WO2012003497A1 - Napht- 2 -ylacetic acid derivatives to treat aids - Google Patents

Napht- 2 -ylacetic acid derivatives to treat aids Download PDF

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Publication number
WO2012003497A1
WO2012003497A1 PCT/US2011/042880 US2011042880W WO2012003497A1 WO 2012003497 A1 WO2012003497 A1 WO 2012003497A1 US 2011042880 W US2011042880 W US 2011042880W WO 2012003497 A1 WO2012003497 A1 WO 2012003497A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
carbocycle
heterocycle
groups
heteroaryl
Prior art date
Application number
PCT/US2011/042880
Other languages
French (fr)
Inventor
Kerim Babaoglu
Kyla Bjornson
Hongyan Guo
Randall L. Halcomb
John O. Link
Ryan Mcfadden
Michael L. Mitchell
Paul Roethle
James D. Trenkle
Randall W. Vivian
Lianhong Xu
Original Assignee
Gilead Sciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=44454746&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2012003497(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to EA201291300A priority Critical patent/EA201291300A1/en
Priority to US13/806,067 priority patent/US9102614B2/en
Priority to EP11738878.5A priority patent/EP2588450B1/en
Priority to ES11738878.5T priority patent/ES2634490T3/en
Priority to SG2012095410A priority patent/SG186820A1/en
Priority to KR1020137002778A priority patent/KR20130135826A/en
Priority to CA2802308A priority patent/CA2802308C/en
Priority to AP2013006706A priority patent/AP2013006706A0/en
Priority to MX2012015097A priority patent/MX2012015097A/en
Priority to CN201180038442XA priority patent/CN103140474A/en
Priority to NZ604598A priority patent/NZ604598A/en
Priority to AU2011274322A priority patent/AU2011274322B2/en
Priority to JP2013518778A priority patent/JP5984218B2/en
Priority to MA35607A priority patent/MA34397B1/en
Priority to BR112013000043A priority patent/BR112013000043A2/en
Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Publication of WO2012003497A1 publication Critical patent/WO2012003497A1/en
Priority to IL223558A priority patent/IL223558A0/en
Priority to ZA2012/09596A priority patent/ZA201209596B/en

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    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/20—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 hydrogenated in the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • HIV-1 Human immunodeficiency virus infection and related diseases are a major public health problem worldwide.
  • Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase.
  • drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have 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 inhibit the replication of HIV. There is also a need for agents that are directed against alternate sites in the viral life cycle including agents that target the interaction of Lens Epithelial Derived Growth Factor (LEDGF/p75) and HIV-1 integrase.
  • LEDGF/p75 Lens Epithelial Derived Growth Factor
  • the invention provides a compound of the invention which is a compound of formula I:
  • R 2 is R 2a or R 2b ;
  • R 3 is R 3a or R 3b ;
  • R 3' is R 3a' or R 3t R 4 is R a or R 4 ;
  • R 5 is R 5a or R 5b ;
  • R 6 is R 6a or R 6 ;
  • R 7 is R 7a or R 7 ";
  • R 8 is R 8a or R 8 ;
  • R la is selected from:
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl; and d) -N(
  • any aryl, heterocycle and heteroaryl of R la is optionally substituted with one or more (e.g. 1, 2 or 3) Z 10 groups;
  • R lb is selected from:
  • Z 1 groups wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C 7 )carbocycle or heterocycle wherein the (C 3 - C 7 )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • Z 2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • any -X(C 2 -C 6 )alkynyl and -X(C 3 -C 7 )carbocycle wherein any -X(Ci-Ce)alkyl and-X(C ! - C 6 )haloalkyl, is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups, and wherein any -X(C 2 -C 6 )alkenyl, -X(C2-C 6 )alkynyl and -X(C 3 -C 7 )carbocycle, is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 4 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • 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 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • (C 2 -C 6 )alkynyl are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and g) -NReR f , -C(0)NReRf, -OC(0)NReR f , -S0 2 NReR f , -(Ci-C 6 )alkyl-NRe f, -(C 1 -C 6 )alkylC(0)-NR e R f , -(C 1 -C 6 )alkyl-0-C(0)-NR e R f and -(C 1 -C 6 )alkyl-S0 2 NR e R f , wherein any (C 1 -C 6 )alkyl, as part of a group is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • R 2a is selected from:
  • each R u is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C )cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl, wherein aryl, hetero
  • each R 9 is independently selected from H, (d-C 6 )alkyl and (C 3 -C 7 )cycloalkyl
  • each R 10 is independently selected from R 11 , -(d-C ⁇ alkyl-R 11 , -S0 2 -R n
  • R is selected from:
  • C )alkenyl, (C 2 -C 6 )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) Z 1 groups;
  • spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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 1 groups, wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C 7 )carbocycle or heterocycle, wherein the
  • (C 3 -C 7 )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • Z 2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • any -X(C 2 -C 6 )alkenyl, -X(C 2 -C 6 )alkynyl and -X(C 3 -C 7 )carbocycle is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 4 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • 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 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • (C 2 -C )alkynyl are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and g) -NReR f , -C(0)NR e R f , -OC(0)NR e R f , -S0 2 NR e R f , -(C 1 -C 6 )alkyl-NR e R f , -(C 1 -C 6 )alkylC(0)-NR e R f , -(C 1 -C 6 )alkyl-0-C(0)-NR e R f and -(Ci-C 6 )alkyl-S0 2 NR e R 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) Z 1
  • R 3a is (Ci-C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl,
  • (C 3 -C )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 (d-C 6 )alkyl, -0(C 1 -C 6 )alkyl, halo, oxo and -CN; and R 3a' is H ;
  • R 3b is -(C 7 -C)4)alkyl, -(C 3 -C7)carbocycle, aryl, heteroaryl, heterocycle,
  • Ci 4 alkyl, -0(d-C 6 )alkyl-NR a R b , -0(C 1 -C 6 )alkylOC(0)-NR c R d , -0(d-C 6 )alkyl-NR a - C(0)-OR b , -0(d-C 6 )alkyl-NR a -C(0)-NR a R b , -0(C 1 -C 6 )alkyl-NR a -S0 2 -(C 1 -C 6 )alkyl, -0(d-C 6 )alkyl-NR a -S0 2 -halo(d-C 6 )alkyl, -0(d-C 6 )alkyl-NR a -S0 2 -(C 2 -C 6 )alkenyl, -0(C 1 -C 6 )alkyl- R a -S0 2 -(C 1
  • 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, (d-C 6 )alkyl, (C 2 -C 6 )alkenyl, (Q-C ⁇ haloalkyl, (C 3 - C 7 )cycloalkyl, -OH, -0(C 1 -C 6 )alkyl, -SH, -S Q-Q alkyl, -NH 2 , -NH d-C alkyl and - N((C 1 -C6)alkyl) 2 , wherein (C 1 -C 6 )alkyl is optionally substituted with hydroxy, -0(Ci- C 6 )alkyl, cyano or oxo;
  • groups each independently selected from halo, (d-C 6 )alkyl, (
  • R 4b is selected from;
  • 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) Z 1 groups, or wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C 7 )carbocycle or heterocycle; and d) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridged- heterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridged- heterocycle heterocycle are each independently substituted with one or more (e.g. 1, 2,
  • R 4 and R 3 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) Z 1 groups; and R 3 is H, (Ci-C 6 )alkyl or -0(C C 6 )alkyl;
  • R 5a is selected from:
  • each R 9 is independently selected from H, (d-C 6 )alkyl and (C 3 -C 7 )cycloalkyl
  • each R 11 is independently selected from H, (d-C 6 )alkyl, (C 2 -
  • R 5b is selected from:
  • Z 1 groups wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C 7 )carbocycle or heterocycle wherein the (C 3 - C 7 )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • any -X(C 2 -C 6 )alkenyl, -X(C 2 -C 6 )alkynyl and -X(C 3 -C 7 )carbocycle is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 4 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • 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 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • (C 2 -C 6 )alkynyl where (C 1 -C 6 )haloalkyl, (C 3 -C )carbocycle, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and
  • R 6a is selected from:
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C6)alkenyl, (
  • each R 9 is independently selected from H, (C ! -C 6 )alkyl and (C 3 -C 7 )cycloalkyl
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and hetero
  • R 6b is selected from:
  • C 7 )cycloalkyl or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • (C 1 -C 6 )alkyl wherein (C 1 -C 6 )alkyl is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • any -X(C 2 -C 6 )alkynyl and -X(C 3 -C7)carbocycle wherein any -X(C C )alkyl and-X ⁇ - C 6 )haloalkyl, is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 3 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups, and wherein any -X(C 2 -C 6 )alkenyl, -X(C 2 -C 6 )alkynyl and -X(C 3 -C 7 )carbocycle, are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 4 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • 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 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • (C 2 -C 6 )alkynyl wherein (d-C 6 )haloalkyl, (C 3 -C 7 )carbocycle, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and
  • R 7a is selected from:
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C6)alkenyl, (C 2 - C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C7)cycloalkyl, aryl, heterocycle and heteroaryl; and d) -N(R 9 )R 10 , -
  • R is selected from:
  • (C3-C 7 )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • (C 1 -C 6 )alkyl wherein (C 1 -C 6 )alkyl is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • any -X(C 2 -C 6 )alkenyl, -X(C2-C 6 )alkynyl and -X(C 3 -C 7 )carbocycle is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 4 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • 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 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • R 8a is selected from:
  • R 8b is selected from:
  • -(d-C 6 )alkyl-Z 14 -(d-C ⁇ alkyl-C ⁇ -id-C ⁇ alkyl-Z 13 , -(d-C 6 )alkyl-C(0)-0(d- C 6 )alkyl-Z 13 , -(d-C 6 )alkyl-0-(d-C6)alkyl-Z 13 , -(d-C ⁇ alkyl-S- d- ⁇ alkyl-Z 13 , -(C C 6 )alkyl-0-(d-C 6 )alkyl-(C 3 -C 7 )carbocycle, -(d-C 6 )alkyl-S-(d- C 6 )alkyl-(C 3 -C 7 )carbocycle, -(C 1 -C 6 )alkyl-S(0)-(C 1 -C 6 )alkyl-(C 3 -C 7 )carbocycle, -(d-
  • 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 1 groups, wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C 7 )carbocycle or heterocycle wherein the (C 3 -C7)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • Z 2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • any -X(C 2 -C 6 )alkynyl and -X(C3-C 7 )carbocycle wherein any -X(C C6)alkyl and-X ⁇ - C 6 )haloalkyl, is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups, and wherein any -X(C 2 -C 6 )alkenyl, -X(C 2 -C 6 )alkynyl and -X(C 3 -C 7 )carbocycle is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 4 groups and optionally substituted with one or more (e.g. 1,
  • 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 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • R 5a and R 6a , R 6a and R 7a , R 7a and R 8a , R 1 and R 8 or R 1 and R 2 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.
  • substituents each independently selected from halo, (Q-C ⁇ alkyl, (C 2 -C 6 )alkenyl, (Q- C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, -OH, -0(C 1 -C 6 )alkyl, -SH, -S d-C ⁇ alkyl, -NH 2 , -NH(C C 6 )alkyl and -N((C C 6 )alkyl) 2 ;
  • R 5 and R 6 , R 6 and R 7 or R 7 and R 8 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) Z 7 or Z 8 groups, wherein when two Z 7 groups are on same atom the two Z 7 groups together with the atom to which they are attached optionally form a (C 3 -C 7 )carbocycle or 4, 5 or 6- membered heterocycle;
  • R 1 and R 8 or R 1 and R 2 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) Z 7 or Z 8 groups; wherein when two Z 7 groups are on same atom the two Z 7 groups together with the atom to which they are attached optionally form a (C 3 -C 7 )carbocycle or 4, 5 or 6-membered heterocycle;
  • X is independently selected from O, -C(O)-, -C(0)0-, -S-, -S(O)-, -S0 2- , -(C C 6 )alkylO-, -(Ci-C 6 )alkylC(0)-, -(C 1 -C 6 )alkylC(0)0-, -(d-C 6 )alkylS-, -(C
  • C 7 halocarbocycle, aryl, heteroaryl or heterocycle of Z 1 , 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, -OR b , -CN, -NR a C(0) 2 R b , -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(0) 2 NRcR ⁇ i;
  • each Z 2 is independently selected from -N0 2 , -CN, spiro-heterocycle, bridge- heterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, NR a S0 2 (C 3 - C 7 )carbocycle, -NR a S0 2 aryl, -NR a S0 2 heteroaryl, -NR a S0 2 NR c R d , -NRaS0 2 0(C 3 - C 7 )carbocycle and -NR a S0 2 Oaryl;
  • each Z 5 is independently selected from -N0 2 , -CN, -NR a S0 2 NRcR ⁇ i, - -NR a S0 2 0(C 3 -C 7 )carbocycle, -NR a S0 2 Oaryl, -NR a S0 2 (C !
  • -NR a S0 2 heterocycle -NR a C(0)alkyl, -NR a C(0)alkenyl, -NR a C(0)alkynyl, -NR a C(0) (C 3 -C 7 )carbocycle, -NR a C(0)(C 3 -C 7 )halocarbocycle, -NR a C(0)aryl,
  • each Z 6 is independently selected from -N0 2 , -CN, -NR a R a , -NR a C(0)R b , -NR a C(0)OR , -C(0)NRcRd, (C 3 -C 7 )halocarbocycle, aryl, heteroaryl, heterocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -0(C 3 -C 7 )halocarbocycle, -0(C C6)alkyl, -0(C 3 - C 7 )carbocycle, -Ohalo(C 1 -C6)alkyl, -Saryl, -Sheteroaryl, -Sheterocycle, -S(C 3 - C 7 )hal
  • -S0 2 heterocycle -S0 2 (d-C 6 )alkyl, -S0 2 halo(C]-C 6 )alkyl, -S0 2 (C3-C 7 )carbocycle, -S0 2 (C 3 -C 7 )halocarbocycle, -S0 2 NR c R d , -NR a S0 2 (C 3 -C 7 )halocarbocycle,
  • halogen 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, -NRaC(0) 2 Rb, heteroaryl, heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle or -S(0) 2 NRcRd;
  • each Z is independently selected from -N0 2 and -CN;
  • each Z 9 is independently selected from -(C 1 -C 6 )alkyl and -0(Ci-C6)alkyl;
  • each Z 10 is independently selected from:
  • aryl, heterocycle and heteroaryl which aryl, heterocycle and heteroaryl is optionally substituted with halo, (CrC 6 )alkyl or COOH;
  • halogen 1, 2, 3, 4 or 5) halogen, -OH, -03 ⁇ 4, -CN, -NR a C(0) 2 R b , -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(0) 2 NR c Rd;
  • halogen 1, 2, 3, 4 or 5) halogen, -OH, -OR b , -CN, -NR a C(0) 2 R b , -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(0) 2 NR c R d ;
  • each R a is independently H, (Q-Ce ⁇ lkyl, (C 2 -C 6 )alkenyl, (C 2 -C )alkynyl, (C 3 -C 7 )carbocycle, heterocycle, aryl, aryl(C 1 -C 6 )alkyl-, heteroaryl or heteroaryl(C ! - C 6 )alkyl-, wherein any (C ! -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C6)alkynyl,
  • (C 3 -C 7 )carbocycle, heterocycle, aryl, or heteroaryl of Ra, either alone or as part of a group, is optionally substituted by halogen, OH and cyano;
  • each R b is independently (d-C6)alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl,
  • (C 3 -C 7 )carbocycle, heterocycle, aryl, or heteroaryl of R b is optionally substituted by halogen, OH and cyano;
  • R c and Ra are each independently selected from H, (Q-C ⁇ alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, aryl, aryl(C 1 -C 6 )alkyl-, heterocycle, heteroaryl and heteroaryl(C 1 -C 6 )alkyl-, wherein any (CrC 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C )alkynyl, (C 3 -C 7 )carbocycle, heterocycle, aryl and heteroaryl of R c or Rj, either alone or as part of a group, is optionally substituted by halogen, OH and cyano; or R c and Ra together with the nitrogen to which they are attached form a heterocycle, wherein any heterocycle of Rc and 3 ⁇ 4 together with the nitrogen to which they
  • each 3 ⁇ 4 is independently selected from -ORa, (C 1 -C 6 )alkyl and
  • (C3-C 7 )carbocycle wherein (C 1 -C 6 )alkyl and (C 3 -C 7 )carbocycle are substituted by one or more (e.g. 1, 2, 3, 4 or 5) Z 6 and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 , (C 2 -C 6 )haloalkyl, (C2-C 6 )alkenyl and (C 2 -C 6 )alkynyl, wherein any
  • (C 2 -C )haloalkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 , and aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl are substituted by one or more Z 5 ;
  • each f is independently selected from -Rg, -ORa, -(Q-C ⁇ alkyl-Z 6 , -S0 2 R g , -C(0)R g , C(0)OR g , and -C(0)NR ⁇ R g ; and
  • each R g is independently selected from H, -ORa, (Q-C ⁇ alkyl,
  • (C 2 -C )alkenyl, (C 2 -C 6 )alkynyl, aryl, heterocycle or heteroaryl of R g is optionally substituted with one or more Z 1 groups;
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
  • the invention also provides method for treating (e.g. preventing, mediating or inhibiting) the proliferation 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 salt thereof, to the mammal.
  • a mammal e.g. a human
  • the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g. for use in treating (e.g.
  • a mammal e.g. a human
  • the invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating (e.g. preventing, mediating or inhibiting) the proliferation 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 salt thereof, for use in the prophylactic or therapeutic treatment (e.g.
  • the invention also provides processes and intermediates disclosed herein that are useful for preparing compounds of formula I or salts thereof.
  • Alkyl is hydrocarbon containing normal, secondary or tertiary atoms.
  • an alkyl group can have 1 to 20 carbon atoms (i.e., (C 1 -C 20 )alkyl), 1 to 10 carbon atoms (i.e., (Ci-Cio)alkyi), 1 to 8 carbon atoms (i.e., (d-C 8 )alkyl)or 1 to 6 carbon atoms (i.e., (CrC 6 alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, - CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1 -butyl (n-Bu, n-butyl, -
  • 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.
  • an alkyl group can have 1 to 10 carbon atoms( .e., (C 1 -C 1 o)alkyl), or 1 to 6 carbon atoms( .e., (C 1 -C 6 )alkyl) or 1-3 carbon atoms(z ' .e., (C 1 -C 3 )alkyl).
  • Typical alkyl radicals include, but are not limited to, methylene(-CH 2 -), 1,1 -ethyl (-CH(CH 3 )-), 1,2-ethyl (-CH 2 CH 2 -), 1,1- propyl (-CH(CH 2 CH 3 )-), 1 ,2-propyl (-CH 2 CH(CH 3 )-), 1 ,3-propyl (-CH 2 CH 2 CH 2 -), 1 ,4- butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • Alkenyl is a straight or branched hydrocarbon containing normal, secondary or tertiary carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp double bond.
  • an alkenyl group can have 2 to 20 carbon atoms ⁇ i.e., C 2 - C 20 alkenyl), 2 to 8 carbon atoms ⁇ i.e., C 2 -C 8 alkenyl), or 2 to 6 carbon atoms ⁇ i.e., C 2 - C 6 alkenyl).
  • Alkynyl is a straight or branched hydrocarbon containing normal, secondary or tertiary carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond.
  • an alkynyl group can have 2 to 20 carbon atoms ⁇ i.e., C 2 -C 20 alkynyl), 2 to 8 carbon atoms ⁇ i.e., C 2 -C 8 alkyne,), or 2 to 6 carbon atoms ⁇ i.e., C 2 -C 6 alkynyl).
  • suitable alkynyl groups include, but are not limited to, acetylenic (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like.
  • halo or halogen as used herein refers to fiuoro, chloro, bromo and iodo.
  • haloalkyl refers to an alkyl as defined herein, wherein one or more hydrogen atoms are each replaced by a halo substituent.
  • a (C C )haloalkyl is a (C 1 -C 6 )alkyl wherein one or more of the hydrogen atoms have been replaced by a halo substituent.
  • Such a range includes one halo substituent on the alkyl group to complete halogenation of the alkyl group.
  • aryl refers to a single aromatic ring or a bicyclic or multicyclic ring.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 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 is 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. 1, 2 or 3) oxo groups on any carbocycle portion of the bicyclic or multicyclic ring.
  • 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(C 1 -C 6 )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.
  • heteroaryl 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 present 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.
  • aryls e.g. indazolyl
  • Such multiple condensed rings may be optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups on the carbocycle portions of the 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.
  • 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, quinoxalyl, quinazolyl, 5,6,7,8- tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl and thianaphthenyl.
  • heterocyclyl 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 present in their oxidized forms.
  • Such rings include but are not limited to azetidinyl, tetrahydrofuranyl 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. decahydronapthyridinyl), heteroaryls (e.g. 1,2,3,4-tetrahydronaphthyridinyl), carbocycles (e.g. decahydroquinolyl) or aryls.
  • 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.
  • heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1 ,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3- benzodioxolyl and 1,4-benzodioxanyl.
  • bridged-heterocycle refers to a 4, 5, 6, 7 or 8- membered 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 (C 3 -C7)carbocycles as defined herein.
  • Such bridged-heterocycles include bicyclic and tricyclic ring systems (e.g. 2-azabicyclo[2.2.1]heptane and 4- azatricyclo[4.3.1.1 3 ' 8 ] undecane).
  • spiro-heterocycle refers to a 3, 4, 5, 6, 7 or 8- membered 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 (C 3 -C 7 )carbocycles as defined herein.
  • spiro- heterocycles include bicyclic and tricyclic ring systems (e.g. l,4-dioxaspiro[4.5]dec-7- enyl).
  • macroheterocycle 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 present 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).
  • a heteroaryl radical as described herein (i.e., a heteroaryl-alkyl- moiety).
  • heteroarylalkyl is typically 1 to 6 carbon atoms (i.e. heteroaryl(C 1 -C6)alkyl).
  • Heteroarylalkyl groups include, but are not limited to heteroaryl-CH 2 -, heteroaryl- CH(CH 3 )-, heteroaryl-CH 2 CH 2 -, 2-(heteroaryl)ethan-l-yl, and the like, wherein the "heteroaryl" portion includes any of the heteroaryl groups described above.
  • 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.
  • heteroarylalkyls include by way of example and not limitation 5- membered sulfur, oxygen, and/or nitrogen containing heteroaryls such as
  • thiadiazolylmethyl etc., 6-membered sulfur, oxygen, and/or nitrogen containing heteroaryls such pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, 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).
  • heterocyclylalkyl is typically 1 to 6 carbon atoms (i.e. heterocyclyl(C 1 -C )alkyl).
  • Typical heterocyclylalkyl groups include, but are not limited to heterocyclyl-CH 2 -, heterocyclyl-CH(CH 3 )-, heterocyclyl-CH 2 CH 2 -, 2-(heterocyclyl)ethan-l-yl, and the like, wherein the "heterocyclyl” portion includes any of the heterocyclyl groups described above.
  • heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon- carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • 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.
  • carbocycle 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.
  • the carbocycle is a monocycle comprising 3-6 ring carbons (i.e. (CrC 6 )carbocycle).
  • Carbocycle includes multicyclic carbocycles have 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.
  • spiro-bicyclic carbocycle refers to a carbocycle bicyclic ring system wherein the rings of the bicyclic ring system are connected to a single carbon atom (e.g. spiropentane, spiro[4,5]decane,
  • fused-bicyclic carbocycle refers to a carbocycle bicyclic ring system wherein the rings of the bicyclic ring system are connected 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 bicyclo [5,6] or [6,6] system (e.g. decahydronaphthalene, norsabinane, norcarane).
  • bridged-bicyclic carbocycle refers to a carbocycle bicyclic ring system wherein the rings of the bicyclic ring system are connected to two non-adjacent carbon atoms (e.g. norbornane, bicyclo[2.2.2]octane, etc).
  • Carbocycle or “carbocyclyl” may be optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups.
  • monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, 1- cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl and l-cyclohex-3- enyl.
  • halocarbocycle refers to a carbocycle as defined herein, wherein one or more hydrogen atoms are each replaced by a halo substituent.
  • (C 3 -C 7 )halocarbocycle is a (C3-C )carbocycle wherein one or more of the hydrogen atoms have been replaced by a halo substituent.
  • Such a range includes one halo substituent on the carbocycle group to complete halogenation of the carbocycle group.
  • macrocarbocycle 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 is replaced with a carbocyclyl radical as described herein (i.e. , a carbocyclyl-alkyl- moiety).
  • Carbocyclylalkyl is typically 1 to 6 carbon atoms (i.e. carbocyclyl(C 1 -C6)alkyl).
  • Typical carbocyclyl alkyl groups include, but are not limited to carbocyclyl-CH 2 -, carbocyclyl-CH(CH 3 )-, carbocyclyl-CH 2 CH 2 -, 2-(carbocyclyl)ethan-l-yl, and the like, wherein the "carbocyclyl” portion includes any of the carbocyclyl groups described above.
  • variable (C 1 -C 6 )alkyl when a variable is substituted, for example as described by the phrase "(Ci-C6)alkyl, either alone or as part of a group, is optionally substituted ", the phrase means that the variable (C 1 -C 6 )alkyl can be substituted when it is alone and that it can also be substituted when the variable "(C 1 -C 6 )alkyl" is part of a larger group such as for example an ary ⁇ Q-C ⁇ alkyl or a -(C 1 -C 6 )alkyl-S0 2 -(C 1 - C 6 )alkyl-(C 3 -C 7 )carbocycle group.
  • other variables e.g. (Ci- C 6 )alkenyl, (C 1 -C 6 )alkynyl, aryl, heteroaryl, heterocycle, etc ..
  • other variables e.g. (Ci- C 6 )alkenyl,
  • the modifier "about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error 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).
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have 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 molecules are not mirror images of one another. Diastereomers typically have different physical properties, 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 non- superimposable 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 R 4 position of formula I as marked by an asterisk in the formula below.
  • the invention includes all 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.
  • the compounds of the invention of formula I are at least 60% a single atropisomer for the R 4 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 R 4 substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I 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 at least 90% a single atropisomer for the R 4 substituent at the asterisk position. In another embodiment, the compounds of the invention of formula I are at least 95% a single atropisomer for the R 4 substituent at the asterisk position.
  • stereochemistry for the R 4 substituent at the carbon marked with an asterisk as shown above for Formula I is the (R) stereochemistry.
  • stereochemistry for the R 4 substituent at the carbon marked with an asterisk as shown above for Formula I is the (S) stereochemistry.
  • treatment or “treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
  • a specific 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 is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • 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 Groups in Organic Chemistry. Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional 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 intermediates 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 resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs.
  • Another function of a protecting group is to convert 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 intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g., alcohols, be physiologically acceptable, although in general it is more desirable 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 prepare 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 dependent upon the chemistry of the reaction 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, hydroxyl, 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 dependent 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.
  • protecting groups for -OH groups include "ether- or ester-forming groups".
  • Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein.
  • some hydroxyl and thio protecting 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.
  • the compounds of the invention may have chiral centers, e.g., chiral carbon or phosphorus atoms.
  • the compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.
  • the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms.
  • the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures.
  • racemic mixtures can be separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances.
  • optically active adjuncts e.g., acids or bases followed by conversion back to the optically active substances.
  • the desired optical isomer is synthesized by means of stereospecific 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 resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
  • ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
  • Examples of pharmaceutically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and
  • salts of a hydrogen atom or an amino group include for example salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic 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 N3 ⁇ 4 + (wherein X is independently selected from H or a C ⁇ -C ⁇ alkyl group).
  • salts of active ingredients of the compounds of the invention will typically be pharmaceutically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of formula I or another compound of the invention. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
  • metal salts which are prepared in this way are salts containing Li + , Na + , and K + .
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • 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.
  • salts of the parental compounds with one or more amino acids are also included within the scope of this invention. Any of the natural or unnatural amino acids are suitable, especially the naturally-occurring amino acids found as protein
  • 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.
  • a basic or acidic group e.g., lysine, arginine or glutamic acid
  • a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( H or D).
  • a -CH 3 group may be substituted with -CD 3 .
  • a specific group of compounds of formula I are compounds of formula la.
  • a specific group of compounds of formula I are compounds wherein at least one of R 1 , R 2 , R 3 , R 3' , R 4 , R 5 , R 6 , R 7 , or R 8 is selected from R lb , R 2b , R 3b , R 3b' , R 4b , R 5b , R 6b , R 7b and R 8b .
  • R 1 , R 2 , R 3 , R 3' , R 4 , R 5 , R 6 , R 7 , or R 8 are selected from R ,b , R 2b , R 3b , R 3b' , R 4b , R 5b , R 6b , R 7b and R 8b .
  • R 1 , R 2 , R 3 , R 3' , R 4 , R 5 , R 6 , R 7 , or R 8 are independently selected from R lb , R 2b , R 3b , R 3b' , R 4b , R 5b , R 6b , R 7 " and R 8b .
  • R 1 , R 2 , R 3 , R 3' , R 4 , R 5 , R 6 , R 7 , or R 8 are selected from R lb , R 2b , R 3b , R 3b' , R 4b , R 5b , R 6b , R 7b and R 8b .
  • R 1 , R 2 , R 3 , R 3' , R 4 , R 5 , R 6 , R 7 , or R 8 are selected from R lb , R 2b , R 3b , R 3b' , R 4b , R 5b , R 6b , R 7 " and R 8b .
  • R 1 , R 2 , R 3 , R 3' , R 4 , R 5 , R 6 , R 7 , or R 8 are independently selected from R lb , R 2b , R 3b , R 3b' , R 4b , R 5b , R 6b , R 7b , or R 8b .
  • R 1 , R 2 , R 3 , R 3' , R 4 , R 5 , R 6 , R 7 , or R 8 are independently selected from R lb , R 2b , R 3b , R 3b' , R 4b , R 5b , R 6b , R 7b and R 8b .
  • R , R 2 , R 3 , R 3' , R 4 , R 5 , R 6 , R 7 , or R 8 are independently selected from R lb , R 2b , R 3b , R 3b' , R 4b , R 5b , R 6b , R 7b and R 8b .
  • R 1 , R 2 , R 3 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are R lb , R 2b , R 3b , R 3b' , R 4b , R 5b , R 6b , R 7b and R 8b .
  • R 3b A specific value for R 3 is R 3b .
  • R 3b A specific value for R 3b is -OC(CH 3 ) 2 CH 2 OH, -OC(CH 3 ) 2 CH 2 OH,
  • R is -(C 1 -C 6 )alkylOH or
  • R 3a Another specific valu lee ff ⁇ or R 3 is R 3a .
  • R 3a A specific value for R 3a is (CrC 6 )alkyl, (C 2 -C 6 )alkenyl or -0(C 1 -C 6 )alkyl, wherein any (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl of R 3a is optionally substituted with one or more groups selected from -0(C 1 -C 6 )alkyl, halo, oxo and -CN.
  • R 3a Another specific value for R 3a is -OC(CH 3 ).
  • R A specific value for R is R .
  • R 3b' is (CrC 6 )alkyl or -0(Ci-C 6 )alkyl.
  • R 3a A specific value for R 3 is R 3a .
  • a specific value for R 3a is H.
  • a specific group of compounds of formula I are compounds wherein R and R together with the carbon to which they are attached form a (C 3 -C 7 )carbocycle or heterocycle, wherein the (C 3 -C 7 )carbocycle or heterocycle is optionally substituted with one or more Z 1 groups.
  • Another specific group of compounds of formula I are compounds wherein R and R 3b together with the carbon to which they are attached form a (C 3 -C 7 )carbocycle or a 4, 5 or 6-membered heterocycle, wherein the (C 3 -C 7 )carbocycle or the 4, 5 or 6- membered heterocycle is optionally substituted with one or more Z 1 groups.
  • Another specific group of compounds of formula I are compounds wherein R and R 3b together with the carbon to which they are attached form a (C4-C 6 )carbocycle or a 5 or 6-membered heterocycle, wherein the (C 4 -C )carbocycle or the 5 or 6- membered heterocycle is optionally substituted with one or more Z 1 groups.
  • Another specific group of compounds of formula I are compounds wherein R and R 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 Z 1 groups.
  • Another specific group of compounds of formula I are compounds wherein R 3b and R together with the carbon to which they are attached form a tetrahydropyran or tetrahydrofuran optionally substituted with one or more Z 1 groups.
  • R 4b A specific value for R 4 is R 4b .
  • R 4b is (C ! -C 6 )alkyl, (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl, wherein (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl are each optionally substituted with one or more Z 1 groups.
  • R 4 Another specific value for R 4 is:
  • R 4b Another specific value for R 4b is (C3-C 7 )carbocycle, wherein (C 3 -C 7 )carbocycle is optionally substituted with one or more Z 1 groups, or wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C 6 )carbocycle or 5-6-membered heterocycle.
  • R 4b Another specific value for R 4b is:
  • R 4b is aryl, heterocycle or heteroaryl, wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R a Another specific value for R is R a .
  • R 4a A specific value for R 4a is:
  • a specific group of compounds of formula I are compounds wherein R 4 and R 3 together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle, wherein any macroheterocycle or macrocarbocycle of R 4 and R 3 together with the atoms to which they are attached may be optionally substituted with one or more Z 1 groups; and R 3 is H, (C 1 -C 6 )alkyl or -0(C!-C6)alkyl.
  • R Another specific value for R is H.
  • Another specific group of compounds of formula I are compounds wherein R 4 and R together with the atoms to which they are attached form the macroheterocycle or a macrocarbocycle further fused to a Z group:
  • Z is aryl, heteroaryl or (C3-C 6 )carbocycle
  • n3 is 2, 3 or 4;
  • W and W are each independently O, NH or CH 2 , and
  • R 1 A specific value for R 1 is R lb .
  • R 1 is R la .
  • R la is H or -CH 3 .
  • R 2b A specific value for R 2 is R 2b .
  • R 2 is R 2a .
  • a specific value for R 2a is H or -CH 3 .
  • R 5b A specific value for R 5 is R 5b .
  • R 5a Another specific value for R 5 is R 5a .
  • a specific value for R 5a is H.
  • R 6b A specific value for R 6 is R 6b .
  • R 6 Another specific value for R 6 is R 6a .
  • a specific value for R 6a is H.
  • R 7 A specific value for R 7 is R .
  • R 7 Another specific value for R 7 is R 7a .
  • R 7a is H, -CH 3 or halogen.
  • R 8b A specific value for R 8 is R 8b .
  • R Another specific value for R is R .
  • R 8a Another specific value for R 8a is H.
  • a specific group of compounds of formula I are compounds wherein R 4b is selected from;
  • aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more Z 7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; or
  • R is selected from;
  • aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more Z 7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; or
  • (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each independently substituted with one or more Z 7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups.
  • R 3 is (C ! -C 6 )alkyl, (C 2 -C 6 )alkenyl or -0(C 1 -C 6 )alkyl, wherein any (C C 6 )alkyl or
  • (C 2 -C 6 )alkenyl of R 3 is optionally substituted with one or more groups selected from -0(C 1 -C 6 )alkyl, halo, oxo and -CN, and wherein R is H.
  • R 4 is selected from:
  • aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (CrC ⁇ haloalkyl, (C 3 -C 7 )cycloalkyl, -OH, -0(C
  • aryl, heteroaryl and fused-heterocycle wherein aryl, heteroaryl and fused-heterocycle are each independently substituted with one or more Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R 4 is selected from:
  • aryl, heterocycle and heteroaryl wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (d-C 6 )alkyl, (C 2 -C 6 )alkenyl, (d-Ce ⁇ aloalkyl, (C 3 -C 7 )cycloalkyl, -OH, -0(d- C 6 )alkyl, -SH, -S(C 1 -C 6 )alkyl, -NH 2 , -NH(d-C 6 )alkyl and -N((C r C 6 )alkyl) 2 , wherein (Q- C 6 )alkyl is optionally substituted with hydroxy, -0(d-C 6 )alkyl, cyano or oxo; and
  • aryl, heteroaryl and fused-heterocycle wherein aryl, heteroaryl and fused-heterocycle are each independently substituted with one or more Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R 4 is selected from:
  • heterocycle and heteroaryl wherein heterocycle and heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (d- C 6 )alkyl, (C 2 -C 6 )alkenyl, (d-C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, -OH, -0(d-C 6 )alkyl, -SH, - S(d-C 6 )alkyl, -NH 2 , -NH(C r C 6 )alkyl and -N((d-C 6 )alkyl) 2 , wherein (C r C 6 )alkyl is optionally substituted with hydroxy, -0(C 1 -C 6 )alkyl, cyano or oxo; and
  • heteroaryl and fused-heterocycle wherein heteroaryl and fused- heterocycle are each independently substituted with one or more Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R 4 is selected from:
  • heterocycle wherein heterocycle is optionally substituted with one or more groups each independently selected from halo, (d-C 6 )alkyl, (C 2 -C 6 )alkenyl, (d- C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, -OH, -0(d-C 6 )alkyl, -SH, -S(d-C 6 )alkyl, -NH 2 , -NH(d- C 6 )alkyl and -N((C 1 -C6)alkyl) 2 , wherein (Q-C ⁇ alkyl is optionally substituted with hydroxy, -0(Ci-C6)alkyl, cyano or oxo; and
  • fused-heterocycle wherein fused-heterocycle is substituted with one or more Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R 4 is selected from:
  • bicyclic aryl, tricyclic aryl, bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl wherein any bicyclic aryl, tricyclic aryl, bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl,is optionally substituted with one or more groups each independently selected from halo, (Q- C 6 )alkyl, (C 2 -C 6 )alkenyl, (Ci-C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, -OH, -0(C 1 -C 6 )alkyl, -SH, - Sid-C ⁇ alkyl, -NH 2 , -NH(C 1 -C 6 )alkyl and -N((C ! -C 6 )alkyl) 2 , wherein (d-C ⁇ alkyl is optionally substituted with hydroxy,
  • 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 Z groups and optionally substituted with one or more Z 1 groups.
  • R 4 is selected from:
  • 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, (d-C 6 )alkyl, (C2-C 6 )alkenyl, (Q-C ⁇ haloalkyl, (C 3 - C 7 )cycloalkyl, -OH, -0(C 1 -C 6 )alkyl, -SH, -SCd-C ⁇ alkyl, -NH 2 , -NHCC C ⁇ alkyl and - N((C 1 -C6)alkyl) 2 , wherein is optionally substituted with hydroxy, -0(C ! - C )alkyl, cyano or oxo; and
  • bicyclic fused-heterocycle and tricyclic fused-heterocycle wherein bicyclic fused-heterocycle and tricyclic fused-heterocycle fused-heterocycle are each
  • R 4 is selected from: a) bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl wherein bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (Q- C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, -OH, -0(d-C 6 )alkyl, -SH, -SCQ-QDalkyl, -NH 2 , -NH(C C 6 )alkyl and -N((C 1 -C 6 )alkyl) 2 , wherein (C 1 -C 6 )alkyl is optionally substituted with hydroxy, -0(Ci-C 6 )alkyl
  • bicyclic fused-heterocycle and tricyclic fused-heterocycle wherein bicyclic fused-heterocycle and tricyclic fused-heterocycle fused-heterocycle are each substituted with one or more Z groups and optionally substituted with one or more Z groups.
  • R 4 is selected from:
  • tricyclic heterocycle wherein tricyclic heterocycle is optionally substituted with one or more groups each independently selected from halo, (Ci-C 6 )alkyl, (C 2 -
  • tricyclic fused-heterocycle wherein tricyclic fused-heterocycle fused- heterocycle is substituted with one or more Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R 4 is selected from:
  • aryl, heteroaryl and fused-heterocycle wherein aryl, heteroaryl and fused-heterocycle are each independently substituted with one or more Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R 4 is selected from aryl, heteroaryl and fused-heterocycle, wherein aryl, heteroaryl and fused-heterocycle are each independently substituted with one or more Z groups and optionally substituted with one or more Z 1 groups.
  • R 4 is selected from fused-heterocycle, wherein fused-heterocycle is substituted with one or more Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R 4 is selected from 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 Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R 4 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 Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R 4 is tricyclic fused-heterocycle, wherein tricyclic fused-heterocycle fused-heterocycle is substituted with one or more Z 7 groups and optionally substituted with one or more Z 1 groups.
  • a specific value for Z 10 is:
  • Z 10 Another specific value for Z 10 is halo.
  • R 4 is selected from heteroaryl and fused-heterocycle, wherein heteroaryl and fused- heterocycle are each independently substituted with one or more Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R 4 is fused-heterocycle, wherein fused-heterocycle is substituted with one or more Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R is selected from 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 Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R 4 is selected from bicyclic fused-heterocycle and tricyclic fused-heterocycle wherein bicyclic fused-heterocycle and tricyclic fused-heterocycle fused-heterocycle are each
  • T 1 substituted with one or more Z groups and optionally substituted with one or more Z groups.
  • R 4 is selected from tricyclic heterocycle, wherein tricyclic heterocycle is optionally substituted with one or more groups each independently selected from halo, (Q-C ⁇ alkyl, (C 2 - C 6 )alkenyl, (Q-Q haloalkyl, (C 3 -C 7 )cycloalkyl, -OH, -0(C 1 -C 6 )alkyl, -SH, -SCd-Q alkyl, -NH 2 , -NH(d-C 6 )alkyl and -N((d-C 6 )alkyl) 2 , wherein (d-C 6 )alkyl is optionally substituted with hydroxy, -0(C 1 -C 6 )alkyl, cyano or oxo; and
  • R 4 is selected from tricyclic fused-heterocycle, wherein tricyclic fused-heterocycle fused- heterocycle is substituted with one or more Z 7 groups and optionally substituted with one or more Z 1 groups.
  • R 4 Another specific group of compounds of formula I are compounds wherein R is selected from:
  • 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, (C C6)alkyl, (C2-C 6 )alkenyl, (C 1 -C6)haloalkyl, (C 3 - C 7 )cycloalkyl, -OH, -OCQ-Q alkyl, -SH, -S(C 1 -C 6 )alkyl, -NH 2 , -NHCd-C ⁇ alkyl and - wherein (C 1 -C 6 )alkyl is optionally substituted with hydroxy, -0(Ci- C 6 )alkyl, cyano or oxo; and
  • aryl, heteroaryl, spiro-heterocycle, fused-heterocycle, and bridged- heterocycle wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridged- heterocycle are each independently substituted with one or more Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5 ) Z 1 groups.
  • R 4 is selected from aryl, heteroaryl, spiro-heterocycle, fused-heterocycle, and bridged- heterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridged- heterocycle are each independently substituted with one or more Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5 ) Z 1 groups.
  • R 4 is selected from:
  • heterocycle wherein any heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) groups each independently selected halo, (Q-C ⁇ alkyl and (Q- C 6 )haloalkyl; and
  • fused-heterocycle wherein fused-heterocycle is substituted with one or
  • R 4 Another specific value for R 4 is heterocycle.
  • Another specific group of compounds of formula I are compounds wherein the stereochemistry of the R 4 substituent relative to the carbon of formula I to which it is attached is the (R) stereochemistry.
  • Another specific group of compounds of formula I are compounds wherein the stereochemistry of the R 4 substituent relative to the carbon of formula I to which it is attached is the (S) stereochemistry.
  • Another specific group of compounds of formula I are compounds wherein R is selected from:
  • each R 9 is independently selected from H, (d-C 6 )alkyl and (C3-C 7 )cycloalkyl
  • each R 11 is independently selected from H, (C 1 -C6)alkyl, (C 2 -C6)alkenyl, (C 2 - C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, and wherein any
  • each R 9 is independently selected from H, (CrC 6 )alkyl and (C 3 -C 7 )cycloalkyl
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, hetero
  • aryl, heteroaryl and heterocycle wherein aryl heteroaryl and heterocycle are each substituted with one or more Z 5 groups and optionally substituted with one or more Z 1 groups;
  • R 1 is selected from:
  • aryl and heteroaryl wherein aryl and heteroaryl are each substituted with one or more Z 5 groups and optionally substituted with one or more Z 1 groups.
  • R 1 is selected from:
  • (C 2 -C 6 )alkynyl wherein (d-C ⁇ haloalkyl, (C 3 -C 7 )carbocycle, (C 2 -C 6 )alkenyl and (C 2 -C )alkynyl are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more Z 1 groups.
  • (d-C ⁇ haloalkyl, (C 3 -C 7 )carbocycle, (C 2 -C 6 )alkenyl and (C 2 -C )alkynyl are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more Z 1 groups.
  • R 1 is selected from:
  • aryl, heteroaryl and heterocycle wherein aryl heteroaryl and heterocycle are each substituted with one or more Z 5 groups and optionally substituted with one or more Z 1 groups;
  • R is halo
  • R is fluoro
  • R Another specific value for R is H.
  • R H halo or (d-C 6 )alkyl.
  • R is H or halo.
  • R 2 is selected from:
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are
  • each R 9 is independently selected from H, (C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl
  • each R 10 is independently selected from R 11 , - (Q-C f alkyl-R 11 , -SO2-R 11
  • R 2 is selected from:
  • each R 11 is independently selected from H, (d-C )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (d- C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more Z 11 groups; d) -(d-C6)alkyl-N(R 9 )R 10 , wherein each R 9 is independently selected from H, (d-C 6 )alkyl and (C3-C )cycloalkyl, and each R 10 is independently selected from R u ,
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C6)alkenyl, (C 2 - C 6 )alkynyl, (C 1 -C )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl;
  • each R 11 is independently selected from H, (CrC 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci- C 6 )haloalkyl, (C3-C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more Z 11 groups; d) -(C 1 -C 6 )alkyl-N(R 9 )R 10 , wherein each R 9 is independently selected from H, (C 1 -C 6 )alkyl and (C 3 -C7)cycloalkyl, and each R 10 is independently selected from R 11 ,
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C7)cycloalkyl, aryl, heterocycle and heteroaryl;
  • R 2 is selected from:
  • (C 2 -C 6 )alkynyl wherein (C 3 -C 7 )carbocycle, (C 2 -C 6 )alkenyl and (C 2 -C )alkynyl are each substituted with one or more Z 6 groups and optionally substituted with one or more Z 1 groups.
  • R 2 is selected from:
  • R is methyl
  • R Another specific value for R is H.
  • R 6 is selected from:
  • R 6 is selected from:
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C )alkenyl, (C 2 -C 6 )alkynyl, (d- C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R 6 is optionally substituted with one or more Z 10 groups; d) -(C 2 -C6)alkynyl-(C 3 -C 7 )carbocycle, -(C 2 -C )alkynyl-aryl,
  • aryl wherein aryl is substituted with one or more Z 5 groups and optionally substituted with one or more Z 1 groups;
  • (C 2 -C 6 )alkynyl are each independently substituted with one or more Z 6 groups and optionally substituted with one or more Z 1 groups.
  • R 6 is selected from:
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C )alkenyl, (C 2 - C 6 )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R 6 is optionally
  • 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 5 groups and optionally substituted with one or more Z'groups;
  • R 6 is selected from:
  • each R 11 is independently selected from H, (CrC 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci- C )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R 6 is optionally substituted with one or more Z 10 groups; d) -(C 2 -C 6 )alkynyl-(C 3 -C 7 )carbocycle, -(C 2 -C 6 )alkynyl-aryl,
  • aryl wherein aryl is substituted with one or more Z 5 groups and optionally substituted with one or more Z 1 groups; and g) (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl, wherein (C 2 -C 6 )alkenyl and
  • (C 2 -C 6 )alkynyl are each independently substituted with one or more Z 6 groups and optionally substituted with one or more Z'groups.
  • R 6 is selected from:
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkeny
  • (C 2 -C 6 )alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z 1 groups;
  • 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 groups and optionally substituted with one or more Z ⁇ oups;
  • R 6 is selected from:
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Cj- C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R 6 is optionally substituted with one or more Z 10 groups; d) -(C 2 -C 6 )alkynyl-(C 3 -C 7 )carbocycle, -(C 2 -C 6 )alkynyl-aryl,
  • aryl wherein aryl is substituted with one or more Z 5 groups and optionally substituted with one or more Z'groups;
  • (C 2 -C 6 )alkynyl are each independently substituted with one or more Z 6 groups and optionally substituted with one or more Z 1 groups.
  • R 6 is selected from:
  • 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 5 groups and optionally substituted with one or more Z 1 groups;
  • R 6 is selected from:
  • each R 11 is independently selected from H, (C 1 -C )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-
  • (C3-C )carbocycle, (C 2 -C 6 )alkynyl, aryl, heterocycle and heteroaryl, as part of a group, is optionally substituted with one or more Z 1 groups;
  • (C 2 -C6)alkynyl are each independently substituted with one or more Z 6 groups and optionally substituted with one or more Z 1 groups.
  • R 6 is selected from:
  • (C 2 -C 6 )alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z 1 groups;
  • 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 5 groups and optionally substituted with one or more Z 1 groups;
  • R 6 is selected from:
  • each R 1 1 is independently selected from H, (Ci-Cejalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci- C 6 )haloalkyl, (C3-C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R 6 is optionally substituted with one or more Z 10 groups; d) -(C 2 -C 6 )alkynyl-(C 3 -C 7 )carbocycle, -(C 2 -C 6 )alkynyl-aryl,
  • aryl wherein aryl is substituted with one or more Z 5 groups and optionally substituted with one or more Z 1 groups;
  • (C 2 -C 6 )alkynyl are each independently substituted with one or more Z 6 groups and optionally substituted with one or more Z 1 groups.
  • R 6 is selected from:
  • 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 5 groups and optionally substituted with one or more Z 1 groups;
  • R 6 is selected from:
  • each R 11 is independently selected from H, (C 2 -C 6 )alkenyl, (C 2 -C )alkynyl, (Cj- C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R 6 is optionally substituted with one or more Z 10 groups; d) -(C 2 -C 6 )alkynyl-(C 3 -C 7 )carbocycle, -(C 2 -C 6 )alkynyl-aryl,
  • aryl wherein aryl is substituted with one or more Z 5 groups and optionally substituted with one or more Z 1 groups;
  • (C 2 -C 6 )alkynyl are each independently substituted with one or more Z 6 groups and optionally substituted with one or more Z 1 groups. Another specific value for R 6 is H.
  • R is selected from:
  • each R 11 is independently selected from H, (C 1 -C6)alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkyny
  • each R 9 is independently selected from H, (C !
  • R 7 is selected from:
  • each R 9 is independently selected from H, and (C 3 -C 7 )cycloalkyl
  • each R u is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (d-Ce ⁇ aloalkyl, (C3-C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z groups;
  • aryl and heteroaryl wherein aryl and heteroaryl are each substituted with one or more Z 5 groups and optionally substituted with one or more Z 1 groups; f) and (C 3 -C 7 )carbocycle are each substituted with one or more Z 6 groups and optionally substituted with one or more Z 1 groups; and
  • R 7 is selected from:
  • R 7 is selected from:
  • aryl and heteroaryl wherein aryl and heteroaryl are each substituted with one or more Z 5 groups and optionally substituted with one or more Z 1 groups
  • R 7 is selected from:
  • each R 9 is independently selected from H, (CrC 6 )alkyl and (C 3 -C 7 )cycloalkyl
  • each R 11 is independently selected from H, (d-C ⁇ alkyl, (C2-C 6 )alkenyl, (C 2 -C 6 )alkynyl, (CrC )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl,
  • R 7 Another specific value for R 7 is H, halo, (C 1 -C 6 )alkyl, (d-C ⁇ haloalkyl and heteroaryl, wherein heteroaryl is optionally substituted with one or more Z 10 groups.
  • R 7 is H, (d-C ⁇ alkyl or (C 1 -C 6 )haloalkyl.
  • R 7 Another specific value for R 7 is H.
  • R 8 is selected from:
  • each R 9 is independently selected from H, (d-C 6 )alkyl and (C 3 -C 7 )cycloalkyl
  • R 8 is selected from:
  • R 11 b) R 11 , -O-R 11 and -(d-C ⁇ alkyl-R 11 , wherein each R 11 is independently selected from H, (C C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Cj-C 6 )haloalkyl, (C 3 - C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z 11 groups;
  • aryl and heteroaryl are each independently substituted with one or more Z 5 groups and optionally substituted with one or more Z 1 groups;
  • R 8 is selected from:
  • R is selected from:
  • aryl and heteroaryl wherein aryl and heteroaryl are each independently substituted with one or more Z 5 groups and optionally substituted with one or more Z 1 groups;
  • R Another specific value for R is H.
  • R is H, (C 1 -C 6 )alkyl or halo.
  • each R g is independently selected from -OR ⁇ (Q-C ⁇ alkyl, (C 3 -C 7 )carbocycle (C!-C 6 )haloalkyl, (C2-C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, heterocycle and heteroaryl, wherein any (C 1 -C 6 )alkyl, (C3-C 7 )carbocycle -(CrC 6 )haloalkyl, (C 2 -C 6 )alkenyl,
  • (C2-C 6 )alkynyl, aryl, heterocycle or heteroaryl of R g is optionally substituted with one or more Z 1 groups.
  • R 1 isR la orR lb
  • R 2 is R 2a or R 2b
  • R 3 isR 3a orR 3b
  • R 3' isR 3a' orR 3b'
  • R 4 isR 4a orR 4b
  • R 5 isR 5a orR 5
  • R 6 is R 6a or R 6b
  • R 8 isR 8a orR 8b
  • R la is selected from:
  • each R 9 is independently selected from H, (C 1 -C 6 )alkyl and (C3-C 7 )cycloalkyl;
  • R lb is selected from:
  • (C 1 -C 6 )haloalkyl, (C 3 -C 7 )carbocycle, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl or heteroaryl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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) Z 1 groups; wherein two Z 1 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.
  • (C2-C 6 )alkynyl are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more Z 1 groups;
  • R 2a is selected from:
  • each R 11 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (d-C 6 )haloalkyl, (C 3 -C 7 )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) Z 11 groups;
  • each R 9 is independently selected from H, (C 1 -C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • R is selected from: a) -(C 1 -C6)alkyl-0-(C 1 -C 6 )alkyl-(C3-C 7 )carbocycle, -(C 1 -C 6 )alkyl-S-(C 1 - C 6 )alkyl-(C 3 -C 7 )carbocycle, -(C 1 -C 6 )alkyl-S(0)-(C 1 -C 6 )alkyl-(C 3 -C 7 )carbocycle, -(C C 6 )alkyl-S0 2 -(C 1 -C 6 )alkyl-(C 3 -C 7 )carbocycle, -(C 2 -C6)alkenyl-(Ci-C6)haloalkyl, -(C 2 - C 6 )alkynyl-(C 1 -C 6 )haloalkyl, -(C 1 -C 6 )alkyl-
  • spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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) Z 1 groups; wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C 7 )carbocycle or heterocycle wherein the
  • (C 3 -C 6 )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • (C 3 -C 7 )carbocycle are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 4 groups and optionally substituted with one or more Z 1 groups;
  • aryl heteroaryl and heterocycle are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1 , 2, 3, 4 or 5) Z 1 groups;
  • (C 2 -C 6 )alkynyl wherein (C 1 -C6)haloalkyl, (C3-C )carbocycle, (C 2 -C6)alkenyl and (C 2 -C 6 )alkynyl are each substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and
  • R 3a is (C 1 -C 6 )alkyl, (d-C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl,
  • any (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl or (C 2 -C 6 )alkynyl of R 3a is optionally substituted with one or more (e.g. 1, 2 or 3) groups selected from -0(d- C 6 )alkyl, halo, oxo and -CN; and wherein any (C 3 -C7)cycloalkyl, aryl, heterocycle, or heteroaryl of R 3a is optionally substituted with one or more (e.g. 1, 2 or 3) groups selected from (d-C 6 )alkyl, -0(C 1 -C 6 )alkyl, halo, oxo and -CN; and R 3a' is H ;
  • R 3b is -(C 3 -C 7 )carbocycle, aryl, heteroaryl, heterocycle, -(C 1 -C 6 )alkylOH, -(d- C 6 )alk l-0-(Ci-C 6 )alkyl-Z 12 , -(C 1 -C 6 )alkyl-0-(C 2 -C 6 )alkenyl-Z 12 , -(C 2 -C 6 )alkyl-0-(C 2 - C 6 )alkynyl-Z 12 , -(d-C 6 )allcyl-S-(Ci-C 6 )alkyl-Z 12 , -(C 1 -C 6 )alkyl-S-(C 2 -C 6 )alkenyl-Z 12 , - (C 2 -C 6 )alkyl-S-(C 2 -C 6 )alkynyl-Z 12 , -(d
  • any (C 1 -C )alkyl, aryl, (C 3 -C 7 )carbocycle, heteroaryl or heterocycle of R is optionally substituted with one or more (e.g.
  • R is H, (CrC 6 )alkyl or -0(C 1 -C 6 )alkyl; or R and R together with the carbon to which they are attached form a heterocycle or (C 3 -C 7 )carbocycle which heterocycle or (C 3 -C )carbocycle of R 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) Z 1 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, (Q-C ⁇ alkyl, (C 2 -C 6 )alkenyl, (C t -C ⁇ haloalkyl, (C 3 - C 7 )cycloalkyl, -OH, -0(C 1 -C 6 )alkyl, -SH, -S Q ⁇ alkyl, -NH 2 , -NH(C,-C 6 )alkyl and - N ⁇ Q-C ⁇ alkyl) ⁇ wherein (C 1 -C6)alkyl is optionally substituted with hydroxy, -0(Ci- C 6 )alkyl, cyano or oxo;
  • R 4b is selected from;
  • aryl, heteroaryl, spiro-, fused-, or bridged-heterocycle wherein aryl, heteroaryl, or spiro-, fused-, or bridged-heterocycle are each independently substituted with one or more Z 7 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; or
  • R 4 and R 3 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) Z groups; and R is H or (C 1 -C 6 )alkyl, -0(Ci-C 6 )alkyl.
  • R 5a is selected from:
  • each R 11 is independently selected from H, (C 1 -C6)alkyl, (C 2 -C 6 )alkenyl, (C 2 - C )alkynyl, (C 1 -C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, aryl, heterocycle and heteroaryl;
  • aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
  • each R 9 is independently selected from H, (C C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • R 5b is selected from:
  • spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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) Z 1 groups; wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C 7 )carbocycle or heterocycle wherein the (C 3 - C 7 )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • aryl heteroaryl are heterocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • (C 2 -C 6 )alkynyl where (C 3 -C 7 )carbocycle, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups; and
  • each (d-C 6 )alkyl is independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • R 6a is selected from:
  • any aryl, heterocycle or heteroaryl of R 6a is optionally substituted with one or more (e.g. 1, 2 or 3) Z 10 groups;
  • R 6b is selected from:
  • aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle wherein aryl heteroaryl and heterocycle are each independently substituted with one or more Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • (C 2 -C )alkynyl wherein (C Ceihaloalkyl, (C 3 -C 7 )carbocycle, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1 , 2, 3, 4 or 5) Z 1 groups; and
  • each (Cj-C 6 )alkyl is independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • R 7a is selected from:
  • any aryl, heterocycle or heteroaryl of R la is optionally substituted with one or more (e.g. 1, 2 or 3) Z 10 groups;
  • R is selected from:
  • spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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) Z 1 groups; wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C )carbocycle or heterocycle wherein the
  • (C 3 -C 6 )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • R 8a is selected from:
  • R 11 is independently selected from H, (d-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 - C6)alkynyl, (d-C6)haloalkyl, (C 3 -C7)cycloalkyl
  • aryl, heterocycle and heteroaryl are each optionally substituted with one or more (e.g. 1, 2 or 3) Z 11 groups;
  • each R 9 is independently selected from H, (d-C 6 )alkyl and (C 3 -C 7 )cycloalkyl;
  • R 8b is selected from:
  • spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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) Z 1 groups; wherein two Z 1 groups together with the atom or atoms to which they are attached optionally form a (C 3 -C 7 )carbocycle or heterocycle wherein the
  • (C3-C 7 )carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • (C2-C 6 )alkenyl, (C 2 -C6)alkynyl and (C3-C 7 )carbocycle are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 4 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • 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) Z 5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • each (Q-C ⁇ alkyl is independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 6 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 1 groups;
  • R 5a and R 6a , R 6a and R 7a , R 7a and R 8a , R 1 and R 8 or R 1 and R 2 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.
  • substituents each independently selected from halo, (Q-C ⁇ alkyl, (C 2 -C 6 )alkenyl, (Q- C 6 )haloalkyl, (C 3 -C 7 )cycloalkyl, -OH, -0(C C 6 )alkyl, -SH, -S(C]-C 6 )alkyl, -NH 2 , -NH(CrC 6 )alkyl and -N((C 1 -C 6 )alkyl) 2 ;
  • R 5 and R 6 , R 6 and R 7 or R 7 and R 8 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) Z 7 or Z 8 groups; wherein when two Z 7 groups are on same atom the two Z 7 groups together with the atom to which they are attached optionally form a (C3-C 7 )carbocycle or 4, 5 or 6- membered heterocycle;
  • X is independently selected from O, -C(O)-, -C(0)0-, -S-, -S(O)-, -S0 2- , -(d- C 6 )alkylO-, -(C 1 -C 6 )alkylC(0)0-, -(d-C 6 )alkylS-, -(C
  • C 7 halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle, -S(0)(C 1 -C 6 )alkyl, -S(0)(C 2 - C 6 )alkenyl, -S(0)(C 2 -C 6 )alkynyl, -S(0)(C 1 -C 6 )haloalkyl, -S(O) (C 3 -C 7 )carbocycle, - S(0)(C 3 -C 7 )halocarbocycle, -S0 2 (C !
  • halogen 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, -NR a C(0) 2 R b , -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, - NHheterocycle, or -S(0) 2 NR c R d ;
  • each Z 2 is independently selected from -N0 2 , -CN, spiro- heterocycle, bridge- heterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, NR a S0 2 (C 3 - C 7 )carbocycle, -NR a S0 2 aryl, -NR a S0 2 heteroaryl, -NR a S0 2 NR c R d , -NR a S0 2 0(C 3 - C 7 )carbocycle and -NR a S0 2 Oaryl;
  • -S0 2 heteroaryl -NR a Rb, -NR a C(0)Rb, -C(0)NR c Rd, -S0 2 NR c R d , -NR a S0 2 NRcRd, -NR a S0 2 0(C 3 -C 7 )carbocycle and -NR a S0 2 Oaryl;
  • each Z 5 is independently selected from -N0 2 , -CN, -NRaS0 2 NRcRd, - NR a S0 2 0(C 3 -C 7 )carbocycle, -NR a S0 2 Oaryl, -NR a SO ⁇ Q-C ⁇ alkyl, -NR a S0 2 (C 2 - C 6 )alkenyl, -NR a S0 2 (C 2 -C 6 )alkynyl, -NR a S0 2 (C 3 -C 7 )carbocycle, -NR a S0 2 (C 3 - C 7 )halocarbocycle, -NR a S0 2 aryl, -NR a S0 2 heteraryl, -NR a S0 2 heteroaryl,
  • -NR a S0 2 heterocycle -NR a C(0)alkyl, -NR a C(0)alkenyl, -NR a C(0)alkynyl, -NR a C(0) (C 3 -C 7 )carbocycle, -NR a C(0)(C 3 -C 7 )halocarbocycle, -NR a C(0)aryl, -NR a C(0)heteroaryl, -NR a C(0)heterocycle, NR a C(0)NR c R ⁇ i and NR a C(0)OR b ;
  • each Z 6 is independently selected from -N0 2 , -CN, -NRaR a , NR a C(0)Rb,- C(0)NR c R d , -(C3-C 7 )halocarbocycle, -aryl, -heteroaryl, -heterocycle, -Oaryl, - Oheteroaryl, -Oheterocycle, -0(C 3 -C 7 )halocarbocycle, -OCQ-Ci alkyl, -0(C 3 - C )carbocycle, -OhaloCCrC ⁇ alkyl, -Saryl, -Sheteroaryl, -Sheterocycle, -S(C 3 - C 7 )halocarbocycle, -SCQ-Ce ⁇ lkyl, -S(C 3 -C 7 )carbocycle, -S(C C 6 )haloalkyl, -S(0)
  • -S0 2 heterocycle -S0 2 (C 1 -C 6 )alkyl, -S0 2 halo(C 1 -C 6 )alkyl, -S0 2 (C 3 -C 7 )carbocycle, -S0 2 (C 3 -C 7 )halocarbocycle, -SOiNRcR d , -NR a S0 2 (C 3 -C 7 )halocarbocycle,
  • halogen 1, 2, 3, 4 or 5) halogen, -OH, -OR b , -CN, -NR a C(0)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, - NHheterocycle, or -S(0) 2 NR c R d.
  • each Z is independently selected from -N0 2 or -CN;
  • each Z 9 is independently selected from -(d-C 6 )alkyl, -0(C 1 -C )alkyl;
  • each Z 10 is independently selected from
  • aryl, heterocycle and heteroaryl which aryl, heterocycle and heteroaryl is optionally substituted with halo, (CrC 6 )alkyl or COOH;
  • any (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, -(C 3 -C 7 )halocarbocycle, (C 3 - C 7 )carbocycle, (C 3 -C 7 )halocarbocycle, aryl, heteroaryl or heterocycle of Z 13 is optionally substituted with one or more (e.g.
  • halogen 1, 2, 3, 4 or 5) halogen, -OH, -OR b , -CN, -NR a C(0) 2 Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, - NHheterocycle, or -S(0) 2 NR c R d ;
  • halogen 1, 2, 3, 4 or 5) halogen, -OH, -OR b , -CN, -NR a C(0) 2 R b , -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, - NHheteroaryl, -NHheterocycle, or -8(0) 2 3 ⁇ 43 ⁇ 4;
  • each Ra is independently H, (C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, heterocycle, aryl, aryl(C 1 -C 6 )alkyl-, heteroaryl or heteroary ⁇ Cr C 6 )alkyl-; wherein any (Q-C ⁇ alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl,
  • (C 3 -C 7 )carbocycle, heterocycle, aryl, or heteroaryl of R a is optionally substituted by halogen, OH and cyano;
  • each R is independently -(C!-C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, heterocycle, aryl, aryl(C 1 -C6)alkyl-, heteroaryl or heteroaryl(C ! - C 6 )alkyl-; wherein any (C 1 -C 6 )alkyl, -(C 2 -C 6 )alkenyl, -(C 2 -C 6 )alkynyl,
  • (C 3 -C 7 )carbocycle, heterocycle, aryl, or heteroaryl of R b is optionally substituted by halogen, OH and cyano;
  • Rc and Ra are each independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, aryl, aryl(C 1 -C 6 )alkyl-, heterocycle, heteroaryl or heteroaryl(C 1 -C 6 )alkyl- wherein any -(C 2 -C )alkenyl, -(C 2 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, heterocycle, aryl, or heteroaryl of Rc or 3 ⁇ 4 is optionally substituted by halogen, OH and cyano; or Rc and R d together with the nitrogen to which they are attached form a heterocycle; wherein any heterocycle of Rc and Ra together with the nitrogen to which they are attached is optionally substituted by halogen, OH or cyano; each
  • each Rf is independently selected from -Rg , -ORa , -(C 1 -C 6 )alkyl-Z 6 , -S0 2 R g , - C(0)R g , C(0)OR g , or -C(0)NReR g ; and
  • each R g is independently selected from -ORa, (CrC ⁇ alkyl, (C 3 -C 7 )carbocycle (C 1 -C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, heterocycle or heteroaryl wherein any (C 1 -C 6 )alkyl, (C 3 -C 7 )carbocycle -(Q-C ⁇ haloalkyl, (C 2 -C 6 )alkenyl,
  • (C 2 -C 6 )alkynyl, aryl, heterocycle or heteroaryl of R g is optionally substituted with one or more Z ⁇ groups;
  • the compounds of formula I include:
  • the compounds of formula I include:
  • the compounds of formula I include:
  • the compounds of formula I include:
  • the compounds of formula I include compounds 151- 180 as described in Example 149.
  • Scheme 1 is provided as a further embodiment of the invention and illustrates a process that was used to prepare a compound of formula I and which can be used to prepare other compounds of formula I.
  • Schemes 2-6 are also provided as further embodiments of the invention and illustrate processes that can be used to prepare compounds of formula I.
  • 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 salt such as, for example, copper(I) iodide, N,N- diisopropylethylamine, tetrakis(triphenylphosphine)palladium(0) and
  • tetrabutylammonium fluoride Metalation of a terminal alkyl (ID) such as, for example, deprotonation with n-butyllithium, yields the corresponding metal acetylide such as, for example lithium acetylide, that undergoes nucleophilic addition to an appropriate electrophile (IE) to give the corresponding hydroxy alkyne addition product IF.
  • ID terminal alkyl
  • IE electrophile
  • 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 IF 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 1G.
  • the substituted naphthalene 1G can undergo a cross-coupling reaction such as, for example Stille cross-coupling 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, for example, vinylnaphthalene 1H.
  • the vinylnaphthalene 1H can be dihydroxylated 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 IK 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 1L.
  • the primary hydroxyl can be oxidized to the corresponding carboxylic acid 1M by methods known to those skilled in the art such as, for example, periodic acid and chromium trioxide.
  • Metalation of a suitably functionalized and protected terminal alkyne such as, for example, deprotonation with n-butyllithium, can yield the corresponding metal acetylide such as, for example lithium acetylide, that undergoes nucleophilic addition to an appropriate electrophile, such as, for example IE, to give the corresponding hydroxy alkyne addition product 2 A.
  • 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 such as, for example iodonaphthalene 2B.
  • the substituted naphthalene 2B can undergo a cross- coupling 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)palladium(II) dichloride to give the corresponding cross- coupled naphthalene such as, for example, vinylnaphthalene 2C.
  • the alkenylnaphthalene 2C can be dihydroxylated using 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 2D can be protected at the primary hydroxyl by an orthogonal protecting groups, such as, for example, pivalate ester using pivaloyl chloride and pyridine.
  • the secondary hydroxyl of 2E can be converted to the corresponding ether 2F, such as a tert-butyl ether using methods known 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 R 4 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.
  • the substituted hydroxyl naphthalene 2 J can undergo halogenation using an appropriate halogen source and catalyst such as, for example N-chlorosuccinimide and zirconium(rV) chloride to provide IK.
  • 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 selective cross-coupling reaction such as, for example Stille cross-coupling 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.
  • a tin reagent such as tributyl(vinyl)tin
  • a palladium catalyst such as bis(triphenylphosphine) palladium(II) dichloride
  • the alkenylnaphthalene can be dihydroxylated to provide 2N by methods known to those skilled in the art such as, Sharpless asymmetric dihydroxylation using, for example, commercially available AD mix-a.
  • 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 tert- butyl 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-coupling using a boronic acid and a palladium catalyst such as palladium(II) 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 trioxide.

Abstract

The invention provides compounds of formula (I): or a salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula (I), intermediates useful for preparing compounds of formula I and therapeutic methods for treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal using compounds of formula (I).

Description

APHT- 2 -YLACETIC ACID DERIVATIVES TO TREAT AIDS
Cross Reference to Related Application
This patent application claims the benefit of priority of U.S. application serial No. 61/361,314, filed July 2, 2010.
Background of the Invention
Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have 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 inhibit the replication of HIV. There is also a need for agents that are directed against alternate sites in the viral life cycle including agents that target the interaction of Lens Epithelial Derived Growth Factor (LEDGF/p75) and HIV-1 integrase.
Summary of the Invention
In one embodiment, the invention provides a compound of the invention which is a compound of formula I:
Figure imgf000002_0001
wherein:
Figure imgf000002_0002
R2 is R2a or R2b;
R3 is R3a or R3b;
R3' is R3a' or R3t R4 is R a or R4 ;
R5 is R5a or R5b;
R6 is R6a or R6 ;
R7 is R7a or R7";
R8 is R8a or R8 ;
Rla is selected from:
a) H, halo, (d-C6)alkyl and (C1-C6)haloalkyl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;
c) ^(^-^ '. -Ci^-O-^^ -O-R11, ^-^1, ^)-^1, ^-^1,
-(C1-C6)alkyl-R11, -(Ci-C6)alkyl-C(=0)-Ru, -(C1-C6)alkyl-C(=0)-0-R11, -(C C6)alkyl- 0-Rn, -(C1-C6)alkyl-S-R11, -(d-C6)alkyl-S(0)-Ru and -(C1-C6)alkyl-S02-R11, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C )alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and d) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10,
-(CrC6)alkyl-N(R9)R10, -(CrC6)alkyl-C(=0)-N(R9)R10, -(C1-C6)alkyl-0-C(=0)- N(R9)R10 and -(C1-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (C1-C6)alkyl and (C3-C7)cycloalkyl and wherein each R10 is independently selected from R^ -Cd-Q alkyl-R11, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and - C(=0)N(R9)R11 , wherein each R11 is independently selected from H, (C i -C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (d-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and
wherein any aryl, heterocycle and heteroaryl of Rla is optionally substituted with one or more (e.g. 1, 2 or 3) Z10 groups;
Rlb is selected from:
a) -(C1-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- C6)alkyl-(C3-C7) carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(Cr C6)alkyl-S02-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S02-(C1-C6)alkyl-Z13, -C(0)-(C1-C6)alkyl-Z13, -0-(C1-C6)alkyl-Z13, -S-(d-C6)alkyl-Z13, -S(0)-(d-C6)alkyl- Z13, -S02-(C1-C6)alkyl-Z13, -(C C6)alkyl-Z14, -(d-C6)alkyl-C(0)-(d-C6)alkyl-Z13, - (Ci-C6)alkyl-C(0)-0(d-C6)alkyl-Z13, -(d-C6)alkyl-0-(d-C6)alkyl-Z13, -(CrC6)alkyl- S-(Ci-C6)alkyl-Z13, -(C2-C6)alkenyl-(C1-C6)haloalkyl,
-(C2-C6)alkynyl-(d-C6)haloalkyl, -(C3-C7)halocarbocycle, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl -(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z and -halo(C!-C6)alkyl-Z , wherein any (C1-C6)alkyl, (Ci-C6)haloalkyl, (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 bridged- bicyclic 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 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) (C1-C6)alkyl, wherein (Q-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)alkyl, -X(C1-C6)haloalkyl, -X(C2-C6)alkenyl,
-X(C2-C6)alkynyl and -X(C3-C7)carbocycle, wherein any -X(Ci-Ce)alkyl and-X(C!- C6)haloalkyl, is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 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-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) (C C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and
(C2-C6)alkynyl, wherein (C1-C6)haloalkyl, (C3-C7)carbocycle, (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 (e.g. 1, 2, 3, 4 or 5) Z1 groups; and g) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(Ci-C6)alkyl-NRe f, -(C1-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NReRf and -(C1-C6)alkyl-S02NReRf, wherein any (C1-C6)alkyl, as part of a group is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
R2a is selected from:
a) H, (CrC6)alkyl and -0(d-C6)alkyl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;
c) -C(=0)-Rn, -C(=0)-0-Rn, -S-R11, -S(0)-Rn, -S02-Rn,
-(d-C6)alkyl-Rn, -(C1-C6)alkyl-C(=0)-R11, -(Ci-C6)alkyl-C(=0)-0-Rn, -(CrC6)alkyl- O-R11, -<d-C6)alkyl-S-Rn, -(C1-C6)alkyl-S(0)-R11 and -(C1-C6)alkyl-S02-R11, wherein each Ru is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-C6)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;
d) -OH, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(C1-C6)haloalkyl, -0(C3- C7)cycloalkyl, -Oaryl, -Oheterocycle and -Oheteroaryl; and
e) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(d- C6)alkyl-N(R9)R10, -(d-C6)alkyl-C(<))-N(R9)R10, -(d-C6)alkyl-0-C( ))-N(R9)R10, and -(CrC6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (d-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(d-C^alkyl-R11, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)RH, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-C )haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
R is selected from:
a) -(C1-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(d- C6)alkyl-S02-(d-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(Cj-C6)haloalkyl, -(C2- C6)alkynyl-(d-C6)haloalkyl, -(d-C^alkyl-SOs-iCj-C^alkyl-Z13, -C(0)-(d-C6)alkyl- Z13, -0-(C!-C6)alkyl-Z13, -S-(d-C6)alkyl-Z13, -S(0)-(d-C6)alkyl-Z13, -S02-(C!-
C6)alkyl-Z13, -(d-C6)alkyl-Z14, -(C1-C6)alkyl-C(0)-(C1-C6)alkyl-Z13, -(d-C6)alkyl- C(0)-0(C C6)alkyl-Z13, -(C1-C6)alkyl-0-(C1-C6)alkyl-Z13, -(d-C6)alkyl-S-(Ci- C6)alkyl-Z13, -(C3-C7)halocarbocycle,-NRaS02NRcRd, -NRaS020(C3-C7)carbocycle, - NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl- heterocycle, -(C3-C7)carbocycle-Z and -halo(CrC6)alkyl-Z , wherein any
(d-C6)alkyl, -(C1-C6)haloalkyl, (C3-C7)carbocycle, (C3-C7)halocarbocycle, (C2-
C )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 bridged- bicyclic 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 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) (C1-C6)alkyl, wherein (Ci-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(C!-C6)alkyl, X(C1-C6)haloalkyl, X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle, wherein any -X(C1-C6)alkyl and -X(C1-C6)haloalkyl, is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 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-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) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and
(C2-C6)alkynyl, wherein (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and
(C2-C )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(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NReRf, -(C1-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NReRf and -(Ci-C6)alkyl-S02NReRf, 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;
R3a is (Ci-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
-(C1-C6)alkyl-(C3-C7)cycloalkyl, -(C1-C6)alkyl-aryl, -(C1-C6)alkyl-heterocycle, -(d-C6)alkyl-heteroaryl, -0(C1-C6)alkyl, -0(C1-C6)haloalkyl, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(C3-C7)cycloalkyl, -Oaryl, -0(Ci-C6)alkyl-(C3-C7)cycloalkyl, -0(C1-C6)alkyl-aryl, -0(C1-C6)alkyl-heterocycle or -0(C1-C6)alkyl-heteroaryl, wherein any (C C6)alkyl, (d-C6)haloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl of R3a either alone or as part of a group, is optionally substituted with one or more (e.g. 1, 2 or 3) groups selected from -0(C!-C6)alkyl, halo, oxo and -CN, and wherein any
(C3-C )cycloalkyl, aryl, heterocycle or heteroaryl of R3a either alone or as part of a group, is optionally substituted with one or more (e.g. 1, 2 or 3) groups selected from (d-C6)alkyl, -0(C1-C6)alkyl, halo, oxo and -CN; and R3a' is H;
R 3b is -(C7-C)4)alkyl, -(C3-C7)carbocycle, aryl, heteroaryl, heterocycle,
-(d-C6)alkylOH, -(C1-C6)alkyl-0-(C1-C6)alkyl-Z12, -(C1-C6)alkyl-0-(C2- C6)alkenyl-Z12, -(d-C6)alkyl-0-(C2-C6)alkynyl-Z12, -(d-C^alkyl-S-id-Ce)^^12, -(d-C6)alkyl-S-(C2-C6)alkenyl-Z12, -(C C^alkyl-S-^-C^alkynyl-Z12, -(d-C6)alkyl- S(0)-(d-C6)alkyl-Z12, -(d-C6)alkyl-S(0)-(C2-C6)alkenyl-Z12, -(d-C6)alkyl-S(0)-(C2- C6)alkynyl-Z12, -(C1-C6)alkyl-S02-(C1-C6)alkyl-Z12, -(Ci-C6)alkyl-S02-(C2- C6)alkenyl-Z12, -(d-C6)alkyl-S02-(C2-C6)alkynyl-Z12, -(d-C6)alkyl-NRaRb,
-(C1-C6)alkylOC(0)-NRcR<i, -(d-C6)alkyl-NRa-C(0)-ORb,
-(C1-C6)alkyl-NRa-C(0)-NRaRb, -(d-C6)alkyl-S02(d-C6)alkyl, -(d-C6)alkyl- SChNRcRd, -(C1-C6)alkyl-NRaS02NRcRd, -(d-C6)alkyl-NRaS020(C3-C7)carbocycle, -(C1-C6)alkyl-NRaS020aryl, -(C1-C6)alkyl-NRa-S02-(C1-C6)alkyl,
-(C1-C6)alkyl-NRa-S02-halo(C1-C6)alkyl, -(d-C6)alkyl-NRa-S02-(C2-C6)alkenyl, -(d-C6)alkyl-NRa-S02-(C2-C6)alkynyl, -(d-C6)alkyl-NRa-S02-(C3-C7)carbocycle, -(d-C6)alkyl-NRa-S02-halo(C3-C7)carbocycle, -(d-C6)alkyl-NRa-S02-aryl,
-(Ci-C6)alkyl-NRa-S02-heteroaryl, -(d-C6)alkyl-NRa-S02-heterocycle, -0(C7-
Ci4)alkyl, -0(d-C6)alkyl-NRaRb, -0(C1-C6)alkylOC(0)-NRcRd, -0(d-C6)alkyl-NRa- C(0)-ORb, -0(d-C6)alkyl-NRa-C(0)-NRaRb, -0(C1-C6)alkyl-NRa-S02-(C1-C6)alkyl, -0(d-C6)alkyl-NRa-S02-halo(d-C6)alkyl, -0(d-C6)alkyl-NRa-S02-(C2-C6)alkenyl, -0(C1-C6)alkyl- Ra-S02-(C2-C6)alkynyl, -0(C1-C6)alkyl-NRa-S02-(C3-C7)carbocycle, -0(C1-C6)alkyl-NRa-S02-halo(C3-C7)carbocycle, -0(Ci-C6)alkyl-NRe-S02-aryl, -0(C1-C6)alkyl-NRa-S02-heteroaryl, -0(C1-C6)alkyl-NRa-S02-heterocycle,
-0(C1-C6)alkyl-NRa-S02-NRaRb, -0(C1-C6)alkyl-NRa-S02-(C3-C7)carbocycle,
-0(C1-C6)alkyl-NRa-S02-halo(C3-C7)carbocycle, -0(C1-C6)alkyl-NRa-S02-aryl, -0(Cr C6)alkyl-NRaS02NRcRd, -0(C1-C6)alkyl-NRaS020(C3-C7)carbocycle, -0(C C6)alkyl- NRaS02Oaryl, -Oheteroaryl, -Oheterocycle, -Sheteroaryl, -Sheterocycle,
-S(0)heteroaryl, -S(0)heterocycle, -S02heteroaryl or -S02heterocycle, wherein any (C1-C6)alkyl, -(C7-C14)alkyl, aryl, (C3-C7)carbocycle, heteroaryl or heterocycle of R3b, 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 R3b' is H, (C C6)alkyl or -0(Ci-C6)alkyl; or R3b and R3b' together with the carbon to which they are attached form a heterocycle or
(C3-C7)carbocycle which heterocycle or (C3-C )carbocycle of R3b and R3b 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;
R4a is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R4a is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) groups each independently selected from halo, (d-C6)alkyl, (C2-C6)alkenyl, (Q-C^haloalkyl, (C3- C7)cycloalkyl, -OH, -0(C1-C6)alkyl, -SH, -S Q-Q alkyl, -NH2, -NH d-C alkyl and - N((C1-C6)alkyl)2, wherein (C1-C6)alkyl is optionally substituted with hydroxy, -0(Ci- C6)alkyl, cyano or oxo;
R4b is selected from;
a) (CrC6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (CrC6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
b) (C3-C14)carbocycle, wherein (C3-C14)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;
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 bridged- heterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridged- heterocycle heterocycle are each independently substituted with one or more (e.g. 1, 2,
7 1
3, 4 or 5) Z 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 R3 is H, (Ci-C6)alkyl or -0(C C6)alkyl;
R5a is selected from:
a) halo, nitro and cyano;
b) R11, -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn, -(C1-C6)alkyl-Rn, -(C1-C6)alkyl-C(=0)-R11, -(Ci-C6)alkyl-C(=0)-0-Rn, -(d-C6)alkyl- O-R11, -(d-C6)alkyl-S-Rn, -(Ci-C6)alkyl-S(0)-RH and -(C1-C6)alkyl-S02-R11, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-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; and
c) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(d-
C6)alkyl-N(R9)R10, -(C1-C6)alkyl-C(=0)-N(R9)R10, -(d-C6)alkyl-0-C(=0)-N(R9)R10, and -(C1-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (d-C6)alkyl and (C3-C7)cycloalkyl, and each R10is independently selected from R11, -(d-C6)alkyl-Ru, -S02-Ru, -C(=0)-Rn, -C(=0)ORu and -C(=0)N(R9)RH, wherein each R11 is independently selected from H, (d-C6)alkyl, (C2-C6)alkenyl, (C2-
C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
R5b is selected from:
a) -(d-C6)alkyl-0-(d-C6)alkyl-(C3-C7)carbocycle,
-(C1-C6)alkyl-S-(C1-C6)alkyl-(C3-C7)carbocycle,
-(d-C6)alkylS(0)-(d-C6)alkyl-(C3-C7)carbocycle,
-(C1-C6)alkylS02(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(d-C6)haloalkyl, -(C2-C6)alkynyl-(d-C6)haloalkyl, -(C3-C7)halocarbocycle, -NRaS02NRcRd,
-NRaS020(C3-C7)carbocycle, -NRaS02Oaryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-aryl, -(C2-C6)alkenyl-heteroaryl, -(C2-C6)alkenyl-heterocycle,
-(C2-C6)alkynyl-(C3-C )carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z1 and -halo(C1-C6)alkyl-Z3, wherein any (CrC6)alkyl, (CrC6)haloalkyl, (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 bridged- bicyclic 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 (C3- C7)carbocycle or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
c) (Ci-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5)
Z1 groups;
d) -X(C1-C6)alkyl,-X(C1-C6)haloalkyl, -X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle, wherein any -X(C!-C6)alkyl and-X(C1-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 (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) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and
(C2-C6)alkynyl, where (C1-C6)haloalkyl, (C3-C )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) -NFU f, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NReRf, -(Ci-C6)alkylC(0)-NReRf,
Figure imgf000010_0001
-(Ci-C6)alkyl-S02NReRf, wherein any (C1-C6)alkyl, as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
R6a is selected from:
a) H, halo, (d-C6)alkyl and (d-C6)haloalkyl
b) (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;
c) -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn, -(Ci-C6)alkyl-Rn, -(C1-C6)alkyl-C(=0)-R11, -(C1-C6)alkyl-C(=0)-0-R11, -(Ci-C6)alkyl- O-R11, -(d-C^alkyl-S-R11, -(C1-C6)alkyl-S(0)-R11 and -(C1-C6)alkyl-S02-R11, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-
C6)alkynyl, (C!-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and d) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(Ci-C6)alkyl-N(R9)R10, -(C1-C6)alkyl-C(=0)-N(R9)R10,
Figure imgf000011_0001
N(R9)R10 and -(C1-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (C!-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(C1-C6)alkyl-R11, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle and heteroaryl of R ais optionally substituted with one or more (e.g. 1, 2 or 3) Z groups;
R6b is selected from:
a) -(C1-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(d- C6)alkyl-S02-(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(C1-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, -halo(C3-C7)carbocycle,-NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -(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-C )alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-ORa,
-(C2-C6)alkyl-(C3-C7)carbocycle-ORa, -(d-C^carbocycle-Z1 and -halo(C1-C6)alkyl-Z3, wherein any (C1-C6)alkyl, (d-C6)haloalkyl, (C3-C7)carbocycle, (C2-C )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 bridged- bicyclic 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 Z1 groups together with the atom or atoms to which they are attached optionally form a (C3-C7)cycloalkyl or heterocycle, wherein the (C3-
C7)cycloalkyl or heterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
c) (C1-C6)alkyl, wherein (C1-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(d-C6)alkyl, -X(C1-C6)haloalkyl, -X(C2-C6)alkenyl,
-X(C2-C6)alkynyl and -X(C3-C7)carbocycle, wherein any -X(C C )alkyl and-X^- 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-C6)alkynyl and -X(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, 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) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and
(C2-C6)alkynyl, wherein (d-C6)haloalkyl, (C3-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) -Ν¾¾ -C(0)NReRf, -OC(0)NReRf, -SChNReRf, -(C1-C6)alkyl-NReRf, -(C,-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NRsRf and -(C1-C6)alkyl-S02NRcRf, wherein any (C1-C6)alkyl, as part of a group, is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
R7a is selected from:
a) H, halo, (C1-C6)alkyl and (C1-C6)haloalkyl; b) (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;
c) -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Ru, -S02-Rn,
Figure imgf000013_0001
-(d-C6)alkyl- O-R11, -(Cj-Cf alkyl-S-R11, -(d-C alkyl-SCC -R11 and -(C1-C6)alkyl-S02-R11, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and d) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(d-C6)alkyl-N(R9)R10, -(C1-C6)alkyl-C(=0)-N(R9)R1°, -(d-C6)alkyl-0-C(=0)- N(R9)R10 and -(CrC6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (d-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(d-C6)alkyl-Rn, -S02-Ru, -C(=0)-Rn, -C(=0)ORu and -C(=0)N(R9)Ru, wherein each R11 is independently selected from H, (d-C6)alkyl, (C2-C6)alkenyl, (C2- C )alkynyl, (C1-C )haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle and heteroaryl of R7a is optionally substituted with one or more (e.g. 1, 2 or 3) Z10 groups;
R is selected from:
a) -(C1-C6)alkyl-S02-(C1-C6)alkyl-Z13, -C(0)-(C!-C6)alkyl-Z13, -0-(d- C6)alkyl-Z13, -S-(C!-C6)alkyl-Z13, -S(0)-(d-C6)alkyl-Z13, -S02-(C!-C6)alkyl-Z13, -(d-C6)alkyl-Z14, -(d-C6)alkyl-C(0)-(d-C6)alkyl-Z13, -(d-C6)alkyl-C(0)-0(d-
C6)alkyl-Z13, -(C1-C6)alkyl-0-(C1-C6)alkyl-Z13, -(C1-C6)alkyl-S-(C1-C6)alkyl-Z13, -(C C6)alkyl-0-(d-C6)alkyl-(C3-C7)carbocycle, -(d-C6)alkyl-S-(d- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(d- C6)alkyl-S02-(d-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(d-C6)haloalkyl, -(C2- C6)alkynyl-(d-C6)haloalkyl, -(C3-C7)halocarbocycle, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z and -halo(C1-C6)alkyl-Z , wherein any (d-C6)alkyl, (CrC6)haloalkyl, (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 bridged- bicyclic 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 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) (C1-C6)alkyl, wherein (C1-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(d-C6)alkyl, X(C1-C6)haloalkyl, X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle, wherein any -X(C1-C )alkyl and-X(C1-C6)haloalkyl, is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 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-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) (d-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (Q-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 (e.g. 1, 2, 3, 4 or 5) Z1 groups; and
g) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NReRf, -(C1-C6)alkylC(0)-NR€Rf, -(C1-C6)alkyl-0-C(0)-NR£Rf and -(C1-C6)alkyl-S02NReRf, 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;
R8a is selected from:
a) halo, nitro and cyano;
b) R11, -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R1 1, -S(0)-Rn, -S02-Rn, -(Ci-C6)alkyl-Rn, -(C1-C6)alkyl-C(=0)-R1 1, -(C1-C6)alkyl-C(=0)-0-R1 1, -(d-C^alkyl- OR11, -(d-C6)alkyl-S-Rn, -(C1-C6)alkyl-S(0)-R11 and -(C1-C6)alkyl-S02-R11, wherein each R1 1 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-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(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(d- C6)alkyl-N(R9)R10, -(C1-C6)alkyl-C(=0)-N(R9)R10, -(C1-C6)alkyl-0-C(=0)-N(R9)R10 and -(C1-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (d-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(C1-C6)alkyl-R11, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
R8b is selected from:
a) -(C1-C6)alkyl-S02-(C1-C6)alkyl-Z13, -C(0)-(C1-C6)alkyl-Z13, -0-(d- C6)alkyl-Z13, -S-(d-C6)alkyl-Z13, -S(0)-(d-C6)alkyl-Z13, -S02-(C C6)alkyl-Z13,
-(d-C6)alkyl-Z14, -(d-C^alkyl-C^-id-C^alkyl-Z13, -(d-C6)alkyl-C(0)-0(d- C6)alkyl-Z13, -(d-C6)alkyl-0-(d-C6)alkyl-Z13, -(d-C^alkyl-S- d-^alkyl-Z13, -(C C6)alkyl-0-(d-C6)alkyl-(C3-C7)carbocycle, -(d-C6)alkyl-S-(d- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(d- C6)alkyl-S02-(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(C1-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, -halo(C3-C7)carbocycle,-NRaS02NRcRd, - NRaS020(C3-C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z and -halo(C1-C6)alkyl-Z , wherein any (C C6)alkyl, (d-C6)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 (e.g. 1, 2, 3, 4 or 5) Z1 groups:
b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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 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) (C1-C6)alkyl, wherein (Q-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) -Xid-C^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^- C6)haloalkyl, is substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z 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-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) (Q-Ce haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (C1-C6)haloalkyl, (C3-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(0)NR<Rf, -OC(0)NReRf, -S02 ReRf, -(C1-C6)alkyl-NReRf, -(C1-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NReRf and -(C1-C6)alkyl-S02NReRf, wherein any
Figure imgf000016_0001
, 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 R5a and R6a, R6a and R7a, R7a and R8a, 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, (Q-C^alkyl, (C2-C6)alkenyl, (Q- C6)haloalkyl, (C3-C7)cycloalkyl, -OH, -0(C1-C6)alkyl, -SH, -S d-C^alkyl, -NH2, -NH(C C6)alkyl and -N((C C6)alkyl)2;
or any of R5 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 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 R 1 and R 8 or R 1 and R 2 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(0)0-, -S-, -S(O)-, -S02-, -(C C6)alkylO-, -(Ci-C6)alkylC(0)-, -(C1-C6)alkylC(0)0-, -(d-C6)alkylS-, -(C
C6)alkylS(0)- and -(C1-C6)alkylS02-;
each Z1 is independently selected from halo, -N02, -OH, =NORa, -SH, -CN, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)carbocycle, (C3- C7)halocarbocycle, aryl, heteroaryl, heterocycle, -0(C!-C6)alkyl, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(C1-C6)haloalkyl, -0(C3-C7)carbocycle, -0(C3-C7)halocarbocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -S(C1-C6)alkyl, -S(C2-C6)alkenyl, -S(C2-
C6)alkynyl, -SiC C^haloalkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle, -S(0)(CrC6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2- C6)alkynyl, -S(0)(C1-C6)haloalkyl, -S(O) (C3-C7)carbocycle, -S(0)(C3- C7)halocarbocycle, -S02(C!-C6)alkyl, -S(0)aryl, -S(0)carbocycle, -S(0)heteroaryl, -S(0)heterocycle, -S02(C2-C6)alkenyl, -S02(C2-C6)alkynyl, -S02(C1-C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, -S02aryl, -S02heteroaryl,
-S02heterocycle, -S02NRcRd, -NRcRd, -NRaC(0)Ra, -NRaC(0)ORa, -NRaC(0)NRcRd -NRaS02Rb, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle, -NRaS02Oaryl, -OS(0)2Ra, -C(0)Ra, -C(0)ORb, -C(0)NRcRd, and -OC(0)NRcRd, wherein any (d-C6)alkyl, (C C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, (C3-
C7)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, -ORb, -CN, -NRaC(0)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(0)2NRcR<i;
each Z2 is independently selected from -N02, -CN, spiro-heterocycle, bridge- heterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, NRaS02(C3- C7)carbocycle, -NRaS02aryl, -NRaS02heteroaryl, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle and -NRaS02Oaryl;
each Z3 is independently selected from -N02, -CN, -OH, oxo, =NORa, thioxo, aryl, heterocycle, heteroaryl, (C3-C )halocarbocycle, -0(Ci-C6)alkyl, -0(C3- C )carbocycle, -Ohalo(C3-C7)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -SfXI C6)alkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -Saryl, -Sheterocycle,
-Sheteroaryl, -S(0)(C!-C6)alkyl, -S(0)(C3-C7)carbocycle, -S(O) (C3-C7)halocarbocycle, -S(0)aryl, -S(0)heterocycle, -S(0)heteroaryl, -S02(Ci-C6)alkyl,
-S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, S02aryl, -S02heterocycle, -S02heteroaryl, -NRaRb, -NRaC(0)Rb, -C(0)NRcRd, -S02NRcRd, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle and -NRaS02Oaryl;
each Z4 is independently selected from halogen, (Ct-C^alkyl, (C3- C7)carbocycle, haloid -C6)alkyl, -N02, -CN, -OH, oxo, =NORa, thioxo, aryl, heterocycle, heteroaryl, (C3-C7)halocarbocycle, -0(C1-C6)alkyl, -0(C3-C7)carbocycle, - 0(C3-C7)halocarbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(C1-C6)alkyl, -S(C3- C7)carbocycle, -S(C3-C7)halocarbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(0)(Ci- C6)alkyl, -S(0)(C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S(0)aryl, - S(0)heterocycle, -S(0)heteroaryl, -S02(C1-C6)alkyl, -S02(C3-C7)carbocycle, -S02(C3- C7)halocarbocycle, S02aryl, -S02heterocycle, -S02heteroaryl, -NRaRb, -NRaC(0)Ra, -C(0)NRcRd, -S02NRcRd, -NR^NRcRa, -NRaS020(C3-C7)carbocycle and - NRaS02Oaryl;
each Z5 is independently selected from -N02, -CN, -NRaS02NRcR<i, - -NRaS020(C3-C7)carbocycle, -NRaS02Oaryl, -NRaS02(C!-C6)alkyl, -NRaS02(C2- C6)alkenyl, -NRaS02(C2-C6)alkynyl, -NRaS02(C3-C7)carbocycle, -NRaS02(C3- C7)halocarbocycle, -NRaS02aryl, -NRaS02heteroaryl, -NRaS02heteroaryl,
-NRaS02heterocycle, -NRaC(0)alkyl, -NRaC(0)alkenyl, -NRaC(0)alkynyl, -NRaC(0) (C3-C7)carbocycle, -NRaC(0)(C3-C7)halocarbocycle, -NRaC(0)aryl,
-NRaC(0)heteroaryl, -NRaC(0)heterocycle, NRaC(0)NRcRd and NRaC(0)ORb; each Z6 is independently selected from -N02, -CN, -NRaRa, -NRaC(0)Rb, -NRaC(0)OR , -C(0)NRcRd, (C3-C7)halocarbocycle, aryl, heteroaryl, heterocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -0(C3-C7)halocarbocycle, -0(C C6)alkyl, -0(C3- C7)carbocycle, -Ohalo(C1-C6)alkyl, -Saryl, -Sheteroaryl, -Sheterocycle, -S(C3- C7)halocarbocycle, -S(C1-C6)alkyl, -S(C3-C7)carbocycle, -S(Ci-C6)haloalkyl, -S(0)aryl, -S(0)heteroaryl, -S(0)heterocycle, -S(0)(C3-C7)halocarbocycle, -S(0)(C1-C6)alkyl, -S(0)(C3-C7)carbocycle, -S(0)halo(C1-C6)alkyl, -S02aryl, -S02heteroaryl,
-S02heterocycle, -S02(d-C6)alkyl, -S02halo(C]-C6)alkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, -S02NRcRd, -NRaS02(C3-C7)halocarbocycle,
-NRaS02aryl, -NRaS02heteroaryl, -NRaS02heteroaryl, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle and -NRaS02Oaryl;
each Z7 is independently selected from -N02, =NORa, -CN, -(d-C6)alkyl-Z12, -(C2-C6)alkenyl-Z12, -(C2-C6)alkenylOH, -(C2-C6)alkynyl-Z12, -(C2-C6)alkynyl-OH, -(Ci-C6)haloalkyl-Z12, -(C C6)haloalkylOH, -(C3-C7)carbocycle-Z12, -(C3- C7)carbocycleOH, (C3-C7)halocarbocycle, -(C1-C6)alkylNRcRd, -(d-
C6)alkylNRaC(0)Ra, -(C1-C6)alkylNRaS02Ra, aryl, heteroaryl, heterocycle, -0(d- C6)alkyl-Z12, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(C1-C6)haloalkyl, -0(C3- C7)carbocycle, -0(C3-C7)halocarbocycle, -Oaryl, -OCd-C^alkylNRcRd, -0(d- C6)alkylNRaC(0)Ra, -0(C1-C6)alkylNRaS02Ra, -Oheteroaryl, -Oheterocycle, -S(d- C6)alkyl-Z12, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, -S(C1-C6)haloalkyl, -S(C3- C7)carbocycle, -S(C3-C7)halocarbocycle, -S(C1-C6)alkylNRcRd, -S(C
C6)alkylNRaC(0)Ra, -S(C1-C6)alkylNRaS02Ra, -Saryl, -Sheteroaryl, -Sheterocycle, -S(0)(d-C6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(d-C6)haloalkyl, - S(0)(C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S02(d-C6)alkyl, -S(0)(d- C6)alkylNRcRd, -S(0)(C1-C6)alkylNRaC(0)Ra, -S(0)(C1-C6)alkylNRaS02Ra, -S(0)aryl, -S(0)heteroaryl, -S(0)heterocycle, -S02(d-C6)alkyl, -S02(C2-C6)alkenyl, -S02(C2- C6)alkynyl, -S02(C1-C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, -S02aryl, -S02heteroaryl, -S02heterocycle, -S02(C1-C6)alkylNRcRd, -S02(Cr
C6)alkylNRaC(0)Ra, -S02(C1-C6)alkylNRaS02Ra, -SO^RcRd, -NRaC(0)ORb,
-NRaC(0)NRcRd -NRaS02Rb, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle,
-NRaS02Oaryl, -OS(0)2Ra, -C(0)NRcRd, and -OC(0)NRcRd, wherein any (d-C6)alkyl, (d-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, (C3- C7)halocarbocycle, aryl, heteroaryl and heterocycle of Z7, 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, -NRaC(0)2Rb, heteroaryl, heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle or -S(0)2NRcRd;
Q
each Z is independently selected from -N02 and -CN;
each Z9 is independently selected from -(C1-C6)alkyl and -0(Ci-C6)alkyl;
each Z10 is independently selected from:
i) halo, oxo, thioxo, (C2-C6)alkenyl, (CrC^haloalkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-, -OH, -0(C
C6)alkyl, -O d-^haloalkyl, -SH, -S(d-C6)alkyl, -SO(d- C6)alkyl, -S02(d-C6)alkyl, -NH2, -NH(Ci-C6)alkyl and
-N((C1-C6)alkyl)2;
ii) (C i -C6)alkyl optionally substituted with -OH, -0-(C i - C6)haloalkyl or -0-(C1-C6)alkyl; and
iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle and heteroaryl is optionally substituted with halo, (CrC6)alkyl or COOH;
each Z11 is independently selected from Z10, -C(=0)-NH2, -C(=0)-NH(d- C4)alkyl, -C(=0)-N((C!-C4)alkyl)2, -C(=0)-aryl, -C(=0)-heterocycle and
-C(=0)-heteroaryl;
each Z12 is independently selected from -N02, =NORa, thioxo, aryl, heterocycle, heteroaryl, (C3-C7)halocarbocycle, (C3-C7)carbocycle, -0(C3-C7)carbocycle,
-Ohalo(C3-C7)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(C1-C6)alkyl, -S(C3-C7)carbocycle, -Shalo(C3-C7)carbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(0)(C1-C6)alkyl, -S(0)(C3-C7)carbocycle, -S(0)halo(C3-C7)carbocycle, -S(0)aryl, -S(0)heterocycle, -S(0)heteroaryl, -S02(C!-C6)alkyl, -S02(C3-C7)carbocycle, -S02(C3- C7)halocarbocycle, S02aryl, -S02heterocycle, -S02heteroaryl, -NRaRa, -NRaC(0)Rb, - C(0)NRcR<1, -SOzNRcRd, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle and
-NRaS02Oaryl;
each Z13 is independently selected from -N02, -OH, =NORa, -SH, -CN, -(C3- C7)halocarbocycle, -0(C!-C6)alkyl, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(d- C )haloalkyl, -0(C3-C7)carbocycle, -0(C3-C7)halocarbocycle, -Oaryl, -Oheteroaryl,
-Oheterocycle, -S(d-C6)alkyl, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, -S(d-C6)haloalkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle, -S(OXd-C6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(d-C6)haloalkyl, -S(0)(C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S(0)aryl, -S(0)heteroaryl, -S(0)heterocycle, -S02(C1-C6)alkyl, -S02(C2-C6)alkenyl, -S02(C2-C6)alkynyl,
-S02(C C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, -S02aryl, -S02heteroaryl, -S02heterocycle, -S02NRcRd, -NRc¾, -NRaC(0)Ra, -NRaC(0)ORb, -NRaC(0)NRcRd -NRaS02Rb,
Figure imgf000021_0001
-NRaS020(C3-C7)carbocycle,
-NRaS02Oaryl, -OS(0)2Ra, -C(0)Ra, -C(0)ORb, -C(0)NRcRd, and -OC(0)NRcRd, wherein any (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3- C7)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, -0¾, -CN, -NRaC(0)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(0)2NRcRd;
each Z14 is independently selected from -N02, =NORa > -CN, (C3- C7)halocarbocycle, -0(C3-C7)halocarbocycle, -S(C3-C7)halocarbocycle, -S(0)(C3- C7)halocarbocycle, -S02(C3-C7)halocarbocycle, -NRaSO^R-Rd, -NRaS020(C3- C7)halocarbocycle, -NRaS02Oaryl and -OS(0)2Ra, 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, -NRaC(0)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(0)2NRcRd;
each Ra is independently H, (Q-Ce^lkyl, (C2-C6)alkenyl, (C2-C )alkynyl, (C3-C7)carbocycle, heterocycle, aryl, aryl(C1-C6)alkyl-, heteroaryl or heteroaryl(C!- C6)alkyl-, wherein any (C!-C6)alkyl, (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 (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C7)carbocycle, heterocycle, aryl, aryl(C1-C )alkyl-, heteroaryl or
Figure imgf000021_0002
C6)alkyl-, wherein any (Q-C^alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,
(C3-C7)carbocycle, heterocycle, aryl, or heteroaryl of Rb, either alone or as part of a group, is optionally substituted by halogen, OH and cyano;
Rc and Ra are each independently selected from H, (Q-C^alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, aryl, aryl(C1-C6)alkyl-, heterocycle, heteroaryl and heteroaryl(C1-C6)alkyl-, wherein any (CrC6)alkyl, -(C2-C6)alkenyl, -(C2-C )alkynyl, (C3-C7)carbocycle, heterocycle, aryl and heteroaryl of Rc or Rj, either alone or as part of a group, is optionally substituted by halogen, OH and cyano; or Rc and Ra together with the nitrogen to which they are attached form a heterocycle, wherein any heterocycle of Rc and ¾ together with the nitrogen to which they are attached is optionally substituted by halogen, OH or cyano;
each ¾ is independently selected from -ORa, (C1-C6)alkyl and
(C3-C7)carbocycle, wherein (C1-C6)alkyl and (C3-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-C )haloalkyl, (C2-C6)alkenyl and (C2-C6)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 f is independently selected from -Rg, -ORa, -(Q-C^alkyl-Z6, -S02Rg, -C(0)Rg, C(0)ORg, and -C(0)NR<Rg; and
each Rg is independently selected from H, -ORa, (Q-C^alkyl,
(C3-C7)carbocycle, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heterocycle and heteroaryl, wherein any (d-C6)alkyl, (C3-C7)carbocycle, (C1-C6)haloalkyl,
(C2-C )alkenyl, (C2-C6)alkynyl, aryl, heterocycle or heteroaryl of Rg is optionally substituted with one or more Z1 groups;
or a salt thereof.
The invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
The invention also provides method for treating (e.g. preventing, mediating or inhibiting) the proliferation 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 salt thereof, to the mammal.
The invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof for use in medical therapy (e.g. for use in treating (e.g.
preventing, mediating or inhibiting) the proliferation 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 salt thereof for use in the manufacture of a medicament for treating (e.g. preventing, mediating or inhibiting) the proliferation 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 salt thereof, for use in the prophylactic or therapeutic treatment (e.g.
prevention, mediation or inhibiting) of the proliferation of the HIV virus or AIDS or for use in the therapeutic treatment of delaying the onset of AIDS or ARC symptoms.
The invention also provides processes and intermediates disclosed herein that are useful for preparing compounds of formula I or salts thereof.
Detailed Description of the Invention
Definitions
Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:
When trade names are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product.
"Alkyl" is hydrocarbon containing normal, secondary or tertiary atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., (C1-C20)alkyl), 1 to 10 carbon atoms (i.e., (Ci-Cio)alkyi), 1 to 8 carbon atoms (i.e., (d-C8)alkyl)or 1 to 6 carbon atoms (i.e., (CrC6 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, s- butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n- pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-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- 1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl
(-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2- pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4- methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 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 example, an alkyl group can have 1 to 10 carbon atoms( .e., (C1-C1o)alkyl), or 1 to 6 carbon atoms( .e., (C1-C6)alkyl) or 1-3 carbon atoms(z'.e., (C1-C3)alkyl). Typical alkyl radicals include, but are not limited to, methylene(-CH2-), 1,1 -ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1- propyl (-CH(CH2CH3)-), 1 ,2-propyl (-CH2CH(CH3)-), 1 ,3-propyl (-CH2CH2CH2-), 1 ,4- butyl (-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, i.e. a carbon-carbon, sp double bond. For example, an alkenyl group can have 2 to 20 carbon atoms {i.e., C2- C20 alkenyl), 2 to 8 carbon atoms {i.e., C2-C8 alkenyl), or 2 to 6 carbon atoms {i.e., C2- C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5- hexenyl (-CH2CH2CH2CH2CH=CH2).
"Alkynyl" is a straight or branched hydrocarbon containing normal, secondary 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 have 2 to 20 carbon atoms {i.e., C2-C20 alkynyl), 2 to 8 carbon atoms {i.e., C2-C8 alkyne,), or 2 to 6 carbon atoms {i.e., C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C≡CH), propargyl (-CH2C≡CH), and the like.
The term "halo" or "halogen" as used herein refers to fiuoro, chloro, bromo and iodo.
The term "haloalkyl" as used herein refers to an alkyl as defined herein, wherein one or more hydrogen atoms are each replaced by a halo substituent. For example, a (C C )haloalkyl is a (C1-C6)alkyl wherein one or more of the hydrogen atoms have been replaced by a halo substituent. Such a range includes one halo substituent on the alkyl group to complete halogenation 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 have 6 to 20 carbon atoms, 6 to 14 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 is 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. 1, 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(C1-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 present 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 of the 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, quinoxalyl, quinazolyl, 5,6,7,8- tetrahydroisoquinolinyl 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 present in their oxidized forms. Such rings include but are not limited to azetidinyl, tetrahydrofuranyl 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. decahydronapthyridinyl), 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, benzoxazinyl, dihydrooxazolyl, chromanyl, 1 ,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3- benzodioxolyl and 1,4-benzodioxanyl.
The term "bridged-heterocycle" as used herein refers to a 4, 5, 6, 7 or 8- membered 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 (C3-C7)carbocycles as defined herein. Such bridged-heterocycles include bicyclic and tricyclic ring systems (e.g. 2-azabicyclo[2.2.1]heptane and 4- azatricyclo[4.3.1.13'8] undecane).
The term "spiro-heterocycle" as used herein refers to a 3, 4, 5, 6, 7 or 8- membered 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 spiro- heterocycles include bicyclic and tricyclic ring systems (e.g. l,4-dioxaspiro[4.5]dec-7- enyl).
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 present 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
"heteroarylalkyl" is typically 1 to 6 carbon atoms (i.e. heteroaryl(C1-C6)alkyl).
Heteroarylalkyl groups include, but are not limited to heteroaryl-CH2-, heteroaryl- CH(CH3)-, heteroaryl-CH2CH2-, 2-(heteroaryl)ethan-l-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 5- membered sulfur, oxygen, and/or nitrogen containing heteroaryls such as
thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolylmethyl, oxazolylmethyl,
thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heteroaryls such pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, 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(C1-C )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 alkyl portion of the heterocyclyl alkyl by means of a carbon- 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 term "carbocycle" or "carbocyclyl" 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 (i.e. (CrC6)carbocycle).
Carbocycle includes multicyclic carbocycles have 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 bicyclic ring system wherein the rings of the bicyclic ring system are connected 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 bicyclic ring system wherein the rings of the bicyclic ring system are connected 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 bicyclo [5,6] or [6,6] system (e.g. decahydronaphthalene, norsabinane, norcarane). The term "bridged-bicyclic carbocycle" refers to a carbocycle bicyclic ring system wherein the rings of the bicyclic ring system are connected to two non-adjacent carbon atoms (e.g. norbornane, 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 examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, 1- cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl and l-cyclohex-3- enyl.
The term "halocarbocycle" as used herein refers to a carbocycle as defined herein, wherein one or more hydrogen atoms are each replaced by a halo substituent. For example, (C3-C7)halocarbocycle is a (C3-C )carbocycle wherein one or more of the hydrogen atoms have been replaced by a halo substituent. Such a range includes one halo substituent on the carbocycle group to complete halogenation 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 is replaced with a carbocyclyl radical as described herein (i.e. , a carbocyclyl-alkyl- moiety). The alkyl group of the
"carbocyclylalkyl" is typically 1 to 6 carbon atoms (i.e. carbocyclyl(C1-C6)alkyl). Typical carbocyclyl alkyl groups include, but are not limited to carbocyclyl-CH2-, carbocyclyl-CH(CH3)-, 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-C6)alkyl, either alone or as part of a group, is optionally substituted ", the phrase means that the variable (C1-C6)alkyl can be substituted when it is alone and that it can also be substituted when the variable "(C1-C6)alkyl" is part of a larger group such as for example an ary^Q-C^alkyl or a -(C1-C6)alkyl-S02-(C1- C6)alkyl-(C3-C7)carbocycle group. Similarly, when stated, other variables (e.g. (Ci- C6)alkenyl, (C1-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(0)0-, -S-, -S(O)-, -S02-, -(Ci-C^alkylO-, -(C1-C6)alkylC(0)-, -(C1-C6)alkylC(0)0-, -(Ci-QdalkylS-, -(Ci-C6)alkylS(0)- and -(Ci-C6)alkylS02-) certain values of X that are not symmetric can be oriented in either direction. For example, the -C(0)0-, can be oriented as either -C(0)0- or -OC(O)-, relative to the groups it connects.
One skilled in the art will recognize that substituents and other moieties of the compounds of formula I 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 have such stability are contemplated as falling within the scope of the present invention.
The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error 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 molecules which have the property of non- superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.
The term "stereoisomers" refers to compounds which have 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 molecules are not mirror images of one another. Diastereomers typically have different physical properties, 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 non- superimposable 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.
Figure imgf000030_0001
The chirality that results from the atropisomers at the asterisk position is a feature of certain compounds of the invention. Accordingly, the invention includes all 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 I 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 at 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 for the R4 substituent at the asterisk position. In 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 is 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 occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book 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 have the ability to rotate the plane of plane- polarized light. In describing an optically active compound, the prefixes (D and L) or (R and S) are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign 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 identical except that they are mirror images of one another. A specific 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 is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
Protecting Groups
In the context of the present 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 Groups in Organic Chemistry. Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional 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 intermediates 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 resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert 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 intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g., alcohols, be physiologically acceptable, although in general it is more desirable 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 prepare 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 dependent upon the chemistry of the reaction 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, hydroxyl, 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 dependent 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, protecting groups for -OH groups (whether hydroxyl, carboxylic acid, phosphonic acid, or other functions) include "ether- or ester-forming groups". Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein. However, some hydroxyl and thio protecting 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 protecting groups and amide-forming groups and corresponding chemical cleavage reactions are described in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) ("Greene"). See also Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated by reference in its entirety herein. In particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-1 17, Chapter 4, Carboxyl Protecting Groups, pages 1 18-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for acids see Greene as set forth below.
Stereoisomers
The compounds of the invention may have chiral centers, e.g., chiral carbon or phosphorus atoms. The compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the invention include enriched or resolved optical isomers at any or all 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 all 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 separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances. In most instances, the desired optical isomer is synthesized by means of stereospecific 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 resonance structure may be depicted, all such forms are contemplated within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all 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 alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and
4+ (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, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, 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 N¾+ (wherein X is independently selected from H or a C\-C^ alkyl group).
For therapeutic use, salts of active ingredients of the compounds of the invention will typically 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 preparation or purification of a compound of formula I or another compound of the invention. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HC1, HBr, H2S04? H3PO4 or organic sulfonic acids, to basic centers, typically amines, or to acidic 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.
Specific values listed below for radicals, 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 in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( H or D). As a non-limiting example, a -CH3 group may be substituted with -CD3.
Compounds of formula I.
A specific group of compounds of formula I are compounds of formula la.
Figure imgf000035_0001
la
Another specific group of compounds of formula I are compounds of formula
Figure imgf000036_0001
lb
Another specific group of compounds of formula I are compounds of formula
Ic.
Figure imgf000036_0002
Ic
Another specific group of compounds of formula I are compounds of formula
Figure imgf000036_0003
Another specific group of compounds of formula I are compounds of formula
Ie.
Figure imgf000037_0001
Ie
Another specific group of compounds of formula I are compounds of formula
If.
Figure imgf000037_0002
If
Another specific group of compounds of formula I are compounds of formula
Ig.
Figure imgf000037_0003
ig
Another specific group of compounds of formula I are compounds of formula
Ih.
Figure imgf000038_0001
Ih
Another specific group of compounds of formula I are compounds of formula Ii.
Figure imgf000038_0002
Another specific group of compounds of formula I are compounds of formula Ij.
Figure imgf000038_0003
Another specific group of compounds of formula I are compounds of formula
Ik.
Figure imgf000039_0001
Ik
Another specific group of compounds of formula I are compounds of formula
Figure imgf000039_0002
Im
Another specific group of compounds of formula I are compounds of formula
Figure imgf000039_0003
In
Another specific group of compounds of formula I are compounds of formula
Figure imgf000040_0001
Io
Specific values listed below are values for compounds of formula I as well as the compounds of formula la, lb, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Im, In and Io.
A specific group of compounds of formula I are compounds wherein at least one of R1, R2, R3, R3', R4, R5, R6, R7, or R8 is selected from Rlb, R2b, R3b, R3b', R4b, R5b, R6b, R7b and R8b.
Another specific group of compounds of formula I are compounds wherein at least two of R1, R2, R3, R3', R4, R5, R6, R7, or R8 are selected from R,b, R2b, R3b, R3b', R4b, R5b, R6b, R7band R8b.
Another specific group of compounds of formula I are compounds wherein at least three of R1, R2, R3, R3', R4, R5, R6, R7, or R8 are independently selected from Rlb, R2b, R3b, R3b', R4b, R5b, R6b, R7" and R8b.
Another specific 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 Rlb, R2b, R3b, R3b', R4b, R5b, R6b, R7b and R8b.
Another specific group of compounds of formula I wherein at least five of R1, R2, R3, R3', R4, R5, R6, R7, or R8 are selected from Rlb, R2b, R3b, R3b', R4b, R5b, R6b, R7" and R8b.
Another specific group of compounds of formula I wherein at least six of R1, R2, R3, R3', R4, R5, R6, R7, or R8 are independently selected from Rlb, R2b, R3b, R3b', R4b, R5b, R6b, R7b, or R8b.
Another specific 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 Rlb, R2b, R3b, R3b', R4b, R5b, R6b, R7b and R8b. Another specific group of compounds of formula I wherein at least eight of R , R2, R3, R3', R4, R5, R6, R7, or R8 are independently selected from Rlb, R2b, R3b, R3b', R4b, R5b, R6b, R7b and R8b.
Another specific group of compounds of formula I wherein R1, R2, R3, R3 , R4, R5, R6, R7 and R8 are Rlb, R2b, R3b, R3b', R4b, R5b, R6b, R7band R8b.
A specific value for R3 is R3b.
A specific value for R3b is -OC(CH3)2CH2OH, -OC(CH3)2CH2OH,
-0(C1-C6)alkyl-0-C(0)-NH2, -0(C C6)alkyl-0-C(0)-N(CH3)2or
-0(C1-C6)alkyl-0-C(0)-NH(phenyl).
Another specific value for R is -(C1-C6)alkylOH or
-0(Ci-C6)alkyl-0-C(0 NRcRd.
Another specific valu lee ff<or R3 is R3a.
A specific value for R3a is (CrC6)alkyl, (C2-C6)alkenyl or -0(C1-C6)alkyl, wherein any (C1-C6)alkyl or (C2-C6)alkenyl of R3a is optionally substituted with one or more groups selected from -0(C1-C6)alkyl, halo, oxo and -CN.
Another specific value for R3a is -OC(CH3).
A specific value for R is R .
A specific value for R3b' is (CrC6)alkyl or -0(Ci-C6)alkyl.
A specific value for R3 is R3a .
A specific value for R3a is H.
A specific group of compounds of formula I are compounds wherein R and R 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 specific group of compounds of formula I are compounds wherein R and R3b 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 6- membered heterocycle is optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R and R3b together with the carbon to which they are attached form a (C4-C6)carbocycle or a 5 or 6-membered heterocycle, wherein the (C4-C )carbocycle or the 5 or 6- membered heterocycle is optionally substituted with one or more Z1 groups. Another specific group of compounds of formula I are compounds wherein R and R 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 specific group of compounds of formula I are compounds wherein R3b and R together with the carbon to which they are attached form a tetrahydropyran or tetrahydrofuran optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R3b and R3b together with the carbon to which the are attached form:
Figure imgf000042_0001
each of which is optionally substituted with one or more Z groups; and wherein "*" denotes the point of attachment to the carbon of the compound of formula I.
A specific value for R4 is R4b.
A specific value for R4b is (C!-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl, wherein (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl are each optionally substituted with one or more Z1 groups.
Another specific value for R4 is:
Figure imgf000042_0002
optionally substituted with one or more Z groups.
Another specific value for R4b is (C3-C7)carbocycle, wherein (C3-C7)carbocycle 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 (C3-C6)carbocycle or 5-6-membered heterocycle.
Another specific value for R4b is:
Figure imgf000043_0001
each of which is optionally substituted with one or more Z groups.
Another specific value for R4b is 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.
Figure imgf000043_0002
Another specific value for R is R a.
A specific value for R4ais:
Figure imgf000044_0001
Figure imgf000044_0002
A specific 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, (C1-C6)alkyl or -0(C!-C6)alkyl.
Another specific value for R is H.
Another specific group of compounds of formula I are compounds wherein R4 and R together with the atoms to which they are attached form the macroheterocycle or a macrocarbocycle further fused to a Z group:
Figure imgf000045_0001
wherein:
Z is aryl, heteroaryl or (C3-C6)carbocycle;
n3 is 2, 3 or 4; and
W and W are each independently O, NH or CH2, and
wherein "*" denotes the R4 point of attachment of the macroheterocycle or macrocarbocycle to the compound of formula I and "**" denotes the R3 point of attachment of the macroheterocycle or macrocarbocycle to the compound of formula I, and wherein the macroheterocycle or a macrocarbocycle is optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein, R4 and R together with the atoms to which the are attached form the macroheterocycle:
Figure imgf000045_0002
wherein:
nl is 3 or 4; n2 is 2, 3 or 4; n3 is 2, 3 or 4; W is O, NH or N(Ci-C4)alk l; and wherein "*" denotes the R4 point of attachment of the macroheterocycle to the compound of formula I and "**" denotes 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 specific value for R1 is Rlb.
Another specific value R1 is Rla.
A specific value for Rla is H or -CH3.
A specific value for R2 is R2b.
Another specific value R2 is R2a.
A specific value for R2a is H or -CH3.
A specific value for R5 is R5b.
Another specific value for R5 is R5a.
A specific value for R5a is H.
A specific value for R6 is R6b.
Another specific value for R6 is R6a.
A specific value for R6a is H.
A specific value for R7 is R .
Another specific value for R7 is R7a.
A specific value for R7a is H, -CH3 or halogen.
A specific value for R8 is R8b.
Another specific value for R is R .
Another specific value for R8a is H.
A specific group of compounds of formula I are compounds wherein R4b is selected from;
a) (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (CrC6)alkyl, (C2-C )alkenyl and (C2-C6)alkynyl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
b) (C3-C14)carbocycle, wherein (C3-C14)carbocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
c) Spiro-heterocycle and bridged-heterocycle, 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 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 specific group of compounds of formula I are compounds wherein R is selected from;
a) (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (C C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
b) (C3-C14)carbocycle, wherein (C3-C14)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; 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 specific group of compounds of formula I are compounds wherein R4b is selected from;
a) (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (C C6)alkyl,
(C2-C6)alkenyl and (C2-C6)alkynyl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
b) (C3-C14)carbocycle, wherein (C3-C14)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 specific group of compounds of formula I are compounds wherein R3 is (C!-C6)alkyl, (C2-C6)alkenyl or -0(C1-C6)alkyl, wherein any (C C6)alkyl or
(C2-C6)alkenyl of R3 is optionally substituted with one or more groups selected from -0(C1-C6)alkyl, halo, oxo and -CN, and wherein R is H.
Another specific group of compounds of formula I are compounds wherein R4 is selected from:
a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (C1-C6)alkyl, (C2-C6)alkenyl, (CrC^haloalkyl, (C3-C7)cycloalkyl, -OH, -0(C
C6)alkyl, -SH, -S(C1-C6)alkyl, -NH2, -NH^-C^aU yl and -N((C1-C6)alkyl)2, wherein (Q- C6)alkyl is optionally substituted with hydroxy, -0(C!-C6)alkyl, cyano or oxo; b) (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
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.
Another specific group of compounds of formula I are compounds wherein R4 is selected from:
a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (d-C6)alkyl, (C2-C6)alkenyl, (d-Ce^aloalkyl, (C3-C7)cycloalkyl, -OH, -0(d- C6)alkyl, -SH, -S(C1-C6)alkyl, -NH2, -NH(d-C6)alkyl and -N((CrC6)alkyl)2, wherein (Q- C6)alkyl is optionally substituted with hydroxy, -0(d-C6)alkyl, 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.
Another specific group of compounds of formula I are compounds wherein R4 is selected from:
a) heterocycle and heteroaryl, wherein heterocycle and heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (d- C6)alkyl, (C2-C6)alkenyl, (d-C6)haloalkyl, (C3-C7)cycloalkyl, -OH, -0(d-C6)alkyl, -SH, - S(d-C6)alkyl, -NH2, -NH(CrC6)alkyl and -N((d-C6)alkyl)2, wherein (CrC6)alkyl is optionally substituted with hydroxy, -0(C1-C6)alkyl, cyano or oxo; and
b) heteroaryl and fused-heterocycle, wherein heteroaryl and fused- heterocycle are each independently substituted with one or more Z7 groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R4 is selected from:
a) heterocycle, wherein heterocycle is optionally substituted with one or more groups each independently selected from halo, (d-C6)alkyl, (C2-C6)alkenyl, (d- C6)haloalkyl, (C3-C7)cycloalkyl, -OH, -0(d-C6)alkyl, -SH, -S(d-C6)alkyl, -NH2, -NH(d- C6)alkyl and -N((C1-C6)alkyl)2, wherein (Q-C^alkyl is optionally substituted with hydroxy, -0(Ci-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.
Another specific group of compounds of formula I are compounds wherein R4 is selected from:
a) bicyclic aryl, tricyclic aryl, bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl, wherein any bicyclic aryl, tricyclic aryl, bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl,is optionally substituted with one or more groups each independently selected from halo, (Q- C6)alkyl, (C2-C6)alkenyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, -OH, -0(C1-C6)alkyl, -SH, - Sid-C^alkyl, -NH2, -NH(C1-C6)alkyl and -N((C!-C6)alkyl)2, wherein (d-C^alkyl is optionally substituted with hydroxy, -0(C1-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 Z groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R4 is 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, (d-C6)alkyl, (C2-C6)alkenyl, (Q-C^haloalkyl, (C3- C7)cycloalkyl, -OH, -0(C1-C6)alkyl, -SH, -SCd-C^alkyl, -NH2, -NHCC C^alkyl and - N((C1-C6)alkyl)2, wherein
Figure imgf000049_0001
is optionally substituted with hydroxy, -0(C!- C )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
7 1 substituted with one or more Z groups and optionally substituted with one or more Z groups.
Another specific group of compounds of formula I are compounds wherein R4 is selected from: a) bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl wherein bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl and tricyclic heteroaryl are each optionally substituted with one or more groups each independently selected from halo, (C1-C6)alkyl, (C2-C6)alkenyl, (Q- C6)haloalkyl, (C3-C7)cycloalkyl, -OH, -0(d-C6)alkyl, -SH, -SCQ-QDalkyl, -NH2, -NH(C C6)alkyl and -N((C1-C6)alkyl)2, wherein (C1-C6)alkyl is optionally substituted with hydroxy, -0(Ci-C6)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 Z groups and optionally substituted with one or more Z groups.
Another specific group of compounds of formula I are compounds wherein R4 is selected from:
a) tricyclic heterocycle, wherein tricyclic heterocycle is optionally substituted with one or more groups each independently selected from halo, (Ci-C6)alkyl, (C2-
C6)alkenyl, (Ci-C6)haloalkyl, (C3-C7)cycloalkyl, -OH, -0(CrC6)alkyl, -SH, -SCd-C^aUcyl, -NH2, -NH(C1-C6)alkyl and -N((Ci-C*)alkyl)¾ wherein (C1-C6)alkyl is optionally substituted with hydroxy, -0(C1-C6)alkyl, cyano or oxo; and
b) tricyclic fused-heterocycle, wherein tricyclic fused-heterocycle fused- heterocycle is substituted with one or more Z7 groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R4 is selected from:
a) (C3-C14)carbocycle, wherein (C3-C14)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
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.
Another specific 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 Z groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R4 is selected from fused-heterocycle, wherein fused-heterocycle is substituted with one or more Z7 groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R4 is selected from 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 Z7 groups and optionally substituted with one or more Z1 groups.
Another specific 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 fused-heterocycle are each substituted with one or more Z7 groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R4 is tricyclic fused-heterocycle, wherein tricyclic fused-heterocycle fused-heterocycle is substituted with one or more Z7 groups and optionally substituted with one or more Z1 groups.
A specific value for Z10 is:
i) halo, (C1-C6)haloalkyl; or
ii) (C1-C )alkyl optionally substituted with -OH, -O- (Ci-C6)haloalkyl.
Another specific value for Z10 is halo.
Another specific group of compounds of formula I are compounds wherein R4 is selected from heteroaryl and fused-heterocycle, wherein heteroaryl and fused- heterocycle are each independently substituted with one or more Z7 groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R4 is fused-heterocycle, wherein fused-heterocycle is substituted with one or more Z7 groups and optionally substituted with one or more Z1 groups. Another specific group of compounds of formula I are compounds wherein R is selected from 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 Z7 groups and optionally substituted with one or more Z1 groups.
Another specific 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 fused-heterocycle are each
T 1 substituted with one or more Z groups and optionally substituted with one or more Z groups.
Another specific 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, (Q-C^alkyl, (C2- C6)alkenyl, (Q-Q haloalkyl, (C3-C7)cycloalkyl, -OH, -0(C1-C6)alkyl, -SH, -SCd-Q alkyl, -NH2, -NH(d-C6)alkyl and -N((d-C6)alkyl)2, wherein (d-C6)alkyl is optionally substituted with hydroxy, -0(C1-C6)alkyl, cyano or oxo; and
Another specific group of compounds of formula I are compounds wherein R4 is selected from tricyclic fused-heterocycle, wherein tricyclic fused-heterocycle fused- heterocycle is substituted with one or more Z7 groups and optionally substituted with one or more Z1 groups.
Figure imgf000053_0001
52
Figure imgf000054_0001
53
Figure imgf000055_0001
54
Figure imgf000056_0001
55 Another specific value for R is:
Figure imgf000057_0001
Another s ecific value for R4 is:
Figure imgf000057_0002
Another specific group of compounds of formula I are compounds wherein R is selected from:
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, (C C6)alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3- C7)cycloalkyl, -OH, -OCQ-Q alkyl, -SH, -S(C1-C6)alkyl, -NH2, -NHCd-C^alkyl and -
Figure imgf000058_0001
wherein (C1-C6)alkyl is optionally substituted with hydroxy, -0(Ci- C6)alkyl, cyano or oxo; and
b) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle, and bridged- heterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridged- heterocycle are each independently substituted with one or more Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5 ) Z1 groups.
Another specific group of compounds of formula I are compounds wherein R4 is selected from aryl, heteroaryl, spiro-heterocycle, fused-heterocycle, and bridged- heterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridged- heterocycle are each independently substituted with one or more Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5 ) Z1 groups.
Another specific group of compounds of formula I are compounds wherein R4 is selected from:
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, (Q-C^alkyl and (Q- C6)haloalkyl; and
b) fused -heterocycle, wherein fused-heterocycle is substituted with one or
7 1 more Z groups and optionally substituted with one or more (e.g. 1 , 2, 3, 4 or5 ) Z groups.
Another specific value for R4 is heterocycle.
Another specific 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 is the (R) stereochemistry.
Another specific 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 is the (S) stereochemistry. Another specific group of compounds of formula I are compounds wherein R is selected from:
a) H, halo, (d-C6)alkyl and (d-C6)haloalkyl;
b) (C2-C6)alkenyl, (C2-C )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(=0)-Ru, -C(O)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn, -(d-Ce^lkyl-R11, -(C1-C6)alkyl-C(=0)-R11, -(d-C6)alkyl-C(O)-0-Rn, -(d-C6)alkyl- 0-Rn, -(C1-C6)alkyl-S-R11, -(C1-C6)alkyl-S(0)-R11 and -(C1-C6)alkyl-S02-R11, wherein each R11 is independently selected from H, (d-C6)alkyl, (C2-C6)alkenyl, (C2-
C6)alkynyl, (C!-C )haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, and wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z groups;
d) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(d-C6)alkyl-N(R9)R10, -(d-C6)alkyl-C(=0)-N(R9)R10, -(d-C6)alkyl-0-C(=0)-
N(R9)R10 and -(C1-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (d-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(C1-C6)alkyl-R11, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, and wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z groups;
e) (Ci-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z groups 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) (d-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (d-C6)haloalkyl, (C3-C7)carbocycle, (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. Another specific group of compounds of formula I are compounds wherein R is selected from:
a) H, halo and (C C6)alkyl;
b) (C2-C6)alkenyl, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z10 groups; c) -(d-C^alkyl-R11 and -(d-C^alkyl-O-R11, wherein each R11 is independently selected from H, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Q- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z10 groups;
d) -C(=0)-N(R9)R10 and -(C1-C6)alkyl-N(R9)R10, wherein each R9 is independently selected from H, (CrC6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(C1-C6)alkyl-R11, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z10 groups;
e) (Cj-C6)alkyl, wherein (CrC^alkyl is substituted with one or more Z2 groups 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 (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.
Another specific group of compounds of formula I are compounds wherein R1 is selected from:
a) H, halo and (C1-C6)alkyl;
b) cyano, aryl, and heteroaryl, wherein any aryl or heteroaryl is optionally substituted with one or more Z10 groups;
c) -(Q-Q alkyl-R11 and -(d-C^alkyl-O-R11, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Q- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z10 groups; d) -C(=0)-N(R9)R10 and -(C1-C6)alkyl-N(R9)R10, wherein each R9 is independently selected from H, (Ci-C6)alkyl and (C3-C7)cycloalkyl, and each R10is independently selected from R11, -(Ci-C^alkyl-R11, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z10 groups;
e) (d-C6)alkyl, wherein (Q-C^alkyl is substituted with one or more Z2 groups 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 Z5 groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R1 is selected from:
a) (C1-C6)alkyl, wherein (C1-C6)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 (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 (d-C^haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C )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.
Another specific group of compounds of formula I are compounds wherein R1 is selected from:
a) (C1-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 groups 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 Z5 groups and optionally substituted with one or more Z1 groups; and
c) (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein (C2-C6)alkenyl and (C2-C )alkynyl are each substituted with one or more Z6 groups and optionally substituted with one or more Z1 groups.
Figure imgf000062_0001
Figure imgf000062_0002
Another specific value for R is halo,
Another specific value for R is fluoro.
Another specific value for R is H.
Another specific value for R H, halo or (d-C6)alkyl.
Another specific value for R is H or halo.
Another specific group of compounds of formula I are compounds wherein R2 is selected from:
a) H, (CrC6)alkyl and -0(d-C6)alkyl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;
c) C(=0)-Rn, -C(=0)-0-Rn, -S-R11, -S(0)-Rn, -S02-RH,
-(d-Ce^lkyl-R11, d-C6)alkyl-C(=0)-Ru, -(C1-C6)alkyl-C(=0)-0-R11, -(CrC6)alkyl- O-R11, -(d-C6)alkyl-S-Rn, -(d-C6)alkyl-S(0)-Ru and -(C1-C6)alkyl-S02-R11, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-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) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(C C6)alkyl-N(R9)R10, -(d-C6)alkyl-C(=0)-N(R9)R10, -(d-C6)alliyl-0-C(=0)-N(R9)R10, and -(C1-C )alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (C1-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, - (Q-Cf alkyl-R11, -SO2-R11, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C )alkynyl, (d-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl.
e) (C C^alkyl, wherein (C!-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z1 groups; and
f) (d-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (d-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C )alkynyl are each substituted with one or more Z6 groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R2 is selected from:
a) (C1-C6)alkyl;
b) (C2-C6)alkenyl and (C1-C6)haloalkyl;
c) -(d-C^alkyl-R11 and -(d-C^alkyl-O-R1 wherein each R11 is independently selected from H, (d-C )alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more Z11 groups; d) -(d-C6)alkyl-N(R9)R10, wherein each R9 is independently selected from H, (d-C6)alkyl and (C3-C )cycloalkyl, and each R10 is independently selected from Ru,
-(d-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-C )haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
e) (d-C6)alkyl, wherein (d-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z1 groups; and
f) (C2-C6)alkenyl, wherein (C2-C6)alkenyl is substituted with one or more Z6 groups and optionally substituted with one or more Z1 groups. Another specific group of compounds of formula I are compounds wherein R2 is selected from:
a) (Ci-C6)alkyl;
b) (C2-C6)alkenyl and (C1-C6)haloalkyl;
c) -(Ci-C6)alkyl-Rn and -(d-C^alkyl-O-R11, wherein each R11 is independently selected from H, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (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; d) -(C1-C6)alkyl-N(R9)R10, wherein each R9 is independently selected from H, (C1-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11,
-(Ci-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORu and -C(=0)N(R9)Ru, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
e) (Ci-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z1 groups; and
f) (C1-C6)haloalkyl and (C2-C6)alkenyl, wherein (C1-C6)haloalkyl and (C2-C6)alkenyl are each substituted with one or more Z6 groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R2 is selected from:
a) (C1-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z1 groups; and
b) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and
(C2-C6)alkynyl, wherein
Figure imgf000064_0001
(C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C )alkynyl are each substituted with one or more Z6 groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R2 is selected from:
a) (C1-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 groups 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. Another specific group of compounds of formula I are compounds wherein R2 is selected from:
a) (C1-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z1 groups; and
b) (d-Ce^aloalkyl and (C2-C6)alkenyl, wherein (C1-C6)haloalkyl and (C2-C6)alkenyl are each substituted with one or more Z6 groups and optionally substituted with one or more Z1 groups.
Anoth r specific value for R is:
Figure imgf000065_0001
Another specific value for R is methyl.
Another specific value for R is H.
Another specific group of compounds of formula I are compounds wherein R6 is selected from:
a) H, halo, (C1-C6)alkyl, and (C1-C6)haloalkyl;
b) (C2-C6)alkenyl, (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(=0)-Rn, -C(=0)-0-Ru, -O-R11, -S-R11, -S(0)-Rn, -S02-Ru, -(d-Ceialkyl-R11, -(C1-C6)alkyl-C(=0)-R11, -(C1-C6)alkyl-C(=0)-0-R11, -(Cj-C6)alkyl- O-R11, -(C1-C6)alkyl-S-R11, -(C1-C6)alkyl-S(0)-R11 and -(Q-Q alkyl-SCVR11, wherein each Ru is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-C6)haloalkyl, (C3-C )cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R6 is optionally substituted with one or more Z10 groups; d) -(d-C^alkyl-O-id-C^alkyl-CCs-C^carbocycle, -(C1-C6)alkyl-S-(C1- C6)alkyl-(C3-C7)carbocycle, -(d-C^alkyl-SCOXC C^alkyl-CCs-C^carbocycle, -(d- C6)alkyl-S02-(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(C1-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, -halo(C3-C7)carbocycle,-NRaS02NRcR<1, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-C6)alkenyl- aryl, -(C2-C6)alkenyl-heteroaryl, -(C2-C6)alkenyl-heterocycle,
-(C2-C6)alkynyl-(C3-C )carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z or -halo(C1-C6)alkyl-Z , wherein any (C C6)alkyl, (C C6)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 Z1 groups;
e) (C1-C )alkyl, wherein (Ci-C6)alkyl is substituted with one or more Z groups 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 Z5 groups and optionally substituted with one or more Z1 groups; and
g) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (C1-C6)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.
Another specific group of compounds of formula I are compounds wherein R6 is selected from:
a) H, halo and (d-C6)alkyl;
b) (C2-C )alkenyl, (C2-C6)alkynyl and aryl, wherein any aryl is optionally substituted with one or more Z10 groups;
c) -(C1-C6)alkyl-R11 and -(d-C^alkyl-O-R1 wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C )alkenyl, (C2-C6)alkynyl, (d- C6)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)alkynyl-(C3-C7)carbocycle, -(C2-C )alkynyl-aryl,
-(C2-C6)alkynyl-heteroaryl and -(C2-C6)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) (Ci-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 groups 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-C6)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.
Another specific group of compounds of formula I are compounds wherein R6 is selected from:
a) H, halo, (C1-C6)alkyl, and (d-C6)haloalkyl
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(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Ru,
-(d-C6)alkyl-Ru, -(d-C^alkyl-C^C -R11, -(C1-C6)alkyl-C(=0)-0-R11, -(C1-C6)alkyl- O-R11, -(d-C6)alkyl-S-Ru, -(C1-C6)alkyl-S(0)-R11 and -(Q-CeJalkyl-SCVR11, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C )alkenyl, (C2- C6)alkynyl, (C1-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) -(C1-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(d- C6)alkyl-S02-(d-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(C1-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, -haloCCs-C^carbocycle^NRaSOz RcRd, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-ORa,
-(C2-C6)alkyl-(C3-C7)carbocycle-ORa, -(C3-C7)carbocycle-Z1 and -halo(d-C6)alkyl-Z3, wherein any (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, (C2-C )alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z'groups;
e) (Ci-C6)alkyl, wherein (Ci-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z^oups;
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) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein any (C1-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.
Another specific group of compounds of formula I are compounds wherein R6 is selected from:
a) H, halo and (C j -C6)alkyl;
b) (C2-C6)alkenyl, (C2-C )alkynyl and aryl, wherein any aryl is optionally substituted with one or more Z10 groups;
c) -(d-Cf alkyl-R11 and -(d-Q alkyl-O-R1 wherein each R11 is independently selected from H, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C )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)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl,
-(C2-C )alkynyl-heteroaryl -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-ORa, and -(C2-C )alkyl-(C3-C7)carbocycle-ORa, wherein -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C2-C )alkynyl-ORa, and -(C2-C6)alkyl-(C3-C7)carbocycle-ORa, are optionally substituted with one or more Z'groups;
e) (C!-C6)alkyl, wherein (C!-C6)alkyl is substituted with one or more Z2 groups 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-C6)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.
Another specific group of compounds of formula I are compounds wherein R6 is selected from:
a) H, halo, (d-C6)alkyl, and (d-C6)haloalkyl
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(=0)-Rn, -C(=0)-0-Rn, -0-R11, -S-R11, -S(0)-Rn, -S02-Rn, -(Ci-C6)alkyl-Rn, -(C1-C6)alkyl-C(=0)-R11, -(C1-C6)alkyl-C(=0)-0-R11, -(d-C6)alkyl- O-R11, -(C1-C6)alkyl-S-R11, -(d-C^alkyl-SCC -R11 and -(C1-C6)alkyl-S02-R11, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-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) -(C1-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(d- C6)alkyl-S02-(C 1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(C 1-C6)haloalkyl, -(C2- C6)alkynyl-(Ci-C6)haloalkyl, -halo(C3-C7)carbocycle,-NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-C6)alkenyl- aryl, -(C2-C )alkenyl-heteroaryl, -(C2-C )alkenyl-heterocycle,
-(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-OH,
-(C2-C6)alkyl-(C3-C7)carbocycle-ORa, -(d-C^carbocycle-Z1 and -halo(C1-C6)alkyl-Z3, wherein any (Cj-C6)alkyl, (d-C )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 Z1 groups;
e) (Ci-C6)alkyl, wherein (d-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z^oups;
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 groups and optionally substituted with one or more Z^oups; and
g) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein any (CrC^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.
Another specific group of compounds of formula I are compounds wherein R6 is selected from:
a) H, halo and (Ci-C6)alkyl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl and aryl, wherein any aryl is optionally substituted with one or more Z10 groups;
c) -(C1-C6)alkyl-R11 and -(C1-C6)alkyl-0-R1 !, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cj- C6)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)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl,
-(C2-C6)alkynyl-heteroaryl -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-ORa, and -(C2-C6)alkyl-(C3-C7)carbocycle-ORa, wherein -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-OH, and -(C2-C6)alkyl-(C3-C7)carbocycle-ORa, are optionally substituted with one or more Z^oups;
e) (C1-C6)alkyl, wherein (C1-C )alkyl 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 Z5 groups and optionally substituted with one or more Z'groups; and
g) (C2-C6)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.
Another specific group of compounds of formula I are compounds wherein R6 is selected from:
a) -(C1-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(C C^alkyl-SO^Cd-C^alkyl-CCs-C^carbocycle, -(C2-C6)alkenyl-(C1-C6)haloalkyl, -(C2- C6)alkynyl-(Ci-C6)haloalkyl, -Mo(C3^7)caitocycle,-NR.S02 R<¾, - R,S020(C3- C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl -heterocycle, -(C3-C7)carbocycle-Z1 and -halo(C1-C6)alkyl-Z3, wherein any (CrC6)alkyl, (Ci-C6)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 Z1 groups;
b) (C1-C6)alkyl, wherein (C!-C6)alkyl 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 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
d) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (C1-C6)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.
Another specific group of compounds of formula I are compounds wherein R6 is selected from:
a) H, halo and (d-C6)alkyl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl and aryl, wherein any aryl is optionally substituted with one or more Z10 groups;
c) -(C1-C6)alkyl-R11 and -(d-C^alkyl-O-R1 wherein each R11 is independently selected from H, (C1-C )alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-
C6)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)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl,
-(C2-C6)alkynyl-heteroaryl and -(C2-C6)alkynyl-heterocycle, wherein any
(C3-C )carbocycle, (C2-C6)alkynyl, aryl, heterocycle and heteroaryl, as part of a group, is optionally substituted with one or more Z1 groups;
e) (C1-C )alkyl, wherein (d-C^alkyl is substituted with one or more Z2 groups 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-C6)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.
Another specific group of compounds of formula I are compounds wherein R6 is selected from:
a) -(Ci-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(C C6)alkyl-S02-(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(C1-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, -halo(C3-C7)carbocycle,-NRaS02NRcR4, -NRaS020(^^ C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-ORa,
-(C2-C6)alkyl-(C3-C7)carbocycle-ORa, -(C3-C7)carbocycle-Z1 and -halo(d-C6)alkyl-Z3, wherein any (C1-C6)alkyl, (C1-C6)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 Z1 groups;
b) (C1-C6)alkyl, wherein (C!-C )alkyl 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 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
d) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (C1-C6)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.
Another specific group of compounds of formula I are compounds wherein R6 is selected from:
a) H, halo and (C1-C6)alkyl; b) (C2-C6)alkenyl, (C2-C6)alkynyl and aryl, wherein any aryl is optionally substituted with one or more Z10 groups;
c) -(Ci-C6)alk l-Rn and
Figure imgf000073_0001
wherein each R1 1 is independently selected from H, (Ci-Cejalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C6)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)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl,
-(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-ORa 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) (Q-C^alkyl, wherein (C]-C6)alkyl is substituted with one or more Z2 groups 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-C6)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.
Another specific group of compounds of formula I are compounds wherein R6 is selected from:
a) -(C1-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(C C6)alkyl-S02-(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(C1-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, -halo(C3-C7)carbocycle,-NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-OH,
-(C2-C6)alkyl-(C3-C7)carbocycle-ORa, -(C3-C7)carbocycle-Z1 and -halo(C1-C6)alkyl-Z3, wherein any (d-C6)alkyl, (C1-C6)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 Z1 groups; b) (C1-C6)alkyl, wherein
Figure imgf000074_0001
is substituted with one or more Z 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 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
d) (d-C^haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (C Ce^aloalkyl, (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.
Another specific group of compounds of formula I are compounds wherein R6 is selected from:
a) H, halo and (C1-C6)alkyl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl and aryl, wherein any aryl is optionally substituted with one or more Z10 groups;
c) -(d-C^alkyl-R11 and -(C Q alkyl-O-R11, wherein each R11 is independently selected from H,
Figure imgf000074_0002
(C2-C6)alkenyl, (C2-C )alkynyl, (Cj- C6)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)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl,
-(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-OH 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) (C!-C6)alkyl, wherein (Q-C^alkyl is substituted with one or more Z2 groups 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-C6)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.
Figure imgf000075_0001
Another specific value for R6 is H.
Another specific group of compounds of formula I are compounds wherein R is selected from:
a) H, halo, (C C6)alkyl and
Figure imgf000076_0001
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(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn, -(CrQ alkyl-R11, -(Ci-C6)alkyl-C(=0)-Rn, -(Ci-C6)alkyl-C(=0)-0-R11, -(d-C^alkyl- O-R11, -(Q-Q alkyl-S-R11, -(d-C^alkyl-S^-R11 and -(C1-C6)alkyl-S02-R11, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C!-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) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10,
-(C1-C6)alkyl-N(R9)R10, -(Ci-C6)alkyl-C(=0)-N(R9)R10, -(CrC6)alkyl-0-C(=0)- N(R9)R10 and -(C1-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (C!-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(C1-C6)alkyl-R11, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Ru, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (CrC^haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z groups;
e) (C1-C6)alkyl, wherein (C1-C6)alkyl 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 aryl, heteroaryl and heterocycle are each substituted with one or more Z5 groups and optionally substituted with one or more Z1 groups;
g) (C!-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (CrC^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 h) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NReRf, -(C1-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NReRf and -(C1-C6)alkyl-S02NRsRf, wherein each (Q-C^alkyl is substituted with one or more Z6 groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R7 is selected from:
a) H, halo, (d-C^alkyl and (Q-C^haloalkyl;
b) (C3-C7)cycloalkyl, cyano, aryl and heteroaryl, wherein any aryl, or heteroaryl is optionally substituted with one or more Z10 groups;
c) -C(=0)-N(R9)R10, wherein each R9 is independently selected from H,
Figure imgf000077_0001
and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, - (d-C^alkyl-R11, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each Ru is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (d-Ce^aloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z groups;
d) (d-C^alkyl, wherein (C 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 substituted with one or more Z5 groups and optionally substituted with one or more Z1 groups; f)
Figure imgf000077_0002
and (C3-C7)carbocycle are each substituted with one or more Z6 groups and optionally substituted with one or more Z1 groups; and
g) -C(0)NReRf.
Another specific group of compounds of formula I are compounds wherein R7 is selected from:
a) (C1-C6)alkyl, wherein (C1-C6)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 aryl, heteroaryl and heterocycle are each substituted with one or more Z5 groups and optionally substituted with one or more Z1 groups;
c) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (CrC^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
d) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NReRf, -(C1-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NReRf and -(C1-C6)alkyl-S02NReRf, wherein each (Ci-C^alkyl is substituted with one or more Z6 groups and optionally substituted with one or more Z1 groups.
Another specific group of compounds of formula I are compounds wherein R7 is selected from:
a) (C1-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 groups 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) (C1-C6)haloalkyl and (C3-C7)carbocycle, wherein (C)[-C6)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(0)NReRf,.
Another specific group of compounds of formula I are compounds wherein R7 is selected from:
a) H, halo, (C1-C6)alkyl and (C1-C6)haloalkyl;
b) (C3-C )cycloalkyl, cyano, aryl and heteroaryl, wherein any aryl, or heteroaryl is optionally substituted with one or more Z10 groups;
c) -O-R11 and -(d-C^alkyl-O-R1 wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z10 groups;
d) -C(=0)-N(R9)R10 and -(C1-C6)alkyl-N(R9)R10, wherein each R9 is independently selected from H, (CrC6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(d-C^alkyl-R11, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (d-C^alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC )haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z10 groups;
e) (C!-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 groups 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) (Ci-C6)haloalkyl and (C3-C7)carbocycle, wherein (C C^haloalkyl 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(0)NReRf.
nother specific value for R is:
Figure imgf000079_0001
Another specific value for R
Figure imgf000079_0002
Another specific value for R7 is H, halo, (C1-C6)alkyl, (d-C^haloalkyl and heteroaryl, wherein heteroaryl is optionally substituted with one or more Z10 groups.
Another specific value for R7 is H, (d-C^alkyl or (C1-C6)haloalkyl.
Another specific value for R7 is H.
Another specific group of compounds of formula I are compounds wherein R8 is selected from:
a) halo, nitro and cyano;
b) R11, -C(=0)-Rn, -C(=0)-0-Ru, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn, - (d-C^alkyl-R1 1, -(d-C^alkyl-C^-R11, -(C1-C6)alkyl-C(=0)-0-R11, -(C C6)alkyl- O-R1 -(C1-C6)alkyl-S-R1 -(Q-Q alkyl-SCC -R11 and -(d-Q alkyl-SCb-R11,wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (d-C^haloalkyl, (C3-C )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(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(d-
C6)alkyl-N(R9)R10, -(d-C6)alkyl-C(=0)-N(R9)R10, -(C1-C6)alkyl-0-C(=0)-N(R9)R10 and -(C1-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (d-C6)alkyl and (C3-C7)cycloalkyl, and each R10is independently selected from R11, - (Ci-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R1 1 is independently selected from H, (C!-C6)alkyl, (C2-C6)alkenyl, (C2-
C6)alkynyl, (d-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
d) (C1-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 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 Z1 groups;
f) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (d-C6)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; and
g) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NReRf, -(C1-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NR€Rf and -(C1-C6)alkyl-S02NReRf, wherein any (C1-C )alkyl, as part of a group, is substituted with one or more Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups.
Another specific group of compounds of formula I are compounds wherein R8 is selected from:
a) halo and cyano;
b) R11, -O-R11 and -(d-C^alkyl-R11, wherein each R11 is independently selected from H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cj-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z11 groups;
c) -C(=0)-N(R9)R10, wherein each R9 is independently selected from H,
(CrC^alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, - (C1-C6)alkyl-R11, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
d) (C1-C6)alkyl, wherein (Ci-Cejalkyl 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 Z5 groups and optionally substituted with one or more Z1 groups;
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(0)NReRf.
Another specific group of compounds of formula I are compounds wherein R8 is selected from:
a) (C1-C6)alkyl, wherein
Figure imgf000081_0001
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!-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (C1-C6)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; and
d) -NReRfe -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NReRf, -(C1-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NReRf and -(C1-C6)alkyl-S02NR€Rf, wherein any (C1-C6)alkyl, 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.
Another specific group of compounds of formula I are compounds wherein R is selected from:
a) (C1-C )alkyl, wherein (Ci-C^alkyl is substituted with one or more Z2 groups 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-C6)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(0)NReRf.
Figure imgf000082_0001
Figure imgf000082_0002
Figure imgf000082_0003
Another specific value for R is H.
Another specific value for R is H, (C1-C6)alkyl or halo.
Another specific group of compounds of formula I are compounds wherein each Rg is independently selected from -OR^ (Q-C^alkyl, (C3-C7)carbocycle (C!-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heterocycle and heteroaryl, wherein any (C1-C6)alkyl, (C3-C7)carbocycle -(CrC6)haloalkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, aryl, heterocycle or heteroaryl of Rg is optionally substituted with one or more Z1 groups.
In one embodiment the compounds of formula I include compounds
wherein:
R1 isRlaorRlb
R2 is R2a or R2b
R3isR3aorR3b
R3'isR3a'orR3b'
R4isR4aorR4b
R5 isR5aorR5
R6 is R6a or R6b
R^sR^orR7"
R8isR8aorR8b
Rla is selected from:
a) H, halo, (C1-C6)alkyl and (C1-C6)haloalkyl;
b) (C2-C6)alkenyl, (C2-C)alkynyl, (C3-C7)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;
c) -CC^-^^-CC^-O-^^-O-R11,^-^1,^)^11,^^11,
-(d-C^alkyl-R11, -(Q-Q alkyl-C^C-R11, -(Q-C^alkyl-C^C-O-R11, -(d-C^alkyl- O-R11, -(C1-C6)alkyl-S-R11, -(C1-C6)alkyl-S(0)-R11 and -(C1-C6)alkyl-S02-R11;
wherein each Ru is independently selected from H, (C1-C)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C]-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and d) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10,
-(Cj-C6)alkyl-N(R9)R10,
Figure imgf000083_0001
N(R9)R10 and -(CrC6)alkyl-S02-N(R9)R10; wherein each R9 is independently selected from H, (C1-C6)alkyl and (C3-C7)cycloalkyl; and
each R10is independently selected from R11,-(C1-C6)alkyl-R11, -S02-Rn, -C(=0)-Rn, - C(=0)OR11 and -C(=0)N(R9)R11 ; wherein each R11 is independently selected from H, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle or heteroaryl of Rla is optionally substituted with one or more (e.g. 1, 2 or 3) Z10 groups;
Rlb is selected from:
a) -(C1-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- C6)alkyl-(C3-C7) carbocycle, -(d-C^alkyl-S^-Cd-C^alkyl-iCs-Ce) carbocycle, -(d- C6)alkyl-S02-(d-C6)alkyl-(C3-C7)carbocycle, -(d-C6)alkyl-S02-(CrC6)alkyl-Z13, - C(0)-(d-C6)alkyl-Z13, -0-(d-C6)alkyl-Z13, -S-(d-C6)alkyl-Z13, -S(0)-(d-C6)alkyl- Z13, -S02-(Ci-C6)alkyl-Z13, -(d-C6)alkyl-Z14, -(C1-C6)alkyl-C(0)-(C1-C6)alkyl-Z13, - (C1-C6)alkyl-C(0)-0(C1-C6)alkyl-Z13, -(d-C6)alkyl-0-(d-C6)alkyl-Z13, -(d-C6)alkyl- S-(d-C6)alkyl-Z13, -(C2-C6)alkenyl-(d-C6)haloalkyl, -(C2-
C6)alkynyl-(d-C6)haloalkyl, - (C3-C7)halocarbocycle,-NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-C6)alkenyl- aryl, -(C2-C6)alkenyl-heteroaryl, -(C2-C6)alkenyl-heterocycle, -(C2-C6)alkynyl-(C3- C )carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl -(C2-C6)alkynyl- heterocycle, -(C3-C7)carbocycle-Z1 or -halo(Ci-C6)alkyl-Z3; wherein (C1-C6)alkyl,
(C1-C6)haloalkyl, (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) Z1 groups;
b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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) (d-C6)alkyl; wherein (d-C )alkyl is substituted with one or more Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; d) -X(d-C6)alkyl, -X(d-C6)haloalkyl, -X(C2-C6)alkenyl,
-X(C2-C6)alkynyl and -X(C3-C7)carbocycle; wherein (d-C6)alkyl and (d-C6)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 )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-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and
(C2-C6)alkynyl; wherein (C1-C6)haloalkyl, (C3-C7)carbocycle, (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; and
g) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NReRf, -(C1-C6)alkylC(0)-NR£Rf, -(C1-C6)alkyl-0-C(0)-NR€Rf and -(C1-C6)alkyl-S02NReRf; wherein each (C1-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 Z1 groups;
R2a is selected from:
a) H, (CrC6)alkyl and -CXd-C^aU yl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;
c) C(=0)-Rn, -C(=0)-0-Rn, -S-R11, -S(0)-Rn, -S02-Rn,
-(C1-C6)alkyl-R11, -(d-Q alkyl-C^C -R11, -(C1-C6)alkyl-C(=0)-0-R11, -(Ci-C6)alkyl- O-R11, -(C1-C6)alkyl-S-R11, -(C1-C6)alkyl-S(0)-R11 and -(C1-C6)alkyl-S02-R11;
wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (d-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, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(d-C6)haloalkyl, -0(C3- C7)cycloalkyl, -Oaryl, -Oheterocycle and -Oheteroaryl;
e) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(d-
C6)alkyl-N(R9)R10, -(Ci-C6)alkyl-C(=0)-N(R9)R10, -(d-C6)alkyl-0-C(=0)-N(R9)R10, and -(C1-C6)alkyl-S02-N(R9)R10; wherein each R9 is independently selected from H, (C1-C6)alkyl and (C3-C7)cycloalkyl; and
each R10is independently selected from R11, -(d-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, - C(=0)ORn and -C(0)N(R9)RH; wherein each R11 is independently selected from H, (CrC6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
R is selected from: a) -(C1-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(C C6)alkyl-S02-(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(Ci-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, -(C1-C6)alkyl-S02-(C1-C6)alkyl-Z13, -C(OMC C6)alkyl- Z13, -0-(C!-C6)alkyl-Z13, -S-(C1-C6)alkyl-Z13, -S(0)-(C1-C6)alkyl-Z13, -S02-(d- C6)alkyl-Z13, -(Q-Q alkyl-Z14, -(C1-C6)alkyl-C(0)-(C1-C6)alkyl-Z13, -(C C6)alkyl- C(0)-0(C1-C6)alkyl-Z13, -(C1-C6)alkyl-0-(C1-C6)alkyl-Z13, -(Ci-C6)alkyl-S-(Ci- C6)alkyl-Z13, -(C3-C7)halocarbocycle,-NRaS02NRcR<1, -NRaS020(C3-C7)carbocycle, - NRaS020aryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl- heterocycle, -(C3-C7)carbocycle-Z1 or -halo(C1-C6)alkyl-Z3; wherein (Q-C^alkyl, -(d-C^haloalkyl, (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) Z1 groups;
b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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) (C1-C6)alkyl; wherein (Cj-Ceialkyl is substituted with one or more Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
d) -X(d-C6)alkyl, X(C1-C6)haloalkyl, X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle; wherein (d-Ceialkyl and (C1-C6)haloalkyl are each substituted with one or more Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; and wherein (C2-C6)alkenyl, (C2-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) Z1 groups;
f) (d-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and
(C2-C6)alkynyl; wherein (C1-C6)haloalkyl, (C3-C )carbocycle, (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 (e.g. 1, 2, 3, 4 or 5) Z1 groups; and
g) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NReRf, -(Cj-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NR€Rf and -(C1-C6)alkyl-S02NReRf; wherein each (Ci-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;
R3a is (C1-C6)alkyl, (d-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
-(d-C6)alkyl-(C3-C7)cycloalkyl, -(C1-C6)alkyl-aryl, -(d-C6)alkyl-heterocycle, -(C1-C6)alkyl-heteroaryl, -0(C1-C6)alkyl, -0(C1-C6)haloalkyl, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(C3-C7)cycloalkyl, -Oaryl, -0(C1-C6)alkyl-(C3-C7)cycloalkyl, -0(C1-C6)alkyl-aryl, -0(C1-C6)alkyl-heterocycle and -0(d-C6)alkyl-heteroaryl;
wherein any (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl of R3a is optionally substituted with one or more (e.g. 1, 2 or 3) groups selected from -0(d- C6)alkyl, halo, oxo and -CN; and wherein any (C3-C7)cycloalkyl, aryl, heterocycle, or heteroaryl of R3a is optionally substituted with one or more (e.g. 1, 2 or 3) groups selected from (d-C6)alkyl, -0(C1-C6)alkyl, halo, oxo and -CN; and R3a' is H;
R3b is -(C3-C7)carbocycle, aryl, heteroaryl, heterocycle, -(C1-C6)alkylOH, -(d- C6)alk l-0-(Ci-C6)alkyl-Z12, -(C1-C6)alkyl-0-(C2-C6)alkenyl-Z12, -(C2-C6)alkyl-0-(C2- C6)alkynyl-Z12, -(d-C6)allcyl-S-(Ci-C6)alkyl-Z12, -(C1-C6)alkyl-S-(C2-C6)alkenyl-Z12, - (C2-C6)alkyl-S-(C2-C6)alkynyl-Z12, -(d-C6)alkyl-S(0)-(d-C6)alkyl-Z12, -(d-C6)alkyl- S(0)-(C2-C6)alkenyl-Z12, -(C2-C6)alkyl-S(0)-(C2-C6)alkynyl-Z12, <Ci-C¼)alkyl-S02- (d-C6)alkyl-Z]2, -(C C6)alkyl-S02-(C2-C6)alkenyl-Z12, -(C2-C6)alkyl-S02-(C2- C6)alkynyl-Z12, -(C2-C6)alkyl-NRaRb, -(C2-C6)alkylOC(0)-NRcRd, -(C2-C6)alkyl-NRa- C(0)-ORb, -(C2-C6)alkyl-NRa-C(0)-NRaRb, -(C1-C6)alkyl-S02(C1-C6)alkyl, -(d- C6)alkyl-S02NRcRd, -(C1-C6)alkyl-NRaS02NRcRd, -(C1-C6)alkyl-NRaS020(C3- C7)carbocycle, -(Cj-C6)alkyl-NRaS020aryl, -(C1-C6)alkyl-NRa-S02-(C1-C6)alkyl, -(d-C6)alkyl-NRa-S02-halo(d-C6)alkyl, -(Ci-C6)alkyl-NRa-S02-(C2-C6)alkenyl, -(C1-C6)alkyl-NRa-S02-(C2-C6)alkynyl, -(d-C6)alkyl-NRa-S02-(C3-C7)carbocycle, -(C1-C6)alkyl-NRa-S02-halo(C3-C7)carbocycle, -(C1-C6)alkyl-NRa-S02-aryl, -(C1-C6)alkyl-NRa-S02-heteroaryl, -(C1-C6)alkyl-NRa-S02-heterocycle, -0(d- C6)alkyl-NRaRb, -0(CrC6)alkylOC(0)-NRcRd, -0(C1-C6)alkyl-NRa-C(0)-ORb, -0(C1-C6)alkyl-NRa-C(0)-NRaRb, -0(C1-C6)alkyl-NRa-S02-(C1-C6)alkyl,
-0(C1-C6)alkyl-NRa-S02-halo(C1-C6)alkyl, -0(C1-C6)alkyl-NRa-S02-(C2-C6)alkenyl, -0(C1-C6)alkyl- Ra-S02-(C2-C6)alkynyl, -0(C1-C6)alkyl-NRa-S02-(C3-C7)carbocycle, -0(C1-C6)alkyl-NRa-S02-halo(C3-C7)carbocycle, -0(C1-C6)alkyl-NRa-S02-aryl, -0(C1-C6)alkyl-NRa-S02-heteroaryl, -0(C1-C6)alkyl-NRa-S02-heterocycle,
-0(C1-C6)alkyl-NRa-S02-NRaRb, -0(C1-C6)alkyl-NRa-S02-(C3-C7)carbocycle, -0(C1-C6)alkyl-NRa-S02-halo(C3-C7)carbocycle, -0(C1-C6)alkyl-NRa-S02-aryl, -0(Cj- C6)alkyl-NRaS02NRcRd, -0(Ci-C6)alkyl-NRaS020(C3-C7)carbocycle, -0(C C6)alkyl- NRaS02Oaryl, -Oheteroaryl, -Oheterocycle, -Sheteroaryl, -Sheterocycle,
-S(0)heteroaryl, -S(0)heterocycle, -S02heteroaryl or -S02heterocycle; wherein any (C1-C )alkyl, aryl, (C3-C7)carbocycle, heteroaryl or heterocycle of R is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups; and R is H, (CrC6)alkyl or -0(C1-C6)alkyl; or R and R together with the carbon to which they are attached form a heterocycle or (C3-C7)carbocycle which heterocycle or (C3-C )carbocycle of R and R3b 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;
R4a is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R4a is optionally substituted with one or more (e.g. 1 , 2, 3, 4 or 5) groups each independently selected from halo, (Q-C^alkyl, (C2-C6)alkenyl, (Ct-C^haloalkyl, (C3- C7)cycloalkyl, -OH, -0(C1-C6)alkyl, -SH, -S Q^alkyl, -NH2, -NH(C,-C6)alkyl and - N^Q-C^alkyl)^ wherein (C1-C6)alkyl is optionally substituted with hydroxy, -0(Ci- C6)alkyl, cyano or oxo;
R4b is selected from;
a) (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl; wherein (C C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl are each optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
b) (C3-C14)carbocycle; wherein (C3-C14)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; c) Spiro-heterocycle or bridged-heterocycle; wherein spiro-heterocycle or bridged-heterocycle is 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;
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) 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 which they are attached may be optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z groups; and R is H or (C1-C6)alkyl, -0(Ci-C6)alkyl.
R5a is selected from:
a) halo, nitro and cyano;
b) Ru, -C(-0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn, -
Figure imgf000089_0001
-(CrC6)alkyl- O-R11, -(CrQ alkyl-S-R11, -(d-C^alkyl-S^-R11 and -(C1-C6)alkyl-S02-R11; wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C )alkynyl, (C1-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(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(C C6)alkyl-N(R9)R10, -(C1-C6)alkyl-C(=0)-N(R9)R10, -(C1-C6)alkyl-0-C(=0)-N(R9)R10, and -(C1-C6)alkyl-S02-N(R9)R10; wherein each R9 is independently selected from H, (C C6)alkyl and (C3-C7)cycloalkyl; and
each R10 is independently selected from R11, -(d-Q alkyl-R11, -S02-Rn, -C(=0)-Rn, - C(=0)ORn and -C(=0)N(R9)Rn; wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
R5b is selected from:
a) -(C1-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle,
-(C1-C6)alkyl-S-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkylS(0)-(Ci-C6)alkyl-(C3-C6)carbocycle,
-(C1-C6)alkylS02(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(C1-C6)haloalkyl, - (Ca-C^alkynyl-id-C^haloalkyl, - (C3-C7)halocarbocycle, -NRaS02NRcRd,
-NRaS020(C3-C7)carbocycle, -NRaS02Oaryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-C )alkenyl-aryl, -(C2-C6)alkenyl-heteroaryl, -(C2-C6)alkenyl-heterocycle,
-(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C )alkynyl-heteroaryl, -(C2-C )alkynyl-heterocycle, -(C3-C7)carbocycle-Z or -halo(CrC6)alkyl-Z ; wherein (d-C6)alkyl, (Q-C^haloalkyl, (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) Z1 groups;
b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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) (d-C6)alkyl; wherein (d-C^alkyl is substituted with one or more Z groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
d) -X(C1-C6)alkyl,-X(C1-C6)haloalkyl, -X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle; wherein (C1-C )alkyl or (Q-C^haloalkyl are each substituted with one or more Z groups and optionally substituted with one or more Z groups; 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) Z1 groups;
f) (Q-C^haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and
(C2-C6)alkynyl; where
Figure imgf000090_0001
(C3-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(0)NReRf, -OC(0)NReRf, -S02NReRf,
Figure imgf000091_0001
-(C1-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NReRf and -(d-C^alkyl-SC^NReRf; wherein each (d-C6)alkyl 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;
R6a is selected from:
a) H, halo, (C1-C6)alkyl, and (d-C6)haloalkyl
b) (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, nitro, cyano, aryl, heterocycle or heteroaryl;
c) -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn, -(d-C6)alkyl-Rn, -(C1-C6)alkyl-C(=0)-R11, -(CrC6)alkyl-C(=0)-0-Rn, -(d-C6)alkyl- O-R11, -(d-C6)alkyl-S-Rn, -(C1-C6)alkyl-S(0)-R11 and -(d-C6)alkyl-S02-R11;
wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (d-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and d) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(d-C6)alkyl-N(R9)R10, -(d-C6)alkyl-C(=0)-N(R9)R10, -(d-C6)alkyl-0-C(=0)- N(R9)R10 and -(C1-C6)alkyl-S02-N(R9)R10; wherein each R9 is independently selected from H, (d-C6)alkyl and (C3-C7)cycloalkyl; and
each R10 is independently selected from R11, -(C C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, - C(=0)ORn and -C(=0)N(R9)Rn; wherein each R11 is independently selected from H, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and
wherein any aryl, heterocycle or heteroaryl of R6a is optionally substituted with one or more (e.g. 1, 2 or 3) Z10 groups;
R6b is selected from:
a) -(C1-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S-(C1- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(d- C6)alkyl-S02-(d-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(d-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, ^^(Cs-C^carbocycle^NRaSO^RcRd, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -{C3-C7)carbocycle-Z or -halo(C1-C6)alkyl-Z ; wherein (d-C6)alkyl, (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, (C2-C6)alkynyl, 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 bridged- bicyclic 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) (C1-C6)alkyl; wherein (C1-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(C1-C6)alkyl, -X Q-Ce^aloalkyl, -X(C2-C6)alkenyl,
-X(C2-C6)alkynyl and -X(C3-C7)carbocycle; wherein (d-C6)alkyl or (C1-C6)haloalkyl are each independently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z groups and optionally substituted with one or more Z1 groups; and wherein (C2-C6)alkenyl, (C2-C6)alkynyl 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) Z1 groups;
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) Z1 groups;
f) (C!-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and
(C2-C )alkynyl; wherein (C Ceihaloalkyl, (C3-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) -N¾Rf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NReRf,
-(C1-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NReRf and -(C1-C6)alkyl-S02NReRf; wherein each (Cj-C6)alkyl 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;
R7a is selected from:
a) H, halo, (C1-C6)alkyl and (C1-C6)haloalkyl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;
c) -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn, -(d-C6)alkyl-Rn, -(Ci-C^alkyl-C^-R11, -(C C6)alkyl-C(=0)-0-Rn, -(C1-C6)alkyl- O-R11, -(d-C6)alkyl-S-Rn, -(d-Q alkyl-S C -R11 and -(Ci-C6)alkyl-S02-Rn;
wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and d) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(C1-C6)alkyl-N(R9)R10,
Figure imgf000093_0001
-(d-C6)alkyl-0-C(=0)- N(R9)R10 and -(C1-C6)alkyl-S02-N(R9)R10; wherein each R9 is independently selected from H, (d-C6)alkyl and (C3-C7)cycloalkyl; and
each R10 is independently selected from R11,-(d-Ceialkyl-R11, -S02-Rn, -C(=0)-Rn, - C(=0)ORn and -C(=0)N(R9)Rn; wherein each R11 is independently selected from H, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and
wherein any aryl, heterocycle or heteroaryl of Rla is optionally substituted with one or more (e.g. 1, 2 or 3) Z10 groups;
R is selected from:
a) -(d-C6)alkyl-S02-(d-C6)alkyl-Z13, -C(0)-(d-C6)alkyl-Z13, -0-(d- C6)alkyl-Z13, -S-(d-C6)alkyl-Z13, -S(0)-(d-C6)alkyl-Z13, -S02-(d-C6)alkyl-Z13,
-(d-C6)alkyl-Z14, -(d-C6)alkyl-C(0)-(d-C6)alkyl-Z13, -(d-C6)alkyl-C(0)-0(d-
C6)alkyl-Z13, -(d-C6)alkyl-0-(d-C6)alkyl-Z13, -(d-Cejallcyl-S-Cd-C^alkyl-Z13, -(d- C6)alkyl-0-(d-C6)alkyl-(C3-C7)carbocycle, -(d-C6)alkyl-S-(d- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(d- C6)alkyl-S02-(C]-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(d-C6)haloalkyl, -(C2- C6)alkynyl-(d-C6)haloalkyl, -(C3-C7)halocarbocycle, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, 1
-(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z or -halo(C1-C6)alkyl-Z ; wherein (Ci-C6)alkyl, (CrC^haloalkyl, (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) Z1 groups;
b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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-C )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) (C1-C6)alkyl; wherein (C1-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
d) -X(d-C6)alkyl, X(C1-C6)haloalkyl, X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle; wherein (Q-C^alkyl and (d-C^haloalkyl are each substituted with one or more Z groups and optionally substituted with one or more Z groups; and wherein (C2-C6)alkenyl, (C2-C6)alkynyl and (C3-C )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 (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 Z5 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
f) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl; wherein
Figure imgf000094_0001
(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) -NReRf, -C(0)NRJR.f, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NRfiRf, -(C1-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NReRf and -(C1-C6)alkyl-S02NReRf; wherein each (C1-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;
R8a is selected from:
a) halo, nitro and cyano; b) R11, -C(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn, - (d-C6)alkyl-Rn,
Figure imgf000095_0001
-(d-C6)alkyl- O-R11, -(d-C^alkyl-S-R11, -(d-C6)alkyl-S(0)-Rn and -(d-C6)alkyl-S02-Rn; wherein each Rn is independently selected from H, (d-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (d-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(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(d- C6)alkyl-N(R9)R10, -(d-C6)alkyl-C(=0)-N(R9)R10, -(d-C6)alkyl-0-C(=0)-N(R9)R10 and -(CrC6)alkyl-S02-N(R9)R10; wherein each R9 is independently selected from H, (d-C6)alkyl and (C3-C7)cycloalkyl; and
each R10 is independently selected from R11, -(C C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, - C(=0)ORn and -C(=0)N(R9)Rn; wherein each R11 is independently selected from H, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
R8b is selected from:
a) -(d-C6)alkyl-S02-(d-C6)alkyl-Z13, -C(0)-(d-C6)alkyl-Z13, -0-(d- C6)alkyl-Z13, -S-(d-C6)alkyl-Z13, -S(0)-(Ci-C6)alkyl-Z13, -S02-(d-C6)alkyl-Z13, -(d-C6)alkyl-Z14, -(d-C6)alkyl-C(0)-(d-C6)alkyl-Z13, -(C1-C6)alkyl-C(0)-0(C1- C6)alkyl-Z13, -(C1-C6)alkyl-0-(C1-C6)alkyl-Z13, -(C1-C6)alkyl-S-(C1-C6)alkyl-Z13, -(d- C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(d-C6)alkyl-S-(d- C6)alkyl-(C3-C7)carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(d- C6)alkyl-S02-(d-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(d-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, -halo(C3-C7)carbocycle,-NRaS02NRcRd, - NRaS020(C3-C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z1 or -halo(C1-C6)alkyl-Z3; wherein (C1-C6)alkyl, (d-C6)haloalkyl, (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) Z1 groups:
b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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) (C1-C6)alkyl; wherein (C1-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z1 groups;
d) -X(C1-C6)alkyl, -X(Ci-C6)haloalk l, -X(C2-C6)alkenyl,
-X(C2-C6)alkynyl and -X(C3-C7)carbocycle; wherein (C1-C6)alkyl and (d-Ce^aloalkyl 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-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 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) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl; wherein (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C )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(0)NReRf, -OC(0)NReRf, -SOzNReRf, -(C1-C6)alkyl-NReRf, -(C1-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NReRf and -(C1-C6)alkyl-S02NRcRf; wherein each (Q-C^alkyl 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;
or any of R5a and R6a, R6a and R7a, R7a and R8a, 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, (Q-C^alkyl, (C2-C6)alkenyl, (Q- C6)haloalkyl, (C3-C7)cycloalkyl, -OH, -0(C C6)alkyl, -SH, -S(C]-C6)alkyl, -NH2, -NH(CrC6)alkyl and -N((C1-C6)alkyl)2;
or any of R5 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 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 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(0)0-, -S-, -S(O)-, -S02-, -(d- C6)alkylO-,
Figure imgf000097_0001
-(C1-C6)alkylC(0)0-, -(d-C6)alkylS-, -(C
C6)alkylS(0)-, -(C1-C6)alkylS02-;
each Z1 is independently selected from halo, -N02, -OH, =NORa, -SH, -CN,
-(Ct-Cf alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C1-C6)haloalkyl, (C3-C7)carbocycle, - (C3-C7)halocarbocycle, -aryl, -heteroaryl, -heterocycle,
Figure imgf000097_0002
-0(C2- C6)alkenyl, -0(C2-C6)alkynyl, -0(C1-C6)haloalkyl, -0(C3-C7)carbocycle, -0(C3- C )halocarbocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -S(CrC6)alkyl, -S(C2- C6)alkenyl, -S(C2-C6)alkynyl, -S d-Ce^aloalkyl, -S(C3-C7)carbocycle, -S(C3-
C7)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle, -S(0)(C1-C6)alkyl, -S(0)(C2- C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(C1-C6)haloalkyl, -S(O) (C3-C7)carbocycle, - S(0)(C3-C7)halocarbocycle, -S02(C!-C6)alkyl, -S(0)aryl, -S(0)carbocycle, - S(0)heteroaryl, -S(0)heterocycle, -S02(C2-C6)alkenyl, -S02(C2-C6)alkynyl, -S02(C)- C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, -S02aryl, -
S02heteroaryl, -S02heterocycle, -S02NRcRd, -NRaC(0)Ra, -NRaC(0)ORa, -NRaC(0)NRcRd -NRaS02Rb, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle, - NRaSOsOaryl, -OS(0)2Ra, -0(0)^, -C(0)ORb, -C(0)NRcRd, and -OC(0)NRcRd, wherein any (d-C^alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(C3-C7)halocarbocycle, (C3- C7)carbocycle, (C3-C )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(0)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, - NHheterocycle, or -S(0)2NRcRd;
each Z2 is independently selected from -N02, -CN, spiro- heterocycle, bridge- heterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, NRaS02(C3- C7)carbocycle, -NRaS02aryl, -NRaS02heteroaryl, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle and -NRaS02Oaryl;
each Z3 is independently selected from -N02, -CN, -OH, oxo, =NORa, thioxo, - aryl, -heterocycle, -heteroaryl, -(C3-C7)halocarbocycle, -0(C1-C6)alkyl, -0(C3- C7)carbocycle, -Ohalo(C3-C7)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(C!- C6)alkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -Saryl, -Sheterocycle, - Sheteroaryl, -SiOXd-C^alkyl, -S(0)(C3-C7)carbocycle, -S(O) (C3-C7)halocarbocycle, -S(0)aryl, -S(0)heterocycle, -S(0)heteroaryl, -S02(C1-C6)alkyl,
-S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, S02aryl, -S02heterocycle,
-S02heteroaryl, -NRaRb, -NRaC(0)Rb, -C(0)NRcRd, -S02NRcRd, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle and -NRaS02Oaryl;
each Z4 is independently selected from halogen, -(C1-C6)alkyl, (C3- C7)carbocycle, -halo(C1-C6)alkyl, -N02, -CN, -OH, oxo, =NORa, thioxo, -aryl,
-heterocycle, -heteroaryl, -(C3-C7)halocarbocycle, -0(C1-C6)alkyl, -0(C3- C7)carbocycle, -0(C3-C7)halocarbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(Ci- C6)alkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -Saryl, -Sheterocycle, - Sheteroaryl, -S(0)(CrC6)alkyl, -S(0)(C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, - S(0)aryl, -S(0)heterocycle, -S(0)heteroaryl, -SO^Q-Cf alkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, S02aryl, -S02heterocycle, -S02heteroaryl, -NRaRb, -NRaC(0)Ra, -C(0)NRcRd, -S02NRc¾, -NRaS02NR<:R<i, -NRaS020(C3-C7)carbocycle and -NRaS02Oaryl;
each Z5 is independently selected from -N02, -CN, -NRaS02NRcRd, - NRaS020(C3-C7)carbocycle, -NRaS02Oaryl, -NRaSO^Q-C^alkyl, -NRaS02(C2- C6)alkenyl, -NRaS02(C2-C6)alkynyl, -NRaS02(C3-C7)carbocycle, -NRaS02(C3- C7)halocarbocycle, -NRaS02aryl, -NRaS02heteraryl, -NRaS02heteroaryl,
-NRaS02heterocycle, -NRaC(0)alkyl, -NRaC(0)alkenyl, -NRaC(0)alkynyl, -NRaC(0) (C3-C7)carbocycle, -NRaC(0)(C3-C7)halocarbocycle, -NRaC(0)aryl, -NRaC(0)heteroaryl, -NRaC(0)heterocycle, NRaC(0)NRcR<i and NRaC(0)ORb;
each Z6 is independently selected from -N02, -CN, -NRaRa, NRaC(0)Rb,- C(0)NRcRd, -(C3-C7)halocarbocycle, -aryl, -heteroaryl, -heterocycle, -Oaryl, - Oheteroaryl, -Oheterocycle, -0(C3-C7)halocarbocycle, -OCQ-Ci alkyl, -0(C3- C )carbocycle, -OhaloCCrC^alkyl, -Saryl, -Sheteroaryl, -Sheterocycle, -S(C3- C7)halocarbocycle, -SCQ-Ce^lkyl, -S(C3-C7)carbocycle, -S(C C6)haloalkyl, -S(0)aryl, -S(0)heteroaryl, -S(0)heterocycle, -S(0)(C3-C7)halocarbocycle, -S(0)(Cj-C6)alkyl, -S(0)(C3-C7)carbocycle, -S(0)halo(C1-C6)alkyl, -S02aryl, -S02heteroaryl,
-S02heterocycle, -S02(C1-C6)alkyl, -S02halo(C1-C6)alkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, -SOiNRcRd, -NRaS02(C3-C7)halocarbocycle,
-NRaS02aryl, -NRaS02heteraryl, -NRaS02heteroaryl, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle and -NRaS02Oaryl.
each Z7 is independently selected from -N02, =NORa, -CN, -(Cj-C6)alkyl-Z12, -(C2-C6)alkenyl-Z12, -(C2-C6)alkenylOH, -(C2-C6)alkynyl-Z12, -(C2-C6)alkynyl-OH, -(Ci-C6)haloalkyl-Z12, -(C C6)haloalkylOH, -(C3-C7)carbocycle-Z12, -(C3- C7)carbocycleOH, -(C3-C7)halocarbocycle, -(C1-C6)alkylNRcRd, -(Ci- C6)alkylNRaC(0)Ra, -(C1-C6)alkylNRaS02Ra, -aryl, -heteroaryl, -heterocycle, -0(C C6)alkyl-Z]2, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -OCd-C^haloalkyl, -0(C3- C7)carbocycle, -0(C3-C7)halocarbocycle, -Oaryl, -0(C1-C6)alkylNRcRd, -0(C
C6)alkylNRaC(0)Ra, -0(C1-C6)alkylNRaS02Ra, -Oheteroaryl, -Oheterocycle, -S(C C6)alkyl-Z12, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, -S(Ci-C6)haloalkyl, -S(C3- C7)carbocycle, -S(C3-C7)halocarbocycle, -SCC C^alkylNRcRd, -S(C
C6)alkylNRaC(0)Ra, -S(C1-C6)alkylNRaS02Ra, -Saryl, -Sheteroaryl, -Sheterocycle, -SCOXQ-Ceialkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(C C6)haloalkyl, - S(0)(C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S02(C1-C6)alkyl, -S(0)(d- C6)alkylNRcRd, -S(0)(C1-C6)alkylNRaC(0)Ra, -S(0)(C1-C6)alkylNRaS02Ra, - S(0)aryl, -S(0)heteroaryl, -S(0)heterocycle, -S02(Cj-C6)alkyl, -S02(C2-C6)alkenyl, -S02(C2-C6)alkynyl, -S02(C1-C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3- C7)halocarbocycle, -S02aryl, -S02heteroaryl, -S02heterocycle, -S02(C]:-
C6)alkylNRcRd, -S02(C1-C6)alkylNRaC(0)Ra, -S02(C1-C6)alkylNRaS02Ra, - 802Ν¾¾, -NRaC(0)ORb, -NRaC(0)NRcRd -NRaS02Rb, -NRaS02NRcRd, - NRaS020(C3-C7)carbocycle, -NRaS02Oaryl, -OS(0)2Ra, -C(0)NRcRd, and - OC(0)NRcRd, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3- C7)carbocycle, (C3-C )halocarbocycle, aryl, heteroaryl or heterocycle of Z7 is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, -NRaC(0)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, - NHheterocycle, or -S(0)2NRcRd.
each Z is independently selected from -N02 or -CN;
each Z9 is independently selected from -(d-C6)alkyl, -0(C1-C )alkyl;
each Z10 is independently selected from
i) halo, oxo, thioxo, (C2-C6)alkenyl, (C1-C6)haloalkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(C1-C6)alkyl-, -OH, -0(Ci-
C6)alkyl, -©(d-C^haloalkyl, -SH, -S(C!-C6)alkyl, -SO(d- C6)alkyl, -S02(C1-C6)alkyl, -NH2, -NH(C!-C6)alkyl and
-N((C1-C6)alkyl)2;
ii) (C1-C6)alkyl optionally substituted with -OH, -0-(C C6)haloalkyl, or -0-(C1-C6)alkyl; and
iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle and heteroaryl is optionally substituted with halo, (CrC6)alkyl or COOH;
each Z11 is independently selected from Z10, -C(=0)-NH2, -C(=0)-NH(C!- C4)alkyl, -C(=0)-N((C1-C4)alkyl)2, -C(=0)-aryl, -C(=0)-heterocycle and
-C(=0)-heteroaryl;
each Z is independently selected from -N02, =NORa, thioxo, -aryl, - heterocycle, -heteroaryl, -(C3-C7)halocarbocycle, -(C3-C7)carbocycle,
-0(C3-C7)carbocycle, -Ohalo(C3-C7)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(C1-C6)alkyl, -S(C3-C7)carbocycle, -Shalo(C3-C7)carbocycle, -Saryl, -Sheterocycle, - Sheteroaryl, -S(0)(CrC6)alkyl, -S(0)(C3-C7)carbocycle, -S(0)halo(C3-C7)carbocycle, -S(0)aryl, -S(0)heterocycle, -S(0)heteroaryl, -S02(C1-C6)alkyl,
-S02(C3-C7)carbocycle, -S02(C3-C )halocarbocycle, S02aryl, -S02heterocycle, - S02heteroaryl, -NRaRa, -NRaC(0)Rb, -C(0)NRcRd, -SOaNRJ^, -NRaS02NRcRd, - NRaS020(C3-C7)carbocycle and -NRaS02Oaryl;
each Z13 is independently selected from -N02, -OH, =NORa, -SH, -CN, -(C3-
C7)halocarbocycle, -0(C1-C6)alkyl, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(C
C6)haloalkyl, -0(C3-C7)carbocycle, -0(C3-C7)halocarbocycle, -Oaryl, -Oheteroaryl, - Oheterocycle, -S(C1-C6)alkyl, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, -S(C1-C6)haloalkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle, -S(0)(Ci-C6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(C1-C6)haloalkyl, - S(0)(C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S(0)aryl, -S(0)heteroaryl, - S(0)heterocycle, -S02(C1-C6)alkyl, -S02(C2-C6)alkenyl, -S02(C2-C6)alkynyl, -S02(d- C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, -S02aryl, -
S02heteroaryl, -S02heterocycle, -S02NRcRd, -NRcRj, -Ν^(0)Κ3, -NRaC(0)ORb, -NRaC(0)NRcRd -NRaS02Rb, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle, - NRaS02Oaryl, -OS(0)2Ra, -C(0)Ra, -C(0)ORb, -C(0)NRcRd, and -OC(0)NRcRd;
wherein any (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(C3-C7)halocarbocycle, (C3- C7)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, -ORb, -CN, -NRaC(0)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, - NHheterocycle, or -S(0)2NRcRd;
each Z14 is independently selected from -N02, =NORa > -CN, -(C3- C7)halocarbocycle, -0(C3-C7)halocarbocycle, -S(C3-C7)halocarbocycle, -S(0)(C3- C7)halocarbocycle, -S02(C3-C7)halocarbocycle, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -OS(0)2Ra; wherein any -(C3-C7)halocarbocycle of Z14 is optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, -OH, -ORb, -CN, -NRaC(0)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, - NHheteroaryl, -NHheterocycle, or -8(0)2 ¾¾;
each Ra is independently H, (C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, aryl, aryl(C1-C6)alkyl-, heteroaryl or heteroary^Cr C6)alkyl-; wherein any (Q-C^alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C7)carbocycle, heterocycle, aryl, or heteroaryl of Ra is optionally substituted by halogen, OH and cyano;
each R is independently -(C!-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, aryl, aryl(C1-C6)alkyl-, heteroaryl or heteroaryl(C!- C6)alkyl-; wherein any (C1-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;
Rc and Ra are each independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, aryl, aryl(C1-C6)alkyl-, heterocycle, heteroaryl or heteroaryl(C1-C6)alkyl- wherein any
Figure imgf000101_0001
-(C2-C )alkenyl, -(C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, aryl, or heteroaryl of Rc or ¾ 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 Ra together with the nitrogen to which they are attached is optionally substituted by halogen, OH or cyano; each Re is independently selected from -ORa, (C!-C6)alkyl or (C3-C7)carbocycle wherein (C1-C6)alkyl or (C3-C7)carbocycle is substituted by one or more Za and optionally substituted with one or more Z\, -(C2-C6)haloalkyl, -(C2-C6)alkenyl, or -(C2-C6)alkynyl wherein any haloalkyl, alkenyl or alkynyl is optionally substituted with one or more Z\ aryl, heterocycle or heteroaryl wherein aryl, heterocycle or heteroaryl is substituted by one or more Zc;
each Rf is independently selected from -Rg, -ORa, -(C1-C6)alkyl-Z6, -S02Rg, - C(0)Rg, C(0)ORg, or -C(0)NReRg; and
each Rg is independently selected from -ORa, (CrC^alkyl, (C3-C7)carbocycle (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heterocycle or heteroaryl wherein any (C1-C6)alkyl, (C3-C7)carbocycle -(Q-C^haloalkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, aryl, heterocycle or heteroaryl of Rg is optionally substituted with one or more Z\ groups;
or a salt thereof.
In one embodiment, the compounds of formula I include:
Figure imgf000103_0001
and salts thereof.
In another embodiment, the compounds of formula I include:
Figure imgf000103_0002
and salts thereof.
Figure imgf000104_0001
5
In another embodiment, the compounds of formula I include:
Figure imgf000105_0001
Figure imgf000106_0001
105
Figure imgf000107_0001
t thereof.
In another embodiment, the compounds of formula I include:
Figure imgf000107_0002
Figure imgf000108_0001
107
Figure imgf000109_0001
108
Figure imgf000110_0001
Figure imgf000111_0001
110
Figure imgf000112_0001
111
Figure imgf000113_0001
112
Figure imgf000114_0001
Figure imgf000115_0001
114
Figure imgf000116_0001
115
Figure imgf000117_0001
Figure imgf000118_0001
117
Figure imgf000119_0001
Figure imgf000120_0001
and salts thereof.
In another embodiment the compounds of formula I include compounds 151- 180 as described in Example 149.
General Synthetic Procedures
Scheme 1 is provided as a further embodiment of the invention and illustrates a process that was used to prepare a compound of formula I and which can be used to prepare other compounds of formula I. Schemes 2-6 are also provided as further embodiments of the invention and illustrate processes that can be used to prepare compounds of formula I.
Scheme 1
Figure imgf000121_0001
Figure imgf000121_0002
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 salt such as, for example, copper(I) iodide, N,N- diisopropylethylamine, tetrakis(triphenylphosphine)palladium(0) and
dimethylformamide or copper(I) iodide, diethylamine, and bis(triphenylphosphine) palladium(II) dichloride. Deprotection of cross-coupled alkyne (1C) 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 metal acetylide such as, for example lithium acetylide, that undergoes nucleophilic addition to an appropriate electrophile (IE) to give the corresponding hydroxy alkyne addition product IF. 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 IF 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 1G. The substituted naphthalene 1G, can undergo a cross-coupling reaction such as, for example Stille cross-coupling 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, for example, vinylnaphthalene 1H. The vinylnaphthalene 1H can be dihydroxylated 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 IK 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 1L. The primary hydroxyl can be oxidized to the corresponding carboxylic acid 1M by methods known to those skilled in the art such as, for example, periodic acid and chromium trioxide. Scheme 2
Figure imgf000123_0001
R3 = -0(CrC6)alkyl, -0(C2-C6)alkenyl, LG = leaving group
-0(C2-C6)alkynyl or -0(C3-C6)cycloalkyl,
Figure imgf000123_0002
Metalation of a suitably functionalized and protected terminal alkyne such as, for example, deprotonation with n-butyllithium, can yield the corresponding metal acetylide such as, for example lithium acetylide, that undergoes nucleophilic addition to an appropriate electrophile, such as, for example IE, to give the corresponding hydroxy alkyne addition product 2 A. 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 such as, for example iodonaphthalene 2B. The substituted naphthalene 2B, can undergo a cross- coupling 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)palladium(II) dichloride to give the corresponding cross- coupled naphthalene such as, for example, vinylnaphthalene 2C. The alkenylnaphthalene 2C can be dihydroxylated using 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 2D can be protected at the primary hydroxyl by an orthogonal protecting groups, such as, for example, pivalate ester using pivaloyl chloride and pyridine. The secondary hydroxyl of 2E can be converted to the corresponding ether 2F, such as a tert-butyl ether using methods known 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.
Scheme 3
Figure imgf000125_0001
Figure imgf000125_0002
The substituted hydroxyl naphthalene 2 J can undergo halogenation using an appropriate halogen source and catalyst such as, for example N-chlorosuccinimide and zirconium(rV) chloride to provide IK. 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 selective cross-coupling reaction such as, for example Stille cross-coupling 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 provide 2N by methods known to those skilled in the art such as, Sharpless asymmetric dihydroxylation using, for example, commercially available AD mix-a. 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 tert- butyl 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-coupling using a boronic acid and a palladium catalyst such as palladium(II) 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 trioxide.
Scheme 4
Figure imgf000127_0001
4C" 4D»
LG = leaving group
Figure imgf000127_0002
4I"
Electrophilic aromatic substitution with a suitably functionalized and protected 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 cross- coupling reactions to provide 4C". The alcohol protecting group can be removed and 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 reduction method such as, for example Corey-Bakshi-Shibata Reduction to provide 4F".
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 4G". The functionalized naphthalene 4G" can undergo 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 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 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 reactions with trialkyltin reagents, Sonogashira reactions with alkynes, and Buchwald-Hartwig reactions with amines and carried forward in a similar manner to provide 41".
Scheme 5
Figure imgf000129_0001
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 reactions with trialkyltin reagents, Sonogashira reactions with alkynes, and Buchwald- Hartwig reactions with arnines 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 protecting group can be removed and the resulting alcohol oxidized to the ketone using an oxidant such as Dess-Martin
Periodinane, for example, to provide 5B". The ketone can be reduced stereoselectively using an asymmetric reduction method such as, for example Corey-Bakshi-Shibata Reduction 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 protecting group under basic conditions, such as, for example sodium hydroxide, to give the corresponding carboxylic acid 5E". It is known to those skilled in the art that the functionalized naphthalenes (e.g. 5A" or 5D") 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 reactions with trialkyltin reagents, Sonogashira reactions with alkynes, and Buchwald-Hartwig reactions with amines and carried forward in a similar manner to provide 5E".
Scheme 6
Figure imgf000131_0001
6L"
It is known to those skilled in the art that 6A" can undergo The Horner- Wadsworth-Emmons with stabilized phosphonate carbanions such as, for example (diethoxyphosphoryl)acetic acid ethyl ester and sodium hydride to provide 6B". The olefin can be reduced by hydrogenation 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 example the deprotection of a ethyl ester protecting group 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, N- bromosuccinimide 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, tert- butyl 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 term "prodrug" as used herein refers to any compound that when administered to a biological system generates a compound of the invention that inhibits the replication of HIV ("the active inhibitory compound"). The compound may be formed from the prodrug as a result of: (i) spontaneous chemical reaction(s), (ii) enzyme catalyzed chemical reaction(s), (iii) photolysis, and/or (iv) metabolic chemical reaction(s).
"Prodrug moiety" refers to a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, 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 Academic Publishers, pp. 113- 191). 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 metabolite or drug itself.
Exemplary prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters -CH2OC(=0)R99 and acyloxymethyl carbonates
-CH2OC(=0)OR" where R" is Ci~C6 alkyl, Ci-C6 substituted alkyl, C6-C20 aryl 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)
-CH2OC(=0)C(CH3)3. An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) -CH2OC(=0)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 have 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 phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g. , esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-0 bond to generate phosphoric acid and a quinone methide intermediate. Examples of this class of prodrugs are described by Mitchell et al. (1992) J Chem. Soc. Perkin Trans. 7/2345; Glazier WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier 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 reduction 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) J 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 sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating 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 about 7 to 10.
While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be 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 association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; 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 emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.
A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, 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 ingredient moistened 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 ingredient therefrom.
For administration to the eye or other external tissues e.g., mouth and skin, the formulations are preferably applied as a topical ointment 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 increments 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 ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream 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-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical
formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs. The oily phase of the emulsions of this invention may be constituted from known ingredients 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 lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the
emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying 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 emulsion 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 lauryl 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, non- 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 di- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 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. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
Pharmaceutical formulations according to the present 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 ingredient 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, emulsions, hard or soft capsules, syrups or elixirs 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 sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic 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 magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including
microencapsulation to delay disintegration and adsorption 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 ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions of the 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, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, 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 stearate), 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 ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral 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 emulsion may also contain sweetening and flavoring agents. Syrups and elixirs 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 sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile 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 isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending 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 preparation of injectables. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form 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 (weightrweight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient 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 ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present 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 ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient 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 salicylate.
Formulations suitable for intrapulmonary or nasal administration have 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 increments 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 ingredient. Formulations suitable for aerosol 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 ingredient such carriers as are known in the art to be appropriate. Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending 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 sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile 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 the active ingredient.
It should be understood that in addition to the ingredients 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 ingredient 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 inert or acceptable in the veterinary art and are compatible with the active ingredient. 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 ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the invention also provides compositions comprising one or more compounds of the invention formulated for sustained or controlled release.
Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (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 ingredients) 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 parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. 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 Assays in MT4 Cells
For the antiviral assay utilizing MT-4 cells, 0.4 μΐ, of 189X test concentration of 3-fold serially diluted compound in DMSO was added to 40 μΐ, 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.
1 mL aliquots of 2x10e6 MT-4 cells are pre-infected for 1 and 3 hrs
respectively, @ 37 °C with 25 μΐ, (MT4) or of either cell growth medium (mock- infected) or a fresh 1 :250 dilution of an HIV-IIIb concentrated ABI stock (0.004 m.o.i. for MT4 cells). Infected and uninfected cells are diluted in cell growth medium and 35 uL of 2000 (for MT4) cells is added to each well of the assay plates.
Assay plates were then incubated in a 37 °C incubator . After 5 days of incubation, 25 μΐ 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 temperature for 2-3 min and then chemiluminescence was read using the Envision reader (PerldnElmer).
Compounds of the present invention demonstrate antiviral activity in this assay (Test A) as depicted in the table below.
Figure imgf000141_0001
4K 0.301
4L 22
5K 4.6
6D 0.014
7D 1.7
7Ε 20
8 0.025
9 1.3
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 0.35
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 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 0.023 101 0.041
102 0.037
103 0.026
104 0.036
105 0.043
106A 0.086
106B 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 10
147 1.1
149 0.20
150A 29.150 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
186A 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 specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with practice of the present invention.
The invention has been described with reference to various specific 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 prepare compounds of the invention.
Example 1. (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)acetic acid (3K)
Figure imgf000147_0001
Figure imgf000147_0002
Figure imgf000147_0003
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% H20) to a volume of 114 mL. This stock solution (0.80 mL) was added to a solution of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)- 3-methylnaphthalen-2-yl)ethanol (3J) (51.7 mg, 0.14 mmol) in wet acetonitrile (2.0 mL), 0.75% H20) at 0 °C. The reaction mixture was stirred for 30 minutes at 0 °C and quenched with 1.5 M K2HP04 solution. Ethyl acetate was added and organic layer separated and washed with 1:1 brine/H20 (2x), then saturated NaHSC«3/brine. The organic layer was dried (MgS04), filtered and concentrated and purified by reverse phase HPLC (Gemini, 50 to 95% ACN/H20 + 0.1% TFA) and the product lyophilized to give 3K as a white powder (27.8 mg). 1H-NMR: 300 MHz, (CDC13) δ 7.73 (d, J = 7.8 Hz, 1H), 7.64 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.50-7.38 (m, 3H), 7.28-7.22 (m, 3 H), 5.25 (s, 1H), 2.54 (s, 3 H), 0.98 (s, 9H). LCMS-ESr (m/z): [M-H]" calcd for C23H22C103: 381.88; Found: 380.9, 382.9. Preparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methylnaphthalen-2- yl)ethanol (3J):
Preparation of l-phenylpropan-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% H20) to a volume of 114 mL. This stock solution (104.5 mL) was added to a solution of l-phenylpropan-2-ol (3A) (5.0 g, 36.71 mmol) in wet acetonitrile (150 mL, 0.75% H20) at 0 °C over 1 h, maintaining internal temperature below 5 °C. The reaction was quenched with K2HP04 (11.5 g, 50.5 mmol) in H20 (60 mL).
Dichloromethane was added and organic layer separated and washed with brine/H20 (2 x 100 mL), followed by saturated NaHS03/brine. The organic layer was dried
(MgS04), filtered and concentrated to give 3B as a yellow oil (5.1 g). 'H-NMR: 300 MHz, (CDC13) δ 7.35-7.10 (m, 5H), 3.65 (s, 2H), 2.11 (s, 3 H).
Preparation of 4-(4-chlorophenyl)-2-methyl-l-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 temperature overnight. The reaction mixture was quenched with saturated NH4CI solution and extracted with diethyl ether (2x). The combined organic layer was dried (MgS04), 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). 1H-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).
Preparation 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 and the combined organic layer was dried (MgS04), filtered, concentrated, adsorbed onto silica gel and purified by flash column chromatography (silica gel, hexanes) to give 3E as an off-white solid (1.8733 g). 1H-NMR: 300 MHz, (CDC13) 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).
Preparation of l-(4-chlorophenyl)-3-methyl-2-vinylnaphthalene (3F): A solution of l-(4-chlorophenyl)-2-iodo-3-methylnaphthalene (3E) (1.50 g, 3.98 mmol), tributyl(vinyl)tin (1.28 mL, 4.37 mmol) and PdCl2(PPh3)2 (0.279 g, 0.398 mmol) in DMF (20 mL) was stirred at 90 °C under argon overnight. The reaction mixture was cooled, diluted with ethyl acetate and washed with 5% LiCl solution (2x), brine and dried (MgS04). The mixture was filtered, concentrated and purified by flash column chromatography (silica gel, hexanes) to give 3F as a white solid (0.9894 g). 1H-NMR: 300 MHz, (CDC13) 6 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).
Preparation of (S)- 1 -(1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethane- 1 ,2- diol (3G): A biphasic mixture of AD-mix-a (4.928 g) in tert-butanol (17.5 mL)/H20 (17.5 mL) was cooled to 0 °C 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 overnight. The reaction was resumed for 10 h at 0 °C, then stored at -20 °C overnight. The reaction was resumed for 8 h at 0 °C until complete. Sodium sulfite (5.3 g) was added at 0 °C, then warmed to room temperature and stirred for 30 min to give a white mixture. The mixture was diluted with dichloromethane and H20. The mixture was extracted with dichloromethane (3x) and the combined organic layer was dried (MgS04), 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). 1H-NMR: 300 MHz, (CDC13) 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, 1H), 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).
Preparation of (S)-2-(l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- hydroxyethyl pivalate (3H): To a solution of (S)-l-(l-(4-chlorophenyl)-3- methylnaphthalen-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 mixture was stirred for 5 h at room temperature and diluted with ethyl acetate. The organic layer was washed with 1 N HC1, saturated sodium bicarbonate solution, dried (MgS04), 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). 1H-NMR: 300 MHz, (CDCI3): δ: 7.72 (d, J = 8.1 Hz, 1H), 7.67 (s, 1H), 7.46-7.37 (m, 3H), 7.26- 7.10 (m, 4H), 4.99 (dd, J = 8.7, 3.0 Hz, 1H), 4.45(dd, J = 11.7, 9.7 Hz, 1H), 4.13 (dd, J = 11.7, 3.3 Hz, 1H), 2.72 (s, 3H), 1.11 (s, 9H).
Preparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methylnaphthalen-2- yl)ethanol (3J): A solution of (S)-2-(l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- hydroxyethyl 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 temperature 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 (MgS04), filtered and concentrated to give (S)- 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)ethyl pivalate (31) that was used in next step without further purification. (S)-2-tert-butoxy-2-(l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)ethyl pivalate (31) from above reaction was dissolved in MeOH (1 mL) and THF (7 mL). Sodium hydroxide (2 M, 0.75 mL, 1.5 mmol) was added and the reaction mixture was stirred at room temperature overnight. Additional sodium hydroxide (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 (MgS04), 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). 1H-NMR: 300 MHz, (CDC13) δ 7.72 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H), 7.46-7.05 (m, 7H), 4.60 (dd, J = 10.5, 4.5 Hz, 1H), 3.77 (dd, J = 11.4, 4.2 Hz, 1H), 3.46 (dd, J = 11.4, 4.2 Hz, 1H), 2.71 (s, 3H), 1.00 (s, 9H). Example 2. (S)-2-tert-butoxy-2-((R)-3-methyl- 1 -(quinolin-8-yl)naphthalen-2-yl)acetic acid (4K) and (S)-2-tert-butoxy-2-((S)-3 -methyl- l-(quinolin-8-yl)naphthalen-2- yl)acetic acid 4L)
Figure imgf000151_0001
4D 4E
Figure imgf000151_0002
Figure imgf000151_0003
Figure imgf000151_0004
(S)-2-tert-butoxy-2-((R)-3 -methyl- 1 -(quinolin-8-yl)naphthalen-2-yl)ethyl pivalate (41) (22 mg, 0.0468 mmol) was dissolved in THF (1.0 mL) and MeOH (0.1 mL) and 2.0 M NaOH (94 μΐ,) was added. The reaction mixture was stirred for 24 h and 2.0 M NaOH (94 μί) was added. After stirring for 60 h at room temperature, the reaction was heated at 55 °C for lh with little change in conversion. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, concentrated and used in next step without further purification. The residue from above was dissolved in wet acetonitrile (0.75% H20), and Η5ΙΟ^ιΌ3 stock solution (0.439 M, 0.266 mL) was added at 0 °C. The reaction mixture was stirred for 30 minutes and additional H5I06/Cr03 stock solution (0.439 M, 0.266 mL) was added. After stirring for 30 minutes, the reaction mixture was quenched with saturated NaHC03 solution and diluted with ethyl acetate. The organic layer was washed with H20 brine, dried (MgSC>4), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% acetonitrile/H20 + 0.1% TFA) to give 4K as a film (12.1 mg, 50%). 1H-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 C26H26N03: 400.5; Found: 400.1.
Compound 4L (1.8 mg, 32%) was prepared following the procedure used to prepare compound 4K except that compound 4J was used instead of compound 41. 1H- NMR: 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), 7.5- 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-ESI+ (m/z): [M+H]+ calcd for C26H26N03: 400.5; Found: 400.1.
Preparation of (S)-2-tert-butoxy-2-((R)-3 -methyl- 1 -(quinolin-8-yl)naphthalen-2- yl)ethyl pivalate (41) and (S)-2-tert-butoxy-2-((S)-3-methyl-l-(quinolin-8- yl)naphthalen-2-yl)ethyl pivalate (4J):
Preparation of l-chloro-3-methylnaphthalen-2-ol (4B): To a solution of N- chlorosuccinimide (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-naphthalen- 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 temperature for 5 h. The reaction was quenched with saturated sodium bicarbonate solution and stirred for 5 minutes. The mixture was diluted with H20, extracted with dichloromethane (3x) and the combined organic layer was dried (MgS04), 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%).
Preparation 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-lutidine (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 H20 brine. The organic layer was dried (MgS04), 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%).
Preparation of l-chloro-3-methyl-2-vinylnaphthalene (4D): To a solution of 1- 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 bis(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 temperature, diluted with ethyl acetate, washed with 5% lithium chloride solution (3x), brine and dried (MgS04), 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).
Preparation of (S)-l-(l-chloro-3-methylnaphthalen-2-yl)ethane-l,2-diol (4E): A biphasic mixture of AD-mix-a (6.907 g) in tert-butanol (24.5 mLJ/FLO (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. The mixture was diluted with dichloromethane and H20. The mixture was extracted with dichloromethane (3x) and the combined organic layer was dried (MgS04), 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).
Preparation of (S)-2-(l-chloro-3-methylnaphthalen-2-yl)-2-hydroxyethyl pivalate (4F): To a solution of (S)-l-(l-chloro-3-methylnaphthalen-2-yl)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 reaction mixture was stirred for 18 h at room temperature. The reaction was incomplete 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 HC1 and diluted with ethyl acetate. The organic layer was washed with 1 N HC1, saturated sodium bicarbonate solution, dried (MgS04), 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-0]+ calcd for C18H21C102: 304.80; Found: 303.0, 305.0.
Preparation of (S)-2-tert-butoxy-2-(l -chloro-3-methylnaphthalen-2-yl)ethyl pivalate (4G): A solution of (S)-2-(l-chloro-3-methylnaphthalen-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 temperature 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 (MgS04), 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%).
Preparation of (S)-2-tert-butoxy-2-((R)-3 -methyl- 1 -(quinolin-8-yl)naphthalen-2- yl)ethyl pivalate (41) and (S)-2-tert-butoxy-2-((S)-3-methyl-l-(quinolin-8- yl)naphthalen-2-yl)ethyl pivalate (4J): To a microwave vial was added (S)-2-tert- butoxy-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 H20 (53 μί) were added and mixture stirred at room temperature for 2 h and then heated at 50 °C for 2 h. The reaction was charged with PdCl2(CH3CN)2 (10 nig) and SPhos (20 mg) and heated overnight at 100 °C. The reaction mixture was diluted with ethyl acetate, washed with brine, dried (MgS04), 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 mg) LCMS-ESf (m/z): [M+H]+ calcd for C31H36N03: 470.62; Found: 470.1 ; and atropisomer 4J (5.2 mg) LCMS-ESf (m/z): [M+H]+ calcd for C31H36N03: 470.62; Found: 470.1.
Example 3. (S -2-tert-Butoxv-2-((S)-l-(2 -dmvdropyranor4,3,2-de1quinolin-7-vl)-3- methylnaphthalen-2-yl)acetic acid (5K)
Figure imgf000156_0001
Figure imgf000156_0002
Figure imgf000156_0003
Figure imgf000156_0004
Figure imgf000156_0005
(S)-2-tert-Butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-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. IH- 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-ESI+ (m/z): [M+H]+calcd for C28H28N04: 442.2; Found: 442.1. Preparation of (S)-2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-3 -methylnaphthalen-2-yl)ethanol (5 J) .
Preparation of l-bromo-3-methylnaphthalen-2-ol (5B): 3-Methylnaphthalen-2- ol (4A) (2.09 g, 13.2 mmol) was taken in acetic acid (50 mL) and bromine (2.11 g) was added to it. The mixture was stirred at room temperature for 20 minutes, concentrated and purified by flash chromatography (silica gel, ethyl acetate/hexanes) to give the desired product (2.7 g, 80%). 1H-NMR: 300 MHz, (CDC13) δ 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).
Preparation of l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-ol (5D): 1 -Bromo-3-methylnaphthalen-2-ol (5B) ( 340 mg, 1.43 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid TFA salt (5C) (566 mg, 1.72 mmol), Pd(PPh3)4 (166 mg, 0.14 mmol) and K2C03 (991 mg, 7.15 mmol) were added to a degassed solution of DMA (6 mL) 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 (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give 5D (136 mg, 29%). LCMS-ESf (m/z): [M+H]+ calcd for
C22H18N02: 328.38; Found: 328.2.
Preparation of l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl trifluoromethanesulfonate (5E): l-(2,3-Dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-ol (5D) (136 mg, 0.415 mmol) was taken in 2 mL DCM at -78 °C and 2,6-lutidine (72 μί, 0.622 mmol) was added to it, followed by trifluoromethanesulfonic anhydride (210 μί, 1.24 mmol) and the reaction was stirred at -78 °C for 1 h. The reaction 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-ESf (m/z): [M+H]+ calcd for C23H17F3N04S: 460.45; Found: 460.0.
Preparation of 7-(3-methyl-2-vinylnaphthalen-l-yl)-2,3-dihydropyrano[4,3,2- dejquinoline (5F): A solution of l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yltrifluoromethanesulfonate (5E) (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 reaction mixture was cooled, diluted with ethyl acetate and washed with saturated NaHC03 solution (2x), brine and dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, hexanes) to give 5F as a white solid (74 mg, 91%). LCMS-ESf (m/z): [M+H]+ calcd for C24H2oNO: 338.42; Found: 338.2.
Preparation of (1 S)-l -(1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)ethane-l,2-diol (5G): Compound 5G was prepared in a similar manner as compound 3G of Example 1, except that compound 5F was used instead of compound 3F: LCMS-ESf (m/z): [M+H]+ calcd for C24H22N03: 372.44; Found: 372.3.
Preparation of (S)-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- 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-ESF" (m/z): [M+H]+ calcd for C29H30NO4: 456.6; Found: 456.1.
Preparation of (S)-2-tert-butoxy-2-((S)-l -(2,3-dihydropyrano [4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-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-ESI1" (m/z) [M+H]+calcd for C33H3gN04: 512.7; Found: 512.1.
Preparation of (S)-2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-
7-yl)-3-methylnaphthalen-2-yl)ethanol (5J): Compound 5 J 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+ (w/z): [M+H]+ calcd for C28H30NO3: 428.5; Found: 428.0.
Example 4. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid (6D)
Figure imgf000159_0001
(2S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid (6D) was prepared in an analogous manner as used for the preparation of compound 5K of Example 3. 1H-NMR: 300 MHz, (CD3OD) 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), 5.18 (s, 1H), 4.61(m, 2 H), 3.56 (dd, 2 H), 2.63 (s, 3 H), 0.84 (s, 9H).
LCMS-ESr (m/z): [M+H]+ calcd for C28H28N04: 442.5; Found: 442.1. Example 5. (R)-2-tert-Butoxy-[3-methyl-l-(5-(triiluoromethyl)quinolin-8-yl)- naphthalen-2-yl]-acetic acid (7D) and (S)-2-tert-butoxy-2-((S)-3 -methyl- 1 -(5- (trifluoromethyl)quinolin-8-yl)naphthalen-2-yl)acetic acid (7E).
Figure imgf000160_0001
7D (S)-2-tert-butoxy-2-((R)-3-methyl-l-(5-(trifluoromethyl)quinolin-8- yl)naphthalen-2-yl)acetic acid (7D) was prepared in a similar manner as compound 4K of Example 2. 1H-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, 1H), 2.78 (s, 3H), 0.75 (s, 9H); 19F-NMR: 376 MHz, (CD3OD) δ: -60.81; LCMS-ES (m/z): [M+H]+ calcd for C27H25F3N03: 468.5; Found: 468.0.
(S)-2-tert-butoxy-2-((S)-3-methyl-l-(5-(trifluoromethyl)quinolin-8- yl)naphthalen-2-yl)acetic acid (7E) was prepared in a similar manner as compound 4L of Example 2. 1H-NMR: 400 MHz, (CD3OD) δ: 8.82 (d, J = 8.4 Hz, 1 H), 7.72 (d, J = 5.2, 1 H), 8.26 (d, J = 7.6 Hz, 1 H), 8.12 (d, J - 7.6 Hz, 1 H), 7.89-7.73 (m, 3 H), 7.40 (dd, J = 7.6, 7.2 Hz, 1 H), 7.14 (dd, J - 7.6, 7.2 Hz, 1 H), 6.76 (d, J - 8.4 Hz, 1 H), 5.06 (s, 1H), 2.70 (s, 3H), 0.75 (s, 9H); 19F-NMR: 376 MHz, (CD3OD) δ: -60.87; LCMS- ESf (m/z): [M+H]+ calcd for C27H25F3N03: 468.5; Found: 468.0.
Example 6. (S)-2-tert-Butoxy-2-(l-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid (8)
Figure imgf000161_0001
(S)-2-ierf-butoxy-2-(1 -chloro-3- (S)-2-ferf-butoxy-2-(1 -chloro-3- methylnaphthalen-2- l)ethyl pivalate methylnaphthalen-2-yl)ethanol
Figure imgf000161_0002
-me y nap t a en- -y ace ate
(S)-2-ierf-butoxy-2-(1-cyclohexenyl-3- methylnaphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-(l -chloro-3 -methylnaphthalen-2-yl) ethanol: (S)-2-tert-Butoxy-2-( 1 -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 reaction mixture was stirred at room temperature 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 organics were dried (MgS04), concentrated in vacuo and purified by flash column
chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give a colorless liquid (1.12 g, 84%). 1H-NMR: 300 MHz, (CD3OD) 5: 8.23 (d, 1H), 7.78 (d, 1H), 7.60 (s, 1H), 7.52 (dd, 2H), 5.69 (m, 1H), 3.83 (dd, 1H), 3.61 (m, 1H), 2.71 (s, 3H), 1.18 (s, 9H).
Preparation of (S)-2-tert-butoxy-2-(l -chloro-3-methylnaphthalen-2-yl)acetic acid: The periodic acid/chromium trioxide stock solution (26 mL) was added to a solution of (S)-2-tert-butoxy-2-(l-chloro-3-methylnaphthalen-2-yl) ethanol (1.12 g, 3.83 mmol) in wet acetonitrile (50 mL) (0.75% H20) at 0 °C. The reaction mixture was stirred for 2 hours at 0 °C and quenched with 1.5 M K2HP04 solution. Ethyl acetate was added and organic layer separated and washed with 1 :1 brine/H20 (2x), then saturated NaHS03 /brine. The organic layer was dried (MgS04), 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%). 1H-NMR: 300 MHz, (CDC13) δ: 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-EST (m/z): [M- H]" calcd for C17H18C103: 305.78; Found: 304.9, 306.9.
Preparation of (S)-ethyl 2-tert-butoxy-2-( 1 -chloro-3 -methylnaphthalen-2- yl)acetate: Ethyl iodide (0.35 mL, 1.5 eq.) was added to a mixture of (S)-2-tert-butoxy- 2-(l -chloro-3 -methylnaphthalen-2-yl)acetic acid (900 mg, 2.93 mmol, 1 eq.) and Cs2C03 (1.91 g, 2 eq.) in DMF (920 mL) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. Ethyl acetate was added and organic layer separated and washed with brine (2x). The organic layer was dried (MgS04) 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%). 1H-NMR: 300 MHz, (CDC13) 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).
Preparation of (S)-2-tert-butoxy-2-(l-cyclohexenyl-3-methylnaphthalen-2- yl)acetic acid (8): A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(l- chloro-3-methylnaphthalen-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 reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), 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- cyclohexenyl-3-methylnaphthalen-2-yl)acetate (8 mg). Analytical HPLC (Gemini, 2- 98% ACN/H20 + 0.05% TFA, 10 minutes run): tR (min) = 7.06.
A solution of above intermediate (S)-ethyl 2-tert-butoxy-2-(l-cyclohexenyl-3- methylnaphthalen-2-yl)acetate (8 mg, 0.021 mmol, 1 eq.) in ethanol (1.5 mL) and 1 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 (MgS04), filtered, concentrated and purified 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/H20 + 0.05% TFA, 10 minutes run): tR (min) = 6.10. 1H-NMR: 400 MHz, (CD3OD) δ: 7.83 (m, 1H), 7.70 (m, 1H), 7.54 (m, 1H), 7.40 (m, 2H), 5.82, 5.62 (s,s, 1H), 2.58 (m, 3H), 2.62-2.16 (m, 4H), 1.92-1.80 (m, 4H), 1.03 (m, 9H). LCMS-EST (m/z): [M-Hf calcd for C23H2703: 351.46; Found: 351.1. Example 7. (S)-2-tert-Butoxy-2-( 1 -((R)-6-fluoroquinolin-8-yl)-3 -methylnaphthalen-2- yl)acetic acid (9)
Figure imgf000163_0001
9
(S)-2-feri-butoxy-2-(1-((f?)-6-fluoroquinolin- 8-yl)-3-methylnaphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-( 1 -((R)-6-fluoroquinolin-8-yl)-3 - methylnaphthalen-2-yl)acetic acid (9): (S)-2-tert-butoxy-2-(l-((R)-6-fluoroquinolin-8- yl)-3-methylnaphthalen-2-yl)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. 1H-NMR: 400 MHz, (CD3OD) δ: 8.81 (d, J = 8.2 Hz, 1H), 8.62 (dd, J = 4.7 Ηζ,ΙΗ), 8.02 (m, 1H), 7.96 (m, 1H), 7.82 (m, 2H), 7.76 (m, 1H), 7.42 (dd, J = 7.5 Hz, 1H), 7.20 (dd, J = 7.8 Ηζ,ΙΗ), 6.84 (d, J = 8.6 Hz, 1H), 5.18 (s, 1H), 2.72 (s, 3H), 0.82 (s, 9H). F-NMR: 377 MHz, (CD3OD) δ: -77.9, -113.1. LCMS-ESI+ (m/z):
[M+H]+calcd for C26H25FN03: 418.48; found: 418.1 1.
Example 8. (2S)-2-tert-Butoxy-2-( 1 -(5-fluoroquinolin-8-yl)-3 -methylnaphthalen-2- yl)acetic acid (10)
Figure imgf000164_0001
10
(2S)-2-ferf-butoxy-2-(1 -(5-fluoroquinolin-8- yl)-3-methylnaphthalen-2-yl)acetic acid
Preparation of (2S)-2-tert-butoxy-2-(l-(5-fluoroquinolin-8-yl)-3- methylnaphthalen-2-yl)acetic acid (10): (2S)-2-tert-Butoxy-2-(l-(5-fluoroquinolin-8- yl)-3-methylnaphthalen-2-yl)acetic acid (10) was prepared following the procedure to make (S)-2-tert-butoxy-2-( 1 -cyclohexenyl-3 -methylnaphthalen-2-yl)acetic acid of Example 6 except 5-fluoroquinolin-8-ylboronic acid was used instead of
cyclohexenylboronic acid. 1H-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, 1H), 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, 1H), 5.18 (s, 1H), 2.68 (s, 3H), 0.80 (s, 9H). 1 F-NMR: 377 MHz, (CD3OD) δ: -77.9, -123.2. LCMS-ESI+ (m/z): [M+H]+calcd for C26H25FN03: 418.47; found: 418.1.
Example 9. (S)-2-tert-Butoxy-2-( 1 -(3,3-dimethyl-6-oxocyclohex- 1 -enyl)-3- methylnaphthalen-2-yl)acetic acid (11)
Figure imgf000165_0001
11
(S)-2-(ieri-butoxy)-2-(1-(3,3-dimethyl-6-oxocyclohex- 1 -en-1 -yl)-3-methylnaphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-( 1 -(3 ,3 -dimethyl-6-oxocyclohex- 1 -enyl)-3- methylnaphthalen-2-yl)acetic acid (11): (S)-2-tert-Butoxy-2-(l-(3,3-dimethyl-6- oxocyclohex- 1 -enyl)-3 -methylnaphthalen-2-yl)acetic acid (11) 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 4,4-dimethyl-2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclohex-2-enone was used instead of cyclohexenylboronic acid. Atropisomers were separated by flash column chromatography. 1H-NMR: 400 MHz, (CD3OD) δ: 7.72 (d, J = 8.2 Hz, 1H), 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 C25H2904: 393.50; found: 393.0.
Example 10. (S)-2-tert-Butoxy-2-(l-cyclopentenyl-3-methylnaphthalen-2-yl)acetic acid (12)
Figure imgf000165_0002
12
(S)-2-terf-butoxy-2-(1-cyclopentenyl-3- methylnaphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-(l -cyclopentenyl-3-methylnaphthalen-2- yl)acetic acid (12): (S)-2-tert-Butoxy-2-(l -cyclopentenyl-3-methylnaphthalen-2- yl)acetic acid (12) 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 cyclopentenylboronic acid was used instead of cyclohexenylboronic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.78 (m, 1H), 7.53 (s,lH), 7.40 (m, 2H), 6.10-5.54 (m, 3H), 2.90 (m ,1H), 2.65 (m, 5H), 2.57 (s, 3H), 1.18 (s, 9H). LCMS-ESF (m/z): [M-H]" calcd for C22H2503: 337.44; found: 337.1.
Example 11. (2S)-2-tert-Butoxy-2-(3-methyl- 1 -(4-methylcyclohex- 1 -enyl)naphthalen- 2-yl)acetic acid (13)
Figure imgf000166_0001
13
(2S)-2-(terf-butoxy)-2-(3- methyl-1 -(4-methylcyclohex-1 - en-1 -yl)naphthalen-2-yl)acetic
acid
Preparation of (2S)-2-tert-butoxy-2-(3-methyl- 1 -(4-methylcyclohex- 1 - enyl)naphthalen-2-yl)acetic acid (13): (2S)-2-tert-Butoxy-2-(3 -methyl- 1 -(4- methylcyclohex-l-enyl)naphthalen-2-yl)acetic 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-l-enylboronic acid was used instead of cyclohexenylboronic acid. 1H-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-ESF (m/z): [M-H]" calcd for C24H2903: 365.49; found: 365.1.
Example 12. (S)-2-tert-Butoxy-2-( 1 -(4,4-dimethylcyclohex- 1 -enyl)-3 - methylnaphthalen-2-yl)acetic acid (14) (S)-ethyl 2-(feri-butoxy)-2-(1-(4,4-dimethylcyclohex- 1 -en-1 -yl)-3-methylnaphthalen-2-yl)acetate
Figure imgf000167_0001
(S)-2-(ferf-butoxy)-2-(1- (4,4-dimethylcyclo ex-1 -en- 1 -yl)-3-methylnaphthalen-2- yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-(l-(4,4-dimethylcyclohex-l-enyl)-3- methylnaphthalen-2-yl)acetate: To a solution of (S)-ethyl 2-tert-butoxy-2-(l-chloro-3- methylnaphthalen-2-yl)acetate (74 mg, 0.22 mmol) and 2-(4,4-dimethylcyclohex-l- 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-dicyclohexyl- phosphino-2',6'-dimethoxy- 1 , 1 '-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) chloride methyl-t-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). 1H-NMR: 400 MHz, (CDC13) δ:
7.83-7.78 (m, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.53 (s, 1H), 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).
Preparation of (S)-2-tert-butoxy-2-( 1 -(4,4-dimethylcyclohex- 1 -enyl)-3 - methylnaphthalen-2-yl)acetic acid (14): To a solution of (S)-ethyl 2-tert-butoxy-2-(l- (4,4-dimethylcyclohex-l-enyl)-3-methylnaphthalen-2-yl)acetate (36 mg, 0.087 mmol) in tetrahydrofuran:ethanol: water (2:2:1, 5 mL) was added lithium hydroxide (21 mg, 0.88 mmol) and the reaction was heated to 35 °C overnight. The reaction was then heated to 45 °C for 2 hours, and subsequently 5 equivalents of lithium hydroxide was added, and the reaction stirred at room temperature over 2 days. The reaction was then heated to 50 °C overnight. The crude reaction was purified by reverse phase HPLC (Gemini, 20-100% ACN/H20 + 0.1% TFA). Product was lyophilized to give a white powder (8.6 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 7.82 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.39 (m, 2H), 5.66 (m, 2H), 2.66 (m, 1H), 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-ESI" (m/z): [M-H]" calcd for C25H3103: 379.24; found: 379.27.
Example 13. (S)-2-tert-Butoxy-2-(3-methyl-l-(spiro[2.5]oct-5-en-6-yl)naphthalen-2- yl)acetic acid (15)
Figure imgf000168_0001
(S)-2-tert-butoxy-2-(3 -methyl- 1 -(spiro [2.5] oct-5 -en-6-yl)- naphthalen-2-yl)acetic acid Preparation of (S)-2-tert-butoxy-2-(3-methyl-l-(spiro[2.5]oct-5-en-6- yl)naphthalen-2-yl)acetic acid (15): (S)-2-tert-butoxy-2-(3-methyl-l-(spiro[2.5]oct-5- en-6-yl)naphthalen-2-yl)acetic acid was prepared following the procedure for (S)-2- tert-butoxy-2-(l-(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,3,2- dioxaborolane instead of 2-(4,4-dimethylcyclohex-l-enyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane and that in the final step the reaction was heated to 50 °C overnight followed by an addition of 10 equivalents of lithium hydroxide and heating to 60 °C for four hours and then at 45 °C overnight. 1H-NMR: 400 MHz, (CD3OD) δ: 7.90 (d, J = 7.6 Hz, 1H), 7.71 (br d, J = 7.2 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.40 (m, 2H), 5.88 (s, 1H), 5.70 (s, 1H), 2.73 (m, 1H), 2.78 (s, 3H), 2.31 (m, 2H), 2.09 (m, 1H), 1.73 (m, 1H), 1.59 (m, 1H), 1.24 (s, 9H), 0.49 (m, 4H). LCMS-ESF (m/z): [M-H]"calcd for
C25H29O3: 377.22; found: 377.34.
Example 14. (S)-2-tert-Butoxy-2-(3-methyl-l-(quinolin-3-yl)naphthalen-2-yl)acetic acid (16)
Figure imgf000169_0001
Preparation of (S)-2-tert-butoxy-2-(3-methyl-l -(quinolin-3-yl)naphthalen-2- yl)acetic acid (16): (S)-2-tert-Butoxy-2-(3 -methyl- l-(quinolin-3 -yl)naphthalen-2- yl)acetic acid (16) was prepared following the procedure to make (S)-2-tert-butoxy-2- (1 -cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid of Example 6, using quinolin-3- ylboronic acid instead of cyclohexenylboronic acid. The compound is an atropisomer mixture. 1H-NMR: 400 MHz, (CD3OD) δ: 9.20-8.50 (m, 2H), 8.18 (m ,1H), 8.08 (m, 1H), 7.95(m, 1H), 7.80 (m, 3H), 7.40 (t.lH), 7.25(t, 1H), 7.06 (m, 1H), 5.19(s, 1H), 2.62 (d, 3H), 0.95, 0.86 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H26N03: 400.48; found: 400.2.
Example 15. (S)-2-(tert-Butoxy)-2-((S)-l-(7-fluoro-2-methylquinolin-8-yl)-3- methylnaphthalen-2-yl)acetic acid (17)
Figure imgf000170_0001
(S)-2-terf-butoxy-2-(1 -chloro-3- 7-fluoro-2- 17
methylnaphthalen-2-yl)ethyl pivalate methylquinolin-8- ylboronic acid
(S)-2-(terf-butoxy)-2-((S)-1-(7- fluoro-2-methylquinolin-8-yl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of (S)-2-(tert-butoxy)-2-((S)- 1 -(7-fluoro-2-methylquinolin-8-yl)-3 - methylnaphthalen-2-yl)acetic acid (17): (S)-2-(tert-butoxy)-2-((S)-l-(7-fluoro-2- methylquinolin-8-yl)-3-methylnaphthalen-2-yl)acetic acid (17) was prepared following the procedure used to prepare compound 4K except that 7-fluoro-2-methylquinolin-8- ylboronic acid was used instead of compound 4H. 1H NMR (400 MHz, CD3OD) δ 9.09 (d, J = 8.5 Hz, 1H), 8.51 (dd, J = 9.1, 5.6 Hz, 1H), 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, 1H), 6.97 (d, J = 8.6 Hz, 1H), 5.17 (s, 1H), 2.80 (s, 3H), 2.79 (s, 3H), 0.87 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C27H27FN03: 432.5; found: 432.1.
Example 16. (S)-Ethyl 2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methylnaphthalen-2-yl)acetate (18)
Figure imgf000170_0002
(S)-ethyl 2-{tert- 2,3-dihydropyrano[4,3,2- 18
butoxy)-2-(1-chloro-3- c/e]quinolin-7-ylboronic
methylnaphthalen-2- acid, HCI salt (S)-ethyl 2-(ierf-butoxy)-2-((R)-1 - yl)acetate (2,3-dihydropyrano[4,3,2- cte]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetate
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (18): A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(l-chloro-3-methylnaphthalen-2-yl)acetate (compound of Example 6) (116 mg, 0.348 mmol), 2,3-dihydropyrano[4,3,2- de]quinolin-7-ylboronic acid, HC1 salt (96 mg, 0.383 mmol), Sphos precatalyst (35 mg, 0.0522 mmol), cesium fluoride (233 mg, 1.54 mmol) and flushed with nitrogen. Dimethoxyethane (3.0 mL, distilled from Na/benzophenone) was added and mixture was heated in microwave at 120 °C for 1.5 hour. The reaction mixture was diluted with ethyl acetate and washed with brine. The aqueous layer was back-extracted and combined organic layer dried (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% acetonitrile/H20 + 0.1% TFA) to give a yellow powder (16.8 mg). 1H-NMR: 400 MHz, (CD3C1) δ: 8.93 (d, J = 4.4 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.45-7.35 (m, 3H), 7.13 (dd, J = 7.2, 7.2 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 5.16 (s, 1H), 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-ESf (m/z): [M+H]+ calcd for C30H32NO4: 470.5; found: 470.1.
Example 17. (S)-2-( 1 -(3 -(Azetidin- 1 -yl)phenyl)-3 -methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (19)
Figure imgf000172_0001
1 ,3-dibromobenzene 1-(3-bromophenyl)azetidine 1-(3-(4,4,5,5-tetramethyl-
1 ,3,2-dioxaborolan-2- ine
Figure imgf000172_0002
19
(S)-2-(1 -(3-(azetidin-1 -yl)phenyl)-3- methylnaphthalen-2-yl)-2-(ferf- butoxy)acetic acid
Preparation of l-(3-bromophenyl)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 tert-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 cooled to room temperature. The resulting mixture was diluted with water and ethyl acetate and washed with water (2x), brine, dried (MgS04), 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-ESI+ (m/z): [M+H]+ calcd for C9HnBrN: 213.1; found: 212.0, 214.0.
Preparation of l-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)azetidine: A mixture of l-(3-bromophenyl)azetidine (0.4474 g, 2.11 mmol), bis-pinacolatodiboron (0.803 g, 3.16 mmol), Pd(dppf)Cl2 (0.172 g, 0.211 mmol), and potassium acetate (0.621 g, 6.33 mmol) in dioxane (21 mL) was sparged with nitrogen for 30 minutes. The reaction mixture was heated at 90 °C for 1.5 hours. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give a yellow wax (0.6474 g). LCMS- ESf (m/z): [M+H]+ calcd for C15H23BN02: 260.2; found: 260.1.
Preparation of (S)-ethyl 2-(l-(3-(azetidin-l-yl)phenyl)-3-methylnaphthalen-2- yl)-2-tert-butoxyacetate: A Smith process vial was charged with (S)-ethyl 2-tert- butoxy-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'-dimethoxy- 1 , 1 '-biphenyl)[2-(2- aminoethylphenyl)]Pd(II)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 microwave at 1 10 °C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, concentrated and purified by flash column
chromatography (silica gel, ethyl acetate/hexanes) to the desired product containing some impurities that was used in the next step without further purification.
Preparation of (S)-2-(l -(3-(azetidin-l-yl)phenyl)-3-methylnaphthalen-2-yl)-2- tert-butoxyacetic acid (19): The above residue containing (S)-ethyl 2-(l-(3-(azetidin-l- yl)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 (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 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/H20 + 0.1% TFA). Product containing fractions were stirred with saturated sodium bicarbonate solution for 30 minutes. The mixture was extracted with ethyl acetate (3x), dried (MgS04), filtered, concentrated and lyophilized from acetonitrile/water to give an atropisomer mixture as a white powder (1.9 mg). 1H NMR (400 MHz, CD3OD) δ 7.81-7.67 (m, 1H), 7.62 (s, 0.6H), 7.60 (s, 0.4H), 7.4-7.18 (m, 4H), 6.78 (s, 0.5H), 6.70 (d, J= 7.7 Hz, 0.5H), 6.64-6.57 (m, 1H), 5.32 (s, 0.6H), 5.30 (s, 0.4H), 3.90-3.83 (m, 3H), 2.60 (s, 3H), 2.40-2.35 (m, 2H), 0.99 (s, 4H), 0.97 (s, 5H). LCMS-ESf (m/z): [M+H]+ calcd for C26H30NO3: 404.5; found: 404.1.
Example 18. (2S)-2-tert-Butoxy-2-(l-((7R)-2,3,3a,4,5,6-hexahydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid (20)
-2-
Figure imgf000174_0001
Preparation of (2S)-2-tert-butoxy-2-(l -((7R)-2,3,3a,4,5,6-hexahydropyrano [4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid (20): (S)-2-tert-Butoxy-2- (l-((R)-2,3-dmydropyrano[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 HO Ac was added to the solution. 10% Pt/C (30 mg) was added the reaction was stirred at room temperature under one atmosphere of hydrogen (balloon) overnight. The reaction mixture was filtered, diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% MeOH/DCM) to give (2S)-2-tert-butoxy-2-(l-((7R)-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid (130 mg). 8 mg of the material was purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give a white powder (5.5 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 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 (s, 3H), 2.12(m, IH), 1.98 (m, IH), 1.70(m, IH), 1.32(m, IH), 1.05 (s, 9H). LCMS- ESf (m/z): [M+H]+ calcd for C28H32N04: 446.55; found: 446.1.
Example 19. (2S)-Methyl 2-tert-butoxy-2-(l-((7R)-2,3,3a,4,5,6- hexahydropyrano [4,3 ,2-de] quinolin-7-yl)-3 -methylnaphthalen-2-yl)acetate (21)
Figure imgf000175_0001
(2S)-2-ferf-butoxy-2-(1-((7R)-2,3,3a,4,5,6- 21
hexahydropyrano[4,3,2-c/e]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid
(2S)-methyl 2-(tert-butoxy)-2-(1 -((7R)- 2,3,3a,4,5,6-hexahydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2- yl)acetate
Preparation of (2S)-methyl 2-tert-butoxy-2-(l-((7R)-2,3,3a,4,5,6- hexahydropyrano[4,3,2-de]quinolin-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,4,5,6- hexahydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-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 μί, excess) was added to the solution. The reaction was 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/H20 + 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]quinolin- 7-yl)-3-methylnaphthalen-2-yl)acetate as white powder (11 mg). 1H-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, IH), 2.08 (m, IH), 1.72(m, IH), 1.39(m, IH), 1.05 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H34N04: 460.58; found: 460.1.
Example 20. (2SV2-tert-Butoxv-2-(3-methvl-l-((7RV6-methvl-2.3.3a.4.5.6- hexahydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)acetic acid (22)
Figure imgf000176_0001
(S)-ethyl 2-ferf-butoxy-2-(1 - (R)-7-(2-((S)-1 -ferf-butoxy-2-
((R)-2,3-dihydropyrano[4,3,2- ethoxy-2-oxoethyl)-3- cte]quinolin-7-yl)-3- methylnaphthalen-1 -yl)-6-methyl- methylnaphthalen-2-yl)acetate 2,3-dihydropyrano[4,3,2-
Figure imgf000176_0002
(2S)-ethyl 2-feri-butoxy-2-(3-methyl- 1-((7R)-6-methyl-2,3,3a,4,5,6- 22
hexahydropyrano[4,3,2-de]quinolin-
7-yl)naphthalen-2-yl)acetate (2S)-2-te/-f-butoxy-2-(3-methyl-1 -
((7R)-6-methyl-2,3,3a,4,5,6- hexahydropyrano[4,3,2-de]quinolin- 7-yl)naphthalen-2-yl)acetic acid
Preparation of (R)-7-(2-((S)-l-tert-butoxy-2-ethoxy-2-oxoethyl)-3- methylnaphthalen-1 -yl)-6-methyl-2,3-dihydropyrano[4,3,2-de]quinolin-6-iurn iodide: A mixture of Mel (0.8 mL, large excess) and (S)-ethyl 2-tert-butoxy-2-(l-((R)-2,3- dmydropyrano[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 MgS04, 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-ESf (m/z): [M calcd for C34H34N04: 484.61 ; found: 484.3.
Preparation of (2S)-ethyl 2-tert-butoxy-2-(3 -methyl- 1 -((7R)-6-methyl- 2,3,3a,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-oxoethyl)-3-methylnaphthalen-l-yl)-6-methyl-2,3- dihydropyrano[4,3,2-de]quinolin-6-ium iodide (50 mg) was dissolved in 20 mL EtOH and 1 drop of HO Ac 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 temperature overnight. The reaction mixture was filtered and diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% MeOH/DCM) to give (2S)-ethyl 2-tert- butoxy-2-(3-memyl-l-((7R)-6-methyl-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin- 7-yl)naphthalen-2-yl)acetate as a grey solid (15 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H38N04: 488.63; found: 488.2.
Preparation of (2S)-2-tert-butoxy-2-(3-methyl- 1 -((7R)-6-methyl-2,3,3a,4,5,6- hexahydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)acetic acid (22): To a solution of (2S)-e 1 2-tert-butoxy-2-(3-memyl-l-((7R)-6-memyl-2,3,3 ,5,6-hexahydro- pyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)acetate (12 mg, 0.021 mmol) in ethanol (1 mL) was added 2 N sodium hydroxide (1 mL) and the resulting reaction mixture was heated at 80 °C overnight. The reaction mixture was then concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). The product was lyophilized to give (2S)-2-tert-butoxy-2-(3-methyl-l-((7R)-6-methyl-2,3,3a,4,5,6- hexahydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)acetic acid (22) as a white powder (2.6 mg). 1H-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, 1H), 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 C29H34N04: 460.58; Found: 461.3.
Example 21. 7-((R)-2-((S)-tert-Butoxy(carboxy)methyl)-3-methylnaphthalen-l-yl)- 2,3-dihydropyrano[4,3,2-de]quinoline 6-oxide (23)
Figure imgf000178_0001
7-((R)-2-((S)-ferf- butoxy(carboxy)methyl)-3- methylnaphthalen-1-yl)-2,3- dihydropyrano[4,3,2-de]quinoline 6- oxide
Preparation of 7-((R)-2-((S)- 1 -tert-butoxy-2-hydroxyethyl)-3-methylnaphthalen -l-yl)-2,3-dihydropyrano[4,3,2-de]quinoline 6-oxide: To a solution of (S)-2-tert- butoxy-2-((R)-l-(2,3-dmydropyrano[4,3,2-de]qumolin-7-yl)-3-rnethylnaphthalen-2- yl)ethanol (6C, 31 mg, 0. 727 mmol) in dichloromethane (1.3 mL) was added 3- chloroperoxybenzoic 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 overnight and quenched with saturated sodium thiosulfate solution. The resulting mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, brine, dried (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). The product was lyophilized to give a yellow powder (4.7 mg).
LCMS-ESI+ (m/z) [M]+calcd for C28H30NO4: 443.5; found: 443.9.
Preparation of 7-((R)-2-((S)-tert-butoxy(carboxy)methyl)-3 -methylnaphthalen- l-yl)-2,3-dihydropyrano[4,3,2-de]quinoline 6-oxide (23): To a solution of 7-((R)-2- ((S)-l-tert-butoxy-2-hydroxyethyl)-3-memylnaphthalen-l-yl)-2,3-dmydropyrano[4,3,2- dejquinoline 6-oxide (4.7 mg, 0.0106 mol) in wet acetonitrile (0.75% H 0, 1 mL) was added HsKVCrC^ stock solution (0.439 M, 0.1 mL, 0.423 mmol) was added at 0 °C. The reaction mixture was stirred for 90 minutes at room temperature and additional H5I06/Cr03 stock solution (0.439 M, 0.1 mL) was added. After stirring for 90 minutes, the reaction mixture was quenched with saturated NaHC03 solution and extracted with ethyl acetate (2x). The organic layer was washed with H20, saturated NaHS03 solution, dried (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100%
Figure imgf000179_0001
+ 0.1% TFA) to give a yellow powder (1.2 mg). 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J = 6.3 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 6.1 Hz, 1H), 7.43-7.37 (m, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.25-7.13 (m, 1H), 6.87 (d, J = 7.8 Hz, 1H), 5.06 (s, 1H), 4.67-4.55 (m, 2H), 3.52-3.46 (m, 2H), 2.61 (s, 3H), 0.97 (s, 9H). LCMS-ESI+ m/z): [M+H]+ calcd for C28H28N05: 458.5; found: 458.1.
Example 22. (S)-2-tert-Butoxy-2-(l -(4-chlorophenyl)-3-(dimethylaminomethyl) naphthalen-2-yl)acetic acid (24)
Figure imgf000180_0001
(S)-ethyl 2-ferf-butoxy-2-(1-(4- (S)-ethyl 2-(3-(bromomethyl)-1 -(4- chlorophenyl)-3-methylnaphthalen-2- chlorophenyl)naphthalen-2-yl)-2
yl)acetate -ferf-butoxyacetate
Figure imgf000180_0002
(S)-ethyl 2-feri-butoxy-2-(1-(4- 24
chlorophenyl)-3- ((dimethylamino)methyl)
naphthalen-2-yl)acetate (S)-2-ferf-butoxy-2-(1-(4-chlorophenyl)-3- ((dimethylamino)methyl)naphthalen-2-yl) acetic acid
Preparation of (S)-ethyl 2-(3-(bromomethyl)-l-(4-chlorophenyl)naphthalen-2- yl)-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 CCI4 (2 mL) was added NBS (24 mg, 0.13 mmol) and AIBN (cat. amount). The reaction mixture was refluxed for 5 h. After cooling to room temperature, the reaction mixture was diluted by DCM, washed with sat. NaHC03, extracted with DCM and the organic layers were combined and dried over MgS04, filtered, concentrated and purified by flash column
chromatography (silica gel, ethyl acetate/hexanes) to provide 12 mg of the desired product. 1H-MNR 400 MHz (CDCI3) 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).
Preparation of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-((dimethyl- amino)methyl)naphthalen-2-yl)acetate: To a solution of (S)-ethyl 2-(3-(bromomethyl)- 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 L). The reaction mixture was stirred at room temperature for 1 h. Removal of the solvent in vacuo followed by purification of the residue by flash chromatography (silica gel, ethyl acetate/hexanes) provided 8 mg of the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for
C27H33C1N03: 454.2; Found: 454.2, 456.1.
Preparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-((dimethyl- amino)methyl)naphthalen-2-yl)acetic acid (24): To a solution of (S)-ethyl 2-tert- butoxy-2-(l-(4-cUorophenyl)-3-((dimethylamino)methyl)naphthalen-2-yl)acetate in THF (0.5 mL) and MeOH (0.5 mL), was added NaOH solution (2N, 100 μΐ,). The reaction mixture was stirred at room temperature for lday. The reaction mixture was neutralized by HO Ac 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). 1H-NMR: 400 MHz, (CD3OD) δ: 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, 1H), 3.12 (s, 3H), 2.89 (s, 3H), 1.12 (s, 9H).
LCMS-ESI+( m/z): [M+H]+ calcd for C25H29C1N03: 426.2; Found: 426.1, 428.1.
Example 23. (S)-2-tert-Butoxy-2-(l -(4-chlorophenyl)-3-((pyridin-3- yloxy)methyl)naphthalen-2-yl)acetic acid (25)
Figure imgf000181_0001
(S)-2-ferf-butoxy-2-(1 -(4-chlorophenyl)-3- ((pyridin-3-yloxy)methyl)naphthalen-2-yl)
acetic acid
Preparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-((pyridin-3- yloxy)methyl)naphthalen-2-yl)acetic acid (25): (S)-2-tert-Butoxy-2-(l-(4- chlorophenyl)-3-((pyridin-3-yloxy)methyl)naphthalen-2-yl)acetic acid (25) was prepared by the similar method of Example 22, except that K2CO3 and pyridin-3-ol were used instead of dimethylamine in step 2. 'H-NMR: 400 MHz, (CD3OD) δ: 8.39 (d, J = 2.8 Hz, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 7.96-7.86 (m, 3H), 7.64-7.49 (m, 5H), 7.34- 7.31 (m, 2H), 6.44(d, J = 7.4 Hz, 1H), 6.12 (d, J = 7.6 Hz, 1H), 5.24 (s, 1H), 0.92 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C28H27C1N04: 476.2; Found: 476.0, 478.0.
Example 24. (S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 -((pyrimidin-5 - yloxy)methyl)naphthalen-2-yl)acetic acid (26)
Figure imgf000182_0001
26
(S)-2-feri-butoxy-2-(1-(4-chlorophenyl)-3- ((pyrimidin-5-yloxy)methyl)naphthalen-2-yl)
acetic acid
Preparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-((pyrimidin-5- yloxy)methyl)naphthalen-2-yl)acetic acid (26): (S)-2-tert-Butoxy-2-(l-(4- chlorophenyl)-3-((pyrimidin-5-yloxy)methyl)naphthalen-2-yl)acetic acid (26) was prepared by the similar method of Example 22, except that K2CO3 and pyrimidin-5 -ol were used instead of dimethylamine in step 2. 1H-NMR: 400 MHz, (CD3OD) δ: 8.75 (s, 1H), 8.60 (s, 1H), 8.08 (s, 1H), 7.88 (d, J = 3.8 Hz, 1H), 7.60(s, 2H), 7.58-7.26 (m, 4H), 5.72-5.70 (m, 2H), 5.21 (s, 1H), 1.02 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C27H26C1N204: 477.2; Found: 477.1, 478.1. Example 25. (S)-2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-(morpholinomethyl) naphthalen-2-yl)acetic acid (27)
Figure imgf000183_0001
27
(S)-2-ierf-butoxy-2-(1-(4-chlorophenyl)-3- (morp olinomethyl)naphthalen-2-yl)
acetic acid
Preparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3- (morpholinomethyl)naphthalen-2-yl)acetic acid (27): (S)-2-tert-Butoxy-2-(l-(4- chlorophenyl)-3-(morpholinomethyl)naphthalen-2-yI)acetic acid (27) was prepared by the similar method of Example 22, except that morpholine was used instead of dimethylamine in step 2. 1H-NMR: 400 MHz, (CD3OD) δ: 8.14 (s, 1H), 7.99 (d, J = 4 Hz, 1H), 7.64-7.60 (m, 3H), 7.53-7.49 (m, 2H), 7.29-7.27 (m, 2H), 5.38 (s, 1H), 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-ESI+ (m z): [M+H]+ calcd for C27H31C1N04: 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)
Figure imgf000183_0002
28
(S)-2-feri-butoxy-2-(1-(4-chlorophenyl)-3- (methoxymethyl)naphthalen-2-yl)
acetic acid Preparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3- (methoxymethyl)naphthalen-2-yl)acetic acid (28): (S)-2-tert-Butoxy-2-(l-(4- chlorophenyl)-3-(methoxymethyl)naphthalen-2-yl)acetic acid (28) was prepared by the 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. 1H- NMR: 400 MHz, (CD3OD) δ: 7.91 (s, 1H), 7.77 (d, J = 4.2 Hz, 1H), 7.50-7.13 (m, 7H), 5.06 (s, 1H), 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-ESf (m/z): [M-H]+ calcd for C24H24C104: 41 1.1 ; Found: 411.0, 413.0.
Example 27. (S)-2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-vinylnaphthalen-2-yl)acetic acid (29A) and (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-ethylnaphthalen-2-yl)acetic acid (29B)
Figure imgf000185_0001
(S)-ethyl 2-(3-(bromomethyl)-1 (S)-ethyl 2-ferf-butoxy-2-(1- -(4-chlorophenyl)naphthalen- (4-chlorophenyl)- 2-yl)-2-ferf-butoxyacetate 3-formylnaphthalen-2-yl)acetate
(S
Figure imgf000185_0002
)-et yl 2-ferf-butoxy-2-(1 -
(4-chlorophenyl)-3- vinylnaphthalen-2-yl)acetate (S)-2-terf-butoxy-2-(1 -(4- chlorophenyl)-3- phthalen-2-yl)acetic acid
Figure imgf000185_0003
29B
(S)-2-ferf-butoxy-2-(1- (4-chlorophenyl)-3- ethylnaphthalen-2-yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3- formylnaphthalen-2-yl)acetate: To a solution of (S)-ethyl 2-(3-(bromomethyl)-l-(4- hlorophenyl)naphthalen-2-yl)-2-tert-butoxyacetate from Example 22 (200 mg, 0.408 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 stirred at room temperature for 2 h. Additional N-methylmorpholine N-oxide (500 mg, 4.27 mmol) was added and the reaction mixture was stirred at room temperature for another 2 h. The reaction mixture was then filtered and the organics washed with sat. NaHC03, extracted by DCM, dried over MgS04. The organic layer was then filtered,
concentrated down and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 110 mg (64%) of the desired product. 'H-MNR 400 MHz (CDC13) δ: 10.82 (s, 1H), 8.55 (s, 1H), 8.01 (d, J = 4 Hz, 1H), 7.55-7.23 (m, 7H), 5.19 (s, 1H), 4.17-4.13 (m, 2H), 1.22 (t, J = 7 Hz, 3H), 1.04 (s, 9H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-vinylnaphthalen- 2-yl)acetate: To a suspension of methyltriphenylphosphonium bromide (60 mg, 0.168 mmol) in THF (1 mL) at -78 °C was added dropwise n-BuLi (1.6 M in hexanes, 90 μί), followed after 30 min by a solution of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3- formylnaphthalen-2-yl)acetate (12 mg, 0.028 mmol) in THF (1 mL). The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. This mixture was added to another mixture, which was made by adding n-BuLi (1.6 M in hexanes, 300 μί) 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 temperature and stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, washed with sat. NFLtCl, and extracted with EtOAc. The organic layers were combined, dried over MgS04, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 7.4 mg of the desired product. 1H-MNR 400 MHz (CDC13) δ: 7.95 (s, 1H), 7.78 (d, J = 4.2 Hz, 1H), 7.57-7.50 (m, 1H), 7.43-7.17 (m, 6H), 5.62 (dd, J = 8.1, 2 Hz, 1H), 5.25 (dd, J = 5.3, 1.8 Hz, 1H),5.07 (s, 1H), 4.06-4.02 (m, 2H), 1.10 (t, J = 7 Hz, 3H), 0.93 (s, 9H).
Preparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-vinylnaphthalen-2- yl)acetic acid (29A): To a solution (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3- vinylnaphthalen-2-yl)acetate (7.4 mg, 0.0175 mmol) in THF/MeOH (1/1, 1 mL), was added NaOH (2 N, 280 μί). The reaction mixture was stirred at room temperature overnight. Then the temperature was raised to 40 °C and the reaction mixture was stirred for 4 h. The reaction was then cooled down and neutralized by adding HO Ac. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA) to provide 5.3 mg of the desired product. 1H-NMR: 400 MHz, (CD3OD) δ: 8.07 (s, 1H), 7.89 (d, J = 4.0 Hz, 1H), 7.60-7.54 (m, 4H), 7.48-7.44 (m, 1H), 7.35-7.31 (m, 2H), 7.25-7.22 (m, 1H), 5.76- 5.71 (m, 1H), 5.29-5.26 (m, 1H), 5.21 (s, 1H), 0.98 (s, 9H). LCMS-ESF (m/z): [M-H]" calcd for C24H23C103: 393.1; Found: 393.0.
Preparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-ethylnaphthalen-2- yl)acetic acid (29B): To a solution of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3- vinylnaphthalen-2-yl)acetic acid (4 mg, 0.010 mmol) in EtOH (1.5 mL) was added Rh/Al203 (cat. amount) and the resulting mixture stirred under hydrogen (1 atm, balloon) at room temperature 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/H20 + 0.1% TFA) to provide 0.8 mg of the desired product.
1H-NMR: 400 MHz, (CD3OD) 6: 7.81 (d, J = 4.2 Hz, 1H), 7.77 (s, 1H), 7.58-7.53 (m, 3H), 7.44-7.41 (m, 1H), 7.33-7.20 (m, 3H), 5.20 (s, 1H), 3.14-3.08 (m, 1H), 2.93-2.87 (m, 1H), 1.34 (t, J = 7.4 Hz, 3H), 0.98 (s, 9H). LCMS-ESF (m/z): [M-H]" calcd for C24H24C103: 395.1; Found: 395.0.
Example 28. (S)-2-tert-Butoxy-2-(l -(4-chlorophenyl)-3-(hydroxymethyl) naphthalen- 2-yl)acetic acid (30)
Figure imgf000188_0001
(S)-ethyl 2-ferf-butoxy-2-(1 - (S)-ethyl 2-feri-butoxy-2-(1 -
(4-chlorophenyl)- (4-chlorophenyl)-3- 3-formylnaphthalen-2-yl)acetate ( ydroxymethyl)naphthalen-2-yl)acetate
Figure imgf000188_0002
30
(S)-2-ferf-butoxy-2-(1 -(4- chlorophenyl)-3-(hydroxy methyl)
naphthalen-2-yl)acetic acid
Preparation 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-formylnaphthalen-2-yl)acetate (12 mg, 0.0283 mmol) in
DCM/EtOH (1/1, 1 mL) at 0 °C, was added NaBH4 (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 MgS04, filtered, concentrated in vacuo and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 8 mg of the desired product. 1H-MNR 400 MHz (CDC13) δ: 7.85 (s, 1H), 7.78 (d, J = 4.0 Hz, 1H), 7.46-7.38 (m, 4H), 7.30-7.26 (m, 1H), 7.20-7.15 (m, 2H), 5.13 (s, 1H), 5.02 (d, J = 6.2 Hz, 1H), 4.54 (d, J = 6 Hz, 1H), 4.12-4.02 (m, 2H), 3.82 (bs, 1H), 1.14 (t, J = 7Hz, 3H), 1.01 (s, 9H).
Preparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-(hydroxymethyl) naphthalen-2-yl)acetic acid (30): This compound was made using a method similar to that used for (S)-2-tert-butoxy-2-(l-(4-cUorophenyl)-3-(dimethylaminomethyl) naphthalen-2-yl)acetic acid in Example 22. The compound was purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20). 1H-NMR: 400 MHz, (CD3OD) δ: 7.98 (s, IH), 7.78 (d, J = 4.2 Hz, IH), 7.52-7.44 (m, 3H), 7.39-7.35 (m, IH), 7.26-7.13 (m, 3H), 5.09 (s, IH), 5.05 (d, J - 7.4 Hz, IH), 4.73 (d, J = 7.2 Hz, IH), 0.92 (s, 9H).
LCMS-ESr (m/z): [M-H]" calcd for C23H22C104: 397.1; Found: 396.9, 399.0.
Example 29. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- (fluoromethyl)naphthalen-2-yl)acetic acid (31)
Figure imgf000189_0001
(S)-2-ferf-butoxy-2-((/?)-1-(2,3- (S)-2-((fi)-3-(bromomethyl)-1-(2,3- dihydropyrano[4,3,2-cte] dihydropyrano[4,3,2-cte] quinolin-7-yl)-3-methylnaphthalen- quinolin-7-yl)naphthalen-2-yl)- 2-yl)ethyl pivalate 2-fert-butoxyethyl pivalate
Figure imgf000189_0002
(S)-2-terf-butoxy-2-((/?)-1-(2,3- (S)-2-ferf-butoxy-2-((/?)-1 -(2,3- dihydropyrano[4,3,2-cte] dihydropyrano[4,3,2-cte]
quinolin-7-yl)-3-(fluoromethyl)naphthalen- quinolin-7-yl)-3-(fluoromethyl)
2-yl)ethyl pivalate na hthalen-2-yl)ethanol
Figure imgf000189_0003
31
(S)-2-ferf-butoxy-2-((/?)-1-(2,3- dihydropyrano[4,3,2-de]
quinolin-7-yl)-3-(fluoromethyl)
naphthalen-2-yl)acetic acid Preparation of (S)-2-((R)-3-(bromomethyl)-l-(2,3-dihydropyrano[4,3,2-de] quinolin-7-yl)naphthalen-2-yl)-2-tert-butoxyethyl pivalate: The compound was made similarly to the method for making (S)-ethyl 2-(3-(bromomethyl)-l-(4-chloro- phenyl)naphthalen-2-yl)-2-tert-butoxyacetate of Example 22. LCMS-ESI+ (m/z):
[M+H]+ calcd for C33H37BrN04: 590.2; Found: 590.0, 592.0.
Preparation of (S)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-3-(fluoromethyl)naphthalen-2-yl)ethyl pivalate: To a solution of (S)-2-(3- (bromomemyl)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)-2-tert- butoxyethyl 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 temperature for 1 day. The reaction mixture was then washed by sat. NaHC03, extracted with EtOAc, dried over MgS04, 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 C33H37FN04: 530.3; Found: 530.1.
Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-
7-yl)-3-(fiuoromethyl)naphthalen-2-yl)ethanol: To a solution of (S)-2-tert-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 μί). The reaction mixture was reacted at room temperature for 1 day. The reaction mixture was washed with sat. NaHC03 and extracted with EtOAc. The organic layers were combined, dried over MgS04, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to provide 5 mg of the desired product. LCMS-ESf (m/z): [M+H]+ calcd for C28H29FN03: 446.2; Found: 446.0.
Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-
7-yl)-3-(fluoromethyl)naphthalen-2-yl)acetic acid (31): To a solution of (2S)-2-tert- butoxy-2-(l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-(fluoromethyl)naphthalen-2- yl)ethanol (5 mg, 0.0112 mmol) in wet acetonitrile (0.75%wt H20) was added
H5I06/Cr03 (0.439 M stock solution in wet acetonitrile, 400 μΐ) at 0 °C. The reaction mixture was stirred at 0 °C for 30 rnin. The reaction mixture was filtered and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA) to provide 0.8 mg of the desired product. 1H-NMR: 400 MHz, (CD3OD) δ: 8.51 (d, J = 2.4 Hz, 1H), 8.15 (s, 1H), 7.92 (d, J = 4.0 Hz, 1H), 7.69 (d, J = 4.2 Hz, 1H), 7.54 (d, J = 2.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, IH), 7.31 (d, J = 4 Hz, IH), 7.24-7.21 (m, IH), 6.88 (d, J - 4.4 Hz, IH), 6.01-5.74 (m, 2H), 5.06 (s, IH), 4.59 (t, J = 6.2Hz, 2H), 3.49 (t, J = 6Hz, 2H), 0.81 (s, 9H). 19F-NMR 400 MHz (CD3OD) δ: -77.51 (s, IF). LCMS-ESf (m/z): [M+H]+ calcd for C28H27FN04: 460.2; Found: 460.1.
Example 30. (S)-2-tert-Butoxy-2-((R)-3-(difluoromethyl)-l -(2,3-dihydropyr;
de]quinolin-7
Figure imgf000191_0001
(S)-2-((R)-3-(bromomethyl)-1-(2,3- (S)-2-t ert-butoxy-2-((R)-1 - dihydropyrano[4,3,2-de] (2,3-dihydropyrano[4,3,2-de]
quinolin-7-yl)naphthalen-2-yl)- quinolin-7-yl)-3-formylnap thalen-2
2-fert-butox ethyl pivalate ethyl pivalate
Figure imgf000191_0002
(S)-2-ierf-butoxy-2-((f?)-3-(difluoromethyl) (S)-2-iert-butoxy-2-((R)-3- -1-(2,3-dihydropyrano[4,3,2-de] (difluoromethyl)-1-(2,3-dihydropyrano quinolin-7-yl)naphthalen-2-yl) [4,3,2-de]quinolin-7-yl)naphthalen-2-yl)
ethyl pivalate ethanol
Figure imgf000191_0003
32
(S)-2-fert-butoxy-2-((R)-3- (difluoromethyl)-1-(2,3-dihydropyrano
[4,3,2-cfe]quinolin-7-yl)naphthalen-2-yl)
acetic acid Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-3-formylnaphthalen-2-yl)ethyl pivalate: The compound was made similarly to (S)-ethyl 2-tert-butoxy-2-(l -(4-chlorophenyl)-3-formylnaphthalen-2-yl)acetate of Example 27. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H36N05: 526.2; Found: 526.1.
Preparation of (S)-2-tert-butoxy-2-((R)-3-(difluoromethyl)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)ethyl pivalate: To a solution of (S)-2-tert-butoxy-2-(l-(2,3-dmydropyrano[4,3,2-de]quinolin-7-yl)-3-formylnaphthalen- 2-yl)ethyl pivalate (18 mg, 0.0343 mmol) in DCM (1.5 mL) was added Deoxofluor (20 μί, 0.105 mmol). The reaction mixture was stirred at room temperature overnight. More Deoxofluor (300 μΐ,, 1.6 mmol) was added and the reaction mixture Was stirred at room temperature over weekend. The reaction mixture was washed by sat. NaHC03 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-ESI+ (m/z): [M+H]+ calcd for
C33H36F2N04: 548.2; Found: 548.1.
Preparation of (S)-2-tert-butoxy-2-((R)-3 -(difluoromethyl)- 1 -(2,3 - dihydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)ethanol: The compound was made by the similar method to make (2S)-2-tert-butoxy-2-(l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-(fluoromethyl)naphthalen-2-yl)ethanol of Example 29. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H28F2N03: 464.2; Found: 464.1.
Preparation of (S)-2-tert-butoxy-2-((R)-3-(difluoromethyl)-l -(2,3-dihydropyrano[4,3,2- de]quinolin-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-dihydropyrano[4,3,2-de]quinolin- 7-yl)-3-(fluoromethyl)naphthalen-2-yl)acetic acid of Example 29. 1H-NMR: 400 MHz, (CD3OD) δ: 8.66 (d, J = 2.8 Hz, 1H), 8.56 (s, 1H), 8.15 (d, J = 4.2 Hz, 1H), 8.00-7.81 (m, 3H), 7.69-7.54 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 4.2 Hz, 1H), 5.10 (s, 1H), 4.75 (t, J = 6Hz, 2H), 3.68 (t, J = 6.2 Hz, 2H), 1.07 (s, 9H). I9F-NMR 400 MHz (CD3OD) δ: -77.77 (s, 2F). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H26F2N04: 478.1 ; Found: 478.1.
Example 31. tert-Butoxy-[l-(2,4-dichloro-phenyl)-3-methyl-naphthalen-2-yl]-acetic acid (33)
Figure imgf000193_0001
1 -(2,4-dichlorophenyl)-3- (1 S)-1 -(1 -(2,4-dichlorophenyl)- methyl-2-vinylnaphthalene 3-methylnaphthalen-2- yl)ethane-1,2-diol
(
Figure imgf000193_0002
(S)-2-ierf-butoxy-2-((S)-1-(2,4-dichlorophenyl)-3
methylnaphthalen-2-yl)ethanol 33
(S)-2-feri-butoxy-2-((S)-1 -(2,4- dichlorophenyl)-3-methylnaphthalen- 2-yl)acetic acid
Preparation of l-(2,4-dichlorophenyl)-3-methylnaphthalen-2-ol: A mixture of 2,4-dichlorophenylboronic acid (1.0 g), tetrakis(triphenylphosphine)palladium(0) (300 mg), l-bromo-3-methyl-naphthalen-2-ol (5B, 625 mg) in K2C03 (2 M, 5.3 mL) and DME (26 mL) was degassed with argon and sealed in a Schlenk tube. The reaction was heated to 80 °C for 75 minutes, then cooled to room temperature. The reaction was diluted with EtOAc and filtered through a pad of silica gel. The silica was washed with EtOAc and the combined organics were concentrated. The crude residue was purified by flash column chromatography (0-18% EtOAc in hexanes) to yield 784 mg of desired product.
Preparation of l-(2,4-dichlorophenyl)-3-methylnaphthalen-2-yl
trifluoromethanesulfonate: l-(2,4-dichlorophenyl)-3-methylnaphthalen-2-yl trifluoromethanesulfonate was prepared in a similar manner as compound 4C in Example 2, except starting from l-(2,4-dichlorophenyl)-3-methylnaphthalen-2-ol instead of 4B. 1H-NMR: 400 MHz, (CDC13) δ: 7.85-7.90 (m, 2H), 7.62 (d, 1H), 7.55 (app dt, 1H), 7.41-7.48 (m, 2H), 7.32-7.49 (m, 2H), 2.64 (s, 3H).
Preparation of tert-butoxy-[l-(2,4-dichloro-phenyl)-3-methyl-naphthalen-2-yl]- acetic acid (33): tert-butoxy-[l-(2,4-dichloro-phenyl)-3-methyl-naphthalen-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-yl
trifluoromethanesulfonate instead of 3E. 1H-NMR: 400 MHz, (CD3CN) δ: 7.84 (d, 1H), 7.78 (s, 1H), 7.69 (d, 1H), 7.63 (d, 1H), 7.47-7.54 (m, 2H), 7.37 (app dt, 1H), 7.16 (d, 1H), 5.17 (s, 1H), 2.60 (s, 3H), 1.06 (s, 9H).
Example 32. tert-Butoxy-[l-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-
Figure imgf000195_0001
4-(2-Methoxy-phenyl)- 4-(2-Methoxy- 3-methyl-butyric acid phenyl)-3-methyl- butyryl chloride
Figure imgf000195_0002
5-Methoxy-3-methyl-
(5-Methoxy-3-methyl-1 - 3,4-dihydro-2H- oxo-3,4-dihydro-1 H- naphthalen-1-one
naphthalen-2-ylidene)- acetic acid ethyl ester
Figure imgf000195_0003
(4-Bromo-5-methoxy-3- (1 -Hydroxy-5-methoxy-3- (4-Methoxy-benzyloxy)-(5- methyl-1 -oxo-3,4-dihydro- methyl-naphthalen-2-yl)- methoxy-3-methyl- 1 - 1 H-naphthalen-2-ylidene)- (4-methoxy-benzyloxy)- trifluoromethanesulfonyloxy acetic acid ethyl ester acetic acid ethyl ester -naphthalen-2-yl)-acetic acid ethyl ester
Figure imgf000196_0001
methoxy-3-methyl- [1 -(4-Chloro-phenyl)-5-methoxy- naphthalen-2-yl]-(4-methoxy- 3-methyl-naphthalen-2-yl]- benzyloxy)-acetic acid ethyl hydroxy-acetic acid ethyl ester ester
Figure imgf000196_0002
terf-Butoxy-[1 -(4-chloro-pheny I)- 5-methoxy-3-methyl-naphthalen-
2-yl]-acetic acid ethyl ester ferf-Butoxy-[1 -(4- chloro-phenyl)-5- methoxy-3-methyl- naphthalen-2-yl]-acetic
acid
Preparation of 4-(2-methoxyphenyl)-3-methyl-but-2-enoic acid ethyl ester: In a 3-neck round bottom flask, fitted with an internal thermometer and addition funnel, a mixture of sodium hydride (60% in mineral 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 evolution), keeping the internal temperature below room temperature. After addition, the reaction mixture was stirred at room temperature 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 to room temperature overnight. With active cooling, the reaction was quenched with H20 (200 mL), then AcOH (to pH ~6) and extracted with EtOAc. The combined organics were washed with NaHC03, water, and brine, dried over Na2S04, and concentrated. The crude residue was purified by flash column chromatography to give the desired compound (5.73 g). 1H-NMR: 400 MHz, (CDC13) δ: 7.24 (app dt, 1H), 7.10 (dd, 1H), 6.92 (d, 1H), 6.88 (d, 1H), 5.58 (s, 1H), 4.13 (q, 2H), 3.82 (s, 3H), 3.46 (s, 2H), 1.26 (t, 3H).
Preparation of 4-(2-methoxyphenyl)-3 -methyl-butyric 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-methoxy-phenyl)-3-methyl-but-2- enoic acid ethyl ester (5.7 g, 24 mmol). Hydrogen was bubbled through the ethanol, and the reaction was stirred under 1 atm of H2 (balloon)overnight. 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 filtrates dried over magnesium sulfate and concentrated. The crude residue was used without further purification. LCMS-ESI+ (m/z): [M calcd for C14H2o03: 236.14; Found: 236.96.
Preparation of 4-(2-methoxyphenyl)-3-methyl-butyric acid: A solution of 4-(2- methoxyphenyl)-3 -methyl-butyric acid ethyl ester (24 mmol, crude from previous reaction) in THF (50 mL), EtOH (50 mL) and LiOH (1 M, 50 mL) was stirred at room temperature overnight. The reaction was acidified with 1 M HC1, 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-ESI+ (m/z): [M]+ calcd for C12H1603: 208.11 ; Found: 208.86
Preparation of 4-(2-methoxyphenyl)-3-methyl-butyryl chloride: To a solution of
4-(2-methoxyphenyl)-3-methylbutyric acid (24 mmol, crude from previous reaction) in dichloromethane (36 mL) was added oxalyl chloride (2 M in DCM, 36 mL). The reaction was stirred for 1 h at room temperature. All volatiles were removed in vacuo and the crude residue used without further purification.
Preparation 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 chloride (24 mmol, crude from previous reaction). The reaction was allowed to warm slowly to room temperature and then quenched by slowly pouring over ice. The mixture was extracted with dichloromethane (3x) and the combined organics were washed with 1 M HC1, 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-phenyl)-3-methyl-but-2-enoic acid ethyl ester). LCMS-ESf (m/z): [M+H]+ calcd for C12H1502: 191.11; Found:
191.19.
Preparation of (5-methoxy-3-methyl-l-oxo-3,4-dihydro-lH-naphthalen-2- ylidene)-acetic acid ethyl ester: In a heavy walled sealed tube, 5-methoxy-3-methyl- 3,4-dihydro-2H-naphthalen-l-one (1.3 g, 6.8 mmol), ethyl glyoxylate (3 mL, 50% solution in toluene), benzenesulfonic acid (100 mg), magnesium sulfate (5 g), and toluene (30 mL) were heated to 120 °C for 13 hours. The reaction was cooled to room temp, filtered, diluted 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-ESf (m/z): [M+H]+calcd for C16H1904: 275.13; Found: 275.26.
Preparation of (4-bromo-5-methoxy-3-methyl-l-oxo-3,4-dihydro-lH- naphthalen-2-ylidene)-acetic acid ethyl ester: A mixture of (5 -methoxy-3 -methyl- 1- oxo-3,4-dihydro-lH-naphthalen-2-ylidene)-acetic acid ethyl ester (480 mg), NBS (420 mg), and AIBN (30 mg) in CCI4 (18 mL) was refluxed for 3 hours. The reaction mixture was then cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (2x). The combined organics were washed with water, dried (Na2S04), concentrated, and purified by flash column chromatography to give a light brown solid (420 mg) LCMS-ESI+ (m/z): [M+H]+ calcd for C16H18Br04: 353.03; Found: 352.91.
Preparation of (1 -hydroxy-5-methoxy-3-methyl-naphthalen-2-yl)-(4-methoxy- benzyloxy)-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 resulting mixture was allowed to stir for 10 min at 0 °C. A solution of (4-bromo-5-methoxy-3 -methyl- 1 -oxo-3 ,4-dihydro- 1 H-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 reaction was quenched with citric acid (1 M) and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2S04 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-ESf (m/z): [M+H]+ calcd for C24H2706: 411.18; Found: 411.21.
Preparation of (4-methoxybenzyloxy)-(5-methoxy-3 -methyl- 1- trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid ethyl ester: A solution of (1- hydroxy-5-methoxy-3-methyl-naphthalen-2-yl)-(4-methoxy-benzyloxy)-acetic acid ethyl ester (157 mg, 0.38 mmol) in dichloromethane (3.8 mL) was cooled to -78 °C under Ar. To the solution was added 2,6-lutidine (0.1 mL) and triflic anhydride (0.1 mL) and stirred at -78 °C for 2.5 hours. Saturated sodium bicarbonate (3 mL) was added and the reaction mixture was warmed to room temperature and diluted with dichloromethane. The dichloromethane was separated, the aqueous layer extracted with CH2C12, 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 CssH^FaNaOgS: 565.11; Found: 565.23.
Preparation of [1 -(4-chlorophenyl)-5-methoxy-3-methylnaphthalen-2-yl]-(4- methoxybenzyloxy)acetic acid ethyl ester: A solution of (4-methoxy-benzyloxy)-(5- methoxy-3 -methyl- 1 -trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid ethyl ester (128 mg, 0.236 mmol), 4-chlorophenylboronic acid (74 mg, 2 equiv), EtOH (0.5 mL), K2C03 (2 M, 0.5 mL), and toluene (1.3 mL) were degassed with argon at room temperature 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 filtered 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 temperature, diluted with EtOAc and filtered 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 C30H29ClNaO5: 527.99; Found: 527.44.
Preparation of [1 -(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]- hydroxy-acetic acid ethyl ester: To a solution of [l-(4-chloro-phenyl)-5-methoxy-3- methyl-naphthalen-2-yl]-(4-methoxy-benzyloxy)-acetic acid ethyl ester (58 mg, 0.1 15 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (58 μί). The reaction mixture was stirred for 2 h at room temperature and then quenched carefully with sat. NaHC03. The aqueous layer was extracted with dichloromethane twice, and then the combined organic layers were washed with water, dried (Na2S04), concentrated and purified by flash column chromatography to give desired (23 mg). Preparation of tert-butoxy-[l -(4-chloro-phenyl)-5-methoxy-3-methyl- naphthalen-2-yl] -acetic acid ethyl ester: A solution of [l-(4-chloro-phenyl)-5-methoxy- 3-methyl-naphthalen-2-yl]-hydroxy-acetic acid ethyl ester (23 mg) and perchloric acid, 70% (3 μί) in tert-butyl acetate (1 mL) was stirred at room temperature for 2 h. After 2 h, the reaction had apparently stalled, so 3 μί, additional perchloric acid was added. After 2 additional hours, 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 (Na2S04), 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 re- subjected to similar reaction conditions to yield an additional 3 mg of desired.
1H-NMR: 400 MHz, (CDC13) δ: 8.10 (s, IH), 7.39-7.48 (m, 3Η), 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 (t, 3H), 0.98 (s, 9H).
Preparation of tert-butoxy-[l-(4-chlorophenyl)-5-methoxy-3-methyl- naphthalen-2-yl] -acetic acid (34): To a solution of tert-butoxy-[l-(4-chloro-phenyl)-5- methoxy-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 reaction was stirred for 30 min at room temperature, 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 temperature. Formic acid was added until pH ~ 5. The reaction mixture was directly purified by HPLC (Gemini, 50-100% MeCN/¾0, with 0.1% TFA). The product was lyophilized to give a white powder (8 mg).
1 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 C20H16ClO3: 339.79; Found: 339.07.
Example 33. Ethyl 2-(5-bromo-3-methyl-l-(trifluoromethylsulfonyl-oxy) naphthalen- 2-yl)-2-(4-methoxybenzyloxy)acetate (35)
Figure imgf000201_0001
ethyl 2-(5-bromo-3-methyl-1-(((trifluoromethyl)sulfonyl)oxy)naphthalen-2-yl)-2- ((4-methoxybenzyl)oxy)acetate
Preparation of ethyl 2-(5-bromo-3-methyl-l-(trifluoromethylsulfonyl- oxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate (35): Ethyl 2-(5-bromo-3- methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyl oxy)acetate (35) was prepared similarly to ethyl 2-(6-methoxy-3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-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. 1H-NMR: 400 MHz, (CDC13) δ: 8.11 (s, 1H), 8.01
(d, J - 8.8 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 7.6 Hz, 2H), 5.61 (s, 1H), 4.62 (q, J = 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- 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- oxoacetate (36A) and Ethyl 2-(l,5-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- oxoacetate (36B):
(
Figure imgf000202_0001
36B
ethyl 2-(5-bromo-1-(4- chlorophenyl)-3- methylnaphthalen-2-yl)-2- ethyl 2-(1 ,5-bis(4-chlorophenyl)-3- oxoacetate methylnaphthalen-2-yl)-2-oxoacetate
Preparation of ethyl 2-(5-bromo-3 -methyl- l-(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-oxoacetate: Prepared similarly to ethyl 2-(7-bromo-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate of Example 67, using ethyl 2-(5-bromo-3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4- methoxybenzyloxy)acetate instead of ethyl 2-(7-bromo-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate. 1H- NMR: 400 MHz, (CDC13) δ: 8.20 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.95 (dd, J = 7.4, 0.8 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 2.54 (s, 3H), 1.40 1, J = 7.6 Hz, 3H).
Preparation of ethyl 2-(5-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-oxoacetate (36A) and ethyl 2-(l,5-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- oxoacetate (36B): To a solution of ethyl 2-(5 -bromo-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (1.2 g, 2.56 mmol) and 4- 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 reaction was stirred at room temperature for 4 hours. The reaction was filtered, diluted with water, extracted with ethyl acetate and concentrated. The crude reaction was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) followed by reverse phase HPLC (Gemini, 40-100%
ACN/H20 + 0.1% TFA). Product was lyophilized to give 670 mg of ethyl 2-(5-bromo- l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (36A) as a yellow oil, 1H- MR: 400 MHz, (CDC13) δ: 8.20 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 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(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (36B) as a white solid. !H- NMR: 400 MHz, (CDCI3) δ: 7.72 (s, 1H), 7.59-7.56 (m, 1H), 7.50 (t, J = 8.0 Hz, 2H), 7.46-7.44 (m, 5H), 7.43 (d, J - 2.4 Hz, 1H), 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- 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (37)
Figure imgf000203_0001
ethyl 2-(5-bromo-1-(4- chlorophenyl)-3- methylnaphthalen-2-yl)- 2-(5-bromo-1 -(4-
2-(ferf-butoxy)acetate chlorophenyl)-3- methylnaphthalen-2-yl)-2- (ierf-butoxy)acetic acid
Preparation of ethyl 2-(5-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-tert-butoxyacetate: Prepared similarly to ethyl 2-(7-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetate of Example 67 using ethyl 2-(5-bromo-l- (4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate instead of ethyl 2-(7-bromo- l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate. Product was carried on crude to next reaction.
Preparation of 2-(5-bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (37): To a solution of ethyl 2-(5-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetate (30 mg, 0.061 mmol) in
tetrahydrofuran:ethanol: water (2:2:1, 3 mL) was added lithium hydroxide (7 mg, 0.31 mmol) and the reaction was heated to 50 °C overnight. Crude reaction purified by reverse phase HPLC (Gemini, 40-100% ACN/¾0 + 0.1%TFA). Product lyophilized to give a white powder (5.9 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 8.07 (s, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.58 (s, 2H), 7.55 (as, 1H), 7.32 (d, J - 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.18 (m, 1H), 5.17 (s, 1H), 2.67 (s, 3H), 0.99 (s, 9H). LCMS-ESF (m/z): [M- H]" calcd for C23H21BrC103: 460.8; found; 460.2.
Example 36. 2-(l,5-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (38)
Figure imgf000204_0001
38
2-( 1 ,5-bis(4-chlorophenyl)-3 -methylnaphthalen-2-yl)-2-tert-butoxyacetic acid
Preparation of 2-(l ,5-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (38): 2-(l,5-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (38) was prepared similarly to 2-(5-bromo-l -(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetic acid of Example 35 using ethyl 2-(l,5- bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate instead of ethyl 2-(5- bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate. 1H-NMR: 400 MHz, (CD3OD) 6: 7.59 (m, 4H), 7.53 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.35 (m, 3H), 7.28 (m, IH), 5.18 (s, IH), 2.51 (s, 3H), 0.99 (s, 9H). LCMS-EST (m/z): [M- H]-calcd for C29H26C1203: 491.13; found: 491.42. Example 37. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-5-(3 -(dimethylamino)prop- 1 -ynyl)- 3-methylnaphthalen-2-yl)acetic acid (39)
Figure imgf000205_0001
2-ierf-butoxy-2-(1-(4- chlorophenyl)-5-(3- (dimethylamino)prop-l -ynyl)-3- methylnaphthalen-2-yl)acetic
acid Preparation of ethyl 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-5-(3 -
(dimethylamino)prop-l-ynyl)-3-methylnaphthalen-2-yl)acetate: To a solution of ethyl 2-(5 -bromo- 1 -(4-chlorophenyl)-3 -methylnaphthalen-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 anhydrous tetrahydrofuran was added copper iodide (8 mg, 0.04 mmol) and
PdCl2(PPh3)2 (14 mg, 0.02 mmol). The reaction was heated to 100 °C overnight. After cooling to room temperature the reaction was charged with PdCl2(PPh3)2 (14 mg, 0.02 mmol), copper iodide (8 mg, 0.04 mmol), N,N-dimethylprop-2-yn-l -amine (0.065 mL, 0.61 mmol) and triethylamine (1 mL). The reaction was heated to 100 °C overnight. To the reaction was then added N,N-dimethylprop-2-yn-l -amine (0.065 mL, 0.61 mmol) and heated to 100 °C overnight. 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 C30H35ClNO3: 492.22; found: 492.15.
Preparation 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- (l -(4-chlorophenyl)-5-(3-(dimethylamino)prop- 1 -ynyl)-3-methylnaphthalen-2- yl)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 overnight. The reaction was purified by reverse phase HPLC (Gemini, 40-60%
ACN/H20 + 0.1 % TFA). The product was lyophilized to give a white powder (1.2 mg).IH-NMR: 400 MHz, (CD3OD) δ: 8.14 (s, IH), 7.74 (d, J = 6.4 Hz, IH), 7.58 (s, 2H), 7.56 (as, IH), 7.33 (m, 3H), 5.18 (s, IH), 4.42 (s, 2H), 3.04 (s, 6H), 2.67 (s, 3H), 0.99 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C28H31C1N03: 464.19; found: 464.51.
Example 38. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 ,5-dimethylnaphthalen-2-yl)acetic acid (40)
Figure imgf000207_0001
ethyl 2-(5-bromo-1-(4- ethyl 2-(ferf-butoxy)-2-(1-(4- chlorophenyl)-3- chlorophenyl)-3,5- methylnaphthalen-2-yl)-2-(fe/-f- dimethylnaphthalen-2- butoxy)acetate
yl)acetate
Figure imgf000207_0002
40
2-(terf-butoxy)-2-(1-(4- chlorophenyl)-3,5- dimethylnaphthalen-2- yl)acetic acid
Preparation of ethyl 2-tert-butoxy-2-(l -(4-chlorophenyl)-3,5- dimethylnaphthalen-2-yl)acetate: To a solution of ethyl 2-(5-bromo-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (100 mg, 0.204 mmol) and 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (0.086 mL, 0.61 mmol) in
toluenerethanol (2:1, 3 mL) and water (1 mL) was added potassium carbonate (282 mg, 2.04 mmol) and PdCl2(dppf) (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 reaction was purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a yellow oil (32 mg) 1H-NMR: 400 MHz, (CD3OD) δ: 8.08-7.87 (m, 2H), 7.87 (s, 1H), 7.65-7.35 (m, 1H), 7.26 (m, 2H), 7.15 (d, J = 7.2 Hz, 1H), 7.09 (d, J - 8.0 Hz, 1H). 5.10 (s, 1H), 4.14 (m, 2H), 2.69 (s, 3H), 2.65 (s, 3H), 1.20 (t, J = 6.8 Hz, 3H), 0.99 (s, 9H).
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-3,5-dimethylnaphthalen-2- yl)acetic acid (40): To a solution of ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3,5- dimethylnaphthalen-2-yl)acetate (32 mg, 0.075 mmol) in tetrahydrofuran:
ethanohwater (2:2:1, 3 mL) was added lithium hydroxide (9 mg, 0.377 mmol) and the reaction was heated to 50 °C overnight. The reaction was purified by reverse phase HPLC (Gemini, 40-100% ACN/H20 + 0.1% TFA). The product was lyophilized to give a white powder (16.8 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 7.86 (s, 1H), 7.54 (m, 3H), 7.29 (m, 2H), 7.16 (t, J - 8.8 Hz, 1H), 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-EST (m/z): [M-H]" calcd for C24H24C103: 395.15; found: 394.97.
Example 39. 2-tert-Butoxy-2-( 1 -(4-cUorophenyl)-3-memyl-5-(pyrirnidin-5- yl)naphthalen-2-yl)acetic acid (41)
Figure imgf000208_0001
41
2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-5- (pyrimidin-5-yl)naphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l-(4-cMorophenyl)-3-methyl-5-( yrirnidin-5- yl)naphthalen-2-yl)acetic acid (41): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyl-5- (pyrimidin-5-yl)naphthalen-2-yl)acetic acid (41) was prepared similarly to 2-tert- butoxy-2-(l-(4-chlorophenyl)-3,5-dimethylnaphthalen-2-yl)acetic acid of Example 38 using pyrimidin-5-ylboronic acid in place of 2,4,6-trimethyl-l,3,5,2,4,6- trioxatriborinane. 1H-NMR: 400 MHz, (CD3OD) δ: 9.27 (s, 1H), 8.95 (s, 2H), 7.60 (s, 2H), 7.58 (s, 1H), 7.54 (s, 1H), 7.43 (m, 3H), 7.36 (d, J = 8.4 Hz, 1H), 5.20 (s, 1H), 2.55 (s, 3H), 1.00 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C27H26C1N203: 461.16; found: 461.45. Example 40. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-6-fluoro-3 -methylnaphthalen-2- yl)acetic acid (42)
Figure imgf000209_0001
42
2-tert-butoxy-2-(l-(4-chlorophenyl)-6-fluoro-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-6-fluoro-3- methylnaphthalen-2-yl)acetic acid (42): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-6-fluoro- 3-methylnaphthalen-2-yl)acetic acid (42) was prepared similarly to 2-(5-bromo-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid of Example 35, using 6-fluoro-3-methyl-3,4-dihydronaphthalen-l (2H)-one instead of 5-bromo-3-methyl-3,4- dihydronaphthalen-l(2H)-one. 1H-NMR: 400 MHz, (CD3OD) δ: 7.67 (s, 1H), 7.57 (s, 2H), 7.55 (as, 1H), 7.45 (dd, J = 9.8, 2.8 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 9.4, 5.2 Hz, 1H), 7.11 (td, J = 9.0, 2.4 Hz, 1H) 5.16 (s, 1H), 2.60 (s, 3H), 0.98 (s, 9H). 19F-NMR: 377 MHz, (CD3OD) δ: -118.01 (s). LCMS-ESI" (m/z): [M-H]" calcd for C23H21C1F03: 399.12; found: 399.19.
Example 41. 2-tert-butoxy-2-((R)- 1 -(2,3-dihydropyrano[4,3 ,2-de]quinolin-7-yl)-6- fluoro-3-methylnaphthalen-2-yl)acetic acid (43):
Figure imgf000210_0001
43
2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-fluoro-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-6-fluoro-3-methylnaphthalen-2-yl)acetic acid (43): 2-tert-Butoxy-2-((R)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-6-fluoro-3-methylnaphthalen-2-yl)acetic acid (43) was prepared similarly to 2-tert-butoxy-2-(l -(4-chlorophenyl)-6-fluoro-3- methylnaphthalen-2-yl)acetic acid of Example 40 using l-(3-fluorophenyl)propan-2- one instead of 1 -(2-bromophenyl)propan-2-one and 2,3-dihydropyrano[4,3,2- de]quinolin-7-ylboronic acid instead of 4-chlorophenylboronic acid. 'H-NMR: 400 MHz, (CD3OD) δ: 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, 1H), 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) 6: -116.92 (s). LCMS-ESI+ (m/z):
[M+H]+ calcd for C28H27FN04: 460.18; found: 460.15.
Example 42. 2-tert-Butoxy-2-(l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro- 3-methylnaphthalen-2-yl)acetic acid (44).
Figure imgf000210_0002
44 2-tert-butoxy-2-(l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-( 1 -(2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-5- fluoro-3 -methylnaphthalen-2-yl)acetic acid (44) : 2-tert-Butoxy-2-( 1 -(2,3 - dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetic acid (44) was prepared similarly to 2-tert-butoxy-2-((R)-l -(2,3 -dihydropyrano [4,3,2- de]quinolin-7-yl)-6-fluoro-3-methylnaphthalen-2-yl)acetic acid (43) using l-(2- fluorophenyl)propan-2-one instead of l-(3-fluorophenyl)propan-2-one. 1H-NMR: 400 MHz, (CD3OD) δ: 8.68 (d, J = 5.6 Hz, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.10 (s, 1H), 7.78 (d, J = 5.6 Hz, 1H), 7.43 m, 1H), 7.19 (m, 2H), 6.73 (M, 1H), 5.23 (s, 1H), 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) δ: -125.97 (t, J = 7.54 Hz). LCMS-ESF (m/z): [M-H]" calcd for C28H27FN04: 458.18; found: 457.76.
Example 43. 2-tert-Butoxy-2-(5-chloro-l-(4-chlorophenyl)-3-methylnaphthalen-2- yl)acetic acid (45).
Figure imgf000211_0001
Preparation of 2-tert-butoxy-2-(5-chloro- 1 -(4-chlorophenyl)-3- methylnaphthalen-2-yl)acetic acid (45): 2-tert-Butoxy-2-(5-chloro-l-(4-chlorophenyl)- 3-methylnaphthalen-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. 1H-NMR: 400 MHz, (CDC13) δ: 8.14 (s, 1H), 7.64 (m, 1H), 7.54 (m, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.23 (m, 3H), 5.27 (s, 1H), 2.64 (s, 3H), 1.03 (s, 9H). LCMS-ESF (m/z): [M-H]" calcd for C23H21C1203: 415.09; found; 415.09.
Example 44. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-5-fluoro-3 -methylnaphthalen-2- yl)acetic acid (46)
Figure imgf000212_0001
46
2-tert-butoxy-2-(l-(4-chlorophenyl)-5-fluoro-3- methylnaphthalen-2-yl)acetic acid Preparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-5 -fluoro-3 - methylnaphthalen-2-yl)acetic acid (46): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-5-fluoro- 3-methylnaphthalen-2-yl)acetic acid (46) 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-fluorophenyl)propan-2-one instead of l-(3-fluorophenyl)propan-2-one. 1H-NMR: 400 MHz, (CD3OD) δ: 7.94 (s, 1H), 7.59 (s, 2H), 7.57 (m, 1H), 7.35 (d, J = 8.8 Hz, lh), 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) δ: -126.85 (dd, J = 10.2, 5.3 Hz). LCMS-ESF (m/z): [M-H]" calcd for C23H21C1F03: 399.12; found: 399.14. Example 45. 2-tert-Butoxy-2-((R)-5-chloro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methylnaphthalen-2-yl)acetic acid (47)
Figure imgf000213_0001
2-tert-butoxy-2-((R)-5-cMoro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid Preparation of 2-tert-butoxy-2-((R)-5-chloro-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid (47): 2-tert-Butoxy-2-((R)-5- cUoro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-rnethylnaphthalen-2-yl)acetic acid (47) was prepared similarly to 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-6-fluoro-3-methylnaphthalen-2-yl)acetic acid of Example 41 using 1- (2-chlorophenyl)propan-2-one instead of l-(3-fluorophenyl)propan-2-one. ^-NMR: 400 MHz, (CD3OD) 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-ESF (m/z): [M-H]' calcd for C28H25C1N04: 474.16; found: 474.08.
Example 46. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2- yl)acetic acid (48)
Figure imgf000214_0001
hydroxyacetate
perchloric acid
t-butylacetate
Figure imgf000214_0002
ethyl 2-(terf-butoxy)-2-(1-(4- chlorophenyl)-6-methoxy-3- methylnaphthalen-2-yl)acetate
2-(ferf-butoxy)-2-(1-(4- chlorophenyl)-6-methoxy-3- methylnaphthalen-2-yl)acetic acid
Preparation of ethyl 2-(6-methoxy-3 -methyl- l-(trifluoromethylsulfonyl- oxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate: Ethyl 2-(6-methoxy-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy) acetate was prepared similarly as the preparation of ethyl 2-(5 -methoxy-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate of Example 32 using 6-methoxy-3-methyl-3,4-dihydronaphthalen-l(2H)-one instead of 5- methoxy-3-methyl-3,4-dihydronaphthalen-l(2H)-one. 1H-NMR: 400 MHz, (CDC13) δ: 7.93 (d, J = 9.2 Hz, 1H), 7.56 (s, 1H), 7.25-7.21 (m, 3H), 7.07 (d, J - 2.4 1H), 6.82 (d, J = 8.8 Hz, 2H), 5.57 (s, 1H), 4.62-4.55 (m, 2H), 4.27-4.13 (m, 2H), 3.93 (s, 3H), 3.77 (s, 3H), 2.53 (s, 3H), 1.18 (t, J - 6.8 Hz, 3H).
Preparation of ethyl 2-(l -(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2- yl)-2-(4-methoxybenzyloxy)acetate: To a solution of ethyl 2-(6-methoxy-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyl-oxy)acetate ( 100 mg, 0.184 mmol) and 4-chlorophenylboronic acid (58 mg, 0.37 mmol) in 1,2- dimethoxyethane (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 in 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). 'H-NMR: 400 MHz, (CDC13) 6: 7.58 (s, 1H), 7.39 (dd, J = 8.2, 1.6 Hz, 1H), 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).
Preparation of ethyl 2-(l-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2- yl)-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-(l-(4- cUorophenyl)-6-methoxy-3-memymaphthalen-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 temperature 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/H20 +0.1% TFA) to give the two products: ethyl 2-(l-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2- yl)-2-hydroxyacetate: 27 mg clear oil. LCMS-ESf (m/z): [M+H- H20]+ calcd for
C22H19C103: 367.09; found: 367.05: and ethyl 2-(l-(4-chlorophenyl)-6-methoxy-5-(4- methoxybenzyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate: 105 mg as a brown oil. LCMS-ESf (m/z): [M+H-H20]+ calcd for C30H27ClO4: 487.15; found: 486.90. Preparation of ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-6-methoxy-3- methylnaphthalen-2-yl)acetate: To a solution of ethyl 2-(l-(4-chlorophenyl)-6- methoxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate (27 mg, 0.07 mmol) in tert- butylacetate (1.0 mL) was added 70% perchloric acid (0.012 mL, 0.14 mmol) and the reaction was stirred at room temperature for 1.5 hours. The reaction was quenched with solid sodium bicarbonate, water (2 mL) added and stirred 1 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). 1H- NMR: 400 MHz, (CDC13) 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), 4.12- 4.02 (m, 2H), 3.82 (s, 3H), 2.52 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H), 0.91 (s, 9H).
Preparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-6-methoxy-3- methylnaphthalen-2-yl)acetic acid (48): To a solution of ethyl 2-tert-butoxy-2-(l-(4- chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)acetate (16.2 mg, 0.037 mmol) in tetrahydrofuran:ethanol: 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). 1H-NM : 400 MHz, (CD3OD) δ: 7.60 (s, 1H), 7.55 (m, 3H), 7.30 (m, 1H), 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-ESI" ( /z): [M-H]" calcd for C24H24C104: 411.14; found: 411.14.
Example 47. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-6-methoxy-5-(4-methoxybenzyl)-3- methylnaphthalen-2-yl)acetic acid (49)
Figure imgf000217_0001
49
2-tert-butoxy-2-( 1 -(4-chlorophenyl)-6-methoxy-5 -(4-methoxybenzyl)-3 - methylnaphthalen-2-yl)acetic acid Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-6-methoxy-5-(4- methoxybenzyl)-3-methylnaphthalen-2-yl)acetic acid (49): 2-tert-Butoxy-2-(l-(4- chlorophenyl)-6-methoxy-5-(4-methoxybenzyl)-3-methylnaphthalen-2-yl)acetic acid (49) was prepared following the procedure for 2-tert-butoxy-2-(l-(4-chlorophenyl)-6- methoxy-3-methylnaphthalen-2-yl)acetic acid of Example 46 using ethyl 2-(l-(4- chlorophenyl)-6-methoxy-5 -(4-methoxybenzyl)-3 -methylnaphthalen-2-yl)-2- hydroxyacetate in place of ethyl 2-(l-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen- 2-yl)-2-hydroxyacetate. 1H-NMR: 400 MHz, (CD3OD) δ: 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-ESr (m/z): [M-H]" calcd for C32H32C105: 531.20; found: 531.01.
Example 48. 6-Bromo-3-methyl-3,4-dihydronaphthalen-l(2H)-one (50)
Figure imgf000218_0001
50
4-(3-bromophenyl)-3- methylbutanoic acid 6-bromo-3-methyl-3,4- dihydronaphthalen- 1(2tf)-one
Preparation of 6-bromo-3-methyl-3,4-dihydronaphthalen-l(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) slowly to produce a clear dark brown solution. After 15 min, the reaction was diluted with 500 mL of CHC13 and poured slowly onto approximately 1 L of crushed ice. The resulting slurry was allowed to stir until the solution warms to room temperature and became biphasic. Following separation of layers, the aqueous layer was extracted with CHC13. The combined organics were washed with brine and dried over anhydrous MgS04 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 CnHnBrO: 239.11 ; found: 239.20.
Example 49. 1).
Figure imgf000218_0002
4-(4-bromophenyl)-3- 51
methylbutanoic acid
7-bromo-3-methyl-3,4- dihydronaphthalen-1 (2 Y)-one
Preparation 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 Example 32 (6.43 g, 25.0 mmol), in H2S04 (25 mL) was stirred at 75 °C for 3 h. The mixture was slowly 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 concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 5.74 g (96%) of the title compound. 1H- NMR: 400 MHz, (CDC13) δ: 8.10 (d, J = 2 Hz, 1H), 7.54 (dd, J = 8, 2 Hz, 1H), 7.11 (d, J = 8 Hz, 1H), 2.91 (d, J = 16 Hz), 2.71 (d, J = 13 Hz), 2.58 (m, 1H), 2.28 (m, 2H), 1.12 (d, J = 6 Hz, 3H).
Example 50. (6-Bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2- yloxy)triisopropylsilane (52)
Figure imgf000220_0001
3-bromo-4-(4- 2-bromo-1-(4-
4-(4-chlorophenyl)-7- chlorophenyl)-7- chlorophenyl)-6-methoxy- methoxy-2-methyl-1 ,2- methoxy-2-methyl-1 ,2- 3-methylnaphthalene dihydronaphthalene
dihydronaphthalene
Figure imgf000220_0002
6-bromo-5-(4- 52
chlorophenyl)-7- methylnaphthalen-2-ol (6-bromo-5-(4- chlorophenyl)-7- methylnaphthalen-2- yloxy)triisopropylsilane
Preparation of (6-bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2- yloxy)triisopropylsilane (52):
Step 1: Preparation of 6-methoxy-3-methyl-3,4-dihydronapb.thalen-l-yl trifluoromethanesulfonate: To a solution of 6-methoxy-3-methyl-3,4- dihydronaphthalen-l(2H)-one (10.06 g, 53 mmol; prepared similarly to 6-bromo-3- methyl-3,4-dihydronaphthalen-l(2H)-one (50) of Example 48 beginning with l-(3- methoxyphenyl)propan-2-one), cooled to 0 °C was added 2,6-di-tert-butyl-4- methylpyridine (19.6 g, 95.4 mmol) followed by trifluoromethanesulfonic anhydride (13.3 mL, 79.4 mmol). The resulting solution was allowed to warm slowly to room temperature over 1.5 h and then quenched by addition of 1 M HC1 (100 mL).
Following separation, the aqueous layer was extracted with DCM (3 X 100 mL) and the combined organics washed with brine. Following concentration in vacuo, the residue was taken up in hexanes. The resulting precipitated solids were removed via filtration and the mother liquor was dried over anhydrous MgS04 and then concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (3% to 35% EtOAc/Hex) to produce 9.88 g (57%) of the title compound as a colorless syrup. 1H-NMR: 400 MHz, (CDC13) δ: 7.28 (s, 1H); 6.75 (m, 2H); 5.74 (d, J - 4 Hz, 1H); 3.82 (s, 3H); 2.77 (m, 1H) 2.89 (dd, J = 15.2, 10 Hz; 1H); 2.61 (dd, J = 15.2, 10 Hz; 1H); 1.14 (d, J =7.2 Hz, 3H).
Step 2: Preparation of 4-(4-chlorophenyl)-7-methoxy-2 -methyl- 1,2- dihydronaphthalene: 6-methoxy-3-methyl-3,4-dihydronaphthalen-l-yl
trifluoromethanesulfonate (9.88 g, 30.7 mmol), 4-chlorophenylboronic acid (6.23 g, 39.9 mmol) and K2C03 (12.7 g, 91.9 mmol) were combined in a mixture of
toluene/ethanol/water (80 mL/40 mL/40 mL) at room temperature in a heavy walled pressure flask. Following sparging of the mixture with Ar for 30 minutes, PdCl2(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 returning to room temperature, 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 MgS04. The resulting solution was absorbed on silica gel in vacuo and purified via Yamazen column chromatography (0-15% EtO Ac/Hex) to provide 7.7 g (88%) of the title compound as an amorphous white solid. 1H-NMR: 400 MHz,
(CDCI3) δ: 7.32 (d, J = 8 Hz, 2H); 7.26 (d, J = 8Hz, 2H); 6.87 (d, J = 8.4 Hz, 1H); 6.57 (d, J = 2.8 Hz, 1H); 6.62 (dd, J = 8.4, 2.8 Hz, 1H); 5.74 (d, J = 2.8 Hz, 1H); 3.79 (s, 3H); 2.81 (ABq, J = 20.8, 12.4 Hz, 1H); 2.60 (m, 1H); 2.59 (ABq, J = 8.4, 2.8 Hz, 1H); 1.14 (d, J = 6.4 Hz, 3H).
Step 3: Preparation of 3-bromo-4-(4-chlorophenyl)-7-methoxy-2 -methyl- 1,2- dihydronaphthalene: A solution of 4-(4-chlorophenyl)-7-methoxy-2-methyl-l,2- dihydronaphthalene (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 Na2S203 (200 mL). The reaction was further diluted with water and DCM before separation and extraction of the aqueous layer with DCM. The combined pink organics were washed with brine and dried over anhydrous MgS04. Following filtration and concentration in vacuo, the resulting residue was purified by Yamazen column chromatography (0-10% EtOAc Hex) to afford 5.5 g (86%) of the title compound as an orange colored gel. LCMS-ESI+ (m/z): [M+H]+calcd for
C18H17BrC10: 364.68; found: 364.89.
Step 4: Preparation of 2-bromo-l-(4-chlorophenyl)-6-methoxy-3- methylnaphthalene: A solution of 3-bromo-4-(4-chlorophenyl)-7-methoxy-2-methyl- 1,2-dihydronaphthalene (5.5 g, 15.1 mmol) in toluene (100 mL) was vacuum flushed 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 temperature 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 compound as an amorphous yellow solid. 1H-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, 3H).
Step 5: Preparation 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-chlorophenyl)-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 temperature over 3.5 h. This procedure was repeated twice on a scale of 1 g and 4.1 g of 2-bromo-l-(4-chlorophenyl)-6-methoxy-3-methylnaphthalene with 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 temperature, the mixture was concentrated in vacuo and the residue was taken up in EtOAc (150 mL), treated with saturated NaHC03 (150 mL) and then small portions of solid NaHC03 until 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 MgS04, and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (5-25% EtO Ac/Hex) to afford 4.54 g (91%) of the title compound as a colorless syrup. LCMS- ESf m/z): [M+H]+ calcd for C17H13BrC10: 348.64; found: 348.79.
Step 6: Preparation of (6-bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2- yloxy)triisopropylsilane (52): 6-Bromo-5-(4-chlorophenyl)-7-methylnaphthalen-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), and DMAP (0.16 g, 1.3 mmol). After stirring at room temperature overnight, the DCM was removed in vacuo and the residue taken up in hexane (200 mL). This solution was washed with 1 M HC1 (100 mL) and the layers separated. Following extraction of the aqueous layer with hexanes, the combined organics were washed with brine, dried over anhydrous MgS04 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 title compound as a colorless syrup. 1H-NMR: 400 MHz, (CDC13) δ: 7.61 (s, 1H); 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, 1H), 7.16 (d, J = 2.4 Hz, 1H); 6.95 (dd, J = 8.8, 2.4 Hz; 1H); 2.60 (s, 3H); 1.30 (hep, J = 7.2 Hz, 3H); 1.12 (d, J = 7.2 Hz, 18H).
Example 51. (S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-(pyridin-4- yl)naphthalen-2-yl)acetic acid (53)
Figure imgf000224_0001
Figure imgf000224_0002
(S)-2-(ierf-butoxy)-2-(1 -(4- chlorophenyl)-3-methyl-6-(pyridin-4- yl)naphthalen-2-yl)acetic acid
Step 1 : Preparation of ethyl 2-(l-(4-chlorophenyl)-3-methyl-6-(triisopropyl- silyloxy)naphthalen-2-yl)-2-oxoacetate: To a solution of (6-bromo-5-(4-chlorophenyl)-
7-methylnaphthalen-2-yloxy)triisopropylsilane (2.5 g, 4.9 mmol) in THF (50 mL) cooled to -78 °C was added /j-BuLi (1.6 M in hexanes, 4.6 mL, 7.4 mmol) dropwise. The resulting solution was allowed to stir at -78 °C for 30 min before addition of diethyl oxalate (1.7 mL, 12.4 mmol). After 45 min at -78 °C, the cold bath was removed and the reaction allowed to warm to room temperature 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 brine, dried over anhydrous MgS04 and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (0-10% EtO Ac/Hex) to afford 2.10 g (81%) of the title compound as a colorless syrup. LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH38C104Si: 526.16; found: 526.89.
Step 2 : Preparation of ethyl 2-( 1 -(4-chlorophenyl)-3 -methyl-6-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate: To a solution of ethyl 2-(l- (4-chlorophenyl)-3-memyl-6-(triisopropylsilyloxy)naphthalen-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 N-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 temperature, 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 MgS04 and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (0-20% EtO Ac/Hex) to produce 3.12 g (64%) as an amorphous pale yellow solid. 1H-NMR: 400 MHz, (CDC13) δ: 7.80 (s, 1H); 7.76 (d, J - 2.4 Hz, 1H); 7.67 (d, J = 9.6 Hz, 1H); 7.48 (br d, J = 8.4 Hz, 2H); 7.30 (dd, J = 9.6, 2.4 Hz, 1H); 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, 3H).
Step 3: Preparation of (S)-ethyl 2-(l-(4-chlorophenyl)-3-methyl-6- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate: To a solution of ethyl 2-(l-(4-cUorophenyl)-3-memyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2- oxoacetate (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 Na2C03 (10 mL) was added, the mixture allowed to warm to room temperature and the layers separated. Following extraction with EtOAc, the combined organic layers were washed with additional saturated Na2C03 (15 mL portions) until the washing was no longer colored and then once with saturated NH4CI (15 mL). After drying over anhydrous MgS04, the solution was absorbed onto silica gel in vacuo and purified by Yamazen column chromatography (10-65% EtO Ac/Hex) to afford 0.61 g (61%, 98% ee) of the title compound as a colorless amorphous solid. 1H-NMR: 400 MHz, (CDC13) δ: 7.72 (s, 1H); 7.69 (d, J = 2.4 Hz, 1H); 7.50 (m, 2H); 7.37 (d, J = 9.2 Hz, 1H); 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: Preparation of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl- 6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)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 tert-butyl acetate (5 mL) at room temperature. After 3 h, solid NaHC03 was added and the slurry stirred vigorously for 30 min. Saturated NaHC03 was added slowly until the mixture was pH ~ 8. Following extraction of the organic layer with EtO Ac, the combined organics were washed with brine, dried over anhydrous MgS04 and concentrated in vacuo. The resulting residue was purified by Yamazen column chromatography (0-35% EtOAc/Hex) to produce 0.52 g (57%) of the title compound as an amorphous solid. 1H-NMR: 400 MHz, (CDC13) 8: 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: Preparation 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-(4- chlorophenyl)-3 -methyl-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) (0.012 g, 0.011 mmol) in DME (1 mL) was treated with 2 M K2C03 (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 C30H31ClNO3: 488.20; found: 488.70.
Step 6: Preparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6- (pyridin-4-yl)naphthalen-2-yl)acetic acid (53): A solution (S)-ethyl 2-tert-butoxy-2-(l- (4-cWorophenyl)-3-memyl-6-(pyridin-4-yl)naphthalen-2-yl)acetate (0.043 g, 0.088 mmol) in THF/MeOH/H20 (1 mL each) was treated with LiOH«H20 (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/H20, 0.1% TFA). Lyophilization of appropriate fractions afforded 0.021 g of 53 as an off-white amorphous powder. 1H-NMR: 400 MHz, (CD3CN) δ: 8.77 (br s, 2H); 8.37 (br s, 1H); 8.17 (br s, 2H); 7.91 (s, 1H); 7.76 (dd, J = 8.8, 2.4 Hz, 1H); 7.62- 7.54 (m, 3H); 7.46 (d, J = 8.8 Hz, 1H); 7.38 (br d, J = 8.8 Hz, 1H); 5.25 (s, 1H); 2.61 (s, 3H); 0.99 (s, 9H). LCMS-ESr m/z): [2M-H]" calcd for C56H51C12N206: 917.31; found: 917.51.
Example 52. (S)-2-tert-Butoxy-2-(l -(4-chlorophenyl)-3-methyl-6-(pyridin-3- yl)naphthalen-2-yl)acetic acid (54)
Figure imgf000227_0001
(S)-2-(ferf-butoxy)-2-(1-(4-chlorophenyl)-3-metriyl-6
-(pyridin-3-yl)naphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(pyridin-3- yl)naphthalen-2-yl)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 Example 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 C56H51C12N206: 917.31 ; found: 917.39. 1H-NMR: 400 MHz, (CD3CN) δ: 9.08 (s, 1H); 8.74 (d, J = 5.2 Hz, 1H); 8.61 (d, J = 8 Hz, 1H); 8.19 (s, 1H); 7.93-7.88 (m, 1H); 7.84 (s, 1H); 7.66-7.53 (m, 4H); 7.44-7.35 (m, 2H); 5.24 (s, 1H); 2.59 (s, 3H); 0.99 (s, 9H). Example 53. (S)-2-tert-Butoxy-2-(l -(4-chlorophenyl)-3-methyl-6- (pyrimidin-5-yl)naphthalen-2-yl)acetic acid (55):
Figure imgf000228_0001
(S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6- (pyrimidin-5 -yl)naphthalen-2-yl)acetic acid
Preparation 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-(4- cUorophenyl)-3-methyl-6-^yrimidin-5-yl)naphthalen-2-yl)acetic acid (55) was prepared in a similar fashion to compound 53 of Example 51 with the substitution of pyrimidin-5-ylboronic 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 C54H49CI2N4O6: 919.30; found: 919.76. 1H-NMR: 400 MHz, (CD3CN) 5: 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).
Example 54. (S)-2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(lH-pyrazol-5- yl)naphthalen-2-yl)acetic acid (56):
Figure imgf000228_0002
56
(S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-( 1 H-pyrazol-5 -yl)
naphthalen-2-yl)acetic acid Preparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-6-(lH-pyrazol- 5-yl)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 (56) was prepared in a similar fashion to compound 53 of Example 51 with the substitution of lH-pyrazol-5-ylboronic 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): [2Μ-Η]" calcd for C52H49C12N406: 895.30; found: 895.45. 1H-NMR: 400 MHz, (CD3CN) δ: 8.23 (br s, IH); 7.93 (d, J = 9.6 Hz, IH); 7.79 (s, IH); 7.68 (s, IH); 7.61-7.53 (m, 3H); 7.40-7.35 (m, IH); 7.30 (d, J = 9.6 Hz, IH); 6.78 (s, IH); 5.22 (s, IH); 2.57 (s, 3H); 0.99 (s, 9H).
Example 55. (S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-( 1 H-pyrazol-4- yl)naphthalen-2-yl)acetic acid (57)
Figure imgf000229_0001
(S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(lH-pyrazol-4-yl)
naphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(lH-pyrazol- 4-yl)naphthalen-2-yl)acetic acid (57): (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3- methyl-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-ylboronic 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 C26H26C1N203: 449.95; found: 449.57. 1H-NMR: 400 MHz, (CD3CN) δ: 8.03 (br s, 2H); 8.00 (br s, IH); 7.71 (s, IH); 7.59-7.52 (m, 4H); 7.38-7.34 (m, IH); 7.26 (d, J = 9.6 Hz, IH); 5.20 (IH); 2.56 (3H); 0.98 (s, 9H). Example 56. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 ,6-dimethylnaphthalen-2-yl)acetic acid (58)
Figure imgf000230_0001
2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 ,6- dimethylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-3,6-dimethylnaphthalen-2- yl)acetic acid (58): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3,6-dimethylnaphthalen-2- yl)acetic acid (58) was prepared with a route similar to that described for compound 53 of Example 51 beginning with 3,6-dimethyl-3,4-dihydronaphthalen-l(2H)-one
(prepared from l-(3-methylphenyl)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 NaBFLt in EtOH at room temperature to afford racemic material. The title compound was isolated (0.075 g) as a white amorphous powder. LCMS-ESI" (m/z): [M-H]- calcd for C24H24C103: 395.14; found: 394.96. 1H-NMR: 400 MHz, (CDCl 3) δ: 7.69-7.61 (m, 1H); 7.58 (s, 1H); 7.54 (s, 1H); 7.53-7.46 (m, 2H); 7.30-7.23 (m, 1H); 7.21 (d, J = 8.4 Hz, 1H); 7.14 (d, J = 8.4 Hz, 1H); 5.27 (s, 2H); 2.56 (s, 3H); 2.48 (s, 3H); 1.01 (s, 9H).
Example 57. (S)-2-tert-butoxy-2-(l -(4-cUorophenyl)-3-methyl-6-( yrimidin-2- yl)naphthalen-2-yl)acetic acid (59)
Figure imgf000231_0001
yl)naphthalen-2-yl)acetate
Figure imgf000231_0002
(S)-ethyl 2-(ferf- butoxy)-2-(1-(4- 59
chlorophenyl)-3-methyl- 6-(pyrimidin-2- (S)-2-(ferf-butoxy)-2-(1 -(4- yl)naphthalen-2- chlorophenyl)-3-methyl-6- yljacetate (pyrimidin-2-yl)naphthalen- 2-yl)acetic acid
Step 1. Preparation of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl- 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2-yl)acetate: A solution of (S)-ethyl 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate (0.56 g, 1 mmol) in DME (6.5 mL ) was treated with bis(pinacolato)diboron (0.51 g, 2 mmol), potassium acetate (0.20 g, 2 mmol) and PdCl2(dppf) (0.073 g, 0.1 mmol) and sparged with Ar for 10 min. After heating at 100 °C in a sealed vessel for 3 h, the mixture was allowed to cool to room temperature and absorbed onto silica gel in vacuo. Purification by Yamazen column chromatography (2-35% EtO Ac/Hex) produced 0.46 g (85%) of the title compound as a colorless oil that was contaminated with a small amount of pinacol. The material was used in subsequent reactions without further purification. 1H-NMR: 400 MHz, (CDC13) δ: 8.28 (s, 1H); 7.69 (s, 1H); 7.63 (br d, J = 8.4 Hz, 1H); 7.51-7.42 (m, 3H); 7.29-7.26 (m, 1H); 7.22 (d, J = 8.4 Hz, 1H); 5.13 (s, 1H); 4.15 (m, 2H); 2.61 (s, 3H); 1.38 (s, 12H); 1.21 (t, J = 7.2 Hz, 3H); 0.99 (s, 9H).
Step 2: Preparation of (S)-ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl- 6-(pyrimidin-2-yl)naphthalen-2-yl)acetate: (S)-Ethyl 2-tert-butoxy-2-(l -(4- chlorophenyl)-3-methyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)naphthalen-2- yl)acetate (0.072 g, 0.13 mmol), 2-bromopyrimidine (0.032 g, 0.20 mmol), PdCl2(dppf) (0.005 g, 0.007 mmol) were taken up in 3/1 PhMe/EtOH (1 mL). The resulting solution was treated with 2 M K2C03 (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 temperature, the crude reaction mixture was purified by Yamazen column chromatography (20-100% EtOAc/Hex) to produce 0.042 g (64%) of a colorless film. LCMS-ESI+ (m/z): [M]+ calcd for C29H29C1N203: 489.01; found: 489.51.
Step 3: Preparation 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-(4- cUorophenyl)-3-methyl-6-( yrimidin-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-white amorphous powder. LCMS-ESf (m/z): [M+H]+ calcd for C27H26C1N203: 461.96; found: 461.34. 1H-NMR: 400 MHz, (CD3CN) δ: 8.92 (s, 1H); 8.87 (d, J = 4.4 Hz, 2H); 8.36 (dd, J = 9.2, 1.6 Hz, 1H); 7.94 (s, 1H); 7.61-7.55 (m, 3H); 7.43-7.36 (m, 2H); 7.34 (t, J = 4.4 Hz, 1H); 5.24 (s, 1H); 2.59 (s, 3H); 1.0 (s, 9H).
Example 58. (S)-2-tert-Butoxy-2-(l -(4-chlorophenyl)-3-methyl-6-(pyrazin-2- yl)naphthalen-2-yl)acetic acid (60)
Figure imgf000233_0001
60
(S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(pyrazin-:
naphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-6-(pyrazin-2- yl)naphthalen-2-yl)acetic acid (60): (S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl- 6-(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-ESI+ (m/z): [M+H]+ calcd for C27H26C1N203: 461.96; found: 461.30. 1H-NMR: 400 MHz, (CD3CN) δ: 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]pyr;
3-methylnaphthalen-2-yl)acetic acid (61)
Figure imgf000233_0002
61
(S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-6-(imidazo[l,2-a]pyrazin-8-yl)
-3 -methylnaphthalen-2-yl)acetic acid Preparation of (S)-2-tert-butoxy-2-( 1 -(4-cMorophenyl)-6-(imidazo [ 1 ,2- a]pyrazin-8-yl)-3-methylnaphthalen-2-yl)acetic acid (61): (S)-2-tert-butoxy-2-(l-(4- cMorophenyl)-6-(irnidazo[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 8- cWoroirnidazo[l,2-a]pyrazine hydrobromide (See Guzi, T.J, Paruch, K., et. al. US 20070105864, p. 121) for 2-bromopyrimidine in step 2. The title compound (0.017 g) was isolated as an amorphous pale yellow powder. LCMS-ES (m/z): [M+H]+ calcd for C29H27C1N303: 500.7; found: 500.0. 1H-NMR: 400 MHz, (CD3CN) δ: 9.00 (d, J = 1.2 Hz, 1H); 8.39 (d, J = 4.4 Hz, 1H); 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, 1H); 7.36 (br d, J = 8.8 Hz, 1H); 5.25 (s, 1H); 2.58 (s, 3H); 0.99 (s, 9H).
Example 60. (S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-(4-methylpyrimidin- 5-yl)naphthalen-2-yl)acetic acid (62)
Figure imgf000235_0001
62
(S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(4-methylpyrimidin-5-yl) naphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-6-(4- memylpyrirnidin-5-yl)naphthalen-2-yl)acetic acid (62): (S)-2-tert-Butoxy-2-(l-(4- chlorophenyl)-3 -methyl-6-(4-methylpyrimidin-5 -yl)naphthalen-2-yl)acetic acid (62) was prepared in a similar fashion to compound 59 with the substitution of 5-bromo-4- methylpyrimidine 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
C28H28C1N203: 475.99; found: 475.69. 1H-NMR: 400 MHz, (CD3CN) δ: 9.13 (br s, 1H); 8.77 (br s, 1H); 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).
Example 61. (S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-(pyridin-2- yl)naphthalen-2-yl)acetic acid (63)
Figure imgf000236_0001
(S)-ethyl 2-(terf-butoxy)-2-(1 - (S)-ethyl 2-(terf-butoxy)-2- (4-chlorophenyl)-3-methyl-6- (1-(4-chlorophenyl)-3- (((trifluoromethyl)sulfonyl)oxy methyl-6-(pyridin-2-
)naphthalen-2-yl)acetate yl)naphthalen-2-yl)acetate
Figure imgf000236_0002
(S)-2-(ferf-butoxy)-2-(1 -(4- chlorophenyl)-3-methyl-6- (pyridin-2-yl)naphthalen-2- yl)acetic acid
Step 1. Preparation of (S)-ethyl 2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-
6-(pyridin-2-yl)naphthalen-2-yl)acetate: A solution of (S)-ethyl 2-tert-butoxy-2-(l-(4- chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate (0.070 g, 0.13 mmol) in NMP (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 reaction mixture was allowed to cool to room temperature 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-ESI+ (m/z): [M+H]+ calcd for C30H31ClNO3 : 488.20; found: 488.90. Step 2. Preparation 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-(4- chlorophenyl)-3-methyl-6-(pyridin-2-yl)naphthalen-2-yl)acetic acid (63) was prepared using a method similar to step 6 of Example 51 to afford 0.0041 g of 63 as an off-white amorphous powder. LCMS-ESf (m/z): [M+H]+ calcd for C28H27C1N03: 460.97; found: 460.70. 1H-NMR: 400 MHz, (CD3CN) δ: 8.75 (d, J = 4.4 Hz, 1H); 8.49 (br s, 1H); 8.07-7.96 (m, 3H); 7.87 (s, 3H); 7.60-7.53 (m, 3H); 7.46 (t, J = 5.6 Hz, 1H); 7.40 (d, J = 8.8 Hz, 1H); 7.39 (br s, 1H); 5.23 (s, 1H); 2.59 (s, 3H); 0.99 (s, 9H). Example 62. (S)-2-tert-Butoxy-2-(l -(4-chlorophenyl)-3-methyl-6-(l -methyl- 1 H- imidazol-4-yl)naphthalen-2-yl)acetic acid (64)
Figure imgf000237_0001
(S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-( 1 -methyl- 1 H-imidazol-4- yl)naphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-( 1 -methyl- lH-imidazol-4-yl)naphthalen-2-yl)acetic acid (64): (S)-2-tert-butoxy-2-(l-(4- chlorophenyl)-3 -methyl-6-( 1 -methyl- 1 H-imidazol-4-yl)naphthalen-2-yl)acetic acid (64) was prepared in a similar fashion 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-ESI+ (m/z): [M+H]+ calcd for C27H28C1N203: 463.98; found: 463.86. 1H-NMR: 400 MHz, (CD3CN) δ: 6.46 (br s, 1H); 8.24 (br s, 1H); 7.73 (br s, 1H); 7.65 (s, 1H); 7.62-7.51 (m, 4H); 7.36-7.25 (m, 2H); 5.21 (s, 1H): 3.85 (s, 3H); 2.56 (s, 3H); 0.97 (s, 9H).
Example 63. (S)-2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-( 1 -methyl- 1 H- imidazol-5-yl)naphthalen-2-yl)acetic acid (65)
Figure imgf000238_0001
(S)-2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-6-(l-inethyl-lH-imidazol-5- yl)naphthalen-2-yl)acetic acid Preparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-6-(l -methyl- lH-imidazol-5-yl)naphthalen-2-yl)acetic acid (65): (S)-2-tert-Butoxy-2-(l-(4- chlorophenyl)-3-methyl-6-(l-methyl-lH-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-(tributylstannyl)pyridine in step 1. The title compound (0.026 g) was isolated as an amorphous white powder. LCMS-ESI* (m/z):
[M+H]+ calcd for C27H28C1N203: 463.98; found: 463.81. 1H-NMR: 400 MHz, (CD3CN) 8: 8.54 (s, IH); 7.99 (s, IH); 7.84 (s, 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).
Example 64. 2-(l,6-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (66)
Figure imgf000239_0001
ethyl 2-(6-bromo-1 -hydroxy-3-methylnaphthalen-2-yl)-2-((4- ethyl 2-(6-bromo-3-methyl-1 - methoxybenzyl)oxy)acetate (perfluorobutylsulfonyloxy)naphthalen-
2-yl)-2-hydroxyacetate
Figure imgf000239_0002
ethyl 2-(1 ,6-bis(4-chlorophenyl)-3- ethyl 2-(1 ,6-bis(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-oxoacetate methylnaphthalen-2-yl)-2-hydroxyacetate
Figure imgf000239_0003
2-(1 ,6-bis(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-(terf- butoxy)acetic acid
Step 1. Preparation of ethyl 2-(6-bromo-3 -methyl- l-(perfluorobutyl- sulfonyloxy)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 (l-hydroxy-5-methoxy-3-methyl-naphthalen-2-yl)-(4- methoxybenzyloxy)acetic acid ethyl ester of Example 32 beginning with l-(3- bromophenyl)propan-2-one) in DCM (17 mL) was cooled 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 temperature overnight. Saturated NaHC03 was added and the mixture extracted with EtO Ac. The combined organics were washed with brine, dried over anhydrous MgS04 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. 1H-NMR: 400 MHz, (CDC13) δ: 7.97 (d, J = 6.4 Hz, 1H); 7.94 (d, J = 9.2 Hz, 1H); 7.66 (dd, J = 9.2, 6.4 Hz, 1H); 7.59 (s, 1H); 5.78 (br s, 1H); 4.31 (m, 1H); 4.22 (m, 1H); 3.39 (br s, 1H): 2.50 (s, 3H); 1.20 (t, J = 7.2 Hz, 3H).
Step 2. Preparation of ethyl 2-(6-bromo-3 -methyl- l-(perfluorobuty 1- 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 temperature. After 1.5 h, a 1/1 mixture of saturated NaHC03 and saturated Na2S203 (10 mL) was added and the slurry allowed to stir at room temperature 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 MgS04. After concentration in vacuo, the residue was purified using Yamazen column chromatography (0-15% EtO Ac/Hex) to produce 0.38 g (73%) of the title compound as an amorphous solid. 1H-NMR: 400 MHz, (CDC13) δ: 8.04 (s, 1H); 7.97 (d, J = 9.2 Hz, 1H); 7.72 (d, J = 9.2 Hz, 1H); 7.68 (s, 1H); 4.41 (q, J = 7.2 Hz, 2H); 2.50 (s, 3H); 1.39 (t, J = 7.2 Hz, 3H).
Step 3. Preparation of ethyl 2-(l,6-bis(4-chlorophenyl)-3-methylnaphthalen-2- yl)-2-oxoacetate: A solution of ethyl 2-(6-bromo-3 -methyl- l-(perfluorobutylsulfonyl- oxy)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 temperature 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 temperature, the reaction was diluted with EtO Ac, and washed with water. The organic layer was absorbed onto silica gel in vacuo and purified by Yamazen column chromatography (0- 20% EtO Ac/Hex) to afford 0.145 g (53%) of the title compound as an amorphous solid. 1H-NMR: 400 MHz, (CDC13) δ: 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. Preparation of ethyl 2-(l,6-bis(4-chlorophenyl)-3-methylnaphthalen-2- yl)-2-hydroxyacetate: A solution of ethyl 2-(l,6-bis(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-oxoacetate (0.145 g, 0.31 mmol) in EtOH (2 mL) and DCM (1 mL) at 0 °C was treated with NaB¾ (0.018 g, 0.048 mmol) in one portion. The reaction was allowed to warm to room temperature over 30 min and treated with saturated NaHC03 (3 mL). The mixture was stirred vigorously for 30 min and then diluted with EtO Ac and water. Following extraction with EtO Ac, the organics were washed with brine, dried over anhydrous Na2S04 and concentrated to produce 0.121 g (84%) of the title compound as a white foam that was used in subsequent steps without further purification. 1H-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. Preparation 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. 1H-NMR: 400 MHz, (CDC13) δ: 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). Example 65. 2-tert-Butoxy-2-(6-chloro-l-(4-chlorophenyl)-3-methylnaphthalen-2- yl)acetic acid (67)
Figure imgf000242_0001
methyl 2-(6-chloro-1-hydroxy-3- methylnaphthalen-2-yl)-2-((4-
(E)-ethyl 2-((3R,4R)-4- methoxybenzyl)oxy)acetate bromo^3-chloro-3-methyl-1 - oxo-3,4-dih dronaphthalen-
Figure imgf000242_0002
methyl 2-(6-chloro-3-methyl-1- methyl 2-(6-chloro-1-(4- (((trifluoromethyl)sulfonyl)oxy)nap chlorophenyl)-3- hthalen-2-yl)-2-((4- methylnaphthalen-2-yl)-2-((4- methoxybenzyl)oxy)acetate methoxybenzyl)oxy)acetate
Figure imgf000242_0003
methyl 2-(6-chloro-1-(4- 67
chlorophenyl)-3-methylnaphthalen-2- yl)-2-hydroxyacetate
2-(ieri-butoxy)-2- (6-chloro-1-(4- chlorophenyl)-3- methylnaphthale n-2-yl)acetic acid
Steps 1-4. Preparation of methyl 2-(6-chloro-l-hydroxy-3-methylnaphthalen-2- yl)-2-(4-methoxybenzyloxy)acetate: /?-methoxybenzyl alcohol (5.9 mL, 47.2 mmol) was diluted with THF (180 mL) and cooled to -78 °C under an Ar atmosphere.
KHMDS (0.5 M PhMe solution, 71 mL, 35.4 mmol) was added dropwise over 20 min and the solution allowed to age for 20 min at this temperature to produce an opaque white suspension. A solution of (E)-ethyl 2-((3R,4R)-4-bromo-6-chloro-3 -methyl- 1- oxo-3,4-dihydronaphthalen-2(lH)-ylidene)acetate (4.22 g, 11.8 mmol; prepared similarly to (4-bromo-5 -methoxy-3 -methyl- 1 -oxo-3 ,4-dihydro- 1 H-naphthalen-2- ylidene)acetic acid ethyl ester of Example 32 beginning with l-(3- chlorophenyl)propan-2-one) was prepared in THF (50 mL) and added to the reaction at a rate that maintained an internal temperature less than -65 °C. After 5 min, propionic acid (10 mL, 134 mmol) was added and the reaction warmed to room temperature over 1.5 h prior to dilution with water (1 0 mL). Extraction of the aqueous layer with ethyl acetate was followed by washing of the combined organics with saturated NaHC03, water and brine. Following drying over anhydrous MgS04 and concentration in vacuo, the resulting residue was eluted on Yamazen column chromatography to produce an inseparable mixture of products (5.56 g) that included ethyl 2-(6-chloro-l-hydroxy-3- methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate, 4-methoxybenzyl 2-(6-chloro- 1 -hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxyben2yloxy)acetate, ethyl 2- ((3R,4R)-4-bromo-6-chloro-3-methyl- 1 -oxo- 1 ,2,3,4-tetrahydronaphthalen-2-yl)-2-(4- methoxybenzyloxy)acetate, and 4-methoxybenzyl 2-((3R,4R)-4-bromo-6-chloro-3- methyl- 1 -oxo- 1 ,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 temperature. 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 MgS04, 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-(4- methoxybenzyloxy)acetate and 4-methoxybenzyl 2-(6-chloro-l-hydroxy-3- methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate. This material was taken up in THF/MeOH/H20 (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 HC1 solution. The aqueous phase was extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford 2-(6-chloro-l -hydroxy-3-methylnaphthalen-2-yl)- 2-(4-methoxybenzyloxy)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 (20 mL each) and treated with TMSCHN2 (2 M in 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 TMSCHN2 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 steps) of the title compound as an amorphous white solid that was used without further purification. 1H- NMR: 400 MHz, (CDC13) δ: 8.54 (s, 1H); 8.18 (d, J = 8.8 Hz, 1H); 7.63 (d, J = 1.6 Hz, 1H); 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, 1H); 4.65 (AB d, J = 11.2 Hz, 1H); 4.59 (AB d, J = 11.2 Hz, 1H); 3.83 (s, 3H); 3.73 (s, 3H); 2.39 (s, 3H).
Step 5. Preparation 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-yl)-2-(4- methoxybenzyloxy)acetate (0.649 g, 1.62 mmol) in DCM (16 mL) under Ar was cooled to -78 °C and treated with 2,6-lutidine (0.56 mL, 4.9 mmol) and
trifluoromethanesulfonic anhydride (1.15 mL, 2.4 mmol). After 4 h, saturated NaHC03 solution was added at -78 °C and the reaction warmed to room temperature 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 MgS04 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. 1H-NMR: 400 MHz, (CDC13) δ: 7.97 (d, J = 9.2 Hz, 1H); 7.78 (d, J = 1.6 Hz, 1H); 7.60 (s, 1H); 7.53 (dd, J = 9.2, 1.6 Hz, 1H); 7.24 (d, J - 8.8 Hz, 2H); 6.82 (d, J = 8.8 Hz, 2H); 5.62 (s, 1H); 4.66 (ABd, J = 11.2 Hz, 1H); 4.59 (ABd, J = 11.2 Hz, 1H); 3.78 (s, 3H); 3.75 (s, 3H); 2.55 (s, 3H).
Step 6. Preparation of methyl 2-(6-chloro-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate: Methyl 2-(6-chloro-3-methyl- 1 -(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 K2C03 solution (1.2 mL, 0.6 mmol). The resulting mixture was sparged with Ar for 10 minutes and then heated in a microwave reactor at 100 °C for 20 min. The resulting mixture was loaded directly onto silica gel and purified with Yamazen column chromatography (3-25% EtO Ac/Hex) to produce 0.051 g of the title compound as an amorphous foam. H-
NMR: 400 MHz, (CDC13) δ: 7.67 (d, J = 2.4 Hz, 1H); 7.60 (s, 1H); 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, lH); 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, 1H);
4.35 (ABd, J = 11.6 Hz, 1H); 3.82 (s, 3H); 3.72 (s, 3H); 2.57 (s, 3H).
Step 7. Preparation of methyl 2-(6-chloro-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-hydroxyacetate: A solution of methyl 2-(6-chloro-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate in DCM (1 mL) was treated with trifluoroacetic acid (0.052 mL, 0.67 mmol) at room temperature.
After 45 min, the reaction was diluted with DCM and treated with saturated NaHC03.
After separation the organic layer was absorbed directly onto silica gel in vacuo.
Purification via Yamazen column chromatography yielded 0.039 g of a colorless film.
1H-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,
1H); 5.23 (s, 1H); 3.74 (s, 3H), 2.49 (s, 3H).
Steps 8 and 9. Preparation of 2-tert-butoxy-2-(6-chloro-l-(4-chlorophenyl)-3- methylnaphthalen-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 C23H21C1203: 415.09; found: 415.56. 1H-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-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid (68A) and (S)-2-tert-Butoxy-2- ((R)-l-(2,3-dmydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetic acid (68B)
Figure imgf000246_0001
(+)-(S)-methyl 2-((R)-6-chloro-1- (2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2- h droxy acetate
Figure imgf000246_0002
(S)-methyl 2-ferf-butoxy-2-((R)-6- 68A
chloro-1-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3- (S)-2-ferf-butoxy-2-((R)-6-chloro-1- methylnaphthalen-2-yl)acetate (2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methylnaphthalen-2-yl)acetic acid trimethylboroxine
°
Figure imgf000246_0003
(S)-methyl 2-terf-butoxy-2-((R)-1 -(2,3- 68B
dihydropyrano[4,3,2-de]quinolin-7-yl)- (S)-2-(feri-butoxy)-2-((f?)-1 - 3,6-dimethylnaphthalen-2-yl)acetate (2,3-dihydropyrano[4,3,2-de]- quinolin-7-yl)-3,6- dimethylnaphthalen-2-yl)acetic acid Step 1 : Preparation of (±)-(S)-methyl 2-((R)-6-chloro-l-(2,3- dihydropyrano [4,3 ,2-de] quinolin-7-yl)-3 -methylnaphthalen-2-yl)-2-(4- methoxybenzyloxy)acetate. Methyl 2-(6-chloro-3-methyl- 1 -(trifluoromethyl- sulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate (1.24 g, 2.32 mmol), 2,3- dihydropyrano [4,3 ,2-de] quinolin-7-ylboronic 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 K2C03 (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 (20- 59% EtO Ac/Hex) to provide two diastereomer pairs as white amorphous solids. Anti racemate: 0.348 g; 1H-NMR: 400 MHz, (CDC13) δ: 8.70 (d, J = 4.4 Hz, lH); 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; 1H- MR: 400 MHz, (CDC13) δ: 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, 1H); 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, 1H); 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-de]quinolin- 7-yl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate was prepared similarly to Step 7 of Example 65 to produce 0.238 g as an amorphous foam. LCMS-ES^ (m/z): [M+H]+ calcd for C25H21C1N04: 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 C25H21C1N04: 434.89; found: 434.57.
Step 3. (S)-methyl 2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate was prepared similarly 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 Chiracel 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-chloro-l-(2,3- dmydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate and 0.057 g of (S)-methyl 2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methylnaphthalen-2-yl)acetate as colorless films. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H29C1N04: 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-ESF^ (m/z): [M+H]+ calcd for C29H29C1N04: 490.99; found: 490.62.
Step 4. (S)-2-tert-butoxy-2-((R)-6-chloro-l -(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-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-ESI" (m/z): [M-H]" calcd for
C28H25C1N04: 474.96; found: 474.37. 1H-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, 1H); 7.34 (d, J = 8 Hz, 1H); 7.20 (dd, J = 8, 2 Hz, 1H); 6.88 (d, J = 8.8 Hz, 1H); 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. Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetic acid (68B): A solution of (S)-methyl 2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2- de]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 K2C03 (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 THF/MeOH/H20 (1 mL each) and treated with LiOH-H20 (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)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6- dimethylnaphthalen-2-yl)acetic acid (68B). LCMS-ES (m/z): [M+H]+ calcd for C29H30NO4: 456.55; found: 456.15. 1H-NMR: 400 MHz, (CD3CN) δ: 8.56 (d, J = 4.8 Hz, 1H); 7.79 (s, 1H); 7.72 (br d, J = 8, 1H); 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, 1H); 4.62 (m, 2H); 3.49 (t, J = 6 Hz, 2H); 2.65 (s, 3H); 2.44 (s, 3H); 0.92 (s, 9H). Example 67. 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -hydroxy-3 -methylbut- 1 -yny 1)- 3-methylnaphthalen-2-yl)acetic acid (69)
Figure imgf000249_0001
ethyl 2-(7-bromo-1-hydroxy-3- ethyl 2-(7-bromo-3-methyl-1- methylnaphthalen-2-yl)-2-(4- (trifluoromethylsulfonyloxy)naphthalen-2-yl)- methoxybenzyloxy)acetate 2-(4-methoxybenzyloxy)acetate
Figure imgf000249_0002
ethyl 2-(7-bromo-3-methyl-1- ethyl 2-(7-bromo-3-methyl-1- (trifluoromethylsulfonyloxy)naphthalen- (trifluoromethylsulfonyloxy)naphthalen- 2-yl)-2-hydroxyacetate 2-yl)-2-oxoacetate
Figure imgf000249_0003
69
2-feri-butoxy-2-(1-(4-chlorophenyl)-7- (3-hydroxy-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid Step 1. Preparation of ethyl 2-(7-bromo-3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate: To a solution of ethyl 2-(7-bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2-(4- methoxybenzyloxy)acetate (4.0 g, 8.7 mmol) in CH2C12 (40 mL) at -78 °C was added triethylamine (1.46 mL, 10.5 mmol) and trifluoromethanesulfonic anhydride (1.0 M solution in CH2C12, 9.6 mL, 9.6 mmol). After 15 min, a saturated solution of H4CI was added. The mixture was warmed to room temperature. The layers were separated, dried, filtered, and concentrated in vacuo. The crude product was taken on without further purification. 1H-NMR: 400 MHz, (CDC13) δ: 8.30 (s, 1H), 7.77 (m, 3H), 7.35 (d, J = 9 Hz, 2H), 6.94 (d, J = 9 Hz, 2H), 5.73 (s, 1H), 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. Preparation of ethyl 2-(7-bromo-3-methyl-l-(trifluoromethyl- sulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate: To a solution of ethyl 2-(7-bromo-3- memyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyl- oxy)acetate (8.7 mmol from previous step) in CH2C12 (40 mL) was added
trifluoroacetic acid (TFA) (4 mL). After 1.5 h, water was added (40 mL). The layers were separated. The organic layer was washed with a saturated solution of NaHC03. The organic layer was dried, filtered, and concentrated in vacuo. The crude product was taken on without further purification. 1H-NMR: 400 MHz, (CDC13) δ: 8.21 (s, 1H), 7.65
(m, 3H), 5.79 (s, 1H), 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. Preparation of ethyl 2-(7-bromo-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate: To a solution of ethyl 2-(7- bromo-3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (-8.7 mmol) in C¾C12 (40 mL) was added Dess-Martin periodinane (4.07 g, 9.6 mmol). After 1.5 h, a saturated solution of Na2S204 (20 mL) and water (20 mL) was added. The mixture was stirred vigorously for 30 min. 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 3.22 g (79%) of the titled compound. 1H-NMR: 400 MHz, (CDC13) δ: 8.22 (s, 1H), 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) δ: -73.2.
Step 4. Preparation of ethyl 2-(7-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-oxoacetate: To a solution of ethyl 2-(7-bromo-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (235 mg, 0.50 mmol) in PhCH3 (1.2 mL), EtOH (0.6 mL), H20 (0.6 mL) was added 4-chlorophenylboronic acid (86 mg, 0.55 mmol), K2C03 (207 mg, 1.5 mmol), and PdCl2dppf (11 mg, 0.015 mmol). The reaction mixture was stirred at room temperature for 2 h and was then diluted with H20 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 bis- coupled product (ethyl 2-(l ,7-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- oxoacetate). 1H-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. Preparation of ethyl 2-(7-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-hydroxyacetate: To a solution of ethyl 2-(7-bromo-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (1.6 g, 2.78 mmol) in EtOH (10 mL) was added sodium borohydride (NaB¾) (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. 1H-NMR: 400 MHz, (CDC13) 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. Preparation of ethyl 2-(7-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetate: To a solution of ethyl 2-(7-bromo-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate (-2.78 mmol) in t-BuOAc (14 mL) was added perchloric acid (HC104) (334 μί, 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. 1H-NMR: 400 MHz, (CDC13) 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, 3H), 1.00 (s, 9H).
Step 7. Preparation of ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-7-(3-hydroxy- 3-methylbut-l-ynyl)-3-methylnaphthalen-2-yl)acetate: To a solution of ethyl 2-(7- bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen-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(PPh3)4 (3 mg, 0.003 mmol), and Et3N (50 μί, 0.36 mmol). The reaction mixture was stirred at 65 °C for 1 h. A saturated solution of NHtCl 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 22 mg of the titled compound. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J = 9 Hz, 1H), 7.67 (s, 1H), 7.57 (m, 2H), 7.48 (m, 1H), 7.40 (d, J = 9 Hz, 1H), 7.29 (d, J = 9 Hz, 1H), 7.24 (s, 1H), 5.15 (s, 1H), 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. Preparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -hydroxy-3 - methylbut-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (69): To a solution of ethyl 2- tert-butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -hydroxy-3 -methylbut- 1 -ynyl)-3 - methylnaphthalen-2-yl)acetate (22 mg, 0.045 mmol) in 2:2:1 THF/MeOH/H20 (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 H20 and purified by reverse phase HPLC (MeCN/H20) to give 12 mg of the titled compound. 1H-NMR: 400 MHz, (CD3OD) 6: 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, 2-100%
MeCN/H20 + 0.05% HO Ac, 5 min run): tR (min) = 3.40.
Example 68. 2-(l,7-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (70)
Figure imgf000252_0001
2-(1 ,7-bis(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-ferf- butoxyacetic acid
Preparation of 2-(l ,7-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (70): 2-(l,7-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (70) was prepared by the method of Example 67. Steps 5,6 and 8 from ethyl 2-(l,7-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate, which was a byproduct in Step 4. 1H-NMR: 400 MHz, (CD3OD) δ: 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, 1H), 2.62 (s, 3H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H20 + 0.05% HO Ac, 5 min run): tR (min) = 3.83.
Example 69. 2-(7-Bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (71)
Figure imgf000253_0001
2-(7-bromo-1 -(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-terf- butoxyacetic acid
Preparation of 2-(7-bromo-l -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (71): 2-(7-Bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- tert-butoxyacetic acid (71) was prepared by the method of Example 67 skipping step 7 from ethyl 2-(7-bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetate. 1H-NMR: 400 MHz, (CD3OD) δ: 7.71 (m, 2H), 7.58 (m, 3H), 7.52 (dd, J = 9, 2 Hz, 1H), 7.33 (m, 2H), 5.15 (s, 1H), 2.59 (s, 3H), 0.97 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H20 + 0.05% HOAc, 5 min run): tR (min) = 3.67.
Example 70. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(3 ,3 -dimethylbut- 1 -ynyl)-3 - methylnaphthalen-2-yl)acetic acid (72)
Figure imgf000254_0001
2-terf-butoxy-2-(1-(4-chlorophenyl)-
7-(3,3-dimethylbut-1-ynyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-7-(3,3-dimethylbut-l -ynyl)-
3-methylnaphthalen-2-yl)acetic acid (72): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-(3,3- dimethylbut-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- yl)-2-tert-butoxyacetate using t-butylacetylene. 1H-NMR: 400 MHz, (CD3OD) δ: 7.70 (d, J = 8 Hz, 1H), 7.65 (s, 1H), 7.57 (m, 3H), 7.33 (m, 2H), 7.19 (s, 1H), 5.16 (s, 1H), 2.59 (s, 3H), 1.27 (s, 9H), 0.97 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2- 100% MeCN/H20 + 0.05% HOAc, 5 min run): tR (min) = 3.78.
Example 71. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(( 1 -hydroxycyclo-pentyl)ethynyl)-
3- methylnaphthalen-2-yl)acetic acid (73)
Figure imgf000254_0002
2-ieri-butoxy-2-(1-(4-chlorophenyl)- 7-((1-hydroxycyclopentyl)ethynyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-7-((l - hydroxycyclopentyl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (73): 2-tert-Butoxy-
2-(l-(4-c orophenyl)-7-((l-hydroxycyclopentyl)ethynyl)-3-methylnaphthalen-2- yl)acetic acid (73) was prepared by the method of Example 67 from ethyl 2-(7-bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 1 - ethynylcyclopentanol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J = 9 Hz, IH), 7.67 (s, IH), 7.56 (m, 3H), 7.39 (d, J = 8 Hz, IH), 7.30 (d, J = 8 Hz, IH), 7.26 (s, IH), 5.17 (s, IH), 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): tR (min) = 3.56.
Example 72. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-(cyclopentylethynyl)-3- methylnaphthalen-2-yl)acetic acid (74)
Figure imgf000255_0001
2-ferf-butoxy-2-(1 -(4-chlorophenyl)-
7-(cyclopentylethynyl)-3- methylnaphthalen-2-yl)acetic acid
2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-(cyclopentylethynyl)-3- methylnaphthalen-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-methylnaphthalen- 2-yl)-2-tert-butoxyacetate using ethynylcyclopentane.
1H-NMR: 400 MHz, (CD3OD) δ: 7.56-7.71 (m, 6H), 7.32 (m, IH), 7.19 (s, IH), 5.16 (s, IH), 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/H20 + 0.05% HOAc, 5 min run): tR (min) = 4.10.
Example 73. 2-tert-Butoxy-2-(l -(4-chlorophenyl)-7-(cyclopropylethynyl)-3- methylnaphthalen-2-yl)acetic acid (75)
Figure imgf000256_0001
2-t erf-butoxy-2-( 1 -(4-ch loropheny I)-
7-(cyclopropylethynyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-7-(cyclopropylethynyl)-3- methylnaphthalen-2-yl)acetic acid (75): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-
(cyclopropylethynyl)-3-methylnaphthalen-2-yl)acetic acid (75) was prepared by the method of Example 67 from ethyl 2-(7-bromo- 1 -(4-chlorophenyl)-3 -methylnaphthalen-
2-yl)-2-tert-butoxyacetate using ethynylcyclopropane. 1H-NMR: 400 MHz, (CD3OD) δ:
7.69 (m, 2H), 7.57 (m, 3H), 7.32 (m, 2H), 7.18 (s, IH), 5.16 (s, IH), 2.59 (s, 3H), 1.42
(br m, IH), 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/H20 + 0.05% HOAc, 5 min run): tR (min) = 3.78.
Example 74. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyl-7-vinylnaphthalen-2- yl)acetic acid (76)
Figure imgf000256_0002
2-ieri-butoxy-2-(1-(4-chlorophenyl)- 3-methyl-7-vinylnaphthalen-2-yl)
acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-7-vinylnaphthalen- 2-yl)acetic acid (76): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyl-7-vinylnaphthalen- 2-yl)acetic acid (76) was prepared by the method of Example 67 from ethyl 2-(7- bromo- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)-2-tert-butoxyacetate using tributyl(vinyl)tin and without triethylamine. 1H-NMR: 400 MHz, (CD3OD) δ: 7.74 (d, J = 9 Hz, 1H), 7.65 (m, 2H), 7.55 (m, 3H), 7.32 (d, J = 9 Hz, 1H), 7.13 (s, 1H), 6.65 (dd, J - 18, 11 Hz, 1H), 5.71 (d, J = 18 Hz, 1H), 5.19 (d, J = 11 Hz, 1H), 5.17 (s, 1H), 2.59 (s, 3H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H20 + 0.05% HO Ac, 5 min run): tR (min) = 3.99.
Example 75. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyl-7-(2-methylprop-l- enyl)naphthalen-2-yl)acetic acid (77)
Figure imgf000257_0001
2-terf-butoxy-2-(1-(4-chlorophenyl)- 3-methyl-7-(2-methylprop-1-enyl)naphthalen-2-yl)
acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-7-(2-methylprop- l-enyl)naphthalen-2-yl)acetic acid (77): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyl- 7-(2-methylprop-l-enyl)naphthalen-2-yl)acetic acid (77) was prepared by the method of Example 67 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- tert-butoxyacetate using 4,4,5,5-tetramethyl-2-(2-methylprop- 1 -enyl)- 1,3,2- dioxaborolane and K2C03 instead of triethylamine, and toluene, ethanol, water as a solvent mixture. 1H-NMR: 400 MHz, (CD3OD) δ: 7.69 (d, J = 8 Hz, 1H), 7.61 (s, 1H), 7.54 (m, 3H), 7.27 (m, 2H), 7.02 (s, 1H), 6.23 (s, 1H), 5.18 (s, 1H), 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/H20 + 0.05% HO Ac, 5 min run): tR (min) = 3.98. Example 76. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3,7-dimethylnaphthalen-2-yl)acetic acid (78)
Figure imgf000258_0001
2-ferf-butoxy-2-(1-(4-chlorophenyl)- 3,7-dimethylnaphthalen-2-yl)
acetic acid
Preparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 ,7-dimethylnaphthalen-2- yl)acetic acid (78): 2-tert-Butoxy-2-(l-(4-c orophenyl)-3,7-dimethylnaphthalen-2- yl)acetic acid (78) was prepared by the method of Example 67 from ethyl 2-(7-bromo- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)-2-tert-butoxyacetate using
trimethylboroxine and K2C03 instead of triethylamine, and toluene, ethanol, water as a solvent mixture.1H-NMR: 400 MHz, (CD3OD) 5: 7.65 (d, J = 8 Hz, 1H), 7.61 (s, 1H), 7.53 (m, 3H), 7.27 (m, 2H), 6.98 (s, 1H), 5.15 (s, 1H), 2.56 (s, 3H), 2.30 (s, 3H), 0.96 (s, 9H). HPLC (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H20 + 0.05% HO Ac, 5 min run): tR (min) = 4.06.
Example 77. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-((4-hydroxy- 1 -methylpiperidin-4- yl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (79)
Figure imgf000258_0002
2-terNbutoxy-2-(1-(4-chlorophenyl)-7- ((4-hydroxy-1-methylpiperidin-4-yl)ethynyl)- 3-methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7-((4-hydroxy- 1 - methylpiperidin-4-yl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (79): 2-tert-Butoxy- 2-(l -(4-chlorophenyl)-7-((4-hydroxy- 1 -methylpiperidin-4-yl)ethynyl)-3- methylnaphthalen-2-yl)acetic acid (79) was prepared by the method of Example 68 from ethyl 2-(7-bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetate using 4-ethynyl-l -methylpiperidin-4-ol. 1H-NMR: 400 MHz, (CD3OD) 5: 7.77 (d, J = 9 Hz, 1H), 7.70 (br s, 1H), 7.58 (m, 3H), 7.41 (d, J = 8 Hz, 1H), 7.30 (m, 2H), 5.16 (s, 1H), 3.35 (m, 4H), 2.89 (s, 3H), 2.60 (s, 3H), 2.15 (m, 4H), 0.98 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C31H35C1N04: 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)
Figure imgf000259_0001
80
2-terf-butoxy-2-(1-(4-chlorophenyl)-7- ((4-hydroxytetrahydro-2AV-pyran-4-yl)ethynyl)- 3-methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-7-((4-hydroxytetrahydro-
2H-pyran-4-yl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (80): 2-tert-Butoxy-2-(l -
(4-chlorophenyl)-7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-3- methylnaphthalen-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-tert- butoxyacetate using 4-ethynyltetrahydro-2H-pyran-4-ol. 1 H-NMR: 400 MHz, (CD3OD) δ: 7.76 (d, J = 8 Hz, 7.68 (s, 1H), 7.57 (m, 3H), 7.42 (d, J = 9 Hz, 1H), 7.30 (m, 2H),
5.16 (s, 1H), 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/H20 + 0.05%
HO Ac, 3.5 min run): tR (min) = 2.41.
Example 79. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-7-(( 1 -methyl- 1 H-imidazol- 5-yl)ethynyl)naphthalen-2-yl)acetic acid (81)
Figure imgf000260_0001
2-ferf-butoxy-2-(1-(4-chlorophenyl)-3-methyl- 7-((1 -methyl-1 H-imidazol-5-yl)ethynyl)
naphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-7-(( 1 -methyl- 1 H- imidazol-5-yl)ethynyl)naphthalen-2-yl)acetic acid (81): 2-tert-Butoxy-2-(l-(4- chlorophenyl)-3 -methyl-7-(( 1 -methyl- 1 H-imidazol-5-yl)ethynyl)naphthalen-2-yl)acetic acid (81) was prepared by the method of Example 67 from ethyl 2-(7-bromo-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 5-ethynyl-l - methyl- lH-imidazole. 1H-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), 7.33 (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
C29H28C1N203: 487.2; found: 487.2.
Example 80. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -ethyl-3 -hydroxypent- 1 -ynyl)-3- methylnaphthalen-2-yl)acetic acid (82)
Figure imgf000260_0002
82
2-f erf-butoxy-2-( 1 -(4-chlorophenyl)-7- (3-ethyl-3-hydroxypent-1 -ynyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(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 by the method of Example 67 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetate using 3-ethylpent-l-yn-3-ol. 1H-NMR: 400 MHz, (CD3OD) 6: 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/H20 + 0.05% HOAc, 3.5 min run): tR (min) = 2.64.
Example 81. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(( 1 -hydroxycyclohexyl)ethynyl)- 3-methylnaphthalen-2-yl)acetic acid (83)
Figure imgf000261_0001
2-ferf-butoxy-2-(1-(4-chlorophenyl)-7- ((1 -hydroxycyclohexyl)ethynyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-7-((l - hydroxycyclohexyl)ethynyl)-3-methylnaphthalen-2-yl)acetic acid (83): 2-tert-Butoxy-
2-(l-(4-chlorophenyl)-7-((l-hydroxycyclohexyl)ethynyl)-3-methylnaphthalen-2- yl)acetic acid (83) was prepared by the method of Example 67 from ethyl 2-(7-bromo-
1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 1 - ethynylcyclohexanol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.75 (d, J - 8 Hz, IH), 7.68 (s,
IH), 7.58 (m, 3H), 7.40 (d, J = 8 Hz, IH), 7.31 (d, J = 8 Hz, IH), 7.28 (s, IH), 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/H20 + 0.05% HOAc, 3.5 min run): tR (min) = 2.66.
Example 82. 2-(7-((l-Aminocyclohexyl)ethynyl)-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (84)
Figure imgf000262_0001
2-(7-((1 -aminocyclohexyl)ethynyl)-1 - (4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-ferf-butoxyacetic acid
Preparation of 2-(7-((l-aminocyclohexyl)ethynyl)-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (84): 2-(7-((l- Aminocyclohexyl)ethynyl)- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (84) was prepared by the method of Example 67 from ethyl 2-(7- bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 1- ethynylcyclohexanamine. 1H-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), 2.1 1 (m, 2H), 1.63-1.85 (m, 8H), 0.99 (s, 9H).
LCMS-ES (m/z): [M-NH2]+ calcd for C31H32C103: 487.2; found: 487.2.
Example 83. 2-(7-(3 - Amino-3 -methylbut- 1 -ynyl)- 1 -(4-chlorophenyl)-3 - methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (85)
Figure imgf000262_0002
2-(7-(3-amino-3-methylbut-1 -ynyl)-1 - (4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-ferf-butoxyacetic acid
Preparation of 2-(7-(3-amino-3 -methylbut- 1 -ynyl)- 1 -(4-chlorophenyl)-3 - methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (85): 2-(7-(3 -Amino-3 -methylbut- 1 - ynyl)-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (85) was prepared by the method of Example 67 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetate using 2-methylbut-3-yn-2-amine. 1H- NMR: 400 MHz, (CD3OD) δ: 7.81 (d, J = 8 Hz, 1H), 7.72 (s, 1H), 7.57 (m, 3H), 7.45 (d, J = 8 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J = 8 Hz, 1H), 5.16 (s, 1H), 2.62 (s, 3H), 1.68 (s, 6H), 0.98 (s, 9H). LCMS-ESf (m/z): [M-NH2]+ calcd for C28H28C103: 447.2; found: 446.9.
Example 84. (S)-2-((R)-7-(3-Ammo-3-methylbut-l-ynyl)-l-(2,3-dihydropyrano[4,3,2- de] quinolin-7-yl)-3 -methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (86)
Figure imgf000263_0001
(S)-2-((f?)-7-(3-amino-3-methylbut-1 -ynyl)-1 - (2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-terf-butoxyacetic acid
Preparation of (S)-2-((R)-7-(3-amino-3-methylbut-l-ynyl)-l-(2,3- dihydropyrano[4,3,2-de]qumolin-7-yl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (86): (S)-2-((R)-7-(3-Amino-3-methylbut-l -ynyl)-l -(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (86) (racemic with relative stereochemistry) was prepared by the method of Example 67 from ethyl 2-(7- bromo-3 -methyl- 1 -(trifluoromethylsulfonyloxy)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. 1H- NMR: 400 MHz, (CD3OD) δ: 8.72 (d, J = 6 Hz, 1H), 8.00 (s, 1H), 7.96 (d, J = 8 Hz, 1H), 7.83 (m, 2H), 7.52 (dd, J = 8, 2 Hz, 1H), 7.46 (d, J = 8 Hz, 1H), 7.07 (s, 1H), 5.21 (s, 1H), 4.73 (m, 2H), 3.68 (t, J = 6 Hz, 2H), 2.78 (s, 3H), 1.61 (s, 6H), 0.92 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C33H35N204: 523.3; found: 523.1.
Example 85. 2-(7-(3-Amino-3-methylbut-l-ynyl)-l-(chroman-6-yl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (87)
Figure imgf000264_0001
2-(7-(3-amino-3-methylbut-1 -ynyl)-1 - (chroman-6-yl)-3-methylnaphthalen-2-yl)- 2-ferf-butoxyacetic acid
Preparation of 2-(7-(3-amino-3-methylbut- 1 -ynyl)- 1 -(chroman-6-yl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (87): 2-(7-(3-Amino-3-methylbut-l- ynyl)-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 -
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate using chroman-6-ylboronic acid. The remainder of the sequence follows the method of Example 67 using 2- methylbut-3-yn-2-amine in Step 7. 1H-NMR: 400 MHz, (CD3OD) δ: 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, 1H), 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 C31H3304: 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)
Figure imgf000264_0002
2-ferf-butoxy-2-(1-(4-chlorophenyl)-7- (3-hydroxy-3-phenylbut-1-ynyl)-3- methylnapht alen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-7-(3-hydroxy-3-phenylbut- l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (88): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-
7-(3-hydroxy-3-phenylbut-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (88) was prepared by the method of Example 67 from ethyl 2-(7-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetate using 2-phenylbut-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.76 (d, J = 8 Hz, IH), 7.69 (s, IH), 7.64 (d, J = 8 Hz, 2H), 7.57 (m, 3H), 7.46 (d, J = 8 Hz, IH), 7.33 (m, 5H), 5.18 (s, IH), 2.61 (s, 3H), 1.75 (s, 3H), 0.98 (s, 9H). LCMS-ESI* (m/z): [M-OH]+ calcd for C33H30ClO3: 509.1 ; found: 508.8.
Example 87. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -hydroxy-3 -methylbutyl)-3 - methylnaphthalen-2-yl)acetic acid (89)
Figure imgf000265_0001
2-ferf-butoxy-2-(1-(4- 89
chlorophenyl)- 7-(3-hydroxy-3-methy lbut-1 - ynyl)-3- 2-terf-butoxy-2-(1-(4-chlorophenyl)- methylnaphthalen-2-yl)acetic 7-(3-hydroxy-3-methylbutyl)-3- acid methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-7-(3 -hydroxy-3 - methylbutyl)-3-methylnaphthalen-2-yl)acetic acid (89): To a solution of 2-tert-butoxy- 2-(l -(4-chlorophenyl)-7-(3 -hydroxy-3 -methylbut- 1 -ynyl)-3-methylnaphthalen-2- yl)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 atmosphere for 1 h. The reaction was filtered and concentrated in vacuo to give 7 mg of the titled compound. 1H-NMR: 400 MHz, (CD3OD) δ: 7.68 (d, J = 8 Hz, IH), 7.63 (m, IH), 7.61 (s, IH), 7.53 (m, 2H), 7.30 (m, 2H), 7.05 (s, IH), 5.12 (s, IH), 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/H20 + 0.05% HOAc, 4.0 min run): tR (min) = 3.52.
Example 88. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(2-cyclopentylethyl)-3 - methylnaphthalen-2-yl)acetic acid (90)
Figure imgf000266_0001
2-terf-butoxy-2-(1-(4-chlorophenyl)-
7-(2-cyclopentylethyl)-3- methylnap thalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7-(2-cyclopentylethyl)-3 - methylnaphthalen-2-yl)acetic acid (90): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-(2- cyclopentylethyl)-3-methylnaphthalen-2-yl)acetic acid (90) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(l-(4-chlorophenyl)-7-
(cyclopentylethynyl)-3-methylnaphthalen-2-yl)acetic acid. 1H-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/H20 + 0.05% HOAc, 5.0 min run): tR (min) = 4.54.
Example 89. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(2-( 1 -hydroxycyclopentyl)ethyl)- 3-methylnaphthalen-2-yl)acetic acid (91)
Figure imgf000266_0002
2-ferf-butoxy-2-( 1 -(4-chlorophenyl)-7- (2-(1-hydroxycyclopentyl)ethyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of 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-chlorophenyl)-7-(2-( 1 -hydroxycyclopentyl)ethyl)-3 -methylnaphthalen-2-yl)acetic acid (91) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(l-(4- chlorophenyl)-7-(( 1 -hydroxycyclopentyl)ethynyl)-3 -methylnaphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.78 (d, J = 8 Hz, IH), 7.67 (d, J = 8 Hz, IH), 7.58 (s, IH), 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 (Kinetex 2.6u, 50 x 4.6 mm, 2-100% MeCN/H20 + 0.05% HO Ac, 4.0 min run): tR (min) = 3.69.
Example 90. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(2-cyclopropylethyl)-3 - methylnaphthalen-2-yl)acetic acid (92)
Figure imgf000267_0001
2-t erf-butoxy-2-( 1 -(4-ch loropheny I)-
7-(2-cyclopropylethyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l-(4-chlorophenyl)-7-(2-cyclopropylethyl)-3- methylnaphthalen-2-yl)acetic acid (92): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-(2- cyclopropylethyl)-3-methylnaphthalen-2-yl)acetic acid (92) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(l-(4-chlorophenyl)-7- (cyclopropylethynyl)-3-methylnaphthalen-2-yl)acetic acid. !H-NMR: 400 MHz, (CD3OD) 6: 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% MeCN/H20 + 0.05% HOAc, 5.0 min run): tR (min) = 4.02. Example 91. 2-tert-Butoxy-2-(l -(4-chlorophenyl)-7-ethyl-3-methylnaphthalen-2- yl)acetic acid (93)
Figure imgf000268_0001
93
2-ferf-butoxy-2-(1-(4-chlorophenyl)- 7-ethyl-3-methylnaphthalen-2-yl)
acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-7-ethyl-3-methylnaphthalen- 2-yl)acetic acid (93): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-ethyl-3-methylnaphthalen- 2-yl)acetic acid (93) was prepared using the procedure of Example 87 from 2-tert- butoxy-2-( 1 -(4-chlorophenyl)-3-methyl-7-vinylnaphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.74 (d, J = 8 Hz, 1H), 7.67 (d, J = 8 Hz, 1H), 7.59 (s, 1H), 7.53 (m, 2H), 7.29 (m, 2H), 7.04 (s, 1H), 5.07 (s, 1H), 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/H20 + 0.05% HOAc, 4.0 min run): tR (min) = 3.81.
Example 92. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-isobutyl-3-methylnaphthalen-2- yl)acetic acid (94)
Figure imgf000268_0002
2-ieri-butoxy-2-(1-(4-chlorophenyl)-7- isobutyl-3-methylnaphthalen-2-yl)
acetic acid
Preparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-7-isobutyl-3 - methylnaphthalen-2-yl)acetic acid (94): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7- isobutyl-3-methylnaphthalen-2-yl)acetic acid (94) was prepared using the procedure of Example 87 from 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-7-(2-methylprop-l- enyl)naphthalen-2-yl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.66 (m, 3H), 7.55 (m, 2H), 7.28 (m, 2H), 6.97 (s, 1H), 5.13 (s, 1H), 2.59 (s, 3H), 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% MeCN/H20 + 0.05% HOAc, 4.0 min run): tR (min) = 3.03.
Example 93. 2-tert-Butoxy-2-(l-(4-cUorophenyl)-7-(3-(dimemylarnino)-3-methylbut- l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (95):
Figure imgf000269_0001
2-(7-(3-amino-3-methylbut-1-ynyl)-1- (4-chlorophenyl)-3-methylnaphthalen-2-yl)- 95
2-terf-butoxyacetic acid
2-feri-butoxy-2-(1-(4-chlorophenyl)-7- (3-(dimethylamino)-3-methylbut-1-ynyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-7-(3-(dimethylamino)-3- methylbut-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (95): To a solution of 2-(7-(3- amino-3 -methylbut- 1 -ynyl)- 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (12 mg, 0.026 mmol) in MeOH (1 mL) was added acetic acid (100 μί), formaldehyde (50 μΐ., 37% in water), and sodium triacetoxyborohydride (10 mg). After 30 min, the reaction mixture was filtered and purified by reverse phase HPLC (MeCN/H20 w/ 0.1 % TF A) to give 4 mg of the titled compound.
Ή- MR: 400 MHz, (CD3OD) δ: 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 = 8 Hz, 1H), 5.16 (s, 1H), 2.97 (s, 6H), 2.62 (s, 3H), 1.75 (s, 6H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for
C30H35ClNO3: 492.2; found: 492.0.
Example 94. 2-(7-(3-Acetamido-3 -methylbut- 1 -ynyl)- 1 -(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (96)
Figure imgf000270_0001
2-(7-(3-amino-3-methylbut-1 -ynyl)-1 - (4-chlorophenyl)-3-met ylnaphthalen-2-yl)- 96
2-ferf-butoxyacetic acid
2-(7-(3-acetamido-3-methylbut-1 -ynyl)-1 - (4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-ferf-butoxyacetic acid
Preparation of 2-(7-(3-acetamido-3-methylbut- 1 -ynyl)- 1 -(4-chloropheny l)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (96): To a solution of 2-(7-(3-amino-3- methylbut- 1 -ynyl)- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (12 mg, 0.026 mmol) in CH2C12 (1 mL) was added triethylamine (50 μΐ,) and acetic anhydride (10 μϋ) and trace DMAP. After 30 min, the reaction mixture was filtered and purified by reverse phase HPLC (MeCN/H20 w/ 0.1% TFA) to give 10 mg of the titled compound. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J = 9 Hz, 1H), 7.67
(s, 1H), 7.58 (m, 3H), 7.40 (d, J - 9 Hz, 1H), 7.32 (d, J = 9 Hz, 1H), 7.27 (s, 1H), 5.16 (s, 1H), 2.60 (s, 3H), 1.90 (s, 3H), 1.61 (s, 6H), 0.98 (s, 9H). LCMS-ESI+ (m/z):
[M+H]+ calcd for C30H33ClNO4: 506.2; found: 506.0.
Example 95. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-7-(3-(methoxycarbonylamino)-3- methylbut-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (97)
Figure imgf000270_0002
2-t erf-butoxy-2-( 1 -(4-chloropheny I )-7- (3-(methoxycarbonylamino)-3-methylbut-1-ynyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chloropheny l)-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- 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-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetic acid using methyl chloroformate. 1H-NMR: 400 MHz, (CD3OD) δ: 7.72 (d, J = 8 Hz, 1H), 7.67 (s, 1H), 7.57 (m, 3H), 7.40 (d, J = 8 Hz, 1H), 7.31 (d, J = 9 Hz, 1H), 7.26 (s, 1H), 5.16 (s, 1H), 3.60 (s, 3H), 2.60 (s, 3H), 1.58 (s, 6H), 0.98 (s, 9H). LCMS-ESf m/z): [M+H]+ calcd for C30H33ClNO5: 522.2; found: 522.1.
Example 96. (S)-2-(7-(3-Amino-3-methylbut-l-ynyl)-l -(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (98)
Figure imgf000271_0001
(S)-2-(7-(3-amino-3-methylbut-1-ynyl)- 1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-terf-butoxyacetic acid
Preparation of (S)-2-(7-(3 -amino-3 -methylbut- 1 -ynyl)- 1 -(4-chlorophenyl)-3 - methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (98): (S)-2-(7-(3 -Amino-3 -methylbut- 1 -ynyl)- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (98) was prepared by the method of Example 67 using the reduction method of Example 51, step 3, for (5)-ethyl 2-(l-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate instead of step 5, NaB¾ step, from ethyl 2-(7- bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate. The remainder of the sequence follows the method of Example 67 using 2-methylbut-3-yn-2-amine in Step 7. 1H-NMR: 400 MHz, (CD3OD) δ: 7.81 (d, J = 8 Hz, 1H), 7.72 (s, 1H), 7.57 (m, 3H), 7.45 (d, J = 8 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J = 8 Hz, 1H), 5.16 (s, 1H), 2.62 (s, 3H), 1.68 (s, 6H), 0.98 (s, 9H). LCMS-ESf (m/z): [M-NH2]+ calcd for C28H28C103: 447.2; found: 446.9. Example 91. (S)-2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-7-(3 -hydroxy-3 -methylbut- 1 - ynyl)-3-methylnaphthalen-2-yl)acetic acid (99)
Figure imgf000272_0001
(S)-2-feri-butoxy-2-(1-(4-chlorophenyl)-7- (3-hydroxy-3-methylbut-1-ynyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-(l -(4-chlorophenyl)-7 -(3 -hydroxy-3 - methylbut- l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (99): (S)-2-tert-Butoxy-2-(l-(4- chlorophenyl)-7-(3-hydroxy-3-methylbut-l-ynyl)-3-methylnaphthalen-2-yl)acetic acid
(99) was prepared by the method of Example 67 using the reduction 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, NaBEU step, from ethyl 2-(7-bromo- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)-2- oxoacetate. The remainder of the sequence follows the method of Example 67 using 2- methylbut-3-yn-2-ol in Step 7. 1H-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, 2-100% MeCN/H20 + 0.05% HOAc, 5 min run): tR (min) = 3.40.
Example 98. (S)-2-(7-(( 1 -Aminocyclohexyl)ethynyl)- 1 -(4-chlorophenyl)-3 - methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (100)
Figure imgf000273_0001
100
(S)-2-(7-((1 -aminocyclohexyl)ethynyl)-1 - (4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-feri-butoxyacetic acid
Preparation of (S)-2-(7-(( 1 -aminocyclohexyl)ethynyl)- 1 -(4-chlorophenyl)-3 - methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (100): (S)-2-(7-((l- Ammocyclohexyl)emynyl)-l-(4-cWorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (100) was prepared by the method of Example 67 using the reduction method of Example 51 step 3 for (5 -ethyl 2-(l-(4-chlorophenyl)-3-methyl-6- (trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate instead of step 5, NaBHf step, from ethyl 2-(7-bromo-l -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- oxoacetate. The remainder of the sequence follows the method of Example 67 using 1- ethynylcyclohexanamine in Step 7. 1H-NMR: 400 MHz, (CD3OD) δ: 7.82 (d, J = 8 Hz, IH), 7.72 (s, IH), 7.56 (m, 3H), 7.47 (d, J = 8 Hz, IH), 7.37 (s, IH), 7.31 (d, J = 8 Hz, IH), 5.20 (s, IH), 2.60 (s, 3H), 2.1 1 (m, 2H), 1.63-1.85 (m, 8H), 0.99 (s, 9H). LCMS- ESf (m/z): [M-NH2]+ calcd for C31H32C103: 487.2; found: 487.2.
Example 99. (S)-2-tert-Butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2- de]quinoli -7-yl)-7-fluoro-3-methylnaphthalen-2-yl) acetic acid (101)
Figure imgf000274_0001
Figure imgf000274_0002
ethyl 2-(6-chloro-7-fluoro-1 - ethy| 2-(6-chloro-7-fluoro-3-methyl-1 - hydroxy-3-methylnaphthalen- (((trifluoromethyl)sulfonyl)oxy)naphtha 2-yl)-2-hydroxyacetate len-2-yl)-2-hydroxyacetate
Figure imgf000274_0003
(S)-ethyl 2-(6-chloro-7- ethyl 2-(6-chloro-7-fluoro-3-methyl-1 - fluoro-3-methyl-1- (((trifluoromethyl)sulfonyl)oxy)naphth (((trifluoromethyl)sulfonyl)o alen-2-yl)-2-oxoacetate xy)naphthalen-2-yl)-2- hydroxyacetate
(S)-ethyl
(((trifluo
Figure imgf000275_0001
101
(S)-2-(ieri-butoxy)-2-((f?)-6-chloro- 1 -(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3- methylnaphthalen-2-yl)acetic acid
Preparation of l-(3-chloro-4-fluorophenyl)propan-2-one: To a solution of 2-(3- chloro-4-fluorophenyl)acetic acid (18.46 g, 97.89 mmol) in acetic anhydride (463 mL) was added N-methylimidazole (3.9 mL) and the reaction mixture was stirred overnight at room temperature. 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 oil (14.5 g, 79%). 1H NMR (400 MHz, CDC13) δ 7.23 (dd, J = 6.9, 2.1 Hz, 1H), 7.14 - 7.00 (m, 2H), 3.66 (s, 2H), 2.19 (s, 3H).
Preparation of ethyl 4-(3-chloro-4-fluorophenyl)-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. l-(3-chloro-4-fluorophenyl)propan-2- one (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: 1H NMR (400 MHz, CDC13): δ 7.19 (dd, J = 7.0, 2.1 Hz, 1H), 7.12 - 6.97 (m, 2H), 5.64 (d, J = 1.2 Hz, 1H), 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: 1H NMR (400 MHz, CDC13): δ 7.28 (dd, J = 7.1, 2.1 Hz, 1H), 7.15 - 6.98 (m, 2H), 5.79 (s, 1H), 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, 3H).
Preparation of 6-chloro-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). 1H-NMR: 400 MHz, (CDC13) δ: 7.83 (d, J = 10.4 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.11 (s, 1H), 6.67 (s, 1H), 2.42 (s, 3H).
Preparation of ethyl 2-(6-chloro-7-fluoro-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(rV) 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 salt solution and stirred at room temperature for 2.5 hours. The resulting mixture was washed with water and aqueous layer back- extracted with dichloromethane (2x). The combined organic layer was dried (MgS04), 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). 1H-NMR: 400 MHz, (CDC13) δ : 8.48 (s, 1H), 7.89 (d, J = 10.5 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.11 (s, 1H), 5.67 (s, 1H), 4.30 (dq, J = 10.8, 7.1 Hz, 1H), 4.15 (dq, J = 10.8, 7.1 Hz, 1H), 3.61 (s, 1 H), 2.52 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). LCMS-ES (m/z): [M+H]+ calcd for C15H13C1F04: 311.7; Found: 311.0.
Preparation 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- 1 -hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate (4.13 g, 13.22 mmol) in anhydrous 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 HC1 solution/brine and organic layer dried (MgS04), filtered, concentrated to give an orange oil that used in next step without further 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. Trifiuoromethanesulfonic 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 temperature. The mixture was diluted with dichloromethane, washed with 1 N HC1 solution, saturated sodium bicarbonate solution/brine and dried (MgS04), 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 temperature 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 (MgS04), 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). 1H-NMR: 400 MHz, (CDCI3) 6 : 7.87 (d, J = 7.1 Hz, 1H), 7.76 (d, J = 10.1 Hz, 1H), 7.59 (s, 1H), 5.76 (d, J = 2.0 Hz, 1H), 4.36 - 4.18 (m, 2H), 3.42 (d, J = 2.4 Hz, 1H), 2.48 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). Preparation of ethyl 2-(6-chloro-7-fluoro-3 -methyl- 1 -(trifluoromethyl- sulfonyloxy)naphthalen-2-yl)-2-oxoacetate: To a solution of ethyl 2-(6-chloro-7-fluoro- 3-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 periodinane (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 (MgS04), filtered, concentrated to give a yellow oil with a white precipitate. The mixture was suspended in diethyl ether, washed with brine, dried (MgS04), 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). 1H NMR (400 MHz, CDC13) δ: 7.93 (d, J = 7.0 Hz, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.67 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).
Preparation of (S)-ethyl 2-(6-chloro-7-fluoro-3-methyl- 1 -(trifluoromethyl- sulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate: To a solution of ethyl 2-(6-chloro-7- fluoro-3 -methyl- 1 -(trifluoromethylsulfonyloxy)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 1 hour and quenched with sodium carbonate solution, diluted with ethyl acetate and stirred vigorously for 20 minutes at -20 °C, then at room temperature for 45 minutes. The aqueous layer was removed and the organic layer was washed with sodium carbonate solution (4x), saturated ammonium chloride solution, dried (MgS04), 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). 1H NMR (400 MHz, CDC13) δ: 7.87 (d, J = 7.1 Hz, 1H), 7.76 (d, J = 10.0 Hz, 1H), 7.59 (s, 1H), 5.76 (d, J = 1.7 Hz, 1H), 4.38 - 4.17 (m, 2H), 3.43 (d, J = 2.3 Hz, 1H), 2.48 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). The enantiomeric excess was determined by chiral column analysis (Chiralpak AD-H, heptanerethanol (80:20)) to be 95%.
Preparation 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-(6- chloro-7-fluoro-3-methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2- hydroxyacetate (4.44 g, 9.99 mmol) in 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 (MgS04), 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). 1H NMR (400 MHz, CDC13) δ: 7.86 (d, J = 7.2 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, 13H).
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-6-chloro-l-(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-chloro-7-fluoro-3- methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (110 mg, 0.199 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (55 mg, 0.220 mmol), PdCl2(dppf) (16 mg, 0.02 mmol), cesium fluoride (133 mg, 0.876 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 110 °C for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), 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)-6-chloro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3- methylnaphthalen-2-yl)acetate (9.7 mg). 1H NMR (400 MHz, CD3OD): δ 8.49 (d, J = 4.4 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.74 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 4.4 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 6.66 (d, J = 11.5 Hz, 1H), 5.13 (s, 1H), 4.56 (dd, J = 9.9, 5.9 Hz, 2H), 3.96 (dd, J = 10.8, 7.1 Hz, 1H), 3.76 (dd, J = 10.7, 7.1 Hz, 1H), 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 C30H3oClFN04: 523.0; Found: 522.1, 524.1.
The other atropisomer, (S)-ethyl 2-tert-butoxy-2-((S)-6-chloro-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate, was also isolated (16.4 mg). 1H NMR (400 MHz, CD3OD): δ 8.47 (d, J = 4.4 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.25 (d, J = 4.4 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 11.4 Hz, 1H), 5.15 (s, 2H), 4.52 (t, J = 5.4 Hz, 2H), 4.22 - 4.04 (m, 2H), 3.37 (t, J = 5.8 Hz, 2H), 2.61 (s, 3H), 1.20 (t, J = 5.9 Hz, 3H), 0.70 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C30H30ClFNO4: 523.0; Found: 522.1, 524.1.
Preparation of (S)-2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (101): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 7-fluoro-3-methylnaphthalen-2-yl)acetate (9.7 mg, 0.186 mmol) and 5 M sodium hydroxide (74 μί, 0.372 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.2 mL) was heated at 50 °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 (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give a yellow powder (6.7 mg). 1H-NMR: 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, 1H), 7.80 (d, J = 5.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 1 1.2 Hz, 1H), 5.21 (s, 1H), 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) δ: -77.7 (s, 3F), -119.2 (dd, J = 10.6, 7.9 Hz, IF). LCMS-ESf (m/z): [M+H]+calcd for C28H26C1FN04: 494.95; Found: 494.4, 496.1. The other atropisomer, (S)-2-tert-butoxy- 2-((S)-6-chloro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3- methylnaphthalen-2-yl)acetic acid, was prepared in a similar manner. 1H 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) 5: -77.7 (s, 3F), -120.0 (br s, IF).
LCMS-ESI+ (m/z): [M+H]+ calcd for C28H26C1FN04: 494.95; Found: 494.4, 496.1.
Example 100. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-
7-fluoro-6-isopropyl-3-methylnaphthalen-2-yl)acetic acid (102)
Figure imgf000281_0001
(S)-ethyl 2-(ferf-butoxy)-2-(6- (S)-ethyl 2-(ferf-butoxy)-2-(7-fluoro-3- 2,3-dihydropyrano[4,3,2- chloro-7-fluoro-3-methyl-1- methyl-6-(prop-1-en-2-yl)-1- de]quinolin-7-ylboronic
(((trifluoromethyl)sulfonyl)oxy)na (((trifluoromethyl)sulfonyl)oxy)naphthalen- acid, HCI salt
phthalen-2-yl)acetate 2-yl)acetate
Figure imgf000281_0002
(S)-ethyl 2-(ferf-butoxy)-2-((S)-1-(2,3- (S)-ethyl 2-(ieri-butoxy)-2-((R)-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)- dihydropyrano[4,3,2-de]quinolin-7-yl)- 7-fluoro-3-methyl-6-(prop-1 -en-2- 7-fluoro-3-methyl-6-(prop-1 -en-2- yl)naphthalen-2-yl)acetate yl)naphthalen-2-yl)acetate
Figure imgf000281_0003
(S)-ethyl 2-(ferf-butoxy)-2-((R)-1-(2,3- 102
dihydropyrano[4,3,2-de]quinolin-7-yl)-
.h '"0^"',50^0^'"3"* ♦ (S)-2-(ferf-butoxy)-2-((R)-1-(2,3- methylnaphthalen-2-yl)acetate dihydropyrano[4,3,2 de]quinolin-7-yl)-
7-fluoro-6-isopropyl-3- methylnaphthalen-2-yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-6-(prop-l-en-2-yl)- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2 -(6-chloro-7-fluoro-3 -methyl- 1-
(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), cesium fluoride (623 mg, 0.405 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 reaction mixture was diluted with ethyl acetate and washed with water, brine, dried (MgS04), filtered, concentrated and purified by flash column
chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give a colorless oil (60 mg). 1H NMR (400 MHz, CDC13) δ 7.85 (d, J = 7.1 Hz, 13H), 7.71 (d, J = 7.5 Hz, 1H), 5.70 (s, lH), 5.35 (s, 1H), 5.32 (s, 1H), 4.18 (dt, J = 19.3, 11.4 Hz, 2H), 2.53 (s, 3H), 2.21 (s, 3H), 1.24 - 1.12 (m, 12H).
Preparation of (S)-ethyl 2-tert-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: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-6- (prop- 1 -en-2-yl)- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (92.3 mg, 0.182 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (50 mg, 0.200 mmol), Sphos Palladacycle (18.4 mg, 0.0273 mmol), cesium 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 (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give impure (S)-ethyl 2- tert-butoxy-2-((R)- 1 -(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/H20 + 0.1% TFA) and lyophilized to give an impure yellow powder (4.3 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H35FN04: 528.6; Found: 528.1, 529.1.
The other atropisomer, (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3- dihydropyrano [4,3 ,2-de] quinolin-7-yl)-7-fluoro-3 -methyl-6-(prop- 1 -en-2- yl)naphthalen-2-yl)acetate, was also isolated (4.3 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H35FN04: 528.6; Found: 528.1, 529.1
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-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-3- methyl-6-(prop-l-en-2-yl)naphthalen-2-yl)acetate (4.3 mg, 0.007 mmol) and 10% Palladium/carbon (5.0 mg) in ethanol (1.5 mL) was stirred under a hydrogen atmosphere (1 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-ESf (m/z): [M+H]+calcd for C33H37FN04: 530.6; Found: 530.2.
Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-
7-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-yl)-7-fluoro-6- isopropyl-3-methylnaphthalen-2-yl)acetate (4.2 mg, 0.007 mmol) and 5 M sodium hydroxide (31 μϋ,, 0.16 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.1 mL) was heated at 50 °C overnight. The reaction mixture was acidified with acetic acid, concentrated, dissolved in DMF and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give a yellow powder (2.6 mg). 1H-NMR: 400 MHz, (CD3OD) 5: 8.67 (d, J = 5.6 Hz, 1H), 7.94 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 6.0 Hz, 1H), 7.78 (d, J = 6.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 12.4 Hz, 1H), 5.21 (s, 1H), 4.75-4.70 (m, 2H), 3.66 (t, J = 6 Hz, 2H), 3.3- 2.2 (m, 1H), 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, IF). LCMS-ESf m/z): [M+H]+calcd for C31H33FN04: 502.69; Found: 502.1(M+H+).
Example 101. (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 (103)
Figure imgf000284_0001
(S)-ethyl 2-(feri-butoxy)-2-(6- chlorc-7-fluorc-3-methyl-1- (((trifluoromethyl)sulfonyl)oxy)nap
hthalen-2-yl)acetate l4,3,2- ronic t p (
Figure imgf000284_0002
di l)-
Figure imgf000284_0003
(S)-2-(ferf-butoxy)-2-((R)-6- (difluovomet yl)-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)- 7-fluoro-3-methylnaphthalen-2- yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-l- (trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-l- (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. DMF (2.0 mL) and sodium carbonate (5.0 mg, 0.0639 mmol) were added and heated in microwave 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 (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give a colorless oil (149.5 mg). 1H NMR (400 MHz, CDC13) δ 7.64 (d, J- 5.1 Hz, 1H), 7.62 (d, 1H), 6.95 (dd, J= 17.7, 11.3 Hz, 1H), 6.00 (d, J= 17.7 Hz, 1H), 5.52 (d, J= 11.3 Hz, 1H), 4.33 - 4.03 (m, 2H), 2.53 (s, 3H), 1.20 (s, 9H), 1.17 (t, J = 7.1 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(7-fluoro-6-formyl-3 -methyl- 1 -
(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: A 3-neck round-bottom flask was charged with (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-l- (trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate (95 mg, 0.193 mmol), methanol (1 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 temperature for lh, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl
acetate/hexanes) to give a colorless oil (74 mg). 1H NMR (400 MHz, CDC13) 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, 1H), 4.39 - 4.00 (m, 2H), 2.56 (s, 3H), 1.20 (s, 9H), 1.17 (t, J = 7.1 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-(difluoromethyl)-7-fluoro-3-methyl- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: To a solution of S)-ethyl 2-tert- butoxy-2-(7-fluoro-6-formyl-3 -methyl- 1 -(trifluoromethyl-sulfonyloxy)naphthalen-2- yl)acetate (37.3 mg, 0.075 mmol) in dichloromethane (0.5 mL) at 0 °C was added
Deoxo-Fluor (28 μί, 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). 1H NMR (400 MHz, CDC13) δ 8.06 (d, J= 6.8 Hz, 1H), 7.75 (s, 1H), 7.73 (d, J= 10.7 Hz, 1H), 6.99 (t, J= 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, J = 7.1 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-6-(difluoromethyl)- 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-(difluoromethyl)-7- fluoro-3 -methyl- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (53.6 mg, 0.104 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (31.3 mg, 0.125 mmol), Sphos Palladacycle (10.5 mg, 0.0156 mmol), cesium fluoride (69.5 mg, 0.458 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 reaction mixture was diluted with ethyl acetate and washed with brine. Aqueous layer back-extracted and combined organic layer dried (MgSC>4), 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)-6-(difluoromethyl)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7- fluoro-3-methylnaphthalen-2-yl)acetate (10 mg). LCMS-ESf (m/z): [M+H]+ calcd for C31H31F3N04: 538.6; found: 538.1.
The other atropisomer, (S)-ethyl 2-tert-butoxy-2-((S)-6-(difluoromethyl)-l -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate, was also isolated (12.0 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H31F3N04: 538.6; found: 538.1.
Preparation of (S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)-l -(2,3- dihyckopyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (103): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-6-(difluoromethyl)- 1 -(2,3- dmydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate (10.0 mg, 0.0186 mmol) and 5 M sodium hydroxide (74 μί, 0.372 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.1 mL) was heated at 50 °C overnight. The reaction mixture was re-suspended in methanol and concentrated to ~1 mL. DMF (0.3 mL) was added and concentrated to -0.3 mL. Acetic acid was added, further diluted with DMF and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give a yellow powder (9.8 mg).
1H NMR (400 MHz, CD3OD) δ 8.70 (d, J= 5.7 Hz, 1H), 8.24 (d, J= 7.2 Hz, 1H), 8.10 (s, 1H), 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, J= 12.2 Hz, 1H), 5.24 (s, 1H), 4.81 - 4.64 (m, 2H), 3.67 (t, J= 6.0 Hz, 2H), 2.79 (s, 3H), 0.93 (s, 9H). 19F NMR (377 MHz, CD3OD) δ -77.77 (s), -114.82 - -118.07 (m), -123.29 (m). LCMS-ESf (m/z): [M+H]+ calcd for C29H27F3N04: 510.5; found: 510.1. Example 102. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 6-ethyl-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (104)
(S)-ethyl 2-(ierf-butoxy)-2-(6-ethyl- 7-fluoro-3-methyl- 1 -
(((trifluoromethyl)sulfonyl)oxy)nap
Figure imgf000287_0001
hthalen-2-yl)acetate
yl)acetate
2,3-dihydropyrano[4,3,2- ofe]qu
Figure imgf000287_0002
inolin-7-ylboronic
add, HCI salt (S)-ethyl 2-(fert-butoxy)-2-((R)-1 -(2,3-
(S)-ethyl 2-(ferf-butoxy)-2-((S)-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)- dihydropyrano[4,3,2-de]quinolin-7-yl)- 6-ethyl-7-fluoro-3-methylnaphthalen- 6-ethyl-7-fluoro-3-methylnaphthalen- 2-yl)acetate 2-yl)acetate
Figure imgf000287_0003
(S)-2-(f ert-butoxy)-2-(( )-1 -(2,3- dihydropyrano[4,3,2-ofe]quinolin-7-yl)- 6-ethyl-7-fluoro-3-methylnaphthalen- 2-yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-ethyl-7-fluoro-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: A mixture of (S)-ethyl 2-tert- butoxy-2-(7-fluoro-3-methyl-l-(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2- yl)acetate (23 mg, 0.050 mmol) and 10% Palladium on carbon (5 mg) in ethanol (2.0 mL) was stirred under a hydrogen atmosphere 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.
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]qumolin-7-yl)-6-ethyl-7-fluoro-3-methyhiaphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(6-ethyl-7-fluoro-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (23.4 mg, 0.0473 mmol), 2,3- dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (14.3 mg, 0.568 mmol), Sphos Palladacycle (4.8 mg, 0.0071 mmol), cesium 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 reaction mixture was diluted with ethyl acetate and washed with brine. Aqueous layer back-extracted and combined organic layer dried (MgS04), 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-de]quinolin-7-yl)-6-ethyl-7-fluoro-3- methylnaphthalen-2-yl)acetate (1.7 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for
C32H35FN04: 516.6; found: 516.1. The other atropisomer, (S)-ethyl 2-tert-butoxy-2- ((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-7-fluoro-3- methylnaphthalen-2-yl)acetate, was also isolated (2.6 mg). LCMS-ESf (m/z): [M+Hf calcd for C32H35FN04: 516.6; found: 516.1.
Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-6-ethyl-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (104): A solution of (S)- ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-7- fluoro-3-methylnaphthalen-2-yl)acetate (1.7 mg, 0.005 mmol) and 5 M sodium hydroxide (21 iL, 0.101 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.1 mL) was heated at 50 °C overnight. The reaction mixture was acidified with acetic acid, concentrated, dissolved in DMF and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give a yellow powder (1.3 mg). 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J= 5.6 Hz, 1H), 7.93 (s, 1H), 7.87 - 7.77 (m, J = 7.0 Hz, 3H), 7.46 (d, J= 8.1 Hz, 1H), 6.49 (d, J= 12.1 Hz, 1H), 5.21 (s, 1H), 4.73 (d, J= 6.3 Hz, 2H), 3.67 (t, J= 6.0 Hz, 2H), 2.83 - 2.72 (m, 6H), 1.28 (t, J= 7.5 Hz, 4H), 0.92 (s, 9H). iyF NMR (377 MHz, CD3OD) δ -77.86 (s), -121.37 (d, J= 7.9 Hz). LCMS-ESf (m/z): [M+H]+ calcd for C3oH31FN04: 488.6; found: 488.1.
Example 103. (S)-2-tert-Butoxy-2-((R)-6-cyclopropyl-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (10
4,3,2- ronic
Figure imgf000290_0001
(S)-ethyl 2-(ferf-butoxy)-2-(6- (S)-ethyl 2-(tert-butoxy)-2-(6- chloro-7-fluoro-3-methyl-1 - cyclopropyl-7-fluoro-3-methyl-1 - (((trifluoromethyl)sulfonyl)oxy)nap (((trifluoromethyl)sulfonyl)oxy)nap
hthalen-2-yl)acetate hthaten-2-yl)acetate
Figure imgf000290_0002
(S)-ethyl 2-(ferf-butoxy)-2-((S)-6- (S)-ethyl 2-{terf-butoxy)-2-((R)-6- cyclopropyl-1-(2,3- cyclopropyl-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)- dihydropyrano[4,3,2-de]quinolin-7-yl)- 7-fluoro-3-methylnaphthalen-2- 7-fluoro-3-methylnaphthalen-2- yl)acetate cetate
Figure imgf000290_0003
105
(S)-2-(ierf-butoxy)-2-((R)-6- cyclopropyl-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)- 7-fluoro-3-methylnaphthalen-2- yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-cyclopropyl-7-fluoro-3 -methyl- 1- (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- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (122.5 mg, 0.245 mmol), cyclopropylboronic acid (23 mg, 0.269 mmol), BrettPhos Palladacycle (27 mg, 0.0368 mmol), cesium fluoride (164 mg, 1.08 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 with ethyl acetate and the combined organic layer was dried (MgS04), 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). Analytical HPLC (Gemini, 2-98% ACN/H20 + 0.05% TFA): tR (min) = 5.53.
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-6-cyclopropyl-l-(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-cyclopropyl-7-fluoro- 3 -methyl- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (83.1 mg, 0.164 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (45.4 mg, 0.180 mmol), Sphos Palladacycle (16.5 mg, 0.0246 mmol), cesium fluoride (1 10 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 (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to give (S)-ethyl 2-tert- butoxy-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 C33H35FN04: 528.6; Found: 528.1 , 529.1. The other atropisomer, (S)-ethyl 2-tert-butoxy-2-((S)-6-cyclopropyl-l-(2,3- dmy(kopyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate, was also isolated (2.8 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C33H34FN04: 528.6;
Found: 528.1, 529.1
Preparation of (S)-2-tert-butoxy-2-((R)-6-cyclopropyl-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (105): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-6-cyclopropyl-l-(2,3- dihydropyrano [4,3, 2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate (2.2 mg, 0.0042 mmol) and 5 M sodium hydroxide (171 iL, 0.083 mmol) in tetrahydrofuran (0.5 mL) and methanol (0.1 mL) was heated at 45 °C overnight. The reaction mixture was concentrated, acidified with acetic acid, diluted in DMF and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give a yellow powder (2.2 mg). 1H-NMR: 400 MHz, (CD3OD) 8: 8.67 (d, J = 5.6 Hz, 1H), 7.89 (s, 1H), 7.82-7.78 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 12.4 Hz, 1H), 5.20 (s, 1H), 4.76-4.49 (m, 2H), 3.66 (t, J = 6 Hz, 2H), 2.73 (s, 3H), 2.15-2.10 (m, 1H), 1.04 (d, J = 8.4 Hz, 2H), 0.92 (s, 9H), 0.86-.83 (m, 2H). 19F- NMR: 377 MHz, (CD3OD) δ: -77.7 (s, 3F), -121.8 (dd, 1F).LCMS-ESI+ (m/z): [M+H]+ calcd for C31H31FN04: 500.6; Found: 500.1.
Example 104. (S)-2-tert-Butoxy-2-((R)-6-cyano-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (106A) and (S)-2-tert- Butoxy-2-((R)-6-carbamoyl-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3- methylnaphthalen-2-yl)acetic acid (106B)
Figure imgf000293_0001
(S)-ethyl 2-(ferf-butoxy)-2- (S)-ethyl 2-(ierf-butoxy)-2-(6-
(6-chloro-7-fluoro-3-methyl- cyano-7-fluoro-3-methyl-1 -
1 - (((trif luoromethyl)sulfonyl)oxy)nap
(((trifluoromethyl)sulfonyl)o hthalen-2-yl)acetate
xy) naphthalen-2-y l)acetate
Figure imgf000293_0002
(S)-ethyl 2-(terf-butoxy)-2-((S)-6- (S)-ethyl 2-(ferf-butoxy)-2-((R)-6- cyano-1-(2,3-dihydropyrano[4,3,2- cyano-1-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3- de]quinolin-7-yl)-7-fluoro-3- methylnaphthalen-2-yl)acetate methylnap thalen-2-yl)acetate
Figure imgf000293_0003
106B
106A
(S)-2-(fer/-butoxy)-2-((R)-6-
(S)-2-(ferf-butoxy)-2-((R)-6-cyano-1- carbamoyl-1-(2,3- (2,3-dihydropyrano[4,3,2-de]quinolin- dihydropyrano[4,3,2-de]quinolin-7-yl)- 7-yl)-7-fluoro-3-methylnaphthalen-2- 7-fluoro-3-methylnaphthalen-2- yl)acetic acid yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-cyano-7-fluoro-3 -methyl- 1- uoromethylsulfonyloxy)naphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-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 reaction mixture was diluted with ethyl acetate and washed with 5% lithium chloride solution (2x), brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give a colorless oil (129 mg).
Analytical HPLC (Gemini, 2-98% ACN/H20 + 0.05% TFA): tR (min) = 5.01.
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-6-cyano- 1 -(2,3 - dmydropyrano[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-3- methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (129 mg, 0.262 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (72.6 mg, 0.289 mmol), Sphos Palladacycle (26 mg, 0.0393 mmol), cesium 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 (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to give impure (S)-ethyl 2- tert-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+ ( /z): [M+H]+ calcd for
C3jH30FN2O4: 513.6; Found: 513.1. The other atropisomer, (S)-ethyl 2-tert-butoxy-2- ((S)-6-cyano-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3- methylnaphthalen-2-yl)acetate, was also isolated (36.8 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H3oFN204: 513.6; Found: 513.1.
Preparation of (S)-2-tert-butoxy-2-((R)-6-cyano-l -(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (106A): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-6-cyano-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7- fluoro-3-methylnaphthalen-2-yl)acetate (36.8 mg, 0.0718 mmol) and 5 M sodium hydroxide (290 iL, 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 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give a yellow powder (26.9 mg). 1H- NMR: 400 MHz, (CD3OD) δ: 8.70 (d, J = 5.6 Hz, 1H), 8.53 (d, J = 6.8 Hz, 1H), 8.11 (s, 1H), 7.82-7.75 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 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 (s, 9H). 19F-NMR: 377 MHz, (CD3OD) δ: -77.8 (s, 3F), -115.5 (br s, IF).
LCMS-ES (m/z): [M+H]+ calcd for C29H26FN204: 485.5; Found: 485.1. A side- product, (S)-2-tert-butoxy-2-((R)-6-carbamoyl-l-(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (106B), was also isolated (2.8 mg). 1H-NMR: 400 MHz, (CD3OD) δ: 8.70 (d, J = 5.6 Hz, 1H), 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). 19F- NMR: 377 MHz, (CD3OD) δ: -77.7 (s, 3F), -118.4 (br s, IF). LCMS-ESI+ (m/z):
[M+H]+ calcd for C2 H28FN2O5: 503.5; Found: 503.1.
Example 105. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 7-fluoro-3-methyl-6-(methylcarbamoyl)naphthalen-2-yl)acetic acid (107):
Figure imgf000296_0001
(S)-ethyl 2-(ferf-butoxy)-2-(6- (S)-ethyl 2-(terf-butoxy)-2-(7- chloro-7-fluoro-3-methyl-1 - fluorc-3-methyl-6- (((trifluoromethyl)sulfonyl)oxy)na (methylcarbamoyl)-l - phthalen-2-yl)acetate (((trifluoromethyl)sulfonyl)oxy)nap
-2-yl)acetate
Figure imgf000296_0002
(S)-ethyl 2-(ieri-butoxy)-2-((S)-1 -(2,3- (S)-ethyl 2-(ferf-butoxy)-2-((R)-1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3- dihydropyrano[4,3,2-de]quinolin-7-yl)- methyl-6-(methylcarbamoyl)naphthalen-2-yl)acetate 7-fluoro-3-methyl-6-
(methylcarbamoyl)naphthalen-2- l)acetate
Figure imgf000296_0003
107
(S)-2-(ferf-butoxy)-2-((R)-1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)- 7-fluoro-3-methyl-6- (methylcarbamoyl)naphthalen-2- yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-6- (methylcarbamoyl)- 1 -(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- (trifluoromethylsulfonyloxy)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 mL, 0.921 mmol). Toluene (1.5 mL) was added and mixture was heated in microwave at 140 °C for 1.5 hour. The reaction mixture was diluted with ethyl acetate, washed brine, dried (MgS04), filtered, concentrated and purified by flash column
chromatography (silica gel, 0 to 50% ethyl acetate/hexanes) to give an off-white solid (19.2 mg). LCMS-ESI+ (m/z): [M+H]+calcd for C22H26F4N07S: 524.5; Found: 524.0.
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3-methyl-6-(methylcarbamoyl)naphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-6- (methylcarbamoyl)- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (19.2 mg, 0.0367 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HC1 salt (11.1 mg, 0.044 mmol), Sphos Palladacycle (3.7 mg, 0.0055 mmol), cesium 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 (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 30 to 80% ethyl acetate/hexanes) to give (S)-ethyl 2-tert- butoxy-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 C32H34FN205: 545.6; Found: 545.1.
The other atropisomer, (S)-ethyl 2-tert-butoxy-2-((S)-l-(2,3- dihydropyrano [4,3 ,2-de] quinolin-7-yl)-7-fluoro-3 -methyl-6- (methylcarbamoyl)naphthalen-2-yl)acetate, was also isolated (7.5 mg). LCMS-ESI1" (m/z): [M+H]+ calcd for C32H34FN205: 545.6; Found: 545.1.
Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-
7-yl)-7-fluoro-3-methyl-6-(methylcarbamoyl)naphthalen-2-yl)acetic acid (107): A solution of (S)-ethyl 2-tert-butoxy-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, 0.012 mmol) and 5 M lithium hydroxide (48 μί, 0.242 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.3 mL) was heated at 55 °C for 3 hours, then overnight at 48 °C.
Additional 5 M lithium hydroxide solution (60 μί) 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% ACN/H20 + 0.1% TFA). Product lyophilized to give a yellow powder (5.0 mg). 1H- NMR: 400 MHz, (CD3OD) δ: 8.70 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.07 (s, 1H), 7.82-7.80 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 12.8 Hz, 1H), 5.24 (s, 1H), 4.76-4.70 (m, 2H), 3.66 (t, J = 6 Hz, 2H), 2.94 (s, 3H), 2.78 (s, 3H), 0.92 (s, 9H). 19F-NMR: 377 MHz, (CD3OD) δ: -77.6 (s, 3F), -115.5 (dd, J = 12.4, 7.16 Hz, IF). LCMS-ESf (m/z): [M+H]+ calcd for C3oH30FN205: 517.6; Found: 517.1.
Example 106. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 6,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (108)
Figure imgf000298_0001
1-(3,4- 108
difluorophenyl)propan-2-one
(S)-2-(ferf-butoxy)-2-((R)-1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7- difluoro-3-methylnaphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-
7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (108): (S)-2-tert-Butoxy-2-
((R)-l-(2,3-dmydropvrano[4,3,2-de]quinolm-7-yl)-6,7-difluoro-3-methylnaphth^ yl)acetic acid (108) was prepared in a similar manner as (S)-2-tert-butoxy-2-((R)-6- chloro- 1 -(2,3 -dihydropyrano[4,3 ,2-de]quinolin-7-yl)-7-fluoro-3 -methylnaphthalen-2- yl)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.
1H-NMR: 400 MHz, (CD3OD) δ: 8.69 (d, J = 5.6 Hz, 1H), 7.96 (s, 1H), 7.83-7.78 (m, 3H), 7.45 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 5.20 (s, 1H), 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, IF), -139.8-139.9 (m, IF). LCMS-ESf (m/z): [M+H]+calcd for
Figure imgf000298_0002
478.5; Found: 478.1. The other atropisomer, (S)-2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-6,7-difluoro-3-methylnaphthalen-2-yl)acetic acid, was prepared in a similar manner. 1H NMR (400 MHz, CD3OD) δ 8.60 (d, J= 5.4 Hz, 1H), 8.12 (d, J= 8.2 Hz, 1H), 7.89 (s, 1H), 7.77 (dd, 7= 11.1, 8.2 Hz, 1H), 7.66 (d, J= 5.4 Hz, 1H), 7.45 (d, J= 8.2 Hz, 1H), 6.71 (dd, 7 = 12.3, 7.9 Hz, 1H), 5.19 (s, 1H), 4.69 (t, J= 6.0 Hz, 2H), 3.60 (t, J= 6.0 Hz, 2H), 2.71 (s, 3H), 0.86 (s, 9H). 19F NMR (377 MHz, CD3OD) δ -78.04 (s), - 139.49 (s), -140.31 (s). LCMS-ESf (m/z): [M+H]+ calcd for C28H26F2N04: 478.5; Found: 478.1.
Example 107. (R)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 6,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (109)
Figure imgf000299_0001
ethyl 2-(6,7-dif luoro-3-methyl-1 - 1 us
(((trifluoromethyl)sulfonyl)oxy)na
phthalen-2-yl)-2-oxoacetate (R)-2-(ferf-butoxy)-2-((f?)-1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7- difluoro-3-methylnaphthalen-2-yl)acetic acid
Preparation of (R)-2-tert-butoxy-2-((R)-l -(2,3 -dihydropyrano [4,3,2- de]quinolin-7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (109): (R)-2-tert- butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7-difluoro-3- methylnaphthalen-2-yl)acetic acid (109) was prepared in a similar manner as (S)-2-tert- butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7-difluoro-3- methylnaphthalen-2-yl)acetic acid of Example 106 except using (S)-2-methyl-CBS- oxazaborolidine instead of (R)-2-methyl-CBS-oxazaborolidine. 1H NMR (400 MHz, CD3OD) δ 8.59 (d, J= 5.3 Hz, 1H), 8.10 (d, J= 8.2 Hz, 1H), 7.88 (s, 1H), 7.76 (dd, J= 11.1, 8.2 Hz, 1H), 7.63 (d, J= 5.3 Hz, 1H), 7.44 (d, J= 8.1 Hz, 1H), 6.71 (dd, J= 12.4, 7.9 Hz, 1H), 5.19 (s, 1H), 4.68 (t, J= 6.0 Hz, 2H), 3.59 (t, J= 6.0 Hz, 2H), 2.70 (s, 3H), 0.85 (s, 8H). 19F NMR (377 MHz, CD3OD) δ -77.84 (s), -139.69 (s), -140.48 (s).
LCMS-ESI+ (m/z): [M+H]+ calcd for C28H26F2N04: 478.5; Found: 478.1.
The other atropisomer, (R)-2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)acetic acid, was prepared in a similar manner. 1H NMR (400 MHz, CD3OD) δ 8.70 (d, J = 5.7 Hz, 1H), 7.96 (s, 1H), 7.86 - 7.76 (m, 3H), 7.45 (d, J = 8.1 Hz, 1H), 6.76 (dd, J = 12.2, 7.9 Hz, 1H), 5.20 (s, 1H), 4.74 (dt, J = 12.4, 6.3 Hz, 2H), 3.66 (t, J = 5.9 Hz, 2H), 2.76 (s, 3H), 0.92 (s, 9H). 19F NMR (377 MHz, CD3OD) δ -77.78 (s, 3F), -138.70 - -139.02 (m, IF), -139.80 - - 139.99 (m, IF). LCMS-ESf (m/z): [M+H]+ calcd for C28H26F2N04: 478.5; Found: 478.1.
Example 108. (S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 5,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (11
1-(2,4-di
Figure imgf000300_0001
(S)-2-(ferf-butoxy)-2-((R)-1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7- difluoro-3-methylnaphthalen-2-yl)acetic acid Preparation of (S)-2-tert-butoxy-2-((R)- 1 -(2,3 -dihydropyrano [4,3 ,2-de] quinolin-
7-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-methylnaphthalen-2- yl)acetic acid (110) was prepared in a similar manner as (S)-2-tert-butoxy-2-((R)-6- cUoro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2- yl)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.
1H-NMR: 400 MHz, (CD3OD) δ: 8.70 (d, J - 6.0 Hz, 1H), 8.16 (s, 1H), 7.82 (d, J - 8.0 Hz, 1H), 7.80 (d, J = 6.0 Hz, 1H),7.45 (d, J = 8.4 Hz, 1H), 7.17 (ddd, J = 8.0, 8.0, 2.4 Hz, lH), 6.43 (d, J = 10.0 Hz, 1H), 5.23 (s, 1H), 4.71-4.70 (m, 2H), 3.66 (t, J = 6.0 Hz, 2H), 2.76 (s, 3H) 0.93 (s, 9H). 19F-NMR: 377 MHz, (CD3OD) δ: -77.9 (s, 3F), -112.86 (d, J = 7.9 Hz, IF), -120.76 (dd, J = 9.0, 9.0 Hz, IF). LCMS-ESf m/z): [M+H]+ calcd for C28H26F2N04: 478.5; Found: 478.1. Example 109. (2S)-2-tert-Butoxy-2-(5-chloro- 1 -(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (111)
Figure imgf000301_0001
(2S)-2-(terNbutoxy)-2-(5-chloro-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-7- fluoro-3-methylnaphthalen-2-yl)acetic acid
Preparation of (2S)-2-tert-butoxy-2-(5-chloro-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (111): (2S)-2-tert-
Butoxy-2-(5-chloro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-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-dihydropyrano[4,3,2-de]quinolin-7-yl)-7- fluoro-3-methylnaphthalen-2-yl)acetic acid of Example 99, except 2-(2-chloro-4- fluorophenyl)acetic acid was used instead of 2-(3-chloro-4-fluorophenyl)acetic acid.
1H-NMR: 400 MHz, (CDC13) δ: 8.59 (s, 1H), 8.30 (s ,1H), 8.1 1 (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-ESI+ (m/z): [M+H]+ calcd for C28H26C1FN04: 494.95; found: 494.1 1.
Example 110. (S)-2-tert-Butoxy-2-((R)- 1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)- 7-fluoro-3,6-dimethylnaphthalen-2-yl)acetic acid (112)
Figure imgf000302_0001
(S)-2-(terf-butoxy)-2-((f?)-1-(2,3- dihydropyrano[4,3,2-cte]quinolin-7- yl)-7-fluoro-3,6- dimethylnaphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-7-fluoro-3,6-dimethylnaphthalen-2-yl)acetic acid (112): (S)-2-tert-butoxy-2-((R)- l-(2,3-dmydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3,6-dimethylnaphthalen-2- yl)acetic acid (112) was prepared following the procedure to make (S)-2-tert-butoxy-2- ((R)-6-chloro- 1 -(2,3 -dihydropyrano [4,3 ,2-de] quinolin-7-yl)-7-fluoro-3 - methylnaphthalen-2-yl)acetic acid of Example 99, except 2-(4-fluoro-3- methylphenyl)acetic acid was used instead of 2-(3-chloro-4-fluorophenyl)acetic acid. Ή-NMR: 400 MHz, (CD3OD) δ: 8.66 (d, J = 5.76 Hz, 1H), 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-ESf (m/z): [M+H]+ calcd for C29H29FN04: 474.54; found: 474.14.
Example 111. (S)-2-tert-Butoxy-2-((R)-5-cyano-l -(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (113A) and (S)-2-tert- Butoxy-2-((R)-5-carbamoyl-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3- methylnaphthalen-2-yl)acetic acid (113B)
2 steps
Figure imgf000303_0001
(S)-ethyl 2-(ferf-butoxy)-2-(5- chloro-7-fluoro-3-methyl-1 - (((trifluoromethyl)sulfonyl)oxy)
naphthalen-2-yl)acetate
Figure imgf000303_0002
113B
113A
(S)-2-(feri-butoxy)-2-((R)-5-
(S)-2-(terf-butoxy)-2-((/?)-5-cyano- carbamoyl-1-(2,3- 1 -(2,3-dihydropyrano[4,3,2- dihydropyrano[4,3,2-cte]quinolin-7-yl)- de]quinolin-7-yl)-7-fluoro-3- 7-fluoro-3-methylnaphthalen-2- methylnaphthalen-2-yl)acetic acid
yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-((R)-5-cyano-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (113A): (S)-2-tert- butoxy-2-((R)-5-cyano-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3- methylnaphthalen-2-yl)acetic acid (113 A) was prepared following the procedure to make (S)-2-tert-butoxy-2-((R)-6-cyano-l-(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-tert- butoxy-2-(5-chloro-7-fluoro-3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2- yl)acetate was used instead of (S)-ethyl 2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. 1H-NMR: 400 MHz, (CD3OD) δ: 8.64 (d, J = 5.48 Hz, 1H), 8.22 (s ,1H), 7.92 (t, J= 7.75 Ηζ,ΙΗ), 7.76 (d, J = 7.82 Hz, 1H), 7.68 (t, J = 10.56Hz, 1H), 7.38 (d, J =7.72 Hz, 1H), 6.98 (m, 1H), 5.21 (s, 1H), 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) δ: -77.8 (s, 3F), -1 15.5 (br s, IF). LCMS-ESf (m/z):
[M+H]+ calcd for C29H26FN204: 485.52; found: 485.09.
Preparation of (S)-2-tert-butoxy-2-((R)-5-carbamoyl-l-(2,3- dihydropyrano [4,3 ,2-de] quinolin-7-yl)-7-fluoro-3 -methylnaphthalen-2-yl)acetic acid (113B): Following the procedure to make (S)-2-tert-butoxy-2-((R)-6-carbamoyl-l-(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-tert-butoxy-2-(5-chloro-7-fluoro-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was used instead of (S)-ethyl 2- tert-butoxy-2-(6-chloro-7-fluoro-3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2- yl)acetate. 1H-NMR: 400 MHz, (CD3OD) δ: 8.64 (d, J = 5.48 Hz, 1H), 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),7.40 (d, J = 8.22 Hz, 1H), 6.68(m, 1H), 5.21 (s, 1H), 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 C29H28F 205: 503.53; found: 503.12.
Example 112. (S)-2-tert-butoxy-2-((R)- 1 -(2,3-dihydropyrano [4,3 ,2-de]quinolin-7-yl)- 7-fluoro-3-memyl-5-(pyrimidin-5-yl)naphthalen-2-yl)acetic acid (114)
Figure imgf000305_0001
(S)-ethyl 2-(feri-butoxy)-2-((R)-
5-chloro-1-(2,3- dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3- methylnaphthalen-2-yl)acetate
Figure imgf000305_0002
114
(S)-ethyl 2-(te/-f-butoxy)-2-((R)-1 -(2,3
dihydropyrano[4,3,2-cte]quinolin-7-yl)- 7-fluoro-3-methyl-5-(pyrimidin-5-
(S)-2-(ierf-butoxy)-2-((R)-1-(2,3- yl)naphthalen-2-yl)acetate dihydropyrano[4,3,2-de]quinolin-7- yl)-7-fluoro-3-methyl-5-(pyrimidin-5- yl)naphthalen-2-yl)acetic acid
Preparation of(S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3-methyl-5-(pyrimidin-5-yl)naphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-((R)-5-chloro-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-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.), cesium 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 (MgS04), 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-de]quinolin-7-yl)-7-fluoro-3-methyl-5-(pyrimidin-5- yl)naphthalen-2-yl)acetate (4 mg). LCMS-ESf (m/z): [M+H]+ calcd for C34H33FN304: 566.63; Found: 566.3.
Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-7-fluoro-3-memyl-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-7- yl)-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 ethanol (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 (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give a yellow powder (1.2 mg). 1H-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).
19F-NMR: 377 MHz, (CD3OD) 5: -77.7 (s, 6F), -115.9 (m, IF). LCMS-ESf (m/z): [M+H]+calcd for C32H39FN304: 538.58 ; Found: 538.03.
Example 113. (S)-2-tert-Butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2- de]quinol -7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetic acid (115)
Figure imgf000306_0001
115
(S)-2-(terf-butoxy)-2-((f?)-6- chloro-1-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-5-fluoro-3- methylnaphthalen-2-yl)acetic acid Preparation of (S)-2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetic acid (115): (S)-2-tert- Butoxy-2-((R)-6-chloro- 1 -(2,3 -dihydropyrano [4,3 ,2-de] quinolin-7-yl)-5 -fluoro-3 - methylnaphthalen-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]quinolin-7-yl)-7- fluoro-3-methylnaphthalen-2-yl)acetic acid of Example 99 , except 2-(3-chloro-2- fluorophenyl)acetic acid was used instead of 2-(3-chloro-4-fluorophenyl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 8.69 (d, J = 5.87 Hz, 1H), 8.18 (s ,1H), 7.80 (m ,2H), 7.42(d, J = 7.72 Hz, 1H), 7.26(t, J = 7.43 Hz, 1H), 6.78 (d, J = 9.38 Hz, 1H), 5.22(s, 1H), 4.64 (m, 2H), 3.62 (t, J = 5.86 Hz, 2H), 2.80(s, 3H), 0.98 (s, 9H). 19F-NMR: 377 MHz, (CD3OD) δ: -77.7 (s, 3F), -127.87 (d, IF). LCMS-ESf (m/z): [M+H]+calcd for C28H26C1FN04: 494.95; found: 494.07. Example 114. (S)-2-tert-Butoxy-2-((R)-5-chloro-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetic acid (116)
Figure imgf000307_0001
116
(S)-2-(terf-butoxy)-2-((R)-5-chloro-1- (2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3,6- dimethylnaphthalen-2-yl)acetic acid
Preparation 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.), tributylmethoxytin (1.11 mL, 1.5 eq.), 4-methylpent-4-en-2-one (0.42 mL, 1.5 eq.), PdCl2 (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 diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to l -(2-chloro-3-methylphenyl)propan-2- one (375 mg, 80% yield). 1H-NMR: 400 MHz, (CDC13) δ : 7.19-7.02 (m, 3H), 3.82(s, 2H), 2.38(s, 3H), 2.18 (s, 3H).
Preparation of (S)-2-tert-butoxy-2-((R)-5-chloro-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-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-2- yl)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-3- methylnaphthalen-2-yl)acetic acid, used l-bromo-2-chloro-3-methylbenzene instead of 2-(3-chloro-4-fluorophenyl)acetic acid. 1H-NMR: 400 MHz, (CD3OD) δ : 8.59 (d, J = 5.08 Hz, 1H), 8.26 (s ,1H), 7.68 (m ,2H), 7.34 (d, J = 8.21 Hz, 1H), 7.08(d, J = 8.60 Hz, 1H), 6.72 (d, J = 8.50 Hz, 1H), 5.16(s, 1H), 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
C29H29C1N04: 490.99; found: 490.33.
Example 1 15. (S)-2-tert-Butoxy-2-((R)- 1 -(2,3 -dihydropyrano[4,3 ,2-de]quinolin-7-yl)- 3,5,6-trimethylnaphthalen-2-yl)acetic acid (117)
Figure imgf000309_0001
117
(S)-2-(fert-butoxy)-2-((R)-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)- 3,5,6-trimethylnaphthalen-2-yl)acetic acid
Preparation (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3,5,6-trimethylnaphthalen-2-yl)acetate: A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-((R)-5-chloro-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetate (16 mg, 0.031 mmol, 1 eq.), methylboronic acid (4 mg, 2 eq.), Sphos Palladacycle (2 mg, 0.1 eq.), cesium fluoride (19 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 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), 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-de]quinolin-7-yl)-3,5,6- trimethylnaphthalen-2-yl)acetate (7 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for
C32H36N04: 498.62; Found: 498.1.
Preparation of (S)-2-tert-butoxy-2-((R)- 1 -(2,3 -dihydropyrano [4,3 ,2-de]quinolin- 7-yl)-3,5,6-trimethylnaphthalen-2-yl)acetic acid (117): A solution of (S)-ethyl 2-tert- butoxy-2-((R)-l-(2,3-dmydropyrano[4,3,2-de]qumolm-7-yl)-3,5,6-1ximethylnaphthalen- 2-yl)acetate (7 mg) and 2 M sodium hydroxide (0.5 mL) in tetrahydrofuran (0.5 mL) and ethanol (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 (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100%
ACN H20 + 0.1% TFA). Product lyophilized to give a yellow powder (4.7 mg). Ή- NMR: 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-ES (m/z): [M+H]+ calcd for C30H32NO4: 470.57; Found: 470.39.
Example 116. (S)-2-tert-Butoxy-2-((R)-5-cyano-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetic acid (118)
Figure imgf000310_0001
118
(S)-2-(terf-butoxy)-2-((R)-5-cyano-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6- dimethylnaphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-((R)-5-cyano-l -(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetic acid (118): (S)-2-tert-butoxy-2- ((R)-5-cyano-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2- yl)acetic acid (118) was prepared following the procedure to make (S)-2-tert-butoxy-2- ((R)- 1 -(2,3 -dihydropyrano[4,3 ,2-de]quinolin-7-yl)-3 ,5 ,6-trimethylnaphthalen-2- yl)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 H20 + 0.05% TFA, 7 minutes run): tR (min) = 4.00. 1H-NMR: 400 MHz, (CD3OD) δ : 8.59 (d, J = 5.48 Hz, 1H), 8.09 (s ,1H), 7.64 (d, J - 8.21 Hz, 1H), 7.62 (d, J = 4.08 Hz, 1H), 7.36 (d, J = 8.21 Hz, 1H), 7.19 (d, J = 8.61 Hz, 1H), 7.12 (d, J = 8.98 Hz, 1H), 5.16 (s, 1H), 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-ESf (m/z): [M+H]+ calcd for
C3oH29N404: 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-dimethylnaphthalen-2-yl)acetic acid (119)
Figure imgf000311_0001
(S)-ethyl 2-(feri-butoxy)-2-((R)-6- (S)-ethy I 2-(terf-butoxy)-2-((R)-1 - chloro-1-(2,3-dihydropyrano[4,3,2- (2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-5-fluoro-3- de]quinolin-7-yl)-5-fluoro-3,6- methylnaphthalen-2- l)acetate dimethylnaphthalen-2-yl)acetate
Figure imgf000311_0002
119
(S)-2-(ferf-butoxy)-2-((R)-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7- yl)-5-fluoro-3,6-dimethylnaphthalen- 2-yl)acetic acid
Preparation (S)-ethyl 2-tert-butoxy-2-((R)- 1 -(2,3 -dihydropyrano[4,3 ,2- de]quinolin-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-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate (10 mg, 0.019 mmol, 1 eq.), methylboronic acid (2 mg, 1.5 eq.), Sphos Palladacycle (1.3 mg, 0.1 eq.), cesium 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 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), 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-de]quinolin-7-yl)-5- fluoro-3,6-dimethylnaphthalen-2-yl)acetate (6 mg). LCMS-ES (m/z): [M+H]+ calcd for C31H33FN04: 502.59; Found: 502.1.
Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-
7-yl)-5-fluoro-3,6-dimethylnaphthalen-2-yl)acetic acid (119): A solution of (S)-ethyl 2-tert-butoxy-2-((R)- 1 -(2,3 -dihydropyrano [4,3 ,2-de] quinolin-7-yl)-5 -fluoro-3 ,6- dimethylnaphthalen-2-yl)acetate (6 mg) and 2 M sodium hydroxide (0.5 mL) in tetrahydrofuran (0.5 mL) and ethanol (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 (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give a yellow powder (4.7 mg). 1H-NMR: 400 MHz, (CD3OD): δ 8.67 (d, J = 5.47 Hz, 1H), 8.12(s, 1H), 7.78 (t, J = 5.87 Hz, 2H), 7.43 (d, J = 8.82 Hz, 1H), 7.1 1 (t, J = 8.21 Hz, 1H), 6.63 (d, J = 8.60 Hz, 1H), 5.22 (s, 1H), 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). 19F-NMR: 377 MHz, (CD3OD) δ: -77.7 (s, 3F), -131.6 (d, IF). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H29FN04: 474.54; Found: 474.33.
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)
Figure imgf000313_0001
120
(S)-2-(ferf-butoxy)-2-((R)-1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl- 5-fluoro-3-methylnaphthalen-2-yl)acetic acid
Preparation 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)-l-(2,3-dmydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-5-fluoro-3- methylnaphthalen-2-yl)acetic acid (120) was prepared following the procedure to make
(S)-2-tert-butoxy-2-((R)-l-(2,3-dmydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3,6- dimethylnaphthalen-2-yl)acetic acid of Example 117, except that ethylboronic acid was used instead of methylboronic acid. Analytical HPLC (Gemini, 2-98% ACN/H20 +
0.05% TFA, 7 minutes run): tR (min) = 4.00.
1H-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) δ: -77.7 (s, 3F), -133.06 (d, IF). LCMS-ESI+ (m/z): [M+H]+ calcd for C3oH31FN04: 488.56 (M+H+); Found:
488.37. Example 119. (S)-2-tert-Butoxy-2-((R)-6-(difluoromethyl)- 1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetic acid (121)
Figure imgf000314_0001
(S)-ethyl 2-(ferf-butoxy)-2-((R)-1- (2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-5-fluoro-6-formyl- -methylnaphthal -2-yl)acetate
Figure imgf000314_0002
(S)-ethyl 2-(ierf-butoxy)-2-((R)-6-
121
(difluoromethyl)-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-5-
(S)-2-(iert-butoxy)-2-(( ?)-6- fluoro-3-methylnaphthalen-2-yl)acetate
(difluoromethyl)-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-5- fluoro-3-methylnaphthalen-2-yl)acetic acid
Preparation (S)-ethyl 2-tert-butoxy-2-((R)- 1 -(2,3 -dihydropyrano[4,3 ,2- de]quinolin-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-l-(2,3- dmy(kopyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate (99 mg, 0.19 mmol, 1 eq.), potassium vinyltrifluoroborate (28 mg, 1.1 eq.), Sphos Palladacycle (13 mg, 0.1 eq.), cesium fluoride (114 mg, 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 (MgS04), 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-dmydropyrano[4,3,2-de]qumolin-7-yl)-5-fluoro-3-memyl-6-vinylnaphthalen-2- yl)acetate (69 mg, 71% yield). LCMS-ESI+ (m/z): [M+H]+calcd for C32H33FN04: 514.60; Found: 514.1.
Preparation (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yI)-5-fluoro-6-formyl-3-methylnaphthalen-2-yl)acetate: (S)-ethyl 2-tert- butoxy-2-((R)-l-(2,3-dmydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methyl-6- vinylnaphthalen-2-yl)acetate (32 mg, 0.062 mmol, 1 eq.) was dissolved in 2 mL THF. This solution was added to the mixture of NaI04 (40 mg, 3 eq.) and K20s04«2H20 (2.3 mg, 0.1 eq.) in 1 mL water at room temperature. The reaction was complete after stirring at room temperature for 30 minutes. The reaction mixture was filtered, the filtrate was diluted with ethyl acetate and washed with brine, dried (MgS04), 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- de]qumolin-7-yl)-5-fluoro-6-formyl-3-methylnaphthalen-2-yl)acetate as a light yellow oil (26 mg, 81% yield). LCMS-ESf (m/z): [M+H]+ calcd for C31H31FN05: 516.57; Found: 516.1.
Preparation (S)-ethyl 2-tert-butoxy-2-((R)-6-(difluoromethyl)- 1 -(2,3 - dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate: (S)- ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6- formyl-3-methylnaphthalen-2-yl)acetate (8 mg) was dissolved in 0.5 mL DCM.
Deoxofluor (50 μί, excess) was added to the solution. The reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), 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)-6-(difluoromethyl)- 1 -(2,3-dihydropyrano[4,3 ,2-de]quinolin-7-yl)-5- fluoro-3-methylnaphthalen-2-yl)acetate as a light yellow oil (6 mg, 76% yield). LCMS- ESf (m/z): [M+H]+ calcd for C31H3iF3N05: 538.57; Found: 538.34.
Preparation of (S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)-l-(2,3- dihydropyrano[4,3,2-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-(2,3- dihy(kopyrano[4,3,2-de]qumolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate (6 mg) in tetrahydrofuran (0.5 mL) and ethanol (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 (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give a yellow powder (4.7 mg). 1H-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). 19F-NMR: 377 MHz, (CD3OD) δ: -77.7 (s, 3F), -113.97 to -116.29 (m, 2F), -131.6 (s, IF). LCMS-ESf
(m/z): [M+H]+ calcd for C29H27F3N04: 510.52; Found: 510.36.
Example 120. (2S)-2-tert-butoxy-2-(l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4- fluoro-3-methylnaphthalen-2-yl)acetic acid (122).
Figure imgf000317_0001
1 -(4-bromophenyl)propan-2-one ethyl 4-(4-bromophenyl)- 3-methylbut-2-enoate
Figure imgf000317_0002
7-bromo-3- 3-methylnaphthalen-1 -ol ethyl 2-hydroxy-2-(1-hydroxy- methylnaphthalen-1 -ol 3
ethyl
Figure imgf000317_0003
2-reri-butoxy-2-(1-hydroxy- 3-methylnaphthalen-2-yl)acetate ethyl 2-terf-butoxy-2-(4-fluoro-1 -hydroxy- 3-meth lna hthalen-2- l acetate
Figure imgf000317_0004
ethyl 2-ferf-butoxy-2-(4-fluoro- 3-methyl-1-(trifluoromethylsulfonyloxy
)naphthalen-2-yl)acetate ethyl 2-(4-fluoro-3-methyl-1-
(trifluoromethylsulfonyloxy)naphthalen
-2-yl)-2-hydroxyacetate
Figure imgf000318_0001
ethyl 2-(4-f luoro-3-methyl-1 - (S)-ethyl 2-(4-f luoro-3-methyl-1 -
(trifluoromethylsulfonyloxy) (trifluoromethylsulfonyloxy)nap
naphthalen-2-yl)-2-oxoacetate hthalen-2-yl)-2-hydroxyacetate
Figure imgf000318_0002
122
(S)-2-terf-butoxy-2-((R)-1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7- yl)-4-fluoro-3-methylnaphthalen-2- yl)acetic acid
Preparation 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-bromophenyl)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 overnight. The next day, saturated NH4CI (250 mL) was added. After 2 h, the reaction was diluted with H20 (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 (MgS04), filtered, and concentrated, giving crude 4-(4-bromophenyl)-3-methylbut-2-enoate as a mixture of E and Z geometric isomers. The residue was carried onward without further purification. (-30 grams; yield was not determined). The 1H NMR reported below was from a crude mixture containing both the E and Z isomer.
1H NMR (400 MHz, CDC13) 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).
Preparation of 7-bromo-3-methylnaphthalen-l-ol: A flask containing the crude ethyl 4-(4-bromophenyl)-3-methylbut-2-enoate from above (~ 30 grams) was treated with concentrated H2S04 (120 mL) and warmed 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 NaHC03, dried (MgS04), filtered, and concentrated to - 55 mL. 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 (16.6 g, 60% yield over 2 steps from l-(4-bromophenyl)propan-2- one. 1H NMR (400 MHz, CDC13) δ 8.29 (d, J = 1.9 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.50 (dd, J = 8.6, 2.0 Hz, 1H), 7.17 (s, 1H), 6.67 (s, 1H), 2.42 (s, 3H).
Preparation of 3 -methylnaphthalen- 1 -ol : A slurry of 7-bromo-3 - methylnaphthalen-l-ol (100 mg, 0.421 mmol), 10% w/w Pd/C (45 mg, 42.1 μπιοΐ 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). 1H NMR (400 MHz, CDC13) δ 8.10 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.47-7.39 (m, 2H), 7.22 (s, 1H), 6.67 (s, 1H), 2.45 (s, 3H).
Preparation of ethyl 2-hydroxy-2-(l-hydroxy-3-methylnaphthalen-2-yl)acetate: A flask containing DCM (5.0 mL) was charged with TiCL, (1.0 M in DCM, 3.16 mL, 3.16 mmol). After cooling to -40 °C (dry ice/CH3CN bath), a solution of 3- methylnaphthalen-l-ol (500 mg, 3.16 mmol) in DCM (5.0 mL) was added dropwise over a 5 min period. The reaction turned deep violet. After 30 min, a solution of ethyl glyoxylate (323 mg, 3.16 mmol, distilled freshly from P205 under 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 later, CH3CN (5.0 mL) was introduced, followed by ¾0 (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 H20 (15 mL) and extracted with DCM (3 x 20 mL). The combined extracts were washed with saturated NaHC03 (20 mL) (this decolorized the organic phase from orange to yellow), dried (Na2S04), filtered, concentrated, treated with 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) giving the desired product (622 mg, 76% yield). 1H MR (400 MHz, CDC13) δ 8.41 (s, 1H), 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).
Preparation of ethyl 2-tert-butoxy-2-(l-hydroxy-3-methylnaphthalen-2- yl)acetate: A solution of ethyl 2-hydroxy-2-(l-hydroxy-3-methylnaphthalen-2- yl)acetate (622 mg, 2.39 mmol) in tert-butyl acetate (12 mL) was treated with 70%
HCIO4 (20 μL) at 23 °C). After 3 h, the reaction was added slowly over 5 min to saturated NaHC03 (25 mL). The resulting system was extracted with DCM (3 x 15 mL). The combined organic layers were dried (Na2S04), 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) giving the desired product (286 mg, 38% yield). 1H 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).
Preparation of ethyl 2-tert-butoxy-2-(4-fluoro-l-hydroxy-3-methylnaphthalen- 2-yl)acetate: A solution of ethyl 2-tert-butoxy-2-(l-hydroxy-3-methylnaphthalen-2- yl)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 warm to 23 °C. After 2 h, the reaction was added slowly to a mixture of saturated Na2HP04 (70 mL) and H20 (30 mL) at 23 °C. More H20 (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
(Na2S04), 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 purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (1.26 g, 79%). 1H NMR (400 MHz, CDC13) δ 8.83 (s, 1H), 8.23 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 6.9, 6.9 Hz, 1H), 7.45 (dd, J = 6.9, 6.9 Hz, 1H), 5.46 (s, 1H), 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, CDC13) δ -137.3 (app. s).
Preparation of ethyl 2-tert-butoxy-2-(4-fluoro-3-methyl- 1 - (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: A flask was charged with Cs2C03 (2.45 g, 7.53 mmol) and N-phenyltriflimide (2.69 g, 7.53 mmol). A solution of ethyl 2- tert-butoxy-2-(4-fluoro-l-hydroxy-3-methylnaphthalen-2-yl)acetate (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 NaHS04 (30 mL) and saturated Na2HP04 (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 (Na2S04), 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 purified by flash chromatography (hexane→ ethyl acetate/hexanes 1 :4) giving the desired product (1.75 g, >99%). 1H NMR (400 MHz, CDC13) δ 8.11-8.02 (m, 2H), 7.66-7.60 (m, 2H), 5.72 (s, 1H), 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). 1 F NMR (377 MHz, CDC13) δ -123.1 (app. s, IF), -73.4 (s, 3F)
Preparation of ethyl 2-(4-fluoro-3 -methyl- l-(trifluoromethylsulfonyl- oxy)naphthalen-2-yl)-2-hydroxyacetate: A solution of ethyl 2-tert-butoxy-2-(4-fluoro- 3 -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 H20 (60 mL) and the system was extracted with DCM (3x 20 mL). Combined organic layers were dried (Na2S04), filtered, and concentrated giving the crude desired product (~ 1.54 g obtained), which was used in the next reaction. 1H NMR (400 MHz, CDC13) δ 8.11-8.06 (m, 1H), 7.67-7.64 (m, 1H), 7.61- 7.52 (m, 2H), 7.41 (d, J = 7.8 Hz, 1H), 5.79 (s, 1H), 4.34-4.22 (m, 2H), 2.40 (d, JHF = 3.2 Hz, 3H), 1.22 (t, J = 7.4 Hz, 3H). 19F NMR (377 MHz, CDC13) δ -122.6 (app. s, IF), -73.3 (s, 3F).
Preparation of ethyl 2-(4-fluoro-3-memyl-l-(trifluoromethylsulfonyl-oxy)naphthalen-2- yl)-2-oxoacetate: A solution of ethyl 2-(4-fluoro-3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (~ 1.54 g, 3.76 mmol) in 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% Na2S203 (28 mL) at 23 °C. After 5 rnin of stirring, the reaction was diluted with H20 (40 mL) and extracted with DCM (3 x 20 mL). Combined organic layers were dried (Na2S04), 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-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate). 1H NMR (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, JHF = 3.2 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H). 19F NMR (377 MHz, CDC13) δ -122.3 (app. s, IF), -73.3 (s, 3F).
Preparation of (S)-ethyl 2-(4-fluoro-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate: A solution of ethyl 2- (4-fluoro-3 -methyl- 1 -(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 ί) 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% Na2C03 (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% Na2C03 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 (MgS04), 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 (1.02 g, 94% yield). 1H NMR (400 MHz, CDC13) δ 8.11-8.06 (m, 2H), 7.67-7.64 (m, 2H), 5.79 (s, 1H), 4.33-4.22 (m, 2H), 2.40 (d, JHF = 3.2 Hz, 3H), 1.22 (t, J = 7.4 Hz, 3H). 19F NMR (377 MHz, CDC13) δ -122.6 (app. s, IF), -73.1 (s, 3F).
Preparation of (S)-ethyl 2-tert-butoxy-2-(4-fluoro-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: A solution of (S)-ethyl 2-(4- fluoro-3-memyl-l-(trifIuoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (1.02 g, 2.49 mmol) in tert-butyl acetate (20 mL) was treated with 70% HC104 (20 μί) at 23 °C). After 5 h, the reaction was added slowly over 5 min to saturated NaHC03 (40 mL). The resulting system was extracted with DCM (3 x 30 mL). The combined organic layers were dried (Na2S04), 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). 1H NMR (400 MHz, CDC13) δ 8.11- 8.02 (m, 2H), 7.65-7.60 (m, 2H), 5.72 (s, 1H), 4.25-4.13 (m, 2H), 2.45 (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 (ap s, IF), -73.3 (s, 3F).
Preparation of (2S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]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, 2- de]quinolin-7-ylboronic 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-butoxy- 2-(4-fluoro-3 -methyl- 1 -(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 cooled to 23 °C and combined by adding to a mixture of brine (30 mL) and H20 (30 mL). The system was extracted with EtOAc (3 x 30 mL). Combined organic layers were dried (Na2S04), 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-loaded onto a 24 g "gold" ISCO silica gel column and purified by flash chromatography (hexane→ ethyl acetate) giving the desired product (2S)-ethyl 2- tert-butoxy-2-((R)- 1 -(2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-4-fluoro-3 - methylnaphthalen-2-yl)acetate (163 mg, 21% yield). 1H NMR (400 MHz, CDC13) 5 8.16 (d, J = 8.6 Hz, 1H), 7.61-7.18 (m, 6H), 6.92 (d, broad, J = 8 Hz, 1H), 5.25 (s, broad, 1H), 4.75-4.60 (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). 19F NMR (377 MHz, CDC13) δ -122 (s, broad) LCMS-ES (m/z): calcd for C3oH30FN04: 488.2 (M+H+); Found: 488.3
(M+H+). The other diastereomer was also obtained; (2S)-ethyl 2-tert-butoxy-2-((S)-l- (2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-rnethylnaphthalen-2-yl)acetate (208 mg, 27% yield):
1H NMR (400 MHz, CDC13) δ 8.13 (d, J = 8.6 Hz, 1H), 7.50-7.16 (m, 6H), 6.88 (d, J = 8.2 Hz, 1H), 5.15 (s, 1H), 4.72-4.60 (m, 2H), 4.30-4.00 (m, 2H), 3.49-3.38 (m, 2H), 2.61 (d, JHF = 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-ESI+ (m/z): [M+H]+ calcd for C30H31FNO4:
488.2; Found: 488.3.
Preparation of (2S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]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-fluoro- 3-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 H20 (2.0 mL). The mixture was stirred vigorously at 100 °C for 2 h. More LiOH
monohydrate (600 mg, 14.2 mmol) and H20 (500 μΐ,) 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 filtrate was purified on a CI 8 Gemini column (Eluent:
H20/CH3CN 95:5→ 0:100 spiked with 0.1% v/v TFA), giving (2S)-2-tert-butoxy-2- ((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2- yl)acetic acid as the mono-trifluoroacetic acid salt (124 mg, 64%). 1H NMR (400 MHz, CD3OD) δ 8.68 (d, J = 5.8 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 5.4 Hz, 1H), 7.60 (dd, J = 7.9, 7.4 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.36 (dd, J = 7.9, 7.4 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 5.19 (s, 1H), 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-ESI+ (m/z): [M+H]+ calcd for C28H27FN04: 460.2; Found: 460.2. The other diastereomer, (2S)-2-tert-butoxy-2-((S)-l-(2,3- dihydropyrano[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)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetate: Ή 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). 1 F NMR (377 MHz, CD3OD) δ -105.6 (s, IF), -77.6 (s, 3F).
LCMS-ESf (m/z): [M+H]+ calcd for C28H27FN04: 460.2; Found: 460.5.
Example 121. (±)-(2S)-2-tert-Butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (123)
Figure imgf000325_0001
1 -(4-f luoropheny l)propan-2-one ethy, 2-ieri_butoxy-2-(7-f luoro-3-methyl-
1 -(trif luoromethylsulfonyloxy)
naphthalen-2-yl)acetate
Figure imgf000325_0002
(S)-ethyl 2-te/-f-butoxy-2-((/?)-1-(2,3- 123
di ydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3- (S)-2-ferf-butoxy-2-((R)-1 - methylnaphthalen-2-yl)acetate (2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3- methylnaphthalen-2- yl)acetic acid
Preparation of ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-l -(trifluoromethyl- sulfonyloxy)naphthalen-2-yl)acetate: Prepared in a similar manner as 2-tert-butoxy-2- (7-chloro-3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate of Example 146 except using 1 -(4-fluorophenyl)propan-2-one. 1H NMR (400 MHz, CDCI3) δ 7.79 (dd, JHH = 9.0 Hz, 5.4 Hz, 1H), 7.66 (s, 1H), 7.65 (dd, JHF = 9.0 Hz, ½Η= 2.3 Hz, 1H), 7.38 (ddd, , JHH = 9.0 Hz, , ½ = 8.0 Hz, , JHH = 2.3 Hz, 1H), 5.72 (s, 1H), 4.25- 4.10 (m, 2H), 2.54 (s, 3H), 1.20 (s, 9H), 1.18 (t, J = 7.0 Hz, 3H). iyF NMR (377 MHz, CDC13) δ -112.0 (ddd, , JHF = 9.0, 8.0, 5.4 Hz ,1F), -73.4 (s, 3F).
Preparation of (±)-(S)-ethyl 2-tert-butoxy-2-((R)l -(2,3 -dihydropyrano [4,3,2- de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate: Prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-((R)-6-chloro- 1 -(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate of Example 99 expect using ethyl 2-tert-butoxy-2-(7-fluoro-3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate as starting material and S-Phos- palladacycle as the catalyst, giving the product as a racemate. LCMS-ESI* (m/z): calcd for C3oH3oFN04: 488.2 (M+H^; Found: 488.2 (M+H+). The other diastereomer (±)- (2S)-ethyl 2-tert-butoxy-2-((S) 1 -(2,3 -dihydropyrano [4,3 ,2-de]quinolin-7-yl)-7-fluoro- 3-methylnaphthalen-2-yl)acetate was also isolated via silica gel chromatography.
LCMS-ESI+ (m/z): [M+H]+ calcd for C30H31FNO4: 488.2; Found: 488.2.
Preparation of (±)-(S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid (123): Prepared in a similar manner as (S)-2-tert-butoxy-2-((R)-6-chloro-l-(2,3-dihydropyrano[4,3,2- de]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-yl)acetate as the starting material, giving the racemate of the desired product as the mono-trifluoroacetic acid salt. !H NMR (400 MHz,
CD3OD) δ 8.68 (d, J = 5.5 Hz, 1H), 8.02-7.97 (m, 2H), 7.81-7.75 (m, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.32 (ddd, J = 5.4, 5.4, 2.4 Hz, 1H), 6.54 (dd, J = 10.0, 2.3 Hz, 1H), 5.24 (s, 1H), 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, IF), -77.6 (s, 3F). LCMS-ESf (m/z): [M+H]+ calcd for C28H27FN04: 460.2; Found: 460.4.
The other racemate, (±)-(S)-2-tert-butoxy-2-((S)-l-(2,3-dihydropyrano [4,3,2- de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetic acid , was prepared in a similar manner. 1H NMR (400 MHz, CD3OD) δ 8.61 (d, J = 5.8 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 5.5 Hz, 1H), 7.58 (dd, J = 7.0, 6.8 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.34 (dd, J = 7.0, 6.8 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 5.20 (s, 1H), 4.72 (dd, J = 6.2, 6.2 Hz, 2H), 3.64 (dd, J = 6.2, 6.2 Hz, 2H), 2.64 (d, JHF = 3.2 Hz, 3H), 0.86 (s, 9H). 19F NMR (377 MHz, CD3OD) δ -77.8 (s).
LCMS-ESf (m/z): [M+H]+ calcd for C28H27FN04: 460.2; Found: 460.4. Example 122. (2S)-2-tert-Butoxy-2-((R)-7-chloro-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-m
Figure imgf000327_0001
ethyl 2-ierNbutoxy-2-(7^hloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate
Figure imgf000327_0002
(±)-(S)-ethyl 2-ieri-butoxy-2-((R)-7- (±)-(S)-2-ferf-butoxy-2-((f?)-7-chloro-1 -(2,3- chloro-1-(2,3-dihydropyrano[4,3,2- dihydropyrano[4,3,2-de]quinolin-7-yl)-3- de]quinolin-7-yl)-3-methylnaphthalen-2- methylnaphthalen-2-yl)acetic acid
yl)acetate
Preparation 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-l-(2,3-dihydropyrano[4,3,2- de]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-(trifluoro- methylsulfonyloxy)naphthalen-2-yl)acetate as the starting material. LCMS-ESI+ (m/z):
[M+H]+ calcd for C30H31ClNO4: 504.2; Found: 504.2. The other racemate (±)-(2S)- ethyl 2-tert-butoxy-2-((S)(7-cUoro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetate was also isolated via silica gel chromatography. LCMS- ESI+ (m/z): [M+H]+ calcd for C30H31ClNO4: 504.2; Found: 504.2.
Preparation of (±)-(S)-2-tert-butoxy-2-((R)-7-chloro- 1 -(2,3 - dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid (124): (±)- (S)-2-tert-butoxy-2-((R)-7-cUoro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid (124) was prepared in a similar manner as (S)-2-tert- butoxy-2-((R)-6-chloro- 1 -(2,3 -dihydropyrano [4,3 ,2-de] quinolin-7-yl)-7-fluoro-3 - methylnaphthalen-2-yl)acetic acid of Example 99, except using (±)-(S)-ethyl 2-tert- butoxy-2-((R)-7-chloro-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetate as the starting material, giving the racemate of the desired product as the mono-trifluoroacetic acid salt. 1H NMR (400 MHz, CD3OD) δ 8.69 (d, J = 5.5 Hz, 1H), 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, 1H), 5.22 (s, 1H), 4.77-4.67 (m, 2H), 3.67-3.62 (m, 2H), 2.77 (s, 3H), 0.93 (s, 9H). 19F NMR (377 MHz, CD3OD) δ -77.6 (s). LCMS-ESI+ (m/z): calcd for C28H26C1N04: 476.2 (M+H+); Found: 476.1 (M+FT). The other racemate, (±)-(S)-2- tert-butoxy-2-((S)-7-chloro- 1 -(2,3 -dihydropyrano[4,3 ,2-de]quinolin-7-yl)-3 - methylnaphthalen-2-yl)acetic acid, was prepared in a similar manner. 1H NMR (400 MHz, CD3OD) 6 8.55 (d, J = 5.1 Hz, 1H), 8.00 (d, J = 6.8 Hz, 1H), 7.88-7.84 (m, 2H), 7.48 (d, broad, J = 4 Hz, 1H), 7.40 (dd, J = 8.6, 1.8 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 1.8 Hz, 1H), 5.20 (s, 1H), 4.68-4.62 (m, 2H), 3.54-3.47 (m, 2H), 2.69 (s, 3H), 0.80 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C28H27C1N04: 476.2; Found: 476.4.
Example 123. Ethyl 2-(4-bromo-l -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetate (125)
Figure imgf000329_0001
1 -p eny lpropan-2-one 3-methyl-4-phenylbutanoic acid
Figure imgf000329_0002
3-methyl-3,4-dihydronaphthalen-1(2H)-one ethyl 2-(4-methoxybenzyloxy)-
2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate
ethyl 2-(4-meth
me
Figure imgf000329_0003
ethyl 2-(4-bromo-1 -(4-chlorophenyl)- 3-methylnaphthalen-2-yl)-2-ferf-butoxyacetate Preparation of 3-methyl-4-phenylbutanoic acid: 3-Methyl-4-phenylbutanoic acid was prepared in a similar manner as 4-(2-methoxy-phenyl)-3 -methyl-butyric acid of Example 32 except using l-phenylpropan-2-one. 1H NMR (400 MHz, CDC13) δ 7.31-7.14 (m, 5H), 2.65 (dd, J = 13.3, 6.7 Hz, 1H), 2.53 (dd, J = 13.3, 7.4 Hz, 1H), 2.38 (dd, 14.9, 5.5 Hz, 1H), 2.28 (app. sext. J = 6.7 Hz, 1H), 2.17 (dd, 14.5, 7.8 Hz, 1 H), 0.98 (d, J = 6.6 Hz, 3H).
Preparation of 3-methyl-3,4-dihydronaphthalen-l(2H)-one: 3-Methyl-3,4- dihydronaphthalen-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-4- phenylbutanoic acid. 1H NMR (400 MHz, CDC13) δ 8.02 (d, J = 7.9 Hz, 1H), 7.47 (dd, J = 7.4, 7.4 Hz, 1H), 7.31 (dd, J = 7.4, 7.4 Hz, 1H), 7.24 (d, J = 7.4 Hz, 1H), 3.01-2.95 (m, 1H), 2.76-2.66 (m, 2H), 2.37-2.27 (m, 2H), 1.15 (d, J = 7.2 Hz, 3H). Preparation of ethyl 2-(4-methoxybenzyloxy)-2-(l-hydroxy-3- methylnaphthalen-2-yl)acetate: Ethyl 2-(4-methoxybenzyloxy)-2-(l -hydroxy-3- methylnaphthalen-2-yl)acetate was prepared in a similar manner as (l-hydroxy-5- methoxy-3-methyl-naphthalen-2-yl)-(4-methoxy-benzyloxy)-acetic acid ethyl ester of Example 32, except using 3-methyl-3,4-dihydronaphthalen-l(2H)-one. 1H NMR (400 MHz, CDC13) δ 8.51 (s, 1H), 8.24 (d, J = 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).
Preparation of ethyl 2-(4-methoxybenzyloxy)-2-(4-bromo- 1 -hydroxy-3- methylnaphthalen-2-yl)acetate: A solution of ethyl 2-(4-methoxybenzyloxy)-2-(l- hydroxy-3-methylnaphthalen-2-yl)acetate (102 mg, 0.268 mmol) in CHC13 (5.0 mL) was treated with solid NaHC03 (46 mg, 0.281 mmol). Br2 (45 mg) in CHC13 (1.0 mL) was added dropwise over 5 min at 23 °C. After 15 min, 10% Na2S203 (10 mL) was added. The reaction was extracted two times with CHC13. Combined organic phases were dried (Na2S04), filtered, 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%). 1H NMR (400 MHz, CDC13) δ 8.69 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H), 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).
Preparation of ethyl 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-tert-butoxyacetate (125): Ethyl 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen- 2-yl)-2-tert-butoxyacetate (125) was prepared in a similar manner as ethyl 2-(7-bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate of Example 67 except using ethyl 2-(4-methoxybenzyloxy)-2-(4-bromo-l-hydroxy-3- methylnaphthalen-2-yl)acetate. 1H NMR (400 MHz, CDC13) 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- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (126)
Figure imgf000331_0001
126
ethyl 2-(4-bromo-1 -(4-chlorophenyl) 2-(4-bromo-1 -(4-chlorophenyl)- 3-methylnaphthalen-2-yl)-2-ferf- 3-methylnaphthalen-2-yl)-2-fert-butoxyacetic acid butoxyacetate
Preparation of 2-(4-bromo- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (126): A solution of ethyl 2-(4-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetate (30 mg, 71.4 μπιοΐ), LiOH monohydrate (15 mg, 0.357 mmol), H20 (500 μΐ), EtOH (absolute, 500 μΐ), and THF (500 iL) was placed in a sealed tube and heated to 100 °C. Once the reaction was complete, 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/H20 + 0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form)(l 1.5 mg, 40%). 1H 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-EST (m/z): [M- C02-H]' calcd for C22H21BrC10: 415.2; Found: 415.0 . Example 125. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 ,4-dimethylnaphthalen-2-yl)acetic acid (127)
Figure imgf000332_0001
ethyl 2-(4-bromo-1 -(4-chlorophenyl)-3- ethyl 2-ferf-butoxy-2-(1 -(4-chlorophenyl)- methylnaphthalen-2-yl)-2-ferf-butoxyacetate 3,4-dimethylnaphthalen-2-yl)acetate
Figure imgf000332_0002
127
2-feri-butoxy-2-(1-(4-chlorophenyl)- 3,4-dimethylnaphthalen-2-yl)acetic acid
Preparation of ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-3,4- dimethylnaphthalen-2-yl)acetate: A suspension of ethyl 2-(4-bromo-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (25 mg, 51 μπιοΐ), trimethylboroxine (21 μΐ,, 0.153 mmol), PdCl2(dppf) (3.7 mg, 5.1 μπιοΐ), K2C03 (70 mg, 0.510 mmol), PhMe (500 μΐ,), EtOH (absolute, 250 μΓ), and H20 (250 μΐ,) was stirred in a sealed vessel at 100 °C for 3 h. The reaction was cooled to 23 °C, diluted with H20 and extracted with EtOAc (3x). Combined organic phases were dried
(Na2S04), filtered, and concentrated, giving crude product. (Yield was not found). LH NMR (400 MHz, CD3OD) δ 8.08 (d, J = 8.2 Hz, 1H), 7.48-7.44 (m, 3H), 7.29-7.26 (m,
4H), 5.15 (s, 1H), 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).
Preparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 ,4-dimethylnaphthalen-2- yl)acetic acid (127): A solution of the crude ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)- 3,4-dimethylnaphthalen-2-yl)acetate in THF (500 μΐ,), EtOH (Absolute, 250 μΐ,), and H20 (250 μί) 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 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form)(8.0 mg, 40% over 2 steps). 1H NMR (400 MHz, DMSO-<¾) δ 12.73 (s, broad, 1H), 8.15 (d, J = 8.2 Hz, 1H), 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, 1H), 5.07 (s, 1H), 2.63 (s, 3H), 2.51 (s, 3H), 0.93 (s, 9H).
LCMS-ESr (m/z): [M-H]" calcd for C48H48Cl2Na06: 813.3; Found: 813.2.
Example 126. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-4- vinylnaphthalen-2- yl)acetic acid (128)
Figure imgf000333_0001
ethyl 2-(4-bromo-1-(4- 128
chlorophenyl)-3-methylnaphthalen- 2-yl)-2-ierf-butoxyacetate 2-terf-butoxy-2-(1-(4-chlorophenyl)- 3-methyl- -vinylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-4-vinylnaphthalen- 2-yl)acetic acid (128): 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-4- vinylnaphthalen-2-yl)acetic acid (128) was prepared in a similar manner as 2-(4-bromo- l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid of Example 125, except using potassium vinyltrifluoroborate in the Suzuki coupling reaction, giving the title compound (parent form). Ή NMR (400 MHz, DMSO-</6) δ 12.78 (s, broad, 1H), 8.13 (d, J = 8.2 Hz, 1H), 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, 1H), 7.11 (dd, J = 18.0, 11.7 Hz, 1H), 5.87 (d, J = 11. 4 Hz, 1H), 5.41 (d, J = 18.0 Hz, 1H), 5.09 (s, 1H), 2.50 (s, 3H), 0.94 (s, 9H). LCMS-ESI" (m/z): [2M- 2H+Na]' calcd for C50H48Cl2NaO6: 839.3; Found: 839.2.
Example 127. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-4-ethyl-3-methylnaphthalen-2- yl)acetic acid (129)
Figure imgf000334_0001
2-ierf-butoxy-2-(1-(4-chlorophenyl)- 3-methyl-4-vinylnaphthalen-2-yl)acetic acid 129
2-terf-butoxy-2-( 1 -(4-chlorophenyl)- 4-ethyl-3-methylnaphthalen-2-yi)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-4-ethyl-3-methylnaphthalen- 2-yl)acetic acid (129): A suspension of 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl- 4-vinylnaphthalen-2-yl)acetic acid (5.0 mg, 12 μιηοΐ), 5% w/w RI1/AI2O3 (10 mg), and EtOH (absolute, 2.0 mL) was evacuated and purged several times (vaccuum/H2 balloon). The suspension was rapidly stirred under a balloon of H2 for 6 h. H20 (500 μί) 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% ACN/H20 + 0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form) 1H NMR (400 MHz, DMSO- 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-ESF m/z): [2M-2H+Na]~ calcd for
Figure imgf000334_0002
841.3; Found: 841.3. Example 128. Ethyl 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-4-formyl-3 - methylnaphthalen-2-yl)acetate (130)
Figure imgf000335_0001
ethyl 2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen- 130
2-yl)-2-terf-butoxyacetate
ethyl 2-ferf-butoxy-2-(1 -(4-chlorophenyl)- 4-formyl-3-methylnaphthalen-2-yl)acetate
Preparation of ethyl 2-tert-butoxy-2-(l-(4-chlorophenyl)-4-formyl-3- methylnaphthalen-2-yl)acetate (130): A solution of ethyl 2-(4-bromo-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (75 mg, 0.153 mmol), K2C03 (317 mg, 2.29 mmol), PdCl2(dppf) (11.2 mg, 15.3 μιηοΐ), and potassium vinyltrifluoroborate (103 mg, 0.766 mmol) in H20 (500 μί), EtOH (absolute, 500 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 H20 (30 mL), and extracted with EtOAc (3x). Combined organic phases were dried (Na2S04), 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 02 for 5 min. After 10 min past the end of the sparge, the reaction was treated with DMS (100 μί) and warmed to 0 °C. 10% Na2S203 (2.0 mL) was added, and the reaction was stirred at 23 °C for several minutes. The reaction was diluted with H20 and DCM, then filtered over Celite. The filtrate was extracted with DCM (2x). Organic phases were combined, dried (Na2S04), filtered, and concentrated. DCM was added, and the solution was wet-loaded 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). 1H NMR (400 MHz, DMSO-</6) δ 11.01 (s, 1H), 8.73 (d, J = 8.2 Hz, 1H), 7.56-7.22 (m, 7H), 5.16 (s, 1H), 4.24-4.12 (m, 2H), 2.81 (s, 3H), 1.23 (t, J = 7.0 Hz, 3H), 1.00 (s, 9H).
Example 129. 2-tert-Butoxy-2-(l-(4-cUorophenyl)-4-(3-(dimethylamino)prop-l-ynyl)- 3-methylnaphthalen-2-yl)acetic acid (131)
Figure imgf000336_0001
131
2-feri-butoxy-2-( 1 -(4-chlorophenyl)-4- (3-(dimethylamino)prop-1-ynyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-cMorophenyl)-4-(3-(dimethylarnino)prop- l-ynyl)-3-methylnaphthalen-2-yl)acetic acid (131): A solution of ethyl 2-(4-bromo-l-
(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (40 mg, 81.7 μπιοΐ), N,N-dimethylpropargylamine (26 μΐ,, 0.245 mmol), PdCl2(PPh3)2 (5.7 mg, 16.3 μιηοΐ),
Cul (3.1 mg, 16.3 μιηοΐ) and THF (1.00 mL) was heated to 70 °C for 18 h in a sealed vessel. Conversion was incomplete, so the vessel was charged with more PdCl2(PPh3)2
(5.7 mg, 16.3 μπιοΐ) and Cul (3.1 mg, 16.3 μιηοΐ) and heated to 100 °C for an additional 26 h. The reaction was cooled to 23 °C. THF (1.0 mL), EtOH (absolute, 500 μΓ), and H20 (500 μΐ,) 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/H20 + 0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (mono trifluoroacetic acid salt)(6.8 mg, 15%). 1H NMR (400 MHz, OMSO-d6) δ 12.92 (s, broad, 1H), 10.26 (s, broad, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.71-7.62 (m, 3H), 7.47-7.43 (m, 2H), 7.34 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 5.03 (s, 1H), 4.56 (s, 2H), 2.96 (s, 6H), 2.72 (s, 3H), 0.90 (s, 9H). 19F NMR (377 MHz, DMSO-tf6) δ -74.1 (s) LCMS-ESI+ (m/z):
[M+H]+ calcd for C28H31C1N03: 464.2; Found: 464.0.
Example 130. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-4-(3 -(dimethylamino)propyl)-3 - methylnaphthalen-2-yl)acetic acid (132)
2-feri-butoxy-2-(1-(4-chlorophenyl)-4-(3- 132
(dimethylamino)prop-1-ynyl)-3-met ylnaphthalen- 2-yl)acetic acid 2-ierf-butoxy-2-(1-(4-chlorophenyl)-4-
(3-(dimethylamino)propyl)- 3-methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-4-(3-
(dimethylamino)propyl)-3-methylnaphthalen-2-yl)acetic acid (132): 2-tert-butoxy-2-(l- (4-cUorophenyl)-4-(3-(dimemylamino)propyl)-3-methylnaphthalen-2-yl)acetic acid (132) was prepared in a manner similar to 2-tert-butoxy-2-(l-(4-chlorophenyl)-4-ethyl- 3-methylnaphthalen-2-yl)acetic acid of Example 127, except using 2-tert-butoxy-2-(l- (4-chlorophenyl)-4-(3 -(dimethylamino)prop- 1 -ynyl)-3 -methylnaphthalen-2-yl)acetic acid. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H35C1N03: 468.2; Found: 468.2.
Example 131. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-4-((dimethylamino)methyl)-3 - methylnaphthalen-2-yl)acetic acid (133)
et
Figure imgf000338_0001
hyl 2-terf-butoxy-2-(1-(4- chlorophenyl)-4-formyl-3- methylnaphthalen-2-yl)acetate 133
2-terf-butoxy-2-(1-(4-chlorophenyl)-4- ((dimethylamino)methyl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-4-((dirnethylarnino)methyl)- 3-methylnaphthalen-2-yl)acetic acid (133): A suspension of ethyl 2-tert-butoxy-2-(l-(4- chlorophenyl)-4-formyl-3-methylnaphthalen-2-yl)acetate (6.0 mg, 13.9 pmol), EtOH (absolute, 500 μΐ,), NaBH(OAc)3 (8.8 mg, 41.7 μπιοΐ), and glacial AcOH (4 μΐ,, 70 μπιοΐ) was treated with a solution of N,N-dimethylamine in MeOH (2 M, 35 μί, 69.5 μπιοΐ). DCM (50 μί) was added to improve solubility. The reaction was sealed and heated to 70 °C. Conversion was limited, so more N,N-dimethylamine in MeOH (2 M, 170 0.337 mmol), glacial AcOH (20 0.35 mmol), NaBH(OAc)3 (50 mg, 0.236 mmol), and DMF (500 μί) were added. Heating was continued. Once conversion was achieved, LiOH monohydrate (200 mg, 4.7 mmol) and H20 (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/H20 + 0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (mono trifluoroacetic acid salt)(1.0 mg, 13%). LCMS-ESf (m/z): [M+H]+ calcd for C26H31C1N03: 440.2; Found: 440.0.
Example 132. 2-tert-Butoxy-2-(l -(4-chlorophenyl)-3-methyl-4- (morpholinomethyl)naphthalen-2-yl)acetic acid (134)
Figure imgf000339_0001
ethyl 2-ferf-butoxy-2-(1 -(4-chlorophenyl)-4-formyl-3- methylnaphthalen-2-yl)acetate 134
2-terf-butoxy-2-(1-(4-chlorophenyl)- 3-methyl-4-(morpholinomethyl) naphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-4- (mo holinomethyl)naphthalen-2-yl)acetic acid (134): 2-tert-Butoxy-2-(l-(4- chlorophenyl)-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 animation step. LCMS-ESI* (m/z): [M+H]+ calcd for C28H33C1N04: 482.2; Found: 482.0.
Example 133. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-4-(hydroxymethyl)- 3-methylnaphthalen-2-yl)acetic acid (135)
Figure imgf000339_0002
3-methylnaphthalen-2-yl)acetic acid (135): A solution of ethyl 2-tert-butoxy-2-(l-(4- chlorophenyl)-4-formyl-3-methylnaphthalen-2-yl)acetate (6.0 mg, 14 μπιοΐ), NaB¾ (1.5 mg, 40 μπιοΐ), THF (250 μΐ), and EtOH (absolute, 500 μΐ) was stirred at 23 °C for 1 h. H20 (500 μί) and LiOH monohydrate (50 mg, 1.18 mmol) were added. The reaction was sealed and heated to 100 °C. After 2 h, the reaction cooled to 23 °C, filtered through a 0.45 micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form)(2.6 mg, 43%). 1H NMR (400 MHz, DMSO-< ) δ 12.76 (s, 1H), 8.27 (d, J = 8.6 Hz, 1H), 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, 1H), 5.07 (s, 1H), 5.01 (d, broad, J = 2.7 Hz, 2H), 2.62 (s, 3H), 0.94 (s, 9H).
LCMS-ESF (m/z): [M-H]" calcd for C24H24C104: 411.1; Found: 410.9.
Example 134. 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3-methyl-4-phenylnaphthalen-2- yl)acetic acid (136)
Figure imgf000341_0001
utoxyacetate 136
2-terf-butoxy-2-(1-(4-chlorophenyl)- 3-methyl-4-phenylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-3-methyl-4- phenylnaphthalen-2-yl)acetic acid (136): 2-tert-Butoxy-2-(l-(4-chlorophenyl)-3- methyl-4-phenylnaphthalen-2-yl)acetic acid (136) was prepared in a manner similar to 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 ,4-dimethylnaphthalen-2-yl)acetic acid of
Example 125 , except using benzeneboronic acid in the Suzuki reaction, giving the title compound (parent form). 1H-NMR: (400 MHz, MeOH- d4): δ 7.67-7.55 (m, 5H); 7.50- 7.48 (m, IH); 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-ESr (m/z): [M-H]" calcd for C29H26C103: 457.2; Found: 457.2.
Example 135. 2-tert-Butoxy-2-(l-(4-cWorophenyl)-4-(6-(dimethylamino)pyridin-3-yl)- 3-methylnaphthalen-2-yl)acetic acid (137)
ethyl 2-(
methylnapht
Figure imgf000342_0001
halen-2-yl)-2-ferf-butoxyacetate
137
2-ferf-butoxy-2-(1-(4-chlorophenyl)-4- (6-(dimethylamino)pyridin-3-yl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-4-(6- (dimemylamino)pyridin-3-yl)-3-methylnaphthalen-2-yl)acetic acid (137): 2-tert- Butoxy-2-(l-(4-chlorophenyl)-4-(6-(dimethylamin^^
2-yl)acetic acid (137) was prepared in a manner similar to 2-tert-butoxy-2-(l-(4- cUorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using 2-(N,N-dimemylarrAino)-pyridin-5-yl-boronic acid in the Suzuki reaction, giving the title compound. Ή-NMR: (400 MHz, DMSO- f) δ 8.02-8.00 (m, 1H); 7.78 (m, broad, 1H); 7.72-7.69 (m, 1H); 7.67-7.65 (m, 1H); 7.52-7.49 (m, 1H); 7.45-7.36 (m, 4H); 7.23 (d, J=8.0 Hz, 2H); 5.11 (s, 1H); 2.29 (d, J=1.2 Hz, 3H); 0.93 (d, J=1.2 Hz, 9H). LCMS- ESf (m/z): [M+H]+ calcd for C30H32ClN2O3: 503.2; Found: 503.3.
Example 136. 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3-methyl-4-(pyridin-3- yl)naphthalen-2-yl)acetic acid (138) ethyl 2-(4-bromo-1 -(
Figure imgf000343_0001
2-ierf-butoxyacetate
138
2-ferf-butoxy-2-(1-(4-chlorophenyl)-3- methyl-4-(pyridin-3-yl)naphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-c orophenyl)-3-methyl-4-(pyridin-3- yl)naphthalen-2-yl)acetic acid (138): 2-tert-butoxy-2-(l-(4-chlorophenyl)-3-methyl-4- (pyridin-3-yl)naphthalen-2-yl)acetic acid (138) 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 pyridin-3-yl-boronic acid in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt). 1H-NMR: (400 MHz, DMSO- d6): δ 12.8 (s, broad, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.62 (d, J = 12.9 Hz, 1H), 7.97-7.92 (m, 1H),
7.76-7.69 (m, 3H), 7.60-7.54 (m, 1H), 7.47-7.40 (m, 3H), 7.28 (d, J = 9.2 Hz, 1H), 7.18 (d, J = 9.4 Hz, 1H), 5.15 (s, 1H), 2.25 (s, 3H), 0.96 (s, 9H). 19F-NMR: (377 MHz, DMSO- cf) δ -74.7 (s) LCMS-ESI+ (m/z): [M+H]+ calcd for C28H27C1N03: 460.2;
Found: 460.2.
Example 137. 2-tert-Butoxy-2-( 1 -(4-cMorophenyl)-3-methyl-4-( yrimidin-5- yl)naphthalen-2-yl)acetic acid (139)
ethyl 2-(4
Figure imgf000344_0001
-bromo-1-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-£erf-butoxyacetate
139
2-t erf-butoxy-2-( 1 -(4-ch loropheny l)-3- methyl-4-(pyrimidin-5-yl)naphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l-(4-c orophenyl)-3-methyl-4-^yrirnidin-5- yl)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 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 ,4-dimethylnaphthalen-2-yl)acetic acid of
Example 125, except using pyrimidin-5-yl-boronic acid in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt^H-NMR: (400 MHz, DMSO- </): δ
12.87 (s, broad, 1H), 9.39 (s, 1H), 8.89 -8.86 (m, 2H), 7.76-7.68 (m, 2H), 7.58-7.55 (s, 1H), 7.49-7.44 (m, 3H), 7.28 (d, J = 8.2 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 5.15 (s, 1H), 2.27 (s, 3H), 0.97 (s, 9H). 19F-NMR: (377 MHz, DMSO- cf) δ -73.9 (s) LCMS-ESI+ (m/z): [M+H]+ calcd for C27H26C1N203: 461.2; Found: 461.2.
Example 138. 2-( 1 ,4-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (140)
Figure imgf000345_0001
140
2-(1 ,4-bis(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-ferf- butoxyacetic acid
Preparation of 2-(l ,4-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (140): 2-(l,4-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic 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 reaction, giving the title compound (mono trifluoroacetic acid salt). 1H-NMR: (400 MHz, DMSO- <f): δ 12.82 (s, 1H), 7.75-7.63 (m, 4H), 7.55 (dd, J = 8.2, 2.4 Hz, 1H), 7.46-7.31 (m, 5H), 7.26-7.21 (m, 2H), 5.14 (s, 1H), 2.24 (s, 3H), 0.96 (s, 9H). LCMS-ESI' (m/z): [2M-2H+Na]" calcd for
C58H5oCl4Na06: 1007.2; Found: 1007.1.
Example 139. 1 -(4-Bromo- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)prop-2-en- 1 - ol (141)
Figure imgf000346_0001
1-phenylpropan-2-one ethyl 2-cyanoacetate (E)-ethyl 2-cyano-3-methyl
-4-phenylbut-2-enoate
Figure imgf000346_0002
1-hydroxy-3-methyl-2-naphthonitrile
4-bromo-1 -hydroxy-3- meth -2-naphthonitrile
4-brom
Figure imgf000346_0003
o-2-cyanonaphthalen-1 -yl
pert luorobutanesu If onate 4-bromo-1 -(4-chlorophenyl)- 3-methyl-2-naphthonitrile
4-bro
Figure imgf000346_0004
mo-1 -(4-chlorophenyl)- 3-methyl-2-naphthaldehyde 1 -(4-bromo-1 -(4-chlorophenyl)-3- methylnaphthalen-2-yl)prop-2-en-1-ol
Preparation of 1 -hydroxy-3 -methyl-2-naphthonitrile : Phenyl-2-propanone (24.93 g, 0.178 mol) was combined with ethylcyanoacetate (19.8 mL, 0.180 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 chiller. 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 off excess (~ 50 mL) benzene. The solution contained crude (E)-ethyl 2-cyano-3- methyl-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 ethanol resulting while the mixture was heated at 240 °C for 60-90 minutes. The mixture was cooled to ~ 100 °C, and poured into room temperature 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). 1H-NMR: (300 MHz, DMSO- cf): δ 1 1.28 (s, 1H); 8.24 (d, J = 8.4 Hz, 1H); 7.80 (d, J = 8.0 Hz, 1H); 7.62-7.58 (m, 1H); 7.52-7.48 (m, 1H); 7.34 (s, 1H); 2.47 (s, 3H).
Preparation of 4-bromo-l -hydroxy-3-methyl-2-naphthonitrile: l-hydroxy-3- methyl-2-naphthonitrile (1.065 g, 5.8 mmol) was dissolved CHC13 (24 mL) and combined with sodium bicarbonate (952 mg, 1 1.3 mmol) and bromine (330
Figure imgf000347_0001
6.43 mmol) and allowed to stir at room temperature overnight. The reaction 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.) 1H-NMR: (300 MHz, DMSO- ): δ 8.334 (d, J = 8.0 Hz, 1H); 8.166 (d, J - 8.4 Hz, 1H); 7.81 -7.77 (m, 1H); 7.65-7.61 (m, 1H); 2.65 (s, 3H).
Preparation of 4-bromo-2-cyanonaphthalen-l-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 μΐ,, 5.37 mmol) at -78 °C. To this cooled solution was added nonafluorobutanesulfonic anhydride (1.10 g, 1.97 mmol) dropwise as a DCM emulsion. 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). 1H-NMR: (400 MHz, DMSO- d6): 6 8.42 (d, J = 8.4 Hz, 1H); 8.1 1 (d, J = 8.8 Hz, 1H); 8.05-8.01 (m, 1H); 7.99-7.95 (m, 1H); 2.81 (s, 3H).
Preparation of 4-bromo-l-(4-chlorophenyl)-3-methyl-2-naphthonitrile: To a SO- SO (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 4- chlorophenylboronic acid (1.65 g, 10.55 mmol) and dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (165 mg, 0.171 mmol) and 6 mL of 2 M K2C03. The vial was sealed, and heated thermally at 60 °C for 30 minutes. The mixture was concentrated in vacuo, redissolved in 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. 1H-NMR: (400 MHz, MeOH-
Figure imgf000348_0001
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).
Preparation 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-bromo- l-(4-chlorophenyl)-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 NI-LCl, and stirred 10-15 minutes. After being filtered though a short pad of Celite 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 aldehyde (1.56 g, 77% yield). Ή-NMR: (400 MHz, DMSO- et): δ 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). Preparation 1 -(4-bromo- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)prop-2- en-l-ol (141): To a 0 °C THF (15 mL) solution of 4-bromo- 1 -(4-chlorophenyl)-3 - methyl-2-naphthaldehyde (500 mg, 1.39 mmol) was added vinyl magnesium bromide (1.40 mL, 1 M in THF, 1.4 mmol) and the mixture allowed to stir and warm to 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). 1H-NMR: (400 MHz,CDCl3): δ 8.40 (d, 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).
Example 140. Methyl 2-(4-bromo-l -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetate (
Figure imgf000350_0001
1 -(4-bromc -(4-chlorophenyl)-3- (1-(4-bromo-1-(4-c lorophenyl)-3- methylnaphthalen-2-yl)prop-2-en-1-ol methylnaphthalen-2-yl)allyloxy)
(ferf-but l)dimethylsilane
Figure imgf000350_0002
2-(4-bromo-1 -{4-c loropheny l)-3-methy I 2-(4-bromo-1 -(4-chlorophenyl)-3- naphthalen-2-yl)-2-(ierf-butyldimethyl methylnaphthalen-2-yl)-2- silyloxyjacetaldehyde (ferf-but ldimethylsilyloxy)acetic acid
m
Figure imgf000350_0003
methyl 2-(4-bromo-1 -(4-chlorophenyl)- 3-methylnaphthalen-2-yl)-2-ferf- butoxyacetate
Preparation of (l-(4-bromo-l -(4-chloropheny l)-3-methylnaphthalen-2- yl)allyloxy)(tert-butyl)dimethylsilane: To a stirring 23 °C DCM solution (32 mL) of 1- (4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)prop-2-en-l-ol (1.47 g, 3.79 mmol) and triethylamine (2.3 mL, 16.5 mmol) was added TBDMS-OTf (2.0 mL, 11.65 mmol) and the reaction 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% NaHC03 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). 1H-NMR: (400 MHz,CDCl3): δ 8.39 (d, J = 8.4 Hz, 1H); 7.55-745 (m, 3H); 7.34-7.30 m, 1H); 7.26-7.24 (m, 1H); 7.24-7.18 (d, J = 8.0 Hz, 1H); 7.16-7.14 (m, 1H); 6.09-6.01 (m, 1H); 5.32-5.30 (m, 1H); 5.13-5.03 (m, 2H); 2.77 (s, 3H); 0.87 (s, 6H); 0.83 (s, 9H).
Preparation 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 ( 1 -(4-bromo- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)allyloxy)(tert- butyl)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 Na2S203 (5 x 20 mL), dried with sodium sulfate and concentrated in vacuo. Silica gel chromatography using EtOAc in Hexanes gave rise to desired aldehyde (1.27 g, 79% yield). 1H-NMR: 400 MHz, (CDC13): δ: 9.94 (s, 1H); 8.41-8.36 (d, J - 8.0 Hz, 1H); 7.60-7.55 (m, 1H); 7.53-7.45 (m, 2H); 7.39-7.32 (m, 2H); 7.29-7.24 (m, 2H); 5.16 (s, 1H); 2.63 (s, 3H); 0.86 (m, 15H).
Preparation of 2-(4-bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- (tert-butyldimethylsilyloxy)acetic acid: A DCM solution (8.0 mL) of 2-(4-bromo-l-(4- chlorophenyl)-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 NaHS04 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 1H NMR analysis and was used without purification. 1H-NMR: (400 MHz, CD3OD): δ 8.35 (d, J = 8.4 Hz, 1H); 7.58-7.51 (m, 3H); 7.46-7.44 (m, 1H); 7.39-7.33 (m, 1H); 7.31-7.22 (m, 2H); 5.33 (s, 1H); 2.72 (s, 3H); 0.825 (s, 9H); -0.03 (s, 3H); -0.26 (s, 3H). Preparation of methyl 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2- yl)-2-(tert-butyldimethylsilyloxy)acetate: Crude 2-(4-bromo-l -(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyloxy)acetic acid 0.740 g, 1.4 mmol)was dissolved in 20 mL DCM-MeOH (50-50, v/v) and combined with TMS- 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 μΐ,) 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-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyloxy)acetaldehyde. 1H-NMR: (400 MHz, MeOH- d4): δ 8.39 (d, J=8.0 Hz, lH); 7.58-7.54 (m, 1H); 7.50-7.47 (m, 2H); 7.37-7.33 (m, 2H); 7.27-7.21 (m, 2H); 5.31 (s, 1H); 3.69 (s, 3H); 2.67 (s, 3H); 0.83 (s, 9H); -0.04 (s, 3H); -0.27 (s, 3H).
Preparation of methyl 2-(4-bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen-2- yl)-2-hydroxyacetate: Methyl 2-(4-bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen-2- yl)-2-(tert-butyldimethylsilyloxy)acetate (537.8 mg, 1.01 mmol) was dissolved in 4.0 mL TFA and heated to 60 °C. The reaction was monitored by HPLC and turned dark quickly after addition of TFA. The reaction was completed after 1 h by HPLC, was removed from heat and diluted with toluene (20 mL) and concentrated in vacuo. This dilution/concentration was repeated twice 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). 1H-NMR: (400 MHz, CDC13): δ 10.34 (s, broad, 1H); 8.40 (d, J=8.0 Hz, 1H); 7.60-7.56 (m, 1H); 7.52-7.46 (m, 2H); 7.38-7.35 (m, 1H); 7.32-7.28 (m, 2H); 5.26 (s, 1H); 3.74 (s, 3H); 2.62 (s, 3H).
Preparation of methyl 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2- yl)-2-tert-butoxyacetate (142): Methyl 2-(4-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-hydroxyacetate (298 mg, 0.71 mmol) was dissolved in t- 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 NaHC03 and stirred for 10-15 minutes. This mixture was extracted with EtOAc, extracts dried with sodium sulfate and concentrated in vacuo. Purification on silica gel using EtOAc in hexanes gave desired product as well as some starting material. 1H-NMR: (400 MHz, CDCI3): δ 8.39 (d, J=8.8 Hz, 1H); 7.57-7.48 (m, 3H); 7.45-7.42 (m, 1H); 7.35-7.31 (m, 1H); 7.28-7.18 (m, 2H); 5.20 (s, 1H); 3.70 (s, 3H); 2.72 (s, 3H); 0.99 (s, 9H).
Example 141. 2-(4-(6-Aminopyridin-3 -yl)- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2- yl)- -tert-butoxyacetic acid (143)
Figure imgf000353_0001
143
2-(4-(6-aminopyridin-3-yl)-1 - (4-c lorop enyl)-3-methylnaphthalen- 2-yl)-2-terf-butoxyacetic acid
Preparation of 2-(4-(6-aminopyridin-3-yl)- 1 -(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (143): 2-(4-(6-Aminopyridin-3-yl)-l- (4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (143) 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 methyl 2-(4-bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetate as the starting material and 2- aminopyridin-5-yl-boronic acid pinacolate ester in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt). 1H-NMR: (400 MHz, DMSO- ): δ 8.06- 7.86 (m, 4H), 7.76-7.68 (m, 2H), 7.56-7.37 (m, 5H), 7.26 (d, J = 8.6 Hz, 1H), 7.17-7.13 (m, 1H), 5.13 (s, 1H), 2.33 (s, 3H), 0.96 (s, 9H). 19F-NMR: (377 MHz, DMSO- ): δ - 74.2 (s). LCMS-ESf (m/z): [M+H]+ calcd for C28H28C1N203: 475.2; Found: 475.2. Example 142. 2-tert-Butoxy-2-(l -(4-chlorophenyl)-3-methyl-4-(6- dihydropyridin-3-yl)naphthalen-2-yl)acetic acid (144)
Figure imgf000354_0001
144
2-ferf-butoxy-2-(1-(4-chlorophenyl)-3- methyl-4-(6-oxo-1 ,6-dihydropyridin-3-yl) naphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-4-(6-oxo- 1 ,6- dihydropyridin-3-yl)naphthalen-2-yl)acetic acid (144): 2-tert-Butoxy-2-(l-(4- cUorophenyl)-3-memyl-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)-3,4- dimethylnaphthalen-2-yl)acetic acid of Example 125 , except using methyl 2-(4-bromo- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)-2-tert-butoxyacetate as the starting material and 2-(lH)pyridone-5-yl-boronic acid pinacolate ester in the Suzuki reaction, giving the title compound (parent form). 1H-NMR: (400 MHz, DMSO- ): δ 12.8 (s, broad, 1H), 11.8 (app. s, broad, 1H), 7.67-7.30 (m, 10H), 7.23 (d, J = 8.2 Hz, 1H), 5.11 (s, 1H), 2.36 (s, 3H), 0.95 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C28H27C1N04: 476.2; Found: 476.2.
Example 143. 2-(4-(2-Aminopyrimidin-5-yl)- 1 -(4-chlorophenyl)-3 -methylnaphthalen- 2-yl -2-ter -butoxyacetic acid (145)
m
Figure imgf000355_0001
145
2- (4-(2-aminopyrimidin-5-yl)-1-(4-chlorophenyl)-
3- methylnaphthalen-2-yl)-2-ierf-butoxyacetic acid
Preparation of 2-(4-(2-aminopyrirnidin-5-yl)-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (145): 2-(4-(2-Aminopyrimidin-5-yl)- l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (145) 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 methyl 2-(4-bromo- l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate as the starting material and 2-aminopyrimidine-5-yl-boronic acid pinacolate ester in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt form).
1H-NMR: (400 MHz, DMSO- et : δ 12.8 (s, broad, 1H), 8.26-8.24 (m, 2H), 7.75-7.67 (m, 2H), 7.55 (dd, J - 7.8, 2.0 Hz, 1H), 7.53-7.41 (m, 4H), 7.24 (d, J = 8.2 Hz, 1H), 7.16 (s, broad, 2H), 5.13 (s, 1H), 2.34 (s, 3H), 0.95 (s, 9H). 19F-NMR: (400 MHz, DMSO- d . δ -74.9 (s). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H27C1N303: 476.2; Found: 476.2.
Example 144. 2-tert-Butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-4-(2- dihydropyrimidin-5-yl)naphthalen-2-yl)acetic acid (146)
Figure imgf000356_0001
146
2-ferNbutoxy-2-(1 -(4-chlorophenyl)-3-methyl-
4- (2-oxo-1 ,2-dihydropyrimidin-
5- yl)naphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-( 1 -(4-chlorophenyl)-3-methyl-4-(2-oxo- 1 ,2- dihydropyrimidin-5-yl)naphthalen-2-yl)acetic acid (146): A suspension methyl 2-(4- bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxy acetate (10.5 mg, 22.1 μιηοΐ), [lH]pyrimidin-2-one-5-yl-boronic acid (25 mg, 0.1 1 mmol), PdCl2(dppf) (3.2 mg, 4.4 μιηοΐ), K2C03 (46 mg, 0.33 mmol), PhMe (500 μΐ,), EtOH (absolute, 250 μί), and H20 (250 μί) was heated to 100 °C for 30 min, but conversion was poor. The reaction was treated with glacial AcOH (60 μΙ>, 1.05 mmol) and KF (40 mg, 0.688 mmol). More PdCl2(dppf) (3.2 mg, 4.4 μπιοΓ) and [lH]pyrimidin-2-one-5-yl-boronic acid (7 mg, 30 μπιοΓ) were added and the reaction was heated to 100 °C. After 2 h, the reaction was added to H20 (15 mL) and glacial AcOH (0.2 mL). The system was extracted with EtOAc (3x 10 mL). Combined organic phases were dried (Na2S04), filtered, and concentrated. The crude material was treated with THF (750 μΚ), EtOH (absolute, 750 μΐ,), H20 (500 μ ), and 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/H20 + 0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form)(3.8 mg, 36% over 2 steps). 1H- NMR: (400 MHz, DMSO- ): δ 12.8 (s, broad, IH), 8.29 (app. s, broad, IH), 7.75-7.68 (m, 2H), 7.58-7.44 (m, 4H), 7.43-7.38 (m, 2H), 7.25 (d, J = 8.2 Hz, 1H), 5.12 (s, 1H), 2.38 (s, 3H), 0.96 (s, 9H). LCMS-ESf (m/z): [M+H]+ calcd for C27H26C1N204: 477.2; Found: 477.2. Example 145. 2-tert-Butoxy-2-(l -(4-chlorophenyl)-4-cyano-3-methylnaphthalen-2-
Figure imgf000357_0001
2-terf-butoxy-2-( 1 -(4-chlorophenyl)-4- cyano-3-methylnaphthalen-2-yl)acetic acid
Preparation of 2-tert-butoxy-2-(l -(4-chlorophenyl)-4-cyano-3- methylnaphthalen-2-yl)acetic acid (147): A suspension of methyl 2-(4-bromo-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (10.5 mg, 22.1 μιηοΐ), CuCN (9.8 mg, 0.11 mmol), and NMP (500 μί) was heated to 200 °C in a microwave. The reaction 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/H20 + 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 all of the CH3CN. The solution was treated with EtOH (absolute, 500 μί) 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 purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). The product-containing fractions were combined and lyophilized, giving the title compound (parent form)(5.2 mg, 55% over 2 steps).
1H-NMR: (400 MHz, DMSO- (f) δ 13.12 (s, IH), 8.16 (d, J = 8.2 Hz, IH), 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 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 5.07 (s, lh), 2.83 (s, 3H), 0.95 (s, 9H). LCMS-ESI" (m/z): [M-H]" calcd for C4SH43C12N204: 813.3; Found: 813.3.
Example 146. Ethyl 2-(7-chloro-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- oxoacetate (148).
Figure imgf000358_0001
1 -(4-chloropheny l)propan-2-one ethyl 2-(7-chloro-1-hydroxy-3- methylnaphthalen-2-yl)-2- hydroxy acetate
Figure imgf000358_0002
ethyl 2-ferf-butoxy-2-(7-chloro-1- ethyl 2-ferf-butoxy-2-(7-chloro-3-methyl-1 - hydroxy-3-methylnaphthalen-2- (trifluoromethylsulfonyloxy)naphthalen-2- yl)acetate yl)acetate
Figure imgf000358_0003
ethyl 2-(7-chloro-3- methyl-1- 148
(trifluoromethylsulfonyl
ethyl 2-(7-chloro-1-(4-chlorophenyl)-3- oxy)naphthalen-2-yl)- methylnaphthalen-2-yl)-2-oxoacetate
2-oxoacetate
Preparation of ethyl 2-(7-chloro-l-hydroxy-3-methylnaphthalen-2-yl)-2- hydroxy acetate: Prepared in a manner similar to ethyl 2-(6-chloro-7-fluoro-l-hydroxy- 3-methylnaphthalen-2-yl)-2-hydroxyacetate of Example 99 except using l-(4- chlorophenyl)propan-2-one. lH-NMR: (400 MHz, CDC13): 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, 1H), 7.18 (s, 1H), 5.68 (s, 1H), 4.33-4.10 (m, 2H), 2.53 (s, 3H), 1.20 (t, J = 7.0 Hz, 3H).
Preparation of ethyl 2-tert-butoxy-2-(7-chloro-l-hydroxy-3-methyl-naphthalen- 2-yl)acetate: Prepared in a similar manner to ethyl 2-tert-butoxy-2-(l-hydroxy-3- methylnaphthalen-2-yl)acetate of Example 120, except using ethyl 2-(7-chloro- 1 - hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate. 1H-NMR: (400 MHz, CDC13): δ 9.01 (s, IH), 8.22 (d, J = 2.0 Hz, IH), 7.56 (d, J = 8.6 Hz, IH), 7.35 (dd, J = 8.6, 2.0 Hz, IH), 7.13 (s, IH), 5.49 (s, IH), 4.22-4.08 (m, 2H), 2.56 (s, 3H), 1.31 (s, 9H), 1.19 (t, J = 7.0 Hz, 3H).
Preparation of ethyl 2-tert-butoxy-2-(7-chloro-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: Ethyl 2-tert-butoxy-2-(7-chloro- 3 -methyl- l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was prepared in a similar manner to ethyl 2-(7-bromo-3 -methyl- l-(trifluoromethylsulfonyloxy)- naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate of Example 67 , except using ethyl 2- tert-butoxy-2-(7-chloro-l -hydroxy-3-methylnaphthalen-2-yl)acetate. !H-NMR: (400 MHz, CDC13): δ 8.00 (d, J = 2.0 Hz, IH), 7.73 (d, J = 8.6 Hz, IH), 7.65 (s, IH), 7.49 (dd, J = 8.6, 2.0 Hz, IH), 5.72 (s, IH), 4.26-4.08 (m, 2H), 2.54 (s, 3H), 1.20 (s, 9H), 1.17 (t, J = 7.0 Hz, 3H).
19F-NMR: (377 MHz, CDCI3): δ -73.2 (s)
Preparation of ethyl 2-(7-chloro-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-oxoacetate: Ethyl 2-(7-chloro-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- oxoacetate was prepared in a similar manner to 2-(6-chloro-7-fluoro-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate of Example 99 , except using ethyl 2-tert-butoxy-2-(7-chloro-3 -methyl- 1 -(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate. 1H-NMR: (400 MHz, CDC13): δ 8.05 (d, J = 2.0 Hz, IH), 7.79 (d, J = 8.6 Hz, IH), 7.74 (s, IH), 7.58 (dd, J = 8.6, 2.0 Hz, IH), 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)
Preparation of ethyl 2-(7-chloro-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-oxoacetate (148): Ethyl 2-(7-chloro-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- oxoacetate (148) was prepared in a manner similar to ethyl 2-(7-bromo-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate of Example 67, except using ethyl 2-(7-chloro-l -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate. 1H-NMR: (400 MHz, CDCI3): δ 7.78 (d, J = 8.6 Hz, IH), 7.73 (s, IH), 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-chloro-l-(4-chlorophenyl)-3-methylnaphthalen-2- yl)acetic acid (149)
Figure imgf000360_0001
ethyl 2-(7-chloro-1 -(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2^xoacetate ethyl 2-(7-chloro-1-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-hydroxyacetate
Figure imgf000360_0002
ethyl 2-ferf-butoxy-2-(7-chloro-1 -(4- chlorophenyl)-3-methylnaphthalen- 14g
2-yl)acetate
2-terf-butoxy-2-(7-chloro-1-(4-chlorophenyl)- 3-methylnaphthalen-2-yl)acetic acid
Preparation of ethyl 2-(7-chloro-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)- 2-hydroxyacetate: A solution of ethyl 2-(7-chloro-l-(4-chlorophenyl)-3-methyl- naphthalen-2-yl)-2-oxoacetate (26 mg, 67 μπιοΐ) in EtOH (absolute, 1.0 mL) and DCM (1.0 mL) was treated with NaB¾ (5.1 mg, 0.134 mmol) at 23 °C. After 1 h, saturated NH4CI (1.0 mL) was added. The reaction was stirred overnight, then diluted with H20 (10 mL). The mixture was extracted with DCM (3x), and the combined organics dried (Na2S04), filtered, and concentrated, giving the title compound (28 mg, > 99% yield). 1H-NMR: (400 MHz, CDC13): δ 7.72 (d, J = 8.6 Hz, 1H), 7.65 (s, 1H), 7.51-7.22 (m, 6H), 5.19 (s, 1H), 4.35-4.17 (m, 2H), 2.49 (s, 3H), 1.20 (t, J = 7.0 Hz, 3H).
Preparation of ethyl 2-tert-butoxy-2-(7-chloro-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)acetate: Ethyl 2-tert-butoxy-2-(7-chloro-l -(4-chlorophenyl)-3- methylnaphthalen-2-yl)acetate was prepared in a manner similar to (S)-ethyl 2-tert- butoxy-2-( 1 -(4-chlorophenyl)-3 -methyl-6-(trifluoromethylsulfonyl-oxy)naphthalen-2- yl)acetate of Example 51 , except using racemic ethyl 2-(7-chloro- 1 -(4-chlorophenyl)-3 - methylnaphthalen-2-yl)-2-hydroxyacetate. Material was carried on crude without further characterization.
Preparation of 2-tert-butoxy-2-(7-chloro- 1 -(4-chlorophenyl)- 3-methylnaphthalen-2-yl)acetic acid (149): 2-tert-Butoxy-2-(7-chloro-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)acetic acid (149) was prepared in a similar manner to 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid of Example 124 , except using ethyl 2-tert-butoxy-2-(7-chloro-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)acetate, giving the title compound (parent form) 1H-NMR: (400 MHz, DMSO- ): δ 12.86 (s, broad, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.73-7.67 (m, 2H), 7.56-7.49 (m, 2H), 7.40 (d, J =8.2 Hz, 1H), 7.11 (d, J = 1.6 Hz, 1H), 5.00 (s, 1H), 2.57 (s, 3H), 0.93 (s, 9H). LCMS-ESr (w/z): [ -H]" calcd for C23H21C1203: 415.1; Found: 415.3.
Example 148. (R)-2-(4-Bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (150A) and (S)-2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen- 2-yl)-2-tert-butoxyacetic acid (150B)
Figure imgf000362_0001
(S)-methyl 2-(4-bromo-1-(4-chloro 150B
phenyl)-3-methylnaph
thalen-2-yl)-2-hydroxyacetate (S)-2-(4-bromo-1 -(4-chloro phenyl)-3-methylnaphthalen- 2-yl)-2-ferf-butoxyacetic acid
Chiral chromatographic separation of the two enantiomers of methyl 2-(4- bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate: A solution of the racemate (36 mg) in MeOH/EtOH 1 : 1 v/v (1.8 mL total) was separated
preparatively into its two enantiomers on an O J-H packed chiral column,
(R)-methyl 2-(4-bromo- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)-2- hydroxyacetate (6.1 mg).
1H-NMR: (400 MHz, CDC13): 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). (S)-methyl 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2- yl)-2-hydroxyacetate (4.8 mg)
Preparation of (R)-2-(4-bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen- 2-yl)-2-tert-butoxyacetic acid (150A): (R)-2-(4-Bromo-l-(4-chlorophenyl)-3- methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (150A) was prepared in a similar manner to 2-(4-bromo- 1 -(4-chlorophenyl)-3 -methylnaphthalen-2-yl)-2-tert- butoxyacetic acid of Example 124, except using (R)-methyl 2-(4-bromo-l-(4- chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate, giving the title compound (parent form). 1H 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): [M- C02-H]" calcd for C22H21BrC10: 415.2; Found: 415.0.
Preparation of (S)-2-(4-bromo- 1 -(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert- butoxyacetic acid (150B): (S)-2-(4-Bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2- yl)-2-tert-butoxyacetic acid (150B) was prepared in a similar manner to 2-(4-bromo-l- (4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid of Example 124, except using (S)-methyl 2-(4-bromo-l-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2- hydroxyacetate, giving the title compound (parent form). 1H 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-ESr (m/z): [M-C02-H]" calcd for C22H21BrC10: 415.2;
Found: 415.0.
Example 149. Compounds 151-180
Compounds 151-180 were prepared by similar methods as described
above Examples.
Figure imgf000363_0001
Figure imgf000364_0001
Figure imgf000365_0001
Figure imgf000366_0001
Figure imgf000367_0001
Figure imgf000368_0001

Figure imgf000369_0001
 180 475.97 476.4
Example 150. Preparation of (S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)-l-(2,3- dihydropyrano [4,3 ,2-de] quinolin-7-yl)-3 -methylna hthalen-2- l acetic acid 181 ).
Figure imgf000370_0001
(S)-ethyl 2-terf-butoxy-2-(6-
(S)-ethyl 2-terf-butoxy-2-(3-methyl-1 - formyl-3-methyl-1- (trifluoromet ylsulfonyloxy)-6-vinylnaphthalen-2- (trifluoromethylsulfonyloxy)
yl)acetate naphthalen-2-yl)acetate
Figure imgf000370_0002
(S)-2-ieri-butoxy-2-((f?)-6-(difluoromethyl)-1-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-(6-formyl-3-methyl-l-(trifluoromethyl- sulfonyloxy)naphthalen-2-yl)acetate: A solution of (S)-ethyl 2-tert-butoxy-2-(3- methyl-l-(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate (0.60 g, 1.3 mmol, prepared similarly to (S)-ethyl 2-tert-butoxy-2-(7-fluoro-3-methyl-l- (trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate from Example 101) in THF (7 mL) at rt was treated with a previously prepared mixture of K^OsO^HiO (0.023 g, 0.063 mmol) and NaI04 (0.81 g, 3.8 mmol) in water (5 mL). The resulting suspension becomes thick and opaque. After vigorous stirring for 20 min, the 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 separation, the aqueous layer is extracted with EtOAc until colorless. The combined organics are washed with brine, dried over anhydrous MgS04 and concentrated in vacuo. The residue is purified by Yamazen column
chromatography (15-35%EtO Ac/hex) to afford 0.348 g (60%) of the desired material as a pale yellow amorphous solid. 1H-NMR: 400 MHz, (CDC13) δ: 10.19 (s, 1H); 8.31 (br s, 1H); 8.16 (d, J = 8.8 Hz, 1H); 8.05 (dd, J = 8.8, 1.6 Hz, 1H); 7.85 (s, 1H); 5.76 (s, 1H); 4.28-4.10 (m, 2H); 2.61 (s, 3H); 1.22 (s, 9H); 1.18 (t, J = 7.2 Hz, 3H).
Preparation of (S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)- 1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid (181): (S)- ethyl 2-tert-butoxy-2-(6-formyl-3-methyl- 1 -(trifluoromethylsulfonyl-oxy)naphthalen-2- yl)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-formyl-3- methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate to (S)-2-tert-butoxy-2- ((R)-6-(difluoromethyl)-l-(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 salt) as an amorphous pale yellow powder. LCMS-ESI+ (m/z):
[M+H]+calcd for C29H28F2N04: 492.2; found: 492.1. 1H-NMR: 400 MHz, (CD3OD) δ: 8.67 (d, J = 4.4 Hz, 1H); 8.13 (s, 1H); 8.08 (s, 1H); 7.85-7.99 (m, 2H); 7.46 (d, J = 8.8 Hz, 1H); 7.40 (d, J = 8.8 Hz, 1H); 7.07 (d, 8.8 Hz, 1H); 6.90 (t, JHF = 56 Hz, 1H); 5.26 (s, 1H); 4.77-4.69 (m, 2H); 3.67 (t, J = 6 Hz, 2H); 2.80 (s, 3H); 0.93 (s, 9H).
Example 151. Preparation of (S)-ethyl 2-tert-butoxy-2-(4-carbamoyl-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (182)
Figure imgf000372_0001
ethyl 2-ferf-butoxy-2-(1- ethyl 2-(4-bromo-1 -hydroxy-3- hydroxy-3-methylnaphthalen- methylnaphthalen-2-yl)-2- 2- l)acetate ferf-butoxyacetate
Figure imgf000372_0002
ethyl 2-(4-bromo-3-methyl-1- ethyl 2-(4-bromo-3-methyl-1- (trifluoromethylsulfonyloxy)naphthalen- (trifluoromethylsulfonyloxy)naphthalen- 2-yl)-2-teAf-butoxyacetate 2-yl)-2-hydroxyacetate
Figure imgf000372_0003
ethyl 2-(4-bromo-3-methyl-1- (S)-ethyl 2-(4-bromo-3-methyl-1- (trifluoromethylsulfonyloxy) (trifluoromethylsulfonyloxy)naphthalen- naphthalen-2-yl)-2-oxoacetate 2-yl)-2-h droxyacetate
Figure imgf000372_0004
(S)-ethyl 2-(4-bromo-3-methyl-1- 182
(trifluoromethylsulfonyloxy)naphthalen-2- yl)-2- (S)-ethyl 2-ferf-butoxy-2-(4- ferf-butoxyacetate carbamoy l-3-methy 1-1 -(trif luoro
methylsulfonyloxy)naphthalen-2-yl)acetate
Preparation of ethyl 2-(4-bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2-tert- butoxyacetate: A solution of ethyl 2-tert-butoxy-2-(l-hydroxy-3-methylnaphthalen-2- yl)acetate ( 1.24 g, 3.92 mmol) in CHC13 (20 mL) was treated with solid NaHC03 (843 mg, 9.80 mmol). Then a solution of Br2 (750 mg, 4.70 mmol) in CHC13 (5.0 mL) was added dropwise over 2 min at 23 °C. After 30 min, the reaction was treated with 10% Na2S203 solution (10 mL). After maximum decolorization was achieved, the reaction was diluted with H20 (10 mL) and extracted with DCM (3 x 10 mL). Combined organic phases were dried (Na2S04), 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). 1H NMR (400 MHz, CDC13) δ 9.18 (s, 1H), 8.28 (d, J = 8.6 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.56 (dd, J = 8.6, 8.6 Hz, 1H), 7.45 (dd, J = 8.6, 8.6 Hz, 1H), 5.60 (s, 1H), 4.24-4.06 (m, 2H), 2.77 (s, 3H), 1.31 (s, 9H), 1.20 (t, J = 7.0 Hz, 3H).
Preparation of ethyl 2-(4-bromo-3 -methyl- l-(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-tert-butoxyacetate: A flask was charged with N-phenyl- trifluoromethanesulfonimide (2.70 g, 7.57 mmol), Cs2C03 (2.47 g, 7.57 mmol), and THF (20 mL). A solution of ethyl 2-(4-bromo-l-hydroxy-3-methylnaphthalen-2-yl)-2- tert-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 NaHS04 (30 mL) and saturated aq. Na2HP04 (100 mL) at 23 °C. The system was extracted with EtOAc/hexane (10:1, 3 x 50 mL). Combined organic phases were dried (Na2S04), filtered, concentrated, dissolved in 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). 1H NMR (400 MHz, CDC13) δ 8.41 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.70 (dd, J - 8.8, 8.8 Hz, 1H), 7.64 (dd, J = 8.8, 8.8 Hz, 1H), 5.77 (s, 1H), 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).
Preparation ethyl 2-(4-bromo-3-methyl-l -(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate: A solution of ethyl 2-(4-bromo-3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-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 H20 (30 mL). The organic phase was collected and the aqueous layer was extracted with DCM (2 x 20 mL). Combined organic layers were dried (Na2S04), filtered, and concentrated giving the desired product as a crude residue (1.22 g), which was immediately used in the next reaction without further purification. 1H NMR (400 MHz, CDC13) δ 8.41 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.71 (dd, J = 8.2, 8.2 Hz, 1H), 7.66 (dd, J = 8.2, 8.2 Hz, 1H), 5.84 (s, 1H), 4.34-4.20 (m, 2H), 2.63 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H). 19F NMR (377 MHz, CDC13) δ -73.0 (s).
Preparation of ethyl 2-(4-bromo-3 -methyl- l-(trifluoromethyl-sulfonyloxy) naphthalen-2-yl)-2-oxoacetate: A solution of ethyl 2-(4-bromo-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (crude, 1.22 g, -2.60 mmol) in DCM (60 mL) was treated with Dess-Martin periodinane (1.32 g, 3.12 mmol) at 23 °C. After 30 min, 10% Na2S203 (30 mL) was added at 23 °C. The system was diluted with H20 (20 mL) and extracted with DCM (3 x 30 mL). Combined organic layers were dried (Na2S04), 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- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate). 1H NMR (400 MHz, CDC13) δ 8.43 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.77 (dd, J = 8.6, 8.2 Hz, 1H), 7.71 (dd, J = 8.6, 8.6 Hz, 1H), 4.42 (q, J = 7.0 Hz, 2H), 2.57 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H). 19F NMR (377 MHz, CDC13) δ -73.3 (s).
Preparation of (S)-ethyl 2-(4-bromo-3 -methyl- 1 -(trifluoromethylsulfonyl- oxy)naphthalen-2-yl)-2-hydroxyacetate: A solution of ethyl 2-(4-bromo-3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (1.18 g, 2.52 mmol) in PhMe (20 mL) was cooled to -40 °C (dry ice/CH3CN). (R)-CBS catalyst (140 mg,
0.504 mmol) was introduced, followed by distilled catecholborane (neat, 402 μί, 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% Na2C03 (10 mL) was added. The reaction was stirred vigorously as it was warmed to 23 °C overnight. The next day, the organic phase was washed (with vigorous stirring) with more 15% Na2C03 (10 mL portions for 30 min each) until the washes were colorless. After the fifth wash, the organic phase was washed once with saturated NH4CI (10 mL) for 10 min, then dried (MgS04), filtered, 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). 1H NMR (400 MHz, CDC13) δ 8.41 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.71 (dd, J = 8.6, 8.2 Hz, 1H), 7.66 (dd, J = 8.6, 8.6 Hz, 1H), 5.84 (d, J = 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).
Preparation of (S)-ethyl 2-(4-bromo-3 -methyl- 1 (trifluoromethylsulfonyloxy naphthalen-2-yl)-2-tert-butoxyacetate: A solution of (S)-ethyl 2-(4-bromo-3-methyl-l- (trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (880 mg, 1.87 mmol) in tert-butyl acetate (20 mL) was treated with 70% HCIO4 (40 μί) at 23 °C. After 5 h, the reaction was added slowly over 5 min to saturated NaHC03 (50 mL) at 23 °C. The system was stirred for 10 min, then extracted with DCM (3 x 20 mL). Combined organic layers were dried ( a2S04), 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, CDC13) δ 8.40 (d, J = 7.8 Hz, IH), 8.06 (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, CDC13) δ -73.2 (s).
Preparation of (S)-ethyl 2-tert-butoxy-2-(4-carbamoyl -3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (182): A solution of (S)-ethyl 2- (4-bromo-3 -methyl- 1 (trifluoromethylsulfonyloxy )naphthalen-2-yl)-2-tert- butoxyacetate (200 mg, 0.380 mmol) in dry THF (7.6 mL) was cooled to -78 °C. tert- butyllithium (1.7 M in pentane, 446 μί, 0.759 mmol) was added dropwise under N2 over 3 min. 10 min later, trimethylsilylisocyanate (62.0 μί, 0.456 mmol) was quickly added. The reaction was warmed to 23 °C. After 1 h, the system was treated with glacial AcOH (87.0 μΐ,, 1.52 mmol) followed by EtOH (absolute, 1.9 mL). The reaction was stirred for 30 min then diluted with saturated NaHC03 (20 mL) and H20 (10 mL). The system was extracted with DCM (3 x 15 mL). Combined organic phases were dried (Na2S04), filtered, and concentrated. The residue was treated with benzene and wet-loaded onto a silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (75 mg, 40% yield.) !H NMR (400 MHz, CDC13) 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, IH), 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). 19F NMR (377 MHz, CDC13) δ -73.2 (s). Example 153. Preparation of (S)-2-tert-butoxy-2-((R)-4-carbamoyl-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid (183)
Figure imgf000376_0001
183
(S)-2-terf-butoxy-2-((f?)-4-carbamoyl-1- (2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methylnaphthalen-2-yl)acetic acid
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-4-carbamoyl-l-(2,3-dihydropyrano [4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-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 μπιοΐ), and CsF (108 mg, 0.708 mmol). The vessel was evacuated under vacuum and backfilled with argon. A solution of (S)-ethyl 2-tert-butoxy-2-(4-carbamoyl-3 -methyl- 1-
(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (182, 79 mg, 0.161 mmol) in 1,2- DME (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 H20 (8 mL). The system was extracted with DCM (3 x 15 mL). Combined organic layers were dried (Na2S04), filtered, and concentrated. The 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)-4- carbamoyl-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2- yl)acetate (3.4 mg) in semipure form. LCMS-ESI+ (m/z): [M+H]+ calcd for
C31H33N205: 513.2; Found: 513.1. The other diastereomer, (2S)-ethyl 2-tert-butoxy-2- ((S)-4-carbamoyl-l-(2,3-dmydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2- yl)acetate, was also obtained from the flash column in semipure form (1.3 mg, yield not found). LCMS-ESI+ (m/z): [M+H]+ calcd for C31H33N205: 513.2; Found: 513.1.
Preparation of (S)-2-tert-butoxy-2-((R)-4-carbamoyl- 1 -(2,3 - dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid (183): A solution of (2S)-ethyl 2-tert-butoxy-2-((R)-4-carbamoyl-l-(2,3-dihydro pyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (3.4 mg, semipure) in THF (1.0 mL) and EtOH (absolute, 500 μί) was added to LiOH»H20 (100 mg) predissolved in H20 (500 μΐ,). The mixture was stirred vigorously at 60 °C for 4 days. The reaction was cooled to 23 °C, diluted with EtOH (absolute, 1.0 mL), and filtered (0.45 micron filter). The filtrate was purified on a C18 Gemini column (eluent: H20/CH3CN 95:5→ 0:100 spiked with 0.1% v/v TFA), giving (S)-2-tert-butoxy-2-((R)-4-carbamoyl-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid as the mono-trifluoroacetic acid salt (1.5 mg, yield not found). 1H 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, CDC13) δ -77.5 (s). LCMS-ESf (m/z): [M+H]+ calcd for C29H29N205: 485.2; Found: 485.1. The other diastereomer, (2S)-2-tert-butoxy-2-((S)-4-carbamoyl-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetic acid, was prepared in a similar manner from (2S)-ethyl 2-tert-butoxy-2-((S)-4-carbamoyl-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate: 1H 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-ESI+ ( /z): [M+H]+ calcd for C29H29N205: 485.2; Found: 485.1.
Example 154. Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-l -(2,3- dihydropyrano [4,3 ,2-de]quinolin-7-yl)-3 -methylnaphthalen-2-yl)acetate (184)
Figure imgf000378_0001
ethyl 2-ferf-butoxy-2-( 1 - eth l 2-ferf-butoxy-2-(3-methy I- hydroxy-3-methyl 1 -(tnfluoromethylsulfonyloxy)
naphthalen-2-yl)acetate naphthalen-2-yl)acetate
Figure imgf000378_0002
ethyl 2-hydroxy-2-(3-methyl-1 - ethyl 2-(3-methyl-1 -
(trifluoromethylsulfonyloxy) (tnfluoromethylsulfonyloxy)
naphthalen-2-yl)acetate naphthalen-2-yl)-2-oxoacetate
Figure imgf000378_0003
(S)-ethyl 2-hydroxy-2-(3-methyl- (S)-ethyl 2-ferf-butoxy-2-(3-
1 -(tnfluoromethylsulfonyloxy) methyl-1 -(trifluoromethylsulfonyloxy)
naphthalen-2-yl)acetate naphthalen-2-yl)acetate
Figure imgf000378_0004
184
(S)-ethyl 2-ferf-butoxy-2-((R)-1- (2 , 3-di hyd ropy rano[4 , 3 , 2- de]quinolin-7-yl)-3- methylnaphthalen-2-yl)acetate
Preparation of ethyl 2-tert-butoxy-2-(3 -methyl-1 -(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate: Ethyl 2-tert-butoxy-2-(3 -methyl- 1-
(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate was prepared in a similar fashion to ethyl 2-tert-butoxy-2-(4-fluoro-3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen- 2-yl)acetate in Example 120 with appropriate adjustments to scale to afford an amorphous white solid that was contaminated with a small amount of PhNH(Tf).
LCMS-ESf (m/z): [M-C4H9+H]+ calcd for C16H15F306S: 392.4; found: 392.6.
Preparation of ethyl 2-hydroxy-2-(3 -methyl- 1 -(trifluoromethylsulfonyl- oxy)naphthalen-2-yl)acetate: A solution of ethyl 2-tert-butoxy-2-(3 -methyl- 1- (trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (6.0 grams, -13 mmol, semipure) in DCM (60 mL) was treated with TFA (6.0 mL) at 23 °C. The reaction was diluted with H20 (60 mL) and the organic phase collected. The aqueous layer was extracted with DCM (2 x 30 mL). The combined organic layers were dried (Na2S04), filtered, and concentrated. The residue (5.5 grams) was used in the next reaction without further purification. 1H NMR (400 MHz, CDC13): δ 8.08-8.06 (m, 1H), 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).
Preparation of ethyl 2-(3 -methyl- l-(trifluoromethylsulfonyloxy)naphthalen-2- yl)-2-oxoacetate: A solution of ethyl 2-hydroxy-2-(3-methyl-l- (trifluoromethylsulfonyloxy) naphthalen-2-yl)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% Na2S203 (100 mL). After 30 min, the reaction was extracted with DCM (3 x 50 mL). The combined organic layers were dried (Na2S04), 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 in semipure form (3.9 g). 1H NMR (400 MHz, CDC13): 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 (t, J = 7.4 Hz, 3H). 19F NMR (377 MHz, CDC13) δ -73.3 (s).
Preparation of (S)-ethyl 2-hydroxy-2-(3-methyl-l -(trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate: Ethyl 2-(3 -methyl- l-(trifluoromethylsulfonyloxy)naphthalen- 2-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 μί, 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% Na2C03 (12 mL) and the mixture was allowed to warm to room temperature. The mixture was washed with 15% Na2C03 (8 x 12 mL) and saturated NH4CI (24 mL), organic layer was dried with sodium sulfate and concentrated in vacuo. Chromatography using silica gel using EtOAc in hexanes produced the desired (S)- ethyl 2-hydroxy-2-(3 -methyl- 1 -(trifluoromethylsulfonyloxy)naphthalen-2-y l)acetate (976 mg, 1.8 mmol) in 74 % yield. 1H-NMR: 400 MHz, (CDC13): δ 8.08-8.06 (m, 1H); 7.81-7.79 (m, 1H); 7.69 (s, 1H); 7.60-7.57 (m, 2H); 5.81-5.80 (m, 1H); 4.35-4.19 (m, 2H); 3.42 (d, J = 2.4 Hz, 1H); 2.50 (s, 3H); 1.21 (t, J - 7.0 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-(3-methyl-l- (trifluoromethylsulfonyloxy) naphthalen-2-yl)acetate: 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 stir at room temperature for 2 hours. The mixture was quenched by pouring it into an ice-cold solution of saturated NaHC03. Extraction with EtOAc (3 x 20 mL), drying with sodium sulfate and column chromatography on silica gel using EtOAc in hexanes produced the desired product (S)-ethyl 2-tert-butoxy-2-(3 -methyl- 1 -(trifluoromethyl-sulfonyloxy)naphthalen-2- yl)acetate (455 mg, 71%). 1H-NMR: 400 MHz, (CDC13): δ 8.06-8.03 (m, 1H); 7.81- 7.78 (m, 1H); 7.67 (s, 1H); 7.59-7.53 (m, 2H); 5.73 (s, 1H); 4.25-4.10 (m, 2H); 2.55 (s, 3H); 1.21 (s, 9H), 1.17 (t, J = 7.2 Hz, 3H).
Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (184): (S)-ethyl 2-tert-butoxy-2-(3- methyl-l-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (555 mg, 1.23 mmol) in freshly distilled 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, HC1 salt (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 μιη particle size silica gel column separated the desired atropisomer (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3- dihydropyrano[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-methylnaphthalen-2-yl)acetate (109.9 mg, 0.234 mmol). 1H-NMR: 400 MHz, (CDC13): δ 8.66 (d, J = 4.4 Hz, 1H); 7.77 (d, J = 8.0 Hz, 1H); 7.72 (s, 1H); 7.50 (d, J = 8.0 Hz, 1H); 7.36-7.33 (m, 1H); 7.13-7.01 (m, 4H); 5.09 (s, 1H); 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).
Figure imgf000381_0001
184 (S)-ethyl 2-((f?)-1-(2,3-
(S)-ethyl 2-terf-butoxy-2-((F?)-1- dihydropyrano[4,3,2-c/e]quinolin- (2,3-dihydropyrano[4,3,2- 7-yl)-3-methylnaphthalen-2-yl)-2- de]quinolin-7-yl)-3- hydroxyacetate
methylnaphthalen-2-yl)acetate
Figure imgf000381_0002
185
(S)-ethyl 2-((R)-1-(2,3- (S)-2-((R)-1-(2,3- dihydropyrano[4,3,2-cfe]quinolin-7- dihydropyrano[4,3,2-de]quinolin-7- yl)-3-methylnaphthalen-2-yl)-2-(ferf- yl)-3-methylnaphthalen-2-yl)-2- pentyloxy)acetate (terf-pentyloxy)acetic acid
Preparation of (S)-ethyl 2-((R)-l-(2,3-dihydropyrano[43,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-hydroxyacetate: To a DCM solution (10 mL) of (S)-ethyl 2- tert-butoxy-2-((R)- 1 -(2,3 -dihydropyrano[4,3 ,2-de]quinolin-7-yl)-3 -methylnaphthalen- 2-yl)acetate (184) (49.0 mg, 0.104 mmol) was added TFA (650 μΐ,, 0.0084 mmol) and stirred at rt overnight. The mixture was quenched by pouring into an ice-cold solution of saturated NaHC03 and extracted with EtOAc to give crude (S)-ethyl 2-((R)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate (30.3 mg, 70%). 1H-NMR: 400 MHz, (CDC13): δ 8.67 (d, J = 4.0 Hz, 1H); 7.79-7.76 (m, 2H); 7.48 (d, J = 7.6 Hz, 1H); 7.38 (t, J = 7.8 Hz, 1H); 7.16-7.10 (m, 3H); 6.97 (d, J = 8.4 Hz, 1H); 5.36 (s, 1H); 4.58-4.55 (m, 2H); 3.89-3.72 (m, 2H); 3.38-3.31 (m, 2H); 2.69 (s, 3H); 1.05 (t, J=7.0 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C26H24N04; 414.17; Found: 414.1.
Preparation of (S)-ethyl 2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetate: (S)-ethyl 2-((R)-l-(2,3- dihydropyrano[4,3,2-de]qumolk-7-y0
(57.6 mg, 0.139 mmol) was slurried in 2.0 mL of tert-pentyl acetate and 500 μΐ. 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 into ice-cold saturated NaHC03. 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)-3- methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetate (58 mg). 1H-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): [M+H]+ calcd for C31H34 04:
484.25; Found: 484.14.
Preparation of (S)-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3- methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetic acid (185): (S)-ethyl 2-((R)-l-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(tert- pentyloxy)acetate (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)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2- (tert-pentyloxy)acetic acid (185) as the TFA salt (11.6 mg). 1H-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, 1H); 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, 6H); 0.62 (t, J = 7.0 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H3oN04: 456.55; Found: 456.11. Example 156. Preparation of (S)-2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-6-((dimethylamino)methyl)-5-fluoro-3-methylnaphthalen-2-yl)acetic acid (186A) and (S)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-5-fluoro-6-(hydroxymethyl)-3-methylnaphthalen-2-yl)acetic acid (186B) (S)-ethyl 2-tert-butoxy-2-((R)-
1-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-5-fluoro-6- formyl-3-methylnaphthalen-2- yl)acetate
O F
Figure imgf000383_0001
(S)-ethyl 2-ferf-butoxy-2-((R)-1 -(2,3- (S)-ethyl 2-ferf-butoxy-2-((/?)-1- dihydropyrano[4,3,2-de]quinolin-7-yl)-6- (2,3-dihydropyrano[4,3,2- ((dimethylamino)methyl)-5-fluoro-3- de]quinolin-7-yl)-5-fluoro-6- methylnaphthalen-2-yl)acetate (hydroxymethyl)-3- methylnaphthalen-2-yl)acetate
Figure imgf000383_0002
(S)-2-ieri-butoxy-2-((R)-1-(2,3- (S)-2-ierf-butoxy-2-((R)-1 -(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)- dihydropyrano[4,3,2-de]quinolin-7-yl)-5- 6-((dimethylamino)methyl)-5-fluoro-3- fluoro-6-(hydroxymethyl)-3- methylnaphthalen-2-yl)acetic acid methylnaphthalen-2-yl)acetic acid Preparation of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-6-(dimethylarrunomemyl)-5-fluoro-3-memylnaphthalen-2-yl)acetate and (S)-ethyl 2-tert-butoxy-2-((R)- 1 -(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5- fluoro-6-(hydroxymethyl)-3-methylnaphthalen-2-yl)acetate and (S)-ethyl 2-tert-butoxy- 2-((R)-l-(2,3-dmydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-(hydroxymethyl)-3- methylnaphthalen-2-yl)acetate: (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3- dihydropyrano[4,3,2-de]qumolin-7-yl)-5-fluoro-6-formyl-3-methymaphthalen-2- yl)acetate (18 mg, 0.035 mmol, 1 eq.) and dimethylamine HC1 salt (9 mg, 3 eq.) were mixed in 1 mL MeCN at room temperature for 1 hour. The reaction was cooled to 0°C and NaHB(OAc)3 (22mg, 3 eq.) was added to the reaction. The reaction was stirred at 0 °C then warmed up to room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 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]quinolin-7-yl)-6-((dimethylamino)methyl)-5-fluoro-3- methylnaphthalen-2-yl)acetate (5 mg); LCMS-ESf (m/z): [M+H]+ calcd for
C32H37FN204: 545.66; Found: 545.21; and (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3- dihydropyrano [4,3 ,2-de] quinolin-7-yl)-5 -fluoro-6-(hydroxymethyl)-3 - methylnaphthalen-2-yl)acetate (4 mg), LCMS-ESI+ (m/z): [M+H]+ calcd for
C31H32FN05: 518.59; Found: 518.12.
Preparation of (S)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-6-((dimethylamino)methyl)-5-fluoro-3-methylnaphthalen-2-yl)acetic acid (186A): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-6-((dimethylamino)methyl)-5-fluoro-3-methylnaphthalen-2-yl)acetate (5 mg) in tetrahydrofuran (0.5 mL) and ethanol (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 (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give a yellow powder (3.4 mg). 1H-NMR: 400 MHz, (CD3OD): δ 8.55 (d, J = 5.08 Hz, 1H), 8.10 (s, 1H), 7.58 (d, J = 8.21 Hz, 1H), 7.53 (d, J = 4.69 Hz, 1H), 7.25 (d, J = 8.22 Hz, 1H), 7.18 (dd, J = 7.82 Hz, 1H), 6.78 (d, J = 8.60 Hz, 1H), 5.15 (s, 1H), 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, 9H). 19F-NMR: 377 MHz, (CD3OD) δ: -77.7 (s, 3F), -126.37 (s, IF). LCMS-ESf (m/z): [M+H]+ calcd for C31H34FN204: 517.60; Found: 517.17.
Preparation of (S)-2-tert-butoxy-2-((R)-l -(2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-5-fluoro-6-(hydroxymethyl)-3-methylnaphthalen-2-yl)acetic acid (186B): A solution of (S)-ethyl 2-tert-butoxy-2-((R)-l-(2,3-dihydropyrano[4,3,2-de]quinolin-7- yl)-5-fluoro-6-(hydroxymethyl)-3-rnethylnaphthalen-2-yl)acetate (4 mg) in
tetrahydrofuran (0.5 mL) and ethanol (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 (MgS04), filtered, concentrated and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H20 + 0.1% TFA). Product lyophilized to give a yellow powder (2.1 mg). 1H-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, 1H), 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, IF). LCMS-ESf m/z): [M+H]+ calcd for C29H29FNO5: 490.53; Found: 490.1.
Example 157. Preparation of (S)-2-tert-butoxy-2-(6-chloro-l-((R)-2,3- dihydropyrano[4,3,2-de]quinolm-7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (187)
Figure imgf000385_0001
1 -bromo-3-chloro-2,4- (S)-2-terf-butoxy-2-(6-chloro-1-((R)-2,3- difluorobenzene dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7- difluoro-3-methylnaphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-(6-chloro-l-((R)-2,3-dihydropyrano [4,3,2- de]quinolin-7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)acetic acid: The title compound was prepared following a procedure similar to make (S)-2-tert-butoxy-2- ((R)-5-cUoro-l-(2,3-dmydropyrano[4,3,2-de]quinolm-7-yl)-3,6-dimethylnaphthalen -2- yl)acetic acid (116) of Example 1 14 except l-bromo-3-chloro-2,4-difluoro-benzene was used instead of l-bromo-2-chloro-3-methylbenzene. 1H-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, 1H), 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, IF), -123.12 (s, IF). LCMS-ESf (m/z): [M+H]+ calcd for C28H25C1F2N04: 512.94; Found: 512.1.
Example 158. Preparation of (S)-2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-5,7-difluor -3,6-dimethylnaphthalen-2-yl)acetic acid (188)
Figure imgf000386_0001
(S)-2-ferf-butoxy-2-(1 -((R)-2,3- dihydropyrano[4,3,2-cfe]quinolin-7-yl)- 5,7-difluoro-3,6-dimethylnaphthalen-2- yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin- 7-yl)-5,7-difluoro-3,6-dimethylnaphthalen-2-yl)acetic acid (188): Following a procedure similar to the preparation of (S)-2-tert-butoxy-2-((R)- 1 -(2,3 - dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3,6-dimethylnaphthalen-2-yl)acetic acid (119) of Example 1 17, (S)-ethyl 2-tert-butoxy-2-(6-chloro-l-((R)-2,3-dihydro- pyrano[4,3,2-de]quinolin-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-(2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate. 1H- NMR: 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, 1H), 4.72 (m, 2H), 3.66 (dd, J = 5.86 Hz, 2H), 2.78 (s, 3H), 2.32 (s, 3H), 0.93 (s, 9H).19F-NMR: 377 MHz, (CD3OD) δ: -77.8 (s, 3F), -117.62 (s, IF), -126.33 (s, IF). LCMS-ESI+ (m/z): [M+H]+ calc'd for C29H28F2N04: 492.53; Found: 492.06. Example 159. Preparation of (S)-2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano[4,3,2- de]quinolin-7-yl)-6-ethyl-5,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (189)
Figure imgf000387_0001
189
(S)-2-terf-butoxy-2-(1-((R)-2,3- dihydropyrano[4,3,2-cte]quinolin-
7-yl)-6-ethyl-5,7-difluoro-3- methylnaphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-
7-yl)-6-ethyl-5,7-difluoro-3-methylnaphthalen-2-yl)acetic acid (189): Following a procedure similar to the preparation of (S)-2-tert-butoxy-2-(l-((R)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-5-fluoro-3-memymaphthalen-2-yl)acetic acid (120) of Example 118, (S)-ethyl 2-tert-butoxy-2-(6-chloro-l-((R)-2,3- dihydropyrano[4,3,2-de]qumolm-7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)acetate (from Example 157) was used instead of (S)-ethyl 2-tert-butoxy-2-(6-chloro-l-((R)-2,3- dihydropyrano[4,3,2-de]quinolm-7-yl)-5-fluoro-3-methyl-naphthalen-2-yl)acetate. 1H- NMR: 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), 5.1 1 (s, 1H), 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, IF), -128.26 (s, IF). LCMS-ESI+ (m/z): [M+H]+ calc'd for C30H3oF2N04: 506.55; Found: 506.1.
Example 160. Preparation of (S)-2-tert-butoxy-2-(l-((R)-2,3 -dihydropyrano [4,3 ,2- de]qumolin-7-yl)-5,7-difluoro-3-methyl-6-( yrirm^in-5-yl)naphthalen-2-yl)acetic acid (190)
Figure imgf000388_0001
(S)-2-terf-butoxy-2-(1 -((R)-2,3- di ydropyrano[4,3,2-de]quinolin-7-yl)-5J- difluoro-3-methyl-6-(pyrimidin-5- yl)naphthalen-2-yl)acetic acid
Preparation of (S)-2-tert-butoxy-2-(l-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-
7-yl)-5,7-difluoro-3-methyl-6-(pyrirriidin-5-yl)naphthalen-2-yl)acetic acid (190):
Following a procedure similar to the preparation of (S)-2-tert-butoxy-2-(l -((R)-2,3- dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3,6-dimethylnaphthalen-2-yl)acetic acid (188) of Example 158, pyrimidin-5-ylboronic acid was utilized instead of methylboronic acid to eventually afford the title compound. 1H-NMR: 400 MHz,
(CD3OD): δ 9.22 (s, 1H), 8.99 (s, 1H), 8.74 (d, J = 5.87 Hz, 1H), 8.24 (s, 1H), 7.84 (d, J
= 7.82 Hz 1H), 7.78 (d, J = 5.48 Hz 1H), 7.46 (d, J = 8.12 Hz, 1H), 6.69 (d, J = 11.34 Hz, 1H), 5.26 (s, 1H), 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) 6: -77.6 (s, 6F), -118.79 (s, IF), -125.06 (s, IF).
LCMS-ESI+ (m/z) [M+H]+ calcd for C32H28F2N304: 556.57; Found: 556.10.
Example 161. The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I ('Compound X'), for therapeutic or prophylactic use in humans.
(ϊ) Tablet 1 mg/tablet
Compound X= 100.0
Lactose 77.5
Povidone 15.0
Croscarmellose sodium 12.0
Macrocrystalline cellulose 92.5
Magnesium stearate 3.0
300.0
n Tablet 2 mg/tablet
Compound X= 20.0 Microcrystalline cellulose 410.0
Starch 50.0
Sodium starch glycolate 15.0
Magnesium stearate 10
500.0
(ni) Capsule mg/capsule
Compound X= 10.0
Colloidal silicon dioxide 1.5
Lactose 465.5
Pregelatinized starch 120.0
Magnesium stearate 0
600.0
(iv) Injection 1 (1 mg/ml) mg/ml
Compound X= (free acid form) 1.0
Dibasic sodium phosphate 12.0
Monobasic sodium phosphate 0.7
Sodium chloride 4.5
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 phosphate 0.3
Dibasic sodium phosphate 1.1
Polyethylene glycol 400 200.0
01 N Sodium hydroxide solution
(pH adjustment to 7.0-7.5) q.s.
Water for injection q.s. ad 1 mL
(vi) Aerosol mg/can
Compound X= 20.0
Oleic acid 10.0
Trichloromonofluoromethane 5,000.0
Dichlorodifluoromethane 10,000.0
Dichlorotetrafluoroethane 5,000.0
The above formulations may be obtained by conventional procedures well known in 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 specific 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.

Claims

CLAIMS claimed is:
A compound of formula I:
Figure imgf000391_0001
wherein:
R1 is R,aorR,b;
R2isR2a orR2b;
R3isR3aorR3b;
R3 isR3a' orR3b';
R4isR4aorR4b;
R5isR5a orR5b;
R6isR6aorR6b;
R7isR7aorR7b;
R8isR8a orR8b;
Rla is selected from:
a) H, halo, (C1-C6)alkyl and (d-C^haloalkyl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;
c) -C(0)-Rn, -C(=0)-0-Rn, -O-R11, -S-Rn, -S(0)-Rn, -S02-Rn,
-(Ci-C6)alkyl-Rn, -(d-C^alkyl-C^-R11, -(Cr^alkyl-C^-O-R11, -(C,-C6)alkyl-0- R11, -(Ci-C6)alkyl-S-Ru, -(CrC^alkyl-S^-R11 and -(Ci-C6)alkyl-S02-Rn, wherein each R11 is independently selected from H, (C!-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Q- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and d) -N(R9)R10, -C(=0)-N(R )R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(Ci-C6)alkyl-N(R9)R10, -(C C6)alkyl-C(=0)-N(R9)R10, -(Ci-C6)alkyl-0-C(-0)-N(R9)R10 and -(C1-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (C C6)alkyl and (C3-C7)cycIoalkyl and wherein each R10 is independently selected from R11, -(C,-C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORu and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (C1-C6)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 Rl is optionally substituted with one or more Z10 groups;
Rlb is selected from:
a) -(Ci-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle, -(CrC6)alkyl-S-(C1- C6)alkyl-(C3-C7) carbocycle, -(C1-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7) carbocycle, -(d- C6)alkyl-S02-(C1-C6)alkyl-(C3-C7)carbocycle, -(Ci-C6)alkyl-S02-(CrC6)alkyl-Z13, -C(O)- (C C6)alkyl-Z13, -0-(C1-C6)alkyl-Z13, -S-CCrQ alkyl-Z13, -S(0)-(Ci-C6)alkyl-Z13, -S02- (C C6)alkyl-Z13, -(Ci-C6)alkyl-Z14, -(Ci-C6)alkyl-C(0)-(Ci -Ce^lkyl-Z1 -(C C6)alkyl- C(0)-0(Ci-C6)alkyl-Z13, -(CrC6)alkyl-0-(Ci-C6)alkyl-Z13, -(C1-C6)alkyl-S-(C1-C6)alkyl- Z13, -(C2-C6)alkenyl-(C1-C6)haloalkyl, -(C2-C6)alkynyl-(Ci-C6)haloalkyl, -(C3- C7)halocarbocycle,-NRaS02 RcRd, -NRaS020(C3-C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl -(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z' or -halo(Ci-C6)alkyl-Z3, wherein any (C1-C6)alkyl, (Cj-C6)haloalkyl, (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 Z1 groups;
b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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 wherein the -(C3-C )carbocycle or heterocycle is optionally substituted with one or more Z1 groups; c) (C]-C6)alkyl, wherein (C]-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z1 groups;
d) -X(d-C6)alkyl, -X(C C6)haloalkyl, -X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle, wherein any -X(C!-C )alkyl and -XCCrC^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 Z1 groups;
f) (C i -C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein (d-C6)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 Z'groups; and
g) -NRJ f, -C(0)NReRf, -OC(0) ReRf, -S02NReRf, -(Ci-C6)alkyl-NReRf, -(Ci-C6)alkylC(0)-NReRf, -(Ci-C6)alkyl-0-C(0)- ReRf and -(Ci-C6)alkyl-S02NReRf; wherein any (Ci-C6)alkyl, as part of a group, is optionally substituted with one or more Z'groups;
R2 is selected from:
a) H, (d-C6)alkyl and -0(C,-C6)alkyl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl, (d-C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;
c) C(=0)-Ru, -C(=0)-0-Ru, -S-R11, -S(0)-Ru, -S02-Rn,
-(d-C6)alkyl-Rn, -(d-C6)alkyl-C(-0)-Rn, -(d-C6)alkyl-C(=0)-0-Rn, -(C C6)alkyl-0- R11, -(d-C^alkyl-S-R1 1, -(Ci-C6)alkyl-S(0)-Ru and -(d-C6)alkyl-S02-Rn, wherein each R11 is independently selected from H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z11 groups; d) -OH, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(Ci-C6)haloalkyl, -0(C3- C7)cycloalkyl, -Oaryl, -Oheterocycle and -Oheteroaryl; and
e) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(d- C6)alkyl-N(R9)R10, -(C1-C6)alkyl-C(=0)-N(R9)R10, -(C1-C6)alkyl-0-C(=0)-N(R9)R10, and -(C i -C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (C i - C6)alkyl and (C3-C7)cycloalkyl, and each R10is independently selected from Rn, -(Cj- C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
R2b is selected from:
a) -(d -C6)alkyl-0-(C1 -C6)alkyl-(C3-C7)carbocycle, -(C j -C6)alkyl-S-(C , - C6)alkyl-(C3-C7)carbocycle, -(Ci-C6)alkyl-S(0)-(Ci-C6)alkyl-(C3-C7)carbocycle, -(d- C6)alkyl-S02-(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(d-C6)haloalkyl, -(C2- C6)alkynyl-(C,-C6)haloalkyl, -(C!^alkyl-SO Cd-Ceialkyl-Z13, -C(0)-(d-C6)alkyl-Z13, -0-(d-C6)alkyl-Z13, -S-(d-C6)alkyl-Z13, -S(0)-(d-C6)alkyl-Z13, -S02-(C C6)alkyl-Z13, -(d-C6)alkyl-Z14, -(C,-C6)alkyl-C(0)-(Ci-C6)alkyl-Z13, -(d-C6)alkyl-C(0)-0(d- C6)alkyl-Z13, -(d-C6)alkyl-0-(d-C6)alkyl-Z13, -(d-C6)alkyl-S-(d-C6)alkyl-Z13, -(C3- C7)halocarbocycle,-NRaS02NRcRd, -NRaS020(C3-C7)carbocycle, -NRaS02Oaryl,
-(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(d-C^carbocycle-Z1 and -halo(d-C6)alkyl-Z3, wherein any (d-C6)alkyl, -(Ci-C6)haloalkyl, (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 Z'groups;
b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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, wherein the (C3-C7)carbocycle or heterocycle is optionally substituted with one or more Z1 groups; c) (C1-C )alkyl, wherein (C C^alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z1 groups;
d) -X(Ci-C6)alkyl, X(C C6)haloalkyl, X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C -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 Z1 groups;
f) (C!-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein (Ci-C6)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^Rf, -C(0)NReRf, -OC(0)NReRf, -SO^Rf, -(C1-C6)alkyl- RcRf, -(C)-C6)alkylC(0)-NR^Rf, -(Ci-C6)alkyl-0-C(0)- RcRf and -(Ci-C6)alkyl-S02NReRf, wherein any (Ci-C6)alkyl, as part of a group, optionally substituted with one or more Z'groups;
R3a is (C,-C6)alkyl, (C C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
-(C i -C6)alkyl-(C3-C7)cycloalkyl, -(C i -C6)alkyl-aryl, -(d -C6)alkyl-heterocycle,
-(d-C6)alkyl-heteroaryl, -0(Ci-C6)alkyl, -0(Ci-C6)haloalkyl, -0(C2-C6)alkenyl,
-0(C2-C6)alkynyl, -0(C3-C7)cycloalkyl, -Oaryl, -0(C1-C6)alkyl-(C3-C7)cycloalkyl, -0(Ci-C6)alkyl-aryl, -0(Ci-C6)alkyl-heterocycle or -0(C1-C6)alkyl-heteroaryl, wherein any (Ci-C6)alkyl, (C C6)haloalkyl, (C2-C6)alkenyl or (C2-C6)alkynyl of R3a is optionally substituted with one or more groups selected from -O^!-C^alkyl, halo, oxo and -CN, and wherein any (C3-C7)cycloalkyl, aryl, heterocycle or heteroaryl of R3a is optionally substituted with one or more groups selected from (Ci-C6)alkyl, -0(Ci-C6)alkyl, halo, oxo and -CN; and R3a' is H; R is (C7-C14)alkyl, (C3-C7)carbocycle, aryl, heteroaryl, heterocycle,
-(d-C6)alkylOH, -(d-C^alkyl-O-Cd^alkyl-Z12, -(C1-C6)alkyl-0-(C2-C6)alkenyl-Z12, -(C2-C6)alkyl-0-(C2-C6)alkynyl-Z12, -(d-C6)alkyl-S-(d-C6)alkyl-Z12, -(d-C6)alkyl-S- (C2-C6)alkenyl-Z12, -(C C^alkyl-S-^-C^alkynyl-Z12, -(d-C6)alkyl-S(0)-(Ci- C6)alkyl-Z12, -(Ci-C6)alkyl-S(0)-(C2-C6)alkenyl-Z12, -(C C6)alkyl-S(0)-(C2-
C6)alkynyl-Z12, -(C1-C6)alkyl-S02-(C1-C6)alkyl-Z12, -(C1-C6)alkyl-S02-(C2-C6)alkenyl-Z12, -(C2-C6)alkyl-S02-(C2-C6)alkynyl-Z12, -(Ci-C6)alkyl- RaRb, -(Ci-C6)alkylOC(0)-NRcRd, - (C1-C6)alkyl-NRa-C(0)-ORb, C6)alkyl-S02(Ci- C6)alkyl, -(C C6)alkyl-S02N
Figure imgf000396_0001
-(Ci-C6)alkyl- RaS020(C3-C7)carbocycle, -(d-C6)alkyl-NRaS020aryl,
-(Ci-C^alkyl-NRa-SOz- d^alkyl, -(d-Cs^ll yl-NRa-SO^haloCd^^lkyl,
-(C,-C6)alkyl-NRa-S02-(C2-C6)alkenyl, -(C1-C6)alkyl-NRa-S02-(C2-C6)alkynyl,
-(Ci-C6)alkyl-NRa-S02-(C3-C7)carbocycle, -(C,-C6)alkyl-NRa-S02-halo(C3-C7)carbocycle, -(Ci-C6)alkyl-NRa-S02-aryl, -(C1-C6)alkyl-NRa-S02-heteroaryl,
-(Ci-C6)alkyl-NRa-S02-heterocycle, -0(C7-CM)alkyl, -0(Ci-C6)alkyl-NRaRb,
-OCCrCeialkylOCCO^NRcRd, -0(d-C6)alkyl-NRa-C(0)-ORb,
-0(Ci-C6)alkyl-NRa-C(0)-NRaRb, -0(d-C6)alkyl-NRa-S02-(Ci-C6)alkyl,
-0(C1-C6)alkyl-NRa-S02-halo(Ci-C6)alkyl, -0(C1-C6)alkyl-NRa-S02-(C2-C6)alkenyl, -0(d-C6)alkyl-NRa-S02-(C2-C6)alkynyl, -0(Ci-C6)alkyl-NRa-S02-(C3-C7)carbocycIe, -0(Ci-C6)alkyl-NRa-S02-halo(C3-C7)carbocycle, -0(C1-C6)alkyl-NRa-S02-aryl,
-0(C i -C6)alkyl-NRa-S02-heteroaryl, -0(C i -C6)alkyl-NRa-S02-heterocycle,
Figure imgf000396_0002
-0(CrC6)alkyl-NRa-S02-(C3-C7)carbocycle,
-0(C i -C6)alkyl-NRa-S02-halo(C3-C7)carbocycle, -0(C i -C6)alkyl-NRa-S02-aryl, -0(C i - C6)alkyl-NRaS02NRcRd, -0(Ci-C6)alkyl-NRaS020(C3-C7)carbocycle, -0(Ci-C6)alkyl- NRaS02Oaryl, -Oheteroaryl, -Oheterocycle, -Sheteroaryl, -Sheterocycle, -S(0)heteroaryl, -S(0)heterocycle, -S02heteroaryl or -S02heterocycle, wherein any (C]-C6)alkyl, -(C7- C]4)alkyl, aryl, (C3-C7)carbocycle, heteroaryl or heterocycle of R3b, either alone or as part of a group, is optionally substituted with one or more Z1 groups, and R3b is H, (C1-C6)alkyl or -0(Ci-C6)alkyl; or R3b and R3b together with the carbon to which they are attached form a heterocycle or (C3-C7)carbocycle which heterocycle or (C3-C7)carbocycle of R3b and R3b together with the carbon to which they are attached is optionally substituted with one or more Z1 groups;
R4a is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R4a is optionally substituted with one or more groups each independently selected from halo, (C!-C6)alkyl, (C2-C6)alkenyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, -OH, -0(Ci-C6)alkyl, -SH, -SCQ-Q alkyl, -NH2, -NH(C1-C6)alkyl and -N((Ci-C6)alkyl)2, wherein (Q-C^alkyl is optionally substituted with hydroxy, -0(Ci-C6)alkyl, cyano or oxo;
R4b is selected from:
a) (CrC6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (C C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl are each optionally substituted with one or more Z1 groups;
b) (C3-C14)carbocycle, wherein (XLVC^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;
c) spiro-heterocycle and bridged-heterocycle, wherein spiro-heterocycle 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 bridged- heterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridged- heterocycle 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 which they are attached may be optionally substituted with one or more Z1 groups; and R3 is H, (Ci-C6)alkyl or -O(C)- C6)alkyl;
R5a is selected from:
a) halo, nitro and cyano; b) R11, -C(=0)-Rn, -C(=0)-0-Rn, -0-R11, -S-R11, -S(0)-Rn, -S02-Rn, -(Cr C6)alkyl-Rn, -(C,-C6)alkyl-C(=0)-Rn, -(C-C^alkyl-CC^-O-R11, -(Ci-C6)alkyl-0-Ru, -(Ci-C6)alkyl-S-Rn, -(C1-C6)alkyl-S(0)-R11 and -(d-CeJalkyl-SOz-R11, wherein each R11 is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cp C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z11 groups; and
c) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(Ci- C6)alkyl-N(R9)R10, -(C1-C6)alkyl-C(=0)-N(R9)R10, -(d-C^alkyl-O-C^C -NCR^R10, and -(Ci-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (d- C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11 , -(C)- C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORH and -C(=0)N(R9)Rn, wherein each Rn is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
R5b is selected from:
a) -(C1-C6)alkyl-0-(C1-C6)alkyl-(C3-C7)carbocycle,
-(C i -C6)alkyl-S-(C i -C6)alkyl-(C3-C7)carbocycle,
-(d-C6)alkylS(0)-(Ci-C6)alkyl-(C3-C7)carbocycle,
-(Ci-C6)alkylS02(Ci-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(Ci-C6)haloalkyl, -(C2- C6)alkynyl-(Ci-C6)haloalkyl, -(C3-C7)halocarbocycle, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C3-C7)carbocycle-Z1 and -halo(Ci-C6)alkyl-Z3, wherein any (d-C6)alkyl, (CrC6)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 Z1 groups;
b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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 wherein the (C3-C7)carbocycle or heterocycle is optionally substituted with one or more Z1 groups;
c) (C]-C6)alkyl, wherein (CrC^alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z1 groups;
d) -X(Ci-C6)alkyl, -XCd-Ce^aloalkyl, -X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle, wherein any -X(C1-C6)alkyl and -X(Ci-C6)haloalkyl is substituted with one or more Z3 groups and optionally substituted with one or more Zl groups, 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'groiips;
f) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein (Ci-C6)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 Z^oups; and
g)
Figure imgf000399_0001
-(Ci-C6)alkylC(0)-NReRf, -(Ci-C6)alkyl-0-C(0)-NReRf and -(Ci-C6)alkyl-S02NReRf, wherein any (Ci-C6)alkyl, as part of a group, is optionally substituted with one or more Z1 groups;
R6a is selected from:
a) H, halo, (C C6)alkyl and (d-C6)haloalkyl
b) (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;
c) -C(=0)-R' 1 , -C^C -O-R11 , -O-R1 1 , -S-R11 , -S^-R11 , -S02-R11 ,
-(C C6)alkyl-Rn, -(Ci-C6)alkyl-C(=0)-Rn, -(C^alkyl-C^OKJ-R1 1 , -(C,-C6)alkyl-0- R11, -(Ci-C6)alkyl-S-Rn, -(C,-C6)alkyl-S(0)-Rn and -(C C6)alkyl-S02-Rn, wherein each R11 is independently selected from H, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and
d) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(Ci-C6)alkyl-N(R9)R10, -(Ci-C6)alkyl-C(=0)-N(R9)R10, -(CrC6)alkyl-0-C(=0)-N(R9)R10 and -(C1-C )alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (Cr C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(Q- C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
and wherein any aryl, heterocycle and heteroaryl of R6a is optionally substituted with one or more Z10 groups;
R6b is selected from:
Figure imgf000400_0001
C6)alkyl-(C3-C7)carbocycle, -(Ci-C6)alkyl-S(0)-(C1-C6)alkyl-(C3-C7)carbocycle, -(C C6)alkyl-S02-(C C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(Ci-C6)haloalkyl, -(C2- C^alkynyl-Cd-C^haloalkyl, -halo(C3-C7)carbocycle,-NRaS02NR<:Rd, -NRaS020(C3- C7)carbocycle, - RaS02Oaryl, -(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-C )alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-ORa, -(C2-C6)alkyl-(C3-C7)carbocycle-ORa, -(C3-C7)carbocycle-Z1 and -halo(CrC6)alkyl-Z3, wherein any (C]-C6)alkyl,
(Ci-C6)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 Z1 groups;
b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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, wherein the (C3-C7)carbocycle or heterocycle is optionally substituted with one or more Z1 groups; c) (C1-C6)alkyl, wherein (Q-C^alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z1 groups;
d) -XCCrCf alkyI, -X(Ci-C6)haloalkyl, -X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle, wherein any -X(C1-C6)alkyl and -X(Ci-C6)haloalkyl is 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 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) (CrC6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein (Ci-C6)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; and
g) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(Ci-C6)alkyl-NReRf, -(Ci-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NReRf and -(Ci-C6)alkyl-S02NReRf, wherein any (C!-C6)alkyl, as part of a group, is optionally substituted with one or more Z'groups;
R7a is selected from:
a) H, halo, (d-C6)alkyl and (C-C^haloalkyl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl;
c) ^Ο^', ^^-Ο-^', -Ο-^', -Β-^^ -Β^-^', -ΞΟ^11,
-(C1-C6)alkyl-R11,
Figure imgf000401_0001
-(C C6)alkyl-0- R11, -(Ci-C6)alkyl-S-RH, -(Ci-C6)alkyl-S(0)-Rn and -(Ci-C6)alkyl-S02-Rn, wherein each R11 is independently selected from H, (d-Ceialkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and d) -N(R9)R10, -C(-0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(d-C6)alkyl-N(R9)R10, -(C)-C6)alkyl-C(=0)-N(R9)R10, -(Ci-C6)alkyl-0-C(=0)-N(R9)R10 and -(C1-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (C C6)alkyl and (C3-C7)cycloalkyl, and each R10is independently selected from Ru, -(Cp C6)alkyl-Rn, -S02-Rn, -C(=0)-Ru, -C(=0)ORu and -C(=0)N(R9)RH, wherein each R11 is independently selected from H, (C]-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Q- C )haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl; and
wherein any aryl, heterocycle and heteroaryl of R7a is optionally substituted with one or more Z10 groups;
R715 is selected from:
a) -(C1-C6)alkyl-S02-(C1-C6)alkyl-Z13, -C(0)-(Ci-C6)alkyl-Z13, -0-(C,- C6)alkyl-Z13, -S-(CrC6)alkyl-Z13, -S(0)-(C1-C6)alkyl-Z13, -S02-(C1-C6)alkyl-Z13, -(Ci-C6)alkyl-Z14, -(d-C^alkyl-C^-Cd-C^alkyl-Z13, -(CrC6)alkyl-C(0)-0(Ci- C6)alkyl-Z13, -(d-C6) lcyl-0-(d-C6)alkyl-Z13, -(Ci-C6)alkyl-S-(C1-C6)alkyl-Z13, -(d- C6)alkyl-0-(d -C6)alkyl-(C3-C7)carbocycle, -(d -C6)alkyl-S-(C , -
C6)alkyl-(C3-C7)carbocycle, -(C i -C6)alkyl-S(0)-(C i -C6)alkyl-(C3-C7)carbocycle, -(C i - C6)alkyl-S02-(Ci-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(Ci-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, -(C3-C7)halocarbocycle, -NRaS02NRcR<j, - RaS020(C3- C7)carbocycle, -NRaS02Oaryl, -(C2-C6)alkenyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-aryl, -(C2-C )alkenyl-heteroaryl, -(C2-C )alkenyl-heterocycle,
-(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(d-C^carbocycle-Z1 and -halo(d-C6)alkyl-Z3 , wherein any (C]-C6)alkyl, (Ci-C6)haloalkyl, (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 Zl groups;
b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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 wherein the (C3-C7)carbocycle or heterocycle is optionally substituted with one or more Z1 groups;
c) (Ci-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z'groups;
d) -X(C!-C6)alkyl, X(CrC6)haloalkyl, X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle, wherein any -X^-C^alkyl and -X(Ci-C6)haloalkyl is substituted with one or more Z 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 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 Z1 groups;
f) (C C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (Q-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 Z1 groups; and
g) -N eRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NReRf, -(C1-C6)alkylC(0)-NReRf, -(C1-C6)alkyl-0-C(0)-NReRf and -(C1-C6)alkyl-S02NReRf, wherein any (Ci-C6)alkyl, as part of a group, is optionally substituted with one or more Z'groups;
R8 is selected from:
a) halo, nitro and cyano;
b) Rn , -C^C -R11 , -C(=0)-0-R' 1 , -O-R11 , -S-R1 1 , -SCC -R11 , -S02-R! \ -(C i -
C6)alkyl-Rn, -(Ci-C6)alkyl-C(=0)-Rn, -(CrC6)alkyl-C(=0)-0-Rn, -(Ci-C6)alkyl-0-Rn, -(d^alkyl-S-R1 1, -(CrC^alkyl-S^-R1 1 and -(Ci-C6)alkyl-S02-Rn, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-Q)alkenyl, (C2-C6)alkynyl, (Q- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z11 groups; and c) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(Cr C6)alkyl-N(R9)R10, -(C1-C6)alkyl-C(=0)-N(R9)R,°, -(C1-C6)alkyl-0-C(-0)-N(R9)R,° and -(C1-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (d- C6)alkyl and (C3-C7)cycloalkyl, and each R10is independently selected from Rn, -(Ci- C6)alkyl-Ru, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
R is selected from:
a) -(Ci-C6)alkyl-S02-(Ci-C6)alkyl-Z13, -C(0)-(Ci-C6)alkyl-Z13, -0-(C
C6)alkyl-Z13, -S-(C C6)alkyl-Z13, -S(0)-(CrC6)alkyl-Z13, -S02-(C1-C6)alkyl-Z13,
-(C C6)alkyl-Z14, -(d-C^alkyl-CCOHCi-C^alkyl-Z13, -(C1-C6)alkyl-C(0)-0(C]- C6)alkyl-Z13, -(d-C6)alkyl-0-(d-C6)alkyl-Z13, -(Ci-C6)alkyl-S-(C1-C6)alkyl-Z13, -(d- C6)alkyl-0-(Ci-C6)alkyl-(C3-C7)carbocycle, -(C C6)alkyl-S-(Ci- C6)alkyl-(C3-C7)carbocycle, -(d-C^alkyl-SCOKd-C^alkyKCs-CT^arbocycle, -(d- C6)alkyl-S02-(Ci-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(d-C6)haloalkyl, -(C2- C6)alkynyl-(C1-C6)haloalkyl, -halo(C3-C7)carbocycle,-NRaS02NRcRd, - NRaS020(C3-C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -{d-C^carbocycle-Z1 and -halo(C1-C6)alkyl-Z3, wherein any (d-C6)alkyl, (C C6)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 Z1 groups:
b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged- bicyclic 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 wherein the (C3-C7)carbocycle or heterocycle is optionally substituted with one or more Z1 groups; c) (C]-C6)alkyl, wherein (C1-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z'groups;
d) -X(Ci-C6)alkyl, -X(C C6)haloalkyl, -X(C2-C6)alkenyl, -X(C2-C6)alkynyl and -X(C3-C7)carbocycle, wherein any -X(C!-C6)alkyl and -X(C]-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 z oups;
e) aryl, heteroaryl, heterocycle, -Xaryl, -Xheteroaryl and -Xheterocycle, 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 Z1 groups;
f) (C1-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (Ci-C6)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 Z' groups; and
g) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C,-C6)alkyl-NReRf, -(C1-C6)alkylC(0)-NRcRf, -(C1-C6)alkyl-0-C(0)- ReRf and -(C,-C6)alkyl-S02 ReRf, wherein any (C1-C6)alkyl, as part of a group, is optionally substituted with one or more Z1 groups;
or any of R5a and R6a, R6a and R7a, R7a and R8a, 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 substituents each independently selected from halo, (CrC6)alkyl, (C2-C6)alkenyl, (C]-C6)haloalkyl, (C3- C7)cycloalkyl, -OH, -0(Ci-C6)alkyl, -SH, -S(Ci-C6)alkyl, -NH2, -NH(C,-C6)alkyl and -N((C1-C6)alkyl)2;
or any of R5 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 Z or Z groups, wherein when two Z 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 6- membered 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 (C3-C7)carbocycle or 4, 5 or 6-membered heterocycle;
X is independently selected from O, -C(O)-, -C(0)0-, -S-, -S(O)-, -S02-, -(C
C6)alkylO-, -(d-C6)alkylC(0)-, -(C!-C6)alkylC(0)0-, -(C C6)alkylS-, -(d-C6)alkylS(0)- and -(Ci-C6)alkylS02-;
each Z1 is independently selected from halo, -N02, -OH, =NORa, -SH, -CN, (d- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d-C6)haloalkyl, (C3-C7)carbocycle, (C3- C7)halocarbocycle, aryl, heteroaryl, heterocycle, -0(d-C )alkyl, -0(C2-C6)alkenyl, -0(C2- C6)alkynyl, -0(C C6)haloalkyl, -0(C3-C7)carbocycle, -0(C3-C7)halocarbocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -S(Ci-C6)alkyl, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, -S(d- C6)haloalkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -Saryl, -Sheteroaryl, -Sheterocycle, -S(0)(C C6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(C C6)haloalkyl, -S(O) (C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S02(d-C6)alkyl, -S(0)aryl, -S(0)carbocycle, -S(0)heteroaryl, -S(0)heterocycle, -S02(C2-C6)alkenyl,
-S02(C2-C6)alkynyl, -S02(Ci-C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3- C7)halocarbocycle, -S0 aryl, -S02heteroaryl, -S02heterocycle, -S02 RcRd, -NRcRd, -NRaC(0)Ra, -NRaC(0)ORa, -NRaC(0)NRcRd -NRaS02Rb, -NRaS02NRcRd,
- RaS020(C3-C7)carbocycle, -NRaS02Oaryl, -OS(0)2Ra, -C(0)Ra, -C(0)ORb,
-C(0)NRcRd, and -OC(0)NRcRd, wherein any (d-C6)alkyl, -(d-C6)haloalkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C7)halocarbocycle, (C3-C7)carbocycle, aryl, heteroaryl and heterocycle of Z1, either alone or as part of a group, is optionally substituted with one or more halogen, -OH, -OR , -CN, -NRaC(0)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, - Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(0)2NRcRd; each Z is independently selected from -N02, -CN, spiro- heterocycle, bridge- heterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, NRaS02(C3- C7)carbocycle, -NRaS02aryl, -NRaS02heteroaryl, -NRaS02NRcR<j, -NRaS020(C3- C )carbocycle and -NRaS02Oaryl;
each Z is independently selected from -N02, -CN, -OH, oxo, ^NORa, thioxo, -aryl,
-heterocycle, -heteroaryl, -(C3-C7)halocarbocycle, -0(C1-C6)alkyl, -0(C3-C7)carbocycle, -Ohalo(C3-C7)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(C1-C6)alkyl, -S(C3- C7)carbocycle, -S(C3-C7)halocarbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(0)(Ci- C6)alkyl, -S(0)(C3-C7)carbocycle, -S(O) (C3-C7)halocarbocycle, -S(0)aryl, - S(0)heterocycle, -S(0)heteroaryl, -S02(Ci-C6)alkyl, -S02(C3-C7)carbocycle, -S02(C3- C7)halocarbocycle, S02aryl, -S02heterocycle, -S02heteroaryl, -NRaRb, -NRaC(0)Rb, -C(0)NRcRd, -S02NRcR<i, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle and
-NRaS02Oaryl;
each Z4 is independently selected from halogen, (CrC6)alkyl, (C3-C7)carbocycle, halo(C)-C6)alkyl, -N02, -CN, -OH, oxo, =NORa, thioxo, -aryl, -heterocycle, -heteroaryl, (C3-C7)halocarbocycle, -0(C1-C6)alkyl, -0(C3-C7)carbocycle, -0(C3-C7)halocarbocycle, Oaryl, -Oheterocycle, -Oheteroaryl, -S(C1-C6)alkyl, -S(C3-C7)carbocycle, -S(C3- C7)halocarbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(0)(C C6)alkyl, -S(0)(C3- C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S(0)aryl, -S(0)heterocycle, -S(0)heteroaryl, -S02(Ci-C6)alkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, S02aryl,
-S02heterocycle, -S02heteroaryl, -NRaRb, -NRaC(0)Ra, -C(0)NRcRd, -S02NRcRd, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle and -NRaS02Oaryl;
each Z5 is independently selected from -N02, -CN, -NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -NRaS02(Ci-C6)alkyl, -NRaS02(C2-C6)alkenyl,
-NRaS02(C2-C6)alkynyl, -NRaS02(C3-C7)carbocycle, -NRaS02(C3-C7)halocarbocycle, -NRaS02aryl, -NRaS02heteroaryl, -NRaS02heteroaryl, -NRaS02heterocycle,
-NRaC(0)alkyl, -NRaC(0)alkenyl, -NRaC(0)alkynyl, -NRaC(O) (C3-C7)carbocycle,
-NRaC(0)(C3-C7)halocarbocycle, -NRaC(0)aryl, -NRaC(0)heteroaryl,
-NRaC(0)heterocycle, NRaC(0)NRcR<i and NRaC(0)ORb; each Z6 is independently selected from -N02, -CN, -NRJRa, -NRaCiOiRb,
-NRaC(0)ORb, -C^NRcRd, -(C3-C7)halocarbocycle, -aryl, -heteroaryl, -heterocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -0(C3-C7)halocarbocycle, -0(Ci-C6)alkyl, -0(C3- C7)carbocycle, -Ohalo(Ci-C6)alkyl, -Saryl, -Sheteroaryl, -Sheterocycle, -S(C3- C7)halocarbocycle, -S(Ci-C6)alkyl, -S(C3-C7)carbocycle, -S(C1-C6)haloalkyl, -S(0)aryl, -S(0)heteroaryl, -S(0)heterocycle, -S(0)(C3-C7)halocarbocycle, -S(0)(C1-C6)alkyl, -S(0)(C3-C7)carbocycle, -S(0)halo(C1-C6)alkyl, -S02aryl, -S02heteroaryl,
-S02heterocycle, -S02(C]-C6)alkyl, -S02halo(C C6)alkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, -S02NRcRd, - RaS02(C3-C7)halocarbocycle, -NRaSCfearyl, -NRaSO^eteroaryl, -NRaS02heteroaryl, - aS02 RcR<J, - RaS020(C3-C7)carbocycle and -NRaSOsOaryl;
each Z7 is independently selected from -N02,
Figure imgf000408_0001
-CN, -(Ci-C6)alkyl-Z12, -(C2- C6)alkenyl-Z12, -(C2-C6)alkenylOH, -(C2-C6)alkynyl-Z12, -(C2-C6)alkynyl-OH, -(d- C6)haloalkyl-Z12, -(d-C6)haloalkylOH, -(C3-C7)carbocycle-Z12, -(C3-C7)carbocycleOH, -(C3-C7)halocarbocycle, -(C C6)alkylNRcR<J, -(C1-C6)alkylNRaC(0)Ra, -(d-
C6)alkylNRaS02Ra, aryl, heteroaryl, heterocycle, -0(d-C6)alkyl-Z]2, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(d-C6)haloalkyl, -0(C3-C7)carbocycle, -0(C3-C7)halocarbocycle, -Oaryl, -0(Ci-C6)alkylNRcRd, -0(C,-C6)alkylN aC(0)Ra, -0(C1-C6)alkylNRaS02Ra, -Oheteroaryl, -Oheterocycle, -S(Ci-C6)alkyl-Z12, -S(C2-C6)alkenyl, -S(C2-C6)alkynyl, -S(C1-C6)haloalkyl, -S(C3-C7)carbocycle, -S(C3-C7)halocarbocycle, -S(C1-C6)alkyl RcR<i, -SCd-C^alkylNRaCCO)!^, -S(Ci-C6)alkylNRaS02Ra, -Saryl, -Sheteroaryl, -Sheterocycle, -S(0)(C1-C6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(Ci-C6)haloalkyl, -S(0)(C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S02(Cj-C6)alkyl, -S(0)(C
C6)alkylNRcR<1, -S(0)(Ci-C6)alkylN aC(0)Ra, -SCOXd-Ce kylNRaSOsRa, -S(0)aryl, -S(0)heteroaryl, -S(0)heterocycle, -S02(C C6)alkyl, -S02(C2-C6)alkenyl, -S02(C2- C6)alkynyl, -S02(CrC6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, -S02aryl, -S02heteroaryl, -S02heterocycle, -S0 (Ci-C6)alkylNR Rd, -S02(d- C6)alkylNRaC(0)Ra, -S02(C C6)alkylNRaS02Ra, -SOzNRcRd, -NRaCCO^Rfc,
-NRaC(0)NRcRd -NRaS02R¾, -NRaS02NRcR<j, -NRaS020(C3-C7)carbocycle,
-NRaS02Oaryl, -OS(0)2Ra, -C(0)NRcRd, and -OC(0)NRcRd, wherein any (d-C6)alkyl, (CrC6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, (C3- C7)halocarbocycle, aryl, heteroaryl and heterocycle of Z7, either alone or as part of a group, is optionally substituted with one or more halogen, -OH, -OR , -CN, -NRaC(0)2Rb, - heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -SCO^NRcRd;
each Z8 is independently selected from -N02 and -CN;
each Z9 is independently selected from -(C1-C6)alkyl and -0(Ci-C6)alkyl;
each Z10 is independently selected from:
i) halo, oxo, thioxo, (C2-C6)alkenyl, (Ci-C6)haloalkyl, (C3- C7)cycloalkyl, (C3-C7)cycloalkyl-(Ci-C6)alkyl-, -OH, -0(Ci-
C6)alkyl, -0(Ci-C6)haloalkyl, -SH, -S(Ci-C6)alkyl, -SO(C
C6)alkyl, -S02(C1-C6)alkyl, -NH2, -NH(Ci-C6)alkyl and
-NCCC.-C^alkyl),;
ii) (Ci-C6)alkyl optionally substituted with -OH, -0-(C
C6)haloalkyl or -0-(CrC6)alkyl; and
iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle and heteroaryl is optionally substituted with halo, (Q-C^alkyl or COOH;
each Z11 is independently selected from Z10, -C(=0)-NH2, -C(=0)-NH(C1-C4)alkyl, -C(=0)-N((C C4)alkyl)2, -C(=0)-aryl, -C(=0)-heterocycle and -C(=0)-heteroaryl;
each Z12 is independently selected from -N02, =NORa, thioxo, aryl, heterocycle, heteroaryl, (C3-C7)halocarbocycle, (C3-C7)carbocycle, -0(C3-C7)carbocycle, -Ohalo(C3- C7)carbocycle, -Oaryl, -Oheterocycle, -Oheteroaryl, -S(CrC6)alkyl, -S(C3-C7)carbocycle, -Shalo(C3-C7)carbocycle, -Saryl, -Sheterocycle, -Sheteroaryl, -S(0)(C]-C6)alkyl,
-S(0)(C3-C7)carbocycle, -S(0)halo(C3-C7)carbocycle, -S(0)aryl, -S(0)heterocycle, -S(0)heteroaryl, -S02(Ci-C6)alkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, S02aryl, -S02heterocycle, -S02heteroaryl, -NRaRa, -NRaC(0)Rb, -C(0)NRcRd, - S02NRcRd, -NRaS02NRcRd, -NRaS020(C3-C7)carbocycle and -NRaS02Oaryl;
each Z13 is independently selected from -N02, -OH, =NORa, -SH, -CN, (C3- C7)halocarbocycle, -0(C!-C6)alk l, -0(C2-C6)alkenyl, -0(C2-C6)alkynyl, -0(Cr
C6)haloalkyl, -0(C3-C7)carbocycle, -0(C3-C7)halocarbocycle, -Oaryl, -Oheteroaryl, -Oheterocycle, -S(d-C6)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(0)(C,-C6)alkyl, -S(0)(C2-C6)alkenyl, -S(0)(C2-C6)alkynyl, -S(0)(C C6)haloalkyl, -S(0)(C3-C7)carbocycle, -S(0)(C3-C7)halocarbocycle, -S(0)aryl, -S(0)heteroaryl, -S(0)heterocycle, -S02(C1-C6)alkyl, -S02(C2-C6)alkenyl, -S02(C2-C6)alkynyl, -S02(Q- C6)haloalkyl, -S02(C3-C7)carbocycle, -S02(C3-C7)halocarbocycle, -S02aryl,
-S02heteroaryl, -S02heterocycle, -S02NRcRd, -N cRd,
Figure imgf000410_0001
-NRaC(0)ORb, -NRaC^NRJRd -NRaS02Rb, - RaS02 RcRd, -NRaS020(C3-C7)carbocycle,
-NRaS02Oaryl, -OS(0)2Ra, -C^Ra, -C(0)ORb, -C(0)NRcR<1, and -OC(0) RcRd, wherein any (C i -C6)alkyl, -(C i -C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -(C3-
C7)halocarbocycle, (C3-C7)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 halogen, -OH, -ORb, -CN, -NRaC(0)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, - Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(0)2NRcR<i;
each Z14 is independently selected from -N02, =NORa , -CN, -(C3-
C7)halocarbocycle, -0(C3-C7)halocarbocycle, -S(C3-C7)halocarbocycle, -S(0)(C3- C7)halocarbocycle, -S02(C3-C7)halocarbocycle, -NRaS02NRcRd, -NRaS020(C3- C7)halocarbocycle, -NRaS02Oaryl and -OS(0)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(0)2Rb, -heteroaryl, -heterocycle, -Oheteroaryl, -Oheterocycle, -NHheteroaryl, -NHheterocycle, or -S(0)2NRcRd;
each Ra is independently H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, aryl, aryl(C1-C6)alkyl-, heteroaryl or heteroaryl(Ci- C6)alkyl-, wherein any (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, aryl or heteroaryl of Rg, 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(C1-C6)alkyl-, heteroaryl or heteroaryl(Ci- C6)alkyl-, wherein any (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C )alkynyl, (C3-C7)carbocycle, heterocycle, aryl or heteroaryl of Rb is optionally substituted by halogen, OH and cyano; Rc and Rd are each independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)carbocycle, aryl, aryl(Ci-C6)alkyl-, heterocycle, heteroaryl and heteroaryl(Ci-C6)alkyl-, wherein any (C)-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, (C3-C7)carbocycle, heterocycle, aryl and heteroaryl of Rc or R , either alone or as part of a group, 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 Re is independently selected from -ORa, (Ci-C^alkyl and (C3-C7)carbocycle, wherein (Ci-C )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-C6)haloalkyl, (C2-C6)alkenyl and (C -C6)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 -Rg, -ORa, -(C1-C6)alkyl-Z6, -S02Rg,
-C(0)Rg, C(0)ORg, and -C^NR^; and
each Rg is independently selected from H, -ORa, (C1-C6)alkyl, (C3-C7)carbocycle, (d-C^haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heterocycle and heteroaryl, wherein any (d-C6)alkyl, (C3-C7)carbocycIe, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heterocycle or heteroaryl of Rg is optionally substituted with one or more Z1 groups; or a salt thereof.
2. The compound of claim 1 wherein R3 is (Ci-C6)alkyl, (C2-C6)alkenyl or -0(d- C6)alkyl wherein any (Ci-C6)alkyl or (C2-C6)alkenyl of R3 is optionally substituted with one or more groups selected from -0(Ci-C6)alkyl, halo, oxo and -CN; and wherein R3 is H.
3. The compound of claim 1 which is a compound of formula Ie:
Figure imgf000412_0001
Ie
or a salt thereof.
4. The compound of any one of claims 1-3 wherein R 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, (Q- C6)alkyl, (C2-C6)alkenyl, (C,-C6)haloalkyl, (C3-C7)cycloalkyl, -OH, -0(C C6)alkyl, -SH, - S(d-C6)alkyl, -NH2, -NH(Ci-C6)alkyl and-NCCd-Ce^l^, wherein(d^alkyl is optionally substituted with hydroxy, -0(C1-C6)alkyl, cyano or oxo;
b) (Q-C^carbocycle, wherein (C3-C14)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
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, (Cr C6)alkyl, (C2-C6)alkenyl, (C,-C6)haloalkyl, (C3-C7)cycloalkyl, -OH, -0(C,-C6)alkyl, -SH, - S(d-C6)alkyl, -NH2, -NH(C C6)alkyl and -N((CrC6)alkyl)2, wherein(d-C6)alkyl is optionally substituted with hydroxy, -0(d-C6)alkyl, cyano or oxo; and b) 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.
6. The compound of any one of claims 1-3 wherein R4 is selected from:
a) heterocycle, wherein heterocycle is optionally substituted with one or more groups each independently selected from halo, (Ci-C6)alkyl, (C2-C6)alkenyl, (Q-C^haloalkyl, (C3-C7)cycloalkyl, -OH, -0(C C6)alkyl, -SH, -S(C C6)alkyl, -NH2, -NH(Ci-C6)alkyl and - N((Ci-C6)alkyl)2, wherein (Ci-C6)alkyl is optionally substituted with hydroxy, -0(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 claims 1-3 wherein R4 is:
Figure imgf000414_0001
8. The compound of any one of claims 1-3 wherein R is:
Figure imgf000414_0002
9. The compound of any one of claims 1-8 wherein R1 is selected from:
a) H, halo, (C , -C6)alkyl and (C i -C6)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 Z10 groups; c) -C(=0)-Rn, -C(=0)-0-Rn, -O-R1 1, -S-R1 1, -S(0)-Rn, -S02-Rn,
-(Ci-C6)alkyl-Rn, -(C1-C6)alkyl-0- R11, -(Cj-Q alkyl-
Figure imgf000415_0001
n, wherein each R11 is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d- C6)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)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10,
Figure imgf000415_0002
and -(C]-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (Cr C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(d- C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R! 1 is independently selected from H, (C1-Ce)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Cj- C6)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) (C i -C )alkyl, wherein (C -C6)alkyl is substituted with one or more Z2 groups 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 Z5 groups and optionally substituted with one or more Z1 groups; and
g) (Q-Ce haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein (d-C6)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 Z'groups.
10. The compound of any one of claims 1-8 wherein R1 is selected from:
a) H, halo and (C1-C6)alkyl;
b) (C2-C6)alkenyl, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z10 groups; c) -C(=0)-N(R9)R10, -(Ci-C6)alkyl-R1 1 and -(Q-C^alkyl-O-R1 wherein each R11 is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Q-C^haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z10 groups;
d) -(C C6)alkyl-N(R9)R10, wherein each R9 is independently selected from H,
(Ci-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(Ci- C6)alkyl-R' ', -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z10 groups;
e) (C!-C6)alkyl, wherein (Q-C^alkyl is substituted with one or more Z2 groups 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-C6)alkenyl, and (C2-C6)alkynyl, wherein (C2-C6)alkenyl and
(C2-C )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:
Figure imgf000417_0001
Figure imgf000417_0002
12. The compound of any one of claims 1-8 wherein R is halo. 13. The compound of any one of claims 1-12 wherein R2 is selected from:
a) H, (Ci-C6)alkyl and -0(C!-C6)alkyl;
b) (C2-C6)alkenyl, (C2-C6)alkynyl, (d-C^haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano;
c) C^O- 11 , -C(-0)-0-R' 1 , -S-R1 1 , -SCC^-R1 ' , -S02-R' 1 ,
-(d-C^alkyl-R11, -(Ci-C6)alkyl-C(=0)-RU, -(C1-C6)alkyl-C(=0)-0-R1 1, -(Ci-C6)alkyl-0- R11, -(Ci-C6)alkyl-S-RN, -(Ci-C6)alkyl-S(0)-RN and -(Ci-C6)alkyl-S02-RH, wherein each RN is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more Zn groups; d) -N(R9)R10, -C(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(C,- C6)alkyl-N(R9)R10, -(C1-C6)alkyl-C(=0)-N(R9)R10, -(C1-C6)alkyl-0-C(=0)-N(R9)R10, and -(Ci-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (C C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from Rn, -(Cj- C6)alkyl-R1 -S02-Rn, -C(=0)-Ru, -CCO R11 and -C(=0)N(R9)R1 wherein each R1 1 is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
e)
Figure imgf000418_0001
wherein (Ci-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z1 groups; and
f) (C C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein any (C]-C )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 Z1 groups. 14. The compound of any one of claims 1-12 wherein R2 is selected from:
a) ( -Qdalkyl;
b) (C2-C6)alkenyl and (C i -C6)haloalkyl;
c) -(Ci-C6)alkyl-R1 1 and
Figure imgf000418_0002
wherein each R1 1 is
independently selected from H, (CrC^alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Q- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more Z1 1 groups;
d) -(Ci-C6)alkyl-N(R9)R10, wherein each R9 is independently selected from H, (C]-C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(C\- C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORu and -C(=0)N(R9)Ru, wherein each Rn is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C )alkynyl, (Ci- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
e) (Ci-C6)alkyl, wherein (Ci-C6)alkyl is substituted with one or more Z2 groups and optionally substituted with one or more Z!groups; and
f) (C2-C6)alkenyl, wherein (C2-C6)alkenyl is substituted with one or more Z6 groups and optionally substituted with one or more Z^oups.
15.
Figure imgf000419_0001
or | "F
F 16. The compound of any one of claims 1-12 wherein R is methyl.
17. The compound of any one of claims 1-16 wherein R6 is selected from:
a) H, halo, (CrC6)alkyl, and (Ci-C6)haloalkyl
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(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn,
-(C-C^alkyl-R11, -(CrC^alkyl-C^-R11, -(d^alkyl-CC^-O-R11, -(C C6)alkyl-0- R11, -(Q-Q alkyl-S-R11, -(C C6)alkyl-S(0)-Rn and -(Q-Q alkyl-SCh-R11, wherein each R11 is independently selected from H, (C i-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- 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) -(C1-C6)alkyl-0-(Ci-C6)alkyl-(C3-C7)carbocycle, -(Ci-C6)alkyl-S-(Ci- C6)alkyl-(C3-C7)carbocycle, -(C i -C6)alkyl-S(0)-(C i -C6)alkyl-(C3-C7)carbocycle, -(C j - C6)alkyl-S02-(C1-C6)alkyl-(C3-C7)carbocycle, -(C2-C6)alkenyl-(Ci-C6)haloalkyl, -(C2- C6)alkynyl-(CrC6)haloalkyl, -halo(C3-C7)carbocycle,-NRaS02NRcRd, -NRaS020(C3- C7)carbocycle, -NRaS02Oaryl, -(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, -(C2-C6)alkynyl-heteroaryl, -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-ORa and
-(C2-C6)alkyl-(C3-C7)carbocycle-ORa, -(C3-C7)carbocycle-Z' and -halo(C,-C6)alkyl-Z3, wherein any (C1-C6)alkyl, (C)-C6)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^oups;
e) (C!-C^alkyl, wherein (d-C )alkyl is substituted with one or more Z2 groups 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 Z5 groups and optionally substituted with one or more Z1 groups; and
g) (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein any (C1-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 Z1 groups.
18. The compound of any one of claims 1-16 wherein R6 is selected from:
a) H, halo and (Ci-C6)alkyl;
b) (C2-C )alkenyl, (C2-C6)alkynyl and aryl, wherein any aryl is optionally substituted with one or more Z10 groups;
c) -(Ci-C6)alkyl-Ru and -(C1-C6)alkyl-0-RH, wherein each R11 is independently selected from H, (Q-Ce^lkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C6)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)alkynyl-(C3-C7)carbocycle, -(C2-C6)alkynyl-aryl, -(C2-C6)alkynyl- heteroaryl -(C2-C6)alkynyl-heterocycle, -(C2-C8)alkynyl-ORa and
-(C2-C6)alkyl-(C3-C7)carbocycle-ORa, wherein -(C2-C6)alkynyl-(C3-C7)carbocycle, -(C2-C )alkynyl-aryl, -(C2-C6)alkynyl-heteroaryl and -(C2-C6)alkynyl-heterocycle, are optionally substituted with one or more Z1 groups;
e) (C]-C6)alky, wherein (d-C )alkyl 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 Z5 groups and optionally substituted with one or more Z'groups; and
g) (C2-C6)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.
19. The compound of any one of claims 1-16 wherein R6 is selected from:
Figure imgf000422_0001
Figure imgf000422_0002
Figure imgf000422_0003
421 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(=0)-Rn, -C(=0)-0-Rn, -O-R11, -S-R11, -S(0)-Rn, -S02-Rn,
-(CrCe^lkyl-R11, -(C^alkyl-CC^-R11, -(d^alkyl-C^-O-R11, -(C C6)alkyl-0- Rn, -(d-C6)alkyl-S-Rn, -(Ci-C6)alkyl-S(0)-RH and -(C1-C6)alkyl-S02-R11, wherein each R11 is independently selected from H, (d-C^alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C )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(=0)-N(R )R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10,
-(C,-C6)alkyl-N(R9)R10, -(Ci-C6)alkyl-C(=O)-N(R9)R10, -(C1-C6)alkyl-0-C(=0)-N(R9)R1° and -(Ci-C6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (Q- C6)alkyl and (C3-C7)cycloalkyl, and each R10is independently selected from R11, -(Ci- C6)alkyl-Ru, -S02-Rn, -C(=0)-Rn, -C(=0)ORn and -C(=0)N(R9)Rn, wherein each R11 is independently selected from H,
Figure imgf000423_0001
(C2-C6)alkenyl, (C2-C6)alkynyl, (Cp C6)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-C6)alkyl, wherein (Ci-C )alkyl is substituted with one or more Z2 groups 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 Z5 groups and optionally substituted with one or more Z1 groups;
g) (Ci-C6)haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein any (C Ce^aloalkyl, (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 Z1 groups; and
h) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(C1-C6)alkyl-NReRf, -(C1-C6)alkylC(0)- ReRf, -(Ci-C6)alkyl-0-C(0)-NReRf and -(Ci-C6)alkyl-S02 ReRf, wherein each any (C1-C6)alkyl, either alone or as part of a group, is substituted with one or more Z6 groups and optionally substituted with one or more Z'groups.
22. The compound of any one of claims 1 -20 wherein R7 is selected from:
a) H, halo, (C1-C6)alkyl and (CrC6)haloalkyl;
b) (C3-C7)cycloalkyl, cyano, aryl and heteroaryl, wherein any aryl and heteroaryl is optionally substituted with one or more Z10 groups;
c) -C(=0)-N(R9)R10, wherein each R9 is independently selected from H, (Cr C6)alkyl and (C3-C )cycloalkyl, and each RI0 is independently selected from Rn, -(Cj- C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORu and -C(0)N(R9)Rn, wherein each R11 is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z10 groups;
d) (Ci-C6)alkyl, 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 substituted with one or more Z5 groups and optionally substituted with one or more Z'groups;
f) (CrC6)haloalkyl and (C3-C7)carbocycle, wherein (C1-C6)haloalkyl and (C3- C7)carbocycle are each substituted with one or more Z6 groups and optionally substituted with one or more Z1 groups; and
g) -C(0)NRsRf.
23. The compound of any one of claims 1-20 wherein R is selected from:
Figure imgf000425_0001
Figure imgf000425_0002
Figure imgf000425_0003
Figure imgf000425_0004
Figure imgf000425_0005
24. The compound of any one of claims 1-20 wherein R7 is H. 25. The compound of any one of claims 1-24 wherein R8 is selected from:
a) halo, nitro and cyano;
b) R11, -C(=0)-Ru, -C(=0)-0-Rn, -0-Rn, -S-R11, -S(0)-Rn, -S02-Rn, -(Cr C6)alkyl-Rn,
Figure imgf000425_0006
-(d-Q alkyl-O-R11, -
Figure imgf000425_0007
-(Ci-C6)alkyl-S(0)-Rn and -(d-Ceialkyl-SOi-R11, wherein each R11 is independently selected from H, (C i -C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C i -
C6)haloalkyl, (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(=0)-N(R9)R10, -0-C(=0)-N(R9)R10, -S02-N(R9)R10, -(C,- C6)alkyl-N(R9)R10,
Figure imgf000426_0001
and - (CrC6)alkyl-S02-N(R9)R10, wherein each R9 is independently selected from H, (C C6)alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(Ci- C6)alkyl-R1 -S02-R' \ -C(=0)-R' -C(=0)OR1 1 and -C(=0)N(R9)R11, wherein each R11 is independently selected from H, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
d) (Ci-C6)alkyl, wherein (d-C^alkyl is substituted with one or more Z2 groups 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 Z1 groups;
f) (d-C^haloalkyl, (C3-C7)carbocycle, (C2-C6)alkenyl and (C2-C6)alkynyl, wherein (Q-C^haloalkyl, (C3-C7)carbocycle, (C2-C )alkenyl and (C2-C6)alkynyl are each independently substituted with one or more Z6 groups and optionally substituted with one or more Z'groups; and
g) -NReRf, -C(0)NReRf, -OC(0)NReRf, -S02NReRf, -(CrC6)alkyl- ReRf, -(Ci-C6)alkylC(0)-NReRf, -(Ci-C6)alkyl-0-C(0)-NReRf and -(C1-C6)alkyl-S02NReRf, wherein any (C]-C6)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) Ru, -O-R11 and -(Ci-C6)alkyl-Ru, wherein each R11 is independently selected from H, (C C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)haloalkyl, (C3- C7)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z1 1 groups;
c) -C(=0)-N(R9)R10, wherein each R9 is independently selected from H, (C C )alkyl and (C3-C7)cycloalkyl, and each R10 is independently selected from R11, -(C\- C6)alkyl-Rn, -S02-Rn, -C(=0)-Rn, -C(=0)ORu and -C(=0)N(R9)Rn, wherein each R1 1 is independently selected from H, (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d- C6)haloalkyl, (C3-C7)cycloalkyl, aryl, heterocycle and heteroaryl;
d) (Ci-C6)alkyl, 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 Z5 groups and optionally substituted with one or more Z^oups;
f) (C2-C6)alkynyl, wherein (C2-C )alkynyl is substituted with one or more Z6 groups and optionally substituted with one or more Z1 groups; and
g) -C(0)NReRf.
Figure imgf000427_0001
Figure imgf000427_0002
Figure imgf000427_0003
28. The compound of any one of claims 1-24 wherein R is H.
29. The compound of claim 1 selected from:
Figure imgf000428_0001
Figure imgf000428_0002
427
Figure imgf000429_0001
428
Figure imgf000430_0001
429
Figure imgf000431_0001
Figure imgf000431_0002
430
431
Figure imgf000433_0001
432
Figure imgf000434_0001
Figure imgf000435_0001
434
Figure imgf000436_0001
435
Figure imgf000437_0001
436
Figure imgf000438_0001
437
Figure imgf000439_0001
438
Figure imgf000440_0001
and salts thereof.
30. A pharmaceutical composition comprising a compound of formula I as described in any one of claims 1-29 or a pharmaceutically acceptable salt thereof, in combination wdth a pharmaceutically acceptable carrier. 31. A method of treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal comprising administering a compound of formula I as described in any one of claims 1-29, or a pharmaceutically acceptable salt thereof, or a composition as described in claim 30, to the mammal.
32. A compound as described in any of claims 1-29 or a pharmaceutically acceptable salt thereof for use in medical therapy.
33. A compound as described in any one of claims 1 -29 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal. 34. A compound as described in any one of claims 1 -29 or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of the proliferation of the HIV virus or AIDS or for use in the therapeutic treatment of delaying the onset of AIDS or ARC symptoms.
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AU2011274322B2 (en) 2015-08-13
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PE20130385A1 (en) 2013-03-30
BR112013000043A2 (en) 2019-09-24
ZA201209596B (en) 2015-06-24
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CR20130045A (en) 2013-05-16
CN103140474A (en) 2013-06-05
PT2588450T (en) 2017-08-03
EA201291300A1 (en) 2013-06-28
ECSP13012417A (en) 2013-03-28
US9102614B2 (en) 2015-08-11
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CA2802308C (en) 2018-08-28
MX2012015097A (en) 2013-05-28
JP2015193671A (en) 2015-11-05
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AP2013006706A0 (en) 2013-02-28
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JP2013535426A (en) 2013-09-12
EP2588450A1 (en) 2013-05-08
KR20130135826A (en) 2013-12-11
CA2802308A1 (en) 2012-01-05
TW201215614A (en) 2012-04-16
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AR082079A1 (en) 2012-11-07
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