WO2010090680A1 - Agonistes de cb2 de type oxindole substitué - Google Patents

Agonistes de cb2 de type oxindole substitué Download PDF

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WO2010090680A1
WO2010090680A1 PCT/US2009/067981 US2009067981W WO2010090680A1 WO 2010090680 A1 WO2010090680 A1 WO 2010090680A1 US 2009067981 W US2009067981 W US 2009067981W WO 2010090680 A1 WO2010090680 A1 WO 2010090680A1
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Prior art keywords
dioxane
spiro
indol
cyclopropylmethyl
heteroaryl
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PCT/US2009/067981
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English (en)
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Minsheng Zhang
Boyd Lynn Harrison
Charles J. Stanton Iii
Lisa Marie Havran
Dan Chaekoo Chong
Wayne Everett Childers
Steven Victor O'neil
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Wyeth Llc
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Publication of WO2010090680A1 publication Critical patent/WO2010090680A1/fr

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    • 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
    • C07D491/10—Spiro-condensed systems

Definitions

  • CBl and CB2 receptors two subtypes of the cannabinoid receptor, both belong to the G-protein- coupled receptor (GPCR) superfamily.
  • GPCR G-protein- coupled receptor
  • the CBl receptor is predominantly expressed in brain to mediate inhibition of transmitter release and affects many neurological and psychological phenomena, such as mood, appetite, emesis control, memory, spatial coordination muscle tone, and analgesia, as described by Goutopoulos et al., m the publication Pharmacol Ther (2002) 95:103.
  • the CB2 receptor is primarily expressed in immune cells to modulate immune response. Activation of the CB2 receptor is known to induce analgesic effects in inflammatory models involved in neurodegeneration diseases, and plays a role in the maintenance of bone density and progression of atherosclerotic lesions.
  • CB2 agonists are potential drug candidates for reducing pain (such as chronic inflammatory pain, post surgical pain, neuropathic pain, and bone pain) and for treating a host of diseases including osteoarthritis, atherosclerosis, osteoporosis, and cancer (e.g., glioma), as described by Malan et al., m the publication Pain (2001) 93:239. Accordingly, there is an ongoing need for new and improved compounds that modulate the CB2 receptor and can function as therapeutics for the treatment of various CB2 receptor-modulated diseases and disorders such as pain. The invented compounds disclosed herein provide a solution to this need.
  • the invention relates to a compound of Formula I:
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the above-described substituted oxindole compounds of the invention, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner.
  • the invention in another aspect, relates to a method of treating a CB2-mediated disorder by administering to a subject in need of this treatment a therapeutically effective amount of one or more of the compounds described above.
  • CB2-mediated disorders include, but are not limited to, pain (such as chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pam), osteoarthritis, atherosclerosis, osteoporosis, and cancer (e.g., glioma).
  • the invention relates to a compound of the invention, or pharmaceutically acceptable salt thereof, for use in therapy.
  • the invention relates to a compound of the invention, or pharmaceutically acceptable salt thereof, for use in the treatment of a CB2-mediated disorder such as pain (e.g., chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), osteoarthritis, atherosclerosis, osteoporosis, or cancer (e.g., glioma).
  • a CB2-mediated disorder such as pain (e.g., chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), osteoarthritis, atherosclerosis, osteoporosis, or cancer (e.g., glioma).
  • the invention relates to a compound of the invention, or pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for use in the treatment of one or more CB2-mediated disorders.
  • the present invention provides substituted oxindole compounds, that function as CB2 agonists, of Formula I:
  • R 1 is selected from -(CH 2 ) n R a , -CH(OH)R a , -CH(OR b )R a , and -C(O)R a , or is selected from OR a , SR a , SOR a , SO 2 R" and NR a R b ;
  • R 2 and R 3 are independently selected from H, halogen, OH, 0R a , 0WR a , Ci -6 alkyl, and WCi -6 alkyl, wherein Ci_ 6 alkyl or 0R a , is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3 _ 8 cycloalkyl, C 6 .io aryl and C 4 _io heteroaryl; or R 2 and R 3 , together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 .
  • R 4 is independently selected from H, d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 - I o aryl, C 4 _i 0 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone and -(CH 2 ) n -Ci_ 6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, Ci. 6 haloalkyl, C 3 .
  • R a and R b are independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 _ 6 alkenyl, C 2 . 6 alkynyl, C 6- io aryl, C 4 . 10 heteroaryl, C 3 . 8 cycloalkyl, C 3 . 8 heterocycloalkyl, C 3 . 8 heterocycloalkenyl C 7 - 14 arylalkyl, C 4 .
  • halogen is selected from F, Cl, Br and I; and at each occurrence, n is 0, 1, 2, or 3.
  • the invented compounds selected from: 5'-benzoyl-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(2-fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 1'- (cyclopropylmethyl)-5'-(3-fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(4-fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[2-(trime), 1,3
  • the invented compounds are certain substituted oxindole compounds of Formula I:
  • R 1 is selected from -Y-R a , -Y-Cy and -Y-Ar;
  • Y is a divalent carbon radical selected from -(CH 2 ) n -, -CH(OH)-, -CH(OR a )-, and -C(O)-, or Y is a heteroatom selected from O, S, SO, SO 2 and NR a R b ;
  • Ar is independently selected from C 6 .io aryl, C 4 . 10 heteroaryl, C 7 . 14 arylalkyl and C 4 . 14 heteroarylalkyl, wherein each of said C ⁇ -io aryl, C 440 heteroaryl, C 744 arylalkyl or C 444 heteroarylalkyl is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , 0R a -W, C 1 - 5 alkyl, C w W-alkyl, C w haloalkyl, C 3 . 8 cycloalkyl, C 3 . 8 W-cycloalkyl, -C(O)-CL 6 alkyl, - C(0)-C 6 _io aryl, C 6 _i 0 aryl and C4.10 heteroaryl;
  • Cy is independently selected from C 3 . 8 cycloalkyl, C 3 _ 8 heterocycloalkyl, C 3 . 8 heterocycloalkenyl, C 4 . 12 W-cycloalkyl, C 4 . 12 W-heterocycloalkyl and C 3 . 8 W-heterocycloalkenyl, wherein each of said C 3 . ? cycloalkyl, C 3 . 8 heterocycloalkyl, C 3 . 8 heterocycloalkenyl, C 4 . 12 W-cycloalkyl, C 4 _i 2 W-heterocycloalkyl or C 3 .
  • W-heterocycloalkenyl is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , 0R a -W, C M alkyl, C w W-alkyl, d. 6 haloalkyl, C 3 . 8 cycloalkyl, C 3 . 8 W- cycloalkyl, -C(O)-Ci. 6 alkyl, -C(O)-Ce- I o aryl, C 6 _io aryl and C 4 . 10 heteroaryl; at each occurrence W is a linker selected from -(CH 2 ) n - and -C(O)-;
  • R 2 and R 3 are independently selected from H, halogen, OH, 0R a , 0R a -W, Ci -6 alkyl, Ci. 6 W-alkyl, wherein Ci_ 6 alkyl or 0R a , is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, Ci_s haloalkyl, C 3 . 8 cycloalkyl, C 6-I o aryl and C 4 .
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl or C 5 -C 7 oxy cycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci. 6 alkyl, Ci. 6 haloalkyl, C 3 . 8 cycloalkyl, C 6-I o aryl and C 4 . 10 heteroaryl;
  • R 4 is independently selected from H, Ci- 6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C 6 -Io aryl, C4-10 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone and -(CH 2 ) n -Ci_ 6 haloalkyl, wherein each of said Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6- io aryl, C 4 .
  • heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci. 6 alkyl, Ci. 6 haloalkyl, C 3 . 8 cycloalkyl, C 6-I o aryl and C 4 _io heteroaryl; at each occurrence, R a is independently selected from H, Ci_e alkyl, Ci.
  • Ci_ 6 haloalkyl C 2 - 6 alkenyl, C 2 - 6 alkynyl, Ci_ 6 haloalkyl, C ⁇ -io aryl, C 4 . 10 heteroaryl, C 3 . 8 cycloalkyl, C 3 _ 8 heterocycloalkyl, C 3 _ 8 heterocycloalkenyl C 7 _i 4 arylalkyl, C 4 _i 4 heteroarylalkyl, C 5- ⁇ cycloalkylalkyl and C 5- ⁇ heterocycloalkylalkyl, wherein said Ci -6 alkyl, Ci -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C ⁇ -io aryl, C4-10 heteroaryl, C 3 .
  • the invented compounds are substituted oxindole compounds of Formula I:
  • R 1 is selected from -(CH 2 ) n R a , -CH(OH)R a , -CH(OR b )R a , and -C(O)R a , or is selected from OR a , SR a , SOR a , SO 2 R a and NR a R b ;
  • R 2 and R 3 are independently selected from H, halogen, OH, OR a , 0WR a , Ci -6 alkyl, and WCi -6 alkyl, wherein Ci_ 6 alkyl or OR a , is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, OR a , Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3 . 8 cycloalkyl, C 6 .io aryl and C 4 .
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3 . 8 cycloalkyl, C 6-I o aryl and C4.10 heteroaryl;
  • R 4 is independently selected from H, d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 - I o aryl, C 4 _i 0 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone and -(CH 2 ) n -Ci_ 6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, OR a , Ci -6 alkyl, Ci. 6 haloalkyl, C 3 .
  • R a and R b are independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2 - 6 alkenyl, C 2 . 6 alkynyl, C 6- io aryl, C 4 . 10 heteroaryl, C 3 . 8 cycloalkyl, C 3-8 heterocycloalkyl, C 3-8 heterocycloalkenyl C 7 - 14 arylalkyl, C 4 .
  • halogen is selected from F, Cl, Br and I; and at each occurrence, n is 0, 1, 2, or 3.
  • R 1 is -N(R a )R b ;
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxy cycloalkyl, C 5 . 7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, OR a , Ci_ 6 alkyl, C 3 . 8 cycloalkyl, C 6 .io aryl and C 4 .
  • R 4 is independently selected from H, Ci - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 . 8 cycloalkyl, WC 3 . 8 cycloalkyl, C 6 .
  • w aryl C 4-I0 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone and -(CH 2 ) n -Ci_ 6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, OR a , Ci_ 6 alkyl, C 3 . 8 cycloalkyl, C 6 .io aryl and C 4-I o heteroaryl.
  • R 1 is -N(R a )R b and at least one of R a and R b are hydrogen or R a and R b , together with the N atom to which they are attached, join to form a 4-6 memebered heterocycloalkyl ring.
  • R 1 is a methylene radical -(CH 2 ) n - further attached to substituents selected from C ⁇ -io aryl, C 4-I0 heteroaryl, benzodioxanyl, oxazolidinonyl, -(CH 2 ) n -Ci_ 6 haloalkyl, C 3 . 8 cycloalkyl and Ci_ 6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, OR a , Ci_ 6 alkyl, and Ci_ 6 haloalkyl, C 3 . 8 cycloalkyl, WC 3 . 8 cycloalkyl, C 6 . 10 aryl and C 4 . 10 heteroaryl.
  • R 1 is -OR a ;
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 - C 7 oxy cycloalkyl, Cs_ 7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, C 3 .
  • R 4 is independently selected from H, Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 _i 0 aryl, C 6- I 0 heteroaryl, -(CH2) n -benzodioxane, -(C ⁇ ) n - oxazolidinone, -(CH2) n -Ci_6 haloalkyl, -(C ⁇ ) n - C 3 .
  • Ci_ 6 haloalkyl each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 . 8 cycloalkyl, C 6-I0 aryl and C 4-I0 heteroaryl.
  • R 1 is -0-, substituted with substituents selected from d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6-I0 aryl, C 4-I0 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n -oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 .
  • R 4 is independently selected from H, Cr 6 alkyl, C 6-I0 aryl, C 4-I0 heteroaryl, -(C ⁇ ) n - C 3 . 8 cycloalkyl, -(C ⁇ ) n - C 3 . 8 heterocycloalkyl, -(C ⁇ ) n - Ci -6 haloalkyl, -(CH 2 ) n - and Ci -6 haloalkyl.
  • R 1 is -SR a ;
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 - C 7 oxy cycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, OR a , Ci_6 alkyl, C3-8 cycloalkyl, C ⁇ -io aryl and C 4 .
  • R 4 is independently selected from H, d-e alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 -io aryl, C 4 . 10 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone, -(CH 2 ) n -Ci_ 6 haloalkyl, -(CH 2 ) n - C 3 .
  • R 1 is -S-, substituted with substituents selected from Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C ⁇ -io aryl, C 4 . 10 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 Voxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a , Ci- 6 alkyl, C 3 . 5 cycloalkyl, C 6- io aryl and C 4 .
  • R 4 is independently selected from H, Ci- 6 alkyl, C 6 _io aryl, C 4 . 10 heteroaryl, -(CH 2 ) n - C 3 . 8 cycloalkyl, -(CH 2 ) n - C 3 . 8 heterocycloalkyl, -(CH 2 V Ci -6 haloalkyl, -(CH 2 ) n - and Q -6 haloalkyl.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, C 3 . 8 cycloalkyl, C 6 .io aryl and C 4 .
  • R 4 is independently selected from H, Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 -Io aryl, C 4 _io heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ),,- oxazolidinone, -(CH 2 ) n -Ci_ 6 haloalkyl, - (CH 2 ) n - C 3 _ 8 cycloalkyl and Ci_ 6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 . 8 cycloalkyl, C 6 _i 0 aryl and C4-10 heteroaryl.
  • R 4 is independently selected from H, C r6 alkyl, C 6 _i 0 aryl, C 4 - I0 heteroaryl, -(CHz) n - C 3 _ 8 cycloalkyl, -(CH 2 V C 3 _ 8 heterocycloalkyl, -(CH 2 V Ci -6 haloalkyl, -(CH 2 V and Ci -6 haloalkyl.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 .
  • R 4 is independently selected from H, Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6- io aryl, C4.10 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 V oxazolidinone, -(CH 2 V C 1 - 6 haloalkyl, -(CH 2 ) n - C 3 .
  • Ci -6 haloalkyl each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, C 3 _ 8 cycloalkyl, C 6 - I o aryl and C 4 . 10 heteroaryl.
  • R 4 is independently selected from H, Ci-6 alkyl, C 6 _io aryl, C4.10 heteroaryl, -(CH 2 V C3.8 cycloalkyl, -(CH 2 ) n - C3.8 heterocycloalkyl, -(CH 2 ) n - Ci- 6 haloalkyl, -(CH 2 ) n - and Ci_ 6 haloalkyl.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 . 8 cycloalkyl, C 6 -io aryl and C 4 .
  • R 4 is independently selected from H, Ci - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 _io aryl, C 4 _io heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 V oxazolidinone, -(CH 2 ) n -Ci_ 6 haloalkyl, - (CH 2 V C 3 - 8 cycloalkyl and Ci_ 6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, C 3 . 8 cycloalkyl, C 6 _i 0 aryl and C4.10 heteroaryl.
  • R 4 is independently selected from H, Cr 6 alkyl, C 640 aryl, C 4 - 10 heteroaryl, -(CH 2 V C 3 . 8 cycloalkyl, -(CH 2 V C 3 . 8 heterocycloalkyl, -(CH 2 ) n - Ci. 6 haloalkyl, -(CH 2 V and Ci_ 6 haloalkyl.
  • R 4 is -(CH 2 ) n -C 3 . 7 cycloalkyl or C 6- io aryl and C 4-I0 heteroaryl, wherein each of C 6 _io aryl and C 4- I 0 heteroaryl is substituted with 1-4 substituents selected from H, CN, OH, 0R a , Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6- I 0 aryl, C 640 heteroaryl, -(CH 2 VCi -6 haloalkyl, -(CH 2 V, Ci -6 haloalkyl, C 3 . 8 cycloalkyl, C 6-I0 aryl and C 6-I0 heteroaryl.
  • R 4 is -(CH 2 )-cyclopropyl, 0R a , C 6 -I 0 aryl, C 4- I 0 heteroaryl, substituted C 6 -I 0 aryl, or substituted C 4-I0 heteroaryl.
  • R 4 is C 6-I0 aryl or C 6-I0 heteroaryl substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a and Ci -6 alkyl.
  • R a is Ci -6 haloalkyl.
  • halogen or halogen OfCi -6 haloalkyl is fluoro. 20.
  • R a is CF 3 or OCF 3 .
  • R 1 is -CH(0H)R a ;
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 . 8 cycloalkyl, C 6- I 0 aryl and C 4 .
  • R 4 is independently selected from H, Ci - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 -Io aryl, C 4 _io heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 V oxazolidinone, -(CH 2 ) n -Ci.
  • Ci -6 haloalkyl - (CH 2 ) n - C 3 _ 8 cycloalkyl and Ci -6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, OR a , Ci_ 6 alkyl, C3-8 cycloalkyl, C 6- I 0 aryl and C4.10 heteroaryl.
  • R 1 is -CH(OH)-, substituted with substituents selected from Cr 6 alkyl, C 2 - 6 alkenyl, C 2 -e alkynyl, C 6 _io aryl, C 4 .
  • R 4 is -(CH 2 ) n -C 3 . 7 cycloalkyl, C 6 _i 0 aryl or C 4-I0 heteroaryl, wherein each of C 6-I o aryl and C 4-I0 heteroaryl is substituted with 1-4 substituents selected from H, CN, OH, 0R a , Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6-I0 aryl, C 6 .
  • R 4 is -(CH 2 )-cyclopropyl, 0R a , C 6-I0 aryl, C 4-I0 heteroaryl, substituted C 6-I0 aryl, or substituted C 4-I0 heteroaryl.
  • R 4 is C 6- io aryl or C 6-I0 heteroaryl substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a and Ci -6 alkyl.
  • R a is Ci -6 haloalkyl.
  • halogen or halogen OfCi -6 haloalkyl is fluoro.
  • R a is CF 3 or OCF 3 .
  • R 1 is -CH(OR b )R a ;
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 .
  • R 4 is independently selected from H, Ci - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 .io aryl, C4.10 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 V oxazolidinone, -(CH 2 VCi -6 haloalkyl, - (CH 2 V C 3 _ 8 cycloalkyl and Ci -6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 . 8 cycloalkyl, C 6-I0 aryl and C 4-I0 heteroaryl.
  • R 1 is -CH(OR a )-, substituted with substituents selected from d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6-I0 aryl, C 4- io heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n -oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 .
  • R 4 is independently selected from H, Cr 6 alkyl, C 6-I0 aryl, C 4-I0 heteroaryl, -(CH 2 V C 3 . 8 cycloalkyl, -(CH 2 V C 3 . 8 heterocycloalkyl, -(CH 2 ) n - Ci -6 haloalkyl, -(CH 2 V and Ci -6 haloalkyl.
  • R 1 is -(CH 2 V; R 2 and R 3 , together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 - C 7 oxy cycloalkyl, C 5 . 7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, OR a , Ci_6 alkyl, C3-8 cycloalkyl, C 6- I 0 aryl and C 4 .
  • R 4 is independently selected from H, d-e alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 -io aryl, C 4 _io heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone, -(CH 2 ) n -Ci_ 6 haloalkyl, -(CH 2 ) n - C 3 .
  • R 1 is -(CH 2 ) n -, substituted with substituents selected from Ci - 6 alkyl, C 2 -e alkenyl, C 2 - 6 alkynyl, C ⁇ -io aryl, C 4-I0 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 Voxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a , Ci- 6 alkyl, C 3 .
  • R 4 is independently selected from H, Ci- 6 alkyl, C 6-I0 aryl, C 4 . 10 heteroaryl, -(CH 2 ) n - C 3 _ 8 cycloalkyl, -(CH 2 ) n - C 3 _ 8 heterocycloalkyl, -(CH 2 V Ci -6 haloalkyl, -(CH 2 ) n - and Q -6 haloalkyl.
  • R 4 is -(CH 2 ) n -C 3 . 7 cycloalkyl or C 6 -io aryl and C 6 -io heteroaryl, wherein each of C 6-I0 aryl and C 6-I0 heteroaryl is substituted with 1-4 substituents selected from H, CN, OH, 0R a , Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6-I0 aryl, C 4-I0 heteroaryl, -(CH 2 VCi -6 haloalkyl, -(CH 2 V, Ci_ 6 haloalkyl, C 3 . 8 cycloalkyl, C 6-I0 aryl and C 4 _i 0 heteroaryl.
  • R 4 is -(CH 2 )-cyclopropyl, 0R a , C 6-I0 aryl, C 4-I0 heteroaryl, substituted C 6 .io aryl, or substituted C 4-I0 heteroaryl.
  • R 4 is C 6-I0 aryl or C 4-I0 heteroaryl substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a and Ci -6 alkyl.
  • R a is Ci -6 haloalkyl.
  • halogen or halogen of Ci -6 haloalkyl is fluoro.
  • R a is CF 3 or OCF 3 .
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • the term "Ci -6 alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • the compounds of the invention are stable. As used herein "stable” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
  • alkyl is meant to refer to a saturated hydrocarbon group, which is straight-chained or branched.
  • Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n- propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • Example alkenyl groups include ethenyl, propenyl, and the like.
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Example alkynyl groups include ethynyl, propynyl, and the like.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • aryl refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups comprise from 6 to about 20 carbon atoms, including comprising from 6 to 10 carbon atoms.
  • arylalkyl refers to an alkyl group substituted by an aryl group.
  • Examplary arylalkyl groups include, but are not limited to, benzyl and phenethyl.
  • cycloalkyl refers to non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spirocycles.
  • cycloalkyl groups comprise from 3 to 20 carbon atoms, including comprising from 3 to 14 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms or 3 to 6 carbon atoms. Cycloalkyl groups can further comprise 0, 1 or 2 double bonds and'or 0, 1, or 2 triple bonds.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, pentene, hexane, and the like.
  • a cycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • One or more ring- forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • cycloalkylalkyl refers to an alkyl group substituted by a cycloalkyl group.
  • An examplary cycloalkylalkyl group includes, but is not limited to cyclopentylmethyl and cyclohexylmethyl.
  • heteroaryl refers to an aromatic heterocycle comprising at least one heteroatom ring member selected from sulfur, oxygen and nitrogen.
  • Heteroaryl groups include monocyclic and fused, polycyclic (e.g., heteroaryl comprising 2, 3 or 4 fused rings) systems. Any ring- forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety or can be functionalized to form an N-functionalized group (e.g. N-alkyl or N-aryl).
  • heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazmyl, furyl, quinolyl, isoquinolyl, thienyl, lmidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purmyl, carbazolyl, benzimidazolyl, indolinyl, and the like.
  • the heteroaryl group comprises from 3 to 20 carbon atoms, and in further embodiments comprises from about 4 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 6 to about 10 ring-forming atoms. In some embodiments, the heteroaryl group comprises from 1 to 4 heteroatoms, including comprising from 1 to 3 heteroatoms or 1 to 2 heteroatoms.
  • heteroarylalkyl refers to an alkyl group substituted by a heteroaryl group.
  • An example of a heteroarylalkyl group is pyridylmethyl.
  • heterocycloalkyl refers to a non-aromatic heterocycle where one or more of the ring-forming atoms comprises a heteroatom selected from O, N and S.
  • heterocycloalkenyl refers to a partially-unsaturated heterocycle or a heterocycle comprising at least one unsaturated bonding of carbon atoms or carbon and heteroatoms, where one or more of the ring- forming atoms comprises a heteroatom selected from O, N and S.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles.
  • heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholmo, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidmyl, thiazolidinyl, imidazolidinyl, and the like.
  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles.
  • a heterocycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non- aromatic portion.
  • moieties where one or more ring-forming atoms is substituted by 1 or 2 oxo or sulfido groups.
  • the heterocycloalkyl group comprises from 4 to 20 carbon atoms, and in further embodiments from 5 to 10 carbon atoms. In some embodiments, the heterocycloalkyl group comprises 5 to 20, 5 to 14, 5 to 12, or 5 to 10 ring-forming atoms. In some embodiments, the heterocycloalkyl group further comprises 1 to 4 heteroatoms, including comprising from 1 to 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group further comprises 0 to 2 double bonds. In some embodiments, the heterocycloalkyl group comprises 0 to 2 triple bonds.
  • heterocycloalkylalkyl refers to an alkyl group substituted by a heterocycloalkyl group.
  • halo or halogen includes fluoro, chloro, bromo, and iodo.
  • haloalkyl refers to an alkyl group substituted by one or more halogen atoms.
  • haloalkyl groups examples include CF3 and CF 2 CF3.
  • alkoxy refers to an -O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds of the present invention that comprise asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, IH- and 3H-imidazole, IH-, 2H- and 4H- 1,2,4-triazole, IH- and 2H- isoindole, and IH- and 2H- pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • compound as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted.
  • the compounds of the invention, and salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions comprising at least 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which comprises a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the compounds of the present invention can be prepared from readily available starting materials in a variety of ways known to one skilled in the art of organic synthesis. For example, they can be synthesized via the reaction pathways and techniques as described below.
  • Certain invented benzyl amine compounds 5 were prepared according to Scheme 1.
  • 5-Nitroisatin (1) was converted to the corresponding cyclic acetal 2 using 1,3 -propanediol and/>-TsOH in benzene.
  • Alkylation of the oxindole nitrogen with organohalides produced nitro acetal compound 3.
  • Reduction of the NO 2 group to the corresponding amine compound 4 was accomplished by catalytic hydrogenation using H 2 A 0% Pd/C.
  • Functionalization of the amine 4 with benzaldehydes under reductive amination conditions produced invented benzyl amine compounds 5.
  • Scheme 2
  • Certain invented 5 -Aryl amine compounds 6 were prepared from amine compounds 4 using aryl boronic acids, copper acetate, amine bases such as Et 3 N in aprotic solvents, such as CH2CI2, as summarized in Scheme 2.
  • Certain invented disubstituted amino compounds were prepared according to Scheme 3.
  • Amine compound 4 was protected as the trifluoroacetamide compound 7 by treatment with trifluoroacetic anhydride and Et 3 N in CH 2 CI 2 .
  • Alkylation of the nitrogen of compound 7 with organohalides produced compound 8, which can be deprotected under basic conditions to provide deprotected compound 9.
  • Invented compounds (10) were then prepared from aryl boronic acids, copper acetate, amine bases such as Et 3 N in aprotic solvents such as CH2CI2.
  • Certain invented sulfides, sulfoxides and sulfone compounds (17 and 19, respectively) were prepared according to Scheme 5.
  • 5-Iodo-isatin (14) was converted to the corresponding cyclic acetal compounds 15 using 1,3 -propanediol or ethylene glycol and/?-TsOH in benzene with heating.
  • Aryl sulfide compounds 16 were prepared from corresponding compounds 15 using aryl thiols, in the presence of CuI and ethylene glycol in isopropanol (Org Lett. 2002, 4, 3517) or CoCl 2 (dppe), zinc and pyridine in acetonitrile (Org. Lett 2006, 8, 5613).
  • N-Alkyl oxmdole compounds 17 or 19, respectively were prepared from corresponding compounds 16 or 18 using organohahdes and K 2 CO 3 in DMF with heating.
  • Corresponding N-Aryl oxmdole compounds 17 or 19 were prepared from respective compounds 16 or 18 using aryl boronic acids, copper acetate, amine bases such as EtrN in aprotic solvents such as CH 2 Cl 2 .
  • TIP S -protected thiol compounds 20 were prepared from protected 5-iodoisatin compound 15 by the treatment with appropriate triisopropylthiols, KH and Pd(PPl ⁇ ) 4 in THF (J.Med. Chem. 2001, 44, 4393).
  • Aryl sulfide compounds were prepared from compound 20 using appropriate aryl iodides in the presence of CuI and ethylene glycol in isopropanol. Oxidation, arylation or alkylation to respective compounds 17 or 19, can be accomplished, as summarized in Scheme 5.
  • 5-Aryl ether compounds (25) were prepared according to the procedure of Scheme 7.
  • 5-methoxyisatin (20) was converted to compound 22 via alkylation with cyclopropylmethyl bromide followed by demethylation of compound 21 with boron tribromide in dichloromethane.
  • Compound 22 was then converted to compound 23 with 1,3 -propanediol and j>-TsOH in toluene.
  • Reaction of compound 23 with an iodonium tetrafluoroborate salt (24) in presence of copper and triethylamine in dichloromethane produced invented 5-Aryl ether compounds 25.
  • reaction of compound 23 with a substituted fluoropyridine (27) in presence of cesium carbonate in dichloromethane also produced other invented 5-Aryl ether compounds (26).
  • Certain invented substituted oxmdole compounds (32) were prepared according to the procedure of Scheme 8. Thus 5-iodoisatm (27) was converted to acetal compound (28) with 1,3-propanediol an ⁇ p- TsOH m toluene. Alkylation of Nl was accomplished using organohalides with CS 2 CO 3 m DMF at 60 0 C, and produced N-functionalized ketone componds (29). Carbonylation of N-functionalized compounds 29 in presence of substituted boronic acid, carbon monoxide and dichloro-bis- triphenylphosphinepallidium in toluene produced ketone compounds (30). Sodium borohydride reduction of ketone compounds 30 produced hydroxyl compounds (31). Deoxygenation of hydroxyl compounds 31 with triethylsilane and trifluoroacetic acid in dichloromethane produced methylene bridged compounds (32).
  • oxindole compounds 38 were synthesized by reaction of N-functionalized compounds 33 with an appropriate borate 37 in DMF in presence of tetrakis(triphenylphosphine)palladium and sodium carbonate. Subsequent catalytic hydrogenation of the alkene group in compound 38 in a Parr apparatus at 40 psi of hydrogen produced the other invented 1, 3, 5-substituted oxindole compounds 39.
  • Conventional synthetic reagents and conditions were employed in accordance with methods for preparing compounds of the invention. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, however, alteration of such conditions may be determined and adjusted by persons skilled in the art.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • HPLC high performance liquid chromatograpy
  • Preparation of compounds can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection of certain functional groups attached to the oxoindole core of the invented compounds, and selection of appropriate protecting groups may be determined by one skilled in the art.
  • the chemistry of protecting groups is described, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991.
  • Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures, which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art.
  • An example method includes fractional recrystallization using a "chiral resolving acid" which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The selection of a suitable elution solvent composition may be determined by one skilled in the art.
  • Compounds of this invention are able to interact with the CB2 receptor and therefore modulate the receptor's activity.
  • modulate is meant to refer to an ability to increase or decrease activity of an the receptor. Modulation can occur in vitro or in vivo. Modulation can further occur in a cell. Accordingly, compounds of the invention can be used in methods of modulating the activity of the CB2 receptor, by contacting the receptor with one or more of the compounds or compositions described herein. As used herein, the term “contacting” refers to bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting includes the administration of a compound of the present invention to an individual or patient, such as a human, as well as, for example, introducing a compound of the invention into a sample comprising a cellular or purified preparation of the receptor.
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds of the present invention can act as CB2 receptor agonists.
  • these compounds can be used to treat CB2-mediated disorders, such as CB2 agonists are potential drug candidates for reducing treating pain (e.g., chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), osteoarthritis, atherosclerosis, osteoporosis, and cancer (e.g., glioma).
  • the treatment includes administration of a therapeutically effective amount of one or more of the invented 3-substituted oxindole compounds described above to a patient in need thereof.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • the term "treating" or “treatment” refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • Examplary cancers treatable by the invented compounds herein include, but are not limited to, glioma, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, cancer of the kidney, liver cancer, lung cancer, nasopharygeal cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, MFH/fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma, multiple myeloma, lymphoma, adult T cell leukemia, acute myelogenous leukemia, chronic myeloid leukemia, glioblastoma, astrocytoma, melanoma, mesothelioma, or WiIm' s tumor, and the like.
  • One or more additional pharmaceutical agents or treatment methods can be used in combination with the compounds of the present invention for treatment of the diseases, disorders or conditions described herein.
  • one or more of the above-described 3-substituted oxindole compounds can be used together with an anti-inflammatory agent, an anti-cancer agent, an analgesic, or other therapeutic agent useful in treating pain, cancer, osteoarthritis, atherosclerosis, osteoporosis or other disease.
  • the agents or therapies can be administered together -with the compounds of the invention (e.g., combined into a single dosage form), or the agents or therapies and may be administered simultaneously or sequentially by separate routes of administration.
  • the compounds of the invention can be administered in the form of pharmaceutical compositions, which is a combination of a compound of the invention, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral.
  • Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which comprise, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments comprising, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to an average particle size of less than 200 mesh. If the active compound is substantially water- soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. an average particle size of about 40 mesh.
  • the compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by methods described in International Patent Application No. WO 2002/000196.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit comprising a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above comprising from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may comprise suitable pharmaceutically acceptable excipients as described supra, and in some embodiments, the compositions are administered by an oral or nasal respiratory route for local or systemic effect.
  • Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices, which deliver the formulation in an appropriate manner.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous earner prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution comprising about 0.1 to about 10% w/v (weight/volume) of the compound for parenteral adminstration. Some typical dose ranges are from about 1 mg/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • kits useful for example, in the treatment or prevention of diseases, such as pain or cancer and other diseases referred to herein, which include one or more containers comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt thereof.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and'or guidelines for mixing the components, can also be included in the kit.
  • Analytical LC/MS Samples were analyzed on an Agilent LC-1100-MSD.
  • the mass spectrometer utilized to confirm the integrity of the compound, was a single quadrapole mass filter scanning from 100-1000 Da.
  • the PDA used to assess compound purity, monitors 254, 215, 230, 280, and 300 nm wavelengths. The compound purity was reported at 254 nm unless stated otherwise.
  • the HPLC mobile phase flow rate was 0.8 ml/mm.
  • Eluent A was 0.1 % HCO 2 H in water and eluent B was 0.1 % HCO 2 H in ACN.
  • HPLC mobile phase gradient w r as initiated at 100% eluent A followed by a linear increase to 100% eluent B in 2.5 minutes. The gradient was held at 100% eluent B for an additional 1.5 minutes (total time 4.0 minutes). The HPLC rapidly equilibrated the column back to 100% eluent A for an additional 1.5 minutes for subsequent injections. The total HPLC/MS run time was 5.5 minutes. Compounds were diluted to ⁇ 1.0 mg/niL in DMSO. The analysis injection volume was 5 ⁇ L. The HPLC column used was a Thermo Electron Corporation, Aquasil Cl 8, 50 x 2.1 mm, 5 ⁇ m particle size. Preparative reverse-phase HPLC (RP-HPLC):
  • Step 2 r-(cyclopropylmethyl)-5'-iodospiro[l,3-dioxane-2,3'-indol]-2'(r//)-one
  • reaction mixture was then stirred at 80° C and exposed to an atmosphere of carbon monoxide via a balloon. After stirring overnight, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, then washed with H 2 O, followed by brine. The organic layer was dried over Na 2 S ⁇ 4 , concentrated and purified by flash chromatography on silica gel to afford product as a white solid (0.7 Ig, 75%).
  • reaction mixture was then stirred at 80° C under an atomosphere of carbon monoxide via balloon. After stirring overnight, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, washed with H 2 O, then followed by brine. The organic layer was dried over Na 2 SO 4 , concentrated and purified by flash chromatography on silica gel to afford product as a white solid (0.22g, 72%).
  • Example 113 A procedure similar to that of Example 113, using different aryl boronic acids for the N-arylation described in step 1, and different aryl boronic acids for the carbonylation described in step 2, provided Examples 114-134.
  • the compounds and their analytical data are shown in Table 4.
  • Example 135 5'-[(2-fluorophenyl)(hydroxy)methyl]-r-phenylspiro[l,3-dioxane-2,3'-indol]-2'(r//)-one
  • Example 135 A procedure similar to that of Example 135, using Examples 114-134 (see Table 4), provided Examples 136-155. The compounds and their analytical data are shown in Table 5.
  • Example 156 A procedure similar to that of Example 156, using Examples 136-155, provided Examples 157- 175. The compounds and their analytical data are shown m Table 6.
  • reaction mixture was then stirred at 80° C under an atmosphere of carbon monoxide via balloon. After stirring overnight, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, then washed with H 2 O, followed by b ⁇ ne. The organic layer was dried over Na 2 S ⁇ 4 , concentrated and then purified by flash chromatography on silica gel to afford product as a brown solid (1.2Og, 43%).
  • reaction mixture was allowed to slowly warm to room temperature. After stirring overnight, TLC analysis indicated that reaction had neared completion, so reaction mixture was quenched with sat. NH 4 Cl and was stirred for 30 minutes. This mixture was then extracted with EtOAc, and organic layers were combined, washed with brine, dried over
  • Examples 186-200 were prepared from 5'-amino4'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]-2'(l ⁇ )-one and the appropriate aldehyde according to the procedure for Example 185.
  • the title compound (0.05Og, 48%) was prepared from 5'-amino-l'-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one using a procedure similar to that of Example 1, using 2 equivalents of cyclohexanecarbaldehyde in Step 4.
  • 1 H NMR 400 MHz, DMSO-d ⁇ : consistent; MS (ES + ) m/z (M+H).
  • Step 3 N-(I '-butyl-2 '-oxo-1 ',2 '-dihydrospiro[l,3-dioxane-2,3 '-indolJ-S '-yl)-2,2,2- trifluoro-N-methylacetamide
  • r-(Cyclopropylmethyl)-5'-[niethylammo]spiro[l,3-dioxane-2,3'-mdol]- 2'(l'H)-one was prepared from 5'-amino-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-mdol]-2'(rH)-one using a procedure similar to that of Example 198.
  • Step 2 5'-(Phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one
  • Step 2 5'-(Phenylthio)spiro[l,3-dioxolane-2,3'-indol]-2'(l'H)-one
  • Examples 214-216 were prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]- 2'(l'H)-one and the appropriate boronic acid according to the procedure for Example 203.
  • Table 8 Compounds Prepared According to the Procedure of Example 203
  • Examples 217-219 were prepared from 5'-(phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(l ⁇ )-one and the appropriate boronic acid according to the procedure for Example 203.
  • Examples 220-249 were prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l ⁇ )- on and the appropriate boronic acid according to the procedure for Example 203.
  • Examples 254-260 were prepared from 1 '-(cyclopropylmethyl)-5'-iodospiro[l ,3-dioxane-2,3'- indol]-2'(l'H)-one and the appropriate substituted thiopheols according to the procedure for Example 252, and oxidized to the sulfones according to the procedure for Example 253.
  • Examples 262-271 were prepared from l'-(cyclopropylmethyl)-5'-iodospiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one and the appropriate substituted thiophenols according to the procedure for Step 2 of Example 207, and oxidized to the sulfones according to the procedure for Example 208.
  • Table 12 Compounds Prepared According to the Procedure of Examples 207 and 208.
  • Examples 272-275 were prepared from l'-(cyclopropylmethyl)-5'-iodospiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one and the appropriate substituted thiophenols according to the procedure for Step 2 of Example 207.
  • Examples 277 and 278 were prepared from Example 273 and 275 respectively according to the procedure for Example 208.
  • Step 2 l '-fCyclopwpylmethyljS'-fpyridin-S-ylsulfanyljspirollJ-dioxane ⁇ J'-indolJ- 2'(l 'H)-one
  • Examples 280-294 were prepared from l'-(cyclopropylmethyl)-5'-
  • Examples 295-310 were prepared by oxidizing the corresponding sulfides (prepared in Examples ) according to the procedure for Example 208.
  • Step 2 1 '-(cyclopropylmethyl)-5'-hydroxyspiro[l,3-dioxane-2,3 '-indol]-2'(l 'H)-one
  • N-cyclopropylmethyl-5-methoxyisatin was dissolved in dichloromethane (60 mL), treated with neat boron tribromide (3.0 mL, 31.7 mmol) and stirred at ambient temperature for 1 hour.
  • the reaction mixture was diluted with dichloromethane ( 100 mL) and extracted from 1.0 N HCl. The organic layer was dried over sodium sulfate and then concentrated to dryness. The residue was dissolved in toluene (200 mL), treated with 1,3 -propanediol (6.O mL, 83.0 mmol) and toluenesulfonic acid (1.0 g, 5.25 mmol).
  • reaction mixture was loaded directly to a flash chromatography column and purified with ethyl acetate/hexanes (0-50% gradient elution) to provide 1'- (cyclopropylmethyl)-5'-(4-methoxyphenoxy) spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one (0.025 g, 18%) as a dark oil.
  • reaction mixture was loaded directly to a flash chromatography column and then purified with ethyl acetate/hexanes (0-50% gradient elution) to provide 1'- (cyclopropylmethyl)-5'-(phenoxy)spiro[l,3-dioxane-2,3'-indol]-2'(r/7)-one (107.0 mg, 42 %, dark oil).
  • Examples 314-318 were prepared from l '-(cyclopropylmethyl)-5'-hydroxyspiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one and the appropriately substituted 4-fTuoropyridines according to the procedure for Example 313.
  • Table 17 Compounds Prepared According to the Procedure of Example 313
  • Step l r-(2-Chloro-4-nitrophenyl)-5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]-2'(r//)-one
  • Examples 330-335 were prepared from 5'-[(4-methoxyphenyl)thio]spiro[l ,3-dioxane-2,3'-mdol]-
  • Examples 336-341 were prepared from 5'-(py ⁇ dm-4-ylsulfonyl)spiro[l,3-dioxolane-2,3'-mdol]- T(VH)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized m Table 13.
  • Table 19 Compounds Prepared According to the Procedure of Example 179, step 2.
  • Examples 342-357 were prepared from 5'-[(4-methoxyphenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l '//)-one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 20.
  • Examples 358-360 were prepared from 5'-iodospiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one and the appropriate trifluoromethoxy thiophenol using a procedure similar to that of Example 201, step 2 and summarized in Table 21.
  • Examples 361-363 were prepared from 5'- ⁇ [2-(trifluoromethoxy)phenyl]sulfanyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(rH)- one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 22.
  • Examples 364-366 were prepared from 5'- ⁇ [3-(trifluoromethoxy)phenyl]sulfanyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(rH)- one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 23.
  • Table 23 Compounds Prepared According to the Procedure of Example 179, step 2.
  • Examples 367-369 were prepared from 5'- ⁇ [4-(trifluoromethoxy)phenyl]sulfanyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(l ⁇ )- one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 24.
  • Examples 373-378 were prepared from 5'- ⁇ [2-(trifluoromethoxy)phenyl]sulfonyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(l 'H)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 26.
  • Examples 379-384 were prepared from 5'- ⁇ [3-(trifluoromethoxy)phenyl]sulfonyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(l '//)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 27.
  • Examples 385-390 were prepared from 5'- ⁇ [4-(trifluoromethoxy)phenyl]sulfonyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 28.
  • Examples 393-398 were prepared from 5'-[(3-fluorophenyl)sulfanyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'//)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 29.
  • Table 29 Compounds Prepared According to the Procedure of Example 179, step 2.
  • Examples 399-428 were prepared from 5'-[(3-fluorophenyl)sulfonyl]spiro[l ,3-dioxane-2,3'- indol]-2'(l '//)-one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 30.
  • Examples 429-440 were prepared from 5'-(py ⁇ din-4-ylsulfonyl)spiro[l ,3-dioxolane-2,3'-indol]-
  • Examples 441-451 were prepared from 5'- ⁇ [3-(trifluoromethoxy)phenyl]sulfonyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 32.
  • Examples 452-455 were prepared from 5'- ⁇ [2-(trifluoromethoxy)phenyl]sulfonyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 33.
  • Examples 456-458 were prepared from 5'- ⁇ [4-(trifluoromethoxy)phenyl]sulfonyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 34.
  • Table 34 Compounds Prepared According to the Procedure of Example 197.
  • Examples 459-472 were prepared from 5'-(pyndm-4-ylsulfon>l)spiro[l,3-dioxane-2,3'-mdol]- 2'( 17/)-one and the appropriate boromc acid using a procedure similar to that of Example 197, step 2 and summarized in Table 35.
  • Examples 473-500 were prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)- one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 36.
  • the title compound (0.056g, 34%) was prepared from 5'-[(4-methoxyphenyl)sulfonyl]spiro[l ,3- dioxane-2,3'-mdol]-2'(rH)-one and 3,4 difhioronitrobenzene using a procedure similar to that of step 1 of example 319.
  • 1 H NMR 400 MHz, DMSO-d6): consistent; MS (ESI + ) m/z 515.0 (M+H).
  • Examples 504-531 were prepared from 5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]- 2'(17/)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 37.
  • the title compound (0.055g, 83%) was prepared from 5'-(phenylsulfonyi)spiro[l,3-dioxane-2,3'- indol]-2'(l'//)-one and 4-(2-chloroethyl)morpholine hydrochloride using a procedure similar to that of Example 179, step 2.
  • 1 H NMR 400 MHz, DMSO-d6): consistent; MS (ESI + ) m/z 459.1 (M+H).
  • the title compound (0.058g, 86%) was prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'- indol]-2'(l'//)-one and 4-bromo-2-methylbutan-2-ol (EP78704) using a procedure similar to that of Example 179, step 2.
  • 1 H NMR 400 MHz, DMSO-d6): consistent; MS (ESI + ) m/z 432.1 (M+H).
  • Examples 545-548 were prepared from prepared from 5'-(pyridin-2-ylsulfanyl)spiro[l,3- dioxolane-2,3'-indol]-2'(l T H)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and are summarized in Table 38.
  • Examples 552-554 were prepared from 5'-[(3-fluorophenyl)sulfonyl]spiro[l ,3-dioxane-2,3'- mdol]-2'(l ⁇ )-one and the appropriate lodo-pyndme using a procedure similar to that of Example 540 and are summarized m Table 39 Table 39: Compounds Prepared According to the Procedure of Example 540.
  • Examples 555-557 were prepared from 5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]-2'(l ⁇ )- one and the appropriate bromomethyl pyridine using a procedure similar to that of Example 179, step 2 and are summarized in Table 40.
  • Table 40 Compounds Prepared According to the Procedure of Example 179, step 2.
  • 2,3'-indol]-2'(l ⁇ )-one (0.108g, 83%) (Example 339) were prepared from l'-propyl-5'-(pyridin-4- ylsulfanyl)spiro[l,3-dioxolane-2,3'-indol]-2'(l ⁇ )-one using a procedure similar to that of Example 551.
  • Example 559 5'-[(2-Chloro-4-fluorophenyl)sulfanyl]-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)- one
  • Examples 560-565 were prepared from r-(cyclopropylmethyl)-5'-[(triisopropylsilyl)sulfanyl]spiro[l,3- dioxane-2,3'-indol]-2'(l'H)-one and the appropriate commercially available or synthesized, according to procedures described in Tetrahedron. 2005, 61, 4779-4784 or WO 2006/004533, substituted aryl or heteroaryl iodides and according to the procedure for Step 2 of Example 201 and are summarized in Table 41.
  • Examples 567-573 were oxidized to the sulfones according to the procedure for Example 202 and are summarized in Table 42.
  • Examples 577-604 were prepared from 5'-(py ⁇ din-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-mdol]-
  • Example 606 5'-(Pyridin-3-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one
  • Examples 608-632 were prepared from 5'-(pyridin-3-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one and the appropriate substituted boronic acids using a procedure similar to that of Example 197 and summarized in Table 44.
  • Table 44 Compounds Prepared According to the Procedure of Example 197.
  • Step l 5 [2-(trifluoromethyl)benzoyl] spiro[ 1 ,3 -dioxane-2,3 '-indol]-2'( 177)-one
  • Step 2 1 '-(2-fluorobenzyl)-5'- ⁇ [2-(trifluoromethyl)phenyl]carbonyl ⁇ spiro[l ,3-dioxane-2,3'-indol]-2'( 1 ⁇ )-one
  • Examples 636 - 656 were prepared from different benzyl bromides by using a procedure similar to that of Example 635 and summarized in Table 45.
  • Table 45 Compounds Prepared According to the Procedure of Example 635.
  • Examples 658-678 were prepared from Examples 636-656 by using a procedure similar to that of Example 657 and are summarized in Table 46.
  • Examples 679-695 were prepared from Examples 658-677 by using a procedure similar to that of Example 678 and are summarized in Table 47.
  • Table 47 Compounds Prepared According to the Procedure of Example 678.
  • CHO Kl cells expressing the human CBl or CB2 receptor were cultured at 37° C, m Ham's F12 (Invitrogen 21765-037 or equivalent) containing 10% fetal bovine serum (US biotechnologies or the equivalent), 100 ⁇ g/ml penicillin and 100 ⁇ g/ml streptomycin (Gibco 10131-035), 400 ⁇ g/ml G418 (Gibco 10131-035).
  • Adherent cell culture cells were maintained by seeding at 2-3 x 10 6 cells m 30 mL medium m a
  • cells were thawed at 37° C, added to 15 mL complete medium, cent ⁇ fuged at 1200 rpm for 2 minutes The cell pellet was resuspended m 5 ml medium and then added to a T 175 containing 25 ml of medium. Frozen cells were also thawed as above and maintained m culture by adding the resuspended cells to 100 ml of medium m a sterilized 250 mL Erlenmeyer flask that was gassed with 5% CO 2 , capped, and placed on an orbital shaker at low RPM (50-100).
  • cAMP Assay Cells were lifted from the plate with dissociation buffer cent ⁇ fuged and resuspended m a small volume of PBS. Cells were plated (15,000/well; 96 well plate, 7,500/well; 384 well plate) and incubated m the presence of 10 ⁇ M forskolm and compound m Krebs bicarbonate buffer (118 mM NaCl, 5 mM KCl, 1 2 mM MgSO 4 , 2.4 mM CaCl 2 1.2 mM KH 2 PO 4 25 mM NaHCO 3 11.1 mM glucose) at 37 0 C for 30 minutes.
  • compound m Krebs bicarbonate buffer 118 mM NaCl, 5 mM KCl, 1 2 mM MgSO 4 , 2.4 mM CaCl 2 1.2 mM KH 2 PO 4 25 mM NaHCO 3 11.1 mM glucose
  • cAMP content was determined using the HitHunter cAMP XS assay (Discoverx 90-0041, 90-0041 L).
  • Discoverx 90-0041, 90-0041 L For the antagonist assay, compound is incubated m the presence of 10 ⁇ M forskolm and 10OnM WIN-55212-2 at 37 0 C for 30 minutes.
  • the HitHunter assay was performed according to the manufacturer's instructions. Briefly, 20 ⁇ L cAMP antibody/lysis mix (1:1 ratio) were added to stimulated cells and incubated at room temperature for 1 hour. 20 ⁇ L of cAMP XS ED reagent was added and incubated at room temperature for 1 hour. 20 ⁇ L of cAMP XS EA reagent and 20 ⁇ L of CL substrate (1 part Galacton-Star, 5 parts Emerald-II, 19 parts substrate diluent) were added and then incubated at room temperature for 3 hours. Chemilummescence was read on a Victor II at 1 s/well. A standard curve was also established with cAMP concentrations ranging from 10 10 to 10 5 M, diluted m Krebs.
  • IC 50 and EC 50 values were calculated using P ⁇ sm GraphPad using a 4-parameter logistic equation.
  • An active agonist displays greater than 40% inhibition of cAMP.
  • An antagonist typically displays greater than 40% reversal of 100 nM WIN55212-2 response.
  • CHO Kl cells expressing the human CBl or CB2 receptor were cultured at 37 0 C, in Ham's F12 (Invitrogen 21765-037 or equivalent) containing 10% fetal bovine serum (US biotechnologies or equivalent), 100 ⁇ g/mL penicillin and 100 ⁇ g/mL streptomycin (Gibco 10131-035), 400 ⁇ g/mL G418 (Gibco 10131-035).
  • Cells were harvested from plates by scraping in a small volume of ice-cold 20 mM HEPES, 2OmM EDTA, pH 7.5. The cells were homogenized and pelleted by centrifugation at 100,000 g for 30 minutes at 4° C. Membranes were resuspended at a concentration of 1- 5mg/mL.
  • Membranes were incubated in 0.5 mL binding buffer (50 mM Tris pH 5.7, 2.5 mM EDTA pH 8.0, 0.25% essentially fatty acid free BSA (Sigma A6003)) in the presence of 4 nM [ 3 H] SR141716 (CBl antagonist) or 0.6 nM [ 3 H] CP 55,940 (non-selective agonist) nM and cold displacing ligand for 1 hour at 3O 0 C.
  • the assay was terminated by filtration on a brandel harvester through Whatman GFB filter paper, previously soaked in 0.15% polyethyleneamine. Samples were washed with 4 x 5 mL ice cold binding buffer and radioactivity was determined by liquid scintillation counting. Non-specific binding values were determined by either 1 ⁇ M CP 55, 940 or 1 ⁇ M WIN 55212-2.

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Abstract

L'invention concerne des composés substitués qui sont des agonistes du récepteur CB2, ou des sels pharmaceutiquement acceptables de ces composés, dans lesquels : R1 est sélectionné parmi -(CH2)nRa, -CH(OH)Ra, -CH(ORb)Ra, et -C(O)Ra, ou est sélectionné parmi ORa, SRa, SORa, SO2Ra et NRaRb; R2 et R3 sont indépendamment sélectionnés parmi H, halogène, OH, ORa, OWRa, alkyle C1-6, et alkyle WC 1-6; alkyle C1-6 ou ORa étant éventuellement substitué par 1, 2, ou 3 substituants indépendamment sélectionnés parmi halogène, CN, OH, ORa, alkyle C1-6, haloalkyle C1-6, cycloalkyle C3-8, aryle C6-10 et hétéroaryle C4-10 ; ou R2 et R3, conjointement à l'atome de carbone auquel ils sont fixés, s'assemblent pour former un cycle sélectionné parmi: un cycloalkyle présentant 3 à 8 éléments, un hétérocycloalkyle présentant 3 à 8 éléments, un oxycycloalkyle C5-C7, un dioxycycloalkyle C5- 7 et un cycle oxazolidinyle, chaque cycle étant éventuellement substitué par 1, 2, ou 3 substituants indépendamment sélectionnés parmi halogène, CN, OH, ORa, alkyle C1-6, haloalkyle C1-6, cycloalkyle C3-8, aryle C6-10 et hétéroaryle C4-10; R4 étant indépendamment sélectionné parmi H, alkyle C1-6, alcényle C2-6, alcynyle C2-6, aryle C6-10, hétéroaryle C4-10, benzodioxane-(CH2)n, oxazolidinone-(CH2)n et haloalkyle-(CH2)n-C1-6, chacun de ces substituants étant éventuellement substitué par 1, 2, ou 3 substituants indépendamment sélectionnés parmi halogène, CN, OH, ORa, alkyle C1-6, haloalkyle C1-6, cycloalkyle C3-8, cycloalkyle WC3-8, aryle C6-10 et hétéroaryle C4-10. L'invention concerne également des compositions pharmaceutiques contenant les composés selon l'invention, et des procédés de traitement associés à des troubles médiés par CB2 (par exemple, la douleur, le cancer, etc.) utilisant les composés d'oxindole substitué et les compositions décrites dans la description.
PCT/US2009/067981 2008-12-15 2009-12-15 Agonistes de cb2 de type oxindole substitué WO2010090680A1 (fr)

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CN115232063A (zh) * 2022-06-16 2022-10-25 西南林业大学 一种多取代含溴或氯的苯并[c,d]吲哚类化合物的合成方法

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CN103936752A (zh) * 2014-05-05 2014-07-23 潍坊博创国际生物医药研究院 靛红类组蛋白去乙酰化酶抑制剂及其制备方法和应用
CN105801350A (zh) * 2016-04-29 2016-07-27 宜春学院 二芳基甲醇类化合物的合成方法
CN115232063A (zh) * 2022-06-16 2022-10-25 西南林业大学 一种多取代含溴或氯的苯并[c,d]吲哚类化合物的合成方法

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