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WO2011072064A1 - Spiro[chromane-4,4'-imidazol]ones en tant qu'inhibiteurs de bêta-sécrétase - Google Patents

Spiro[chromane-4,4'-imidazol]ones en tant qu'inhibiteurs de bêta-sécrétase Download PDF

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Publication number
WO2011072064A1
WO2011072064A1 PCT/US2010/059553 US2010059553W WO2011072064A1 WO 2011072064 A1 WO2011072064 A1 WO 2011072064A1 US 2010059553 W US2010059553 W US 2010059553W WO 2011072064 A1 WO2011072064 A1 WO 2011072064A1
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Prior art keywords
optionally substituted
halogen
phenyl
alkyl
amino
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Kevin W. Hunt
James P. Rizzi
Adam Cook
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Array Biopharma Inc
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Array Biopharma Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to organic compounds useful for inhibition of ⁇ -secretase enzymatic activity and the therapy and/or prophylaxis of neurodegenerative diseases associated therewith. More particularly, certain spirochroman compounds useful in the treatment and prevention of neurodegenerative diseases, such as Alzheimer's Disease, are provided herein.
  • heterocyclylalkyl are optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl;
  • R 2 and R 2 ' are independently H, hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, a carbocycle or a heterocycle wherein said alkyl, alkoxy, acyl, acyloxy, alkoxycarbonyl, sulfonyl, sulfinyl, sulfanyl, carbocycle and heterocycle are optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl, haloalkyl and a carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino cyano, nitro alkyl, alkoxy, acyl and haloalkyl.
  • 'm' is an integer from 0 to 4.
  • m is 0 to 3.
  • m is 0 to 2.
  • m is 0.
  • m is 1.
  • m is 2.
  • m is 3.
  • m is 4.
  • R$ is hydrogen, benzyl or C1-C3 alkyl optionally substituted with Ra;
  • R 7 and R T are independently selected from hydrogen, halogen and Ci-Ce alkyl optionally substituted with R b Struktur or
  • each Rj is independently selected from halogen and C1-C6 alkyl
  • each Rj is independently selected from hydrogen and Q-Ce alkyl optionally substituted with halogen, CN, OH, OCH3 or phenyl;
  • each Ri and n is independently selected from hydrogen and Ci-C 6 alkyl
  • each Rp is independently selected from hydrogen, Q-C alkyl and phenyl
  • each Rg is independently selected from halogen and cyclopropyl
  • R9 is hydrogen, halogen, CN, C C g alkyl optionally substituted with Rc, Q-Cg alkenyl optionally
  • Rc substituted with Rc, C r Cg alkynyl optionally substituted with Rc, Q-Cg alkoxy optionally substituted with Rc, phenyl optionally substituted with Rj, a 5-6 membered heteroaryl optionally substituted with Re, a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with R f , a 3- 6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg, a 9-10 membered bicyclic heteroaryl optionally substituted with R h , phenylamino, or phenoxy optionally substituted with R ; ;
  • each R a is independently selected from OH, OCH 3 and halogen
  • each R b is independently selected from halogen, hydroxyl, methoxy, phenyl, C3-C6 carbocyclyl, a 5 to 6 membered heteroaryl, a 4 to 6 membered heterocyclyl, -O(phenyl) and -S(phenyl), wherein the phenyl, carbocyclyl, heterocyclyl and heteroaryl are optionally substituted with halogen, CN and C
  • each R g is independently selected from halogen and C C 6 alkyl
  • each Rj is independently selected from halogen and ben2yl
  • each is independently selected from halogen and C 3 -C 6 carbocyclyl;
  • each Re is independently selected from halogen, CN, NH 2 , cyclopropyl, OR p , C r C 6 alkyl optionally substituted with ORq, and C C 6 alkynyl optionally substituted with OR s .
  • X 2 is CRio, wherein R 10 is halogen. In certain embodiments, X 2 is CRio, wherein
  • R5 is hydrogen or halogen. In certain embodiments, R5 is hydrogen or F. In a certain embodiment, R 5 is hydrogen.
  • Rf is selected from hydrogen, benzyl or Ci-C 3 alkyl optionally substituted with R a .
  • R $ is selected from benzyl or C C 3 alkyl optionally substituted with R ⁇ .
  • each R a is independently selected from OH, OCH 3 , halogen, a 5-6 membered heteroaryl, and a 3-6 membered heterocyclyl optionally substituted with C1-C3 alkyl optionally substituted with oxo.
  • R a is a 5-6 membered heteroaryl, wherein the heteroaryl contains one, two or three heteroatoms selected from oxygen, nitrogen and sulfur.
  • R 7 and R T are independently selected from hydrogen, halogen and methyl. In certain embodiments, R 7 and R 7 > are hydrogen. In certain embodiments, R 7 and R7 are methyl. In certain embodiments, R 7 and R T are F. In certain embodiments, R 7 is F and R T is hydrogen. In certain embodiments, R 7 and R 7 - together with the atom to which they are attached form cyclopropyl. In this embodiment, R 7 and R 7 form a spirocycle with the carbon atom to which they are attached.
  • each R b is independently selected from halogen, oxo, NRiRm, C C 3 alkyl optionally substituted with halogen or OH, -0(C]-C 3 alkyl) optionally substituted with halogen or OH, phenyl, C 3 -C 6 carbocyclyl, a 4-6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the phenyl, carbocyclyl, heterocyclyl and heteroaryl are optionally substituted with halogen, CN, OH, OCH 3 , and Ci-C 6 alkyl optionally substituted with halogen, OH or OCH 3 .
  • each R b is independently selected from halogen, oxo, NRjRn,, C 1 -C3 alkyl optionally substituted with halogen or OH, -0(C r C3 alkyl) optionally substituted with halogen or OH, phenyl, C3-C6 carbocyclyl, a 4-6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the phenyl, carbocyclyl, heterocyclyl and heteroaryl are optionally substituted with halogen, CN, OH, OCH 3 , and C]-C 6 alkyl optionally substituted with halogen, OH or OCH 3 , wherein the heterocyclyl and heteroaryl contain one, two or three heteroatoms selected from oxygen, nitrogen and sulfur.
  • each R ⁇ is independently selected from halogen, NRiRm, cyclopropyl, C r C 3 alkyl optionally substituted with halogen or OH, and - 0(Ci-C 3 alkyl) optionally substituted with halogen or OH.
  • Rg and 3 ⁇ 4 ⁇ are independently selected from hydrogen, cyclopropyl or Ci-C 6 alkyl optionally substituted with R3 ⁇ 4.
  • R3 ⁇ 4 is halogen, phenyl, cyclopropyl or a 4-6 membered heterocyclyl.
  • R3 ⁇ 4 is halogen, phenyl, cyclopropyl or a 4-6 membered heterocyclyl, wherein the heterocyclyl contains one heteroatom selected from oxygen, nitrogen and sulfur.
  • R 3 ⁇ 4 is halogen, phenyl, cyclopropyl or a 4-6 membered heterocyclyl, wherein the heterocyclyl is tetrahydropyranyl.
  • Rg and R ' are independently alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
  • Rg is alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl and R # is H.
  • Rg is methyl and Rg' is H.
  • Rg is 2-propyl and Rg is H.
  • Rg is t-butyl and Rg- is H.
  • Rg is cyclopropyl and R ' is H.
  • Rg is benzyl and Rg' is H.
  • each R3 ⁇ 4 is independently selected from halogen, oxo, NRjRm, Q-C 3 alkyl optionally substituted with halogen or OH, -0(Ci-C 3 alkyl) optionally substituted with halogen or OH, phenyl, C 3 -C6 carbocyclyl, a 4-6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the phenyl, carbocyclyl, heterocyclyl and heteroaryl are optionally substituted with halogen, CN, OH, OCH 3 , and Ci-C 6 alkyl optionally substituted with halogen, OH or OCH 3 , wherein the heterocyclyl or heteroaryl contain one, two or three heteroatoms selected from oxygen, nitrogen and sulfur.
  • each Rj is independently selected from halogen, oxo, NR ⁇ , C1-C 3 alkyl optionally substituted with halogen or OH, - ⁇ (0 ⁇ -0 3 alkyl) optionally substituted with halogen or OH, phenyl, C 3 -Q carbocyclyl, a 4-6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the phenyl, carbocyclyl, heterocyclyl and heteroaryl are optionally substituted with halogen, CN, OH, OCH 3 , and C1-C6 alkyl optionally substituted with halogen, OH or OCH 3 , wherein the heterocyclyl is tetrahydropyranyl.
  • Rg and Rg- are
  • R ' is methyl and Rg is C1-C6 alkyl substituted with R b .
  • Rg' is methyl in the (S)-configuration, and Rg is C C 6 alkyl substituted with Rb in the (Reconfiguration.
  • Rg' is methyl in the (Reconfiguration, and Rg is Ci-C 6 alkyl substituted with Rb in the (S)-configuration.
  • Rg- is methyl and Rg is -CH 2 (Rb). In certain embodiments, Rg is -CH 2 (Rb).
  • Rg- is methyl and Rg is selected from benzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4-fluorobenzyl, 3- fluorobenzyl, 2-fluorobenzyl, 3-chlorobenzyl, 4-(difIuoromethoxy)benzyl, 3-(difluoromethoxy)benzyl, 3- fluoro-4-methoxybenzyl, 3-cyanobenzyl, cyclopropylmethyl, (tetrahydropyran-4-yl)methyl, pyridin-2- ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, (5-fluoropyridin-2-yl)methyl, pyrimidin-2-ylmethyl, (lH-pyrazol-l-yl)methyl, (lH-l,2,4-triazol-l-yl)methyl, (lH-imidazol-l-yl)methyl.
  • Rg ' is methyl and Rg is selected from benzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4-fluorobenzyl, 3- fluorobenzyl, 2-fluorobenzyl, 3-chlorobenzyl, 4-(difluoromethoxy)benzyl, 3-(difluoromethoxy)benzyl, 3- fluoro-4-methoxybenzyl and 3-cyanobenzyl.
  • Rg ' is methyl and Rg is selected from 3-methoxybenzyl, 4-methoxybenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 3-chlorobenzyl, 4- (difluoromethoxy)benzyl, 3-(difluoromethoxy)benzyl, 3-fluoro-4-methoxybenzyl and 3-cyanobenzyl.
  • Rg- is methyl and Rg is cyclopropylmethyl.
  • Rg' is methyl and Rg is (tetrahydropyran-4-yl)methyl.
  • R ' is methyl and Rg is selected from pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, (5-fluoropyridin-2-yl)methyl, pyrimidin-2- ylmethyl, (lH-pyrazol-l-yl)methyl, (lH-l,2,4-triazol-l-yi)methyl and (lH-imidazol-l-yl)methyl.
  • Rg ' is methyl and Rg is selected from Ci-C 6 alkyl optionally substituted with Rj, wherein R t , is selected from -O(phenyl) and -S(phenyl), wherein the phenyl is optionally substituted with halogen.
  • Rg> is methyl and Rg is selected from
  • Rg and Rg- together with the atom to which they are attached form a 3 to 6 membered carbocyclyl or heterocyclyl optionally substituted with Q-C3 alkyl optionally substituted with halogen.
  • Rg and R ' together with the atom to which they are attached form a 3 to 6 membered carbocyclyl optionally substituted with Q-C3 alkyl optionally substituted with halogen.
  • Rg and R ' together with the atom to which they are attached form a 3 to 6
  • heterocyclyl optionally substituted with CrC 3 alkyl optionally substituted with halogen, wherein the heterocyclyl contains one heteroatom selected from oxygen, nitrogen and sulfur.
  • Rg and Rg' together with the atom to which they are attached form a 3 to 6 membered heterocyclyl optionally substituted with Q-C3 alkyl optionally substituted with halogen, wherein the heterocyclyl is selected from tetrahydropyranyl and piperdinyl.
  • Rg and Rg' together with the atom to which they are attached form a 3 to 6 membered carbocyclyl or heterocyclyl optionally substituted with Q-C3 alkyl optionally substituted with halogen, wherein Rg and Rg' are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, l-(2,2,2-trifluoroethyl)tetrahyrdropyran- 4-yl and piperdin-4-yl.
  • Rg and R ' together with the atom to which they are attached form a 3 to 6 membered carbocyclyl or heterocyclyl.
  • Rg and Rg' form a spirocycle with the carbon atom to which they are attached.
  • Rg and Rg' together with the atom to which they are attached form a 3 to 6 membered carbocyclyl.
  • Rg and Rg ' together with the atom to which they are attached form a 3 to 6 membered heterocyclyl.
  • Rg and Rg ' together with the atom to which they are attached form a 3 to 6 membered carbocyclyl or heterocyclyl, wherein Rg and Rg ' are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and tetrahyrdropyran-4-yl.
  • Rg and R ' together form a 3 to 6 member carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl.
  • Rg and Rg> together form a cycloalkyl ring.
  • R 7 and R r together with the atom to which they are attached may form a 3 to 6 membered carbocyclyl or heterocyclyl; or Rg and Rg- together with the atom to which they are attached may form cyclopropyl, wherein only one of R 7 and R T or Rg and R may together form a ring.
  • R 9 is hydrogen, halogen, CN, C Cg alkyl optionally substituted with Rc, C Cg alkenyl optionally substituted with Rc, Q-Cg alkynyl optionally substituted with Rc, phenyl optionally substituted with R ⁇ a 5-6 membered heteroaryl optionally substituted with Re, a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with R f , a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with R g , a 9-10 membered bicyclic heteroaryl optionally substituted with R h , phenylamino, or phenoxy optionally substituted with R.
  • R9 is phenyl optionally substituted with Rj, a 5-6 membered heteroaryl optionally substituted with Rg, a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with R f , , a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with R g , a 9-10 membered bicyclic heteroaryl optionally substituted with R h , phenylamino, or phenoxy optionally substituted with R ; .
  • R 9 is phenyl optionally substituted with R d or a 5-6 membered heteroaryl optionally substituted with Re.
  • each R ⁇ j is independently selected from halogen, CN, cyclopropyl, ORj, SR ⁇ , NRiRm, C r C 8 alkyl optionally substituted with Rdung, -0(C r Cg alkyl) optionally substituted with Rdung, Q-Cg alkynyl optionally substituted with Ro.
  • each R ⁇ is independently selected from halogen, CN, cyclopropyl, ORj, SR ⁇ , NRiR,,,, Q-Cg alkyl optionally substituted with R forum, C r C 8 alkynyl optionally substituted with Ro.
  • each R is independently selected from halogen, CN, oxide, NH 2 , cyclopropyl, ORp, SRk, C r C 6 alkyl optionally substituted with halogen and ORq, and Ci-C 6 alkynyl optionally substituted with OR s .
  • each Re is independently selected from halogen, CN, NH 2 , cyclopropyl, ORp, Q-C6 alkyl optionally substituted with ORq, and C]-C6 alkynyl optionally substituted
  • each Re is independently selected from halogen, CN, NH 2 , cyclopropyl, ORp, SRk, C]-C 6 alkyl optionally substituted with halogen and ORq, and C]-C 6 alkynyl optionally substituted with OR s .
  • each R. is independently selected from halogen, CN, NH 2 ,
  • each Rf is independently selected from halogen, oxo, C C 6 alkyl optionally substituted with halogen, and Q-C6 alkoxycarbonyl. In certain embodiments, each Rf is independently selected from halogen, oxo, Ci-C 6 alkyl, and C C 6 alkoxycarbonyl.
  • each Rg is independently selected from halogen, OH, OCH 3 and Ci-C 6 alkyl optionally substituted with halogen. In certain embodiments, each Rg is independently selected from halogen and Ci-C 6 alkyl.
  • each Rj is independently selected from hydrogen and C r C6 alkyl optionally substituted with halogen, CN, OH, OCH 3 and benzyl. In certain embodiments, each R j is independently selected from hydrogen and C1-C6 alkyl optionally substituted with halogen or phenyl.
  • each Rj and RTM is independently selected from hydrogen and C C 6 alkyl.
  • each R Q is independently selected from halogen and C3-C6 carbocyclyl.
  • each Rp is independently selected from hydrogen, C ⁇ -Ce alkyl and phenyl.
  • each Rq is halogen
  • each Rj is independently selected from halogen and cyclopropyl.
  • R 9 is selected from hydrogen, Br, CN, butyl, isobutyl, propyl, isopentyl, -CH 2 CH 2 C(CH 3 )3, -CH 2 CH 2 CH 2 CN, -CH 2 CH 2 CH 2 OCH 3 , -CH 2 (phenyl), -CH 2 CH 2 (phenyl),
  • R 9 is selected from hydrogen, Br, CN, butyl, isobutyl, propyl, isopentyl, -CH 2 CH 2 C(CH 3 )3, -CH 2 CH 2 CH 2 CN, -CH 2 CH 2 CH 2 OCH 3 , cyclohexylmethyl, -CH 2 (phenyl),
  • R9 is selected from hydrogen, Br, CN, butyl, isobutyl, propyl, isopentyl, -CH 2 CH 2 C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CN, -CH 2 CH 2 CH 2 OCH 3 , cyclohexylmethyl, -CH 2 (phenyl),
  • R 9 is Q-Cg alkyl optionally substituted with Rc.
  • each R c is independently selected from halogen, CN, OH, OCH 3 , Q-C 3 alkyl optionally substituted with halogen or OH, -0(C]-C 3 alkyl) optionally substituted with halogen or OH, C 3 -C 6 carbocyclyl and phenyl optionally substituted with halogen, OH or OCH 3 .
  • each Rc is independently selected from CN, OCH 3 , cyclohexyl and phenyl optionally substituted with OCH 3 .
  • R 9 is selected from butyl, isoburyl, propyl, isopentyl, -CH 2 CH 2 C(CH 3 ) 3 , -CH 2 CH 2 CH 2 CN, - CH 2 CH 2 CH 2 OCH 3 , cyclohexylmethyl,
  • R is Ci-Cg alkyl optionally substituted with Rc.
  • each R c is independently selected from halogen, CN, OH, OCH 3 , cyclopropyl and phenyl optionally substituted with halogen, OH or OCH 3 .
  • each Rc is independently selected from CN, OCH 3 and phenyl optionally substituted with OCH 3 .
  • R 9 is selected from butyl, isobutyl, propyl, isopentyl, -CH 2 CH 2 C(CH 3 ) 3 ,
  • R 9 is C r Cg alkenyl optionally substituted with Rc.
  • each Rc is independently selected from halogen, CN, OH, OCH 3 , C1-C 3 alkyl optionally substituted with halogen or OH, -0(Ci-C 3 alkyl) optionally substituted with halogen or OH, C 3 -C6 carbocyclyl and phenyl optionally substituted with halogen, OH or OCH 3 .
  • R c is selected from OCH 3 and cyclopropyl.
  • R 9 is Q-Cg alkenyl optionally substituted with R-.
  • each Rc is independently selected from halogen, CN, OH, OCH 3 , cyclopropyl and phenyl optionally substituted with halogen, OH or OCH 3 .
  • R c is OCH 3 .
  • R 9 is Ci-C 8 alkynyl optionally substituted with R c .
  • each Rc is independently selected from halogen, CN, OH, OCH 3 , C 1 -C 3 alkyl optionally substituted with halogen or OH, -0(Ci-C 3 alkyl) optionally substituted with halogen or OH, C 3 -C 6 carbocyclyl and phenyl optionally substituted with halogen, OH or OCH 3 .
  • R c is cyclopropyl.
  • R 9 is selected from -C ⁇ CCH 2 CH 2 CH 3 , -C ⁇ CCH(CH 3 ) 2 , -C ⁇ CC(CH 3 ) 3 , -C ⁇ CCH 2 CH(CH 3 ) 2 , and -C ⁇ C(cyclopropyl).
  • R is Ci-C 8 alkynyl optionally substituted with Rc.
  • each Rc is independently selected from halogen, CN, OH, OCH 3 , cyclopropyl and phenyl optionally substituted with halogen, OH or OCH 3 .
  • Rc is cyclopropyl.
  • R 9 is selected from -C ⁇ CH(CH 3 ) 2 , -C ⁇ CC(CH 3 ) 3 ,
  • R 9 is phenyl optionally substituted with 3 ⁇ 4.
  • each 3 ⁇ 4 is independently selected from halogen, CN, cyclopropyl, OR j , SR k , NRiR,,,, Q-Cg alkyl optionally substituted with Rdung, -0(C r Cg alkyl) optionally substituted with R forum, C r Cg alkynyl optionally substituted with R o .
  • each R j is independently selected from hydrogen and Ci-C 6 alkyl optionally substituted with halogen, CN, OH, OCH 3 and benzyl.
  • each 3 ⁇ 4 is independently selected from hydrogen and Ci-C 6 alkyl optionally substituted with halogen or phenyl.
  • each is C r C 6 alkyl.
  • each Rj and R privilege is independently selected from hydrogen and C C 6 alkyl.
  • each R cargo is independently selected from halogen, OH, OCH 3 , CN and phenyl.
  • each R shelter is independently selected from halogen, OCH 3 and phenyl.
  • each R ⁇ is independently selected from halogen and C 3 -C 6 carbocyclyl.
  • each R Q is C 3 -C 6 carbocyclyl.
  • R9 is selected from phenyl, 3 -fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 3- cyanophenyl, 2-(3-phenyl)acetonitrile, m-tolyl, 3-ethylphenyl, 3-isopropylphenyl, 3- (trifluoromethyl)phenyl, 3-benzylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 3-isopropoxyphenyl, 3-isobutoxyphenyl, 3- (difluoromethoxy)phenyl, 3-(trifluoromethoxy)phenyl, 3-(methoxymethyl)phenyl, 3-(benzyloxy)phenyl, 3-(3-phenylpropoxy)phenyl, 3-cyclopropy
  • R9 is phenyl optionally substituted with 3 ⁇ 4.
  • each R d is independently selected from halogen, CN, cyclopropyl, OR j , SR k , NRiRm, C C 8 alkyl optionally substituted with R classroom, C r C 8 alkynyl optionally substituted with R ⁇ ,.
  • each is independently selected from hydrogen and C C6 alkyl optionally substituted with halogen or phenyl.
  • each R k is Q-C6 alkyl.
  • each Rj and Rn is independently selected from hydrogen and C r e alkyl.
  • R 9 is a 5-6 membered heteroaryl optionally substituted with Re, wherein the heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thiophenyl, furanyl, isothiazolyl, thiazolyl, pyrazolyl, oxazolyl, and imidazolyl.
  • each R ⁇ .
  • halogen is independently selected from halogen, CN, oxide, N3 ⁇ 4, cyclopropyl, ORp, SRk, Ci-C 6 alkyl optionally substituted with halogen and O q, and C r C 6 alkynyl optionally substituted with OR j .
  • R 9 is selected from 4-methylpyridin-2-yl, 4-cyanopyridin-2-yl, 4-methoxypyridin-2-yl, 4- chloropyridin-2-yl, 4-fluoropyridin-2-yl, 6-trifluoromethylpyridin-2-yl, pyridin-3-yl, 2-fluoropyridin-3-yl, 5-chloropyridin-3-yl, 5-trifluoromethylpyridin-3-yl, 5-methoxypyridin-3-yl, 5-fluoropyridin-3-yl, 5- methylpyridin-3-yl, 5-chloro-2-fIuoropyridin-3-yl, 5-ethynylpyridin-3-yl, 5-(prop- l-ynyl)pyridin-3-yl, 5- (cyclopropylethynyl)pyridin-3-yl, 5-cyanopyridin-3-yl, 5-cyclopropylpyr
  • R9 is a 5-6 membered heteroaryl optionally substituted with Re. In certain embodiments, R9 is a 5-6 membered heteroaryl optionally substituted with R e , wherein the heteroaryl contains one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain embodiments, R 9 is a 5-6 membered heteroaryl optionally substituted with R « , wherein the heteroaryl contains one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • each R e is independently selected from halogen, CN, NH 2 , cyclopropyl, ORp, SR ⁇ , C]-C 6 alkyl optionally substituted with halogen and OR q , and Q-C6 alkynyl optionally substituted with ORj.
  • R9 is a 5-6 membered heteroaryl optionally substituted with R «.
  • R 9 is a 5-6 membered heteroaryl optionally substituted with Re, wherein the heteroaryl contains one, two or three heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • R 9 is a 5-6 membered heteroaryl optionally substituted with Re, wherein the heteroaryl contains one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • R9 is selected from 4-cyanopyridin-2-yl (isoniconitrile), 4-methoxypyridin-2-yl, 4-chloropyridin-2-yl, 6- trifluoromethylpyridin-2-yl, 5-chloropyridin-3-yl, 5-trifluoromethylpyridin-3-yl, 5-methoxypyridin-3-yl, 5- fluoropyridin-3-yl, 5-methylpyridin-3-yl, 5-chloro-2-fluoropyridin-3-yl, 5-ethynylpyridin-3-yl, 5-(prop-l- ynyl)pyridin-3-yl, 5-(cyclopropylethynyl)pyridin-3-yl, 5-cyanopyridin-3-yl (nicitinonitrile), 5- cyclopropylpyridin-3-yl, 5-bromopyridin-3-yl, 5-chloro-2-methoxypyridin
  • R9 is a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with Rf, wherein the heterocyclyl is selected from tetrahydropyranyl, 1 ,2-dihydropyridinyl, 1 ,6-dihydropyridinyl, 5,6- dihydropyridinyl, 1 ,2,5,6-tetrahydropyridinyl, and 3,6-dihydropyranyl.
  • each Rf is independently selected from halogen, oxo, CrC alkyl, and Q-C6 alkoxycarbonyl.
  • each Rf is independently selected from halogen, oxo, and Q-Ce alkoxycarbonyl. In certain embodiments, each R f is independently selected from halogen, oxo, and Ci-Ce alkoxycarbonyl. In certain embodiments, R f is tert-butyl carboxylate.
  • R 9 is selected from tetrahydropyran-4- yl, tetrahydropyran-3-yl, 5-chloro-l-methyl-2-oxo-l,2-dihydropyridin-3-yl, 5-chloro-2-oxo-l,2- dihydropyridin-3-yl, 6-oxo- 1 ,6-dihydropyridin-3-yl, tert-butyl 5,6-dihydropyridine- 1 (2H)-carboxylate, l ,2,5,6-tetrahydropyridin-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl and 3,4-dihydro- 2H-pyran-6-yl.
  • R9 is a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with R f . In certain embodiments, R 9 is a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with R f , wherein the heterocyclyl contains one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • R9 is a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with Rf, wherein the heterocyclyl is selected from tetrahydropyranyl, 1,2-dihydropyridinyl, 1,6-dihydropyridinyl, 5,6- dihydropyndinyl, 1 ,2,5,6-tetrahydropyridinyl, and 3,6-dihydropyranyl.
  • each R f is independently selected from halogen, oxo, C Ce alkyl, and Ci-C 6 alkoxycarbonyl.
  • each Rf is independently selected from halogen, oxo, and C ⁇ -C alkoxycarbonyl. In certain embodiments, each R f is independently selected from halogen, oxo, and Ci-C 6 alkoxycarbonyl. In certain embodiments, R f is tert-butyl carboxylate.
  • R 9 is selected from tetrahydropyran-4- yl, 5-chloro- l-methyl-2-oxo- 1 ,2-dihydropyridin-3-yl, 5-chloro-2-oxo- 1 ,2-dihydropyridin-3-yl, 6-oxo- 1 ,6- dihydropyridin-3-yl, tert-butyl 5,6-dihydropyridine-l(2H)-carboxylate, l,2,5,6-tetrahydropyridin-3-yl, and 3 ,6-dihydro-2H-pyran-4-yl.
  • R 9 is a 5-6 membered saturated heterocyclyl optionally substituted with R f . In certain embodiments, R 9 is a 5-6 membered saturated heterocyclyl optionally substituted with R f , wherein the heterocyclyl contains one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain embodiments, R 9 is a 5-6 membered saturated heterocyclyl optionally substituted with R f , wherein the heterocyclyl contains one oxygen heteroatom. In certain embodiments, R 9 is a 5-6 membered saturated heterocyclyl optionally substituted with R f , wherein the heterocyclyl is
  • each R f is independently selected from halogen, oxo, Ci-C alkyl, and CpC 6 alkoxycarbonyl. In certain embodiments, each Rf is independently selected from halogen, oxo, C r C alkyl, and Ci- 6 alkoxycarbonyl. In certain embodiments, R 9 is tetrahydropyran-4-yl.
  • R 9 is a 5-6 membered partially unsaturated heterocyclyl optionally substituted with Rf, wherein the heterocyclyl contains one heteroatom selected from the group consisting of oxygen and nitrogen.
  • R 9 is a 5-6 membered partially unsaturated heterocyclyl optionally substituted with R f , wherein the heterocyclyl is selected from 1 ,2-dihydropyridinyl, 1 ,6-dihydropyridinyl, 5,6- dihydropyridinyl, 1 ,2,5,6-tetrahydropyridinyl, and 3,6-dihydropyranyl.
  • each R f is independently selected from halogen, oxo, Ci-C 6 alkyl, and Ci-C 6 alkoxycarbonyl.
  • each R f is independently selected from halogen, oxo, and C r C alkoxycarbonyl.
  • R f is tert-butyl carboxylate.
  • R 9 is selected from 5-chloro- 1-methyl- 2-oxo- l ,2-dihydropyridin-3-yl, 5-chloro-2-oxo-l ,2-dihydropyridin-3-yl, 6-oxo- 1 ,6-dihydropyridin-3-yl, tert-butyl 5,6-dihydropyridine-l(2H)-carboxylate, l ,2,5,6-tetrahydropyridin-3-yl, and 3,6-dihydro-2H- pyran-4-yl.
  • R 9 is a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with R g .
  • each R g is independently selected from halogen, OH, OCH 3 and C C alkyl optionally substituted with halogen.
  • each R g is selected from OCH 3 and Q-C6 alkyl.
  • R 9 is selected from cyclopropyl, cyclopentyl, cyclohexyl, (3R,5S)-3,5-dimethylcyclohexyl, 4,4-dimethylcyclohexyl, 3-hydroxycyclohexyl, (3R,5S)-3,5- dimethylcyclohex- l -enyl, 4,4-dimethylcyclohex-l -enyl and 3-methoxycyclohex-l-enyl.
  • R 9 is a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with R g .
  • each R g is independently selected from halogen, OH, OCH 3 and Ci-C 6 alkyl optionally substituted with halogen.
  • each R g is selected from OCH 3 and Ci-C 6 alkyl.
  • R 9 is selected from cyclopentyl, cyclohexyl, (3R,5S)-3,5- dimethylcyclohexyl, 4,4-dimethylcyclohexyl, 3-hydroxycyclohexyl, (3R,5S)-3,5-dimethylcyclohex-l-enyl, 4,4-dimethylcyclohex-l -enyl and 3-methoxycyclohex-l -enyl.
  • R 9 is a 3-6 membered saturated carbocyclyl optionally substituted with R g .
  • each R g is independently selected from halogen and Q-C6 alkyl.
  • each R g is Ci-C 6 alkyl.
  • R 9 is selected from cyclopentyl, cyclohexyl, (3R,5S)-3,5-dimethylcyclohexyl, and 4,4-dimethylcyclohexyl.
  • R 9 is a 3-6 membered partially unsaturated carbocyclyl optionally substituted with R g .
  • each R g is independently selected from halogen, OH, OCH 3 and C C 6 alkyl optionally substituted with halogen.
  • each R g is selected from OCH 3 and C C6 alkyl.
  • R 9 is selected from (3R,5S)-3,5-dimethylcyclohex-l-enyl, 4,4- dimethylcyclohex-l-enyl and 3-methoxycyclohex-l-enyl.
  • R is a 3-6 membered partially unsaturated carbocyclyl optionally substituted with R g .
  • each R g is independently selected from halogen and CpC6 alkyl.
  • each R g is C C6 alkyl.
  • R 9 is selected from (3R,5S)-3,5- dimethylcyclohex- 1 -enyl and 4,4-dimethylcyclohex- 1 -enyl.
  • each R h is independently selected from halogen and C ⁇ -C 6 alkyl.
  • R 9 is selected from 6- chloroimidazo[l,2-a]pyridin-5-yl, lH-indol-5-yl, 1 -methyl- lH-indol-5-yl, lH-indol-6-yl, lH-indol-7-yl, lH-pyrrolo[3,2-b]pyridin-6-yl, isoquinoline-4-yl, and quinolin-3-yl.
  • R is phenylamino. In certain embodiments, R 9 is phenoxy optionally substituted with Rj. In certain embodiments, each Rj is independently selected from halogen and benzyl. In certain embodiments, R 9 is selected from phenoxy and 3-benzyl-5-fluorophenoxy.
  • Rio is hydrogen, halogen or methyl. In certain embodiments, Rio is hydrogen, F, CI or methyl.
  • R J0 is hydrogen. In a certain embodiment, R ]0 is F. In a certain embodiment, Ri 0 is CI. In a certain embodiment, R ]0 is methyl.
  • At least one of R 5 , R ⁇ ;, R 7 , R T , 3 ⁇ 4, Rg' and R 9 is not hydrogen. In certain embodiments, at least one of R 7 , R T , R «, 3 ⁇ 4 ⁇ is not hydrogen.
  • Compounds of the invention contain one or more asymmetric or chiral centers, e.g., a chiral carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof.
  • the syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Diastereomeric compounds may be separated by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated using the same techniques or others known in the art.
  • Each of the asymmetric carbon atoms may be in the R or S configuration and both of these configurations are within the scope of the invention.
  • compounds of the invention have the stereochemical orientation represented by Formula ⁇ or Formula ⁇
  • compounds of the invention have the general Formula III - XXXIV:
  • prodrugs of the compounds described above include known amino-protecting and carboxy-protecting groups which are released, for example hydrolyzed, to yield the parent compound under physiologic conditions.
  • a particular class of prodrugs are compounds in which a nitrogen atom in an amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidino group is substituted with a hydroxy (OH) group, an alkylcarbonyl (-CO- R) group, an alkoxycarbonyl (-CO-OR), an acyloxyalkyl-alkoxycarbonyl (-CO-O-R-O-CO-R) group where R is a monovalent or divalent group and as defined above or a group having the formula -C(0)-0- CPlP2-haloalkyl, where PI and P2 are the same or different and are H, lower alkyl, lower alkoxy, cyano, halo lower alkyl or aryl
  • the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of the invention.
  • These prodrug compounds are prepared by reacting the compounds of the invention described above with an activated acyl compound to bond a nitrogen atom in the compound of the invention to the carbonyl of the activated acyl compound.
  • Suitable activated carbonyl compounds contain a good leaving group bonded to the carbonyl carbon and include acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, in particular acyl phenoxides such as p- nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, and difluorophenoxy acyl.
  • the reactions are generally exothermic and are carried out in inert solvents at reduced temperatures such as -78°C to about 50°C.
  • the reactions are usually also carried out in the presence of an inorganic base such as potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, triethylamine, etc.
  • an inorganic base such as potassium carbonate or sodium bicarbonate
  • an organic base such as an amine, including pyridine, triethylamine, etc.
  • Compounds of the invention are prepared using standard organic synthetic techniques from starting materials and reagents generally available from commercial sources such as Sigma-Aldrich (St. Louis, MO), Alfa Aesar (Ward Hill, MA), or TCI (Portland, OR), or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Fieser, Louis F., and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, New York: Wiley 1967-2006 ed. (also available via the Wiley InterScience® website), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)).
  • l-(5-bromo-2-hydroxyphenyl)ethanone a (or alternatively l-(2-bromo-5-hydroxypyridin-4-yl)ethanone when X is N) is reacted with the appropriate ketone or aldehyde b to give chromanone c which is reacted with ammonium carbonate to give spirochroman d.
  • Spirochroman d is reacted with the desired R iodide e to give f followed by Lawesson's reagent to give thioxospirochroman g which is converted to amine h by reacting with ammonium hydroxide.
  • h is reacted with boronic acid i to give the final compound of Formula I.
  • Step 2 l-(5-Bromo-2-hydroxyphenyl)ethanone a (or alternatively l-(2-bromo-5-hydroxypyridin-4-yl)ethanone when X 2 is N) is reacted with the appropriate ketone or aldehyde b to give chromanone c.
  • Step lb is then necessary.
  • the ketone is then converted to the converted to the corresponding hydantoin (Step 2) to provide spirochroman e.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • Enantiomers can also be separated by use of a chiral HPLC column.
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Lough, W.J., ed. Chiral Liquid Chromatography. New York: Chapman and Hall, 1989; Okamoto, Yoshio, et al. "Optical resolution of dihydropyridine enantiomers by high-performance liquid chromatography using
  • Step E 6-Bromo-r,2,2-trimethyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (2.0 g, 5.63 mmol) was diluted with methanol (40 mL), followed by the addition of tert-butyl hydroperoxide (1 1.7 mL, 84.4 mmol) and concentrated NH 4 OH (19.7 mL, 563 mmol). The reaction was heated to 40°C and stirred for 2 hours. The reaction was removed from the heat and stirred for an additional 2 hours. The reaction was diluted with water and extracted with DCM. The combined organics were dried over MgS0 4 , filtered and concentrated. The material was purified on silica gel eluting with 1-10% methanol/DCM with 1%
  • Step F 2'-Amino-6-bromo-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (50 mg, 0.15 mmol), 5-chloropyridin-3-ylboronic acid (28 mg, 0.18 mmol) and tetrakis(triphenylphosphine)palladium (0) (8.5 mg, 0.0074 mmol) were combined in a vial and diluted with dioxane (1 mL). Na2CC>3 (370 ⁇ , 0.74 mmol) was added, and the vial was sealed, heated to 95°C and stirred overnight.
  • Step A 2'-Amino- 1 '-(2-(tert-butyldimethylsilyloxy)ethyl)-6-(3-chlorophenyl)-2,2-dimethylspiro- [chroman-4,4'-imidazol]-5'( H)-one was prepared according to the procedures of Example 1, substituting (2-bromoethoxy)(tert-butyl)dimethylsilane for iodomethane, K2CO 3 for NaH, and heating to 60°C overnight in Step C, and substituting 3-chlorophenylboronic acid for 5-chloropyridin-3-ylboronic acid in acid in Step F.
  • Step B 1M Tetrabutylammonium floride ("TBAF") in tetrahydrofuran (“THF”) (0.152 mL, 0.152 mmol) was added to a solution of 2'-amino- -(2-(tert-butyldimethylsilyloxy)ethyl)-6-(3-chlorophenyl)-2,2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (0.039 g, 0.0759 mmol) in THF (1 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated to dryness.
  • THF tetrahydrofuran
  • Step A 2'- Amino- 1 '-(3-(tert-butyldimethylsilyloxy)propyl)-6-(3-chlorophenyl)-2,2-dimethylspiro- [chroman-4,4'-imidazol]-5'(rH)-one was prepared according to the procedures of Example 1, substituting (3-bromopropoxy)(tert-butyl)dimethylsilane for iodomethane, K 2 C0 3 for NaH, and heating to 60°C overnight in Step C, and substituting 3-chlorophenylboronic acid for 5-chloropyridin-3-ylboronic acid in Step F.
  • Step B 1M TBAF in THF (0.0417 mL, 0.0417 mmol) was added to a solution of 2'-amino-r-(3-(tert- butyldimethylsilyloxy)propyl)-6-(3-chlorophenyl)-2,2-dimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (0.01 1 g, 0.0208 mmol) in THF (0.7 mL). The reaction mixture was stirred at room temperature for 2 hours, and the reaction mixture was concentrated to dryness.
  • Example 1 was separated by SFC chromatography using a chiralpak AD-H (2 X 15 cm) 901061 column. The column was eluted with 15% ethanol (0.2% DEA)/C0 2 at 100 mL/min (100 bar). The retention time of the title compound was 2.06 minutes, and the retention time of the opposite enantiomer was 1.75 minutes. Chiral separation provided (R)-2'-amino-6-(5-chloropyridin-3-yl)-l',2,2-trimethylspiro[chroman- 4,4'-imidazol]-5'(l'H)-one (13.5 g, chemical purity >99% and >98% enantiomeric excess). !
  • Step A Methyl 2-cyclopropylideneacetate was prepared as described in WO 2007/107243. (1- Ethoxycyclopropoxy)trimethylsilane (29.6 g, 170 mmol), toluene (500 mL), methyl
  • Example 46 2"-amino-6'-(5-methoxypyrid-3-yl)-l"-methyldispiro[cyclopentane-l,2'-chroman-4',4"- imidazol]-5 * (l'H)-one
  • Step A KOtBu (18.5 g, 165 mmol) was added portionwise to a cooled
  • Step B 6-Bromo-3,3-dimethylchroman-4-one (1 g, 3.9 mmol), KCN (0.51 g, 7.8 mmol), ammonium carbonate (3.0 g, 31 mmol) and NaHS0 3 (0.41 g, 3.9 mmol) were diluted with ethanol (4 mL), sealed and heated to 130°C. After stirring for 12 hours, the reaction was allowed to cool and poured into ice water. The pH was adjusted to about 5, and the mixture was filtered, rinsed with water and dried under vacuum to yield 6-bromo-3,3-dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (1.2 g, 3.7 mmol, 94% yield).
  • Step C 6-Bromo-3,3-dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (765 mg, 2.35 mmol) was diluted with DMF (7 mL), followed by the addition of K 2 C0 3 (390 mg, 2.82 mmol) and Mel (147 ⁇ , 2.35 mmol, d 2.275). After stirring for 3 hours, the reaction was diluted with ethyl acetate and washed with IN HC1, water and brine.
  • Step D 6-Bromo-1 ⁇ 3,34rimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (800 mg, 2.36 mmol) was diluted with toluene (10 mL), followed by the addition of Lawesson's Reagent (715 mg, 1.77 mmol).
  • Step E 6-Bromo- ,3,3-trimethyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (375 mg, 1.06 mmol) was diluted with methanol (10 mL), followed by the addition of tert-butyl hydroperoxide (2265 ⁇ ,, 15.8 mmol) and NH 4 OH (4563 iL, 39.1 mmol). The reaction was heated to 40°C, stirred for 2 hours and then left to stir overnight at ambient temperature. The reaction was concentrated to about half volume, diluted with DCM and washed with water. The organic layer was dried over MgS0 4 , filtered and concentrated.
  • Step F 2'-Amino-6-bromo- ,3,3-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (50 mg, 0.15 mmol), 5-chloropyridin-3-ylboronic acid (35 mg, 0.22 mmol) and Pd(PPh 3 ) 4 (8.5 mg, 0.0074 mmol) were combined in a vial and diluted with dioxane (1 mL). Sodium carbonate (222 ⁇ , 0.44 mmol) was added, and the vial was sealed, heated to 95°C and stirred overnight.
  • reaction was allowed to cool and loaded onto silica gel running a gradient of 1-10% MeOH/DCM with 1% NH 4 OH to yield 2'-amino-6-(5- chloropyridin-3-yl)- ,3,3-trimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (20 mg, 0.054 mmol, 36% yield).
  • Example 54 2'-amino-6-(3-chlorophen l)- ,3,3-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one
  • 2-Chloro-4-methoxypyridine (0.019 g, 0.13 mmol), 20% aqueous sodium carbonate (0.028 g, 0.26 mmol), and tetrakis(triphenylphospine)palladium(0) (7.5 mg, 0.0065 mmol) were added to a solution of 2'-amino- 1 ',2,2-trimethyl-6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)spiro[chroman-4,4'-imidazol]-5'( 1 'H)-one (0.050 g, 0.13 mmol) in dioxane (1 ml), and the reaction was degassed with argon.
  • 2,4-Dichloropyridine (0.038 g, 0.26 mmol), 20% aqueous sodium carbonate (0.18 g, 0.34 mmol), and tetrakis(triphenylphospine)palladium(0) (7.5 mg, 0.0065 mmol) were added to a solution of 2'-amino- 1 ⁇ 2,2-trimethyl-6-(4,4,5,5 etramethyl-l,3,2-dioxaborolan-2-yl)spiro[chroman-4,4'-imidazol]-5 H)-one (0.050 g, 0.13 mmol) in dioxane (1 ml), and the reaction was degassed with argon.
  • Ethynyltrimethylsilane (132 mg, 1.35 mmol) was then added, and the tube was capped under argon with a Teflon cap and stirred at 70°C for 2 hours. The reaction mixture was allowed to cool to room
  • the product isolated was repurified on C-18 reverse phase HPLC (Gilson Unipoint) eluting with 5-95% MeOH/water containing 0.1% formic acid gradient to provide 2'-amino-6-(5-ethynylpyridin-3-yl)- 1 ',2,2- trimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one (16 mg, 32.9% yield) as a solid.
  • Step A A resealable pressure bottle (300 mL) was charged with 3,5-dibromopyridine (1.00 g, 4.22 mmol), copper(I) iodide (0.241 g, 1.27 mmol), Pd(PPh 3 ) 4 (0.244 g, 0.21 1 mmol), tetrabutylammonium fluoride 1M solution in THF (4.22 mL, 4.22 mmol), triethylamine (1.94 mL, 13.9 mmol), and toluene (160 mL). The mixture was cooled to 0°C and N 2 was bubbled through the mixture for 5 minutes.
  • Trimethyl(prop-l-ynyl)silane (0.630 mL, 4.22 mmol) was then added slowly via a septum. Once the addition was complete, the pressure bottle was sealed with a Teflon screw cap, and the mixture was stirred at room temperature. After 18 hours, the mixture was poured in to water (50 mL), and the layers were separated. The organic layer was then washed with brine (2 X 50 mL), dried over MgS0 4 and filtered through a pad of Celite ® .
  • Step B A resealable glass pressure tube was charged with 2'-amino-l ⁇ 2,2-trimethyl-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)spiro[chroman-4,4'-imidazol]-5'(rH)-one (30 mg, 0.078 mmol), 3- bromo-5-(prop-l-ynyl)pyridine (18 mg, 0.093 mmol), dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (3.2 mg, 0.004 mmol), 20% aqueous Na 2 C0 3 (144 ⁇ ,, 0.27 mmol), and 1,4-dioxane (779 ⁇ , 0.078 mmol).
  • Example 65 2'-amino-6-(3-chloro-5-ethynylphenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-
  • Step A A resealable glass pressure tube was charged with 2'-amino-6-bromo-l',2,2- trimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one (1971 ⁇ , 0.296 mmol), ((3-chloro-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethynyl)trimethylsilane (128.7 mg, 0.3844 mmol), 20% aqueous sodium carbonate (548.4 ⁇ , 1.035 mmol), dichloro[l ,l'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (12.2 mg, 0.0148 mmol) and 1,4- dioxane (2957 ⁇ , 0.2957 mmol).
  • Step A Pyrrolidine (1.33 mL, 15.9 mmol) was added slowly dropwise by syringe to a 0°C solution of 1- (5-bromo-2-hydroxyphenyl)ethanone (2.85 g, 13.3 mmol) and l,3-difluoropropan-2-one (3.12 g, 33.1 mmol) in MeOH (40 mL). The reaction mixture was stirred for 10 minutes, then warmed to ambient temperature and stirred for 6 hours. The reaction mixture was transferred to a 175 mL sealed tube, then heated in an 85°C sand bath and stirred for 12 hours.
  • the reaction mixture was concentrated to dryness, diluted with EtOAc, washed with 1M HC1 (3 X), 1M NaOH (3 X), brine (1 X), dried (Na 2 S0 4 ), filtered, and concentrated.
  • the crude was purified on silica gel (2-20% EtOAc in hexanes gradient) to give solids. The solids were suspended in ether, digested in a freezer for 30 minutes, then isolated by vacuum filtration, rinsed with cold ether, and dried in vacuo to give 6-bromo-2,2-bis(fluoromethyl)chroman-4-one (1.43 g, 37.1% yield) as a crystalline solid.
  • Step B A resealable glass pressure tube was charged with 2'-amino-l',2,2-trimethyl-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)spiro[chroman-4,4'-imidazol]-5'( H)-one (50 mg, 0.13 mmol), 1- bromo-3-cyclopropyl-5-fluorobenzene (28 mg, 0.13 mmol), dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (5.3 mg, 0.0065 mmol), 20% aqueous Na 2 C0 3 (241 ⁇ , 0.45 mmol), and 1 ,4-dioxane (1.3 mL, 0.13 mmol).
  • the reaction mixture was sparged with N? for 5 minutes, capped, stirred at 90°C for 2 hours and allowed to cool to room temperature.
  • the mixture was then diluted with EtOAc ( 10 mL) and washed with water (2 mL).
  • the organic layer was separated, dried (MgS0 4 ), filtered and concentrated in vacuo.
  • the residue obtained was purified by flash chromatography on silica gel (Biotage Flash 40S+) eluting with 5% MeOH/DCM.
  • the product isolated was triturated with EtOAc.
  • Step A 3-Bromo-5-cyclopropylbenzonitrile was prepared as a solid according to the general procedures of Example 83, Step A, using a mixture of 3,5-dibromobenzonitrile (500 mg, 1.92 mmol) and potassium cyclopropyltrifluoroborate (340 mg, 2.30 mmol).
  • Step A 3-Bromo-5-cyclopropylpyridine (210 mg, 50% yield) was prepared as a solid according to the general procedures of Example 83, Step A, using 3,5-dibromopyridine (500 mg, 2.11 mmol) and potassium cyclopropyltrifluoroborate (375 mg, 2.53 mmol).
  • Step A 3-Bromo-5-(prop-l-ynyl)benzonitrile was prepared from 3,5-dibromobenzonitrile (1.00 g, 3.83 mmol) according to the general procedures described in Example 64, Step A.
  • Step B 2'-Amino- ,2,2-trimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)spiro[chroman-4,4'- imidazol]-5'(l'H)-one (50 mg, 0.13 mmol) and 3-bromo-5-(prop-l-ynyl)benzonitrile (46 mg, 0.16 mmol) were processed as described in the general procedures of Example 64, Step B, to provide 3-(2'-amino- 1 ',2,2-trimethyl-5'-oxo- 1 ',5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-5-(prop- 1 -ynyl)benzonitrile ( 18 mg, 35%) as a solid.
  • Step B A mixture of ethyl l-(hydroxymethyl)cyclopropanecarboxylate (1.9 g, 13.2 mmol),
  • Step C A mixture of 4-bromophenol (1.6 g, 9.25 mmol), ethyl 1- ((methylsulfonyloxy)methyl)cyclopropanecarboxylate (2.26 g, 10.2 mmol) and CS2CO3 (3.31 g, 10.2 mmol) in DMF (25 mL, 9.25 mmol) was heated to 130°C for 5 hours. EtOAc and water were added to the solution, and the organics were washed with water (5 X). The organics were washed with brine and dried with Na 2 S0 4 .
  • Step D A solution of ethyl l-((4-bromophenoxy)methyl)cyclopropanecarboxylate (1.99 g, 6.65 mmol) and NaOH (9.98 mL, 20.0 mmol) in MeOH (50 mL, 1234 mmol; d. 0.791) was stirred for 4 hours at 50°C. The mixture was poured onto ice water, and the pH was adjusted to 3 with HC1. The organics were extracted with EtOAc, then washed with brine and dried with Na 2 S0 4 .
  • Step E l-((4-Bromophenoxy)methyl)cyclopropanecarboxylic acid (1.59 g, 5.86 mmol) in concentrated H 2 S0 4 (5 mL, 90.0 mmol) was stirred for one hour at room temperature. The mixture was taken up in EtOAc, washed with water, brine and dried with Na 2 S0 4 . The mixture was purified on a column using EtOAc:hexanes to give the 6-bromospiro[chroman-3,l'-cyclopropan]-4-one (0.855 g, 3.38 mmol, 57%) as a solid.
  • Step F A mixture of 6-bromospiro[chroman-3,l'-cyclopropan]-4-one (0.855 g, 3.38 mmol), ammonium carbonate (2.60 g, 27.0 mmol), KCN (0.440 g, 6.76 mmol) and NaHS0 3 (0.352 g, 3.38 mmol) in EtOH (3.38 mL, 3.38 mmol) was heated in a bomb to 130°C overnight. HC1 was added to the mixture to bring the pH to 3. This was stirred for 1 hour and a solid crashed out of the mixture.
  • Step H Lawesson's Reagent (0.533 g, 1.32 mmol) was added to 6'-bromo-l "- methyldispiro[cyclopropane-l,3'-chroman-4',4"-imidazolidine]-2",5"-dione (0.635 g, 1.88 mmol; Formula 91g) in toluene (10 mL, 1.88 mmol), and this was refluxed overnight. The mixture was taken up in EtOAc, washed with water, brine and dried with Na 2 S0 4 .
  • Step I A mixture of 6'-bromo-l "-methyl-2"-thioxodispiro[cyclopropane-l,3'-chroman-4',4"- imidazolidine]-5"-dione (0.31 g, 0.878 mmol; Formula 91h), 2-hydroperoxy-2-methylpropane (3.77 mL, 26.3 mmol) and ⁇ 3 ⁇ 4 ⁇ (3.73 mL, 52.7 mmol) in MeOH (8 mL, 197 mmol; d. 0.791) was heated to 40°C for 2 hours. All of the reagents went into solution. This was then stirred at room temperature overnight. The mixture was partitioned between DCM and water.
  • Step J A mixture of 2"-amino-6'-bromo-l"-methyldispiro[cyclopropane-l,3'-chroman-4',4"-imidazol]- 5'(l'H)-one (0.040 g, 0.1 19 mmol; Formula 91i), 3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (0.034 g, 0.14 mmol), Pd(PPh 3 ) 4 (0.0137 g, 0.01 19 mmol) and Na 2 C0 3 (0.119 mL, 0.238 mmol) in dioxane (9 mL, 0.1 19 mmol) was heated in a sealed vial overnight at 90°C.
  • Step A A mixture of 2'-amino-6-bromo- ,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (2.0 g, 5.91 mmol), 4,4,4',4',5,5,5',5 , -octamethyl-2,2*-bi(l,3,2-dioxaborolane) (9.1 g, 35.5 mmol), Pd(PPh 3 ) 4
  • Step A Ammonium carbonate (8.46 g, 88.1 mmol), KCN (1.43 g, 22.0 mmol), and NaHS0 3 (0.458 g, 4.40 mmol) were added in a teflon-lined steel pressure reactor to a solution of 6-bromochroman-4-one (2.50 g, 1 1.0 mmol) in EtOH (l 1.0 mL, 1 1.0 mmol). The reactor was sealed and heated at 150°C for 18 hours. The reactor was cooled to ambient temperature. The reaction mixture was partitioned between ethyl acetate/water, and the aqueous layer was extracted with ethyl acetate (2 X).
  • Step B K 2 C0 3 (0.352 g, 2.54 mmol) and Mel (0.106 mL, 1.70 mmol) was added to a solution of 6- bromospiro[chroman-4,4'-imidazolidine]-2',5'-dione (0.504 g, 1.70 mmol) in DMF (5.65 mL, 1.70 mmol), and the resulting slurry was stirred at ambient temperature for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated.
  • Step C A mixture of 6-bromo- -methylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (0.488 g, 1.57 mmol) and Lawesson's reagent (0.381 g, 0.941 mmol) was diluted with toluene (7.84 mL, 1.57 mmol), and the resulting solution was heated at 100°C for 24 hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate then washed with NaHC(3 ⁇ 4 and brine.
  • Step D t-Butyl hydroperoxide (70% aq, 3.06 mL, 30.6 mmol) and ⁇ 3 ⁇ 4 ⁇ (2.14 mL, 61.1 mmol) was added to a solution of 6-bromo-r-methyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (0.501 g, 1.53 mmol) in MeOH (10.2 mL, 1.53 mmol). The resulting mixture was stirred at 40°C for 2 hours and then at room temperature overnight. The residue was purified by flash chromatography, eluting with
  • Step E A mixture of 2'-amino-6-bromo- -methylspiro[chroman-4,4'-imidazol]-5'(rH)-one (41.6 mg, 0.134 mmol), 5-chloropyridin-3-ylboronic acid (21.1 mg, 0.134 mmol), Pd(PPh 3 ) 4 (7.75 mg, 0.00671 mmol), Na 2 C03 (2.0M solution, 200 ⁇ , 0.402 mmol) in dioxane (671 ⁇ , 0.134 mmol) in a pressure vial was degassed with nitrogen and heated to 90°C for 24 hours.
  • Step A A thick wall glass pressure tube with a stir bar was charged with l-(3-methoxyphenyl)propan-2- one (10.7 g, 65.0 mmol), l-(5-bromo-2-hydroxyphenyl)ethanone (10.8 g, 50.0 mmol), and toluene (15 mL). Pyrrolidine (4.1 1 mL, 50.0 mmol) was then added, followed by acetic acid (2.86 mL, 50.0 mmol). The mixture was heated to 80°C for 18 hours. After cooling to room temperature, the mixture was partitioned between EtOAc (100 mL) and aqueous IN HC1 (100 mL).
  • Step B A stainless steel bomb (50 mL capacity) containing a Teflon® insert and stir bar was charged with EtOH (10 mL) and 6-bromo-2-(3-methoxybenzyl)-2-methylchroman-4-one (3.6 g, 10 mmol). Next, ammonium carbonate (4.8 g, 50 mmol), KCN (1.3 g, 20 mmol) and sodium hydrogensulfite (0.26 g, 2.5 mmol) were added. The reaction was heated to 130°C for 18 hours with stirring. The reaction contents were transferred to an Erlenmeyer flask with EtOAc (50 mL) and water (30 mL). The contents were carefully acidified with concentrated HC1 (approximately 8 mL).
  • Step C A round bottomed flask with a stir bar was charged with 6-bromo-2-(3-methoxybenzyl)-2- methylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (4.38 g, 10.2 mmol), DMF (50 mL), potassium carbonate (1.82 g, 13.2 mmol), and lastly iodomethane (0.569 mL, 9.14 mmol). The mixture was stirred at room temperature for 15 hours. The reaction mixture was worked up by partitioning between EtOAc (100 mL) and water (100 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (100 mL).
  • Step D A thick wall glass pressure tube was charged with 6-bromo-2-(3-methoxybenzyl)-l',2- dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (2.4 g, 5.4 mmol), Lawesson's Reagent (1.3 g, 3.2 mmol), and toluene (20 mL). The mixture was sparged with N 2 . The mixture was heated to 100°C for 15 hours. After cooling to room temperature, the mixture was partioned between EtOAc (50 mL) and saturated aqueous NaHC(3 ⁇ 4 (50 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (20 mL).
  • Step E A round bottomed flask with a stir bar was charged with 6-bromo-2-(3-methoxybenzyl)-l',2- dimethyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (2.5 g, 5.4 mmol), MeOH (40 mL), t-butyl hydroperoxide 70% aqueous (11 mL, 81 mmol), and 30% aqueous NH 4 OH (21 mL, 163 mmol). The reaction was stirred for 15 hours at room temperature. Water (5 mL) was added and concentrated in vacuo. The mixture was partitioned between EtOAc (50 mL) and water (50 mL).
  • Yield isomer A (eluted before isomer B): (2S',4R')-2'-amino-6-bromo-2-(3- methoxybenzyl)-r,2-dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one: 410 mg (17%);
  • Yield isomer B (eluted after isomer A): (2R',4R')-2'-amino-6-bromo-2-(3-methoxybenzyl)-l',2-dimethylspiro[chroman- 4,4'-imidazol]-5'(l'H)-one: 500 mg (21%).
  • Step F A 2 dram vial was charged with (2S',4R')-2'-amino-6-bromo-2-(3-methoxybenzyl)-r,2- dimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one (50 mg, 0.1 1 mmol), dioxane (0.5 mL), 5- chloropyridin-3-ylboronic acid (19 mg, 0.12 mmol), Pd(PPh 3 ) 4 (13 mg, 0.011 mmol), and 2N aqueous Na 2 C0 3 (141 ⁇ , 0.28 mmol). The mixture was sparged with N 2 for 30 seconds and then heated to 90°C for 15 hours. After cooling to room temperature, the reaction mixture was loaded directly on to preparative TLC plate (1 mm thickness, R 0.46) and eluted with 7.5% MeOH (containing 7N
  • (2R',4R')-2'-Amino-2-(4-methoxybenzyl)-r,2-dimethyl-6-(pyridin-3-yl)spiro[chroman-4,4'-imidazol]- 5'(l'H)-one was prepared from (2R',4R')-2'-amino-6-bromo-2-(4-methoxybenzyl)- ,2- dimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (as prepared according to procedures described for synthesis of Example 297, substituting l-(3-methoxyphenyl)propan-2-one with l-(4- methoxyphenyl)propan-2-one in Example 297, Step A; 20 mg, 0.05 mmol) according to the procedure described for Example 297, Step F, substituting pyridin-3-ylboronic acid for 5-chloropyridin-3-ylboronic acid.
  • Step B A stainless steel bomb (50 mL capacity) with teflon insert was charged with EtOH (10 mL) and 6-bromo-2-(4-fluorobenzyl)-2-methylchroman-4-one (3.5 g, 10 mmol). Next, ammonium carbonate (4.8 g, 50 mmol), KCN (1.3 g, 20 mmol) and sodium hydrogensulfite (0.26 g, 2.5 mmol) were added. The mixture was heated with stirring to 130°C for 18 hours. The reaction contents were transferred to an Erlenmeyer flask with EtOAc (50 mL) and water (30 mL). The reaction mixture was carefully neutralized to a pH of about 7 to 8 with concentrated HCI near back of hood.

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Abstract

L'invention concerne de nouveaux composés de spirochromane de formules I et II qui inhibent le clivage de β-sécrétase d'APP et sont utiles en tant qu'agents thérapeutiques pour traiter des maladies neurodégénératives.
PCT/US2010/059553 2009-12-08 2010-12-08 Spiro[chromane-4,4'-imidazol]ones en tant qu'inhibiteurs de bêta-sécrétase Ceased WO2011072064A1 (fr)

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