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WO2007061670A1 - Modulateurs de beta-secretase et procedes d'utilisation associes - Google Patents

Modulateurs de beta-secretase et procedes d'utilisation associes Download PDF

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Publication number
WO2007061670A1
WO2007061670A1 PCT/US2006/044058 US2006044058W WO2007061670A1 WO 2007061670 A1 WO2007061670 A1 WO 2007061670A1 US 2006044058 W US2006044058 W US 2006044058W WO 2007061670 A1 WO2007061670 A1 WO 2007061670A1
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WIPO (PCT)
Prior art keywords
amino
acetamide
methyl
dihydrospiro
pyrano
Prior art date
Application number
PCT/US2006/044058
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English (en)
Inventor
Wenge Zhong
Stephen Hitchcock
Brian K Albrecht
Michael Bartberger
James Brown
Ryan Brown
Stuart C. Chaffee
Yuan Cheng
Michael Croghan
Russell Graceffa
Scott Harried
Dean Hickman
Daniel Horne
Randall Hungate
Ted Judd
Matthew Kaller
Charles Kreiman
Daniel La
Patricia Lopez
Craig E. Masse
Holger Monenschein
Thomas Nguyen
Thomas Nixey
Vinod F. Patel
Lewis Pennington
Matthew Weiss
Qiufen Xue
Bryant Yang
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Amgen Inc.
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=39708735&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2007061670(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Amgen Inc. filed Critical Amgen Inc.
Priority to CA2629402A priority Critical patent/CA2629402C/fr
Priority to EP06837478A priority patent/EP1971598A1/fr
Priority to JP2008541258A priority patent/JP5274258B2/ja
Priority to AU2006316620A priority patent/AU2006316620B2/en
Publication of WO2007061670A1 publication Critical patent/WO2007061670A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • the invention relates generally to pharmaceutically active compounds, pharmaceutical compositions and methods of use thereof, to treat Beta-Secretase mediated disorders, including Alzheimer's disease, plaque formation on the brain and related conditions.
  • AD Alzheimer's disease
  • AD is a disease that affects greater than 12 million aging people worldwide. AD accounts for the majority of dementia clinically diagnosed after the age of 60. AD is generally characterized by the progressive decline of memory, reasoning, judgement and orientation. As the disease progresses, motor, sensory, and vocal abilities are affected until there is global impairment of multiple cognitive functions. The loss of cognitive function occurs gradually, typically leading to a diminished cognition of self, family and friends. Patients with severe cognitive impairment and/or diagnosed as end-stage AD are generally bedridden, incontinent, and dependent on custodial care. The AD patient eventually dies in about nine to ten years, on average, after initial diagnosis. Due to the incapacitating, generally humiliating and ultimately fatal effects of AD, there is a need to effectively treat AD upon diagnosis.
  • AD Alzheimer's disease
  • A-beta beta- amyloid peptide
  • Amyloid containing plaques and vascular amyloid angiopathy were also found in the brains of individuals with Down's Syndrome, Herditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative disorders.
  • A-Beta formation is a causative precursor or factor in the development of AD.
  • Deposition of A-beta in areas of the brain responsible for cognitive factors is a major factor in the development of AD.
  • Beta amyloid plaques are primarily composed of amyloid beta peptide (A-beta peptide).
  • A-beta peptide is derived from the proteolytic cleavage of a large transmembrane amyloid precursor protein (APP), and is a peptide ranging in about 39-42 amino acids.
  • APP transmembrane amyloid precursor protein
  • A-beta 42 (42 amino acids long) is thought to be the major component of these plaque deposits.
  • Beta secretase (BACE, also commonly referred to as memapsin) is thought to first cleave APP to generate two fragments of the A-beta peptide: (1) a first N-termin us fragment and (2) a second C-99 fragment, which is subsequently cleaved by gamma secretase to generate the C-terminus fragment of the A-beta peptide.
  • APP has also found to be cleaved by alpha-secretase to produce alpha-sAPP, a secreted form of APP that does not result in beta-amyloid plaque formation.
  • BACE is an aspartyl protease enzyme comprising 501 amino acids and responsible for processing APP at the beta-secretase specific cleavage site. BACE is present in two forms, BACE 1 and BACE 2, designated as such depending upon the specific cleavage site of APP. Beta secretase is described in Sinha et ah, Nature, 402:537- 554 (1999) (p510) and PCT application WO 2000/17369.
  • A- beta peptide accumulates as a result of APP processing by BACE. Moreoevr, in vivo processing of APP at the beta secretase cleavage site is thought to be a rate-limiting step in A-beta production. Sabbagh, M. et a ⁇ ., ⁇ lz. Dis. Rev. 3:1-19 (1997). Thus, inhibition of the BACE enzyme activity is desirable for the treatment of AD. Studies have shown that the inhibition of BACE may be linked to the treatment of AD. BACE 1 knockout mice fail to produce A-beta, and present a normal phenotype.
  • WO 03/050073 describes inhibitors of beta secretase, useful for treating AD and other beta-secretase mediated disorders.
  • the present invention provides a new class of compounds useful for the modulation of beta secretase and, to that end, useful for the regulation or reduction of the formation of A-beta peptide and consequently, the reduction of beta amyloid plaque formation on the brain. Accordingly, the compounds of the invention are useful for the treatment of Alzheimer's disease and other beta secretase mediated disorders.
  • the compounds provided by the invention including stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, derivatives or prodrugs thereof, are defined by general Formula I
  • the compounds provided by the invention are capable of modulating beta secretase.
  • the invention further provides for the use of these compounds for therapeutic, prophylactic, acute and/or chronic treatment of beta secretase mediated diseases, such as those described herein.
  • the compounds are useful for the prophylaxis and treatment of AD and other diseases or conditions involving amyloid plaque formation on the brain.
  • the invention also provides pharmaceutical compositions, which comprise one or more compounds of the invention, methods for the treatment of beta secretase mediated diseases, such as AD, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
  • the invention also provides the preparation of a a pharmaceutical composition or of a medicament, containing one or more of the compounds, useful to attenuate, alleviate, or treat disorders through inhibition of beta secretase.
  • the invention provides a pharmaceutical composition comprising an effective dosage amount of a compound of Formula I in association with at least one pharmaceutically acceptable carrier.
  • the compounds including stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, derivatives or prodrugs thereof, are defined by
  • A is Ci.io-alkyl, C 2 .io-alkenyl, C 2- ⁇ raIkynyl, R'-Ci-io-alkyl-, R ⁇ C 2-10 - alkenyl- or R'-C 2 -io-alkynyl-, wherein
  • C 2 -io-alkenyl- or R 1 -C 2- io-alkynyl- is optionally replaced with a heteroatom selected from O, S, S(O), S(O) 2 and
  • R 1 is a fully saturated or a partially or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms and optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein said ring system is substituted independently with one or more substituents of oxo, R 7 , R 8 , R 9 ,
  • B is R 2 -(CR 2a R 2a ) h -, R 2 -O-(CR 2a R 2a ) h -, R 2 -S-(CR 2a R 2a ) h - or R 2 -N(R 2a )-(CR 2a R 2a ) h -, wherein - S -
  • R 2 is Cj-Cio alkyl, C r Ci 0 haloalkyl, C r Cio alkenyl, C r Ci 0 alkynyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein said Ci-Ci 0 alkyl, Ci-Ci 0 alkenyl, Ci-Ci 0 alkynyl is optionally substituted independently with one or more substituents of R 9 , and said ring system is optionally substituted independently with one or more substituents of oxo, R 7 , R 8 , R 9 , NR 7 R 7 , NR 7 R 8 , OR 7
  • R 4 is H, haloalkyl, CN, C M0 -aIkyl, C 2- i 0 -alkenyl, C 2- i 0 -alkynyl, C 3- i 0 -cycloalkyl or C 4- io-cycloalkenyl, each of the Ci.i ⁇ -alkyl, C 2 .] 0 -alkenyl, C 2 _i 0 -alkynyl, Cs-io-cycloalkyl and C 4- io-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-5 substituents of R 8 or R 9 ;
  • R 5 is
  • R 8 is a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and wherein said ring system is optionally substituted independently with 1 -5 substituents of R 9 , oxo, NR 9 R 9 , OR 9 ; SR 9 , C(O)R 9 or a partially or fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and optionally substituted independently with 1-5 substituents of R 9 ;
  • R 9 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, Ci.io-alkyl, C 2 .i 0 -alkenyl, C 2 , 10 -alkynyl, C 3- io-cycloalkyl, Ci.io-alkylamino-, Ci.
  • Ci-io-alkylamino-, Cj.jo-dialkylamino-, C 1-10 - alkoxyl, Ci.io-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN 5 NO 2 , NH 2 , OH, oxo, methyl, tnethoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert- butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, Ci.io-alkylamino-, C] -I0 - dialky
  • R n is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, Ci.io-alkyl, C 2- io-alkenyl, C 2- 1 0-alkynyl, Cs.io-cycloalkyl, C 4 -io-cycloalkenyl, Ci.io-alkylamino-, Ci-io-dialkylamino-, Q.
  • Ci.io-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of the Ci-io-alkyl, C 2- io-alkenyl, C 2-1O - alkynyl, C 3- i 0 -cycloalkyl, C 4 .i 0 -cycloalkenyl, Ci-io-alkylamino-, Ci_io-dialkylamino-, Ci -I0 - alkoxyl, Ci.io-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2
  • R 12 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, oxo, C 1-]0 -alkyl, C 2-10 - alkenyl, C 2- io-alkynyl, C 3- i 0 -cycloalkyl, C 4 .
  • R 13 is NR 14 R 15 , NR 15 R 15 , OR 14 , SR 14 , OR 15 , SR 15 , C(O)R 14 , OC(O)R 14 , COOR 14 , C(O)R' 5 , OC(O)R 15 , COOR 15 , C(O)NR 14 R 15 , C(O)NR 15 R 15 , NR 14 C(O)R 14 , NR 15 C(O)R 14 , NR 14 C(O)R 15 , NR 15 C(O)R 15 , NR 15 C(O)R 15 , NR 15 C(O)NR 14 R 15 , NR 15 C(O)NR 14 R 15 , NR 15 (COOR 14 ), NR 15 (COOR IS ), OC(O)NR 14 R 15 , OC(O)NR 15 R 15 , S(O) 2 R 14 , S(O) 2 R 15 , S(O) 2 NR 14 R 15 , S(O
  • R 14 is a saturated or partially or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and wherein said ring system is optionally substituted independently with 1 -5 substituents of R 15 ; and
  • R 15 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert- butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl, Ci-io- alkylamino-, d.io-dialkylatnino-, Ci-io-thioalkoxyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring system
  • Formula 1 includes compounds wherein A is Cwalkyl, C 2-6 alkenyl, C 2-6 -alkynyl, R'-O-C ⁇ -alkyl-, R 1 -S-C ]-6 -alkyl-.
  • 6-alkenyK R'-NH-Ca-e-alkenyl-, R'-O-C ⁇ -alkynyl-, R'-S-Cuealkynyl-, R 1 -S(O) 2 -C 1 .*- alkynyl-, R'-NH-C ⁇ -alkynyl-, R'-C ⁇ alkyl-O-C ⁇ -alkyl-, R'-C ⁇ -alkyl-S-Ce-alkyl-, R 1 - C ⁇ -alkyl-SCO ⁇ -C ⁇ e-alkyl- ⁇ '-Ce-alkyl-NH-Ci.e-alkyl- ⁇ '-C ⁇ -alkyl-O-C-e-alkenyl-, R 1 -C,.
  • Formula I includes compounds wherein A is 3-alkyl-, C, ⁇ -alkyl-S(O) 2 -C 1-3 -alkyl-, C-e-alkyl-NH-Cj.s-alkyl, di-(C I-6 -alkyl)-N-C,,3- alkyl, C ⁇ -e-alkenyl-O-CLs-alkyl-, C 2-6 -alkenyl-S-Ci -3 -alkyl-, C 2 . 6 -alkenyl-S(O) 2 -C,.
  • the compounds of Formula I include as R 1 , phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, tetra
  • pyrazolinyl morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a ring system of
  • R la is R 7 , R 8 , R 9 , C(O)R 7 , C(O)R 8 , C(O)NR 7 R 7 , C(S)NR 7 R 7 , C(O)NR 7 R 8 , C(S)NR 7 R 8 , S(O) 2 NR 7 R 7 , S(O) 2 R 8 , or S(O) 2 NR 7 R 8 ;
  • each R Ib , R lc and R ld independently, is R 7 , R 8 , R 9 , NR 7 R 7 , NR 7 R 8 , OR 7 , SR 7 ,
  • the compounds of Formula I include R 7 , R 8 or R 9 , independently, as each of R Ia , R lb , R lc and R Id , independently, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include R 2 -(CR 2a R 2a ) h - as B wherein each R 2a , independently, is H, OH, NO 2 , CN, NH 2 , Ci-C 10 alkyl, Ci-Ci 0 alkoxyl or haloalkyl, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include R 2 -O-(CR 2a R 2a ) h - as B wherein each R 2a , independently, is H, OH, NO 2 , CN, NH 2 , C 1 -Ci 0 alkyl, C r Ci 0 alkoxyl or haloalkyl, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include R 2 -S-(CR 2a R 2a ) h - as
  • each R 2a independently, is H, OH, NO 2 , CN, NH 2 , C r Ci 0 alkyl, C r Ci 0 alkoxyl or haloalkyl, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include R 2 -NR 2a -(CR 2a R 2a ) h - as B wherein each R 2a , independently, is H, OH, NO 2 , CN, NH 2 , C,-C 10 alkyl, C]-Ci 0 alkoxyl or haloalkyl, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include R 2 -(CHR 2a ) h - as B wherein R 2a is OH, NO 2 , CN, NH 2 , C 1 -Ci 0 alkyl, C r C I0 alkoxyl or haloalkyl, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include R 2 -(CH 2 ) h - as B, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include R 2 -O-(CH 2 ) h - as B, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include R 2 -S-(CH 2 ) h - as B, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include R 2 -NH-(CH 2 ) h - as
  • Formula I includes compounds wherein R 2 is a Ci- Qalkyl, Ci-C 4 alkenyl, Ci-Qalkynyl, Ci-Ci 0 haloalkyl or an optionally substituted ring system selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimi
  • the compounds of Formula I include an optionally substituted ring system selected from phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyU benzofuranyl, benzothiophenyl and benzimidazoly as R 2 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include Ci-Cjo alkyl, Ci-Cio alkenyl or Ci-Ci 0 alkynyl as R 2 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include Cj-Cio haloalkyl as R 2 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include H, haloalkyl, CN,
  • Ci.io-alkyl, C 2 -io-alkenyl or C 2 .io-alkynyl as R 3 in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include H as R 3 , in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include Ci.io-alkyl as R 3 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include H, haloalkyl, CN, Ci-io-alkyl, C 2 -io-alkenyl or C 2- io-alkynyl as R 4 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include H as R 4 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include haloalkyl or Cj.io- alkyl as R 4 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include h as 0, 1, 2 or 3, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include h as 1 or 2, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include i as 1, 2 or 3, in conjunction with any of the above or below embodiments. In another embodiment, the compounds of Formula I include i as 1, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include j as 0, 1 or 2, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include j as 0, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include as R 5
  • m, o, R 12 , X 1 , X 2 , Y 1 , Y 2 and Y 3 are as defined hereinabove;
  • Z 2 taken together with the carbon atoms to which it is attached is a partially or fully unsaturated 5-8 membered monocyclic ring, said ring formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, provided that (a) no more than two of Y 1 , Y 2 and Y 3 is O, S or NR 12 and (b) when o is 0, then each of Y 1 and Y 2 is CR 12 R 12 ; and p is 0, 1, 2, 3, 4 or 5, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include
  • the compounds of Formula I include CHR 12 as X 1 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include CH 2 as X 1 , in conjunction with any of the above or below embodiments. In the preceeding embodiment, the compounds of Formula I include O as X 1 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include S as X 1 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include S(O) 2 as X 1 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include NR 12 as X 1 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include NH as X 1 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include CR 12 R 12 as each X 2 , independently, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include CHR 12 as each X 2 , independently, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include CH 2 as each X 2 , independently, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include CR 12 R 12 as each of Y 1 , Y 2 and Y 3 , independently, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include CHR 12 as each of Y 1 , Y 2 and Y 3 , independently, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include CH 2 as each of Y 1 , Y 2 and Y 3 , independently, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include O as any one or two of Y 1 , Y 2 and Y 3 , independently, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include S as any one or two of Y 1 , Y 2 and Y 3 , independently, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include NR 12 as any one or two of Y 1 , Y 2 and Y 3 , independently, in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include O as Y 2 and CHa as each of Y 1 and Y 3 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include S as Y 2 and CH 2 as each of Y 1 and Y 3 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include NR 12 as Y 2 and CH 2 as each of Y 1 and Y 3 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include an optionally substituted benzene, pyridine, pyrimidine, triazine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, triazole, thiophene, thiazole, thiadiazole, isothiazole, furan, oxazole, oxadiazole or isoxazole ring as Z 2 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula I include compounds wherein R 5 is
  • n 0 or 1
  • X 2 is CH
  • Y 3 is CR 12 or O; and each R 12 , independently, is H, halo, haloalkyl, CN, OH,
  • the compounds of Formula I include as R 5
  • the compounds of Formula I include as R 5
  • the invention provides compounds of Formula I, wherein h is 1 or 2; i is 1 ; j is 0;
  • A is Ci-e-alkyl, C 2-6 -alkenyl, alkyl, R 1 -S(O) 2 -Ci - 6 -alkyk R 1 - S(O) 2 -C 2 .6-alkenyl-, R'-NH-Q ⁇ -alkenyl-, R'-C 1-6 -alkyl-O-C ⁇ -alkyl-, R ⁇ Ce-alkyl-S-C,. 6 -alkyl-, R 1 -Ci -6 -aIkyl-S(O) 2 -Ci -6 -alkyl- or R'-d-e-alkyl-NH-d-e-alkyl-, wherein
  • R 1 is phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl, pyrrolidin
  • R 2 is an optionally substituted ring system selected from phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl and benzimidazolyl; each R 3 , independently, is H, haloalkyl, CN, Ci -10 -alkyl, C 2 -io-alkenyl or C 2-
  • R 4 is H, CN or C M0 -alkyl;
  • R 5 is
  • m, o, R 12 , X 2 , Y 1 , Y 2 and Y 3 are as defined in claim 1;
  • Z 2 is an optionally substituted phenyl, pyridine, pyrimidine, triazine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, triazole, thiophene, thiazole, thiadiazole, isothiazole, furan, oxazole, oxadiazole or isoxazole ring; and p is O, 1, 2, 3, 4 or 5.
  • R 7 is H, Ci.io-alkyl or C 2 .i 0 -alkenyl, each of the Ci.io-alkyl, or C 2- io-alkenyl optionally substituted with 1-3 substituents of R 9 ;
  • R 8 is a ring system selected from phenyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno- pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl, isothiazolyl, tndolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl
  • R 9 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, Ci -10 -alkyl, C 2- i 0 -alkenyl, C 2- l o-alkynyl, C 3-7 -cycloalkyl, C ⁇ -cycloalkenyl, Ci-io-alkylamino-, C 1-10 -dialkylamino-, Ci- l o-alkoxyl, Ci.io-thioalkoxyl; and
  • R 12 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, Ci-io-alkyl, C 2- i 0 -alkenyl, C 2- l o-alkynyl, Cs-io-cycloalkyl, C 4- i 0 -cycloalkenyl, Ci-io-alkylamino-, Ci.io-dialkylamino-, Ci- l o-alkoxyl, Ci.io-thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1 -3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of the Cuio-alkyl, C 2 .i 0 -alkenyl, C
  • the invention provides compounds of Formula IT,
  • A is C ⁇ -alkyl, C 2 -6-alkenyl, C 2-6 alkynyl :> R'-C ⁇ -alkyl-, R ⁇ -e-alkenyl- or R 1 -C 2 . 6-alkynyl-, wherein
  • V is -(CR 23 R 2 V, -O-(CR 2a R 2a ) h -, -S-(CR 2a R 2a ) h - or -NR 2a -(CR 2a R 2a ) h -, wherein each R 2a , independently, is H, C 1 -C 10 alkyl or haloalkyl, and h is O, 1 or 2;
  • R 2 is a Ci-Cioalkyl, Ci-Ciohaloalkyl, Ci-Ci O alkenyl, C 1 -Ci 0 alkynyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein said ring system is optionally substituted independently with one or more substituents of oxo, R 7 , R 8 , R 9 , NR 7 R 7 , NR 7 R 8 , OR 7 , SR 7 , OR 8 , SR 8 , C(O)R 7 , OC(O)R 7 , COOR 7 , C(O)R 8 , OC(O)
  • R 4 is H, haloalkyl, CN, Ci.jo-alkyl, C 2 . 10 -alkenyl, C 2 .i 0 -alkynyl, Cs-io-cycloalkyl or C 4- io-cycloalkenyl, each of the C ]-10 -alkyl, C 2- i 0 -alkenyl, C 2- i 0 -alkynyl, Ca.io-cycloalkyl and C ⁇ io-cycloalkenyl optionally comprising 1 -4 heteroatoms selected from N, O and S and optionally substituted with 1-5 substituents of R 8 or R 9 ;
  • R 7 is H, Q.io-alkyl, C 2- io-alkenyl, C 2 -io-alkynyl, C 3-I0 -CyClOaIlCyI or C 4 .
  • NR 9 C(O)R 8 NR 9 C(O)R 9 , NR 9 C(O)NR 8 R 9 , NR 9 C(O)NR 9 R 9 , NR 9 (COOR 8 ), NR 9 (COOR 9 ), OC(O)NR 8 R 9 , OC(O)NR 9 R 9 , S(O) 2 R 8 , S(O) 2 NR 8 R 9 , S(O) 2 R 9 , S(O) 2 NR 9 R 9 , NR 9 S(O) 2 NR 8 R 9 , NR 9 S(O) 2 NR 9 R 9 , NR 9 S(O) 2 NR 8 R 9 , NR 9 S(O) 2 NR 9 R 9 , NR 9 S(O) 2 R 8 , NR 9 S(O) 2 R 9 , R 8 or R 9 ;
  • R 8 is a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and wherein said ring system is optionally substituted independently with 1-5 substituents of R 9 , oxo, NR 9 R 9 , OR 9 ; SR 9 , C(O)R 9 or a partially or fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and optionally substituted independently with 1-5 substituents of R 9 ;
  • R 9 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 2 -io-alkenyl, C 2 . l o-alkynyl, Ca.io-cycloalkyl, C ⁇ io-cycloalkenyl, Ci.io-alkylamino-, Ci_io-dialkylamino-, C 1 .
  • l o-alkoxyl Ci.io-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of the Cj.io-alkyl, C 2 -io-alkenyl, C 2- io- alkynyl, Cs ⁇ o-cycloalkyl, C 4- io-cycioalkenyl, C ⁇ io-alkylamino-, Ci.io-dialkylamino-, Q-io- alkoxyl, Ci- 10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO 2 , NH 2 ,
  • R 10 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, d.io-alkyl, C 2- i 0 -alkenyl, C 2 .
  • R 11 is H, halo, haloalkyl * CN, OH, NO 2 , NH 2 , acetyl, Ci -10 -alkyl, C 2 . 10 -alkenyl, C 2- 10 -alkynyl, C 3 .io-cycloalkyl, Q-io-cycloalkenyl, Ci.io-alkylamino-, Ci.
  • R 12 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, oxo, Ci.io-alkyl, C 2-10 - alkenyl, C 2- io-alkynyl, C 3 _io-cycloalkyl, Gno-cycloalkenyl, Q-io-alkylamino-, Ci -10 - dialkylamino-, Ci.io-alkoxyl, Ci.io-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of the Ci.io-alkyl, C 2- i 0 -alkenyl, C 2- io-
  • R 15 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cycloburyl, Cuio-alkylamino-, Ci-io-dialkylamino-, Q-io-thioalkoxyl, benzyl, phenyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, and optionally substituted independently with 1-5 substituents of halo, haloalkyl
  • the compounds of Formula II include O as X 1 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula II include S as X 1 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula II include NR 12 as X 1 , in conjunction with any of the above or below embodiments.
  • the compounds of Formula II include methyl, ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl as R 16 , independently, in conjunction with any of the above or below embodiments.
  • the compounds of Formula II include each independent embodiment, as described herein for variables A, B, R 1 , R la , R lb , R Ic , R ld , R 2 , R 3 , R 4 , R s , R 6 , R 7 , R 8 , R 9 , R 10 , R 1 ', R 12 , R 13 , R 14 , R 15 , W, V, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Z 1 and Z 2 for compounds of Formula I, independently, in conjunction with any of the above or below embodiments for compounds of Formula II.
  • the compounds of Formula I or II include compounds wherein R 5 is
  • X 2 is CH
  • Y 3 is CR 12 or O; and each R 12 , independently, is H, halo, haloalkyl, CN, OH,
  • the invention provides compounds generally defined by Formula III, III or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, derivative or prodrug thereof, wherein A is Ci.io-alkyl, C 2- io-alkenyl, C 2- i 0 -alkynyl, R'-Ci.io-alkyl-, or
  • R 1 is a fully saturated or a partially or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms and optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein said ring system is substituted independently with one or more substituents of oxo, R 7 , R 8 , R 9 , NR 7 R 7 , NR 7 R 8 , OR 7 , SR 7 , OR 8 , SR 8 , C(O)R 7 , OC(O)R 7 , COOR 7 , C(O)R 8 , OC(O)R 8 , COOR 8 , C(O)NR 7 R 7 , C(S)NR 7 R 7 , NR 7 C(O)R 7 , NR 7 C
  • B is R 2 -(CR 2a R 2a ) h -, R 2 -O-(CR 2a R 2a ) h -, R 2 -S-(CR 2a R 2a ) h - or R 2 -NR 2a -(CR 2a R 2a ) h -, wherein
  • R 2 is Ci-C] 0 alkyl, Ci-C t0 haloalkyl, CrQo alkenyl, C r Ci 0 alkynyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein said Ci-C 10 alkyl, Ci-Cio alkenyl, Ci-Ci 0 alkynyl is optionally substituted independently with one or more substituents of R 9 , and said ring system is optionally substituted independently with one or more substituents of oxo, R 7 , R 8 , R 9 , NR 7 R 7 , NR 7 R 8 , OR 7 , SR 7
  • each R 2a independently, is H, OH, NO 2 , CN, NH 2 , Ci-Ci 0 alkyl, C 1 -Ci 0 alkoxyl or haloalkyl; and h is O, 1, 2 or 3; i is 1, 2 or 3; j is O, 1 or 2; each R 3 , independently, is H, haloalkyl, CN, Ci.io-alkyl, C 2 -i O -alkenyl, C 2-I0 - alkynyl, C3.io-cycloalkyl or each of the Ci.io-alkyl, C 2- io-alkenyl, C 2 .] 0 - alkynyl, Cs-io-cycloal
  • R 4 is H, haloalkyl, CN, Ci. ]0 -alkyl, C 2- i 0 -alkenyl, C 2 . 10 -alkynyl, Cs-io-cycloalkyl or C 4- io-cycloalkenyl, each of the Cj.io-alkyl, C 2 -i 0 -alkenyl, C 2 _i 0 -alkynyl, C 3- i 0 -cycloalkyl and C 4- io-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-5 substituents of R 8 or R 9 ;
  • R 7 is H, Ci.,o-alkyl, C 2 -io-alkenyl, C 2- io-alkynyl, Ca ⁇ o-cycloalkyl or C 4-I0 - cycloalkenyl, each of the Ci.io-alkyl, C 2- i 0 -alkenyl, C 2 ,i 0 -alkynyl, C 3 .io-cycloalkyl and C 4- l o-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, O and S and optionally substituted with 1-5 substituents OfNR 8 R 9 , NR 9 R 9 , OR 8 , SR 8 , OR 9 , SR 9 , C(O)R 8 , OC(O)R 8 , COOR 8 , C(O)R 9 , OC(O)R 9 , COOR 9 , C(O)NR 8 R 9 , C(O)NR 9 R 9 , NR 9
  • R s is a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, and wherein said ring system is optionally substituted independently with 1-5 substituents of R 9 , oxo, NR 9 R 9 , OR 9 ; SR 9 , C(O)R 9 or a partially or fully saturated or unsaturated 5-6 membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and optionally substituted independently with 1-5 substituents of R 9 ;
  • R 9 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, Ci -10 -alkyl, C 2- i 0 -alkenyl, C 2- )0 -alkynyl, Cs-io-cycloalkyl, C 4- i 0 -cycIoalkenyl, Ci.io-alkylamino-, d.io-dialkylamino-, Ci- l o-alkoxyl, Ci.io-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of the Ci.io-alkyl, C 2 _io-alkenyl
  • R 10 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, Ci-io-alkyl, C 2 .]o-alkenyl, C 2- l o-alkynyl, Cs.io-cycloalkyl, C 4 .i 0 -cycloalkenyl, Ci.io-alkylamino-, Ci-io-dialkylamino-, Q- l o-alkoxyl, Ci.io-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N 5 or S, wherein each of the Ci.io-alkyl, C 2- io-alkenyl, C 2- i
  • R 11 is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , acetyl, d.io-alkyl, C 2- i 0 -alkenyl, C 2- l o-alkynyl, Cs ⁇ o-cycloalkyl, C 4 .io-cycloalkenyl, Ci.io-alkylamino-, Ci.io-dialkylamino-, Ci- l o-alkoxyl, Ci.io-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, wherein each of the Ci.io-alkyl, C 2- io-alkenyl, C 2-] o
  • R 12 is H, halo, haloalkyl, CN, OH 5 NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2 . l o-alkynyl, Ca-io-cycloalkyl, C 4- io-cycloalkenyl 5 Ci.io-alkylamino-, Ci-io-dialkylamino-, Ci- io-alkoxyl 5 Ci.io-thioalkoxyl or a saturated or partially or fully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selected from O 5 N, or S 5 wherein each of the Ci-io-alkyl, C 2- i 0 -alkenyl 5 C 2-I0 - al
  • R 13 IsNR 14 R 15 , NR 15 R 15 , OR 14 ; SR 14 , OR 15 ; SR 15 , C(O)R 14 , OC(O)R 14 , COOR 14 , C(O)R 15 , OC(O)R 15 , COOR 15 , C(O)NR 14 R 15 , C(O)NR 15 R 15 , NR 14 C(O)R 14 , NR 15 C(O)R 14 , NR 14 C(O)R 15 , NR 15 C(O)R 15 , NR 15 C(O)NR 14 R 15 , NR 15 C(O)NR 14 R 15 , NR 15 (COOR 14 ) 5 NR 15 (COOR 15 ) 5 OC(O)NR 14 R 15 , OC(O)NR 15 R 15 , S(O) 2 R 14 , S(O) 2 R 15 , S(O) 2 NR 14 R 15 , S(O) 2 NR 15 , NR 15
  • R 14 is a saturated or partially or fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O 5 N 5 or S 5 and wherein said ring system is optionally substituted independently with 1-5 substituents of R 15 , and
  • R 15 is H, halo, haloalkyl, CN 5 OH 5 NO 2 , NH 2 , oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert- butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl, Q.io- alkylamino-, C ⁇ o-dialkylamino-, Ci -]0 -thioalkoxyl or a partially or fully saturated or unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring system, said
  • the compounds of Formula III include each independent embodiment, as described herein for variables A, B, R 1 , R 1a , R lb , R Ic , R Id , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R", R 12 , R 13 , R 14 , R IS , W, V, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Z 1 and Z 2 for compounds of Formula I 5 independently, in conjunction with any of the above or below embodiments for compounds of Formula III.
  • the invention provides each of the Examplary compounds, and stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, derivatives or prodrugs thereof, and related intermediates, described herein.
  • H denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
  • C a-P alkyl when used either alone or within other terms such as
  • haloalkyl and “alkylamino” embraces linear or branched radicals having ⁇ to ⁇ number of carbon atoms (such as Ci-C 1O ). One or more carbon atoms of the "alkyl” radical may be substituted, such as with a cycloalkyl moeity.
  • alkyl radicals include methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, ethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, n-propyl, isopropyl, n-butyl, cyclopropylbutyl, isobutyl, sec-butyl, fer/-buty1, pentyl, isoamyl, hexyl and the like.
  • alkylenyl embraces bridging divalent alkyl radicals such as methylenyl and ethylenyl.
  • alkenyl when used alone or in combination, embraces linear or branched radicals having at least one carbon-carbon double bond in a moiety having between two and ten carbon atoms. Included within alkenyl radicals are “lower alkenyl” radicals having two to about six carbon atoms and, for example, those radicals having two to about four carbon atoms. Examples of alkenyl radicals include, without limitation, ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl and “lower alkenyl” embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations, as appreciated by those of ordinary skill in the art.
  • alkynyl when used alone or in combination, denotes linear or branched radicals having at least one carbon-carbon triple bond and having two to ten carbon atoms.
  • alkynyl radicals include "lower alkynyl” radicals having two to about six carbon atoms and, for example, lower alkynyl radicals having two to about four carbon atoms.
  • examples of such radicals include, without limitation, ethynyl, propynyl (propargyl), butynyl, and the like.
  • C a-P alkoxyl when used alone or in combination, embraces linear or branched oxygen-containing alkyl radicals each having ⁇ to ⁇ number of carbon atoms (such as Ci-C 1O ).
  • alkoxy and alkoxyl when used alone or in combination, embraces linear or branched oxygen-containing radicals each having alkyl and substituted alkyl portions of one or more carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and fert-butoxy.
  • Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals or with other substitution.
  • radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, fluoropropoxy and cyclopropylmethoxy.
  • aryl when used alone or in combination, means a carbocyclic aromatic moiety containing one, two or even three rings wherein such rings may be attached together in a fused manner. Every ring of an "aryl" multi-ring system need not be aromatic, and the ring(s) fused to the aromatic ring may be partially or fully unsaturated and include one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl, benzodioxazinyl, and the like.
  • the "aryl” group may be substituted, such as with 1 to 5 substituents including lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino, and the like. Phenyl substituted with -O-CH2-O- or -0-CH 2 -CH 2 -O- forms an aryl benzodioxolyl substituent.
  • carbocyclic also referred to herein as "cycloalkyl”, when used alone or in combination, means a partially or fully saturated ring moiety containing one (“monocyclic"), two (“bicyclic") or even three (“tricyclic") rings wherein such rings may be attached together in a fused manner and formed from carbon atoms.
  • saturated carbocyclic radicals include saturated 3 to 6-membered monocyclic groups such as cyclopropane, cyclobutane, cyclopentane and cyclohexane.
  • ring and ring system refer to a ring comprising the delineated number of atoms, the atoms being carbon or, where indicated, a heteroatom such as nitrogen, oxygen or sulfur. Where the number of atoms is not delineated, such as a “monocyclic ring system” or a “bicyclic ring system", the numbers of atoms are 3-8 for a monocyclic and 6-12 for a bicyclic ring.
  • the ring itself, as well as any substitutents thereon, may be attached at any atom that allows a stable compound to be formed.
  • nonaromatic ring or ring system refers to the fact that at least one, but not necessarily all, rings in a bicyclic or tricyclic ring system is nonaromatic.
  • cycloalkenyl when used alone or in combination, means a partially or fully saturated cycloalkyl containing one, two or even three rings in a structure having at least one carbon-carbon double bond in the structure.
  • cycloalkenyl groups include C 3 -C 6 rings, such as compounds including, without limitation, cyclopropene, cyclobutene, cyclopentene and cyclohexene.
  • the term also includes carbocyclic groups having two or more carbon-carbon double bonds such as “cycloalkyldienyl” compounds.
  • cycloalkyldienyl groups include, without limitation, cyclopentadiene and cycloheptadiene.
  • halo when used alone or in combination, means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl when used alone or in combination, embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above.
  • this term includes monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as a perhaloalkyl.
  • a monohaloalkyl radical for example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafiuoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • Perfluoroalkyl refers to alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
  • heteroaryl means a fully unsaturated (aromatic) ring moiety formed from carbon atoms and having one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • the ring moiety or ring system may contain one ("monocyclic"), two ("bicyclic") or even three (“tricyclic") rings wherein such rings are attached together in a fused manner. Every ring of a “heteroaryl” ring system need not be aromatic, and the r ⁇ ng(s) fused thereto (to the heteroaromatic ring) may be partially or fully saturated and optionally include one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl does not include rings having ring members of -O-O-, -O-S- or -S-S-.
  • unsaturated heteroaryl radicals include unsaturated 5- to 6- membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, including for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, IH-1, 2,3 -triazolyl, 2H-1,2,3- triazolyl] and tetrazole; unsaturated 7- to 10- membered heterobicyclyl groups containing 1 to 4 nitrogen atoms, including for example, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and the like; unsaturated 5- to 6-membered heteromonocyclic group containing
  • heterocyclic when used alone or in combination, means a partially or fully saturated ring moiety containing one, two or even three rings wherein such rings may be attached together in a fused manner, formed from carbon atoms and including one or more heteroatoms selected from N, O or S.
  • saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • morpholinyl saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
  • partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.
  • heterocycle also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5- b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • heterocyclic radicals include five to ten membered fused or unfused radicals.
  • Examples of partially saturated and fully saturated heterocyclyls include, without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro- benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-lH-3-aza-fluorenyl, 5,6, 7-trihydro- 1,2,4- triazolo[3.,4-a]
  • alkylamino includes "N- alkylamino" where amino radicals are independently substituted with one alkyl radical.
  • Preferred alkylamino radicals are "lower alkylamino” radicals having one to six carbon atoms. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Examples of such lower alkylamino radicals include N-methylamino, and N- ethylamino, N-propylamino, N-isopropylamino and the like.
  • dialkylamino includes "N, N- dialkylamino" where amino radicals are independently substituted with two alkyl radicals.
  • Preferred alkylamino radicals are "lower alkylamino” radicals having one to six carbon atoms. Even more preferred are lower alkylamino radicals having one to three carbon atoms. Examples of such lower alkylamino radicals include N,N-dimethylamino, N 5 N- diethyl amino, and the like.
  • Carbonyl is also used herein synonymously with the term “oxo”.
  • alkylthio or “thioalkoxy” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
  • An example of “alkylthio” or “thioalkoxy” is methylthio,(CH 3 S-).
  • haloalkylthio embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
  • An example of “haloalkylthio” is trifluoromethylthio.
  • alkylaminoalkyl embraces alkyl radicals substituted with alkylamino radicals.
  • alkylaminoalkyl radicals include "lower alkylaminoalkyl” radicals having alkyl radicals of one to six carbon atoms.
  • Suitable alkylaminoalkyl radicals may be mono or dialkyl substituted, such as N-methylaminomethyl, N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl and the like.
  • alkylaminoalkoxy embraces alkoxy radicals substituted with alkylamino radicals.
  • alkylaminoalkoxy radicals include "lower alkylaminoalkoxy” radicals having alkoxy radicals of one to six carbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkyl substituted, such as N- methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy and the like.
  • the term “Formula I” includes any sub formulas, such as Formula II.
  • Formmula II includes any sub formulas
  • Formmula III includes any sub formulas.
  • a pharmaceutically-acceptable when used with reference to a compound of Formulas I-III is intended to refer to a form of the compound that is safe for administration.
  • a salt form, a solvate, a hydrate or derivative form of a compound of Formula I, II or of Formula III which has been approved for mammalian use, via oral ingestion or other routes of administration, by a governing body or regulatory agency, such as the Food and Drug Administration (FDA) of the United States, is pharmaceutically acceptable.
  • FDA Food and Drug Administration
  • salts include the pharmaceutically acceptable salt forms of the free-base compounds.
  • pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • salts may be formed from ionic associations, charge-charge interactions, covalent bonding, complexation, coordination, etc.
  • the nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds of
  • Formulas I-III may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, hydrofluoric, nitric, carbonic, sulfuric and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include, without limitation, formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethan
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formulas I, II and III include metallic salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including, without limitation, primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, disopropylethylamine and trimethylamine.
  • metallic salts such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc
  • organic bases including, without limitation, primary, secondary and tertiary amines, substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethy
  • salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of Formulas I-III.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
  • Other examples include salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium or magnesium, or with organic bases. Additional examples of such salts can be found in Berge et al. 5 J. Pharm. Sci.,
  • a phosphate salt of a compound of the invention may be made by combining the desired compound free base in a desired solvent, or combination of solvents, with phosphoric acid in a desired stoichiometric amount, at a desired temperature, typically under heat (depending upon the boiling point of the solvent).
  • the salt can be precipitated upon cooling (slow or fast) and may crystallize (i.e., if crystalline in nature), as appreciated by those of ordinary skill in the art.
  • hemi-, mono-, di, tri- and poly-salt forms of the compounds of the present invention are also contemplated herein.
  • hemi-, mono-, di, tri- and poly-hydrated forms of the compounds, salts and derivatives thereof are also contemplated herein.
  • derivative is broadly construed herein, and intended to encompass any salt of a compound of this invention, any ester of a compound of this invention, or any other compound, which upon administration to a patient is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to the ability to modulate an enzyme.
  • pharmaceutically-acceptable derivative denotes a derivative which is pharmaceutically acceptable.
  • prodrug denotes a compound which upon administration to a subject or patient is capable of providing (directly or indirectly) a compound of this invention.
  • examples of prodrugs would include esterified or hydroxylated compounds where the ester or hydroxyl groups would cleave in vivo, such as in the gut, to produce a compound according to Formula I-III.
  • a "pharmaceutically- acceptable prodrug” as used herein, denotes a prodrug which is pharmaceutically acceptable. Pharmaceutically acceptable modifications to the compounds of Formula I-III are readily appreciated by those of ordinary skill in the art.
  • the com ⁇ ound(s) of Formulas I-III may be used to treat a subject by administering the compound(s) as a pharmaceutical composition.
  • the compound(s) can be combined with one or more carriers, diluents or adjuvants to form a suitable composition, which is described in more detail herein.
  • carrier denotes any pharmaceutically acceptable additive, excipient, adjuvant, or other suitable ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration purposes.
  • API active pharmaceutical ingredient
  • “Diluent” and “adjuvant” are defined hereinafter.
  • the terms “treat”, “treating,” “treatment,” and “therapy” as used herein refer to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy.
  • Prophylactic treatment generally constitutes either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals.
  • the phrase "effective dosage amount” is intended to quantify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. Accordingly, this term is not limited to a single dose, but may comprise multiple dosages required to bring about a therapeutic or prophylactic response in the subject.
  • “effective dosage amount” is not limited to a single capsule or tablet, but may include more than one capsule or tablet, which is the dose prescribed by a qualified physician or medical care giver to the subject.
  • the term “leaving group” (also denoted as "LG”) generally refers to groups that are displaceable by a nucleophile. Such leaving groups are known in the art.
  • Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH 3 ), N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like.
  • Nucleophiles are species that are capable of attacking a molecule at the point of attachment of the leaving group causing displacement of the leaving group. Nucleophiles are known in the art. Examples of nucleophilic groups include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions) and the like.
  • Pd(PPh 3 ) 4 paIladium(0)triphenylphosphine tetrakis Pd(dppf)Cl 2 palladium(l,l- bisdiphenylphosphinoferrocene)
  • each squiggly line represents a possible point of bond- construction, whose order is generally dependent upon the particular compound being synthesized.
  • Such bond construction methods are generally described in synthetic Schemes 1 - 5 below.
  • Scheme 1 describes a few methods for preparing A-W acids, useful for preparing compounds of Formulas I-III (see scheme 2) wherein W is -C(O)- or -S(O) 2 - and A is C 1- ,o-alkyl, C 2-10 -alkenyl, C 2- io-alkynyl, R'-Cuio-alkyl-, R'-C 2 -io-alkenyl- orR'-C 2- io-alkynyl- ("L" in scheme 1 corresponds to the Ci.io-alkyl, C 2 -io-alkenyl or C 2- i 0 -alkynyl of A defined in A-W above).
  • Desired A-W groups may be commercially available and purchased, or may be made by known, conventional methods.
  • esters 1 can be hydrolyzed to their corresponding acids 2 using known bases, such as NaOH or LiOH. Acids 2 can then be coupled to an amine (not shown) to prepare compounds of Formula I- III.
  • sulfonic acids 1* can be converted to an activated sulfonate V by reaction with oxalyl chloride, for example, to prepare the corresponding sulfonyl chloride 2'.
  • the sulfonyl chloride 2' can be reacted with an amine to prepare compounds of Formula I-III.
  • a desired ring R 1 of compounds 1 where A is a spacer "L” between the R 1 ring and W, may first be functionalized prior to coupling to the amino- backbone, as shown in scheme 2.
  • a methyl ester-halo substituted compound 1" can be reacted in a Mitsunobu-type reaction with a desired hydroxyl-substituted R la compound under suitable conditions, such as in the presence of tri-phenyl phosphine and diethylazodicarboxylate (commonly referred to as DEAD) for a suitable time period to form the ring N-R la substituted adduct 2".
  • DEAD tri-phenyl phosphine and diethylazodicarboxylate
  • Intermediate 2" may also be formed using a suitable reductive amination method as well utilizing an aldehyde, for example (not shown in scheme 1).
  • Compound 2" can be reacted in a palladium-catalyzed coupling reaction, such as a suzuki-type reaction, in the presence of suitable solvents and accompanying reagents, such as a base, to form the R'-R 11 * substituted compound 3. Formation of compound 3 may require heat, up to and including reflux temperatures depending on the particular substrate, solvent and reagent(s) concentration, as appreciated by those skilled in the art. Compound 3 can then be hydrolyzed in the presence of a suitable base and solvent to form the corresponding acid-adduct 4. Acid 4 is then utilized as an intermediate to couple, as described in scheme 2 below, with desired intermediates or other building blocks to make compounds of Formulas I-III.
  • a palladium-catalyzed coupling reaction such as a suzuki-type reaction
  • suitable solvents and accompanying reagents such as a base
  • compound 1 can be hydrolyzed directly to the corresponding acid 5.
  • Ester-Halo-substituted compound 5 is a useful intermediate for coupling the backbone core compounds with desired B, R 3 and R 4 substitutions already in place.
  • Compound 5 can then be modified to include desirable R 1 substitutions, including R Ia , R 7 , R 8 and R 9 groups.
  • R 1 substitutions including R Ia , R 7 , R 8 and R 9 groups.
  • A-W groups which may be substituted with various substitutions including one or more R 7 , R 8 or R 9 groups, can be coupled to the core hydroxyl-propyl, hydroxyl-butyl or hydroxyl-pentyl backbone structure, generally designated in Scheme 2 as "Pr” group, by various coupling methods as described in Scheme 2.
  • X refers generally to a "LG” or a "leaving group” such as a halide (bromine, chlorine, iodine or fluorine), alkylsulfonate and other known groups (also see definitions herein) which generally forms an electrophilic species (E + ) and m is an integer from 0-1.
  • the NH 2 group (primary amine) is a nucleophilic species (Nu ' ), as is secondary amines, hydroxides, alkoxides, an anionic carbon species and the like, which should be sufficiently strong to the attack the E + species and displace the leaving group X thereby effecting a coupling of A-W to the Pr backbone.
  • electrophilic carbonyl species include, without limitation, acid halides, mixed anhydrides, aldehydes, carbamoyl-chlorides, sulfonyl chlorides, acids activated by coupling with activating reagents such as TBTU, HBTU, HATU 5 HOBT, BOP, PyBOP and carbodiimides (DCC, EDC and the like), and other electrophilic species including halides, isocyanates, daizonium ions and the like.
  • activating reagents such as TBTU, HBTU, HATU 5 HOBT, BOP, PyBOP and carbodiimides (DCC, EDC and the like
  • electrophilic species including halides, isocyanates, daizonium ions and the like.
  • the coupled adduct of A-W and Pr shown as products in sub-schemes 1-4, can be brought about using various conventional methods.
  • an amide or a sulfonamide linkage can be made utilizing an amine on the Pr intermediate and an activated electrophilic species, on the A-W group such as the acid chloride or sulfonyl chloride as shown.
  • the reaction proceeds generally in the presence of a suitable solvent and/or base.
  • suitable solvents include, without limitation, generally non-nucleophilic, anhydrous solvents such as toluene, CH 2 CI 2 , THF, DMF, DMSO, N,N-dimethylacetamide and the like, including solvent combinations thereof.
  • the solvent may range in polarity, as appreciated by those skilled in the art.
  • Suitable bases include, for example, tertiary amine bases such as DIEA, TEA, carbonate bases such as Na 2 COs, K 2 CO 3 , CS 2 CO3, hydrides such as NaH, KH, borohydrides, cyanoborohydrides and the like, alkoxides such as NaOCH 3 , and the like.
  • the base itself may also serve as a solvent.
  • the reaction may optionally be run neat, i.e., without any base and/or solvent. These coupling reactions are generally fast and conversion occurs typically in ambient conditions. However, depending upon the particular substrate, such reactions may require heat, as appreciated by those skilled in the art.
  • carbamates as illustrated in sub-scheme 1 and ureas as illustrated in sub-scheme 3 may be made as shown, wherein X has the same definition as above, using the same coupling methods described above for sub-schemes 2 and 4. While the above methods are so described, they are not exhaustive, and other methods for linking A-W groups and desired Pr groups together may be utilized as appreciated by those skilled in the art. ⁇
  • a suitable reducing agent or by known methods, including triphenylphosphene, trimethylphos
  • Yet another method of forming the amine adduct 9, can be via an imine formation to form compound 10.
  • the imine double bond of compound 10 may then be successively reduced and hydrolyzed to yield the primary amine product 9.
  • Such steps may be conducted using known, convention methods, as appreciated by those skilled in the art.
  • Scheme 4 describes, generally, multiple different methods for constructing the bond between the Pr starting material or intermediate 12' (sub-scheme 1) or 12 (sub- scheme 2) and an R 5 ring intermediate 9, thereby synthesizing a desired intermediate 14' or a final compound 14 of Formulas I-III.
  • One method to make this bond is to react an epoxide intermediate 12 or 12' (Note: the epoxide 12 or 12' may be purchased commercially or made via known, published methods such as from the olefin precursor), with an amino-R 5 intermediate 9, as shown.
  • the reaction may proceed in the presence of a polar solvent, such as an alcohol or dioxanes, and may require additional reagents, as appreciated by those skilled in the art.
  • reaction may require heat for a period of time.
  • the protecting group may be removed using an acid, such as HCl, such that the bonded adduct 14' is recovered as an HCI salt.
  • desired intermediates 14' may be synthesized starting with an amine-protected aldehyde intermediate 13' (sub-scheme 3) or 13 (sub-scheme 4) and condensing the aldehyde with a primary or secondary amine 9 to form an imine (not shown, generally formed in-situ and not isolated).
  • the imine can then be reduced using a known reducing agent, such as a hydride or borohydride, the reduced intermediate may be deprotected to provide an intermediate 14' having an amine useful to prepare compounds 14 of Formulas I-III.
  • Scheme 5 describes, generally, two different methods (Methods A and B) for constructing intermediates 18' (Method A) or 18 (Method B) which are useful for making compounds of Formula HI.
  • the acid group of an olefinic amino- acid compound 15 may be modified with a desired B group to form a compound 16, by first activating the acid of 15 with a known activating agent, such as HATU in the presence of a suitable base, and treating activated 15 with a B-substituted grignard reagent or B-ligand metal reagent, which delivers the desired B group to displace the carbonyl activating group and form compound 16.
  • a known activating agent such as HATU
  • B-substituted grignard reagent or B-ligand metal reagent which delivers the desired B group to displace the carbonyl activating group and form compound 16.
  • Compound 16 may be oxidized to the corresponding ketone 17 by known methods, such as with sodium periodiate and osmium tetroxide. Ketone 17 may then be reacted with amine 9, via a reductive amination step, to form an amino protected intermediate, which can be deprotected to yield intermediate 18*, as shown.
  • intermediate 18 may be made using a reductive amination step with an amine-protected diamine compound 19 and a ketone 6.
  • reductive amination step may be employed with conventional conditions using known reducing reagents in suitable solvents, at suitable temperatures, as appreciated by one of ordinary skill in the art.
  • Amine compounds 18 and 18' can then be coupled to acids and sulfonic acid compounds 2_ 2', 4 and 5, described in scheme 1, to make amides and sulfonamide compounds ("W" groups) of Formulas I-III by methods described in scheme 2.
  • Model 1100 series system LC/MSD SL using one of the two following Columns: (a) Phenomenex Sernegi (4 micron, C 18, 50x2 mm) or (b) a Gemini column (5 micron, C 18, 100x2 mm). A typical run through the instrument included: eluting at 1 ml/min with an linear gradient of 10%(v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 10 minutes; conditions may be varied to achieve optimal separation.
  • the compounds described herein were purified via reverse phase HPLC using one of the following instruments: Shimadzu, varian, Gilson; utilizing one of the following two HPLC columns: (a) a Phenomenex Luna or (b) a Gemini column (5 micron or 10 micron, C18, 150x50 mm)
  • Step 1 2.2-spirocvclobutylchroman-4-one l-(2-hydroxyphenyl)ethanone (3.2 ml, 26.6 mmol), cyclobutanone (4 ml, 53.3 mmol), pyrrolidine (2.6 ml, 32 mmol), and diisopropylethyl amine (4.5 ml, 26.6 mmol) were dissolved in 30 ml toluene and refluxed under a Dean Stark trap for 3.5 h. The reaction was terminated (although a large amount of starting material was still present). The cooled reaction mixture was diluted with 100 ml ether, washed with 30 ml HCl (aq., 5M), dried over MgSO 4 and evaporated.
  • the title compound was synthesized by a method analogous to that described in Example 1 , using(2S,3R)-3-amino-l-((S)-6-ethyl-2,2-spirocyclobutylchroman-4- ylamino)-4-phenylbutan-2-ol dihydrochloride salt and 2-(pyridin-4-yl)acetic acid hydrochloride (Aldrich) in the presence of DIPEA to obtain the title compound as a colorless solid. MS m/z: 500.3(M+l).
  • Pd 2 (dba) 3 (15 mg, 0.017 mmol), (S)-tert-butyl 6-bromo-2,2-spirocyclobutyl ⁇ 3,4- dihydro-2H-chromen-4-ylcarbamate (15 mg, 0.041 mmol), 2-(dicyclohexylphosphino)- 2'-methylbiphenyl (80 mg, 0.170 mmol), potassium phosphate (179 mg, 0.845 mmol), and acetone (2.5 ml, 33.8 mmol) were dissolved in 1 ml THF in a sealed tube. The tube was sealed and heated to 70 0 C for 8 hours.
  • Step 2 (SV6-(2-fluoro-2-methyl ⁇ ropyl ' )-2.2-spirocvclobutyl-3.4-dihvdro-2H-chromen-4- amine
  • the reaction was quenched with saturated ammonium chloride (10 mL) and the aqueous layer was extracted with EtOAc 3 x 20 mL. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to provide the corresponding alcohol (209 mg, 99%) as a yellow oil.
  • the derived alcohol (209 mg, 0.578 mmol) was taken up in 1 mL of DCM cooled to -78 0 C and treated with DAST (0.153 mL, 1.16 mmol). After stirring for 45 minutes the reaction was warmed to 0 0 C and quenched with saturated potassium carbonate (10 mL). The layers were separated and the aqueous layer was extracted with dichloromethane 3 x 10 mL.
  • Step 3 N-Cf 1 S.2R)-3-Cf f 4SV 6-(2-fluoro-2-methylpropyIV3.4-dihvdrospirorchromene-2.1 '- cyclobutan1-4-vDaminoV24ivdroxy-l-fphenylmethyl')propyl ' )acetamide
  • the amine from step 2 was carried on by methods analogous to those described in Example 464, Steps 8-10 herein to afford the title compound. MS found: m/z: 469 (M+l).
  • Example 462
  • Step 1 (SVtert-butyl 6-f2-oxopropylV2,2-spirocvclobutyl-3.4-dihvdro-2H-pyranor2,3- bipyridin-4-ylcarbamate
  • Step 2 fS * )-6-(2-fluoro-2-methylpropyl')-2,2-spirocvclobutyl-3,4-dihvdro-2H-pyranor2,3- blpyridin-4-amine
  • Step 3 N-(Tl S.2RV3-ff(4'SV6'-f2-fluoro-2-methylpropylV3 ⁇ 4'-dihvdrospirorcvclobutane- l ⁇ '-pyranol ⁇ J-blpyridinl ⁇ '-v ⁇ amino ' t ⁇ -hydroxy-l-Cphenylmethv ⁇ propy ⁇ acetamide
  • Step 2 l-(2,2-dimethoxyethyl)cyclopent-3-enol
  • the reaction was diluted with water (1 L) and poured into a seperatory funnel.
  • the DCM layer was separated and the aqueous was extracted with DCM (3x100 mL).
  • the combined organics were concentrated to a dark oil which was purified by flash chromatography on a 33Og ISCO column el ⁇ ting by gradient hexanes to 20% EtOAc/ hexanes over a 50 minute period. Product fractions were combined to afford the title compound.
  • Step 3 2-(l-(tert-butv1dimethyIsilyloxy')cvclopent-3-enyl) acetaldehvde l-(2,2-dimethoxyethyl)cyclopent-3-enol (13.5g, 78mmol) was dissolved in DCM (25OmL). This was chilled to 0 0 C under nitrogen and 2,4,6-trimethyIpyridine (42mL, 314mmol) was added dropwise over 10 minutes. Tert-butyldimethylsilyl trifluoromethanesulfonate (18 mL, 78mmol) was added dropwise via syringe very slowly over 20 minutes keeping the internal temperature below 5 0 C.
  • the reaction was allowed to come to RT. By TLC (20% EtOAc/hexanes; KMnO4 stain), the starting material was completely consumed ( ⁇ 2 hours). The reaction was then chilled back to O 0 C and triethylsilyl trifluoromethanesulfonate (35mL, 157mmol) was added in dropwise over a 10 minute period. This was allowed to stir at 0 0 C for 1 hour before adding water (250 mL). The ice bath was removed and this mixture was stirred vigorously for ⁇ 18 hours. The reaction was poured into a seperatory funnel and the DCM layer was separated.
  • Step 4 (ZVN-(2-( 1 -(tert-butyldimethylsi1yloxy)cvclopent-3 -envnethylidene-2- methylpropane-2-sulf ⁇ namide
  • Step 5 (2S)-N-(2-f 1 -ftertbutyldimethylsilyloxy ' )cvclopent--3-enylV 1 -C2-fluoro-5- neo ⁇ enrv1pyridi-3-vOethvO-2-methvIproDane-2-suIfinamide
  • Step 7 N-(T 1 S.2R)-3-(( ' ( ' 4'S')-6'-f2.2-dimethylpropylV3',4'-dihvdrospirorcvclopent-3-ene- L2'-pyranof2,3-b]pyridinl-4 t -yl)amino)-l-f( ' 4-fluorophenv ⁇ methv ⁇ -2- hydroxypropyPacetamide
  • the title compound was obtained using 3',4'-dihydrospiro[cyclopent-3-ene-l,2'- pyrano[2,3-b]pyridin]-4'-yl)amine in a method analogous to that described in Example 464 below, Steps 8-10. MS found: m/z: 496 (M+l).
  • TEA 8.87 ml, 63.7 mmol
  • TEA 8.87 ml, 63.7 mmol
  • the reaction was allowed to stir for 5 min before the dropwise addition of tert-butyldimethylsilyl triflate (10.2 ml, 44.6 mmol) via syringe.
  • the reaction was allowed to stir for 1 h and then quenched by pouring into HCl (0.1 N, 100 mL).
  • HCl 0.1 N, 100 mL
  • DCM 2 x 75 mL
  • the combined organics were washed with HCl (0.1 N 3 2 x 150 mL), sodium bicarbonate (1 x 150 mL, sat), brine, dried sodium sulfate.
  • Step 2 fS>2.3-bisftert-butyldimethylsilyloxy)propan-l-ol
  • DCM 100 mL
  • DIBAL-H 1.0 M, hexanes
  • Step 3 (R)-2 ⁇ 3-bis(tert-butyldirnethylsilyloxy')propanaIdehvde
  • DCM 100 mL
  • SODIUM BICARBONATE 3.69 g, 44.0 mmol
  • Dess-MartinPeriodinane 7.46 g, 17.6 mmol
  • Step 4 (S.EVN-fCS ⁇ J-bisftert-butyldimethylsilyloxy ⁇ propylidene ⁇ -methylpropane ⁇ - sulf ⁇ namide
  • TMEDA (492 ⁇ l, 3260 ⁇ mol) was added via a syringe and then THF (10 mL) was added via a syringe and the mixture was allowed to stir for 15 min before the addition of (S,E)-N-((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2- sulfinamide (550.00 mg, 1304 ⁇ mol) (14 mL THF) via a syringe. The reaction was allowed to stir for 30 min and then quenched with ammonium chloride (sat, 100 mL). The aq. layer was extracted with EtOAc (3 x 100 mL).
  • Step 6 (S)-N-((2S.3S)-3-(tert-butyldimethylsilyloxy')-l-('3-chloro-5-fluorophenyl ' )-4- hvdroxybutan-2-yl)-2-methylpropane-2-sulflnamide
  • PYRIDINE (2699 ⁇ l, 33371 ⁇ mol) was added via syringe before the addition of HF-Pyridine, 70% HF 30% pyr (1782 ⁇ l, 19775 ⁇ mol) via a syringe.
  • the reaction was allowed to stir at this temp for 2h and then quenched by pouring into sodium bicarbonate (sat 150 ml).
  • the aq. layer was extracted with EtOAc 94 x 75 mL).
  • the combined organics were washed with HCl (0.1 N, 3 x 100 mL), bicarbonate (sat, 100 mL), brine and dried with sodium sulfate.
  • Step 7 (SVN-r(2S.3SV3-ftert-butyldimethylsilyloxy')-l-(3-chloro-5-fluorophenvn-4- oxobutan-2-ylV2-methylpropane-2-sulfinamide
  • Step 8 ( • SVN-f(2S.3RV3-ftert-butyldimethylsilyloxyV l-r3-chloro-5-fluorophenvn-4-r(SV
  • 6-ethyl-2,2-spirocyclobutyl-8-azachromanyl-4-amine 36 mg, 167 ⁇ mol
  • DCE 5mL
  • TRIMETHYL ORTHOFORMATE 276 ⁇ l, 2500 ⁇ mol
  • the reaction was allowed to stir for 20 min when FIA/MS indicated that imine had formed.
  • SODIUM TRIACETOXYBOROHYDRIDE 141 mg, 667 ⁇ mol was added in one portion and the reaction was allowed to stir for 12 h.
  • the reaction was quenched by the addition of sodium carbonate (10%, 30 mL) and diluted with DCM (50 mL). The aq.
  • Step 9 ⁇ RJSVB-amino ⁇ -O-chloro-S-fluorophenylVl-ffSV ⁇ -ethyl- ⁇ . ⁇ -spirocvclobutyl- 3.4-dihydro-2H-pyranof ' 2,3-b ' )pyridin-4-ylamino ' )butan-2-ol
  • HCl is the reactive reagent for the removal of sulfinyl or other protecting groups involved in the synthesis of this compound or analogs.
  • commercially available reagent HCl e.g., 4.0 M in dioxane
  • HCl can be used directly.
  • Step l0 N-((lS.2RVl-f(3-chloro-5-fluoroDhenvnmethylV3-fff4'SV6'-ethyl-3'.4'- dihvdrospirofcvclobutane-1.2'- ⁇ yranor2,3-b1pyridin1-4'-yl')amino ' )-2- hydroxypropyDacetamide
  • the title compound was prepared using l-(lH-imidazol-l-yl)ethanone (18 mg, 159 ⁇ mol) and (2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-l-((S)-6-ethyl-2,2-spirocycloburyl-3,4- dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)butan-2-ol in DMF.
  • Step 2 tert-Butyl r2S.3S)-3-(tert-butyldimethylsilyloxy)-l-(3-fluorophenyl)-4- hydroxybutan-2-ylcarbamate
  • the crude oil was purified on a 12Og Isco column (10 to 35% EtOAc in hexanes) to give the title compound as a colorless oil.
  • Step 3 Tert-Butyl (2S,3S)-3-ftert-butyldimethylsilyloxy)-l-f3-fluorophenyl)-4-oxobutan- 2-ylcarbamate
  • a 150 mL RBF containing tert-butyl (2S,3S)-3-(tert-buryldimethylsilyloxy)-l-(3- fluorophenyl)-4-hydroxybutan-2-ylcarbamate 17.
  • Step 4 N-f ⁇ S.2RV3-r((4'SV6'-f2.2-dimethylpropyn-3'.4'-dihvdrospirorcvclobutane-l .2'- pyranof2,3-b1pyridin1-4'-yl')ammoVl-((3-fluorophenyl')methyl')-2- hydroxypropyl ⁇ acetamide
  • Step 1 l-r2.2-dimethoxyethyl ' )cvclopropanol
  • Step 2 2-(l-(tert-butyldimethylsilyloxy)cvclopropyI)acetaldehyde To a 2.0 L RBF containing l-(2,2-dimethoxyethyl)cyclopropanol (17.40Og, 119 mmol) was added DCM (550 ml) and the mixture was allowed to stir at 0 0 C for 15 min.
  • Step 3 (R.E)-N-(2-( 1 -(tert-buMdimethylsilyloxy)cvclopropyDethylidene)-2- methylpropane-2-sulf ⁇ namide
  • 2-(l -(tert- butyldimethylsilyloxy)cyclopropyl)acetaldehyde (5.00 g, 23.3 mmol) (crude 10.5 g with TESOH 5 IHNMR showed about 50/50 sm to impurity) was added DCM (200 mL) and the mixture was allowed to stir at 23 0 C for 5 min.
  • Step 4 (26R)-N-(2-d-( " tert-butyldimethylsilyloxy)cyclopropyn-l -C2-fluoro-5- neopen ⁇ ylpyridin-3-yl)ethyl')--2-rnethylpropane-2-sulfinamide Prepared following the procedure described for Example 272, Step 7 utilizing 2,2,6,6-tetramethylpiperidine (2.21 ml, 13.0 mmol), buryllithium (4.62 ml, 11.6 mmol), 2-fluoro-5-neopentylpyridine (1.610 g, 9.63 mmol), and (R,E)-N-(2-(l-(tert-butyldimethyIsilyloxy)cyclopropyl)ethylidene)-2- methylpropane-2-sulf ⁇ namide (3.97 g, 12.5 mmol).
  • Step 5 (SVl -( ⁇ -amino- ⁇ -f ⁇ -fluoro-S-neopentylpyridin- ⁇ -vPethvPcyclopropanol
  • Rf 0.45 in 35% EtOAc in hexanes
  • Step 5 (SVl -( ⁇ -amino- ⁇ -f ⁇ -fluoro-S-neopentylpyridin- ⁇ -vPethvPcyclopropanol
  • THF 13 ml
  • Step 7 N-((2S.3R)-4-((S)-2,2-spirocvcIopropyl-6-neopentyl-3,4-dihvdro-2H-pyranor2.3- b1pyridin-4-ylamino)-l-(4-fluorophenylV3-hvdroxybutan-2-yl)acetamide
  • the title compound was prepared by a method analogous to that described in Example
  • Step 1 2-bromo-5 -( methoxvmeth oxVtavri dine
  • DMF 300 rnL
  • NaH 5.7 g, 144 mmol
  • Saturated sodium bicarbonate 500 mL was added slowly and the suspension stirred 30 min and warmed to rt.
  • Step 2 5-fmethoxymethoxy>2-neopentylpyridine
  • 2-bromo-5-(methoxymethoxy) ⁇ yridine 30.5 g, 140 mmol
  • THF 5 mL
  • neopentylmagnesium chloride 155 mL, 155 mmol
  • Step 3 l-(5-(methoxymethoxyy2-neopentylpyridin-4-vDethanol To a solution of 5-(methoxymethoxy)-2-neopentylpyridine (16.5 g, 79 mmol) and in THF (200 mL) -78°C is added tert-buryllithium (46 ml, 79 mmol) (1.7 M in pentane ) over 2 min via cannula. The reaction was stirred at -78°C 30 min, and acetaldehyde (11 ml, 197 mmol) was added. The reaction was stirred at -78°C 10 min, then the reaction was warmed to rt and stirred 3 h.
  • Step 6 2.2-spirocvclobutyl-6-neopentyl-2,3-dihvdropyranor2.3-c1pyridin-4-one
  • Step 7 2.2-spirocvclobutyl-6-neopentyl-7-oxo-2.3-dihvdropyrano r2.3-c1pyridin-4-one 2,2-spirocyclobutyl-6-neopentyl-2,3-dihydropyrano[2,3-c]pyridin-4-one (5.00 g, 19 mmol) was dissolved in 100 ml CHCl 3 and cooled to 0 0 C, mCPBA (10.0 g, 58 mmol) was added portionwise and the reaction was stirred under N 2 and allowed to warm slowly to rt; stirring was continued for 17 h.
  • Step 8 S-chloro ⁇ . ⁇ -spirocycIobutyl- ⁇ -neopentyl- ⁇ .S-dihydro ⁇ yrano r 23-c1pyridin-4-one 2,2-spirocyclobutyl-6-neopentyl-7-oxo-2,3-dihydropyrano[2,3-c]pyridin-4-one. (5.3 g, 19 mmol) was taken up in phosphoryl trichloride (20 mL, 218 mmol) and the mixture was heated to 8O 0 C for 2 h under N 2 .
  • the reaction was stirred an additional 30 min, then was quenched by dropwise addition (1 drop/10 sec) of 5 M HCl (25 mL) at 0 0 C, after 15 mL HCI was added, bubbling had ceased and the addition rate was increased as the ice bath was removed.
  • the reaction was stirred an additional 2 h at rt.
  • the reaction was recooled to 0 0 C and neutralized with 5 M NaOH (27 mL).
  • the mixture was then extracted with EtOAc (2 x 150 mL), washed with saturated aqueous NaCl (200 mL), dried (MgSO 4 ), and concentrated in vacuo.
  • Step 1 1 (SV8-chloro-2,2-spirocvclobutyl-6-neopentyl-3.4-dihvdro-2H-pyranoF2.3- cIpyridin-4-amine
  • the vial was purged with N 2 5 x, then methanamine (949 ⁇ l, 1898 ⁇ mol) and LiHMDS (475 ⁇ l, 475 ⁇ mol, 1.0 M in THF) were added.
  • the vial was sealed and heated in a microwave at 110 0 C for 10 min.
  • the reaction mixture was directly purified by reverse phase HPLC on a Phenomenex Synergi column (5 micron, MAX-RP, 80 A, 150x30 mm) eluting at 45 ml/min with an linear gradient of 10%(v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 30 minutes to give to give the title compound as a white amorphous solid.
  • Step 1 (4S.,5S)-tert-butyl 5-((tert-but ⁇ ldimethylsilyloxy)methyl)-2,2-dimethyl-4-(thiazol- 4-ylmethyl)oxazolidine-3-carboxylate
  • Step 2 (4S.5S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2q-dimethyl-4-((2- methylthiazol-4-yl)methvOoxazolidine-3-carboxylate
  • Step 3 f4S.5SVtert-butyl 5-(hvdroxymethviy2.2-dimethv1-4-fr2-methylthiazol-4- yDmethyl)oxazolidine-3-carboxy1ate (4S,5S)-Tert-butyl 5-((tert- butyldimethyIsilyloxy)methyl)-2,2-dimethyl-4-((2-methylthiazoI-4-yl)methyl)oxazolidine- 3-carboxylate (0.100 g, 0.219 mmol) was dissolved in THF (4mL) and cooled to O 0 C.
  • Step 1 (4S,5SVtert-butyI 4-((2-(tert-butyldimethylsilyl ' )thiazol-4-vnmethyl ' )-5-f(tert- butyldimethylsilyloxy)methylV2.2-dimethyloxazolidine-3-carboxylate (4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(thiazol-4- ylmethyl)oxazolidine-3-carboxylate (0.148 g, 0.334mmol) in THF (3mL) was cooled to - 78 0 C when n-butyllithium (2.5 M in hexanes)(0.160 ml, 0.401 mmol) was added dropwise.
  • Step 2 (4S,5S)-tert-butyl 4-rf2-ftert-butyldimethylsilvn-5- ⁇ ro ⁇ ylthiazol-4-yl')methvn-5- fCtert-butyldimethylsilyloxy ⁇ methvD ⁇ -dimethyloxazolidine-S-carboxylate (4S,5S)-Tert-butyl 4-((2-(tert-butyldimethylsilyl)thiazol-4-yl)methyl)-5-((tert- butyldimethylsiIyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.150 g, 0.269 mmol) in THF (3 niL) was cooled to -78°C when N-BUTYLLITHJUM (2.5 M in hexanes)(0.1 19 ml, 0.296 mmol) was added dropwise.
  • Step 3 (4S.5SVtert-butv1 5-fhvdroxymethylV2.2-dimethyl-4-f(5-propylthiazol-4- vnmethvnoxazolidine-3-carboxylate (4S,5S)-Tert-butyl 4-((2-(tert-butyldimethylsilyl)-5- propylthiazol-4-yl)methyl)-5-((tert-butyldimethylsilyloxy)methyl)-2,2- dimethyloxazolidine-3-carboxylate was dissolved in THF (3mL) and cooled to O 0 C when TBAF (0.808 ml, 0.808mmol) was added.
  • the reaction was stirred one hour before being quenched with saturated ammonium chloride.
  • the layers were separated and the aqueous layer was extracted with EtOAc.
  • the combined organic layers were washed with water, brine and dried over sodium sulfate to afford the title compound.
  • Step 1 fSVmethyl 2-(tert-butoxycarbonylV3-(4-(trifluoromethyl * )phenyl')propanoate Iodine (0.0140 g, 0.0553 mmol) was added to zinc (0.542 g, 8.29mmol) and the solid mixture was heated under vacuum for 10 minutes. The flask was flushed with nitrogen three times and allowed to cool. DMF (0.5mL, degassed with nitrogen) was added and the suspension was cooled to O 0 C and stirred while (R)-methyl 2-(tert-butoxycarbonyl)-3- iodopropanoate (1.82 g, 5.53 mmol) in DMF (2.8 niL) was added dropwise.
  • DMF 0.5mL, degassed with nitrogen
  • Step 1 (4S,5S)-tert-butyl 5-(ftert-butyldimethy1silyloxy')methyl')-2,2-di ⁇ nethvI-4-('pyridin-4- ylmethyl)oxazolidine-3-carboxylate
  • the title compound was synthesized in manner analogous to that described in Example 472, using (4S,5 S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(pyridin-4- ylmethyl)oxazolidine-3-carboxylate in the presence of TBSCl and imidazole, and was used without further purification.
  • Step 2 f4S.5SVtert-butyl S-(ftert-butyldimethylsilylo ⁇ y)methvO-2 > 2-dimethyl-4-((2- methylpyridin-4-yl ' )rnethyl ' )oxazolidine-3-carboxylate
  • Step 3 (4S.5S>tert-butyl 5-(hydroxymethvn-2,2-dimethyl-4-((2-methylpyridin-4- v ⁇ methyl " )oxazolidine-3-carboxylate
  • Step 1 (4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloropyridin-4- yl)methyI)-2,2-dimethyloxazolidine-3-carboxylate.
  • the title compound was synthesized in a manner analogous to Example 475, step 1 via (4S,5S)-tert-butyl 4-((2-chloropyridin-4- yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate in the presence of TBSCl and imidazole and was used without further purification.
  • Step 2 (4S.5SVtert-butyl 5-frtert-butv1dimethylsilyloxy ⁇ methvn-4-(Y2-chloro-6- methylpyridin-4-y0methylV2.2-dimethv1oxazolidine-3-carboxylate
  • Dimethylethanolamine (0.128 ml, 1.27mmol) was added to anhydrous hexanes (1.4 L) and cooled to O 0 C.
  • N-BUTYLLITHIUM (2.5 M in hexanes)(1.02 ml, 2.55mmol) was added dropwise and stirred for 30 minutes before being cooled to -78 0 C.
  • the reaction was diluted with ethyl acetate and water and separated.
  • the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated to give the titled compound which was used directly for the next step without purification.
  • Step 1 (S)-tert-butyl 6-bromo-2,2-spirocvclobutyl-3,4-dihvdro-2H- ⁇ yranor2.3-b] ⁇ yridin-
  • Step 2 (SVtert-butyl allvIf6-bromo-2.2-spirocvclobutyl-3.4-dihvdro-2H-Pyranor2,3- b]pyridin-4-yl " )carbamate
  • Step 3 (S)-tert-butyl allvK ⁇ -fhvdroxymethyD ⁇ . ⁇ -spirocyclobutyl-S ⁇ -dihvdro- ⁇ H- . pyranor2,3-b1 ⁇ yridin-4-yl')carbamate
  • the crude material was dissolved in 80 mL of methanol and cooled to 0 0 C when sodium tetrahydroborate (1.62 g, 42.9 mmol) was added. After stirring 40 minutes the reaction was quenched by addition of saturated ammonium chloride and water. The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated. The product was purified by column chromatography (1:1 Hex/EtOAc to EtOAc) to give the titled compound.
  • Step 4 (S)-tert-butyl allyl(6-( " 2-cvano-2-methylpropyl)-2,2-spirocvclobutyl-3.4-dihvdro- 2H-pyranor2,3-b1pyridin-4-yl)carbamate
  • Step Si CSVS- ⁇ -amino-a ⁇ -spirocvclobutyl-S ⁇ -dihydro ⁇ H-pyranofl.S-bipyridin- ⁇ -yl') ⁇ - dimethylpropanenitrile (S)-Tert-butyl allyl(6-(2-cyano-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H- pyrano[2,3-b]pyridin-4-yl)carbamate (0.100g, 0.24 mmol) was stirred in DCM (2mL) with TFA (1.0 ml, 13mmol). After 3 hrs the reaction was concentrated.
  • the crude product was dissolved in degassed (N 2 ) DCM (2 mL) and 1,3- dimethylbarbituric acid (0.11 g, 0.73 mmol) was added. After two minutes, tetrakis(triphenylphosphine)palladium(0) (0.014 g, 0.012 mmol) was added and the reaction was stirred at 35 0 C for 3 hours. The reaction was diluted with DCM and 10% aqueous sodium carbonate and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated.
  • Step 1 (S)-tert-butyl allyl(6-(2,2-spirocyclobutyl-3-oxopropylV2.2-dimethyl-3.4-dihvdro- 2H-pyranor2.3-b1pyridin-4-yl ' )carbamate
  • S)-tert-butyl allyl(6-(2-cyano-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H- py ⁇ ano[2,3-b]pyridin-4-yl)carbamate (0.708 g, 1.72 mmol) was dissolved in toluene (12 mL) and cooled to 0 0 C.
  • Step 2 (SVtert-butyl allyl(6-G.3-difluoro-2,2-dimethylpropyl>2,2-spirocyc1obutyl-3.,4- dihvdro-2H-pyranor2,3-b '
  • Step 3 N-(Cl S.2RVl-r(4-chlorophenvnmethvn-3-((f4'SV6'-('3.3-difluoro-2.2- dimethylpropyl ' )-3'.4'-dihvdrospirorcvclobutane-1.2'-pyranor2,3-b1pyridin]-4'-yl)amino * )-
  • Step 1 (SVtert-butyl allyl( " 6-(2.2-dimethylbut-3-vnv ⁇ -2.2-spirocvclobutyl-3,4-dihvdro- 2H-pyranor2.3-blpyridin-4-yl ' )carbamate Potassium carbonate (0.155 g, 1.12 mmol) was added to a solution of (S)-tert-butyl atlyKe- ⁇ -spirocyclobutyl-S-oxopropyl ⁇ -dimethyl-S ⁇ -dihydro ⁇ H-pyranop ⁇ b]pyridin-4-yl)carbamate (0.233 g, 0.562 mmol) and Ohira's Reagent (0.130 g, 0.674 mmol) in MeOH (6 mL).
  • Step 2 N-(Tl S.2RVl-fr4-chlorophenvnmethylV3-rff4'SV6'-(2.2-dimethyl-3-butvn-l -ylV 3',4'-dihvdrospirorcvclobutane-U2'-pyranor2,3-blpyridin1-4'-yl ' )aminoV2- hvdroxypropyDacetamide
  • Step 1 2,6-difluoro-3-neopentylpyridine To a 500 mL RBF was added neopentylmagnesium chloride, 1.0M in ether (28.0 ml, 28 mmol) and an ice bath. After cooling, zinc(II) chloride, 0.5M in THF (56.0 ml, 28 mmol) was added dropwise. The cooling bath was removed and after stirring for 45 minutes, Reactant 1 (0.26 g, 0.32 mmol) was added followed by 2,6-difluoro-3-iodopyridine (2.74 g, 8.0 mmol) in THF (10 mL), which was added dropwise. The yellow solution was then heated to 60 0 C.
  • Step 2 N-((S)-2-fl -(tert-butyldimethylsilyloxy)cvclobutvD-l -(2,6-difluoro-5- neo ⁇ entylpyridin-3-vDethv0-2-methylpropane-2-sulfinamide
  • 2,2,6,6-tetramethylpiperidine (0.34 ml, 2 mmol)
  • THF 1,4-difluoro-5- neo ⁇ entylpyridin-3-vDethv0-2-methylpropane-2-sulfinamide
  • Step 3 N-fCS'-7-fluoro-2.2-dimethyl-6-neopentyl-3.4-dihvdro-2H-pyranor2.3-b1pyridin-4- vn-2-methylpropane-2-sulfinamide
  • N-((S)-2-(l -(tert- butyldimethylsilyloxy)cyclobutyl)-l-(2,6-difluoro-5-neopentylpyridin-3-yl)ethyl)-2- methylpropane-2-sulfinamide (0.070 g, 0.14mmol), THF (3mL), and TBAF, IM in THF (0.14 ml, 0.14mmol).
  • reaction was stirred at RT. After 20 minutes, the reaction was eluted through a plug of silica gel with THF. The resulting filtrate was concentrated in vacuo and taken up in THF (2OmL) and treated with NaH (0.035 g, 0.88 mmol, 60% in mineral oil). The reaction was stirred at 40 0 C for 16 hours. The reaction was allowed to cool to RT and quenched with sat'd NH 4 Cl 5 and extracted with EtOAc (25 mL).
  • Step 4 (S)-7-fluoro-2,2-spirocvclobutane-6-neopentyl-3,4-dihydro-2H-pyrano[ " 2,3- bipyridin-4-amine
  • N-((S)-7-fluoro-2,2-dimethyl-6-neopentyl-3,4-dihydro-2H- pyrano[2,3-b]pyridin-4-yl)-2-methylpropane-2-sulf ⁇ namide (1.71 g, 4.5mmol), dichloromethane (2OmL), and hydrogen chloride, 4.0M in dioxane (2.00 ml, 8.0mmol).
  • the reaction was stirred at RT.
  • Step 5 N-ff 1 S.2RV3-(f(4'S V6'-(2.2-dimethylproDylV7'-fluoro-3'.4'- dihvdrospirorcvclobutane-l,2'-pyranor2.3-b1pyridin1-4'-v ⁇ amino)-2-hvdroxy-l- (phenylmethvDpropyDacetamide
  • Step 1 N-allyl-N-f-burylcarbamate-f4'SV6'-f l-hvdroxy-2.2-dirnethylpropyn-3'.4'- dihvdrospirorcvclobutane-l,2'-pyrano r 2,3-b]pyridin1-4 t -amine
  • N-allyl-N-/-butylcarbamate-(4'S)-6 I -(bromo)-3',4'-dihydrospiro[cyclobutane- l,2 r -pyrano[2,3-b]pyridin]-4'-amine (4.12 g, 10.1 mmol) in ether (8OmL) was cooled to - 78°C and then ⁇ -butyllithium (12.5 ml, 21.3 mmol) was added and stirred for 15 minutes before the pivalaldehyde (3.80 ml, 35.0 mmol) (Note: freshly
  • Step 2 N-allyl-r4'S)-6'-(l-fluoro-2.2-dimethylpropyl)-3'.4'-dihvdrospiro[cyclobutane-l,2'- pyranor2.3-b1pyridin1-4'-amine
  • N-allyl-N-/-butylcarbamate- (4'S)-6'-(l-hydroxy-2,2-dimethylpropyl)-3',4 l -dihydrospiro[cyclobutane-l,2'-pyrano[2,3- b]pyridin]-4'-amine (4.01 g, 9.6mmol), toluene (10OmL), a dry ice bath, and after cooling for 20 minutes DAST (1.81 ml, Hmmol) was added.
  • Step 3 (4'SV6'-(1 -fluoro- ⁇ -dimethylpropyD-S' ⁇ '-dihvdrospirorcvclobutane-l ⁇ '- pyranor2.3-b1pyridin1-4'-amine
  • N-allyl-(4'S)-6 l -(l-fluoro- 2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 1 ,2'-pyrano[2,3-b]pyridin]-4'-amine (3.10 g, 9.7 mmol)
  • degassed DCM 80 mL
  • 1,3-dimethylbarbituric acid (4.58 g, 29 mmol).
  • the combined organic layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with 50% to 80% EtOAc in hexane, to provide a mixture of product and triphenyl-phosphine oxide.
  • the material was taken up in EtOAc and extracted with HCl (IN, 2 X 20 mL). The aqueous layer was then neutralized and extracted with EtOAc (2 X 20 mL).
  • Step 4 N-ffl S.2RV3-fff4'SV6'-n-fluoro-2.2-dimethylproDvn-3'.4'- dihydros ⁇ irorcvclobutane-L2'-pyranor2.3-b1pyridin1-4'-yl)aminoVl-f(4- fluorophenyl)methyl)-2-hvdroxypropyT)acetamide
  • Step 1 (SVtert-butyl 6-allyl-2.2-spirocvclobutyl-3.4-dihvdro-2H-pyranor2,3-b1pyridin-4- ylcarbamate
  • Step 2 (S)-6-Ccvclopro ⁇ ylmethyl)-2,2-spirocvclobutv1-3.4-dihydro-2H-pyranol2.3- blpyridin-4-am ine
  • diethylzinc 1.0 M in hexanes, 9.00 mL, 9.00 mmol
  • TFA 0.70 ml, 9.0 mmol
  • diiodomethane 0.70 ml, 9.0 mmol
  • Step 3 N-(( 1 S,2RV3-(((4'S " )-6'-(cvclopropyImethvn-3',4'-dihvdrospirorcyclobutane-l,2'- pyranor2.3-b7pyridi ⁇ ' l-4'-v ⁇ amino)-l-((4-fluorophenyl)methyl)-2-hvdroxypro ⁇ yl)acetamide
  • Step 1 (S)-tert-butyl ⁇ -te-methylallyl ⁇ -spirocvclobutyl-S ⁇ -dihvdro ⁇ H-pyranore ⁇ - bipyridin-4-ylcarbamate A mixture of Pd 2 (dba)3 (133 mg, 0.145 mmol) tri-t-butylphosphonium tetrafluoroborate
  • Step 2 (SVtert-butyl 6-( ⁇ -methylcvclopropyDmethviy2.2-spiroevclobutyl-3.4-dihvdro-
  • the reaction was quenched with methanol (10 mL) and saturated sodium bicarbonate (3 mL). The slurry was then treated with DIEA (0.80 mL, 4.00 mmol) and di-tert-butyl dicarbonate (1.0 mL, 4.0 mmol) and allowed to stir for 3 hours. The reaction was then diluted with EtOAc (25 mL) and washed successively with saturated sodium bicarbonate (30 mL), water and brine before being dried over magnesium sulfate.
  • Step 3 (SV6-f(l-methylcvclopropyl)methy ⁇ -2.2-spirocvclobutyl-3,4-dihydro-2H- pyranor2.3-b " lpyridin-4-amine
  • (S)-tert-butyl 6-((l-methylcyclopropyl)methyl)-2,2-spirocyclobutyl-3,4- dihydro-2H-pyrano[2,3-b]pyridin-4-yIcarbamate (0.860 g, 2.4 mmol) and 2,6-lutidine (2.80 ml, 24.0 mmol) in 10 mL of DCM was cooled to 0 0 C and treated with trimethylsilyl triflate (2.30 ml, 12.0 mmol).
  • Step 4 N-(Y 1 S.2RV 1 -f f4-fluorophenvnmethylV2-hvdroxy-3 -(Tf 4'SV 6'-(T 1 - methylcvclopropyl ' )methv ⁇ -3',4'-dihvdrospirorcvclobutane-l,2'-pyranor2.3-b]pyridin1-4'- yl)amino)propyl)acetamide
  • Step 1 Tert-butyl CSV6-( ' 2-methyl-3-oxopropyl " )-2,2-spirocyclobutyl-3,4-dihvdro-2H- pyranoF2.,3-b1pyridin-4-ylcarbamate
  • reaction vessel was then sealed and heated to 80 0 C for 10 hours.
  • the cooled reaction mixture was quenched with saturated sodium bicarbonate (50 mL), and the aqueous layer was extracted with EtOAc 3 x 50 mL. The combined organics were washed with brine, dried over sodium sulfate and concentrated. Purification of the crude residue by column chromatography (0-50% EtOAc in hexanes) provided the title compound as a colorless oil. MS m/z: 361 (M+l).
  • Step 2 Tert-butyl fS ) -6-f3.3-difluoro-2-methylproPvn-2.2-spirocvclobutyl-3.4-dihvdro-2H- pyranor2,3-b]pyridin-4-ylcarbainate
  • Step 4 N-f ⁇ S.2RV3-frf4'SV6'-G.3-difluoro-2-methylpropyn-3'.4'- dihydrospirof cyclobutane- 1 ,2'- ⁇ yranor2,3-b1pyridinl-4'-yl ' )aminoV 1 -(Y 4- fluorophenyl)methyl)-2-hydroxypropy1)acetamide
  • Step 1 Tert-butyl (S)-6-(3-(tert-butyldimethylsilyloxy)-2-methy1 ⁇ ropyn-2.2- spirocvclobutyl-3,4-dihydro-2H-pyranor2,3-b1pyridin-4-ylcarbamate
  • Tert-butyldimethyl(2-methylallyloxy)silane was treated with 9-BBN (0.5 M in diethyl ether, 53.0 ml, 26.0 mmol) and the resulting solution was purged with nitrogen for 15 minutes before being allowed to stir at RT for 10 hours.
  • 9-BBN 0.5 M in diethyl ether, 53.0 ml, 26.0 mmol
  • reaction mixture was purged with nitrogen for 15 minutes and heated to 90 0 C for 3 hours at which point it was cooled to RT, diluted with EtOAc (50 mL) and filtered through a plug of celite. The filtrate was washed with water, brine, and the organics were dried over sodium sulfate and concentrated. Purification of the crude residue by column chromatography (0-25% EtOAc in hexanes) provided the title compound, contaminated with starting olefin, as a colorless oil.
  • Step 2 Tert-butyl (SVe-O-hvdroxy- ⁇ -methylpropyiV ⁇ . ⁇ -spirocyclobutyl-S ⁇ -dihvdro ⁇ H- pyrano
  • Step 4 (4S ' )-6-f3-fluoro-2-methylpropyn-2.2-spirocvclobutyl-3,4-dihvdro-2H-pyranor2J- blpyridin-4-amine
  • TBAF 1.0 M in THF, 14.0 ml, 14.0 mmol
  • Step 5 N-C(I S.2RV3-f (T ⁇ Sye'- ⁇ SVS-fluoro- ⁇ -methylpropyn-SU'- dihvdrospirorcyclobutane-L2'-pyrano
  • the title compounds were made by a method analogous
  • Step 2 6-bromo-2.2-dimethyl-L2-dihvdroquinoline To a solution of 4-bromo-N-(2-methylbut-3-yn-2-yl)benzenamine (3.30 g, 14 mmol) in toluene (14 ml, 14 mmol) was added copper(I) chloride (0.300 g, 3.0 mmol) in one portion.
  • the reaction vessel was sealed and the resulting mixture was heated to 90 deg C. After stirring overnight, the mixture was transferred to a separatory funnel containing water and EtOAc. The aqueous layer was washed IX with EtOAc and 3X with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated. The crude oil was purified with an MPLC (100% DCM to 10% (91/10/1 DCM:MeOH:NH4OH)) to provide the product. MS m/z: 238.
  • Step 3 6-bromo-2.2-dimethyl-L2.3,4-tetrahvdro ⁇ uinolin-4-ol
  • 6-bromo-2,2-dimethyl-l,2-dihydroquinoline (4.50 g, 18.9 mmol) in tetrahydrofuran (37.8 ml, 18.9 mmol)
  • BH3DMS (3.58 ml, 37.8 mmol) dropwise at 0 deg C.
  • the resulting solution was allowed to warm to RT and stirred for 1 hour.
  • Step 4 and 5 6-bromo-2.2-dimethyl-L2.3.4-tetrahvdroquinolin-4-amine
  • 6-bromo-2,2-dimethyl-l,2,3,4-tetrahydroquinolin-4-ol (3.16 g, 12.3 mmol) and DPPA (1.76 ml, 8.14 mmol) in THF (41.1 ml, 12.3 mmol) at O 0 C was added DBU (1.22 ml, 8.14 mmol) dropwise.
  • the resulting mixture was warmed to RT and stirred for 18 hours.
  • the crude mixture was poured into a sep. funnel containing water. The aqueous layer was washed 3X with EtOAc.
  • Step 6 2.2-dimemyl-6-neopentvI-L2.3.4-tetrahvdroquinolin-4-arnine
  • Step 7 Tert-butyl f2S JR)-3-ftert-butyldimethylsiMoxy)-4-f(Sy2,2-dimethyl-6- neopentyl-1.2.3.4-tetrahvdroquinolin-4-ylaminoVl-(3-fluorophenyl')butan-2-ylcarbamate
  • tert-butyl (2S,3S)-3-(tert-butyldimethylsilyloxy)-l-(3-fluorophenyl)-4- oxobutan-2-ylcarbamate (0.148 g, 0.360 mmol)
  • (S)-2,2-dimethyl-6-neopentyl- l,2,3,4-tetrahydroquinolin-4-amine (0.0886 g, 0.360 mmol) in DCM (7.19 ml, 0.360 mmol) was added trimethoxymethane (0.394 ml,
  • Step 8 Tert-butyl ( ' 2S.3R)-4-((SV2 ⁇ 2-dimethvI-6-neopentyl-K2,3.4-tetrahvdroquinolin-4- ylaminoVl-f3-fluorophenyl>-3-hvdroxybutan-2-ylcarbamate
  • tert-butyl (2S,3R)-3-(tert-butyldimethylsilyloxy)-4-((S)-2,2-dimethyl-6- neopentyl-l,2,3,4-tetrahydroquinolin-4-ylamino)-l-(3-fluorophenyl)butan-2-ylcarbamate 0.231 g, 0.360 mmol) in DCM (1.20 ml, 0.360 mmol) was added tetrabutylammonium fluoride (1.44 ml, 1.44 mmol).
  • Steps 9 and 10 N-(T2S3R)-4-f(SV2.2-dimethyl-6-neopentyl-1.2.3.4-tetrahvdro ⁇ uinolin- 4-ylamino)-l -(3-fluorophenyl)-3-hvdroxybutan-2-yl)acetamide 4N HCl in MeOH (15.0 ml, 0.379 mmol) was added to tert-butyl (2S,3R)-4-((S)-2,2- dimethyl-6-neopenty 1- 1 ,2 ,3 ,4-tetrahydroquinolin-4-ylamino)- 1 -(3 -fluoropheny l)-3 - hydroxybutan-2-ylcarbamate (0.200 g, 0.379 mmol) in a RBF and the resulting solution was stirred overnight. The solution was then concentrated and the solid product was taken on to the next step.
  • Step 1 N-((2S ⁇ R)-l-(allyloxy)-3-hydroxy-4-(2 ⁇ -spirocyclobutyl-6-neopentyl-3,4-dihydro- 2H-pyrano[2,3-b]pyridin-5-ylamino)butan-2-yl)acetamide
  • Step 1 tert-butyl (SV2-(allyloxyVl-((S)-oxiran-2-vnethy1carbamate
  • Step 4 Tert-butyl (2S,3S ⁇ )-l-(allyloxyV3- ⁇ ert-butyldimethv1silyloxy)-4-hvdroxybutan-2- ylcarbamate
  • (2S,3S)-4-(allyloxy)-3-(tert-butoxycarbonyl)-2-(tert- butyldimethylsilyloxy)butyl acetate 0.060 g, 0.1 mmol
  • Step 6 Tert-butyl (2S.3RVl-fallyloxyV3-ftert-butyldimethylsilyloxyV4-(2.2- spirocyclobutyl-6-neopentyl-3.4-dihvdro-2H-Dyranor2.3-b ' lpyridin-5-ylamino > )butan-2- ylcarbamate
  • Step 7 N-f (2S,3R)- 1 -fallyloxy>3 -hvdroxy-4-f 2,2-spiroevclobutyl-6-neo ⁇ entyl-3,4- dihydro-2H-pyranof2.3-blpyridin-5-ylamino)butan-2-v ⁇ acetamide
  • tert-butyl (2S,3R)-l-(allyloxy)-3-(tert-butyldimethylsilyIoxy)-4-(2,2- spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-ylamino)butan-2- ylcarbamate (0.033 g, 0.05 mmol) in 1,4-dioxane (1.0 mL), was added a solution of HCl (0.6 mL, 4 M in 1,4-dioxane).
  • Step 2 7-Methoxy-3.3-dimethyl-3.4-dihvdronaphthalen-U2H * )-one contaminated with 2- chloro-7-methoxy-3.3-dimethvI-3 , 4-dihydronaphthalen-lf2ro-one
  • Step 4 7-Hvdroxy-3.3-dimethyl-3,4-dihvdronaphthalen-U2H>one 7-Methoxy-3,3-dimethyl-3,4-dihydronaphthalen-l(2H)-one (2.25 g, 11.0 mmol) was dissolved in 30 ml CH2C12 and cooled to -78 0 C. Boron tribromide (25.000 ml, 25.0 mmol) was added and the reaction was stirred for 6h. The temperature was elevated to 0 0 C during this time. The mixture was pored into ice and extracted 3 x EtOAc (300 ml each). The combined organic extracts were dried over MgSO4 and evaporated. Glass col. Chrom.
  • Step 6 N-(Y 1 S.2RV3-(((1 SV3.3-dimethyl-7-ff3SVtetrahvdro-3-furanyloxyV1.2.3,4- tetrahydro-1 -naphthalenvPamino>2-hvdroxy- 1 -( ⁇ henylmethyl)propyDacetamide
  • Step l N-(2-(l-(tert-butyldimethylsilyloxy')cvclobutyl')-l-f3-chloro-6- neopentylpyridazin-4-vDethviy2-methylpropane-2 ⁇ sulf ⁇ namide 2,2,6,6-Tetramethylpiperidine (0.68 ml, 4.0 mmol) was dissolved in 120ml THF and 1- butyllithium (1.5 ml, 3.8 mmol) was added at -78 ⁇ C drop wise. The mixture was allowed to warm to 0 0 C (over a period of 5 min) and kept there for 5 min.
  • Step 2 (SV7.7-Spirocvclobutyl-3-neopentyl-6.7-dihvdro-5H-pyranor2.3-c]pyridazin-5- amine
  • N-(2-(l -(tert-Butyldimethylsilyloxy)cyclobutyl)- 1 -(3-chloro-6-neopentylpyridazin-4- yl)ethyl)-2-methylpropane-2-sulfinamide (0.870 g, 2 mmol) was dissolved in 20 ml of THF and tetrabutylammonium fluoride, LOm in THF (0.5 ml, 2 mmol) was added at RT. The mixture was stirred for 10 min and filtered through a plug of silica (wash with THF). The mixture was died over MgSO4 and evaporated and re-dissolved in 200 ml of THF.
  • TSIaH (60%) (0.3 g, 7mmol) was added and the mixture was heated to 66 for 3h. The mixture was hydrolyzed with water and extracted 3 times with EtOAc (200 ml each). The crude product (MS m/z: 366.2 (M+l)) was re-dissoolved in 5 ml MeOH and 15 ml 4M HCl in dioxane was added. The mixture was stirred for Ih and evaporated and purified on the HPLC. The Product was obtained as a brown solid.
  • Step 3 N-(T 1 S,2RV 1 -(G.,5-difluorophenvnmethviy3-(Y(S'Sy3i(2.2-dimethylproDvn- S'. ⁇ '-dihydrospirorcvclobutane-l.T'-pyranor ⁇ .S-clpyridazinl-S'-v ⁇ aminoV ⁇ - hvdroxypropyDacetamide
  • Step 2 3 -Methyl- l-fmethylsulfinviyi-(rnethylthio)cyclobutane Methylsulfmyl(methylthio)methane (29.927 g, 240.91 mmol) was dissolved in 500 ml
  • Methylcyclobutanone (3.200 g, 38.043 mmol) was dissolved in 200 ml THF and allylmagnesium bromide (190.21 ml, 190.21 mmol) was added in one portion. The mixture was stirred for 4h at RT, hydrolyzed with water and extracted. The combined organic extracts were dried over MgSO4 and evaporated and purified via glass col. Chrom. (25-75% hex. in EtOAc). l-Allyl-3-methylcyclobutanol (2.250 g, 46.9% yield) was obtained as a mixture of cis-trans isomers approx4:l (where the major compound is the one Me-cis to OH) based on NMR,
  • Step 5 ⁇ -Allyl-S-methylcvclobutoxyYtert-butv ⁇ dimethylsilane l-Allyl-3-methylcyclobutanol (2.25000 g, 17.8 mmol) (the 4:1 mixture of cis/trans- isomers) was dissolved in 50 ml of CH2C12 and DIEA (5.59 ml, 32.1 mmol) and tert- butyldimethylsilyl triflate (5.73 ml, 25.0 mmol) were added. The mixture was stirred for 2h and hydrolyzed with water, extracted with 200 ml Et2O (3x each), dried over MgSO4 and evaporated. Glass col. chrom.
  • Step 6 (EVN-f 2-( 1 -(tert-butyldimethvisilyloxyVS-methylcyclobutvnethylidene ' t- ⁇ - methylpropane-2-sulfinamide
  • 2,2,6,6-Tetramethylpiperidine (2.47 ml, 14.7 mmol) was dissolved in 100 ml THF and cooled to -78°C.
  • 1-Butyllithium (5.23 ml, 13.1 mmol, 2.5M) was added and the reaction was allowed to warm up to 0 0 C for 5 min before it was cooled back to -78°C again.
  • a solution of 2-fluoro-5-neopentylpyridine (1.75000 g, 10.5 mmol) was added dropwise and the reaction was stirred for Ih.
  • Butyldimethylsilyloxy)-3-methylcyclobutyl)-l-(2-fluoro-5-neopentylpyridin-3-yl)ethyl)- 2-methylpropane-2-sulf ⁇ namide (3.30 g, 61.5% yield) was obtained after glass col. Chrom. (20-70% EtOAc in Hex.). Low yield due to the formation of a minor diastereomer at the NH center (approx 30%). Mixture of cis/trans at the cyclobutylring (4: 1).
  • Step 8 N-(H S.2RV3-f(f4'SV6'-f2.2-Dimethylpropyn-3-methyl-3'.4'- dihvdrospirolcyclobutane-L2 l -pyranor2.3-b1pyridin]-4'-yl ' >aminoVl-(f4- fluorophenvOmethvD- ⁇ -hvdroxypropyOacetarnide; and N-r(lS.2RV3-((fls.3R,4'SV6'-(2,2-dimethylpropyn-3-methvI-3'.4'- dihvdrospiro[cyclobutane-1.2'-pyranor2.3-b1pyridinl-4'-yl)amino)-l-f(4- fluorophenvOmethyl ⁇ -hydroxypropyDacetarnide
  • N-((S)-2-(l-(Tert-butyldimethylsilyloxy)-3-methylcyclobutyl)-l-(2-fluoro-5- neopentylpyridin-3-yl)ethyl)-2-methyIpropane-2-sulfinamide (3.30 g, 6.435 mmol) was dissolved in 60 ml THF and tetrabutylammonium fluoride, (1.0 M in THF; 6.435 ml, 6.435 mmol) was added. The mixture was stirred for 30 min and filtered through a plug of silica (wash with THF). The solution was evaporated and redissolved in 600 ml THF.
  • the major isomer was identified to be the one where the O and the Me group are cis to each other (NOE). Prior to separation, the title compound, a 4: 1 mixture, was made by the method described in Example 464, steps 8-10. MS Found m/z: 498.2 (M+l).
  • Step 1 l-(fl .3-Dibromopropan-2-yloxy)methyl)benzene
  • Step 2 3-(Benzyloxy ' )cvclobutanone Methylsulfinyl(methylthio)methane (13 ml, 125 mmol) was dissolved in 250 ml THF and cooled to -20 0 C. n-Butyllithium (50 ml, 125 mmol) was added and the mixture was stirred for 3h at -20 0 C. The mixture was cooled down to -78°C and a solution of l-((l,3-dibromopropan-2-yloxy)methyl)benzene (16.000 g, 52 mmol) was added. The reaction was stirred over night and allowed to warm up to RT.
  • Step 3 N-r ⁇ S.2RV3-f((ls.3S.4'SV6'-f2.2-dimethylpropylV3-hvdroxy-3'-4'- dihvdrospirorcyclobutane-l,2'-pyranor2.3-b1pyridinl-4'-yl ' )aminoVl-f(4- fluorophenv0methvI')-2-hvdroxypropyDacetarnide
  • Step 1 (4S,5RVtert-butyl 4-benzyl-2.2-dimethyl-5-rf(SV6-fftetrahvdrofuran-2-vnmethylV 2.2-spirocvclobutyl-3.4-dihvdro-2H- ⁇ yranor2,3-b1pyridin-4-ylamino)methv ⁇ oxazolidine-3- carboxylate
  • Step 2 N-f f 1 S.2RV2-hvdroxy- 1 -f phenylmethylV3 -( (T 4'S1-6'-f f2S Vtetrahvdro-2- furanylmethyl * )-3'.4'-dihvdrospiro
  • Step 1 (4S,5R)-tert-butyl 4-benzyl-2.2-dimethyl-5-f « ' S ' )-6-f( ' 2-inethyl-tetrahvdrofiiran-2- v ⁇ methyl)-2,2-spirocvclobutyl-3.4-dihydro-2H-pyranor2.,3-b1pyridin-4- ylamino ' )methyl ' )oxazolidine-3-carboxylate l-(diphenylphosphino)-2-(2-(diphenylphosphino)phenoxy)benzene (29 mg, 0.054 mmol) and Pd 2 (dba) 3 (25 mg, 0.027 mmol) were combined in a sealed tube and ImL of THF was introduced.
  • Step 2 N-(Cl S.2RV2-hvdroxy-3-f(T4'SV6'-ffr2SV2-methyltetrahvdro-2-furanvnmethylV S' ⁇ '-dihydrospirorcvclobutane-l ⁇ '-pyranor ⁇ J-bipyridinM'-vDaminoVI - Cphenylmethvnpropynacetamide: and N-(Tl S.2R)-2-hvdroxy-3-(ff4'SV6'-ffr2RV2- methyltetrahvdro-2-furanyl)methyl)-3'.4'-dihvdrospirorcvclobutane-1.2'-pyranor2.3- blpyridin1-4WDaminoVl-(phenylrnethvDpropyl)acetarnide
  • Step T fZV2-(l-(benzylimino ' )ethvD-4-bromophenol
  • Step 2 (ZV4-(ben2ylaminoV4-(5-bromo-2-hvdroxyphenylVl .1,1 -trifluorobut-3-en-2-one
  • (Z)-2-(l-(benzylimino)ethyl)-4-bromophenol (18.0 g, 59.2 mmol) in anhydrous THF was added lithium hydride (1.65 g, 207 mmol) portion wise at room temperature.
  • the resulting mixture was heated in a oil bath (6O 0 C) to initialize the reaction (cool down the mixture with a ice bath).
  • Step 3 (Z)-N-(6-bromo-2-(trifluoromethyl')-4H-chromen-4-ylidene)(phenyl)methanamine
  • EtOH 96 ml
  • (Z)-4-(ben2ylamino)-4-(5-bromo-2-hydroxyphenyl)-l !> l,l-trifluorobut-3-en-2-one (24.0 g, 60 mmol) was then added in one portion to this solution. The reaction was stirred at RT for 36 h.
  • Step 4 6-bromo-2-methyl-2-(trifluorornethvl')chroman-4-one
  • raalonic acid 1.2 ml, 19 ramol
  • (Z)-N-(6-bromo-2-(trifIuoromethyl)-4H- chromen-4-ylidene)(phenyl)methanamine 6.63 g, 17 mmol
  • the mixture was cooled to RT and treated with 50% EtOH/H2O (20 ml) followed by cone. HCl (5.0 ml). The resulted mixture was left to stand at RT for 40 min, and then diluted with water (500 ml).
  • Step 8 tert-Butyl f2S3RV4-f(4S)-6-bromo-2-methyl-2-(trifluoromethv0-3,4-dihvdro-2H- chromen-4-y lamino)-3 -hydroxy- 1 -phenylbutan-2-ylcarbamate
  • Step 9 N-fd S.2RV3-fff2R.4SV6-bromo-2-methyl-2-ftrifluoromethylV3.4-dihvdro-2H- chromen-4-vDaminoV2-hvdroxy- 1 -(phenylmethv ⁇ propyl)acetamide;
  • Step 5 l-( * 2-hvdroxy-5-(2 1 2,2-trifluoroethyl ' )phenyl ' )ethanone
  • 4-(2,2 5 2- trifluoroethyl)phenol (1.00 g, 5.68 mmol) in CH2C12 (5.0 ml) was added trifluoromethanesulfonic acid (0.0151 ml, 0.170 mmol) with stirring.
  • a solution of acetic chloride (0.444 ml, 6.25 mmol) in CH2C12 (5.0 ml) was added drop wise to the reaction. After stirred 45 min at RT, all the phenol was consumed.
  • the product mixture was diluted with CH2C12, washed with saturated sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dried in vacuum until no weight loss was observed.
  • anhydrous aluminum(III) chloride (0.757 g, 5.68 mmol). The mixture was heated at 15O 0 C for Ih until all the starting material was consumed (monitored by TLC). The resulted brown gum was cooled to 0 0 C, diluted with diethyl ether and IN HCl. Layers were separated. The aqueous layer was extracted with ether. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column (2-15% EtOAc/hexane) to afford the title compound.
  • Step 6 2.2-spirocvclobutyl-6-f2,2.2-trifluoroethyl * )-2,3-dihydrochromen-4-one
  • a solution of l-(2-hydroxy-5-(2,2,2-trifluoroethyl)phenyl)ethanone (320 mg, 1467 ⁇ mol), cyclobutanone (617 mg, 8800 ⁇ mol), N-ethyl-N-isopropylpropan-2-amine (569 mg, 4400 ⁇ mol) and pyrrolidine (313 mg, 4400 ⁇ mol) in ACN was heated in microwave at 75 0 C for 2h. The resulted mixture was diluted with EtOAc, washed with IN HCl, saturated Na2CO3 and brine.
  • Step 7 (RV2.2-spirocvclobuM-6-(2.Z2-trifluoroethylV3.4-dihvdro-2H-chromen-4-ol
  • the title compound was prepared according to the methods described in step 5 of Example 509. MS m/z: 255(M+1-H2O).
  • Step 8 (S-4-azido-2,2-spirocvclobutyl-6-(2,2,2-trifluoroethyl)-3,4-dihvdro-2H-chromene
  • the title compound was prepared according to the methods described in step 6 of Example 509. MS m/z: 270(M+l -N2).
  • Step 9 (S)-2,2-spirocyclobutyl-6-(2,2.2-trifluoroethv ⁇ -3.4-dihvdro-2H-chromen-4-amine
  • the title compound was prepared according to the methods described in step 7 of Example 509. MS m/z: 255(M-NH2).
  • Step 10 (4R. 5SVtert-butyl5-benzyl-4-f(6-(2.2.2-trifluoroethyl)-2,2-s ⁇ irocvclobutyl-3.4- dihvdro-2H-chromen-4-ylamino)methylV2.2-dimethylpyrrolidine-l-carboxylate
  • Step 2 1 -C4-(tert-butyldimethylsilyloxyV2.2-spirolcvclobutyl-3,4-dihvdro-2H-pyranof 2,3- b ⁇ )pyridine-6-yl)-2,2,2-trifluoroethanone
  • Step 3 1 -(4-(tert-butyldimethylsilyloxy)-2,2-spirolcvclobutyl-3.4-dihvdro-2H-pyranof 2.3- b ⁇ )pyridine-6-yl)-2,2.2-trifluoroethanol
  • sodium borohydride (0.333 ml, 9.45 mmol). The reaction was stirred 4h at ambient temperature. At this point, all the starting material was consumed. Water was added to quench the reaction.
  • Step 4 4-(tert-butyldimethylsilyloxyV6-(l -chloro-2,2,2-trif1uoroethyl)-2.2- spirolcvclobutyl-3.4-dihvdro-2H-pyranof2.3-b * )pyridine
  • compound 3 (2.34 g, 5.8 mmol) (from step 3) and pyridine
  • Step 5 4-(tert-butyldimethylsilyloxy)-6-(2,2.2-trifluoroethyl)-2.2-spirolcvclobutyl-3.4- dihvdro-2H-pyrano(2.3-b)pyrid ⁇ ne
  • sodium tetrahydroborate 0.239 g, 6.33 mmol
  • the reaction was heated under refluxing for 15 h and all the starting chloride was consumed. After cooled to room temperature, water was added to quench the reaction. The mixture was extracted with EtOAc (3x). The organic layers were dried over MgSO4, filtered and concentrated. The residue was dried in vacuum to afford the title compound. It was carried to the next step without further purification.
  • Step 6 6-(2,2.2-trifluoroethyl)-2,2-spirolcyclobutyl-3.4-dihvdro-2H-pyrano(2,3-b)pyridine- 4-ol
  • compound 5 (1.21 g, 3 mmol) (crude from step 5) was added 4 N HCl/dioxane. The reaction was stirred at room temperature until all the starting material was consumed. The mixture was concentrated and dried in vacuum to give the title compound. It was carried to the next step without further purification.
  • Step 7 6-(2,2,2-trifluoroethylV2.2-spirolcvclobutyl-2.3.-dihvdropyrano(2 ⁇ 3-b'>pyridin-4-one
  • sodium bicarbonate (0.12 ml, 3.0 mmol) in one portion
  • Dess martin Reactant 3 1.3 g, 3.0 mmol
  • Step 9 fS)-4-azido-2.2-spirolcyclobutyl-6-f2,2,2-trifluoroethv ⁇ -3.4-dihvdro-2H- ⁇ yrano(23-b)pyridine
  • Step 10 ( SV2.2-spirolcvclobutyl-6-f2.2.2-trifluoroethvn-3.4-dihvdro-2H-pyranof 2.3- b")pyridine-4-amine
  • (S)-4-azido-2,2-spirolcyclobutyl-6-(2,2,2-trifluoroethyl)- 3,4-dihydro-2H-pyrano(2,3-b)pyridine 196 mg, 657 ⁇ mol
  • lithium aluminum hydride (657 ⁇ l, 1314 ⁇ mol
  • Step 1 N-f ⁇ S.2RV2-hvdroxy-l-rphenylmethylV3-fff4'SV6'-f2.2.2-trifluoroethvn-3'.4'- dihvdrospirorcvclobutane- 1.2'-pyranor2.3-b1pyridin1-4'-yl)arnino)propyl)acetamide.
  • TFA salt The title compound was prepared according to the methods described in steps 10 and 11 of Example 510. MS m/z: 478.1 (M+l).
  • Step 1 Tert-butyl allvKfSVl. ⁇ -spirolcyclobutyl- ⁇ -OJJ-trifluoro-l-hvdroxy-l- methylpropyl * )-3.4-dihvdro-2H-pyrano(2,3-b)pyridine-4-v ⁇ carbamate
  • (S)-tert-butyl allyl(6-bromo-2,2-spirocyclobutyl-3,4- dihydro-2H-pyrano(2 :J 3-b)pyridine-4-yl)carbamate (8.70 g, 21 mmol) in diethylether was added tert-butyllithium (25 ml, 43 mmol) dropwise.
  • Step 2 Tert-butyl allyl(fS)-2.2-spirolcvclobutyl-6-(3.3,3-trifluoro-l-chloro-2- methylpropyl)-3,4-dihydro-2H-pyrano('2,3-b N )pyridine-4-yl')carbamate
  • compound 1 (1.33 g, 2.9 mmol) (from step 1) and pyridine
  • SOC12 thionyl chloride
  • Step 3 (4S)-6-f3.33-trifluoro-l-chloro-2-rnethylpropylV2.2 spirocvclobutyl-3.4-dihvdro- 2H-pyrano(2,3-b)pyridine-4-amine
  • step 3 (4S)-6-f3.33-trifluoro-l-chloro-2-rnethylpropylV2.2 spirocvclobutyl-3.4-dihvdro- 2H-pyrano(2,3-b)pyridine-4-amine
  • Step 4 N-(Yl S,2R>-l-((3-fluoro ⁇ henvnmethvn-2-hvdroxy-3-( ' (f4'SV6'-rf2R ' )-3.3.3-trifluoro- 2-methylpropyl')-3',4'-dihvdrospirofcvclobutane-1.2'-pyranor2J-b1pyridin1-4'- yl ' )amino ' )propyl')acetamide; and methylpropyl ' )-3'.4'-dihvdrospirorcvclobutane-1.2'-pyranol2.,3-b1pyridinl-4'- vPam ino * )propyDacetam ide
  • Step 1 2-Azido-N-( " f 2S,3RV4-f ( " SV6-bromo-2.2-spirocvclobutylchroman-4-ylamino)-3- hvdroxy-l-phenylbutan ⁇ -vOacetamide
  • Step 2 Ethyl l-(2-(((lS.2RV3-r((4SV6-bromo-3.4-dihvdrospirorchromene-2.1'- cvclobutan1-4-yi)amino')-2-hvdroxy-1-(phenylmethyl * )propyl)amino ' )-2-oxoethyl)-1H- 1.2.3-triazole-4-carboxylate
  • ethyl propiolate 0.0067 ml, 0.066 mmol
  • 2-azido-N-((2S,3R)-4- ((S)-6-bromo-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-l -phenylbutan-2- yl)acetamide 0.020 g, 0.039 mmol
  • the vessel was sealed and placed in an 80 deg oil bath for 12 h.
  • the reaction was cooled, taken up in EtOAc (60 mL) and the organic layer was extracted with dilute NaHCO3 (5 mL), half- saturated brine (5 mL) and saturated brine (5 mL), then was dried over sodium sulfate and concentrated.
  • the material was purified through silica gel (15 mL) which had been deactivated with Et 3 N (2 mL), eluting with 3% MeOH-EtOAc, yielding the title compound as a white solid. MS m/z 612/614 (M+l).
  • Step 1 (3-Bromo-4-fluorophenvQmethanol 3-Bromo-4-fluorobenzaldehyde (0.300 g, 1.48 mmol) was dissolved in methanol (3 mL). Sodium borohydride (0.0671 g, 1.77 mmol) was added. After 3 h, the reaction was quenched with methanol (1 mL), and the mixture was concentrated. The residue was taken up in 2:1 EtOAc-hexane (60 mL). The organic layer was extracted with dilute NaHCO 3 (6 mL) then half-saturated brine (6 mL), then was dried over sodium sulfate and concentrated. The material was purified through silica gel (45 mL) using 30% to 40% EtOAc-hexane to afford the title compound. Step 2: 2-Brorno-4-(bromomethvO-l-fluorobenzene
  • Step 3 N-ff 1 S.2RV1 -f(3-Bromo-4-fluorophenvnmethylV3-(f(4'S')-6'-('2.2- dimethylpropy ⁇ -3 '. ⁇ '-dihvdrospirorcvclobutane- 1 ,2'-pyranof ⁇ J-bipyridinM'-yPammo)- 2-h vdroxypropyl )acetam ide 2-Bromo-4-(bromomethyl)-l-fluorobenzene was converted to the title compound using a method analogous to that described in Examples 509 and 510.
  • Step 2 (SVN-f('2S3S')-3.4-Bisftert-butyldimethylsilyloxyVl-( r 3-cvano-4- fluorophenv ⁇ butan-2-viy2-methvIpro ⁇ ane-2-sulfinamide
  • Step 3 N-ffl S.2RVl-((3-Cvano-4-fluorophenvnmethyl)-3-(((4'SV6'-(2.2- dimethylpropyl ' )-3'.4'-dihvdrospirorcvclobutane-1.2'-pyrano
  • Step 1 (3-Chloro-2,4-difluorophenyl)methanol
  • the material was concentrated on the rotovap to a white solid.
  • the residue was acidified with 3M aqueous HCl (30 mL), diluted with dichloromethane (50 mL), and the mixture was filtered through Celite. The layers were separated, and the organic layer was dried over sodium sulfate and concentrated.
  • the residue was purified through silica gel (500 mL) using 30% EtOAc-hexane, to afford the title compound.
  • Step 3 N-ffl S.2RV1 -(G-Chloro-2.4-difluorophenvnmethvn-3-fff4'SV6'-f2.2- dimethvIpropyD-3'.4'-dihvdrospirorcvclobutane-l.,2'-pyranof2,3-b]pyridin1-4'-v ⁇ amino ' )-
  • Step 1 (SVtert-Butyl 6-bromo-2.2-s ⁇ irocyclobutyl-3,4-dihvdro-2H-pyrano[2.3-blpyridin-
  • Step 2 f SVtert-Butyl allylf6-bromo-2,2-spirocvclobutyl-3.4-dihvdro-2H-pyrano[23- b "
  • S -tert-Butyl 6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2.,3-b]pyridin-4- ylcarbamate
  • Step 3 (S)-tert-Butyl allyl(6-hvdro ⁇ y-2.2-spirocvclobutyl-3.4-dihvdro-2H-pyrano[ " 2.3- b1pyridin-4-yl)carbamate
  • Step 4 (SVtert-Butyl allyl(6-isopropoxy-2,2-spirocyclobutyl-3.4-dihvdro-2H- ⁇ yranor2.3- b1pyridin-4-yl)carbamate
  • (S)-tert-butyl allyl(6-hydroxy-2,2-spirocyclobutyl-3,4-dihydro-2H- pyrano[2,3-b]pyridin-4-yl)carbamate 180 mg, 0.52 mmol
  • cetyltrimethylammonium bromide (19 mg, 0.052 mmol) were dissolved in dioxane (0.42 mL) and 3.0 M aqueous potassium hydroxide (0.866 mL, 2.6 mmol) was added.
  • (S)-tert-butyl allyK ⁇ -isopropoxy ⁇ -spirocyclobutyl- ⁇ -dihydro- ⁇ H- pyrano[2,3-b]pyridin-4-yl)carbamate (246 mg, 0.63 mmol) was dissolved in dichloromethane (3.5 mL). TFA (0.488 mL, 6.3 mmol) was added. The vessel was sealed and heated at 50 deg for 6 h. The mixture was concentrated, and the residue was neutralized with 10% aqueous sodium carbonate (8 mL). The aqueous phase was extracted with 5% MeOH-dichloromethane (60 mL).
  • Step 7 N-f f 1 S.2RV 1 -f f 4-Chlorophenvnrnethvn-2-hvdroxy-3-f (T4'SV6'-( ( 1 - methylethyl)oxy)-3',4'-dihvdrospiro[cvclobutane-1.2'-pyranor2.3-b1pyridin1-4'- yl)amino)propyl)acetamide (S)-6-Iso ⁇ ropoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine was converted to the title compound using a method analogous to that described in Examples 509 and 510. MS m/z 488 (M+l).

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Abstract

Cette invention concerne une nouvelle classe de composés utilisés pour la modulation de l'activité de l'enzyme bêta-secrétase et pour le traitement des maladies induites par la bêta-secrétase, parmi lesquelles la maladie d'Alzheimer et des pathologies associées. Dans un mode de réalisation, les composés sont représentés par la formule générale (I); dans cette formule, A, B, W, R3, R4, R5, i et j sont tels que définis dans la description. Cette invention concerne également des compositions pharmaceutiques contenant un ou plusieurs composés représentés par la formule (I), des méthodes permettant d'utiliser ces composés, parmi lesquelles le traitement de la maladie d'Alzheimer et des maladies associées, par administration à un sujet d'un ou de plusieurs composés représentés par la formule (I), ou des compositions contenant ces composés. Cette invention concerne également des composés représentés par les formules (II) et (III), des produits intermédiaires et des processus utiles pour la préparation de ces composés.
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WO2008147547A1 (fr) * 2007-05-25 2008-12-04 Amgen Inc. Composés d'hydroxyéthylamine substitués en tant que modulateurs de la bêta-sécrétase et procédés d'utilisation
WO2008147544A1 (fr) * 2007-05-25 2008-12-04 Amgen Inc. Composés d'hydroxyéthylamine substitués en tant que modulateurs de la bêta-sécrétase et méthodes d'utilisation
US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
US8946483B2 (en) 2011-07-21 2015-02-03 Ge Healthcare Limited Precursor compounds and methods for making same
EP2827857A4 (fr) * 2012-03-20 2016-03-30 Elan Pharm Inc Dihydro-thiazine spirocycliques et inhibiteurs de bace dihydro-oxazine et compositions et utilisations de ceux-ci
WO2020179859A1 (fr) 2019-03-06 2020-09-10 第一三共株式会社 Dérivé de pyrrolopyrazole

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WO2016010092A1 (fr) * 2014-07-16 2016-01-21 国立研究開発法人科学技術振興機構 Composé benzothiazole et médicament le contenant

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US8183252B2 (en) 2003-12-15 2012-05-22 Schering Corporation Heterocyclic aspartyl protease inhibitors
US8691833B2 (en) 2007-02-23 2014-04-08 Merck Sharp & Dohme Corp. Heterocyclic aspartyl protease inhibitors
US8691831B2 (en) 2007-02-23 2014-04-08 Merck Sharp & Dohme Corp. Heterocyclic aspartyl protease inhibitors
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AU2006316620A1 (en) 2007-05-31
AR057985A1 (es) 2008-01-09
AU2006316620B2 (en) 2011-03-03
PE20070645A1 (es) 2007-08-24
TW200800966A (en) 2008-01-01
CA2629402C (fr) 2011-07-26
JP5274258B2 (ja) 2013-08-28
EP1971598A1 (fr) 2008-09-24
JP2009516684A (ja) 2009-04-23
CA2629402A1 (fr) 2007-05-31

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