OA18538A

OA18538A - Substituted dihydroisoquinolinone compounds

Info

Publication number: OA18538A
Application number: OA1201600494
Authority: OA
Inventors: Michael Raymond Collins; Pei-Pei Kung; Robert Steven Kania; Robert Arnold Kumpf; Daniel Tyler Richter; Scott Channing Sutton; Martin James Wythes
Original assignee: Pfizer Inc.
Priority date: 2014-06-17
Filing date: 2015-06-05
Publication date: 2018-12-14

Abstract

This invention relates to compounds of general formula (I)

Description

Substituted Dihvdroisoquinolinone Compounds

Cross-Reference to Related Applications

This application daims the benefit of priority to U.S. Provisional Application No. 62/013,410, filed on June 17, 2014, and to U.S. Provisional Application No. 62/156,533, filed on May 4, 2015, each of which is incorporated by reference herein in its entirety.

Field of the Invention

The présent invention relates to compounds of Formulae I, Γ, II, II’ and III, and their pharmaceutically acceptable salts, to pharmaceutical compositions comprising such compounds and salts, and to the uses thereof. The compounds, salts and compositions of the présent invention may be useful for treating or ameliorating abnormal cell proliférative disorders, such as cancer.

Backqround

Epigenetic alterations play an important rôle in the régulation of cellular processes, including cell prolifération, cell différentiation and cell survival. The epigenetic silencing of tumor suppressor genes and activation of oncogenes may occur through alteration of CpG island méthylation patterns, histone modification, and dysrégulation of DNA binding protein. Polycomb genes are a set of epigenetic effectors. EZH2 (enhancer of zeste homolog 2) is the catalytic component of the Polycomb Repressor Complex 2 (PRC2), a conserved multi-subunit complex that represses gene transcription by methylating lysine 27 on Histone H3 (H3K27). EZH2 plans a key rôle in regulating gene expression patterns that regulate cell fate decisions, such as différentiation and self-renewal. EZH2 is overexpressed in certain cancer cells, where it has been linked to cell prolifération, cell invasion, chemoresistance and metastasis.

High EZH2 expression has been correlated with poor prognosis, high grade, and high stage in several cancer types, including breast, colorectal, endométrial, gastric, liver, kidney, lung, melanoma, ovarian, pancreatic, prostate, and bladder cancers. SeeCrea et al., Crit. Rev. Oncol. Hematol. 2012, 83:184-193, and référencés cited therein; see also Kleer et al., Proc. Natl. Acad. Sci. USA 2003, 100:11606-11; Mimori et al., Eur. J. Surg. Oncol. 2005, 31:376-80; Bachmann et al., J. Clin. Oncol. 2006, 24:268-273; Matsukawa et al., Cancer Sci. 2006, 97:484-491; Sasaki et al. Lab. Invest. 2008, 88:873-882; Sudo et al., Br. J. Cancer 2005, 92(9):1754-1758; Breuer et al., Neoplasia 2004, 6:736-43; Lu et al., Cancer Res. 2007, 67:1757-1768; Ougolkov et al., Clin. Cancer Res. 2008, 14:6790-6796; Varambally et al., Nature 2002, 419:624-629; Wagener et al., Int. J. Cancer 20Q8, 123:1545-1550; and Weikert et al., Int. J. Mol. Med. 2005, 16:349-353.

Recurring somatic mutations in EZH2 hâve been identified in diffuse large B-cell lymphoma (DLBCL) and follicular lymphomas (FL). Mutations altering EZH2 tyrosine 641 (e.g., Y641C, Y641F, Y641N, Y641S, and Y641H) were reportedly observed in upto 22% of germinal center B-cell DLBCL and 7% of FL. Morin et al. Nat. Genetics 2010 Feb; 42(2):181-185. Mutations of alanine 677 (A677) and alanine 687 (A687) hâve also been reported. McCabe et al., Proc. Natl. Acad. Sci. USA 2012, 109:2989-2994; Majer et al. FEBS Letters 2012, 586:3448-3451. EZH2 activating mutations hâve been suggested to alter substrate specificity resulting in elevated levels of trimethylated H3K27 (H3K27me3).

Accordingly, compounds that inhibit the activity of wild type and/or mutant forms of EZH2 may be of interest for the treatment of cancer.

Summary

The présent invention provides, in part, novel compounds and pharmaceutically acceptable salts. Such compounds may modulate the activity of EZH2, thereby effecting biological fonctions, for example by inhibiting cell prolifération and cell invasiveness, inhibiting metastasis, inducing apoptosis or inhibiting angiogenesis. Also provided are pharmaceutical compositions and médicaments, comprising the compounds or salts of the invention, alone or in combination with other therapeutic agents or palliative agents. The présent invention also provides, in part, methods for preparing the novel compounds, salts and compositions thereof, and methods of using the foregoing.

In one aspect, the invention provides a compound of formula (I):

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is selected from the group consisting of H, F, C1-C4 alkyl, C1-C4 alkoxy, C(O)R⁵, C3-C8 cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C1-C4 alkyl or C1-C4 alkoxy is optionally substituted by one or more R⁶, and each saidC3-C8 cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

R² is H, F or C1-C4 alkyl;

L is a bond or a C1-C4 alkylene;

R³ is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, OH, CN, C(O)R⁸, COOR⁹, NR¹⁰R¹¹, OR¹², C3-C8 cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C1-C4 alkyl or C1-C4 alkoxy is optionally substituted by one or more R⁶, and each said Ca-Ce cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

R⁴ is H, halo or C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R⁶;

R⁵ is C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁴;

each R⁶ is independently OH, F, CN or C1-C4 alkoxy;

each R⁷ is independently C1-C4 alkyl, OH, F, CN, C1-C4 alkoxy, =0, CHO, C(O)R¹³, SO2R¹³ or 3-6 membered heterocyclyl;

R⁸ is C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁴;

R⁹ is H or C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁴;

R¹⁰ and R¹¹ are independently H or C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁴;

R¹² is selected from the group consisting of C3-C8 cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C3-C8 cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

each R¹³ is independently C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁵;

each R¹⁴ and R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

X and Z are independently C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy.

In some embodiments, the compound of Formula (I) has the absolute stereochemistry at the carbon atom bearing the R¹ and R² substituents as shown in Formula (l-A) or (l-B):

or a pharmaceutically acceptable sait thereof, wherein:

R¹, R², L, R³, R⁴, X and Z are defined as for Formula (I).

In another aspect, the invention provides a compound of Formula (II), (ll-A) or (IIB):

wherein:

R¹, L, R³ and X are defined as for Formula (I); and

R⁴ is H, Cl, Br, F or CH3.

or a pharmaceutically acceptable sait thereof, wherein:

R¹ and R³ are taken together to form a 3-12 membered heterocyclyî optionally substituted by one or more R⁷;

R² isH, ForCi-C₄ alkyl;

each R⁶ is independently OH, F, CN or C1-C4 alkoxy;

each R⁷ is independently C1-C4 alkyl, OH, F, CN, C1-C4 alkoxy, =0, CHO, C(O)R¹³, SO2R¹³ or 3-6 membered heterocyclyî;

each R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

In another aspect, the invention provides a pharmaceutical composition comprising a compound of one of the formulae described herein, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients.

The invention also provides therapeutic methods and uses comprising administering a compound of the invention, or a pharmaceutically acceptable sait thereof.

In one aspect, the invention provides a method for the treatment of abnormal cell growth in a subject comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable sait thereof.

In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer. In some embodiments, the methods provided resuit in one or more of the following effects: (1) inhibiting cancer cell prolifération; (2) inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibiting cancer cell metastasis; or (5) inhibiting angiogenesis.

In another aspect, the invention provides a method for the treatment of a disorder mediated by EZH2 in a subject comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable sait thereof, in an amount that is effective for treating said disorder. The compounds and salts of the présent invention may inhibit wildtype and certain mutant forms of human histone methyltransferase EZH2.

In another aspect, the invention provides a compound of one of the formulae described herein, or pharmaceutically acceptable sait thereof, for use in the treatment of abnormal cell growth in a subject.

In a further aspect, the invention provides the use of a compound of one of the formulae described herein, or pharmaceutically acceptable sait thereof, for the treatment of abnormal cell growth in a subject.

In yet another aspect, the invention provides the use of a compound of one of the formulae described herein, or a pharmaceutically acceptable sait thereof, for the préparation of a médicament for the treatment of abnormal cell growth.

In frequent embodiments, the abnormal cell growth is cancer and the subject is a human.

In some embodiments, the methods described herein further comprise administering to the subject an amount of an anti-cancer therapeutic agent or a palliative agent, which amounts may be together effective in treating said abnormal cell growth. In some embodiments, the one or more anti-cancer therapeutic agent is selected from antitumor agents, anti-angiogenesis agents, signal transduction inhibitors and antiproliférative agents, which amounts are together effective in treating said abnormal cell growth. In some such embodiments, the anti-tumor agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

In other embodiments, the uses described herein comprise the use of a compound of one of the formulae described herein or pharmaceutically acceptable sait thereof, in combination with one or more substances selected from anti-tumor agents, antiangiogenesis agents, signal transduction inhibitors and antiproliférative agents.

In some embodiments, the médicaments described herein may be adapted for use in combination with one or more substances selected from anti-tumor agents, antiangiogenesis agents, signal transduction inhibitors and antiproliférative agents.

Each of the embodiments of the compounds of the présent invention described below may be combined with one or more other embodiments of the compounds of the présent invention described herein not inconsistent with the embodiment(s) with which it is combined. In addition, each of the embodiments below describing the invention envisions within its scope the pharmaceutically acceptable salts of the compounds of the invention. Accordingly, the phrase “or a pharmaceutically acceptable sait thereof is implicit in the description of ail compounds described herein.

Detailed Description

The présent invention may be understood more readily by reference to the following detailed description of the preferred embodiments of the invention and the Examples included herein. It is to be understood that the terminology used herein is for the purpose of describing spécifie embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defîned herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.

As used herein, the singular form a, an, and the include plural references unless indicated otherwise. For example, a substituent includes one or more substituents.

Alkyl refers to a saturated, monovalent aliphatic hydrocarbon radical including straight chain and branched chain groups having the specified number of carbon atoms. Alkyl substituents typically contain 1 to 20 carbon atoms (“C1-C20 alkyl”), preferably 1 to 12 carbon atoms (C1-C12 alkyl), more preferably 1 to 8 carbon atoms (“Ci-Cs alkyl”), or 1 to 6 carbon atoms (“C1-C6 alkyl”), or 1 to 4 carbon atoms (“C1-C4 alkyl). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl and the like. Alkyl groups may be substituted or unsubstituted. In particular, unless otherwise specified, alkyl groups may be substituted by one or more halo groups, up to the total number of hydrogen atoms présent on the alkyl moiety. Thus, C1-C4 alkyl includes halogenated alkyl groups, and in particular fluorinated alkyl groups, having 1 to 4 carbon atoms, e.g., trifluoromethyl or difluoroethyl (i.e., CF3 and -CH2CHF2).

Alkyl groups described herein as optionally substituted by may be substituted by one or more substituent groups, which are selected independently unless otherwise indicated. The total number of substituent groups may equal the total number of hydrogen atoms on the alkyl moiety, to the extent such substitution makes chemical sense. Optionally substituted alkyl groups typically contain from 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, preferably from 1 to 4 optional substituents, or more preferably from 1 to 3 optional substituents.

Optional substituent groups suitable for alkyl include, but are not limited to C3-Ce cycloalkyl, 3-12 membered heterocyclyl,C6-Ci2 aryl and 5-12 membered heteroaryl, halo, =0 (oxo), =S (thiono), =N-CN, =N-0R^x, =NR^X, -CN, -C(O)R^X, -COeR^x, -C(O)NR^xRy, -SR^X, -SOR^X, -SO2R^x, -SO2NR^xRy, -NO2, -NR^xR^y, -NR^xC(O)Ry, -NR^xC(0)NR^xRy, NR^XC(O)OR^X, -NR^xSO2Ry, -NR^xSO2NR^xRy, -OR^X, -OC(O)R^X and -OC(O)NR^xRy; wherein each R^x and Ry is independently H, Ci-Cb alkyl, Ci-Ce acyl, C2-Ce alkenyl, C₂-Cs alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, Ce-Ci₂ aryl, or 5-12 membered heteroaryl, or R^x and Ry may be taken together with the N atom to which they are attached to form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each optionally containing 1, 2 or 3 additional heteroatoms selected from O, N and S; each R^x and Ry is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, =0, =S, =N-CN, =N-OR', =NR', -CN, -C(O)R‘, -CO₂R', -C(O)NR'₂, -SR', -SOR', SO₂R', -SO₂NR'_2i -NO₂, -NR'_2i -NR'C(0)R·, -NR‘C(O)NR'₂, -NR'C(O)OR', -NR'SO₂R', NR'SO₂NR'₂, -OR', -OC(O)R' and -OC(O)NR'₂, wherein each R' is independently H, C1Ce alkyl, Ci-Ce acyl, C₂-Ce alkenyl, C₂-Cb alkynyl, Ce-Ca cycloalkyl, 3-12 membered heterocyclyl, Ce-Ci₂ aryl, or Cs-Ci₂ heteroaryl; and wherein each said C3-C8 cycloalkyl, 312 membered heterocyclyl, C6-Ci₂ aryl and 5-12 membered heteroaryl is optionally substituted as further defined herein.

Typical substituent groups on alkyl include halo, -OH, C1-C4 alkoxy, -O-Cb-Ci₂ aryl, -CN, =0, -COOR^X, -OC(O)R^X, -C(O)NR^xRy, -NR^xC(O)Ry, -NR^xRy, Ca-Ce cycloalkyl, Ce-Ci2 aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl; where each R^x and R* is independently H or C1-C4 alkyl, or R^x and Ry may be taken together with the N to which they are attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each optionally containing 1, 2 or 3 additional heteroatoms selected from O, N and S; wherein each said Ca-Ce cycloalkyl, Ce-Ci2 aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, -OH, =0, C1-C4 alkyl, C1-C4 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C4 alkoxy-Ci-Ce alkyl, -CN, -NH₂, -NH(Ci-C4 alkyl), and -N(Ci-C4 alkyl)₂.

In some embodiments, alkyl is optionally substituted by one or more substituents, and preferably by 1 to 3 substituents, which are independently selected from the group consisting of halo, -OH, C1-C4 alkoxy, -O-Ce-Ci₂ aryl, -CN, =0, -C00R^x, -OC(O)R^X, C(O)NR^xRv, -NR^xC(O)R^y, -NR^xR^y, Ca-Ca cycloalkyl, Ce-Ci₂ aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl; where each R^x and R^y is independently H or C1-C4 alkyl, or R^x and R^y may be taken together with the N to which they are attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each optionally containing 1,2 or 3 additional heteroatoms selected from O, N and S; and each said C3Ce cycloalkyl, C6-C12 aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, -OH, =0, C1-C4 alkyl, C1-C4 alkoxy, Ct-Ce haloalkyl, Ci-Ce hydroxyalkyl, C1-C4 alkoxy-Ci-Ce alkyl, -CN, -NH2, -NH(Ci-C4 alkyl) and -N(Ci-C₄ alkyl)a.

In other embodiments, alkyl is optionally substituted by one or more substituent, and preferably by 1 to 3 substituents, independently selected from the group consisting of halo, -OH, C1-C4 alkoxy, -CN, -NR^XR*, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl and 5-12 membered heteroaryl; where each R^x and R^y is independently H or C1-C4 alkyl, or R^x and R^y may be taken togetherwith the N to which they are attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each optionally containing 1, 2 or 3 additional heteroatoms selected from O, N and S; and where each said cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, -OH, =0, C1-C4 alkyl, C1-C4 alkoxy, Ci-Ce haloalkyl, C1-C6 hydroxyalkyl, C1-C4 alkoxy-Ci-Ce alkyl, -CN, NH2, -NH(Ci-C₄ alkyl) and -N(Ci-C4 alkyl)₂.

In some instances, substituted alkyl groups may be specifically named with référencé to the substituent group. For example, haloalkyl refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more halo substituents, and typically contain 1-6 carbon atoms and 1,2 or 3 halo atoms (i.e., Ci-Ce haloalkyl) or sometimes 1-4 carbon atoms and 1, 2 or 3 halo atoms (i.e., “C1-C4 haloalkyl). Thus, a C1-C4 haloalkyl group includes trifluoromethyl (-CF3) and difluoromethyl (-CF2H). More specifically, fluorinated alkyl groups may be specifically referred to as fluoroalkyl groups, e.g., Ci-Ce or C1-C4 fluoroalkyl groups.

Similarly, “hydroxyalkyl refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more hydroxy substituents, and typically contain 1-6 carbon atoms and 1,2 or 3 hydroxy (i.e., “Ci-Ce hydroxyalkyl”). Thus, Ci-Ce hydroxyalkyl includes hydroxymethyl (-CH2OH) and 2-hydroxyethyl (-CH2CH2OH).

‘'AlkoxyalkyF refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more alkoxy substituents. Alkoxyalkyl groups typically contain

1-6 carbon atoms in the alkyl portion and are substituted by 1, 2 or 3 C1-C4 alkyoxy substituents. Such groups are sometimes described herein as C1-C4 alkyoxy-Ci-Ce alkyl.

Aminoalkyl” refers to alkyl group having the specified number of carbon atoms that is substituted by one or more substituted or unsubstituted amino groups, as such groups are further defined herein. Aminoalkyl groups typically contain 1-6 carbon atoms in the alkyl portion and are substituted by 1,2 or 3 amino substituents. Thus, a Ci-Ce aminoalkyl group includes, for example, aminomethyl (-CH2NH2), A/./V-dimethylamino-ethyl (CH2CH2N(CH3)2), 3-(/V-cyclopropylamino)propyl (-CH2CH2CH2NH-^cPr) and Npyrrolidinylethyl (-CH2CH2-N-pyrrolidinyl).

Alkenyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Typically, alkenyl groups hâve 2 to 20 carbon atoms (“C2-C20 alkenyl), preferably 2 to 12 carbon atoms (C2-C12 alkenyl”), more preferably 2 to 8 carbon atoms (C2-C0 alkenyl”), or 2 to 6 carbon atoms (“C2-C6 alkenyl”), or 2 to 4 carbon atoms (C2-C4 alkenyl”). Représentative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be unsubstituted or substituted by the same groups that are described herein as suitable for alkyl.

Alkynyl refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups hâve 2 to 20 carbon atoms (“C2-C20 alkynyl”), preferably 2 to 12 carbon atoms (C2-C12 alkynyl), more preferably 2 to 8 carbon atoms (“C2-C8 alkynyl), or 2 to 6 carbon atoms (“C2-C6 alkynyl), or 2 to 4 carbon atoms (“C2-C4 alkynyl”). Représentative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or3-butynyl, and the like. Alkynyl groups may be unsubstituted or substituted by the same groups that are described herein as suitable for alkyl.

Alkylene as used herein refers to a divalent hydrocarbyl group having the specified number of carbon atoms which can link two other groups together. Sometimes it refers to a group -(CH2)n- where n is 1-8, and preferably n is 1-4. Where specified, an alkylene may also be substituted by other groups and may include one or more degrees of unsaturation (i.e., an alkenylene or alkynlene moiety) or rings. The open valences of an alkylene need not be at opposite ends of the chain. Thus branched alkylene groups such as -CH(Me) - and -C(Me)2- are also included within the scope of the term 'alkylenes', as are cyclic groups such as cyclopropan-1,1-diyl and unsaturated groups such as ethylene (-CH=CH-) or propylene (-CH2-CH=CH-). Where an alkylene group is described as optionally substituted, the substituents include those typically présent on alkyl groups as described herein.

Heteroalkylene refers to an alkylene group as described above, wherein one or more non-contiguous carbon atoms of the alkylene chain are replaced by -N(R)-, -O- or

S(O)q-, where R is H or C1-C4 alkyl and q is 0-2. For example, the group -O-(CH2)i-4- is a ‘Ca-Cs’-heteroalkylene group, where one of the carbon atoms of the corresponding alkylene is replaced by O.

“Alkoxy” refers to a monovalent -O-alkyl group, wherein the alkyl portion has the specified number of carbon atoms. Alkoxy groups typically contain 1 to 8 carbon atoms (“Ci-Ce alkoxy”), or 1 to 6 carbon atoms (“Ci-Ce alkoxy”), or 1 to 4 carbon atoms (“C1-C4 alkoxy”). For example, C1-C4 alkoxy includes -OCH3, -OCH2CH3, -OCH(CH3)2, OC(CH₃)3, and the like. Such groups may also be referred to herein as methoxy, ethoxy, isopropoxy, tert-butyloxy, etc. Alkoxy groups may be unsubstituted or substituted on the alkyl portion by the same groups that are described herein as suitable for alkyl. In particular, alkoxy groups may be substituted by one or more halo groups, up to the total number of hydrogen atoms présent on the alkyl portion. Thus, C1-C4 alkoxy includes halogenated alkoxy groups, e.g., trifluoromethoxy and 2,2-difluoroethoxy (i.e., -OCF₃ and -OCH2CHF2). In some instances, such groups may be referred to as “haloalkoxy” (or, where fluorinated, more specifically as “fluoroalkoxy) groups having the specified number of carbon atoms and substituted by one or more halo substituents, and typically contain

1-6 carbon atoms and 1, 2 or 3 halo atoms (i.e., “Ci-Ce haloalkoxy) or sometimes 1-4 carbon atoms and 1,2 or 3 halo atoms (i.e., “C1-C4 haloalkoxy”). Thus, a C1-C4 haloalkoxy group includes trifluoromethoxy (-OCF3) and difluoromethoxy (-OCF2H). More specif ically, fluorinated alkyl groups may be specifically referred to as fluoroalkoxy groups, e.g., Ci-Ce or C1-C4 fluoroalkoxy groups.

Similarly, “thioalkoxy refers to a monovalent -S-alkyl group, wherein the alkyl portion has the specified number of carbon atoms, and may be optionally substituted on the alkyl portion by the same groups that are described herein as suitable for alkyl. For example, a C1-C4 thioalkoxy includes -SCH₃ and -SCH2CH3.

Cycloalkyl refers to a non-aromatic, saturated or partially unsaturated carbocyclic ring System containing the specified number of carbon atoms, which may be a monocyclic, bridged or fused bicyclic or polycyclic ring System that is connected to the base molécule through a carbon atom of the cycloalkyl ring. Typically, the cycloalkyl groups of the invention contain 3 to 12 carbon atoms (“C3-C12 cycloalkyl”), preferably 3 to 8 carbon atoms (“C3-C8 cycloalkyl”). Représentative examples include, e.g., cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, adamantane, and the like. Cycloalkyl groups may be unsubstituted or substituted by the same groups that are described herein as suitable for alkyl.

Illustrative examples of cycloalkyl rings include, but are not limited to, the following:

Cycloalkylalkyl may be used to describe a cycloalkyl ring, typically a C3-Ce cycloalkyl, which is connected to the base molécule through an alkylene linker, typically a C1-C4 alkylene. Cycloalkylalkyl groups are described by the total number of carbon atoms in the carbocyclic ring and linker, and typically contain from 4-12 carbon atoms (C4-C12 cycloalkylalkyl”). Thus a cyclopropylmethyl group is a C4-cycloalkylalkyl group and a cyclohexylethyl is a Ce-cycloalkylalkyl. Cycloalkylalkyl groups may be unsubstituted or substituted on the cycloalkyl and/or alkylene portions by the same groups that are described herein as suitable for alkyl groups.

The terms heterocyclyl, heterocyclic or heteroalicyclic” may be used interchangeably herein to refer to a non-aromatic, saturated or partially unsaturated ring System containing the specified number of ring atoms, including at least one heteroatom selected from N, O and S as a ring member, wherein the heterocyclic ring is connected to the base molécule via a ring atom, which may be C or N. Heterocyclic rings may be fused to one or more other heterocyclic or carbocyclic rings, which fused rings may be saturated, partially unsaturated or aromatic. Preferably, heterocyclic rings contain 1 to 4 heteroatoms selected from N, O, and S as ring members, and more preferably 1 to 2 ring heteroatoms, provided that such heterocyclic rings do not contain two contiguous oxygen atoms. Heterocyclyl groups may be unsubstituted or substituted by the same groups that are described herein as suitable for alkyl, aryl or heteroaryl. In addition, ring N atoms may be optionally substituted by groups suitable for an amine, e.g., alkyl, acyl, carbamoyl, sulfonyl substituents, etc., and ring S atoms may be optionally substituted by one or two oxo groups (i.e., S(O)q, where q is 0, 1 or 2).

Preferred heterocycles include 3-12 membered heterocyclyl groups in accordance with the définition herein.

Illustrative examples of partially unsaturated heterocyclic groups include, but are not limited to:

0	0	0
3,4-dihydro-2H-pyran	5,6-dihydro-2H-pyran	2H-pyran
(3,4-dihydro-2H-pyranyl)	(5,6-dihydro-2H-pyranyl)	(2H-pyranyl)
H	H
A	A
U	A
1,2,3,4-tetrahydropyridine	1,2,5,6-tetrahydropyridine
(1,2,3,4-tetrahydropyridinyl)	(1,2,5,6-tetrahydiOpyridinyl)

Illustrative examples of bridged and fused heterocyclic groups include, but are not limited to:

2-oxa-5-azabicyclo[2.2.1]heptane

3-oxa-8-azabicyclo[3.2.1]octane

3-azabicyclo[3.1 .Ojhexane

2-azabicyclo[3.1.0]hexane

Illustrative examples of saturated heterocyclic groups include, but are not limited to:

oxirane (oxiranyl) thiarane aziridine (thiaranyl) (aziridinyl) □° ü^s rf ô oxetane thiatane azetidine tetrahydrofuran (oxetanyl) (thiatanyl) (azetidinyl) (tetrahydrofuranyl)

tetrahydrothiophene (tetrahydrothiophenyl) pyrrolidine (pyrrolidinyl) tetrahydropyran tetrahydrothiopyran (tetrahydropyranyl) (tetrahydrothiopyranyl)

piperidine (piperidinyl)

1,4-dioxane (1,4-dioxanyl) û s

1,4-oxathîane (1,4-oxathianyl) morpholine (morpholinyl)

Û s

1,4-dithiane (1,4-dithianyl)

H CD N H	H Û s	O	O	H O
piperazine	1,4-azathiane	oxepane	thiepane	azepane
(piperazinyl)	(1,4-azathianyl)	(oxepanyl)	(thiepanyl)	(azepanyl)

H

1,4-dioxepane (1,4-dioxepanyl)

1,4-oxathiepane (1,4-oxathiepanyl)

1,4-oxaazepane (1,4-oxaazepanyl)

1,4-dithiepane (1,4-dithiepanyl)

H

1,4-thieazepane (1,4-thieazepanyl)

1,4-diazepane (1,4-diazepany!)

In frequent embodiments, heterocyclic groups contain 3-12 ring members, including both carbon and non-carbon heteroatoms, and preferably 4-6 ring members. In certain embodiments, substituent groups comprising 3-12 membered heterocycles are selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, each of which may be optionally substituted to the extent such substitution makes chemical sense. In other embodiments, substituent groups comprising 3-12 membered heterocycles are selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyanyl, each of which may be optionally substituted to the extent such substitution makes chemical sense. In particular embodiments, said 3-12 membered heterocycle is oxetanyl, optionally substituted to the extent such substitution makes chemical sense.

It is understood that no more than two N, O or S atoms are ordinarily connected sequentially except where an oxo group is attached to N or S to form a nitro or sulfonyl group, or in the case of certain heteroaromatic rings, such as triazine, triazole, tetrazole, oxadiazole, thiadiazole, and the like.

The term heterocyclylalkyl may be used to describe a heterocyclic group of the specified size that is connected to the base molécule through an alkylene linker of the specified length. Typically, such groups contain an optionally substituted 3-12 membered heterocycle attached to the base molécule through a C1-C4 alkylene linker. Where so indicated, such groups may be optionally substituted on the alkylene portion by the same groups that are described herein as suitable for alkyl groups and on the heterocyclic portion by groups described as suitable for heterocyclic rings.

Aryl or “aromatic” refer to an optionally substituted monocyclic, biaryl or fused bicyclic or polycyclic ring Systems, having the well-known characteristics of aromaticity, wherein at least one ring contains a completely conjugated pi-electron System. Typically, aryl groups contain 6 to 20 carbon atoms (C6-C20 aryl) as ring members, preferably 6 to 14 carbon atoms (C6-C14aryl) or more preferably, 6 to 12 carbon atoms (C6-Ci2aryl). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring, or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring. The point of attachment to the base molécule on such fused aryl ring Systems may be a C atom the aromatic portion or a C or N atom of the non-aromatic portion of the ring System. Examples, without limitation, of aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl. The aryl group may be unsubstituted or substituted as further described herein.

Similarly, heteroaryl or “heteroaromatic refer to monocyclic, heterobiaryl or fused bicyclic or polycyclic ring Systems having the well-known characteristics of aromaticity that contain the specified number of ring atoms and include at least one heteroatom selected from N, O and S as a ring member in an aromatic ring. The inclusion of a heteroatom permits aromaticity in 5-membered rings as well as 6-membered rings. Typically, heteroaryl groups contain 5 to 20 ring atoms (5-20 membered heteroaryl”), preferably 5 to 14 ring atoms (“5-14 membered heteroaryl), and more preferably 5 to 12 ring atoms (“5-12 membered heteroaryl). Heteroaryl rings are attached to the base molécule via a ring atom of the heteroaromatic ring, such that aromaticity is maintained. Thus, 6membered heteroaryl rings may be attached to the base molécule via a ring C atom, while

5- membered heteroaryl rings may be attached to the base molécule via a ring C or N atom. Examples of unsubstituted heteroaryl groups often include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, quinoline, isoquinoline, purine, triazine, naphthryidine and carbazole. In frequent preferred embodiments, 5- or

6- membered heteroaryl groups are selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl rings. The heteroaryl group may be unsubstituted or substituted as further described herein.

Aryl, heteroaryl and heterocyclyl moieties described herein as optionally substituted by may be substituted by one or more substituent groups, which are selected independently unless otherwise indicated. The total number of substituent groups may equal the total number of hydrogen atoms on the aryl, heteroaryl or heterocyclyl moiety, to the extent such substitution makes chemical sense and aromaticity is maintained in the case of aryl and heteroaryl rings. Optionally substituted aryl, heteroaryl or heterocyclyl groups typically contain from 1 to 5 optional substituents, sometimes 1 to 4 optional substituents, preferably 1 to 3 optional substituents, or more preferably 1-2 optional substituents.

Optional substituent groups suitable for aryl, heteroaryl and heterocyclyl rings include, but are not limited to: Ci-Cs alkyl, C2-Ca alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl and 5-12 membered heteroaryl; and halo, =0, CN, -C(O)R^X, -CO2R^X, -C(O)NR^xRv, - SR^X, -SOR^X, -SO2R^X, -SO2NR^xRy, -NO2, -NR^xRy, NR^xC(O)Ry, -NR^xC(O)NR^xR^y, -NR^XC(O)OR^X, -NR^xSO2Ry, -NR^xSO₂NR^xRy, -OR^X, OC(O)R^X and -OC(O)NR^xRy; where each R^x and R^y is independently H, Ci-Cs alkyl, C1Ce acyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, CeC12 aryl, or 5-12 membered heteroaryl, or R^x and R^y may be taken together with the N atom to which they are attached to form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each optionally containing 1,2 or 3 additional heteroatoms selected from O, N and S; each R^x and R* is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, =0, =S, =N-CN, =N-OR', =NR', -CN, -C(O)R', -CO2R', -C(O)NR'2, -SR¹, -SOR', -SO2R', -SOaNR'z, -NOa, -NR'a, -NR'C(O)R', NR'C(O)NR'2, -NR'C(O)OR', -NR'SChR', -NR'SO₂NR'2, -OR¹, -OC(O)R‘ and -OC(O)NR'₂, wherein each R’ is independently H, Ci-Ce alkyl, Ci-Cb acyl, C₂-Cb alkenyl, C₂-Cb alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl, or 5-12 membered heteroaryl; and each said Ci-Cb alkyl, C₂-Ce alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl and 5-12 membered heteroaryl is optionally substituted as further defined herein.

In typical embodiments, optional substitution on aryl, heteroaryl and heterocyclyl rings includes one or more substituents, and preferably 1 to 3 substituents, independently selected from the group consisting of halo, Ci-Ce alkyl, -OH, Ci-Ce alkoxy, CN, =0, C(O)R^X, -COOR^X, -OC(O)R^X, -C(O)NR^xRy, -NR^xC(O)Ry, -SR^X, -SOR^X, -SO2R^X, SO2NR^xRy, -NOa, -NR^xRy, -NR^xC(O)Rv, -NR^xC(O)NR^xRy, -NR^XC(O)OR* -NR^xSO2Ry, NR^xSO2NR^xRy, -OC(O)R^X, -OC(O)NR^XR*, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl, 5-12 membered heteroaryl, -O-(C3-C8 cycloalkyl),-0-(3-12 membered heterocyclyl), -O-(Ce-Ci2 aryl) and -0-(5-12 membered heteroaryl); where each R^x and Ry is independently H or C1-C4 alkyl, or R^x and Ry may be taken togetherwith the N to which they are attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each optionally containing 1,2 or 3 additional heteroatoms selected from O, N and S; and wherein each said Ci-Ce alkyl, Ci-Cs alkoxy, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl, 5-12 membered heteroaryl, -O-(C3-Cb cycloalkyl),-0-(3-12 membered heterocyclyl), -O-(Ce-Ci2 aryl) and -0-(5-12 membered heteroaryl) that is described as an optional substituent or is part of R^x or Ry is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, -OH, =0, C1-C4 alkyl, C1-C4 alkoxy, Ci-Ce haloalkyl, Ci-Ce hydroxyalkyl, C1-C4 alkoxy-Ci-C6 alkyl, -CN, NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2 and N-pyrrolidinyl.

Illustrative examples of monocyclic heteroaryl groups include, but are not limited to:

O	O	O	O	O N
pyrrole (pyrrolyl)	furan (furanyl)	thiophene (thiophenyl)	pyrazole (pyrazolyl)	imidazole (imidazolyl)
ô	ô ^ln	O	ô N	H O N
isoxazole (isoxazolyl)	oxazole (oxazolyl)	isothiazole (isothiazolyl)	thiazolyl (thiazolyl)	1,2,3-trïazole (1,2,3-triazolyl)

N-N

1,3,4-triazole (1,3,4-triazolyl)

1-oxa-2,3-diazole (1-oxa-2,3-diazolyl)

1-oxa-2,4-diazole (1-oxa-2_t4-diazolyl)

1-oxa-2,5-diazole (1-oxa-2,5-diazolyl)

A

N-N

1-oxa-3,4-diazole (1-oxa-3,4-diazolyl)

1-thia-2,3-diazole (1-thia-2,3-diazolyl)

1-thia-2,4-diazole (1 -thia-2,4-diazolyl)

1-thia-2,5-diazole (1 -thia-2,5-diazolyl)

1-thia-3,4-diazole tetrazole (1-thia-3,4-diazolyl) (tetrazolyi) pyridine (pyridinyl) pyridazine (pyridazinyl) pyrimidine (pyrimidinyi)

N pyrazine (pyrazinyl)

Illustrative examples of fused ring heteroaryl groups include, but are not limited to:

H

benzofuran (benzofuranyl) benzothiophene (benzothiophenyl) indole (indolyl) benzimidazole (benzimidazolyl) indazole (indazolyl)

benzotriazole (benzotriazolyl) pyrrolo[2,3-b]pyridine (pyrrolo[2,3-b]pyridinyl) pyrrolo[2,3-c]pyridine (pyrrolo[2,3-c]pyridinyl) pyrrolo[3,2-c]pyrldlne (pyrro!o[3,2-c]pyridinyl)

pyrrolo[3,2-b]pyridine (pyrrolo[3,2-b]pyridinyl) imidazo[4,5-b]pyridine (imidazo[4,5-b]pyridinyl) imidazo[4,5-c]pyridine (lmidazo[4,5-c]pyridlnyl) pyrazolo[4,3-d]pyridine (pyrazolo[4,3-d]pyidinyl)

pyrazolo[4,3-c]pyrldine (py razo I o [4,3-c]py i d i ny I ) pyrazolotS^-cJpyridine (pyrazolo[3,4-c]pyidinyl) pyrazolo[3,4-b]pyridine (pyrazolo[3,4-b]pyidinyl) isoindole (Isoindolyl)

indazole (indazolyl) purine (purinyl) indolizine (indolininyl) imidazo[1,2-a]pyridine (imidazo[1,2-a]pyridinyl) imidazo[1,5-a]pyridine (imidazo[1,5-a]pyridinyl)

pyrazoto[1,5-a]pyridine (pyrazolo[1,5-a]pyridinyl) pyrro I o[ 1,2-b]pyridazine (py rroîo[ 1 -2, bjpyridazinyl) imidazo[1,2-c]pyrimidine (imidazo[1,2-c]pyrimidinyi)

quinoline (quinolinyl)

isoquinoline (isoquinolinyl)

N I N

cinnoline (cînnoiinyl)

quinazolîne (azaquinazoline)

quinoxaline (quinoxalinyl) phthalazine (phthalazinyl)

1,6-naphthyridine (1,6-naphthyridinyl)

1,7-naphthyrïdine (1,7-naphthyridinyl)

1,8-naphthyridine (1,8-naphthyridinyl)

1,5-naphthyridine (1,5-naphthyridinyl)

2,6-naphthyridine (2,6-naphthyridinyl)

2,7-naphthyridine (2,7-naphthyridinyl)

pyrido[3,2-d]pyrimidine (pyrido[3,2-d]pyrimidinyl) pyridot^S-dlpyrimidine (pyrfdo[4,3-d]pyrimidinyl) pyrido[3₁4-d]pyrimidine (pyrido[3,4-d]pyrimidinyl)

pyrido[2,3-d]pyrimidine (pyrîdo[2,3-d]pynmidinyl) pyrido[2,3-b]pyrazi n e (pyrido[2,3-b]pyrazinyl) pyrido[3,4-b]pyrazine ( py ri do[3,4-b] py razi ny I )

pyrïmido[5,4-d]pyrimidine (pyrimido[5,4-d]pyrimidinyl) pyrazino[2,3-b]pyrazine (pyrazino[2,3-b]pyrazinyl) pyrimido[4,5-d]pyrimidine (pyrimido[4,5-d]pyrimidinyl)

An arylalkyl group refers to an aryl group as described herein which is linked to the base molécule through an alkylene or similar linker. Arylalkyl groups are described by the total number of carbon atoms in the ring and linker. Thus a benzyl group is a Cz5 arylalkyl group and a phenylethyl is a Ce-arylalkyl. Typically, arylalkyl groups contain 716 carbon atoms (“Cz-Cie arylalkyl”), wherein the aryl portion contains 6-12 carbon atoms and the alkylene portion contains 1-4 carbon atoms. Such groups may also be represented as -Ci-C4alkylene-C6-Ci2aryl.

Heteroarylalkyl'' refers to a heteroaryl group as described above that is attached 10 to the base molécule through an alkylene linker, and differs from arylalkyl in that at least one ring atom of the aromatic moiety is a heteroatom selected from N, O and S. Heteroarylalkyl groups are sometimes described herein according to the total number of non-hydrogen atoms (i.e., C, N, S and O atoms) in the ring and linker combined, excluding substituent groups. Thus, for example, pyridinylmethyl may be referred to as a ‘'C7heteroarylalkyl. Typically, unsubstituted heteroarylalkyl groups contain 6-20 nonhydrogen atoms (including C, N, S and O atoms), wherein the heteroaryl portion typically contains 5-12 atoms and the alkylene portion typically contains 1-4 carbon atoms. Such groups may also be represented as -Ci-C4alkylene-5-12 membered heteroaryl.

Similarly, “arylalkoxy” and “heteroarylalkoxy refer to aryl and heteroaryl groups, attached to the base molécule through a heteroalkylene linker (i.e., -O-alkylene-), wherein the groups are described according to the total number of non-hydrogen atoms (i.e., C, N, S and O atoms) in the ring and linker combined. Thus, -O-Chte-phenyl and -O-CH2pyridinyl groups would be referred to as Cs-arylalkoxy and Ce-heteroarylalkoxy groups, respectively.

Where an arylalkyl, arylalkoxy, heteroarylalkyl or heteroarylalkoxy group is described as optionally substituted, the substituents may be on either the divalent linker portion or on the aryl or heteroaryl portion of the group. The substituents optionally présent on the alkylene or heteroalkylene portion are the same as those described above for alkyl or alkoxy groups generally, while the substituents optionally présent on the aryl or heteroaryl portion are the same as those described above for aryl or heteroaryl groups generally.

Hydroxy refers to an -OH group.

“Acyloxy” refers to a monovalent group -OC(O)alkyl, wherein the alkyl portion has the specified number of carbon atoms (typically Ci-Ce, preferably C1-C6 or C1-C4) and may be optionally substituted by groups suitable for alkyl. Thus, C1-C4 acyloxy includes an -OC(O)Ci-C4 alkyl substituent, e.g., -OC(O)CHa.

“Acylamino refers to a monovalent group, -NHC(O)alkyl or-NRC(O)alkyl, wherein the alkyl portion has the specified number of carbon atoms (typically Ci-Cb, preferably C1Ce or C1-C4) and may be optionally substituted by groups suitable for alkyl. Thus, C1-C4 acylamino includes an -NHC(O)Ci-C4 alkyl substituent, e.g., -NHC(O)CH3.

Aryloxy” or “heteroaryloxy refer to optionally substituted -O-aryl or-O-heteroaryl, in each case where aryl and heteroaryl are as further defined herein.

Arylamino or heteroarylamino” refer to optionally substituted -NH-aryl, -NR-aryl, -NH-heteroaryl or-NR-heteroaryl, in each case where aryl and heteroaryl are as further defined herein and R represents a substituent suitable for an amine, e.g., an alkyl, acyl, carbamoyl or sulfonyl group, or the like.

Cyano refers to a -C=N group.

Unsubstituted amino refers to a group -NH2. Where the amino is described as substituted or optionally substituted, the term includes groups of the form -NR^xR^y, where each or R* and R* is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, acyl, thioacyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or heteroarylalkyl, in each case having the specified number of atoms and optionally substituted as described herein. For example, alkylamino” refers to a group -NR^xR^y, wherein one of R^x and R^y is an alkyl moiety and the other is H, and “dialkylamino” refers to -NR^xR^y wherein both of R^x and R^yare alkyl moieties, where the alkyl moieties having the specified number of carbon atoms (e.g., -NH-C1-C4 alkyl or-N(Ci-C4 alkyl)2). Typically, alkyl substituents on amines contain 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, or more preferably 1 to 4 carbon atoms. The term also includes forms wherein R^x and R^y are taken together with the N atom to which they are attached to form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which may itself be optionally substituted as described herein for heterocyclyl or heteroaryl rings, and which may contain 1 to 3 additional heteroatoms selected from N, O and S as ring members, provided that such rings do not contain two contiguous oxygen atoms.

“Halogen” or “halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I). Preferably, halo refers to fluoro or chloro (F or Cl).

Heteroform is sometimes used herein to refer to a dérivative of a group such as, e.g., an alkyl, aryl, or acyl, wherein at least one carbon atom of the designated carbocyclic group has been replaced by a heteroatom selected from N, O and S. Thus the heteroforms of alkyl, alkenyl, alkynyl, acyl, aryl, and arylalkyl are heteroalkyl, heteroalkenyl, heteroalkynyl, heteroacyl, heteroaryl, and heteroarylalkyl, respectively. It is understood that no more than two N, O or S atoms are ordinarily connected sequentially, except where an oxo group is attached to N or S to form a nitro or sulfonyl group.

Optional or optionally means thaï the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances in which it does not.

The terms “optionally substituted” and “substituted or unsubstituted” may be used interchangeably to indicate that the particular group being described may hâve no nonhydrogen substituents (i.e., unsubstituted), or the group may hâve one or more nonhydrogen substituents (i.e., substituted). If not otherwise specified, the total number of substituents that may be présent is equal to the number of H atoms présent on the unsubstituted form of the group being described, to the extent that such substitution makes chemical sense. Where an optional substituent is attached via a double bond, such as an oxo (=0) substituent, the group occupies two available valences, so the total number of other substituents that may be included is reduced by two. In the case where optional substituents are selected independently from a list of alternatives, the selected groups may be the same or different.

In one aspect, the invention provides a compound of formula (I):

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is selected from the group consisting of H, F, C1-C4 alkyl, C1-C4 alkoxy, C(O)R⁵, C3-C8 cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C1-C4 alkyl or C1-C4 alkoxy is optionally substituted by one or more R⁶, and each saidCa-Cs cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

R² is H, F or C1-C4 alkyl;

L is a bond or a C1-C4 alkylene;

R³ is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, OH, CN, C(O)R⁸, COOR⁹, NR¹⁰R¹¹, OR¹², C3-C8 cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C1-C4 alkyl or C1-C4 alkoxy is optionally substituted by one or more R⁶, and each said C3-Ce cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

each R⁶ is independently OH, F, CN or C1-C4 alkoxy;

R® is C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁴;

R¹² is selected from the group consisting of C3-C8 cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said Cs-Ce cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

each R¹⁴ and R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

or a pharmaceutically acceptable sait thereof, wherein:

R¹, R², L, R³, R⁴, X and Z are defined as for Formula (I).

Each of the aspects and embodiments described herein with respect to Formula (I) is also applicable to compounds of Formula (l-A) or (l-B).

In frequent embodiments of Formula (I), R² is H.

In frequent embodiments of Formula (l), R⁴ is H, Cl, Br, F or CH3. In some such embodiments, R⁴ is H or Cl. In some embodiments, R⁴ is H. In other embodiments, R⁴ is Cl. In further embodiments, R⁴ is Cl or Br.

In compounds of Formula (I), X and Z are independently C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy. In some embodiments, Z is C1-C4 alkyl, for example CH3 or C2H5 (i.e., methyl or ethyl). In some embodiments, X is C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy. In spécifie embodiments, X is CH3, OCH3 or OCHF2 (i.e., methyl, methoxy or difluoromethoxy). In further embodiments, X is CH3, OCH3 or OCHF2, and Z is CH3.

In some embodiments of Formula (I), R¹ is H or F.

In other embodiments of Formula (I), R¹ is C1-C4 alkyl or C1-C4 alkoxy, each optionally substituted by one or more R⁶. In some such embodiments, said alkyl or alkoxy is substituted by at least one OH or CN. In spécifie embodiments, R¹ is CH3, C2H5, CH2OH, CH2CH2OH, CH(OH)CH3 or CH2CN (i.e., methyl, ethyl, hydroxymethyl, 2hydroxyethyl, 1 -hydroxyethyl or cyanomethyl). In other spécifie embodiments, R¹ is OCH3 (i.e., methoxy).

In other embodiments of Formula (I), R¹ is C(O)R⁵, where R⁵ is C1-C4 alkyl optionally substituted by one or more R¹⁴. In some such embodiments, R⁵ is C1-C4 alkyl optionally substituted by OH. In spécifie embodiments, R⁵ is CH3, CH2OH, CH2CH2OH or CH(CH3)OH such that R¹ is C(O)CH3, C(O)CH₂OH, C(O)CH₂CH2OH or C(O)CH(CH3)OH (i.e., acetyl, α-hydroxyacetyl, 3-hydroxypropionyl or 2hydroxypropionyl).

In still other embodiments of Formula (I), R¹ is C3-C8 cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, where each said C3-C8 cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷.

In some such embodiments, R¹ is C3-C8 cycloalkyl optionally substituted by one or more R⁷. In some such embodiments, R¹ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted by one or more R⁷.

In other embodiments, R¹ is 3-12 membered heterocyclyl optionally substituted by one or more R⁷. In some such embodiments, said 3-12 membered heterocyclyl is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, piperidinyl and morpholinyl, each optionally substituted by one or more R⁷. In other such embodiments, said 3-12 membered heterocyclyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each optionally substituted by one or more R⁷. In spécifie embodiments, said 3-12 membered heterocyclyl is oxetanyl optionally substituted by one or more R⁷. In some such embodiments, said oxetanyl is unsubstituted.

In still other such embodiments, R¹ is 5-12 membered heteroaryl, where each said

5- 12 membered heteroaryl is optionally substituted by one or more R⁷. In some such embodiments, R¹ is a 5- or 6-membered heteroaryl. In spécifie embodiments, said 5- or

6- membered heteroaryl is selected from the group consisting of pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, and triazolyl groups, each optionally substituted by one or more R⁷.

In certain embodiments, when R¹ is Ca-Cs cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each R⁷ is independently CH3, OH, F, CN, OCH3, =0, CHO, C(O)R¹³, SO2R¹³ or 3-6 membered heterocyclyl, where R¹³ is CH3 or C2H5 each optionally substituted by OH (e.g., R¹³ is CHs, CH2OH, CH2CH2OH or CH(CH₃)OH.

In compounds of Formula (I), L is a bond or a C1-C4 alkylene. In some embodiments of Formula (I), L is a bond. In other embodiments of Formula (I), L is a C1-C4 alkylene. In spécifie embodiments, L is a methylene or ethylene.

In compounds of Formula (I), R³ is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, OH, CN, C(O)R⁰, COOR⁹, NR¹⁰R¹¹, OR¹², Cs-Ce cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C1-C4 alkyl or C1-C4 alkoxy is optionally substituted by one or more R⁶, and each said C3-Cb cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷.

In some embodiments, R³ is C1-C4 alkyl, C1-C4 alkoxy or 3-12 membered heterocyclyl, each optionally substituted as described above. In some embodiments, R³is C1-C4 alkyl or C1-C4 alkoxy, in particular CH3 or OCH3 (i.e., methyl or methoxy).

In further embodiments, R³ is 3-12 membered heterocyclyl optionally substituted by one or more R⁷. In some such embodiments, said 3-12 membered heterocyclyl is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, piperidinyl and morpholinyl, each optionally substituted by one or more R⁷. In other such embodiments, said 3-12 membered heterocyclyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each optionally substituted by one or more R⁷. In spécifie embodiments, said 3-12 membered heterocyclyl is oxetanyl, optionally substituted by one or more R⁷. In some such embodiments, said oxetanyl is unsubstituted.

In further embodiments, L is a bond and R³ is C1-C4 alkyl, C1-C4 alkoxy or 3-12 membered heterocyclyl, each optionally substituted as described above. In spécifie embodiments, L is a bond and R³ is C1-C4 alkyl or C1-C4 alkoxy, in particular CHa or OCH3 (i.e., methyl or methoxy).

In still further embodiments, L is a bond and R³ is 3-12 membered heterocyclyl optionally substituted by one or more R⁷. In some such embodiments, L is a bond and said 3-12 membered heterocyclyl is selected from the group consisting of tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrrolidinyl, piperidinyl and morpholinyl, each optionally substituted by one or more R⁷. In other such embodiments, L is a bond and said 3-12 membered heterocyclyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each optionally substituted by one or more R⁷. In spécifie embodiments, L is a bond and said 3-12 membered heterocyclyl is oxetanyl, optionally substituted by one or more R⁷. In some such embodiments, said oxetanyl is unsubstituted.

In other such embodiments, L is a C1-C4 alkylene and R³ is C1-C4 alkyl, C1-C4 alkoxy or 3-12 membered heterocyclyl, each optionally substituted as described above.

In still other embodiments, R³ is OH, CN, C(O)R⁸ or COOR⁹, where R⁸ is C1-C4 alkyl optionally substituted by one or more R¹⁴, and R⁹ is H or C1-C4 alkyl optionally substituted by one or more R¹⁴.

In some such embodiments, L is a bond and R³ is OH, CN, C(O)R⁸ or COOR⁹, where R⁸ and R⁹ are described as above.

In other embodiments, L is a C1-C4 alkylene and R³ is OH, CN, C(O)R⁸ or COOR⁹, where R⁸ and R⁹ are described as above. In spécifie embodiments, L is a C1-C4 alkylene, for example methylene or ethylene, and R³ is OH or CN.

In further embodiments, R³ is OR¹², C3-Ce cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, where each said C3-C8 cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷, and where R¹² is C3-Ca cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each optionally substituted by one or more R⁷.

ln some such embodiments, L is a bond and R³ is OR¹², C3-Ce cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, as described above. In other such embodiments, L is a C1-C4 alkylene and R³ is OR¹², C3-Cs cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl, as described above.

In compounds of Formula (I), each R⁶ is independently OH, F, CN or C1-C4 alkoxy. In frequent embodiments, at least one R⁶ is OH or F.

In compounds of Formula (I), each R⁷ is independently C1-C4 alkyl, OH, F, CN, C1C4 alkoxy, =0, CHO, C(O)R¹³, SO2R¹³ or 3-6 membered heterocyclyl. In some embodiments, at least one R⁷ is C(O)R¹³, where R¹³isCi-C4 alkyl and said C1-C4 alkyl is optionally further substituted by one or more R¹⁵. In some embodiments, at least one R⁷is SO2R¹³, where R¹³ is C1-C4 alkyl and said C1-C4 alkyl is optionally further substituted by one or more R¹⁵. In other spécifie embodiments, at least one R⁷ is OH, F or C1-C4 alkyl, e.g., CH3.

In spécifie embodiments, R¹ and/or R³ is a 3-12 membered heterocyclyl substituted by one or more R⁷, where at least one R⁷ is CHO or C(O)R¹³, and where R¹³ is CHs, CH2OH or CHaCN, such that R⁷ is CHO, C(O)CH₃, C(O)CH₂OH or C(O)CH₂CN (i.e., formyl, acetyl, hydroxyacetyl or cyanoacetyl, respectively).

In spécifie embodiments, R¹ and/or R³ is a 3-12 membered heterocyclyl substituted by one or more R⁷, where at least one R⁷ is SO2R¹³, and where R¹³ is CH3, CH2OH or CH2CN, such that R⁷ is SO2CH3, SO2CH2OH or SO2CH2CN.

In further spécifie embodiments, R¹ and/or R³ is a 3-12 membered heterocyclyl substituted by one or more R⁷, where at least one R⁷ is OH.

In compounds of Formula (I), R⁸ is C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁴.

In compounds of Formula (I), R⁹ is H or C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁴. In some such embodiments, R⁹ is H. In other such embodiments, R⁹ is C1-C4 alkyl, optionally substituted as described above.

In compounds of Formula (I), R¹⁰ and R¹¹ are independently H or C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁴.

Each R¹⁴ and R¹⁵is independently OH, F, CN or C1-C4 alkoxy.

In one preferred embodiment, the invention provides a compound of Formula (I), (l-A) or (l-B), or a pharmaceutically acceptable sait thereof, wherein:

R¹ is 3-12 membered heterocyclyl or 5-12 membered heteroaryl, where each said 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

R² is H;

L is C1-C4 alkylene;

R³ is OH or CN;

R⁴ is HorCI;

each R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

In another preferred embodiment, the invention provides a compound of Formula (I), (l-A) or (l-B), or a pharmaceutically acceptable sait thereof, wherein:

R¹ is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by one or more R⁶;

R² is H;

L is a bond or C1-C4 alkylene;

R³ is selected from the group consisting of C1-C4 alkyl, OH, CN, C(O)R⁸, COOR⁹, NR¹⁰R¹¹, C3-Ca cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C1-C4 alkyl is optionally substituted by one or more R⁶, and each said C3Ce cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

R⁴ is H or Cl;

each R⁶ is independently OH, F, CN or C1-C4 alkoxy;

each R⁷ is independently C1-C4 alkyl, OH, F, CN, C1-C4 alkoxy, =0, CHO, C(0)R¹³, SO2R¹³ or 3-6 membered heterocyclyl;

each R¹⁴ and R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

R¹ is C1-C4 alkoxy, where said C1-C4 alkoxy is optionally substituted by one or more R⁶;

R² is H;

L is a bond or a C1-C4 alkylene;

R³ is selected from the group consisting of C1-C4 alkyl, OH, C(O)R⁰ and 3-12 membered heterocyclyl, where each said C1-C4 alkyl is optionally substituted by one or more R⁶, and each said 3-12 membered heterocyclyl is optionally substituted by one or more R⁷;

R⁴ is H or Cl;

each R⁶ is independently OH, F, CN or C1-C4 alkoxy;

each R⁷ is independently C1-C4 alkyl, OH, F, CN, C1-C4 alkoxy, =O, CHO, C(O)R¹³, SO2R¹³ or 3-6 membered heterocyclyl;

R⁹ is C1-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁴;

each R¹⁴ and R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

R¹ is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by one or more R⁶;

R² is H;

L is a bond or a C1-C4 alkylene;

R³ is OR¹²;

R⁴ is H or Cl;

each R⁶ is independently OH, F, CN or C1-C4 alkoxy;

each R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

R¹ is C1-C4 alkoxy;

R² is H;

L is a bond;

R³ is 3-12 membered heterocyclyl, preferably selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each optionally substituted by one or more R⁷;

R⁴ is H or Cl;

each R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

R¹ is 3-12 membered heterocyclyl, preferably selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each optionally substituted by one or more R⁷;

R² is H;

L is a bond;

R³ is C1-C4 alkoxy, optionally substituted by one or more R⁶,

R⁴ is H or Cl;

each R⁶ is independently OH, F, CN or C1-C4 alkoxy;

each R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

(ll-A) (ll-B) or a pharmaceutically acceptable sait thereof, wherein:

R¹, L, R³ and X are defined as for Formula (I); and

R⁴ is H, Cl, Br, F or CH3.

The embodiments described herein for Formula (I), (l-A) and (l-B) are also applicable to compounds of Formulae (II), (ll-A) and (ll-B) to the extent they are not inconsistent.

In a further aspect, the invention provides a compound of formula (III):

or a pharmaceutically acceptable sait thereof, wherein:

R¹ and R³ are taken together to form a 3-12 membered heterocyclyl optionally substituted by one or more R⁷;

R² is H, F or C1-C4 alkyl;

each R⁶ is independently OH, F, CN or C1-C4 alkoxy;

each R⁷ is independently C1-C4 alkyl, OH, F, CN, C1-C4 alkoxy, =0, CHO, C(O)R¹³, SOaR¹³ or 3-6 membered heterocyclyl;

each R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

In some embodiments of Formula (III), R² is F or CH3.

In compounds of Formula (III), R¹ and R³ are taken together to form a 3-12 membered heterocyclyl optionally substituted by one or more R⁷. In some such embodiments, said 3-12 membered heterocyclyl is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl and homopiperidinyl, each optionally substituted by one or more R⁷. In other such embodiments, said 3-12 membered heterocyclyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each optionally substituted by one or more R⁷.

In compounds of Formula (III), each R⁷ is independently C1-C4 alkyl, OH, F, CN, C1-C4 alkoxy, =0, CHO, C(O)R¹³, SO2R¹³ or 3-6 membered heterocyclyl. In some embodiments, R⁷ isCHO, C(O)R¹³orSO2R¹³, where each R¹³is independently C1-C4 alkyl optionally substituted by one or more R¹⁵. In some such embodiments, R¹³ is C1-C4 alkyl optionally substituted by one or more R¹⁵ and each R¹⁵ is independently OH, F, CN or Ci

C4 alkoxy. In particular embodiments, R¹³ is C1-C4 alkyl optionally substituted by OH. In spécifie embodiments, R¹³ is CH3 or CH2OH, such that R⁷ is C(O)CH3, C(O)CH2OH, SO2CH3 or SO2CH2OH (i.e., acetyl, α-hydroxyacetyl, methylsulfonyl or ahydroxymethylsulfonyl).

In some embodiments, R⁴ is H, CH3 or Cl.

In some embodiments, Z is CH3.

In some embodiments, X is CHaorOCHs.

In a preferred embodiment, the invention provides a compound of Formula (III), or a pharmaceutically acceptable sait thereof, wherein:

R² is F or CH₃;

R¹ and R³ are taken together to form a 3-12 membered heterocyclyl, each optionally substituted by one or more R⁷;

R⁴ is H, CH₃ or CI;

Z is CH3; and

X is CH3orOCH3.

In another preferred embodiment, the invention provides a compound of Formula (III), or a pharmaceutically acceptable sait thereof, wherein:

R² is F or CH3;

R¹ and R³ are taken together to form a 3-12 membered heterocyclyl selected from the group consisting of azetidînyl, pyrrolidinyl, piperidinyl and homopiperidinyl, each optionally substituted by one or more R⁷;

R⁴ isH.CHsorCI;

R⁷ is C(O)R¹³ or SO2R¹³;

each R¹³ is independently C1-C4 alkyl optionally substituted by one or more R¹⁵; each R¹⁵ is independently OH, F, CN or C1-C4 alkoxy;

Z is CH3; and

X is CHsorOCHs.

In another aspect, the invention provides a compound of formula (Γ):

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is selected from the group consisting of H, F, C1-C4 alkyl, C1-C4 alkoxy, C(O)R⁵, C3-C8 cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C1-C4 alkyl or C1-C4 alkoxy is optionally substituted by one or more R⁶, and each said C₃-Cs cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

R² is H, F or C1-C4 alkyl;

L is a bond or a C1-C4 alkylene;

R³ is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, OH, CN, C(O)R⁸, COOR⁹, NR¹⁰R¹¹, OR¹², C3-Ce cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C1-C4 alkyl or C1-C4 alkoxy is optionally substituted by one or more R⁶, and each said C3-Ce cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

each R⁶ is independently OH, F, CN or C1-C4 alkoxy;

each R⁷ is independently C1-C4 alkyl, OH, F, CN, C1-C4 alkoxy, =0 or C(O)R¹³;

R¹² is selected from the group consisting of C₃-Ce cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C₃-Cb cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

each R¹³ is independently H orCi-C4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁵;

each R¹⁴ and R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

In some embodiments, the compound of Formula (I’) has the absolute stereochemistry at the carbon atom bearing the R¹ and R² substituents as shown in Formula (l-A’) or (l-B’):

or a pharmaceutically acceptable sait thereof, wherein:

R¹, R², L, R³, R⁴, X and Z are defined as for Formula (I).

The embodiments described herein for Formula (I), (l-A) and (l-B) are also applicable to compounds of Formulae (I’), (l-A’) and (l-B*) to the extent they are not inconsistent.

In another aspect, the invention provides a compound of Formula (ΙΓ), (Il-A’) or (IIB’):

or a pharmaceutically acceptable sait thereof, wherein:

R¹, L, R³ and X are defined as for Formula (Γ); and

R⁴ is H, Cl, Br, F or CH3.

The embodiments described herein for Formula (I), (l-A) and (l-B) are also applicable to compounds of Formulae (II·), (ll-A’) and (ll-B’) to the extent they are not inconsistent.

A pharmaceutical composition refers to a mixture of one or more of the compounds described herein, or a pharmaceutically acceptable sait, solvaté, hydrate or prodrug thereof as an active ingrédient, and at least one pharmaceutically acceptable carrier or excipient.

In another aspect the invention provides a pharmaceutical composition comprising a compound of one of the formulas described herein, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients.

In some embodiments, the pharmaceutical composition may further comprise at least one additional an anti-cancer therapeutic agent or a palliative agent. In some such embodiments, the at least one additional médicinal or pharmaceutical agent is an anticancer agent as described below. In some such embodiments, the combination provides an additive, greater than additive, or synergistic anti-cancer effect. In some such embodiments, the one or more anti-cancer therapeutic agent is selected from the group consisting of anti-tumor agents, anti-angiogenesis agents, signal transduction inhibitors and antiproliférative agents.

In some embodiments, the methods described herein further comprise administering to the subject an amount of an anti-cancer therapeutic agent or a palliative agent, which amounts are together effective in treating said abnormal cell growth. In some embodiments, the one or more anti-cancer therapeutic agent are selected from antitumor agents, anti-angiogenesis agents, signal transduction inhibitors and antiproliférative agents, which amounts are together effective in treating said abnormal cell growth. In some such embodiments, the anti-tumor agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.

In another aspect, the invention provides a method for the treatment of a disorder mediated by EZH2 in a subject comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable sait thereof, in an amount that is effective for treating said disorder.

Unless indicated otherwise, ail references herein to the inventive compounds include references to salts, solvatés, hydrates and complexes thereof, and to solvatés, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof.

Compounds of the invention may exist in the form of pharmaceutically acceptable salts such as, e.g., acid addition salts and base addition salts of the compounds of one of the formulae provided herein. As used herein, the term “pharmaceutically acceptable sait refers to those salts which retain the biological effectiveness and properties of the parent compound. The phrase “pharmaceutically acceptable salt(s), as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be présent in the compounds of the formulae disclosed herein.

For example, the compounds of the invention that are basic in nature may be capable of forming a wide variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animais, it is often désirable in practice to initially isolate the compound of the présent invention from the reaction mixture as a pharmaceutically unacceptable sait and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition sait. The acid addition salts of the base compounds of this invention may be prepared by treating the base compound with a substantially équivalent amount of the selected minerai or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or éthanol. Upon évaporation of the solvent, the desired solid sait is obtained. The desired acid sait may also be precipitated from a solution of the free base in an organic solvent by adding an appropriate minerai or organic acid to the solution.

The acids that may be used to préparé pharmaceutically acceptable acid addition salts of such basic compounds of those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p toluenesulfonate and pamoate [i.e., 1,r-methylene-bis-(2-hydroxy3-naphthoate)] salts.

Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, γhydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methane-sulfonate, methylsulfate, monohydrogenphosphate, mucate, napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phospate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stéarate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.

Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnésium, manganèse, iron, copper, zinc, aluminum and lithium.

The compounds of the invention that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

Those compounds of the invention that are acidic in nature may be capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali métal or alkaline-earth métal salts and particularly, the sodium and potassium salts. These salts may be prepared by conventional techniques. The chemical bases which may be used as reagents to préparé the pharmaceutically acceptable base salts of this invention include those which form non-toxic base salts with the acidic compounds herein. These salts may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali métal hydroxide or alkaline earth métal hydroxide, or the like. These salts may also be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali métal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantifies of reagents may be employed in order to ensure completeness of reaction and maximum yields of the desired final product.

The chemical bases that may be used as reagents to préparé pharmaceutically acceptable base salts of the compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali métal cations (e.g., potassium and sodium) and alkaline earth métal cations (e.g., calcium and magnésium), ammonium or water-soluble amine addition salts such as Nmethylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Sélection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts are known to those of skill in the art.

Salts of the présent invention may be prepared according to methods known to those of skill in the art. A pharmaceutically acceptable sait of the inventive compounds may be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate. The sait may precipitate from solution and be collected by filtration or may be recovered by évaporation of the solvent. The degree of ionization in the sait may vary from completely ionized to almost non-ionized.

It will be understood by those of skill in the art that the compounds of the invention in free base form having a basic functionality may be converted to the acid addition salts by treating with a stoichiometric excess of the appropriate acid. The acid addition salts of the compounds of the invention may be reconverted to the corresponding free base by treating with a stoichiometric excess of a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of aqueous solvent, and at a température of between about 0° C. and 100° C. The free base form may be isolated by conventional means, such as extraction with an organic solvent. In addition, acid addition salts of the compounds of the invention may be interchanged by taking advantage of differential solubilities of the salts, volatilities or acidities of the acids, or by treating with the appropriately loaded ion exchange resin. For example, the interchange may be affected by the reaction of a sait of the compounds of the invention with a slight stoichiometric excess of an acid of a lower pK than the acid component of the starting sait. This conversion is typically carried out at a température between about 0°C and the boiling point of the solvent being used as the medium for the procedure. Similar exchanges are possible with base addition salts, typically via the intermediacy of the free base form.

The compounds of the invention may exist in both unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will hâve a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvatés and hygroscopic compounds, the water/solvent content will be dépendent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The term ‘solvaté’ is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molécules, for example, éthanol. The term ‘hydrate’ is employed when the solvent is water. Pharmaceutically acceptable solvatés in accordance with the invention include hydrates and solvatés wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, de-acetone and de-DMSO.

Also included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvatés, the drug and host are présent in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975), the disclosure of which is incorporated herein by reference in its entirety.

The invention also relates to prodrugs of the compounds of the formulae provided herein. Thus, certain dérivatives of compounds of the invention which may hâve little or no pharmacological activity themselves may, when administered to a subject, be converted into the inventive compounds, for example, by hydrolytic cleavage. Such dérivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in ‘Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Sériés (T Higuchi and W Stella) and ‘Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in therr entireties. As used herein, subject may refer to a human or animal subject.

Prodrugs in accordance with the invention may, for example, be produced by repiacing appropriate functionalities présent in the inventive compounds with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

Some non-limiting examples of potentiel prodrugs in accordance with the invention include:

(i) where the compound contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (Ci-Ce)alkyl;

(ii) where the compound contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (Ci-Cejalkanoyloxymethyl; and (iii) where the compound contains a primary or secondary amino functionality (Nhteor -NHR where R / H), an amide thereof, for example, replacement of one or both hydrogens with a suitably metabolically labile group, such as an amide, carbamate, urea, phosphonate, sulfonate, etc..

Further examples of replacement groups in accordance with the foregoing examples and examples of other potential prodrug types may be found in the aforementioned references.

Finally, certain inventive compounds may themselves act as potential prodrugs of other of the inventive compounds.

Also included within the scope of the invention are métabolites of compounds of the formulae described herein, i.e., compounds formed in vivo upon administration of a drug.

The compounds of the formulae provided herein may hâve asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the invention may be depicted herein using a solid line ( ), a solid wedge ( ), or a dotted wedge (.....Η·).

The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that ail possible stereoisomers (e.g. spécifie enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that ail possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds of the invention may exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is présent.

Compounds of the invention that hâve chiral centers may exist as stereoisomers, such as racemates, enantiomers, or diastereomers.

Stereoisomers of the compounds of the formulae herein may include cis and trans isomers, optical isomers such as (R) and (S) enantiomers, diastereomers, géométrie isomers, rotational isomers, atropisomers, conformational isomers, and tautomers of the compounds of the invention, including compounds exhibîting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid addition or base addition salts wherein the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

When a racemate crystallizes, crystals of two different types may be possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

The compounds of the invention may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds may exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and géométrie isomers and mixtures thereof. Ail such tautomeric forms are included within the scope of compounds of the invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer prédominâtes. Even though one tautomer may be described, the présent invention includes ali tautomers of the compounds of the formulae provided.

In addition, some of the compounds of the invention may form atropisomers (e.g., substituted biaryls). Atropisomers are conformational stereoisomers which occur when rotation about a single bond in the molécule is prevented, or greatly slowed, as a resuit of steric interactions with other parts of the molécule and the substituents at both ends of the single bond are unsymmetrical. The interconversion of atropisomers is slow enough to allow séparation and isolation under predetermined conditions. The energy barrier to thermal racemization may be determined by the steric hindrance to free rotation of one or more bonds forming a chiral axis.

Where a compound of the invention contains an alkenyl or alkenylene group, géométrie cis/trans (or Z/E) isomers may be possible. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography or fractional crystallization.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a sait or dérivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

Stereoisomeric conglomérâtes may be separated by conventional techniques known to those skilled in the art; see, for example, “Stereochemistry of Organic

Compounds” by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

“Enantiomerically pure” as used herein, describes a compound that is présent as a single enantiomer and which is described in terms of enantiomeric excess (e.e.). Preferably, wherein the compound is présent as an enantiomer, the enantiomer is présent at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%. Similarly, “diastereomerically pure as used herein, describes a compound that is présent as a diastereomer and which is described in terms of diasteriomeric excess (d.e.). Preferably, wherein the compound is présent as a diastereomer, the diastereomer is présent at an diastereomeric excess of greater than or equal to about 80%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.

The présent invention also includes isotopically-labeled compounds, which are identical to those recited in one of the formulae provided, 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.

Isotopically-labeled compounds of the invention may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

Examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ²H, ³H, ¹³C, ¹⁴C, ^1SN, ^1ΘΟ, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁰F, and ³⁶CI. Certain isotopically-labeled compounds of the invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, may be useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes may be particularly preferred for their ease of préparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, may afford certain potential therapeutic advantages resulting from potentially greater metabolic stability, for example potentially increased in vivo half-life or potentially reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically-labeled compounds of the invention may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Préparations below, by substituting an isotopicallylabeled reagent for a non-isotopically-labeled reagent.

Compounds of the invention may be used as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as précipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. Therapeutic Methods and Uses

The invention further provides therapeutic methods and uses comprising administering a compound of the invention, or pharmaceutically acceptable sait thereof, alone or in combination with one or more other therapeutic agents or palliative agents.

In another aspect, the invention provides a method for the treatment of abnormal cell growth in a subject comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable sait thereof, in combination with an amount of an anti-tumor agent, which amounts are together effective in treating said abnormal cell growth. In some such embodiments, the anti-tumor agent is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, antihormones, and anti-androgens.

Compounds of the invention include compounds of any of the formulae described herein, namely compounds of formulae I, Γ, II, II’, l-A, l-A’, l-B, l-B’, ll-A, ll-A’, ll-B, ll-B' and III as provided and defined herein, or a pharmaceutically acceptable sait thereof.

In another aspect, the invention provides a method for the treatment of abnormal cell growth in a subject comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable sait thereof, that is effective in treating abnormal cell growth.

In still another aspect, the invention provides a method of inhibiting cancer cell prolifération in a subject, comprising administering to the subject a compound of the invention, or pharmaceutically acceptable sait thereof, in an amount effective to inhibit cell prolifération.

In another aspect, the invention provides a method of inhibiting cancer cell invasiveness in a subject, comprising administering to the subject a compound of the invention, or pharmaceutically acceptable sait thereof, in an amount effective to inhibit cell invasiveness.

In another aspect, the invention provides a method of inducing apoptosis in cancer cells in a subject, comprising administering to the subject a compound of the invention, or pharmaceutically acceptable sait thereof, in an amount effective to induce apoptosis.

In a further aspect, the invention provides a method of inducing apoptosis in a subject, comprising administering to the subject a therapeutically effective amount of a compound of one of the formulae described herein, or pharmaceutically acceptable sait thereof.

In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer, wherein said cancer is selected from the group consisting of basal cell cancer, medulloblastoma cancer, liver cancer, rhabdomyosarcoma, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal région, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine System, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pénis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, rénal cell carcinoma, carcinoma of the rénal pelvis, neoplasms of the central nervous System (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers.

In some embodiments, a compound of the invention is sélective for the mutant form of the EZH2, such that trimethylation of H3K27, which is associated with certain cancers, is inhibited. The methods and uses provided herein may be used to treat cancers including follicular lymphoma and diffuse large B-cell lymphoma (DLBCL).

Compounds of the invention may be useful for the treatment of cancers, such as tumors such as brain, breast, cervical, colorectal, endométrial, esophageal, gastric/stomach, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, testicular and thyroid carcinomas and sarcomas.

The term therapeutically effective amount as used herein refers to that amount of a compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and/or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer.

As used herein, subject refers to a human or animal subject. In certain preferred embodiments, the subject is a human.

The term treating, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term treatment, as used herein, unless otherwise indicated, refers to the act of treating as treating is defined immediately above. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject.

The terms “abnormal cell growth” and “hyperproliferative disorder” are used interchangeably in this application.

“Abnormal cell growth”, as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (not cancerous), or malignant (cancerous). This includes the abnormal growth of: (1) tumor cells (tumors) that show increased expression of EZH2; (2) benign and malignant cells of other proliférative diseases in which EZH2 is over-expressed; (3) tumors that proliferate by aberrant EZH2 activation; and (4) benign and malignant cells of other proliférative diseases in which aberrant EZH2 activation occurs.

As used herein “cancer” refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. As used herein “cancer” refers to solid tumors named for the type of cells that form them, cancer of blood, bone marrow, or the lymphatic System. Examples of solid tumors include but not limited to sarcomas and carcinomas.

Examples of cancers of the blood include but not limited to leukemias, lymphomas and myeloma. The term “cancer” includes but is not limited to a primary cancer that originates at a spécifie site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a récurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of different type from latter one. The compounds of the invention may inhibit EZH2, and thus may be useful as antiproliférative agents (e.g., cancer) or antitumor agent (e.g., effect against solid tumors) in mammals, particularly in humans. In particular, the compounds of the invention may be useful in the prévention and treatment of a variety of human hyperproliferative disorders, such as malignant or benign abnormal cell growth.

The compounds, compositions and methods provided herein may be useful for the treatment of cancers including but not limited to cancers of the:

circulatory System, for example, heart (sarcoma [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyoma, fibroma, lipoma and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors and tumor-associated vascular tissue;

respiratory tract, for example, nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung such as small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

gastrointestinal System, for example, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), gastric, pancréas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

genitourinary tract, for example, kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and/or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);

liver, for example, hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, islet cell tumor and glucagonoma);

bone, for example, ostéogénie sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (réticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;

nervous System, for example, neoplasms of the central nervous System (CNS), primary CNS lymphoma, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), méningés (meningioma, meningiosarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congénital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);

reproductive System, for example, gynecological, utérus (endométrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithélial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma) and other sites associated with female génital organs; placenta, pénis, prostate, testis, and other sites associated with male génital organs;

hématologie System, for example, blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma];

oral cavity, for example, îip, tongue, gum, floor of mouth, palate, and other parts of mouth, parotid gland, and other parts of the salivary glands, tonsil, oropharynx, nasopharynx, pyriform sinus, hypopharynx, and other sites in the Iip, oral cavity and pharynx;

skin, for example, malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids;

adrenal glands: neuroblastoma; and other tissues including connective and soft tissue, retroperitoneum and peritoneum, eye, intraocular melanoma, and adnexa, breast, head or/and neck, anal région, thyroid, parathyroid, adrenal gland and other endocrine glands and related structures, secondary and unspecified malignant neoplasm of lymph nodes, secondary malignant neoplasm of respiratory and digestive Systems and secondary malignant neoplasm of other sites.

More specifically, examples of “cancer” when used herein in connection with the présent invention include cancer selected from lung cancer (NSCLC and SCLC), cancer of the head or neck, ovarian cancer, colon cancer, rectal cancer, cancer of the anal région, stomach cancer, breast cancer, cancer of the kidney or ureter, rénal cell carcinoma, carcinoma of the rénal pelvis, neoplasms of the central nervous System (CNS), primary CNS lymphoma, non-Hodgkin’s lymphoma, spinal axis tumors, or a combination of one or more of the foregoing cancers .

Still more specifically, examples of “cancer” when used herein in connection with the présent invention include cancer selected from lung cancer (NSCLC and SCLC), breast cancer, ovarian cancer, colon cancer, rectal cancer, cancer of the anal région, or a combination of one or more of the foregoing cancers.

In one embodiment of the présent invention the non-cancerous conditions include such hyperplastic conditions such as benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH).

In another aspect, the invention provides a method for inhibiting cell prolifération, comprising contacting cells with a compound of the invention or a pharmaceutically acceptable sait thereof in an amount effective to inhibit prolifération of the cells.

In another aspect, the invention provides methods for inducing cell apoptosis, comprising contacting cells with a compound described herein in an amount effective to induce apoptosis of the cells.

Contacting refers to bringing a compound or pharmaceutically acceptable sait of the invention and a cell expressing EZH2 together in such a manner that the compound may affect the activity of EZH2, either directly or indirectly. Contacting may be accomplished in vitro (i.e., in an artificiel environment such as, e.g., without limitation, in a test tube or culture medium) or in vivo (i.e., within a living organism such as, without limitation, a mouse, rat or rabbit.)

In some embodiments, the cells are in a cell line, such as a cancer cell line. In other embodiments, the cells are in a tissue or tumor, and the tissue or tumor may be in a subject, including a human.

Dosage Forms and Regimens

Administration of compounds of the invention may be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parentéral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.

Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parentéral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrète units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The spécification for the dosage unit forms of the invention may be dictated by and directly dépendent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inhérent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods wellknown in the therapeutic arts. That is, the maximum tolerable dose may be readily established, and the effective amount providing a détectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a détectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the présent invention.

It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is to be further understood that for any particular subject, spécifie dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamie parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the présent invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

The amount of the compound of the invention administered will be dépendent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discrétion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g/day, preferably about 0.1 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adéquate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. Formulations and Routes of Administration

As used herein, a pharmaceutically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the active compound.

The pharmaceutical acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. The choice of carrier and/or excipient will to a large extent dépend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvatés). The pharmaceutical compositions may, if desired, contain additional ingrédients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose dérivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnésium stéarate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Nonlimiting examples of materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or élixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, éthanol, propylene glycol, glycerin, or combinations thereof.

The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution or suspension, for parentéral injection as a stérile solution, suspension or émulsion, for topical administration as an ointment or cream, or for rectal administration as a supposîtory.

Exemplary parentéral administration forms include solutions or suspensions of an active compound in a stérile aqueous solution, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.

The pharmaceutical composition may be in unit dosage forms suitable for single administration of précisé amounts.

Pharmaceutical compositions suitable for the delivery of active agents and methods for their préparation will be readily apparent to those skilled in the art. Such compositions and methods for their préparation may be found, for example, in ‘Remington’s Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.

Compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and élixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, éthanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

Compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001), the disclosure of which is incorporated herein by reference in its entirety.

For tablet dosage forms, the active agent may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the active agent, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant may comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.

Binders are generally used to impart cohesive qualifies to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When présent, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.

Tablets also generally contain lubricants such as magnésium stéarate, calcium stéarate, zinc stéarate, sodium stearyl fumarate, and mixtures of magnésium stéarate with sodium lauryl sulphate. Lubricants generally are présent in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.

Other conventional ingrédients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.

Exemplary tablets may contain up to about 80 wt% active agent, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.

Tablet blends may be compressed directly or by roder to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.

The formulation of tablets is discussed in detail in “Pharmaceutical Dosage Forms: Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety.

Solid formulations for oral administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles may be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties.

Parentéral Administration

Compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internai organ. Suitable means for parentéral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parentéral administration include needle (including micro needle) injectors, needle-free injectors and infusion techniques.

Parentéral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a stérile non aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as stérile, pyrogen-free water.

The préparation of parentéral formulations under stérile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of the invention used in the préparation of parentéral solutions may potentially be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Formulations for parentéral administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may potentially be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.

The compounds of the invention may also potentially be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, minerai oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Pénétration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and micro needle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. The disclosures of these référencés are incorporated herein by référencé in their entireties.

Formulations for topical administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Compounds of the invention may also potentially be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aérosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurized container, pump, spray, atomizer, or nebulizer may contain a solution or suspension of the compound(s) of the invention comprising, for example, éthanol, aqueous éthanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the compound may be micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnésium stéarate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 pg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 pl_ to 10OpL. A typical formulation includes a compound of the invention, propylene glycol, stérile water, éthanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated to be immédiate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

In the case of dry powder inhalers and aérosols, the dosage unît is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or “puff” containing a desired mount of the compound of the invention. The overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day.

Compounds of the invention may potentially be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

Compounds of the invention may also potentially be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonie, pH-adjusted, stérile saline. Other formulations suitable for ocular and aurai administration may include ointments, biodégradable (e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular Systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.

Other Technologies

Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable dérivatives thereof or polyethylene glycolcontaining polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, may be useful for different dosage forms and administration routes. Both inclusion and non-inclusion complexes may potentially be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91/11172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by référencé in their entireties.

Dosage

The amount of the active compound administered will be dépendent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discrétion of the prescribing physician. However, an effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg/day, preferably about 0.7 to about 2500 mg/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adéquate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.

Kit-of-Parts

Inasmuch as it may désirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the présent invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

The kit of the invention may be particularly suitable for administering different dosage forms, for example, oral and parentéral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically includes directions for administration and may be provided with a memory aid.

Combination Therapy

As used herein, the term combination therapy” refers to the administration of a compound of the invention together with an at least one additional pharmaceutical or médicinal agent (e.g., an anti-cancer agent), either sequentially or simultaneously.

As noted above, the compounds of the invention may potentially be used in combination with one or more additional anti-cancer agents which are described below. When a combination therapy is used, the one or more additional anti-cancer agents may be administered sequentially or simultaneously with the compound of the invention. In one embodiment, the additional anti-cancer agent is administered to a mammal (e.g., a human) prior to administration of the compound of the invention. In another embodiment, the additional anti-cancer agent is administered to the mammal after administration of the compound of the invention. In another embodiment, the additional anti-cancer agent is administered to the mammal (e.g., a human) simultaneously with the administration of the compound of the invention.

The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of a compound of the invention, as defined above (including hydrates, solvatés and polymorphs of said compound or pharmaceutically acceptable salts thereof), in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of anti-angiogenesis agents and signal transduction inhibitors and a pharmaceutically acceptable carrier, wherein the amounts of the active agent and the combination anti-cancer agents when taken as a whole is therapeutically effective for treating said abnormal cell growth.

In one embodiment of the présent invention the anti-cancer agent used in conjunction with a compound of the invention and pharmaceutical compositions described herein is an anti-angiogenesis agent (e.g., an agent that stops tumors from developing new blood vessels). Examples of anti-angiogenesis agents include for example VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, ΡΚΟβ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v/beta-3), MMP-2 (matrix-metalloprotienase 2) inhibitors, and MMP-9 (matrix-metalloprotienase 9) inhibitors.

Preferred anti-angiogenesis agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU 14813 (Pfizef), and AG 13958 (Pfizer).

Additional anti-angiogenesis agents include vatalanib (CGP 79787), Sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE 941), tetrathiomolybdata (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer).

Other anti-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™) and UCN 01 (Kyowa Hakko).

Other examples of anti-angiogenesis agents which may be used in conjunction with a compound of the invention and pharmaceutical compositions described herein include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (Invedus), SC-58125 (Pharmacia) and etoricoxib (Arcoxia™).

Other anti-angiogenesis agents include exisulind (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™).

Other anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon).

Other anti-angiogenesis agents include acitretin (Neotigason™), plitidepsin (aplidine™), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4 RPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC 631570), Vitaxin™ (MEDI 522), and zoledronic acid (Zometa™).

In another embodiment the anti-cancer agent is a so called signal transduction inhibitor (e.g., inhibiting the means by which regulatory molécules that govern the fundamental processes of cell growth, différentiation, and survival communicated within the cell). Signal transduction inhibitors include small molécules, antibodies, and antisense molécules. Signal transduction inhibitors include for example kinase inhibitors (e.g., tyrosine kinase inhibitors or serine/threonine kinase inhibitors) and cell cycle inhibitors. More specifically signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors, inhibitors of the WNT pathway and so called multi-targeted kinase inhibitors.

Preferred signal transduction inhibitors include gefitinib (Iressa™), cetuximab (Erbitux™), erlotinib (Tarceva™), trastuzumab (Herceptin™), sunitinib (Sutent™), imatinib (Gleevec™), and PD325901 (Pfizer).

Additional examples of signal transduction inhibitors which may be used in conjunction with a compound of the invention and pharmaceutical compositions described herein include BMS 214662 (Bristol-Myers Squibb), lonafarnib (Sarasar™), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIM h-R3™), panitumumab (Vectibix™), Vandetanib (Zactima™), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer lngelheim),and Cervene™ (TP 38).

Other examples of signal transduction inhibitor include PF-2341066 (Pfizer), PF299804 (Pfizer), canertinib (Cl 1033), pertuzumab (Omnitarg™), Lapatinib (Tycerb™), pelitinib (EKB 569), miltefosine (Miltefosin™), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM 1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), lapatinib (Tycerb™), PF-299804 (Pfizer), pelitinib (EKB 569), and pertuzumab (Omnitarg™).

Other examples of signal transduction inhibitors include ARRY 142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Torisel™), AP 23573 (ARIAD), and VX 680 (Vertex).

Additionaily, other signal transduction inhibitors include XL 647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GI-4000 (Globelmmune).

Other signal transduction inhibitors include ABT 751 (Abbott), alvocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (Onc Bio), BMS 387032 (Bristol-Myers Squibb), PD 0332991 (Pfizer), and AG 024322 (Pfizer).

This invention contemplâtes the use of a compound of the invention together with classical antineoplastic agents. Classical antineoplastic agents include but are not limited to hormonal modulators such as hormonal, anti-hormonal, androgen agonist, androgen antagonist and anti-estrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, gene silencing agents or gene activating agents, ribonucleases, proteosomics, Topoisomerase I inhibitors, Camptothecin dérivatives, Topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor, microtubulin inhibitors, antibiotics, plant derived spindle inhibitors, platinum-coordinated compounds, gene therapeutic agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins

Examples of classical antineoplastic agents used in combination therapy with a compound of the invention, optionally with one or more other agents include, but are not limited to, glucocorticoïde, such as dexamethasone, prednisone, prednisolone, méthylprednisolone, hydrocortisone, and progestins such as medroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486), Sélective Estrogen Receptor Modulators (SERMs; such as tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane and CH F 4227 (Cheisi), Sélective Estrogen-Receptor Downregulators (SERD’s; such as fulvestrant), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), gonadotropin-releasing hormone (GnRH; also commonly referred to as luteinizing hormone-releasing hormone [LHRH]) agonists such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar), abarelix (Plenaxis), bicalutamide (Casodex), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandron), and osaterone, dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide, tamoxifen, exemestane, anastrozole, fadrozole, formestane, letrozole, and combinations thereof.

Other examples of classical antineoplastic agents used in combination with a compound of the invention include but are not limited to suberolanilide hydroxamic acid (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M777, MS-275, pivaloyloxymethyl butyrate and PXD-101; Onconase (ranpirnase),PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10hydroxycamptothecin, irinotecan HCl (Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 9aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan, aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds such as cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin, and combinations thereof.

The invention also contemplâtes the use of the a compound of the invention together with dihydrofolate reductase inhibitors (such as methotrexate and NeuTrexin (trimetresate glucuronate)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed), pyrimidine antagonists (such as 5-fluorouracil (5-FU), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine, Eli Lilly), Tegafur (UFT Orzel or Uforal and including TS-1 combination of tegafur, gimestat and otostat), doxifluridine, carmofur, cytarabine (including ocfosfate, phosphate stéarate, sustained release and liposomal forms), enocitabine, 5-azacitidine (Vidaza), decitabine, and ethynylcytidine) and other antimetabolites such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Thymitaq), triapine, trimetrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-Nmethylamino]-2-thenoyl)-L-glutamic acid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals) and GPI 18180 (Guilford Pharm Inc) and combinations thereof.

Other examples of classical antineoplastic cytotoxic agents used in combination therapy with a compound of the invention, optionally with one or more other agents include, but are not limited to, Abraxane (Abraxis BioScience, Inc.), Batabulin (Amgen), EPO 906 (Novartis), Vinflunine (Bristol- Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin), Vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxel (Taxotere), Ortataxel, paclitaxel (including Taxoprexin a DHA/paciltaxel conjugate), cisplatin, carboplatin, Nedaplatin, oxaliplatin (Eloxatin), Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin, Canfosfamide (Telcyta™), DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargase (Oncaspar™), Efaproxiral (Efaproxyn™ - radiation therapy), bexarotene (Targretin™), Tesmilifene (DPPE - enhances efficacy of cytotoxics), Theratope™ (Biomira), Tretinoin (Vesanoid™), tirapazamine (Trizaone™), motexafin gadolinium (Xcytrin™) Cotara™ (mAb), and NBI-3001 (Protox Therapeutics), polyglutamatepaclitaxel (Xyotax™) and combinations thereof.

Further examples of classical antineoplastic agents used in combination therapy with a compound of the invention, optionally with one or more other agents include, but are not limited to, as Advexin (ING 201 ), TNFerade (GeneVec, a compound which express TNFalpha in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT1027, Atorvastatin (Lipitor, Pfizer Inc.), Provastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mévacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and combinations thereof.

Another embodiment of the présent invention of particular interest relates to a method for the treatment of breast cancer in a human in need of such treatment, comprising administering to said human an amount of a compound of the invention, in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of trastuzumab, tamoxifen, docetaxel, paclitaxel, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole and anastrozole.

In one embodiment the invention provides a method of treating colorectal cancer in a mammal, such as a human, in need of such treatment, by administering an amount of a compound of the invention, in combination with one or more (preferably one to three) anti-cancer agents. Examples of particular anti-cancer agents include those typically used in adjuvant chemotherapy, such as FOLFOX, a combination of 5-fluorouracil (5-FU) or capecitabine (Xeloda), leucovorin and oxaliplatin (Eloxatin). Further examples of particular anti-cancer agents include those typically used in chemotherapy for metastatic disease, such as FOLFOX or FOLFOX in combination with bevacizumab (Avastin); and FOLFIRI, a combination of 5-FU or capecitabine, leucovorin and irinotecan (Camptosar). Further examples include 17-DMAG, ABX-EFR, AMG-706, AMT-2003, ANX-510 (CoFactor), aplidine (plitidepsin, Aplidin), Aroplatin, axitinib (AG-13736), AZD-0530, AZD2171, bacillus Calmette-Guerin (BCG), bevacizumab (Avastin), BIO-117, BIO-145, BMS184476, BMS-275183, BMS-528664, bortezomib (Velcade), C-1311 (Symadex), cantuzumab mertansine, capecitabine (Xeloda), cetuximab (Erbitux), clofarabine (Clofarex), CMD-193, combretastatin, Cotara, CT-2106, CV-247, decitabine (Dacogen), E-7070, E-7820, edotecarin, EMD-273066, enzastaurin (LY-317615)epothilone B (EPO906), erlotinib (Tarceva), flavopyridol, GCAN-101, gefitinib (Iressa), huA33, huC242-DM4, imatinib (Gleevec), indisulam, ING-1, irinotecan (CPT-11, Camptosar) ISIS 2503, ixabepilone, lapatinib (Tykerb), mapatumumab (HGS-ETR1), MBT-0206, MEDI-522 (Abregrin), Mitomycin, MK-0457 (VX-680), MLN-8054, NB-1011, NGR-TNF, NV-1020, oblimersen (Genasense, G3139), OncoVex, ONYX 015 (CI-1042), oxaliplatin (Eloxatin), panitumumab (ABX-EGF, Vectibix), pelitinib (EKB-569), pemetrexed (Alimta), PD325901, PF-0337210, PF-2341066, RAD-001 (Everolimus), RAV-12, Resveratrol, RexinG, S-1 (TS-1), seliciclib, SN-38 liposome, Sodium stibogluconate (SSG), sorafenib (Nexavar), SU-14813, sunitinib (Sutent), temsirolimus (CCI 779), tetrathiomolybdate, thalomide, TLK-286 (Telcyta), topotecan (Hycamtin), trabectedin (Yondelis), vatalanib (PTK-787), vorinostat (SAHA, Zolinza), WX-UK1, and ZYC300, wherein the amounts of the active agent together with the amounts of the combination anticancer agents are effective in treating colorectal cancer.

Another embodiment of the présent invention of particular interest relates to a method for the treatment of rénal cell carcinoma in a human in need of such treatment, comprising administering to said human an amount of a compound of the invention, in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of axitinib (AG 13736), capecitabine (Xeloda), interferon alpha, interleukin-2, bevacizumab (Avastin), gemcitabine (Gemzar), thalidomide, cetuximab (Erbitux), vatalanib (PTK-787), sunitinib (Sutent™), AG-13736, SU-11248, Tarceva, Iressa, Lapatinib and Gleevec, wherein the amounts of the active agent together with the amounts of the combination anticancer agents is effective in treating rénal cell carcinoma.

Another embodiment of the présent invention of particular interest relates to a method for the treatment of melanoma in a human in need of such treatment, comprising administering to said human an amount of a compound of the invention, in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of interferon alpha, interleukin-2, temozolomide (Temodar), docetaxel (Taxotere), paclitaxel, Dacarbazine (DTIC), carmustine (also known as BCNU), Cisplatin, Vinblastine, tamoxifen, PD-325,901, axitinib (AG 13736), bevacizumab (Avastin), thalidomide, sorafanib, vatalanib (PTK-787), sunitinib (Sutent™), CpG-7909, AG-13736, Iressa, Lapatinib and Gleevec, wherein the amounts of the active agent together with the amounts of the combination anticancer agents is effective in treating melanoma.

Another embodiment of the présent invention of particular interest relates to a method for the treatment of lung cancer in a human in need of such treatment, comprising administering to said human an amount of a compound of the invention, in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of capecitabine (Xeloda), axitinib (AG 13736), bevacizumab (Avastin), gemcitabine (Gemzar), docetaxel (Taxotere), paclitaxel, premetrexed disodium (Alimta), Tarceva, Iressa, Vinorelbine, Irinotecan, Etoposide, Vinblastine, sunitinib (Sutent™), and Paraplatin (carboplatin), wherein the amounts of the active agent together with the amounts of the combination anticancer agents is effective in treating lung cancer.

Synthetic Methods

Compounds of the invention may be prepared according to the exemplary procedures provided herein and modifications thereof known to those of skill in the art. In addition, synthetic routes for the formation of various compounds useful as staring materials for the préparation of the compounds claimed herein are described in International Application No. PCT/IB2013/060682, the content of which is incorporated by reference herein in its entirely.

These and other methods are exemplified in the préparation of the examples provided herein. It will be understood by those of skill in the art that the sélection of starting materials and the particular order of the steps, including, e.g., formation of the lactam ring, installation or manipulation of various substituent groups on the fused lactam or its precursors, and installation of the pyridinone moiety, may be varied by sélection of a suitable synthetic strategy.

Synthetic examples are provided throughout the Examples and in Table 1 below. EZH2 IC50 values (μΜ) for WT EZH2 and Mutant Y641N EZH2 are provided in Table 2 for exemplary compounds of the invention.

The following abbreviations are used throughout the Examples: “Ac” means acetyl, AcO or “OAc means acetoxy, “AC2O” means acetic anhydride, ‘'ACN” or MeCN” means acetonitrile, “AIBN” means azobisisobutyronitrile, BOC”, “Boc” or “boc” means N-tertbutoxycarbonyl, “Brï¹ means benzyl, “BPO” means dibenzoyl peroxide, “Bu” means butyl, “iBu means isobutyl, sBu” means sec-butyl, “tBu” means tert-butyl, “tBuOK” or “KOtBu means potassium tert-butoxide, “CDI” means carbonyldiimidazole, “DCE” means 1,2dichloroethane, DCM” (CH2CI2) means methylene chloride, “DEAD means diethyl azodicarboxylate, “DIAD” means diisopropyl azodicarboxylate, “DIPEA” or “DIEA” means diisopropyl ethyl amine, “DBU” means 1,8-diazabicyclo[5.4.0]undec-7-ene, DIBAL-H” means diisobutylaluminum hydride, “DMA” means Ν,Ν-dimethylacetamide, “DMAP means 4-dimethylaminopyridine, “DME means dimethoxyethane, DMF means N-N dimethyf formamide, DMS means dimethylsulfide, DMSO means dimethylsulfoxide, “dppf” means (diphenylphosphino)ferrocene, DPPP” means 1,3bis(diphenylphosphino)propane, “Et” means ethyl, “EtOAc¹’ means ethyl acetate, “EtOH means éthanol, HATU” means 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3tetramethyluronium hexafluorophosphate, “HOAc or AcOH means acetlc acid, “i-Pr” or “’Pr” means isopropyl, ΊΡΑ” means isopropyl alcohol, KHMDS” means potassium hexamethyldisilazide (potassium bis(trimethylsilyl)amide), “LiHMDS” means lithium hexamethyldisilazide (lithium bis(trimethylsilyl)amide), “mCPBA” means metachloroperoxy-benzoic acid, “Me means methyl, “MeOH means methanol, Ms” means methanesulfonate (commonly called ‘mesylate’), MTBE means methyl t-butyl ether, “NBS” means N-bromosuccinimide, NCS” means N-chlorosuccinimide, “NIS” means Niodosuccinimide, “NMM” means N-methylmorpholine, “NMP” means 1-methyl 2pyrrolidinone, Ph means phenyl, “RuPhos” means 2-Dicyclohexylphosphino-2',6'diisopropoxybiphenyl, “Selectfluor” means Chloromethyl-4-fluoro-1,4diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), “TEA” means triethylamine, TFA” means trifluoroacetic acid, Tf means trifluoromethanesulfonate (commonly called ‘triflate’), “THF” means tetrahydrofuran, “TMS” means trimethylsilyl, “TMSA” means trimethylsilylazide, TsCÎ” means toluenesulfonyl chloride (commonly called ‘tosylate’), “SFC” means supercritical fluid chromatography, “TLC” means thin layer chromatography, Rf” means rétention fraction, means approximately, rt means room température, “h” means hours, “min” means minutes, “eq.” means équivalents.

Préparation of Synthetic Inter médiates

Compound D: 2-(benzvloxv)-3-(chloromethvl)-4,6-dimethvlpyridine

NaBH<

MeOH

To a solution of 2-hydroxy-4,6-dimethylpyridine-3-carbonitrile (85.0 g, 0.574 mol) and benzyl chloride (87.0 g, 0.688 mol) in toluene (800 mL) was added Ag2Ü (146 g, 0.631 mol). The reaction mixture was stirred at 110 °C overnight. The reaction mixture was filtered through CELITE® and the solids washed with dichloromethane. The filtrate was concentrated under vacuum and purified by column chromatography (petroleum ether/ethyl acetate) to give 2-(benzyloxy)-4,6-dimethylpyridine-3-carbonitrile (Cpd A, 89 g, 65%) as a white solid.

44.5 g X 2 batches: To a stirred solution of 2-(benzyloxy)-4,6-dimethylpyridine-3carbonitrile (Cpd A, 44.5 g, 187 mmol) in dichloromethane (500 mL) was added drop wise DIBAL-H (224 mL, 224 mmol, 1M in toluene) at 0 - 5 °C. The reaction mixture was allowed to warm to room température and stirred for an additional 3 hours. The mixture was quenched with 1N HCl (200 mL) and was stirred vigorously for 30 minutes. The reaction mixture was neutralized with 4N NaOH (20 mL) and the biphasic mixture was filtered and washed with dichloromethane (500 mL). The aqueous layer was extracted with dichloromethane (200 mL), the combined organic layers were dried over sodium sulfate, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc) to give 2-(benzyloxy)-4,6-dimethylpyridine-3-carbaldehyde (Cpd B, 70 g, 78%) as a yellow solid.

g X 2 batches: To a 0 °C solution of 2-(benzyloxy)-4,6-dimethylpyridine-3carbaldehyde (Cpd B, 35.0 g, 145 mmol) in methanol (1000 mL) was added sodium borohydride (6.60 g, 174 mmol) in portions. The reaction mixture was stirred at room température for 2 hours. The reaction mixture was concentrated under vacuum and the residue was diluted with NaHCO₃ (sat., aq.). Afterthe bubbling had stopped, the aqueous solution was extracted with ethyl acetate (2 x 500 mL). The combined organic layers were dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (petroleum ether/ethyl acetate) to give [2-(benzyloxy)-4,6dimethylpyridin-3-yl]methanol (Cpd C, 43 g, 61%) as a colorless oil.

21.5 g x 2 batches: To a solution of [2-(benzyloxy)-4,6-dimethylpyridin-3yljmethanol (Cpd C, 21,5 g, 88.5 mmol) in anhydrous dichloromethane (400 mL) was 5 added thionyl chloride (16.0 g, 133 mmol) at -40 °C under N₂. The mixture was stirred at -40 °C for 30 minutes. The reaction mixture was poured into ice-water (300 mL) and adjusted to pH 7~8 with NaHCO3 (solid). The mixture was separated and the aqueous layer was extracted with dichloromethane (300 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, and concentrated under vacuum.

The residue was purified by column chromatography (petroleum ether/ethyl acetate, 100:1) to give 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd D, 27.5 g, 60%) as a white solid. ¹H NMR (400 MHz, CDCI3) 6 7.51-7.49 (d, 2H), 7.41-7.37 (t, 2H), 7.347.30 (t, 1 H), 6.62 (s, 1 H), 5.45 (s, 2H), 4.73 (s, 2H), 2.42 (s, 3H), 2.37 (s, 3H). MS: 261.9 [M+H]⁺.

Compound L: 2-(benzyloxv)-3-(chloromethvl)-4-(difluoromethoxv)-6-methvlpvridine

1) NC CN NaH.THF	^0H
2) 4M HCl	H
	Cpd E

POCI₃,PCI₅	Cl Λ		BnCI
chci₃	H Cpd F	O	Ag₂O,Toluene

Cpd G

Cpd H

	F
CIF₂CCO₂Na	F^O l
DMF	fS
		OBn

Cpd I

DIBAL-H

DCM

To a cooled (-10 °C) suspension of sodium hydride (60 wt% dispersion in minerai oil, 59.9 g, 1500 mmol) in dry tetrahydrofuran (1200 mL) was added solution of malononitrile (100 g, 1190 mmol) in dry tetrahydrofuran (30 mL) dropwise, slowly enough to maintain the internai température below 5 °C. After the addition was complété, the mixture was stirred at 0 °C for 1.5 hours, then diketene (80.1 g, 1190 mmol) was added dropwise, slowly enough to maintain the internai température below 0 °C. The mixture was stirred at -10 °C for 1.5 hours, then neutralized with 4N aq. HCl, and concentrated to remove volatiles. The remaining suspension in 4N aq. HCl (2000 ml_) was stirred at reflux for 5 hours, then stirred at room température overnight. The resulting white precipitate was collected by suction filtration. The fiîter cake was washed sequentially with water (500 ml_), éthanol (500 mL) and MTBE (300 mL). The solid was dried to obtain 4-hydroxy-6methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (Cpd E, 108 g, 60.3%) as a yellow powder. ¹H NMR (400 MHz, DMSO-d6) δ 12.40 (br. s., 1H), 11.72 (br. s„ 1H), 5.82 (s, 1H), 2.17 (s, 3H).

A suspension of 4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (Cpd

E, 91 g, 610 mmol), phosphorus oxychloride (195 g, 1270 mmol) and phosphorus pentachloride (265 g, 1270 mmol) in chloroform (1200 mL) was heated at reflux for 5 hours, resulting in a red homogeneous mixture. The mixture was poured into water (2000 mL) carefully with stirring, then neutralized by ammonium hydroxide (28% aqueous). The resulting solid precipitate was filtered off, washed sequential with dichloromethane (400 mL) and éthanol (500 mL), and dried to give 4-chloro-6-methyl-2-oxo-1,2-dihydropyridine3-carbonitrile (Cpd F, 78 g, 76%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 12.43 (br. s., 1H), 6.53 (s, 1H), 2.28 (s, 3H).

A suspension of 4-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (Cpd

F, 90 g, 530 mmol), silver(l) oxide (136 g, 587 mmol) and benzyl chloride (81.1 g, 641 mmol) in anhydrous toluene (1500 mL) was heated at reflux for 12 hours. The mixture was filtered through a CELITE® pad and the filter cake washed with dichloromethane (500 mLJ.The filtrate was concentrated to give a residue (-100 g), which was purified by column chromatography (silica gel, petroleum ether/EtOAc= 50:1-30:1), affording 2(benzyloxy)-4-chloro-6-methylnicotinonitrile (Cpd G, 70 g, 51%) as a light yellow solid. ¹H NMR (400 MHz, CDCI3) δ 7.49-7.47 (m, 2H), 7.40-7.33 (m, 3H), 6.91 (s, 1 H), 5.05 (s, 2H), 2.50 (s, 3H).

To a stirred solution of 2-(benzyloxy)-4-chloro-6-methylnicotinonitrile (Cpd G, 70 g, 270.58 mmol) in N,N-dimethylformamide (300 mL) was added césium acetate (156.0 g, 812 mmol) at room température. The resulting mixture was stirred at 80 °C for 40 hours. The mixture was diluted with ethyl acetate (500 mL) and washed with brine (3 x 400 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to give a residue (—50 g), which was purified by column chromatography (silica gel, petroleum ether/EtOAc=10:1~3:1) to give 2-(benzyloxy)-4-hydroxy-6-methylnicotinonitrile (Cpd H, 31 g, 48%) as a light yellow solid. Ή NMR (400 MHz, DMSO-d6) δ 12.28 (br. s., 1 H), 7.51-6.98 (m, 5H), 6.50 (s, 1 H), 5.41 (s, 2H), 2.34 (s, 3H). MS 226.8 [M+Na]⁺.

To a suspension of 2-(benzyloxy)-4-hydroxy-6-methylnicotinonitrile (Cpd H, 20.0 g, 83 mmol) and sodium chlorodifluoroacetate (25.4 g, 166 mmol) in N,Ndîmethylformamide (200 ml_) was added potassium carbonate (34.5 g, 250 mmol) at room température. The resulting mixture was heated to 100 °C for 10 minutes. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with sat. aq. NH4CI (3 x 400 mL), and brine (3 x 400 mL). The aqueous layer was back-extracted with ethyl acetate (400 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a residue (18 g), which was purified by column chromatography (silica gel, petroleum ether/EtOAc= 50:1-20:1) to give 2-(benzyloxy)-4-(difluoromethoxy)6-methylnicotinonitrile (Cpd I, 16.3 g, 67%) as light yellow solid. ¹H NMR (400 MHz, CDCI3) S 7.49-7.46 (m, 2H), 7.40-7.33 (m, 3H), 6.69 (t, J=71 Hz, 1H), 6.67 (s, 1H), 5.51 (s, 2H), 2.52 (s, 3H).

To a solution of 2-(benzyloxy)-4-(difluoromethoxy)-6-methylnicotinonitrile (Cpd I, 11 g, 38 mmol) in dry dichloromethane (250 mL) under nitrogen was added diisobutylaluminium hydride (1.0 M in toluene, 72 mL, 72 mmol) dropwise at 0 °C. After the addition was complété, the mixture was stirred at room température for 2.5 hours. The mixture was acidified to pH - 5 with 1M aq. HCl. After stirring at room température for 2 hours, the mixture was neutralized with 4.0 M aq. NaOH. The mixture was filtered off through a CELITE® pad and the filter cake was washed with dichloromethane (300 mL). The filtrate was extracted with dichloromethane (2 x 500 mL). The combined organic layers were washed with brine (800 mL), dried over sodium sulfate, and concentrated to give a residue (13.4 g), which was purified by column chromatography (silica gel, petroleum ether/ EtOAc= 30:1-10:1) to give 2-(benzyloxy)-4-(difluoromethoxy)-6methylnicotinaldehyde (Cpd J, 6 g, 50%) as a light yellow solid. ¹H NMR (400 MHz, CDCI3) δ 10.40 (s, 1H), 7.49-7.48 (m, 2H), 7.40-7.31 (m, 3H), 6.68 (t, J=72 Hz, 1H), 6.62 (s, 1H), 5.53 (s, 2H), 2.50 (s, 3H).

To a solution of 2-(benzyloxy)-4-(difluoromethoxy)-6-methylnicotinaldehyde (Cpd J, 12 g, 41 mmol) in methanol (120 mL) was added sodium borohydride (1.86 g, 49.16 mmol) portion-wise at 0 °C. After the addition was complété, the mixture was stirred at room température for 2 hours. The reaction was quenched with sat. aq. NH4CI (50 mL), then diluted with ethyl acetate (500 mL) and water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate and concentrated to give a residue (-13.1 g), which was purified by column chromatography (silica gel, petroleum ether: EtOAc =6:1) to give (2(benzyloxy)-4-(difluoromethoxy)-6-methylpyridin-3-yl)methanol (Cpd K, 11.7 g, 97%) as a white solid. Ή NMR (400 MHz, CDCI3) δ 7.52-7.46 (m, 2H), 7.44-7.33 (m, 3H), 6.60 (t, J=73 Hz, 1H), 6.55 (s, 1H), 5.46 (s, 2H), 2.46 (s, 3H).

To a solution of (2-(benzyloxy)-4-(difluoromethoxy)-6-methylpyridin-3-yl)methanol (Cpd K, 7.6 g, 26 mmol) in anhydrous dichloromethane (120 mL) was added thionyl chloride (3.67 g, 30.9 mmol) dropwise at -20 °C. The mixture was stirred at -20 °C for 1 hour, then poured into water (50 mL), and neutralized with saturated aq. NaHCO3. The aqueous phase was extracted with dichloromethane (2 x 90 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to give a residue (~6.1 g), which was purified by silica gel chromatography (petroleum ether/EtOAc=6:1) to give the title compound, 2-(benzyloxy)-3-(chloromethyl)-4-(difluoromethoxy)-6-methylpyridine (Cpd L, 5.7 g, 71%) as a white solid. ¹H NMR (400 MHz, CDCI3) δ 7.50 (d, J = 7.2, 2H), 7.41-7.33 (m, 3H), 6.64 (t, J=73 Hz, 1 H),.6.56 (s, 1H), 5.48 (s, 2H), 4.69 (s, 2H), 2.47 (s, 3H). MS: 314 [M+H]⁺.

Compound S: 2-fr2-(benzvloxv)-4,6-dimethvlpvridin-3-vl1methyl}-7-bromo-5,8-dichloro-

3,4-dihydroisoquinolin-1 (2H)-one.

NaCN

DMSO/HoO

DMF

CoCI₂ 6H₂O NaBH<

EtOH

A mixture of 3-chloro-2-methylbenzoic acid (100 g, 0.58 mol), N-chlorosuccinimide (90 g, 0.67 mol) and palladium (II) acetate (14.7 g, 65.7 mmol) in N,N-dimethylformamide (1 L) was stirred at 110 °C under a nitrogen atmosphère overnight. After cooling to room température, césium carbonate (378 g, 1.16 mol) and iodoethane (317 g, 2.03 mol) were added and stirring continued at room température for 1.5 hours. The reaction mixture was poured into a mixture of water (1 L) and methyl tert-butyl ether (800 mL). Solids were removed by filtration, and the filtrate layers separated. The aqueous layer was extracted with more methyl tert-butyl ether (600 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (1.2 L), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 50:1 petroleum ether/ethyl acetate), affording ethyl 3,6-dichloro-2-methylbenzoate (Cpd N, 110 g, ~ 80% pure, 80% yield) as a yellow oil.

A solution of ethyl 3,6-dichloro-2-methylbenzoate (Cpd N, 120 g, 0.52 mol) and Nbromosuccinimide (147 g, 0.82 mol) in chloroform (1 L) was treated with azobisisobutyronitrile (25.3 g, 0.15 mol) and the mixture refluxed overnight. After cooling to room température, the mixture was diluted with dichloromethane (800 mL) and washed with water (1.2 L). The aqueous layer was extracted with dichloromethane (800 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (1.5 L), dried over sodium sulfate, and concentrated in vacuo to give ethyl 2 (bromomethyl)-3,6-dichlorobenzoate (Cpd 0,160 g, 100% yield) which was used without further purification.

A solution of sodium cyanide (75.12 g, 1.53 mol) in water (300 ml_) was added dropwise to a solution of ethyl 2-(bromomethyl)-3,6-dichlorobenzoate (Cpd 0,320 g, 1.03 mol) in dimethysulfoxide (2.4 L) at room température. The mixture was stirred at room température for 1.5 hours. The reaction mixture was poured into a mixture of water (4 L) and methyl tert-butyl ether (2 L), and the layers separated. The organic layer was washed with water (2L) and with saturated aqueous sodium chloride solution (2 L), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 30:1 petroleum ether/ethyl acetate), affording ethyl 3,6dichloro-2-(cyanomethyl)benzoate (Cpd P, 150 g, -75% pure, 47% yield) as a yellow oil.

Cobalt (II) chloride hexahydrate (166 g, 0.70 mol) was added to a room température solution of ethyl 3,6-dichloro-2-(cyanomethyl)benzoate (Cpd P, 90 g, 0.35mol) in éthanol (1.5 L), and the resulting mixture cooled to 0 °C. Sodium borohydride (66.3 g, 1.74 mol) was added in portions. The mixture was stirred at room température for 1 hour, and then refluxed overnight. The resulting suspension was filtered and the filtrate concentrated in vacuo. The solids in the filter cake were stirred in ethyl acetate (600 mL), and then filtered again. This procedure was repeated a second time. The combined filtrâtes were added to the original filtrate residue, and this organic solution washed with water (800 mL) and saturated aqueous sodium chloride solution (800 mL), dried over sodium sulfate, and concentrated in vacuo to give 5,8-dichloro-3,4-dihydroisoquinolin1 (2A7)-one (Cpd Q, 29.3 g, 39% yield) as an off-white solid.

To a solution of 5,8-dichloro-3,4-dihydroisoquinolin-1(2/-/)-one (Cpd Q, 40 g, 0.186 mol) in concentrated sulfuric acid (200 mL) at 60°C was added N-bromosuccinimide (49.7 g, 0.279 mol) in portions. Stirring was continued at 60 °C for 2 hours, then more Nbromosuccinimide (5 g. 28 mmol) was added. After stirring at 60 °C for 1 hour more, the mixture was poured onto ice water (500 mL), then extracted with dichloromethane (3 x 500 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (800 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was stirred in ethyl acetate (40 mL) and petroleum ether (20 mL), and the resulting solids collected by filtration and dried under vacuum to give 7-bromo-5,8-dichloro-3,4dihydroisoquinolin-1 (2/7)-one (Cpd R, 41 g, 75% yield) as an off-white solid.

Potassium te/t-butoxide solution in tetrahydrofuran (1.0 M, 190 mL, 0.19 mol) was added dropwise to a cooled (0 °C) solution of 7-bromo-5,8-dichloro-3,4 dihydroisoquinolin-1 (2W)-one (Cpd R, 47 g, 0.16 mol) in anhydrous N,Ndimethylformamide (500 mL) under a nitrogen atmosphère. Stirring was continued at 0 °C for 5 minutes, then 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd D, 40.2 g, 0.15 mol) was added in one portion. After stirring for 10 minutes at 0 °C, the mixture was treated with concentrated acetic acid (2 mL) and poured into methyl terf-butyl ether (600 mL). The organic solution was washed with water (800 mL) and saturated aqueous sodium chloride solution (800 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 30:1 to 20:1 petroleum ether/ethyl acetate), affording 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (Cpd S, 50 g, 64% yield) as an offwhite solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.45-7.43 (m, 2H), 7.32-7.29 (m, 3H), 6.76 (s, 1 H), 5.38 (s, 2H), 4.71 (s, 2H), 3.24 (t, J = 6 Hz, 2H), 2.72 (t, J = 6 Hz, 2H), 2.36 (s, 3H), 2.31 (s, 3H). MS: 521 [M+H]⁺.

Compound T: Methyl 2-(2-((2-(benzvloxv)-4,6-dimethvlpyridin-3-vl)methyl)-5.8-dichloro-

-oxo-1.2.3,4-tetrahydroisoquinolin-7-vl)acetate.

A mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-bromo-5,8dichloro-3,4-dihydroisoquinolin-1(2/-/)-one (Cpd S, 1.0 g, 1.9222 mmol), 1-(tertbutyldimethylsilyloxy)-1-methoxyethene (1.09 g, 5.77 mmol), bis(tri-fertbutylphosphine)palladium(O) (98.2 mg, 0.192 mmol) and lithium fluoride (299 mg, 11.5 mmol) in dry N,N-dimethylformamide (18 mL) was degassed with nitrogen for 10 minutes. Then the mixture was heated in a microwave reactor at 100 °C for 3 hours. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with brine (4 x 50 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether/EtOAc = 3:1, Rf ~ 0.45) to give methyl 2-(2-((2(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4tetrahydroisoquinolin-7-yl)acetate (Cpd T, 600 mg, 60.8%) as a light yellow solid. ¹H NMR (400 MHz, CDCI3) Ô 7.45 (d, J = 6.8 Hz, 2H), 7.37-7.30 (m, 4H), 6.62 (s, 1 H), 5.42 (s, 2H),

4.87 (s, 2H), 3.80 (s, 2H), 3.72 (s, 3H), 3.28 (t, J = 6.4 Hz, 2H), 2.73 (t, J = 6.4 Hz, 2H),

2.42 (s, 3H), 2.32 (s, 3H). MS: 535.0 [M+Na]⁺.

Compound U: Methyl 2-(2-((2-(benzvloxv)-4,6-dimethy|pvridin-3-yl)methvl)-5.8-dichloro-

-oxo-1.2.3,4-tetrahydroisoquinolin-7-vl)-2-diazoacetate

Cpd T

DBU

MeCN

OBn

To a solution of methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)acetate (500 mg, 0.974 mmol) and 4acetyl aminobenzenesulfonyl azide (281 mg, 1.17 mmol) in anhydrous acetonitrile (8 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL, 1.47 mmol). The resulting reaction mixture was stirred at room température for 3 h. After removing solvent, the resulting residue was purified by a silica gel column with a gradient elution of 0->40%EtOAc/heptane to afford methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolÎn-7-yl)-2-diazoacetate as a foam like solid (Cpd U, 454 mg, 86%yield). LCMS: 511.10/512.10 (M - Na). ¹H NMR (400 MHz, CDCI3) Ô 7.64 (s, 1H), 7.44 (d, J=6.60 Hz, 2H), 7.29 - 7.39 (m, 3H), 6.63 (s, 1H), 5.47 (s, 2H), 4.89 (s, 2H), 3.86 (s, 3H), 3.30 (t, J=5.99 Hz, 2H), 2.74 - 2.86 (m, 2H), 2.43 (s, 3H), 2.36 (s, 3H).

Compound W: Methyl 2-(2-((2-(benzvloxv)-4-(difluoromethoxv)-6-methvlpyridin-3vl)meÎhvl)-5,8-dichloro-1-oxo-1,2,3,4-tetrahvdroisoquinolin-7-vl)acetate

Cl O	Cl OBn \| \|		Cl T	O II	OBn I
	₊ V4	KOtBu ^ΒΓχ	A		^AN
UU		DMF
T Cl	F^F		Cl	F^F
Cpd R	Cpd L			Cpd V

Pd[P(t-Bu)₃J₂

LiF

DMF

Cpd W

Potassium tert-butoxide solution in tetrahydrofuran (1.0 M, 3.2 mL, 3.2 mmol) was added dropwise to a cooled (0 °C) solution of 7-bromo-5,8-dichloro-3,4dihydroisoquinolin-1 (2H)-one (Cpd R, 750 mg, 2.54 mmol) in dry Ν,Ν-dimethylformamide (15 mL). The mixture was stirred at 0 °C for 15 minutes, and then a solution of 2(benzyloxy)-3-(chloromethyl)-4-(difluoromethoxy)-6-methylpyridine (Cpd L, 798 mg, 2.54 mmol) in dry Ν,Ν-dimethylformamide (5 mL) was added dropwise. After stirring at 0 °C for 30 minutes, the solution was quenched with water (30 mL) and extracted with ethyl acetate (3x15 mL). The combined organic layers were washed sequentially with water (2 x 20 mL) and brine (20 mL), dried over sodium sulfate, filtered, concentrated, and was purified by column chromatography (silica gel, petroleum ether/EtOAc=7:1) to give 2-((2(benzyloxy)-4-(difluoromethoxy)-6-methylpyridin-3-yl)methyl)-7-bromo-5,8-dichloro-3,4dihydroisoquinolin-1(2H)-one (Cpd V, 0.97 g, 67%) as a light-yellow solid.

A mixture of 2-((2-(benzyloxy)-4-(difluoromethoxy)-6-methylpyridin-3-yl)methyl)-7bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (Cpd V, 500 mg, 0.874 mmol), 1(tert-butyldimethylsilyloxy)-l-methoxyethene (494 mg, 2.62 mmol), bis(tri-tertbutylphosphine)palladium(O) (67 mg, 0.313 mmol) and lithium fluoride (136 mg, 5.24 mmol) in dry Ν,Ν-dimethylformamide (15 mL) was degassed with nitrogen for 10 minutes., then heated to 100 °C in a microwave reactor for 3 hours. After cooling, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (4 x 20 mL). The combined organic layers were washed with water (3 x 15 mL) and brine (15 mL), dried and concentrated. The residue was purified by prep. TLC (silica gel, petroleum ether/EtOAc=2:1, Rf~0.35) to give methyl 2-(2-((2-(benzyloxy)-4-(difluoromethoxy)-6methylpyridin-3-yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)acetate (Cpd W, 175mg, 35.4%) as a white solid. ¹H NMR (400 MHz, CDCI3) δ 7.42-7.41 (m, 2H), 7.37 (s, 1H), 7.29-7.27 (m, 3H), 6.66 (t, J=72 Hz, 1H), 6.62 (s, 1H), 5.45 (s, 2H), 4.82 (s, 2H), 3.80 (s, 2H), 3.72 (s, 3H), 3.26 (t, J = 6.0 Hz, 2H), 2.73 (t, J = 6.4 Hz, 2H), 2.46 (s, 3H).

Compound Z: 2-f(2-(benzvloxv)-4,6-dimethvlpyridin-3-vl)methyl)-7-bromo-8-chloro-3.4dihydro-isoquinolin-1 (2H)-one.

O

CpdX

Cpd D

KOiBu DMF

A solution of 7-amino-3,4-dihydroisoquinolin-1 (2H)-one (1.01 g, 6.23 mmol) and Nchlorosuccinimide (832 mg, 6.23 mmol) in N,N-dimethylformamide (10 mL) was and heated to 55 °C for 5 hours. The mixture was poured into water and extracted with ethyl acetate (3 x). The combined ethyl acetate layers were concentrated, and residual DMF was removed on high vacuum ovemight. The resulting dark oil was purified on silica gel (Biotage SNAP, 50g, gradient of 50-100% ethyl acetate in heptanes) to give 7-amino-8chloro-3,4-dihydroisoquinolin-1(2H)-one (Cpd X, 0.539g, 44%) as a white solid. ¹H NMR (400 MHz, DMSO-de) δ 7.87 (br. s., 1 H), 6.96 (d, J=8.19Hz, 1H), 6.87 (d, J=8.19 Hz, 1 H), 5.32 (s, 2H), 3.20 (dt, J=3.79, 6.17 Hz, 2H), 2.69 (t, J=6.24 Hz, 2H); MS 197 [M+H]⁺.

A suspension of copper(l)bromide (1.04 g, 7.28 mmol) in acetonitrile (20 mL) was stirred at 60 °C for 10 minutes. Isoamyl nitrite (0.348 mL, 2.91 mmol) was added, followed by 7-amino-8-chloro-3,4-dihydroisoquinolin-1 (2H)-one (Cpd X, 0.477 g, 2.43 mmol) in one portion. The reaction mixture was stirred at 60 °C for 1 hour. After cooling to room température, saturated aq. NH4CI and EtOAc were added to the solution, and the biphasic mixture stirred vigorously for 20 minutes. The layers were separated, the organic layer concentrated, and the residue was purified on silica gel (Biotage SNAP, 10g, HP-Sil, gradient of 40-100% ethyl acetate in heptane) to give 7-bromo-8-chloro-3,418538 dihydroisoquinolin-1 (2H)-one (Cpd Y, 0.287 g, 45%) as a yellow solid. ¹H NMR (400 MHz, CDCI3) δ 7.70 (d, J=8.07 Hz, 1 H), 7.03 (d, J=8.07 Hz, 1 H), 6.14 (br. s., 1 H), 3.43-3.57 (m, 2H), 2.95 (t, J=6.36 Hz, 2H); MS 260, 262 [M+H]⁺.

Potassium t-butoxide (1.3 mL, 1.3 mmol, 1.0 M in THF) was added to a cooled (0 °C) solution of 7-bromo-8-chloro-3,4-dihydroisoquinolin-1(2H)-one (Cpd Y, 0.287 g, 1.10 mmol) in N,N-dimethylformamide (10 mL). After 5 minutes, 2-(benzyloxy)-3(chloromethyl)-4,6-dimethylpyridine (Cpd D 0.311 g, 1.19 mmol) was added in one portion. The mixture was stirred for 30 minutes, then quenched with acetic acid (3 drops), diluted with MTBE, and washed with water (2 x). The organic layer was concentrated, and the resulting oil purified on silica gel (Biotage SNAP, 10g, gradient of 0-25% ethyl acetate in heptane) to 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-7-bromo-8-chioro-3,4dihydroisoquinolin-1 (2H)-one (Cpd Z, 0.387 g, 72%) as a clear gum. ¹H NMR (400 MHz, CDCI3) δ 7.61 (d, J=8.07 Hz, 1H), 7.42-7.47 (m, 2H), 7.28-7.38 (m, 3H), 6.89 (d, J=8.07 Hz, 1H), 6.63 (s, 1H), 5.43 (s, 2H), 4.90 (s, 2H), 3.22-3.29 (m, 2H), 2.60-2.66 (m, 2H),

2.42 (s, 3H), 2.34 (s, 3H); MS 485, 487 [M+Hj*.

Compound FF: 2-((2-(benzvioxv)-4,6-dimeÎhvlpyridin-3-vl)methyl)-5-bromo-8-chloro-7iodo-3,4-dihvdroisoquinolin-1(2H)-one.

Cpd cc

Cpd DD

NajCOg nh₂ ----------1,2-DCE

OBn

DMF

Br

Cpd FF

Two batches were run in parallel under the following conditions, then combined for workup and purification: To a room température (15-20 °C) solution of 2-(2-bromo-5 chlorophenyl)acetic acid (25.0 g, 100.2 mmol) in anhydrous THF (300 mL) was added oxalyl chloride (14.5 g, 9.97 mL, 114 mmol) and DMF (150 mg, 2.05 mmol), initiating gas évolution. The mixture was stirred at room température for two hours, until TLC showed the starting acid was completely consumed. The mixture was cooled to 0 °C, and ammonium hydroxide (28 wt% in water, 154 mL) was added in one portion, causing the internai température to rise to 40°C. The cooling bath was removed, and the solution stirred vigorously at room température for one hour. The two batches were combined, diluted with water (500 mL), and extracted with ethyl acetate (2 x 1000 mL). The combined organic extracts were washed with water (2 x 500 mL), 1N aqueous HCl (500 mL), and brine (500 mL), then dried over anhydrous sodium sulfate and concentrated to give crude product (-50 g) as a yellow solid. The crude product was crystallized from 5/1 petroleum ether/ethyl acetate (200 mL x2) and dried to give 2-(2-bromo-5-chlorophenyl)acetamide (Cpd AA, 44.0 g, 88% combined yield for the two batches) as a white solid. ¹H NMR (400 MHz, CDCI3) δ 7.52 (d, J= 8.8 Hz, 1H), 7.37 (d, J=2.8 Hz, 1H), 7.16 (dd, J= 2.8, 8.8 Hz, 1 H), 5.67 (br s, 1 H), 5.50 (br s, 1 H), 3.70 (s, 2H).

Two batches were run in parallel underthe following conditions, then combined for purification: Borane-THF complex (1.0 M in THF, 400 mL, 400 mmol) was added dropwise to a cooled (0 °C) suspension of 2-(2-bromo-5-chlorophenyl)acetamide (Cpd AA, 22.0 g,

88.5 mmol) in anhydrous THF (300 mL). The resulting clear solution was heated to 80 °C for two hours, then cooled again to 0 °C. The mixture was quenched by sequential addition of water (45 mL) and conc. HCl (120 mL), causing significant gas évolution. Stirring was continued at 10-15 °C for 16 hours, after which the mixture was concentrated to remove THF. The aqueous residue was cooled to 0°C, then 12 N aqueous sodium hydroxide was added to bring the pH to 11. The basified solution was extracted with ethyi acetate (3 x 500 mL). The combined organic extracts were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product (-25 g) as a yellow oil. Two -25 g batches of this crude product were combined, treated with 4N HCI/MeOH (500 mL), and stirred at 10-15 °C for 16 hours. The mixture was concentrated, and the residue stirred in ethyl acetate (500 mL) for 30 minutes. The resulting white solid was collected by filtration, and the filter cake washed with ethyl acetate (3 x 100 mL). The solids were dissolved in water (500 mL), filtered to remove insolubles, and the filtrate extracted with ethyl acetate (2 x 500 mL). The aqueous layer was basified with solid NaOH to pH 10, then extracted with ethyl acetate (2 x 500 mL). The combined organic extracts were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-(2-bromo-5-chlorophenyl)ethan-1-amine (Cpd BB, 30.0 g, 72% combined yield for the two batches) as a colorless oil. ¹H NMR (400 MHz, CDCI3) δ 7.47 (d, J= 8.4 Hz, 1 H), 7.23 (d, J=2.4 Hz, 1 H), 7.07 (dd, J= 2.4, 8.4 Hz, 1 H), 2.98 (t, J=6.8 Hz, 2H), 2.86 (t, J=6.8 Hz, 2H), 1.28 (m, 2H).

To a cooled (0 °C) suspension of 2-(2-bromo-5-chlorophenyl)ethan-1 -amine (Cpd BB, 28.0 g, 119 mmol) and sodium carbonate (32.3 g, 304 mmol) in anhydrous 1,2dichloroethane (600 mL) was added 4-nitrophenyl chloroformate (25.5 g, 127 mmol). The mixture was stirred at 0 °C for 30 minutes, then at 10-15 °C for 16 hours. The solution was diluted with water (1000 mL) and extracted with dichloromethane (3 x 1000 mL). The combined organic extracts were washed with water (1000 mL) and brine (1000 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product (—55 g, yellow solid) was crystallized from 5/1 petroleum ether/EtOAc (100 mL x2) to give 4-nitrophenyl (2bromo-5-chlorophenethyl)carbamate (Cpd CC, 40.0 g, 84% yield) as a white solid. ¹H NMR (400 MHz, CDCI3) δ 8.25 (d, J=9.2 Hz, 2H), 7.51 (d, J= 8.4 Hz, 1H), 7.31 (m, 3H), 7.13 (dd, J= 2.0, 8.4 Hz, 1H), 5.22 (br s, 1H), 3.57 (t, J=6.8 Hz, 2H), 3.05 (t, J=6.8 Hz, 2H).

Trifluoromethanesulfonic acid (150 g, 1000 mmol) was added dropwise to a cooled (0 °C) suspension of 4-nitrophenyl (2-bromo-5-chlorophenethyl)carbamate (Cpd CC, 40.0 g, 100 mmol) in anhydrous 1,2-dichloroethane (300 mL). Solids gradually dissolve over the course of the addition, resulting in a clear yellow solution. The mixture was stirred at 0 °C for 10 minutes, then heated at 60-70 °C for 3 hours. The resulting brown solution was poured into ice-water (1000 mL) and stirred until ail the ice had melted. The layers were separated, and the aqueous layer extracted with dichloromethane (2 x 1000 mL). The combined organic layers were washed with 2N aqueous sodium hydroxide (3 x 500 mL), water (500 mL), and brine (500 mL), then dried over anhydrous sodium sulfate and concentrated. The crude product (—30 g brown solid) was crystalized from 2/1 petroleum ether/ethyl acetate (150 mL x2), to give 5-bromo-8-chloro-3,4-dihydroisoquinolin-1 (2H)one (Cpd DD, 20.7 g, 80% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.25 (brs, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 3.12 (t, J=4.4 Hz, 2H), 2.95 (t, J=6.2 Hz, 2H).

N-iodosuccinimide (53.7 g, 239 mmol) was added to a cooled (0 °C) solution of 5bromo-8-chloro-3,4-dihydroisoquinolin-1(2H)-one (Cpd DD, 20.7 g, 79.6 mmol) in conc. sulfuric acid (98% w/w, 300 mL). The resulting brown suspension was stirred at 10-15 °C for 16 hours., then poured into ice-water (1000 mL) and stirred until ail the ice had melted.

The resulting aqueous suspension was extracted with ethyl acetate (3 x 1000 mL). The combined organic extracts were washed with saturated aqueous NaHSO3 (2 x 500 mL), 2N aqueous sodium hydroxide (2 x 500 mL), and brine (500 mL), then dried over anhydrous sodium sulfate and concentrated. The crude product (-30 g yellow solid) was crystalized with 1/1 petroleum ether/ethyl acetate (100 mL x2) to give 5-bromo-8-chloro-

7-iodo-3,4-dihydroisoquinolin-1 (2H)-one (Cpd EE, 23.0 g, 75% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.35 (br. s, 1H), 8.33 (s, 1H), 3.30-3.25 (2H, m), 2.89 (t, J - 6.0 Hz, 2H). MS: 386 [M+H]⁺.

Potassium fert-butoxide (1.0M solution in THF, 7.30 mL, 7.30 mmol) was added dropwise to a cooled (0 °C) suspension of 5-bromo-8-chloro-7-iodo-3,4dihydroisoquinolin-1(2H)-one (Cpd EE, 2.35 g, 6.08 mmol) in anhydrous DMF (30 mL). The mixture was stirred at 0 °C for 30 minutes, then a solution of 2-(benzyloxy)-3(chloromethyl)-4,6-dimethylpyridine (Cpd D, 1.75 g, 6.69 mmol) in anhydrous DMF (10 mL) was added, and stirring continued at 0 °C for 30 minutes. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with water (1 x 100mL) and brine (1x100mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography, eluting with a gradient of 0-40% ethyl acetate in heptane to afford 2-((2-(benzyloxy)-4,6-dimethylpyridin-3yl)methyl)-5-bromo-8-chloro-7-iodo-3,4-dihydroisoquinolin-1(2H)-one (Cpd FF, 2.95 g, 79% yield) as a gum. ¹H NMR (400 MHz, CDCI3) δ ppm 8.11 (s, 1 H), 7.40 - 7.47 (m, 2H), 7.27 - 7.37 (m, 3H), 6.62 (s, 1H), 5.42 (s, 2H), 4.85 (s, 2H), 3.25 (t, J=6.24 Hz, 2H), 2.68 (t, J=6.24 Hz, 2H), 2.41 (s, 3H), 2.32 (s, 3H). MS: 611, 613 [M+H]⁺.

Compound KK: 2-(benzvloxv)-3-(chloromethvl)-4-methoxv-6-methylpvridine

THF

BnBr

Ag₂CO₃

THF

SOCI₂

EtOAc ch₃i K₂CO₃

DMF

Benzyl bromide (19.1 g, 112 mmol) was added to a room température solution of ethyl 2,4-dihydroxy-6-methylnicotinate (20.0 g, 101.4 mmol) and silver carbonate (15.4 g, 55.8 mmol) in THF (100 mL), then the mixture was heated to 60 °C for 18 hours. After cooling to room température, the suspension was filtered through a CELITE® pad, the filtrate concentrated and purified by silica gel chromatography (eluting with 5% ethyl acetate in heptane) to give ethyl 2-(benzyloxy)-4-hydroxy-6-methylnicotinate (Cpd GG, 18 g, 62% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 7.40-

7.44 (m, 2H), 7.36 (t, J=7.34 Hz, 2H), 7.27-7.33 (m, 1H), 6.44 (s, 1H), 5.35 (s, 2H), 4.23 (q, J=7.13 Hz, 2H), 2.30 (s, 3H), 1.22 (t, J=7.09 Hz, 3H). MS: 288 [M+H]⁺.

A solution of ethyl 2-(benzyloxy)-4-hydroxy-6-methylnicotinate (Cpd GG, 18.0 g,

62.6 mmol) and potassium carbonate (9.52 g, 68.9 mmol) in DMF (50 mL) was stirred at room température for 10 minutes, then iodomethane (9.98 g, 68.9 mmol) was added and stirring continued at room température for 18 hours. The mixture was partitioned between water and ethyl acetate. The organic extracts were washed with sat. aq. NaCI, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-35% ethyl acetate in heptane), affording ethyl 2-(benzyloxy)-4-methoxy-6methylnicotinate (Cpd HH, 16.7 g, 89 % yield) as a colorless oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.33-7.42 (m, 4H), 7.26-7.33 (m, 1H), 6.75 (s, 1H), 5.36 (s, 2H), 4.22 (q, J=7.13 Hz, 2H), 3.83 (s, 3H), 2.39 (s, 3H), 1.20 (t, J=7.09 Hz, 3H). ). MS: 302 [M+H]⁺.

Lithium aluminium hydride solution (2.0M in THF) was added dropwise to a cooled (0 °C) solution of ethyl 2-(benzyloxy)-4-methoxy-6-methylnicotinate (Cpd HH, 16.7 g, 55.4 mmol) in THF (100 mL). After addition was complété, the solution was allowed to gradually warm to room température with stirring for 18 hours. The mixture was diluted with THF (200 mL), cooled to 0 °C, and quenched by sequential dropwise addition of water (3.4 mL), 15% aq. sodium hydroxide, and water (10.2 mL). The resulting slurry was stirred at room température for 2 hours, then filtered through a pad of CELITE®. Concentration of the filtrate yielded (2-(benzyloxy)-4-methoxy-6-methylpyridin-3-yl)methanol (Cpd JJ, 14 g, 97 % yield) as colorless oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=7.09 Hz, 2H), 7.36 (t, J=7.40 Hz, 2H), 7.25-7.33 (m, 1H), 6.63 (s, 1H), 5.35 (s, 2H), 4.37-4.46 (m, 3H),

3.82 (s, 3H), 2.35 (s, 3H). MS: 260 [M+H]⁺.

Thionyl chloride (6.57 g, 54.7 mmol) was added dropwise to a cooled (0 °C) solution of (2-(benzyloxy)-4-methoxy-6-methylpyridin-3-yl)methanol (Cpd JJ, 13.5 g, 52.1 mmol) in ethyl acetate (300 mL), causing formation of a solid precipitate. The slurry was stirred in the cooling bath for 30 minutes, then water was added to dissolve the solids.

After séparation of the phases, the organic layer was washed with sat. aq. NaCI, dried over sodium sulfate, and concentrated to dryness. The residue was dissolved in heptane and again concentrated to dryness, affording 2-(benzyloxy)-3-(chloromethyl)-4-methoxy6-methylpyridine (Cpd KK, 13.9 g, 95 % yield) as white solid. ¹H NMR (400 MHz, DMSOd6) δ 7.47 (d, J=7.34 Hz, 2H), 7.38 (t, J=7.40 Hz, 2H), 7.27-7.34 (m, 1H), 6.71 (s, 1H), 5.40 (s, 2H), 4.66 (s, 2H), 3.89 (s, 3H), 2.38 (s, 3H). MS: 260 [M+H]⁺.

Compound RR: 8-chloro-7-iodo-5-methvl-3_t4-dihvdroisoquinolin-1 (2H)-one.

bh₃-dms

MeTHF

Cpd MM

NaCN

DMSO

Cpd LL

1) bh₃-dms MeTHF

2) HCl

Cpd OO

Cpd PP

Cpd QQ

Cpd RR

To a cooled (0 °C) solution of 5-chloro-2-methylbenzoic acid (20.0 g, 117 mmol) in anhydrous 2-methyltetrahydrofuran (200 mL), borane-dimethylsulfide complex (28.0 g, 35.0 mL, 369 mmol) was added dropwise over 1 hour, slowly enough to maintain the internai température below 10 °C. Gas évolution was observed, and some precipitate formed. After the addition was complété, the cooling bath was removed and stirring continuée! at room température overnight. Methanol (50 mL) was carefully added to quench the mixture. The solution was concentrated to dryness, and the residue partitioned between ether (200 mL) and saturated aqueous sodium bicarbonate. The organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated to give ethyl 2-(benzyloxy)-4-hydroxy-6-methylnicotinate (Cpd LL, 18.4 g, 100% yield) as an oil. 1H NMR (400 MHz, CDCI3) δ 7.36 (d, J=2.08 Hz, 1H), 7.13 - 7.19 (m, 1H), 7.04 - 7.11 (m, 1H), 4.63 (s, 2H), 2.27 (s, 3H), 2.12 (s, 1H).

A solution of 2-(benzyloxy)-4-hydroxy-6-methylnicotinate (Cpd LL, 18.0 g, 115 mmol) in anhydrous toluene (300 mL) was cooled to below 10 °C internai. Thionyl chloride (21.3 g, 179 mmol) was added dropwise, slowly enough to maintain the internai température below 10 °C. The mixture was stirred at this température for 30 minutes, then the cooling bath was removed and stirring continued at room température for 5 hours. The solution was concentrated to remove volatiles, and the residue partitioned between ethyl acetate (200 mL) and sodium bicarbonate (200 mL). The organic phase was washed with brine (200 mL), dried over sodium sulfate, and concentrated to give 4-chloro-2(chloromethyl)-l -methylbenzene (Cpd MM, 17.5 g, 87% yield) as an oil. ¹H NMR (400 MHz, CDCI3) δ 7.33 (d, J=2.20 Hz, 1 H), 7.20 - 7.25 (m, 1 H), 7.14 (d, J=8.07 Hz, 1 H), 4.55 (s, 2H), 2.39 (s, 3H).

To a solution of 4-chloro-2-(chloromethyl)-1 -methylbenzene ((Cpd MM, 17.5 g, 100 mmol) in DMSO (200.0 mL) and water (50.0 mL) was added solid sodium cyanide (5.88 g, 120 mmol) in one portion. The reaction was slightly exothermic, and the internai température of the reaction mixture rose to 43 °C. Stirring was continued for one hour. The reaction mixture was partitioned between ethyl acetate (300 mL) and water (300 mL). The organic phase was washed with sodium bicarbonate (300mL) and brine (300mL), dried over sodium sulfate, and concentrated to give 2-(5-chloro-2methylphenyljacetonitrile (Cpd NN, 16.1 g, 97% yield) as an oil. ¹H NMR (400 MHz, CDCI3) δ 7.37 (d, J=1.96 Hz, 1H), 7.21 -7.26 (m, 1H), 7.13 - 7.17 (m, 1H), 3.64 (s, 2H), 2.32 (s, 3H).

Borane dimethylsulfide complex (22.3 g, 293 mmol, 26.0 mL) was added dropwise to a solution of 2-(5-chloro-2-methylphenyl)acetonitrile (Cpd NN, 16.0 g, 96.6 mmol) in 2methyl tetrahydrofuran (150 mL), causing gas évolution. Afterthe addition was complété, the mixture was heated to reflux for 5 hours. After cooling to room température, methanol was added to quench the mixture until no more bubbles were generated. The solution was concentrated to dryness. The residue was dissolved in methanol and treated with 4M

HCI/dioxane solution (100 mL) to break up the boron complex. The solution was concentrated to dryness. The white solid residue was dissolved in minimal methanol (-20 mL), ethyl acetate (-200 mL) was added, and the mixture stirred vigorously until a thick paste formed. The solids were collected by filtration, washed with ethyl acetate, and dried to give 2-(5-chloro-2-methylphenyl)ethan-1 -amine hydrochloride (Cpd OO, 9.5 g, 48% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) Ô 8.24 (br. s., 3H), 7.26 (s, 1H), 7.20 (d, J=1.34 Hz, 2H), 2.84 - 3.02 (m, 4H), 2.27 (s, 3H). MS: 170 [M+H]⁺.

A cooled (0 °C) solution of 2-(5-chloro-2-methylphenyl)ethanamine hydrochloride (Cpd OO, 8.41 g, 40.8 mmol) in DMF (200 mL) was stirred with triethylamine(10.3 g, 102 mmol) for 10 minutes, then solid 4-nitrophenyl chloroformate (8.14 g, 38.8 mmol) was added in one portion. A thick paste formed, and the reaction mixture became slightly yellow. Stirring was continued at 0 °C for 1 hour. The reaction mixture was partitioned between ethyl acetate (300 mL) and water (300 mL). The organic phase was washed with water (200mL), 10% sodium carbonate (200mL), and brine (200mL), then dried over sodium sulfate, and concentrated to give 4-nitrophenyl (5-chloro-2methylphenethyljcarbamate (Cpd PP, 9.94 g, 73% yield) as a solid. ¹H NMR (400 MHz, CDCI3) δ 8.18 - 8.29 (m, 2H), 7.24 - 7.32 (m, 2H), 7.11 - 7.17 (m, 3H), 5.28 (br. s., 1 H),

3.45 - 3.53 (m, 2H), 2.85 - 2.92 (m, 2H), 2.32 (s, 3H).

A cooled (0 °C) suspension of 4-nitrophenyl (5-chloro-2methylphenethyl)carbamate (Cpd PP, 9.94 g, 29.7 mmol) in anhydrous 1,2dichloroethane (120 mL) was treated with freshly opened trifluoromethylsulfonic acid (45.8 g, 305 mmol, 27.0 mL), and stirring continued at 0 °C for 30 minutes. The reaction mixture was then heated to 70 °C for 3 hours. After cooling to room température, the reaction mixture was carefully poured into ice water (200 mL), and stirred until ail the ice had melted. The biphasic mixture was extracted with dichloromethane (2 x 200 mL). The combined organic extracts were washed with 2M sodium carbonate (200mL). The aqueous phase was back-extracted with dichloromethane (200mL). The dichloromethane extracts were combined, dried over sodium sulfate, and concentrated to give 8-chloro-5methyl-3,4-dihydroisoquinolin-1(2H)-one (Cpd QQ, 4.17 g, 72% yield) as a solid. ¹H NMR (400 MHz, CDCI3) δ: 7.15 - 7.22 (m, 1 H), 7.08 (d, J=13.69 Hz, 1 H), 6.46 (br. s., 1 H), 3.43 - 3.51 (m, 2H), 2.88 (t, J=6.17 Hz, 2H), 2.28 (s, 3H). MS: 196 [M+H]⁺.

A flask containing 8-chloro-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (Cpd QQ, 6.0 g, 30.7 mmol) was cooled in an ice bath. Concentrated sulfuric acid (125.0 mL) was added, and the mixture stirred at 0 °C for 30 min. N-iodosuccinimide (20.7 g, 92.0 mmol) was added as a solid in one portion, and the mixture stirred at 0 °C for 3 hours. The solution was carefully poured into ice water (300 mL), causing a precipitate to form. The suspension was extracted with ethyl acetate (300 mL). Both organic and aqueous phases contained précipitâtes. The organic phase was washed with 10% Na2S2Û3 (300 mL) to remove excess iodine, and the aqueous layerwas extracted with ethyl acetate (200mL). The combined organic phases were dried over sodium sulfate and concentrated to dryness. The solid residue was stirred in methanol (100 mL). Insolubles were collected by filtration, and the precipitate (—14 g white solid) was slurried in carbon disulfide (100 mL). Solids were collected by filtration, washed with carbon disulfide, and dried under vacuum to yield 8-chloro-7-iodo-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (Cpd RR, 8.57 g, 87% yield) as a solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.15 (br. s., 1H), 7.94 (s, 1H), 3.26 (td, J=6.17, 4.03 Hz, 2H), 2.75 (t, J=6.24 Hz, 2H), 2.22 (s, 3H). MS; 321 [M=H]⁺.

Compound SS: 2-((2-(benzvloxv)-4-methoxv-6-methvlpvridin-3-vl)methvl)-7-bromo-5,8dichloro-3,4-dihvdroisoquinolin-1(2H)-one.

KOtBu

Cpd R _Cpd kk

EtOAc

Cpd SS

A room-temperature suspension of 7-bromo-5,8-dich)oro-3,4-dihydroisoquinolin1(2/-/)-one (Cpd R, 14.9 g, 50.4 mmol) in ethyl acetate (300 mL) was treated with potassium tert-butoxide (1.0 M solution in THF, 65.5 mL, 65.5 mmol), causing the solids to dissolve. After a few minutes, a precipitate begins to form. To this was added 2(benzyloxy)-3-(chloromethyl)-4-methoxy-6-methylpyridine (Cpd KK, 14.0 g, 50.4 mmol), and the resulting suspension heated at 75 °C for 4 hours. After cooling to room température, the mixture was washed with water (2x) and sat. aq. NaCI, concentrated, and the residue crystalized from ethyl acetate, affording 2-((2-(benzyloxy)-4-methoxy-6methylpyridin-3-yl)methyl)-7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (Cpd SS, 21.96 g, 81% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.34-7.40 (m, 2H), 7.18-7.25 (m, 3H), 6.70 (s, 1 H), 5.36 (s, 2H), 4.68 (s, 2H), 3.83 (s, 3H), 3.16 (t, J=6.17 Hz, 2H), 2.71 (t, J=6.17 Hz, 2H), 2.38 (s, 3H). MS: 535, 537 [M+H]⁺.

Compound TT: 2-((2-(benzvloxv)-4,6-dimethvlpvridin-3-vl)methvl)-8-chloro-7-iodo-5methvl-3,4-dihvdroisoquinolin-1 (2H)-one.

KOtBu

DMF

To a cooled (0 °C) solution of 8-chloro-7-iodo-5-methyl-3,4-dihydroîsoquinolin1(2H)-one (Cpd RR, 1.52 g, 4.73 mmol) in anhydrous DMF (20 mL) was added solid potassium tert-butoxide (796 mg, 7.09 mmol) in portions. Stirring was continued at 0 °C for 30 minutes, then a solution of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd D, 1 .18 g, 4.49 mmol) in anhydrous DMF (5 mL) was added dropwise. After stirring for 20 more minutes at 0 °C, the mixture was poured into ice-water (50 mL) and extracted with ethyl acetate (4 x 50 mL). The combined organic layers were washed with brine (4 x 50 mL), dried over sodium sulfate, filtered, and concentrated. The crude product (-2.4 g yellow solid) was purified by silica gel chromatography, eluting with 5/1 petroleum ether/ethyl acetate, affording 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-8-chloro-

7-iodo-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (Cpd TT, 1.7 g, 66% yield) as an offwhite solid. ¹H NMR (400 MHz, CDCI3) δ 7.76 (s, 1H), 7.45 (d, J=7.2 Hz, 2H), 7.36-7.30 (m, 3H), 6.62 (s, 1H), 5.42 (s, 2H), 4.88 (s, 2H), 3.24 (t, J = 6.2 Hz, 2H), 2.50 (t, J = 6 Hz, 2H), 2.42 (s, 3H), 2.32 (s, 3H), 2.13 (s, 3H). MS: 547 [M+H]⁺.

Compound UU: 2-((2-(benzvloxv)-4“meÎhoxv-6-methvlpvridin-3-vl)methvl)-8-chloro-7-

iodo-5-methyl-3,4-dihydroisoquinolin-1(2H)-one.
Cl O T π		Cl O OBn 1U i
'Ύτ r *		ΊΓΤΪ Fï
UU	Ά·ΛθΒη	UAU ₀ AU
Cpd RR	Cpd KK	Cpd UU

To a cooled (0 °C) solution of 8-chloro-7-iodo-5-methyl-3,4-dihydroisoquinolin1(2H)-one (Cpd RR, 3.2 g, 9.95 mmol) in anhydrous DMF (50 mL) was added solid potassium tert-butoxide (1.68 g, 14.9 mmol) in portions. Stirring was continued at 0 °C for 30 minutes, then a solution of 2-(benzyloxy)-3-(chloromethyl)-4-methoxy-6methylpyridine (Cpd KK, 2.63 g, 14.9 mmol) in anhydrous DMF (50 mL) was added dropwise. After stirring for 30 more minutes at 0 °C, the mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (4 x 100 mL), dried over sodium sulfate, filtered, and concentrated. The crude product (~5 g yellow solid) was purified by silica gel chromatography, eluting with 20-50% ethyl acetate in petroleum ether. The resulting product was dissolved in dichloromethane (10 mL), added to petroleum ether (30 mL) and stirred at room température until a precipitate forms (30 minutes). The precipitate was collected by filtration and dried to a white solid. TLC of the precipitate still showed impurities, so it was repurified by silica gel chromatography, eluting with 0-10% methanol in dichloromethane, yielding 2-((2-(benzyloxy)-4-methoxy-6-methylpyridin-3-yl)methyl)-8chloro-7-iodo-5-methyl-3,4-dihydroisoquinolin-1 (2H)-one (Cpd UU, 2.8 g, 50% yield) as a white solid. ¹H NMR (400 MHz, CDCI3) δ 7.75 (s, 1H), 7.42-7.40 (m, 2H), 7.29-7.27 (m, 1H), 7.25-7.22 (m, 2H), 6.38 (s, 1H), 5.42 (s, 2H), 4.87 (s, 2H), 3.83 (s, 3H), 3.14 (t, J = 6.2 Hz, 2H), 2.50 (t, J = 6.2 Hz, 2H), 2.44 (s, 3H), 2.13 (s, 3H). MS: 563 [M+H]⁺.

Examples

General Methods and Représentative Examples

Method A

Example 1: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihvdropyridin-3-vl)methvll-7-{(1R)-

2-hvdroxv-1-[(3R)-Îetrahvdrofuran-3-vl1ethvl)-3,4-dihvdroisoquinolin-1(2H)-one Example 2: 5.8-dichloro-2-F(4,6-dimethyl-2-oxo-1,2-dihvdropvridin-3-vDmethvl1-7-((1 R*)-

2-hvdroxv-1-r(3S*)-tetrahvdrofuran-3-vllethvl)-3.4-dihvdroisoquinolin-1(2H)-one Example 3: 5,8-dichloro-2-[(4_t6-dimethvl-2-oxo-1,2-dihydropvridin-3-vl)methvn-7-{(1S*l2-hvdroxv-1-i(3R*)-tetrahvdrofuran-3-vl1ethvl)-3,4-dihvdroisoquinolin-1(2H)-one Example 4: 5,8-dichloro-2-F(4,6-dimethvl-2-oxo-1.2-dihvdropvridin-3-vl)methyll-7-{(1S)2-hvdroxv-1-[(3S)-tetrahydrofuran-3-vllethvll·3,4-dihvdroisoquinolin-1(2H)-one

A cooled (0 °C) solution of methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3yl)methyl)-5,8-dichloro-1-oxo-1_}2,3,4-tetrahydroisoquinolin-7-yl)acetate (Cpd T, 800 mg, 0.487 mmol) in anhydrous N,N-dimethylformamide (70 mL) was treated with sodium hydride (60 wt% dispersion in minerai oil, 125 mg, 3.12 mmol), then stirred at 10 °C for 15 minutes. The mixture was cooled again to 0°C and 3-iodotetrahydrofuran (463 mg,

2.34 mmol) was added. After stirring at room température for 12 hours, glacial acetic acid (2 drops) and water (10 mL) were added, and the mixture extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, concentrated, and purified by column chromatography (silica gel, Petroleum ether/EtOAc = 5:1-1:1) to obtain 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(tetrahydrofuran-3yl)acetic acid (1a, 500 mg, 56.3%) as a white solid; and methyl 2-(2-((2-(benzyloxy)-4,6dimethylpyridin-3-yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2(tetrahydrofuran-3-yl)acetate (1b, 150 mg, 16.5%) as a yellow solid.

A solution of 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-1oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(tetrahydrofuran-3-yl)acetic acid (1a, 650 mg, 1.14 mmol), potassium carbonate (315 mg, 2.28 mmol), and iodomethane (324 mg, 2.28 mmol) in N.N-dimethylformamide (8 mL) was stirred at room température for 12 hours. The mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2x15 mL). The organic layers were combined, washed with brine (3x10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (silica gel, Petroleum ether/EtOAc = 1:1) to obtain methyl 2-(2-((2(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4tetrahydroisoquinolin-7-yl)-2-(tetrahydrofuran-3-yl)acetate (1b 600 mg, 90.1%) as a white solid.

Lithium borohydride (28 mg, 1.29 mmol) was added in one portion to a room température solution of methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(tetrahydrofuran-3-yl)acetate (1 b, 250 mg, 0.428 mmol) in anhydrous tetrahydrofuran (25 mL). The resulting mixture was heated at 60 °C for 2 hours. The mixture was quenched with water (5 mL) and then extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, washed with brine (5 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by prep. TLC (Petroleum ether/EtOAc = 1:1) to obtain 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-(2-hydroxy-1(tetrahydrofuran-3-yl)ethyl)-3,4-dihydroisoquinolin-1(2H)-one (mixture of 4 stereoisomers, 160 mg, 67.2%) as a white solid. Combined batches (500 mg total) of this stereoisomer mixture was resolved by préparative chiral SFC (Chiralpak AD, 250x30mm

I.D., 5 pm, mobile phase 35% EtOH NHa H2O, flow rate 50mL/min) to obtain separated isomers 1c (peak one, 80 mg, 15.9%), 2c (peak two, 90 mg, 17.9%), 3c (peak three, 110 mg, 21.9%) and 4c (peak four, 100 mg, 19.9%) as white solids. Absolute stereochemistry of each isomer was not determined at this stage.

A solution of 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-(2hydroxy-1-(tetrahydrofuran-3-yl)ethyl)-3,4-dihydroisoquinolin-1 (2H)-one stereoisomer 1c (80 mg, 0.144 mmol) in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was stirred at 35 °C for 5 hours, and then evaporated to dryness. The residue was taken up in methanol (10 mL), cooled to 10 °C, and potassium carbonate (99.5 mg, 0.720 mmol) added. After stirring for 30 minutes at 10 °C, the reaction mixture was filtered, and the filter pad washed with dichloromethane/methanol (10:1, 10 mL).The filtrate was concentrated in vacuo and the residue, purified by prep. TLC (CH2CI2/MeOH = 10:1, Rf = 0.4 in CH2CI2/MeOH = 10:1) to obtain Example 1 (38 mg, 57%) as a white solid.

By the same procedure, stereoisomer 2c (90 mg, 0.162 mmol) afforded Example 2 (44 mg, 59%); stereoisomer 3c (110 mg, 0.198 mmol) afforded Example 3 (61 mg, 66%); and stereoisomer 4c (100 mg, 0.18 mmol) afforded Example 4 (35 mg, 41%); ail as white solids.

A small-molecule X-Ray crystal structure of Example 4 shows it to hâve absolute (S,S) stereochemistry. Absolute (R,R) stereochemistry was attributed to Example 1 because its ¹HNMR spectrum is identical to that of Example 4. The ¹HNMR spectra of Example 2 and Example 3 are identical to each other, and clearly different from that of Example 4, suggesting they are the (R,S) and (S,R) stereoisomers, though the absolute configuration of each was not determined.

Example 1: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7{(1R)-2-hydroxy-1-[(3R)-tetrahydrofuran-3-yl]ethyl}-3,4-dihydroisoquinolin-1(2H)-one (absolute stereochemistry assigned based on crystal structure of enantiomeric compound). ¹H NMR (400 MHz, CD3OD) δ 7.63 (s, 1H), 6.12 (s, 1H), 4.77 (s, 2H), 3.943.90 (m, 1H), 3.81-3.80 (m, 3H), 3.59-3.57 (m, 2H), 3.51-3.49 (m, 2H), 3.17-3.10 (m, 1H), 2.98-2.95 (m, 2H), 2.71 (brs, 1 H), 2.30 (s, 3H), 2.29-2.25 (m, 1H), 2.25 (s, 3H), 1.83-1.78 (m, 1H). MS: 465 [M+H]⁺. Chiral analysis: 95.66% ee/de; rétention time: 6.867 min; column: Chiralpak AD-3 150x4.6mm I.D., 3pm; mobile phase: éthanol (0.05% DEA) in CO2 from 5% to 40%; flow rate: 2.5mL/min; wavelength 220 nm.

Example 2: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyIJ-7{(1 R*)-2-hydroxy-1 -[(3S*)-tetrahydrofuran-3-yl]ethyl}-3,4-dihydroisoquinolin-1 (2H)-one (relative stereochemistry known, absolute stereochemistry undetermined). ¹H NMR (400 MHz, CD3OD) δ 7.62 (s, 1 H), 6.11 (s, 1 H), 4.76 (s, 2H), 4.13-4.11 (m, 1H), 3.78-3.75 (m, 1H), 3.69-3.68 (m, 2H), 3.61-3.59 (m, 3H), 3.51-3.50 (m, 2H), 2.98-2.95 (m, 2H), 2.65 (br s, 1 H), 2.30 (s, 3H), 2.25 (s, 3H), 1.77-1.75 (m, 1 H), 1.42-1.37 (m, 1 H). ). MS: 465 [M+H]⁺. Chiral analysis: 98.70% ee/de; rétention time: 7.309 min; column: Chiralpak AD-3 150x4.6mm I.D., 3pm; mobile phase: éthanol (0.05% DEA) in CO2 from 5% to 40%; flow rate: 2.5mL/min; wavelength 220 nm.

Example 3: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7{(1 S*)-2-hydroxy-1 -[(3R*)-tetrahydrofuran-3-yl]ethyl}-3,4-dihydroisoquinolin-1 (2H)-one (relative stereochemistry known, absolute stereochemistry undetermined). ^jH NMR (400 MHz, CD3OD) δ 7.62 (s, 1 H), 6.11 (s, 1 H), 4.76 (s, 2H), 4.12-4.11 (m, 1 H), 3.80-3.78 (m, 1H), 3.69-3.67 (m, 3H), 3.67-3.62 (m, 2H), 3.61-3.50 (m, 2H), 2.98-2.95 (m, 2H), 2.65 (br s, 1H), 2.29 (s, 3H), 2.25 (s, 3H), 1.77-1.74 (m, 1H), 1.42-1.37 (m, 1H). MS: 465 [M+H]⁺. Chiral analysis: 96.48% ee/de; rétention time: 8.021 min; column: Chiralpak AD-3 150x4.6mm I.D., 3pm; mobile phase: éthanol (0.05% DEA) in CO2 from 5% to 40%; flow rate: 2.5mUmin; wavelength 220 nm.

Example 4: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7{(1S)-2-hydroxy-1-[(3S)-tetrahydrofuran-3-yl]ethyl)-3,4-dihydroisoquinolin-1(2H)-one (absolute stereochemistry determined by X-Ray crystal structure). ¹H NMR (400 MHz, CD3OD) δ 7.64 (s, 1H), 6.13 (s, 1H), 4.78 (s, 2H), 3.95-3.90 (m, 1H), 3.83-3.81 (m, 3H), 3.60-3.55 (m, 2H), 3.55-3.52 (m, 2H), 3.32-3.19, (m, 1H), 2.99-2.96 (m, 2H), 2.75 (br s, 1H), 2.32 (s, 3H), 2.31-2.29 (m, 1H), 2.27 (s, 3H), 1.84-1.79 (m, 1H). MS: 465 [M+H]⁺. Chiral analysis: 99.18% ee/de; rétention time: 8.429 min; column: Chiralpak AD-3 150x4.6mm I.D., 3pm; mobile phase: éthanol (0.05% DEA) in CO2 from 5% to 40%; flow rate: 2.5mL/min; wavelength 220 nm.

Method B

Example 5: 5,8-dichloro-2-f(4.6-dimethvl-2-oxo-1,2-dihvdropvridin-3-vl)methvll-7-{1[(3R)-3-fluoropvrrolidin-1-vl1-2-hvdroxvethvlÎ-3.4-dihvdroisoquinolin-1(2H)-one.

Example 6: 5,8-dichloro-2-r(4.6-dimethvl-2-oxo-1,2-dihvdropvridin-3-vl)methyl1~7-{(R)-1 [(3R)-3-fluoropyrrolidin-1 -vl1-2-hvdroxvethvl}-3,4-dihvdroisoquinolin-1 (2H)-one isomer A

Example 7: 5,8-dichloro-2-f(4.6-dimethvl-2-oxo-1,2-dihvdropyridin-3-vl)methvl1-7-f(1£)-1[(3R)-3-fluoropyrrolidin-1 -vll-2-hvdroxvethvl)-3.4-dihvdroisoquinolin-1 (2H)-one isomer B

Example 6

To an ice bath-cooled solution of methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-

3-yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-diazoacetate (Cpd

IJ, 800 mg, 1.48 mmol) in anhydrous dichloromethane (10 mL) was added HBr (800 uL,

4.42 mmol, 33%wt in HOAc), causlng gas évolution. The solution was allowed to warm to room température and stirred overnight. The reaction mixture was carefully quenched with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate (2 x 50mL). The combined organic phases were dried over sodium sulfate, concentrated to dryness, and purified by a silica gel column with a gradient elution of 0->10%MeOH/EA to afford racemic methyl 2-bromo-2-(5,8-dichloro-2-((4,6-dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)acetate (5a, 655 mg, 88%) as a solid. MS: 501.00/502.05. ¹H NMR (400 MHz, CDCI3) δ 7.91 (s, 1 H), 6.18 (s, 1H), 6.03 (s, 1H), 4.76 (s, 2H), 3.81 (s, 3H), 3.68 (t, J=6.24 Hz, 2H), 2.98 (t, J=6.24 Hz, 2H), 2.45 (s, 3H), 2.37 (s, 3H).

A mixture of methyl 2-bromo-2-(5,8-dichloro-2-((4,6-dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)acetate (5a, 162 mg, 0.323 mmol), (3R)-3-fluoropyrrolidine hydrochloride (144 mg, 1.15 mmol), N,Ndiisopropylethylamine (0.35 mL, 2.01 mmol), and anhydrous N,N-dimethylformamide (4 mL) was stirred at room température overnight. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was separated, washed sequentially with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated to dryness to give crude methyl 2-(5_I8-dichloro-2-((4,6-dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-((R)-3fluoropyrrolidin-1 -yl)acetate, as a mixture of diastereomers (5b, 162 mg, 98% yield), which was used in the next step without further purification. LCMS: T=510.15/511.10/512.20.

The crude mixture of methyl 2-(5,8^ϊοΙ'ΊΐθΓθ-2-((4,6^ίπΊβΐΐΊνΙ-2-οχο-1,2dihydropyridin-3-yl)methyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-((R)-3fluoropyrrolidin-1-yl)acetate diastereomers (5b, 152 mg, 0.298 mmol) in anhydrous tetrahydrofuran (4.0 mL) was treated with lithium borohydride (2.0 M solution in THF, 0.45 mL, 0.90 mmol) followed by a few drops of methanol. The process of addition was repeated 4 times, then the reaction was quenched with 2 M NH4CI (20mL) and extracted with ethyl acetate (2 x 20mL). The combined organic phases were dried over sodium sulfate, concentrated to dryness, and purified by préparative HPLC to afford 5,8-dichloro2-[(4,6-dimethyl-2-oxo-1,2-dihydropy ridin-3-yl)methy l]-7-{ 1 -[(3R)-3-f luoropy rrolidin-1 -yl]2-hydroxyethyl}-3,4-dihydroisoquinolin-1(2H)-one as a mixture of diastereomers at the benzylic carbon (Example 5, 32.2 mg, 22% yield over two steps). ¹H NMR (400 MHz, DMSO-d6) δ 11.66 (br. s., 1 H), 7.80 (d, J=3.67 Hz, 1 H), 6.00 (s, 1 H), 5.15 - 5.43 (m, 1 H),

4.85 (br. s., 1 H), 4.69 (s, 2H), 4.03 - 4.13 (m, 1 H), 3.66 - 3.84 (m, 2H), 3.50 - 3.63 (m, 2H), 3.02 - 3.10 (m, 1H), 2.94 - 3.02 (m, 2H), 2.71 - 2.90 (m, 2H), 2.42 - 2.55 (m, 1 H), 2.28 (s, 3H), 2.24 (s, 3H), 2.09 - 2.23 (m, 1 H), 1.87 - 2.08 (m, 1 H). MS: 482 [M+H]⁺.

The mixture of diastereomers of 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-7-{1-[(3R)-3-fluoropyrrolidin-1-yl]-2-hydroxyethyl}-3,4 dihydroisoquinolin-1 (2H)-one (Example 5, 20.0 mg, 0.0415 mmol) was separated by chiral préparative SFC on a Chiralcel OJ-3 4.6 x 100 mm 3u column, eluting with 10% MeOH/DEA @ 120 bar, 4 mL/min, affording, after lyophilization, Example 6 (Peak 1, rétention time 1.18 min, 5.65 mg, 28%) and Example 7 (Peak 2, rétention time 1.42 min, 6.23 mg, 31%). The absolute configuration of the benzylic carbon in each isomer was not determined.

Example 6: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7{(1 ξ)-1 -[(3R)-3-fluoropyrroIidin-1 -yl]-2-hydroxyethyl]-3,4-dihydroisoquinolin-1 (2H)-one isomer A. MS: 482 [M+H]⁺. Chiral analysis: -88% de, [oc]D = +62.1° (c 0.01 MeOH)

Example 7: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7{(1Ç)-1-[(3R)-3-fluoropyrrolidin-1-yl]-2-hydroxyethyl}-3,4-dihydroisoquinolin-1(2H)-one isomer B. MS: 482 [M+H]⁺. Chiral analysis: -98% de; [a]D = -58.9° (c 0.01 MeOH)

Method C

Example 8: (+)-5.8-dichloro-2-f(4,6-dimethvl-2-oxo-1,2-dihvdropvridin-3-vl)methvl1-7(fluorof 1 -(hvdroxvacetvl)oiperidin-4-vl1methvl)-3,4-dihvdroisoquinolin-1 (2H)-one

Example 9: (-)-5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihvdropvridin-3-vl)methyl]-7(fluorof 1 -(hvdroxvacetvl)piperidin-4-vHmethvlF3,4-dihvdroisoquinolin-1 (2H)-one

o

DeoxoFluor(R)

DCM

O

1. TEA, DCM

2. K₂CO₃, MeOH

(-) enantiomcr Example 9

To a solution 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-bromo-5,8 dichloro-3,4-dihydroisoquinolin-1(2H)-one (Cpd S, 311.0 mg, 0.598 mmol) in tetrahydrofuran (5.0 mL) and 1,4-dioxane (0.5 mL) at -40 °C (in an acetonitrile/dry ice bath) was added iPrMgCI-LiCI (1.3 M in THF, 0.850 mL, 1.10 mmol) and the reaction was stirred for 1 hour. N-Boc-4-formylpiperidine (0.242 g, 1.14 mmol) was then added, and the flask was warmed to 0 °C in an ice bath. After 1 hour at 0 °C, the solution was quenched with sat. aq. NH4CI and extracted with MTBE. The MTBE layer was concentrated, and the resulting oil purified on silica gel (Isco RediSepRf, 12 g, 10-70% gradient of ethyl acetate in heptane) to give racemic tert-butyl 4-((2-((2-(benzyloxy)-4,6-dimethylpyridin-3yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7yl)(hydroxy)methyl)piperidine-1-carboxylate (8a, 0.229 g, 59%) as a white solid. ¹H NMR (400 MHz, CD3OD) δ 7.66 (s, 1H), 7.36-7.44 (m, 2H), 7.18-7.31 (m, 3H), 6.71 (s, 1H),

5.42 (s, 2H), 5.04 (d, J=5.14 Hz, 1H), 4.83 (d, J=1.96 Hz, 2H), 4.08 (d, J=12.72 Hz, 2H), 3.23 (t, J=6.24 Hz, 2H), 2.73 (t, J=6.11 Hz, 2H), 2.53-2.71 (m, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 1.76-1.90 (m, 1H), 1.32-1.62 (m, 13H); MS 654, 656 [M + H]⁺.

To a solution of racemic tert-butyl 4-((2-((2-(benzyloxy)-4,6-dimethylpyridin-3yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7yl)(hydroxy)methyl)piperidine-1-carboxylate (8a, 88 mg, 0.13 mmol) in dichloromethane (4 ML) cooled in a dry ice/acetone bath was added Deoxo-Fluor™ (50% in THF, 0.165 mL, 0.39 mmol). After stirring at -78 °C for 5 minutes, the cooling bath was removed and the mixture stirred for 5 minutes. The reaction was quenched with the addition of sat. aq. NaHCO3, the layers were separated, and the dichloromethane layer was concentrated. The resulting oil was purified on silica gel (Biotage SNAP, HP-Sil, 10g, 0-40% gradient of ethyl acetate in heptane) to give racemic tert-butyl 4-((2-((2-(benzyloxy)-4,6dimethylpyridin-3-yl)methyl)-5,8-dichloro- 1-oxo-1,2,3,4-tetrahydroisoquinolin-7yl)fluoromethyl)piperidine-1-carboxylate (8b, 0.075 g, 85%) as a white, sticky solid. MS: 656, 658 [M + Hj⁺.

A solution of racemic tert-butyl 4-((2-((2-(benzyloxy)-4,6-dimethylpyridin-3yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)fluoromethyl)piperîdine-

1- carboxylate (8b, (0.075 g, 0.11 mmol) in trifluoroacetic acid (5.0 mL) was heated to 50 °C for 1hour. The reaction mixture was diluted with heptane and concentrated under vacuum. The residue was dissolved in éthanol and concentrated again. The remaining white solid was dried under vacuum to give crude, racemic 5,8-dichloro-2-((4,6-dimethyl-

2- oxo-1,2-dihydropyridin-3-yl)methyl)-7-(fluoro(piperidin-4-yl)methyl)-3,4dihydroisoquinolin-1(2H)-one (8c 0.085 g) as the TFA sait. MS 466, 468 [M + H]⁺. This material was dissolved in dichloromethane (5 mL) and cooled to 0 °C. Triethylamine (0.060 mL, 0.43 mmol) and then 2-acetoxyacetyl chloride (0.017 mL, 0.16 mmol) were added, the mixture stirred for 30 minutes, and then a few drops of methanol were added to quench the excess reagent. The solution was concentrated under vacuum, and the residue was dissolved in methanol (5 mL) and treated with potassium carbonate (0.100 g, 0.724 mmol). After 4 hours at room température, the reaction was filtered, concentrated, and purified by préparative chiral SFC (OJ-H, 21 x 250mm column, 32 mL MeOH: 8 mL CO2, 100 bar, 40 mL/min) to give separated enantiomers Example 8 (peak 1, 9.6 mg, 15%) and Example 9 (peak 2, 8.1 mg, 13%) as white solids. The absolute stereochemistry of each isomer was not determined, but optical rotation measurements were obtained.

Example 8: (+)-5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3yl)methyl]-7-{fluoro[1-(hydroxyacetyl)piperidin-4-yl]methyl)-3,4-dihydroisoquinolin-1(2H)one. MS 524, 526 [M+H]⁺. Optical rotation: [oc]d = +9.9° (c, 0.1, DMSO). Chiral analysis: >99% ee; Rétention time 8.13 min on Lux Cellulose-2 4.6 x 100 mm 3u column, 60% MeOH @ 120 bar, 4 mL/min.

Example 9: (-)-5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3yl)methyl]-7-{fluoro[1-(hydroxyacetyl)piperidin-4-yl]methyl)-3,4-dihydroisoquinolin-1(2H)one. ¹H NMR (600 MHz, DMSO-de) δ 11.55 (s, 1 H), 7.58 (d, J=4.95 Hz, 1 H), 5.88 (s, 1 H),

5.72 - 5.84 (m, 1H), 4.55 (q, J=13.75 Hz, 2H), 4.46 (br. s., 1H), 4.30 - 4.42 (m, 1H), 4.05 -4.13(m, 1H), 3.97-4.04 (m, 1H), 3.69 (t, J=13.39 Hz, 1H), 3.45 (t, J=5.78 Hz, 2H), 2.80 -2.98 (m, 3H), 2.20 (d, J=18.71 Hz, 1H), 2.11 (s, 3H), 1.61 (br. s., 1H), 1.46 (br. s., 1H),

1.34 - 1.42 (m, 1H), 1.23 (s, 5H); MS 524, 526 [M+H]⁺. Optical rotation: [oc]d = -6.5° (c, 0.1, DMSO). Chiral analysis: -95% ee; Rétention time 10.29 min on Lux Cellulose-2 4.6 x 100 mm 3u column, 60% MeOH @ 120 bar, 4 mL/min.

Method D

Example 10: 5,8-dichloro-2-f(4,6-dimethyl-2-oxo-1,2-dihvdropyridin-3-vl)methvl1-7-(2hvdroxv-1-methoxvethvl)-3,4-dihydroisoquinolin-1(2H)-one - isomer A

Example 11: 5_l8-dichloro-2-r(4_l6-dimethyl-2-oxo-1,2-dihvdropvridin-3-vl)rnethvll-7-(2hvdroxv-1-methoxveÎhvl)-3,4-dihydroisoquinolin-1(2H)-one - isomer B

100

Example 10 Example 11

To a stirred solution of dry methanol (12 mg, 0.36 mmol) and dirhodium tetraacetate (1.2 mg, 0.0028 mmol) in dichloromethane (5 mL) was added a solution of methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4tetrahydroisoquinolin-7-yl)-2-diazoacetate (Cpd U, 150 mg, 0.278 mmol) in dichloromethane (5 mL) dropwise over a period of 60 minutes at room température. After the addition, the réaction was heated to reflux for 18 hours. The mixture was concentrated and purified by flash chromatography (eluting with petroleum ether/EtOAc=10:1, Rf ~0.3) to afford racemic methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxyacetate (11a, 100 mg, 66%) as brown oil.

To a stirred solution of racemic methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxyacetate (11a, 100 mg, 0.184 mmol) in anhydrous tetrahydrofuran (10 mL) was added solid lithium borohydride (12 mg, 0.55 mmol) in one portion at room température. The resulting mixture was heated at 60 °C for 1 hour. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (3x15 mL). The combined organic extracts were washed with saturated aq. NaCI (15 mL), dried over sodium sulfate, filtered and concentrated to afford the crude product (91 mg). Purification was accomplished using flash chromatography (eluting with petroleum ether/EtOAc = 1:1) to afford racemic 2-((2(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-(2-hydroxy-1-methoxyethyl)-

3,4-dihydroisoquinolin-1 (2H)-one (11b, 60 mg, 63%) as a white solid.

A solution of racemic 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8dichloro-7-(2-hydroxy-1-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one (11b 60 mg, 0.12 mmol) in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was stirred at room température for 18 hours. Analysis by LC-MS showed complété deprotection of the benzyl

101 group, but some trifluoroacetate ester at the pyridone oxygen, so the mixture was concentrated and then methanol (10 mL) and potassium carbonate (80.9 mg, 0.585 mmol) were added. The resulting mixture was stirred at room température for 30 minutes, at which time analysis by LC-MS showed complété deprotection of the TFA-ester. The mixture was filtered, the collected solid was washed with DCM/MeOH (10:1, 10 mL) and the filtrate was concentrated. Purification was accomplished using flash chromatography (eluting with DCM/MeOH = 10:1, Rf ~ 0.6) to obtain a racemic 5,8-dichloro-2-[(4,6dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-(2-hydroxy-1-methoxyethyl)-3,4dîhydroisoquinolin-1(2H)-one (37 mg, 75%) as a white solid.

Combined batches of racemic 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-7-(2-hydroxy-1-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)one (total 100 mg, 0.235 mmol) were separated by chiral SFC on a Chiralpak IC 250 mm x 30 mm, 10 pm column, eluting with 50% EtOH / NH4OH at a flow rate of 70ml_/min. After lyophilization, Example 10 (peak 1,33 mg, 33%) and Example 11 (peak 2, 35 mg, 35%) were obtained as off-white solids. Absolute stereochemistry for each isomer was not determined.

Example 10: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]7-(2-hydroxy-1-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one - isomer A. ¹H NMR (400 MHz, CDCI3) δ 12.23 (br. s„ 1H), 7.53 (s, 1H), 5.95 (s, 1H), 4.92-4.89 (m, 1H), 4.78 (s, 2H), 3.80-3.71 (m, 1H), 3.68-3.62 (m, 2H), 3.53-3.51 (m, 1H), 3.33 (s, 3H), 2.94 (t, J = 6.0 Hz, 2H), 2.35 (s, 3H), 2.29 (s, 3H). MS: 425 [M+H]⁺. Chiral analysis: 100% ee, rétention time 7.717 min, column: Chiralpak IC-3 150 x 4.6mm I.D., 3 pm; mobile phase: 40% éthanol (0.05% DEA) in CO2; flow rate: 2.35mL/min.

Example 11 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7(2-hydroxy-1-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one - isomer B. ¹H NMR (400 MHz, CDCI3) δ 12.15 (br. s., 1H), 7.53 (s, 1H), 5.95 (s, 1H), 4.92-4.89 (m, 1H), 4.78 (s, 2H), 3.80-3.71 (m, 1 H), 3.68-3.63 (m, 2H), 3.55-3.51 (m, 1 H), 3.34 (s, 3H), 2.94 (t, J = 5.6 Hz, 2H), 2.35 (s, 3H), 2.29 (s, 3H). MS: 425 [M+H]⁺. Chiral analysis: 100% ee, rétention time 11.063 min, column: Chiralpak IC-3 150 x 4.6mm I.D., 3 pm; mobile phase: 40% éthanol (0.05% DEA) in CO2; flow rate: 2.35mL/min.

Method E

102

Example 12: 5.8-dichloro-2-f(4,6-dimethvl-2-oxo-1,2-dihvdropvridin-3-vl)methvn-7-f(1 R)

2-hvdroxv-1-i(2S)-tetrahvdrofuran-2-vl1ethvn-3,4-dihvdroisoquinolin-1(2H)“One

Example 13: 5,8-dichloro-2-r(4₁6-dimethvl-2-oxo-1,2-dihvdropyridin-3-vl)methvl1-7-f(1 R)2-hvdroxv-1-[(2R)-tetrahvdrofuran-2-vnethvB-3.4-dihvdroisoquinolin-1(2H)-one

Cpd u

Example 12 minor

Example 13 major

To a solution methyl 2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8 dichloro-1-oxo-1₎2,3,4-tetrahydroisoquinolin-7-yl)-2-diazoacetate (Cpd U,1.78 g, 3.29 mmol) in anhydrous tetrahydrofuran (20 mL ) was added a solution of copper (II) triflate (120 mg, 0.332 mmol) and (S)-(-)-2,2^,-isopropylidene-bis(4-phenyl-2-oxazoline) (130 mg, 0.389 mmol) in anhydrous tetrahydrofuran (4 mL). The resulting solution was heated to reflux overnight in an 80°C oil bath. After cooling to room température, the reaction mixture was concentrated to dryness and purified by a silica gel column with a gradient elution of 0-»40% EA/HEP to afford a mixture of diastereomers with (S) geometry at the benzylic carbon (stereochemical assignment by analogy to Jiménez-Osés, G. et al., J. Org. Chem. 2013, 78, 5851-5857), methyl (2S)-2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-

5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(tetrahydrofuran-2-yl)acetate (12a, 333 mg, 17%). MS:583.10/584.20 [M+H]⁺. ¹H NMR (400 MHz, CDCI3) δ 7.69 (d, J=2.20 Hz, 1H), 7.45 (d, J=7.58 Hz, 2H), 7.30 - 7.39 (m, 3H), 6.64 (s, 1H), 5.45 (s, 2H), 4.80 - 4.92 (m, 2H), 4.41 - 4.59 (m, 1 H), 3.79 - 4.02 (m, 1 H), 3.72 - 3.80 (m, 1 H), 3.70 (d, J=5.01 Hz, 3H), 3.23 - 3.31 (m, 2H), 2.69 - 2.76 (m, 2H), 2.44 (s, 3H), 2.34 (d, J=3.79 Hz, 3H), 1.93 - 2.18 (m, 1 H), 1.80 - 1.94 (m, 2H), 1.55 - 1.80 (m, 2H).

[Under the same conditions, use of the enantiomeric (R)-(-)-2,2'-isopropylidenebis(4-phenyl-2-oxazoline) ligand produces a mixture of diastereomers with (R) geometry at the benzylic position, methyl (2R)-2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(tetrahydrofuran-2 yl)acetate.]

103

Lithium borohydride (2.0 M solution in THF, 1.0 mL, 2.0 mmol) was added to a solution of methyl (2S)-2-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyi)-5,8-dichloro1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(tetrahydrofuran-2-yl)acetate (12a 333 mg, 0.571 mmol) in anhydrous tetrahydrofuran (10 mL), followed by a few drops of methanol. Gas was evolved. The mixture was stirred at room température for 1 hour, then quenched with 10 mL 2 M NH4CI, diluted with water, and extracted with ether (3 x 50mL). The combined organic phases were dried over sodium sulfate, concentrated to dryness, to give crude 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-((1 R)-2hydroxy-1-(tetrahydrofuran-2-yl)ethyl)-3,4-dihydroisoquinolin-1(2H)-one (12b, 280 mg, 88%)., as a mixture of diastereomers with (R) geometry at the benzylic carbon. This mixture was used in the next step without further purification. MS: 555.20/557.20.

A solution of the crude mixture of diastereomers, 2-((2-(benzyloxy)-4,6dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-((1R)-2-hydroxy-1-(tetrahydrofuran-2yl)ethyl)-3,4-dihydroisoquinolin-1(2H)-one (12b, 280 mg, 0.504 mmol) in trifluoroacetic acid (8 mL) was stirred at 50 °C for 1 hour. After removing excess trifluoroacetic acid, the residue was dissolved in methanol (10 mL) and treated with 4 M NaOH for 30 minutes at 50 °C. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated. The aqueous phase was acidified to pH -2-3, and extracted with ethyl acetate (2 x 50mL), The combined organic phases were dried over sodium sulfate, concentrated to dryness, and purified by chiral SFC (Chiralpak AD3 4.6 x 100 mm 3u column; eluting with 5-60% MeOH in 3 minutes, 120 bar, 4 mL/min) yielding the separated diastereomeric products, Example 12 (peak 1,32 mg, 14%) and Example 13 (peak 2, 77 mg, 33%). Stereochemistry of the isolated products were assigned by analogy to Jiménez-Osés, G. et al., J. Org. Chem. 2013, 78, 5851-5857.

Example 12: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]7-{( 1 R)-2-hydroxy-1 -[(2S)-tetrahydrofuran-2-yl]ethyl)-3,4-dihydroisoquinolin-1 (2H)-one. ¹H NMR (400 MHz, CD3OD) δ 7.58 (s, 1 H), 6.11 (s, 1 H), 4.76 (s, 2H), 4.10-4.21 (m, 1H),

3.86 - 3.99 (m, 3H), 3.75 - 3.84 (m, 1H), 3.64 - 3.72 (m, 1H), 3.46 - 3.55 (m, 2H), 2.91 3.01 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.73 -1.97 (m, 3H), 1.44 -1.58 (m, 1 H). MS: 465 {M+H]⁺. Chiral analysis: 91% ee/de; rétention time 2.91 min on Chiralpak AD-3 4.6 x 100 mm 3μ column; eluting with 5-60% MeOH in 3 minutes, 120 bar, 4 mL/min.

Example 13: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]7-{( 1 R)-2-hydroxy-1 -[(2R)-tetrahydrofuran-2-yl]ethyl}-3,4-dihydroisoquinolin-1 (2H)-one. ¹H NMR (400 MHz, CD3OD) δ 7.66 (s, 1H), 6.10 (s, 1H), 4.77 (s, 2H), 4.27 (dt, J=7.86,

104

6.16 Hz, 1H), 3.72 - 3.91 (m, 3H), 3.67 (t, J=6.79 Hz, 2H), 3.49 (t, J=6.24 Hz, 2H), 2.95 (t, J=6.17 Hz, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 2.01 -2.13 (m, 1H), 1.68- 1.92 (m, 2H), 1.491.62 (m, 1H). MS: 465 (M+H]⁺. Chiral analysis: 93% ee/de; rétention time 3.21 minutes on Chiralpak AD-3 4.6 x 100 mm 3μ column; eluting with 5-60% MeOH in 3 minutes, 120 bar, 4 mL/min.

Method F

Example 14: 5_l8-dichloro-2-[(4,6-dimethvl-2-oxo-1,2-dihvdropyridin-3-vl)methvll-7(propan-2-vl)-3,4-dihydroisoquinolin-1(2H)-one

Pd(dppf)CI₂

Et₃N, IPrOH

Pt₂O, H₂

EtOAc

Cl

Example 14

A solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl)-7-bromo-5,8dichloro-3,4-dihydroisoquinolin-1(2H)-one (Cpd S, 500 mg, 0.961 mmol), triethylamine (0.30 mL, 2.2 mmol), and [1.1’-bis(diphenylphosphino)ferrocene]dich1oropalladium(ll)dichloromethane complex (24 mg, 0.028 mmol) in 2-propanol (15 mL) under nitrogen in a capped microwave tube was heated at 100 °C for 1 hour in a microwave reactor. After removal of the solvent, the product was extracted into ether (3 x 10 mL) and the combined organic extracts were washed with water (2 x), dried over magnésium sulfate, concentrated, and purified by flash chromatography (silica gel, 0 - 60% EtOAc in heptane) to afford 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-(prop-1 -en-2yî)-3,4-dihydroisoquinolin-1(2H)-one (14a, 240 mg, 52%) as a white foam. ¹H NMR (400MHz, CDCI3) δ 7.37 (d, J=6.8 Hz, 2H), 7.30 - 7.20 (m, 3H), 7.18 (d, J=2.6 Hz, 1H),

6.55 (s, 1H), 5.35 (s, 2H), 5.16 (d, J=1.5 Hz, 1H), 4.85 (d, J=1.5 Hz, 1H), 4.80 (s, 2H),

3.20 (t, J=6.2 Hz, 2H), 2.65 (t, J=6.2 Hz, 2H), 2.34 (s, 3H), 2.26 (s, 3H), 2.01 (s, 3H). MS:

481 [M+H]⁺.

A solution of 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7(prop-1-en-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (14a, 75 mg, 0.16 mmol) and platinum(IV) oxide (71 mg, 0.31 mmol) in ethyl acetate (5 mL) was stirred under a hydrogen balloon for 2 hours. The catalyst was filtered off and the solvent removed in vacuo. The crude product was purified via supercritical fluid chromatography (SFC/ZymorSpher HAP 150 x 21.2mm column with 8% MeOH @ 100 bar, 58 mUmin) to

105 afford 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-(propan-2yl)-3,4-dihydroisoquinolin-1 (2H)-one (Example 14 (7 mg, 10%), as a white solid. ¹H NMR (400 MHz, CDCI3) δ 7.35 (s, 1 H), 5.90 (s, 1 H), 4.78 (s, 2 H), 3.63 (t, J=6.30 Hz, 2 H), 3.5 - 3.6 (m, 1 H), 2.90 (t, J=6.11 Hz, 2 H), 2.35 (s, 3 H), 2.24 (s, 3 H), 1.24 (d, J=6.85 Hz, 6 H). MS: 393 [M+H].

Method G

Example 15: 5.8^ίοΝθΓθ-2-Κ4,6^ίΓΠ6ίΙτ/Ι-2-οχο-1,2-dihvdropyridin-3-vl)methvl1-7-(1 methoxvpropvl)-3,4-dihvdroisoquinolin-1 (2H)-one - isomer A

Example 16 : 5,8-dichloro-2-K4,6-dimethyl-2-oxo-1,2-dihydropvridin-3-yl)methvl1-7-(1 methoxvpropyl)-3,4-dihvdroisoquinolin-1 (2H)-one - isomer B

2-{[2-(benzyloxy)-4,6-dimethylpyridin-3'yl]methyl)-7-bromo-5,8-

O₃, DMS

MeOH

mixture of

A dichloro-3,4-dihydroisoquinolin-1(2/-/)-one (Cpd S, 200 mg, 0.384 mmol), (Z)-3-Hexenyl3-boronic acid catechol ester (155 mg, 0.769 mmol) and césium fluoride (182 mg, 1.20 mmol) in dioxane (2 mL) and water (0.4 mL) was degassed with nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (44.4 mg, 0.0384 mmol) was added, the mixture degassed with nitrogen again, and then heated to 100 °C for 4 hours. The mixture was diluted with water (15 mL) and extracted with EtOAc (3x15 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, concentrated, and purified by column chromatography (silica gel, Petroleum ether/EtOAc=10:1, Rf-0.5) to give (E)-2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-(hex-3-en-3yl)-3,4-dihydroisoquinolin-1(2H)-one (15a, 150 mg, 74.5%) as colorless oil. ¹H NMR (400

106

MHz, CDCI3) δ 7.45 (d, J=7.7 Hz, 2H), 7.37 - 7.34 (m, 3H), 7.19 (s, 1 H), 6.62 (s, 1 H), 5.43 (s, 2H), 5.28 (t, J=6.8 Hz, 1H), 4.88 (s, 2H), 3.28 (t, J=6.4 Hz, 2H), 2.73 (t, J=6.4 Hz, 2H), 2.45-2.43 (m, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 2.19 (quint, J= 7.6 Hz, 2H), 1.04 (t, J=7.6 Hz, 3H), 0.89-0.86 (m, 4H).

A flow of ozone was bubbled through a stirred solution of (E)-2-((2-(benzyloxy)-4,6dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-(hex-3-en-3-yl)-3,4-dihydroisoquinolin-1(2H)one (15a, 864 mg, 1.65 mmol) in methanol (46 mL) at-78 °C until a light purple color was obtained (—10 minutes). Nitrogen was bubbled into the solution until the purple color had disappeared, then dimethylsulfide (0.4 mL) was added, and the solution stirred at 10 °C for 3 hours. The reaction mixture was concentrated in vacuum and the residue purified by column chromatography (silica gel, petroleum ether/EtOAc= 6:1, Rf~0.5) to give 2-((2(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-propionyl-3,4dihydroisoquinolin-1(2H)-one (15b, 346 mg, 42.1%) as yellow oil.

Sodium borohydride (52.6 mg, 1.39 mmol) was added to a cooled (0 °C) solution of 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-propionyl-3,4dihydroisoquinolin-1(2H)-one (15b, 346 mg, 0.696 mmol) in methanol (20 mL), and stirring continued for 1 hour at 10 °C. The reaction was quenched with Sat.NH4CI (30 mL), extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over sodium sulfate, and concentrated in vacuum. The residue was purified by column chromatography (silica gel, Petroleum ether/EtOAc=2:1, Rf~0.6), affording racemic 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-(1 hydroxypropyl)-3,4-dihydroisoquinolin-1 (2H)-one (15c, 300 mg, 86.4%) as colorless oil.

Potassium te/t-butoxide (111 mg, 0.985 mmol) and iodomethane (140 mg, 0.985 mmol) were added to a cooled (10 °C) solution of 2-((2-(benzyloxy)-4,6-dimethylpyridin-

3-yl)methyl)-5,8-dichloro-7-(1-hydroxypropyl)-3,4-dihydroisoquinolin-1(2H)-one (15c, 246 mg, 0.493 mmol) in N,N-dimethylformamide (25 mL), and stirred at 10 °C overnight. The reaction was quenched with water (30 mL), extracted with EtOAc (3 x 35 mL). The combined organic layers were washed with brine (35 mL), dried over sodium sulfate, concentrated, and purified by column chromatography (silica gel, Petroleum ether/EtOAc=5:1), yielding racemic 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-

5,8-dichloro-7-(1-methoxypropyl)-3,4-dihydroisoquinolin-1 (2H)-one (15d, 148 mg, 58.5%) as yellow oil.

Trifluoroacetic acid (9 mL) was added dropwise to a stirred solution of 2-((2(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-(1-methoxypropyl)-3,4

107 dihydroisoquinolin-1(2H)-one (15d, 218 mg, 0.423 mmol) In dichloromethane (9 mL) at 10 °C. The resulting mixture was stirred at 25 °C overnight. The mixture was concentrated in vacuum and the residue purified by column chromatography (silica gel, CH2CI2/MeOH=10:1, Rf~0.55) to give racemic 5,8-dichloro-2-((4,6-dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl)-7-(1-methoxypropyl)-3,4-dihydroisoquinolin-1(2H)-one (15e, 150 mg, 83.8%) as pink oil. This racemic mixture was separated by preparatory SFC [column: (AD (250 mm*30 mm, 5um)), mobile phase: 25% MeOH NH3H2O, Flow rate: 50mL/min, wavelength: 220 nm, workup: lyophilization] to give Isomer A (Example 15, 45.65 mg, 31.4%) as a white solid and Isomer B (Example 16, 31.8 mg, 21.2%) as an offwhite solid. The absolute stereochemistry of each isomer was not determined.

Example 15: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]7-(1-methoxypropyl)-3,4-dihydroisoquinolin-1(2H)-one - isomer A. ¹H NMR (400 MHz, CDCI3) δ 11.88 (br s, 1 H), 7.53 (s, 1 H), 5.94 (s, 1 H), 4.78 (s, 2H), 4.69-4.66 (m, 1 H), 3.65 (t, J = 4.8 Hz, 2H), 3.24 (s, 3H), 2.93 (t, J = 6.2 Hz, 2H), 2.36 (s, 3H), 2.29 (s, 3H), 1.76-

1.72 (m, 1 H), 1.65-1.60 (m, 1 H), 0.96 (t, J = 7.0 Hz, 3H). MS: 423 [M+H]⁺. Chiral analysis: 100% ee; column: Chiralpak AD-H 250 x 4.6mm I.D., 5um; rétention time: 8.04 min; mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%; flow rate: 2.5mL/min; wavelength: 220nm.

Example 16: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]7-(1-methoxypropyl)-3,4-dihydroisoquinolin-1(2H)-one - isomer B, ¹H NMR (400 MHz, CDCI3) δ 10.88 (br s, 1 H), 7.53 (s, 1 H), 5.93 (s, 1 H), 4.77 (s, 2H), 4.69-4.66 (m, 1 H), 3.673.63 (m, 2H), 3.24 (s, 3H), 2.93 (t, J = 5.8 Hz, 2H), 2.36 (s, 3H), 2.28 (s, 3H), 1.78-1.73 (m, 1H), 1.65-1.58 (m, 1H), 0.96 (t, J = 7.2 Hz, 3H). MS: 423 [M+H]⁺. Chiral analysis: 99.6% ee; column: Chiralpak AD-H 250 x 4.6mm I.D., 5um; rétention time: 8.34 min; mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%; flow rate: 2.5mL7min; wavelength: 220nm.

Method H

Example 75: 5,8-dichloro-2-[(4,6-dimethvl-2-oxo-1,2-dihvdropvridin-3-vnmethvl1-7-{1-f1(hvdroxvacetvl)azetidin-3-vlidene1ethvn-3,4-dihvdroisoquinolin-1(2H)-one.

108

DCM

CBr₄, PPh₃

76a

C!	O	OBn
^b,yS		Il V	iPrMgCI-LiCI, (Bu)₃SnCI Bu₃Sn
	s		THF
I et	Cpd S

O

Jk^OAc

1) Cl

Et₃N, DCM

2) Cs₂CO₃, MeOH

A solution of triphenylphosphine (15.83 g,

60.35 mmol) in anhydrous dichloromethane (16 mL) was cooled to 0 °C and degassed by sparging with nitrogen for minutes. Carbon tetrabromide (9.98 g, 30.1 mmol) was added, and the solution stirred at 0 °C for 5 minutes before a solution of 3-oxo-azetidine-1 -carboxylic acid fert-butyl ester (2.52 g, 14.7 mmol) in anhydrous dichloromethane (7 mL) was added dropwise via syringe, over 1 minutes. After stirring at 0 °C for 20 minutes, the reaction was allowed to stir at room température for 22.5 hours. Heptane (100 mL) was added and the resulting precipitate removed by filtration. The filtrate was concentrated to give 7.82 g off-white solid. This solid was stirred in 100 mL heptane with sonication, and then residual solids removed by suction filtration. The filtrate was concentrated to give fert-butyl 3(dibromomethylene)azetidine-l-carboxylate (75a, 4.59 g, 95% yield) as a white solid. ¹H

NMR (400 MHz, CDCI3) δ 4.32 (s, 4H), 1.46 (s, 9H). MS: 226, 228, 230 [M-Boc+H]⁺.

To a solution of fert-butyl 3-(dibromomethylene)azetidine-1-carboxylate (75a, 542 mg, 1.66 mmol) in THF (16.6 mL) at -78 °C was added n-butyllithium (1.6M solution in hexanes, 1.86 mL, 2.98 mmol). After 30 minutes, the reaction was treated with

109 iodomethane (325 uL, 5.22 mmol) and stirring continued at -78 °C for one hour. The reaction was quenched with sat. aq. NhhCI and extracted with MTBE. The organic layer was concentrated and purified on silica gel (Eluting with 0-25% ethyl acetate in heptane) to give tert-butyl 3-(1-bromoethylidene)azetidine-1-carboxylate (75b 0.230g, 53% yield) as a clear oil. ¹H NMR (400 MHz, CDCI3) δ 4.38-4.43 (m, 2H), 4.31-4.37 (m, 2H), 2.14 (quint, J=1.74 Hz, 3H), 1.46 (s, 9H).

Isdpropylmagnesium chloride lithium chloride complex (1.3M solution in THF, 2.00 mL, 2.60 mmol , 2.00 mL) was added to a cooled (-40 °C, acetonitrile/dry ice bath) solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-7-bromo-5,8-dichloro-3,4dihydroisoquinolin-1(2H)-one (Cpd S, 657 mg, 1.26 mmol) in THF (12.6 mL), and the mixture stirred for one hour. Tri-n-butyltin chloride (600 uL, 72.2 mmol) was added, and the flask was warmed to 0 °C in an ice bath for 30 minutes. The reaction was quenched with sat. aq. NH4CI and extracted with MTBE. The MTBE layer was washed with brine, concentrated, and the resulting crude oil purified on silica gel (eluting with 0-30% ethyl acetate in heptane) to give 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8dichloro-7-(tributylstannyl)-3,4-dihydroisoquinolin-1(2H)-one (75c, 0.699 g, 76%) as a clear, thick oil. ¹H NMR (400 MHz, DMSO-de) δ 7.42 (d, J=7.09 Hz, 2H), 7.37 (s, 1H), 7.22-7.34 (m, 3H), 6.74 (s, 1H), 5.37 (s, 2H), 4.69 (s, 2H), 3.22 (t, J=5.99 Hz, 2H), 2.72 (t, J=5.87 Hz, 2H), 2.35 (s, 3H), 2.30 (s, 3H), 1.51 (quint, J=7.76 Hz, 6H), 1.08-1.35 (m, 12H), 0.85 (t, J=7.34 Hz, 9H). MS: 731 [M+H]⁺ = 731.

A mixture of 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7(tributylstannyl)-3,4-dihydroisoquinolin-1(2H)-one (75c, 251 mg, 0.344 mmol) and tertbutyl 3-(1-bromoethylidene)azetidine-1-carboxylate (75b, 103 mg, 0.393 mmol) 1,4dioxane (4.00 mL) was treated with tetrakis(triphenylphosphino)palladium(0) (60.8 mg, 0.0526 mmol), and copper (I) iodide (10.0 mg, 0.0525 mmol). Nitrogen was bubbled through the mixture for 10 minutes, then the vial was sealed and irradiated in a microwave reactor at 120 °C for 2 hours. Dioxane was removed under vacuum, and the resulting oil was purified on silica gel (eluting with 0-40% ethyl acetate in heptane) to give tert-butyl 3(1-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4tetrahydroisoquinolin-7-yl)ethylidene)azetidine-1-carboxylate (75d, 49 mg, 23% yield) as a clear gum. ¹H NMR (400 MHz, CDCI3) δ 7.43-7.49 (m, 2H), 7.30-7.39 (m, 3H), 7.21 (s, 1H), 6.65 (s, 1H), 5.47 (s, 2H), 4.87 (s, 2H), 4.57 (br. s., 2H), 4.24 (br. s., 2H), 3.29 (t, J=6.24 Hz, 2H), 2.73 (t, J=6.24 Hz, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 1.87 (s, 3H), 1.45 (s, 9H). MS: 622, 624 [M+H]⁺.

110

A solution of fert-butyl 3-(1-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)ethylidene)azetidine-1 -carboxylate (75d, 49 mg, 0.079 mmol) in trifluoroacetic acid (5 mL, 70 mmol) was stirred at room température for 6 hours. The solution was concentrated to dryness. The residue was dissolved in methanol and purified by SCX column (Varian Bond elute SCX, 2g, 100 % MeOH to 3.5M NH3 in MeOH) to give crude 7-(1-(azetidin-3-ylidene)ethyl)-5,8-dichloro-2((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2W)-one (Example 74, 38 mg, 100% yield) as a clear gum, which was used without further purification in the next step. MS: 432, 434 [M+H]⁺.

To a cooled (0 °C) solution of crude 7-(1-(azetidin-3-ylidene)ethyl)-5,8-dichloro-2((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (Example 74, 24 mg, 0.056 mmol) in dichloromethane (3.0 mL) was added triethylamine (10 uL, 0.072 mmol) and then acetoxy acetyl chloride (6.5 uL, 0.060 mmol). The reaction was stirred for 30 minutes and then quenched with methanol. The mixture was concentrated, re-dissolved in methanol (5 mL), treated with césium carbonate (45 mg, 0.14 mmol), and stirred at room température overnight. The resulting solution was concentrated to dryness. The residue was dissolved in DMF, filtered, and purified by préparative HPLC to give 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3yl) methy l]-7-{ 1 -[1 -(hydroxyacetyl)azetidin-3-ylidene]ethyl)-3,4-dihydroisoquinolin-1 (2H)one (Example 75, 9.38 mg, 34% yield) as a white powder. ¹H NMR (400 MHz, DMSO-de) δ 11.54 (br. s., 1H), 7.51 (s, 1H), 5.89 (s, 1H), 4.81-4.99 (m, 2H), 4.51-4.60 (m, 3H), 4.48 (br. s., 1H), 4.19 (br. s., 1H), 3.83-4.01 (m, 2H), 3.46 (t, J=6.11 Hz, 2H), 2.88 (t, J=5.87 Hz, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.85 (br. s., 3H). MS; 490, 492 [M+H]⁺.

Method I

Example 34: (±)-5,8-dichloro-2-r(4,6-dimethyl-2-oxo-1,2-dihydropvridin-3-vl)methvl1-7(f1-(hvdroxvacetvl)piperidin-4-vl](methoxv)methvn-3_l4-dihvdroisoquinolin-1(2H)-one.

Example 35: 5,8-dichloro-2-r(4,6-dimethvl-2-oxo-1,2-dihvdropyridin-3-vl)methvl1-7-if1(hvdroxvacetyl)piperidin-4-vn(methoxv)methyn-3,4-dihvdroisoquinolin-1(2H)-one_______₌

Isomer B.

Example 36: 5,8-dichloro-2-f(4,6-dimethvl-2-oxo-1,2-dihvdropyridin-3-vl)methvl1-7-{f1(hvdroxvacetvl)piperidin-4-vl1(methoxv)methvlÎ-3,4-dihvdroisoquinolin-1(2H)-one________:

Isomer A.:

111

^Cl Cpd S

\l-Boc iPrMgCt-LICI THF/Dioxane

O Cl

Ricemata

Eximpie 34

To a solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl)-7-bromo-5,8dichloro-3,4-dihydroisoquinolin-1(2H)-one (Cpd S, 311.0 mg, 0.598 mmol) in tetrahydrofuran (5.0 mL) and 1,4-dioxane (0.5 mL) at -40 °C (in an acetonitrile/dry ice bath) was added isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 0.850 mL, 1.10 mmol) and the reaction was stirred for 1 hour. N-Boc-4-formylpiperidine (0.242 g, 1.14 mmol) was then added, and the flask was warmed to 0 °C in an ice bath. After 1 hour at 0 °C, the solution was quenched with sat. aq. NH4CI and extracted with MTBE. The MTBE layer was concentrated, and the resulting oil purified on silica gel (Isco RediSepRf, 12 g, 10-70% gradient of ethyl acetate in heptane) to give racemic tert-butyl 4-((2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4tetrahydroisoquinolin-7-yl)(hydroxy)methyl)piperidine-1-carboxylate (8a, 0.229 g, 59%) as a white solid. ¹H NMR (400 MHz, CD3OD) δ 7.66 (s, 1H), 7.36-7.44 (m, 2H), 7.18-7.31 (m, 3H), 6.71 (s, 1H), 5.42 (s, 2H), 5.04 (d, J=5.14 Hz, 1H), 4.83 (d, J=1.96 Hz, 2H), 4.08 (d, J=12.72 Hz, 2H), 3.23 (t, J=6.24 Hz, 2H), 2.73 (t, J=6.11 Hz, 2H), 2.53-2.71 (m, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 1.76-1.90 (m, 1H), 1.32-1.62 (m, 13H); MS 654, 656 [M + H]⁺.

A cooled (0 °C) solution of racemic tert-butyl 4-((2-((2-(benzyloxy)-4,6dimethylpyridin-3-yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7yl)(hydroxy)methyl)piperidine-1-carboxylate (8a, 91.0 mg, 0.139 mmol) in THF (3.0 mL) was treatéd with iodomethane (34 mg, 0.24 mmol) and potassium tert-butoxide (0.155 mL of a 1.0M solution in THF, 0.155 mmol). Stirring was continued at 0 °C for 30 minutes, then the mixture partitioned between brine and MTBE. The organic phase was concentrated to dryness, to give crude racemic tert-butyl 4-((2-((2-(benzyloxy)-4,618538

112 dimethylpyridin-3-yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7yl)(methoxy)methyl)piperidine-1-carboxylate (34b, 97 mg, 100%) as a gum. MS: 612,614 [M+H - tBu]⁺.

Trifluoroacetic acid (0.10 mL, 1.35 mmol) was added to a room température solution of crude racemic fert-butyl 4-((2-((2-(benzyloxy)-4,6-dimethylpyridin-3yl)methyl)-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7yl)(methoxy)methyl)piperidine-1-carboxylate (34b, 97 mg, 0.139 mmol) in dichloromethane (5.0 mL). The mixture was stirred at room température for 2 hours, at 35 °C for 4 hours, at room température overnight, then at 40 °C for 6 hours. The solution was diluted with heptane and concentrated to dryness, leaving crude racemic 2-((2(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-(methoxy(piperidin-4yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (34c, 124 mg, 100%) as a gum. MS: 568, 570 [M+H]⁺.

To a cooled (0 °C) solution of crude racemic 2-((2-(benzyloxy)-4,6-dimethylpyridin3-yl)methyl)-5,8-dichloro-7-(methoxy(piperidin-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)one (34c, 124 mg, 0.139 mmol) in dichloromethane (3.0 mL) was added triethylamine (75 uL, 0.54 mmol) and 2-acetoxyacetyl chloride (16 uL, 0.15 mmol). The mixture was stirred at 0 °C for 30 minutes. Trifluoroacetic acid (2.0 mL) was then added and the mixture stirred at room température for 1 hour, then at 40 °C for 7 hours. The solution was concentrated to dryness and further dried under high vacuum for 2 days, giving crude racemic 2-(4-((5,8-dichloro-2-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1 -oxo-

1,2,3,4-tetrahydroisoquinolin-7-yl)(methoxy)methyl)piperidin-1 -yl)-2-oxoethyl acetate (34d, 204 mg, 100%) as a golden oil. MS: 578, 580 [M+H]⁺.

The crude racemic 2-(4-((5,8-dichloro-2-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3yl)methyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)(methoxy)methyl)piperidin-1 -yl)-2oxoethyl acetate (34d, 204 mg, 0.139 mmol) was dissolved in a 7N solution of ammonia in methanol (4 mL, 28 mmol NH3), stirred at room température for 1 hour, then stirred at 40 °C for 4 hours. The solution was concentrated to dryness and the residue purified by préparative HPLC to give (±)-5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3yl)methyl]-7-{[1-(hydroxyacetyl)piperidin-4-yl](methoxy)methyl)-3,4-dihydroisoquinolin1(2H)-one (Example 34, 19.87 mg, 27% yield from 8a) as a white solid. ¹H NMR (400 MHz, CD3OD) δ 7.44 (s, 1H), 6.01 (s, 1H), 4.66 (s, 2H), 4.56 (d, J=5.62 Hz, 1H), 4.35-

4.45 (m, 1H), 4.02-4.17 (m, 2H), 3.57-3.68 (m, 1H), 3.43 (t, J=6.24 Hz, 2H), 3.10 (s, 3H),

113

2.86-2.92 (m, 2H), 2.75-2.85 (m, 1H), 2.40-2.54 (m, 1H), 2.20 (s, 3H), 2.15 (s, 3H), 1.781.87 (m, 1H), 1.60-1.69 (m, 1H), 1.18-1.47 (m, 3H). MS: 536, 538 [M+H]⁺.

The racemate (Example 34) wàs further purified by chiral préparative SFC, affording, after lyophilization, Example 35 (Isomer B, rétention time 13.019 min, 9.09 mg, 12% yield from 8a) and Example 36 (Isomer A, rétention time 10.712 min, 8.36 mg, 11% yield from 8a) as white solids. The absolute configuration of the benzylic carbon in each isomer was not determined.

Example 35: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]7-{[1 -(hydroxyacetyl)piperidin-4-yl](methoxy)methyl}-3,4-dihydroisoquinolin-1 (2H)-one Isomer B. MS: 536, 538 [M+H]⁺. Chiral analysis: -97% ee, rétention time 13.019 min on a Lux Cellulose-4 4.6 x 100 mm 3u column, eluting with 50% MeOH, 120 bar, 4 mL/min.

Example 36: 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]7-{[1 -(hydroxyacetyl)piperidin-4-yl](methoxy)methyl}-3,4-dihydroisoquinolin-1 (2H)-one Isomer A. MS: 536, 538 [M+H]⁺. Chiral analysis: >99% ee, rétention time 10.712 min on a Lux Cellulose-4 4.6 x 100 mm 3u column, eluting with 50% MeOH, 120 bar, 4 mL/min.

Example 81: 5,8-dichloro-2-Î(4-methoxv-6-methvl-2-oxo-1.2-dihvdropvridin-3-vl)methyl17-|‘(R)-methoxv(oxetan-3-vl)methvll-3,4-dihvdroisoquinolin-1(2H)-one.

Example 82: 5,8-dichloro-2-[(4-methoxv-6-methvl-2-oxo-1,2-dihvdropvridin-3-vl)methvn7-[(S)-methoxv(oxetan-3-vl)methvl1-3_t4-dihvdroisoquinolin-1(2H)-one.

	OH Cl	O	OBn	''O CH₃I V	Cl	O	OBn
IPrMgCI-LiCI f~-	MT	['•'ΎιΓ'	yS	KOtBu			A N
THF	M	O O·		THF V-J	Ψ	O'	M
	Cl	T			Cl	I
		81b				81c

To a stirred, room température solution of oxetan-3-ylmethanol (2.20 g, 24.97 mmol) in dichloromethane (110 mL) was added solid pyridinium dichromate (5.87 g, 15.6 mmol) in five portions. The resulting black mixture was stirred at room température for 16 hours. The deep brown suspension was then filtered through a silica gel pad and the filter

114 cake rinsed with dichloromethane (8 x 120 mL). The combined dichloromethane filtrâtes were partially concentrated under reduced pressure at room température (27-30 °C) to afford oxetane-3-carbaldehyde (81a, 3 g, -26% yield) as a colorless solution, 18.7 wt% solution in dichloromethane by NMR. The solution was dried over magnésium sulfate, filtered and used immediately in the next step. 1H NMR (400 MHz, CDCI3) δ 9.95 (d, J=2.4 Hz, 1H), 4.87 (m, 4H), 3.81 (m, 1H).

A solution of 2-((2-(benzyloxy)-4-methoxy-6-methylpyridin-3-yl)methyl)-7-bromo-

5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (Cpd SS, 500 mg, 0.932 mmol) in anhydrous THF (7 mL) was cooled to -65 °C, then isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 2.15 mL, 2.80 mmol) was added dropwise over 3 minutes. The resulting brown solution was stirred at -65 °C for 10 minutes, then warmed to -10 °C for 30 minutes. To this was oxetane-3-carbaldehyde (81a, -2.2 g, -4.8 mmol, -18.7 wt% solution in dichloromethane) dropwise over 2 minutes, causing the color to change to Irght yellow. Stirring was continued at -5 °C for 30 minutes. The reaction was quenched with glacial acetic acid (0.5 mL) and diluted with ethyl acetate (10 mL), then washed with sat. aq. NaHCO3/sat. aq. NaCI (1/1 v/v, 3x15 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 1/1 petroleum ether/ethyl acetate) to give 2-((2-(benzyloxy)-4-methoxy-6methylpyridin-3-yl)methyl)-5,8-dichloro-7-(hydroxy(oxetan-3-yl)methyl)-3,4dihydroisoquinolin-1(2H)-one (81b, 300 mg, 59% yield, racemate) as a white solid. MS: 543 [M+H]⁺.

lodomethane (133 mg, 0.938 mmol) was added dropwise to a cooled (-5 °C) suspension of 2-((2-(benzyloxy)-4-methoxy-6-methylpyrîdin-3-yl)methyl)-5,8-dichloro-7(hydroxy(oxetan-3-yl)methyl)~3,4-dihydroisoquinolin-1(2H)-one (81b, 300 mg, 0.552 mmol) in anhydrous THF (5 mL). Potassium tert-butoxide (1.0M solution in THF, 0.938 mL, 0.938 mmol) was added, and the mixture stirred at 0 °C for 1 hour. The reaction mixture was partitioned between sat. aq. NaCI (15 mL) and MTBE (3x15 mL). The combined organic extracts were washed with sat. aq. NaCI (30 mL), dried over sodium sulfate, concentrated, and purified by silica gel chromatography (eluting with 1/1 petroleum ether/ethyl acetate) to give racemic 2-((2-(benzyloxy)-4-methoxy-6methylpyridin-3-yl)methyl)-5,8-dichloro-7-(methoxy(oxetan-3-yl)methyl)-3,4dihydroisoquinolin-1(2H)-one (81c, 280 mg, 91% yield) as a yellow gum. MS: 557 [M+H]⁺.

A room-temperature mixture of 2-((2-(benzyloxy)-4-methoxy-6-methylpyridin-3yl)methyl)-5,8-dichloro-7-(methoxy(oxetan-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one

115 (81c, 100 mg, 0.179 mmol) and PtO2 (21 mg, 0.092 mmol) in ethyl acetate (4 mL) was stirred under a hydrogen balloon for 3 days. The solution was filtered through a Celite pad. The flask and filter pad were rinsed with ethyl acetate (2x10 mL). The combined filtrâtes were concentrated and purified by préparative thin layer chromatography (silica gel, eluting with 10/1 dichloromethane/methanol) to give racemic 5,8-dichloro-2-[(4methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[methoxy(oxetan-3-yl)methyl]-

3,4-dihydroisoquinolin-1(2H)-one (81 d, 45 mg, 54% yield) as a white solid.

Multiple batches of racemic 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-7-[methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)one (81 d, 140 mg total) were combined for chiral séparation by préparative SFC [Column: (R.R)Whelk 01 250mm*30mm,5um; mobile phase: base-ETOH; wavelength: 220 nm; workup: lyophilization] to give Example 81 (50.34 mg, 36% yield) as a gray solid, and, after further purification by préparative TLC (silica gel, eluting with 10/1 dichloromethane/methanol), Example 82 (22.83 g, 16% yield) as a brown solid. A smallmolecule X-Ray crystal structure of Example 82 shows it to hâve absolute (S) stereochemistry, so absolute (R) stereochemistry was attributed to its enantiomer, Example 81.

Example 81: 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3yl)methyl]-7-[(fî)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1 (2H)-one. ¹H NMR (400 MHz, CDCI3) δ 12.34 (brs, 1H), 7.49 (s, 1H), 5.93 (s, 1H), 5.05 (d, J=6.0 Hz, 1H),

4.78- 4.61 (m, 6H), 3.88 (s, 3H), 3.50-3.48 (m, 2H), 3.38-3.37 (m, 1H), 3.31 (s, 3H), 2.94 (t, J=6.2 Hz, 2H), 2.35 (s, 3H). MS: 489 [M+Na]+. Chiral analysis: 100% ee; rétention time 9.85 min; column (R.R)Whelk 01, 250x4.6mm I.D., 5um; mobile phase 50% éthanol (0.05% DEA) in CO2; wavelength 220 nm.

Example 82: 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3yl)methyl]-7-[(fî)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1 (2H)-one.¹H NMR (400 MHz, CDCI3) δ 12.38 (brs, 1H), 7.49 (s, 1H), 5.92 (s, 1H), 5.05 (d, J=6.0 Hz, 1H),

4.78- 4.64 (m, 6H), 3.87 (s, 3H), 3.50-3.47 (m, 2H), 3.38-3.37 (m, 1H), 3.31 (s, 3H), 2.93 (t, J=6.2 Hz, 2H), 2.35 (s, 3H). MS: 467 [M+H]⁺. Chiral analysis: 98% ee; rétention time 8.65 min; column: (R.R)Whelk 01, 250x4.6mm I.D., 5um; mobile phase 50% éthanol (0.05% DEA) in CO2; wavelength 220 nm.

116

Example 83: 8-chloro-2-i(4-methoxy-6-methvl-2-oxo-1,2-dihvdropyridin-3-yl)methvll-7{(H)-methoxvK3fî)-tetrahvdrofuran-3-vllmethvlÎ-5-methvl-3.4-dihvdroisoqiiinolin-1(2H)one

Example 84: 8-chloro-2-r(4-methoxv-6-methyl-2-oxo-1,2-dihvdropyridin-3-yl)methvl1-7((F?*)-methoxy[(3S*)-tetrahvdrofuran-3-vl1methvlT5-methvl-3,4-dihydroisoquinolin-1(2H)one.

Example 85: 8-chloro-2-i(4-methoxv-6-methvl-2-oxo-1₁2-dihvdropvridin-3-vl)methyll-7{(S^-methoxvr(3R>tetrahvdrofuran-3-vllmethvn-5-methvl-3,4-dihvdroisoquinolin-1(2H)one

Example 86: 8-chloro-2-lï4-methoxv-6-meÎhvl-2-oxo-1,2-dihvdropyridin-3-vl)methyl1-7{(S)-methoxvlï3S)-tetrahvdrofuran-3-vilmethvn-5-methvl-3,4-dihvdroisoquinolin-1(2H)one.

Cpd U U 83a

CHJ KOtBu

THF

Chiral prep SFC

Aqueous tetrahydrofuran-3-carboxaldehyde solution (~4.0 mL of 50 wt% in water, 4.0 g) was extracted with dichloromethane (2 x 2.5 mL). The combined organic layers were cooled (15 °C) and phosphorus pentoxide slowly added. The resulting dark solution was filtered to remove solids and the yellow filtrate (—16 wt% tetrahydrofuran-3carboxaldehyde in dichloromethane by NMR) was promptly used as described below.

Isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 3.73 mL, 4.85 mmol) was added dropwise to a cooled (-70 °C) solution of 2-((2-(benzyloxy)-4methoxy-6-methylpyridin-3-yl)methyl)-8-chloro-7-iodo-5-methyl·3,4-dihydroisoquinolin1(2H)-one (Cpd UU, 910 mg, 1.617 mmol) in anhydrous THF (10 mL) over 5 minutes. The resulting brown mixture was stirred at -70 °C for 30 minutes, then the tetrahydrofuran

117

3-carboxaldehyde solution prepared above (3.98 g of -16 wt% in dichloromethane, -636 mg tetrahydrofuran-3-carboxaldehyde, -16.35 mmol) was added dropwise over 5 minutes. Stirring was continued at -70 °C for 30 minutes. The reaction was quenched with glacial acetic acid (0.5 mL) and diluted with ethyl acetate (80 mL), then washed with sat. aq. NaHCO3/sat. aq. NaCI (1/1 v/v, 3 x 35 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 1/1 petroleum ether/ethyl acetate) to give 2-((2-(benzyloxy)-4-methoxy-6methylpyridin-3-yl)methyl)-8-chloro-7-(hydroxy(tetrahydrofuran-3-yl)methyl)-5-methyl-

3,4-dihydroisoquinolin-1 (2H)-one (83a, 450 mg, 52% yield, mixture of 4 diastereomers) as a white solid. ¹H NMR (400 MHz, CDCI3) δ 7.37-7.46 (m, 3H), 7.20-7.31 (m, 3H), 6.39 (s, 1 H), 5.44 (s, 2H), 5.22-5.31 (m, 1 H), 4.87 (s, 2H), 3.88-4.02 (m, 1 H), 3.83 (s, 3H), 3.65-

3.82 (m, 3H), 3.16 (t, J=5.99 Hz, 2H), 2.71-2.89 (m, 1H), 2.55 (t, J=6.17 Hz, 2H), 2.44 (s, 3H), 2.20 (s, 3H), 1.66-1.95 (m, 3H).

lodomethane (225 mg, 1.58 mmol) was added dropwise to a cooled (-5 °C) suspension of 2-((2-(benzyloxy)-4-methoxy-6-methylpyridin-3-yl)methyl)-8-chloro-7(hydroxy(tetrahydrofuran-3-yl)methyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (83a, 500 mg, 0.931 mmol in THF (15 mL), followed by potassium tert-butoxide (1.0M solution in THF, 1.58 mL, 1.58 mmol). The mixture was stirred at 0 °C for 1 hour. Glacial acetic acid (0.5 mL) and ethyl acetate (100 mL) were added, and the solution washed with sat. aq. NaHCO3 (3 x 20 mL) and brine (30 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 1/1 petroleum ether/ethyl acetate), to give 2-((2-(benzyloxy)-4-methoxy-6-methylpyridin-3yl)methyl)-8-chloro-7-(methoxy(tetrahydrofuran-3-yl)methyl)-5-methyl-3,4dihydroisoquinolin-1(2H)-one as a mixture of 4 diastereomers (400 mg, 70% yield).

The stereoisomers were separated by préparative chiral SFC (column: AD, 250*30mm, 5um, mobile phase: 30% IPA+NH3H2O 60mL/min, wavelength: 220 nm, workup: lyophilization) to give 140 mg of peak 12 (mixture of peak 1 and 2) and 120 mg of peak 34 (mixture of peak 3 and 4) as white solids.

The peak 12 mixture (140 mg) was re-separated by préparative SFC (column: AD, 250*30mm, 5um, mobile phase: 25% MeOH+NH3H2O 60mL/min, wavelength: 220 nm, workup: lyophilization) to give enantio-enriched peak 1 (60 mg, 81% chiral purity, further purified as described below) and pure peak 2 (1610b, 60 mg, 12% yield, 96% chiral purity, used without further purification).

118

The peak 34 mixture (120 mg) was re-separated by préparative SFC (Column: AD, 250*30mm, 5um, mobile phase: 25% MeOH+NH3H2O 60mL/min, wavelength: 220 nm, workup: lyophilization) to give pure peak 3 (1613b, 50 mg, 9.8% yield, 95% chiral purity, used without further purification) and enantio-enriched peak 4 (50 mg, 88% chiral purity, further purified as described below).

The enantio-enriched peak 1 material (60 mg, 81% chiral purity) was further purified by préparative SFC (column: AD, 250*30mm, 5um, mobile phase: 25% MeOH+NH3H2O 70mL7min, wavelength: 220 nm, workup: lyophilization) to give pure peak 1 (83b, 45 mg, 8.7% yield, 98% chiral purity).

The enantio-enriched peak 4 material (50 mg, 88% chiral purity) was further purified by préparative SFC (column: AD, 250*30mm, 5um, mobile: 25% MeOH+NH3H2O 70mL/min, wavelength: 220 nm, workup: lyophilization) to give pure peak 4 (1613b, 45 mg, 8.7% yield, 99% chiral purity). Absolute or relative stereochemistry of each isomer was not determined at this stage.

A stirred solution of 2-((2-(benzyloxy)-4-methoxy-6-methylpyridin-3-yl)methyl)-8chloro-7-(methoxy(tetrahydrofuran-3-yl)methyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)one peak 1 (83b, 45 mg, 0.082 mmol) in dichloromethane (2 mL) was treated with TFA (2 mL) at room température. The mixture was heated to 30 °C for 16 hours, then the solution was diluted with dichloromethane (20 mL) and concentrated to dryness. The residue was purified by silica gel chromatography (eluting with 10/1 dichloromethane/methanol) to give

8-chloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-{(R)methoxy[(3R)-tetrahydrofuran-3-yl]methyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (Example 83, 18.55 mg, 50% yield, 100% ee) as a white solid. A small molécule X-Ray crystal structure of Example 83confirms it has absolute (R,R) configuration. ¹H NMR (400 MHz, CDCI3) δ 12.36 (brs, 1H), 7.29 (s, 1H), 5.91 (s, 1H), 4.85-4.75 (m, 3H), 3.89-3.83 (m, 6H), 3.71-3.69 (m, 1H), 3.47-3.44 (m, 2H), 3.16 (s, 3H), 2.76-2.73 (m, 2H), 2.58-2.54 (m, 1H), 2.34 (s, 3H), 2.26 (s, 3H), 1.73-1.70 (m, 2H). MS: 461 [M+H]⁺. Chiral analysis: 100% ee; rétention time 34.91 min; column: Chiralpak IC 250x4.6mm I.D., 5um; mobile phase: 50% éthanol (0.05% DEA) in CO2; flow rate: 2.0mL/min; wavelength: 220 nm.

By the same procedure, the peak 2 stereoisomer (1610b, 60.0 mg, 0.109 mmol) afforded 8-chloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-{(R*)methoxy[(3S*)-tetrahydrofuran-3-yl]methyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (Example 84, 30 mg, 60% yield, 97% ee) as a white solid. The absolute stereochemistry of this isomer was not determined, but the ¹HNMR spectrum shows clear différences from

119 that of Example 83, suggesting that Example 84is either the R,S or S,R isomer. ¹H NMR (400 MHz, CDCI3) δ 12.33 (br. s, 1 H), 7.30 (s, 1 H), 5.91 (s, 1 H), 4.84-4.77 (m, 3H), 3.89-

3.86 (m, 4H), 3.73-3.68 (m, 2H), 3.60-3.58 (m, 1H), 3.46-3.44 (m, 2H), 3.19 (s, 3H), 2.75-

2.73 (m, 2H), 2.64-2.62 (m, 1H), 2.34 (s, 3H), 2.24 (s, 3H), 1.98-1.95 (m, 2H). MS: 461 [M+H]⁺. Chiral analysis: 97% ee, rétention time 39.01 min; column: Chiralpak IC 250x4.6mm I.D., 5um; mobile phase: 50% éthanol (0.05% DEA) in CO2; flow rate: 2.0mL/min; wavelength: 220 nm.

By the same procedure, the peak 3 stereoisomer (85b, 50.0 mg, 0.091 mmol) afforded 8-chloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-{(S*)methoxy[(3R*)-tetrahydrofuran-3-yl]methyl)-5-methyl-3,4-dihydroisoquinolin-1(2H)-one (Example 85, 16.06 mg, 38% yield, 100% ee) as a white solid. The absolute stereochemistry of this isomer was not determined, but the ¹HNMR spectrum shows clear différences from that of Example 83, and is identical to that of Example 84, suggesting that Example 85is either the S,R or R,S isomer. ¹H NMR (400 MHz, CDCI3) δ 12.30 (br s, 1 H), 7.30 (s, 1 H), 5.91 (s, 1 H), 4.84-4.77 (m, 3H), 3.89-3.86 (m, 4H), 3.74-3.66 (m, 2H), 3.59-3.58 (m, 1H), 3.46-3.44 (m, 2H), 3.19 (s, 3H), 2.75-2.73 (m, 2H), 2.65-2.63 (m, 1H),

2.34 (s, 3H), 2.24 (s, 3H), 1.98-1.95 (m, 2H). MS: 461 [M+H]⁺. Chiral analysis: 100% ee, rétention time 29.05 min; column: Chiralpak IC 250x4.6mm I.D., 5um; mobile phase; 50% éthanol (0.05% DEA) in CO2; flow rate: 2.0mL/min; wavelength: 220 nm.

By the same procedure, the peak 4 stereoisomer (86b, 45.0 mg, 0.082 mmol) afforded 8-chloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-{(S)ΠΊβίίΊθχν[(33)-ΙβίΓ3ΐ^ΓθίυΓ3η-3-νΙ]ΠΊβ1ΐΊνΙ}-5-Γηβ^Ι-3,4^ίί^Γθί8ορυίηοΙΐη-1(2Η)-οηβ (Example 86, 14.79 mg, 39% yield, 100% ee) as a white solid. Though it has a different rétention time on the chiral column, the ¹HNMR spectrum of this compound is identical to that of Example 83, which was shown to hâve R,R configuration by X-Ray crystal structure. This suggests that Example 86 is the S,S stereoisomer. ¹H NMR (400 MHz, CDCI3) δ 12.29 (br. s, 1H), 7.30 (s, 1H), 5.91 (s, 1H), 4.84-4.75 (m, 3H), 3.89-3.83 (m, 6H), 3.71-3.69 (m, 1H), 3.47-3.44 (m, 2H), 3.16 (s, 3H), 2.76-2.73 (m, 2H), 2.58-2.56 (m, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 1.73-1.70 (m, 2H). MS: 461 [M+H]⁺. Chiral analysis: 100% ee, rétention time 32.28 min; column: Chiralpak IC 250x4.6mm I.D., 5um; mobile phase: 50% éthanol (0.05% DEA) in CO2; flow rate: 2.0mL7min; wavelength: 220 nm.

Method J

120

Example 87: 5,8-dichloro-2-[(4-methoxy-6-methvl-2-oxo-1,2-dihvdropyridin-3-vl)methvll7-11-(1-methvlazetidin-3-vl)ethvn-3,4-dihvdroisoquinolin-1 (2H)-one - Isomer A.

Example 88: 5.8-dichloro-2-r(4-methoxv-6-methyl~2-oxo-1,2-dihvdropyridin-3-vl)methvl17-[1-(1-methvlazetidin-3-vl)ethvll-3,4-dihvdroisoquinolin-1 (2H)-one - Isomer B.

87b

MeMgBr

THF

H₂C=O

NaBH₃CN Chiral AcOH SFC

MeOH

Isomer A	Isomer B
Exemple 87	Exemple 88

A solution of 1-boc-azetidine-3-carboxylic acid (5.00 g, 24.8 mmol, and CDI (4.23 g, 26.1 mmol) in dichloromethane (100 mL) was stirred at room température for 1 hour, then Ν,Ο-dimethylhydroxylamine hydrochloride (4.0 g, 29.8 mmol) was added and stirring continued at room température for 16 hours. The resulting suspension was washed with water (3 x 30 mL), sat. aq. NaHCO3 (3 x 30 mL), and brine (3 x 30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give tert-butyl 3(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (87a, 5.1 g, 84% yield) as a colorless oil. ¹H NMR (400 MHz, CDCI3) δ 4.14 (br s, 2H), 4.05 (t, J=8.6 Hz, 2H), 3.66 (s, 3H), 3.65 (m, 1H), 3.20 (s, 3H), 1.43 (s, 9H).

Méthylmagnésium bromide (3M solution in THF, 10.4 mL, 31.3 mmol) was added dropwise to a cooled (0 °C) solution of tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine1-carboxylate (87a, 5.1 g, 20.88 mmol) in anhydrous THF (100 mL). Stirring was continued at 0°C for one hour, then at room température for 16 hours. The mixture was cooled to 0 °C and quenched with sat. aq. NaHCO3 (35 mL), then extracted with ethyl

121 acetate (3 x 40 mL). The combined organic extracts were washed with brine (3 x 40 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate from 10:1 to 3:1) to give tert-butyl 3acetylazetidine-1-carboxylate (87b, (3.20 g, 77% yield) as light yellow oil. ¹H NMR (400 MHz, CDCI3) δ 4.05 (d, J=7.6 Hz, 4H), 3.41 (quint, J=7.6 Hz, 1H), 2.18 (s, 3H), 1.43 (s, 9H).

A solution of 2-((2-(benzyloxy)-4-methoxy-6-methylpyridin-3-yl)methyl)-7-bromo-

5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (Cpd SS, 1.20 g, 2.238 mmol) in anhydrous THF (15 mL) was cooled to -60 °C, then isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 5.16 mL, 6.71 mmol) was added dropwise via syringe over 3 minutes. Stîrring was continued at -60 °C for 10 minutes, then at 0 °C for 20 minutes. To this was added tert-butyl 3-(methoxy(methyl)carbamoyl)azetidine-1carboxylate (87a, 892 mg, 4.48 mmol) dropwise, then the mixture stirred at 0 °C for 1 hour. . The mixture was quenched with glacial acetic acid (1 mL) and diluted with ethyl acetate (100 mL). The organic phase was washed with NaHCO3/brine (v/v=1/1,3 x 50 mL) and brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated to give the crude product (2.0 g, yellow oil), which was purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate = 1:1) to give racemic tertbutyl 3-( 1 -(2-((2-(benzyloxy)-4-methoxy-6-methylpyridin-3-yl)methyl)-5,8-dichloro-1 -oxo-

1,2,3,4-tetrahydroisoquinolin-7-yl)-1-hydroxyethyl)azetidine-1-carboxylate (87c, 450 mg, 31% yield) as a white solid. MS: 656 [M+H]⁺.

Trifluoromethanesulfonic acid (0.54 mL, 6.15 mmol) was added dropwise to a cooled (0 °C) solution of racemic tert-butyl 3-(1-(2-((2-(benzyloxy)-4-methoxy-6methylpyridin-3-yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 hydroxyethyl)azetidine-1-carboxylate (87c, 450 mg, 0.685 mmol) in anhydrous dichloromethane (10 mL). The mixture was stirred at 5-10 °C for 1 hour, then re-cooled to 0 °C and more trifluoromethanesulfonic acid (0.54 mL, 6.15 mmol) was added. After stîrring at 2-5 °C for 12 hours, sat. aq. sodium bicarbonate was added to bring the solution to pH ~8. The mixture was concentrated to remove dichloromethane, and the aqueous residue diluted with THF (20 mL). Solid sodium bicarbonate (288 mg, 3.43 mmol) and ditert-butyl dicarbonate (448 mg, 2.06 mmol) were added and the mixture stirred at 2-5 °C for 16 hours, then let stand at 15 °C for 18 hours. The solution was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated to give the crude

122 product (1 g, yellow solid), which was purified first by silica gel chromatography (eluting with 10% methanol in dichloromethane) and then re-purified by préparative SFC (column: AD 250mm*30mm, 5um; mobile phase: 35%Base-ETOH; wavelength: 220 nm; workup: concentration) to give tert-butyl 3-(1-(5,8-dichloro-2-((4-methoxy-6-methyl-2-oxo-1,2dihydropyridin-3-yl)methyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)vinyl)azetidine-1 carboxylate (87d, 256 mg, 68.1%) as a yellow solid. MS: 548 [M+H]⁺.

A suspension of tert-butyl 3-(1-(5,8-dichloro-2-((4-methoxy-6-methyl-2-oxo-1,2dihydropyridin-3-yl)methyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)vinyl)azetidine-1carboxylate (87d, 236 mg, 0.43 mmol) and platinum oxide (80 mg, 0.35 mmol) in ethyl acetate (15 mL) and methanol (5 mL) was stirred at room température under a hydrogen balloon for 3 hours. After filtration to remove solids, the filtrate was concentrated and purified by préparative TLC (silica gel, dichloromethane/methanol = 15:1 to give racemic tert-butyl 3-(1 -(5,8-dichloro-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3yl)methyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)ethyl)azetidine-1 -carboxylate (87e,

180 mg, 76% yield) as a white solid. MS: 549 [M+H]⁺.

A solution of give racemic tert-butyl 3-(1-(5,8-dichloro-2-((4-methoxy-6-methyl-2oxo-1,2-dihydropyridin-3-yl)methyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7yl)ethyl)azetidine-1-carboxylate (87e, 180 mg, 0.327 mmol) in dichloromethane (10 mL) was stirred with HCl (4.0 M solution in methanol, 5 mL, 20 mmol) at 14 °C for 30 minutes. The solution was concentrated to dryness, and the residue dissolved in methanol (5 mL). Concentrated NH4OH was added to bring the pH to -8, and the mixture was again concentrated to dryness, leaving crude, racemic 7-(1-(azetidin-3-yl)ethyl)-5,8-dichloro-2({4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin1(2H)-one (87f, 180 mg, 100%) as a white solid, which was used without further purification.

Glacial acetic acid (0.1 mL) was added to a 15 °C solution of crude, racemic 7-(1 (azetidin-3-yl)ethyl)-5,8-dichloro-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3yl)methyl)-3,4-dihydroisoquinolin-1 (2H)-one (87f, 180 mg, 0.327 mmol) and formaldéhyde (37 wt% in water, 79.5 mg, 0.980 mmol) in methanol (5 mL), and the mixture stirred at 15 °C for 45 minutes. Sodium cyanoborohydride (41 mg, 0.653 mmol) was added and stirring continued at room température for 12 hours. The mixture was quenched with saturated NH4CI solution (2 mL) and stirred at 15 °C for 30 minutes, then concentrated to remove the solvent. The residue was dissolved in dichloromethane/methanol (v/v = 10:1, 50 mL) and filtered. The filtrate was concentrated and purified by préparative HPLC [column:

123

Phenomenex Gemini C18 250*50 10u; mobile phase: from 4% to 34% acetonitrile(with 0.225% formic acid) in water; wavelength: 220 nm; workup: lyophilization] to give the formate sait of (±)-5,8-dichloro-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3yl)methyl)-7-(1-(1-methylazetidin-3-yl)ethyl)-3,4-dihydroisoquinolin-1(2H)-one (110 mg, 66%) as a white solid. The enantiomers of this racemic sait were separated by préparative SFC [column: AD(250mm*30mm,5um); mobile phase: 30%base-ETOH; wavelength: 220 nm; workup: lyophilization], and each enantiomer separately re-purified by préparative HPLC [column: Phenomenex Gemini C18 250*50 10u; mobile phase: from 28% MeCN (0.05%ammonia) in water to 48% MeCN (0.05%ammonia) in water; wavelength: 220 nm; workup: lyophilization], affording isomer A (Example 87,15.67 mg, 16% yield) and isomer B (Example 88, 13.35 mg, 13% yield) as white solids. The absolute stereochemistry was not determined for either isomer.

Example 87: 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3yl)methyl]-7-[ 1 -(1 -methylazetidin-3-yl)ethyl]-3,4-dihydroisoquinolin-1 (2H)-one - Isomer

A. ¹H NMR (400 MHz, CD3OD) δ 7.44 (s, 1H), 6.27 (s, 1H), 4.73 (s, 2H), 3.91 (m, 3H), 3.77-3.68 (m, 2H), 3.41-3.37 (m, 3H), 3.16 (t, J = 7.4 Hz, 1H), 2.95-2.92 (m, 2H), 2.90-

2.83 (m, 2H), 2.39 (s, 3H), 2.34 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H). MS: 464 [M+H]⁺. Chiral analysis: 99% ee; rétention time 5.511 min on Chiralpak AD-3 150x4.6mm I.D., 3um column [mobile phase: A: CO2 B:ethanol (0.05% DEA); gradient: from 5% to 40% of B in 5.0min and hold 40% for 2.5 min, then 5% of B for 2.5 min; wavelength: 220 nm].

Example 88: 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3yl)methyl]-7-[1-(1-methylazetidin-3-yl)ethyl]-3,4-dihydroisoquinolin-1(2H)-one - Isomer

B. ¹H NMR (400 MHz, CD3OD) δ 7.43 (s, 1H), 6.26 (s, 1H), 4.73 (s, 2H), 3.91 (m, 3H), 3.77-3.68 (m, 2H), 3.41-3.37 (m, 3H), 3.12 (brs, 1H), 2.95-2.92 (m, 2H), 2.90-2.83 (m, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 1.16 (d, J = 6.4 Hz, 3H). MS: 464 [M+H]⁺. Chiral analysis: 100% ee; rétention time 5.997 min on Chiralpak AD-3 150x4.6mm I.D., 3um column [mobile phase: A: CO2 B:ethanol (0.05% DEA); gradient: from 5% to 40% of B in 5.0min and hold 40% for 2.5 min, then 5% of B for 2.5 min; wavelength: 220 nm].

Method K

Example 89: (±)-5,8-dichloro-2-r(4,6-dimethvl-2-oxo-1,2-dihvdropvridin-3-vl)methvl1-7[ 1 -(morpholin-4-vÎ)ethvl1-3,4-dihydroisoquinolin-1 (2H)-one.

Example 90: (+)-5,8-dichloro-2-[(4,6-dimethvl-2-oxo-1,2-dihvdropvridin-3-vl)methvH-7f1-(morpholin-4-vl)ethvl]-3,4-dihvdroisoquinolin-1(2H)-one.

124

Example 91 : (-)-5,8-dichloro-2-[(4,6-dimethvl-2-oxo-1,2-dihvdroDvridin-3-vl)methvl1-7 ri-(morpholin-4-vl)ethvll-3.4-dihvdroisoquinolin-1(2H)-one,

Cl O OBn

Cl

O

A,

IPrMgCI-LiCI ZnCI₂, (PhjP^Pd

THF/1,4-dioxane

Cpd S

89d

Example 89

(+) isomer Example 90 (-} leomer Example 91

To a cooled (-40 °C) solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}7-bromo-5,8-dichloro-3,4-dihydroisoquinolin-1(2H)-one (Cpd S, 5.00 g, 9.61 mmol) in anhydrous THF (50 mL) and 1,4-dioxane (5 mL) was added isopropylmagnesium chloride-lithium chloride complex (1.3 M solution in THF, 22.2 mL, 28.8 mmol) via syringe. After stirring at -40 °C for 30 minutes, zinc chloride (1.0 M solution in ether, 11.5 mL, 11.5 mmol) was added. Stirring was continued at -40 °C for 30 minutes, then tetrakis(triphenylphosphine)palladium(0) (1.11 g, 0.961 mmol) and acetyl chloride (1.51 g, 19.2 mmol) were added. The mixture was stirred and allowed to warm to room température over 18 hours. The reaction was quenched with sat. aq. NH4CI (5 mL), diluted with ethyl acetate (30 mL), and washed with sat. aq. NH4CI (40 mL) and brine (40 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 0-30% ethyl acetate in petroleum ether) to give 7-acetyl-2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-3,4dihydroisoquinolin-1(2H)-one (89a, 4.00 g, 78% yield) as a yellow solid. ¹H NMR (400MHz, CDCI3) δ 7.45 (d, J=6.8 Hz, 2H), 7.39 (s, 1 H), 7.38 - 7.27 (m, 3H), 6.63 (s, 1 H),

5.43 (s, 2H), 4.86 (s, 2H), 3.29 (t, J=6.3 Hz, 2H), 2.75 (t, J=6.3 Hz, 2H), 2.63 (s, 3H), 2.42 (s, 3H), 2.34 (s, 3H). MS: 483 [M+H]⁺.

125

Sodium borohydride (47.0 mg, 1.24 mmol) was added to a room température solution of 7-acetyl-2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-3,4dihydroisoquinolin-1 (2H)-one (89a, 200 mg, 0.414 mmol) in methanol (5 mL). After stirring at room température for 30 minutes, the reaction mixture was concentrated and purified by silica gel chromatography (eluting with 0-30% ethyl acetate in petroleum ether) to give

2- ((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8-dichloro-7-(1-hydroxyethyl)-3,4dihydroisoquinolin-1 (2H)-one (89b, 190 mg, 95% yield) as a white solid.

A cooled (0 °C) solution of 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8dichloro-7-(1-hydroxyethyl)-3,4-dihydroisoquinolin-1(2H)-one (89b, 190 mg, 0.391 mmol) and triethylamine (119 mg, 1.17 mmol) in dichloromethane (5 mL) was treated with methanesulfonyl chloride (67.3 mg, 0.587 mmol), then stirred at 0 °C for one hour. The reaction mixture was diluted with dichloromethane (30 mL); washed sequentially with sat. aq. NH4CI, sat. aq. NaHCO3, and sat. aq. NaCI; dried over sodium sulfate, and concentrated to dryness, leavingcrude racemic 1-(2-((2-(benzyloxy)-4,6-dimethylpyridin-

3- yl)methyl)-5,8-dichloro-1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)ethyl methanesulfonate (89c, 225 mg, 100% yield) as a white solid, which was used immediately without further purification.

A suspension of 1-(2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)ethyl methanesulfonate (89c, 100 mg, 0.177 mmol), morpholine (46.4 mg, 0.532 mmol), and potassium carbonate (73.6 mg, 0.532 mmol) in acetonitrile (5 mL) was stirred at reflux (85 °C) for 2 hours. After cooling to room température, the suspension was filtered to remove solids. The filtrate was concentrated and purified by silica gel chromatography (eluting with 0-30% ethyl acetate in petroleum ether) to give racemic 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-

5,8-dichloro-7-(1-morpholinoethyl)-3,4-dihydroisoquinolin-1(2H)-one (89d, 90 mg, 91% yield, 80% pure by LCMS) as a gum. MS: 576 [M+Na]⁺.

A solution of racemic 2-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-5,8dichloro-7-( 1 -morpholinoethyl)-3,4-dihydroisoquinolin-1 (2H)-one (89d, 90 mg, 0.16 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was stirred at room température for 19 hours. The solution was evaporated to dryness, and then the residue was dissolved in toluene (10 mL) and basified to pH 8-9 by adding a few drops of conc. NH4OH. The solution was concentrated and purified by préparative HPLC to give (±)-5,8-dichloro-2[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[1-(morpholin-4-yl)ethyl]-3,4dihydroisoquinolin-1 (2H)-one (Example 89, 29.49 mg, 39% yield) as a white solid.

126

NMR (400MHz, CDCI3) δ 7.74 (s, 1H), 5.94 (s, 1H), 4.87 - 4.70 (m, 2H), 4.00 (q, J=6.3 Hz, 1H), 3.76 - 3.59 (m, 6H), 2.99 - 2.81 (m, 2H), 2.53 (br. s., 2H), 2.36 (m, 5H), 2.29 (s, 3H), 1.24 (d, J=6.5 Hz, 3H). MS: 464 [M+H]⁺.

The racemic material (Example 89) was further purified by chiral SFC séparation 5 conditions to provide the compounds of Example 90 and Example 91.

Additional compounds of the invention were prepared by modifications of the methods exemplified herein. Selected compounds prepared and corresponding characterization data are presented in Table 1 below.

127

Table 1

Ex. No.	Structure/IUPAC name	Method	LCMs [M+H]⁺	¹H NMR (ppm)	Stereochemistry Note
1	HCL _n > Cl 0 0 Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{(1 R)-2-hydroxy-1[(3R)-tetrahydrofuran-3-yl]ethyl}3,4-dihydroisoquinolin-1(2H)-one	A	465	¹H NMR (400 MHz, CD30D) δ 7.63 (s, 1H), 6.12 (s, 1H), 4.77 (s, 2H), 3.94-3.90 (m, 1 H), 3.81- 3.80 (m, 3H), 3.59-3.57 (m, 2H), 3.51-3.49 (m, 2H), 3.17-3.10 (m, 1H), 2.98-2.95 (m, 2H), 2.71 (br s, 1H), 2.30 (s, 3H), 2.29-2.25 (m, 1H), 2.25 (s, 3H), 1.83-1.78 (m, 1H)	R,R isomer; stereochemistry determined from x-ray crystal structure of enantiomeric compound (Ex. 4); Chiral purity: 95.66%; rétention time: 6.867 min; column: Chiralpak AD-3 150x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2; flow rate: 2.5mL/min
2	^H0> Cl 0 0 /ΎϊΎ'Ν'Υ'ΝΗ v ÇU Λα Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3-	A	465	¹H NMR (400 MHz, CD3OD) δ 7.62 (s, 1H), 6.11 (s, 1H), 4.76 (s, 2H), 4.13-4.11 (m, 1 H), 3.78- 3.75 (m, 1H), 3.69-3.68 (m, 2H), 3.61-3.59 (m, 3H), 3.51-3.50 (m, 2H), 2.98-2.95 (m, 2H), 2.65 (br	Single enantiomer, either R,S or S,R but absolute stereochemistry unknown; Enantiomer of Ex. 3; Chiral purity: 98.70%; rétention time: 7.309 min; column:

128

	y I) m ethyl]-7-{( 1 R)-2-hydroxy-1 - [(3S)-tetrahydrofuran-3-yl]ethyl}- 3,4-dihydroisoquinolîn-1(2H)-one			s, 1 H), 2.30 (s, 3H), 2.25 (s, 3H), 1.77-1.75 (m, 1 H), 1.42-1.37 (m, 1H)	Chiralpak AD-3 150x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2; flow rate: 2.5mL/min
3	HCL				Single enantiomer, either S,R or
	1 Cl U □ 1 T IL H			¹H NMR (400 MHz, CD30D) δ
					R,S isomer but absolute
	\T il ΪΪΓ			7.62 (s, 1H), 6.11 (s, 1H), 4.76
					stereochemistry unknown;
	l			(s, 2H), 4.12-4.11 (m, 1 H), 3.80-
	Cl				Enantiomer of Ex. 2
	5,8-dichloro-2-[(4,6-dimethyl-2-			3.78 (m, 1H), 3.69-3.67 (m, 3H),	Chiral purity: 96.48%; rétention
		A	465	3.67-3.62 (m, 2H), 3.61-3.50 (m,
	oxo-1,2-dihydropyridin-3-				time: 8.021 min; column:
	y I) methy l]-7-{( 1 S*)-2-hydroxy-1 -			2H), 2.98-2.95 (m, 2H), 2.65 (br	Chiralpak AD-3 150x4.6mm I.D.,
	[(3R*)-tetrahydrofuran-3-yl]ethyl}-			s, 1 H), 2.29 (s, 3H), 2.25 (s, 3H),	3um; mobile phase: 5-40%
	3,4-dihydroisoquinolin-1 (2H)-on			1.77-1.74 (m, 1 H), 1.42-1.37 (m, 1 kh	éthanol (0.05% DEA) in CO2; flow
				1ΙΊ)	rate: 2.5mL/min
4	ho. „ \ Cl 0 0			¹H NMR (400 MHz, CD3OD) δ	Known to be S,S by X-ray crystal
				7.64 (s, 1H), 6.13 (s, 1H), 4.78	structure;
	w ÇU AA			(s, 2H), 3.95-3.90 (m, 1 H), 3.83-	Enantiomer of Ex. 1 ;
		A	465
	Cl			3.81 (m, 3H), 3.60-3.55 (m, 2H),	Chiral purity: 99.18%; rétention
	5,8-dichloro-2-[(4,6-dimethyl-2-			3.55-3.52 (m, 2H), 3.32-3.19,	time: 8.429 min; column:
	oxo-1,2-dihydropyridin-3-			(m, 1H), 2.99-2.96 (m, 2H), 2.75	Chiralpak AD-3 150x4.6mm I.D.,

129

	y I) methyl]-7-{( 1 S)-2-hydroxy-1 [(3S)-tetrahydrofuran-3-yl]ethyl}3,4-dihydroisoquinolin-1(2H)-one			(br s, 1 H), 2.32 (s, 3H), 2.31- 2.29 (m, 1H), 2.27 (s, 3H), 1.84- 1.79 (m, 1H)	3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2; flow rate: 2.5mL/min
5	Cl 0 0 Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{1-[(3R)-3f I uo ropy rrolidin-1 -yl]-2hydroxyethyl}-3,4dihydroisoquinolin-1 (2H)-one	B	482	¹H NMR (400 MHz, DMSO-d6) δ 11.66 (br. s., 1H), 7.80 (d, J=3.67 Hz, 1H), 6.00 (s, 1H), 5.15-5.43 (m, 1 H), 4.85 (br. s., 1 H), 4.69 (s, 2H), 4.03 - 4.13 (m, 1H), 3.66 - 3.84 (m, 2H), 3.50 3.63 (m, 2H), 3.02 - 3.10 (m, 1H), 2.94 - 3.02 (m, 2H), 2.71 2.90 (m, 2H), 2.42 - 2.55 (m, 1 H), 2.28 (s, 3H), 2.24 (s, 3H), 2.09 - 2.23 (m, 1 H), 1.87-2.08 (m, 1H)	Mixture of diastereomers containing (R)-3-fluoropyrrolidine Mixture separated to Ex. 6 and Ex. 7

130

6	/ τι ci ο o °ΑόΆ Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yljmethy l]-7-{(1 ξ)-1 -[(3R)-3f luoropyrrolidin-1 -yl]-2hydroxyethyl}-3,4dihydroîsoquinolin-1 (2H)-one Isomer A	B	482	HNMR was not taken due to limited quantity. See Ex. 5	One component of the Ex. 5 mixture. Single diasteromer, containing (R)-3-fluoropyrrolidîne, other chiral center undetermined; >99% de (). [ot]D =-51.3° (cO.01 MeOH) 1 st peak; RT 1.18 min Chiralcel OJ-3 4.6 x 100 mm 3u column; 10% MeOH/DEA @ 120 bar, 4 mL/min
7	Cl 0 o Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{(1Ç)-1-[(3R)-3-	B	482	HNMR was not taken due to limited quantity. See Ex. 5	One component of the Ex. 5 mixture; single diasteromer containing (R)-3-fluoropyrrolidine, other chiral center undetermined; -88% de (+) [a]D = +62.1° (c 0.01 MeOH) 2nd peak; RT 1.42 min Chiralcel OJ-3 4.6 x 100 mm 3u

131

	f luoropyrrolidin-1 -y l]-2hydroxyethyl}-3,4dihydroisoquinolin-1 (2H)-one Isomer B				column; 10% MeOH/DEA @ 120 bar, 4 mL/min;
8	F Cl 0 0 0 Cl (+)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3- y l)methyl]-7-(f I uoro[ 1 - ( hyd roxy acety I) p i pe ridin-4yl]methyl}-3,4-dihydroisoquinolin1(2H)-one	C	524	NMR of Enantiomer, Ex. 9: ¹H NMR (600 MHz, DMSO-d6) δ ppm 11.55 (s, 1 H), 7.58 (d, J=4.95 Hz, 1 H), 5.88 (s, 1 H), 5.72 - 5.84 (m, 1 H), 4.55 (q, J=13.75 Hz, 2 H), 4.46 (br. s., 1 H), 4.30 - 4.42 (m, 1 H), 4.05 4.13 (m, 1 H), 3.97-4.04 (m, 1 H), 3.69 (t, J=13.39 Hz, 1 H), 3.45 (t, J=5.78 Hz, 2 H), 2.80 2.98 (m, 3 H), 2.20 (d, J=18.71 Hz, 1 H), 2.11 (s, 3 H), 1.61 (br. s., 1 H), 1.46 (br. s., 1 H), 1.341.42 (m, 1 H), 1.23 (s, 5 H)	>99% ee (+), [a]D = +9.9° (c 0.1 DMSO) First peak off column: Lux Cellulose-2 4.6 x 100 mm 3u column 60% MeOH @ 120 bar, 4 mL/min Peak 1 @8.13 min (prep: OJ-H, 21 x 250mm column, 32 mL MeOH: 8 mL CO2, 100 bar, 40 mL/min)

132

9	F Cl 0 0 0 Cl (- )-5,8-dichloro-2-[(4,6-dimethyl- 2-oxo-1,2-dihydropyridin-3yl)methyl]-7-{fluoro[1 (hydroxyacetyl)piperidin-4yl]methyl}-3,4-dihydroisoquinolin1(2H)-one	C	524	¹H NMR (600 MHz, DMSO-d6) δ ppm 11.55 (s, 1 H), 7.58 (d, J=4.95 Hz, 1 H), 5.88 (s, 1 H), 5.72 - 5.84 (m, 1 H), 4.55 (q, J=13.75 Hz, 2 H), 4.46 (br. s., 1 H), 4.30 - 4.42 (m, 1 H), 4.05 4.13 (m, 1 H), 3.97-4.04 (m, 1 H), 3.69 (t, J=13.39 Hz, 1 H), 3.45 (t, J=5.78 Hz, 2 H), 2.80 2.98 (m, 3 H), 2.20 (d, J=18.71 Hz, 1 H), 2.11 (s, 3 H), 1.61 (br. s., 1 H), 1.46 (br. s., 1 H), 1.341.42 (m, 1 H), 1.23 (s, 5 H)	-95% ee (-), [a]D = -6.5° (c 0.1 DMSO) Second peak off column: Lux Cellulose-2 4.6 x 100 mm 3u column 60% MeOH @ 120 bar, 4 mUmin Peak 2 @ 10.29 min (prep: OJ-H, 21 x 250mm column, 32 mL MeOH: 8 mL CO2,100 bar, 40 mL/min)
10	^0 Cl 0 0 Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-(2-hydroxy-1 -	D	425	¹H NMR (400 MHz, CDCI3) δ 12.23 (br. s., 1H), 7.53 (s, 1H), 5.95 (s, 1H), 4.92-4.89 (m, 1H), 4.78 (s, 2H), 3.80-3.71 (m, 1 H), 3.68-3.62 (m,2H), 3.53-3.51 (m, 1H), 3.33 (s, 3H), 2.94 (t, J = 6.0	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 11 ; 100% ee; rétention time 7.717 min; column: Chiralpak IC-3 150 x 4.6mm I.D., 3um; mobile phase:

133

	methoxyethyl)-3,4dihydroisoquinolin-1 (2H)-one Isomer A			Hz, 2H), 2.35 (s, 3H), 2.29 (s, 3H)	40% éthanol (0.05% DEA) in CO2; flow rate: 2.35ml_/min
11	C< Cl o o Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-(2-hydroxy-1 methoxyethyl)-3,4dihydroisoquinolin-1(2H)-one Isomer B	D	425	¹H NMR (400 MHz, CDCI3) δ 12.15 (br. s., 1H), 7.53 (s, 1H), 5.95 (s, 1H), 4.92-4.89 (m, 1H), 4.78 (s, 2H), 3.80-3.71 (m, 1H), 3.68-3.63 (m, 2H), 3.55-3.51 (m, 1 H), 3.34 (s, 3H), 2.94 (t, J = 5.6 Hz, 2H), 2.35 (s, 3H), 2.29 (s, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 10; 100% ee;: rétention time 11.063 min; column: Chiralpak IC-3 150x4.6mm I.D., 3um; mobile phase: 40% éthanol (0.05% DEA) in CO2; flow rate: 2.35mL7min
12	^HC\ et 0 0 apô-'ïk Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{(1 R)-2-hydroxy-1 -	E	465	¹H NMR (400 MHz, CD3OD) δ 7.58 (s, 1H), 6.11 (s, 1H), 4.76 (s, 2H), 4.10-4.21 (m, 1 H), 3.86 - 3.99 (m, 3H), 3.75 - 3.84 (m, 1H), 3.64 - 3.72 (m, 1H), 3.46 - 3.55 (m, 2H), 2.91 - 3.01 (m, 2H), 2.29 (s, 3H), 2.25 (s, 3H),	Single enantiomer: (R) at benzylic carbon and (S) at THF 91% ee 1 st peak; RT 2.91 min Chiralpak AD-3 4.6 x 100 mm 3u column; 5-60% MeOH in 3 minutes, 120 bar, 4 mL/min

134

	[(2S)-tetrahydrofuran-2-yl]ethyl}- 3,4-dihydroisoquinolin-1(2H)-one			1.73- 1.97 (m, 3H), 1.44- 1.58 (m, 1H)
13	HO. _n Ci ο o Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{(1 R)-2-hydroxy-1[(2R)-tetrahydrofuran-2-yl]ethyl}3,4-dihydroisoquinolin-1(2H)-one	E	465	¹H NMR (400 MHz, CD30D) δ 7.66 (s, 1H), 6.10 (s, 1H), 4.77 (s, 2H), 4.27 (dt, J=7.86, 6.16 Hz, 1H), 3.72 - 3.91 (m, 3H), 3.67 (t, J=6.79 Hz, 2H), 3.49 (t, J=6.24 Hz, 2H), 2.95 (t, J=6.17 Hz, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 2.01 -2.13 (m, 1H), 1.68 - 1.92 (m, 2H), 1.49-1.62 (m, 1H)	Single enantiomer (R,R); 93% ee 2nd Peak; RT 3.21 min Chiralpak AD-3 4.6 x 100 mm 3u column; 5-60% MeOH in 3 minutes, 120 bar, 4 mL/min
14	Cl 5,8-dichloro-2~[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-(propan-2-yl)-3,4dihydroisoquinolin-1 (2H)-one	F	393	¹H NMR (400 MHz, CDCI3) δ 7.35 (s, 1H), 5.90 (s, 1H), 4.78 (s, 2H), 3.63 (t, J=6.30 Hz, 2H), 3.5-3.6 (m, 1 H), 2.90 (t, J=6.11 Hz, 2H), 2.35 (s, 3H), 2.24 (s, 3H), 1.24 (d, J=6.85 Hz, 6H)	N/A

135

15	Cl 0 0 Cl 5,8 -d ich loro-2-[(4,6-d im ethy I -2oxo-1,2-dihydropyridin-3yl)methyl]-7-( 1 -methoxypropyl)3,4-dihydroisoquinolin-1(2H)-one - Isomer A	G	423	¹H NMR (400 MHz, CDCI3) δ 11.88 (br. s., 1H), 7.53 (s, 1H), 5.94 (s, 1H), 4.78 (s, 2H), 4.694.66 (m, 1 H), 3.65 (t, J = 4.8 Hz, 2H),3.24(s, 3H), 2.93 (t, J = 6.2 Hz, 2H), 2.36 (s, 3H), 2.29 (s, 3H), 1.76-1.72 (m, 1H), 1.651.60 (m, 1 H), 0.96 (t, J =7.0 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 16; 100% Chiral Purity; 1st peak, RT 8.04 min; column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2; flow rate: 2.5mL/min
16	^0 Cl 0 0 Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1 ^-dihydropyridin-SyOmethylJ-T-fl -methoxypropyl)3,4-dihydroisoquinolin-1 (2H)-one - Isomer B	G	423	¹H NMR (400 MHz, CDCI3) δ 10.88 (br s, 1H), 7.53 (s, 1H), 5.93 (S, 1H), 4,77 (s, 2H), 4.694.66 (m, 1H), 3.67-3.63 (m, 2H), 3.24 (s, 3H), 2.93 (t, J = 5.8 Hz, 2H), 2.36 (s, 3H), 2.28 (s, 3H), 1.78-1.73 (m, 1 H), 1.65-1.58 (m, 1H), 0.96 (t, J = 7.2 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 15; 99.6194% Chiral Purity; 2nd peak, RT 8.34 min; column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2; flow rate: 2.5ml_/min

136

17	Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-(1-hydroxypropan-2yl)-3,4-dihydroisoquinolin-1 (2H)~ one	A	409	¹H NMR (400 MHz, CDCI3) Ô 11.54 (s, 1 H), 7.37 (s, 1H), 5.93 (s, 1 H), 4.78 (s, 2H), 3.79-3.71 (m, 3H), 3.64-3.61 (m, 2H), 2.91 (t, J = 6 Hz, 2H), 2.34 (s, 3H), 2.28 (s, 3H), 1.43 (s, 1H), 1.27 (t, J = 6.4 Hz, 3H)	Racemic mixture
18	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[(2S)-1hyd roxyp ropan-2-yl]-3,4dihydroisoquinolin-1 (2H)-one	A	409	¹H NMR (400 MHz, CDCI3) δ 11.54 (s, 1H),7.37(s, 1H), 5.93 (s, 1H), 4.78 (s, 2H), 3.79-3.71 (m, 3H), 3.64-3.61 (m, 2H), 2.91 (t, J = 6 Hz, 2H), 2.34 (s, 3H), 2.28 (s, 3H), 1.43 (s, 1H), 1.27 (t, J = 6.4 Hz, 3H)	Single isomer, known; (S) stereochemistry determined from x-ray crystal structure; 1 st peak underthe following SFC conditions: Chiralpak AS-H 4.6 x 100 mm 5u column; 20% MeOH @ 120 barCO2, 4 mUrnin

137

19	— Cl 0 0 Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[(2R)-1hydroxypropan-2-yl]-3,4dihydroisoquinolin-1 (2H)-one	A	409	¹H NMR (400 MHz, CDCÎ3) δ 11.54 (s, 1H), 7.37 (s, 1H), 5.93 (s, 1H), 4.78 (s, 2H), 3.79-3.71 (m, 3H), 3.64-3.61 (m, 2H), 2.91 (t, J = 6 Hz, 2H), 2.34 (s, 3H), 2.28 (s, 3H), 1.43 (s, 1H), 1.27 (t, J = 6.4 Hz, 3H)	Single isomer, known; (R) stereochemistry determined from x-ray crystal structure of enantiomeric compound (Ex. 18); 2nd peak under the following SFC conditions: Chiralpak AS-H 4.6 x 100 mm 5u column; 20% MeOH @ 120 bar CO2, 4 mL/min
20	Cl 0 0 Ci (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-1,2-dihydropyridin-3yl)methyl]-7-(1 -hydroxybutan-2yl)-3,4-dihydroisoquinolin-1(2H)one	A	423	¹H NMR (400 MHz, CD3OD) δ 7.49 (s, 1 H), 6.11 (s, 1 H), 4.76 (S, 2H), 3.94 (S, 2H), 3.71-3.66 (m, 2H), 3.52-3.50 (m, 3H), 2.95 (t, J= 6.4 Hz, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.90-1.82 (m, 1H), 1.65-1.55 (m, 1H), 0.85 (t, J= 7.6 Hz, 3H)	Racemic mixture

138

21	Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-{1-[(2hydroxyethyl)(methyl)amino]prop an-2-yl}-3,4-dihydroisoquinolin1(2H)-one	A	466	¹H NMR (400 MHz, CD3OD) δ 7.63 (s, 1H), 6.10 (s, 1H), 4.75 (s, 2H), 3.97 (sxt, J=6.94 Hz, 1H), 3.79 (t, J=5.38 Hz, 2H), 3.52 (t, J=6.17 Hz, 2H), 3.33 - 3.40 (m, 1H), 3.00 - 3.19 (m, 3H), 2.92 - 3.00 (m, 2H), 2.72 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 1.33 (d, J=6.85 Hz, 3H)	Racemic mixture
22	ηφότά: Cl {5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-1-oxo-1,2,3,4tetrahydroisoquinolin-7-yl}acetic acid	A	409	¹H NMR (400 MHz, DMSO-d6) δ 12.50 (br.s., 1H), 11.54 (br. s., 1H), 7.66 (s, 1H), 5.88 (s, 1H), 4.57 (s, 2H), 3.77 (s, 2H), 3.45 (t, J=5.50 Hz, 2H), 2.88 (t, J=5.07 Hz, 2H), 2.16 (s, 3H), 2.12 (s, 3H)	N/A

139

23	Cl 0 0 0 Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyi]-7-{[1 - (hydroxyacetyl)piperidin-4yl]methyl}-3,4-dîhydroisoquinolin- 1 (2H)-one	F	506	¹H NMR (400 MHz, CD3OD) δ 7.48 (s, 1H), 6.12 (s, 1H), 4.77 (s, 2H), 4.50 (d, J=13.57 Hz, 1 H), 4.14-4.29 (m, 2H), 3.73 (d, J=13.45 Hz, 1H), 3.48-3.56 (m, 2H), 2.92-3.03 (m, 3H), 2.79 (d, J=7.09 Hz, 2H), 2.66 (t, J=12.53 Hz, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 1.93-2.06 (m, 1H), 1.70 (d, J=13.57 Hz, 2H), 1.21-1.34 (m, 2H)	N/A
24	..^cAJô-Â 0 Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-{1-[1- (hydroxyacetyl)piperidin-4yl]ethyl}-3,4-dihydroisoquinolin- 1 (2H)-one	J	520	¹H NMR (400 MHz, CD3OD) δ 7.40 (s, 1H), 6.01 (s, 1H), 4.66 (S, 2H), 4.27-4.49 (m, 1H), 4.00- 4.18 (m, 2H), 3.49-3.73 (m, 1H), 3.41 (t, J=6.24 Hz, 2H), 3.23- 3.30 (m, 1H), 2.75-2.95 (m, 3H), 2.41-2.63 (m, 1H), 2.19 (s, 3H), 2.15 (s, 3H), 1.80-1.89 (m, 1H),	Racemic mixture

140

				1.67-1.79 (m, 1 H), 1.28-1.36 (m, 1H), 0.97-1.22 (m, 5H)
25	OH Cl 0 0 Cl (±)-5,8-dichioro-2-[(4,6-dimethyl2-oxo-1,2-dihydropyridin-3yl)methyl]-7-(1 -hydroxypropyl)3,4-dihydroisoquinolin-1(2H)-one	G	409	¹H NMR (400 MHz, CDCI3) δ 13.22 (br. s., 1H), 7.41 (s, 1H), 6.01 (s, 1H), 5.13 (dd, J=7.76, 3.36 Hz, 1H), 4.85 (d, J=13.94 Hz, 1H), 4.53 (d, J=13.94 Hz, 1H), 3.70 (dt, J=12.50, 4.94 Hz, 1 H), 3.41 -3.53 (m, 1 H), 2.79 (t, J=5.99 Hz, 2H), 2.42 (s, 3H), 2.31 (s,3H), 1.67-1.82 (m, 1H), 1.41 - 1.57 (m, 1H), 0.96 (t, J=7.34 Hz, 3H)	Racemic mixture
26	xsycû. Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[(2S,3R)-3-	A	423	¹H NMR (400 MHz, CD3OD) δ 7.52 (s, 1H), 6.13 (s, 1H), 4.78 (s, 2H), 3.91-3.84 (m, 1 H), 3.53- 3.48 (m, 3H), 2.97 (t, J = 6.2 Hz, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 1.29 (d, J =7.2 Hz, 3H), 1.14 (d, J = 6.0 Hz, 3H)	Racemic mixture of (2R,3S) and (2S,3R) isomers separated enantiomers are Ex. 47 and Ex. 48

141

	hydroxybutan-2-yl]-3,4dihydroisoquinolin-1 (2H)-one
27	OH Cl 0 0 Cl (+)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-(1 -hydroxypropyl)3,4-dihydroisoquinolin-1(2H)-one	G	409	¹H NMR (400 MHz, CDCI3) δ 13.22 (br. s., 1H), 7.41 (s, 1H), 6.01 (s, 1H), 5.13 (dd, J=7.76, 3.36 Hz, 1H), 4.85 (d, J=13.94 Hz, 1H), 4.53 (d, J=13.94 Hz, 1H), 3.70 (dt, J=12.50, 4.94 Hz, 1 H), 3.41 -3.53 (m, 1H), 2.79 (t, J=5.99 Hz, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 1.67-1.82 (m, 1H), 1.41 - 1.57 (m, 1H), 0.96 (t, J=7.34 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 28; [a]D = +48.8°(c 0.1 MeOH) >99% ee (+); RT 1.407 min; column: Chiralpak AS-3 4.6 x 100 mm 3u; 20% MeOH/DEA @ 120 bar CO2, 4 mL/min;
28	OH Cl 0 o Cl (-)-5,8-dichloro-2-[(4,6-dimethyl- 2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-(1 -hydroxypropyl)- 3,4-dihydroisoquinolin-1(2H)-one	G	409	¹H NMR (400 MHz, CDCI3) δ 13.22 (br. s., 1H), 7.41 (s, 1H), 6.01 (s, 1H), 5.13 (dd, J=7.76, 3.36 Hz, 1H), 4.85 (d, J=13.94 Hz, 1H), 4.53 (d, J=13.94 Hz, 1H), 3.70 (dt, J=12.50, 4.94 Hz, 1 H), 3.41 -3.53 (m, 1H), 2.79 (t,	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 27; [ot]D =-47.5° (c 0.1 MeOH) -99% ee (-); RT 1.893 min ; column: Chiralpak AS-3 4.6 x 100

142

				J=5.99 Hz, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 1.67-1.82 (m. 1H), 1.41 - 1.57 (m, 1H), 0.96 (t, J=7.34 Hz, 3H)	mm 3u ; 20% MeOH/DEA @ 120 bar CO2, 4 mL/mîn;
29	\ ci ο ο Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methy l]-7-( 1 -hydroxybutan-2yl)-3,4-dihydroisoquinolin-1(2H)one - Isomer A	A	423	¹H NMR (400 MHz, CD30D) δ 7.49 (s, 1H), 6.11 (s, 1H), 4.76 (s, 2H), 3.71-3.66 (m, 2H), 3.52- 3.50 (m, 3H), 2.95 (t, J= 6.4 Hz, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.90-1.82 (m, 1 H), 1.65-1.55 (m, 1 H), 0.85 (t, J= 7.6 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 30; 1st peak under the following SFC conditions: Chiralpak AD-3 4.6 x 100 mm 3u column; 30% MeOH @ 120 bar CO2, 4 mL/min
30	> Cl 0 0 Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl) methyl]-7-( 1 -hydroxybutan-2-	A	423	¹H NMR (400 MHz, CD3OD) δ 7.49 (s, 1H), 6.11 (S, 1H), 4.76 (s, 2H), 3.71-3.66 (m, 2H), 3.52- 3.50 (m, 3H), 2.95 (t, J= 6.4 Hz, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.90-1.82 (m, 1 H), 1.65-1.55 (m, 1H), 0.85 (t, J= 7.6 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 29; 2nd peak under the following SFC conditions: Chiralpak AD-3 4.6 x 100 mm 3u column; 30% MeOH @ 120 bar CO2, 4 mLJmin

143

	yl)-3,4-dihydroisoquinolin-1(2H)one - Isomer B
31	^H0> Cl 0 0 □ J ipu Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-ΟΧΟ-1,2-dihydropyridin-3yl)methyl]-7-[2-hydroxy-1 (tetrahydro-2H-pyran-4-yl)ethyl]3,4-dihydroisoquînolin-l(2H)-one	A	479	’H NMR (400 MHz, CD3OD) δ 11.65 (bs, 1H), 7.43 (s, 1H), 5.95 (s, 1H), 4.77 (s, 2H), 4.043.87 (m, 4H), 3.68-3.40 (m, 3H), 3.31-3.30 (m, 2H), 2.92 (t, J= 6.4 Hz, 2H), 2.37(s, 3H), 2.29 (s, 3H), 2.05-1.82 (m, 2H), 1.321.28 (m,4H)	Racemic mixture
32	Cl (±)-2-{5,8-dichloro-2-[(4,6dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-1-oxo- 1,2,3,4-tetrahydroisoquinolin-7yl}propanenîtrîle	G	404	¹H NMR (400 MHz, DMSO-d6) δ 11.55 (br. s., 1 H), 7.77 (s, 1H), 5.89 (s, 1H), 4.61-4.68 (m, 1H), 4.58 (s, 2H), 3.42-3.50 (m, 2H), 2.87-2.95 (m, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 1.56-1.63 (m, 3H)	Racemic mixture

144

33	Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-1,2-dihydropyridin-3yl)methyl]-7-(4-hydroxybutan-2yl)-3,4-dihydroisoquinolin-1 (2H)one	A	423	¹H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1 H), 5.92 (s, 1 H), 4.57 (s, 2H), 3.48-3.47 (m, 1H), 3.41 (t, J = 6.2 Hz, 2H), 3.34 (t, J = 6.6 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 2.16 (s, 3H), 2.13 (s, 3H), 1.78-1.68 (m, 2H), 1.15 (d, J = 6.8 Hz, 3H)	Racemic mixture
34	'O CI 0 0 Ηθ^γ^Ν^ o ci (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-{[1 - (hydroxyacetyl)piperidin-4yl](methoxy)methyl}-3,4dihydroisoquinolin-1 (2H)-one	l	536	¹H NMR (400 MHz, CD3OD) δ 7.44 (s, 1H), 6.01 (s, 1H), 4.66 (s, 2H), 4.56 (d, J=5.62 Hz, 1 H), 4.35-4.45 (m, 1 H), 4.02-4.17 (m, 2H), 3.57-3.68 (m, 1H), 3.43 (t, J=6.24 Hz, 2H), 3.10 (s, 3H), 2.86-2.92 (m, 2H), 2.75-2.85 (m, 1H), 2.40-2.54 (m, 1H), 2.20 (s, 3H), 2.15 (s, 3H), 1.78-1.87 (m, 1H), 1.60-1.69 (m, 1H), 1.181.47 (m, 3H)	Racemic mixture

145

35	Yl Cl 0 0 Ο Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihyd ropyridin-3yl)methyl]-7-{[1 - (hydroxyacetyl)piperidin-4yl](methoxy)methyl}-3,4dihydroisoquinolin-1(2H)-one Isomer B	I	536	NMR of Racemate, Ex. 34: ¹H NMR (400 MHz, CD3OD) δ 7.44 (s, 1H), 6.01 (s, 1H), 4.66 (s, 2H), 4.56 (d, J=5.62 Hz, 1H), 4.35-4.45 (m, 1H), 4.02-4.17 (m, 2H), 3.57-3.68 (m, 1H), 3.43 (t, J=6.24 Hz, 2H), 3.10 (s, 3H), 2.86-2.92 (m, 2H), 2.75-2.85 (m, 1H), 2.40-2.54 (m, 1H), 2.20 (s, 3H), 2.15 (s, 3H), 1.78-1.87 (m, 1H), 1.60-1.69 (m, 1H), 1.181.47 (m, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 36; -97% ee; rétention time 13.019 min; Lux Cellulose-4 4.6 x 100 mm 3u column; 50% MeOH @ 120 bar CO2, 4 mUmin
36	O Cl 0 0 0 Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{[1- (hydroxyacetyl)piperidin-4- yl](methoxy)methyl}-3,4-	I	536	NMR of Racemate, Ex. 34: ¹H NMR (400 MHz, CD3OD) δ 7.44 (s, 1H), 6.01 (s, 1H), 4.66 (s, 2H), 4.56 (d, J=5.62 Hz, 1 H), 4.35-4.45 (m, 1 H), 4.02-4.17 (m, 2H), 3.57-3.68 (m, 1H), 3.43 (t, J=6.24 Hz, 2H), 3.10 (s, 3H), 2.86-2.92 (m, 2H), 2.75-2.85 (m,	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 35; >99% ee; rétention time 10.712 min; Lux Cellulose-4 4.6 x 100 mm 3u column; 50% MeOH @ 120 bar CO2, 4mUmin

146

	dihydroisoquinolin-1 (2H)-one - Isomer A			1H), 2.40-2.54 (m, 1H), 2.20 (s, 3H), 2.15 (s, 3H), 1.78-1.87 (m, 1H), 1.60-1.69 (m, 1H), 1.18- 1.47 (m, 3H)
37	d 0 0 U ΛΛ Cl 5,8-dichloro-2-[(4,6-dimethyî-2oxo-1 ,2-dihydropyridin-3yl)methyl]-7-[2-hydroxy-1 (tetrahydro-2H-pyran-4-yl)ethyl]3,4-dihydroisoquinolin-1(2H)-one - Isomer A	A	479	¹H NMR (400 MHz, CD3OD) δ 11.65 (bs, 1H), 7.43 (s, 1H), 5.95 (s, 1H), 4.77 (s, 2H), 4.043.87 (m, 4H), 3.68-3.40 (m, 3H), 3.31-3.30 (m, 2H), 2.92 (t, J= 6.4 Hz, 2H), 2.37 (s, 3H), 2.29 (s, 3H), 2.05-1.82 (m, 2H), 1.321.28 (m, 4H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 38; 1 st peak under the following SFC conditions: Chiralpak AD-3 4.6 x 100 mm 3u column; 30% MeOH @120 barCO2, 4 mL/min
38	^HCS Cl 0 0 U ΛΑ Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[2-hydroxy-1 -	A	479	¹H NMR (400 MHz, CD3OD) δ 11.65 (bs, 1H), 7.43 (s, 1H), 5.95 (s, 1H), 4.77 (s, 2H), 4.043.87 (m, 4H), 3.68-3.40 (m, 3H), 3.31-3.30 (m, 2H), 2.92 (t, J= 6.4 Hz, 2H), 2.37 (s, 3H), 2.29	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 37; 2nd peak under the following SFC conditions: Chiralpak AD-3 4.6 x 100 mm 3u column; 30% MeOH @ 120 bar CO2, 4 mL7min

147

	(tetrahydro-2H-pyran-4-yl)ethyl]- 3_l4-dihydroisoquinolin-1(2H)-one - Isomer B			(s, 3H), 2.05-1.82 (m, 2H), 1.32- 1.28 (m, 4H)
39	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-(4-hydroxybutan-2yl)-3,4-dihydroisoquinolin-1(2H)one - Isomer A	A	423	¹H NMR (400 MHz, DMS0-d6) δ 7.53 (s, 1 H), 5.92 (s, 1 H), 4.57 (s, 2H), 3.48-3.47 (m, 1H), 3.41 (t, J = 6.2 Hz, 2H), 3.34 (t, J = 6.6 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 2.16 (s, 3H), 2.13 (s, 3H), 1.78-1.68 (m, 2H), 1.15 (d, J = 6.8 Hz, 3H)	Single enantiomer, absolute stereochemistry unknown; 1 st peak under the following SFC conditions: Lux Cellulose-4 4.6 x 100 mm 3u column; 50% MeOH @120 bar, 4 mUmin
40	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-(4-hydroxybutan-2yl)-3,4-dihydroisoquinolin-1(2H)one - Isomer B	A	423	¹H NMR (400 MHz, DMS0-d6) δ 7.53 (s, 1 H), 5.92 (s, 1 H), 4.57 (s, 2H), 3.48-3.47 (m, 1H), 3.41 (t, J = 6.2 Hz, 2H), 3.34 (t, J = 6.6 Hz, 2H), 2.85 (t, J = 6.0 Hz, 2H), 2.16 (S, 3H), 2.13 (s, 3H), 1.78-1.68 (m, 2H), 1.15 (d, J = 6.8 Hz, 3H)	Single enantiomer, absolute stereochemistry unknown; 2nd peak under the following SFC conditions: Lux Cellulose-4 4.6 x 100 mm 3u column; 50% MeOH @ 120 bar, 4 mL/min

148

41	^H0-fci 0 0 Cl (±)-5,8-dichloro-7-[(2R,3^4R)2,4-dihydroxypentan-3-yl]-2-[(4,6- dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one	G	453	¹H NMR (400 MHz, CDCI3) δ 12.02 (br. s., 1H), 7.78 (s, 1 H), 6.28 (s, 1 H), 4.74 (s, 2H), 4.58 (dq, J=3.06, 6.48 Hz, 1H), 4.24 (qd, J=6.21, 7.79 Hz, 1H), 3.68 (t, J=6.11 Hz, 2H), 3.54 (dd, J=2.93, 8.07 Hz, 1H), 2.97 (t, J=6.11 Hz, 2H), 2.52 (s, 3H), 2.40 (s, 3H), 1.18 (d, J=6.36 Hz, 3H), 1.05 (d, J=6.36 Hz, 3H)	Racemic mixture of 2,4-anti diols, stereochemistry at 3-position unknown.
42	ci ο o Cl 5,8-dichloro-7-[(2R,3t4S)-2,4dihydroxypentan-3-yl]-2-[(4,6dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one	G	453	¹H NMR (400 MHz, DMSO-d6) δ 11.54 (br. s., 1 H), 7.74 (s, 1 H), 5.88 (s, 1H), 4.57 (s, 2H), 4.54 (br. s., 2H), 4.07 (quin, J=5.81 Hz, 2H), 3.44 (t, J=6.11 Hz, 2H), 3.24 (t, J=5.87 Hz, 1H), 2.86 (t, J=5.99 Hz, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.02 (d, J=6.11 Hz, 6H)	Single achiral/meso 2,4-syn diol, stereochemistry at 3-position unknown

149

43	ΗΟ. η α ο ο Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[2-hydroxy-1 -(1,2oxazol-3-yl)ethyl]-3,4dihydroisoquinolin-1 (2H)-one	A	462	¹H NMR (700 MHz, DMSO-d6) δ 8.84 (d, J=1.51 Hz, 1H), 7.60 (s, 1H), 6.65 (d, J=1.51 Hz, 1H), 5.88 (s, 1H), 5.14 (br. s, 1H), 4.88 (t, J=6.99 Hz, 1 H), 4.57 (s, 2H), 3.93-4.00 (m, 2H), 3.43 (t, J=6.24 Hz, 2H), 2.86 (t, J=6.24 Hz, 2H), 2.15 (S, 3H), 2.12 (s, 3H)	Racemîc Mixture
44	A Cl 0 o Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-1,2-dihydropyridin-3yl)methyl]-7-(1 -methoxyethyl)3,4-dihydroisoquinolin-1(2H)-one	G	409	¹H NMR (400 MHz, DMSO-d6) δ 11.53 (br. s., 1 H), 7.52 (s, 1H), 5.88 (s, 1H), 4.78 (q, J=6.24 Hz, 1 H), 4.57 (s, 2H), 3.45 (t, J=6.24 Hz, 2H), 3.18 (s, 3H), 2.89 (t, J=6.11 Hz, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 1.32 (d, J=6.36 Hz, 3H)	Racemic mixture

150

45	^H0>. Cl Ο 0 Fçôcû: Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3y l)methyl]-7-{( 1 S)-2-hydroxy-1 [(2 R)-tetrahyd rof u ran-2-yl]ethy I}3,4-dihydroisoquinolin-1(2H)-one	E	465	¹H NMR (400 MHz, CD30D) δ 7.58 (s, 1 H), 6.10 (s, 1H), 4.76 (s, 2H), 4.09-4.22 (m, 1 H), 3.86 - 4.00 (m, 3H), 3.75 - 3.84 (m, 1H), 3.62 - 3.72 (m, 1H), 3.45 - 3.55 (m, 2H), 2.95 (t, J=6.17 Hz, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 1.72 - 1.98 (m, 3H), 1.44 - 1.58 (m, 1H)	Single enantiomer, S at benzyl, R atTHF 91% ee 1 st peak; RT 2.91 min Chiralpak AD-3 4.6 x 100 mm 3u column, 5-60% MeOH in 3 minutes, 120 bar, 4 mL/min
46	^H0- Cl 0 O Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3y IJmethy l]-7-{( 1 S)-2-hydroxy-1 [(2S)-tetrahydrofuran-2-yl]ethyl}3,4-dihydroisoquinolin-1(2H)-one	E	465	¹H NMR (400 MHz, CD30D) δ 7.66 (s, 1H), 6.10 (s, 1H), 4.76 (s, 2H), 4.23 - 4.32 (m, 1 H), 3.73 - 3.91 (m, 3H), 3.67 (t, J=6.79 Hz, 2H), 3.50 (t, J=6.24 Hz, 2H), 2.95 (t, J=6.17 Hz, 2H), 2.29 (s, 3H), 2.25 (s, 3H), 2.01 - 2.11 (m, 1H), 1.80 - 1.92 (m, 1H), 1.69 - 1.80 (m, 1H), 1.49-1.62 (m, 1H)	Single enantiomer, S,S 92% ee 2nd peak; RT 3.21 min Chiralpak AD-3 4.6 x 100 mm 3u column, 5-60% MeOH in 3 minutes, 120 bar, 4 mL/min

151

47	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[(2S,3R)-3hydroxybutan-2-yl]-3,4dihydroisoquinolin-1 (2H)-one Isomer A	A	423	¹H NMR (400 MHz, CD30D) δ 7.52 (s, 1H), 6.13 (s, 1H), 4.78 (s, 2H), 3.89-3.86 (m, 1H), 3.54- 3.48 (m, 3H), 2.97 (t, J= 6.2 Hz, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 1.29 (d, J= 7.2 Hz, 3H), 1.14 (d, J= 6.4 Hz, 3H)	Single enantiomer; relative stereochemistry known; absolute stereochemistry unknown; 99.08% ee; 1st peak, RT 9.67 min Column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% isopropanol (0.05% DEA) in CO2; flow rate: 2.5mL/min
48	I Cl 0 0 Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[(2R,3S)-3hydroxybutan-2-yl]-3,4dihydroisoquinolin-1 (2H)-one Isomer B	A	423	¹H NMR (400 MHz, CD30D) δ 7.52 (s, 1H), 6.13 (s, 1H), 4.78 (s, 2H), 3.91-3.84 (m, 1H), 3.53- 3.48 (m, 3H), 2.97 (t, J= 6.0 Hz, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 1.29 (d, J= 7.2 Hz, 3H), 1.14 (d, J= 6.0 Hz, 3H)	Single enantiomer; relative stereochemistry known; absolute stereochemistry unknown; 96.73% ee; 2nd peak, RT 10.21 min Column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% isopropanol (0.05% DEA) in CO2; flow rate: 2.5mL/min

152

49	Ό Cl 0 0 Υτφόςΰ. Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-(1 -methoxy-2oxopropyl)-3,4- dihydroisoquinolin-1 (2H)-one	D	437	¹H NMR (400 MHz, CDCI3) δ 7.51 (s, 1H), 5.93 (s, 1H), 5.32 (s, 1H), 4.76 (s, 2H), 3.75-3.60 (m, 2H), 3.39 (s, 3H), 3.00-2.90 (m, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 2.19 (s, 3H), 1.26 (s, 1H)	Racemic mixture
50	Cl (-)-5,8-dichloro-2-[(4,6-dimethyl- 2-oxo-1,2-dihydropyridin-3yl)methyl]-7-[methoxy(tetrahydro- 2H-pyran-4-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one	I	479	¹H NMR (400 MHz, DMSO-d6) δ 11.54 (br. s., 1 H), 7.45 (s, 1H), 5.88 (s, 1H), 4.56 (s, 3H), 3.74- 3.89 (m, 2H), 3.46 (t, J=6.11 Hz, 2H), 3.14-3.24 (m, 2H), 3.13 (s, 3H), 2.89 (t, J=6.11 Hz, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.76- 1.90 (m, 1H), 1.32-1.56 (m, 3H), 1.17-1.27 (m, 1H)	[a]D = -56.4° (c0.1, MeOH) -96% ee (-); rétention time 3.17 min; Lux Cellulose-4 4.6 x 100 mm 3u column; mobile phase: 50% MeOH @120 bar, 4 mL/min

153

51	σγάΑ Cl (+)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-1,2-dihydropyridin-3yl)methyl]-7-[methoxy(tetrahydro- 2H-pyran-4-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one	I	479	¹H NMR (400 MHz, DMSO-d6) δ 11.54 (br. s., 1 H), 7.45 (s, 1H), 5.89 (s, 1 H), 4.56 (s, 3H), 3.75- 3.89 (m, 2H), 3.46 (t, J=6.11 Hz, 2H), 3.14-3.23 (m, 2H), 3.13 (s, 3H), 2.89 (t, J=6.24 Hz, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.76- 1.89 (m, 1 H), 1.32-1.57 (m, 3H), 1.16-1.26 (m, 1H)	[a]D = +80.9° (c 0.1, MeOH) -99% ee (+); rétention time 4.15 min; Lux Cellulose-4 4.6 x 100 mm 3u column; mobile phase 50% MeOH @ 120 bar CO2, 4 mL/min
52	ôW Cl (-)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[(4- hydroxytetrahydro-2H-pyran-4yî)(methoxy)methyl]-3,4dihydroisoquinolin-1 (2H)-one	I	495	¹H NMR (400 MHz, DMSO-d6) δ 11.54 (br. s., 1 H), 7.62 (s, 1H), 5.88 (s, 1H), 4.65 (s, 1H), 4.62 (s, 1H), 4.56 (s, 2H), 3.61-3.69 (m, 1H), 3.43-3.59 (m, 5H), 3.12 (s, 3H), 2.86-2.92 (m, 2H), 2.18 (s, 3H), 2.12 (s, 3H), 1.57-1.75 (m, 3H), 0.92 (d, J=12.72 Hz, 1H)	[ct]D=-51.3° (c 0.1, MeOH) >99% ee (-); rétention time 2.51 min; Lux Cellulose-4 4.6 x 100 mm 3u column; mobile phase: 50% MeOH @ 120 bar CO2; 4 mL/min

154

53	Cl (+)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyî]-7-[(4- hydroxytetrahydro-2H-pyran-4y I ) (m ethoxy) m ethy l]-3,4dihydroisoquinolin-1 (2H)-one	I	495	¹H NMR (400 MHz, DMSO-d6) 511.54 (br. s., 1 H), 7.62 (s, 1 H), 5.88 (s, 1H), 4.65 (s, 1H), 4.62 (s, 1H), 4.56 (s, 2H), 3.62-3.68 (m, 1H), 3.43-3.59 (m, 5H), 3.12 (s, 3H), 2.85-2.93 (m, 2H), 2.18 (s, 3H), 2.12 (s, 3H), 1.57-1.74 (m, 3H), 0.92 (d, J=13.45 Hz, 1H)	[a]D = +73.8° (c 0.1, MeOH) -99% ee (+); rétention time 3.85 min; Lux Cellulose-4 4.6 x 100 mm 3u column; mobile phase: 50% MeOH @ 120 bar CO2, 4 mL/min
54	K, T ci ο o Cl (3S)-3-{5,8-dichloro-2-[(4,6dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-1-oxo- 1,2,3,4-tetrahydroisoquinolin-7yl}-3-[(3S)-tetrahydrofuran-3yl]propanenitrile	A	474	¹H NMR (400 MHz, CDCI3) δ 11.80 - 13.19 (m, 1H), 7.49 (s, 1H), 6.01 (s, 1H), 4.78 (s, 2H), 4.09 (t, J=7.76 Hz, 1H), 3.82 - 3.90 (m, 1H), 3.73 - 3.81 (m, 2H), 3.64 - 3.73 (m, 2H), 3.57 - 3.64 (m, 1H), 2.87 - 3.03 (m, 2H), 2.73 - 2.87 (m, 1H), 2.59 - 2.73 (m, 2H), 2.38 (s, 3H), 2.32 (s, 3H), 1.84-1.97 (m, 1 H), 1.34 -1.47 (m, 1 H)	single enantiomer from chiral reagents; absolute stereochemistry S,S

155

55	,<X Cl 0 0 ^Cl f^Af 5,8-dichloro-2-{[4(difluoromethoxy)-6-methyl-2oxo-1 ,2-dihydropyridin-3yl]methyl)-7-[2-hydroxy-1 (tetrahydro-2H-pyran-4-yl)ethyl]3,4-dihydroisoquinolin-1(2H)-one - Isomer B	A	531	¹H NMR (400 MHz, CD3OD) δ 7.59 (s, 1H), 7.21-6.85 (m, 1H), 6.21 (s, 1H), 4.71 (s, 2H), 3.983.96 (m, 1H), 3.85-3.81 (m, 3H), 3.52-3.49(m, 5H), 2.98(t, J=6.2 Hz, 2H), 2.31 (s, 3H), 1.92-1.89 (m, 2H), 1.46-1.43 (m, 1H), 1.29-1.23 (m, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 56: 98.46% ee; rétention time: 3.767 min; column: Chiralpak AS-H 150*4.6mm I.D., 5um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2; flow rate: 3 mL/min
56				¹H NMR (400 MHz, CD3OD) δ	Single isomer, absolute
	Cl 0 0			7.59 (s, 1H), 7.21-6.85 (m, 1H),	stereochemistry unknown;
	^Η°'-^χύ\^ΛνΑι ^nh			6.21 (s, 1H), 4.71 (S, 2H), 3.96-	Enantiomer of Ex. 55:
				3.94 (m, 1H), 3.85-3.81 (m, 3H),	99.02% ee; rétention time: 3.585
	a _fA_f	A	531	3.52-3.43(m, 5H), 2.98(t, J=6.2	min; column: Chiralpak AS-H
	5,8-dichloro-2-{[4-			Hz, 2H), 2.31 (s, 3H), 1.92-1.89	150*4.6mm I.D., 5um; mobile
	(difluoromethoxy)-6-methyl-2-			(m, 2H), 1.46-1.42 (m, 1H),	phase: 5-40% éthanol (0.05%
	oxo-1,2-dihydropyridin-3-			1.29-1.23 (m, 3H)	DEA) in CO2; flow rate: 3 mUmin

156

	yl]methy l}-7-[2-hyd roxy-1 (tetrahydro-2H-pyran-4-yl)ethyl]3,4-dihydroisoquinolin-1(2H)-one - Isomer A
57	Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[2-hydroxy-1 (pyrrolidin-1 -yl) ethy IJ-3,4dihydroisoquinolin-1 (2H)-one	B	464	¹H NMR (400 MHz, DMSO-d6) 511.50 (br.s., 1 H), 7.68 (s, 1H), 5.89 (s, 1H), 4.65 (br. s., 1H), 4.58 (s, 2H), 3.90 (t, J=4.52 Hz, 1 H), 3.56 - 3.76 (m, 2H), 3.40 3.49 (m, 2H), 2.87 (t, J=6.11 Hz, 2H), 2.33 - 2.44 (m, 2H), 2.17 (s, 3H), 2.13 (s, 3H), 1.67 (br. s„ 4H), two Hs obscured by DMSO peak.	Racemic mixture
58	Cl 5,8-dichloro-2-[(4,6-dimethyl-2-	B	482	¹H NMR (400 MHz, DMSO-d6) δ 11.51 (br. s., 1H), 7.68 (d, J=3.55 Hz, 1H), 5.89 (s, 1H), 5.03-5.31 (m, 1 H), 4.75 (br.s., 1 H), 4.58 (s, 2H), 3.92 - 4.01 (m, 1H), 3.54 - 3.73 (m, 2H), 3.38 -	Mixture of diastereomers containing (S)-3-fluoropyrrolidine Mixture separated to give Ex. 62 and Ex. 63

157

	oxo-1,2-dihydropyridin-3yl)methyl]-7-{1 -[(3S)-3fluoropyrrolidin-1 -yl]-2hydroxyethyl}-3,4dihydroisoquinolin-1 (2H)-one			3.52 (m, 2H), 2.91 - 2.99 (m, 1H), 2.84 - 2.91 (m, 2H), 2.59 - 2.78 (m, 2H), 2.29 - 2.43 (m, 1H), 2.17 (s, 3H), 2.13 (s, 3H), 1.99 - 2.12 (m, 1H), 1.76 - 1.97 (m, 1H)
59	F F-4__ Cl 0 0 Cl (±)-5,8-dichloro-7-[1 -(3,3dif luoropy rrolïdin-1 -yl)-2hydroxyethyl]-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-3,4-dihydroisoquinolin1(2H)-one	B	500	¹H NMR (400 MHz, DMSO-d6) δ 11.51 (br. s., 1 H), 7.66 (s, 1H), 5.88 (s, 1H), 4.83 (br. s., 1 H), 4.57 (s, 2H), 4.03 (t, J=4.52 Hz, 1H), 3.54-3.70 (m, 2H), 3.383.50 (m, 2H), 3.04 (dt, J=14.37, 11.10 Hz, 1H), 2.79 - 2.94 (m, 3H), 2.62 - 2.78 (m, 2H), 2.18 2.30 (m, 2H), 2.16 (s, 3H), 2.12 (s, 3H)	Racemic mixture

158

60	^ΗΟη Cl 0 0 □U ψΛ Λ Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-1 ^-dihydropyridin-SylJmethylJ^-^-hydroxy-l (morpholin-4-yl)ethyl]-3,4dihydroisoquinolin-1 (2H)-one	B	480	¹H NMR (400 MHz, DMS0-d6) 611.54 (br. s., 1H), 7.72 (s, 1H), 5.89 (s, 1H), 4.71 (br. s., 1H), 4.58 (s, 2H), 3.95 (t, J=4.65 Hz, 1H), 3.68-3.78 (m, 1H), 3.51 3.67 (m, 5H), 3.45 (t, J=6.54 Hz, 2H), 2.87 (t, J=6.11 Hz, 2H), 2.54 (br. s., 2H), 2.27 - 2.39 (m, 2H), 2.17 (s, 3H), 2.13 (s, 3H)	Racemic mixture
61	'o ci o o O Cl 3-{4-[{5,8-dichloro-2-[(4,6dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-1-oxo1,2,3,4-tetrahydroisoquinolin-7yl}(methoxy)methyl]piperidin-1 yl}-3-oxopropanenîtrile - Isomer B	I	545	¹H NMR (400 MHz, CD3OD) δ 11.40 (br. s., 1H) 7.46 (s, 1H), 5.95 (s, 1H), 4.82-4.73 (m, 2H), 4.64-4.57 (m, 2H), 3.68 (t, J=5.4 Hz, 3H), 3.47 (s, 2H), 3.20 (s, 3H), 3.09-3.02 (m, 1 H), 2.95 (t, J=6 Hz, 2H), 2.52-2.48 (m, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 1.89- 1.87 (m, 1 H), 1.75-1.68 (m, 2H), 1.61-1.51 (m, 2H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 71 ; 96.42% ee; rétention time: 9.135 min; column: Chiralpak AS-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2; flow rate: 2.35 mL/min

159

62	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{(^)-1-[(3S)-3fluoropyrrolidin-1 -yl]-2hydroxyethyl}-3,4dihydroisoquinolin-1 (2H)-one Isomer A	B	482	HNMR was not taken due to limited quantity. See Ex. 58	One component of the Ex. 58 mixture. Single diasteromer containing (S)3-fluoropyrrolidine, other chiral center undetermined; [<x]D = -58.9° (c 0.01 MeOH) -98% de (-); 1 st peak; RT 1.233 min; Chiralcel OJ-3 4.6 x 100 mm 3u column; 10% MeOH/DEA @ 120 bar, 4 mUmin
63	Cl 0 0 Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{(K)-1-[(3S)-3-	B	482	HNMR was not taken due to limited quantity. See Ex. 58	One component of the Ex. 58 mixture. Single diasteromer containing (S)3-fluoropyrrolidine, other chiral center undetermined; -90% de (+); 2nd peak; RT 1.489 min; Chiralcel OJ-3 4.6 x 100 mm

160

	fluoropyrrolidin-1 -yl]-2hydroxyethyl}-3,4dihydroisoquinolin-1 (2H)-one Isomer B				3u column; 10% MeOH/DEA @ 120 bar, 4 mL/min
64	HO. „ _n (±)-8-chloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3y I) methyl]-7-{( 1 S)-2-hydroxy-1 [(3S)-tetrahydrofuran-3-yl]ethyl}3,4-dihydroisoquinolin-1(2H)-one	A	431	¹H NMR (400 MHz, CD3OD) δ 7.50 (d, J=7.83 Hz, 1 H), 7.20 (d, J=7.83 Hz, 1H), 6.13 (s, 1H), 4.79 (s, 2H), 3.95 (dt, J=3.67, 8.31 Hz, 1 H), 3.76-3.87 (m, 3H), 3.58 (t, J=7.95 Hz, 2H), 3.433.52 (m, 2H), 3.18 (t, J=8.44 Hz, 1H), 2.87 (dd, J=5.14, 7.09 Hz, 2H), 2.75 (dd, J=7.83,15.89 Hz, 1H), 2.33-2.25 (m, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 1.83 (qd, J=8.60, 12.10 Hz, 1H)	Racemic Mixture of R,R and S,S isomers (Assigned by analogy to Ex. 4, which had a crystal structure showing S,S stereochemistry)
65	^H% d 0 0 (±)-8-chloro-2-[(4,6-dimethyl-2-	A	431	¹H NMR (400 MHz, CD3OD) δ 7.48 (d, J=8.07 Hz, 1 H), 7.19 (d, J=7.83 Hz, 1H), 6.11 (s, 1H), 4.78 (s, 2H), 4.13 (t, J=7.95 Hz,	Racemic Mixture of R,S and S,R isomers

161

	oxo-1,2-dihydropy ridin-3yl)methyl]-7-{(1 R)-2-hydroxy-1[(3S)-tetrahydrofuran-3-yl]ethyl}3,4-dihydroisoquinolin-1(2H)-one			1 H), 3.78 (dt, J=4.16, 8.31 Hz, 1H), 3.55-3.73 (m, 5H), 3.47 (t, J=5.26 Hz, 2H), 2.86 (dd, J=4.40, 6.85 Hz, 2H), 2.60-2.74 (m, 1H), 2.29 (s, 3H), 2.25 (s, 3H), 1.68-1.80 (m, 1H), 1.40 (qd, J=8.56, 12.23 Hz, 1H)
66	F Ci (-)-5,8-dichloro-7-[1-(3,3difluoropyrrolidin-1 -y l)-2hydroxyethyl]-2-[(4,6-dimethyl-2- oxo-1,2-dihydropyridin-3yl)methyl]-3,4-dihydroisoquinolin- 1 (2H)-one	B	500	¹H NMR (400 MHz, DMSO-d6) δ 11.51 (br. s.,1H), 7.66 (s, 1H), 5.88 (s, 1H), 4.83 (br. s., 1H), 4.57 (s, 2H), 4.03 (t, J=4.52 Hz, 1H), 3.54 - 3.70 (m, 2H), 3.38 3.50 (m, 2H), 3.04 (dt, J=14.37, 11.10 Hz, 1H), 2.79 - 2.94 (m, 3H), 2.62 - 2.78 (m, 2H), 2.18 2.30 (m, 2H), 2.16 (s, 3H), 2.12 (s, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 67; [a]D = -65.35° (c 0.01 MeOH) >99% ee (-); 1 st peak; RT 2.120 min; Chiralpak IC-3 4.6 x 100 mm 3u column; 40% MeOH @ 120 bar, 4 mL/min

162

67	F TT Cl 0 0 Ci (+)-5,8-dichloro-7-[1-(3,3d if I uoropy rrol id in-1 -yl)-2hydroxyethyl]-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyll-3,4-dihydroisoquinolin1(2H)-one	B	500	¹H NMR (400 MHz, DMS0-d6) δ 11.51 (br.s., 1 H), 7.66 (s, 1H), 5.88 (s, 1H), 4.83 (br. s., 1H), 4.57 (s, 2H), 4.03 (t, J=4.52 Hz, 1H), 3.54-3.70 (m, 2H), 3.38 3.50 (m, 2H), 3.04 (dt, J=14.37, 11.10 Hz, 1H), 2.79 - 2.94 (m, 3H), 2.62 - 2.78 (m, 2H), 2.182.30 (m, 2H), 2.16 (s, 3H), 2.12 (s, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 66; [a]D = +92.77° (c 0.01 MeOH) -99% ee (+); 2nd peak; RT 2.866 min; Chiralpak IC-3 4.6 x 100 mm 3u column; 40% MeOH @ 120 bar, 4 mUmin
68	C! 0 0 Ο ιψυ ΛΛ Cl (-)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-1,2-dihydropyridin-3yl)methyl]-7-[2-hydroxy-1 (morpholin-4-yl)ethyl]-3,4dihydroisoquinolin-1 (2H)-one	B	480	¹H NMR (400 MHz, DMSO-d6) δ 11.54 (br.s., 1 H), 7.72 (s, 1H), 5.89 (s, 1H), 4.71 (br. s., 1H), 4.58 (s, 2H), 3.95 (t, J=4.65 Hz, 1H), 3.68 - 3.78 (m, 1H), 3.51 3.67 (m, 5H), 3.45 (t, J=6.54 Hz, 2H), 2.87 (t, J=6.11 Hz, 2H), 2.54 (br. s., 2H), 2.27 - 2.39 (m, 2H),2.17(s, 3H), 2.13 (s, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 69; [a]D = -52.63° (c 0.01 MeOH) >99% ee (-) ; 1st peak; RT 3.039 min; Chiralpak AD-3 4.6 x 100 mm 3u column; 20% MeOH/DEA @ 120 bar, 4 mL/min

163

69	^H0> Cl 0 O m ÇU ΛΑ Cl (+)-5,8-d ich lo ro-2- [ (4,6-d i met h y I 2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[2-hydroxy-1 (morpholin-4-yl)ethyl]-3,4dihydroisoquinolin-1 (2H)-one	B	480	¹H NMR (400 MHz, DMSO-d6) δ 11.54 (br. s., 1 H), 7.72 (s, 1H), 5.89 (s, 1H), 4.71 (br. s., 1H), 4.58 (s, 2H), 3.95 (t, J=4.65 Hz, 1H), 3.68 - 3.78 (m, 1H), 3.51 3.67 (m, 5H), 3.45 (t, J=6.54 Hz, 2H), 2.87 (t, J=6.11 Hz, 2H), 2.54 (br. s., 2H), 2.27 - 2.39 (m, 2H), 2.17 (s, 3H), 2.13 (s, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 68; [a]D = +75.09° (c 0.01 MeOH) -97.6% ee (+); 2nd peak; RT 4.327 min; Chiralpak AD-3 4.6 x 100 mm 3u column; 20% MeOH/DEA @120 bar, 4 mL/min;
70	^D>< D^O Cl 0 0 0 Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-{[1- (hydroxyacetyl)piperidin-4yl][(²H3)methy!oxy]methyl}-3,4dihydroisoquinolin-1 (2H)-one	I	539	Ή NMR (400 MHz, CD3OD) δ 7.54 (s, 1H), 6.11 (s, 1H), 4.76 (s, 2H), 4.66 (d, J=5.62 Hz, 1H), 4.43-4.56 (m, 1 H), 4.11 -4.28 (m, 2H), 3.66-3.80 (m, 1 H), 3.53 (t, J=6.11 Hz, 2H), 2.99 (t, J=6.11 Hz, 2H), 2.84-2.96 (m, 1H), 2.50-2.64 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 1.86-2.01 (m, 1H), 1.74 (dd, J=2.20,13.20 Hz, 1 H), 1.28-1.58 (m, 3H)	Racemic Mixture

164

71	''O Cl 0 0 _nAî^nJ 0 Cl 3-{4-[{5,8-dichioro-2-[(4,6dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-1-oxo1,2,3,4-tetrahydroisoquinolin-7yl}(methoxy)methyl]piperidin-1 yl}-3-oxopropanenitrile - Isomer A	I	545	¹H NMR (400 MHz, CD3OD) δ 11.61 (br. s., 1H) 7.46 (s, 1H), 5.95 (s, 1H), 4.82-4.73 (m, 2H), 4.64-4.57 (m, 2H), 3.68 (t, J=5.4 Hz, 3H), 3.47 (s, 2H), 3.20 (s, 3H), 3.09-3.02 (m, 1H), 2.95 (t, J=6 Hz, 2H), 2.52-2.49 (m, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 1.89- 1.87 (m, 1 H), 1.75-1.68 (m, 2H), 1.62-1.51 (m, 2H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 61 ; 97.43% ee; rétention time: 8.742 min; column: Chiralpak AS-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2; flow rate: 2.35 mL/min
72	A Cl O 0 0 Cl 4-[{5,8-dichîoro-2-[(4,6-dimethyl2-oxo-1,2-dihydropyridin-3yl)methyl]-1 -oxo-1,2,3,4tetrahydroisoquinolin-7yl}(methoxy)methyl]piperidine-1 carbaldehyde - Isomer A	I	506	¹H NMR (400 MHz, CDCI3) δ 11.52 (br s, 1H), 7.99 (s, 1H), 7.47 (s, 1H), 5.96 (s, 1H), 4.77 (s, 2H), 4.63 (d, J=4.8 Hz, 1H), 4.42 (d, J=11.6 Hz, 1 H), 3.68 (t, J=6 Hz, 2H), 3.61 (t, J=13.2 Hz, 1 H), 3.20 (s, 3H), 2.97-2.94 (m, 3H), 2.49-2.47 (m, 1H), 2.38 (s, 3H), 2.29 (s, 3H), 1.89-1.87 (m, 1H), 1.36-1.26 (m, 4H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 73; 94.43% ee; rétention time: 8.623 min; column: Chiralpak AS-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2; flow rate: 2.35 mL/min.

165

73	O Cl 4-[{5,8-dichloro-2-[(4,6-dimethyl2-oxo-1,2-dihydropyridin-3yl)methyl]-1 -oxo-1,2,3,4tetrahydroisoquinolin-7yl)(methoxy)methyl]piperidine-1 carbaldehyde - Isomer B	l	506	¹H NMR (400 MHz, CDCI3) δ 11.29 (br s, 1H), 7.99 (s, 1H), 7.47 (S, 1H), 5.95 (s, 1H), 4.77 (s, 2H), 4.63 (d, J=4.8 Hz, 1 H), 4.42 (d, J=12.0 Hz, 1H), 3.68 (t, J=6 Hz, 2H), 3.61 (t, J=12.8 Hz, 1H), 3.20 (s, 3H), 2.97-2.94 (m, 3H), 2.49-2.47 (m, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 1.89-1.87 (m, 1H), 1.36-1.26 (m, 4H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 72; 92.36% ee; rétention time: 9.05 min; column: Chiralpak AS-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2; flow rate: 2.35 mL/min
74	Cl 7-[l-(azetidin-3-ylidene)ethyl]5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-3,4-dihydroisoquinolin1(2H)-one	H	432	N/A	N/A

166

75	° Cf 5,8-dichloro-2-[(4,6-dimethyl-2οχο-1,2-dihydropyridin-3yl)methyl]-7-{1-[1- (hydroxyacetyl)azetidin-3- ylidene]ethyl}-3,4dihydroisoquinolin-1 (2H)-one	H	490	¹H NMR (400 MHz, DMS0-d6) δ 11.54 (br. s., 1H), 7.51 (s, 1H), 5.89 (s, 1H), 4.81-4.99 (m, 2H), 4.51-4.60 (m, 3H), 4.48 (br. s., 1H), 4.19 (br. s., 1H), 3.83-4.01 (m, 2H), 3.46 (t, J=6.11 Hz, 2H), 2.88 (t, J=5.87 Hz, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.85 (br. s., 3H)	N/A
76	vXXA ⁰ Cl 7-[ 1 -(1 -acetylazetidin-3ylidene)ethyl]-5,8-dichloro-2[(4,6-dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one	H	474	¹H NMR (400 MHz, DMSO-d6) δ 11.46 (br. s., 1H), 7.44 (s, 0.56H), 7.43 (s, 0.44H), 5.81 (s, 1 H), 4.72 (br. s., 0.88H), 4.49 (s, 2H), 4.40 (br. s., 1.12H), 4.36 (br. s., 1.12H), 4.05 (br. s., 0.88H), 3.39 (t, J=6.24 Hz, 2H), 2.81 (t, J=6.11 Hz, 2H), 2.10 (s, 3H), 2.05 (s, 3H), 1.78 (br. s., 3H), 1.76 (s, 1.32H), 1.68 (s, 1.68H) Rotamers (-4:5 ratio).	N/A

167

77	8-chloro-2-[(4,6-dimethyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl]-5methyl-7-{1-[1- (methylsulfonyl)azetidin-3ylidene]ethyl}-3,4dihydroisoquinolin-1 (2H)-one	H	490	¹H NMR (400 MHz, CDCI3) δ 11.72 (br. s., 1H), 6.98 (s, 1H), 5.93 (s, 1H), 4.79 (s, 2H), 4.65 (br. s., 2H), 4.29 (br. s., 2H), 3.62 (t, J=6.15 Hz, 2H), 2.89 (s, 3H), 2.73 (t, J=6.15 Hz, 2H), 2.36 (s, 3H), 2.23-2.30 (m, 3H), 2.21 (s, 3H), 1.87 (s, 3H)	N/A
78	8-chloro-2-[(4-methoxy-6-methyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-5-methyl-7-{1 -[1 (methylsulfonyl)azetidin-3ylidene]ethyl}-3,4dihydroisoquinolin-1 (2H)-one	H	[M+Na] ⁺528	¹H NMR (400 MHz, CD3OD) δ 7.17 (s, 1H), 6.28 (s, 1H), 4.74 (s, 2H), 4.68 (br. s., 2H), 4.244.33 (m, 2H), 3.91 (s, 3H), 3.38 (t, J=6.27 Hz, 2H), 2.99 (s, 3H), 2.80 (t, J=6.27 Hz, 2H), 2.34 (s, 3H), 2.27 (s, 3H), 1.91 (t, J=1.51 Hz, 3H)	N/A

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79	⁰ C! S.Q-dichloro-S-ttA.e-dimethyl-Soxo-1,2-dihydropyridin-3yl)methyl]-7-{fluoro[1 (hydroxyacetyl)azetidin-3ylidene]methyl}-3,4dihydroisoquinolin-1 (2H)-one	H	494	¹H NMR (400 MHz, DMSO-d6) δ 11.58 (brs, 1H), 7.84 (d, J=5.6 Hz, 1H), 5.89 (s, 1H), 5.15-5.00 (m, 1H), 5.00-4.95 (m, 1H), 4.80-4.75 (m, 1 H), 4.65-4.60 (m, 1H), 4.57 (s, 2H), 4.50-4.45 (m, 1H), 4.00-3.95 (m, 2H), 3.47 (t, J=6.0 Hz, 2H), 2.93 (t, J=4.8 Hz, 2H), 2.16 (s, 3H), 2.12 (s, 3H).	N/A
80	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3- yl) methyl]-7-[ 1 -(pipe ridin-4ylidene)ethyl]-3,4dihydroisoquinolin-1 (2H)-one	H	460	¹H NMR (400 MHz, CD3OD) δ 7.36 (s, 1H), 6.18 (s, 1 H), 4.784.83 (m, 2H), 3.60 (t, J=6.24 Hz, 2H), 2.98 - 3.12 (m, 4H), 2.91 (t, J=5.14 Hz, 2H), 2.58 -2.69 (m, 1 H), 2.47-2.58 (m, 1 H), 2.37 (s, 3H), 2.32 (s, 3H), 2.05 (d, J=7.58 Hz, 2H), 1.97-2.01 (m, 3H)	N/A

169

81	5,8-dich Ιο ro-2-[(4-methoxy-6methyl-2-oxo-1,2-dihydropyridin3-yl)methyl]-7-[(R)methoxy(oxetan-3-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one	1	[M+Na] ⁺489	¹H NMR (400 MHz, CDCI3) δ 12.34 (brs, 1H), 7.49 (s, 1H), 5.93 (s, 1H), 5.05 (d, J=6.0 Hz, 1H), 4.61-4.78 (m, 6H), 3.88 (s, 3H), 3.48-3.50 (m, 2H), 3.373.38 (m, 1H), 3.31 (s, 3H), 2.94 (t, J=6.2 Hz, 2H), 2.35 (s, 3H).	R isomer; stereochemistry determined from X-ray crystal structure of enantiomeric compound Ex.82; 100% ee; rétention time 9.85 min; Column: (R.R)Whelk 01, 250x4.6mm I.D., 5um; Mobile phase: 50% éthanol (0.05% DEA) in CO2; wavelength 220 nm
82	^0 Cl 0 0 Cl ¹ 5,8-dichloro-2-[(4-methoxy-6methyl-2-oxo-1,2-dihydropyridin3-yl)methyl]-7-[(S)methoxy(oxetan-3-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one	1	467	¹H NMR (400 MHz, CDCI3) δ 12.38 (brs, 1H), 7.49 (s, 1H), 5.92 (s, 1H), 5.05 (d, J=6.0 Hz, 1H), 4.64-4.78 (m, 6H), 3.87 (s, 3H), 3.47-3.50 (m, 2H), 3.37- 3.38 (m, 1H), 3.31 (s, 3H), 2.93 (t, J=6.2 Hz, 2H), 2.35 (s, 3H).	Known to be S isomer by X-ray crystal structure; Enantiomer of Ex.81 ; 98% ee; rétention time 8.65 min; column: (R.R)Whelk 01, 250x4.6mm I.D., 5um; mobile phase: 50% éthanol (0.05% DEA) in CO2; wavelength 220 nm

170

83	8-chloro-2-[(4-methoxy-6-methyl2-oxo-l ,2-dihydropynclin-3yl)methyl]-7-((R)-methoxy[(3R)tetrahydrofuran-3-yl]methyl}-5methyl-3,4-dihydroisoquinolin- 1 (2H)-one	I	461	¹H NMR (400 MHz, CDCI3) δ 12.36 (brs, 1H), 7.29 (s, 1H), 5.91 (s, 1H), 4.75-4.85 (m, 3H), 3.83-3.89 (m, 6H), 3.69-3.71 (m, 1H), 3.44-3.47 (m, 2H), 3.16 (s, 3H), 2.73-2.76 (m, 2H), 2.542.58 (m, 1 H), 2.34 (s, 3H), 2.26 (s, 3H), 1.70-1.73 (m, 2H).	Known to be R, R isomer by X-ray crystal structure; Enantiomer of Ex.86; Diastereomer of Ex.84 and Ex.85; 100% ee; rétention time 34.91 min; column: Chiralpak IC 250x4.6mm I.D., 5um; mobile phase: 50% éthanol (0.05% DEA) in CO2; flow rate: 2.0mL/min
84	8-chloro-2-[(4-methoxy-6-methyl- 2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-{(R)-methoxy[(3S)tetrahydrofuran-3-yl]methyl}-5methyl-3,4-dihydroisoquinolin- 1 (2H)-one	I	461	¹H NMR (400 MHz, CDCI3) δ 12.33 (brs, 1H), 7.30 (s, 1H), 5.91 (s, 1H), 4.77-4.84 (m, 3H), 3.86-3.89 (m, 4H), 3.68-3.73 (m, 2H), 3.58-3.60 (m, 1H), 3.443.46 (m, 2H), 3.19 (s, 3H), 2.732.75 (m, 2H), 2.62-2.64 (m, 1 H), 2.34 (s, 3H), 2.24 (s, 3H), 1.951.98 (m,2H).	Single enantiomer, either R,S or S,R, but absolute stereochemistry unknown; Enantiomer of Ex.85; Diastereomer of Ex.83 and Ex.86; 97% ee; rétention time 39.01 min; column: Chiralpak IC 250x4.6mm I.D., 5um; mobile phase: 50% éthanol (0.05% DEA) in CO2; flow rate: 2.0mL/min

171

85	oVoi 8-chloro-2-[(4-methoxy-6-methyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-{(S)-methoxy[(3R)tetrahydrofuran-3-yl]methyl}-5methyl-3,4-dihydroisoquinolin1(2H)-one	1	461	¹H NMR (400 MHz, CDCI3) δ 12.30 (brs, 1H), 7.30 (s, 1H), 5.91 (s, 1H), 4.77-4.84(m, 3H), 3.86-3.89 (m, 4H), 3.66-3.74 (m, 2H), 3.58-3.59 (m, 1H), 3.443.46 (m, 2H), 3.19 (s, 3H), 2.732.75 (m, 2H), 2.63-2.65 (m, 1 H), 2.34 (s, 3H), 2.24 (s, 3H), 1.951.98 (m, 2H).	Single enantiomer, either R,S or S,R, but absolute stereochemistry unknown; Enantiomer of Ex.84; Diastereomer of Ex.83 and Ex.86; 100% ee; rétention time 29.05 min; column: Chiralpak IC 250x4.6mm I.D., 5um; mobile phase: 50% éthanol (0.05% DEA) in CO2; flow rate: 2.0mL/min
86	o^z Cl O 0				S,S isomer; stereochemistry
				¹H NMR (400 MHz, CDCI3) δ	determined by X-ray crystal
	O—'			12.29 (brs, 1H), 7.30 (s, 1H),	structure of enantiomeric
	8-chloro-2-[(4-methoxy-6-methyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-{(S)-methoxy[(3S)tetrahydrofuran-3-yl]methyl}-5methyl-3,4-dihydroisoquinolin- 1 (2H)-one	1	461	5.91 (s, 1H), 4.75-4.84 (m, 3H), 3.83-3.89 (m, 6H), 3.69-3.71 (m, 1H), 3.44-3.47 (m, 2H), 3.16 (s, 3H), 2.73-2.76 (m, 2H), 2.56- 2.58 (m, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 1.70-1.73 (m, 2H).	compound Ex.83; Diastereomer of Ex.84 and Ex.85; 100% ee; rétention time 32.28 min; column: Chiralpak IC 250x4.6mm I.D., 5um; mobile phase: 50% éthanol (0.05% DEA) in CO2; flow rate: 2.0mL7min

172

87	Cl ¹ 5,8-dichloro-2-[(4-methoxy-6methyl-2-oxo-1,2-dihydropyridin3-yl)methyl]-7-[1-(1methylazetidin-3-yl)ethyl]-3,4dihydroisoquinolin-1(2H)-one Isomer A	J	464	Ή NMR (400 MHz, CD3OD) δ 7.44 (s, 1H), 6.27 (s, 1H), 4.73 (s, 2H), 3.91 (s, 3H), 3.67-3.78 (m, 2H), 3.36-3.42 (m, 3H), 3.16 (t, J=7.40 Hz, 1H), 2.90-2.96 (m, 2H), 2.82-2.90 (m, 2H), 2.39 (s, 3H), 2.33 (s, 3H), 1.16 (d, J=6.78 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.88; 99% ee; rétention time 5.511 min; Column: Chiralpak AD-3 150x4.6 mm I.D., 3 um; mobile phase; éthanol (0.05% DEA) in CO2
88	5,8-dichloro-2-[(4-methoxy-6methyl^-oxo-l^-dihydropyridin3-yl)methyl]-7-[1-(1methylazetidin-3-yl)ethyl]-3,4dihydroisoquinolin-1(2H)-one Isomer B	J	464	¹H NMR (400 MHz, CD3OD) δ 7.43 (s, 1H), 6.26 (s, 1H), 4.73 (s, 2H), 3.91 (s, 3H), 3.64-3.75 (m, 2H), 3.34-3.42 (m, 3H), 3.12 (br. s., 1H), 2.93 (t, J=6.02 Hz, 2H), 2.83 (br. s., 2H), 2.35-2.40 (m, 3H), 2.33 (s, 3H), 1.16 (d, J=6.78 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.87; 100% ee; rétention time 55.997 min; Column: Chiralpak AD-3 150x4.6 mm I.D., 3 um; mobile phase; éthanol (0.05% DEA) in CO2

173

89	Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[1 -(morpholin-4yl)ethyl]-3,4-dihydroisoquinolin1(2H)-one	K	464	¹H NMR (400MHz, CDCI3) δ 7.74 (S, 1 H), 5.94 (s, 1H), 4.874.70 (m, 2H), 4.00 (q, J=6.3 Hz, 1H), 3.76-3.59 (m, 6H), 2.992.81 (m, 2H), 2.53 (br. s., 2H), 2.36 (m, 5H), 2.29 (s, 3H), 1.24 (d, J=6.5 Hz, 3H)	racemic mixture
90	Cl (+)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[1 -(morpholin-4yl)ethyl]-3,4-dihydroisoquinoiin1(2H)-one	K			(+) isomer of Ex.89

174

91	Cl (-)-5,8-dichloro-2-[{4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[1 -{morpholin-4yl)ethyl]-3,4-dihydroisoquinolin- 1 (2H)-one	K			(-) isomer of Ex.89
92	°—\ γ² ci ο o “AA-ΑΓ ^Cl F^F 5,8-dichloro-2-{[4(difluoromethoxy)-6-methyl-2oxo-1,2-dihydropyridin-3yl]methyl}-7-[2-hydroxy-1 (tetrahydrofuran-3-yl)ethyl]-3,4dihydroisoquinolin-1 (2H)-one Isomer A	A	517	¹H NMR (400 MHz, CDCI3) 6 12.31 (br.s., 1H), 7.42 (s, 1H), 6.72 (t, J=72 Hz, 1H), 6.09 (s, 1 H), 4.70 (s, 2H), 3.82-3.96 (m, 4H), 3.61-3.65 (m, 4H), 3.20 (t, J=8.4 Hz, 2H), 2.97 (t, J=6.2 Hz, 2H), 2.70-2.72 (m, 1H), 2.35 (s, 3H), 2.21-2.23 (m, 1H), 1.751.81 (m, 1H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.93; Diastereomer of Ex.94 and Ex.95; 100% ee; rétention time 5.37 min; column: Chiralcel OJ-H 250x4.6mm I.D., 5um; mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%; flow rate; 2.5 mUmin

175

93	0—y γ² ci ο ο Λό-Λ ^Cl f^Af 5,8-dichloro-2-{[4(difluoromethoxy)-6-methyl-2oxo-1,2-dihydropyridin-3yl]methyl}-7-[2-hydroxy-1 (tetrahydrofuran-3-yl)ethyl]-3,4dihydroisoquinolin-1(2H)-one Isomer B	A	517	¹H NMR (400 MHz, CDCI3) δ 12.25 (br.s., 1H), 7.42 (s, 1H), 6.72 (t, J=72 Hz, 1 H), 6.09 (s, 1H), 4.70 (s, 2H), 3.82-3.89 (m, 4H), 3.61-3.66 (m, 4H), 3.20 (t, J=8.4 Hz, 2H), 2.98 (t, J=6.2 Hz, 2H), 2.70-2.72 (m, 1H), 2.35 (s, 3H), 2.21-2.23 (m, 1H), 1.761.81 (m, 1H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.92; Diastereomer of Ex.94 and Ex.95; 100% ee; rétention time 5.54 min; column: Chiralcel OJ-H 250x4.6mm I.D., 5um; mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%; flow rate; 2.5 mL/min
94	0—\ Y Cl 0 0 ΛόΛ c _FA_F 5,8-dichloro-2-{[4(difluoromethoxy)-6-methyl-2- oxo-1,2-dihydropyridin-3-	A	517	¹H NMR (400 MHz, CDCI3) δ 12.12 (br.s., 1H), 7.45 (s, 1H), 6.73 (t, J=72 Hz, 1H), 6.10 (s, 1H), 4.71 (t, J=13.3 Hz, 2H), 4.07-4.10 (m, 1 H), 3.82-3.70 (m, 4H), 3.60-3.65 (m, 4H), 2.99 (t, J=6.2 Hz, 2H), 2.63-2.65 (m,	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.95; Diastereomer of Ex.92 and Ex.93; 100% ee; rétention time 5.80 min; column: Chiralcel OJ-H 250x4.6mm I.D., 5um; mobile phase: methanol (0.05% DEA) in

176

	y l]methy l}-7-[2-hyd roxy-1 (tetrahydrofuran-3-yl)ethyl]-3,4dihydroisoquînolin-1(2H)-one Isomer C			1 H), 2.35 (s, 3H), 1.78-1.8 (m, 1H), 1.40-1.45 (m, 1H).	CO2 from 5% to 40%; flow rate; 2.5 mL/min
95	γ² ci ο o ^Cl F^F 5,8-dichloro-2-{[4(difluoromethoxy)-6-methyl-2oxo-1,2-dihydropyridin-3yl]methyl}-7-[2-hydroxy-1 (tetrahydrofuran-3-yl)ethyl]-3,4dihydroisoquinolin-1(2H)-one Isomer D	A	517	¹H NMR (400 MHz, CDCI3) δ 12.36 (br.s., 1H), 7.45 (s, 1H), 6.72 (t, J=73 Hz, 1H), 6.09 (s, 1H), 4.71 (q, J=13.9 Hz, 2H), 4.06-4.08 (m, 1 H), 3.70-3.83 (m, 4H), 3.59-3.63 (m, 4H), 2.98(t, J=5.4 Hz, 2H), 2.63-2.65 (m, 1H), 2.35 (s, 3H), 1.78-1.8 (m, 1H), 1.39-1.45 (m, 1H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.94; Diastereomer of Ex.92 and Ex.93; 100% ee; rétention time 5.98 min; column: Chiralcel OJ-H 250x4.6mm I.D., 5um; mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%; flow rate; 2.5 mL/min
96	HO. _Λ > Cl 0 0 aAAt nAî nh (+)-8-chloro-2-[(4,6-dimethyl-2-	A	431	Ή NMR (400 MHz, CD3OD) δ 7.48 (d, J=7.34 Hz, 1H), 7.18 (d, J=7.83 Hz, 1H), 6.10 (s, 1H), 4.77 (s, 2H), 3.89-3.98 (m, 1H),	[a]_D =+51.7° (c 0.2 MeOH); (+) isomer of Ex. 64 racemate; either R,R or S,S isomer; absolute

177

	oxo-1,2-dihydropyridin-3yl)methyl]-7-{(1S)-2-hydroxy-1[(3S)-tetrahydrofuran-3-yl]ethyl)3,4-dihydroisoquinolin-1(2H)-one			3.74-3.86 (m, 3H), 3.57 (t, J=7.70 Hz, 2H), 3.42-3.51 (m, 2H), 3.16 (t, J=8.31 Hz, 1H), 2.82-2.89 (m, 2H), 2.64-2.80 (m, 1H), 2.32-2.23 (m, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 1.74-1.89 (m, 1H)	stereochemistry undetermined; Enantiomer of Ex.97
97	^H0> Cl O o (-)-8-chloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3y IJmethy l]-7-{(1 R)-2-hydroxy-1 [(3 R)-tetrahyd rof u ran-3-y I] et hy I} 3,4-dihydroisoquinolin-l (2H)-one	A	431	¹H NMR (400 MHz, CD30D) δ 7.48 (d, J=7.58 Hz, 1 H), 7.18 (d, J=7.83 Hz, 1H), 6.10 (s, 1H), 4.77 (s, 2H), 3.93 (dt, J=3.79, 8.13 Hz, 1H), 3.74-3.86 (m, 3H), 3.57 (t, J=7.83 Hz, 2H), 3.433.51 (m, 2H), 3.16 (t, J=8.44 Hz, 1H), 2.85 (t, J=5.75 Hz, 2H), 2.65-2.80 (m, 1 H), 2.32-2.23 (m, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 1.75-1.89 (m, 1 H)	[a]_D= -27.4° (c 0.1 MeOH); (-) isomer of Ex. 64 racemate; either R,R or S,S isomer; absolute stereochemistry undetermined; Enantiomer of Ex.96

178

98	^H0> Cl 0 0 (+)-8-chloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3y l)methy l]-7-{(1 R)-2-hydroxy-1 - [(3S)-tetrahydrofuran-3-yl]ethyl}- 3,4-dihydroisoquinolin-1(2H)-one	A	431	¹H NMR (400 MHz, CD30D) δ 7.48 (d, J=7.83 Hz, 1H), 7.19 (d, J=7.82 Hz, 1H), 6.10 (s, 1H), 4.78 (s, 2H), 4.13 (t, J=7.83 Hz, 1H), 3.78 (dt, J=4.16, 8.31 Hz, 1H), 3.55-3.73 (m, 5H), 3.433.50 (m, 2H), 2.83-2.89 (m, 2H), 2.61-2.74 (m, 1H), 2.29 (s, 3H), 2.24 (s, 3H), 1.69-1.79 (m, 1H), 1.34-1.45 (m, 1H)	[a]o =+20.5° (c 0.1 MeOH); (+) isomer of Ex. 65 racemate; either R,S or S,R isomer; absoiute stereochemistry undetermined; Enantiomer of Ex.99
99	^HCS Cl 0 0 0-J (-)-8-chloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{(1 S)-2-hydroxy-1 [(3R)-tetrahydrofuran-3-yl]ethyl)3,4-dihydroisoquinolin-1(2H)-one	A	431	¹H NMR (400 MHz, CD3OD) δ 7.48 (d, J=7.83 Hz, 1H),7.19(d, J=8.07 Hz, 1H), 6.10 (s, 1H), 4.78 (s, 2H), 4.13 (t, J=7.83 Hz, 1H), 3.78 (dt, J=4.16, 8.31 Hz, 1H), 3.56-3.74 (m, 5H), 3.42- 3.52 (m, 2H), 2.82-2.89 (m, 2H), 2.59-2.75 (m, 1H), 2.29 (s, 3H), 2.24 (s, 3H), 1.68-1.79 (m, 1H), 1.40 (qd, J=8.57, 12.20 Hz, 1H)	[a]_D =-33.1° (c 0.1 MeOH); (-) isomer of Ex. 65 racemate; either R,S or S,R isomer; absoiute stereochemistry undetermined; Enantiomer of Ex.98

179

100	.CL Cl 0 0 (+)-8-chloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[2-hydroxy-1 (tetrahydro-2H-pyran-4-yl)ethylJ5-methyl-3,4-dihydroisoquinolin- 1(2H)-one	A	459	Ή NMR (700 MHz, DMSO-d6) 5 7.27 (br. s., 1H), 5.89 (s, 1H), 4.50 - 4.61 (m, 2H), 3.84 (d, J=8.88 Hz, 1 H), 3.21 - 3.74 (m, 7H), 3.15 (td, J=10.76, 3.59 Hz, 1H), 2.67 (t, J=5.81 Hz, 2H), 2.19 (s, 3H), 2.15 (s, 3H), 2.12 (s,3H), 1.82-1.91 (m, 1 H), 1.78 (d, J=12.64 Hz, 1H), 1.20-1.31 (m, 1H), 1.05-1.15 (m, 2H)	[q]d = +10.8° (c 0.1 MeOH); 99% ee; absolute stereochemistry undetermined; Enantiomer of Ex.101
101	.CL Y Cl 0 0 (-)-8-chloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3- yl)methyl]-7-[2-hydroxy-1 (tetrahydro-2H-pyran-4-yl)ethyl]-	A	459	¹H NMR (700 MHz, DMSO-d6) δ 7.27 (br. s., 1H), 5.89 (s, 1H), 4.50 - 4.63 (m, 2H), 3.84 (d, J=11.10 Hz, 1 H), 3.20-3.75 (m, 7H), 3.15 (td, J=10.89, 3.67 Hz, 1H), 2.67 (t, J=5.89 Hz, 2H), 2.19 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H), 1.82-1.91 (m, 1H), 1.78 (d, J=12.98 Hz, 1H), 1.20-1.30 (m, 1H), 1.06-1.15 (m, 2H)	[a]o = -9.7° (c 0.1 MeOH); >99% ee; absolute stereochemistry undetermined; Enantiomer of Ex.100

180

	5-methyl-3,4-dihydroisoquinolin- 1 (2H)-one
102	A Cl 0 0 Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-(2-hydroxy-1 methoxypropyl)-3,4dihydroisoquinolin-1 (2H)-one	D	439	¹H NMR (400 MHz, CDCI3) δ 11.52 (br. s., 1H), 7.54 (s, 1H), 5.96 (s, 1H), 4.88 (br. s., 1H), 4.77 (s, 2H), 4.08-4.11 (m, 1H), 3.65-3.70 (m, 2H), 3.31 (s, 3H), 2.99-2.91 (m, 2H), 2.37 (s, 3H), 2.29 (s, 3H), 1.05 (d, J=6.4 Hz, 3H).	Mixture of 4 possible diastereomers
103	^H0> Cl 0 0 O iAïnAi nh A iÇU AA '—O Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{2-hydroxy-1 -[(3R)tetrahydrofuran-3-yloxy]ethyl}3,4-dihydroisoquinolin-1(2H)-one	D	481	¹H NMR (400 MHz, CD3OD) δ 7.52 (s, 1H), 6.00 (s, 1H), 4.97 (dd, J=7.15, 2.87 Hz, 1H), 4.66 (s, 2H), 4.00 - 4.05 (m, 1 H), 3.83 - 3.91 (m, 1H), 3.72 (td, J=8.34, 4.10 Hz, 1H), 3.56 - 3.66 (m, 3H), 3.37 - 3.45 (m, 3H), 2.88 (t, J=6.24 Hz, 2H), 2.19 (s, 3H),	Single isomer, (R) at THF center, other chiral center undetermined; Diastereomer of Ex. 104; 99% de; rétention time 1.088 min on Chiralcel OJ-3 4.6 x 100 mm 3u column; 10% MeOH @ 120 bar, 4 mL/min

181

				2.15 (s, 3H), 2.05-2.13 (m, 1 H), 1.85-1.97 (m, 1H)
104	^H0> Cl Ο ο O AAA N '''Ai N H X ÇU AA '-O Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-(2-hydroxy-1-[(3R)tetrahydrofuran-3-yloxy]ethyl}3,4-dihydroisoquinolîn-1 (2H)-one	D	481	¹H NMR (400 MHz, CD3OD) δ 7.57 (s, 1H), 6.00 (S, 1H), 4.91 (dd, J=7.03, 2.87 Hz, 1H), 4.65 (s, 2H), 4.04 - 4.11 (m, 1 H), 3.90 (d, J=9.66 Hz, 1H), 3.78 (q, J=8.07 Hz, 1H), 3.62 - 3.69 (m, 2H), 3.59 (dd, J=11.86,2.93 Hz, 1 H), 3.37 - 3.45 (m, 3H), 2.88 (t, J=6.24 Hz, 2H), 2.19 (s, 3H), 2.15 (s, 3H), 1.74 -1.96 (m, 2H)	Single isomer, (R) at THF center, other chiral center undetermined; Diastereomer of Ex. 103; 94% de; rétention time 1.558 min on Chiralcel OJ-3 4.6 x 100 mm 3u column; 10% MeOH @ 120 bar, 4 mUmin
105	ho. „ Ί Cl 0 0 Cl ¹ 5,8-dichloro-7-{(1 R)-2-hydroxy-1 [(2R)-tetrahydrofuran-2-yl]ethyl}2-[(4-methoxy-6-methyl-2-oxo-	E	481	¹H NMR (400 MHz, CD3OD) δ 7.67 (s, 1H), 6.27 (s, 1H), 4.74 (s, 2H), 4.28-4.29 (m, 1H), 3.90- 3.79 (m, 6H), 3.69 (t, J=6.8 Hz, 2H), 3.40 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.0 Hz, 2H), 2.34 (s, 3H), 2.10-2.07 (m, 1 H), 1.90-1.86 (m,	1 R,2R isomer; Diastereomer of Ex. 106; rétention time: 3.480 min; column: Chiralpak AD-3 150x4.6 mm I.D., 3 um; mobile phase 40% éthanol (0.05% DEA) in CO2

182

	1,2-dîhydropyridin-3-yl)methyl]- 3,4-dihydroisoquinolin-1(2H)-one			1H), 1.77-1.75 (m, 1H), 1.60- 1.56 (m, 1H).
106	HCL Λ Cl 0 0 x Cl I 5,8-dichloro-7-{(1 R)-2-hydroxy-1 [(2S)-tetrahydrofuran-2-yl]ethyl)2-[(4-methoxy-6-methyl-2-oxo1,2-dihydropyridin-3-yl)methyl]3,4-dihydroisoquinolin-1(2H)-one	E	481	¹H NMR (400 MHz, CD3OD) δ 7.60 (s, 1H), 6.27 (s, 1H), 4.74 (s, 2H), 4.20-4.18 (m, 1H), 3.97- 3.92 (m, 6H), 3.91-3.80 (m, 1H), 3.70 (s, 1 H), 3.40 (t, J=5.6 Hz, 2H), 2.95 (t, J=6.0 Hz, 2H), 2.34 (s, 3H), 1.96-1.82 (m, 3H), 1.55- 1.50 (m, 1H).	1 R,2S isomer; Diastereomer of Ex. 105; rétention time: 2.507 min; column: Chiralpak AD-3 150x4.6 mm I.D., 3 um; mobile phase 40% éthanol (0.05% DEA) in CO2
107	O^z Cl 0 0 'XûXr Cl ¹ 5,8-dichloro-2-[(4-methoxy-6methyl-2-οχοΊ ,2-dihydropyridin3-yl)methyl]-7-(1-methoxypropyl)3,4-dihydroisoquinolin-1(2H)-one - Isomer A	G	439	¹H NMR (400 MHz, CD3OD) δ 7.56 (s, 1H), 6.27 (s, 1H), 4.73 (s, 2H), 4.70-4.72 (m, 1H), 3.91 (s, 3H), 3.40-3.43 (m, 2H), 3.26 (s, 3H), 2.95-2.99 (m, 2H), 2.34 (s, 3H), 1.74-1.79 (m, 1H), 1.621.67 (m, 1H), 0.99 (t, J=7.2 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 108; 100% ee; rétention time 11.41 min; column: Pheno Lux Cellulose-2,150x4.6mm I.D., 5um; mobile phase: 50% MeOH (0.05% DEA) in CO2; Flow rate: 2.0 mL/min

183

108	O^Z Cl Ο 0 Aàô'Xr Cl ¹ 5,8-dichloro-2-[(4-methoxy-6methyl-2-oxo-1,2-dihydropyridin3-yl)methyl]-7-(1-methoxypropyl)3,4-dihydroisoquinoiin-1(2H)-one - Isomer B	G	439	¹H NMR (400 MHz, CD3OD) δ 7.56 (s, 1H), 6.27 (s, 1H), 4.74 (s, 2H), 4.70-4.72 (m, 1 H), 3.91 (s, 3H), 3.40-3.43 (m, 2H), 3.26 (s, 3H), 2.95-2.99 (m, 2H), 2.34 (s, 3H), 1.73-1.77 (m, 1 H), 1.621.67 (m, 1H), 0.99 (t, J=7.4 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.107; 99% ee; rétention time 15.01 min; column: Pheno Lux Cellulose-2, 150x4.6mm I.D., 5um; mobile phase: 50% MeOH (0.05% DEA) in CO2; Flow rate: 2.0 mL/min
109	0 Cl 7-((1 -acetylpiperidin-4yl)(methoxy)methyl]-5,8-dichloro2-[(4,6-dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-3,4dihydroisoquinolin-1(2H)-one Isomer A	1	520	¹H NMR (400 MHz, CDCI3) δ 12.03 (br.s., 1H), 7.46 (s, 1H), 5.95 (s, 1H), 4.74-4.82 (m, 2H), 4.64-4.65 (m, 2H), 3.77-3.79 (m, 1H), 3.68 (t, J=5.8 Hz, 2H), 3.19 (s, 3H), 2.90-2.96 (m, 3H), 2.412.47 (m, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 2.07 (s, 3H), 1.83-1.86 (m, 1H), 1.52-1.57 (m, 2H), 1.34-1.41 (m,2H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 110; 100% ee; rétention time: 10.42 min; column: ChiralpakAD-H 250x4.6 mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2; flow rate: 2.5 mL/min

184

110	0 Cl 7-[( 1 -acetylpiperidin-4yl)(methoxy)methyl]-5,8-dichloro2-[(4,6-dîmethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-3,4dihydroisoquinolin-1(2H)-one Isomer B	1	520	Ή NMR (400 MHz, CDCI3) δ 12.01 (br.s., 1H), 7.47 (s, 1H), 5.95 (s, 1 H), 4.74-4.82 (m, 2H), 4.62-4.65 (m, 2H), 3.76-3.79 (m, 1H), 3.69 (t, J=6 Hz, 2H), 3.19 (s, 3H), 2.90-2.96 (m, 3H), 2.412.47 (m, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 2.07 (s, 3H), 1.83-1.86 (m, 1H), 1.52-1.58 (m, 2H), 1.34-1.40 (m, 2H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 109; 93% ee; rétention time: 11.08 min; column: ChiralpakAD-H 250x4.6 mm I.D., 5um; mobile phase: 540% methanol (0.05% DEA) in CO2; fiow rate: 2.5 mL/min
111	yCÀJÔF HO^ ^Cl 5,8-dichloro-7-{[1- (hyd roxyacetyl) pipe ridiri-4yl](methoxy)methyl}-2-[(4methoxy-6-methyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-3,4dihydroisoquinolin-1(2H)-one Isomer A	1	[M+Na] ⁺ 574	¹H NMR (400 MHz, CDCI3) δ 12.06 (s, 1 H), 7.44 (d, J=3.2 Hz, 1H), 5.93 (s, 1H), 4.78 (s, 2H), 4.62-4.64 (m, 2H), 4.10-4.14 (m, 2H), 3.88 (s, 3H), 3.72 (s, 1H), 3.47-3.53 (m, 3H), 3.20 (s, 3H), 2.84-2.96 (m, 3H), 2.46-2.60 (m, 1H), 2.35 (s, 3H), 1.70-1.72 (m, 1H), 1.58-1.59 (m, 2H), 1.331.46 (m, 2H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.112; 100% ee; rétention time: 9.21 min; column: Chiralpak AD-3 150x4.6mm I.D., 3um; mobile phase: 30% ethanol(0.1% ethanolamine) in CO2

185

112	A Cl 0 O oyCrçÔGY hct ^Cl 5,8-dichloro-7-{[1(hydroxyacetyl)piperidin-4yl](methoxy)methyl}-2-[(4methoxy-6-methyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one Isomer B	1	[M+Na] ⁺ 574	¹H NMR (400 MHz, CDCI3) δ 11.98 (s, 1 H), 7.44 (d,J=3.6 Hz, 1H), 5.93 (s, 1H), 4.77-4.81 (m, 2H), 4.59-4.64 (m, 2H), 4.104.14 (m, 2H), 3.88 (s, 3H), 3.72 (s, 1H), 3.47-3.53 (m, 3H), 3.20 (s, 3H), 2.83-2.96 (m, 3H), 2.462.60 (m, 1H), 2.35 (s, 3H), 1.891.90 (m, 1 H), 1.58-1.59 (m, 2H), 1.33-1.48 (m, 2H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.111 ; 100% ee; rétention time: 11.45 min; column: Chiralpak AD-3 150x4.6mm I.D., 3um; mobile phase: 30% ethanol(0.1% ethanolamine) in CO2
113	ΑφΑ 0=^ ci HO 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{[1 - (hydroxyacetyl)pyrrolidin-3yl](methoxy)methyl}-3,4dihydroisoquinolin-1 (2H)-one	1	522	¹H NMR (400 MHz, CD3OD) δ 7.63 (s, 1H), 6.13 (s, 1H), 4.78 (s, 2H), 4.09-4.17 (m, 2H), 3.67 (brs, 1H), 3.52-3.60 (m, 3H), 3.40-3.50 (m, 1 H), 3.22-3.25 (m, 3H), 3.00-3.03 (m, 2H), 2.54- 2.74 (m, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 1.73-2.07 (m, 3H)	mixture of diastereomers

186

114	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[methoxy(1 oxidotetrahydro-2H-thiopyran-4yl)methyl]-3,4-dihydroisoquinolin1(2H)-one - Isomer A	I	511	¹H NMR (400 MHz, CD30D) δ 7.54 (s, 1 H), 6.11 (s, 1H), 4.754.81 (m, 2H), 4.60-4.68 (m, 1H), 3.53 (t, J=6.2 Hz, 2H), 3.31-3.37 (m, 2H), 3.20 (s, 3H), 2.98-2.99 (m, 2H), 2.59-2.66 (m, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 2.06-2.15 (m, 1H), 1.71-1.92 (m, 4H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.115; 100% ee; rétention time: 6.190 min; column: Chiralcel OJ-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
115	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[methoxy(1 oxidotetrahydro-2H-thiopyran-4yl)methyl]-3,4-dihydroisoquinolin1(2H)-one - Isomer B	1	511	¹H NMR (400 MHz, CD3OD) δ 7.54 (s, 1H), 6.11 (s, 1 H), 4.754.76 (m, 2H), 4.66-4.68 (m, 1H), 3.52 (t, J=6.4 Hz, 2H), 3.37-3.51 (m, 2H), 3.20 (s, 3H), 2.99 (t, J=6.0 Hz, 2H), 2.60-2.68 (m, 2H), 2.30 (s, 3H), 2.25 (s, 3H), 2.06-2.09 (m, 1 H), 1.71-1.96 (m, 4H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.114; 98% ee; rétention time: 6.995 min; column: Chiralcel OJ-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2

187

116	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[(1,1 dioxidotetrahydro-2H-thiopyran4-yl)(methoxy)methyl]-3,4dihydroisoquinolin-1(2H)-one Isomer A	I	527	¹H NMR (400 MHz, CD30D) δ 7.56 (s, 1 H), 6.11 (s, 1 H), 4.83 (s, 2H), 4.70-4.75 (m, 1 H), 3.52 (t, J=6.2 Hz, 2H), 3.23 (s, 3H), 2.99-3.20 (m, 6H), 2.30 (s, 3H), 2.24 (s, 3H), 1.97-1.99 (m, 2H), 1.91-1.95 (m, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 117; 100% ee; rétention time: 1.170 min; column: Chiralcel OJ-3 50*4.6mm I.D., 3um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
117	'O Cl O 0 Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[(1,1dioxidotetrahydro-2H-thiopyran4-yl)(methoxy)methyl]-3,4-	I	527	¹H NMR (400 MHz, CD3OD) δ 7.56 (s, 1H), 6.12 (s, 1H), 4.81 (s, 2H), 4.71-4.79 (m, 1H), 3.53 (t, J=6.0 Hz, 2H), 3.23 (s, 3H), 2.99-3.20 (m, 6H), 2.30 (s, 3H), 2.25 (s, 3H), 2.10-2.16 (m, 2H), 1.92-2.00 (m, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.116; 92% ee; rétention time: 1.364 min; column: Chiralcel OJ-3 50*4.6mm I.D., 3um; mobile phase: 5-40% methanol (0.05% DEA) in CO2

188

	dihydroisoquinolin-1(2H)-one - Isomer B
118	0 Cl ¹ 4-[{5,8-dichloro-2-[(4-methoxy-6methyl-2-oxo-1,2-dihydropyridin3-yl)methyl]-1-oxo-1,2,3,4tetrahydroisoquinolin-7yl}(methoxy)methyl]piperidine-1 carbaldehyde - Isomer A	I	522	¹H NMR (400 MHz, CDCI3) δ 12.40 (s, 1 H), 7.99 (s, 1H), 7.45 (d, J=2.0 Hz, 1H), 5.94 (s, 1H), 4.78-4.82 (m, 2H), 4.63 (d, J=4.8 Hz, 1H), 4.40-4.44 (m, 1H), 3.88 (s, 3H), 3.59-3.62 (m, 1H), 3.49-3.52 (m, 2H), 3.20 (s, 3H), 2.91-2.96 (m, 3H), 2.462.50 (m, 1 H), 2.36 (s, 3H), 1.881.89 (m, 1 H), 1.26-1.57 (m,4H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.119; 100% ee; rétention time: 7.866 min; column: Chiralpak AS-H 250x4.6mm I.D., 5um; mobile phase: 20% methanol (0.1% ethanolamine) in CO2
119	0 Cl ï 4-[{5,8-dichloro-2-[(4-methoxy-6methyl-2-oxo-1,2-dihydropyridin3-yl)methyl]-1 -oxo-1,2,3,4tetrahydroisoquinolin-7-	1	522	¹H NMR (400 MHz, CDCI3) δ 12.29 (s, 1H), 8.00 (s, 1H), 7.45 (d, J=2.4 Hz, 1H), 5.93 (s, 1H), 4.74-4.78 (m, 2H), 4.64 (d, J=5.2 Hz, 1H), 4.41-4.44 (m, 1H), 3.88 (s, 3H), 3.59-3.63 (m, 1H), 3.51-3.52 (m, 2H), 3.20 (s, 3H), 2.93-3.01 (m, 3H), 2.47-	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 118: 94% ee; rétention time: 9.458 min; column: Chiralpak AS-H 250x4.6mm I.D., 5um; mobile phase: 20% methanol (0.1% ethanolamine) in CO2

189

	yl}(methoxy)methyl]piperidine-1 carbaldehyde - Isomer B			2.53 (m, 1 H), 2.35 (s, 3H), 1.89- 1.90 (m, 1H), 1.75-1.77 (m, 1H), 1.26-1.57 (m, 3H).
120	,d 5,8-dic oxo-1,; yl)mett m ethyl yl)(met dihydrc Isomer	. O^z Cl O O CI hloro-2-[(4,6-dimethyl-22-dihydropyridin-3iyl]-7-[(4-fluoro-13iperidin-4hoxy)methyl]-3,4)isoquinolin-1(2H)-one - A	1	510	¹H NMR (400 MHz, DMSO-d6) δ 11.58 (brs, 1H), 7.49 (s, 1 H), 5.90 (s, 1H), 4.85 (d, J=18.8 Hz, 1H), 4.57 (s, 2H), 3.51-3.46 (m, 2H), 3.16 (s, 3H), 2.91 (t, J=6 Hz, 2H), 2.58-2.64 (m, 2H), 2.19 (s, 3H), 2.14 (s, 3H), 2.13 (s, 3H), 1.93-2.03 (m, 3H), 1.681.87 (m, 2H), 1.36 (t, J=10.8 Hz, 1H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 121; 90% ee; rétention time: 7.533 min; column: AD-H 250x4.6mm I.D., 5 um; mobile phase: 5-40% isopropanol (0.05% DEA) in CO2
121	,c 5,8-dic oxo-1 ,i yl)mett	. 0^Z Cl 0 0 Ci hloro-2-[(4,6-dimethyl-2?-dihydropyridin-3iyl]-7-[(4-fluoro-1 -	1	[M+Na] ⁺ 532	¹H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 10.77 (brs, 1H), 7.51 (s, 1H), 5.90 (s, 1H), 4.93 (d, J=18.4 Hz, 1 H), 4.57 (s, 2H), 3.50-3.52 (m, 3H), 3.19 (s, 3H), 2.92-3.05 (m, 4H), 2.72 (s, 3H),	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 120; 91% ee; rétention time: 7.810 min; column: AD-H 250x4.6mm I.D., 5 um; mobile phase: 5-40% isopropanol (0.05% DEA) in CO2

190

	methylpiperidin-4yl)(methoxy)methyl]-3,4dihydroisoquinolin-1 (2H)-one Isomer B			2.13-2.34 (m, 9H), 1.65 (brs, 1H)
122	7-((1 -acetylpiperidin-4yl)(methoxy)methyl]-5,8-dichloro2-[(4-methoxy-6-methyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl]- 3,4-dihydroisoquinolin-1(2H)-one - Isomer A	I	536	¹H NMR (400 MHz, CDCI3) δ 12.40 (brs, 1H), 7.45 (d, J=2 Hz, 1 H), 5.94 (s, 1 H), 4.77-4.79 (m, 2H), 4.63 (d, J=5.2 Hz, 2H), 3.88 (s, 3H), 3.80-3.83 (m, 1 H), 3.51 (s, 2H), 3.20 (s, 3H), 2.93-2.96 (m, 3H), 2.36-2.38 (m, 4H), 2.07 (s, 3H), 1.71-1.72 (m, 1H), 1.421.52 (m, 4H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 123; 100% ee; rétention time: 9.93 min; column: ChiralpakAD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
123	7-((1 -acetylpiperidin-4yl)(methoxy)methyl]-5,8-dichloro2-[(4-methoxy-6-methyl-2-oxo1,2-dihydropyridin-3-yl)methyl]-	I	536	¹H NMR (400 MHz, CDC13) δ 12.26 (brs, 1H), 7.45 (d, J=2.4 Hz, 1 H), 5.95 (s, 1 H), 4.73-4.82 (m, 2H), 4.63 (d, J=4.8 Hz, 2H), 3.89 (s, 3H), 3.79-3.82 (m, 1H), 3.51 (s, 2H), 3.20 (s, 3H), 2.91-	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.122; 97% ee; rétention time: 10.60 min; column: ChiralpakAD-H 250x4.6mm I.D., 5um; mobile

191

	3,4-dihydroisoquinolin-1(2H)-one - Isomer B			2.96 (m, 3H), 2.36-2.44 (m, 4H), 2.07 (s, 3H), 1.38-1.71 (m, 5H).	phase: 5-40% methanol (0.05% DEA) in CO2
124	AAÂ 5,8-dichloro-2-[(4-methoxy-6methyl-2-oxo-1,2-dihydropyridin3-yl)methyl]-7- [methoxy(tetrahydrofuran-3yl)methyl]-3,4-dihydroisoquinolin1(2H)-one - Isomer A	I	481	¹H NMR (400 MHz, CDCI3) δ 12.35 (s, 1H), 7.53 (s, 1H), 5.93 (s, 1 H), 4.78-4.84 (m, 3H), 3.72- 3.88 (m, 6H), 3.51-3.70 (m, 1H), 3.48-3.50 (m, 2H), 3.18 (s, 3H), 2.95-2.96 (m, 2H), 2.55-2.60 (m, 1H), 2.35 (s, 3H), 1.70-1.76 (m, 2H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 126; Diastereomer of Ex. 125 and Ex. 127; 92% ee; rétention time: 12.59 min; column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase: 40/60 hexane(0.1 %DEA)/isopropanol(0. 1%ethanolamine)
125	AAâ Cl ¹ 5,8-dichloro-2-[(4-methoxy-6methyl-2-oxo-1,2-dihydropyridin3-yl)methyl]-7-	I	481	¹H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 7.57 (s, 1 H), 6.10 (s, 1H), 4.72 (d, J=8.8 Hz, 1H), 4.51 (s, 2H), 3.78 (s, 3H), 3.74-3.69 (m, 3H), 3.59-3.57 (m, 1H), 3.30-3.29 (m, 2H), 3.09 (s, 3H), 2.89-2.87 (m, 2H), 2.51-	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.127; Diastereomer of Ex.124 and Ex. 126; 98% ee; rétention time: 13.43 min; column: Chiralpak AD-H

192

	[methoxy(tetrahydrofuran-3yl)methyl]-3,4-dihydroisoquinolin1(2H)-one - Isomer B			2.50 (m, 1H),2.19(s, 3H), 1.51- 1.47 (m, 2H).	250x4.6mm I.D., 5um; mobile phase: 70/30 hexane(0.1 %DEA)/isopropanol(0. 1 %ethanolamine)
126	σγύ-Λ 5,8-dich lo ro-2-[(4-methoxy-6methyl-2-oxo-1,2-dihydropyridin3-yl)methyl]-7- [m et hoxy (tetrahyd rof u ran-3yl)methyl]-3,4-dihydroisoquinolin- 1 (2H)-one - Isomer C	1	481	¹H NMR (400 MHz, CDCI3) δ 12.62 (s, 1 H), 7.52 (s, 1H), 5.93 (s, 1H), 4.77-4.83 (m, 3H), 3.87- 3.91 (m, 4H), 3.72-3.76 (m, 2H), 3.62-3.63 (m, 1 H), 3.48-3.51 (m, 2H), 3.22 (s, 3H), 2.94-2.96 (m, 2H), 2.63-2.65 (m, 1H), 2.35 (s, 3H), 1.95-1.96 (m, 1H), 1.80- 1.82 (m, 1H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 124; Diastereomer of Ex. 125 and Ex. 127; 100% ee; rétention time: 13.65 min; column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase: 40/60 hexane(0.1%DEA)/isoropanol(0.1 %ethanolamine)
127	cAjôXr 5,8-dichloro-2-[(4-methoxy-6-	1	481	¹H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 7.53 (s, 1H), 6.09 (s, 1H), 4.70 (d, J=6.4 Hz, 1H), 4.50 (s, 2H), 3.70-3.77 (m, 4H), 3.58-3.60 (m, 2H), 3.37-	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 125; Diastereomer of Ex. 124 and Ex. 126;

193

	methyl-2-oxo-1,2-dihydropyridin- 3-yl)methyl]-7[methoxy(tetrahydrofuran-3yl)methyl]-3,4-dihydroisoquinolin- 1 (2H)-one - Isomer D			3.41 (m, 2H), 3.13 (s, 3H), 2.86- 2.88 (m, 2H), 2.57-2.59 (m, 1H), 2.18 (s, 3H), 1.70-1.85 (m, 2H).	99% ee; rétention time: 14.76 min; column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase: 70/30 hexane(0.1 %DEA)/isopropanol(0. 1%ethanolamine)
128	''O Cl 0 0 ⁰ Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{[1 - (hydroxyacetyl)azetidin-3yl](methoxy)methyl}-3,4dihydroisoquinolin-1(2H)-one Isomer A	1	[M+Na] ⁺ 530	¹H NMR (400 MHz, DMS0-d6) Ô 11.57 (s, 1H), 7.56 (s, 1H), 5.89 (s, 1H), 4.85-4.92 (m, 2H), 4.57 (s, 2H), 4.09-4.19 (m, 1H), 3.97-4.04 (m, 1 H), 3.81-3.90 (m, 3H), 3.71-3.78 (m, 1H), 3.46 (t, J=6.40 Hz, 2H), 3.22 (s, 3H), 2.95-3.05 (m, 1H), 2.90 (t, J=5.9 Hz, 2H), 2.17 (s, 3H), 2.13 (s, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 129; 100% ee; rétention time: 8.161 min; column: Chiracel OD-H 150x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
129	'‘O Cl 0 o ⁰ Cl 5,8-d ich lo ro-2- [ (4,6-d imethy I-2-	1	[M+Na] ⁺ 530	¹H NMR (400 MHz, DMSO-d6) δ 11.46 (brs, 1H), 7.56 (s, 1H), 5.90 (s, 1H), 5.07-4.74 (m, 2H), 4.58 (s, 2H), 4.18-4.10 (m, 1H),	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 128; 96% ee; rétention time: 8.511 min;

194

	oxo-1,2-dihydropy ridin-3yl)methyl]-7-{[1 (hydroxyacetyl)azetidin-3yl](methoxy)methyl}-3,4dihydroisoquinolin-1(2H)-one Isomer B			4.02-3.98 (m, 1 H), 3.93-3.81 (m, 3H), 3.77-3.71 (m, 1 H), 3.46 (t, J=6 Hz, 2H), 3.22 (s, 3H), 3.032.96 (m, 1H), 2.90 (t, J=6 Hz, 2H), 2.17 (s, 3H), 2.13 (s, 3H)	column: Chiracel OD-H 150x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
130	ΑγΑ 8-chloro-2-[(4,6-dimethyl-2-oxo1,2-dihydropyridin-3-yl)methyl]-7[(1,1 -dioxidotetrahydro-2Hthiopyran-4-yl)(methoxy)methyl]5-methyl-3,4-dihydroisoquinolin- 1 (2H)-one - Isomer A	1	507	¹H NMR (400 MHz, CDCI3) δ 11.75 (brs, 1H), 7.24 (s, 1H), 5.94 (s, 1H), 4.78-4.83 (m, 2H), 4.69 (d, J=5.20 Hz, 1H), 3.63 (t, J=6.00 Hz, 2H), 3.18 (s, 3H), 3.02-3.10 (m, 2H), 2.79-2.94 (m, 2H), 2.75 (t, J=6.00 Hz, 2H), 2.36 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H), 2.03-2.22 (m, 3H), 1.862.02 (m, 2H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 131 ; 99% ee; rétention time: 3.455 min; column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase; 40% methanol (0.05% DEA) in CO2
131	8-chloro-2-[(4,6-dimethyl-2-oxo-	1	507	¹H NMR (400 MHz, CDCI3) δ 11.75 (brs, 1H), 7.24 (s, 1H), 5.94 (s, 1H), 4.78-4.83 (m, 2H), 4.69 (d, J=5.20 Hz, 1H), 3.63 (t,	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.130; 99% ee; rétention time: 6.221 min;

195

	1,2-dihydropyridin-3-yl)methyl]-7[(1,1 -dioxidotetrahydro-2Hthiopyran-4-yl)(methoxy)methyl]5-methyl-3,4-dihydroisoquinolin1(2H)-one - Isomer B			J=6.00 Hz, 2H), 3.18 (s, 3H), 3.02-3.10 (m, 2H), 2.79-2.94 (m, 2H), 2.75 (t, J=6.00 Hz, 2H), 2.36 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H), 2.03-2.22 (m, 3H), 1.86- 2.02 (m, 2H)	column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase; 40% methanol (0.05% DEA) in CO2
132	oAôA 8-chloro-2-[(4,6-dimethyl-2-oxo1,2-dihydropyridin-3-yl)methyl]-7[methoxy(tetrahydrofuran-3yl)methyl]-3,4-dihydroisoquinolin1(2H)-one - Isomer A	I	431	¹H NMR (400 MHz, CDCI3) δ 12.11 (brs, 1H), 7. 47 (d, J=8 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 5.95 (s, 1H), 4.81-4.83 (m, 3H), 3.83-3.89 (m, 1H), 3.70-3.73 (m, 2H), 3.61-3.64 (m, 3H), 3.19 (s, 3H), 2.82-2.85 (m, 2H), 2.64- 2.66 (m, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 1.95-1.97 (m, 1H), 1.81- 1.84 (m, 1H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 133; Diastereomer of Ex. 135 and Ex.134; 99% ee; rétention time: 6.84 min; column: ChiralpakAD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
133	AÔÂ 8-chloro-2-[(4,6-dimethyl-2-oxo-	1	431	Ή NMR (400 MHz, CDCI3) δ 12.18 (brs, 1H), 7. 47 (d, J=7.6 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 5.96 (s, 1H), 4.81-4.83 (m, 3H),	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.132; Diastereomer of Ex.135 and

196

	1,2-dihydropyridin-3-yl)methyl]-7[methoxy(tetrahydrofuran-3yl)methyl]-3,4-dihydroisoquinolin1(2H)-one - Isomer B			3.87-3.89 (m, 1 H), 3.70-3.73 (m, 2H), 3.61-3.64 (m, 3H), 3.19 (s, 3H), 2.82-2.85 (m, 2H), 2.64- 2.65 (m, 1H), 2.37 (s, 3H), 2.29 (s, 3H), 1.95-1.97 (m, 1 H), 1.801.6 (m, 1H).	Ex. 134; 100% ee; rétention time: 7.13 min; column: ChiralpakAD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
134	8-chloro-2-[(4,6-dimethyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl]-7[methoxy(tetrahydrofuran-3yl)methyl]-3,4-dihydroisoquinolin- 1 (2H)-one - Isomer C	1	431	¹H NMR (400 MHz, CDCI3) δ 11.84 (brs, 1H), 7. 47 (d, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 5.96 (s, 1H), 4.80-4.88 (m, 3H), 3.71-3.88 (m, 3H), 3.63-3.65 (m, 3H), 3.16 (s, 3H), 2.83-2.86 (m, 2H), 2.51-2.60 (m, 1H), 2.38 (s, 3H), 2.29 (s, 3H), 1.69-1.74 (m, 2H).	Single isomer, absolute stereochemistry unknown; enantiomer of Ex. 135; diastereomer of Ex. 132 and Ex. 133; 100% ee; rétention time: 7.21 min; column: ChiralpakAD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2; wavelength: 220 nm
135	^XO Cl 0 0 oAiôoï 8-chloro-2-[(4,6-dimethyl-2-oxo1,2-dihydropyridin-3-yl)methyl]-7-	1	431	¹H NMR (400 MHz, CDCI3) δ 11.71 (brs, 1H), 7. 47 (d, J=7.6 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 5.95 (s, 1H), 4.80-4.88 (m, 3H), 3.83-3.88 (m, 3H), 3.64-3.72 (m,	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 134; Diastereomer of Ex. 132 and Ex.133;

197

	[methoxy(tetrahydrofuran-3yl)methyl]-3,4-dihydroisoquinolin1(2H)-one - Isomer D			3H), 3.16 (s, 3H), 2.83-2.86 (m, 2H), 2.55-2.60 (m, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 1.69-1.74 (m, 2H).	99% ee; rétention time: 7.32 min; column: ChiralpakAD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
136	Cl (+)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[methoxy(1 methylpiperidin-4-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one	1	492	¹H NMR (400 MHz, CD3OD) Ô 7.58 (S, 1H), 6.16 (s, 1H), 4.81 (S, 2H), 4.72 (d, J=4.65 Hz, 1H), 3.58 (t, J=6.24 Hz, 2H), 3.26 (s, 3H), 2.99 - 3.10 (m, 4H), 2.40 (s, 3H), 2.35 (s, 3H), 2.30 (s, 3H), 2.17 (d,J=11.86 Hz, 2H), 1.68- 1.85 (m, 3H), 1.54 (d, J=7.70 Hz, 2H).	[a]D22= +70.1° (c=0.2, MeOH); Single isomer, absoiute stereochemistry unknown; Enantiomer of Ex. 137; -99% ee; rétention time 10.03 min; column: Lux Cellulose-4 4.6 x 100 mm 3u; mobile phase: 50% MeOH/DEA in CO2, 4 mL/min
137	Cl (-)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[methoxy(1 -	1	492	¹H NMR (400 MHz, CD3OD) δ 7.58 (s, 1H), 6.16 (s, 1H), 4.81 (s, 2H), 4.72 (d, J=4.65 Hz, 1H), 3.58 (t, J=6.24 Hz, 2H), 3.26 (s, 3H), 2.99 - 3.10 (m, 4H), 2.40 (s, 3H), 2.35 (s, 3H), 2.30 (s, 3H),	[ct]D22= -59.5° (c=0.2, MeOH); Single isomer, absoiute stereochemistry unknown; Enantiomer of Ex. 136; >99% ee; rétention time 7.25 min; column: Lux Cellulose-4 4.6 x 100

198

	methylpiperidin-4-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one			2.17 (d, J=11.86 Hz, 2H), 1.68 - 1.85 (m, 3H), 1.54 (d, J=7.70 Hz, 2H).	mm 3u; mobile phase: 50% MeOH/DEA in CO2, 4 mL/min
138	F Cl 0 o Hcr ^Br 5-bromo-8-chloro-2-[(4,6dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-7-{[1- (hydroxyacetyl)azetidin-3yl](methoxy)methyl}-3,4dihydroisoquinolin-1(2H)-one Isomer A	1	554	¹H NMR (400 MHz, CD3OD) δ 7.77 (d, J=4.00 Hz, 1H), 6.11 (s, 1H), 4.97-4.98 (m, 2H), 4.75 (s, 2H), 4.22-4.27 (m, 2H), 3.98- 4.09 (m, 5H), 3.84-3.86 (m, 1H), 3.52 (t, J=6.40 Hz, 2H), 3.08- 3.12 (m, 1 H), 2.97-3.00 (m, 2H), 2.30 (s, 3H), 2.25 (s, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 139; 96% ee; rétention time: 6.104 min; column: Chiralcel OD-3 150x4.6mm I.D., 3um; mobile phase: 5-40% methanol (0.05% DEA) in CO2; flow rate: 2.5mL/min
139	HO'J Br 5-bromo-8-chloro-2-[(4,6dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-7-{[1 -	1	554	¹H NMR (400 MHz, CD3OD) δ 7.77 (d, J=4.00 Hz, 1 H), 6.11 (s, 1 H), 4.92-4.98 (m, 2H), 4.57 (s, 2H), 4.22-4.27 (m, 2H), 3.984.08 (m, 5H), 3.84-3.86 (m, 1H), 3.52 (t, J=6.40 Hz, 2H), 3.08-	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 138; 98% ee; rétention time: 6.403 min; column: Chiralcel OD-3 150x4.6mm I.D., 3um; mobile phase: 5-40% methanol (0.05%

199

	(hyd roxyacetyl)azetid in-3yl](methoxy)methyl}-3,4dihydroisoquinolin-1 (2H)-one Isomer B			3.12 (m, 1 H), 2.98-3.00 (m, 2H), 2.30 (s, 3H), 2.25 (s, 3H).	DEA) in CO2; flow rate: 2.5mL/min
140	o Cl 0 0 1 ï Π ïï				Single (2R) isomer, other
	ν'Άι ⁿ			¹H NMR (400 MHz, DMSO-d6)	stereocenter unknown;
	^Ξ zAA			δ 11.55 (brs, 1H), 7.47 (s, 1H),	Enantiomer of Ex. 142;
	Cl 5,8-di ch lo ro-2- [(4,6-d i methy 1-2oxo-1,2-dihydropyridîn-3yl)methyl]-7-[(2R)-3-hydroxy-1 methoxy-2-methylpropyl]-3,4dihydroisoquinolin-1(2H)-one Isomer A	1	[M+Na] ⁺ 475	5.89 (s, 1H), 4.66 (d, J=7.2 Hz, 1 H), 4.57 (s, 2H), 4.38 (t, J=5.6 Hz, 1 H), 3.40-3.50 (m, 4H), 3.09 (s, 3H), 2.85-2.95 (m, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.80-1.85 (m, 1H), 0.78 (d, J=6.8 Hz, 3H).	Diastereomer of Ex.143 and Ex.141; 95% ee; rétention time 6.36 min; column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
141	^0 Cl 0 O ζχΑΛΛ A			¹H NMR (400 MHz, DMSO-d6)	Single (2R) isomer, other
	ΗΟ γ^ N'^ïf NH			δ 11.58 (brs, 1H), 7.42 (s, 1H),	stereocenter unknown;
	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[(2R)-3-hydroxy-1 -	1	[M+Na] ⁺ 475	5.89 (s, 1H), 4.83 (d, J=2.8 Hz, 1 H), 4.65 (t, J=5.2 Hz, 1 H), 4.57 (s, 2H), 3.40-3.48 (m, 3H), 3.27- 3.28 (m, 1H), 3.15 (s, 3H), 2.89	Enantiomer of Ex.143; Diastereomer of Ex. 140 and Ex. 142; 99% ee; rétention time 7.69 min;

200

	methoxy-2-methylpropyl]-3,4dihydroisoquinolin-1(2H)-one Isomer B			(t, J=6.0 Hz, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 1.85-1.89 (m, 1H), 0.66 (d, J=6.8 Hz, 3H).	column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% isopropanoî (0.05% DEA) in CO2
142	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[(2S)-3-hydroxy-1 methoxy-2-methylpropyl]-3,4dihydroisoquinolin-1(2H)-one Isomer A	1	[M+Na] *475	¹H NMR (400 MHz, DMS0-d6) δ 11.56 (brs, 1H), 7.47 (s, 1H), 5.89 (s, 1H), 4.66 (d, J=7.2 Hz, 1H), 4.56 (s, 2H), 3.40-3.50 (m, 5H), 3.09 (s, 3H), 2.89 (t, J=5.6 Hz, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.80-1.85 (m, 1H), 0.78 (d, J=6.4 Hz, 3H).	Single (2S) isomer, other stereocenter unknown; Enantiomer of Ex. 140; Diastereomer of Ex. 143 and Ex.141; 100% ee; rétention time: 6.64 min; column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
143	λλλ Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyi]-7-[(2S)-3-hydroxy-1 -	1	453	¹H NMR (400 MHz, DMSO-d6) δ 11.57 (brs, 1H), 7.42 (s, 1H), 5.89 (s, 1H), 4.83 (d, J=2.8 Hz, 1H), 4.57 (s, 2H), 3.40-3.50 (m, 5H), 3.16 (s, 3H), 2.89 (t, J=6.4 Hz, 2H), 2.16 (s, 3H), 2.12 (s,	Single (28) isomer, other stereocenter unknown; Enantiomer of Ex.141 ; Diastereomer of Ex. 142 and Ex. 140; 98% ee; rétention time: 7.43 min;

201

	methoxy-2-methylpropyl]-3,4dihydroisoquinolin-1(2H)-one Isomer B			3H), 1.86-1.89 (m, 1H), 0.66 (d, J=6.8 Hz, 3H).	column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase: 5-40% isopropanol (0.05% DEA) in CO2
144	'''O Cl 0 0 8-chloro-2-[(4-methoxy-6-methyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[methoxy(oxetan-3yl)methyl]-5-methyî-3,4dihydroisoquinolin-1 (2H)-one Isomer A	1	447	¹H NMR (400 MHz, CDCI3) δ 12.06 (brs, 1H), 7.26 (s, 1H), 5.92 (s, 1H), 5.11 (d, J=6.8 Hz, 1H), 4.75-4.79 (m, 3H), 4.62- 4.68 (m, 3H), 3.87 (s, 3H), 3.37- 3.47 (m, 3H), 3.28 (s, 3H), 2.74 (d, J=3.2 Hz, 2H), 2.34 (s, 3H), 2.24 (s, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 145; 100% ee; rétention time: 5.041 min; column: Chiralcel OD-3 150x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2
145	AJÔÂ 8-chloro-2-[(4-methoxy-6-methyl- 2-oxo-l ,2-dihydropyridin-3y[)methyl]-7-[methoxy(oxetan-3-	1	447	¹H NMR (400 MHz, CDCI3) δ 7.26 (s, 1H), 5.92 (s, 1H), 5.115.12 (m, 1H), 4.76-4.78 (m, 3H), 4.62-4.68 (m, 3H), 3.87 (s, 3H), 3.37-3.47 (m, 3H), 3.28 (s, 3H), 2.74-2.75 (m, 2H), 2.33 (s, 3H), 2.24 (s, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.144; 99% ee; rétention time: 5.168 min; column: Chiralcel OD-3 150x4.6mm I.D., 3um; mobile

202

	yl)methyl]-5-methyl-3,4dihydroisoquinolin-1(2H)-one Isomer B				phase: 5-40% éthanol (0.05% DEA) in CO2
146 147	Br 5-bromo-8-chloro-2-[(4,6dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-7[methoxy(1 -methylpiperidin-4yl)methyl]-3,4-dihydroisoquinolin- 1(2H)-one - Isomer A	I	538	¹H NMR (400 MHz, CDCI3) 5 11.45 (brs, 1H), 7.55 (s, 1H), 5.88 (s, 1H), 4.70-4.73 (m, 2H), 4.58 (d, J=4.40Hz, 1H), 3.573.60 (m, 2H), 3.30-3.33 (m, 2H), 3.14 (s, 3H), 2.86-2.89 (m, 2H), 2.63 (s, 3H), 2.48-2.53 (m, 2H), 2.29 (s, 3H), 2.22 (s, 3H), 1.982.02 (m, 1H), 1.83-1.88(m, 1H), 1.74-1.79 (m, 2H), 1.58-1.63 (m, 1H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 147; 100% ee; rétention time; 4.177 min; column: Chiralcel OD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2
Br 5-bromo-8-chloro-2-[(4,6dimethyl-2-oxo-1,2dihydropyridin-3-yl)methyl]-7-	1	538	¹H NMR (400 MHz, CDCI3) δ 11.82 (brs, 1H), 7.57 (s, 1H), 5.87 (s, 1H), 4.69 (s, 2H), 4.58 (d, J=4.40Hz, 1H), 3.57-3.60(m, 2H), 3.12 (s, 3H), 3.01-3.07 (m, 2H), 2.85-2.88 (m, 2H), 2.38	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 146; 100% ee; rétention time; 4.202 min; column: Chiralcel OD-3 100x4.6mm I.D., 3um; mobile

203

	[methoxy(1 -methylpiperidin-4yl)methyl]-3,4-dihydroisoquinolin1(2H)-one - Isomer B			(s, 3H), 2.29 (s, 3H) , 2.22 (s, 3H), 2.08-2.13 (m, 2H), 1.82- 1.88 (m, 1 H), 1.69-1.75 (m, 2H), 1.58-1.63 (m, 1 H), 1.40-1.46 (m, 1H).	phase: 5-40% éthanol (0.05% DEA) in CO2
148	^0 Cl o o				Single isomer, absolute
	V UU ΛΛ			¹H NMR (400 MHz, CDCI3) δ	stereochemistry unknown;
	⁰ 0 '				Enantiomer of Ex.151 ;
	^u Cl			11.25 (br. s., 1H), 7.43 (s, 1H),
	5,8-dichloro-2-[(4,6-dimethyl-2-			5.95 (s, 1 H), 4.71-4.85 (m, 3H),	Diastereomer of Ex. 149 and
	oxo-1,2-dihydropyridin-3-	I	[M+Na]	3.60-3.76 (m, 2H), 3.27 (s, 3H),	Ex. 150;
			⁺ 535		97% ee; rétention time: 1.865 min;
	yl)methyl]-7-[(1,1 -			3.18-3.25 (m, 1 H), 2.88-3.16 (m,
	dioxidotetrahydrothiophen-3-			5H), 2.79 (m, 1H), 2.37 (s, 3H),	column: Chiralcel OJ-3
	yl)(methoxy)methyl]-3,4-			2.29 (s, 3H), 2.16-2.27 (m, 2H)	100x4.6mm I.D., 3um; mobile
	dihydroisoquinolin-1(2H)-one -				phase: 15% methanol (0.05%
	Isomer A				DEA) in CO2
149	~O Cl 0 0			¹H NMR (400 MHz, CDCI3) δ	Single isomer, absolute
				10.79 (br. s., 1H), 7.48 (s, 1H),	stereochemistry unknown;
	⁰ Cl	1	[M-rlNdJ ⁺ 535	5.93 (s, 1 H), 4.70-4.84 (m, 3H),	Enantiomer of Ex. 150;
				3.61-3.74 (m, 2H), 3.26 (s, 3H),	Diastereomer of Ex. 148 and
	5,8-dichloro-2-[(4,6-dimethyl-2-			3.18-3.25 (m, 1H), 3.14-3.16 (m,	Ex.151;

204

	oxo-1,2-dihydropyrid ΐη-3yl)methyl]-7-[(1,1 dioxidotetrahydrothiophen-3yl)(methoxy)methyl]-3,4dihydroisoquinolin-1(2H)-one Isomer B			2H), 2.96 (t, J=6.27 Hz, 2H), 2.74-2.93 (m, 2H), 2.36 (s, 3H), 2.27 (s, 3H), 1.94-2.19 (m, 2H)	100% ee; rétention time: 1.949 min; column: Chiralcel OJ-3 100x4.6mm I.D., 3um; mobile phase: 15% methanol (0.05% DEA) in CO2
150	>3 Cl 0 0 V UL· ΛΛ °° Y 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[(1,1dioxidotetrahydrothiophen-3yl)(methoxy)methyl]-3,4dihydroisoquinolin-1(2H)-one Isomer C	1	[M+Na] ⁺ 535	¹H NMR (400 MHz, CDCI3) δ 11.61 (br. s., 1H), 7.49 (s, 1H), 5.95 (s, 1H), 4.68-4.86 (m, 3H), 3.58-3.77 (m, 2H), 3.27 (s, 3H), 3.19-3.25 (m, 1H), 3.14-3.17 (m, 2H), 2.96 (t, J=6.15 Hz, 2H), 2.75-2.94 (m, 2H), 2.37 (s, 3H), 2.29 (s, 3H), 1.96-2.21 (m, 2H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.149; Diastereomer of Ex.148 and Ex.151; 97% ee; rétention time: 2.253 min; column: Chiralcel OJ-3 100x4.6mm I.D., 3um; mobile phase: 15% methanol (0.05% DEA) in CO2

205

151	'Ό Cl 0 0 P UU ΛΛ ° cT 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[(1,1dioxidotetrahydrothiophen-3yl)(methoxy)methyl]-3,4dihydroisoquinolin-1(2H)-one Isomer D	1	[M+Na] ⁺ 535	¹H NMR (400 MHz, CDCI3) δ 11.72 (br. s., 1H), 7.43 (s, 1H), 5.96 (s, 1 H), 4.71-4.86 (m, 3H), 3.58-3.78 (m, 2H), 3.22-3.31 (m, 4H), 2.87-3.19 (m, 5H), 2.732.85 (m, 1 H), 2.36 (s, 3H), 2.29 (s, 3H), 2.16-2.27 (m, 2H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 148; Diastereomer of Ex. 149 and Ex.150; 100% ee; rétention time: 2.596 min; column: Chiralcel OJ-3 100x4.6mm I.D., 3um; mobile phase: 15% methanol (0.05% DEA) in CO2
152	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3y l)methyl]-7-[( 1,1 -dioxidothietan3-yl)(methoxy)methyl]-3,4dihydroisoquinolin-1(2H)-one Isomer A	1	499	¹H NMR (400 MHz, CDCI3) δ 7.47 (S, 1H), 5.96 (s, 1 H), 4.93 (d, J=4.8, 1H), 4.77 (s, 2H), 4.22-4.28 (m, 2H), 4.05-4.08 (m, 1H), 3.67-3.79 (m, 3H), 3.32 (s, 3H), 2.92-2.98 (m, 3H), 2.37 (s, 3H), 2.29 (s, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.153; 100% ee; rétention time 5.106 min; column: Chiralpak AD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2

206

153	''o ci ο ο Cl 5₁8-dichloro-2-[(4,6-dimethyl-2οχο-1,2-dihydropyridin-3yl)methyl]-7-[(1,1 -dioxidothietan3-yl)(methoxy)methyl]-3,4dihydroisoquinolin-1(2H)-one Isomer B	1	499	¹H NMR (400 MHz, CDCI3) δ 7.47 (s, 1H), 5.96 (s, 1H), 4.93 (d, J=4.8, 1H), 4.77 (s, 2H), 4.22-4.28 (m, 2H), 4.05-4.08 (m, 1H), 3.67-3.78 (m, 3H), 3.32 (s, 3H), 2.92-2.98 (m, 3H), 2.37 (s, 3H), 2.29 (s, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.152; 100% ee; rétention time 4.69 min; column: Chiralpak AD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2
154	^o Cl o o 8-chloro-2-[(4,6-dimethyl-2-oxo1,2-dihydropyridin-3-yl)methyl]-7(methoxy[1 -(oxetan-3yl)piperidin-4-yl]methyl}-5-methyl- 3,4-dihydroisoquinolin-1(2H)-one - Isomer A	1	514	¹H NMR (400 MHz, CD3OD) δ 7.35 (s, 1H), 6.13 (s, 1H), 4.79 (s, 2H), 4.56-4.70 (m, 6H), 3.423.53 (m, 3H), 3.19 (s, 3H), 2.722.87 (m, 5H), 2.31 (s, 6H), 2.252.28 (m, 3H), 1.64-1.83 (m, 5H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 155; 99% ee; rétention time: 4.001 min; column: Chiralpak AD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% methanol (0.05% DEA) in CO2

207

155	8-chloro-2-[(4,6-dimethyl-2-oxo1,2-dihydropyridin-3-yl)methyl]-7{methoxy[1 -(oxetan-3yl)piperidin-4-yl]methyl}-5-methyl3,4-dihydroisoquinolin-1(2H)-one - Isomer B	1	514	¹H NMR (400 MHz, CD3OD) δ 7.35 (s, 1H), 6.13 (s, 1H), 4.79 (s, 2H), 4.54-4.69 (m, 6H), 3.41- 3.51 (m, 4H), 3.19 (s, 3H), 2.73- 2.86 (m, 4H), 2.30 (s, 6H), 2.26 (s, 3H), 1.64-1.86 (m, 5H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.154; 96% ee; rétention time: 4.312 min; column: Chiralpak AD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
156	ΑΆ 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{methoxy[1 -(oxetan- 3-yl)piperidin-4-yl]methyl}-3,4dihydroisoquinolin-1(2H)-one Isomer A	1	534	¹H NMR (400 MHz, DMSO-d6) δ 11.57 (brs, 1H), 7.44 (s, 1H), 5.89 (s, 1 H), 4.50-4.65 (m, 3H), 4.45-4.50 (m, 2H), 4.35-4.40 (m, 2H), 3.46 (t, J=6.0 Hz, 2H), 3.30-3.35 (m, 3H), 3.12 (s, 3H), 2.89 (t, J=6.0 Hz, 2H), 2.60-2.70 (m, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.50-1.65 (m, 4H), 1.351.45 (m, 1H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 157; 100% ee; rétention time: 2.263 min; column: Chiralpak AY 100x4.6 mm I.D., 3 um; mobile phase: 5-40% methanol (0.05% DEA) in CO2

208

157	5,8-dichloro-2-[(4,6-dimethyl-2- oxo-1,2-dihydropyridin-3yl)methyl]-7-{methoxy[1-(oxetan3-yl)piperidin-4-yl]methyl}-3,4dihydroisoquinolin-1(2H)-one Isomer B	1	534	¹H NMR (400 MHz, DMS0-d6) δ 11.58 (brs, 1H), 7.44 (s, 1H), 5.89 (s, 1H), 4.50-4.65 (m, 3H), 4.45-4.50 (m, 2H), 4.35-4.40 (m, 2H), 3.46 (t, J=6.0 Hz, 2H), 3.30-3.35 (m, 3H), 3.12 (s, 3H), 2.89 (t, J=5.6 Hz, 2H), 2.60-2.70 (m, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.50-1.65 (m, 4H), 1.351.45 (m, 1H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 156; 100% ee; rétention time: 3.339 min; column: Chiralpak AY 100x4.6 mm I.D., 3 um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
158	Λμ Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3y I) met hy l]-7-[( 1,1 -dioxidothietan3-yl)(ethoxy)methyl]-3,4dihydroisoquinolin-1(2H)-one Isomer A	1	513	¹H NMR (400 MHz, CDCI3) δ 11.26 (brs, 1H), 7.49 (s, 1H), 5.94 (s, 1H), 5.03 (d, J=4.4 Hz, 1H), 4.77 (s, 2H), 4.21-4.26 (m, 2H), 4.03-4.04 (m, 1H), 3.683.76 (m, 3H), 3.40-3.48 (m, 2H), 2.94-2.97 (m, 3H), 2.37 (s, 3H), 2.28 (s, 3H), 1.25 (t, J=7 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 159; 100% ee; rétention time: 2.535 min; column: Chiralcel OJ-3 100x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2

209

159	Λα Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methy t]-7-[(1,1 -dioxidothietan3-y l ) (ethoxy ) m ethy l]-3,4dihydroisoquinolin-1(2H)-one Isomer B	1	513	¹H NMR (400 MHz, CDCI3) δ 11.35 (brs, 1H), 7.49 (s, 1H), 5.95 (s, 1H), 5.02 (d, J=4.8 Hz, 1 H), 4.77-4.8 (m, 2H), 4.21-4.26 (m, 2H), 4.03-4.04 (m, 1H), 3.68-3.76 (m, 3H), 3.40-3.48 (m, 2H), 2.94-2.97 (m, 3H), 2.37 (s, 3H), 2.28 (s, 3H), 1.25 (t, J=6.8 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.158; 100% ee; rétention time: 22.782 min; column: Chiralcel OJ-3 100x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2
160	ΑγΆ Cl (-)-5,8-dichloro-2-[(4,6-dimethyl- 2-oxo-l ,2-dihydropyridin-3yl)methyl]-7[methoxy(tetrahydrofuran-3yl)methyl]-3,4-dihydroisoquinolin- 1(2H)-one - Isomer A	1	465	¹H NMR (400 MHz, CD3OD) δ 7.61 (s, 1 H), 6.10 (s, 1H), 4.76 (s, 2H), 3.83-3.91 (m, 1 H), 3.67- 3.76 (m, 2H), 3.58 (t, J=7.83 Hz, 1H), 3.53 (t, J=6.24 Hz, 2H), 3.22 (s, 3H), 2.99 (t, J=6.24 Hz, 2H), 2.64 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 1.93-2.05 (m, 1H), 1.78-1.89 (m, 1H) One proton obscured by solvent.	[a]_D = -48.0° (c 0.1 MeOH), >99% ee; Absolute and relative stereochemistry undetermined; Enantiomer of Ex.161; Diastereomer of Ex.162 and Ex. 163

210

161	Cl (+)-5,8-dichioro-2-[(4,6-dimethyl- 2-oxo-l ,2-dîhydropyridin-3yl)methyl]-7[methoxy(tetrahydrofuran-3yl)methyl]-3,4-dihydroisoquinolin1(2H)-one - Isomer B	1	465	¹H NMR (400 MHz, CD3OD) δ 7.61 (S, 1H), 6.10 (s, 1 H), 4.76 (s, 2H), 3.83-3.92 (m, 1 H), 3.67- 3.76 (m, 2H), 3.58 (t, J=7.82 Hz, 1H), 3.53 (t, J=6.24 Hz, 2H), 3.22 (s, 3H), 2.99 (t, J=6.11 Hz, 2H), 2.64 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 1.93-2.04 (m, 1H), 1.78-1.92 (m, 1H) One proton obscured by solvent.	[a]o = +74.7° (c 0.1 MeOH), 90% ee, Absolute and relative stereochemistry undetermined; Enantiomer of Ex. 160; Diastereomer of Ex. 162 and Ex. 163
162	Cl (-)-5,8-dichloro-2-[(4,6-dimethyl- 2-oxo-1,2-dihydropyridin-3yl)methyl]-7[methoxy(tetrahydrofuran-3yl)methyl]-3,4-dihydroisoquinolin- 1 (2H)-one - Isomer C	1	465	¹H NMR (400 MHz, CD3OD) δ 7.61 (s, 1H), 6.11 (s, 1H), 4.76 (s, 2H), 3.76-3.90 (m, 3H), 3.70 (q, J=7.50 Hz, 1H), 3.53 (t, J=6.24 Hz, 2H), 3.18 (s, 3H), 2.97-3.03 (m, 2H), 2.54-2.66 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 1.62-1.81 (m, 2H) One proton obscured by solvent.	[a]_D = -68.8° (c 0.1 MeOH); >99% ee; Absolute and relative stereochemistry undetermined; Enantiomer of Ex. 163; Diastereomer Ex.160 and Ex. 161

211

163	Cl (+)-5,8-dichloro-2-[(4,6-dimethyl2-οχοΊ ,2-dihydropyridin-3yl)methyl]-7- [m et hoxy(tetrahyd rof u ran-3yl)methyî]-3,4-dihydroisoquinolin1(2H)-one - Isomer D	1	465	¹H NMR (400 MHz, CD3OD) δ 7.61 (s, 1H), 6.11 (s, 1H), 4.76 (s, 2H), 3.76-3.91 (m, 3H), 3.70 (q, J=7.58 Hz, 1H), 3.53 (t, J=6.24 Hz, 2H), 3.18 (s, 3H), 2.96-3.03 (m, 2H), 2.60 (sxt, J=7.38 Hz, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 1.63-1.81 (m, 2H) One proton obscured by solvent.	[o]d = +59.4° (c 0.1 MeOH); >99% ee; Absolute and relative stereochemistry undetermined; Enantiomer of Ex. 162; Diastereomer of Ex.160 and Ex.161
164	D O Cl O O 0 Cl (-)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-{[1 - (hydroxyacetyl)piperidîn-4yl][(²H3)methyloxy]methyl}-3,4dihydroisoquinolin-1 (2H)-one	1	539	¹H NMR (400 MHz, CD3OD) δ 7.54 (s, 1H), 6.11 (s, 1H), 4.76 (s, 2H), 4.66 (d, J=5.62 Hz, 1H), 4.44-4.56 (m, 1H), 4.12-4.27 (m, 2H), 3.66-3.78 (m, 1H), 3.53 (t, J=6.24 Hz, 2H), 2.99 (t, J=6.11 Hz, 2H), 2.85-2.96 (m, 1H), 2.51-2.66 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 1.86-2.00 (m, 1H),	[a]o =-36.9° (c 0.1 MeOH); Absolute stereochemistry undetermined; Enantiomer of Ex. 165; (-) isomer of Ex. 70 racemate

212

				1.69-1.79 (m, 1 H), 1.31-1.54 (m, 3H)
165	D O Cl Ο 0 αΦ* Ο Cl (+)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-{[1 - (hydroxyacetyl)piperidin-4yl][(²H3)methyloxy]methyl}-3,4dihydroisoquinolin-1 (2H)-one	1	539	Ή NMR (400 MHz, CD3OD) δ 7.54 (s, 1H), 6.11 (s, 1H), 4.76 (s, 2H), 4.66 (d, J=5.62 Hz, 1H), 4.43-4.56 (m, 1H), 4.12-4.27 (m, 2H), 3.67-3.78 (m, 1H), 3.53 (t, J=6.11 Hz, 2H), 2.99 (t, J=6.11 Hz, 2H), 2.84-2.96 (m, 1H), 2.49-2.67 (m, 1H), 2.30 (s, 3H), 2.25 (s, 3H), 1.86-2.01 (m, 1H), 1.69-1.79 (m, 1 H), 1.32-1.56 (m, 3H)	[a]o = +139.1° (c 0.1 MeOH); Absolute stereochemistry undetermined; Enantiomer of Ex. 164; (+) isomer of Ex. 70 racemate
166	ΛφΛ Cl (+)-5,8-dichloro-2-[(4,6-dimethyl- 2-oxo-l ,2-dihydropyridin-3- yl)methyl]-7-[methoxy(piperidin-4-	1	478	¹H NMR (600 MHz, DMSO-d6) 6 7.42 (s, 1 H), 5.91 (s, 1 H), 4.55 (s, 2H),4.51 (d, J=5.50 Hz, 1H), 3.43 - 3.45 (m, 2H), 3.10 (s, 3H), 2.87 (t, J=5.59 Hz, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 1.45-1.74 (m,	[q]d = +73.0° (c 0.1 MeOH); 97% ee; Absolute stereochemistry undetermined; Enantiomer of Ex. 167

213

	yl)methyl]-3,4-dihydroisoquinolin- 1(2H)-one			2H), 1.20 - 1.40 (m, 3H) Four protons obscured by solvent
167	..0¾½ Cl (-)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-1,2-dihydropyridin-3yl)methyl]-7-[methoxy(piperidin-4yl)methyl]-3,4-dihydroisoquinolin- 1 (2H)-one	1	478	¹H NMR (700 MHz, DMSO-d6) δ 7.43 (s, 1 H), 5.89 (s, 1 H), 4.54 -4.58 (m, 2H), 4.52 (d, J=5.72 Hz, 1 H), 3.46 (t, J=5.94 Hz, 2H), 3.11 (s, 3H), 2.83 - 3.00 (m, 4H), 2.17 (s, 3H), 2.12 (s, 3H), 1.621.72 (m, 1H), 1.51 - 1.62 (m, 1H), 1.29 - 1.42 (m, 1H), 1.19 1.28 (m, 2H). Two protons obscured by solvent	[a]_D = -59.7° (c 0.1 MeOH); 99% ee; Absolute stereochemistry undetermined; Enantiomer of Ex. 166
168	^X0 Cl 0 0 (+)-8-chloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{[1 - (hyd roxyacety I) pi perid in-4-	1	516	¹H NMR (700 MHz, DMSO-d6) δ 11.55 (br. s., 1 H), 7.26 (s, 1H), 5.88 (s, 1H), 4.52-4.62 (m, 3H), 4.44 (br. s., 1H), 4.28-4.39 (m, 1H), 4.04-4.11 (m, 1H), 3.964.04 (m, 1H), 3.57-3.71 (m, 1H), 3.40 (br. s., 2H), 3.08 (s, 3H), 2.82 (t, J=11.88 Hz, 1H),2.72(t,	[a]o = +60.2° (c 0.1 MeOH); 99% ee; Absolute stereochemistry undetermined; Enantiomer of Ex. 169

214

	yl](methoxy)methyl)-5-methyl- 3,4-dihydroisoquinolin-1(2H)-one			J=5.94 Hz, 2H), 2.43-2.48 (m, 1H), 2.24 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H), 1.79-1.88 (m, 1H), 1.65-1.74 (m, 1 H), 1.15-1.37 (m, 3H)
169	(-)-8-chloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yt)methyl]-7-{[1 - (hydroxyacetyl)piperidin-4yl](methoxy)methyl}-5-methyl3,4-dihydroisoquinolin-1(2H)-one	1	516	¹H NMR (700 MHz, DMSO-d6) δ 11.55 (br. s.,1H), 7.26 (s, 1H), 5.88 (s, 1H), 4.51-4.60 (m, 3H), 4.44 (br. s., 1H), 4.29-4.39 (m, 1H), 4.04-4.10 (m, 1H), 3.954.04 (m, 1H), 3.58-3.70 (m, 1H), 3.40 (br. s., 2H), 3.08 (s, 3H), 2.82 (t, J=11.99 Hz, 1 H), 2.72 (t, J=5.94 Hz, 2H), 2.43-2.47 (m, 1H), 2.24 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H), 1.79-1.87 (m, 1H), 1.66-1.72 (m, 1 H), 1.16-1.36 (m, 3H)	[o]d = -31.2° (c 0.1 MeOH): -80% ee; Absolute stereochemistry undetermined; Enantiomer of Ex. 168

215

170	Ό Cl 0 0 -^'ΌΗ ^Cl (+)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihyd ropy ridin-3yl)methyl]-7-[(1-[(2R)-2hydroxypropanoyl]azetidin-3yl}(methoxy)methyl]-3,4dihydroisoquinolin-1 (2H)-one	1	522	¹H NMR (400 MHz, DMSO-d6) δ 11.54 (br. s., 1 H), 7.55 (s, 1H), 5.88 (s, 1H), 5.00 (dd, J=4.89, 5.87 Hz, 1H), 4.91 (d, J=4.89 Hz, 1 H), 4.57 (s, 2H), 4.02-4.24 (m, 3H), 3.78-3.89 (m, 1H), 3.66-3.75 (m, 1H), 3.46 (t_TJ=5.99 Hz, 2H), 3.21 (s, 3H), 2.94-3.04 (m, 1H), 2.90 (t, J=6.11 Hz, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.15 (d, J=6.85 Hz, 3H)	[q]d = +123.5° (c=0.1, MeOH); >99% de; Single diastereomer containing (R)-2-hydroxypropanamide; other chiral center undetermîned; Enantiomer of Ex. 173 Diastereomer of Ex. 171 and Ex. 172
171	''O Cl 0 o ^'OH C’ (-)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyi]-7-[{1-[(2R)-2hydroxypropanoyl]azetidin-3-	1	522	¹H NMR (400 MHz, DMSO-d6) 511.54 (br. s., 1 H), 7.55 (s, 1H), 5.89 (s, 1H), 4.97 (dd, J=6.05, 15.34 Hz, 1H), 4.91 (t, J=6.42 Hz, 1 H), 4.57 (s, 2H), 4.17-4.29 (m, 1H), 4.00-4.14 (m, 2H), 3.70-3.86 (m, 2H), 3.46 (t, J=5.62 Hz, 2H), 3.21 (d, J=1.96	[a]_D = -110.6° (c=0.1, MeOH); >99% de; Single diastereomer containing (R)-2-hydroxypropanamide; other chiral center undetermîned; Enantiomer of Ex. 172 Diastereomer of Ex. 170 and Ex. 173

216

	yl}(methoxy)methyl]-3,4dihydroisoquinolin-1 (2H)-one			Hz, 3H), 2.93-3.03 (m, 1 H), 2.90 (t, J=5.99 Hz, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.14 (dd, J=4.34, 6.66 Hz, 3H)
172	0 Cl 0 o ^*0H Cl (+)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[{1-[(2S)-2hydroxypropanoyl]azetidin-3yl)(methoxy)methyl]-3,4dihydroisoquinolin-1 (2H)-one	1	522	¹H NMR (400 MHz, DMSO-d6) δ 11.53 (br. s., 1 H), 7.55 (s, 1H), 5.88 (s, 1H), 4.96 (dd, J=6.11, 15.41 Hz, 1H), 4.90 (t, J=6.36 Hz, 1H), 4.56 (s, 2H), 4.17-4.27 (m, 1H), 4.00-4.12 (m, 2H), 3.68-3.87 (m, 2H), 3.46 (t, J=5.87 Hz, 2H), 3.21 (d, J=1.96 Hz, 3H), 2.93-3.02 (m, 1 H), 2.89 (t, J=6.11 Hz, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 1.14 (dd, J=4.16, 6.60 Hz, 3H).	[α]ο = +69.5° (c=0.1, MeOH); >99% de; Single diastereomer containing (S)-2-hydroxypropanamide; other chiral center undetermined; Enantiomer of Ex. 171 Diastereomer of Ex. 173 and Ex. 170
173	O Cl 0 0 yywx ^0H Cl (-)-5,8-dichloro-2-[(4,6-dimethyl-	1	522	¹H NMR (400 MHz, DMSO-d6) δ 11.54 (br. s., 1 H), 7.54 (s, 1 H), 5.89 (s, 1 H), 5.00 (t, J=5.26 Hz, 1H), 4.91 (d, J=4.89 Hz, 1H),	[a]o = -105.1° (c=0.1, MeOH); -88% de; Single diastereomer containing (S)-2-hydroxypropanamide; other

217

	2-oxo-1,2-dihydropy ridin-3- yl)methyl]-7-[{1-[(2S)-2hydroxypropanoyl]azetidin-3yl}(methoxy)methyl]-3,4dihydroisoquinolin-1 (2H)-one			4.57 (s, 2H), 4.01-4.26 (m, 3H), 3.77-3.90 (m, 1 H), 3.66-3.74 (m, 1H), 3.46 (t, J=5.87 Hz, 2H), 3.21 (s, 3H), 2.93-3.03 (m, 1H), 2.90 (t, J=6.11 Hz, 2H), 2.17 (s, 3H), 2.12 (s, 3H), 1.15 (d, J=6.36 Hz, 3H)	chiral center undetermined; Enantiomer of Ex. 170 Diastereomer of Ex. 172 and Ex.171
174	A Cl 0 o Cl (+)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[methoxy(1 methylazetidin-3-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one	I	464	¹H NMR (400 MHz, DMSO-d6) δ 11.48 (br. s., 1 H), 7.47 (s, 1H), 5.88 (s, 1 H), 4.89 (d, J=7.09 Hz, 1 H), 4.56 (s, 2H), 3.46 (t, J=6.11 Hz, 2H), 3.10-3.19 (m, 4H), 2.97-3.09 (m, 2H), 2.79-2.94 (m, 3H), 2.62-2.71 (m, 1H), 2.17 (s, 3H), 2.15 (s, 3H),2.12(s, 3H)	[o]d = +88.5° (c=0.1, MeOH); >99% ee; Absolute stereochemistry undetermined; Enantiomer of Ex. 175
175	.-AôA Cl (-)-5,8-dichloro-2-[(4,6-dimethyl-	I	464	¹H NMR (400 MHz, DMSO-d6) δ 11.48 (br. s., 1H), 7.47 (s, 1H), 5.88 (s, 1H), 4.89 (d, J=7.09 Hz, 1 H), 4.56 (s, 2H), 3.46 (t, J=6.11 Hz, 2H), 3.10-3.19 (m, 4H),	[a]_D = -70.2° (c=0.1, MeOH); >99% ee; Absolute stereochemistry

218

	2-oxo-1,2-dihydropy ridin-3yl)methyl]-7-[methoxy(1 methylazetidin-3-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one			2.97-3.09 (m, 2H), 2.79-2.94 (m, 3H), 2.62-2.71 (m, 1 H), 2.17 (s, 3H), 2.15 (s, 3H), 2.12 (s, 3H)	undetermined; Enantiomer of Ex. 174
176	νΑχΑ ⁰ Cl (+)-5,8-dichloro-2-[(4,6-dimethyl- 2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-{methoxy[1 (methylsulfonyl)azetidin-3yl]methyl}-3,4-dihydroisoquinolin1(2H)-one	1	528	¹H NMR (400 MHz, DMSO-d6) δ 11.54 (br. s., 1 H), 7.61 (s, 1H), 5.88 (s, 1 H), 4.87 (d, J=5.14 Hz, 1 H), 4.57 (s, 2H), 3.97 (t, J=7.46 Hz, 1 H), 3.75-3.87 (m, 2H), 3.67 (t, J=8.31 Hz, 1H), 3.45 (t, J=6.24 Hz, 2H), 3.23 (s, 3H), 2.99 (s, 3H), 2.93-3.03 (m, 1H), 2.89 (t, J=5.99 Hz, 2H), 2.17 (s, 3H), 2.12 (s, 3H)	[o]d = +104.4° (c=0.2, MeOH); >99% ee; Absolute stereochemistry undetermined; Enantiomer of Ex. 177
177	'° Cl (-)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-1 ,2-dihydropyridin-3yl)methyl]-7-{methoxy[1 -	1	528	¹H NMR (400 MHz, DMSO-d6) δ 11.54 (br.s.,1H),7.61 (s, 1 H), 5.88 (s, 1 H), 4.87 (d, J=5.14 Hz, 1 H), 4.57 (s, 2H), 3.97 (t, J=7.34 Hz, 1 H), 3.76-3.86 (m, 2H), 3.67 (t, J=8.31 Hz, 1H), 3.45 (t,	[a]o = -111.7° (c=0.1, MeOH); -97% ee; Absolute stereochemistry undetermined; Enantiomer of Ex. 176

219

	(methylsulfonyl)azetidin-3yl]methyl}-3,4-dihydroisoquînolin1(2H)-one			J=6.11 Hz, 2H), 3.23 (s, 3H), 2.99 (s, 3H), 2.94-3.02 (m, 1H), 2.89 (t, J=6.11 Hz, 2H),2.17(s, 3H), 2.12 (s, 3H)
178	~^0 Cl 0 o -.γόΧτ (±)-7-[azetidin-3yl(methoxy)methyl]-8-chloro-2[(4,6-dimethyl~2-oxo-1,2dihydropyridin-3-yl)methyl]-5methyl-3,4-dihydroisoquinolin- 1 (2H)-one	1	430	¹H NMR (400 MHz, CD3OD) δ 7.37 (s, 1H), 6.10 (s, 1H), 4.99 (d, J=5.50 Hz, 1 H), 4.77 (s, 2H), 3.79-3.95 (m, 2H), 3.55-3.72 (m, 2H), 3.46 (t, J=5.99 Hz, 2H), 3.29 (s, 3H), 3.16 (dd, J=7.76, 14.12 Hz, 1H), 2.81 (t, J=5.93 Hz, 2H), 2.29 (s, 6H), 2.25 (s, 3H)	racemic mixture
179	⁰ Cl (+)-5,8-dichloro-2-[(4,6-dimethyl- 2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[methoxy(1 -methyl-	1	492	¹H NMR (400 MHz, DMSO-d6) δ 11.54 (br. s., 1 H), 7.55 (s, 1H), 5.89 (s, 1H), 4.74 (d, J=5.87 Hz, 1 H), 4.56 (s, 2H), 3.47 (t, J=6.11 Hz, 2H), 3.16 (s, 3H), 3.09 (dd, J=6.36, 9.54 Hz, 1H), 2.90 (t, J=5.87 Hz, 2H), 2.70-2.78 (m,	[a]_D = +51.2° (c=0.1, MeOH) ; >99% de; Absolute and relative stereochemistry undetermined; Enantiomer of Ex.180

220

	5-oxopyrrolidin-3-yl)methyl]-3,4- dihydroisoquinolin-1 (2H)-one			1H), 2.67 (s, 3H), 2.26-2.35 (m, 1H), 2.17 (s, 3H), 2.07-2.16 (m, 4H) One proton under water peak.
180	-ρχόΧτ ⁰ Cl (-)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[methoxy(1 -methyl5-oxopyrrolidin-3-yl)methyl]-3,4dihydroisoquino!in-1 (2H)-one	I	492	¹H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 7.55 (s, 1H), 5.89 (s, 1H), 4.74 (d, J=6.11 Hz, 1 H), 4.56 (S, 2H), 3.47 (t, J=6.24 Hz, 2H), 3.16 (s, 3H), 3.09 (dd, J=6.24, 9.66 Hz, 1H), 2.90 (t, J=6.11 Hz, 2H), 2.69-2.77 (m, 1H), 2.67 (s, 3H), 2.26-2.34 (m, 1H), 2.18 (s, 3H), 2.08-2.16 (m, 4H) One proton under water peak.	[a]_D=-69.5° (c=0.1, MeOH); -99% de; Absolute and relative stereochemistry undetermined; Enantiomer of Ex. 179
181	''O Cl 0 0 (+)-8-chloro-2-[(4,6-dimethyl-2- oxo-1,2-dihydropyridin-3-	1	486	¹H NMR (400 MHz, DMSO-d6) δ 11.52 (br. s., 1 H), 7.29 (s, 1 H), 5.88 (s, 1 H), 4.91 (d, J=6.85 Hz, 1 H), 4.56 (s, 2H), 4.52 (t, J=6.48 Hz, 2H), 4.28-4.38 (m, 2H),	[q]d = 4-110.8° (c=0.1, MeOH); -99% ee; Absolute stereochemistry undetermined; Enantiomer of Ex. 182

221

	yl)methyl]-7-{methoxy[1-(oxetan- 3-yl)azetidin-3-yl]methyl}-5methyl-3,4-dihydroisoquinolin1(2H)-one			3.60-3.74 (m, 1H), 3.40 (1, J=6.11 Hz, 2H), 3.16-3.25 (m, 2H), 3.06-3.15 (m, 4H), 2.973.06 (m, 1H), 2.68-2.79 (m, 3H), 2.22 (s, 3H), 2.17 (s, 3H), 2.12 (s, 3H)
182	A Ci 0 o (-)-8-chloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-(methoxy[1-(oxetan- 3-yl)azetidin-3-yl]methyl}-5methyl-3,4-dihydroisoquinolin- 1 (2H)-one	1	486	¹H NMR (400 MHz, DMSO-d6) 511.53 (br. s., 1 H), 7.29 (s, 1H), 5.88 (s, 1H), 4.91 (d, J=7.09 Hz, 1 H), 4.56 (s, 2H), 4.52 (t, J=6.48 Hz, 2H), 4.33 (td, J=5.93, 8.19 Hz, 2H), 3.66 (quin, J=5.93 Hz, 1H), 3.40 (t, J=5.99 Hz, 2H), 3.15-3.23 (m, 2H), 3.13 (s, 3H), 3.09 (t, J=7.46 Hz, 1H), 3.00 (t, J=6.97 Hz, 1H), 2.68-2.78 (m, 3H), 2.22 (s, 3H), 2.17 (s, 3H), 2.12 (s, 3H)	[q]d = -85.3° (c=0.1, MeOH); >99% ee; Absolute stereochemistry undetermined; Enantiomer of Ex.181

222

183	HCj Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{1-[1- (hydroxyacetyl)azetidin-3yl]ethyl}-3,4-dihydroisoquinolin- 1 (2H)-one - Isomer A	J	492	¹H NMR (400 MHz,CDCI3) δ 11.37 (brs, 1H), 7.17 (s, 1H), 5.94 (s, 1H), 4.77 (s, 2H), 4.194.27 (m, 1H), 3.92-4.00 (m, 4H), 3.57-3.74 (m, 4H), 3.16-3.22 (m, 1H), 3.01-2.88 (m 3H), 2.36 (s, 3H), 2.27 (s, 3H), 1.19 (d, J=6.01 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 184; 96% ee; rétention time: 2.459 min; column: Chiralcel OJ-3 100x4.6mm I.D., 3um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
184	H0^ Cl 5,8-dîchloro-2-[(4,6-dimethyl-2oxo-1 ^-dihydropyridin-SynmethylH-fl-flihydroxyacetyOazetidin-Syl]ethyl}-3,4-dihydroisoquinolin- 1 (2H)-one - Isomer B	J	492	¹H NMR (400 MHz,CDCI3) δ 11.70 (brs, 1H), 7.17 (s, 1H), 5.94 (s, 1H), 4.77 (s, 2H), 4.224.38 (m, 1H), 3.89-4.00 (m, 4H), 3.55-3.75 (m, 4H), 3.16-3.23 (m, 1H), 2.99-2.86 (m 3H), 2.36 (s, 3H), 2.28 (s, 3H), 1.19 (d, J=6.01 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 183; 94% ee; rétention time: 2.661 min; column: Chiralcel OJ-3 100x4.6mm I.D., 3um; mobile phase: 5-40% methanol (0.05% DEA) in CO2

223

185	⁰ Cl 5,8-dichloro-2-[(4,6-dîmethy1-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{1-[1(methylsulfonyl)azetidin-3yl]ethyl]-3,4-dihydroisoquinolin- 1 (2H)-one - Isomer A	J	[M+Na] ⁺ 534	¹H NMR (400 MHz, DMS0-d6) δ 11.59 (br. s., 1H), 7.55 (s, 1H), 5.89 (br. s., 1H), 4.57 (br. s., 2H), 3.97 (br. s., 2H), 3.77 (d, J=12.30 Hz, 2H), 3.62 (br. s., 2H), 3.44-3.47 (m, 2H), 2.98 (s, 3H), 2.85 (br. s., 2H), 2.15 (d, J=14.05 Hz, 6H), 1.13 (d, J=6.02 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 186; 100% ee; rétention time 5.299 min; column: Chiralpak AD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2
186	5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-{1 -[1 (methylsulfonyl)azetidin-3yl]ethyl]-3,4-dihydroisoquinolin- 1 (2H)-one - Isomer B	J	[M+Na] ⁺ 534	Ή NMR (400 MHz, DMS0-d6) δ 11.57 (br. s., 1H), 7.55 (s, 1H), 5.89 (s, 1H), 4.57 (s, 2H), 3.97 (t, J=8.03 Hz, 2H), 3.74-3.83 (m, 2H), 3.62 (d, J=9.29 Hz, 2H), 3.44 (br. s., 2H), 2.99 (s, 3H), 2.87 (d, J=6.02 Hz, 2H), 2.15 (d, J=16.56 Hz, 6H), 1.13 (d, J=6.78 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 185; 99% ee; rétention time 5.807 min; column: Chiralpak AD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2

224

187	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3y I) methyl]-7-[1 -(1 -methylazetidin3-yl)ethyl]-3,4-dihydroisoquinolin- 1 (2H)-one - Isomer A	J	448	¹H NMR (400 MHz, CD30D) δ 7.50 (br. s., 1H), 6.14 (s, 1H), 4.77 (s, 2H), 4.13 (d, J=7.53 Hz, 2H), 3.77-4.02 (m, 3H), 3.68 (d, J=10.29 Hz, 1H), 3.53 (t, J=6.02 Hz, 2H), 2.88-3.01 (m, 5H), 2.32 (s, 3H), 2.27 (s, 3H), 1.22 (d, J=6.78 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.188; 100% ee; rétention time 5.295 min; column: Chiralpak AD-3 150x4.6mm I.D., 3um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
188	Cl 5,8-dichloro-2-[(4,6-dimethyl-2oxo-1,2-dihydropyridin-3yl)methyl]-7-[1-(1-methylazetidin3-yl)ethyl]-3,4-dihydroisoquînolin1(2H)-one - Isomer B	J	448	¹H NMR (400 MHz, CD30D) δ 7.48 (s, 1H), 6.14 (s, 1H), 4.77 (s, 2H), 4.09 (t, J=8.41 Hz, 1H), 3.73-3.89 (m, 3H), 3.53 (t, J=6.27 Hz, 2H), 3.44 (t, J=8.53 Hz, 1 H), 3.07-3.19 (m, 1 H), 2.97 (q, J=5.77 Hz, 2H), 2.74 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H), 1.20 (d, J=6.78 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.187; 100% ee; rétention time 5.420 min; column: Chiralpak AD-3 150x4.6mm I.D., 3um; mobile phase: 5-40% methanol (0.05% DEA) in CO2

225

189	Cl 7-[1 -(azetidin-3-yl)ethyl]-5,8dichloro-2-[(4,6-dimethyl-2-oxo1,2-dihydropyridin-3-yl)methyl]3,4-dihydroisoquinolin-1 (2H)-one - Isomer A	J	[M+Na] ⁺ 456	¹H NMR (400 MHz, CDCI3) δ 7.12 (s, 1H), 5.92 (s, 1H), 5.33- 5.37 (m, 1 H), 4.89-4.93 (m, 1 H), 4.36-4.39 (m, 1 H), 4.13-4.17 (m, 1H), 3.82-3.91 (m, 3H), 3.65- 3.70 (m, 3H), 3.19-3.23 (m, 1H), 2.88-2.91 (m, 2H), 2.40 (s, 3H), 2.30 (s, 3H), 1.15 (d, J=6.80 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.190; 100% ee; rétention time 6.673 min; column: Chiralcel OD-3 150x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2
190	Cl 7-[1 -(azetid in-3-y I) ethy l]-5,8d ich lo ro-2-[(4,6-di methyl-2-oxo1,2-dihydropyridin-3-yl)methyl]3,4-dihydroisoquinolin-1(2H)-one - Isomer B	J	434	¹H NMR (400 MHz,CDCI3) δ 7.15 (s, 1H), 5.95 (s, 1H), 5.33- 5.37 (m, 1 H), 4.82-4.92 (m, 1 H), 4.38-4.42 (m, 1 H), 4.13-4.17 (m, 1H), 3.82-3.91 (m, 3H), 3.65- 3.70 (m, 3H), 3.19-3.23 (m, 1 H), 2.88-2.91 (m, 2H), 2.40 (s, 3H), 2.30 (s, 3H), 1.15 (d, J=6.80 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer Ex.189; 97% ee; rétention time 5.996 min; column: Chiralcel OD-3 150x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2

226

191	8-chloro-2-[(4-methoxy-6-methyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-5-methyl-7-{1 -[1 (methylsulfonyl)azetidin-3yl]ethyl}-3,4-dihydroisoquinolin1(2H)-one - Isomer A	J	508	¹H NMR (400 MHz, CD3OD) δ 7.23 (s, 1H), 6.27 (s, 1H), 4.69- 4.78 (m, 2H), 4.10 (t, J=8.03 Hz, 1H), 3.91 (s, 3H), 3.74-3.85 (m, 3H), 3.46 (dd, J=6.78, 8.03 Hz, 1H), 3.34-3.38 (m, 2H), 3.02 (dd, J=6.78,17.32 Hz, 1 H), 2.93 (s, 3H), 2.77 (t, J=6.27 Hz, 2H), 2.33 (s, 3H), 2.28 (s, 3H), 1.20 (d, J=6.78 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.192; 96% ee; rétention time 4.765 min; column: Chiralpak AD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2
192	8-chloro-2-[(4-methoxy-6-methyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-5-methyl-7-{1-[1(methylsulfonyl)azetidin-3yl]ethyl}-3,4-dihydroisoquinolin1(2H)-one - Isomer B	J	[M+Na] ⁺ 530	¹H NMR (400 MHz, CD3OD) δ 7.23 (s, 1H), 6.27 (s, 1H), 4.74 (d, J=1.25 Hz, 2H), 4.10 (t, J=8.16 Hz, 1H), 3.90 (s, 3H), 3.74-3.86 (m, 3H), 3.46 (dd, J=6.65, 7.91 Hz, 1H), 3.34-3.38 (m, 2H), 3.05 (m, 1H), 2.93 (s, 3H), 2.74-2.81 (m, 2H), 2.33 (s, 3H), 2.28 (s, 3H), 1.20 (d, J=6.78 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 191 ; 100% ee; rétention time 5.207 min; column: Chiralpak AD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2

227

193	aa·* 8-chloro-2-[(4,6-dimethyl-2-oxo1,2-dihydropyridin-3-yl)methyl]-5methyl-7-{1-[1- (methylsulfonyl)azetidin-3yl]ethyl}-3,4-dihydroisoquinolin1(2H)-one - Isomer A	J	492	'H NMR (400 MHz, CDCI3) 6 11.33 (br. s., 1H), 6.96 (s, 1H), 5.93 (s, 1H), 4.72-4.87 (m, 2H), 4.10 (t, J=8.03 Hz, 1H), 3.693.84 (m, 3H), 3.60 (t, J=6.02 Hz, 2H), 3.50 (t, J=7.28 Hz, 1H), 2.85-2.95 (m, 1 H), 2.84 (s, 3H), 2.71 (t, J=6.02 Hz, 2H), 2.36 (s, 3H), 2.27 (S, 3H), 2.21 (s, 3H), 1.17 (d, J=6.78 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.194; 100% ee; rétention time 5.024 min; column: Chiralpak AD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2
194	8-chloro-2-[(4,6-dimethyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl]-5methyl-7-{1-[1- (methylsulfonyl)azetidin-3yl]ethyl}-3,4-dihydroisoquinolin- 1 (2H)-one - Isomer B	J	492	¹H NMR (400 MHz, CDCI3) 5 11.82 (br. s., 1H), 6.96 (s, 1H), 5.93 (s, 1H), 4.72-4.87 (m, 2H), 4.09 (t, J=8.03 Hz, 1H), 3.673.84 (m, 3H), 3.60 (t, J=6.02 Hz, 2H), 3.50 (t, J=7.28 Hz, 1H), 2.89 (d, J=9.29 Hz, 1H), 2.84 (s, 3H), 2.71 (t, J=6.15 Hz, 2H), 2.36 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 1.17 (d, J=6.78 Hz, 3H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 193; 95% ee; rétention time 5.219 min; column: Chiralpak AD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% éthanol (0.05% DEA) in CO2

228

195	8-chloro-2-[(4,6-dimethyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl]-5methyl-7-[1-(oxetan-3-yl)ethyl]3,4-dihydroisoquinolin-1(2H)-one - Isomer A	J	415	¹H NMR (400 MHz, CDCI3) δ 11.67 (brs, 1H), 6.91 (s, 1H), 5.94 (s, 1H), 4.86 (t, J=6.8 Hz, 1 H), 4.80 (2H, s), 4.55-4.65 (m, 2H), 4.30 (t, J=6.0 Hz, 1H), 3.90-4.00 (m, 1H), 3.60 (t, J=6.0 Hz, 2H), 3.25-3.40 (m, 1H), 2.70 (t, J=6.0 Hz, 2H), 2.69 (s, 3H), 2.37 (s, 3H), 2.28 (s, 3H), 1.13 (d, J=6.8 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.196; 99% ee; rétention time: 2.854 min; column: OJ-3 100x4.6 mm I.D., 3 um; mobile phase: 5-40% methanol (0.05% DEA) in CO2
196	8-chloro-2-[(4,6-dimethyl-2-oxo- 1,2-dihydropyridin-3-yl)methyl]-5methyl-7-[1-(oxetan-3-yl)ethyl]3,4-dihydroisoquinolin-1(2H)-one - Isomer B	J	415	¹H NMR (400 MHz, CDCI3) δ 11.72 (brs, 1H), 6.91 (s, 1H), 5.94 (s, 1H), 4.86 (t, J=6.8 Hz, 1H), 4.80 (s, 2H), 4.55-4.65 (m, 2H), 4.31 (t, J=6.4 Hz, 1H), 3.90-4.00 (m, 1 H), 3.60 (t, J=6.0 Hz, 2H), 3.25-3.40 (m, 1 H), 2.70 (t, J=6.0 Hz, 2H), 2.69 (s, 3H), 2.37 (s, 3H), 2.28 (s, 3H), 1.13 (d, J=6.8 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 195; 99% ee; rétention time: 3.078 min; column: OJ-3 100x4.6 mm I.D., 3 um; mobile phase: 5-40% methanol (0.05% DEA) in CO2

229

197	8-chloro-2-[(4-methoxy-6-methyl- 2- oxo-1,2-dihydropyridin-3yl)methyl]-5-methyl-7-[1-(oxetan- 3- yl)ethyl]-3,4-dihydroisoquinolin- 1 (2H)-one - Isomer A	J	431	¹H NMR (400 MHz, CDCI3) δ 12.75 (brs, 1H), 6.89 (s, 1H), 5.91 (s, 1H), 4.80-4.88 (m, 3H), 4.57-4.61 (m, 2H), 4.28 (t, J=6.4 Hz, 1H), 3.86-3.93 (m, 4H), 3.31-3.42 (m, 3H), 2.70 (t, J=6.0 Hz, 2H), 2.34 (s, 3H), 2.20 (s, 3H), 1.13 (d, J=6.8 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 198; 97% ee; rétention time: 1.521 min; column: Chiralpak AD-3 150x4.6mm I.D., 3um; mobile phase: 40% isopropanol (0.05% DEA) in CO2
198	8-ch lo ro-2-[(4-methoxy-6-methyl- 2- oxo-l ,2-dihydropyridin-3yl)methyl]-5-methyl-7-[1-(oxetan- 3- yl)ethyl]-3,4-dihydroisoquinolin1(2H)-one - Isomer B	J	431	¹H NMR (400 MHz, CDCI3) δ 12.39 (brs, 1H), 6.90 (s, 1 H), 5.92 (s, 1H), 4.81-4.89 (m, 3H), 4.57-4.61 (m, 2H), 4.30 (t, J=6.0 Hz, 1H), 3.87-3.94 (m, 4H), 3.31-3.43 (m, 3H), 2.71 (t, J=5.2 Hz, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 1.13 (d, J=6.8 Hz, 3H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex. 197; 94% ee; rétention time: 2.081 min; column: Chiralpak AD-3 150x4.6mm I.D., 3um; mobile phase: 40% isopropanol (0.05% DEA) in CO2

230

199	^H0> ci ο ο πΔίΎΝ'Υ'ΝΗ ^ν φΟ ΑΛ Cl (±)-5,8-dichloro-7-(1-cyclopropyl2-hydroxyethyl)-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-3,4-dihydroisoquinolin- 1 (2H)-one	J	435	¹H NMR (400 MHz, CD3OD) δ 7.67 (s, 1H), 6.10 (s, 1H), 4.76 (s, 2H), 3.77-3.90 (m, 2H), 3.45- 3.55 (m, 2H), 2.96 (t, J=6.24 Hz, 2H), 2.79-2.86 (m, 1 H), 2.28 (s, 3H), 2.25 (s, 3H), 1.11-1.22 (m, 1H), 0.64-0.74 (m, 1H), 0.35- 0.50 (m,2H), 0.02-0.11 (m, 1H)	racemic mixture
200	0 Cl ¹ 5,8-dichloro-7-{1-[1(hydroxyacetyl)piperidin-4yl]ethyl}-2-[(4-methoxy-6-methyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-3,4-dihydroisoquinolin1(2H)-one - Isomer A	J	536	¹H NMR (400 MHz, CDCI3) δ 12.19 (s, 1H),7.23(d, J=3.2 Hz, 1H), 5.91 (s, 1H), 4.82-4.73 (m, 2H), 4.70-4.50 (m, 1H), 4.15- 4.11 (m, 2H), 3.87 (s, 3H), 3.703.66 (m, 1 H), 3.54-3.40 (m, 4H), 2.92-2.86 (m, 3H), 2.64-2.58 (m, 1H), 2.34 (s, 3H), 1.84-1.62 (m, 2H), 1.50-1.40 (m, 1H), 1.26- 1.19 (m, 5H).	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.201; 90% ee; rétention time 26.03 min; column: Chiralpak AD-H 250x4.6mm I.D., 5u; mobile phase: 50/50 hexane(0.1% DEA)/ethanol(0.1 % ethanolamine)

231

201	0 Cl ¹ 5,8-dichloro-7-{1-[1- (hydroxyacetyl)piperidin-4yl]ethyl}-2-[(4-methoxy-6-methyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-3,4-dihydroisoquinolin1(2H)-one - Isomer B	J	536	¹H NMR (400 MHz, CDCI3) δ 12.03 (s, 1 H), 7.23 (d, J=3.2 Hz, 1H), 5.92 (s, 1H), 4.82-4.73 (m, 2H), 4.70-4.50 (m, 1H), 4.14- 4.11 (m, 2H), 3.87 (s, 3H), 3.70- 3.66 (m, 1 H), 3.47-3.40 (m, 4H), 2.92-2.86 (m, 3H), 2.64-2.61 (m, 1H), 2.34 (s, 3H), 1.84-1.62 (m, 2H), 1.50-1.40 (m, 1H), 1.26- 1.19 (m, 5H).	Single isomer, absolute stereochemistry unknown; Enantiomer Ex.200; 97% ee; rétention time: 51.00 min; column: Chiralpak AD-H 250x4.6mm I.D., 5um; mobile phase: 50/50 hexane(0.1% DEA)/ethanol(0.1 % ethanolamine);
202	Cl (±)-5,8-dichloro-2-[(4,6-dimethyl- 2-oxo-1,2-dihydropyridin-3yl)methyl]-7-[1-(4methylpiperazin-1 -yl)ethyl]-3,4dihydroisoquinolin-1 (2H)-one	K	477	¹H NMR (400MHz, CDCI3) δ 7.72 (s, 1 H), 5.93 (s, 1 H), 4.84 - 4.71 (m, 2H), 4.01 (q, J=6.3 Hz, 1 H), 3.63 (t, J=6.1 Hz, 2H), 2.90 (d, J=3.5 Hz, 2H), 2.42 (br. s., 6H), 2.35 (s, 3H), 2.28 (s, 6H), 1.79 (br. s., 2H), 1.24 (d, J=6.5 Hz, 3H)	racemic mixture

232

203	rA ci ο o ΑφΥΑ 5,8-dichloro-7- [(dimethylamino)(oxetan-3- yl)methyl]-2-[(4-methoxy-6methyl-2-oxo-1,2-dihydropyridin3-yl)methyl]-3,4dihydroisoquinolin-1 (2H)-one Isomer A	K	480	¹H NMR (400 MHz, CDCI3) δ 12.34 (br.s., 1H), 7.43 (s, 1H), 5.95 (s, 1 H), 4.61-4.88 (m, 4H), 4.48 (d, J=10.04 Hz, 1H), 4.25- 4.34 (m, 1 H), 4.21 (t, J=6.90 Hz, 1H), 3.82-3.95 (m, 3H), 3.49 (d, J=1.76 Hz, 3H), 2.89 (t, J=6.02 Hz, 2H), 2.35 (s, 3H), 2.13 (s, 6H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.204; 88% ee; rétention time 3.994 min; column: Chiralpak AD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% isopropanol (0.05% DEA) in CO2
204	Ci 0 0 5,8-dichloro-7[(dimethylamino)(oxetan-3yl)methyl]-2-[(4-methoxy-6methyl-2-oxo-1,2-dihydropyridin- 3-yl)methyl]-3,4-	K	480	¹H NMR (400 MHz, CDCI3) δ 12.32 (brs, 1H), 7.46 (brs, 1H), 5.96 (s, 1H), 4.57-4.88 (m, 4H), 4.50 (brs, 1H), 4.28 (t, J=6.90 Hz, 1H), 4.19 (d, J=6.27 Hz, 1H), 3.88 (s, 3H), 3.52 (br. s„ 3H), 2.88 (brs, 2H), 2.37 (brs, 4H), 2.15 (brs, 5H)	Single isomer, absolute stereochemistry unknown; Enantiomer of Ex.203; 97% ee; rétention time 4.325 min; column: Chiralpak AD-3 100x4.6mm I.D., 3um; mobile phase: 5-40% isopropanol (0.05% DEA) in CO2

233

	dihydroisoquinolin-1 (2H)-one - Isomer B
205	Cl (±)-5,8-dichloro-2-[(4,6-dimethyl2-oxo-l ,2-dihydropyridin-3yl)methyl]-7-[1 -(piperazin-1 yl)ethyl]-3,4-dihydroisoquinolin1(2H)-one	K	463	¹H NMR (400MHz, CDCI3) δ 7.72 (s, 1H). 5.94 (s, 1H), 4.85- 4.69 (m, 2H), 4.02 (q, J=6.4 Hz, 2H), 3.62 (t, J=6.4 Hz, 2H), 2.90 (br. s„ 6H), 2.55 (br. s., 2H), 2.42 - 2.31 (m, 5H), 2.29 (s, 3H), 1.24 (d, J=6.5 Hz, 3H)	racemic mixture

234

Bioloqical Assays and Data

Purification of WT and mutant EZH2 Y641N

WT and mutant EZH2 were purified using the same procedure. The genes for EZH2, EED, SUZ12, and RBBP4 proteins were cloned into pBacPAK9 vectors (Clontech). RBBP4 was FLAG tagged on the N-terminal end. The baculovirus expressions of these proteins were used to co-infect SF9 insect cells. Insect cell pellets were lysed in a buffer containing 25mM Tris pH8.0, 300mM NaCI, 0. 5mM TCEP, complété EDTA-free protease inhibitor (Roche), 0.1% NP-40. The supernatant from the lysate was incubated with FLAG® M2 antibody resin (Sigma). The resin was washed on the chromatography column and eluted with 0.2 mg/ml FLAG peptide. The elute was incubated with omnicleave nucleases (Epicentre Technologies) at 4°C overnight, then concentrated and loaded onto a Superdex 200 (GE Healthcare) column. The Superdex 200 column was eluted with 25mM Tris pH8.0, 150mM NaCI, 0.5mM TCEP. Fractions containing the PRC2 complex were pooled.

Nucléosome Assav Protocol: (The same protocol was used for the WT and mutant EZH2 Y6412N assays)

A. Compound préparation

1. Préparé 10 mM stock solutions in 100 % DMSO from solid material

2. Serial dilute 10 mM compound stocks either 2 or 3-fold in 100% DMSO to generate compounds for 11 point dose response

B. Reagent préparation

1. Préparé 1x assay buffer containing 100 mM Tris pH 8.5, 4 mM DTT and 0.01% Tween-20

2. Dilute purified HeLa oligonucleosomes and recombinant histone H1 (New England Biolabs) in assay buffer to 1.67x.

3. Dilute PRC2 4 protein complex (EZH2, EED, SUZ12, RbAp48) to 3.5x in assay buffer

4. Préparé 10x ³H SAM solution in assay buffer using 0.94 pCi/well of radioactive SAM (Perkin Elmer) and sufficient non-labeled SAM (Sigma) for 1.5 μΜ final concentration.

5. Dilute TCA to 20% in DI water

C. Enzyme reaction

235

1. Final reaction conditions are PRC2 4-protein complex at 4 nM when using WT EZH2 or 6 nM when using Y641N mutant EZH2,1.5 μΜ SAM, 25 pg/mL oligonucleosomes, 50 nM rH1 in a 50 μΙ reaction volume.

2. Add 1 μΙ of diluted compound to the assay plate (96-well V-bottom polypropylene plates) or 1 μΙ of DMSO for control wells.

3. Add 30 μΙ of nucléosomes to the assay plate

4. Add 14 μΙ of either WT or Y641N mutant PRC2 4 protein complex to the assay plate

5. Add 5 μΙ of ³H SAM to start the reaction.

6. Stop the reaction after 60 minutes with the addition of 100 μΙ of 20% TCA

7. Transfer 150 μΙ of quenched reaction into a prepared filterplate (Millipore #MSIPN4B10)

8. Apply vacuum to the filterplate to filter the reaction mix through the membrane.

9. Wash the filterplate with 5x200 μΙ of PBS, blot dry and dry in an oven for 30 minutes

10. Add 50 μΙ of microscint-20 scintillation fluid (Perkin Elmer) to each well, wait 30 minutes and count on a liquid scintillation counter.

11. Some compounds were tested under high SAM conditions. In this case, the assay is as described above except that the reaction contains 15 uM SAM. SAM is added to the assay as a 3.3x stock with a total of 14.5 uCi/well.

D. Data analysis

1. IC50 values were determined by fitting the data to a 4-parameter ICso équation using proprietary curve fitting software.

2. For compounds tested under high SAM conditions, Kî³pp values were obtained by fitting the dose response curve to a model for compétitive inhibition using proprietary curve fitting software.

Préparation of HeLa oligonucleosomes:

Reaqents

- Cell Pellet: 15L HeLa S3 (Accelgen) + 6L HeLa S3 (in house)

- Mnase (Worthington Biochemicals)

Equipment

236

- SW-28 Rotor

- Dounce Homogenizer/ B Pestle

Buffers

- Lysis: 20 mM Hepes pH 7.5, 0.25M Sucrose, 3 mM MgCfe, 0.5% Nonidet P-40, 0.5 mM TCEP, 1 Roche Protease Tablet

- B: 20 mM Hepes pH7.5, 3 mM MgCl2, 0.5mM EDTA, 0.5 mM TCEP, 1 Roche Protease Tablet

- MSB: 20 mM Hepes pH7.5, 0.4 M NaCI, 1mM EDTA, 5% v/v Glycerol, 0.5 mM TCEP, 0. 2mM PMSF

- LSB: 20 mM Hepes pH7.5, 0.1 M NaCI, 1mM EDTA, 0.5mM TCEP, 0.2 mM PMSF

- NG: 20 mM Hepes pH7.5, 1 mM EDTA, 0.4m NaCI, 0.2 mM PMSF, 0.5 mM TCEP

- Storage: 20 mM Hepes pH7.5, 1mM EDTA, 10% Glycerol, 0.2 mM PMSF, 0.5 mM TCEP

Protocol

A. Nuclei

1. Resuspend -10L pellet in 2x40 mL lysis using dounce homogenizer

2. Spin 3000xg 15’

3. Repeat 2 more times

4. Resuspend pellet in 2x40 mL B

5. Spin 3000xg 15’

B. Nuclei Resuspension

1. Resuspend pellet in 2x40 mL MSB. Spin 5000xg 20’

2. Resuspend pellet in 2x15 mL HSB

3. Pool and Homogenize 40 Strokes to shear DNA

4. Pellet 10OOOxg 20’

5. Dialyze O/N 4°C in LSB except for Batch A which was Dialyzed LSB at 50nM NaCI for3hr

C. Mnase Digestion

Test Mnase digestion (200ul)

1. Warm to 37°C for 5’

2. Add CaCh to 3mM and add 10U of Mnase

237

3. 37°C 30’ taking 25μΙ_ sample every 5'

4. Process reaction with 1 μ!_ 0.5M EDTA, 40 μΙ_ H20,15 μ!_ 10% SDS, 10 μί 5M NaCI, and 100 pL phenol-chloroform vortexing after each addition

5. Spin 5’ 13k

6. Run 5 pL of Aqueous phase on 1 % agarose gel

7. Take time that yields ~2kb fragments

8. Selected 15’ for A & B and 20' for C & D for scale up

Added NaCI to 0.6M

D. Sucrose Gradient 1

1. Poured 6x 34 mL gradient from 5 to 35% sucrose in NG using AKTA purifier in 38.5 mL pollyallomer tubes

2. Lead ~4.0mL on top of MN1 digest

3. Spin 26k 16hr4°C

4. Take 2 mL fractions from top

5. Run on Page Gel

6. Dialyze Fractions 7-14 0/N 4°C in 4L LSB except Batch D which had 2x 2hr

7. Repeat 3X

E. Final

1. Pool ail and concentrate in Amicon (somewhat cloudy)

2. Added 10% Glycerol

3. Spun5K15’

4. 1.8 mg/mL at 80 mL for 144mg Total

Bioloqical Activitv

Biological activity of selected examples in the EZH2 nucléosome assay are provided in Tables 3. Data are presented as WT and Mutant Y641N EZH2 IC50 value (μΜ) or Ki^app (μΜ) as indicated.

Table 2.

238

Ex. No.	WT EZH2 Nucléosome assay ICso (μΜ)	WTEZH2 Nucléosome assay (10X SAM) Ki (μΜ)	EZH2 Mutant Y641N Nucléosome assay ICso (μΜ)
1	0.001		0.003
2	0.002		0.004
3	0.066		0.302
4	0.316		1.954
5		0.033	0.189
6		0.019	0.136
7		0.171	1.617
8		0.652	5.016
9		0.005	0.035
10	0.326		1.980
11	0.038		0.174
12		0.004	0.016
13		0.003	0.018
14	0.008		0.040
15		0.003	0.019
16		0.004	0.040
17	0.035		0.125
18	0.126	0.115	0.995
19	0.013	0.010	0.132
20	0.011		0.053
21	0.015		0.109
22	7.817		95.165
23	0.009		0.067
24	0.004		0.008
25	0.084		0.693
26	0.027		0.057
27	0.037		0.300
28	0.126		1.894
29	0.017		0.107
30	0.004		0.020
31	0.004		0.006
32	0.093		1.133
33	0.012		0.070
35	0.002	0.000	0.002
36	0.105	0.136	0.443
37	0.001		0.002
38	0.378		0.740
39	0.040		0.242
40	0.006		0.024
41	0.012		0.082
42	0.012		0.102
43		0.039	0.348

239

44	0.022	0.144
45	0.103	0.345
46	0.121	0.423
47	0.138	0.847
48	0.008	0.050
49	0.215	0.996
50	0.077	0.129
51	0.000	0.002
52	0.298	1.038
53	0.001	0.017
54	0.004	0.012
55	0.162	0.843
56	0.000	0.004
57	0.406	1.352
58	0.057	0.513
59	0.025	0.155
60	0.031	0.180
61	0.031	0.127
62	0.035	0.262
63	0.528	4.104
64	0.007	0.043
65	0.006	0.047
66	0.009	0.081
67	1.599	19.543
68	0.007	0.074
69	0.417	4.308
70	0.000	0.006
71	0.000	0.003
72	0.041	0.128
73	0.000	0.002
74	0.005	0.051
75	0.002	0.020
76	0.005	0.043
77	0.022	0.132
78	0.004	0.040
79	0.017	0.133
80	0.001	0.007
81	0.0002	0.003
82	0.006	0.131
83	0.0004	0.004
84	0.0002	0.002
85	0.052	0.238
86	0.061	0.637
87	0.00001	0.002
88	0.028	0.122
89	0.008	0.088
90	0.459	5.634
91	0.001	0.023

240

92	0.001	0.009
93	0.159	1.332
94	0.323	4.870
95	0.001	0.012
96	0.204	2.99
97	0.003	0.027
98	1.22	8.72
99	0.003	0.017
100	0.309	3.73
101	0.0003	0.007
102	0.018	0.178
103	0.052	0.320
104	0.673	7.77
105	0.0008	0.013
106	0.0006	0.008
107	0.0019	0.018
108	0.0017	0.016
109	0.086	0.911
110	0.00004	0.002
111	0.00002	0.001
112	0.021	0.125
113	0.0008	0.005
114	0.016	0.152
115	0.0003	0.005
116	0.071	0.340
117	0.0004	0.005
118	0.0001	0.003
119	0.015	0.100
120	0.002	0.014
121	0.029	0.255
122	0.073	0.236
123	0.0002	0.005
124	0.058	0.892
125	0.0009	0.008
126	0.056	0.165
127	0.0002	0.0022
128	0.184	1.167
129	0.0008	0.008
130	0.220	1.99
131	0.0007	0.005
132	0.001	0.013
133	0.837	8.635
134	0.131	1.926
135	0.002	0.014
136	0.0001	0.003
137	0.133	1.166
138	0.046	0.249
139	0.0005	0.0085

241

140	0.103	1.17
141	0.002	0.016
142	0.008	0.109
143	0.276	1.77
144	0.0002	0.005
145	0.070	0.272
146	0.0001	0.0035
147	0.128	0.543
148	0.056	0.439
149	0.539	2.267
150	0.0001	0.003
151	0.0008	0.009
152	0.0003	0.004
153	0.416	3.10
154	0.0446	0.553
155	0.0013	0.027
156	0.375	1.711
157	0.0006	0.009
158	0.578	5.13
159	0.0016	0.017
160	0.021	0.086
161	0.0004	0.004
162	0.148	2.971
163	0.0004	0.004
164	0.200	1.971
165	0.0003	0.005
166	0.0002	0.002
167	0.062	0.850
168	0.0007	0.008
169	0.0151	0.070
170	0.0008	0.014
171	0.328	2.63
172	0.0008	0.012
173	0.016	0.206
174	0.0006	0.013
175	0.085	1.00
176	0.0003	0.005
177	0.049	0.282
178	0.003	0.020
179	0.001	0.009
180	0.390	2.16
181	0.001	0.041
182	2.23	9.15
183	0.056	0.517
184	0.0006	0.005
185	0.001	0.012
186	0.014	0.240
187	0.001	0.010

242

188	0.014	0.151
189	0.0007	0.006
190	0.016	0.100
191	0.0003	0.005
192	0.117	0.605
193	0.001	0.010
194	0.044	0.309
195	0.046	0.216
196	0.0002	0.003
197	0.033	0.062
198	0.00001	0.001
199	0.003	0.037
200	0.0001	0.002
201	0.007	0.037
202	0.016	0.207
203	0.055	0.204
204	0.002	0.062
205	0.0007	0.008

Ail publications and patent applications cited in the spécification are herein incorporated by reference in their entirety. Although the foregoing invention has been described in some detail by way of illustration and example, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended daims.

Claims

Claims We Claîm:

1. A compound of formula (I):

or a pharmaceutically acceptable sait thereof, wherein:

R¹ is selected from the group consisting of F, C1-C4 alkyl, C1-C4 alkoxy, C(O)R⁵, C3-Cb cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C1-C4 alkyl or C1-C4 alkoxy is optionally substituted by one or more R⁶, and each said C3-Cg cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

R² is H, F or C1-C4 alkyl;

L is a bond or a C1-C4 alkylene;

R³ is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, OH, CN, C(O)R^e, COOR⁹, NR¹⁰R¹¹, OR¹², C3-Cg cycloalkyl, 3-12 membered heterocyclyl and 512 membered heteroaryl, where each said CrC4 alkyl or CrC4 alkoxy is optionally substituted by one or more R⁶, and each said C3-C₈ cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

R⁵ is C1-C4 alkyl, where each said 0^04 alkyl is optionally substituted by one or more R¹⁴;

each R⁶ is independently OH, F, CN or C1-C4 alkoxy;

R⁸ is C_rC4 alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁴;

244

R¹⁰ and R¹¹ are independently H or C_rC₄ alkyl, where each said C1-C4 alkyl is optionally substituted by one or more R¹⁴;

R¹² is selected from the group consisting of C₃-C₈ cycloalkyl, 3-12 membered heterocyclyl and 5-12 membered heteroaryl, where each said C3-C8 cycloalkyl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted by one or more R⁷;

each R¹³ is independently C1-C4 alkyl, where each said CTC4 alkyl is optionally substituted by one or more R¹⁵;

each R¹⁴ and R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

X and Z are independently CrC₄ alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy.

2. The compound or sait of claim 1, wherein R² is H.

3. The compound or sait of claim 1 or 2, wherein R⁴ is Cl, F, Br or CH3.

4. The compound or sait of claim 1,2 or 3, wherein X is CH₃, OCH3 or OCHF2 and Z is CH₃.

5. The compound or sait any one of daims 1 to 4, wherein R¹ is C,-C₄ alkoxy optionally substituted by one or more R⁶.

6. The compound or sait of claim 5 wherein said C1-C4 alkoxy is OCH₃.

7. The compound or sait of any one of daims 1 to 4, wherein R¹ is C1-C4 alkyl optionally substituted by one or more R⁶.

8. The compound or sait of any one of daims 1 to 7, wherein L is a bond and R³ is 3-12 membered heterocyclyl optionally substituted by one or more R⁷.

9. The compound or sait of claim 8, wherein said 3-12 membered heterocyclyl is selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each optionally substituted by one or more R⁷.

10, A compound of Formula (l-A):

245 or a pharmaceutically acceptable sait thereof, wherein:

R¹ is C1-C4 alkoxy;

R² is H;

L is a bond;

R³ is 3-12 membered heterocyclyî, optionally substituted by one or more R⁷;

R⁴ is H or Cl;

each R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

11. The compound or sait of claim 10, wherein R³ is 3-12 membered heterocyclyî selected from the group consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, each optionally substituted by one or more R⁷.

12. A compound that is 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(R)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2/7)one, or a pharmaceutically acceptable sait thereof.

13. A compound that is 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(/^:?)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2/-/)one.

14. A compound that is 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable sait thereof,

246

15. A compound that is 5,8-dichloro-2-[(4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-[(S)-methoxy(oxetan-3-yl)methyl]-3,4-dihydroisoquinolin-1(2H)one, or a pharmaceutically acceptable sait thereof.

16. A compound of formula (III): R² CI 0 0 T il il R³ I! γν _ΧΛΑ_Ζ R⁴ (III)

or a pharmaceutically acceptable sait thereof, wherein:

R² is H, F or C1-C4 alkyl;

R⁴ is H, halo or C1-C4 alkyl, where each said CrC₄ alkyl is optionally substituted by one or more R⁶;

each R⁶ is independently OH, F, CN or C1-C4 alkoxy;

each R¹⁵ is independently OH, F, CN or C1-C4 alkoxy; and

X and Z are independently C1-C4 alkyl, Ci-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy.

17. The compound or sait of claim 16, wherein R¹ and R³ are taken together to form a 3-12 membered heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl and homopiperidinyl, each optionally substituted by one or more R⁷.

18. The compound or sait of claim 17, wherein R⁷ is CHO, C(O)R¹³ or SO2R¹³ and each R¹³ is independently C1-C4 alkyl optionally substituted by one or more R¹⁵.

247

19. A pharmaceutical composition comprising a compound of any one of daims 1 to 18, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier or excipient.

5

20. Use of a compound of any one of daims 1 to 18 or a pharmaceutically acceptable sait thereof in the manufacture of a pharmaceutical composition for the treatment of abnormal cell growth in a subject.

21. The use of claim 20, wherein the abnormal cell growth is cancer.

22. The use of claim 20 or 21, wherein the subject is a human.

23. A compound of any one of daims 1 to 18, or a pharmaceutically acceptable sait thereof, for use in a method for the treatment of abnormal cell growth in a subject.

24. A combination of a compound according to any one of daims 1 to 18, or a pharmaceutically acceptable sait thereof, and one or more additional anti-cancer agents.