WDR5 inhibitors and modulators

Abstract

Isoquinolmone compounds and derivatives inhibit WDR5 and associated protein-protein interactions, and the compounds and their pharmaceutical compositions are useful for treating disorders and conditions in a subject, such as cancer cell proliferation.

Description

WDRA INHIBITORS AND MODULATORS RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 62 / 933,065, filed November 8, 2019, which is hereby incorporated by reference in its entirety. STATEMENT OF GOVERNMENT INTEREST

[0002] This invention was made with government support under Contract No. HHSN261200800001E, awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD

[0003] The present invention relates generally to compounds that inhibit the binding of transcription factors, regulatory regulators, and chromatin to WDRS and methods of use thereof. In particular embodiments, the present invention provides compositions comprising imino-azacycle-benzamide compounds and methods of use thereof to inhibit or modulate the interaction of WDRS with chromatin, cognate transcription and other regulatory factors, including for example the histone methyliransferase MLL1, for the treatment of leukemia, solid cancers and other diseases dependent on activity of WDRS, BACKGROUND

[0004] Mixed lineage leukemia (MLL) presents a heterogeneous group of acute myeloid leukemia and acute lymphoblastic leukemia bearing features of more than one hematopoietic cell lineage. MLL accounts for about 80% of infant acute leukemia cases (Tomizawa, D.; et. al. Leukemia, 2007, 21, 2258-63.) and 10% of all acute leukemia cases (Marschalek, R. Br. J. Haematol. 2011, 152, 141-54.). MLL leukemia patients have a poor prognosis with overall 5- year survival ratio around 35% (Dimartino, J. F.; Cleary, M. L., Br. J. Haematol. 1999, 106, 614-626; Pui, C., et al. Leukemia, 2003, 4, 700-706.; Tomizawa, D.; et. al. Leukemia, 2007, 21, 2258-63.)

[0005] MLL is composed of heterogeneous cell lineages with different molecular biology, cell biology and immunology features. However, MLL does share a common feature, which involves the chromosomal rearrangement of Mixed Lineage Leukemia (MLL) gene. MLL gene locates on chromosome 11q23 and the encoded MLL protein is a homolog of Drosophila trithorax (Trx) (Thachuk, D. C; etal. Cell, 1992, 71, 691-700.). Wild type MLL binds to regulatory regions of homeox (HOX) genes (Milne, T. A; et al. Cancer Res., 2005, 65, 11367- 74.) through the amino terminal fragment while the catalytic C-terminal domain catalyzes the Histone 3 lysine 4 (H3K4) methylation via interaction with WDRS and up regulates target gene transcription (Nakamura, T ; etal Mol. Cell, 2002, 10, 1119-28; Yokoyama, A. et al. Mol. Cell Biol., 2004, 24, 5639-49.: Milne, T. A ; etal. Aol. Cell, 2002, 0, 1107-17). Wild type MLL in conjunction with WDRS is required for maintenance HOX genes expression and is widely expressed not only during embryo development but also in adult tissues including myeloid and lymphoid cells (Yu, B. D.; etal. Proc. Natl. Acad. Sci., 1998, 95, 10632-10636.). Reciprocal translocations of MLL gene result in-frame fusion of the 5’-end MLL with the 3’-end of another partner gene. A common feature of MLL abnormality in leukemia is the preservation of one wild-type MLL] allele. Currently, more than 80 partner genes have been identified, with MLL-AF4, MLL-AF9 and MLL-ENL being the three most frequently found fusion genes (Pui, C., etal. Leukentia, 2003, +4, 700-706; herein incorporated by reference in its entirety). Expression of MLL fusion proteins promotes over expression of target genes such as HOXA9 and MEIS1, which blocks differentiation, enhances blast expansion and ultimately leads to leukemic transformation (Caslini, C.; et al. Cancer Res., 2007, 67, 7275-83.; Yokoyama, A.; et al. Cell, 2005, 123, 207-18.). The numerous chromosomal translocations of MLL gene and partner genes add to the complexity of MLL leukemia treatment. Although HOX9 and MEIS1T overexpression are commonly observed among MLL leukemia patients, each rearrangement leads to distinct dysregulated target gene expression patterns and downstream events (Slany, R. K., Haematologica, 2009, 94, 984-993). Clinical studies reveal that MLL of different chromosomal translocations are associated with different prognosis and are treated differently under current protocols (Tamai, H., et al. J. Clin. Exp. Hematop., 2010, 50, 91-98; Balgobind, B. V., etal Leukemia, 2011, 8, 1239-1248; Pigazzi, M.; et al. Leukemia, 2011, 25, 560-563).

[0006] Intrinsic histone methyltransferase (HMT) activity of MLL1 is extremely low and requires a complex assembly of WDRS, RbBPS, ASH2L, and DPY30 protein partners for effective H3K4 trimethylation, the so-called WRAD complex (Patel, A.; et al. J. Biol. Chem., 2009, 284, 24242-56). The binding of MLL1I to WDRS (WD40 repeat protein 5) is particularly critical for HMT activity and occurs through a conserved arginine containing motif on MLL1 called the “Win” or WDRS interaction motif. Thus, targeting inhibitors of the MLL1-WDRS interaction at the WIN site in order to block MLL1 methyltransferase activity could represent a promising therapeutic strategy for treating MLL leukemia patients. Peptidomimetics have been discovered that bind tightly to WDRS at the MLL site, inhibit MLL] methyltransferase activity, and block proliferation of MLLI cells by inducing cell-cycle arrest, apoptosis, and myeloid differentiation (Cao, F.; et al. Molecular Cell, 2014, 53, 247-61, Karatas, H.; et al. J. Med. Chem., 2017, 60, 4818-4839.). In addition, altered gene expression patterns similar to MLL1 deletion are observed, supporting a role for MLL1 activity in regulating MLL 1-dependent leukemia transcription. Thus, interruption of the WDRS-MLLI1 interaction may be a useful strategy for treating patients with MLL leukemias. In addition to the highly characterized WDRS-MLLI interaction, disruption of WDRS with other transcription factors / epigenetic writers or displacement from chromatin itself could have a desirable benefit as a cancer treatment strategy. For example, WDRS acts as a scaffold protein with the following chromatin complexes / structures, including histone H3 (via R2 residues, e.g. see Song, J.-I., et al. .J. Biol. Chem. 2008, 283, 35258-64), NSL / MOF (Li, X, et al. Molecular and Cellular Biology, 2010, 30, 5335-47, Dias, J., etal. Genes & Development, 2014, 28, 929-942), C / EBP p30 (Senisterra, G., et al. Biochem. J., 2013, 449, 151-159.), ¢-MYC (Thomas, L. R.; et al. Molecular Cell, 2015, 58, 440-52., herein incorporated by reference in its entirety), and the NuRD complex (Ee, L.-S., et al. Stem Cell Reports, 2017, &, 1488-96). In addition, WDRS expression levels have been reported to be correlative and connected to patient prognosis in several other cancer types, including neuroblastoma (Sun, Y. et al. Cancer Research, 2018, 73, 5143-54.), breast cancer (Dai, X. et al. PLoSOne, 2015, 10, PMC4365643), bladder cancer (Chen, X. et al. Scientific Reports, 2015, 5, 8293.), and colorectal cancer (Tan, X. et al. Cell Death & Disease, 2017, 8, PMC5386518). In addition, in an unbiased shRNA screen in human xenografts, WDRS was identified as an important target in pancreatic cancer (Carugo, A. etal. Cell Reports, 2016, 16, 133-147.). Based on the growing number of complexes identified, which utilize WDRS3 to maintain tumor fitness and growth, the emerging importance of WDRS in several cancer types is not unexpected. In the case of the c-MYC-WDRS interaction, the MYC oncoprotein utilizes a molecularly defined interaction with WDRS to bind to its target genes on chromatin. MYC is overexpressed in a majority of malignancies and contributes to an estimated 70,000-100,000 cancer deaths per year in the United States. Thus, disruption of WDRS from chromatin as a strategy to displace MYC from its target genes may provide a beneficial strategy to treat MY C-driven tumors. SUMMARY

[0007] The molecules described herein can inhibit or modulate the interaction of WDRS with chromatin, cognate transcription and other regulatory factors, including for example the histone methyltransferase MLL, and can provide a therapeutic approach to treat cancers associated with such interactions (e.g., the MLL 1-WDRS interaction).

[0008] In one aspect, the invention provides compounds of formala (1), Ra a R3b R* i “SG: AN R7 R Oo R* R® mn or a pharmaceutically acceptable salt thereof, wherein: nis0, 1, 0r2; R'i is GU G' is a 9- to 12-membered bicyclic aryl, an 8- to 12-membered bicyclic heteroaryl, an 8- to 12- membered fused bicyclic heterocyclyl, or a Ca.wocarbocyclyl fused to a 6-membered arene or to a 5- to 6-membered heteroarene, wherein G' is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, Cisalkyl, C1. shaloalkyl, oxo, -L'-X!, and -L.'-G'%, X!, at each occurrence, is independently OR, -N(R!?)2, -SR'%, cyano, ~C(O)OR™, — C(O)N(R), ~C(O)NRHSO:R®, -C(NH)NHOH, ~C(O)H, ~C(Q)R™®, -SOR®, ~SQ;R!®, ~SO:N(R),, ~NRIC(0)H, ~-NREC(O)R', -NRC(Q)ORY, ~NREC(O)N(R2), ~ NRE§(0)R, or -NRES(0)2N(R4)a; RY, at each occurrence, is independently hydrogen, Ci.calkyl, Cishaloalkyl, ~Cz4alkylene— ORY, ~Cy4alkylene-N(R'%), ~Caalkylene-N(R'¥)C(O)R', G*, or ~Cjsalkylene-G'%; R™, at each occurrence, is independently Cisalkyl, Cishaloalkyl, ~Ciaalkylene~-OR', ~C;. salkylene-N(R'®)y, ~Cr.salkylene-N(R')C(O)R'S, G*, or ~C1.calkylene-G*; L’, at each occurrence, is independently a bond or Ci.zalkylene; G' at each occurrence, is independently Cs.scycloalkyl, 6- to 10-membered aryl, 5- to 10- membered heteroaryl, or 4- to 10-membered heterocyclyl, wherein G'? is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C4alkyl, Ci-shaloalkyl, oxo, -L*~X?, and -L>-G"; X? at each occurrence, is independently “ORS, -N(R')2, —SR', e¢yano, —C(O)OR'®, — C(O)N(R¥), -C(O)R'®, —-SOR™ —S0:R™ —SON(R%), -NRFC(O)R', -NR’*C(Q)OR'®, “NREC(O)N(R Fz, -NRS(0):RY™, or -NR*S(0):N(R')2: RY at each occurrence, is independently hydrogen, Ci-alkyl, Cishaloalkyl, G™, or —C1. salkylene—G™, wherein alternatively two R'S, together with a common nitrogen atom to which the RI€ attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of Craalkyl, Ciahaloalkyl, oxo, ~OH, and ~OC alkyl; RY, at each occurrence, is independently Ciealkyl, Cishaloalkyl, G', or ~C1zalkylene-G'; RY, at each occurrence, is independently hydrogen, Craalkyl, Ci<haloalkyl, G'®, or ~C1. salkylene~G!, wherein alternatively two RY, together with a common nitrogen atom to which the R® attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of Ciualkyl, Ci-haloalkyl, oxo, ~OH, and -QC14alkyl; L2, at each occurrence, is independently a bond or Ci.salkylene; GY is a Cascycloalkyl, a 4- to 6-membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and S, a 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and 8, or a phenyl, wherein G' is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, Ciwalkyl, Ci<haloalkyl, oxo, ~OH, and ~OCr-alkyl; R® R™ R%* and R* are independently hydrogen, halogen, Ci-alkyl, Ci.shaloalkyl, or ~OCi- salkyl; or alternatively any two of R*, R?®, R* and R*® are taken together with the atom or atoms to which they attach to form a 3-8 membered saturated or partially unsaturated carbocyclic or heterocyclic ring that is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Cj.salkyl, Cishaloalkyl, and — OCi.salkyl; or alternatively one R* and one R™ are taken together to form an oxo group; R* is hydrogen, halogen, Cisalkyl, Cichaloalkyl, Cishaloalkenyl, ~OR*, ~SR* -N(R¥),, — S(OIR™, ~S(0)R™, ~S(0) NR), ~C(OIN(R®):, ~C(O)R™, -NR¥C(O)R™, NR*C(0)OR*, -NR*C(O)N(R*)2, -NR*'S(0):R*, -NR*S(0)2N(R*)z, or G?,; R* at each occurrence, is independently hydrogen, Cjsalkyl, Ci.shaloalkyl, G?, or —Ci- salkylene—G?; R¥ is Cisalkyl, Cichaloalkyl, G*, or —C).:alkylene—G?; G*, at each occurrence, is independently a Cs.wcarbocyelyl, a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 4- to 12-membered heterocyclyl, wherein G? is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, Cisalkyl, Crshaloalkyl, oxo, ~<OR¥*, -N(R*),, ~SR*, cyano, ~C(Q)OR*, — C(O)N(R¥), <C(O)R¥, SOR, —SO:R¥, ~SO2N(R*),, -NR¥C(O)R¥, -NR*C(Q)OR*, “NR C(O)N(R*)2, -NR*S(0):R¥, -NR¥S(0)2N(R*)2, Cs-scycloalkyl, and ~Cr.zalkylene— Cascycloalkyl, wherein each Cascycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Cisalky] and halogen; R¥*, at each occurrence, is independently hydrogen, Ciealkyl, Cishaloalkyl, Cs.scycloalkyl, or ~Cialkvlene-Csgeycloalkyl, wherein each Cascycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci«alkyl and halogen, wherein alternatively two R*, together with a common nitrogen atom to which the R¥ attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of Cralkyl, Ciabaloalkyl, oxo, ~OH, and ~OC1-alkyl; R*, at each occurrence, is independently Cisalkyl, Cishaloalkyl, Ca.scycloalkyl, or —Ci- calkylene~Cs.scycloalkyl, wherein each Cascycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci4alkyl and halogen; R® and R° are each independently hydrogen, halogen, C14alkyl, Ciuhaloalkyl, or ~OCialkyl; R™ and R™ are independently selected from the group consisting of hydrogen, halogen, hydroxy, Cialkyl, and Ci.shaloalkyl, or R™ and R™ are taken together to form an oxo group; and R¥ is a 5- to 6-membered heterocyclic ring containing 1-3 heteroatoms and 1-3 double bonds, wherein one of the 1-3 heteroatoms is a nitrogen and the remaining heteroatoms are independently selected from nitrogen and oxygen, wherein R® is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, Cisalkyl, Ci. shaloalkyl, imino. oxo, NO2, NH», -NH(C.salkyl), -N(Ci4alkyl)z, Cs-scycloalkyl, and —C- aalkylene—Csscyeloalkyl, wherein each Cascycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Ci-salkyl, Cio shaloalkyl, OH, and —OC4alkyl.

[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 corapound of formula (T), or a pharmaceutically acceptable salt or composition thereof.

[0011] Tn another aspect, the invention provides a method for inhibiting the binding of MILLI to WDRS, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (1), 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 MLL1 to WDRA.

[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 MLL1 to WDRS.

[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 DESCRIPTION

[0017] Disclosed herein are inhibitors of WDRS, which bind at the WDRS interaction or WIN-site. The inhibitors can be compounds of formula (I). Compounds of formula (I) can be used to treat cancers associated with the MLL1-WDRS interaction. In one aspect, disclosed are compounds of formula (1) as WDRS-WIN-site inhibitors. 1. Definitions

[0018] 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.

[0019] 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.

[0020] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for exarople, 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.

[0021] 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, 75% Ed., 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 Chemismy, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5% Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc, New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.

[0022] 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 exaroples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert- butoxy.

[0023] The term “alkyl.” as used herein, means a straight or branched, saturated hydrocarbon chain. The term “lower alkyl” or “Crealkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “Ci4alkyl” 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, n-propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, fert-butyl, n-pentyl, iso-pentyl, neopentyl, n-hexyl, 3-methylbexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. 10024] The term “alkenyl,” as used herein, means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond. 10025) The term “alkylene,” as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon, for example, of 2 to 5 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2CHa-, -CH2CH2CHa-, -CH2CH2CH2CHe-, and - CH>CH>CH>CH2CH-.

[0026] 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][1,3]dioxol-5-y1). 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).

[0027] 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., decahydronaphthalenyl), 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., bicyelo[2.2.1]heptanyl). Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, eyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl,

[0028] The term “cycloalkenyl” or “cycloalkene,” as used herein, means a non-aromatic monocyclic or multicyclic 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., octahydronaphthalenyl), 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.

[0029] 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.

[0030] The term “halogen” or “halo,” as used herein, means CI, Br, I, or F.

[0031] 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.

[0032] The term “heteroaryl,” as used herein, refers to an aromatic monocyclic heteroatom- containing 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, 107 electron system) such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indol-1-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 107 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[blpyridinyl), or a monocyclic heteroaryl ring fused to a monocyclic heterocycle (e.g., 2,3-dihydrofurof3,2-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-1-yl, indol-2-y1, indol-4-y1), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-y1), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g, triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2-a]pyridinyl (e.g.. imidazo[1,2-a]pyridin-6-y1), naphthyridinyl, pyridoimidazolyl, thiazolo[3,4-b]pyridin-2-yl, and thiazolo[5,4-d|pyrimidin-2- yl.

[0033] 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 0, 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, imidazoliny!, 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- thwazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1.1- dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. The bicyclic heterocyclyl is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-1-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, 1,2,3 4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa- 6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]hepty! (including 2-azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexany! (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-1A-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.

[0034] The term “imino” refers to the group “=NH.”

[0035] 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., "Craalkyl," "Cascycloalkyl," "Crialkylene"). 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, "Csalkyl" is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in "C14," the members of the group that follows may have any number of carbon atoms falling within the recited range. A "Ci4alkyl," for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).

[0036] 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, =() (0x0), =§ (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.

[0037] The term “allosteric site” as used herein refers to a ligand binding site that is topographically distinct from the orthosteric binding site.

[0038] The term “modulator” as used herein refers to a molecular entity (e.g., but not limited 10, a ligand and a disclosed compound) that modulates the activity of the target receptor protein.

[0039] The term “ligand” as used herein refers to a natural or synthetic molecular entity that is capable of associating or binding to a receptor to form a complex and mediate, prevent or modify a biological effect. Thus, the term “ligand” encompasses allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates and analogs of natural substrates.

[0040] The terms “natural ligand” and “endogenous ligand” as used herein are used interchangeably, and refer to a naturally occurring ligand, found in nature, which binds toa receptor.

[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] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated. 2. Compounds

[0043] In one aspect, disclosed are compounds of formula (I), wherein R!, R%, R? R* R®, RY, R®, RS, R™ R™, R®, and n are as defined herein. Embodiments of formula (I) include the following descriptions of R!, R*™, R™ R* R™ R* R* R® R™ R™, R* and n, and any combinations thereof. 10044] R*is a 5- to 6-membered heterocyclic ring containing 1-3 heteroatoms and 1-3 double bonds, wherein one of the 1-3 heteroatoms is a nitrogen and the remaining heteroatoms are independently selected from nitrogen and oxygen, wherein R* is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, Ciaalkyl, Ci- shaloalkyl, imino, oxo, NO2, NHa, ~-NH(C4alkyl), ~N(Crsalkyl)z, Cascycloalkyl, and ~Ci. salkylene~Ci.scycloalkyl, wherein each Cs.scycloalky! is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Cisalkyl, Ci- shaloalkyl, OH, and ~OC.salkyl. R® may be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, Ci-salkyl, Ci.shaloalkyl, imino, oxo, NH, -NH(Cisalkyl), -N(Csalkyl)z, Cascycloalkyl, and —Ci-salkylene—Cscycloalkyl, wherein each Cs.scycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Ci4alkyl, Cishaloalkyl, OH, and -OCi-salkyl. For example, R® may be an optionally substituted imidazolyl or pyridinyl. R® may be a 5- membered heterocyclic ring containing 2 heteroatoms, wherein one of the 2 heteroatoms is a nitrogen and the remaining heteroatom is nitrogen or oxygen and the 5-membered heterocyclic ring is substituted with an imino group (i.e., “=NH").

[0045] RS may be an optionally substituted imidazolyl, as defined herein. R® may be EN S—(RP,, | (RO), selected from the group consisting of H o HH 2) re (R29) 4 N Pr" NT H N ~ > (R®).5 N . —N or N— / ; wherein R*, at each occurrence, is independently halogen, Ci.salkyl, Ci-shaloalkyl, NHz, -NH(Cialkyl), -N(Ci-salkyl), Ca. scycloalkyl, or —Ci-salkylene—Cs.scycloalkyl, wherein each Ca.scycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Craalkyl, Cj.shaloalkyl, OH, and —OC).salkyl. R® may be selected from the group consisting of R20b R20d in ¥ XT In i N 2 R20e ~ N anf J FA N i R20¢ $ N Tr mA N R20f \r20d R20a R20 RY ‘R20d Land R20g 3 1 N 20h § ht J R20 ; RY ; wherein R%® is hydrogen, Ci.alkyl (e.g., methyl, ethyl, isopropyl), NHz, -NH(Ci4alkyl) (e.g., ~NHCH:), -=N(Cr4alkyl), or Cs.scycloalkyl (e.g., cyclopropyl); and RM R20 R204 Re RIL R202 RM and RY, are each independently hydrogen, Cralkyl (e.g. methyl, ethyl), or Cascycloalkyl. The optionally substituted imidazolyl at R® may be selected ~~ Cy _calkyl Ay Ny Ny & Ny EN A from the group consisting of ~~ \= / \em / (eg, |= \es / \e / ), Vv Evy Evy EA Cascycioalkyl Y NH, - NTR == wr Ev Foy Boggehe, Ey Need (eg, |\== / ) = “NTN Cyalkyl (e.g. NHC alkyl Endy Cy.qalkyl ~ Wy EA, “NH ay A, +f NN ENN rN IN ig tingt mm % & " = = Ik = kyl Hot oN Cy gay! Coaalyl” Tsay gy \ee / (eg. = / ), 148 (e.g, ) “NTN Cy.qalkyl (eg | NN N N. N N N. a ~Q ~Q (eg. ~, av) and 2 (e.g, ). NHz NO, Eady And

[0046] R® may be Nem / or Ce

[0047] R® may be an optionally substituted pyridinyl, as defined herein. For example R® ©... 0 may be F N such as 2N

[0048] R'is G'; and G'is a 9- to 12-membered bicyclic aryl, an 8- to 12-membered bicyc

[0048] R'is GY; and G'is a 9- to 12-membered bicyclic aryl, an 8- to 12-membered bicyclic heteroaryl, an 8- to 12-membered fused bicyclic heterocyclyl, or a Ca.wcarbocyclyl fused to a 6-membered arene or to a 5- to 6-membered heteroarene, wherein G' is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, Ci.salkyl, Cushaloalkyl, oxo, -L'-X", and ~L'-G"%; wherein L!, X*, and G'* are as defined herein.

[0049] X', at each occurrence, is independently ~OR', -N(R);, -8R™, cyano, ~C(O)OR™, ~C(OIN(R)z, ~C(OIN(R'SO:R™, ~C(NH)NHOH, ~C(O)H, ~C(O)R™, ~SOR'®, ~SO:R'®, — SON(R'), ~NR*C(O)MH, ~NR¥C(O)R'®, -NR¥C(O)OR', -NRPC(O)N(R'),, NRES(O)R'®, or ~NRUS(O)N(R™),.

[0050] In some embodiments, G' is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, Cisalkyl, Ci-shaloalkyl, oxo, — OR’, -N(R'%),, ~SR', cyano, —C(0)OR'?, —C(O)N(R'*)2, ~C(O)H, ~C(O)R™, SOR, — SO:R'®, —SO2N(R'?);, -NRC(O)H, -NR!"C(O)R’®, -NR!"C(O)OR", -NR*C(O)N(R*)z, — NR'S(0):R", -NRMS(0)2N(R™)z, and ~L'-G'; wherein R'?, R'®, L!, and G" are as defined herein.

[0051] At G', The 8- to 12-membered fused bicyclic heterocyclyl and the Cs.iocarbocyelyl fused to a 6-membered arene or to a 5- to 6-membered heteroarene may have (S) or (R) stereochemistry at the point of attachment to the parent molecular moiety.

[0052] L'isa bond or Ciaalkylene. Tn some embodiments, I! is a bond. In other embodiments, L' is Crsalkylene (e.g., CHz, CH2CHz).

[0053] At G', the 9- to 12-membered bicyclic aryl may be a naphthalenyl; the 8- to 12- membered bicyclic heteroaryl may be an 8- to 10-membered fused bicyclic heteroaromatic ring systern; the 8- to 12-membered fused bicyclic heterocyclyl may be a 5- to 7-membered monocyclic heterocyclyl fused to a 6-membered arene or fused to a 5- to 6-membered heteroarene; and the Cs-ocarbocyclyl fused to a 6-membered arene or to a 5- to 6-membered heteroarene may be a Csrcarboeyclyl fused to a 6-membered arene or fused to a 5- to 6- membered heteroarene, wherein these G! options are optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, Crealkyl, Ci. chaloalkyl, oxo, ~OR', N(R"), ~SRY, cyano, ~C(O)OR'?, ~C(OIN(R)z, -C(O)H, ~C(O)R™, ~SOR'™, ~SO:R'®, ~SO:N(R'¥)2, ~-NR¥C(O)H, ~-NR“¥C(O)R'?, -NR*C(0)ORY, NR'C(O)N(R')2, ~-NR'3§(0)2R?, ~-NR1¥S(0)2N(R¥)2, and ~L-G'3.

[0054] In the compounds and embodiments described herein, G;' may be optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, Cursalkyl, Cishaloalkyl, ~OR'%, -N(R!#);, ~C(O)OR?, ~C(O)N(R'),, ~C(O)R'®, and G2, wherein Gi'? is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C).salkyl, Cihaloalkyl, oxo, ~OH (i.e., ~-OR'® where R'¢ is hydrogen), ~OC14alkyl (i.e., ~OR'® where R¥ is C.salkyl), -C(0)Cr4alkyl (i.e., ~C(O)R'® where R* is Ci.alkyl), ~C(0)0C14alkyl (i.e. ~C(O)OR' where R' is Crualkyl), Ca. scycloalkyl, and ~Ci.zalkylene-Csscycloalkyl. In the compounds and embodiments described herein, G' may be optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, Ci-alkyl, Cishaloalkyl, ~OCi4alkyl (i.e., OR" where R™* is C1. salkyl), ~OC;shaloalkyl (i.e., OR'® where R'is Cishaloalkyl), -NH: (i.e, -N(R'); where R'? is hydrogen), -NHC 4alkyl (i.e., -N(R'?)2 where one R'® is hydrogen and one R'® is Ci4alkyl), ~N(Ci-salkyl): (i.e, -N(R'"): where R% is Ci4alkyl), -N(Ci-salkyl)-Czsalkylene-N(Ci-alkyl): (i.e, ~N(R"); where one R"" is Ci-alkyl and one R'is —Cz.salkylene-N(C1.4alkyl):), -C(O)OH (i.e, —C(O)OR"™ where R'® is hydrogen), —C(0)OC.4alkyl (i.e., C(O)OR" where R'is Ci. alkyl), —C(O)NH: (i.e, ~C(O)N(R'?): where R'® is hydrogen), —C(Q)NH(Cialkyl) (i.e, — C(O)N(R'®)2 where one R'® is hydrogen and one R'* is Cialkyl), ~C(O)NH-(24alkylene—OC;. alkyl (i.e., ~C(O)N(R'™)2 where one R' is hydrogen and one RY is ~Ca-salkylene-OC alkyl), ~C(O)N(Craalkyl): (i.e., ~C(O)N(R™)2 where Ris Ci4alkyl), ~C(0)G' (i.e., ~C(O)R™ where R™ is G'2), and G*, wherein G'? is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Ci4alkyl, Ci.shaloalkyl, oxo, ~OH, ~OC1.salkyl, ~C(0)Craalkyl, -C(0)OCi-salkyl, Cs-scycloalkyl, and ~Ciaalkylene-Csscycloalkyl.

[0055] R!% at each occurrence, is independently hydrogen, Cisalkyl, Cishaloalkyl, ~Ca- salkylene-OR, ~Ca.aalkylene- N(R), ~Czaalkylene-N(R¥)C(O)RY, G2, or ~Cicalkylene- G' wherein R! and G™ are as defined herein. In some embodiments, R', at each occurrence, is independently hydrogen, Cisalkyl, Cishaloalkyl, ~Ca-alkylene-OR, -Czalkylene- NR), G, or ~Cisalkylene-G? In the compounds and embodiments described herein, R1 may be hydrogen, Cisalkyl, Cishaloalkyl, -~Cz4alkylene-OR', ~Caalkylene-N(R™)z, or G4, wherein R' is Cialkyl; and G'* is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Ci4alkyl, Cishaloalkyl, oxo, OH (i.e., ~OR'® where R' is hydrogen), ~OCi-alkyl (i.e, “OR where R'® is Crsalkyl), ~C(0)Craalkyl (ie, — C(0)R® where R* is Cr.alkyl), ~C(0)OC14alkyl (i.e., ~C(O)OR' where R'® is Crsalkyl), Ca. scycloalkyl, and ~Ci.zalkylene~Csscycloalkyl. In the compounds and embodiments described herein, R' may be hydrogen, Ci.salkyl, Cishaloalkyl, ~C24alkylene-OR', or ~C.salkylene~ N(R™),, wherein R® is Ciaalkyl.

[0056] R', at each occurrence, is independently Ci.salkyl, Cishaloalkyl, ~Ch.1alkylene- OR", ~C1ialkylene-N(R'¢),, ~C14alkylene-N(R*)C(O)R, G*, or ~Ci.salkylene-G'?, wherein R'¢ and G' are as defined herein. In some embodiments, R'®, at each occurrence, is independently Cr.ealkyl, C-shaloalkyl, ~C.salkylene-OR, —Ciaalkylene-N(R')2, G', or ~Ci. calkylene-G'. In the compounds and embodiments described herein, R'> may be Cialkyl, C1. shaloalkyl, —Ci.salkylene—OR'®, —Ci.salkylene-N(R'®):, or G'%, wherein R' is Cjalkyl; and G'* is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Cialkyl, Cihaloalkyl, oxo, “OH (i.e, OR’ where R'® is hydrogen), — OC alkyl (i.e, OR’ where RY is C.alkyl), ~C(O)Ciuialkyl (i.e, ~C(O)R' where RI< is Ci. alkyl), —C(0)OC1alkyl (i.e, —C(O)OR'® where R¥ is Ciualkyl), Cs-scycloalkyl, and —Ci- salkylene—Cs.eycloalkyl. In the compounds and embodiments described herein, R'® may be GY wherein G! is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Ci.salkyl, Cishaloalkyl, oxo, OH (i.e., OR where R!¢ is hydrogen), ~OC14alkyl (i.e., “ORY where RY is Ciaalkyl), <C(0)Cisalkyl (i.e., ~C(O)RY where R'is Craalkyl), ~C(0)OC1 alkyl (i.e., ~<C(O)OR'® where RY is Cralkyl), Cs- scycloalkyl, and ~Cr.:alkylene~Cascycloalkyl,

[0057] RY at each occurrence, is independently hydrogen, Crsalkyl, Cr.ehaloalkyl, G'®, or — Crsalkylene-G'®, wherein alternatively two RY, together with a common nitrogen atom to which the R!® attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of Cialkyl, Ci4haloalkyl, oxo, ~OH, and ~OC1.salkyl, wherein G' is as defined herein. In some embodiments, RY, at each occurrence, is independently hydrogen, Crealkyl, Crehaloalkyl, Cs-scycloalkyl, or ~Ciealkylene-Ciscycloalkyl, wherein each Cs.scycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Crsalkyl and halogen, wherein alternatively two R, together with a common nitrogen atom to which the R' attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of Cr.salkyl, Cishaloalkyl, oxo, ~OH, and ~OC).alkyl. In the compounds and embodiments described herein, R'® may be hydrogen or Crsalkyl.

[0058] RY, at each occurrence, is independently Ci.salkyl, Cishaloalkyl, G'®, or ~Ci- salkylene-G'®, wherein GY is as defined herein. In some embodiments, R', at each occurrence, is independently Cisalkyl, Cishaloalkyl, Ciscycloalkyl, or ~Cisalkylene-Ca. scycloalkyl, wherein each Cs.scycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci.salkyl and halogen. In the compounds and embodiments described herein R'® may be Ciaalkyl.

[0059] R' at each occurrence, is independently hydrogen, Ci-salkyl, C1shaloalkyl, G™, or — Cusalkylene—G'™, wherein alternatively two R'%, together with a common nitrogen atom to which the R'® attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of Crsalkyl, Cishaloalkyl, oxo, OH, and —OC .salkyl, wherein G' is as defined herein. In some embodiments, RY, at each occurrence, is independently hydrogen, Cisalkyl, Ci.shaloalkyl, Cs.scycloalkyl, or —Ci-salkylene—Cs.ceycloalkyl, wherein alternatively two RU, together with a common nitrogen atom to which the R'® attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of Craalkyl, Cisbaloalkyl, oxo, ~OH, and ~ OCuaalkyl. Tn the compounds and embodiments described herein R' may be Cr.salkyl.

[0060] G' at each occurrence, is independently Czscycloalkyl, 6 to 10-membered aryl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl, wherein G* is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Cralkyl, Crshaloalkyl, oxo, -L2-X2, and -L*-G™; wherein L2, X2, and G™® are as defined herein.

[0061] 12 at each occurrence, is independently a bond or Ci.salkylene. In some embodiments, L? is a bond. In other embodiments, L? is Cialkylene (e.g, CHz, CH:CH2).

[0062] X2, at each occurrence, is independently ~OR, ~N(R¥),, SR, cyano, ~C(Q)ORY, ~C(O)N(R), ~C(O)R”, SOR, ~S0:RY, -SO:N(R')2, -NRFC(O)RY, ~NR**C(Q)OR, - NREC(OIN(R'®)2, -NR¥S(0)2R', or ~-NR*<S(0)2N(R)s.

[0063] In some embodiments, G'* is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Ci.salkyl, Cishaloalkyl, oxo, — OR'¢, -N(R'), ~SR', cyano, ~C(O)OR'®, ~C(O)N(R'*)z, ~C(O)R™, ~SOR'Y, ~SOR'Y, SO:N(R!),, -NREC(O)R, -NREC(Q)OR'S, ~NREC(O)N(R!®)a, -NRES(0)R!, ~ NR 8(0):N(R'®), Csscycloalkyl, and ~Craalkylene—Cs.scycloalkyl. In the compounds and embodiments described herein, G'* may be the optionally substituted 4- to 10-membered heterocyclyl. The optionally substituted heterocyclyl may be a 4- to 8-membered monocyclic heterocyclyl.

[0064] In some embodiments, G'* is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Ci.salkyl, Ci-shaloalkyl, oxo, — OR'®, -N(R);, ~SR', cyano, ~C(O)OR'®, ~C(O)N(R')z, ~C(OIRY, ~SOR'Y, ~SO:R'4, SO:N(R!)2, -NRC(O)R', -NR**C(0)OR'?, -NR“C(O)N(R'%)2, -NR"“S(0):R!, — NR®S(0):N(R'®)z, Cs.seyeloalkyl, and —Cisalkylene—Cs.seycloalkyl. In the compounds and embodiments described herein, G'* may be optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C;-alkyl, Ci-shaloalkyl, oxo, — OH (i.e., “OR* where R' is hydrogen), —OCi.salkyl (i.e., OR" where R'¢ is Cisalkyl), — C(0)Ciusalkyl (i.e, ~C(O)R' where R™ is Cialkyl), -C(O)OCsalkyl (i.e.. ~C(O)OR' where R'is Craalkyl), Cascycloalkyl, and —Ci-salkylene-Cascycloalkyl.

[0065] The optionally substituted heterocyclyl at G'* may have a first nitrogen ring atom and optionally a second ring heteroatom selected from nitrogen and oxygen, the heterocyclyl of G'* being attached at the first nitrogen ring atom and being optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Cr-salkyl, Ci- shaloalkyl, oxo, ~C(0)Cralkyl, ~C(Q)OC14alkyl, Cascycloalkyl, and —Cisalkylene~Cs. cycloalkyl. For example, the heterocyclyl of G'* may be a pyrrolidin-1-yl, morpholin-d-yl, or piperazin-1-yl, and optionally substituted with Ci4alkyl, oxo, or ~C(O)Cisalkyl.

[0066] In some embodiments, G' may be the optionally substituted naphthalenyl. In some embodiments, G* is naphthalen-1-yl.

[0067] In some embodiments, G' may be the optionally substituted 8- to 10-membered fused bicyclic heteroaromatic ring system. The 8- to 10-membered fused bicyclic heteroaromatic ring system may be quinolinyl, isoquinolinyl, indolyl, indazolyl, benzoxazolyl, quinazolinyl, or pyrrolo[2,3-b]pyridinyl. The 8- to 10-membered fused bicyclic heteroaromatic ring system may be quinolin-4-yl, quinolin-5-yl, isoquinolin-1-yl, isoquinolin-4-yl, quinazolin-4-yl, indol- 3-yl, indol-4-vl, indazol-3-yl, benzo[d]oxazol-7-yl, pyrrolo[2.3-b]pyridin-3-yl. or pyrrolo[2,3- N, N, [ [ Lo # OCq_qalkyl # C-qalkyl b]pyridin-4-yl. Accordingly, G' may be ~ ” OC. _4alkyl C._4alkyl halo N, halo ( x J r OC _4alky! AN x # C_qalkyl Cy 4alkyl halo N N [ [> INS OC alkyl 0C4_qalkyl QC, salkyl halo N(C_salkyl)z OC, 4alkyl N N N [ [ » Z Cy alkyl Z C.4alkyl Z OC, 4alkyl N(C4_salkyl)z N NS NF Cy.4alkyl 0.0 Craalkyl” FF N (s C..n 0.0 HO. _O HOO HNO Cqalkyl” “¥ sp 7 2 Na N N, N, N, [ [ i» [ 7 Ciqalkyl # OC, _salkyl # Cy.salkyl 7 OC1_qalkyl H H H NO N._O N._O Craalkyl” FF Craalkylo” Cyqaliyl” N N N | ( ® # OC, qalkyl 7 OC 4alkyl # Cyqalkyl Ciqalkyl Coated” 3 Crogalkyls | 60 > I 7 OC .4alkyl CETTONT Ta N re # Crakk! Crasalkyl N Cqqalkyl” 2 N, (hs 7 OC alkyl i Ng, C.4alkyl # OCH qalkyl Gla Gla N N [0 [0 Z OC qakyl Cs.calkyl Cy_qalkyl i Ny, Na # OC, .4alkyl halo Z OC .qalkyl OC, 4alkyl QU 4aikyl Cr.qalkylnNg, Ng Ny | 7 OC, 4alkyl ZN0C,, alkyl Ze, alkyl QC 4alkyl halo NZ ZF Z FNC, alkyl OC alkyl Cyaalkyl he Ane OCq.4alkyl NT i # QC aalkyl OCy.4alkyl NT | Pe : : OC. 4alkyl Cy.4alkyl halo NT NT | | 7 OC alkyl OC 4alkyl OC, 4alkyl Cqgalkyl, Co Ciqalkyl N, [ 'S # OC 4alkyl aaikyl Li1.4diRyl N \ OCH qalkyl Kyl, N \ OC alkyl C1 .4alkyl Craalkyl, edly Crqalkyl, alkyl Caalkyi N Nes N Nes \ AF halo N\A 00, alkyl an, Ma, , or Cqalkyl gods = Ng —N, Ny Ny ~~ Ciuaalkyl | | ZF or C oor: r For examnle (# nav ba OCH, OCH; CN rs Go OCH3 OCHa Br os Cl [= ris fe (hs # # # # ocH; OCH; Br ~nT OCH, SOO OO SL S Cs s ® Z Z 7 OCH, OCH; H H HOO HO._O HNO N_o Ro Ae ~¥ oY i i “NF N N N N N [ lL [ 9 | Z OCH; # OCH, OCH; HNO HN. 0 HN. 0 ¢ + + HN. _O ~ I r b N N N [ [ ® # OCH, 7 OCH; Z OCH; 1 _N_O N ( 5 , OCH; oS SNS 0. \ Oy AVN 1 in ™ SN 0 Sng NO NAN FE SN £0 Rp I i I S ® S # ocH, OCH; Z OCH; “ N As y OCH; X ~N | | : \ N Og N N ON MN NS 5S cr 0 rr “ “~ W Sy SN ~ Oo ® $ * J # OCH; # OCH, ~~ OCH; | PLN ~~ N N [ [> Z 7 OCH, N rs A N [rs TC. OCH; OCH» OCH; OCH, Nz # OCH; > 0cH, Z Z OCH; Cl NT I = wh Cl SSN TONS Vo CQ N = ZZ 2 | # # OCH; OCH; N, 7 A OCH, 3 x ZF OCH; al NT | 7 OCH, N x Pa OCH; H,CO al - Na AL Na HCO \ N sy OCH; HCO \ \ \ / \ N N N N N N Tos, EO A Hoon, o- Se 4 flo 3 Poon N NewreV N 3 \ a N Na, A Cx J VAs .« by > | ocH, § | o [ ;. CHa ZF . , Or

[0068] In some embodiments, G' may be the optionally substituted 5- to 7-membered monocyclic heterocyclyl fused to a 6-membered arene or fused to a 5- to 6-membered heteroarene. The 5- to 7-membered monocyclic heterocyclyl fused to a 6-membered arene or fused to a 5- to 6-membered heteroarene may have (S) or (R) stereochemistry at the point of attachment to the parent molecular moiety. The 5- to 7-membered monocyclic heterocyclyl fused to a 6-membered arene or fused to a 5- to 6-membered heteroarene may be a 5- to 7- membered monocyclic heterocyclyl having one oxygen ring atom or one nitrogen atom and fused to a 6-membered arene or fused to a S- to 6-membered heteroarene. The 5- to 6- membered heteroarene may be a pyridine. A fused 6-membered arene or pyridine may be optionally substituted with 1-2 substituents independently selected from the group consisting of’ oo halo, Cralkyl, ~OC1alkyl, and Cs.ceycloalkyl. Accordingly, G' may be 0. 0. 0. © halo Ci.q4alkyl OC alkyl Ca.gcycloalky! Ci qalkyl | i © Ns AN i Ns P ° LH Z halo halo ,or , such as 0. Q. 0. ON. ~ ~ - OS Cy.qalkyl OC, 4alkyl Ca.ecycloalkyl Z halo has has has nhas , or Craalkyl AN ois Z halo Cr.qalkyl 0. 0. oN As 0 - Z halo Br For example, G' may be 1 0 0 LO AN MN Ns o OCH; Z| Ze , or , such as 0 © ~© © ~© rs Br OCH; Ze , or LO r AN rs Zc o HN N OC, 4 alkyl 1} | TE bray G' may be ww For example, G' may be

[0069] In some embodiments, G' may be the optionally substituted Cszcarbocyclyl fused to a 6-membered arene or fused to a 5- to 6-membered heteroarene. The Cs.7carbocyelyl fused to a 6-membered arene or fused to a 5- to 6-membered heteroarene may have (S) or (R) stereochemistry at the point of attachment to the parent molecular moiety. The Cs.7carbocyelyl fused to a 6-membered arene or fused to a 5- to 6-membered heteroarene may be a monocyclic Cs.cycloalkyl fused to a 6-membered arene or fused to a 5- to 6-membered heteroarene. The 5- to 6-membered heteroarene may be a pyridine. A fused 6-membered arene or pyridine may be optionally substituted with halo, Ci-alkyl, ~OC;aalkyl, or Cascycloalkyl. Accordingly, G N, X halo 0G _salkyl 7 may be , or N; N, [ ® Foc, alkyl halo OC .qalkyl # . such as N, [s 3 J ( I pl Cen Br , or For example, G' may be N, N, (J ® OCH; Z ZN0CH, Br Lor , such as N, N, 9 is OCH; F # OCH; Cor , or

[0070] In the compounds and embodiments described herein, G! may attach at a ring atom in IO ring atom ring fusion adjacent G! adjacent to a ring fusion in G, (e.g., fing fusion ).

[0071] In the compounds and embodiments described herein, G' may be Io CANA Rf I I i Anns « wherein X10 js CRW ol rN; Xs CR! or N; X'is CR!* or N; XE is C CR or N Xi s CR! o rN provided that no more than two of X!%-X" are N; R'% is hydrogen, halogen, C1.salkyl, or Cisfluoroalkyl; R'® is hydrogen, halogen, Ci-salkyl, or Ci.sfluoroalkyl; R¢ is hydrogen, halogen, Ci.salkyl, Ciafluoroalkyl, or OCi.salkyl; R!% js hydrogen, halogen, Cj.salkyl, Cisfluoroalkyl, -L'-X', or -L'-G'*: RY¢ is hydrogen, halogen, Ci.salkyl, or Crafluoroalkyl; and R'% is hydrogen, halogen, C1alkyl, Cjfluoroalkyl. OH, OCialkyl, OCi4fluoroalkyl, NHz, NHC14alkyl, N(Ci-salkyl):, or a 4- to 8-membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, Ci- salkyl, Cr4fluoroalkyl, OH, OCialkyl, OC 4flucroalkyl, NHa, NHC alkyl, and N(Ci-salkyl)z.

[0072] In the compounds and embodiments described herein, G! may be an optionally 106 12 13 R xX XS x14 R10 2 ZF RI substituted 10-membered fused bicyclic ring system of formula wv each "======" represents a double bond or a single bond; Xs N 3 CRY, or HR 1%: XH s CRY or N X"is CR or N; R'% is hydrogen, halogen, Ci-salkyl, or C;.sfluoroalkyl; RY is hydrogen, halogen, Crsalkyl, or Ci.4fluoroalkyl; R'% is hydrogen, halogen, C1.salkyl, C14fluoroalkyl, or OC alkyl; RY js LX". hydrogen, halogen, Ci.salkyl, Cisfluoroalkyl, or —L'-G'2; R'% is hydrogen, halogen, Ci.4alkyl, or C;.4fluoroalkyl; and Ris Ciaalkyl, —-OC1salkyl, hydrogen, halogen, Ci4fluoroalkyl, OH, ~OC.4fluoroalkyl, NH, NHC1.4alkyl, N(Cr4alkyl)z, or a 4- to 8-membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, Ci- salkyl, Crafluoroalkyl, OH, ~OCi4alkyl, ~OCsfluoroalkyl, NHz, ~NHC<alkyl, and ~-N(Ci- aalkyl)a.

[0073] In some embodiments, each "======" represents a double bond; X'? is N; and X'* is CR". in some embodiments, R'™ is hydrogen; R'® is hydrogen or Cralkyl; R'® is C(O)N(R'H; or ~OR™; R'* is hydrogen; and R'*! is C1alkyl or OCialkyl.

[0074] In some embodiments, each "======" represents a double bond; X'* is CR'%;, X'* is N; and X™* is CR". In some embodiments, R'”" is hydrogen; R'?® is hydrogen or Cialkyl; RY is hydrogen, Cj.ialkyl, or —OCialkyl; R'% is hydrogen or Crsalkyl: and R'is Cj.alkyl N, N, XN Lo “OC alkyl C - “Cy alkyl or ~OCualkyl. Accordingly, G! may be OC, aalkyl Ne Ciqalkyl Ne Ciqalkyl ZF FNC, alkyl OC, alkyl N, x & C1 qalkyl Craalkyl Ny Ngo Craglkyl Cyqalkyl Ny Te... Se ora Tm Ciqalkyl Ny, Craalkyl » - . Cy alkyl N, > = ‘OC 4alkyl or wn ~~ For example, G' may be bbs Ne Ny Ng Ng Ng Ng, = OCH; =“ = = = =~ N N, N N, N, 'S N 'S is 5 Ny Ny Ny Ny = = = OCH3 OCH Z OCH; OCH; a ds a Lor naw

[0075] In some embodiments, each "======" represents a single bond; X'? is CHR; X'* is N: and X* is CR'®. In some embodiments, R'% is hydrogen; R'*® is hydrogen or C1alkyl; R'¢ is hydrogen or Cialkyl; R' is hydrogen or Craalkyl; and R'is Craalkyl or ~OCialkyl. Ns N ~ ( : 0 Ca Accordingly, G' may be C1-salkyl {es OC 4alkyl Accordingly, G' may be wb oo (e.g. or oo a such as N,; x en were ).

[0076] R'™ may be hydrogen or chloro.

[0077] R'™ may be hydrogen or methyl.

[0078] R'™ may be hydrogen, methyl, chloro, or OCHs.

[0079] R'™ may be hydrogen, halogen, C1-aalkyl, cyano, OC alkyl, OC.4fluoroalkyl, NHa, Cradlkyl Q ne NHC:salkyl, N(Ciaalkyl)s, NHC(O)Cialkyl, N(Ci-salkyl)C(O)Crsalkyl, - Craalkyl Craalkyl aN AN Fos combbs ok ne ibs Craalkyl Hoy Bur? G1 .aalkyl HN. Oo HN Oo “YY Craalkyl Craalkyl J Neg, alkyl oh Nag, alkyl @ ha Craalkyls hia anbas Pr or Craalkyl OH Craalkyl~ -Craalkyl x ST Cr4alkyl Craalky! vo Ne HNC Or Ne HN Q Sri Ne HN Oo ¥ il HN hg Hn Cyaalkyl” Rag oY Craalkyl _N._O Cyqalkyl YY Cy 4alkyl oO ala AN Gr48lky 0, N, Phe he HN._O HN__O HN._O HN _O pO HN DH 0 0 N, Wn o Dre A, Wt hia 1a hia IN oH he or y o mio Li Xs ~ il OO w wean wan o 2, ute lg oa Z ( 12 1.0 Oo a his 72 HN. oO XL Craakyh 0 L 0 aaloh 0 HH J12 Hg NE "yr? HN “pe o ey ea © dia te ! HO “So o alk, Cisalkyln lo 1 he H C1aalkyls, ) NTH) 12 had 7. Sarg tg Ship I Hop Rig Lie Cho Hop H Cq4alkyl ( 2 ) ( N ) «0 12 Xe 13 12 13 12 13 0 0 x gar LOWY CL FY OF CHO - © ¢ ~° © Cake oe RW A ow he alkyl cyl 7 Pug Lri ky Puy Ba yl a ay Corea oN C1 4alkyl Mery The Ts Ay | | oO oO 1 AL A ycraaii AN C,aalkyl Nr) r Ny ¥. I yw: 1 Ye bo = I , i ah OC 4alkyl ; ~~. Aer, Cy.4alkyl a phe NG Gla AIS 1a ~C ANTS he E F145 Fahy \ N O30 eG C #7 Gh Sh \, Oia ~ ) J wd Je des I Supt So Mer, a 4 L ba 2 4 ! | 3) } SN 13 Ae alkyl OC 4alkyl I kyl C1aalkyln_O PH )i2 SF ro —_—_— N Cyqalkyl oO PN ; ~ ag © NH Ciaalkyl Cqqalkyl 7H SH ig Craalkyl So =N nia i) Ny NN WL SN SN “nn _— ahi wh or yr wh whe wh or ake In RY GY may be a 5- to 6- membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S$, and optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, Ciaalkyl, Crsfluoroalkyl, OCiaalkyl, OCiafluoroalkyl, Ciucycloalkyl, and CHaCacycloalkyl. In RY, G'® may be a 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, and optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, Cisalkyl, Ci- sfluoroalkyl, OCi4alkyl, OCuafluoroalkyl, Ciacycloalkyl, and CH2Cs.cycloalkyl. For example, R'” may be hydrogen, fluoro, chloro, bromo, methyl, ethyl, cyano, OCHs, OCF3, ! | ! © AN AN ” ~o 0._0 o o N HOO HaN.___O NHz, N(CHs)z, NHC(O)CH:, wan, kas bes xX x x NON Sey wy NS Boom ao Woo woo woo To ~ HN. _O HN. _O HN. _.O HN. _O HN. _O TY Y YY I Y I od co od DE | HNO HNO HNO HN_O HNO _N_O rr Ir Yr I I> HH Hoo 0 rr | oe HL Pt o o o NT Nar Se™S Xr ONT > NTN ao (J HR oI Va oC Wa ha NF ~~ ZF ~~ : i HN rr o Noe OY TY N? HNL [o] HN. O N 7 HN I N-NH AON 7 ON NNN ™ sh rom 7 NAN ~¢ IA / oo £ “3 £3 I Ul \ Lo LX ~F 7° HN 20 ~ ~° HN 7© HN. 20 HN. 20 MN. 20 whe a J TP VP UR A oo ¥ ¥ Gs AN Q, Sn ig Ng Nel N, x J pe ¥ HN. _.O Y I "7 lL nl IF HN HN +° pr x HN Oo hg oO = o HN ye & o Q o ~a oral arn a X, ay HN ht 0 oo I oo I oo I ! HN. _O HN._O HN._.O ve Y I Y o™S ry H © Ape IN x | oO ‘No / =N SA po N SNS MO HNO 0 MNO 0 A UNGO Yr ™ XY "rr >Y So | 1 oO oN J ON” Bh ~&o Ta J 1 1 “a on no om Q ag ts ~&o , Y J H i NANO NANO ght go om © © H Hop i H NSN rs ® IT YY ¥YTY % rr re TS PrP pO ey NM Be 1 ew de ae aw a ade de de ae O Oo OCH: J ~~ oo ae Ar Q A Lod mM NS y Iv a 0 UN NN [o] Oo ™ ~~ yO NT Ay ~s rt or OCH CHa “o SN ~~ ™ A \ = NN ALO 1 n 1 i UN AN = Nz 7 H 1 54 Cs bd -" % 3 i | I 5 H ! who Law , wha | wha , wh y id cH 3 YY, Nort Yl \ A 7 NN N=N NH ON Ae N 5 / N N N N N N re en N=N Yn > CNN NN YN Oy! ~N N Na NH N A xn Ne Y Y yr he “7 hg Sv Sn SN “7 / \ rn 4 3 Y Ro a I An Vib 2 oN Ny Sa Si” Raph oy WONT SN SY SN SN W | oH, Ae NG To To OCH; A 4 4 A 9 9 SC CCC OS No Yy wYYXYY YY oY .. ] =N NN Nz ~n

[0080] R!% may be hydrogen, methyl, ethyl, or chloro.

[0081] R“ may be hydrogen, methyl, ethyl, isopropyl, OCHs, NHz, NHCH3, or 4- fluoroazeidin-1-yl. R'* may be hydrogen, methyl, ethyl, isopropyl, or OCHs, R'% may be ethyl or QCHs.

[0082] The compounds and embodiments described herein include compounds and embodiments wherein X!? is N; X!! is CR; X12 is CR!%: X!3 js CRI: and X!* is CR!%,

[0083] The compounds and embodiments described herein include compounds and embodiments wherein X'° is CR'%; X!! js N; X'? is CR; X!* is CR'%; and X'* is CR,

[0084] The compounds and embodiments described herein include compounds and embodiments wherein X'° is CR'%; X!! js CR; X? js N; X* is CR'%; and X'* is CRI.

[0085] The compounds and embodiments described herein include compounds and embodiments wherein X'° is CR'%; X!! js CR; X'? js CR; X'* is N; and X'* is CR,

[0086] The compounds and embodiments described herein include compounds and embodiments wherein X'¢ is N; X'! is CR'®; X'? is N; X'* is CR'®; and X'* is CR".

[0087] The compounds and embodiments described herein include compounds and embodiments wherein X'¢ is CR'%; X'! js CR; X js N; X" is CR'%; and X' is N.

[0088] The compounds and embodiments described herein include compounds and embodiments wherein X'¢ is CR'%; X'! js N; X* is CR!%%; X** is N; and X' is CR!%.

[0089] The compounds and embodiments described herein include compounds and embodiments wherein X'© is CR: XM is N: X12 is N: XV is CR: and X'4 is CRI. RIM i, Gd RI® NN Ky AN gon

[0090] In the compounds and embodiments described herein, G! may be nn ; wherein X™ is CR!% or N; RI® is hydrogen, halogen, Ci4alkyl, or Ci.afluoroalkyl; RI is hydrogen, halogen, Cialkyl, Ci4fluoroalkyl, ~L1-X!, or ~-L1-G'%; R* is hydrogen, halogen, Cralkyl, or Crsfluoroalkyl; and R** is hydrogen, halogen, Cr.aalkyl, Cisfluoroalkyl, OH, OCraalkyl, OCisfluoroalkyl, NHz, NHC14alkyl, or N(Ci-salkyl)2. Tocluded are compounds and embodiments, wherein X' is CR! Included are compounds and embodiments, wherein XM is N. Included are compounds and embodiments, wherein R™ is -LL-X1 In -L1-X1, X! may be ~OR, ~N(R14)2, cyano, ~C(O)OR™, ~C(OIN(R¥)z, ~C(O)N(RH)SOR?, -- CNH)NHOH, ~C(O)R™, -NR¥C(O)H, or -NR¥C(O)R', wherein RI and RI? are as defined herein. In Rand R™ in ~L1-X!, G1 may be Ci.scycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl, wherein G' is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Ci.alkyl, Ci-shaloalkyl, oxo, - L2-X% and L2G"; wherein X?, at each occurrence, is independently ~OR', ~N(R'%)z, C(O)N(R*),, ~C(O)R*, -NR¥C(O)R', and L?, G'®, and R* are as defined herein. In -L'-X!, RY at each occurrence, may be independently Cisalkyl or G In RY and R™® in -L!-X%, Re, at each occurrence, may be independently hydrogen, Cisalkyl, or G®. In-L'-X' X? at each occurrence, may be independently ~C(O)R'. In -L'-X!, G"* may be a Ca.scycloalkyl, a 5- to 6-membered heteroaryl containing 1-2 heteroatoms independently selected from O, N, and S, or a 4- to 8-membered monocyclic heterocyclyl containing 1-3 heteroatoms independently selected from O, N, and S$, the heterocyclyl being attached at a ring carbon atom, wherein G'# is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Cialkyl, Ci-shaloalkyl, oxo, ~L*-X?, and -L*-G®. In-L'-X', G™ may be a 4- to 6- membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and S, or a 5- to 6-membered heteroaryl containing 1-2 heteroatoms independently selected from O, N, and S. In -L'-X’, R, at each occurrence, may be independently hydrogen, C;. alkyl or G'°. Rod RI®N, BS & RI

[0091] In the compounds and embodiments described herein, G' may be ana ; wherein R'® is hydrogen or Cisalkyl; R'® is -C(O)OR'®, ~C(O)N(R'®):, -C(NH)NHOH, or — C(O)N(H)SO:R™; and R' is Cir.salky] or OCialkyl.

[0092] In the compounds and embodiments described herein, R'® may be ~C(O)NHR,

[0093] Tn the R!™ of R'%, are compounds and embodiments wherein at least one occurrence of R'is G* or -C1salkylene-G'®. The G'* may be Cascycloalkyl, 4- to 6~-membered heterocyclyl containing 1-3 heteroatoms independently selected from O, N, and S and attached at a ring carbon atom, or a 5+ to 6-membered heteroaryl containing 1-2 heteroatoms independently selected from O, N, and S, wherein G' is optionally substituted with Ci.salkyl, oxo, or ~C(O)RY. The 4- to 6-membered heterocyclyl at G'* may be tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, or 2,3-dihydro-1.3,4-oxadiazolyl; and the 5- to 6- membered heteroaryl at G' may be imidazolyl, pyrazolyl, oxazolyl, pyridinyl, or pyrazinyl. In embodiments wherein R™ is ~C(O)NHR', R" is G'* or ~C1ealkylene-GY, G'* is cyclopropyl, cyclopentyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, 2,3-dihydro-1,3,4-oxadiazolyl, imidazolyl, pyrazolyl, oxazolyl, pyridinyl, or pyrazinyl, and G' is optionally substituted with | 7 a AON o£ \J ~N NN ™ / ™ VY ~~ NN “iy? Xp hd HNO ~ Yo a ox hahah gs HN > C1salkyl or oxo, RY may be we wo om win / \ gy NT / \ oN Bogs Ig gg Ne N-NH ¥ “Ng M0 i ! HNO Y he + “" Y In HN, 0 HN 20 HN. OO HN__.O HN__O HN.__O HN. O PRET Ry eR hy ksi abun ne - wn wh won| OF ww To embodiments wherein R'% is ~C(O)NHR'™, R™ is G" or -C1.calkylene-G'e, G1 is azetidinyl, G' is optionally substituted with ~C(O)RY, RY is Crsalkyl or G'°, and G™ is " A, a I ! HN Oo HN. Oo tetrahydropyranyl, pyridinyl, or thiazolyl, R1% may be xX I 0 OQ 0 ~° o._ thm - HN v° o™SN I, pn) OQ N. A 0 N or bois www OT ~~ 1] Ji ir SAR SAN Ape Gh 1 A k HN._.O ¥ YY n 's HN._,O HN._.O HN._O | rN TY cr inns ww OT wns GH may be ane HN. _O A I N, ( T J 7 Ciaalkyl Jad and G* is as defined above.

[0094] In the R' of R'™, are compounds and embodiments wherein RY, at each occurrence, is independently hydrogen, Ci.salkyl, Cichaloalkyl, ~Cz4alkylene-OH, —Cz.1alkylene~OC;. salkyl, ~Casalkylene-N(Crsalkyl)s, ~Casalkylene-N(H)C(O)Cialkyl, or ~Caaalkylene- N(H)C(0)G' and G' is as defined herein. In embodiments wherein R'™ is ~C(O)NHR'", and R'“, at each occurrence, is independently hydrogen, Ci.calkyl, Cshaloalkyl, ~Ca4alkylene-OH, ~Ca4alkylene-OCi.salkyl, ~Ca.aalkylene~N(Ci.salkyl)z, or ~C24alkylene-N(H)C(O)Ci-aalkyl, NN SoS HON H Sern I ! ob Cd HN. _.O HN __O HN. _O Y °° XY N Q o i Hebi! R'“ may be le whe oO NNN LS H HN. _O ~ oi I HN. _.O Y wn wav OF bw In embodiments wherein R™* is ~C(O)NHRY, R'®_ at each occurrence, is independently hydrogen or ~C-salkylene-N(H)C(O)G™, and G™ is OO oO u o Cy N HN. oO NT HN _.O Nz HNL IT SN ol p© N. ~~ 5 nyl, pyridinyl or thiazolyl, R'*™ may be nas ane, OF oO H Q N Lr po Ra 3 ~° RI® N, XN

[0095] In the compounds and embodiments described herein, G! may be wan J RM is Craalkyl or G1; Gis Cs.scycloalkyl, a 5- to 6-membered heteroaryl containing 1-2 heteroatoms independently selected from O, N, and S, or a 4- to 8-membered monocyclic heterocyclyl containing one heteroatom selected from O, N, and §, the heterocyclyl being attached at a ring carbon atom, wherein G' is optionally substituted with Crsalkyl; R® is hydrogen or Ci4alkyl; and R!% js Cr.alkyl or OCialkyl. G' may be cyclopropyl, cyclobutyl, azetidinyl, piperidinyl, oxetanyl, tetrahydropyranyl, or pyridinyl, wherein the azetidinyl, piperidinyl, oxetanyl, and tetrahydropyrany! are attached at a ring carbon atom and G" is optionally substituted with C12alkyl. G** may be cyclopropyl, cyclobutyl, azetidin-3-yl, piperidin-4-yl, oxetan-3-vl, tetrahydropyran-4-yl. or pyridin-4-yl, wherein G'# is optionally ala ala L Et Pe) © k ¥ N, N © [ 5 . 7 OC14alkyt 7 Craalkyl substituted with Croalkyl. G! may be ww or ww 3 O10 Lo mu Rakin ad ahnan: R10d Eo, El 2 Nay xe ANF gio { wan : Rix RN, i FZ RIO 1 ad :

[0096] Included rs © and po Care compounds and embodiments, wherein R'is ~L'~G!, In-L~G'®, G' may be independently a 5- to 10- membered heteroaryl or 4- to 10-membered heterocyclyl, wherein G*# is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Ci-salkyl, Crshaloalkyl, oxo, -L2-X2, and -L2-G"™; wherein G™ is a Csscycloalkyl or a 4- to 6- membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and S, wherein G™® is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, Cialkyl, Cishaloalkyl, oxo, ~OH, and -OC1. salkyl; X2, at each occurrence, is independently ~ORY, ~N(R')z, ~C(O)N(R!), ~C(O)R, or ~ NREC(O)RY; and RY, at each occurrence, is independently hydrogen, Crealkyl, Ci-shaloalkyl, G™, or ~Cralkylene-G™, wherein alternatively two RS, together with a common nitrogen atom to which the R'® attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of Crsalkyl, Ci<haloalkyl, oxo, ~OH, and ~OCi.alkyl. G' may bea 4- to 6- membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and S. X?, at each occurrence, may be independently ~OR", ~C(O)R*, or ~NR*C(O)R® R'¢, at each occurrence, may be independently Ci.ealkyl. 1a Le RI® N, X

[0097] In the compounds and embodiments described herein, G! may be nnn , wherein Gis a 5-membered heteroaryl containing 1-3 heteroatoms independently selected from O, N, and S, a 4- to 8-membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and S, or an 8- to 10-membered fused bicyclic heterocyclyl containing 1-3 heteroatoms independently selected from O, N, and S, the heterocyclyl and heteroaryl being attached at a ring nitrogen atom, wherein the 4- to 8-membered monocyclic heterocyclyl is optionally substituted with 1-2 substituents independently selected from oxo, C1. alkyl, OChraalkyl, C(O)Crsalkyl, —Casalkylene-OCiaalkyl, GY, and ~C1salkylene-G'% G' is Cs.scycloalkyl or a 4- to 6-membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and $; R'® is hydrogen or Ci4alkyl; and R'is Ci.ialkyl or OCialkyl. G" may be a piperazin-1-yl, piperidin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, imidazol-1-yl, or hexahydropyrazino[2,1-¢c][1,4]oxazin-8(1H)-yl, wherein the piperazin-1-yl and piperidin-1-yl are optionally substituted with 1-2 substituents independently selected from oxo, Cjaalkyl, OC; aalkyl, C(O)Cualkyl, —Crzalkvlene—OC 4alkyl, and G'*. G'* may be 0 oO 1 I Nn 1 Nr a 1 0 3H rq oN” Ns A 9 J 3 JO i Wr N_~ \ 3 No 3 x or OCH: So oN FS NT ey wid rN WN ~~ VY A 0 Lo , or wr wh HO H oo Yq ” , or G’ may be N | = # OC1 alkyl hr: , wherein G'? is as described above. fe] RI®N, Z RIO

[0098] In the compounds and embodiments described herein, G' may be an ; wherein G' is a 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and §, a 4- to 8-membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and §, or an 8- to 10-membered fused bicyclic heterocyclyl containing 1-3 heteroatoms independently selected from O, N, and §, wherein G'* 1s optionally substituted with 1-2 substituents independently selected from oxo, Craalkyl, OCi. salkyl, C(0)Crsalkyl, -NHC(0)Crsalkyl, ~Casalkylene-OC alkyl, G'°, and ~C)-3alkylene— G"; G' is Cscycloalkyl or a 4- to 6-membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and 8; R'® is hydrogen or Ci.salkyl; and R'is Cralkyl or OCralkyl. G'™ may be a piperazinyl, piperidinyl, tetrahydropyridinyl, morpholinyl, imidazolidinyl, tetrahydropyranyl, dihydropyranyl, 1,3,4-oxadiazol-2(3H)-yl, pyrimidinyl, pyrrolyl, pyrazolyl, tetrazolyl, hexahydropyrazino[2,1-¢][1,4]oxazin-8(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, or 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, wherein G1 is optionally substituted with 1-2 substituents independently selected from oxo, C1- alkyl, OC1aalkyl, C(Q)Craalkyl, ~NHC(Q)Cr4alkyl, ~Casalkylene-OC1salkyl, G, and ~C1- salkylene~G'®. G'* may be a piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, tetrahydropyridin-4- yl, morpholin-4-yl, imidazolidin-1-y}, tetrahydropyran-4-yl, dihydropyran-4-yl, 1,3,4~ oxadiazol-2(3H)-yl, pyrimidin-3-yl, pyrrol-2-yl, pyrazol-4-yl, tetrazol-3-yl, hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl, hexahydropyrrolo[3,4-¢]pyrrol-2(1H)-yl, or 5,6~dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, wherein the piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, tetrahydropyridin-4-yl, morpholin-4-yl, imidazolidin-1-yl, tetrahydropyran-4-yl, dihydropyran-4-yl, 1,3,4-oxadiazol-2(3H)-yl, pyrimidin-5-yl, pyrrol-2-yl, pyrazol-4-yl, and hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl are optionally substituted with 1-2 substituents independently selected from oxo, Cialkyl, OC1alkyl, C(O)Ci~alkyl, ~-NHC(0)Cralkyl, Ca. salkylene-OC1alkyl, GI, and ~Crsalkylene-G'®. G optionally substituted with oxo, C1. salkyl, OCraatkyl, C(O)Crdalkyl, -NHC(0)Ci-salkyl, or ~Cz3alkylene-QCi4alkyl include CH3 YO N° ANS ANS N=N ad Ba N. \ | x W-N N=N Send nN AN ANN NS NS Q, Q, Sn YN Ty NSN = a & - | YS N ~~ / Marah & ~~ SNS Sy CLL LLL Ant 1 oH, Po NN To aN ON A ALAN AN S WEN PEN og A Ar \N / _N_. we, TC) NT OSN Ny nN hg ~N SN So =N NN Ng No ~ Fa oy Ny N Jor ww G'* optionally substituted with G'®, wherein G'™ is oxetanyl, include Gla N, x | # OC14alkyl Y ou 2 Ny oy # Cyaalkyl ww G' may be aa ata Gla Craalkyh Ne Craalkyh Ng lL | Cr4alkyl 7 OC 4alkyl aan , or ~ > | a ERT | mnt A MATA Lda ann , or Ea , wherein G'* is as described above. ala Gla NT | = OCq4alkyl Fann . Gh x | = Craalkyl 3

[0099] G' may be nn TT or ww RE wherein G* is as defined herein. GY may bea S- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, a 4- to 8-membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and S, or an 8- to 10-membered fused bicyclic heterocyclyl containing 1-3 heteroatoms independently selected from O, N, and S, wherein G!* is optionally substituted with 1-2 substituents independently selected from oxo, Craalkyl, OCraalkyl, C(0)Ci4alkyl, -NHC(O)C14alkyl, ~Ca.zalkylene-OC.salkyl, G'°, and ~ Ci.aalkylene~G'; G' is Cascycloalkyl or a 4- to 6-membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and §. G'* may be a piperazinyl, piperidinyl, tetrahydropyridinyl, morpholinyl, imidazolidinyl, tetrahydropyranyl, dihydropyranyl, 1,3,4-oxadiazol-2(3H)-yl, pyrimidinyl, pyrrolyl, pyrazolyl, tetrazolyl, hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl, hexahydropyrrolo[3.4-c]pyrrol-2(1H)-yl, or 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl, wherein G' is optionally substituted with 1-2 substituents independently selected from oxo, Cisalkyl, OCialkyl, C(O)Crsalkyl, NHC(0)Cr-salkyl, C:salkylene-OCiualkyl, G®, and —Cusalkylene-G'™. G'* may be a piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, tetrahydropyridin-4-yl, morpholin-4-yl, imidazolidin-1-yl, tetrahydropyran-4-yl, dihydropyran-4-yl, 1.3,4-oxadiazol-2(3H)-yl, pyrimidin-5-yl, pyrrol-2-yl, pyrazol-4-yl, tetrazol-5-yl, hexahydropyrazino[2,1-c][1,4]oxazin- 8(1H)-yl, hexahydropyrrolo[3.4-c]pyrrol-2(1H)-yl, or 5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl, wherein the piperazin-1-yl, piperidin-1-yl, piperidin-4-yl, tetrahydropyridin-4-yl, morpholin-4-yl, imidazolidin-1-yl, tetrahydropyran-4-yl, dihydropyran- 4-y1, 1,3 4-oxadiazol-2(3H)-yl, pyrimidin-5-yl, pyrrol-2-yl, pyrazol-4-yl, and hexahydropyrrolo[3,4-c]pyrrol-2(1H)-y1 are optionally substituted with 1-2 substituents independently selected from oxo, Craalkyl, OCr4alkyl, C(O)Cr4alkyl, ~-NHC(Q)C14alkyl, ~Ca- aalkylene-OC14alkyl, G', and -Ciaalkylene-G'®. G'® optionally substituted with oxo, Ci. aalkyl, OCraalkyl, C(0)Cr4alkyl, ~NHC(Q)C14alkyl, or ~C2.3alkylene~-QCi4alkyl include QCH3 “Sy ~° NN ANS NS N=N at Bat No. _N. \ N Sen nen Sen BN NN ANN NG NS Q, Q, DENTE y Kg Ye p Rki ge LE yy. Fy LA 3 NUR N Sy” Sy MOE OY WY yy Pn | OCH3 A | i NS To oN og A A ANN NN oy pon male wy TI J Ny NN, N hg “w’ Sy oN po A Ny RN ON ON YY YLYY So =N NN AN No ~ @ oy SN CL 2. OF OC 4 fluoroatkyl CN CN re S CS Z Ciaalyl halo Craalkyl

[00100] G! may be ww ahs 2 oN oN oN NH, N N N N, [2 [ © [ C. kyl Z OCraakyl Ne N 148kyl SF Cy aalkyl Crqalkyl ~OH ~OC aalkyl r r N N [ [ | Sf CCraakyl OC 4alkyl mT Dh N, ( »®! yl Z Cigalkyl o Crayon Bo = I Cralkyl ala ala 1 1 OC salkyl ~° © ANH: CS ® ( 7 # Coaakyl OCiaalkyl Craakyl Craalkyl Cyaalkyl Craalkyl Ox, red © NC salkyl rd NH NH No NH eC rd TC 4alkyl Fl N, N, N, N. I [7 | | Z Cr.4alkyl 7 Cyaalkyl Z Cr.4alkyl 7 Craalkyl ne go J J Gla N(C4alkyl)y Ye Ho), HN +° NL 1 int Yha Mk Gla a Ge HO Hi go ee 2 C ® Cs ZZ = Zo alkyl Craalkyl Craakyl 7 Craalkyl oer wee ne 0 OO Hs HM HN. _O kd I N, i ) : “Craalkyl Q o cra 0 "0 i n 3 HN. _O HN. OC Y Y iy N N, N. S ( Y N ( )@ X.. # Cy4alkyl 7 Ciqalkyl Cc, AO Cy 4alkyl fo} | | HN._O HN._.O HO 0S i Ww = 7 Craalkyl OCsakyl Craalkyl eo I H H HO HN._O HO N, N N. ® [> [ 7 OCraalkyl Craalkyl OC alkyl 0 H Cy Oo MN 1 Crqalkyl ha ar Naa HNY13 wl i ( 12 ( 12 ia 2 HN Oo HN _O . ” ® ® = r AAA VW AYN Sui bo We) *Y OF hs le ols el AN Hp HN Oo HN AN re Na Nor | | l Z F oo a NF MH MH HN._.O i N, hy halo Cyqalkyl : Ng 7 Craalkyl halo OC alkyl Cqaalkyl Ny Cy 4alkyl Ny. # OC 4alkyl 7 Craalkyl CN OC 4alkyl CIN LE Cq4alkyl Ny Cy 4alkyl Ny | | 7 OCH 4alkyl 7 Craalkyl ale ata Cj 4alkyl Ny. C,.4alkyl Ny | | ZZ Craalkyl # OC4alkyl Cray O20 Cq4alkyl Ny PFC alkyl HOO Cray Ng, # OCH alkyl Crallyl—0. 0 FN. 20 Cy qalkyl Ng Cy aalkyl Ny # OC 4alkyl # C+ 4alkyl Cyqalkyl Cr4alkyl Craalkyl baa ratty HNO HN 0 Cyaalkyh Ng Craalkyi Ng | | 7 Cy4alkyl 7 OC 1 4alkyl Crave) N(C1 alkyl), Ns © Cy4alkyl Ny l ll # Ci.4alkyl LA Hi p© Cradlkyin Ny | 7 Cray! oye CN SAN Cy alkyl NS Cy4alkyl Ns = Z a3 Cyqalkyl Gla HNO Ci4alkyl rs ZZ OC 14alkyl Craalkying2 Te=o0 OH 0 HN NH Cqaalkyl Ny Cy 4alkyl: Ng. Z ‘OC 14 alkyl 7 OCq4alkyl Cia alkyl, | OH QO » 1 Cy 4alkyl / = or y! Cy4alkyl © Oo i AN ZZ oy Cradlkyl Cq4alkyis NH INP o Ps Ne Ciralkyl Ng_-Craalkyl C14alkyl z or Craik Z PG cali lens] sas AN aap AN =. . atbewl «. alleul Tour NE Cy4alkyl Ny Noo Craglkyl Cygalkyl Ny ~ ( X x Te OC alkyl Ta Cy qalkyl N, ( bi J FZ ‘OC salkyl Ci4alkyl: Ny, Ciaalkyl TL, halo NT | 7 Craalkyl C1 alkyl Oras” cv hia ) OC alkyl OC 4alkyl oF 1% Ga = i x N = NT 1 | — 7 Craalkyl OC14alkyl # Crealkyl Ci4alkyl a" N14 SIRYE xX rs NN NT Ny x Na | | Ar SA As # OC 4alkyl Craalkyl Craalkyl OC alkyl Ns | 7 OC 4alkyl or NO NO C.qalicyl Ci.qalkyl” « 1-4alkyl kd 001 r -

[00101] G' may be el! Y OC 4alky! HNO N, rhs > i" “OC 4alkyl OC, 4alky! QC, alkyl N N [ | Z Craalyl OC, qalkyl - Cy.qalkyl OC1.4fluoroalky N, [rs 7 Cirualkyl H ren Co galkylo™ AO Cray” ( fs 7 OC; alkyl 7 OC alkyl Gla N(C1.4alkyl)2 Yi. a HN _O ~ HO), HNO Ne NL HN._.O HN. _O “i HN. _O ki YY N° YY 2 2 Craalkyl Cradkyl Craalkyl Craalkyl "I any ol a o o HTS =H o eo MA HN. _O NP HN +° N ( @ 7 Craalkyl 1 N ( - = Craalkyl so hi: HN O N, = eo, Cc an 7 Oo Cc al 7 0 al C0 | | HN._.O HNO HN._O ~ " hid ® * # Cr4alkyl 7 OC 4alkyl Craalkyl ih 0 | <Q 0 N,; ( TX 3 # OC4alkyl el HN 7° HN © id Na Ny = = = OCq4alkyl Craalkyl ‘OC 4alkyl 0 oo 0 i oto oto Cqalkyl 0 x {Pho HN 0 HN HN._O HN._O ZZ = o = = 5 H H Ck jo} ¥ Na Co OC, alkyl Cy 4lkyl Ng 7 Craalkyl ll il Cq4alkyl Ny # OC 14 alkyl Cy 4alkyl p© Craalkylh Ny | : # Craalkyl Crealig™y ), . Np Cy4alkyl Na 7 Craalkyl Cyqalkyl iN. Cq4alkyl Ny Z OC 14 alkyl ww ala NC 4alkyl)y Ne OC 4alkyl CC FNP, alkyl Anan i 1s Ge No HNO Craalkyl Ng Craaliyh Ng | | Z C1 alkyl Z OC1.4alkyl Oo a (8 HN N, | =) - > ~Cyaalkyl 4

[00102] In the compounds and embodiments, wherein G' is wan eo eo o 0 ? or | [ HN Oo HN Oo N, N [> [ 7 Cralkyl 7 OCH alkyl ann ana nan wanns or eto ns ©, G™ may be a 4- to 6-membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and §, or a 5- to 6-membered heteroaryl containing 1-2 heteroatoms independently selected from O, N, and S.

[00103] CN CN CN CN Br OCF 3 CN a | & wus whe xT OCH3 do JT Br CN CN CN CN NH» N, N, [> {I J Co F OCHa 1. 1 CN CN NH, N, N. N, ® [ i» ; ZF NH; = 'g = to] oy oH OCH ~OCH; mn ¥ MA o oH Ng Ng Ng ZZ = Ca y I I do N N. | [0 NP OCH; Lo he H Wo PAN Y $ NY | | I | o = ~~ - = ! ¥ 3 E x = ocHs OocH, # ocH, wher oh wh i nh ON N, rs ® ~~ ¥ Y NH NH ~~ ! ! pe © ANH N, N, N, N, N, x x x i = i x = = = = = A AAA Aa AAA IU 0 Ng oO gs NS NA ° Oo; o ANON NN N pe NS nN Ny NH Ns Ie ANH Ns S S ® oo ~ > = 5 ~ — X x xX xT OO SN So mn A ™ ze: iN I 1 1 iE 1 nr 4 Ne 1 I \ | 3 rd rr iA 3s PA ANS AN AN s ( S CS Z ocHs ocHs OCH; OCH3 “So ~ NN po ON NO 1 a Pr TE 1] NN PUN NL PLN Ns ¥ . wr LE : H () ® S S = Z 7 OCH, OCH 7 OCH; OCH; hr whe who wb ON \ N-N NT NSN 0 AN SS re rs ® S ZZ OCH = 2 Ca No Pn =N N=N MN ANN CA AN Si Jno oe rm N. NH Sag? Nv N ve Sy” N ry ® rs rs s ZZ #7 OCH # # oH: oo ne do ne ne OCH, ANN AN ANS CR Sn ~ “~# ~~ 1 1 1 1 fe r™ Te ZZ ZZ =F = OCHs fam ~~ #2 NAN ~N p Yo o os Lo n 7° N 7° N, Ny N I TL J { N. pr N* pe @ il oo gy oh —~N_N xn N NY al of “yr NE ~~ Lobe HNO LO NG LO HN hn Ws Ho Ng N, Na 0 oO oN LL HN QO HNO Y Y Na Ny o Nl Ad Ae No 1 = NT LU Nl Hoo i I tN. oO Orn N HN. A \ Ne) N, (S oh t N, A CQL OO oO "OL H H SH OH OL 1 o re CJ 3 o NON | H N. HN. o HN N, oS = & haa ss oo ap® HN. _.O S ™ = = = 0 OO 0 o_ fo, ofa ora HN. OQ ka N, re 2 I. ow XL H H “¢® ol 8A N N, N, noo 9 HY 0 ARAN AAA AANA OCHa o™ o™ | [ET ~~ NA SA NZ x J oO ‘N. HN © 1 i x 7 OCH3 | © HN Oo N L rs #Z OCH; NZ ] / =N N o SAO ‘N NC i HN. _.O ¥ N, XJ 7 OCH3 Br N, ry TOL ~ OCH; CN OCH, Br N, x CL.. OCH3 CN © N, N, N i » i = = OCH: = oh ” at “~~ | ¥ N | NN NN oN ONS ' ! Sn N, x : = OCH3 > 4 ~ON ON Ay \ ON Sn N, A TO. RE “ Nes, : LJ OCH ass “So PLN MN On PN ~~ I T N N [ © Z OCH3 # OCH3 OCH3 ANS ALAN eee Se Opn I N iN I ® re ® ® # OCHS # OCH Z 7 OCH OO ~OO HNO N, N, N, N, [ [> [ [0 # ‘OCH3 # # OCH # ‘OCH SoS SNS Yo i HN._O N rs 7 OCH; NS = Q, Nn HN. _O hd r N, a To... I HN. _O N os = oh No 2 Seo ON” OH CN N, A Too oY L ~ $20 Hag N i x ZF OCH3a al HNC NH N, x = ] OCH3 OH at & NH TQ b <i] NH N. AN YS a > ZF = I oul o” = o” Ne, Ny Na Ny Na =F ZF = ZZ = Ne Na Na Nay AN Ny = & Z & # & Na Na Ny Ny = # % Z 5 = . wn wo mm . AN o” BE OCH4 OCH oo XC = x NT NX | | | I Z ZocH; OcH; 1 1 t ON ~ MN ~ AN N NN (As I 3 yr X x # Sn “Nn SN OCH, Na NY NX rs SN | 1 | = ZZ NF # OCH3 Ns | 7 OCH; Lor NT Ne | A OCH;

[00104] In the compounds and embodiments described herein, R* is hydrogen, halogen, Ci- alkyl, Cishaloalkyl, Ci-shaloalkenyl, ~OR*, ~SR*, —~N(R*)z, ~S(O)R?, ~§(0):R*, S(ORNR¥):, ~C(O)N(R¥)z, ~C(O)R™, -NR¥C(O)R*, ~-NR*¥(C(0)OR*, -NR*¥C(O)N(R*),, NR¥S(0)R*®, -NR*S$(0):N(R*)z, or (7, wherein R* R*, and * are as described herein.

[00105] In some embodiments, R* is G?, wherein ( is as defined herein. Compounds wherein R* is (2, include formula (I-b), wherein G', G*, R?, RS, and R® are as defined herein. oO RS 0 . RS : 8 (I-b)

[00106] In some embodiments, R* is G%; and G? is a Cs.ocarbocyclyl, a 6- to 12-membered aryl, or a 5- to 12-membered heteroaryl, and optionally substituted as defined herein. R* may be G2, wherein G* may be a Cs.scycloalkyl, a phenyl, or a S- to 6-membered heteroaryl, and optionally substituted as defined herein. The S- to 6-membered heteroaryl of G? may contain 1- 3 heteroatoms independently selected from the group consisting of oxygen and nitrogen. R* may be GG, wherein G* may be phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, or isoxazolyl, and is optionally substituted as defined herein. For example, G* may be substituted with 1-4 substituents independently selected from the group consisting of halogen, halo A |__Z-Cuaalkyl Cusalkyl, and Cshaloalkyl. In further embodiments, R* may be phenyl, ww [SX " | | PNCr atkins PG. dnaloalkyl halo I~ Mc aky = 1-4 Crealkyl, and Crcha halo ) |__5—Cranaloalky! NTN Fount po Glen. N, x [ C4.shaloalkyl Z 1-4! Lo SA (Groom ~N COTTON ~N HN "uCrshaloalkyl > C4 haloalkyl = Wr > = yo Caalkyly ~N 1 NTN raha Aw C1 .qalkyl Fh o-! MN ly (Craalioioz My Me caly a Calls _n Lg (Creation rom who . Lor ww In still further CQ ©! ( Call embodiments, R* may be phenyl, 1.48lkyl Cy.ghaloalkyl Z Ch Cy4alkyl halo IN xN XN halo. SN x N FNC, haloalkyl Craalkyl” YF Cyalkyl Pe, alkyl NF Cogalkyl halo. i # Cy alkyl Ci4alkyl rs C.4alkyl = rs re Cy4alkyl rs C1.qalkyl NSN Casaliy” FF Cyhaloalkyl” FF 7 Grea” N TE NY N HN HN oe fog Crist poe a Cray iy | bo Try Wo Craaliyls, _N a alkyl Ca.salkyl \ Craalyls _N bog alkyl 3 A ary A A A Crd N C | oy ~ . Ps Cy ualkyl = oN I C.salkyl \ Ny Mca Se Lor wher . In yet further embodiments, R* may be F phenyl, [) a ~N on Fe A N jos = OI ORS 1) re N) ZF” 7 re ~ N. ~ Ns AP ~N, I> zt ~N yo? SN SN-N, Sn-N, SNC SN, ~N 2, 3 oy =, = a, =, = A op A A A, . Mw or == ops -N, HN Loner In vet further embodiments, R* may be () FC, haloalkyl a halo Ci4alkyl Crain N bog Tratntte Re has hw Lor aes ) In yet further F Sn-N Lon = -N, HN No Sn-N, TN : Soo 7 CF, 2 dor de embodiments, R* may be or pw ee pe Lor hw

[00107] In the embodiments and compounds described herein, R*, at each occurrence, may independently be hydrogen, C;salkyl, or Cishaloalkyl.

[00108] In the embodiments and compounds described herein, R*, at each occurrence, may independently be Ci-salkyl or Ci1chaloalkyl.

[00109] Included in the embodiments herein R%, R%, R*, and R™® may each be hydrogen.

[00110] In the embodiments herein n may be 0. In the embodiments herein n may be 1. In the embodiments herein n may be 2.

[00111] In the embodiments herein, R may be hydrogen or halogen

[00112] Tn the embodiments herein, R® may be hydrogen.

[00113] In the embodiments herein, R™ and R”™ may each be hydrogen. In the embodiments and compounds described herein R™ may be hydroxy and R” may be hydrogen.

[00114] In the compounds of formula (I) are compounds of formula (I-a), wherein R}, R*, and RS are as defined herein. 1 L rR” " oO RS [oe]

[00115] In certain embodiments, the compound of formula (I) is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds. \ 3 1% I NCR Cry ~o NCE cl 7 = ™ £1] 5 N N NN N NAAN GN 4 . Nef i ~ 1 4 ) N © o 1-1 1-2 1-3 NN NN \ i=l LL LL hy bY 3 ~o Nery ~o Nes “o N = =\ Qf J Nog os N Ng A NA © N © NA © \ N-N N-N Oo 1-2 < A “a oF N io N i vy N ° N-N N-N N-N 3 4 ~o CFy So CFs ~0 NCR ® ~ OR! 5 yf NA © NAA, O 1-7 1-8 1-9 N\ N-N \ N-N N-N 3 Fs 4,000 Lr N N-N “hen Ney - N = on (J io ! N. NN N. Ney N N. ¢ N 1g ryt KY JY N 1-12 1-10 I-11 y NN No N-N NTI 1-10 IH 1-12 “N-n Nn \ ~o Pers ~o = 3 Fy 5 Ne N. # 0 1 Ng 0 o we i T.18 1-13 1-14 I-15 1-13 1-14 i=10 bs. Wen en or ~o Pers o Y @! Se) 7 ; ov 2D O00 YR © Joo 9) 1-14 < 3 “0 NP-ck Loo Ny 0 I-17 I-16 1-17 1-18 1-19 2 > L2 1-21 “ *y . N-N Men a NCR Ng = N = AN NN N N ion on ~or so o “YY " ind © ~0 0 5 © 1.2 1.24 ° “ot © Sv © 1-22 1-23 1-24 Ne Neil Nain 1-22 1-23 1-24 New Ny “en “0 NCR Ny Fa N CFy - % - Yo — QUOC Doon Boon Na o o TC T NE ry 1-25 1-26 1-27 nN N — 1 \ N-N ~g 1-25 N\ 0 NSCs om ll —N, A N NN NZ 0 1-28 1-28 1-29 Ama W-n Sen en NS Nor, ~~ ~o Fy = { on { on AL oN | Or N. Oy Y Nog! ATTY Spe fo? & vr ° 131 1-32 1-33 1-31 1-32 1-33 Wn ew en cr, NPE Hor SLOSS or I An Ne © I wy 0 0. x 1-34 1-35 1-36 1-37 1-38 A= i=22 — 3 ey he oR CFs No CFy i) 7 Fa i { =, 2 rE 50 wn OL be | Pp 137 ALTON 2 ° 19 © . 1-38 . 1-39 | 1 1-37 1-38 1-39 \ N-N \ \ Oy N-N NN ~o Nes So Par, ~o en ay Xn 1 £ i i 3) [ i LN l AN [oN ol oN oo LL i OH Nop © NMa Nod © un NJ & 1-40 1-41 1-42 < 140 1-41 1-42 Nn LY 3 N-N N ~ NN CFy 3 N-N 0, AN AA NN 7% Ny em Qo” 5 ro CLOUD N ey No Ns © I oo T.44 1-45 XS 43 I=% Th ee 1 3 “0 Fs ~o CF ~o ery No Np - oN I | oN a { ie | OLS On i Ny Nz Hg ie | MNO WN 0 g™ ~ oO ks oo — —— 1.46 1-47 . 1-48 | 1-40 Sr Se - 7 " | 1-46 gi 1 = Sy New Sey 3 ~o J CFy ~o CFs ay LATA oh MN © MY Ow ] eg x 3 3 JY 0 1-49 50 1-51 pI A= dow mene a \ sy \ N-N \ N-N I Aor, “0 8 on Na 7 5 ~~ x == N ( 000 RA Gio ° 5 © 1-52 1-53 1-54 N No NN 5 N N, =) N-N N= \) NCR, SNCF; NCR, / N N N N [> N 0S N Lp» “ ] N Z ] N al I N x, a, , H » o © vw © of Sy © Bh © h Sy © OH I-55 1-56 1-57 o , / © N N-N een he CF Ny CFy Br NS CFy / " Cy = AN Lo oN x N Ny J J 3 3 © N SN Cn 1.60 nw 1.58 1-59 1-60 Se Sen + Sen “ § or, Nery Nem A p= =\ bi: = o. ° oJ) © o. 0 I-61 1-62 1-63 x... NL N-N N=N LL’ © 4 \’ © hy Ny 2 pei CF ~o NGF : 4 Fy k; LL’ © A © 1-63 \ ig ~ SNCF, o h 3 I-64 1-65 1-66 ADs uhh pid _ HE NT NN NN NY ~o NCR ~o Ny CF, “0 NS CFy N {oN Qo N i N d J N io N 4 + Q 0 LA 0 0. ° 1-67 % 1-68 » 1-69 Oy oOo. © 1-07 1-00 1-07 < pN N-N N-N en \) ~0 \ / CFs ~o Ny CF a NCR = (7 = 7 = Qu NN NAN. NN NAN NN o’ a { o o’ © 1-70 3 1-71 i 72 | 1-7 / 0 =r i-ls nN / 3 Ty \ N-N = \ \ “nen NN Y \ ? NGF; N 3 Nv ~~ s of ~o CF; 0 Ss % =\ { IN NAAN Ng N ny ©. © PLN 0) © © Tr ~2 1-73 1.74 1-75 N\ N-N \ ‘N-N oO i Nor = =\ Qi AA I) “hey « Kors =e r = L JO oN QR if N-N GS “CFs OS N 2 TY rrr emer eee] Siar MN -N Nel Nein N-N _ N=N * Oh * hi 4 Ny CF, Ny CF; CFs od 2 J 3 4 SOO OUO0LS > \ N Ny N Ng ) N Ney oy yA Ly ¥ ¥ N © N 0 W-N 0 NM © NN © wi Qo 7 en of Ker, - = \ / SOV: N QAR N o 1-79 1-80 1-81 Q N— © i Shes ssSsSiiRsEEs re \ -N Men N-N YL 3 (LU) , boda, Nek J CF, o ® a ~ pe ha 7 ¢ N on = x NN Z § N Noy {JN 7 OT Nd 1 i 4 ng S » N o N 7 of 1-82 1-83 1-84 B 1b noo (Fo N— © N N / a mmmmmnniIamnsssannnss EN Many Ten Ny : NX 3 ~ CF, o Per o CFs © TN EA % i) NAA NN N Ng A N. J © #2 0° Q © N- vr / N co 1-85 | 1-86 | 1-87 oO CJ oo RZ 0 \ i \ I NN NN S-N \) \ N XN 3 ~0 CF CF NS =e =o N idl) ill i y AN NN LN NN N N Ng | NG Oo l Ni 0 o a — 1.00 1-88 1-89 1-90 Nan No Noo 1-88 1-87 rod \ NN Men Mert CFy CFs CF; ~~ © N. J o oN | Q 2 N, I o I a 1.09 1.03 1-91 1-92 1-93 \, Neeiy ne Sy So CF; So NCR x. 72, x ® HO, N. Ng 2 ® , Ng NS SW Z J y o NS © Ld NS © TOA : 1 06 Ney ey ey oF ~o cry Per PN N N= = i ! N x ON NN vv | AN AA y o ° Ng © Ld NS © 1-94 Ez 1.95 1-96 A~ 1-95 oli Ad Ney Mn Ney Sor ~s Her CFy N= AN = ~\ bo ( A { AN on J wh NN © y & [ 0 oN N 1-97 H 1.00 1-97 Ho 1.99 1-98 Ce Sedge rg MeN Ney fi vi Na 3 y \ NCES Sp oy $y oo = je os oN £2, Ee | ay oo NY Be AS Ls © H © MN rl 1-100 LIL N= I JO SN = ! 7S = r i nr ; N. A DOL NA 0. 7! A ¥ ¥ 7 £ § 5 2 1 90 1-101 Ci < NT on 3 “GF; § er, “2 Fs % ! Le N oN A eek on In N OLD (YY Ned AJ 1 < 'e oo N-N 3 "GF; = i \ N. N Nz oS 1-103 1-104 1-105 2 N-N N-N Ny CFs J CFy § er, 7 N= ~ - SNS = A A os TY 2 LA Aes © o {4 o 1-106 1-107 1-108 1-106 1-107 1-108 \ \ — N-N N-N ) 1-108 —_— ~~ NS © Y 1-106 1-107 \ N N-N N-N ) ( OL bol { Ov ie L110 [I MNS NF 0 whine? Nog © ° Y Tr 1.109 ; 1-110 1m 1-109 PRN Co \ hE en Men A” ~CFy 5 CFs “o § er, RS Rr pe A i I = oN = ~~ or AANA ANA NN 3 N on NJ 2 ! J Ay We © a I 0 o . oo ra Ce T1114 112 T-113 1-114 Men en en & CF} NCE NCR, N = = oN SE | N. on ~o CL N NN N. A nN FY) LJ 2 5 Na) N Se 116 1117 1-115 ; 1-116 , 1-117 f-1%D aE sah Neen Non Sppaty > 3 “0 Per, = N. NN i) * W © No, eh Nek Te NCE NCR, ¥ \ ~ re / N 0) % eA N Ng ™~ N * ea Nd © Q NO, ° 1~110 \ 2 Nery 7) VW N N IN oO I-18 d=1417 i= lait 5 il Nn N= oO NH, LJ o N N-N (LD ~ CFs yA nA be Sos 4 © 3 ann Lia 1-122 1-123 1-124 1-125 1-126 1-121 Amid i B= =n § en uo “CFs Br CFs AN - ; - 8 OU ; on 5 oh oT LETT “TY 1-124 L125 1-126 SE N N-N : | { on ~ op! Ig 1} N, Q 1-124 1-125 1-126 en Seen hy 1 “5 Ker ~o Hce, ors N f = c = 7 _ 5 & NA © ® 1-127 199 1-129 ) No CFs YY oy, N. N. No o ity Sen nen Net \ 3 a NCE ~o CF, AcE, SN = = i £2 £0 Ng \ OL NN Nt AN ! ON N Nt OJ JY ~ NS 0 ay 120 N 1-131 1 114 N 1-130 1-131 l 1-132 Ney Sen Soo “gy er, a) ~o Kes, [i CLL | Ty [of ¥ Kw ory # | 1-133 1-134 1-135 0 \, 5 Nei 4 Oy 0 ~ Ser Son ~o Noe ro} 3 oh oN - N = / = | ~~ 1 A MN a { BEN fg AO > No, Ng yr M ° |] Ng? 3 Yd 1-138 am 1.137 oO ger 1-139 1-140 1-141 < N-N ~o J CFy 7s - OOS on io 1-139 1-139 I= 15) ATi=i ~o Fors I. ~ Scr, , ~ cr Lo N= - Ne TY = Ii In 1 HN, © N, o N. Q L142 L143 Lids 1-146 1-147 he Mey Neen SCE ~o Pers Por = = = NYS ® ng EY ett Sry = | oJ NS © oN © AN N © i YR Yl ; 1-146 % 1-147 1-145 I-14 Co NN LT -N oO 1-150 ———— Se Ro Sy NACE ~o J CFs ~o NCE N on | g On | LN on | oN. Joe 7) w Ns © NZ © : 1-150 . 1-148 . 1-149 . . 1-148 1-149 1-148 1-147 f- Nets SN=N Ney ~o NS CFy Fa ce, = | I CLIO OS Qn bp 2g Jey A LT ry 4 a NS © Spl. Nope 1-152 ® 1-153 ~~ oO \ ig Ny CFy % 2 AP Nog! N.# © 1-151 \ \, N-N N-N Men » 4) 4 “5 CFy “0 NCE N x _— il ny = 3 LL N N CAAA SS NL, Nos 4 0. AP A. NZ © © NZ © LEA 1-158 YR 1-154 J 1-155 ; 1-156 ew. rdq 00000 4 00000000000Oo+ev~ 4 =I0 0000 1-104 Coo 1-150 1 \ 5 \, en igi! a ~o “CF, Nery ~ Nor, . N= ~ W = i i] | N N 0, N. 7 Nz oN Ng! Ney AN NY ~ f { 1 Ne © A. NA © NS © NS © 1-158 1-159 T te 1-158 1-159 1-157 \ s ‘N-N NN TN N-N = oN N, NN os NO NF © MN Loy Ser, ix Por, a Ny pe == wn RA A NA a “LO N on | 5 YY ~ LJ Ll oN © © NF © Boe os 1-160 L161 Goss < Non en 'N=N Nt = > Fy So CFs 3 = = Qs l AA Ow H i | n Nog [ N N. Ng Ty sd 4 CY YY id os wh & Zo NS © I I-163 T1164 1-165 > x N-N i i " 1 = | { | . is Ow wn ON NN Sd oN 7! TiJ1l | No# © 1-168 — Ser, AOL f & Nd 1-166 S 1-166 | NZ 0 1-168 I-167 N S x Ln = = Ory AA ory 1-169 170 1-171 Su Me Neu hp ~ cry i. 7 oN N. NZ No? o AR Ny? © Mp 2 1-173 } oo 1-172 . 1-170 Ne-ne CFs SJ 8 1-173 N\ N-N \) CFy 1 CL a vIIJY 1-172 ds i-1 / a rrr ree rrr] 2 1-174 rem mgr rn N=N N-N N Se SN-n Mon 3 “So Ker, SO CFs ) Fy \ N= = v 1 | J or OLS [Fes AAA NN | HN AN NN Nd © i i NA © Ne © T 17a 1-176 Y177 1-175 1-176 1-177 1-179 : 1-180 1-178 ; Seen \ \ :} N-N N-N Neck Nees ~ Aer, ' = N pt J o. N oN Cl Dy 5nd oi’ St NT on™ rile aad or 7 i= Nez © HN NF © TTR 1-179 : 1-180 1-178 A=2.0% 3 1-180 } Oe Ney Sen ~o Sen Ng 5 & cr, ALOUD - 0 ~gN NA Nog i > A N > 1 0, NZ Q ¥ % ¥ 1-181 1-182 1-183 oN FE A102 ERE = ; oo | ot oO 1-186 fe) 1-102 N @ CFs \ Sore Nog! NA o © a 1-185 N-N \ F ~5 x | E H rt NH Ny o N wl N 1-184 3 Neen ey 8 Hc, ~o “CFy ~CFy IN . y o | W N AN. Is ee on | AL Net Oy YOYY fi i [| N & o { JE | 1-187 1-188 1-189 eed 45107 ST 1~18%7 Sen [ he 8 er, Acer, ~o CFy 2 : = = A ANOS | WOOD OD TIJl INT Ay ide L190 1-191 1-192 5 N= — \ N-N ) 5 = LOO “TTY 1-193 h oy ~g Ker, IN So fp? o 1-171 Ny | ei OO i] em AOD Toba 8 1-194 ee ei ™] < N-N 3 ~o CFs \ f HN. Art Ng! o NF © IT 100 - 1-196 1-197 "1.198 ee Aes 1-199 \ 1-200 . 1-201 ~ <n ey po o - ~o oF, ~o J CF MAAN 2 aS Mwy a SJ 3 ey YS T1994 T2200 l200 1-1 =a UU AL 1 \ , F \ x 3 Su G ~o NCE % Ne Nc = Sa I'd =X f = z == n N i» N @ on N HN | O NETS ~ a EY o Ns © i No © Co oo 1-204 i 1-202 1.203 L204 i TT Rn ‘NN N-N “N-N ~o Fig! Co Ne, y == i ~% N N Ns © — mh Ny Seen A ~ aS =, 3 F 3 . oe - er, Ge, = S = NN Ne N A o © ® > 1-205 1-206 id Poo 1-208 1=2U0 So oo TL Ho A pela Leg N "Y fre LE s o snd oY ~ | 1.208 1-209 1-210 1-213 hog | 1-209 1-210 208 . - h hg 'CFy - 2 LAXALT - | 2 5 CX Th | rary ¥ o re A N. ! SS ae oN oe 1-213 1-212 Ney i. Fy N = N N. on S NZ © % RAW 1-211 oo < N Na N-N N-N NN N Ny 5 i OL JT oes or No | fre Ti ” (J! og ee 1-216 xX Nae? Nags OQ 1 Le ® | &7 1-216 1-214 1-215 Net Men Yor J Fy ° & er, oil os A, = CYA L 2 | | 8 { Oh | Ok Be¥ Ne) | C Sa QS SW) rig! ° Ng 0 1.919 Ng © Vor 1-219 1-217 1-218 To ; Yn . Oren a N Ae - ros O00 | CuLoCUn ; ~ 5 ASE Ye ng AN Nd ha a HN oN 0 22 1-220 oo 1.999 1.221 ; 1-222 fread TT Sick 3) cr, <r, © - 5 . OL yy { | OY Ned 5 ° I~ T ¥ wT 5 on 5 ® oo T Ane YIN YY 1.223 ! SS 1-225 1-224 1-223 . 1-224 ATLL Ne Nien ety ~ 3 ory 5 Heer <r; u OL 7 OLE =| oy el | : J SR TAL | 3 Y TOY jx ri wy PAS o © oo 1.99% ae 1.226 } 1-227 . Laz To Mn & lg) HN ~ NS © m= 1-230 1-231 Neng Sen en CFs % "CFs CFy % J { > or nL! S| aH " | ~Y LJ TY 1.939 . 1-233 . 1.974 . 1-2: 1-233 i 1-234 N-N Men p % 3 3 3 % oF, ~o or, ~o Ser A 4 - ™S IY fr os 9] 2 [Ax CLAD YY IY oe he Ha ns TN 'N-N CFy | HN N or NA 0 1-239 1.238 1-239 1-240 2 g— N-N 5 N-N h Ww [YOY A s 1 = ; ALTO sig QL - AC A | 3, oe | 1S Si MATEY J! a | 2 ¥ RE 1-243 1.242 1-243 1-241

[00116] Compound names are assigned by using Struct=Name naming algorithm as part of CHEMDRAW® ULTRA.

[00117] The compound may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” 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. 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", Sth 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.

[00118] Tt 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.

[00119] The present disclosure also includes an isotopically-labeled compound, which is identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. 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 to ?H, *H, *C, *C, '*N, 180, 170, ¥'P, ?P, 3S, 1*F, and (Cl, respectively. Substitution with heavier isotopes such as deuterium, i.e, *H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron- emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated in compounds of formula (I) are ''C, VN, 0, and °F. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent.

[00120] In the compounds of formula (I), any "hydrogen" or "H." whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes 'H (protium) and *H (deuterium).

[00121] 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, thrichloroacetate, 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.

[00122] 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, diethanolaniine, piperidine, piperazine, and the like. A. Binding to WDRS

[00123] The disclosed compounds may bind to WDRS and prevent the association of MLL1 or other transcription factors and proteins dependent on WDRS. The compounds may bind to WDRS and prevent oncogenic processes associated with MLL1, ¢-MYC, or other oncogenic proteins dependent on WDRS.

[00124] Compounds of formula (T) can bind to WDRS resulting in a Ki ranging from about 0.01 nM to about 250 uM. The compounds may have a Ki of about 250 pM, about 200 pM, about 150 HM, about 100 uM, about 90 uM, about 80 uM, about 70 uM, about 60 uM, about 50 uM, about 40 uM, about 30 uM, about 20 uM, about 10 pM, about 9 uM, about 8 uM, about 7 uM, about 6 uM, about 5 uM, about 4 pM, about 3 pM, about 2 uM, about 1 uM, about 950 nM, about 900 nM, about 850 nM, about 800 nM, about 850 nM, about 800 nM, about 750 nM, about 700 nM, about 650 nM, about 600 nM, about 550 nM, about 500 nM, about 450 nM, about 400 nM, about 350 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, about 50 nM, about 10 nM, about 5 nM, about | nM, about 0.3 nM, about 0.1 nM, about 0.03 nM, or about 0.01 nM. Compounds of formula (I) can bind to WDRS resulting in a Ki of less than 250uM, less than 200 pM, less than 150 uM, less than 100 uM, less than 90 uM, less than 80 pM, less than 70 pM, less than 60 uM, less than 50 uM, less than 40 pM, less than 30 uM, less than 20 pM, less than 10 uM, less than 9 uM, less than 8 uM, less than 7 uM, less than 6 pM, less than 5 uM, less than 4 uM, less than 3 pM, less than 2 uM, less than 1 uM, less than 950 nM, less than 900 nM, less than 850 nM, less than 800 nM, less than 850 nM, less than 800 nM, less than 750 nM, less than 700 nM, less than 650 nM, less than 600 nM, less than 550 nM, less than 500 nM, less than 450 nM, less than 400 nM, less than 350 nM, less than 300 nM, less than 250 nM, less than 200 nM, less than 150 nM, less than 100 nM, less than 50 nM, less than 10 nM, less than 5 nM, less than 1 nM, less than 0.3 nM, less than 0.1 nM, or less than 0.03 nM. B. General Synthesis

[00125] 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.

[00126] 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 vive) or processes occurring in vitro,

[00127] 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. Oue skilled in the art of organic synthesis understands that the functionality present on various portions of the edict molecule must be compatible with the reagents and reactions proposed. Not all compounds of the disclosure falling into a given class may be compatible with some of the reaction 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. OMe OH OMe HO hare) OMe MeO” NF, vvenmoeremoremmorontteemmeeee ie. MeO) NN TNF NA OOMe - Dw MeO”, 8 remem MyCY COOMe MeOOC 'COOMe 0 0 3 nnnnnnnnnnnnnnsnnnnnsne in rT] a | | | LI, OMe orf Arl-B(OH),5 OMe Ar! jel \ ; jel \ N of N MeO’ COOMe pig + MeO’ Y 0 ge oO o / Ar'-B oO a4 6 7 Art Art Art — 1 —~ —— | HN OH ~ 0 ~ oO 0 Oo 8 9 10 X=Cl Br, |, OMs, OTs 12 cee dl] dT IN eres X =Br, | YA AX Art PR 12 CO HN Bgl T————— N ~ X= Br, | Aa” Ar! WH COL On N Nos A” a OQ - 0 1 13

[00128] In some embodiments, compounds of Formula 13 may be synthesized by procedures illustrated in Scheme 1. Hemiacetal 1 can be coupled with (2.4-dimethoxyphenyl)methanamine 2 under the reductive amination condition employing a reducing agent including, but not limited to, NaBH(OAc): or NaCNBH: followed by spontaneous cyclization to yield intermediate 3. After activation of phenol moiety of 3 as a triflate, intermediate 4 may be coupled with a variety of boronic acids 5 or borates 6, which are commercially available or can be prepared, via e.g., Suzuki-Miyaura coupling protocol to afford biaryl adducts 7 (Miyaura, N., Suzuki, A., Chem. Rev. (1995), 2457) in the presence of a catalytic Pd species, such as Pd(PPhs)s, PdCla(dppf), Pd(PPh3)2Clz, Pd(OAc):, Pda(dba)s and a suitable ligand such as PPhs, AsPhs, etc., or other such Pd catalyst, and a base such as Na:COz, Cs2C0s3, K2COs, Ba(OH): or EtsN. The dimethoxybenzyl moiety of 7 can be removed using, but not limited to, TFA to prepare lactam 8. The methyl ester functional group of 8 may be converted to an alcohol under various reduction conditions that are routine for those skilled in the art of organic synthesis. The hydroxy group of formula 9 may be activated by converting to a bromide, chloride, mesylate or tosylate group by a number of conditions that are routine for those skilled in the art of organic synthesis. The resulting intermediate 10 may be reacted with variety of nucleophiles such as optionally substituted imidazole in the presence of appropriate bases, such as DIEA, TEA, Cs2COs, K2COs, LiOH or NaOH, to yield Intermediate 11. The lactam NH of 11 may undergo cross-coupling reactions with a variety of aryl or heteroaryl halides of formula 12, wherein X’ is Br or L, in the presence of a catalytic Pd species, such as Pd(OAc): or Pdx(dba): and a suitable ligand such as Xantphos or BrettPhos and a base such as Na2COs, Cs2COs, or K2COs to generate compounds of formula 13. Alternatively, compounds of formula 13 can be produced using the Ullman coupling conditions in the presence of Cul and a suitable ligand such as (trans)-1,2-N,A'- dimethylaminocyclohexane or L-Proline and a base such as Cs:COs, K2COs or K2POs in a suitable solvent such as toluene or DMF. Scheme 2. NH; 2 OH y= As, > 14 — A=CorN Z os A=CorN z yO 2=C, OorNR" N12 HO, OH »o at n RA R= | Aa AspAsp~ 14 AMON Aca CooMe =Cor 00C COOMe AoduN a 2 dn © n=0-2 15 [eo] 2. Ha O Ar! Art ) R R R Aa A \ As N. COM> As N. Nz ra In O Z on O Ar! Art ) R R R Aa A oY — Ag N coo =P N IN Zz In O Zz Jn O 0 47 16 17

[00129] In some embodiments, provided compounds of this invention may be prepared as shown in Scheme 2. Optionally substituted partially unsaturated fused-bicyclic amine 14 may be coupled with hemiacetal 1 under the reductive amination conditions described above to give intermediate 15. Then, it can be subjected to the reaction sequence illustrated in Scheme 1 from intermediate 3 to 7 to afford intermediate 16 followed by the sequence from intermediate 8 to 11 to obtain compounds of formula 17. Scheme 3. Ar! Art Art 12 oe -X' 5 HN sole 2 N = - T COOMe X=Br| A? T COOMe Art ~~ OU ee A Aa 0 bi SE ii oO Re oO 8 18 19 PG Ar Ar 21 XMg N Pa. a O00 A a pa ee Ar HN i 3 — a2” N OO 97 : 0 24 OH 0 27 Ar! . PG Ar Ar Art ao A r a N Ar { py ~ LL, a” 20 N rN WN \ pe Y a -—— AN MN Mn ar OF AZ PY dels 0 0 25 OH 0 28 20 +5 oo . Ar Ar z wx A \ N bi J nnn - y ) 3 <N Ar N | C1 of a SN no 0 gg OH 0 og

[00130] Alternatively, intermediates of formula 8 may undergo cross-coupling reactions with a variety of aryl or heteroaryl halides of formula 12 under the condition described in Scheme 1 to give intermediate 18. The methy! ester functional group of 18 may be converted to an alcohol under various reduction conditions that are routine for those skilled in the art of organic synthesis. The primary alcohol of intermediate 19 may be oxidized by appropriate reagents at a number of conditions that are routine for those skilled in the art to give aldehyde 20. A variety of N- substituted imidazolyl Grignard reagents such (i.e. 21 - 23) as (1-trityl-1H-imidazol-5- yl)magnesium iodide, (1-trityl-1H-imidazol-2-yl)magnesium iodide or (I1-methyl-1A4-imidazol- 2-yl)magnesium iodide, but not limited to, may react with aldehyde 20 to generate corresponding secondary alcohols 24 — 26. Compounds of formula 27 — 29 may be produced by reduction of corresponding alcohols 24 — 26 using, but not limited to, triethylsilane and TFA in a polar aprotic solvent such as 1,2-dichloroethane with heat. Scheme 4. oO Oo 0 oO NS HY < SY oe — Fh — Ard in N iN Ny R > NH R D> R [ x 31 A x Z In 2 n Z n N N N < NH, R i N ; NZ In 30 32 a3 34

[00131] Optically pure amine intermediate of formula 34 may be prepared by procedures illustrated in Scheme 4. Suitably sabstituted bicyclic ketone 30 may undergo condensation reaction with oprically pure rerr-butanesulfinamide using Ti(OEt)+ as a Lewis acid and water scavenger. The resulting optically pure N-sulfinyl imine intermediate 32 may be then reduced using appropriate hydrides, such as NaBH or L-Selectride, to afford the diastereomerically enriched sulfinamide 33. The serr-butanesulfiny! group may be then removed by appropriate acids to yield optically pure bicyclic amine of formular 34, Scheme 5. —_—ee YY eee RYT OY 0 0 0 oO y $ 8 $ S., - 4 - § >i, I TX yx a6 R R R — 1r 1 — 1 cl NZ al Poe SN Ne Son 1 “CL » Nel 35 37 39 | 1¥ oO ¥ 0 Yo WON ae ae HSN atfrnennnnnsnnsnnee. rr ri TN tn NPN Nel SN No” HY “OC Na Sy ar H 43 42 40 ¥ TNH, OC NSN 41 N 1 44

[00132] In some embodiments, optically pure bicyclic amines of formula 41 and 44 were used as reagents and may be synthesized by procedures illustrated in Scheme 5 using optionally substituted 2-chloronicotinaldehyde 35, which may be converted to optically pure N-sulfinyl imine intermediate 37 using the condensation protocol descried in Scheme 4 using CuSO4 as a Lewis acid. Allylmagnesium bromide may react with the imine functional group of Intermediate 37 in stereoselective manner to yield the diastereomerically enriched sulfinamide 38. Subsequent ozonalysis followed by reductive work-up in the presence of NaBH, but not limited to, using Intermediate 38 may be performed. The resulting alcohol 39 may be cyclized through SNar reaction using potassium tert-butoxide, but not limited to, as a base to yield dihydro-pyranopyridine intermediate 40. Alternatively, the secondary amine 42 may be produced from Intermediate 38 through ozonalysis followed by reductive amination work-up using methylamine and NaBH:CN, which is routine for those skilled in the art of organic synthesis. Intermediate 42 may be then cyclized to tetrahydro-1.8-naphthyridine 43 under the SNar reaction condition using organic base, such as DIPEA, at high temperature. The zerr- butanesulfinyl group of both Intermediate 40 and 43 may be removed under acidic condition to yield chiral amines 41 and 44. Scheme 6. R! R! Sa 0 —eee. NAL UX FaN Aa Bl 4 X=Brorl 45 A=CHyorQ RRR R' z=¢cN 42A 433A 44A 46

[00133] Intermediates of formula 43A and 46 may be prepared by reactions shown in Scheme 6. Suitably substituted quinolone 42A may be halogenated in a regio-selective manner using, but not limited to, NBS or NBI to yield 5-halo-quinoline 43A. In addition, optionally substituted 2-amino-6-bromobenzaldehyde or 3-amino-5-bromoisonicotinaldehyde 44A may undergo a thermal condensation reaction with butyraldehyde or 2-methoxyacetaldehyde under microwave irradiation to give the corresponding 5-halo-quinoline or 5-bromo-1,7-naphthyridine 46. In some embodiments, intermediate of formula 43A and 46 were coupled to lactam 8 or 11 in Scheme 1 and 3 Scheme 7. O50 + + A 0 =» oil BHeNH H»-0 > —» So Y Yoho 070 R! RZ— = AF NH, a7 48 49 R! 50 _— 52 Rt —— Th 51 53 54 Q R? RY Np 1 oO | oo” + + | ~oo~ N° — ed) § N hd R2 Q Xo NH 0 — o X= NH o ) R2 X=Cl,Br, | a7 48 55 56

[00134] In some embodiments, 4-halo-quinoline of formula $2 and 54 were used as reagents and may be prepared by procedures illustrated in Scheme 7. A mixture of suitably substituted aniline 47, Meldrum's acid 48 and triethyl orthoformate 49 may be heated to produce intermediate 50, which may undergo thermal cyclization to give quinolin-4-0l 51. 4-Bromo-quinoline $2 may be prepared directly from 51 using, but not limited to, PBrs. Similarly, intermediate 51 may be converted to 4-chloro-quinoline 53 using a chlorination reagent such as POCls. 4-Iodoquinoline 54 may be generated from 53 using KI under acidic condition. Alternatively, intermediate of formula 57 may be prepared using the same sequences of reaction by substituting trimethyl orthoacetate 55 for triethyl orthoformate 49 in the first step. Scheme 8. R Ar! ALS 1 R 1 R f Mom hd 7 " AR r¥ 0. =. " 0 —" N NN A Ac J bovidmeis Bo” o ~~ © Re: i 1 A A=CHyorO ~ on 58 - 59 hi 60

[00135] In some embodiments, compounds of formula 60 can be synthesized by procedures depicted in Scheme 8. Bicyclic ketone 58 may be converted to bromide 59 by reduction of the carbonyl group followed by bronination of the resulting alcohol intermediate using a number of conditions that are routine for those skilled in the art of organic synthesis. Lactam 11 may be deprotonated using, but not limited to, sodium hydride as a base then may react with bromide 59 under the Sn2 reaction condition to yield products of formula 60. Scheme 9. el) — v 7 N Rl Roa ek J =CorN Ng A R! > : ref N 7 N \ R3 61 62 63

[00136] Preparation of intermediate of formula 63 is depicted in Scheme 9. Suitably substituted indole or azaindole 61 may be regio-selectively iodinated using KI and iodine in the presence of base such as aqueous NaOH to produce 3-iodo intermediate 62. A variety of alkyl groups may be introduced to the NH of 62 using a number of conditions that are routine for those skilled in the art of organic synthesis to give intermediate of formula 63, which may be reacted with lactam 11 in Scheme 1. Scheme 10. 1 1 0.90 Tes w NH, LL “64 eH oO. 87+ oO. 68 89 R! TN Rg F - FN Sn J 68 Br ar 2 21z0RorNR'RZ °N” 22 = OR or NR'R2 70 So mm ST 72

[00137] In some embodiments, isoquinoline of formula 69 were used as a substrate for lactam 11 in Buchwald-Hartwig coupling reaction and may be synthesized by procedures depicted in Scheme 10. Appropriately substituted benzaldehyde 64 may undergo a reductive amination reaction with acetal-amine 65 to produce benzyl amine 66. The secondary amino-group of 66 may be tosylated, and the resulting intermediate 67 may undergo Friedel-Craft reaction followed by aromatization using, but not limited to, AICI3 as a Lewis acid to yield isoquinoline 68. Then it may be regio-selectively iodinated using, but not limited to, NBI to yield 4-iodo-isoquinoline 69. In addition, 6-Bromo-8-fluoro-4-iodoisoquinoline 70, which was prepared using the above reaction sequence, may undergo regioselective sequential SxAr reactions to introduce alkoxy or alkyl amino group to produce isoquinoline 72. Scheme 11. ~ A Art " 1 1 =R 0 wv No 7 uv o hdl 74 ~ 1 A ar , PR o. N Ns fl Oo N 0 74 R Lh 1 Ar’ 3 FY ~~ Br + SO - OO NZ 0 73 R A=CHyorO n © Rz=HorMa R=Hor Me Ad ~a mA AN LN YN 0 N..2 OO ri v ~, A A | Ar! n R 3 ~ A N On re oS ~7 0 Nz o 5 R T a Y Al, Rt 1 i PR, " i. NE No ; oN ° 7% Rr #

[00138] In some embodiments, compounds of Formula 75 may be synthesized by procedures illustrated in Scheme 11. Optionally substituted ethyl 4-bromo-quinolineacetate 73, which was produced by the reaction sequence depicted in Scheme 7, may be coupled to lactam 11 to yield compounds of formula 74. The ester functional group of 74 may be converted to amide to give a product of formula 75 through saponification followed by amide coupling reaction sequence that are routine for those skilled in the art of organic synthesis. Alternatively, the same reaction sequence may be applied to ester 73 to generate intermediate 76, which may be coupled to lactam 11 to form product 75. Scheme 12. 0 A=CHyorQ R mit, aa. _-— Rr -e R SA Sa 0. c NA N Br : Tr HO. $ xn Br N A= ~ Be A=CH,orQ NY ’ i a —— R * 73 © R=HorMe nn 78 “A v Sa Ri asasadfive 7 R 80 Rr

[00139] Additional utility of a versatile ethyl 4-bromo-quinolineacetate 73 is illustrated in Scheme 12. The ester functional group of 73 may be reduced to alcohol 77 using a number of conditions that are routine for those skilled in the art of organic synthesis. Ether 78 may be prepared by alkylating 77 using, but not limited to, an alkyl halide in the presence of base. Alternatively, alcohol 77 may be converted to bromide 79 using procedures that are routine for those skilled in the art of organic synthesis. Subsequent Sx2 reactions with nucleophilic amines or nitrogen containing heterocycles may produce intermediates of formula 80. Both 4-bromo- quinoline 78 and 80 may be coupled to lactam 11 to produce some embodiments using the protocol tllustrated in Scheme 1. Scheme 13. Na ~a Na SNA n——— BEE eee—pe HH} e— R R R R “A BocHN OS Br 5 DE rR Tr 81 . B82 V |e ~a Art RA ~A A LRA AAR fi | wf a. as oO A=CH,orO N..zZ O ~, 1 >a 1 A Ar’ ” o Ar’ 1 R A ee Rn | Py we | ih N A OU BocN oS N Ng N_ ~# 0 A=CHyorO Nz 0 = alkyl, 85 R=H or Me 84 COR © n R or R

[00140] In some embodiments, compounds of formula 85 may be synthesized using the protocols shown in Scheme 13. Alcohol 77 may be converted to azide 81 using, but not limited to, diphenylphosphiny! azide in the presence of an organic base such as 2,3,4,6,7,8,9,10- octahydropyrimido[1,2-ajazepine. Subsequent reduction of an azide followed by in situ protection of the resulting primary amine using (Boc):0 may give intermediate 82, which may be methylated to yield intermediate 83. Both quinolone 82 and 83 may be coupled with lactam 11 using the protocol depicted in Scheme 1. The Boc protecting group in 84 may be removed, and the resulting free amine may be subjected to a number of reactions, including alkylation, reductive amination and amide coupling, that are routine for those skilled in the art of organic synthesis to produce compounds of formula 85. Scheme 14. IN nT ; 9 NN fo) 1 mm——————————: ff Sa Ar! " Py ay N No Nz o 0 a A=CHyorO R Am ST20f Mm R 87 ¥ ~Na a ~a Art 7 R oo Tr TT R n * , 1 n 0° m2 Nd 0 88 1 89 or A An ; RANA N NN “...R2 N_z# © I 89 v T R a ay Led N. ~# Q 88 R

[00141] In some embodiments, compounds of Formula 88 and 89 may be prepared using procedures shown in Scheme 14. Optionally substituted 8-bromo-4-iodo-quinoline 86, which was produced by reaction sequence depicted in Scheme 7, may be coupled to lactam 11 to yield compounds of formula 87. Using the bromide group of 87, compounds of formula 38 and 89 may be produced through Suzuki-Miyaura coupling and Buchwald-Hartwig coupling protocols that were described in Scheme 1.

[00142] Precursor reagents and intermediates for core aryl or phenyl structure were either commercially available or prepared using known methods in the literature. Procedures towards key intermediates are detailed within specified examples or below.

[00143] 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 Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

[00144] 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 anacid 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.

[00145] 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 coramercially 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.

[00146] 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 Wats and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4% ed.), 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.

[00147] 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).

[00148] 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.

[00149] 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

[00150] ABBREVIATIONS

[00151] The following abbreviations are employed in the Examples and elsewhere herein: AcOH = acetic acid Ad2PBu = di(1-adamantyl)-n-butylphosphine AIBN = Azobisisobutyronitrile aq. = aqueous BINAP = 2 2'-bis(diphenylphosphino)-1,1'-binaphthy! (Boc)20 = di-tert-butyl dicarbonate BrettPhos = 2-(Dicyclohexylphosphine)3,6-dimethoxy-2',4 6 -triisopropyl-1,1'-biphenyl CH2Clz = methylene chloride conc. = concentrated Cs2C0: = cesium carbonate DBU = 1,8-diazabicyclo[5.4.0Jundec-7-ene DCE = dichloroethane DCM = dichloromethane DIPEA / DIEA = N,N-diisopropylethylamine DMA = dimethylacetamide DMF = dimethylformamide DMSO = dimethylsulfoxide Dowtherm A = eutectic mixture of 26.5% diphenyl + 73.5% diphenyl oxide EDC = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide eq. or equiv = equivalent(s) ether = diethyl ether Et:N = triethylamine EtOAc = ethyl acetate EtOH = ethanol g = gram(s) h or hr = hour(s) HATU = 1-[Bis(dimethylamino)methylene]-14-1,2,3-triazolo[4.5-b]pyridinium 3-0» hexafluorophosphate HCI = hydrochloric acid Hex = hexanes HOBt = hydroxybenzotriazole K2CO0s = potassiumm carbonate KOH = potassium hydroxide LRMS = low resolution mass spectrometry L-selectride = Lithium tri-sec-butylborohydride [MH] = the protonated mass of the free base of the compound MeCN = acetonitrile MeOH == methanol MeONa = sodium methoxide 2-MeTHF = 2-methyltetrahydrofuran mg = milligram(s) MgSO0s = magnesium sulfate min = minute(s) mL or ml = milliliter mmol = millimole(s) Na>CO: == sodium carbonate NaH = sodium hydride NaHCO: = sodium bicarbonate NaNz = sodium azide NaOH = sodium hydroxide NBS = N-bromo succinimide NIS = N-iodo succinimide NMP = N-methyl-2-pyrrolidone NMR = nuclear magnetic resonance PdClx(dppf) / Pd(dppf)Clz = [1,1"-Bis(diphenylphosphino)ferrocene]dichloropalladium(Il) Pda(dba)s = Tris(dibenzylideneacetone)dipalladium(0) Pd(PPha)s = tetrakis(triphenylphosphine)palladiun(0) Pd(PPhs):Cl; = Bis(triphenylphosphine)palladium(II) dichloride Pd(OAc): = Palladium(II) acetate Pd(z-BusP), = Bis(tri-tert-butylphosphine)palladium(0) PPh; = triphenylphosphine RockPhos = 2-Di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl RT or r.t. = room temperature R= retention time (in minutes) sat. = saturated SPhos = 2-Dicvclobexylphosphino-2',6'-dimethoxy biphenyl TBAF = tetra n-butyl ammonium fluoride TEA = triethylamine THF = tetrahydrofuran TFA = trifluoroacetic acid trityl = triphenylmethyl wt. = weight Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene min = minute(s) h or hr = hour(s) mL or ml = milliliter g = gram(s) mg = milligram(s) mmol = millimole(s) RT or r.t. = room temperature LRMS = low resolution mass spectrometry NMR = nuclear magnetic resonance [M+H]™ = the protonated mass of the free base of the compound Rr = retention time (in minutes)

[00152] Microwave assisted reactions are performed in a single-mode reactor: Emrys™ Optimizer microwave reactor (Personal Chemistry A B., currently Biotage).

[00153] Hydrogenation reactions are performed using an atmospheric balloon or using a Parr hydrogenation shaker apparatus.

[00154] 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 ym on a Combi-flash Companion chromatography system from ISCO.

[00155] 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, 596[0.05%TFA / CH:CN]:95%[0.05% TF A / H20] to 100%[0.05%TFA / CH:CN]. Preparative RP- HPLC purification is performed on a custom HP1100 automated purification system with collection triggered by mass detection or using a Gilson Inc. preparative UV-based system using a Phenomenex Luna C18 column (30 x 30 mm LD., 5 pm) with an acetonitrile (unmodified)- water (0.1% TFA) custom gradient.

[00156] For LC-MS characterization of the compounds of the present invention, the following methods are used.

[00157] 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 um) from Phenomenex, with a flow rate of 1.5 mL / min, at 45 °C. The gradient conditions used are: 93% A (water + 0.1% TFA), 7% B (acetonitrile), to 95% B in 1.1 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.

[00158] Method 2: Using method 1 instrument and column conditions. The gradient conditions used are: 95% A (water + 0.1% TFA), 5% 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.

[00159] Method 3: 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-tesolution 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.,

[00160] '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 (8) 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.

[00161] 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. | OH SO, é 0 0 Intermediate 1 Methyl 2-(2,4-dimethoxybenzyl)-5-hydroxy-1-ox0-1,2,3,4-tetrahydroisoquinoline-7- carboxylate

[00162] Standard Reductive Amination Procedure: Dimethyl 2-hydroxy-2,3- dihydrobenzofuran-4,6-dicarboxylate (15.0 g, 59.5 mmol, equiv) and (24- dimethoxyphenyl)methanamine (13.4 mL, 89.2 mmol, 1.5 equiv) were dissolved in CH2Cl2 (200 mL) and stirred at 30 °C for 30 min. Then sodium triacetoxyborohydride (25.2 g, 118.9 mmol, 2 equiv) was added and the reaction was stirred at 30 °C for 3 h. The reaction mixture was concentrated and dissolved in 1,4-dioxane (100 mL) and heated at 110 °C overnight. Saturated aqueous NaHCO; was added and the mixture was extracted with CH2Cl> (3 x 30 mL). The combined organic phases were dried over MgSOs and concentrated under reduced pressure to afford the title compound (22 g, 59.2 mmol, quant.), which was used without further purification. 'H NMR (400 MHz, Chloroform-d) § 8.26 (d,J=1.6 Hz, 1H), 7.71 (d,J = 1.6 Hz, 1H), 7.22 (d, J=38.0Hz, 1H), 6.39 (d, J=7.8 Hz, 2H), 4.73 (s, 2H), 3.76 (s, 3H), 3.75 (s, 3H), 3.74 (s, 3H). 3.50 (t,J=6.7 Hz, 2H), 2.94 (t, J = 6.7 Hz, 2H); LCMS (ESI): Method 2: Rr = 1.965 min, mz = 372.1 [M+H]". 1 ort _o. 0 N o. o o Intermediate 2 Methyl 2-(2.4-dimethoxybenzyl)-1-oxo0~-5-(({trifluoromethyl)sulfonyl)oxy)-1,2,3,4~ tetrahydroisoquinoline-7-carboxylate

[00163] Standard Triflation Procedure: Phenyl triflimide (34.6 g, 96.9 mmol, 1.2 equiv) was added to a solution of methyl 2-(2,4-dimethoxybenzyl)-5-hydroxy-1-0x0-1,2,3,4- tetrahydroisoquinoline~7-carboxylate (Intermediate 1, 30.0 g, 80.8 mmol, 1 equiv) and NN- diisopropylethylamine (35 mL, 201.9 mmol, 2.5 equiv) in THF: CH:Cl2 (5:1, 360 mL) at 23 °C and stirred for 14 h. Saturated aqueous NaHCO: was added and the mixture was extracted with CH>Cl2(3 x 30 mL). The combined organic phases were dried over MgSQa and concentrated under reduced pressure. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient) to afford the title compound (24.5 g, 48.7 mmol, 82% yield) as an oil. "H NMR (400 MHz, Chloroform-d) 6 8.80 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.33 = 7.27 (m, 1H), 6.49 — 6.43 (m, 2H), 4.74 (s, 2H), 3.95 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H), 3.59 (t, J = 6.6 Hz, 2H), 3.04 (t, J = 6.6 Hz, 2H); LCMS (ESI): Method 3: Rx = 2.546 min, m / z = 504.0 [M+H]". “Nn . § Fy 0. 0 y [SES SUN oO = Intermediate 3 Methyl 2-(2,4-dimethoxybenzyl)-5-(1-methyl-3-(trifluoromethyl)-1LH-pyrazol-4-yh-1-ox0- 1.2.3 4-tetrahydroisoquinoline-7-carboxylate

[00164] Standard Suzuki Coupling Procedure: Methyl 2-(2,4-dimethoxybenzyl)-1-ox0-5- (((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (Intermediate 2, 12.3 g, 24.3 mmol, 1 equiv), (1-methyl-3-(trifluoromethy!)-1H-pyrazol-4-yl)boronic acid (7.1 mg, 36.4 mmol, 1.5 equiv), potassium carbonate (8.4 mg, 60.8 mmol, 2.5 equiv), and PdCla(dppf) (890 mg, 1.2 mmol, 0.05 equiv) were dissolved in 1,4-dioxane:water (4:1, 5 mL) under an Ar atmosphere in a sealed tube. The reaction mixture was stirred for 14 h at 90 °C then cooled to 23 °C. Brine was added to the mixture and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSOa and concentrated under reduced pressure. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient) to afford the title compound (11.0 g, 21.8 mmol, 90% yield). 'H NMR (400 MHz, Chloroform-d) & 8.81 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.36 (d, / = 1.1 Hz, 1H), 7.31 — 7.27 (m, 1H), 6.45 (dd, J =6.2,2.5 Hz, 2H), 4.73 (s, 2H), 4.00 (s, 3H), 3.92 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.46 (t, J = 6.6 Hz, 2H), 2.75 (t, J = 6.5 Hz, 2H): LCMS (ESI): Method 2: Rr = 1.072 min, m / z = 504.4 [M=+H]", N\ N-N Ny hg CF HN 0 o o Intermediate 4 Methyl 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-1,2,3,4- tetrahydroisoquinoline-7-carboxylate

[00165] Standard TFA Deprotection Procedure: Anisole (24 mL, 218 mmol, 5 equiv.) was added to a solution of methyl 2-(2,4-dimethoxybenzyl)-5-(1-methyl-3-(trifluoromethyl)-14- pyrazol-4-yl)-1-ox0-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (Intermediate 3, 22.0 g, 43.7 mmol, 1 equiv.) in CH:Clz (50 mL) and TFA (100 mL). The reaction was stirred at room temperature overnight then concentrated under reduced pressure. The residue was dissolved in EtOAc, and washed with sat. NaHCOs. The organic layer was dried (MgSO4) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient followed by MeOH / CH:Cl: = 0-10% gradient) to provide the title compound (13.5 g, 38.2 mmol, 87% yield). "H NMR (400 MHz, Chloroform-d) 8.77 (d, J= 1.6 Hz, 1H), 8.05 (d, J =1.6Hz, 1H), 7.40 (s, 1H), 6.25 (s, 1H), 4.03 (s, 3H), 3.92 (s, 3H), 3.51 (td, / = 6.5, 2.8 Hz, 2H), 2.84 (t..J = 6.5 Hz, 1H); LCMS (EST): Method 2; Rr = 1,363 min, mz =354.1 [M+H]". N SS \CFy HN. OH o Intermediate 5 7-(Hydroxymethyl)-5-(1~-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl)-3,4- dihydroisoquinolin-1(2H)-one

[00166] Standard Methylester Reduction Procedure: Lithium triethylborohydride (4 mL, 3.9 mmol, 3 equiv) was added dropwise to a solution of methyl 5-(1~methyl-3-(trifluotomethyl)- 1H-pyrazol-4-yl)-1-ox0-1,2,3 4-tetrahydroisoquinoline-7-carboxylate (Intermediate 4, 457 mg, 1.3 mmol, 1 equiv) in THF at 0 °C. The reaction was stirred for 40 min, then quenched with sat. aq. NaHCOs. The mixture was extracted with EtOAc. The combined organic layers were dried over MgSQs, concentrated, and dried under reduced pressure to provide the title compound (420 mg, 1.3 mmol, quant.), which was used without further purification. LCMS (ESI): Method 2: Rr =1,145 min, mz = 326.1 [M+H]". N i$ NN CFy HN. Br o Intermediate 6 7-(Bromomethyl)-5-(1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl)-3.4- dihydroisoquinolin-1(2H)-one

[00167] Standard Bromination Procedure: PBrs (0.2 mL, 2.6 mmol, 2 equiv) was added to a solution of 7-(hydroxymethyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-y1)-3,4- dihydroisoquinolin-1(2H)-one (Intermediate 5, 420 mg, 1.3 mmol, 1 equiv) in CH2Clz (10 mL) at 0 °C. The reaction was warmed to room temperature and stirred overnight. Sat. aq. NaHCO: was added and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSOs, concentrated to provide the title compound (440 mg, 1.3 mmol, quant.), which was used in the next step without further purification. 'H NMR (400 MHz, Chloroform-d) 8.15 (d, J=2.0Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 1.1 Hz, 1H), 4.51 (s, 2H), 4.02 (s, 3H), 3.48 (td. J = 6.5, 2.7 Hz, 2H), 2.79 (t, J = 6.5 Hz, 2H); LCMS (ESI): m / z = 387.9 [M+H]". \ N-N a hg CF ™% HN Noy o Intermediate 7 7-((2-Methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)~ 3.4-dihydroisoquinolin-1(2H)-one

[00168] Standard Bromide Displacement Procedure: 2-Methyl-1H-imidazole (846 mg, 10.3 mmol, 4 equiv) was added to a solution of 7-(bromomethyl)-5-(1-methyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl)-3,4~dihydroisoquinolin-1(2)-one (Intermediate 6, 1.0 g, 2.6 mmol, 1 equiv) in Acetonitrile (15 mL) at 23 °C. The reaction mixture was stirred for 12 h at 30 °C, then cooled to ambient temperature, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM / MeOH = 0-10% gradient) to afford the title compound (700 mg, 1.8 mmol, 70% yield). 'H NMR (400 MHz, Chloroform-d) § 8.01 (d, J = 2.0 Hz, 1H), 7.32.(s, 1H), 6.95 (d, J = 1.4 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 1.4 Hz, 1H), 5.99 (s, 1H), 5.09 (s, 2H), 4.00 (s, 3H), 3.48 (td, J = 6.5, 2.8 Hz, 2H), 2.79 (t, J = 6.5 Hz, 2H), 2.35 (s, 3H); LCMS (ESI): Method 2: Ry = 0.973 min, m / z = 390.0 [M+H]". \ N-N N-N \) NCR = HN. NN jis oO Intermediate 8 7-((1H-Imidazol-1-yl)methyl)-5-( I-methyl-3-(triflnoromethyl)- LH-pyrazol-4-yl)-3,4- dihydroisoquinolin-1(2H)-one

[00169] The title compound (750 mg, 2 mmol, 60% yield) was prepared following the bromide displacement procedure described for Intermediate 7, substituting 14-Imidazole for 2-methyl- 1H-imidazole (0.91 g, 13 mmol, 4 equiv). 'H NMR (400 MHz, DMSO-ds) 6 8.03 (brs, 1H), 8.01 (d,J=1.1 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.75 (d, J= 1.2 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.19-7.15 (m, 1H), 6.90 (t, J = 1.1 Hz, 1H), 5.25 (s, 2H), 3.96 (5, 3H), 3.26 (td, J=6.6, 2.7 Hz, 2H). 2.64 (t, J = 6.5 Hz, 2H); LCMS (ESI): Method 2: Rt = 0.979 min, m.z = 376.0 [M+H]". Intermediate 9 Methyl 1-0x0-5-(((trifluoromethyl)sulfonyl)oxy)-1.2,3,4-tetrahydroisoquinoline-7- carboxylate

[00170] The title compound (1.0 g, 2.8 mmol, 78% yield) was prepared following the TFA deprotection procedure described for Intermediate 4 using methyl 2-(2,4-dimethoxybenzyl)-1- 0x%0-5-(((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahy droisoquinoline-7-carboxylate (Intermediate 2). "H NMR (400 MHz, CDCls) 3 8.77 (s, 1H), 8.09 (s, 1H), 6.74 (brs, 1H), 3.97 (s, 3H), 3.65 (m, 2H), 3.16 (t, J = 6.4 Hz, 2H); LCMS (ESI): Method 2: Ry = 1.517 min, m / z = 354.2 [M + HT". Intermediate 10 Methyl 5-(1-ethyl-3-(triflnoromethyl)- 1H-pyrazol-4-yl)-1-0x0-1,2,3,4- tetrahydroisoquinoline-7-carboxylate

[00171] The title compound (2.6 g, 5.7 mmol, 98% yield) was prepared following the Suzuki coupling procedure described for Intermediate 3, substituting (1-ethyl-3-(trifluoromethyl)-1+- pyrazol-4-yl)boronic acid (1.3 g, 6.2 mmol, 1.1 equiv) for (1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl)boronic acid and tetrakis(triphenylphosphine)palladium(0) for PACL(dppf) (196 mg, 0.17 mmol, 0.03 equiv) at 80 °C; LCMS (ESI): m / z = 368.0 [M + HJ". AN N-N \ NCR HN Br o Intermediate 11 7-(Bromomethyl)-5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin- 1(2H)-one

[00172] The title compound (2.0 g, 5.7 mmol, 87% yield, 2 steps) was prepared following the methylester reduction procedure described for Intermediate 5 followed by the bromination procedure described for Intermediate 6 using methyl 5~(1-ethyl-3-(trifluoromethyl)-1H-pyrazol- 4-yl)-1-0x0-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (Intermediate 10, 2.6 g, 5.7 mmol) LCMS (ESI): m / z =402.9 [M+H]". \ "N-N oy CFs 7 HN. AN < 0 Intermediate 12 5-(1-Ethyl-3-(triffluoromethyl)-1 H-pyrazol-4-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)- 3.4-dihydroisoquinolin-1(2H)-one

[00173] The title compound (522 mg, 1.3 mmol, 57% yield) was prepared following the bromide displacement procedure described for Intermediate 7 substituting 7-(bromomethyl)-5- (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one for 7- (bromomethyl)-5-(1-mthyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3.4-dihydroisoquinolin- 1(2H)-one. 'H NMR (400 MHz, Chloroform-d) § 8.01 (d, J = 2.1 Hz, 1H), 7.34 (d, J = 1.1 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 1.4 Hz, 1H), 6.85 (d, J = 1.4 Hz, 1H), 5.97 (s, 1H), 5.09 (s, 2H), 4.26 (q, J = 7.3 Hz, 2H), 3.48 (td, J= 6.5, 2.8 Hz, 2H), 2.78 (1, J = 6.5 Hz, 2H), 2.34 (s. 3H), 1.58 (t,.J=7.3 Hz, 3H); LCMS (ESI): m / z = 404.0 [M+H]". Intermediate 13 7-((1H-Imidazol-1-yl)methyl)-5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4- dihydroisoquinolin-1(2H)~-one

[00174] The title compound (548 mg, 1.4 mmol, 57% yield) was prepared following the bromide displacement procedure described for Intermediate 7, substituting 1H-Imidazole (506 mg, 7.4 mmol, 3 equiv) for 2-methyl-1H-imidazole. '"H NMR (400 MHz, Chloroform-d) & 8.04 (d,J=2.0Hz, 1H), 7.55 (d, J= 1.2 Hz, 1H), 7.35 (d, J= 1.1 Hz, 1H), 7.11 (d, J=2.0 Hz, 1H), 7.08 (t.J=1.1 Hz, 1H), 6.91 (t, J = 1.3 Hz, 1H), 6.26 (s, 1H), 5.15 (5. 2H), 4.26 (q, / = 7.3 Hz, 2H), 3.48 (td, J=6.5, 2.8 Hz, 2H), 2.79 (t, J= 6.5 Hz, 2H), 1.57 (t,.J = 7.4 Hz, 3H), LCMS (ESI): m / z =390,0 [M+H]" Intermediate 14 S-Bromo-8-methoxy-3-methylquinoline

[00175] To a solution of 8-methoxy-3-methylquinoline (100 mg, 0.58 mmol, 1 equiv) in MeCN (4 mL) was added NBS (103 mg, 0.58 mmol, 1 equiv) at 0 °C. the reaction mixture was warmed to 23 °C and stirred overnight then concentrated under reduced pressure. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient) to afford the title compound (150 mg, 0.60 mmol, quant.). "HNMR (400 MHz, Chloroform-d) § 8.79 (s, 1H), 8.28 ~ 8.20 (m, 1H), 7.69 (dd, J = 8.3, 1.4 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 4.07 (3, 3H), 2.58 (5, 3H); LCMS (ESI); Method 2: Rr = 1.352 min, mz = 252.0 [M+H]". Intermediate 15 6-Bromo-8-methoxyquinolin-4-ol

[00176] Step A. Preparation of 5-(((4-bromo-2-methoxyphenyl)amino)methylene)-2,2- dimethyl-1,3-dioxane-4,6-dione. To a solution of 4-bromo-2-methoxyaniline (6.3 g, 31.2 mmol, 1 equiv) and Meldrum's acid (5.39 g, 37.4 mmol, 1.2 equiv) in EtOH (50 mL) was added triethyl orthoformate (5.2 mL, 31.2 mmol, 1 equiv). The reaction was stirred at 80 °C overnight. The reaction was cooled to 0 °C, filtered, and washed with cold EtOH to yield the title compound (10.96 g, 30.8 mmol, 99% yield). 'H NMR (400 MHz, Chloroform-d) 6 11.46 (s, 1H), 8.61 (d, J =14.6 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.12 (d, J= 1.7 Hz, 1H), 3.96 (s, 4H), 1.75 (s, 6H).

[00177] Step B. Preparation of 6-Bromo-8-methoxyquinolin-4-ol. 5-(((4-Bromo-2- methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.96 g, 30.8 mmol, 1 equiv) was added portionwise to Dowtherm A (20 mL) at 260 °C and stirred for 30 min. The reaction was cooled to room temperature, and hexanes were added. The resulting mixture was filtered, and solid was washed with hexanes to yield the title compound (7.20 g, 28.3 mmol, 92% yield). 'H NMR (400 MHz, DMSO-ds) 8 11.50 (s, 1H), 7.77 (t, J = 6.7 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 6.08 (d, J = 7.4 Hz, 1H), 4.01 (s, 3H). Intermediate 16 6-Ethyl-8-methoxyquinolin-4-ol

[00178] A mixture of 6-Bromo-8-methoxyquinolin-4-ol (215 mg, 0.85 mmol, 1 equiv), triethylborane (2 ml, 1.7 mmol, 2 equiv, 1 M THF), cesium carbonate (551 mg, 1.7 mmol, 2 equiv), and Pd(dppf)Clz (31.0 mg, 42.3 umol, 0.05 equiv) in THF (3 mL) was stirred for 3 h at 60 °C under Ar in a sealed tube. The reaction was cooled to 0 °C and quenched by 10% aq. NaOH and 30% aq. H20:. The resulting mixture was warmed to 23 °C, brine was added, and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSQu4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient followed by DCM / MeOH = 0-10% gradient) to afford the title compound (173 mg, 0.85 mmol, quant). 'H NMR (400 MHz, DMSO-d) & 11.28 (s, 1H), 7.46 (d, J = 1.7 Hz, 1H), 7.11 (d, J = 1.7 Hz, 1H), 6.00 (d, J = 7.3 Hz, 1H), 5.75 (s, 1H), 3.98 (s, 3H), 2.70 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H); LCMS (ESI): Method 2: Ry = 1.185 min, mz = 204.1 [M+H]". Intermediate 17 4-Bromo-6-ethyl-8-methoxyquinoline

[00179] To a solution of 6-ethyl-8-methoxyquinolin-4-ol (170 mg, 0.84 mmol, 1 equiv) in DMF (5 mL) was added PBr3 (0.16 mL, 1.67 mmol, 2 equiv) dropwise at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with ice, and the pH was adjusted to 7 with NaHCOs. The solid was filtered, washed with water, and dried to yield the title compound (169 mg, 0.64 mmol, 76% yield). 'H NMR (400 MHz, Chloroform-d) & 8.46 (d, J = 4.6 Hz, 1H), 7.53 (d, J = 4.6 Hz, 1H), 7.39 (dt, J= 1.8, 0.9 Hz, 1H), 6.81 (d,J=1.7 Hz, 1H), 3.96 (s, 3H), 2.70 (q. J = 7.5 Hz, 2H), 1.23 (1, J = 7.6 Hz, 3H); LCMS (ESI): Method 2: Ry = 1.231 min, mz = 266.0 [M+H]". Intermediate 18 5-Jodo-8-methoxy-3-methylquinoline

[00180] The title compound (300 mg, quant.) was prepared following the procedure described for Intermediate 14, substituting N-iodosuccinimide (205 mg, 0.91 mmol, 1.05 equiv) for N- bromosuccinimide and was stirred at 60 °C overnight. 'H NMR (400 MHz, Chloroform-d) § 8.76 (d,J=2.0 Hz, 1H), 8.10 (dd, J=2.1, 1.1 Hz, 1H), 7.98 (d, J= 8.3 Hz, 1H). 6.79 (d, / = 8.3 Hz, 1H), 4.08 (s, 3H), 2.58 (s, 3H); LCMS (ESI): Method 2: Rr = 1.393 min, m / z = 300.0 [M+H]". Intermediate 19 8-Bromo-6-methoxyquinolin-4-ol

[00181] The title compound (3.2 g, 12.7 mmol, 84% yield) was prepared following the synthetic sequence described in Intermediate 15, substituting 2-bromo-4-methoxyaniline (5.4 g, 15.1 mmol, 1 equiv) for 4-bromo-2-methoxyaniline in Step A. 'H NMR (400 MHz, Chloroform- d) 58.97 8.53 (m, 1H), 7.76 (d, J = 2.8 Hz, 1H), 7.68 (d..J = 7.5 Hz, 1H), 7.52 (d, J= 2.8 Hz, 1H), 6.32 (d, J=7.5 Hz, 1H), 3.91 (s, 3H). Intermediate 20 8-Bromo-4-iodo-6-methoxyquinoline

[00182] Step A. Preparation of 8-bromo-4-chloro-6-methoxyquinoline. 8-Bromo-6- methoxyquinolin-4-ol (Intermediate 19, 400 mg, 1.6 mmol, 1 equiv) was dissolved in POCls (3.7 mL) and stirred at 100 °C for 2 h. The reaction was quenched with ice and NaHCO; was added to adjust to pH 7. The solid was filtered, washed with water, and dried to yield the title compound (430 mg, 1.6 mmol, quant.). 'H NMR (400 MHz, Chloroform-d) 8 8.76 (d, J = 4.7 Hz, 1H), 7.81 (d.J=2.7 Hz, 1H), 7.52 (d, J = 4.7 Hz, 1H), 7.46 (d, J = 2.7 Hz, 1H), 3.98 (s, 3H); LCMS (ESI): Method 2: Rr = 1.706 min, mz = 272.0 [M+H]".

[00183] Step B. Preparation of 8-Bromo-4-iodo-6-methoxyquinoline. 8-Bromo-4-chloro-6- methoxyquinoline (430 mg, 1.6 mmol, 1 equiv) was dissolved in 4 M HCI dioxane and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The HCl salt was dissolved in MeCN (9 mL) and potassium iodide (1.5 g, 8.9 mmol, 5 equiv) was added and reaction was stirred at 90 °C overnight. The reaction mixture was cooled to 23 °C, water was added to the mixture and extracted with EtOAc (3 x 20 mL). The organic layer was washed with 10% sodium thiosultate, and brine. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient) to afford the title compound (325 mg, 0.89 mmol, 57% yield), 'H NMR (400 MHz, Chloroform-d) § 8.43 (d, J = 4.6 Hz, 1H), 8.00 (d, J = 4.5 Hz, 1H), 7.80 (d, J = 2.7 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 3.98 (5, 3H).; LCMS (ESI): Method 2: Rt = 1,783 min, m / z = 363.9 [M+H]". Intermediate 21 8-Bromo-6-ethyl-4-iodoquinoline

[00184] The title compound (484 mg, 1.3 mmol) was prepared following the synthetic sequence described in Tatermediate 15 followed by Intermediate 20 substituting 2-bromo-4- ethylaniline for 4-bromo-2-methoxyaniline in Intermediate 15 Step A. 'H NMR (400 MHz, Chloroform-d) § 8.51 (d, J = 4.5 Hz, 1H), 8.02 (d, J = 4.5 Hz, 1H), 8.00 (d, / = 1.9 Hz, 1H), 7.79 (s, 1H), 2.87 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H); LCMS (ESI): Method 2: Rr = 1.983 min, mz = 361.1 [M+H]". Intermediate 22 Ethyl 4-bromo-6-methoxyquinoline-8-carboxylate

[00185] The title compound (430 mg, 1.39 mmol) was prepared following the synthetic sequence described in Intermediate 15 followed by Intermediate 17 substituting ethyl 2-amino- 5-methoxybenzoate for 4-bromo-2-methoxyaniline in Intermediate 15 Step A. 'H NMR (400 MHz, Chloroform-d) & 8.63 (d, J = 4.7 Hz, TH), 7.70 (d, J = 4.6 Hz, 1H), 7.66 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 2.8 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H); LCMS (ESI): Method 2: Ry = 1.284 min, m / z = 310.0 [M+H]". Br Intermediate 23 1,7-Dibromo-1,2.3,4-tetrahydronaphthalene

[00186] To a solution of 7-bromo-3,4-dihydronaphthalen-1(2H)-one (200 mg, 0.90 mmol, 1 equiv) in EtOH (4 mL) was added sodium borohydride (50.4 mg, 1.33 mmol, 1.5 equiv) was added in one portion and stirred at room temperature. Progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was concentrated, dissolved in EtOAc, and washed with water. The organic layer was dried over MgSO and concentrated. The residue was dissolved in CHzClz2 (4 mL) and cooled to 0 °C. PBrs (481 mg, 1.78 mmol, 2 equiv) was added dropwise to the reaction nuxture. The reaction was warmed to room temperature and followed by TLC, NaHCO: (sat.) was added and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSOa and concentrated to give the title compound (263 mg, 0.90 mmol, quant), which was used in the next step without further purification, 'H NMR (400 MHz, Chloroform-~d) 6 7.49 (d, J=2.1 Hz, 1H), 7.28 (dd,.7=8.2,2.1 Hz, 1H), 6.94 (d, / =8.2 Hz, 1H), 5.48 (t,J= 3.8 Hz, 1H), 3.06 -- 2.70 (m, 4H), 2.38 (d, J = 14.4 Hz, TH), 2.29 -- 2.03 (m, 3H), 1.97 ~1.81 (m, 2H). Br Intermediate 24 4,6-Dibromochromane

[00187] The title compound (120 mg, 0.41 mmol, 93% yield) was prepared following the procedure described for Intermediate 23, using 6-bromochroman-4-one (100 mg, 0.44 mmol, 1 equiv). 'H NMR (400 MHz, Chloroform-d) & 7.41 (d, J = 2.4 Hz, 1H), 7.28 (dd, J= 8.8, 2.4 Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 5.42 — 5.35 (m, 1H), 4.57 (td, J= 11.7, 2.3 Hz, 1H), 4.44 — 4.37 (m, 1H), 2.51 (ddt, J=16.0, 12.0, 4.0 Hz, 1H), 2.38 (dq. J = 15.3, 2.6 Hz, 1H). AL No Intermediate 25 1-Bromo-7-methoxy-1,2,3,4-tetrahydronaphthalene

[00188] The title compound (140 mg, 0.57 mmol, quant.) was prepared following the procedure described for Intermediate 23, using 7-methoxy-3,4-dihydronaphthalen-1(2H)-one (100 mg, 0.57 mol, 1 equiv). 'H NMR (400 MHz, Chloroform-d) 3 6.99 (d, J = 8.5 Hz, 1H), 6.88 (d, J=2.7 Hz, TH), 6.79 (dd, J = 8.4, 2.7 Hz, 1H), 5.56 (t,.J = 3.7 Hz, 1H), 3.80 (s, 3H), 2.94 - 2.69 (m, 2H), 2.44 — 2.06 (m, 3H). 1.93 ~ 1.86 (m, 1H). Intermediate 26 4-Bromo-6-methoxychromane

[00189] The title compound (13 mg, 0.56 mmol, quant.) was prepared following the procedure described for Intermediate 23, using 6-methoxychroman-4-one (100 mg, 0.56 mmol, 1 equiv), 'H NMR (400 MHz, Chloroform-d) 5 6.81 - 6.75 (m, 2H), 6.74 ~ 6.70 (m, 1H), 5.43 (p, J= 1.8 Hz, 1H), 4.52 (ddd, J=12.1, 11.1, 2.1 Hz, 1H), 4.32 (dddd, J= 11.2, 4.1, 2.9, 1.5 Hz, 1H), 3.76 (s, 3H), 2.52 (ddt, J = 15.2, 12.1, 4.0 Hz, 1H), 2.36 (da, J = 15.2, 2.6 Hz, 1H). \ N-N (3 NCE; 2 T N oN SN Q Oo Intermediate 27 Methyl 6'-methyl-5-(1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl)-1-oxo-3.4-dihydro- 1H-[2,4'-biisoquinoline]-7-carboxylate

[00190] The title compound (2.9 g, 62%) was prepared following the Buchwald coupling procedure described for Example 2, using methyl S~(1-methyl-3-(trifluoromethyl)- 1 F-pyrazol~ 4-y1)-1-0x0-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (Intermediate 4, 3.4 g, 9.5 mmol) and 4-bromo-6-methylisoquinoline (4.2 g, 19.0 mmol) according to the standard Buchwald coupling procedure from Example 2. \ N-N 4 CF3 Qf OH N Q Intermediate 28 7-(Hydroxymethyl)-6'-methyl-5-( 1-methyl-3-(trifluoromethyl)- LH-pyrazol-4-yl)-3,4- dihydro-1H-[2,4'-biisoquinolin]-1-one

[00191] The title compound (2.1 g, 77%) was prepared following the standard methyl ester reduction procedure described for Intermediate 5 using methyl 6'-methyl-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-1-0x0-3,4-dihydro- 1H-[2,4'-biisoquinoline]-7-carboxylate (Intermediate 27, 2.9 g, 5.9 mmol). \ NN \ NCE Q ’ bo Q c Intermediate 29 6'~-Methyl-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo-3,4-dihydro-1H-[2,4'~ biisoquinoline]-7-carbaldehyde

[00192] To a solution of 7-(hydroxymethyl)-6-methyl-5-(1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-y1)-3,4-dihydro-1H-[2,4'-biisoquinolin]-1-one (Intermediate 28, 2.1g, 4.5 mmol) in CH2Clz (45 ml.) was added Dess-Martin periodinane (1.92 g, 4.5 mmol, 1 eq.). The reaction was stirred at RT for 20 h then concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM / MeOH = 0-10% gradient) to afford the title compound (1.7 g, 82% yield). Cl CO L N Intermediate 30 5-Chloro-5,6,7,8-tetrahydroquinoline

[00193] Step A. Preparation of 5,6,7,8-Tetrahydroquinolin-S-ol. To a solution of 7,8- dihydroquinolin-5(6H)-one (188.0 mg, 1.28 mmol, 1 equiv) in MeOH (6 mL) at 0 °C was added NaBHa (72.5 mg, 1.92 mmol, 1.5 equiv). The mixture was stirred for 1 h, then concentrated. The residue was dissolved in Et20, and the solution was wash with brine, dried (Na:SO4) and concentrated to provide the title compound (121 mg, 0.81 mmol, 63% yield): 'H NMR (400 MHz, Chloroform-d) § 8.34 (dd, J=1.6, 4.8 Hz, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.14 (dd, J= 4.8, 7.6 Hz, 1H), 4.76 (m, 1H), 2.90 (m, 2H), 2.05 (m, 2H), 1.81 (m, 2H); LCMS (ESI): mz = 150.4 [M-+H]".

[00194] Step B. Preparation of 5-chloro-5,6,7,8-tetrahydroquinoline. To a solution of 5,6,7,8-tetrahydroquinolin-5-ol (25.6 mg, 0.17 mmol, 1 equiv) in dichloromethane (2 mL) at 0 °C was added EtsN (58 pL, 0.41 mmol, 2.4 equiv), methanesulfonyl chloride (28 ul., 0.36 mmol, 2.1 equiv). The mixture was warmed to room temperature and stirred overnight. Sat. aq. NHaCl was added, and the mixture was extracted with EtOAc. The combined organic layers were dried (Na:80s) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-40% gradient) to afford the title compound (16 mg, 0.17 mmol, 56% yield). 'H NMR (400 MHz, Chloroform-d) & 8.46 (dd, J = 1.6, 4.8 Hz, 1H), 7.69 (dd, J = 1.6, 8.0 Hz, 1H), 7.14 (dd, J = 4.8, 8.0 Hz, 1H), 5.27 (t, J=4.0 Hz, 1H), 3.08 (m, 1H), 2.91 (m, 1H), 2.26 (m, 3H), 1.97 (m, 1H); LCMS (ESI): m / z = 168.3 [M+H]". cl “CC L / N Intermediate 31 5-Chloro-3-methoxy-5,6,7,8-tetrahydroquinoline

[00195] Step A. Preparation of 3-methoxy-5,6,7,8-tetrahydroquinolin-5-ol. The title compound (81 mg, 0.45 mmol, quant.) was prepared following the procedure described for Intermediate 30 step A, substituting 3-methoxy-7,8-dibydroquinolin-5(6H)-one (80.3 mg, 0.45 mmol, 1 equiv) for 7,8-dihydroquinolin-5(64)-one. 'H NMR (400 MHz, Chloroform-d) 5 8.18 (d, J=2.8 Hz, 1H), 7.35 (d, J = 2.4 Hz. 1H), 4.81 (m, 1H), 3.86 (s, 3H), 2.90 (m, 2H), 2.08 (m, 2H), 1.85 (m, 2H); LCMS (ESI): mz = 180.4 [M+H]".

[00196] Step B. Preparation of 5-chloro-3-methoxy-5,6,7,8-tetrahydroquinoline. To a solution of 3-methoxy-5,6.7,8-tetrahydroquinolin-5-ol (81.2 mg, 0.45 mmol, 1 equiv) in dichloromethane (4.5 mL) at 0 °C was added thionyl chloride (43 pL, 0.59 mmol, 1.3 equiv). The reaction was warmed to room temperature slowly and stirred for 5 h, then quenched with sat. aq. NaHCOs. The mixture was extracted with E20, and the combined organic layers were dried (Na2804) and concentrated. The residue was purified by flash chromatography (Combi- flash Rf, Hex / EtOAc = 0-50% gradient) to afford the title compound (76 mg, 0.38 mmol, 85% yield). "H NMR (400 MHz, Chloroform-d) § 8.20 (d, J = 2.8 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 5.24 (t, J = 4.0 Hz, 1H), 3.85 (s, 3H), 2.99 (m, 1H), 2.85 (m, 1H), 2.23 (m, 3H), 1.95 (m, 1H); LCMS (ESI): mz = 198.4 [M+H]". HCI NH, AO ZF H | N Intermediate 32 (8)-3-Methoxy-5,6,7,8-tetrahydroquinolin-5-amine hydrochloride

[00197] Step A. Preparation of (R,E)-N-(3-Methoxy-7,8-dihydroquinolin-5(6H)-ylidene)- 2-methylpropane-2-sulfinamide. To a solution of 3-methoxy-7,8-dihydroquinolin-5(6H)-one (241.0 mg, 1.36 mmol, 1 equiv) in THF (9 mL) was added (R)-2-methylpropane-2-sulfinamide (164.8 mg, 1.36 mmol, 1 equiv) and tetraethoxytitanium (570 pL, 2.72 mmol, 2 equiv). The reaction was stirred at 65 °C for 24 h, then quenched with brine. The mixture was extracted with EtOAc. The combined organic layers were dried (Na:SO4) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-90% gradient) to afford the title compound (220 mg, 0.78 mmol, 57% yield). 'H NMR (400 MHz, Chloroform-d) & 8.35 (d, J=2.8Hz, 1H), 7.97 (brs, 1H), 3.90 (s, 3H), 3.29 (m, 1H), 3.09 (m, 3H), 2.09 (m, 2H), 1.34 (s, 9H); LCMS (ESI): mz = 281.4 [M+H]".

[00198] Step B. Preparation of (R)-N-((S)-3-Methoxy-5,6,7,8-tetrahydroquinolin-5-yl)-2~ methylpropane-2-sulfinamide. To a solution of (R E)-N-(3-methoxy-7,8-dihydroquinolin- 5(6H)-ylidene)-2-methylpropane-2-sulfinamide (185.0 mg, 0.66 mmol, 12 / 0.66 equiv) in THF (6.5 mL) at 0 °C was added L-selectride (1.0 M in THF, 2.0 mL, 2.0 mmol, 3.03 equiv). The reaction was stirred for S h, then quenched with sat. ag. NaHCO:, The mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM / MeOH = 0-10% gradient) to afford the title compound (185 mg, 0.66 mmol, 99% vield). 'H NMR (400 MHz, Chloroform-d) 58.17 (d.J=2.8 Hz, 1H), 7.29 (d, J = 2.8 Hz, 1H), 4.48 (m, 1H), 3.83 (s, 3H), 3.40 (d, / = 10.0 Hz, 1H), 2.89 (m, 2H), 2.38 (m, 1H), 2.02 (m, 1H), 1.88 (m, 2H), 1.28 (s, 9H); LCMS (ESI): mz = 283.2 [M+H]".

[00199] Step C. Preparation of (8)-3-Methoxy-5,6,7,8-tetrahydroquinolin-5-amine hydrochloride. To a solution of (R)-N-(($)-3-methoxy-5.6,7,8-tetrahydroquinolin-5-y1)-2- methylpropane-2-sulfinamide (220 mg, 0.78 mmol, 1 equiv) in THF (8 mL) at room temperature was added HCI (4 M in 1.4-dioxane, 1.95 mL, 7.8 mmol, 10 equiv). The mixture was stirred for 2 h then concentrated to provide the title compound (210 mg, 0.78 mmol, quant.), which was used without further purification. 'H NMR (400 MHz, Methanol-d+) § 8.54 (s, 1H), 8.27 (s, 1H), 4.79 (m, 1H), 4.06 (s, 3H), 3.10 (m, 2H), 2.29 (m, 1H), 2.09 (m, 3H); LCMS (ESI): mz = 179.3 [M+H]", No OH i xX Nae COOMe © Intermediate 33 Methyl (S)-5-hydroxy-2-(3-methoxy-5,6,7,8-tetrahydroquinolin-5-yl)-1-oxo-1,2,3,4~ tetrahydroisoquinoline-7-carboxylate

[00200] To a suspension of (S)-3-methoxy-5,6,7,8-tetrahydroquinolin-5-amine hydrochloride (595 mg, 2.36 mmol, 1.1 equiv) in dichloromethane (20 mL) at 30 °C was added DIPEA (1.12 ml, 6.42 mmol). The mixture was stirred for 15 min, then dimethyl 2-hydroxy-2,3- dihydrobenzofuran-4,6-dicarboxylate (540.0 mg, 2.14 mmol, 1 equiv) and NaBH(OAc): (680.3 mg, 3.21 mmol, 1.3 equiv) were added sequentially. The reaction was stirred at 30 °C for 2 h, then concentrated. The residue was dissolved in 1,4-dioxane (10 mL) and heated at 90 °C for 1 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried (Na:804) and concentrated to provide the title compound (1.1 g), which was used without further purification, 'H NMR (400 MHz, Chloroform-d) § 8.30 (d, J = 1.6 Hz, 1H), 8.10 (d,J =2.4 Hz, 1H), 7.52 9d, J = 1.6 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.07 (m, 1H), 3.91 (s, 3H), 3.75 (s, 3H), 3.35 (mn, 1H), 3.15 (m, 1H), 3.00 (m, 1H), 2.89 (m, 2H), 2.79 (m, 1H), 2.12 (m, 2H), 1.94 (m, 1H), 1.80 (m, 1H); LCMS (ESI): m / z = 383.4 [M+H]". \ 8g! ~o NCE, ( fi NZ N ‘COOMe ~S © Intermediate 34 Methyl ($)-2-(3-methoxy-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3- (trifluoromethyl)-1LH-pyrazol-4-yl)-1-0x0-1,2,3,4-tetrahydroisoquinoline-7-carboxylate

[00201] Step A. Preparation of methyl ($)-2-(3-methoxy-5,6,7,8-tetrahydroquinolin-5-yl)- 1-0x0-5-(((trifluoromethyl)sulfonyloxy)-1,2,3.4-tetrahydroisoquinoline-7-carboxylate. To a suspension of methyl (8)-5-hydroxy-2-(3-methoxy-5,6,7,8-tetrahydroquinolin-5-yl)-1-oxo- 1.2,3,4-tetrahydroisoquinoline-7-carboxylate (1.1 g crude, 2.14 mmol, equiv) In THF / acetonitrile (10 mL / 10 mL) was added DIPEA (2.24 mL, 12.84 mmol, 6 equiv) and 1,1,1- trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.15 g, 3.21 mmol, 1.5 equiv). The reaction mixture was stirred at 45 °C for 2 h, then quenched with sat. aq. NaHCO3 and extracted with EtOAc. The combined organic layers were dried (Na:2804) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 10-90% gradient) to afford the title compound (912 mg, 1.77 mmol, 82% yield over two steps). '"H NMR (400 MHz, Chloroform-d) § 8.85 (d, J= 1.6 Hz, 1H), 8.18 (d, / =2.4 Hz, 1H), 8.07 (d. / =1.6 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.09 (m, 1H), 3.98 (s, 3H), 3.78 (s, 3H), 3.43 (m, 1H), 3.25 (m, 1H), 3.08 (m, 1H), 2.96 (m, 3H), 2.15 (m, 2H), 1.93 (m, 1H), 1.80 (mn, 1H). LCMS (ESI): mz=75154 [M+H]".

[00202] Step B. methyl (S)-2~(3-methoxy-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-1-0x0-1,2,3,4-tetrahydroisoquinoline-7-carboxylate. To a solution of methyl (§)-2-(3-methoxy-5,6,78-tetrahydroquinolin-5-yl)-1-oxo-5- (((trifluoromethysulfonyl)oxy)~1,2,3 4-tetrahydroisoquinoline~7~carboxylate (310.0 mg, 0.6 mmol, 1 equiv) in 1,4~dioxane (6 mL) at room temperature was added sequentially (1-methyl-3~ (trifluoromethyl)~1 H-pyrazol-4-yljboronic acid (152 mg, 0.78 mmol, 1.3 equiv), Na2COs (160 mg, 1.51 mmol, 2.5 equiv), Pd(PPhz)s (41.8 mg, 0.36 mmol, 0.06 equiv), and water (0.6 mL). The resulting mixture was stirred at 80 °C for 16 h, then diluted with water. The mixture was extracted with EtOAc. The combined organic layers were dried (Na2S04) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM / MeOH = 0-10% gradient) to afford the title compound (348 mg, quant.), which was used without further purification. 'H NMR (400 MHz, Chloroform-d) & 8.86 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.38 (s, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.12 (m, 1H), 4.01 (s, 3H), 3.96 (s. 3H), 3.77 (s, 3H), 3.33 (m, 1H), 3.10 (m, TH), 2.93 (m, 2H), 2.73 (m, 2H), 2.15 (m, 2H), 1.94 (m, 1H), 1.79 (my, 1H); LCMS (ESI): m / z = 515.4 [M+H]". N\ 53 ~~ NACE ( = NZ N. OH © Intermediate 35 (8)-7-(Hydroxymethyl)-2-(3-methoxy-5,6,7,8-tetrahydroquinolin-5-yl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00203] The title compound (290 mg, 0.6 mmol, 99% yield over two steps) was prepared following the standard methylester reduction procedure described for Intermediate 5, using methyl (8)-2-(3-methoxy-5,6,7,8-tetrahydroquinolin-5-y1)-5-(1-methyl-3-(trifluoromethyl)-14- pyrazol-4-yl)-1-oxo0-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (Intermediate 34, 348 mg, 0.6 mmol, 1 equiv). 'H NMR (400 MHz, Chloroform-d) § 8.20 (d, J= 1.6 Hz, 1H), 8.16 (d, / J=2.4 Hz, 1H), 7.43 (d, / =1.6 Hz, 1H), 7.36 (s, 1H), 7.03 (d, J =2.0 Hz, 1H), 6.12 (m, 1H), 4.79 (d, J =6.0 Hz, 2H), 4.01 (s, 3H), 3.77 (5, 3H), 3.29 (m, 1H), 3.08 (m, 1H), 2.92 (m, 2H), 2.68 (m, 2H), 2.13 (m, 2H), 1.93 (m, 1H), 1.778 (m, 1H); LCMS (ESI): mz = 487.4 [M+H]". \ 3 ~~ GS i NAAN Br Ao Intermediate 36 (S)-7-(Bromomethyl)-2-(3-methoxy-5,6,7,8-tetrahydroquinolin-3-yl)-3-( 1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00204] To a solution of (8)-7-(hydroxymethyl)-2-(3-methoxy-5,6,7,8-tetrahydroquinolin-S- v1)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3 4-dihydroisoquinolin-1(2H)-one (Intermediate 35, 200 mg, 0.41 mmol, 1 equiv) in dichloromethane ( 10 mL) at room temperature was added CBrs (272 mg, 0.82 mmol, 2 equiv) and PPhs (113 mg, 0.41 mmol, 1 equiv). The mixture was stirred for 20 min, then a second portion of PPh (113mg, 0.41mmol, 1 equiv) was added. The reaction was stirred for additional 2 h then concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 30-100% gradient) to afford the title compound (563 mg), which was used without further purification: LCMS (ESI): m / z = 549.4 [M+H]™. HCI NH; “00 o Intermediate 37 (S)-6-Methoxychroman-4-amine hydrochloride

[00205] The title compound was prepared following the synthetic sequence described in Intermediate 32, substituting 6-methoxychroman-4-one for 3-methoxy-7,8-dihydroquinolin- 5(6H)-one in Step A. ~o OH il ~ SAAN Oo. o_’ ©0 0 Intermediate 38 Methyl ($)-5-hydroxy-2-(6-methoxychroman-4-yl)-1-0x0-1,2,3,4-tetrahydroisoquinoline-7- carboxylate

[00206] The title compound (370 mg, 0.97 mmol, quant.) was prepared following the reductive amination procedure described for Intermediate 1, substituting (S)-6-methoxychroman-4-amine (172 mg, 0.96 mmol, 1 equiv). "H NMR (400 MHz, Chloroform-d) § 8.40 (s, 1H), 7.66 (s, 1H), 6.80 (d, J= 8.9 Hz, 1H), 6.76 (dd, J = 8.9, 2.9 Hz, 1H), 6.67 (d, J = 2.9 Hz, 1H), 6.16 (t, J =8.3 Hz, 1H), 4.32 (dt, J = 11.3, 4.0 Hz, 1H), 4.20 (ddd, J = 11.2, 8.3, 4.6 Hz, 1H), 3.92 (s, 3H), 3.69 (s, 3H), 3.36 (td, J = 11.4, 10.3, 4.6 Hz, 1H), 3.27 (dt, J = 12.1, 5.5 Hz, 1H), 3.00 (dt, J = 16.9, 5.3 Hz, 2H), 2.86 (ddd, J = 16.4, 10.3, 5.5 Hz, 2H), 2.22 ~ 2.13 (m, 3H); LCMS (ESI) Method 2: Rr = 1.560 min, mz = 384.0 [M+H]". \ N-N aR ~o N CF o_* © 0 Intermediate 39 Methyl (5)-2-(6-methoxychroman-4-yl)-3-( 1-methyl-3-(trifluoromethyl)- 1LH-pyrazol-4-yl)- 1-0x0-1,2,3,4-tetrahydroisoquinoline-7-carboxylate

[00207] The title compound (138 mg, 0.27 mmol, 48% yield, over two steps) was prepared following the synthetic sequence described in Intermediate 2 and 3, using methyl (S)-5-hydroxy- 2-(6-methoxychroman-4-yl)-1-oxo0-1,2,3,4-tetrahy droisoquinoline-7-carboxylate (Intermediate 38, 370 mg, 097 mmol) in Intermediate 2 and substituting tetrakis(triphenylphosphine)palladium(0) (0.05 equiv) for PdCl(dppf) in Intermediate 3. 'H NMR (400 MHz, Chloroform-d) & 8.85 (d, / = 1.9 Hz, 1H), 8.05 (d, J = 1.9 Hz, 1H), 7.37 (s, 1H), 6.79 (d. J =8.8 Hz, 1H), 6.75 (dd, J=8.8, 2.7 Hz, 1H), 6.65 (d, J=2.9 Hz, 1H), 6.20-6.13 (m, 1H), 4.30 (dt, J=11.3, 4.0 Hz, 1H), 4.19 (td, J= 11.2, 10.6, 3.1 Hz, 1H), 4.01 (s, 3H), 3.95 (s. 3H), 3.69 (s, 3H), 3.36 — 3.24 (m, 1H), 3.19 (dt, J = 12.0, 5.4 Hz, 1H), 2.80 — 2.68 (m, 2H), 224-210 (m, 2H); LCMS (ESI) Method 2: Rr = 1.822 min, mz = 516.0 [M+H]". » N-N N-N ~o N / CF Gy AN Br oo.’ © Intermediate 40 (8)-7-(Bromomethyl)-2-(6-methoxychroman-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1 H- pyrazol-4-yl)-3,4-dihydroisoquinolin-1{2H)-one

[00208] The title compound (151 mg, 0.27 mmol, quant, over two steps) was prepared following the methylester reduction procedure described for Intermediate S, using Methyl (S)-2- (6-methoxychroman-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-oxo0-1,2,3,4- tetrahydroisoquinoline-7-carboxylate (Intermediate 39, 138 mg, 0.27 mmol, 1 equiv) followed by the bromination procedure described for Intermediate 6. "H NMR (400 MHz, Chloroform-d) §8.23(d, J=2.0Hz, 1H), 7.42 (d, J=2.0Hz, 1H), 7.37 (d, J= 1.0 Hz, 1H), 6.78 (d, / =8.9 Hz, 1H), 6.74 (dd, J = 8.9, 2.6 Hz, 1H), 6.65 (d, J = 2.9 Hz, 1H), 6.19 — 6.09 (m, 1H), 4.54 (s, 2H), 430 (dt, J = 11.3, 4.0 Hz, 1H), 4.23 — 4.14 (m, 1H), 4.00 (s, 3H), 3.69 (s, 3H), 3.28 (ddd, J = 12.4, 10.1, 4.8 Hz, 1H), 3.23 = 3.11 (m, 1H), 2.75 = 2.57 (m, 2H), 2.21 = 2.10 (m, 2H); LCMS (EST) Method 2: RT = 1.921 min, mz = 5499 [M+H]". \ N-N MN “0 Nor © KAN Oo. or 0 Intermediate 41 Methyl (5)-5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yh-2-(6-methoxychroman-4-yl)-1- 0x0-1,2,3.4-tetrahydroisoquinoline-7-carboxylate

[00209] The title compound (132 mg, 0.25 mmol) was prepared following the Suzuki coupling procedure described for Intermediate 3, using the synthetic sequence described in Intermediate 2 and 3, using methyl (8)-5-hydroxy-2-(6-methoxychroman-4-yl)-1-oxo0-1,2,3,4- tetrahydroisoquinoline-7-carboxylate (Intermediate 38, 370 mg, 0.97 mmol) in Intermediate 2 and substituting (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid and tetrakis(triphenylphosphine)palladium(0) (0.05 equiv) for (1-methyl-3-(trifluoromethyl)-14- pyrazol-d-yl)boronic acid and PdClx(dppf) in Intermediate 3, respectively. *H NMR (400 MHz, Chloroform-d) § 8.85 (d, J = 1.9 Hz, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 1.0 Hz, 1H), 6.79 (d.J=8.9 Hz, 1H), 6.74 (dd, J= 8.9, 2.8 Hz, 1H), 6.66 (d, J = 2.9 Hz, 1H), 6.23 ~ 6.13 (m, 1H), 437-415 (m, 4H), 3.95 (s, 3H), 3.69 (s, 3H), 3.38 — 3.25 (m, 1H), 3.24 — 3.13 (m, 1H), 2.80 — 2.68 (m, 2H), 2.23 — 2.10 (m, 2H), 1.57 (t, J = 7.3 Hz, 3H); LCMS (ESI) Method 2: Rr = 1.934 min, m'z=>529.9 [M+H]". \ N-N Oo) ~o0 NCR QL. oo) © Intermediate 42 (8)-7-(Bromomethyl)-5-(1-ethyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl)-2-(6- methoxychroman-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00210] The title compound (131 mg, 0.23 mmol, 93% yield, over two steps) was prepared following the methylester reduction procedure described for Intermediate 5, using methyl (S)-5- (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-2-(6-methoxychroman-4-yl)-1-oxo0-1,2,3,4- tetrahydroisoquinoline-7-carboxylate (Intermediate 41, 132 mg, 0.25 mmol) followed by the bromination procedure described for Intermediate 6. 'H NMR (400 MHz, Chloroform-d) § 8.23 (d.J = 2.0 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.39 (d, J= 1.0 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 6.76 ~ 6.72 (m, 1H), 6.66 (d, J = 2.8 Hz, 1H), 6.20 ~ 6.10 (m, 1H), 4.54 (s, 2H), 4.33 ~ 4.15 (m, 4H), 3.69 (s, 3H), 3.34 ~ 3.23 (m, 1H), 3.23 ~ 3.10 (mm, 1H), 2.77 ~ 2.60 (mm, 2H), 2.18 ~ 2.12 (m, 2H), 1.56 (t, J = 8.0 Hz, 3H); LCMS (ESI) Method 2: Rr = 1.994 min, m / z = 563.8 [M+H]". HCI “RN NH, Ree 2 N’ NT Intermediate 43 (:5)-6-Chloro-1-methyl-1,2,3,4-tetrahydro-1,8-naphthyridin-4-amine hydrochloride

[00211] Step A. Preparation of (8)-N-(($)-1-(2,5-Dichloropyridin-3-yl)-3~ (methylamino)propyl)-2-methylpropane-2-sulfinamide. Ozone was bubbled through a solution of (S)-N-((S)-1~(2,5-dichloropyridin-3-yl)but-3-en-1-y1)-2-methylpropane-2- sulfinamide (Intermediate 46 Step B, 610.0 mg, 1.9 mmol, 1 equiv) in dichloromethane (50 mL) at -78 °C, and the reaction was monitored by LCMS. After the starting material was consumed, nitrogen gas was bubbled through the reaction mixture for 3 min to remove the excess ozone, Then TBAF (1.0 M in THF, 2.1 mL, 2.09 mmol, 1.1 equiv) was added, and the mixture was warmed to 0 °C and stirred for 1.5 h until the ozonides were decomposed. The organic phase was washed with water, dried (Na2SQOa), and concentrated. The residue was dissolved in MeOH (10 mL). To this solution was added methylamine hydrochloride (641.0 mg, 9.49 mmol, 5 equiv) and DIPEA (1.3 mL, 7.60 mmol, 4 equiv). The mixture was stirred at room temperature for 5 min then dichloromethane (10 ml.) was added followed by addition of NaBH:CN (418.0 mg, 6.65 mmol, 3.5 equiv). The resulting mixture was stirred at room temperature for 16 h then concentrated. The residue was dissolved in EtOAc and washed with water. The combined organic layers were dried (Na2S04) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient) to afford the title compound (1.0 g). LCMS (ESI): m / z = 338.4 [M+H]".

[00212] Step B. Preparation of (S)-N-((8)-6-Chloro-1-methyl-1,2,3,4-tetrahydro-1,8- naphthyridin-4-yl)-2-methylpropane-2-sulfinamide. To a solution of (S)-N-((5)-1-(2,5- dichloropyridin-3-yl)-3-(methylamino)propyl)-2-methylpropane-2-sulfinamide (1.0 g, 1.9 mmol, 1 equiv) in 1,4-dioxane (20 mL) was added DIPEA (1.0 mL, 5.7 mmol, 3 equiv). The mixture was stirred at 90 °C for 16 h, then concentrated. The residue was dissolved in EtAQc and washed with water. The organic layer was dried (Na2$Os) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-80% gradient) to afford the title compound (112 mg, 0.37 mmol, 20% yield over two steps). 'H NMR (400 MHz, Chloroform-d) 8 8.00 (d, J = 2.8 Hz, 1H), 7.43 (d, J= 2.8 Hz, 1H), 4.51 (m, 1H), 3.46 (td, J = 3.6, 11.6 Hz, 1H), 3.30 (m, 1H), 3.11 (s. 3H), 2.09 (m, 1H), 1.97 (m, 1H), 1.23 (s, 9H); LCMS (ESI): mz =302.4 [M+H]".

[00213] Step C. Preparation of (8)-6-Chloro-1-methyl-1,2,3,4-tetrahydro-1.8- naphthyridin-4-amine hydrochloride. To a solution of (8)-N-((S)-6-chloro-1-methyl-1,2,3,4- tetrahydro-1,8-naphthyridin-4-yl)-2-methylpropane-2-sulfinamide (112 mg, 0.37 mmol, 1 equiv) in 1,4-dioxane (4 ml.) at room temperature was added potassium tert-butoxide (90 mg, 0.74 mmol, 2 equiv). The mixture was warmed up to 50-55 °C and stirred for 1 h. The reaction was quenched with saturated aqueous NHiCl, and the mixture was extracted with EtOAc. The combined organic layers were dried (Na:804) and concentrated. The residue was purified on ISCO (10-95% EtOAc in hexane) to provide the desired product (110 mg, 0.37 mmol, quant.). LCMS (ESI): mz = 198.3 [M+H]". \ IY a NCR f = N A N. OH N 0 rss Prin Intermediate 44 (S)~2~(6-Chloro-1-methyl-1,2,3,4-tetrahydro-1,8-naphthyridin-4-yl)-7-(hydroxymethyl)-5- (1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00214] The title compound was prepared following the synthetic sequence described in Intermediate 33 - 35, substituting (.5)-6-chloro-1-methyl-1,2.3,4-tetrahydro-1,8-naphthyridin-4- amine hydrochloride (Intermediate 43) for (S$)-3-methoxy-5,6.7,8-tetrahydroquinolin-5-amine hydrochloride in Intermediate 33. LCMS (ESI): m / z = 506.4 [M+H]". x N-N 3 | N CFy i =X NF N. Br ANS 0 Intermediate 45 (S)-7-(Bromomethyl)-2-(6-chloro-1-methyl-1,2,3 4-tetrahydro-1,8-naphthyvidin-4-yl)-5-(1- methyl-3-(trifluoromethyl)- 1 H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00215] To a solution of (8)-2-(6-chloro-1-methyl-1,2,3,4-tetrahydro-1,8-naphthyridin-4-yl)- 7-(hydroxymethyl)-5-(1-methyl-3~(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin- 1(2H)-one (Intermediate 44, 35.0 mg, 0.069 mmol, 1 equiv) in dichloromethane (2 mL) at 0 °C was added PBr3 (1.0 M in dichloromethane, 0.14 mL, 0.14 mmol, 2 equiv). The mixture was stirred at 0 °C for 30 min then warmed to 40 °C. The reaction mixture was stirred for additional 1 h then quenched with sat. aq. NaHCO: and extracted with EtOAc. The combined organic layers were dried (Na2804) and concentrated to provide the title compound (38 mg, 0.069 mmol, quant.) which was used without further purification. LCMS (ESI): m / z = 568.4 [M+H]" 2HCI NH, No” Intermediate 46 (5)-6-Chloro-34-dihydro-2H-pyrano[2,3-b]pyridin-4-amine hydrochloride

[00216] Step A. Preparation of (S,E)-N-((2,5-dichloropyridin-3-yl)methylene)-2- methylpropane-2-sulfinamide To a solution of 2,5-dichloronicotinaldehyde (1.15 g, 6.53 mmol, 1 equiv) in dichloromethane (25 mL) at room temperature was added (S)-2- methylpropane-2-sulfinamide (792.0 mg, 6.53 mmol, 1 equiv) and Cs2C0: (3.19 g, 9.80 mmol, 1.5 equiv). The mixture was stirred for 16 h then filtered. The filtrate was concentrated and the residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-20% gradient) to afford the title compound (1.7 g, 6.09 mmol, 93% yield). '"H NMR (400 MHz, Chloroform-d) 88.92 (s, 1H), 8.48 (d, J = 2.8 Hz, 1H), 8.32 (d, J = 2.8 Hz, 1H), 1.30 (5, 9H); LCMS (ESI): mz =279.1 [M+H]".

[00217] Step B. Preparation of (S)-N-((8)-1-(2,5-dichloropyridin-3-yl)but-3-en-1-yl)-2- methylpropane-2-sulfinamide To a solution of allylmagnesium bromide (1.0 M in diethyl ether, 52 mL, 5.2 mmol, 1.8 equiv) in THF (15 mL) at room temperature was added dropwise dimethylzinc (1.0 M in heptane, 5.7 mL, 5.7 mmol, 2.0 equiv). The mixture was stirred at room temperature for 30 min then was added slowly to a solution of (8,E)-N-((2,5-dichloropyridin-3- yl)methylene)-2-methylpropane-2-sulfinamide (800.0 mg, 2.9 mmol, 1 equiv) in THF (15 mL) at -78 °C. The resulting mixture was stirred for 1.5 h then quenched with sat. aq. NHsCL The mixture was extracted with EtOAc. The combined organic layers were dried (Na:SO4) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-90% gradient) to afford the title compound (600 mg, 1.87 mmol, 65% yield) 'H NMR (400 MHz, Chloroform-d) 8 8.29 (d, J=2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 5.65 (m, 1H), 5.16 (m, 2H), 4.82 (q, J = 6.4 Hz, 1H), 3.84 (brd, J = 6.8 Hz, 1H), 2.64 (m, 2H), 1.23 (s, 9H); LCMS (EST): m / z =1321.2 [M+H]",

[00218] Step C. Preparation of ($)-N-((5)-1-(2,5-dichlorepyridin-3-yl)-3-hydroxypropyl)- 2-methylpropane-2-sulfinamide Ozone was bubbled through a solution of (S)-N«((S)-1+(2,5- dichloropyridin-3-yl)but-3-en-1-y1)-2-methylpropane-2-sulfinamide (520.0 mg, 1.62 mmol, 1 equiv) in dichloromethane (50 ml.) at ~78 °C while monitored the reaction by LCMS. After the starting material was consumed, nitrogen gas was bubbled through the reaction mixture for 5 min to remove the excess ozone. Then TBAF (1.0 M in THF, 2.05 mL, 2.05 mmol, 1.26 equiv) was added, and the mixture was allowed to warm to 0 °C and stirred for 1.5 bh until the ozonides were decomposed. Then MeOH (4 mL) was added and followed by addition of NaBH4 (200.0 mg, 5.29 mmol). The resulting mixture was stirred for 30 min then quenched with water. The mixture was extracted with EtOAc. The combined organic layers were dried (Na2804) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 45-95% gradient) to afford the title compound (322 mg, 0.99 mmol, 61% yield). 'H NMR (400 MHz, Chloroform-d) § 8.29 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 4.96 (m, 1H), 4.79 (d, J= 7.6 Hz, 1H), 3.78 (dd, J= 4.4, 6.8 Hz, 2H), 2.13 (m, 1H), 1.95 (m, 1H), 1.18 (s, 9H); LCMS (ESI): m / z = 325.2 [M+H]".

[00219] Step D. Preparation of (S)-N-((S)-6-chlore-3,4-dihydro-2H-pyrano(2,3- b|pyridin-4-yl)-2-methylpropane-2-sulfinamide To a solution of (S)-N-((5)-1-(2,5- dichloropyridin-3-yl)-3-hydroxypropyl)-2-methylpropane-2-sulfinamide (250.0 mg, 0.77 mmol, 1 equiv) in 1,4-dioxane (8 mL) at room temperature was added potassium tert-butoxide (172.0 mg, 1.54 mmol, 2 equiv). The mixture was warmed to 50-55 °C and stirred for 1 h. The reaction was quenched with saturated aqueous NHaCl and extracted with EtOAc. The combined organic layers were dried (Na2804) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 10-95% gradient) to afford the title compound (169 mg, 0.58 mmol, 76%). 'H NMR (400 MHz, Chloroform-d) § 8.14 (d, J=2.4 Hz, 1H), 7.82 (d, J=2.4 Hz, 1H), 4.61 (q, J = 4.4 Hz, 1H), 4.41 (m, 2H), 3.33 (brd, J = 4.0 Hz, 1H), 2.14 (m, 2H), 1.25 (s, 9H); LCMS (ESI): mz = 289.2 [M+H]".

[00220] Step E. Preparation of (8)-6-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4- amine hydrochloride. The title compound (169 mg, 0.63 mmol, quant ) was prepared following the procedure described for Intermediate 43 Step C using (S)-N-~((S)-6-Chloro-3,4-dihydro-2H- pyrano[2,3-blpyridin-4-y1)-2-methylpropane-2-sulfinamide (183.0 mg, 0.63 mmol, 1 equiv). 'H NMR (400 MHz, Methanol-d-) § 8.22 (d, J= 2.4 Hz, 1H), 7.93 (d, J= 2.4 Hz, 1H), 4.67 (t,J= 6.0 Hz, 1H), 4.48 (m, 2H), 2.43 (m, 1H), 2.18 (m. 1H); LCMS (EST): m / z = 185.3 [M+H]". N Ng a Ny CFs | NAAN OH ot © Intermediate 47 (8)-2-(6-Chloro-3.4-dihydro-2H-pyrano[2,3-b] pyridin-4-yl)-7-(hydroxymethyl)-5-(1- methyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00221] The title compound (37 mg, 0.075 mmol) was prepared following the synthetic sequence described in Intermediates 33 - 35, substituting (S)-6-chloro-3,4-dihydro-2H- pyrano[2,3-b]pyridin-d-amine hydrochloride (Intermediate 46) for (S)-3-methoxy-5,6,7,8- tetrahydroquinolin-5-amine hydrochloride in Intermediate 33. 'H NMR (400 MHz, Chloroform- ad) 88.19(d, J= 1.6 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.47 (m, 2H), 7.37 (s, 1H), 6.23 (m, 1H), 4.78 (d, J = 3.2 Hz, 2H), 4.57 (m, 1H), 4.38 (m, 1H), 4.01 (s, 3H), 3.29 (m, 1H), 3.11 (m, 1H), 2.72 (m, 2H), 2.19 (m, 2H); LCMS (ESI): m / z = 493.4 [M+H]" \ N=N N N=N ) ci CF3 7S NAN 8r o.’ © Intermediate 48 (8)-7-(Bromomethyl)-2-(6-chloro-3,4-dihydro-2H-pyrano[2,3-b] pyridin-4-yl)-5-(1-methyl- 3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00222] The title compound (45 mg crude) was prepared following the bromination procedure described for Intermediate 6, substituting (5)-2-(6-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridin- 4-y1)-7-(hydroxymethyl)-5-(1-methyl-3-(triflaoromethyl)-1H-pyrazol-4-y1)-3.4- dihydroisoquinolin-1(2H)-one (Intermediate 47, 37 mg. 0.075 mmol, J equiv) for 7- (hydroxymethyl)-5-(1-methyl-3-(triflucromethy!)-1 H-pyrazol-4-y1)-3,4-dihydroisoquinolin- 1(2H)-one. LOMS (ESD): m / z = 555.4 [M+H]". \ N~N N Fs © Trtarvnord iota 40 Intermediate 49 (8)-7-(Bromomethyl)-2-(2,3-dihydro-1H-inden-1-yl)-5-( 1-methyl-3-(trifluoromethyl)- 1 H-~ pyrazol-4-yl)-3.4-dihydroisoquinolin-1(2H)-one

[00223] The title compound (160 mg, 0.32 mmol) was prepared following the synthetic sequence described in Intermediates 1-3, 5 and 6, substituting (5)-2,3-Dihydro-1H-inden-1- amine for (2,4-dimethoxyphenyl)methanamine in Intermediate 1. LCMS (ESI): m / z = 504.4 [M+H], \ N=-N \ Ny CF; Qy 8r o [} Intermediate 50 7-(Bromomethyl)-2-(2,3~dihydrobenzofuran-3-yl)-5-(1-methyl-3-(trifluoromethyl )-14- pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00224] The title compound (91.3 mg, 0.15 mmol) was prepared following the synthetic sequence described in Intermediates 1-3, S and 6, substituting 2,3~dihydrobenzofuran-3-amine for (2.4-dimethoxyphenyl)methanamine in Intermediate 1. LCMS (ESI): m / z = 506.4 [M+H]". 1 0. To PN NTN Intermediate 51 3-Jodo-5-methoxy-1-methyl-1H-~pyrrolo[2,3-b| pyridine

[00225] Step A. Preparation of 3-Iodo-S-methoxy-1H-pyrrolo[2,3-b]pyridine. To a suspension of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (200.0 mg, 1.35 mmol, 1 equiv) in EtOH (8 mL) at room temperature was added KI (336 mg, 2.03 mmol, 1.5 equiv), iodine (514 mg, 2.03 mmol, 1.5 equiv), and | MNaOH (2 mL, 2.0 mmol, 1.5 equiv). The resulting mixture was stirred for 4 h then diluted with EtOAc, washed with saturated aqueous Na2S:0s. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (Combi- flash Rf, Hex / EtOAc = 0-25% gradient) to afford the title compound (301 mg, 1.1 mmol, 81%). T.CMS (ESI): mz = 275.2 [M+H]".

[00226] Step B. Preparation of 3-Todo-5-methoxy-1-methyl-1H-pyrrolo[2,3-b] pyridine. To a solution of 3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine (370 mg, 1.35 mmol, 1 equiv) in DMEF (6.5 mL) at 0 °C was added NaH (60% in mineral oil, 81 mg, 2.03 mmol, 1.5 equiv). The mixture was stirred for 20 min then iodomethane (109 pL, 1.76 mmol, 1.3 equiv) was added. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried (Na2804) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-25% gradient) to afford the title compound (350 mg, 1.21 mmol, 90%). ‘H NMR (400 MHz, Chloroform-d) 5 8.11 (d, J = 2.8 Hz, 1H), 7.26 (s, 1H), 7.18 (d, J =2.8 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H); LCMS (ESI): mz = 289.1 [M+H]". 1 0. Co- N \ A Intermediate 52 3-Todo-5-methoxy-1,2-dimethyl-1H-indole

[00227] The title compound (51 mg, 0.17 mmol, 14% yield) was prepared following the procedure described for Intermediate 51, substituting 5-methoxy-2-methyl-1H-indole (200 mg, 1.24 mmol, 1 equiv) for 5-methoxy-1H-pyrrolo[2,3-b]pyridine in Step A. LCMS (ESI): mz = 302.2 [M+H]™ I “C3 N N RY Intermediate 53 3-Iodo-5-methoxy-1-methyl-1H-indazole

[00228] The title compound (54 mg. 0.19 mmol, 62% yield) was prepared following the procedure described for Tntermediate 51 Step B, substituting 3-iodo-~S-methoxy-1H-indazole (83 mg, 0.30 mmol, 1 equiv) for 3-iodo-3-methoxy-1H-pyrrolo[2,3-b]pyridine. LCMS (ESI); mz = 289.0 [M-+H]". 8 SR) AOS NTN A Intermediate 54 5-Fluoro-3-iodo-1-methyl-1H-pyrrolo[2,3-b] pyridine

[00229] The title compound (300 mg, 1.09 mmol, 74% yield) was prepared following the procedure described for Intermediate 51, substituting 5-fluoro-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.47 mmol, 1 equiv) for 5-methoxy-1H-pyrrolo[2,3-b]pyridine in Step A. 'H NMR (400 MHz, Chloroform-d) 3 8.21 (s, 1H), 7.42 (dd, J = 2.4, 8.4 Hz, 1H), 7.34 (s, 1H), 3.89 (s, 3H); LCMS (ESD): mz = 277.1 [M+H]". 0 Ry 0 NZ TN A Intermediate 85 1-Ethyl-3-iodo-5-methoxy-1H-pyrrolo[2.3-b]pyridine

[00230] The title compound (71 mg, 0.24 mmol, 81% yield) was prepared following the procedure described for Intermediate 51 Step B, substituting bromoethane (43 pL, 0.58 mmol, 2 equiv) for iodomethane. LCMS (ESI): m / z = 303.2 [M+H]". 0. To N \ Ou Intermediate 56 3-Iodo-5,7-dimethoxy-1-methyl-1H-indole

[00231] The title compound (100 mg, 0.31 mmol, 71% yield) was prepared following the procedure described for Intermediate 51, substituting 5,7-dimethoxy-1H-indole (108 mg, 0.61 mmol, 1 equiv) for 5-methoxy-1H-pyrrolo[2,3-b]pyridine in Step A. LCMS (ESI): m / z = 318.0 [M-+H]". Br ( = ZN Tor bmarsns cord lobo == Intermediate 537 4-Bromo-6-ethylisoquinoline

[00232] To a solution of 6-ethylisoquinoline (100 mg, 0.64 mmol) in dichloromethane (2 mL) was added N-bromosuccinimide (1.2 eq). The reaction was stirred at room temperature for 24 h then concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-15% gradient) to afford the title compound (75 mg, 50% yield). 'H NMR (400 MHz, Chloroform-d) § 9.10 (s, 1H), 8.68 (s, 1H), 7.93 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.54 (dd, J=84,154Hz 1H), 2.91 (q, / = 7.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H). Br Br “00 x, N Intermediate 58 5-Bromo-3-ethylquinoline

[00233] Toa solution of 2-amino-6-bromobenzaldehyde (200 mg, 1.0 mmol) in ethanol (2 mL) was added butyraldehyde (1.2 eq) and 1M aq. NaOH solution (2.0 eq). The reaction was heated under the microwave at 110 °C for 30 min. The reaction was cooled to room temperature, poured into dichloromethane and washed with brine. The layers were separated and the organic layer was concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-15% gradient) to afford the title compound (157 mg, 67% yield). 'H NMR (400 MHz, Chloroform-d) § 8.79 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.05 (d, / = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 8.4, 8.4 Hz, 1H), 2.90 (q, J = 7.6 Hz, 2H), 1.38 (tJ =7.6 Hz, 3H). OH Br. NN » N ~~ Intermediate 59 Ethyl 6-bromo-4-hydroxyquinoline-8-carboxylate

[00234] The title compound (3.70 g, 12.5 mmol, 79.9% yield in two steps) was prepared following the procedure described for Intermediate 15, substituting ethyl 2-amino-S- bromobenzoate (5.0 g, 16.6 mmol) for 4-bromo-2-methoxyaniline in Step A. 'H NMR (400 MHz, Chloroform-d) 8 8.75 (d, J = 2.2 Hz 1H), 8.45 (d, J = 2.3 Hz, 1H), 7.69-7.65 (m, 1H), 6.35 (dd, J=1.1Hz, 1H), 446 (q,J=7.0 2H), 1.46 (t, J = 7.1 3H): LCMS (ESI): m / z = 295.9 [M+H]|" OH CO Z N Np Intermediate 60 Ethyl 6-ethyl-4-hydroxyquinoline-8-carboxylate

[00235] The title compound (700 mg, 2.85 mmol, 57% yield) was prepared following the procedure described for Intermediate 16, substituting ethyl 6-bromo-4-hydroxyquinoline-8- carboxylate (Intermediate 59, 1.49 g, 5.03 mmol) for 6-bromo-8-methoxyquinolin-4-ol. '"H NMR (400 MHz, Chloroform-d) & 8.49 (s, 1H), 8.25 (s, 1H), 7.69 (t, J = 7.7 Hz, 1H), 6.35 (d, J = 4.1 Haz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 2.80 (q, J = 7.6 Hz, 2H), 1.47 (t, J = 7.1 3H), 1.35 (tJ = 7.6 3H): LCMS (ESI): mz = 246.1 [M+H]". Br = | = N A~rNp Intermediate 61 Ethyl 4-bromo-6-ethylquinoline-8-carboxylate

[00236] The title compound (630 mg, 2.04 mmol, 82.2 % yield) was prepared following the procedure described for Intermediate 17, substituting ethyl 6-ethyl-4-hydroxyquinoline-8- carboxylate (Intermediate 60, 610 mg, 2.49 mmol) for 6-ethyl-8-methoxyquinolin-4-0l, "TH NMR (400 MHz, Chloroform-d) § 8.48 (s, 1H), 8.35 (s, 1H), 8.27 (t, J = 7.0 Hz, 1H), 7.04 (d, J= 7.0 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.80 (q, J = 7.6 Hz, 2H), 1.49 (t,.J = 7.4 3H), 1.33 (t, J= 7.6 3H); LCMS (ESI): m / z = 309.1 [M+H]". ~o Intermediate 62 8-Bromo-4-iodo-6-methoxy-2-methylquinoline

[00237] Step A. Preparation of 5-(1-((2-bromo-4-methoxyphenylamino)ethylidene)-2,2- dimethyl-1,3-dioxane-4,6-dione. In round bottorn flask, Meldrum's acid (15 g, 104 mmol, 2 equiv) and trimethyl orthoacetate (20 mL, 160 mmol, 3 equiv) were mixed together neat at 110 °C for 15 min. The reaction was cooled to room temperature and 2-bromo-4-methoxyaniline (10.5 g. 52 mmol, 1 equiv) was added portionwise. The reaction was heated at 110 °C for 3 hand cooled to room temperature. The precipitate was filtered and washed with ethanol to afford the title compound (18.5 g, 50 mmol, 96 % yield), which was used in the next step without further purification. 'H NMR (400 MHz, Chloroform-d) § 7.22 (d, J = 2.8 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.92 (dd, J= 8.8, 2.8 Hz, 1H), 3.84 (s, 3H), 2.46 (5, 3H), 1.74 (s, 6H).

[00238] Step B. Preparation of 8-bromo-6-methoxy-2-methylquinolin-4-ol. 5-(1-((2- Bromo-4-methoxyphenyl)amino)ethylidene)-2.2-dimethyl-1,3-dioxane-4,6-dione (18.5 g, 50 mmol, 1 equiv) in Dowtherm A (15 mL) at was heated to 250 °C and stirred for 30 min. The reaction was cooled to room temperature. Hexanes were added and precipitate was filtered and washed with hexanes to afford the title compound (9.8 g, 37 mmol, 73 % yield). 'H NMR (400 MHz, Chloroform-d) 6 8.22 (s, 1H), 7.73 (d, J=2.8 Hz, 1H), 7.48 (d, J = 2.8 Hz, 1H), 6.14 (dd, J=1.7,0.8 Hz, 1H), 3.90 (s, 3H), 2.45 (s, 3H); LCMS (ESI): Method 2: Rt = 1.135 min, mz = 268.0 [M+H]",

[00239] Step C. Preparation of 8-bromo-6-methoxy-2-methylquinolin-4-yl trifluoromethanesulfonate. 8-Bromo-6-methoxy-2-methylquinolin-4-ol (9.8 g, 36.6 mmol) was dissolved in THF:CH2Clz2 (4:1, 125 mL) and stirred at room temperature. 1,1,1- trifluoro-N-phenyl-N~((trifluoromethyl)sulfonyl)methanesulfonamide (19.6 ¢, 54.8 mmol, 1.5 equiv) followed by N,N-diisoproplyethylamine (16 mL, 91.4 mmol, 2.5 equiv) were added and reaction was stirred at 50 °C overnight. The reaction was diluted with CH2Cl2 and sat. NaHCO: and extracted with CH2Clz2 (3 x 20 mL). The organic layer was dried over MgSOsq, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Combi- flash Rf, Hex / EtOAc = 0-100% gradient) to afford the title compound (17.7 g, 44.2 mmol, quant.). 'H NMR (400 MHz, Chloroform-d) § 7.81 (d, J = 2.6 Hz, 1H), 7.30 (s, 1H), 7.21 (d, J = 2.7 Hz, TH), 3.94 (s, 3H), 2.82 (s, 3H); LCMS (ESI): Method 2: Rr = 2.026 min, mz = 399.9 [MAH]

[00240] Step D. Preparation of 8-Bromo-4-iodo-6-methoxy-2-methylquinoline. Triflic acid (3.9 mL 44.2 mmol, 1 equiv) was added to a solution of 8-bromo-6-methoxy-2-methylquinolin- 4-y1 trifluoromethanesulfonate (17.7 g, 44.2 mmol, 1 equiv) and potassium iodide (22.0 g, 133 mmol, 3 equiv) in acetonitrile (100 mL). The reaction mixture was stirred at 25 °C and stirred for 20 min. The reaction mixture was diluted with EtOAc and extracted with a sat. sodium thiosulfate solution. The combined organic layer was washed with brine, dried over MgSOs, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient) to afford the title compound (11.2 g, 29.7 mmol, 67 % yield). 'H NMR (400 MHz, Chloroform-d) § 7.89 (s, 1H), 7.74 (d, J=2.7 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 3.96 (s, 3H), 2.71 (s, 3H); LCMS (ESI); Method 2; Rr = 1.885 min, m / z = 377.9 [M+H]". Intermediate 63 8-Bromo-6-ethyl-4-iodo-2-methylquinoline

[00241] Step A. Preparation of 8-bromo-6-ethyl-2-methylquinolin-4-ol. In a round bottom flask, 2-bromo-4-ethylaniline (10 g, 50 mmol, 1 equiv), ethyl 3-oxobutanoate (13 rl, 0.10 mol, 2 equiv), AcOH (1.4 mL, 25 mmol, 0.5 equiv), were dissolved in EtOH (30 mL) and heated at 90 °C overnight to form the imine intermediate. Dowtherm A (10 mL) was added to the reaction mixture and the temperature was increased to 250 °C. The reaction was kept at 250 °C for 30 min. The reaction was cooled to room temperature and poured into hexane. The precipitate was filtered and washed with bexanes. The title compound (13 g, 20 mmol, 40% yield) was used without further purification. "H NMR (400 MHz, DMSO-ds) § 10.36 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H), 5.96 (s, 1H), 2.69 (q, J = 7.5 Hz, 2H), 2.42 (s, 3H), 1.21 (t, J = 7.6 Hz, 3H); LCMS (ESI): Method 2: Rr = 1.267 min, m / z = 266.1 [M+H]™.

[00242] Step B. Preparation of 8-bromo-6-ethyl-2-methylquinolin-4-yl trifluoromethanesulfonate. The title compound (4.71 g, 11.8 mmol, 24% yield) was prepared following the synthetic procedure described for Intermediate 62 Step C using 8-bromo-6-ethyl- 2-methylquinolin-4-ol (13 g, 20 mmol). 'H NMR (400 MHz, Chloroform-d) § 8.01 (d, J = 1.8 Hz, 1H), 7.78 ~ 7.72 (m, 1H), 7.10 (d, J = 1.2 Hz, 1H), 2.88 2.81 (m, 4H), 1.34 (t, / = 7.6 Hz, 3H): LCMS (ESI): Method 2: Rr =2.018 min, mz = 384.0 [M+H]".

[00243] Step C. Preparation of 8-bromo-6-ethyl-4-iodo-2~methylquinoline. Acetic anhydride (1.68 mL, 17.7 mmol, 1.5 equiv) was added to a solution of 8-bromo-6-ethyl-2- methylquinolin-4-yl trifluoromethanesulfonate (4.71 g. 11.8 mmol, 1 equiv) and potassium iodide (19.6 g, 118 mmol, 10 equiv) in DMF (50 mL). The reaction mixture was stirred for 2h at 110 °C then diluted with EtOAc and extracted with a sat. sodium thiosulfate solution. The combined organic layer was washed with brine, dried over MgSOs, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient) to afford the title compound (1.78 g, 4.73 mmol, 40% yield). 'H NMR (400 MHz, Chloroform-d) 8 7.93 (d,J=19Hz 1H), 7.91 (s, 1H), 7.72 (dt, J= 1.8, 0.9 Hz, 1H), 2.83 (q..J = 7.6 Hz, 2H), 2.73 (s, 3H), 1.35 (t, J = 7.6 Hz, 3H); LCMS (ESI): Method 2: Rt = 2.089 min, m / z = 375.9 [M+H]". ~o 0. ~~ Br 0 Ny Intermediate 64 Ethyl 4-bromo-6-methoxy-2-methylquinoline-8-carboxylate

[00244] Step A. Preparation of ethyl 2-((1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5- ylidene)ethyl)amino)-S-methoxybenzoate. The title compound (18.5 g, 50.9 mmol, 82% yield) was prepared following the procedure described for Intermediate 62 Step A using ethyl 2-amino- S-methoxybenzoate (12.2 g, 62.5 mmol). "H NMR (400 MHz, Chloroform-d) § 7.57 (t, J= 1.7 Hz, 1H), 7.12 (d, J = 1.7 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 2.47 (s, 3H), 1.74 (5, 6H), 1.33 (t,.J=7.1 Hz, 3H).

[00245] Step B. Preparation of ethyl 4-hydroxy-6-methoxy-2-methylquinoline-8- carboxylate. The title compound (10.3 g, 39.4 mmol, 77% yield) was prepared following the procedure described for Intermediate 62 Step B using ethyl 2-((1-(2,2-dimethyl-4,6-dioxo-1,3- dioxan-S-ylidene)ethyl)amino)-5-methoxybenzoate (18.5 g, 50.9 mmol). 'H NMR (400 MHz, Chloroform-d) § 11.44 (s, 1H), 8.05 (d, J = 3.1 Hz, 1H), 7.98 (dd, J= 3.0, 1.3 Hz, 1H), 6.20 ~ 6.15 (m, 1H), 4.45 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 2.43 (s, 3H), 1.45 (t,J= 7.1 Hz, 3H); LCMS (ESI): Method 2: Rr = 1.306 min, mz = 262.2 [M+H]".

[00246] Step C. Preparation of ethyl 4-bromo-6-methoxy-2-methylquinoline-8- carboxylate. The title compound (4.10 g, 12.6 mmol, 32% yield) was prepared following the procedure described for Intermediate 17 using ethyl 4-hydroxy-6-methoxy-2-methylquinoline- 8-carboxylate (10.3 g, 39.4 mmol). 'H NMR (400 MHz, Chloroform-d) 8 7.61 — 7.56 (m, 2H), 7.51(d,J=2.9 Hz, 1H), 451 (q,J=7.1 Hz, 2H), 3.97 (s, 3H), 2.67 (s, 3H), 1.45 (t, J=7.1 Hz, 3H); LCMS (ESI): Method 2: Rr = 1.249 min, mz = 324.1 [M+H]". Br Intermediate 65 6-Bromo-4-iodo-2-methylquinoline-3-carbonitrile

[00247] Step A. Preparation of S5-bromo-2-((1-(2.2-dimethyl-4,6-dioxo-1,3-dioxan-5- ylidene)ethyl)amino)benzonitrile, The title compound (14.1 g, 38.6 mmol, 63% yield) was prepared following the procedure described for Intermediate 62 Step A using ethyl 2-amino-S- methoxybenzoate (12 g, 60.9 mmol). 'H NMR (400 MHz, Chloroform-d) § 7.91 (d, J = 2.2 Hz, 1H), 7.84 (dd, J=8.6, 2.3 Hz, 1H), 7.24 (d,J=8.7 Hz, 1H), 2.56 (s, 3H), 1.75 (s, 6H).

[00248] Step B. Preparation of 6-bromo-4-hydroxy-2-methylquinoline-8-carbonitrile. The title compound (10.2 g, 38.8 mmol, quant.) was prepared following the procedure described for Intermediate 62 Step Busing 5-bromo-2-((1-(2.2-dimethyl-4,6~dioxo-1,3-dioxan-5- ylidene)ethyl)amino)benzonitrile (14.1 g, 38.8 mmol). 'H NMR (400 MHz, Chloroform-d) § 8.67 (d, J=2.3 Hz, 1H), 8.30 (brs, 1H), 7.98 (d, J = 2.3 Hz, 1H), 6.22 (s, 1H), 2.47 (s, 3H); LCMS (ESI): Method 2: Ry == 1.168 min, mz = 263.1 [M+H]".

[00249] Step C. Preparation of 6-bromo-4-iodo-2-methylquinoline-8-carbonitrile. A round-bottom flask was charge with 6-bromo-4-hydroxy-2-methylquinoline-8-carbonitrile (10.2 2. 38.8 mmol) and pyridine (3.61 mL, 44.6 mmol, 1.15 equiv) was dissolved in MeCN (100 mL) and cooled to 0 °C. Then trifluoromethanesulfonic anhydride (7.20 mL, 42.6 mmol, 1.1 equiv) was added dropwise. After complete triflate formation, sodium iodide (29.1 g, 194 mmol, 5 equiv) was added portionwise. Then trifluoromethanesulfonic acid (3.44 mL, 38.8 mmol, 1 equiv) was added dropwise. The reaction was diluted with water and NaHCOs was added to adjust pH 7-9. The reaction mixture was diluted with CHzCl: and extracted (3 x 20 mL). The organic layer was dried over MgSOs, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-50% gradient) to afford the title compound (3.87 g, 10.36 mmol, 27% yield). 'H NMR (400 MHz, DMSO-ds) § 8.61 (d,J=2.1 Hz, 1H), 8.31 (d,J=2.1 Hz, 1H), 8.30 (s, 1H), 2.66 (5, 3H): LCMS (ESI): Method 2: Rr=1.868 min, m=z =372.9 [M+H]". ~o 2 Br IN Nog Intermediate 66 Methyl 4-bromo-6-methoxyquinoline-2-carboxylate

[00250] Step A. Preparation of dimethyl 2-((4-methoxyphenyl)amino)fumarate. Dimethyl acetylenedicarboxylate (5.5 mL, 45 mmol, 1.1 equiv) was added dropwise to a solution of 4- methoxyaniline (5.0 g. 41 mmol, 1 equiv) in MeOH (120 mL) at 0 °C (reaction is exothermic). The reaction was stirred at room temperature overnight. More dimethyl acetylenedicarboxylate (1 mL) was added at room temperature and the reaction was heated at 50 °C for 1 h. The mixture was cooled to room temperature and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100%) to afford the title compound (10 g, 38 mmol, 93% yield). LCMS (ESI): Method 2: Rt = 1.785 min, mz = 266.1 [M+H]",

[00251] Step B. Preparation of methyl 6-methoxy-4-oxo-1,4-dihydroquinoline-2- carboxylate, The title compound (5.53 g, 23.7 mmol, 63% yield) was prepared following the procedure described for Intermediate 62 Step Busing dimethyl 2-((4- methoxyphenyl)amino)fumarate (10 g, 38 mmol). "TH NMR (400 MHz, DMSO-ds) § 7.91 (d, J = 9.1 Hz, 1H), 7.47 (s,J = 2.9 Hz, 1H), 7.37 (dd, J = 9.2 Hz, 2.9 Hz, 1H), 6.60 (d, J = 1.7 Hz, 1H), 3.96 (s, 3H), 3.84 (s, 3H); LCMS (ESI): Method 2: Ry = 1.134 min, mz = 234.1 [M+H]".

[00252] Step C. Preparation of methyl 4-bromo-6-methoxyquinoline-2-carboxylate Methyl 6-methoxy-4-0xo-1.4-dihydroquinoline-2-carboxylate (1.0 g, 4.3 mmol, 1 equiv) was dissolved in acetonitrile (20 mL) and stirred at room temperature. Potassium carbonate (1.8 g, 12.9 mmol, 3 equiv) and phosphorus oxybromide (3.7 g, 12.9 mmol, 3 equiv) were added and the reaction was stirred at 80 °C. The reaction was quenched with addition of ice and water and sat. aq. NaHCO: was added to adjust the pH to 7-9. The aqueous layer was extracted with CH2Clz (3x20 mL). The combined organic layers were dried over MgSOs and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100%) to afford the title compound (1.03 g, 3.5 mmol, 81% yield). 'H NMR (400 MHz, Chloroform-d) § 8.46 (s, 1H), 8.19 (d,J=8.7 Hz, 1H), 7.46 - 7.45 (m, 2H), 4.07 (s, 3H), 4.01 (s, 3H); LCMS (ESI): Method 2: Rr= 1.761 min, mz = 295.9 [M+H]". ~o Intermediate 67 4-Bromo-6-methoxycinnoline

[00253] Step A. Preparation of 1-(2-amino-S-methoxyphenyl)ethan-1-one. A 3.4 M solution of methylmagnesium bromide in 2-MeTHF (6.0 mL, 20.3 mmol, 3 equiv) in dry THF (6 ml) was cooled to 0 °C. Then a solution of 2~-amino-5-methoxybenzonitrile (1.0 g, 6.75 mmol, 1 equiv) in THF was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The suspension was cooled to 0 °C, sat. aq. NH4Cl was added and the resulting mixture was vigorously stirred until complete hydrolysis of the corresponding imine. The reaction mixture was diluted with CH2Cl2 and extracted (3 x 20 mL). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient followed by MeOH / CH2Clz = 0-10% gradient) to afford the title compound (138 mg, 0.084 mmol, 12% yield). '"H NMR (400 MHz, Chloroform-d) 6 7.19 (d, J = 2.9 Hz, 1H), 6.97 (dd, J = 9.4, 2.9 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 5.95 (brs, 2H), 3.78 (s, 3H), 2.57 (s, 3H); LCMS (ESI): Method 2: Rt = 0.406 min, mz =166.2 [M+H]".

[00254] Step B. Preparation of 6-methoxycinnolin-4-ol. 1-(2-Amino-5- methoxyphenyl)ethan-1-one (130 mg, 0.78 mmol) was taken up in conc. HCI (2.08 mL) and stirred at 0 °C. A solution of sodium nitrite (81 mg, 1.18 mmol, 1.5 equiv) in water (1 mL) was added dropwise at 0 °C. The reaction was stirred for 1 h at 0 °C and allowed to warm to room temperature. The pH was adjusted to pH 7-9 by addition of NaHCOs. The reaction mixture was extracted with CH2Cl: (3 x 20 mL). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient followed by MeOH / CH:Clz = 0-10% gradient) to afford the title compound (84 mg, 0.048 mmol, 61% yield). "H NMR (400 MHz, DMSO-ds) § 7.70 (s, 1H), 7.61 (d, J=9.1 Hz, 1H), 7.46 (dd, J=9.3, 2.9 Hz, 1H), 7.38 (d, / =2.8 Hz, 1H), 3.87 (s, 3H); LCMS (ESI): Method 2: Rr=1.074 min, mz =177.1 [M+H]".

[00255] Step C. Preparation of 4-bromo-6-methoxycinnoline. 6-Methoxycinnolin-4-ol (84.0 mg, 0.48 mmol, 1 equiv) was dissolved in acetonitrile (4 mL) and stirred at room temperature, Potassium carbonate (198 mg, 1.43 mmol, 3 equiv) and phosphorus oxybromide (410 mg, 1.43 mmol, 3 equiv) were added, and the reaction was stirred at 60 °C. The reaction was quenched with addition of ice and water, Sat. ag. NaHCO: was added to adjust the pH to 7- 9. The aqueous layer was extracted with CH2Clz (3 x 20 mL). The combined organic layers were dried over MgSO. and concentrated. The residue was purified by flash chromatography (Combi- flash Rf, Hex / EtOAc = 0-100% gradient) to afford the title compound (38 mg, 0.016 mmol, 33% yield). 'H NMR (400 MHz, Chloroform-d) § 9.34 (s, 1H), 8.39 (d, J = 9.3 Hz, 1H), 7.51 (dd, J = 9.4, 2.4 Hz, 1H), 7.24 (d, J = 2.5 Hz, 1H), 4.04 (s, 3H); LCMS (ESI): Method 2: RT = 1.429 min, mz = 239.1 [M+H]". Intermediate 68 8-Bromo-4-iodo-6-methylisoquinoline

[00256] Step A. Preparation of N-(2-bromo-4-methylbenzyl)-2,2-dimethoxyethan-1- amine. A solution of 2-bromo-4-methylbenzaldehyde (8.16 g, 41.0 mmol, 1 equiv) and 2,2- dimethoxyethan-1-amine (5.17 g, 49.2 mmol, 1.2 equiv) in toluene 80 mL was heated under reflux with Dean Stark trap for 3 h then concentrated. The residue was dissolved in EtOH (80 mL), and NaBHa (2.33 g, 61.5 mmol, 1.5 equiv) was added. The resulting reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was dissolved in EtOAc, washed with sat. aq. NaHCOs, dried (Na:80s), filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 10-70% gradient) to afford the title compound (10.1 g. 35 mmol, 85% vield).

[00257] Step B. Preparation of N-(2~-bromo-4-methylbenzyl)-N-(2,2-dimethoxyethyl)-4- methylbenzenesulfonamide. To a solution of N-(2-bromo-4-methylbenzyl)-2,2- dimethoxyethan-1-amine (10.1 g, 35.0 mmol, 1 equiv) in dichloromethane (350 mL) at room temperature were added pyridine (8.5 mL, 105 mmol, 3 equiv) and p-toluenesufonyl chloride (8.02 g, 42.1 mmol, 1.2 equiv). The mixture was stirred for 16 h, and then washed with sat. aq. NaHCOs and brine. The organic layer was dried (Naz2S04), filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtQAc = 10-60% gradient) to afford the title compound (15.4 g, 34.8 mmol, quantitative yield). "H NMR (400 MHz, Chloroform-d) 67.73 (d. J = 8.4 Hz, 2H), 7.33 (rm, 4H), 7.09 (d, J = 8.0 Hz, 1H), 4.51 (s, 2H), 436 (t, J=52 Hz, 1H), 3.29 (d, J= 5.2 Hz, 2H), 3.21 (s, 6H), 2.44 (s, 3H), 2.30 (s. 3H).

[00258] Step C. Preparation of 8-bromo-6-methylisoquinoline. To a solution of N-(2- bromo-4-methylbenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (14.7 g, 33.2 mmol, 1 equiv) in dichloromethane (333 ml.) at room temperature was added AICI; (26.5 g, 199.0 mmol, 6 equiv). The mixture was stirred for 16 h then quenched with water. The mixture was extracted with EtOAc. The combined organic layers were dried (Na2S04), filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtQOAc = 10-60% gradient) to afford the title compound (3.57 g, 16.1 mmol, 48% yield). 'H NMR (400 MHz, Chloroform-d) 8 9.54 (s, 1H), 8.56 (d, J = 5.6 Hz, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 7.53 (d, J=56 Hz, 1H), 2.54 (s, 3H).

[00259] Step D. Preparation of 8-bromo-4-iodo-6-methylisoquinoline. To a solution of 8- bromo-6-methylisoquinoline (2.0 g, 9.0 mmol, 1 equiv) in AcOH (60 mL) was added NIS (3.04 g, 13.5 mmol, 1.5 equiv). The mixture was stirred at 80 °C for 16 h. An aliquot of reaction mixture was taken and analyzed by LCMS, which showed presence of the starting material. Additional NIS (1.01 g, 4.5 mmol, 0.5 equiv) was added and the reaction was stirred for additional 5 h then concentrated. The residue was dissolved in EtOAc and washed with sat. aq. NaHCOs, dried (Na2S0s), filtered, and concentrated. The residue was purified by flash chromatography (Combi- flash Rf, Hex / EtOAc = 10-50% gradient) to afford the title compound (1.88 g, 5.4 mmol, 60% yield). "H NMR (400 MHz, Chloroform-d) 5 9.45 (s, 1H), 8.97 (s, 1H), 7.78 (m, 2H), 2.60 (s, 3H). Intermediate 69 6~-Ethyl-8-fluoro-4-iodoisoquinoline

[00260] Step A. Preparation of N-(4-bromo-2-fluorobenzyl)-2,2-dimethoxyethan-1~ amine. The title compound (10.05 ¢, 34.4 mmol, 85% yield) was prepared following the procedure described for Intermediate 68 Step A, substituting 2-bromo-4-methylbenzaldehyde for 4-bromo-2-fluorobenzaldehyde (8.19 g, 40.3 mmol, 1 equiv). 'H NMR (400 MHz, Chloroform- d) 87.24 (m, 3H), 4.47 (t, J = 5.6 Hz, 1H), 3.82 (s, 2H), 3.37 (s, 6H), 2.73 (d, J = 5.6 Hz, 2H).

[00261] Step B. Preparation of N-(4-bromo-2-fluorobenzyl)-N~(2,2-dimethoxyethyl)-4- methylbenzenesulfonamide, The title compound (14.0 g, 31.4 mmol, 91% yield) was prepared following the procedure described for Intermediate 68 Step B, using N-(4-bromo-2- fluorobenzyl)-2,2-dimethoxyethan-1-amine (10.05 g, 34.4 mmol, 1 equiv). 'H NMR (400 MHz, Chloroform-d) § 7.67 (d, J = 8.0 Hz, 2H), 7.29 (m, 4H), 7.16 (dd, J = 1.6, 9.6 Hz, 1H), 4.46 (s, 2H), 4.39 (t, J= 5.2 Hz, 1H), 3.26 (5, 6H), 3.25 (d, J = 5.2 Hz, 2H), 2.44 (s, 3H).

[00262] Step C. Preparation of 6-bromo-8-fluoroisoquinoline, The title compound (0.59 g, 2.6 mmol, 53% yield) was prepared following the procedure described for Intermediate 68 Step C, using N-(4-bromo-2-fluorobenzyl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (2.2 g. 4.9 mmol, 1 equiv). 'H NMR (400 MHz, Chloroform-d) § 9.50 (s, 1H), 8.63 (d, J = 6.0 Hz, 1H), 7.82 (s, 1H), 7.59 (d, J = 5.6 Hz, 1H), 7.40 (dd, J = 1.6, 9.2 Hz, 1H).

[00263] Step D. Preparation of 8-fluoro-6-vinylisoquinoline. To a solution of 6-bromo-8- fluoroisoquinoline (1.17 g, 5.17 mmol, 1 equiv) in EtOH (35 ml) was added potassium trifluoro(vinyl)borate (970.0 mg, 7.24 mmol, 1.5 equiv), PdCL(dppf) (171.0 mg, 0.21 mmol, 0.04 equiv), and EN (1.8 mL, 12.9 mmol, 2.5 equiv). The mixture was stirred at 80 °C for 16 h then concentrated. The residue was dissolved in EtOAc and washed with brine / water, dried (Na280a), filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-40% gradient) to afford the title compound (800 mg, 4.6 mmol, 89% yield). 'H NMR (400 MHz, Chloroform-d) & 9.47 (s, 1H), 8.58 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 6.0 Hz, 1H), 7.51 (s, 1H), 7.39 (dd, J = 1.2, 11.6 Hz, 1H), 6.86 (dd, J = 10.8, 17.6 Hz, 1H), 5.93 (d, J = 17.6 Hz, 1H), 5.50 (d, J=10.8 Hz, 1H).

[00264] Step C. Preparation of 6-ethyl-8-fluoroisoquinoline. To a solution of 8-fluoro-6- vinylisoquinoline (800.0 mg, 4.62 mmol, 1 equiv) in EtOH (35 mL) was added 10% Pd / C (246.0 mg, 0.23 mmol, 0.05 equiv). The resulting mixture was stirred under H> atmosphere for 2 h then filtered. The filtrate was concentrated, and the residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-60% gradient) to afford the title compound (667.0 mg, 3.61 mmol, 77%). 'H NMR (400 MHz, Chloroform-d) 8 9.47 (s, 1H), 8.55 (d, J = 6.0 Hz, 1H), 7.59 (d, J= 5.6 Hz, 1H), 7.40 (s, 1H), 7.12 (dd, J = 1.2, 11.2 Hz, 1H), 2.84 (q, J = 7.6 Hz, 2H), 1.34 (t.J=7.6 Hz, 3H).

[00265] Step D. Preparation of 6-ethyl-8-fluoro-4-iodoisoquinoline, The title compound (763.0 mg, 2.53 mmol, 66% yield) was prepared following the procedure described for Intermediate 68 Step D, using 6-ethyl-8-fluoroisoquinoline (667.0 mg, 3.61 mmol, 1 equiv). 'H NMR (400 MHz, Chloroform-d) 8 9.37 (s, TH), 8.99 (s, 1H), 7.61 (s, 1H), 7.23 (d, J = 10.8 Hz, TH), 2.91 (q, J = 7.6 Hz, 2H), 1.39 (t..J = 7.6 Hz, 3H). Intermediate 70 6-Ethyl-8-fluoro-4-iodoisoquinoline

[00266] The title compound (997.0 mg, 2.83 mmol, 69% yield) was prepared following the procedure described for Intermediate 68 Step D, using 6-bromo-8-fluoroisoquinoline (Intermediate 69 Step C, 920 mg, 4.07 mmol, 1 equiv). 'H NMR (400 MHz, Chloroform-d) 3 9.39 (s, 1H), 9.04 (s, 1H), 8.04 (s, 1H), 7.49 (dd, J = 1.6, 9.2 Hz, 1H). Intermediate 71 6-Ethyl-8-fluoro-4-iodoisoquinoline

[00267] To a solution of 6-bromo-8-fluoro-4-iodoisoquinoline (23.8 mg, 65.4 pmol, 1 equiv) in NMP (0.3 mL) at room temperature was added 5.4 M MeONa in MeOH (49 pl, 0.26 mmol, 4 equiv). The resulting mixture was stirred at 60 °C for 2 h then quenched with sat. aq. NHaCL The mixture was extracted with EtOAc. The combined organic layers were dried (Na:80a), filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-40% gradient) to afford the title compound (20.0 mg, 54.9 pmol, 93% yield). 'H NMR (400 MHz, Chloroform-d) 8 9.34 (s, 1H), 8.87 (s, 1H), 6.85 (d, J= 2.0 Hz, 1H), 6.58 (d, J =2,0 Hz, 1H), 4.01 (s, 3H), 4.00 (s, 3H). Intermediate 72 4-lodo-6-methoxy-8-(4-methylpiperazin-1-ylisoquinoline

[00268] Step A. Preparation of 6-bromo-4-iodo-8-(4-methylpiperazin-1-yl)isoquinoline. To a solution of 6-bromo-8-fluoro-4-iodoisoquinoline (Intermediate 70, 27.0 mg, 77 pmol, 1 equiv) in NMP (0.5 mL) were added 1-methylpiperazine (25.6 nL, 0.23 mmol, 3 equiv) and DIPEA (40.3 pL, 0.23 mmol, 3 equiv). The mixture was stirred in a sealed tube at 130 °C for 3.5 h then diluted with EtOAc. The organic layer was washed with water, dried (Na2S04), filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM / MeOH = 0-20% gradient) to afford the title compound (31.0 mg, 71 pmol, 93% yield, contaminated with small amount of byproduct). '"H NMR (400 MHz, Chloroform-d) § 9.38 (s, 1H), 8.91 (s, 1H), 7.86 (s, 1H), 7.23 (d, J = 1.6 Hz, 1H), 3.20 (brs, 4H), 2.72 (brs, 4H), 2.42 (s, 3H).

[00269] Step B. Preparation of 4-iodo-6-methoxy-8-(4-methylpiperazin-1-yl)isoquinoline. To a solution of 6-bromo-4-iodo-8-(4-methylpiperazin-1-yl)isoquinoline (47.0 mg, 110 umol, 1 equiv) in NMP (0.3 mL) was added 5.4 M MeONa in MeOH (50 pL, 270 pmol, 2.5 eq). The mixture was stirred in a sealed tube at 55 °C for 3 h then quenched with sat. ag. NHsCl. The mixture was extracted with EtOAc and the combined organic layer was dried (Na2S0a), filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, DCM / MeOH = 0-10% gradient) to afford the title compound (31.0 mg, 81 umol, 74% yield). 'H NMR (400 MHz, Chloroform-d) 9.27 (s, 1H), 8.83 (s, 1H), 6.97 (d, J = 1.6 Hz, 1H), 6.80 (d, J =1.6 Hz, 1H), 3.98 (s, 3H), 3.18 (brs, 4H), 2.74 (brs, 4H), 2.42 (s, 3H). { Br Boe” ] N Intermediate 73 fert-Butyl ((4-bromo-6-ethylquinolin-8-yl)methyl)carbamate

[00270] Step A. Preparation of 8-(azidomethyl)-4-bromo-6-ethylquinoline, To a solution of (4-bromo-~6-ethylquinolin-8-yl)methanol (510 mg, 1.92 mmol, 1 equiv) in THF (10 mL) at 0 °C were added diphenylphosphinyl azide (0.51 mL, 2.68 mmol, 1.4 equiv) and 2.3,4,6,7.8,9,10- octahydropyrimido[1,2-ajazepine (0.4 mL, 2.68 mmol, 1.4 equiv). The mixture was allowed to warm to room temperature slowly and stirred overnight. The reaction mixture was concentrated, and the residue was dissolved in EtOAc and washed with brine / water. The organic layer was dried (Na2S04), filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-30% gradient) to afford the title compound (478 mg, 1.64 mmol, 85% yield). 'H NMR (400 MHz, Chloroform-d) § 8.63 (d, J = 4.8 Hz, 1H), 7.97 (s, 1H), 7.71 (d,J = 6.4 Hz, 1H), 7.66 (s, 1H), 5.03 (s, 2H), 2.90 (q, J = 7.2 Hz, 2H), 1.38 (t, / = 7.2 Hz, 3H).

[00271] Step B. Preparation of tert-butyl ((4-bromo-6-ethylquinolin-8- yl)methyl)carbamate. To a solution of 8-(azidomethyl)-4-bromo-6-ethylquinoline (488.7 mg, 1.68 mmol, 1 equiv) in a mixture of THF (9 mL) and water (0.9 mL) was added PPh3 (575.0 mg, 2.18 mmol, 1.3 equiv). The mixture was stirred at 45 °C for 16 h. Then water (1 mL), NaHCOs3 (282 mg, 3.36 mmol, 2 equiv), and (Boc):0 (495 mg, 2.27 mmol, 1.35 equiv) were added. The resulting mixture was stirred at room temperature for 4 h. Then water was added, and the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SOs), filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-20% gradient) to afford the title compound (1.11 g, 3.03 mmol, 91% yield). 'H LCMS (ESI): >95%, m / z = 365.3 [M+H]". | Boe # Br N. Intermediate 74 tert-Butyl ((4-bromo-6-ethylquinolin-8-yl)methyl)(methyl)carbamate

[00272] To a solution of tert-butyl ((4-bromo-6-ethylquinolin-8-yl)methyljcarbamate (Intermediate 73, 388.7 mg, 1.06 mmol, 1 equiv) in DMF (3 mL) at 0 °C was added 60% NaH in mineral oil (63.8 mg, 1.6 mmol, 1.5 equiv). The mixture was stirred for 40 min, and then iodomethane (100 pL, 1.6 mmol, 1.5 equiv) was added. The mixture was allowed to warm to room teraperature and stirred overnight. The reaction was quenched with saturated aqueous NH:Cl and the mixture was extracted with EtOAc. The combined organic layers were dried (Na:S0a), filtered, and concentrated. The residue was purified by flash chromatography (Combi~ flash Rf, Hex / EtOAc = 0-20% gradient) to afford the title compound (392 mg, 1.03 mmol, 97% vield). 'H NMR (400 MHz, Chloroform-d) & 8.59 (d, J = 4.8 Hz, 1H), 7.89 (s, 1H), 7.69 (s, 1H), 7.45 (m, 1H), 5.11 (s, 2H), 2.95 (m, 2H), 2.87 (q, J = 7.6 Hz, 2H), 1.48 (m, 9H), 1.35 (t, J = 7.6 Hz, 3H). Intermediate 75 (4-Bromo-6-methoxyquinolin-8-yl)methanol

[00273] A solution of diisobutylaluminum hydride (247 mg, 1.74 mL, 1.00 molar, 2.00 equiv, 1.74 mmol) in toluene was added drop wise to a stirring solution of ethyl 4-bromo-6- methoxyquinoline-8-carboxylate (Intermediate 22, 270 mg, 1.00 equiv, 0.870 mmol) in anhydrous THF (3.00 mL) at 0 °C. The reaction was stirred for 30 min, then it was quenched with sat. ag. NaHCOs3 (2 mL). The mixture was extracted with EtOAc (10 ml x 2). The combined organic layers were dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient) to afford the title compound (177 mg, 660 pmol, 75.9 %). 'H NMR (400 MHz, Chloroform-d) 8 8.48 (d, J = 4.7 Hz, 1H), 7.70 (d, J = 4.7 Hz, 1H), 7.35 (d, J = 2.7 Hz, 1H), 7.31 (d, J = 2.7 Hz, 1H), 5.13 (d, J = 5.4 Hz, 2H), 4.70 (t, J = 5.6 Hz, 1H), 3.98 (s, 3H); LCMS (ESL): m / z = 269.1 [M+H]". S N. Br Intermediate 76 S-Bromo-2-methylquinoline

[00274] The title compound was prepared following the procedure described for Intermediate 58 substituting acetone for butyraldehyde. Intermediate 77 S5-Bromo-3-methylquinoline

[00275] The title compound was prepared following the procedure described for Intermediate 58 substituting propionaldehyde for butyraldehyde. Intermediate 78 5-Bromo-2-ethylquinoline

[00276] The title compound was prepared following the procedure described for Intermediate 58 substituting 2-butanone for butyraldehyde. This reaction yielded a mixture of 5-bromo-2- ethvlquinoline and 5-bromo-2,3-dimethylquinoline. The title compound was obtained by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient). 'H NMR (400 MHz, Chloroform-d) § 8.44 (d, J= 8.7 Hz, 1H), 8.01 (d, J= 8.4 Hz, 1H), 7.75 (dd, J=7.5, 0.9 Hz, 1H), 7.55-7.51 (m, 1H), 7.41 (d, J= 8.7 Hz, 1H), 3.03 (q, J = 7.6 Hz, 2H), 1.40 (t, J=7.6 Hz, 3H) Intermediate 79 5-Bromo-2-ethylquinoline

[00277] The title compound was prepared following the procedure described for Intermediate 58 substituting 2-butanone for butyraldehyde. This reaction yielded a mixtare of 3-bromo-2- ethylquinoline and 5-bromo-2,3-dimethylquinoline. The title compound was obtained by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient). 'H NMR (400 MHz, Chloroform-d) 8 8.19 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.72 (dd, J=7.5, 0.8 Hz, 1H), 7.48-7.44 (m, 2H), 2.71 (s, 3H), 2.51 (5, 3H). ~o Intermediate 80 S-Bromo-3-methoxy-2-methylquinoline

[00278] The title compound was prepared following the procedure described for Intermediate 58 substituting methoxyacetone for butyraldehyde. 'H NMR (400 MHz, Chloroform-d) 8 7.94 (d, J=8.4 Hz, 1H), 7.73 (dd, . / =7.6, 0.8 Hz, LH), 7.62 (s, 1H), 7.40-7.36 (rm, 1H), 4.01 (s, 3H), 2.67 (s, 3H), Intermediate 81 5-Bromo-3-ethyl-2-methylquinoline

[00279] The title compound was prepared following the procedure described for Intermediate 58 substituting 2-pentanone for butyraldehyde. '"H NMR (400 MHz, Chloroform-d) 3 8.20 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.73 (d, / =6.8 Hz, 1H), 7.49-7.45 (m, 1H), 2.86 (q, / =7.4 Hz, 2 H), 2.74 (s, 3H), 1.38 (t, J=7.4 Hz, 3H). Intermediate 82 5-Bromo-2-ethyl-3-methylquinoline

[00280] The title compound was prepared following the procedure described for Intermediate 58 substituting diethyl ketone for butyraldehyde. "H NMR (400 MHz, Chloroform-d) 6 8.18 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.71 (dd, J=7.5, 0.8 Hz, 1H), 7.47-7.43 (m, 1H), 3.01 (q, J=7.5 Hz, 2H). 2.54 (s, 3H), 1.38 (t. J=7.5 Hz, 3H). Now oe HN. N. 5 Yo, Intermediate 83 5-(1-Methyl-3-(trifluoromethyl)- 1 H-pyrazol-4-yl)-7-((2-nitro-1 H-imid azol-1-yl)methyl)- 3.4-dihydroisoquinolin-1(2H)-one

[00281] The title compound was prepared following the procedure described for Intermediate 7 substituting 2-nitro-1H-imidazole for 2-methyl-1H~-imidazole. 'H NMR (400 MHz, Chloroform-d) 6 8.01 (d, J=1.9 Hz, 1H), 7.36 (s, 1H), 7.20-7.19 (m, 2H), 7.16 (d, .2=0.9 Hz, 1H), 6.04 (bs, 1H), 5.64 (s, 2H), 4.01 (s, 3H), 3.50-3.46 (m, 2H), 2.80 (t, J=6.6 Hz, 2H). Intermediate 84 5-Bromo-3-ethyl-7-methylquinoline

[00282] Step A. Preparation of 2,6-dibromo-4-methylbenzaldehyde. To a solution of 1,3- dibromo-5-methylbenzene (21.0 g, 84 mmol) in anhydrous THF (200 mL) was added 2.0 M lithium diisopropylamide solution (58.8 mL, 1.4 eq) was drop-wise at -78 °C. The reaction mixture was stirred for 30 minutes then DMF (7.8 mL, 1.2 eq) was added. The reaction was stirred for 1 h at -78 °C then quenched with IN HCl and EtOAc. The quenched mixture was extracted with EtOAc (2 x 200 mL), and the organic layer was washed with brine, dried over MgSO0s, filtered, and concentrated to give the title compound (23.0 g, 98%). 'H NMR (400 MHz, Chloroform-d) § 10.26 (s, 1H), 7.49 (s, 2H), 2.39 (s. 3H).

[00283] Step B. Preparation of 2-(2,6~-dibromo-4-methylphenyl)-1,3-dioxolane. A mixture of 2,6-dibromo-4-methylbenzaldehyde (23.0 g, 83 mmol), ethane-1,2-diol (11 mL, 2.3 eq), and p-toluenesulfonic acid monohydrate (7.9 g, 0.5 eq) in anhydrous toluene (200 mL) was refluxed using a DeanStark trap until TLC showed no starting material. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in DCM (200 mL), washed with IN aq NaOH (50 mL) and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / FtOAc = 0-5% gradient) to afford the title compound (15.7 g, 59%). 'H NMR (400 MHz, Chloroform~d) § 7.39 (s, 2H), 6.36 (s, 1H), 4.35-4.31 (m, 2H), 4.08-4.05 (m, 2H), 2.29 (s, 3).

[00284] Step C. Preparation of N-(3-bromo-2-(1,3-dioxolan-2-yl)-5-methylphenyl)-1,1- diphenylmethanimine. A mixture of 2-(2,6-dibromo-4-methylphenyl)-1.3-dioxolane (15.7 g, 48.8 mmol), benzophenone imine (8.2 mL, 1.0 eq), cesium carbonate (31.8 g, 2.0 eq), BINAP (3.0g, 0.1 eq), and palladium(IT) acetate (0.55 g, 0.05 eq) in anhydrous toluene (200 mL) was purged with Ar then stirred for 16 h at 80 °C. The reaction mixture was cooled to ambient temperature and quenched with ¥120 (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO, filtered, and concentrated. The residue was triturated with DCM (200 mL). The solid was filtered to give the title compound. The filtrate was concentrated, and the residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-10% gradient) to afford the additional title compound (17.1 g. 83% vield). 'H NMR (400 MHz, DMSO-d6) § 7.67-7.62 (mm, 2H), 7.57-7.46 (m, 3H), 7.34 (bs, 3H), 7.24 (bs, 2H), 7.00 (s, 1H), 6.16 (s, 1H), 6.14 (s, 1H), 4.02-3.98 (m, 2H), 3.88-3.84 (m, 2H), 2.01 (s, 3H). 100285] Step D. Preparation of 2-amino-6-bromo-4-methylbenzaldehyde. To a solution of N-(3-bromo-2-(1,3-dioxolan-2-yl)-5-methylphenyl)-1,1-diphenylmethanimine (17.1 g, 40.5 mmol) in THF (100 mL) was added aq. IN HCI (100 mL, 2.5 eq). The reaction mixture stirred for 2 h at 80 °C than cooled to ambient temperature. The mixture was neutralized with aq. 6N NaOH. The mixture was extracted with EtOAc, and the combined organic layer was washed with brine, dried over MgSOs, filtered, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-10% gradient) to afford the title compound (6.3 g, 73%) as a yellow oil. "H NMR (400 MHz, Chloroform-d) 8 10.30 (s, 1H), 6.73 (s, 1H), 6.38 (s, 1H), 2.23 (s, 3H); LCMS Method 2: >95% purity 254 nm, Rr = 1.74 min, MS (ESI) 214.0 [M+H]".

[00286] Step E. Preparation of 5-bromo-3-ethyl-7-methylquinoline. The title compound was prepared following the procedure described for Intermediate 58 utilizing 2-amino-6-bromo- 4-methylbenzaldehyde and butyraldehyde. 'H NMR (400 MHz, Chloroform-d) & 8.74 (s, 1H), 8.21 (s, IH), 7.81 (s, 1H), 8.21 (s, 1H), 7.66 (s, 1H), 2.87 (q, / =7.6 Hz, 2H), 2.53 (s, 3H), 1.37 (q, / =7.6 Hz, 2H). Intermediate 85 S-Bromo-3-cyclopropylquinoline 00287] The title compound was prepared following the procedure described for Intermediate 58 substituting 2-cyclopropylacetaldehyde for butyraldehyde. 'H NMR (400 MHz, Chloroform- d) 58.74 (d,J=2.2 Hz, 1H), 8.08 (d, / =2.2 Hz, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 7.79 (d, / =0.9 Hz, 1H), 7.77 (d, J=0.9 Hz, 1H), 2.16-2.10 (m, 1H), 1.18-1.13 (m, 2H), 0.93-0.89 (m, 2H). Intermediate 86 5-Bromo-3-methoxy-2,7-dimethylquinoline

[00288] The title compound was prepared following the procedure described for Intermediate 58 utilizing 2-amino-6-bromo-4-methylbenzaldehyde (intermediate 84 Step D) and methoxyacetone. 'H NMR (400 MHz, Chloroform-d) 8 7.72 (s, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 3.99 (s, 3H), 2.64 (s, 3H), 2.49 (s, 3H). Intermediate 87 5-Bromo-3-methoxy-2,7-dimethylquinoline

[00289] The title compound was prepared following the procedures described for Intermediates 15 through 17, substituting ethyl 2-amino-5-bromobenzoate for 4-bromo-2-methoxyaniline and trimethylorthoacetate for triethyl orthoformate in the procedures for Intermediate 15. 'H NMR (400 MHz, Chloroform-d) & 8.01 (s, 1H), 7.80 (s, 1H), 7.59 (s, 1H), 4.52 (q, J=7.1 Hz, 2H), 2.87 (q, J=7.6 Hz. 2H), 2.69 (s, 3H), 1.46 (t, J=7.1 Hz, 3H), 1.46 (t, .J=7.6 Hz, 3H), Feu Br Ig Intermediate 88 4-Bromo-6-ethyl-8-(trifluoromethoxy)quinoline

[00290] The title compound was prepared following the procedures described for Intermediates 15 through 17, substituting 4-bromo-2-(trifluoromethoxy)aniline for 4-bromo-2-methoxyaniline IH NMR (400 MHz, Chloroform-d) § 8.71 (d, J=4.6 Hz, 1H), 7.94-7.93 (m, 1H), 7.75 (d, J=4.6 Hz, 1H), 7.56-7.55 (m, 1H), 2.90 (q, J=7.6 Hz, 2H), 1.37 (t. J=7.6 Hz, 3H). Intermediate 89 7-((1LH-Imidazol-1-yhmethyl)-5-(2-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin- 1(2H)-one

[00291] The title compound was prepared according to the procedures for Intermediates 3-7 substituting (2-(trifluoromethy!l)pyridin-3-yl)boronic acid for (1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl)boronic acid in the procedure for Intermediate 3 and imidazole for 2- methylimidazole in the procedure for Intermediate 7. Intermediate 90 5-Bromo-3-methoxy-7-methylquinoline

[00292] The title compound was prepared following the procedure described for Intermediate 58 utilizing 2-amino-6-bromo-4-methylbenzaldehyde (intermediate 84 Step D) and methoxyacetaldehyde. 'H NMR (400 MHz, Chloroform-d) § 8.63 (d, J=2.7 Hz, 1H), 7.80 (s, 1H), 7.68-7.66 (m, 2H), 3.99 (5, 3H), 2.51 (5, 3H). ~o 3 N. Br Intermediate 91 5-Bromo-3-methoxy-8-methylquinoline

[00293] Step A. Preparation of 2-amino-3-methylbenzaldehyde. To a solution of 2-amino- 3-methylbenzyl alcohol (1.0 g, 7.6 mmol) in dichloromethane (20 mL) was added manganese dioxide. The reaction was stirred at RT for 16 h then filtered through celite. The filtrate was concentrated, and the residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-25% gradient) to afford the title compound. 'H NMR (400 MHz, Chloroforni-d) 59.87 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.23 (d, J=7.8, 1H), 6.72-7.68 (m, 1H), 6.20 (bs, 2H), 2.17 (s, 3H).

[00294] Step B. Preparation of 3-methoxy-8-methylquinoline. The title compound was prepared following the procedure described for Intermediate S58 utilizing 2-amino-3- methylbenzaldehyde and methoxyacetaldehyde. 'H NMR (400 MHz, Chloroform-d) § 8.70 (d, J=2.9 Hz, 1H), 7.58 (t, J=5.6 Hz, 1H), 7.41 (s, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.37 (d, J=2.9 Hz, 1H), 3.95 (s. 3H), 2.79 (s. 3H).

[00295] Step C. Preparation of 5-bromo-3-methoxy-8-methylquinoline. To a solution of 3- methoxy-8-methylquinoline (114 mg, 0.66 mmol) and silver sulfate (103 mg, 0.5 eq) in sulfuric acid (1.0 mL) was added bromine (34 pL, 1.0 eq). The reaction was stirred at RT for 1 h then quenched with ice. The mixture was basified with 6.0 N aq. NaOH and extracted with dichloromethane. The organic layer was concentrated, and the residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-10% gradient) to afford the title compound. 'H NMR (400 MHz, Chloroform-d) 8 8.69 (d, J=2.8 Hz, 1H), 7.73 (d, J=2.8 Hz, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.29-7.27 (m, 2H), 4.01 (s, 3H), 2.74 (s, 3H). Intermediate 92 4-Bromo-6-ethyl-8-methoxy-1,7-naphthyridine

[00296] Step A. Preparation of 6-ethyl-2-methoxypyridin-3-amine. The title compound was prepared from 6-bromo-2-methoxypyridin-3-amine and triethylborane according to the procedure for Intermediate 16. 'H NMR (400 MHz, Chloroform-d) 8 6.84 (d, J=7.6 Hz, 1H), 6.57 (d, / =7.6 Hz, 1H), 4.00 (s, 3H), 2.65 (q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H).

[00297] Step B. Preparation of 6-ethyl-8-methoxy-1,7-naphthyridin-4(1H)-one. The title compound was prepared from 6-ethyl-2-methoxypyridin-3-amine according to the procedures for Intermediate 15. "H NMR (400 MHz, Chloroform-d) 8 7.66 (d, J=7.4 Hz, 1H), 7.52 (s, 1H), 7.39 (d, / =7.4 Hz, 1H), 4.12 (s, 3H), 2.87 (q, J=7.5 Hz, 2H), 1.38 (t, J=7.5 Hz, 3H).

[00298] Step C. Preparation of 4-bromo-6-ethyl-8-methoxy-1,7-naphthyridine. The title compound was prepared from 6-ethyl-8-methoxy-1,7-naphthyridin-4(1H)-one according to the procedure for Intermediate 17. '"H NMR (400 MHz, Chloroform-d) 8 8.63 (d, J=4.6 Hz, 1H), 7.80 (d, J=4.6 Hz, 1H), 7.31 (s, 1H), 4.22 (s, 3H), 2.80 (q, J=7.5 Hz, 2H), 1.31 (t, J=7.5 Hz, 3H). Intermediate 93 S-Bromo-3-ethyl-1,7-naphthyridine

[00299] Step A. Preparation of 3-amino-S-bromoisonicotinaldehyde. The title compound was prepared from 3,5-dibromopyridine according to the procedures for intermediate 84 from Step A to Step I. 'H NMR (400 MHz, Chloroform-d) 5 10.39 (s, 1H), 8.12 (s, 1H), 8.05 (s, 1H), 6.36 (bs, 2H).

[00300] Step B. Preparation of 5-bromo-3-ethyl-1,7-naphthyridine. The title compound was prepared following the procedure described for Intermediate 58 utilizing 3-amino-5- bromoisonicotinaldehyde and butyraldehyde. "TH NMR (400 MHz, Chloroform-d) § 9.38 (5, 1H), 8.91 (d, J=1.8 Hz, 1H), 8.76 (s, 1H), 8.20 (d, J=1.8 Hz, 1H), 2.94 (q, J=7.5 Hz, 2H), 1.40 (t, J=7.5 Hz, 3H). Intermediate 94 5-Bromo-3-methoxy-1,7-naphthyridine

[00301] The title compound was prepared following the procedure described for Intermediate 58 utilizing 3-amino-5-bromoisonicotinaldehyde (intermediate 93 Step A) and methoxyacetaldehyde. 'H NMR (400 MHz, Chloroform-d) 6 9.30 (s, 1H), 8.74-8.73 (m, 2H), 7.56 (d, J =2.6 Hz, 1H), 4.05 (s, 3H). Intermediate 95 4-Bromo-8-(bromomethyl)-6-methoxyquinoline

[00302] To a solution of (4-bromo-6-methoxyquinolin-8-yl)methanol (Intermediate 75, 536 mg, 2.00 mmol, 1 equiv) in DCM (10 mL) at 0 °C, PBr: (650 mg, 226 pL, 1.2 eq, 2.40 mmol) was added dropwise. The reaction mixture was stirred for 40 min, then quenched with slow addition of sat. aq. sodium carbonate solution (5 mL). The mixture was extracted with EtOAc (10 mL x 2), and the combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-50% gradient) to afford the title compound (490 mg, 1.48 mmol, 74.0 %). '"H NMR (400 MHz, Chloroform-d) 68.59 (d, J=4.7Hz, 1H), 7.70 (d, J=4.7Hz, 1H), 7.54 (d, J=2.8 Hz, 1H), 7.42 (d, / J=2.8 Hz, 1H), 5.15 (s, 2H), 3.98 (s, 3H); LCMS (ESI): mz = 332.1 [M+H]" ~o QO tL Intermediate 96 4-Bromo-6-methoxy-8-(piperidin- 1-ylmethyl)quinoline

[00303] To a solution of 4-bromo-8-(bromomethyl)-6-methoxyquinoline (99.3 mg, 0.300 mmol, T equiv) in acetonitrile (3 mL), piperidine (76.6 mg, 900 pmol, 3 equiv) was added and stirred for 2 h at 30 °C. The reaction mixture was concentrated, and the residue was purified by flash chromatography (Combi-flash Rf, DCM / MeOH = 0-15% gradient) to afford the title compound (55.00 mg, 164.1 pmol, 54.7 %). 'H NMR (400 MHz, Chloroform-d) 8 8.50 (d, J = 4.6 Hz, 1H), 7.68 (s, 1H), 7.65 (d, J = 4.6 Hz, 1H), 7.34 (d, J = 2.8 Hz, 1H), 4.19 (s, 2H), 3.98 (s, 3H), 2.57 (s, 4H), 1.66 (t, J = 5.0 Hz, 4H), 1.49 (d, J= 5.0 Hz, 2H); LCMS (ESI): m / z = 336.2 [M+H]™. Intermediate 97 4-Bromo-6-methoxy-8-(pyrrolidin-1-ylmethyl)quinoline

[00304] The title compound (51 mg, 0.16 mmol, 53 %) was prepared following the procedure described for Intermediate 96 substituting pyrrolidine for piperidine.'H NMR (400 MHz, Chloroform-d) 3 8.52 (d, J = 4.6 Hz, 1H), 7.70 (d, J = 4.4 Hz, 1H), 7.66 (d, J = 4.6 Hz, 1H), 7.37 (d, J = 2.7 Hz, 1H), 4.41 (s, 2H), 3.99 (s, 3H), 2.78 (s, 4H), 1.88 (s, 4H); LCMS (ESI): mz = 322.1 [M+H]". a0 N. r Intermediate 98 8-((1H-Imidazol-1-yl)methyl)-4-bromo-6-methoxyquinoline

[00305] The title compound (47 mg, 0.15 mmol, 49 %) was prepared following the procedure described for Intermediate 96 substituting 1H-imidazole for piperidine. 'H NMR (400 MHz, Chloroform-d) § 8.54 (d, J= 4.7 Hz, 1H), 7.76 (s, 1H), 7.72 (d,J=4.7 Hz, 1H), 7.39 (d, J=2.7 Hz, 1H), 7.10 (s, 1H), 7.04 (t, J = 5.4 Hz, 1H), 5.75 (s, 2H), 3.94 (s, 3H); LCMS (ESI): m / z = 319.2 [M+H]™. ~o Qype Intermediate 99 4-((4-Bromo-6-methoxyquinolin-8-yl)methyl)morpholine

[00306] The title compound (33 mg, 0.16 mmol, 532 %) was prepared following the procedure described for Intermediate 96 substituting morpholine for piperidine.’H NMR (400 MHz, Chloroform-d) § 8.51 (d, J = 4.6 Hz, 1H), 7.67 (d, J = 4.6 Hz, 2H), 7.37 (s, 1H), 4.24 (s, 2H), 3.99 (s, 3H), 3.80 (s, 4H), 2.65 (s, 4H); LCMS (ESI): m / z = 338.2 [M+H]". “So SN QU, Ne S Intermediate 100 4-Bromo-6-methoxy-8-((4-methylpiperazin-1-yl)methyl)quinoline

[00307] The title compound (56 mg, 0.16 mmol, 53 %) was prepared following the procedure described for Intermediate 96 substituting 1-methylpiperazine for piperidine. 'H NMR (400 MHz, Chloroform-d) § 8.51 (d, J = 4.6 Hz, 1H), 7.66 (d, J = 4.6 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J = 2.8 Hz, 1H), 4.27 (s, 2H), 3.98 (s, 3H), 2.74 (d, J = 33.0 Hz, 8H), 2.42 (s, 3H); LCMS (ESI): m / z = 351.1 [M=+H]", Intermediate 101 4-((4-Bromo-6-methoxyquinolin-8-ylymethyl)-1-methylpiperazin-2-one

[00308] The title compound (37 mg, 0.10 mmol, 34 %) was prepared following the procedure described for Intermediate 96 substituting 1-methylpiperazin-2-one for piperidine. LCMS (ESI): mz = 365.2 [MH] IX Intermediate 102 1~(4~((4-Bromo-6-methoxyquinolin-8-yl)methyl)piperazin-1-yl)ethan-1-one

[00309] The title compound (42 mg, 0.11 mmol, 37 %) was prepared following the procedure described for Intermediate 96 substituting 1-(piperazin-1-yl)ethan-1-one for piperidine. LCMS (ESI): mz=379.2 [M+H]". ~o 0. N Br aw Intermediate 103 4-Bromo-6-methoxy-8-((4-methoxypiperidin-1-yl)methyl)quinoline

[00310] The title compound (47 mg, 0.13 mmol, 51 %) was prepared following the procedure described for Intermediate 96 substituting 4-methoxypiperidine for piperidine. LCMS (ESI): mz =366.2 [M+H]" No Oy N. Intermediate 104 4-Bromo-6-methoxy-8-((4-(2-methoxyethyl)piperazin-1-yl)methyl)quinoline

[00311] The title compound (43 mg, 0.11 mmol, 44 %) was prepared following the procedure described for Intermediate 96 substituting 1-(2-methoxyethy piperazine for piperidine, 'H NMR (400 MHz, Chloroform-d) & 8.50 (d. J = 4.6 Hz, 1H), 7.66 (d, J = 4.6 Hz, 2H), 7.35 (d,J=2.8 Hz, 1H), 4.29 (s, 2H), 3.98 (5, 3H), 3.55 (1, J = 5.5 Hz, 2H), 3.34 (5, 3H), 2.77 (s. 4H), 2.68 (q, J = 6.4 Hz, 6H); LCMS (ESI): m / z = 395.2 [M+H]". Ch, J CQ Intermediate 105 4-Bromo-6-methoxy-8-((4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)quinoline

[00312] The title compound (49 mg, 0.12 mmol, 47 %) was prepared following the procedure described for Intermediate 96 substituting 1-(tetrahydro-2H-pyran-4-yl)piperazine for piperidine. 'H NMR (400 MHz, Chloroform-d) § 8.51 (d, J=4.6 Hz, 1H), 7.66 (d, J = 4.6 Hz, 1H), 7.62 (s. 1H), 7.35 (d. J =2.8 Hz, 1H), 4.25 (s, 2H), 4.03 (t, J= 5.6 Hz, 2H), 3.98 (s, 3H), 3.38 (m, / = 5.0 Hz, 2H), 2.71 (s, 8H), 2.48 (s, 1H), 1.80 (d, J= 11.9 Hz, 2H), 1.60 (m, J= 5.8 Hz, 2H); LCMS (ESI): mz =421.2 [M+H]". So Intermediate 106 (S)-8-((4-Bromo-6-methoxyquinolin-8-yl)methyl)octahydropyrazino[2,1-¢][1,4]oxazine

[00313] The title compound (47 mg, 0.12 mmol, 48 %) was prepared following the procedure described for Intermediate 96 substituting (S)-octahydropyrazino[2.1-c][1,4)oxazine for piperidine. 'H NMR (400 MHz, Chloroform-d) 8 8.50 (d, J = 4.6 Hz, 1H), 7.67 (d, J = 4.6 Hz, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 3.99 (s, 3H), 3.85 (d, J = 10.9 Hz, 1H), 3.68 (m, J = 6.6 Hz, 3H), 3.12 (q, J = 7.3 Hz, 1H), 2.80 (s, 1H), 2.48 (d, J = 11.6 Hz, 1H), 1.58 (q, J = 6.9 Hz, 4H), 1.47 (d, J = 6.6 Hz, 4H); LCMS (ESL): m / z = 393.2 [M+H]". Intermediate 107 4-Bromo-6-methoxy-8-(methoxymethyl)quinoline

[00314] To a solution of (4-bromo-6-methoxyquinolin-8-yl)methanol (Intermediate 75, 67 mg, 0.25 mmol, 1 equiv) and iodomethane (141.9 mg, 1.0 mmol, 4 equiv) in N,N-dimethylformamide (2 mL) at 0 °C, sodium hydride (12 mg, 500 umol, 2 equiv) was added. The reaction mixture was stirred for 1 min then quenched with water. The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-70% gradient) to afford the title compound (47 mg, 0.17 mmol, 67 %). '"H NMR (400 MHz, Chloroform-d) 88.52 (d, J=4.7 Hz, 1H), 7.68 (d, J =4.7 Hz, 1H), 7.55 (t, J = 1.4 Hz, 1H), 7.36 (d,.J=2.8 Hz, 1H), 5.13 (s, 2H), 3.98 (s, 3H), 3.57 (s, 3H); LCMS (ESI): m / z = 283 1 [M+H]". Few Intermediate 108 4-Bromo-6-methoxy-8-(((1-methylpiperidin-4-yl)oxy)methyl)quinoline

[00315] The title compound (35 mg, 96 pmol, 38 %) was prepared following the procedure described for Intermediate 107 utilizing 4-bromo-8-(bromomethyl)-6-methoxyquinoline (Intermediate 95, 83 mg, 0.25 mmol) and 1-methylpiperidin-4-ol (29 mg, 0.25 mmol). '"H NMR (400 MHz, CDCl3)."H NMR (400 MHz, Chloroform-d) & 8.48 (d, J = 4.7 Hz, 1H), 7.68 (d, J = 4.7 Hz, 1H), 7.56 (s, 1H), 7.36 (d, J = 2.8 Hz, 1H), 5.18 (s, 2H), 3.99 (s, 3H), 3.74 (d, J = 27.8 Hz, 1H), 2.97 (s, 2H), 2.51 (s, 2H), 2.25 (s, 2H), 2.04 (s, 2H), 1.57 (s, 2H); LCMS (ESL): mz = 366.2 [M+H]". Intermediate 109 4-Bromo-8-(cyclopropoxymethyl)-6-methoxyquinoline

[00316] The title compound (35 mg, 0.11 mmol, 60 %) was prepared following the procedure described for Intermediate 107 utilizing 4-bromo-8-(bromomethyl)-6-methoxyquinoline (Intermediate 95, 83 mg, 0.25 mmol) and cyclopropanol (33 mg, 0.75 mmol). ‘H NMR (400 MHz, CDCl). 'H NMR (400 MHz, Chloroform-d) $8.51 (d,.J = 4.7 Hz, 1H), 7.67 (d, J = 4.7 Hz, 1H), 7.53 (t,J=1.4 Hz, 1H), 7.34 (d,.J = 2.8 Hz, IH), 5.23 (s, 2H), 3.97 (s, 3H), 3.54 (m, J=3.0 Hz, 1H), 0.72 (m, J = 2.3 Hz, 2H), 0.54 (m, J = 3.1 Hz, 2H); LCMS (EST): mz = 309.2 [M+H]". oy Intermediate 110 4-Bromo-8-(cyclobutoxymethyl)-6-methoxyquinoline

[00317] The title compound (49 mg, 0.15 mmol, 61 %) was prepared following the procedure described for Intermediate 107 utilizing 4-bromo-8-(bromomethyl)-6-methoxyquinoline (Intermediate 95, 83 mg, 0.25 mmol) and cyclobutanol (54 mg, 0.75 mmol). 'H NMR (400 MHz, CDCls)."H NMR (400 MHz, Chloroform-d) 3 8 49 (d, J = 4.7 Hz, 1H), 7.66 (d, J = 4.7 Hz, 1H), 7.59 (t,J= 1.4 Hz, 1H), 7.34 (d, J= 2.8 Hz, 1H), 5.08 (s, 2H), 4.19 (m, J = 7.3 Hz, 1H), 3.98 (s, 3H), 2.29 (m, J = 3.2 Hz, 2H), 2.07 (m, J= 4.0 Hz, 2H), 1.74 (q, J=10.1 Hz, 1H), 1.55 (m,J = 3.9 Hz, 1H); LCMS (ESI): mz = 323.2 [M+H]". HO. Z Br Ny Intermediate 111 (4-Bromo-6-ethylquinolin-8-ylymethanol

[00318] The title compound (0.98 g, 3.7 mmol, 74 %) was prepared following the procedure described for Intermediate 75 utilizing ethyl 4-bromo-6-ethylquinoline-8-carboxylate (Intermediate 61, 1.54 g, 5.0 mmol). 'H NMR (400 MHz, Chloroform-d) & 8.60 (d, J = 4.8 Hz, 1H), 7.93 (s. 1H), 7.77 (d, J = 4.8 Hz, 1H), 7.57 (s, 1H), 5.18 (s, 2H), 2.88 (q, .J = 7.5 Hz, 2H), 1.36 (t,.J = 7.6 Hz, 3H): LOMS(ESI): m / z = 267.2 [M+H]". Intermediate 112 4-Bromo-8-(bromomethyl)-6-ethylquinoline

[00319] The title compound (410 mg, 1.25 mmol, 79.0 %) was prepared following the procedure described for Intermediate 93 utilizing (4-bromo-6-ethylquinolin-8-yl)methanol (Intermediate 111, 0.42 g, 1.58 mmol). ‘H NMR (400 MHz, Chloroform-d) § 8.75 (d, J = 4.8 Hz, 1H), 7.99 (t, J = 0.8 Hz, 1H), 7.79 (q, J = 2.7 Hz, 2H), 5.24 (s, 2H), 2.89 (q, J = 7.6 Hz, 2H), 1.38 (t, J=7.6 Hz, 3H); LCMS (ESL): m / z = 330.2 [M+H]". 0. Br N Intermediate 113 4-Bromo-6-ethyl-8-(methoxymethyl)quinoline 00320] The title compound (43 mg, 0.15 mmol, 80 %) was prepared following the procedure described for Intermediate 107 utilizing 4-bromo-8-(bromomethyl)-6-ethylquinoline (Intermediate 112, 63 mg, 191 pmol) and methanol (6.1 mg, 191 pmol). LCMS (ESI): mz = 281.2 [M+H]" oy Intermediate 114 4-Bromo-6-ethyl-8-((pyridin-4-yloxy)methyl)quinoline

[00321] The title compound (42 mg, 0.12 mmol, 64 %) was prepared following the procedure described for Intermediate 107 utilizing 4-bromo-8-(bromomethyl)-6-ethylquinoline (Intermediate 112, 63 mg, 191 pmol) and pyridin-4-ol (54.4 mg, 572 pmol). 'H NMR (400 MHz, Chloroform-d) § 8.62 (d, J = 4.7 Hz, 1H), 8.02 (s, 1H), 7.75 (d, J = 4.6 Hz, 1H), 7.70 (d, J = 7.4 Hz, 2H), 7.49 (d, J=1.1 Hz, 1H), 6.51 (d, J = 7.2 Hz, 1H), 5.60 (s, 2H), 2.88 (q, J = 7.6 Hz, 2H), 1.36 (t, J = 7.6 Hz, 3H); LCMS (ESI): m / z = 344.2 [M+H]", Intermediate 115 4-Bromo-6-ethyl-8-(((tetrahydro-2H-pyran-4-yljoxy)methyl)quinoline

[00322] The title compound (49 mg, 0.14 mmol, 73 %) was prepared following the procedure described for Intermediate 197 utilizing 4-bromo-8-(bromomethyl)-6-ethylquinoline (Intermediate 112, 64 mg, 191 pmol)) and tetrahydro-2H-pyran-4-ol (58 mg, 572 pmol). LCMS (ESI): m / z = 351.2 [M+H]". Ay Intermediate 116 4-Bromo-6-ethyl-8-((oxetan-3-yloxy)methyl)quinoline

[00323] The title compound (42 mg, 0.13 ramol, 68 %) was prepared following the procedure described for Intermediate 107 utilizing 4-bromo-8-(bromomethyl)-6-ethylquinoline (Intermediate 112, 64 mg, 191 pmol)) and oxetan-3-ol (42 mg, 572 pmol). 'H NMR (400 MHz, Chloroform-d) 6 8.58 (d, J= 4.6 Hz, 1H), 7.92 (s, 1H), 7.78 (s, 1H), 7.69 (d, J = 4.6 Hz, 1H), 5.13 (s, 2H), 4.81 (m, J = 4.8 Hz, 3H), 4.73 (q.J = 3.8 Hz, 2H), 2.89 (m, J = 5.6 Hz, 2H), 1.38 (tJ = 7.5 Hz, 3H); LCMS (ESI): m / z = 323.2 [M+H]". FES Intermediate 117 tert-Butyl 3~((4-bromo-6-ethylquinolin-8-yl)methoxy)azetidine-1-carboxylate

[00324] The title compound (57 mg, 0.14 mmol, 45 %) was prepared following the procedure described for Intermediate 107 utilizing 4-bromo-8-(bromomethyl)-6-ethylquinoline (Intermediate 112, 99 mg, 300 pmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (156 mg, 900 pmol). LCMS (ESI): m / z = 422.2 [M-+H]". 0 Ny Ay tie Cy N Intermediate 118 N-(2-Aminoethyl)pyrazine-2-carboxamide

[00325] Step A. Preparation of tert-butyl (2-(pyrazine-2-carboxamido)ethyl)carbamate. To a stirring solution of pyrazine-2-carboxylic acid (248 mg, 2.0 mmol, 1.0 equiv) in anhydrous DMEF (S mL), N-ethyl-N-isopropylpropan-2-amine (776 mg, 1.1 mL, 6.0 mmol, 3.0 equiv), and the reaction is cooled to 0 °C under Ar. 1-(1-(11-Oxidaneyl)-3AH-114-[1,2,3]triazolo[4,5- b]pyridin-3-y1)-1-(dimethylamino)-N-(hexafluoro-17-phosphaney)-N.N-~ dimethylmethanideanminium (760 mg, 2.0 mmol, 1.0 equiv) was added, and the reaction mixture was stirred at 0 °C for another 20 min then fert-butyl (2-aminoethyl)carbamate (961 mg, 0.80 mL, 6.0 mmol, 3.0 equiv) was added. The resulting mixture was warmed to room temperature and stirred for 7 h. The reaction was quenched by addition of S mL sat. aq. sodium bicarbonate then extracted with dichloromethane (10 mL x 2) The combined organic layer was washed with water followed by brine, dried over sodium sulfate, and concentrated. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient) to afford the title compound.

[00326] Step B. Preparation of N-(2-Aminoethyl)pyrazine-2-carboxamide. fert-Butyl (2- (pyrazine-2-carboxamido)ethy!l)carbamate was dissolved in DCM (10 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred for 30 min then concentrated. The residue was dissolved in DCM (10 mL), washed successively with sat. aq. sodium bicarbonate (10 ml x 2) and water, dried over sodium sulfate and concentrated to obtain the title compound (150 mg, 903 umol, 45.1 %). LCMS (ESI): m / z = 167.2 [M+H]" 0 BPN H Intermediate 119 N-(2-Aminoethyh) acetamide

[00327] The title compound (125 mg, 1.2 mmol, 61 %) was prepared following the procedure described for Intermediate 118 Step A and B substituting acetic acid (120 mg, 2.0 mmol) for pyrazine-2-carboxvlic acid. LCMS (ESI): mz = 103.2 [M-+H]". or Intermediate 120 N-(2~-Aminoethyl)isonicotinamide

[00328] The title compound (165 mg, 1.0 mmol, 50 %) was prepared following the procedure described for Intermediate 118 Step A and B substituting isonicotinic acid (246 mg, 2.0 mmol) for pyrazine-2-carboxylic acid. LCMS (ESI): mz = 166.2 [M+H]". 0 N ANH ory Intermediate 121 N-(2~ Aminoethyl)thiazole-4-carboxamide

[00329] The title compound (140 mg, 818 nmol, 401 %) was prepared following the procedure described for Intermediate 118 Step A and B substituting thiazole-4-carboxylic acid (258 mg, 2.0 mmol) for pyrazine-2-carboxylic acid. LCMS (ESI): mz = 172.2 [M+H]". Uh, ey 0 Example 1 7~((2~-Methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)~ 2-(naphthalen-1-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00330] Step A. Preparation of methyl 5-hydroxy-2-(naphthalen-1-yl)-1-0x0-1,2,34- tetrahydroisoquinoline-7-carboxylate. Dimethyl 2-hydroxy-2,3-dihydrobenzofuran-4,6- dicarboxylate (400 mg, 1.59 mmol, 1 equiv) and naphthalen-l-amine (454 mg, 3.17 mmol, 2 equiv) were dissolved in DCE (10 ml) and stirred at 80 °C for 1 h under Ar. Sodium triacetoxyborohydride (1.01 g, 4.76 mmol, 3 equiv) was then added to the reaction mixture and stirred at 80 °C overnight under Ar. Sat. aq. NaHCO: was added and the mixture was extracted with CH2Clz (3 x 30 mL). The combined organic phases were dried over Mg8QOs and concentrated under reduced pressure. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0-100% gradient) to afford the title compound (578 mg, 1.60 mmol, quant.). 'H NMR (400 MHz, Chloroform-d) 8.38 (d, J = 1.6 Hz, 1H), 7.93 ~ 7.78 (m, 3H), 7.60 (d, J = 1.6 Hz, 1H), 7.55 7.43 (m, 4H), 3.99 (dt, J = 12.4, 7.4 Hz, 1H), 3.90 (s, 3H), 3.87 (dd, J =12.4,59 Hz, 1H). 3.18 (dd, J = 7.5, 5.8 Hz, 2H); LCMS (ESI): m / z = 349.0 [M+H]".

[00331] Step B. Preparation of methyl 2-(naphthalen-1-yl)-1-o0x0-5- (((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate. The title compound (306 mg, 1.06 mmol, 63% yield) was prepared following the triflation procedure described for Intermediate 2, using methyl 3-hydroxy-2-(naphthalen-1-yl)-1-ox0-1,2,3,4- tetrahydroisoquinoline-7-carboxylate (580 mg, 1.67 mmol, 1 equiv). ‘H NMR (400 MHz, Chloroform-d) § 8.89 (d. J = 1.6 Hz, 1H), 8.15 (d, J = 1.6 Hz, 1H), 7.98 ~ 7.93 (m, 1H), 7.90 (dt, J =8.4, 1.1 Hz, 1H), 7.85 ~ 7.79 (m, 1H), 7.58 ~ 7.51 (m, 3H), 7.47 (dd, J = 7.3, 1.2 Hz, 1H), 4.10 (ddd, J=12.7, 9.4, 5.1 Hz, 1H), 4.04 — 3.99 (m, 1H), 3.98 (s, 3H), 3.51 — 3.33 (m, 2H); LCMS (ESI): mz =479.9 [M+H]".

[00332] Step C. Preparation of methyl 5-(1-methyl-3-(trifluoromethyl)-1H-~pyrazol-4-yl)- 2-(naphthalen-1-yl)-1-ox0-1,2,3,4-tetrahydroisoquinoline-7-carboxylate. The title compound (80.4 mg, 0.17 mmol, 32% yield) was prepared following the Suzuki coupling procedure described for Intermediate 3, using methyl 2-(naphthalen-1-yl)-1-oxo0-5- (((trifluoromethyl)sulfonyl)oxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (250 mg, 0.52 mmol, 1 equiv). 'H NMR (400 MHz, Chloroform-d) 8.88 (d, J = 1.9 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H), 7.93 ~ 7.87 (mn, 1H), 7.86 ~ 7.82 (m, 2H), 7.54 ~ 7.47 (m, 4H), 7.46 ~ 7.43 (m, 3H), 3.99 (s, 3H), 3.98 ~ 3.94 (m, 1H), 3.92 (s, 3H), 3.89 ~ 3.80 (m, 1H), 3.18 (ddd, J = 16.5, 9.8, 5.2 Hz, 1H), 3.03 (ddd, J = 16.6, 6.3, 4.7 Hz, 1H); LCMS (ESI): m'z = 480.0 [M + HJ",

[00333] Step D. Preparation of 7-(hydroxymethyl)-5-(1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl)-2-(naphthalen-1-yl)-3,4-dihydroisoquinolin-1(2H)-one. Sodium borohydride (127 mg, 3.35 mmol, 20 equiv) was added to a solution of methyl 5-(1-methyl-3- (trifluoromethyl)-1 H-pyrazol-4-yl)-2-(naphthalen-1-yl)- 1-ox0-1,2,3,4-tetrahydroisoquinoline- 7-carboxylate (80 mg, 0.17 mmol, 1 equiv) in ethanol (4 mL) at 23 °C. The reaction mixture was stirred for 12 hat 80 °C then concentrated. Water was added to the resultant residue and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over MgSO and concentrated under reduced pressure. The residue was used without further purification. LCMS (ESI): mz =451.0 [M+H]".

[00334] Step E. Preparation of 7-(bromomethyl)-5-(1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl)-2-(naphthalen-1-yl1)-3.4-dihydroisoquinolin-1(2H)-one. The residue from Step D was dissolved in CH2Cl2 (2 mL) and cooled to 0 °C. PBr: (31.6 4L, 0.34 mmol, 2 equiv) was added dropwise and reaction mixture was warmed to room temperatare and stirred overnight. The reaction was quenched with sat. aq. NaHCO: and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Mg80s and concentrated under reduced pressure to afford the crude title compound, which was used without further purification. LCMS (ESI): mz = 515.8 [M+H]".

[00335] Step F. Preparation of 7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-2-(naphthalen-1-yl)-3,4-dihydroisoquinolin-1(2H)-one. The title compound (10.3 mg, 0.020 mmol, 34% yield) was prepared following the bromide displacement procedure described for Intermediate 7, using 7-(bromomethyl)-53-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-y1)-2-(naphthalen-1-yl)-3,4-dihydroisoquinolin-1(2H)-one (30 mg, 0.058 mmol, 1 equiv). *H NMR (400 MHz, Chloroform-d) 5 8.14 (d, J = 2.0 Hz, 1H), 7.92 (dt, J = 6.9, 3.4 Hz, 1H), 7.86 (ddd, J = 7.6, 6.4, 2.3 Hz, 2H), 7.57 — 7.48 (m, 3H), 7.45 (dd. J = 7.3, 1.2 Hz, 1H), 7.38 (d, J= 1.1 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 1.4 Hz, 1H), 6.88 (d, J=1.4 Hz, 1H), 5.11 (s, 2H), 4.01 (s, 3H), 4.00 — 3.93 (m, 1H), 3.83 (dt, J = 12.4, 5.6 Hz, 1H), 3.14 (ddd, J = 15.7, 10.1, 5.2 Hz, 1H), 3.03 ~ 2.92 (m, 1H), 2.36 (s, 3H); '’F NMR (376 MHz, CDClz) § -63.12; LCMS (ESI): 95%, m / z = 516.0 [M + H|". \ N=N N N=N A ) CFy Cl. = A ae Ny J oO Example 2 2-(7-Chloroquinolin-4-y1)-7-((2-methyl- 1 H-imidazol-1-yl)methyl)-5-( 1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3.4-dihydroisoquinolin-1(2H)-one

[00336] Standard Buchwald Coupling Procedure: 7-((2-Methyl-1H-imidazol-1-yl)methyl)- 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-y1)-3 4-dihydroisoquinolin-1(2H)-one (20 mg, 0.051 mmol, 1 equiv), 7-chloro-4-iodogainoline (30 mg, 0.10 mmol, 2 equiv), cesium carbonate (33 mg, 0.10 mmol, 2 equiv), Xantphos (5.9 mg, 10 umol, 0.2 equiv), and Pd2(dba); (4.7 mg, 5.1 pmol, 0.1 equiv) were dissolved in 1,4-dioxane (1 mL) under an Ar. The reaction mixture was stirred for 14 h at 110 °C then cooled to 23 °C. Brine was added to the mixture and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSQa and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Phenomenex Gemini (18, H2O / CH3CN gradient from 15-85% CHzCN, 0.1% TFA) followed by neutralization with sat. aq. NaHCO:s to yield the title compound (25.1 mg, 0.046 mmol, 89% yield). 'H NMR (400 MHz, Chloroform-d) & 8.97 (d, J = 4.7 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.50 (dd, J = 9.0, 2.1 Hz, 1H), 7.38 (s, 1H), 7.32 (d, J = 4.7 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 1.4 Hz, 1H), 6.86 (d, J = 1.4 Hz, 1H), 5.11 (s, 2H), 4.10 - 4.02 (m, 1H), 4.01 (s, 3H), 3.80 (dt, / =12.1, 5.2 Hz, 1H), 3.14 (ddd, / =16.2, 10.9, 5.2 Hz, 1H), 2.96 (dt, .J= 16.4, 4.7 Hz, 1H), 2.34 (s, 3H); LCMS (ESI) Method 2: >95%, Rr=1.252 min, m / z=73550.9 [M+H]". \ 3 “ 2 I'S NA LS # ng Example 3 2-(3-Methoxyquinolin-8-yh)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3.4-dihydroisoquinolin-1(2H)-one

[00337] The title compound (21 mg, 0.039 mmol, 60% yield) was prepared following the Buchwald coupling procedure described for Example 2, substituting 5-bromo-3- methoxyquinoline (31 mg, 0.13 mmol, 2 equiv) for 7-chloro-4-iodoquinoline. ‘H NMR (400 MHz, Chloroform-d) § 8.70 (d, J = 2.8 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 8.4, 7.4 Hz, 1H), 7.47 (dd, J = 7.4, 1.2 Hz, 1H), 7.39 (s, 1H), 7.31 (d, J= 2.8 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.94 (d, J= 1.4 Hz, 1H), 6.87 (d, J= 1.3 Hz, 1H), 5.12 (s, 2H), 4.04 - 3.97 (m, 4H), 3.88 (s, 3H), 3.76 (dt, J = 12.4, 5.3 Hz, 1H), 3.11 (ddd, J= 16.0, 10.7, 5.3 Hz, 1H), 2.97 (dt, J = 16.3, 4.9 Hz, 1H), 2.36 (s, 3H); LCMS (EST) Method 2: >95%, Rr = 1.27 min, m / z = 546.9 [M+H]". \ 3 ~ NCR QUOC TX ~ Ne © Example 4 2-(6-Methoxyquinolin-4-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3- (trifluoromethyl)- 1 H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one 00338] The title compound (27 mg, 0.050 mmol, 78% yield) was prepared following the Buchwald coupling procedure described for Example 2, substituting 4-bromo-6- methoxyquinoline (31 mg, 0.13 mmol, 2 equiv) for 7-chloro-4-iodoquinoline. 'H NMR (400 MHz, Chloroform-d) 6 8.82 (d, J = 4.6 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.31 (d, J = 4.6 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.94 (d, J=1.4 Hz, 1H), 6.87 (d, J=1.4 Hz, 1H), 5.12 (s, 2H), 4.01 (s, 3H), 4.00 - 3.94 (m, 1H), 3.86 (s, 3H), 3.80 (dt, . / J=12.2, 5.2 Hz, 1H), 3.14 (ddd, / = 16.2, 10.9, 5.2 Hz, 1H), 2.96 (dt, J=16.4,4.7 Hz, 1H), 2.35 (s, 3H); LCMS (ESI) Method 2: >95%, Ry = 1.182 min, m / z = 546.9 [MHHT \ N-N St ~\ N N. lon & hl Example 5 7-Methoxy~7 ~((2~methyl-1H-imidazol-1~yl)methyl)-3 ~(1-methyl-3~(trifluoromethyl)-1H- pyrazol-4-yl)-3'4"-dihydro-1'H-[1,2"-biisoquinolin}-1"-one

[00339] The title compound (19 mg, 0.035 mmol, 55% yield) was prepared following the Buchwald coupling procedure described for Example 2, substituting I-chloro-7- methoxyisoquinoline (25 mg, 0.13 mmol, 2 equiv) for 7-chloro-4-iodoquinoline. "H NMR (400 MHz, Chloroform-d) 8 8.32 (d, J = 5.6 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 5.6 Hz, 1H), 7.41 = 7.35 (m, 2H), 7.15 (d, J = 2.5 Hz, 1H), 6.99 (d, J= 2.0 Hz, 1H), 6.95 (d, J = 1.4 Hz, 1H), 6.87 (d,.J= 1.4 Hz, 1H), 5.11 (s, 2H), 4.33 — 4.28 (m, 1H), 4.02 (s. 3H), 3.86 (s, 3H), 3.83 ~ 3.76 (m, 1H), 3.15 = 3.08 (d, J = 12.3 Hz, 1H), 3.00 = 2.96 (m, 1H), 2.36 (5, 3H); UF NMR (376 MHz, CDClz) § -60.17; LCMS (ESI): 295%, m / z = 546 9 [M+H]", \ 'N-N ~o Cen Example 6 2-(6-Methoxy-7-methylquinolin-4-yl)-7-((2-methyl-1 H-imidazol- 1-yl)methyl-5-(1-methyl- 3-(triflnoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00340] The title compound (12 mg, 0.021 mmol, 42% yield) was prepared following the Buchwald coupling procedure described for Example 2, substituting 4-bromo-6-methoxy-7- methylquinoline (26 mg, 0.10 mmol, 2 equiv) for 7-chloro-4-iodoquinoline. 'H NMR (400 MHz, Chloroform-d) § 8.77 (d, J = 4.7 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.89 (d, / = 1.2 Hz, 1H), 7.39 (d, J=1.1 Hz, 1H), 7.25 (d, J = 4.6 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.95 (s, 1H), 6.95 (d, J = 1.3 Hz, 1H), 6.87 (d, J = 1.3 Hz, 1H), 5.12 (s. 2H), 4.01 (s, 3H), 4.00 — 3.93 (m, 1H), 3.86 (s, 3H), 3.79 (dt, J = 12.3, 5.2 Hz, 1H), 3.13 (ddd, J = 16.2, 10.9, 5.2 Hz, 1H), 2.96 (dt, J = 16.3, 4.7 Hz, 1H), 2.40 (s, 3H), 2.35 (s, 3H); “F NMR (376 MHz, CDCl3) 8-60.16; LCMS (ESI) Method 2: 595%, Ry = 1.29 min, m / z = 561.0 [M+H]". \ 3 @ Q N Ny i ~{ No © Example 7 2-(6-Methoxy-8-methylquinolin~4~yl)~7-((2~-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl- 3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)~one

[00341] The title compound (36 mg, 0.064 mmol, 63% yield) was prepared following the Buchwald coupling procedure described for Example 2, substituting 4-bromo-6-methoxy-8- methylquinoline (52 mg, 0.21 mmol, 2 equiv) for 7-chloro-d-iodoquinoline. 'H NMR (400 MHz, Chloroform-d) 8 8.85 (d, J=4.6 Hz, 1H), 8.13 (d,J=2.0 Hz, 1H), 7.39 (d,J= 1.1 Hz, 1H), 7.32 (d,J=4.6 Hz, 1H), 7.28 (dd, J=2.8, 1.2 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H). 6.96 (d, / = 1.4 Hz, 1H), 6.93 (d, J= 2.8 Hz, 1H), 6.88 (d,J= 1.3 Hz, 1H), 5.13 (s, 2H), 4.02 (s, 3H), 3.97 (ddd, J = 12.2, 10.9, 4.3 Hz, 1H), 3.85 (s, 3H), 3.79 (dt, J = 12.3, 5.2 Hz, 1H), 3.14 (ddd, J = 16.2, 10.9, 5.2 Hz, 1H), 2.96 (dt, J = 16.4, 4.7 Hz, 1H), 2.80 (s, 3H), 2.36 (s, 3H); °F NMR (376 MHz, CDCl3) § -60.16; LCMS (EST): 95%, m / z = 561.0 [M+H]". bs ~o CFs [ 7, Se Example 8 2-(6-Methoxy-2-methylquinolin-4-yl)-7-((2-methyl-1 H-imidazol- 1-yl)methyl)-5-(1-methyl- 3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00342] The title compound (12 mg, 0.022 mmol, 43% yield) was prepared following the Buchwald coupling procedure described for Example 2, substituting 4-bromo-6-methoxy-2- methylquinoline (26 mg, 0.10 mmol, 2 equiv) for 7-chloro-4-iodoquinoline. 'H NMR (400 MHz, Chloroform-d) 8 8.12 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.40 ~ 7.35 (m, 2H), 7.23 (s, 1H), 7.03 (d, J = 2.7 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.96 (d, J=1.3 Hz, 1H), 6.88 (d,J=1.4 Hz, 1H), 5.13 (s, 2H), 4.02 (s, 3H), 3.96 (ddd, J = 12.3, 10.9, 4.4 Hz, 1H), 3.85 (s, 3H), 3.84 — 3.74 (m, 1H), 3.13 (ddd, J = 16.2, 10.9, 5.3 Hz, 1H), 2.96 (dt, J= 16.3, 4.7 Hz, 1H), 2.72 (s, 3H), 2.36 (s, 3H); "F NMR (376 MHz, CDCl3) § 60.16; LCMS (ESI) Method 2: >95%, Ry = 1.114 min, m / z = 561.0 [M+H]". bs! “0 CF, Ti i x Niza 0 Example 9 2-(3~Chloro-6-methoxyquinolin-4-yl)-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl~ 3-(trifluoromethyl)-1H-pyrazol-4-yl)-3.4-dihydroisoquinolin-1(2H)-one

[00343] The title compound (21 mg, 0.036 mmol, 69% yield) was prepared following the Buchwald coupling procedure described for Example 2, substituting 4-bromo-3-chloro-6- methoxyquinoline (28 mg, 0.10 mmol, 2 equiv) for 7-chloro~-4-iodoquinoline. 'H NMR (400 MHz, Chloroform-d) 8 8.81 (s, 1H), 8.13 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.43 — 7.37 (m, 2H), 7.04 (d,.J = 2.7 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 1.3 Hz, 1H), 6.88 (d, J=1,3 Hz, 1H), 5.13 (s, 2H), 4.02 (s, 3H), 3.93 (ddd, J= 12.3, 7.8, 5.8 Hz, 1H), 3.87 (s, 3H), 3.74 (dt, J=12.2, 6.0 Hz, 1H), 3.13 = 3.07 (m, 2H), 2.37 (s, 3H); °F NMR (376 MHz, CDCl3) 6-60.13; LCMS (ESI) Method 2: >95%, Rr = 1.411 min, m / z = 580.9 [M+H]". be CFs iD N Example 10 6'-Methyl-7-((2-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl-3-( trifluoromethyl)-1 H- pyrazol-4-yl)-3,4-dihydro~1H-[2.4'-biisoquinolin]-1-one

[00344] The title compound (19 mg, 0.036 mmol, 57% yield) was prepared following the Buchwald coupling procedure described for Example 2, substituting 4-bromo-6- methylisoquinoline (29 mg, 0.13 mmol, 2 equiv) for 7-chloro-4-iodoquinoline. "H NMR (400 MHz, Chloroform-d) § 9.17 (s, 1H), 8.46 (s, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.52 ~ 7.45 (m, 1H), 7.39 (d, J = 1.3 Hz, 1H). 7.01 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 1.4 Hz, 1H), 6.87 (d, J = 1.3 Hz, 1H), 5.12 (s, 2H), 4.05 ~ 3.95 (im. SH), 3.89 ~ 3.80 (mm, 1H), 3.12 (ddd, J = 15.1, 9.5, 5.2 Hz, 1H), 3.06 ~ 2.96 (m, 1H), 2.54 (s, 3H), 2.36 (5, 3H); “EF NMR (376 MHz, CDCl) § -60.05; LCMS (ESI) Method 2; 95%, Ry = 1.202 min, m / z = 531.0 [M+H]" 4 0 Se 55 D0 Example 11 2-(8-Methoxy-3-methylquinolin~5~yl)~7-((2~-methyl-1H-imidazol-1-yl)methyl)-5-(1-methyl- 3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00345] The title compound (4.5 mg, 8.0 umol 16%) was prepared following the Buchwald coupling procedure described for Example 2, substituting 5-bromo-8-methoxy~3~ methylquinoline (Intermediate 14, 26 mg, 0.10 mmol, 2 equiv) and BrettPhos (5.5 mg, 10 gmol, 0.2 equiv) for 7-chloro-4-iodoquinoline and Xantphos, respectively, 'H NMR (400 MHz, Chloroform-d) 6 8.79 (d, J = 2,2 Hz, 1H), 8.11 (d,.J= 2.0 Hz, 1H), 7.93 (d, = 2.1 Hz, 1H), 7.54 (d,J=87Hz, IH), 7.48 (d,J=8.7 Hz, 1H), 7.38 (s, IH), 6.99 (d, J = 2.0 Hz, IH), 6.96 (s, 1H), 6.88 (d, J = 1.4 Hz, 1H), 5.12 (s. 2H), 4.13 (s, 3H), 4.02 (s, 3H), 3.89 (d, J = 15.8 Hz, 2H), 3.00 (t, J = 6.3 Hz, 2H), 2.53 (s, 3H), 2.37 (s, 3H); F NMR (376 MHz, CDCl) $ -60.07, LCMS (ESI) Method 2: 95%, Rr = 1.193 min, m / z = 561.0 [M+H]". \ ry “0 Sy" CFy x Np f i ~\ NAN AAA NZ lJ o Example 12 7-((1LH-Imidazol- 1-yl)methyl)-2-(3-methoxyquinolin-5-yl)-5-(1-methyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00346] The title compound (195 mg, 0.16 mmol, 55% yield) was prepared following the Buchwald coupling procedure described for Example 2, using 7-((1H-imidazol-1-yl)methyl)-3- (1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 250 mg, 0.66 mmol, 1 equiv), 5-bromo-3-methoxyquinoline (317 mg, 1.33 mmol, 2 equiv), and Xantphos (116 mg, 0.20 mmol, 0.3 equiv) at 115 °C. 'H NMR (400 MHz, Chloroform-d) § 8.71 (d, J = 2.9 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.08 (dt, J = 8.5, 1.0 Hz, 1H), 7.64 7.58 (m, 2H), 7.48 (dd, J = 7.4, 1.2 Hz, 1H), 7.41 (d, J = 1.1 Hz, 1H), 7.31 (d, J = 2.9 Hz, 1H), 7.17 (d,J=2.0 Hz, 1H), 7.11 (t, J = 1.1 Hz, 1H), 6.96 (t, / =1.3 Hz, 1H), 5.20 (s, 2H), 4.05 - 3.98 (s,4H), 3.89 (s, 3H), 3.77 (dt, J=12.4, 5.3 Hz, 1H), 3.12 (ddd, / = 16.0, 10.6, 5.2 Hz, 1H), 2.99 (dt, J = 16.3, 49 Hz, 1H); LCMS (ESI) Method 2: »95%, Rr = 1.310 min, mz = 532.9 [M+H]". \ N-N NN Nr, Na Example 13 7~((1H-Imidazol-1-yl)methyl)-2-(6-methoxyquinolin-4-y1)-5-(1-methyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00347] The title compound (23 mg, 0.043 mumol, 54% yield) was prepared following the Buchwald coupling procedure described for Example 12, substituting 4-bromo-6- methoxyquinoline (38 mg, 0.16 mmol, 2 equiv) for 5-bromo-3-methoxyquinoline. 'H NMR (400 MHz, Chloroform-d) 8 8.81 (d, J = 4.6 Hz, 1H), 8.14 (d, J= 2.0 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.55 (s, 1H), 7.42 - 7.37 (m, 2H), 7.30 (d, J = 4.6 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.08 (s, 1H), 7.05 (d, J = 2.7 Hz, 1H), 6.93 (d, J = 1.7 Hz, 1H), 5.17 (s, 2H), 4.00 (s, 3H), 3.99 -- 3.95 (m, 1H), 3.85 (s, 3H), 3.79 (dt, J = 12.3, 5.2 Hz, 1H), 3.13 (ddd, J = 16.2, 10.9, 5.2 Hz, 1H), 2.96 (dt, J = 16.4, 4.8 Hz, 1H); LCMS (ESI) Method 2: >95%, Rt == 1.223 min, m / z = 532.9 [M+H]". ey ~o NCE Dx A N NJ NS © Example 14 7-((1H-Imidazol-1-yl)methyl)-2-(6-methoxy-2-methylquinolin-4-yI)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00348] The title compound (30 mg, 0.054 mmol, 68% yield) was prepared following the Buchwald coupling procedure described for Example 12, substituting 4-bromo-6-methoxy=-2- methylquinoline (40 mg, 0.16 mmol, 2 equiv) for S-bromo-3-methoxyquinoline. 'H NMR (400 MHz, Chloroform-d) 8 8.14 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.35 (s, 1H), 7.40 (s, 1H), 7.35 (dd, J=9.1, 2.8 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.07 (s, 1H), 7.01 (d, J=2.8Hz, 1H), 6.93 (s, 1H), 5.17 (s, 2H), 4.00 (s, 3H), 3.99 — 3.91 (m, 1H), 3.83 (s, 3H), 3.78 (dt, J=12.2, 5.2 Hz, 1H), 3.12 (ddd, J = 16.0, 10.7, 5.2 Hz, 1H), 2.95 (dt, J= 16.4, 4.8 Hz, 1H), 2.70 (s, 3H); LCMS (ESI) Method 2: >95%, Rr = 1.178 min, m / z = 546.9 [M+H]". ey Ns CFs Soe i 8 Example 15 7-((LH-Imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)- 1 H-pyrazol-4-yl)-2-(6- methylquinolin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00349] The title compound (45 mg, 0.087 mmol, 82% yield) was prepared following the Buchwald coupling procedure described for Example 12, substituting 4-bromo-6- methylquinoline (47 mg, 0.21 mmol, 2 equiv) for 5-bromo-3-methoxyquinoline. 'H NMR (400 MHz, Chloroform-d) 8.89 (d, J = 4.6 Hz, 1H), 8.15 (d, J= 2.0 Hz, 1H), 8.09 — 8.02 (m, 1H), 7.59 7.53 (m, 3H), 7.40 (d, J= 1.1 Hz, 1H), 7.30 (d, J=4.6 Hz, 1H), 7.18 (d, / =2.0 Hz, 1H), 7.08 (s, 1H), 6.93 (s, 1H), 5.18 (s, 2H), 4.03 — 4.96 (m, 4H), 3.82 (dt, J = 12.2, 5.4 Hz, 1H), 3.15 (ddd, J = 15.9, 10.5, 5.2 Hz, 1H), 2.97 (dt, J = 16.3, 4.9 Hz, 1H), 2.51 (s, 3H); °F NMR (376 MHz, CDClz) 6 -60.04; LCMS (ESI) Method 2: >95%, Rr =1.116 min, m / z = 517.0 [M + HI. Xx XY XN CFs. aM Nos N o Example 16 7-((LH-Imidazol~1~yl)methyl)-6'-methyl-5-(1-methyl-3-( trifluoromethyl) 1 H-pyrazol-4-yl)~ 3,4-dihydro-1H-([2,4'-biisoquinolin|-1-one

[00350] The title compound (22 mg. 0.043 mmol, 53% yield) was prepared following the Buchwald coupling procedure described for Example 12, substituting 4-bromo-6- methylisoquinoline (36 mg, 0.16 mmol, 2 equiv) for 5-bromo-3-methoxyquinoline. *H NMR (400 MHz, Chloroform-d) 3 9.19 — 9.17 (m, 1H), 8.46 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.95 (d, J=8.4Hz, 1H), 7.56 (5, 1H), 7.56 ~ 7.53 (m, 1H), 7.48 (dd, J= 8.4, 1.6 Hz, 1H), 7.41 (d,J= 1.1 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.09 (s, 1H), 6.94 (d, J=1.4 Hz, 1H), 5.19 (s, 2H), 4.01 (s, 3H), 4.00 - 3.94 (m, 1H), 3.85 (ddd, J = 12.1, 6.5, 5.2 Hz, 1H), 3.12 (ddd, J = 16.3, 9.5, 5.1 Hz, 1H), 3.01 (ddd, J = 16.3, 6.5, 4.8 Hz, 1H), 2.54 (s, 3H); LCMS (EST) Method 2: 95%, Rt = 1.229 min, mz = 517.0 [M+H]". “wen ~o Hcy Song NA NN Nyt © Example 17 T-((1LH-Imidazol-1-yl)methyl)-2-(6,8-dimethoxyquinolin-4-yl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00351] The title compound (30 mg, 0.053 mmol, 50% yield) was prepared following the Buchwald coupling procedure described for Example 12, substituting 4-bromo-6,8- dimethoxyquinoline (57 mg, 0.21 mmol, 2 equiv) for S-bromo-3-methoxyquinoline. 'H NMR (400 MHz, Chloroform-d) 8 8.81 (dd, J= 4.6, 1.2 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.56 (5, 1H), 7.40 (s, 1H), 7.34 (dd, J = 4.7, 1.2 Hz, TH), 7.17 (d, J = 1.9 Hz, 1H), 7.09 (s, 1H), 6.94 (d, J = 1.6 Hz, 1H), 6.74 (t, J = 1.8 Hz, 1H), 6.63 (dd, J = 2.5, 1.3 Hz, 1H), 5.18 (s, 2H), 4.06 (s, 3H), 4.01 (s, 3H), 3.99 ~ 3.91 (m, 1H), 3.84 (d, J = 1.3 Hz, 3H), 3.79 (td, J= 11.6, 10.3, 4.6 Hz, 1H), 3.13 (ddd, J = 16.3, 10.9, 5.3 Hz, 1H), 2.96 (dt, J = 16.4, 4.9 Hz, 1H); "°F NMR (376 MHz, CDCl) 5-60.16; LEMS (ESI) Method 2: >95%, Rr = 1.162 min, m / z = 562.9 [M+H]". \ 3 ~ or 7 oA N NN nd © Example 18 7-((LH-Imidazol-1-yl)methyl)-2-(6,8-dimethoxy-2-methylquinolin-4-yl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)~one

[00352] The title compound (22 mg, 0.038 mmol, 36% yield) was prepared following the Buchwald coupling procedure described for Example 12, substituting 4-bromo-6,8-dimethoxy- 2-methylquinoline (60 mg, 0.21 mmol, 2 equiv) for 5-bromo-3-methoxyquinoline. "H NMR (400 MHz, Chloroform-d) § 8.14 (d, J=2.0 Hz, 1H), 7.56 (s, 1H), 7.40 (d, J = 1.0 Hz, 1H), 7.25 (s, 1H), 7.16 (d, J=2.0 Hz, 1H), 7.08 (t, J = 1.1 Hz, 1H), 6.94 (d,.J= 1.3 Hz, 1H), 6.72 (d, J=2.5 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 5.18 (s, 2H), 4.04 (s, 3H), 4.01 (s, 3H), 3.97 — 3.88 (m, 1H), 3.82 (s, 3H), 3.77 (dt, J= 12.3, 5.3 Hz, 1H), 3.12 (ddd, J= 16.2, 10.8, 5.3 Hz, 1H), 2.94 (dt, J = 16.4, 4.8 Hz, 1H), 2.75 (s, 3H); 1F NMR (376 MHz, CDCI3) § -60.2; LCMS (EST) Method 2: >95%, RT = 1.440 min, mz = 376.9 [M+ H]". \ N-N £0) cry ™W AN Ns nS © a a¥ e Example 19 7-((1H-Imidazol-1-yl)methyl)-2-(8-methoxy-6-methylquinolin-4-yl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00353] The title compound (32 mg, 0.059 mmol, 55% yield) was prepared following the Buchwald coupling procedure described for Example 12, substituting 4-bromo-8-methoxy-6~ methylquinoline (54 mg, 0.21 mmol, 2 equiv) for S-bromo-3-methoxyquinoline. 'H NMR (400 MHz, Chloroform-d) § 8.89 (d, J = 4.6 Hz, 1H), 8.14 (d. J = 2.0 Hz, 1H), 7.55 (s, 1H), 7.40 (s, 1H), 7.32 (d, J = 4.6 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.14 (d, J = 1.4 Hz, 1H), 7.08 (s. 1H), 6.93 (d, J= 1.5 Hz, 1H), 6.90 (d, J= 1.6 Hz, 1H), 5.17 (s, 2H), 4.07 (s, 3H), 4.00 (s, 3H), 3.99 ~ 3.91 (m, 1H), 3.80 (dt, J= 11.7, 5.4 Hz, 1H), 3.14 (ddd, J = 15.9, 10.5, 5.2 Hz, 1H), 2.96 (dt, J = 16.5, 4.9 Hz, 1H), 2.49 (5, 3H); '%F NMR (376 MHz, CDCl3) 3 -60.04; LCMS (ESI) Method 2: 395%, Ry = 1.097 min, m’z = 546.9 [M+H]". \ 3 x CFa = “oT NY N NJ! Ny, o Example 20 T-((LH-Imidazol-1-yl)methyl)-2-(6-ethyl-8-methoxyquinolin-4-yl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3.4-dihydroisoquinolin-1(2H)-one

[00354] Step A. Preparation of 5-(((4-bromo-2-methoxyphenyhamino)methylene)-2,2- dimethyl-1,3-dioxane-4,6-dione. To a solution of 4-bromo-2-methoxyaniline (6.3 g, 31.2 mmol, 1 equiv) and Meldrum's acid (5.39 g, 37.4 mmol, 1.2 equiv) in EtOH (50 mL) was added triethyl orthoformate (5.2 mL, 31.2 mmol, 1 equiv). The reaction was stirred at 80 °C overnight. The reaction was cooled to 0 °C, filtered, and washed with cold EtOH to yield the title compound (10.96 g, 30.8 mmol, 99% yield). '"H NMR (400 MHz, Chloroform-d) & 11.46 (s, 1H), 8.61 (d, J = 14.6 Hz, 1H), 7.23 ~ 7.14 (m, 2H), 7.12 (d, J = 1.7 Hz, 1H), 3.96 (s, 4H), 1.75 (s, 6H).

[00355] Step B. Preparation of 6-bromo-8-methoxyquinolin-4-ol. 5-(((4-Bromo-2- methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10.96 g, 30.8 mmol, 1 equiv) was added portionwise to Dowtherm A (20 mL) at 260 °C and stirred for 30 min. The reaction was cooled to room temperature, and hexanes were added. The resulting mixture was filtered, and solid was washed with hexanes to yield the title compound (7.20 g, 28.3 mmol, 92% yield). "H NMR (400 MHz, DMSO-d) § 11.50 (s, 1H), 7.77 (t, J= 6.7 Hz, 1H), 7.73 (d,J =2.0Hz 1H), 7.38 (d.J=2.1 Hz, 1H), 6.08 (d, / J= 7.4 Hz, 1H), 4.01 (s, 3H). 100356] Step C. Preparation of 6-ethyl-8-methoxyquinolin-4-ol. A mixture of 6-bromo-8- methoxyquinolin-4-ol (215 mg, 0.85 mmol, I equiv), triethylborane (2 mL, 1.7 mmol, 2 equiv, 1 M THF), cesium carbonate (551 mg, 1.7 mmol, 2 equiv), and Pd(dppf)Cl> (31.0 mg, 42.3 pmol, 0.05 equiv) in THF (3 mL) was stirred for 3 h at 60 °C under Ar in a sealed tube. The reaction was cooled to 0 °C and quenched by 10% aq. NaOH and 30% aq. H202. The resulting mixture was warmed to 23 °C, brine was added, and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSQOsand concentrated under reduced pressure. The residue was purified by flash chromatography (Combi-flash Rf, Hex / EtOAc = 0- 100% gradient followed by DCM / MeOH = 0-10% gradient) to afford the title compound (173 mg, 0.85 mmol, quant.). '"H NMR (400 MHz, DMSO-ds) § 11.28 (s, 1H), 7.46 (d,J= 1.7 Hz, 1H), 7.11 (d, J=1.7 Hz, 1H), 6.00 (d, J = 7.3 Hz, 1H), 5.75 (s, 1H), 3.98 (s, 3H), 2.70 (9, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). LCMS (ESI): Method 2: Rr = 1.185 min, mz = 204.1 [M+H]"

[00357] Step D. Preparation of 4-bromo-6-ethyl-8-methoxyquinoline. To a solution of 6- ethyl-8-methoxyquinolin-4-ol (170 mg, 0.84 mmol, 1 equiv) in DMF (5 mL) was added PBrs (0.16 mL, 1.67 mmol, 2 equiv) dropwise at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with ice, and the pH was adjusted to 7 with NaHCO: The solid was filtered, washed with water, and dried to yield the title compound (169 mg, 0.64 mmol, 76% yield). 'H NMR (400 MHz, Chloroform-d) & 8.46 (d, J=4.6 Hz, 1H), 7.53 (d, J = 4.6 Hz, 1H). 7.39 (dt..J = 1.8, 0.9 Hz, 1H), 6.81 (d, / = 1.7 Hz, 1H), 3.96 (s, 3H). 2.70 (q, J = 7.5 Hz, 2H), 1.23 (t. J = 7.6 Hz, 3H); LCMS (ESI): Method 2: Rr = 1.231 min, m / z = 266.0 [M+H]".

[00358] Step E. Preparation of 7-((1H-Imidazol-1-y)methyl)-2-(6-ethyl-8- methoxyquinolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)- 1 H-pyrazol-4-yl)-3,4- dihydroisoquinolin-1(2H)-one. 7-((1H-Imidazol-1-yl)methy!)-5-(1-methyl-3- (trifluoromethyl)-1 H-pyrazol-4-y1)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 1.0 equiv), 4-bromo-6-ethyl-8-methoxyquinoline (Intermediate 17, 57 mg, 0.21 mmol, 2 equiv), cesium carbonate (2.0 equiv), Xantphos (0.2 equiv), and Pd2(dba)s (0.1 equiv) were dissolved in 1,4-dioxane under an Ar. The reaction mixture was stirred for 14 hat 110 °C then cooled to 23 °C. Brine was added to the mixture and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over MgSQasand concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H20 / CH3CN gradient from 10-70% CH3CN, 0.1% TFA) followed by neutralization with sat. ag. NaHCO: to yield the title compound (30 mg, 0.054 mmol, 50% yield). 'H NMR (400 MHz, Chloroform-d) § 8.92 (d, J = 4.6 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.59 (s, 1H), 7.41 (d, J = 1.1 Hz, 1H), 7.35 (d, J = 4.6 Hz, 1H), 7.18 (t, J = 2.2 Hz, 2H), 7.10 (d, J = 1.3 Hz, 1H), 6.95 (d, J = 1.6 Hz, 2H), 5.20 (s, 2H), 4.10 (s, 3H), 4.02 (s, 3H), 3.96 (ddd, J = 12.2, 10.6, 4.4 Hz, 1H), 3.82 (dt, J= 12.3, 5.3 Hz, 1H), 3.15 (ddd, J = 16.0, 10.6, 5.2 Hz, 1H), 2.97 (dt, J = 16.3, 4.9 Hz, 1H), 2.80 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H); “F NMR (376 MHz, Chloroform-d) § -60.11. LCMS (ESI) Method 3: >95%, Rr = 1.849 min, mz = 561.1 [M+H]". x N-N o Ser, A | an © Example 21 7-((LH-Imidazol-1-yl)methyl)~1'-chloro-6'~-methoxy-5-(1-methyl-3-(trifluoromethyl)-1 H- pyrazol-4-y1)-3,4-dihydro-1H-[2,4'-biisoquinolin]-1-one

[00359] The title compound (52 mg, 0.092 mmol, 75% yield) was prepared following the procedures described in Example 12, substituting 1-chloro-4-iodo-6-methoxyisoquinoline (78 mg, 0.25 mmol, 2 equiv) for S-bromo-3-methoxyquinoline. LCMS (ESI) Method 2: »95%, Rr = 1.300 min, m / z = 566.8 [M + HJ". \ *y ~o NCR Id =\ ANN LL ~o Se ° Example 22 7-((LH-Imidazol-1-yl)methyl)-1',6'-dimethoxy-5-(1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl)-3,4-dihydro-1H-[2,4'-biisoquinolin]-1-one

[00360] To a solution of 7-((1H-imidazol-1-yl)methyl)-1'-chloro-6'-methoxy-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydro-1H-[2,4'-biisoquinolin]-1-one (Example 21, 25 mg, 0.044 mmol, 1 equiv) in MeOH (0.6 mL) was added sodium methoxide (15 xL, 0.066 mmol, 1.5 equiv) dropwise at 23 “C. The reaction mixture was stirred for 12 h at 23 “°C then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H2O / CH3CN gradient from 10-80% CHaCN, 0.1% TFA) to vield the title compound (3.0 mg, 0.005 mmol, 12% yield). TH NMR (400 MHz, Chloroform-d) 5 8.22 (d, J= 9.1 Hz, 1H), 8.17 (d, J= 2.0 Hz, 1H), 7.96 (s, 1H), 7.60 (s, 1H), 7.40 (d, J = 1.1 Hz, 1H), 7.19 (dd, J = 9.1, 2.5 Hz, 1H), 7.15 (d, J= 2.0 Hz, 1H), 7.11 (s, 1H), 6.96 (s, 1H), 6.94 (d, J = 2.5 Hz, 1H), 5.20 (5. 2H), 4.12 (s, 3H), 4.02 (s, 3H), 3.93 (ddd, J= 12.4, 9.7, 4.6 Hz, 1H), 3.87 (s, 3H), 3.79 (dt, J= 12.2, 5.5 Hz, 1H), 3.09 (ddd, J= 15.3, 9.8, 5.2 Hz, 1H), 2.98 (dt, J = 16.3, 5.4 Hz, 1H); "°F NMR (376 MHz, CDCls) § -60.14; LCMS (ESI) Method 2: >95%, Ry = 1.422 min, m / z = 562.9 [M+H]". N-n } Fy a s Example 23 7-((1H-Imidazol-1-yl)methyl)-2-(8-methoxy-3-methylquinolin-5-yl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00361] 7-((1H-Imidazol-1-yl)methyl)-5-( 1-methyl-3-(trifluoromethyl)- 1 H-pyrazol-4-yl)-3,4~ dihydroisoquinolin-1(2H)-one (Intermediate 8, 20 mg, 0.053 mmol, 1 equiv), 3-iodo-8-methoxy- 3-methylquinoline (Intermediate 18, 32 mg, 0.11 mmol, 2 equiv), potassium phosphate tribasic (23 mg, 0.11 mmol, 2 equiv), (15,25)-N1.N2-dimethylcyclohexane-1,2-diamine (0.76 mg, 0.84 ul, 5.3 pmol, 0.1 equiv), and copper(I) iodide (1.0 mg, 5.3 pmol, 0.1 equiv) were dissolved in 1,4-dioxane (1 mL) under Ar. The reaction mixture was stirred for 14 h at 113 °C then cooled to 23 °C. Brine was added to the mixture and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H20 / CH:CN gradient from 15-80% CH:CN, 0.1% TFA) followed by neutralization with sat. aq. NaHCO:s to yield the title compound (14 mg, 0.025 mmol, 47% yield). *H NMR (400 MHz, Chloroform-d) 8 8.80 (d, J = 2.1 Hz, 1H), 8.15 (d, J=2.0Hz, 1H), 7.82 (dd, J = 2.2, 1.2 Hz, 1H), 7.58 (s, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.16 (d. J =2.0 Hz, 1H), 7.10 (s, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.95 (s, 1H), 5.18 (s, 2H), 4.10 (s, 3H), 4.01 (s, 3H), 3.96 (ddd, J = 12.3, 9.8, 4.5 Hz, 1H), 3.76 (dt, J = 12.0, 5.6 Hz, 1H), 3.11 (ddd, J = 15.5, 10.0, 5.2 Hz, 1H), 2.98 (dt, J = 16.3, 5.3 Hz, 1H), 2.50 (s, 3H); '’F NMR (376 MHz, CDCl3) § - 60.07; LCMS (ESI) Method 3: >95%, Rr = 1.824 min, m / z = 547.2 [M+H]* \ N-N \ CFs cr | N Oo Example 24 7-((1H-Imidazol-1-yl)methyl)-8'-chloro-6'-methyl-5-( 1-methyl-3-(trifluoromethyl)- 1 H- pyrazol-4-yl)-3.4-dihydro-1H-[2.4'-biisoquinolin]-1-one

[00362] The title compound (35 mg, 0.064 mmol, 79% yield) was prepared following the Buchwald coupling procedure described for Example 2, using 7-((1H-imidazol-1-yl)methyl)-5- (1-methyl-3-(trifluotomethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (30 mg, 0.080 mmol, 1 equiv) and 4-bromo-8-chloro-6-methylisoquinoline (41 mg, 0.16 mmol, 2 equiv). IH NMR (400 MHz, Chloroform-d) & 9.60 (s, 1H), 8.55 (s, 1H), 8.16 (s, 1H), 7.57 (s, 1H), 7.54 (d,J=2.0 Hz, 1H), 7.48 (s, 1H), 7.41 (s, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.10 (s, 1H), 6.95 (s, 1H), 5.20 (s, 2H), 4.04 (s, 3H), 4.02 (m, 1H), 3.83 (m, 1H), 3.12 (m, 1H), 3.04 (m, 1H), 2.52 (s, 3H); LOMS (ESI): >88%, m / z = 551.4 [M+H]". en “ Son \ oS N. Ng NN © Example 25 7-((LH-Imidazol-1-yl)methyl)-2-(6-methoxyquinazolin-4-yl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00363] The title compound (11 mg, 0.021 mmol, 13% yield) was prepared following the Buchwald coupling procedure described for Example 12, substituting 4-chloro-6- methoxyquinazoline (62 mg, 0.32 mmol, 2 equiv) for 5-bromo-3-methoxyquinoline. 'H NMR (400 MHz, Chloroform-d) 8 9.09 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.57 (dd, J=9.2,2.8 Hz, 2H), 7.41 (d, J = 1.1 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.11 (s, 1H), 7.04 (d, J=2.8 Hz, 1H), 6.95 (s, 1H), 5.20 (s, 2H), 4.16 (s, 2H), 4.03 (s, 3H), 3.88 (s, 3H), 3.06 (t, J = 6.3 Hz, 2H); "°F NMR (376 MHz, CDCl) § -60.10; LCMS (ESI) Method 2: >95%, Ry = 1.305 min, mz = 534.0 [M+H]". \ = CFs Y= = —N, N. NN 0 Example 26 7-((1H-Imidazol-1-yl)methyl)-2-(1,2-dimethyl-1 H-indol-4-y1)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00364] The title compound (8 mg, 0.016 mmol, 24% yield) was prepared following the Buchwald coupling procedure described for Example 12, substituting 4-bromo-1,2-dimethyl-1H- indole (30 mg, 0.13 mmol, 2 equiv) for 5-bromo-3-methoxyquinoline. 'H NMR (400 MHz, Chloroform-d) § 8.19 (d, J = 2.0 Hz, 1H), 7.58 (s, 1H), 7.37 (s, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 7.09 (s, 1H), 7.01 (dd, J = 7.3, 1.1 Hz, 1H), 6.94 (s, 1H), 6.12 (s, 1H), 5.17 (s, 2H), 4.01 (s, 3H), 3.98 ~ 3.91 (mm, 2H), 3.67 (s, 3H), 2.97 (, J = 6.4 Hz, 2H), 2.41 (d, J = 0.9 Hz, 3H); '“F NMR (376 MHz, CDCl) 3 60.09; LCMS (ESI) Method 2: >95%, Rr = 1.501 min, mz = 519.0 [M+H]". \ ¥ NCR Yo = i N N NN 0 Example 27 7-((LH-Imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)- 1 H-pyrazol-4-yl)-2-(2~ methylbenzo|d]oxazol-7-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00365] The title compound (5 mg, 0.01 mmol, 20% yield) was prepared following the Buchwald coupling procedure described in Example 12, substituting 7-bromo-2- methylbenzo[doxazole (23 mg, 0.11 mmol, 2 equiv) for S-bromo-3-methoxyquinoline. ‘H NMR (400 MHz, Chloroform-d) § 8.11 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.6 Hz, 2H), 7.37 (s, 1H), 7.17 (d,J=2.0Hz, 1H), 7.11 (d, J= 1.1 Hz, 1H), 6.95 — 6.90 (m, 2H), 6.86 (t, J = 8.0 Hz, 1H), 5.20 (s, 2H), 4.02 (s, 3H), 3.93 (t, J = 6.5 Hz, 2H), 2.97 (t, J = 6.5 Hz, 2H), 2.17 (s, 3H); °F NMR (376 MHz, CDCls) § -60.06; LCMS (ESI) Method 2: >95%, Ry = 1.226 min, mz = 507.0 [M+H]", \ N-N 3 Nery —N AN NN NA © Example 28 7-((1LH-Imidazol-1-yl)methyl)-2-(1,2-dimethyl-1H~pyrrolo[2,3-b|pyridin~-4~yl)-5-(1-methyl~ 3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00366] The title compound (23 mg. 0.044 mmol, 65% yield) was prepared following the Buchwald coupling procedure described in Example 12, substituting 4-bromo-1,2-dimethyl-1H- pyrrolo[2,3-b]pyridine (30 mg, 0.13 mmol, 2 equiv) for 5-bromo-3-methoxyquinoline. '"H NMR (400 MHz, Chloroform-d) 8 8.26 (d,J=52Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H). 7.55 (s, 1H), 7.37 (s. 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.08 (s, 1H), 6.97 (d, J = 5.2 Hz, 1H), 6.93 (s, 1H), 6.10 (d, J = 1.2 Hz, 1H), 5.17 (3, 2H), 4.02 - 3.99 (m, SH), 3.79 (5, 3H), 2.97 (t, / = 6.3 Hz, 2H), 2.44 (d, J = 1.0 Hz, 3H); LCMS (ESD) Method 2: >95%, Rt = 1.204 niin, mz = 520.0 [M+H]". \ ig! ~0 NX / "CFy A NA AN aN Br Fo Ed Ne” © Example 29 7~((1H-Imidazol-1-yl)methyl)-2-(8-bromo-6-methoxyquinolin-4-yl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin- 1(2H)-one

[00367] The title compound (1.01 g, 1.66 mmol, 96% yield) was prepared following the Buchwald coupling procedure described for Example 12, using 7-((1 H-imidazol-1-yl)methy])-5- (1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 650 mg, 1.73 mmol, | equiv) and 8-bromo-4-iodo-6-methoxyquinoline (Intermediate 20, 1.07 g, 2.94 mmol, 1.7 equiv). *H NMR (400 MHz, Chloroform-d) & 8.96 (d, J =4.6 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 2.7 Hz, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.38 (d.J = 4.6 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.11 (d, J = 1.4 Hz, 1H), 7.07 (d, J = 2.7 Hz, 1H), 6.95 (t, J = 1.3 Hz, 1H), 5.20 (s, 2H), 4.03 (s, 3H), 3.99 (dd, J = 11.5, 4.3 Hz, 1H), 3.87 (s, 3H), 3.82 3.75 (m, 1H), 3.15 (ddd, J = 16.2, 11.0, 5.3 Hz, 1H), 3.03 ~ 2.93 (m, 1H); LCMS (ESI) Method 2: »95%, Rr = 1.204min, mz = 611.0 [M+H]". AY N-N » IY “0 SCF = NN N Nes! oJ NJ © Fyvamnle 0 Example 30 7-((1H-Imidazol-1-yl)methyl)-2-(6~-methoxy-8-morpholinoquinolin-4-yl)-5-( 1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)~one

[00368] The title compound (12 mg, 0.019 mmol, 30% yield) was prepared following the Buchwald coupling procedure described in Example 12, using 7~((1 A-Tmidazol-1~yl)methyl)-2- (8-bromo-6-methoxyquinolin-4-y1)-5-(1-methyl-3-(trifluoromethyl)- 1 H-pyrazol-4-yl)-3,4~ dihydroisoquinolin-1(2H)-one (Example 29, 40 mg, 0.065 mmol, 1 equiv) and morpholine (11 mg, 0.13 mmol, 2 equiv). 'H NMR (400 MHz, Chloroform-d) & 8.77 (d, J = 4.6 Hz, 1H), 8.16 (d. J =2.0 Hz, 1H), 7.39 (s, 1H), 7.40 (d. J = 1.0 Hz, 1H), 7.30 (d, J = 4.6 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.10 (s, 1H), 6.95 (s, 1H), 6.81 (d, J = 2.6 Hz, 1H), 6.72 (d, J = 2.6 Hz, TH), 5.20 (s, 2H), 4.05 -- 4.00 (m, 7H), 4.00 -- 3.91 (m, TH), 3.84 (s, 3H), 3.78 (dt. J = 12.4, 5.2 Hz, 1H), 3.58 - 3.48 (m, 2H), 3.30 (dd, / =10.9, 5.3 Hz, 2H), 3.13 (ddd, / = 16.3, 11.0, 5.2 Hz, 1H), 2.96 (dt, J = 16.3, 4.7 Hz, 1H); ’F NMR (376 MHz, CDCls) -60.18; LCMS (ESI) Method 2: 95%, Rr = 1.204 min, m / z = 618.1 [M+H]|". zx N-N ~o N CF ) 9. CYT NS on 0 ad Example 31 7-((LH-Imidazol-1-yl)methyl)-2-(6-methoxy-8-(4-methylpiperazin-1-yl)quinolin-4-y1)-5-(1- methyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00369] The title compound (28 mg, 0.045 mmol, 34% yield) was prepared following the Buchwald coupling procedure described in Example 12, using 7-((1H-Imidazol-1-yl)methyl)-2- (8-bromo-6-methoxyquinolin-4-y1)-5-(1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl)-3,4- dihydroisoquinolin-1(2H)-one (Example 29, 80 mg, 0.13 mmol, 1 equiv), I-methylpiperazine (26 mg, 0.26 mmol, 2 equiv), and sodium ferr-butoxide (31 mg, 0.33 mmol, 2.5 equiv) at a reaction temperature of 100 °C. 'H NMR (400 MHz, Chloroform-d) 8 8.76 (d, J = 4.6 Hz, 1H), 8.15 (d, J=2.0Hz, 1H), 7.55 (d, J=1.1 Hz, 1H), 7.39 (d, J= 1.1 Hz, 1H), 7.28 (d, / =4.5 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.08 (d. / =1.1 Hz, 1H), 6.93 (1, / =1.3 Hz, 1H), 6.81 (d, J=2.6 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 5.18 (s, 2H), 4.01 (s, 3H), 3.94 (ddd, J =12.3, 10.9, 4.3 Hz, 1H), 3.82 (s, 3H), 3.77 (dt, J= 12.4, 5.2 Hz, 1H), 3.51 (brs, 2H), 3.34 (brs, 2H), 3.12 (ddd, J = 16.3,11.0, 5.2 Hz, 1H), 2.94 (dt, J=16.3, 4.7 Hz, 1H), 2.76 (brs, 4H), 2.40 (s, 3H); LCMS (ESI) Method 2: >95%, Rr = 1.471 min, m / z = 631.1 [M+H]" wv ou yr o Example 32 T-((1H-Imidazol-1-yl)methyl)-2-(8-(4-acetylpiperazin-1-yl)-6-methoxyquinolin-4-yl)-5-(1- methyl-3-(trifluoromethyl)- LH-pyrazol-4-yl)-3 4-dihydroisoquinolin-1(2H)-one

[00370] The title compound (28 mg, 0.042 mmol, 32% yield) was prepared following the Buchwald coupling procedure described in Example 31, substituting 1-acetylpiperazine (34 mg, 0.26 mmol, 2 equiv) for 1-methylpiperazine. 'H NMR (400 MHz, Chloroform-d) 5 8.78 (d, J = 4.6 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J= 1.1 Hz, 1H), 7.30 (d, J= 4.6 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.08 (d,.J= 1.3 Hz, 1H), 6.94 (d, J = 1.3 Hz, 1H), 6.78 (d, J =2.6 Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H), 5.18 (s, 2H), 4.05 ~ 3.99 (s, 4H), 3.99 ~ 3.92 (m, 1H), 3.86 ~ 3.75 (m, 7H), 3.58 (dt, J = 10.2, 4.7 Hz, 1H), 3.36 (ddd, J = 10.9, 7.3, 3.3 Hz, 1H), 3.31 ~ 3.19 (m, 2H), 3.13 (ddd, J = 16.3, 11.0, 5.2 Hz, 1H), 2.95 (dt, J = 16.3, 4.7 Hz, 1H), 2.15 (s, 3H); °F NMR (376 MHz, CDCls) § -60.16; LCMS (ESI) Method 2: >95%, Ry = 1.142 min, mz = 659.2 [MHHT Ney ~o Dory = TAR AN. Na 5 Y Example 33 7-((LH-Imidazol-1-yl)methyl)-2-(6-methoxy-8-(4-methyl-3-oxopiperazin-1-yl)quinolin-4- ¥1)-5-(1-methyl-3~(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00371] The title compound (19 mg, 0.029 mmol, 23% yield) was prepared following the Buchwald coupling procedure described in Example 31, substituting 1-methylpiperazin-2-one (30 mg, 0.26 mmol, 2 equiv) for 1-methylpiperazine. 'H NMR (400 MHz, Chloroform-d) § 8.77 (d, T=4.6 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H). 7.40 (s, 1H), 7.32 (d, } =4.6 Hz, 1H), 7.17(d, J=2.0Hz, 1H), 7.09 (s, 1H), 6.94 (s, 1H), 6.77 (d, I =2.5 Hz, 1H), 6.74 (d, J =2.5 Hz, 1H), 5.19 (s, 2H), 4.05 (s, 2H), 4.02 (s, 3H), 4.00 — 3.89 (m, 2H). 3.83 (s, 3H), 3.78 (dt, J=12.3, 5.1 Hz, 1H), 3.63 (tt, J = 10.6, 5.3 Hz, 2H), 3.56 — 3.47 (m, 1H), 3.13 (ddd, T= 16.2, 10.9, 5.2 Hz, 1H), 3.05 (s, 3H), 2.96 (dt, J = 16.3, 4.7 Hz, 1H); "F NMR (376 MHz, CDCI3) § -60.16; LCMS (ESI) Method 2: 95%, RT = 1.135 min, m / z = 645.2 [M+H]". \ ig! NCR mS A | NN BS N ANZ Ns © Example 34 7-((1H-Imidazol-1-yl)methyl)-2-(8-bromo-6-ethylquinolin-4-yl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00372] The title compound (398 mg, 0.65 mmol, 98% yield) was prepared following the Buchwald coupling procedure described for Example 29, using 7-((1H-imidazol- 1-yl)methyl)-5- (1-methyl-3-(trifluoromethyl)- 1 H-pyrazol-4-y1)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8, 250 mg, 0.66 mmol, | equiv) and 8-bromo-6-ethyl-4-iodoquinoline (Intermediate 21, 482 mg, 1.33 mmol, 2 equiv). LCMS (ESI): mz = 609.0 [M+H]". \ 3 XCF = a N NN NY I ned © Ss a a Example 35 7-((1H-Imidazol-1-yl)methyl)-2-(8-(dimethylamino)-6-ethylquinolin-4-yl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00373] The title compound (28 mg, 0.048 mmol, 29% yield) was prepared following the Buchwald coupling procedure described in Example 31, using 7-((1H-Imidazol-1-yl)methyl)-2- (8-bromo-6-ethylquinolin-4-y1)-5-(1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-y1)-3.4- dihydroisoquinolin-1(2H)-one (Example 34, 100 mg, 0.16 mmol, 1 equiv) and dimethylamine hydrochloride (27 mg, 0.33 mmol, 2 equiv) at 115 °C. "TH NMR (400 MHz, Chloroform-d) § 8.87 (d,J=4.5 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 7.29 (d, J = 4.5 Hz, 1H), 7.19 (d, J+ 1.7 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.09 (s, 1H), 7.00 (d, J = 1.8 Hz, 1H), 6.94 (s, 1H), 5.18 (s, 2H), 4.01 (s, 3H), 3.95 (ddd, J = 12.3, 10.6, 4.4 Hz, 1H), 3.81 (dt, / = 12.3, 5.3 Hz, 1H), 3.14 (ddd, J = 16.0, 10.6, 5.2 Hz, 1H), 3.08 (s, 6H), 2.95 (dt, J = 16.3, 4.9 Hz, 1H), 2.75 (q, J =175 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H); "°F NMR (376 MHz, CDCls) § -60.09; LCMS (ESI): >95%, mz = 574.2 [M+H]". WN 8 cr oJ wd 6 Framnle IH Example 36 7-((1H-Imidazol~1~yl)methyl)-2-(6-ethyl-8-morpholinoquinolin-4-yl )-5-( 1-methyl-3~ (trifluoromethyl)-LH-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one

[00374] The title compound (14 mg, 0.022 mmol, 22% yield) was prepared following the Buchwald coupling procedure described in Example 35, substituting morpholine (17 mg, 0.20 mmol, 2 equiv) for dimethylamine hydrochloride. "H NMR (400 MHz, Chloroform-d) & 8.87 (d, J = 4.6 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.57 (5, 1H), 7.40 (5, 1H), 7.30 (d, J = 4.5 Hz, 1H), 7.25 (s, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.10 (s, 1H), 7.02 (d, J= 1.7 Hz, 1H), 6.95 (s, 1H), 5.19 (s, 2H), 4.09 ~ 4.03 (m, 4H), 4.02 (s, 3H), 3.96 (ddd, J = 12.2, 10.6, 4.3 Hz, 1H), 3.80 (dt, J = 12.3, 5.3 Hz, 1H), 3.57 = 3.47 (m, 2H), 3.34 — 3.23 (m, 2H), 3.15 (ddd, J = 16.1, 10.7, 5.3 Hz, 1H), 2.96 (dt, J = 16.3, 4.8 Hz, 1H), 2.77 (q, J = 7.5 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H); "’F NMR (376 MHz, CDCls) § -60.11; LCMS (ESL) Method 2: >95%, Rr = 1.204 min, mz = 6162 [M+H]", Sn Ng or NS Rd © Fxamnle 37 Example 37 T-((1H-Imidazol-1-yl)methyl)-2-(6-ethyl-8-(4-methylpiperazin- 1-yl)quinolin-4-y1)-5-(1- methyl-3~(trifluoromethyl)- LH-pyvazol-4-y1)-3,4-dihydroisoquinolin-1(2H)-one

[00375] The title compound (23 mg, 0.036 mmol, 28% yield) was prepared following the Buchwald coupling procedure described in Example 35, substituting 1~-methylpiperazine (26 mg, 0.26 mmol, 2 equiv) for dimethylamine hydrochloride. 'H NMR (400 MHz, CDCls) & 8.86 (d, J =4.6 Hz, 1H), 8.15 (d,.J=2.0 Hz, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 7.28 (d, J = 4.5 Hz, 1H), 7.23 (d, J=1.6 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.09 (d,.J= 1.1 Hz, 1H), 7.02 (d, J = 1.9 Hz, 1H), 6.94 (d, J =1.4 Hz, 1H), 5.18 (s, 2H), 4.01 (s, 3H), 3.94 (ddd, J = 12.3, 10.7, 4.3 Hz, 1H), 3.80 (dt, J=12.3, 5.3 Hz, 1H), 3.52 (5, 2H), 3.34 (5, 2H), 3.14 (ddd, J = 16.0, 10.6, 5.2 Hz, 1H), 2.95 (dt, J = 16.3, 4.9 Hz, 1H), 2.83 - 2.70 (m, 6H), 2.42 (s, 3H), 1.27 (t.J = 7.6 Hz, 3H); F NMR (376 MHz, CDCls) 8 -60.10; LCMS (ESI) Method 2: >95%, Rr = 1.083 min, m=z = 629.2 [M+H]". Nn 3 CF eS N LN NN A AO or 0 Fxamnle IR Example 38 7-((1H-1Imidazol-1-yl)methyl)-2-(8-((2-(dimethylamino)ethyl)(methyl)amino)-6- ethylquinolin-4-yl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3.4- dihydroisoquinolin-1(2H)-one

[00376] The title compound (22 mg, 0.034 mmol, 28% yield) was prepared following the Buchwald coupling procedure described in Example 31, using 7-((1H-Imidazol-1-yl)methyl)-2- (8-bromo-6-ethylquinolin-4-y1)-5-(1-methyl-3-(trifluoromethyl)-1 4-pyrazol-4-yl)-3,4- dihydroisoquinolin-1(2H)-one (Example 34, 74 mg, 0.12 mmol, 1 equiv) and N, N, N- trimethylethylenediamine (25 mg, 0.24 mmol, 2 equiv). 'H NMR (400 MHz, Chloroform-d) & 8.84 (d, J=4.5 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.56 (d, / = 1.1 Hz, 1H), 7.40 (d, J= 1.1 Hz, 1H), 7.28 (d, J=4.5 Hz, 1H), 7.16 (d, J=1.9 Hz, 2H), 7.09 (t, J = 1.1 Hz, 1H), 7.00 (d, J=1.8 Hz, 1H), 6.94 (t, J = 1.3 Hz, 1H), 5.19 (s, 2H), 4.01 (5, 3H), 3.94 (ddd, J = 123, 10.5, 43 Hz, 1H), 3.80 (dt, J=12.2, 5.3 Hz, 1H), 3.69 — 3.58 (m, 2H), 3.14 (ddd, J= 16.0, 11.8, 5.2 Hz, 1H), 3.06 (s, 3H), 2.95 (dt, J= 16.3, 49 Hz, 1H), 2.74 (q, J = 7.5 Hz, 2H), 2.68 (dt, / =8.0, 5.4 Hz, 2H), 2.28 (s, 6H), 1.27 (t. J = 7.6 Hz, 3H); “F NMR (376 MHz, CDCl) 6 -60.09; LCMS (ESI) Method 2; »95%, Rr = 1.461 min, mz = 631.2 [M+H]", 5 3 0 Nery 7% 0. A N. N.S oN © ~ Example 39 Ethyl 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)- LH-pyrazol-4-yl)- 1-0x0-3,4-dihydroisoquinolin-2(1H)-yl)-6-methoxyquinoline-8-carboxylate

[00377] The title compound (1.91 g, 3.16 mmol, 99% yield) was prepared following the Buchwald coupling procedure described for Example 12, using 7-((1H-imidazol-1-yl)methyl)-5- (1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate 8) and ethyl 4-bromo-6-methoxyquinoline-8-carboxylate (Intermediate 22, 1.88 g, 6.07 mmol, 1.9 equiv). '"H NMR (400 MHz, Chloroform-d) § 8.90 (dd, J=4.6, 1.3 Hz, 1H), 8.11 (d,J=2.0Hz, 1H), 7.64 (d, J=2.8 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 7.32 (d, J=4.6 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 7.16 (d, J = 2.8 Hz, 1H), 7.06 (s, 1H), 6.92 (t, J = 1.3 Hz, 1H), 5.16 (s, 2H), 4.50 (q, J = 7.1 Hz, 2H), 4.04 — 3.93 (m, 4H), 3.85 (s, 3H), 3.74 (dt, J= 12.3, 5.1 Hz, 1H), 3.12 (ddd, J = 16.3, 10.9, 5.2 Hz, 1H), 2.96 (dt, J = 16.4, 4.7 Hz, 1H), 1.42 (t, J = 7.1 Hz, 3H); LCMS (ESI) Method 2: >95%, Rt = 1.190 min, mz = 605.4 [M-+H]". \ 'N-N bia] ~~ NG. RN = | ™N o AN No i oH NZ © Example 40 4=(7-((1 H-Imidazol-1-yl)methyl)-5-( 1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl)-1-oxo- 3.4-dihydroisoquinolin-2(1LH)-yl)-6-methoxyquinoline-8-carboxylic acid

[00378] Ethyl 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol- 4-y1)-1-0x0-3,4-dibydroisoquinolin-2(1 H)-y1)-6-methoxyquinoline-8-carboxylate (Example 39, 1.9123 g, 3.16 mmol) was dissolved in THF (12 mL) at room temperature. Water (4.0 mL) and LiOH (151.5 mg, 6.33 mmol) were added and the reaction mixture was stirred overnight. The reaction was concentrated and was purified by silica gel chromatography (0 - 10% MeOH:CH2CL2) to yield Example 41 (1.54 g, 2.67 mmol, 85% yield). LCMS (ESI) Method 2: >095%, Rr = 1.180 min, m / z = 577.2 [M + H]", \ y A © | \ on N Nt NH 151 [} x ax Example 41 4-(7-((1H-Imidazol-1-yl)methyl)~5-(1~-methyl-3-(trifluoromethyl)-1H-~pyrazol-4-yl)-1-0xo0- 3.4-dihydroisoquinolin-2(1H)-yl)-6-methoxyquinoline-8-carboxamide

[00379] To a solution of 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)-6-methoxyquinoline-8-carboxylic acid (60 mg, 0,10 mmol, 1 equiv) in 1,4-dioxane (1 mL) was added EDC-HCI (47 mg, 0.21 numol, 2 equiv), HOBt (32 mg, 0.21 mmol, 2 equiv), and N,N-diisopropylethylamine (54 mg, 0.42 mmol, 4 equiv). The reaction mixture was stirred at room temperature for 10 min then ammonium chloride (45 mg, 0.83 mmol, 8 equiv) was added. After stirring for 14 h at 90 °C, the reaction mixture was diluted with EtOAc and washed with 1 M HCI, water, and brine in sequence. The organic layer was dried (MgSO), filtered and concentrated. The residue was purified by reverse phase HPLC (Phenomenex Gemini C18, H:0 / CH;CN gradient from 15-80% CH;CN, 0.1% TFA) followed by neutralization with sat. aq. NaHCO: to yield the title compound (23.7 mg, 0.041 mmol, 40% yield). 'H NMR (400 MHz, Chloroform-d) 8 10.93 (d, J = 5.1 Hz, 1H), 8.84 (d. J = 4.6 Hz, 1H), 8.60 (d, J = 3.0 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.57 (s, 1H), 7.40 (d, J = 4.5 Hz, 2H), 7.30 (d, J = 3.0 Hz, 1H), 7.19 (d, J= 2.0 Hz, 1H), 7.11 (d, J = 1.1 Hz, 1H), 6.95 (t, J=1.3 Hz, 1H), 6.11 (d, J = 5.1 Hz, 1H), 5.20 (s, 2H), 4.05 - 3.98 (m, 4H), 3.93 (s, 3H), 3.81 (dt, J=122, 5.2 Hz, 1H), 3.17 (ddd, J = 163, 11.0, 5.2 Hz, 1H), 2.99 (dt, J = 16.4, 4.7 Hz, 1H): "%F NMR (376 MHz, CDCl) § -60.13: LCMS, 95%, mz = 576.2 [M+H]". N NN 3 “o ~CFy a AN Nog! NH NA © dh A Example 42 4-(7-((1H-Imidazol-1-yl)methyl)-5-( 1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-1-ox0-~ 3,4-dihydroisoquinolin-2(1LH)-yl)-6-methoxy- / V-methylquinoline-8-carboxamide

[00380] Step A. Preparation of ethyl 4-(7-((1H-imidazol-1-yl)methyl)-5-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)-1-0x0-3,4-dihydroisoquinolin-2(1H)-yl)-6- methoxyquino...

Claims

CLAIMS What is claimed is’ 1. A compound of formula (I-b) oO RS G ox 17 » Oo : RS ” (I-b) or a pharmaceutically acceptable salt thereof, wherein: G! is an optionally substituted 10-membered fused bicyclic ring system of formula 3 i we 4 R / JL, 10a R each "===" represents a double bond or a single bond; X'? is N, CRY, or CHR: XU i Ss CR or N; X"is CR or N; R!% is hydrogen, halogen, C1.salkyl, or Cifluoroalkyl; RY“ is hydrogen, halogen, Cr4alkyl, or Ci.sfluoroalkyl; R!% is hydrogen, halogen, Cisalkyl, Ciufluoroalkyl, or -OC1salkyl; R!% js -1.1-X!, hydrogen, halogen, Ci.salkyl, Crsfluoroalkyl, or —=L!-G'2; R!% is hydrogen, halogen, Ci.salkyl, or Cisfluoroalkyl; Ris Craalkyl, ~OCi4alkyl, hydrogen, halogen, Ci4fluoroalkyl, OH, —~OC1.4fluoroalkyl, NH, NHC 1.4alkyl, N(Cr4alkyl)2, or a 4- to 8-membered monocyclic heterocyclyl containing 1-2 heteroatoms selected from N, OQ, and S, wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, oxo, Cr.salkyl, Ciafluoroalkyl, OH, ~OCi-salkyl, ~QCiafluoroalkyl, NH3, ~NHC.salkyl, and ~N(Cigalkyl)2; L' is a bond or Cialkylene; X! is ~C(O)N(R¥), OR ~N(R'¥),, ~SR¥, cyano, ~C(O)OR'™ ~C(O)N(R#)SO;RY, C(NH)NHOH, -C(O)H, -C(O)R'®, ~SOR™, -80:R™, -S0:N(R')2, ~-NR?C(0)H, NRYC(O)R', -NRHC(O)ORY, -NR“C(O)N(R')z, ~NR“S(0):R™, or ~NR¥S(0):N(R)z; RY, at each occurrence, is independently hydrogen, Ci.ealkyl, Cishaloalkyl, ~Ca4alkylene— ORY, —Cz.alkylene-N(R'®)2, —Caalkylene-N(R©)C(O)R'®, G*%, or —C;salkylene—G'%, R™ at each occurrence, is independently Cisalkyl, Cishaloalkyl, —Ciualkylene—OR'S, —C;. salkylene-N(R'®), —Csalkylene-N(R')C(O)R'¢, G*, or —Crsalkylene-G'%, G'? is Cascycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 4- to 10- membered heterocyclyl, wherein G2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Cj.alkyl, Ci-shaloalkyl, oxo, LAY 2 an d LAG 1b. 1.2, at each occurrence, is independently a bond or Cralkylene: X2, at each occurrence, is independently —OR'S, ~N(R), ~SR, cyano, ~C(O)OR, —~ C(ONRE), ~C(O)Re, =SORM, —SO-R 4, ~SON(R):, ~NREC(O)R IS, -NREC(O)OR!s, ~NREC(O)N(R)z, -NRS(0)RY, or ~NR*S(0)2N(R 1%); RY, at each occurrence, is independently hydrogen, Crsalkyl, Cishaloalkyl, G'®, or ~Ci1. salkylene~G!, wherein alternatively two RY, together with a common nitrogen atom to which the R® attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of Ciualkyl, Ci-haloalkyl, oxo, ~OH, and -QC14alkyl; RY, at each occurrence, is independently Cisalkyl, C1shaloalkyl, G™, or ~Ci.alkylene-G'®; RI at each occurrence, is independently hydrogen, Ciwalkyl, Cishaloalkyl, G®, or ~Ci. salkylene~G'®, wherein alternatively two R™, together with a common nitrogen atom to which the R® attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-alkyl, C14haloalkyl, oxo, ~OH, and ~OCr.4alkyl; G'" is a Csscycloalkyl, a 4- to 6-membered monocyclic heterocyclyl containing 1-2 heteroatoms independently selected from O, N, and §, a 5- to 6-membered heteroaryl containing 1-4 heteroatoms independently selected from O, N, and S, or a phenyl, wherein GY is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, Ciaalkyl, Cishaloalkyl, oxo, ~OH, and —~OC;.salkyl; (is a 5- to 12-membered heteroaryl, a Ca.1carbocyclyl, a 6- to 12-membered aryl, or a 4- to 12-membered heterocyclyl, wherein G* is optionally substituted with 1-5 substituents independently selected from the group consisting of Ci.salkyl, Ci.shaloalkyl, halogen, oxo, ~OR*, -N(R¥)z, ~SR*, cvano, ~C(O)OR¥, ~C(OIN(R*), -C(O)R*, ~SOR™, ~SO,R™. - SO:N(R¥)z, -NR*C(0)R*, -NR*C(0)OR*, -NR*C(O)N(R*)2, -NR*S(0):R* . NR¥S(0)N(R*):, Csscyeloalkyl, and —Cialkylene—Cs.scycloalkyl, wherein each Ca. scycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci-salkyl and halogen; R¥*, at each occurrence, is independently hydrogen, C.salkyl, C1shaloalkyl, Cs-scycloalkyl, or —C;salkylene—Cascycloalkyl, wherein each Ciscycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci4alkyl and halogen, wherein alternatively two R¥, together with a common nitrogen atom to which the R% attach form a 4-~ to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of Craalkyl, Cishaloalkyl, oxo, ~QH, and ~OC1.alkyl; R*™, at each occurrence, are independently Cr.ealkyl, C1.shaloalkyl, Csscycloalkyl, or =Ci- salkylene-Cs-scycloalkyl, wherein each Cascycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of Ci4alkyl and halogen. R® and R® are each independently hydrogen, halogen, Cisalkyl, Cihaloalkyl, or ~OC1alkyl; and R® is an imidazolyl unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, Cisalkyl, Cishaloalkyl, NOz, NH, ~NH(Ci-alkyl), — N(Ci-salkyl)z2, Cascycloalkyl, and ~Ciaalkylene-Cascycloalkyl, wherein each Cs. scycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Ciaalkyl, Cishaloalkyl, OH, and ~OC;.alkyl. 2 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R?20b R20d I ~ 8 R208 Xx, — Re TW N N OOF 020f LW \ 20d 20f i Ra R Reis , or R207 dr H N 20h $ Ava R20 R*" is hydrogen, Cj.ialkyl, NHz, -NH(C4alkyl), -N(C14alkyl):, or Cs.scycloalkyl; and R¥P R2% R24 RR R22 RPM and R™ are each independently hydrogen, C;aalkyl, or Csscycloalkyl, 3, The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R® is H Croqalkyl ENG RB Crqalkyl Edy yy a dA RNS BN LY N NN En 0 W Neoaallyl ~0 cuticatly acceptaoie sali | N, ~~ N, 1 C.qalkyl Jor 4, The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof. wherein each "======" represents a double bond; X'* is N; and X¥ is CR!%. 5 The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein RY is hydrogen; R'% is hydrogen or C14alkyl; RY is —C(O)N(R') or —OR'2, R'% is hydrogen; and RY is Crualkyl or OChalkyl 6. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein G' is H H QC, .salky! N X | C1.qalkyl H H N._O N Ciaalkyl” ~F Cyqalkyl” o N N, | ® 7 Cy.aalkyl 7 OC; qalkyl H QC _qalkyl N ph 7 OC; alkyl H HNO OC+alkyl Pig Cralkylo” AN 2 clille ~ ZN0C aakyl NF OC calkyl # OC _qalkyl Cyqalkyl nnn Ho ss HN___O | Y NL OC 4fluoroalkyl I S ® = ZZ Craalkyl Cr4alkyl yy Cruaalkyi- Np N, rs # OC qalky! ala = N(C14alkyl); Ye HN._O hd N rs PN ak HNO Hp ® ® or ~ Cy4alkyl Cr4alkyl a i oO oO Atl hd AL Cut? er, H o o IN. N N, [0 [ 7 Cranky! 7 Craalkyl o eo ait’ TN ~ 0 MA 1 I HN. _O NP HN +° N ( @ 7 Craalkyl 1 N ( - = Craalkyl so hi: HN 0 N, = eo, Cc an 7 Oo Cc al 7 0 al! C0 I H H Mp HN © t.0 N,; N, N, [ [ [_ # OC4alkyl Z Cr4alkyl # OC14alkyl Oo n oO i oto oto Cqalkyl 0 x {Pho HN 0 HN HN._O HN._O ZZ = o = = 5 H H Ck Oo ¥ Na Co OC, alkyl Cy 4lkyl Ng 7 Craalkyl ll il Cq4alkyl Ny # OC 14 alkyl Cr4alkyl p© Craalkylh Ny | ; # Cyaalkyl Crealsg™y ), . Np Cq4alkyl Na 7 Craalkyl Cyqalkyl iN. Cq4alkyl Ny Z OC 14 alkyl ww ala NC 4alkyl)y Ne OC 4alkyl CC FNP, alkyl Anan i 1s Ge No HNO Craalkyl Ng Craaliyh Ng | | Z C1 alkyl Z OC1.4alkyl 7 The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein H ANogr® RIV jg abu , hydrogen, fluoro, chloro, bromo, methyl, ethyl, cvano, OCH3, OCF:, NH, 1 | 1 0 AN AN HNO i ~ : o o ~p HO. _.O O_O N(CHs)z, NHC(O)CHs, ab, abv 2 x XY HON NN SoS HON STN i Yt thy B or oo eg 7 hp NO “ Oo 1 oO 0 oO Sy Ha 2 X i 3 7 pt il (; bt Bg Cr ta Sry o . I I I Oo NT HN. _O Nz HNL XL Z AON N—NH £N NNN ¥ um £ NA ~ Lo a a XX ~ HNO HNO ¥ N20 HN. 0 HNO ~ ye go © Bg "hp? Ae ip ie xn Y oo dos © "rr Fp Brgy oN gy gg WAN mo ea ae NO HO HNO a Y I np Sh Bo tng po 08 hp ) po Lo oral oral eta a A os Rop© HN hg HN r° hyo o™ H ~° NA NG x J Oo ‘N Pi N Se N SN ng i HN © yr? ol Sarky® So oN ON” “Lo Y N_~ Cpe 7 Nl i 3 ” rob lo on 5 _o XX LL H | NSN NY YY Ne N, ts ® ANH Sy PAN oo 0 0 0 Me POLO oO 0 ee MH he abe ae Lede Lae abe ae Ld ede 0 oO QCH3 SN A NS i’ = ir NA oN AN AN IN oN p- LE AT Ns NS Pad AN 3 ro 3 oo he r oo b ho Ae a A Ae A Ha NT | N 0 OCH OH “So Ns EAN I] 8 oe a bd & NS AN NS A e liad oN NNT NY A NON N._~ PLN NS NRO ANN pv | i i H 1 | + id Gas - £) 2 i I | H l FL | , ww La , OCH3 kal ~p° I q y ANS ANN NY ONS i WTR N-N- N=N RH EN Sn ery “WF uN ONG ON \ | \ | NN N=N NHN TN Phy py py 0) DN NN Y Ny A aN Ne NS NS w Sw “Sw [LW J EN ot i “rN Y Ra AH yr SOS OW SW SN SN Lor LoL LoLoyoror Na! N FONG NS Nagi Y hv N NT SvYOSNT LL Loa A LL ow odo So o OCH, | A . 1 ANS PP GN SL NE JO AS A ol on mdm A Ae ~, N } ANS EN NT eM NC CY CY PCY TEI pl, 7, By oy, po YY YTS =N NN Nz Sn 8. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof. wherein each "======" represents a double bond; X'* is CR'*; X** is N; and X'* is CR.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein RY js hydrogen; R'® is hydrogen or Cralkyl; RY is hydrogen, Ci-alkyl, or ~OCh.salkyl; R'% is hydrogen or Cralkyl; and RY is Crualkyl or —OC=alkyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein G' WMA Ng, Ng Ng Ny_Craclkyl } ZN0C, alkyl ZC, alkyl ZC, salkyl Z 18 Anan Na Cigalkyl Cqgalkyl Ny PCy qalkyl ZC aalkyl Ng_-Craalkyl FN 0c 4alkyl Cy4alkyl Na Na Cqqalkyl Ny, Craglkyl Cla FN 0G alkyl CU AAA AAA or WAY + Or 11. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof. wherein each "======" represents a single bond; X'* is CHR'*; X'? is N; and X'* is CR!" 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R'is hydrogen; R'® is hydrogen or Calkyl; RY is hydrogen or Cjaalkyl; R'% is hydrogen or Cisalkyl; and RY is Crualkyl or OC alkyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein N, EN J alkyl Glis 14. The compound of any of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein (7 is a 5- to 6-membered heteroaryl, and optionally substituted as defined in claim 1.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein G* is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, Cisalkyl, and Cichaloalkyl.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein, G* is C1.qalkyl 1-48 YIonN ba Satin \ 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein, G* is “n-N Sn-N or 18. The compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R® is hydrogen.

19. The compound of any of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R® is hydrogen.

20. A pharmaceutical composition comprising the compound of any of claims 1-19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. The compound of any of claims 1-19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20, for use in the treatment of cancer.

22. The compound of any of claims 1-19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20, for use in the inhibition of cancer cell proliferation.