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WO2010077839A1 - Substituted oxindol cb2 agonists for pain treatment - Google Patents

Substituted oxindol cb2 agonists for pain treatment Download PDF

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Publication number
WO2010077839A1
WO2010077839A1 PCT/US2009/067967 US2009067967W WO2010077839A1 WO 2010077839 A1 WO2010077839 A1 WO 2010077839A1 US 2009067967 W US2009067967 W US 2009067967W WO 2010077839 A1 WO2010077839 A1 WO 2010077839A1
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Prior art keywords
indol
dioxane
spiro
ylsulfonyl
oxo
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PCT/US2009/067967
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French (fr)
Inventor
Paul Jeffrey Dollings
Andrew Forrest Donnell
Adam Matthew Gilbert
Minsheng Zhang
Boyd Lynn Harrison
Charles John Stanton Iii
Steven Victor O'neil
Lisa Marie Havran
Dan Chaekoo Chong
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Wyeth LLC
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Wyeth LLC
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Publication of WO2010077839A1 publication Critical patent/WO2010077839A1/en
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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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin

Definitions

  • CB 1 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 CB 1 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., in 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, athe
  • 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 oxmdole compounds of the invention, oi pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner.
  • the invention relates to a method of treating a CB2-tnediated 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 disordeis include, but are not limited to, pain (such as chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), 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 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 are CB2 agonists having Formula I
  • R 1 is selected from Q. 6 alkyl, C 2 ⁇ alkenyl, C 2 . 6 alkynyl, C
  • R 2 and R 3 are independently selected from H, halogen, C, 6 alkyl, C 2 6 alkenyl, C 2 . 6 alkynyl, Ci -6 haloalkyl, C, ⁇ hydroxyalkyl, C N6 cyanoalkyl, C 6 . ⁇ o aryl, C 4 . l0 heteroaryl, C 3 . 8 cycloalk>'l, C 3 . g heterocycloalkyl, C 3 .
  • R 4 is selected from C(O)NR 6 R 7 , SO 2 NR 6 R 7 , NR 8 C(O)R 9 , NR 8 SO 2 R 9 and C(O)C(O)NR 6 R 7 ;
  • R 5 is selected from H, halogen and Q 6 alkyl.
  • R 6 and R 7 are independently selected from H, Ci 6 alkyl, C 1 ⁇ haloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 6-I 0 aryl, Cm heteroaryl, C 3 8 cycloalkyl, C 3 8 heterocycloalkyl, C 3 . 8 heterocycloalkenyl and C,. 6 hydroxyallcyl, wherein said C u alkyl C, 6 haloalkyl, C 2 6 alkenyl, C 2 ⁇ alkynyl, C 6 10 aryl, C 4 10 heteroaryl, C 8 cycloalkyl, C 3 8 heterocycloalkyl, C 3 . ?
  • heterocycloalkenyl and Ci 6 hydroxyalkyl is optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from OH, cyano, amino, halo, C
  • C 3 . 8 heterocycloalkenyl or C 6 hydi oxyalkyl is optionally substituted with 1 , 2, 3 4, or 5 substituents independently selected from 0R a , cyano, ammo, halo, NO 2 , Cu alkyl, C 6 - I o aryl, Cm heteroaryl, C 8 cycloalkyl, C, % heterocycloalkyl and C 8 heterocycloalkenyl,
  • R* and R 9 are independently selected from H, C 1 - O alkyl.
  • R ⁇ R b , R c and R f are independently selected from II, C 1 ⁇ alkyl, C
  • R c and R c are independently selected from H, C
  • heteroarylalkyl C 5 .1 2 cycloalkylalkyl and C 5 . 12 heterocycloalkylalkyl, wherein said C,. 6 alkyl. C
  • C 4 .i 4 heteroarylalkyl, C 5 . ⁇ 2 cycloalkylalkyl or C 5 . ⁇ 2 heterocycloalkylalkyl. is optionally substituted with OH, cyano, amino, halogen, Q 6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R c and R d , together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring, each optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, C
  • the invented compounds selected from:
  • R 4 when R 4 is SOjNR 6 R 7 , n is 0, R 2 and R 3 , together with the carbon atom to which they are attached, form a l ,3-dioxan-2,2-diyl ring, and R 6 and R 7 , together with the carbon atom to which they are attached, form a pyrrohdinyl ring, then R 1 is not alkyl substituted with NH 2 , CN, N 3 , bromo, or a 7-membered cycloalkyl ring optionally substituted by CN or cyanoalkyl In related embodiments, R 4 is substituted at the 5-position of the oxindole core.
  • R 1 is selected from C ⁇ alkyl, C 2 . 6 alkenyl, C 2 . ft alkynyl, Q 6 haloalkyl, C,. t , hydroxy alkyl, C, 6 cyanoalkyl, C 6 io aryl, GH 0 heteroaryl, C 3 . 8 cycloalkyl, C 3 . 8 heterocycloalkyl and C 3 8 heterocycloalkenyl, wherein said Ci 6 alkyl, C 2 . 6 alkenyl, C;.
  • U heteroaryl, C 3 .g cycloalkyl, C 3 8 heterocycloalkyl, or C 3 8 heterocycloalkenyl is optionally substituted with 1 , 2, or 3 substitutents independently selected from halogen, CN, N,, NO 2 , OR a , SR 8 , C 6-I0 aryl, C 4 10 heteroaryl, C 3 8 cycloalkyl, C, 8 heterocycloalkyl, and C 3 . 8 heterocycloalkenyl.
  • R' is selected fiom C 6 alkyl, C
  • R 1 is C
  • R 1 is C t 6 alkyl, optionally substituted with one substituent selected from Q-io aryl, C 4 - I0 heteroaryl, C 3 . s cycloalkyl, C 1 .* heterocycloalkyl, and C 1 .* heterocycloalkenyl.
  • R' is is C 3 . ? cycloalkyl.
  • R' is cyclopropyl
  • R' is C
  • R' is C 6 . io aryl or C 4 .
  • R 1 is C 1 6 cyanoalkyl.
  • R' is C]. 6 haloalky!.
  • halogen is fluoro
  • R' is CF 3 .
  • R 2 and R 3 are independently selected from H, halogen, d. 6 alkyl, C 2 _ 6 alkenyl. C? 6 alkynyl. C]. 6 haloalkyl, C
  • R 2 and R 3 are independently selected from H, halogen, C
  • R 2 and R 3 are independently selected from halogen, Cu alkyl, and OR".
  • one of R 2 and R 3 is Ci ⁇ alkyl.
  • one of R 2 and R 3 is 0R ⁇
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 3-8 membered cycloalkyl ⁇ ng, said ring comprising 1-3 hetcroatoms selected from N, O and S, optionally substituted with 1 , 2, or 3 substituents independently selected from halo, C
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 3-8 membered cycloalkyl ⁇ ng
  • R 2 and R 3 together with the carbon atom to which they arc attached, join to form a 5-7 membered cycloalkyl ⁇ ng
  • R 1 and R 3 together with the carbon atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ⁇ ng, optionally substituted with 1, 2, or 3 substitucnts independently selected from halogen, Ci.., alkyl, C 2 ⁇ , alkenyl, C 2 .,, alkynyl, C b ., Q aryl, Ci 0 heteroaryl, C 3 . 8 cycloalkyl, C 3 , heterocycloalkyl, C 3 .
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ⁇ ng.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 6-membered heterocycloalky] ⁇ ng.
  • the 6-membered heterocycloalkyl ⁇ ng comprises 1 or 2 heteroatoms
  • At least one heteroatom is O.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 1.3-dioxan-2,2-diyl ring, 1.3-dioxolan-2,2-diyl, or tetrahydropyran-2,2-diyl ring.
  • R 4 is C(O)NR 6 R 7 .
  • At least one of R 6 and R 7 is H.
  • At least one of R 6 and R 7 is C,. 6 alkyl.
  • both of R 6 and R 7 are C
  • one of R 6 and R 7 is C 3 .g cycloalkyl, C 7 . u arylalkyl, or C 6 10 aryl
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ⁇ ng, optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, C,. o alkyl, C,. 6 alkenyl, C 2 . 6 alkynyl, CN, NO 2 , N 3 , 0R a , and SR a .
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ⁇ ng.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a pyrrolidinyl, morpholino, piperazinyl, or pipe ⁇ dinyl ⁇ ng.
  • R 4 is SO 2 NR 6 R 7
  • At leabl one of R 6 and R 7 is H
  • At least one of R 6 and R 7 is Ci 6 alkyl.
  • both of R 6 and R 7 are C
  • one of R 6 and R' is C 3 . 8 cycloalkyl, C 7 u arylalkyl, or C 6-I0 aryl.
  • R° and R 7 together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ⁇ ng, optionally substituted with 1 , 2, or 3 substituents independently selected from halogen.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a pyrrolidinyl, morpholino, piperazinyl, or piperidinyl ring.
  • R 4 is NR 8 C(O)R 9 or NR 8 SO 2 R 9 .
  • R 8 is H or C
  • R 9 is H, C
  • 8 heterocycloalkenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halogen, 0R a , cyano, amino, NO 2 , Cu alkyl, C 1 . 4 haloalkyl, Ci 6 hydroxyalkyl, C 3 g cycloalkyl, and C 3 . 8 heterocycloalkyl.
  • R 9 is Cu alkyl, Cu haloalkyl, or Cu hydroxyalkyl, each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, 0R a , C 3 . 8 cycloalkyl, and C 3 .g heterocycloalkyl.
  • R 9 is cycloalkyl or aryl.
  • R 9 is phenyl or cycloalkyl having 3-8 carbon atoms.
  • R 4 is C(O)C(O)NR 6 R 7 .
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a pyrrolidinyl, morpholino, piperazinyl, or piperidinyl ring.
  • R 5 is H, halo, Cu alkyl, Cu haloalkyl, C 1-6 hydroxyalkyl, Cu cyanoalkyl, CN, NO 2 , N 3 , 0R a , or SR a .
  • R 5 is H, halogen, or C M alkyl.
  • n O or 1.
  • n O
  • the invention includes a compound of Formula (I):
  • R' is C
  • cycloalkyl, C 1 ., heterocycloalkyl or C 3 . 8 heterocycloalkenyl is optionally substituted with 1, 2, or 3 substitutents independently selected from C 6 - ⁇ o aryl, C 4 .i 0 heteroaryl, C 3 . g cycloalkyl, C 3 . 8 heterocycloalkyl, C 3 . 8 heterocycloalkenyl, halogen, CN, N 3 , NO 2 , OR", SR a ;
  • R 2 and R 3 are independently selected from H, halogen, C
  • R 4 is C(O)NR 6 R 7 , C(O)C(O)NR 6 R 7 , SO 2 NR 6 R 7 , NR*C(0)R 9 , or NR 8 SO 2 R 9 ;
  • R 5 is H , halogen, or C M alkyl
  • R 6 and R 7 are independently selected from H, C ⁇ _s alkyl, d. 6 haloalkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C
  • R 8 and R 9 are independently selected from H, C
  • R 2 and R 3 arc independently selected from H, halo, CV 6 alkyl, C 2 . 6 alkenyl, C 2 . o alkynyl, C,. 6 haloalkyl, C 6 hydroxyalkyl, C 6 cyanoalkyl, C 6 . ⁇ aryl, C 6 - I o heteroaryl, C 3 . s cycloalkyl, C 8 heterocycloalkyl, C 3 .
  • R a , R b , R", and R f are each independently selected from H, C
  • 4 heterocycloalkylalkyl is optionally substituted with OH, cyano, amino, halo, C ⁇ . 6 alkyl, C 6 -Io aryl, Ci 4 arylalkyl, C4-10 heteroaryl, C 4 . ⁇ heteroarylalkyl, Cs cycloalkyl, or C 3 . 8 heterocycloalkyl;
  • R c and R d are independently selected from H, Cs > alkyl, C
  • R 4 when R 4 is SO 2 NR 0 R 7 , n is O, R 2 and R 3 , together with the carbon atom to which they are attached, join to form a 1 ,3-dioxan-2,2-diyl ring, and R 6 and R 7 , together with the carbon atom to which they are attached, join to form a pyrrolidinyl ring, R 1 is not alkyl substituted with NH 2 , CN, N 3 , bromo, or a 7-membered cycloalkyl ring optionally substituted by CN or C 6 cyanoalkyl.
  • the invention provides compounds of Formula II:
  • R' is C 6 haloalkyl, Ci ⁇ hydroxyalkyl, or C 6 cyanoalkyl.
  • R' is Ci -6 haloalkyl.
  • halogen is fluoro
  • R' is CF 3
  • one of R 2 and R 3 is C,. 6 alkyl.
  • one of R 2 and R 3 is OR a .
  • R 2 and R 3 together wilh the carbon atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 6-membered heterocycloalkyl ring.
  • the 6-membered helerocycloallcyl ring contains 1 or 2 heteroatoms.
  • At least one heteroatom is O
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a l,3-dioxan-2,2-diyl ring, l ,3-dioxolan-2,2-diyl. or tetrahydropyran-2,2-diyl ring.
  • R" and R 7 together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ⁇ ng.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a pyrrolidinyl, morpholino, piperaziny!, or piperidinyl ring.
  • the invention provides compounds of Formula III:
  • the invention includes a compound selected from Formulas IVa, FVb, and
  • R is C 1 ⁇ alkyl. optionally substituted with 1, 2, or 3 substituenls ..elected from C 6 - I O aiyl, C 3 g cycloalkyl, C 6-I0 heteioaryl and C 3 8 heterocycloalkyl
  • R is Ci 6 alkyl substituted with one substituent selected from C 6 , 0 aryl, C, 8 cycloalkyl, C 4 , 0 heteroaryl and C 3 8 heterocycloalkyl
  • Ci 6 alkyl is propyl
  • Cy is C 3 7 cycloalkyl
  • Cy is cyclopropyl
  • R 1 is C . 6 haloalkyl, C 1 * hydroxyalkyl, or Ci 6 cyanoalkyl.
  • R' is C, 6 haloalkyl
  • halogen is fluoro
  • R 1 is CF 3 .
  • one of R 3 and R 1 is C,. 6 alkyl.
  • one of R 2 and R 3 is OR a
  • R : and R 3 together with the carbon atom to which they are attached, join to form a 5-7 membered cycloalkyl ring.
  • R 2 ana R 1 together with the carbon atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a 6-membered heterocycloalkyl ring.
  • the 6-membered heterocycloalkyl ring comprises 1 or 2 heteroatoms.
  • At least one heteroatom is O.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a l ,3-dioxan-2,2-diyl nng, l,3-dioxolan-2,2-diyl, or tet ⁇ ahydropyran-2,2-diyl ring
  • R 6 and R 7 together w ith the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
  • R 6 and R 7 together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
  • R" and R 7 together with the N atom to which they are attached, join to form a pyrrohdinyl, morphohno, piperazmyl, or pipe ⁇ dmyl nng
  • the invention provides compounds of Formula V:
  • substituents of compounds of the invention are disclosed in groups or m ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • C 1 ⁇ 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 tha; 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- propy] and isopropyl), butyl (e.g., n-b ⁇ tyl, lsobuty ' , t-buryl), 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 , CIICl 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.
  • 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. Examp ' .ary 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 cither 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 sulfide substituent.
  • Example cycloalkyl groups include eycl ⁇ propyl, cyelobufyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadier.yl, cyclohcptat ⁇ cnyl. norbornyl, norpinyl, norcarnyl. adamantyl, and the like.
  • a "cycloalkylalkyl” group refers to an alky! group substituted by a eyeloalkyl group
  • An exemplary cycloalkylalkyl group includes, bul 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, poiycyclic (e.g., heteroaryl comprising 2, 3 or 4 fused rings) systems. Any ring- forming N atom m a heteroaryl group can also be oxidized to form an N-ox o moiety or can be functionahzed to form an N-functionahzed group (e.g. N-alkyl or N-aryl).
  • heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, py ⁇ midinyl, pyrazinyl, py ⁇ dazinyl, triazinyl, furyl.
  • quinolyl isoquinolyl, thienyl. linidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl. benzofuryl, benzothienyl, benzthtazolyl, isoxazolyl, pyrazolyl.
  • the heteroaryl group comprises from 2 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 nng-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.
  • a heteroarylalkyl refers to an alkyl group substituted by a heteroaryl group. An example of a heteroarylalkyl group is py ⁇ dylmethyl.
  • 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 iings) ring systems as well as spirocycles.
  • heterocycloalkyl groups include, but are not limited to, morpholmo, thi ⁇ morphohno, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2.3-dihydrobenzofuryl, 1.3-benzodioxole, benzo-l ,4-dioxane, pipendmyl, pyrrolidinyl, isoxazolidmyl. lsothiazohdinyl, pyrazolidinyl, oxazohdinyl, thiazolidinyl. imidazokdin ⁇ !, 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 phthahmidyl. 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- aiomatic portion.
  • moieties where one or more ring-forming atoms is substituted by 1 or 2 oxo or sulfide 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 heteroeyeloalkyl group further comprises 0 to 2 double bonds. In some embodiments, the heterocycloalkyl group comprises 0 to 2 triple bonds. As used herein, "heterocyeloalkylalkyl" 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 CF 3 and CF 2 CF 3 .
  • 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 m optically active or raecmic 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. Many geometric isomers of olefins, C-N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers arc contemplated m the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • 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 - imidie 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.
  • 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. For example, isotopes of hydrogen include tritium and deuterium.
  • compound as used herein is meant to include all stereoisomers, geometric losomers, tautomers. and isotopes of the structures depicted. All compounds, and pharmaceutical) acceptable salts thereof, are also meant to include solrated or hydra ted forms.
  • 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, cthanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17* 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, withm 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 presen: 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. Scheme 1
  • spiro oxindole sulf ⁇ namideb VIII
  • VT spiro oxindole
  • VII sulfonamide compounds
  • Alkylation of the oxindole nitrogen was accomplished using organohalides and organotosylates with K 2 CO 3 in DMF at 60° C, and produced invented compounds (VTII).
  • Oxmdole (XII) was eomerted to oxmdole sulfonamides (XIIT) using ClSO 3 H, followed b> reaction with various amines Deprotonation with LDA in THF followed by trapomg with acrylomt ⁇ le and warming to 23 °C produced the desired imented comrjounds (XIV).
  • oxindole sulfonamides (XXIII) were synthesized according to Scheme 10.
  • Tert- alcohol compounds (XXI) were chlorinated using SOCIi, and produced intermediate chloro compounds, winch were reduced with Zn/IIOAc/THF, and produced the desired invented compounds (XXIII).
  • Ceitain invented oxindole dimethylacetals were prepared according to Scheme 14 Isatm sulfonamides (1) were converted to the corresponding dimethylacetal compounds (XXIX) using MeOWp- TsOH. Alkylation or arylatton of the oxindole nitrogen proceeded using organohalides or organotosylates in therailnce Of K 2 CO 3 in warm DMF, and produced the N-functionahzed dimethylacetal compounds (XXX)
  • oxindote acetal amide compounds were prepared according to Scheme 17. Iodo-isatin (XLII) is converted to the corresponding cyclic acetal using 1 ,3 -propanediol andp-TsOH in benzene solvent with heating. Pd-catalyzed carbonylation of the aryliodide followed by trapping with MeOH produced the corresponding methyl ester compound (XLIV). Alkylation or arylation of the oxindole nitrogen ws accomplished organohalides and K 2 CO 3 m DMF solvent with heating and produced corresponding N-functionalized acetal compounds (XLV). Saponification of the ester compounds produces the corresponding carboxylic acid compounds (XLVI). The invented amide compounds (XLVII) were produced from reaction of amines and peptide coupling agents, EDCI'HOBt.
  • N-Aryl oxmdole compounds were prepared from corresponding 1'- hydro-5'-(pyrrolidin-1-ylsulfonyl)spiro[[1,3]dioxane-2.3'-indolin]-2'-one compounds using aryl boronie acids (Ar is a substituted aryl), copper acetate, amine bases such as Lt 3 N m aprotic solvents such as CH 2 Cl; (Scheme 19) .
  • lodooxindolc acctai (XLIII) was alkylated using alkyl or benzylic halides in the presence of a weak base such as K 2 CO 3 or Cs 2 COi in a polar aprotic solvent such as DMF, DMSO or acetone solvent, and produced N-alkyl- or N-benzyl-functionalized acetal compounds (LLX).
  • Palladium catalyzed carbonylative animation was carried out using piperidine to produce amide oxoindole acetal compounds (LX).
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or ' 3 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.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or ' 3 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry
  • chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • 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 the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • Suitable solvents can be substantially non-rcacti ⁇ c 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.
  • An example method includes fractional recrystallization using a "cbiral resolving acid" which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystalliza ⁇ ' on methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacet)'ltartaric acid, dibenzoyl tartaric 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).
  • 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.
  • Modulation is meant to refer to an ability to increase or decrease aclivity of an the receptor. Modulation can occur in vitro or in vivo. Modulation can further occur in a cell.
  • 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.
  • contacting refers to bringing together of indicated moieties m an in vitro system or an in vivo system.
  • "contacting" a compound of the invention with the CB2 receptor 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 CD2 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-substitutcd 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, vetc ⁇ narian, 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.
  • 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
  • inhibiting the disease for example, inhibiting a disease, condition or disorder
  • 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, sjTio vial 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 oxindolc 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 m 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 deliver, 1 can include topical administration (eye drops), subconjunctival, periocular or mtravitreal 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.
  • 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.
  • This invention also includes pharmaceutical 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 cxc ⁇ ient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient when it 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,
  • the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or m 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.
  • suitable exeipients 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.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending agents such as methyl- and propylhydroxy-benzoates
  • sweetening agents and flavoring agents.
  • the 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.
  • 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, l he term "unit dosage forms 1' 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. It will be understood, however, that 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.
  • 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 m 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.
  • 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.
  • the amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like.
  • 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 seventy 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 lyophihzed. the lyophihzed preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 1 1 , more preferably from 5 to 9 and most preferably from 1 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 adrninstration. 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.
  • the invention will be described in greater detail by way of specific examples.
  • 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 7 MS ran time was 5.5 minutes.
  • Compounds were diluted to -1.0 mg/mL 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.
  • Step 2 3-[2'-Oxo-5' ⁇ pyrrolidin-l-yhulfonyl)spiro ⁇ t ⁇ clohexane-l,3'-ind ⁇ l/ ⁇ l '(2 ⁇ )-ylJpropanenitriIe
  • Step 2 3-[3-Cyclohexyl-2- ⁇ xo-5-(p ⁇ rolidin-l-ylsulfonyl ⁇ -2y3-dih ⁇ o-lU-indol-3- ⁇ ilpr#panenitrile
  • Example 12 A procedure similar to that of Example 12, using different G ⁇ gnard reagents, provided Examples 13-20. The compounds and their analytical data are shown in Table 1.
  • Example 21 ⁇ procedure similar to that of Example 21 provided Examples 22-30.
  • the compounds and their analytical data are shown in Table 2.
  • Example 44 A procedure similar to that of Example 43, using different alkyl halides, provided Examples 44- 59.
  • the compounds and their analytical data are shown in Table 4.
  • Step 2 5 '-A ⁇ nm ⁇ irolll,3]dioxane-2,3 '-indolinJ-2 '-one
  • Step I neopentyl 1 '-(cycl ⁇ propyI ⁇ nethyl)-2 '-oxo-1 ',2 '-dihydrospiro[l,3 ⁇ dioxane-2,3 '-mdolej-5 'sulfonate
  • DMF dimethylfo ⁇ namide
  • Step 4 l '-(cyclopropylmethyl)-4'-[oxo(piperidin-l-yl)acetyl] ⁇ iroll,3-dioxane-2,3'-indoll-2'(l ⁇ )-one
  • Example 161 A procedure similar to that of Example 161 , using different alkyl halides, provided Examples 162 - 166.
  • the compounds and their analytical data are shown in Table 12.
  • Step 1 7-(piperidin-l-ylcarhonyl)-lH-ind ⁇ le-2,3-dione
  • Step 2 7'-(piperidin-l-ykarb ⁇ nyl)spiro[l,3-di ⁇ xane-2,3 '-ittdolJ-2 '(I 'H)-one
  • Example 167 A procedure similar to that of Example 167, using different alkyl hahdes, provided Examples 168 - 172, The compounds and their analytical data are shown in Table 13.
  • Step 2 r-(cycl()propylmeth ⁇ l)-4'-(piperidm-l- ⁇ lcarbonyl) ⁇ iro(l,3-dioxane-2,3'- ⁇ ndol]-2 '(l ⁇ )-one
  • Step l 6 '-iodospiro(l,3-dioxane-2,3 '-indoIJ-2 '(I 'H)- ⁇ ne
  • Step 3 6 '-(piperidin-l-ylcarbonyl)spir ⁇ [l,3-dioxane-2,3 '-indolJ-2 '(I ⁇ )-one
  • Step 3 / '-(cyclopropylmethyl)-2 '-oxo-1 ',2 '-dihydrospiro[l,3-dioxolane-2,3 '-indole J -5 'suifonyl chloride
  • Step 4 l '-( ⁇ ciopropylmethyl)-5'-f(2,6-dimethylpiperidin-l-yI)sulfo» ⁇ ijsph" ⁇ fl,3-di ⁇ xolane-2,3'-ind»Ij-2'(r one
  • Example 185 A procedure similar to that of Example 185, using different amines, provided Examples 186- 196.
  • the compounds and their analytical data are shown in Table 16.
  • Examples 202-207 were prepared from 5 '-(piper dm-1-ylsullbnyl)spiro[1.3-dioxanc-2,3'-indolJ- 2'(l ⁇ )-one (prepared m procedure similar to Example 151) according to the procedure for Example 198,
  • Examples 210-215 were prepared from 5'- ⁇ pipe ⁇ dm-l ,3-dio ⁇ olane -2,3'- indol]-2 ( 1 II)-one and different alkjl hahdes according to the procedure for Example 198 The compounds and their analytical data are shown m Table 19 Table 19 Compounds Prepared According to the Procedure of Example 198
  • Step 3 4-chIoro-N-(l '-(cyclopropylmethyl)-2 ' ⁇ oxospiro[[l,3]dioxane-2,3 '-indolineJ-5 '-yljbenzenesulfonamide
  • Example 21 A procedure similar to that of Example 221, using different boronic acids, provided Examples 221 - 259 The compounds and their analytical data are shown m Table 21 Table 21 : Compounds Prepared According to the Procedure of Example 221.
  • Step 2 5'-(3-Fluoropyrrotidin-l-ytsutfonyi)spiro([l ⁇ 3]dioxane-2,3'-indolin]-2'-one
  • Step 2 S'-(3J-Diflu ⁇ ropyrrolidin-l-ykulfonyl)spiro([l,3]dioxane-2,3'-indotin]-2'-one
  • Step 3 5'-(3,3-Difluoropyrrolidin-l-ylsulf ⁇ nyI)-] '-pIienylspir ⁇ //l,3Jdi ⁇ xane-2,3'-lndolinJ-2'-o ⁇ e
  • Example 271 A procedure similar to that of Example 271 , using different borome acids, provided Examples 272 - 274. The compounds and their analytical data are shown in Table 23. Table 23: Compounds Prepared According to the Procedure of Example 271.
  • Example 275 A procedure similar to that of Example 275, using different boronic acids, prouded Examples 276 - S ⁇ The compounds and their analjtical data are shown m Table 24 Table 24: Compounds Prepared According Io the Procedure of Example 275.

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Abstract

Provided are 3-substituted oxindole derivatives which are agonists of the CB2 receptor, pharmaceutical compositions containing the same, and methods of treatment related to CB2-mediated disorders (e.g., pain, cancer etc.) using the 3-substituted oxindole derivatives and compositions described herein.

Description

SUBSTITUTED OXINDOL CB2 AGONISTS FOR PAIN TREATMENT
BACKGROUND
CB 1 and CB2 receptors, two subtypes of the cannabinoid receptor, both belong to the G-protein- coupled receptor (GPCR) superfamily The CB 1 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., in 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 It has been known that 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 descπbed by Malan et al., in 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 compounds disclosed herein provide a solution to this need.
SUMMARY OF THE INVENTION In one aspect, the invention relates to a compound of Formula I:
or pharmaceutically acceptable salts thereof, wherein the variables are defined herein.
In another aspect, the invention relates to a pharmaceutical composition comprising one or more of the above-described substituted oxmdole compounds of the invention, oi pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner.
In another aspect, the invention relates to a method of treating a CB2-tnediated 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 disordeis include, but are not limited to, pain (such as chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), osteoarthritis, atherosclerosis, osteoporosis, and cancer (e g , glioma)
In another aspect, the invention relates to a compound of the invention, or pharmaceutically acceptable salt thereof, for use in therapy In another aspect, 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) In another aspect, 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 details of one or more embodiments of the invention are set forth in the accompanying the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides substituted oxindole compounds that are CB2 agonists having Formula I
Figure imgf000003_0001
I or pharmaceutically acceptable salts thereof, wherein:
R1 is selected from Q.6 alkyl, C2^ alkenyl, C2.6 alkynyl, C|.6 haloalkyl, C|.6 hydroxyalkyl, C|.6 cyanoalkyl, C4.|0 aryl, C6.ιo heteroaryl, C3.8 cycloallcyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl, C(O)ORa, C(O)Rb, C(0)NRcRd, C^NR^NR^, S(O)Ra, S(O)NRcRd, S(O)2R6 and S(O)2NRcRd, wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl comprising 1-4 heteroatoms selected from N. O and S, and wherein said C,.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C6.,0 aryl, C4-I0 heteroaryl, Cj.8 cycloalkyl, C3.8 heterocycloalkyl, and C3.8 heterocycloaikenyl, is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, N3, NO2. 0Ra. SR", C(O)OR3, C(O)Rb, C(0)NRcRd, 0C(0)Rb, OC(O)NRcRd, NRcRd, NReC(O)Rb, NReC(O)NRcRd, NR'C(0)0Ra, S(O)Rb, S(O)NRcRd, S(O)2Rb, NReS(O)2Rb, and S(0)2NRcRd;
R2 and R3 are independently selected from H, halogen, C, 6 alkyl, C2 6 alkenyl, C2.6 alkynyl, Ci-6 haloalkyl, C,^ hydroxyalkyl, CN6 cyanoalkyl, C6.ιo aryl, C4.l0 heteroaryl, C3.8 cycloalk>'l, C3.g heterocycloalkyl, C3.8 heterocycloalkenyl, CN, NO2, OH, 0Ra, SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, OC(O)Rb, 0C(0)NRrRri, NR°Rd, NReC(0)Rb, NReC(0)NRcRd, NReC(0)0Ra, S(O)R0, S(O)NRcRd, S(O)2Rb, NReS(O)2Rb. and S(O)2NRcRd, wherein said C1^ alkyl, C2 6 alkenyl, C2 6 alkynyl, C6-I0 aryl, C4.ιo heteroaryl, C3.g cycloalkyl, C3.g heterocycloalkyl, and C3.? heterocycloalkenyl is optionally substituted with 1 , 2, or 3 substitutents independently selected from halogen, CN, NO2, N3, C6-Io aryl, C4-I0 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.3 heterocycloalkenyl, 0Ra, SRa, C(0)Rb, C(0)NRcRd,
2 C(O)OR3, 0C(0)Rn, 0C(0)NRcRα, NRcRd, NReC(0)Rb, NR£C(0)NRcRd, NReC(0)0Ra, S(0)Rb, S(0)NRuRJ, S(0)2Rb, NReS(O)2Rb, and S(0)2NRcRd, provided that at least one of R2 and R3 is other than H;
R2
or R2 and R1 together with carbon atoms to which they are attached, join to form a
Figure imgf000004_0001
group or a C=O group; or R2 and R3, together with the carbon atom to which they are attached, join to form a 3-8 membered cycloalkyl nng or 3-8 membered heterocycloalkyl πng, said heterocycloalkyl nng comprising 1-3 heteroatoms selected from N, O and S, each πng optionally substituted with 1 , 2. or 3 substituents independently selected fiom halogen, C^ alkyl, C2 6 alkenyl, C2 6 alkynyl, C6 io aryl, Gn0 heteroaryl, C3 s cycloalkyl, C8 heterocycloalkyl. Q 8 heterocyclo-alkenyl, CN, NO2, N3, 0Ra, SRa, C(0)Rb, C(0)NRcRd, C(0)0R\ 0C(0)Rb, 0C(0)NRcRd, NRcRd, NReQ0)Rb, NReC(0)NRcRd, NR6C(O)OR8, C(=NR )NRrRd, NReC(=NRf)NRcRd, S(O)Rh, S(O)NRcRd, S(O)2Rb, NR6S(O)2R", and S(O)2NRcRd, wherein said C1 6 alkyl, C;^ alkenyl, C2 6 alkynyl, C6 ,0 aryl, C, ,0 heteroaryl, C3 s cycloalkyl, Cs heterocycloalkyl, and C8 heterocycloalkenyl is optionally substituted with 1, 2, or 3 substitutents independently selected from CN, NO2, 0R\ C6.,o aryl, and Ci0 heteroaryl;
R4 is selected from C(O)NR6R7, SO2NR6R7, NR8C(O)R9, NR8SO2R9 and C(O)C(O)NR6R7;
R5 is selected from H, halogen and Q 6 alkyl.
R6 and R7 are independently selected from H, Ci 6 alkyl, C1^ haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C6-I 0 aryl, Cm heteroaryl, C3 8 cycloalkyl, C3 8 heterocycloalkyl, C3.8 heterocycloalkenyl and C,.6 hydroxyallcyl, wherein said Cu alkyl C, 6 haloalkyl, C2 6 alkenyl, C2^ alkynyl, C6 10 aryl, C4 10 heteroaryl, C8 cycloalkyl, C3 8 heterocycloalkyl, C3.? heterocycloalkenyl and Ci 6 hydroxyalkyl is optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from OH, cyano, amino, halo, C|.6 alkyl, C6 ,<, aryl, and C4-10 heteroaryl; or R6 and R7, together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring, each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C alkyl, C2 6 alkenyl, C2 6 alkynyl, C6 haloalkyl, C0 aryl, C4.10 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl, C1., hydroxyalkyl, CN, NO2, N3. 0R\ SRa, C(0)Rb, C(0)NRcRd, C(0)0Ra, 0C(0)Rb. 0C(0)NRcRd, NRcRd, NReC(0)Rb, NRcC(0)0Ra, C(=NRf)NRcRd, NReC(=NRf)NRcRd, S(O)Rb, S(O)NR:Rd, S(O)2Rb, and S(0)2NRcRd, wherein said C1.* alkyl, C,.« haloalkyl, C2^ alkenyl, C2.6 alkynyl, C6.|0 aryl, C4.|0 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl. C3.8 heterocycloalkenyl or C6 hydi oxyalkyl is optionally substituted with 1 , 2, 3 4, or 5 substituents independently selected from 0Ra, cyano, ammo, halo, NO2, Cu alkyl, C6-Io aryl, Cm heteroaryl, C8 cycloalkyl, C, % heterocycloalkyl and C8 heterocycloalkenyl,
R* and R9 are independently selected from H, C1-O alkyl. C6 haloalkyl, C2 6 alkenyl, C6 alkynyl, C1 1 hydroxyalkyl, C1 6 alkyl, C2 6 alkenyl, C2 6 alkynyl, C, 6 haloalkyl, C6 10 aryl, d !0 heteroaryl, C3.g cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl, wherein said C|.6 alkyl, Q-6 haloalkyl, C2.6 alkenyl, or C2.6 alkynyl, Ct.6 alkyl, C2-6 alkenyl. C2.6 alkynyl, Ct.6 haloalkyl, C6-I0 aryl, C4.|0 heteroaryl, C3. g cycloalkyl, C3.g heterocycloalkyl or Q.g heterocycloalkenyl is optionally substituted with 1 , 2, 3, 4, or 5 substirucnts independently selected from halo, OR\ cyano, amino, NO2, C|.6 alkyl, C2.6 alkenyl, C2.ft alkynyl, C|.6 haloalkyl, Ct.6 hydroxyalkyl, C|.6 cyanoalkyl, C,.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, Ci.6 haloalkyl, Q,.ιo aryl, C4- I0 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl and C3.8 heterocycloalkenyl; at each occurrence, R\ Rb, Rc and Rf are independently selected from II, C1^ alkyl, C|.6 haloalkyl, C2* alkenyl, C2.6 alkynyl, Ci-* haloalkyl, Cn.10 ar>'l, C4.n1 heteroaryl, C3.8 cycloalkyl, C3.g heterocycloalkyl, C3.8 heterocycloalkenyl C7-M arylalkyl, C4-K heteroarylalkyl, C5.|2 cycloalkylalkyl and C5.|2 heterocycloalkylalkyl. wherein said C|.6 alkyl, C,.6 haloalkyl, C2^ alkenyl, C2.6 alkynyl, C6- I0 aryl, C4.:o heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl C7.14 arylalkyl, C4.14 heteroarylalkyl, C5-ι? cycloalkylalkyl or C5-I2 heterocycloalkylalkyl, is optionally substituted with 0Ra, cyano, amino, halo, Q-6 alkyl, C6-I0 aryl, C6-I0 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl C7.u arylalkyl, C4.14 heteroarylalkyl, C5.π cycloalkylalkyl and Cs.12 heterocycloalkylalkyl; at each occurrence. Rc and Rc are independently selected from H, C|.6 alkyl, C|.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C6-I0 aryl. C4.10 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl C7.|4 arylalkyl, C4. μ heteroarylalkyl, C5.12 cycloalkylalkyl and C5.12 heterocycloalkylalkyl, wherein said C,.6 alkyl. C|.ή haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C6.10 aryl, C4-10 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl C7.14 arylalkyl. C4.i4 heteroarylalkyl, C5.ι2 cycloalkylalkyl or C5.ι2 heterocycloalkylalkyl. is optionally substituted with OH, cyano, amino, halogen, Q 6 alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd, together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring, each optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, C|.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C6-Ic aryl, C6-Io heteroaryl, C3.8 cycloalkyl, C3^ heterocycloalkyl, C3.8 heterocycloalkenyl C^4 arylalkyl, Gn4 heteroarylalkyl, C5.|2 cycloalkylalkyl and C5-U heterocycloalkylalkyl, C,.» haloalkyl, CN, NO2, N3, 0R\ SRa, C(O)R2, C(O)NR0R", C(O)OR3, OC(O)R3, OC(O)NRcRd, NRcRd, NR11C(O)R", NR6C(O)NR1R11, NReC(0)0Ra, C(=NRf)NRςRd, NRcC(=NRf)NRcRd, S(O)R8, S(O)NR1Rb, S(O)2R8, NReS(0)2Rs, and S(O)2NR8R"; halogen is selected from F, Cl, Br and I; and n is O, I , 2. or 3.
According to one embodiment, the invented compounds selected from:
3-[2,3-dioxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro- l//-indol-l -yljpropanenitπle;
3-[2-oxo-5-(pyrrohdin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1-yl]propanenitrile;
3-[2'-oxo-5'-(pyrrolidin-l -ylsulfonyl)spiro[cyclohexane-1.3'-indol]-r(2l/:f)-yl]propanenitrile;
3,3',3"-[2-oxo-5-(p>τroIidin- l -ylsulfόnyl)-2,3-d]hydro-l//-indole-1,3,3-tπyl]tπpropanenitrile;
3-[3l-benzyl-2-oxo-5-(pyrrolidin- l -ylsulfonyl)sp:ro[indole-3,5'-[1,3]oxazolidin]-l(2//)-
4 yl]propanenitπle:
3-[3-hydroxy-3-(4-hydroxybutyl)-2-oxo-5 -(pyrrolidin- 1 -ylsulf onyl)-2,3-dihydro- 1 //-indol- 1 - yljpropanenitπle;
3-[2 -oxo-5 -(pyrcolidin- 1 -y lsul fony l)-3 ',4',5 ',6'-tetrahydrospiro[indole-3 ,2 -pyran]- 1 (2H)- yljpropanenitrile,
S-P-cycIohcxyl-S-hydroxy^-oxo-S-φyrrohdin-l -ylsulfonyO^^-dihydro-l H-indol-l - yl]propanenitrile,
3-[3-butyl-3-hydroxy-2-oxo-5-(pyπolidin-1-y]sulfonyl)-2,3-dιhydro-l//-indυl-1- yljpropanenitnle,
3-[3-hydroxy-3-isobutyl-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-d)hydro-l/f-indol-1- yl]propanenitnte; 3-[3-hydroxy-3-isopropyl-2-oxo-5-(pyπOlidin-1-ylsulfυnyl)-2,3-dihydrϋ-l//-indol-1- yljpropanenitnle;
3-[3-cyclopropyl-3-hydroxy-2-oxo-5-(pyrrohdin- 1 -ylsulfonyl)-2,3-dihydro- l//-indol- 1 - ylipropanenitnle;
3-[3-cyclυpenlyl-3-hydroxy-2-oxo-5-(pyττolidin-1-ylsulfonyl)-2,3-dιhydro-l//-ιndol-l - yl]propanenitrile;
3-[3-hydroxy-2-oxo-3-phenyl-5-(pyrrolidm- l -ylsulfonyl)-2,3-dihydro-l//-indol-l - yljpropanenitrile;
3-[3-ben7yl-3-hydroxy-2-oxo-5-(pyrrohdin-1-ylsulfonyl)-2,3-dihydro-l//-indol-l - yl]propancnitrile; 3-[3-hydroxy-2-oxo-3-(2-phenylethyl)-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l //-indol-1- yljpropanenitrile;
3-[3-cyclohexyl-3-methoxy-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-l - yl]propanenitrile;
3-[3-methoxy-3-methyl-2-oxo-5-(pyrrolidin-l -ylsulfony])-2,3-dihydro-l//-mdol-1- yl]propanenitnle,
3-[3-butyl-3-methoxy-2-oxo-5-(pyrrolidin-1-ylsulfonyl)-2,3-dιhydro-l//-indol-1- yl]propanenitnle,
3-[3-isobut>'l-3-methoxy-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1- yl]propanenitrιle, 3-[3-isoprop>l-3-methoxy-2-oxo-5-(pyτrohdin-l -ylsulfonyl)-2,3-dihydro-l//-ιndol-l - yl]propanenitnle,
3-[3-cyclopropyl-3-methoxy-2-oxo-5-(pyrrolidin-1-yIsulfonyl)-2,3-dihydro-l//-indol- l - yl]propanemtrile,
3-[3-cyclopentyl-3-methoxy-2-oxo-5-(pyττolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1- yllpropanemtrile, 3-r3-methoxy-2-oxo-3-phenyl-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihydro-l//-indol-1- yl]propanenitrile;
3-[3-benzyl-3-methoκy-2-oxo-5-(pyrrolidιn-1-ylsulfonyl)-2!3-dihydro-l//-indol-1- yljpropanenitnle: 3-[3-methoxy-2-oxo-3-(2-phenylethyl)-5-(pyiτohdin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1- yljpropaπenitπle,
3-[3-cyclohexyl-2-oxo-5-(p>τrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-l -ylJpropanenitπle, 3-[3-butyl-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-l -yllpropanenιtπle; 3-[3-isobutyl-2-oxo-5-(pyrro]idin-l -ylsulfonyl)-2,3-dihydro-l//-indol-l -yl]propanenilπle; 3-[3-isopι opyl-2-oxo-5-(pyrrolid]n-1-ylsulfonyl)-2,3-dihydro-1H-indol-1-y]]propanenitπle,
3-l3-ter/-butyl-2-oxo-5-(pyrrohdin-l -ylsulfonyl)-2,3-dihydro-1H-indol- 1 -yljpropanenitπle, 3-[3-cyclopropyl-2-oxo-5-(p>τrolidin-1-ylsulfonyl)-2,3-dihydro-l//-indol-1-yl]propanenitnle; 3-[3-cyclopentyl-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-l -yl]propanenitπle, 3-[2-oxo-3-phenyl-5-(pyrrolιdin-1-ylsulfonyl)-2,3-dihydro-l//-indol-l -yl]propaπenitnle, 3-[3-benzyl-2-oxo-5-(pyiτolidin-1-yIsulfonyl)-2,3-dihydro-l//-indol-1-yl]propanenitrile;
3-f2-oxo-3-(2-phenylethyl)-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-l -yl]propanenitrile; 3-[3-ter?-butyl-3-chloro-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1- yljpropanenitrile;
3-[3-?ert-butyl-3-fluoro-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1- yljpropanenitπle; r-but-3-yn-1-yl-5'-(pyrrolidιn-l -ylsulfonyl)spiro[ l ,3-dioxane-2.3'-indol]-2'(rH)-one; 1 '-but>'l-5'-(pyrrolidin-l -ylsultonyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 'A)-one; 1 '-pent-4-yn- 1 -y l-5'-(pym)lidin-l -ylsulfonyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 17/)-one, r-prop-2-yn-l -yl-5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l '//)-one, 1 '-but-3-en-l -yl-5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r//)-one;
] '-ethyl-5'-(pyτrolidin-l -ylsulfonyl)spiro[ 1,3-dioxane-2,3'-indol]-2'(170-one; l '-(4-fluorobutyl)-5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r/y)-one; ] '-(2-fluoroethyl)-5'-(pyπOlidin-l -y]sulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r//)-one, r-(2-cyclohexylethyl)-5'-(pyrrohdin-1-ylsulfonyl)spiro[1,3-dioxanc-2,3'-indolJ-2'(l '//)-one; 1 '-(2-phenylethyl)-5'-(pyrrolidin- 1 -y lsulfonyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 Η)-one; r-(2-methoxyethyl)-5'-(pyrrolidin-1-ylsulfonyi)spiro[1,3-dioxane-2,3'-indol]-2l(r//)-one; l '-[2-(l/!-mdo]-3-yl)ethyl]-5'-(pyrrohdm-1-ylsυlfonyl)spiιo[ l ,3-dioxane-2,3'-indol]-2'(r//)-one; r-[(2-θλθ-l ,3-oxazolιdm-5-yl)methyl]-5'-(pyrro]idin-l -ylsulfonyI)spiro[ 1,3-dioxane-2,3'-indol]- 2'(l '//)-one; r-(2)3-dihydro-l )4-benzodioxin-2-ylmethyl)-5'-(pyiτolιdin-1-ylsulfonyl)spiro[1,3-dioxane-2.3'- ιndol]-2'( l 'H)-one, r-[4-(4-;er/-butylphen>l)-4-oxobutyl]-5'-(pyrrolidin-l -ylsuIfonyl)spirot l ,3-dioxane-2,3'-indol]- 2'(l'//)-oπe; 1 '-f4-(2,4-dimethoxyphenyl)-4-oxobutyI]-5 '-(pyrrohdin- 1 -ylsulfonyl)spiro[ 1 ,3-dioxane-2,3'- ιndol]-2'(lW)-one, tert-butyl {3-[2'-oxo-5'-(pyrrolidin-l -ylsulfonyl)spiro[1,3-dio\ane-2,3'-indol]-l '(27/)- yl]propyl}carbamatc, 3-?ert-butyl-l -but-3-yn-1-yl-3-fluoro-5-(pyrrohdin-l -ylsulfonyl)-1,3-dih>dro-2//-indol-2-one, l-butyl-3-/^/-butyl-3-nuoro-5-(pyrrohdin-1-ylsalfonyl)- l ,3-dihydro-2//-indol-2-one, 3-^rf-butyl-3-fluoro-l -pent-4-yn-l -yl-5-(pyrrolidin-l -ylsulfonyl)-1,3-dihydro-2//-indol-2-one, 3-/ert-but>l-3-fluoro-l -prop-2-yn- l -yl-5-(p>τrolidin-l -ylsulfonyl)- l ,3-dihydro-2//-mdol-2-one, l-but-3-en-1-yl-3-/erf-butyl-3-fluoro-5-(pyrrohdin-1-ylsulfonyl)-l ,3-dihydro-2//-indol-2-oπe, 3-/4'rt-butyl-l -ethyl-3-fluoro-5-(pytτolidin-1 -ylsulfonyI)-l ,3-dihydro-2//-indol-2-one,
3-fert-butyl-3-fluoro-1-methyl-5-(pyrrolidin-l -ylsulfonyl)-l ,3-dihydro-2//-indol-2-one, 3-tert-butyl-3-fluoro-l -(4-fluorobutyl)-5-(pyrrohdin-1-ylsulfonyl)-l ,3-dihydro-2//-indol-2-one, 3-f^r/-butyl-3-fluoro-l -(2-flυoroethyl)-5-(pyrrolidin-l -ylsulfonyl)-l ,3-dih>dro-2//-indol-2-oπe, 3-tert-butyl-l -(2-cyclohexylethyl)-3-fluoro-5-(pyττolidin-1-yIsulfonyl)-1,3-dihydro-2//-indol-2- one,
3-^r/-butyl-3-fluoro-l -(2-phenylethyl)-5-(pyrrolidin-l -ylsulfonyl)-l ,3-dihydro-2//-indol-2-one, 3-rer/-butyl-3-fluoro-l -(2-meLhoxyethyl)-5-(pyrrυlidin-l -ylsulfonyl)-l ,3-dihydro-2//-indol-2- one.
3-/ert-butyl-3-fluoro-l -[2-( lh-mdol-3-yl)ethyl]-5-(pyrrolidin- 1 -ylsulfonyl)-l ,3-dihydro-2//-indol- 2-one,
3-/ert-butyl-3-πuoro-l -[(2-oxo-l ,3-oxazolidin-5-yl)methyl]-5-(pyrrolιdιn-l -ylsulfonyl)-l ,3- dihydro-2//-ιndol-2-one,
3-/e//-butyl-l -(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-3-fluoro-5-(pyrrohdin-1-ylsulfonyl)- 1 ,3-dihydro-2//-indol-2-one. 3-tert-butyl-l -[4-(2,4-dimethoxyphenyl)-4-oxobutyl]-3-fluoro-5-(pyπolidin-1-ylsulfonyl)-l ,3- dihydro-2//-ιndol-2-onc,
/ert-butyl {3-f3-/ert-butyl-3-fluoro-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l/f-indol-l - y]]propyl } carbamate, l -but-3->τi-l -yl-3,3-dimethoxy-5-(pyrrolidm-l -ylsulfonyl)-1,3-dihydro-2//-indol-2-one, r-but-3-yn- l -yl-n,«-dimethyl-2'-oxo- r.2'-dihydrospiro[l ,3-dioxane-2,3'-ιndole]-5'-suIfonamιde, r-but-S-yn- l -yl-n.rt-diethyW-oxo^ '^'-dihydrospirotl^-dioxane^^'-indolej-S'-sulfonamide, l '-but-3-yn-1-yl-n-cyclohexyl-M-isυpropyl-2'-oxo-r,2'-dihydrosptro[1,3-dioxane-2,3'-indole]-5'- sulfonamide jV,N-dibenzyl-r-but-3-yn- l-yl-2'-oxo-l',2'-dihydrospiro[l ,3-dioxane-2,3'-indole]-5'-sulforam!de, r-but-3-yn-1-yl-«-methyl-2'-oxo-r,2'-dihydrospiro[ 1,3-dioxane-2,3'-indole]-5'-sulfonamide r-but-Vyn-1-yl-21-oxo-«-(2-thienylmethyl)-l ',2'-dihydrospiro[l ,3-dioxane-2)3l-indole]-5'- sulfonamide, 1 '-but-3 -yn- 1 -yl-rt-( 1 -naphthylmethy I)-2'-oxo- 1 ',2'-dihydrospiro{ 1 ,3-dioxane-2,3 '-indole]-5 '- sulfonamide,
N-{ 1 //-benzimidazol^-ylmethyl)- 1 '-but-3-yn- 1 -yl-2'-oxo-r,2'-d]hydrospiro[ 1 ,3-dioxane-2,3'- lndole] -5 '-sulfonamide, r-butyl- yv,jV -dimethyl-2'-oxo-r,2'-dιhydrospiro[1,3-dioxane-2,3'-indole]-5'-sulfonamide,
1 '-butyl- ,V,N -diethyl -2'-OXO-I '^'-dihydrospirof l^-dioxane^'-indolej-S'-sulfonarmde; r-butyl-w-cyclohexyl-N-isopropyl^'-oxo-l '^'-dihydrospirotl.S-dioxane^^'-indoleJ-S'- sulfonamide;
N^V-dibenzyl-r-butyl-2'-oxo-r,2'-dihydrospiro[l ,3-dioxane-2,3'-indole]-5'-sulfonainιde, r-butyl-jV-methyl-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indole]-5'-sulfonamide, r-butyl-2'-oxo-n-(2-thienylmethyl)- r,2'-dihydrospiro[1,3-dioxane-2,3'-indole]-5'-sulfonamide, r-butyl-^ l-naphthylmethyO^'-oxo-l'^'-dihydrospirof l J-dioxane^^'-indolej-S'-sulfonamide, ^-(l/Z-benzimidazol^-ylmethyl^r-butyl^'-oxo-r^'-dihydrospirotl^-dioxane^^'-indolej-S'- sulfonamide, 3-fert-butyl-l -but-3-yn-l -yl-3-fluoro- N,N -dimethyl-2-oxoindohne-5-sulfonamide;
3 -tert-bυty\-\ -but-3 -jτi- 1 -yl- N 'ft -d iethyl-3 -fluoro-2-oxoindol ine-5-sul fonamide, 3-^^-butyl-l -but-3-yn-l -yl-N-cyclohexyl-3-fluoro-n-isopropyl-2-oxoindoline-5-sulfonamide, N,N -dibenzyl-3-/ert-butyl-l -but-3-yn-l -yl-3-fluoro-2-oxoindoline-5-sulfonamide, 3-tert-butyl-1-but-3-yn-1-yl-3-fluoro-.V-methyl-2-oxoindoline-5-sulfonamide, 3-ter/-butyl-l -but-3-yn-l -yl-3-fluoro-2-oxo-N-(2-thienylmethyl)indohne-5-sulfondmide,
3 -/erf-butyl -1 -but-3-yn-l -yl-3-fluoro-N-( l-naphthylmethyl)-2-oxoindoline-5-sulfonatτude; jV-(l//-benzimidazol-2-ylmethyl)-3-<ert-butyl-1-but-3-tyn-1-yl-3-fluoro-2-oxomdoline-5- sulfonamide, l-bulyl-3-/^rt-butyl-3-fluoro- iV,N -dimethyl-2-oxoιndohne-5-sulfonamide, l-butyl-3-/e/t-butyl- .\r,N-diethyl-3-fluoro-2-oxoindoline-5-sulfonamide, l -butyl-3-/ert-butyl-N-cyclohexyl-3-fluoro-«-isopropyl-2-oxoindohne-5-sulfonamide; N,N-diben2yl-l -butyl-3-/ert-butyl-3-fluoro-2-oxoindoline-5-sulfonamide. l -butyl-3-to/-butyl-3-fluoro-IV-methyl-2-oxoindohne-5-sulfonamide, l -butyl-3-/ert-butyl-3-fluoro-2-oxo-N-(2-tnienylmethyI)indoline-5 -sulfonamide, 1 -butyl-3-/ert-butyl-3-fluoro-jV-( 1 -naphthylmethyl)-2-oxoindoline-5-sulfonamide;
N-(l//-benzimidazol-2-ylmethyl)-l -butyl-3-/err-butyI-3-fluoro-2-oxo]ndoline-5-bulfondmide, 3-;ert-butyl-3-fluoro-l -(2-fluoroethyl)- N,N -dimethyl-2-oxoindoline-5-sulfonamide; 3-tert-but>l- ,V,;V -diethyl-3-fluoro-1-('2-fluoroethyl)-2-oxoindoline-5-sulfonamide, 3-/er?-butyl-N-cyclohexyI-3-fluoro-l -(2-fluoroethyl)-N-isopropyI-2-oxoindohne-5-suIfonamtde; Λ^rN-dibenzyl-3-rø'/-butyl-3-πuoro-1-(2-fluoroethyl)-2-υxϋindohπe-5-i5ulfonamide)
3-/e/-?-butyl-3-fluoro-l -(2-fluoroethyl)-2-oxo-λ-(2-thienylmethyl)indoline-5-sulfonamide; 3-/£?rt-butyl-3-fluoro- l -(2-fluoroethyl)-yV-(l -naphthylmethyl)-2-oxoindoline-5-sulfonamide; A'-( l//-benzimidazol-2-ylmethyl)-3-rerf-butyl-3-fluoro-1-(2-fluoroethyl)-2-oxoindoline-5- sulfonamide; l'-butO-yn-l -yl-iV-isopropyl^'-oxo-r^'-dihydrospirot l .S-dioxane-Z^'-indolcJ-S'-carboxamide; r-but-3-yn-l -yl-5'-(pyτrolidin-l -ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r//)-one, r-but-3-yn-1-yl-5'-(pipeπdin-1-ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r//)-one; l'-but-3-yn-l -yl- NA^iethyl^'-oxo-t '^'-dihydrospirofl^-dioxane^^'-mdoleJ-S'-carboxarnide; r-but-3-yn-l -yl-n-ethyl-2'-oxo-r,2'-dihydrospiro[l ,3-dioxanc-2,3'-indole]-5'-carboxamide; ^-benzyl-l'-but-S-yn- l -yl^'-oxo-r^'-dihydrospirof l ^-dioxane^^'-indolel-S'-carboxamide; l'^Z-fluoroethylJ-n-isopropyl^'-oxo-r^'-dihydrospiroCl^-dioxane-Z^'-indoleJ-S'-carboxamide; r-(2-fluoroethyl)-5'-(pyrrolidin-l -ylcarbonyl)spiro[1 ,3-dioxane-2,3'-indol]-2'(rH)-one, r-(2-fluorocthyl)-5'-(pιpeπdm-l -ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]-2'(r//)-one, NJN -di ethyl- r-(2-fluoroethyl)-2'-oxo-r,2'-dihydrospiro[ l ,3-dioxane-2,3'-mdole]-5'-carboxamide; w-ethyl - 1 '-(2-fluoroethy l)-2'-oxo- 1 ',2'-dihydrospiro[ 1 ,3-dioxane-2, 3 '-indole] -5 '-carboxamide N'-butyl-H-isopropyl-2'-oxo-r,2'-dihydrospiro[l ,3-dioxane-2,3'-indole]-5'-carboxamide; l'-butyl-SHpyiTolidin-1-ylcarbonyOspirofl ^-dioxane^^'-indolJ^'C r/fJ-one. r-butyl-5'-(pipeπdin-l -ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]-2'(rH)-one; 1 '-butyl-N,N -diethyl-2'-oxo- 1 ',2'-dihydrospiro[ 1 ,3-dioxane-2,3'-indole]-5'-carboxamide; I '-butyl- N-ethyl-2'-oxo- 1 ',2'-dihydrospiro[ 1 ,3 -dioxanc-2,3 '-indole]-5'-carboxamide, jV-benzyl-1 '-butyl-2'-oxo-l ',2'-dihydrospiro[l ,3-dioxane-2,3'-ιndole]-5'-carboxamide, ^-(l'-butyl^'-oxo-l '^'-dihydrospirofl ^-dioxane^^'-indoπ-S'-yOacetamide;
N-(r-butyl-2'-oxo-l ',2'-dihydιospιro[l ,3-dioxane-2,3'-indol]-5'-yl)cyclopropanecarboxamide; ^-(r-butyl^'-oxo-r^'-dihydrospirof l ^-dioxane^^'-indolJ-S'-yOcyclobutanecarboxamide; ^-(r-butyl^'-oxo-r^'-dihydrospirori ^-dioxane^.S'-indoll-S'-yOcyclopentanecarboxamide; yV-(r-butyl-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indol]-5'-yl)-benzamide, Λ^-(r-butyl-2'-oxo-r,2'-dihydrospiro[l ,3-dioxane-2,3'-indol]-5'-yl)methanesulfonam]de; yV-(r-butyl-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indol]-5'-yl)benzenesulfonamide; ΛΗl'-butyl^'-oxo-l '^'-dihydrospirotl^-dioxane^^'-indoll-S'-yl)-! - cyclohexylmelhanes>ulfonamide,
^-[r-(2-fluoroethyl)-2'-oxo-r,2'-dihydrospiro[ l ,3-dioxane-2.3'-indol]-5'-yl]acetamide, Λ^-[l'-(2-fluoroethyl)-2(-oxo-l',2'-dihydrospiro[ l ,3-dιoxane-2,3'-indol]-5'- yl]cyclopropanecarboxamide,
N-f l'^-nuoroethyO^'-oxo-l'^'-dihydrospirotl 3-dioxane-2,3'-indol]-5'- yl]cyclobutanecarboxamidc,
N[ l '-(2-fluoroethyl)-2'-oxo-l'.2'-dihydrospiroπ ,3-dioxane-2,3'-indol]-5'- yljcyclopentanecarboxamide;
^-[I'^-nuoioethyl^'-oxo-r^'-dihydrospirofl ^-dioxane^^'-indo^-S'-y^benzamide; N^r^-fluoroethyO-Z'-oxo-l'^'-dihydrospirotl J-dioxane^J'-indoll-S'-ynmethanesulfonamide; 1,1,1 -trifluoro-N-f 1 '-(2-fluoroethyl)-2'-oxo- 1 ',2'-dihydrospiro[ 1 ,3-dioxane-2,3'-indol]-5'- yl]methanesulfonamide;
N-[ r-(2-fluoroethyl)-2l-oxo-r)2'-dihydrosp!ro[1,3-dioxane-2,3'-indol]-5'-yl]benzcncsulibnamidc; l-cyclohexyl-«-[l '-(2-fluoroethyl)-2'-oxo-l ',2'-dihydrospiro[ l.3-dioxane-2,3'-indo]]-5'- yl]methanesulfonamide, r-(cyclϋpropylmelhy])-5'-[(2.6-dimethylmorpholin-4-yl)sulfonyl]spiro[l ,3-dιoxane-2,31-ιndol]-
2'( π i)-one; jV-tert-butyl- r-(cyclopropylmethyl)-«-methyl-2'-oxo-r,2'-dihydrospiro[ l ,3-dioxane-2,3'-indole]- 5'-sulfonamide; r-(cyclopropylmefhyl)-«-(2-τnorpholin-4-ylethyl)-2l-oxo-l l,2'-dihydrospiro[1.3-dioxane-2,3'- ιndole]-5'-sulfonamide,
1 '-(cyclopropylmethyO-S1- { [4-(3,4-dimethylphenyl)piperazin- 1 -yljsulfonyl } spiro[ 1 ,3-dioxane- 2,3'-indol]-21(17/)-one, r-(cyclopτopylmethyl)-5'-[(3-methylpipeπdm-l -yl)sulfonyl]spiro[1 3-dioxane-2,3'-indol]- 2'(l '//)-onc; l '^cyclopropylmethyO-S'-^-methylpiperazin-1-y^sulfonylJspirof l jS-dioxane^^'-indol]-
2'(l 'H)-one;
5'-[(4-benzylpiperazin-1-yl)sulfonyl]-r-(cyclopropylraethyl)spiro[ l ,3-dioxane-2,3'-indol]- 2'( l 'H)-one; l '-(cyclopropylmethyl)-5'-[(3,5-dimethylpipendin-1-yl)sulfonyl]spiro[ l ,3-dioxane-213'-indol]- 2'( 1 'H)-OtIe, r-(cyclopropylmethyl)-5'-[(2-cthylpipeπdin-l -yl)sulfonyl]spiro[l ,3-dioxane-2,3'-indol]-2'(rH)- one, r-(cyclopropylmethyl)-5'-(morpholin4-y]sulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylmeth>l)-4'-[oxo(pipeπdin-l -yl)acetyl]spiro[l ,3-dioxane-2,3'-indol]-2'(rΗ)-one; 4'-[oxo(pipcπdin-1-yl)acetyl]-r-propylspiro[ l ,3-dιoxane-2,3'-indol]-2'(r//)-one;
4'-[oxo(pipeπdin-l -yl)acetyl]-r-(2,2,2-tπfluoroethyl)spirof ] ,3-dioxane-2,31-indol]-2'(l'f/)-one; r-butyl4'-[oxo(pipeπdin-1-yl)acety]]spiro[1,3-dioxane-2,3'-indυl]-2'(rH)-one;
4'-[oxo(pipendm- 1 -yl)acetyl]- 1 '-pent-4-yn- 1 -ylspiro[ 1 ,3 -dioxane-2,3 '-indol]-2'( 1 'H)-onc,
1 '-methyl-4'-[oxo(pipeπdin- 1 -yl)acetyl]spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 17/)-one; 7'-(piperidm-l -ylcarbonyl)-r-(2)2,2-tπfluoroethyl)spiro[l ,3-dioxane-2>31-indol]-2'(l'Η)-one;
7'-(pipeπdm-1-ylcarbonyl)-r-propylspiro[l ,3-dιoxane-2,3'-mdol]-2'( 1 '//)-one; r-(cyclopropylmethyl)-7'-(pipeπdin-1-ylcarbon>l)spiro[ l ,3-dioxanc-2,3'-]ndol]-2'(rH)-one; r-butyl-7'-(pipendin-l -ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]-2'(r/f)-one;
I '-pent-4-yn-l -yl-7'-(pipeπdm-l -ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l 'H)-one, r-methyl-7'-(pipeπdin-l -ylcarbonyl)spiro[l )3-dioxane-2,3'-indol]-2l( l'//)-one; l'-(cyclopropylmethyl)-4'-(pipeπdin-l -ylcarbonyl)spiro[ l )3-dioxane-2,3'-indol]-2'( rΗ)-one;
4'-(piperidin-l -ylcarbonyl)-r-propylspirori ,3-dioxane-2,3'-indoll-2'(rH)-one;
4'-(pipendin-1-ylcarbonyl)-r-(2,2,2-trifluoroethyl)spiro[ l ,3-dioxane-2,3'-]ndul]-2'(rH)-one, 1 '-butyl-4'-(pipeπdin- l-ylcarbonyl)spiro[ 1 ,3-dιoxane-2,3'-indol]-2'( 1 'H)-one; r-pent-4-yn-1-yl-4'-(pipeπdin-l -ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r//)-one, l '-niethjl^'^pipeπdin-l -ylcai bonyOspirof l ^-dioxane^S'-indoπ^^r/fl-one, r-(cyclopropylmethyl)-6'-(pipcπdin-1-ylcarbonyl)spiro[1,3-dioxane-2,3'-indoI]-2'( lΗ)-one; 6'-(pipendin-I -ylcarbonyl)-r-propylspiro[1,3-dioxane-2,3'-indol]-2'(r//)-one;
6'-(pipeπdin-l -ylcdrbonyl)-r-(2,2,2-tπfIιιoroethyl)spiro[l 3-dioxane-2,3'-indol]-2'( 17/)-one; r-butyl-6'-(pipeπdin-1-ylcarbonyl)spιro[l ,3-dioxane-2,3'-indol]-2'(r//)-one; 1 '-pent-4-yn- 1 -yl-6'-(pipeπdm-l -ylcarbonyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 'H) -one, r-methyl-6'-(piperidin-l -ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]-2'(r/f)-one; r-(cyclopropylmethyl)-5'-f(2.6-dimethylpipeπdιn-l -yl)sulfonyl]spiro[1,3-dioxolane-2,3 -indol]-
2'(l 'Η)-one, r-(cyclopropylmethyl)-5'-[(2,6-dimethylmorpholin-4-yl)sulfonyl]spiro[ 1,3-dioxolane-2,3'-indol]- T(VH)-om; r-(cyclopropylmethyl)-5l-[(2-methylpιpeπdm-1 -yl)sulfonyl]spιro[1 ,3-dιoxolane-2,3l-ιndol]- 2'( l H)-one;
N-tert-buty[-\ '-(cyclopropylmeth>l)-n-methyl-2'-oxo-l ',2'-dihydrospiro[l ,3-dioxolane-2,3'- indole]-5'-sulfonamide, r-(cyclopropylmethyl)-5'-(pipeπdin-1-ylsulfonyl)spiro[1,3-dioxolane-2,3'-indol]-2'(r//)-one; r-(cyclopropy1methyl)-5'- {[4-(3,4-dιmethylphenyl)piperazin-l -yl]sulfonyl}spiro[l ,3-dioxolane- 2,3'-indol]-2'( l '//)-one, l '-(cyclopropylmethyl)-5'-[(3-methy]pipeπdin-1-yl)sulfonyl]spιro[l ,3-d]oxolane-2,3'-indol]- 2'(l'H)-one.
1 '-(cyclopropylmethyl)-5'-[(4-methylpiperazin- 1 -yl)sulfonyl]spιro[ 1 ,3-dιoxolane-2,3'-indoI]- 2\VH)-one, S'-^-benzylpipera/in-t-y^sulfoTiylJ-l '^cyclopropylmethy^spirof l ^-dioxolane^^'-indol]-
2'(1H)-one; r-(cyclopropylmethyl)-5'-[(3.5-dimethylp:pendin-1-yl)sulfonyllspirof l .3-dioxolane-2,3'-indol]- 2'(l'H)-one, r-(cyclopropylmethyl)-5'-[(2-ethylpipeπdin-1-yl)sulfonyl]sp!ro[l ,3-dioxolane-2,3'-indol]- 2'(l Η)-one, r-(cyclopropylmethyl)-5'-(morpholin4-ylsulfonyl)spiro[l ,3-dioxolane-2,3'-indol]-2'( l'H)-one; r-pent-4-yn-l -yl-5'-(pyrro]idin-1-ylsulfonyl)sptro[l ,3-dioxolane-2,3'-indol]- 2'( rH)-one, l '-Ccyclopropylmethyl^S'-Cpyrrolidin-l -ylsulfonyOspirotU-dioxolanc^^'-indolJ^^rFD-one; r-propyl-5'-(pyrrolidin- l -ylsuIfonyl)spiro[ 1.3-dioxolane-2,3'-indol]-2'(l'H)- one, 1 '-butyl-5 '-(pyrrolidin- 1 -ylsulfonyl)spiro[ 1 ,3-dioxolane-2,3'-indol]-2'( 1 Η)-one,
5'-(pyrrolidin-l -ylsulfonyl)-1 '-(2,2,2-tiifIuoroetliyl)spιro[ l ,3-dioxolane-2,3'-indo!]-2'( rH)-one, ! '-meth>!-5'-(pyπolidin-1-yisulfonyl)spiro l ,3-dioxolane-2,3'-mdol]-2'( I 1H)- one, r-pent-4-yn-l -yl-5'-(pipeπdin-1-ylsulfonyl)sptrof l ,3-dioxane-2,3'-indol]- 2'(rH)-one, 5'-(pιpeπdin-1-ylsulfonyl)-l'-(212,2-trifluoroethyl)spiro[l ,3-dioxane-2,3'-indol]-2'(rH)-one, r-(cyclopropylmethyl)-5'-(pipendin-1-ylsulfon>l)spiro[ l ,3-dioxane-2,3'-indol]- 2'( rH)-one, 5'-(pipeπdin- l-ylsulfonyl)-r-propylspirotl ,3-dioxane-2,3'-indol]-2'( l Η)-one; 1 '-butyl-5'-(pipeπdin- 1 -ylsulfonyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'(l Η)-one; r-methyl-5'-(pιpeπdin-l -ylsulfonyl)spiro[ l ,3-dioxane-2 3'-indol]-2'( l 'H)-one, r-butyl-S'^pipendin-1-ylcarbonyOspirotl ^-dioxolanc^^'-indolJ^Xl 'Hj-one. r-pent-4-yn-1-yl-51-(pipeπdin-l -ylcarbonyl)spirofl ,3-dioxolane-2,31-mdol]-21(rH)-one, 5'-(pipendin-l -ylcarbonyl)-r-prop>lspiro'r1.3-dioxolane-2,3'-mdol]-21(rH)-one1 r^cyclopropylmethyO-SXpipeπdin-1-ylcarbonyOspirofl ^-dioxolane^^'-indolJ^X ri^-one. 5'-(pipeπdin-l -ylcarboπy]J-] '-(2,2,2-tπfiuoroethyl)spiro[] ,3-dioxolane-2,3'-indol]-2\ rH)-one, r-methyl-S'^piperidm-l -ylcarbonyOspirotl^-d'Oxolane^.S'-mdoll^^rHVone; 4-chlυro-N-(r-(cyclopropylmethyl)-2'-oxospiro[[l 3]dioxane-2,3'-indoline]-5'- yl)benzenesulfonamide, iV-[l '-(cyclopropylmethyl)-2'-oxo-l ,2'-dihydrospiro[1,3-dioxane-2,3'-indol]-5'-yl]-4- methoxybenzenesulfonamide,
JV-[1 '-(cyclopropylmethyl)-2'-oxo-l ,2'-dihydrospiro[l ,3-dioxane-2,3'-indol]-5'-yl]-4- methylbenzenesultonamide,
3,4-dich]oro-«-[l'-(cycloProPylmethyl)-2'-oxo-r,2'-dihydrospiro[l ,3-dioxane-2,3'-indol]-5'- yl]benzenesulfonamide, r-phenyl-5'-(pyrrolidin-l -ylsulfonyl)spiro[[l ,3]dioxane-2,3'-indohn]-2'-one, r-(2-chlorophenyl)-5'-(pyrrohdin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r//)-one, r^-chlorophenyO-S'-tpyrrohdin-l -ylsulfonyOspirofl ^-dioxane^^'-indolJ^Xr/^-one; r-(4-chlorophenyl)-5'-(pyiτϋlidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'( r//)-ϋne, r-(2-methylphenyl)-5'-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3l-indol]-2'(r//)-one) r-(3-methylpheny])-5'-(pyrrolidιn-1-ylsulfonyl)εpiro[1,3-dioxane-2,3'-indol]-2'(r//)-one; r-(4-methylpheny])-5'-(pyπOlidin-1-ylsulfonyl)spiro[1.3-dioxane-2,3'-indol]-2'(r//)-one, l '-(2-methoxypheny])-5'-(pyrrolidin-1-yl!5ulfonyl)sp]ro[l ,3-dioxane-2,3'-indol]-2'(r//)-one, r-(3-methoxyphenyl)-5'-(p)ττol]din-1-ylsulfonyl)spiro[ l 13-dioxane-2)3'-indol]-2'(r//)-one; r-(4-methoxyphenyl)-5'-(pyrrolidin-1-ylsulfonyl)spiro[ l 3-dioxane-2,3'-indol]-2'(l'//)-one) SXpyrrohdin-1-ylsulfonyO-r-^trifluoromethyOphenylJspirof l ^-dioxane^^'-indolj-ZCr//)- one,
5'-(pyrrohdin- 1 -y lsulfonyl)-l '-[3-(trιfluoromethyl)phenylJspirol 1 ,3-dioxanc-2,3'-indolJ-2'( 1 'h)- one,
S'^pyrrohdin- l-ylsulfoπyO-r-^-CtTifluoromethyOphenyllspirotl ^-dioxaπe^^'-indol]^!'//)- one, r-(2-f!uorophen>l)-5'-(pyπOlidin-l -ylsulfonγl)spiro[l ,3-dioxane-2,3'-indol]-2'( r//)-one, r-(3-fIuorophenyI)-5'-(pyrrolidιn-l -ylsu!fonyl)spiro[l ,3-dioxane-2,3'-indol]-2'( l '//)-one, r-(4-fluorophenyl)-5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,V-indol]-2'(r/y)-one, 2-[2'-oxo-5'-(pyrrohdin- 1 -ylsulfonyl)spiro[ 1 ,3-dioxane-2,3'-indol]- 1 '(2 W)-yl]benzonitπle; 3-[2'-oxo-5'-(pyrrolidin- l-ylsulfon>l)spiro[l >3-dioxane-2,3'-indol]-r(2'//)-yl]benzonitπle; IXZ-propoxyphenylXV^pyrtOlidin-1-ylsulfonyOspirof l^l-dioxane^.S'-'ndoll^^r/^-one, r-(3-propoxyphenyl)-5'-(pyrrolidin-1-ylsulfonyl)spiroL1,3-dioκanc-2,3'-indolJ-2'(r//)-onc: r-(4-propox>rphenyl)-5'-(pyrrolidin-1-ylsulfony!)spiro[1,3-dioxane-2,3'-indol]-2'(r//)-one;
5'-(pyrrolidin-l -ylsulfonyl)-r-[3-(trifluoromethoxy)phenyl]spiro[ l ,3-dioxane-2,3'-indoI]-2'(r//)- one,
S'^pyTrohdin-l -ylsulfonyO- r-^trifluoromethoxyOphenyφpirof l J-dioxane^^'-indolJ^'Cl '/f)- one, r-(2,4-dichlorophenyl)-5'-(pyrrolιdin-1-ylsulfonyl)spιro[1,3-dioxane-2,3'-indol]-2'(r//)-one, r^S^-dichlorophenyO-SXpyπOlidin-1-ylsulfonyOspiroLl ^-dioxane-Z.S'-indolJ^'CrΛO-one, r-(3,5-dichlorophenyl)-5'-(pyπ"θlidin-l -ylsulfonyl)spiro[1.3-dioxane-2,3'-indol]-2'(r//)-one; 1 '-(3-chloro-4-fluoropheny])-5'-(pyrrohdm-l -ylsulfony l)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 'H)- one r-(3-chloro4-methoxyphenyl)-5'-(pyiτohdin-1-ylsulfonyl)spiro[l ,3-dioxanc-2,3'-indol]-2'(r//)- one, r-(3,5-dimethy]phenyl)-5'-(pyrro!idin-1-ylsulfonyl)spiro[ 1,3-dioxane-2,3'-indol]-2'(r//)-one, r-(4-fluoro-3-methylphenyl)-5'-(pyrrolidin-l -ylsu]fonyl)spiro[1,3-dioxane-2,3'-indol]-2'(17/)- one, r-(2.5-difluorophenyl)-5'-(pynOlidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r//)-one; r-(2,4-difIuorophenyl)-5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'( r//)-one, r-(3,4-difluorophenyl)-5'-(pyrrolidm-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l'/y)-one; r-(3,5-difluorophenyl)-5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r//)-one; r-(1,3-benzodioxol-5-yl)-5'-(pyrrolidin-1-ylsulfony])spiro[1,3-dioxane-2,3'-indol]-2'(r//)-one, 5 '-(pyi rol i din-1 -ylsulfony I)-I '-(3-thienyl)spiro[l 3-dioxane-2,3'-indol]-2'(I '//)-one, l '-pyπdin-S-yl-S'-Cpyrrolidin-l -ylsulfonyljspirofl ^-dioxane-Z^'-indoπ^'Cr^-one, r-pyridin-4-yl-5'-(pyπ"θlidm-1-ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r//)-one, r-pyrimidin-5-yl-5'-(pyrrolidin-l -ylsulfoπyl)spiro[1,3-dioxane-2,3'-indol]-2'(l'//)-one, 5l-(3-fIuoropyrrolidin-1-ylsulfonyl)-l '-phenylspiro[[ 1,3]dioxane-2)3'-indohn]-2'-one; l '-(3-fluorophenyl)-5'-f(3-fluorop\τrolidin-1-yl)sulfonyl]spiro[ l ,3-dioxane-2,3l-indol]-2'(r//)- one;
1 '-(4-fluorophenyl)-5'-[(3-fluoropyrrolidin- 1 -yl)sulfonyl]spiro[ 1.3-dioxane-2,3'-indol]-2'( 1 'H)- one;
2-{5'-[(3-fluoropyrrolidin-l -yl)sulfonyl]-2'-oxospiro[l ,3-dioxane-2,3'-indol]- r(21//)- yljbenzonitnle; r-(3,4-dichlorophenyl)-5l-[(3-fluoiopyrrolidin-1-yl)suironyl]spiro[1.3-dioxane-2J3l-indo]]-2'(l '/j)- one; r-(2,4-dichlorophenyl)-5'-[(3-fluoropyrrolidin-1-yl)sulfonyl]spiro[l ,3-dioxane-2,3'-indol]- 2'(l(H)-one, r-(3-chloro-4-tluorophenyl)-5'-[(3-fluoropyτrolidin-l -yl)sulfonyl]spiro[ 1,3-diθλane-2,3'-mdol]- 2'(VH)-OTX. r-(2,5-difluorophenyl)-5'-[(3-fluorop>Trolidin-1-yl)su]fonyl]spiro[ l ,3-dioxane-2,3'-mdol]-
2'( l W)-one; r-(3,4-di{luorophenyl)-5'-[(3-fluorop>τrolidin-1-yl)su]fonyl]spiro[l ,3-dioxane-2,3'-indol]- 2'(r//)-one; r-(4-fluoro-3-methylphenyl)-5'-[(3-fluorop>'τrϋlidin-l -yl)sulfonyl]spiro[l ,3-dιoxane-2,3'-ιndol]- 2'( 17/)-one,
5'-[(3 -fluoropyrrolidm- 1 -yl)sulfonyl]- 1 '-(3 -thienyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 '//)-one; 5'-(3,3-difluoropyrrolidin-1-yIsulfonyl)-r-phenylspiro[[l ,3]dioxane-2,3'-indolin]-2'-one, 5'-[(3,3-difluoiopyrrolidin-1-yl)sulfonyl]-r-(3-fluorophenyl)spiro[l ,3-dioxane-2,3l-indol]- 2'( l 'H)-one; 5'-[(3 ,3 -difluoropyTTohdin- 1 -yl)sulfonyl]- 1 '-(4-fluorophenyl)spirof 1 ,3 -dioxane-2,3'-indol]-
2'(l 'H)-one;
2-{51-[(3>3-difluoropyrrolιdin-1 -yl)su!fonyl]-2'-oxospiro[l ,3-dioxane-2,3'-indol]-r(21//)- yljbenzomtrile;
5'-(morphohnosulfonyl)-r-phenylspiro[[l ,3]dioxane-2,3'-indolin]-2'-one; r-CS-fluorophenyO-S'^morphohn^-ylsulfonyOspirof l^-dioxane^^'-indolJ^'Cr/^-one; r-(4-fluorophenyl)-5'-(morphohn4-ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]-2'(r//)-one; 2-[5'-(morpholin-4-ylsulfonyl)-2'-oxospiro[l ,3-dioxane-2,3'-indol]-r(2'//)-yl]benzonitri]e; 3-[5'-(morpholin4-ylsulfonyl)-2'-oxospiro[l ,3-dioxane-2,3'-indol]-r(2'//)-yl]benzonitrιle; 51-(morpholin4-ylsulfonyl)-r-[2-(trifluoromethyl)phenyl]spiiO[l ,3-dioxane-2,3'-indol]-2'(r//)- one,
51-(morphohn4-ylsulfonyl)-r-[3-(trifluoromethyl)phenyl]spiro[ 1,3-dioxane-2,31-indol]-2'(r//)- one; l '-(3,4-d)chlorophenyl)-5'-(morpholin4-ylsulfonyl)spLro[l ,3-<iioxane-2,3'-indθl]-2'(r//)-onc; l'-(2,4-dichlorophenyl)-5'-(morpholin4-ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l'//)-one, r-(3,4-difluorophenyl)-5'-(morpholin4-ylsulfonyl)spiro[l ,3-dioxane-2,3l-indol]-2'(r//)-one; r-(2,5-difluorophenyl)-5'-(morpholin4-ylsulfonyl)bpiro[l ,3-dioxane-2131-indol]-2'(r/f)-one, ] '-(3-chloro4-fluorophenyl)-5'-(morphoIin4-ylsulfonyl)spiro[ l )3-dioxane-2,3'-indol]-2'( l'//)- one;
5'-(morpholin4-ylsuIfonyl)-r-(3-thienyl)spiro[ 1,3-diθxane-2,3'-indol]-2'(r//)-one: 5'-(morpholιno&ulfonyl)-r-phenylspiro[[l 3]dioxolane-2.3'-indoIm]-2'-one, r-(3-fluoropheny])-5'-(morphohn4-ylsulfonyl)spiro[l ,3-dioxolanc-2,3'-indolJ-2'( r//)-one; r-(4-fluorophenyl)-5'-(morpholin4-yIsulfonyl)spiro[1,3-dioxolane-2,3'-ιndol]-2'( r//)-one; 2-[5'-(morpholin4-yIsulfonyl)-2'-oxospiro[1,3-dioxolane-2,3'-indol]-r(2'//)-yl]benzonUrile, 5'-(morpholin-4-ylsulfonyl)-l '-[2-(tnfluoromethyl)phenyl]spiro[l ,3-dioxolane-2,31-indoll-2'(r//)- one, r-(2,5-difluorophenyl)-5'-(morpholιn-4-ylsulfonyl)spiro[l ,3-dioxolane-2,3'-indol]-2'( 17/)-one, r-(2,4-difluorophenyl)-5'-(morphohn-4-ylsullonyl)spiro[l ,3-dioxolanc-2,3'-indol]-2'( r/y)-one, r-(3,4-difluorophen>l)-5'-(morpholin-4-ylsulfonyl)spiro[l ,3-dioxolane-2,31-indol]-2'(r//)-one)
5'-(morpho]in-4-ylsulfonyl)-l '-(3-thienyl)spiro[l ,3-dioxolane-2,3'-indol]-2'( rΛT)-υne, r-phenyl-5'-(pyrrohdm-l -ylsulfon>])spiro[[l )3]dioxolane-2,3'-indolin]-2'-one, r-(3-tluorophenyl)-5'-(pyπOlidin-l -ylsulfonyl)spiro[l 3-dioxolane-2 3'-indol]-2'( l'/f)-one, I ' (4-fluorophenyl)-5'-(pyrrolidin-l -ylsulfonyl)spiro[ l 3-dio\olane-2 3'-indol]-2'( r//)-one, 2-[2'-oxo-51-(pyrrolidin-1-ylsu]fony])spiro[ l ;3-dioxolane-2,31-indul]-r(2'//)-yl]benzonitri]e,
V[2'-oxo-5'-(pyrrolidin-1 -)'lsulfony])spiro[l ,3-dioxolane-2,3l-indol]-r(2'/ι)-yl]benzonitπlc, 5'-(pyπ"θlidin-l -ylsu]fonyl)-r-[2-(trifluoromethyl)phenyl]spiro[ l ,3-dioxolane-2,31-indol|-21(r//)- one,
5'-(pyττolidin-1-ylsulfonyl)-r-[3-(tτιfluoromethyl)phenyl]spτro[1,3-dioxolane-2,3'-indol]-2'( 17/)- one, r-(3,4-dichlorophenyl)-5'-(pyπOlidιn-l -ylsulfonyl)spiro[ 1,3-dioxolane-2,3'-indol]-2'(r//)-one, r-(2,4-dichlorophenyl)-5'-(pyrrolidιn-1-y]sulfonyl)spiro[ l ,3-dioxulane-2,3'-indol]-2'(r//)-one, l'-(3 4-difluoiopheny])-5'-(pyτro]idin-l -ylsu]fony])spiro[1.3-dioxolane-2,3l-mdol]-2'( r//)-one; r-(2,5-dif!uorophenyl)-5'-(pyπOhdin-l -ylsulfonyl)spiro[ l 3-dioxolane-2,3'-mdol]-2'( rf/)-one, 1 '-(3 -chloro-4-fluoropheny])-5'-(pyrrohdin- 1 -ylsulfonyl)spiro[ 1 ,3-dioxolane-2,3'-indol]-2'( 1 'H)- one,
5'-(pyrrolidin-] -ylsulfonyl)-l -(3-thienyl)spiro[ l ,3-dioxolane-2,3'-indol]-2'(r//)-one, r-phenyl-S'-Cpipendine-1-carbonyOspirottl ^ldioxane^^'-indolinJ^'-one,
I ' (2-chlorophenyl)-5'-(pipendin-l -ylcarbonyl)spiro[ 1,3-dioxane-2,3'-iiidoI]-2'(r//)-one 1 '-(3-chbrophenyl)-5'-(pipeπdin- 1 -ylcarbυn> l)s,piro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 '//)-one r-(4-chlorophenyl)-5'-(pipeπdin-1-ylcarbonyl)spiro[1,3-dioxane-2,3'-indolJ-2'(r//)-one r^-fluorophenyO-S'-Cpipeπdin-l -ylcarbonyπspirof l ^-dioxane^^'-indolJ^Xr/^-one, 1 '-(4-fluorophenyl)-5'-(pipeπdin-l -ylcarbony])spiro[ 1 ,3-dioxdne-2,3'-indol]-2'( 17f)-one, 2-[2'-oxo-5'-(pipe"di"-1 -ylcai bony])spiro[ l ,3-dioxane-2,3'-indol]-r(27/)-yl]benzonitn]e; 5'-(pipeπdin-1-ylcarbonyl)-r-[2-(tπfluoromethyl)pheny]]spiro[ l ,3-dioxane-2,3'-indol]-2'(r//)- one, l '-(3,4-dichlorophenyl)-5'-(p!peπdin-l -ylcarbonyl)spiro[l ,3-dioxdne-2,3'-indol]-2'( r//)-one, l '-(2,4-dichloropheny])-5'-(pineπdin-1 -ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l'//)-one, 1 '-(3-chloro-4-fluorophenyl)-5'-(pipeπdin-l -ylcarbon> l)spiro[ l ,3-dioxane-2,3l-indo]]-2'(ll//)-one, l l-(2,5-difluorophenyl)-5'-(pipeπdin-1-ylcarbonyl)spiro[ l 13-dioxane-2,3'-mdol]-2'(r//)-one, r-(3,4-difluorophenyl)-5'-(pipeπdin-1-ylcarbon>l)spiro[l ,3-dioxane-2,3'-indol]-21( 1 '//)-one, I '^-tluoro^-methylphenyO-SXpipeπdin-1-j-lcarbonyOspirot l^-dioxane^^'-indolJ^trA/)- one, 2-chloro-6-(2'-oxo-51-(pyrroI]din-l -ylsulfonyl)spiro[[1 ,1]dioxane-2,T-indoline]- r-yl)benzonitnle, 2-fluoro-6-(2'-oxo-5'-(pyrrolidin-l -ylsulfonyl)spiro[[1,3]dioxane-2,3'-indoline]-r-yl)benzonitnle, 3-fluoro-2-(2'-oxo-5'-(pyrrolidin-l -ylsulfonyl)spiro[[l ,3]dioxane-2,3'-indoline]-r-yl)benzonιtnle, 2-(2'-oxo-5'-(pyπOlidin-1->lsulfonyl)spiro[[1.3]dioxane-2)3'-indohne]-r-yl)nicotinonitπle, 5l-(3-fluoropynolidπi- l -ylsulfonyl)-r-proρylspiro[[l ,3]dioxane-2,3'-indolin]-2'-one) r^cyclopropylmethyO-S'^-fluoropyTroIidm-1-ylsulfonyOspirotf l Jldioxane^J'-indolin]^'- one,
5'-(3.3-difluϋropyτrolidiπ-1-ylsulfonyl)-r-prϋpylt>piro[[1,3]dioxane-2,3'-indolin]-2'-one, r-(cyclopropylmethyl)-5'-(3.3-difluoropyrrolidin-l -ylsulfonyl)spiro[[ l ,3]dioxane-2,3'-indohn]- 2'-one,
S'-Cpyrrohdin-l -ylsulfonyO-l'^^^-tπfluorobutyOspirof lJ-dioxane^^'-mdoll^'C rHJ-one, r-butyryl-5'-(pyrrohdin-1-ylMilfonyl)bpiro[l ,3-dioxane-2,3'-indol]-2'( rH)-one,
1 '-(cyclobutylmethy l)-5 '-(pyrrohdin- 1 -ylsulfonyl)spιro[ 1 ,3-dioxane-2,3 '-indol] -2 '( 1 Η)-onc, r-(2-ethylbutyl)-5'-(pyrrolidin-l -ylsulfonyl)spiro[ 1 ,3-dioxane-2,3'-ιndol]-2'( 1 Η)-one, r-isobutyl-5'-(p>τrolidin-l -ylsulfonyl)spiro[ l ,3-dioxane-2,3'-indol]-2'(rH)-one, r-(2,2-d[methylpropyl)-5'-(pyττolidin-1 -ylsulfonyl)spiro[l ,3-dioxane-2,3l-indol]-2l( lΗ)-onc, l HcyclopropylmethyO-S'^pyTrohdin-l -ylsulfonylJspirof l ^-dioxane^.S'-indo^^^ rH^one, r^cycIohexylmethy^-S'^pyrrolidin-l -ylsulfonylJspirotl .S-dioxane^, 3'-indol]-2'(l Ti)-OnC, r-^^-fluorophenuxyJethyn-SHpyrrolidin-l -ylsulfonyOspirof l^-dioxane^^'-indolj^l 'H)- one, r-[2-(4-chIorophenoxy)ethyl]-5'-(pyrrolιdin-1-y'sulfonyl)spiro[1,3-dioxane-2,3'-indol]-2'(rH)- one, r-(2-phenoxyethyl)-5'-(pyrrohdin-1-ylsulfonyl)!spiro[ 1,3-dioxane-2,3'-indol]-2'(rH)-one, 1 '-(3-phenoxypropyl)-5'-(pyrrolidin- 1 -ylsulfonyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 'H)-one. 1 '-benzyl -5 '-(pyrrohdin- 1 -ylsul fonyl)spiro[ 1 ,3-dioxane-2,3 '-indol] -2'( 1 'H)-one,
5'-(pyτrolidιn-1-ylsulfonyl)-r-(3,3,3-tπfluoropropyl)spiro[ 1,3-dioxane-2,3'-indol]-2'(l 'H)-one, 5'-(pyrrolidin-1->]sulfonyl)-r-(2,2,2-trιfluoroethy])spiro[1 ,3-dioxane-2,31-indol]-2'(rH)-one, 1 '-cyclopcnt>'l-5'-(pyrrohdin-l -ylsulfonyl)spiro[ 1 ,3-dioxane-2,3'-mdol]-2'( 1 Η)-one; 1 '-propyl-5'-(pyrrohdin-l -ylsulfonyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( l'H)-one, r-methyl-S'-φyrrohdin-1-ylsulfonyDspirof l^-d'oxane^ 3'-indol]-2'(l Η)-one,
5'-(PyTTOlIdIn- l -ylsulfonyl)-l '-[3, 3,3-trifluoro-2-(tnfluoromethy])propyl]spiro[l ,3-dioxane-2.3'- mdolJ-2'( l 'H)-one, r-sec-butyl-5'-(pyrro!idin-1-ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'( rH)-one, r-(l -phenylethyl)-5'-(pyττolidin-1-ylsulfυnyl)!spirυ[ l ,3-dioxane-2,3'-indol]-2'(rH)-one, r-isopropyl-5'-(pyrrolidin-1-ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'( rH)-onc;
4-[2'-oxo-5'-( pyrrohdin- l -ylsulfonyl)spiro[ l ,3-dioxane-2,3'-indol]-r(2Η)-yl]butanenitnle, l'-( 1 -methyjbuty l)-5 '-(pyrrohdin- 1 ->lsulfonyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 "H)-one; 5'-(pipeπdin-l -ylcarboπyl)-r-(4,4,4-trifluorobut)'l)spiro[l ,3-dioxane-2,3'-ιndol]-2'(lΗ)-one, 5'-(pιpeπdin- 1 -ylcarbonyl)- 1 '-(2,2,2-trifluoroeth>l)spiro[ 1 ,3 -dioxane-2,3'-mdol]-2'( 1 Η)-one,
1 '-(cyclobutylmethyl)-5'-(piperidin-l -ylcarbonyl)spiro[ 1,3-dioxane-2,3'-indol]-2'(l 'H)-υne, r-isobutyl-S'-Cpipendin-l -ylcarbonyOspirotl .S-dioxane^.S'-indolj-Z^ ri^-one; r^Z^-dimethylpropyOό'^pipeπdin-1-ylcarbonyOspirofl^-dioxane-Z^'-indolj^'Cl'^-one, r-(cyclopropylmethyl)-5'-(pipeπdin-1-ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]-2'(rH)-one;
1 '-ethyl-5'-(pipeπdm- 1 -ylcarbonyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 'H)-one, 5'-(pipeπdin-l -ylcarbonyl)- r-propylspiro[l ,3-dioxane-2,3'-indol]-2'(rH)-one. 1 '-(cyclohexylmethyl)-5 '-(pipeπdin- 1 -ylcarbonyl)spiro[ 1 ,3 -dioxane-2,3'-indol]-2'( 1 'H)-one, [2'-oxo-5'-(pipeπdin-l -ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]-r(2'H)-yl]acetonιtπle, r-melhyl-5'-(pipeπdιn-1-ylcarbonyl)spiro[l ,3-dLθxane-2,3'-ιndol]-2'(rH)-otie,
1 '-but-3-en- 1 -yl-5 '-(pipeπdm- 1 -ylcarbonyl)spiro[ 1 ,3-dioxanc-2,3'-indol J-2'( 1 Η)-one, 1 '-(2-methoxyethyl)-5'-(pipeπdin- 1 -ylcarbonyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 'H)-one; r-(4-fIuorobutyl)-5'-(pιpeπdin-l -ylcarbonyl)spiro[1.3-dioxane-2,3'-indol]-2'(rH)-one, r-pent-4-yn-l -yl-5'-(pipeπdin-l -ylcarbonyl)spiro[1 ,3-dιoxane-2,3'-indol]-2'( l Η)-one, r-[(2-oxo-l ,3-oλazolidin-5-yl)methyl]-5'-(Pφcπdin-l -ylcarbonyl)spiro[ 1,3-dioxane-2,3'-indol]-
2'(l 'H)-one,
1 '-(2-ethylbutyl)-5'-(pipeπdin- 1 -ylcarbonyl)spιro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 'H)-one, r-(2-cyclohexylethyl)-5'-(pipeπdin-1-ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(rH)-onc, 5'-(pιpeπdm- l -ylcarbonyl)- r-[3,3,3-tπfIuoro-2-(tπfluoromethyl)propyl]spiro[l ,3-dioxane-2.3'- indol]-2'(l'H)-one; r-sec-but>l-5'-(pipeπdιn-1-y]carbonyl)spiro[ l ,3-dιoxane-2,3'-mdol]-2'(rH)-one,
1 '-(1 -phenylethyl)-5'-(Pφcπdin-l -ylcarbonyl)spiro[ 1 ,3-dioxane-2,3'-mdol]-2'( 1 'H)-one; r-C l-methylbutyO-S'-fpipeπdin-l -ylcarbonyOspirot l^-dioxane^^'-mdolj^^rHVone;
4-[2'-o\o-5'-(pipeπdin-l -ylcarbonyl)spiro[l ,3-diθλane-2,3'-indol]-r(2'H)-yl]butanenitπle, r-ιsopropyl-5'-(pιperιdin-l -y'carbonyl)spiιo[l (3-dioxane-2,3'-indol]-2'(rH)-one,
1 '-benzyl -5 '-(pipeπdin- 1 -ylcarbonyl)spiro[ 1 ,3-dioxanc-2,3'-indol]-2'( 1 'H)-one, 5-[2'-oxo-5'-(pipeπdtn-l -ylcarbonyl)spirof l ,3-dioxane-2,3'-indol]-r(2'H)-yl]pentanenitπle, 6-[2'-oxo-5'-(pipeπdin-1-ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]- r(2'H)-yl]hexanenitπle, r-penM-en-l -yl-SXpipeπdin-l -ylcarbonyOspiroCl ^-dioxane^^'-indolj^tr^-one, l '-(cyclopropylmethyl)-5'-(morpholin-4-ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]- 2'(rH)-one,
! '-butyl-5'-(morpholin-4-ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-2'( lΗ)-one, 5'-(morphυIin4-ylcarbonyl)- 1 '-propyl spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 'H)-one, 5'-(morpholin-4-ylcarbonyl)-l '-(2,2,2-trifluorocthyl)spirol l ,3-dioxane-2,3'-indol]-2'(rH)-one, 5'-(morpholin-4-ylcarbonyl)- l'-pent-4-yn- 1 -ylspiro[ 1 ,3-dioxane-2,3'-indoll-2'( 1 'H)-one; 4-[5'-(morpholin-4-yIcarbonyi)-2'-oxospiro[ 1,3-dioxane-2,3'-indol]-r(2'H)-yl]butanenitple, r-(4-fluoioburyl)-5'-(morpholin-4-ylcarbonyl)spιro[1,3-dioxane-273'-indol]-2'(πi)-one. r-(cyclopropylmethyl)-5,5-dimethyI-5'-(pipeπdn-l -ylcarbony!)spiro[ l ,3-dioxane-2,3'-indol]- '( l'H)-one, 5,5-dimethyl-5'-(piperidin-l -ylcarbonyl)-r-propylspiro[l ,3-dioxane-2,3'-indol]-2'(rH)-one;
5,5-dimethy]-5'-(pipeπdin-1 -ylcarbonyl)-l '-{2,2,2 -tπfluoroethyl)spiro[ l ,3-dioxane-2,3'-indol]- 2'(I1H)-OIIc;
S.S-dimethyl-l'-pent-^yn- l-yl-S'-tpipendin-1-ylcarbonylJspirofl^-dioxane^^'-indon-Z'CrH)- one,
4-[5,5-dimethyl-2'-oxo-5'-(pipeπdm-1-ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-r(2'H)- yljbutanenitπle;
3-[2'-oxo-5'-(pipeπdin-l -ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-r(2'H)- yl]propanenitnle;
3-[5'-(morpholin-4-ylcarbonyl)-2'-oxospiro[1.3-dιoxane-2,3'-ιndol]-r(2'H)-yl]propanenitrιle, 5'-(pipendin-1-ylcarbony])-r-(3,3,3-tritluoropropyl)spiro[l ,3-dioxane-2,3'- indo]]-2'(rH)-onc; l-(cyclopropylmethyl)-5-(pipeπdin-1-ylcarbonyl)-3',4',5',6'- tetrahydrospiro[mdole-3,2'-pyran]- 2(1H)-one:
(3r)-1-(cyclopropylmethyl)-5-(pipeπdin-1-ylcarbonyl)-3',4',5',6'- tetrahydrospiro[indole-3,2'- pyran]-2(1H)-one; (3s)-1-(cyclopropylmethyl)-5-(pipendin-1-ylcarbonyl)-3',4',5',6c- tetrahydrospirofindole-3,2'- pyran]-2(1H)-one;
5-(ptperιdin-1 -ylcarbonyl)-l -(2>2,2-trifluoroethyl)-3',4',5',6'- tetrahydrospiro[indole-3,2'-pyran]- 2(1H)-one; r-(cyclopropylmethyl)-5'-(pipeπdin-l -ylcarbonyl)spiro[1,3-dioxepane-2,3'-indol]-2'(rH)-one; 3-lert-butyl-l -(cyclopropylmethyl)-3-hydroxy-5-(pιpendιn-1 -ylcarbonyl)-] ,3-dιhydro-2H-tndol-
2 -one, and
3-tert-butyl-1-(cyclopropylmethyl)-3-fluoro-5-(pipeπdin- l-ylcarbonyl)-l ,3-dihydro-2H-indol-2- one and pharmaceutically acceptable salts thereof
In some embodiments, when R4 is SOjNR6R7, n is 0, R2 and R3, together with the carbon atom to which they are attached, form a l ,3-dioxan-2,2-diyl ring, and R6 and R7, together with the carbon atom to which they are attached, form a pyrrohdinyl ring, then R1 is not alkyl substituted with NH2, CN, N3, bromo, or a 7-membered cycloalkyl ring optionally substituted by CN or cyanoalkyl In related embodiments, R4 is substituted at the 5-position of the oxindole core.
In some embodiments, R1 is selected from C^ alkyl, C2.6 alkenyl, C2.ft alkynyl, Q 6 haloalkyl, C,. t, hydroxy alkyl, C, 6 cyanoalkyl, C6 io aryl, GH0 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl and C3 8 heterocycloalkenyl, wherein said Ci 6 alkyl, C2.6 alkenyl, C;.t alkynyl, C^.io aryl, C4 |U heteroaryl, C3.g cycloalkyl, C3 8 heterocycloalkyl, or C3 8 heterocycloalkenyl is optionally substituted with 1 , 2, or 3 substitutents independently selected from halogen, CN, N,, NO2, ORa, SR8, C6-I0 aryl, C4 10 heteroaryl, C3 8 cycloalkyl, C, 8 heterocycloalkyl, and C3.8 heterocycloalkenyl.
In some embodiments, R' is selected fiom C 6 alkyl, C| 6 haloalkyl, C1 b hydroxyalkyl and C, 6 cyanoalkyl, each optionally substituted with 1 , 2, or 3 substitutents independently selected from halogen, CN, N3, NO2, OR", SRa, C6 ,0 aryl, C4-I0 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl and C3 8 heterocycloalkenyl In some embodiments, R1 is C|.6 alkyl, optionally substituted with 1 , 2, or 3 substituents selected from C6-I0 aryl, C4 )0 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, and C3.8 heterocycloalkenyl.
In some embodiments, R1 is Ct 6 alkyl, optionally substituted with one substituent selected from Q-io aryl, C4-I0 heteroaryl, C3.s cycloalkyl, C1.* heterocycloalkyl, and C1.* heterocycloalkenyl.
In some embodiments, R' is is C3.? cycloalkyl.
In some embodiments, R' is cyclopropyl.
In some embodiments, R' is C|.6 haloalkyl, C|.6 hydroxyalkyl, or C|.6 cyanoalkyl.
In some embodiments, R' is C6. io aryl or C4.|0 heteroaryl, optionally substituted by 1, 2, or 3 substitutents selected from halogen, CM alkyl, CM haloalkyl, CN, NO2, and 0Ra.
In some embodiments, R1 is C1 6 cyanoalkyl.
In some embodiments, R' is C].6 haloalky!.
In some embodiments, halogen is fluoro.
In some embodiments, R' is CF3.
In some embodiments, R2 and R3 are independently selected from H, halogen, d.6 alkyl, C2_6 alkenyl. C? 6 alkynyl. C].6 haloalkyl, C|.6 hydroxyalkyl, Cu, cyanoalkyl, Cft.ιo aryl, C4.|0 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl and ORa , wherein said C|.6 alkyl, C2 6 alkenyl, C2-6 alkynyl, C6-Io aryl, GM0 heteroaryl, C3.8 cycloalkyl, C3 8 heteiocycloalkyl or C3.8 heterocycloalkenyl is optionally substituted with 1 , 2, or 3 substitutents independently selected from C6-ιo aryl, C4.10 heteroaryl, C3.8 cycloalkyl, C3 8 heterocycloalkyl, C3.8 heterocycloalkenyl, CN, NO2, N3, 0R\ SRa, C(O)Rb, C(0)NRcRd, C(O)OR3, OC(O)Rb, OC(O)NRcRd, NR°Rd, NReC(0)Rh, NReC(0)NRcRd, NReC(0)0Ra, S(O)Rb, S(O)NRl-Rd, S(O)2Rb, NReS(O)2Rb and S(O):NRcRd.
In some embodiments, R2 and R3 are independently selected from H, halogen, C|.6 alkyl, C2.h alkenyl, C2.6 alkynyl, C,.6 haloalkyl, C,.6 hydroxyalkyl, C,.6 cyanoalkyl, C6.,0 aryl, C4.10 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl. C3.8 helerocycloalkenyl and 0Ra
In some embodiments, R2 and R3 are independently selected from halogen, Cu alkyl, and OR".
In some embodiments, one of R2 and R3 is Ci^ alkyl.
In some embodiments, one of R2 and R3 is 0R\
In some embodiments, R2 and R3, together with the carbon atom to which they are attached, join to form a 3-8 membered cycloalkyl πng, said ring comprising 1-3 hetcroatoms selected from N, O and S, optionally substituted with 1 , 2, or 3 substituents independently selected from halo, C| 6 alkyl, C2 6 alkenyl, C2.6 alkynyl, C6. i0 aryl, C4 )0 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 helerocycloalkenyl, CN, NO2, N3, 0R\ SRa, C(0)Rb, C(O)NRςRd. C(O)OR', OC(O)Rb, 0C(0)NR'Rd, NRcRd, NReC(O)Rb, NReC(O)NRcRd, and NReC(O)ORa.
In some embodiments, R2 and R3, together with the carbon atom to which they are attached, join to form a 3-8 membered cycloalkyl πng
In some embodiments, R2 and R3, together with the carbon atom to which they arc attached, join to form a 5-7 membered cycloalkyl πng In some embodiments, R1 and R3, together with the carbon atom to which they are attached, join to form a 3-8 membered heterocycloalkyl πng, optionally substituted with 1, 2, or 3 substitucnts independently selected from halogen, Ci.., alkyl, C2 <, alkenyl, C2.,, alkynyl, Cb.,Q aryl, Ci0 heteroaryl, C3.8 cycloalkyl, C3 , heterocycloalkyl, C3.8 heterocycloalkenyl, CN, NO2, N3, 0Ra, SRa, C(0)RB, C(O)KRcRd, C(O)OR3, OC(O)Rb. 0C(0)NRcRd, NRcRd, NReC(O)Rb, NReC(0)NRcRd, and NR6C(O)OR3.
In some embodiments, R2 and R3, together with the carbon atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
In some embodiments, R2 and R3, together with the carbon atom to which they are attached, join to form a 5-7 membered heterocycloalkyl πng.
In some embodiments, R2 and R3, together with the carbon atom to which they are attached, join to form a 6-membered heterocycloalky] πng.
In some embodiments, the 6-membered heterocycloalkyl πng comprises 1 or 2 heteroatoms
In some embodiments, at least one heteroatom is O.
In some embodiments, R2 and R3, together with the carbon atom to which they are attached, join to form a 1.3-dioxan-2,2-diyl ring, 1.3-dioxolan-2,2-diyl, or tetrahydropyran-2,2-diyl ring.
In some embodiments, R4 is C(O)NR6R7.
In some embodiments, at least one of R6 and R7 is H.
In some embodiments, at least one of R6 and R7 is C,.6 alkyl.
In some embodiments, both of R6 and R7 are C|.6alkyl.
In some embodiments, one of R6 and R7 is C3.g cycloalkyl, C7. u arylalkyl, or C6 10 aryl
In some embodiments, R6 and R7, together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl πng, optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, C,.o alkyl, C,.6 alkenyl, C2.6 alkynyl, CN, NO2, N3, 0Ra, and SRa.
In some embodiments, R6 and R7, together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
In some embodiments. R6 and R7, together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl πng.
In some embodiments, R6 and R7, together with the N atom to which they are attached, join to form a pyrrolidinyl, morpholino, piperazinyl, or pipeπdinyl πng.
In some embodiments, R4 is SO2NR6R7
In some embodiments, at leabl one of R6 and R7 is H
In some embodiments, at least one of R6 and R7 is Ci 6 alkyl.
In some embodiments, both of R6 and R7 are C|.6 alkyl.
In some embodiments, one of R6 and R' is C3.8 cycloalkyl, C7 u arylalkyl, or C6-I0 aryl.
In some embodiments, R° and R7, together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl πng, optionally substituted with 1 , 2, or 3 substituents independently selected from halogen. Ci 6 alkyl, C2^ alkenyl, C2.β alkynyl, CN, NO2, N3, 0Ra, and SRa.
20 In some embodiments, R6 and R7, together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
In some embodiments, R6 and R7, together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
In some embodiments, R6 and R7, together with the N atom to which they are attached, join to form a pyrrolidinyl, morpholino, piperazinyl, or piperidinyl ring.
In some embodiments, R4 is NR8C(O)R9 or NR8SO2R9.
In some embodiments, R8 is H or C|.6 alkyl.
In some embodiments, R9 is H, C|.6 alkyl, Cu6 haloalkyl, C,.6 hydroxyalkyl, C6-I0 aryl, C.|0 heteroaiyl, C3.8 cycloalkyl, C3.8 heterocycloalkyl or C3.g heterocycloalkenyl, wherein said Cu alkyl, Cu haloalkyl, Cι.6 hydroxyalkyl, C6.ιo aryl, C_.ιo heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl or C3.8 heterocycloalkenyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halogen, 0Ra, cyano, amino, NO2, Cu alkyl, C1.4 haloalkyl, Ci 6 hydroxyalkyl, C3 g cycloalkyl, and C3.8 heterocycloalkyl.
In some embodiments, R9 is Cu alkyl, Cu haloalkyl, or Cu hydroxyalkyl, each of which is optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, 0Ra, C3.8 cycloalkyl, and C3.g heterocycloalkyl.
In some embodiments, R9 is cycloalkyl or aryl.
In some embodiments, R9 is phenyl or cycloalkyl having 3-8 carbon atoms.
In some embodiments, R4 is C(O)C(O)NR6R7.
In some embodiments, R6 and R7, together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
In some embodiments, R6 and R7, together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
In some embodiments, R6 and R7, together with the N atom to which they are attached, join to form a pyrrolidinyl, morpholino, piperazinyl, or piperidinyl ring.
In some embodiments, R5 is H, halo, Cu alkyl, Cu haloalkyl, C1-6 hydroxyalkyl, Cu cyanoalkyl, CN, NO2, N3, 0Ra, or SRa.
In some embodiments, R5 is H, halogen, or CM alkyl.
In some embodiments, n is O or 1.
In some embodiments, n is O.
In some embodiments, the invention includes a compound of Formula (I):
R2
Figure imgf000022_0001
I or pharmaceutically acceptable salts thereof, wherein:
R' is C|.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C].ύ haloalkyl, C\.6 hydroxyalkyl, Ci.6 cyanoalkyl, C6.ιo aryl, C4-Io heteroaryl, C34 cycloalkyl, C3.8 heterocycloalkyl and C3.8 heterocycloalkenyl, wherein said CV6 alkyl, C?.ό alkenyl, C2.6 alkynyl, Cό-io aryl, C__ι0 heteroaryl, C3.8 cycloalkyl, C1., heterocycloalkyl or C3.8 heterocycloalkenyl is optionally substituted with 1, 2, or 3 substitutents independently selected from C6-ιo aryl, C4.i0 heteroaryl, C3.g cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl, halogen, CN, N3, NO2, OR", SRa;
R2 and R3 are independently selected from H, halogen, C|.6 alkyl, C2.t, alkenyl, C2.6 alkynyl, C^ haloalkyl, C|.6 hydroxyalkyl, C|.6 cyanoalkyl, C6.|0 aryl, C4.|0 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl, CN, NO2, OH, 0Ra, SRa ; C(0)Rb, C(0)NRcRd, C(O)OR\ OC(O)Rb, OC(O)NR0R", NRCRJ, NRcC(0)Rb, NRcC(0)NRcRd, NRcC(0)0Ra, S(O)Rb, S(0)NRcRd, S(O)2R\ NReS(0)2Rb, and S(0)2NRcRd, wherein said C,.6 alkyl, C2.& alkenyl, C2.6 alkynyl, C6., 0 aryl, C4-10 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl or C3.8 heterocycloalkenyl is optionally substituted with 1 , 2, or 3 substitutents independently selected from C^i0 aryl, C4.i0 heteroaryl, C3.8 cycloalkyl, C;,.8 heterocycloalkyl, C3.g heterocycloalkenyl, CN, NO2, N3, OR", SR", C(O)Rb, C(0)NRcRd, C(O)OR3, OC(O)Rb, OC(O)NR0R", NRcRd, NReC(0)Rb, NReC(0)NRcRd, NReC(0)0Ra, S(O)Rb, S(O)NR0R", S(O)2Rb, NReS(0)2Rb, and S(O)2NR0R", provided that at least one of R2 and R3 is other than II;
R2' or R2 and R3 together form a R3 or C=O group; or R2 and R3, together with the carbon atom to which they are attached, join to form a 5-7 membered cycloalkyl ring or 5-7 membered heterocycloalkyl ring;
R4 is C(O)NR6R7, C(O)C(O)NR6R7, SO2NR6R7, NR*C(0)R9, or NR8SO2R9;
R5 is H , halogen, or CM alkyl;
R6 and R7 are independently selected from H, Cι_s alkyl, d.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C|.6 hydroxyalkyl, C3.8 cycloalkyl, and C3.8 heterocycloalkyl. wherein said C,.6 alkyl, Cw haloalkyl, C24 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, or C3.8 heterocycloalkyl is optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from OH, cyano, amino, halogen, Q.6 alkyl, C&.10 aryl, and C4.10 heteroaryl; or R6 and R7, together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring, each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, C,.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C6.10 aryl, C3.8 cycloalkyl, C4-Io heteroaryl, C7. )4 heterocycloalkyl, C6 haloalkyl, CN, NO2, N3, OR1, SRa, C(0)Rb, C(0)NR°Rd, C(O)OR3, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NReC(0)Rb, NReC(0)0R\ C(=NRr)NR0Rd, NReC(=NRf)NRcRd, S(O)Rb, S(O)NR0R4, S(O)2Rb, and S(O)2NR0R";
R8 and R9 are independently selected from H, C|.6 alkyl, CY4 haloalkyl, C2^, alkenyl, C2.* alkynyl, C|.ft hydroxyalkyl, C3.8 cycloalkyl, C3.s heterocycloalkyl and heterocycloalkenyl, wherein said d.6 alkyl, C|.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C3.8 cycloalkyl, or C3.8 heterocycloalkyl is optionally substituted
22 with 1, 2, 3, 4, or 5 substitυents selected from halogen, Ra, cyano, amino, NO2, CV6 alkyl, C6 alkenyl, C2. 6 alkynyl, CO haloalkyl, CV6 hydroxyalkyl, or C\ 6 cyanoalkyl, C6. io aryl, and Ci0 heteroaryl;
R2 and R3 arc independently selected from H, halo, CV6 alkyl, C2.6 alkenyl, C2.o alkynyl, C,.6 haloalkyl, C6 hydroxyalkyl, C6 cyanoalkyl, C6.^ aryl, C6-Io heteroaryl, C3.s cycloalkyl, C8 heterocycloalkyl, C3.8 heterocycloalkenyl and NO2; or R2 and R3 together with the carbon atom to which they are attached, join to form a 3-8 membered cycloalkyl πng or 3-8 membered heterocycloalkyl ring, each optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, Q.6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C6-Io aryl. CY 10 heteroaryl OR\ and NO2;
Ra, Rb, R", and Rf are each independently selected from H, C|.6 alkyl, C|.6 haloalkyl, C6 alkenyl, C2.6 alkynyl, C6.io ar>rl, and C4. m heteroaryl, Cu cycloalkylalkyl, and C4.14 heterocycloalkylalkyl, wherein said C6 alkyl, C,.6 haloalkyl, C2.6 alkenyl, C2.6 alkynyl, C6., 0 aryl, and C4.10 heteroaryl, Cj. ,2 cycloalkylalkyl, or C4.) 4 heterocycloalkylalkyl is optionally substituted with OH, cyano, amino, halo, Cι.6 alkyl, C6-Io aryl, Ci4 arylalkyl, C4-10 heteroaryl, C4. μ heteroarylalkyl, Cs cycloalkyl, or C3.8 heterocycloalkyl;
Rc and Rdare independently selected from H, Cs> alkyl, C|.6 haloalkyl, C2 6 alkenyl, C2.6 alkynyl, C6-I0 aryl, C3.8 cycloalkyl, C4 ! 0 heteroaryl, C3.8 heterocycloalkyl, Cu arylalkyl, C4-I4 heteroarylalkyl, C ι2 cycloalkylalkyl, and CVn heterocycloalkylalkyl, wherein said C,.6 alkyl, C|.6 haloalkyl, C2.6 alkenyl, C6 alkynyl, C6.10 aryl, C3.8 cycloalkyi, C4.|0 heteroaryl, C3.8 heterocycloalkyl, C7.|4 arylalkyl, C4.ι4 heteroarylalkyl, C5.|2 cycloalkylalkyl or C5.|2 heterocycloalkylalkyl is optionally substituted with OH, cyano, amino, halogen, C|-6 alkyl, C6.10 aryl, C7.|4 arylalkyl, Cβ-io heteroar>'l, CT.14 heteroarylalkyl, C3.8 cycloalkyl or C3.g heterocycloalkyl; or Rc and Rd, together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring, each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, Q 6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C6.10 aryl, C3.8 cycloalkyl, CYm heteroaryl, C3.g heterocycloalkyl. C6 haloalkyl, CN, NO2, N3, 0R\ and SR"; and n is O, 1 , 2, or 3.
In some embodiments, when R4 is SO2NR0R7, n is O, R2 and R3, together with the carbon atom to which they are attached, join to form a 1 ,3-dioxan-2,2-diyl ring, and R6 and R7, together with the carbon atom to which they are attached, join to form a pyrrolidinyl ring, R1 is not alkyl substituted with NH2, CN, N3, bromo, or a 7-membered cycloalkyl ring optionally substituted by CN or C6 cyanoalkyl.
In some embodiments, the invention provides compounds of Formula II:
Figure imgf000024_0001
(II). In some embodiments, R' is C6 haloalkyl, Ci^ hydroxyalkyl, or C6 cyanoalkyl.
23 In some embodiments, R' is Ci-6 haloalkyl.
In some embodiments, halogen is fluoro.
In some embodiments, R' is CF3
In some embodiments, one of R2 and R3 is C,.6 alkyl.
In some embodiments, one of R2 and R3 is ORa.
In some embodiments, R2 and R3, together wilh the carbon atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
In some embodiments, R2 and R3, together with the carbon atom to which they are attached, join to form a 6-membered heterocycloalkyl ring.
In some embodiments, the 6-membered helerocycloallcyl ring contains 1 or 2 heteroatoms.
In some embodiments, at least one heteroatom is O
In some embodiments, R2 and R3, together with the carbon atom to which they are attached, join to form a l,3-dioxan-2,2-diyl ring, l ,3-dioxolan-2,2-diyl. or tetrahydropyran-2,2-diyl ring.
In some embodiments, R" and R7, together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl πng.
In some embodiments, R6 and R7, together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
In some embodiments, R6 and R7, together with the N atom to which they are attached, join to form a pyrrolidinyl, morpholino, piperaziny!, or piperidinyl ring.
In some embodiments, the invention provides compounds of Formula III:
Figure imgf000025_0001
(III) wherein m is O, 1, 2, or 3 In some embodiments, m is. 2 or 3 In some embodiments, the invention includes a compound selected from Formulas IVa, FVb, and
IVc-
R7' R3
Figure imgf000025_0002
Figure imgf000025_0003
(IVa) (IVb)
Figure imgf000025_0004
24 In some embodiments, R is C1^ alkyl. optionally substituted with 1, 2, or 3 substituenls ..elected from C6-IO aiyl, C3 g cycloalkyl, C6-I0 heteioaryl and C3 8 heterocycloalkyl
In some embodiments, R is Ci 6 alkyl substituted with one substituent selected from C6 ,0 aryl, C, 8 cycloalkyl, C4 ,0 heteroaryl and C3 8 heterocycloalkyl
In some embodiments, Ci 6 alkyl is propyl
In some embodtments, Cy is C3 7 cycloalkyl
In some embodiments, Cy is cyclopropyl
In some embodiments, R1 is C .6 haloalkyl, C1* hydroxyalkyl, or Ci 6 cyanoalkyl.
In some embodiments, R' is C, 6 haloalkyl
In some embodiments, halogen is fluoro
In some embodiments, R1 is CF3.
In some embodiments, one of R3 and R1 is C,.6 alkyl.
In some embodiments, one of R2 and R3 is ORa
In some embodiments. R: and R3, together with the carbon atom to which they are attached, join to form a 5-7 membered cycloalkyl ring.
In some embodiments, R2 ana R1, together with the carbon atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring
In some embodiments. R2 and R3, together with the carbon atom to which they are attached, join to form a 6-membered heterocycloalkyl ring.
In some embodiments, the 6-membered heterocycloalkyl ring comprises 1 or 2 heteroatoms.
In some embodiments, at least one heteroatom is O.
In some embodiments, R2 and R3, together with the carbon atom to which they are attached, join to form a l ,3-dioxan-2,2-diyl nng, l,3-dioxolan-2,2-diyl, or tetτahydropyran-2,2-diyl ring
In some embodiments, R6 and R7, together w ith the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring.
In some embodiments, R6 and R7, together with the N atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring.
In some embodiments, R" and R7, together with the N atom to which they are attached, join to form a pyrrohdinyl, morphohno, piperazmyl, or pipeπdmyl nng
In some embodiments, the invention provides compounds of Formula V:
°
Figure imgf000026_0001
(V) wherein p ls ϋ. 1, 2, or 3 In some embodiments, p is 2 or 3.
25 At various places in the present specification, substituents of compounds of the invention are disclosed in groups or m ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "C1^ alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. It is further intended that the compounds of the invention are stable. As used herein ''stable" refers to a compound tha; 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.
It is further appreciated that certain features of the invention, which are, for clarity, described m the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.
As used herein, the term "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- propy] and isopropyl), butyl (e.g., n-bυtyl, lsobuty', t-buryl), 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.
As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include ethenyl. propenyl, and the like.
As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. Example alkynyl groups include ethynyl, propynyl, and the like.
As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include CF3, C2F5, CHF2, CCl3, CIICl2, C2Cl5, and the like.
As used herein, -'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,
As used herein, "arylalkyl" refers to an alkyl group substituted by an aryl group. Examp'.ary arylalkyl groups include, but are not limited to, benzyl and phenethyl.
As used herein, "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. In some embodiments, 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. Also included in the definition of cycloalkyl are 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 cither 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 sulfide substituent. Example cycloalkyl groups include eyclυpropyl, cyelobufyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadier.yl, cyclohcptatπcnyl. norbornyl, norpinyl, norcarnyl. adamantyl, and the like.
As used herein, a "cycloalkylalkyl" group refers to an alky! group substituted by a eyeloalkyl group An exemplary cycloalkylalkyl group includes, bul is not limited to cyclopentylmethyl and cyclohexylmethyl.
As used herein, a "heteroaryl" group refers to an aromatic heterocycle comprising at least one heteroatom ring member selected from sulfur, oxygen and nitrogen. Heteroaryl groups include monocyclic and fused, poiycyclic (e.g., heteroaryl comprising 2, 3 or 4 fused rings) systems. Any ring- forming N atom m a heteroaryl group can also be oxidized to form an N-ox o moiety or can be functionahzed to form an N-functionahzed group (e.g. N-alkyl or N-aryl). Examples of heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyπmidinyl, pyrazinyl, pyπdazinyl, triazinyl, furyl. quinolyl, isoquinolyl, thienyl. linidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl. benzofuryl, benzothienyl, benzthtazolyl, isoxazolyl, pyrazolyl. triazolyl, tetrazolyl, indazolyl, 1 ,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group comprises from 2 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 nng-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. As used herein, a "heteroarylalkyl" group refers to an alkyl group substituted by a heteroaryl group. An example of a heteroarylalkyl group is pyπdylmethyl.
As used herein, "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. As used herein, '"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 iings) ring systems as well as spirocycles. Examplary "heterocycloalkyl" groups include, but are not limited to, morpholmo, thiαmorphohno, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2.3-dihydrobenzofuryl, 1.3-benzodioxole, benzo-l ,4-dioxane, pipendmyl, pyrrolidinyl, isoxazolidmyl. lsothiazohdinyl, pyrazolidinyl, oxazohdinyl, thiazolidinyl. imidazokdin}!, and the like. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused ( i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthahmidyl. 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- aiomatic portion. Also included in the definition of heterocycloalkyl are moieties where one or more ring-forming atoms is substituted by 1 or 2 oxo or sulfide groups. In some embodiments, 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 heteroeyeloalkyl group further comprises 0 to 2 double bonds. In some embodiments, the heterocycloalkyl group comprises 0 to 2 triple bonds. As used herein, "heterocyeloalkylalkyl" refers to an alkyl group substituted by a heterocycloalkyl group.
As used herein, "halo" or "halogen'- includes fluoro, chloro. bromo. and iodo.
As used herein, "haloalkyl" refers to an alkyl group substituted by one or more halogen atoms.
Examples of haloalkyl groups include CF3 and CF2CF3. As used herein, "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 m optically active or raecmic 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. Many geometric isomers of olefins, C-N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers arc contemplated m the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
Compounds of the invention also include tautomeric forms. 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 - imidie 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.
1H- and 3H-imidazole, 1H-. 2H- and 4H- 1 ,2,4-triazole, 1H- and 2H- isoindole, and I H- 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. For example, isotopes of hydrogen include tritium and deuterium.
The term, "compound," as used herein is meant to include all stereoisomers, geometric losomers, tautomers. and isotopes of the structures depicted. All compounds, and pharmaceutical) acceptable salts thereof, are also meant to include solrated or hydra ted forms.
In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By "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. Methods for isolating compounds and their salts are routine in the art.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used 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. Generally, 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, cthanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17* ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977). The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, withm 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.
Synthesis
The compounds of the presen: 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. Scheme 1
Figure imgf000030_0001
Certain invented compounds (IV) were prepared according to the procedure of Scheme 1. Thus isatine sulfanamide (I) was converted to acetal (II) with 1,3-propanediol and /J-TsOH in benzene. Alkylation of the ring nitrogen was aceomplisehd using organohalides and organotosylates with K2CO:, m DMF at 60° C to produce (III), Deprotection of the aeetal in hot aqueous HClTHF produced the invented compounds (IV).
Scheme 2
Figure imgf000031_0001
(IV) (V)
Certain invented compounds (V) were prepared according to Scheme 2. Isatin sulfonamides (IV) were reduced in hot hydrazine monohydrate (90° C) and produced (V).
Scheme 3
Figure imgf000031_0002
Certain spiro oxindole sulfυnamideb (VIII) were prepared according to Scheme 3. Thus spiro oxindole (VT) was converted to the corresponding sulfonamide compounds (VII) using ClSOjH followed by treatment with amines. Alkylation of the oxindole nitrogen was accomplished using organohalides and organotosylates with K2CO3 in DMF at 60° C, and produced invented compounds (VTII).
Scheme 4
Figure imgf000031_0003
Certain invented compounds (XI) were prepared as shown in Scheme 4, Oxindole (IX) was converted to oxindole sulfonamides (X) via reaction with ClSO3H followed by treatement with amines. Peralkylalion (Nl and C3) was accomplished by treating (X) with 2-bromoacetonitπle, and produced invented compounds (Xl). Scheme 5
Figure imgf000032_0001
(XlI) CH2CI2, it (XiII) IXIV)
Certain imented compounds iXIV) were prepared according Io Scheme 5 Oxmdole (XII) was eomerted to oxmdole sulfonamides (XIIT) using ClSO3H, followed b> reaction with various amines Deprotonation with LDA in THF followed by trapomg with acrylomtπle and warming to 23 °C produced the desired imented comrjounds (XIV).
Scheme 6
Figure imgf000032_0002
(X) (XV) Certain imented compounds (XV) were prepared according to Scheme 6 Thus oxmdole sulfonamides (X) were condensed with cyclohexanone and pyrrolidine m warm benzene, and produced the imented compounds as Knovenegal adducts (XV)
Scheme 7
Figure imgf000032_0003
(!V) (XVI)
Certain imented oxazohnes (XVI) were prepared according to Scheme 7. Thus isatin sultonamides (IV) were combined with N-(Methox>methyl)-N-(tτimethylsilyl)benzylamme and TFA. and produced the desired im ented compounds (XVI).
J i Scheme 3
Figure imgf000033_0001
(XVIII) (XIX) (XX)
Certain invented spirotetrahydropyrans (XX) were prepared according to Scheme 8. Thus isatin sulfonamides (IV) were alkylated with the Grignard reagent formed using «-butyl(4- iodobutoxy)dimethylsilane, and produced n-butylalcohol compounds (XVIIl). Dcprotection of the TBS group with tetra-rt-butylammonium fluoride in THF produced bis(diol) compounds (XVIII). Selective conversion of the secondary butyl alcohol group to the corresponding tosylate produced (XIX). Cyclization via intermolecular ether formation was accomplished in the presence of KiCO3 in warm DMF and produced (XX).
Scheme 9
THF
Figure imgf000033_0002
Figure imgf000033_0003
(IV) (XXl)
Figure imgf000033_0004
Certain imented methoxy-oxindoles (XXII) were prepared as described in Scheme 9. Isatin sulfonamides (IV) were condensed with Grignard reagents in cold THF to proudce ffrf-alcohol compounds (XXI). Alky'.ation of the tert-alcohol compoαnds to the ether compounds in (XXI) mas accomplished using Me2SO4Zn-Bu4I in aqueous NaOHCHCl2 and produced the desired invented compounds (XXII).
11 Scheme 10
Figure imgf000034_0001
(XXI) (XXIII)
Certain invented oxindole sulfonamides (XXIII) were synthesized according to Scheme 10. Tert- alcohol compounds (XXI) were chlorinated using SOCIi, and produced intermediate chloro compounds, winch were reduced with Zn/IIOAc/THF, and produced the desired invented compounds (XXIII).
Scheme 11
Figure imgf000034_0002
(XXI) (XXIV)
Certain invented chloro-deπvatives (XXIV) were produced according to Scheme 11. Tert- alcohol compounds (XXI) were converted Io the corresponding chloro-derivatives (XXlV) using SOCl2.
Scheme 12
Figure imgf000034_0003
(XXI) (XXV)
Certain invented tluoro compounds (XXV) were produced according to Scheme 12. Alcohol compounds (XXI) were treated with DAST in CH2CU and provided the corresponding fluoro compounds (XXV).
Scheme 13
Figure imgf000034_0004
(I) (XXVI)
Figure imgf000034_0005
A similar method was employed to prepare other invented compounds, as summarized in Scheme
13. Thus isatm sulfonoamides (I) were condensed with Grignard reagents in at low temperatures in THF solvent, followed by warming to 23° C that produced teπ-alcoho compoundss (XXXVI). Conversion of the /erf-alcohol compounds (XXXVI) to corresponding fluoro compounds (XXXVII) was accomplished using DAST Alkylation of the oxindole mtiogen proceeded using organohalides or organotosylates in the presence Of K2COs m 1AaIm DMF, and produced N-iunctionahzed fluoro compounds (XXIII j
Scieme 14
Figure imgf000035_0001
(I) <xxιx) (XXX)
Ceitain invented oxindole dimethylacetals (XXX) were prepared according to Scheme 14 Isatm sulfonamides (1) were converted to the corresponding dimethylacetal compounds (XXIX) using MeOWp- TsOH. Alkylation or arylatton of the oxindole nitrogen proceeded using organohalides or organotosylates in the piesence Of K2CO3 in warm DMF, and produced the N-functionahzed dimethylacetal compounds (XXX)
Scheme 15
Figure imgf000035_0002
(XXXI) (XXXII) DMF
Figure imgf000035_0003
(XXXIII) (XXXIV)
Figure imgf000035_0004
(XXXV) (XXXVI)
Certain invented oxindole sulfonamide aeetals (III), summarized in Scheme 1 , were also synthesized according to Scheme 15 Thus isatm sulfonylchloπde (XXXI) was protected as a neopentyl ester (XXXIl) The corresponding eyclieacetal was synthesized by combining (XXXII) with 1.3- piαpanediol and /J-TsOH in benzene Alk) lation or arylation of the oλindole nitrogen was accomplished usmg organohalides or organotosylates to give N-fjnctionahzed acetal compounds (XXXIII) Deprotection of the sulfonic acid and conversion to the corresponding sulfonyl chlorides (XXXV) was accomplished using tetramethylam-momum chlonde m DMF sohent and heating, followed by tieatment with SOCl; in CHiCIi Convei«ion to the m\ented sulfonamide compounds (XXXM) was accomplished by treating the chlorosulfone compounds (λXX\ ) with various amines. Scheme 16
Figure imgf000036_0001
(XXXVIII) (XXX ,X)
Figure imgf000036_0002
(XL) (XLI)
Certain invented fluoro oxmdole sulfonamide compounds (XXIII), summarized in Scheme 13. were also prepared according to Scheme 16. Isatin sulfonic ester (XXXII) was converted to the corresponding tert-huXv\ carbmol using ?-BuMgCl at low temperatures m THF solvent. The corresponding fluoro compound (XXXVIIl) was prepared from (XXXVII) using DAST. Alkylation or arylation of the oxmdole nitrogen was accomplished using organohahdes or υrganotosylates and provided N-functionalized fluoro compounds (XXXIX). Deprotection of the sulfonic ester compounds and conversion to the corresponding sulfonyl chloride compounds (XL) was effected using using tetramethylammonium chloride in DMF solvent with heating, followed by SOCl2 m CH2Cl2 The invented compounds (XLI) are prepared by reacting the chlorosulfonyl compounds (XT ) with various amines in CH-Ch,
Scheme 17 Preparation of 1 '-Alkyl-2'-oxo-l ',2'-dihydrospiro[1,3-dioxane-2,3'-indole]-5'-earboxamides
Figure imgf000036_0003
(XLII) (XLIII (XLIV)
Figure imgf000036_0004
Figure imgf000037_0001
Certain invented oxindote acetal amide compounds (XLVIl) were prepared according to Scheme 17. Iodo-isatin (XLII) is converted to the corresponding cyclic acetal using 1 ,3 -propanediol andp-TsOH in benzene solvent with heating. Pd-catalyzed carbonylation of the aryliodide followed by trapping with MeOH produced the corresponding methyl ester compound (XLIV). Alkylation or arylation of the oxindole nitrogen ws accomplished organohalides and K2CO3 m DMF solvent with heating and produced corresponding N-functionalized acetal compounds (XLV). Saponification of the ester compounds produces the corresponding carboxylic acid compounds (XLVI). The invented amide compounds (XLVII) were produced from reaction of amines and peptide coupling agents, EDCI'HOBt.
Scheme 18
Preparation ofiV-[l'-Alkyl-2'-oxo-r.2'-dihvdrospiro[1,3-dioxane-2,3'-mdol1-5'-yl] amides and sulfonamides
Figure imgf000037_0002
Certain invented reversed amide compounds and reversed sulfonamide compounds (LV εnd LVl) were prepared according to Scheme 18. Nilru isatin (XLVIII) was converted to the corresponding cyclic acetal compound (XLIX) using 1 ,3-propanediol and/?-TsOH in benzene with heating. Reduction of the NO2 group to the corresponding amine compound (L) was accomplished using Raney Nickel and N2H4Η1O. Protection of the amine as the phthalimide (LI) was accomplished using phthalic anhydride; Et3N followed by heating in toluene, Alkylation or arylation of the oxmdole nitrogen with organohahdes produced N-functionakzed acetal compounds (LII). Deprotection of the amine with hydrazine in warm MeOH produced amino acetal compounds (LIII). Functionalization of the deprotected amine with sulfonyl chlorides and/or acid chlorides produced corresponding desired invented reversed amide compounds and reversed sulfonamide compounds (LV and LVl).
Scheme 19 Preparation of r-Aryl-5'-(pyrroIidin-l -ylsulfonyl)spirorri.31dioxane-2,3'-mdolin1-2'-ones.
Figure imgf000038_0001
(LVII) (LVIII)
Certain invented N-Aryl oxmdole compounds (LVIII) were prepared from corresponding 1'- hydro-5'-(pyrrolidin-1-ylsulfonyl)spiro[[1,3]dioxane-2.3'-indolin]-2'-one compounds using aryl boronie acids (Ar is a substituted aryl), copper acetate, amine bases such as Lt3N m aprotic solvents such as CH2Cl; (Scheme 19) .
Scheme 20
Preparation of Spirotetrahydropyran Amides.
Figure imgf000038_0002
(XLIII) (LIX) (LX)
Figure imgf000038_0003
(LXI) (LXII)
PdC
Figure imgf000038_0004
Figure imgf000038_0005
(LXIII) (LXIV) (LXV) Certain spirotelrahydrυpyran amide compounds (LXV) were prepared according to Scheme 20. Thus lodooxindolc acctai (XLIII) was alkylated using alkyl or benzylic halides in the presence of a weak base such as K2CO3 or Cs2COi in a polar aprotic solvent such as DMF, DMSO or acetone solvent, and produced N-alkyl- or N-benzyl-functionalized acetal compounds (LLX). Palladium catalyzed carbonylative animation was carried out using piperidine to produce amide oxoindole acetal compounds (LX). Hydrolysis of the acetal using 6N aqueous HCl produced isatin compounds (LXl). Selective addition of allyl magnesium bromide to the 3-carbonyl groupof the oxoindole core of (LXI) was accomplished in THF solvent at low temperatures. Alkylation of the resulting tertiary-1 alcohol compounds (LXII) using ally bromide was accomplished using NaOH or KOII in the presence of a catalytic amount of tri-n — buyl ammonium iodide, TBΛI. Cyclization/ring closure was accomplished using Grubbs catalyst on the resulting diene compounds (LXIII), and produced dihydropyran compounds (LXIV). Hydrogenalion using H2 in the presence of Pd/C catalyst, produced the desired invented compounds (LXV).
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. The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or '3C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography. 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 the selection of appropriate protecting groups can be readily 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. The reactions of the processes described herein can be carried out in suitable solvents, which can be readily selected by one of skill m the art of organic synthesis. Suitable solvents can be substantially non-rcacti\c 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. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.
Resolution of racemic mixtures of compounds cai be carried out by any of numerous methods known in the ait. An example method includes fractional recrystallization using a "cbiral resolving acid" which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallizaπ'on methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacet)'ltartaric acid, dibenzoyl tartaric 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.
Methods of Use
Compounds of this invention are able to interact with the CB2 receptor and therefore modulate the receptor's activity. The term "modulate" is meant to refer to an ability to increase or decrease aclivity 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 m an in vitro system or an in vivo system. For example, "contacting" a compound of the invention with the CB2 receptor 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.
As used herein, 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 CD2 receptor agonists. Thus, 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-substitutcd oxindole compounds described above to a patient in need thereof,
As used herein, 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, vetcπnarian, medical doctor or other clinician,
As used herein, 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, sjTio vial 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.
Combination Therapy
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. For example, one or more of the above-described 3-substituted oxindolc 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.
Pharmaceutical Formulations and Dosage Forms
When employed as pharmaceuticals, 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 These compositions can be prepared in a manner well known m 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 deliver,1 can include topical administration (eye drops), subconjunctival, periocular or mtravitreal 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. This invention also includes pharmaceutical 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. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an cxcφient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When 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, Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or m 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.
Tn preparing a formulation, 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. Some examples of suitable exeipients 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. The 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, l he term "unit dosage forms1' 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. It will be understood, however, that 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, For preparing solid compositions such as tablets, 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. When referring to these preformulation compositions as homogeneous, 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. For example, 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 m release, A variety of materials can be used for such 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.
The 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. The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, 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 seventy of the disease, the age, weight and general condition of the patient, and the like.
The 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 lyophihzed. the lyophihzed preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 1 1 , more preferably from 5 to 9 and most preferably from 1 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. For example, 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 adrninstration. Some typical dose ranges are from about 1 mg/kg to about 1 g/kg of body weight per day. In some embodiments, 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
The present invention also includes pharmaceutical 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. Such 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. The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncπtical parameters, which can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be CB2 agonists according to one or more of the assays provided herein. EXAMPLES Analytical LOMS
Samples were analyzed on an Agilent LC-1100-MSD. The mass spectrometer, utilized to confirm the integrity of the compound, was a single quadrapolc mass filter scanning from 100-1000 Da. 'I he 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 mi/mm. Eluent A was 0.1% HCO2H in water and eluent B was 0.1% HCO2II in ACN. The HPLC mobile phase gradient was initiated at 100% eluent A followed by a linear increase to 100% eluent B m 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 HPLC7MS ran time was 5.5 minutes. Compounds were diluted to -1.0 mg/mL in DMSO. The analysis injection volume was 5 μL. The HPLC column used was a Thermo Electron Corporation. Aquasil Cl 8, 50 x 2, 1 mm, 5 μm particle size.
Preparative reverse-phase HPLC (RP-HPLO:
Compounds were in dissolved in 2 niL of 1 : 1 DMSO:McCN, filtered through a 0,45 μm GMF, and purified on a Gilson HPLC, using a Phenomencx LUNA Cs column: 60 mm x 21.2 mm I.D., 5 μm particle size: with ACN/H2ϋ (containing 0.2% TFA) gradient elution (95:5 H:O:MeCN to 10:90
H2OiMeCN; 8 minutes running time.
Example 1
5'-(Pyrrolidin-1-yIsuIfonyl)spiro[1,3-dioxane-2,3'-indol]-2'(ri/)-one
Figure imgf000045_0001
To a slurry of 5-(pyrrolidin-1-ylsulfonyl)-l//-indole-2,3-dione (Lee, D. et al. J. Med. Chem. 2001, 44, 2015) (6.090 g, 21.73 mmol) in benzene (435 mL) was added 1 ,3-propanediol (6.28 mL, 86.9 mmol) and/?-toluenesulfonic acid monohydrate (827 mg, 4.35 mmol). The reaction was heated at reflux under a Dean-Stark trap for 4 hours, becoming a clear, brown solution, then cooled to room temperature and concentrated in vacuo. The residue was dissolved m CHiCl; (500 mL). washed with saturated aqueous NaHCOj (300 mL) and saturated aqueous NaCl (300 mL). then dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash chromatography (40 g silica gel, 10% EtOAc CH2Cl2) to provide the title compound as a white solid (5.88 g, 81%). 1H NMR (400 MHz, DMSO-4): consistent; MS (ES ) m/z 337.1 (M-H). Example 2 3-{2'-Oxospiro[1,3-dioxane-1.3'-|3//]indol]-5'-(l-pyrrϋlidinylsuIfonyl)}propanenitrile
Figure imgf000046_0001
To a slurr>τ of 5l-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-indolJ-2'(l '//)-one (3.555 g. 10,51 mmol) in EtOH (53 mL) was added benzyltπmethylammonium hydroxide (477 μL of a 40% w/ w solution in MeOH, 1.05 mmol) The reaction was heated at reflux temperature for 1 hour, becoming a clear, brown solution. The reaction was cooled to room temperature (rt), causing the precipitation of a solid, which was collected by vacuum filtration to provide the title compound as a tan solid (2.679 g. 65%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES-) m/z 392 (M+H).
Example 3 3-[2,3-l)ioxo-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihydro-l//-indol-1-yl]propanenitrile
Figure imgf000046_0002
To a slurry of 3H2'-oxospiro[1,3-dioxane-1,3t-[3//]indol]-5'-(l- pyrrohdinylsulfonyljjpropancnitrilc (4.526 g, 1 1.56 mmol) in THF (58 mL) was added HCl (58 mL of a 6 M aqueous solution). The reaction was heated at 70° C for 6 hours, becoming a clear, orange solution. The reaction was cooled to rt. causing the precipitation of a solid, which was collected by vacuum filtration to provide the title compound as a yellow solid (3.400 g, 88%). 1H NMR (400 MHz, DMSO- db): consistent; MS (ES1) m/z 334.1 (M+H).
Example 4 3-[2-Oxo-5-(pyrrnlidin-1-ylsulfoπyl)-2,3-dihydro-l//-indol-1-yl]propanenitrile
Figure imgf000046_0003
A slurry of 3-[2,3-dioxo-5-(p>rrrolid:n- l -y]sulfonyl)-2J-dihydro-l//-indυl-1-yl]propanenitrile (40.0 mg, 0.120 mmol) in hydrazine monohydrate (367 μL, 7.56 mmol) was heated to 90° C for 3 hours, becoming a black solution. I he reaction was cooled to rt, diluted with HiO (5 mL) and extracted with CH2Cl2 (3 χ 2 mL). The combined organic extracts were washed with H2O (3 * 2 mL), then dried over N^SQ4, filtered, and concentrated in vacuo to an orange solid that was purified by flash chromatography (4 g silica gel, 10% LtOAc-CIl2CIz to 5% MeOIt-CH2CL step gradient) to provide the title compound as a white solid (4.0 mg, 5%). 1H NMR (400 MHz, CDCl3), consistent; MS (ES-) m/z 320 (M+H). Example 5 3-[2'-Oxo-S'-(pyrrolidin-1-yIsulfonyl)spiro(cyclohexaπe-1,3'-indol]-r(2'//)-yl]propanenitrile
Figure imgf000047_0001
Step 1
5 '-(Pyrrolidin-l-ylsulfonyl)spiro[cyclohexane-l,3 '-lndolln]-2 '-one
Figure imgf000047_0002
To spiro[cyclohexane-1.3'-indolin]-2'-one (Kende, A. S.; Hodges, J C. Synth Cominun. 1982, 12, 1 ) (641.0 mg, 3.185 mmol) was added 0° C chlorosulfonic acid (1 mL). The resulting red solution was stirred at rt for 1 hour then heated at 70° C for 1 hour. The reaction was cooled to 0° C and quenched by the dropwise addition Of H2O (3 rnL), causing the precipitation of the sulfonyl chloride, which was collected by vacuum filtration.
To a solution of the crude sulfonyl chloride m CH2CI2 ( 15.9 mL) was added pyrrolidine (665 μL, 7.96 mmol). The brown solution was stirred at rt for 1 hour, then concentrated in vacuo to a brown oil that was purified by flash chromatography (40 g silica gel, 0-2% MeOH-CH2Cl2 step gradient) to provide the title compound as a red foam (498.9 mg, 47%). 1II NMR (400 MlIz, CDCl3): consistent.
Step 2 3-[2'-Oxo-5'^pyrrolidin-l-yhulfonyl)spiro{tγclohexane-l,3'-indυl/~l '(2Η)-ylJpropanenitriIe
Figure imgf000047_0003
To a solution of 5'-(pyrrolidm-l -ylsulfonyl)spiro[cyclohexane-l ,3'-indohnJ-2'-one ( 139.8 mg.
0.4180 mmol) m DMF (418 μL) was added K2CO3 (173 mg, 1.25 mmol) then 3-bromopropionitπle (41.6 μL, 0.502 mmol). The reaction was stirred at rt for 2 hours, then passed through a plug of silica gel (eluting with CII2CL). The eluent was concentrated in vacuo, and the residue was dissolved in CILCI2 (4 mL). washed with HO (3 * 4 mL) and saturated aqueous NaCl (4 mL), dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound as an orange film (96.8 mg, 60%). 1H NMR (400 MH/, CDCl3): consistent; MS (RS^) m>'z 388.1 fM+Hj. Example 6 3,3'!3"-[2-Oxo-5-(pyi roIidin-1-ylsulfonyl)-2,3-dihydro-l//-indole-1,3,3-triyl]tripropanenitrile
Figure imgf000048_0001
Step 1
S-(Pyrrolidin-l-ylsulfotιyI)mdolin-2-one
Figure imgf000048_0002
A procedure similar to that of Step 1 of Example 5, using oxindole (506,4 mg, 3,803 mmol), provided the title compound as a pink solid (430.1 mg, 42%), 1H NMR (400 MHz, CDCl3): consistent; MS (ES*) mlz 267.1 (M+H).
Step 2 3,3',3"-[2-Oxo-5-(pyrrolidin-l-yhulfonyl)-2,3-dihydro-l\{-indole-l,3,3-triyl]triprυpanenHrile
Figure imgf000048_0003
To a solution of 5-(pyiτolidm-l -ylsulfonyl)indolrn-2-one (21.1 mg, 0.0792 mmol) in DMF (80 uL) was added K2CO5 (53 mg) then 3-bromopropionitπle (19.7 μL). The reaction was stirred at rt for lhour. Tetrabutylammonium iodide (catalyst) was added, and the reaction was heated at 50° C for 16 hours. The reaction was cooled to rt, and directly subjected to flash chromatography (4 g silica gel, 0-1% MeOII-CH3Cb step gradient) to provide the title compound as a colorless film (14,2 mg, 42%). 1H NMR (400 MHz, CDCl,): consistent; MS (ES') m/z 426.2 (M+H).
Example 7 3-[3-Cyclohexyl-2-øxo-5-(pyrrolidin-1-ylsulfonyI)-2,3-dihydro-l//-indol-3-yIlpropancnitrile
Figure imgf000048_0004
Step l
3-Cyclohex)'I-5-φyrroIidin-l-ylsulfonyl)indolin-2-one
Figure imgf000049_0001
A procedure similar to that of Step 1 of Example 5, using 3-eyelohexyhndohn-2-one (VoIk, B.t Mezei, T . Sirnig, G. Synthesis 2002, 595) (383.9 nig, 1.783 mmol), provided the title compound, m the form of a yellow foam (562.6 rag. 91S). 1H NMR (400 MHz, CDCL): consistent
Step 2 3-[3-Cyclohexyl-2-øxo-5-(p}ψrolidin-l-ylsulfonyl}-2y3-dih}Φo-lU-indol-3-}ilpr#panenitrile
Figure imgf000049_0002
To a -78 °C solution of 3-cycloheκy]-5-(pyiτolidin-1-ylsulfonyl)indohn-2-one (38.2 mg, 0.110 mmol) in I HP (1.10 mL) was added lithium dπsopropylamide (60.3 μL of a 2.0 M solution, 0.121 mmol) dropwise. The reaction was stirred at -78° C for 1 hour, then acrylomtπle (7.4 μL, 0 12 mmol) was added The reaction was stirred at -78° C for 1 hour, then rt for 16 houis The reaction was quenched by the addition of saturated aqueous NII4Cl (4 mL) and extracted with CHiCU (4 mL). The organic extract was dried over Na2SO4, filtered, and then concentrated in vacuo to a yellow oil that was purified by flash chromatography (4 g silica gel, 10% EtOAc-CHiCl2) to provide the title compound as a colorless film (3 6 mg. 8%) 1H NMR (400 MHz, CDCl3) consistent MS (FS") m/z 402 (M+H)
Example 8
S-Cjclohexjlidene-S^pyrrolidin-1-jlsulfonjlJ-l^-dihjdro-l/f-indol-1-one
Figure imgf000049_0003
I o a solution of cyclohexanone ( 134.1 μL, 1 294 mmol) m PhH ( 10 mL) was added pyrrolidine ( 124 6 μL, 1 ,493 mmol). The reaction was heated at reflux under a Dean-Stark trap for 1 hour, then cooled to rt and added to 5-(pyrrolidm-1-\lsulfonyl)indolm-2-υne (201 0 mg, 0 7547 mmol) The iesulttng pmk slurry was heated at 50° C for 24 hour, then concentrated in \ acuo to an orange solid that m as purified by flash chromatography (9 g silica gel, 10-15% EtOAc-CH2Cl2 step gradient) to provide
4« the title compound as a tan solid (183 O mg. 53%) 1H NMR (400 MHz5 CDCl3): consistent: MS (ES+)
Figure imgf000050_0001
Example 9 3-[3'-Beπzyl-2-oxo-5-(pyrrolidin-1-ylsulfonyl)spiro[indole-3,5'-[1,3]oxazoIidinJ-l(2i^)- jl]propanenitrile
Figure imgf000050_0002
To a slurry of 3-[2.3-dioxo-5-(pyrrohdin-1-)/lsulfon}4)-2,3-dihydro-l//-mdol-1-yI]propanenilnle (52 2 mg, 0 157 mmol) m CH2CI2 (2 6 mL) w as added A'-metho\y-N-(tnmethylsilylmethyl)benzylamme (44 1 μL, 0 172 mmol). then tnfluoracetic acid (1 ,2 μL, 0.016 mmol). l he reaction was stirred at rt for 4 hours, becoming a clear, yellow solution. The reaction was concentrated in vacuo to a yellow film that was purified by flash chromatography (12 g silica gel, 10-20% EtOAe-CH^CU step gradient) to provide the title compound as a yellow foam (34 3 mg. 47%) 1H NMR (400 MIIz, CDCl3): consistent; MS (ES ) m/z 467.3 (M HI).
Example 10
3-[3-Hydroxy-3-(4-h}droxybutyl)-2-oxo-5-(pyrroIidin-1-ylsulfonyI)-2,3-dihydro-l//-indol-1- yljpropaneiiitrile
Figure imgf000050_0003
Step ! l-β-(4-(tert-Butyldimeώylsilyloxy)buiyl)-3-hydroxy-2-oxo-S-(pynolidin-I-ylsulfonylJindolin-l- yljpropanenitrile
Figure imgf000050_0004
To a mixture of magnesium turnings (609 mg, 25 1 mmol) and bt->0 (5 mL) was added iodine (cat ) then a solution of terrtutyl(4-iodobuto'(cy)diniethylsilane (6.49 mL. 25.0 mmol) m Et2O (45 mL) dropwise o\er 30 minutes, during which time the brown; iodine color dispersed and the ieaction began to reflux. The ieaction was stirred for an additional 30 minutes at rt, then added dropwise to a -78° C slurry of 3-[2,3-dioxo-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihydro-l //'-indol-1-yl]propanenitrile (2.088 g, 6.263 mmol) in THF (63 inL). The reaction was stirred at -78 DC for 30 minutes then 0c C for 1 5 hours, becoming a brown solution. The reaction was quenched by the addition of saturated aqueous NH4Cl (300 mL) and extracted with Et2O (2 "< 200 niL) and CH2Cl2 (2 x 200 mL). The combined organic extracts were washed with saturated aqueous NaCl (200 mL), then dried over Na2SO4, filtered, concentrated in vacuo, and purified b> flash chromatography (40 g silica gel, 10-40% EtOAc-CII2Cl2 linear gradient) to provide the title compound as an orange foam ( 1.56 g, 48%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES") m/z 522.1 (M+H).
Step 2
3-f3-Hydroxy-3-f44ιydroxγbutyl)-2-oxo-5-(pyrrolidin-l-ylsulfϋnyl)-2,3-dihydro-lll-indol-l- yljpropanenitrile
Figure imgf000051_0001
To a 0c C solution of 3-(3-(4-(/erf-but>rldimethylsilyloxy)butyl)-3-hydroxy-2-oxo-5-(pyrrolidin- l -ylsulfonyl)indolin-l -yl)propanenitrile (247.0 mg, 0.4734 mmol) in THF (4.7 mL) was added tetrabutylammonium fluoride (521 μL of a 1.0 M solution in THF, 0.521 mmol). The reaction was stirred at rt for 5 hours, becoming a green solution. The reaction was diluted with HjO (25 mL) and then extracted with BtOAc (2 * 25 mL). The combined organic extracts were washed with saturated aqueous NaCl (25 mL), then dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash chromatography (9 g silica gel, 5% MeOH-CH2CL) to provide the title compound as a yellow foam (138.8 mg, 72%). 1H NMR (400 MIIz, CDCl3): consistent; MS (ES") m/∑ 408.2 (M+H).
Example 11
S-Il-Oxo-S-djyrrolidiii-1-ylsulfoπyl^'^'^'.ό'-tetrahjdrospirolindole-S.Z'-pyranj-lfl//)- yllpropanenitrile
Figure imgf000051_0002
Step 1
4-(l-(2-Cyattoethyl)-3-hydroxy-2-υxo-5-(p) rroHdiιi-l-ykuIfonyl)indalin- 1-yl)hutyl 4- methylhenzenesulfonate
.,OTs
Figure imgf000052_0001
To a solution of 3^34wdrox.y-3-(44iydroxybutyl)-2-oxo-5-(pyτiohdir)-1 -ylsulfonyl)-2 ''-dihydro- l //-indol-l -jl]propanenitπle (594 6 mg, 1 459 mmol) in CHiCl2 ( 14 6 niL) was added tπethylamme (813 5 μL, 5 837 mmol) then p-toluenesulfonvl chloride (417,3 mg, 2 189 mmol) The reaction was stirred at rt for 18 hours, "hen diluted with H2O (100 rriL) and extraced wiih CH2Cl2 (3 x 100 niL) The combined organic exttacts were w ashed with H2O (100 ml ) and satuiated aqueous NaCl (100 mL), then dried ovei Na2SO4, filtered, concentrated in vacuo, and purified by flash cinematography (12 g silica gel, 0 14% MeOH m CH2Cl2 linear gradient) to provide the title compound as a white foam (810 7 mg, 99%) 1H NMR (400 MHz, CDCL) consistent MS (EST) m/z 562 1 (M+H)
Step !
3-f2-Oxo-5~(pyrwlidin-l-ylsιιlfønyl)-3',4',5',6'-tetrahydrospiro[indole-3,2'-pymnJ-l(2Η)- yljpropanen itrile
Figure imgf000052_0002
I o a solution of 4-(l-(2-c>anoethyl)-3-hydro\y-2-o\o-5-(pwolidm- l-ylsulfonyl)indolm-3- yl)butyl 4-methylbenzenesulfonate (810 7 mg, 1 443 mmol) m DMF (14 4 mL) was added K2CO3 (997 mg, 7 22 mmol) The reaction was headed at 60° C for 20 houi* The ieaction was cooled to rt, diluted with HiO (200 mL), and extracted w ith CH2Cl2 (3 * 100 TiL). The combined organic exttacts weie washed with H7O (3 v 100 mL) and saturated aqueous, NaCl (100 mL), then dried o\ei Na2SO4 concentrated in vacuo, and purified by flash chromatography ( 12 g silica gel, 0-5% MeOH-CH2CL lineal gradient) to pi ovide the title compound as a white solid (294 4 mg, 52%) 1II NMR (400 MIIz, CDCL) consistent MS (ES ) m z 390 2 (M+H)
Sl Example 12
S-lS-CycIohexyl-S-hydroxy-1-oxo-S-fpyrroHdin-1-ylsulfonylJ-ZjS-dihydro-1H-iπdol-1- yl I propancnitrilc
Figure imgf000053_0001
To -78 °C slurry of 3-[2,3-dioxo-5-(pyrrϋlidin-l -ylsulfonyl)-2,3-dihydro-1 //-indol-l - yl]propanenitrile (169.2 mg. 0,5076 mmol) in TIIF (5.1 mL) was added cyclohcxylmagnesium chloride (38U.7 μL of a 2.0 M solution m Et;O, 0.7613 mmol). The reaction was stirred at -78° C for 1 hour. Additional cyclohexylmagiiesium chloride (380,7 μL of a 2.0 M solution in Et2O, 0.7613 mmol) was added. The reaction was stirred at -78° C for I hour, then quenched by the addition of saturated aqueous NH4Cl (20 mL), and extracted with CII2CK (3 * 20 mL). The combined organic extracts were washed with saturated aqueous NaCl (20 mL). then dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash chromatography (12 g silica gel, 10-20% EtOAc in CH2Cl2 step gradient) to provide the title compound as a yellow film (90.0 mg, 43%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES') mlz 418.1 (M-H).
A procedure similar to that of Example 12, using different Gπgnard reagents, provided Examples 13-20. The compounds and their analytical data are shown in Table 1.
Table 1 Compounds Prepared According to the Procedure of Example 12.
Figure imgf000054_0001
Example 21
3-[3-Cyclohe.\yl-3-meHioxy-2-o\o-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihydro-l//-indol-1- yl]propanenitrile
Figure imgf000055_0001
To a solution of 3-[3-eydohexyl-3-rtydroxy-2-oxo-5-(pyrrolidin-1 -y1sulfonyl)-2,3-dihydro-l//- mdol-l -yl]piopanenitπ1e (22.5 mg, 0.0539 mmol) in CII^Cl2 (539 μL) was added tetra-«-butylammonium iodide (0.2 mg, 0.0005 mmol) then NaOH (65 μL of a 2.5 M aqueous solution, 0, 16 mmol) then dimethylsulfate (10,2 μL. 0, 108 mmol). The yellow solution was stirred at rt for 18 hours. The reaction was diluted with a mixture of H2O (1 πiL) and saturated aqueous NH4Cl (1 mL) and extracted with
CH2CI2 (3 >■' 2 mL). The combined organic extracts were then dried over Na2SO4, filtered, concentrated in vacuo, and purified by HPLC (Phenomenex Luna C 18, 10-100% MeCN-H2O linear gradient containing 0.05% NH4OH) to provide the title compound as a white foam (7.2 mg, 31%). MS (ES+) m/z 432 1 (NHH).
Λ procedure similar to that of Example 21 provided Examples 22-30. The compounds and their analytical data are shown in Table 2.
Table 2: Compounds Prepared According to the Procedure of Example 21
Figure imgf000056_0001
Example 31 3-[3-Cyclohexyl-2-oxo-5-(py» rolidin-1-ylsulfonyI)-2,3-dihydro-l//-indol-1-yl]propanenitriIe
Figure imgf000056_0002
To a 0° C solution of 3-[3-cyclohexyl-3-hy<jroxy-2-oxo-5-(p>τrolid)π-1-ylsulfonyl)-2,3-dihydro- l //-indol-l -yl]propanenitrile (57,5 mg. 0, 138 mmol) m CII2Cl2 (1.38 mL) was added ,V,Λ- dπsopropylethylamine (98.3 μL, 0.551 mmol) then thionyl chloride (138 μL of a 2.0 M solution m CH2Cl2, 0,275 mmol) dropwise. The resulting brown solution was stirred at rt for 10 minutes. The reaction was quenched by the addition of saturated aqueous NaHCO3 (5 mL) and extracted with CHiCh (3 * 2 mL). The combined organic extracts were then dried over Na2SO^ filtered, and concentrated in vacuo to provide the chloride as a brown oil.
To a 0° C solution of the crude chloride in 9: 1 THF-AcOH (1.38 mL) was added zmc dust (270 mg, 4.13 mmol). The resulting browr suspension was stirred at rt for 24 hours. The reaction was filtered through Celite (washing with EtOAc and H2O). The filtrate was diluted with H2O (4 mL) and extracted with EtOAc (2 χ 4 mL), The combined organic extracts were washed with saturated aqueous NaHCO3 (2 mL) and saturated aqueous NaCl (2 mL), then dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash chromatography (4 g silica gel, 3-5% EtOAc m CII2Cl2 step gradient) to provide the title compound as a yellow oil (25.4 mg, 46%), 1H NMR (400 MHz, CDCl5): consistent; MS (ES') m/z 402,2 (M+H),
A procedure similar to that of Example 31 provided Examples 32-40. The compounds and their analytical data are shown in Table 3.
Fable 3: Compounds Prepared According to the Procedure of Example 31
Figure imgf000058_0001
Example 41 3-[3-tert-Butyl-3-chloro-2-oxo-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihydro-l//-indol-1-ylJpropanenitrile
Figure imgf000059_0001
To a 0° C slurry of 3-f3-/ert-butyl-3-hydroxy-2-oxo-5-(pyrrolidin- 1 -ylsulfonyl)-2,3-dihydro-l//- indol- 1 -yljpropanenitrile (46.4 mg, 0.119 mmol) in CH2Cl2 ( 1.2 mL) was added ALV-
Figure imgf000059_0002
(84.6 μl,, 0.474 mmol) then thionyl chloride (1 19 μL of a 2.0 M solution .n CH2Cl2, 0.237 mmol), dropwise. I he resulting brown solution was stirred at rt for 10 minutes. The reaction was quenched by the addition of saturated aqueous NaHCO3 (5 mL) and extracted with CH2Cl2 (3 χ 2 mL). The combined organic extracts were washed with saturated aqueous NaCl (3 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to a brown oil that was triturated with 1 : 1 H2O-McClN to provide the title compound as a yellow solid (10.5 mg, 22%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES*) mlz 410.2 (M+H).
Example 42
3-(3-tert-Butyl-3-fluoro-2-oxo-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihyclro-li/-indol-1-yl]propanenitrile
Figure imgf000059_0003
To a 0° C slurry of 3-[3-rcrt-butyl-3-hydroxy-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//- indol-1-yl]propancmtπlc (55.5 mg, 0.142 mmol) ir, CH2Cl2 (473 μL) was added NA'-diethylaminosulfur tri fluoride (DAST, 24.4 μL, 0.184 mmol). The resulting yellow solution was stirred at 0° C for 10 minutes, then quenched by the addition of saturated aqueous NaHCO3 (3 mL), and extracted with CH2Cl2 (3 x 2 mL). The combined organic extracts were washed with saturated aqueous NaCl (3 mL), then dried over Na2SO4. filtered, and concentrated in vacuo to a white solid that was triturated with H2O to provide the title compound as a white solid (42.8 mg, 77%). 1H NMR (400 MHz, CDCl-): consistent; MS (ES ') m/z 394.2 (M+H).
Example 43
1 '-But-3-yπ-1-j'l-5' -(p yrrolidin-l -ylsu!fonyl)spiro[ 1 ,3-dioxane-2,3 '-indøl] -2 ' (l'H)-one
Figure imgf000059_0004
To a solution of 5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l '//)-one (60.0 mg,
0.1 V mmol) m DMF (355 μL) was added K2CO3 (73.5 mg. 0.532 mmol) then 3-butynyl p- toluenesulfonate (37.6 μL, 0.213 mmol). The reaction was heated at 60° C for 24 hours. Additional 3- butynyl p-toluenesulfonate (37.6 μL, 0.213 mmol) was added. The reaction was heated at 60° C for 24 hours. The reaction was cooled to it. diluted with CH2Cl2 (4 mL), washed with H2O (3 x 2 mL) and saturated aqueous NaCl (2 mL), then dried over Na2SO4, filtered, concentrated in vacuo, and purified by HPLC (Phenomenex Lur.a Cl 8, 10-100% MeCN-H2O linear gradient containing 0.05% NH4OH) to provide the title compound as a white solid (48.5 mg, 70%). MS (ES") ink 391.2 (M+H).
A procedure similar to that of Example 43, using different alkyl halides, provided Examples 44- 59. The compounds and their analytical data are shown in Table 4.
Table 4; Compounds Prepared According to the Procedure of Example 43.
Figure imgf000061_0001
Figure imgf000062_0001
Example 60 3-tert-Bιιtjl-1-but-3-yn-1-yl-3-fluoro-5-(pyrrolidin-1-ylsullonyl)-1,3-dihydro-2//-indol-2-onc
Figure imgf000062_0002
Step 1
3-tert-Butyl-3-hydroxy-5-(pyrrølidin-l-ylsulfonyl)indolin-2-one
Figure imgf000062_0003
To a -78 ϋC slurry of 5-(pyrrolidin-1-ylsulfonyl)-l//-mdole-2.3-dione (2,320 g. 8,277 mmol) m
THF (82.8 mL) was added tøf/-butytmagnesium chloride (20.7 mL of a 2.0 M solution in Et20, 4'..4 mmol), The reaction was stirred at 78° C for 1 hour, thenwarmed to rt and stiiτed for 19 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl (300 mL) and extracted with CH2Cl2 (3 "< 200 mL). The combined organic extracts were washed with saturated aqueous NaCl (300 mL), then dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash chromatography (90 g silica gel, 20 30% EtOAc in CH2Cl2 step gradient) to provide the title compound as a yellow solid (970 mg, 35%). 1H NMR (400 MHz, DMSO-J6): consistent; MS (ESl m'z 339.2 (M+H).
Step 2 3-tert-Butyl-3-fluoro-5~(pyrrolidin-l-yl$ulfonyl)indølin-2-onέ
O TJ>° H
A procedure similar to that of Example 42, using 3-f^rf-butyl-3-hvdroxy-S-(p}<rrolidin-l - ylsulfonyl)indohn-2-one (851 mg, 2.51 mmol), provided the title compound as a pink foam (798 mg, 93%). 1H NMR (400 MHz, CDCh): consistent.
Step 3
3Aert-Butyl-l-hut-3-yn-l-yl-3-fluøro-5-(pyrrølidin-l-yhulfonyl)-l,3-dihydro-2il-indol-2-one
Figure imgf000063_0001
A procedure similar to that of Example 43. using 3~tørf~butyl-3-fluoπ>5-(pyrrolidin-l - ylsulfonyl)indolm-2-one (26.7 mg, 0.0784 mmol), provided the title compound as a white film (17.9 mg. 58%). MS (ESl mk 393.1 (M+H).
A procedure similar to that of Example 43, using 3-/erf-butyl-3-fluoro-5-(pyrrolidin-l - }<lsulfonyl)indolin-2-one (30.0 mg. 0.0881 mmol) and different alkyl halides. provided Examples 61 -76 The compounds and their analytical data are shown in Table 5.
Table 5 Compounds Prepared According to the Procedure of Example 43.
Figure imgf000064_0001
Figure imgf000065_0001
Example 77 l-But-3-yn-1-yl-3,3-dimethoxy-5-(pyrroIidin-1-ylsulfon\l)-1,3-dihydro-2i/-indol-2-one
Figure imgf000065_0002
Step l
$f3-Dimethøxy-5-(pyrrohdin-l-ykulfonyl)indolin-2-one
Figure imgf000065_0003
To a solution of 5-(pyrrolidin-1-ylbulfon>l ι-1H-mdole-2,3-dione (96 O mg. 0 342 mrnol) n MeOH (6 8 ml ) was added />toluenesulfonic acid monohydrate (13 0 mg, 0 0685 ramol). The reaction was heated at reflux for 3 days, then cooled to it, quenched by the addition of saturated aqueoαs NaHCO-, (30 ml), and extracted with CH2Cl2 (2 χ 60 mL) The combined organic extracts were washed with saturated aqueous NaCl (30 mL}, then dried over N^SO4 filtered, and concentiated to pio^ ide the title compound as a black film that was used without further purification (97 9 mg, 88%). Step 2 l-But-3-yn-l-yl-3,3-dimethoxy-5-(pyrrolidin-l-ylsulfonyl)-l,3-difιydro-2H-indol-2-one
Figure imgf000066_0001
A procedure similar to that of Example 43, using 3,3-dimethoxy-5-(pyrrohdin-l - y!sulfonyl)mdohn-2-one (97,9 mg, 0.300 mmol). provided the title compound as a clear, colorless oil (46.6 mg, 41%). MS (ES ') m/z 379 1 (MtH).
Example 78 r-But-3-yn-1-yl-NVV-dimethyl-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indoIe]-5'-sulfonamide
Figure imgf000066_0002
Step I
Neopentyl 2,3-dioxoindoline-S-sulfonate
Figure imgf000066_0003
To a slurry of 2,3-dioxomdoline-5-sulfonyl chloride (Lee, D. et al. J. Med. Chem. 2001, 44, 2015) (7,07 g, 28.8 mmol) m CH2Cl2 (288 mL) at rt was added neopentyl alcohol (7.61 g, 86.3 mmol) then pyridine (11.6 mL, 143 mmol). The reaction was stirred at rt for 22 hours, becoming a clear, oiange solution. The reaction was diluted with ILO (300 mL) and extracted with EtOAc (2 χ 600 mL). The combined organic extracts were washed with 0.1 M aqueous HCl (3 * 300 mL), saturated aqueous NaHCO3 (300 mL), and saturated aqueous NaCl (300 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound as a yellow solid (6.40 g, 92%). 1H NMR (400 MHz, CDClj): consistent; MS (ES ) m'z 315.1 (,VHH2O).
Step 2
Neopentyl 2 '-oxospiro[[J ,3Jdio.xane-2,3 '-indølineJ-5 'sulfonate
Figure imgf000066_0004
A procedure similar to that of Example 78, Step 1 using neopentyl 2,3-dioxomdolme-5-sulfonate (6,40 g, 21.5 mmol), provided the title compound as a white solid (5.27 g, 69%). 1H NMR (400 MHz, CDCl1): consistent; MS (ES-) m/z 373.1 (Mi-H2O).
Step 3
Neopentyl 1 '-(but-3-ynyl)-2 '-øxospiro[[l ,3]dioxane-2,3 '-indolineJ-5 'sulfonate
Figure imgf000067_0001
A procedure similar to that of 43, using neopentyl 2'-oxospiro[[l,3]dioxane-2,3'-indohne]-5'- sulfonate (1.015 g, 2.856 mmol). provided the title compound as a colorless oil ( 1.016 g, 87%). 1H NMR (400 MHz, CDCl3): consistent.
Step 4
1 '-(But-3-ynyl)-2 '-oxospiroHl,3]dwxane-2,3 '-indolineJ-S '-sulfonyl chloride
Figure imgf000067_0002
To a solution of neopentyl 2'-oxospiro[[l,3]dioxane-2,3'-indoline]-5'-sulfonate (1.016 g, 2.493 mmol) in DMF (2.49 mL) was added tetramethylatnmonium chloride (301 mg, 2.742 mmol). The reaction was heated at 160° C for 1 hour, then cooled to rt and concentrated by stirring at 50° C under high vacuum. The residue was dissolved in CH2Cl2 and concentrated in vacuo to provide the sulfonic acid. To the crude sulfonic acid was added thionyl chloride (6.23 mL of a 2.0 M solution m CH2Cl3,
12.5 mmol). The reaction was heated at 40° C for 20 hours, then concentrated in vacuo. The residue was dissolved in CHiCl? and concentrated in vacuo to provide the title compound as a brown oil lhat was used without further purification. MS (ES*) m/z 356.0 (M+H).
Step 5
1 '-But-3-yn-l-yl-yi,^-dimethyl-2 '-oxo-1 ',2 '-dihydrospiro[l,3-dioxane-2,3 '-indolef-5 'sulfonamide
Figure imgf000067_0003
To a solution of r-(but-3-ynyl)-2'-oxospiro[[l ,3Jdioκane-2,3l-indoline]-5'-sιtlfonyl chloride (44 mg, 0.12 mmol) in CH2Cl2 ( 120 μL) was added dimethylamine ( 186 μL of a 2.0 M solution in THF, 0.371 mmol). After 10 minutes, the solvent was allowed to evaporate and the reaction was purified by HPLC (Phenomenex Luna C 18. 10-100% MeCN-H2O linear gradient containing 0.05% NH4OH) to provide the title compound as a colorless oil (24.2 mg, 56%). MS (ES-) m'z 365.1 (M+H).
A procedure similar to that of Step 5 of Example 78, using different amines, provided Examples 79-S5. The compounds and their analytical data are shown in Table 6.
Table 6: Compounds Prepared According to the Procedure of Step 5 of Example 78
Figure imgf000068_0001
Example 86 r-Butyl-iV^¥-diraethyl-2'-oxo-l',2'-dihydrospiro[1,3-dioxane-2,3!-indole]-5'-sulfonamide
Figure imgf000069_0001
Step I
Neopentyl 1 '-butyl-2 '-oxospiro[[l,3/dioxane-2,3 '-indolinej-5 'sulfonate
Figure imgf000069_0002
A procedure similar to that of Example 43, using neopentyl 2'-oxospiro[[1,3]dioxane-2,3'- indolinc]-5'-sulfonatc (554.0 mg, 1.559 mmoi) and 1-iodobutane (266.1 μL, 2,338 mmol) at rt, provided the title compound as a colorless oil (494 mg. 77%). 1H KMR (400 MHz, CDCl3): consistent.
Step 2
1 '-Butyl-2 '-oxospirof/ l,3/dioxane-2,3 '-indolinej-S 'sulfonyl chloride
Figure imgf000069_0003
A procedure similar to that of Step 4 of Example 43, using neopentyl l'-butyl-2'- nxospiro[[1 ,3]dioxane-2.3'-indoline]-5'-sulfonate (494 mg, 1.20 mmol) provided the title compound as a brown oil that was used without further purification, MS (ES-) m/z 365.1 (M+H).
Step 3
1 '-Butyl-N,^\-dinιethyl-2 '-oxo-1 \2 '-dihydmφirύf 1 ,3-dioxane-2,3 '-indølej-5 'sulfonamide
Figure imgf000069_0004
A procedure simi'ar to that of Step 5 of Example 78, using r-butyl-2'-oxospiro[[l ,3Jdioxane-2,3'- indohne]-5'-sulfonyl chloride (43.0 mg. 0.120 mmol). provided the title compound as a colorless oil (23 mg, 52%). MS (ES') m'z 369.1 (M+H). A procedure similar to that of Step 5 of Example 78, using r-butyl-2'-o\ospiro[[l ,3]dioxane-2.3'- mdohne]-5'-sulfonyl chloride (43 0 mg, 0 120 mmol) and different amines, piovided Examples 87-93 The compounds and their analytical data are shown in Table 7
Table 7 Compounds Prepared According to the Procedure of Step 5 of Example 78
Figure imgf000070_0001
Example 94 3-rfrt-Butvl-1-but-3-\n-1-jl-3-ttuoro-N^V-dimethjl-2-oxomdoline-5-sulfonamide
Figure imgf000070_0002
Step l
Neøpentyl 3-iart-butyl-3-hydroxy-2-oxoindoline-5-sulfonate
Figure imgf000071_0001
H To a -78° C solution of neopentyl 2.3-dioxoindoline-5-sulfonate (4,98 g, 16.7 mmol) in THF
( 170 mL) was added tert-butylmagnesium chloride (17,6 mL of a 2,0 M solution in Et2O, 35.2 mmol) dropwise over 30 minutes, The resulting brown solution was stirred at 78 °C for 30 mm then 0° C for 1 hour. The reaction was quenched by the addition of saturated aqueous NH4Cl (200 ml) and extracted with EtOAc (3 * 300 mL). The combined organic extracts were washed with saturated aqueous NaCl (200 mL), then dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash chromatography (12O g silica gel, 0-30% EtOAc in CH2CL linear gradient) to provide the title compound as a yellow solid (2.89 g, 49%). 1H NMR (400 MHz. CDCl3): consistent; MS (ES') ιn/z 373.1 (M+H:O).
Step 2 Neopentyl 3-tert-but)i-3-fluoro-2-oxoindoline-5-sulfonate
Figure imgf000071_0002
A procedure similar to that of Example 43, using 3-(er(-buty\-3 -hydroxy -2-oxoindoline-5- sulfonate (2.89 g. 8.13 mmol). provided the title compound as a white solid (2.02 g, 69%). 1H NMR (400 MHz. CDCl3): consistent.
Step 3
Neopentyl l-(but-3-ynyl)-3-teri-butyl-3-fluoro-2-oxoindoline-5-sulfonate
Figure imgf000071_0003
A procedure similar to that of Example 43, using neopentyl 3-?ert-butyL3-fluoro-2-oxomdolme- 5-sulfonate (50.5 mg. 0.141 mmol), provided the title compound as a colorless oil (40.3 mg, 70%), 1H NMR (400 MfIz, CDCl3) consistent: MS (ES ) int 410, 1 (M+H:O). Step 4 l-(But-3-ynyl)-3-Xtrt-butyl-3-fluoro-2-oxoindoline-5-sulfonyl chloride
Figure imgf000072_0001
A procedure similar to that of Step 4 of Example 78, using neopentyl 1 -(but-3-ynyl)-3-tot-butyl-
3-fluoro-2-oκoindoline-5-sulfonate (320 nig. 0,781 mmol) provided the title compound as a brown oil that was used without further purification. MS (ES ) tn/z 358 (M+H).
Step S 34ert-Bufyl-l-but-3-yn-l-yl-3-fluoro-NfN-dimethyl-2-oxoiιιdoIint?-5-sulf(mamide
Figure imgf000072_0002
A procedure similar to that of Step 5 of Example 78. using l -(but-3-ynyl)-3-fert-butyl-3-fluoro-2- oxoindohnc-5-sulfonyl chloride (28 mg, 0.0782 mmol), provided the title compound as a colorless oil (6 mg, 21 %). MS (ESl m/z 367.1 (M+H).
A procedure similar to that of Step 5 of Example 78, using l-(but-3-ynyl)-3-tert-butyl-3-fluoro-2- oxoindohne-5-sulfonyl chloride (28 mg, 0.0782 mmol) and different amines, provided Examples 95-101. The compounds and their analytical data are shown in Table 8.
1 able 8 Compounds Prepared According to the Procedure of Step 5 of Example 78
i
Figure imgf000073_0001
Example 102
1 -But^ l-3-^rf-biit\l-3-fIuoiO-,Y,V-rt>niethvl-2-n\oindoline-5-sulfonamide
Figure imgf000073_0002
Il Step J
Neopentyl 3-tert-butyl-l-hutyl-3-fluoro-2-oxoindoline-S-sulfonate
Figure imgf000074_0001
A procedure similar to that of Example 43, using neopentyl 3-fø/Y-butyl-3-fluoro-2-oxoindoline-
5-sulfonate (432.6 mg, 1.210 mmol) and 1-iodobιιtane (206.6 μL, 1.815 mmol) at rt and without chromatography, provided the title compound as a colorless oil (483 mg, 97%) that was used without further purification. 1H NMR (400 MHz. CDCl): consistent.
Step 2
3-ttrt-Butyl-l-butyl-3-fluoro-2-oxoindoline-S-sulfonyl chloride
Figure imgf000074_0002
A procedure similar to that of Step 4 of Example 78, using neopentyl 3-tert -butyl- l-butyl-3- fluoro-2-oxomdolme-5-sulfonate (483 mg. 1.168 mmol) provided the title compound as a brown oil that was used without further purification. MS (ES-) m/z 362 1 (M+H).
Step 3 l-But)i-3-lert-butyI-3-fluoro-N,N-dimethyl-2-oxoindoIine-5-sutfotwmide
Figure imgf000074_0003
A procedure similar to that of Step 5 of Example 78, using 3-tert -butyl- l-butyl-3-fluoro-2- oxoindoline-5-sulfonyl chloride (42 mg, 0.12 mmol), provided the title compound as a colorless oil (34 mg, 79%). MS (ES") mά 371.2 (M+H).
A procedure similar to that of Step 5 of Example 78, using 3-/m-buty]-l -butyl-3-fluoro-2- oxoindoline-5-sulfonyl chloride (42 m_>. 0.12 mmol) and different amines, provided Examples 103-109. The compounds and their analytical data are shown m Table 9. Table 9: Compounds Prepared According to the Procedure of Step 5 of Example 78
Figure imgf000075_0001
Example 110 3-tert-Butjl-3-fluoro-1-(2-tluoroethyI)-ΛvV-diniethyI-2-oxoiπdoIine-5-sulfonamide
Figure imgf000075_0002
Step l
Neopentyl 3-Urt-butyl-3-fluoro-l-(2-fluυroethyl)-2-uxomdolme-5-sulfonate
Figure imgf000076_0001
A procedure similar to that of Example 43. using neopentyl 3-?ert-butyl-3-fluoro-2-oxoindolme-
5-sulfonate (250.0 mg, 0.6994 mmol) and 1 -bromo-2-fluoroethane (78.0 μl_, 1.05 mmol), prox ided the title compound as a colorless oil (241 mg, 85%) that was used without further purification.
Step 2 3-tert-But}'l-3-fluoro-l-(2-fluoroethyl}-2-oxoindoline-5-sulfonyl chloride
Figure imgf000076_0002
A procedure similar to that of Step 4 of Example 78, using neopentyl 3-ter/-butyl-3-fluoro-l -(2- fluoroethyl)-2-oxoindoline-5 -sulfonate (241 mg, 0.597 mmol) provided the title compound as a brown oil that was used without further purification. MS (ES+) m/z 352.2 (M+H).
Step 3 3-tert-Butyl-3-fluorø-l-(2-fluoroethyl)-N,N-dimetltyl-2-oxøindolitιe-5-sulfønamide
Figure imgf000076_0003
A procedure similar to that of Step 5 of Example 78, using 3-/t7Ϋ-butyl-3-fluoro-1 -(2- fluoroethyl)-2-oxoindoline-5-sulfonyl chloride (21.0 mg, 0.60 mmol), provided the title compound as a colorless oil (4 mg, 19%). MS (ES*) m/z 361.1 (M+H).
A procedure similar to that of Step 5 of Example 78, using 3-fert-butyl-3-fluoro-l -(2- tluofoetliyl)-2-oxoindoline-5-sulfonyl chloride (21 ,0 mg, 0.60 mmol) and different amines, provided Examples 1 11-1 16. The compounds and their analytical data are shown in Table 10. Table 10: Compounds Prepared According to the Procedure of Step 5 of Example 78
Figure imgf000077_0001
Example 117 r-But-3-yn-1-yl-Λ-isopropyl-2'-oxo-r,2'-dihjdrospiro[1,3-dioxane-2,3'-indolel-5f-carboxaniide
Figure imgf000077_0002
Step l
5 '-IodospirolflJ/dioxane-2,3 '-indotinJ-2 '-one
Figure imgf000078_0001
A stirred mixture containing 5-iodoisatin (4,06 g, 14.9 mmol), 1,3-propanediol (3,23 mL, 44,6 mmol) and p-toluene sulfonic acid monohydrate (0,565 g, 2.97 mmol) in benzene ( 149 mL) was refluxed for 15 hours. The reaction was cooled to room temperature, washed with saturated aqueous NaHCOj (3x), then dried (Ka2SO4) and concentrated. The crude product was purified on RediSep silica elutmg with a 0 to 100% EtOAc/hexane linear gradient to give 4.00 g (81%) of the title compound as a white solid. 1H NMR: consistent
Step 2
Methyl 2'~oxospirof/ 1,3 Jdioxane-2, 3 '-indølinef-S'-carboxylate
Figure imgf000078_0002
At room temperature, carbon monoxide was bubbled through a stirred solution containing 5'- iodospiro[[1,3]dioxane-2,3'-indolin]-2Lone (1.07 g. 3.23 mmol), dich]orobis(triphenylphosphme)palladium(II) (0.1 13 g, 0.162 mmol), methanol (37.2 mL), and triethylamine (1.35 mL. 9.70 mmol) in N5N-DMF (32.3 mL) for 13 minutes. The reaction was sealed and heated at 60° C for 16 hours. The reaction was cooled to room temperature, quenched with H2O (200 mL) and extracted with ether. The combined ethereal extracts were then dried (Na3SO4) and concentrated. The crude product was purified on RediSep silica eluting with a 0 to 100% EtOAc/hexane linear gradient to give 0.798 g (94%) of the title compound. ;H NMR; consistent
Step 3 Methyl 1 '-(but-3-ynyl)-2 '-oxospiroffl ',3]dioxane-2,3 '-indoline]-5 '-carboxylate
Figure imgf000078_0003
To a stirred mixture containing methyl 2'-oxospiro[[1.3]dioxane-2.3'-indoline]-5'-carbox>late
(0.224 g, 0.852 mmol) and K2CO3 (0.294 g, 2.13 mmol) m N.N-DMF (8.52 mL) was added 3-butynyl p- toluenesulfonate (0,528 niL. 2.56 mmol). The reaction was heated at 100° C for 2 hours. The reaction was cooled to room temperature, quenched with H2O (50 niL) and extracted with ether. The combined ethereal extracts were then dried (Na2SO4) and concentrated. The crude product was purified on RediSep silica gel elutmg with a 0 to 100% EtOAc/hexane linear gradient to give 0.213 g, (79%) of the title compound. 1H NMR; consistent; MS: (ESF) m/z 316 (M+H)
Step 4
I '-(But-3-ynyl)-2 '-oxmpiro[fl,3Jdioxane-2,3 '-indolineJ-S '-carboxylic acid
Figure imgf000079_0001
To a stirred solution of methyl r-(but-3-ynyl)-2l-oxospiro[[1,3]dioxane-2,3'-indoline]-5'- carboxylate (0.215 g, 0.684 mmol) in THF (6.84 mmol) was added IN KOH (6.84 ml). The reaction was heated at 60° C for 2 hours. The reaction was cooled to room temperature, treated with 2N HCl (3,42 mL) and pH4 buffer (10 mL). The aqueous mixture was extracted with EtOAc. The combined organic extracts were then dried (MgSO.)) and concentrated. The crude product was suspended and stirred in ether (30 mL) and the product collected by filtration to give 65 mg of the title compound. 1H NMR: consistent: MS: (ESI I ) m/z 302 (M t II). (ESI-) m/z 300 (M-H)
Step 5 / '~But-3-yn-l-yl-N-isopropyl-2 '-oxo-1 ',2 '-dihydrospiroll,3-dioxane-2,3 '-indoleJ-5 '-carhoxamide
Figure imgf000079_0002
At room temperature, to a stirred mixture containing l'-fbut-3-ynyl)-2'-oxospiro[[1.3]dioxane- 2,3'-indohne]-5'-carboxylic acid (20,1 mg, 0.0667 mmol), isoprøpyl amine (1 1.4 μL, 0.133 mmol). l-(3- dimethvlaminopropy])-3-ethylcarbodiimide hydrochloride (25.6 mg, 0.133 mmol), and 1- hydroxybenzotriazole hydrate (20.4 mg, 0.133 mmol) in CH2CIj (0.667 mL) was added N- methylrnorpholinc (36.7 μL. 0.334 mmol). I he reaction was stirred overnight. The reaction was then concentrated. The crude product was purified on Phenomenex Luna Cl 8 eluting with a 10 to 100% CH3CNZH2O linear gradient to give 13 mg of the title compound. MS: (ESI+) m/z 343 (M+H)
7S Example 118 r-But-3-yn-1-yl-5l-(pyrrolidin-1-ykarbonyl)spiro[1,3-dioxane-2,3'-indolI-2'(ri/)-υπe
Figure imgf000080_0001
Using r-(but-3-ynyl)-2l-oxospiro[[1,3]dioxane-2,3'-indoline]-5'-carboxylic acid and pyrrolidine the title compound was prepared in a similar manner to the procedure in Example 1 17. Step 5 to give 17 mg of the title compound. MS: (ESI+) m/z 355 (M-H)
Example 119 r-But-S-yn-1-yl-S'-Cpiperidin-1-ykarbonylJspiroIl^-dioxane-ljS'-indoll-I'CrHJ-one
Figure imgf000080_0002
Using r-(but-3-ynyl)-2'-oxospiro[[1,3]dioxane-2,3'-indoline]-5'-carboxyhc acid and pipcridinc the title compound was prepared m a similar manner to the procedure in Example 1 17, Step 5 to give 17 mg of the title compound. MS : (ESI+ ) m/z 369 (M+Η)
Example 120 r-But-S-yn-1-yl-ΛW-dicthyl-I'-oxo-r^'-dihydrospiroll^-dioxane-l^'-indolel-S'-carboxamide
Figure imgf000080_0003
Using l'-(but-3->Tiyl)-2'-oxospiro[[1.3]dioxane-2,3I-indolmel-5'-carboxy]ic acid and diethylamine the title compound was prepared in a similar manner to the procedure in Example 1 17, Step 5 to give 17 mg of the title compound. MS: (FSf+) m-'z 357 (M+Η) Example 121 l'-But-S-j n-1-yl-Λ-etliyl-l'-oxo-i 'J'-dihydrospiroll^-diosane-l^'-indoIeJ-S'-carboxaniidc
Figure imgf000081_0001
Using r-(but-3-yiy])-2'-oxospiro[[l ,3]dioxanc-2,3l-indolmeJ-5'-carboxyhc acid and ethylamine the title compound was prepared m a similar manner to the procedure in Example 1 17» Step 5 to give 16 mg of the title compound. MS: (ESR) m/z 329 (M+H
Examplel22 i¥-Benzyl-l'-but-3-yn-1-yl-2'-oxo-l!,2l-dihydrospiro[1,3-dioxane-2,3t-indole]-5'-carboxamide
Figure imgf000081_0002
Using r-(but-3-ynyl)-2'-oxospiro[[ 1,3]dioxane-2,3'-indohne]-5'-carboxylic acid and benzylamme the title compound was prepared in a similar manner to the procedure in Example 1 17, Step 5 to give 18 mg of the title compound. MS: (ESR) m/z 391 (M+H)
Example 123 r^-FluoroethylJ-iV-isopropyl-l'-oxu-r^'-dihydrospirofl^-dinxane^^'-indokj-S'-carboxamide
Figure imgf000081_0003
Step 1
Methyl 1 '-(2-fluoroethyl)-2 '-oxmpiro([l,3]dioxane-2,3 '-indoiinej-S '-carboxylate
Figure imgf000082_0001
Using methyl 2'-oxospiro[[1,3Jdioxane-2,3'-indoline]-5'-carboxytate ancj j -bromo-2-fluoτoethane the title compound was prepared in a similar manner to the procedure in Example 1 17, Step 3 to give 0,224 g of the title compound. 1H NxMR: consistent: MS: (ESI+) m/z 310 (M+H)
Step 2 / '-(2-Fluoroethyl)-2 '-oxospiroHl,3]dioxane-2,3 '-indolinej-5 '-carboxylk acid
Figure imgf000082_0002
Using methyl l '-(2-fluoiOethyl)-2l-oxospiro[[1,3]dioxane-2,31-indoline]-5l-carboxylate the title compound was prepared in a similar manner to the procedure in Example 1 17, Step 4 to give 0.116 g of the title compound. 1H NMR: consistent; MS: (ESI+) m/z 296 (M+H), (ESI-) m/z 294 (M-H)
Step 3
1 '-(2-Fluoroethyl)-N-isopropyl-2 '-oxo-1 ',2 '-dihydrospiro[l,3-dioxane-2,3 '-indole]-5 '-carboxamide
Figure imgf000082_0003
Using r-(2-πuoroethyl)-2l-oxospirϋ[[1,3]dioxarie-2,3'-indolme]-5l-carboxylic acid and lsυprυpylamine the title compound was prepared in a similar manner to the procedure in Example 1 17, Step 5 to give 20 mg of the title compound. MS: (ESI+) m/z 337 (M+H) Example 124 r-(2-Fluoroethyl)-5'-(pyrrolidin-1-ylcarbonyl)spJro[1,3-dioxane-2,3'-itidol]-2'(l'//)-one
Figure imgf000083_0001
Using r-(2-fluoroethyl)-2'-oxospiror[l )3]dioxane-2,3'-indoline]-5'-carboxylic acid and pyrrolidine the title compound was prepared in a similar manner to the procedure in Example 1 17, Step 5 to give 21 mg of the title compound. MS: (CSH ) me 349 (M+II)
Example 125 r-(2-Fluoroethyl)-5'-(piperidin-1-ylcarbϋn\l)spiro[1,3-dioxane-2,3'-intlol]-2'(r/7)-one
Figure imgf000083_0002
Using r-(2-fluoroethyl)-2'-oxospiro[[1,3]dioxane-2,3'-indoline]-5'-carboxylic acid and pipeπdme the title compound was prepared in a similar manner to the procedure in Example 1 17, Step 5 to give 21 mg of the title compound. MS: (ESI+) m/z 363 (M+H)
Example 126 iVΛ-PiethyI-r-(2-nuoroethyl)-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indole]-5'-earbϋxamide
Figure imgf000083_0003
Using r-(2-fluoroethyl)-2'-oxospiro[[1,3]dioxane-2,3'-indoline]-5'-carboxylic acid and diethylamine the title compound was prepared in a similar manner to the procedure in Example 1 -, 7. Step 5 to give 20 mg of the title compound, MS: (ESI+) m/z 351 (M+H) Example 127 Λ-Ethyl-r-(2-πuoroethyl)-2'-oxo-r,2'-dihydrospiro|1,3-dioxane-2,3'-indolel-5'-carboxaniide
Figure imgf000084_0001
Using l'-(2-fluoroethyl)-2'-oxospiro[[ 1.3Jdioxanc-2,3l-mdohnc]-5'-carboxylic acid and ethylamme the title compound was prepared in a similar manner to the procedure in Example 117, Step 5 to give 16 mg of the title compound, MS: (ESI+) m/z 323 (M+H)
Example 128 1 '-Bιιtyl-iV-isopropyl-2 '-oxo- 1 ',2'-dihydrospiro [ 1 ,3-dioxane-2,3'-indole)-5'-earboxamide
Figure imgf000084_0002
Step l
Methyl 1 '-butyl-2 '-oxospiroffl,3/dioxane-2,3 '-indoline/S '-carboxylate
Figure imgf000084_0003
Using methyl 2'-oxospiro[[1,3]diovane-2.3 -indolιne]-5'-carboxylate and 1 -iodobutane the title compound was prepared in a similar manner to the procecurc m Example 1 17, Step 3 to gne 0 222 g of the title compound, 1H MMR; consistent; MS: (ESF) m/z 320 (M+H) Step 2
1 ''Butyl-2 '-oxospiro[[l,3Jdioxane-2,3 '-indolim]-5 '-carboxylic acid
Figure imgf000085_0001
Using methyl 1 '-butyl-2'-oxospiro[[ 1 ,3]dioxane-2.3'-indoline]-5'-carboxylate the title compound was prepared in a similar manner to the procedure in Example 1 17, Step 4, The crude product was purified on Phenomenex Luna Cl 8 eluting with a 10 to 100% CH3CN/H2O linear gradient to give 0.169 g of the title compound. 1H NMR: consistent; MS: (ESI+) m/z 306 (M+H), (BSI-) m/z 304 (M-H)
Step 3
1 '-Butyl-N-hυprυpyl-2 '-oxo-1 ',2 '-dihydrospiro[J,3-dioxane-2,3 '-indole] -5 '-carboxamide
Figure imgf000085_0002
Using r-butyl-2'-oxospiro|jl ,3Jdioxane-2,3'-mdohne]-5'~carboxylic acid and isopropylamine the title compound was prepared in a similar manner to the procedure in Example 117, Step 5 to give 19 mg of the title compound. MS: (ESI+) m/z 347 (M+H)
Example 129
I '-Butyl-5^pyrrolidin4-ylcarbonyI)spiro[1,3-dioxane-2,3'-indol]-2'(l 'H)-om
Figure imgf000085_0003
Using l'-butyl-2'-oxospiro[[l J]dioxane-2.3'-indoline]-5l-carboxylic acid and pyrrolidine the title compound was prepared in a similar manner to the procedure in Example 1 17, Step 5 to give 23 mg of the title compound MS: (ΕSI+) m/z 359 (M+H) Example 130 l'-Butyl-S'^piperidin-1-ylcarbonylJspirofl^-dioxane-l^'-indull-l'Crfll-one
Figure imgf000086_0001
Using l '-butyl-2l-oxospiro[[1.3]dioxane-2,3'-indolinc]-5'-carboxyhc acid and pipeπdme the title compound was prepared in a similar manner to the procedure in Example 1 17. Step 5 to give 23 mg of the title compound. MS; (ESI+) m/z 373 (M+H)
Example 131 l'-Butyl-ΛVV-diethyl-I'-oso-rjI'-dihydrospiroll^-dioxane-l^'-indolel-S'-carboxamide
Figure imgf000086_0002
Using r-butyl-2'-oxospiro[[1,3]dioxane-2,3'-mdoline]-5'-carboxylic acid and diethylamine the title compound was prepared in a similar manner to the procedure in Example 1 17, Step 5 to give 19 mg of the title compound. MS: (ES1+) m/z 361 (M+H)
Example 132 l'-Butyl-Λ-ethyl-2l-oxo-l',2'-dihydrospiro[13-dioxane-2,3l-ii'doleI-5'-carboxamide
Figure imgf000086_0003
Using r-butyl-2'-oxospiro[[1,3]dioxane-2,3'-indohne]-5'-carboxylic acid and ethylamine the title compound was prepared in a similar manner to the procedure in Example 1 17, Step 5 to give 20 mg of the title compound MS: (ESI+) me 333 (M+H) Example 133 .V-Benz\l-r-butyI-2'-oxo-r,2(-dihydrospiro[1,3-(iiosane-2,3'-indoIej-5'-carboxamide
Figure imgf000087_0001
Using r-butyl-2'-oλospιro[[1,3]dioxane-2,3'-indoline]-5'-carboxyhc acid and benzylaππne the title compound was prepared m a similar manner to the procedure in Example 1 17, Step 5 to give 6 mg of the title compound MS (ESI+) m/z 395 (M til)
Example 134 jV-(r-But}l-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indoI|-5'-yl)acetamide
Figure imgf000087_0002
Step l
5 '-Nitrospiro[[l,3]dioxane-2,3 '-indolinJ-2 '-one
Figure imgf000087_0003
Using 5-nitroisatin the title compound was prepared in a similar manner to the procedure in Example 1 17, Step 1 to give 2.40 g of the title compound 1H NMR* consistent
Step 2 5 '-Aιnmøφirolll,3]dioxane-2,3 '-indolinJ-2 '-one
Figure imgf000087_0004
At 0° C, to a stirred suspension containing 5'-nitrospiro[[l ,3jdioxanc-2.3'-indohn]-2'-one (2,41 g, 9.64 mrnoij and 50 \vt% Raney Nickel H-U (2 41 g) m MeOH (96.4 mi) was added hydrazine monohydrate (2.34 niL. 48.2 mmol). After the addition was complete, the ice bath was removed and the reaction was stirred overnight. The ieaction was filtered thiough a sulka floe pad while rinsing with methanol. The filtrate was then eoncentrated. The crude product was dissolved in a minimal amoαnt of 50% EtOAc CH2Cl;, then dried (Na2SO4) and concentrated to give 2 07 g (98%) of the title compound 1H NMR consistent
Step 3
2-(2 '-Oxospiroffl ,3]dioxane-2,3 '-indolinej-5 '-yl)isoindoline-l,3-dione
Figure imgf000088_0001
A stirred solution containing 5'-ammospiro[[1,3]dio\ane-2,3'-indolin]-2'-one (1 96 g 8 91 mmol). phthalic anh}dπde (2 22 g, H 4 mmol) and tnethylamine (3.72 mL, 26.7 mL) in THF (90 mL) was heated at 60° C for 1 hour 1 he reaction was cooled to room temperature and concentrated. The resulting oil was suspended m toluene (90 mL) and refluxed overnight The reaction was cooled to room temperature and then concentrated. The crude pioduct was partitioned between FtOAc (100 mL) and saturated aqueous NaHCO1 (100 mL). The Diphasic mixture was separated and the organic layer washed with saturated aqueous NaHCO1 (2x), then dried (Na^SO4) and concentrated to give 2.86 g (92%) of the title compound. 1H NMR: consistent; MS (ESI+) mlz 351 (M+H), (ESl-) m/z 349 (M-H)
Step 4
2-fl '-Butyl-2 '-oxospiroffl, 3jdioxane-2, 3 '-indolinef-S '-yl)isoindoline-l,3-dione
Figure imgf000088_0002
Using 2-(2'-oxo«piro[[1,3]dioxane-2,3'-indolinc]-5'-yl)isoindoline-l ,3-dione and 1 -iodobutane the title compound was prepared in a similar manner to the procedure m Example 1 17, Step 3 to give 0 306 g (53%) of the title compound. 1H NMR. consistent. MS (ESI+) m z 407 (M+H) Step S
5 '-Λmino-1 '-butyhpiro[[l,3]dioxane-2,3 '-indolinJ-2 '-one
Figure imgf000089_0001
To a stirred suspension of 2-(^4)utyL2(-oxosplro[[13]dioxane-23'-indohne]-5'-yl)lSOIncoline- l !3-dlone (0,298 g, 0,734 mmol) m MeOH (Q. IM) was added hydrazine (10 equiv). The reaction was heated at 50° C for 16 hours. The reaction was cooled to room temperature, quenched with O2O (50 ml) and extracted with CH2Cl2. The organic extracts were then dried (Na2SO4) and concentrated to give 0.204 g (1001Ko) of the title compound, 1H KMR: consistent; MS: (ESI+) m/z 111 (M+H)
Step 6
N-(I '-Butyl-2 ' -oxo-l ',2 '-dihydrospiro[l,3-dioxane-2,3 '-indolJ-5 '-yl)aeetamide
Figure imgf000089_0002
Λt room temperature, to a stirred mixture containing 5'-ammo-l'-butylspiro-[[1,3]dioxane-2,3'- mdolin]-2'-one (19,9 mg, 0.0721 mmol) and diisopropylethylamme (50.2 μL. 0.288 mmol) in CH2Cl2 (0.721 niL) was added acetyl chloride (10.3 μL, 0.144 mmol) and the reaction was stirred overnight. The reaction was concentrated. The crude product was purified on Phenomenex Luna Cl 8 eluting with a 0 to 100% CH3CN/H;O linear gradient to give 15 mg of the title compound. 1H NMR; consistent; MS: (ESI+) ra/:; 319 (M+H)
Example 135
Figure imgf000089_0003
y-dihydrospiroll^-dioxane-ZJ'-indolI-S'-ylJcyclopropanecarboxamide
Figure imgf000089_0004
Using 5'-amino-r-butylsρiro[[1.3]dioxane-2.3'-mdolm]-2'-one and eyclopropanecarbonyl chloride the title compound was prepared in a similar manner to the procedure in Example 134, Step 6 to give 17 mg of the title compound. MS: (ESI+) m/z 345 (M+H)
Example 136 iV-tr-Butyl-l'-oxo-l'J'-dihydrospirolljS-dioxane-ljS'-indoll-S'-ylJcyclobutanecarboxamide
Figure imgf000090_0001
Using 5'-amino-r-bulylspiro[[1,3]d:oxane-2,3'-indol in]-2'-one and cyclobutanecarbonyl chloride the title compound was prepared in a similar manner to the procedure in Example 134. Step 6 to give 1 1 mg of the title compound. MS: (ESI+) m/z 359 {M+H)
Example 137 ^-(l'-Butyl-Z'-oso-rJ'-dihydrospiroll^-dioxane^^'-indolJ-S'-yljcyclopcntaπecarboxamide
Figure imgf000090_0002
Using 5'-amino-r-butylspiro[[1,3]dioxane-2,3'-indolin]-2l-one and cyclopentane-carbonyl chloride the title compound was prepared in a similar manner to the procedure in Example 134, Step 6 to give 1 7 mg of the title compound. MS: (ESI I ) m/z 373 (M+H)
Example 138 .^'-(r-Butyl-l'-oxo-rjl'-dihydrυspirofl^-tlioxane-I^'-indolj-S'-yiJbenzamide
Figure imgf000090_0003
Using 5t-ammo-l'-butylspiro[[ 1.3jdioxane-2,3'-indolin]-2'-one and benzoyl chloride the title compound was prepared in a similar manner to the procedure in Example 134, Step 6 to give 16 mg of the title compound. MS: (ESI+) m/z 381 (M+H) Example 139
Λ-(1'-Butj l-2'-oxo-l ',2'-dih>drospiro[1,3-dio\ane-2,3'-indoI]-5'-\l)methanesuIfonamide
Figure imgf000091_0001
Using 5'-amino- i
Figure imgf000091_0002
1 ,3]dio\ane-2,3'-indohn]-2'-one and methanesulionyl chloride the title compound was prepared in a similar manner to the procedure in Example 134, Step 6 to give 10 mg of the title compound MS (ESI+) mh 355 (M+H)
Example 140 ^-(r-Butyl-l'-oxo-r^'-dihydrospiroIl^-dioiane-l^'-indoiJ-S'-yOben/enesuIfonamicle
Figure imgf000091_0003
Using S'-ammo-l '-butykpirof[l ,l]dioxaπe-2,3'-indohn]-2'-one and benzenesulfonyl chloiide the title compound was prepared m a similar manner to the procedure m Example 134, Step 6 to give 8 mg of the title compound MS: (ESI+) m/z 417 (M+H)
Fxample 141
Λ'-(T-Butyl-2'-oso-r,2'-dihydrospiro[1,3-dioxane-2,3'-indoI]-5'-yl)-1- c\elohex\Imethanesulfonamide
Figure imgf000091_0004
Uiing 5'-amino-r-bul>lspiro[[ l 3]diϋxane-2.3 -indυhn]-2'-one anc1
Figure imgf000091_0005
chloride the title compound was piepared in a similar manner to the procedure in Example 134, Step 6 to gne 1 1 mg of the title compound MS (ESI- j m/z 437 (M+H) Example 142 V-[l '-(2-Fhioι oethyl)-2'-oxo-T,2'-dihydrospiiO[1,3-dioxane-2,3'-indoI]-5'-yllacetamide
Figure imgf000092_0001
Step l 2-(l ''(2-Fluoroethyl)-2'-oxospira[ll,3]dioxane-2,3'-indoline]-5'-}'l)lsoindoline-l,3-dione
Figure imgf000092_0002
Using 2-(2'-oxospiro[[i ,3]dio\ane-2,3'-indolme]-5'-yl)isomdoline-l ,3-d[one and l-biomo-2- fluoroefhane the title compound was prepared in a similar manner to the procedure m Example 117, Step 3 to give 0.360 g (64%) of the title compound 1H NMR- consistent; MS: (ESI+) m/z 397 (M+H)
Step 2
5 '-Amino-1 '-(2-fluomethyl)spiro[[1,ϊjdwxane-2,3 '-mdolinj-2 '-one
Figure imgf000092_0003
Lsmg 2-( r-(2-ftuoroethyl)-2'-oxospiro[[l ,3]dioxane-2 3'-indoline]-5'-yl)isoindohne-1,3-dione the title compound was prepared in a similar manner Iu the pioceduie m Example 134, Step 5 to give 0,241 g of the title compound 1H NMR: consistent; MS; (ESP ) m/z 267 (M+H) Step 3 ^-[l '-(2-Fluoroeth}i)-2'-oxo-l ',2'-dihydrospiro[l,3-dioxane-2,3 '-indol]-S'-yi]acetamide
Figure imgf000093_0001
Using 5'-amino-l'-(2-fluoroethyl)spiro[[l ,3]dioxane-2.3'-indolin]-2'-one and acetyl chloride the title compound was prepared in a similar manner to the procedure in Example 134, Step 6 to give 14 mg of the title compound. MS: (ESF) m/z 309 (M II)
Example 143 N-[l'-(2-Fluoroethyl)-2'-oxo-l',2'-tlihydrospiro[1,3-dioxaιie-2,3'-indol]-5'- yl] cyclopropanecarboxamide
Figure imgf000093_0002
Using 5'-amino-r-(2-fluoroethyl)spiro[[1,3]dioxane-2,3'-indolin]-2'-one and cyclopropanecarbonyl chloride the title compound was prepared in a similar manner to the procedure in Example 134, Step 6 to give 4 mg of the title compound. MS: (ES1+) m/z 335 (M+H)
Example 144
TV-[I '^-FluoroethyO^'-oxo-i '^'-dihydrospiroπ^-dioxane^^'-indoll-S1- yl] cy clobutanecarboxamide
Figure imgf000093_0003
Using 5'-aniino-r-(2-fluoroethyl)sρiro[[1.3]dioxane-2,3'-indolin]-2'-one and cyclobutanecarbonyl chloride the title compound was prepared in a similar manner to the procedure in Example 134, Step 6 to give 16 mg of the title compound. MS: (ES1+) m/z 349 (M+H) Example 145
A-ll'-Cl-FiuoroethyO-l'-oxo-r^'-dihydrospiroIl^-dbxane-l^'-indoll-S' yl] eyclopentanecarboxaniide
Figure imgf000094_0001
Using 5'-amino-r-(2-fiuoroethyl)spiro[[l ,3]dioxane-2.3'-indolm]-2'-one and cyclopentanecarbonyl chloride the title compound was prepared in a similar manner to the procedure m Example 134. Step 6 to give 16 mg of the title compound. MS: (ESI+) m/z 363 (M+H)
Example 146
A-[r-(2-Fluoroethyl)-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indol]-5'-yl]benzamide
Figure imgf000094_0002
Using 5'-ammo-Λ(2-fluoroethyl)spiro[[1,3]dioxane-2,3'-mdohn]-2'-one and benzoyl chloride the title compound was prepared in a similar manner to the procedure in Example 134, Step 6 to give 14 mg of the title compound. MS: (ESI+) m/z 371 (M+H)
Example 147 N-|r-(2-Fluoroethyl)-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indol]-5t-yl]methanesulfonamide
Figure imgf000094_0003
Using 5'-ammo-ll-(2-fluoroethyl)spirof[1.3]dioxaπe-2.3'-indolin]-2l-one and methanesulfonyl chloride the title compound was prepared m a similar manner to the procedure in Example 134, Step 6 to give 3 mg of the title compound. MS (ES1+) m/z 343 (M+H)
«π Example 148 l.Ll-Trifluoro-A-ll '-Cl-fluoroethylJ-l'-oxo-r^'-dihjdrospiroll^-dioxane-l^'-mdolJ-S'- yl]methanesulfonamide
Figure imgf000095_0001
Using 5'-amiπo-i '-(2-fluoroethyl)spiro[[l ,3]dioxane-2,3'-indolinJ-2'-oπe and trifluoromethanesulfonyl chloride the title compound was prepared in a similar manner to the procedure in Example 134, Step 6 to give 7 mg of the title compound, MS: (ESI+) m/z 397 (M+Hj
Example 149 N-[l'-(2-Fluoroethyl)-2'-oxo-l',2'-dihydrospiro[1,3-dioxane-2,3'-indol]-5'-yllbenzenesulfoiiamide
Figure imgf000095_0002
Using 5t-amino-r-(2-fluoroethyl)spiro[[1,3]dioxane-2,3'-indolin]-2'-one and benzenesulfonyl chloride the title compound was prepared in a similar manner to the procedure in Example 134, Step 6 to give 4 mg of the title compound. MS: (ESl I ) m/z 405 (M t II)
Example 150 l-CycIohexyl-iV-ll'-ll-πuoroetliy^-Z'-oxo-r^'-dihydrospiroll^-dioxane-l^'-HidolJ-S'- yljmethanesulfonamide
Figure imgf000095_0003
Usmg 5l-ammo-r-(2-fluoroeth3'l)spiro[[l ,3]dioxane-2,3'-indolin]-2(-one and cvclohexylmelhanesulfonyl chloride the title compound was prepaied in a similar manner to the procedure m Example 134. Step 6 to give 1 1 mg of the title compound, MS: (ESI+) m/z 425 (M-H) Example 151 r^cyclopropylmethy^-S'-Kl^-dimethylmorpholin-ΦylJsulfoiiyllspirojl^-dioxane-lJ'-indoI]-
Figure imgf000096_0001
Step I neopentyl 1 '-(cyclυpropyIιnethyl)-2 '-oxo-1 ',2 '-dihydrospiro[l,3~dioxane-2,3 '-mdolej-5 'sulfonate
Figure imgf000096_0002
A procedure similar to that of Example 77, Step 3. using neopentyl 2'-oxospiro[[1,3]dioxane-2,3'- indoline]-5'-sulfonate (1.24 g, 3,49mmol) provided the title compound as a clear oil ( 1.17 g 82%). 1H NMR (400 MHz, DMSO-d6): consistent.
Step 2 r-(cydopropylmeth)d)-2 '-oxoA \2'-dihydrospiro[l,3-dioxane-2,3'-indole]-5'-mlfonyi chloride
Figure imgf000096_0003
A piocedure similar to that of Fxample 77, Step 4, using neopentyl 1 '-(cyclopropylmethyl)-2'- oxo-r(2'-dihydrospiro[1,3-dioxanc-2,3'-indolcJ-5'-sulfonate (0.45 g. 1.1 mmol) provided the title compound as a sticky white solid (0.072 g 83%). 1H NMR (400 MHz, DMSO-d6): consistent
Step 3
1 '-(cyclopropylmelhyl)-5 '-[(2, 6-dimethylmorpholin-4-yl)sulfønyi]spiro[l,3-dioxane-2,3 '-indolJ-2 '(I 'H)- one
Figure imgf000096_0004
A procedure sirπlar to that of Example 77, Step 5, using r-(cyclopropylmethyl)-2'-oxo-r.2'- dihydrospirofl ^-dioxane^.V-indoleJ-S'-sulfonyl chloride (0 07 g 0 2 mmol ) provided the title compound as a sticky white solid (0 072 g 83%). 1H NMR (400 MHz. DMbϋ-d6): consistent; MS (Eb ) me 437 2 (M-H)
A procedure similar to that of Example 151. using different amines, pro\ ided Examples 152 - 160 The compounds and their analytical data are shown m Table 11.
Table 1 1 Compounds Piepared According to the Piocedwe of Example 1 *? 1
Figure imgf000097_0001
Figure imgf000098_0004
Example 161 r-(cycIopropylmethyl)-4'-[oxo(piperidin-1-yl)acetylJspiro[1,3-dioxane-2,3'-indol]-2((l'H)-one
Figure imgf000098_0001
Step l
4'-iodoψiro[l,3-dioxane-2,3 'AmIoIJ-T(I 'H)-one
Figure imgf000098_0002
A procedure similar to that of Example 1 17, Step 1, using 4-iodoisatin (Meijer L. et al, J.Med. C hem. 2004, 47, 935.) (1.68 g, 6.17 mmol) provided the title compound as an orange solid (1.54 g, 77%). 1H NMR (400 MHz, DMSO-dό): consistent.
Step 2 tert-butyl 4 '-iodo-2 '-oxoφiro[l,3-dioxane-2,3 '-indole j '-1 '(2 'H)-carboxylate
Figure imgf000098_0003
A solution containing 4l-iodospirof[l ,3]dioxane-2,3'-indolin]-2'-one (0.45 g, 1.36 mmol), di-tert- butyl dicarbonate (0,326 g, 1.5 mmol), DMAP (0,042 g, 0.34 mmol) and Et3N (0.379 niL, 2,72 mmol) in CH;Cl2 (20 mL) was stirred at rt for 2 hours. The reaction was quenched with NH4CI, extracted with CH2Cl2, The organic layer was then dried (MgSO4), filtered, concentrated, and purified by flash chromatography on silica gel (0 to 30% acetone in hexane) to provide 0.55 g (94%) of product as a light yellow solid, 1II NMR (400 MIIz. DMSO-d6): consistent. Step 3 4 '-[oxo(piperidin-l-yl)acetyl]spiro[l,3-dioxane-2,3 '-indolJ-2 '(I Ηj-one
Figure imgf000099_0001
A suspension, m a sealed vessel, consisting of tert-buty] 4'-iodo-2t-oxospiro[1.3-dioxane-2,3'- indole]-! '(2Η)-carboxylate (1.0 g, 2.3 mmol), dichlorobis(triphenylphospine)-palladium(II) (81 mg, 0.115 mmol), Et3N (1.04 niL, 7.48 mmol), and piperidine (4.54 niL, 46 mmol) in dimethylfoπnamide (DMF) (3OmL) was bubbled with CO for 30 minutes then heated at 6O0 C overnight (pin). The reaction was quenched with water (50 ml), extracted with EtOAc (30 mL x 3). The organic layer was washed with brine, thendried over Na2SO4, filtered and purified by flash chromatography on silica gel (30% Acctone/TIexane) to yield two compounds: O.353g (45%) of the title compound as a off white solid; 1H NMR (400 MHz. DMSO-d6): consistent: MS (ES') m/z 345.3 (M+H), and 4'-(pipcridin-l - ylearbonyl)spiro[l ,3-dioxane-2,3'-indol]-2l( l'H)-one as a off white solid (0.187 g, 26%). 1H NMR (400 MHz, DMSO-dβ). consistent; MS (EST) ink 317.3 (M+H).
Step 4 l '-(cyclopropylmethyl)-4'-[oxo(piperidin-l-yl)acetyl]ψiroll,3-dioxane-2,3'-indoll-2'(l Η)-one
Figure imgf000099_0002
A procedure similar to that of Example 42. using 4'-[oxo(prperidin-l -yl)acety]]spiro[1,3-dioxane- 2,3'-indol]-2'(l'H)-one (0.1 g, 0.29 mmol) provided the title compound as a sticky yellow oil (0.061 g. 53%). 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES') m/z 399.2 (M+H).
A procedure similar to that of Example 161 , using different alkyl halides, provided Examples 162 - 166. The compounds and their analytical data are shown in Table 12.
Table 12: Compounds Prepared According to the Procedure of Example 161 ,
Figure imgf000099_0003
Figure imgf000100_0003
Example 167 7'-(piperidiii-1-ylcarboiiyl)-l'-(2,2,2-tritluoroethyl)spiro[1,3-dioxane-2,3!-iiidol]-2'(l 'H)-OIiC
Figure imgf000100_0001
Step 1 7-(piperidin-l-ylcarhonyl)-lH-indøle-2,3-dione
Figure imgf000100_0002
A procedure similar to that of Example 1 17, Step 5, using 2,3-dioxoindolmc-7-carboxyl;c acid
( 1.0 g. 5.23 mmol) provided the title compound as a sticky yellow oil (0.365 g, 27%). 1H NMR (400 MHz, DMSO-d6): consistent.
Step 2 7'-(piperidin-l-ykarbϋnyl)spiro[l,3-diϋxane-2,3 '-ittdolJ-2 '(I 'H)-one
Figure imgf000101_0001
A ptoceduie similai to that of Example 1 17, Step 1 , using 7-(pipeπdin-1-ylcaibonyl)-1H-mdole- 2,3-dιonc (0 355 g, 1 37 mmol) pro\ided the title compound as a white powder (0.315 g, 73%). 1II NMR (400 MHz, DMSO-d6): consistent.
Step i
7'-(piperiiin-l-ylcarbonyl)-l '-(2,2,2~triflιtoroethyl)$pirofl,3-dioxane-2,3 '-indolJ-2 '(I Η)-otιe
Figure imgf000101_0002
A procedure similar to that of Example 42, using 7'-(pipcπdin-1-ylcarbonyl)spiτo[1,3-dioxane-
2,3'-indol]-2'(lΗ)-one (0 052 g, 0.16 mmol) provided the title compound as a white solid (0.046g (72%) 1H NMR (400 MHz, DMSO-d6) consistent; MS (ES") m'z 399 3 (M+H)
A procedure similar to that of Example 167, using different alkyl hahdes, provided Examples 168 - 172, The compounds and their analytical data are shown in Table 13.
Table 13 Compounds Prepared According to the Procedure ol Example 167.
Figure imgf000101_0003
Figure imgf000102_0004
Example 173
1 '-(cyclσpropylmethylj-4 '-(piperidm-1-ylcarhonyl) spiro[l,2-dioxane-2,3 '-indolJ-2 '(I Η)-one
Figure imgf000102_0001
Step 1
4 '-(piperidin-l-ylcarbonyl)spirofl ,3-dioxane-2,3 '-indoIJ-2 '(I 'H)-one
Figure imgf000102_0002
Λ procedure similar to that of Example 161, Step 3, using tcrt-butyl 4'-iodo-2'-oxospiro[l ,3- dioxane-2.3 '-indole]- l'(2'H)-carboxy late (1.0 g, 0.29 mmolj provided the title compound as a off white solid (0.187 g, 26%) 1H NMR (400 MHz, DMSO-dό): consistent.
Step 2 r-(cycl()propylmethγl)-4'-(piperidm-l-γlcarbonyl)ψiro(l,3-dioxane-2,3'-ιndol]-2 '(l Η)-one
Figure imgf000102_0003
A procedure similar to that of Example 42. using 4'-(piperidin-l -ykarbonyl)spiro[l ,3-dioxanc-
2,3'-mdol]-2'( lΗ)-one (0 04 g, 0.124 mrnoD provided the title compound as a light yellow solid i0 04 g, 91%). 1H XMR (400 MHz, DMSO-d6): consistent, MS (ES+) m/z TΛ λ (M+H). A procedure similar to that of Example 173, using different alkyl halides, provided Examples 174 - 178. The compounds and their analytical data arc shown m Table 14.
Table 14: Compounds Prepared According to the Procedure of Example 173.
Figure imgf000103_0003
Example 179 ll-(cyclopropylmethyl)-6l-(piperidin-1-ylcarbonyl)spiro[1,3-dioxane-2,3'-iiidol]-2'(l llI)-one
Figure imgf000103_0001
Step l 6 '-iodospiro(l,3-dioxane-2,3 '-indoIJ-2 '(I 'H)-øne
Figure imgf000103_0002
A procedure similar to that of Example 1 16, Step 1. using 6-iodoisatin (Meijer L. et al. J Med. Chan, 2004. 47, 935.) (0 51 g, 1.87 mmol) provided the title compound as a light yellow solid (0.51 g. 83%). 1H NMR (400 MHz, DMSO-d6): consistent, Step 2 tert-butyl 6 '-iodo-2 '-oxospirofl,3-dioxane-2,3 ' -indole j-1 '(2'H)-carbovylate
Figure imgf000104_0001
A procedure similar to that (r Example 161, Step 2, using 6'-iodospiro[l ,3-dio\ane-2.3'-indolJ-
2'(lΗ)-one l ϋ 51 g. 1 54 mmol) provided the title compound as a light yellow solid (O 63 g, 95%) 1H NMR (400 MHz, DMSO-d6): consistent.
Step 3 6 '-(piperidin-l-ylcarbonyl)spirø[l,3-dioxane-2,3 '-indolJ-2 '(I Η)-one
Figure imgf000104_0002
A procedure similar to that of Example 161. Step 3, using tert-butyl 6'-iodo-2'-oxospiro[l ,3- dio\ane-2,3'-indole]-l'(2Η)-carboxylate (0.63 g, 1.46 mmol) provided the title compound as a o T white solid (0 35 g, 76%) 1H KMR (400 MHz, DMSO-dό) consistent
Step 4
1 '-(cyclopropylmethyl)-6 '-(piperidin-l-ylcarbonyl)spirofl,3-dioxane-2,3 '-indolj-2 '(I 'H)-one
Figure imgf000104_0003
A procedure sim lar to that of Example 42, using 6'-fpφeπdin-l -ylcaibonyl )spiro[l ,3-dio\ane- 2,3'-indol]-2'(l H)-one (0 05 g 0 158 mmol) prυuJed the title compound as off white solid (0 016 g, 62%) 1H NMR (400 MHz, DMSO-dβ) consistent MS (ES ) m z Vl 1 (M-4I) A procedure similar to that of Example 179, using alkyl halides, provided Examples 180 - 184 The compounds and their analytical data are shown in Table 15
Table 15: Compounds Prepared According to the Procedure of Example 179.
Figure imgf000105_0002
Example 185 r-(c)clopropylraethyl)-5'-[(2,6-dimethylpiperidin-1-yl)sulfonyl]spirol1,3-dioxolanc-2,3'-iπdoll- 2'(l'H)-one
Figure imgf000105_0001
Step 1
2,2-dimethylpropyl 2'-oxø-l ',2'-dihydro$pirofl,3-dwxolane-2,3'-indoleJ-5'-sulfonate
Figure imgf000106_0001
A procedure similar to that of Example 77, Step 2, using neopentyl 2,3-dto\oindolme-5-sulfonate (3.4 g. 11.43 mmol) and ethylene glycol (2 51 ml , 45 7 mmol), provided the title compound as a white solid (3 8 g, 97%) 1H NMR (400 MHz, DMSO-d6) consistent.
Step 2
2,2-dimethylρropy I 1 '-(cyclopmpylmethytj-2 '-oxo- V, 2 '-dihydrospiro[1,3-dwxolane-2,3 '-indole j-5 '- sulfonate
Figure imgf000106_0002
A procedure similar to that of Example 77, Step 3. using 2,2-dimethylpropyl 2!-oxo-r,2'- dihydrospiro[1,3-dioxolane-2,3'-mdole]-5'-sulfonate (1.85 g, 5.42 mmol provided the title compound as a white solid (1 93 g, 90%) 1H NMR (400 MHz, DMSO-d6): consistent.
Step 3 / '-(cyclopropylmethyl)-2 '-oxo-1 ',2 '-dihydrospiro[l,3-dioxolane-2,3 '-indole J -5 'suifonyl chloride
Figure imgf000106_0003
Λ procedure similar to that of Example 77, Step 4, using 2,2-dιmethylpropyl 1'-
(cyclopropylmethyl)-2'-o\o-l'.2l-dihydrospirof l ,3-dioxolane-2,3'-indoleJ-5'-sulfonate (1 88 g. 4 75 mmol) prouded the title compound as a sticky white foamy solid (1 45 g 89%) 1H NMR (400 MHz, DMSO- do): consistent.
Step 4 l '-(ιγciopropylmethyl)-5'-f(2,6-dimethylpiperidin-l-yI)sulfo»}ijsph"θfl,3-diøxolane-2,3'-ind»Ij-2'(r one
Figure imgf000107_0001
A procedure similar to that of Example 77. Step 5. using l '-(cyclopropylmethyl)-2'-oxo-l',2'- dihydrospiro[1,3-dioxolane-2,3'-indole]-5'-sulfonyl chloride (0.1 g, 0.29 mmol) provided the title compound as a clear oil (0,027 g 22%). 1H NMR (400 MHz, DMSϋ-dό): consistent; MS (bS ) m/z 421.1 (M-H).
A procedure similar to that of Example 185, using different amines, provided Examples 186- 196. The compounds and their analytical data are shown in Table 16.
Table 16: Compounds Prepared According to the Procedure of Example 185
Figure imgf000107_0002
Figure imgf000108_0003
Example 197 S'-CFyrrolidin-1-yisuItonyOspiroll^-dioxolane^^'-indolJ^'Cl'HJ-one
Figure imgf000108_0001
5 5'-(Pyrrolidin-l -ylsullonyl)spiro[l ,3-dio\olane-2.3'-indolJ-2'( rH)-one was prepared trom 5-
(pyτrolidm-l -ylsulfon>l)-1H-indole-2,3-dione (Lee, D et al J Med C hem 2001 , 44, 2015) and ethylene glycol using a procedure bimilar to that of Example 1 1H NMR (400 MHz, DMSO-(Z6): consistent, MS (ES ) m/z 323 1 (M-H)
Example 198
Figure imgf000108_0002
To a solution of 5' (pyrrolidm-1-ylsulfonyl)spiro[1.3-dio\olane-2,3t-mdol]-2l(lΗ)-one (0 050 g.
0 14 πmo.) in DMF (2 mL) was added Cs2CO, (0 150 g 0 36 mmol) and 5-chloro-1-pentyne (0 050rnL, 0 48 mmol) The reactior was heated at 50° C overnight The reaction was cooled to it, then dill ted ft ithD H?O and e\ti acted with CH1Cl2 The combined oiganic extracts wei e dned ovei MgSO,, filtered, then concentrated in xaaω, ard purified by flash chromatography (12 g silica gel, 0-100% htt) Ax-Hex, linear gradient) to pro\ ide the title compound as a w hite solid (0 044 mg, 880O) H NMR (400 MHz DMSO- J1) consistent, MS (ES*) m z 391 0 (M+H)
\ procedui e similar to that of Example 19B, using alkyl halides, provided Examples 199 201 ,
208, and 209 The compounds and their analytical data are shown in Table 1? Table 17: Compounds Prepared According to the Procedure of Example 198.
Figure imgf000109_0001
Examples 202-207
Examples 202-207 were prepared from 5 '-(piper dm-1-ylsullbnyl)spiro[1.3-dioxanc-2,3'-indolJ- 2'(l Η)-one (prepared m procedure similar to Example 151) according to the procedure for Example 198,
Table 18: Compounds Prepared According to the Procedure of Example 198
Figure imgf000110_0003
Examples 208-66
Step J
S'-(Pipendιn-l-ykarbϋiιyl)spiroll ,3- dioxolane -2,3'-indoll-2'(rH)-mte
Figure imgf000110_0001
5'-(Pipeπdin-l -yk-irbonyl)spiro[1.3- dioxolane -2,3'-ιndol]-2'(l Η)-one was prepared from 5'-iodospiro[1.3-dioxolane -2,3'-indol]-2'(lΗ)-one (Rajopadhye, λf et al J Med Chem 1988, 3 /, 1001 ) and pipeπdine using a procedure similar to that of Example 161. Step 3
Examples 210-215 were prepared from 5'-ιpipeπdm-l
Figure imgf000110_0002
,3-dio\olane -2,3'- indol]-2 ( 1 II)-one and different alkjl hahdes according to the procedure for Example 198 The compounds and their analytical data are shown m Table 19 Table 19 Compounds Prepared According to the Procedure of Example 198
Figure imgf000111_0002
Example 216
Φchloro-N-fr-feycIopropylmethyl^Z'-oxospiroIfl^ldioxane-l^'-indolinel-S'- yl)benzenesulfonamide
Figure imgf000111_0001
Step l
1 '-(cyclopropylmethyl)-5 '-nitrospirojl,3-diύxane-2,3 '-indølj-2 '(I 'H)-one
Figure imgf000112_0001
A procedure similar Io that of Example 77, Step 5, using 5'-nitrospiro[1.3-dioxane-2,3'-mdol]- 2'(πi)-one (2 0 g. 7.99 mraol) provided the title compound as off white solid (1 .98 g 81%). 1H NMR (400 MHz, DMS0-d6).
Step ! 5'-amino-lf-(cyclopropylmethyl)spiro[1,3-dioxane-2,3'-indol]-2'(l'H)-one
Figure imgf000112_0002
A procedure similar to that of Example 133, Step 2, using r-(cyclopropylmethyl)-5'- nitrospirof l ,3-dioxane-2,3'-indol]-2'(l Η)-one (1.92 g, 7 99 mmol) provided the title compound (1.5g 86%). 1H NMR (400 MHz, DMSO-d6).
Step 3 4-chIoro-N-(l '-(cyclopropylmethyl)-2 '~oxospiro[[l,3]dioxane-2,3 '-indolineJ-5 '-yljbenzenesulfonamide
Figure imgf000112_0003
To a stirred solution of 5'-amino-r-(cyclopropyhiethyl)spiro[l ,3-dioxane-2,3'-indol]-2'(lΗ)-one (0.2 g, 0.73 mmol) in CBiCIi (5 mL) was added 4-chloro sulfonyl chloride ( 1 1 eq), and Et3N (3 equiv.) The reaction was stired at it over night. The reaction was concentrated, and purified by flash chromatography on silica gel (30% EtoΛc in Hexane). The resulting di-sulfonylated byproduct was suspended in THF (5mL) and treated with 2 5 N NaOH and heated at 70° C over night. Reaction was cooled to room temperate re. quenched with H2O ( I O mL) and then extracted with CH2CL concentrated, and purified by flash chromatography on silica gel (30% EtoAc m Hexane) to give 0.045 g (13%) of the title compound as a light brown solid. 1H NMR (400 MHz, DMSO-d6); consistent; MS (ESl m/z 449, 1 (M+H). A procedure similar to that of Example 216, using different sulfonyl chlorides, provided Examples 217- 219, The compounds and their analytical data are shown m Table 20,
Table 20 Compounds Prepared According to the Piocedute of Example 216,
Figure imgf000113_0002
Example 220 r-Phenyl-5'-(pyrrolidin-1->Isulfonyl)spirol[1,3]dioxane-2,3'-indolin]-2'-OHe
Figure imgf000113_0001
A suspension consisting of 5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r//)-one
( 169 mg, 0.5 mmol), PhB(OH)2 ( 183 mg, 1.5 mmol). Et3N (0,21 mL. 1.5 mmol), Cu(OAe)2 (182 mg, l .O mtnol). and 4A molecular sieves (-250 mg) m CH2Cl2 (5 mL) was stiπed at room temperature for 24 hours. The reaction mixture was diluted with CII2Cl2 (IO mL) and treated w ith aqueojs NaHCOi (l ϋ mL). 1 he organic layer was separated, filtered, and then directly purified by flash chromatography on silica gel (30: 1 CH2Cl2, EtOAc) to vie d 140 mg (68%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl1): consistent: MS (ESl m/∑ 415 1 (M-H)
A procedure similar to that of Example 221, using different boronic acids, provided Examples 221 - 259 The compounds and their analytical data are shown m Table 21 Table 21 : Compounds Prepared According to the Procedure of Example 221.
Figure imgf000114_0001
[ 13
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0004
Example 260 5l-(3-FluoropyrroHdin-1-vkulfonyl)-l'-phenylspirof[1,31dioxane-2,3'-indolin]-2'-one
Figure imgf000118_0001
Step 1 5-(3-Fluoropyrrotidm-l-ylsulfonyI)indoline-2,3-dione
Figure imgf000118_0002
The hydrochloride salt of racemic 3-fluoropyrrolidinc (628 mg, 5mmol) was added to a solution of 2,3-ώoxoindohne-5-sulfonyl chloride (1.2 g, 4.9 mmol) and diisopropylethyl amine (2.6 mL, 15 mmol) in 1 :1 CH2Cl2ZTHF (50 mL) at -50° C. The solution was warmed to room temperature and slirred at that temperature for 12 hours. The reaction mixture was concentrated, dissolved in CII2CI2. and then washed with saturated NaHCO3 and brine. I he organic layer was dried (MgSO4), filtered, concentrated, and purified by flash chromatography on silica gel (5% MeOH in CH2Cl2) to provide 1.4 g of the product as an orange solid.
Step 2 5'-(3-Fluoropyrrotidin-l-ytsutfonyi)spiro([l}3]dioxane-2,3'-indolin]-2'-one
Figure imgf000118_0003
A slurry containing 5-(3-fluoiopyrro1idin-l -ylsulfonyl)indolme-2,3-dione (1.4 g. 3.9 mmol), 1 ,3- dihydroxypropane (2 mL. 28 mmol) and/?-toluenesulfonic acid monhydrate (200 mg, 1.0 mmol) in benzene (100 mL) was heated at reflux temperature under a Dean Stark trap for 4 hours. The reaction mixture was concentrated, dissolved in CH2Cl2, and washed with saturated NaHCO3. The organic layer was diied (MgSO4). filtered, then concentrated, and purified by flash chromatography on silica gel (20% EtOAc m CH2Cl2) to provide 1.2 g of product as a pale yellow solid. 1H NMR (400 MHz, DMSQ-dό): consistent; MS (ES') m/z 357, 1 (M+H). Step 3
5 '-(3-FluoropyrroUdin-l-ylmlfonyl)-l '-phenyhpiro[[l,3]dioxane-2,3 '-indolinJ-2 '-one
Figure imgf000119_0001
A suspension consisting of S'-fS-fluoropyrrolidm-1-^lsulfonyOspirottUJdioxane^.S'-mdoIm]^1- one (54 mg, 0 15 mmol), PhB(OH)2 (61 mg. 0,5 mniol), Et3N (70 μL, 0.5 mmol). Cu(OAc)2 (63 mg, 0,35 mraol), and 4A molecular sieves (~150 mg) in CH2Cl2 (4 mL) was stirred at room temperature for 24 hours The reaction mixture was filtered and directly purified by flash chromatography on silica gel (30: 1 CHnCk EtOAc) to yield 4δ mg (74% J of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) consistent; MS (ES*) /»£ 433 2 (M+H).
A procedure sim.lar to that of Example 260, using different boronic acids, provided Examples 261 - 270 The compounds and their analytical data are shown m Table 22,
Table 22" Compounds Prepared According to the Procedure of Example 260.
Figure imgf000119_0002
Figure imgf000120_0001
Example 271 S'^S^-Difluoropyrrolidin-1-ylsulfonyO-r-phenylspirolll^jdioxanc-l^'-Jndolinl-l'-one
Figure imgf000120_0002
Step l 5-β,3-Difluøropyrrolidin~l-ylsulfmi}i)indoline-2,3-dione
Figure imgf000120_0003
T he hydrochloride salt of 3,3-difluoropyrrolidine (475 mg, 3,3 mmol) \^as added to a solution of
2.3-dioxoιndo!me-5-suifonyl chloride (1 ,0 g, 4, 1 mmol) and diisopropyleth) 1 amine (2 0 ml, 12 mmol) in 1 : 1 CH2Cl2ZTHF (40 mL) at -50° C. The solution was warmed to room temperature and stirred at that temperature for 12 hours The reaction mixture was then concentrated, dissolved in CH2Cl2. and washed with saturated NaHCOj and brine. The organic layer was dried (MgSO4), filtered, concentrated, and purified by flash chromatography on silica gel (5% MeOH in CH2Cl2) to provide 575 mg of the product as an orange solid.
Step 2 S'-(3J-Difluσropyrrolidin-l-ykulfonyl)spiro([l,3]dioxane-2,3'-indotin]-2'-one
Figure imgf000121_0001
A slurry containing 5-(3,3-difluoropyrrolidin-1-ylsulfonyl)indoline-2,3-dione (575 mg. 1.5 mmol), 1 ,3-dihydroxypropane (1 ml., 14 mmol) and/7-toluenesulfonic acid monhydrate (100 mg, 0.5 mmol) in benzene (50 mL) was heated at reflux under a Dean Stark trap for 4 hours. The reaction mixture was concentrated, dissolved in CH2Cl2, and washed with saturated NaHCθ3. The organic layer was then dried (MgSO4), filtered, concentrated, and purified by flash chromatography on silica gεl (20% EtOAc in CH2Cl2) to provide 410 mg of product as a white solid. MS (EST) m/z 375.1 (M+H).
Step 3 5'-(3,3-Difluoropyrrolidin-l-ylsulfønyI)-] '-pIienylspirυ//l,3Jdiυxane-2,3'-lndolinJ-2'-oιιe
Figure imgf000121_0002
A suspension consisting of S'-QJ-difluorϋpyrrølidin-l -ylsulfonylJspirolll
Figure imgf000121_0003
mdohn]-2'-one (56 mg, 0.15 mmol). PhB(OH)2 (61 mg. 0.5 mmol), Et3N (70 μL. 0.5 mmol), Cu(OAc)2 (63 mg, 0.35 mmol), and 4 angstrom molecular sieves ( — 150 mg) m CH2Cl2 (4 mL) was stirred a; room temperature for 24 hours. The reaction mixture was filtered and directly purified by flash chromatography on silica gel (30: 1 CH2Cl2/ EtOAc) to yield 50 mg (74%) of the title compound as a white solid. H NMR (400 MHz, CDCl3): consistent; MS (ESl we 451.1 (M+H).
A procedure similar to that of Example 271 , using different borome acids, provided Examples 272 - 274. The compounds and their analytical data are shown in Table 23. Table 23: Compounds Prepared According to the Procedure of Example 271.
Figure imgf000122_0001
Example 275 5'-(Morpholinosulfonyl)-r-phenylspiro[[1,3]diuxane-2,3'-iiidolin]-2'-one
Figure imgf000122_0002
Step l 5-(MorphoHnosulfonyl)indoUne-2,3-dione
Figure imgf000122_0003
Morpholine (1.1 mL, 12.2 mmol) was added to a solution of 2,3-diυxoLndoline-5-sulfonyl chloride (3.0 g, 12.2 mmol) and diibopropylethyl amine (7,0 mL, 40 mmol) m 1 :1 CH2CWTHF ( 120 mL at -50° C. The solution was warmed to room temperature and stirred at that temperature for 12 hours. The reaction mixture was concentrated, then dissolved m CHjCl2. and washed with saturated NaHCO3 and brine. The organic layer was dried (MgSO4), filtered, then concentrated, and purified by flash chromatography on silica gel (5% MeOH in CH:CU) to provide 2.4 g of the product. Step 2
5 '-(Morpholinosulfonyl)spiro[[l,3]dioxane-2,3 '-ittdolinJ-2 '-one
Figure imgf000123_0001
A slurry containing 5-(morpholmosulfony )mdolmc-2,3-dione (1 2 g, 4 O mmol), 1,3- dihydroxypropane (2 inL, 28 mmol) and/Holuertesulfon c acid monohydrate (200 mg, 1 0 mmol) in toluene (100 niL) was heated at reflux under a Dean Star< trap for 4 hours. The reaction mixture was concentrated, dissolved m CH2Cl2 and washed with satirated NaHCOs The organic layer was dried (MgSOi), filtered, then concentrated, and purified by flash chromatography on silica gel (2: 1 CH1Cl ,EtOAc) to provide 1 1 g of product as tan solid. 1H NMR (400 MHz. DMSO-d6): consistent; MS (ES ) OT 2 353.1 (M-H).
Step 3
5 '-(Morpholinosulfonyl)-l '-phenylspiro[[l,3Jdioxane-2,3 '-indolin]-2 '-one
Figure imgf000123_0002
A suspension consisting of 5l-(morpholmosulfonyl)spirol[1.3Jdioxane-2.3'-mdolm]-2'-one (53 mg, 0 15 mmol), PhB(OH), (61 mg, 0.5 mmol), Et3N (70 uL, 0 5 mmol), Cu(OAc)2 (63 mg, 0.35 mmol), and 4 angstrom molecular sieves (~150 mg) m CH2Cl2 (4 mL) was stirred at room tempeiatuie for 24 hours The reaction mixture was diluted with CH2Cl2 (4 mL) and treated with aqueous NaHCθ3 (5 mL). The organic layer was separated, filtered, and then direct y purified by flash chromatography on silica gel ( 10; 1 C H ,CWEtOAe) to yield 48 mg (74%) of the title compound as a white solid 1H NMR (400 MHz, CDClJ- consistent MS (ES') m/z 431.1 (MTTT).
A procedure similar to that of Example 275, using different boronic acids, prouded Examples 276 - S^ The compounds and their analjtical data are shown m Table 24 Table 24: Compounds Prepared According Io the Procedure of Example 275.
Figure imgf000124_0001
Figure imgf000125_0004
Example 288 5'-(Morpholinosulfonyl)-r-phenylspiro[[1,3]dioxolane-2,3'-indolinJ-2'-one
Figure imgf000125_0001
Step !
5 '-(Morpholinosulfonyl)spirolll,3]dioxolane-2,3 '-indolinj-2 '-one
Figure imgf000125_0002
h slurry containing 5-(morpholmosulfony )indolme-2,3-dione (1 2 g, 4 0 mmol), 1,2-
Figure imgf000125_0003
(2 mL, 36 mmol) and/j-tuluenesulfomc acid tnonohydiate (200 mg, 1 0 mmol) in toluene ( 100 rrl ) was heated at reflux temperature under a Dean Stark trap for 4 hour 1 he reaction iriλtυrc was coneeitiatec, dissohed n CH.C1 , and washed with saturated NaHCO1 The orgamc la}er was then dried (MgSO4), filtered, concentrated, and purified by flash chromatography on silica gel (2 1 CH2Cl;' EtOAc) to proude 0 9 g of product as tan solid 1H NMR (400 MH/, DMSO-dό) consistent, MS (ES ) m/z 139 I (M-H) Step 2
5 '-(Morpholinosulfonyl)-l '-phenyIspiro[[l,3]dioxolaιιe-2, ? '-indolinJ-2 '-one
Figure imgf000126_0001
A suspension consisting of 5^morpholmosulfon} l)spiro[[0]dio\olane-23'-indolm]-2'-one (51 mg, 0 15 mmol). PhB(OH), (61 mg. 0.5 mmol), Et3N (70 μL, 0 5 mmolj, Cu(OAc)2 (63 mg, 0 35 mmol), and 4 A molecular sieves (-150 mg) m CH2Cl2 (4 mL) % as stirred at room temperature for 24 hours. The ieaction mixtute was diluted with CH2Cl2 (4 mL) and treated with aqueous NaHCO (5 mL) The oiganic layer w as separated, filtccd. and then direetly purified by flash chromatography on silica gel (10: 1 CH2Cl2/Et0Ac) to yield 46 mg (74%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) consistent, MS (APPI) m/z 417 (M+H).
A procedure sinrlar to that of Example 288, using different boromc acids, provided Examples 289 - 296 The compounds and their analytical data are shown in Table 25.
Table 25: Compounds Prepared According to the Procedure ot Example 288.
Figure imgf000127_0002
Example 297 r-Phenyl-5t-(pyrrϋlidiπ-1-ylsuIfonyI)spiro[[1,3]dioxolane-2,3'-indolin]-2l-one
Figure imgf000127_0001
A suspension consisting of 5'-(pyrrolidin-1-ylsulfonyl)spiro[[1,3]dioxolane-2,3'-indolin]-2'-onc (49 mg, 0.15 mmol), PhB(OH)2 (61 mg. 0.5 mmoFi, Et, N (70 μL, 0.5 mmol), Cu(OAc)2 (63 mg; 0.35 mmol), and 4 A molecular sieves (-150 mg) in CH2Cl2 (4 niL) was stirred at room temperature for 24 hours. The reaction mixliirc was diluted with CHiCl2 (4 TiL) and treated with aqueous NaHCOi (5 mL). The organic layer was separated, filtered, and then directly purified by flash chromatography on silica gel (20: 1 CH2Cl2, EtOAc) to yield 45 mg (75%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 401.1 (M+H),
A procedure similar to that of Example 297, using different boronic acids, provided Examples 298 - 309. The compounds and their analytical data are shown in Table 26. Table 26: Compounds Prepared According to the Procedure of Example 297.
Figure imgf000128_0001
Figure imgf000129_0002
Example 310 l'-Phenyl-S'-Cpiperidine-1-carbonylJspirollljSJdioxanc-l^'-indolinl-I'-one
Figure imgf000129_0001
A suspension consisting of 5'-(piperidine-l -carbonyl)spiiO[[1,3]dioxane-2,3'-indolin]-2l-one (55 mg, 0.17 mmol), PhB(OH)2 (61 mg, 0.5 mmol), Et3N (70 μL, 0.5 mmol), Cu(OAc)2 (63 mg, 0.35 mmol), and 4 A molecular sieves (-150 mg) m CH2Cl? (4 mLj was stirred at room temperature for 24 hours. The reaction mixture was diluted with CH2C^ (4 mL) and treated with aqueous NaHCOa (5 mL). The organic layer was separated, filtered, and directly purified by flash chromatography on silica gel (10: 1 CH2CWEtQAc) to yield 44 mg (66%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl1): consistent: MS (ES) m,'z 393.1 (M+H).
A procedure similar to that of Fx ample 310, using different boronic acids, provided Examples 311 - 323. The compounds and their analytical data are shown m Table 27. Table 27: Compounds Prepared According to the Procedure of Example 312.
Figure imgf000130_0001
Figure imgf000131_0002
Example 324 l-Chloro-ό-fl'-oxo-S'-tpyπ olidin-1-ylsulfonylJspirolfl^Jdioxane-Iβ'-indolinel-r-ylJbenzonitrile
Figure imgf000131_0001
To a solution of 5'-(pyiτolidm-1-yIsulfoπyl)spiro[1,3-dioxane-2,3'-indol]-2'(T//)-one (680 mg, 2.0 mmol) in DMF (10 m.L) was added 60% NaH (88 mg, 2.2 mmol). After stirring for 10 minutes at room temperature, a 2.0 mL aliquot of this solution (0.4 mmol) was added to 2-chloro-6- tluorobenzonitrile (78 mg, 0.5 mmol) in DMF (2 ml .). The resulting solution was stirred at 60° C for 12 hours. The reaction was diluted with EtOAc, washed with H2O and brine, then dried (MgSOi), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (30: 1 CH2Cl3ZEtOAc) to provide 70 mg (37%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): consistent; MS (ES) ma 474.1 (M+H). Example 325 2-FIuoro-6-(2'-oxo-5l-(pyrroIidin-1-j lsulfoi]yl)spiro[[1,3Jdioxane-2,3t-indoline]-r-yl)ben/onitrile
Figure imgf000132_0001
To a solution of 5'-(pyrrolidin-1-ylsαlfonyl)spiro[1,3-dioxane-2,3'-indol]-2l(r//)-one (400 mg, 1 2 mmol) m DMF (12 ml ) was added 60% KaH (60 mg, 1 5 mmol) After stirπng foi 10 minutes at room temperature, a 3.0 mL aliquot of this solution (0 3 mmol) was added to 2,6-difluorobenzonitπlc (83 mg, 0.6 mmol) m DMF (2 mL). The resulting solution was stirred at 60° C for 12 hours. The reaction was diluted with EtOAc, washed with H2O and brine, then dried (MgSO4), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (30: 1 CH2Cl2ZEtOAc) to provide 52 mg (38%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl,): consistent; MS (ES) m/z 458.1 (M+H).
Example 326 3-FIuoro-2-(2'-oxo-5'-(pyrrolidin-1-^lsulfonyl)spiro[[1,3]dioxanc-2,3'-indolinc]-r-yl)benzonitrilc
Figure imgf000132_0002
To a solution of 51-(pynOlidm-1-ylsulfonyl)spirofl ,3-dioxane-2,3'-indol]-2'(r//)-one (400 mg, 1.2 mmol) in DMF (12 mL) was added 60% NaH (60 mg, 1 5 mmol). After stirπng for 10 minutes at room temperature, a 3.0 mL aliquot of this solution (0.3 mmol) was added to 2,3-difluorobenzonitπle (83 mg, 0.6 mmol) in DMF (2 mL), The resulting solution was stirred at 60° C for 12 hours. The reεction was diluted with EtOAc, washed with H;O and brme, then dried (MgSO4), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (30 1 CH2CI1/ EtOAc) to provide 87 mg (630O) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) consistent, MS (ES) m,z 458.1 (M-H). Example 327 Z-fl'-Oxo-S'-fpyrroIidin-1-ylsulfonylJspirollljSJdioxanc-I^'-indolinel-r-yOnkotinonitrile
Figure imgf000133_0001
To a solution of 5'-(pyrrohdin-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]-2'(r//)-one (85 mg,
0,25 mmol) in DMF (3 mL) was added 60% NaH ( 12 mg, 0.3 mmol). After stirring for 10 ininuteb at room temperature, 2-fluoronicotinonitrile (37 mg, 0.3 mmol) was added to the reaction mixture. The resulting solution was stirred at 60° C for 12 hours, l'hc reaction was diluted with EtOΛc, washed with H2O and brine, then dried (MgSO4), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (CH2Cl2'Et0Ac) to provide 68 rng (62%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): consistent; MS (ES) mh 441.1 (M I II).
Example 328 5l-(3-Fluoropyrrolidin-1-ylsulfon\I)-ll-propyIspiro[[1,3]ιlioxane-2,3'-indolin]-2'-one
Figure imgf000133_0002
Propyl bromide (75 μL. 0.83 mmol) was added to a suspension of 5'-(3-fluoropyrrolidin-1- ylsulfonyl)spiio[[l ,3]dioxane-2,3'-iπdolm]-2'-one (56 mg, 0.16 mmol) and excess CS2CO3 m 3 mL of DMF. The reaction was heated at 603 C for 1.5 hours and then stirred at room temperature for an additional 12 hours. The reaction mixture was diluted with EtOAc, washed with H2O and brine, then dried (MgSO,), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (30: 1 CH2Cl2/Et0Ac) to provide 46 mg (77%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): consistent; MS (ESj m/z 399.2 (MAH).
Example 329 r-(CycIopropylmethyI)-5'-(3-tluoropyrrolidin-1-jlsulfonyl)spiro[|1,3)dioxanc-2,3l4ndolin]-2'-one
Figure imgf000133_0003
C> c lopropyl methyl bromide (75 μL, 0 77 mmol) was added to a suspension of 5'-(3- fluoropyrrolidin-l -) lsulfonyl)spiro[[1,3]dio\ane-2.3'-indolin]-2'-one (56 mg 0 16 mmol) and excess Cs2CO3 in 3 ml of DMF The i eaction was heated at 60° C for 1 5 hours and then stirred at room temperature for an additional 12 hours 1 he reaction mixture was diluted \\ ith EtO \c, washed with H2O and bnne, then dried (MgSO4) filtered, and concentrated The crude residue was purified by flash chromatography on silica gel (30 1 CH2CL EtOAc) to picmde 47 mg (760O) of the title compound as a white solid 1H NMR (400 MHz, CDCl3) consistent, MS (ES) m 'z 41 1 1 (M+H)
Example 330 S'-tSJ-Difluoropyrrolidin-1-yhulfony^-r-propvkpiroHlβldioxaue-lJ'-indnlinJ-l'-one
Figure imgf000134_0001
Pi opyl bromide (75 μL, 0 83 mmol) was added to a suspension of 5'-(3,3-difluoropyrrolidm-1- ylbulfonyl)spiro[[1,3]dioxane-2,3'-indolin]-2'-one (56 mg, 0 15 mmol) and excess Cs2CO3 m 3 niL of DMF The reaction was heated at 60° C for 1 5 hours and then stirred at room temperature for ar additional 12 hours The ieaction mixture was diluted with FtOΛc, washed with H2O and brine, then dried (MgSO4), filtered, and concentiatcd The crude residue was purified by flash chromatography on sihea gel (30 1 CH, Cl EOAc) to provide 37 mg (59%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 417 1 (M+H)
Example 331 r-(C5clopropylraethyl)-5'-(3,3-difluorop\rrolidin-1-ylsulfon}l)spiro[[ly3|dioxane-2,3'-indolinI-2l- one
Figure imgf000134_0002
Cyclopropylmethyl bromide (75 μL 0 77 mmol) was added to a suspension of 5'-(3,3- difluorop>rrohdin-1->lsu foml)i>pιio[ l ,3]Ciθλane-2 3'-indolm]-2'-one (56 mg, 0 15 mmol) and excess Cs2CO in 3 mL of DMF The reaction was heated at 60° C for 1 5 hours and then stirred at room temperature for an additional 12 houis The reaction rrixture was diluted with EtOAc, washed with H2O and bnne. then dried (MgSO4), filtered, and concentrated The crude residue was purified by flash chromatography on sihca gel (30 1 CH2CU FtO 4c) to pro\ide 25 mg (39° o) of the title compound as a white solid 1II NMR (400 MHz, CDCl,) consistent, Mb (ΛPPI) tnt 429 (M-H). Example 332 S'-CPyrrolidin-1-ylsultonylJ-l'-Cl^^-trifluorobutyOspirofl^-dioxane-I^'- indoll-l'frHJ-one
Figure imgf000135_0001
A suspension consisting of 5l-(p)τrolidin-1-ylsulfonyl)spiro[1.3-dioxane-2,3'-iπdol]-2'(lΗ)-one
(0.1 Og. 0.30 mmol), alkyi bromide (0.1 1 ml., 0.89 mmol), K2CO3 (0.12g, 0.888) in DMF (3.0OmL) was irradiated m microwave at 80° C for 10 minutes. TLC analysis showed reaction to be complete, εo reaction mixture was diluted with EtOAc, washed with H2O, followed by brine. Organic layer was then dried over Na2SO4, concentrated and purified by flash chromatography on silica gel to afford product as a white solid (0.1 1 g. 85%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 449.1 (M+H).
A procedure similar to that of Example 332, using different alkyl halides, provided Examples 333 - 355. The compounds and their analytical data are shown in Table 28.
Table 28: Compounds Prepared According to the Procedure of Example
Figure imgf000135_0002
Figure imgf000136_0001
Figure imgf000137_0003
Example 356
5'-(Piperidin-1-ylcarbonyl)-lf-(4,4,4-trifluorobutyl)spiro[1,3-diϋλane-2,3'- indol]-2'(l'H)-one
Figure imgf000137_0001
Step I
S '-(Piperidin-l-ylcarbon}i)spiw[l,3-dioxane-2,3 '-indolJ-2 '(I 'H)-one
Figure imgf000137_0002
5'-Iodospiro[[1,3]dioxane-2,3 '-mdohn]-2'-one (2.0Og, 6,04mmol) was dissolved in DMF (60.0OmL) and to this solution were added trans-dichlorobis(triphenylphosphine)-palladium(II) (0.2 Ig, 0.30 mmol), piperidine C 1 93 inL, 120.80 mmol) and Et3N (2.74 πiL, 19.63 mmol). This solution was cooled to 0° C w hile CO was bubbled through reaction mixture for 1 hour. After 1 hour, the reaction vessel was sealed and heated at 60° C overnight. TLC analysis confirmed the reaction to be near completion, so the reaction mixture was then quenched with H2O and extracted with EtOAc, The organic layer was washed with brine, then dried over Na2SO4 and purified by flash chromatography on silica gel to afford the product as a light yellow solid. This solid was rccrystallizcd from HtOAc'Hex to afford the desired product as a white solid ( 1.00 g. 52%). 1H NMR (400 MHz, CDCl1); consistent; MS (ES) m/z 315 1 (M-H).
Step 2
S '-(3-FluøropyrroUdin-l-yl$ulfon)i)$pim[[l,3fdioxane-2,3 '-indølinJ-2 '-one
Figure imgf000138_0001
A suspension consisting of 5'-(piperidm-1-ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l Η)-one (0.050 g, 0.16 mmol), alkyl iodide (0.10 mL, 0.79 mmol), Cs2CO3 (0.24 g, 0.79 mmol) in DMF (3.00 mL) was irradiated in a microwave at 100°C for 15 minutes. TLC analysis showed reaction to be complete, so the reaction mixture was diluted with EtOAc, washed with H2O, followed by brine. The organic layer was then dried over Na2SO^ then concentrated and purified by flash chromatography on silica gel to afford the product as a white solid (0.054 g. 81%). 1II NMR (400 MIIz. CDCl3): consistent; MS (tS)
Figure imgf000138_0002
A procedure similar to that of Examnle 356, using different alkyl halides, provided Examples 357 - 383, The compounds and their analytical data arc shown m Table 29.
Table 29: Compounds Prepared According to the Procedure of Example 25,
Figure imgf000138_0003
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0004
Example 384 r-(Cjclopropylmeth\l)-5'-(morphoUn-4-jlcarbonyl)spiro[1,3-dioxane-2,3'-indoI]- 2'(rH)-onc
Figure imgf000141_0001
Step l
5 '-(Morpholin-4-ylcarbonyi)spiro[l,3-dioxane-2,3 '-indolj-2 '(I 'H)-one
Figure imgf000141_0002
5 '-Iodospiro[[1,3]dioxane-2,3'-mdolm]-2'-one ( 1 0Og, 3.02mmol) was dissolved m DMF (60.00 mL) and to this solution were added trans-diehlorobis(tπphenylphosphine)-palladium(II) (0.1 1 g. 0.15 mmol), morphohne (5 27 mL, 60 40 mmol) and Et3N (1 37 mL, 9.82 mmol). This solution was cooled to 0° C while CO was bubbled through the reaction mixture for 1 hour After 1 hour, the reaction vessel was sealed and heated at 60° C overnight. TLC analysis confirmed the reaction to be near completion, so the reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was washed with brine, then dried over NaiSOi, and purified by flash chromatography on silica gel to afford the product as a light yellow solid. This solid was recrystallized from EtO Ac/Hex to afford the desired product as a white solid (0.40 g, 42%). 1H NMR (400 MHz, CDCl3) consistent: MS (ES) m/z 317 1 (M-H)
Step 2
1 '-(Cyclopropylmethyl)S '-(moφholw-4-ykarbϋnyl)spiro[l,3-dioxane-2,3 '-indolj- 2 '(I Η)-one
Figure imgf000141_0003
A suspension corsistmg of 5'-(morphohn-4-ylcarbonyljspiro[1,3-dioxane-2,3'-mdol]-2'( TH)-OrIe
(0 060 g. 0.19 mmol), alky] bromide (0.054 ml, 0.56 mmol), Cs2CO3 (0.18 g, 0 56, mmo) in DMF (2 00 mL) was irradiated m a rricrow, a\ e at 80° C Oi 15 rrrnutes TLC analysis show ed the reaction to be complete, so reaction mixture was diluted wth ttOAc, washed with HjO. followed by brine Organic .aver was then dπed over Ka2SO4. concentrated, and purified by flash chromatography on silica gel to afford product as a white solid (0,060 g, 86%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 373.2 (M+H).
A procedure similar to that of Example 384, using different alkyl hahdes. provided Exarrples 385 - 390. The compounds and then analytical data are shown in Table 30.
Table 30: Compounds Prepared According to the Procedure of Example 52.
Figure imgf000142_0002
Example 391 l'^CyclopropylraethylJ-SjS-dimethyl-S'-tpiperidin-1-ykarbunjIjspiroll^-dJoxaiie-ljS'-indol]-
2'(lΗ)-one
Figure imgf000142_0001
Step l
5 '-Iodθ'5,5-dimethylspiro[l,3'dioxane-2,3 '-indolj-2 '(I 'H)-one
Figure imgf000143_0001
Λ slurry' containing 5-iodoisatin (5.00 g, 18.31 mmol), 2,2-dimethyl -1 ,3 -propanediol (5.72 g. 54.95 mmol), and /Moluenesulfomc acid monohydrate 0,698 g, 3.66 mmol) in toluene (150.00 niL) was healed to reflux temperature under a Dean Stark trap overnight. TLC analysis indicated the reaction was complete, so the reaction mixture was cooled to room temperature, and diluted with HiO. The mixture was then extracted with EtOAc, and the organic layer was washed with brine, then dried over Na2SO4, concentrated, and purified by flash chromatography on silica gel io afford the product as a white solid (5.00 g, 76%). 1H NMR (400 MHz, CDCl3): consistent: MS (ES) m/z 358.0 (M-II).
Step 2 5,S-Dimethyl-5'-(piperidine-l-carbonyl)spiwl[l,3]dioxane-2,3 '"indolinJ-2'-one
Figure imgf000143_0002
5'-iodo-5,5-dimethylsptro[1.3-dioxane-2,3'-indol]-2'(rH)-one (2.0Og, 5.57mmol) was dissolved in DMF (50.0OmL) and to this solution were added trans-dichlorobis(triphenylphos-phine)palladium(II) (0,20 g, 0.28 mmol), pφeridine (l LOO mL, 1 11.40 mmol) and Et3N (2.52 ml., 18.10 mmol). This solution was cooled to O11C while CO was bubbled through reaction mixture for 1 hour. After 1 hour, the reaction vessel was sealed and heated at 60° C overnight. TLC analysis confirmed the reaction to be near completion, so the reaction mixture was quenched with H2O, and extracted with EtOAc. The organic layer was washed with brine, then dried over Na2SO4 and purified by flash chromatography on silica gel to afford product as a light yellow oil, which was used in the following step with no further purification.
Step 3 / '-(Cydopropylmethyl)-5,5-dimethyl-5 '-(piperidin- l-ylcarhonyl)spirofl,3-diøxane-2,3 '-indolj-2 '(I 'H)- one
Figure imgf000143_0003
S.S-Dimethyl-S'Hpipendme-1-carbonylJspirofflpJdioxane^J'-mdolml^'-one (0, 18 g. 052 mmol), alk>l bromide (0.15 mL, 1 ,57 mmol) and Cs2O3 (0.51 g, 1.57 mmol) were stirred together in DMF at 6O0 C. After 1 hour, TLC analysis confirmed the reaction to be near completion, so the reaction mixture was quenched with H2O, and extracted with EtOAc. The organic layer was washed with brine, then dried over Na2SO4, and purified by flash chromatography on silica gel to afford the product as a white solid (0.088 g, 42%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 399.2 (M+H).
A procedure similar to that of Example 391, using different alkyl halides, provided Examples 392-395. The compounds and their analytical data are shown in Table 31.
Table 31 : Compounds Prepared According to the Procedure of Example 56.
Figure imgf000144_0002
Example 396
3-[2'-Oxo-5'-(piperidin-1-ylcarbonyI)spiro[1,3-dioxane-2,3'-indoll-r(2'H)- yl]propanenitrile
Figure imgf000144_0001
Step I
3-(5'-Iodo-2 '-axoψirø/l,3-dioxane-2J '-indol]-l '(2 Η)-yl)propaneaitrile
Figure imgf000145_0001
5'-Iodospiro[[ 1.3]dioxane-2,3'-indolin]-2'-one (3.48 g, 10.51 mmol) was stirred in EtOH (52,5 mL) and to this solution was added triton B (40% w/w: 0 48 mL, 1 ,05 mL). This mixture was then heated to 80° C, and to this warmed solution was added aciylomtrile (1.70 mL, 26.26 mmol) rapidly, After 1 hour, TLC analysis indicated the reaction was nearly completed, so the reaction mixture was cooled down and then concentrated to give a beige solid which was purified by flash chromatography on silica gel to afford the product as a white solid (3.24 g, 80%). H NMR (400 MHz, CDCl3): consistent: MS (HS) m/z 385.0 (M+H)
Step 2
Methyl 1 '-(2-cyanoethyl)-2 '-oxo-1 ',2 '~dihydrospiro[l,3-dioxane-2,3 '-iπdokJS '- carboxylate
Figure imgf000145_0002
3-(5'-lodo-2'-oxospiro[1,3-dioxane-2,3'-indol]-r(2Η)-yl)propanenitnle (1.50g, 3.90mmol) was dissolved in DMF (40.00 mL) and to this solution were added trans- dichlorobis(triphenylphosphine)palladium(II) (0.14 g. 0.20 mmol), methanol (44.77 mL) and Et3N (1.77 mL, 12.60 mmol). This solution was cooled to 0° C, while CO was bubbled through the reaction mixture for 1 hour. After 1 hour, the reaction vessel was sealed and heated at 60° C overnight. TLC analysis confirmed the reaction to be near completion, so the reaction mixture was quenched with H2O. and extracted with EtOAc. The organic layer was washed with brine, then dried over Na2SO4 and purified by flash chromatography on silica gel to afford product as a light yellow solid. This light yellow solid was recrystalhzed from EtOAc/hexanes to afford product as a pure white powder (T .00 g, 81%). 1H NMR (400 MHz, CDCl3): consistent: MS (ES) m/z 317.1 (M+H).
Step 3 1 '-(2-cyanσethyl)-2 '-oxospiroff 1 ,3Jdioxane-2,3 'indøtinef-5 'carboxylic acid
Figure imgf000145_0003
To a stirred solution of methyl l'-(2-cyanocthyl)-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3l- indolei-51- carboxylate (0.90 g. 2.85 ramol) in tetrahydrofuran (THF) (28.50 mL) was added IN KOH (28.50 mL, 28.50 mmol). The reaction mixture was heated at 60' C for 2 hours, after which TLC analysis indicated reaction was. complete. The reaction mixture was cooled to O11 C and acidified with 2N HCl (pH~7). The resulting mixture was extracted with HtOAc, and the resulting organic layers were then dried over Na2SO4 and concentrated to afford a vellow solid. The solid was stirred in Et2O for 5 minutes, and the Et2O was then filtered off to give product as a light yellow solid, which was used in the following step with no further purification.
Step 4
3-[2'-Oxo-S '-(piperidm-l-ylcarbonyljψirofl,3-diuxane-2,3 '-indolj-l '(2 'H)- yljpropanenifrile
Figure imgf000146_0001
r-(2-cyanocthyl)-2'-oxospiro[[1.3Jdioxane-2,3 'mdoline]-5'carboxylic acid (0, 100 g, 0.33 mmol), piperdine (0.040 mL, 0.40 mmol), Et3N (0.19 mL, 1.32 mmol) and N-methyl morpholine (1.50 mL) were stirred together in DMF (3.00 mL) and cooled to O°C. To this cooled solution was added TBTU (0,13 g, 0.40 mmol), and this mixture was allowed to stir overnight at room temperature. LC/MS indicated that starting material had been consumed, so reaction mixture was diluted with H2O and extracted with EtOAc. Organic layer was washed with brme, then dried over Na2SO4 and purified by flash chromatography on silica gel to afford the product as a colorless oil. Product was recrystallized from EtOAc/hexanes to afford desired product as a white solid (0.030g, 25%). 1H NMR (400 MHz, CDCl .): consistent; MS (ES) mlz 370.1 (M+H).
Example 397 3-[5l-(MorphoIin-4-ykarbonyl)-2'-oxospiro[13-dioxane-2,3'-indoI]-l'(2'H)-yl]propanenitrile
Figure imgf000146_0002
r-(2-Cyanoethyl)-2'-oxospiro[[1,3]dioxane-2,3'indoline]-5'carboxyhc acid (O. lOg, 0.33 mmol), morpholine (0.035 mL, 0.40 mmol), Et3N (0.185 mL, 1.324 mmol) and N-melhyl morpholine (-1.50 mL) were stirred together in DMF (3.00 mL) and cooled to 0 °C. To this cooled solution was added TBTU (0.13 g, 0.40 mmol), and this mixture was allowed to stir overnight at room temperature. LG'MS indicated that starting material had been consumed, so the reaction mixture was diluted with H2O and extracted w ith EtOAc. The organic layer was washed with brme, then dried over Na2SO4 and purified by flash chromatography on silica gel to afford the product as a white solid. Product was recrystalhzed from EtOAc/hexanes to afford desired product as a white solid (0.035 g, 29%). 1H NMR (400 MHz, CDCl,): consistent; MS (ES) nf∑ 372.1 (M+H).
Example 398
5'-(Piperidin-1-ylcarboiiyl)-r-(3,3,3-trifIiioropropyl)spIro|1,3-dioxanc-2,3'- indol]-2'(l'H)-one
Figure imgf000147_0001
Step I 5 '-Iodo-1 '-(3,3,3-trifluoropropyl)spiroll,3-dioxane-2,3 '-indølJ-2 '(I 'H)-one
Figure imgf000147_0002
To a slurry of 5'-iodospiro[[1,3]dioxane-2,3 '-indolm]-2'-one (1.00 g, 3.02 ramol) and Cs2CO3 (2.95 g, 9.06 mmol) in DMF (30.00 ml,) was added the alkyl iodidc(1.06 niL, 9.06 mmol). This reaction mixture was heated to 100°C, and was monitored by TLC. After stirring overnight. TLC analysis indicated that product had formed, so the reaction mixture was diluted with EtOAc, and washed with H2O followed by brine. The organic layer was then dried over Na2SO4, concentrated, and purified by flash chromatography on silica gel to afford product as a white solid (0.27 g, 21%). 1H NMR (400 MHz, CDCl3): consistent; MS (APPl) m/z 427.
Step 2
5'-(Piperidin-l-ylcarbonyl)-l '-(3,3,3-trifluoropropyl)spiro[l,3-dioxane-2,3 '- indol]-2'(l 'Hj-one
Figure imgf000147_0003
5'-Iodo-l'-{3.3,3-tπfluoropropyl)spiro[1,3-dioxaiie-2,3'-indol]-2'(riI)-onc (0.25g, 0.59 mmol) was dissolved in DMF (6.00 ml.) and to this solution were added trans- dichlorobis(triphenylphosphmc)palladium(II) (0.021 g, 0.029 mmol), piperidine (1.15 mL, 11 ,70 mmol) and Et1N (0.27 mL, 1.90 mmol). This solution was cooled to 0° C while CO was bubbled through the reaction mixture for 1 hour. After 1 hour, the reaction vessel was sealed and heated at 60° C overnight. TLC analysis confirmed reaction to be near completion, so reaction mixture was quenched with H2O and extracted with HtOAc. The organic layer was washed with brine, then dried over Na2SO4 and purified by flash chromatography on silica gel to afford product as a white solid (0.13 g, 56%). 1H KMR (400 MHz. CDCl3): consistent; MS (ES) m/z 413.1 (M+H).
Example 399 l-(Cyclopropylmethyl)-5-(piperidin-1-ylcarbonj'l)-3',4f,5f,6'- tetrahydrospiro[indole-3,2'-pyran]- 2(1H)-one
Figure imgf000148_0001
Step l l-(CydopropyImethyl)-5-(piperidin-l-ylcarbonyl)-lH-indole-2,3-dione
Figure imgf000148_0002
l'-(Cyclopropylmethyl)-5'-(pir)eridin-1-ylcarbonyl)spiro[1,3-dioxane-2,3t-mdol]-2'(rH)-one
(4.89 g, 13.20 mmol) was dissolved in THF (66.00 niL) and treated with 6 M HCL (66.00 mL, 396 mmol). This solution was warmed to 80° C, then the reaction was monitored by TLC. After 2 hours, the reaction was cooled to 0° C and was carefully neutralized with NaHCO3 (pH~8). The resulting mixture was then extracted with EtOAc, and the organic layer was washed with brine, dthen ried over Na2SO4, and concentrated to afford the product as a reddish oil. The oil was recrystallized from EtOAc/'hexanes to affoid pioduct as a red solid (2.10 g, 51%). 1H NlVlR (400 MHz, DMSO-d6): consistent; MS (ES) m/z 313.1 (M+H).
Step 2 3-AUyl-U(cyxlopropylmethyl)-3-hydroxy-S^piperidin-l-ylcarbonyl)-l,3-dihydro- 2H-indol-2-om
Figure imgf000148_0003
l -(C>clopropylmethyI)-5-{piperidm-1-ylcarbonyl)-1H-mdole-2,3-dione (0.50 g, 1 ,60 mmol) was dissolved in THF (16,00 mL), and this solution was cooled to -7S0 C. Once cooled, allyl magnesium bromide (1.0 M in ether; 3.2 OmL. 3.20 mmol) was added dropwise, and upon completion of the addition, the reaction mixture was taken out of ice bath, allowed to reach room temperature, and then stirred for an additional 1 hour. TLC analysis indicated reaction completion, so the mixture was quenched with saturated NH4Cl, and extracted with Ff2O. Organic layers were washed with brine, then dried over Na2SOi, and concentrated. Crude product was purified by flash chromatography on silica gel to afford
14' product as a light yellow solid (0 30 g, 53%). 1II NMR (400 MHz, CDCl,): consistent; MS (ES) nvz
Step 3 S-AIIyl-S-fallyloxvj-J-fcyclopropylmethylJ-S-φiperidin-l-ylcarbonyl)-!^- dihydro-2H-indol-2-one
Figure imgf000149_0001
3-Allyl-l -(c}-clopropylmeth>l)-3-hydrox>-5-(pipeπdin-l -ylcarbonyl) 1 ,3 dihydro- 2H-indol-2- one (0.29 g, 0.82 mmol) was dissolved in a DCM.NaOH (aq. 50°/o) mixture (1: 1 ; 1600 mL) This solution was then treated with TBAI (0.030 g, 0.0S2 mmol) and allyl bromide (0 10 mL, 1 2 mmol) and was allowed Io stir o\einight TI C analysis indicated reaction was complete, so reaction was neutralized with sat MI4Cl and was then extracted with btOAc. Organic layers were washed with bnne, then dπed over Na^SO4, and concentrated. Crude product was purified by flash chromatography on silica gel to afford product as a light yellow oil (0 30 g, 53%) 1H NMR (400 MHz. CDCl3). consistent; MS (ES) m/z 395 2 (M+H)
Step 4 l-iCyclopropylmethyiyS-ipiperidin-l-ylcarbonyij-S'fβ'-dihydroψirolindoleS,!'- pyran]-2(l H)-one
Figure imgf000149_0002
3-AllyI-3-(allyloxy)-l -(cyclopropylmethyl)-5-(pipeπdin-l -ylcarbonyl)-1,3- dihydro-2H-indol-2- one (0.20 g. 0.49 mmol) was dissolved m toluene (15.00 mL) and was then treated with Giubb's catalyst (lςt generation, 0 021 g. 0 025 mmol) The ieaction mixture was then heated to reflux and after 1 hour, TI C analysis indicated reaction was nearly complete so additional catalyst (0.010 g) was added and mixture was then stirred at reflux for an add.tional 1 hour. TLC analysis then indicated that reaction was complete so the mixture w as cooled to room temperature and diluted v\ ith H2O The i eaction mixture was then extracted with ethyl acetate, and otganic layers were washed with bπnc, then dπed o\er Na->SO4. and concentrated to gne crude product as a black oil Crude product was purified by flash chromatography on sihca gel to afford the product as an off-white solid (0 16 g, 86%) 1H NMR (400 MHz. CDCl3)- consistent, MS (ES) m'z 367 2 (M+Hj.
Step 5 l-(Cyclopropylmethyl)-5-(piperidin-l-ylcatϋonyi)-3\4\5\6'- tetrahydrospiro[indole-3,2'φyran]-2(lT{)' one
Figure imgf000150_0001
l -(Cyclopropy]methyl)-5-(pipeπdm-1-ylcarbonyl)-3',6'-dihydrospiro[indole-3,2'- p>τanJ-2(1H)- one (0.14 g, 0.38 ramol) was dissolved in EtOAc (-5.00 mL) and treated with Pd/C (5%. wet; -0.50 g). A balloon filled with H2 was attached to the system, and the flask was flushed with H2 for 5 minutes, after which the system was closed. The reaction mixture was stirred at room temperature for 2 hours, and TLC analysis indicated that the reaction was complete. The reaction mixture was filtered through celite. and then concentrated to afford product as a white solid (0.14 g, 96%). 1H NMR (400 MHz. CDCl3): consistent: MS (ES) mlz 369.2 (M+H).
Example 400
(3R)-1-(Cyclopropylmethyl)-5-(piperidin-1-ylcarbonyl)-3(,4l,5t,6(- tetrahydrospiro[indole-3,2'- pyran]-2(l H)-one
Figure imgf000150_0002
l ^Cyclopropylmetriy^-S-Qiiperidin-l -ylcarbony^-.T^'jS'jό'- tetrahydrospiro[indole-3,2'-pyran]- 2(1H)-one was separated by HPLC on a Chiracel AD column (2 x 25 cm), eluting with 15% IFA
(isopropyl alcohol) m hexane/DEA. R-Enantiomer was isolated with a purity of 99.9%; 1H NMR (400 MHz, CDCl3): consistent; MS (ES) mil 369.2 (M-H).
Example 401 (3S)-1-(Cyclopropylmethyl)-5-(piperidin-1-ylearbonyl)-3',4',5',6'- tetrahydrospiro[indole-3,2'- pyranj-2(l H)-one
Figure imgf000150_0003
l-(CycIopropylmethyl)-5-(pipeπdin4 -ylearbønyl)-3',4',5',ό'- tetrahydrospiro[ir.dole-3.2'-pyran]- 2(l H)-one was separated by HPLC on a Chiracel AD column (2 x 25 cm), eluting with 15% IPA in hexanoDEΛ. b-Enantiomer was isolated with a purity of 99.9%; 1H NMR (400 MHz. CDCl,): consistent: MS (ES) nvz 369.2 (M-H)1 Example 402
5-(Piperidin-1-ylcarbonyl)-1-(2,2,24rifluoroethyl)-3',4'.,5',6f- tetrahydrospirø[indole-3,2'-pyran]- 2(1H)-oπe
Figure imgf000151_0001
Step l 5-(Piperidin-l-ykarbonyl)-l-(2,2,2-trifluorocthyl)-lH-indole-2,3-dione
Figure imgf000151_0002
5'-(Piperidin-1-ylcarbonyl)-r-(2,2,2-trifluoroethyl)spiro[1,3-dioxane-2,3'-indol]-2'(rH)-one (2.15 g, 5.39 mmol) was dissolved in THF (27.00 mL) and was treated with 6 M HCL (27.00 mL). This solution was warmed to 80c C, then the reaction was monitored by TLC, After 2 hours, reaction seemed to be complete so reaction was cooled to O3C and was carefully neutralized with NaHCO3 (pH-8). Mixture was then extracted with EtOAc, and organic layer was washed with brine, then dried over Na2SO4, and concentrated to afford product as a reddish oil. Oil was recrystallized from ElOAc/hexanes to afford product as a yellow solid (1.70 g, 93%). 1II NMR (400 MIIz, DMSO-dό): consistent; MS (ES) m/z 341.1 (M+H).
Step 2
3-Λllyl-3-hydroxy-5-(piperidin-l-ykarbøfty!)-l-(2,2,2-trifluoroethyl)-l,3- dihydro-2II-indol-2-one
Figure imgf000151_0003
5-(Pipeπdin-l -ylcarbonyl)-1 -(2,2,2-tfifluoroethyl)-1H-indole-2,3-dione (1.00 g, 2.94 mmol) was dissolved in THF (30.00 mL) and this solution was cooled to -78°C. Once cooled, allyl magnesium bromide (1.0 M m ether; 5.88 mL, 5.88 mmol) was added dropwise, and upon completion of the addition, the reaction mixture was taken out of the ice bath and allowed to reach room temperature and stirred for an additional 1 hour. TLC analysis indicated the reaction to be complete, so the mixture was quenched with saturated NH4Cl, and extracted with Et/), Organic iayers were washed with brine, then dried over Na2SO4, and concentrated. Crude product was purified by flash chromatography on silica gel to afford product as a light yellow solid (0.27 g, 24%) 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/τ 383, 1 (M i ll). Step 3
3-Allyl-3-(allyioxyj-S-(piperidin-l-ylcarbonyl)-l-(2,2,2-trifluoroethyl)-l,3- dihydro-2H-indol-2-one
Figure imgf000152_0001
3-Allyl-3-hydroxy-5-(pipendin-1-ylcarbonyl)-l -(2.2,2-tnfluoroethyl)-l ,3- dihydro-2H-indol-2- øne (0.25g, 0.65mmol) was dissolved in a DCM:NaOH (aq. 50%) mixture (1 : 1; 14.00 niL). This solution was then treated with TBAI (0,024 g, 0.065 mmol) and ailyl bromide (0.083 mL, 0.98 mmol) and was allowed to stir overnight. TLC analysis indicated the reaction was complete, so the reaction was neutralized with saturated NH4Cl and then extracted with EtOAc. Organic layers were washed with brine, then dried over Na2SO], and concentrated. Crude product was purified by flash chromatography on silica gel to afford product as a light yellow oil (0.16 g, 56%). 'H NMR (400 MHz, CDCl1): consistent; MS (ES) m/∑ 423.2 (M-H).
Step 4 5-(Piperidin-l-ylcarbonyl)A-(2,2,24rif\uoroethyl)-3\6'-dihydroi<pirolindole- 3,2'-pyran]-2(ΪH)-one
Figure imgf000152_0002
3-A11y1-3-(allylθλy)-5-(piperidiπ-1 -ylcarbonyl)-1-(2,2,2-trifIuoroethyl)-l ,3- dihydio-2H- ndol-2- onc (0.15 g, 0.36 mmol) was dissolved in toluene (11.00 mL) and then treated with Grubb's catalyst (lbt generation: 0.015 g, 0.018 mmol). Reaction mixture was then heated to reflux and after 1 hour, TLC analysis indicated the reaction was nearly complete so additional catalyst (0.010 g) was added and the mixture was stirred at reflux for an additional 1 hour TLC analysis then indicated that the reaction was complete so the mixture was cooled to room temperature and diluted with H3O, 1 he reaction mixture was extracted with ethyl acetate and the organic
Figure imgf000152_0003
were washed with brine, then dried over NajSO,}, and concentrated to give crude product as a black oil. Crude product was purified by flash chromatography on silica gel to afford product as a grey solid (0.11 g, 75%), 1I I NMR (400 MIIz. CDCl3): consistent: \1S (ES) m'z i95Λ (M+ll).
Step 5
5-(Piperidm-l-ylcarbonyl)-l-(2J,2-tήfluoroeth}i)-3',4\5',6'- tetrahydrospiro[indole-3,2''pyran]-2(llϊ)~ one
Figure imgf000153_0001
5HPipeπdm-l -ylcarbonyl)-l -(2,2,2 -trifluoroethyO-S'.θ'-dihydrospiropndole-
Figure imgf000153_0002
one (0,090 g, 0.23 mmolj was dissolved in EtOAc (-5.00 mL) and treated with Pd/C (5%, wet: ~0.500g ). A balloon filled with H2 was attached to the system, and the flask was flushed with H2 for 5 minutes, after which the system was closed. The reaction mixture was stirred at room temperature for 2 hours, and TLC analysis indicated reaction completion. The reaction mixture was filtered through celite. and concentrated to afford product as a white solid (0.090 g, 100%). 1H NMR (400 MHz, CDCIj): consistent; MS (ES) m/z 397.2 (M+H).
Example 403 r^CyclopropylmethylJ-S'-fpiperidin-1-ylcarbonylJspirolljS-dioxepane-IjS'-iiidoll-lXrKO-one
Figure imgf000153_0003
A slurry containing l -(cyclopropylmethyl)-5-(piperidin-1-ylcarbonyl)- 1H-indole-2,3-dione (0.20 g, 0.64 mmol), 1 ,4-butanediol (0.17 mL, 1 ,92 mmol), and p-toluenesulfonic acid monohydrate (0.024 g, 0.128 mmol) in toluene (6.50 mL) was heated to reflux temperature under a Dean Stark trap overnight. TLC analysis indicated the reaction was complete, so the reaction mixture was cooled to room temperature, and diluted with H2O. The mixture was then extracted with EtOAc, and the organic layer was washed with brine, then dried over Na2SO4, concentrated, and purified by flash chromatography on silica gel to afford product as a white solid (0.18 g, 7%). 1II NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 385.2 (M-H).
Example 404
3-tert-bιιtj1-1-(cyclopropylmethyl)-3-hydroxy-5-(piperidin-1-ykarbonyl)-13-dihydro-2II-indol-2- one
Figure imgf000153_0004
l-(Cyclopropylmelhyl)-5-(pipendin-l -ylcarbonyl)-1H-indole-2,3-dione (0 156 g) was dissohed in THF and cooled to -783C under nitrogen. This cooled solution was then treated with a 1.0 M solution of t-BuMgCl in THF (0.6 mL) dropwise. The resulting mixture was stirred at -78" C to rt under nitrogen over 4 hours. It was then diluted with a saturated solution OfNH4Cl (50 mL), extracted with CH2Cl2 (3X50 mL), then dried (Na2SOj), and conceπtratec under reduced pressure. Chromatography with EtOAc- Hexanes (0-100% gradient elution) afforded the title compound as yellow oil (0.10 g). 1H NMR (400 MHz. CDCl3): consistent; MS (ESl m'i 371.2 (M+H).
Example 405 3-tert-Butyl-1-(cyeIopropylmeth\l)-3-fluoro-5-(piperidin-1-ylcarbonyI)-1,3-dihydro-2H-indol-2-one
Figure imgf000154_0001
3-tert-Butyl-1-(cyclopropylmethyl)-3-hydroxy-5-(piperidin-l -ylcarbonyl)-l ,3-dihydro-2H-indol- 2 -one (0.050 g) was dissolved in CH2CL (2.0 mL), cooled to O0 C and treated with diethylaminosulfur tπfluoπdc (ϋ.05 mL) dropwise. The resulting mixture was stirred at O0 C for 30 minutes, diluted with CH2Cl2 (50 mL), and extracted from saturated NaHCO3. The organic phase was separated, then dried (Na2SO^, and concentrated under reduced pressure. Chromatography with EtOAc-Hexanes (0-100% gradient elution) afforded the title compound as a yellow oil (0.038 g). 1II KMR (400 MIIz, CDCl3): consistent; MS (ESl "^ 373.2 (M+H).
Example 406 r-(cyclopropylmethyl)-5'-[(4,4-difluoropiperidin-1-yl)carbonyllspiiO[1,3-dioxane-2,3'-indol]-
Figure imgf000154_0002
A solution containing l'-(cyclopropylmethyl)-5'-iodospiro[[1.3]dioxane-2.3l-indolm]-2'-one (1.04 g, 2.7 mmol ), 4.4-difluoropiperidine hydrochloride (1.36 g, 8.73 mmol), and triethylamine (3 mL, 21.4 mmol) in toluene (24 mL) was purged with nitrogen for 5 minutes. Bis(triphenylphosphme)palladium(ll) dichloπde ( 140 mg. 0 1 mmol) was added and the reaction was stirred at 60° C under a carbon monoxide balloon atmosphere overnight. 1 he reaction was concentrated at reduced pressure and purified by flash chromatography on silica gel (5: 1 DCM/EtOAc) to yield 514 mg (47% )of product as a tan solid. H WfR (400 MHz, CDCl;): consistent; MS (ES ) mfz 407.1 (M-H), Using a procedure similar to that of Example 406, using different secondary amines, Examples 407 - 410 were prepared, The compounds and their analytical data are shown in Table 32,
Table 32: Compounds Prepared According to the Procedure of Example 406,
Figure imgf000155_0003
Example 411 5'-(7-azabicyclo[2.2.11hept-7-ylcarbonyl)-l'-(3,4-difluorophenyl)spiro[1,3-dioxane-2,3'-indolj- 2'(1 'H)-oiie
Figure imgf000155_0001
Step 1 r-(3,4-difluorophenyl)-5'-iodospiro[[1.3]dioxane-2,3'-indolin]-2'-one
Figure imgf000155_0002
A suspension consisting of 5l-iodospiro[[1,3]dioxane-2,3'-indolin]-2'-onc (662 mg, 2.0 mmol).
3,4-difluorophenyl boronic acid (947 mg. 6 mmol). Et3N (0.84 mL, 6 mmol), Cu(OAc)2 (726 mg, 4.0 mmol). and 4A molecular sieves (~1 g) in CH2Cl2 (20 niL) was stirred at room temperature overnight. The reaction mixture was diluted with CH;C1; (20 mL) and treated with aqueous NaIICOj (20 rnL). The organic layer was separated, filtered, and directly purified by flash chromatography on silica gel ( 1 : 1 CH:Cl;/EtOAc) to yield 800 mg (90 %) of the title compound.
Step 2
5'-(7-azabic>clo[2.2.1]hept-7-ylcarbonyl)-I'-(3,4-diiluorophenyl)spiro[ l ,3-dioxane-2,3'-mdoll-21(l'H)- one
Figure imgf000156_0001
A solution containing l '-(3,4-difluorophenyl)-5'-iodospiro[[l ,3]dioxane-2,3l-indolin]-2'-one (91 mg, 0.2 mmol), 7-azabicyclo[2.2.l]heptane (84 mg, 0.625 mmol), and tπethylamine (0.8 mL) in toluene (24 mL) was purged with nitrogen for 5 minutes. Bis(triphenylphosphine)palladium(ll) dichloride (18 mg, 0.025 mmol) was added and the reaction was stirred at 60° C under a carbon monoxide balloon atmosphere overnight. The reaction was concentrated at reduced pressure and purified by flash chromatography on silica gel (5: 1 DCM/EtOΛc) to yield 85 mg (94%) of the title compound as an off- white solid. 1H NMR (400 MHz, CDCl3): consistent; MS (ES+) m/z 441.2 (M+H).
Using a procedure similar to that of Example 41 1, using different secondary amines. Examples 412 415 were prepared. The compounds and their analytical data are shown in Table 33.
Table 33 Compounds Prepared According to the Procedure of Example 41 1.
Example Compound Name MS r-(3,4-difluorophenyl)-5'-{[(2S)-2- (metho\yrnelh>l)pyrrϋlidin-1-yl]carbonylj spiro[1.3- (ES) IWt 459.1
412 dioxane-2,3'-mdol]-2'{ l'II)-one (M+H) r-(3,4-difluorophenyl)-N,N-diethyl-2'-oxo-
1 ,2'-dihydrospiro| 1 ,3-dioxane-2.3'-indole]-5'- (ES) m/z 417.1
413 carboxamide (M-rH)
1 '-( 3,4-difluorophenyl)-N-etpyl-N-(2- methoxyethyl)-2'-oxo-I '.2'-dihydrospiro[l ,3-dioxane- (ES) Wt 447 1
414 2,3 '-indole-) -5 '-carboxamide (M-H)
Figure imgf000157_0004
Example 416
1 '-(cyclopropylmethyl)-5'-(l H-pyrrol- 1 -ylsulfonyl)spiro [ 1 ,3-dioxane-2,3'-iiidoI] -2'(TH)-one
Figure imgf000157_0001
Step 1
Ncopcntyl 1 '-(cyclopropylmethyl^'-oxospirojj 1 ,3 Jdioxanc-2,3'-indolineJ-5'-sulfonate
Figure imgf000157_0002
Neopentyl 2'-oxospiro[|T ,3]dioxane-2,3'-indoline]-5'-sulfonate (3.1 g, 8.7 mmol) was dissolved in DMF (100 mL) and treated with K2CO3 (5 g, 36.5 mmυl) and cyclopropylmethyl bromide (4.1 mL, 42.2 mmol). The reaction was stirred at room temperature overnight, diluted with EtOAc (500 mL), washed with water and brine, dried (MgSO4), filtered, and concentrated. The crude residue obtained was purified by flash chromatography on silica gel (4: 1 hexane/EtOAc) to yield 3.32 g (93%) of the product.
Step 2
1Hcycloprσpylmethyl^'-oxospiroβ l^dioxane^^'-indolmel-S'-sulfonyl chloride
Figure imgf000157_0003
Neopentyl r-(cyclopropylmethyl)-2'-oxospiro[[1,3]dioxane-2,3'-indoline]-5'-sulfonate (3.32 g. 8.1 mmol) was dissolved in DMF ( 10 ml.) and treated with tetramethyl ammonium chloride (888 mg, 8 1 mmol). The resulting mixture was heated at 160° C for 1 hour, cooled, and concentrated at reduced pressure. The remaining residue was dissolved in methylene chloride (20 mL) and treated with thionyl chloride. The reaction was heated al 40° C overnight and concentrated to dryness at reduced pressure to yield 3.64 g of crude title compound that was used without additional purification. Step 3 r-(cyclopropylmethyl)-5'-(l H-p>τroI-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-mdol]-2'(lΗ)-one
Figure imgf000158_0001
Pyrrole (58 uL, 0.84 mmol) mas dissolved in dicnloroethane (2 mL) and treated with NaOH (100 mg, 2.5 mmol). The resulting mixture wa» stirred for 10 minutes and then treated with crude 1'-
(cyclopropylmethyl)-2l-oxospiro[[1,3-dioxane-2,3'-ιndoline]-5'-sulfonyl chloride (200 mg, 0.56 mmol). The reaction was stirred at rt
Figure imgf000158_0002
diluted with water and extracted with EtOΛc. The combined organic layers were washed with water and bπne, dried (MgSO4). filtered, and concentrated at reduced pressure The ci ude pioduct was. purified by flash chromatography on silica gel (5 1 Hexane/ ETOAc) to yield 44 mg (20%) of the product as a white solid 1H NMR (400 MHz, CDCl3): consistent: MS (ES ) m-'z 389 1 (M+H).
Example 417 5'-(azetidin-1-ylsulfon\I)-l'-(cycIoprop^lniethyl)spiro[1,3-dioxane-2,3'-indoI]-2'(rH)-one
Figure imgf000158_0003
r-fCyclopropylmethyl^'-oxospiroffUldioxane^jS'-indolmel-S'-sulfonyl chloride (200 mg,
0 56 mmol) was added to a solution containing cyclobutyl amine (76 uL. 1 12 mmol) and Et3N (156 iiL,
1 12 mmol) in DCM (3 rrL). The reaction was stirred at rt until a completed reaction was observed by LCMS. 1 he reaction was concentrated at reduced pressure and purified by flash chromatography on silica gel (DCM/ EtOAc) to yield 171 mg (81%) of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl1) consistent, MS (ES ) mh 379 1 (M+H)
Using a procedure similar to that of Example 417, and using different nucleophiles. Examples 418 - 425 were prepared The compounds and their analytical data are shown in Table 34
Table 34 Compounds Prepared According to the Procedure of Example 417.
Figure imgf000158_0004
Figure imgf000159_0002
Example 426 r-(3,4-difluorophen>l)-5l-(1H-p>razol-1-ylsulfonjl)spiro|1,3-dioxane-2,3'-indolJ-2l(lΗ)-one
Figure imgf000159_0001
Step 1 neopent)! l '-(3,4-d *luorophenyl)-2'-oxospiro[[l ,3 diθ\anc-2 3'-mdohncJ-5'-sulfonate
A suspension consisting of neopentvl 2' o\ospiro[[l ,3]dioxane-2,3l-indohne]-5'-su!forate (2 3 g 6 5 mmol). 3.4-difluorophenyl borontc acid (3 06 g, 14 4 mmol), Et3N (2 7 mL, 14 4 mmol), Cu(OAc). (2 31 g 12 4 mmol) and 4A moleculai sieves i --2 g) m CH2CIi (80 mL) was stiπed at room tempeiature oλcrmght The reaction mixture was diluted with CHiCIi (20 mL) and treated with aqueous NaHCO1 (20 mL) The oreanic la%er was separated, filtered, and concentrated at reduced pressure Purification b\ flash chromatography on sihta gel (3 1 hexane EtO 4t) yielded 1 9^ g (64%) of the title compound
b8 Step 2 r-(3,4-difluorophenyl)-2'-oxospiro[[1,3]dio\ane-2,3'-mdoline]-5'-sulfonyl chloride
Figure imgf000160_0001
Neopentyl 1 '-(3Λ-difluorophenyl)-2'-oxospiro[[1,31dioxane-2,3'-mdolme]-5'-sulfonate (1.95 g, 4,2 mmol) was dissolved in DMF (10 mL) and treated with tetramethyl ammonium chloride (594 mg, 5.4 mmol). The resulting mixture was heated at 160O C for 1 hour, cooled, and concentrated at reduced pressure. The remaining residue was dissolved in methylene chloride (30 mL) and treated with thionyl chloride ( 1.56 mL). The reaction was heated at 40° C overnight and concentrated to dryness at reduced pressure to yield 2.0 g of crude title compound that was used without additional purification.
Step 3 r-(3,4-difluorophenyl)-5i-(1H-pyτazol-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]-2'(lΗ)-one
Figure imgf000160_0002
r-(3,4-difluorophenyl)-2'-oxospiro[π .3]dioxane-2,3l-indoline]-5l-sulfonyl chloride (200 mg, 0.48 mmol) was added to a solution containing pyrazole (74 mg. 0.96 mmol) and Et3N (134 μL, 0.96 mmol) in methylene (3 mL). The reaction was stirred at room temperature until a completed reaction was observed by LCMS. The reaction was concentrated al reduced pressure and purified by flash chromatography on silica gel (DCM/EtOAc) to yield 37 mg (17%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): consistent; MS (ES4) m/z 448.0 (M+H).
Using a procedure similar to that of Example £26, and using different nucleophiles. Examples 427 - 429 were prepared. The compounds and their analytical data arc shown in Fable 35, Table 35: Compounds Prepared According to the Procedure of Example 426,
Figure imgf000161_0003
Example 430 S'-KSJ-dinuϋroazetidin-1-ylJsulfonyll-l'-phenylspiroll^-dioxane-I^'-indolJ-lXl'^-one
Figure imgf000161_0001
Step l 5 -(3 ,3 -difluoroazeti dm- 1 -ylsulfonyl )mdohne-2,3 -dione
Figure imgf000161_0002
The hydrochloride salt of 3,3-difluoroazetidme (650 mg, 5 mmol) was added to a solution of 2,3- dioxoindohne-5-sulfonyl chloride (1.2 g. 4.9 mmol) and diisopropylethyl amine (2.6 mL. 15 mmol) m 1 : 1
CH3CyTHF (50 mL) at (P C. The solution was wεrmed to room temperature and stirred at that temperature for 12 hours. The reaction mixture was concentrated and purified by flash chromatography on silica gel (5% MeOH in CH7Cl7 ) to provide 960 mg of the product as an orange solid.
Step 2 5'-(3,3-difluoroazetsdm-1-ylsulfonyI)spiro[[1,3]dio\ane-2,3'-indolin]-2l-one
Figure imgf000162_0001
A slurry containing 5-(3,3-ditluoroazctidin-1-ylsulfonyl)mdoiine-2,3-dione (960 mg, 3.2 mmol), 1 ,3-dihydroxypropane ( 1.5 mL) and /3-toluenesulfonic acid monhydrate (100 mg) in benzene (75 mL) was heated at reflux under a Dean Stark trap for 4 hours, The reaction mixture was concentrated, dissolved in CII2Cl2, and washed with saturated NaHCO3. The organic layer was dried (MgSO4). filtered, concentrated, and purified by flash chromatography on silica gel (20% EtOAc in CH2CU) to provide 710 mg of product as a pale pink solid. Step 3 5l-L(3)3-diiluoroazetidin-1-yl)sulfonyl]-r-phenylspiro[l ,3-dioxane-2,3l-indol]-2l(lΗ)-one
Figure imgf000162_0002
A suspension consisting of 5'-(33-difluoroazetidin-1-ylsulfonyl)spiro[[1,3]dioxane-2,3'-indolin]- 2'-one (54 mg, 0.15 mmol), PhB(OH)2 (61 mg, 0.5 mmol), Et3N (70 μL, 0.5 mmol), Cu(OAc)2 (63 mg, 0.35 mmol), and 4A molecular sieves (-150 mg) m CH2Cl3 (3 mL) was stirred at room temperature for 24 hours. The reaction mixture was diluted with methylene chloride (5 mL) and washed with half saturated NaHCO} solution The organic layer was separated and directly purified by flash chromatography on silica gel (CH2Cl2ZEtOAc) to yield 42 mg (65%) of the title compound as a white solid. 1II NMR (400 MHz. CDCl3): consistent; MS (ES' ) m/z 437.1 (M+H).
Using a procedure similar to that of Rxanpie 430, and using different boionic acids, Examples 431 - 439 were prepared. 'I he compounds and their analytical data are shown in Table 36,
Table 36 Compounds Prepared According to the Procedure of Example 430.
Figure imgf000162_0003
Figure imgf000163_0002
Example 440 r-(tyelopropylmethyl)-5'-f(3,3-difluoroazetidin-1-yl)sulfonyllspiro[1,3-dioxane-2,3'-indol|-2'(rH)- one
Figure imgf000163_0001
Cyclopropylmethyl bromide (19 μL, 0.2 mmol) was added to a suspension of 5'-(3,3- difluoroazetidin-l -ylsulfonyl)spiro[[l ,3]dioxane-2,3'-indolin]-2'-one (36 mg, 0.1 mmol) and Cs2CO3 (163 nig, 0.5 mmol) m 2 riiL of DMF. The reaction was heated at 60° C for 4 hours and then diluted with EtOAc, washed with H2O and brine, dried (Na2SO1), filtered, and concentrated. The crude residue was purified b> flash chromatography on silica gel (CH2Cl2ZEtUAc) to provide 37 mg (89%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3); consistent; MS (ES) m/z 415.0 (M+H)
L sing procedure similar to that of Example 440, and using different alky] bromides, Examples 441 - 442 were prepared. The compounds and their analytical data are summarized in Table 37. Table 37: Compounds Prepared According to the Procedure of Example 440,
Figure imgf000164_0003
Example 443 2-{5'-[(3,3-difluoiOazetidin-1-yl)sulfonyl]-2'-oxospiro[1,3-dioxaπe-2,3t-iπdϋl]-l'(2Η)- ylfnkotinonitrile
Figure imgf000164_0001
To a solution of 5'-(3,3-difluoroa7etidin-l -ylsulfonyl)spiro[[1,3]dioxane-2.3'-indolin]-2'-one (407 mg. 1.13 ramol) m UMF ( 10 mL) was added 60% NaH (60 mg, 1.5 mmol). After stirring for 10 minutes at room temperature, 2-fluoronieotinonitrile (183 mg, 1 ,5 mmol) was added to the reaction mixture. The resulting solution was stirred at rt overnight. The reaction was diluted with EtOAc, washed with H2O and brine, dried (MgSO^), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (CH2Cl2ZEtOAc) to provide 326 mg (62%) of the product as a white solid. 1H NMR (400 MHz, CDCl3); consistent; MS (ES) m/z 463.0 (M+H).
Example 444
2-{5'-[(3-fluoropyrrolidin-1-yl)sulfonyl]-2'-oxospiro[1.3-dioxane-2,3'-indol]-r(2'H)- yljnicotinonitrile
Figure imgf000164_0002
To a solution of 5L(3-fluoropyrrojdin-1-ylsulfonyl)spiro[[l ,3]dioxane-2,3'-indohnJ-2'-one (89 mg. 0.25 mmol) in DMF (3 mL) was added 60% NaH (12 mg, 0.3 mmol). After stirring for 10 minutes at room temperatuie, 2-fluoronicotinoniti ile (37 mg, 0.3 mmol) was added to the reaction mixture. The resulting solution was stirred at 60° C for 1 hour and then at room temperature overnight. The reaction was diluted with HtUAc, washed with O2O and brine, dried (MgSO4), filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (CH2CLZEtOAc) to provide 55 mg (48%) of the title compound as a white solid. 1H KMR (400 MHz, CDCl3): consistent; MS (ES) m/z 459.1 (M+H).
Example 445 2-[5'-(morphoIin-4-ylsuIfonyl)-2'-oxospirof1,3-dioxane-2,3l-iπdol]-r(2Η)-yl]nicotinonitrile
Figure imgf000165_0001
To a solution of 5Hmorpholmosulfonyl)spiro[[1,3]dioxane-2,3'-indohn]-2'-one (89 mg, 0,25 mmol) in DMF (3 mL) was added 60% NaH (12 mg, 0.3 mmol). After stirring for 10 minutes at room temperature, 2-fluoromcotinonitπle (37 mg, 0.3 mmol) was added to the reaction mixture. The resulting solution was stirred at 60° C for 1 hour and then at room temperature overnight. The reaction was diluted with EtOAc, washed with H2O and brine, dried (MgSO4), filtered, and concentrated. The crude residue was purified by Hash chromatography on silica gel (CHiCL/EtOAc) to provide 73 mg (64%) of the product as a white solid. 1II NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 457.2 (M+H).
Example 446 r-(eytiopropyImethyl)-5'-(7,8-dihydro-1,6-naphthyridin-6(5//)-ylcarbonyl)spiro[1,3-(lioxane-2,3'- indol]-2'(17/)-one
Figure imgf000165_0002
Tπethylamme (0.082 ml, 0.593 mmol) was added to a mixture of r-(cyclopropylmethyl)-2'- oxospiro[[l ,3]dioxane-2,3l-mdolme]-5'-carboxyhc acid (60 mg, 0.198 mmol). Kl - ((ethylimmo)methylene)-N3.N3-dimethylρroρane-l ,3-diamine hydrochloride (49.3 mg, 0.257 mmol), 3H- [l ,2,3]tria7θ1o[4,5-b]pyπdin-?-o1 (35.0 mg, 0.257 mmol) and 5,6.7,8-tetrahydro-1.6-naphthyπdine (35.9 mg. 0.27 mmol) m DCM (3 mL) with stirring at room temperature under an atmosphere of nitrogen. The reaction mixture was then stirred at room temperature overnight. After the reaction completed the reaction w as quenched with small amount of water. The mixture was concentrated and the residue was purified by revise phase HPLC (gradient elution using 14-100 % acetonitrile with 0,075% TFA in water with 0.075% TFA) to afford 106 mg (64%) of the title compound as a light yellow solid. 1H NMR (400 MH/, CDCl3): consistent; MS (ES ') m/z 420.2 (M+H).
Using a procedure similar to that of Example 446, and using different secondary amines. Examples 447 - 458 were prepared. The compounds and their analytical data are shown in Table 38.
Table 38: Compounds Prepared According to the Procedure of Example 446.
Example Compound Name MS
5'-[(4-acetylpiperazin-1-yl)carbonyl]-T- (cyclopropylmethyl)spiro[l ,3-dioxanc-2,3'-indolJ- (ES) m/z 414.2
447 2'(17/)-one (M+H) r-(cyclopropylmethyl)-5'-[(4-methylpiperazin- (ES) m/z 386.2
448 l-yl)carbonyl]spiro[1,3-dioxane-2,3'-indol]-2'(l'ff)-one (M+H)
1 '-(cyclopropylmethyl)-5'- f [4-(pyridm-2- yl)pφerazin- 1 -yljcarbonyl} spiro[ 1 ,3-dioxane-2,3'- (ES) m/z 449.2
449 indol]-2'(lΗ)-one (M+H) l '-(cyclopropylmethyl)-5'-[(7-methoxy-6- methyl-l ,3-dihydro-2//-pyrrolo[3,4-c]pyridin-2- (ES) m/z 450.2
450 yl)carbony 1] spiro [ 1.3 -dioxane-2,3 '-indol]-2'( 17/) -one (M+H) r-(cyclopropylmethyl)-5l-(3,4.6.7-tetrahydro- 5//-imidazo[4,5-c]p>τidm-5-ylcarbonyl)spiro[1,3- (ES) m/z 409 2
451 dioxane-2,3'-indol]-2'(r/7)-one (M+H) r-(cyclopropylmethyl)-5'-(5.7-dihydro-6i/- pyrrolo[3,4-b]pyridin-6-ylcarbonyl)spiro[l ,3-dioxane- (ES) m/z 406.2
452 2,3'-indol]-2'(l 1H)-one (M+H) r-(cyclopropylmelhyl)-H-(4-methylpiperazin- l-yl)-2'-oxo-r.2'-dihydrospiro[l ,3-dioxanc-2,3'- (ES) m/z 401.2
453 indole]-5'-carboxamide (M+Η)
5'-f ( 3-chloro-7,8-dihydro- 1 ,6-naphthyπdin- 6(5Hι->πcarbonyl]-r-(cyclopropylmethy'.)spiro[1,3- (ES) m/z 454,2
454 dιoxane-2,3'-indol]-2l(r//)-one (M+Η) r-(cyclopropylmethyl)-5'-[(2-methyl-3.4,6,7- tetrahydro-5H-imidazof4.5-c]p>τidin-5- (ES) m/z 423.2 455 I yl)carbonyllspiro[1,3-dioxane-2,3'-indol]-2'(r//)-one (M-H) r-(cycloprυp}lmeιhyl)-5'-(6.7- (ES) m/z 425.2
456 dihydrothicno[3.2-c]p\τidm-5(4//)- (M-H)
Figure imgf000167_0004
Example 459 5'-[(4,4-clifl«oropiperidin-1-yl)carbonyl]spiro[1,3-dioxaiie-2,3'-iiidoIJ-2'(rΗ)-one
Figure imgf000167_0001
Step 1 5'-Iodospiro[[1,3]dioxane-2.3'-indolin]-2'-one
Figure imgf000167_0002
A stirred mixture containing 5-iodoisatin (4.06 g. 14.9 mmol), 1,3 -propanediol (3.23 mL, 44.6 mmol) and p-toluene sulfonic acid monohydrate (0.565 g, 2.97 mmol) in benzene (149 ml.) was refluxed for 15 hours. The reaction was cooled to room temperature, washed with saturated aqueous NaHCOs (3 x), dried (NaiSO4) and concentrated. The crude product was purified on RediSep silica eluting with a 0 to 100% EtOAc/hexane linear gradient to give 4.00 g (81%) of the title compound as a white solid. 1H NMR (400 MHz. CDCl3): consistent
Step 2 5'-[(4,4-difluoropiperidin-1-yl)carbonγl]spiro[1,3-dioxanc-2,3'-indol]-2'(lΗ)-one
Figure imgf000167_0003
In a 100 mL round-bottomed flask was added 5'-!odo3piro[[1.3Jdioxane-2.3'-indohn]-2'-one (2.00 g, 6.04 mmol), 4,4-difluoropiperidin:um chloride (4.76 g, 30,2 mmol), triethylamme (8.42 mL, 60.4 mmol), and Dichlorobis(triphenylphosphine)-palladium(II) (0.297 g, 0.423 mmol) in Io give a yellow solution. This reaction mixture was heated after 60° C under a CO atmosphere over weekend. TLC indicated that all starting material had been consumed, so reaction mixture was diluted with ethyl acetate washed with H2O. Aqueous laj-er was then back extracted with ethyl acetate, and the organic layers were combined, washed with brine, dried over Na2SOφ filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanes:ethyl acetate (10-80%). Product was afforded as a light-brown solid (1.3Og, 61%). 1H NMR (400 MHz, CDCl3): consistent; MS (ESI) m/z 353.1 (M+H).
Example 460
5'-I(4,4-diπuoropipericlin-1-yl)carbonyl]-l '-(3-hydroxy-3-methyIbutyl)spiro[1,3-diosane-2,3'-indoI]-
Figure imgf000168_0001
In a 100 niL round-bottomed flask was added 5'-(4,4-difluoropipeπdme-1- carbonyl)spiroff1,3]dioxane-2,3'-mdoiin]-2'-one (0.200 g, 0.568 mmol), cesium carbonate (0.555 g, 1.703 mmol), and 4-bromo-2-methylbutan-2-ol (0.284 g, 1.703 mmol) in DMF (2.84 mL). This mixture was heated at 60° C for 2 hours, afterwhich TLC (hex-ea:4-l ) indicated that reaction was complete. Reaction mixture was cooled to room temperature, dilutee with ethyl acetate, washed with saturated NaHCOg, followed by bπne. The organic was dried over Na2SOφ filtered and concentrated. The crude product was added to a silica gel column and was eluted with hexanesxthyl acetate (0-50%). Product afforded as a white solid (0.205g. 82%). 1Il NMR (400 MIIz, CDCl3): consistent; MS (ESI) m/z 439,2 (M 1 II),
Example 461 5'-|(4,4-diπuoropiperidin-1-yl)earbonyl]-r-(pyridin-3-yl)spiro[1,3-dioxane-2,3'-indolJ-2'(rH)-one
Figure imgf000169_0001
In a 500 ml, round-bottomed flask was added 5'-(4,4-difluoropipeπdine-1- carbonyl)spiro[[1.3]dioxane-2,3'-indolm]-2'-one (0.250 g, 0,710 mmol), pyridin-3-ylboronic acid (0.131 g, 1 064 mmol). and coppei (II) acetate (0.258 g, 1,419 mmol) in DCM (3 55 mL). tπethylamine (0.297 mL, 2.129 mmol) was added to this solution dropwisc. The reaction was stirred at room temperature for 1 week. After 1 week, some reactants still persisted, however, the reaction mixture was absorbed onto celite, evaporated, and the crude product was added to a silica gel column and was eluted with hexanes- EtOAc (0-80%, gradient elution) to afford product as a clear, colorless oil (0.091 g, 30%). 1H NMR (400 MHz, CDCl3); consistent; MS (LSI) m/z 430.2 (M+H).
Example 462 5l-[(4,4-difluoropiperidin-1-yl)carbonyl]-l'-(pyridin-4-yl)spiro[1,3-dioxane-2,3'-indol]-2'(l 'H)-one
Figure imgf000169_0002
In a 500 mL round-bottomed flask was added 5'-(4,4-difluoroprρcπdmc-1- carbonyl)spiro[[1,3]dioxane-2,3'-indolin]-2'-one (0.250 g, 0.710 mmol), pyridin-4-ylboronic ae:d (0.131 g, 1.064 mmol), and copper (II) acetate (0.258 g, 1.419 mmol) m DCM (3.55 mL). triethylamine (0.297 mL. 2.129 mmol) was added to this solution dropwise. The reaction was stirred at room temperature for 1 week. After 1 week, some reactants still persisted, however, the reaction mixture was absorbed onto celite, evaporated, and the crude product was added to a silica gel column and was eluted with hexanes- EtOAc (0-80%, gradient elution) to afford product as a white solid (0.104 g, 34%). 1H NMR (400 MHz, CDCl3); consistent; MS (ESl) m/z 430.2 (M+H).
Example 463 r-(cvclϋpropylmethyI)-5'-[(4-hydro3C\piperidiii-1-yl)carboiiyl]spiro[l53-dioxa!ie-2J'-indolI-2'(lΗ)- one
Figure imgf000170_0001
In a 25 mL round-bottomed flask was added r-(cyclopropylmethyl)-5'-iodospiro[[1,3]dioxane- 2,3'-indolin]-2'-one (0.200 g, 0.519 mtnol), piperidin-4-ol (0.263 g, 2.60 mmol), trietliylamine (0.724 ml , 5, 19 mmol), and ϋichlorobis(triphenylphosphine)-palladiuτn(ll) (0.026 g, 0.036 mmol) tn Toluene (2.60 mL). This solution was then stirred under a CO atmosphere at 60° C overrate. LC/MS following morning indicated that product had been formed, so reaction was cooled and concentrated. Crude material was dissolved in DMSO (5rr!) and purified by HPLC (25-80% ACN). Product was afforded as a clear, colorless oil (0.028g, 14%). 1H NMR (400 MHz. CDCl,): consistent; MS (ESI) m/z 387.2 (M+H),
Examples 464-467
Figure imgf000170_0002
Examples 464-467 were prepared from 5'-amino-l'-(cyclopropylmethyl)spiro[l ,3-dioxane-2,3'- indol]-2'( r//)-one and the appropriate sulfonyl chloride using a procedure similar to that of step 3 of Example 216 and are summarized in Table 39,
Table 39: Compounds prepared using a procedure similar to that of step 3 of Example 216
Figure imgf000171_0004
Example 468 r-(Pyridin-2-yl)-5'-(pyrrolidin-1-ylsuIfon>l)spiro[13-dio\ane-2,3'-indol]-2'(rH)-onc
Figure imgf000171_0001
To a solution of
Figure imgf000171_0002
nohdin-1-ylbulfonyl)spiro[[l 3]dio\ane-2 3'-indohn]-2'-one (0 065g, 0 192 mrnol) in dioxane (2 ml) πas added potassium phosphate (0 082 g. 0 384 mmol),
Figure imgf000171_0003
1 ,2-diamine (6 90 μl. 0 077 mmol), 2-iodop>πdme (0 041 ml, 0 384 mmol) and copper(I) iodide (0 015 g. 0 077 mmol) The reaction mixture was purged with N2 for 15 minutes and then heated at 110° C over night Aftei cooling the solids wei e flteied off and washed with EtOAc The filtrate was concentiated and the crude mixture was purified on RcdiScp™ silica gel cluting with a 0 to 100% EtOAe hcxane + 1 Et N linear gradient to gπe 0.063g ( 79%) of the title compound as a white solid
: NMR (400 MIIz, DMSO-d6) consistent, MS (ESI ) m z 416 1 (M I H) Example 469 r-(3-Hydroxy-3-methylbutyl)-5'-(pyrrolidin-1-ylsulfonyl)spiro[1,3-diosane-2,31-indol]-2'(l'H)-one
Figure imgf000172_0001
The product (0.048g. 93%) was prepared from 5'-(pyrrolidm-1-ylsulfbnyl)spiro[[1,3Jdioxane-2.3'- indolin]-2'-one and 4-bromo-2-methylbutan-2-ol (EP78704) using a procedure similar to that of Example 328. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 425.2 (M+H).
Examples 470-472
Figure imgf000172_0002
Examples 470-472 were prepared from 5'-( 3 ,3 -difluoroazetidin- 1 -ylsulfonyl)spiro[[1,3]dioxane-
2,3'-indolin]-2'-one and the appropriate iodo-pyridine using a procedure similar to that of Example 468, summarized in Table 40
Table 40 Compounds pi epared using a procedure similar to that of Example 468
Figure imgf000173_0003
Examples 473-475
Figure imgf000173_0001
Fxamples 4^3-475 weie prepared fiom 5'-(3,3-difluoroazetidin-1->lsulfonyl)spiio[[1,3]dioxane- 2,3'-mdolm]-2 -one and the appropriate bromomethyl
Figure imgf000173_0002
using a procedure similar to that of Example 328, summarized m Table 41
[72 Table 41 : Compounds prepared using a procedure similai to that of Example 328.
Figure imgf000174_0002
Example 476 S'-[(3,3-Ditluoroazetidin-1-yl)sulfonyll-r-(3-hydroxy-3-methylbutyI)spiro[1,3-dioxaπe-2,3'-indolI- 2'(l'//)-one
Figure imgf000174_0001
The product (0 O53g, 84%) was prepared from 5 '-(3 ,3 -difluoioazet idi n- 1 - ylsulfonyl)spiro[[1,3]dioxane-2,3'-indohn]-2'-onc and 4-bromo-2-methylbutan-2-ol (bP78704) using a procedure similar to that of Example 328 1H NMR (400 MHz. DMSO-dό) consistent; MS (ESI ) nv'z 447 1 (M-^H).
Examples 477-479
Figure imgf000175_0001
Examples 477-479 were prepared from 5'-[(3.3-difluorop>τrolidin-l -yl)sulfonyl]spirof1,3- dioxane-2.3'-indol]-2'(l 'H)-OtIe and the appropriate iodo-pyridine using a procedure similar to that of Example 468, summarized in Table 42.
Table 42: Compounds prepared using a procedure similar to that of Example 468.
Figure imgf000175_0003
Examples 480-482
Figure imgf000175_0002
Examples 480-482 were prepared from 5'-[(3,3-difluoropyrrolidin-1-yl)sulfonyl]spirof 1 ,3- dioxane-2,3'-indol]-2'(l'//)-one and the appropriate bromomethyl pyridine using a procedure similar to that of Example 328, summarized in Table 43,
Table 43 : Compounds prepared using a procedure similar to that of Example 328.
Figure imgf000176_0002
Example 483 r-Benzyl-S'-KS^-difluoropyrrolidin-1-yπsulfonyllspiroll^-dioxane-I^'- indoll-lXrHl-oiie
Figure imgf000176_0001
The title compound (0.067g, 87%) was prepared from 5'-[(3,3-difluoropyrrohdin-1- y!)suIfonyl]spiro[1,3-dioxane-2,3'-indol]-2'(r//)-one and benzyl bromide using a procedure similar to that of Example 328. 1H KMR (400 MHz, DMSO-dό): consistent; MS (ESf) m/z 465.1 (M+H).
Example 484
S'-l(3,3-Difluoropyrrulidiπ-1-yI)sulfonyl]-r-(3-h>droλy-3- methylb«ityl)spiro(1,3-tlioxane-2.3t- indolJ-2'(17/)-one
Figure imgf000177_0001
The product (0.065g, 81 %) was prepared from 5'-[(3,3-difluoiopyrrolidIn-1-yl)suIfonyl]spiro[1,3- dioxane-2,3'-mdolJ-2'( 1 '//)-one and 4-bromo-2-methylbutan-2-ol (EP78704) using a procedure similar to that of Example 328. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESF) m/z 461.2 (M+H).
Example 485 r-tCyclopropylmethylJ-S'-Cpiperidin-1-ylcarbony1H.S-dihydro-SH-spirolfuran- l^'-indoll-l'ClΗ)- one
Figure imgf000177_0002
Step 1 3-Allyl-3-hydroxy-5-iodoindolin-2-one
Figure imgf000177_0003
To a solution of 5-iodoisatin (5.00 g, 18.3 mmol), in DMF (100 ml) at 0 CC was added ally! bromide (3.096 ml, 36.6 mmol), indium (2.62 g, 22.9 mmol), and sodium iodide (4.43 g. 36.6 mnol). The reaction was stirred εt 0° C for 15 minutes, then 1 hr at room temperature (until starting material was consumed, as determined by TLC). The reaction was poured into water, added (UN HCL (20 ml) and extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous NaHCO3, Organic layer dried over MgSO4, filtered, concentrated in vacuo, and purified on RediSep silica gel during with a O to 70% acetone, hexane 'inear gradient to give 5.12g (88%) of the pioduct as a light yellow solid, 1H N.MR (400 MHz, DMSO-d6): consistent; MS (ESI ) m'z 315.9 (M+H).
Step 2 51-Iodo-4-(phenylselanyl)-4,5-dihydro-3H-spiro[furan-2.3'-indolin]-2'-one
Figure imgf000178_0001
To a solution of 3-allyl-3-hydroxy-5-iodomdolin-2-onc (2.00 g, 6 35 mmol), m DCM (100 ml) was added camphorsulfonic acid (0.44 g, 1.89 mmol) and λr-phenylselenophthahmide (2.29 g, 7.57 mmol). The reaction was heated at reflux overnight, then cooled and filtered over a silica gel pad and concentrated in xacuo The residue was purified on RediSep™ silica gel eluting with a 0 to 30% acctone/hexane linear gradient to gi\e 1.46g (49%) of the product. 1H NMR (400 MHz, UMSO-d6): consistent: MS (ESI ) m/z 471.9 (M+H).
Step 3 S'-Iodo-SH-spiiOffuran^'-indolm^'-one
Figure imgf000178_0002
To a solution 5'-iodo-4-(phen> lselaryl)-4.5-dihydro-3H-spiro[furan-2,3'-indolinl-2'-one (5 00 g, I S.3 mmol), in THF (35 ml) at 0 °C mas added pyridine ( 10 drops) and 30% H2O2 (4.0 ml, 35,4 iimol). The reaction was sliπed iΛ for 1 hour and then quenched wiih water The reaction was ettiacted w ith DCM, dried o\er MgSO4, filtered, concentrated in xacuo and purified on RediSep silica gel eluting w ith a 0 to 100% EtOAc/hexane linear gradient to give l .47g (79%) of the product. 1H NMR (400 MHz, DMS0-d6): consistent; MS (ESF) mh 313.9 (M+H).
Step 4 5'-(Piperidme-l -carbonyl)-5H-spiro[furan-2.3'-indolin]-2'-one
Figure imgf000179_0001
The product (1.09 g, 78%) was prepared from 5'-iodo-5H-spiro[fiιraιi-2,3l-indolin]-2l-one using a procedure similar to that of Step 3 of Example 161 . 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESF) m/z 299.1 (M+H). Step 5 5'-(Piperidine-l -carbonyl)-4,5-dihydro-3H-spiro[furan-2,3'-indolin]-2'-one
Figure imgf000179_0002
The product (1.09 g, 78%) was prepared from 5'-(piperidine-1 -carbonyl)-5H-spiro[furan-2.3'- indolm]-2'-one using a procedure similar to that of Step 5 of Example 402. 1H NMR (400 MHz, DMSO- dό): consistent; MS (ESf) m/z 301.1 (M+H).
Step 6 r-(Cyclopropylmethyl)-5'-(pipcridm-1-ylcarbonyl)-4,5-dihydro-3H-spiro[furan- 2,3'-indolJ-2'(lΗ)-one
Figure imgf000179_0003
1 he product (0.59 g, 98%) was prepared from 5'-(pipendme-1-carbonyl)-4,5-dihydro-3II- spiroffuran-2,3'-indolin]-2'-one using a procedure similar to that of Step 2 of Example 5 1H NMR (400 MHz, DMSO-dό) consistent. MS (ESI ) m/z 355 2 (M^Hj
Examples 486-490
Figure imgf000180_0001
Examples 486-490 were prepared from 5'-(pipeπdine-l -carbonyl)-4,5-dihydro-3H-spiro[furan-
2,3'-mdolm]-2'-one and the appropriate alkylating agent using a procedure similar to that of Step 2 of F\ ample 5, summai ized in Table 44
1 able 44 Compounds prepared using a procedure similar to that Step 2 ot Example 5
Figure imgf000180_0002
Example Λ
Functional Assessment of Human CB2 and CBl Cannabinoid Receptor Activity
Cell Culture CHO Kl cells expressing the human CBl or CB2 receptor were cultured at 370 C, in Ham's F12
(Invitrogen 21765-037 or equivalent) containing 10% fetal bovine serum (US biotechnologies or the equivalent), 100 μg'iτil penicillin and 100 μg/ml streptomycin (Gibco 10131-035), 400 μg/nil G418 (Gibco 10131 -035).
Adherent cell culture cells were maintained by seeding at 2-3 x 106 cells in 30 mL medium in a T175.
For assays using frozen aliquots of cells, cells were thawed at 37° C, added to 15 mL complete medium, ccntπfugcd at 1200 rpm for 2 minutes. The cell pellet was resuspended in 5 ml medium and then added to a T 175 containing 25 ml of medium.
Frozen cells were also thawed as above and maintained in culture by adding the resuspended cells to 100 ml of medium in a sterilized 250 mL Erlenmeyer flask that was gassed with 5% CO2, capped, and placed on an orbital shaker at low RPM (50-100).
cAMP Assay
Cells were lifted from the plate with dissociation buffer centrifuged and resuspended in a small volume of PBS. Cells were plated (15.000/well; 96 well plate, 7,500/well; 384 well plate) and incubated in the presence of 10 μM forskolin and compound in Krebs bicarbonate buffer (1 18 mM NaCl, 5 niM KCl, 1.2 mM MgSO4, 2.4 mM CaCl2, 1.2 mM KH2PO4< 25 mM NaHCO3. 1 1.1 mM glucose) at 37° C for 30 minutes. cAMP content was determined using the HitHunter cAMP XS assay (Discoverx 90-0041, 90-0041L). For the antagonist assay, compound is incubated in the presence of 10 μM forskolin and 10OnM WIN-55212-2 at 37 ° C for 30 minutes.
The HitHunter assay was performed according to the manufacturer's instructions. Briefly, 20 μL cAMP anti body/lysis mix (1 : 1 ratio) were added to stimulated cells and incubated at room temperature for 1 hour. 20 μL of c AMP XS ED reagent was added and incubated at room temperature for 1 hour. 20 μL of cAMP XS EA reagent and 20 μL of CL substrate (1 part Galacton-Star, 5 parts F.merald-N, 19 parts substrate diluent) were added and then incubated at room temperature for 3 h. Chcmilumincsccncc was read on a Victor II at 1 s/well, Λ standard curve was also established with cAMP concentrations ranging from 10"° to 10~5 M, diluted in Krebs.
Analysis of Results For agonists activating Gi coupled receptors (i.e. those which couple to the inhibition of cAMP formation) results were expressed as % inhibition of forskolin stimulated eAMP levels. Raw chemiiiiminescent data was converted to pMol cAMP using the standard curve and then % inhibition calculated as follows: 1 - ( Forskolin - Test ) x 100
Forskolin
IC3P and ECs0 values were calculated using Prism GraphPad using a 4-parameter logistic equation. An active agonist displays greater than 40% inhibition of cAMP. Λn antagonist typically displays greater than 40% reversal of 100 nM WIN 55212-2 response,
EC50 values and binding constants for selected inventive compounds are provided m Table 45 below.
Table 45. Selected Inhibition Data Example Ki (uM) EC50 (nM)
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
EC\o value ranges for selected compounds are provided in Table 46 below. Table 46. Selected EC50 Value Range Data.
Figure imgf000195_0002
Figure imgf000195_0003
Figure imgf000195_0004
Figure imgf000196_0001
Figure imgf000196_0002
Figure imgf000196_0003
Figure imgf000197_0001
Figure imgf000197_0002
Figure imgf000197_0003
Figure imgf000198_0002
Figure imgf000198_0001
where '"+'- indicates that the EC50 value is less than or equal to 0.5 μM; ''-H-" indicates that the tCso value is between 0.5 -10 μM; and "M f (-" indicates that the EC5l) value is equal to or greater than 10 μM. Example B
Assessment of Compound Affinity at the Human CB2 and CBl Cannabinoid Receptors Cell Culture and Membrane Preparation
CHO Kl cells expressing the human CB l or CB2 receptor were cultured at 37 0C. in Ham's F12 (Jnvitrogen 21765-037 or equivalent) containing 10% fetal bovine serum (US biotechnologies or equivalent), 100 μg<'mL penicillin and 100 μg/mL streptomycin (Gibco 10131 -035 ). 400 μg/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.
Radioligand Binding Assay
30 μg Membranes were incubated m 0.5 ml. binding buffer (50 mM Tn s 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 [3H] SR141716 (CB l antagonist) or 0.6 nM [3HJ CP 55,940 (non-selective agonist) nM and cold displacing ligand for 1 hour at 30u 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 niL ice cold binding buffer and radioactivity was determined by liquid scintillation counting Non-specific binding values were detei mi ned by either 1 μM CP 55 , 940 or 1 μM WfN 55212-2.
Analysis of Results
IC5ϋ values are calculated using GraphPad by fitting to a 1 or 2 site-binding model. Ki values are calculated from the apparent ICs0 v alues using the Cheng-Prussof equation: Ki = ICjo
1- ([L]ZKd)
where [L] = concentration of free radioligand and Kd = dissociation constant of radioligand for the receptor.
1% Compounds in this invention were found to have CB2 IC50S ranging from 0.062 to 20 μM.
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, c:ted in the present application is incorporated herein by reference in its entirety.

Claims

WHAT IS CLAIMED IS:
I . A compound of Formula I
Figure imgf000201_0001
1 or pharmaceutically acceptable salts thereof, wherein
R1 is selected from C|.6 alkyl, C2 6 alkenyl, C2^6 alkynyl, Ci 6 haloalkyl, Ci t hydroxyalkyl, C) 6 cyanoalkyl. C4-10 aryl, Cu !0 heteroaryl, C3 8 cycloalkyl. C3 8 heterocycloalkyl. C 8 heteiocycloalkenyl. C(O)OR', C(0)Rb, C(0)NRcRd, C(=NRf)NRLRd, S(O)R", S(0)NRcRd, S(O)2Rb and S(0)2NRcRd, whercm said heteroaryl. heterocycloalkyl and heterocycloalkenyl comprising 1-4 heteroatoms selected from N, O and S, and wherein said C] 6 alkyl, C2 & alkenyl, C? ( alkynyl, Cf-ιυ aryl. C4 i0 heteroaryl, C3 8 cycloalkyl, C3 8 heterocycloalkyl, and C3 8 heterocycloalkenyl, is optionally substituted with 1 , 2, or 3 substitutents independently selected from halogen, CN, N3, NO2, 0R\ SR', C(O)OR", C(0)Rb, C(0)NRcRd, OC(O)R", 0C(0)NRcRJ, NRcRd, NReC(0)Rb, NReC(0)NRcRd, NReC(0)0Ra S(O)Rb, S(O)NR0R", S(O)2Rb, NR6S(O)2R*. and S(0),NRcRd,
R3 and R3 are independently selected from II, halogen, C 6 alkyl, C2 6 alkenyl, C2 6 alkynyl, Ci ,, haloalkyl, Ci ή hydroxyalkyl, Ci h cyanoalkyl, C6 [( aryl, C4 1 j heteroaryl. C? s cycloalkyl, C1 & heterocycloalkyl, C1-, heterocycloalkenyl, CN, NO2, OH, 0Ra, SRa, C(O)R1, C(0)NRcRd, C(O)ORJ, OC(O)R1', 0C(0)NRcRd, NRcRd NRcC(0)Rb. NRT(O)NR1R", NRcC(ϋ)0Ra, S(O)Rb, S(O)NRςRd, b(ϋ)2Rb, NRcS(ϋ)2Rb, and S(0)2NRcRd, wherein said C1 6 alkyl, C2 ^ alkem l, C2 5 alkynj l, Cc )0 aryl, C4 !0 heteroaryl, C3 , cycloalkyl, C3 s heterocycloalkyl, and C3 >, heterocycloalkenyl is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, NO2, Ks. C6 0 aryl, C4 |f, heteroaryl, C > cycloalkyl, C „ heterocyeloalk} !. C, „ heterocycloalkenyl, 0Ra, SR", C(OjRb, C(0)NRcRd. C(O)OR2, OC(O)Rb. 0C(0)NRLRd. \τRιRd, NReC(0)Rb, NR1C(O)NR1R*. NR C(O)OR1, S(O)R11, S(0)NR'Rd, S(O)2R1. NR1S(O)2R", and S(0)2NRcRd, provided that at least one of R2 and R"1 is other than H, or R2 and R3 together with carbon atoms to which they are attached, join to form a
Figure imgf000202_0001
group or a C-O group: or R' and R\ together with the carbon atorr. to which they are attached, join to form a 3-8 membered cycloalkyl ring or 3-8 membered heterocycloalkyl ring, said heterocycloalkyl ring comprising 1 -3 heteroaioms selected from N, O and S, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CV6 alkyl, C2-6 alkenyl. C2 a alkynyl, CVm aryl. C4.10 heteroaryl, C34 cycloalkyl, Ci.g heterocycloalkyl. C3-8 hctcrocyelo- alkenyl. CK, NO2, N3, ORJ, SRJ, C(0)Rb, C(O)NR1-R11, C(O)ORa, 0C(0)Rb, OC(O)NR0R4, NRcRd, NR6C(O)R1', NReC(0)NRcRd, NReC(0)0Ra, C(=NRf)NRcRd, NReC(=NRf)NRcRd, S(O)Rb, S(0)NRcRd, S(O)2R\ NRcS(0)2Rb, and S(O)2NR0R11, wherein said CV6 alkyl, C24 alkenyl, C2.n alkynyl, C6-H) aryl, CVm heteroaryl, CVJ cycloalkyl, C3^ heterocycloalkyl. and C3, g heterocycloalkenyl is optionally substituted with 1 , 2, or 3 substitutents independently selected from CN, NO2, 0Ra, CMo aryl, and C4.10 heteroaryl:
R4 is selected from C(O)NR6R7, SO2NR6R7. NR8C(O)R9, NR8SO2R9 and C(O)C(O)NR6R7;
R3 is selected from H, halogen and C^ alkyl;
R* and R7 are independently se'ected from H, CV^ alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2-6 alkynyl, C6-Io aryl, Cue heteroaryl. C34 cycloalkyl, C3.8 heterocycloalkyl, C3-8 heterocycloalkenyl and C|.6 hydroxyalkyl, wherein said C1-6 alkyl. C|.<, haloalkyl. C2-6 alkenyl, C2-S alkynyl, C6.!0 aryl, C4.., 0 heteroaryl. C3-8 cycloalkyl, C3-5 heterocycloalkyl, C3.8 heterocycloalkenyl and Ci 6 hydroxyalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from OH. cyano, ammo, halo, CVe alkyl, C6-Io aryl, and C4-I0 heteroaryl; or Rf and R , together w ith the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring, each optionally substituted with 1 , 2, or 3 substituents independently selected from halogen. CVd alkyl. CV6 alkenyl, CV, alkynyl, C].Λ haloalkyl. Q- K aryl, C4 [0 heteroaryl, C3.& cycloalkyl, C3^ heterocycloalkyl, C3^ heterocycloalkenyl, C1^ hydroxyalkyl, CN, NO2. N3. 0Ra, SRJ, C(O)Rb, C(0)NRιRJ. C(0)0Ra, 0C(0)Rb, 0C(0)NRcRd, NRcRd, NR6Q- 0)Rb, NReC(0)0Ra, C(=NRf)NRςRd, NRϊC(=NRf)NRtRd, S(O)R1*, S(O)NRcRd. S(O)2R'0, and S(0]2NRcRd. wherein said C1-., alkyl. C14, haioalkyi, C^ alkenyl. C2_6 alkynyl, C6-1(, aryl. C4-; j heteroaryl, C34 cycloalkyl, C3-15 heterocycloalkyl, C3_b hcterocycloalkenyl 01 C1^ hydros yalkyl h optionally substituted with 1 , 2, 3. 4. or 5 substituenls independently selected from OR/, cyano. ammo, halo, NO2, C|.(, alkyl, C6. io aryl, C4.10 heteroaryl, C34 cycloalkyl, C;.g heterocycloalkyl and C3-8 heterocycloalkenyl:
Rs and R9 are independently selected from H, d.ft alkyl, C^6 haloalkyl. C2.ft alkenyl, C;.u alkynyl, Ci.,, hydroxyalkyl, C|.6 alkyl, C2 4 alkenyl, C2-6 alkynyl, Q.* haloalkyl. Cwo aryl. C4 k) heteroaryl, C34 cycloalkyl, C3.s heterocycloalkyl, C3.s heterocycloalkenyl. wherein said Cj.6 alkyl. C1-0 haloalkyl, CM alkenyl, or C;.6 alkynyl, C1^ alkyl, C2^, alkenyl, C2-<, alkynyl, Cj. 6 haloalkyl, C0-I0 aryl, C4.10 heteroaryl, C3.g cycloalkyl,
Figure imgf000203_0001
heterocycloalkyl or C3^ heterocycloalkenyl is optionally substituted with 1. 2, 3. 4, or 5 subsntuents independently selected fiom halo, OR4, cyano, amino. NO2, C] c alkyl. C2 θ alkenyl, C2 c alkynyl, Ci b haloalkyl. CV6 hydroxyalk> l, CV1, cyanoalkyl, CV6 alkyl, C2.,, alkenyl, C2-6 alkynyl, Cue haloalkyl. Co.j0 aryl, C4. i0 heteroaryl, C3.8 cycloalkyl, C3-8 heterocycloalkyl and C;.g helerocycloalkenyl; at each occurrence, R\ Rb, Rε and R1 are independently selected from H, C, b alkyl. C1.6 haloalkyl, C2.6 alkenyl, C2.5 alkynyl, CV6 haloalkyl, C6.10 aryl, C4-H, heteroaryl, CVs cycloalkyl, C3., heterocycloalkyl, C3.5 heterocycloalkenyl C7.14 arylalkyl, C4., 4 heteroarylalkyl, C5-17 cycloalkylalkyl and C5.12 heterocycloalkylalkyl, wherein said Ci.« alkyl, C1.6 haloalkyl, C2.6 alkenyl. C2.o alkynyl, C6.io aryl. C4.10 heteroaryl, C3.8 cycloalkyl. C3.g heterocycloalkyl, C3.8 heterocycloalkenyl C7 ]4 arylalkyl, C4.14 heteroarylalkyl. C^-12 cycloalkylalkyl or Cvi ; heterocycloalkylalkyl, is optionally substituted with ORa, cyano, ammo, halo, C].6 alkyl, C6 i0 aryl, C6 K, heteroaryl, C3 8 cycloa'kyl, C3.8 heterocycloalkyl, C3.g heterocycloalkenyl C;.|4 arylalkyl. C4.14 heteroarylalkyl. CVi2 cycloalkylalkyl and C5.12 heterocycloalkylalkyl; at each occurrence, Rc and Rd are independently selected from H, C|.o alkyl, C^6 haloalkyl, C2-< alkenyl, C2-o alkynyl, C6 10 aryl, C4-I0 heteroaryl, C3^ cycloalkyl, C3.3 heterocycloalkyl, (\ g heterocycloalkenyl C7 n arylalkyl, C4 1 ^ heteroarylalkyl, C$ i2 cycloalkylalkyl and Cs-i2 heterocycloalkylalkyl, wherein said CV6 alkyl. Ci-t haloalkyl, C2-C, alkenyl. C2.6 alkynyl. Q.|0 aryl, C4-I0 heteroaryl, C1 8 cycloalkyl, C3.8 heterocycloalkyl, C3.g heterocyeloalkenyl C7-H arylalkyl, C4.14 heteroarylalkyl. C5.12 cycloalkylalkyl or C5.12 heterocycloalkylalkyl. is optionally substituted with OH, cyano, ammo, halogen, Q.6 alkyl. aryl. arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or Rc and Rd, together with the N aton to which they are attached, join to form a 3-8 membered heteroeytloalkyl ring, each optionally substituted with I , 2, 01 3 substituents independently selected from halogen. Q.6 alkyl, C2 1 alkenyl, C2^ alkynyl. Cj 10 aryl, tV-io heteroaryl, CJ-K cycloalkyl, C1., heterocycloalkyl, C% s heterocycloalkenyl C-.)4 arylalkyl, C4.t4 heteroarylalkyl. C5.12 cycloalkylalkyl ar.d C5. 2 heterocycloalkj'laikyl, CV0 haloalkyl. CN, NO2. \V 0Ra, SRa. C(O)R1. C(0»NRlRd, C(O)0Ra. OC(O)Ra, OC(O)NR-Rd. NR1R", NReC(O)Ra, NReC(O)NRcRd, NReC(O)OR\ C(-NRf)NRcRd, NReCC"NRf)NRcRd. S(O)R", S(O)NRJRb, S(O):Ra, NR6S(O)2R". and S(O)2NR3R": halogen is selected fi otn F, Cl, Br and I: and n is O, 1 , 2, or 3,
2. The compound of claim 1. wherein R4 is SO2NR6R7, n is O, R2 and R!, together with the carbon atom to which they are attached, form a 1,3-dioxan-2-yl ring, and R6 and R . together with the carbon atom to which they are attached, form a pyrrohdinyl ring, and R1 is not alkyl substituted with NH2, CN, N3, bromo, or a 7-membered cycloalkyl ring optionally substituted b} CN or cyanoalkyl.
3. The compound of claim 1, wherein R1 is selected from C]4, alkyl, C14} alkenyl, C2-0 alkynyl, C,-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C6-13 aryl, C4 10 hetetoatyl, C3-g cycloalkyl, C3-g heterocycloalkyl, ard C3-g heterocycloalkenyl, wherein said C1 -6 alkyl, C2-6 alkenyl. C2.6 alkynyl, CM 0 aryl, C4-I 0 hcteroaryl, C3 $ cycloalkyl. C3-8 heterocycloalkyl or C3-8 heterocycloalkenyl, is optionally substituted with 1, 2, or 3 substitutents independently selected from C6.10 aryl, C4-I0 heteroaryl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3 3 heterocycloalkenyl, halogen, CN, N3, NO2, OR", and SR*1.
4. The compound of claim 1, wherein R1 is C1 -6 alkyl, optionally substituted with one sub&tituent selected from Q.ic aryl, C4.10 heteroaryl, C3-S cycloalkyl, C3-g heterocycloalkyl. and C3-i heterocycloalkenyl.
5. The compound of claim 4, wherein R1 is methylenecyclopropyl.
6. The compound of claim 1, wherein R1 is CV0 haloalkyl. C1-6 hydroxyalkyl, or C1-0 cyanoalkyl.
"1 ' . The compound of claim 6. wherein the halogen of the Ci „ haloalkyl is fluoro.
8. The compound of claim 6, wherein R1 is CF3.
9 The compound of claim 1. wherein R is C6 iυ aiyl or C4-I0 heteroaryl , optionally substituted by 1 , 2. or 3 substitutents selected from halogen. CM alkyl. CM haloalkvl, CN. NO2, and OR1.
10. The compound of claim 1 , wherein R2 and R3 are independently selected from H. halogen, C^6 alkyl, CV6 alkcnyl, C24 alkynyl, d.6 haloalkyl, C1^ hydroxyalkyl. C,_6 cyanoalkyl, C(>10 aryl, C4^0 heteroaryl, C3.g eycloalkyl, C3.? heterocycloalkyl, C3., heterocycloalkenyl and ORa. wherein said ChC alkyl, CM alkenyl, C;.<; alkynyl, C6.13 aryl, C4.i0 heteroaryl, C3 5 cycloalkyl, C3 g heterocycloalkyl or C3 s heterocycloalkenyl is optionally substituted with 1 , 2, or 3 substitutents independently selected from C6-Io aryl, C4.10 heteroaryl, C3^ cycloalkyl, CM heterocycloalkyl, C3^8 heterocycloalkenyl, CN, NO2, N3, ORa, SRJ, C(O)R", C(O)NRcRd, C(O)OR11. 0C(0)Rb, OC(O)NRcRd, NRCRJ. NReC(0)Rb, NReC(0)NRcRd. NReC(O)ORa, S(O)R11, S(O)NRcRd, S(O):Rb. NRcS(O)2Rb, and S(O)2NRcRϋ.
11. The compound of claim 1. wherein R2 and R3 are independently selected from is halogen, C^,-, alkyl. and OR1
12. The compound of claim 1, wherein one of R2 and R3 is C1^ alkyl.
13. The compound of claim 1 , wherein one of R2 and R3 is OR4.
14. The compound of claim 1, wherein R" and R •,3 , together with the carbon atom to which they are attached, join to form a 3-8 membered cycloalkyl ring, optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, C1 6 alkyl, C2 6 alkenyl. CV6 alkynyl, CWn aryl. Cwn heteroaryl,
Figure imgf000205_0001
cycloalkyl, Cu« heterocycloalkyl, Ca heterocycloalkenyl, CN, NO2, N3, 0Ra, SRa, C(0)Rb, C(0)NRcIRJI, C(O)ORal, OC(O)Rbl, 0C(0)NRclRdl, NRCIRdl, NReIC(O)Rbl, NReC(0)NRcRd, and NReC(O)ORa.
15. The compound of claim 1, wherein R2 and R3. together with the carbon atom to which they are attached, join to form a 3-8 membered cycloalkyl ring, optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, C^ alkyl, C 2.6 alkenyl. C?.ό alkynyl, CVi0 aryl. C4.10 heteroaryl. C3.? cycloalkyl. C5.g heterocycloalkyl, CVS heterocycloalkenyl, CN, NO2, N3, 0RJ, SR\ C(0)Rb, C(0)NRcRd, C(O)OR3, OC(O)Rb, 0C(0)NRrRd, NRLRd, NReC(0)Rb. NReC(O)NRcRd. and NReC(0)0Rd.
16. The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R2 and RJ, together % ith the carbon atom to which they are attached, join to form a 3- 8 membered heterocycloalkyl ring, optionally substituted with 1, 2, or 3 substituents independently selected from halogen. C(_(, alky!. C2 1 alkenyl, C2^0 alkynyl, C0 10 aryl, C4^n heteroaryi, Cw cycloalkyl. C< heterocycloalkyl, C,.« heterocycloalkenyl, CN, NO^. N-,, 0Ra, SRa, C(O )Rb, C(O)NR0RA C(O)OR3, OC(O)R1'. 0C(0)NRcRd, NRcRd, NReC(0)Rb, NReC(0)NRcRd, and NReC(0)0Ra.
17. The compound of claim 1, wherein R~ and R . together with the carbon atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring comprising 1 or 2 heteroatoms.
18. The compound of claim 17, wherein at least one heteroatom is O.
19. The compound of claim 1 , wherein R' and R3, together with the carbon atom to which they are attached, join to form a 1,3-dioxan-2,2-diyl ring, l ,3-dioxolan-2,2-diyl, or tetrahydropyran-2,2-diyl ring.
20. The compound of claim 1, wherein R4 is C(O)NR6R7.
21. The compound of claim 20, wherein at least one of R ' and R' is H or C.$ alkyl.
22. The compound of claim 20, wherein both of R6 and R are H or C|.ft alkyl.
23. The compound of claim 20, wherein one of R6 and R; is selected from C3^8 cycloalkyl, C7.14 arylalkyl, and C6-K) aryl.
24. The compound of claim 20, wherein R6 and R ', together with the N atom to which they are attached, form a 3-8 membered C3 8 heterocycloalkyl ring, optionally substituted with 1 , 2. or 3 substituents independently selected from halogen, Cu6 alkyl, CY6 alkenyl, C2* alkynyl, CN, NO2, N3. OR1, and SRa,
25. The compound of claim 24, wherein R5 and R', together with the N atom to which they are attached, join to form a heterocycloalkyl ring selected from pyrrolidinyl, morpholino, piperazinyL and pipeπdtrryl.
26. The compound of claim 2. wherein Rή and R', together with the N atom to which they are attached, form a 3-8 membered heterocycloalkyl ring selected from pyrrolidinyl, morpholino, piperazinyl and piperidinyl,
27. The compound of claim 1, wherein R4 is NR^C(O)R9 or NR8SO2R9.
28. The compound of claim 27, wherein R* is H or CVe alkyl.
29. The compound of claim 27, wherein R' is selected from H, CV1, alkyl. CVc haloalkyl, C1-6 hydroxyalkyl, C6. 0 aryl, C6 )3 heteroaryl, C3 8 cycloalkyl, C3 g heterocycloalkyl and C1-S heterocycloalkenyl, wherein said CVo alkyl, CVc haloalkyl, C1-& hydroxyalkyl,
Figure imgf000207_0001
aryl, C4^0 heteroaryl, C3.g cycloalkyl, C3-8 heterocycloalkyl or C3.8 heterocycloalkenyl is optionally substituted with 1, 2, 3, 4, or 5 subslituenls selected from halogen, 0Ra, cyano, amino, NOi, CV6 alkyl, CVδ haloalkyl, Ci.6 hydroxyalkyl, C3.g cycloalkyl, and CM heterocycloalkyl.
30. The compound of claim 1 , wherein R4 is C(O)C(O)NR6R7.
31. The compound of claim 30, wherein R6 and R', together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring selected from pyrrolidinyl, morpholino, piperazinyl and piperidinyl.
32. The compound of claim 1, wherein R5 is H, halo, CV6 alkyl, CV6 haloalkyl, C1-6 hydroxyalkyl, CM cyanoalkyl, CN. NO2, N3, ORa, or SRa.
33. The compound of claim 1, wherein R3 is H, halogen, or C1.4 alkyl.
34. The compound of claim 1 , wherein n is 0 or 1.
35. The compound of claim 1 , wherein n is 0.
36. The compound of claim 1 , wherein R4 is SO2NR0R7, 11 is 0, R2 and R3, together with the carbon atom to which they are attached, form a 1.3-dioxan-2,2-diyl ring, and R4 and R ', together with the carbon atom to which they are attached, form a pyrrolidinyl ring, then R1 is not alkyl substituted with Nft, CN, N3, bromo, or a 7 -membered cycloalkyl ring optionally substituted by CN or cyanoalkyl,
37. The compound of claim 1, of Formula II:
Figure imgf000208_0001
(II).
38. The compound of claim 37, wherein R1 is Ci 6 haloalkyl, C 6 hydroxyalkyl, or C].ή cyanoalkyl.
39. The compound of claim 38, wherein halogen is fluoro.
40. The compound of claim 38, wherein R1 is CF5.
41. The compound of claim 38, wherein one of R2 and R is C\.(, alkyl.
42. The compound of claim 38. wherein one of R2 and R3 is ORa.
43. The compound of claim 38, wherein R and R , together with the carbon atom to which they are attached, join to form a 5-7 membered heterocycloalkyl ring comprising 1 or 2 heteroatoms.
44. The compound of claim 43, wherein at least one heteroatoin is O.
45. The compound of claim 43, wherein R2 and RJ, together with the carbon atom to which they are attached, join to form a 1 ,3-dioxan-2,2-diyl ring, 1 .3-dioxolan-2,2-diy1, or tetrahydropyran-2,2-diyl ring,
46. The compound of claim 38. wherein R" and R', together with the N atom to which they are attached, join to form a 3-8 membered heterocycloalkyl ring selected from pyrrolidinyl, morpholino, piperazinyl and piperidinyl.
47. The compound of claim 38, of Formula III:
Figure imgf000209_0001
(III) wherein m is 0, 1 , 2, or 3,
48. The compound of claim 47, wherein m is 2 or 3.
49, The compound of claim 1, of a formula selected from one of Formula IVa, Ivb and IVc:
Figure imgf000209_0002
(IVa) (IVb) (IVc).
50. The compound of claim 49, wherein R1 is Cu, alkyl optionally substituted with 1, 2, or 3 substituents selected from Cwo aryl, C+)0 heteroaryl, C3-8 cycloalkyl, C3_8 heterocycloalkyl and C3^ heterocycloalkenyl.
51. The compound of claim 50. wherein R1 is propyl,
52. The compound of claim 50, wherein R is Cj_g cycloalkyl.
53. The compound of claim 50, wherein R is cyclopropyl,
54. The compound of claim 49, whereir. R1 is Cj.6 haloalkyl. Q 4 hydrox>alkyl, or CV* cyanoalkyl.
55. The compound of claim 54, wherein halogen is fltioro.
56. The compound of claim 54, wherein R' is CF3.
57. The compound of claim 49. wherein one of R- and R' is C]_6 alkyl.
58. The compound of claim 49, wherein one of R2 and R3 is ORa.
59. The compound of claim 49, wherein R2 and R3, together with the carbon atom to which the}' are attached, form a 5-7 membered cycloalkyl ring.
60. The compound of claim 59, wherein R2 and R3, together with the carbon atom to which they are attached, form a 1,3-dioxan-2,2-diyl ring, 1,3-dioxolan-2,2-diyl, or tetrahydropyran-2.2~diyl ring.
61. The compound of claim 59, wherein R6 and R', together with the N atom to which they are attached, join to form a 3-8 membered hctcrocycloalkyl ring selected from pyrrolidinyl, morpholino, piperazinyl and piperidinyl ring.
62. The compound of claim 49, of Formula V:
Figure imgf000210_0001
(V) wherein p is 0, 1. 2, or 3.
63. The compound of claim 1 selected from:
3-[2,3-dioxo-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihydro-1H-mdol-l -yl]propanenimle;
3 -f 2-oxo-5-(pyrrolidin- 1 -ylsul fonyl)-2,3 -dihydro- 1 H-indol- 1 -yljpropanenitrile:
3-[2l-oxo-5'-(pyrrolidm-l -ylsulfonyl)spiro[cyclohexane-l ,3'-indol]-r(21//)- yl]propanemtrile;
3.3 ',3 "-[2-OXO-5 -(pyrrolidm- 1 -ylsulfonyl)-2,3 -dihydro- 1 //-indole- 1 ,3.3 - Iriyl] tripropanenitrile;
3-[3'-benzyl-2-oxo-5-(pyrrolidin-l -ylsulfonyl)spiro[indolc-3,5'-[l ,3]oxazohdin]- 1 (2//)-yl]propanenitrile;
3-[3-hydroxy-3-(4-hydroxybutyl)-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//- indol-1 -yljpropanenitrile:
3-[2-oxo-5-f pyrrolidm- l -ylsulfonyl)-3',4'.5l.6'-tetrahydrospiro[mdole-3,2l-pyran]-
1 (2//)-yllpropaπenitrile; 3-[3-cyclohexyl-3-hydroxy-2-oxo-5-(pyrrolidin-l -y]sulfonyl)-2,3-dihydro-1H-indol- 1 -yljpropanenitrile;
3-[3-butyl-3-hydroxy-2-oxo-5-(p>τrolidin-1-ylsulfonyl)-2,3-dihydro-l//-indol-l - yljpropanenitrile;
3-[3-hydroxy-3-isobutyl-2-oxo-5-(pjτrolidin-1-ylsu]fonyl)-2,3-dihydro-l//-indol-1- yl]propanenitrile; 3-[3-hydroxy-3-isopropyl-2-oxo-5-(ρyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1- yljpropanenitrile;
3-[3-cyclopropyl-3-hydroxy-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dih}'dro-li;/-indol- l -yl]propanenitπle;
3-[3-cyclopenty]-3-hydroxy-2-oxo-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihydro-li/-mdol- l-yl]propancmtπle;
3-[3-hydroxy-2-oxo-3-phenyl-5-(p}τrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1- yl]propanenitτile;
3-[3-benzyl-3-hydroxy-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1- yljpropanenitrile; 3"[3-hydroxy-2-oxo-3-(2-phenylethyl)-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihydro-li/- indol-1 -yl]ρroρanen;trile;
3-[3-cyclohcxyl-3-methoxy-2-oxo-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihydro-l//-indol- 1 -yljpropanenitrile;
3-[3-methoxy-3-methyl-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1- yljpropanenitrile;
3-[3-butyl-3-methoxy-2-oxo-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihydro-li/-indol-1- yljpropanenitrile;
3-[3-isobutyl-3-methoxy-2-oxo-5-(pytτolidin-1-ylsulfonyl)-2,3-dihydro-lH-indol-l - yljpropanenitrile; 3-[3-isoprop}'l-3-methoxy-2-oxo-5-fpyiτolidin-1-ylsulfonyl)-2,3-dihydro-lflr-indol-l - yljpropanenitrile;
3-[3-cycloprυpyl-3-methoxy-2-oxo-5-(pyrrolidin-l -ylsu1fonyl)-2,3-dihydro-1H-indol- 1 -yljpropanenitrile:
3-[3-cyclopentyl-3-methoxy-2-oxo-5-(p\τrolidin-l -ylsulfonyl)-2.3-dihydro-l//-mdcl- 1 -yljpropanenitrile;
3-[3-methoxy-2-oxo-3-phenyl-5-(ρyrrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1- yljpropanenitrile;
3-[3-benzyl-3-methoxy-2-oxo-5-(p3τrolidm-l -ylsulfonyl)-2,3-dihydro-l//-indol-l - yl]propanenitrile: 3-[3-methoxy-2-oxo-3-(2-phenylethyl)-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihydro-l//- indol-l -yl]propanenitrile;
3-[3-cyclohcxyl-2-oxo-5-(pyrrolidm-1-ylsulfonyl)-2,3-dihydro-l//-indol-1- yl]propanenitrilε; 3-[3-butyl-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-1H-indol-l - yl]propanenitrile:
3-[3-isobutyl-2-oxo-5-(pyrroliCin-l -ylsulfonyl)-2,3-dihydro-I//-indol-l - y!]propanenitrile;
3-[3-isupropyl-2-oxo-5-(pyrri)lidin-1-ylsulfonyl)-2,3-dihydro-l//-indol-1- yljpropanenitrile:
3-[3-fer/-butyl-2-oxo-5-(p>τrohdin-l -ylsulfonyl)-2,3-dihydro-1H-indol-l - yljpropanenitrile;
3-[3-cyc1opropy1-2-oxo-5-(p)τrolidin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1- yl]propancnitrilc; 3-[3-c)'clopentyl-2-oxo-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-lH-indol-l - yl]propanenitrile;
3-[2-oxo-3-phenyl-5-(pyrrohdin-l -ylsulfonyl)-2,3-dihydro-l//-indol-1- yljpropanenitrile;
3-[3-benzyl-2-oxo-5-(pyrrolidm-1-ylsulfonyl)-2,3-dihydro-l//-indol-1- yl]propanenitrile;
3-[2-oxo-3-(2-phenylethyl)-5-(pyrrolidin-l -ylsulfonyl)-2,3-dihydro-1H-indol-l - yljpropanemtrile;
3-[3-/^rt-butyl-3-chloro-2-oxo-5-(pyrrolidin-1-ylsulfonyl)-2,3-dihydro-l//-indol-1- yl]propanenitrile; 3-[3-tert-butyl-3-fluoro-2-oxo-5-(p>τrohdm-1-ylsulfonyl)-2,3-dihydro-l//-indol-1- yl]propanenitrile; l '-but-3-yn-l -yl-5'-(pyrrolidin-l -ylsulfonyl)spiro[i ,3-dioxane-2.3 '-indol]-2'( l 'H)-one;
1 '-butyl-5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'( 1 'Λ)-one; l '-pcnt-4->τι-l -yl-5'-(p}'rrolidin-l -ylsulfonyl)spiro[ 1.3-dioxane-2,3'-indol]-2l(r//)- one; r-prop-2-yn-l -yi-5'-(pyττolidin-l -ylsulfυny'.)spiro[l,3-dioxane-2,3'-indol]-2l(r//)- one; r-but-3-en- l -yl-5'-(pyrrohdin-l -)isulfonyl)spirofl ,3-dioxane-2,3l-mdol]-2'(17/}-one; 1 '-ethyl-5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2s3'-mdol]-2'(l 'Λ)-one; r-(4-fluυrobutyl)-5'-(pyrrolidiπ-l -y]suIfonyI)spiro[l ,3-dioxane-2,3'-indol]-2'(l'//)- onc; 1 '-(2-fluoroethyl)-5'-(p>τrolidin- 1 -ylsulfonyl)spiro[ 1.3-dioxane-2,3'-indol]-2'( 1 'ϋ/)- υne. r-CZ-cycIohexylethylj-S'-CpN-Trohdin-1-ylsulfonyOspirofl
Figure imgf000213_0001
2'(VH)-one: ll-(2-phem'lethyl)-5'-(p>τrolidm-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-mdolJ-2'(l Η)- one; l'-(2-methoxyethyl)-5'-(pyrrolidin-l -ylsultbnyl)spiro[l ,3-dioxane-2,3'-indol]-2'(17i)- one; r-[2-( lΛ-indol-3-yl)ethyl]-5'-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]-
1 '-[(2-0XO- l ,3-oxazolidm-5-yl)methylJ-5'-(pyrrohdm-1-ylsulfonyl)spιro[1,3-dioxanc- 2,3'-itidoll-2'(l7/)-one;
1 '-(2,3-dihydro-l ,4-benzodioxin-2-ylmethyl)-5'-(pyrro]idin- 1 -ylsulfonyl)spiro[ 1 ,3- dioxane-2,3'-indol]-2'(l 'H)-one; r-[4-(4-tert-butylphenyl)-4-oxobutyl]-5'-(pyrrohdm-1-ylsulfonyl)spιro[ 1,3-dioxane-
2.3'-indol]-2'( l 7/)-one; r-[4-(2.4-dimethoxyphenyl)-4-oxobutyl]-5l-(pyrrolidin-l -ylbulfonyl)spiro[l ,3- dioxane-2,3'-indol]-2'(17/)-one;
?ert-butyl {3-[2t-oxo-5'-(pyrrohdm-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-mdol]-l'(2'F)- yljpropyl} carbamate;
3-tert-huty]-] -but-3-yn- l-yl-3-fluoro-5-(pyrrolidin-1-ylsulfonyt)- 1 ,3-dihydro-2//- mdol-2-onc; l-butγl-3-/cjrt-butyl-3-f]uoro-5-(pyrrolidin-1-ylsulfonyl)-l ,3-dihydro-2//-indol-2-one; 3-tert-butyl-3-fluoro-l -pent-4-yn-1-yl-5-(pyrrolidin-1-ylsulfonyl)-l ,3-dihydro-2//- indol-2-one;
3-?ert-butyl-3-fluoro-1-prop-2-yn-1-yl-5-(p>τrohdin-l -ylsulfonyl)-1,3-dihydτo-2/i- indol-2-one; l -but-3-en-1-yl-3-terr-bulyl-3-fluoro-5-(pyrrolidm-1-ylsulibnyl)-l ,3-dihydro-2//- indol-2-one; 3-?cr/-butyl-l -ethyl-3-fluoro-5-(p>τro!idin- l-ylsulfonyI)-1.3-dihydro-2//-indol-2-one;
3-fer/-butyl-3-fluoro-1-methyl-5-(pyrrolidm-1-> lsulfonyl)-l ,3-dihydro-2//-indol-2- one:
3-fert-butyl-3-f!uoro- 1 -(4-fluorobutyl)-5-(pyrrohdin- 1 -ylsulfonyl )-l ,3-dihydro-2//- indol-2-one; 3-/<?rt-butyI-3-fluoro- 1 -(2-fluoroethylJ-5-(p\τrolidin-l -ylsulfonyl)- 1 ,3-dihydro-2//- indol-2-one, 3-rerr-butyl- 1 -(2-cyclohexylethyl)-3 -fluoro-5-(pyrrolidin- 1 -ylsulfonyl)- 1 ,3 -dihydro- 2//-indoI-2-one;
3-tef-butyl-3 -fluoro-1 -(2-phenylcthyl)-5-(pyrrolidin-l -ylsulfonyl)- 1 ,3 -dihydro-2//- indol-2-one; 3-ter/-butyl-3-fluoro-1-(2-methoxyethyl)-5-(pynOlidin-1-ylsulfonyl)-l ,3-dihydro-2i/- indol-2-one;
3-rer/-butyl-3-fluoro- l -[2-(lh-mdol-3-}i)cthyl]-5-(pyrrolidm-1-ylsulfonyl)-1,3- dihydrø-2//-indol-2 -one :
3-/βt-bulyl-3 -fluoro-1 -[(2-oxo-l, 3-oxazolidin-5-yl)methyl]-5-(pyrrolidm-1- ylsulfonyl)-! .3-dihydro-2//-mdo'-2-one;
3-tert-but}fl-l -(2,3-dihydro-1,4-ben2odioxm-2-ylraethyl}-3-fluoro-5-(pyrrolidm- l - ylsulfonyl)-l ,3-dihydro-2//-:ndol-2-one;
3-/'CTf-butyl-l -[4-(2,4-dιmetho>yphenyl)-4-oxobutyl]-3-fluoiO-5-(pyrrolidin-l - ylsulfonyl)-L3-dihydro-2//-indol-2-one: tert-butyl { 3 -f 3 -/erf-butyl-3 -fluoro-2 -oxo-5 -I pyrrolidin- 1 -ylsulfonyl)-2,3 -dihydro- 1 H- indol-1 -yl]propyl} carbamate;
1 -but-3 -yn-1 -yl -3 ,3 -diinethoxy-5-(pyrrolid:n- 1 -ylsulfonyl)- 1 ,3 -dihydro-2//-indol -2- one; l'-but-3-yn-1-yl-fl,n-dimethyl-2'-oxo-l',2'-dihydrospirof 1 , 3 -dioxane -2,3'-indole]-5'- sulfonamide; r-but-3-yn-l -yl-n,H-d:ethyl-2'-oxo-l'.2'-dihydrospiro[1,3-dioxane-2,3l-indole]-5l- sulfonamide; r-but-3-yn-l -yl-«-cyclohexyl-«-isopropyl-2'-oxo-r,2'-dihydrospiro[l ,3-dJoxane-2,3'- indole]-5'-s>ulfonamide; iVN-dibenzyl-l'-but^-yn-1-yl^'-oxo-l'^'-dihydrospiiOlUS-dioxaπe^J'-indolej-S1- sulfonamide:
1 '-but-3 -yn- 1 -yl-n-methyl -2'-oxo- 1 ',2'-dihydrospiro[ 1 ,3-dioxane-2 ,3 '-indole] -5 '- sulfonamide, r-but-3-yn-] -yl-2'-oxo-«-(2-thienyImethyl)-r,2'-dihydrospiro[1,3-dioxane-2,3'- indole]-5'-suIfonarnide; r-but-3-yn-l -yl-n-(l -naphthylmethylj-2'-oxo-r.2l-dihydrospiro[1,3-dioxane-2,3'- indole]-5'-sulfonamide;
,¥-( l//-benzimidazol-2-ylmethyl)-l'-but-3-yn-l -yl-2'-oxo-r,2'-dihydrospiro[l ,3- dioxane-2.3'-indole]-5'-sulfonaimde: r-buf}l- Λι',iV -dimefhyl-2'-oxo-r,2'-dihyι1rospiro[1,3-diθ!tane-2,3'-inJole]-5l- siilfonamidc; 1 '-butyl- N,N -dietbλ l-2'-oxo-l ',2'-dihydrospiro[l ,3-dioxane -2, 3 '-indole] -5'- sulfonamide: l'-butyl-H-cyclohex}'l-N-isopropyl-2'-oxo-l l,2'-dihydrospiro[l,3-dioxane-2,3'-indole]- 5'-sulfonamide: ,V,N-dibenzyl-l '-butyl-2'-oxo-r.2I-dihydrobpiro[1,3-dioxane-2,3'-indole]-5'- sulfonamide; r-but)'l-N-methyl-2'-oxo-l',2'-dihydrospiro[1.3-dioxane-2.3'-indole]-5I-sulfonamide; r-butyl-2'-oxo-«-(2-thienylmethyl)-l \2'-dihydrospiro[1,3-dioxane-2,3'-indole]-5'- sulfonamide; l'-butyl-.¥-(l-naphthylmethyl)-2t-oxo-r,2'-dihydrospiro[13-dioxanc-2>3'-indolc]-5'- sulfonamide;
N-(lH-benzimidazol-2-ylmethyl)-r-butyl-2'-oxo-r,2'-dihydrosρiro[1,3-dioxane-2,3l- mdole]-5'-sulfonamide:
3-/ert-butyl-1-but-3-yn-1-yl-3-fluoro- 7V.A' -dimethyl-2-oxoindoline-5-sulfonamide; 3-f£τ/-butyl-1-but-3-yn-1-yl- Λf,iV -diethyl-3-fluoro-2-oxomdohne-5-sulfonamide:
3-tert-butyl-1-but-3-yπ-1-yl-Λ''-cyclohexyl-3-fluoro-«-isopropyl-2-oxoindoline-5- sulfonamide;
N,N -dibenzyl-3-fe/"/-butyl-l -but-3-yn-1-yl-3-fluoro-2-oxoindolme-5-sulfonamide;
3-tert-but>'l-l -but-3-yn-1-yl-3-fluoro-N-methyl-2-oxomdoline-5-sulfonamide: 3-/έ"rt-butyl-1-but-3-yn-1-yl-3-fluoro-2-oxo-N-(2-thxenylmethyl)indoline-5- sulfonamide:
3-?ert-butyl-1-but-3-yn-1-yl-3-fluoro-N-( l-naphthylmethyl)-2-oxoindoline-5- sulfonamide; iV-(l//-beπzimidazol-2-ylmethyl)-3-/'eτ?-butyl-1 -but-3-tyn-l -yl-3-f!uoro-2- oxoindolme-5 -sulfonamide;
1 -butyl-S-tert-butyl-S-fluoro- N,N -dimethyW-oxoindoline-S-sulfonamide;
1 -buty 1-3 -fc«-butyl- iV,iV-diethyl-3-fluoro-2-oxoindoline-5 -sulfonamide; l -butyl-3-fert-butyl-JV-cyclohexyl-3-f.uoro-n-isoρτoρyl-2-oxoindoline-5 -sulfonamide;
Figure imgf000215_0001
l-butyl-3-ierf-butyl-3-fluoro-.V-methyl-2-oxoindolme-5-sulfonamide; l-bulyl-3-ter/-butyl-3-fluoro-2-oxo-iV-(2-tlneny!melhyl)indoline-5-sulfonamide; l -butyl-3-Jert-butyl-3-fluoro-i¥-( l-naphthylmethyl)-2-oxoindolinc-5-sulfonamidc;
.'V-( 1H-benzimidazol-2-ylmethyl)-l-but)'l-3-tert-butyl-3-fluoro-2-oxoindoline-5- sulfonamide: 3-/CT'/-but}l-3-πuoro-l -(2-flιioroethyl)- JV..V -dimethyl-2-oxoindo!ine-5-«ulfonamide,
3-terr-butyl- N.N -dicthyl-3-iluoro-l -(2-lluorocthy!)-2-oxomdohnc-5-sulfonamide: 3-tert-butyl-N-cyclohexy1-3-fluoro-l -(2-fluoroethyl)-Λ''-isopropyl-2-oxoindolme-5- sulfonamide; iV,N' -dibenzyl-3-/fr/-butyl-3-f!uoro-l -(2-fluoroethyl)-2-oxoindoline-5-sulfonamide;
3-fert-butyl-3-fluoro-1-(2-fluoroethyl)-2-oxo-N-(2-thienylmethyl)mdoline-5- sulfonamide;
Figure imgf000216_0001
-(2 -fluoroethyl )-N-( 1 -naphthylmethyl)-2-oxoindoline-5 - sulfonamide;
Λ'-(l^-benzimidazol-2-ylmethyl)-3-tert-butyl-3-fluoro-1-('2-fluoroethyl)-2- oxoindoline-5 -sulfonamide; r-but-3-yn-l -yl-N-isopropy l-2'-oxo-l ',2'-dihydrospiro[l ,3-dioxane-2,3'-indole]-5'- carboxamide; r-but-3-yn- l -yl-5'-fpyrrolidin- l-ylcarbonyl)spirof1,3-dioxane-2,3'-indol]-2'(r//)- one; r-but-S-yri-l -yl-S'-Cpipei idin-l -ylcaibonyljspirofl
Figure imgf000216_0002
r/fl-one;
Figure imgf000216_0003
carboxamide; l '-but-3-yn-l -yl-H-ethyl-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indole]-5'- carboxamide;
A/-benzyl-r-but-3-yn-1-yl-2'-oxo-l ',2'-dihydrospiro[1,3-dioxane-2,3'-indole]-5'- carboxamide; r-(2-fluoroethyl)-«-isopropyl-2'-oxo-r,2'-dihydiospirofl ,3-dioxane-2,3'-indole]-5'- carboxamide; r-(2-fluoroethyl)-5l-(pyrrolidin-1-ylcarbonyl)spiro[13-dioxane-2,3Lindol]-2'(r/:f)- one; r-(2-fluoiOethyl)-5'-(pipeπdin-1-ylcarbonyl)spiro[1.3-dioxane-2.3'-indol]-2'(l'//)- one;
N,J¥ -diethyl- r-(2-fluoroethyl)-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indole]-5'- carboxamide;
«-ethyl-l '-(2-fluoroethyl)-2'-oxo-l '.2'-dihydrospiro[l ,3-dioxane-2,3'-indole]-5'- carboxamide;
N'-but>'l-n-isopropyl-2'-oxo-r,2'-dihydrospiro[1.3-dioxane-2,3'-indole]-5l- carboxamide; r-bufy1-5'-(pynOlidin-l -ylcarbonyl)sρiro[l ,3-dioxane-2.3'-mdolJ-2'(r//)-oπe; r-butyl-5'-(pipeπdin-1-y carbonyl)spiro[ l ,3-dioxane-2,3'-indol]-2'(r//)-one; r-butyl-/V,Λf -dietliyl-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indoleJ-5'- carboxamide; 1 '-butyl- jV-ethyl-l'-oxo-l'^'-dihydiospirofl ^-dioxane^^'-indolej-S'-carboxamide, iV-benzyl-r-butyl-2t-oxo-r,2'-dihydrospiro[l ,3-dioxane-2,3l-indolc]-5'-carboxamidc: jV^r-butyl^'-oxo-r^'-dihydrospirofl ^-dioxane-l^'-mdo^-S'-y^acetamide;
Λ'r-(r-butyl-2'-oxo-l ',2'-dihγdrospiro[l ,3-dioxane-2,3l-indol]-5'- yDcyciopropanecarboxamide;
N-( 1 '-butyl-2'-oxo-l ',2'-dihydrospiro[l ,3-dioxanc-2,3'-mdolJ-5'- yDcyclobutanecarboxamide;
N-(I '-butyl -2'-OXO-I '.2'-dihydrospiro[l ,3-dioxane-2,3'-indol]-5'- y 1 )cyclopentanec arboxami de; N-(l '-butyl-2'-oxo- l '.2'-dihydrospiro[1,3-dioxane-2,3'-indol]-5'-yl)-benzamide;
N-(r-butyl-2'-oxo-l ',2'-dihydrospiro[1,3-dioxane-2,3'-indol]-5'- yl)methanesulfonamide;
N-(I '-butyl-2'-oxo-l ',2'-dihydrospiro[l ,3-dioxane-2,3'-mdol]-5'- yl)benzenesulfonam:de; N-(l'-butyl-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indol]-5'-yl)-1- cyclohexylmethanesulfonamide: iV-[l '-(2-nuoroclhyl)-2'-oxo-l',21-dihydrospiroll,3-dioxanc-2,3'-indolJ-5'- yl]acetamide: iVT-[r-(2-fluoroethyl)-2'-oxo-r,2'-dihydrospiro[l,3-dioxane-2,3'-indol]-5'- yljcyclopropanecarboxamide; iV-[l'-(2-fluoroethyl)-2'-oxo-l',2'-dihydrospiro[1.3-dioxane-2.3l-indol]-5'- yl]cyclobutanecarboxamide; iV-[l'-(2-πuoroethyl)-2'-ϋλo-l',2l-dihydrobpiro[l,3-diϋxane-2,3l-indol]-5l- yl]cyclopentanecarboxamide; Λ;-[l'-(2-fluoroethyl)-2'-oxo-l',2'-dihydrospiro[ l,3-dioxane-2,3'-indol]-5'- yljbenzamide:
Ν-[l'-(2-fluoroethyl)-2'-oxo-r,2'-dihydrospiro[1,3-dioxane-2,3'-indol]-5'- yl]methancsulfonamidc;
1 ,1.1 -trifluoro-N-f 1 '-(2-fluoroethyl)-2'-oxo- 1 ",2'-dihydrospiro[ 1.3-dioxane-2,3'-indol]- 5'-yl]methanesulfonamide;
Λ^-[r-(2-fluoroethyl)-2'-oxo-r,2'-dihydrospiro[l,3-dioxane-2,3'-indol]-5r- yljbenzenesulfonamide: l-cyclohexyl-«-ri l-(2-fluoroethyl)-2'-oxo-r,2'-dihydrospiro[l ,3-dioxane-2,3'-mdol]- 5 '-yljmethaπesulfonamide ; 1 '-(cyclopropylmethyl)-5'-[(2.6-dimethylmoφholin-4-yl)sulfonyl]spiro[ 1 ,3-dioxane-
2J'-mdor-2'( l'H )-one; N-tert~buty\- 1 '-(cyclopropylmethyl)-«-methyl-2'-oxo- 1 ',2'-dihydτospiro[ 1 ,3-dioxane- 2,3'-πidole]-5'-su1fonamide: r-(cyclopropylmethyl)-«-(2-morpholin-4-}iethyl)-2'-oxo-l',2'-dihydrospiro[1,3- dioxane-2,3'-indole]-5'-sulfonamide; r-(cycloprop>lmethyl)-5'-{[4-(3.4-dimethy]phenyl)piperazin-1-yl]sulfonyUspiro[1.3- dioxane-2,3'-indol]-2'(r//)-one; r-(cyclopropylmethyl)-5'-[(3-methylpipeπdm-l -yl)sulfonyl]spiro[l ,3-dioxane-2,3'- mdoll-2'(l'/f)-one; r-(cyclopropylmethyl)-5'-[(4-methylpiperazin-1-yl)sulfonyl]spiro[l ,3-dioxane-2,3'- mdol]-2'(17/)-one;
5'-[(4-benzylpiperazm- 1 -y])sulfonyl]- 1 '-(cyclopropylmethyl)spiro[l ,3-dioxane-2.3'- mdol]-2'(l '//)-one; l '-(cyclopropylmethyl)-5'-[(3)5-dimethylpiperidin-1 -yl)sulfonyl]spiro[1 ,3-dioxane- 2,3'-mdolJ-2'(l 1//)-one; r-(cyclopropylmethyl)-5'-[(2-ethylpiperidin-1-yl)sulfonyl]spirof1,3-dioxane-2,3'- mdol]-2'(r//)-one; r^cyclopropylmethyO-S'-Onorpholin^-ylsulfonyOspirof l.S-dioxane^.S'-indol]- 2'(lW)-onc; r-(cyclopropylmethyl)-4'-foxo(piperidin-l -yl)acetyl]spiro[1,3-dioxane-2.3'-indol]- 2'(l'H)-one:
4'-[oxo(piperidin-1-yl)acetyl]-r-propylspiro[1,3-dioxanc-2,3t-indolJ-2'(ri;^)-onc;
4'-[oxo(pipeπdin-1-yl)acetyl]-l'-(2,2,2-tπfluoτoethyl)spiro[l
Figure imgf000218_0001
2'(l'H)-one: r-butyl-4'-[oxo(piperidin-1-yl)acetyl]spiro[l ,3-diuxane-2,3'-indol]-2'(rW)-one; 4l-[oxo(pipeπdin-1-y])acetyl]-r-pent-4-yn-1-ylspiro[1,3-dioxanc-2,3'-mdolJ-2'(r//)- one:
1 '-methyl-4'-[oxo(piperidin-l -yl)acetyl]spiro[l ,3-dioxane-2,3'-indol]-2'(l 'H)-one;
7'-(pipeπdιn-1-ylcarbonyl)-l l-(2,2,2-tπfluoroethyl)spiro[1,3-dioxane-2,3'-indol]- 2'(11H)-OiIe; 7'-(piperidm-1-ylcarbonyl)-r-propylspirofl .3-dioxane-2,3l-indol]-2'(r//)-one; r-(cyclopropylmethyl)-7'-(piperidin-1-y]carbonyl)spiro[l ,3-dioxane-2.3'-indol]- 2\\ 'Hhone; r-bιityl-7'-(pipeπdin-l -y.carbonyl)spiro[1,3-dioxane-2J'-indol]-2'( l'/f)-one; r-pent-4-yn- l -yl-7'-(piperidin-'. -ylcarboπy!jspiro[1,3-dioxane-2,3'-mdol]-2'(rH)- one; r-methyl-7'-(p!peridm-l -ylcarbonyl)spiro[l ,3-dioxanc-2,3'-indolj-2'(r//)-one: r-(cyclopropylmethyl)-4'-(piperidin-1-ylcarbonyl)sρiro[1,3-dioxane-2,3'-indol]- 2'(l 'H)-one;
4'-(pipcπdin-1-ylcarbonyl}-r-propylspiro[1,3-dioxane-2,3'-indol]-2'(ri;/)-one;
4'-(piperidin-l -ylcarbonyl)-l'-(2,252-trifluoroethyl)spiro[l ,3-dioxane-2,3'-indol]- 2'{VH)-one; r-but>'l-4'-(piperidin-1-ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]-2'( 17/)-one;
1 '-pent-4-yn-l -yI-4'-(pipeπdm-l -ylcarbonyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 'H)- one; r-melhyl-4'-(piperidin-l -ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]-2'(r//)-one; r-(cyclopτopylmethyl)-6'-(piperidin-l -ylcarbonyl)spiro[l ,3-dioxanc-2.3'-mdolJ-
2'd 'H)-one;
6'-(piperidin-l -ylcarbonyl)-r-propylspiro[l 13-dioxane-2,3'-indol]-2'(r//)-one;
Figure imgf000219_0001
2'(VH)-Om; 1 '-butyl -δ'^piperidin-l -ylcarbony^spirofl^-dioxane^^'-indoll^^rHJ-one; r-pent-4-yn-l -yl-6'-(pipeπdin-1-ylcarbonyl)spiro[l J3-dioxane-2.3'-indϋl]-2'(r//)- one;
1 '-methyl -6'-(piperidin-l -ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]-2l(r//)-one; r-(cyclopropylmethyl)-5'-f(2,6-dimethylpiperidin-1-yl)sulfonyl]spiro[l ,3-dioxolane- 2,3'-indol]-2'(l 'Η)-one; l '-(cyclopropylmethyl)-5'-[(2,6-dimethylmorpholin-4-yl)sulfonylJspiro[1,3- dioxolane-2.3'-indol]-2'( rH)-one; r-(cyclopropylmethyl)-5'-[(2-methylpiperidin-1-yl)sulfonyl]spiro[1,3-dioxolane-2,3'- indol]-2'(l'H)-one; iV-tert-butyl- 1 '-(cyclopropylmethyl)-«-methyl-2'-oxo-l ',2'-dihydrospiro[l ,3- dioxolane-2,3'-indole]-5'-sulfonaraide; r-(cyclopropylmethyl)-5'-(piperidiπ-l -ylsulfonyl)spiro[l ,3-dioxolane-2.3'-iπdol]- 2'(I 'W) -one: r-fcyclopropylmethyO-S'-J ^-tB^-dimethylphenyljpiperazin- l-y^sulfonyll spirofl J- dioxolane-2,3'-indol]-2'( r//)-one: l '-(cyclopropylmethyl)-5l-[(3-melhylpiperidin-l -yl)sulfonyl]spifo[1,3-dioxolane-2.3l- indøl]-2'(17i)-one; r-(cycloproρylmethyl)-5'-[(4-methylpiperazin- l-yπsulfonyl]spiro[1,3-dioxolane-2,3'- indoll-2'( l '//)-one; 5'-f'(4-benzylpiperazin-1-yl)sulfonyl]-l l-(cycloproρylmethjl)spiro[1,3-dioxolane-2,3'- indol]-2'( l 1H)-OiIc; 1 t-(cyclopropylmethyl)-5l-[(3,5-dimethylpiperidin- 1 -yl)sulfonyl]spiro[ 1 ,3-dioxolane- 2>3'-mdol]-2'(r//)-one; r-(cyclopropylmethyl)-5'-[(2-ethylpiperidin-1-yl)sulfonyl]spiro[1,3-dioxolane-2,3'- indol]-2'(l'//)-one: r-CcyciopropylniethylJ-S'-fmoiplioliii^-ylsulfonylJspirofl^i-dioxoiane-Z^'-indol]-
r-pent-4-yn-1-yl-5'-(p>ττolidin-1-ylsulfonyl)spirof 1,3-dioxolane-2,3'-mdol]- 2'(1 'H)- one; r-(cyclopropylmethyl)-5l-(pyrrolidin-l -ylsulfonyl)spiro[1.3-dioxolane-2,3l-indol]- 2'( l'H)-one;
1 '-propyl -5'-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxolane-2,3'-indol]-2'(l Η)- one; l'-bulyl-5'-(pyrrolidin-1-ylsulfonyl)spiro[1.3-dioxolane-2,3'-indol]-2'( rH)-one; 5'-(pyrrolidin-1-ylsulfonyl)-r-(2,2,2-trifluoroethyl)spiro[l ,3-dioxolane-2,3'-indol]- 2'(l'H)-one; r-methyl-5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxolane-2.3'-indol]-2'(lΗ)- one; r-pent-4-yn-1-yl-5'-(piperidin-1-ylsulfonyl)spiro[l ,3-dioxane-2(3'-indol]- 2'(11H)- one;
5'-(piperidin-l -ylsulfonyl)-r-(2,2,2-trifluoroethyl)spiro[ l ,3-dioxane-2,3'-indol]- 2'(l'H)-one; r-(cyc1opropylmethyl)-5'-(piperidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-
2'(l 'H)-one:
5'-(piperidin-1-ylsulfon)d)-r-propylspiro[l ,3-dioxane-2,3'-indol]-2'(l'H)-one; 1 '-butyl -5'-(piperidin- l -ylsulfϋnyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l Η)-one; 1 '-methyl-5'-(piρeridin-l -ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]-2l(riI)-one; r-butyl-5'-(Pφeridin-l -ylcarbonyl)spiro[ 1,3-dioxolane-2,3'-indol]-2'(rH)-one; r-pent-4-yn- l -yl-5'-(piperidin-1-ylcaTbonyrispiro[l ,3-dioxolane-2,3'-indol]-2'(rH)- one:
5 '-(piperidm- 1 -ylcarbonyl)- 1 '-propyl spiro[ 1 ,3 -dioxolanc-2 ,3 '-indol J-2'( 1 Η)-onc; 1 '-(cyclopropylmethyl)-5 -(piped din-1 -y!carbonyl)spiro[ 1 ,3-dioxolane-2,3'-indol]- 2'(l 'H)-one:
5'-(piperidin-l -ylcarbonyl)-! '-(2.2, 2-trifluoroethyl)spiro[l ,3-dioxolane-2,3'-indol]- 2'(l'H)-onc; r-methyl-5'-(pipendin-1-ylcarbonyl)spiro[l ,3-dioxolane-2,3l-indol]-2'f l 'H)-one; 4-chloro-K-(r-(cyclopropylmethyl)-2'-oxospiro[[lJ3]dioxane-2,3'-indϋline]-51- vl)ben7enesulfonamide; N-[r-{cyclθDropylmethyl)-2'-o\o-r,2'-dihj'drospiro[1,3-dioxane-2,3'-indol]-5'-yl]-4- methoxybenzenesulfonamide.
N-[l'-(c>clopropylmethyl)-2'-oto-r,2'-dihydrobpiro[l ,3-dioxane-2,3'-indol]-5'-yl]-4- methylbenzenesulfonamide: 3,4-dichloro-«-[r-(cyc!oprop>lmethyl)-2'-oxo-r,2'-dihydrospiro[l ,3-dioλane-2,3l- mdol]-5'-yl]benzenesulfonamide; r-pheml-5'-(pyrrolidin-l -ylsulfonyl)spιro[[1 ,3]dιoxane-2,?l-indo]in]-2l-one, r-(2-chlorophcπyl)-5'-(p>τro]idm-1-ylsulfony])spiro[1.3-dioxaπe-2,3'-mdol]-2'(r//)- one; r-(3-ch]orophenyl)-5'-(pyrrohdin-1-yls.ulfonyl)spiro[1.3-dioxane-2,3'-indol]-21( rH)- one, r-(4-chlorophenyl)-5'-(pyrrolidin-1-y]sulfonyl)spiro[1.3-dioxane-2,3'-indol]-2'(r//)- one; r-(2-methylphenyl)-5'-(pyπOhdin-1-ylsulfonyl)s.piro[l ,3-dioxane-2,3l-indol]-2'(r//)- one, r-(3-methylphenyl)-5'-(pyrro]idin-1-ylsulfoπyl)spiro[l ,3-dioxane-2,3'-mdol]-2<(r/f)- one; r-(4-methylphenyl)-5'-(pyrrolidm-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-mdol]-2'(r//)- one, r-(2-methoxypheny])-5'-(pyrrolidm-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]-
2'(l'//)-one; r-(3-methoxyphenyl)-5l-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]- T(YH)-Om: r-(4-methoxyphenyl)-5'-(pyrrohdm-1-ylsulfonyl)spirof1,3-dioxane-2,3'-indol]- 2'( l'H)-one:
5l-(pynolidin-1-ylsulfonyl)-l l-[2-(trifluoromethyl)phenyl]spiro[1,3-dioxanc-2,31- indolJ-2'( lW)-onc:
5'-(pyrrolidin-l -ylsulfonyl)-r-[3-(trifluoromethyl)phenyl]spiro[1.3-dioxane-2,3'- indol]-2'( 17i)-one;
Figure imgf000221_0001
indolJ-2'(l'//)-one; r-(2-fluorophenyl)-5'-(pyrrohd!n-1-y!sulfonyl)spiro[1,3-dioxane-2.3'-indυl]-2'(r//)- one:
1 '-(3-fluorophenyl)-5'-(pyrrohdm-l -yisulfoii} l)spiro[ 1 ,3-dioxane-2,3'-mdol]-2'( 11Zf)- one; r-(4-fluϋrophenyl)-5'-(pyrrolidin-l -ylsulfonyl)spiro[1.3-dioxane-2,3'-indol]-2'(17/)- one;
2-[2'-oxo-5'-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3l-mdol]-r(2'H)- yljbenzonitπle; 3-[2'-oxo-5'-(pyrrolidin-1 -ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]-r(2'H)- yl]benzonitrile; r-(2-propoxyphenyl)-5'-{pyrro]idin-l -ylsulfonyl)spiro[l ,3-dioxane-2.3'-indol]- 2'(VH)-om:
1 '-(3-propoxyph.enyl)-5 '-(pyrrolidin- 1 -ylsulfonyl)spiro[ 1 ,3 -dioxanc-2,3'-indolj- 2\VH)-om: r-(4-propoxyphenyl)-5'-(pyπOΗdin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]- 2'(17/)-one;
5'-(pyrrohdin-1-ylsulfonyl)-r-[3-(tπfluoromethoxy)phenylJspiiO[1.3-dioxane-2.3'- indol]-2'(l'Λ)-one; 5'-(pyrrolidin-1-ylsulfonyl)-l r-[4-(trifluoromethoxy)phenyl]spiro[1.3-dioxane-2,3'- indol]-2'(l '//)-one; l '-(2,4-dichlorophenyl)-5'-(pyτrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]- 2\VH)-om: r-(3,4-dichlorophenyl)-5'-(pyπOlidin-l -ylsulfϋnyl)spirϋ[l ,3-dioxane-2,3'-indol]- 2'(VH)-om; r-(3,5-dichlorophenyl)-5'-(pyrrolidin- l -ylsulfonyl)5piro[1.3-dioxane-2,3'-indol]- 2'(VH)-Om: r-(3-chloro-4-fluorophenyl)-5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'- indol]-2'( l'f/)-one; r-(3-chloro-4-methoxyphenyl)-5'-(pyrrolidin-1-ylsulfonyl)spirof1,3-dioxane-2,3'- indoll-2'( l 'Λ)-one; l '-(3 ,5-dimeιhylphenyl)-5 '-(pyrrolidin- 1 -yi sul fonyl )spiro[ 1 ,3 -dioxane-2,3 '-indol] - 2'(l '//)-one;
1 '-{4-fluoro-3-methylphenyl)-5 '-(pyrrolidin- 1 -ylsulfonyl)spiro[l ,3-dioxane-2,3'- indoll-2'( l'//)-one; l'-(2,5-diflυorophenyl)-5'-(ρyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indolJ- 2'(VH)-onc: l'-(2,4-difluorophenyl)-5'-(pyτrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]- 2'( 11W)-OHe; r-(3,4-difluorophenyl)-5'-(pyrrolidin-l -ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]-
2'dW-one: l'-(3,5-diiluorophenyl)-5'-(pynOlidm-1-ylsulfonyl)spiro[1.3-dioxane-2.3'-indol]- 2'( 17/)-one;
Figure imgf000223_0001
2'(VJi)-Om; 5'-(pyiτolidin-l -ylsulfonyl)-r-(3-th:enyl)spiro[1,3-dioxane-2,3'-inclϋl]-2'(rH)-one; r-pyτidin-3-yl-5'-(pyrrolidin-1-ylsulfonyl)spiro[1.3-dioxane-2,3'-indol]-2'(r//)-one;
1 '-pyridin-Φyl-S'-φyrrolidin- 1 -ylsulfonyl)spiro[ 1 ,3-dioxane-2.3 '-mdol]-2'( 17/)-one;
Figure imgf000223_0002
one; 5'-(3-fluoropyrrohdm-l -ylsulfonyl)-! l-phenylspiro[[1,3]dioxanc-2,3'-indolm]-2'-onc; r-CS-fluorophenyll-S'-fCB-fluoropyrrolidin-l -yOsulfonylJspirofl^-dioxane^^1- indol]-2'(r//)-one: l '-(4-fluoiOphenyl)-5l-[(3-fluoropyπ'θlidin-1-yl)su[fonyl]spiro[l,l-dioxaπe-2,3l- mdol]-2'(l'//)-one; 2- { 5 '-[(3 -fluoropyrrolidin- 1 -yl)sulfonyl]-2'-oxospirof 1 ,3 -dioxane-2,3 '-indol] - 1 '(2'H)- yl}benzonitrile; r-(3,4-dichlorophenyl)-5'-[(3-fluoropyrrolidin-1-yl)5ulfonyl]spiro[l ,3-dioxane-2.3'- indol]-2'( l'A)-one; r-(2,4-dichlorophenyl)-5'-[(3-fluoropyrrolidin-1-yl)sulfonyl]spiro[l ,3-dioxane-2,3'- indol]-2'(l'//)-one; r-(3-chloro-4-fluorophenyl)-5'-[(3-fluoropyrrolidin-1-yl)sulfonyl]spirof1,3-dioxane- 2,3'-indoll-2'(l '//)-one; l'-(2,5-difIuorophenyl)-5 -[(3-fluoropyrrolidin-1-yl)sulfonyl]spiro[1,3-dioxane-2,3'- indol]-2'(l '/0-one; r-(3,4-difluorophenyl)-5'-[(3-f]uoropyπOhdin-1-yl)sulfonylJspiro[1,3-dioxanc-2,3l- indol]-2'(l'H)-one; r-(4-flLiϋro-3-melhylphenyI)-5'-[(3-fluoropyrrolidm-l -yl)sulfυnyl]spirϋ[1,3-diϋλane- 2,y-mάol]-2\VlD-om:
5l-[(3-fluoropyrrolidin-1-yl)sulfonyl]-r-(3-thienyl)spiro[l ,3-dioxane-2,3'-indol]-
5'-(3,3-difluoropyrrolidin-1-yliulfonyl)-r-phenylspiro[[1,3]dio\ane-2,3l-indυlin]-2l- one:
5'-[(3,3-difluoropvrrolidin-I-yl)sulfonyl]-ll-(3-fluorophenyl)spiro[ [.3-dioxane-2>31- indol]-2'( l'H)-one; 5'-[(3,3-difluoropyirolidin-l -}»1)suIfonyl]-r-(4-fluoroplienyl)spnO[] .3-dioxane-2,3'- indolj-2'(l r//)-one; 2- {5'-[(3,3-cifluoropyrrolidin-1-yl)sulfonyl]-2l-oxospiro[l ,3-dioxane-2,3l-mdol]- l '(2'H)-yHbenzonitπle;
5'-(morpholinosulfonyl)-r-phenylspiro[[1,3]dioxane-2,3'-indolin]-2'-one; r-(3-fluorophenyl)-5'-(morpholin4->lsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l<i:f)- one: l'-(4-fluorophenyl)-5'-(morpholin4->lsulfon>.l)spiro[1.3-dioxane-2,3'-indol]-2'(11//)- one;
245'-(morpholin4-ylsulfonyl)-2'-oxospiro[l ,3-dioxane-2,3l-mdol]-l'(2'//)- yljbenzonitrile; 3-[5l-(morpholm-4-ylsulfonyl)-2l-oxospiro[l ,3-dioxane-2.3'-indol]-r(27/)- yljbenzonitrile:
5'-(morpholin4-ylsulfonyl)-r-f2-(trifluororaethyl)phenyl]spiro[l ,3-dioxane-2,3'- indol]-2'( I1H) -one;
5'-(morpholin-4-ylsulfonyl)-r-[3-(trifluoromethyl)phenyl]spiiO[l ,3-diθxane-2,3'- indolJ-2'(l'H)-one; r-(3,4-dichlorophenyl)-5'-(morpholin-4-ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]- 2'(YH) -one; l '-(2,4-dichlorophenyl)-5'-(niθrpholin-4-ylsulfonyl)spiro[1,3-dioxane-2,3'-indolJ- 2'(l 'H)-one; r-(3,4-difluorophenyl)-51-(morpholm4-ylsulfonyl)spiro[ l 13-dioxane-2.3'-indol]-
2'(11H) -one; l1-(2,5-difluorophenyl)-5'-(morpholin-4-ylsulfonyl)spiro[l (3-dioλane-2,3l-indol]- 2'(l 'H)-one: r-(3-chloro4-fluorophenyl)-5'-(morpholin-4-ylsulfonyl)spiro[l ,3-dioxane-2,3l- indol]-2'(l'H)-one;
5'-(motphohn4-ylsulfonyl)-r-(3-thienyl)sp:ro[1,3-dioxane-2,3Lindol]-2'(l 'H)-one;
5l-(morpholinosulfonyl)-r-phenylspiro[[1.3]dioxolane-2,3'-indolin]-2'-one; l '-(3-fluoropheπyl)-5l-(morpholin-4-ylsulfonyl)spiro[l ,3-dioxolane-2.31-indol]- 2'(VH)-om; r-(4-fluorophenyl)-5'-(morpholin4-ylsulfoπyl)spiro[1.3-dioxolane-2,3'-indol]-
2'(l'H)-one:
2-[5'-(morpholin4-)lsulfony])-2'-oxospi!O[l ,3-dioxolane-2,3'-indol]-T(27/)- yljbenzonitrile;
5l-(morpholiπ4-ylsulfonγlj-i '-[2-(trifluoromethyl)phenyl]spirof1,3-dio\olane-2.3l- indol]-2'( l'H)-one; 1 '-(2.5-difluorophenyl)-5'-(morpholin-4-y1sulfonyl)spiro[l ,3-dioxolane-2.3'-indol]- 2'( l Η)-one; r-(2,4-difluorophenyl)-5'-(morpholin-4-y1sulfonyl)spirof1,3-dioxolane-2,3'-indol]- 2'( l'H)-one; r-(3,4-difluorophenyl)-5'-(raorpholin-4-ylsulfonyl)spiro[1,3-dioxolane-2,3'-indol]-
2\VH)-om;
5l-(morpholin-4-ylsulfonyl)-r-(3-thienyl)spiro[1,3-dioxolane-2,3'-indol]-2'(rH)-one;
1 '-phenyl -5'-(pyrrolidin-l -ylsulfonyl)spiro[[l ,3]dioxolane-2, 3 '-indolin]-2'-one; r-(3-fluorophenyl)-5'-(pyrrohdin-l -ylsulfonyl)spiro[1,3-dioxolane-2,3'-indol]- 2'(VH)-om; r-(4-f!uorophenyl)-5'-(pyπOlidin-l -ylsulfonyl)spiro[1,3-dioxoiane-2,3'-indol]-
2-[2'-oxo-5'-(pyττolidin-l -yIsulfonyl)spiro[1,3-dioxolane-2,3'-indol]-r(2W)- yl]benzonitrile; 3-[2'-oxo-5'-(pyπOlidin-1-ylsulfonyl)spiro[1,3-diox:olane-2,3l-indol]-r(27i)- yl]benzonitrile;
5'-(pyrrohdin-l -ylsulfonyl}- r-[2-(trifluoromethyl)phenyl]spiro[1,3-dioxolane-213'- indol] -2'(11ZZ)-OTIe;
5'-(pyrrohdin-l -ylsulfonyl)-r-[3-(trifluoromethyl)phenyl]spiro[1,3-dioxolane-2.3'- indol]-2'( 177)-one;
1 '-(3,4-dichlorophenyl)-5'-(pyrrolidin- 1 -ylsulfonyl)spiro[l .3 -dioxolane-2,3'-indol]- 2'(VH)-Om:
1 '-(2.4-dichlorop1ienyl)-5'-(pyiτolidin-l -y1su1fonyl)spiro[l .3-dioxolane-2,3'-indol]- 2"(l'H)-onc; r-(3,4-difluorophenyl)-5'-(pyrrolidin-l -ylsulfonyl)spirof1,3-dioxolane-2,3'-indoll-
2'(17/) -one; r-(2,5-difIuorophenyl)-5'-(pyrrolidin-1-ylsulfonyl)spiro[l ,3-dioxolane-2.3'-indol]- 2\VH)-one: r-(3-chloro-4-fluorophenyl)-5'-(pyrrolidin-1-ylsulfony])spiro[1,3-dioxolane-2.3'- indol]-2'(l'H)-one;
5 '-(pyrrol ldm- 1 -v Isulfonyl)- l'-(3-thienyl)spiro[ 1 ,3 -dioxolane-2 ,3 '-mdol] -2'( l '//)-oπe; r-phenyl-5'-(,pipendine-1-carbonyl)spiro[[ 1.3]dioxane-2,3'-indolin]-2'-one: r-(2-chlorophenyl)-5l-(piperidm-l -ylcarbonyl)spiro[1.3-dioxane-2,3l-indol]-2'(r//)- one; r-(3-chlorophenyl)-5'-(pipcridin-1-ylcarbonyl)spiro[1,3-dioxanc-2.3'-indolJ-2'(r//)- one; r-(4-chlorophenyl)-5'-(pipeπdin-1-ylcarbor.yl)spiro[1.3-dioxane-2,3'-indol]-2'(r//)- one; r-C.VfluorophenylJ-S'-φ.peridin-1-ylcarbonyOspirof l .S-dioxane-Z.S'-indoll^'Cr//)- one; r-(4-fluorophenyl)-5'-(p:peridin-1-ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(r//)- one;
2-[2'-oxo-5'-(piperidin-l -ylcarbonyl)spiro[l)3-dioxane-2,3'-indol]-ll(27/)- yl]benzonitπle;
5'-(piperidin-l -ylcarbonyl)-l'-[2-(trifluoromethyl)phenyl]spiro[1.3-dioxane-2,3'- indol]-2'(l'//)-one: r^S^-dichloropheny^-S'-fpipeπdin-1-ylcarbonyOspirofUS-dioxanc-Z^'-indolJ- 2'(l'//)-one; l'-(2,4-dichlorophenyl)-5'-(piperidin-1-ylcarbonyl)spiro[l ,3-dioxane-2,3l-indol]- 2'(l'H)-one; r-(3-chloro-4-fluorophenyl)-5'-(pipcridin-l -ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]-
2'(l'//)-one; r-(2,5-difluorophenyl)-5'-(piperidin-l -ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]- 2'(l'H)-one; r-(3,4-difluorophenyl)-5'-(piperidin-l -ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]- 2'(VH)-ow, r-(4-fluoro-3-methylphenyl)-5'-(pipeπdin-1-ylcarbonyl)spiro[l ,3-dioxane-2,3'- indol]-2'(l'//)-one;
2-chloro-6-(2'-oxo-5'-(pyrrolidin-l -ylsulfonyl)spiro[[1,3]dioxane-2,3Lindolme]-r- yl)benzonitπle; 2-fluoro-6-(2'-oxo-5'-(pyrrolidm-1-ylsulfony])spiro[[1,3]dioxane-2.3'-indoline]-r- yl)benzonitπle;
3-fluoro-2-(2'~oxo-5^(pyrrohdin-I-ylsulfonyl)spiro[f 1,3-]dioxane-2.3'-indoline]-r- y])benzon:tπle;
2-(2l-oλθ-5'-(pyrrolidiπ-l -ylsulff)nyl)spiro[[1.3]dioxane-2,3'-indolme]-r- yl)mcotmonitπlc:
5'-(3-fluoroρyrrohdin-1-ylsulfony])-r-propylspiro[[1.3]dioxane-2,3'-mdolin]-2'-one; r-(cyclopropylmethyl)-5'-(3-fluoropyrrolidin-l -ylsulfonyl)spiro[[1,3]dioxane-2,3'- iπdolm]-2'-one;
5'-(3,3-difluoropyrrolidin-1-ylsulfonyl}-l '-propylspiro[[ 1,3]dio\ane-2,3'-mdolin]-2'- one;
223 l'-(cyclopropylmethyl)-5'-(3,3-<lifluoropyrrolidin-1-ylsulfonyl)spiro[[1.3]dioxane- 2.3'-indolin]-2'-one;
5'-(pyrrolidin- 1 -ylsulfonyl)- 1 '-(4,4,4-trifluorobutyl)spiro[ 1 ,3 -dioxane-2,3'-indol]- 2r( l Η)-one; r-butyr>'l-5'-(pyrrolidin-1-ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(lΗ)-one; l'-(cyclobutylmethyt)-5'-(pyrrolidin-l-ylsulfonyl)spiro[1,3-dioxane-2,3'-mdol]- 2'( 1 'H)-OnC;
I'^-ethylbutylj-S'-Cp^olidin-1-ylsulfonyDspirofl^-dioxane^^'-indolj^'Cl 'H)- one; r-isobut>'l-5'-(pyπOlidin-l-ylsulfony])spiroJ ,3-dioxanc-2.3'-mdolJ-2'(l 'H)-one; r-(2,2-dimethylpropyl)-5'-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3'-indol]- 2'(l 'H)-one; l '-(cyclopropylmethyl)-5'-(pyrrolidin-l -ylsulfonyl)spiro[1,3-dioxane-2.3'-indol]- 2'(l 'H)-one; l '-(cyclohexylmethyl)-5'-(pyrrolidin-1-ylsulfonyl)spiro[1.3-dioxane-2,3'-indol]-
r-[2-(4-fluorophenoxy)ethyl]-5'-fpyrrolidin-l-ylsulfonyl)spiro[l,3-dioxane-2,3l- indol]-2'(lΗ)-one; r-[2-(4-chlorophenoxy)ethyl]-5'-(pyrrolidin-1-ylsulfonyl)spiro[1,3-dioxane-2,3'- mdol]-2'( l'H)-one; l '-(2-phenoxyethyl)-5'-(pyrrolidin-1-ylsulfonyl)spiro[l,3-dioxanc-2,3'-indol]-2'(rH)- one; r-(3-phenoxypropyl)-5'-(pyrrolidin-1-ylsulfony])spiro[1.3-dioxane-2,3'-indol]- 2'(lΗ)-one; r-benzyl-5'-(p\τiOlidin-l-ylsulfonyl)spiro[1,3-dioxanc-2,3'-indolJ-2'(l'H)-onc;
5'-(pyrrolidin-1-y]sulfonyl)-r-(3,3,3-trifluoropropyl)spirof1,3-dioxane-2,3'-indol]- 2'(l 'H)-one;
5'-(pyrrolidin-1-ylsulfony])-l '-(2,2,2 -trifluoroethyl)spiro[ 1 ,3 -dioxane-2,3'-indol]- 2'(l 'H)-onc; r-cyc]opentyl-5'-(pyrrolidin-l -ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(rH)-one; r-propyl-5'-φ>τrolidin-1-ylsulfonyl)spiro[1.3-dioxane-2,3'-indυl]-2'(l Η)-one; r-methyl-5'-(pyrrolidin-l -ylsulfonyl)spϊro[l,3-dioxane-2,3'-indol]-2l(l Η)-onc;
5'-(p\τrolidm-1-ylsulfonyl)-r-[3,3,3-trifluoro-2-(trifluoromethylJpropyl]spiro[l,3- dioxane-2,3 '-indol]-2 '( 11H) -one : l'-sec-bulyl-51-(pyrrolidin-1-ylsι:lfυπyl)spiro[1.3-diυxane-2,3'-indo1]-2l(rH)-one; l'-(l-phenylethyl)-5l-(pyrrolidin-1-ylsulfonyl)s)piro[1,3-dioxane-2,3'-indol]-2'(lΗ)- one; r-isopropyl-5'-(pyrrolidin-1-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one:
4-[2'-oxo-5'-(pyrrolidin-1-ylsulfonyl)spiro[1.3-dioxane-2,3'-mdol]-r(2Η)- yljbutaπenitrile; l '-(l-methylbutyl)-5'-(pyτrolidin-1-ylsulfonylJspiro[l ,3-dioxanc-2,3'-indol]-2'(l Η)- one;
D'-Cpipeπdin-1-ylcarbony^-r-C^^^-tπfluorobutyUspirofU-dioxane-I.S'-indol]- 2'(l'H)-one; 5'-(pipcndin-1-ylcarbonyl)-l'-(2,2,2-trifluoroethyl)spiro[l ,3-dioxane-2,3'-indoIJ-
2'(11H)-OiIe; r-(cyclobutylmethyl)-5'-(piperidm-1-ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]- 2'(l'H)-one;
1 '-isobutyl-5'-(pipeπdm- 1 -ylcarbonyl)spiro[ 1 ,3-dioxane-2,3'-mdol]-2'( 1 Η)-one: r-(2,2-dimethylpropyD-5'-(piperidin-1-ylcarbonyl)spiro[l !3-dioxane-2.3'-indol]-
2'(l'H)-oπe; r-(cyclopropylmethyl)-5'-(piperidin-1-ylcarbonyl)spiro[l,3-dioxanc-2,3'-mdolJ- 2'(l'H)-one; r-ethyl-5'-(piperidin-1-ylcarbonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one; 5'-(piperidin-1-ylcarbonyl)-r-propylspiro[l ,3-dioxaτie-2,3'-indol]-2'(l 'H)-oτie; r-(cyclohcxylmethyl)-5'-(pipcndm-1-ylcarbonyl)spiro[ 1,3-dioxane-2,3'-indol]- 2'(l Η)-one;
[2'-oxo-5'-(pipeπdin-1-ylcarbonyl)spiro[l,3-dioxane-2.3'-indol]-r(2Η)- yljacetonitπie; r-methyI-5'-(pipendm-1-ylcarboriyl)spiro[l 13-dioxane-2,3'-indol]-2'(l'H)-one; r-but-3-en-1-yl-5'-(piperidm-l-ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]-2'(rH)-one; r-(2-methoxyelhyl)-5'-(piperidin-l-ylcarbϋnyl)i>piro[l,3-dιoxane-2)3l-indol]-2l(lΗ)- one;
1 '-( 4-fluorobuty1)-5 '-(pipeπdin- 1 -ylcarbonyl)spiro[ 1.3 -dioxane-2,3 '-indol] -2'( 11H)- one; r-penl-4->n-l -yl-5'-(piperidin-] -yIcatbony1)spnO[1 ,3-dioxane-2,3'-indol]-2'(rH)- one; l'-[(2-oxo-I ,3-oxazolidm-5-yI)methylj-5'-(p:pendin-1-ylcarbonyl)spiro[1,3-dioxane- 2,3I-mdol]-2'(lΗ)-or.e; lt-(2-ethy1butyl)-51-(pipetidin-1 -y1carbonyl)spiro[1.3-dioxane-2,3'-indol]-2'(l Η)-one; ll-(2-cyclohexylethyl)-5'-(piperidin-l -ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]- 2'(lΗ)-one;
5l-(pipeπdin-l -ylcarbon>l)-r-[3,3,3-tπfluoro-2-(trifluoromethyl)propyl]spiro[l ,3- dioxane-2.3'-indol]-2'(l Η)-one; r-sec-butyl-5'-(pipeπdm-1-ylcarbonyl)spiro[1,3-dioxane-2,3'-indol]-2'( l Η)-one;
1 '-(1-phenylethyl)-5'-(pipeπdin-1-}icarbonyl)spiro[1,3-dioxane-2,3'-indol]-2'( I 1II)- onc;
1 '-( 1 -methylbutyl)-5 '-(piperidin- 1 -ylcarbonyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 'H)- one; 4-[2'-oxo-5 '-(piperidin- 1 -ylcarbonyl)spiro[ 1 ,3 -dioxane-2 ,3 '-indol] - 1 '(2'H)- yljbutanenitrile; r-isopropyl-5'-(piperidin-1-ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(lΗj-one; r-benzyl-5'-(piperidin-1-ylcarbonyl)spiro[ l ,3-dioxane-2.3'-indol]-2'(l 'H)-one;
5-[2'-oxo-5'-(piperidin-l -3?lcarbonyl)spirol l ,3-dioxanc-2,3'-indol]-r(2'H)- yl]pentanenitrile;
6-[2'-oxo-5'-(pipeπdin-l -ylcarbonyl)spiro[l ,3-dioxane-2.3'-indol]-l'(2lH)- yl]hexanenitrile; r-pent-4-cn-l -yl-5'-(pipcπdin-l -ylcaτbonyl)spiro[1,3-dioxane-2,3'-indol]-2'( lΗ)- one; 1 '-(cyclopropylmethyl)-5'-(morpholin-4-ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-
2'(1 Η)-one: r-butyl-5'-(morphohn-4-ylcarbonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(rH)-one;
5'-(morpholin-4-ylcarbonyl)-r-propylspiro[1,3-dioxane-2,3'-indol]-2'(lΗ)-one;
5'-(morpholin-4-ylcarbonyl)-l '-(2,2,2-trifluoroethyl)spiro[l ,3-dioxane-2,3'-indol]- 2'(l 'H)-one;
5'-(morphohn-4-ylcarbonyl)- r-pent-4-yn-I -ylspiro[l ,3-dioxane-2,3'-indol]-2'(rH)- one:
4-[5'-(morpholin-4-y1carbonyl)-2l-oxospiro[l ,3-dioxane-2.3'-indol]-l l(2lII)- yl]butanenitrile: r-(4-fluorobutyl)-5'-(morpholin-4-ylcarbonyl)spirof1,3-dioxane-2,3'-indol]-2'( lΗ)- oiie: r-(cyclopropylmethyl)-5.5-dimethyl-5'-(piperidin-l -ylcarbonyl)spiro[1,3-dioxane- 2,3t-mdolJ-2'(lΗ)-onc;
5,5-dimethyl-5'-(piperidin-1-ylcarbonyl)-r-propylspiro[1,3-dioxane-2,3'-indol]- 2ϊl 'H )-one; 5,5-dimethyl-5'-(piperidin-1-ylcarbonyl)-l'-(2.2.2-trτfluoroethyl)spiro[1.3-dioxane- 2.3'-indol]-21(l 1II)-one:
5.5-dimethyl-l Lpent-4-}τi-1-yl-5'-(piperidin-1-ylcarbonyl)spirofl.3-dioλane-2,3'- indol]-2'(l'H)-one; 4-[5,5-dimethyl-2'-oxo-5'-(pipeπdin-1-)'lcarbonyl)spiro[l ,3-dioxane-2,31-indolJ- l '(2'H)-ylJbutancnitnlc;
3 -[2'-oxo-5 '-(pipeπdm- 1 -ylcarbonyl)spiro[ 1 ,3 -dioxane-2.3 -indol] - 1 '(2'H)- yl]propanenitrile;
3-[5'-(morjiholin-4-ylcarbonyl)-2'-oxospiro[1,3-dioxane-2,3'-mdol]-r(2'H)- yljpropanenitrile;
S'-Cpipendm-l
Figure imgf000230_0001
iπdol]- 2'(l'H)-one;
1 -(cyclopropylmethyl)-5-(piperidin-l -ylcarbonyl)-3'.4',5',6'- tetrahydrospiro|mdole- 3.2'-pyran]-2(l H)-one: (3r)-l -(cyclopropylmethyl)-5-(piperidin-1-ylearborryl)-3',4',5',6'- tetrahydrospiro[indole-3,2'-pyran]-2(1H)-one;
(3s)-l -(cyclopropylmethyl)-5-(pipcπdin-1-ylcarbonyl)-3',4',5',6'- tetrahydrospiro[indole-3,2'-pyran]-2(1H)-one;
5-(piperidin-l -ylcarbonyl)-1-(2,2,2-tπfluoroethyl)-3',4',5',6'- tetrahydrospiro[indole- 3.2'-pyran]-2(1 H)-one: r-(cyclopropyImethyl)-5'-(pipeπdin-l -ylcarbonyl)spiro[ l ,3-dioxφane-2,3'-indol]- 2'(l'H)-one;
3-tert-buiyl-1-(cyclopropylmethyl)-3-hydroxy-5-(piperidin-l -ylcarbonyl)-l ,3- dihydro-2H-indol-2-one; and 3-tcrt-butyl-1-(cycloρropylmethyl)-3-fluoro-5-(piperidm-l -ylcarbonyl)-l ,3-dihydro-
2H-indol-2-one, and pharmaceutically acceptable salts thereof.
64, A pharmaceutical composition comprising a compound of any one of claims 1 to 63, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable earner.
65. A method for treating a CB2-mediated disorder, comprising administering to a subject m need thereof an effective amount of a conpound of any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof.
66, The method of claim 65 wherein the CB2-mediated disorder is pain, osteoarthritis, atherosclerosis, osteoporosis, or cancer.
67, The method of claim 66 wherein said cancer is glioma,
68. A method for reducing pain in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof.
69. The method of claim 68. wherein the pain is inflammatory pain, post surgical pain, neuropathic pam, or bone pain.
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JP7482324B2 (en) 2020-10-08 2024-05-13 メルク・シャープ・アンド・ドーム・エルエルシー Preparation of oxindole derivatives as novel diacylglyceride O-acyltransferase 2 inhibitors
US12410159B2 (en) 2020-10-08 2025-09-09 Merck Sharp & Dohme Llc Preparation of oxindole derivatives as novel diacylglyceride O-acyltransferase 2 inhibitors
US12428411B2 (en) 2020-10-08 2025-09-30 Merck Sharp & Dohme Llc Preparation of oxindole derivatives as novel diacylglyceride o-acyltransferase 2 inhibitors

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