OA16293A

OA16293A - Napht-2-Y lacetic acid derivatives to treat AIDS.

Info

Publication number: OA16293A
Application number: OA1201200547
Authority: OA
Inventors: Kerim Babaoglu; Kyla Bjornson; Hongyan Guo; Randall L. Halcomb; John O. Link; Ryan Mcfadden; Hongtao Liu; Michael L. Mitchell; Paul A. Roethle; James D. Trenkle; Randall W. Vivian; Lianhong Xu; James Taylor; Elizabeth Bacon; Paul Hrvatin
Original assignee: Gilead Sciences, Inc.
Priority date: 2010-07-02
Filing date: 2011-07-01
Publication date: 2015-04-24

Abstract

The invention provides compounds of formula (I) :

Description

NAPHT-2-YLACETIC ACID DERIVATIVES TO TREAT AIDS

Cross Référencé to Related Application

This patent application daims the benefit of priority of U.S. application serial

No. 61/361,314, filed July 2, 2010.

Background of the Invention

Human immunodeficiency virus (HTV) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HTV-1) encodes three enzymes which are required for viral réplication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and hâve shown effectiveness, particularly when employed in combination, toxicity and development of résistant strains hâve limited their usefulness (Palella, et al N. Engl. J. Med (1998) 338:853-860; Richman, D. D. Nature (2001) 410:995-1001). Accordingly, there is a need for new agents that inhibît the réplication of HIV. There is also a need for agents that are directed against altemate sites in the viral life cycle including agents that target the interaction of Lcns Epithelial Derived Growth Factor (LEDGF/p75) and HIV-1 integrase.

Summarv of the Invention

In one embodiment, the invention provides a compound of the invention which is a compound of formula I:

OH wherein:

R¹ isR^laorR^lbR² is R^2a or R^2b;

R³ is R^3a or R^3b;

R⁴ is R⁴® or R^4b;

R⁵ is R^5a or R^5b;

R⁶ îsR^orR⁶*;

R⁷ is R⁷¹ or R^7b;

R* is R⁸* or R^gb;

R¹* is selected from:

a) H, halo, (C i -Cejalkyl and (Ci -Cé)haloalkyl;

b) (CF-Cejalkenyl, (C2-C6)alkynyl, (C₃-C₇)cycloalkyl_s nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O)-R¹¹, <XO>0-Rⁿ, -O-R¹¹, -S-R¹¹, -S(O)-R^U, -SC^-R¹¹, -(Cj-CiJalkyl-R'¹, -(Ci-^Jalkyl-C^OJ-R¹', -(Cr^alkyl-Cf^O-O-R¹¹, -(Ci-C6)alkylO-R”, -(CrCfcjalkyl-S-R, -(CrC^alkyl-SiCO-R¹¹ and -(Cj-CfiJalkyl-SCVR¹¹, wherein each R¹¹ is independently selected from H, (Ci-Céjalkyl, (C2-C6)alkenyl, (C₂C₆)alkynyl, (Ci-Côjhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R^t0, -Cf-Oj-N/R^R¹⁰, -O-C(-O)-N(R⁹)R’°, -SO2-N(R⁹)R¹⁰, <CI-C₆)alkyl-N(R⁹)R^,°, -(C1-C6)alkyl-C(=O)-N(R⁹)R¹⁰, -(C1-C₆)alkyl-O-C(=O)N(R⁹)R¹⁰ and -(Cs-C(>)aIkyl-SO2-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C j-Csjalkyl and (C3-C7)cycloalkyl and wherein each R¹⁰ is independently selected from R^H,-(Ci-C6)alkyl-R^H, -SOrR^;i, -C(=O)-R¹¹, -C(=O)0Rⁿ and C(=O)N(R⁹)R¹¹, wherein each R¹’ is independently selected from H, (Ci-Cfi)alkyl, (C2C₆)alkenyl, ((^-C^alkynyi, (C]-C6)haîoalkyl, (C₃-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle and heteroaryl of R*‘ is optionally substituted with one or more (e.g. 1,2 or 3) Z¹⁰ groups;

R^lb is selected from:

a) -(Ci-C6)alkyl’O'(Ci-C6)alkyl-(C3-C₇)carbocycle, -(Ci-C₆)aIkyl-S-(CiC₆)alkyl-(C₃-C₇) carbocycle, -(Ci-C6)alkyl-S(O)-(Ci-C₆)alkyl-(C3-C₇)carbocycle, -(CjC6)alkyl-SO₂-(Ci-C6)alkyl-(C3-C₇)carbocycle, (Ci-C6)alkyl-SO2-(Ci-C₆)alkyl-Z¹³, -C(O)-(Ci-C6)alkyl-Zⁿ, -O-(Cj-C6)alkyl-Z¹³, -S-(Ct-C6)alkyl-Z^B, -S(O)-(C]-C6)alkylZ¹³, -SO2-(CrC6)alkyl-Z¹³, -(C,-C6)alkyÎ-Z^!4, -(Ci-C^alkyl-CXO^Ci-C^jalkyl-Z¹³, (Cj-CsJalkyl-QOJ-OfCi-Ceïalkyl-Z¹³, -(CrC^alkyl-O-iCi-C^alkyl-Z¹³, -(Ci-C₆)alkyl-

S-(Ci-C₆)alkyl-Z¹³, -(C₂-C₆)alkenyl-(Ci-C₆)haloalkyl, -(C2-C₆)alkynyl-(C]-Cô)haloalkyl, -(C3-C₇)halocarbocycle, -NRaSOjNRcRd,

ΙΟ

-NR_aS02Û(C3-C7)carbocycle, -NRaSOiOaryl, -(C2-C6)alkenyl-(Cî-C7)carbocycle, -(C₂-C6)alkenyl-aryl, -(C2-C6)alkenyl-heteroaryl, -(C₂-C(,)alkenyl-heterocyde, -(C2-C6)alkynyl-(C3-C7)carbocycle_f -(C2-C₆)alkyny]-aryl, -(C2-C6)alkynyl-heteroaryl -(C2-C₆)alkynyl-heterocycle, -(Cs-Cvjcarbocycle-Z¹ and -halo(Ci-Cfi)aIkyl-Z³, wherein any (C]-C₆)alkyl, (Ci-Cyhaloalkyl, (C3-C₇)carbocycle, (C3-C7)halocarbocycle, (C2-C6)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fiised-bicyclic carbocycle and bridgedbicyclic carbocycle, wherein any spiro-bîcyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they aie attached optionally form a (C3-C7)carbocycle or heterocycle wherein the (C3C₇)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

c) (Cf-C^jalkyl, wherein (Ci-C^Jalkyl is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z² groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

d) -X(C]-C₆)alkyl, -X(C_rC₆)haloalkyl, -X(C₂-C₆)alkenyl, -X(C2-Cfi)alkynyl and -X(C3-C7)carbocycle, wherein any -X(Ci-C6)alkyl and-X(C!Câ)haloalkyl, is substituted with one or more (e.g. 1,2,3,4 or 5) Z³ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, and wherein any -X(C2-Ce)alkenyl, -X(C₂-C6)alkynyl and -X(C3-C7)caibocycle, is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g.

1,2, 3, 4 or 5) Z^f groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1,2,3,4 or 5) Z^s groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

f) (C]-C₆)haloalkyl, (C3-C₇)carbocycle, (C2-C₆)alkenyl, and (C₂-C6)aikynyl, wherein (Ci-C^jhaloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C₂-Cfi)alkynyl are each substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups; and

g) -NReRf, -C(O)NKRf, -0C(O)NReRf, -SO₂NR<Rf, -(Ci-C^alkyl-NRJif. -(C,-C₆)alkyIC(O)-NR_<R_f, -(Cj-Qûalkyl-O-CiOJ-NR^Rf and -(Cj-Ceialkyl-SOzNR^f, wherein any (C|-C6)alkyl, as part of a group is optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

R²* is selected from:

a) H, (CpCgjalkyl and -OiCc-Cyalkyl;

b) (C2-C₆)alkenyl, (C2-C₆)alkynyl, (Ci-C₆)haloalkyl, (Cj-C₇)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;

c) -C(-O)-R”, -C(=O)-O-Rⁿ, -S-R¹¹, -S(O)-Rⁿ, -SO2-Rⁿ, -(CpC^alkyl-R¹¹, -(Ci-C6)alkyl-C(=O)-R, -(C_rC_fi)alkyl-C(=O)-O-R^,1I -(Ci-C6)alkylO-R¹¹,(CrCOalkyl-S-R¹¹, -(C,-C6)alkyl-S(O)-R¹¹ and -(Ci-Ceialkyl-SCh-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-C6)alkyl, (CT-Cfijalkenyl, (C2Côjalkynyl, (Cj-CeJhaloalkyl, (Cj-CvJcycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups;

d) -OH, -O(C2~C₆)alkenyl, -O(C₂-C₆)alkynyl, -O(Ci-C₆)haloalkyl, -O(C₃C₇)cycloalkyl, -Oaryl, -Oheterocycle and -Oheteroaryl; and

e) -N(R⁹)R¹⁰, -C(-O)-N(R⁹)R^iû, -O-C(=O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R¹⁰, -(Cr qjalkyl-NiR^R¹⁰, -(CrC6)alky!-C(<))-N(R⁹)R^l(), -(Ci-C6)alkyl-O-Cf O)-N(R⁹)R'°, and -(C]-C6)alkyl-SO2-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Ci-Ce)alkyl and (C3-C7)cycloalkyl, and each R¹⁰is independently selected from R¹¹, -(Ci-C6)alkyl-R”, -SO2-R¹¹, -C(=O)-Rⁿ,-C(=O)OR¹¹ and -C(=O)N(R⁹)Rⁿ, wherein each R¹¹ is independently selected from H, (Ci-Cfijalkyl, (C2-C6)alkenyl, (C₂C6)alkynyl, (Ci-C₆)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

R^2b is selected from:

a) -(C₁-C6)alkyi-O-(C₁-C6)alkyl-(C3-C₇)carbocycle,-(C₁-C₆)alkyl-S-(CiCe)alkyl-(C3-C7)carbocycle, -(C]-C6)alkyl-S(O)-(C]-C6)alkyl-(C3-C₇)carbocycle, -(CiC₆)alkyl-SO2-(C]-C₆)alkyl-(C3-C₇)carbccyc'ie, -(C2-C6)alkenyl-(Ci-C6)haloalkyl, -(C2CfiJalkynyHCi-C^haloalkyl, -(CrCejalkyl-SOz-iCrCeJalkyl-Z¹³,-C(O)-(Ci-C6)alkylZ¹³, -O-(Ci-C6)alkyI-Z¹³, -S-(Ci-C6)aIkyl-Z¹³, -S(O)-(Ci-C6)alkyl-Z¹³, -SO2-(Cr C6)alkyl-Z¹³, -(Cj-C^alkyl-Z¹⁴, -(Ci-CÉjalkyl-CiOXCi-Cfijalkyl-Z¹³, -(Ci-C6)alkylC(O)-O(Ci-C₆)alkyl-Z¹³, -(Cl-Cf,)alkyl-O-(CrC6)alky]-Z^!-(Ci-C6)alkyI-S-(CiC₆)alkyl-Z¹³, -(CrCjjhalocarbocycic.-NRaSOjNRcRj, -NRaSO2O(C3-C₇)carbocycIe₅ 16293

NR_lSO₂Oaryl, -(C₂-C6)alkenyl-(C3-C7)carbocycle, -(C₂-C₆)alkenyi-aryl, -(C₂-C_b)alkenyl-heteroaryl, -(C₂-C_b)alkenyl-heterocycle, -(C₂-C_b)alkynyl(Ü3-C₇)carbocycle, -(C₂-C_b)alkynyl-aryl, -(C2-C6)alkynyI-heteroaryl, -(C₂-C₆)alkynylheterocycle, -(Cs-Cyjcarbocycle-Z¹ and -halo(C]~C6)alkyl-Z³, wherein any (Ci-Ce)alkyl, -(Ci-Cgjhaloalkyl, (C3-C₇)carbocycle, (C3-C₇)halocarbocycle, (C₂C₆)aikenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups, wherein two Z* groups together with the atom or atoms to which they are attached optionally form a (C3-C₇)carbocycle or heterocycle, wherein the (C3-C₇)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (Cj-Cèjalkyl, wherein (Cj-CeJalkyl is substituted with one or more (e.g.

1,2, 3,4 or 5) Z² groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(Ci-C₆)alkyl, X(C_rC₆)haloalkyl, X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C3-C₇)carbocycle, wherein any -X(Ci~Cg)alkyl and -X(Ci-C6)haloalkyl, is substituted with one or more (e.g. 1, 2,3,4 or 5) Z³ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, and wherein any -X(C₂-C₆)alkenyl, -X(C₂-C_b)alkynyl and -X(Cj-C₇)carbocycle is substituted with one or more (e.g. 1,2,3, 4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹groups;

e) aryl, heteroaryl, heterocycle, -Xaiyl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, îs substituted with onc or more (e.g. I, 2,3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

f) (Ci-Cfijhaloalkyl, (C3-C₇)carbocycle, (C₂-C_b)alkenyl, and (Cî-C_b)alkynyl, wherein (Ci-Cé)haloalkyl, (C3-C₇)carbocycle, (C₂-C_b)alkenyl and (C'2-C₆)alkynyl are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, and

g) -NReRf, -C(O)NR;Rf, -0C(O)NKRf, -SO₂NR<Rf, -(Ci-C₆)alkyl-NR_eRf, -(Cj-CejalkylCiOJ-NRcRf, -(Ci-C₆)alkyl-O-C(O>NR_eR_f and -(C₁-C₆)alkyl-SO₂NR_eR_f, wherein any (Ci-Céjalkyl, as part of a group is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

R³ is (Cj-Céialkyl, (Ci-Côjhaloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(Ci-C6)alkyl-(C3-C7)cyc]oalkyL -(Ci-C6)alkybaryl, -(Ci-C6)alkyl-heterocycIe, -(C]-C6)alkyl-heteroarylf -O(C]-C6)alky], -0(C]-C6)haloalkyl, -O(C2-C6)alkenyl, -O(C2-C«)alkynyl, -O(C3-C7)cycloajkyl, -Oaryl, -0(C]-C6)alkyl-(C3-C7)cycloalkyl, -O(C[-C(,)alkyl-aryl, -O(Cj-C6)alkyl-heterocycle or -O(Ci-C6)alkyl-heteroaryl, wherein any (Ci-Csjalkyi, (CrC6)haioalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl of R³¹ either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2 or 3) groups selected from -OfCi-CeJalkyl, halo, oxo and -CN, and wherein any (C3-C7)cycloalkyl, aryl, heterocycle or heteroaryl of R^3a either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2 or 3) groups selected from (C]-C₆)alkyl, -O(Cj-Cô)alkyl, halo, oxo and -CN; and R^3a is H’

R^3b is -(CrCiOalkyl, -(C3-C7)cafbocycle, aryl, heteroaryl, heterocycle, -(Ci-C6)alkylOH, -(CrCfiJalkyl-O-fCj-Cejalkyl-Z¹², -(Ci-C6)alkyl-Ü-(C₂Côjalkenyl-Z¹², -(Ci-C6)alkyl-O-(C2-C6)alkynyl-Z¹², -(C]-C₆)alkyl-S-(C₁-C₆)alkyl-Z¹², -(Ci-Cs)alkyI-S-(C2-C6)alkenyl-Z¹², -(C1-C₆)alkyl-S-(C₂-C₆)alkynyl-Z’², -(Ci-C6)alkyiSiOXCrCejalkyl-Z¹², -(C,-C6)alkyl-S(O)<C₂-C₆)alkenyl-Z¹², -(Ci-C6)aIkyl-S(OXC2C6)alkynyl-Z¹², -(CrCeJalkyl-SOa-ÎCi-CfiJalkyl-Z¹², -(Ci-C6)alkyl-SO₂-(C₂C₆)alkenyl-Z¹², -(CrCeJalkyl-SOz-iCj-CeJalkynyl-Z¹², -(CrCeJalkyl-NR^, -(Ci-C6)alkyl0C(O)-NRcR<f, -(C_rC₆)alkyl-NR_a-C(O)-OR_b, -(Ci-C₆)alkyl-NRa-C(O)-NR_aRb, -(C₁-C₆)alkyl-SO₂(C₁-C₆)alkyI, -(Ci-C₆)alkylSChNRJld, -(C₁-C₆)alkyl-NR_flSO₂NR_cK_i, -(C_rC6)alkyl-NR_aSO₂O(C3-C₇)carbocycle, -(Ci-C^alkyl-NRaSChOaryl, -(C₁-C₆)alkyI-NR_a-SO₂-(C₁-C₆)alkyl, -(Ci-Csjaïkyl-NRa-SOa-halofCrCeJalkyl, -(C₁-C₆)alkyl-NR_a-SO₂-(C2-C₆)alkenyl_l-(Ci -C_É)alkyl-NRa-SO₂-(C₂-C₆)alkynyl, -(C i -C₆)alkyl-NRa-SO₂-(C3-C₇)carbocycle, -(Ci -C6)alkyl-NRa-SO₂-halo(C3-C₇)carbocycle, -(Ci-C₆)alkyl-NR_a~SO₂-aryl, -(C i -C6)alkyl-NRa-SO₂-heteroaiy], -(C j -C^alkyl-NRrSCh-heterocycle, -O(C₇Ci₄)alkyl, -O(C,-C₆)alkyl-NR_aR_b, -O(C|-C₆)alkylOC(O) NR_<R₍₁, O(C |-C₆) alkyl-NR_aC(O)-ORb, -O(C)-C6)alkyl-NRa-C(O)-NRaRï>, -O(Ci-C₆)alkyl-NR^-SOî-fCrCÉÏalkyl, -O(C₁-C₆)alkyl-NR_a-SO₂-halo(C₁-C₆)alkyl,-O(C_rC₆)alkyl -NR,-SO₂-((’₂-C₆)alkenyl.

-O(C i -C6)alkyl-NRa-SO2-(C2-C6)alkynyl, -O(C i -C_f,)alkyl-NR_J-SO₂-(C3-C7)carbocycle, -O(Cj-C6)alkyl-NI^-SO2-halo(C3-C7)carbocycle,-O(CrC6)alkyl-NR.-SO2aryl, -OfCj-Cèjalkyl-NRg-SCh-hcteroaryl, -0(Ci-C6)alkyl-NRa-S02-heterocycle, -OtCi-Céialkyl-NRa-SOj-NR^Ri,, -0(C]-C6)alkyl-NR»-SO2-(C3-C₇)carbocycle, -O(Ci-C6)alkyl“NR_a-SO2-halo(C3-C7)carbocycle, -O(Ci-C6)dkyi-NRa-SO₂-aryl, -O(Cr CéJalkyl-NR.SChNRcRd, -O(Ci-C₆)aikyl-NR_aSO2O(C3-C₇)caibocycle, -O(C]-C(;)alkylNRaSOiOaryl, -Oheteroaryl, -Oheterocycle, -Sheteroaryl, -Sheterocycle, -S(O)heteroaryI, -S(O)heterocycle, -SOjheteroaryl or -SCLheterocycle, wherein any (Ci-Céjalkyl, -(C₇-Ci4)alkyl, aryl, (C3-C₇)carbocycle, heteroaryl or heterocycle of R^3b, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups, and R^3b is H, (Ci-C6)alkyl or -O(Ci-C6)alkyl; or R^3b and R^3btogether with the carbon to which they are attached form a heterocycle or (C3-C7)caibocycle which heterocycle or (C₃-C₇)carbocycle of R^3b and R^3b together with the carbon to which they are attached is optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

R⁴⁸ is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R^4a is optionally substituted with one or more (e.g. 1,2,3,4 or 5) groups each independently selected from halo, (CrC6)aIkyl, (C2-C6)alkenyl, (C]-C₆)haloalkyl, (C3C₇)cycloalkyl, -OH, -O(C]-C6)alkyl, -SH, -S(C_t-C₆)a]kyl, -NH₂, -NHiCi-C^alkyl and N((Ci-Câ)alkyl)2, wherein (C|-C₆)aîkyl is optionally substituted with hydroxy, -O(C| C6)alkyl, cyano or oxo;

R^4b is selected from;

a) (Ci-Ce)alkyl, (C2-Cé)alkenyl and (Cj-Cfijalkynyl, wherein (Cj-Csjalkyl, (C2-Ce)alkenyl and (C2-Cfi)alkynyl are each optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) (C3-C njcarbocycle, wherein (C3-Ci₄)carbocycle is optionally substituted with one or more (e.g. i, 2,3,4 or 5) Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃C₇)carbocycle or heterocycle;

c) spiro-heterocycle and bridged-heterocycle, wherein spiro-heterocycle and bridged-heterocycle are optionally substituted with one or more (e.g, 1, 2, 3,4 or 5) Z¹ groups, or wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle; and

d) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedheterocycie, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedhcterocycle heterocycle are each independently substituted with one or more (e.g. 1,2,

3,4 or 5) Z⁷ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹groups; or

R⁴ and R³ together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle wherein any macroheterocycle or macrocarbocycle of R and R together with the atoms to which they are attached may be optionally substituted with one or more (e.g. 1, 2,3,4 or 5) Z¹ groups; and R³ is H, (Cq-Côjalkyl or -OfCrC^alkyl;

R⁵* is selected from:

a) halo, nitro and cyano;

b) R”, -C(=O)-Rⁿ, -C(=O)-O-Rⁿ, -O-R¹¹, -S-R¹¹, -S(O)-Rⁿ, -SO2-Rⁿ, -(Ci-Cejalkyl-R¹¹, -(CrCfijalkyl-CÎ^Oj-R¹¹, -(CrC^alkyl-CZOj-O-R^{1 [}, -(C]-C6)alkylO-R¹¹, -(Ci-Ce)alkyl-S-R¹¹, -(CrC6)alkyl-S(O)-Rⁿ and -(C1-C₆)alkyl-SO₂-R^H, wherein each R¹¹ is independently selected from H, (C|-Cf,)alkyl, (Cî-Cfijaikenyl, (C₂C^alkynyi, (Ci-C₆)haloalkyl, (Cj-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups; and

c) -N(R⁹)R¹⁰, -C(=O)-N(R⁹)R¹⁰, -O C(-0)-N(R⁹)R¹⁰, -SO2-N(R⁹)R¹⁰, -(Cr C6)alkyI-N(R⁹)R¹⁰, -(C|-C6)alkyl-C(O)-N(R⁹)R¹⁰, -(Cj-Ceïalkyl-O-CiOJ-N^jR¹⁰, and -(Ci-C6)aIkyI-SO2-N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (CrCfi)alkyl and (C3-C7)cycloalkyl, and each R^iOis independently selected from R¹¹, -(Ci-C6)alkyl-Rⁿ, -SO2-R¹¹, -C(=O)-Rⁿ, -C( O)OR^U and -C(=O)N(R⁹)Rⁿ, wherein each R^u is independently selected from H, (Ci-Céjalkyl, (Cî-Csjalkenyl, (C2C₆)alkynyl, (Ci-C₆)haloalkyl, (C’3-C7)cycloaikyl, aryl, heterocycle and heteroaryl;

R^îb is selected from:

a) -(Ci-C6)alkyl-O-(C t -C6)alkyl-(C3-C7)carbocycle,

-(C i-C6)alkyl-S-(Ci -C₆)alkyI-(C3-C₇)carbocycle,

-(C i-Cfi)alkylS(O)-(C i-C6)alkyl-(C3-C7)carbocycle, • (C ! -C₆)aIkylSO₂(C t -Cfijalkyl^Cî-Cvjcarbocycle, (C₂-C₆)alkenyl-(C i-Cejhaloalkyl,

-(C₂-C6)alkynyI-(Ci-C6)haIoalkyl, -(C3-C7)halocarbocycle, -NRaSChNRcRd,

-NRaS020(C3-C₇)carbocycle, -NR_dSO_?Oaryl, -(C2-C6)alkenyl-(C₃-C7)carbocycle,

-(CrC^lalkenyl-aryl, -(C₂-C₆)alkenyl-heteroaryl, -(C₂-C₆)alkenyl-heterocycle, -(C₂-C6)alkyny]-(C3-C7)carbocycle, -(C₂-C₆)alkynyl-aryl, -(C₂-C₆)alkynyl-heteroaryI, -(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z’ and -halo(Ci-C₆)alkyl-Z^s,wherein any (Cj-Célalkyl, (Ci-Cfi)haioalkyl, (C₃-C7)carbocycle, (C₃-C7)halocarbocycle, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more(e.g. 1,2,3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C7)carbocycle or heterocycle wherein the (C₃C?)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

c) (Ci-C&)alkyl, wherein (Ci-Ce)alkyl is substituted with one or more (e.g.

d) -X(Ci-C6)alkyl,-X(Ci-C6)haloalkyl, -X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C7>carbocycle, wherein any -X(Ci-C6)alkyl and-X(Ci-C6)haloalkyl, is substituted with one or more Z groups and optionally substituted with one or more Z groups, and wherein any -X(Cï-C6)alkenyl, -X(C2-C6)alkynyl and -X(C₃-C7)carbocycle is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1,2, 3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

f) (Cj-CeJhaloalkyl, (C₃-C7)carbocycle, (C2-Cô)alkenyl, and (C₂-C6)alkynyl, where (Cj-CeJhaloalkyl, (C₃-C7)carbocycle, (C2-C6)alkenyl and (C2-C₆)alkynyl are cach independently substituted with one or more (e.g. 1, 2, 3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1, 2,3,4 or 5) Z¹ groups; and

g) -NReRf, -C(O)NR_€R_f, -OC(O)NR_eR_t, -SO.NR^Rf, -(Ci-Qlalkyl-.NR^Rf, -(Ci-C6)alkyIC(O)-NRcRf, -(Cj-C₆)alkyl-O-C(O)-NReR_f and -(Ci-C₆)alkyl-SO₂NR_cR_f.

wherein any (Ct-Csjalkyl, as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z* groups;

R⁶* is selected from:

a) H, halo, (C ]-Cé)alkyl and (C ] -C^haloalkyl

b) (C2-C6)alkenyl, (C2-Ce)alkynyl, (C3-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(-O)-R*^l, -C'(O)-O-R^il, -O-R¹ -S-R¹¹, -S(O)-R’ *, -SO2-Rⁿ, -(Ci-Csjalkyl-R¹¹, -(Ci-Cg^Ikyl-CC^R¹¹, -(CrCélalkyl-C^Oj-O-R¹¹, -(Ci-Cfc)alkylO-R¹¹, <CrC6)aLkyl-S-R, -(Ci-C6)alkyl-S(O)-Rⁿ and -(C]-C₆)alkyl-SO₂-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Cfi)alkyl, (C2-Cô)alkenyl, (C2<_'f,)alkynyl, (Cj-Csjhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R¹⁰, -C(O)-N(R⁹)R^!û, -O-C(“O)-N(R⁹)R¹⁰, -SOz-NfR^R¹⁰, -(Ci-Cgjalkyl-NfR^R¹⁰,-(C]-C6)alkyl-C(-O)-N(R⁹)R^lt),-(Ci-C6)aIkyl-O-C(^;O)N(R⁹)Rⁱ⁰ and -(Cj-C6)alkyl-SO2-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Ci-C6)allcyl and (C3-C7)cycloalkyl, and each R¹⁰ is independently selected from R^ll,-(CrC6)alkyl-Rⁿ, -SO2-R¹', -C(=O)-Rⁿ, -C(=O)ORⁿ and -C(=O)N(R⁹)Rⁿ, wherein each R¹¹ is independently selected from H, (Ci-Cejalkyl, (C2-C6)alkenyl, (C2Cfi)alkynyl, (Ct-Cs)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;

and wherein any aryl, heterocycle and heteroaryl of R^6ais optionally substituted with one or more (e.g. 1,2 or 3) Z¹⁰ groups;

R⁶⁶ is selected from:

a) -(C₁-C₆)aIkyl-O-(C_l-C₆)alkyl-(C₃-C₇)carbocycle,-(C_rC₆)alkyl-S-(CiC₆)alkyl-(C3-C₇)carbocycle, -(C i -C6)alkyl-S(O)-(C i -C^alkyl-^-CvjcarbocycIe, -(C 1 C<.)alkyl-SO2-(Ci -Cfi)alkyl-(C₃-C₇)carbocyc]e, -(C->-C6)alkenyl-(C 1 -C^jhaloalkyl, -(C2C6)alkynyl-(Ci-C₆)haloaIkyl, -halo(C₃-C7)carbocycle,-NR_aSO₂NRcR<i, -NRaSO₂0(C3C₇)carbocycle, -NR_aSO2Oaryl, -(C2-C(î)alkeny]-(C3-C₇)carbocycle, -(C₂-Cf;)alkenylaryl, -(C2-C6)alkenyl-heteroaryl, (C2-C6)alkenyl-heterocycle, -(C2-C6)alkynyl-(C3-C7)carbocycle, -(Cî-Cgjalkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C₆)alkynyl-heterocycle, -(Cz-Cgjalkynyl-ORa, -(C2-C6)alkyl-(C₃-C₇)carbocycle-ORa, “(C3-C₇)carbocycle-Z¹ and -halo(Ci-C6)alkyl-Z³, wherein any (C]-C$)alkyl, (Ci-Céjhaloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbîcyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z^l groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C^-Cijcycloalkyl or heterocycle, wherein the (C3C₇)cycloalkyl or heterocycle is optionally substituted with one or more (e.g. 1,2, 3,4 or

5) Z¹ groups;

c) (Ci-Ce)alkyl, wherein (CT-C₆)alkyl is substituted with one or more (e.g.

1,2,3,4 or 5) Z² groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(Ci-C₆)alkyl, -X(Ci-C₆)haloalkyI, -X(C₂-C₆)alkenyl_f-X(C2-Ce)alkynyI and -X(C3-C₇)carbocycle, wherein any -XfCi-Cejalkyl and-X(CiCijhaloalkyl, is substituted with one or more (e.g. 1,2,3,4 or 5) Z³ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups, and wherein any -XfCî-Cftjalkenyl, -X(C₂-C6)alkynyl and -X(C3-C₇)carbocycle, are each independently substituted with one or more (e.g. 1,2, 3,4 or 5) groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1, 2, 3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z* groups;

f) (C]-C₆)haloalkyl, (C3-C₇)carbocycle, (Cî-C^alkenyl, and (C₂-C6)alkynyl, wherein (C]-C6)haloalkyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl and (C2-Cfi)alkynyl are each independently substituted with one or more (e.g. 1, 2, 3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z^! groups; and

g) -NKR_f, -QOjNR^Rf, -OC(O)NR_tR_f, -SO₂NR_<R_î, -(C_rC₆)alkyl-NR_eR_f. -(CrCejalkylCiOj-NReRf, -(C₁-C₆)alkyl-O-C(O)-NR_tR_f and -(Ci-C₆)alkyl-SO₂NR_cR_f, wherein any (Ci-C₆)alkyl, as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

R^7a is selected from:

a) H, halo, (Ci-C^jalkyl and (Ci-Cs)haloalkyl;

b) (Cî-Céjalkenyl, (C₂-C6)alkynyl, (Cj^Jcycloalkyl. nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O>R^h, -C(=O)-O-Rⁿ, -O-Rⁿ, -S-R, -SO-R^1l, -SOz-R”, -(Ci-C6)alkyl-R^H, -(CrC6)aIkyl-C(=O)-R¹¹, -(Cj-C6)alkyl-C(=O>O-R¹¹, -(C]-C6)alkylO-R¹¹, -(CrC6)alkyI-S-R^1J, -(CrC₆)alkyl-S(O)-R^!1 and -(Ci-Cb)alky]-SO2-R^1!, wherein each R¹¹ is independently selected from H, (Ci-Cejalkyl, (C2-C_b)alkenyl, (C₂Céjalkynyl, (Ci-Csjhaloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R’)R'°, -C(=O)-N(R⁹)R¹⁰, -0-C(=O>N(R*)R^m, -SCb-NCR^R¹⁰, -(CrC6)alkyl-N(R⁹)R¹⁰, -(Ci-C6)alkyl-C(=O)-N(R⁹)R¹⁰, -(CrC6)aIkyl-O-C(=O)NfR’jR¹⁰ and -(Ci-C6)alkyl-SO2-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Ci-Cfi)alkyl and (Cs-Cvjcycloalkyl, and each R¹⁰ is independently selected from RX-CCj-Cijalkyl-R, -SO2-R^H, -C(=O)-Rⁿ, -C(=O)OR^U and -C(-O)N(R⁹)R, wherein each R¹¹ is independently selected from H, (Cj-C6)alkyl, (C₂-C6)alkenyl, (C₂C_b)alkynyl, (C]-C_b)haloalkyl, (Cj-Cîjcycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle and heteroaryl of R⁷¹ is optionally substituted with one or more (e.g. 1,2 or 3) Z¹⁰ groups;

R⁷¹* is selected from:

a) -(CrCeïalkyl-SOi-tCrCejalkyl-Z¹³, -C(O)-(CrC6)alkyl-Z¹³, -O-(Cr C₆)alkyl-Z¹³, -S^CrCfiJalkyl-Z¹³, -S(O)-(Ci-C6)alkyl-Z¹³, -SCMQ-Céjalkyl-Z¹-(Cl-C6)alkyl-Z^u, -(C)-C6)alkyl-C(O)-(C_rC₆)alkyl-Z¹³, -(CrC6)alkyl-C(O)-O(Cr C6)alkyl-Z^i;\ -(Ci-CsJalkyl-O-tCrCejalkyl-Z¹³, -(CrC6)alkyd-S-(Ci-C₆)dkyl-Z¹³, -(CiCôJalkyl-O-tCj-CéJalkyl-tCa-Cvicarbocycle^tCrCfijalkyl-S-tCr C6)alkyl-(Cî-C7)carbocyclc, -(Ci-C6)aIkyI-S(O)-(C t -C6)alkyI-(C3-C7)carbocycle, -(CiC6)alkyl-SO2-(CrCb)alkyf(CrC7)carbocycle, -(C2-C(;)alkcnyi-(C|-Cb)haloalkyL -(C2Cejalkynyl-CCi-Côjhaloalkyl, -(Cj-C^jhalocarbocyclc, -NRaSOjNRçRd, -NRaSO2O(C3C7)carbocycle, -NRiSO2Oaryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-Cû)alkenylaryl, -(C2~Cb)alkenyl-heteroaryl, -(C2-Ce)alkenyl-heterocycle, -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(Cj-Czjcarbocyclc-Z¹ and -halo(Ci-C6)alkyl-Z³ , wherein any (Ci-Csjalkyl, (C]-C_b)haloalkyi, (Cj-C₇)carbocycle, (C3-C₇)halocarbocycle, (C₂-C6)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more(e.g. 1, 2, 3,4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle, wherein any spîro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C3-C7)cafbocyclc or heterocycle wherein the (Cj-C7)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (Ci-Cgjalkyl, wherein (Ci-Cgjalkyl is substituted with one or more (e.g.

d) -X(C_rC6)alkyl, X(Ci-C_s)haloalkyl, X(C_rC_s)alkenyl, -X(C₂-C₆)alkynyl and -X(C3-C?)carbocycIe, wherein any -X(C)-Cf,)alkyl and-X(Cj-C6)haloalkyl, is substituted with one or more (e.g. 1,2,3,4 or 5) Z³ groups and optionally substituted with one or more (e.g. I, 2,3,4 or 5) Z¹ groups, and wherein any -X(C₂-Cs)aIkenyl, -X(C₂-Ce)alkynyl and -X(C₃-C7)carbocycle is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1, 2,3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

f) (CrCgjhaloalkyl, (C3-C7)carbocycle, (C₂-Cfi)alkenyl and (C₂-Ce)alkynyl, wherein (Ci-Cgjhaloalkyl, (C₃-C7)carbocycle, (C₂-C6)alkenyl and (C₂-C6)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -NR«Rf, -C(O)NReRf, -OC(O)NR<Rf, -SO₂NR_€Rf, -(C_rC_fi)alkyl-NR_çR_f, -(CrC₆)alkyIC(O)-NReR_f, -(C|-C₆)alkyl-()-C(O)-NR_cRf and -(Ci-Ojalkyl-SChNRJtf. wherein any (Cj-Cejalkyl, as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

R^8s is selected from:

a) halo, nitro and cyano;

b) R¹¹, -C(-O)-R, -C(=O)-O-R^h, -OR¹¹, -S-R¹¹, -S(O)-Rⁿ, -SO2-Rⁿ, -(Cj-C^alkyl-R¹¹, -(CrCftlalkyl-Cf OI-R¹', -(CrC^alkyl-CC^ij-O-R¹¹, -(Cj-C6)alkyl16293

O-Rⁿ, -(Ci-Céfalkyl-S-R¹¹, -tCi<6)alkyl-S(O)-Rⁿ and -(Ci-Céialkyl-SOrR¹¹, wherein each R^li is independently selected from H, (Ci-Ce)alkyl, (C2-C6)alkenyl, (C₂Cejalkynyl, (Ci-C^haloalkyl, (C3-C?)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1,2 or 3) Z¹¹ groups;

c) -N(R⁹)R¹⁰, -C(O)-N(R⁹)R^IC, -o-c^co-ncr^r*⁰, -so2-n(r⁹)r'⁰, -(CiC6)alkyl-N(R⁹)R¹⁰J -(C]-C₆)dkyl-C(=O)-N(R⁹)R¹⁰, -(CrC6)alkyl-O-C(=O)-N(R⁹)R¹⁰and -(Ci-C6)alkyl-SO2-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Ci-Cô)alkyl and (C3-C₇)cycloalkyl, and each R¹⁰is independently selected from R¹¹, -(Ci-Cejalkyl-R¹¹, -SCh-R¹¹, -C(=O)-R, -C(=O)0Rⁿ and -C(=O)N(R⁹)Rⁿ, wherein each R¹¹ is independently selected from H, (Cj-Csjalkyl, (C₂-C6)alkenyl, (C2Cejalkynyl, (Ci-Cbfhaloalkyl, (C3-C₇)cycioalkyl, aryl, heterocycle and heteroaryl;

R^Bb is selected from:

a) -(C_rC₆)alkyI-SOr(C]-C_fi)alkyI-Zⁱ³, -C(O)-(C)-C6)aIkyl-Z¹³, -O-fC,Cfijalkyl-Z¹³, -S-fCrQlalkyl-Z¹³, -S(O)-(CrC₆)alkyl-Z¹³, -SO^Cj-Côjalkyl-Z¹³, -(Ci-Cejalkyl-Z¹⁴,-(Ci-C6)alkyl-C(O)-(CrC6)alkyl-Z¹³, -(Cj-C6)alkyl-C(O)-O(C_rC₆)alkyl-Z¹³, -(CpCsjalkyl-O-CCrCejalkyl-Z¹³, -(CrC^alkyl-S-fCi-C^alkyl-Z¹³, -(CiC6)alkyI-O-(Ci-C₆)aIkyI-(C₃-C₇)carbocycle, -(Ci-C₆)alkyl-S-(C_r

C₆)alkyl -(C₃-C₇)carbocycle, -(C i-C6)alkyl-S(O)-(Cj -C6)alkyI-(C₃-C₇)carbocycle, -(C i Cejalkyl-SOi-fCi -C₆)alkyl-(C₃-C₇)carbocycle, -(C₂-C6)alkenyl-(Ci-C6)haloaIkyl, -(C₂Ce)alkynyl-(Ci-C6)haloalkyl, -halo(C₃-C₇)carbocycle,-NRaS02NIt_<Rd_I NR_aS020(C₃-C₇)carbocycle, -NRaSO₂Oaryl, -(C₂-C6)alkenyl-(C3-C₇)carbocycle, -(C₂-C6)alkenyl-aryl, -(C₂-C6)alkenyl-heteroaryl, -(C₂-C6)alkenyl-heterocycIe, (C₂-C6)alkynyl-(C3-C₇)carbocycle, -(C₂-C6)alkynyl-aryl, -(C₂-C&)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C₃-C₇)carbocycle-Z¹ and -halo(C]-C6)alkyl-Z³, wherein any (Ci-Cjfalkyl, (Ci-C₆)haioalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups:

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclîc carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bîcyclic carbocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle wherein the

C

ΙΟ (C3-C?)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (Cj-CfiJalkyl, wherein (Ci-C$)alkyl is substituted with one or more (e.g.

1, 2,3,4 or 5) Z² groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(Ci-C₆)alkyI, -X(C]-C₆)haloalky], -X(C₂-C₆)alkenyl, -X(C2-Ci)alkynyI and -X(C3-C7)carbocycle, wherein any -X(Cj-Cô)alkyl and-X(Cr Cé)haloalkyl, is substituted with one or more (e.g. 1,2, 3, 4 or 5) Z³ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, and wherein any -X(C₂-Cfi)alkenyl, -X(C₂-Cô)alkynyl and -X(C3~C7)carbocycle is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1,

2,3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

f) (Ci-C6)haloalkyl, (Cj-C^carbocycle, (C₂-Cè)alkenyl and (C₂-C6)alkynyl, wherein (Cj-CeJhaloalkyl, (C₃-C7)carbocycle, (C₂-Ce)alkenyl and (C₂-C₆)alkynyl are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -NRcRfe -CiOJNRcRf, -0C(O)NRcR_r, -SOiNR^Rf, -(Ci-C₆)aIkyl-NR_eR_f, -(Ci-C6)alkylC(O)-NReRf, -(Ci-C^alkyl-O-C/OJ-NJ^Rf and -(Ci-C₆)alkyl-SO₂NR_cR_r, wherein any (Ci-Cfi)alkyl,, as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

or any of R^Sa and R⁶³, R^6a and R^7a, R^7a and R^8a, R¹ and R⁸ or R¹ and R² together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or a 4,5,6 or

7-membered heterocycle is optionally substituted with one or more (e.g. 1, 2 or 3) substituents each independently selected from halo, (Ci-C^alky), (C₂-C₆)alkenyl, (C_rC^haloalkyl, (C₃-C₇)cycloalkyl, -OH, -O(C₁-C₆)alkyl, -SH, -S(Ci-C₆)alkyl, -NH₂, -NH(Ci-C₆)alkyl and -NKCrC^alkylb;

or any of R^s and R⁶, R⁶ and R⁷ or R⁷ and R⁸, together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered

heterocycle, wherein the 5 or 6-membered carbocycle or a 4, 5,6 or 7-membered heterocycle are each independently substituted with one or more (e.g. 1,2 or 3) Z⁷ or Z⁸groups, wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionally form a (C₃-C₇)carbocycle or 4,5 or 6membered heterocycle;

St I or R and R or R and R together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4,5,6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle are each independently substituted with one or more (e.g. 1,2 or 3) Z⁷ or Z⁸ groups; wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionally form a (C₃-C₇)carbocycle or 4,5 or 6-membered heterocycle;

X is independently selected from O, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -(CjC₆)alkylO-, -(CrCfûalkylQO)-, -(C:₁-C₆)alkylC(O)O-, -(C_rC₆)alkyIS-, (CiC₆)alkylS(O)- and -(Cj-C₆)alkylSO₂-;

each Z¹ is independently selected from halo, -NO₂, -OH, =NOR_a, -SH, -CN, (C_rC₆)alkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (Cj-Cgjhaloalkyl, (C₃-C₇)carbocycle, (C₃C₇)halocaibocycle, aryl, heteroaryl, heterocycle, -O(Ci-C6)alkyl, -O(C₂-C6)alkenyl, -O(C2-Cft)alkynyl, -O(Cj-C&)haloaikyl, -0(C₃-C7)carbocycle, -0(C₃-C7)halocarbocycle, Oaryl, -Oheteroaryl, -Oheterocycle, -S(C]-C6)alkyl, -S(C₂-C₆)alkenyl, -S(C₂Csjalkynyl, -S(Ci-C₆)haloalkyI, -S(C3-C₇)carbocyclc, -S(C₃-C₇)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle, -S(O)(Ci-C6)alkyl, -S(O)(C₂-C6)alkenyl, -S(O)(C₂C₆)aïkynyl, -S(O)(Ci-C₆)haIoalkyl, -S(O) (C₃-C₇)carbocycle, -S(O)(C₃C7)halocarbocycle, -SO2(C_rC₆)alkyl, -S(O)aryl, -S(O)carbocycIe, -S(O)heteroaryl, -S(0)heterocycle, -SO₂(C₂-C6)alkenyl, -SOî(C₂-C6)alkynyl, -S0₂(Cj-C6)haloalkyl, -SO2(C₃-C₇)carbocycIe, -SO₂(C₃-C₇)halocarbocycle, -SO₂aryl, -SO₂heteroaryl, -SO₂heterocycIe, -SO₂NRcR<i, -NR^Rd, -NR_aC(O)R_a, -NRaC(0)ORa, -NRaCtOjNRcRd -NR_sSO₂Rb, -NRaSOzNRcRd, -NR^SChOiCV^caibocycle, -NR_a8O₂Oaryl, -OS(O)₂K_a, -C(O)Ra, -C(O)ORb, -C(O)NR_cRd, and -OC(O)NR_cR<i, wherein any (Cj-C₆)alkyl, (CjCs)haloalkyl, (C₂-C6)alkenyl, (C₂-C6)alkynyl, (C₃-C₇)carbocycle, (C₃C₇)halocarbocycle, aryl, heteroaryl or heterocycle of Z¹, either alone or as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, -OH,

C

ΙΟ

-ORb, -CN, -NR_HC(O)₂Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(O)₂NRcR<j;

each Z² is independently selected from -NO₂, -CN, spiio-heterocycle, bridgeheterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, NR_aSO₂(C₃C₇)carbocycle, -NRsSO₇aryl, -NR,SO₂heteroaryl, -NR_aSO₂NR_cR_d, -NR,SO2O(C₃C₇)carbocycle and -NR,SO₂Oaryl;

each Z³ is independently selected from -NO₂, -CN, -OH, oxo, =NORa, thioxo, aryl, heterocycle, heteroaryl, (C₃-C7)halocarbocycle, -O(C|-Cs)alkyl, -O(C₃C₇)carbocycle, -Ohalo(C₃-C₇)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(CjCgjalkyl, -S(C₃-C₇)carbocycle, -S(C₃-C7)halocarbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(O)(Cj-C6)alkyl, -S(O)(C₃-C₇)carbocycle, -S(O) (C₃-C7)halocarbocycle, -S(O)aryI, -S(0)heterocycle, -S(0)heteroaiyl, -SO₂(C]-C6)alkyl, -SO2(C₃-C₇)carbocycle, -SO₂(C₃-C7)halocarbocycle, SOiaryl, -SO₂hetcrocycle, -SO₂heteroaryl, -NR_aRb, -NReC(O)Rb, -C(O)NlXRd, -SO^NR^Rd, -NRjSCbNRcRd, -NR_aSO2O(C₃-C₇)carbocycle and -NRaSO₂Oaryl;

each Z⁴ is independently selected from halogen, (Ci-C^alkyl, (C₃C₇)carbocycle, halo(Ci-C₆)alky], -NO₂, -CN, -OH, oxo, =NORa, thioxo, aryl, heterocycle, heteroaryl, (C₃-C₇)halocarbocycle, -O(Ci-C6)alkyl, -O(C₃-C₇)carbocycle, O(C₃-C7)halocarbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(C_t-C6)alkyl, -S(C₃C₇)carbocycle, -S(C₃-C₇)halocarbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(O)(Cr C₆)alkyl, -S(O)(C₃-C₇)carbocycle, -S(OXC₃-C₇)halocarbocycle, -S(O)aryl, S(O)heterocycle, -S(O)heteroaryl, -SO₂(C]-C₆)aIkyl, -SO2(C₃-C₇)carbocycle, -SO₂(C₃C₇)halocarbocycle, SO₂aryl, -SO₂heterocycle, -SO₂heteroaryl, -NR_aRb, -NR*C(O)Ra, -C(O)NR<Rd, -SO2NRJV -NR_aSO₂NR_cR_d, -NR_aS0₂0(C₃-C₇)carbocycle and NR_aSO₂Oaryl;

each Z⁵ is independently selected from -NO2, -CN, -NRaSÜ^RçRj, -NRaS0₂0(C₃-C₇)carbocycle, -NR_aS0₂0aryl, -NR_aSO₂(Ci-C₆)alkyl -NR_aSO₂(C₂C₆)alkenyl, -NRaSO2(C2-C₆)aIkynyl, -NR_ttSO₂(C₃-C₇)caTbocycle, -NRaSO₂(C₃C₇)halocarbocycle, -NR_aSO₂aryl, -NR_BS0₂hcteroaryl, -NRaS0₂heteroaryl, -NR_aSO₂heterocycle, -NRaC(O)alkyl, -NR_aC(O)alkenyl, -NR_aC(O)alkynyI, -NR_aC(O) (C₃-C₇)carbocycle, ~NR_aC(0)(C₃-C₇)halocarbocycle, -NRaC(O)aryl, -NRaC(O)heteroaryl, -NR_aC(O)heterocycle, NR_aC(O)NR_cR_<j and NR_aC(O)OR},;

C

C each Z⁶ is independently selected from -NO₂, -CN, -NR»Ra, -NR_aC(O)Rt>, -NRaC(0)ORt>, -0(0)ΝΙΜ<<ι, (C3-C₇)halocarbocycle, aryl, heteroaryl, heterocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -0(C3-C7)halocarbocycIe, -O(Cj-Cfi)aIkyl, -O(C₃C7>carbocycle, -Ohalo(Ci-C6)alkyl, -Sary), -Sheteroaryl, -Sheterocycle, -S(C₃C7)halocarbocycle, -S(Ci-C₆)alkyl, -S(C₃-C₇)carbocycle, -S(C]-C6)haloalkyl, -S(O)aryl, -S(O)heteroaryl, -S(O)heterocycIe, -S(OXC3-C₇)halocarbocycle, -S(OXCi-Cé)alkyl, -S(OXC₃-C₇)carbocycle, -S(O)halo(Ci-C6)alkyl, -SO₂aryI, -SO₂heteroaryI, -SO₂heterocycle, -SO2(Ci-C₆)alkyl, -SO₂halo(Ci-C₆)alkyl, -S02(C₃-C₇)carbocycle, -SO₂(C3-C₇)halocarbocycle, -SO₂NR_cR_<j, -NRaSOzfCa-C-Ohalocarbocycle, -NR_aSO₂aryl, -NR_aSO₂heteroaryl, -NR₈SO₂hcteroaryl, -NR^SO^RJld, -NReSO^fCr C₇)carbocycle and -NRaSO₂Oaryl;

each Z⁷ is independently selected from -NO2, =NORa, -CN, -(Cj-Cs)alkyl-Zⁿ, -(C2-C₆)alkenyl-Z'², -(C2-C6)alkenylOH, -(C2-C6)alkynyl-Z¹², -(C2-C₆)alkynyl-OH, -(Ci-Cô)lialoalkyTZ¹², -(Cj-CyhaloalkylOH, -(C3-C7)carboeycle-Z¹², -(C3C₇)carbocycleOH, (C₃-C₇)halocarbocycle, -(Ci-CôjalkylNRcRj, -(CiCsjalkylNRaCfOjRa, -(Ci-CgjalkylNRgSChRa, aiyl, heteroaryl, heterocycle, -O(CiCf,)alkyl-Z¹², -O(C2-C6)alkenyl, -O(C2-C6)alkynyl, -O(C]-C6)haloalkyl, -O(C3C7)carbocycle, -O(C3-C7)halocarbocycle, -Oaryl, -O(C]-C6)alkylNRcR(j, -O(CiC6)alkylNRàC(O)Ra, -O(C1-C6)alkylNRaSO2Ra, -Oheteroaryl, -Oheterocycle, -S(CiCfi)alkyl-Z^lz, -S(C2-C6)aIkenyl, -S(C2-C₀)alkynyl, -S(Ci-C₆)haloalkyI, -S(C₃C₇)carbocycle, -S(C3-C₇)halocarbocycle, -S/Ci-C^alkylNR^Rj, -S(CiC6)alkylNRaC(O)Ra, -SfCi-C^JalkylNRaSOiRa, -Saryl, -Sheteroaryl, -Sheterocycle, -S(OXCi-C₆)alkyl, -S(O)(C₂-C₆)alkenyl, -S(O)(C₂-C«)alkynyl, -S(0)(C_rC₆)haloalkyl, S(O)(C₃-C7)carbocycle, -S(0)(C3~C₇)halocarbocycIe, -SO₂(Ci-Cé)alkyl, -S(O)(Cr CejalkylNRcRd, -SfOXCrCéjalkylNRXXOjR,, -S(O)(Ci-C₆)alkylNR_aSO₂R₀, -S(O)aryl, -S(O)heteroaryl, -S(O)heterocycle, -SO₂(C_l-C6)alkyl, -SO₂(C₂-C6)alkenyl, -SO₂(C₂Cfjalkynyl, -S0₂(C)-C6)haloalkyl, -SO₂(C3-C₇)carbocycle, -SO₂(Cî-C₇)halocarbocycle, -SO₂aryI, -SO₂heteroaryl, -SO₂heterocycle, -SO₂(Ci-C6)alkylNR_cRd_J -SO₂(CiC₆)alkyINR_aC(O)R^, -SO₂(C_rC₆)alkylNR_aSO₂R_a, -SO₂NR_cR_d, -NR_aC(O)OR_b, -NR_aC(O)NR_cR<! -NRaSO₂Rb, -NR_aSO₂NR_cRd, -NRaS0₂0(C3-C₇Xarbocycle, -NRaSO₂Oaryl_f -OS(O)₂Ra, -CfOjNRJ^, and -OC(O)NR_cR<j, wherein any (Ci-Cb)alkyl, (Ci-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (C3-C₇)caibocycle, (C₃C₇)halocarbocycle, aryl, heteroaryl and heterocycle of Z⁷, either alone or as part of a

C

C group, is optionally substituted with one or more (e.g. 1,2, 3,4 or 5) halogen, -OH, -ORb, -CN, -NRaCtOjîRb, heteroaryl, heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle or -SfO^NR^Ra;

each Z⁸ is independently selected from -NO₂ and -CN;

each Z⁹ is independently selected from -(Ci-Cejalkyl and -O(Ci-C6)alkyl;

each Z¹⁰ is independently selected from:

i) halo, oxo, thioxo, (C₂-Cb)alkenyl, (Ci-Ce)haloalkyl, (C₃-

C₇)cycloalkyl, (C₃-C₇)cycloalkyl-(Ci-C6)alkyi-, -OH, -O(C]C^alkyl, -O/Ci-QOhaloalkyl, -SH, -S(Ci-C₆)alkyl, -SO(CjC₆)alkyl, -SO^Ci-Csjalkyl, -NH₂, -NH(CrC₆)alkyl and

-NtfCj-qdalkylh;

ii) (Ci-Cfi)alkyl optionally substituted with -OH, -O-(Ci-

Ce)haloalkyl or -O-(Cj-C₆)alkyl; and iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle and heteroaryl is optionally substituted with halo, (Ci-Ce)alkyl or COOH;

each Z^!l is independently selected from Z¹⁰, -C( -O)-NH₂, -C(=O)-NH(CiCijalkyl, -C(=O)-N((Ci-C4)alkyl)2, -C(=O)-aryl, -C(=0)-heterocycle and -C(^_O)-hetcroaryl;

each Z is independently selected from -NO₂, =N0Ra, thioxo, aryl, heterocycle, heteroaryl, (C3-C7)halocarbocycle, (Cî-C₇)carbocycle, -O(C₃-C7)carbocycle, -Ohalo(C₃-C₇)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(Ci-C6)alkyl, -S(C₃-C₇)carbocycIe, -ShaIo(C₃-C₇)carbocycle, SaryJ, -Sheterocycle, -Sheteroaryl, -S(O)(Ci-Cs)alkyl, -S(O)(C₃-C₇)caibocycle, -S(O)halo(C₃-C₇)carbocycle, -S(0)aryl, -S(0)heterocycle, -S(O)heteroaryl, -SO₂(C|-C₆)alkyl, -SO₂(C₃-C₇)carbocycle, -S0₂(C₃C₇)halocarbocycle, SO₂aryI, -SO₂heterocycle, -SO₂heteroaryI, -NR_aR_a, -NR_aC(O)Rb, C(O)NR«Rd, -SOjNRçRd, -NR»SO₂NR_cR_ij, -NRaSO₂O(C₃-C7)carbocycle and -NRaS0₂0aryl;

each Z¹³ is independently selected from -N0₂, -OH, =NOR_S, -SH, -CN, -(C₃C₇)halocarbocycle, -O(C]-C6)alkyl, -O(C₂-C₆)alkenyl, -0(C₂-C6)alkynyl, -0(CjCs)haloalkyl, -O(C₃-C7)carbocycle, -O(C₃-C₇)halocarbocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -SfCrCsjalkyl, -S(C₂-C()alkenyl, -S(C₂-C6)alkynyl, -S(Ci-C₆)haloalky], -S(C3-C₇)carbocycIe, -S(C₃-C7)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle, -S(OXCi-C₆)alkyl, -S(O)(C₂-C₆)alkenyl, -S(OXC₂-C₆)alkynyl, -S(O)(C]-C₆)haloalkyl,

C

-S(0)(C3-C₇)carbocycle, -S(0)(C3-C₇)halocarbocycle, -S(O)aryI, -S(O)heteroaiyl, -S(O)heterocycle, -SO₂(C!-C₆)alkyl, -SOi(C₂-Cé)alkenyl, -SO2(C2-C₆)alkynyl, -SChfCt-CsJbaloalkyl, -SO₂(C3-C₇)carbocycle, -SO₂(C3-C₇)halocarbocycle, -SO₂aryl, -SO₂heteroaryl, -SO₂heterocycIe, -SO₂NR<Rd, -NR^Ra, -NR*C(0)Ra, -NR_sC(O)ORb, -NR_aC(O)NR_cR_<j -NRaSCW -NRaSOjNR^, -NR,S0₂O(C3-C7)carbocycle, -NR^SOiOaryl, -OS(O)₂R_fc -C(O)R_H! -C(O)ORb, and -OC(O)NRcR<!, wherein any (Ci-C$)alkyl, (C2-C₆)alkenyl, (C₂-C6)alkynyl, (Cj-C₆)haloalkyl, (C₃C₇)carbocycle, (C3-C₇)halocarbocycle, aryl, heteroaryl or heterocycle of Z¹³, either alone or as part of a group, is optionally substituted with one or more (e.g. 1,2,3,4 or 5) halogen, -OH, -ORb, -CN, -NR_aC(O)₂Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -SfO^NRcR^;

each Z¹⁴ is independently selected from -NO₂, =NORa_f -CN, (C3C₇)halocarbocycle, -0(C3-C₇)halocarbocycle, -S(C3-C7)halocarbocycle, -S(O)(C₃C₇)halocarbocycle, -S0₂(C3-C7)haIocaibocycle, -NRaSOjNRcRj, -NRaSO2O(C3C7)halocarbocycle, -NR_aSO₂Oaryl and -OSfO^Ra, wherein any (C3-C₇)halocarbocycle of Z¹⁴, either alone or as part of a group, is optionally substituted with one or more (e.g.

1,2,3,4 or 5) halogen, -OH, -ORb, -CN, -NR_aC(O)₂Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(O}₂NR_cR_ii;

each Ra is independently H, (Ci-Cejalkyl, (C₂-C6)alkenyl, (C₂-C6)alkynyl, (C3-C₇)carbocycle, heterocycle, aryl, aiyl(Cj-C₆)alkyl-, heteroaryl or heteroarylfCjCô)alkyl-, wherein any (Ci-Qjalkyl, (C₂-C6)alkenyl, (C₂-C₆)alkynyl, (C3-C₇)carbocycle, heterocycle, aryl, or heteroaryl of Ra, either alone or as part of a group, is optionally substituted by halogen, OH and cyano;

each Rb is independently (Ci-C₆)alkyl, (C₂-C6)alkenyl, (C₂-C6)alkynyl, (C3-C₇)carbocycle, heterocycle, aryl, aryl(Cj-Cb)alkyl-, heteroaryl or heteroaryl (CiC₆)alkyl-, wherein any (Ci-C₆)alkyl, -(C₂-C6)alkenyl, -(C₂-C6)alkynyl, (C3-C₇)carbocycle, heterocycle, aryl, or heteroaryl of Rb, either alone or as partof a group, is optionally substituted by halogen, OH and cyano;

Rc and Rj are each independently selected from H, (C|-C₆)alkyl, (C₂-C6)alkenyl, (C2-C6)alkynyl, (C3-C₇)carbocycle, aryl, aryl/Cj-C^alkyl-, heterocycle, heteroaryl and heteroaryl(Ci-C₆)alkyl-, wherein any (C]-C₆)alkyl, -(C₂-Cô)alkenyl, -(C₂-C₆)alkynyl, (Cî-C₇)carbocycle, heterocycle, aryl and heteroaryl of Rc or Ra, either alone or as part of a group, is optionally substituted by halogen, OH and cyano; or Rcand Rj together with the nitrogen to which they arc attached form a heterocycle, wherein any heterocycle of R«and Rd together with the nitrogen to which they are attached is optionally substituted by halogen, OH or cyano;

each Rc is independently selected from -OR^, (Ci-Ci)alkyl and (C3-C₇)carbocycle, wherein (Cj-C^alkyl and (Cî-C₇)carbocycle are substituted by one or more (e.g, 1,2,3,4 or 5) Z⁶and optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹, (C2-C₆)haloalkyl, (C₂-C₆)alkenyl and (C₂-C6)alkynyl, wherein any (C₂-C₆)haloalkyl, (C₂-Ce)alkenyl and (Cj-C^alkynyl is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹, and aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl are substituted by one or more Z⁵;

each Rf is independently selected from -R_g -OR_A -(Ch-C'ôjalkyl-Z⁶, -SO₂Rg, -0(0)^, C(O)ORg, and -C(O)NR₄R_ê; and each Rg is independently selected from H, -OR^ (C;-Cf>)alkyl, (C3-C₇)carbocycle, (Ci-C^jhaloalkyl, (C2-Cé)alkenyl, (C2-C₆)alkynyl, aryl, heterocycle and heteroaryl, wherein any (Cj-CeJalkyl, (C3-C₇)carbocycle> (C]-C6)haloalkyl, (C₂-C₆)alkcnyl, (C^-C^alkynyl, aryl, heterocycle or heteroaryl of R_g is optionally substituted with one or more Z¹ groups;

or a sait thereof.

The invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable sait thereof, in combination with a pharmaceutically acceptable carrier.

The invention also provides method for treating (e.g. preventing, mediating or inhibiting) the prolifération of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. a human), comprising administering a compound of formula I, or a pharmaceutically acceptable sait thereof, to the mammal.

The invention also provides a compound of formula I, or a pharmaceutically acceptable sait thereof for use in medical therapy (e.g. for use in treating (e.g. preventing, mediating or inhibiting) the prolifération of the HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. a human)).

The invention also provides a compound of formula I, or a pharmaceutically acceptable sait thereof for use in the manufacture of a médicament for treating (e.g. preventing, mediating or inhibiting) the prolifération of the HIV virus or AIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. a human).

The invention also provides a compound of formula I, or a pharmaceutically acceptable sait thereof, for use in the prophylactic or therapeutic treatment (e.g. prévention, médiation or inhibiting) of the prolifération of the HIV virus or AIDS or for use in the therapeutic treatment of delaying the onset of AIDS or ARC symptoms.

Die invention also provides processes and intermediates disclosed herein that are useful for preparing compounds of formula I or salts thereof.

Detailed Description ofthe Invention

Définitions

Unless stated otherwise, the following terms and phrases as used herein are intended to hâve the following meanings:

When trade names are used herein, applicants intend to independently include the tradename product and the active pharmaceutical îngredient(s) of the tradename product.

“Alkyl” is hydrocarbon containing normal, secondary or tertiary atoms. For example, an alkyl group can hâve 1 to 20 carbon atoms (i.e., (Ci-C2o)alkyl), 1 to 10 carbon atoms (i.e., (Ci-Ci₀)alkyl), 1 to 8 carbon atoms (i.e., (Ci-Cgjalkyljor 1 to 6 carbon atoms (i.e., (Cj-Ce alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH₂CH₃), 1-propyl (n-Pr, n-propyl, CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH₃)2), 1-butyl (n-Bu, n-butyl, CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, -CH2CH(CH₃)₂), 2-butyl (s-Bu, sbutyl, -CH(CH₃)CH2CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, -CfCH^), 1-pentyl (iipentyl, -CH₂CH₂CH₇CH₂CH₃), 2-pentyi (-CH(CH₃)CH2CH₂CH₃), 3-pentyl (-CH(CH₂CH₃)₂), 2-methyl-2-butyl (-C(CH₃)2CH₂CH3), 3-methyl-2-butyl (-CH(CH₃)CH(CH₃)₂), 3-methyl-l-butyl (-CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (-CH₂CH(CH₃)CH₂CH₃), 1-hexyl (-CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (-CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (-CH(CH₂CH₃)(CH₂CH₂CH₃», 2-methyl-2pentyl (-C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (-CH(CH₃)CH(CH₃)CH₂CH₃), 4methyl-2-pentyl (-CH(CH₃)CH₂CH(CH₃h)_i 3-methyl-3-pentyl (-CCCHjXCHiCHah),

2-methyl-3-pentyl (-CH(CH₂CH₃)CH(CH₃)2), 2,3-dimethyl-2-butyl (-C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (-CH(CH₃)C(CH₃)₃, and octyl (-(CH₂)7CH₃), “Alkyl” also refers to a saturated, branched or straight chain hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For exemple, an alkyl group can hâve 1 to 10 carbon atoms(f.e._s (Ci-Cio)alkyl), or 1 to 6 carbon aiomsfie., (Ci-Ci)alkyl) or 1-3 carbon atoms(i.e., (Cj-C₃)alkyl). Typical alkyl radîcals include, but are not limited to, methylene(-CH2-), 1,1-ethyl (-CH(CH₃)-), 1,2-ethyl (-CH2CH2-), 1,15 propyl (-CH(CH₂CH₃>), 1,2-propyl (-CH₂CII(CH₃)-), 1,3-propyl (-CH₂CH₂CH₂-), 1,4butyl (-CH₂CH2CH₂CH₂-), and the like.

“Alkenyl” is a straight or branched hydrocarbon containing normal, secondary or tertiary carbon atoms with at least one site of unsaturation, Le. a carbon-carbon, sp²double bond. For example, an alkenyl group can hâve 2 to 20 carbon atoms (i.e., C₂10 C₂o alkenyl), 2 to 8 carbon atoms C₂-Cg alkenyl), or 2 to 6 carbon atoms (Le., C₂Cs alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH₂), allyl (-CH₂CH=CH₂), cyclopentenyl (-C5H7), and 5hexenyl (-CH₂CH₂CH2CH₂CH=CH₂).

“Alkynyl” is a straight or branched hydrocarbon containing normal, secondary 15 or tertiary carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. For example, an alkynyl group can hâve 2 to 20 carbon atoms (Le., C₂-C2o alkynyl), 2 to 8 carbon atoms (i e., C₂-Cg alkyne,), or 2 to 6 carbon atoms (i. e., C₂-C₆alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C^CH), propargyl (-CH₂CsCH), and the like.

The term “halo” or “halogen” as used herein refers to fluoro, chloro, bromo and iodo.

The term “haloalkyl” as used herein refers to an alkyl as defîned herein, wherein one or more hydrogen atoms are each replaced by a halo substituent. For example, a 25 (Cj-CeJhaloalkyl is a (Ci-Csjalkyl wherein one or more of the hydrogen atoms hâve been replaced by a halo substituent. Such a range includes one halo substituent on the alkyl group to complété halogénation of the alkyl group.

The term “aryl” as used herein refers to a single aromatic ring or a bicyclic or multicyclic ring. For example, an aryl group can hâve 6 to 20 carbon atoms, 6 to 14 30 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical or an ortho-fused bicyclic or multicyclic radical having about 9 to 14 atoms in which at least one ring îs aromatic (e.g. an aryl fused to one or more aryl or carbocycle). Such bicyclic or

multicyclic rings may be optionally substituted with one or more (e.g. I, 2 or 3) oxo groups on any carbocycle portion of the bicyclic or multicyclic ring. It is to be understood that the point of attachment of a bicyclic or multicyclic radical, as defined above, can be at any position of the ring including an aryl or a carbocycle portion of the ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, anthracenyl, and the like.

“Arylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl radical as described herein {i.e., an aryl-alkyl-moiety). The alkyl group of the “arylalkyl” is typically 1 to 6 carbon atoms (i.e. aryl(Ci-C6)alkyl). Arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 1-phenylpropan-l-yl, naphthylmethyl, 2-naphthylethan-l-yl and the like.

The term “heteroaryl as used herein refers to a single aromatic ring or a multiple condensed ring. The term includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings. The sulfur and nitrogen atoms may also be présent in an oxidized form provided the ring is aromatic. Such rings include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. The term also includes multiple condensed ring Systems (e.g. ring Systems comprising 2 or 3 rings) wherein a heteroaryl group, as defined above, can be fused with one or more heteroaryls (e.g. naphthyridinyl), carbocycles (e.g. 5,6,7,8-tetrahydroquinolyl) or aryls (e.g. indazolyl) to form a multiple condensed ring. Such multiple condensed rings may be optionally substituted with one or more (e.g. 1,2 or 3) oxo groups on the carbocycle portions ofthe condensed ring. It is to be understood that the point of attachment of a heteroaryl multiple condensed ring, as defined above, can be at any position of the ring including a heteroaryl, aryl or a carbocycle portion of the ring. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quînoxalyl, quinazolyl, 5,6,7,8tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl and thianaphthenyl.

The term “heterocyclyl” or “heterocycle” as used herein refers to a single saturated or partially unsaturated ring or a multiple condensed ring System. The term includes single saturated or partially unsaturated ring (e.g. 3,4, 5, 6 or 7-membered

ring) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The ring may be substituted with one or more (e.g. 1,2 or 3) oxo groups and the sulfur and nitrogen atoms may also be présent in their oxidized forms. Such rings include but are not limited to azetidinyl, tetrahydrofiiranyl or piperidinyl. The term also includes multiple condensed ring Systems (e.g. ring Systems comprising 2 or 3 rings) wherein a heterocycle group (as defined above) can be connected to two adjacent atoms (fused heterocycle) with one or more heterocycles (e.g. decahydronapfhyridinyl), heteroaryls (e.g. 1,2,3,4-tetrahydronaphthyridinyl), carbocycles (e.g. decahydroquinolyl) or aryls, It is to be understood that the point of attachment of a heterocycle multiple condensed ring, as defined above, can be at any position of the ring including a heterocycle, heteroaryl, aryl or a carbocycle portion of the ring. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazînyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3benzodioxolyl and 1,4-benzodioxanyl.

The term “bridged-heterocycle” as used herein refers to a 4, 5, 6,7 or 8membered heterocycle as defined herein connected at two non-adjacent atoms of the 4, 5,6, 7 or 8-membered heterocycle with one or more (e.g. 1 or 2) 3,4, 5 or 6-membered heterocycles or a (CR-CRjcarbocydes as defined herein. Such bridged-heterocycles include bicyclic and tricyclic ring Systems (e.g. 2-azabicyclo[2.2.1]heptane and 4azatricyclo[4.3.1.1^3,8J undecane).

The term “spiro-heterocycle” as used herein refers to a 3, 4, 5, 6, 7 or 8membered heterocycle as defined herein connected to one or more (e.g. 1 or 2) single atoms of the 3,4,5,6,7 or 8-membered heterocycle with one or more (e.g. 1 or 2) 3, 4,

5,6-membered heterocycles or a (C3-C7)carbocycles as defined herein. Such spiroheterocycles include bicyclic and tricyclic ring Systems (e.g. l,4-dioxaspiro[4.5]dec-7enyl).

The term “macroheterocycle” as used herein refers to a saturated or partially unsaturated 8, 9,10, 11 or 12-membered ring comprising about 5 to 11 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring which may be optionally fused at two adjacent atoms of the

macroheterocycle to one or more (e.g. 1,2 or 3) aryls, carbocycles, heteroaryls or heterocycles. The macroheterocycle may be substituted with one or more (e.g. 1,2 or

3) oxo groups and the sulfur and nitrogen atoms may also be présent in their oxidized forms.

“Heteroarylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl radical as described herein (i. e., a heteroaryl-alkyl- moiety). The alkyl group of the “heteroarylalkyr is typically 1 to 6 carbon atoms (i.e. heteroaryl(Ci-C₆)alkyl). Heteroarylalkyl groups include, but are not limited to heteroaryl-CHî-, heteroaryl10 CH(CHî)-, heteroaryl-CH₂CH₂-, 2-(heteroaryl)ethan-1 -yl, and the like, wherein the “heteroaryl” portion includes any of the heteroaryl groups described above. One skilled in the art will also understand that the heteroaryl group can be attached to the alkyl portion of the heteroarylalkyl by means of a carbon-carbon bond or a carbon heteroatom bond, with the proviso that the resulting group is chemically stable.

Examples of heteroarylalkyls include by way of example and not limitation 5membered sulfiir, oxygen, and/or nitrogen containing heteroaryls such as thiazolylmethyl, 2-thiazolylethan-I-yl, imîdazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered suliur, oxygen, and/or nitrogen containing heteroaryls such pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, 20 etc.

“Heterocyclylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heterocyclyl radical as described herein (i.e., a heterocyclyl-alkyl- moiety). The alkyl group of the “heterocyclylalkyl” is typically 1 to 6 carbon atoms (i.e. heterocyclyl(Ci-Ce)alkyl).

Typical heterocyclylalkyl groups include, but are not limited to heterocyclyl-CH₂-, heterocyclyl-CH(CH3)-, heterocyclyl-CH₂CH₂-, 2-(heterocyclyl)ethan-l-yl, and the like, wherein the “heterocyclyl” portion includes any of the heterocyclyl groups described above. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkyi portion of the heterocyclyl alkyl by means of a carbon30 carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. Examples of heterocyclylalkyls include by way of example and not limitation 5-membered sulfur, oxygen, and/or nitrogen containing heterocycles such tetrahydrofuranylmethyl and pyrroldinylmethyl, etc., and 6-membered sulfur, oxygen,

and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, etc.

The tenn “carbocycle” or “carbocyclyr refers to a saturated (i.e., cycloalkyl) or partially unsaturated (e.g., cycloalkenyl, cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms as a monocycle or a multicyclic ring System. In one embodiment the carbocycle is a monocycle comprising 3-6 ring carbons (î.e. (Ci-C6)carbocycle). Carbocycle includes multicyclic carbocycles hâve 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle provided that the largest single ring of a multicyclic carbocycle is 7 carbon atoms. The term “spiro-bicyclic carbocycle” refers to a carbocycle bîcyclic ring system wherein the rings of the bîcyclic ring system are cormected to a single carbon atom (e.g. spiropentane, spiro[4,5]decane, spiro[4.5]decane, etc). The term “fused-bicyclic carbocycle” refers to a carbocycle bîcyclic ring system wherein the rings of the bîcyclic ring system are cormected to two adjacent carbon atoms such as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bîcyclo [5,6] or [6,6] system (e.g. decahydronaphthalene, norsabinane, norcarane). The term “bridged-bicyclic carbocycle” refers to a carbocycle bîcyclic ring system wherein the rings of the bîcyclic ring system are connected to two non-adjacent carbon atoms (e.g. norbomane, bicyclo[2.2.2]octane, etc). The “carbocycle” or “carbocyclyl may be optionally substituted with one or more (e.g. 1,2 or 3) oxo groups. Non-limiting exemples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, 1cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl and l-cyclohex-3enyl.

The term “halocarbocycle” as used herein refers to a carbocycle as defined herein, wherein one or more hydrogen atoms are cach replaced by a halo substituent. For example, (C3-C₇)halocarbocycle îs a (Cj-CvJcarbocycle wherein one or more of the hydrogen atoms hâve been replaced by a halo substituent. Such a range includes one halo substituent on the carbocycle group to complété halogénation of the carbocycle group.

The term “macrocarbocycle” as used herein refers to a saturated or partially unsaturated 8,9,10,11 or 12-membered ring comprising 8 to 12 carbon atoms which may be optionally fused at two adjacent atoms of the macrocarbocycle to one or more (e.g, 1, 2 or 3) aryls, carbocycles, heteroaryls or heterocycles. The macrocarbocycle

may be substituted with one or more (e.g. 1, 2 or 3) oxo groups.

“Carbocyclylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom îs replaced with a carbocyclyl radical as described herein a carbocyclyl-alkyl- moiety). The alkyl group of the “carbocyclylalkyl” is typically 1 to 6 carbon atoms (i.e. carbocyclylCCi-CeJalkyl). Typical carbocyclyl alkyl groups include, but are not limited to carbocyclyl-CH₂-, carbocyclyl-CH(CHï)-, carbocyclyl-CH₂CH₂-, 2-(carbocyclyl)ethan-l-yl, and the like, wherein the “carbocyclyl” portion includes any of the carbocyclyl groups described above.

It is to be understood that when a variable is substituted, for example as described by the phrase “(Ci-C^jalkyl, either alone or as part of a group, is optionally substituted ”, the phrase means that the variable (Ci-C^jalkyl can be substituted when it îs alone and that it can also be substituted when the variable “(Ci-C₆)alkyl” is part of a larger group such as for example an arylfCi-Céjalkyl or a -(Ci-C6)aIkyl-SO₂-(CiCgJalkyl-fCî-C^carbocycle group. Similarly, when stated, other variables (e.g. (CiC^alkenyl, (Ci-C₆)alkynyl, aryl, heteroaryl, heterocycle, etc...) can also be substituted “either alone or as part of a group.”

It is to be understood that certain variables of formula I that connect two chemical groups may be oriented in either direction. Thus, for the X group of formula

I (e.g. O, -C(O)-, -C(O)O-, -S-, -S(O>, -SO₂_, -(Cj-C^alkylO-, -(C_rC₆)aIkylC(O)-, -(C_rC₆)alkylC(O)O-, -(C_rC₆)alkylS-, -(C,-C₆)alkylS(O)- and -(C;-C₆)alkylSO₂-) certain values of X that are not symmetric can be oriented in either direction. For example, the -C(O)O-, can be oriented as either -C(O)O- or -OC(())-, relative to the groups it connects.

One skilled in the art will recognizc that substituents and other moieties of the compounds of formula 1 should be selected in order to provide a compound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated into an acceptably stable pharmaceutical composition. Compounds of formula I which hâve such stability are contemplated as falling within the scope of the présent invention.

The modifier “about” used în connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of errer associated with measurement of the particular quantity). The word “about” may

also be represented symbolically by in the context of a chemical measurement (e.g.

~ 50 mg or pH ~ 7).

The term “chiral” refers to molécules which hâve the property of nonsuperimposability of the mirror image partner, while the term “achiral” refers to molécules which are superimposable on their mirror image partner.

The term “stereoisomers” refers to compounds which hâve identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers or axes of chirality and whose molécules are not mirror images of one another. Diastereomers typically hâve different physîcal propertîes, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which are nonsuperimposable mirror images of one another.

Certain compounds of the invention can exist as atropisomers. For example, it has been discovered that atropisomers exist for certain substituents at the R⁴ position of formula I as marked by an asterisk in the formula below.

	R⁵	? ^R\	R³'
R®	ÎT		<.OH
R⁷	T		O R²
	R⁸	R¹

The chirality that results from the atropisomers at the asterisk position is a feature of certain compounds of the invention. Accordingly, the invention includes ail atropisomers of compounds of the invention including mixtures of atropisomers and well as mixtures that are enriched in an atropisomer as well as single atropisomers, which mixtures or compounds possess the useful properties described herein.

In one embodiment, the compounds of the invention of formula I are at least 60% a single atropisomer for the R⁴ substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 70% a single atropisomer for the R⁴ substituent at the asterisk position. In another embodiment, the compounds of the invention of formula 1 are at least 80% a single atropisomer for the

R* substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are ai least 90% a single atropisomer for the R⁴ substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 95% a single atropisomer far the R⁴ substituent at the asterisk position. In 5 one embodiment the stereochemistry for the R⁴ substituent at the carbon marked with an asterisk as shown above for Formula I is the (R) stereochemistry. In another embodiment the stereochemistry for the R⁴ substituent at the carbon marked with an asterisk as shown above for Formula I îs the (S) stereochemistry.

The term “treatment” or “treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occumng, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.

Stereochemical définitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book 15 Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they hâve the ability to rotate the plane of planepolarized light. In describing an optically active compound, the préfixés (D and L) or (R and S) are used to dénoté the absoluie configuration of the molécule about its chiral 20 center(s). The préfixés d and 1 or (+) and (-) are employed to designate the sigu of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identîcal except that they are mirror images of one another. A spécifie stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers îs referred to as a racémie mixture or a racemate, which may occur where there has been no stereoselection or stereospecîficity in a chemical réaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optîcal activity.

Protecting Groups

In the context ofthe présent invention, protecting groups include prodrug moieties and chemical protecting groups.

“Protecting group” refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g.. Protective Croups în Organic Chemistrv. Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain ftmctional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intennediates may themselves be biologically active or inactive.

Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and résistance to enzymatic dégradation or séquestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to couvert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intennediates, or in vivo, in the case of prodrugs. With chemical intennediates, it is not particulariy important that the resulting products after deprotection, e.g., alcohols, be physiologically acceptable, although în general it is more désirable if the products are pharmacologically innocuous.

Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to préparé the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group “PG” will be dépendent upon the chemistry of the réaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. PGs do not need to be, and generally are not, the same if the compound is substituted with multiple PG. In general, PG will be used to protect functional groups such as carboxyl, hydroxy], thio, or amino groups and to thus

prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free deprotected groups is dépendent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.

Various functional groups of the compounds of the invention may be protected. For example, protectîng groups for -OH groups (whether hydroxyl, carboxylic acid, phosphonic acid, or other fonctions) include “ether- or ester-forming groups”. Ether- or ester-forming groups are capable of fonctioning as chemical protectîng groups in the synthetic schemes set forth herein. However, some hydroxyl and thio protectîng groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.

A very large number of hydroxyl protectîng groups and amide-forming groups and corresponding chemical cleavage reactions are described in Protective Groups in Oreanic Synthesis. Théodore W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301 -6) (“Greene”). See also Kocienski, Philip J.; Protectîng Groups (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated by reference in its entirety herein. In particular Chapter 1, Protectîng Groups: An Overview, pages

1-20, Chapter 2, Hydroxyl Protectîng Groups, pages 21-94, Chapter 3, Diol Protectîng Groups, pages 95-117, Chapter 4, Carboxyl Protectîng Groups, pages 118-154, Chapter 5, Carbonyl Protectîng Groups, pages 155-184. For protectîng groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protectîng groups for acids see Greene as set forth below.

Stereoisomers

The compounds of the invention may hâve chiral centers, e.g,_t chiral carbon or phosphorus atoms. The compounds of the invention thus include racemic mixtures of ail stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the invention include enriched or rcsolved optical isomers at any or ail asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are ail within the scope of the invention. The racemic mixtures can be separated into their

individual, substantially optically pure isomers through well-known techniques such as, for example, the séparation of diastereomeric salis formed with optically active adjuncts, e.g._t acids or bases followed by conversion back to the optically active substances. In most instances, the desired optical isomer is synthesized by means of stereospecifîc reactions, beginning with the appropriate stereoisomer of the desired starting material.

The compounds of the invention can also exist as tautomeric isomers in certain cases. Although only one delocalized résonance structure may be depicted, ail such forms are contcmplatcd within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole Systems and ail their possible tautomeric forms are within the scope of the invention.

Salts and Hydrates

Examples of pharmaceutically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkalî métal (for example, sodium), an alkaline earth métal (for example, magnésium), ammonium and NX? (wherein X is C1-C4 alkyl). Pharmaceutically acceptable salts of a hydrogen atom or an amino group include for example salts of organic carboxylic acids such as acetic, benzoic, lactic, fiimaric, tartane, maleic, malonic, malic, isethionîc, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfomc and p-toluenesulfonic acids; and inorganic acids, such as hydroehloric, hydrobromic, sulfuric, phosphoric and sulfamic acids. Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na⁺ and NX/ (wherein X is independently selected from H or a Cj-Cî alkyl group).

For therapeutic use, salts of active ingrédients of the compounds of the invention will typîcally be pharmaceutically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the préparation or purification of a compound of formula I or another compound of the invention. Ail salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the présent invention.

Métal salts typîcally are prepared by reacting the métal hydroxïde with a

compound of this invention. Examples of métal salts which are prepared in this way are salts containing Li⁺, Na⁴', and K⁺. A less soluble métal sait can be precipitated from the solution of a more soluble sait by addition of the suitable métal compound.

In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCl, HBr, H2SO4, H3PO4 or organic sulfonic acids, to basic centers, typically amines, or to acidîc groups. Finally, it is to be understood that the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids. Any of the natural or unnatural amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.

Spécifie values listed below for radîcals, substituents, and ranges in the embodiments of the invention are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. Isotopes

It is understood by one skilled în the art that this invention also includes any compound claimed that may be enriched at any or ail atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (²H or D). As a non-lîmiting example, a -Cl fi group may be substituted with -CD3.

Compounds of formula I.

A spécifie group of compounds of formula I are compounds of formula la.

	R⁵	R⁴	R³
R⁸	ίΎ	ί
FF	T		O ^R²
	R⁸	R¹

la

Another spécifie group of compounds of formula I are compounds of formula le.

	R⁴	R³
R⁸			Â/OH
r^7>	T		'''R² °
	R⁸	R¹
		Ib

Another spécifie group of compounds of formula I are compounds of formula

R⁸ R¹

Id.

le

Another spécifie group of compounds of formula I are compounds of formula

Another spécifie group of compounds of formula I are compounds of formula le.

le

Another spécifie group of compounds of formula I are compounds of formula

If.

If

Another spécifie group of compounds of formula I are compounds of formula

Ig.

O

Ig

Another spécifie group of compounds of formula I are compounds of formula

Ih

Another spécifie group of compounds of formula I are compounds of formula Ii.

Ii

Another spécifie group of compounds of formula I are compounds of formula Ij.

Ij

Another spécifie group of compounds of formula I are compounds of formula

Im.

Im

Another spécifie group of compounds of formula I are compounds of formula

In.

Another spécifie group of compounds of formula I are compounds of formula

Io.

OH

Ιο

Spécifie values listed below are values for compounds of formula I as well as the compounds of formula la, Ib, le, Id, le, If, Ig, Ih, Ii, IJ, Ik, Im, In and Io.

A spécifie group of compounds of formula I are compounds wherein at least one of R¹, R², R³, R³’, R⁴, R^s, R⁶, R⁷, or R⁸ is selected from R^lb, R^2b, R^3b, R^3b', R^4b, R^Sb, R^6b,R^7bandR^8b.

Another spécifie group of compounds of formula I are compounds wherein at least two of R¹, R², R³, R³’, R⁴, R^s, R⁶, R⁷, or R⁸ are selected from R^lb, R^2b, R^3b, R^3b’, R^4b,R^Sb,R^6b,R^7bandR^8b.

Another spécifie group of compounds of formula I are compounds wherein at least three of R¹, R², R³, R³, R⁴, R^s, R⁶, R⁷, or R⁸ are independently selected from R^lb,

R^2b, R^3b, R^3b, R^4b, R^5b, R^6b, R⁷¹* and R^8b.

Another spécifie group of compounds of formula I are compounds wherein at least four of R¹, R², R³, R³’, R⁴, R⁵, R⁶, R⁷, or R⁸ are selected from R^lb, R^2b, R^3b, R^3b’, r^r» _R» R^7b andR^8b.

Another spécifie group of compounds of formula I wherein at least five of R¹,

R², R³, R³’, R⁴, R*, R⁶, R⁷, or R⁸ are selected from R^lb, R^2b, R^3b, R^3b’, R^4b, R^sb, R^6b, Rⁿ and R^8b.

Another spécifie group of compounds of formula I wherein at least six of R^!, R², R³, R³', R⁴, R^s, R⁶, R⁷, or R⁸ are independently selected from R^lb, R^2b, R^3b, R^3b',

R^4b,R^5b, R^6b,R^7b,orR^8b.

Another spécifie group of compounds of formula I wherein at least seven of R¹, R², R³, R³', R⁴, R⁵, R⁶, R⁷, or R⁸ are independently selected from R^lb, R^2b, R^3b, R^3b', R^4b, R^Sb, R⁶**, R^7bandR^8b.

Another spécifie group of compounds of formula I wherein at least eight of R¹, R², R³, R³, R⁴, R⁵, R⁶, R⁷, or R⁸ are independently selected from R^lb, R^2b, R^3b, R^3b, R^4b,R^Sb,R^6b,R^7bandR^Sb.

Another spécifie group of compounds of formula I wherein R¹, R², R³, R³’, R⁴, R⁵, R⁶, R⁷ and R⁸ are R^lb, R^2b, R^3b, R^3b’, R^4b, R^5b, R^6b, R^7band R⁸¹¹.

A spécifie value for R³ is R^3b.

A spécifie value for R^3b is -OCfCll^CILOH, -OCfCH^CH.OlI, -OCCrCbjalkyl-O-CXOj-NHa,-O(C_rC₆)alkyl-O-C(O)-N(CH₃)₂or -O(C|-C₆)alkyl-O-C(O)-NH(phenyl).

Another spécifie value for R^3b is -(Cj-CfiJalkylOH or -OCCi-CsJalkyl-O-CCOJ-NRcRd.

Another spécifie value for R³ is R^3a.

A spécifie value for R³* is (C|-C_É)alkyl, (C2-C₆)alkenyl or -O(Ci-C₆)alkyl, wherein any (Ci-Cé)alkyl or (C₂-C₆)a!kcnyl of R^3a is optionally substituted with one or more groups selected from -O(Ci-C6)alkyl, halo, oxo and -CN.

Another spécifie value for R³’ is OC(CH₃).

A spécifie value for R³ is R^3b .

A spécifie value for R^3b is (C[-Cg)alkyl or -O(Ci-C$)alkyl.

A spécifie value for R³ is R^3a.

A spécifie value for R^3a is H.

A spécifie group of compounds of formula I are compounds wherein R^3b and R^3b together with the carbon to which they are attached form a (C3-C₇)carbocycle or heterocycle, wherein the (C3-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R^3band R^3b together with the carbon to which they are attached form a (C₃-C7)carbocycle or a 4, 5 or 6-membered heterocycle, wherein the (C₃-C₇)carbocycle or the 4, 5 or 6membered heterocycle is optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R^3band R^3b together with the carbon to which they are attached form a (C4-C₆)carbocycle or a 5 or 6-membered heterocycle, wherein the (C.rC₆)^carbocyc]e or the 5 or 6membered heterocycle is optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R^3band R^3b together with the carbon to which they are attached form a 5 or 6-membered heterocycle, wherein the 5 or 6-membered heterocycle is optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R^3band R^3b together with the carbon to which they are attached form a tetrahydropyran or tetrahydrofuran optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R³⁶and R^3b together with the carbon to which they are attached form:

each of which is optionally substituted with one or more Z¹ groups; and wherein dénotés the point of attachment to the carbon ofthe compound of formula I.

A spécifie value for R⁴ is R^4b.

A spécifie value for R^4b is (Ci Cé)alkyl, (C₂-C6)alkenyl or (C₂-Cf,)alkynyl, wherein (Ci-C^alkyl, (C₂-C(,)alkenyl and (C₂-C.6)alkynyl are each optionally substituted with one or more Z¹ groups.

Another spécifie value for R^4b is:

optionally substituted with one or more Z¹ groups.

Another spécifie value for R^4bis (Cj-Cîjcarbocycle, wherein (Cî-C₇)caTbocycle is optionally substituted with one or more Z¹ groups, or wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (Ci-Cejcafbocycle or 5-6-membered heterocycle.

Another spécifie value for R^4t> is:

each of which is optionally substituted with one or more Z¹ groups.

Another spécifie value for R^4b îs aryl, heterocycle or heteroaryl, wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

Another spécifie value for R⁴*¹ is:

Another spécifie value for R⁴ is R^4a.

A spécifie value for R^4a is:

/wv

Λ/W

•^V

A spécifie group of compounds of formula I are compounds wherein R⁴ and R³ together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle, wherein any macroheterocycle or macrocarbocycle of R⁴ and R³

together with the atoms to which they are attached may be optionally substituted with one or more Z¹ groups; and R³’ is H, (Cj-C^alkyl or -O(Ci-C6)alkyl.

Another spécifie value for R³ is H.

Another spécifie group of compounds of formula I are compounds wherein R⁴ and R³ together with the atoms to which they are attached form the macroheterocycle or a macrocarbocycle further fused to a Z group:

uw wherein:

Z is aryl, heteroaryl or (C₃-Cé)carb(K:ycle;

n3 is 2,3 or 4; and

W¹ and W² are each independently O, NH or CH₂, and wherein dénotés the R⁴ point of attachment of the macroheterocycle or macrocarbocycle to the compound of formula I and “♦»” dénotés the R³ point of attachment of the macroheterocycle or macrocarbocycle to the compound of formula I, 15 and wherein the macroheterocycle or a macrocarbocycle is optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein, R⁴and R³ together with the atoms to which they are attached form the macroheterocycle:

wherein:

ni is 3 or 4; n2 is 2, 3 or 4; n3 is 2,3 or 4; W is O, NH or N(Ci-C4)alkyl; and wherein dénotés the R⁴ point of attachment of the macroheterocycle to the compound of formula I and “♦*” dénotés the R³ point of attachment of the

macroheterocycle to the compound of formula I, and wherein the macroheterocycle or a macrocarbocycle is optionally substituted with one or more Z¹ groups

A spécifie value for R¹ is R^lb.

Another spécifie value R¹ is R¹*.

A spécifie value for R¹* is H or -CH3.

A spécifie value for R² is R^2b.

Another spécifie value R² is R²*.

A spécifie value for R²⁴ is H or -CH₃.

A spécifie value for R^s is R^îb.

Another spécifie value for R^s is R⁵’.

A spécifie value for R⁵‘ is H.

A spécifie value for R⁶ is R*^fc.

Another spécifie value for R⁶ is R^6a.

A spécifie value for R^6a is H.

A spécifie value for R⁷ is R⁷⁶.

Another spécifie value for R⁷ is R^7a.

A spécifie value for R⁷“ is H, -CHj or halogen.

A spécifie value for R⁸ is R^ib.

Another spécifie value for R⁸ is R^8a.

Another spécifie value for R^is H.

A spécifie group of compounds of formula I are compounds wherein R^4b is selected from;

a) (Cj-C'ôjalkyl, (Cî-C'éjalkenyl and (C^-CUalkynyl, wherein (C|-C&)alkyl, (C₂-C₆)alkenyl and (C₂-C<,)alkynyl are each optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) (C3-Cj4)carbocycle, wherein (C₃-Cj4)carbocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

c) Spiro-heterocycle and bridged-heteTocycle, wherein spiro-heterocycle and bridged-heterocycle are each optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups; and

d) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl arc each independently substituted with one or more Z⁷ groups and optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups; or

Another spécifie group of compounds of formula I are compounds wherein R⁴*⁵is selected from;

a) (C j -C6)alkyl, (C₂-C6>alkenyl and (C₂-C₆)alkynyl, wherein (C _rC₆)alkyI, (C2-Cs)alkenyl and (C2-Cs)alkynyl are each optionally substituted with one or more (e.g. I,2,3,4 or 5) Z¹ groups;

b) (C3-Cn)caTbocycle, wherein (C₃-Cn)carbocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C.3C₇)carbocycle or heterocycle; and

c) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; or

Another spécifie group of compounds of formula I are compounds wherein R^4bis selected from;

a) (Ci-Cô)alkyl, (C₂-C6)alkenyl and (C₂-C6)alkynyl, wherein (Ci-Cô)alkyl, (C₂-C6)alkeuyl and (C₂-C6)alkynyl are each optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

b) (C3-Ci₄)carbocycle, wherein (C₃-Ci₄)carbocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

c) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R³ is (Ci-Ce)alkyl, (C₂-C(s)alkenyl or -O(C]-Ci)alkyl, wherein any (Cj-C^alkyl or (C2-Cs)alkenyl of R³ is optionally substituted with one or more groups selected from -O(C_rC<,)a]kyl, halo, oxo and -CN, and wherein R³ is H.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from:

a) aryl, heterocycle and heteroary], wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (Ci-Câjalkyl, (C₂-Cs)aikenyl, (Ci-CeJhaloalkyl, (C₃-C₇)cycloalkyl, -OH, -O(CiC₆)alkyl, -SH, -S(C_rC6)aIkyl, -NH₂, -NH(Ci-C₆)alkyl and -N((CrQ)alkyl)₂, wherein (CiCs)alkyl is optionally substituted with hydroxy, -O(C]-C₆)alkyl, cyano or oxo;

?

b) (C₃-Cj4)carbocycle, wherein (C₃-C_i4)carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally fonn a (C₃-C₇)carbocycle or heterocycle; and

c) aryl, heteroaryl and fused-heterocycle, wherein aryl, heteroaryl and fused-heterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (Ci-C6)alkyl, (C2-Ce)alkenyl, (C)-C₆)haloalkyl, (C₃-C₇)cycloalkyl, -OH, -O(CiQ)alkyl, -SH, -SfCj-QVlkyl, -NH₂, -NHfCi-Qjalkyl and -N((Ci-C₆)alkyl)2, wherein (C_rCô)alkyl is optionally substituted with hydroxy, -O(Ci-C6)alky], cyano or oxo; and

b) aryl, heteroaryl and fused-heterocycle, wherein aryl, heteroaryl and fused-heterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

a) heterocycle and heteroaryl, wherein heterocycle and heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (CiCejalkyl, (C₂-C₆)alkenyl, (Ci-Csjhaloalkyl, (C₃-C₇)cycloalkyl, -OH, -O(Ci-C6)alkyl, -SH, S(Ci-Cb)alkyl, -NH₂, -NHfCrCôJalkyl and -NifCi-CôJalkyl^, wherein (Ci-Ce)alkyl is optionally substituted with hydroxy, -O(C_rC6)alkyl, cyano or oxo; and

b) heteroaryl and fused-heterocycle, wherein heteroaryl and fused- * -y heterocycle are each independently substituted with one or more Z groups and optionally substituted with one or more Z¹ groups.

a) heterocycle, wherein heterocycle is optionally substituted with one or more groups each independently selected from halo, (Ci-Céjalkyl, (C₂ C6)alkenyl, (C r Cô)haloalkyl, (C₃-C₇)cycloalkyl, -OH, -O(C_t-C₆)alkyl, -SH, -SfQ-CeJalkyl, -NH₂, -NH(C|16293

CeJalkyl and -N^Ci-COalky]^, wherein (Ci-Cs) alkyl is optionally substituted with hydroxy, -O(Ci-Cs)alkyl, cyano or oxo; and

b) fused-heterocycle, wherein fused-heterocycle is substituted with onc or more Z groups and optionally substituted with one or more Z groups.

a) bîcyclic aryl, tricyclic aryl, bîcyclic heterocycle, tricyclic heterocycle, bîcyclic heteroaryl and tricyclic heteroaryl, wherein any bîcyclic aryl, tricyclic aryl, bicyclic heterocycle, tricyclic heterocycle, bîcyclic heteroaryl and tricyclic heteroaryl,is optionally substituted with one or more groups each independently selected from halo, (CjC₆)alkyl, (C₂-C₆)a]kenyl, (Ci-C^Jhaloalkyl, (C₃-C₇)cycloalkyl, -OH, -OfCj-Côjalkyl, -SH, StCt-CeJalkyl, -NH₂, -NH(Ci-C₆)alkyl and -NGCrC^Jalky]^, wherein (Cj-CeJalkyl is optionally substituted with hydroxy, -O(C|-C₆)alkyl, cyano or oxo; and

b) bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, tricyclic heteroaryl bicyclic fused-heterocycle, and tricyclic fused-heterocycle, wherein bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, tricyclic heteroaryl bicyclic fused-heterocycle and tricyclic fused-heterocycle are each independently substituted with one or more Z⁷groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is 20 selected from:

a) bicyclic heterocycle and tricyclic heterocycle, wherein bicyclic heterocycle and tricyclic heterocycle are each optionally substituted with one or more groups each independently selected from halo, (Cj-C^alkyl, (C₂-Ce)alkenyl, (Ci-Cgjhaloalkyl, (C₃C₇)cycloalkyl, -OH, -O(Ci-C₆)alkyI, -SH, -S(Ci-C6)alkyl, -NH₂, -NII(C]-C₆)alkyl and -

N((Cj-C6)alkyl)2, wherein (Cj-Côjalkyl îs optionally substituted with hydroxy, -O(CiCf,)aikyl, cyano or oxo; and

b) bicyclic fused-heterocycle and tricyclic fused-heterocycle wherein bicyclic fused-heterocycle and tricyclic fused-heterocycle fused-heterocycle are each substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

a) bicyclic heterocycle, tncyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl wherein bicyclic heterocycle, tncyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl are each optionally substituted with one or more groups each mdepeùdentiy selectedfrom halo, (Ci-C^jalkyl, (C2-Ce)alkenyl, (CiCfijhaloalkyl, (C₃-C₇)cycloalkyl, -OH, -OCCj-Côjalkyl, -SH, -5((^-Ujalkyl, -NH₂, -NH(C_rCe)alkyl and -N^Cj-C^jalkyljz, wherein (Ci-C₆)alkyl is optionally substituted with hydroxy, -O(Cj-Ce)alkyl, cyano or oxo; and

b) bicyclic fused-heterocycle and tricyclic fused-heterocycle, wherein bicyclic fused-heterocycle and tricyclic fused-heterocycle fused-heterocycle are each substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹groups,

a) tricyclic heterocycle, wherein tricyclic heterocycle is optionally substituted with one or more groups each independently selected from halo, (C_t-C₆)alkyl, (C₂C₆)alkenyl, (C_rC(,)haloalkyl, (C₃-C₇)cycloalkyl, -OH, -O(Ci-C6)alkyl, -SH, -SCCi-C^alkyl, -NH₂₎ -NH(Ci-Ce)alkyl and -N((Ci-C6)alkyl)2, wherein (Ci-C₆)alkyl is optionally substituted with hydroxy, -OfCi-CeJalkyl, cyano or oxo; and

b) tricyclic fused-heterocycle, wherein tricyclic fused-heterocycle fusedheterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

a) (C3-C14) carbocycle, wherein (C₃-Ci4)carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle; and

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from aryl, heteroaryl and fused-heterocycle, wherein aryl, heteroaryl and

fused-heterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z^l groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from fused-heterocycle, wherein fiised-heterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from bicyclîc aryl, tricyclic aryl, bicyclîc heteroaryl, tricyclic heteroaryl, bicyclic fused-heterocycle and tricyclic fused-heterocycle, wherein bicyclîc aryl, tricyclic aryl, bicyclic heteroaryl, tricyclic heteroaryl, bicyclic fused-heterocycle, and tricyclic fused-heterocycle are each independently substituted with one or more Z⁷groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from bicyclic fused-heterocycle and tricyclic fused-heterocycle, wherein bicyclic fused-heterocycle and tricyclic fused-heterocycle fiised-heterocycle are each substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is tricyclic fiised-heterocycle, wherein tricyclic fused-heterocycle fiised-heterocycle is ï

substituted with one or more Z groups and optionally substituted with one or more Z groups.

A spécifie value for Z¹⁰ is:

i) halo, (Ci-C6)haloalkyl; or ii) (Ci-Cfi)alkyl optionally substituted with -OH, -O(Ci-C₆)haloalkyl.

Another spécifie value for Zⁱ⁰ is halo.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from heteroaryl and fused-heterocycle, wherein heteroaryl and fusedheterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is fused-heterocycle, wherein fiised-heterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from bicyclîc aryl, tricyciic aryl, bicyclic heteroaryl, tricyclic heteroaryl bicyclic fused-heterocycle, and tricyclic fused-heterocycle, wherein bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, tricyclic heteroaryl bicyclic fused-heterocycle and tricyclic fused-heterocycle are each independently substituted with one or more Z⁷groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I arc compounds wherein R⁴ is selected from bicyclic fused-heterocycle and tricyclic fused-heterocycle wherein bicyclic fused-heterocycle and tricyclic fused-heterocycle fused-heterocycle are each substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from tricyclic heterocycle, wherein tricyclic heterocycle is optionally substituted with one or more groups each independently selected from halo, (Ci-C^Jalkyl, (C?C6)alkenyl, (Ci-C₆)haloalkyi, (C₃-C₇)cycloalkyl, -OH, -OtCi-C^alkyl, -SH, -S^-Cijalkyl, -NH2, -NH(Ci-Ci)alkyl and -N((Ci-C₆)alkyI)2, wherein (Cj-Cejalkyl is optionally substituted with hydroxy, -O(Ci-Cû)alkyl, cyano or oxo; and

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from tricyclic fused-heterocycle, wherein tricyclic fused-heterocycle fusedheterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.

__ - I

Another spécifie value for R⁴ is:

Cl

WW

WW f

Another spécifie value for R⁴ is:

Another spécifie value for R⁴ is;

Another spécifie value for R⁴ is:

ΛΛΛ/

Another spécifie value for R⁴ is:

AW

Another spécifie value for R⁴ is:

a) aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl is optionally substituted with one or more (e.g. 1,2,3,4 or 5) groups each independently selected from halo, (Ci-C₆)alkyl, (Cj-C^alkenyl, (Ci-C₆)haloalkyl, (C₃C₇)cycloalkyl, -OH, -OfC^Jalkyl, -SH, -SfCj-Csjalkyl, -NH₂, -N’HfCrCôfalkyl and NffCi-Cejalkyl^, wherein (C|-C₆)alkyl is optionally substituted with hydroxy, -O(CiCé)alkyl, cyano or oxo; and

b) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle, and bridgedheterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedheterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more (e.g. 1,2,3,4 or5 ) Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁴ is selected from aryl, heteroaryl, spiro-heterocycle, fused-heterocycle, and bridgedheterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedheterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or5 ) Z¹ groups.

a) heterocycle, wherein any heterocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) groups each independently selected halo, (Ci-Ce)alkyl and (Cityhaloalkyl; and

b) fused -heterocycle, wherein fused-heterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or5 ) Z¹groups.

Another spécifie value for R⁴ is heterocycle.

Another spécifie group of compounds of formula I are compounds wherein the stereochemistry of the R⁴ substituent relative to the carbon of formula I to which it is attached îs the (R) stereochemistry.

Another spécifie group of compounds of formula I are compounds wherein the stereochemistry of the R⁴ substituent relative to the carbon of formula 1 to which it is attached is the (S) stereochemistry.

Another spécifie group of compounds of formula I are compounds wherein R¹ is selected from:

a) H, halo, (CpC$)alkyl and (Ci-Céjhaloalkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C3-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) -C(=O)-Rⁿ, -CiOyO-R¹’, -O-R¹¹, -S-R¹¹, -StOJ-R¹¹, -SCh-R¹¹, -(CrCfejalkyl-R¹', -(CrC^alkyl-C^Oj-R¹¹, -(Ci-C6)alkyl-C(=O)-O-R¹¹, -(Ct-C6)alkylO-R'¹, -(Cj-CfiJalkyl-S-R¹¹, -(Ci-CgJalkyl-SiOJ-R¹¹ and -(Ci-C6)alkyl-SO_?-R, wherein each R¹¹ is independently selected from H, (Ci-C^jalkyl, (C₂-C(,)alkenyl, (C₂C₆)alkynyl, (Ci-C$)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, and wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

d) -N(R⁹)R^1ü, -CX-CO-NCR^R¹⁰, -O-C(-O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R¹⁰, -(Ci-C6)alkyl-N(R⁹)R^lc, -(Ci-Cfi^kyl-Ct^OJ-NCR^R¹⁰, -(CrC6)alkyl-O-C(=O)N(R⁹)R^W and -(Ci-C6)alkyl-SO2-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Ci-C6)alkyl and (C3-C7)cycloalkyl, and each R¹⁰is independently selected from R’^XCrCfiJalkyl-R¹¹, -SO2-R^H, -C(=O)-Rⁿ, -C(=O)ORⁿ and -C(-O)N(R⁹)R, wherein each R¹¹ is independently selected from H, (C]-C₆)alkyL (C₂-C6)alkenyl, (C₂Cs)alkynyl, (Cj-Cs)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, and wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more „10

Z groups;

e) (Cj-C$)alkyl, wherein (Ci-C^alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and-Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁵ groups and optionally substituted with one or more Z¹ groups; and

g) (Ci-C₆)haloalliyl, (Cj C₇)carbocyclc, (C₂-C6)alkenyl and (C₂-C6)alkynyl, wherein (Cj-Csjhaloalkyl, (C3-C₇)caibocycle, (C₂-C6)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more (e.g. 1,2, 3,4 or 5) Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) H, halo and (Ci-C6>alkyl;

b) (C2-Cfi)alkenyi, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) -(Ci-Cejalkyi-R¹¹ and -(Ct-C6)alkyl-O-R^I], wherein each R¹¹ is independently selected from H, (Ci-C6)alkyl, (C₂-C6)alkenyl, (C₂-C$)alkynyl, (CjCeJhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

d) -C^Oj-NCR^R¹⁰ and <CrC6)a1kyl-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Ci-C6)alkyl and (C3-C?)cycloalkyl, and each R¹⁰ is independently selected from R^!l,-(Ci-C6)alkyl-R^l!, -SO2-R¹¹, “C(=O)-Rⁿ, -C(=O)ORⁿand -C(=O)N(R⁹)R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Cfi)alkyl, (C2-Ce)alkenyl, (C₂-C6)alkynyl, (Cq-C^haloalkyl, (C₃-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

e) (Ci-Cejalkyl, wherein (Ci-Ctjalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, heteroaryl and heterocycle, wherein aryl heteroaryl and heterocycle are each substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; and

g) (C₂-C6)alkenyl, and (C₂-C6)alkynyl, wherein (C₂Cé)alkenyl and (C₂-Cs)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) H, halo and (Ct-C^alkyl;

b) cyano, aryl, and heteroaryl, wherein any aryl or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) -(Ci-Côjalkyl-R¹ ’ and -(Ci-C6)alkyl-O-R^l wherein each R¹¹ is independently selected from H, (Ci-C6)aikyl, (C₂-C6)alkenyl, (C₂-Cô)aJkynyl. (CiCfjhaloalkyl, (C₃-C7)cycloalkyl, aiyl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

d) -CÎOÏ-NtR’jR¹⁰ and -(Ci-C6)alkyl-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (CrC₆)alkyl and (C₃-C₇)cycloalkyl, and each R^I0is independently selected from R¹¹, -(Q-Cdalkyl-R¹¹, -SOrR¹¹, -C(=O)-Rⁿ, -C(=O)OR^Uand -C(=O)N(R⁹)R”, wherein each Rⁿ îs independently selected from H, (Ci-C_b)alkyl, (C₂-C_b)alkenyl, (C₂-Ce)alkynyl, (Cj-C₆)haloalkyl, (C₃-C₇)cycloalky], aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroary) is optionally substituted with one or more Z¹⁰ groups;

e) (Ci-Cijalkyl, wherein (CrC_b)aIkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

f) aryl and heteroaryl, wherein aryl and heteroaryl are each substituted with one or more Z^s groups and optionally substituted with one or more Z¹ groups.

a) (C 1 -('èjalkyl, wherein (C i-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

b) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and-Xheterocycle; wherein any aryl heteroaryl and heterocycle either alone or as part of a group, is substituted with one or more (e.g. 1,2,3,4 or 5) Z⁵ groups and optionally substituted with one or more Z¹ groups; and

c) (Ci-C6)haloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl, and (C₂-C6)alkynyl, wherein (Cj-Csjhaloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C6)alkynyl aie each substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R¹ îs selected from:

a) (C)-C,₆)alkyl, wherein (Ci-C^jalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

b) aryl, heteroaryl and heterocycle, wherein aryl heteroaryl and heterocycle are each substituted with one or more Z^s groups and optionally substituted with one or more Z¹ groups; and

c) (C₂-C&)alkenyl, and (C₂-C₆)alkynyl, wherein (C₂-C6)alkenyl and (C₂-Cé)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

Another spécifie value for R¹ is:

Τ' JVW V

WW . k.

WW

ΛΛ/V

II . N and

Another spécifie value for R¹ is halo.

Another spécifie value for R¹ is fluoro.

Another spécifie value for R¹ is H.

Another spécifie value for R¹ H, halo or (Ci-Cf,)alkyl.

Another spécifie value for R¹ is H or halo.

Another spécifie group of compounds of formula I are compounds wherein R² is selected from:

a)

b)

H, (CpCfiJalkyl and -OfCi-C^alkyl;

(C₂-C₆)alkenyl, (C₂-C₆)aikynyl, (Ci-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;

c) C(^TO)-R^H, -C(=O)-O-Rⁿ, -S-R¹¹, -S(O)-Rⁿ, -SO2-R, -(CrC6)alkyl-R¹¹, -(CrC^alkyl-C^OJ-R¹¹, -(Ci-C^aikyl-C^Oj-O-R¹¹, -(Cl-C₆)alkyl· O-R¹¹, XCj-Céjalkyl-S-R'¹, -(CVC6)alkyl-S(O)-R^H and -(CrC^alkyl-SOj-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Ce)alkyl, (C2-C₆)alkenyl, (C₂Celalkynyl, (Ci-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl,

wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more Z¹¹ groups; and

d) -NfR^R¹⁰, -C(=O)-N(R⁹)R¹⁰) -O-C(=O)-N(R⁹)R¹⁰, -SCh-NfR^R¹⁰, -(Cr C₆)alkyl-N(R⁹)R¹⁰, <Ci-C6)alkyl-C(=O)-N(R⁹)R¹⁰, -(Ci-C6)alkyl-O-C(=O)-N(R⁹)R¹⁰, and -(Ci-C6)alkyl-SO2-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Ci-Ce)alkyl and (C3-C7)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, (Ci-CéXlkyl-R¹¹, -SO2-R¹¹, -C(=O>Rⁿ, -C(-O)OR¹¹ and -C(=O)N(R*)Rⁿ, wherein each R¹¹ is independently selected from H, (C]-Ci)alkyl, (C₂-C₆)alkenyl, (C₂C<j)alkynyl, (Cj-C^haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl.

e) (C₅-C₆)alkyl, wherein (C[-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

f) (Ci-Cfijhaloalkyl, (C3-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C]-C6)haloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more Z^s groups and optionally substituted with one or more Z¹ groups.

a) (C_I-C₆)alkyl;

b) (C₂-C6)alkeny! and (Ci-CeJhaloalkyl;

c) -(Cj-CeJalkyl-R¹¹ and -(CpC^alkyl-O-R¹¹, wherein each R¹¹ is independently selected from H, (Cj-Csjalkyl, (C₂-C6)alkenyl, (Cî-C^alkynyl, (CiCfi)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more Z¹¹ groups;

d) -(Ci-Csialkyl-NfR^R¹⁰, wherein each R⁹ is independently selected from H, (Q-C^alkyl and (C3-C7)cycloalkyl, and each R¹⁰ îs independently selected from R¹¹, -(Ci-Cfijalkyl-R¹¹, -SO2-Rⁿ, -C(=O)-Rⁿ, -C(=O)OR^1] and -C(=O)N(R⁹)R¹¹, wherein each R¹¹ is independently selected from H, (Cj-Csjalkyl, (C₂-C6)alkenyl, (C₂Câ)alkynyl, (Ci-Csjhaloalkyl, (Cî-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

e) (Ci-Ce)alkyl, wherein (Ci-C_fi)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

f) (C₂-Cé)alkenyl, wherein (C₂-C6)alkenyl is substituted with one or more Z⁶ groups and optionally substituted with onc or more Z¹ groups.

a) (Ci-C₆)alkyl;

b) (Cî-Cgjalkenyl and (Cj-Cejhaloalkyl;

c) -(Cj-Cejalkyl-R¹¹ and -(Ci-Cejalkyl-O-R¹¹, wherein each R¹¹ is independently selected from H, (C_rC^)alkyl, (C₂-Ci)alkenvl, (C₂-C₆)alkynyl, (CiC₆)haloalkyl, (Cj-CyJcycIoalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more Z¹¹ groups;

d) -(Ci-CeJalkyl-NiR^R¹⁰, wherein each R⁹ is independently selected from H, (Ci-Ce)alkyl and (C3-C?)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, -(Cj-CfiJalkyl-R¹¹, -SCh-R’¹, -C(=O)-R¹¹, -CÎ^OJOR¹¹ and -C(=O)N(R⁹)R^H, wherein each R¹¹ is independently selected from H, (C]-Cs)alkyl, (C2-Ce)aikenyl, (C₂Cû)alkynyl, (Cj-Cô)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

e) (Ci-C(,)a.ikyl, wherein (Ci-C^alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

f) (Ci-Cé)haloalkyl and (CrC^alkenyl, wherein (C_rC_b)haloalkyl and (C₂-Cfi)alkenyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) (Ci-Cejalkyl, wherein (Ci-Ce)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

b) (Cj-Cé)haloalkyl, (C3-C7)carbocycle, (CrCeJalkenyl, and (C₂-C₆)alkynyl, wherein (C|-C₆)baloalkyl, (C3-C7)carbocycle, (C₂-C₆)alkenyl and (C₂-C6)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) (Ci-Cû)alkyl, wherein (Ci-Cftjalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

b) (C₂-C6)alkenyl, wherein (C₂-C6)alkenyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) (Cj-Cejalkyl, wherein (Cj-Cs)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

b) (Ci-Céjhaloalkyl and (C₂-C6)alkenyl, wherein (Ci-Cb)haloalkyl and (C₂-C6)alkenyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

Another spécifie value for R is:

< Λ S ^ζί

0,, o

-s

0'

ΙΟ • ΊΙ 1· 1 or XyF

F

Another spécifie value for R² is methyl.

A

Another spécifie value for R is H.

Another spécifie group of compounds of formula I are compounds wherein R⁶ is selected from:

a)

b)

H, halo, (C|-Cfi)alkyl, and (Ci-Ce)haloalkyl;

(Cj-Cûjalkenyl, (C₂-C6)alkynyl, (C3-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups;

c) -C^Oj-R¹¹, -C(=O)-O-Rⁿ, -O-R¹¹, -S-Rⁿ, -S(O)-Rⁿ, -SCh-R, -(Ci-Côjalkyl-R¹¹, -(CrC6)alkyl-C(=O)-R¹¹, -(Ci-C6)alkyl-C(=0)-O-R¹¹, -(Ci-C6)alkylO-R¹¹, -(Ci-Ce)alkyl-S-R³¹, (C] C6)alkyl-S(O) R^,! and -(Ci-C6)alkyl-SO2-Rⁿ, wherein each R¹¹ is independently selected from H, (Ci-Céjalkyl, (C2-C6)alkenyl, (C₂Csjalkynyl, (Ci-C₆)haloalky!, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶ is optionally substituted with one or

α) -(Ci-C6)alkyI-O-(Ci-C6)aIky]-(C3-C7)carbQcycle, -(Ci-Ce)alkyl-S-(CiC6)alkyl-(C₃-C7)carb(x:ycle, -(C i -C6)alkyl-S(O)-(C i-C₆)alkyI-(C3-C7)carbocycle, -( C i Ce)alkyl-S02-(Ci-C6)alkyi-(C3-C7)caibocycle, -(C₂-C6)alkcnyl-(Ci-Cô)haloalkyl, -(C₂C₆)alkynyl-(C]-C₆)haloalkyl, -halo(Cî-C7)carbocycle_J-NR_<SO2NR_<:Rd_J -NR.SChOiCaC₇)carbocycle, -NR_aSO₂Oaryl, -(C₂-C6)alkenyl-(C3-C7)carbocycle, -(C₂-C₆)alkenylaryl, -(Cî-C^alkenyl-heteroaryl, -(C₂-C£)alkenyl-heterocyc)e, -(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, -(C₂-C6)aIkynyl-aryl, -<C₂-C₆)alkynyl-heteroaryl, -(^-Ο^ΗΠτγηγΙ-ΙιεΙεΓΟϋγοΙβ, -(C₃-C₇)carbocycle-Z^l or -halo(Ci-C6)alkyl-Z³, wherein any (Ci-C₆)alkyl, (Cj-C^haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle or heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z^J groups;

e) (Ci-Cé)alkyl, wherein (Ci-Cgjalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and—Xheterocycle, wherein any aryl heteroaryl and heterocycle either alone or as paît of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹groups; and

g) (Ci-Cé)haloalkyl, (C₃-C₇)carbocyc]e, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (Ci-Cejhaloalkyl, (C₃-C7)carbocycle, (C₂-C6)alkenyl and (C₂-Ce)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) H, halo and (C i -C^alkyl;

b) (C₂-C(i)alkenyl, (C₂-C₆)alkyny] and aryl, wherein any aryl is optionally substituted with one or more Z¹⁰ groups;

c) -(Cj-CfiJalkyl-R¹¹ and -(Ci-CfQalkyl O R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Ci)alkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (CiCfi)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶is optionally substituted with one or more Z¹⁰ groups;

d) -(C₂-C6)alkynyl-(C₃-C7)carbocycle, -(C₂-(^)alkynyl-aryl, -(C₂-C₆)alkynyl-heteroaryl and -(C₂-C₆)alkynyl-heterocycIe, wherein any

(C3-C₇)carbocyclc, (C2-C_b)alkynyl, aryl, heterocycle and heteroaryl, as part of a group, is optionally substituted with one or more Z* groups;

c) (C)-Cé)alkyl, wherein (Ci-Cé)alky) is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, wherein aryl is substituted with one or more Z^s groups and optionally substituted with one or more Z¹ groups; and

g) (C2-Cô)alkenyl and (C₂-C$)alkynyl, wherein (Cj-Cejalkenyl and (C2-C6)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) H, halo, (Ci-Cô)alkyl, and (Ci-Cgjhaloalkyl

b) (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (C3-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups;

c) -c(-o)-r'‘, -c(=o)-o-r‘ -s-r¹¹, -s(O)-r^h, -so₂-r^h,

-(Ci-C₆)alkyl-Rⁿ, -(Cj-C^alkyl-C^OJ-R¹¹, -(Cj-C^kyl-^OJ-O-R¹¹, -(Ci-C6)alkylO-R¹¹, -(C,-C6)alkyl S-R^l!, -(Ci-C6)alkyl-S(O)-R^H and -(CrCéJalkyl-SOz-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Cô)alkyl, (C2-Cô)alkenyl, (C_?Cejalkynyl, (C]-C₆)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups;

d) -(Ci-C6)alkyI-O-tC_l-C₆)alkyl-(C3-C7)carbocycle, -(Ci-C₆)alkyl-S-(CjC₆)alkyl-(C₃-C₇)carbocycle, -(CrC^alkyl-StOHCi-C^alkyl-lXYCvjcarbocyclc, -(CiC₆)alkyl-SO₂-(C 1 -C6)alkyl-(C3-C₇)carbocycle, -(C₂-C₆)alkenyl-(C] -Céjhaloalkyl, -(C₂C6)alkynyl-(Cj-C6)haloalkyl, -halo(C3-C₇)carbocycle,-NR_aSO2NR<Rd, -NRaSO₂O(C₃C₇)carbocycle, -NRaSO₂OaryI, -(C2-C_b)alkenyl-(C3-C₇)carbocyclc, -(C₂-C6)alkenylaryl, -(C₂-C6)alkenyl-heteroaryl, -(C2-C_fc)alkenyl-heterocycle, -(C2-C6)alkynyl-(C3-C₇)carbocycle, -(C2-C₆)alkynyl-aryl, -(C₂-C6)alkynyl-heteroaryl, -(C₂-C6)alkynyl-heterocycle, -(C₂-Cg)alkynyl-ORa, -(C₂-C6)alkyI-(C3-C₇)carbocycle-ORa, -(C3-C₇)carbocycle-Z^l and -halo(Ci-C6)alkyl-Z³, wherein any (Ci-Cf>)alkyl, (Cf-C^jhaloalkyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl,

(C2-Cfi)alkyiiyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups;

e) (Ci-Cfi)alkyl, wherein (Cj-Cs)alkyi is substituted with one or more Z²groups and optionally substituted with one or more Z'groups;

f) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; and

g) (Cj-Céjhaloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C(,)alkynyl, wherein any (Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C6)alkynyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z'groups.

a) H, halo and (CpC^alkyl;

b) (Cj-Cèlalkenyl, (C₂-C6)alkynyl and aryl, wherein any aryl is optionally substituted with one or more Z^t£> groups;

c) -(0,-0(,)3^141¹^ -(CrCfijalkyl-O-R¹¹, wherein each R¹¹ is independently selected from H, (C]-C₆)a]kyl, (C₂-C₆)alkcnyl, (C₂-C₆)alkynyl, (CjCgjhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶ is optionally substituted with one ot more Z¹⁰ groups;

d) -(C₂-C6)alkynyl-(C3-C₇)caTbocycle, -(C₂-C6)alkynyl-aryl, -(C₂-C6)alkynyl-heteroaryl -(C₂-C6)alkynyl-heterocycle, -(C₂-C_s)alkynyl-OR₃, and -(C2-C₆)aIkyl-(C₃-C₇)carbocycIe-OR_i, wherein -(C2-C₆)alkynyl-(C₃-C₇)carbocycle, -(C₂-C₆)alkynyl-aryl, -(C₂-C6)alkynyl-heteroaryl, -(C₂-C(,)alkynyl-heterocyclc, -(C2-C_g)alkynyl-ORa, and -(C2-C6)alkyl-(C3-C₇)carbocycle-OR<|, are optionally substituted with one or more Z¹ groups;

e) (Ci-Céjalkyl, wherein (Cj-Côjalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, wherein aryl is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; and

g) (C2-C&)alkenyi and (C₂-C6)alkynyl, wherein (C2-C₆)a]kenyl and (C₂-Cb)alky^rnyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z'groups.

a) H, halo, (Ci-Ce)alkyl, and (Ci-C^Jhaloalkyl

b) (C₂-C6)alkenyl, (C₂-C6)alkynyl, (C₃-C7)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R⁶is optionally substituted with one or more Z¹⁰ groups;

c) -C(- O)-R, -0(=0)-0^,-0^¹¹. -S-R¹¹, -S(0)-Rⁿ, -SO2-R¹¹, -(Ci-Csjalkyl-R¹¹, -(C]-C6)alkyl-C(-O)-R^1J, -(Ci-Cs^lkyl-Cf^-O-R¹¹, -(Ci-Ce)alkylO-R¹¹, -(CrQjalkyl-S-R¹¹, -(Ci-C6)alkyl-S(O)-Rⁿ and -(CpCeMkyl-SCb-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Câjalkyl, (C2-C₆)alkenyl, (C₂C(,)alkynyl, (Ci-Csjhalo alkyl, (Ci-Cîjcycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R⁶îs optionally substituted with one or more Z¹⁰ groups;

d) -(C!-C6)alkyl-O-(Ci-C6)alkyl-(C₃-C7)carbocycle, -(Ci-C6)alkyl-S-(Cr C6)alkyl-(C₃-C₇)carbocycle, -(C_rCe)alkyl-S(O)-(C i-C₆)alkyl-(C₃-C₇)carbocycle, -(C i C6)alkyl-SO2-(Ci-Cs)alkyl-(C3-C₇)carbocycle,-(C2-C6)a]kenyl-(Ci-C₆)haloaIkyl, -(C₂C6)alkynyl-(C]-C₆)haloalkyl, -halo(C₃-C₇)carbocycle,-NR₄SO2NR_<Rd, -NRaSO2O(C₃C₇)carbocycle, -NRaSOjOaryl, -(C2-C6)alkenyl-(C₃X3₇)carbocycle, -(Cî-Cejalkenylaryl, -(C₂-C6)aIkenyl-heteroaryl, -(C2-C₆)alkenyl-heterocycle, -(C2-Ce)alkynyl-(C3-C₇)carbocycle_i -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C₂-C₆)alkynyl-heterocycle, -(Cï-Cgjalkynyl-OH, -(C2'C₆)alkyl-(C3-C₇)carbocycle-OR_a, -(Ci-Cîjcarbocycle-Z¹ and -halo(Ci-C6)alkyl-Z³, wherein any (Cj-Côjalkyl, (Ci-C^jhaloalkyl, (C₃-C₇)carbocycle, (C2-C₆)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups;

e) (CrCgJalkyl, wherein (C|-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z’groups;

f) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is

g) (C2-Cé)alkenyl and (C₂-C6)alkynyl, wherein (C₂-C6)alkenyl and (C₂-C6)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z’groups.

a) H, halo, (Cj-CôjaJkyl, and (Ci-C6)haloalkyl

b) (C₂-C₆)alkenyl, (C2-C₆)alkynyl, (C₃--C/)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R⁶is optionally substituted with one or more Z¹⁰ groups;

c) -C(=O)-Rⁿ, -C(=O)-O-R^h, -O-R¹¹, -S-R^il, -S(O)-Rⁿ, -SO2-Rⁿ, -(Ci-C^alkyi-R¹¹, -(Ci-C^alkyl-C^Oj-R¹¹, -(CrCôjalkyl-C^O^O-R¹¹, -(CrC₆)alkylO-R¹¹, -(Ci-C6)alkyl-S-R^H, -ÎCj-CeJaJkyl-SÎO^R¹¹ and -(Cj-COalkyl-SOa-R¹¹, wherein each R¹¹ is independently selected from H, (C rCe)alkyl, (C₂-C₆)alkenyl, (C₂Cf,)alkynyl, (Ci-C6)haloalkyl, (C^-C-jcvcioalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups;

d) -(Ci-C6)alkyl-0-(Ci-C₆)alkyl-(C3-C7)carbocycle, -(Ci-C₆)alkyl-S-(C_tC₆)alkyl-(C₃-C₇)carbocycle, -(CrCéjalkyl-SiOXCrCeJalkyl-fCrCjjcarbocycle, -(C[C6)alkyl-S0₂-(Ci-C₆)alkyl-(C₃-C7)carbocycle, -(C₂-C6)alkenyl-(Ci-C₆)haloaIkyl, -(C₂C₆)alkynyl-(C_rC₆)haIoalkyl, -halo(C₃-C₇)carbocycle,-NR_aS0₂NRcR₍i, -NRaSO₂O(C₃C₇)carbocycie, -NR_aSO₂Oaryl, -(C₂-C6)alkenyl-(C₃-C₇)carbocycle, -(C₂-C₆)alkenylaryl, -(C^-C^alkenyl-heteroaryl, -(C₂-C₆)a!kenyl-heterocycle, -(C₂-C6)alkynyi-(C₃-C₇)carbocycle, -(CrCfJalkynyl-aryl. -(C₂-C6)alkynyl-heteroaryl, -(C₂-C6)alkynyl-heterocycle, -(C₂-Ca)alkynyl-OH, ~(C2-C₆)alkyl·(C₃-C₇)carbocycle-ORa, -(Ca-Cvjcarbocycle-Z¹ and -halo(Ci-C6)alkyl-Z³, wherein any (Ci-C₆)alkyl, (C|-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroary], either alone or as part of a group, is optionally substituted with one or more Z’groups;

e) (Ci-Côjalkyl, wherein (Ci-C^)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z’groups;

substituted with one or more Z⁵ groups and optionally substituted with one or more Z^J groups; and

g) (Ci-CsJhaloalkyl, (Cs-Cjjcarbocvcle, (C₂-Cô)alkenyl and (C₂-C6)alkynyl, wherein any (Ci-Cb)haloalkyl, (C₃-C₇)carbocycle, (C₂-C^)alkenyl and (C₂-C6)alkynyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) H, halo and (C|-C₆)alkyl;

b) (C₂“C6)alkenyI, (C₂-C6)aikynyl and aryl, wherein any aryl is optionally substituted with one or more Z¹⁰ groups;

c) -(C]-C6)alkyl-R^lland -(Ci-Célalkyl-O-R¹', wherein each R¹¹ is independently selected from H, (C|-C₆)alkyl, (C₂-C6)alkenyl, (C₂-C6)alkynyl, (CjC₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups;

d) -(C₂-C6)alkynyI-(C₃-C₇)carbocycle, -(C2-Cs)alkynyl-a.ryI, -(C₂-C₆)alkynyl-heteroaryl -(C₂-C6)alkynyl-heterocycle, -(C₂-Cg)alkynyl-OR_a, and -(C2-C6)alkyl-(C₃-C₇)carbocycle-ORa, wherein -(C₂-C6)alkynyl-(C3-C₇)carbocycle, -(C₂-C6)aIkynyl-aryl, -(C₂-C6)alkynyl-heteroaryl, -(Cj-C<,)alkynyl-hcterocycle, -(C₂-C8)alkynyl-OH, and -(C₂-C₆)a]kyl (C_rC7)carbocyde-OR_a, are optionally substituted with one or more //groups;

e) (Cj-C^aikyl, wherein (Ci-Cc)aikyl is substituted with one or more Z²groups and optionally substituted with one or more Z’groups;

f) aryl, wherein aryl is substituted with one or more Z⁵ groups and optionally substituted with one or more Z'groups; and

g) (C₂-Cô)alkenyl and (C₂-C6)alkynyl, wherein (C₂-C6>alkenyl and (C₂-C(,)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁶ is selected from;

a) -(CrC6)alkyl-O-(C_t-C6)alkyl-(C₃-C₇)carbocycle,-(Ci-C₆)alkyl-S-(CiC6)alkyl-(C₃-C₇)carbocycle, -(Ci-C7,)alkyl S(O)-(Cj-Q)alkyl-(C_rC₇)carbocyclc, -(Ci

C₆)alkyl-SO₂-(Ci -C6)alkyl-(C₃-C₇)carbocycle, -((.’₂-Cf,)alkcnyl-(CrCr,)haloajkyl, -(C₂16293

C6)alkynyl-(C]-C6)haloalkyI, -halo(C3-C₇)carbocycle,-NRaS02NR<;R<j, -NRaSGhOær C₇)carbocycle. -NR_BSO2Oaryl, -(C2-Ci,)alkenyl-(C₇-C₇)carbocycle, -(Cî-Csjalkenylaryl, -(Cz-CôJalkenyl-heteroaryk -(C₂-C6)alkenyl-hetcrocycle, -(C₂-C6)alkynyl-(C3-C7)carbocycle, -(Ci-CsJalkynyl-aryl, -(C₂-C6)alkynyl-heteroaryl, -(C₂-Cs)alkynyl-heterocycle, (Cs-Cjjcarbocycle-Z¹ and -halo(Ci-C6)aIkyl-Z³, wherein any (Ci-Cijalkyl, (Cj-Côjhaloalkyl, (C7-C₇)carbocycle_T (C₂-C₆)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroary], either alone or as part of a group, is optionally substituted with one or more Z¹ groups;

b) (Cj-C₆)alkyl, wherein (Ci-Cgjalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

c) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹groups; and

d) (Ci-Côjhaloalkyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C6)alkynyl, wherein (CpC^haloalkyl, (C3-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂~C6)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) H, halo and (Ci-Côjalkyl;

b) (C₂-C₆)alkenyl, (C₂-C6)alkynyl and aryl, wherein any aryl is optionally substituted with one or more Z¹⁰ groups;

c) -(Ci-Cfijalkyl-R¹¹ and-(Ci-C6)alkyl-O-R^!1, wherein each R¹¹ is independently selected from H, (Cj-Csjalkyl, (C₂-C6)alkenyl, (CS-CfJalkynyl. (CiCgjhaloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups;

d) -(C₂-C6)alkynyl-(C₃-C₇)carbocycle, -(C₂-C₆)alkynyI-aryl, -(C₂-C6)alkynyl-heteroaryl and -(C₂-C$)alkynyl-heterocycle, wherein any (C₃-C₇)carbocycle, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, as part of a group, is optionally substituted with one or more Z¹ groups;

e) (C|-Cf,)alkyl, wherein (Ci-Ce)alkyl is substituted with one or more Z²groups and optionally substituted with one or more 7? groups;

C

g) (C₂-C6)alkenyl and (Cj-C^jalkyiiyl, wherein (C2-Ce)alkenyl and (C2-Ce)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) -(C_t-C₆)alkyl-0-(CrC₆)alkyl-(C3-C7)carbocycle,-(C,-C₆)alkyl-S-(CiC₆)alkyl-(C3-C₇)carbocycle, -(Ci-C6)alkyl-S(O)-(Cj-C6)alkyl-(C3-C₇)carbocycle, -(Ci10 Cô)alkyl-SO2-(Ci-C6)alkyl-(C3-C₇)carbocycle, -(C2-Q)alkenyl-(Cj-C₆)haloalkyl, -(C₂C₆)alkynyl-(Ci-C6)haloaIkyl, -halo(C3-C₇)carbocycle,-NR_aSO2NR_cR<i, -NR^SOîCXCsC₇)carbocycle, -NR_aSO₂Oaryl, -(C^-C^alkciiyHCfoC^carbocyde, -(C₇-C0)alkenylaryl, ~(C₂-C₆)alkenyl-heteroaryl, -(C₂-CÉ)alkenyl-heterocycle, -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C^-Cejalkynyl-ary!, -(C2-Cè)alkynyl-hetcroaryl,

-(C₂-C6)alkynyl-heterocycle, -(C₂-C8)aikynyl-OR_a. -(C₂-C6)alkyl-(C3-C₇)carbocycle-ORa, -(Cî-C^carbocycle-Z¹ and -halo(C]-C6)alkyl-Z³, wherein any (C|-C_fc)alkyl, (Ci-Cfijhaloalkyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either aione or as part of a group, is optionally substituted with one or more Z¹ groups;

b) (C|-Cô)alkyl, wherein (C| C₆)alkyI is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups;

c) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle wherein any aryl heteroaryl and heterocycle, either aione or as part of a group, is substituted with one or more Z^s groups and optionally substituted with one or more Z¹ groups; and

d) (Cj-CgJhaloalkyl, (Cs-C-jJcarbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (CfoQlhaloalkyl, (C3-C₇)carbocycle, (C₂-C₆)alkcnyl and (C₂-C₆)alkynyl arc each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) H, halo and (CrCs)alkyl;

C

b) (Cî-Côjalkenyl, (Cp-Csjalkynyl and aryl, wherein any aryl is optionally substituted with one or more Z¹⁰ groups;

c) -(Cj-Csjalkyl-R¹¹ and -(CpCyalkyl-O-R¹¹, wherein each R¹¹ is independently selected from H, (CpCéJalkyl, (C₂-Cé)alkenyl, (C₂-C₆)alkynyl, (Cp

C₆)haloalkyl, (C₃0₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups;

d) -(C₂-C6)alkynyl-(C₃-C₇)carbocycle, -(C₂-C6)alkynyl-aryI, -(Ci-Csjalkynyl-heteroaryl, -(C₂-C₆)aIkynyl-hcterocycle, -(C₂-Cs)alkynyl-OR_a and -(C₂-C6)alkyl-(C₃-C₇)carbocycle-ORa, wherein any (C₃-C₇)carbocycle, (C2-C6)alkynyl, aryl, heterocycle and heteroaryl, as part of a group, is optionally substituted with one or more Z¹ groups;

e) (Cj-Csjalkyl, wherein (CpCfi)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

g) (C₂-Cé)alkenyl and (C₂-C₆)alkynyl, wherein (C₂-C6)alkenyl and (C₂-C6)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) -(CrC6)alkyl-O-(Ci-C6)alkyl-(C₃-C7)carbocycle, -(Ci -Cejalkyl-S-fCp C6)alkyl-(C₃-C₇)carbocycle, -(C]-C6)alkyl-S(O) (C_rC₆)alkyl-(C_vC₇)carbocycle, -(Cp Cs)alkyl-SO2-(Ci -C6)alkyl-(C₃-C₇)carbocycle, -(Cj-Cejalkenyl-tCpCsjhaloalkyl, -(C₂C6)alkynyI-(Ci-C₆)haIoaikyl,-haIo(C₃-C₇)carbocycle,-NR_aS02NR_cRd, -NR_aS0₂O(C325 C₇)carbocycle, -NR_aSO₂()aryl, -(C2-C6)alkenyI-(C₃-C₇)carbocycle, -(C₂-C6)alkenylaryl, -(C₂-C₆)alkenyl-heteroaryl, -(C2-C₆)alkenyl-heterocycle, -(C2-Câ)alkynyl-(C₃“C₇)carbocycle, -fC₂-C₆)alkynyl-aryl, -(C₂-C$)alkynyl-heteroaryl, -(C₂-C₆)alkynyI-heterocycle, -(C₂-Cg)alkynyl-OH, -(C₂-C₆)alkyl-(C₃-C7)carbocycle-ORa, -(CpC^carbocycle-Z¹ and -ha!o(Ci-Ct,)alky|-Z’, wherein any (C]-C₆)alkyl, (C|-C₆)haloalkyl, (C₃-C7)carbocycle, (C₂-C₆)alkenyl, (C₂-Cé)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups;

b) (Cj-CsJalkyl, wherein (Cj-Céjalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

d) (Ci-Ceïhaloalkyl, (C3-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C_r C₆)haloalky], (C3-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C6)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

a) H, halo and (Cj-Côjalkyi;

b) (C₂-C6)alkenyl, (CVCôjalkynyl and aryl, wherein any aryl is optionally substituted with one or more Z¹⁰ groups;

c) -(Ci-Cslaikyl-R¹¹ and -(C'i-Cô/aikyl-O-R¹¹. wherein each R¹¹ is independently selected from H, (Ci-Cgjalkyl, (C2-C_é)alkenyl, (C₂-C₆)alkynyl, (C_tCfjhaloalkyi. (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups;

d) -(C2-C6)alkynyi-(C3-C₇)carbocycle, (C₂’C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryI, -(C2“C6)alkynyl-heterocycle, -(C₂-C8)alkynyI-OH and -(C₂-C6)alkyl-(C3-C₇)carbocycle-OR_a, wherein any (C3-C₇)carbocycle, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, as part of a group, is optionally substituted with one or more Z¹ groups;

e) (C;-Cfc)alkyl, wherein (Cj-CsJalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

g) (C₂-Cé)alkenyl and (CrCeJalkynyl, wherein (C₂-C₆)alkenyl and (C₂-Cfi)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

Another spécifie value for R⁶ is:

Another spécifie value for R⁶ is

HO.

.OH

HO.

Another spécifie value for R⁶ is H.

Another spécifie group of compounds of formula I are compounds wherein R is selected from:

a) H, halo, (CT-C₆)alkyl and (Cj-Cf,)haloalkyl;

b) (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z⁾⁰ groups;

c) -C(=())-O-R, -O-R¹¹, -S-Rⁿ, -SlOî-R¹-SOs-R¹¹, -(Ci-C6)alkyl-R¹¹, -(Ci-C6)alkyl-C(-O)-Rⁿ, -(Cj-C^alkyl-C^-O-R¹¹, -(Ci-C6)alkylO-R’‘,-(CrC6)alkyl-S-R¹¹, <CrC₆)alkyl-S(O)-R^H and -(CrCsÎalkyl-SO^R¹¹, wherein each Rⁿ is independently selected from H, (Ci-Ce)alkyl, (C₂-C5)alkenyl, (C₂Cg)alkynyl, (Ci-Ce)haloalkyl, (C₃-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl îs optionally substituted with one or more

Z groups;

d) -N(R⁹)Rⁱ⁰, -C(=O)-N(R’)R¹⁰, -O-C(=O)-N(R⁹)R¹⁰, -SO2-N(R⁹)Rⁱ⁰, -(CT-C6)alkyl-N(R⁹)R^!0, -(C]-C6)alkyl C(-O)-N(R⁹)R(Ci-C6)alkyl-O-C(=O)N(R⁹)R¹⁰ and -(Ci-C6)alkyl-SO2-N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (Ci-Côjalkyl and (C3-C7)cycloalkyl, and each R¹⁰ is independently selected ίππη R^{1 È},-((T-Côjalkyl-R¹*SO?“R^!-C( -O)-R^1!, -C(=O)0Rⁿ and -C(-O)N(R⁹)R^!wherein each R^I] is independently selected from H, (Ci-C6)alkyl, (C₂-C6)alkenyl, (C₂C'ôjalkynyl, (CrQjhaloalkyl, (C₃-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z groups;

e) (Ci-Csïalkyl, wherein (CrCôjalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein aryl, heteroaryl and heterocycle are each substituted with one or more Z^sgroups and optionally substituted with one or more Z¹ groups;

g) (Cj-Cftlhaloalkyl, (C₃-C₇)carbocycle, (C₂-Ce)alkenyl and (Cî-Cgjalkynyi, wherein (Ci-Côjhaloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C6)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

h) -NRcRt, -CXOJNRcRf, -OC(0)NReR_f, -SO_?NR_eR_{, -(CrCsjalkyl-NReRf, -(Ci-CeialkylCtOJ-NR.Rf, -(Ci-^alkyl-O-QOJ-NReRf and -(CrC^alkyl-SOiNR^Rf, wherein each (Ci-Cf,)alkyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

Another spécifie group of compounds of formula I are compounds wherein R⁷ is selected from:

a) H, halo, (Ci-(X)alkyl and (C]-C₆)haloalkyl;

b) (C₃-C₇)cycloalkyl, cyano, aryl and heteroaryl, wheiein any aryl, or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) -C( - O)-N(R⁹)R^] °, wherein each R⁹ is independently selected from H, (Ci-C6)alkyl and (C3-C7)cycloalkyl, and each R^,ois independently selected from R¹¹, (C]-C6)alkyl-Rⁿ, -SO2-R^H, -C(=O)-R^H, -C(-O)OR and -C(=O)N(R⁹)R^H, wherein each R¹¹ is independently selected from H, (Ci-C^alkyl, (C2-C6)alkenyl, (C₂C&)alkynyl, (Ci-C6)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z groups;

d) (Ci-Célalkyl, wherein (Ct-Cejalkyl is substituted with one or more Z²groups and optionally substituted with onc or more Z¹ groups;

e) aryl and heteroaryl, wherein aryl and heteroaryl are each substituted with one or more Z^s groups and optionally substituted with one or more Z¹ groups;

f) (C[ -C(,)haloalkyl and (C₃-C₇)carbocycle, wherein (Cj-C^haloalkyl and (C₃-C₇)carbocycle are each substituted with one or more Z^& groups and optionally substituted with one or more Z¹ groups; and

g) -C(O)NReRf.

a) (Ci-Cejalkyl, wherein (C|-C&)alky] is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

b) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein aryl, heteroaryl and heterocycle are each substituted with one or more Z⁵groups and optionally substituted with one or more Z¹ groups;

c) (Cj-Cyhaloalkyl, (C₃'C₇)carbocycIe, (C₂-C6)alkenyl and (C₂-Cfi)alkynyl, wherein (Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (G.>-(X,)alkenyl and (C₂-C_â)alkynyl are

each substituted with one or more Ζ^δ groups and optionally substituted with one or more Z¹ groups; and

d) -NR^Rf, -CCOJNReRf, -OCyOjNR^Rf, -SC^NR^f, -(CrCéjalkyl-NKRf, -(Ci-CfOalkylCO-NKRf, -(CrC^alkyl-O-CO-NR^ and -(Ci-C₆)alkyl-SO₂NR_cR_f, wherein each (Ci-Ce)alkyl is substituted with one or more Ζ^ύ groups and optionally substituted with one or more Z¹ groups.

a) (Cj-C₆)alkyl, wherein (Ci-Cejalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

b) aryl and heteroaryl, wherein aryl and heteroaryl are each substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups;

c) (Cj-CéJhaloalkyl and (CrCvjcarbocycle, wherein (Ci-Ce)haloalkyl and (C₃-C₇)carbocycle are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

d) -C(O)NReRf,.

a) H, halo, (Ci-Côjalkyl and (Ci-C₆)haloalkyl;

b) (C3-C₇)cycloalkyl, cyano, aryl and heteroaryl, wherein any aryl, or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) -O-R¹¹ and -(Ct-C^alkyl-O-R¹¹, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

d) -C(=O)-N(R⁹)R¹⁰ and -(C|-C6)alkyl-N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (CpCyalkyl and (C3-C7)cycloalkyl, and each R¹⁰is independently selected from R^II,-(Cl-CÉ)alkyl-R’¹, -SO2-R¹¹, -C( OJ-R¹ *, -C(=O)OR¹¹and C(’“O)N(R⁹)R¹ *, wherein each R¹¹ is independently selected from H, (Cj-C^jalkyl, (C₂-C6)alkenyl, (C₂-C₆)alkynyl, (C|-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl îs optionally substituted with one or more Z¹⁰ groups;

e) (C|-C₆)alkyl, wherein (Ci-Cô)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl and heteroaryl, wherein aryl and heteroaryl are each substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; and

g) (Cj-CY) haloalkyl and (Cs-C-jcarbocycle, wherein (Cj-Csjhaloalkyl and (C₃-C7)carbocycle are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

h) -C(O)NReRf.

Another spécifie value for R⁷ is:

Η^λ . ^XO		ιΡΛ	σ'	σ'
n-nh	HN-		(Y KJ	σ'
		Ιτ
Ί	σ'.	\^N 1	C?	Cl^ 1
	Y .	F^A- F ’	r\

Λ

OH and

Another spécifie value for R⁷ is

A . a -v F

Another spécifie value for R⁷ is H, halo, (Ci-Ct)alkyl, (Ci-C6)haloalkyl and heteroaryl, wherein heteroaryl is optionally substituted with one or more Z¹⁰ groups.

Another spécifie value for R⁷ is H, (Ci-Cô)alkyl or (Ci-C₆)haloalkyl.

Another spécifie value for R is H.

Another spécifie group of compounds of formula I are compounds wherein R⁸ is selected from:

a) halo, nitro and cyano;

b) R¹¹, -C(=O>R^1J, -C(=O)-O-R“, -O-R^h, -S-R, -SCO)-Rⁿ, -SO2-R? (Ci-C6)alkyl-Rⁿ, -(Ci-CeJalkyl-C^R¹¹, -(Cr^alkyl-Cf^-O-R¹¹, -(Cj-C6)alkylO-R¹¹, -(Ci-C^alkyl-S-R¹¹, -(C1-C6)alkyl-S(O)-R^u and -(C'i-C6)a!kyl-SO₂-R¹¹,wherein each R¹¹ is independently selected from H, (Ci-Cé)alkyl, (C₂-C6)alkenyl, (C₂Cs)alkynyl, (Ci-C^lhaloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹¹ groups;

c) -N(R⁹)R¹⁰. -C(=O)-N(R⁹)R¹⁰, -O-C( ())-N(R⁹)R‘°, -SO2-N(R⁹)R¹⁰, -(CjC6)alkyl-N(R⁹)R¹⁰, -(ÎT-C^alkyl-CC-Oj-N/RV'⁰, -(CrC6)alkyl-O-C(=O)-N(R⁹)R¹⁰and -(CrC6)alkyl-SO₂-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Ci-Ce)alkyl and (C3-C7)cycloalkyl, and each R^l0is independently selected from R¹¹, (Ci-Cgjalkyl-R¹¹, -SO2-R”, -C(=O)-Rⁿ, -C(=0)ORⁿ and -C(=O)N(R⁹)Rⁿ, wherein each R¹¹ is independently selected from H, (Cj C^alkyl, (C₂-C₆)alkenyl, (C₂C6)alkynyl, (Cj-Cslhaloalkyl, (C₃-C7)cycloalkyl, aryl, heterocycle and heteroaryl;

d) (Ci-C6)alkyl, wherein (Ci-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, îs substituted with one or more Z^s groups and optionally substituted with one or more Z¹groups;

f) (C₍-C_s)haloaikyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C6)alkynyl, wherein (Ci-C₆)haloalkyl, (Cj-C/jcarbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

g) -NReRf, -C(O)NR_eR_f, -OC(0)NR_eR,. -SO₂NR_rR_f, -(CrCyalkyl-NR^Rf, -(CrCeialkylQOkNR^Rf, -(CrCeïalkyl-O-CÎOJ-NIkRf and -(C]-CJalkyl-SO.NRJ^-.

t 80 wherein any (Cj-C^jalkyl, as part of a group, is substituted with one or more Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups.

a) halo and cyano;

b) R¹¹, -O-R¹¹ and -(Ci-C^alkyl-R¹ \ wherein each R¹¹ is independently selected from H, (Ci-C₆)alkyl, (C₂-C6)alkenyl, (C₂-C₆)alkynyl, (Ci-C₆)haloalkyl, (C₃C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹¹ groups;

c) -C(=O)-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C|-C₆)alkyl and (C₃-C₇)cycloalkyl, and each Rⁱ⁰ is independently selected from R¹¹, (Ci-Côjalkyl-R¹¹, -SO^-R¹¹. -C^Oj-R¹¹, -C(-O)ORⁿ and -C( O)N(R⁹)r, wherein each R^u is independently selected from H, (Ci-Ce)alkyl, (C₂-C6)alkenyl, (C₂·C₆)alkynyl, (Ci-Cftjhaloalkyt, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

d) (CrC₆)alkyi, wherein (Ci-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups;

e) aryl and heteroaryl, wherein aryl and heteroaryl are each independently substituted with one or more Z^s groups and optionally substituted with one or more Z¹groups;

f) (C₂-C6)alkynyl, wherein (C₂-C6)alkynyl is substituted with one or more

Z⁶ groups and optionally substituted with one or more Z¹ groups; and

g) -C(O)NReR_f.

Another spécifie group of compounds of formula I are compounds wherein R⁸is selected from:

a) (Cj-CeJalkyl, wherein (C ; -C<,)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups;

b) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups;

c) (C]-Cô)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (Cj-C^jhaloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C6)alkynyl are

each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

d) -NReRf, -C(O)NR<Rf, -OC(O)NR*R_f, -SCANR^Rf, -(C_rC₆)alkyl-NR_<R_f, -(C_t-C₆)alkylC(O)-NR<Rf, -(Ci-C₆)alkyl-O-C(O)-NR_eR_f and -(C_l-C₍₁)alkyl-SO₂NR_<R_f. wherein any (Ci-C<,)alkvl, as part of a group, is substituted with one or more Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups.

a) (Cj-Côjalkyl, wherein (Ci-Ce)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

b) aryl and heteroaryl, wherein aryl and heteroaryl are each independently substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups;

c) (C₂-C&)alkynyl, wherein (C₂-C6)alkynyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

d) -C(O)NReR_f.

Another spécifie value for R⁸ îs.

uwv [ /O

II h₂n

Λ/W

WW

Λ

Another spécifie value for R is H.

Another spécifie value for R⁸ is H, (Ct-C^alkyl or halo.

Another spécifie group of compounds of formula I are compounds wherein each Rg is independently selected from OR_a (Ci-Cejalkyl, (C3-C7)carbocycle

(Ci-C6)haloalkyl, (CS-CsjalkenyL (C₂-Ce)alkynyl, aryl, heterocycle and heteroaryl, wherein any (C]-C₆)alkyl, (C₃-C₇)carbocycle -(Ci-C₆)haloalkyl, (C₂- C₆)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle or heteroaiyl of Rg is optionally substituted with one or more Z¹ groups.

In one embodiment the compounds of formula I include compounds wherein:

R¹ is R^laorR^lb

R³ is R²® or R^2b

R³ isR^3aorR^3b

R³’ is R³® or R^3b

R⁴ is R^4a or R^4b

R⁵ isR^5aorR^5b

R⁶ is R⁶® or R⁶¹’

R⁷isR^7aorR^7b

R⁸ is R^8a or R^Sb

R^la îs selected from:

a) H, halo, (C]-C₆)alkyl and (C]-Ct)haloalkyl;

b) (C₂-C6)alkeny], (C₂-C₆)alkynyl, (C3-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O)-R¹¹, -C(O)-ORⁿ, -O-R^h, S-R”, -S(O)-Rⁿ, -SOz-R¹¹, -(Ci-Cfijalkyl-R¹¹, -(C]-C6)alkyl-C( =O)-R, -(CrC^alkyl-CCOj-O-R¹¹, -(CrC₆)alkylO-R¹¹, -(Ci-C6)alkyl-S-R, -(Cj-C6)alkyl-S(O) R¹¹ and (CrCéialkyl-SOz-R¹¹; wherein each R^L1 is independently selected from H, (Ci-Cgjalkyl, (C2-C6)alkenyl, (C₂C₍,)alkynyk (C[-C₆)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R¹⁰, -C(=O)-N(R⁹)R'°, -O-C(- -O)-N(R⁹)R^1ü, -SO2-N(R⁹)R^w, • (C1-L'_f>)alky)-N(R⁹)R^lc,-(C]-C6)alkyI-C(“O)-N(R⁹)R¹⁰, -(Cj-Cejalkyl-O-C^O)N(R⁹)R¹⁰ and -(Cj-C6)alkyl-SO2-N(R⁹)R¹⁰; wherein each R⁹ îs independently selected from H, (Ci-Cs)alkyl and (C3-C₇)cycloalkyl; and each R¹⁰is independently selected from R'^-fCi-C^alkyl-R¹¹, -SO2-R, -C(=O)-R^]1, C(=O)ORⁿ and -C(=O)N(R⁹)Rⁿ; wherein each Rⁿ is independently selected from H, (Ci~C6)alkyl, (C₂-C₆)alkenyl, (C₂ G,)alkynyl, (C_rC₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

wherein any aryl, heterocycle or heteroarylof R isoptionally substituted with one or more (e.g. 1, 2 or 3) Z¹⁰ groups;

R^lb is selected from;

a) -(C_I-C₆)alkyl-0-(Ci-C6)alkyl-(C3-C7)carbocycle_i-(C_I-C₆)alkyl-S-(C₁C₆)alkyl-(C₃-C7) carbocycle, -(C_rC_b)aikyl-S(O)-(Ci-(Y)alkyl-(C3-C6) carbocycle, -(CjC₆)alkyl-S02-(C₁-C₆)a]kyl-(C₃-C₇)carbocycle, -(Ci-C₆)alkyl-SO2-(Ci-C₆)alkyl-Z¹³,C(O)-(CrC6)alkyl-Z¹³, -O-(CrC6)alkyl-Z¹³, -S-fCi-CejalkyLZ’³, -S(O)-(Ci-C6)alkylZ¹³, -SO2-(Ci-C6)a]kyl-Z¹³, -(C,-C6)alkyl-Z¹⁴, -(CI-C6)alkyl-C(O)-(Ci-C6)alkyl-Z¹³, (CrCsjalkyl-CtOl-OiCrCeJalkyl-Z¹³, -(CrCsJalkyl-O-iCrCeJalkyl-Z¹³, -(CrC₆)alkyl-

S-(Ci-C₆)alkyl-Z¹³, -(C2-C6)alkenyl-(C1-C6)haloalkyl, -(C2C6)alkynyl-(CrCi)haloalkyl, - (C3-C7)halocarbocycle,-NRaS02NRcRdî -NRaSO2O(C3C7)carbocycle, -NRaSO?Oaryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(Cï-Csjalkenylaryl, -(C2-C6)alkenyl-heteroaryl, -(C2-C6)alkenyl-heterocycle, -(C2-CÉ)alkynyl-(C3CLjcarbocyde. -(C2-C6)alkynyl-aryl, -(C2-Cb)alkynyl-heteroary'l -(Cj-C/alkyuylheterocycle, -(Ca-C^jcarbocycle-Z¹ or -halo(Cj-C6)alkyl-Z³; wherein (Ci-Ce)alkyl, (Cj-Cejhaloalkyl, (C3-C₇)carbocycle, (C2-C₆)aikenyl, (C₂-C6)alkynyl, aryl or heteroaryl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a carbocycle or heterocycle wherein the carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

c) (Ci-C_b)alkyl; wherein (CfCYlalkyl is substituted wîth one or more Z²groups and optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups;

d) -X(Ci-C₆)alkyl, -X(Ci-C₆)haloalkyl, -X(C₂-C«)alkenyl, -X(C₂-C6)alkynyl and -X(C₃-C7)carbocycle; wherein (Ci-C₆)alkyl and (Cj-C_b)haloalkyl are each substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups; and wherein (C₂-C6)alkenyl, (C₂-C_b)alkynyl and (C₃-C₇)carbocycle are each substituted with one or more (e.g. 1,2, 3,4 or 5) Z⁴ groups and optionally substituted with one or more Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and-Xheterocycle; wherein aryl heteroaryl and heterocycle are each substituted with one or more (e.g. 1,2,

3,4 or 5) Z⁵ groups and optionally substituted with one or more Z¹ groups;

f) (Ci-CôJhaloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and (Ci-Cejalkynyl; wherein (C]-C₆)haioalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl and (C2'Cé)alkynyI are each substituted with one or more (e.g. I,2,3,4or5) Z⁶ groups and optionally substituted with one or more Z¹ groups; and

g) -NReRf, -C(O)NR_eR_f, -OC(O)NR_cR_1? -SO₂NR_eR_f, -(Ci-C₆)alkyl-NR_cR_t(CrCejalkylCXOj NR^Rf, -(Ci-C₆)alkyl-O-C(O)-NR_eR_f and -(C_t- C₆)alkylSO₂.NR_<R₁; wherein each (Ci-C₆)alkyl is substituted with one or more (e.g. 1,2, 3,4 or 5) Z⁶groups and optionally substituted with one or more Z¹ groups;

R^2a is selected from:

a) H, (C_t-C₆)alkyl and -O(Ci-C₆)alkyl;

b) (Cz-CbJalkenyl, (C₂-C6)alkynyl, (Ci-C^jhaloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;

c) C(O)-R“, -C(--O)-O-R^h, -S-R¹¹, -S(O)-Rⁿ, -SOrR¹¹, -(Cj-C^alkyl-R¹¹, -(CrC^alkyl-C^OJ-R¹¹, -(Ci-C6)aIkyl-C(=O)-O-R^H, -(Ci-C6)alkylO-R’ViCrCfOalkyl-S-R¹’, -(CYC6)aikyl-S(O)-R^1! and -(CrC₆)alkyl-SO₂-R^1!; wherein each R¹¹ is independently selected from H, (Ci-C6)alkyl, (C₂-C6)alkenyl, (C₂C₍,)alkynyk (Ci-C₆)haloalkyl, (C₃~C₇)cycloalkyl, aryl and heterocycle and heteroaryl; wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z¹¹ groups;

d) -OH, -O(C₂-C₆)alkenyl, -O(C₂-C₆)alkyTiyl. -O(C]-C₆)haloalkyl, -O(C₃C₇)cycioalkyl, -Oaryl, -Oheterocycle and -Oheteroaryl;

e) -N(R⁹)R¹⁰, -C(=O)-N(R⁹)R¹⁰, -O-C(=O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R¹⁰, -(Cr C₆)a!kyl-N(R⁹)R¹⁰, -(Ct -C6)alkyl-C(=O)-N(R⁹)R¹⁰, -(CrC₆)alkyl-O-C(=O)-N(R⁹)R^l°, and -(Ci“C6)alkyl-SO2-N(R⁹)R¹⁰; wherein each R⁹ is independently selected from H, (Ci-Céjalkyl and (C3-C₇)cycloalkyl; and each R¹⁰is independently selected from R¹’, -(Cj-C<$)alkyl-R^H, -SO2-Rⁿ, -C(= O)-R^1:, C(=O)ORⁿ and -C(=O)N(R⁹)Rⁿ; wherein each R¹¹ is independently selected from H, (Ci-Céjalkyl, (C2-C₆)alkenyl, (CrC’ôlaikynyl, (Ct-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

R^2b is selected from:

ΙΟ

a) -(Ci-C6)alkyl-O-(Ci-C6)alkyl-(C3-C7)carb0cycle, -(C_t -C«)alkyl-S-(CiCfjalkyl-(C'3-C₇)carbocycle, -(C_]-C₆)alkyl-S(O)-(Ci-C₆)alkyl-(C₃-C₇)carb<)cycJe.(CiC6)alkyl-SO₂-(Ci -C₆)alkyl-(C3-C7)carbocycle, -(C2-C₆)alkenyl-(C i-C₍₎)haloalkyL -(C₂Cejalkynyl-CCrC^haloalkyl, -(CrC₆)alkyl-SO₂-(Ci-C₆)alkyl-Z¹³, -C(OXCj-C6)alkylZ'³, -O-(CI-C₆)aikyl-Z¹³, -S-(C,-C6)alkyl-Z¹³, -S(O)-(C!-C6)alkyl-Z¹³, -SO2-(Cr C6)alkyl-Z¹³, -(CrC₆)aIkyl-Z¹⁴, -(Ci-Cfiialkyl-CtOXCj-Câjalkyl-Z¹³, -(C^alkylC(O)-O(C,-C6)alkyl-Z¹³, -(CrC^alkyl-O-CCrCUalkyl-Z¹³, -(Ci-C6)alkyl-S-(C]Cejalkyi-Z¹³, -(C3-C7)halocarbocycle,-NReS02NRçR(f, -NRaSO2O(C3-C7)carbocycle, NRaSO2Oaryl, -(C2-C6)alkenyI-(C3-C7)carbocycle, -(C2-C6)alkenyl-aryl, -(C2-C6)alkenyl-heteroaryl, -(Cj-Cô/alkenyl-heterocyclc, -(C2-C6)alkynyl(C3-C7)carbocycle, ~(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynylheterocycle, -(C^-C^jcartecyde-Z¹ or -halo(Cj-C6)alkyl-Z³; wherein (Cj ~C\)alkyl, -(Ci-C6)haloalkyl, (C3-C7)carbocycle, (C₂-C6)alkenyl, (CrCsjalkynyl, aryl or heteroaryl are each optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle wherein the (C₃-C6)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (Ci-CsJalkyl; wherein (Ci-Cs)alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(C_rC₆)alkyl, X(C₁-C₆)haloalkyi, X(C₂-C₆)alkenyI, -X(C₂-C₆)alkynyl and -X(C₃-C₇)carbocycle; wherein (C]-C_fc)alkyi and (C]-C_fi)haloalkyl are each substituted with one or more Z³ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups; and wherein (C₂-C₆)alkenyl, (C_?-C₆)alkynyl and (C₃-C₇)carbocycle are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁴ groups and optionally substituted with one or more Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle; wherein aryl heteroaryl and heterocycle are each substituted with one or more (e.g. 1, 2,

3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹groups;

f) (C]-C6)haloalkyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl, and (C₂-C₆)alkynyl; wherein (Ci-C6)haloalkyl, (Ci-C-Jcarbocycle, (C₂-Cg)alkenyl and (C2-Ce)alkynyl are each substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -NReRf, -CONR^Rî, -OCfOjNR^Rf, -SO₂NReRf, -(C]-C₆)alkyl-NReR_f, -(C₁-C₆)alkylC(O)-NR_:Rf, -(Ci-COalkyl-O-C/OTNI^Rf and -(C₁-C₆)alkyl-SO₂NR_cR_f; wherein each (C_t -C₆)alkyl is substituted with one or more (e.g. 1,2,3, 4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

R³* is (Ci-Qjalkyl, (Ci-Côjhaloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(Ci-C6)alkyl-(CrC7)cycloalkyl, -(Ci-Cô)alkyl-aiyl, -(Cj-Cé/alkyl-heterocycle, ~(Ci-C6)alkyl-heteroaryl, -O(C]-C6)alkyi, -0(Ci-C6)haloalkyl, -O(C2-C6)alkenyl, -O(C2-C6)alkynyl, -0(C3-C;)cycloalkyl, -Oaryl, -O(Ci-C6)alkyl-(C3-C7)cycloalkyl, -O(C]-C6)alkyl-aryI, -O(CrC6)alkyl-hetcrocycle and -O(Ci-C6)alkyl-heteroaryl; wherein any (Cj-C6)alkyl, (Cj-C6)haloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl of R^3a is optionally substituted with one or more (e.g. I, 2 or 3) groups selected from -O(C]Céjalkyl, halo, oxo and -CN; and wherein any (C3-C7)cycloalkyl, aryl, heterocycle, or heteroaryl of R^îa is optionally substituted with one or more (e.g. 1, 2 or 3) groups selected from (Ci-C₆)alkyl, -O(Ci-C₆)alkyl, halo, oxo and -CN; and R^3a is H’

R^3b is -(C3-C7)carbocycte, aryl, heteroaryl, heterocycle, -(Ci-C6)alkylOH, -(Cr C6)alkyl-O-(Cl-C6)alkyl-Z¹², -(Cj-CfiJalkyl-O-tCz-Céialkenyl-Z¹²,-(C2-C₆)alkyl-O-(C₂C₆)alkynyl-Z¹², -(CrC6)aikyl-S-(CrC6)alkyl-Z¹², -(Ci-C6)alkyl-S-(C₂-C₆)alkenyl-Zⁿ (Ci-Céialkyl-S-fCz-C^alkynyl-Z¹², -(C] -C6)alkyl-S(O)-(C] -C6)alkyl-Z¹², -(Ci-C6)alkylS(O)-(C₂-C_s)alkenyl-Z¹², -(C2-C6)alkyl-S(O)-(C2-C6)alkynyl-Z¹², -(C,-C6)alkyl-SO2(Ci-C₆)alkyl-Z¹², -(Cri^alkyl-Sth-FF CNjaikenyl-Z’², -(C2-C6)alkyl-SO2-(C2C6)alkynyl-Z¹², -(C2-C₆)alkyl-NR_aR_b, (C₂-C₆)aIkylOC(O)-NRJLt, -(C₂-C₆)alkyI-NR_aC(O)-ORi„ -(C₂-C₆)alkyl-NR_a-C(O)-NR_aRb, -(Ci-C₆)aIkyl-SO₂l(’_;-C₆)alkyl. -(CjCejalkyl SO.NILRj, -(Ci-C₆)alkyl-NR_aSO₂NR_cR_d, -(C_t-C₆)alky!-NR_:.SO₂O(C₃. C7)carbocycle, -(Ci-C6)alkyl-NRaSO₂Oaryl, -(Ci-C6)alkyl-NR_a-SO₂-(C]-C6)alkyl, -(Ci-Cfi)alkyl-NRa-SO₂-halo(Ci-C6)alkyl, -(C_[-C₆)alkyl-NR_a-SO₂-(C₂-C₆)aIkenyl, -(C rC6)alkyl-NRa-SO₂-(C2-C6)alkyny 1, -(C j -Q/alkyl -NR_s-S02-(C3-C₇)carbocycle, -(C_I-C₆)alkyl-NR_a-S0₂-halo(C₃-C₇)carbocycle, -(C_I-C₆)alkyl-NR_a-SO2-aryl,

-(Ci-Cejalkyl-NRa-SOî-heteroaryl, -(C|-C6)alkyLNi<a-SO?-heterocycle, -O(C'r Cejalkyl-NRJLb, -OÎCi-QalkylOCÎOJ-NRJÎd, -OiCi-CéJalkyl-NRXXOj-ORb, -O(Ci-C6)alkyl-NR_M-C(O)-NR»Rh, -O(C_l-C₆)alkyl-NR_a-SO₂-(C_l-C_f>)alky], -O(C₁-C6)alkyl-NR_a-SO₂-halo(C_l-C6)alkyl, -O(Ci-C₆)alkyl-NR_a-SO₂-(C₂-C₆)alkeny], -O(C_t-C₆)alkyl-NR_a-SO₂-(C₂-C₆)alkynyl, -OtCi-Côjalkyl-NR^-SOaTCs-Cvjcarbocycle, -O(C_l-C6)alkyl-NR_a-SO₂-halo(C3-C7)carbocycle. -O(C _I-C6)alkyI-NR_a-SO₂-aryl, -O(Ci-C6)alkyl-NRa-SO₂-heteroaryl, -O(C)-C6)alkyl-NR_a-SO₂-heterocyclc, -O(C i -Cejalkyl-NRa-SC^-NRaRb, -O(C i-C₆)alkyl-NRa-SO₂-(C₃-C7)carbocycle, -0(C_J-C6)alkyl-NR_a-S0₂-halo(C₃-C₇)carbocycle, -O(Ci-C6)alkyl-NR_a-SO2-aryl, -O(CiC₆)alkyl-NR_aSO₂NR_cR_d, -O(C_l-C₆)alkyl-NR_aSO₂O(C3-C7)c:irbocyc!e, -O(C_rC₆)alkylNR_aSO₂OaiyI, -Oheteroaryl, -Oheterocyclc, -Sheteroaiyl, -Sheterocycle, -S(O)heteroaryl, -S(O)heterocycle, -SO₂heteroaryl or -SO₂heterocycle; wherein any (Cj-Cejalkyl, aryl, (C₃-C₇)carbocycle, heteroaryl or heterocycle of R^3b is optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups; and R^3b is H, (Ci-Cejalkyl or -O(Ci-C6)alkyl; or R^3b and R^3b together with the carbon to which they are attached form a heterocycle or (C₃-C7)carbocycle which heterocycle or (C₃-C₇)carbocycle of R^3band R^3b together with the carbon to which they are attached is optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups;

R^4a is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R^4a is optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) groups each independently selected from halo, (Ci-Ce)alkyl, (CrGQalkenyl, (Ci-C^Jhaloalkyl, (C₃C₇)cycloalkyl, -OH, -O(C|-C₆)alkyl, -SH, -SfCi-Csjalkyl, -NH₂₎ -NH(Ci-C₆)alkyl and N((Ci-C6)alkyl)2; wherein (Ci-C^alkyl is optionally substituted with hydroxy, -O(CiCijalkyl, cyano or oxo;

R^4b is selected from;

a) (Ci-Céjalkyl, (C₂-Cé)alkenyl and (C₂-C₆)alkynyl; wherein (Cj-Céjalkyl, (CrC(,)alkenyl or (C₂-Cs)alkynyl are each optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups;

b) (C₃-Ci4)carbocycle; wherein (C₃-Ci4)carbocycle is optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃C₇)carbocycle or heterocycle;

c) Spiro-heterocycle or bridged-heterocycle; wherein spiro-heterocycle ot bridged-heterocycle is optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹groups; or wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle;

d) aryl, heteroaryl, spiro-, fused-, or bridged-heterocycle; wherein aryl, heteroaryl, or spiro-, fused-, or bridged-heterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z^! groups; or

R⁴ and R³ together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle wherein any macroheterocycle or macrocarbocycle of R⁴ and R³ together with the atoms to which they are attached may be optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and R^3b is H or (Ci-C6)alkyl, -O(Ct-Cô)alkyl.

R^5a is selected from:

a) halo, nitro and cyano;

b) R¹ ’, -C(=O)-R‘ -C(-0)-0-R¹¹, -O-R¹ *, -S-R¹¹, -S(O)-R^[ *, -SO2-R^] \ (Ci-C6)alkyl-Rⁿ, -(CrC6)alkyl-C(=O)-R, -(Cj-Céialkyl-C^Oj-O-R¹¹, -(CrC₆)alkylO-R¹¹, -(CrC6)alkyl-S-R^H, -(Ci-C6)alkyl-S(O)-R^H and -(Cj-C^alkyl-SOz-R¹¹; wherein each R¹¹ is independently selected from H, (C]-C6)alkyl, (C₂-C6)alkenyl, (C₂C_g)alkynyl, (Cj-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z¹¹ groups;

c) -N(R⁹)R¹⁰, -C( O)-N(R⁹)R^1ü, -O-C(=O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R¹⁰, -(CiC6)alkyl-N(R⁹)R¹⁰, -(Cj-C6)alkyl-C( O)-N(R⁹)R^,c\ -(CrC₆)alkyl-O-C(-=O)-N(R⁹)R¹⁰, and -(CrCéjalkyl-SCh-bKR’jR¹⁰; wherein each R⁹ is independently selected from H, (Ci-C₆)alkyl and (C₃-C₇)cycloalkyi; and each R^iOis independently selected from R¹¹, -(Ci-CsJalkyl-R¹¹, -SO2-R¹¹, -C(=O)-R, C(=O)ORⁿ and -C(=O)N(R⁹)R^H; wherein each R¹¹ is independently selected from H, (Cj-Cejalkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (Ci-C₆)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

R^5b is selected from:

a) -(Ci-C6)alkyl-O-(Ci-C6)alkyl-(C3-C₇)carbocycle, -(C]-C6)alkyl-S-(CrC6)alkyl-(C3-C7)carbocycle,

-(C i -C6)alkyIS(O)-(Ci -C6)alkyl-(C3-C6)carbocycle,

-(C i-Cé)aIkylSO2(Ci-C6)alkyl-(C₃-C7)carbocycle, -(C₂-C₆)alkenyl-(Ci-C6)haIoaIkyl, (C₂-C₆)alkynyl-(Ci-C6)haloaIkyl, - (C₃-C₇)halocarbocycle, -NReSOîNRcRj, -NRaSO₂O(C₃-C₇)carbocycle, -NR_aSO₂Oaryl, -(C₂-C6)alkenyl-(C₃-C₇)carbocycle, -(Ci-Cfijalkenyl-aryl, -(C₂-C₆)alkenyl-heteroaryl, -(C₂-C₆)alkcnyl-heterocyclc, -(C₂-C6)alkynyI-(C₃-C₇)carbocycle, -(C2-C₆)alkynyl-aryl, -(C₂-C(i)alkynyI-heteroaryl, -(C₂-C₆)alkynyl-heterocycle, -(C₃-C₇)carbocycle-Z^l or -haIo(C]-C6)alkyl-Z³; wherein (Ci-C6)alkyl, (Ci-Csjhaloalkyl, (C₃-C7)carbocycle, (C₂-C6)alkenyl, (C₂-C₆)alkynyl. aryl or heteroaryl are each optionally substituted with one or more(e.g. 1,2, 3,4 or 5) Z¹groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbîcyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C7)carbocycle or heterocycle wherein the (C₃C₇)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups;

c) (Cj-Céjalkyl; wherein (Ci-C_b)alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

d) -X(C_rC₆)alkyl,-X(Ci-C₆)haloalkyL-X((’₂-C₆)alkenyl,-X(G₂-C₆)alkynyl and -X(C₃-C₇)carbocycIe; wherein (Cj-CsJalkyl or (C|-C₍,(haloalkyl are each substituted with one or more Z³ groups and optionally substituted with one or more Z¹groups; and wherein (C₂-C6)alkenyl, (C₂-C₆)alkynyl and (C₃-C₇)carbocycle are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle; wherein aryl heteroaryl are heterocycle are each independently substituted with one or more (e.g. 1,2, 3, 4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z^! groups;

f) (C]-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl; where (Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl and (C^-Cûjalkynyl are each independently substituted with onc or more (e.g. 1, 2, 3, 4 or 5)

Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z groups; and

g) -NReRf, -C(O)NR<.Rf, -Οϋ(Ο)Μ<Λη -SOiNR^Rf, -(Ci-C₆)alkyl-NR_<R_f, -(CrCeiaikylCiOJ-NR^Rf, -(CrCejalkyl-O-CtOJ-NRcRf and -(C₁-C₆)alkyl-SO_?NR_<R_f; wherein each (CrCgjalkyl is independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

R^6a ïs selected from:

a) H, halo, (Ci-Cgjalkyl, and (Ci-Cg)haloalkyl

b) (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (C₃-C7)cycloalkyl, nitro, cyano, aryl, heterocycle or heteroaryl;

c) -C(=O)-R’ -C(=O)-O-R' -O-R' -S-R'^! *, -S(O)-R^l \ -SOz-R¹-(CrC6)alkyl-Rⁿ, -(Ci-C6)alkyl-C(=O)-Rⁿ, ^C^Jalkyl-C^Oj-O-R¹¹, -(Ci-C6)alkylO-R¹¹, -(Ci-Côalkyl-S-R.'¹, -(C]-C6)alkyl-S(O)-R^H and<Ci-C6)alkyI-SO2-R^H; wherein each R¹¹ is independently selected from H, (Ci-Cejalkyl, (C2-C6)alkenyl, (C₂Cû)alkynyl, (Ci-Cfi)haloalkyl, (C₃-C₇)cycloalkyl, atyl, heterocycle and heteroaryl; and

d) -N(R⁹)R¹⁰, -C( O)-N(R⁵)R¹⁰, -O-C(O)-N(R⁹)R^!0. -SO2-N(R⁹)R¹⁰, -(Ci-C6)alkyl-N(R⁹)R¹⁰, -(CrC6)alkyl-C(-O)-N(R⁹)R¹⁰, -(CrC6)alkyl-O-C(=O>· N(R⁹)R¹⁰ and -(CrC6)alkyI-SO2-N(R⁹)R^,û; wherein each R⁹ is independently selected from H, (CrC6)alkyl and (C₃-C₇)cycloalkyl; and each R¹⁰is independently selected from R’^-fCrC^alkyl-R¹¹, -SO2-Rⁿ, -C(=O)-Rⁿ, C(y-O)ORⁿ and -C(=O)N(R⁹)Rⁿ; wherein each Rⁿ is independently selected from H, (CrC_s)alkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (Ci-C₆)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle or heteroaryl of R^6a is optionally substituted with one or more (e.g. 1,2 or 3) Z¹⁰ groups;

R^6b îs selected from:

a) (Ci-CéJalky 1-O-(Ci-Cfijalkyl-^-Cylcarbocycle, -(Ci-C₆)alkyl-S-(CiCâ)alkyJ-(C3-C₇)carbocycle, -(CiC₀)alkyl-S(O)-((C4:₆)alkyl-(C3-C_;)carbocyde, -(C₃C₆)alkyl-SO₂-(C j 'C₆)alkyl-(C₃-C₇)carbocycle, -(C2-CT)alkenyl (Ci<:₆)haloalkyl, -(C₂C6)alkynyl-(C_t-C6)haloalkyl, -halo(C3-C7)carbocyclc,-NR_aSO?NR_<R_àj, -NRaSO₂O(C₃C₇)carbocycle, -NRgSChOaryl, -(C₂-C6)alkenyl-(C3-C₇)carbocycle, -(C₂-C6)alkenylaryl, -(C₂-C₆)alkenyl-heteroaryl, ~(C₂-C6)alkenyl-heterocycle,

-(C2-C6)alkynyl-(C₃-C7)carbocycle, -(C₂-Cf,)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(Ci-Céjalkynyl-heterocycle, -{C'3-C7)caibocyde-Z^! or -halo(Ci-Cé)alkyl-Z³; wherein (Ci-Céjalkyl, (Cj-Céjhaloalkyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl, (C^-Côjalkynyi, aryl or heteroaryl are optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a carbocycle or heterocycle wherein the carbocycle or heterocycle is optionally substituted with one or more Z¹ groups;

c) (C]-C₆)alkyl; wherein (Ci-Cejalkyl is substituted with one or more (e.g.

d) -X(Ci-C₆)alkyl, -X(C]-C₆)haloalkyl, -X(C₂-C₆)alkenyl, -X(C₂-C6)alkynyl and -X(C₃-C₇)carbocycle; wherein (Ci-C₆)alkyl or (Ci-C₆)haloalkyl are each independently substituted with one or more (e.g. 1,2, 3,4 or 5) Z³ groups and optionally substituted with one or more Z¹ groups; and wherein (C₂-C₆)alkenyl, (CVC'bjalkynyl and (C3-C₇)carbocycle are each independently substituted with one or more Z⁴ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle wherein aryl heteroaryl and heterocycle are each independently substituted with one or more Z⁵ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹groups;

f) (Ci-Cfi)haloalkyl, (C3~C₇)carbocycle, (C₂-C6)alkenyl, and (C2-Ce)alkynyl; wherein (Cj-C^jhaloalkyl, (Cî-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C6)alkynyl are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1, 2,3,4 or 5) Z¹ groups; and

g) -NReRf, C(O)NR_tR_f. -OC(O)NR_fR_t, -S0₂M<.R_f, -(Ci-C₆)alkyl-NKRf, -(C_rC₆)alkylC(O)-NReRf, -(Ci-C^alkyl-O-QOj-NR^Rf and -(Ci-QJalkyl-SOzNReRf; wherein each (Cj-Csjalkyl is independently substituted wîth one or more (e.g. 1, 2, 3,4

or 5) Z⁶groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

R^7a îs selected from:

a) H, halo, (Ci-Csjalkyl and (Ci-C₆)haloalkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(-O)-R”, -C(=O)-O-R¹¹, -O-R¹¹, -S-R¹¹, -S(O)-R^U, -SO2-R”, -(Ci-Ci)alkyl-R¹¹, -(Ci-C6)alkyl-CC=O)-Rⁿ, -(Cj-C^alkyl-C^Oj-O-R¹¹, <Ci-C6)alkylO-Rⁿ, -(CT C6)alkyl-S-R^u, -(C,-C6)alkyl-S(O) R¹¹ and -(Ci-C6)alkyl-SO₂-Rⁿ; wherein each R¹¹ is independently selected from H, (Cj-CfJalkyl, (C₂-Cà)alkenyL (C₂C₆)alkynyl, (Cj-C₆)haloalkyl, (C₃-C₇)cycbalkyl. aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R¹⁰, -C(-O)-N(R⁹)R'⁰, -O-C(-O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R¹⁰, -(C1-C₆)alkyl-N(R⁹)R¹⁰,-(CI-C0)alkyl-C(=O)-N(R⁹)R¹⁰, -(CrC6)alkyl-O-C(=O)N(R⁹)R¹⁰ and -(Ci-C6)alkyl-SO2-N(R⁹)R¹⁰; wherein each R⁹ is independently selected from H, (CrC₆)alkyl and (C₃-C₇)cycloalkyl; and each R¹⁰is independently selected from R¹¹, -(CrC6)alkyl-R’*, -SO2-R^!1, -C(-O)-R^:i, C(=O)ORⁿ and -C(=O)N(R⁹)R^H; wherein each Rⁿ is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (CrCejalkynyl, (CrCejhaJoalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle or heteroaryl of R¹⁸ îs optionally substituted with one or more (e.g. 1,2 or 3) Z¹⁰ groups;

R⁷¹* is selected from:

a) -(Ct-CsÎalkyl-SOHCi-Cfijalkyl-Z¹³, -C(O)-(C]-C6)alkyl-Z¹³, -O-(CiC6)alkyl-Z¹³, -S-(Ci-C6)aIkyl-Z¹³, -S(OXCrC₆)alkyl-Z¹³, -SO2-(Ci-C6)alkyI-Z¹³, -(CrC₆)alkyl-Z¹⁴, -(Ci-C6)alkyl-C(O)-(C]-C6)alkyl-Z¹³, -(Ci-C6)alkyl-C(O)-O(C,C₆)alkyl-Z¹³, -(CrC6)alkyl-O-(CrC6)alkyl-Z¹³, -(Ci-Côjalkyl-S-CCT-COalkyl-Z¹³, -(Cr C^alkyl-O-tCrCsjalkyl-tCî-Cvjcarbocycle, -(CrC₆)alkyl-S-(CiCe)alkyl“(C3-C₇)carbocyc]e, -(C i-C₆)alkyl-S(O)-(C ] ~C₆)alkyl-(C₃-C₇)carbocycl e, -(CiC6)alkyl-SO₂-(Ci-C₆)alkyl-(C₃-C₇)carbocycle, (C₂-C₆)alkenyl-(C i -C₆)haloalkyl, -(C₂C6)alkynyl-(Ci-C6)haloalkyl, -(C₃-C₇)halocarbocycle, -NRaSC^NRcRd, -NRaSO₂O(C₃C₇)carbocycle, -NRaSO₂Oaryl, -(C₂-C₆)alkeny]-(C₃-C₇)carbocycle, -(C₂-C₆)alkenylaxyl, -(C₂-Ce)alkenyl-heteroaryl, -(C₂-C6)alkenyl-heterocycle, -(C₂-C6)alkynyl-(C₃-C₇)carbocycle, -(C₂-C₆)alkynyI-aiyl, -(C₂-C₆)alkynyl-heteroaryl,

-(C2-C6)aIkynyl-heterocycle, -(C3-C₇)carbocyc1e-Z or -halo(Ci-C₆)alkyl-7? ; wherein (Cj-C₆)alkyl, (Ci-C6)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, aryl or heteroaryl aie each optionally substituted with one or more(e.g. I, 2,3,4 or 5) Z¹groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C3-C₇)carbocycle or heterocycle wherein the (C₃-C₆)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (Ci-Ce)alkyl; wherein (C|-C6)alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups;

d) -X(Ci-C₆)alkyl, X(Ci-C₆)haloalkyl, X(C₂-C₆)alkenyl, -X(C₂-C6)aIkynyl and -X(C3-C₇)carbocycle; wherein (Ci-C₆)alkyl and (Ci-C^haloalkyl are each substituted with one or more Z³ groups and optionally substituted with one or more Z* groups; and wherein (C₂-C₆)alkenyl, (C₂-C(>)alkynyl and (C3-C₇)carbocycle are each substituted with one or more (e.g. 1,2, 3,4 or 5) Z⁴groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle; wherein aryl, heteroaryl and heterocycle are each substituted with one or more Z⁵groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups;

f) (Ci-C6)haloalkyl, (C₃-C₇)caibocycle, (C₂-C6)alkenyl and (C₂-C₆)alkynyl; wherein (Cj-Celhaloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -NRJRf, -CiOJNRJRf, -OC(O)NKR_f, -SO₂NR_fR_t. -(Ci-QOalkyl-NRJU -(Cj-C^alkyiCfOhNReRf, -(Ci-C^alkyl-O-CiCO-NR^Rf and -(C_rC^alkyl-SChNReRf; wherein each (Cj-C^alkyl is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

R^8a is selected from:

a) halo, nîtro and cyano;

t 94

b) Rⁿ, -0(=0^¹-C(=O)-O-Rⁿ, -0-R, -S-R^1!, -5(0)-^', -SO2-R^h, (Ci-C6)alkyl-Rⁿ, -(Ci^jalkyl-C^Oj-R¹¹, -(CrCbïalkyl-C^-O-R¹¹, -(Ci-C6)alkyl0-R¹¹, -(Ci-C6)alkyl-S-R, XC^alkyl-SCOXR¹¹ and -(CVCXalkyl-SOrR¹¹; wherein each R¹¹ is independently selected from H, (Ci-C^jalkyl, (C₂-C₆)alkenyl, (C₂-

Côjalkynyl, (Ci-Cejhaloalkyl, (C₃-C7)cycloalkyl, aryl, heterocycle and heteroaryl; wherein aryl, heterocycle aod heteroaryl are each optionally substituted with one or more(e.g. 1,2ot3)Z^h grnops;

c) -N/R^R¹⁰, -C(=O)-N(R⁹)R¹⁰, -O-C(=O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R¹⁰, -(CjCôialkyl-NfR’jR¹⁰, -iCrC6)alkyl-C(=O)-N(R⁹)R¹⁰, -(C_]-C₆)alkyl-O-C(-())-N(R⁹)R^lcl and -(Ci-C6)alkyl-SO₂-N(R⁹)R¹⁰; wherein each R⁹ is independently selected from H, (Ci-Céjalkyl and (C₃-C7)cycloalkyl; and each R¹⁰is independently selected fromR¹¹,-(C]-C6)alkyl-R¹¹, -SO2-R¹¹, -C(=O)-Rⁿ, C(=0)0Rⁿ and -C(-0)N(R⁹)R¹¹; wherein each R¹¹ is independently selected from H, (Ci-Ce)alkyl, (C2-Cô)alkenyl, (C₂-C6)alkynyl, (Ci-Csjhaloalkyl, (C₃-C7)cycloalkyl, aryl, heterocycle and heteroaryl;

R^8b is selected from:

a) -(Ci-C₆)alkyl-SO₂-(Ci-C₆)alkyl-Z’³, -CtOHCrC^alkyl-Z¹³, -O-(CiC6)alkyl-Z¹³, -S-(Ci-C6)aIkyl-Z¹³, -S(O)-(CrC6)alkyl-Z¹³, -SO2-(Ci-C₆)alkyl-Z¹³, -(Cj-Cfijalkyl-Z¹⁴, -(CrC6)alkyl-C(O)-(Ci-C6)alkyl-Z¹³, -(C ,-C6)alky 1-0(0)-0(0^

C₆)alkyl-Z¹³, -(CrCôjalkyl-O-fCrCôjalkyl-Z’³, -(Ci-CbJalkyl-S-CCj-Cbjalkyl-Z¹³, <C_r

C₆)alkyl-O-(Ci-C₆)alkyi-(C3-C7)carbQcycle, -(Ci-C₆)alkyl-S-(CjC6)alkyl-(C₃-C₇)carbocycle, -(Ci-C6)alkyl-S(O)-(C] -C6)alkyl-(C₃-C7)carbocycle, -(CjC6)alkyl-SO₂-(C i-C₆)alkyI-(C3-C7)carbocycle, -(C₂-C₆)alkeny 1-(C i -C₆)haloalkyl, -(C₂CôJalkynyl-fCi-CeJhaloalkyl, -haloiCs-CvJcarbocycle.-NRjSOjNRcRd, 25 NRaSO2O(C3-C₇)carbocycle, -NR<|SO?Oary l, -(C₂-C6)alkenyl-(C₃-C₇)carbocycle, -(C₂-C6)alkenyl-aryl, -(C₂-C₆)alkenyl-heteroaryl, -(C₂-C6)alkenyl-heterocycle, -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, -(CVCbJalkynyl-hetcroaryl, -(C₂-C₆)alkynyl-heterocycle, - {(O-CXcarbocycle-Z¹ or -halo(Ci-C6)alkyl-Z³; wherein (CrCejalkyl, (Cj-C₆)haloalkyl, (C₃-C7)carbocycle, (C₂-C₍,)alkenyl, (C₂-C₆)alkynyl, aryl or heteroaryl are each optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹groups:

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle; wherein spiro-bicyclic carbocycle, fused-bicyclic carbocycle or

bridged-bicyclic carbocycle are optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups; wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1,2,3, 4 or 5) Z¹ groups;

c) (Cj-Cbjalkyl; wherein (Cj-C^alkyl is substituted with one or more Z²groups and optionally substituted with one or more (c_g. L 2,3,4 or 5) Z¹ groups;

d) -XfQ-CsJalkyl, -X(CrC₆)haloalkyl, -X(C₂-C₆)alkenyl, -X(C₂-C6)alkynyl and -X(C₃-C₇)carbocycle; wherein (Ci-C₆)alkyl and (Ci-Cô)haloalkyl are each independently substituted with one or more Z³ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups; and wherein any (C₂-C6)alkenyl, (C₂-Cf,)alkynyl and (C₃-C₇)carbocycle are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle wherein any aryl heteroaryl and heterocycle are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁵ groups and optionally substituted with one or more (e.g. 1,2, 3,4 or 5) Z¹ groups;

f) (Cj-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)aJkenyl and (C₂-C₆)alkynyl; wherein (Ci-C^jhaloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-Cû)alkynyl are each independently substituted with one or more (e.g. 1,2,3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2,3,4 or 5) Z¹ groups; and

g) -NRcRf, -C(O)NR_eR_f, -OC(O)NReR_f, -SO?NR.Rf, -(CrCejalkyl-NReRf, -(CrCslalkylCXOj-NReRf, -(Ci-C₆)alkyl-O-C(O)-NR_eR_f and -(Ci-C₆)aIkyI-SO₂NR_<R_f; wherein each (CT-C^alkyl is independently substituted with one or more (e.g. 1, 2, 3,4 or 5) Z⁶ groupsand optionally substituted with one ormore(e.g. 1,2,3,4or 5) Z¹groups;

or any of R^Sa and R⁶¹, R^6a and R^7a, R^7a and R^Sa, R¹ and R⁸ or R¹ and R² together with the atoms to which they are attached form a 5 or 6 membered carbocycle or a 4, 5, 6 or 7-membered heterocycle; wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or

7-membered heterocycle is optionally substituted with one or more (e.g. 1, 2 or 3) substituents each independently selected from halo, (C'i-Cfjalkyl, (C₂-Cô)alkenyl, (Cr

C₆)haloalkyl, (C₃-C₇)cycloalkyl, -OH, -O(C_l-C₆)alkyl. -SH, -S(C]-C₆)alkyl, -NH₂, -NH(C_rC₆)alkyi and -N((C_rC₆)alkyl)₂;

or any of R⁵ and R⁶, R⁶ and R⁷ or R⁷ and R*, together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4,5,6 or 7-membered heterocycle; wherein the 5 or 6-membered carbocycle or a 4,5,6 or 7-membered heterocycle are each independently substituted with one or more (e.g. 1,2 or 3) Z⁷ or Z* groups; wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionally form a (C₃-C₇)carbocycle or 4, 5 or 6membered heterocycle;

or R¹ and R⁸ or R¹ and R² together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4,5,6 or 7-membered heterocycle; wherein the 5 or 6-membered carbocycle or a 4,5,6 or 7-membered heterocycle are each independently substituted with one or more (e.g. 1, 2 or 3) Z⁷ or Z⁸ groups; wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionally form a (C'₃-C₇)carbocycle or 4, 5 or 6-membered heterocycle;

X is independently selected from O, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂., -(CiC₆)alkylO-, -(C]-C₆)aJkylC(O)-, -(Ci-C₆)alkylC(O)O-, -(C_rC₆)alkyIS-, -(C_rC₆)alkylS(O)-> -(C_rC₆)alkylSO₂-;

each Z¹ is independently selected from halo, -ΝΟ2, -OH, ^zNORa, -SH, -CN, -(Ci-C6)alkyl, -(C₂-C₆)alkenyl, -(C₂-C6)alkynyl, -(Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle, -aryl, -heteroaryl, -heterocycle, -O(CpCô)alky!, -O(C₂C₆)alkenyl, -O(C₂-C6)alkynyl, -O(Ci-C6)haloalkyl, -O(C₃-C₇)carbocycle, -O(C₃C₇)halocarbocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -S(Ci-Ce)alkyl, -S(C₂C₆)alkenyl, -S(C₂-C6)alkynyI, -S(Ci-C6)haloalkyl, -S(C₃-C₇)carbocycle, -S(C₃C₇)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle, -S(O)(C]-C₆)alkyl, -S(O)(C₂Cô/alkenyl, -S(O)(C₂-C6)alkynyl, -S(O)(Ci-C6)haloalkyl, -S (O) (C₃-C₇)carbocycle, S(O)(C₃-C₇)halocarbocycle, -SO^Ci-Cejalkyl, -S(O)aryl, -S(O)carbocycle, S(O)heteroaryl, -S(O)heterocycle, -SO₂(C₂-C₆)alkenyl. -SO₂(C2-C₆)alkynyl, -SO₂(CjCsjhaloalkyl, -SO₂(C₃-C₇)carbocycle, -S0₂(C₃-C₇)halocarbocycle, -SO₂aryl, SO₂heteroaryl, -SO₂heterocycle, -SO₂NR_cR_<j, -NR^Rj, -NRaC(O)Ra, -NR_aC(O)ORa, -NRiC(O)NRcRd -NRaSOiRb, -NR_aSO₂NR<R<₁, -NR_aSO₂O(C₃-C₇)carbocycle, NR_iSO₂Oaryl, -OS(O)₂R_a, -C(O)R_a: -C(O)OR_h, -C(O)NR_cR₁₎, and -OCfONR^R^, wherein any (Ci-C_É)aIkyl, (C₂-C₆)alkenyl, (C₂-C_fe)alkynyl, -(C₃-C7)halocarbocycle, (C₃C₇)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl or heterocycle of Z¹ is optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) halogen, -OH, -ORb, -CN, -NRaC(O)₂Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, NHheterocycle, or -S(O)₂NR<Rd;

each Z² is independently selected from -NO₂, -CN, spiro- heterocycle, bridgeheterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, NRaSO₂(C₃C₇)carbocycle, -NR_<SO₂ary], -NR_aSO₂heteiOaryl. -NR_aSO₂NRJkd, -NRaSQîOfCîC7)carbocycle and -NR_uSO₂Oaryl;

each Z³ is independently selected from -NO₂, -CN, -OH, oxo, =NOR_n, thioxo, aryl, -heterocycle, -heteroaryl, -(C₃-C₇)halocarbocycle, -O(C]-C6)alkyI, -O(C₃C₇)carbocycle, -OhaIo(C3-C₇)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(CiC₆)alkyl, -S(C3-C₇)carbocycle, -S(C₃-C₇)halocarbocycle, -Saryl, -Sheterocycle, Sheteroaryl, -S(O)(C|-Cf,)alkyl, -S(O)(C₃-C₇)carbocycle, -S(O) (C3-C7)halocarbocycle, -S(O)aryl, -S(O)heterocycle, -S(O)hetercaryl, -SO₂(C|-C6)alkyl, -SO₂(C3-C₇)carbocycle, -S0₂(C3-C7)haiocarbocycle, SO₂aryl, -SO₂heterocycle, -SO₂heteroaryl, -NRaRb, -NReC(O)Rb, -C(O)NRcRd, -SO₂NRJ<d, -NRaSC^NRcRd, -NRaSO₂O(C₃-C7)carbocycle and -NR_aSO₂Oaryl;

each Z⁴ is independently selected from halogen, -(Ci-Cè)alkyl, (C₃C₇)carbocycle, -hak>(Ci C₆)alkyl, -NO₂, -CN, -OH, oxo, =NORa, thioxo, -aryl, -heterocycle, -heteroaryl, -(C₃-C₇)halocarbocycle, -O(Cj-C6)alkyl, -O(C3C₇)carbûcycle, -O(C₃-C₇)halocarbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(CiCfi)alkyl, -S(C₃-C₇)carbocycle, -S(C₃-C₇)balocarbocycle, -Saryl, -Sheterocycle, Sheteroaryl, -S(O)(Ci-C₆)alkyl, -S(O)(C₃-C₇)carbocycle, -S(O)(C₃-C₇)halocarbocycle, S(O)aryl, -S(O)heterocycle, -S(O)heteroaryl, -SO₂(Ci-Ce)alkyl, -S0₂(C₃-C₇)carbocycle, -SO₂(C3-C₇)halocarbocycle, SO₂aryl, -S0₂heterocycle, -S0₂heteroaryl, -NRaRb, -NR_aC(O)R_a, -C'(O)NR_cR_d, -SO₂NR^, -NR^O-NR^^. -NR_aS0₂0(C₃-C₇)carbocycle and -NR_aSO₂Oaryl;

each Z⁵ is independently selected from -NO₂, -CN, -NRaSO₂NRcR<i, NReSO₂O(C3-C₇)caibocycle, -NRaSO-Oaryl, -NRaSO₂(Cj-C6)alkyl, -NR*SO₂(C₂~ C₆)alkenyl, -NRaSO₂(C₂-C6)alkynyl, -NRaS0₂(C3-C₇)carbocycIe, -NRaSO₂(C₃C₇)halocarbocycle, -NRsSO₂aryl, -NRaSO₂heteraryJ, -NR_aSO₂heteroaryl, -NR^SO-hetcrocycle, -NR_aC(O)alkyl, -NRaC(O)alkenyl, -NRaC(O)alkynyl, -NRaC(O)

(C₃-C₇)caTbocycle, -NR₂C(0)(C₃-C7)halocarbocycle, -NR_aC(O)aryl, -NR₃C(O)heteroaryl, -NR_aC(O)heterocycle, NRaC(O)NRçR<i and NRaC(O)ORb;

each Z⁶ is independently selected from -NO₂, -CN, -NRaRa, NR_aC(O)Rb< C(O)NRcRd, -(C3-C7)halocarbocycle, -aryl, -heteroary], -heterocycle, -Oaryl, Oheteroaryl, -Oheterocycle, -0(C₃-C₇)halocarbocycle, -O(Cj-C6)alkyl, -O(C₃C₇)carbocycle₎ -OhalofCi-Csjalkyl, -Saryl, -Sheteroaryl, -Sheterocycle, -S(C₃C₇)halocarbocycle, -S(Ci-C₆)alkyl, -S(C3-C₇)carbocycle, -S(Ci-C6)haloalkyl, -S(O)aryl, -S(O)heteroaryl, -S(O)heterocycle, -S(O)(C3-C₇)halocarbocycle, -S(O)(Ci-C₆)alkyl, -S(OXC₃-C₇)carbocycle, -S(O)halo(C|-C6)alkyl, -SO₂aryl, -SChhetcroaryl, -SO₂heterocycle, -SOîfCi-Cejalkyl, -SO₂haio(Ci-C₆)alkyl_? -SO₂(C₃-C₇)carbocycle, -SO₂(C3-C₇)halocarbocycle, -SO^NRcRj, -NRaSO₂(C₃-C₇)halocarbocycle, -NRaSO₂aryl, -NR_aSO₂heteraryl, -NR_aS0₂heteroaiyl, -NRaSO^RJCj, -NRaSO₂O(C₃C₇)carbocycle and -NR_aSO₂Oaryl.

each Z⁷ is independently selected from -NO2, =NORa, -CN, -(Cj-Cblalkyl-Z'⁷, -(C2-C₆)alkenyl-Z¹², -(C2-C6)alkenylOH, -(C2-C6)aikyny]-Z¹², -(C2-C₆)alkynyl-OH, -(Ci-C6)haloalkyl-Z¹², -(Ci-CsJhaloalkylOH, -(C3-C7)carbocycle-Z¹², -(C3C₇)carbocycleOH, -(C₃-C₇)halocarbocycle, -(Ci-C6)alkylNR_cRj, -(CiC₆)alkylNR_aC(O)R_a. -(C]-C6)alkylNR_aSO₂R_a, -aryl, -heteroaryl, -heterocycle, -O(CiC₆)alkyl-Z¹², -O^-C^alkenyl, -0(C2-C6)alkynyl, -O(Ci-C6)haloalkyl, -O(C3C7)carbocycle, -O(C3-C7)halocarbocycle, -Oaryl, -OtCi-C^jalkylNRcRd, -O(C|CéjalkylNRaCfOjRa, -O(C]-C6)alkylNRaSO2Ra, -Oheteroaryl, -Oheterocycle, -S(CiC6)alkyl-Z¹², -S(C2-C₆)alkenyl, -S(C₂-C₆)alkynyl, -SfCj-Céihaloalkyl, -S(C₃C₇)carbocycle, -S(C₃-C₇)halocarbocycle, -SfCi-CsjalkylNRcRj, -S(CiCijalkylNRaCfOJRa, -S(Cj-C6)alkylNR_aSO₂Ra, -Saryl, -Sheteroaryl, -Sheterocycle, -S(OXCi-C₆)alkyl, -S(0)(C₂-C₆)alkenyl, -S(O)(C₂-C6)alkynyl, -S(0)(Ci-C₆)haloalkyl, S(O)(C₃-C₇)carbocycle, -S(0)(C₃-C₇)halocarbocycIe, -SO₂(Ci-C(>)alkyl, -S(OXCjCfijalkylNRcRj, -S(O)(Ci-C₆)alkylNR_aC(O)K₁, -S(OXCi-C₆)alkyINR_aSO₂R_a, S(O)aryl, -S(O)heteroaryl, -S(O)heterocycle, -SO₂(C]-C₆)alkyl, -S0₂(C₂-C₆)alkenyl, -SO₂(C2-C₆)alkynyl, -S0₂(Cj-C₆)haloalkyl, -SO₂(C₃-C₇)carbocycle, -SO₂(C₃C₇)halocarbocycle, -SO₂aryl, -SO₂heteroaryl, -SO₂heterocycIe, -SO2(C_rCsjalkylNRcRd, -SOXCrCiJalkylNRsQOJRa, -SO₂(C₁-C₆)alkylNR_aSO₂R_a, SO₂NRcRa, -NR_aC(O)ORj„ -NR_aC(O)NR_cR_d -NR_aSO₂R_b. -NR_aSO₂NR_£R_d, NRaS0₂0(C₃-C₇)carbocycle, -NRaSO₂Oaryl, -OS(O)₂R_a. -C(O)NR_<R_<i, and 16293

0C(O)NK-R<i, wherein any (CpCfijalkyl, (C₂-C<i)alkenyl, (C₂-C₆)alkynyl, (C₃C₇)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl or heterocycle of Z⁷ is optionally substituted with one or more (e.g. 1,2,3,4 or 5) halogen, -OH, -ORt, -CN, -NR_aC(O)2R4„ -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, NHheterocycle, or -S(O)?NR_cR<j each Z⁸ îs independently selected from -NO; or -CN;

each Z⁹ is independently selected from -(Ci-Cé)alkyl, -OfCj-Cfijalkyl;

each Z¹⁰ îs independently selected from

i) halo, oxo, thioxo, (C₂-C6)alkenyl, (Cj-C^jhaloalkyl, (C₃-

C₇)cycloalkyl, (C₃-C₇)cycloalkyl-(Ci-C6)alkyl-, -OH, -O(CjC₆)alkyl, -O(C]-C₆)haloalkyl, -SH, -S(Ci-C₆)alkyl, -SO(C_r

C₆)alkyl, -SO₂(Ci-C₆)alkyl, -NH₂, -NH(Cj-C₆)alkyl and -NiCCj-CeJalkylh;

ii) (Ci-Cô)alkyl optionally substituted with -OH, -O-(CjCô)haloalkyl, or -O-(C]-C₆)alkyl; and iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle and heteroaryl is optionally substituted with halo, (CpC^alkyl or COOH;

each Z¹¹ is independently selected from Z¹⁰, -C(=O)-NH₂, -C(=O)-NH(CiC₄)alkyl, -C(=O)-N((Ci-C₄)alkyl)₂, -C(=O>aryl, -C(=O)-heterocycle and -C(O)-heteroaryl ;

each Z¹² is independently selected from -NO₂, =NORa, thioxo, -aryl, heterocycle, -heteroaryl, -(C₃-C₇)halocarbocycle, -(C₃-C₇)carbocycle, -O(C₃-C₇)carbocycle, -Ohalo(C₃-C₇)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(Ci-Cé)alkyl, -S(C₃-C₇)carbocycle, -Shalo(C₃-C₇)carbocycle, -Saryl, -Sheterocycle, Sheteroaryl, -S(0)(Ci-C6)alkyl, -S(O)(C₃-C₇)carbocycle, -S(0)halo(C₃-C₇)carbocycle, -S(O)aryl, -S(O)heterocycle, -S(O)heteroaryl, -SO₂(Ci-C₆)alkyl, -SO₂(C₃-C₇)carbocycle, -SO2(C₃-C₇)halocarbocycle, SO₂aryl, -SO2heterocyclc, SO₂heteroaryI, -NR_aR_a, -NRaC(O)Rb, -C(O)NR_cR_<j, -SO2NR_cR_d, -NR_aSO_?NR_cR_d, NR_aSO2O(C₃-C₇)carbocycIe and -NR_aSO2Oaryl;

each Z¹³ is independently selected from -NO₂, -OH, =N0R_a, -SH, -CN, -(C₃C₇)halocarbocycle, -O(Cj-C₆)alkyl, -O(C₂-C₆)alkenyl, -O(C₂-C6)alkynyl, O(C₍C6)haloalkyl, -O(C₃-C₇)carbocycle, -O(C₃-C₇)halocarbocycle, -Oaryl, -Oheteroaryl, Oheterocycle, -S(Ci-Cé)alkyl, -S(C₂-C₆)alkenyl, -S(C₂-C6)alkynyi, -S(Ci-C₆)haloalkyl,

-S(C₃-C₇)carbocycle, -S(C3-C₇)haiocarbocycle, -Saryl, -Sheteroaryl, -Sheterocvcle, -S(OXC₁-C₆)aIkyl_î -S(O)(C₂-C₆)alkenyl, -S(OXC₂-C₆)alkynyl, -S(O)(Ci-C₆)haloalkyl, S(OXC₃-C7)carbocycle, -S(0)(C₃-C7)halocarbocycle, -S(O)aryl, -S(O)heteroaryl, S(O)heterocycle, -SO₂(Ci-C₆)alkyl, -SO₂(C₂-C₆)alkeny], -SO₂(C₂-C₆)alkynyl, -SO₂(CiC6)haloalkyl, -SO2(C₃-C₇)carbocycle, -SOXC3-C₇)halocarbocycle, “SO₂aryl, SQtbeteroaryl, -SChheterocycle, -SChNRJTj, -NR<R<t, -NR_eC(O)Ra, -NR*C(O)ORb, -NReQO^NRcRd -NR_aSO₂Rb, -NR_aSO₂NR_cR_<j, -NRaSO₂O(C₃-C7)carbocycle, NR_aSO₃Oaryl, -OS(O)₂R_a, -C(O)R_a, -C(())OR_k, -C.(O)NR_<R_d, and -OC(O)NR_cR_d; wherein any (C]-C6)alkyl, (Cj-CçJalkenyl, (C₂-C6)alkynyl, -(C3-C₇)halocarbocycle, (C₃C7)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl or heterocycle of Z¹³ is optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) halogen, -OH, -OR*, -CN, -NRaC(O)₂Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, NHheterocycle, or -S(O)₂NR_cRj;

each Z¹⁴ is independently selected from -NO2, =NORa, -CN, -(C3C7)halocarbocycle, -O(C3-C7)halocarbocycle, -S(C3-C7)halocarbocycle, -S(O)(C3C7)halocarbocycle, -S02(C3-C7)halocarbocycle, -NReSO2NRcRd, -NRaSO2O(C3C7)carbocycle, -NRaSO2Oaryl, -OS(O)2Rl; wherein any -(C3-C7)halocarbocycle of Z¹⁴is optionally substituted with one or more (e.g. 1,2,3,4 or 5) halogen, -OH, -ORt,, -CN, -NRaC(O)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, NHheteroaryl, -NHheterocycle, or -S(O)2NRcR<j;

each Ra is independently H, (Cj-C^alkyl, -(C₂-C₆)alkenyl, -(C₂-C6)alkynyl, (C₃-C7)carbocycle, heterocycle, aryl, aiyl(Ci-C₆)alkyl-, heteroaryl or heteroaryl(CiCfe)alkyl-; wherein any (Ci-C6)alkyl, (CrCgJalkenyl, (C₂-C6)alkynyl, (C3-C₇)carbocycle, heterocycle, aryl, or heteroaryl of R_a is optionally substituted by halogen, OH and cyano;

each Rb is independently -(C|-C₆)alkyl, -(C₂-C6)aikenyl, -(C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl, aryi(CrC₆)alkyl-, heteroaryl or heteroaryl(C_tCsialkyl-; wherein any (C|-C₆)alkyl, -(C₂-C6)alkenyl, -(C₂-C6)alkynyl, (C3-C₇)carbocycle, heterocycle, aryl, or heteroaryl of Rb is optionally substituted by halogen, OH and cyano;

Ro and R<i are each independently selected from H, (Ci-C6)alkyl, (C₂-Cb)alkenyl, (C₂-C₆)alkynyl, (C₃-C7)carbocycle, aryl, aryl(Ci-C6)alkyl-, heterocycle, heteroaryl or heteroaryl(Cj-C6)alkyl- wherein any (Ci-Ctjalkyl, (C₂-C₆)alkenyl, -(C₂-C6)alkynyk

ΙΟΙ (C₃-C₇)carbocycle, heterocycle, aryl, or heteroaryl of Rc or Rj is optionally substituted by halogen, OH and cyano; or Rc and Rd together with the nitrogen to which they are attached form a heterocycle; wherein any heterocycle of Rc and Rd together with the nitrogen to which they are attached is optionally substituted by halogen, OH or cyano;

each R< is independently selected fiom -OR^ (C]-Cf,)alky! or (C₃-C7)carbocycle wherein (Cj-Cejalkyl or (C3-C₇)carbocycleis substituted by one or more Zj and optionally substituted with one or mat Zj; -(C2-C6)haloalkyl, -(C₂-C6)alkenyl, or -(Ci-Cejalkynyl wherein any haloalkyl, alkenyl or alkynyl is optionally substituted with one or more Zi; aryl, heterocycle or heteroaryl wherein aryl, heterocycle or heteroaryl is substituted by one or more Z_c;

each Rf is independently selected &om -R_& OR_a, -(Ci C₆)alky]-Z⁶, -SO₂Rg, C(O)Rg, CXOjORg, or -C(O)NRcR*; and each R_g is independently selected fiom -ORa, (Ci-Cejalkyl, (C3-C₇)carbocycle (Ci-Cé)haloalkyl, (C₂-C6)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle or heteroaryl wherein any (Ci-C₆)alkyl, (C₃-C₇)carbocycle -(Ci-Cejhaloalkyl, (C₂-C₆)alkenyl, (C2-C₆)alkynyl, aryl, heterocycle or heteroaryl of R_g is optionally substituted with one or more Zj groups;

or a sait thereof.

In one embodiment, the compounds of formula I include:

102

and

and salts thereof.

In another embodiment, the compounds of formula I include:

and salts thereof.

103

In another embodiment, the compounds of formula I include:

wherein each R^y is independently H or (Cj-C_f,)alkyl and salts thereof.

104

In another embodiment, the compounds of formula I include:

105

or a sait thereof.

In another embodiment, the compounds of formula I include:

O

109

HO

Ci

Cl Ci Ci

ni

Cl o

o

112

113

114

I

C

H6

118

and salts thereof.

In another embodiment, the compounds of formula I include:

119

and salts thereof.

In another embodiment the compounds of formula I include compounds 151180 as described in Example 149.

General Synthetic Procedures

Scheme 1 is provided as a further embodiment of the invention and illustrâtes a process that was used to préparé a compound of formula I and which can be used to préparé other compounds of formula I. Schemcs 2-6 are also provided as further embodiments of the invention and illustrate processes that can be used to préparé compounds of formula I.

120

Scheme 1

G-X

1A

G

II

PG

G lil

1D

G = heteroaryl, aryl ar cydoalcyi X = Q, Br, I, ΟΠ

	R⁵	R⁴	OH
R⁷.	A		,Α^,οη
R⁶^	ψ		r²
	R^e
		11

	R⁵	R⁴	R³
R®			^A^opg

R'	M		R²
	R⁸
		1K

R³= -OtCi-CgJalkyl, -O(C2-C_e)afkenyl, -0{C2-C_e)alkynyl or -OÎC^-Cg) cycloalkyl,

An aromatic or heteroaromatic halide or triflate (1 A) can be crossed-coupled to a suitably protected alkyne (IB) such as ethynyl(trimethyl)silane using a palladium catalyst and copper halide sait such as, for example, copper(I) iodide, N,Ndiisopropylethylamine, tetFakis(triphenylphosphîne)palladium(0) and dimethylformamide or copper(I) iodide, diethylamîne, and bis(triphenylphosphine)

I2l

ΙΟ palladium(IÏ) dichloride. Deprotection of cross-coupled alkyne (IC) yields the corresponding terminal alkyne (ID) such as, for example, deprotection of a trimethylsilyl-protected alkyne with a fluoride source such as, for example, tetrabutylammonium fluoride. Metalation of a terminal alkyl (ID) such as, for example, deprotonation with n-butyllithium, yields the corresponding métal acetylide such as, for example lithium acetylide, that mdergoes nucleophilic addition to an appropriate electrophile (1E) to give the corresponding hydroxy alkyne addition product 1F. A suitably substituted phenyl electrophile such as phenyl-2-propanone can be purchased or prepared by those skilled in the art through, for example, Friedel-Crafts alkylation of benzene with chloroacetone.

The hydroxyl alkyne 1F can undergo 6-endo-dig electrophilic cyclization under suitable reaction conditions such as, for example iodine and sodium bicarbonate to give the corresponding substituted naphthalene such as, for example the iodonaphthalene IG. The substituted naphthalene IG, can undergo a cross-coupling reaction such as, for example Stilie cross-coupling using a tin reagent such as tributyl(vinyl)tin and a palladium catalyst such as bis(tripheuylphosphine) palladium(II) dichloride to give the corresponding cross-coupled naphthalene such as, for example, vinylnaphthalene IH. The vinylnaphthalene IH can be dîhydroxylated by methods known to those skilled in the art such as, for example Sharpless asymmetric dihydroxylation using, for example, commercially available AD-mix-a.

The resulting diol II can be protected at the primary hydroxyl by suitable protecting groups such as, for example, pivalate ester using pivaloyl chloride and pyridine to provide 1 J. The secondary hydroxyl can be converted to the corresponding ether 1K such as tert-butyl ether using methods known to those skilled in the art such as, for example, tert-butyl acetate and perchloric acid. The protected primary hydroxyl can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a pivalate protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding primary hydroxyl compound IL. The primary hydroxyl can be oxidized to the corresponding carboxylic acid IM by methods known to those skilled in the art such as, for example, periodic acid and chromium trioxide.

122

Scheme 2

PG1 = protecting group

R³ = -O/Cj-C^alkyl -OCCj-CeJalkenyl, -O/Cj-CeJalkynyl or -O(C3-C_e)cydoaikyi,

LG = leaving group

	R⁵	R*	R³	R⁵	R⁴	R³
^RS	ό	'Xr'	A^OPG²	R®	ώ
R'			R²	* R⁷^			r²°
	R®	2H			R®	21

Metalation of a suitably functionalized and protected terminal alkyne such as, for example, deprotonation with n-butyllithium, can yield the corresponding meta] acetyüde such as, for example lithium acetylide, that undergoes nucleophilic addition to an appropriate electrophile, such as, for example 1E, to give the corresponding hydroxy alkyne addition product 2A. The hydroxyl alkyne 2A can undergo 6-endo-dig electrophilic cyclization under suitable reaction conditions such as, for example iodine and sodium bicarbonate to give the corresponding substituted naphthalene sueh as, for example îodonaphthalcne 2B. The substituted naphthalene 2B, can undergo a crosscoupling reaction such as, for example Stille cross-coupling using a tin reagent such as, for example, tributyl(vinyl)tin and a palladium catalyst such as, for example, bis(triphenylphosphine)palladiuin(n) dichloride to give the corresponding cross-

123 coupled naphthalene such as, for example, vinylnaphthalene 2C. The alkenylnaphthalene 2C can be dîhydroxylaied using methods known to those skilled in the art such as, for example Sharpless asymmefric dihydroxylation using, for example, commercially available AD-mix-a.

The resulting diol 2D can be protected at the primaiy hydroxyl by an orthogonal protecting groups, such as, for example, pivalate ester using pivaloyl chloride and pyridîne. The secondary hydroxyl of 2E can be converted to the corresponding ether 2F, such as a tert-butyl ether using methods kDown to those skilled in the art for example, using tert-butyl acetate and perchloric acid. The naphthol protecting group can be differentially deprotected by methods known to those skilled in the art and converted to a leaving group (e.g. triflate) known to undergo cross-coupling reactions. The corresponding activated naphthalene 2G can undergo cross-coupling reactions such as but not limited to Suzuki reactions with boronic acids or esters, Stille reactions with trialkylstannane reagents, and Buchwald-Hartwig reactions with amines thus providing carbon linked and nitrogen linked R⁴ groups of 2H. The protected primary hydroxyl can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a pivalate protecting group under Basic conditions, such as, for example sodium hydroxide, to give the corresponding primary hydroxyl. The primary hydroxyl can be oxidized to the corresponding carboxylic acid analog 21 by methods known to those skilled in the art such as, for example, periodic acid and chromium trioxide.

C

124

Scheme 3

The substituted hydroxyl naphthalene 2J can undergo halogénation using an appropriate halogen source and catalyst such as, for example N-chlorosuccinimide and zirconium(rV) chloride to provide 2K, The hydroxyl naphthalene 2K can be converted to a leaving group such as, for example trifluoromethanesulfonate ester by treatment with trifluoromethanesulfonic anhydride and base such as, for example, 2,6-lutidine to provide 2L. Naphthalene 2L can undergo a sélective cross-coupling reaction such as, for example Stille cross-conpling using a tin reagent such as tributyl(vinyl)tin and a palladium catalyst such as bis(triphenylphosphine) palladium(II) dichloride to give the corresponding cross-coupled naphthalene such as vinylnaphthalene 2M. The alkenylnaphthalene can be dihydroxylated to provîde 2N by methods known to those skilled in the art such as, Shaipless asymmetric dihydroxylation using, for example, commercîally available AD mix-a.

C

125

The resulting diol 2N can be protected at the primary hydroxyl by suitable protecting groups such as pivalate ester using pivaloyl chloride and pyridine to provide 2P. The secondary hydroxyl can be converted to the corresponding ether such as tertbutyl ether using methods known to those skilled in the art such as, tert-butyl acetate and perchloric acid to provide 2Q. The halogenated naphthalene 2Q can undergo cross-coupling reaction such as Suzuki cross-coupting using a boronic acid and a . palladium catalyst such as palladium(ll) acetate with SPhos to give the corresponding cross-coupled naphthalene 2R. The protected primary hydroxyl can be deprotected by methods known to those skilled in the art such as the deprotection of a pivalate protecting group under basic conditions for example, using sodium hydroxide, to give the corresponding primary hydroxyl compound 2R. The primary hydroxyl can be oxidized to the corresponding carboxylic acid 2S by methods known to those skilled in the art such as, for example, periodic acid and chromium trioxîde.

126

Scheme 4

	R^s	OH	OH
R®			À^OPG¹
R'	LA	sA	'r²°
	R⁸	R¹
	4B

4C

LG = leavîng group

R^s LG O
R^s	îS		A.OPG¹
R'	M R®	R¹	R*°

4E

	R^s	LG	OH
Ri			xk^OPG¹
rT	LA
	R®	R¹
	4F'	n

R® R¹

4H“

Electrophilic aromatic substitution with a suîtably functionalized and protected 5 naphthol such as, for example 4A”, with an electrophile such as, for example, ethyl glyoxylate under appropriate conditions such as, for example, titanium tetrachloride, can provide 4B”. The secondary alcohol can be protected with a protecting group and the naphthol converted to a leaving group (e.g. triflate) known to undergo crosscoupling reactions to provide 4C”. The alcohol protecting group can be removed and

C

127 the resulting alcohol oxidized to the ketone using an oxidant such as Dess-Martin Periodinane, for example, to provide 4E”. The ketone can be reduced stereoselectively using an asymmetric réduction method such as, for example Corey-Bakshi-Shibata Réduction to provide 4F”.

The secondary hydroxyl can be converted to the corresponding ether such as tert-butyl ether using methods known to those skilled în the art such as, tert-butyl acetate and perchloric acid to provide 4G”. The functionalized naphthalene 4G” can undergo can undergo cross-coupling reactions such as but not limited to Suzuki réactions with boronic acids or esters, Stille reactions with trialkylstannane reagents, 10 and Buchwald-Hartwig reactions with amines thus providing carbon linked and nitrogen linked products using a palladium catalyst such as palladium(II) acetate with SPhos to give the corresponding cross-coupled naphthalene 4H”. The protected ester can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a ethyl ester protecting group under basic conditions, such as, for 15 example sodium hydroxide, to give the corresponding carboxylic acid 41”.

It is known to those skilled in the art that the functionalized naphthalenes (e.g. 4E”, 4G”, or 4H”) that contain a halogen or pseudohalogen (e.g. triflate), can undergo cross-coupling reactions such as but not limited to Suzuki reactions with boronic acids or esters, Stille réactions with trialkyltin reagents, Sonogashira reactions with alkynes, 20 and Buchwald-Hartwig réactions with amines and carried forwaid in a similar manner to provide 41”.

C

128

Scheme 5

	R^s	LG OPG²
R⁶x
R⁷'	O
	R⁸	R¹
		4C
	LG =	leaving group

The functionalized naphthalene 4C” can undergo can undergo cross-coupling reactions such as but not limited to Suzuki reactions with boronic acids or esters, Stille 5 reactions with trialkyltin reagents, Sonogashira reactions with alkynes, and BuchwaldHartwig reactions with amines thus providing carbon linked and nitrogen linked products using a palladium catalyst such as palladium tetrakis to give the corresponding cross-coupled naphthalene 5A”. The alcohol protectîng group can be removed and the resulting alcohol oxîdized to the ketone using an oxidant such as Dess-Martin

Periodinanc, for example, to provide 5B”. The ketone can be reduced stereoselectively using an asymmetric réduction method such as, for example Corey-Bakshi-Shibata Réduction to provide 5C”. The secondary hydroxyl can be converted to the corresponding ether such as tert-butyl ether using methods known to those skilled in the art such as, tert-butyl acetate and perchloric acid to provide 5D”. The protected ester can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a ethyl ester protectîng group under basic conditions, such as, for example sodium hydroxide, to give the corresponding carboxylic acid 5E”.

129

It is known to those skilled in the art that the functionaltzed naphthalenes (e.g. SA” or SD”) that contain a halogen or pseudohalogen (e.g. triflate), can undergo crosscoupling reactions such as but not limited to Suzuki reactions with boronic acids or esters, Stille reactions with trialkyitin reagents, Sonogashira réactions with alkynes, and

Buchwald-Hartwig reactions with amines and canied forward in a similar manner to provide 5E”.

Scheme 6

WO 2012/003497

130

PCT/US2011/042880

6A 5B gc

6F· 6G-

R⁵	LG OPG³
^r‘yS
R’-Χ·	Jl_rî°

R®

LG = leasing group

It is known to those skilled in the art that 6A” can undergo The HomerWadsworth-Emmons with stabilized phosphonate carbanions such as, for example 5 (diethoxyphosphoryl)acetic acid ethyl ester and sodium hydride to provide 6B”. The olefin can be reduced by hydrogénation with palladium on carbon, for example, to provide 6C”. The protected ester can be deprotected by methods known to those skilled in the art such as, for exampie the deprotection of a ethyl ester protecting group

- Ί ex

I3l under basic conditions, such as, for example lithium hydroxide, to give the corresponding carboxylic acid that can be converted to the corresponding acid chloride using oxalyl chloride to give 6D”. Friedel Crafts reaction catalyzed by a Lewis acid such as, for example, aluminum trichloride provides tetralone 6E”.

Condensation of 6E” with, for example, ethyl glyoxylate under acid catalysis provides 6F” which can be brominated under radical conditions such as, for example, Nbromosuccinimide and AIBN, and converted to 6H” using an alkoxide such as that derived from reaction of 4-methoxybenzyl alcohol and LHMDS, for example.

The naphthol 6H” can be converted to a leaving group (e.g. triflate) known to undergo cross-coupling reactions by methods known to those skilled in the art. Compound 61” can undergo cross-coupling reactions such as but not limited to Suzuki reactions with boronic acids or esters, Stille reactions with trialkyltin reagents, Sonogashira reactions with alkynes, and Buchwald-Hartwig reactions with amines thus providing carbon linked and nitrogen linked products using a palladium catalyst such as palladium tetrakis to give the corresponding cross-coupled naphthalene 6J”.

The alcohol protecting group can be removed by methods known to those skilled in the art and the resulting hydroxyl can be converted to the corresponding ether such as tert-butyl ether using methods known to those skilled in the art such as, tertbutyl acetate and perchloric acid to provide 6K”. The protected ester can be deprotected by methods known to those skilled in the art such as, for example the deprotection of a ethyl ester protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding carboxylic acid 6L”.

Prodrugs

In one embodiment, the invention provides for a prodrug of a compound of the invention. The terra “prodrug” as used herein refers to any compound that when administered to a biological System générâtes a compound of the invention that inhibits the réplication of HIV (“the active inhibitory compound”). The compound may be formed from the prodrug as a resuit of: (i) spontaneous chemical reaction(s), (ii) enzyme catalyzed chemical reaction(s), (iii) phoiolysis, and/or (iv) metabolic chemical reaction(s).

“Prodrug moiety” refers to a labile functional group whîch séparâtes from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis,

C

132 enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academie Publishers, pp. 113191). Enzymes which are capable of an enzymatic activation mechanism with the prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases. Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy. A prodrug moiety may include an active métabolite or drug itself.

Exemplary prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters -CH₂OC(=O)R and acyloxymethyl carbonates -ÎH20C(=0)0R where R⁹⁹ is CT-Cf, alkyl, C|-Cf, substituted alkyl, C6-C20 atyl or C6-C20 substituted aryl. The acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al.

(1983) J. Pharm. Sci. 72: 324; also US Patent Nos. 4816570,4968788,5663159 and

5792756. Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention. An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM) -CH₂0C(=O)C(CH₃)j. An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) -CH20C(=O)OC(CH3)3.

Aryl esters of phosphorus groups, especially phenyl esters, are reported to enhance oral bioavailability (De Lombaert et al. (1994) J. Med Chem. 37: 498).

Phenyl esters containing a carboxylic ester ortho to a phosphate hâve also been described (Khamnei and Torrence, (1996) J Med. Chem. 39:4109-4115). Benzyl esters are reported to generate parent phosphonic acids. In some cases, substituents at the ortho- or para- position may accelerate the hydrolysis. Benzyl analogs with an acylated phénol or an alkylated phénol may generate the phenolic compound through the action of enzymes, e.g., esterases, oxidases, etc., which in tum undergoes cleavage at the benzylïc C-0 bond to generate phosphoric acid and a quinone methide intermediate. Examples of this class of prodrugs are described by Mitchell et al.

C

133 (1992)7 Chem. Soc. Perkin Trans. Il 2345; GlazierWO 91/19721. Still other benzylic prodrugs hâve been described contaîning a carboxylic ester-containing group attached to the benzylic methylene (Glazîer WO 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Deesterification or réduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide (Puech et al. (1993) Antiviral Res., 22; 155-174; Benzaria et al. (1996)7 Med Chem. 39: 4958).

Pharmaceutical Formulations

The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in stérile form, and when intended for delivery by other than oral administration generally 15 will be isotonie. Ail formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, ehelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily 20 about 7 to 10.

While it is possible for the active ingrédients to be administered alone it may be préférable to présent them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingrédient, as above defined, together with one or more acceptable carriers and optionally other 25 therapeutic ingrédients. The camer(s) must be “acceptable” in the sense of being compatible with the other ingrédients of the formulation and physiologically innocuous to the récipient thereof.

The formulations include those suitable for the foregoing administration routes.

The formulations may conveniently be presented in unit dosage form and may be 30 prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into

134 association the active ingrédient with the carrier which constitutes one or more accessory ingrédients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingrédient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the présent invention suitable for oral administration may be presented as discrète units such as capsules, cachets or tablets each containing a predetermined amount of the active ingrédient: as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid émulsion or a water-in-oil liquid émulsion. The active ingrédient may also be administered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or more accessory ingrédients. Compressed tablets may be prepared by compressing in a suitable machine the active ingrédient in a free-flowing form such as a powder or granules, optionally mixed with a binder, fabricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingrédient moistencd with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingrédient therefrom.

For administration to the eye or other extemal tissues e.g., mouth and skin, the formulations are preferably applied as a topical oîntment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in incréments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an oîntment, the active ingrédients may be employed with either a paraffmic or a water-miscible oîntment base. Alternatively, the active ingrédients may be formulated in a cream with an oil-in-water CTeam base.

If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-dîol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof- The topical formulations may desirably include a compound which enhances absorption or pénétration of the active ingrédient through the skin or other affected areas. Examples of such dermal pénétration enhancers include dimethyl sulfoxide and related analogs.

C

135

The oily phase of the émulsions of this invention may be conslituted from known ingrédients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilie emulsifier which acts as a stabilîzer. It is also preferred to include both an oil and a fet Together, the emulsifierfs) with or wîthout stabilizerfs) make up the so-called emulsifymg wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Emulgents and émulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium iauryl sulfate.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non15 staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as diisoadipate, isocetyl stéarate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stéarate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Altematively, high melting point lipids such as white soft parafïin and/or liquid paraffm or other minerai oils are used.

Pharmaceutical formulations according to the présent invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingrédient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, émulsions, hard or soft capsules, syrups or élixirs may be prepared.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetenîng agents, flavoring agents, coloring

136 agents and preserving agents, m order to provide a palatable préparation. Tablets containing the active ingrédient in admixture with non-toxîc pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnésium stéarate, stearic acid or talc. Tablets may be uncoaied or may be coated by known techniques including microencapsulation to delay disintegration and adsorptîon in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingrédient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingrédient is mixed with water or an oil medium, such as peanirt oil, liquid paraffin or olive oil.

Aqueous suspensions ofthe invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylccllulose, hydroxypropyl methylcelluose, sodium alginate, polyvïnylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkyl oxide with a fatty acid (e.g., polyoxyethylene stéarate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingrédient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a minerai oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as

beeswax, hard paraffin or cetyi alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral préparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules of the invention suitable for préparation of an aqueous suspension by the addition of water provide the active ingrédient in admixture with a dispersing or wetting agent, a suspendîng agent, and one or more preservatîves. Suitable dispersing or wetting agents and suspendîng agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be présent.

The pharmaceutical compositions of the invention may also be in the form of oil-în-water émulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a minerai oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The émulsion may also contain sweetening and flavoring agents. Syrups and élixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of a stérile injectable préparation, such as a stérile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspendîng agents which hâve been mentioned above. The stérile injectable préparation may also be a stérile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonie sodium chloride solution. In addition, stérile fixed oils may conventionally be employed as a solvent or suspendîng medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the préparation of injectables.

138

The amount of active ingrédient that may be combined with the carrier material to produce a single dosage fonn will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for întravenous infusion may contain from about 3 to 500 pg of the active ingrédient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye drops wherein the active ingrédient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingrédient. The active ingrédient is preferably présent in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingrédient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingrédient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingrédient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salîcylate.

Formulations suitable for întrapulmonary or nasal administration hâve a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in incréments microns such as 0.5,1,30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingrédient. Formulations suitable for aérosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingrédient such carriers as are known in the art to be appropriate.

I39

Formulations suitable for parentéral administration include aqueous and nonaqueous stérile injection solutions which may contain anti-oxidants, buffers. bacteriostats and solutés which render the formulation isotonie with the blood of the intended récipient; and aqueous and non-aqueous stérile suspensions which mav include suspendîng agents and thickening agents.

The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the stérile liquid carrier, for example water for injection, îmmediately prior to use. Extemporaneous injection solutions and suspensions are prepared from stérile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of tbe active ingrédient.

It should be understood that in addition to the ingrédients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The invention further provides veterinary compositions comprising at least one active ingrédient as above defined together with a veterinary carrier.

Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise ïnert or acceptable in the veterinary art and are compatible with the active ingrédient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

Compounds of the invention can also be formulated to provide controlled release of the active ingrédient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingrédient. Accordingly, the invention also provides compositions comprising one or more compounds of the invention formulated for sustaîned or controlled release.

Effective dose of active ingrédient dépends at least on the nature of the condition being treated, toxicity, whether the compound is being used propbylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.

Routes of Administration

One or more compounds of the invention (herein referred to as the active ingrédients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parentéral (including subcutaneous, intramuscular, intravenous, intradermal, întrathecal and épidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the récipient. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.

The antiviral properties of a compound of the invention may be determined using Test A described below.

Test A: Antiviral Assavs in MT4 Cells

For the antiviral assay utilizing MT-4 cells, 0.4 pL of 189X test concentration of 3-fold serially diluted compound in DMSO was added to 40 pL of cell growth medium (RPMI 1640, 10%FBS, 1% penicillin/Streptomycin, 1% L-Glutamine, 1% HEPES) in each well of 384-well assay plates (10 concentrations) in quadruplicate.

mL aliquots of 2xl0e6 MT-4 cells are pre-infected for 1 and 3 hrs respectively, @ 37 °C with 25 pL (MT4) or of either cell growth medium (mockinfected) or a fresh 1:25O dilution of an HlV-IIIb concentrated ABI stock (0.004 m.o.î. for MT4 cells). Infected and uninfected cells are diluted în cell growth medium and 35 uL of 2000 (for MT4) cells is added to each well ofthe assay plates.

Assay plates were then incubated in a 37 °C incubator. After 5 days of incubation, 25 pl of 2X concentrated CellTiter-Glo™ Reagent (catalog # G7573, Promega Biosciences, Inc., Madison, WI) was added to each well of the assay plate. Cell lysis was carried out by incubating at room température for 2-3 min and then chemiluminescence was read using the Envision reader (PerkinElmer).

Compounds of the présent invention demonstrate antiviral activity in this assay 30 (Test A) as depicted in the table below.

Compound Number	EC50 (pM)
3K	0.056

I4l

4K	0301
4L	22
5K	4.6
6D	0.014
7D	1.7
7Ε	20
8	0.025
9	13
10	36
11	8.9
12	0.11
13	0.010
14	0.011
15	0.015
16	7.0
17	7.7
19	5.4
20	0.093
22	0.54
23	0.024
24	29
25	26
26	0.84
27	3.5
28	0.40
29Α	0.13
29Β	0.50
30	0.044
31	0.11
32	0.086
33	0.12
34	035
37	1.2
38	3.4
39	0.70
40	0.21
41	0.40
42	0.11
43	0.022
44	0.12
45	1.8
46	1.4
47	0.11
48	0.21
49	0.65
53	0.12
54	0.055

142

55	0.054
56	0.21
57	0.082
58	0.042
59	0.16
60	0.032
61	0.264
62	0.136
63	0.099
64	0.052
65	0.19
66	0.29
67	0.29
68A	0.014
68B	0.005
69	0.38
70	8.8
71	35
72	2.0
73	0.13
74	1.2
75	0.98
76	0.93
77	8.9
78	0.30
79	0.089
80	0.051
81	0.15
82	0.058
83	0.078
84	0.014
85	0.018
86	0.98
87	0.072
88	0.024
89	0.28
90	31
91	0.25
92	7.1
93	0.086
94	12
95	0.38
96	0.088
97	0.30
98	0.010
99	0.107
100	0.023

143

ΙΟΙ	0.041
102	0.037
103	0.026
104	0.036
105	0.043
1O6A	0.086
1O6B	0.091
107	0.092
108	0.028
109	29
110	0.067
111	1.1
112	0.009
113A	0.91
113B	0.46
114	1.9
115	0.037
116	0.016
117	0.011
118	0.036
119	0.011
120	0.032
121	0.014
122	0.036
123	0.024
124	0.15
126	0.833
127	0.087
128	5.3
129	0.17
131	0.062
132	0.118
133	0.123
134	0.15
135	0.045
136	0.34
137	0.13
138	0.040
139	0.010
140	1.6
143	0.056
144	1.3
145	0.050
146	ΙΟ
147	1.1
149	0.20
150A	29.150

144

150B	0.26
151	0.85
152	5.8
153	11
154	29
155	29
156	7.3
157	10
158	35
159	1.3
160	36
161	4.7
162	1.4
163	16
164	25
165	53
166	16
167	29
168	45
169	18
170	29
171	36
172	50
173	3.2
174	3.2
175	20
176	12
177	37
178	34
179	18.7
180	29
181	0.005
183	0.351
185	0.024
186 A	1.694
186B	0.024

In certain embodiments, the compounds demonstrate an EC50 of < 50 μΜ. In certain embodiments, the compounds demonstrate an EC50 of < 30 μΜ. In certain embodiments, the compounds demonstrate an EC50 of < 10 μΜ. In certain embodiments, the compounds demonstrate an EC50 of < 1 μΜ.

The spécifie pharmacological responses observed may vary according to and dependîng on the particular active compound selected or whether there are présent pharmaceutical carriers, as well as the type of formulation and mode of administration

Î45 employée!, and such expected variations or différences in the results are contemplated in accordance with practice of the présent invention,

The invention has been described with reference to various spécifie and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

The invention will now be illustrated by the following non-limiting Examples. The Examples provided herein describe the synthesis of compounds of the invention (i.e. compounds of Formula I) as well as intermediates used to prépare compounds of the invention.

Example 1. (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)acetic acid (3K)

145

A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H₂O) to a volume of 114 mL. This stock solution (0.80 mL) was added to a solution of (S)-2-tert-butoxy- 2 ( 1 -(4-chlorophenyl)-

3-methylnaphthalen-2-yl)ethanol (3J) (51.7 mg, 0.14 mmol) in wet acetonitrile (2.0 mL), 0.75% H₂O) at 0 ^DC. The reaction mixture was stirred for 30 minutes at 0 °C and quenched with 1.5 M Κ₂ΗΡΟ₄ solution. Ethyl acetate was added and organic layer separated and washed with 1:1 brineiH₂0 (2x), then saturated NaHSOj/brine. The organic layer was dried (MgSO₄), filtered and concentrated and purified by reverse phase HPLC (Gemini, 50 to 95% ACN/H₂O + 0.1% TFA) and the product lyophilized to give 3K as a white powder (27.8 mg). ’H-NMR: 300 MHz, (CDC1₃) Ô 7.73 (d, J =

ΙΟ

7.8 Hz, IH), 7.64(s, IH), 7.62 (d, J = 7.8 Hz, IH), 7.50-7.38 (m, 3H), 7.28-7.22 (m, 3 H), 5.25 (s, IH), 2.54 (s. 3 H). 0 98 (s. 9H) LCMS-ESF (»ii): [M-H]'cal cd for GJLT’IO.: 381.88; Found: 380.9. 382.9.

Préparation of (S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3-methylnaphthalen-2yl)ethanol (3J):

Préparation of l-pbenyIpropan-2-one (3B): A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H₂O) to a volume of 114 mL. This stock solution (104.5 mL) was added to a solution of 1-phenylpropan-2-ol (3A) (5.0 g, 36.71 mmol) in wet acetonitrile (150 mL, 0.75% H₂O) at 0 °C over 1 h, maintaining internai température below 5 °C. The reaction was quenched with K₂HPO₄ (11.5 g, 50.5 mmol) in H₂O (60 mL). Dichloromethane was added and organic layer separated and washed with brine/H₂O (2 x 100 mL), followed by saturated NaHSCh/brine. The organic layer was dried (MgSÛ4), filtered and concentrated to give 3B as a yellow oil (5.1 g). ’ll-NMR: 300 MHz, (CDCI3) 5 7.35-7.10 (m, 5H), 3.65 (s, 2H), 2. i 1 (s, 3 H).

Préparation of 4-(4-chIorophenyl)-2-methy 1-1-phenylbut-3-yn-2-ol (3D); To a solution of l-chloro-4-ethynylbenzene (3C) (1.75 mL, 12.81 mmol) in THF (40 mL) at 0 °C was added n-butyllithium (2.5 M in hexanes, 5.13 mL, 12.81 mmol) and stirred for 1 h. A solution of l-phenylpropan-2-one (3B) (1.38 g, 10.25 mmol) in THF (5 mL) was added and the reaction mixture was warmed to room température ovemight. The reaction mixture was quenched with saturated NH4CI solution and extracted with diethyl ether (2x). The combined organic layer was dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 3D as a yellow oil (2.29 g). ^]H-NMR: 300 MHz, (CDC1₃) δ 7.35-7.20 (m, 9H), 3.0 (AB quart, J = 13.2,9.9 Hz, 2H), 1.59 (s, 3 H).

Préparation of l-(4-chlorophenyl)-2-iodo-3-methylnaphthalene (3E): To a solution of 4-(4-chlorophenyl)-2-methyl-l-phenylbut-3-yn-2-ol (3D) (1.77 g, 6.53 mmol) in acetonitrile (50 mL) was added sodium bicarbonate (1.097 g, 13.06 mmol), followed by iodine (4.974 g, 19.60 mmol). The reaction mixture was stirred for 1.5 h, then diluted with diethyl ether. The organic layer was washed with 1 M sodium thiosulfate solution (50 mL). The aqueous layer was back-extracted with diethyl ether

148 and the combined organic layer was dried (MgSOj. filtered, concentrated. adsorbed onto silica gel and purified by flash column chromatography (silica gei. hexanes) to give 3E as an ofT-white solid (1.8733 g). 'H-NMR: 300 MHz, (CDClj) δ 7.74 (d, J =

6.6 Hz, 1H), 7.73 (s, 1H), 7.48-7.40 (m, 3H), 7.24-7.20 (m, 2H),7.13 (d, J = 8.1 Hz, 2H), 2.64 (s, 3 H).

Préparation of l-(4-chlorophenyl)-3-methyl-2-vinyliiaphthalene (3F): A solution of 1-(4-chlorophenyl)-2-iodo-3-methylnaphthalcnc (3E) (130 g, 3.98 mmol), tributyl(vinyl)tin (1.28 mL, 4.37 mmol) and PdCIafPPlb^ (0.279 g, 0.398 mmol) in DMF (20 mL) was stirred at 90 °C under argon ovemight. The reaction mixture was cooled, diiuted with ethyl acetate and washed with 5% LiCl solution (2x), brine and dried (MgSO₄). The mixture was filtered, concentrated and purified by flash column chromatography (silica gel, hexanes) to give 3F as a white solid (0.9894 g). 'H-NMR: 300 MHz, (CDC1₃) δ 7.74 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.40-7.13 (m, 5H), 7.15 (d, J = 8.1Hz, 2H), 6.50 (dd, J = 18,11.7 Hz, 1H), 5.27 (d, J = 11.7 Hz, 1H), 5.03 (d, J = 18 Hz, 1H), 2.50 (s, 3 H).

Préparation of (S)-l-(l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethane-l,2diol (3G): A biphasic mixture of AD-mix-a (4.928 g) in tert-butanol (17.5 mL)TI₂O (17.5 mL) was cooled to 0 and l-(4-chlorophenyl)-3-methyl-2-vinyl-naphthalene (3F) (0.980 g, 3.52 mmol) was added. The reaction mixture was stirred for 6 h at 0 °C then stored at -20 °C ovemight. The reaction was resumed for 10 h at 0 °C, then stored at -20 °C ovemight. The réaction was resumed for 8 h at 0 °C until complété. Sodium sulfite (5.3 g) was added at 0 °C, then waimed to room température and stirred for 30 min to give a white mixture. The mixture was diiuted with dichloromethane and ILO. The mixture was extracted with dichloromethane (3x) and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give 3G as a white solid (0.9813 g). 'H-NMR: 300 MHz, (CDCI₃) δ 7.72 (d, J = 8.1 Hz, 1H), 7.65 (s, 1H), 7.50-7.303 (m, 3H), 7.26-7.07 (m, 4H), 4.92 (dd, J = 9.9, 3.6 Hz, 1 H), 3.94 (dd, J =

10.2, 10.2 Hz, 1H), 3.57 (dd, J = 11.1, 3.6 Hz, 1H), 2.69 (s, 3 H).

Préparation of (S)-2-(l -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2hydroxyethy] pivalate (3H): To a solution of (S)-l -(l-(4-chlorophenyl)-3methylnaphthalen-2-yl)ethane-l,2-diol (3G) (0.981 g, 3.14 mmol) in pyridine (5.0 mL)/ DCM (15.0 mL) was added pivaloyl chloride (0.463 mL, 3.77 mmol). The reaction

149 mixture was stirred for 5 h at room température and diluted with ethyl acetate. The organic layer was washed with I N HCl. saturated sodium bicarbonate solution, dried (MgSOd). filtered. concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to give 3H as a white solid (1.296 g). H-XMR: 300 MHz, (CDCh): Ô: 7.72 (d, J = 8.1 Hz, IH), 7.67 (s, IH), 7.46-7.37 (m, 3H), 7.267.l0(m, 4H), 4.99 (dd, J = 8.7, 3.0 Hz, lH),4.45(dd, J = 11.7, 9.7 Hz, 1H),4.13 (dd. J = Π.7, 3.3 Hz, IH), 2.72 (s, 3H), 1,11 (s, 9H).

Préparation of (S)-2-tert-butoxy-2-(i-(4-chlorophenyl)-3-methylnaphthalen-2yl)ethanol (3J); A solution of (S)-2-(l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2hydroxyethyl pivalate (3H) (0.4582 g, 1.15 mmol) and perchloric acid, (70%, 0.138 mL, 2.3 mmol) in tert-butyl acetate (10 mL) was stirred at room température for 3 h. The reaction mixture was quenched with solid sodium bicarbonate (0.5 g) for 1 h. Saturated sodium bicarbonate solution was added and extracted with ethyl acetate (3x). The combined organic layer was dried (MgSOi), filtered and concentrated to give (S)-

2-tert-butoxy-2-(l-(4-chIorophenyl)-3-methylnaphthalen-2-yl)ethyl pivalate (31) that was used in next step without further purification. (S)-2-tert-butoxy-2-(l-(4chlorophenyl)-3-methyInaphthalen-2-yl)ethyl pivalate (31) from above reaction was dissolved in MeOH (1 mL) and THF (7 mL). Sodium hydroxîde (2 M, 0.75 mL, 1.5 mmol) was added and the reaction mixture was stirred at room température ovemight. Additional sodium hydroxîde (2 M, 0.75 mL, 1.5 mmol) was added and reaction mixture was stirred for an additional 24 hours. The reaction mixture was then diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and combined organic layer was dried (MgSCh), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 3J as a white solid (0.1889 g). ’H-NMR: 300 MHz, (CDCh) δ 7.72 (d, J = 8.1 Hz, IH), 7.63 (s, IH), 7.46-7.05 (m, 7H), 4.60 (dd, J = 10.5, 4.5 Hz, IH), 3.77 (dd, J = 11.4,

4.2 Hz, IH), 3.46 (dd, J = i 1.4, 4.2 Hz, IH), 2.71 (s, 3H), 1.00 (s, 9H).

I50

Example 2. (S)-2-tert-butoxy-2X(R)-3-methyl-1-(quinolin-8-yl)naphthalen-2-yl)acetic acid (4K) and (S)-2-tert-butoxy-2-((S)-3-methy]-1-(quÎnolin-8-yl)naphtha]en-2vl)acetic acid (4L)

I5l (S)-2-tert-butoxy-2-((R)-3-merhyl-l-(quÎnolin-8-yl)naphthalen-2-yl)ethyl pîvalate (41) (22 mg. 0 0468 mmol) was dissolved in THF (1.0 mL) and MeOH (0.1 mL) and 2.0 M NaOH (94 pL) was added. The reaction mixture was stirred for 24 h and 2.0 M NaOH (94 pL) was added. After stirring for 60 h al room température, the reaction was heated at 55 °C for Ih with little change in conversion. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO₄), filtered, concentrated and used in next step without further purification. The residue from above was dissolved in wet acetonitrile (0.75% H₂O), and HJO^/CrOj stock solution (0.439 M, 0.266 mL) was added at 0 °C. The reaction mixture was stirred for 30 minutes and additional HsIOfi/CrOî stock solution (0.439 M, 0.266 mL) was added. After stirring for 30 minutes, the reaction mixture was quenched with saturated NaHCO₃ solution and diluted with ethyl acetate. The organic layer was washed with H₂O/brine_f dried (MgSCb), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% acetonitrile/H₂O + 0.1% TFA) to give 4K as a film (12.1 mg, 50%). ’H-NMR:

400 MHz, (CD₃OD) δ 9.35 (dd, J = 8.4, 1.6 Hz, 1 H), 8.86 (dd, J = 5.6, 1.2 Hz, 1 H),

8.51 (dd, J = 8.4,1.2 Hz, 1 H), 8.13-8.07 (m, 2H), 8.01 (s, 1H), 7.95 (d, J - 8.0 Hz, 1 H), 7.52-7.45 (m, 1H), 7.28-7.24 (m, 1H), 6.83 (d, J = 8.4 Hz, 1 H), 5.23 (s, 1H), 2.80 (s, 3H), 0.84 (s, 9H). ¹⁹F-NMR: 376 MHz, (CD3OD) δ: -77.87. LCMS-ESI* (m/z): [M+H]⁺ calcd for C26H₂6NO₃: 400.5; Found: 400.1.

Compound 4L (1.8 mg, 32%) was prepared following the procedure used to préparé compound 4K except that compound 4J was used instead of compound 41. ’HNMR: 400 MHz, (CD₃OD) δ 9.23 (dd, J = 8.4, 1.6 Hz, 1 H), 8.75 (dd, J = 5.2, 1.6 Hz, 1 H), 8.48 (dd, J = 8.8, 1.6 Hz, 1 H), 8.31 (dd, J = 7.2,1.2 Hz, 1 H), 8.13 (dd, J = 7.6,7.2 Hz, 1 H), 7.99 (dd, J = 8.4,5.2 Hz, 1 H), 7.96 (s, 1H), 7.94 (d, J = 8.4 Hz, 1 H), 7.525 7.45 (m, 1H), 7.25-7.21 (m, 1H), 6.83 (d, J = 8.8 Hz, 1 H), 5.16 (s, 1H), 2.75 (s, 3H),

0.83 (s, 9H). LCMS-ESÏ⁺ (m/z): [M+H]⁺ calcd for C₂₆H₂₆NO₃: 400.5; Found: 400.1.

Préparation of(S)-2-tert-butoxy-2-((R)-3-methyl-l-(quinolin-8-yl)naphthalen-2yl)ethyl pîvalate (41) and (S)-2-tert-butoxy-2-((S)-3-methyL 1 -(qumoIin-830 yl)naphthalen-2-yl)ethyl pîvalate (4J):

Préparation of 1 chloro-3 -methylnaphthalen-2-ol (4B): To a solution ofNchlorosuccinimide (8.02 g, 60.05 mmol) in dichloromethane (475 mL) at -78 °C was added zirconium(IV)chloride (2.80 g, 12.01 mmol), followed by 3-methyl-naphthalen16293

2-ol (4A) (9.5 g, 60.05 mmol) under Ar. The reaction mixture was stirred at -78 °C for 5 minutes, the cooling bath was removed and the reaction was stirred at room température for 5 h. The reaction was quenched wiih saturated sodium bicarbonate solution and stirred for 5 minutes. The mixture was diluted with H-O, extracted with dichloromethane (3x) and the combined organic layer was dried (MgSÛ4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 4B as a white solid (9.05 g, 78%).

Préparation of l -chloro-3-methylnaphthalen-2-yl trifluoromethanesulfonate (4C): To a solution of l -chloro-3-methylnaphthalen-2-ol (4B) (9.05 g, 46.98 mmol) in dichloromethane (235 mL) at -78 °C was added trifluoromethanesulfonic anhydride (11.9 mL, 70.47 mmol), followed by 2,6-iutidîne (8.2 mL, 70.47 mmol). The reaction mixture was stirred for 3 h to give a yellow solution, which was diluted with dichloromethane and washed with H₂O/brine. The organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 4C as a white solid (14.75 g, 97%).

Préparation of 1 -chloro3-methyl-2-vmylnaphthalene (4D): To a solution of I chloro-3-methylnaphthalen-2-yl trifluoromethanesulfonate (4C) (14.75 g, 45.43 mmol), tributyl(vinyl)tin (14.59 mL, 49.97 mmol) and lithium chloride (5.78 g, 136.29 mmol) was added bîs(triphenylphosphine)palladium(II) dichloride under Ar. The reaction mixture was heated at 50 °C for 20 h, then heated at 90 °C for 8 h. The reaction mixture was than cooled to room température, diluted with ethyl acetate, washed with 5% lithium chloride solution (3x), brine and dried (MgSO₄), filtered and then concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 4D contaminated by organotin. The residue was dissolved in dichloromethane and stirred with 10% KF solution overnight. The resulting white mixture was filtered through a pad of Celite and extracted with dichloromethane (2x). The organic layer was concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 4D as a pale yellow oil (10.1 g).

Préparation of (S)-l-(l-chloro-3-ïnethylnaphthalen-2-yl)ethane'l,2-diol (4E): A biphasic mixture of AD-mix-a (6.907 g) in tert-butanol (24.5 mL)/H₂O (24.5 mL) was cooled to 0 °C and l-chloro-3-methyl-2-vinylnaphthalene (4D) (1.00 g, 4.93 mmol) was added. The reaction mixture was stirred for 8 h at 0 °C. Sodium sulfite (7.4 g) was added at 0 °C and the reaction was stirred for 40 minutes to give a white mixture.

153

The mixture was diluted with dichloromethane and IbO. The mixture was extracted with dichloromethane ( 3x ) and the combined organic layer was dried (MgSO₄). filtered. concentrated and purified by flash column chromatography (silica gel. 0 to 100% ethyl acetate/hexanes) to give 4E as a white solid (0.920 g).

Préparation of (S)-2-(I-ch]oro-3-methylnaphthalen-2-yI)-2-hydroxyethyl pivalate (4F): Te a solution of (S)-l-(l-chloro-3-methylnaphthalen-2-y])ethane-l,2-diol (4E) (0.920 g, 3.89 mmol) in pyridine (5.0 mL)/dichloromethane (15.0 mL) was added pivaloyl chloride (0.574 mL, 4.67 mmol). The réaction mixture was stirred for 18 h at room température. The reaction was incomplète and additional pivaloyl chloride (0.574 mL, 4.67 mmol) was added. After stirring for 1 h, the reaction mixture was quenched with 1 N HCl and diluted with ethyl acetate. The organic layer was washed with 1 N HCI, saturated sodium bicarbonate solution, dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to give 4F as a colorless oil (1.139 g). LCMS-ESI⁺ (m/z): [M-O]⁺calcd for Ci₈H2jCIO₂: 304.80; Found: 303.0, 305.0.

Préparation of (S)-2-tert-butoxy-2-(l-chloro-3-methylnaphthalen-2-yl)ethyl pivalate (4G): A solution of (S)-2-(l-chloro-3-methylnaphtha]en-2-yl)-2-hydroxyethyl pivalate (4F) (1.13 g, 3.52 mmol) and perchloric acid, (70%, 0.605 mL, 7.04 mmol) in tert-butyl acetate (35 mL) was stirred at room température for 1.5 h. The reaction mixture was quenched with solid sodium bicarbonate (1.5 g) for 1 h. Saturated sodium bicarbonate solution was added and the reaction was extracted with ethyl acetate (3x). The combined organic layer was dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 4G as a colorless oil (1.1889 g, 90%).

Préparation of(S)-2-tert-butoxy-2-((R)-3-methyl-l-(quinolin-8-yl)naphthalen-2yl)ethyl pivalate (41) and (S)-2-tert-butoxy-2-((S)-3-methyl-1 -(quinolin-8yl)naphthalen-2-yl)ethy] pivalate (4J): To a mîcrowave vial was added (S)-2-tertbutoxy-2-(l-chloro-3-methylnaphthalen-2-yl)ethyl pivalate (4G) (0.100 g, 0.265 mmol), 8-quinoline boronic acid (4H) (0.069 g, 0.398 mmol), palladium(II) acetate (0.003 g, 0.013 mmol), SPhos (0.011 g, 0.0265 mmol) and potassium phosphate (0.169 g, 0.795 mmol). The vial was evacuated and backfilled with argon (3x). Anhydrous THF (0.53 mL) and H₂O (53 pL) were added and mixture stirred at room température for 2 h and then heated at 50 “C for 2 h. The reaction was charged with

154

PdChfCHjCN); (ΊΟ mg) and SPhos (20 mg) and heated overnight at 100 °C. The reaction mixture was diluted with ethyl acetate. washed with brine. dried (MgSÔA filtered. concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give the separated atropisomers; atropisomer 41 (22.0 5 mg) LCMS-ESf (m/z); [M+H]⁺ calcd for CiiH^NŒ: 470.62; Found: 470.1 ; and atropisomer 4J (5.2 mg) LCMS-ESF («): [M-H] calcd for C31H36NO3: 470.62; Found: 470.1.

Example 3. (S)-2-tert-Butoxy-2-((S)-1 -(2,3-dihydropyrano[4,3,2-de]quinolin7- yl)-310 methy!naphthaIen-2-yl)acetic acid (5K)

I55

(S)-2'tert-Butoxy-2-((S)-1-(2,3-dihydropyrano [4,3,2-de]quinolin-7-yl )-3methylnaphtha!en-2-yl)acetic acid (5K) was prepared in a similar manner as compound 3K of Example 1 except that compound 5J was used instead of compound 3J. ^lH5 NMR: 300 MHz, (CD₃OD) δ 8.54(d, 1 H), 8.08(d, 1 H), 7.86(m, 2 H), 7.57(m, 1 H),

7.40 (m, 2 H), 7.20 (m, 1 H), 6.88 (m, 1 H), 5.21 (s, 1H), 4.64(dd, 2 H), 3.58 (dd, 2 H),

2.66 (s, 3 H), 0.84 (s, 9H). LCMS-ES1⁺ (m/z)·. [M+H]⁺calcd for C_2SH₂₈NO₄: 442.2; Found: 442.1.

Ï56

Préparation of (S)-2-tert-butoxy-2-((S)-H2,3-dihydrop>Tano[4,3,2-deJquinolin- ⁷-\lt-3-methylnaphthalen-2-yi)ethanol (5Ji

Préparation of lrbromo-3-methyInaphthalen-2-<jl (5B): 3-MethyInaphthalen-2ol (4A) (2.09 g, 13.2 mmol) was taken m acetic acid (50 mL) and bromine (2.11 g) was added to it. The mixture was stirred at room température for 20 minutes, concentrated and purified by flash chromatography (silica gel, ethyl acetate/hexanes) to give the desired product (2.7 g, 80%). *H-NMR: 300 MHz, (CDCI₃) 5 7.98 (d, 1 H), 7.60 (d, 1 H), 7.58 (s, 1 H), 7.53 (dd, 1 H), 7.38 (dd, 1 H), 6.05 (s, 1 H), 2.48 (s, 3 H).

Préparation of l-(2,3-dihydropyrano[4_î3,2-de]quinolin-7-yl)-3methylnaphthalen-2-ol (SD): l-Bromo-3-methylnaphthalen-2-ol (5B) ( 340 mg, 1.43 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-yIboronic acid TFA sait (5C) (566 mg, 1,72 mmol), Pd(PPh₃)4 (166 mg, 0.14 mmol) and K₂CO₃ (991 mg, 7.15 mmol) were added to a degassed solution ofDMA(6mL)and water (2 mL) and heated to 110 ° C in a microwave for 1 h. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, brine and dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give SD (136 mg, 29%). LCMS-ESr* (m/z): [M+H]⁺ calcd for CziHigNOz: 328.38; Found: 328.2.

Préparation of l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3methylnaphthalen-2-yl trifluoromethanesulfonate (5E): l-(2,3-Dihydropyrano[4,3,2de]quinolin-7-yl)-3-methyInaphthalen-2-oI (SD) (136 mg, 0.415 mmol) was taken in 2 mL DCM at -78 °C and 2,6-lutidine (72 pL, 0.622 mmol) was added to it, followed by trifluoromethanesulfonic anhydride (210 pL, 1.24 mmol) and the reaction was stirred at -78 °C for 1 h. The réaction was quenched by adding saturated NaCl solution. The reaction was extracted with DCM, washed with brine, and concentrated. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexanes) to provide the desired product 5E (79 mg, 41%). LCMS-ESfi (m/z): [M+H]⁺ calcd for C₂₃H₁₇F₃NO₄S.· 460.45; Found: 460.0.

Préparation of 7-(3-methyl-2-vinylnaphthalen-l-yl)-2,3-dihydropyrano[4,3,2dejquinoline (5F): A solution of l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3methylnaphthalen-2-yItrifiuoromethanesuIfonate (SE) (89 mg, 0.194 mmol), tributyl(vinyl)tin (0.23 mL, 0/776 mmol), Pd(PPh₃)4 (34 mg, 0.029 mmol) and LiCl (16 mg, 0.39 mmol) in dioxane (3 mL) was stirred at 110 °C under Ar for 5 hours. The

I57 reaction mixture was cooled, diluted with ethyl acetate and washed with saturated NaHCOi solution (2xk brine and dried (MgSOj. fîltered. concentrated and purified by flash column chromatography (silica gel, hexanes) to give 5F as a white solid (74 mg, 9l%). LCMS-ESI* (m/z): [M+H]* calcd for C24H20NO: 338.42; Found: 338.2.

Préparation of ( l S)-1 -(l -(2,3-dihydropyrano[4.3,2-de]quinolin-7-yl)-3mfthylnaphthalen-2-yl)ethane-l ,2-diol (5G): Compound 5G was prepared in a similar manner as compound 3G of Example I, except that compound 5F was used instead of compound 3F: LCMS-ESI* (m/z): [M+H]* calcd for ί^Ι^ΝΟι: 372.44; Found: 372.3.

Préparation of (S)-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolm-7-yl)-310 methylnaphthalen-2-yl)-2-hydroxyethyl pivalate (5H): Compound 5H was prepared in a similar manner as compound 3H of Example 1 except that compound 5G was used instead of compound 3G. The two atropisomers (compounds 5H and 6A) were separated at this stage and carried forward separately. LCMS-ESI* (m/z): [M+H]* calcd for C29H30NO4: 456.6; Found: 456.1.

Préparation of (S)-2-tert-butoxy-2-((S)-1 -(2,3-dihydropyrano [4,3,2de]quinolin-7-yl)-3-methyInaphthalen-2-yl)ethyl pivalate (51): Compound 51 was prepared in a similar manner as compound 31 of Example 1 except that compound 5H was used instead of compound 3H, LCMS-ESI* (m/z): [M+H]*calcd for C33H38NO4: 512.7; Found: 512.1.

Préparation of (S)-2-tert-butoxy-2-((S)-1 -(2,3 -dihydropyrano [4,3,2-de]quinolin7-yl)-3-methylnaphthaIen-2-yl)ethanol (SJ): Compound 5J was prepared in a similar manner as compound 3 J of Example 1 except that compound 51 was used instead of compound 31. LCMS-ESI* (m/z): [M+H]*calcd for C28H30NO3: 428.5; Found: 428.0.

158

Example 4. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dîhydropyTano[4.3,2-de]quinolin-7-yl)-3methyinaphthalen*2-y] (acetic acid (6Di

(2S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyianD[4,3,2-de]quinolin-7-yl)-3methylnaphthalen-2-yI)acetic acid (6D) was prepared in an analogous marner as used for the préparation of compound 5K of Example 3. ’H-NMR: 300 MHz, (CDjOD) δ 8.58(d, 1 H), 7.83(m, 2 H), 7.66(m, 2 H), 7.38(m, 2 H), 7.17 (m, 1 H), 6.80 (m, 1 H), 10 5.18 (s, 1 H), 4.61 (m, 2 H), 3.56 (dd, 2 H), 2.63 (s, 3 H), 0.84 (s, 9H).

LCMS-ESf (m/z); [M+H]⁺ calcd for 442.5; Found: 442.1.

Example 5. (R)-2-tert-Buioxy-[3-methy!-l-(5-(trifluoroniethyl)quinolin-8-yl)naphthaIen-2-y! [-acetic acid (7D> and iSE2-tert-butoxy-24(S!-3-methyl-l-(5itnnuoromethy) )quinoiin-8-yl maphthalen-2-yhacetiC acid (7E).

I59

7B 7C

7D

7E (S)-2-tcrt-butoxy-2-((R)3-methyl-1 -(5-(trifluoromethyl)qumolin-8yl)naphthalen-2-yI)acetic acid (7D) was prepared in a similar manner as compound 4K of Example 2. ^lH-NMR: 400 MHz, (CD₃OD) δ: 9.02 (d, J = 8.8 Hz, 1 H), 8.83 (dd, J =

4.8,1.2 Hz, 1 H), 8.26 (d, J = 7.6 Hz, 1 H), 7.99-7.88 (m, 3 H), 7.77 (d, J = 7.6 Hz, 1

H), 7.45 (dd, J = 8.0, 7.2 Hz, 1 H), 7.20 (dd, J = 8.0, 7.2 Hz, 1 H), 6.83 (d, J = 8.4 Hz, 1

H), 5.29 (s, IH), 2.78 (s, 3H), 0.75 (s, 9H); ’^{5 * * * 9 10}F-NMR: 376 MHz, (CD₃OD) Ô: -60.81;

LCMS-ESI⁴ (m/z): [M+H]⁺ calcd for C^H^NCh: 468.5; Found: 468.0. (S)-2-tert-butoxy-2-((S)-3-methyl-1 -(5 -(trifluoromethyl)quinoIïn-8yl)naphthalen-2-yl)acetîc acid (7E) was prepared in a similar manner as compound 4L of Example 2. ‘H-NMR: 400 MHz, (CD₃OD) δ: 8.82 (d, J = 8.4 Hz, 1 H), 7.72 (d, J =

160

5.2, l H). 8.26 (d, J = 7.6 Hz. I H), 8.12 (d. J = 7 6 Hz. I H). 7.89-7.73 (m, 3 H), 7.40 (dd, J = 7.6. 7.2 Hz, l HL 7 I4 (dd. J = 7 6. 7.2 Hz. I Ht. 6 76 (d, J - 8 4 Hz. I H). 5 06 is. IH). 2.70 (s. 3H). 0.75 is. 9H j_ ⁿF-NMR: 376 MHz. (CD₃OD)ô: -60.87; LCMSESL [M~Hf calcd for C2-H25F3NOÇ 468.5; Found: 468.0.

Example 6. (S)-2-tert-Butoxy-2-f l -cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid (8)

(S)-2-f ert-butoxy-2-(1 -chforo-3methylnaphthalen-2-yl)ettiyl pivalate

NaOH

(S}-2-tert-butoxy-2-(1 -chioro-3methylnaphthalen-2-yl)ethanol

H₅ÎO_G,CrO3

(S}-2-tert-butoxy-2-( 1 -ch loro-3méthyinaphthaten-2-yl)acetic acid

Etl.CSgCOg DMF

(S)-ethyl 2-feri-butoxy-2-(1-chloro3-methyinaphthalen-2-y1)acetate

1. Suzuki coupling

2. NaOH

(S)-2-iert-butoxy-2-(1 -cydohexenyl-3methylnapbthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(l-chloro-3-methylnaphthalen-2-yl) éthanol:

(S)-2-tert-Butoxy-2-(l -chloro-3-methylnaphthalen-2-yl)ethyl pivalate (4G, 1.72 g, 4.56 mmol) was dissolved in MeOH (10 mL) and THF (10 mL). Sodium hydroxide (2 M,

9.13 mL) was added and the réaction mixture was stirred at room température overnight. The réaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-cxtracted with ethyl acetate and the combined organics were dried (MgSOi), concentrated in vacuo and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give a colorless liquid

Ifil (I.l2 g, 84%). H-NMR: 300 MHz, (CD₃OD) δ: 8.23 (d, ÎH). 7.78 (d. l H), 7.60 (s, IR) ⁷ <2 (dd. 2H). 5.69 <m. IHl 3 83 'dd. IHk 3 61 (m. i Hl 2 71 <_S.3H>. 1 18 (s. 9Hi.

Préparation of (S)-2-tert-butoxy-2-(l-chloro-3-methyInaphthalen-2-yl)acetÎc acid: The periodic acid/chromîum trioxidc stock solution (26 mL) was added to a solution of (S)-2-tert-butoxy-2-(l-chloro-3-methylnaphthalen-2-yl) éthanol (1.12 g,

3.83 mmol) in wet acetonitrile (50 mL) (0.75% H₂O) at 0 ’C. The reaction mixture was stirred for 2 hours at 0 °C and quenched with 1.5 M K₂HPC>4 solution. Ethyl acetate was added and organic layer separated and washed with 1:1 brine/H₂O (2x), then saturated NaHSO₃ /brine. The organic layer was dried (MgSO^), and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give a white solid (0.9 g, 78%). ’H-NMR: 300 MHz, (CDC1₃) Ô: 8.24 (d, 1H), 7.73 (d, 1H), 7.56 (m, 3H), 6.22 (br, 1H), 2.57(s, 3H), 1.23 (s, 9H). LCMS-ESL (m/z): [ΜΗ]' calcd for C17H18CIO3; 305.78; Found: 304.9, 306.9.

Préparation of (S)-ethyl 2-tert-butoxy-2-(l-chloro-3-methy]naphthalen-2yl)acetate: Ethyl iodide (0.35 mL, 1.5 eq.) was added to a mixture of (S)-2-tert-butoxy-

2-(l-chIoro-3-methylnaphthalen-2-yl)acetic acid (900 mg, 2.93 mmol, 1 eq.) and Cs₂CO₃ (1.91 g, 2 eq.) in DMT (920 mL) at room température. The reaction mixture was stirred for 1 hour at room température. Ethyl acetate was added and organic layer separated and washed with brine (2x). The organic layer was dried (MgSCL) and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give a colorless oil (0.911 g, 93%). ^lH-NMR: 300 MHz, (CDCI3) δ:

8.23 (d, 1H), 7.62 (d, 1H), 7.63 (s, 1H), 7.46 (m, 3H), 6.10 (s, 1H), 4.06 (dd, 2H), 2.42 (s, 3H), 1.18 (s, 9H), 1.08 (t, 3H).

Préparation of (S)-2-tert-butoxy-2-(l -cyclohexenyl-3-methylnaphthalen-2yl)acetic acid (8): A Smith process via! was charged with (S)-ethyl 2-tert-butoxy-2-(lchloro-3-methylnaphthaIen-2-yl)acetate (15 mg, 0.045 mmol, 1 eq.), cyclohexenylboronic acid (9 mg, 1.5 eq.), Sphos precatalyst (5 mg, 15%) and potassium phosphate (29 mg, 3 eq.), THF (0.2 mL) and water (0.2 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 110 °C for 1 hour. The réaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSOi), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-(l-

J*· cyclohexenyl-3-methyInaphLhalen-2-yl)acetate (8 mg). Analytic-al HPLC (Gemini. 2^8% AC VELO - (.i 05% II· A. 10 minutes run): Ir (mini = ⁷ 06

A solution of above intermediate (Sl-ethyi 2-tert-butoxy-2-( l-cycÎohexenyl-3methylnaphthalen-2-yHacetate (8 mg, 0.021 mmol. l eq.) in éthanol (1.5 ml.) and l N sodium hydroxide (0.42 mL, 20 eq.) was heated at 60 °C overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgSO₄), filtered, concentrated and purifîed by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). Product lyophilized to give 8 as a white powder (4.4 mg), Analytical HPLC (Gemini, 2-98% ACN/H₂O + 0.05% TFA, 10 minutes run): Ir (min) = 6.10. ^!H-NMR: 400 MHz, (CD₃OD) δ: 7.83 (m, IH), 7.70 (m, IH), 7.54 (m, IH),

7.40 (m, 2H), 5.82,5.62 (s,s, IH), 2.58 (m, 3H), 2.62-2.16 (m, 4H), 1.92-1.80 (m, 4H), 1.03 (m, 9H). LCMS-ESI' (m/z): [M-H]'calcd forC^TÛ?: 351.46; Found: 351.1.

Example 7. (S)-2-tert-Butoxy-2-(l-((R)-6-fluoroquinolin-8-yl)-3-methylnaphthalen-2yl)acetic acid (9)

(S)-2-fert-bijtoxy-2-( 1 -f(R)-6-fluoroq uinolin8-yl}-3-methylnaphthalen-2-yl)acetic add

Préparation of (S)-2-tert-butoxy-2-(l-((R)-6-fluoroquniolin-8-yl)-3methylnaphthalen-2-yl)acetic acid (9): (S)-2-tert-butoxy-2-(l-((R)-6-fluoroquinolin-8yl)-3-methylnaphthalen-2-yI)acetic acid (9) was prepared following the procedure to make (S)-2-tert-butoxy-2-(l-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid of Example 6 except that 6-fluoroquinolin-8-ylboronic acid was used instead of cyclohexenylboronic acid. Atropisomers were separated by flash column chromatography. ’H-NMR: 400 MHz, (CD3OD) δ: 8.81 (d, J = 8.2 Hz, IH), 8.62 (dd, J = 4.7 Ηζ,ΙΗ), 8.02 (m, IH), 7.96 (m, IH), 7.82 (m, 2H), 7.76 (m, IH), 7.42 (dd, J = 7.5 Hz, IH), 7.20 (dd, J = 7.8 Ηζ,ΙΗ), 6.84 (d, J = 8.6 Hz, IH), 5.18 (s, IH), 2.72 (s, 3H),

Ο 82 (s. 9Η). ^l9F-NMR: 377 MHz. (CD₃OD) Ô; -77.9, -l I3.l. LCMS-ESI’ (w-'z): [M-H]’calcd for C_:t.H^FNO<: 418 48: found 4)8 11

Example 8. (2S)-2-tert-Butoxy-2-(l-(5-f]uoroquinoiin-8-yl)-3-methylnaphthalen-25 yl)acetic acid (10)

(2S)-2-tert-butoxy-2-(1-(5-fluoroquinoliri-8yt)-3-methy!naplïthalen-2-yl)acetic acid

Préparation of (2S)-2-tert-butoxy-2-(l-(5-fluoroquinolin-8-yl)-3methylnaphthalen-2-yI)acetic acid (10): (2S)-2-tert-Butoxy-2-(l-(5-fluoroquinolin-8yl)-3-ïnethylnaphthalen-2-yl)acetic acid (10) was prepared following the procedure to make (S)-2-tert-butoxy-2-( 1 -cyclohexenyl-3-methylnaphthalen-2-y l)acetic acid of

Example 6 except 5-fluoroquinolin-8-ylboronic acid was used instead of cyclohexenylboronic acid. ^lH-NMR: 400 MHz, (CD₃OD) δ; 8.81 (d, J — 8.2 Hz, 1H),

8.70 (dd, J = 3.3 Hz, J = 4.7 Ηζ,ΙΗ), 8.09 (t, J = 6.2 Hz, 1H), 7.92 (m, 2H), 7.78 (m, IH), 7.63 (t, J = 9.0 Hz, 1H), 7.42 (t, J - 7.0 Hz, 1H), 7.18 (t, J = 7.8 Ηζ,ΙΗ), 6.84 (d, J =7.6 Hz, 1 H), 5.18 (s, 1H), 2.68 (s, 3H), 0.80 (s, 9H). ^I9F-NMR: 377 MHz, (CD₃OD) δ: -77.9, -123.2. LCMS-ESI* (m/z): [M+Hf calcd for C₂₆H_2SFNO₃: 418.47; found:

418.1.

Example 9. (S)-2-tert-Butoxy-2-( 1 -(3,3-dimethyi-6-oxocyclohex-1 -enyl)-320 methylnaphthalen-2-yl)acetic acid (11)

(S)-2-(terf-butoxy)-2-( 1-(3,3-dimeth yl-6-oxocyclohex-

1-eri-1-y!)-3-rnethylnaphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(l-(3,3-dimethyl-6-oxocyclohex-l -enyl)-3methylnaphthalen-2-yl)acetic acid (11): (S)-2-tert-Butoxy-2-(l-(3,3-dîinethyl-6oxocyclohex-l-enyl)-3-methyInaphthalen-2-yl)acetic acid (11) was prepared following the procedure to make (S)-2-tert-butoxy-2-(l-cyclohexenyI-3-methylnaphthalen-2yl)acetic acid of Example 6 except that 4,4-dimethyl-2-(4,4,5,5-tetramethy 1-1,3,2dioxaborolan-2-yl)cydohex-2-enone was used instead of cyclohexenylboronic acid. Atropisomers were separated by flash column chromatography. *H-NMR: 400 MHz, (CD₃OD) δ: 7.72 (d, J = 8.2 Hz, 1 H), 7.59 (s ,1H), 7.39 (m, 2H), 7.37 (m, 1H), 7.02 (s, 1H), 5.42 (s ,1H), 2.82 (m, 1H), 2.67 (m, 1H), 2.58 (s, 3H), 2.18(m, 2H), 1.38(s, 6H), 1.08 (s, 9H). LCMS-ESI* (m/z): [M-H]'calcd for C25H29O4: 393.50; found: 393.0.

Example 10. (S)-2-tert-Butoxy-2-( 1 -cyclopentenyl-3-methylnaphthalen-2-yl)acetic acid (12)

(S)-2-terf-butoxy-2-(1-cyclopentenyl-3methy!naphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(l-cyclopentenyI-3-methylnaphthalen-2yl)acetic acid (12): (S)-2 tert-Butoxy-2-(l -cyclopentenyl-3-methylnaphthalen-2yl)acetic acid (12) was prepared following the procedure to make (S)-2-tert-butoxy-2(l-cyclohexenyl-3-methyInapbthaJen“2-yl)acetic acid of Example 6, except that

cyclopentenylboronic acid was used instead of cyclohexenylboronic acid H-NMR:

400 MHz ⁷ ?ίΐ (m. ! Ht. ⁷ 53 ts.lHi. ⁷ 4u (m. 2H). 6J0-' 54 tm. ’Ήι.

2.90 tm J H). 2.65 tm. 5Hi. 2.57 (s. 3H). 1.18 is. 9Hi. LCMS-ESI [M-H¹/calcd forC₂₂H_2îO₃: 337.44: found: 337.1.

Example 11. (2S)-2-tert-Butoxy-2-(3-methyl- î -(4-methylcyclohex- ] -enyl)naphthalen-

2-yl)acetic acid (13)

(2S)-2-(ferf-butoxy)-2-{3methyl-1 -(4-methylcyclohex-1 en-1 -yi)naphthalen-2-y l)acetic acid

Préparation of (2S)-2-tert~butoxy-2-(3-methyl-l-(4-methylcyclohex-lenyl)naphthalen-2-yl)acetic acid (13): (2S)-2-tert-Butoxy-2-(3-methyl-l-(4methylcycl<)hcx-l-enyl)naphthalen-2-yl)acctic acid was prepared following the procedure to make (S)-2-tert-butoxy-2-(l-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid of Example 6, except that 4-methylcyclohex-1-enylboronic acid was used instead of cyclohexenylboronic acid.¹ H-NMR: 400 MHz, (CD₃OD) δ: 7.92-7.78 (m, 1H), 7.70 (m ,1H), 7.52 (s, 1H), 7.39(m, 2H), 6.10-5.58 (m, 2H), 2.56 (s ,3H), 2.65-1.84 (m, 6H),

1.50 (m, 1H), 1.22 (s,9H), 1.14 (t,3H). LCMS-ESI’(m/z): [M-H]’calcd for C₂₄H_2i>0₃: 365.49; found: 365.1.

Example 12. (S)-2-tert-Butoxy-2-( 1 -(4,4-dimeÎhylcyclohex-1 -enyl)-3methylnaphthalen-2-y|)acetic acid (14)

166

(S)-ethy1 2-(ferTtxjtoxy )-2-( 1 -ctiorl· S-meihytna^'dhaten2-yÇ3cet3te (S)-ethyl 2-(tert-butoxy)-2-(1-(4,4-dimethyicyclohex1 -en-1 -yl)-3-methyJnaphthalen-2-yt)acetaie

LiOH

THF/EtOH/water

244,4-dîmethylcydohex1-en-1-yl)-4,4.5,5tetrafnethyl-1,3,2dioxaborolane

(S)-2-(ferî-butoxy)-2-(1(4,4-dimethyicyc!ohex-1-en1 -yi)-3-methylnaphthalen-2yl)acetic acid

Préparation of (S)-ethyl 2-tert-butoxy-2-(l-(4,4-dimethylcyclohex-l-enyl)-3methylnaphthalen-2-yI)acetate: To a solution of (S)-ethyl 2-tert-butoxy-2-(l-chloro-35 methylnaphthalen-2-yl)acctate (74 mg, 0.22 mmol) and 2-(4,4-dimethyIcyclohex-1 enyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (78 mg, 0.33 mmol) in tetrahydrofuran (2 mL) was added potassium phosphate (153 mg, 0.66 mmol) and (2-dicyclohexylphosphino-2',6'-dimethoxy-l,r-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) chloride methyl ί-butyl ether adduct, (SPhos) palladium(II) phenethylamine chloride (15 mg, 0.022 mmol) and the reaction was degassed 10 minutes with argon. The reaction was heated to 110 °C for 1 hour in a microwave reactor. The crude reaction was absorbed onto silica and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a clear white oil (36 mg). ^JH-NMR: 400 MHz, (CDCI3) δ: 7,83-7.78 (m, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.53 (s, IH), 7.43-7.36 (m, 2H), 5.66-5.61 (m, 2H), 4.20-4.03 (m, 2H), 2.66-2.60 (m, 2H), 2.26-2.03 (m, 4H), 1.87-1.59 (m, 5H),

1.24-1.20 (m,9H), 1.19-1.11 (m, 6H).

Préparation of (S)-2-tert-butoxy-2-(l -(4,4-dimethylcyclohex-l -enyl)-3methylnaphthalen-2-yl)acetic acid (14): To a solution of (S)-ethyl 2-tert-butoxy-2-(l-

(4.4-djmethylcyclohex-l-enyi)-3-methylnaphlhalen-2-yl)acelate (36 mg, 0.08’ mmol) m îetrah\drofuran'éthanol'U’ate¹· C 2’ I ^s mL ) was 3dded lithium hydroxide 121 mg. 0 88 mmol) and lhe réaction was heated to 35 ’C evenught The réaction *as then heated to 45 °C for 2 hours, and subsequentîy 5 équivalents of lithium hydroxide was added, and the reaction stirred at room température over 2 days. The reaction was then heated to 50 °C overnight. The crude réaction was purified by reverse phase HPLC (Gemini, 20-100% ACN/H₂O + 0.1 % TFA j. Product was lyophilized to give a white powder (8.6 mg). *H-NMR: 400 MHz, (CD₃OD) δ: 7.82 (d, J = 8.0 Hz, 111), 7.71 (d, J = 7.6 Hz, IH), 7.54 (s, IH), 7.39 (m, 2H), 5.66 (m, 2H), 2.66 (m, IH), 2.58 (s, 3H),

2.13 (m, 3H), 1.64 (m, 2H), 1.23 (s, 9H), 1.16 (s, 3H), 1.14 (s, 3H). LCMS-EST (m/z): [M-H]* calcd for C₂₃H₃iO₃: 379.24; found: 379.27.

Example 13. (S)-2-tert-Butoxy-2-(3-methyl-l-(spiro[2.5]oct-5-en“6-yl)naphthalen-2yl)acetic acid (15)

OH (S)-2-tert-butoxy-2-(3-niethyl-l-(spiro[2.5]oct-5-en-6-yl)naphthaien-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(3-methyl-l-(spiro[2.5]oct-5-en-6yl)naphthalen-2-yI)acetic acid (15): (S)-2-tert-butoxy-2-(3-methyl~l -(spiro[2.5]oct-5en-6-yl)naphthalen-2-yl)acetic acid was prepared following the procedure for (S)-2tert-butoxy-2-( 1 -(4,4-dimethylcyclohex-l -enyl)-3-methylnaphthalen-2-yl)acetic acid of Example 12 except using 4,4,5,5-tetramethyl-2-(spiro[2.5]oct-5-en-6-yl)-l,3,2dioxaborolane instead of 2-(4,4-diniethykyclohcx-1-eny 1)-4,4,5,5-tetramethyLl ,3,2dioxaborolane and that in the final step the reaction was heated to 50 °C overnight followed by an addition of 10 équivalents of lithium hydroxide and heating to 60 °C for four hours and then at 45 °C overnight. ’H-NMR: 400 MHz, (CD₃OD) δ: 7.90 (d, J =

6 Hz. IH). 7.71 (brd, J = 7.2 Hz. IH). 7.53 (d. J = 8.0 Hz. IH). 7.40 (m. 2Ht, 5.88 (s.

IH). * W 1H>. 2 7; t_m. illi. 2 78 rs. 3Hï 2 H fm. 2H. 2 ÎW im. ÏH). i 3 tm. IHi.

1.59 (m. I Ht. 1.24 (s. 9Ht. 0.49 (m. 4H ) LC MS-ESI' in:i' j M-Hf calcd for C_3îH_nO_?: 377.22: found: 377.34

Example 14. (S)-2-tert-Butoxy-2-(3-melhyl-l-(quinolm-3-yl)naphthalen-2-yilacetic acid (16)

(S) 2-(fert-butoxy)-2-(3-methyl-1(quinolin-3-yl)naphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(3-methyl-l -(quinolin-3-yl)naphthalen-2yl)acetic acid (16): (S)-2-tert-Butoxy-2-(3-methyl-l-(qumolm-3-yl)naphtlialen-2yl)acetic acid (16) was prepared following the procedure to make (S)-2-tert-butoxy-2(l-cyclohexenyl-3-methylnaphthaleu-2-yl)acetic acid of Example 6, using qumolm-3ylboronic acid instead of cyclohexenylboronic acid. The compound is an atropisomer mixture. ’H-NMR: 400 MHz, (CD₃OD) δ: 9.20-8.50 (m, 2H), 8.18 (m ,1H), 8.08 (m, IH), 7.95(m, IH), 7.80 (m, 3H), 7.40 (t.lH), 7.25(t, IH), 7.06 (m, IH), 5.19(s, IH),

2.62 (d, 3H), 0.95,0.86 (s, 9H). LCMS-ESI* (m/z); [M+HJ* calcd for C₂₆H26NO₃: 400.48; found: 400.2.

Example 15. (S)-2-(tert-Butoxy)-2-((S)-l-(7-fluoro-2-methylquinolin-8-yl)-3methylnaphthalen-2-yl)acetîc acid (17)

169

B(OH)₂ (S)-2-tert-butoxy-2-(1 -chloro-3methylnaphthalen-2-yl)ethyl pivalate

7-fluoro-2methylquinoltn-βylboronic acid

(S)-2-(tert-butoxy )-2-((5)-1-(7fiuoro-2-methylqijinolrn-8-yÎ)-3methylnaphthaten-2-yl)acetic acid

Préparation of (S)-2-(tert-butoxy)-2-((S)-1 -(7“fluoro-2-methylqumolin-8-yl)-35 methylnaphthalen-2-yl)acetic acid (17): (S)-2-(tert-butoxy)-2-((S)-l-(7-fluoro2mcŒylquinolm-8-yl)-3-methylnaphthaien-2-yl)acetic acid (17) was prepared following the procedure used to prépare compound 4K except that 7-fluoro-2-methylquinolin-8ylboronic acid was used instead of compound 4H. *H NMR (400 MHz, CD₃OD) δ 9.09 (d, J = 8.5 Hz, 1H), 8.51 (dd, J = 9.1, 5.6 Hz, IH), 8.01 (s, 1H), 7.95 (d, J = 8.1 Hz,

1H), 7.92-7.76 (m, 2H), 7.58-7.43 (m, 1H), 7.30 (ddd, J = 8.2,6.9,1.2 Hz, 1 H), 6.97 (d, J = 8.6 Hz, 1 H), 5.17 (s, 1H), 2.80 (s, 3H), 2.79 (s, 3H), 0.87 (s, 9H). LCMS-ESI* (m/z): [M+H]* calcd for C₂₇H₂₇FNO₃:432.5; found: 432.1.

Example 16. (S)-Ethyl 2-tert-butoxy-2-((R)- J -(2,3-dihydropyrano[4,3,2-de]quinolin-715 yl)-3-methyliiaphthalen-2-yl)acetate (18)

(S)-ethyl 2-(tertbutoxy)-2-[1 -chloro-3methylnaphthaien-2yl)acetate

2,3-dihydropyranoI4,3,2de]quinolin-7-ylboronic acid, HCI sait

(S)-ethy ! 2-{tarf-butoxy)-2-((/?)-1 (2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-3mettiylnaphthalen-2-y!)acetate

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (18): A Smith process vial was

C chargcd wiîh (Sl-ethyl 2-tert-butoxy-2-( l -chloro-3-meihylnaphthalen-2-yl)acetate ;U’mpmind <>f F xample 6 μ ] ΐ 6 rng 0 '48 mmol k 2. '-dihvdropvranoj4.3.2de]quinolin-7-yiboronic acid, i ICi saitmg. 0 383 moij. Sphos precatalyst < 35 mg. 0.0522 mmol). césium fluoride (233 mg, 1.54 mmol) and flushed with nitrogen.

Dimethoxyethane (3.0 mL, dîstilied from Na/benzophenone) was added and mixture was heated in microwave at 120 °C for l .5 hour. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted and combined organic layer dried (MgSCL), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% acetonitrileÆLO + 0.1% TFA) to give a yellow powder (16.8 mg). ^lH-NMR: 400 MHz, (CD₃C1) Ô: 8.93 (d, J = 4.4 Hz, IH), 8.06 (d, J = 8.0 Hz, IH), 7.82 (s, IH), 7.81 (d, J = 8.8 Hz, IH), 7.45-7.35 (m, 3H), 7.13 (dd, J =

7.2,7.2 Hz, IH), 6.73 (d, J = 8.8 Hz, IH), 5.16 (s, IH), 4.68-4.65 (m, 2H), 3.98-3.86 (m, 2H), 3.52 (q, J = 5.6 Hz, 2H), 2.69 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 0.86 (s, 9H). LCMS-ESr (m/z): (M+H]'calcd for C30H32NO4: 470.5; found: 470.1.

Example 17. (S)-2-(l~(3-(Azetidîn-l-yl)phenyI)-3-methylnaphthalen-2-yI)-2-tertbutoxyacetic acid (19) /

|7ί

ΒΛ.

/ χ

--. y

Ν

1,3-dibromobenzene

-( 3-bromopheny IJazetidine

(S)-ethyl 2Ttert-bLrtoxy)-2(1-chk)ro-3methylnaphthaien-2yi)acetate

(S)-ethyl 2-(1-(3-(azetidÎn-1yl)phenyl)-3methylnaphthalen-2-yl)-2(fert-butoxy)acetate

(S)-2-(1 -(3-(azetidin-1 -y l)phenyi)-3methylnaphthalen-2-yl)-2-(fertbutoxy)acetic acid

Préparation of 1-(3-bromopheny l)azetidine: A mixture of 1,3-bromobenzene (1.0 g, 4.24 mmol), azetidine (0.19 mL, 2.83 mmol), Pd2(dba)₃ (0.129 g, 0.142 mmol), Xantphos (0.164 g, 0.283 mmol), and sodium terZ-butoxide (0.816 g, 8.49 mmol) in dioxane (20 mL) was sparged with nitrogen for 15 minutes. The reaction mixture was heated at 100 °C for 3 hours and then cooied to room température. The resulting mixture was diluted with water and ethyl acetate and washed with water (2x), brine, dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give a yellow oil (0.4474 g). LCMS-EST 10 (m/z): [M+H]⁺caIcd for CçHnBrN: 213.1; found: 212.0, 214.0.

Préparation of 1 -(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)azetidine: A mixture of l-(3-bromophenyl)azetidine (0.4474 g, 2.11 mmol),

bis-pinacolalodiboron (0.803 g. 3 16 mmol), Pd( dpp f)CL |O ï 72 g, 0 211 mmol), and potassium acetate (0 621 g. 6.33 mmoh in diuxanc <21 ml_i λ as sparged v, ith nitrogen for 30 minutes The réaction mixture was heated at ^0 ^;’C for 1.5 hours l'he reaction was cooled to room température, diluted with ethy! acetate and washed with brine, dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give a yellow wax (0.6474 g). LCMSΕ5Γ (m/z): [M+Hf calcd for CisH^BNOj: 260.2; found: 260.1.

Préparation of (S)-ethyl 2-(l-(3-(azetidin-l-yI)phenyl)-3-methylnaphthalen-2yl)-2-tert-butoxyacetate: A Smith process vial was charged with (S)-ethyl 2-tertbutoxy-2-(l-chloro-3-methylnaphthalen-2-yl)acetate (60.5 mg, 0.181 mmol), l-(3(4,4,5,5-tetramethyl-l,3.2-dioxaborolan 2-yl)phenyl)azetidine (93.7 mg, 0.361 mmol), chloro(2-dicyclohexylphosphino-2’,6'-dnnethoxy-l,r-biphenyl)[2-(2aminoethylphenyl)]Pd(I[)methyl-t-butyl ether adduct (12.2 mg, 0.0181 mmol) and potassium phosphate (153 mg, 0.543 mmol), THF (2 mL) and water (1 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in micro wave at 110 °C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to the desired product contaîning some impurities that was used in the next step without further purification.

Préparation of (8)-2-(1 -(3-(azetidin-l-yl)phenyI)-3-methylnaphthalen-2-yl)-2tert-butoxyacetic acid (19): The above residue contaîning (S)-ethyl 2-(l-(3-(azetidin-Iy))phenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate in THF (1.0 mL), MeOH (0.1 mL) and 5 M NaOH (0.1 mL) was heated at 45 °C for 18 hours. The reaction mixture was concentrated, diluted with ethyl acetate and water and washed with saturated ammonium chloride solution. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgSO£, filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). The product was lyophilized to give a white powder (4.6 mg) which was resubjected to reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). Product contaîning fractions were stirred with saturated sodium bicarbonate solution for 30 minutes. The mixture was extracted with ethyl acetate (3x), dried (MgSO₄), filtered, concentrated and lyophilized from acetonitrile/water to give an atropisomer mixture as a white powder (1.9 mg). ‘H NMR (400 MHz, CD₃OD) δ 7.81-7.67 (m, 1 H), 7.62 (s, 0.6H), 7.60 (s,

173

4HK 7.4-7 l8(m.4Hï. 6.78 (s, 0.5H). 6.70 (d. J = 7 7 Hz, O.5H), 6 64-6 57 (m. IH).

32 * s. O f>H>. 5 -Tiit ü 4H i 3 0< :-, R7 <ni, 3H », 2.60 i s, 3H t. 2 40-2. '5 < m. 2H i. (). 99 (s. 4H , 0.97 (>. 5Hl LCMS-ESI' fin : >: [M + H]’ calcd for C?_f.Hx>NC>< 404.5. found 404 I.

Example 18. (2Sh2-tert-Butoxy-2-(l-((7R)-2,3,3a,4,5,6-hexahydropyrano[4,3,2de]quînolin-7-yl)-3-methyÎiïaphtha]en-2-yl)acetic acid (20)

Pt/C, h₂ (S}-2-(tert-butoxy )-2-(1 -((F?)-2,3dihydropyrano[4,3,2-de]quinolin-7-ylp 3-methylnaphthalen-2-yl)acetic acid

(25)-2-( tert-butoxy )-2-(1 -f(7R>

2,3,3a, 4,5,6-hexahydropyrano{4,3,2de]quinolin-7-yl)-3-methylnaphthaten-2yl)acetic acid

Préparation of (2S)-2-tert-butoxy-2-(l-((7R)-2,3,3a,4,5,6-hexahydropyrano

[4,3,2-de]quinolin-7-yI)-3-methylnaphthalen-2-yl)acetic acid (20): (S)-2-tert-Butoxy-2(!-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid (130 mg) was dissolved in 20 mL EtOH and 1 drop of HOAc was added to the solution.

10% Pt/C (30 mg) was added the reaction was stirred at room température under one atmosphère of hydrogen (balloon) overnight. The reaction mixture was fîltered, diluted with ethyl acetate and washed with brine, dried (MgSOj), fîltered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% MeOHZDCM) to give (2S)-2-tert-butoxy-2-( 1 -((7R)-2,3,3a,4,5,6-hexahydropyrano| 4,3,2-de]quinolin-7-y 1)-3 20 methylnaphthaIen-2-yl)acetîc acid (130 mg). 8 mg of the material was purified by reverse phase HPLC (Gemini, 5 to 100% ACN/1HO +0.1% TFA). Product lyophilized to give a white powder (5.5 mg). 'H-NMR: 400 MHz, (CDjOD) 6: 7.78 (d, J = 8.2 Hz, 1H), 7.63 (s, 1H), 7.40 (m ,2H), 7.27 (m, 1H), 6.70 (d, J = 8.21 Hz, 1H), 6.22 (d, J =

8.21 Hz, 1H), 5.26 (s, 1H), 4.41 (m, 1H), 4.22 (m,lH), 3.18 (m, 2H), 2.83 (m, 1H), 2.59

Γ4 (s. 3Η). 2 I2(m. IH). I 98 (m. IH). I l H). I 32(m. IH}. I 05 (s.9H). LCMSFSI '.rn z i i M-Hl calcd k >r (;·χΗ N O, 4-it> 5 v found: 44b ;.

Example 19. f2S)-Methyl 2-ten-buloxy-2-i!-((7R)-2,3.3a.4.5.t>hexahydropyrano(4,3.2-de]quinolin-7-yl)-3-methylnaphlhaien-2-yl)acetate (21)

(2S)-2-tert-butoxy-2-(1-K7R)-2_l3.3a_l4,5_I6- 21 hexahydropyrano[4,3,2-de}quinolin-7-yl)-3methylnaphthaten-2-yl)acetic acid (2S)-methyl 2-(terf-butoxy)-2-(1-((7R)2,3,3a, 4,5,6- hexahydropyrano[4,3,2 de}quinolin-7-yl)-3-methylnaphthaleri-2yl)acetate

Préparation of (2S)-methyl 2-tcrt-butoxy-2-(l-((7R)-2,3,3a,4,5,6hexahydropyrano[4,3,2-deJquinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (21): At 0 °C, NaH (60%, 5 mg) was added to (2S)-2-tert-butoxy-2-(l-((7R)-2,3,3a,4,5,6hexahydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphtha]en-2-yl)acetic acid (26 mg,

0.06 mmol, 1 eq.) in 1.5 mL DMF at 0 °C. After stirring for 30 minutes, Mel (50 pL, excess) was added to the solution. The reaction wts stirred at 0 °C for 1 h. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/HjO + 0.1% TFA). The product was lyophilized to give (2S)-methyl 2-tert-butoxy-2-(l-((7R)-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]qumoIin7-yl)-3-methyInaphthaIen-2-yl)acetate as white powder (11 mg). ’H-NMR: 400 MHz, (CD₃OD) δ: 7.78 (d, J = 8.2 Hz ,1H), 7.63 (s, IH), 7.42 (m ,1H), 7.32 (m, 2H), 6.70 (m, IH), 6.34 (d, IH), 5.26 (s, IH), 4.41 (m, IH), 4.22 (m,lH), 3.72 (s, 3H), 3.22 (m, 2H),

2.91 (m, IH), 2.59 (s, 3H), 2.18(m, 1H),2.O8 (m, IH), 1.72(m, IH), 1.39(m, IH), 1.05 (s, 9H). LCMS-ESr (m/z): [M+H]⁺calcd for C29H34NO4: 460.58; found: 460.1.

Example 20. (2S)-2-tert-Butoxy-2-(3-methyi-l-((7R)-6-înethyl-2,3,3a,4,5,6hexahydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)acetic acid (22)

(S)-ethyl 2-tert-butoxy-2-{1((R)-2,3-dîhydropyrano[4.3,2do]quinoln-7-yl)-3methy I naphthalen-2-y IJacetate

Mei

(/?)-7-(2-((S)-1-fert-butoxy-2ethoxy-2-oxoethyl)-3methy Inapbtfiaien-1 -y l)6-methy I2,3-dihy d ropy rano[4,3,2de]quinolin-6-ium iodide

(2S)-ethyl 2-tert-butoxy-2-(3-rrtettiyÎ1 -((7R)-6-methyl-2,3.3a,4.5,6hexahydropyrano[4,3,2-de]quinolin7-yl)naphthalen-2-yl)acetate (2S)-2-Îerf-butoxy-2-(3-methyl-1 ((7R)-6-methyl-2,3,3a,4,5,6hexahydropyrano[4,3,2-de]quinolin7-yl)naphthalen-2-yl)acetic acid

Préparation of (R)-7-(2-((S)-l-tert-butoxy-2-ethoxy-2-oxoethyl)-3methylnaphthalen-1 -yl)-6-methyl-2,3-dihydropyrano[4,3,2-de]quinolm-6-ium iodide: A mixture of Mel (0.8 mL, large excess) and (S)-ethyl 2-tert-butoxy-2-(l-((R)-2,35 dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (37 mg). The reaction was heated at 50 °C for 2 days. The reaction mixture was diluted with ethyl acetate and washed with brine, dried over MgSO₄, filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% MeOH/DCM) to give the desired material as a green oil (50 mg). LCMS-ESI* (m/z); [M]⁺ calcd for 484.61 ;

found: 484.3.

Préparation of (2S)-ethyl 2-tert-butoxy-2-(3-methyl-l-((7R)-6-methyl2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)acetate: (R)-7-(2((S)-l-tert-butoxy-2~ethoxy-2~oxocthyl)-3-methylnaphthalen-l-yl)-6-methyl-2,3dihydropyrano[4,3,2-de]quinolin-6-ium iodide (50 mg) was dissolved in 20 mL EtOH 15 and I drop of HOAc was added to the solution. 10% Pt/C (30 mg) was added and the resulting reaction mixture was stirred under hydrogen (1 atm, balloon) at room température overnight. The reaction mixture was filtered and diluted with ethyl acetate

and washed with bnne. dried (MgSCrik filtered, concentrated and purified by flash ;'oiumn chromât ographv τ sinus gel O îo 20% Mt<>HT>CM) to give i_S'> ethv! 2-tertbLi’.L'W-2-(3-mt'Lhvl· 1-Η~Η>-6·ίηϋίΒ} Ι-2_333.4.5.6-Κεχ31ι_νάΓορ>τίΐηο[4.'_?-de|qumoi;n7-yi)naphthalen-2-yl)ac.etale as a grey solid 11 5 mg), LCMS-ESI' (m. z): [M-H]' calcd for CjiHî&NOî: 488.63; found: 488.2.

Préparation of (2S)-2-tert-butoxy-2-(3-methy)-l-((7R)-6-rncthy 1-2.3,3æ4.5.6hexahydropyrano[4,3,2-de]quÎnolin-7-yi)naphthalen-2-yl)acetic acid (22): To a solution of (2S)-ethyl 2-tert-butoxy-2-(3-methyl-l-((7R)-6-methyl-2,3,3a,4,5,6-hexahydropyrano[4,3_s2-de]quinolin-7-yl)naphthalen-2-yl)acetate (12 mg, 0.021 mmol) in éthanol (1 mL) was added 2 N sodium hydioxide (1 mL) and the resulting reaction mixture was heated at 80 °C ovemight. The réaction mixture was then concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). The product was lyophilized to give (2S)-2-tert-butoxy-2-(3-methyl-I-((7R)-6-methyl-2_J3,3a,4,5,6hcxahydropyrano[4,3,2-de]quinolin-7-yl)naphthaJcn-2-yl)acetic acid (22) as a white powder (2.6 mg). ^!H-NMR: 400 MHz, (CD₃OD) δ: 7.82 (d, J = 8.2 Hz, 1H), 7.67 (s, 1H), 7.43 (m, 2H), 7.38 (m, 1H), 6.92 (m, 1H), 6.71 (m, 1H), 5.06 (s, 1H), 4.41 (m, 1H), 4.28 (m,lH), 3.52 (m, IH), 3.04 (m, 2H), 2.67,2.62 (s, s, 3H), 2.29 (s, 3H), 2.28 (m, 1H), 2.08 (m, 1H), 1.72 (m, 1H), 1.59(m, 1H), 0.95 (s, 9H). LCMS-ESI* (m/z): [M+H]*calcd for CjsHmNO^: 460.58; Found: 461.3.

Example 21. 7-((R)-2-((S)-tert-Butoxy(carboxy)methyl)-3 -methylnaphthalen-1 -yl)2,3-dihydropyrano[4,3,2-de]qumoline 6-oxide (23)

(S)-2-terf-butoxy-2-((R)-1-(2,3dihydropyrano[4,3,2-de]quinolrn-7yl)-3-methylnaphthaien-2-yl)ethanol

7-((R)-2-((S)-1 -tert-butoxy-2hydroxy ethyl)- 3-methylnaphthalen1 -yl)-2,3-<iihydropyranc[4,3,2de]quinoline 6-oxide

7-((/V)-2-((S)-ferfbutoxy(carboxy)methyl)-3methylnaphthalen-1-yl)-2,3dihydropyrano[4,3,2-cfe]quino|ine 6oxide

Préparation of7-((R)-2-((S)-l-teit-butoxy-2-hydroxyethyl)-3-methylnaphthalen -l-yl)-2.3-dihydropyrano[4,3.2-de]quinoline 6-oxide: To a solution of (S)-2-tert5 butoxy-2-((R)-1 -(2,3-dihydropyrano(4,3,2-de]quinolin-7-y l)-3 -methy lnaphthalen-2yl)ethanol (6C, 31 mg, 0. 727 mmol) in dichloromethane (1.3 mL) was added 3chloroperoxybenzoic acid (77%, 36 mg, 0.161 mmol) and reaction mixture was stirred for 7 hours. Additional 3-chloroperoxybenzoic acid (26 mg, 0.116 mmol) was added and reaction mixture was stirred ovemight and quenched with saturated sodium thiosulfate solution. The resultîng mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, brine, dried (MgSO₄), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). The product was lyophilized to give a yellow powder (4.7 mg). LCMS-ESI* (m/z): [MJ*calcd for C₂₈H_3ONO₄: 443.5; found: 443.9.

Préparation of 7-((R)-2-((S)-tcrt-butoxy(carboxy)methyl)-3-melhy]naphthalen- l-yl)-2,3-dihydropyrano[4,3,2-de]quinoline 6-oxide (23): To a solution of 7-((R)-2-

0Sl-l-îert-bulttxy-2-hydruÀyethv])-%methylnaphlhaien-l-yh-2.3-dihydropxTano[43.2de jqumorinc 6-oxide i4.7 rrqj. G.0106 mob in wel acetonitnle (0 ~^;·% H?O. I mï } was added H«lCh,CrO₍ simk solution >0 434 M. G I ml... d 423 mmol) was added ai U C The réaction mixture was stnred for 90 minutes at room température and additional

HsIOô/CrOj stock solution (0.439 M, 0.1 mL) was added. After stirring for 90 minutes, the reaction mixture was quenched with saturated \aIiCO3 solution and extracted with ethyl acetate (2x). The organic layer was washed with 1LO, saturated NaHS0₃solution, dried (MgSO₄), filtered, concentrated and purifîed by reverse phase HPLC (Gemini, 5 to 100% acetonitrilc/11₂O + 0.1% TFA) to give a yellow powder (1.2 mg).

'11 NMR (400 MHz, CD3OD) δ 8.51 (d, J = 6.3 Hz, IH), 7.79 (d, J 8.2 Hz, IH), 7.69 (s, IH), 7.57 (d, J = 8.0 Hz, IH), 7.44 (d, J = 6.1 Hz, IH), 7.43-7.37 (m, IH), 7.34 (d, J = 8.3 Hz, IH), 7.25-7.13 (m, IH), 6.87(d, J = 7.8 Hz, IH), 5.06 (s, IH), 4.67-^1.55 (m, 2H), 3.52-3.46 (m, 2H), 2.61 (s, 3H), 0.97 (s, 9H). LCMS-ESf (m/z); [M+Rf calcd for C^HzgNOs: 458.5; found: 458.1.

Example 22. (S)-2-tert-Butoxy-2-(l -(4-chlorophenyJ)-3-(dimethylamÎnomethyl) naphthalen-2-yl)acetic acid (24)

Cl

C!

Λ

S-eTryf 2*fert-butoxy-2-(1-(4chkropherryl}-3-methyinaphthaien-2ytjacetate

(S)-ethyi 2-(3-( bromometfiyl)-1-{4chlorophenyi)naphthalen-2-yl)-2 -iert-butoxyacetate

(S)-ethyl 2-fert-butoxy-2-(1-(4chlorophenyl)-3((dimettiylarnino)metfiyl) naphttialen-2-yl)acetate

(S)-2-ferf-bL.toxy-2-(1-(4-chlorophenyl)-3((dimethylamino)fnettiy1)naphthalen-2-yi) aceüc acid

Préparation of (S)-ethyl 2-(3~(bromomethyl)-l-(4-chlorophenyl)naphthalen-2yl)-2-tert-butoxyacetate: To a solution of(S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-

3-methylnaphthalen-2-yl)acetate (3K, 43 mg, 0.0105 mmol) in CCLj (2 mL) was added

NBS (24 mg, 0.13 mmol) and ΑΠ3Ν (cat, amount). The reaction mixture was refluxed for 5 h. After cooling to room température, the reaction mixture was diluted by DCM, washed with sat. NallCO^ extracted with DCM and the organic layers were combined and dried over MgSOi, filtered, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 12 mg of the desired product. ^lH-MNR 400 MHz (CDC1₃) δ: 8.01 (s, 1H), 7.77 (d, J = 4Hz, 1H), 7.43-7.15 (m, 7H), 5.11 (d, J = 5.2 Hz, 1H), 5.06 (s, 1H), 5.00 (d, J = 5,2 Hz, 1H), 4.07-4.02 (m, 2H), 1.20-1.15 (m, 3H), 0.96 (s, 9H).

Préparation of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-((dimethylamino)methyl)naphthalen-2-yi)acetate: To a solution of (S)-ethyl 2 (3-(bromomethyl) 15 l-(4-chlorophenyl)naphthalen-2-yl)-2-tert-butoxyacetate (12 mg, 0.0245 mmol) in THF ( 1 mL) was added dimethylamine (2 M in THF, 0.12 pL). The reaction mixture was

stirred at room température for l h Removal ut the sols ent in vacuo followed by purification c»f the residue bv flash chromatography (silica gel, ethyl acetate hexanesi provided 8 mg oi ihe desired product H.MS LSi* im ;} jM’H'f calcd for CrH^ClNOo 454.2; bound 454.2. 456 l

Préparation of (S )-2-tert-butoxy-2-( l -<4-chlorophenyl )-3-((dimethylamîno)methyl)naphthalen-2-yl)acetic acid <24 ): To a solution of (S)-ethyl 2-tertbutoxy-2-(l-(4-chIorophenyl)-34(dimethyianiino)methyi)naphthalen-2-yl)acetate in THF (0.5 mL) and MeOH (0.5 mL), was added NaOH solution (2N, 100 pL). The reaction mixture was stirred at room température for lday. The reaction mixture was neutralized by HOAc and concentrated down. The residue was dissolved in MeOH and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂0 + 0.1% TFA) to provide the desired product (3.7 mg). ¹ H-NMR: 400 MHz, (CD₃0D) Ô: 8.12 (s, 1H), 8.00 (d, J = 4.2 Hz, 1H), 7.65-7.52 (m, 5H), 7.32-7.30 (m, 2H), 5.36 (s, 1H), 4.93 (d, J = 6.8 Hz, 1H), 4.47 (d, J = 7 Hz, IH), 3.12 (s, 3H), 2.89 (s, 3H), 1.12 (s, 9H). LCMS-ESI⁴( m/z): [M+H]⁴ calcd for CîsH^CINOj: 426.2; Found: 426.1,428.1.

Example 23. (S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3-((pyridin-3yloxy)methyl)naphthaien-2-yl)acetïc acid (25)

(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3((pyridin-3-yloxy)nnethyl)naphthalen-2-yl) acetic acid

Préparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-((pyridin-3yloxy)methyl)naphthalen-2-yl)acetïc acid (25): (S)-2-tert-Butoxy-2-(l-(4chlorophenyl)-3-((pyridin-3-yloxy)methyl)naphthalen-2-yl)acetic acid (25) was

Ιϋί prepared by the similar method of Example 22. except thaï KXO; and pyridin-^-oi ΆβΓί- used insiead of dimethvlamine in step 2 H-NMR- 4iXî MHz. iCDT/Eh ό. S.39 ni.

J “ 2 8 Hz. 1 Hk 8 31 (s. 1H J. 8.05 (s, ! H j. 7 96-7 86 un. ?H r ⁷ 64-7 44 ? m. ^ςΗ i. 7 M7 31 im. 2H). 6.44(d. J - 7.4 Hz. 1H J. 6.12 (d. J = 7.6 Hz. 1 H i. 5.24 ts. HH. 0.92 (s.

9H). LCMS-ESE (m^Y [M + H]’ calcd for C_2RH₂-ClNOr 476.2. Found: 476.0. 478.0.

Example 24. (S)-2-tcrt Botoxy-2-( 1 *(4-chlorophenyl)-3-{(pyriniidin-5yioxy)methyl)naphthalen-2-yI)acetic acid (26)

(S)-2-fert-butoxy-2-(1-(4-chiorophenyl)-3((pynmidin-5-ytoxy)methyi)naphthalen-2-yl) acetic acid

Préparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-((pyiimidin-5yloxy)methyl)naphthalen-2-yl)acetic acid (26): (S)-2-tert-Butcxy-2-(l-(4chlorophenyl)-3-((pyriniidin-5-yloxy)methyl)naphthalen-2-yl)acetic acid (26) was prepared by the similar method of Example 22, except that K₂CO₃ and pyrimidin-5-oI were used instead of dimethylamine in step 2. *H-NMR: 400 MHz, (CD₃OD) δ: 8.75 (s, IH), 8.60 (s, IH), 8.08 (s, IH), 7.88 (d, J = 3.8 Hz, IH), 7.60(s, 2H), 7.58-7.26 (m, 4H), 5.72-5.70 (m, 2H), 5.21 (s, IH), 1.02 (s, 9H). LCMS-ESI’ (m/z): [M+H]⁺ calcd for C₂₇H₂₆C1N₂O₄; 477.2; Found: 477.1,478.1.

Example 25. (S)-2-tert-Butoxy-2-( 1 -(4-chiorophenyl)-3-(morpholinomethyl) naphthalen-2-yl)acetic acid (27)

Ah

C

Cl

( S)-2-te/7butoxy-2-( 1 -(4-chlorophenyl)-3(morpholinomethyl)naphthalen-2-yl) acetic acid

Préparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3(morphoIînomethyl)naphthalen-2-yl)acetic acid (27): (S)-2-tert-Butoxy-2-(l-(45 chlorophenyl)-3'(morphoIinomethyl)naphthalen-2-yl)acetÎc acid (27) was prepared by the similar method of Example 22, except that morpholine was used instead of dimethylamine în step 2. 'H-NMR: 400 MHz, (CD₃OD) δ: 8.14 (s, IH), 7.99 (d, J = 4 Hz, IH), 7.64-7.60 (m, 3H), 7.53-7.49 (m, 2H), 7.29-7.27 (m, 2H), 5.38 (s, IH), 4.81-

4.78 (m, 2H), 4.11-4.08 (m, 2H), 3.81-3.78 (m, 2H), 3.55-3.41 (m, 4H), 1.16 (s, 9H).

LCMS-ESr*· (m/z): [M+H)⁺ calcd for C27H31CINO4: 468.2; Found: 468.0, 470.1.

Example 26. (S)-2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-(methoxymethyl) naphthalen·

2-yl)acetic acid (28)

(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3(methoxymethyl)naphthalen-2-yl) acetic acid

Préparation et (Si-2-tert-buioxy-2-( I-(4-chlorophenxl »-3imcrhoxymcthy 1 inapbthaii.-n-2· >î)acctu. aûd (28 k 1 S;-2-lcrt-Rutu.xy-2-( l-t4chlorophenvi)-i-i meih(ixymi’lhyi )naphihaien-2-ybacetic acid t28) was prepared by lhe similar method of Example 22. except that sodium methoxide and methanol were used instead of dimethylamine and THF and the reaction was heated at 50 °C for 3 h. 'HNMR: 400 MHz. (CD₃OD) δ: 7.91 (s, IH), 7.77 (d, J = 4.2 Hz, IH), 7.50-7.13 (m, 7H), 5.06 (s, IH), 4.84 (d, J ’ 6.6 Hz, 2H), 4.71 (d, J = 6.4 Hz, 2H), 3.32 (s, 3H), 0.90(s, 9H). LCMS-ESI (m/z): [M-H]⁺ calcd forC^^ClC^: 411.1; Found: 411.0,413.0.

Exemple 27. (S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 -vînylnaphthalen-2-yl)açetic acid (29A) and (S)-2~tert-butoxy-2-(l-(4-chlorophenyl)-3-ethylnaphthalen-2-yl)acetic acid (29B)

Cl

(S)-ethyl 2-(3-(bromomethyi)-1 -(4-chlorophenyl)naphthalen2-yl)-2-tert-butoxyacetate

(S)-ethyl 2-tert-butoxy-2-(1 (4-chlorophenyl)3-forrnylnaphthalen-2-yl)acetate

Cl

(S)-ethyl 2-terLbutoxy-2-(1(4-chloroptienyl)-3vinylnaphthalen-2-yl)acetate

Cl

29A ( S)-2-ferf-b u toxy-2-(1-(4chlorophenyl)-3vinylnaphthalen-2-yl)acetic acid

(S)-2-tert-butoxy-2-(1 (4-ch!orophenyl)-3ethylnaphthalen-2-yl)acetic acid

Préparation of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyi)-3formylnaphthalen-2-yl)acetate: To a solution of (S)-ethyl 2-(3-(bromomethyl)-l-(4hlorophenyl)naphthalen-2-yl)-2-tert-butoxyacetate from Example 22 (200 mg, 0.408 5 mmol) in acetonitrile (4 mL) was added N-methylmorpholine N-oxide (478 mg, 4.08 mmol) and 4A molecular sieves (200 mg). The reaction mixture was stined at room température for 2 h. Additional N-methylmorpholine N-oxide (500 mg, 4.27 mmol) was added and the réaction mixture was stirred at room température for another 2 h. The reaction mixture was then filtered and the organics washed with sat. NaHCO₃,

: N?

extracted by DCM. dned user MgSO₄ Phe organic laver was then filtered. .oncentraied down anc- purified rw flash column chromaiographv rsihca ueî. eihvi acetate 'hexanes l lu prwide l IO mg (t>4^o o) of the desired product Ή-MNR 4-00 MH? fCDCIùÔ: 10.82 (s. IH). 8.55 (s. IHl. 8.01 fd.J = 4 Hz. IH). 7.55-T23 (m. 7H). S 19 's. 1 H), 4.17-4.13 (τη, 2H). 1.22 (t, J = 7 Hz. 3H), 1.04 is, 9H).

Préparation of (S)-ethyl 2-tert-butoxy-2-(l -(4-chlorophenyl)-3-vinylnaphthalen2-yl)acctate: To a suspension of methyltiiphenylphosphonium bromide (60 mg, 0.168 mmol) in THF (I mL) at -78 °C was added dropwise n-BuLi (1.6 M in hexanes, 90 pL), followed after 30 min by a solution of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3formylnaphthalen-2-yl)acetate (12 mg, 0.028 mmol) in THF (1 mL). The reaction mixture was allowed to warm to room température and stined at room température for 2 hours. This mixture was added to another mixture, which was made by adding n-BuLi (1.6 M in hexanes, 300 pL) to a suspension of methyltriphenylphosphonium bromide (200 mg, 0.56 mmol) in THF (2 mL) and stirred at -78 °C for 15 min. Then the reaction mixture was allowed to warm to room température and stirred at room température for 1 h. The reaction mixture was diluted with EtOAc, washed with sat. NH4CI, and extracted with EtOAc. The organic layers were combined, dried over MgSOj, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, efhyl acetate/hexanes) to provide 7.4 mg of the desired product. ’H-MNR 400 MHz (CDClj) δ: 7.95 (s, IH), 7.78 (d, J = 4.2 Hz, IH), 7.57-7.50 (m, IH), 7.43-7.17 (m, 6H), 5.62 (dd, J - 8.1.2 Hz, 1 H), 5.25 (dd, J = 5.3,1.8 Hz, 1 H),5.07 (s, IH), 4.06-1.02 (m, 2H),

1.10 (t, J = 7 Hz, 3H), 0.93 (s, 9H).

Préparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-vinylnaphthalen-2yl)acetic acid (29A): To a solution (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3vinylnaphthaIen-2-yl)acetate (7.4 mg, 0.0175 mmol) in THF/MeOH (1/1,1 mL), was added NaOH (2 N, 280 pL). The reaction mixture was stirred at room température overnight. Then the température was raiscd to 40 °C and the reaction mixture was stirred for 4 h. The reaction was then cooled down and neutralized by adding HOAc. The réaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (Gemini, 5 to 100% ACN/FLO + 0.1% TFA) to provide 5.3 mg of the desired product. ‘H-NMR: 400 MHz, (CD3OD) δ: 8.07 (s, IH), 7.89 (d, J = 4.0 Hz, IH), 7.60-7.54 (m, 4H), 7.48-7.44 (m, IH), 7.35-7.31 (m, 2H), 7.25-7.22 (m, IH), 5.7616293

71 (m, IH). 5 29-5 26 (m. IH i. 5.21 (s, 111).0 98 (s. 9H». l.CMS-ESJ (m.zi [M-Hf caii'd lor < il »·. . Found' 3^ ' 6

Préparation et iS t-2-tert-buloxy-2-( l-M-chiorophenvi )-t-ethvlnaphthaien 2 ybacetic acid f29Bi ! o a soFjuon of (S>-2-tert-butox>-2-( l-<4-chloropheny 1 >-3vinylnaphthalen-2-yl lacetic acid (4 mg. 0.010 mmol) in EtOH (1.5 mL) was added RhALO: tcat amount i and the resulting mixture stirred under hydrogen (1 atm, balloon) at room temperarure for 2 h. The reaction mixture was filtered over Celite, concentrated in vacuo and the residue was purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O + 0.1% TFA) to provide 0.8 mg of the desired product.

’H-NMR: 400 MHz, (CD₃OD) δ: 7.81 (d, J - 4.2 Hz, IH), 7.77 (s, IH), 7.58-7.53 (m, 3H), 7.44-7.41 (m, IH), 7.33-7.20 (m, 3H), 5.20 (s, IH), 3.14-3.08 (m, IH), 2.93-2.87 (m, 1 H), 1.34 (t, J = 7.4 Hz, 3H), 0.98 (s, 9H). LCMS-ESr (m/z); [M-H] calcd for C24H24CIO3: 395.1; Found: 395.0.

Example 28. (S)-2-tert-Butoxy-2-(]-(4-chlorophenyl)-3-(hydroxymethyl) naphthalen2-yl)acetic acid (30)

C ii(7

(S)-ethyl 2-fert-butoxy-2-(1(4-ch!orophenyt)3-formyinaphthalen-2-yl)aceiate

'SV-eCiyl 2-ter t-butoxy-2-( 1 i*-Cltorophenyl)-3(hydroxymethyl)naphthalen-2-yl)acetate

(S)-2-/er'-buioxy-2-( 1 -(4chlorophenyl)-3-(hydroxymethyl) naptrthaten-2-yl)acet3c acid

Préparation of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3(hydroxymethyl)naphthalen-2-yl)acetate: To a solution of (S)-ethyl 2-tert-butoxy-2-(l(4-chlorophenyl)-3-fonnylnaphthalen-2-yl)acetate (12 mg, 0.0283 mmol) in

DCM/EtOH (1/1,1 mL) at 0 °C, was added NaBIL (2 mg, 0.053 mmol) and the reaction mixture stirred at 0 °C for 2 h. The reaction was quenched by adding sat. NH4CI. The resulting mixture was extracted with DCM, dried over MgSO₄, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 8 mg of the desired product. ’H-MNR 400 MHz (CDCI3) δ:

7.85 (s, IH), 7.78 (d, J = 4.0 Hz, IH), 7.46-7.38 (m, 4H), 7.30-7.26 (m, 1 H), 7.20-7.15 (m, 2H), 5.13 (s, IH), 5.02 (d, J = 6.2 Hz, IH), 4.54 (d, J = 6 Hz, IH), 4.12-4.02 (m, 2H), 3.82 (bs, IH), L14 (t, J = 7Hz, 3H), 1.01 (s, 9H).

Préparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)~3-(hydroxymethyl) naphthalen-2-yl)acetîc acid (30): This compound was made using a method similar to that used for (S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 -(dimethylaminomethyl) naphthalen-2-yl)acetic acid în Example 22. The compound was purified by reverse

phase MPI C (Gemini 5 to *00% ACN'H^O) ’H-NMR 4(>0 MHz. iCD:0D) â ⁷ 9g ; s ? H \ * 7χ 1 - j Hz ! H ΐ * ^s2- * 44 (m. 'H k ? 3o. 35 < m. i H >. 7 26-7 : t it 3Hi. 5 r>Q îs, 1H-. 5 B' (d. J - ? 4 Hz. Hl;. 4 .73 (J. J - ⁷ 2 Hz. îHk Û.< <>. 9H) ! CMS-FSl' tni'i ÎM-H]’calcd forCy.H^ClO* 397 1. Found: 396 9. 390 0

Example 29. (S)-2-tert-Butoxy-2-((R)-l -(2,3-dihydropyrano[4.3,2-de]quînolin-⁷-yl v-3 (fluoromethyl)naphthalen-2-yl)acetic acid (31)

(S)-2-ter0b jtoxy-2-((K)-1 -(2,3dihydrapyrano[4,3.2-ffe] quino(in-7-ylÊ3-methylnaphthaten-

2-yl)ethyl pivalate (Sy2-((/?)-3-(bromomethylF1 -(2,3dîhydropyrano[4,3,2-de] quino!in-7-y))naphttiaten-2-yi)-

2-tert-butoxyethyl pivalate

(S)-2-fert-butoxy-2-((R)-1-(2,3dihydrapyrano{4.3,2-dej quinolin-7-yl}-3-(flùoromethyl)naphthaten-

2-yl)ethyl pivalate (S>2-tert-butoxy-2-((K)-1 -(2,3dihydropyrano[4,3,2-de] quino1iT>7-yl)-3-(fluoromethyl) naphthalen-2-yQethanol

(S)-2-tert-butoxy-2-((R)-1 -(2,3dihydropyrano[4,3,2-de] quinolin-7-yl)-3-(fluorornethyl) naphthalen-2-yl)acetic acid

ΙΟ

Préparai ion of ($1-2-(( R }-3-(bromomethv l.i-1 -(2.3-dihydropyrano 14,3.2 -de] quini'lir: ''-'••l ’naph’haien- j-v! i- ·’(en huhnyethv p;\ aSaie l’he compi'unu -vas made similarb tû die method for rnaking (Steih>i 2-(^ (br:>rnoirxrthyi)-I-(4-chli!^ri»phern hnaphthalen-2-yÎ f-2-tert-binoxvaceîate cf hxample 22. L< MS-hSl (m c). [M-H]’ calcd for C₃₃H₃7BrNO₄: 590.2; Found; 590.0, 592.0.

Préparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3.2-de]quinolin7-yl)-3-(fluoromethyl)naphthalen-2-yl)ethyl pivalate: To a solution of (S)-2-(3(bromomethyl)-l-(2,3-dihydropyrano[4,3_!2-dc]quinolin-7-yl)naphthalen-2-yl)-2-tertbutoxyethyl pivalate (15 mg, 0.0255 mmol) in acetonitrile (1 mL), was added AgF (8 mg, 0.063 mmol). The reaction mixture was stirred at room température for 1 day. The reaction mixture was then washed by sat. NaHCO₃, extracted with EtOAc, dried over MgSOi, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to provide 13 mg of the desired product. LCMS-ESI* (m/z); [M+H]* calcd for C33H37FNO4: 530.3; Found; 530.1.

Préparation of(S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-3-(fiuoromethyl)naphthalen-2-yl)ethanol: To a solution of (S)-2-tcrt-butoxy-2-(l(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-(fluoromethyl) naphthalen-2-yl)ethyl pivalate (13 mg, 0.024 mol) in THF (1 mL) and MeOH (0.5 mL), was added NaOH (2 N, 240 pL), The réaction mixture was reacted at room température for 1 day. The reaction mixture was washed with sat. NaHCO₃ and extracted with EtOAc. The organic layers were combined, dried over MgSÛ4, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 5 mg of the desired product. LCMS-ESI* (m/z); [M+H]* calcd for C2gH29FNO₃: 446.2; Found: 446.0.

Préparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-3-(fluoromethyl)naphtha!en-2-yl)acetic acid (31): To a solution of(2S)-2-tertbutoxy-2-(l-(2,3-dihydropyrano[4,3,2-de]quinohn-7-yl)-3-(fluoromethyl)naphthalen-2yl)ethanol (5 mg, 0.0112 mmol) in wet acetonitrile (0.75%wt H₂O) was added HiIOft/CrOa (0.439 M stock solution in wet acetonitrile, 400 pL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was filtered and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA) to provide 0.8 mg ofthe desired product ’H-NMR: 400 MHz, (CD₃OD) δ: 8.51 (d, J = 2.4 Hz, 1H), 8.15 (s, 1H), 7.92 (d, J = 4.0 Hz, IH), 7.69 (d, J = 4.2 Hz, 1H), 7.54 (d, J = 2.6 Hz, 1H), 7.43

ÎL J = 76 Hz. Iii). 7 '1 <d. J = 4 Hz. 1 Ht. 7.24-7 21 _([n. IHi, 6 88 (d, J - 4 4 Hz. lHk rn.« H ! X ÎJfr : H ; 4 it J -- 0 JHz. 2H ). 4 4m u i =· _hj 2H I t! Xi _!k 'JH l ^;’F-NM R 4üf! XîHz < < ' f >,<JD t à - 7? 5 î i s. i ! ? t t MS-FSl {mzi i.VMÎ] calcd for (Ά H _;-FN O « 4ôi! 2: Found: 460 1

Example 30. (S)-2-tert-Butoxy-2-((R)-3-(dif]uoromethyl)-l-(2.3-dihydropyrano[4,3,2de]quinolin-7-yl)naphthalen-2-yI)acetic acid (32)

(S)-2-((fl)-3-(bromomethyl)-1-(2,3dihydropyraoo[4,3,2-de] quinolin-7-yl)naphthaien-2-yl)2-tert-butoxyethyi pivafate (S)-2-fert-butoxy-2-((P)-1 (2,3-dihydropyrano[4,3.2~de] quino!in-7-ylF3-forniylnaphttialen-2-yl) ethyl pivalate

(S)-2-tert-butoxy-2-((R)-3-(difluoromethyl) -1-(2,3-dihydropyrano[4,3,2-de] quinolin-7-yl)naphthaten-2-yl) ethyl pivalate (S)~2-tert-butoxy-2-((R)-3(dif)uoroînethyl)-1-(2,3-dihydropyranQ f4,3,2-de]quinolin-7-yl)naphthalen-2-yl)

(S)-2-tert-butoxy-2-((ff)-3(difluoromethylj-l -(2,3-dihydropyrano (4,3,2-de]quinolin-7-yl)naphthalen-2-yl) acetic acid

Préparation of < S )-2-tert-rHjtoxy-2-H R l· ^! -( 2.'-dihvdropxTanof*,^.J-delquirnOir'wlï t-iormy fnaphLhaitn 2-yî)ethx! pnalatc. Ihe compound was made smularE to tS i-ethyj 2-tert-hutoxy-2-( 1 -(4-chlorophenyl t-3-formylnaphlhalen-2-y})acetate of Example 27. LCMS-ESF _tm,zp (M+H]' calcd for C33H3e.NO.: 526.2. Found. 526.1.

Préparation of (S)-2-tert-butoxy-2-((R)-3-(difluoromethyl)-l-(2,3dihydropyrano[4,3.2-de]quinolin-7-yl)naphthalen-2-yl)ethyl pivalate: To a solution of (S)-2-tert-butoxy-2-( 1 -(2.3 -dihydropyrano[4,3,2-de] quinolîn-7-yl)-3 -formy lnaphthalen2-yl)ethyl pivalate (18 mg, 0.0343 mmol) in DCM (1.5 mL) was added Deoxofluor (20 pL, 0.105 mmol). The réaction mixture was stirred at room température overnight. More Deoxofluor (300 pL, 1.6 mmol) was added and the reaction mixture Was stirred at room température over weekend. The reaction mixture was washed by sat. NaHCCh and extracted with DCM. The organic layers were combined, concentrated in vacuo and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to produce 20 mg of the desired product. LCMS-ESf (m/z): [M+H]⁺ calcd for C33H36F2NO4: 548.2; Found; 548.1.

Préparation of (S)-2-tcrt-butoxy-2-((R)-3-(difluoromethyl)-l -(2,3dîhydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)ethanol: The compound was made by the similar method to make (2S)-2-tert-buloxy-2-(l-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-3-(fluoromethyl)naphthalen-2-yl)ethanoI of Example 29. LCMS ES J⁺(m/z): [M+H]⁺ calcd for C28H28F2NO3:464.2; Found: 464.1.

Préparation of (S)-2-tert-butoxy-2-((R)-3-(difIuoromethyl)-1 -(2,3-dihydropyrano[4,3,2de]quinolm-7-yl)naphthalen-2-yl)acetic acid (32): The compound was made by the similar method to make (2S)-2-tert-butoxy-2-(l-(2,3-dîhydropyrano[4,3,2-de]quinolin7-yI)-3-(fluoromethyl)naphthalen-2-yl)acetic acid of Example 29. ^:11-NMR: 400 MHz, (CD3OD) δ: 8.66 (d, J = 2.8 Hz, IH), 8.56 (s, IH), 8.15 (d, J = 4.2 Hz, IH), 8.00-7.81 (m, 3H), 7.69-7.54 (m, 2H), 7.45 (t, J =7.8 Hz, IH), 7.04 (d, J = 4.2 Hz, IH), 5.10 (s, 1 H), 4.75 (t, J = 6Hz, 2H), 3.68 (t, J = 6.2 Hz, 2H), 1.07 (s, 9H). ¹⁹F-NMR 400 MHz (CD3OD) δ: -77.77 (s, 2F). LCMS-ESF (m/z): [M+H]⁺ calcd for C28H26F2NO4: 478.1; Found: 478.1.

Example 31. ieri-Butoxy-(l-(2,4-dichloro-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid (33)

Γ')	y' k/
Br	i ;

	Pd(PPh₃)₄
l-oromo-3-	H₂O/DME

^BC ’-'YSrYtoac/’tftalen-Z-ol

C!

À

-(2,4-dichlorophenyl)-3methylnaphthalen-2-o!

1-(2,4-dichlorcphenyl)-3mettiylnaphthalen-2-yl tnfluoromethanesijlfonate

PivCI

---► pyr/DCM

1-(2,4~dichkxciphenyl)-3- methyl-2-vinylnaphthalene (1 S)-1 -(1 -(2,4-dichlorapheny I)-

3-methylnaphthafen-2y l)ethane-1,2-diol

NaOH (S)-2-((S)-1-(2,4-dichlorophenyi)-

3-methylnaphthaler)-2-yi}-2hydroxyethyl pivalate (S}-2-terf-butoxy-2-((S)-1 -(2,4dichlorophenyi)-3-methylnaphthalen-2yljethyl pivalate

wet ACN (S)-2-tert-butoxy-2-((S)-1-(2,4-dichlorophenyl)-3methylnaphthalen-2-yl)ethanol

CrO₃, H_slO_e

(S)-2-teri-butoxy-2-((S)-1-(2,4dichlorophenyl)-3-niethylnaphthalen2-yl)acetic acid

Préparation of l-(2,4-dichlorophenyl)-3-methylnaphthalen-2-ol.· A mixture of

2,4-dichlorophenyIboronic acid (1.0 g), tetrakis(trîphenylphosphine)palladiuin(0) (300 5 mg), l-bromo-3-methyI-naphthalen-2-ol (5B, 625 mg) in K2CO3 (2 M, 5.3 mL) and

LA

DMF 126 ml. J was degassed with argon and sealed in a Schlenk tube The réaction was heated tu 80 *&r minutes then et—!ed * «ντ iemperaTu’v ! be reaction was diluted with EtOAc on J filtered through a pad of silica gri Ihe s: ht a wxs washed w ith EtOAc and the combined orgames were concentrated The crude residue was puniied by flash column chromatography i0-l 8% EtOAc in hexanes > to yield 784 mg of desired product.

Préparation of I-(2,4-djchkKopbenyl)-3-inethylnaphthalen-2-yl trifluoromethanesulfonate: 1 -(2,4-dichlorophenyl)-3-methylnaphthalen-2-y 1 trifluoromethanesulfonate was prepared in a similar manner as compound 4C in Example 2, except starting from l-(2,4-dichIorophenyl)-3-inethylnaphthaIen-2-ol instead of 4B. Ή-NMR: 400 MHz, (CDC1₃) δ: 7.85-7.90 (m, 2H), 7.62 (d, IH), 7.55 (app dt, IH), 7.41-7.48 (m, 2H), 7.32-7.49 (m, 2H), 2.64 (s, 3H).

Préparation of terf-butoxy-[l-(2,4-dichloro-phenyl)-3-methyl-naphthalen-2-yl]acetic acid (33): rcr/-butoxy-[l-(2,4-dich]oro-phenyl)-3-methy]-naphthaJen~2-yl]-acetic acid (33) was prepared in a similar manner as compound 3K in Example 1, except starting from l-(2,4-dichlorophenyl)-3-methylnaphthalen-2-yI trifluoromethanesulfonate instead of 3E. ’H-NMR: 400 MHz, (CD₃CN) S: 7.84 (d, IH),

7.78 (s, IH), 7.69 (d, IH), 7.63 (d, IH), 7.47 7.54 (m, 2H), 7.37 (app dt, IH), 7.16 (d, IH), 5.17 (s, IH), 2.60 (s, 3H), 1.06 (s, 9H).

'.ert-Butux>-[ l-(4-th]oro-phen\ i H5-methi>xj -3-methy--naphthalen-2-yll-

o

2-methoxyphenyl acetone

^mî

Po/C EtOH

OEl

LiOH

HjO/EtOH/THF

4-(2-Methoxy-ptienyi)3-methyt-but-2-enoic acid ethyl ester

4-i2-Methoxy-phenyl )3-methyl-bLrtyric add ethyl ester

4-(2-Methoxy-phenyJ)3-methyl-biJtyric add

4-(2-Methoxyphenyl)-3-meithylbutyryi chloride

AIBN NBS

CCI4, reflux

5-Methoxy-3-methyL 3,4-dihydro-2Hnaphthaten-1-one (5-Methoxy-3-methyl-1 oxo-3,4-dihydro-1 Hnaphttialen-2-yüdme)acetic acid ethyl ester

4-MeOBnOH

KHMDS THF, 0 ’C

Tf₂O

2,6-lut

CH₂CI_z-78‘C

(4-Bromo-5- methoxy-3methyi-1 -oxo-3,4-dihydro1 H-naphthalen-2-ylidéne)acetic acid ethyl ester (1 -Hydroxy-5-methoxy-3methyl-naphthalen-2-yl)(4-methoxy-benzytoxy)acetic add ethyl ester (4-Methoxy-benzy!oxyH5methoxy-3-methyl-1 t rrfluoromethanesutfonyloxy -naphthaten-2-y I)- acetic acid ethyl ester

Pd(dppf)Cl₂

Pd(PPh₃)₄tol/EtOH/H₂O 60-100 °C

[1-(4-Chloro-phenyl)-5methoxy-3-methyJnaphthalen-2-yi]-(4-fnethoxybenzytoxy)-acetic acid ethyl ester

[1 -(4-ChJoro-phenyl)-5-methoxy3-methyl-naphthalen-2-yf]hydroxy-acetic acid ethyl ester

tert-Biitoxy-[1 -(4-chloro-pheny I)5-methoxy-3-rriethyl-naphthalen2-yl]-acetic acid ethyl ester

tert-Butoxy-[1-(4chforo-phenyl)-5methoxy-3-methylnaphthalen-2-yl]-acetic acid

Préparation of 4-(2-methoxyphenyl)-3-methyl-but-2-enoic acid ethyl ester: In a

3-neck round bottom flask, fitted with an internai thermometer and addition tunnel, a mixture of sodium hydride (60% in minerai oil, 4.14 g) in THF (200 mL), under argon, was cooled to 10 °C. (Diethoxyphosphoryl)acetic acid ethyl ester (21 mL) was added dropwise (heat and gas évolution), keeping the internai température below room température. After addition, the reaction mixture was stirred at room température for 10 minutes, and then cooled to 0 °C. A solution of 2-methoxyphenyl acetone (5 g) in THF (25 mL) was added dropwise over 5 minutes. The reaction was allowed to warm 10 to room température ovemight. With active cooling, the reaction was quenched with H₂O (200 mL), then AcOH (to pH ~6) and extracted with EtOAc. The combined organics were washed with NaHCO₃, water, and brine, dried overNa₂S04, and concentrated. The crude residue was purified by flash column chromatography to give

the desired compound (5.73 gi. H-NMR 4(K) MHz, (Cl)Ci-J δ 7.24 (appdt. Illk 7 ]0 :-jd ‘ H s 6 U? fd ! II! 6 XX i l. i Hl- > 58 +. !H !. 4. l 3 iq. 2H I. ΐ X2 t\. 3Hi t 46 is. 2liî. I 26 = t. 3Hs

P'-eparation of 4-i 2-meihoxyphen\h-.'-methyl-burvnc acid ethyl ester: Palladium on carbon (10%. wet Degussa, 300 mg) was degassed. Ethanol (60 mL), degassed with argon, was added followed by 4-(2-rnethoxy-phenyl)-3-melhyl-but-2 enoic acid ethyl ester (5.7 g, 24 mmol). Hydrogen was bubbled through the cthanol, and the reaction was stirred under 1 atm of H₂ (balloon)ovemight. The balloon was removed, and the reaction was flushed with argon and the reaction was filtered through Celite. The Celite was washed with ethyl acetate and the filtrâtes dried over magnésium sulfate and concentrated. The crude residue was used without further purification. LCMS-ESI⁴ (m/z): [M]⁴ calcd for C]4H₂oOs: 236.14; Found: 236.96.

Préparation of 4-(2-methoxyphenyl)-3-methyl-butyric acid: A solution of 4-(2methoxyphenyl)-3-methyl-butyric acid ethyl ester (24 mmol, crude from previous réaction) în THF (50 mL), EtOH (50 mL) and LiOH (1 M, 50 mL) was stirred at room température overnight. The reaction was acidified with 1 M HCl, and extracted with EtOAc. The combined extracts were washed with brine and dried over sodium sulfate. Concentration gave the desired product, which was used without further purification. LCMS-ESI⁴ (m/z): [M]⁺ calcd for Ci₂Hi₆O₃: 208.11; Found: 208.86

Préparation of 4-(2-methoxyphenyl)-3-methyl-butyryl chioride: To a solution of

4-(2-methoxyphenyl)-3-methylbutyric acid (24 mmol, crude from previous réaction) in dichloromethane (36 mL) was added oxalyl chioride (2 M in DCM, 36 mL). The reaction was stirred for 1 h at room température. AU volatiles were removed in vacuo and the crude residue used without further purification.

Préparation of 5-methoxy-3-methyl-3,4-dihydro-2H-naphthalen-l-one: A mixture of A1C1₃ (6.4 g) and CH₂C1₂ (100 mL) was cooled to 0 °C. To the mixture was added 4-(2 methoxyphenyl) 3-methylbutyryl chioride (24 mmol, crude from previous reaction). The reaction was aliowed to wann slowly to room température and then quenched by slowly pouring over ice. The mixture was extracted with dichloromethane (3x) and the combined organics were washed with 1 M HCl, water, dried over sodium sulfate, and concentrated. Purification by flash column chromatography yielded the desired product (1.65 g, 36% yield from 4-(2-methoxy-phcnyl)-3-mcthyLbut-2-enoic

pr aod ethx I ester) l.CMS-ESi tm.-| IM^H] calcd for (’μΗ.Λ)? ]9l ll.iûund.

Préparation td ( 5-meiboxç-'‘-methyl· ' -oxi>-^; 4-dih>dro- i i l-naphihaicn-2vîidenei-acetic acid ethyl ester' In a heavy walled seaied tube. ^-methoxy-Î-methyl-

3.4-dihydro-2H-naphthalen-l-one (T 3 g, 6 8 mmol). ethyl glyoxylate (3 mL. 50% solution in toluene), benzenesulfonic acid (100 mg), magnésium sulfate (5 g), and toluene (30 mL) were heated to 120 ^ÛC for 13 hours. The reaction was cooled to room temp, filtered, diiuted with water, and extracted with ethyl acetate. The extracts were washed with brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography to yield the desired product (960 mg, 51% yield). LCMS-ESI* (m/z): [M+H]*calcd for C₁₆H₁₉O4: 275.13; Found: 275.26.

Préparation of (4-bromo-5-methoxy-3-methyl-I-oxo-3,4-dihydro-lHnaphthalen-2-ylidene)-acetic acid ethyl ester: A mixture of (5-methoxy-3 -methy 1-1oxo-3,4-dihydro-lH-naphthalen-2-ylidene)-acetic acid ethyl ester (480 mg), NBS (420 mg), and AIBN (30 mg) in CCL» (18 mL) was refluxed for 3 hours. The reaction mixture was then cooled to room température, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (2x). The combined organics were washed with water, dried (Na₂SO4), concentrated, and purified by flash column chromatography to give a light brown solid (420 mg) LCMS-ESI* (m/z): [M+H]* calcd for Ci6HigBrO₄: 353.03; Found: 352.91.

Préparation of ( 1 -hydroxy-5-methoxy-3-niethyl-naphthalen-2-yl)-(4-methoxybenzyloxy)-acetic acid ethyl ester: To a solution of 4-methoxybenzyl alcohol (0.27 mL, 4 equiv) in THF (11 mL) at 0 °C was added KHMDS (0.5 M in toluene, 3.4 mL, 3 equiv) and the resultîng mixture was allowed to stir for 10 min at 0 °C. A solution of (4-bromo-5-methoxy-3-methyl-l-oxo-3,4-dihydro-lH-naphthalen-2-ylidene)-acetic acid ethyl ester (200 mg) in THF (1 mL) was added slowly. After stirring for 3 min at 0 °C, the réaction was quenched with citric acid (1 M) and extracted with EtOAc. The organic extracts were washed with brine, dried over Na₂SO₄ and concentrated. The crude residue was purified by flash column chromatography (5-20% EtOAc/hexanes) to give 157 mg of pale orange oil (68% yield). LCMS-ESI* (m/z): [M+H]*calcd for C₂₄H₂₇O₆: 411.18; Found: 411.21.

Préparation of (4-methoxybenzyloxy)-(5-methoxy-3 -methyl-1trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid ethyl ester: A solution of (1 16293

hvdrox>-‘'-Tnethoxy-3-methv' naphihaien-2-vl h4-rncthcxy-bcnzy !uxy i-acetic acid .Χν ! î ! ? γτϊ^ !> 78 mmeh m du hloromethane > 3 k ml i was _xi»u,ec, ir- t' under Ai i u the solution was added 2.(>-'ubdtnc il’ : ml. i aud U iflu anhydrnie <v ’ ml i and stirred at -78 ^CC L>r 2 5 hours baturated sodium bicarbonate < 3 mi. > was added and the réaction mixture was warmed to room température and diluted with dichloromethane. The dichloromethane was separated, the aqueous layer extracted with CH2CI2, and the combined organics dried over sodium sulfate and concentrated. The crude residue was purified by flash column chromatography to give the desired product (128 mg, 62% yield), LCMS-ESI* (m/z): [M+Na]* calcd for CislLsFjNaO^S: 565.11;Found: 565,23.

Préparation of [1 -(4-chlorophenyl)-5-methoxy-3-mcthylnaphthaIen-2yl]-(4methoxybenzyloxy)acetic acid ethyl ester: A solution of (4-methoxy-benzyloxy)-(5methoxy-3-methyl- l-trifluoromethanesulfonyloxy-naphthalen-2-yI)-acetic acid ethyl ester (128 mg, 0.236 mmol), 4-chlorophenylboronic acid (74 mg, 2 equiv), EtOH (0.5 mL), K2CO3 (2 M, 0.5 mL), and toluene (1.3 mL) were degassed with argon atroom température in a Schlenk tube. Pd(dppf)Cl₂ was then added (17 mg) and the tube sealed. The reaction was heated to 60 °C for 14 hours. Analysis of the reaction mixture by LCMS showed 40% conversion, with visual analysis showing significant amount of palladium black. The crude mixture was fîltered via syringe through a microfilter into a new sealable tube charged with Pd(PPh₃)4. The tube was sealed and heated to 100 “C for 16 hours. The reaction was cooled to room température, diluted with EtOAc and fîltered through Celite. The filtrate was concentrated, and the crude residue purified by flash column chromatography to give the desired product (60 mg, 50% yield). LCMS-ESI* (m/z): [M+Na]* calcd for C₃oH₂9ClNa0₅: 527.99; Found: 527.44.

Préparation of [l-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]hydroxy-acetic acid ethyl ester: To a solution of [l-(4-chioro-phenyl)-5-methoxy-3methyl-naphthalen-2-yl]-(4-methoxy-benzyloxy)-acetic acid ethyl ester (58 mg, 0.115 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (58 pL). The reaction mixture was stirred for 2 h at room température and then quenched carefully with sat. NaHCO₃. The aqueous layer was extracted with dichloromethane twice, and then the combined organic layers were washed with water, dried (Na₂SO4), concentrated and purified by flash column chromatography to give desired (23 mg).

P’-cparation cf ten-butoxy-l l -(4-chloro-pher.yli-5-methovv-.'-methylnaph’haier nw acid ethsl ester 4 solution o! H -<4-chl.»n»-phen\l»->-methoxx '-me’-fnÎ-naphlha cr-2 vil-hvdroxy-atetK .und ethyl ester ?’* ιτψ! and pcnhloru acid. 70®o G u[ lin len-Gn i acetate ( l mi i was stirred at nx>m température for 2 h -Xfier 2 h. the reaction had apparently slaiied, so 3 pL additional perchlonc acid was added. After Z additional bours. no further conversion was observed (LCMS analysis). Saturated sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate (3x). The combined organic layer was dried (Na₂S()4), and concentrated. The crude mixture was purified by flash column chromatography to give tert-butoxy[l-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-acetic acid ethyl ester (9 mg) plus 7 mg of recovered starting material. The recovered starting material was resubjected to similar reaction conditions to yield an additional 3 mg of desired. ’H-NMR: 400 MHz, (CDC1₃) δ: 8.10 (s, IH), 7.39-7.48 (m, 3H), 7.25 (s, IH), 7.17 (app t, IH), 6.78 (app t, 2H), 5.09 (s, IH), 4.06-4.20 (m, 2H), 3.99 (s, 3H), 2.61 (s, 3H), 1.185 (ζ3Η), 0.98 (s,9H).

Préparation of tert-butoxy-[i-(4-chlorophenyl)-5-methoxy-3-methylnaphthalen-2-yl]-acetic acid (34): To a solution of teit-butoxy-[l-(4-chloro-phenyl)-5methoxy-3-methyl-naphthalen-2-yl]-acetic acid ethyl ester (12 mg) in THF (0.3 mL) and EtOH (0.1 mL) was added 0.1 mL of 1 M LiOH. The réaction was stirred for 30 min at room température, then 0.3 mL each of THF, EtOH, and 1 M NaOH were added. The reaction was heated to 70 °C for 2.5 hours, and then cooled to room température. Formic acid was added until pH ~ 5. The reaction mixture was directly purified by HPLC (Gemini, 50-100% McCN/TLO. with 0.1% TFA). The product was lyophilized to give a white powder (8 mg).

’H-NMR: 400 MHz, (CD₃CN) δ: 8.09 (s, IH), 7.49-7.58 (m, 3H), 7.32 (br d, IH), 7.26 (app t, IH), 6.91 (d, IH), 6.81 (d, IH), 5.19(s, IH),3.99 (s, 3H), 2.57 (s, 3H), 0.99 (s, 9H). LCMS-ESI⁺ (m/z): [M-OtBuf calcd for C₂₀Hi₆ClO₃: 339.79; Found: 339.07.

Example 33. Ethyl 2-(5-bromo-3-methyl-l-(trifluoromethylsulfonyl-oxy) naphthalen2-yl)-2-(4-methoxybenzyloxy)acetate (35)

C

2il0

QTf OPMB x F O ethyl 2-i5'bromo-3-methyt-l -(((tnfluQrorneîryiJsurfonyltoxyjnaphthalen-Z-yl^((4-methaxyt)enzy^r>axy lacetate

Préparation of ethyl 2-(5-bromo-3-nierhyl-l-(tnfluoromethylsulfonyl· oxy)naphthalen-2-yl)-2-(4-methoxybenzyioxy)acetate (35): Ethyl 2-(5-bromo-3methyl-1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzy 1 oxy)acetate (35) was prepared similarly to ethyl 2-(6-methoxy-3-methyl-l(trifluoromethylsulfonyloxy)naphthalen-2-y])-2-(4-methoxybenzyloxy)acetate of Example 32, using l-(2-bromophenyl)propan-2-one as the starting material instead of l-(3-methoxyphenyl)propan-2-one. ’H-NMR: 400 MHz, (CDCI3) δ: 8.11 (s, IH), 8.01 (d, J = 8.8 Hz, IH), 7.85 (d, J = 7.6 Hz, IH), 7.40 (t, J — 7.6 Hz, IH), 7.23 (d, J = 8.4

Hz, 2H), 6.81 (d, J = 7.6 Hz, 2H), 5.61 (s, IH), 4.62 (q, 3-11.2 Hz, 2H), 4.26-4.15 (m, 2H), 3.75 (s, 3H), 2.62 (s, 3H), 1.18 (t, J = 6.8 Hz, 3H).

Example 34. Ethyl 2-(5-bromo-l-(4-chloropheiiyl)-3-methylnaphthalen-2-yl)-2oxoacetate (36A) and Ethyl 2-(l,5-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-215 oxoacetate (36B):

OTf o

-o .·’ ‘<ir *<rx ·O

Bf ethyi 2~(5-brofno-3-rT>ethyl-1d(tnftuorometnyl)sijifonyl)oxy)n aphttialen-2-y I )-2 -oxoacetaie

36A i4-cnforophenyi)boron>c acd

36B ethyl 2-(5-bromo-1-(4chlorophenyl)-3methylnaphthalen-2-yl)-2oxoacetate ethyl 2-(1,5-bis(4-chlorophenyl)-3methylnaphthalen-2-yl}-2-oxoacetate

Préparation of ethyl 2-(5-bromo-3-methyl-l-(trifluoromethylsulfonyloxy) naphthalen-2 yl)-2-oxoacetaie: Prepared sîmilarly to ethyl 2-(7-bromo-3-mcthyl-l(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate of Example 67, using ethyl

2-(5-bromo-3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4methoxybenzyloxy)acetate instead of ethyl 2-(7-bromo-3-methyl-l(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyioxy)acetate. '11NMR: 400 MHz, (CDC1₃) δ; 8.20 (s, IH), 8.08 (d, J = 8.4 Hz, IH), 7.95 (dd, J = 7.4,

0.8 Hz, IH), 7.48 (t, J = 8.4 Hz, IH), 4.42 (q, J = 7.2 Hz, 2H), 2.54 (s, 3H), 1.40 t, J = 10 7.6 Hz, 3H).

Préparation of ethyl 2-(5-bromo-l-(4-chloropheny])-3-methylnaphthalen-2-yl)-

2-oxoacetate (36A) and ethyl 2-(l,5-bîs(4-chlorophenyl)-3-niethylnaphthalen-2-yl)-2oxoacetate (36B): To a solution of ethyl 2-(5-bromo-3-methyl-l(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (1.2 g, 2.56 mmol) and 415 chlorophenylboronic acid (440 mg,. 2.81 mmol) in toluene was added 2 M potassium carbonate (2.8 mL, 5.63 mmol) and PdCl₂(dppf) (187 mg, 0.256 mmol) and the reaction was degassed with argon 10 minutes. The réaction was stirred at room température for

hours Ihe réaction csas filtered. dtluled with csaicr. extracted csith etbsl acetate and ..m-.entrared the crude réaction άοα puntie.i hs flash culurri: chrurnaloçraphs (sihca gel. ethsⁱ acetate hecanes t fi4lcwed bc reverse phase HH t’ (Gemini. 4d-ii)0% AGS H₂i > * 0 !% Γ E A r Product was hophilizcd to gtce 6⁷U mg of ethyl 2-i5-bromo5 !-(4-chlorophenyl)-3-methctnaphihalen-2-yl)-2-oxoacetate (36A) as a cellow oil. ’HNMR: 400 MHz,(CDCh)S: 8.20 (s, IH), 8.13 (d, J = 8.8 Hz, IH), 7.85 (d, J =6.8 Hz, IH), 7.68 (t, J = 7.2 Hz, IH), 7.51 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 3.95 (q, J = 6.8 Hz, 2H), 2.41 (s, 3H), 1.14 (t, J = 7.2 Hz, 5H); and 109 mg of ethyl 2-(l,5-bis(4chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (36B) as a white solid. ¹II-

NMR: 400 MHz, (CDC1₃) Ô: 7.72 (s, IH), 7.59-7.56 (m, IH), 7.50 (t, J = 8.0 Hz, 2H), 7.46-7.44 (m, 5H), 7.43 (d, J = 2.4 Hz, IH), 7.28 (d, J = 8.0 Hz, 2H), 3.94 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H).

Example 35. 2-(5-Bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tcrt15 butoxyacetic acid (37)

ethyl 2-(5-bromo-1-{4chlorophenyl)-3methylnaphttiaien-2-yl}2-(tert-butoxy)acetate

2-(5-bromo-1-(4chlorophenyl)-3methylnaphthalen-2-yl)-2· (tert-birtoxy)acetic acid

Préparation of ethyl 2-(5-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)20 2-tert-butoxyacetate: Prepared similarly to ethyl 2-(7-bromo-l-(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-tert-butoxyacetate of Example 67 using ethyl 2-(5-bromo-l(4-chlorophenyI)-3-methylnaphthalen-2-yl)-2-oxoacetate instead of ethyl 2-{7-bromo-

5(1 i !-(4-Λ.ΗΙν>τί iphcn^ > >-'-rïieÎri>înciphlhalen-2-’ih-2-i’ixoact'iaie Product was carried on rnidc^;t- ’»<·*» -eaction

Préparation of 2-(5 broino-l-i I-chlorophenj 11-‘-meihy Inaphthaler-? yh 2 tert butoxyacetic acid (37). Tu a solution of ethy! 2-<5-bromo-1 i4-chlorophenv] »-3methj lnaphthaIen-2-yl )-2-tert-butoxyacetate i30 mg. 0.061 mmol) in tetrahydrofuran: éthanol: water (2:2:1, 3 mL) was added lithium hydroxide (7 mg, 0.31 mmol) and the réaction was heated to 50 °C ovemight. Crude reaction purified by reverse phase HPLC (Gemini, 40-100% ACN/H2O + 0.1%TFA). Product lyophilized to give a white powder (5.9 mg). ’H-NMR: 400 MHz, (CD3OD) δ: 8.07 (s, 1H), 7.77 (d, J - 6.0 Hz, 1 H), 7.58 (s, 2H), 7.55 (as, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1 H), 7.18 (m, 1 H), 5.17 (s, 1 H), 2.67 (s, 3H), 0.99 (s, 9H). LCMS-ESI' (m/z): [ΜΗ]'calcd for C23H2_tBrC10₃:460.8; found; 460.2.

Example 36. 2-(l_}5-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (38)

2-(l,5-bis(4-chlorophenyI)-3-methylnaphthalcn-2-yl)-2-tert-butoxyacetic acid

Préparation of 2-(l,5-bis(4-chlorophenyl)-3-mcthylnaphthaJen-2-yl)-2-tertbutoxyacetîc acid (38): 2-(l,5-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tertbutoxyacetic acid (38) was prepared similarly to 2-(5-bromo-l-(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-tert-butoxyacetîc acid of Example 35 using ethyl 2-(1,5bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate instead of ethyl 2-(5bromo-l~(4-chlorophcnyl)-3-methyinaphthalen-2-yl)-2-oxoacetaÎe. ’H-NMR: 400

C

MHz. (CDR)D) rt- 7 ?9(m, 4Hi, J - 8.4 Hz. 2H 7.45 (d. J - 8 4 Hz. 2Hi, 7.35 m Wi. ' ?8»rr·. ÎH·. ^c ÎH i H >. 2 ⁱ i ; Tf i, ù <s 9rb I ( Ah tSi im.-r iMHj cakJ fort _;JbH I <> 4^î J X f_vQnij 4Qi 42

Exampie 37. 2-tert-Butoxy-2-( l-(4-chiorophcny!)-5-(3-(dimethylaniino)prop-l-ynyl )-

3-methylnaphthalen-2-yl)acetic acid (39)

ethyl 2-(5-bromo-1-(4chlorophenyl)-3methylnaphttiaten-2-yiy· 2-tert-butoxyacetate

C!

LiOH

THF/EtOH/water

2-ferPbLrtoxy-2-(1 -(4chloropheny1)-5-(3(dinriethylamino)prop-l -ynyl)-3methyinaphthalen-2-yl)acetic acid

Préparation of ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-5-(3(dimethylanuno)prop-l-ynyl)-3-methylnaphthalen-2-yl)acetate: To a solution of ethyl 2-(5-bromo-l-(4-chlorophenyl)-3-methybiaphthalen-2-yl)-2-tert-butoxyacetate (100 mg, 0.20 mmol) and N,N-dimethylprop-2-yn-l-amine (0.065 mL, 0.61 mmol) in

anhvdrous tetrahydroruran was added copper induit- ( 8 mg. V +4 mmol | and '^J1t ?-:PPb· >· < !- Tf a \>2 mmeif i be reaction heaied in ! i>J i <Tvern!ghî Aîter cooiing î-.i room température lhe réaction *a.s tharged w-iih PdCl.'i ΡΡΙυπι 14 mg. t) 02 τη·./ t. copper lodide (8 mg. 0 t)4 mmol t. \.N-dimethylprop-2-yn- l-amtne (0 065 mL.

0.6! mmol) and triethylamine fl mLj. The reaction was heated to 100 “C oc enughi.

To the reaction was then added N,N-dimethylprop-2-yn-l -amine (0.065 mL, 0.61 mmoÎ i and heated to 100 °C ovemight. The crude reaction mixture was absorbed onto silica gel and purified by flash column chromatography (silica gel, ethyl acetate/hexanes, methanol/ethyl acetate) to give a yellow oil (6.5 mg).

LCMS-ESf (m/z): [M+H]⁺calcd for C₃₀H_3sC1NO₃: 492.22; found: 492.15.

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-5-(3-(dimethylamino)prop-

1- ynyl)-3-methylnaphthalen-2-yl)acetic acid (39); To a solution of ethyl 2-tert-butoxy-

2- ( 1 -(4-chlorophenyl)-5-(3-(dimethyIamino)prop-1 -ynyI)-3-methylnaphthalen-2yl)acetate (6.5 mg, 0.013 mmol) in tetrahydrofuran:ethanol:water (2:2:1,4 mL) was added lithium hydroxide (2 mg, 0.066 mmol) and the reaction was heated to 50 °C ovemight. The reaction was purified by reverse phase HPLC (Gemini, 40-60% ACN/H₂O + 0.1% TFA). The product was lyophilized to give a white powder (1.2 mgVH-NMR: 400 MHz, (CD₃OD) δ: 8.14 (s, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.58 (s, 2H), 7.56 (as, 1H), 7.33 (m, 3H), 5.18 (s, 1H), 4.42 (s, 2H), 3.04 (s, 6H), 2.67 (s, 3H),

0.99 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C_2SH₃iC1NO₃; 464.19; found:

464.51.

Example 3ÎL 2-’.ert-Buk»xy-2-i l -i4-chjoR’phenyl)-V5-d!rnelh) înaphihalen-2-y! tarent

ethyl 2-(5-bromo-1-(4chlorophenyl)-3methylnaphthalen-2-yl)-2-(tertbutoxy)acetate

2.4.5-trifnethyl1,3,5,2,4,6trioxatnborinane

PdCI₂(dppf)

K₂CO₃totuene/ethanol

ethyl 2-(terf-butoxy)-2-{1-(4chlorophenyl)-3,5dimethylnaphthalen-2yl)acetate

LiOH

THF/EtOH/water

2-(tert-butoxy)-2-(1 -(4chlorophenyl)-3,5dimethylnaphthaien-2yljacetic acid

Préparation of ethyl 2-tert-butoxy-2-(l-(4-chIorophenyl)-3,5dimethylnaphthalen-2-yl)acciate: To a solution of ethyl 2-(5-bromo-l -(4chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (100 mg, 0.204 mmol) and 2,4,6-tnmethyM ,3,5,2,4,6-trioxatriborinane (0.086 mL, 0.61 mmol) in toluène :ethanol (2:1, 3 mL) and water (1 mL) was added potassium carbonate (282 mg,

2.04 mmol) and PdCLidppf) (15 mg, 0.02 mmol) and the reaction was degassed with argon for 10 minutes. The reaction was heated to 100 °C for 20 minutes in a microwave reactor. The crude réaction was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oîl (32 mg) ’H-NMR: 400 MHz, (CD3OD) Ô: 8.08-7.87 (m, 2H), 7.87 (s, IH), 7.65-7.35 (m, IH), 7.26 (m, 2H), 7.15 (d,

2(-7

J - 7.2 Hz. Ilit. 7 09 (d. .! - 8 0 Hz. HH 5 Iths. I H t. 4 H ,_m. 2H>. 2 64(.. 3H). 2 65 <> 'H> i 20(6 J MHz Μ.Κ'Α'βΝΗι

Préparation cl 2-tert-buti.>K\·?-< il·-V'-dimethxhiaph:haien-2xhacetjc and (40 > lu a solution of ethyl 2-tert-bu'oxy-2-( I -<4-chlorephenyl>-3.5dimethylnaphthalen-2-yi)acetate (32 mg. 0.075 mmol) in tetrahydrofuran;

éthanol:water (2:2:1. 3 mL) was added lithium hydroxide ^Q mg. 0.377 mmol) and the reaction was heated to 50 °C overnight. The réaction was purified by reverse phase HPLC (Gemini, 40-100% ACN/H2O + 0.1% TFA). The product was lyophilized to give a white powder (16.8 mg). ¹ H-NMR: 400 MHz, (CD3OD) δ: 7.86 (s, IH), 7.54 (m, 3Η), 7.29 (m, 2H), 7.16 (t, J = 8.8 Hz, 1Η), 7.08 (d, J= 8.8 Hz, 1H), 5.17 (s, 1H), 2.69 (s, 3H), 2.65 (s, 3H), 0.98 (s, 9H). LCMS-ESL (m/z)·. [M-H]’ calcd for C₂₄H₂4C10î: 395.15; found: 394.97.

Example 39. 2-tert-Butoxy-2-( ] -(4-chlorophenyl)-3-methyl-5-(pyrimidin-5yl)naphtbalen-2-yl)acetic acid (41)

2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-5 (pyrimidin-5-yl)naphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-5-(pyrimidin-5yl)naphthalen-2-yi)acetic acid (41): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyI-5(pyrimidm-5-yl)naphthalen-2-yl)acetic acid (41) was prepared similarly to 2-tertbutoxy-2-(l-(4-chlorophenyl)-3,5-dimethylnaphthalen-2-yl)acetic acid of Example 38 using pyrintidin-5-ylboronic acid in place of 2,4,6-trimethyl-1,3,5,2,4,6trioxatriborinane. ¹ H-NMR: 400 MHz, (CD3OD) δ: 9.27 (s, 1Η), 8.95 (s, 2H), 7.60 (s,

-HL ^π -=8 f'*. IHj. sq ï H L 7 43 im. 3Hi. 7 Vj td. J - 8.4 Hz. IHi. 5.29 ο. ίHj.

' ''' 'Ht ÎTüirs 9H₍ i ( MS Isl’<WI-t (M-Hl’L-ajfJ for ( -H>< iX.O. 46 J ! t~ h'und 46’ 45

Example 4Q. 2-tert Butoxy 2 (l-(4 chlorophenylf-ô-tluoro-3 methylnaph:haJen<yDacetic acid (42)

2-tert-butoxy-2-( 1 -(4-chloTophenyl)-6-fluoro-3methylnaphthalen-2-y])acetic acid

Préparation of 2-tert-butoxy-2-(l -(4-chloropbenyl)-6-fluoro-3methyInaphthalen-2-yl)acctic acid (42): 2-tert-Butoxy-2-(l-(4-chlorophenyi)-6-fIuoro-

3-methylnaphthalen-2-yl)acetic acid (42) was prepared similarly to 2-(5-bromo-l -(4chlorophcnyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid of Example 35, using 15 6-fluoro-3-methyl-3,4-dihydronaphthalen-1 (2H)-one instead of 5-bromo-3-methyl-3,4- dihydronaphthalen-I(2H)-one. ’H-NMR: 400 MHz, (CD3OD) δ: 7.67 (s, IH), 7.5⁷ (s, 2H), 7.55 (as, IH), 7.45 (dd, J = 9.8,2.8 Hz, IH), 7.32 (d, J = 8.4 Hz, IH), 7.27 (dd, J =

9.4, 5.2 Hz, IH), 7.11 (td, J = 9.0, 2.4 Hz, IH) 5.16 (s, IH), 2.60 (s, 3H), 0.98 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD3OD) δ: -118.01 (s). LCMS-EST (m/z): [M-Hpcalcd for

C2311_2IC1FO₃: 399.12; found: 399.19.

Example 41. 2-tert-butoxy-2-((R)-!-(2,3-dihydropyrano[4,3,2-de]quiiiolin-7-yl)-6fluoro-3-methylnaphthaIen-2-yl)acetic acid (43):

2-tert-butoxy-2-((R)-1 (2,3-dihydropyrano|4,3,2-de |qumolin-7-yl)-6-fluoro-3methylnaphthalen-2-yi)acetic acid

Préparation of 2-tert-butoxy-2-((R)-l-(2.3-dihydropyrano[4,3.2-dc]quinolin-7yl)-6-fluoro-3-methylnaphthaIen-2-y])acetic acid (43): 2-tert-Butoxy-2-((R)-l -(2,3dihydropyrano[4,3,2-de]qumoIin-7-yl)-6-fluoro-3-mcthylnaphthalen-2-y])acetic acid (43) was prepared similariy to 2-tert-butoxy-2-(l-(4-chlorophenyl)-6-fluoro-3methylnaphthalen-2-yl)acetic acid of Example 40 using l-(3-fluorophenyl)propan-2one instead of l-(2-bromophenyl)propan-2-onc and 2,3-dihydropyrano[4,3_>2de]quinolin-7-ylboronic acid instead of 4-chlorophenylboronic acid. 'iI-NMR: 400 MHz, (CD₃OD) S: 8.67 (d, J = 5.6 Hz, 1H), 7.93 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.59 (dd, J = 9.6, 2.8 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.07 (td, J =

9.2,2.8 Hz, 1H), 6.98 (m, IH), 5.21 (s, 1H), 4.71 (m, 2H), 3.64 (t, J - 6.0 Hz, 2H), 2.77 (s, 3H), 0.93 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD3OD) Ô: -l 16.92 (s). LCMS-ESf (m/z): [M+H]⁺calcd for C_2gH₂₇FNO₄: 460.18; found: 460.15.

Example 42. 2-tert-Butoxy-2-( 1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-

3-methyInaphthalen-2-yl)acetic acid (44).

Λ : ί

- *ien-but οχ y-_t : i -(2. ' -dihydropj rano’’4,3,2 de]qui.rM’I:n-?-\ ! r S - t'ui>rv-3rnethy Inaphlha’en- 2- \ l jacetit ac id

Préparation ut 2-tert-butoxv 2 < 1-(2.3 dihvdrop₃Tanv!4.?.2-de jqumolui-T-s l *-5-

i]uoro-3-rneÙiyÎnaplnhalen-2-y[)acet!t· acid (441 2-tert-Butoxv-24 1-(2.3dihydropyrano[4,3,2-de]quinolin-'^,-yj )-5-rluoro-3-methyinaphthalen-2-yl jacetic acid (44) was prepared similarly to 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano [4,3.2deJquinolin-7-yT)-6-fluoro-3-rriethylnaphthalcn-2-yl)acetic acid (43) using l-(2fluorophenyl)propan-2-one instead of l-(3-fluorophenyl)propan-2-one. 'H-NMR: 400 MHz, (CD3OD) δ: 8.68 (d, J = 5.6 Hz, IH), 8.56 (d, J = 5.2 Hz, IH), 8.10 (s, IH), 7.78 (d, J = 5.6 Hz, IH), 7.43 m, IH), 7.19 (m, 2H), 6.73 (M, IH), 5.23 (s, IH), 4.67 (m, 2H), 3.57 (t, J = 5.6 Hz, 2H), 2.75 (s, 3H), 0.85 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD3OD) 5: -125.97 (t, J = 7.54 Hz). LCMS-ESF (m/z): [M-H]' calcd for Cis^FNC^: 458.18; found: 457.76.

Example 43. 2-tert-Butuxy-2-(5-chloro-1 -(4-chlorophenyi)-3 -methylnaphthalen-2yl)acetic acid (45).

2-tert-butoxy-2-(5-chloro-l-(4-ch]orophenyl)-3methylnaphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(5-chloro-l-(4-chlorophenyl)-3methylnaphthalen-2-yl)acetic acid (45): 2-tert-Butoxy-2-(5-chloro-l-(4-chlorophenyl)-

3-methylnaphthaIen-2-yl)acetic acid (45) was prepared similarly to 2-tert-butoxy-2-(l(4-chlorophenyl)-6-fluoro-3-methylnaphthalen-2-yl)acetic acid of Example 40 using 1(2-chlorophenyl)propan-2-one instead of l-(3-fluorophenyl)propan-2-one. 'H-NMR: 400 MHz, (CDC1₃) δ: 8.14 (s, IH), 7.64 (m, IH), 7.54 (m, 2H), 7.50 (d, J = 7.6 Hz,

ΐ H ). 7 2''3Ιί ). 5 2'î s. I Ut. 2.M <s. .'Hî. I Π3 (s. t I C.MS-F.SI <rn:i [M-H] vakd ior > '. Ji-.C!.t >. -il«. jQ found. 4: 500 fxampie 44 2-rert-HuToxy- '-ί ! -i4-< hloropheny| j-A-fluoro- i-rrïethvînaphthalen-2yllaceltc acid (46)

2-tert-butoxy-2-(l-(4-chlorophenyl)-5-fluoro-3methyInaphthalen-2-yi)acetic acid

Préparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-5-fliioro-3methylnaphthalen-2-yl)acetic acid (46): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-5-f!uoro3-methylnaphthaIen-2-yl)acetic acid (46) was prepared similarly to 2-tert-butoxy-2-(l(4-chlorophenyl)-6-fluoro-3-inethylnaphthalen-2-y])acetic acid of Example 40 using l(2-fluorophenyl)propan-2-one instead of l-(3-fluorophenyl)propan-2-one. ’H-NMR:

400 MHz, (CD₃0D) ô: 7.94 (s, 1 H), 7.59 (s, 2H), 7.57 (m, 1 H), 7.35 (d, J = 8.8 Hz, 1 h),

7.27 (m, lh), 7.16 (m, 1H), 7.07 (d, J = 8.8 Hz, 1H), 5.21 (s, 1H), 2.66 (s, 3H), 1.01 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD₃OD) 5: -126.85 (dd, J = 10.2, 5.3 Hz). LCMS-ESF (m/z): [M-H] calcd forC₂₃H₂iClFO₃: 399.12; found: 399.14.

Example 45. 2-tert-Butoxy-2-((R)-5-chloro-1 -(2,3 -dîhydropyrano[4,3,2-de]quînolîn-7yl)-3-methylnaphthalen-2-yl)acctic acid (47)

2-tert-butoxy-2-((R)-5-chloro-1 -(2_;.3-dihydropyrano[4,3,2-deJquinolm-7-yl)-3methylnaphthalen-2-yl)acetic acîd

Préparation of 2-tert-butoxy-2-((R)-5-chloro-l-(2,3-dihydropyrano[4,3,2de]quinolÎn-7-yl)-3-methylnaphthalen-2-yl)acetic acid (47): 2-tcrt-Butoxy-2-((R)-5chloro-1 -(2,3 -dihydropyrano[4,3,2-de]quinolin-7-y l)-3 -methylnaphthaIen-2-yl)acetîc acid (47) was prepared similarly to 2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-6-fluoro-3-methylnaphthalen-2-yl)acetic acid of Example 41 using 110 (2-chlorophenyl)propan-2-one instead of 1 -(3-fluorophenyl)propan-2-one.¹II-NMR: 400 MHz, (CD₃0D) δ: 8.65 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 5.2 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.19 (t, J =

8.4 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 5.24 (s, 1H), 4.70 (m, 2H), 3.61 (t, J = 6.0 Hz, 2H), 2.82 (s, 3H), 0.93 (s, 9H). LCMS-ESI' (m/z): [M-H]’ caicd for C28H25CINO4:

474.16; found: 474.08.

Example 46. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2yl)acetic acid (48)

·—SI

OTf OPMB	₄-cr>io.'Cjçne~v-ccron< aoc	OPMB
-S Λ- · ·	...< .0.		· - ⁰
h· >**,	0	ΡΛΡΡ-4^	: 1
Ό'		KjCCr	'₀ ⁰

ettiyt 2-(6-methoxy-3-methyl-'!(trif l u o rometh y Isutfon y le xy tnapu thaten-2-y 1)-2-(4methoxybenzyloxy)aceta*e ethyf 241-(4-chloraphenyl)-6-methoxy-3methylnaphthalen-2-yl)-2-((4methoxybenzyl)oxy)acetate

ethyl 2-(1~(4-chlorophenyl)-6methoxy-3methyÎnaphthalen-

2-y l)-2 -hydroxy acetate ethyl 2-(1 -(4-chlorophenyl)-6methoxy-5-(4-methoxybenzyl)-3methylnaphthalen-2-yl)-2hydroxyacetate perchtoric acid t-butylacetate

LiOH ethyl 2-(tert-butoxy)-241-(4chlorophenyl)-6-methoxy-3methylnaphthalen-2-yl)acetate

THF/EtOH/water

2-(tert-butoxy)-2-(1-(4ch1orophenyl)-6-methoxy-3methylnaphthalen-2-y[)acetic acid

Préparation of ethyl 2-(6-methoxy-3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate; Ethyl 2-(6-methoxy-3-methyl-l5 (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy) acetate was prepared similarly as the préparation of ethyl 2-(5-methoxy-3-methyl-l(trifluoromethylsulfonyloxy)naphthaIen-2-yl)-2-(4-methoxybenzyloxy)acetate of Example 32 using 6-methoxy-3-methyl-3₍4-dihydronaphthalen-l(2H)-one instead of 5-

methoxx ’» methyl·3.4-dihydronaphthaten-b2H)-onc H \MR 4(K; MHz. ;('IX i,> 5 79'' d. J 9? Hz îH) . ' is. IHi -'\·;1ίπι. ’Ήί.'ΐ-’ί·!-’ _'4 HL. 6 83 (d. j - K 8 Hz. 2Hl 5 57 (s. HL. 4 t>2-4 55 <m. 2Hl. 4 27-4 ! .· -m. 2H \. 3 < >. *H>. < (5. UH. ? * ' iv 'Hi ί I 8 it J - 6 8 Hz 'rib

Préparation of ethyl 2-( 1-(4^Η1θΓορ^πνΙρ6-Γτκ·!.ηοχν-'-πκΐ}Ίν1η3ρηΐ5Μ1εη-2yl)-2-(4-methoxybenzyloxy)acetate: To a solution of ethyl 2-i6-methcxy-3-methyl·](trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybeiizyl-cxy lacetaie (100 mg, 0.184 mmol) and 4-chlorophenylboronic acid (58 mg, 0.37 mmol) in 1,2dimethoxyethane (2 mL) was added 2 M potassium carbonate (0.368 mL, 0.74 mmol) and Pd(PPh₃)4 (21 mg, 0,018 mmol) and the reaction was degassed for 15 minutes with argon. The mixture was heated to 120 “C for 20 minutes în a microwave reactor. The crude reaction was absorbed onto silica and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to produce a yellow oil (66 mg). ¹ H-NMR: 400 MHz, (CDCI3) δ: 7.58 (s, IH), 7.39 (dd, J = 8.2, 1.6 Hz, 1 H), 7.31-7.26 (m, 2H), 7.13-7.07 (m, 4H), 7.01 (dd, J = 8.2, 2.4 Hz, 1H), 6.94 (dd, J = 9.2, 2.8 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.77 (m, 1H), 4.50 (s, 1H), 4.42 (ABd, J = 11.2 Hz, 1H), 4.34 (ABd, J = 11.2 Hz, 1H), 4.20-4.15 (m, 2H), 3.91 (s, 3H), 3.81 (s, 3H), 2.60 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H).

Préparation of ethyl 2-(l-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2yI)-2-hydroxyacetate and ethyl 2-(l-(4-chlorophenyl)-6-methoxy-5-(4-methoxybenzyl)3-methylnaphthalen-2-yl)-2-hydroxyacetate: To a solution of ethyl 2-(1-(4chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate (185 mg, 0.37 mmol) in dichloromethane at 0 °C was added trifluoroacetic acid (0.185 mL, 2.4 mmol) and the reaction was allowed to warm to room température over 2 hours. The reaction was quenched with saturated sodium bicarbonate with active cooling, extracted with dichloromethane and concentrated. The crude reaction was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) and then further purified by reverse phase HPLC (Gemini, 20-100% ACN/H2O +0.1% TFA) to give the two products: ethyl 2-(l -(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2yl)-2-hydroxyacetate: 27 mg clear oil. LCMS-ESI* (m/z): [M+H- H₂O]* calcd for C22H19CIO3: 367.09; found: 367.05: and ethyl 2-(l-(4-chlorophenyl)-6-methoxy-5-(4mcthoxybenzyl)-3-methy!naphthalen-2-yl)-2-hydroxyacetate: 105 mg as a brown oil. LCMS-ESI* (m/z): [M+H-H₂O]*calcd for C3₀H₂₇C]O₄: 487.15; found: 486.90.

Préparation of ethyl 2 tert-butino-Z-i i -(4-thioropheri^li b-nicÜKixs-3· methv inaphthaïen- 2 > I iacetaie ! o a solution et et.h> ! J -< ; <4 chk»n>pbem 11 6mt'thox\’ '-melhxinaphthaien-l-v: i-2-hvdrox\ameute <2⁷ mg. 0 O⁷ mmob in len traîylacetaïe ί î if ml J was added Λ’% perchlonc acid fù ÙI2 ml . 0 14 mmoh and the reacîion was stirred at room température for l .5 hours Ihc reaction was quenched with solid sodium bicarbonate, water (2 mL) added and stirred l hour. The product was extracted with ethyl acetate, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a colorless oil (16.2 mg). *HNMR: 400 MHz, (CDCIj) δ: 7.48 (s, 1H), 7.41-7.36 (m, 3H), 7.19 (d, J = 6.4 Hz, 1H),

7.06 (d, J = 9.2 Hz, 1H), 6.99 (br s, 1H), 6.86 (d, J = 9.2 Hz, 1H), 5.00 (s, 1H), 4.124.02 (m, 2H), 3.82 (s, 3H), 2.52 (s, 3H), Ï.13 (t, J = 7.2 Hz, 3H), 0.91 (s, 9H).

Préparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-6-methoxy-3 methylnaphthalen-2-yI)acetic acid (48): To a solution of ethyl 2-tert-butoxy-2-(l-(4chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)acetate (16.2 mg, 0.037 mmol) in tetrahydrofuramethanol:water (2:2:1, 2.5 mL) was added lithium hydroxide (4 mg, 0.183 mmol) and the reaction was heated at 50 °C overnight. The reaction was purified by reverse phase HPLC (Gemini, 20-90% ACN/H₂0 + 0.1%TFA) to give a white powder (12 mg). ’H-NMR: 400 MHz, (CD₃OD) δ: 7.60 (s, 1H), 7.55 (m, 3H), 7.30 (m, IH), 7.17 (d, J - 2.8 Hz, 1H), 7.13 (d, J-9.6 Hz, 1H), 6.94 (dd, J = 9.2, 2.8 Hz, 1H),

5,15 (s, 1H), 3.90 (s, 3H), 2.58 (s, 3H), 0.98 (s, 9H). LCMS-EST (m/z); (M-H]'calcd for C24H34CIO4: 411.14; found: 411.14.

Example 47. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-6-methoxy-5-(4-methoxybenzyl)-3methylnaphthalen-2-yl)acetic acid (49)

2-icrt-butoxy-2-(l-(4-ch]orophenyl)-6-methoxy-5-(4-mcthoxybenzyl)-3mcthylnaphthalcn-2-y])acetic acid

Préparation of 2-tcrt-butoxy-2-( 1 -(4-chlorophenyl)-6-methoxy-5-(4methoxybenzyI)-3-methytnaphthalen-2-yl)acetic acid (49): 2-tert-Butoxy-2-(l-(4chlorophenyl)-6-methoxy-5-(4-methoxybenzyl)-3-niethylnaphthalen-2-yl)acetic acid (49) was prepared following the procedure for 2-tert-butoxy-2-(l-(4-ch]orophenyl)-6methoxy-3-methylnaphthalen-2-yl)acetic acid of Example 46 using ethyl 2-(1-(4chlorophenyl)-6-methoxy-5-(4-mcÎhoxybenzyi)-3-raethylnaphthalen-2-yl)-2hydroxyacetate in place of ethyl 2-(l-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen2-yl)-2-hydroxyacetate. 'H-NMR: 400 MHz, (CD3OD) 5: 7.75 (s, 1H), 7.54 (m, 3H),

7.32 (d, J = 6.8 Hz, 1H), 7.22 (m, 2H), 7.07 (d, J - 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 5.12 (s, 1H), 4.38 (s, 2H), 3.90 (s, 3H), 3.72 (s, 3H), 2.52 (s, 3H), 0.97 (s, 9H). LCMS-ESI (m/z): [M-H]' calcd for C32H32CIO5: 531.20; found: 531.01.

Example 48. 6-Bromo-3-methyI-3,4-dihydronaphthalen-l(2H)-one (50)

Br ' ’ ' [k ' 50

4H 3-txornopheny l y 3methylbutanoc ac,d e-bromo-S-methy^Adihydronaphthalen1(2H)-one

Préparation of 6-bromo-3-methyl-3,4-dihydronaphthalen-](2H)-one (50): A flask was charged with trifluoromethane sulfonic acid (450 g, 3 mol) and cooled to 0 °C with an ice-water bath. 4-(3-bromophenyl)-3-methylbutanoic acid, prepared in a similar manner as described in Example 32 (15.5 g, 60 mmol), was added as a solution in DCM (30 mL) siowly to produce a clear dark brown solution. After 15 min, the reaction was diluted with 500 mL of CHCI3 and poured siowly onto approximately 1 L of crushed ice. The resulting slurry was allowed to stir until the solution waims to room température and became biphasic. Following séparation of layers, the aqueous layer was extracted with CHCI3. The combined organics were washed with brine and dried over anhydrous MgSOi prior to concentration in vacuo. Purification via Isco column chromatography (50% DCM/hex isocratic) provided a quantitative yield of the named compound as a pale yellow amorphous solid. LCMS-ESI* (m/z): [M]⁺ calcd for CnHuBiO: 239.11; found: 239.20.

Example 49. 7-Bromo-3-methyl-3,4-dihydronaphthalen-l(2H)-one (51).

O	O
	- ΎΛ
4-(4-bromophenyl)-3methylbutanoic acid	51 7-bromo-3-methyl-3,4dihydronaphthalen-1 (2H)-one

Préparation of 7-bromo-3-methyl-3,4-dihydronaphthalen-l(2H)-one (51): A solution of 4-(4-bromophenyl)-3-methylbutanoic acid, prepared in a similar manner as described in Exampïe 32 (6.43 g, 25.0 mmol), in H2SO4 (25 mL) was stirred at 75 °C for 3 h. The mixture was siowly poured onto ice. The resulting slurry was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried,

✓!

filtered. and consentiated in mJluu The <.rudc nidienal v>æ, purified bs coinmn cbruina:i’graphy U iOAl hexanes: w 5 74 g uî the ntic zompound H xMK 4îk; MHz. i(TK h j ό 8 10(J. J - 'Hz. ’Ht. ⁷ 54 tdd. J - 8. 2 Hz. I Hi. ? ii (d.

J - 8 Hz. iH». 2 9] (d. J - 16 Hz). 2 71 (dJ ’ I 3 Hz). 2.58 (m. IHi. 2 28 (m. 2H L ! 12 d. J =6 Hz. 3H :

Example 5 6 ' 6 B π >mo -^c -i 4 < hl orophe γλ l r 7- metb > ; naphthalen - 2 yïc-xy = 52 i

OTf ^fi<c

4-CtPhBiOHî,

6 0· t-txjtyt

P> raine Mço

OCM

Pdi PPh-jU

MeC

6-metnoxy-3methy»-3 4dihydrOGaptithater1(2/7}-one

6-methoxy-3-methy 1-3,4dihydronaphthalen-1-yl trifluorornethanesulfonate

2-bromo-1-(4chlorophenyl)-6-rnethoxy3-methylnaphthalene

4-(4-chlorophenyl)-7mettioxy-2-methyl-1,2dihydronaphthalene

3-bromo-4-{4chlorophenyl)-7methoxy-2-methyl-1,2dihydronaphthalene

chlorophenyl)-7methylnaphthaten-2-ol (6-bromo-5-(4chlorophenyl)-7methylnaphthalen-2yloxy)tnisopropylsilane

Préparation of (6-bromo-5-(4-chJorophenvl)-7-methylnaphthalen-25 yloxy)triisopropylsilane (52):

Step 1: Préparation of 6-mcthoxy-3-mcthyl-3,4-dihydronaphthalen-l-yl trifluoromethanesulfonate: To a solution of 6-methoxy-3-methyl-3,4dihydronaphthalen-l(2H)-one (10.06 g, 53 mmol; prepared similarly to 6-bromo-3methyl-3,4-dihydronaphthalen-l(2H)-one (50) of Example 48 beginning with l-(310 methoxyphenyl)propan-2-one), cooled to 0 °C was added 2,6-di-ierr-butyl-4methylpyridine (19.6 g, 95.4 mmol) followed by trifluoromethanesulfonic anhydride

ï ?,3 mL, /9.4 mnii’ll Ihe resulung x>Îirtmr. «as alfoweJ t:; warm slowiv io rc>om ’emperamrc over : ' h and toen quenched b·. addition . ί ’ Μ H< Ί ί ΐόό pil.l. ruilowmg séparation, the aqueous layer «as extracted wp.h I.K M <3 X IW mLï and the combined organics washed with bnnc. Following concentration in vûcue. the residue was taken up in hexanes. The resulting ptecipitated soiids were removed via filtration and the mother liquor was dried over anhydrous MgSCh and then concentrated in vacuo. The resulting residue was purified by Yamazen cohimn chromatography (3% to 35% EtOAc/Hex) to produce 9.88 g (57%) of the title compound as a colorless syrup. *H-NMR: 400 MHz, (CDCfj) Ô: 7.28 (s, IH); 6.75 (m, 2H); 5.74 (d, J = 4 Hz, IH); 3.82 (s, 3H); 2.77 (m, IH) 2.89 (dd, J = 15.2,10 Hz; IH); 2.61 (dd, J= 15.2,10 Hz; IH);

1.14 (d, J =7.2 Hz, 3H).

Step 2: Préparation of 4-(4-chlorophenvl)-7-mcthoxy-2-methy 1-1.2dihydronaphthalene: 6-methoxy-3 -methyl-3,4-dihydronaphthalen-1 -yl trifluoromethanesulfonate (9.88 g, 30.7 mmol), 4-chlorophenylboronic acid (6.23 g, 39.9 mmol) and K2CO3 (12.7 g, 91.9 mmol) were combined in a mixture of toluene/ethanol/water (80 mL/40 mL/40 mL) at room température in a heavy walled pressure flask. Following spargjng of the mixture with Ar for 30 minutes, PdCF/dppf) (1.12 g, 1.53 mmol) was added in one portion and the flask was sealed and heated to 50 °C for 2.5 h. After retuming to room température, the layers were separated and the aqueous layer was extracted with EtOAc and Hex (2 X 50 mL each). The combined organics were washed with brine, filtered through a pad of Celite, and dried over anhydrous MgSO4. The resulting solution was absorbed on silica gel in vacuo and purified via Yamazen column chromatography (0-15% EtOAc/Hex) to provide 7.7 g (88%) of the title compound as an amorphous white solid. ^-NMR: 400 MHz, (CDCI3) S: 7.32 (d, J = 8 Hz, 2H); 7.26 (d, J = 8Hz, 2H); 6.87 (d, J = 8.4 Hz, IH); 6.57 (d, J = 2.8 Hz, IH); 6.62 (dd, J = 8.4,2.8 Hz, 1 H); 5.74 (d, J = 2.8 Hz, 1 H); 3.79 (s, 3H); 2.81 (ABq, J = 20.8, 12.4 Hz, IH); 2.60 (m, IH); 2.59 (ABq, J = 8.4, 2.8 Hz, IH);

1.14 (d, J = 6.4 Hz, 3H).

Step 3: Préparation of 3-bromo^4-(4-chlorophenyl)-7-methoxy-2-methyl-l,2dihydronaphthalene: A solution of 4-(4-chlorophcnyl)-7-mcthoxy-2-methyl-1,2dihydronaphthalene (5 g, 17.6 mmol) in DCM (120 mL) was cooled in an ice-water bath prior to addition of solid pyridinium perbromide (6.2 g, 19.3 mmol) in one portion. The dark blue solution was allowed to stir for 30 min and was quenched by addition of

saturated Na’S+J; : 2îhj m! .1. Ihc icauüt.»!: ^as fùrther diluted vmh water and LX M beîore séparation and extraction ot the aqueoas ia^er wnh [XM The combined pirik organio ^crt washed with bnnr and dned oser anhvdrous Mebth t jiicuag filtration and concentration in vacuo. the resulting residue was purified bs Yamazen > cojumn chromatography tu-10% EtOAc 1 lex i to afford 5.5 g < 86%) et the tiîle cornpound as an orange colored gel. LCMS-ESI* (m/z): [M-f-H]⁺ calcd for CigHpBrClO: 364.68; found: 364.89.

Step 4: Préparation of 2-bromo-l-(4-chlorophenyl)-6-methoxy-3methylnaphthalene: A solution of 3-bromo-4-(4-chlorophenyl)-7-methoxy-2-methyl10 1,2-dihy dronaphlhalene (5.5 g, 15.1 mmol) in toluene (100 mL) was vacuum fiushed with Ar. DDQ (5.2 g, 22.7 mmol) was added and the mixture heated to reflux for 1.5 h. The heterogeneous red-brown mixture was cooled to room température and the toluene removed in vacuo. The resulting residue was taken up in DCM (300 mL) and filtered to remove precipitated DDHQ. The resulting mother liquor was absorbed on silica gel and purified by Yamazen column chromatography (15% DCM/Hex) to afford 5.21 g (95%) of the title cornpound as an amorphous yellow solid. ¹ II-NMR: 400 MHz, (CDC1₃) δ: 7.66 (s, 1H); 7.49 (br d, J = 2 Hz, 2H); 7.24-7.18 (m, 3H); 7.07 (d, J = 2 Hz, 1H); 6.97 (dd, J = 9.2,2 Hz, 1H); 3.91 (s, 3H); 2.60 (s, 3 H).

Step 5: Préparation of 6-bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2-ol: A vessel was charged with boron tribromide (1 M in DCM, 0.7 mL, 0.7 mmol) and cooled to -78 °C. 2-bromo-l-(4-chIorophenyl)-6-methoxy-3-methylnaphthalene (0.1 g, 0.28 mmol) was added as a solution in DCM (0.5 mL). The reaction was allowed to slowly warm to room température over 3.5 h. This procedure was repeated twice on a scale of 1 gand 4.1 gof2-bromo-l-(4-chlorophenyl)-6-methoxy-3-methylnaphthalenewith appropriate adjustments in the scale of other reagents. The three lots were combined, cooled to 0 °C and the volume of the reaction was slowly doubled with MeOH. After warming to room température, the mixture was concentrated in vacuo and the residue was taken up in EtOAc (150 mL), treated with saturated NalICO; (150 mL) and then small portions of solid NaHCO₃ untïl the solution was pH ~ 7. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (5-25%

222

EtOAc/Hex) to afford 4.54 g (91%) of the tille compound as a coloriess syrup. LCMSESf (Wz): [M+Hf calcd for C₁₇Hi₃BrC10: 348.64; found: 348.79.

Step 6: Préparation of (6-bromo-5-(4-€hlorophenyl)-7-methylnaphthalen-2yloxy)triisopropylsilane (52): 6-Bromo-5-(4-chlorophenyl)-7-methyInaphthalen-2-ol (4.5 g, 12.9 mmol) was taken up in DCM (65 mL). Added to this solution were TIPSCl (4.1 mL, 19.4 mmol), DBU (3.5 mL, 23.2 mmol), andDMAP (0.16 g, 1.3 mmol). After stirring at room température ovemîght, the DCM was removed in vacuo and the residue taken up in hexane (200 mL). This solution was washed with 1 M HCl (100 mL) and the layers separated. Following extraction of the aqueous layer with hexanes, the combined organics were washed with brine, dried over anhydrous MgSCU and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (2-5% DCM/Hex) to afford 5.12 g (79%) of the tille compound as a coloriess syrup. ’H-NMR: 400 MHz, (CDC1₃) Ô: 7.61 (s, IH); 7.49 (br d, J = 8.4 Hz, 2H); 7.23 (br d, J = 8.4 Hz, 2H); 7.17 (d, J = 8.8 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H); 6.95 (dd, J = 8.8, 2.4 Hz; IH); 2.60 (s, 3H); 1.30 (hep, J = 7.2 Hz, 3H); 1.12 (d, J = 7.2 Hz, 18H).

223

Example 51. (S)-2-tcrt-Butoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(pyridin-4yl)naphthalen-2-yl)acetic acid (53)

1)TBAF

2) PhNTf₂

K₂CC>3 ((6-bromo-5-(4chlorophenylÿ-7methylnaphthalen-2yl)oxy)triisopropyisi!ane ethyl 2-(1-(4-chkxopbienyl)-3-methyl-6((triisopropylsilyl)axy)napWiaien-2-yi)-2oxoacetate

tBuOAc

HCiO₄ ethyl 2-(1-(4etilorophenyl)-3-methyl-6(((trifluoromethyl)sulfonyl) oxy)naphthaien-2-yi)-2oxoacetate (S)-ethyl 2-(1-(4chlorophenyl)-3-methyl-6· (trifluoromettiylsulfonylaxy ) naphthaten-2-yl}-2hycfroxy acetate

( S)-2-(tert-butoxy )-2-( 1 (4chlorophenyÎ)-3-metfiyl-6-(pyridin-4yl)naphthalen-2-yl)acetic acid

Step 1: Préparation of ethyl 2-(l-(4-chlorophenyl)-3-methyl-6-(triisopropyl5 silyloxy)naphthalen-2-yl)-2-oxoacetate: To a solution of (6-bromo-5-(4-chlorophenyl)7-methylnaphthaIen-2-yloxy)triisopropylsilane (2.5 g, 4.9 mmol) in THF (50 mL) cooled to -78 °C was added w-BuLi (1.6 M in hexanes, 4.6 mL, 7.4 mmol) dropwise.

224

The resulting solution was allowed to stir at -78 °C for 30 min before addition of diethyl oxalate (l .7 mL, 12.4 mmol). After 45 min at -78 °C, the cold bath was removed and the reaction allowed to warm to room température over 1 h. 5% citric acid (50 mL) solution was added and the layers separated. Following extraction with EtOAc, the combined organics were washed with brinc, dried over anhydrous MgSÛ4 and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (0-10% EtOAc/Hex) to afford 2.10 g (81 %) of the title compound as a colorless syrup. LCMS-ESf (m/z): [M+H]⁺calcd for CjoHîgClOiSi: 526.16; found: 526.89.

Step 2: Préparation of ethyl 2-(l-(4-chlorophenyl)-3-methyl-6(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate: To a solution of ethyl 2-(l(4-chlorophenyl)-3-methyl-6-(triisopropylsîlyloxy)naphtha]en-2-yl)-2-oxoacetate (5.11 g, 9.7 mmol) in THF (25 mL) cooled to 0 °C was added TBAF (1 M in THF, 10.7 mL,

10.7 mmol). After 15 min, a solution of ïV-Phenyl-bis(trifluoromethane-sulfonimide) (5.2 g, 14.6 mmol) in THF (20 mL) was added to produce a clear yellow solution. Solid potassium carbonate (2.7 g, 19.4 mmol) was added and the cold bath removed. After 4 h at room température, the reaction was diluted with EtOAc and 1 M NaOH (100 mL each) and shaken vigorously for 5 min. The layers were separated and the aqueous extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (0-20% EtOAc/Hex) to produce 3.12 g (64%) as an amorphous pale yellow solid. ’ll-NMR: 400 MHz, (CDCI3) δ: 7.80 (s, IH); 7.76 (d, J = 2.4 Hz, IH); 7.67 (d, J = 9.6 Hz, IH); 7.48 (br d, J = 8.4 Hz, 2H); 7.30 (dd, J = 9.6,

2.4 Hz, IH); 7.25 (br d, J = 8.4 Hz, 2H); 3.95 (q, J = 7.2 Hz, 2H); 2.53 (s, 3H); 1.15 (t, J = 7.2 Hz, 3 H).

Step 3: Préparation of (S)-ethyl 2-(l-(4-chlorophenyl)-3-niethyl-6(trifluoromethylsulfonyloxy)naphthaien-2-yl)-2-hydroxyacetate: To a solution of ethyl 2-(l-(4-chIorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphÎhalen-2-yl)-2oxoacetate (1 g, 2 mmol) and (R)-(+)-2-methyl-CBS-oxazaborolidine (0.11 g, 0.4 mmol) in toluene (7 mL) cooled to -20 °C was added a solution of freshly distilled catecholborane (0.29 mL, 2.6 mmol) in toluene (3 mL). After 3 h, saturated Na₂CO₃(10 mL) was added, the mixture allowed to warm to room température and the layers separated. Following extraction with EtOAc, the combined organic layers were washed

225 with additional saturated Na₂CO₃ (l 5 mL portions) until the washing was no longer colored and then once with saturated NH4CI (15 mL). After drying over anhydrous MgSO₄, the solution was absorbed onto silica gel in vacuo and purified by Yamazen column chromatography (10-65% EtOAc/Hex) to afford 0.61 g (61%, 98% ee) ofthe title compound as a colorless amorphous solid. ’H-NMR: 400 MHz, (CDCI3) δ: 7.72 (s, 1H); 7.69 (d, J = 2.4 Hz, 1H); 7.50 (m, 2H); 7.37 (d, J = 9.2 Hz, IH); 7.30 (m, 2H);

7.19 (dd, J = 9.2, 2.4 Hz, 1H); 5.21 (d, J = 2 Hz, 1H); 4.21 (m, 2H); 3.25 (d, J = 2 Hz, 1H); 2.53 (s, 3H); 1.22 (t, J = 7.2 Hz, 3H).

Step 4: Préparation of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyI)-3-methyl-

6-(trifluoromethylsulfonyloxy)naphtha]en-2-yI)acetate: Perchloric acid (70%, 0.28 mL,

3.2 mmol) was added to a solution of (S)-ethyl 2-(l-(4-chlorophenyl)-3-methyl-6(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate (0.82 g, 1.6 mmol) in /ert-butyl acetate (5 mL) at room température. After 3 h, solid NaHCO₃ was added and the sluny stirred vigorously for 30 min. Saturated NaHCO₃ was added slowly until the mixture was pH ~ 8. Following extraction ofthe organic layer with EtOAc, the combined organics were washed with brine, dried over anhydrous MgSÛ4 and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (0-35% EtOAc/Hex) to produce 0.52 g (57%) ofthe title compound as an amorphous solid. ’H-NMR: 400 MHz, (CDCI3) Ô: 7.69 (s, 1H); 7.66 (d, J = 2.4 Hz, 1H); 7.51 (m, 2H); 7.44 (m, 1H); 7.34 (d, J = 9.4 Hz, 1H); 7.27 (m, 1H); 7.15 (dd, J =

9.4, 2.4 Hz, 1H); 5.12 (s, 1H); 4.17 (m, 2H); 2.63 (s, 3H); 1.23 (t, J = 7.2 Hz, 3H); 1.01 (s, 9H).

Step 5: Préparation of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-

6-(pyridin-4-yl)naphthalen-2-yl)acetate: A solution of (S)-ethyl 2-tert-butoxy-2-(l-(4chlorophenyl)-3-methyI-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (0.060 g, 0.11 mmol), pyridin-4-ylboronic acid (0.020 g, 0.16 mmol), and Pd(PPh₃)₄ (0.012 g, 0.011 mmol) in DME (1 mL) was treated with 2 M K.2CO3 (0.16 mL, 0.32 mmol) and sparged with Ar for 10 min. Following microwave heating at 110 °C for 20 min, the reaction mixture was absorbed onto silica gel in vacuo and purified by Yamazen column chromatography (15-100% EtOAc/Hex) to afford 0.043 g (82%) as a colorless glass. LCMS-ESI* (m/z): [M+H]* calcd for C30H31CINO3: 488.20; found: 488.70.

Step 6: Préparation of(S)-2-tert-butoxy-2-(I-(4-chlorophenyl)-3-methyl-6(pyridin-4-yl)naphthalen-2-yl)acetic acid (53): A solution (S)-ethyl 2-tert-butoxy-2-(l-

226 (4-chlorophenyI)-3-methyl-6-(pyridm-4-yl)naphthalen-2-yl)acetate (0.043 g, 0.088 mmol) in THF/MeOH/H₂O (l mL each) was treated with LiOH’HoO (0.025 g, 0.59 mmol) and heated to 50 °C overnight The resulting solution was diluted with DMF and purified by preparatory reverse phase HPLC (Gemini column, 15 to 100% MeCN/H2O, 0.1% TFA). Lyophilization of appropriate fractions afforded 0.021 g of 53 as an off-white amorphous powder. ’H-NMR: 400 MHz, (CD₃CN) δ: 8.77 (br s, 2H); 8.37 (br s, IH); 8.17 (br s, 2H); 7.91 (s, IH); 7.76 (dd, J = 8.8,2.4 Hz, IH); 7.627.54 (m, 3 H); 7.46 (d, J = 8.8 Hz, 1 H); 7.38 (br d, J = 8.8 Hz, IH); 5.25 (s, IH); 2.61 (s, 3H); 0.99 (s, 9H). LCMS-ESF (m/z): [2M-H]'calcd for C₅₆H_S1C1₂N₂O₆; 917.31; found:

917.51.

Example 52. (S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-(pyridin-3 yl)naphthalen-2-yl)acetic acid (54)

(S)-2-(tert-butoxy}-2-(1-(4-chlorophenyl)-3-methyl-6 -(pyridin-3-yi)naphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyI-6-(pyridin-3yl)naphthalen-2-yI)acetic acid (54): (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-

6-(pyridin-3-yl)naphthalen-2-yl)acetic acid (54) was prepared in a similar fashion to compound 53 of Exampie 51 with the substitution of pyridin-3-ylboronic acid for pyridin-4-ylboronic acid in step 5. The title compound (0,024 g) was isolated as an amorphous white powder. LCMS-ESI' (m/z): [2M-H]‘ calcd for Cs^H^CLN^Of,: 917.31; found: 917.39. ’H-NMR: 400 MHz, (CD₃CN) δ: 9.08 (s, IH); 8.74 (d, J - 5.2 Hz, 1H),

8.61 (d, J = 8 Hz, IH); 8.19 (s, IH); 7.93-7.88 (m, IH); 7.84 (s, IH); 7.66-7.53 (m, 4H);

7.44-7.35 (m, 2H); 5.24 (s, IH); 2.59 (s, 3H); 0.99 (s, 9H).

Example 53. (S)-2-tert-Butoxy-2-(l-(4-chIorophenyl)-3-methyl-6-

227 (pyrimidin-5-yl)naphthalen-2-yI)acetic acid (55):

(S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6(pyrimidin-5-yl)naphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6(pyrimidin-5-yl)naphthalen-2-yl)acetic acid (55): (S)-2-tert-butoxy-2-(l-(4chlorophenyl)-3-methyl-6-(pyrimidin-5-yl)naphtha]en-2-yl)acetic acid (55) was prepared in a similar fashion to compound 53 of Example 51 with the substitution of pyrimîdin-5-yIboronic acid for pyridm-4-ylboronic acid in step 5. The title compound (0.004 g) was isolated as an amorphous white powder. LCMS-ESI' (m/z): [2M-H]' calcd for C54H49CI2N4O6: 919.30; found: 919.76. *H-NMR: 400 MHz, (CD₃CN) 6: 9.16 (s, 1H); 9.12 (br s, 2H); 8.19 (br s, 1H); 7.85 (br s, 1H); 7.67 (dd. J = 9.2 H, 1.6 Hz, 1H); 7.61-7.54 (m, 3H); 7.43 (d, J = 9.2 Hz, 1H); 7.41-7.37 (m, 1H); 5.24 (s, 1H); 2.60 (s, 3H); 0.99 (s, 9H).

Examüle 54. (S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-( 1 H-pyrazol-5yl)naphthalen-2-yl)acetic acid (56):

(S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(lH-pyrazol-5-yl) naphthalen-2-yl)acetic acid

228

Préparation of (S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-(l H-pyrazol-

5-yi)naphthalcn-2-yI)acetic acid (56): (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3methyl-6-(lH-pyrazol-5-yl)naphthalen-2-yl)acetic acid (56) was prepared in a similar fashion to compound 53 of Example 51 with the substitution of 1 H-pyrazol-5-ylboromc acid for pyridin-4-ylboronic acid in step 5. The title compound (0.004 g) was isolated as an amorphous white powder. LCMS-ESI' (m/z): [2M-H]' calcd for C52H49CI2N4O6: 895.30; found: 895.45. 'Η-NMR; 400 MHz, (CD₃CN) δ: 8.23 (br s, 1H); 7.93 (d, J -

9.6 Hz, 1H); 7.79 (s, IH); 7.68 (s, 1H); 7.61-7.53 (m, 3H); 7.40-7.35 (m, 1H); 7.30 (d, J = 9.6 Hz, 1 H); 6.78 (s, 1H); 5.22 (s, 1H); 2.57 (s, 3H); 0.99 (s, 9H).

Example 55. (S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3-methyl-6-( 1 H-pyrazoI-4yl)naphthalen-2-yl)acetic acid (57)

OH (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-6-(l H-pyrazol-4-yl) naphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-6-(lH-pyrazol-

4-yl)naphthalen-2-yI)acetic acid (57): (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3methyl-6-(lH-pyrazol-4-yl)naphthalen-2-yl)acetic acid (57) was prepared in a similar fashion to compound 53 of Example 51 with the substitution of 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole for pyridin-4-ylboromc acid in step 5. The title compound (0.004 g) was isolated as an amorphous white powder. LCMS-ESI* (m/z): [M+H]*calcd for CbJbôClN’Oy 449.95; found: 449.57. *H-NMR: 400 MHz, (CD₃CN) δ: 8.03 (br s, 2H); 8.00 (br s, 1H); 7.71 (s, 1H); 7.59-7.52 (m, 4H); 7.38-7.34 (m, 1H); 7.26 (d, J = 9.6 Hz, 1H); 5.20 (1H); 2.56 (3H); 0.98 (s, 9H).

229

Examnle 56. 2-tert-Butoxy-2-(l-(4-ch]orophenyl)-3,6-dÎmethylnaphthalen-2-yI)acetic acid (58)

2-tert-butoxy-2-(l -(4-chlorophenyl)-3,6dimethylnaphthalen-2 vl)acetic acid

Préparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-3,6-dimethylnaphthalen-2yl)acetic acid (58): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3,6-dimethylnaphthalen-2yl)acetic acid (58) was prepared with a route similar to that described for compound 53 of Example 51 begiiming with 3,6-dimethyl-3,4-dihydronaphthalen-l(2II)-one (prepared from l-(3-œethylphenyl)propan-2-one) and omitting steps 5 and 6 of Example 50, and steps 2 and 5 of Example 51. Step 3 of Example 51 was replaced by treatment with NaBIL in EtOH at room température to afford racemic material. The title compound was isoiated (0.075 g) as a white amorphcus powder. LCMS-ESI' (m/z): [M-H]'calcd for C24H24CIO3: 395.14; found: 394.96. ’H-NMR: 400 MHz, (CDC1 3) δ: 7.69-7.61 (m, IH); 7.58 (s, IH); 7.54 (s, IH); 7.53-7.46 (m, 2H); 7.30-7.23 (m, IH); 7.21 (d, J = 8.4 Hz, IH); 7.14 (d, J = 8.4 Hz, IH); 5.27 (s, 2H); 2.56 (s, 3H); 2.48 (s, 3H); 1.01 (s,9H).

230

Example 57. (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-6-(pyrimidin-2yl)naphthalen-2-yl)acetic acid (59)

(S)-ettiyl 2-(fert-t>utoxy)-2-(1(4-chlorophenyl)-3-mettiyl-6(((trifluo^romethyÎ)sulfonyl)oxy )naphthalen-2-yl)acetate

(Sj-etfiyI 2-(tert-biitoxy)-2( 1 -{4-chloroplTenyl)-3methy 66-(4,4,5,5tetramethyl-1,3,2dioxaborolan-2yl)naphthalen-2-yl)acetate

chlorophenyl)-3-methyl6-{pyrimidin-2yl)naphthalen-2yljacetate (S)-2-(tert-butoxy)-2-(l -(4chlorophenyl)-3-methyl-6(pynmidin-2-yl)napMhalen2-yl)acetic acid

Step 1. Préparation of(S)-ethyl 2-tert-butoxy-2-(]-(4-chlorophenyl)-3-methyl-

6-(4_ï4_î5_t5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen~2-yl)acetate: A solution of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-niethyl-6-(trifluoroinethyIsulfonyloxy) naphthalen-2-yl)acetate (0.56 g, 1 mmol) în DME (6.5 mL ) was treated with bis(pinacolato)diboron (0.51 g, 2 mmol), potassium acetate (0.20 g, 2 mmol) and PdCh(dppf) (0.073 g, 0.1 mmol) and sparged with Ar for 10 min. After heating at 100 °C în a sealed vessel for 3 h, the mixture was allowed to cool to room température and absorbed onto silica gel in vacuo. Purification by Yamazen column chromatography

231 (2-35% EtOAc/Hex) produced 0.46 g (85%) of the title compound as a coloriess oil that was contaminated with a small amount of pinacol. The material was used in subséquent reactions without further purification. 'H-NMR; 400 MHz, (CDCf) δ: 8.28 (s, IH); 7.69 (s, IH); 7.63 (br d, J = 8.4 Hz, IH); 7.51-7.42 (m, 3H); 7.29-7.26 (m, IH);

7.22 (d, J = 8.4 Hz, IH); 5.13 (s, 1 H); 4.15 (m, 2H); 2.61 (s, 3H); 1.38 (s, 12H); 1.21 (t, J = 7.2 Hz, 3 H); 0.99 (s, 9H).

Step 2: Préparation of (S)-ethyl 2-tert-butoxY-2-(l-(4-chlorophenyl)-3 methyl6-(pyrimidin-2-yI)naphthalen-2-yl)acetate: (S)-Ethyl 2-tert-butoxy-2-(l-(4chlorophenyl)-3-methyI-6-(4,4,5,5-tetramethyl-l,3_t2-dioxaborolan-2-yl)naphthalen-2yl)acetate (0.072 g, 0.13 mmol), 2-bromopyrimidine (0.032 g, 0.20 mmol), PdCftdppf) (0.005 g, 0.007 mmol) were taken up in 3/1 PhMe/EtOH (1 mL). The resulting solution was treated with 2 M K2CO3 (0.35 mL, 0.70 mmol), sealed and sparged with Ar for 10 min. After 2.5 h of heating at 50 °C and cooling to room température, the crude reaction mixture was purified by Yamazcn column chromatography (20-100% EtOAc/Hex) to produce 0.042 g (64%) of a coloriess film. LCMS-ESf (m/z): [M]⁺calcd for C^HsjCINîOj: 489.01; found: 489.51.

Step 3: Préparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6(pyrimidin-2-yl)naphthalen-2-yl)acetic acid (59): (S)-2-tert-butoxy-2-(l -(4chlorophenyl)-3-methyl-6-(pyrimidin-2-yl)naphthalen-2-yl)acetic acid (59) was prepared using a method similar to step 6 of Example 51 to afford 0.021 g of 59 as an off-whîte amorphous powder. LCMS-ESf (m/z): [M+Hf calcd for C27H26CIN2O3: 461.96; found: 461.34. ^-NMR: 400 MHz, (CD3CN) δ: 8.92 (s, IH); 8.87 (d, J = 4.4 Hz, 2H); 8.36 (dd, J = 9.2,1.6 Hz, IH); 7.94 (s, IH); 7.61-7.55 (m, 3H); 7.43-7.36 (m, 2H); 7.34 (t, J = 4.4 Hz, IH); 5.24 (s, IH); 2.59 (s, 3H); 1.0 (s, 9H).

Example 58. (S)-2-tert-Butoxy-2-(l -(4-chloropheny])-3-methyl-6-(pyrazin-2yl)naphthalen-2-yl)acetic acid (60)

232

(S)-2-tert-butoxy-2-( l -(4-chlorophenyl)-3-methyl-6-(pyrazin-2-yl) naphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(pyrazin-2yl)naphthalen-2-yl)acetic acid (60): (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl6-(pyrazin-2-yl)naphthalen-2-yl)acetic acid was prepared in a similar fashion to compound 59 with the substitution of 2-chloropyrazine for 2-bromopyrimidine in step 2. The title compound (0.026 g) was isolated as an amorphous pale yellow powder. LCMS-ESf (m/z): [M+H]⁺calcd for C_?7H26ClN₂O₃: 461.96; found: 461.30. ‘H-NMR: 400 MHz, (CD₃CN) Ô: 9.23 (s, 1H); 8.67 (s, 1H); 8.56 (s, 2H); 8.05 (d, J = 8.8 Hz, 1H); 7.89 (s, 1H); 7.61-7.54 (m, 3H); 7.42 (d, J = 8.8 Hz, 1H); 7.39 (br d, J = 8.8 Hz, 1H);

5.23 (s, 1H); 2.60 (s, 3H); 1.00 (s, 9H).

Example 59. (S)-2-tert-Butoxy-2-(l-(4-chlorophenyl)-6-(imidazo[l,2-a]pyrazin-8-yl)3-methylnaphthalen-2-yl)acetic acid (61)

(S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-6-(imidazo[l,2-a]pyrazin-8-yl)

-3-mcthy!naphtha!en-2-yl)acctic acid

233

Préparation of (S)-2-tert-bu1oxy-2-(]-(4-chlorophenyl)-6-(imidazo[ l,2a]pyrazin-8-yI)-3-methylnaphthalen-2-yI)acetic acid (61): (S)-2-tcrt-butoxy-2-(I-(4chlorophenyl)-6-(imidazo[l,2-a]pyrazin-8-yl)-3-methyLnaphthalen-2-yl)acetic acid (61) was prepared in a similar fashion to compound 59 with the substitution of 8chloroiimdazo[l,2-a]pyrazine hydrobromide (See Guzi, T.J, Paruch, K., et. al. US 20070105864, p. 121) for 2-bromopyriïnidine in step 2. The tîtle compound (0.017 g) was isolated as an amorphous pale yellow powder. LCMS-ESI* (m/z): [Μ+Η]’ calcd for C29H27CIN3O3: 500.7; found: 500.0. ’H-.NMR: 400 MHz, (CD₃CN) Ô: 9.00 (d, J = 1.2

Hz, 1H); 8.39 (d, J = 4.4 Hz, 1 H); 8.20 (dd, J = 8.8,1.2 Hz, 1H); 8.11 (d, J = 4.4 Hz, 1H); 8.06 (d, J = 1.2 Hz, 1H); 7.99 (s, 1 H); 7.62-7.56 (m, 3H); 7.38 (d, J = 8.8 Hz, 1 H); 7.36 (br d, J = 8.8 Hz, 1H); 5.25 (s, 1H); 2.58 (s, 3H); 0.99 (s, 9H).

234

Example 60. (S)-2-tert-Butoxy-2-( l -(4-chlorophenyl)-3 -methyl-6-(4-methylpyrimidin-

5-yl)naphthalen-2-yI)acetic acid (62)

(S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(4-methylpyrimidin-5-yI) naphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-n)ethyi-6-(410 methylpyriniÎdm-5-yl)naphthaIen-2-yl)acetic acid (62): (S)-2-tert-Butoxy-2-(1-(4chlorophenyl)-3-methyl-6-(4-methylpyrimidiii-5-yl)naphthalen~2-yl)acetic acid (62) was prepared in a similar fashion to compound 59 with the substitution of 5-bromo-4methylpyrimidine for 2-bromopyrimidine in step 2. The title compound (0.015 g) was isolated as an amorphous white powder. LCMS-ESI* (m/z): [M+H]* calcd for

CîgHîgCINiOa: 475.99; found: 475.69. 'H-NMR: 400 MHz, (CD₃CN) Ô: 9.13 (br s, 1H); 8.77 (br s, IH); 7.87 (s, 1H); 7.81 (s, 1H); 7.60-7.54 (m, 3H); 7.42-7.37 (m, 3H);

5.25 (s, 1H); 2.59 (s, 3H); 2.50 (s, 3H); 1.00 (s, 9H).

235

Example 61. (S)-2-tert-Butoxy-2-(l-(4-ch]orophenyl)-3-methyI-6-(pyridin-2- yl)naphthalen-2-yl)acetic acid (63)

(S)-ethyl 2-(teri-butoxy)-2(1 -(4-chlorophenyi)-3methyl-6-(pyridin-2yl)naphtiiaten-2-yl)acetate (S)-ethyl 2-(ter6butoxy)-2-<1(4-chlorophenyl)-3-methyl-6(((trifluoromethyl)sulfonyt)oxy )naphthalen-2-yl)aGetate

( S)-2-(ter t-butoxy )-2-( 1 -(4chloropheny!)-3-methyi-6(pyridin-2-yl)naphthalen-2yljacetic acid

Step 1. Préparation of(S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-

6-(pyridin-2-yl)naphthalen-2-yl)acetatc: A solution of (S)-ethyl 2-tert-butoxy-2-(l-(4chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate (0.070 g, 0.13 mmol) inNMP (1 mL) was treated with LiCl (0.008 g, 0.19 mmol), Pd(PPh₃)₄(0.014 g, 0.013 mmol) and 2-(tributylstannyl)pyridine (85%, 0.071 mL, 0.19 mmol).

After sparging the mixture with Ar for 10 min and microwave heating at 100 °C for 10 min, the réaction mixture was allowed to cool to room température and loaded directly onto silica for purification by Yamazen column chromatography (20-100% EtOAc/Hex) to produce 0.015 g (25%) as a colorless film. LCMS-ESI⁴ (m/z): [M+H]⁺calcd for C30H31CINO3 :488.20; found: 488.90.

236

Step 2. Préparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6(pyridin-2-yl)naphthalen-2-yl)acetic acid (63): ( S)-2-tert-Butoxy-2-(l-(4chlorophenyI)-3-methyl-6-(pyridin-2-yl)naphthalen-2-yl)acetic acid (63) was prepared using a method similar to step 6 of Exampie 51 to afford 0.0041 g of 63 as an off-white amorphous powder. LCMS-ESr (m/z): [M+H]⁺calcd for C28H27CINO3: 460.97; found; 460.70. ^JH-NMR: 400 MHz, (CD₃CN) δ: 8.75 (d, J = 4.4 Hz, IH); 8.49 (br s, 1 H); 8.07-7.96 (m, 3H); 7.87 (s, 3H); 7.60-7.53 (m, 3H); 7.46 (t, J = 5.6 Hz, IH); 7.40 (d, J =

8.8 Hz, IH); 7.39 (br s, IH); 5.23 (s, IH); 2.59 (s, 3H); 0.99 (s, 9H).

Example 62. (S)-2-tert-Butoxy-2-(l-(4-chloropheny])-3-methyl-6-(l-methyl-IHimidazol-4-yl)naphÜialen-2-yl)acetic acid (64)

(S)-2-tert-butoxy-2-( 1 -(4-chloropheny l)-3-methyl-6-(l -methyl-1 H-imidazol-4yl)naphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(l-methyllH-imidazol-4-yl)naphthalen-2-yl)acetic acid (64); (S)-2-tert-butoxy-2-(l-(4chlorophenyl)-3-methyl-6-(l-methyl-lH-imidazol-4-yl)naphthalen-2-yl)aceticacid (64) was prepared in a similar fashîon to compound 63 with the substitution of l-methyl-4(tributylstannyl)-lH-imidazole for 2-(tributylstannyl)pyridine in step 1. The title compound (0.026 g) was isolated as an amorphous white powder. LCMS-EST (m/z): [M+Hf calcd for C₃7H28CIN₂O₃:463.98; found: 463.86. ‘H-NMR: 400 MHz, (CD₃CN) δ: 6.46 (br s, IH); 8.24 (br s, IH); 7.73 (br s, IH); 7.65 (s, IH); 7.62-7.51 (m, 4H); 7.36-7.25 (m, 2H); 5.21 (s, IH): 3.85 (s, 3H); 2.56 (s, 3H); 0.97 (s, 9H).

Exampie 63. (S)-2-tert-butoxy-2-( l-(4-chlorophenyl)-3-methyI-6-(l -methyl-1 Himidazol-5-yl)naphthalen-2-yI)acetic acid (65)

237

(S)-2-tert-butoxy-2-(l-(4-chiorophenyl)-3-methyl-6-(l-methyl-lH-imidazol-5yl)naphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-niethyI-6-(l-methylllI-imidazol-5-yl)naphthalen-2-yl)acctic acid (65): (S)-2-tert-Butoxy-2-(l-(4chlorophenyl)-3-methyl-6-(l -methyl-1 H-imidazol-5-yl)naphthalen-2-yl)acetic acid (65) was prepared in a similar fashion to compound 63 with the substitution of l-methyl-5(tributylstannyl)-lH-imidazole for 2-(tributylstaiiny3)pyridine in step 1. The title compound (0.026 g) was isolated as an amorphous white powder. LCMS-ES1⁴ (m/z): [M+H]⁺calcd for C77H2t(ClN2O3: 463.98; found; 463.81. ^lH-NMR: 400 MHz, (CD3CN) 5: 8.54 (s, IH); 7.99 (s, IH); 7.84 (s_t IH): 7.62-7.50 (m, 3H); 7.45-7.32 (m, 3H), 5.24 (s, IH); 3.80 (s, 3H); 2.60 (s, 3H); 0.99 (s, 9H).

238

Example 64. 2-(l,6-Bis(4-chlorophenyl)-3-melhyhiaphthalen-2-yl)-2-tert-butoxyacetic acid (66)

	OH OPMB	ONf OH rvMv^OEt
CtS	A^OEt	Nf₂O, DIPEA -----------► I
Br		⁰	DCM _BrJ	o

ethyl 2-(6-bromo-1 -hydraxy-3-methylnaphthalen-2-yl)-2-((4methoxybenzyl)oxy)acetate ethyl 2-(6-bromo-3-methyi-1(perflLJorobutylsulfonyloxy)naphthalen2-yf)-2-hydroxyacetate

ONf O

ethyl 2-(64>romo-3-mefryl-1 (perfiuorobutylsuffonytoxy) naphthalen-2-yl)-2-oxoacetate

ethyl 2-(1,6-bis(4-chloropheny t)-3methylnaphthalen-2-yl)-2-oxoacetate ethyl 2-(1,6-bis(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-hydroxy acetate

2-( 1,6-bîs(4-chlorophenyl)-3methylnaphthaten-2-yl)-2-(tertbutoxyjacetic acid

Step 1. Préparation of ethyl 2-(6-bromO’3-methyl-l-(perfluorobutylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate: A solution of ethyl 2-(6-bromo-l hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate (0.78 g, 1.7 mmol;

prepared similarly to (1 -hydroxy- 5-methoxy-3-methyl-naphthalen-2-yl)-(4methoxybenzyloxy)acetic acid ethyl ester of Example 32 beginning with l-(3bromophenyl)propan-2-one) in DCM (17 mL) was cooied to -78 °C and treated with DIPEA (0.44 mL, 2.6 mmol) and perfluorobutanesulfonic anhydride (0.68 mL, 2.2 mmol). The resulting slurry was allowed to slowly warm to room température ovemight. Saturated NaHCOj was added and the mixture extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous MgSCU and concentrated in vacuo. The residue was purified via Yamazen column chromatography (0-15% EtOAc/Hex) to afford 0.52 g (95%) of the title compound as a yellow solid that was used without further purification. ’H-NMR: 400 MHz, (CDCI3) δ: 7.97 (d, J = 6.4 Hz, IH); 7.94 (d, J = 9.2 Hz, IH); 7.66 (dd, J = 9.2,6.4 Hz, IH); 7.59 (s, IH); 5.78 (br s, IH); 4.31 (m, IH); 4.22 (m, IH); 3.39 (br s, IH): 2.50 (s, 3H); 1.20 (t, J = 7.2 Hz, 3H).

Step 2. Préparation of ethyl 2-(6-bromo-3-methyl-l-(perfluorobutyl15 sulfonyloxy)naphthalen-2-yl)-2-oxoacetate: A solution of ethyl 2-(6-bromo-3-methyl- l-(perfluorobutylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (0.52 g, 0.84 mmol) in DCM (8.5 mL) was treated with Dess-Martin periodinane (0.43 g, 1.01 mmol) at room température. After 1.5 h, a 1/1 mixture of saturated NaHCO₃ and saturated Na₇S₂O3 (10 mL) was added and the slurry allowed to stir at room température for 10 min. The reaction was further diluted with water and DCM and the aqueous layer extracted with DCM. The combined organics were washed with water, brine, and dried over anhydrous MgSCU. After concentration in vacuo, the residue was purified using Yamazen column chromatography (0-15% EtOAc/Hex) to produce 0.38 g (73%) of the title compound as an amorphous solid. ’H-NMR: 400 MHz, (CDCI3) 5: 8.04 (s, 1 H);

7.97 (d, J = 9.2 Hz, 1H); 7.72 (d, J = 9.2 Hz, IH); 7.68 (s, IH); 4.41 (q, J = 7.2 Hz, 2H);

2.50 (s, 3H); 1.39 (t, J = 7.2 Hz, 3H).

Step 3. Préparation of ethyl 2-(l,6-bis(4-chIorophenyl)-3-methylnaphthalen-2yl)-2-oxoacetate: A solution of ethyl 2-(6-bromo-3-methyl-l-(perfluorobutylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (0.379 g, 0.612 mmol), 4-chlorophenylboronic acid (0.105 g, 0.67 mmol), potassium carbonate (0.254 g, 1.84 mmol), and Pd(dppf)Cl₂ (0.022 g, 0.031 mmol) was prepared in PhMe (3 mL), EtOH (1.5 mL) and water (1.5 mL). The dark brown solution was sparged with argon for 10 min, then allowed to stir at room température for 2.5 h. Following purification, the product was determined to

be a mixture of mono and bis substitution. The mixture was resubmitted to reaction conditions and was heated to 50 °C for 2 h. After cooling to room température, the reaction was diluted with EtOAc, and washed with water. The organic layer was absorbed onto silica gel irt vacuo and purified by Yamazen column chromatography (020% EtOAc/Hex) to afford 0.145 g (53%) of the title compound as an amorphous solid.

*H-NMR: 400 MHz, (CDC1₃) Ô: 7.98 (s, 1H); 7.78 (s, 1H); 7.64-7.56 (m, 4H); 7.48-

7.41 (m, 4H); 7.30-7.22 (m, 2H); 3.91 (q, J = 7.2 Hz, 2H); 2.51 (s, 3H); 1.12 (t, J = 7.2

Hz, 3H).

Step 4. Préparationof ethyl 2-(l,6-bis(4-chlorophenyI)-3-methylnaphthalen-2yl)-2-hydroxyacetate: A solution of ethyl 2-(l,6-bis(4-chlorophenyl)-3methylnaphthalen-2-yI)-2-oxoacetate (0.145 g, 0.31 mmol) in EtOH (2 mL) and DCM (1 mL) at 0 °C was treated with NaBHi (0.018 g, 0.048 mmol) in one portion. The reaction was allowed to warm to room température over 30 min and treated with saturated NaHCO₃ (3 mL). The mixture was stirred vigorously for 30 min and then diluted with EtOAc and water. Following extraction with EtOAc, the organics were washed with brine, dried over anhydrous Na₂SO₄ and concentrated to produce 0.121 g (84%) of the title compound as a white foam that was used in subséquent steps without further purification. *H-NMR: 400 MHz, (CDC1₃) δ: 7.94 (s, 1H); 7.73 (s, 1H); 7.60 (d, J = 8.4 Hz, 2H); 7.56-7.42 (m, 6H); 7.38-7.30 (m, 2H); 5.23 (s, 1H); 4.20 (m, 2H); 2.52 (s, 3H); 1.21 (t, J = 7.2 Hz, 3H).

Steps 5 and 6. Préparation of 2-(l,6-bis(4-chlorophenyl)-3-methylnaphthalen-

2-yl)-2-tert-butoxyacetic acid (66): Step 5 was performed similarly to step 4 of Example 51. Step 6 was performed similarly to Step 6 of Example 51 with heating at 60 °C overnight to produce 0.053 g of the title compound as an amorphous white powder. LCMS-ESI' (m/z): [2M-2H+Na]‘calcd for C5₈H₅₀Cl₄NaO₆: 1007.82; found: 1007.05. ’H-NMR: 400 MHz, (CDC1₃) Ô: 7.93 (br s, 1H); 7.23 (s, 1H); 7.60 (br d, J -

8.8 Hz, 2H); 7.58-7.49 (m, 3H); 7.43 (br d, J = 8.8 Hz, 2H); 7.39 (br d, J = 8.8 Hz, 1H);

7.32 (br s, 1H); 5.30 (s, 1H); 2.60 (s, 3H); 1.03 (s, 9H).

241

Example 65. 2-tert-Butoxy-2-(6-chloro-1 -(4-chlorophenyl)-3 -methylnaphthalen-2- yl)acetic acid (67)

1) PMBOH, KHMDS, -78 °C

2) DBU, CHC)₃

3) LiOH

4) TMSCHN₂

OH OPMB

(E)-ethyl 2-((3R,4R)-4bromo-6-chloro-3-methy 1-1 oxo-3,4-dihydronaphthalen2(1 R)-ylidene)acetate methyl 2-{6-chloro-1-hydraxy-3methylnaphthalen-2-yl}-2-((4methoxybenzyl)oxy)acetate

OTf OPMB

methyl 2-(6-chloro-3-methyl-1(((trifluoramethyl)sutfonyl)oxy)nap hthalen-2-yl)-2-{(4methoxybenzyl)oxy)acetate methyl 2-(6-chtoro-1-(4chlorophenyl)-3mettiylnaphthalen-2-yl)-2-((4· methoxybenzyl)oxy)acetate

methyl 2-(6-chloro-1-(4-

chlorophenyl)-3-methylnaphthalen-2yl)-2-hydroxy acetate

2-(tert-butoxy)-2(6-chloro-1-{4chiorophenyl)-3methylnaphthaie n-2-yl)acetic acid

Steps 1-4. Préparation of methyl 2-(6-chloro-l-hydroxy-3-methylnaphthalen-2yl)-2-(4-methoxybenzyIoxy)acetate: p-methoxybenzyl alcohol (5.9 mL, 47.2 mmol) was diluted with THF (180 mL) and cooled to -78 °C under an Ar atmosphère. KHMDS (0.5 M PhMe solution, 71 mL, 35.4 mmol) was added dropwise over 20 min and the solution allowed to âge for 20 min at this température to produce an opaque

242 white suspension. A solution of (E)-ethyl 2-((3R,4R)-4-broino-6-chloro-3-rnethyl-loxo-3_}4-dihydronaphthalen-2(lH)-ylidene)acetate (4.22 g, 11.8 mmol; prepared similarly to (4-bromo-5-methoxy-3-mcthyl-l-oxo-3,4-dihvdro-lH-naphthaleri-2ylidene)acetic acid ethyl ester of Example 32 beginning with l-(3chlorophenyl)propan-2-one) was prepared in THF (50 mL) and added to the reaction at a rate that maintained an internai température less than -65 °C. After 5 min, propionic acid (10 mL, 134 mmol) was added and the reaction warmed to room température over

1.5 h prior to dilution with water (150 mL). Extraction ofthe aqueous layer with ethyl acetate was followed by washing of the combined organics with saturated NaHCCh, water and brine. Following drying over anhydrous MgSO₄ and concentration in vacuo, the resulting residue was eluted on Yamazen column chromatography to produce an inséparable mixture of products (5.56 g) that included ethyl 2-(6-chloro-l-hydroxy-3methylnaphthalen-2-yl)-2-(4-methoxybeiizyloxy)acetate, 4-methoxybenzyl 2-(6-chloro-

1- hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate, ethyl 2((3R,4R)A-bromo-6-chloro-3-methyl-l-oxo-l,2,3,4-tetrahydronaphthalen-2-yl)-2-(4methoxybenzyloxy)acetate, and 4-methoxybenzyl 2-((3R,4R)-4-bromo-6-chloro-3methyl-l-oxo-l,2,3,4-tetrahydronaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate.

This material was taken up in chloroform (60 mL) and treated with DBU (5.1 mL, 33.9 mmol) at room température. After 1 h, 5% citric acid solution was added and the aqueous phase extracted with DCM. The combined organics were washed with brine, dried over anhydrous MgSO₄. and concentrated in vacuo. Following elution by Yamazen column chromatography, 1.68 g of material was recovered that was primarily a mixture of ethyl 2-(6-chloro-l -hydroxy-3-methylnaphthalen-2-yl)-2-(4methoxybenzyloxy)acetate and 4-methoxybenzyl 2-(6-chloro-l-hydroxy-3methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate. This material was taken up in ΤΗΡ/ΜεΟΗ/Η₂Ο (10/5/5 mL respectively) and treated with LiOH monohydrate (0.86 g, 20.5 mmol). The mixture was heated to 50 °C for 1.5 h and then allowed to cool before acidifying with 2 M HCl solution. The aqueous phase was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na₂SO₄and concentrated in vacuo to afford 2-(6-chloro-l-hydroxy-3-methylnaphthalen-2-yl)-

2- (4-methoxybenzyIoxy)acetic acid (0.658 g) as a white foam that was used in the next step without further purification. 2-(6-chloro-l-hydroxy-3-methylnaphthalen-2-yl)-2(4-methoxybenzyloxy)acetic acid (0.658 g, 1.7 mmol) was diluted in DCM and MeOH

243 (20 mL each) and treated with TMSCHN; (2 M m hexanes) until the reaction remained a bright yellow color. After 45 min, glacial acetic acid was added dropwise until the reaction faded to a pale yellow color, indicating any remaining TMSCHN- had been destroyed. The reaction was absorbed onto silica gel in vacuo and was purified by Yamazen column chromatography to produce 0.649 g (14% over four sleps) ofthe title compound as an amorphous white solid that was used without further purification. ^lHNMR: 400 MHz, (CDCl₃) δ: 8.54 (s, lH); 8.18 (d, J = 8.8 Hz, 1H); 7.63 (d, J = 1.6 Hz, IH); 7.33 (dd, J - 8.8,1.6 Hz, 1H); 7.27 (d, J = 8.8 Hz, 2H); 7.09 (s, 1H); 6.90 (s, J =

8.8 Hz, 2H); 5.38 (s, IH); 4.65 (AB d, J = 11.2 Hz, IH); 4.59 (AB d, J = 11.2 Hz, IH);

3.83 (s, 3H); 3.73 (s, 3H); 2.39 (s, 3H).

Step 5. Préparation of methyl 2-(6-chloro-3-methyl-l(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate: A solution of methyl 2-(6-chloro-l-hydroxy-3-methylnaphthalen-2-y 1)-2-(4methoxybenzyloxy)acetate (0.649 g, 1.62 mmol) in DCM (16 mL) under Ar was cooled to -78 °C and treated with 2,6-lutidÎne (0.56 mL, 4.9 mmol) and trifluoromethanesulfonic anhydride (1.15 mL, 2.4 mmol). After 4 h, saturated NaHCO₃solution was added at -78 °C and the reaction warmed to room température with stirring. Following dilution with water and DCM, the aqueous layer was extracted with DCM and the combined organics were washed with brine, dried over anhydrous MgSOi and concentrated in vacuo. The residue was purified using Yamazen column chromatography (5-25% EtOAc/hex) to produce 0.765 g of the title compound as an amorphous solid. ‘H-N.MR: 400 MHz, (CDCI3) δ: 7.97 (d, J = 9.2 Hz, IH); 7.78 (d, J =

1.6 Hz, 1 H); 7.60 (s, IH); 7.53 (dd, J = 9.2,1.6 Hz, IH); 7.24 (d, J = 8.8 Hz, 2H); 6.82 (d, J = 8.8 Hz, 2H); 5.62 (s, I H); 4.66 (ABd, J =] 1.2 Hz, 1 H); 4.59 (ABd, J = 11.2 Hz, IH); 3.78 (s, 3H); 3.75 (s, 3H); 2.55 (s, 3H).

Step 6. Préparation of methyl 2-(6-chloro-l -(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate: Methyl 2-(6-chloro-3-methyl- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate (0.106 g, 0.2 mmol), 4-chlorophenylboronic acid (0.038 g, 0.24 mmol), and Pd(PPh₃)4 (0.23 g, 0.02 mmol) were combined in DME (1 mL) and treated with 2 M K2CO3 solution (1.2 mL, 0.6 mmol). The resulting mixture was sparged with Ar for 10 minutes and then heated in a mîcrowave reactor at 100 °C for 20 min. The resulting mixture was loaded directly onto silica gel and purified with Yamazen column chromatography (3-25%

244

EtOAc/Hex) to produce 0.051 g of the title compound as an amorphous foam. ^lHNMR: 400 MHz, (CDCI₃) δ: 7.67 (d, J = 2.4 Hz, 1H); 7.60 (s, IH); 7.42 (dd, J = 8,2.4 Hz, 1H); 7.32 (dd, J = 8.2,2.4 Hz, 1H); 7.28 (dd (obscured), J = 8.2, 2.4 Hz, 1H); 7.22 (dd, J = 8.8,2 Hz, 1H); 7.15 (d, J = 8.8 Hz, 1H); 7.08 (br d, J = 8.4 Hz, 2H); 6.99 (dd, J = 8,2 Hz, 1H); 6.79 (br d, J = 8.4 Hz, 2H); 5.05 (s, 1H); 4.46 (ABd, J = 11.6 Hz, 1 H); 4.35 (ABd, J = 11.6 Hz, 1 H); 3.82 (s, 3H); 3.72 (s, 3H); 2.57 (s, 3H).

Step 7. Préparation of methyl 2-(6-chloro-l-(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-hydroxyacetatc: A solution of methyl 2-(6-chloro-l-(4chlorophenyl)-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyIoxy)acetate in DCM (1 mL) was treated with trifluoroacetic acid (0.052 mL, 0.67 mmol) at room température. After 45 min, the reaction was diiuted with DCM and treated with saturated NaHCO₃. After séparation the organic layer was absorbcd directly onto silica gel in vacuo. Purification via Yamazen column chromatography yielded 0.039 g of a colorless film. ‘H-NMR: 400 MHz, (CDC1₃) δ: 7.76 (d, J = 1.6 Hz, 1H); 7.60 (s, 1H); 7.52-7.45 (m, 2H); 7.34-7.27 (m, 2H); 7.25 (dd (obscured) J = 8.8, 2 Hz, 1H); 7.20 (d, J = 8.8 Hz, 1 H); 5.23 (s, 1H); 3.74 (s, 3H), 2.49 (s, 3H).

Steps 8 and 9. Préparation of 2-tert-butoxy-2-(6-chloro-l-(4-chlorophenyI)-3methylnaphthalen-2- yl)acetic acid (67): Step 8 was performed similarly to Step 4 of Example 51. Step 9 was performed similarly to Step 6 of Example 51 with appropriate adjustments for scale to produce 0.006 g of a racemic mixture of the title compound as an amorphous white powder . LCMS-ESI' (m/z); [M-H]’ calcd for C23H₂]C1₂O₃: 415.09; found: 415.56.³H-NMR: 400 MHz, (CD₃CN) δ: 7.85 (d, J = 2 Hz, 1H); 7.70 (s, 1H); 7.59-7.50 (m, 3H); 7.36-7.23 (m, 3H); 5.20 (s, 1H); 2.56 (s, 3H); 0.97 (s, 9H).

Example 66. (S)-2-tert-Butoxy-2-((R)-6-chloro-1 -(2,3-dihydropyrano[4,3,2de]quinolin-7-yI)-3-methy InaphthaIen-2-yl)acetic acid (68A) and (S)-2-tert-Butoxy-2((R)-I-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetic acid (68B)

245

OTf ΟΡΜΒ

methyl 2-(6-chloro-3methyM(trifluoromethylsulfbnyloxy) naphthalen-2-yl)-2-(4methoxybenzyloxy)acetate

OMe

TFA

(±HS)-methyl 2-((R)-6άι10Γ0-Ή2,3dihydropyrano[4,3,2de]quinolin-7-yl)-3methylnaphthalen-2-yl)-2-(4methoxybenzyloxy)acetate tBuOAc

.........

cat HCIO4 (±HS)-methyl 2-((R)-6-chloro-1(2,3-dihydropyranc[4,3.2dejquino!in-7-yl)-3methylnaphtbalen-2-yi)-2hydroxy acetate

(S)-methyl 2-tert-butoxy-2-((R)-6chloro-1-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-3~ methylnaphthalen-2-yl)acetate

(S)-2-fert-butoxy-2-((R)-6-chloro-1 (2.3H5ihydropyrano[4,3,2-dQ]quinolin 7ylj-3-methylnaphtha1en-2-yl)acetic acid (S)-methyl 2-terf-butoxy-2-((R)-1-(2,3dihydropyrano[4,3,2-de]quinolîn-7-yl)3,6-drmethylnaphtha!en-2-yl)acetate

(S)-2-(tert-butoxy)-2-((R)-1 (2,3-dihydropyrano[4,3,2-c/e]quinolin 7 yl)-3,6 dimethylnaphthalen-2-yl)acetic acid

246

Step 1: Préparation of (±)-(S)-meÜiyl 2-((R)-6-chloro-1-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnapbthalen-2-yl)-2-(4methoxybenzyloxy)acetatc. Methyl 2-(6-chloro-3-methyI-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate (1.24 g, 2.32 mmol), 2,3dihydropyrano[4,3,2-dc]quinolin-7-ylboTonic acid hydrochloride (0.70 g, 2.79 mmol) and Pd(PPh₃)₄ (0.27 g, 0.232 mmol) were combined in DME (6.2 mL) and treated with 2 M K₂CO₃ (4.6 mL, 9.3 mmol). After sparging for 10 min with Ar, the reaction was heated in a microwave reactor at 100 °C for 20 min. The reaction mixture was then absorbed directly onto silica gel and purified by Yamazen column chromatography (2059% EtOAc/Hex) to provide two diastereomer pairs as white amorphous solids. Anti racemate: 0.348 g; ‘iLNMR: 400 MHz, (CDCI₃) δ: 8.70 (d, J = 4.4 Hz, 1H); 7.75 (d, J = 2 Hz, 1H); 7.63 (s, 1H); 7.35 (d, J = 8 Hz, 1H); 7.15 (d, J = 8.8 Hz, 2H); 7.09 (d, J =

4.4 Hz, 1H); 7.06 (dd, J = 8, 2 Hz, 1H); 6.99 (d, J = 8 Hz, 1H); 6.95 (d, J = 8.8 Hz, 1H);

6.81 (d, J = 8.8 Hz, 2H); 4.97 (s, 1H); 4.57 (t, J = 5.6 Hz, 2H); 4.53 (AX d, J = 11.2 Hz, 1H); 4.24 (AX d, J = 11.2 Hz, 1H); 3.81 (s, 3H); 3.58 (s, 3H); 3.33 (t, J = 5.6 Hz, 2H);

2.59 (s, 3H).

Syn racemate: 0.166 g; ^lH-NMR: 400 MHz, (CDC1₃) Ô: 8.64 (d, J = 4 Hz, 1H); 7.74 (d, J = 2 Hz, 1H); 7.62 (s, 1H); 7.57 (d, J = 8 Hz, 1H); 7.08 (br d, J - 4 Hz, 1 H); 7.04 (dd, J = 8,2 Hz, 1H); 7.03 (d, J = 9 Hz, 1H); 6.87 (d, J = 9 Hz, 1H); 6.77 (d, J = 8.4 Hz, 2H);

6.57 (d, J = 8.4 Hz, 2H); 5.04 (s, IH); 4.52 (m, 2H); 4.23 (AM d, J - 12.4 Hz, 1H); 3.99 (AM d, J = 12.4 Hz, 1H); 3.71 (s, 3H); 3.67 (s, 3H); 3.31 (m, 2H); 2.56 (s, 3H).

Step 2. (+)-(S)-methyl 2-((R)-6-chloro-l-(2,3-dihydropyrano [4,3,2-dejquinolin-

7-yl)-3-methylnaphthaIen-2-yl)-2-hydroxyacetate was prepared similariy to Step 7 of Example 65 to produce 0.238 g as an amorphous foam. LCMS-ESI* (m/z): [M+H]* calcd for C_2iH2iClNO₄: 434.89; found: 434.53. The syn racemate was treated in the same fashion to produce 0.106 g of an amorphous foam. LCMS-ESI* (m/z): [M+H]* calcd for C25H21CINO4: 434.89; found: 434.57.

Step 3. (S)-methyl 2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2de]quino!în-7-yl)-3-methyInaphthaIen-2-yl)acetate was prepared similariy to Step 4 of Example 51 with appropriate adjustments for scale to produce 0.154 g of the anti enantiomers as a colorless film, which were separated by preparatory HPLC on a Chîracel OJ-H column (4.6 X 250 mm, 15 mL/min) with 100 % MeOH elution to produce 0.063 g of (R)-methyl 2-tert-butoxy-2-((S)-6-ehloro-1-(2,316293

247 dihydropyrano[4,3,2-dc]quinolin-7-yl)-3-rncthylnaphthalen-2-y])acelalc and 0.057 g of (S)-methyl 2-terr-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2-de]quino]in-7yl)-3-methylnaphthalen-2-yl)acetate as colorless films. LCMS-ESl^- (m/z): [M+H]⁺calcd for C29H29CINO4: 490.99; found; 490.59. The syn enantiomers were treated in a similar fashion to produce 0.047 g of a colorless film as a racemic mixture. LCMS-ESL (m/z): [M+H]⁺ calcd for C29II29CINO4:490.99; found: 490.62.

Step 4. (S)-2-tert-butoxv2-((R)-6-chloro-1-(2,3-dihydropyrano [4,3,2deJquinolin-7-yl)-3-methylnaphthaien-2-yl)acetic acid (68A) was prepared in a similar fashion to step 6 of Example 51 with appropriate adjustments for scale to produce 0.043 g of a pale yellow amorphous powder. LCMS-ESr (m/z): [M-H] calcd for C28H25CÎNO4: 474.96; found: 474.37. ’H-NMR: 400 MHz, (CD3CN) δ: 8.58 (d, J = 5.2 Hz, 1H); 7.93 (d, J = 2 Hz, 1H); 7.75 (d, J = 8.8 Hz, 1H); 7.60 (d, J = 5.2 Hz, 1 H); 7.34 (d, J = 8 Hz, 1H); 7.20 (dd, J = 8, 2 Hz, 1H); 6.88 (d, J = 8.8 Hz, IH); 5.16 (s, 1H); 4.64 (m, 2H); 3.52 (t, J = 5.6 Hz, 2H); 2.68 (s, 3H); 0.92 (s, 9H).

Step 5 and 6. Préparation of(S)-2-lert-butoxy-2-((R)-l-(2,3dihydropyrano[4,3,2-de]quinohn-7'-yl)-3,6-dimethylnaphthalen-2-yl)acetic acid (68B): A solution of (S)-methyl 2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (0.020 g, 0.041 mmol) in toluene (0.5 mL) and EtOH (0.25 mL) was treated with trimethylboroxine (0.021 mL, 0.123 mmol), S-Phos precatalyst (0.001 g, 0.002 mmol) and K2CO3 (2 M, 0.105 mL, 0.21 mmol). The mixture was sparged with Ar for 10 min and then heated in a microwave reactor at 100 °C for 30 min. The reaction mixture was loaded directly onto silica gel and eluted with Yamazen column chromatography. The collected material was taken up in THFZMeOHÆhO (1 mL each) and treated with LiOH’H₂O (0.030 g, 0.72 mmol) at 50 °C overnight. Following purification by preparatory HPLC to produce 0.007 g of (S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y])-3,6dimethylnaphthalen-2-yl)acetic acid (68B). LCMS-ESr (m/z): [M+H]⁺ calcd for C29H30NO4; 456.55; found: 456.15. ’H-NMR; 400 MHz, (CDjCN) Ô: 8.56 (d, J = 4.8 Hz, 1H); 7.79 (s, 1H); 7.72 (brd, J = 8, JH); 7.65 (s, 1H); 7.53 (br s, 1H); 7.30 (d, J = 8 Hz, 1H); 7.08 (d, J = 8 Hz, 1H); 6.76 (d, J 8 Hz, 1H); 5.15 (br s, 1 H); 4.62 (m, 2H); 3.49 (t, J = 6 Hz, 2H); 2.65 (s, 3H); 2.44 (s, 3H); 0.92 (s, 9H).

248

Example 67. 2-tert-butoxy-2-(l-(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-I-ynyl)-

3-methylnaphthalen-2-yl)acetic acid (69)

OH 0PM8

OTf OPMB

ethyl 2-(7-bromo-1-hydroxy-3methylnaphthaïen-2-yÎ)-2-H(4methoxybenzyioxyjacetate

OTf OH

ethyl 2-(7-bromo-3-methyH(trifluorometbylsiitfonyloxy)naphthalen-2-yl)2-(4-methoxybenzyloxy)acetate

OTf O

ethyl 2-(7-brofno-3-methyl-1(trifluoromethylsulfonyloxy)naphthalen2-yl)-2-hydroxyacetate ethyl 2-(7-bramo-3-methyi-1(trrfluoromethylsulfonyloxy)naphthalen2-yl)-2-oxoacetate

ethyl 2<7-bromo-1-(4-chtorophenyl)-

3-methylnaphthalen-2-yi}-2-oxoacetate ethyl 2-(7-bromo-1-(4-chlorophenyl)-

3-methylnaphthalen-2-yt)-2-hydroxyacetate

ethyl 2-(7-bromo-1-(4-chlorophenyl)3-methylnaphthalen-2-yl)-2-teriethyl 2-ferf-butoxy-2-(1-(4-chlorophenyl)7-(3-hy droxy-3-methylbut-1 -yny l)-3-

2-fer(-butoxy-2-(1-(4-chtorophenyl)-7(3-hydroxy-3-methylbut-1 -ynyi)-3-methylnaphthalen-2-yl)acetic acid

Step 1. Préparation of ethyl 2-(7-bromo-3-methyl-l(trifluoromethylsuIfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyIoxy)acetate: To a solution of ethyl 2-(7-bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2-(4

249 methoxybenzyloxy)acetate (4.0 g, 8.7 mmol) în CH2CI2 (40 mL) at -78 °C was added triethylamine (1.46 mL, 10.5 mmol) and trifluoromethanesulfonic anhydride (1.0 M solution in CH2CI2,9.6 mL, 9.6 mmol). After 15 min, a saturated solution of NH4CI was added. The mixture was warmed to room température. The layers were separated, dried, filtered, and concentrated in vacuo. The crude product was taken on without further purification. ‘H-NMR: 400 MHz, (CDC1₃) δ: 8.30 (s, IH), 7.77 (m, 3H), 7.35 (d, J = 9 Hz, 2H), 6.94 (d, J = 9 Hz, 2H), 5.73 (s, IH), 4.73 (m, 2H), 4.36 (m, 2H), 3.89 (s, 3H), 2.67 (s, 3H), 1.32 (t, J = 7 Hz, 3H).

Step 2. Préparation of ethyl 2-(7-bromo-3~methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate: To a solution of ethyl 2-(7-bromo-3methyl-1 -(trifïuoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate (8.7 mmol from previous step) in CH2CI2 (40 mL) was added trifluoroacetic acid (TFA) (4mL). After 1.5 h, water was added (40 mL). The layers were separated. The organic layer was washed with a saturated solution of NaHCO₃. The organic layer was dried, filtered, and concentrated in vacuo. The crude product was taken on without further purification. ’H-NMR: 400 MHz, (CDC1₃) Ô: 8.21 (s, IH), 7.65 (m, 3H), 5.79 (s, IH), 4.27 (m, 2H), 2.48 (s, 3H), 1.20 (t, J = 7 Hz, 3H). ¹⁹F-NMR: 377 MHz, (CDC1₃) δ: -73.0.

Step 3. Préparation of ethyl 2-(7-bromo-3-methyl-l(trifluoromethyisuIfonyloxy)naphthalen-2“y])-2-oxoacetate: To a solution of ethyl 2-(7bromo-3-methyl-l-(trifluoromethylsulfony)oxy)naphthalen-2-yl)-?-hydroxyaœtate (-8.7 mmol) în CH2CI2 (40 mL) was added Dess-Martin periodînane (4.07 g, 9.6 mmol). After 1.5 h, a saturated solution of Na2S₂O₄ (20 mL) and water (20 mL) was added. The mixture was stirred vigorousiy for 30 min. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purifîed by column chromatography (EtOAc/hexanes) to give 3.22 g (79%) of the titled compound. 'H-NMR: 400 MHz, (CDC1₃) δ: 8.22 (s, IH), 7.70 (m, 3H), 4.41 (q, J = 7 Hz, 2H), 2.47 (s, 3H), 1.39 (t, J = 7 Hz, 3H). ¹⁹F-NMR: 377 MHz, (CDC1₃) Ô: -73.2.

Step 4. Préparation of ethyl 2-(7-bromo-l-(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-oxoacetate: To a solution of ethyl 2-(7-bromo-3-methyl-l(trifluoromethylsuIfonyloxy)naphthalen-2-yl)-2-oxoacetate (235 mg, 0.50 mmol) in PhCH₃ (1.2 mL), EtOH (0.6 mL), H₂O (0.6 mL) was added 4-chlorophenylboronic acid (86 mg, 0.55 mmol), K₂CO₃ (207 mg, 1.5 mmol), and PdCl₂dppf (11 mg, 0.015 mmol).

ΙΟ

The reaction mixture was stirred at room température for 2 h and was then diluted with H₂O and EtOAc. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 129 mg (60%) of the titled compound and 37 mg of the biscoupled product (ethyl 2-(l,7-bis(4-chiorophenyl)-3-methylnaphthalen-2-yl)-2oxoacetate). ^!H-NMR: 400 MHz, (CDC1₃) δ: 7.60-7.72 (m, 4H), 7.45 (m, 2H), 7.23 (m, 2H), 3.93 (q, J = 7 Hz, 2H), 2.48 (s, 3H), 1.13 (t, J = 7 Hz, 3H).

Step 5. Préparation of ethyl 2-(7-bromo-l-(4-chlorophenyl)-3mcthylnaphlhalen-2-yl)-2-hydroxyacetate: To a solution of ethyl 2-(7-bromo-l-(4chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (1.6 g, 2.78 mmol) in EtOH (10 mL) was added sodium borohydride (NaBH₄) (157 mg, 4.17 mmol). After 20 min, a saturated solution of NH4CI was added and EtOAc. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was taken on without further purification. ^!H-NMR: 400 MHz, (CDCI3) δ: 7.64{m, 2H), 7.45 (m, 3H), 7.39 (s, 1H), 7.28 (m, 2H), 5.18 (s, 1H), 4.17 (m, 2H), 2.48 (s, 3H), 1.20 (t, J = 7 Hz, 3H).

Step 6. Préparation of ethyl 2-(7-brorao-l-(4-chlorophenyl)-3methyInaphthalen-2-yl)-2-tert-butoxyacetate: To a solution of ethyl 2-(7-bromo-l-(4chlorophenyl)-3-methyInaphthalen-2-yl)-2-hydroxyacetate (-2.78 mmol) in i-BuOAc (14 mL) was added perchloric acid (HCIO4) (334 pL, 5.56 mmol). After 3 h, water was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 877 mg of the titled compound. ^JH-NMR: 400 MHz, (CDCI3) δ: 7.62 (m, 2H), 7.51 (m, 4H), 7.27 (m, 2H), 5.09 (s, 1H), 4.15 (m, 2H), 2.59 (s, 3H), 1.19 (t, J = 7 Hz, 3 H), 1.00 (s, 9H).

Step 7. Préparation ofethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-7-(3-hydroxy3-methylbut-l-ynyI)-3-methylnaphthalen-2-yl)acetate: To a solution of ethyl 2-(7bromo-l-(4-chlorophenyl)-3-rnethylnaphthalen-2-yl)-2-tert-butoxyacetate (30 mg, 0.061 mmol) in THF (1 mL) was added 2-methylbut-3-yn-2-ol (15 mg, 0.18 mmol), Cul (1 mg, 0.006 mmol), Pd(PPhî)4 (3 mg, 0.003 mmol), and Et₃N (50 pL, 0.36 mmol). The reaction mixture was stirred at 65 °C for 1 h. A saturated solution of NH4CI was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography

251 (EtOAc/hexanes) to give 22 mg of the titled compound. ‘H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J = 9 Hz, IH), 7.67 (s, IH), 7.57 (m, 2H), 7.48 (m, IH), 7.40 (d, J = 9 Hz, IH), 7.29 (d. J - 9 Hz, IH), 7.24 (s, IH), 5.15 (s, IH), 4.16 (m, 2H), 2.57 (s, 3H), 1.51 (s, 6H), 1.20 (t, J = 7 Hz, 3H), 0.99 (s, 9H).

Step 8. Préparation of2-tert-butoxy-2-(l-(4-chlorophenyl)-7-(3-hydroxy-3methylbut-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (69): To a solution of ethyl 2tert-butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -hydroxy-3 -methylbut-1 -ynyl)-3 methylnaphthalen-2-yl)acctate (22 mg, 0.045 mmol) in 2:2:1 THF/MeOH/H₂O (1 mL total) was added a NaOH solution (4 M, 0.2 mL). The reaction mixture was stirred at 60 °C for 2 h. The mixture was partially concentrated and diluted with MeCN and H₂O and purified by reverse phase HPLC (MeCN/H₂O) to give 12 mg of the titled compound. 'H-NMR: 400 MHz, (CD₃OD) δ: 7.73 (d, J = 9 Hz, IH), 7.67 (s, IH), 7.57 (m, 3H), 7.38 (d, J 9 Hz, IH), 7.30 (d, J = 9 Hz, IH), 7.26 (s, 1 H), 5.16 (s, IH), 2.60 (s, 3H), 1.51 (s, 6H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H₂O + 0.05% HOAc, 5 min nin): t_R (min) = 3.40.

Example 68. 2-( 1,7-Bis(4-chIorophenyI)-3-in€thylnaphtha]en-2-yl)-2-tert-butoxyacetic acid (70)

2-( 1,7-bis(4-chloropheny l)-3methyinaphthalen-2-yl)-2-tertbutoxyacetic acid

Préparation of 2-( 1,7-bis(4-chlorophenyI)-3-methylnaphthalcn-2-yl)-2-tertbutoxyacetic acid (70): 2-(l,7-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tertbutoxyacetic acid (70)was prepared by the method of Example 67. Steps 5,6 and 8 from ethyl 2-(] ,7-bis(4-chlorophenyl) 3-methylnaphthaien 2-yl)-2 oxoacetate. which was a byproduct in Step 4. *H-NMR: 400 MHz, (CD3OD) ô: 7.88 (d, J = 8 Hz, 2H), 7.72 (m, 2H), 7.58 (m, 3H), 7.44 (m, 3H), 7.38 (d, J = 8 Hz, 2H), 5.19 (s, 1 H), 2.62 (s,

252

H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H₂O + 0.05%

HOAc, 5 min run): îr (min) = 3.83.

Example 69. 2-(7-Bromo-1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert5 butoxyacetic acid (71)

2-(7-bromQ-1-(4-chÎoraphenyl)-3' methylnaphthalen-2-yl)-2-terL butoxyacetic acid

Préparation of 2-(7-bromo- l-(4-chiorophenyl)-3-methylnaphthalen-2-yl)-2-tertbutoxyacetic acid (71): 2-(7-Bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-210 tert-butoxyacetic acid (71) was prepared by the method of Example 67 skipping step 7 from ethyl 2-(7-bromo-l-(4-chIorophenyl)-3-methylnaphthalen-2-yl)-2-tert~ butoxyacetate. ’H-NMR: 400 MHz, (CDjOD) Ô: 7.71 (m, 2H), 7.58 (m, 3H), 7.52 (dd, J = 9,2 Hz, IH), 7.33 (m, 2H), 5.15 (s, IH), 2.59 (s, 3H), 0.97 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H₂O + 0.05% HOAc, 5 min run): t_R (min) = 3.67.

Example 70. 2-tert-Butoxy-2-( 1 -(4-chloropheny 1)-7-(3,3-dimethylbut-1 -ynyl)-3 methylnaphthalen-2-yI)acetîc acid (72)

253

2-fert-butoxy-2-(l -(4-chloropheny I}7-(3,3-dimettiylbut-1 -ynyl)-3methylnaphthalen-2-yl)acetic acid

Préparation of2-tert-butoxy-2-(I-(4-chlorophenyl)-7-(3,3-dimethylbut-l-ynyl)3-methylnaphthalen-2-yl)acetic acid (72): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-(3,3dimethylbut-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (72) was prepared by the method of Example 67 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-

2- yI)-2-tert-butoxyacetate using t-butylacetylenc. ’H-NMR: 400 MHz, (CD3OD) δ:

7.70 (d, J = 8 Hz, 1H), 7.65 (s, 1Η), 7.57 (m, 3H), 7.33 (m, 2H), 7.19 (s, 1H), 5.16 (s,

1H), 2.59 (s, 3H), 1.27 (s, 9Η), 0.97 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2100% MeCN/H₂O + 0.05% HOAc, 5 min mn): t_R (min) = 3.78.

Examplc 71. 2-tert-Butoxy-2-(l -(4-chIorophenyl)-7-((l -hydroxycyclo-pentyljethynyl)-

3- methylnaphthalen-2-yI)acetic acid (73)

2-ter bbutoxy-2-( 1 -(4-chlorophenyl)7-((1 -hydroxycydopentyl)ethyny l)-3methylnaphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(l -(4-chloropheny 1)-7-((1 15 hydroxycyclopenty[)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (73): 2-tert-Butoxy2-(l-(4-chlorophenyI)-7-((l-hydroxycyclopentyl)ethynyl)-3-methylnaphthalen-2yl)acetic acid (73) was prepared by the method of Example 67 from ethyl 2-(7-bromo-

254 l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 1ethynylcyclopentanol. ’H-NMR: 400 MHz, (CD₃OD) δ: 7.73 (d, J = 9 Hz, 1H), 7.67 (s, 1H), 7.56 (m, 3H), 7.39 (d, J = 8 Hz, 1H), 7.30 (d, J = 8 Hz, 1H), 7.26 (s, 1H), 5.17 (s, 1H), 2.60 (s, 3H), 1.93 (m, 4H), 1.78 (m, 4H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50 x

4.6 mm, 2-100% MeCN/H₂0 + 0.05% HOAc, 5 min run): îr (min) = 3.56.

Example 72. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(cyclopentylethynyl)-3 methylnaphthaIen-2-yl)aœtic acid (74)

Cl

OH

2-tert-butoxy-2-(1 -(4-chtorophenyl)7-(cyc!openty!ethynyl)-3methylnaphthalen-2-yl)acetic acid

2-tert-Butoxy-2-( I -(4-chlorophenyi)-7-(cyclopentylethynyl)-3methylnaphthalen-2-yl)acetic acid (74): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7(cyclopentylethynyl)-3-methylnaphthalen-2-yl)acetic acid (74) was prepared by the method of Example 67 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen2-yl)-2-tert-butoxyacetate using ethynylcyclopentane.

‘H-NMR: 400 MHz, (CD3OD) δ: 7.56-7.71 (m, 6H), 7.32 (m, 1H), 7.19 (s, 1H), 5.16 (s, 1H), 2.79 (m, IH), 2.59 (s, 3H), 1.57-1.75 (m, 8H), 0.97 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H₂O + 0.05% HOAc, 5 min run): Ir (min) = 4.10.

Example 73. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-(cyclopropylethynyl)-3methylnaphthalen-2-yI)acetic acid (75)

255

2-terf-butoxy-2-(1 -(4-ctilorophenyl)7-(cyciopropylethynyl)-3methylnaphthalen-2-yl)acetic acid

Préparation of 2-tcrt-butoxy-2-(l -(4-chlorophenyl)-7-(cyclopropylethynyl)-3methylnaphthalen-2-yl)acetîc acid (75): 2-tert-Butoxy-2-(I-(4-chlorophenyi)'7(cyclopropylethynyl)-3-methyInaphthalen-2-yl)acetic acid (75) was prepared by the method of Example 67 from ethyl 2-(7-bromo-l-(4-chJorophenyl)-3-methylnaphthalen2-yl)-2-tert-butoxyacetate using ethynylcyclopropane.¹ H-NMR: 400 MHz, (CD3OD) δ;

7.69 (m, 2H), 7.57 (m, 3Η), 7.32 (m, 2Η), 7.18 (s, 1Η), 5.16 (s, 1H), 2.59 (s, 3H), 1.42 (br m, 1H), 0.97 (s, 9H), 0.83 (br m, 2H), 0.68 (br m, 2H). HPLC (Kinetex 2.6u, 50 x

4.6 mm, 2-100% MeCN/H₂O + 0.05% HOAc, 5 min run): t_R (min) = 3.78.

Example 74. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3-methyl-7-vinylnaphthalen-2yl)acetic acid (76)

2-fert-butoxy-2-(1-(4-chlorophenyl)3-methyl-7-vînylnaphthalen-2-yl) acetic acid

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-7-vinylnaphthalen15 2-yl)acetic acid (76): 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3-methyl-7-vinylnaphthalen2-yl)acetic acid (76) was prepared by the method of Example 67 from ethyl 2-(7bromo-l-(4-chlorophenyl)-3-methylnaphtha]en-2-yl)-2-tert-butoxyacetate using tributyl(vinyl)tin and without triethylamine.¹ H-NMR: 400 MHz, (CD3OD) Ô: 7.74 (d, J

256 = 9 Hz, IH), 7.65 (m, 2H), 7.55 (m, 3H), 7.32 (d, J = 9 Hz, I H), 7.13 (s, IH), 6.65 (dd, J = 18, Il Hz, IH), 5.71 (d, J= 18 Hz, IH), 5.19 (d, J = 11 Hz, lH),5.17(s, 1H),2.59 (s, 3H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H₂O + 0.05% HOAc, 5 min rua): t_R (min) = 3.99.

Example 75. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3-methyl-7-(2-mcthyIprop-1 enyl)naphthalen-2-yl)acetic acid (77)

2-Zeri-butoxy-2-( 1 -(4-chlorophenyl)-

3-methyk7-(2-fTteftiylpfop-1-enyi)naphthalen-2-yl) acetic acid

Préparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-7-(2-methylpropl-enyl)naphthalen-2-yl)acetic acid (77): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyl-

7-(2-methylprop-l-enyl)naphthalen-2-yI)acetic acid (77) was prepared by the method of Example 67 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2tert-butoxyacetate using 4,4,5,5-tetranjethyl-2-(2-methylprop-l-enyl)-l ,3,2dioxaborolane and K2CO3 instead of triethylamine, and toluene, éthanol, water as a solvent mixture. 'll-NMR: 400 MHz, (CD₃OD) δ: 7.69 (d, J = 8 Hz, IH), 7.61 (s, IH), 7.54 (m, 3 H), 7.27 (m, 2H), 7.02 (s, 1H),6.23 (s, IH), 5.18 (s, IH), 2.57 (s, 3H), 1.83 (s, 3H), 1.68 (s, 3H), 0.97 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H₂O + 0.05% HOAc, 5 min run): t_R (min) = 3.98.

Example 76. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3,7-dimethylnaphthalen-2-yl)acetic acid (78)

257

2-ierf-butoxy-2-( 1 -(4-chloropheny I)3,7-dimethylnaphthalen-2-yl) acetic acid

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-3,7-dimethylnaphthalen-2yl)acetic acid (78): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3,7-dimethylnaphthalen-2yl)acetic acid (78) was prepared by the method of Example 67 from ethyl 2-(7-bromo5 1-(4-chloropheny ])-3-methyInaphthalen-2-yl)-2-tert-buloxy acetate using trimethylboroxine and K.2CO3 instead of triethylamine, and toluene, éthanol, water as a solvent mixture.’H-NMR: 400 MHz, (CD5OD) δ: 7.65 (d, J = 8 Hz, IH), 7.61 (s, IH), 7.53 (m, 3H), 7.27 (m, 2H), 6.98 (s, IH), 5.15 (s, IH), 2.56 (s, 3H), 2.30 (s, 3H), 0.96 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% McCN/HjO + 0.05% HOAc, 5 min run): îr (min) 4.06.

Examnle 77. 2-tert-Butoxy-2-( 1 -(4-chIorophenyl)-7-((4-hydroxy-1 -methylpiperidin-4yl)ethynyl)-3-methylnaphthalen-2-yI)acetic acid (79)

2-ferf-butoxy-2-(1-(4-chlorophenyl)-7((4-hydroxy-1 -methy lpiperidin-4-y IJethy nyl)3-methylnaphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-7-((4-hydroxy-i methylpiperidîn-4-yl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (79): 2-tert-Butoxy2-(l -(4chlorophenyl)-7-((4-hydroxy-1 -methylpîperidin-4-yl)ethynyl)-3methylnaphthalen-2-yl)acetic acid (79) was prepared by the method of Example 68

258

from ethyl 2-(7-bromo-l-(4-chlorophenyI)-3-methylnaphthalen-2-yl)-2-tertbutoxyacetate using 4-ethyny]-l-methylpiperidin-4-ol. ’H-NMR: 400 MHz, (CD3OD) 8: 7.77 (d, J = 9 Hz, IH), 7.70 (br s, IH), 7.58 (m, 3H), 7.41 (d, J = 8 Hz, IH), 7.30 (m, 2H), 5.16 (s, IH), 3.35 (m, 4H), 2.89 (s, 3H), 2.60 (s, 3H), 2.15 (m, 4H), 0.98 (s, 9H). LCMS-ESI* (m/z): [M+H]*calcd for CnHjsCINCh: 520.2; found: 520.1.

Example 78. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-((4 -hydroxytetrahydro-2H-pyran-

4-yl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (80)

2-tert-butoxy-2-(1 (4-chlorophenyl)-7((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)3-methyinaphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7-((4-hydioxytetrahydro2H-pyran-4-yl)eÎhynyI)-3-methyliiaphthalen-2-yl)acetic acid (80): 2-tert-Butoxy-2-(l(4-chlorophenyl)-7-((4-hydroxytetrahydTo-2H-pyran-4-yl)ethynyl)-3methylnaphthalen-2-yl)acetic acid (80) was prepared by the method of Example 67 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen~2-yl)-2-tertbutoxyacetate using 4-ethynyltetrahydro-2H-pyran-4-ol. ’H-NMR: 400 MHz, (CD3OD) δ: 7.76 (d, J = 8 Hz, 7.68 (s, IH), 7.57 (m, 3H), 7.42 (d, J = 9 Hz, IH), 7.30 (m, 2H),

5.16 (s, IH), 3.85 (br m, 2H), 3.65 (br m, 2H), 2.60 (s, 3H), 1.92 (br m, 2H), 1.77 (br m, 2H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H₂O + 0.05% HOAc, 3.5 minrun): îr (min) = 2.41.

Example 79. 2-tert-Butoxy-2-( l-(4-chlorophenyl)-3-methyl-7-((l -methyl-1 H-imidazol-

5-yl)ethynyl)naph.thalen-2-yl)acetic acid (81)

259

2-tert-butoxy-2-(1-(4-chlorophenyl)-3-rnethyl7-((1-methyÎ-1H-irTi!dazol-5-yl)ethyny[) naphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-7-(( 1 -methyl-1Himidazol-5-yl)ethynyl)naphthalen-2-yl)acetic acid (81): 2-tert-Butoxy-2-(l-(4chlorophenyl)-3 -methyl-7-(( 1 -methyl-1 H-imidazoI-5-yI)ethynyl)naphthalen-2-yl)acetic 5 acid (81 ) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1 -(4chlorophenyl)-3-methylnaphthalen-2-y])-2-tert-butoxyacetate using 5-ethynyl-lmethyl-lH-imidazole. *H-NMR: 400 MHz, (CD₃OD) δ: 8.80 (br s, 1H), 7.87 (d, J = 8 Hz, 1H), 7.76 (s, 1H), 7.58 (m, 5H), 7.48 (s, 1H), 733 (d, J = 8 Hz, 1H), 5.18 (s, 1H),

3.92 (s, 3H), 2.63 (s, 3H), 0.98 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for

C29H28C1N₂O₃: 487.2; found: 487.2.

Example 80. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(3-ethyl-3-hydroxypent-1 -ynyl)-3metliylnaphthalen-2-yl)acetic acid (82)

2-tert-butoxy-2-(1-(4-chlorophenyl)-7(3-ethyl-3-hydroxypent-1 -yny))-3methy1naphthàlen-2-y))acetic acid

Préparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7-(3-ethyl-3-hydroxypent-1 ynyl)-3-methylnaphthalen-2-yl)acetic acid (82); 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7(3-ethyl-3-hydroxypent-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (82) was prepared

260 by the method of Example 67 from ethyl 2-(7-bromo-l-(4-chIorophenyI)-3methylnaphthalen-2-yl)-2-tert-butoxyacetaîe using 3-ethylpent-l-yn-3-ol. ’H-NMR:

400 MHz, (CD₃OD) Ô: 7.74 (d, J = 8 Hz, IH), 7.67 (s, IH), 7.58 (m, 3H), 7.40 (d, J = 8 Hz, IH), 7.30 (m, 2H), 5.17 (s, IH), 2.59 (s, 3H), 1.69 (m, 4H), 1.01 (m, 6H), 0.98 (s,

9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H₂O + 0.05% HOAc, 3.5 min run): te (min) = 2.64.

Example 81, 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-((l-hydroxycyclohexyl)ethynyl)-

3-methylnaphthalen-2-yl)acetic acid (83)

2-tert-butoxy-2-( 1 -{4-chloroptienyl)-7((1 -hydroxy cyclohexyljethy ny lj-3IQ methylnaptittialen-2-yi)acetic acid

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-7-((lhydroxycyclohexyl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (83): 2-tert-Butoxy2-(l-(4-chlorophenyI)-7-((l-hydroxycyclohexyl)ethynyl)-3-methylnaphthalen-2yl)acetic acid (83) was prepared by the method of Example 67 from ethyl 2-(7-bromo15 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-y l)-2-tert-butoxyacetate using 1 ethynylcyclohexanol. ’H-NMR: 400 MHz, (CD₃OD) δ: 7.75 (d, J = 8 Hz, IH), 7.68 (s,

IH), 7.58 (m, 3 H), 7.40 (d, J = 8 Hz, IH), 7.31 (d, J = 8 Hz, IH), 7.28 (s, lH),5.17(s, IH), 2,60 (s, 3H),1.91 (m, 2H), 1.57-1.71 (m, 8H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H₂O + 0.05% HOAc, 3.5 min run): t_R (min) = 2.66.

Example 82. 2-(7-(( 1 -Aminocyclohexyl)ethyiiyl)-1 -(4-chlorophcnyl)-3 methylnaphthalen-2-yI)-2-tert-butoxyacetic acid (84)

261

2-(7-((1-aminocydohexyl)ethynyl)-1(4-chbropheriyI)-3-methylnaphthalen-2-y1)2-fôrt-butoxyacetic acid

Préparation of2-(7-((l-aminocyclohexyl)ethynyl)-l-(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (84): 2-(7-((1Amînocyclohexyl)ethynyl)-1 -(4-chlorophenyi)-3-methylnaphthalen-2-yl)-2-tert5 butoxyacetic acid (84) was prepared by the method of Example 67 from ethyl 2-(7bromo-H4-chlorophenyl)-3-methylnaphthalen-2-yI)-2-tert-butoxyacetatc using 1ethynylcyclohexanamine. ’H-NMR: 400 MHz, (CDjOD) δ: 7.82 (d, J = 8 Hz, IH), 7.72 (s, IH), 7.56 (m, 3H), 7.47 (d, J = 8 Hz, 1 H), 7.37 (s, IH), 7.31 (d, J = 8 Hz, IH), 5.20 (s, IH), 2.60 (s, 3H), 2.11 (m, 2H), 1.63-1.85 (m, 8H), 0.99 (s, 9H).

LCMS-ESr (m/z): [M-NH₂]⁺ calcd for C₃|H₃₂CIO₃: 487.2; found: 487.2.

Example 83. 2-(7-(3-Amino-3 -methylbut-1 -ynyl)-1 (4-chlorophenyl)-3 methylnaphthalen-2-yI)-2-tert-butoxyacetic acid (85)

2-(7-( 3-amino-3-methy lbut-1 -yny l)-1 (4-chtorophenyl)-3-methylnaphthalen-2-yl)2-te/7-butoxyacetic acid

Préparation of 2-(7-(3-amino-3-methylbut-l-ynvl) l (4-chlorophcnyl)-3 methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (85): 2-(7-(3-Amino-3-methylbut-lynyl)-l-(4-chlorophenyl)-3-methylnaphthaien-2-yl)-2-tert-butoxyacetic acid (85) was prepared by the method of Example 67 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-

262 methylnaphthalen-2-yl)-2-tert-buÎoxyacetate using 2-methylbut-3-yn-2-amine. ΉNMR: 400 MHz, (CD₃OD) δ: 7.8J (d. J - 8 Hz, IH), 7.72 (s, IH), 7.57 (m, 3H), 7.45 (d, J “S Hz. IH), 7.35 (s, IH), 7.30 (d,J = 8Hz, lH),5.16(s, 1H),2.62 (s, 3H), 1.68 (s, 6H), 0.98 (s, 9H). LCMS-ESI* (m/z): [M-NH₂]* calcd for Cis^gClCh: 447.2; found: 446.9.

Example 84. (S)-2-((R)-7-(3-Amino-3 -methylbut-1 -ynyl)-1 -(2,3 -dihydropyrano[4,3,2de]quinolin-7-yl)-3-methylnaphthalen-2-yI)-2-tert-butoxyacetic acid (86)

(S)-2-((R)-7-(3-amino-3-methylbut-1 -y ny l)-1 (2,3-dihydrapyrano[4,3₁2-de}quinoNn-7-yl)-3methylnaphthalen-2-yl)-2-terf-butoxyacetic acid

Préparation of (S)-2-((R)-7(3-amino-3-methylbut-l-ynyl)-l-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yI)-2-tert-butoxyacetic acid (86): (S)-2-((R)-7-(3-Amino-3-methylbut-l -ynyl)-l-(2,3-dihydropyrano[4,3,2de]qumolm-7-yl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (86) (racemic with relative stereochenûstry) was prepared by the method of Example 67 from ethyl 2-(7bromo-3-methyl-l-(trifluoromeÎhylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate using

2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid. The remainder of the sequence follows the method of Example 67 using 2-methylbut-3-yn-2-amine was Step 7. 'HNMR: 400 MHz, (CD₃OD) δ: 8.72 (d, J = 6 Hz, IH), 8.00 (s, IH), 7.96 (d, J = 8 Hz, IH), 7.83 (m, 2H), 7.52 (dd, J = 8,2 Hz, 1 H), 7.46 (d, J = 8 Hz, IH), 7.07 (s, IH), 5.21 (s, IH), 4.73 (m, 2H), 3.68 (t, J = 6 Hz, 2H), 2.78 (s, 3H), 1.61 (s, 6H), 0.92 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]*calcd for C3₃H₃sN₂O₄: 523.3; found: 523.1.

Example 85. 2-(7-(3-Amino-3-methylbut-l-ynyl)-l-(chroman-6-yl)-3methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (87)

263

2-(7-( 3-am!no-3-methyibut-1-ynyÎ)-1(chroman-6-yf)-3-methylnaphthalen-2-yl)2-terf-butoxyacetic acid

Préparation of 2-(7-(3-amino-3-methylbut-l -ynyl)-l -(chroman-6-yl)-3methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (87): 2-(7-(3 - Aniino-3-methy lbut-1ynyl)-l-(chroman-6-yl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (87) was prepared by the method of Example 67 from ethyl 2-(7-bromo-3 -methyl-1(trifluoromethylsulfonyIoxy)naphthalen-2-y])-2-oxoacetate using chroman-6-ylboronic acid. The remainder of the sequence follows the method of Example 67 using 2methylbut-3-yn-2-aniine in Step 7.¹ H-NMR: 400 MHz, (CD₃OD) S: 7.77 (d, J = 8 Hz, 1H), 7.66 (s, 1H), 7.48 (s, 1H), 7.45 (m, 1H), 7.23 (m, 1H), 6.90 (m, 2H), 5.31 (s, 1H),

4.28 (t, J = 5 Hz, 1 H), 2.87 (m, 2H), 2.58 (s, 3H), 2.08 (m, 2H), 1.68 (s, 6H), 0.99 (s,

9H). LCMS-ESI* (m/z): [M-NH₂]* calcd for C₃₁H₃₃O₄:469.2; found: 469.2.

Example 86. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-(3-hydroxy-3-phenylbut-l-ynyl)3-methylnaphthalen-2-yl)acetic acid (88)

2-fert-butoxy-2-(1-(4-chlorophenyl}-7(3-hydroxy-3-pheny ibut-1 -ynyl)-3methylnaphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-( 1 -(4-chloropheny 1)-7-(3 -hydroxy-3 -phenylbutl-ynyi)-3-niethylnaphthalen-2-yl)acetic acid (88): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-

7-(3-hydroxy-3-phenylbut-l-ynyl)-3-methy!naphthalen-2-yl)acetic acid (88) was

264

prepared by the method of Example 67 from ethyl 2-(7-bromo-l-(4-chlorophenyI)-3methylnaphthalen-2-yI)-2-tert-butoxyacetate using 2-phenylbut-3-yn-2-ol. ’HAMR: 400 MHz, (CD₃OD) δ: 7.76 (d, J = 8 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J = 8 Hz, 2H), 7.57 (m, 3H), 7.46 (d, J = 8 Hz, 1H), 7.33 (m, 5H), 5.18 (s, 1H), 2.61 (s, 3H), 1.75 (s, 3H), 5 0.98 (s, 9H). LCMS-ESI* (m/z): [M-OH]⁺calcd for C33H30CIO3: 509.1; found: 508.8.

Example 87. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(3 hydroxy-3 -methylbutyl)-3methylnaphthalen-2-yl)acetic acid (89)

2-tert-bLrtoxy-2-( 1-(4chlorophenyl)7-(3-hydroxy-3-methylbut-1 ynyl)-3methylnaphthalen-2-yl)acetic acid

2-tert-butoxy-2-(1-{4-chlorophenyl)7-(3-hydroxy-3-methyfbutyl)-3methylnaphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -hydroxy-3methylbutyl)-3-methylnaphthalen-2-yl)acetic acid (89): To a solution of 2-tert-butoxy2-(l -(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-1 -ynyl)-3-methylnaphthalen-2yl)acetic acid (8 mg, 0.017 mmol) in EtOH (1 mL) was added rhodium on alumina (2 mg). The reaction was flushed with hydrogen gas and then stirred under and hydrogen atmosphère for 1 h. The reaction was filtered and concentrated in vacuo to give 7 mg of the titled compound. ^lH-NMR: 400 MHz, (CD3OD) δ: 7.68 (d, J = 8 Hz, 1H), 7.63 (m, 1H), 7.61 (s, 1H), 7.53 (m, 2H), 7.30 (m, 2H), 7.05 (s, 1H), 5.12 (s, 1H), 2.65 (m, 2H),

2.59 (s, 3H), 1.66 (m, 2H), 1.19 (s, 6H), 0.96 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100%MeCN/HzO + 0.05% HOAc, 4.0 min run): t_R (min) = 3.52.

Example 88. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(2-cyclopcntylethyl )-3 methylnaphthalen-2-yl)acetic acid (90)

X

265

2-terf-butoxy-2-( 1 -(4-chiorophenyl)7-(2-cydopentylethyl)-3methyfnaphthaten-2-y!)acetic acid

Préparation of 2-tert-butoxy-2-(l -(4-chloropheny 1)-7-(2-cyclopentylethyl)-3 methylnaphthalen-2-yl)acetic acid (90): 2-tert-Butoxy-2-(l-(4-chloropheny 1)-7-(2cyclopentylethyI)-3-methylnaphthalen-2-yl)acetic acid (90) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7(cyclopentylethynyI)-3-methylnaphthalen-2-yl)acetic acid. ^lH-NMR: 400 MHz, (CD3OD) δ: 7.69 (d, J = 9 Hz, IH), 7.63 (s, IH), 7.56 (m, 3H), 7.29 (m, 2H), 6.99 (s,

IH), 5.18 (s, IH), 2.60 (m, 2H), 2.58 (s, 3H), 1.71 (m, 3H), 1.52 (m, 6H), 1.07 (m, 2H),

0.98 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H₂O + 0.05% HOAc,

5.0 min run): îr (min) = 4.54.

Example 89. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-(2-(l-hydroxycyclopentyl)ethyl)3-methylnaphthalen-2-yl)acetic acid (91)

2-tert-butoxy-2-(1-(4-chloropheny l)-7 (2-(1-hydroxycydopentyl)ethyl)-3methy)naptithalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl )-7-(2-( 1 hydroxycyclopentyl)ethyI)-3-methylnaphthalen-2-yl)acetic acid (91): 2-tert-Butoxy-2( 1 -(4-chloropheny 1)-7-(2-( 1 -hydroxycyclopenty l)ethy l)-3-methylnaphthalen-2-yl)acetic acid (91) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(l-(4-

Cr 266 chlorophenyl)-7-(( I -hydroxycyclopentyl)ethynyl)-3 -methyInaphthalen-2-yl)acetic acid. ’H-NMR: 400 MHz, (CD₃OD) δ: 7.78 (d, J = 8 Hz, IH), 7.67 (d, J = 8 Hz, IH), 7.58 (s, 1H), 7.51 (m, 2H), 7.29 (m, 2H), 7.07 (s, IH), 5.05 (s, IH), 2.70 (m, 2H), 2.62 (s, 3H),

1.75 (m, 4H), 1.61 (m, 6H), 0.94 (s, 9H). HPLC (Kjnetex 2.6u, 50 x 4.6 mm, 2-100%

MeCN/HzO + 0.05% HOAc, 4.0 min nin): Ir (min) = 3.69.

Example 90. 2-tert-Butoxy-2-(l-(4-ch]orophenyl)-7-(2-cyclopropylethyl)-3methylnaphthalen-2-yI)acetic acid (92)

2-tert-butoxy-2-(1-(4“Chiorophenyl)7-(2-cyclopropylethyl)-3methy!naphthalen-2-y))acetic acid

Préparation of 2-tert-butoxy-2-(I-(4-chlorophenyI)-7-(2-cycIopropylethyl)-3methyInaphthalen-2-yl)acetic acid (92): 2-tcrt-Butoxy-2-(l-(4-chlorophenyI)-7-(2cyclopropylethyl)-3-methyInaphthalen-2-yl)acetic acid (92) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(l-(4-chlorophenyl)-7(cyclopropylethynyl)-3-methylnaphtha]en-2-yl)acetic acid. ’H-NMR: 400 MHz, (CD₃OD) δ: 7.73 (d, J = 9 Hz, IH), 7.67 (s, IH), 7.60 (m, 3H), 7.35 (m, 2H), 7.06 (s, IH), 5.21 (s, IH), 2.72 (t, J = 7 Hz, 2H), 2.62 (s, 3H), 1.48 (m, 2H), 0.94 (s, 9H), 0.65 (m, IH), 0.37 (m, 2H), 0.01 (m, 2H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% McCN/HjO + 0.05% HOAc, 5.0 min run): îr (min) = 4.02.

Example 91. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-ethyl-3-methylnaphthalen-2yl)acetic acid (93)

267

2-terf-butoxy-2-( 1 -(4-chiorophenyf)7-ethyl'3-mettiyinaphthaten'2-yi) acetic acid

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-7-ethyl-3-methylnaphthalen2-yl)acetic acid (93): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-ethyl-3-methylnaphthalen2-yl)acetic acid (93) was prepared using the procedure of Example 87 from 2-tert5 butoxy-2-(l-(4-chlorophenyl)-3-methy]-7-vinylnaphthalen-2-yl)acetic acid. ’H-NMR:

400 MHz, (CD₃OD) Ô: 7.74 (d, J = 8 Hz, IH), 7.67 (d, J = 8 Hz, IH), 7.59 (s, IH), 7.53 (m, 2H), 7.29 (m, 2H), 7.04 (s, IH), 5.07 (s, IH), 2.60 (m, 5H), 1.15 (t, J = 7 Hz, 3H), 0.94 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H₂O + 0.05% HOAc, 4.0 min run): t_R (min) = 3.81.

Example 92. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7~i sobutyl-3-methylnaphthalen-2yi)acetic acid (94)

2-tert-butoxy-2-(1-(4-chlorophenyl)-7isobutyl-3-methylnaphthaien-2-yl) acetic acid

Préparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-7-isobutyl-3methylnaphthalen-2-yI)acetic acid (94): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7isobutyl-3-methylnaphthalen-2-yl)acetic acid (94) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(l-(4-cMorophenyl)-3-methyl-7-(2-methylprop~lA

268 enyl)naphthalen-2-yl)acetic acid. Ή-NMR: 400 MHz, (CD^OD) δ: 7.66 (m, 3H), 7.55 (m, 2H), 7.28 (m, 2H), 6.97 (s, I H), 5.13 (s, 1H), 2.59 (s, 3 H), 2.44 (d, J = 7 Hz, 2H), 0.96 (s, 9H), 0.83 (m, 6H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCNZH₂O + 0.05% HOAc, 4.0 min run): t_R (min) = 3.03.

Examnle 93, 2-tert-Sutoxy-2-( 1 -(4-chlorophenyl)-7-(3-(dnnethylamino)-3 -methylbut-

l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (95): Cl	Cl
1 il h₂nJ A-A	₀A	I ₍/NJ
	Λ,οη	*	fVvSr^OH
	\ ⁰		Av+k ⁰
2-(7-(3-amino-3-methylbut-1-yny!)-1 (4-chlorophenyt)-3-methyfnaphtha!en-2-ylF		95

2-fert-butoxyacetic acid

2-fert-butoxy-2-( 1 -(4-chloropheny l)-7(3-(dimethylamino)-3-methylbLit-1-ynyl)-3metbylnaphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-7-(3-(dimethylamino)-3methylbut-l-ynyI)-3-methyInaphthalen-2-yl)acetic acid (95): To a solution of 2-(7-(3amino-3-methylbut-1 -ynyl)-l -(4-chIorophenyl)-3-methylnaphthalen-2-yl)-2-tertbutoxyacetic acid (12 mg, 0.026 mmol) in MeOH (1 mL) was added acetic acid (100 pL), formaldéhyde (50 pL, 37% in water), and sodium triacetoxyborohydride (10 mg). After 30 min, the reaction mixture was fîltered and purified by reverse phase HPLC (MeCN/FLO w/ 0.1% TFA) to give 4 mg of the titled compound.

’H-NMR: 400 MHz, (CDjOD) Ô: 7.85 (d, J = 8 Hz, 1H), 7.74 (s, 1H), 7.57 (m, 3H),

7.51 (d, J =8 Hz, 1H), 7.40 (s, 1H), 7.31 (d,J = 8Hz, 1H), 5.16 (s, lH),2.97(s, 6H),

2.62 (s, 3H), 1.75 (s, 6H), 0.98 (s, 9H). LCMS-ESI* (m/z): [M+H]* calcd for C30H35CINO3: 492.2; found: 492.0.

Example 94. 2-(7-(3-Acetamido-3-methylbut-1 -ynyl)-1 -(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (96)

269

2-(7-( 3-amino-3-methylbut-1 -y nyl)-1 (4-chloraphenyl)-3-methylnaphthalen-2-yl)2-tert-butoxyacetic acid

2-(7-(3-acetamido-3-methy lbut-1 -y nyl)-1 (4-chlorophenyl)-3-methylnaphthalen-2-yl)2-tert-butoxyacetic acid

Préparation of 2-(7-(3-acetamido-3-methylbut-l -ynyl)-1 -(4-chlorophenyl)-3methylnaphthalcn-2-yl)-2-tert-butoxyacctic acid (96): To a solution of2-(7-(3-amino-3methylbut-l-ynyl)-l-(4-chIorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (12 mg, 0.026 mmol) in CH₂C1₂ (1 mL) was added triethylamine (50 pL) and acetic anhydride (10 pL) and trace DMAP. After 30 min, the réaction mixture was filtered and purified by reverse phase HPLC (MeCN/H₂O w/ 0.1% TFA) to give 10 mg ofthe titled compound. 'il-NMR: 400 MHz, (CD3OD) Ô: 7.73 (d, J = 9 Hz, IH), 7.67 (s, IH), 7.58 (m, 3H), 7.40 (d, J = 9 Hz, IH), 7.32 (d, J = 9 Hz, IH), 7.27 (s, IH), 5.16 (s, IH), 2.60 (s, 3H), i .90 (s, 3H), 1.61 (s, 6H), 0.98 (s, 9H). LCMS-ESΓ (m/z):

[M+H]⁺ calcd for C30H33CINO4: 506.2; found: 506.0.

Example 95. 2-tert-Butoxy-2-(l (4-chlorophenyl)-7-(3-(methoxycarbonylamino)-3methyIbut-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (97)

2-tert-butoxy-2-(1-(4-chlorQphenyl)-7(3-(methoxycarbonylamino)-3-methylbut-1-yny[)-3methyînaphtha1en-2-y1)acetic acid

Préparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-7-(3(methoxycarbonylamino)-3-methylbut-1 -ynyl)-3-methylnaphthalen-2-yl)acetic acid (97): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-(3-(methoxycarbonylamino)-3-methylbut-

270 l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (97) was prepared by the method of Example 94 from 2-(7-(3-amino-3-methylbut-l-ynyl)-l-(4-chlorophenyi)-3methylnaphthalen-2-yl)-2-tert-butoxyacetic acid using methyl chloroformate. 'H-NMR: 400 MHz, (CD₃OD) δ: 7.72 (d, J = 8 Hz, IH), 7.67 (s, 1H), 7.57 (m, 3H), 7.40 (d, J = 8 Hz, IH), 7.31 (d, J = 9 Hz, 1H), 7.26 (s, IH), 5.16 (s, IH), 3.60 (s, 3H), 2.60 (s, 3H),

1.58 (s, 6H), 0.98 (s, 9H). LCMS-ESI* (m/z): [M+HJ*calcd for C30H33CINO5: 522.2; found: 522.1.

Example 96. (S)-2-(7-(3-Amino-3 -methylbut-1 -yny 1)-1 -(4-chlorophenyl)-3 methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (98)

(S)-2-(7-(3-amino-3-metbylbut-1-ynyl)1-(4-chlorophenyl)-3-methylnaphthaten-2-yl}2-terf-butoxyacetic acid

Préparation of (S)-2-(7-(3-ammo-3-methylbut-l-ynyl)-l-(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (98): (S)-2-(7-(3-Amino-3-rnethyIbutl-ynyl)-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (98) was prepared by the method of Example 67 using the réduction method of Example 51, step 3, for (S)-ethyI 2-(l-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate instead of step 5, NaBH₄ step, from ethyl 2-(7biomo-l-(4-chlorophenyl)-3-methylr.aphlha!en-2-yl)-2-oxoacetate. The remaînder of the sequence follows the method of Exampie 67 using 2-methylbut-3-yn-2-amine in Step 7. ¹ H-NMR: 400 MHz, (CD3OD) δ; 7.81 (d. J - 8 Hz, 1II), 7.72 (s, IH), 7.57 (m, 3H), 7.45 (d, J = 8 Hz, IH), 7.35 (s, 1 H), 7.30 (d, J = 8 Hz, 1 H), 5.16 (s, IH), 2.62 (s, 3H), 1.68 (s, 6H), 0.98 (s, 9H). LCMS-ESI* (m/z): [M-NH2]⁺calcd for C2èîH_?._xClO₍: 447.2; found: 446.9.

Exampïe 97. (S)-2-tert-Butoxy-2-( l -(4-chlorophenyl)-7-(3-hydroxy-3 -methylbut-1 ynyl)-3-methylnaphthalen-2-yl)acetic acid (99)

(S)-2-fert-butoxy-2-( 1 -(4-ch!orophenyl}-7(3-hydroxy-3-methylbut-1 -ynyl)-3methylnaphthalen-2-y))acetic acid

Préparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-7-(3-hydroxy-35 methylbut-l-ynyl)-3-methyInaphthalen-2-yl)acetic acid (99): (S)-2-tert-Butoxy-2-(l-(4chlorophenyl)-7-(3-hydroxy-3-methylbut-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (99) was prepared by the method of Example 67 using the réduction method of Example 51 step 3 for (5)-ethyl 2-(l-(4-chlorophcnyI)-3-methyl-6(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate instead of step 5,

NaBlfr step, from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2oxoacetate. The remainder of the sequence follows the method of Example 67 using 2methylbut-3-yn-2-ol in Step 7. ’H-NMR: 400 MHz, (CD₃OD) δ: 7.73 (d, J = 9 Hz, 1H),

7.67 (s, 1H), 7.57 (m, 3H), 7.38 (d, J - 9 Hz, 1H), 7.30 (d, J = 9 Hz, 1H), 7.26 (s, 1H),

5.16 (s, 1H), 2.60 (s, 3H), 1.51 (s, 6H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 15 2-100% MeCN/lEO + 0.05% HOAc, 5 min run): îr (min) = 3.40.

Exampïe 98. (S)-2-(7-(( 1 -Aminocyclohexyl)ethynyl)-1 -(4-chloiophenyl)-3 methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (100)

272

(8)-2-(7-(( 1 -aminocyclohexy l)ethynyl)-1 (4-chlorophenyl)-3-methylnaphthalen-2-yi)2-tert-butoxyacetic acid

Préparation of (S)-2-(7-((l-aminocyclohexyl)ethynyi)-l -(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (100): (S)-2-(7-((lAminocyclohexyl)ethynyl)-l-(4-chiorophenyl)-3-mcthylnaphthalen-2-y!)-2-tert5 butoxyacetîc acid (100) was prepared by the method of Example 67 using the réduction method of Example 51 step 3 for (S)-ethyl 2-(l-(4-chlorophenyl)-3-methyl-6(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate instead of step 5, NaBiLstep, from ethyl 2-(7-bromo-l-(4-chloropheny])-3-methylnaphthalen-2-yl)-2oxoacetate. The remainder of the sequence follows the method of Example 67 using 110 ethynylcyclohexanamine in Step 7. ¹ H-NMR: 400 MHz, (CD3OD) δ: 7.82 (d, J = 8 Hz, 1H), 7.72 (s, 1H), 7.56 (m, 3H), 7.47 (d, J = 8 Hz, 1H), 7.37 (s, 1H), 7.31 (d, J = 8 Hz, 1H), 5.20 (s, 1H), 2.60 (s, 3H), 2.11 (m, 2H), 1.63-1.85 (m, 8H), 0.99 (s, 9H). LCMSESf (m/z): [M-NH₂f calcd for Cs^ClOj: 487.2; found: 487.2.

273

Example 99. (S)-2-tert-Butoxy-2-((R)-6-chJoro-l -(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-fïuoro-3-methyliiaphthalen-2-yl) acetic acid (101)

2-(3-chtoro-4fluorophenyljacebc acid

1-(3-chtoro-4fluorophenyl)propan 2-one

ethyl 4-(3-chloro-4fluorophenyl)-3methylbut-2-enoate

6-chloro-7-fluoro-3methylnaphthalen-1 -ol

ethyl 2-(6-chloro-7-fluoro-1hydroxy-3-methylnaphthalen2-yl)-2-hydroxyacetate ethyl 2-{6-chloro-7-fluDro-3-methyH(((trffluoromettiyl)sulfonyl)oxy)naphtha len-2-yl)-2-hydroxyacetate

OTf O

OTf OH

ethyl 2-(6-ctiloro-7-fluoro-3-methyl-1(((trifluoromethyl)sulfonyl)oxy)naphth aleri’2-yl)-2-oxoacetate (S)-ethyl 2-(6-chioro-7fluoro-3-m ethyl-1 (((trifluorofnethyl)sulfonyl)o xy) naphthalen-2-yl)-2hydroxyacetate

274

2,3-dihydropyrano[4,3,2de}quinolin-7-y!boronic aod, HCl sait (fî)-ethyl 2-(ferf-butaxy)-2-(6-chloro-7-fluorc-3-mettiyl-1 (((trifluoromethyl)sulfonyl)oxy)naptiihaÎen-2-yl)acetate

(S}-ethyl 2-(fert-butoxy)-2-((R)-6chloro-1-(2,3-dihydropyrano[4,3,2cfe]quinolin-7-y[)-7-fluoro-3methylnaphthaIen-2-yt)acetate (S)-ethy 12-(teff-butoxy)-2-((S)-6chtoro-1 -(2,3-dihydropy rano[4,3,2de]quinolin-7-yl)-7-fluoro-3methylnaphthalen-2-yl)acetate

101 ( S)-2-(te/7-butoxy)-2-((R)-6-chloro1 -(2,3-dihydropyrano[4,3,2de}quinolin-7-yl)-7-fluoro-3methylnaphthalen-2-yl)acetic acid

Préparation of l-(3-chloro-4-fluorophenyl)propan-2-one: To a solution of 2-(3chloro-4-fluorophenyl)acetic acid (18.46 g, 97.89 mmol) în acetic anhydride (463 mL) was added À'-methylimidazolc (3.9 mL) and the reaction mixture was stirred overnight 5 at room température. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution and organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a colorless

275 oil (14.5 g, 79%). Ή NMR (400 MHz, CDC1₃) δ 7.23 (dd, J = 6.9, 2.1 Hz, IH), 7.14 7.00 (m, 2H), 3.66 (s, 2H), 2.19 (s, 3H).

Préparation of ethyl 4-(3-chloro-4-fluorophenyI)-3-methylbut-2-enoate: To a solution of triethylphosphonoacetate (25.3 mL, 126.2 mmol) in anhydrous tetrahydrofuran (250 mL) at 0 °C was added 60% sodium hydride (5.15 g, 126.2 mmol) and the resulting mixture stirred for 30 minutes. 1 ~(3-chloro-4-fluoropbenyl)propan-2one (15.7 g, 84,13 mmol) in tetrahydrofuran (10 mL) added and the reaction mixture was stirred for 2 hours and quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate and organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give mixture of E/Z isomers (17.2 g, 80%). E isomer: Ή NMR (400 MHz, CDCI3): δ 7.19 (dd, J = 7.0,2.1 Hz, IH), 7.12 - 6.97 (m, 2H), 5.64 (d, J = 1.2 Hz, 1 H), 4.13 (dq, J =

14.4, 7.2 Hz, 3H), 3.36 (s, 2H), 2.03 (s, 3H), 1.26 (dd, J = 15.9, 7.2 Hz, 3H); Z isomer: ‘H NMR (400 MHz, CDCI3): δ 7.28 (dd, J = 7.1, 2.1 Hz, IH), 7.15-6.98 (m, 2H), 5.79 (s, IH), 4.17 (dq, J = 14.3, 7.1 Hz, 2H), 3.37 (s, 2H), 1.79 (s, 3H), 1.29 (dd, J = 15.1,

7.2 Hz, 3 H).

Préparation of 6-chioro-7-fluoro-3-methylnaphthalen-l-ol: A solution of ethyl

4-(3-chloro-4-fluorophenyl)-3-methylbut-2-enoate (9.7 g, 37.8 mmol) in concentrated sulfuric acid (40 mL) was stirred at 50 °C overnight. The reaction mixture was poured onto ice and diluted with water and extracted with ethyl acetate. The organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a pale yellow solid (1.57 g). ’H-NMR: 400 MHz, (CDCI3) Ô:

7.83 (d, J10.4 Hz, IH), 7.75 (d, J = 7.2 Hz, IH), 7.11 (s, IH), 6.67 (s, IH), 2.42 (s, 3H).

Préparation of ethyl 2-(6-chloro-7-lluoro-l hydroxy-3-methylnaphthalen-2-yl)2-hydroxyacetate: To a mixture of 6-chloro-7-fluoro-3-methylnaphthalen-l -ol (2.24 g,

13.78 mmol) in anhydrous dichloromethane (100 mL) at -40 °C was added a 1 M titanium(FV) chloride solution in dichloromethane (13.78 mL, 13.78 mmol) and stirred for 45 min. Ethyl glyoxylate (1.69 g, 16.54 mmol) dissolved in dichloromethane (5 mL) was added over 15 minutes and stirred for 1 hour at -40 °C. The reaction was quenched by the addition of Rochelle’s sait solution and stirred at room température for

2.5 hours. The resulting mixture was washed with water and aqueous layer backextracted with dichloromethane (2x). The combined organic layer was dried (MgSO₄),

276 filtered, concentrated and purified by flash column chromatography (silica gel, 5 to 30% ethyl acetate/hexanes) to give an off-white solid (2.53 g). ’H-NMR: 400 MHz, (CDCl₃) δ : 8.48 (s, IH), 7.89 (d, J = I0.5 Hz, IH), 7.70 (d, J = 7.2 Hz, IH), 7.11 (s, IH), 5.67 (s, IH), 4.30 (dq J = 10.8, 7.1 Hz, IH), 4.15 (dq,J= 10.8, 7.1 Hz, 1 H), 3.61 (s, IH), 2.52 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). LCMS-ESI* (m/z): [M+H]⁺calcd for C15H13CIFO4: 311.7; Found: 311.0.

Préparation of ethyl 2-(6-chloro-7-fluoro-3 -methyl-1(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate: To a solution of ethyl 2-(6-chloro-7-fluoro-l -hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate (4.13 g,

13.22 mmol) inanhydrous dichloromethane (120 mL)at 0 °C was added imidazole (1.215 g, 17.85 mmol), followed by chlorotriethylsilane (2.55 mL, 15.2 mmol). The cloudy reaction mixture was stirred for 1.5 hours, quenched with water and diluted with dichloromethane. The mixture was washed with 1 N HCl solution/brine and organic layer dried (MgSCL), filtered, concentrated to give an orange oil that used in next step without forther purification.

The above residue was dissolved in anhydrous dichloromethane (130 mL) containing triethylamine (2.21 mL, 15.86 mmol) and cooled in a dry ice/acetone bath. Trifluoromethanesulfonic anhydride (2.45 mL, 14.54 mmol) was added dropwise over 20 minutes and stirred for 1 hour. The reaction was quenched with brine and stirred for 15 minutes at room température. The mixture was diluted with dichloromethane, washed with 1 N HCl solution, saturated sodium bicarbonate solution/brine and dried (MgSO/;), filtered, concentrated to give an orange oil that used in next step without further purification.

The above residue was dissolved in tetrahydrofuran (100 mL) and 48% hydrofluoric acid (16.77 mL, 462.7 mmol) was added. The reaction mixture was stirred overnight at room température and quenched with solid sodium bicarbonate and stirred for 30 minutes. Water and saturated sodium bicarbonate were added and the mixture was extracted with ethyl acetate (2x). The combined organic layer was dried (\tgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 5 to 30% ethyl acetate/hexanes) to give an off-white solid (4.89 g). ’H-NMR: 400

MHz, (CDCh) 5 : 7.87 (d, J = 7.1 Hz, 1 H), 7.76 (d, J = 10.1 Hz, IH), 7.59 (s, IH), 5.76 (d, J = 2.0 Hz, IH), 4.36 - 4.18 (m, 2H), 3.42 (d, J = 2.4 Hz, IH), 2.48 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H).

277

Préparation of ethyl 2-(6-chloro-7-fluoro-3-methyl-l-(trifluoromethyIsulfonyloxy)naphthalen-2-yl )-2-oxoacetate: To a solution of ethyl 2-(6-chloro-7-fluoro3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (4.89 g, 10.99 mmol) in anhydrous dichloromethane (100 mL) at 0 °C was added Dess-Martin periodînane (5.59 g, 13.18 mmol) portion-wise over 5 minutes. The reaction mixture was stirred at 0 °C for 1 hour and quenched with sodium thiosulfate solution and saturated sodium bicarbonate solution and stirred for 30 minutes. The mixture was diluted with ethyl ether and washed with saturated sodium bicarbonate solution (3x), brine and dried (MgSO₄). filtered, concentrated to give a yellow oil with a white precipitate. The mixture was suspended in dîethyl ether, washed with brine, dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give an off-white solid (4.60 g). *H NMR (400 MHz, CDC1₃) δ: 7.93 (d, J = 7.0 Hz, IH), 7.78 (d, J = 9.6 Hz, IH), 7.67 (s, IH), 4.41 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).

Préparation of (S)-ethyl 2-(6-chloro-7-fluoro-3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate: To a solution of ethyl 2-(6-chloro-7fluoro-3-methyl-1 -(trifluoromethylsulfony loxy)naphthalen-2-yl)-2-oxoacetate (4.60 g,

10.79 mmol) and (R)-2-methyl-CBS-oxazaborolidine (0.598 g, 2.16 mmol) in anhydrous toluene at -40 °C was added a solution of catecholborane (1.55 mL, 14.67 mmol) in toluene ( 10 mL) over 40 minutes. The reaction mixture was stirred for I hour and quenched with sodium carbonate solution, diluted with ethyl acetate and stirred vigorously for 20 minutes at -20 °C, then at room température for 45 minutes. The aqueous layer was removed and the organic layer was washed with sodium carbonate solution (4x), saturated ammonium chloride solution, dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give an off-white solid (4.44 g). 'H NMR (400 MHz, CDC1₃) δ: 7.87 (d, J = 7.1 Hz, IH), 7.76 (d, J = 10.0Hz, IH), 7.59 (s, IH), 5.76 (d, J = 1.7 Hz, IH), 4.38 - 4.17 (m,2H), 3.43 (d, J = 2.3 Hz, IH), 2.48 (s, 3H), 1.20 (L J = 7.1 Hz, 3H). The enantiomeric excess was determined by chiral column analysis (Chiralpak AD-H, heptane:cthanol (80:20)) to be 95%.

Préparation of (S)-ethyl 2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-1(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: To a solution of (S)-ethyl 2-(6chloro-7-fluoro-3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-216293

278 hydroxyacetate (4.44 g, 9.99 mmol) m tert-butylacetate (100 mL) was added 70% perchloric acid (1.20 mL, 19.98 mmol). The reaction mixture was stirred for 2.5 hours and quenched with solid sodium bicarbonate and stirred for 45 minutes. Water and solid sodium bicarbonate were carefully added and stirred for another 15 minutes. The mixture was diluted with ethyl acetate, washed with saturated bicarbonate solution (2x), brine, dried (MgSCL), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give an pale orange oil (4.26 g). ‘H NMR (400 MHz, CDClj) Ô: 7.86 (d, J = 12 Hz, 4H), 7.74 (d, J = 10.2 Hz, 4H), 7.58 (s, 4H), 7.26 (s, 3H), 5.69 (s, 4H), 4.26 - 4.08 (m, 9H), 2.53 (s, 12H), 1.20 (s, 34H), 1.17 (t, J = 7.1 Hz, I3H).

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-6-chloro-1-(2,3dibydropyrano[4,3,2-de]quinoIin-7-yI)-7-iluoro-3-mcthylnaphthalcn-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(6-chloro-7-fluoro-3mcthyl-1 (tnfluoromethy!sulfonyloxy)naphthalen 2 yl)acetate (110 mg, 0.199 mmol),

2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HCl sait (55 mg, 0.220 mmol), PdCl₂(dppf) (16 mg, 0.02 mmol), césium fluoride (133 mg, 0.876 mmol) and flushed with nitrogen. DimethoxyethaDe (1.0 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in micro wave at 110 °C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO.*), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tertbutoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3methylnaphthalen-2-yl)acetate (9.7 mg). ’H NMR (400 MHz, CD₃OD): δ 8.49 (d, J =

4.4 Hz, IH), 7.97 (d, J = 7.5 Hz, IH), 7.74 (s, IH), 7.46 (d, J = 7.9 Hz, IH), 7.27 (d, J =

4.4 Hz, IH), 7.14 (d, J = 7.9 Hz, IH), 6.66 (d, J = 11.5 Hz, IH), 5.13 (s, IH), 4.56 (dd, J = 9.9,5.9 Hz, 2H), 3.96 (dd, J = 10.8,7.1 Hz, IH), 3.76 (dd, J = 10.7, 7.1 Hz, IH),

3.38 (t, J = 5.8 Hz, 2H), 2.74 (s, 3H), 0.98 - 0.85 (m, 12H). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C30H30CIFNO4: 523.0; Found: 522.1, 524.1.

The other atropisomer, (S)-ethyl 2-tert-butoxy-2-((S)-6-chloro-l-(2,3dihydropyrano[4,3,2-de]quinolm-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate, was also isolated (16.4 mg). *H NMR (400 MHz, CD₃OD): 5 8.47 (d, J = 4.4 Hz, IH), 7.94 (d, J = 7.6 Hz, IH), 7.77 (d, J = 8.0 Hz, IH), 7.70 (s, IH), 7.25 (d, J = 4.4 Hz, IH), 7.18 (d, J = 8.0 Hz, IH), 6.56 (d, J = 1L4 Hz, IH), 5.15 (s, 2H), 4.52 (t, J = 5.4 Hz, 2H),

279

4.22 - 4.04 (m, 2H), 3.37 (1. J - 5.8 Hz, 2H), 2.61 (s, 3H), 1.20 (t, J = 5.9 Hz, 3H), 0.70 (s, 9H). LCMS-EST (m/z): [M+H]' calcd for C30H30CIFNO4: 523.0; Found: 522.1,

524.1.

Préparation of (S)-2-tert-butoxy-2-((R)-6-chloro-l -(2,3-dihydropyrano[4.3,2de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (101): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-6-chloro-1 -(2,3-dihydropyrano[4,3,2-de]quinolîn-7-yl)-

7-fluoro-3-methyinaphthalen-2-yl)acetate(9.7 mg, 0.186 mmol) and 5 M sodium hydroxide (74 pL, 0.372 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.2 mL) was heated at 50 °C ovemight. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgSO₄), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O + 0.1% TFA). Product lyophilized to give a yellow powder (6.7 mg). 400 MHz, (CD3OD): δ 8.69 (d, J = 5.2 Hz,

1H), 8.12 (d, J = 7.6 Hz, 1H), 7.96 (s, 1H), 7.81 (d, J = 7.6 Hz, 1 H), 7.80 (d, J = 5.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 11.2 Hz, 1H), 5.21 (s, IH), 4.75-4.70 (m, 2H), 3.66 (t, J = 6 Hz, 2H), 2.76 (s, 3H) 0.92 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD3OD) Ô: -77.7 (s, 3F), -119.2 (dd, J = 10.6, 7.9 Hz, 1F). LCMS-EST (m/z): [M+H]⁺calcd for C28H26CIFNO4: 494.95; Found: 494.4,496.1. The other atropisomer, (S)-2-tert-butoxy2-((S)-6-chloro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3methylnaphthalen-2-yl)acetic acid, was prepared in a similar manner. *H NMR (400 MHz, CD3OD); δ 8.59 (d, J = 5.3 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.88 (s, 1H), 7.63 (d, J = 5.2 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 11.2 Hz, 1H), 5.20 (s, 1H), 4.68 (t, J = 6.0 Hz, 2H), 3.58 (t, J = 5.9 Hz, 2H), 2.71 (s, 3H), 0.85 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD3OD) δ: -77.7 (s, 3F), -120.0 (br s, 1F). LCMS-EST (m/z): [M+H]⁺ calcd for C₂₈H₂₆CIFNO₄:494.95; Found: 494.4,496.1.

280

Example 100. (S)-2-tert-Butoxy-2-((R)-I-(2,3-dihydropyrano[4,3,2-de]quÎnolin-7-yl)-

7-fluoro-6-Îsopropyl-3-methylnaphthalen-2-yl)acetic acid (102)

(S)-ethyi 2 -(tert-butoxy )-2-( 6chloro-7-fiuoro-3-m ethyl-1 (( (tri ftuoro methyl )su lion yl )oxy )na phthalen-2-y I ) acetate (S)-ethyt 2-(!afT-outaary>2-(7-f1uoro-3meJnyÎe-lpnp- 1-er-2-yl}-1 (( (tnftuxOmethyi)sutfony( jcxy inaphthalen2-yl)acetate

2,3-d ihydropy ran o[4,3,2dejquirtol i n-7 -ytooronic acid. HCl sait

(S)-ethyl 2-{ tert-butoxy ^-((Shl-ÎZ.SdihydropyrarK^i.SZ-deJquinolin-T-yl)-

7-fiuorô-3-methyl-6-(prop-1 -erv-2yl)naphthaten-2-yt)acetate (S)-ethyl 2-{ ter f-butoxy )-2-(( Ry 1-(2,3dihydropyrarto[4₍3,2-de}qLiinolin-7-yl)7-fluoro-3-methy l-6-(prop-1 -e n-2yl)naphthalen-2-yl)acetate

(S)-ethyl 2-(tert-butoxy)-2-((R)-1-(2,3dihydropyrano[4,3,2-de}quino)in-7-yÎ)7-fluoro-6-isopropyl-3methykiaphthaien-2-yl)acetate

(S)-2-(teft-butoxy)-2-((R)-1 -(2,3dihydrOpyraro(4,3,2-de)qLiinolin-7-yl)7-fiuoro-6-tsopropyk3methylnaphtfiaten-2-yl)acetic acid

Préparation of (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-6-(prop-l-en“2-yl)5 1 -(trifluoromethylsuIfonyloxy)naphtha]en-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyI-l (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (184.2 mg, 0.368 mmol), potassium isopropenyltrifluoroborate (60 mg, 0.405 mmol), BrettPhos Palladacycle (41 mg, 0.0552 mmol), césium fluoride (623 mg, 0.405 mmol) and flushed with nitrogen.

Dimethoxyethane (1.0 mL, distilled from Na/benzophenone) was added and mixture

28Ï ίο sparged with nitrogen for 10 minutes and then heated in microwave at 120 °C for 1.5 hour. The reaction mixture was diluted with ethyl acetate and washed with water, brine, dried (MgSOj). filtered, concentrated and purifîed by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give a colorless oil (60 mg). ^!HNMR (400 MHz, CDC1₃) δ 7.85 (d, J = 7.1 Hz, 13H), 7.71 (d, J = 7.5 Hz, IH), 5.70 (s, IH), 5.35 (s, IH), 5.32 (s, IH), 4.18 (dt, J = 19.3, 11.4 Hz, 2H), 2.53 (s. 3H). 2.21 (s,3H), 1.24 - 1.12 (m, 12H).

Préparation of(S)-ethyl 2-tert-butoxy-2-((R)-l -(2,3-dihy drop yrano [4,3,2deJquinolin-7-yl)-7-fluoro-3-methyl-6-(prop-1 -en-2-yl)naphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(7-fIuoro-3-methyl-6(prop-l-en-2-yl)-l-(trifluoromethylsulfonyloxy)naphtha]en-2-yl)acetate (92.3 mg, 0.182 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HCl sait (50 mg, 0.200 mmol), Sphos Palladacycle (18.4 mg, 0.0273 mmol), césium fluoride (122 mg, 0.801 mmol) and flushed with nitrogen. Dimethoxyethane (1.5 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120 °C for 1.5 hour. The reaction mixture was diluted with ethyl acetate and washed with brine. Aqueous layer back-extracted and combined organic layer dried (MgSCU), filtered, concentrated and purifîed by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give impure (S)-ethyl 2tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-6(prop-l-en-2-yl)naphthalen-2-yl)acetate (10 mg). Repurified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O + 0.1% TFA) and lyophîlized to give an impure yellow powder (4.3 mg). LCMS-ESl' (m/z): [M+H]⁺calcd for C3₃H₃₅FNO4: 528.6; Found: 528.1,529.1.

The other atropisomer, (S)-ethyl 2-tert-butoxy-2-((S)-1-(2,3dihydropyrano [4,3,2-de]quinolin-7-yl)-7-fluoro-3 -methyl-6-(prop-1 -en-2yl)naphthalen-2-yl)acetate, was also isoiated (4.3 mg). LCMS-ESI* (m/z): [M+H]⁺calcd for C33H35FNO4: 528.6; Found: 528.1,529.1

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2de]qumolin-7-yl)-7-fiuoro-6-isopropyl-3-methylnaphthalen-2-yl)acetate: A mixture of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]qumolin-7-yl)-7-fluoro-3methyl-6-(prop-I-en-2-yl)naphthalen-2-yl)acetate (4,3 mg, 0.007 nunol) and 10% Palladium/carbon (5.0 mg) in éthanol (1.5 mL) was stirred under a hydrogen

282 atmosphère (I atm) for 2 hours. The reaction mixture was filtered through a pad of Celite and concentrated to give a film that was used in the next step without further purification (4.2 mg). LCMS-ESI⁴ (m/z): [M+H]⁴ calcd for C33H37FNO4: 530.6; Found:

530.2.

Préparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyTano[4,3.2-de]quinolin7-yl)-7-fluoro-6-isopropyl-3-methylnaphthalen-2-yl)acetic acid (102): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yi)-7-fluoro-6isopropyl-3-methylnaphthalen-2-yl)acelate (4.2 mg, 0.007 mmol) and 5 M sodium hydroxide (31 pL, 0.16 mmol) in tetrahydrofiiran (1.0 mL) and methanol (0.1 mL) was heated at 50 °C overnight. Ihe reaction mixture was acidified with acetic acid, concentrated, dissolved in DMF and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O + 0.1% TFA). Product lyophilized to give a yellow powder (2.6 mg). ^[H-NMR: 400 MHz, (CDjOD) δ: 8.67 (d, J = 5.6 Hz, IH), 7.94 (s, IH), 7.84 (d, J = 7.6 Hz, IH), 7.80 (d, J = 6.0 Hz, IH), 7.78 (d, J = 6.0 Hz, IH), 7.43 (d, J = 8.0 Hz, IH),

6.47 (d, J = 12.4 Hz, IH), 5.21 (s, IH), 4.75-4.70 (m, 2H), 3.66 (t, J = 6 Hz, 2H), 3.3-

2.2 (m, IH), 2.75 (s, 3H), 1.33 (d, J = 8.4 Hz, 3H), 1.31 (d, J = 8.8 Hz, 3H), 0.92 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD3OD) δ: -77.6 (s, 3F), -121.4 (dd, J = 10.6, 7.9 Hz, 1F). LCMS-ESI⁴ (m/z): [M+H]⁺calcd for C3|H₃₃FNO₄; 502.69; Found: 502.1 (M+H⁴).

Example 101. (S)-2-tert-Butoxy-2-((R)-6-(difluoromethyl)-l-(2,320 dihydropyrano [4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (103)

283

(S)-ethyl 2-(tert-butoxy)-2-(6chloro-7-fluoro-3-methyi-1{( (trifl uorometfiy () sutfony o xyjnap hthal en-2-y [ ) acetate (S)-ethy1 2-(ierf-butoxy}-2-(7-fluoro-3methyl-i( ( (tnfiuoromethy ! jsutfony IJoxy )-6vinyinaphthalen-2-yl)aoetate

2,3-dihydropyrano[4,3,2de)quin olin-7-y I boron ic acid, HCl sait (S)-ethyl 2-(fert-butoxy)-2-(7fluoro-6-formyb3-niethyl-1(((trifluofomethyl)suifonyi)oxy)nap h thalen-2-yl) acetate (S)-ethyl 2-(f ert-butoxy )-2-(6(difîuOTomeÜiy!)-7-ftiK>ro-3-metfiyH (((trifluorom ethyl) sul tony l)oxy Jnaphtha len-2-yl)acetate

(S)-ethyl 2-(tert-butoxy)-2-((S)-6(difluorOTiethyl)-1-(2,3di hy d ropy rar»o[4,3,2-cfe]qui nolin-7-y I)7-fl Lioro-3-m ethy lnaphthalen-2yljaœtate

103 (S)-ethy1 2-(tert-butoxy)-2-((R)-6(difluoromethyl)-1-(2,3dihy dropy ra no[4.3,2-de]q uinolin-7-y I )7-fluoro-3-methylnaphthalen-2yl)acetate (S)-2-(fert-butoxy)-2-((ff)-6(difliioiomethy 1)-1-(2.3dihy dropy rano[4,3,2-dejquinol i n-7-y I)7-fluoro-3-rôethy1naphthalen-2yljacetic acid

Préparation of (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-l(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yI)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy 2-(6-chloro-7-fluoro-3-mcthyl-1 (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (213.6 mg, 0.426 mmol),

tributyl(vinyl)tin (0.137 mL, 0.469 mmol), BrettPhos Palladacycle (47 mg, 0.0639 mmol) and flushed with nitrogen. DMP (2.0 mL) and sodium carbonate (5.0 mg, 0.0639 mmol) were added and heated in micro wave at 120 °C for 1.5 hour. The reaction mixture was diluted with ethyl acetate and washed with 5% lithium chloride solution (2x), brine, dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give a colorless oil (149.5 mg).‘H NMR (400 MHz, CDCJ₃) δ 7.64 (d,7 = 5.1 Hz, 1H), 7.62 (d. 1H), 6.95 (dd,7 = 17.7, 11.3 Hz, 1H), 6.00 (d,- 17.7 Hz, 1H), 5.52 (d, J= 11.3 Hz, 1 H), 4.33 4.03 (m, 2H), 2.53 (s, 3H), 1.20 (s, 9H), L17 (t, J = 7.1 Hz, 3H).

Préparation of (S)-ethyl 2-tert-butoxy-2-(7-fluoro-6-formy 1-3-methyl-1(trifluoromethylsulfonyloxy)naphthaien-2-yl)acetate: A 3-neck round-bottom flask was charged with (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-1(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate (95 mg, 0.193 mmol), methanol (I mL) and dichloromethane (1 mL) and cooled to -78 °C. Ozone was bubbled into the reaction mixture until blue color persisted (2 minutes). The reaction was sparged with oxygen until blue color faded and quenched with methyl sulfide (0.06 mL, 0.828 mmol). The mixture was stirred at room température for lh, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give a colorless oil (74 mg). NMR (400 MHz, CDCi₃) δ 10.45 (s, 1H), 8.37 (d, J= 6.8 Hz, 1H), 7.80 (s, 1H), 7.75 (d, J= 11.7 Hz, 1H), 5.72 (s, IH), 4.39 -4.00(m,2H), 2.56 (s, 3H), 1.20 (s, 9H), 1.17 (t, J =7.1 Hz, 3H).

Préparation of (S)-ethyl 2-tert-butoxy-2-(6-(difluoromethyl)-7-fluoTo-3-methyll-(trifluoromethylsulfonyIoxy)naphthalen-2-yl)acetate: To a solution of S)-ethyl 2-tertbutoxy-2-(7-fluoro-6-formyl-3 -methyl-1 -(trifluoromethyl-sulfonyloxy)naphthaIen-2yl)acetate (37.3 mg, 0.075 mmol) in dichloromethane (0.5 mL) at 0 °C was added Deoxo-Fluor (28 pL, 0.151 mmol). The reaction mixture was stirred for 2.5 hours at 0 °C, then loaded directly onto a silica gel column and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give a colorless oil (32.7 mg). *H NMR (400 MHz, CDC1₃)S 8.06 (d,7= 6.8 Hz, 1H), 7.75 (s, 1H), 7.73 (d, J=

10.7 Hz, 1H), 6.99 (t, 7= 54.8 Hz, 1H), 5.72 (s, 1H), 4.36 - 3.93 (m, 2H), 2.56 (s, 3H),

1.20 (s, 9H), 1.17 (t, 7= 7.1 Hz, 3H).

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yi)acetate: A

285

Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(6-(difluoromethyl)-7Îluoro-3-methyI-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (53.6 mg, 0.104 mmol), 2,3-dihydropvrano[4.3,2-de]quinolin-7-ylboronic acid, HCl sait (31.3 mg, 0.125 mmol), Sphos Palladacycle (10.5 mg, 0.0156 mmol), césium fluoride (69.5 mg, 0.458 mmol) and flushed with nitrogen. Dimethoxyethane (1.0 mL, distilled from Xa-benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120 °C for 1.5 hour. The reaction mixture was diiuted with ethyl acetate and washed with brine. Aqueous layer back-cxtracted and combined organic layer dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tertbutoxy-2-((R)-6-(difluoromethyl)- 1 -(2,3-dihydropyTano[4,3,2-de ]quinolin-7-yl)-7fluoro-3-methylnaphthalen-2-yl)acetate(IOmg). LCMS-ESI* (m/z): [M+H]* calcd for C₃iH₃iF₃NO₄: 538.6; found: 538.1.

The other atropisomer, (S)-ethyl 2-tert-butoxy-2-((S)-6-(difluoromethyl)-l -(2,3dihydropyrano[4,3,2-de]qumolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate, was also isolated (12.0 mg). LCMS-ESI* (m/z): [M+H]*calcd for C₃jH₃₁F₃NO₄: 538.6; found: 538.1.

Préparation of (S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)-l -(2,3dihydropyrano[4,3,2-de]qumolin-7-yl)-7-fluoro-3-methylnaphthalen-2-y!)acetic acid (103); A solution of (S)-ethyl 2-tert-butoxy-2-((R)-6-(difluoromethyl)l-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyinaphthalen-2-yI)acetate (10.0 mg, 0.0186 mmol) and 5 M sodium hydroxide (74 pL, 0.372 mmol) in tetrahydrofuran (1.0 mL) and méthanol (0.1 mL) was heated at 50 °C ovemight. The reaction mixture was re-suspended in méthanol and concentrated to ~1 mL. DMF (0.3 mL) was added and concentrated to —0.3 mL. Acetic acid was added, further diiuted with DMF and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). Product lyophilized to give a yellow powder (9.8 mg),

Ή NMR (400 MHz, CD₃OD) Ô 8.70 (d, 7- 5.7 Hz, 1H), 8.24 (d, J= 7.2 Hz, 1Η), 8.10 (s, 1Η), 7.82 (t, J= 7.1 Hz, 2H), 7.46 (d,J=8.1 Hz, 1H), 7.04 (t, J= 54.5 Hz, 1H), 6.71 (d. .7- 12.2 Hz, 1H), 5.24 (s, 1H),4.81 -4.64 (m, 2H), 3.67 (t, .7 - 6.0 Hz, 2H), 2.79 (s, 3H), 0.93 (s, 9H). ^I9F NMR (377 MHz, CD₃OD) δ -77.77 (s), -114.82 - -118.07 (m), -123.29 (m). LCMS-ESI* (m/z): [M+H]*calcd for C₂₉H₂7F₃NO₄: 510.5; found: 510.1.

286

Example 102. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]qumolin-7-yl)-

6-ethyl-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (104)

(S)-ethyl 2-((erf-butoxy)-2(7-fluoro-3-methyt-1 (((tnfluoromethyl)sulfonyl)o xy)-6-vinylnaphthaten-2yl)acetate (S) ethyl 2-(tert-butoxy)-2-(6-ethy17-fl uoro-3-metti y M (((trifluoromethyf)$ulfonyi)oxy)nap hthalen-2-yl)acetate

2,3-dihydropyrano[4,3,2dejquin olin-7-y Iboronic aari, HCl sait

(S)-ethyl 2-(/ert-birtoxy)-2-((S)-1-(2,3dihydropyrano(4₁3.2-de)qutnolin-7-yi}6-éthyÎ-7-fluon>3-meth^naph1halefl·2-yl)acetate (S)-ethyl 2-(ferf-bLrtoxy)-2-((/?)-1-(2,3dihydropyrano(4,3,2-de]quinolirF7-yl)6-ethyl-7-fluoro-3-rT»ethyinaphthalen2-yi)acetate

(S)-2-(tert-buioxy)-2-((R)1 -{2,3dihydropyranoÎ4,3,2-de}quinofin-7-yl)6-ethy!-7-ftuoro-3-methy I na phthalen5 2-yf)acetic acid

Préparation of (S)-ethyl 2-tert-butoxy-2-(6-ethyl-7-fluoro-3-methyl-1 (trifluoromethylsuIfonyloxy)naphthalen-2-yl)acetate: A mixture of (S)-ethyl 2-tert butoxy-2-(7-î]uoro-3“inethyl-l-(trifluoroinetiiylsulfonyloxy)-6-vinyinaphthalen-210 yl)acetate (23 mg, 0.050 mmol) and 10% Palladium on carbon (5 mg) in éthanol (2.0

mL) was stirred under a hydrogen atmosphère for 4 hours, then filtered through a pad of Celite. Filtrate was concentrated to give a thin film (23 mg) that was used in the next step without further purification.

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2de]quinolin-7-yi)-6-ethyl-7-fluoro-3-methylnaphlhalen-2-yl)acetatc: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(6-ethyl-7-fluoro-3-methyl-l(trifluoromethylsulfonyIoxy)naphthaien-2-yl)aceiate (23 4 ry. 0.0473 mmol), 2,3dihydropyrano[4,3,2-de]quinolin-7-yiboronic acid, HCl sait (14.3 mg, 0.568 mmol), Sphos Palladacycle (4.8 mg, 0.0071 mmol), césium fluoride (31.6 mg, 0.208 mmol) and flushed with nitrogen. Dimethoxyethane (1.0 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120 °C for 1.5 hour. The réaction mixture was diluted with ethyl acetate and washed with brine. Aqueous layer back-extracted and combined organic layer dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tertbutoxy-2-((R)-1 -(2,3 -dihydropyrano [4,3,2-de]quinolin-7-yl)-6-ethyl-7-fluoro-3 methylnaphthalen-2-yl)acetate(1.7mg). LCMS-EST (m/z): [M+H]* calcd for C32H₃₅FNO₄: 516.6; found: 516.1. The other atropisomer, (S)-ethyl 2-tert-butoxy-2((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-y l)-6-ethyI-7-fl uoro-3methylnaphthalen-2-yI)acetate, was also isolated (2.6 mg). LCMS-ESI* (m/z): [M+H]* calcd for C32H₃5FNO₄: 516.6; found: 516.1.

Préparation of (S)-2-tert-butoxy-2-((R)- l-(2,3-dihydropyrano[4,3,2-de]quinolin7 yl)-6-ethyl-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (104): A solution of (S)ethyl 2-tert-butoxy-2-((R)-1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-7fluoro-3-methyinaphthalen-2-yl)acetate (1.7 mg, 0.005 mmol) and 5 M sodium hydroxide (21 pL, 0.101 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.1 mL) was heated at 50 °C overnight. The reaction mixture was acidifïed with acetic acid, concentrated, dissolved in DMF and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). Product lyophilized to give a yellow powder (1.3 mg). *H NMR (400 MHz, CD3OD) δ 8.68 (d, J- 5.6 Hz, IH), 7.93 (s, IH), 7.87 - 7.77 (m, J = 7.0 Hz, 3H), 7.46 (d, J= 8.1 Hz, IH), 6.49 (d, J = 12.1 Hz, IH), 5.21 (s, IH), 4.73 (d, J= 6.3 Hz, 2H), 3.67 (t, 6.0 Hz, 2H), 2.83 - 2.72 (m, 6H), 1.28 (t, J-7.5 Hz, 4H),

288

0.92 (s, 9H). ^,9F NMR (377 MHz, CD₃OD) δ -77.86 (s), -I2l .37 (d, J = 7.9 Hz).

LCMS-ESr (m/z): | M calcd for CsoHïiFNCV 488.6; found: 488.1.

289

Example 103. (S)-2-tert-Butoxy-2-((R)-6-cyclopropyl-l-(2,3-dihydropyrano[4,3,2de]qiiinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (105)

2,3-dihydropyrarx>(43.2de)q u i nol l rv7 - yfboron ic aod HCl sait

(SJ-ethyl 2-(tert-butoxy)-2-(6chioro- 7-fl uoro-3-methy t-1 (( (trifluoromethy I )su Ifony l)oxy )n ap hthafen-2-yl)acetate (SVethyt 2-(fert-butoKy )-2-(6cydopropyl-7-fluoro-3-methy 1-1 (((trifluoromethyl)su)fony))oxy)nap htha len-2-yl Jacetate

(S)-ethyl 2(ter!butoxy)-2-((S)-6cydopropyl-1-(2,3dihy dropy rano[4,3,2-de)qu inolin-7-y I)7-fluoro-3-rr>ethy!naphthaten-2(Syethyl 2-(ferf-butoxy)-2-((R)-6cydopropy 1-1 -(2,3di hydropyrano[4,3,2-deiquinol in-7-y l>7 -f)uoro-3-methy lnaphthalen-2-

(S)-2-(ierfbutoxy)-2-((R)6 cydopropyl-1-(2,3d i hydropyra no[4,3,2-de]quinolin-7-y I > 7-fluoro-3-methyinaphthaten-2yljacetic acid

Préparation of (S)-ethyl 2-tert-butoxy-2-(6-cyclopropyl-7-fiuoro-3-methyl-15 (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate; A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-l(trifluoromethylsulfonyIoxy)naphthalen-2-yl)acetate (122.5 mg, 0.245 mmol), cyclopropylboronic acid (23 mg, 0.269 mmol), BrettPhos Palladacycle (27 mg, 0.0368 mmol), césium fluoride (164 mg, 1.08 mmol) and fiushed with nitrogen.

A

Dimethoxyethane (1.5 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 15 minutes and then heated in micro wave at 120 °C for 1.5 hour. The réaction mixture was diluted with ethyl acetate and washed with brine. Aqueous layer back-extracted with ethyl acetate and the combined organic layer was dried (MgSCL). filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give an impure colorless oil (83.1 mg). Analytica] HPLC (Gemini, 2-98% ACN/H_:O + 0.05% TFA): t_R (min) = 5.53.

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-6-cyclopropyl-l -(2,3 dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-mcthylnaphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(6-cyclopropyl-7-fluoro3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (83.1 mg, 0.164 mmol), 2,3-dihydropyrano[4,3,2-de]quinoIin-7-ylboronic acid, HCl sait (45.4 mg, 0.180 mmol), Sphos Palladacycle (16.5 mg, 0.0246 mmol), césium fluoride (110 mg, 0.722 mmol) and flushed with nitrogen. Dimethoxyethane (1.5 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 15 minutes and then heated in microwave at 120 °C for 1.5 hour. The reaction mixture was diluted with ethyl acetate and washed with brine. Aqueous layer back-extracted and combined organic layer dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to give (S)-ethyl 2-tertbutoxy-2-((R)-6-cyclopropyl-1 -(2,3-dihydropyrano [4,3,2-de]quinolin-7-yl)-7-fluoro-3 methylnaphthalen-2-yl)acetate (2.2 mg).

LCMS-ESI* (m/z): [M+H]*calcd for C33H35FNO4: 528.6; Found: 528.1, 529.1. The other atropîsomer, (S)-cthyl 2-tert-butoxy-2-((S)-6-cyclopropyl-l-(2,3dihydropyrano[43,2-de]quinoIin-7-yl)-7-fluoro-3-niethylnaphthalen~2-yl)acetate, was also isolated (2.8 mg). LCMS-ESI* (m/z): [M+H]*calcd for C33H34FNO4: 528.6; Found: 528.1,529.1

Préparation of (S)-2-tert-butoxy-2-((R)-6-cyclopropyI-l-(2,3dihydropyrano[43,2'de]quinolin-7-yl)-7-fluoro-3-methyInaphthalen-2-yl)acetic acid (105): A solution of (S)-ethyl 2-terî-butoxy-2-((R)-6-cyclopropyl-l-(2,3dihydropyrano [4,3,2-de]quinolîn-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate (2.2 mg, 0.0042 mmol) and 5 M sodium hydroxide(171 pL, 0.083 mmol) in tetrahydrofuran (0.5 mL) and mcthanol (0.1 mL) was heated at 45 °C ovemight. The reaction mixture was concentrated, acidified with acetic acid, diluted in DMF and purified by reverse r

phase HPLC (Gemini, 5 to ! 00% ACN LLO - 0. l% TFA). Product lyophilized to give a yellow powder (2.2 mg). ^lH-NMR: 400 MHz, (C1LOD) Ô: 8.67 (d, J = 5.6 Hz, IH),

7.89 (s. IH), 7.82-7.78 (m. 2H), 7.54 (d, J = 7.6 Hz, IH), 7.44 (d, J = 8.0 Hz, IH), 6.47 (d, J = 12.4 Hz, IH). 5.20 (s, IH), 4.76-4.49 (m. 2H), 3.66 (t J = 6 Hz, 2H), 2.73 (s,

3H), 2Ί5-2.10 (m. IH), l.04 (d, J = 8.4 Hz, 2H), 0.92 (s, 9H), 0.86-.83 (m, 2H). ^iyFNMR: 377 MHz, (CD₃OD) Ô: -77.7 (s, 3F), -12L8 (dd. 1F).LCMS-ESF (m/z): [M+HJ⁺calcd for C31H51FNO4: 500.6; Found: 500.1.

Example 104. (S)-2-tert-Butoxy-2-((R)-6-cyano-l-(2,3-dihydropyrano(4,3,210 de]quinolin-7-yl)-7-fIuoro-3-methylnaphthaien-2-yl)acetic acid (106A) and (S)-2-tertButoxy-2-((R)-6-carbamoy l-1 -(2,3 -dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3 methylnaphthalen-2-yl)acetic acid (106B)

292

iS)-ett~yi 2->:eri-DuToxy}-2t6-cnkxo- 7 -fuyu 3-metb y l· > (((tnfluoromethyi)sulfonyQo xy)napbÜialen-2-yl)acetate

2,3-chhydropyrano[4,3,2de}quinolin-7-ylborontc acid, HCl sait (S)-ethyl 2-(terf-butoxy)-2-(6- --------------------------„ cyano-7-fluoro-3-methyi-1 (((ü'ifluoromethyi)suKonyl)oxy)nap htha I en-2-y l) acetate

(S)-ethyl 2-(terbbutoxy)-2-((S)-6cyano-1 -(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-fluoro-3methylnaphthaten-2-yl)acetate (S)-ethyl 2-ftert-butoxy)-2-((R)-6cyant>1-(2,3-dihydropyrano[4,3,2de]quindin-7-yl)-7-fluoro-3m ethy I n aphthalen-2-y l)acetate

(S)-2-(fert-butoxy}-2-((R)-6-cyano-1 (2,3-dihydropyrano[4,3,2-de]quinolin7-yi)-7-fluoro-3-methylnaphthalen-2yl)acetic acid (S)-2-(terf-butoxy)-2-((R)-6carbamoy 1-1-(2,3dihydropyrantX4,3_r2-de]quinolin-7-yl)7-fluoro-3-methylnaphthaien-2yl) acetic acid

Préparation of (S)-ethyl 2-tert-butoxy-2-(6-cyano-7-fluoro-3-mcthyl-1 5 (trifluoromethyIsulfonyloxy)naphthalen-2-yl)acetate: A Smith process vial was

charged with (S)-ethyl 2-tert-buloxy-2-(6-chloro-7-fluoro-3-methyl-l(trifluoromethylsulfonyloxy)naphthalen-2-yl(acetate (180 mg, 0.359 mmol), zinc(II) cyanide (25 mg. 0.215 mmol). BrettPhos Palladacycle (26 mg, 0.0359 mmol), sodium bicarbonate (3 mg, 0.0359 mmol). DMF (1.5 mL) was added and mixture was heated in microwave at 110 °C for 1.0 hour. The réaction mixture was diluted with ethyl acetate and washed with 5% lithium chloride solution (2x), brine, dried (MgSO₄), filtered, concentrated and purified by flæn column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give a colorless oil (129 mg).

Analytical HPLC (Gemini, 2-98% ACN/H₂O + 0.05% TFA): t_R (min) = 5.01.

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-6-cyano-1-(2,3 dihydropyrano [4,3,2-de]quinolin-7-yl)-7-fluoro-3 -methylnaphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(6-cyano-7-fluoro-3methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-y])acetate (129 mg, 0.262 mmol),

2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HCl sait (72.6 mg, 0.289 mmol), Sphos Palladacycle (26 mg, 0.0393 mmol), césium fluoride (175 mg, 1.15 mmol) and flushed with nitrogen. Dimethoxyethane ( 1.5 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 15 minutes and then heated in microwave at 120 °C for 1.5 hour. The reaction mixture was diluted with ethyl acetate and washed with brine. Aqueous layer back-extracted and combined organic layer dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to give impure (S)-ethyl 2tert-butoxy-2-((R)-6-cyano-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3 methylnaphthalen-2-yl)acetate (36.6 mg). LCMS-ESI* (m/z): [M+H]*calcd for C31H30FN2O4: 513.6; Found: 513.1. The other atropîsomer, (S)-ethyl 2-tert-butoxy-2((S)-6-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3methylnaphthalen-2-yl)acetate, was also isolated (36.8 mg). LCMS-ESI* (m/z): [M+H]* calcd for C₃iH3oFN₂0₄: 513.6; Found: 513.1.

Préparation of (S)-2-tert-butoxy-2-((R)-6-cyano-l -(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (106A): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-6-cyano-1 -(2,3 -dihydropyrano[4,3,2-de]quinolin-7-yl)-7fluoro-3-methyInaphthalen-2-yl)acetate (36.8 mg, 0.0718 mmol) and 5 M sodium hydroxide (290 pL, 1.44 mmol) in tetrahydrofuran (1.5 mL) and methanol (0.3 mL) was heated at 35 °C overnight. The reaction mixture was concentrated, acidified with acetic acid, diluted in DMF and purified by reverse phase HPLC (Gemini, 5 ιο 100% ACN/H₂0 + 0.1% TFA). Product Ivophilized to give a yellow powder (26.9 me). ^!HNMR:400 MHz. (CD3OD) Ô: 8.70 (d, J = 5.6 Hz. 1 H), 8.53 (d. J = 6.8 Hz. lHk8.11 (s, 1H),7.82-7.75 (m, 2H). 7.44 td, J = 8.0 Hz. 1 H)_: 6.83 (d, J = 11.2 Hz. 1H). 5.24 (s, 1H). 4 76-4.68 (m, 2H), 3.66 (t, J = 6 Hz. 2H), 2.79 (s. 3H). 0 92 rs. 9Hi ^:T-NMR· 377 MHz, (CD3OD) δ: -77.8 (s, 3F), -115.5 (br s. 1 F).

LCMS-ESI* (m/z): [M+H]*calcd for C29H26FN2O4: 485.5; Found; 485.1. A sideproduct, (S)-2-tert-butoxy-2-((R)-6-carbamoyl-l -(2,3-dihydropyrano|1,3,2 dejquinolin

7-yl)-7-fluoro-3-methylnaphthalen-2-yi)acetic acid (106B), was also isolated (2.8 mg). ’H-NMR: 400 MHz, (CD3OD) Ô: 8.70 (d, J = 5.6 Hz, IH), 8.44 (d, J = 7.2 Hz, 1H), 8.09 (s, 1H), 7.82-7.80 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 13.2 Hz, 1H),

5,24 (s, 1H), 4.76-4.70 (m, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.78 (s, 3H), 0.93 (s, 9H). ¹⁹FNMR: 377 MHz, (CD3OD) δ: -77.7 (s, 3F),-118.4 (br s, 1 F). LCMS-ESI* (m/z): [M+HJ*calcd for C₂₉H₂₈FN₂O₅: 503.5; Found: 503.1.

Example 105. (S)-2-tert-Butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinoIin-7-yl)7-fluoro-3-methyI-6-(methyIcarbamoyl)naphthalen-2-yl)acetîc acid (107):

294

3-dihydropyrano[4,3 2de]qu inoli n- 7-y Iboron ic acid. HCl sak (S)-ethyl 2-(fert-butoxy )-2-(6chtoro- 7-nuoro-3-methyi-1(((trifluoromethy I) suif onyt)oxy)na phthalen-2-yl)acetate (S)-ethy1 2-(tert-butoxy)-2-(7fl uoro-3- met hyf-6(mettryfcarbamoy I)-1 (((triflüoromêthyl)sutfonyl)oxy)nap hthalen-2-yl)acetate

(S)-ethyi 2-(ferf-butoxy)-2-((S)-1 -(2,3- (S)-elhyl 2-(terf-butoxy)-2-((R)-1 -(2.3ditydropyrano[4,3,2-de]quîrroiin-7-yl)-7-fluoro-3· dihydropyrano[4,3,2-de]quinolin-7-yl)methyl-6-(methylcarbamoyf)naphthaÎen-2-yl)acetate 7-fluoro-3-methyt-6(methytcarbamoyl)naphthalen-2-

(S)-2-(terf-butoxy)-2-((fi)-1 -(2,3cühydropyrano(4,32-<ie]quinolin-7-yl)7-fli»ro-3-melhyl-6(metbylcart)amoyl)aaf>hthaten-2yl)acetic acid

Préparation of (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-6(methylcarbamoyl)-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: A Smith process vîal was charged with (S)-ethyl 2-tert-butoxy-2-(6-chloro-7-f]uoro-3-methyl-1(trifluoromethylsulfbnyloxy)naphthalen-2-yl)acetate (131.8 mg, 0.263 mmol), 2 M methylamine in THF (0.66 mL, 1.32 mmol), molybdenum hexacarbonyl (0.069g, 0.263 mmol), BrettPhos Palladacycle (29 mg, 0.0395 mmol), and triethylamine (0.128

296 mL, 0.921 mmol). Toluene ( l .5 mL) was added and mixture was heated in microwave at 140 °C for l .5 hour. The reaction mixture was diluted with ethyl acetate, washed brine. dried (MgSO₄). filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 50% ethyl acetate/hexanes Ho give an off-white solid (19.2 mg). LCMS-ESL (nï): [KL Hf calcd for C-Hî^NOtS: 524.5, Found. 524.0.

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-]-(2.3-dihydropyrano[4,3,2de]quinolÎn-7-yl)-7-fluoro-3-methyL6-(methyIcarbamoyl)naphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-6(methylcarbamoyl)-l -(trifIuoromethylsulfonyloxy)naphthalen-2-yl)acetate ( 19.2 mg, 0.0367 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HCl sait (11.1 mg, 0.044 mmol), Sphos Palladacycle (3.7 mg, 0.0055 mmol), césium fluoride (25 mg, 0.161 mmol) and flushed with nitrogen. Dimethoxyethane (0.5 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120 °C for 1,5 hour. The reaction mixture was diluted with ethyl acetate and washed with brine. Aqueous layer back-extracted and combined organic layer dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 30 to 80% ethyl acetate/hexanes) to give (S)-ethyl 2-tertbutoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-6(methylcarbamoyl)naphthalen-2-yl)acetate (6.6 mg). LCMS-ESI* (m/z): [M+H]* calcd for C32H34FN2O5: 545.6; Found: 545.1.

The other atropisomer, (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3dihydropyrano[4,3,2-de]qumolin-7-yl)-7-fluoro-3-methyl-6(methylcarbamoyl)naphtha!en-2-yl)acetate, was also isolated (7.5 mg). LCMS-ESI* (m/z): [M+H]*calcd for C₃2H₃₄FN₂O5: 545.6; Found: 545.1.

Préparation of (S)-2-tert-butoxy-2-((R)-l -^jS-dihydropyTano^S^-deJquinolinT-yO^-fluoro-S-methyl-ô-imethylcarbaiïioyOnaphthalen^-yljacetic acid (107): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]qiiinoIin-7yl)-7-fluoro-3-methyI-6-(methylcarbanioyl)naphthalen-2-y])acetate (6.6 mg, 0.012 mmol) and 5 M lithium hydroxide (48 pL, 0.242 mmol) in tetrahydrofiiran (1.0 mL) and methanol (0.3 mL) was heated at 55 ^DC for 3 hours, then overnight at 48 °C. Additional 5 M lithium hydroxide solution (60 pL) was added and the reaction mixture stirred for 2 hours at 60 °C. The reaction mixture was acidified with acetic acid, concentrated, diluted in DMF and purified by reverse phase HPLC (Gemini, 5 to 100%

297

ACN'HjO + 0.1 % TFA). Product lyophilized to give a yellow powder {5.0 mg). HX'MR 400 MHz, (CD₃OD) δ: 8.70 (d, J ’ 5.6 Hz. IHk 8.35 (d, J = 7.2 Hz. IHk 8.07 (s. IH), 7.82-7.80 (m. 2H). 7 44 (d, J = 8.4 Hz, IH), 6.66 (d. J = 12.8 Hz, IH), 5.24 (s, IH). 4.76-4.70 (m. 2H), 3.66(1. J - 6 Hz, 2H). 2.94 (s. 3H). 2.78 (s, 3H). 0 92 (s. 9H) ^;9F-NMR: 377 MHz. (ŒhOD) δ: -77.6 (s. 3F), 115.5 (dd. J = 12.4. 7.16 Hz. 1F). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for CjcJLoFNîOç 517.6; Found: 517.1.

Example 106. (S)-2-tert-Butoxy-2-((R)-i-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-

6,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (108)

1-(3,4difluorophenyl)propan-2-one

(S)-2-(fert-butoxy)-2-((R)-1 -(2.3dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7difluoro-3-rnethylnaphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-((R)-1 -(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (108): (S)-2-tert-Butoxy-2((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolm-7-yl)-6,7-difluoro-3-methylnaphthalen-2yl)acetic acid (108) was prepared in a similar manner as (S)-2-tert~butoxy-2-((R)-6chloro-1-(2,3-dihydropyrano[4,3,2-de Jquinolin-7-yl)-7-fluoro-3-methyInaphthalen-2yl)acetic acid of Example 99 except starting with l-(3,4-difluorophenyl)propan-2-one instead of l-(3-chloro-4-fluorophenyl)propan-2-one.

*H-NMR: 400 MHz, (CD₃OD) δ: 8.69 (d, J = 5.6 Hz, IH), 7.96 (s, IH), 7.83-7.78 (m, 3H), 7.45 (d, J = 8.4 Hz, IH), 6.77 (d, J = 8.0 Hz, 1 H), 6.74 (d, J = 8.0 Hz, IH), 5.20 (s, IH), 4.75-4.70 (m, 2H), 3.66 (t, J = 5.6 Hz, 2H), 2.76 (s, 3H) 0.92 (s, 9H).

¹⁹F-NMR: 377 MHz, (CD3OD) δ: -77.9 (s, 3F), -138.8-138.9 (m, 1F), -139.8-139.9 (m, 1F). LCMS-ESf (m/z): [M+H]⁺ calcd for C2«H₂₆F₂NO< 478.5; Found: 478.1. The other atropisomer, (S)-2-tert-butoxy-2-((S)-l-(2,3~dihydropyrano[4,3,2-de]quinolin-7yl)-6,7-difluoro-3-methylnaphthaIen-2-yl)acetic acid, was prepared in a similar manner. *H NMR (400 MHz, CD₃OD) δ 8.60 (d, J= 5.4 Hz, IH), 8.12 (d, J = 8.2 Hz, IH), 7.89

(s, IH), 7.77 (dd. 7 = ILE 8.2 Hz. IH). 766 id, J = 5.4 Hz. JH). 7 45 id, 7-8.2 Hz.

IH), 6 71 idd,7 = 12.3, 7.9 Hz. IH), 5.l9(s. IH). 4 .69 (L 7 = 6.0 Hz. 2H), 3.60 (1.7 =

6.0 Hz. 2H). 2.71 (s. 3H), 0.86 (s, 9H). ^l9FNMR (377 MHz. CD^OD) δ -78 04 (s). i 39 49 (s). -140.31 is). LCMS-ESI’ iX'): [M+H]'calcd for C-gH^tJGNCG 478.5: Found: 478 l.

Example 107. (R)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyTano[4,3,2-de]quÎnolin-7-yl)-

(((trifluoromethyl)sulfonyl)oxy}na phthaten-2-yl)-2-oxoacetate (/?)-2-(terf-butoxy)-2-((R)-1-{2,3dihydropyrano[4,3,2-cfe]quinolin-7-yl)-6,7difluoro-3-methylnaphthaten-2-yl)aceticacid

Préparation of (R)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano [4,3,2de]qumolin-7-yl)-6,7-difluoro-3-methylnaphthaJen-2-yl)acetic acid (109): (R)-2-tertbutoxy-2-((R)-1 -(2,3-dihydropyrano [4,3,2-de]quinolin-7-yl)-6,7-difluoro-3methylnaphthalen-2-yl)acetic acid (109) was prepared in a similar manner as (S)-2-tertbutoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7-difluoro-3methylnaphthalen-2-yl)acetic acid of Example 106 except using (S)-2-methyl-CBSoxazaborolidine instead of (R)-2-methyl-CBS-oxazaborolidine. ’H NMR (400 MHz, CD3OD) δ 8.59 (d, 7= 5.3 Hz, lH),8.I0(d, 7=8.2 Hz, IH), 7.88 (s, IH), 7.76 (dd, J=

11.1,8.2 Hz, IH), 7.63 (d,7= 5.3 Hz, IH), 7.44 (d, J= 8.1 Hz, IH), 6.71 (dd,7= 12.4,

7.9 Hz, IH), 5.19 (s, IH), 4.68 (t, 7 - 6.0 Hz, 2H), 3.59 (t, 7= 6.0 Hz, 2H), 2.70 (s, 3H), 0.85 (s, 8H). ^I9F NMR (377 MHz, CD3OD) Ô -77.84 (s), -139.69 (s), -140.48 (s). LCMS-ESI⁺ (m/z): [M+Hf calcd for CÆH₂₆F₂NO₄: 478.5; Found: 478.1.

The other atropisomer, (R)-2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-6,7-difIuoro-3-methyInaphthalen-2-yl)acetic acid, was prepared in a similar manner. *H NMR (400 MHz, CDjOD) δ 8.70 (d, J = 5.7 Hz, IH), 7.96 (s, IH),

7,86 - 7.76 (m, 3H), 7.45 (d. J = 8.l Hz, IH), 6.76 (dd, J = 12.2.7.9 Hz, IH). 5.20 (s.

I H), 4 74 (dt, J = 12.4.6.3 Hz, 2H). 3 66 (t, J =5.9 Hz, 2H_f. 2.76 (s, 3H), 0.92 (s, 9H ). ⁱ⁹F NMR (377 MHz. CILOD) δ -77.78 (s, 3F).-138.7039.02 (m. 1F).-139.80 - 139 99 (m. 1 F). l.CMS-ESf (m/z): |M+Hf calcd for C_;gH_;6F_:NO₄: 478.5. Found 478.].

Example 108. (S)-2-tert-BiJtoxy-2-((R)-l-(2,3-dihydropyTano[4,3,2-de]quinolin-7-yl )-

5,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (110)

F

-(2,4-difluorophenyl)propan-2-one

(S)-2-(terf-butoxy)-2-((R)-1 -(2,3dihydropyrano[4,3,2-cfe]quinolin-7-yl)-5,7difluoro-3-methylnaphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (110): (S)-2-tert-Butoxy-2-((R)l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3-methyInaphthalen-2yl)acetic acid (110) was prepared in a similar manner as (S)-2-tert-butoxy-2-((R)-6chloro-1 -(2,3-dihydropyrano[4,3,2-de]quinolîn-7-yI)-7-fluoro-3 -methyInaphthalen-2yl)acetic acid of Example 99 except starting with l-(2,4-difluorophenyl)propan-2-one instead of l-(3-chloro-4-fluorophenyl)propan-2-one.

’H-NMR: 400 MHz, (CD₃OD) δ: 8.70 (d, J = 6.0 Hz, IH), 8.16 (s, IH), 7.82 (d, J = 8.0 Hz, IH), 7.80 (d, J = 6.0 Hz, 1 H),7.45 (d, J = 8.4 Hz, 1 H), 7.17 (ddd, J= 8.0, 8.0, 2.4 Hz, IH), 6.43 (d, J = 10.0 Hz, IH), 5.23 (s, IH), 4.71-4.70 (m, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.76 (s, 3H) 0.93 (s, 9H). ^,9F-NMR: 377 MHz, (CD₃OD) δ: -77.9 (s, 3F), -112.86 (d, J = 7.9 Hz, 1 F), -120.76 (dd, J = 9.0, 9.0 Hz, 1 F). LCMS-ESf (m/z): [M+H]⁺ calcd for CîsHzeFïNCU: 478.5; Found: 478.1.

X

300

Example 109. (2S)-2-tert-Butoxy-2-(5-chloro-1 -(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-7-fluoro-3-methylnaphthaien-2-yl)acetic acid (111)

Cl

2-{2-chloro-4f)uorophenyl)acetic acid steps

111 (2S)-2-(fert-butoxy)-2-(5-chtoro-1 -(2,3dihydropyrano{4_I3,2-</e]quinolin-7-yl)-7fluoro-3-methylnaphthalen-2-yl)acetic acid

Préparation of (2S)-2-tert-butoxy-2-(5-chloro-l-(2,3-dîhydropyrano[4,3,25 de]quinolin-7-yl)-7-fluoro-3 -methylnaphthalen-2-yl)acetic acid (111): (2S)-2-tertButoxy-2-(5 -chloro-1 -(2,3 -dihydropyraiK>[4,3,2-de|quinoIin-7-yl)-7-fluoro-3 methylnaphthalen-2-yl)acetic acid (111) was prepared following the procedure to make (S)-2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyTano[4,3,2-de]quinolin-7-yl)-7fluoro-3-methyInaphthalen-2-yl)acetic acid of Example 99, except 2-(2-chloro-410 fluorophenyl)acetic acid was used instead of 2-(3-chloro-4-fluorophenyl)acetic acid. ‘H-NMR: 400 MHz, (CDC1₃) δ: 8.59 (s, 1H), 8.30 (s ,1H), 8.11 (d, J= 8.21 Ηζ,ΙΗ), 7.46(d, J = 5.47 Hz, 1H), 7.19 (m, 2H), 6.35 (m. 1H), 5.38(s, 1H), 4.64 (m, 2H), 3.57 (m, 2H), 2.78(s, 3H), 1.16, 0.98 (s, 9H).

LCMS-EST (m/z): [M+H f calcd for CidkôCIFNO,: 494.95; found: 494.11.

301

Example 110, (S)-2-tert-Butoxy-2-((R)-1 -(2,3 -dihydropyrano[4,3,2-de]quinolîn-7-yl)7-fluoro-3,6-dimethylnaphthalen-2-yl)acetic acid (112) ^FY% O ^ste?^s —

2-(4-fluoro-3rTiethylphenyl)acetic acid

112 (S)2-(terLbutoxy)-2-((R)-1 -(2,3dihydropy rano[4,3,2-cfe]quino(in-7ylj-ï-fluoro-S.edimethy1naphthalen-2-y1)acetic acid

Préparation of (S)-2-tert-butoxy-2-((R)-1 -(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-7-fluoro-3,6-dimethylnaphthalen-2-y])acetic acid (112): (S)-2-tert-butoxy-2-((R)1 -(2,3 -dîhydropyrano [4,3,2-de]quinolin-7-yl)-7-fluoro-3,6-dimethylnaphthaIen-2yl)acetic acid (112) was prepared following the procedure to make (S)-2-tert-butoxy-2((R)-6-chloro-l -(2,3 -dihydropyrano[4,3,2-de]quinolin-7-yI)-7-fluoro-310 methylnaphthalen-2-yl)acetic acid of Example 99, except 2-(4-fluoro-3methylpbenyl)acetic acid was used instead of 2-(3-chloro-4-fluorophenyl)acetic acid. ’H-NMR: 400 MHz, (CDjOD) S: 8.66 (d, J = 5.76 Hz, 1 H), 7.90 (s ,1H), 7.80 (d, J=

6.65 Hz,3H), 7.42(d, J = 7.82 Hz, 1H), 6.46 (d, J = 11.73 Hz, 1H), 5.21 (s, 1H), 4.71 (m. 2H), 3.63(t, J = 6.26 Hz, 2H), 2.75 (s, 3H), 2.39 (s, 3H), 0.92 (s, 9H). LCMS-ESI* (m/z); [M+H]* calcd for C29H29FNO4: 474.54; found: 474.14.

302

Example I1L (S)-2-tert-Butoxy-2-((R)-5-cyano-1 -(2,3 -dihydropyrano [4,3,2de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (113A) and (S)-2-tertButoxy-2-((R)-5-carbamoyl-l-(2,3-dîhydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3methyinaphthaIen-2-yI)acetic acid (113B)

steps (S)-ethyl 2-(terÎ-butoxy )-2-(5chloro-7-fluoro-3-niethyl-1 (((trifiuoromethyl)sulfonyl)oxy) naphthafen-2-yl)acetate

(S>2-{ierf-butoxy)-2-((R)-5-cyanoiq2,3-dihydropyrano[4_r3,2dejqu inoiin-7-yl)-7-f luoro-3methylnaphthalen-2-yl)acetic acid

(S)-2-(tert-butoxy)-2-((R)-5carbamoyl-1-{2,3dihydropyrano[4,3,2-deJquinolin-7-yf)· 7-fluoro-3-methylnaphthalen-2yi)acetic acid

Préparation of (S)-2-tert-butoxy-2-((R)-5-cyano-l -(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (113A): (S)-2-tertbutoxy-2-((R)-5-cyano-1 -(2,3-dihydropyrano[4,3,2-de]quinolm-7-yl)-7-fluoro-3 methylnaphthalen-2-yl)acetic acid (113A) was prepared following the procedure to make (S)-2-tert-butoxy-2-((R)-6-cyano-1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)~

7-fluoro-3-methylnaphthalen-2-yl)acetic acid of Example 104, except (S)-ethyl 2-tertbutoxy-2-(5-chloro-7-fluoro-3-methyi-l-(trifluoromeLhylsulfoQyioxy)naphthalen-2yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-(6-chloro-7-fIuoro-3-methyl-l(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. ’H-NMR: 400 MHz, (CD₃OD) δ:

8.64 (d, J = 5.48 Hz, IH), 8.22 (s ,IH), 7.92 (t, J= 7.75 Ηζ,ΙΗ), 7.76 (d, J = 7.82 Hz,

303

IH), 7.68 (t, J = 10.56Hz, IH), 7.38 (d, J =7.72 Hz, IH), 6.98 (m, IH), 5.21 (s, IH),

4.71 (m. 2H), 3.60(t, J = 5.86 Hz, 2H), 2.82 (s, 3H), 0.92 (s, 9H).

¹⁹F-NMR: 377 MHz, (CD₃OD) Ô: -77.8 (s, 3F), -115.5 (br s, 1F). LCMS-ESF (m/z): [VFH| ' calcd for C29H26FN2O4: 485.52; found: 485.09.

Préparation of (S)-2-tert-butoxy-2-((R)-5-carbamoyl-l-(2,3dihydropyrano [4,3,2-de]quinoIin-7-yl)-7-fiuoro-3 -methylnaphthalen-2-yl)acetic acid (113B): Following the procedure to make (S)-2-tert-butoxy-2-((R)-6-carbamoyl-1-(2,3dihydropyrano[4,3 J-dc]qumolin-7-yi)-7-fluoro-3 -methylnaphthalen-2-yl)acetic acid of Example 104, except (S)-ethyl 2-tert-butoxy-2-(5-chloro-7-fluoro-3-methyl-l(trifluoromethylsulfonyIoxy)naphthalen-2-yl)acetate was used instead of (S)-ethyl 2tert-butoxy-2-(6-chIoro-7-fIuoro-3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2yl)acetate. 'H-NMR: 400 MHz, (CD3OD) δ: 8.64 (d, J = 5.48 Hz, IH), 8.32 (s ,1H), 7.78 (d, J= 7.82, 1 H), 7.72 (d, J= 5.87 Ηζ,ΙΗ), 7.50 (t, J = 8.21 Hz, 1H),7.4O (d, J =

8.22 Hz, lH),6.68(m, IH), 5.21 (s, IH),4.75 (m. 2H), 3.60 (t, J = 5.87 Hz, 2H), 2.82 (s, 3H), 0.92 (s, 9H).

LCMS-ESf (m/z): [M+H]⁺calcd for CzçHzgFNaOj: 503.53; found: 503.12.

304

Example 112. (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-deJquinolin-7-yl)7-fluoro-3-methyl-5-(pyrimidin-5-yl)naphthalen-2-yl)acetic acid (114)

(S)-ethyl 2-{terPbutoxy)-2-((R)5-chloro-1-(2,3dihydropy rano[4,3,2de]quinolin-7-yl)-7-fluora-3methy(naphthalen-2-y()acetate

(S)-ethyl 2-((erf-butoxy)-2-((R>1-(2,3dihydropyrano{4,3.2-de]quinolin-7-yl)7-fluoro-3-methyl-5-(pyrimidin-5yl)naphthalen-2-yl)acetate

114 (S)-2-(tert-butoxy )-2-((R)-1 -{2.3dihydropyrano[4_I3,2-de]quinolin-7yl)-7-fluoro-3-methyl-5-(pyrimidin-5yl)naphthalen-2-yl)acetic acid

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano [4,3,25 de]quinolin-7-yl)-7-fluoro-3-inethyl-5-(pyrimidin-5-yI)naphthalen-2-yl)acetate : A

Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-((R)-5-chloro-l-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthaIen-2-yl)acetate (12 mg, 0.023 mmol, 1 eq.), pyrimidin-5-ylboronic acid (5 mg, 1.5 eq.), Sphos Palladacycle (3 mg, 0.1 eq.), césium fluoride (12 mg, 3 eq.) and flushed with nitrogen.

Dimethoxyethane (0.5 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120 °C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried

305 (MgSOd), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-((R)-1-(2,3dihyïlropyrano[4,3,2-de]quinolin-7-yl)-7-f)uc)ro-3-rnethyl-5-(pyriinidiri-5yl)naphthalen-2-yl)acetate (4 mg). LCMS-ESI* (m/z): [M+H]* calcd for C34H33FN3O4: 566.63; Found: 566.3.

Préparation of (S)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano [4,3,2 -de]quinolin7-yl)-7-fluoro-3-methy!-5-(pyrimidin-5-yl)naphthalen-2-yl)acetic acid (114): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7yl)-7-fluoro-3-methyl-5-(pyrimidin-5-yl)naphthalen-2-yl)acetate (4 mg) and 2 M sodium hydroxide (0.5 mL) in tetrahydrofuran (0.5 mL) and éthanol (0.5 mL) was heated at 50 °C for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgSCL), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). Product lyophilized to give a yellow powder (1.2 mg). ’H-NMR: 400 MHz, (CD3OD): δ 9.23 (d, J = 5.09 Hz, 1H), 8.82 (s, 1H), 7.96 (s, 1H), 8.60 (m, 1H), 7.80 (m, 1H), 7.52 (d, J = 5.08 Hz, 1H), 7.32 (m, 2H), 7.19 (s, 1 H), 6.82 (m, 1 H), 5.02 (m, 1H), 4.76 (m, 2H), 3.50 (t, J 6 Hz, 2H), 2.37 (s, 3H) 0.92 (s, 9H).

^l9F-NMR: 377 MHz, (CD₃OD) Ô: -77.7 (s, 6F), -115.9 (m, 1F). LCMS-ESI* (m/z): [M+H]*calcd for C32H39FN3O4:538.58 ; Found: 538.03.

Example 113. (S)-2-tert-Butoxy-2-{(R)-6-chioro-l-(2,3-dihydropyrano [4,3,2de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)aeetic acid (115)

F

2-(3-chloro-2fluorophenyl)acetic acid steps

115 (S)-2-(teri-butoxy)-2-((R)-6chloro-1-(2_I3-dihydropyrano(4,3,2cte]quinolîn-7-yl)-5-fluoro-3methylnaphthaien-2-yl)acetic acid

Préparation of (S)-2-tert-buÎOxy-2-((R)-6-chloro-l -(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetic acid (115): (S)-2-tertButoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2-de]quînolin-7-yl)-5-fluoro-3methylnaphthalen-2-yl)acetic acid (115) was prepared following the procedure to make (S)-2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2-de]quinoîin-7-yl)-7fluoro-3-methylnaphthalen-2-yI)acetîc acid of Example 99, except 2-(3-chloro-2fluorophenyl)acetic acid was used instead of 2-(3-chloro-4-fluorophenyl)acetic acid. ^]H-NMR: 400 MHz, (CD3OD) δ: 8.69 (d, J = 5.87 Hz, 1H), 8.18 (s ,1 H), 7.80 (m ,2H), 7.42(d, J = 7.72 Hz, IH), 7.26(t, J = 7.43 Hz, 1H), 6.78 (d, J = 9.38 Hz, 1Η), 5.22(s, 1H), 4.64 (m, 2H), 3.62 (t, J = 5.86 Hz, 2H), 2.80(s, 3H), 0.98 (s, 9Η). ^l9F-NMR: 377 MHz, (CD30D) S: -77.7 (s, 3F),-127.87 (d, 1 F). LCMS-ESI* (m/z); [M+H]* calcd for C₂₈H₂₆C1FNO4: 494.95; found: 494.07.

Example 114. (S)-2-tert-Butoxy-2-((R)-5-chIoro-1 -(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetic acid (116)

Cl

-bromo-2-chloro-3 methylbenzene

- JÇXA

Cl

1-(2-chloro-3methylphenyl) propan-2-one

116 (S)-2-(tert-butoxy)-2-((R)-5~ctiloro-1 (2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-3,6dimethylnaphthalen-2-yl)acetic acid

Préparation of l-(2-chloro-3-methylphenyl)propan-2-one: A Smith process vial was charged with l-bromo-2-chloro-3-methylbenzene (528 mg, 2.57 mmol, 1 eq.), tributyhnethoxytin (1.11 mL, 1.5 eq.), 4-methylpent-4-en-2-one (0.42 mL, 1.5 eq.), PdCI₂ (23 mg, 5%) and tri(o-tolyl)phosphine (79 mg, 10%), toluene (1 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in oil bath at 100 °C for 5 hours. The reaction mixture was diiuted with ethyl acetate and washed with brine,

307 dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to 1 -(2-chloro-3-methylphenyl)propan-2one (375 mg, 80% yield). ’H-NMR: 400 MHz, (CDC1₃) δ : 7.19-7.02 (m, 3H), 3.82(s, 2H),2.38(s, 3H), 2.18 (s, 3H).

Préparation of (S)-2-tert-butoxy-2-((R)-5-chloro-1 -(2,3 -dîhydropyrano[4,3,2de]quinolin-7-yI)-3,6-dimethylnaphthalen-2-yl)acetic acid (116): (S)-2-tert-butoxy-2((R)-5-chloro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2yl)acetic acid (116) was prepared following the procedure to make (S)-2-tert-butoxy-2((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3methylnaphthalen-2-yl)acetîc acid, used l-bromo-2-chloro-3-methylbenzene instead of 2-(3-chloro-4-fluorophenyl)acetic acid. ’H-NMR: 400 MHz, (CD₃OD) δ : 8.59 (d, J = 5.08 Hz, IH), 8.26 (s ,1H), 7.68 (m ,2H), 7.34 (d, J = 8.21 Hz, IH), 7.08(d, J = 8.60 Hz, IH), 6.72 (d, J = 8.50 Hz, IH), 5.16(s, IH), 4.62 (m, 2H), 3.56 (t, J = 6.26 Hz, 2H), 2.72(s, 3H), 2.42(s, 3H), 0.92 (s, 9H). LCMS-ESI* (m/z): [M+H]* calcd for C29H29CINO4: 490.99; found: 490.33.

Example 115. (S)-2-tert-Butoxy-2-((R)-I-(2,3-dihydropyrano[4,3,2-de]quinoIm-7-yl)-

3.5,6-trimethylnaphthaIen-2-yI)aeetic acid (117)

308

(S)-ethyl 2-(fert-butoxy)-2-((R)-5-chloro- (S)-ethy' 2-terf-butoxy-2-((fî)-1-(2,31-(2,3dihydropyrano[4,3,2-de]quinolin- dihydropyrano{4,3,2-i/e]quinolin-7-yl)7-yl)-3,6-dimethylnaphthalen-2- 3,5,6-trimethylnaphthalen-2y)acetate yl)acetate

(S)-2-(fert-butoxy)-2-((R)-142,3dihydrapyrano[4,3,2-Îfe]quinolin-7-yl)3,5,6-tr»methyinaphthalen-2-yl)acetic acid

Préparation (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihYdropyrano[4,3,2dejquinolin-7-yI)-3,5,6-trimethylnaphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2 ((R)-S-chloro-l-(2,3-dihydropyrano[4,3.25 de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetate (16 mg, 0.031 ππηοΐ, 1 eq.), methylboronic acid (4 mg, 2 eq.), Sphos Palladacycle (2 mg, 0.1 eq.), césium fluoride (19 mg, 4 cq.) and flushed with nitrogen. Dimethoxyethane (0.5 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120 °C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-((R)-1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5,6trimethylnaphthalen-2-yl)acetate (7 mg). LCMS-ES1⁺ (m/z): [M+H]⁺ calcd for C32H36NO4; 498.62; Found: 498.1.

Préparation of (S)-2-tert-butoxy-2-((R)-1 -(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-3,5,6-trimethylnaphthalen-2-yl)acetic acid (117): A solution of (S)-ethyl 2-tert-

butoxy-2-((R)-1 -(2,3-dihydropyrano[4,3,2-de]quinoiin-7-yl)-3,5,6-tnmethyInaphthaien2-yl)acetate (7 mg) and 2 M sodium hydroxide (0.5 mL) in tetrahydrofuran (0.5 mL) and éthanol (0.5 mL) was heated at 50 °C for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was backextracted with ethyl acetate and the combined organic layer was dried (MgSO₄), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O +0.1% TFA). Product lyophilized to give a yellow powder (4.7 mg). ’ 11NMR: 400 MHz, (CD₃OD): δ 8.64 (d, J = 5.86 Hz, 1H), 8.15 (s, 1H), 7.76 (t, J = 8.90 Hz, 2H), 7.43 (d, J = 8.99 Hz, 1H), 7.07 (d, J = 8.99 Hz, 1H), 6.65 (d, J = 8.60 Hz, 1H),

5.21 (s, 1H), 4.70 (m, 2H), 3.64 (t, J = 7.77 Hz, 2H), 2.79 (s, 3H), 2.67 (s, 3H), 2.43 (s, 3H), 0.92 (s, 9H). LCMS-ESÏ* (m/z): [M+H]⁺calcd for C₃qH₃₂NO₄:470.57; Found: 470.39.

Example 116. (S)-2-tert-Butoxy-2-((R)-5-cyano-1 -(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-3,6-dimethyinaphthalen-2-yl)acetic acid (118)

118 (S)-2-(tert-butoxy)-2 ((R)-5-cyano-1-{2,3dihydropyrano[4,3,2-deJquinolin-7-yl)~3,6dimethylnaphtfJaten-2-y))acetic acid

Préparation of (S)-2-tert-butoxy-2-((R)-5-cyano-l -(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetîc acid (118): (S)-2-tert-butoxy-2((R)-5-cyano-1 -(2,3-dihydropyrano(4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2yl)acetic acid (118) was prepared following the procedure to make (S)-2-tert-butoxy-2((R)-l-(2,3-dihydropyrano[4,3,2-delquinolm-7-yl)-3,5,6-trimethylnaphthalen-2yl)acetic acid of Example 115, except used Zn(CN)₂ was used instead of methylboronic acid, and DMF was used instead of DME. Analytical HPLC (Gemini, 2-98% ACN/H₂O + 0.05% TFA, 7 minutes run): t_R (min) = 4.00.

310

H-NMR: 400 MHz, (CD₃OD) δ ; 8.59 (d, J = 5.48 Hz, IH), 8.09 (s ,1H), 7.64(d, J =

8.21 Hz, IH), 7.62 (d, J = 4.08 Hz, IH), 7.36 (d, J = 8.21 Hz, IH), 7.19 (d, J = 8.61 Hz, IH), 7.12 (d, J = 8.98 Hz, IH), 5.16 (s, IH), 4.62 (m, 2H), 3.56 (t, J = 5.86 Hz, 2H), 2.72(s, 3H), 2.62(s, 3H), 0.92 (s, 9H). LCMS-ESI* (m/z): [M+H]* calcd for

C₃₀H₂₉N₄O₄: 481.55; found: 481.32.

Example 117. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-

5-fluoro-3,6-dîmethylnaphthalen-2-yl)acetic acid (119)

(S)-ethyl 2-(tert-butoxy)-2-((R)-6chloro-1 -(2,3-dihydropyrano[4,3,2deJquinofin-7-yl)-5-fluoro-3methylnaphthalen-2-yl)acetate

(Spethyl 2-(tert-butoxy)-2-{(R)-1(2,3-dîhy dropy rano[4,3,2de]quinolin-7-yl)-5-fluoro-3,6dimethylnaphthalen-2-yl)acetate

NaOH

(S)-2-(ferf-butoxy)-2-((/?)-1 -(2,3dihydropyrano[4,3,2-deJquinolin-7yl)-5-fluoro-3,6-dimethylnaptithalen2-yl)acetic acid

Préparation (S)-ethyl 2-tert-butaxy-2-((R)-l-(2,3-dihydropyrano[4,3,2de]quinolîn-7-yl)-5-fluoro-3,6-dimethylnaphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-((R)-6-chloro-1-(2,3 -dihydropyiano[4,3,215 de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yI)acetate (10 mg, 0.019 mmol, 1

eq.), methylboronîc acid (2 mg, 1.5 eq.), Sphos Palladacycle (1.3 mg, 0.1 eq.), césium fluoride (14 mg, 4 eq.) and flushed with nitrogen. Dimethoxyethane (0.5 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120 °C for l hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO₄), filtered, concentrated and purifîed by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyTano[4,3,2-de]quinolin-7-yl)-5fluoro-3,6-dimethylnaphthalen-2-yl)acetate (6 mg). LCMS-ES1* (m/z): [M+H]⁺calcd for C_3]H₃3FNO₄: 502.59; Found: 502.1.

Préparation of (S)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-5-fluoro-3,6-dimethylnaphthalen-2-yl)acetic acid (119): A solution of (S)-ethyl 2tert-butoxy-2-((R)-l-(2,3-’dihy<iropyrano[4,3,2-de]quînolin-7-yl)-5-fluoro-3,6dimethylnaphthalen-2-yl)acetate (6 mg) and 2 M sodium hydroxide (0.5 mL) in tetrahydrofuran (0.5 mL) and éthanol (0.5 mL) was heated at 50 °C for overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgSO₄), filtered, concentrated and purifîed by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). Product lyophilized to give a yellow powder (4.7 mg). 'H-NMR: 400 MHz, (CD₃OD): δ 8.67 (d, J = 5.47 Hz, IH), 8.12(s, IH), 7.78 (t, J =

5.87 Hz, 2H), 7.43 (d, J = 8.82 Hz, IH), 7.11 (t, J = 8.21 Hz, IH), 6.63 (d, J = 8.60 Hz, IH), 5.22 (s, IH), 4.70 (m, 2H), 3.64 (t, J = 5.86 Hz, 2H), 2.79 (s, 3H), 2.38 (d, J = 1.47 Hz, 3H), 0.92 (s, 9H). ^I9F-NMR: 377 MHz, (CD3OD) 5: -77.7 (s, 3F), -131.6 (d, 1F). LCMS-ESf (m/z): [M+H]⁺calcd for C29H29FNO4: 474.54; Found: 474.33.

312

Example 118. (S)-2-tert-Butoxy-2-((R)-1-(2,3 -dihydropyrano[4,3,2-de]quinolin-7-yl)-

6-ethyl-5-fluoro-3-methylnaphthalen-2-yl)acetic acid (120)

OH

F

120 (S)-2-(fert-butoxy)-2-((H)-1 -(2,3drhydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-

5-fIuoro3-methylnaphthalen-2-yl)aceticacid

Préparation of (S)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-

7-yl)-6-ethyl-5-fluoro-3-methylnaphthalen-2-yl)acetic acid (120): (S)-2-tert-Butoxy-2((R)-1 -(2,3-dihydiopyrano[4,3,2de]qumolm-7-yl)-6-cthyi-5-fiuoro-3methylnaphthalen-2-yl)acetic acid (120) was prepared following the procedure to make (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3^-de]quinolin-7-yl)-5-fluoro-3,6dimethylnaphthaIen-2-yl)acctic acid of Example 117, except that ethylboronic acid was used instead of methylboronic acid. Analytical HPLC (Gemini, 2-98% ACN/H₂O + 0.05% TFA, 7 minutes run): t& (min) = 4.00.

'H-NMR: 400 MHz, (CD₃OD): δ 8.67 (d, J = 5.47 Hz, 1H), 8.14 (s, 1H), 7.81 (t, J =

8.21 Hz, 2H), 7.46 (d, J = 8.21 Hz, 1H), 7.16 (t, J = 8.23 Hz, 1H), 6.67 (d, J = 9.0 Hz, 1H), 5.22 (s, 1H), 4.71 (m, 2H), 3.66 (t, J = 5.86 Hz, 2H), 2.79 (m, s, 5H), 1,23 (t, J =

7.82 Hz, 3H), 0.93 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD3OD) 8: -77.7 (s, 3F), -133.06 (d, 1F). LCMS-ESI⁴ (m/z): [M+H]⁴ calcd forC30H₃iFNO4: 488.56 (M+H⁴); Found: 488.37.

313

Example 1I9. (S)-2-tert-Butoxy-2-((R)-6-(difluoromethyl)-l-(2,3dihydropyrano[4_i3,2-de]quinolin-7-yl)-5-fluoro-3-njethylnaphthalen-2-yl)acetic acid (121)

(S)-ettiyl 2-(tert-butoxy)-2-((R)-6chloro-1-(2,3-dihydropyrmio[4,3,2de]quinolin-7-yl)-5-fluoro-3metfiylnaphthalen-2-yl)acetate

(S)-ethyl 2-{teft-butoxy)-2-((R)-1(2,3-dihydropyrano(4,32de)quinoiin-7-y))-5-fluoro-3-methyl

6-vinylnaptrthalen-2-yl)acetate (S)-ethyi 2-(fert-tiutoxy)-2-((/î)-1(2,3-dihydropyraiw[4,3,2de]qutnolin-7-yl)-5-fluoro-6-fomiyl· 3-methylnaphthalen-2-yl)acetate

F F (S>ethyl 2-(tert-butoxy)-2-((R)-6(difluoramethyl)-1-(2,3dihydropyrano[4,3,2-de]quinofin-7-yl)-5fluoro-3-methylnaphthalen-2-y!)acetate

F F

121 (S)-2-(/orf-butoxy)-2-((ff)-6(difluoromethyl)-1 -(2,3dihydropyrano[4,3,2-tie]quÎnoîin-7-yl)-5fluon>3-methylnaphthaten-2-yl)acetic add

Préparation (S)-ethyl 2-tert-butoxy-2-((R)-l-(2.3-dihydropyrdno|4,3,2de]quinoIm-7-yl)-5-fluoro-3-methyl-6-vinylnaphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-((R)-6-chloro-1-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-5-HiiOTo-3-methylnaphthalen-2-yl)acetatc (99

314 mg, 0.19 mmol, 1 eq.), potassium vinyltrifluoroborate (28 mg, 1.1 eq.), Sphos Palladacycle (13 mg, 0.1 eq.), césium fluoride (114mg, 4 eq.) and flushed with nitrogen. Dimethoxyethane (2 mL, distilled from Na/benzophenone) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 110 °C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-((R)-l(2,3-dihydropyrano[4,3,2-delqumolin-7-yl)-5-fluoro-3-methyl-6-vinylnaphthalen-2yl)acetate (69 mg, 71 % yield). LCMS-ESf (m/z): [M+H]⁺ calcd for C32H3ÎFNO4: 514.60; Found: 514.1.

Préparation (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dîhydropyrano[4,3,2de]quinolin-7-yl)-5-fluoro-6-formyl-3“methylnaphthalen-2-yl)acetate: (S)-ethyl 2-tertbutoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methyl-6vinylnaphthalen~2-yl)acetate (32 mg, 0.062 mmol, 1 eq.) was dissolved in 2 mL THF. This solution was added to the mixture of NalCU (40 mg, 3 eq.) and K₂OsÛ4*2H2O (2.3 mg, 0.1 eq.) in I mL water at room température. The reaction was complété after stiiring at room température for 30 minutes. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate and washed with brine, dried (MgSO₄), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-((R)-l-(2₎3-dihydropyrano[4_î3,2de]quinolin-7-yl)-5-fluoro-6-formyl-3-methyLnaphtha]en-2-yl)acetate as a light yellow oil (26 mg, 81% yield). LCMS-ESf (m/z): [M+Hf calcd for CgiHjiFNOj: 516.57; Found: 516.1.

Préparation (S)-ethyl 2-tert-butoxy-2-((R)-6-(difluoromethyl)-l-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3 -methylnaphthalen-2-yl)acetate : (8)ethyl 2-tert-butoxy-2-((R)-1 -(2,3 -dihydropyrano[4,3,2-de]quinolîn-7-yl)-5-fluoro-6formyl-3-methylnaphthalen-2-yl)acetate (8 mg) was dissolved in 0.5 mL DCM. Deoxofluor (50 pL, excess) was added to the solution. The reaction was stirred at room température for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tertbutoxy-2-((R)-6-(difluoromethyl)-1 -(2,3-dîhydropyrano[4,3^2-dé|qümolin-7-yl)-516293

315 fluoro-3-methylnaphthalen-2-yl)acetate as a light yellow oil (6 mg, 76% yield). LCMSΕ8Γ (m/z): [M+H]’ calcd for C_3IH3iF₃NO_s: 538.57; Found: 538.34.

Préparation of (S)-2-tert~butoxy-2-((R)-6-(difluoromethyl)-l-(2,3dihydropyrano[4,3^-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetic acid (121): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-6-(difluoromethyl)-l-(2,3dihydropyrano[4,3,2-de]quinoIin-7-yl)-5-fluoro-3-methylnaphthaleii-2-yl)acetate (6 mg) in tetrahydrofuran (0.5 mL) and éthanol (0.5 mL) and 2 M sodium hydroxide (0.5 mL) was heated at 50 °C for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgSCU), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). Product lyophilîzed to give a yellow powder (4.7 mg). ’H-NMR: 400 MHz, (CD₃OD): δ 8.69 (d, J = 5.48 Hz, 1H), 8.26 (s, 1H), 7.84 (d, J - 8.22 Hz, 1H), 7.80 (d, J = 5.87 Hz, 1H),

7.43 (m, 2H), 7.34, 7.21, 7.07 (t, J = 54.74 Hz, 1H), 6.90 (d, J = 9.38 Hz), 5.25 (s, 1H),

4.73 (m, 2H), 3.64 (t, J = 5.86 Hz, 2H), 2.83 (s, 3H), 0.93 (s, 9H). ^l9F-NMR: 377 MHz, (CD₃OD) δ: -77.7 (s, 3F), -113.97 to -116.29 (m, 2F), -131.6 (s, 1F). LCMS-ESf (m/z): [M+H]⁺calcd for C29H27F3NO4; 510.52; Found: 510.36.

316

Exemple 120. (2S)-2-tert-butoxy-2-( 1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-y 1)-4nuuro-3-methylnaphthalen-2-yl)acetic acid (122).

O

ethyl 4-(4-bromophenyl)3-methylbut-2-enoate

OH

OH OH

7-bromo-3- methylnaphthalen-1 -ol

3-methy lnaphthalen-1 -ol ethyl 2-hydroxy-2-(1-hydroxy3-methylnaphthalen-2-yl)acetate

ethyl 2-tert-butoxy-2-(1-hydroxy3-methylnaphthaten-2-yi)acetate

ethyl 2-fert-butoxy-2-(4-fluoro-1 -hydroxy3-methylnaphthalen-2-yl)acetate

ethyl 2-tert-butoxy-2-(4-fluoro3-methy 1-1 -(trifluoromethylsulfonyloxy )naphthalen-2-y1)acetate ethyl 2-(4-fluoro-3-methyH(tnfiuoromethylsulfonyloxy)naphthalen -2-yl)-2-hydroxyacetate

317

ethyl 2-(4-fluoro-3-methyl-1(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-oxoacetate

(S)-ethyl 2-(4-fluaro-3-methyl-1(trifluoromethylsulfonyloxy)nap hthalen-2-y|)-2-hydroxy acetate

(S)-ethyl 2-terf-butoxy-2-(4-fluoro-3-methyl-1- (S)-ethyl 2-tert-butoxy-2-((R)-1(trifluoromethyisulfonytoxy)nap (2,3-dihydropyrano[4,3,2hthalen-2-yl)acetate de]quinolin-7-yl)-4-fluoro-3methy(naphthalen-2-yl)acetate

(S)-2-ierf-bLftoxy-2-((R)-1 -(2,3dihydropyrano[4,3,2-de]quinolin-7yl)-4-fiuoro-3-methylnaphthalen-2yl)acetic acid

Préparation of ethyl 4-(4-bromophenyl)-3-methylbut-2-enoate: At 0 °C, a suspension of 60% w/w NaH/mineral oil (7.13 g, 0.176 mol) in THF (250 mL) was treated dropwise with a solution of triethylphosphonoacetate (39.5 g, 0.176 mol) in

THF (72 mL) over a 30 min period. The reaction was stirred for another 30 min, and a solution of l-(4-bromophenyI)propan-2-one (25.0 g, 0.117 mol) in THF (108 mL) was added dropwise over 1 h (reaction was kept at 0 “C during addition. The reaction was allowed to warm to 23 °C as it was stirred ovemight. The next day, saturated NH4CI (250 mL) was added. After 2 h, the reaction was diluted with H2O (250 mL) and hexane (100 mL). The organic phase was collected. The aqueous layer was extracted with EtOAc (2 x 150 mL). Combined organic phases were dried (MgSOi), filtered, and

318 concentrated, giving crude 4-(4-bromophenyl)-3-methyibut-2-cnoate as a mixture of E and Z géométrie isomers. The residue was canied onward without further purification. (~30 grains; yield was not determined). The 'il NMR reported below was from a crude mixture containing both the E and Z isomer.

Ή NMR (400 MHz, CDCi₃) δ 7.43 (d, J = 8.6 Hz, 1.6H), 7.39 (d, J = 8.6 Hz, 0.4H), 7.12 (d, J = 8.2 Hz, 0.4H), 7.04 (d, J = 8.2 Hz, 1.6H), 4.42-4.21 (m, 2H), 3.96 (s, 0.4H),

3.38 (s, 1.6H), 2.10 (s, 2.4H), 1.77 (s, 0.6H), 1.37-1.23 (m, 3H).

Préparation of 7-bromo-3-methylnaphthalen-l-ol: A flask containing the crude ethyl 4-(4-bromophenyl)-3-methylbut-2-enoate fiom above (- 30 grains) was treated with concentrated H₂SO₄ (120 mL) and wanned to 50 °C for 2.5 h. The reaction was poured onto ~500 mL of crushed ice. Once the ice had thawed, the brown suspension was extracted with two portions of EtOAc (500 mL and 100 mL, respectively). The two extracts were combined, washed with saturated NaHCO₃, dried (MgSO₄), filtered, and concentrated to ~ 55 mL. The residue was treated with DCM and wct-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (16.6 g, 60% yield over 2 steps from l-(4-bromophenyl)propan-2one. 'H NMR (400 MHz, CDC1₃) δ 8.29 (d, J - 1.9 Hz, IH), 7.57 (d, J = 8.6 Hz, IH),

7.50 (dd, J = 8.6, 2.0 Hz, IH), 7.17 (s, IH), 6.67 (s, IH), 2.42 (s, 3H).

Préparation of 3-methylnaphthalen-l-ol: A sluny of 7-bromo-3methylnaphthalen-l-ol (100 mg, 0.421 mmol), 10% w/w Pd/C (45 mg, 42.1 pmol Pd), and absolute EtOH (2.0 mL) was purged under vacuum and backfilled with H₂ from a balloon several times. The suspension was stirred under a balloon of H₂ at 23 °C overnight. The reaction was filtered over Celite, the cake was washed with EtOAc. The filtrate was concentrated and dissolved in DCM. The solution was wet-loaded onto a 12 g “gold” ISCO silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (yield was not found). ^]H NMR (400 MHz, CDC1₃) δ 8.10 (d, J = 7.8 Hz, IH), 7.72 (d, J = 7.8 Hz, IH), 7.47-7.39 (m, 2H), 7.22 (s, IH), 6.67 (s, IH), 2.45 (s, 3H).

Préparation of ethyl 2-hydroxy-2-(l-hydroxy-3-methyhiaphthalen-2-yl)acetate: A flask containing DCM (5.0 mL) was charged with T1CI4 (1.0 M in DCM, 3.16 mL,

3.16 mmol). After cooling to -40 °C (dry ice/CH₃CN bath), a solution of 3methylnaphthalen-l-ol (500 mg, 3.16 mmol) in DCM (5.0 mL) was added dropwise over a 5 min period. The reaction tumed deep violet. After 30 min, a solution of ethyl

319 glyoxylate (323 mg, 3.16 mmol, distilled freshly from P2O5 trader N₂ from the 50% w/w toluene solution of ethyl glyoxylate) in DCM (2.0 mL) was added quickly. The reaction was warmed to 0 °C. After 1 h, glacial AcOH (1.0 mL) was added. 5 min iater, CH3CN (5.0 mL) was introduced, followed by H₂O (10 mL). The reaction transitioned from violet to yellow-orange. The reaction was warmed to 23 °C and stirred for 30 min. The reaction was diluted with H₂O (15 mL) and extracted with DCM (3 x 20 mL). The combined extracts were washed with saturated NaHCOj (20 mL) (this decolorized the organic phase from orange to yellow), dried (Na₂SO4), filtered, concentrated, treated wîth DCM (10 mL), and concentrated again. The residue was dissolved in DCM and loaded onto a 24 g “gold” ISCO silica gel column and purified by flash chromatography (ethyl acetate/hexanes) gîving the desired product (622 mg, 76% yield). ‘H NMR (400 MHz, CDCI3) δ 8.41 (s, IH), 8.20 (d, J = 8.2 Hz, 1H), 7.67 (d, J =

8.8 Hz, 1H), 7.46 (dd, J = 8.8, 8.0 Hz, 1H), 7.40 (dd, J = 8.2, 8.0 Hz, 1H), 7.20 (s, 1H),

5.68 (s, 1H), 4.31-4.08 (m, 2H), 3.94 (s,broad, 1H), 2.52 (s, 3H), 1.18 (t, J = 7.0 Hz, 3H).

Préparation of ethyl 2-tert-butoxy-2-(l-hydroxy-3-methylnaphthalen-2yl)acetate: A solution of ethyl 2-hydroxy-2-(l-hydroxy-3-methylnaphthalen-2yl)acetate (622 mg, 2.39 mmol) in tert-butyl acetate (12 mL) was treated with 70% HCIO4 (20 pL) at 23 °C). After 3 h, the reaction was added slowly over 5 min to saturated NaHCO₃ (25 mL). The resulting System was extracted with DCM (3x15 mL). The combined organic layers were dried (Na₂SO4), filtered, and concentrated. Hexane (10 mL) was added, and the mixture was concentrated again. The residue was dissolved in benzene. The solution was wet-loaded onto a 24 g “gold” ISCO silica gel column and purified by flash chromatography (hexane —► ethyl acetate) gîving the desired product (286 mg, 38% yield). ^lH NMR (400 MHz, CDCI3) δ 9.00 (s, 1H), 8.26 (d, J = 8.2 Hz, 1H), 7.65 (d, J - 8.8 Hz, 1H), 7.44 (dd, J = 8.2, 8.0 Hz, 1H), 7/39 (dd, J = 8.8, 8.0 Hz, 1H), 7.17 (s, 1H), 5.52 (s, 1H), 4.25-4.06 (m, 2H), 2.59 (s, 3H), 1.33 (s, 9H), 1.20 (t, J = 7.0 Hz, 3H).

Préparation of ethyl 2-tert-butoxy-2-(4-fluoro-l-hydroxy-3-methylnaphthalen2-yl)acetate: A solution of ethyl 2-tert-butoxy-2-(l-hydroxy-3-methylnaphthalen-2yl)acetate (1.50 g, 4.74 mmol) in CH₃CN (37.5 mL) was cooled to 0 °C. Selectfluor (1,70 g, 4.74 mmol) was added, and the reaction was allowed to wann to 23 °C. After 2 h, the reaction was added slowly to a mixture of saturated Na₂HPO4 (70 mL) and H₂O

320 (30 mL) at 23 °C. More H2O (40 mL) was added, and the System was extracted with DCM (3x 40 mL). The combined organic phases were treated with hexane (20 mL). The phase that separated was removed. The remaining organic phase was dried (NaîSCh), filtered, and concentrated. The filtrate was concentrated and dissolved in benzene. The solution was wet-loaded onto a 24 g “gold” ISCO silica gel column and purifîed by flash chromatography (ethyl acetate/hexanes) giving the desired product (1.26 g, 79%). ’H NMR (400 MHz, CDC1₃) S 8.83 (s, IH), 8.23 (d, J = 8.2 Hz, IH),

7.93 (d, J = 8.4 Hz, IH), 7.51 (dd../- 6.9,6.9 Hz, IH), 7.45 (dd, J = 6.9,6.9 Hz, IH),

5.46 (s, IH), 4.23-4.14 (m, 2H), 2.49 (d, Jhf = 3.2 Hz, 3H), 1.31 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H). ¹⁹F NMR (377 MHz, CDCI3) δ -137.3 (app. s).

Préparation of ethyl 2-tert-butoxy-2-(4-fluoro-3-methyl-1 (trifluoromethylsuIfonyloxy)naphthalen-2-yl)acetate: A flask was charged with CS2CO3 (2.45 g, 7.53 mmol) and iV-phenyltriflimide (2.69 g, 7.53 mmol). A solution of ethyl 2tert-butoxy-2-(4f[uoro-l-hydroxy-3-mcthy lnaphlhalen-2-y l)acctatc (1.26 g, 3.76 mmol) in THF (38 mL) was added at 23 °C. After 30 min, the reaction was added slowly to a pre-stirred mixture of 2 M NaHSO₄ (30 mL) and saturated Na₂HPO4 (100 mL) at 23 °C. The system was extracted with a mixture of ethyl acetate/hexane (10:l)(3x 50 mL). Combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The residue was concentrated once more from hexane. The residue was dissolved in benzene. The solution was wet-loaded onto a 40 g “gold” ISCO silica gel column and purifîed by flash chromatography (hexane —► ethyl acetate/hexanes 1:4) giving the desired product (1.75 g, >99%). ^lH NMR (400 MHz, CDC1₃) δ 8.11-8.02 (m, 2H), 7.66-7.60 (m, 2H), 5.72 (s, IH), 4.27 4.10 (m, 2H), 2.44 (d, Jhf = 3.2 Hz, 3H),

1.21 (s, 9H), 1.18 (t, J = 7.0 Hz, 3H). ¹⁹F NMR (377 MHz, CDC1₃) δ -123.1 (app. s, 1F), -73.4 (s, 3F)

Préparation of ethyl 2-(4-fluoro-3-methyl-1-(trifluoromethylsulfony 1oxy)naphthalen-2-yl)-2-hydroxyacetate: A solution of ethyl 2-tert-butoxy-2-(4-fluoro3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (1.75 g, 3.76 mmol) in DCM (30 mL) was treated dropwise with TFA (3.0 mL) over 3 min at 23 °C. After 16 h, the reaction was diluted with H₂O (60 mL) and the system was extracted with DCM (3x 20 mL). Combined organic layers were dried (Na2SO₄), filtered, and concentrated giving the crude desired product (~ 1.54 g obtained), which was used in the next reaction. ^lH NMR(400 MHz, CDCI3) δ 8.11-8.06 (m, IH), 7.67-7.64 (m, IH), 7.6116293

321

7.52 (m, 2H), 7.41 (d, J = 7.8 Hz, IH), 5.79 (s, IH), 4.34-4.22 (m, 2H), 2.40 (d, Jhf =

3.2 Hz, 3H), 1.22 (t, J =7.4 Hz, 3H). ^l9FNMR(377 MHz, CDClj) δ-122.6 (app. s, 1F), -73.3 (s, 3F).

Préparation of ethyl 2-(4-fluoro-3-methyI-l-(trifluoromethylsulfonyl-oxy)naphthalen-2yl)-2-oxoacetate: A solution of ethyl 2-(4-fiuoro-3-methyl-l(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (~ 1.54 g, 3.76 mmol) în DCM (60 mL) was treated with Dess-Martin periodinane (1.91 g, 4.51 mmol) at 23 °C. After 4 h, the orange reaction was slowly added to 10% Na₂S₂O3 (28 mL) at 23 °C. After 5 min of stirring, the reaction was diluted with H₂O (40 mL) and extracted with DCM (3 x 20 mL). Combined organic layers were dried (Na^SCU), filtered, and concentrated. The residue was dissolved in benzene. The solution was wet-loaded onto a 40 g “gold” ISCO silica gel column and purified by flash chromatography (hexane —* ethyl acetate/hexanes 1:4) giving the desired product (1.08 g, 70% yield over 2 steps from ethyl 2-tert-butoxy-2-(4-fluoro-3-msthyl-l(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate). ’HNMR (400 MHz, CDC1₃) δ

8.16-8.08 (m, 2H), 7.76-7.68 (m, 2H), 4.41 (q, J = 7.1 Hz, 2H), 2.39 (d, Jrf = 3-2 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H). ^l9F NMR (377 MHz, CDC1₃) δ -122.3 (app. s, 1F), -73.3 (s, 3F).

Préparation of (S)-ethyl 2-(4-fluoro-3-methyl-l(trifluoromethylsulfonyloxy)naphthaIen-2-yl)-2-hydroxyacetate: A solution of ethyl 2(4-fluoro-3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate(1.08 g, 2.64 mmol) in PhMe (20 mL) was cooled to - 40 °C (dry ice/CH₃CN bath). (R)-CBS catalyst (146 mg, 0.528 mmol) was introduced. Distilled catecholborane (423 pL) was added dropwise over a 5 min period. After 30 min, the reaction was warmed to - 20 °C and treated with EtOAc (20 mL). Then 15% Na₂CO₃ (10 mL) was added. The reaction was warmed to 23 °C and stirred vigorously. The organic phase was collected after 30 min. It was washed (vigorous stirring) with 10 mL portions of 15% Na₂CO₃ for 30 min each until the layer was colorless. (Early washes tended to be dark greenish-brown). After six such washings, the organic phase was treated with saturated NH4CI (20 mL) for 30 min. The organic phase was dried (MgSOR, filtered, and concentrated. The residue was treated with hexanes and concentrated again. The material was dissolved in benzene. The solution was wet-loaded onto a 40 g “gold” ISCO silica gel column and purified by flash chromatography (hexane —► ethyl acetate) giving the desired product

322 (1.02 g, 94% yield). Ή NMR (400 MHz, CDC1₃) δ 8.11-8.06 (m, 2H), 7.67-7.64 (m, 2H), 5.79 (s, IH), 4.33-4.22 (m, 2H), 2.40 (d, = 3.2 Hz, 3H), 1.22 (t, J = 7.4 Hz,

3H). ^t9F NMR (377 MHz, CDC1₃) δ -122.6 (app. s, 1F), -73.1 (s, 3F).

Préparation of (S)-ethyl 2-tert-butoxy-2-(4-fluoro-3-mcthyl-l(trifluoromethyIsuIfonyloxy)naphthalen-2-yl)acetate: A solution of (S)-ethyl 2-(4fluoro-3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxy acetate (1.02 g, 2.49 mmol) in tert-butyl acetate (20 mL) was treated with 70% HCIO4 (20 pL) at 23 °C). After 5 h, the reaction was added slowly over 5 min to saturated NaHCO₃ (40 mL). The resulting System was extracted with DCM (3 x 30 mL). The combined organic layers were dried (Na₂SÛ4), filtered, and concentrated. The residue was dissolved in benzene. The solution was wet-loaded onto a 40 g “gold” ISCO silica gel column and purified by flash chromatography (hexane —» ethyl acetate/hexane 1:4) giving the desired product (942 mg, 81% yield). ’H NMR (400 MHz, CDCI3) δ 8.118.02 (m, 211), 7.65-7.60 (m, 2H), 5.72 (s, IH), 4.25-4.13 (m, 2H), 2.45 (d, /«f = 3.2 Hz, 3H), 1.21 (s, 9H), 1.18 (t, J= 7.0 Hz, 3H). ^I9FNMR(377MHz,CDCI₃)Ô-123.1 (aps, 1F), -73.3 (s, 3F).

Préparation of (2S)-ethyI 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetate: The following reaction was run in triplicate: A sealable tube was charged with 2,3-dihydropyrano[4,3,2deJquinolin-7-yIboronic acid monohydrochloride (160 mg, 0.636 mmol), S-Phos palladacycle (71.3 mg, 0.106 mmol), and CsF (354 mg, 2.33 mmol). The tubes were placed under vacuum, then backfilled with argon. A solution of (S)-ethyl 2-tert-butoxy2-(4-fluoro-3-methyl-l -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (247 mg, 0.530 mmol) in 1,2-dimethoxyethane (distilled from Na°/benzophenone, 1.25 mL) was added. The System was stirred for 1 min to dislodge any clumps of solid, then wrapped in foil. The reaction was heated with vigorous stirring to 120 °C for 1.5 h. The three reactions were cooied to 23 “C and combined by adding to a mixture of brine (30 mL) and H₂O (30 mL). The System was extracted with EtOAc (3x30 mL). Combined organic layers were dried (Na2SO₄), filtered, and concentrated. Hexane was added, and the System was concentrated again. The residue was dissolved in DCM/PhH 1:1. The solution was wet-ioaded onto a 24 g “gold” ISCO silica gel column and purified by flash chromatography (hexane —» ethyl acetate) giving the desired product (2S)-ethyl 2tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-316293

323 methylnaphthaIen-2-yI)acetate (163 mg, 21% yield). Ή NMR (400 MHz, CDC1₃) Ô

8.16 (d, J = 8.6 Hz, IH), 7.61-7.18 (m, 6H), 6.92 (d, broad, J = 8 Hz, 1 H), 5.25 (s, broad, IH), 4.754.60 (m, 2H), 4.30-4.00(m, 2H), 3.55-3.40 (m, 2H), 2.68 (d, Jhf = 3.2 Hz, 3H), 1.20-1.00 (m, 3H), 0.90 (s, 9H). ^,9F NMR (377 MHz, CDCI3) δ -122 (s, broad) LCMS-ESf (m/z): calcd for C₃₀H₃₍₎FNO₄: 488.2 (M+H⁴); Found: 488.3 (M+H⁴). The other diastereomer was also obtained; (2S)-ethyl 2-tert-butoxy-2-((S)-1 (2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetate (208 mg, 27% yield):

*H NMR (400 MHz, CDC1₃) δ 8.13 (d, J = 8.6 Hz, IH), 7.50-7.16 (m, 6H), 6.88 (d, J =

8.2 Hz, IH), 5.15 (s, IH), 4.72-4.60 (m, 2H), 4.30-4.00 (m, 2H), 3.49-3.38 (m, 2H),

2.61 (d, J_IIF = 3.2 Hz, 3H), 1.27-1.19 (m, 3H), 0.83 (s, 9H). ¹⁹F NMR (377 MHz, CDC13) δ -124 (app. s, broad). LCMS-ESf (m/z): [M+H]⁴ calcd for C3oH₃iFN0₄: 488.2; Found: 488.3.

Préparation of (2S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetic acid (122): A solution of (2S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro3-methylnaphthalen-2-yl)acetate (163 mg, 0.334 mmol) in THF (6.0 mL) and EtOH (absolute, 2.0 mL) was treated with LiOH monohydrate (400 mg, 9.48 mmol) in H₂O (2.0 mL). The mixture was stirred vigorously ai 100 °C for 2 h. More LiOH monohydrate (600 mg, 14.2 mmol) and H₂O (500 pL) were added, and heating was continued for another 4 h. The reaction was cooled to 23 °C and filtered through a 0,45 micron filter pad. The fîltrate was purified on a Cl 8 Gemini column (Eluent: H2O/CH3CN 95:5 -> 0:100 spiked with 0.1% v/v TFA), giving (2S)-2-tcrt-butoxy-2((R)-l-(2_>3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2yl)acetîc acid as the mono-trifluoroacetic acid sait (124 mg, 64%). ’H NMR (400 MHz, CD₃OD) 5 8.68 (d, 5.8 Hz, IH), 8.20(d, J = 8.2 Hz, IH), 7.87 (d, J = 7.8 Hz, 1H),

7.81 (d, J = 5.4 Hz, IH), 7.60 (dd, J = 7.9,7.4 Hz, IH), 7.48 (d, J = 8.2 Hz, IH), 7.36 (dd, J = 7.9, 7.4 Hz, IH), 6.98 (d, J= 8.6 Hz, IH), 5.19 (s, IH), 4.77-4.70 (m, 2H), 3.67 (dd, J - 7.2, 5.9 Hz, 2H), 2.67 (d, Jhf = 3.2 Hz, 3H), 0.97 (s, 9H). ¹⁹F NMR (377 MHz, CD3OD) δ -77.7 (s). LCMS-ESf (m/z): [M+H]⁺ calcd for C28H₂₇FNO₄:460.2; Found: 460.2. The other diastereomer, (2S)-2-tert-butoxy-2-((S)-1-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetic acid, was prepared in a similar manner from (2S)-ethyl 2-tert-butoxy-2-((S)-1-(2,316293

324 dihydropyrano [4,3,2-de]quinolin-7-yl)-4-fiuoro-3-methylnaphthalen-2-yI)acetate;¹H NMR (400 MHz, CD₃OD) δ 8.56 (d, J = 5.1 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 7.94 (dd, J = 9.0, 5.9 Hz, 1H), 7.88 (s, 1H), 7.54 (d, J = 5.6 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.25 (ddd, J = 8.7, 8.6,2.4 Hz, 1H), 6.49 (dd, J = 10.3, 2.4 Hz, 1H), 5.22 (s, 1H),

4.67 (dd, J = 5.8, 5.8 Hz, 2H), 3.55 (dd, J = 5.8, 5.8 Hz, 2H), 2.70 (s, 3H), 0.83 (s, 9H).

¹⁹F NMR (377 MHz, CD₃OD) δ -105.6 (s, 1F), -77.6 (s, 3F).

LCMS-ESI* (m/z): [M+H]* calcd for C_2SH₂₇FNO₄: 460.2; Found: 460.5.

Example 121. (±)-(2S)-2-tert-Butoxy-2-((R)-1 -(2,3-dihydropyrano[4,3,2-de]quinolin10 7-yl)-7-fluoro-3 -methylnaphthalen-2-yl)acetic acid (123)

ethyl 2-tert-butoxy-2-(7-fluoro-3-mettiy)1 -(trifJuoromethy Isulfony Joxy) naphthalen-2-yl)acetate

-(4-fluoropheny l)propan-2-one

(S)-ethyl 2-tert-butoxy-2-((R)-1 -(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fiuoro-3methy Inaph thalen-2-y[)acetate

(S)-2-fert-butoxy-2-((R)-1 (2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-fluoro-3methylnaphthalen-2yl)acetic acid

Préparation of ethyl 2-tert-butoxy-2-(7-fluoro-3-metiiyl-l-(trifluoromethylsulfonyioxy)naphthaIen-2-yl)acetate: Prepared in a similar manner as 2-tert-butoxy-2(7-chloro-3 -methyl-1 -(trifluoromcthylsulfonyloxy)naphthalen-2-yl)acetate of Example 15 146 except using l-(4-fluorophenyl)propan-2-one. ^lH NMR (400 MHz, CDC1₃) δ 7.79 (dd, Jhh = 9.0 Hz, Jhf= 5.4 Hz, 1H), 7.66 (s, 1H), 7.65 (dd, Jhf = 9.0 Hz, Jhh= 2.3 Hz, 1H), 7.38 (ddd,, Jhh = 9.0 Hz,, Jhf = 8.0 Hz,, Jhh = 2.3 Hz, 1H), 5.72 (s, 1H), 4.25-

325

4.ΙΟ (m, 2Η), 2.54 (s, 3H), 1.20 (s, 9H), 1.18 (t, J = 7.0 Hz, 3H). ^l9F NMR (377 MHz, CDCI₃) δ -112.0 (ddd,, Jhf = 9.0, 8.0,5.4 Hz ,1F), -73.4 (s, 3F).

Préparation of (±)-(S)-ethyl 2-tert-butoxy-2-((R)I-(2,3-dihydropyrano [4,3,2de]quinolin-7-yI)-7-fluoro-3-methylnaphthalen-2-y])acetate: Prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2de]quinolin-7-yI)-7-fluoro-3-methylnaphthalen-2-yl)acetate of Example 99 expect using ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-l(trifluoromethylsulfonyIoxy)naphthalen-2-yl)acetate as starting material and S-Phospalladacycie as the catalyst, giving the product as a racemate. LCMS-ESI* (m/z): calcd for C30H30FNO4:488.2 (M+H*); Found: 488.2 (M+H*). The other diastereomer (±)(2S)-ethyl 2-tert-butoxy-2-((S)l-(2,3-dihydropyrano [4,3,2-de]quinolin-7-yl)-7-fluoro3-methyInaphthalen-2-yl)acetate was also isolated via silica gel chromatography. LCMS-ESI* (m/z): [M+H]* calcd for C30H31FNO4: 488.2; Found: 488.2.

Préparation of (±)-(S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-fluoro-3-methyliiaphthalen-2-yl)acetic acid (123): Prepared in a similar manner as (S)-2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid of Example 99, except using (±)-(S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)7-fluoro-3-methylnaphthalen-2-yI)acetate as the starting material, giving the racemate of the desired product as the mono-trifluoroacetic acid sait. ’H NMR (400 MHz, CD3OD) δ 8.68 (d, J = 5.5 Hz, 1 H), 8.02-7.97 (m, 2H), 7.81-7.75 (m, 2H), 7.43 (d, J =

8.2 Hz, IH), 7.32 (ddd, J = 5.4, 5.4, 2.4 Hz, 1H), 6.54 (dd, J = 10.0, 2.3 Hz, IH), 5.24 (s, IH), 4.78-4.67 (m, 2H), 3.67-3.62 (m, 2H), 2.77 (s, 3H), 0.93 (s, 9H). ¹⁹F NMR (377 MHz, CD3OD) δ -105.6 (s, 1F), -77.6 (s, 3F). LCMS-ESI* (m/z): [M+H]* calcd for C_2SH₂₇FNO₄:460.2; Found: 460.4.

The other racemate, (±)-(S)-2-tert-butoxy-2-((S)-l -(2,3-dihydropyrano [4,3,2de]quinolin-7-yl)-7-fIuoro-3-methylnaphthalen-2-yl)acetic acid, was prepared in a similar manner. ^lH NMR (400 MHz, CD₃OD) δ 8.61 (d, J = 5.8 Hz, IH), 8.18 (d, J =

8.2 Hz, IH), 7.71 (d, J = 5.5 Hz, IH), 7.58 (dd, J= 7.0, 6.8 Hz, IH), 7.51 (d,./-8.2 Hz, IH), 7.34 (dd, J = 7.0,6.8 Hz, IH), 6.96 (d, J = 8.6 Hz, IH), 5.20 (s, IH), 4.72 (dd, J = 6.2, 6.2 Hz, 2H), 3.64 (dd, J = 6.2, 6.2 Hz, 2H), 2.64 (d, J_Hj = 3.2 Hz, 3H), 0.86 (s, 9H). ¹⁹F NMR (377 MHz, CD3OD) Ô -77.8 (s).

LCMS-ESI* (m/z): [M+H]* calcd for C₂gH₂₇FNO₄: 460.2; Found: 460.4.

326

Example 122. (2S)-2-tert-Butoxy-2-((R)-7-chloro-1 -(2,3-dihydropyrano[4,3,2de]quinoIin-7-yI)-3-methyInaphthalen-2-yl)acetic acid (124)

ethyl 2-iert-birtoxy 2 (7-chloro-3-methyl-1-(triflL!oromethylsulfonyloxy)naphthalen-2-yl)acetate

(±)-(S)-ethyl 2-terFbutoxy-2-((R)-7chtoro-1 -(2,3-dihydropyranoI4,3,2de]quinolin-7-yl)-3-fnethylnaphthalen-2yljacetata

124 (:t)-(S)-2-ferf-butoxy-2-((R)-7-chloro-1-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-3methylnaphthalen-2-yl)acetic acid

Préparation of (+)-(2S)-ethyl 2-tert-butoxy-2-((R)-(7-chloro-1-(2,3 dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate: Prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano [4,3,2de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate of Example 99 except using ethyl 2-tert-butoxy-2-(7-chloro 3-methyl- l-(trifluoromethylsulfonyIoxy)naphthalen-2-yl)acetate as the starting material. LCMS-ESI* (m/z): [M+H]⁺ calcd for CaoHjiClNC^: 504.2; Found: 504.2. The other racemate (±)-(2S) ethyl 2-tert-butoxy-2-((S)(7-chloro-1 -(2,3-dihydropyrano [4,3,2-de]quino!in-7-y 1 )-3 methylnaphthalen-2-yI)acetate was also isolated via silica gel chromatography. LCMSESr (m/z): [M+HJ* calcd for C30H31CINO4: 504.2; Found: 504.2.

Préparation of (+)-(S)-2-tert-butoxy-2-((R)-7-chloro-l-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylBaphthalen-2-yl)acetic acid (124): (±)(S)-2-tert-butoxy-2-((R)-7-chloro-l-(2,3-dihydrDpyrano[4,3^-de]quino]m-7-yl)-3methylnaphthalen-2-yI)acetic acid (124) was prepared in a similar manner as (S)-2-tertbuloxy-2-((R)-6-chloro-l-(2,3-<lihydropyrario[4,3,2-de]quinolin-7-yl)-7-fluoro-3methylnaphthalen-2-yl)acetic acid of Example 99, except using (±)-(S)-ethyl 2-tertbutoxy-2-((R)-7-chloro-1 -(2,3-dihydropyrano[4,3,2-de]qumolin-7-yl)-3-

327 methylnaphthalen~2-yl)acetate as the starting material, giving the racemate of the desired product as the mono-tri fluoroacetic acid sait. *H NMR (400 MHz, CD3OD) Ô

8.69 (d, J = 5.5 Hz, IH), 7.99-7.93 (m, 2H), 7.81-7.75 (m, 2H), 7.48-7.43 (m, 2H), 6.90 (d, J - 2.0 Hz, IH), 5.22 (s, IH), 4.77-4.67 (m, 2H), 3.67-3.62 (m, 2H), 2.77 (s, 3H),

0.93 (s, 9H). ^l9F NMR (377 MHz, CD₃OD) δ -77.6 (s). LCMS-ESI* (m/z): calcd for

C28H26CINO4; 476.2 (M+H*); Found: 476.1 (M+H*). The other racemate, (±)-(S)-2tert-butoxy-2-((S)-7-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3methylnaphthalen-2-yl)acetîc acid, was prepared in a similar manner. *H NMR (400 MHz, CD3OD) δ 8.55 (d, J = 5.1 Hz, 1 H), 8.00 (d, J = 6.8 Hz, IH), 7.88-7.84 (m, 2H),

7.48 (d, broad. J - 4 Hz, IH), 7.40 (dd, 8.6, 1.8 Hz, IH), 7.34 (d, J - 8.2 Hz, IH),

6.85 (d, J = 1.8 Hz, IH), 5.20 (s, IH), 4.6M.62 (m, 2H), 3.54-3.47 (m, 2H), 2.69 (s, 3H), 0.80 (s, 9H). LCMS-ESI* (m/z): [M+H]* calcd for C28H27CINO4: 476.2; Found:

476.4.

328

Example 123. Ethyl 2-(4-bromo-l -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tertbutoxyacetate (125)

OA------1-pheny(propan-2one 3 methy14 phenylbutanoïc acid

OH OPMB

3-methyl-3,4-dihydronaphthalen-1(2H)-one _ethy, ₂ (4-methoxybenzyloxy)2-( 1 -hydroxy-3-metbiy lnaphttialen-2-y l)acetata

ethyl 2-(4-methoxybenzyloxy)-2-(4-bromO’1-hydroxy -3 methylnaphthalen-2-yl)acetate

125 ethyl 2-(4-bromo-1-(4-chloraphenyl)3-methylnaphthalen-2-yl)-2-tert-bütoxyacetate

Préparation of 3-methyl-4-phenylbutanoic acid: 3-Methyl-4-phenylbutanoic acid was prepared in a similar manner as 4-(2-methoxy-phenyI)-3-methyl-butyric acid of Example 32 except using l-phenylpropan-2-one. *H NMR (400 MHz, CDCh) δ 7.31-7.14 (m, 5H), 2.65 (dd, J = 13.3,6.7 Hz, IH), 2.53 (dd, J= 13.3, 7.4 Hz, IH),

2.38 (dd, 14.9, 5.5 Hz, IH), 2.28 (app. sext. J= 6.7 Hz, IH), 2.17 (dd, 14.5, 7.8 Hz,

1 H), 0.98 (d, J = 6.6 Hz, 3H).

Préparation of 3-methyl-3,4-dihydronaphthalen-l(2H)-one; 3-Methyl-3,4dihydronaphthaleu-l(2H)-one was prepared in a similar manner as 6-bromo-3-methyl-

3,4-dihydronaphthalen-l(2H)-one of Example 48, except using 3-methyl-4phenylbutanoic acid. ’H NMR (400 MHz, CDCl·,) δ 8.02 (d.- 7.9 Hz, IH), 7.47 (dd,

J = 7.4, 7.4 Hz, IH), 7.31 (dd, J = 7.4, 7.4 Hz, IH), 7.24 (d, J = 7.4 Hz, IH), 3.01-2.95 (m, 1 H), 2.76-2.66 (m, 2H), 2.37-2.27 (m, 2H), 1.15 (d, J = 7.2 Hz, 3H).

329

Préparation of ethyl 2-(4-methoxybenzyloxy)-2-( l-hydroxy-3methylnaphthalen-2-yl)acetate: Ethyl 2-(4-methoxybenzyloxy)-2-(l-hydroxy-3methylnaphthalen-2-yl)acetate was prepared in a similar manner as (l-hydroxy-5methoxy-3-methyl-naphthalen-2-yl)-(4-methoxy-benzyloxy)-acetic acid ethyl ester of Example 32, except using 3-methyl-3,4-dihydronaphthaIen-l(2H)-one. *H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 8.24 (d,8.2 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.48-

7.36 (m, 2H), 7.27 (d, 8.5 Hz, 2H), 7.18 (s, 1H), 6.89 (d, J = 8.4 Hz, 2H), 5.30 (s, 1H), 4.67-4.55 (m, 2H), 4.27-4.08 (m, 2H), 3.82 (s, 3H), 2.40 (s, 3H), 1.19 (t, J= 7.0 Hz, 3H).

Préparation of ethyl 2-(4-methoxybenzyloxy)-2-(4-bromo-l-hydroxy-3methylnaphthalen-2-yl)acetate: A solution of ethyl 2-(4-methoxybenzyloxy )-2-(1hydroxy-3-methylnaphthalen-2-yl)acetate (102 mg, 0.268 mmol) in CHCI3 (5.0 mL) was treated with solid NaHCOî (46 mg, 0.281 mmol). Br₂ (45 mg) in CHCI3 (1.0 mL) was added dropwise over 5 min at 23 °C. After 15 min, 10%Na₂S₂O3 (10 mL) was added. The reaction was extracted two times with CHC1₃. Combined organic phases were dried (Na₂SO4), fîltered, and concentrated. The residue was dissolved in DCM. The solution was wet-loaded onto a 12 g “gold” ISCO silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (83 mg, 67%). ’H NMR (400 MHz, CDCI₃) δ 8.69 (s, IH), 8.29 (d, J = 8.2 Hz, 1 H), 8.22 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 7.4, 7.4 Hz, 1H), 7.47 (dd, J = 7.8, 7.8 Hz, 1H), 7.26 (d, J = 8.2 Hz, 2H), 6.91 (d, J- 8.6 Hz, 2H), 5.47 (s, 1H), 4.67-4.56 (m, 2H), 4.26-4.08 (m, 2H),

3.81 (s, 3H), 2.60 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H).

Préparation of ethyl 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthaIen-2-yl)2-tert-butoxyacetate (125): Ethyl 2-(4-bromo-l-(4-chlorophenyI)-3-methylnaphthalen2-yl)-2-tert-butoxyacetate (125) was prepared în a similar manner as ethyl 2-(7-bromo1 -(4-chlorophenyI)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate of Example 67 except using ethyl 2-(4-methoxybenzyloxy)-2-(4-bromo-l-hydroxy-3methylnaphthalen-2-yl)acetate. *H NMR (400 MHz, CDCI3) δ 8.39 (d, J= 8.6 Hz, 1H), 7.57-7.42 (m, 4H), 7.36-7.24 (m, 3H), 5.16 (s, 1H), 4.24-4.09 (m, 2H), 2.75 (s, 3H),

1.23 (t, J = 7.1 Hz, 3H), 1.00 (s, 9H).

Example 124. 2-(4-Bromo-l -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tertbutoxyacetic acid (126)

330

Cl	Cl
ô		iS L·
		'A 0^
	A.0B
	\ ⁰	ο
Br		Br
		126
ethyl 2-(4-bromo-1-(4-chk>rophenyi)3-methylnaphthaten-2-yt)-2-tertbutoxyacetate	2-(4-bromo-1 -(4-ctilorophenyl)- 3-meihylnaphthaten-2-yl)-2-tert-butoxyacetic acid

Préparation of 2-(4-bromo-l -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tertbutoxyacetic acid (126): A solution of ethyl 2-(4-bromo-l-(4-chlorophenyl)-35 methylnaphthalen-2-yl)-2-tert-butoxyacetate (30 mg, 71.4 μιηοΐ), LiOH monohydrate (15 mg, 0.357 mmol), H₂O (500 pL), EtOH (absolute, 500 pL), and THF (500 pL) was placed in a sealed tube and heated to 100 “C. Once the reaction was complété, it was cooled to 23 °C, filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). The product-containing fractions were combined and lyophilîzed, giving the title compound (parent form)(l 1.5 mg, 40%). ’H NMR (400 MHz, CD₃OD) δ 8.38 (d, J = 8.6 Hz, 1H), 7.63-7.47 (m, 4H), 7.38-7.20 (m, 3H), 5.30 (s, 1H), 2.69 (s, 3H), 1.00 (s, 9H). LCMS-ESI' (m/z): [MCO₂-H]' calcd for C^jBrClO: 415.2; Found: 415.0’.

Example 125. 2-tert-Butoxy-2-(l -(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)aceÎÎc acid (127)

331

ethyl 2-(4-bromo-1-(4-chlorophenyl)-3methyInaphthalen-2-yÎ)-2-terf-butoxyacetate ethyl 2-tert-butoxy-2-(1-(4-chlorophenyi)3,4dimethylnaphthalen-2-yl)aœtate

2-terbbutoxy-2-(1 -(4-chlorophenyl)3.4-difnelhylnaphthalen-2-yl)acetic acid

Préparation of ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3,4dimethylnaphthalen-2-yl)acetate: A suspension of ethyl 2-(4-bromo-l-(4chlorophenyl)-3-methylnaphthalen-2yl)-2-tert-butoxyacetate (25 mg, 51 pmoi), trimethylboroxine (21 pL, 0.153 mmol), PdCh(dppf) (3.7 mg, 5.1 pmol), K₂CO₃ (70 mg, 0.510 mmol), PhMe (500 pL), EtOH (absolute, 250 pL), and H₂O (250 pL) was stirred in a sealed vessel at 100 C for 3 h. The reaction was cooled to 23 C, diluted with H₂O and extracted with EtOAc (3x). Combined organic phases were dried (Na₂SO.0, filtered, and concentrated, giving crude product. (Yield was not found). ’ H

NMR (400 MHz, CD₃OD) δ 8.08 (d, J = 8.2 Hz, IH), 7.48-7.44 (m, 3H), 7.29-7.26 (m, 4H), 5.15 (s, IH), 4.20-4.12 (m, 2H), 2.65 (s, 3H), 2.55 (s, 3H), 1.21 (t, J = 7 Hz, 3H), 1.00 (s, 9H).

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-3,4-dimethylnaphthalen-2yl)acetic acid (127): A solution of the crude ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)15 3,4-dimethylnaphthalen-2-yl)aceÎate in THF (500 pL), EtOH (Absolute, 250 pL), and H₂O (250 pL) was treated with LiOH monohydrate (61 mg, 1.45 mmol) and heated to 100 “C in a sealed vessel for 4 h. The reaction was cooled to 23 °C, filtered through a

332

0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/HiO + 0.1% TFA). The product-containing fractions were combined and lyophilized, giving the tîtle compound (parent form)(8.0 mg, 40% over 2 steps). ’tl NMR (400 MHz, DMSO-d₆) 5 12.73 (s,broad, 1H), 8.15 (d, J = 8.2 Hz, IH), 7.72-7.62 (m, 2H), 7.57-7.47 (m, 2H), 7.39-7.32 (m, 2H), 7.19 (d, J = 8.2 Hz, IH), 5.07 (s, IH),

2.63 (s, 3H), 2.51 (s, 3H), 0.93 (s, 9H).

LCMS-ESI* (m/z): [M-H]' calcd for C^ChNaOô: 813.3; Found: 813.2.

Example 126. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyl-4-vinylnaphthalen-2yl)acetic acid (128)

ethyi 2-(4-t>ramo-1-(4chloropheflyO-3-methylnaphthaten2-yl)-2-tert-butoxyacetate

128

2-ter6butoxy-2-(1-(4-chtorophenyi)3-methyF+vinytnaphthalen-2-yl)acetic acid

Préparation of2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-4-vinyInaphthalen2-yl)acetîc acid (128): 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-4vinylnaphthalen-2-yl)acetic acid (128) was prepared in a similar manner as 2-(4-bromol-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid of Example 125, except using potassium vinyltrifluoroboraie in the Suzuki coupling reaction, giving the tîtle compound (parent form).¹H NMR (400 MHz, DMSO-ίή,) 5 12.78 (s, broad, IH), 8.13 (d, J = 8.2 Hz, IH), 7.73-7.65 (m, 2H), 7.54-7.48 (m, 2H), 7.41-7.36 (m, 2H), 7.20 (d, J -8.2 Hz, IH), 7.11 (dd,J= 18.0,11.7 Hz, IH), 5.87 (d,7- 11.4 Hz, IH), 5.41 (d, J = 18.0 Hz, IH), 5.09 (s, IH), 2.50 (s, 3H), 0.94 (s, 9H). LCMS-ESF (m/z): [2M2H+Na]‘ calcd for Cs₀H._î8Cl₂NaO₆: 839.3; Found: 839.2.

Example 127. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-4-ethyl-3-methyInaphthalen-2yl)acetic acid (129)

Cl	333	Cf
ό	A<.	ô	A<
	Â^OH		A.OH
CO	0	ί I 1	0
o
2-terf-butoxy-2-( 1 -(4-chlorophenyl)- 3-methyl-4-vinylnaphthaten-2-yi)acetic acid	129

2-terf-butoxy-2-( 1 -(4-chlorophenyl)-

4-ethyi-3-methylnaphthalen-2-yl)acetic acid

Préparation of 2-iert-butoxy-2-(l-(4-ch]orophenyl)-4-elhyl-3-methylnaphthalen2-yl)acetic acid (129): A suspension of 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-

4-vinylnaphthalcn-2-yl)acetic acid (5.0 mg, 12 pmol), 5% w/w Rh/Al₂O3 (10 mg), and

EtOH (absolute, 2.0 mL) was evacuated aad purged several times (vaccuum/H₂balloon). The suspension was rapidly stîned under a balloon of H₂ for 6 h. H₂O (500 pL) was added and the reaction was filtered through a 0.45 micron filter. The filtrate was directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN7H₂O + 0.1% TFA). The product-contaîning fractions were combined and lyophilized, gîving the title cornpound (parent form) *H NMR (400 MHz, DMSO-Jê) δ 12.71 (s, broad, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.70-7.62 (m, 2H), 7.60-7.47 (m, 2H), 7.34-7.33 (m, 2H), 7.20 (d, J = 8.2 Hz, 1H), 5.06 (s, 1H), 3.40-3.20 (m, 2H), 1.25 (t, J = 7.4 Hz, 3H), 0.93 (s, 9H). LCMS-ESI' (m/z): [2M-2H+Na]'calcd forC₅₀H_S2Cl₂Na0₆: 841.3; Found: 841.3.

Example 128. Ethyl 2-tert-butoxy-2-(l -(4-chlorophenyl)-4-formyl-3methylnaphthalen-2-yl)acetate (130)

334

Cl	Cl

-------------
	0
Br
ethyl 2-(4-bromo-1 -(4-chlorophenyl)-3-methylnaphthalen-	130

2-yl)-2-tert-butoxyacetate ethyl 2-tcrt-butoxy-2-(1-(4-chlorophenyl)4-formyl-3-methylnaphttialen-2^yl)acetate

Préparation of ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-4-formyl-3methylnaphthalen-2-yl)acetate (130): A solution of ethyl 2-(4-bromo-l-(4chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (75 mg, 0.153 mmol), K2CO3 (317 mg, 2.29 mmol), PdCl₂(dppf) (11.2 mg, 15.3 μ mol), and potassium vinyltrifluoroborate (103 mg, 0.766 mmol) in H₂O (500 pL), EtOH (absolute, 500 pL), and PhMe (1.0 mL) was heated to 100 °C for 4 h in a sealed vessel. The reaction was cooled to 23 °C, diluted with H₂O (30 mL), and extracted with EtOAc (3x). Combined organic phases were dried (Na₂SO₄), filtered, concentrated, and evaporated from MeOH in vacuo (2x). The residue was treated with MeOH (3.0 mL), and DCM (3.0 mL), and cooled to -78 °C. The solution was sparged with ozone in O₂ for 5 min. After 10 min past the end of the sparge, the réaction was treated with DMS (100 pL) and warmed to 0 °C. 10% Na₂S₂O₃ (2.0 mL) was added, and the reaction was stirred at 23 °C for several minutes. The reaction was diluted with H₂O and DCM, then filtered over Celite. The filtrate was extracted with DCM (2x). Organic phases were combined, dried (Na₂SO₄), filtered, and concentrated. DCM was added, and the solution was wet-Ioaded onto a 12 g “gold” ISCO silica gel column and purified by flash chromatography (ethyl acetate/hexanes 3:97 isocratic) giving the desired product (34 mg, 51% yield). NMR (400 MHz, DMSO-tfc) δ 11.01 (s, 1H), 8.73 (d, J = 8.2 Hz, 1H), 7J6-7J2 (m, 7H),

5.16 (s, 1H), 4.24-4.12 (m, 2H), 2.81 (s, 3H), 1.23 (t, J = 7.0 Hz, 3H), ΙΌ0 (s, 9H).

Examnle 129. 2-tert-Butoxy-2-( I -(4-chlorophenyl)-4-{3-(dime±ylamino)pTop-l -ynyl)3-methylnaphthalen-2-yl)acetic acid (131)

335

131

2-tert-butoxy-2-( 1 -(4-chloropheny l)-4(3-(dimethylamino)prop-1 -ynyl)-3methylnaphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)~4-(3-(dÎmethylamnio)propl-ynyl)-3-methyInaphthalen-2-yl)acetic acid (131): A solution of ethyl 2-(4-bromo-I(4-chlorophenyl)-3-methylnaphthaien-2-yl)-2-tcrt-butoxyacetate (40 mg, 81.7 pmol), A'À'-dimethylpropargylamine (26 pL, 0.245 mmol), PdCI₂(PPh3)₂ (5.7 mg, 16.3 pmol), Cul (3.1 mg, 16.3 pmol) and THF (1.00 mL) was heated to 70 °C for 18 h in a sealed vessel. Conversion was incomplète, so the vessel was charged with more PdChfPPhjL (5.7 mg, 16.3 pmol) and Cul (3.1 mg, 16.3 pmol) and heated to 100 °C for an additional 26 h. The reaction was cooled to 23 °C. THF ( 1.0 mL), EtOH (absolute, 500 pL), and H₂O (500 pL) were added followed by LiOH monohydrate (100 mg, 2.37 mmol). The reaction was heated to 100 °C for 4 h. After cooling to 23 °C, the crude reaction was filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (mono trifluoroacetic acid saltX6.8 mg, 15%). ’H NMR (400 MHz, DMSO-J_é) δ 12.92 (s, broad, IH), 10.26 (s, broad, IH), 8.30 (d, J = 8.6 Hz, IH), 7.71-7.62 (m, 3H), 7.47-7.43 (m, 2H), 7.34 (d, J =

8.2 Hz, IH), 7.22 (d, J = 8.6 Hz, IH), 5_E (1, IH), 456 (s, 2H), 2.96 (s, 6H), 2.72 (s, 3H), 0.90 (s, 9H). ¹⁹F NMR (377 MHz, DMSO-<4) Ô -74.1 (s) LCMS-ESf (m/z): [M+H]⁺calcd for C₂₈H3jCINOî.· 464.2; Found: 464.0.

Examnle 130, 2-tert-Butoxy-2-(l-(4-chloiophenyl)-4-(3-(dimethylamino)propyi)-3methylnaphthalen-2-yl)acetic acid (132)

336

2-iert-butoxy-2-( 1 -<4-chlorophenyi)-4-(3(diirffithylamina)prop-1-ynyl)-3-rnethyiriaphthalen2-yl)acetic acid

2-tert-butoxy-2-(1-(4-chlorophenyl)-4(3-{dimethylamino)propyi)3-methylnaphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-4-(3(dimethylamino)propyl)-3-methyInaphthalen-2-yl)acetic acid (132): 2-tert-butoxy-2-(l(4-chlorophenyl)-4-(3-(dimethylamino)propyl)-3-methylnaphthalen-2-yl)acetic acid (132) was prepared in a manner similar to 2-tert-buÎoxy-2-(l-(4-chlorophenyl)-4-ethyl3-methylnaphthalen-2-yl)acetic acid of Example 127, except using 2-tert-butoxy-2-(l10 (4-chlorophenyl)-4-(3-(dimethylamino)prop-1 -ynyl)-3-methyInaphthalen-2-yl)acetic acid. LCMS-ESI* (m/z): [M+H]* calcd for C28H35CINO3: 468.2; Found: 468.2.

Example 131. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-4-((diniethylaniino)mcthyl) 3methylnaphthalen-2-yl)acetîc acid (133)

337

ethyl 2-terf-butoxy-2-( 1-(4ch loropheny f)-4-formy 63mettiylnaphthalen-2-yi)acetate

2-feri-butoxy-2-(1 -(4-chlorophenyl)-4((dimethylamino)methyl)-3rnethylnaphthafen-2-yl)acetic acid

Préparation of2-tert-butoxy-2-(l-(4-chlorophenyl)-4-((dimethylamino)methyl)3-methylnaphthalen-2-yl)acetic acid (133): A suspension of ethyl 2-tert-butoxy-2-(1-(4chlorophenyl)-4-fonnyl-3-methylnaphthalen-2-yl)acetate (6.0 mg, 13.9 pmol), EtOH (absolute, 500 pL), NaBH(OAc)₃ (8.8 mg, 41.7 pmol), and glacial AcOH (4 pL, 70 pmol) was treated with a solution of A;A^r dimethylamine in MeOH (2 M, 35 pL, 69.5 pmol). DCM (50 pL) was added to improve solubility. The reaction was sealed and heated to 70 °C. Conversion was limited, so more N, A’-dimethylamine in MeOH (2 M, 170 pL, 0.337 mmol), glacial AcOH (20 pL, 0.35 mmol), NaBH(OAc)3 (50 mg, 0.236 mmol), and DMF (500 pL) were added. Heating was continued. Once conversion was achieved, LiOH monohydrate (200 mg, 4.7 mmol) and H2O (1.0 mL) were added. The reaction was sealed and heated to 100 °C overnight. Afterward, the reaction was filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O + 0.1% TFA). The product-containing fractions were combined and lyophilized, giving the titlecompound (mono trifluoroacetic acid saltXl.O mg, 13%). LCMS-ESI⁴ (m/z): [M+H]⁴ calcd for C26H₃₁C1NO₃:440.2; Found: 440.0.

Example 132. 2-tcrt-Butoxy-2-( 1 -(4-chlorophenyl)-3-methyI-4(morpholinomethyI)naphthalen-2-yI)acetjc acid (134)

338

ethyl 2-ferf-butoxy-2-(1-(4-chlorophenyt)-4-formy!-3methyfnaphthaten-2-yl)acetate

2-tert-butoxy-2-( 1 -(4-chlorapheny I)3-methyl-4-(morpholinomethyl) naphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl^(morpholinomethyl)naphthalen-2-yl)acetic acid (134): 2-tert-Butoxy-2-(1-(4chlorophenyi)-3-methyl-4-(morpholinomethyl)naphthalen-2-yl)acetic acid (134) was prepared in a manner similar to 2-tert-butoxy-2-(l-(4-chlorophenyl)-4((dimethylamino)methyl)-3-methylnaphthalen-2-yl) acetic acid of Example 131, except using morpholine in the reductive amination step. LCMS-ESf (m/z): [M+H]⁺ calcd for C28H33CINO4: 482.2; Found: 482.0.

Example 133. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-4-(hydroxymethyl)-

3-methylnaphthalen-2-yI)acetic acid (135)

ethyl 2-tert-butoxy-2-(1-{4-chIoropbenyl)-4formyl-S-methylnaphthalen^-ylJacetate

2-tert-butoxy-2-(1 -(4-chlorophenyl)-4(hydroxymethyt)-3-methylnaph thalen-2-yl)acetic acid

Préparation of2-tert-butoxy-2-(l-(4-chlorophenyl)-4-(hydroxymethyl)16293

339

3-mclhylnaphi.halcn-2-yl)acctic acid (135): A solution of ethyl 2-tert-butoxy-2-(l-(4chlorophenyl)-4-fonnyl-3-methylnaphthalen-2-yl)acetate (6.0 mg, 14 pmol), NaBIL (1.5 mg, 40 μιηοΐ), THF (250 pL), and EtOH (absolute, 500 pL) was stirred at 23 °C for 1 h. H₂O (500 pL) and LiOH monohydrate (50 mg, 1.18 mmol) were added. The 5 reaction was sealed and heated to 100 °C. After 2 h, the reaction cooied to 23 °C, filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form)(2.6 mg, 43%). ’H NMR (400 MHz, DMSCMj) δ 12.76 (s, IH), 8.27 (d, J = 8.6 Hz, IH), 7.72-7.65 (m,

2H), 7.58-7.48 (m, 2H), 7.39-7.33 (m, 2H), 7.18 (d, J = 8.6 Hz, IH), 5.07 (s, IH), 5.01 (d, broad, J= 2.7 Hz, 2H), 2.62 (s, 3H), 0.94 (s, 9H).

LCMS-EST {m/z): [M-H]' calcd for C24H24CIO4; 411.1; Found: 410.9.

Example 134. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyl-4-phenylnaphthalen-2340 yl)acetic acid (136)

ethyl 2-(4-bromo-1-(4-chlorophenyl)-3methyinaphthalen-2-yt)-2-ierfbutoxy acetate

2-/erf-butoxy-2-(1 -(4-chlorophenyl)3-methyl-4-phenylnaphthalen-2-yl)acet>c acid

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-4pheaylnaphtha!en-2-yl)acetic acîd (136): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3methyl-4-phenylnaphthalen-2-yI)acetic acîd (136) was prepared in a manner similar to 10 2-tert-butoxy-2-(l-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of

Example 125 , except using benzeneboronîc acid in the Suzuki reaction, giving the title compound (parent form). *H-NMR: (400 MHz, MeOH- </): δ 7.67-7.55 (m, 5H); 7.507.48 (m, 1 H); 7.41-7.39 (m, IH); 7.33-7.23 (m, 6H); 5.31 (s, IH); 2.28 (s, 3H); 1.02 (s, 9H). LCMS-ESI' (m/z): (M-Hf calcd forCi^CK^: 457.2; Found: 457.2.

341

Example 135. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-4-(6-(dimethylamino)pyridin-3-yl)-

3-methylnaphthalen-2-yI)acetic acid (137)

ethyl 2-(4-brorno-1-(4-ch!orophenyl)-3methylriaphthafen-2-yi)-2-terf-butoxyacetate

137

2-fert-butoxy-2-( 1 -(4-chloraphenyl)-4(6-(dimethylamino)pyridin-3-yl)-3methylnaphthaien-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(l (4-chloropheny 1)-4-(6(dimethylamino)pyridin-3-yl)-3-methylnaphthalen-2-yl)acetic acid (137): 2-tertButoxy-2-(l-(4-chIorophenyl)-4-(6-(iiimethylamino)pyridin-3-yl)-3-methyInaphthalen2-yl)acetic acid (137) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4chlorophenyl)-3_î4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using 2-(A’_i;V-dimethylamino)-pyridin-5-yl-boronic acid in the Suzuki reaction, giving the title compound. 'H-NMR: (400 MHz, DMSO- (f): δ 8.02-8.00 (m, IH); 7.78 (m, broad, IH); 7.72-7.69 (m, IH); 7.67-7.65 (m, IH); 7.52-7.49 (m, IH); 7.45-7.36 (m, 4H); 7.23 (d, >8.0 Hz, 2H); 5.11 (s, IH); 2.29 (d, J=1.2 Hz, 3H); 0.93 (d, J=1.2 Hz, 9H). LCMSESI⁺ (m/z): [M+H]⁺ calcd for C30H32CIN2O3: 503.2; Found: 503.3.

Example 136. 2-tert-butoxy-2-( 1 -(4-chlorophenyI)-3-»esfeyl-4-(pyridm-3yl)naphthalen-2-yI)acetic acid (138)

342

138

24erf-butoxy-2-(1-(4-chloropheny1}-3methyl-4-(pyridin-3-yl)naphthalen-2-yl)acetic acid

Préparation of2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-4-(pyridin-3yl)naphthalen-2-yl)acetic acid (138): 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-45 (pyridin-3-yl)naphthalen-2-yl)acetic acid (138) was prepared in a manner similar to 2tert-butoxy-2-(l -(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using pyridin-3-yl-boronic acid in the Suzuki reaction, giving the title compound (mono trifiuoroacetic acid sait). ’H-NMR: (400 MHz, DMSO- ff. δ 12.8 (s, broad, IH), 8.80 (d, 7-5.1 Hz, IH), 8.62 (d, J = 12.9 Hz, IH), 7.97-7.92 (m, IH),

7.76-7.69 (m, 3H), 7.60-7.54(m, IH), 7.47-7.40 (m, 3H), 7.28 (d, J= 9.2 Hz, IH), 7.18 (¢1,.7-9.4 Hz, IH), 5.15 (s, IH), 2.25 (s, 3H), 0.96 (s, 9H). ¹⁹F-NMR: (377 MHz, DMSO- et}; δ -74.7 (s) LCMS-ESI⁴ (wi): [M+H]⁺ calcd for C₂₈H₂₇C1NO₃:460.2; Found: 460.2.

343

Exemple 137. 2-tert-Butoxy-2-(l -(4-chlorophenyl)-3-inethyl-4-(pyriimdin-5vl)naphthalen-2-yl)acetic acid (139)

methylnaphthalen-2-ylj-2-tert-butoxy acetate

139

2-ter/-butoxy-2-(1 -(4-chlorophenyl)-3methy!~4-(pynmidrn-5-yi)naphtfialen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-4-(pyriniidin-5yl)naphthalen-2-yl)acetic acid (139): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyl-4(pyrimidin-5-yl)naphthalen-2-yl)acetic acid (139) was prepared in a manner similar to 10 2-tert-butoxy-2-(l-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using pyrimidin-5-yI-boronic acid in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid saIt)?H-NMR: (400 MHz, DMSO- d⁶): δ

12.87 (s, broad, IH), 9.39 (s, IH), 8.89 -8.86 (m, 2H), 7.76-7.68 (m, 2H), 7.58-7.55 (s, IH), 7.49-7.44 (m, 3H), 7.28 (d, J= 8.2 Hz, IH), 7.20 (d, J= 8.2 Hz, 1 H), 5.15 (s, IH), 15 2.27 (s, 3H), 0.97 (s, 9H). ¹⁹F-NMR: (377 MHz, DMSO- d⁶): δ -73.9 (s) LCMS-ESI* (m/z): [M+H]* calcd for C27H26CIN2O3:461.2; Found; 461.2.

344

Example 138. 2-(i,4-Bis(4-chloiOphenyl)-3-methylnaphthaIcn-2-yl)-2-tertbutoxyacetie acid (140)

ethyl 2-(4-bromo-1-(4-chlorophenyi)-3methylrraphthalen-2-y1)-2-tert-butoxyacetate

140

2-(1,4-bts(4-chloraphenyî)-3methylnaphthalen-2-yl)-2-tertbutoxyacetic acid

Préparation of 2-( 1,4-bis(4-chlorophenyl)-3-methylnaphthalen“2-yl)-2-tertbutoxyacetic acid(140): 2-(l,4-bis(4-chlorophenyl)-3-methylnaphthalen-2-yI)-2-tertbutoxyacetic acid (140) was prepared in a manner similar to 2-tert-butoxy-2-(l-(4 chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using

4-chlorobenzene boronic acid in the Suzuki réaction, giving the title compound (mono trifluoroacetic acid sait). ’H-NMR: (400 MHz, DMSO-1/): δ 12.82 (s, IH), 7.75-7.63

IH), 2.24 (s, 3H), 0.96 (s, 9H). LCMS-ESr (m/z): [2M-2H+Na]' calcd for

C₅₈H₅oCUNa0₆:1007.2; Found: 1007.1.

345

Example 139. l-(4-Bromo-l-(4-chlorophenyl)-3-methyInaphthalen-2-yl)prop-2-en-Ιοί (141)

Cm ·	E_IOA^CN
1-pheny lpropan-2-one	ethyl 2-cyanoacetate

(E)-ethyl 2-cyano-3-methyl -4-phenylbut-2-enoate

OH

-hydroxy-3-methyt-2-naphthonitrile

4-bromo-1 -hydroxy-3methyl-2-naphthonitrile

4-bromo-2-cyananaphtfialen-1 -yl perfluorobutanesulfonate

4-bromo-1 -{4-chlorophenyl)3-methyl-2-naphthonitriie

4-bromo-1 -(4-chlorophenyl)3-methyl-2-naphthaldehyde

141

-{4-bromQ-1 -(4-ch torophenyl}-3methylnaphthalen-2-yl)prop-2-en-1 -ol

Préparation of 1 -hydroxy-3-methyl-2-naphthomtrile: Phenyl-2-propanone (24.93 g, 0.178 mol) was combined with ethylcyanoacetate (19.8 mL, 0. 1 80 mol), acetic acid (8.0 mL, 0.14 mol), ammonium acetate (2.82 g, 0.0370 mol) and 80 mL of benzene in a round bottom flask equipped with a Dean-Stark trap and condenser cooled by a chilien The reaction was heated to 160 °C for 4 h. The mixture was removed from heat and the trap drained so that the mixture could be concentrated by distilling

346 off excess (~ 50 mL) benzene. The solution contained crude (E)-ethyl 2-cyano-3methyI-4-phenylbut-2-enoate. The concentrated mixture was removed from heat and heat adjusted to 240 °C. Acetamide (50.9483 g, 0.862 mol) was added, and a Claisen head attached to distill any éthanol resulting while the mixture was heated at 240 °C for 60-90 minutes. The mixture was cooled to ~ 100 °C, and poured into room température water to quench the reaction. A clumpy orange solid was formed, removed by filtration and triturated with ice cold absolute EtOH. The solid was filtered off and the process repeated 4 times to harvest additional material. The resulting product was a pale yellow fine powder (13.20 g, 36% yield). ^lH-NMR: (300 MHz, DMSO- <f): δ 11.28 (s, 1 H); 8.24 (d, J = 8.4 Hz, 1 H); 7.80 (d, J - 8.0 Hz, IH); 7.62-7.58 (m, IH); 7.52-7.48 (m, IH); 7.34 (s, 1 H); 2.47 (s, 3H).

Préparation of 4-bromo-1 -hydroxy-3-methyl-2-naphthonitriIc: 1 -hydroxy-3methyl-2-naphthonitriIe (1.065 g, 5.8 mmol) was dissolved CHC1₃ (24 mL) and combined with sodium bicarbonate (952 mg, 11.3 mmol) and bromfne (330 pL, 6.43 mmol) and allowed to stir at room température overnight. The réaction was quenched by adding 10 mL of 10% sodium thiosulfate and the mixture stirred until decolorization was maximal. The solids were removed by filtration as crude product (1.47 g, 97% yield.) Tl-NMR: (300 MHz, DMSO- <?): δ 8.334 (d, J = 8.0 Hz, IH); 8.166 (d, J = 8.4 Hz, IH); 7.81-7.77 (m, IH); 7.65-7.61 (m, IH); 2.65 (s, 3H).

Préparation of 4-bromo-2-cyanonaphthalen-1 -yl perfluorobutanesulfonate: A dichloromethane solution (20 mL) of 4-bromo- l-hydroxy-3-methyl-2-naphthonitrile (518 mg, 1.97 mmol) was treated with triethylamine (800 pL, 5.37 mmol) at -78 °C. To this cooled solution was added nonafluorobutanesulfonic anhydride (1.10 g, 1.97 mmol) dropwise as a DCM émulsion. After 15 min reaction was allowed warm to room temp. Reaction was quenched with saturated sodium bicarbonate and allowed to stir at 23 °C overnight. The mixture diluted with DCM, washed with brine and chromatographed on silica gel using EtOAc and hexanes to give desired product (330 mg, 31% yield) as well as recovered starting material (245 mg, 47% yield). *H-NMR: (400 MHz, DMSO- d⁶): δ 8.42 (d, J = 8.4 Hz, IH); 8.11 (d, J = 8.8 Hz, IH); 8.05-8.01 (m, IH); 7.99-7.95 (m, IH); 2.81 (s, 3H).

Préparation of 4-bromo-l-(4-chlorophenyl)-3-methyl-2-naphthonitrile: To a 5050 (v/v) EtOH-toluene solution (4 mL) of 4-bromo-2-cyanonaphthalen-l-yl perfluorobutanesulfonate (3.99g, 7.33 mmol) in a 2-5 mL microwave vial was added 416293

347 chlorophenylboronic acid (1.65 g, 10.55 mmol) and dichloro[l,rbis(diphenylphosphino)feirocene]palladium(ll) dichloromethane adduct (165 mg, 0.171 mmol) and 6 mL of 2 M K₂COj. The vial was sealed, and heated thermally at 60 °C for 30 minutes. The mixture was concentrated in vacuo, redissolved în EtOAc and washed with saturated NH4CI and brine then dried with sodium sulfate and concentrated. The residue was chromatographed on silica gel using EtOAc and hexanes to give a mixture of products. This mixture was then purified by hot filtration using neat hexanes (50 mL) to give rise to desired pure product (731 mg, 28 % yield). A second crop (600 mg) was obtained by repeating the hot filtration that was contaminated with starting material. (400 MHz, MeOH- d*): δ 8.361 (d, J-8.4Hz, 1H); 7.89-7.85 (m,

1H); 7.69-7.62 (m, 3H); 7.56-7.49 (m, 3H); 2.81 (s, 3H).

Préparation of 4-bromo-l -(4-chlorophenyl)-3-methyl-2-naphthaldehyde: DIBAL-H (11.2 ml, 1.0 M in DCM) was added to a -40 °C DCM solution of 4-bromol-(4-chlorophenyI)-3-methyl-2-naphthonitrile (2.01 g, 5.63 mmol) slowly. The mixture was allowed to stir and gradually rise to 23 °C over 3-4 hours. The mixture was then cooled back to 0 °C and quenched with the addition of EtOAc (15 mL, 18.9 mmol) and stirred with vigor for 20-30 minutes. This mixture was poured into 30 mL of saturated NH4CI, and stirred 10-15 minutes. After being fîltered though a short pad ofCelîte followed by extraction with DCM, the extracts were dried with sodium sulfate and concentrated in vacuo. Chromatography on silica gel using EtOAc in hexanes gave rise to desired aldéhyde (1.56 g, 77% yield). ‘H-NMR: (400 MHz, DMSO- A Ô 9.81 (s, 1H); 8.36 (d, J=8.8Hz, 1H); 7.83-7.79 (m, 1H); 7.64-7.62 (m, 1H); 7.60-7.56 (m, 2H);

7.44-7.39 (m, 3H); 2.775 (s, 3H).

Préparation 1 -(4-bromo-1 -(4-chlorophenyl)-3-mcthylnaphthalen-2-yl)prop-2en-I-ol (141): To a 0 °C THF (15 mL) solution of 4-bromo-1-(4-chlorophenyl)-3methyl-2-naphthaldehyde (500 mg, 1.39 mmol) was added vinyl magnésium bcomide (1.40 mL, 1 M in THF, 1.4 mmol) and the mixture allowed to stir aod warm » 23 C for 4 hours. Reaction was quenched by the addition of 10 mL of saturated aqueous NH4CI and extracted with ethyl acetate. Extracts were dried with sodium sulfate, concentrated in vacuo and chromatographed on silica gel using EtOAc in hexanes to give desired product (401.8 mg, 75% yield).¹ H-NMR: (400 MHZjCDCfi): δ 8.40 (d,

348

J=8.8 Hz, IH); 7,57-7.53 (m, IH); 7.50-7.44 (m, 2H); 7.36-7.32 (m, IH); 7.25-7.15 (m,

4H); 6.18-6.10 (m, IH); 5.42-5.40 (m, IH); 5.19-5.03 (m, 2H); 2.79 (s, 3H).

349

Example 140. Methyl 2-(4-bromo-l -(4-dilorophenyl)-3-methylnaphthalen-2-yl)-2-Îertbutoxyacetate (142)

-(4-ixomo-1 -{4-chtoropheny l)-3methyl naphthaten-2-ytJprop-2-en-1 -d (1-{44xomo-1-(4-chlorophenyl)-3methyl naphthaten-2-yt)ailyloxy) (fert-butyijdimethylsilane

2-(4-bromo-1-(4-chlorophenyl)-3-methyl naph thaïe n-2-y1)-2-(ferr-butyMimethyl sîlytoxy)acetaktehyde

2-(4-bromo-1-(4-chtorophenyi)-3metfiyinaphthaten-2-yl)-2(tert-butykiimeÎhytsîtyloxy)acetic add

methyl 2-(4-bromo-1-(-4-chlOTopbenyi}-3methylnaphtha len-2-yl)-2(ferf-birty Wimettiylsilyloxy }a cetate methyl 2-(4-brDrrio-1-(4-chlorophenyl)-3methylnaphthaten-2-yi J-2-hydroxyaœtate

142 netiyt 2-Î4-bromo-1 -<4-chiorapheny1)3-methylnaptthalen-2-yi)-2-fartbutoxyacetate

Préparation of (l-(4-bromo4 -{4-chIorophenyl)-3-methylnaphthalen-25 yl)allyloxyXtert-butyl)dimethylsilane: To a stirring 23 °C DCM solution (32 mL) of 1(4-bromo-l-(4-chlorophenyI)-3-methylnaphthalen-2-yl)prop-2-en l ol (1.47 g, 3.79

350 mmol) and tnethylamine (2.3 mL, 16.5 mmol) was added TBDMS-OTf (2.0 mL, 11.65 mmol) and the réaction was stirred and monitored by TLC. After 45 minutes, an additional 2 mL of TBDMSOTf was added and the mixture allowed to stir overnight. The dark mixture was then quenched 10% NaHCO₃ and the color dissipated. The mixture was washed with brine, dried with sodium sulfate and concentrated in vacuo. Column chromatography using silica gel with EtOAc in hexanes gave desired silylated product (1.60 g, 84% yield). 'H-NMR: (400 MHz,CDC1₃): δ 8.39 (d, J = 8.4 Hz, 1 H); 7.55-745 (m, 3H); 7.34-7.30 m, 1 H); 7.26-7.24 (m, 1 H); 7.24-7.18 (d, J = 8.0 Hz, 1 H); 7.16-7.14 (m, IH); 6.09-6.01 (m, IH); 5.32-5.30 (m, 1 H); 5.13-5.03 (m, 2H); 2.77 (s, 3H); 0.87 (s, 6H); 0.83 (s, 9H).

Préparation of 2-(4-bromo-1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2(tert-butyldimethylsilyloxy)acetaldehyde.· A -78 °C 50-50 (v/v) (MeOH/DCM) solution of ( l -(4-bromo-1 -(4-chlorophenyI)-3 -methylnaphthalen-2-yl)allyloxyXtertbutyl)dimethylsilane (1.6 g, 3.19 mmol) was ozonolyzed for 5-10 minutes. The mixture was quenched with the addition of 1 mL of DMS to and then allowed to warm to 23 °C. After being diluted with DCM, the mixture was washed with 10% aqueous Na₂S₂O₃ (5 x 20 mL), dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography using EtOAc in Hexanes gave rise to desired aldéhyde (1.27 g, 79% yield). ‘H-NMR: 400 MHz, (CDC1₃): δ: 9.94 (s, IH); 8.41-8.36 (d, J = 8.0 Hz, IH); 7.60-7.55 (m, IH); 7.53-7.45 (m, 2H); 7.39-7.32 (m, 2H); 7.29-7.24 (m, 2H); 5.16 (s, IH); 2.63 (s, 3H); 0.86 (m, I5H).

Préparation of2-(4-bromo-l-(4-chiorophenyl)-3-methylnaphthalen-2-yl)-2(tert-butyldimethylsilyloxy)acetic acid: A DCM solution (8.0 mL) of 2-(4-bromo-l-(4chlorophenyI)-3-methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyl-oxy)acetaldehyde (0.65 g, 1.29 mmol) was combined with 2-methyl-2-butene (1.5 mL, 14.1 mmol), sodium dihydrogen phosphate (8.0 mL, 1.0 M) and sodium chlorite (1.37 g, 14.46 mmol) and stirred vigorously overnight The mixture was diluted 200% with DCM, the acidity adjusted to pH < 5 with 2 M NaHSCL and extracted with DCM (3 x 20 mL). The extracts were combined dried and concentrated under vacuo. The crude mixture was observed to contain the desired carboxylic acid (0.741 g) according to *H NMR analysis and was used without purification. ’H-NMR: (400 MHz, CD₃OD): δ 8.35 (d, J = 8.4 Hz, IH); 7.58-7.51 (m, 3H); 7.46-7.44 (m, IH); 7.39-7.33 (m, IH); 7.31-7.22 (m, 2H); 5.33 (s, IH); 2.72 (s, 3H); 0.825 (s, 9H); -0.03 (s, 3H); -0.26 (s, 3H).

351

Préparation of methyl 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2yl)-2-(tert-butyldimethylsiiyIoxy)acetate: Crude 2-(4-bromo-l -(4-chlorophenyl)-3methylnaphthaJen-2-yl)-2-(tert-butyldimethylsilyloxy)acetic acid 0.740 g, 1.4 mrnol)was dissolved in 20 mL DCM-MeOH (50-50, v/v) and combined with IMS5 diazomethane solution (7.0 mL, 2.0 M in hexanes) and allowed to stir 6 hrs at 23 °C. The reaction was cooled on ice and quenched by the slow addition of TFA (500 pL) which simultaneously removed the yellow color from the reaction mixture. Mixture was diluted with DCM and washed with brine, then dried and concentrated in vacuo. Purification by silica gel chromatography with EtOAc in hexanes provided purified material (537.8 mg, 78% yield) from the 2-(4-bronio-1 -(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyloxy)acetaldehyde. ’H-NMR: (400 MHz, MeOH- rf*); δ 8.39 (d, 1=8.0 Hz, IH); 7.58-7.54 (m, 1 H); 7.50-7.47 (m, 2H); 7.37-7.33 (m, 2H); 7.27-7.21 (m, 2H); 5.31 (s, IH); 3.69 (s, 3H); 2.67 (s, 3H); 0.83 (s, 9H); -0.04 (s, 3H); -0.27 (s, 3H).

Préparation of methyl 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2yl)-2-hydroxyacetate: Methyl 2-(4-bromo-l -(4-chlorophenyl)-3-methylnaphthalen-2yl)-2-(tert-butyldimethylsilyloxy)acetate (537.8 mg, 1.01 mmol) was dissolved în 4.0 mL TFA and heated to 60 °C The reaction was monitored by HPLC and tumed dark quickly after addition of TFA. The reaction was completed after I h by HPLC, was removed from heat and diluted with toluene (20 mL) and concentrated in vacuo. This dilution/concentration was repeated twîce more and the color was observed to diminished on each cycle. Purification via column chromatography using silica gel with EtOAc and heptane gave rise to desired product (297.9 mg, 0.71 mmol). ^lH-NMR: (400 MHz, CDCh): δ 10.34 (s, broad, IH); 8.40 (d, J=8.0 Hz, IH); 7.60-7.56 (m, IH);

7.52-7.46 (m, 2H); 7.38-7.35 (m, IH); 7.32-7.28 (m, 2H); 5.26 (s, IH); 3.74 (s, 3H);

2.62 (s, 3H),

Préparation of methyl 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2yl)-2-tert-butoxyacetate (142): Methyl 2-(4-bromo-l-(4-chlorophenyl)-3methylnaphthaleu-2-yl)-2-hydroxyacetaie (298 mg, 0.71 mmol) was dissolved in t30 BuOAc (18.0 mL, 134 mmol) and 7 drops of perchloric acid were added. The reaction was monitored by HPLC and TLC for progress. After 4.5 hours, the mixture was added to icy saturated NaHCO₃ and stirred for 10-15 minutes. This mixture was extracted with EtOAc, extracts dried with sodium sulfate and concentrated in vacuo. Purification

352 on silica gel using EtOAc in hexanes gave desired product as well as some starting material. *H-NMR: (400 MHz, CDCl₃): δ 8.39 (d, J=8.8 Hz, IH); 7.57-7.48 (m, 3H);

7.45-7.42 (m, IH); 7.35-7.31 (m, l H); 7.28-7.18 (m, 2H); 5.20 (s, IH); 3.70 (s, 3H);

2.72 (s, 3H); 0.99 (s, 9H).

Example 141. 2-(4-(6-Ammopyridin-3-yl)-1 -(4-chlorophenyI)-3-methylnaphthaIen-2yl)-2-tert-butoxyacetîc acid (143)

methyl 2-(4-bramo-1-(4-chlorophenyl)-3mettiylnaphthalen-2-yi)-2-tert-butoxyacetate

143

2-(4-(6-aminopyndin-3-yl)-1 (4-chlorophenyl)-3-rnethylnaphthalen2-ylJ-2-terf-biitoxyacetic acid

Préparation of 2-(4-(6-aminopyridin-3-yl)-1 -(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (143); 2-(4-(6-Annnopyridin-3-yl)-l(4-chlorophenyl)-3-methylnaphthaIen-2-yl)-2-tert-butoxyacetic acid (143) was prepared in a manner similar to 2-tert-butoxy-2-(l-(4-chlorophenyl)-3,4-dimethylnaphthalen-2yl)acetic acid of Example 125 , except using methyl 2-(4-bromo-l-(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-tert-butoxyacetate as the starting material and 2aminopyridin-5-yl-boronic acid pinacolate ester in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid sait). ’ H-NMR: (400 MHz, DMSO- ¢/): δ 8.067.86 (m, 4H), 7.76-7.68 (m, 2H), 7.56-7.37 (m, 5H), 7.26 (d, J = 8.6 Hz, IH), 7.17-7.13 (m, IH), 5.13 (s, IH), 2.33 (s, 3H), 0.96 (s, 9H). ¹⁹F-NMR: (377 MHz, DMSO- c/): δ -

74.2 (s). LCMS-ESI' (m/z): [M+H]⁺ calcd for C₂₈H₂₈C1N₂O₃: 475.2; Found: 475.2.

353

Example 142. 2-tert-Butoxy-2-(l -(4-chlorophcnyl)-3-methyl =l-(6-oxo-l ,6dihydropyridin-3-yl)naphthalen-2-yl)acctic acid (144)

144

2-to7-butoxy-2-(1 -(4-chlorophenyl)-3methyl-4-(6-oxo-1,6-dihydropyndin-3-yl) naphthalen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-3 -methyl -4-(6-oxo-1,6dihydropyridin-3-yl)naphthalen-2-yl)acetic acid (144): 2-tert-Butoxy-2-(1-(4chlorophenyI)-3-methyl-4-(6-oxo-l,6-dihydropyridin-3-yl)naphthalen-2-yl)acetic acid (144) was prepared in a manner similar to 2-tert-butoxy-2-(l-(4-chlorophenyl)-3,4dimethylnaphthaIen-2-y!)acetic acid of Example 125, except using methyl 2-(4-bromo10 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate as the startîng material and 2-(lH)pyridone-5-yl-boronic acid pinacolate ester in the Suzuki reaction, giving the title compound (parent form). 'H-NMR: (400 MHz, DMSO- i/fi. δ 12.8 (s, broad, 1 H), 11.8 (app. s, broad, IH), 7.67-7.30 (m, 10H), 7.23 (d, J = 8.2 Hz, IH), 5.11 (s, IH), 2.36 (s, 3H), 0.95 (s, 9H). LCMS-ESf (m/z): [M+H]⁺ calcd for Ο₂₈Η₂₇αΝΟ₄:

476.2; Found: 476.2.

C

354

Example 143. 2-(4-(2-Aminopyrimidin-5-yl)-1 -(4-chlorophenyl)-3 -methylnaphthalen2-yl)-2-tert-butoxyacetic acid (145)

methyl 2-(4-bromo-1 -(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-tert-butoxyacetate

145

2- (4-(2-aminopyrimidin-5-yl)-1-(4-cNorophenyl)-

3- fnethylnaphthalen-2-yt)-2-tert-butoxyaœticacid

Préparation of 2-(4-(2-aminopyrimidin-5-yl)-l-(4-chlorophenyl)-35 methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (145): 2-(4-(2-Aminopyrimidin-5-yl)l-(4-chlorophenyl)-3-methyInaphthalen-2-yl)-2-tert-butoxyacetic acid (145) was prepared in a manner similar to 2-tert-butoxy-2-( 1 ~(4-chlorophenyl)-3,4dimethylnaphthalen-2-yl)acetic acid of Example 125, except using methyl 2-(4-bromol-(4-chlorophenyl)-3-methyInaphthalen-2-yl)-2-tert-buÎoxyacetate as the starting material and 2-ammopyrimidine-5-yl-boronic acid pinacolate ester in the Suzuki réaction, giving the title compound (mono trifluoroacetic acid sait form).

’H-NMR: (400 MHz, DMSO- ¢/): δ 12.8 (s, broad, IH), 8.26-8.24 (m, 2H), 7.75-7.67 (m, 2H), 7.55 (dd, J = 7.8, 2.0 Hz, IH), 7.53-7.41 (m, 4H), 7.24 (d, J = 8.2 Hz, IH),

7.16 (s, broad, 2H), 5.13 (s, IH), 2.34(s, 3H), 0.95 (s, 9H). ¹⁹F-NMR: (400 MHz,

DMSO- </): δ -74.9 (s). LCMS-ESf (m/z): [M+H]⁺ calcd for C^/ibrClNjO-j: 476.2; Found: 476.2.

355

Example 144. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3-methyl-4-(2-oxo-1,2dîhydropyrimidin-5-yI)naphthalen-2-yl)acetic acid (146)

methyl 2-(4-bromo-1-(4-chîorophenyl)-3methylnaphthalen-2-yi)-2-tert-butoxyacetate

146

2-terf-butoxy-2-{1-(4-chlorophenyl)-3-methyl-

4- (2-oxo-1,2-dihydropyrimiclin-

5- yl)naphthaien-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(l-(4-chJoropheny])-3-methyL4-(2-oxo-l_>2dihydropyrimidin-5-yl)naphthalen-2-yl)acetic acid (146): A suspension methyl 2-(4bromo-1 -(4-chlorophenyl)-3-inethylnaphthalen-2-yl)-2-tert-butoxyacetate ( 10.5 mg,

22.1 pmol), [lH]pyrimidin-2-one-5-yl-boronic acid (25 mg, 0.11 mmol), PdCl₂(dppf) (3.2 mg, 4.4 pmol), K2CO3 (46 mg, 0.33 mmol), PhMe (500 pL), EtOH (absolute, 250 pL), and H₂O (250 pL) was heated to 100°C for 30 min, but conversion was poor. The reaction was treated with glacial AcOH (60 pL, 1.05 mmol) and KF (40 mg, 0.688 mmol). More PdCl₂(dppf) (3.2 mg, 4.4 pmol) and [lH]pyrimidin-2-one-5-yl-boronic acid (7 mg, 30 pmol) were added and the reaction was heated to 100 “C. After 2 h, the reaction was added to H₂O (15 mL) and glacial AcOH (0.2 mL). The System was extracted with EtOAc (3x 10 mL). Combined organic phases were dried (Na₂SO4), filtered, and concentrated. The crude material was treated with THF (750 pL), EtOH (absolute, 750 pL), H₂O (500 pL), ni LiOH monohydrate (50 mg 1.2 mmol). The suspension was heated to 100 C for 30 min. The reaction was cooled to 23 “C, filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O + 0.1% TFA). Tbe product-containing fractions were combined and lyophilized, giving the title compound (parent formX3.8 mg, 36% over 2 steps). ^lHNMR: (400 MHz, DMSO- cf): δ 12.8 (s, broad, 1H), 8.29 (app. s, broad, 1H), 7.75-7.68

C

356 (m, 2H), 7.58-7.44 (m, 4H), 7.43-7.38 (m, 2H), 7.25 (d, J - 8.2 Hz, IH), 5.12 (s, IH),

2.38 (s, 3H), 0.96 (s, 9H). LCMS-ESf (m'z): [M+HJ* calcd for C^HaClNiO,: 477.2;

Found: 477.2.

Example 145. 2-tert-Butoxy-2-(l -(4-chlorophenyl)-4-cyano-3 -methylnaphthalen-2yl)acetic acid (147)

2-terf-biitoxy-2-( 1 -(4-chlorophenyl)-4cyano-3-metTiylnaphttialen-2-yl)acetic acid

Préparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-4-cyano-3methylnaphthalen-2-yl)acetic acid (147): A suspension of methyl 2-(4-bromo-l-(410 chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (10.5 mg, 22,1 pmol), CuCN (9.8 mg, 0.11 mmol), and NMP (500 pL) was heated to 200 °C in a microwave. The réaction was cooled to 23 °C, treated with EtOH (2.5 mL), filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/HjO + 0.1% TFA). The product-containing fractions were combined and treated with LiOH monohydrate until the pH was distinctly basic. The mixture was concentrated with warming to remove most of the water and ail of the CH3CN, The solution was treated with EtOH (absolute, 500 pL) and THF (1,0 mL). The suspension was stirred at 23 °C for 1 h. It was filtered through a 0.45 micron filter, and directly [wified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂0 + 0,1% TFA). The praiict-cortaining fractions were combined and lyophilized, giving the title compound (parent formX5.2 mg, 55% over 2 steps), ‘H-NMR: (400 MHz, DMSO- d⁶); δ 13.12 (s, HT), 8.16 (d, 7 - 8.2 Hz, 1H), 7.82 (dd, J = 7,8, 7,7 Hz, IH), 7.77-7,70 (m, 2H), 7.60 (dd, J = 8.0, 80 Hz, IH), 7,48 (d, J = 8.2

C

357

Hz, 1H), 7.43 (d, J- 8.2 Hz, ÎH), 7.33 (d, J 8.2 Hz, 1H), 5.07 (s, lh), 2.83 (s, 3H), 0.95 (s, 9H). LCMS-EST (m/z): [M-H] calcd for C^HoChNzO^ 813.3; Found: 813.3.

Example 146. Ethyl 2-(7-chloro-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-25 oxoacetate (148).

OH OH

1-{4-chlorophenyl)propan-2-one

ethyl 2-tert-butoxy-2-(7-chforo-1hydroxy-3-methylnaphthalen-2yljacetate ethyl 2-(7-chloro-1 -hydroxy-3methylnaphthalen-2-yl)-2hydroxyacetate

OTf O

ethyl 2-(7-chloro-3methyl-1(trifluoromethylsulfonyl oxy)naphthalen-2-yl)2-oxoacetate ethyl 2-terf-butoxy-2-(7-ch loro-3-methyI-1 (trifluoromethylsulfonyloxy)naphthaien-2yl)acetate

ethyl 2-(7-chloro-1-(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-oxoacetate

Préparation of ethyl 2-(7-chloro-l-bydroxy-3-methylnaphthalen-2-yl)-2hydroxyacetate: Prepared in a manner similar to ethyl 2-(6-chloro-7-fluoro-1 -hydroxy3-methylnaphthalen-2-yl)-2-hydroxyacetate of Example 99 except using l-(410 chlorophenyl)propan-2-one. ’H-NMR: (400 MHz, CITCij): δ 8.42 (s, broad, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.38 (dd, J = 8.6, 2.0 Hz, 1 H), 7.18 (s, 1H), 5.68 (s, 1H), 4.33-4.10 (m, 2H), 2.53 (s, 3H), 1.20 (ζ J = 7.0 Hz, 3H).

Préparation of ethyl 2-tert-butoxy-2-(7-chloro-l-hydioxy-3-methyl-naphthalen2-yl)acetate: Prepared in a similar manner to ethyl 2-tert-butoxy-2-(l -hydroxy-315 methy)naphthalen-2-yI)acetate of Example 120, except using ethyl 2-(7-chloro-1 hydroxy-3-methylnaphthaIen-2-yl)-2-hydioxyacetate. ’H-NMR: (400 MHz, CDCl·,): δ

358

9.01 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.35 (dd, J = 8.6,2.0 Hz, 1H), 7.13 (s, 1H), 5.49 (s, 1H), 4.22+1.08 (m, 2H), 2.56 (s, 3H), 1.31 (s, 9H), 1.19 (t, J = 7.0 Hz, 3H).

Préparation of ethyl 2-tert-butoxy-2-(7-chloro-3-methyl-l(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: Ethyl 2-tert~butoxy-2-(7-chloro-

3-niethyl-l-(trifluoromethyîsulfonyloxy)naphthaieri-2-yl)acetate was prepared in a similar manner to ethyl 2-(7-bromo-3 -methyl-l-(trifluoromethyIsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzy!oxy)acetate of Example 67 , except using ethyl 2tert-butoxy-2-(7-chloro-l -hydroxy-3-methylnaphthalen-2-yl)acetate. ^lH-NMR: (400 MHz, CDC1₃): δ 8.00 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.65 (s, 1H), 7.49 (dd, J = 8.6, 2.0 Hz, 1H), 5.72 (s, 1H), 4.26-4.08 (m, 2H), 2.54 (s, 3H), 1.20 (s, 9H),

1.17 (t, J - 7.0 Hz, 311).

¹⁹F-NMR: (377 MHz, CDCI₃): δ -73.2 (s)

Préparation of ethyl 2-(7-chloro-l-(4-chloropheny])-3-methylnaphthalen“2-yl)2-oxoacetate: Ethyl 2-(7-chIoro-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2oxoacetate was prepared in a similar manner to 2-(6-chloro-7-fluoro-3-methyl-l(trifluoromethylsulfonyIoxy)naphthalen-2-yl)-2-oxoacetate of Example 99, except using ethyl 2-tert-butoxy-2-(7-chloro-3-methyl-l-(trifluoromethyIsulfonyloxy) naphthalen-2-yl)acetate. ^lH-NMR: (400 MHz, CDC13): δ 8.05 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.74 (s, 1H), 7.58 (dd, J = 8.6,2.0 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 2.48 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H). ¹⁹F-NMR: (377 MHz, CDC13): δ -73.2 (s)

Préparation of ethyl 2-(7-chloro-l-(4-chiorophenyl)-3-methylnaphthalen-2-yl)2-oxoacetate (148): Ethyl 2-(7-chJoro-l-(4-chlorophenyI)-3-methylnaphthalen-2-yl)-2oxoacetate (148) was prepared in a manner similar to ethyl 2-(7-bromo-l -(4chlorophenyl)-3-methylnaphthaien-2-yl)-2-oxoacetate of Example 67, except using ethyl 2-(7-chloro-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate. ’H-NMR: (400 MHz, CDCfi): δ 7.78 (d, J = 8.6 Hz, 1H), 7.73 (s, 1H), 7.50-7.22 (m, 6H), 4.12 (q, J = 7.0 Hz, 2H), 2.49 (s, 3H), 1.13 (t, J = 7.0 Hz, 3H).

Example 147. 2-tert-Butoxy-2-(7-chIoro-l -(4-chlorophenyl)-3-methylnaphthalen-2yl)acetic acid (149)

359

ethyl 2-(7-chloro-1-(4-chlorophenyl)-3methylnaphthalen-2-yl}-2-oxoacetate

ethyl 2-(7-chloro-1-(4-chlorophenyl)-3methylnaphthalen-2-yl)-2-hydroxyacetate

ethyl 2-tert-butoxy-2-(7-chloro-1-(4chtorophenyl)-3-methylnaphthalen2-y[)acetate

149

2-tert-butoxy-2-(7-chloro-1-(4-chlorophenyl)3-methylnaphthalen-2-yl)acetic acid

Préparation of ethyl 2-(7-chloro-l-(4-chlorophenyl)-3-methyInaphthalen-2-yl)2-hydroxyacetate: A solution of ethyl 2-(7-chloro-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (26 mg, 67 pmol) in EtOH (absolute, 1.0 mL) and DCM (1.0 mL) was treated with NaBH₄ (5.1 mg, 0.134 mmol) at 23 °C. After 1 h, saturated

NH4CI (1.0 mL) was added. The réaction was stirred overnight, then diluted with H₂O (10 mL). The mixture was extracted with DCM (3x), and the combined organics dried (Na₂SO₄), filtered, and concentrated, giving the title compound (28 mg, > 99% yield). ‘H-NMR: (400 MHz, CDCh): δ 7.72 (d, J = 8.6 Hz, IH), 7.65 (s, IH), 7.51-7.22 (m,

6H), 5.19 (s, IH), 4.35-4.17 (m, 2H), 2.49 (s, 3H), 1.20 (t, J = 7.0 Hz, 3H).

Préparation of ethyl 2-tert-butoxy-2-(7-chloro-l-(4-chlorophenyl)-3methylnaphthalen-2-yl)acetate: Ethyl 2-tert-butoxy-2-(7-chIoro-l -(4-chlorophenyl)-3methylnaphtha!en-2-yl)acetate was prepared in a manner similar to (S)-ethyl 2-tertbutoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyl-oxy)naphthalen-215 yl)acetate of Example 51, except using racemic ethyl 2-(7-chloro-l-(4~chlorophenyl)-3methylnaphthaIen-2-yl)-2-hydroxyacetate. Material was carried on crude without further characterization.

Préparation of 2-tert-butoxy-2-(7-chloro-l -(4-chlorophenyl)-

360

3-methylnaphthalen-2-yl)acetîc acid (149): 2-tert-Butoxy-2-(7-chloro-l-(4chlorophcnyl)-3-mcthylnaphthalen-2-yl)acetic acid (149) was prepared in a similar manner to 2-(4-bromo-I-(4-chlorophcnyl)'3-methy]naphthalen-2-yl)-2-tertbutoxyacetic acid of Example 124 , except using ethyl 2-tert-butoxy-2-(7-chloro-I-(45 chlorophenyl)-3-methylnaphthalcn-2-yl)acetate, giving the title compound (parent form) ‘H-NMR: (400 MHz, DMSO- </): δ 12.86 (s, broad, IH), 7.94 (d, J = 8.0 Hz,

IH), 7.83 (s, IH), 7.73-7.67 (m, 2H), 7.56-7.49 (m, 2H), 7.40 (d, J -8.2 Hz, IH), 7.11 (d, J - 1.6 Hz, 1 H), 5.00 (s, lH),2.57(s,3H), 0.93 (s,9H). LCMS-ESF (m/z): [M-H]' calcd for C23H21CI2O3:415.1; Found: 415.3.

361

Example 148. (R)-2-(4-Bromo-1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tertbutoxyacetïc acid (150A) and (S)-2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen2-yl)-2-tert-butoxyacetic acid (150B)

Br mettiyl 2-(4-bromo-1-(4chlorophenyl)-3-

methylnaphthalen-2-yl)2-hydroxyacetate	Cl 0 ZVvV^0Me	Cl ίΤΥΎ^ΟΗ
	°	* ο
	Br	Br
	{S)-methy! 2-(4-brorr.o-1-(4-chlcro phenyl)-3-methylnaph thalen-2-yl)-2-hydroxyacetate	150B (S)-2-(4-bromo-1 -(4-chloro

phenyl)-3-methylnaphthaien2-y()-2-tert-birtoxyacetic acid

Chiral chromatographie séparation of the two enantiomers of methyl 2-(4bromo-1-(4-chlorophenyl)-3-mcthyinaphthaïen-2-y 1)-2-hydroxyacetate: A solution of the racemate (36 mg) in MeOH/EtOH 1:1 y/v (1.8 mL total) was separated preparatively into its two enantiomers on an OJ-H pacfcrd chiral column, (R)-methyl 2-(4-bromo-l -(4-chlorophenyI)-3-mcthylnaphthalen-2-yl)-2hydroxyacetate (6.1 mg).

’H-NMR: (400 MHz, CDC1₃): δ 10.34 (s,broad, IH); 8.40 (d, >8.0 Hz, IH); 7.60-7.56 (m, IH); 7.52-7.46 (m, 2H); 7.38-7.35 (m, IH): 7.32-728 (m,2H); 5.26 (s, IH); 3.74

362 (s, 3 H); 2.62 (s, 3H). (S)-methyl 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthaïen-2yl)-2-hydroxyacetate (4.8 mg)

Préparation of (R)-2-(4-bromo-l-(4-chlorophenyl)-3-meüiylnaphtha!en2-yl)-2-teit-butoxyacetic acid (150A): (R)-2-(4-Bromo-l-(4-chlorophenyl)-3methylnaphthalen-2-yI)-2-tert-butoxyacetic acid (150A) was prepared in a similar manner to 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-terÎbutoxyacetic acid of Example 124, except using (R)-methyl 2-(4-bromo-l -(4chiorophenyl)-3-methylnaphthalen-2-yi)-2-hydroxyacctate, giving the title compound (parent form). NMR (400 MHz, CD₃0D) δ 8.38 (d, J = 8.6 Hz, IH), 7.63-7.47 (m, 4H), 7.38-7.20 (m, 3H), 5.30 (s, IH), 2.69 (s, 3H), 1.00 (s, 9H). LCMS-ESF (m/z): [MCO₂-H]' calcd for C₂₂H₂iBrC10:415.2; Found: 415.0.

Préparation of (S)-2-(4-bromo-l -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tertbutoxyacetic acid (150B): (S)-2-(4-Bromo-l-(4-chlorophenyl)-3-methylnaphthaleu-2yl)-2-tert-butoxyacetîc acid (150B) was prepared in a similar manner to 2-(4-bromo-l(4-chlorophenyl)-3-methyInaphthalen-2-yl)-2-tert-butoxyacetic acid of Example 124, except using (S)-methyl 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2hydroxyacetate, giving the title compound (parent form). *H NMR (400 MH2, CD3OD) δ 8.38 (d, J= 8.6 Hz, IH), 7.63-7.47 (m,4H), 7.38-7.20 (m, 3H), 5.30 (s, IH), 2.69 (s, 3H), 1.00 (s, 9H). LCMS-ESI (m/z): [M-COi-H]' calcd for C^ÎfiBrClO: 415.2; Found: 415.0.

Example 149. Compounds 151-180

Compounds 151-180 were prepared by similar methods as described in the above Exemples.

Compound	Compound	Mass	Measured mass
Number

363

151	Cl	490	490.33
152	UÔA (γγΥ* .,ΥΜχ 0 F	493.96	494.07
153	^fYYYy^oh Νς^Ν	537.59	538.03
154	^ρΥίίΥ°^ηk^k^k ° N	484.53	485.1

364

155	ΎΎΎΎ^οη η₂ν^ο	502.54	503.1
156	^ΡΎΎπΊΓ°^Η	473.54	474.14
157	_OKffÇ< i^iîtV⁰ ⁰	394.51	393.0 9(Μ-Η)
158	^^χ^χ ⁰	417.48	418.1
159	ο^· γΎίϊ^οη	417.48	418.1

365

160	θ	417.48	418.1
161	éô χ ν ο ΠίΊΪ°^Η	441.53	442.1
162	A	459.52	460.16
163	«A ίί^νη^^Γθ'π 8 Cl	475.97	473.91/475.48
164	VoV^{H f}\AAz\ ⁰ F	509.5	506.1

366

165	^γΥΥίΤ^οη	488.6	489.1
166	Η ^FY17^T^OHχ'^νύΑ^Α^Α ο ο	516.57	517.1
167	^ρΎΎίΥ°^η	501.6	502.1
168	^ρΥΥίΥ°^ηΠζ^'ΑΑΑΑ^ ⁰ 0	502.54	503.1
169	^ρΎΎίΊΓ°^ηJkAA\ ° A	484.53	485.1

367

170	ΥΥΥϊ^0Η	499.58	500.2
171	YtyV JXk 0	494.96	494.4/496.1
172	^ρΥΎύΎ^οη F	477.51	478.1
173	fÙ^^A^oh _FAsAsÿ*k o	477.51	478.1
174	^ΡΊΤ^Αί^0Η _F A^k^k o	47731	478.1

368

175	F F-J_-F OÔ k n o iTvS^At^0H	467.49	468.1
176	HjN J k. J>k n o'^· θ	522.64	523.1
177	ι/ΥΊΐί°^Η _CIA/Ao	475.97	474.37
178	° F	459.52	460.5
179		459.52	460.4

369

Example 150. Préparation of (S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3dihydropyrano [4,3,2-de] quinolin-7-yl)-3-methylnaphthalen-2-yIJacetic acid (181).

(S)-ethyl 2-fert-butoxy-2-(6formyl-3-methy 1-1 (trifluoromethylsuîfonyioxy) naphttialen-2-yl)acetate

(S)-ethyl 2-tfcrf-butoxy-2-(3-meffiyl-1(trifluoromethy(sulfonyloxy}O-vinylnaphthalen-2yljacetate

(S)-2-fert-butoxy-2-((R)-6-{difluoromethyl)-1-(2,3dihydropyranoi4,3,2-cfe]quino!in-7-yl)-3methylnaphthalen-2-yl)acetic acid

Préparation of (S)-ethyl 2-tert-butoxy-2-(6-formyl-3-methyI-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetaÎe: A solution of (S)-ethyl 2-tert-butoxy-2-(3mfflhyi-I /uifiuoroinethylsulfonyloxy)-6-Yinylnaphthalen-2-y])acetate (0.60 g, 1.3 mmoL [Mcpaed snnilariy to (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-ΙΙΟ (tnfluoTOmethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate from Example 101) in THF (7 mL) at it was treated with a previously prepared mixture of Κ₂Ο5Ο₄·2Η₂Ο (0.023 g, 0.063 mmol) and NaIO₄ (0.81 g, 3.8 mmol) in water (5 mL). The resulting suspension becomes thick and opaque. After vigorous stirring for 20 min, the

370 suspension is filtered through a pad of Celite, and the filtrate is washed with batches of EtOAc until white in color. The collected mother liquor is further diluted with water and EtOAc. Following séparation, the aqueous layer is extracted with EtOAc until colorless. The combined organics are washed with brine, dried over anhydrous MgSCh and concentrated in vacuo. The residue is purified by Yamazen column chromatography (l5-35%EtOAc/hex) to afford 0.348 g (60%) of the desired material as a pale yellow amorphous solid. ’H-NMR: 400 MHz, (CDCl₃) δ: 10.19 (s, IH); 8.31 (br s, IH); 8.16 (d, J = 8.8 Hz, 1 H); 8.05 (dd,J = 8.8, 1.6 Hz, IH); 7.85 (s, lH);5.76(s, 1 H); 4.28-4.10 (m, 2H); 2.61 (s, 3H); 1.22 (s,9H); 1.18 (t, J = 7.2 Hz, 3H).

Préparation of (S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)-l-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methyinaphthalen-2-yl)acetic acid (181): (S)ethyl 2-tert-butoxy-2-(6-fonnyI-3-methyl-l-(trifluoromethylsulfonyl-oxy)naphthalen-2yl)acetate was treated to a sequence of synthetic steps with appropriate adjustments for scale similar to the conversion of (S)-ethyl 2-tert-butoxy-2-(7-fluoro-6-fonnyl-3methy 1-1-(trifluoro methy isul fonyloxy)naphth alen-2-y J)acelate to (S)-2-tert-butoxy-2((R)-6-(difluoromethyl)-1 -(2,3-dihydropyrano [4,3,2-de]quinolin-7-yl)-7-fluoro-3 methylnaphthalen-2-yl)acetic acid in Example 101 to produce 0.039 g of the title compound (TFA sait) as an amorphous pale yellow powder. LCMS-ESF (m/z): [M+H]⁺calcd for C₂9H_2ItF₂NO4:492.2; found: 492.1. ’H-NMR: 400 MHz, (CD₃OD) δ: 8.67 (d, J = 4.4 Hz, 1 H); 8.13 (s, IH); 8.08 (s, IH); 7.85-7.99 (m, 2H); 7,46 (d, J = 8.8 Hz, IH); 7.40 (d, J = 8.8 Hz, IH); 7.07 (d,8.8 Hz, IH); 6.90 (t, Jhf = 56 Hz, IH); 5.26 (s, IH); 4.77-4.69 (m, 2H); 3.67 (t, J = 6 Hz, 2H); 2.80 (s, 3H); 0.93 (s, 9H).

Example 151. Préparation of (S)-ethyl 2-tert-butoxy-2-(4-carbamoyl-3-niethyl-l(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(182)

371

ethyl 2-tert-butoxy-2-(1hydroxy-3-methylnaphthalen2-yl)acetate ethyl 2-(4-bromo-1-hydroxy-3methylnaphthalen-2-yl)-2tert-butoxyacetate

Br ethyl 2-(4-brorrK>-3-methyl-1(tnfluoromethylsutfonyloxy)naphthaien2-yl)-2-tert-birtoxyacetate ethyl 2-{4-bromo-3-methyJ-1(trifluorornethylsulfonyloxyjnaphthalen2-yI)-2-hydroxyacetate

ethyl 2-(4-bramo-3-methyl-1(trifluoromethylsulfonyloxy) naphthalen-2-yl )-2-oxoacetate (S)-ethyl 2-(4-bromo-3-methyl-1(trifluoromethylsulfonyloxy)naphthalen2yl)2-hydroxyacetate

Br (S)-ethyl 244-bromo-3-methyl-1(trifluoiOmethylsulfonytoxy)naphthalen-2-yl)· tert-butoxyacetate

182 (S)-ethyl 24er(-butoxy-2-(4carbamoy l-3-methy l-1 -(trifluoro methylsulfonyloxy)naph:halen-2-yl)acetate

Préparation of ethyl 2-(4~bromo-l-hydroxy-3-rnethyinaphthalen-2-yl)-2-tertbutoxyacetate: A solution of ethyl 2-tert-butoxy-2-( 1 -hydroxy-3-methylnaphthalen-25 yl)acetate (1.24 g, 3.92 mmol) in CHCh (20 mL) was treated with solid NalICO₃ (843 mg, 9.80 mmol). Then a solution of Br₂ (750 mg, 4.70 mmol) in CHCI3 (5.0 mL) was added dropwise over 2 min at 23 °C. After 30 min, the reaction was treated with 10%

372

Na₂S₂O3 solution (10 mL). After maximum decolorization was achîeved, the reaction was diluted with H₂() (10 mL) and extracted with DCM (3 x 10 mL). Combined organic phases were dried (Na₂SO₄), filtered, and concentrated. The residue was treated with DCM and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (1.50 g, 97% yield). 'H NMR (400 MHz, CDC1₃) δ 9.18 (s, IH), 8.28 (d, J = 8.6 Hz, IH), 8.20 (d, J = 8.6 Hz, IH), 7.56 (dd, J = 8.6,8.6 Hz, IH), 7.45 (dd, J = 8.6,8.6 Hz, IH), 5.60 (s, IH), 4.24-4.06 (m, 2H), 2.77 (s, 3H), 1.31 (s, 9H), 1.20 (t, J = 7.0 Hz, 3H).

Préparation of ethyl 2-(4-bromo-3-methyl-l-(trifluoromethylsulfonyloxy) naphthalen-2-yI)-2-tert-butoxyacetate: A flask was chargcd with A’-pheiiyltrifluoromethanesulfonimide (2.70 g, 7.57 mmol), Cs₂CO₃ (2.47 g, 7.57 mmol), and THF (20 mL). A solution of ethyl 2-(4~bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2tert-butoxyacetate (1.50 g, 3.78 mmol) in THF (25 mL) was added with stirring at 23 °C. After 30 min, the reaction was added over 5 min to a premixed solution of 2 M NaHSO₄ (30 mL) and saturated aq. Na₂HPO₄ (100 mL) at 23 °C. The system was extracted with EtOAc/hexane (10:1,3 x 50 mL). Combined organic phases were dried (Na₂SO₄), filtered, concentrated, dissolved în hexane, and concentrated again. The residue was treated with benzene and wet-loaded onto a silica gel column and purified by flash chromatography (hexanes —» ethyl acetate/hexanes 1:4) giving the desired product (1.37 g, 69% yield). ’li NMR (400 MHz, CDC1₃) δ 8.41 (d, J = 8.8 Hz, IH), 8.06 (d, J = 8.8 Hz, IH), 7.70 (dd, J = 8.8,8.8 Hz, IH), 7.64 (dd, J = 8.8, 8.8 Hz, IH), 5.77 (s, IH), 4.28-.4.02 (m, 2H), 2.66 (s, 3H), 1.21 (s, 9H), 1.20 (t, J = 7.0 Hz, 3H). ¹⁹F NMR (377 MHz, CDC1₃) δ -73.2 (s).

Préparation ethyl 2-(4-bromo-3-methyl-l-(trifluoromethylsulfonyloxy) naphthaien-2-yI)-2-hydroxyacetate: A solution of ethyl 2-(4-bromo-3-methyl-l(trifluoromethylsulfonyIoxy)naphthaleu-2-yl)-2-tert-butoxyacetate (1.37 g, 2.60 mmol) in DCM (30 mL) was treated with TFA (3.0 mL) at 23 °C. After 2 h, the reaction was diluted with H₂O (30 mL). The organic phase was collected and the aqueous layer was extracted with DCM (2 x 20 mL). Combined organic layers were dried (Na₂SO₄), filtered, and concentrated giving the desired product as a crude residue ( 1.22 g), which was îmmediately used in the next reaction wîthout further purification. ’H NMR (400 MHz, CDC1₃) δ 8.41 (d, J = 8.2 Hz, IH), 8.09 (d, J = 8.2 Hz, IH), 7.71 (dd, J = 8.2, 8.2

373

Hz, IH), 7.66 (dd, J = 8.2,8.2 Hz, IH), 5.84 (s, IH), 4.34-4.20 (m, 2H), 2.63 (s, 3H),

1.22 (t, J = 7.0 Hz, 3H). ¹⁹F NMR (377 MHz, CDC1₃) 5 -73.0 (s).

Préparation of ethyl 2-(4-bromo-3-methyl-l-(trifluoromethyl-sulfonyloxy) naphthalen-2-yl)-2-oxoacetaie: A solution of ethyl 2-(4-bromo-3-methyi-l(trifluoromethylsulfonyIoxy)naphthalen-2-yl)-2-hydroxyacetate (crude, 1.22 g, -2.60 mmol) in DCM (60 mL) was treated with Dess-Martin periodînane (1.32 g, 3.12 mmol) at 23 °C. After 30 min, 10% Na₂S₂O₃ (30 mL) was added at 23 °C. The System was diluted with H₂O (20 mL) and extracted with DCM (3 x 30 mL). Combined organic layers were dried (Na₂SO4), filtered, and concentrated. The residue was treated with benzene, filtered, and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (1.18 g, 98% yield over 2 steps from ethyl 2-(4-bromo-3-methyl-l(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate). ^]H NMR (400 MHz, CDC1₃) δ 8.43 (d, J = 8.6 Hz, 1 H), 8.13 (d, J = 8.2 Hz, IH), 7.77 (dd, J = 8.6,8.2 Hz, IH), 7.71 (dd, J = 8.6, 8.6 Hz, IH), 4.42 (q, J = 7.0 Hz, 2H), 2.57 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H). ¹⁹F NMR (377 MHz, CDCI3) δ -73.3 (s).

Préparation of (S)-ethyl 2-(4-bromo-3 -methyl-1 -(trifluoromethylsulfonyloxy)naphthalen-2-yI)-2-hydroxyacetate: A solution of ethyl 2-(4-bromo-3-methyI-l(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (1.18 g, 2.52 mmol) in PhMe (20 mL) was cooled to -40 °C (dry ice/CH₃ChI). (R)-CBS catalyst (140 mg, 0.504 mmol) was întroduced, followed by distilled catecholborane (neat, 402 pL, 3.77 mmol) over a 5 min period. After 30 min, the reaction was warmed to —20 °C. EtOAc (20 mL) was added. Then 15%Na₂CO₃ (10 mL) was added. The reaction was stirred vigorously as it was warmed to 23 °C ovemight. The next day, the organic phase was washed (with vigorous stirring) with more 15% Na₂CO₃ (10 mL portions for 30 min each) until the washes were coloriess. After the fifth wash, the organic phase was washed once with saturated NH4CI (10 mL) for 10 min, then dried (MgSO₄\ fiteered and concentrated. The residue was dissolved in hexane and re-concentrated. The residue was treated with benzene, filtered, and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (886 mg, 75% yield). ‘H NMR (400 MHz, CDC1₃) ô 8.41 (d, J = 8.2 Hz, IH), 8.09 (d, J = 8.6 Hz, IH), 7.71 (dd, J = 8.6, 8.2 Hz, IH), 7.66 (dd, J = 8.6, 8.6 Hz, IH), 5.84 (d, J =

374

2.4 Hz, IH), 4.34-4.20 (m, 2H), 3.41 (d, J - 2.4 Hz, IH), 2.63 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H). ¹⁹F NMR (377 MHz, CDC1₃) δ -73.0 (s).

Préparation of (S)-ethyl 2-(4-bromo-3-methyl-l (trifluoromethylsulfonyloxy naphthalen-2-yl)-2-tert-butoxyacetate: A solution of (S)-ethyl 2-(4-bromo-3-methyl-l(trifluoromethylsulfonyIoxy)naphthalen-2-yl)-2-hydroxyacetate (880 mg, 1.87 mmol) in tert-butyl acetate (20 mL) was treated with 70% HCIO4 (40 μΐ ) at 23 °C. After 5 h, the reaction was added slowly over 5 min to saturated NaHCO₃ (50 mL) at 23 °C. The system was stirred for 10 min, then exüacted with DCM (3 x 20 mL). Combined organic layers were dried (Na₂SO4), filtered, and concentrated. The residue was treated with hexane and concentrated once more. The residue was treated with benzene, filtered, and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (816 mg, 83% yield). ’H NMR (400 MHz, CDCI3) δ 8.40 (d, J - 7.8 Hz, IH), «.06 (d, J = 7.8 Hz, IH), 7.70-7.58 (m, 2H), 5.77 (s, IH), 4.27-4.09 (m, 2H), 2.66 (s, 3H), 1.21 (s, 9H), 1.20 (t, J = 7.0 Hz, 3H). ¹⁹F NMR (377 MHz, CDCI3) δ -73.2 (s).

Préparation of (S)-ethyl 2-tert-butoxy-2 -(4-carbamoyl-3-methyl-I (trifluoromethylsulfonyIoxy)naphthalen-2-yl)acetate (182): A solution of (S)-ethyl 2(4-bromo-3-methyl-l (trifluoromethylsulfonyloxy )naphthalen-2-yl)-2-tertbutoxyacetate (200 mg, 0.380 mmol) in dry THF (7.6 mL) was cooled to -78 °C. tertbutyllithium (1.7 M in pentane, 446 pL, 0.759 mmol) was added dropwise under N₂over 3 min. 10 min later, trimethylsilylisocyanate (62.0 pL, 0.456 mmol) was quickly added. The reaction was warmed to 23 °C. After I h, the system was treated with glacial AcOH (87.0 pL, 1.52 mmol) followed by EtOH (absolute, 1.9 mL). The reaction was stirred for 30 min then diluted with saturated NaHCO₃ (20 mL) and H₂O (10 mL). The system was extracted with DCM (3 x 15 mL). Combined organic phases were dried (Na₂SÛ4), filtered, and concentrated. The residue was treated with benzene and wet-loaded onto a silica gel column and purified by frash chromatography (ethyl acetate/hexanes) giving the desired product (75 mg- -*0% yieid.) Ή NMR (400 MHz, CDCh) δ 8.10-8.05 (m, IH), 7.96-7.86 (m, IH), 7.64-7.58 (m, 2H), 6.19 (s, broad, IH), 6.06 (s, broad, 1 H), 5.75 (s, IH), 4.30-4.07(m, 2H),2.53 (s, 3H), 1.21 (s, 9H), 1.20 (t, J = 7.0 Hz, 3H). ^,9F NMR (377 MHz, CDClj) δ -732 (s).

375

Example 153. Préparation of (S)-2-tcrt-butoxy-2-((R)-4-carbainoy 1-1-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid (183)

(S)-ethyl 2-tert-butoxy-2-{(R)4-carbamoy 1-1 -(2,3dihydropyrano[4,3,2de]quinolin-7-yl)-3methylnaphthalen-2-yl)acetate (S)-ethyI 2-tert-butoxy-2-(4carbamoyl-3-methyl-1 -(trifluoro methylsulfonyloxy)naphthalen-2-yl)acatate

(S)-2-terf-butoxy-2-((R)-4-carbamoyJ-1 (2,3-dihydropyrano[4,3,2-de]quinolin-7yl)-3-methylnaphthalen-2-yl)acetk: acid

Préparation of (S)-ethyl 2-lert-butoxy-2-((R)-4-carbamoyl-i-(23-dihydropyrano [4,3,2-de]quinolin-7-yl)-3-methyInaphthalen-2-yl)acetate: A vessel was charged with

2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, monohydrochloride (49 mg, 0.193 mmol), S-Phos-palladacycle (22 mg, 32.2 pmol), and CsF (108 mg, 0.708 mmol). The vessel was rvacualcd under vacuum and backfilled with argon. A solution of (S)-ethyl 2-tert4x>OTy-2-4-c3rbamoyd-3-methyl-1(trifluoromethylsulfooyioxy)naphthaIen-2-yl)acetate (182, 79 mg, 0.161 mmol) in 1,2DME (distilled from Na°/benzophenone, 1.4 mL) was added. The vessel was sealed and heated with vigorous stirring to 120 °C for 3 h. The reaction was cooled to 23 °C and diluted with brine (8 mL) and ILO (8 mL). The System was extracted with DCM (3 x mL). Combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The

376 residue was dissolved in DCM and concentrated once more. The residue was treated with benzene and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving (2S)-ethyl 2-tert-butoxy-2-((R)-4carbamoyl-I-(2,3-dihydropyrano[43>2-de]quinolin-7-yl)-3-methylnaphthalen-2yl)acetate (3.4 mg) in semipure form. LCMS-ESI⁴ (m/z): [M+H]⁴ calcd for C31H33N2O5: 513.2; Found: 513.1. The other diastereomer, (2S)-ethyl 2-tert-butoxy-2((S)-4-carbamoyI-1 -(2,3-dihydropyrano [4,3,2-de]quinolin-7-yl)-3 -methyinaphthalen-2yl)acetate, was also obtained from the flash column in semipure form (1.3 mg, yield not found). LCMS-ESI⁴ (m/z): [M+H]⁴calcd for C31H33N2O5: 513.2; Found: 513.1.

Préparation of (S)-2-tert-butoxy-2-((R)-4-carbamoyl-l-(2,3dîhydropyrano[4,3,2-de]quinolin-7-yl)-3-methyinaphthalen-2-yl)acetic acid (183): A solution of (2S)-ethyl 2-tert-butoxy-2-((R)-4-carbamoyl-l-(2,3-dihydro pyrano [4,3,2de]quinoIin-7-yl)-3-methyInaphthalen-2-yl)acetate (3.4 mg, semipure) in THF (1.0 mL) and EtOH (absolute, 500 pL) was added to LiOH«H₂O (100 mg) predissolved in H₂O (500 pL). The mixture was stirred vigorously ai 60 °C for 4 days. The reaction was cooled to 23 °C, diluted with EtOH (absolute, 1.0 mL), and filtered (0.45 micron filtcr). The filtrate was purified on a C18 Gemini column (eluent: H2O/CH3CN 95:5 —* 0:100 spiked with 0.1% v/v TFA), giving (S)-2-tert-butoxy-2-((R)-4-carbamoyl-1-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid as the mono-trifluoroacetic acid sait (1.5 mg, yield not found). ^!H NMR (400 MHz, CD3OD) δ 8.72-8.69 (m, 1H), 8.06-7.26 (m, 6H), 6.98 (d, J = 8.6 Hz, 1H), 5.25 (s, 1H), 3.66-

3.32 (m, 2H), 3.30-3.16 (m, 2H), 2.78 (s, 3H), 0.94 (s, 9H). ¹⁹F NMR (377 MHz, CDCI3) δ -77.5 (s). LCMS-ESI⁴ (m/z): [M+H]⁴ calcd for C₂₉H_;9N₇O₅: 485.2; Found:

485.1. The other diastereomer, (2S)-2-tert-butoxy-2-((S)-4-carbamoyl-l -(2,3dihydropyrano [4,3,2-de]quinoIin-7-yl)-3-methylnaphthalen-2-yl)acetic acid, was prepared in a sîmilar manner from (2S)-ethyl 2-tert-butoxy-2-((S)-4-carbamoyl-1-(2,3dihydropyrano[4,3,2-de]quinoiin-7-yl)-3-niethyInaphthalen-2-yl)acetate: *H NMR (400 MHz, CD3OD) δ 8.66-7.19 (m, 7H), 6.96 (d, J = 8.6 Hz, 1H), 5.25 (s, 1H), 3.67-3.32 (m, 2H), 3.30-3.14 (m, 2H), 2.72 (s, 3H), 0.77 (s, 9H). ¹⁹F NMR (377 MHz, CD₃OD) δ -77.6 (s). LCMS-ESI⁴ (m/z): [M+H]⁴ calcd for C^I^bLOc 485.2; Found: 485.1.

Example 154. Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-1-(2,3dîhydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (184)

377

ethyl 2-te/-f-butoxy-2-CL hydroxy-3-methyl naphthalen-2-yl)acetate ethyl 2-ferf-butoxy-2-(3-methyl

-(trifluoromethy Isulfonyloxy) naphthalen-2-yl)acetate

OTf OH

OTf O

ethyl 2-hydroxy-2'(3-methyl-1(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate ethyl 2-(3-methyl-1(trifluoromethylsu Ifony loxy ) naphthalen-2-yl)-2-oxoacetate

OTf OH

(SRethyl 2-hydroxy-2-(3-methyl1 -(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate (S)-ethyl 2-ferf-butoxy-2-(3methyl-1-(trifluoromethylsu Ifony loxy) naphthalen-2-yl)acetate

(S)-ethyl 2-tert-butoxy-2-((/?}-1(2,3-dihydfopyrano[4,3,2dejquinolin-7-yl)-3methylnaphthalen-2-yi)acetate

Préparation of ethyl 2-tert-butoxy-2-(3-methyl-l-(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate: Ethyl 2-tert-butoxy-2-(3-methyl-l(trifluoromethylsulfonyloxy) naphtha!en-2-yl)acetate was prepared in a similar fashion 5 to ethyl 2-tert-butoxy-2-(4-fluoro-3 -methyl-1 -(trifluoromethyIsulfonyloxy)naphthalen2-yl)acetate in Example 120 with appropriate adjustments to scale to afford an

378 amorphous white solid that was contaminated with a small amount of PhNH(Tf). LCMS-ESI* (m/z): [M-C4H9+H]* calcd for CieHieFsOgS: 392.4; found: 392.6.

Préparation of ethyl 2-hydroxy-2-(3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: A solution of ethyl 2-tert-butoxy-2-(3-methyl-l5 (trifluoromethylsulfonyloxy)naphthaIen-2-yl)acetate (6.0 grains, ~I3 mmol, semipure) în DCM (60 mL) was treated with TFA (6.0 mL) at 23 °C. The reaction was diluted with H₂O (60 mL) and the organic phase collected. The aqueous layer was extracted with DCM (2 x 30 mL). The combined organic layers were dried (Na₂SO4), fîltered, and concentrated. The residue (5.5 grams) was used in the next reaction without further 10 purification. ’H NMR (400 MHz, CDClj): δ 8.08-8.06 (m, l H), 7.81-7.78 (m, 1H), 7.69 (s, 1H), 7.62-7.55 (m, 2H), 5.81 (app. s, 1H), 4.35-4.21 (m, 2H), 3.26 (app. s, broad, 1H), 2.50 (s, 3H), 1.21 (t, J = 7.0 Hz, 3H).

Préparation of ethyl 2-(3-methyl-l-(triiluoromethy]sulfonyloxy)naphthalen-2yl)-2-oxoacetate: A solution of ethyl 2-hydroxy-2-(3-methyl-115 (trifluoromethylsulfonyloxy) naphthalen-2-yI)acetate (5.5 g, crude) in DCM (160 mL) was treated with Dess-Martin periodinane (7.18 g, 16.9 mmol) at 23 °C. After 1 h, the reaction was added slowly over 5 min to 10% Na₂S₂O3 (100 mL). After 30 min, the reaction was extracted with DCM (3 x 50 mL). The combined organic layers were dried (Na₂SO₄), fîltered, and concentrated. The residue was treated with benzene, fîltered, and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product in semipure form (3.9 g). 'H NMR (400 MHz, CDCI3): δ 8.11-8.08 (m, 1H), 7.86-7.83 (m, 1H), 7.76 (s, 1H), 7.66-7.60 (m, 2H),

4.41 (q, J = 7.4 Hz, 2H), 2.50 (s, 3H), 1.40 (LJ 7.4 Hz, 3H). ^I9F NMR (377 MHz, CDCI3) δ -73.3 (s).

Préparation of (S)-ethyl 2-hydroxy-2-(3-methyl-l -(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate: Ethyl 2-(3 -methyl-1 -(trifluoromethylsulfonyloxy)naphthalen2-yl)-2-oxoacetate (1.31 g, 3.3 mmol) was dissolved in toluene (20 mL) and cooled to 40 °C. After stirring for 20 minutes, (R)-(+)-2-Methyl-CBS-oxazaborolidine (219 mg,

7.5 mmol) and catechol borane (750 pL, 7.04 mmol) were added and the mixture stirred at -40 °C. After 2 hrs at -40 °C the reaction was quenched by the addition of 15% Na;CO₃ (12 mL) and the mixture was allowed to warm to room température. The mixture was washed with 15% Na₂COî (8x12 mL) and saturated NH4CI (24 mL), organic layer was dried with sodium sulfate and concentrated in vacuo.

379

Chromatography using silica gel using EtOAc în hexanes produced the desired (S)ethyl 2-hydroxy-2-(3-methyl- ] -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (976 mg, 1.8 mmol) in 74 % yield. ^]H-NMR: 400 MHz, (CDCl₃): δ 8.08-8.06 (m, IH); 7.81-7.79 (m, IH); 7.69 (s, IH); 7.60-7.57 (m, 2H); 5.81-5.80 (m, IH); 4.35-4.19 (m, 2H); 3.42 (d, J = 2.4 Hz, IH); 2.50 (s, 3H); 1.21 (t, J = 7.0 Hz, 3H).

Préparation of (S)-ethyl 2-tert-butoxy-2-(3-methyl-l(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetale: To a stirring solution of (560 mg, 1.42 mmol) in t-BuOAc (32.0 mL, 381 mmol) was added 4 drops (catalytic) of 70% HCIO4 and the mixture allowed to stîr at room température for 2 hours. The mixture was quenched by pouring it into an ice-cold solution of saturated NaHCO₃. Extraction with EtOAc (3 x 20 mL), drying with sodium sulfate and column chromatography on silica gel using EtOAc în hexanes produced the desired product (S)-ethyl 2-tert-butoxy-2-(3-methyl-l-(trifluoromethyl-sulfony]oxy)naphthalen-2yl)acetate (455 mg, 71%). ‘H-NMR: 400 MHz, (CDC1₃): δ 8.06-8.03 (m, IH); 7.817.78 (m, lH); 7.67 (s, IH); 7.59-7.53 (m, 2H); 5.73 (s, IH); 4.25-4.10 (m, 2H); 2.55 (s, 3H); 1.21 (s,9H), 1.17(t, J = 7.2Hz, 3H).

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (184): (S)-ethyl 2-tert-butoxy-2-(3methyl-l-(trifIuoromethyIsulfonyloxy)naphthalen-2-yl)acetate (555 mg, 1.23 mmol) in freshly dîstilled DME (5.0 mL) was added to a 5-10 mL microwave vial charged with a mixture of 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HCl sait (368 mg,

1.46 mmol); S-Phos palladacycle (155 mg, 0.23 mmol), and CsF (743 mg, 4.89 mmol). This heterogeneous mixture was then microwaved at 125 °C for 60 minutes. The mixture was then diluted 400% with EtOAc, extracted with saturated NH4CI, brine, and dried with sodium sulfate. Chromatography via ISCO using a 15 pm particle size silica gel column separated the desired atropisomer (S)-ethyl 2-tert-butoxy-2-((R)-1-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (184) (79.7 mg, 0.17 mmol, 14%) and the undesired atropisomer (S)-ethyl 2-tert-butoxy-2-((S)-l(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methyInaphthalen-2-yl)acetate ( 109.9 mg, 0.234 mmol). ’H-NMR: 400 MHz, (CDC1₃): δ 8.66 (d, J = 4.4 Hz, IH); 7-77 (d, J = 8.0 Hz, IH); 7.72 (s, IH); 7.50 (d, J = 8.0 Hz, IH); 7.36-7.33 (m, IH); 7.13-7.01 (m, 4H); 5.09 (s, IH); 4.58-4.52 (m, 2H); 4.03-3.78 (m, 2H); 3.38-3.23 (m, 2H); 2.79 (s, 3H); 0.97 (s, 9H); 0.96 (t, J = 7.6 Hz, 3H).

380

(S)-ethyl 2-tert-butoxy-2-((R)-1(2,3-dihydropyrano[4,3,2de]quinolin-7-y()-3methylnaphthalen-2-yl)acetate (Sfethyl 2-((R)-1-(2,3dihydropyrano[4,3,2-de]quinolin7-yl)-3-methylnaphthalen-2-yl)-2hydroxy acetate

(S)-ethyl 2-((R)-1-(2,3dihydropyrano[4,3,2-de]quinolin-7yl)-3-methylnaphthalen-2-yl)-2-(tertpentyloxyjacetate (S)-2-((R)-1-(2,3dihydropyrano[4,3,2-de]quinolin-7yl)-3-methylnaphthaten-2-y()-2(fert-pentyloxyjacetic acid

Préparation of (S)-ethyl 2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3methylnaphthalen-2-yl)-2-hydroxyacetate: To a DCM solution (10 mL) of (S)-ethyi 25 tert-butoxy-2-((R)-l-(2,3-dihydropyrano(4,3,2-de]quinolm-7-yl)-3-methylnaphthalen2-yl)acetate (184) (49.0 mg, 0.104 mmol) was added TFA (650 pL, 0.0084 mmol) and stirred at rt overnight. The mixture was quenched by pouring into an ice-cold solution of saturated NalICO;, and extracted withEtOAc to give crude (S)-ethyl 2-((R)-l-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate 10 (30.3 mg, 70%). ^lH-NMR: 400 MHz, (CDC1₃): δ 8.67 (d, J = 4.0 Hz. iH t; 7.79-7.76 (m, 2H); 7.48 (d, J = 7.6 Hz, IH); 7.38 (t, J = 7.8 Hz, 1 H); 7.16-7.10 tx. 3H1. 6.97 (d. J = 8.4 Hz, IH); 5.36 (s, IH); 4.58-4.55 (m, 2H); 3.89-3.72 (m, 2H): 338-3.31 (m, 2H):

2.69 (s, 3H); 1.05 (t, J=7.0 Hz, 3H). LCMS-ESf (m/z): [M+H]⁺ calcd for C26H24NO4; 414.17; Found: 414.1.

Préparation of (S)-ethyl 2-((R)-l-(2,3-dihydropyTano[4,3,2-de]quinolîn-7-yI)-3methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetate: (S)-ethyl 2-((R)-1-(23-

381 dihydropyrano[4,3,2-de]quinorm-7-yl)-3-methyInaphthalen-2-yl)-2-hydroxyacetate (57.6 mg, 0.139 mmol) was slurried in 2.0 mL of tert-pentyl acetate and 500 pL of DCM and treated with one drop of 70% perchloric acid. The mixture was allowed to stir 5 hours. The reaction was quenched by pouring înto ice-cold saturated NaHCOa. This mixture was extracted with EtOAc (3x 20 mL), dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography using EtOAc in hexanes produced the desired (S)-ethyl 2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3methylnaphthaIen-2-yl)-2-(tert-pentyloxy)acetate (58 mg). ‘H-NMR: 400 MHz (CDC1₃): δ 8.66 (s, 1H); 7.77-7.75 (m, 2H); 7.49 (d, J=8.0 Hz, 1H); 7.35 (t, J= 7.6 Hz, 1H), 7.13-7.07 (m, 3H); 7.02 (d, J = 8.4 Hz, 1H); 5.08 (s, 1H); 4.45 (t, J= 5.6 Hz, 2H); 4.02-3.76 (m, 2H); 3.39-3.29 (m, 2H); 2.79 (s, 3H); 1.28-1.24 (m, 2H); 0.97-0.84 (m, 9H); 0.70 (t, J — 7.0 Hz, 3H). LCMS-ESI* (m/z)z [M+HJ* calcd for C31H34NO4: 484.25; Found: 484.14.

Préparation of (S)-2-((R.)-l-(2,3-dihydropyiano|4,3,2-de]qumolin-7-yl)-3methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetic acid (185): (S)-ethyl 2-((R)-1-(2,3dihydropyrano[4,3,2-de]quinolm-7-yl)-3-meLhylnaphthalen-2-yl)-2-(tertpentyloxy)acctate (58 mg, 0.12 mmol) was dissolved in THF (6.0 mL), MeOH (2mL) and water (2 mL). LiOH was added (209 mg, 4.98 mmol) and the mixture was microwaved at 100 °C for 45 minutes. The mixture was then diluted 400% with EtOAc, washed with water, brine, dried and concentrated in vacuo. The crude product was dissolved in MeOH and purified via preparatory HPLC and lyophilized to produce (S)-2-((R)-1 -(2,3-dihydropyrano[4,3,2-de]quînolin-7 -yl)-3-methylnaphthalen-2-yl)-2(tert-pentyloxy)acetic acid (185) as the TFA sait (11.6 mg). 41-NMR: 400 MHz, (CD3OD): δ 8.67 (d, J = 5.6 Hz, 1H); 7.97 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H); 7.87 (d, J =

8.4 Hz, 1H); 7.81 (d, J = 5.6 Hz, 1H); 7.51-7.47 (m, 2H); 7.28-7.25 (m, 1H); 6.93 (d, J = 8.8 Hz, IH); 5.19 (s, 1H); 4.76-4.67 (m, 2H); 3.67 (t, J=6.0 Hz, 2H); 2.78 (s, 3H); 1.29-1.12 (m, 2H); 0.93 (d, J = 8.4 Hz. 0 62 (L J = 7.0 Hz, 3H). LCMS-ESI* (m/z): [M+H]* calcd for C29H30NO4: 45é_?5; Found: 456.1 L

Example 156. Préparation of(S)-2-tert-butoxy-2-((R)-1 -(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-6-((dimethylamino)methyl>-5-fluoro-3-inethylnaphthalen-2-yl)acetic acid (186A) and (S)-2-tert-buioxy-2-uFO-l-(2.3-dihydropyrano[4,3,2-de]quinolin-7yl)-5-fluoro-6-(hydroxymethyl)-3-methyiiiaphthalen-2-yl)acetic acid (186B)

382 (S)-ethyl 2-tert-butoxy-2-((R)1-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-5-fluoro-6formyl-3-mettiylnaphthalen-2’ yl)acetate

(S)-ettiyi 2-tert-butoxy-2-((R)-1-(2,3dihydropyrano{4,3,2-Îfe]quino!h'ï-7-y()-6((dimethylamino)methyl)-5-fluoro-3metfiylnaphthaten-2-yl)acetate (S)-ethyl 2-ierf-butoxy-2-((F?)-1 (2,3-dihydropyrano[4,3,2de]qutnolin-7-yI)-5-fluoro-6(hydroxymethyl)-3methylnaphttiaien-2-yl)acetate

1MA

186B (S)-2-tert-butoxy-2-((R)-1 -{2.3dthydropyrano(4₁3,2-de]quinolîn-7-yl)-

6-((dimeîhylamino)fnethyl)-5-fluoro-3methykiaphthaten-2-yl)acetic acid (S)-2-tert-butoxy-2-([R)-1-(2,3dihydropyrano[4,3,2-cfe]quinoiin-7-yl)-5fluoro-6-(hydroxyrnethyl)-3methylnaphthalen-2-y))acetic acid

383

Préparation of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-6-(dimethylaminomethyl)-5-fluoro-3-methylnaphthalen-2-yl)acetate and (S)-ethyl 2-tert-butoxy 2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5fluoro-6-(hydroxymethyl)-3-methylnaphtha]en-2-yl)acetate and (S)-ethyl 2-tert-butoxy2-((R)-1 -(2,3 -dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-(hydroxymethyl)-3 methylnaphthalen-2-yl)acetate: (S)-ethyl 2-tert-butoxy-2-((R)-1-(2,3dihydropyrano[4,3^-de]quinoIin-7-yl)-5-fluoro-6-formyl-3-methylnaphthalen-2yl)acetate (18 mg, 0.035 mmol, l eq.) and dimethylamine HCl sait (9 mg, 3 eq.) were mixed in 1 mL MeCN at room température for 1 hour. The reaction was cooled to 0°C and NaHB(OAc)₃ (22mg, 3 eq.) was added to the reaction. The réaction was stirred at 0 °C then warmed up to room température for l hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSCM, filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). Products were lyophilized to give yellow powders of (S)-ethyl 2-tert-butoxy-2-((R)-l(2,3-dihydropyrano[4,3,2-de]qumolin-7-yl)-6-((dimethylamino)methyl)-5-fluoro-3methylnaphthalen-2-yl)acetate (5 mg); LCMS-ESr (m/z): [M+H]* calcd for C₃₂H₃7FN₂O4: 545.66; Found: 545.21; and(S)-ethyI 2-tert-butoxy-2-((R)-1-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-(hydroxymethyl)-3methylnaphtha!en-2-yl)acetate (4 mg), LCMS-ESI* (m/z): [M+H]* calcd for C₃iH₃₂FNO₅: 518.59; Found: 518.12.

Préparation of (S)-2-tcrt-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-6-((dimethylamino)methyl)-5-f]uoro-3-methylnaphthalen-2-yl)aceÎic acid (186A): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-1-(2,3 -dihydropyrano[4,3,2-de]quinolin-7yl)-6-((dimethylamino)methyl)-5-fluoro-3-methylnaphthalen-2-yl)acetate (5 mg) in tetrahydrofuran (0.5 mL) and éthanol (0.5 mL) and 2 M sodium hydroxide (0.5 mL) was heated at 50 °C for 2 hours. The réaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and tbe combined organic layer was dried (MgS(h). filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1% TFA). Product lyophilized to give a yellow powder (3.4 mg). ^lH-NMR: 400 MHz, (CD₃OD): δ 8.55 (d, J = 5.08 Hz, IH), 8.10 (s, IH), 7.58 (d, J = 8.21 Hz, IH), 7.53 (d, J = 4.69 Hz, IH), 7.25 (d, J =

8.22 Hz, IH), 7.18 (dd, J = 7.82 Hz, 1 H), 6.78 (d, J = 8.60 Hz, 1H),5.15(s, IH), 4.55 (m, 2H), 4.44 (m, 2H), 3.48 (t, J = 5.87 Hz, 2H), 2.81 (s, 6H), 2.72 (s, 3H), 0.82 (s,

384

9H). ⁵F-NMR: 377 MHz, (CD₃OD) 5: -77.7 (s, 3F), -126.37 (s, 1F). LCMS-ESI* (m/z): [M+H]* calcd for C₃iH₃4FN₂O₄: 517.60; Found: 517.17.

Préparation of (S)-2-tert-butoxy-2-((R)-1 -(2,3 -dihydropyrano [4,3,2-de]quinolin7-yl)-5-fluoro-6-(hydroxymethyl)-3-methybaphthalen-2-yl)acetic acid (186B): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinoIin-7yl)-5-fluoro-6-(hydroxymethyl)-3-methylnaphthalen-2-yl)acetate (4 mg) in tetrahydrofiiran (0.5 mL) and éthanol (0.5 mL) and 2 M sodium hydroxide (0.5 mL) was heated at 50 °C for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted with ethyl acetate and the combined organic layer was dried (MgSO₄), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O + 0.1 % TFA). Product lyophilized to give a yellowpowder (2.1 mg). ’H-NMR: 400 MHz, (CD₃OD): δ 8.57 (d, J = 5.08 Hz, 1H), 8.07 (s, 1H), 7.71-7.66 (m, 2H), 7.34 (d, J = 8.22 Hz, 1H), 7.25 (dd, J = 7.82 Hz, 1H), 6.66 (d, J = 8.60 Hz, IH), 5.14 (s, 1H), 4.62 (m, 2H), 3.54 (t, J = 5.87 Hz, 2H),

2.70 (s, 3H), 0.83 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD3OD) δ: -77.7 (s, 3F), -132.63 (d, 1F). LCMS-ESI' (m/z): [M+H]* calcd for CmHzsFNOs: 490.53; Found: 490.1.

Example 157. Preparationof(S)-2-tert-butoxy-2-(6-chloro-l-((R)-2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (187)

F

-bromo-3-chloro-2,4difluorobenzene

(SF2-tert-butoxy-2-(6-chloro-1-((RF2,3dihydropy rario[4,3,2-cfe]quînolin-7-yl)-5,7drfluoro-3-methylnaphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(6-chloro-l-((R)-2,3-dihydrOpyrano [4,3,2de]quinolin-7-y])-5,7-difIuoro-3-methylnaphthalen-2-yI)acetic acid: The tîtle cornpound was prepared following a procedure similar to make (S)-2-tert-butoxy-2((R)-5-chlGro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yi)-3,6-diniethylnaphthalen -2-

385 yl)acetic acid (116) of Example 114 except l-bromo-3-chloro-2,4-dinuoro-benzene was used instead of l-bromo-2-chloro-3-methylbenzene. ’lI-NMR: 400 MHz, (CD3OD): δ 8.72 (d, J = 5.48 Hz, 1H), 8.16 (s, 1H), 7.81 (m, 2H), 7.46 (d, J = 8.21 Hz, 1H), 6.65 (d, J = 10.56 Hz, 1H), 5.22 (s, IH), 4.72 (m, 2H), 3.66 (dd, J = 5.87 Hz, 2H),

2.81 (s, 3H), 0.93 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD3OD) δ: -77.8 (s, 3F), -118.07 (d, 1F), -123.12 (s, 1F). LCMS-EST (m/z): [M+H]⁺ calcd for C₂₈H₂₅C1F₂NO₄: 512.94; Found: 512.1.

Example 158. Préparation of(S)-2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano[4,3,2de] quinolin-7-yl)-5,7-difluoro-3,6-dime1hylnaphthalen-2-yl)acetic acid (188)

( S)-2-tert-butoxy-2-(1 -((R)-2,3dihydropyranc[4,3,2-<de]qu!nolin-7-yl)5,7-difluoro-3,6--dÎmethylnaphthaleri-2yljacetfc acid

Préparation of (S)-2-tert-butoxy-2-(l -((R)-2,3-dihydropyrano [4,3,2-de]quinolin7-yl)-5,7-difluoro-3,6-dimethylnaphthalen-2-yl)acetic acid (188): Following a procedure similar to the préparation of (S)-2-tert-butoxy-2-((R)-l-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3,6-dimethylnaphthalen-2-yl)acetic acid (119) of Example 117, (S)-ethyl 2-tert-butoxy-2-(6-chloro-l-((R)-2,3-dihydropyrano[4,3,2-de]quinoKn-7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)acetate (from Example 157) was used instead of (S)-ethyl 2-tert-butoxy-2-((R)-6-chloro-l-(2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate. *HNMR: 400 MHz, (CD3OD): δ 8.69 (d, J = 5.47 Hz, 1H), 8.10 (s, 1H), 7.81 (m, 2H), 7.44 (d, J = 8.21 Hz, 1H), 6.41 (d, J = 10.95 Hz, 1H),5.21 (s, 1 H), 4.72 (m, 2H), 3.66 (dd, J = 5.86 Hz, 2H), 2.78 (s, 3 H), 2.32 (s, 3H), 0.93 (s, 9H).¹⁹F-NMR: 377 MHz, (CD3OD) Ô: -77.8 (s, 3F),-117.62 (s, 1F),-126.33 (s, 1F). LCMS-ESÉ (m/z): [M+H]⁺calc’d for C₂₉H₂₈F₂NO₄: 492.53; Found: 492.06.

386

Example 159. Préparation of (S)-2-tert-butoxy-2-( 1 -((R)-2,3-dihydropyrano[4,3,2de]quÎnolin-7-yl)-6-ethyl-5_}7-difluoro-3-methyinaphthalen-2-yl)acetic acid (189)

(S)-2-terf-butoxy-2-(1 -((R}-2,3dîhydropyrano[4,3,2-de]quinolin-

7-yl)-6-ethyf-5,7-difluoro-3methytnaphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(l -((R)-2,3-dihydropyrano[4,3,2-de]quinolin7-yl)-6-ethyl-5,7-difluoro-3-methylnaphthalen-2-yI)acetic acid (189): Following a procedure similar to the préparation of (S)-2-tert-butoxy-2-(l-((R)-2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-5-fluoro-3-methylnaphthalen-2-yl)acetic acid (120) of Example 118, (S)-ethyl 2-tert-butoxy-2-(6-chloro-l-((R)-2,3dihydropyrano|4,3,2-de]quinolin-7-yl)-5,7difluoro-3-methylnaphthalen-2-yl)acetate (from Example 157) was used instead of(S)-ethyl 2-tert-butoxy-2-(6-chIoro-l-((R)-2,3dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3 -methy l-naphthalen-2-yl)acetate.¹HNMR: 400 MHz, (CD3OD): δ 8.59 (d, J = 5.47 Hz, 1H), 8.00 (s, 1H), 7.69 (m, 2H), 7.33 (d, J = 8.21 Hz, 1H), 6.32 (d, J = 11.34 Hz, 1H), 5.11 (s, 1 H), 4.61 (m, 2H), 3.55 (dd, J = 5.48 Hz, 2H), 2.73 (m, 2H), 2.68 (s, 3H), 1.18 (dd, J = 7.42 Hz, 2H), 0.93 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD3OD) δ: -77.6 (s, 3F), -119.81 (s, 1F), -128.26 (s, 1F). LCMS-ESI* (m/z): [M+H]* calc’d for C₃₀H₃₀F₂NO₄: 506.55; Found: 506.1.

Example 160. Préparation of (S)-2-tert butoxy-2-(l-((R)-2,3-dihydropyrano[4.32de]quinolin-7-yl)-5,7-difluoro-3-methyl-6-(pyrimidin-5-yl)naphthalen-2-yl)acetic acid (190)

387

(S)-2-iert-butoxy-2-( 1 -{(R}-2,3dihydropyrano{4_t3,2-de]quinolin-7-yl)-5,7dif{uoro-3-methyl-6-(pyrimidin-5yi)naphthalen-2-yl)acetic acid

Préparation of (S)-2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano[4,3.2-deJquinolin7-yl)-5,7-difluoro-3 -methyl-6-(pyrimidin-5-yl)naphÎhalen-2-yl)acctic acid (190): Following a procedure similar to the préparation of (S)-2-tert-butoxy-2-(l-((R)-2,3dihydropyrano[4,3,2-dc]quinolin-7-yl)-5,7-difluoro-3,6'dimethylnaphthalen-2-yl)acetic acid (188) of Example 158, pynmidin-5-ylboronic acid was utilized instead of methylboronic acid to eventually afford the title compound. ^JH-NMR: 400 MHz, (CD₃OD): Ô 9.22 (s, IH), 8.99 (s, IH), 8.74 (d, J = 5.87 Hz, IH), 8.24 (s, IH), 7.84 (d, J = 7.82 Hz IH), 7.78 (d, J = 5.48 Hz IH), 7.46 (d, J = 8.12 Hz, IH), 6.69 (d, J -11.34 Hz, IH), 5.26 (s, IH), 4.78 (m, 2H), 3.66 (dd, J = 5.86 Hz, 2H), 2.82 (m, 2H), 0.93 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD3OD) δ: -77.6 (s, 6F), -118.79 (s, 1F), -125.06 (s, 1F). LCMS-ESf (m/z): [M+H]' calcd for (^H^NjCU: 556.57; Found: 556.10.

Example 161. The following illustrate représentative pharmaceutical dosage forms, containing a compound of formula I ('Compound X'), for therapeutic or prophylactic use in humans.

(i) Tablet 1

Compound X=

Lactose

Povidone

Croscarmellose sodium Microcrystalline cellulose Magnésium stéarate mg/tablet

100.0

77.5

15.0

12.0

92.5

T0

300.0 (ii) Tablet 2 mg/tablet

Compound X= 20.0

388

Microcrystalline cellulose410.0

Starch50.0

Sodium starch glycolate15.0

Magnésium stéarate5.0

5500.0

	(iii) Capsule	mg/capsule
	Compound X-	10.0
	Colloïdal silicon dioxide	1.5
10	Lactose	465.5
	Pregelatimzed starch	120.0
	Magnésium stéarate	3Ό
		600.0
15	(iv) Injection 1 (I me/ml)		mg/ml
	Compound X= (free acid form)	1.0
	Dibasic sodium phosphate		12.0
	Monobasic sodium phosphate	0.7
	Sodium chloride		4.5
20	1.0 N Sodium hydroxide solution
	(pH adjustment to 7.0-7.5)		q.s.
	Water for injection		q.s. ad 1 mL

(v) Injection 2 (10 mg/ml)mg/ml

Compound X= (free acid form)10.0

Monobasic sodium phosphate0.3

Dibasic sodium phosphate1.1

Polyethylene glycol 400200.0

N Sodium hydroxide solution (pH adjustment to 7.0-7.5)q.s.

Water for injection q.s. ad I mL (vi) Aérosol mg/can

Compound X=20.0

Oleic acid10.0

Trichloromonofluoromethane 5,000.0

Dichlorodifluoromethane 10,000.0

Dichlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional procedures well known în the pharmaceutical art.

All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various spécifie and prefeired embodiments and techniques.

389

However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

What is claimed is:

l. A compound of formula I:

wherein:

R¹ isR^laorR^tb;

R² is R^2a or R^2t>;

R³ is R^3a or R^3b;

R³’ is R^3a or R^3b ;

R⁴ is R^4a or R^4b;

R⁵ is R^5a or R^5b;

R⁶ is R^6a or R^6b;

R⁷ is R^7a or R⁷⁶;

R⁸ is R^8a or R^8b;

R^,a is selected from:

a) H, halo, (Ci-Cfi)alkyl and (Ci-C₆)haloalkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O)-R, -C(=O)-O-R^,;,-O-R^h,-S-R”, -S(O)-R”, -SO2-R^u, ACrCtlalkyl-R, -(CT-C6)alkvl-C(-O)-R, -(C -C₆)alkyi C(=O) O-R¹ -(C!-C6)alkyl-O Rⁿ, -(CrCoialkyl-S-R¹ \ -(Cj-Celalkyl-SfOI-R¹¹ and -(CrCsjalkyl-SOi-R¹¹, wherein each R ^! is independently selected from H, (CrCÉ)alkyl, (Q-CJalkenyl, (C₂-C₆)alkynyL (C_rCijhaloalkyl, fCj-C-’kycloalkyi. aryl, heterocycle and heteroaryl; and

Z¹

391

d) -N(R⁹)R^IÛ, -C(- O)-N(R’)R^j, -O-C(=O)-N(R⁹)Rⁱ⁰, SO2-N(R⁹)R' -(Cl-C₆)a!kyl-N(R⁹)R^l0,-(CI-C6)alkyl-C(-O)-N(R⁹)R^lü,-(Ci-C6)alkyl-O-C(-O)-N(R⁹)R^IGand -(C|-C6)alkyl-SO2-N(R⁹)R^l0î whereineach R⁹ is independently selected from H, (Cr C6)alkyl and (Cî-C?)cycloalkyl and wherein each R¹⁰ is independently selected from Rⁿ, -(CrC_É)alkyl-R^! *, -SO₂-R¹¹, -C(=O)-R' -C(=0)OR’¹ and *, wherein each

R¹¹ is independently selected from H, (CpCfijalkyl, (C_:-C₆)alkenyl, (C₂-C₆)alkynyl, (CiQjhaloalkyl, (C3-C?)cycloalkyl, aryl, heterocycle and heteroary); and wherein any aryl, heterocycle and heteroaryl of R^la is optionally substituted with one or more Z¹⁰ groups;

R^lb is selected from:

a) -(Ci-Ce)alkyl-0-(CrC6)alkyl-(C3-C7)cafbocycle, -(Ci-CÉ)alkyl-S-(CiCe)alkyl-(C3-C7) carbocycle, -(C₁-C₆)alkyl-S(O)-(C₁-C6)alkvl-(C3-C₇) carbocycle, -(CiC₆)alkyl-S0₂-(C₁-C₆)a[kyl-(C3-C7)carbocycle, -(CrCeW^SOHCrCfiJalkyl-Z¹³, -C(O)(Ci-C6)alkyl-Z¹³, -O-(Ci-C6)alkyl-Z'\ -S-ÎC_L-C₆)alkyl-Zⁿ, -S(O>(CrC6)alkyl-Z¹³, -SO2(Cj-C'ûlalkyl-Z¹³, -(Ct-C6)alkyl-Z¹⁴, -(Ci-CeJalkyl-CCOXCrCeïalkyl-Z¹³, (CrC₆)alkyl0(0)-0((^-C₆)alkyl-Z¹³, -(C^alkylO-ÎCi-Cejalkyl-Z¹³, -(C|-C6)alkyl-S-(Ci-C6)alkylZ¹³, -(C2-C6)alkenyl-(Ci-C^,)haloalkyl, 4C₂-C6)alkynyl<Ci-C₆)haloalkyl, -(C3C7)halocarbocycle,-NR₄SO₂NR_cRi, -NRjSO-O/Cj-Cyjcarbocycle, -NRySCbOaryl, -(C₂-C₆)alkenyl-(C3-C7)carbocycie, -(C+-C₍,)alkenyi-aryL -(C₂-Cé)alkenyl-heteroaryl, -(C₂-C₆)alkenyl-heterocycle, -(C₂-C₆)aikyiiyl-(Cj-C7)carbocycle, -(C₂-C₆)alkynyl-aryl, -(C₂-C6)alkynyl-heteroaryl -(C₂-Ce)alkynyi-heterocycle, -(C3-C₇)carbocycle-Z^l or -halo(Ci-C6)alkyl-Z³, wherein any (Cj-Cfijaikyl, (CpCéjhaloalkyl, (C3-C₇)carbocycle, (C₃C7)halocarbocycle, (C₂-C₆)alkenyl, (C₂-Cfi)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle îs optionally substituted with one or more Z¹ groups, wherein two Z¹groups together with the atom or atoms to which they are attached optionally form a (C3C₇)carbocycle or heterocycle wherein the -(Cj-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups;

392

c) (Ci-G)alkyl, wherein (CpC^alkyl is substituted with one or more Z groups and optionally substituted with one or more Z¹ groups;

d) -X(C_f-C₆)alkyl, -X(Ci-C₆)haloalkyl, -X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C3-C₇)carbocycle, wherein any -X(C]-C6)alkyl and -X(Ci-C6)haloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more

Z¹ groups, and wherein any -X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C₇)carbocycle is substituted with one or more Z⁴groups and optionally substituted with one or more Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and-Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z'groups;

f) (Ci-Côjhaloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl, and (C₂-C₆)alkynyl, wherein (Ci-Cû)haloalkyl, (C₃-C₇)carbocycle, (C₂-G)aikenyl and (C₂-C₆)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more

Z'groups; and

g) -NR& -C(O)NReR_f, -OC(O)NR_<Rf, -SO₂NR_cR_f, -(C₁-C₆)alkyl-NR_cR_f, -(Ci-C'₆)alkylC(O)-NR,R_f, -(Ci-C^aikyl-O CO-NRJkf and -(Ci-C₆)alkyl-SO₂NReR_f; wherein any (C|-C₆)a!kyl, as part of a group, is optionally substituted with one or more Z¹ groups;

R²’ is selected from:

a) H, (G-G)alkyl and -OÎCrC₆)alkyl;

b) (C₂-Ce)alkenyl, (C₂-Cô)alkynyl, (C j -C₆)haloalkyi. (C₃-C₇)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;

c) C(=O)’Rⁿ, -C(-O)-0-R, -S-R¹¹, -S(O)-Rⁿ, -SO2-Rⁿ, -(C|-C6)alkyl-R, -(Cj-Celalkyl-CGOl-R, -(Ci-C₆)alkyl-C(=O)-O-R'-(Ci-Celalkyl-OR”, -ÎCt-Cejalkyl-S-R¹¹, -(CrCâ)alkyl-S(O)-Rⁱ¹ and -(CrC₆)a!kyl-SO₂-R^!!. wherein each R^H is independently selected from H, (G-G)alkyl, (C₂-C₆)alkenyl, (C₂-Cé)alkynyl, (CiG) halo alkyl. (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl. heterocycle and heteroaryl are each optionally substituted with one or more Z^!1 groups;

393

d) -OH, -O(C₂-C₆)alkcnvl. -O(C₂-C₆)aikynyI, -O(Ci-C₆)haloaIkyl, -O(C₃C₇)cycloalkyl, -Oaryl, -Oheterocycle and -Oheteroaryl; and

e) -N(R⁹)R'°, -C(=O)-N(R⁹)R^1ü, -O-C( O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R¹⁰, -(Cr C6)alkyl-N(R⁹)R¹⁰, -(C,-(^)alkyl-C(<>)-N(R⁹)R¹⁰, -(Ci-C6)alkyl-O-C(=O)-N(R⁹)R¹⁰, and -(Ci-C^alkyl-SOrNÎR^R¹⁰, wherein each R⁹ is independently selected from H, (CiC6)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, -(Ci C6)alkyl-R¹¹, -SOî-R¹¹, -C(=O)-Rⁿ, C(=O)OR and -C(=O)N(R⁹)R”, wherein each R¹¹is independently selected from H, (C|-Cs)alkyl, (C2-Cfi)alkenyl, (C2-Cft)alkynyl, (C ₇C6)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

R^2b is selected from:

a) -(CrC₆)alkyl-O-(C, -C₆)alkyl-(C₃-C₇)caibocycle, -(Ci-Ce^kyl-S-ÎCi C_fc)alkyl-(C₃-C₇)carbocycle, -(Ci-C₆)aUcyl-S(O)-(Ci-C6)alkyl-(C₃-C₇)carbocycle_i -(CiC6)alkyl-SO₂-(Ci -C₆)alky 1-(C₃-C₇)carbocycie, -(C₂-C₆)alkenyl-(C i -C₆)haloalky 1, -(C₂Ci)alkynyl-(Ci-C6)haIoalkyl,-(Ci-CéJalkyl-SOi-ÎCi-CéJalkyl-Z¹³, -CfOHCt-C6)alkyl-Z¹³, -O-fCt-Csialkyl-Z¹³, -S-fCrCzJalkyl-Z¹³, -S(OXCi-C6)alkyl-Z¹³, -SOXCrC^alkyl-Z¹³, (C,-Câ)alkyl-Z¹⁴, -(C^Cô^kyl-CfOXCrQXIkyl-Z'³, <C!-Q)alkyl-C(O)-O(Cr C6)alkyl-Z’³, -(Ci-C6)alkyl-O-(Ci-C6)alkyl-Zⁿ, -(Ci-CiJalkyl-S-ÎCj-CeJalkyl-Z¹³, -(C3C^halocarbocyclej-NReSOiNRcRj, -NRaSO2O(C₃-C₇)carbocycle, -NRaSO₂Oaryl, -(C₂-C₆)alkenyi-(C_Î-C₇)carbocycle, -(C₂-C6)alkenyl-aryl, -(C₂-C6)alkenyl-heteroaryl, -(C₂-C6)alkenyl-heterocycle, -(C2-Cô)aîkyny1-(C₃-C₇)carbocycle, -(C₂-C₆)alkynyl-aryl, -(C₂-C6)alkynyl-heteroaryl, -(C₂-C₆)alkynyi-heterocycle, -(C₃-C₇)carbocycle-Z¹ and -halo(Ci-C6)alkyl-Z³, wherein any (Ci-C^Jalkyl, -(Cj-Q, (haloalkyl, (C₃-C₇)carbocycle, (C₃C₇)halocarbocycle, (C₂-Cs)alkenyl, (C₂-Cé)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z'groups;

b) spiro-bicyclic carbocycle, fused-bicyciic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyciic carbocycle »d bridgedbicyclic carbocycle is optionally substituted with one or more Z¹ groups. w Z groups together with the atom or atoms to which they are attached optionalh form a (C₃-C₇)carbocycÎe or heterocycle, wherein the (C₃-C₇(carbocycle or heterocycle is optionally substituted with one or more Z¹ groups;

394

c) (C]-C₆)alkyl, wherein (Ci-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

d) -XCCi-C_é)alkyl, X(C₁-C₆)haloalkyl, X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C₇)carbocycle, wherein any -X(Ci-C₆)alkyl and -X(Ci-C₆)haloalkyl is

5 substituted with one or more Z³ groups and optionally substituted with one or more Z/groups, and wherein any -X(C₂-C₆)alkenyl, -X(C₂-C6)alkynyl and -X(C₃-C₇)carbocycIe is substituted with one or more) Z⁴groups and optionally substituted with one or more Z^lgroups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and —Xheterocycle,

10 wherein any aryl heteroaryl and heterocycle, either aione or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups;

f) (Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-Cé)alkenyl, and (C₂-Cô)alkynyl, wherein (C]-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-Cé)alkenyl and (C₂-Cs)alkynyl are each

15 substituted with one or more Z⁶ groups and optionally substituted with one or more Z'groups; and

g) -NReRf, -C(O)NReRf, -OC(0)NR_cR_}, -SO₂NR_cR_f, -(Ci-Csjalkyl-NR^Rf, -(C'|-C₆)alkylC(O)-M/_<R_f,-(Crt^Jalkyl-O-CXO^-NR^Rfand-(CrCéjalkyl-SO.NReR,, wherein any (C]-C₆)alkyl, as part of a group, optionally substituted with one or more

20 Z¹ groups;

R^3ï is (C]-C₆)aikyl, (C_rC_s)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, -(Ci-Cejalkyl-ÎCi-CvXycloalkyl, -(C|-C6)aikyl-aryl, -(Ci-Cfflalkyl-heterocycle. -(Ci-C₆)alkyl-heteroaryl, -O(C|-C₆)alkyl, -O(C ₁-C₆)haloalkyl_; -O(C₂-C₆)alkenyl, -O(C₂-C₆)alkynyl, -O(C₃-C₇)cycloalkyI. -Oaryl, -O(Ci-C₆)alkyl-(C_rC₇)cycloalky[.

25 -O(C [-C₆)alkyl-aryl, -O(C i-Cô)alkyl-heterocycle or -O(C ι-CDalkyl-heteroaryl, wherein any (Cj-Csjalkyl, (Ci-C_s)haloa]kyl, jaienyi or (C_;-C*)alkynyl of R^ja is optionally substituted with one or more groups selected bw. -OC -C-fâlkyl. halo, oxo and -CN, and wherein any (C₃-C₇)cycloalkyl, aryl, heterOcycîc or heteroary l of R³* is optionally substituted with one or more groups selected from (C_t-C₆)alkyi, -O(C_t-C₆)aIkyl, halo, oxo

30 and-CN; and R^3a is H;

•Ύ

A

395 _R3b is (C₇-C]₄)alkyl, (C₃-C₇)carbocycle, aryl, heteroaryl, heterocycle, -(Ci-C₆)alkylOH, -(CrCôXkyl-O-fCrCôjalkyl-Z¹², -fCrC^alkyl-O-CCz-C^alkeriyl-Z¹², -(C7-Cfi)alkyl-O-(C2-C6)alkynyl-Z¹², -(C,-C6)alkyl-S-(C]-C₆)alkyl-Z¹², -(CrC6)alkyl-S(Cî-Qûalkenyl-Z’², -ÎCrCsJalkyl-S-tCî-CÈjalkynyl-Z¹², -(CrC^aikyl-StOXCr C6)alkyl-Z¹², -(Ct-C6)alkyl-S(O)-(C2-C6)aikenyl-Zⁱ²,-(C;-C₆)alkyl-S(O)-(C₂-

C.,)alkynyl-Z¹², -(C1-C6)alkyl-SO2-(Cl-CÉ)alkyl-Z⁵ⁱ, -(C1-C₆)alkyl-SO₂-(C₂-C_û)alkenyl-Z¹², -(C2-C6)alkyl-SO2-(C2-C6)alkynyl-Z¹², -(CpC^alkyl-NILRb, -(C1-C₆)alky]OC(O)-NR_cR_ii, (C₁-C₆)alkyl-NR_a-C(O)-OR_h, -(Ci-C^alkyi-NK-CiORNR^, -(Ci-C₆)alkyl-SO₂(CiC()a!kyl, -(C_rC₆)a!kyl-SO₂NR_cRd, -(CrQialkyl-NKSO.NRcRd, -(Ci -C₆)alkyI-NRaS€>2O(C3-C7)carbocycle, -(C |-C₆)alkyl-NR_âSO₂Oaryl, <C|-C₆)alkyl-NR_s-SO₂-(CrC6)alkyl,-(CrC^ikyl-NRa-SOj-haXCrCélalkyl, -ÎC₁-C₆)alkyl-NR_e-SO₂-(C2-C6)alkenyl,-(C₁-C6)alkyl-NR_a-SO2-(C2-C₆)alkynyl, -(C| C₆)alkyl-NR_d-S0₂-(C3-C/)€arbocycle, -(C i-C6)alkyl-NRa-SO₂-halo(C3-C7)carbocycle, -(Ci-CfiJalkyl-NRa-SOî-aryl, -(Ct-C₆)alkyi-NR_a-SO₂-heteroaryl,

-(Ci-C₆)alkyl-NRa-SO₂-heterocycle, -O(C7-C_l4)alkyl, -OfCi-C^kyl-NRaRb, -OfCj-CeialkylOCiOJ-NRcRd, -OtCi-CôJaikyl-NRrCiCO-ORb, -O(Ci-C6)alkyI-NR_a-C(O)-NR_ïR,. -O(C₁-C6)alkyl-NR_a-SO₂-(C₁-C₆)alkyl,

-O(C i-C₆)alkyl-NR_e-SO₂-halo(C [-C₆)alkyl, -0(C_rC₆)alkyl-NR₁-S0₂-(C2-C6)alkenyL -0(C₁-Ce)alkyl-NR_e-SO2-(C2-C6)alkynyl, -0(C₁-C₆)alkyl-NR_a-SO₂-(C₃-C₇Karbocycle, -0(C₁-C₆)alkyl-NR_a-S02-halo(C3-C7)carbocycle, -O(C]-C₆)alkyl-NR_d-SO₂-aryI. -CXCi-CsJalkyl-blRe-SOj-heteroaryl, -CXC_l-C₆)alkyi-NR_a-SO₂-heterocycle, -CXCi-Cô^lkyl-NRe-SOï-NR^Rb,-O(Ci-C6)alkyI-NRa-S02-(C3-C7)carbocycle,

-O(C _rC6)alkyl-NRa-SO2-halo(C3-C7)carbocycle, ~O(Ci-C₆)alkyl-NR,-SO₂-aryL -O(CjQJalkyl-NRaSOîNR^Rd, -0(0-C₆)aIkyl-NR_aS0₂0(C₃-C₇)carbocycle, -O(C[-C₆)alkylNRâSOzOaryl, -Oheteroaryl, -Oheterocycle, -Sheteroaryl, -Sheterocycle, -S(O)heteroaryl, -S(O)heterocycle. -SO;heteroaryl or -SO;heterocycle, wherein any (Ci-Cgjalkyl, -(C₇Ch (alky l. ary L carbocy cle. heteroaryl or heterocycle of R^3b. either alone or as part of a group. is optionally substituted with one or more Z¹ groups, and R^îh is H, (Ci-Cô)alkyl or -O(C ] -C_t jalkyk or R^în and R'^b together with the carbon to which they are attached form a heterocycle or (Cj-C-jjcarbocycle which heterocycle or (Cj-C7)carbocycle of R^3b and R^Sb

396 together with the carbon to which they are attached is optionally substituted with one or more Z* groups;

R^4a is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R^4a is optionally substituted with one or more groups each independently selected from halo, (C_rC₆)alkyl, (C₂-C₆)alkenyl, (Ci-Cejhaloalkyl, (C₃-C₇)cycloalkyl, -OH, -O(C]-C6)alkyl, -SH, -S(C_rQ)aIkyl, -NH₂, -NH(C_t-C6)alkyl and -NKCt-Qûalkylh, wherein (Ci-C₆)alkyl is optionally substituted with hydroxy, -O(C_l-CÉ)alkyl, cyano or oxo;

R^4b is selected from:

a) (Ci-Cs)alkyl, (C^-CLJalkenyl and (C₂-C₆)alkynyl, wherein (Ci-Qjalkyl, (C₂-C₆)alkenyl and (C₂-C₆)a!kynyl are each optionally substituted with one or more Z¹groups;

b) (C₃-Ci₄)carba cycle, wherein (C₃-Ci₄)carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocyc]e or heterocycle;

c) spiro-heterocycle and bridged-heterocycle, wherein spiro-heteroeycle and bridged-heterocycle are optionally substituted with one or more Z¹ groups, or wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle; and

d) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedheterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridgedheterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups; or

R⁴ and R³ together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle wherein any macroheterocycle or macrocarbocycle of R⁴ and R³ together with the atoms to whîch they are attached may be optionally substituted with one or more Z¹ groups; and R³ is H, (Cr-CDalkyl or -O(C| C- nlkj-1;

R^ia is selected from:

a) halo, nitro and cyano;

397

b) R¹¹, -QOj-R¹¹, -CH))-O.R, -0-R¹¹, -S-R¹¹,-S(O)-Rⁿ, -SOz-R¹¹, -(Cr Cejalkyl-R¹-(Ci-C6)alkyl-C(=O)-R^ll)-(C]-C6)alkyi-C(=O)-O-R¹¹,-(Ci-C6)alkyl-O-R^,,J -(C!-C₆)alkyl-S-Rⁿ, -(Ci-C6)alkyl-S(O)-R and -<Ci-C6)alkyl-SO2-Rⁿ, wherein each R¹¹îs independently selected from H, (C t-Cyalkyl, (C2-C₆)aikenyl, (C₂-C₆)alkynyl, (Cj-

5 C₆)haloalkyl, (Cj-C-Ocycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹¹ groups; and

c) -N/R^R¹⁰, -Cf-Oj-NfR^R¹⁰, -Ο-Cf-O)-N(R⁹)R^1C, -S€>2-N(R⁹)R¹⁰, -(CiC6)alkyl-N(R⁹)R¹⁰, -(CrC₆)alkyl-C(-O)-N(R⁹)R¹⁰, -(CrCélalkyl-O-Cf-Ol-NCR^R¹³, and -tCi-C6)alkyl-SO2-N(R⁹)R^l<), wherein each R⁹ is independently selected from H, (C;-

10 C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R*^!, -(C i Cfijalkyl-R¹¹, -SO2-Rⁿ, -C(=O)-R^1], -C^OjOR” and -C(O)N(R⁹)R^H, wherein each R¹’ is independently selected from H, (Ci-C&)alkyl, (C₂-Ce)alkenyl, (C₂-C₆)alkynyl, (C₃C_é)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

R⁵¹⁵ is selected from:

15 a) -(Ci-C6)alkyl-O-(Ci-C₆)alkyl-(C₃-C₇)carbocycle,

-(C i -Ce)alkyl-S-(C [ -C₆)alkyl-(C₃-C₇Xarbocycle,

-(C ] -Cé)alky 1S(O)<Ci -C6)aIkyl-(C₃-C₇Xarbocycle,

-(C i-C₆)alkylS0₂(C₁-C₆)alkyl-(Cj-C₇)carbocycie, -(C₂-C₆)alkenyl-(Ci<₆)haloalkyl, -(C₂C_f)alkwnyl-(CVC₆)haloalkyl, -(C₃-C₇)halocarbocycle, -NR_aSO₂NR_cRd, -NRaSOiOfCj20 C₇)carbocycle, -NR»SO₂Oaryl, -(C₂-C6)alkenyl-(C₃-C₇)carbocycle, -(C₂-C6)alkenyl-aryl, -(C₂-C₆)alkenyl-hetcroaryl, -(C₂-C₆)aIkenyl-heterocycle, -(C₂-C6)alkynyl-(C₃-C₇)carbocycle, -fCi-CéJalkynyl-aryl, -(C₂-C₆)alkynyl-heteroaryl. -(C₂-C6)alkynyl-heterocycle, -ÎC₃-C₇)carbocycle-Z^l and -halo(C|-C6)alkyl-Z³, wherein any (CrCéjalkyl, (Cj-C6)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl,

25 heterocycle and heteroaryl, either alone or as part of a group, îs optionally substituted with one or more Z⁵ groups:

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹

30 groups together with the atom or atoms to which they are attached optionally form a (C₃-

398

C₇)carbocycle or heterocycle wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups;

c) (Ci-Cé)aJkyl, wherein (C i-Céjalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

d) -X(C_t-C₆)aIkyl, -X(Ci-C₆)haloalkyl, -X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C₇)carbocycle, wherein any -X(Ci-C₆)alkyl and -X(Ci-Cyhaloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more Z^lgroups, and wherein any -X(C₂-C6)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C₇)carbocycle is substituted with one or more Z⁴ groups and optionally substituted with one or more

Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z'groups;

f) (Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and (C₂-Cô)alkynyl, wherein (C_rC₆)haloalkyl, (C₃-C₇)carbocycle, (Ch-C^alkenyl and (C₂-C₆)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

g) -NRJtf, -C(O)NRJ<f, -OCONR^Rf. -SOjNR^Rf, -(Ci-C^alkyl-NR^Rf-(C_l-Q)alkylC(O)-N^rR_<R_f.-(CrC^alkyl-O-CCOENRJtfand -(Ci-C_fi)alkyi-SO_;NR<.Rf, wherein any (Cj-Càjalkyl, as part of a group, is optionally substituted with one or more Z¹ groups;

R^6a is selected from:

a) H, halo, (C_rC₆)alkyl and (Ci-C₆)haloalkyl

b) (Cî-Cejalkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O)-R,-C(=O)-O-R O-R¹-S-R¹¹,-S(O)-R^U,-SO2-R^h, -(Ci-Célalkyl-R¹¹, -(CrC₆)alkyl-C(=O)-R¹¹. -(CrCJalkyl-Ci-Of-O-R¹ -(Ci-Qlalkyl-OR¹¹.-iCt-C^jalkyl-S-R¹¹,-(Ci-Ci.Jalkyl-StOER¹¹ and -(C^-C6)alkyl-SO2-R^,,. whereineach

399

R ¹ is independently selected from H, (Ci-C_É)alkyl, (C₂-C₆)alkenyL (C₂-C₆)alkynyl, (C,C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R^!Ü, -C(=O)-N(R⁹)Rⁱ⁰, -O-C(=O)-N(R⁹)R¹⁰, -SO2-\(R⁹)Rⁱ⁰, -(Ci-C6)alkyl-N(R⁹)R¹⁰, -(C,-C6)a!kyl-C(=O)-N(R⁹)R¹⁰, (CrC₆)alkyl-O-C(-O)-N(R⁹)R¹⁰and -(Cj-C6)alkyl-SO2-N(R⁹)Rⁱ⁰i wherein each R⁹ is independently selected from H, (CiC6)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, -(C>Cfijalkyl-R¹¹, -SO2-R^I!, -C( O)-R¹¹, -C(=0)ORⁿ and -C(=O)N(R⁹)Rⁿ, wherein each Rⁿis independently selected from H, (Ci-Cô)alkyl, (C2-C₆)alkenyl, (C₂-C6)alkynyl, (C_rC₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

and wherein any aryl, heterocycle and heteroaryl of R⁶® is optionally substituted with one or more Z¹⁰ groups;

R^€b is selected from:

a) -(C|-C₆)alkyl-0-(Ci-C_t)alkyl-(C3-C_/)carbocycle_> -(Ci-Ce)alkyl-S-(CiC₆)alkyl-(C3-C7)carbocycle, -(C_Î-k₆)alkyl-S(O)-(C₁-C₆)alkyl-(C3-C7)carbocycle, -(C_tC(,)alkyI-SO₂-(C|-C6)alky[--(C3-C₇)carbocycle. -(C₂-C₆)alkenyl-(Ci-C6)haloalkyl, -(C₂C₆)alkynyl-(Ci-C6)haloalkyl, -halo(C_î-C₇)carbocycle,-NR_aSO₂NR_€R₄i, -NRaSO₂O(C₃C₇)carbocycle, -NR₂SO₂Oaryl, -fC₂-C₆)alkenyl-(C3-C₇)carbocycle, -(C₂-C₆)alkcnyl-aryl, -(C₂-C6)alkenyI-heteroaryl, -(C₂-(%)alkeny]-heterocycle, -(C₂-C6)alkynyl-(C₃-C₇Xarbocycle,-fC₂-Cfi)alkynyl-aryl, -{C₂-C<;)alkynyl-heteroaryI, -(C₂-Cfi)alkynyl-heterocycle, -(C₂-C_s)alkynyl-OR_fi, -(C₂-Cô)alkyl-(C3-C₂)carb<)cycle-OR_a. -(Ck-C 'jcarbocycle-Z¹ and -halo(Ci-Cf,(alkyl-Z¹, wherein any (G C'6)alkyi, (Cj-Cg(haloalkyl, (C₃-C₇)carbocycle, (CrCôJalkenyl, (C₂-Ce)a]kynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle. wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle is optionally substituted with one or moTe Z¹ groups, wherein two Z groups together with the atom or atoms to which they are attached optionally form a (Cj-C₇(carbocycle or heterocycle, wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups;

V¹ 399

R¹¹ is independently selected from H, (Ci-C_e)alkyl, (C2-C₆)alkenyl, (C₂-C₆)alkynyl, (CjCe)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) -N(R⁹)R'k -C(- -O)-N(R⁹)Rⁱ⁰, -O-C(=O)-N(R⁹)R^lc, -SO2-N(R⁹)R’⁰, -(C,-C6)aikyl-N(R⁹)R'°_;-(C| -C₆)alkyl-C(=O)-N(R⁹)R'°, (CpCj^lkyl-O-C^O)-N(R⁹)R¹⁰

5 and -(CYCf,)alkyl-SO₂-N(R⁹)R^!0, whereineach R⁹ is independently selected from H, (CiCÉ)alkyl and (C3-C7)cycloalkyl, and each R^wis independently selected from Rⁿ, -(Cr Cejalkyl-R¹ ', -SO2-R' *, -C(=O)-R' -C(=O)ORⁿ and -C(H3)N(R⁹)R^H, wherein each R¹¹îs independently selected from H, (Ci-Ci)alkyl, (C2-C6>alkenyl, (C₂-C6)alkynyl, (CiC₆)haloalkyi, (C3-C?)cycloalkyl, aryl, heterocycle and heteroaryl;

10 and wherein any aryl, heterocycle and heteroaryl of R⁶® is optionally substituted with one or more Z^IQ groups;

R^éb is selected from:

a) -(C_rC₆)alkyl-O-(C₁-C₆)alkyl-(C3-C7)carbocycle, -(Ci-C6)alkyl-S-(CiCs)alkyl-(C3-C7)carbocycle, -(Ci-C6)alkyl-S(O)-(Ci-C6)alkyl-<C3-C₇)carbocycle, <Ci15 C₆)alkyl-SO2-(Ci-Cé)alkyl-(C3-C₇)carbocycle, -(C₂-C6)alkenyl-(Ci-C₆)haloalkyl, -(C₂C₆)alkynyl-CC|-C₆)baloalkyl, -halo(C₃-C₇)carbocycle,-NR_aS02NR_cR_<i, -NRaSO^O/C^C₇)carbocycle, -NR_sSO₂Oaryl, -(C₂-C6)alkeny]-(C3-C₇karbocyc]e, -(C₂-C6)aIkcnyl-aryl, -CC2-C₆)alkenyl-heteroaryl, -(C₂-C₆)alkenyl-heterocycle, -(C₂-C₆)alkynyl-(C3-C₇)carbocycle, -(C₂-C6)alkynyl-aryl, -(Cj-Qlalkynyl-heteroaryl,

20 -((XQîalkynyl -heterocycle, -(CE-C^alkynyl-OR,,, -(C₂-C₀)alkyl-ÎC j-C^)carbocycle-OR*. -(Ci-Cvkaibocycle-Z¹ and -haio(C_rC₆)alkyl-Z\ wherein any (Ci-C₆)alkyl, (Ci-Cfi)haloalkyl, (C3-C₇)carbocycle, (C₂-C6)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z'groups;

25 b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclk carbocycle and bndgedbicyclic carbocycle is optionally substituted with one or more 7 greurs. wherein two Z' groups together with the atom or atoms to which they are aitached opuonally form a (CrC₇)carbocycIe or heterocycle, wherein the (Cj-C₇)carbocycie or heterocycle is

30 optionally substituted with one or more Z¹ groups;

400

c) (C|-C₍,)alkyl, wherein (C’i-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

d) -X(C_t -C₆)alky 1, -X(C j -C₆)haloalky 1, -X(C₂-C₆)alkenyI, -X(C₂-C₆)aIkynyl and -XtCj-CîXarbocycle, wherein any -X(C|-C₆)alkyl and -X(Ci -C_t])haloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more

Z¹ groups, and wherein any -X(C2~C_é)a!kenyl, -X(C₂-C₆)alkynyl and -X(C₃-C7)carbocycle is substituted with one or more Z⁴groups and optionally substituted with one or more Z'groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and —Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z’groups;

f) (Ci-C₆)haloalkyl, (C₃-C7)carbocycle, (C₂-Cé)alkenyl, and (C₂-C6)alkynyl, wherein (C’rCéihaloalkyl, CCrC₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and

g) -NReRr, -C(O)NReR_f, -OC(0)NR,Rf, -SChNRRf, -(C₁-C₆)alkyl-NR_cR_f, <C_rC₆)alkylC(O)-NReRf, -(CrC^alkyl-O-C/OENR^Rf and -(C₁-C₆)alkyl-SO2NR_eRf, wherein any (Ci-C^alkyl, as part of a group, is optionally substituted with one or more Z’groups;

R^7a is selected from:

a) H, halo, (Ci-CéJalkyl and (Ci-Ce)haloalkyl;

b) (Cî-Cgfalkenyl, (C₂-C₆)alkynyl. (C₃-C7)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;

c) -C(=O)-R”, -C(=O)-O-R. -O-R¹', -S-R¹', -S(O)-R”, -SO2-Rⁿ, -(Ci-C6)alkyl-R^,!, -<Cj-C6)alkyM?: O+R”. 4C;-C6)alkyl-C(=O)-O-R, -(Ci-C6)alkyl-OR¹’, -(CpCAalk)! S-R' . (C -C-a^yi-S-O+R'¹ and -(Ci-CôJalkyl-SOs-R’¹. whereineach R¹¹ is independently selected from H. (Ci-Cé.alkyl. (C2-C6)alkenyl, (Cr-Celalkynyl, (CjC_fe)haioalkyl, (C₃-C₇)cycioalkyl. aryl, heterocycle and heteroaryl; and

401

d) -N(R⁹)R'°, -C( O)-N(R^r?)R^lü, -O-C(=O)-N(R⁹)R^lû, -SO2-N(R⁹)R¹³, -(CrCMalkyl-N(R⁹)R¹⁰. -(Cr(4)alkyl-C(-O)-N(R⁹)R¹⁰,-(CrC6)dlkyl-O-C(-O)-N(R⁹)R¹⁰and -(Ci-C6)alkyI-SO2-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (CjC6)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰is independently selected from Rⁿ,-(Ci-

5 Cjalkyl-R¹ -SOz-R¹ \ -C(=O)-Rⁿ, -C(=O)OR'¹ and -C(=O)N(R⁹)R¹ wherein each R¹¹is independently selected from H, (C_rC₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C;C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle and heteroaryl of R^7a is optionally substituted with one or more Z¹⁰ groups;

10 R⁷¹¹ is selected from:

a) -(CrQ.ialkyi-SO^Ci-CMalkyl-Z¹¹, -C(OXCi-C6)alkyl-Z¹³, -O-(CiC$)alkyl-Z¹³, -S-fCj-CdJalkyl-Z¹³, -S(OXCrC_b)alkyl-Zⁿ, -SO2-(C1-C6)alkyI-Zⁱ³, -(Ci-C6)alkyi-Z¹⁴, -(Ci-C6)alkyl-C(O)-(C1-C6)alkyl-Z^,\ -(CrC₆)alkyl-CCO>O(CiC₆)alkyl-Z¹³, -(Ci-QlalkykO-CCcUialkyl-Z¹³, -(Ci-Ceialkyl-S-CCrC^iaikyl-Z¹³, -(C_r

15 C₆)alkyl-O-(C_rC_i)alkyl-(C_î-C7>carbocycle₎ -(C_rC₆)alkyI-S-(Ci C₆)alkyl-(C₃-C₇)carbocycle, -(C, -C_b)alky l-S(O)-(C j -C6)alkyl-(C₃-C₇)carbocycle, -(C i Cé)alkyl-S02-(CrC6)alky]-(C3-C7)carbocycie, -(C₂-C₆)alkeriyl-(C j -C6)haloalkyl, -(C₂C₆)alkynyl-(C_rCé)haloalkyl, -(C₃-C₇)halocarbocycle, -NRaSOîNRJLj, -NRaSO₂O(C₃C₇)carbocycle, -NRaSO₂Oaryl, -(C2-C6)alkenyl-(C₃-C7)carbocycle, -(Cj-C^falkenyl-ary l,

20 -(C2-C6)alkenyl-heteroaryl, -(C₂-C6)alkenyl-heterocycle, -(C2-C₆)alkyny1-(C'3-C₇)carbocycle, -{C₂-C_b)alkynyi-aryl, -(Cî-C^alkynyl-heteroaryi, -(C₂-C6)aIkynyl-heterocycle, -(C₃“C₇)carbocycle-Z¹ and -halo(Ci-C6)alkyl-Z³ , wherein any (Ci-C6)alkyl, (Ci-C^haloalkyl, (C₃-C₇)carbocycle, -(C₃-C₇)halocarbocycle, (C₂-Ce)alkenyl, (C₂-C6)alkynyJ, aryl, heterocycle and heteroaryl, either alone or as part of a

25 group, is optionally substituted with one or more Z^! groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic ca_—*<ycie. wherein any spiro-bicyclic carbocycle. fused-bicyclic carbocycle and bridgedbicycix carbocycle is optionally substituted with one or more Z^] groups. wherein rwo Z groups together with the atom or atoms to which they are attached optionally form a

402 (C₃-C₇)carbocycle or heterocycle wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups;

c) (Ci-C₆)alkyl, wherein (Ci-CsJaJkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

d) -X(C]-C₆)alkyl, X(C_rC₆)haloalkyl, X(C₂-C₆)alkenyl, -X(C₂-C₆)aIkynyl and -X(Cj-C₇)carbocycle, wherein any -X(CrC₆)alkyl and -X(Ci-C₆)haloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more

Z¹ groups, and wherein any -X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(C₃-C₇)carbocycle îs substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹ groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaiyl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, îs substituted with one or more Z⁵ groups and optionally substituted with one or more Z’groups;

f) (Ci-Cejhaloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C₆)alkynyl, wherein (C]-C_f.)haloalkyl, (C₃~C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C6)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more

Z¹ groups; and

g) -NR<-R_f, -C(O)NReR_f, -OC(O)NR_cRf, -SO₂NR_fR_f, -(Ci-C^alkyl-NReRf, -(CrCfi^lkylCCOj-NReRf, -(Ci-C₆)alkyl-O-C(O>NKR_f and -(Ci-C₆)alkyl-SO₂NR<R_f. wherein any (C_rC₆)alkyi, as part of a group, is optionally substituted with one or more Z’groups;

R⁸¹ is selected from:

a) halo, nitro and cyano;

b) R¹¹, -CC’OyR¹¹, -C(-O)-0-R, -O-R, -S-R¹¹, -StOj-R¹¹, -SCVR¹', -(CjCe)alkyi-R, -(CT-Qjaikyl-('(=O)-R·', -(C^Jalkyl^OFO-R¹', -(C-CJalkyl-O-R¹¹, -(CiX^jalkyRS-R¹¹, -(CrC₆)alkyl-S(O)-R^N and -(€i-Cb)alkykSO.-R¹¹, wherein each R¹¹is independently selected from H, (Ci-Csialkyi, (C2-C₆)alkenyL (C;-C6)alkynyl, (C_tC«)haloalkyl. (C₃-C₇)cycloalkyl, aryl heterocycle and heteroaryl, wherein ary l, heterocycle and heteroaryl are each optionally substituted with one or more Z¹ groups; and

403

c) -N(R⁹)Rⁱ⁰, -Ct’OJ-NiR^R¹⁰, -O-6(=O)-N(R⁹)R¹⁰, -SO2-N(R⁹)R¹⁰, -(Ci66)alkyI-N(R⁹)R^lû, -(C1-C₆)alkyl-C(=O)-N(R⁹)R¹⁰, -(Ci-C6)alkyl-O-C(=O)-N(R⁹)R¹⁰ and -(C]-C6)alkyl-SO2-N(R⁹)R^t0, wherein each R⁹ is independently selected from H, (6tCg)alkyl and (C₇-C₇)cycloalkyi, and each R¹⁰is independently selected from Rⁿ,-(CtCûjalkyl-R¹', -SO^R¹¹, -C(-O)-Rⁿ, -C(=O)ORⁿ and -6(=O)N(R⁹)R^H, wherein each R^uis independently selected from H, (C|-Ce)alkyl, (C7-C₆)alkenyl, (C₂-C6)alkynyl, (Cr C6)haloalkyl, (Cî-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

R*^b is selected from:

a) -(CrQjalkyl-SOHCj-CôJalkyl-Z¹³, -C(O)-(C1-C6)alkyl-/¹³, -0<Cr

C_fc)alkyl-Z^!\ -S-CCrC6)aIkyl-Z¹³, -SfOXCrC^alkyl-Z¹³, -SO2-(C_rC₆)alkyl-Z¹³, -(Cj-Côlalkyl-Z¹⁴, -(Ci-C₆)alkyl-C(O)-O(Cr

C₆)alkyl-Z¹³, -(Ci-C^alkyl-iHC.-C^dkyl-Z¹⁵, -(Ci-Celalkyl-S^Ci-Qjalkyl-Z¹³, -(CiCùjalkyl-O-fCj-CôJalkyKCj-C^carijocycie, -(C1-C6)alkyl-S-(C1 C6)alkyl-(C3-C7)carbocycle, -<C|-C6)aikyl-S(O)-(Ct-C6)alkyl-(C3-C7)carbocycle, -(CiC6)alkyl-SO2-(C] -C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(C i -C^haloalkyl, -(C2C6)alkynyl-(Ci-C6)haloalkyl, -halo(C3-C7)carbocycle,-NRaSO2NRÎR<j, NRaSChOiCs-CiJcarbocycle, -NR^SO-Oaryl, -(C2-C6)alkenyI-(C3-C7)carbocycle, -(C2'C6)alkenyI-aryl, -(C2-C6)alkenyl-heteroaryl, -(62-C6)alkenyl-heterocycle, -(C2-Cfi)alkynyl-(C3-C7)carbocycle, -(67-6(,)alkynyl-aryl,-(CF^'ôfalkynyl-hctcroaryl. -(Cj-Csialkynyl-heterocycle, -(C3-C7)carbocycle-Z^! and -halo(C]-C5)alkyl-Z³, wherein any (Cj-C₆)alkyl, (C]-C₆)haloalkyl, (C3-C7)carbocycle, (C2-C₆)alkenyl, (C₂-C₅)alkynyl, aryl, heterocycle or heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups:

b) spîro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spîro-bicyclic carbocycle, fused-bicyclic carbocycle and bridgedbicyclic carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹groups together with the atom or atoms to which they are attached optionally form a (Cj-6₇)carbocycle or heterocycle wherein the (63-C₇)carbocycle or heterocycle is optionally substituted with one or more Z‘ groups:

404

c) (Cj-C₆)aJkyl, wherein (Ci-C&)alkyl is substituted with one or more Z²groups and optionally substituted with one or more /'groups;

d) -X(C i -C₆)alkyl, -X(C i -Céjhaloalky 1, -X(C₂-C₆)alkenyl, -X(C₂-C₆)alkynyl and -X(Cj-C₇)carbocycle, wherein any -X(Ci-C₆)alkyl and -X(C_rC6)haloalkyl is

5 substituted with one or more Z³ groups and optionally substituted with one or more Z’groups, and wherein any -X(C₂-C₆)alkenyl, -X(C₂-C6)alkynyl and -X(C₃-C₇)carbocycle is substituted with one or more Z⁺groups and optionally substituted with one or more Z’groups;

e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle,

10 wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is independently substituted with one or more Z⁵ groups and optionally substituted with one or more Z’groups;

f) (C[-C₆)haloalkyl, (C₃-C₇)carbocycic, (C₂-C₆)alkenyl and (C₂-C6)alkynyl, wherein (Ci-C6)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each

15 independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z’groups; and

g) -NR^Rf, -C(O)NR<R·, -OC(0)NR<Rf, -SO₂NR<R_f, -(C₁-C₆)aIkyl-NR_;R_f, -(C'i-Q)alky[C(O)-NRJ<_f, -(C_l-C₆)alkyi-O-C(O)-NR_vR_f and -(CrC^alkyl-SChNReRf, wherein any (C_t-Cb)alkyl, as part of a group, is optionally substituted with one or more

20 Z’groups;

or any of R^Sa and R^6a, R⁶³ and R^7a, R⁷ⁱ and R^8a, R¹ and R^s or R¹ and R² together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5,6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or 7membered heterocycle is optionally substituted with one or more substituents each

25 independently selected from halo, (C i-CDalkyL (C₂-C₆)àlkenyl, (Ct-C₆)haloalkyl, (C₃C₇)cycloalkyL -OH, -O(Ci-C₆)alkyl, -SH, -S(C|-C₆)alkyl, -NH₂, -NHiCi-C^alkyl and -N((Ci-C₆)alkyl)₂;

or any of R and R⁶. R⁶ and R ' or R⁷ and R⁸, together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle,

30 wherein the 5 or 6-membered carbocycle or a 4. 5, 6 or 7-mcmbered heterocycle are each

405 independently substituted with one or more Z⁷ or Z⁸ groups, wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionally form a (C₃-C₇)carbocycle or 4,5 or 6-membered heterocycle;

or R¹ and R⁸ or R¹ and R² together with the atoms to which they are attached form a

5 or 6-membered carbocycle or a 4,5,6 or 7-membered heterocycle, wherein the 5 or 6membered carbocycle or a 4,5,6 or 7-membered heterocycle are each independently substituted with one or more Z⁷ or Z⁸ groups; wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionally form a (CvC₇)carbocycle or 4,5 or 6-membered heterocycle;

X is independently selected from O, -C(O)-, -C(O)O-, -S-, -S(O)-, -SO₂-, -(C_rCg)alkylO-, -(C,-C₆)alkylC(O)-, -(C]-C₆)alkylC(O)O-, -fC_rC₆)aIkylS-, -(C]-C₆)alkylS(O)and -(C_rC6jalkylSO₂-;

each Z¹ is independently selected from halo, -NO₂, -OH, =NORa, -SH, -CN, (Cj CfOalkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, (Ci-Cejhaloalkyl, (C₃-C₇)carbocycle, (C₃C₇)halocarbocycle, aryl, heteroaryl, heterocycle, -O(Ci-C₆)alky], -O(C₂-C_ft)alkenyl, -O(C₂Cejalkynyl, -O(Cj-C6)haloalkyl, -O(C₃-C₇)carbocycIe, -O(C₃-C₇)halocarbocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -S(C|-(T)alkyl, -S(C₂-C₆)alkenyl. -S(C₂-C₆)alkynyl, -S(C]C₆)haloalkyl, -S(C₃-C₇)carbocycle, -S(C3-C₇)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle, -S(OXC₍-C₆)alkyl, -S(O)(C_rC₆)alkenyl. -S(OXC₂-C₆)alkynyl, -S(O)(C_rCi)haloalkyl, -S(O) (C₃-C₇)carbocycle, -S(OXC₃-C₇)halocarbocycle, -SOXCj-Cfijalkyl, -S(O)aryl, -S(O)carbocycle, -S(0)heteroaiyl, -S(O)heterocycle, -SO₂(C₂-C₆)aikenyl, -SO₂(C₂-C6)alkynyl, -SO₂(Ci-Cô)haloalkyl, -SO₂(C₃-C₇)carbocycle, -SOXC₃C₇)halocarbocycle, -SO₂aryl, -SO₂heteroaryi, -SO₂hetercKycle, -SO₂NR_€Rj, -NR^Rj, -\R_aC(O)Ra, -NR_aC(O)OR_a, -NRaCfOjNRtRj -NR^SO.R^ -NR_aSO₂NR_cRd_I-NR_aSO_:0(C;-C₇karbocycle, -NR_aSO_?Oanl, -OS(O)₂R,. -C(O)R_a, -C(O)OR_h. -C(O)NRcR<i, and -OC(())NR_vRj, wherein any (C|-C₆)alkyl, -(Ci-C₆)haloalky'. C₂Cô)alkenyl, (C₂-C5)alkynyl, (C}-C₇)halocarbocycle, (Ci-C/Xarbocycle. aryl. hete^wy ind heterocycle of Z', either alone or as part of a group, is optionally substituted with one or more halogen. -OH. -OR_b, -CN, -NR/?(O};Rb. -heteroaryl, -heterocycle. -Oheteroaryl. Oheterocycle. -NHheteroary l. -NHheterocycle, or -S(()kN'R_<R,_:.

406 each Z² is independently selected from -N()₂, -CN, spiro- heterocycle, bridgeheterocycle, spîro-bicyclic carbocycle, bridged-bicyclic carbocycle, NRaSO2(C₃C?)carbocycle, -NRaSO₂aryl, -NR^SOzheteroaryl, -NR_aSO₂NR_cR_d, -NR_aSO₂O(C-iC’₇)carb<>cycle and -NRaSOïOaryl;

each Z³ is independently selected from -NO2, -CN, -OH, oxo, =NORe, thioxo, -aryl, -heterocycle, -heteroaryl, -(Cî-C₇)halocarbocycle, -O(Cj-C6)alkyl, -O(C3-C₇)carbocycle, -Ohalo(C₃-C₇)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(C_rC₆)alkyl, -S(C₂C₇)carbocycle, -S(C₃-C₇)halocarbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(OXCiCé)alkyl, -S(O)(C₃-C₇)carbocycie, -S(O) (Cî-C₇)halocarbocycle, -S(O)aryl, S(O)heterocycle, -S(O)heteroaryl, -SO₂(C_rC_fc)alkyl, -SO₂(C₃-C₇)carbocycle, -SO2(C₃C₇)halocarbocycle, SO₂aryl, -SO₂heterocycle, -SO₂heteroaryl, -NRaRb, -NR_aC(O)R_d, -C(O)NR_cRd-, -SOiNRJtd, -NR^SO^RJLj, -NRaSG₂0(C3-C₇)carbocycle and -NR₃SO₂Oaryl;

each Z⁴ is îndependently selected from halogen, (Ci-Ce)alkyl, (C₃-C₇)carbocycle, halo(Ci-C6)alkyI, -NO₂, -CN, -OH, oxo, =NORe, thioxo, -aryl, -heterocycle, -heteroaryl, (Cî-C₇)halocarbocycle, -O(C]-C6)alkyl, -0(C₃-C₇)carbocycle, -0(C₃-C₇)halocarbocycle, Oaryl, -Oheterocycle, -Oheteroaryl, -S(Ci-C6)alkyl, -S(C₃-C₇)carbocycle, -S(C₃C₇)halocarbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(O)(C]-C6)alkyl, -S(OXC₃C₇Xarbocycle, -S(O)(C₃-C₇)halocarbocycle, -S(O)aryl, -S(O)heterocycle, -S(O)heteroaryl, -SO;(Ci-Cft)alkyl, -S0₂(C₃-C₇)carbocycle,-S0₂(C3-C₇)halocarbocycle, SO₂aryl, -SO₂heterocycle, -SO₂heteroaryl, -NR^R^, -NRaC(O)Ra, -CiOJNRcRa, -SO₂NR_€R_d, -NRaSO-NRJLd, -NRaSOîOfCj-CiJcarbocycle and -NRaSO₂Oaryl, each Z⁵ is independently selected from -NO₂, -CN, -NR_aSO₂NR_<R_d, -NR_aSO₂O(C iC₇)carbocycle, -NRaSO₂Oaryl, -NR_aSO₂(Ci-C6)alkyi, -NR_aSO2(C₂-C₆)alkenyl, -NRaSOïiCs-Ckialkynyl, -NRaSO^fCrCiXarbocycte. -NR_aSO2(C3-C₇)halocarbocycle, -NRiSO.aryl, -NRaSO-beteroaryl. -NRjSCbhereroar.;. -NR,SO:’neterocycle, -NRaC(O)alkyi, -NR_aC(O)alkenyl, -NRjCiOialky-’yi ’C ;-C-)carbocycle.

-NRaCiOXCj-Cîlhalocarbocycle, -NR,C(O)ary k -NRjCtOjheteroaryk -NRaCiOlheterocycle. NRaCiOiNRcRc andNR_iOO)OR,.

407 each Z⁶ is independently selected from -NO2, -CN, -NR_aR_a. -NRaC/OJRb, -NRaC(O)ORb, -C(O)NRcRa, -(C3-C₇)halocarbocycle, -aryl, -heteroaryl, -heterocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -0(C3-C₇)halocarbocycle, -O(C]-Ce)alkyl, -O(C₃C₇)carbocycle, -Ohalo(C]-C₆)alkyl, -Saryl, -Sheteroaryl, -Sheterocycle, -S(C₃C₇)halocarbocycle, -S(Ci-C₆)alkyl, -S(C3-C₇)carbocycle, -S(Ci-C6)haloalkyl, -S(O)aryl, -S(0)heteroaryl, -S(O)heterocycle, -S(0)(C₃-C₇)halocarbocycle_; -S(O)(C_;-C₆)aikyL -S(OXC₃-C₇)carbocycIe, -S(O)halo(C]-C6)alkyi, -SO₂arvl, -SO₂heteroaryl, -SO₂heterocycle, -SO₂(Ci-Cfi)alkyl, -SO₂halo(Ci-Cé)alkyl, -S0₂(C₃-C₇)carbocycle, -SO₂(C₃-C₇)halocarbocycle, -SO₂NR_cR_<i, -NR_aSO₂(C₃-C₇)lialocarbocycle, -NRaSO₂aryl, -NRaSO₂heteroaryl, -NRaSO₂heteroaryl, -NR_aSO₂NR_<:R_<J, -NR_aSO₂O(C3-C₇)carbocycle and -NRaSO₂Oaryl;

each Z⁷ is independently selected from -NO7, =NORa, -CN, -(Ci-Cô'Jalkyl-Z¹², -(C2C₆)alkenyl-Z¹², -(C2-C6)alkcnylOH, <C2-C6)alkynyl-Zⁱ², -(C2-C₆)alkynyl-OH. -(C_:C₆)haloalkyl-Z¹², -(Ci-CejhaloalkylOH, -(C3-C7)carbocycle-Z¹², -(C3-C₇)cafbocycieOH, XC₃-C₇)halocarbocycle_} -(Ci-CûjalkylNRcRd, -(Ci-CéjalkylNRaCfOjRa, (C _rC_A)alkyINR_aSO₂R_ft, aryl, heteroaryl, heterocycle, -O(Cj-C&)alkyl-Z¹², -O(C2-C6)alkenyl, -O(C2-C6)alkynyl, -O(Ci-C6)haloalkyl, -O(C3-C7)carbocycle, -O(C3-C7)halocarbocycle, -Oaryl, -(XC.k-C/JalkylNKR.!, -OÎCj-CéJalkylNTUCÎOiR,, -O(C1-C6)alkylNRaSO2Ra! -Oheteroaryl, -Oheterocycle, -S(Cj-C6)alkyI-Z’², -S(C2-C₆)aIkenyl, -S(C₂-C₆)alkynyl, -S(Ci-C₆)haloalkyl, -SfC₃-C₇)carbocycle, -S(C3-C₇)halocarbocycle, -S(C₁-C_il)alkylNR_<R^, -StÇi-CùjalkylNRaQOjRa, -S(Cj-C₆)alkylNR_aS()2R_a, -Saryl, -Sheteroaryl, -Sheterocycle, -S(OXC₍-C₆)alkyl, -S(OXC₂-C₆)alkenyl, -S(O)(C₂-C6)alkynyl, -S(O)(C)-C₆)haloalkyl, -S(OXC₃-C₇)carbocycle, -S(OXC₃-C₇)halocarbocycle, -SOXCi-C^alkyl, -S(O)(CjC^alkylNRcRd, -S(OXC_rC₆)a!kvtNR_aC(O)R_a, S(OXC_rC₆)alkylNR^SO₂R_a<--S(O)aryl. -S(O)heteroaryl, -S(O)heterocycle, -SOXCrCsjalkyl, -SO₂(C₂-C₆)alkenyl, -SO₂(C₂C_t)alkynyL -^(),( ^4 621031^+. -SO;(C₃-C₇)carbocycle, -S0₂(C₃-C7)halocarbocycle. -SO₂aryl. -SO:heie-v.<r>.. -^O₂beteTocycle, -SOXCi-C^jalkylNRcR^. -S0₂(C|C₆)a!ky!NR»C(O1R». -><><( ,-C-ialkylXR,SO-R..-SOAR^R.;. -NR/XOjOR^ -NRsCiOtNRcIC -NRjSO^fL.. -NR^SOzNRçRj. -NRaS0₂O(C₃-C7)carbocycle.

-NRaSO;OaryL -OSîO^Rj. -CiOlNRçRi, and -OCCOlNRcRe. wherein any (C]-C_e)alkyL

408 (C_rC₆)haloalkyl· (C2-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle, (C₃C₇)halocarbocycle, aryl, heteroaryl and heterocycle of Z⁷, either alone or as part of a group, is optionally substituted with one or more halogen, -OH, -ORt>, -CN, -NR_eC(O)2Ri>, heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -SiOhNKR,;

each Z^g is independently selected from -NO2 and -CN;

each Z⁹ is independently selected from -(C]-C₆)alkyl and -OfCi-Cgjalkyl;

each Z¹⁰ is independently selected from:

i) halo, oxo, thioxo, (C₂-C₆)alkenyl, (Ci-C₆)haloalkyl, (C₃-

C₇)cycloalkyl, (C₃-C₇)cycloalkyl-(C|-C₆)alkyl-, -OH, -O(C|C₆)aJkyl. -O(Ci-C6)haloalkyl, -SH,-S(Ci-C₆)alkyl, -SOtCr C₆)alkyl, -SOifCrCsjalkyl, -NH₂, -NH(Ci-C₆)alkyl and -N((C_t-C₆)alkyl)2;

ii) (C_rC₆)alkyl optionally substituted with -OH, -O-(CiCôjhaloalkyl or -O-^CrC^alkyl; and iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle and heteroaryl is optionally substituted with halo, (Ci-C₆)alkyl or COOH;

each Zⁿ is independently selected from Z¹⁰, -C(=O)-NH2, -C(=O)-NH(CrC4)alkyl, -C(=O)-N((Cj-C4)alkyl)2, -C(^_ O)-aryl, -C(=O)-heterocycle and -C(=O)-heteroaryl;

each Z¹² is independently selected from -NO₂, =N0Ra, thioxo, aryl, heterocycle, heteroaryl, (C₃-C7)halocarbocycle, (C₃-C₇)carbocycie, -O(C₃-C7)carbocycle, -Ohaio(C₃C₇)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(C|-C6)alkyl, -S(C₃-C₇)carbocycle, -Shalo(C₃-C₇)carbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(OXCi-C₆)alkyl, -S(O)(C₃-C₇)carbocycle, -S(O)halo(C₃-C₇)carbocycle, -S(O)aryl, -S(O)heterocycle, -S(O)heteroaryl, -SO₂(C_rC6)alkyl. -SO2(C₃-C₇)carbocycle, -S0₂(C₃-C7)halocarbocyc)e, SO₂anl. -SO₂heterocycle. -SO₂ heteroaryl,-NR^Ri, -NRaC(O)R_b. -C(O)NR;R4. SC+NFCRi. -NR^SCENRJLj. -NR^SCEOfCrCvlcarbocycle and -NR^SCEOan,L each Z'³ is independently selected from -NO₂, -OH. =NOR_a. -SH, -CN. (C·,C^)halocarbocycle, -OtCi-Cxlalkyl. -O(C₂-O)alkenyl, -0(C₂-Oialkynyl, -0(0C\)haloalkyl. -CKCi-CSkarbocycle. -O(C;-C₇)halocarbocvcle. -Oaryl. -Oheteroaryl.

409

-Oheterocycle, -S(Ci-C₆)alkyl, -S(C₂-C6)alkenyl, -S(C₂-C6)alkynyl, -S(C|-C₆)haloaJkyl, -S(C)-C7)carbo cycle, -S(C₃-C7)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycie, -S(OXC_t-C₆)alkyl_f -S(O)(C,-C₆)alkenyI, -S(O)(C₂-C₆)alkynyl, -S(O)(C_rC₆)haloalkyl, -S(OXC₃-C₇)carbocycle, -S(OXC3-C₇)halocarbocycle, -S(O)aryl, -S(O)heteroaryl, -S(O)heterocycle, -SO₂(C|-C^)aikyI, -SO₂(C₂-C₆)alkenyl, -SO₂(C₂-C₆)alkynyl, -SO₂(C_rC₆)haloalkyl, -S0₂(C₃-C₇Xarbocycle, -SO₂(C₃-C₇)halocarbocycle, -SO₂aryl, -SO₂heteroaryl, -SO₂heterocycle, -SO₂NR_cRd, -NR^Rj, NRaC(O)Ra, -NR_aC(O)ORb, -NRaCtOjNRcRd -NRaSO₂Rb, -NRaSChNRcRd, -NRaSO₂O(C₃-C₇)carbocycle, -NïESOjOaryl, -OSfO^Rn, -C(O)R_Ü, -C(O)OR_b, -C(O)NR<:Kb and -OCÇOjNR^Rd, wherein any (Cj-Côjalkyl, -(Ci-C₆)haloalkyl, (C₂ C₆)alkenyl, (C₂-C6)alkynyl, -(C₃C₇)halocarbocycle, (C₃-C₇)carbocycle, (Cj-C₇)halocarbocycle, aryl, heteroaryl or heterocycle of Z¹³, either alone or as part of a group, is optionally substituted with one or more halogen, -OH, OR_b, -CN, -NR_aC(O)2Rt» -heteroaryl, -heterocycle, -Oheteroaryl, Oheterocycle, -NHheteroaryl, -NHheterocycle, or -SfOXNRcRj;

each Z¹⁴ is independently selected from -NO2, =NORa t -CN, -(C3C7)halocarbocycle, -0(C3-C7)haiocarbocycle, -S(C3-C7)halocarbocycIe, -S(OXC3C7)halocarbocycle, -SO2(C3-C7)halocarbocyc!e, -NRaSO2NR<Rd, -NRaSO2O(C3C7)halocarbocycle, -NRaSO2Oaryi and -OS(())2Ra, wherein any -(C3-C7)halocarbocycle of Z¹⁴, either alone or as part of a group, is optionally substituted with one or more halogen, -OH, -ORb, -CN, -NRaC(O)₂Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -StOhNRcRdj each Ra is independently H, (Ci-CeJalkyl, (C₂-C6)alkenyl, (C₂-C6)alkynyl, (C₃-C₇)carbocyclc, heterocycle, aryl, aryl(Ci-C6)alkyl-, heteroaryl or heteroaryl(CiCejalkyl-, wherein any (Ci-QJalkyl, (C₂-C₆)alkenyl, (C₂-Cé)aikynyl, (C₃-C₇)carbocycle_Jheterocycle, aryl or heteroaryl of Ra, either alone or as part of a group, is optionally substituted by halogen, OH and cyano;

each Rb is independently (C >-C$)alkyL (C₂-C₆)alkenyï, (C₂-C₆)alkynyl, (C₃-C7)carbocycle, heterocycle. arvl. aryl(C_rC(,)alkyl-. heteroaryl or heteroary 1(CjCbjalky I-, wherein any (Ci-C_ft)alkyl. (C₂-COaikenyL (C₂-Ct,)alkynyL (Cj-C-pcarbocycteheterocycle, aryl or heteroaryl of R_t is optionally substituted by halogen, OH and cyano;

410

R< and Ra are each independently selected from H, (('_t-C₆)aIky], (C₂-Cô)alkenyl, (C₂-C6)alkynyl, (C₃-C₇)carbocyclc, aryl, aiyl(C|-C6)alkyl-, heterocycle, heteroaryl and heteroarylfCj-Céjalkyl-, wherein any (Ci-Cejalkyl, -(C₂-C₆)alkenyl, -(C₂-C(,)alkynyL (C₃-C₇)carbocycle, heterocycle, aryl and heteroaryl of R. or Rj, either alone or as part ofa group, is optionally substituted by halogen, OH and cyano; or R< and Ri together with the nitrogen to which they are attached form a heterocycle, wherein any heterocycle of Rc and Rd together with the nitrogen to which they are attached is optionally substituted by halogen, OH or cyano;

each R_c is independently selected from -OR_â (Ci-C_g)alkyl and (C₃-C₇)carbocycle, wherein (Ci-C₆)alkyl and (C₃-C₇)carbocycle are substituted by one or more Z⁶and optionally substituted with one or more Z¹, (C₂-C6)haloalkyl, (C₂-C₆)alkenyl and (C₂-C6)alkynyl, wherein any (C₂-C_g)haloalkyl, (C₂-C_g)alkenyl and (C₂-C<.)alkynyl is optionally substituted with one or more Z¹, and aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are substituted by one or more Z⁵;

each Rf is independently selected from -R_fc -OR^ -((^-Cbjalkyl-Z⁶, -SO₂R_g)-C(O)Rg, C(O)OR_g, and -C(O)NR_tR_g; and each Rg is independently selected from H, -OR^ (Cj-Ce)alkyl, (C₃-C₇)carbocycle, (Ci-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C6)alkynyl, aryl, heterocycle and heteroaryl, wherein any (Ci-QJalkyl, (C₃-C₇)carbocycle, (Ci-C₆)haloalkyl, (C₂-C_g)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle or heteroaryl of R_g is optionally substituted with one or more Z¹ groups;

or a sait thereof.
2. The compound of claim 1 wherein R³ is (Ct-C_g)alkyl, (C₂-C₆)alkenyl or -O(Cp C₆)alkyl wherein any (C’i-CJalkyl or (C₂-C_g)alkenyl of R³ is optionally substituted with •î* , one or more groups selected from -O(Ci-C6)alkyl, halo, oxo and -CN; and wherein R is H
3. The compound of claim 1 which is a compound of formula le:

le or a sait thereof.
4. The compound of any one of claims 1-3 wherein R⁴ is selected from:

a) aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl is optionally substituted with one or more groups each independently selected from halo, (C_rC(,)alkyl, (C₂-C6)alkenyl, (Ci-QhaJoalkyl, (C₃-C₇)cycloalkyl, -OH, -OfCi-Ce^dkyl, -SH, S(Ci-C.₀)alkyl. -NH₂, -NH(C)-Q)alkyl and -NiCCrQ^lkylb, wherein (C^-Qjalkyl is optionally substituted with hydroxy, -OfC|-Ce)alkyl, cyano or oxo;

b) (C₃-Ci4)carbocycle, wherein (C₃-Ci4)carbocycle is optionally substituted with one or more Z^{1 *} groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C3-C7)carbocycle or heterocycle; and

c) aryl, heteroaryl and fused-heterocycle, wherein any aryl, heteroaryl and fused-heterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.
5. The compound of any one of claims 1-3 wherein R⁴ is selected from:

a) aryl. heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl is optionally substituted with one or more groups each independently selected from halo. (C:Cftlalkyl. (C₂-C_é)alkenyl, (Ci-C*)haloalkyl. (C₃-C₇)cycloalkyl. -OH. -OtCi-C₆)alkyl. -SH. S(Ci-Cf,ialkyL-ΝΉ;. -XH(Ci-C,lalkyl and-N((Ci-C'6)alkyih. whereir (C:-C* Jalkyl is optionally substituted with hydroxy. -OfCj-COalkyl. cyano or oxo. and

C

C

412

b) aryl, heteroaryl and fused-heterocycle, wherein any aryl, heteroaryl and fused-heterocycle îs substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.
6. The compound of any one of daims 1 -3 wherein R⁴ is selected from:

a) heterocycle, wherein heterocycle is optionally substituted with one or more groups each independently selected from halo, (C|C₆)alkyl, (Cî-CeJalkenyl, (Ci-Cejhaloalkyl, (C₃-C₇)cycloalkyl, -OH, -OÎC^jalkyl, -SH, -S(C|·^!, -NH, -NH(C_rC_è)alkyl and Ni/Ci-QjalkylL, wherein (C]-C₆)alkyl is optionally substituted with hydroxy, -O(C]C₆)alkyl, cyano or oxo; and

b) fused-heterocycle, wherein fused -heterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.
7. The compound of any one of daims 1-3 wherein R⁴ is:

C

413

JWV »ΛΛΛΤ JWV

8. The compound of any one of claims 1-3 wherein R⁴ is: (AA L 1 ΓιΓί 5 9. The compound of'any one c rrs i -8 wherein R¹ is selected from a) H, halo, (C;-C_s>aiky ana Y -k- maicaiky ï.

b) (C₂-C$)alkeny!. (C₂-C,jalkyrsyl. (CrCrJcycloalkyi. nitro. cyano, aryl. heterocycle and heteroaryl. wherein an y aryl. heterocycie or heteroaryl is cptionaliy iO substituted with one or more Z¹¹ groups.

414

c) -C( =O)-R'¹, -C(=OH>R'-O-R¹¹, -S-R¹ -S(O)-R'\ -SO2-R'¹, -(Ci-Cé)alkyl-R^!f, -(CrCelaikyl-C^OJ-R¹¹, -(Ci-C6)alkyFC(-O)-O-R'-(Cj-C6)alkyl-OR¹ -(CrQJalkyl-S-R¹ -(Ci-C^alkyl-SfOFR¹¹ and -(C1-C₆)a]kyl-SO2-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Cû)alkyl, (Cj-CeJalkenyl, (C₂-Ce)alkynyl, (CiC₆)haloalkyl, (Cj-C-fcycloalkyl, aryl, heterocycle and heteroaryl, and wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

d) -N(R’)R¹⁰, -C(=O)-N(R⁵)R¹⁰, -O-C(=O)-N(R⁹)R¹⁰, SO2-N(R⁹)R^1û, -(Ci-Cé)alkyl-N(R⁹)R'⁰, -(Cl-C6)alkyl-C(-O)-N(R⁹)R¹⁰, -[C1-C₆)alkyl-O-C(=O)-N(RkR^iCand -<CrC6)aikyl-SO2-N(R⁹)R^1(,f wherein each R⁹ is independently selected from H, (Cr C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰is independently selected from R¹¹,-(C1C6)alkyl-R^l,,.SO2-R‘¹,-C(=O)-Rⁿ,-C(=OX)R^H and -C( O)N(R⁹)R^H, wherein each R¹¹is independently selected from H, (Cj-C&)alkyt, (C₂-C₆)alkenyl, (C₂-Cô)a]kynyl, (CiC6)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, and wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

e) (Cj-CôJalkyi, wherein (Ci-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z'groups;

f) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and-Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z'groups; and

g) (Q-Célhaloalkyl, (C₃-C₇)carbocycle, (C₂-C_é)alkenyl, and (C₂-C6)alkynyl, wherein (Ci-C^haloalkyl, (C₃-C₇)carbocycle, (C₂-C6)alkenyl and (C₂-C6)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more

IC compound of any one of daims l-SwhereinR¹ is selected from:

-ΐ. halo and (Ci-Cc)alkyl, :Cz-Ckjalkeny!. cyano, aryl, heterocycle and heteroaryl. wherein any aryl.

J r heterocycle or heteroaryl is optionally substituted with one or more Z ¹¹ groups;

C

C

415

c) -C(=O)-N(R⁹)R¹⁰, -(Ci-Cejalkyl-R¹¹ and -(CrC6)alkyl-O-R¹¹, wherein each R¹¹ is independently selected from H, (Ci-Côjalkyl, (Cj-Côjalkenvl, (C2-C<,)alkynyi, (C|-C<.)haloalkyl, (C3-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl îs optionally substituted with one or more Zⁱ⁰ groups;

d) -(C_rC6)alkyl-N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (CrC6)alkyl and (C3-C7)cycloalkyl, and each R^lûis independently selected from R¹¹, -(CiC6)alkyl-Rⁿ, -SO^-R¹¹, -C(=O)-Rⁿ, -C(=OK)Rⁿ and -C(-O)N(R^y)R^l\ wherein each R¹¹is independently selected from H, (Ci-Cgjalkyl, (C₂-C_ô)alkenyl, (C₂-C₆)alkynyl, (C₃C$)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, whcrcin any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

e) (Ci-Cé)alkyl, wherein (Ci-C₆)aîkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, heteroaryl and heterocycle, wherein any aryl heteroaryl and heterocycle is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; and

g) (C₂-Ce)alkenyl, and (C₂-Ci)alkynyl, wherein (C₂-Cé)alkenyl and (C₂-Ce)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.

11. The compound of any one of claims 1-8 wherein R¹ is selected from:

C

416

Cl NH_Z

JVW

12. The compound of any one of claims 1 -8 wherein R¹ is halo.

5 13. The compound of any one of claims 1-12 wherein R is selected from:

a) H, (Ci-Céialkyl and -O(Ci-C6)alkyl;

b) (C--C₆)alkcnyl, (Cj-CôJalkynyk (Ci-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;

c) C^OJ-R¹¹, -CtOVO-R, -S-R¹', -S(O)-R“, -S02-R¹¹,
10 -(Ci-C_È)alkyl-R, -(C₁-C₆)alkyl-C(---O)-R, -(C_rC« ia]kyl-C(-O)-O-R' -(Cj-CeJalkyl-OR¹¹. -fCi-C6)alkyl-S-R^t;. -(C;-Cé)alkyl-S(O)-R and -(C_t-C₆)alkyl-SO2-R, wherein each R¹¹ is independently selected from H. (Cj-Qjalkyl, (C₂-Cé)aikenyl. (C-Cfjalkynyl, (C|CA)haloalkyi, (C;-C-)cycloalky 1. aryl. heterocycle and heteroaryl. wherein aryl, beterocycîe or heteroary l are each optionally substituted with one or more 7 ^! groups;

417

d) -N(R⁹)R^I0, -C( O)-N(R⁹)R¹⁰, -O-C(=O)-N(R⁹)R ^î0, -SO2-N(R⁹)R^iü, -(Cr Cfijalkyl-NCR^R¹⁰, -(CrC₆)alkyl-C(=O)-N(R⁹)R^t0J -(Ci-C6)alkyl-O-C(=O)-N(R⁹)R¹⁰, and -(C1-C₆)alkyI-SO2-N(R⁹)R^,<), wherein each R⁹ îs independently selected from H, (C]C6)alkyl and (C3-C7)cycioaikyl, and each R^iOis independently selected from Rⁿ,-(CtC6)alkyl-R^! -SO2-R”, -C(-O)-R' -C(=O)ORⁿ and -CCOJNiR’jR¹¹, wherein each R¹¹is independently selected from H, (C)-C6)a]kyi, (C₂-C₆)alkenvl, (C₂-C6)alkynyl, (C_rCe)haloalkyl, (Cj-Cb/cycloalkyl, aryl, heterocycle and heteroaryl;

e) (Ci-Cô)alkyl, wherein (Ci-Qjalkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

f) (C_t-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-Cf,)alkcnyl, and (C₂-C6)alkynyl, wherein any (Ci-CJhaloalkyl, (C₃-C₇)carbocycle, (C₂-Ce)alkenyl and (C₂-C₆)alkynyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z^lgroups.
14. The compound of any one of daims 1 -12 wherein R² is selected from:

a) (C₁-C₆)alkyl;

b) (C₂-C_s)alkenyl and (C|-C₆)haloalkyl;

c) -(Cj-Ctlalkyl-R¹¹ and -(C|-C6)alkyl-O-R'‘ wherein each R¹¹ is independently selected from H, (CrCejaikyl, (C?-C6)alkenyl, (C₂-C₆)alkynyl, (CjC₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more Z¹¹ groups;

d) -(Ci-C6)alkyl-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Ci-Ce)alkyl and (C3-C7)cycloalkyi, and each R^,ois independently selected from Rⁿ,-(CiCeÎalkyl-R¹¹, -SCh-R¹¹, -C(=O)-R, -CKïjOR¹¹ and -0(=0)14^¼¹ *, wherein each R¹¹is independently selected from H, (C-Côlaikyl, (C2-C6)alkenyl, (C₂-C6)alkynyl, (C_rC₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

e ) ( C i -Cf, Jalkyl. wherein ( C1 -Ct,)aIky 1 i s substituted with one or more Z groups and optionally substituted with one or more Z¹ groups: and fi (C _;-C„lalkenyL wherein (C:-C<,»alkenyl is substituted with one cr more F groups and optionally substituted with ene or more Z. groups.

418
15. The compound of any one of ciaims 1-12 wherein R^z is:

F

-J
16. The compound of any one of ciaims 1-12 wherein R is methyl.
17. The compound of any one of ciaims 1-16 wherein R⁶ is selected from:

a) H, halo, (Ci-Céjalkyl, and (Ci-CeJhaloalkyl

b) (C₂-Cô)alkenyl, (C₂-C₆)alkynyl, (Cj-CvTcycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R⁶is optionally substituted with one or more Z¹⁰ groups;

c) -C(=O>R'¹, -C(=O)-O-R'^l, -O-R¹¹, -S-R¹¹, -S(O)-R'-SCk-R¹¹,

-(Ci-C₆)alkyl-R‘-(C_rC₆)alkyl-C(=O>R¹¹, -(C^/alkyl-CC-OT-O-R¹¹. -(C:-C6)alkyl-OR”, -(Ci-Cfelalkyl-S-R¹¹, -(CrCGlalkyl-S/OfR¹¹ and -(CrC^alkyl-SOrR¹¹, wherein each R¹¹ is independently selected from H, (Ci-C6)alkyl, (C₂-C6)alkenyl, (C₂-C_t.)alkynyl, (CiC(.)haloalkvL (Cj-Cî^ycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl ofR⁶is optionally substituted with one or more Z¹⁰ groups;

d) -(C₁-C_s)alkyl-O-(C₁-C6)alkyl-(C3-C7)carbocycle, -(C|-C_fl)alkyl-S-,C'.· Ojalky}-{C:-C'^TKarbocycie. -iCf-OjalkyTSiOi-i'Ct-CÂÎaJkyl-iCî-CrKarbocvcie. ->C CAialkyl-SO^HC^-Gtalkyl-iCï-CTicarbocycle, -{Cz-CftKlkenyl-ÎCT-C^lhaloalkv ;. -<C_;- jaikynvHC i-CjJhaloaikyL -haio(Cj-C->)carbocycie,-NR_aSO;NR<_:Rj. -NÎR»SO:O<C_;

Cîicarbocycle. -NRaSCbOaryl. -(C₂-C*)aikenyl-{C3-C7)carbocycle, -<C₂-O )aik envi-dry i.

419

-(C₂-C₆)aIkenyl-heteroaryl, -(C₂-C₆)alkenyi-heterocycle, -(C2-Cé)alkynyl-(C₃-C₇)carbocyc]e, -(C₂-C₆)aikynyi-aryl, -(Cj-Côjalkynyl-hctcroaryl, -<C₂-C6)alkynyI-heterocycle, -(Cî-Cglalkynyl-ORa and -(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_a, -(C₃-C₇)carbocycle-Z’ and -haJo((/-C₆)alkyl-Z³, wherein any (Ci-C₆)alkyl, (Ci-CéJhaloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z’groups;

n

e) (Ci-Ce)alkyl, wherein (Ci-C()aikyl is substituted with one or more Z groups and optionally substituted with one or more z’groups;

f) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z^s groups and optionally substituted with one or more Z’groups; and

g) (C_t-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-Cé)alkenyl and (C₂-C₆)alkynyl, wherein any (Ci-C₆)haloalkyl, (C₃-C₇)carbocycle, (Cy-Cgjalkenyl and (C₂-C₆)alkynyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z’groups.
18. The compound of any one of claims 1-16 wherein R⁶ is selected from:

a) H, halo and (C i -C'élalkyi;

b) (C₂-C₆)alkenyl, (C₂-C6)alkynyl and aryl, wherein any aryl is optionally substituted with one or more Z¹⁰ groups;

c) -(Ci-C₆)alkyl-R” and -(Ci-C₆)alkyl-O-Rⁿ, wherein each Rⁿ is independently selected from H, (C|-C<,)aikyl, (Cï-C^Jalkenyl, (C₂-C₆)alkynyl, (CiQ)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶ is optionally substituted with cne or more Z¹⁰ groups;

d) -(C₂-C\Jalkvnyl-(Ci-C->)carbocycle. aikynyI-ary 1. +C₂-C₍,)alkynyl- heteroaryl -(C₂-C_b)alkyTiyl-heterocycle, -{Cz-Cglalkyr.vOR; and

-(C₂-Ck(alkylTC vC+lcarbocycle-OR_a. wherein -(C--C*ialkynyi+Cj-C-(carbocycle.

420

-(C₂-C₆)aIkynyl-aryl, -(C₂-C6)alkynyl-heteroaiyl and -(Cj-C^alkynyl-hcterocvcle. are optionally substituted with one or more Z'groups;

e) (C)-C₆)alky, wherein (C|-Q)aîkyl is substituted with one or more Z² groups and optionally substituted with one or more Z'groups;

f) aryl, wherein aryl is substituted with one or more Z^s groups and optionally substituted with one or more Z’groups; and

g) (C₂-C_â)alkenyl and (C₂-Cs)alkynyl, wherein (C₂-Cô)alkenyl and (C₂-Cû)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z'groups.
19. The compound of any one of claims l -16 wherein R⁶ is selected from:

421

The compound of any one of claims 1-I6 wherem R⁶ is H.

The compound of any one of daims I-20 wherein R' is selected from· ai H. ha:o. (C -C,alkyl and «C Olhaloalkyl.

422

b) (C₂'C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) -C(=O)-R”, C(=O)-O-R^,!, -O-R, -S-R¹¹, -S(O)-R' -SCh-R¹¹, <C|-Ci)alkyl-Rⁿ, XCrCsMkyl-CK^R¹¹, -CC.-Célalkyl-CFOLO-R¹', -(Cr-QOalkyl-ORⁿ, -(CrC6)alkyl-S-Rⁿ, -(Ci-C^alkyl-SfOl-R¹¹ and -(CrC^)alkyl-SO₂-R^l!, wherein each R¹¹ is independently selected from H, (C_rC₆)alkyl, (C₂-Q;)a]kenyl, (C₂-C6)alkynyl, (CjC_k)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

d) -N(R⁹)R¹⁰, -C(=O)-N(R⁹)R^w, -O-C(=O>N(R⁹)R¹⁰, -SOz-NfR^R¹⁰, -CCrC6)aikyl-N(R⁹)R^,0i-(Ci-C₆)alkyl-C(=O>N(R⁹)R¹⁰,-(C1-C6)alkyl-O-C(=O)-N(R⁹)R¹'^ïand -(Ci-C6)alkyl-SO₂-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (Cr Cfi)alkyl and (C3-C7)cycloalkyl, and each R^l0is independently selected from R¹¹, -(CiCilalkyl-R”, -SCh-R¹¹, -C(=O)-Rⁿ, -C(=O)ORⁿ and -C(=O)N(R⁹)R^1], wherein each R¹¹is independently selected from H, (CpC^alkyl, (C2-C₆)alkenyl, (C₂-C(,)alkynyl, (C_rC₆)haloalkyl, (Cj-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

e) (Ci-C₆)alkyl, wherein (C]-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z’groups;

f) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z’groups;

g) (Cj-C₆)haloalkyl, (Cî-C₇)carbocycle, (C₂-Cé)alkenyl and (C₂-Cs)alkynyl, wherein any (Ct-C6)haïoalkyl, (C3-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z^;groups; and

h) -NR^Rf. -C(O)NR,R_f. -OCtOlNRrRf. -SC+NR^Rf. -(Ci-(\}alkyl-NReRf. -(C -CKlaikylC'(ObNRJtf. qCi-C^jalkyl-O-CtOj-NIL.Rf and -i.C-C^jalkyi SO_:NI<Rf

423 wherein each any (Ci-CeJalkyl, either alone or as part of a group, is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.
22. The compound of any one of daims 1-20 wherein R⁷ is selected from:

a) H, halo, (Ci-Ce)alkyl and (Ci-C^Jhaloalkyl;

b) (Cj-CZJcycloalkyl, cyano, aryl and heteroaryl, wherein any aryl and heteroaryl is optionally substituted with one or more Z^î0 groups;

c) -C(=O)-N(R⁹)R^l(1, whereineach R⁹ is independently selected from H, (CiC())alkyl and (C3-C7>cycloalkyL and each R¹⁰is independently selected from Rⁿ, -(Cr Céjalkyl-R¹ -SOrR¹¹, -C(=O)-R^] *, -C(-O)OR'¹ and -C(-O)N(R⁹)R, wherein each R¹¹is independently selected from H, (Ci-Ci)alkyi, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (CiCdhaloalkyl, (C₃-C₇)cydoalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups;

d) (Ci-Cejalkyl, wherein (C|-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

e) aryl and heteroaryl, wherein aryl and heteroary] are each substituted with one or more Z⁵ groups and optionally substituted with one or more Z’groups;

f) (C|-C₆)haloalkyl and (C3-C₇)carbocycle, wherein (Ci-Cgjhaloalkyl and (C₃C₇)carbocycle are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z’groups; and

g) -C(O)NRçRf.
23. The compound of any one of daims 1-20 wherein R⁷ is selected from:

424

Η^λ . > Y . Y . rV (A. N n^A M n-nh . N.Y HN . Cf. (Y Kl (Y Ν^Λ _Ν IN _N-k>s. A O i r Cf cA 1 Y F\À F ' c 1 A <A H₂N^>- 0 A. n Λ OH c and n
24. The compound of any one of daims l-20 wherein R⁷ is H.

5
25. The compound of any one of daims l -24 wherein R⁸ is seieded from:

a) halo, nitro and cyano;

b) R¹¹, -C(=O>R^!1, -C(=O)-O-R^h, -Ο-R¹', -S-R¹¹, -SiOTR¹¹. -SO2-Rⁿ, -(Cr C_fi)alkyl-R^1,,-(C!-Cft)alkyl-C(=O)-R¹¹,-(C1-C₆)alkyl-C(=O)-O-R^1,,-(Ci-C₆)alkyl-O-Rⁿ. (C-.-CftJalkji-S-R¹'. -(Ci-CkJalkyl-SfOj-R¹¹ and -iCi-C^lkyl-StT-R¹¹,wherein eachR^!l is

10 independently selected from H. (Ci-C₆)alk}l, (C;-Cf,)alkenYl, (C^-C^ialkynyl, (C<Gjhaloaikyl, iCj-C’jcydoalkyl. aryl. heterocycle and heteroaryl, wherein aryl. heterocyde and heteroaryl are each optionally substituted with one or more Z groups:

Λ

425

c) -n(r⁹)r¹⁰, -c^yNoOir, -o-C(=o>n(R⁹)r^I0, -so2-n(r⁹)r¹⁰, -(cr C₆)alkyl-N(R⁹)Rⁱ⁰, -(CrC6W^C(=O)-N(R⁹)R¹⁰, -(CI-C₆)alkyl-O-C(=O)-N(R⁹)R¹⁰ and (Ci-Cejalkyi-SOi-NfR’jR¹⁰, wherein each R⁹ is independently selected from H, (C|C6)alkyl and (C3-C7)cycloalkyl, and each R¹⁰is independently selected from R¹ -(CiC6)alkyl-R^H, -SOp-R¹¹, -C(=O)-Rⁿ, -C(=O)OR^H and -C^W’jR¹¹, wherein each R¹¹is independently selected from H, (Ci-Qlaikyi, (C^-Cejalkenyl, (C₂-C₆)alkynyl, (CjC₆)haloalkyl, (C₃-C?)cycloalkyl, aryl, heterocycle and heteroaryl;

d) (Ci-Cé)alkyl, wherein (Ci-C₆)alkyl îs substituted with one or more Z²groups and optionally substituted with one or more Z¹groups;

e) aryl, heteroaryl, heterocycle, -Xaiyl, -Xheteroaryl and -Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z^s groups and optionally substituted with one or more Z¹ groups;

f) (CrC«)haloalkyl, (Cj-C₇)carbocycle, (Cb-CDalkeny! and (C₂-C₆)alkynyl, wherein (Ci-C6)haloalkyl, (C₃-C₇)caibocycle, (C₂-C₆)alkenyl and (C₂-Ce)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more z’groups; and

g) -NReRr, -C(O)NReRf, -OC(0)NR_tR_f, -SO.NR^Rf, -(Ci-CeJalkyl-NR^Rf, XC)-C₆)alkylC(O)-NR«Rf, -(Ci-C₆)alkyl-O-C(O)-NReR_tand -(Ci-Csjalkyl-SOîNR^Rf, wherein any (Ci-Ce)alky, as part of a group, is substituted with one or more Z⁶ groups and optionally substituted with one or more Z'groups.
26. The compound of any one of claims 1-24 wherein R is selected from:

a) halo and cyano;

b) R¹¹, -0-R” and -(C>-C6)a!kyl-R¹'. wherein each R¹¹ is independently selected from H, (Ci-C6)alkyl, (C₂-C₆)alkenyl, (Cj-CeJalkynyl, (('·-( -ihaicolkyi. ‘C-.C?)cycloalkyl, aryl. heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl arc each optionally substituted with one or more Z groups;

c) -C(-U)-N(R⁹)R 'λ whereineach K’ is independently seiected from H. (CsCùaiky i and iCi-C-fcycioalky L and cach R is independently seiected from R ,hC 16293

426

QJalkyl-R¹ -SOj-R¹ -C(=O)-R' C(»O)OR'¹ and -C(=O)N(R’)R¹¹, wherein each R¹ ' is independently selected from H, (Cj-GJaikyl, (C'-Céjalkenyl, (C2-C_g)alkynyl, (C|Cejhaloalkyl, (C₃-C7)cycloalkyl_f aryl, heterocycle and heteroaryl;

d) (Ci-C₆)alkyl, wherein (C|-C₆)alkyl is substituted with one or more Z²

5 groups and optionally substituted with one or more Z¹ groups;

e) aryl and heteroaryl, wherein aryl and heteroaryl are each independently substituted with one or more Z⁵ groups and optionally substituted with one or more

Z¹ groups;

f) (Cï-Céjalkynyl, wherein (C2-C₆)alkynyl is substituted with one or more Z^É

10 groups and optionally substituted with one or more Z¹ groups; and

g) -CÎO)NReRr.
27. The compound of any one of claims 1 -24 wherein R* is selected from:

h₂n

JVW jwv

AW

Λ/W and I
28 The compound of any one of c;a;T' -2* wnerem R’ is H
29 fhe compound of cîaim I sefectedfrom

427

428 \ //

429 // \

430

N N

431

C

432

433

C

434

Cl Cl Cl

C

C

435

C

436

437 /

/

438

439 and salts thereof

440
30. A pharmaceutical composition comprising a cornpound of formula 1 as described in any one of claims 1-29 or a pharmaceutically acceptable sait thereof, in combination with a pharmaceutically acceptable carrier.

5
31. A cornpound as ôesoribcd in wry of claims 1-29 or a phaHnaceuikaHy acceptable sait thereof for use n» medical therapy .
32 A cornpound as described in any one of claims 1 -29 or a pharmaceutically acceptable sait tbœeof, for the manufacture of « medrcamen! for treating the prolifération of the HIV virus, treeling AIDS ot delaying the ooset of AIDS or ARC sympœoms in a

10 manæaai.
33. A corapound as described in any one of daim s 1 -29 or a pharmaceuttcaily acceptable sait thereof, for ubc in the prophyiactk: or therapeutic treatment of te proliferation ofthe HIV virus er AIDS or for use in the therapeuric treetoeni of dehying the ooset of AIDS or ARC symptews.