz, 1H), 6.93 (s, 1H), 6.79 (s, 1H), 6.68 (s, 2H), 4.46 (dd, J= 12.3, 5.9 Hz, 1H), 4.09 (dd, J= 16.5, 8.5 Hz, 2H), 3.97 (s, 3H), 3.91 (t, J= 6.6 Hz, 2H), 3.82 (s, 3H), 3.58 (dd, J= 17.1, 11.1 Hz, 2H), 3.48 - 3.40 (m, 1H), 3.30 (s, 1H), 3.28 - 3.20 (m, 2H), 3.12 - 2.87 (m, 8H), 2.34 (s, 3H), 2.24 (s, 6H), 2.02 (t, J = 7.1 Hz, 2H), 1.80 - 1.67 (m, 1H), 1.63 - 1.50 (m, 1H), 1.08 (d, J= 6.6 Hz, 3H).Example 161(2^3^a, 1^2^Ra, 2^7?)-21®-(3-(3,5-Dimethylphenoxy)propyl)-l^-methoxy-l^,2^,3^- trimethyl-12-(4-methylpiperazine-l-carbonyl)-21,22,23,2 -tetrahydro-llH,31Z7-5-oxa- 2(2,6)-pyrazino[l,2-tf]indola-l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphan-21-one

[0521] The title compound (40 mg, 43% yield) was prepared following General Procedure D using Example 158 (100 mg, 0.12 mmol, 1.0 eq) and allowing the reaction to stir at 50 °C for 16 h. The crude product was purified by reverse phase HPLC afford the desired product. LCMS (ESI) Method 1: RT = 1.879 min, m / z = 798.0 (M+H)+.Example 162(2f>3^ / ?„.1 2‘ / ?,„2^ / ?)-2 l**-(3-(3.5-l)iinethylphenoxy)propyl)-P-methoxy-V, V. l"*.2^,3l- pentamethyl-21-oxo- 21,2^,2^,2^-tetrahydro-l ^H,3 ^H-5 -oxa-2(2,6)-pyrazino[l,2-«]indola- l(7,l)-indola-3(4,3)-pyi'azolacyclooctaphane-l^-carboxamide

[0522] Example 160 (100 mg, 0.123 mmol, 1.0 eq.) was stirred in MeOH (10 mL) / DCM (10 mb) at rt, followed by addition of palladium on carbon (79 mg, 10 wt %, 0.010 mmol, 0.6 eq.) and dihydroxypalladium (87 mg, 20% Wt, 0.16 mmol, 1.0 eq.) under argon. The flask was purged with vacuum and backfilled with argon (3x), then vacuum and backfilled with H2 gas (3x). The reaction was then stirred vigorously under H2 gas at 1 atm at rt for 24 h. The reaction was filtered through Celite® and concentrated. The crude product was purified by reverse phase HPLC to afford the desired product (16 mg, 17 %). LCMS (ESI) Method 2: RT = 1.366 min, m / z = 743.1 (M+H)+.Example 163(2634l?fl,l722l?fl,2^1?)-21®-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-l^-methoxy-l^,2^,31- trimethyl- / V-(2-morpholinoethyl)-2*-oxo- 21,2^,2^,2^-tetrahydr o-l ^H,3 l / / -5-oxa-2(2,6)- pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carboxamide

[0523] The title compound (9 mg, 40% yield) was prepared following General Procedure J using Example 239 (20 mg, 0.027 mmol) and then 2-(4-morpholinyl)ethanamine (6.9 mg, 7.0 pL, 0.053 mmol, 2.0 eq). The crude product was purified by reverse phase HPLC using a Phenomenex Gemini column eluting with MeCN / H2O and 0.1% TFA as mobile phase to afford the desired product. After concentration, the residue was dissolved in EtOAc and washed with sat. aq. NaHCCh. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound. LCMS (ESI) Method 2: RT = 1.034 min, m / z = 862.0 (M+H)+.Example 164(2^3^7?«,1722 / ?fl,2^ / ?)-210-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)-l ^-methoxy- 1, 2^,31 - trimethyl-12-(4-methylpiperazine-l-carbonyl)-21,22,23,2 -tetrahydro-l lH,31 / 7-5-oxa- 2(2,6)-pyrazino[l,2-tf]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphan-21-one

[0524] The title compound (27 mg, 70% yield) was prepared following General Procedure H using Example 239 (35 mg, 0.047 mmol, 1.0 eq.) and 1 -methylpiperazine (9.3 mg, 0.093 mmol, 2.0 eq.). LCMS (ESI) Method 2: RT = 0.996 min, m / z = 832.0 (M+H)+. ' H NMR (400 MHz, DMSO) 87.95 (s, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.10 - 7.03 (m, 1H), 6.95 (s, 1H), 6.75 (s, 1H), 6.70 (s, 2H), 4.51 (dd, J= 12.2, 6.0 Hz, 1H), 4.38 - 4.30 (m, 1H), 4.17 - 4.04 (m, 2H), 4.03 - 3.87 (m, 7H), 3.82 (s, 3H), 3.61 (d, J= 10.6 Hz, 3H), 3.50 (s, 2H), 3.32 - 3.23 (m, 4H), 2.96 (t, J= 10.2 Hz, 1H), 2.34 (s, 3H), 2.23 (s, 6H), 2.20 (s, 2H), 2.04 (t, J = 7.0 Hz, 2H), 1.87 - 1.76 (m, 1H), 1.66 - 1.58 (m, 1H), 1.26 (q, J= 6.5 Hz, 4H), 1.03 (d, J= 6.6 Hz, 3H).Example 165(2634l?a,l722l?fl,2^1?)-210-(3-(4-Chloro-3,5-dimethylphenoxy)propyl)- 1 -methoxy- V.\. H.2^.3 l-pentaniethyl-2'-oxo-21.22.2^.2^-tetrahydro-l ' / / .3' / / -5-oxa-2(2.6(- pyrazino[l,2-«]indoIa-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12-carboxamide

[0525] The title compound was isolated from the same reaction conditions as Example 162 (40 mg, 42% yield). LCMS (ESI) Method 2: RT = 1.530 min, m / z = 777.0 (M+H)+. 'H NMR (400 MHz, DMSO) 87.95 (s, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.16 (t, J= 7.5 Hz, 1H), 7.06 (d, J = 1A Hz, 1H), 6.94 (s, 1H), 6.79 (s, 1H), 6.69 (s, 2H), 4.51 (dd, J= 12.5, 6.0 Hz, 1H), 4.34 (t, J = 6.7 Hz, 1H), 4.16 - 3.86 (m, 8H), 3.82 (s, 3H), 3.61 (d, J= 10.9 Hz, 2H), 3.49 -3.44 (m, 1H), 3.27 (t, J = 8.4 Hz, 2H), 3.11 - 2.89 (m, 7H), 2.34 (s, 3H), 2.23 (s, 6H), 2.08 - 2.00 (m, 2H), 1.82 - 1.71 (m, 1H), 1.69 - 1.56 (m, 1H), 1.03 (d, J= 6.6 Hz, 3H).Example 166Ethylchloro-21 ®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)- 1 - hydroxy-l4-methoxy-24,34-dimethyl-21-oxo- 2l.22.2.24-tetrahydro-ll / / ,3l / / -5-oxa- 2(2,6)-pyrazino [l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l2-carboxylate

[0526] Step A: Ethyl 5-(benzyloxy)-7-((41?)-7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(l-methyl-3-((3-((tetrahydro-2 / / -pyran-2-yl)o\y [propoxy )methyl)- 1 / / -pyrazol-4-yl)-l -()x()-3.4-dihvdropyrazino| 1,2-< / |indol-2( 1 / / )-yl)-4-methoxy-l / / -indole-2-carboxylate. The title compound (4.14 g, 56% yield) was prepared following General Procedure F using Intermediate 6 (5.04 g, 7.37 mmol, 1.0 eq) and Intermediate 16 (7.2 g, 16.0 mmol, 2.2 eq), palladium K-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]

[0527] 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-1 -oxo-3, 4-dihydropyrazino[l,2-«|indol-2(l / / )-yl)-4-methoxy-l / / -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 room temperature. Tosic acid monohydrate (250 mg, 1.31 mmol, 0.32 eq) was added, and the reaction was allowed to stir at room temperature for 2 h. The reaction was extracted with EtOAc, washed with FEO, 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]+.

[0528] Step C: Ethyl (fl)-5-(benzyloxy)-7-(7-chloro-10-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-methyl-6-(l-methyl-3-((3-(tosyloxy)propoxy)methyl)-lET-pyrazol-4-yl)-l-oxo-3,4-dihydro pyrazino[l,2-fl]indol-2(lH)-yl)-4-inethoxy-l / / -indole-2-carboxylate. The title compound (1.80 g, 77% yield) was prepared following General Procedure G 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]+.

[0529] Step D: Ethyl (26345fl,l722 / ?fl,24 / ?)-l5-(benzyloxy)-27-chloro-210-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4-methoxy-24,3^-dimethyl-21-oxo- 21, 2^,23, 24-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-l^-carboxylate. The title compound (1.20 g, 79% yield) was prepared following General Procedure H 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]+.Example 166AEthyl (26345'fl, 1722 / ?fl,24l?)-27-chlor o-21 ®-(3-(4-chlor o-3,5-dimethylphenoxy) propyl)-!^- hydroxy-l4-methoxy-24,3l-dimethyl-2*-oxo-2l,22,2^,24-tetrahydro-l* / / ,3* / / -5-oxa- 2(2,6)-pyrazino[l,2-fl]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12-carboxylate

[0530] The title compound (1.05 g, 97% yield) was prepared following General Procedure D using Example 166 (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]+.Example 166BEthyl ( 2^3417227?fl,24l?)-2^-chloro-21 ®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)- 1 methoxy-2,31-dimethyl-21-oxo-15-((tetrahydro-2Zf-pyran-4-yl)methoxy)-21, 2^,23,2 - tetrahydro-1 l / / .3' / / -5-oxa-2(2.6)-pyrazino|1.2-< / |indola-l(7.1 )-indola-3(4.3)- pyrazolacyclooctaphane-l^-carboxylate

[0531] (General Procedure L) Example 166A (250 mg, 0.310 mmol, 1.0 eq.) was dissolved in DMF (5 mL). Cesium carbonate (450 mg, 1.40 mmol, 4.5 eq) was added, followed by (tetrahydro-2 / / -pyran-4-yl)methyl 4-methylbenzenesulfonate (165 mg, 0.62 mmol, 2.0 eq.). The reaction was heated to 80 °C and allowed to stir for 6 h. The reaction was extracted with EtOAc, washed with TEO, brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes. LCMS (ESI) Method 2: RT = 1.917 min, m / z = 912.0 (M+H)+.Example 166C(263 5fl,l722l?fl,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^- methoxy-2,31-dimethyl-21-oxo-1 -((tetrahydro-2 / / -pyran-4-yl)methoxy)-21, 2^,23,24- tetrahydro-ll / / ,3^TT-5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)- pyrazolacyclooctaphane-l^-carboxylic acid

[0532] The title compound (210 mg, 96% yield) was prepared following General Procedure I using Example 166B (226 mg, 0.25 mmol). Aqueous workup furnished the desired product without further purification. LCMS (ESI) Method 2: RT = 1.455 min, m / z = 884.0 (M+H)+.Example 167Ethyl (2634Afl,l722l?n,24l?)-2^-chloro-24®-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-!4- methoxy-l^-(2-methoxyethoxy)-24,3*-dimethyl-2*-oxo-2*,22,2^,24-tetrahydro-l* / / ,3^ / / - 5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyi*azolacyclooctaphane-1 - carboxylate

[0533] The title compound (14 mg, 65% yield) was prepared following General Procedure L using Example 166 (20 mg, 0.025 mmol, 1.0 eq) and 2-bromoethyl methyl ether (10 mg, 0.072 mmol, 3.0 eq). LCMS (ESI) Method 2: RT = 1.816 min, m / z = 871.9 (M+H).Example 167A(26345fl,l722l?fl,24lf)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4- methoxy-l^-(2-methoxyethoxy)-2^,3^-dimethyl-21-oxo-21,2^,2^,2^-tetrahydro-ll / / ,34^- 5-oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane-12- carboxylic acid

[0534] The title compound (12 mg, 89% yield) was prepared following General Procedure T using Example 167 (14 mg, 0.016 mmol). The crude product was purified by reverse phase HPLC. LCMS (ESI) Method 2: RT = 1.352 min, m / z = 843.9 (M+H).Example 168Ethylchloro-21®-(3-(4-chloro-3,5-dimethylphenoxy) propyl)-!4- methoxy-2^,34-dimethyl-l^-(2-morpholinoethoxy)-21-oxo- 21,22,2^,2^-tetrahydro- I ' / ZA' / LS -oxa-2(2,6)-pyrazino[l,2-a]indola-l(7,l)-indola-3(4,3)-pyrazolacyclo octaphane-l^-carboxylate

[0535] The title compound (165 mg, 97% yield) was prepared following General Procedure L using Example 166 (150 mg, 0.184 mmol) and 4-(2-bromoethyl)morpholine hydrobromide (100 mg, 0.363 mmol). Following aqueous workup, the reaction was purified by flash column chromatography eluting with 0 to 10% MeOH in DCM. LCMS (ESI) Method 2: RT = 1.376 min, m / z = 927.0 (M+H).Example 168A(263 5fl,l722?«,2^1f)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l4- methoxy-2,3 -dimethyl-1 -(2-morpholinoethoxy)-21-oxo- 21,2^,2^,2^-tetrahydro--oxa-2(2,6)-pyrazino[l,2-ff]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- l^-carboxylic acid

[0536] The title compound (151 mg, 94% yield) was prepared following General Procedure I using Example 168 (165 mg, 0.18 mmol). LCMS (ESI) Method B: RT = 0.885 min, m / z = 898.9 (M+H).ane- l^-carboxamide

[0537] The title compound (5.6 mg, 92% yield) was prepared following General Procedure J using Example 167A (6 mg, 0.007 mmol, 1.0 eq) and methylamine hydrochloride (1.4 mg, 0.021 mmol, 3.0 eq). Following aqueous workup, the residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes. LCMS (ESI) Method 2: RT = 1.481 min, m / z = 857.2 (M+H).(26345«,l722?a,2^1?)-2^-Chloro-21®-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-l^- methoxy-l^-(2-methoxyethoxy)-f^V,2^,3^-tetramethyl-21-oxo-21,22,2'5,2^-tetrahydro- -oxa-2(2,6)-pyrazino[l,2-«]indola-l(7,l)-indola-3(4,3)-pyrazolacyclooctaphane- l^-carboxamide

[0538] The title compound (6.1 mg, 99% yield) was prepared following General Procedure J using Example 167A (6 mg, 0.007 mmol, 1.0 eq) and dimethylamine hydrochloride (1.7 mg, 0.021 mmol, 3.0 eq). Following aqueous workup, the residue was purified by flash column chromatography eluting with 0 to 100% EtOAc in hexanes. LCMS (ESI) Method 2: RT = 1.528 min, m / z = 871.3 (M+H). 'HNMR (400 MHz, CDC13) 57.66 (d, J= 8.5 Hz, 1H), 7.61 (s, 1H), 7.29 (d, J= 8.5 Hz, 1H), 6.94 (s, 1H), 6.77 (s, 1H), 6.60 (s, 2H), 4.76 (dd, J= 12.4, 5.7 Hz, 1H), 4.29 - 4.15 (m, 5H), 4.07 (d, J= 10.2 Hz, 6H), 3.96 (dt, J= 6.8, 3.3 Hz, 2H), 3.80 -3.70 (m, 3H), 3.60 (dd, J= 9.5, 4.4 Hz, 1H), 3.48 (s, 3H), 3.43 - 3.26 (m, 4H), 3.12 -3.00 (m, 5H), 2.33 (s, 6H), 2.17 (q, J = 7.1 Hz, ...

Claims

CLAIMSWhat 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-3alkylene-G1, -OG1, or–O–Ci-3alkylene–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 independentlyselected 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- to7-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, Czalkylene, Csalkylene, C4alkylene, Csalkylene, Cealkylene, Cvalkylene, Csalkylene, C2alkenylene, C2alkynylene, -O-, -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 -NR2aR2b, -OCi-6alkyl, OH, Ci-ealkyl, or H;R2ais H, Ci-ealkyl, SO2R20, SO2N(R20)2, -C2-3alkylene-Y2, G2, or-Ci-salkylene-G2;R2bis H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3-4cycloalkyl;R3is H, halogen, Ci-4alkyl, C3-4cycloalkyl, C(O)OR3a, or -CH2NR3aR3b;R3ais H or Ci-ealkyl;R3bis H, Ci-ealkyl, -C2-3alkylene-Y3, G3, or-Ci-3alkylene-G3;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, -OR21, -N(R21)2, -NR22C(O)R21, C(0)R21, C(0)0R21, Ci-4alkyl, Ci- 4fluoroalkyl, -Ci-4alkylene-OR22, -Ci-4alkylene-N(R22)2, G2a, and -Ci-4alkylene-G2a, and optionally further substituted with 1-3 substituents independently selected from the group consisting of halogen, oxo, OH, Ci-4alkyl, and Ci-4fluoroalkyl;or R3and R2b, together with the atom to which each attaches, form a 5-membered heterocycle; Y2is -OR22or-N(R22)2;G2is a 4- to 12-membered heterocyclyl containing 1-3 heteroatoms, a Cs-iocarbocyclyl, a 5- to 12-membered heteroaryl containing 1-3 heteroatoms, or a 6- to 12- membered aryl, eachoptionally substituted with a first substituent selected from the group consisting of halogen, Ci-4alkyl, Ci-4fluoroalkyl, -OR21, -N(R21)2, C(O)OR21, 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 G2are independently selected from the group consisting of O, N, and S;R20, at each occurrence, is independently H, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3- 4cycloalkyl;R21, at each occurrence, is independently ene-OCi-4alkyl, -Ci- 3alkylene-N(Ci-4alkyl)2, G2b, or -Ci-3R22, at each occurrence, is independentlyi-salkylene-G211;G2ais 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, G2c, and -Ci-3alkylene-G2cand 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 G2aare independently selected from the group consisting of O, N, and S;G2bis 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 G2bcontains 1-2 heteroatoms independently selected from the group consisting of O, N, and S;G2cis a 4- to 7-membered heterocyclyl containing 1-2 heteroatoms, a 5- to 6-membered heteroaryl containing 1-3 heteroatoms, or a C3-6cycloalkyl, wherein the heteroatoms contained in the heterocyclyl and heteroaryl of G2care independently selected from the group consisting of O, N, and S;Y3is -OR30or-N(R30)2;R30, at each occurrence, is independently H, Ci-4alkyl, G3a, or -Ci-salkylene-G311;G3and G3aare independently a C3-6cycloalkyl or a 4- to 7-membered heterocyclyl, each optionally substituted with 1-4 substituents independently selected from the groupconsisting of halogen and Ci-4alkyl, wherein the heterocyclyl in G3contains 1-2 heteroatoms 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-salkylene-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 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;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.

2. 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 a pharmaceutically acceptable salt thereof, wherein G is a 6-membered aromatic heterocyclic ring containing 1-3 nitrogen atoms.

4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1, at each occurrence, is independently Ci-4alkyl.

5. The compound of any of claims 1-4, 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).

6. 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)-.

7. The compound of any of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein L is a straight chain C4-salkylene, wherein optionally 1 propylene unit is replaced with -OC(O)N(RX)-.

8. The compound of any of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R2is -NR2aR2b.

9. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein:R2ais H, Ci-6alkyl, SO2R20, SO2N(R20)2, -C2-3alkylene-Y2, G2, or-Ci-salkylene-G2; and R2bisH, Ci-4alkyl, C3-4cycloalkyl, or -Ci-3alkylene-C3-4cycloalkyl.

10. The compound of any of claims 1-8, 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.

11. The compound of any of claims 1-8 or 10, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand R2bis a 4- to 8-membered monocyclic heterocyclyl optionally in which two non-adjacent atoms are linked by an alkylene bridge of 1, 2, or 3 carbon atoms, a 7- to 12-membered spiro heterocyclyl, or a 7- to 12-membered fused bicyclic heterocyclyl in which two non-adjacent atoms are optionally linked by an alkylene bridge of 1, 2, or 3 carbon atoms.

12. The compound of claim 11, or a pharmaceutrically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand R2bis the 4- to 8-membered monocyclic heterocyclyl optionally in which two non-adjacent atoms are linked by an alkylene bridge of 1, 2, or 3 carbon atoms.

13. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand R2bis the 7- to 12-membered spiro heterocyclyl.

14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 4- to 12-membered heterocyclyl formed by R2aand R2bis the 7- to 12-membered fused bicyclic heterocyclyl in which two non-adjacent atoms are optionally linked by an alkylene bridge of 1, 2, or 3 carbon atoms.

15. The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R3and R2b, together with the atom to which each attaches, form the 5-membered heterocycle.

16. The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R4ais OCH3, OCH2CH3, methyl, ethyl, or H.

17. The compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R4bis -OR40.

18. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R40is H, Ci-4alkyl, or Ci-4haloalkyl.

19. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R40is -C2-4alkylene-OH, -C2-4alkylene-OCi-4alkyl, -C2-4alkylene-NH2, -C2-4alkylene-NHCi-4alkyl, or -C2-4alkylene-N(Ci-4alkyl)2.

20. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R40is G4or -Ci-3alkylene-G4.

21. The compound of any of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R5is -(CH2)3-O-G3.

22. The compound of any of claims 1-21, 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, indan-5-yl, or naphthalenyl.

23. The compound of any of claims 1-22, 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.

24. The compound of any of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein p is 1.

25. The compound of any of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R7is methyl.

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

27. The compound of any of claims 23-26, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) has formula (IV):

28. The compound of any of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R3is H.

29. A compound selected from the group of compounds of embodiment E29, or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising the compound of any of claims 1 -29, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

31. The compound of any of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, for use in the treatment of cancer.

32. The compound of any of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, for use in the inhibition of cancer cell proliferation.

33. A method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of any of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30.

34. A method of inhibiting cancer cell proliferation, comprising administering to a subject in need thereof, the compound of any of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, in an amount effective to inhibit the cancer cell proliferation.

35. Use of the compound of any of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, in the manufacture of a medicament for the treatment of cancer.

36. Use of the compound of any of claims 1-29, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, in the manufacture of a medicament for the inhibition of cancer cell proliferation.

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