WO2011072064A1 - S piro [chroman - 4, 4 ' - imidazol] ones as beta - secretase inhibitors - Google Patents

S piro [chroman - 4, 4 ' - imidazol] ones as beta - secretase inhibitors Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
halogen
phenyl
alkyl
amino
Prior art date
Application number
PCT/US2010/059553
Other languages
French (fr)
Inventor
Kevin W. Hunt
James P. Rizzi
Adam Cook
Original Assignee
Array Biopharma Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Array Biopharma Inc. filed Critical Array Biopharma Inc.
Publication of WO2011072064A1 publication Critical patent/WO2011072064A1/en

Links

Classifications

    • 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.

Abstract

The invention provides novel spirochroman compounds of Formulas I and II that inhibit β-secretase cleavage of APP and are useful as therapeutic agents for treating neurodegenerative diseases.

Description

S PIRO [CHROMAN - 4 , 4 ' - IMIDAZOL] ONES AS BETA - SECRETASE INHIBITORS
PRIORITY OF INVENTION
This application claims priority to United States Provisional Application Number 61/267810 that was filed on 08 December 2009; United States Provisional Application Number 61/267809 that was filed on 08 December 2009; and United States Provisional Application Number 61/307400 that was filed on 23 February 2010. The entire content of the provisional applications is hereby incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to organic compounds useful for inhibition of β-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.
BACKGROUND OF THE INVENTION
Alzheimer's Disease (AD) is a neurological disorder thought to be primarily caused by amyloid plaques, an accumulation of abnormal protein deposits in the brain. It is believed that an increase in the production and accumulation of amyloid beta peptides (also referred to as Αβ or A-beta) in plaques leads to nerve cell death, which contributes to the development and progression of AD. Loss of nerve cells due to amyloid plaques in strategic brain areas, in turn, causes reduction in the neurotransmitters and impairment of memory. The proteins principally responsible for the plaque build up include amyloid precursor protein (APP) and presenilin I and II (PSI and PSII). Mutations in each of these three proteins have been observed to enhance proteolytic processing of APP via an intracellular pathway that produces Αβ peptides ranging from 39 to 43 amino acids. The Αβ 1-42 fragment has a particularly high propensity of forming aggregates due to two very hydrophobic amino acid residues at its C-terminus. Thus, Αβ 1-42 fragment is believed to be mainly responsible for the initiation of neuritic amyloid plaque formation in AD and is therefore actively being pursued as a therapeutic target. Anti-Αβ antibodies have been shown to reverse the histologic and cognitive impairments in mice which overexpress Αβ and are currently being tested in human clinical trials. Effective treatment requires anti-Αβ antibodies to cross the blood-brain barrier (BBB), however, antibodies typically cross the BBB very poorly and accumulate in the brain in low concentration. Different forms of APP range in size from 695-770 amino acids, localize to the cell surface, and have a single C-terminal transmembrane domain. Αβ is derived from a region of APP adjacent to and containing a portion of the transmembrane domain. Normally, processing of APP by a-secretase cleaves the midregion of the Αβ sequence adjacent to the membrane and releases a soluble, extracellular domain fragment of APP from the cell surface referred to as APP-a. APP-a is not thought to contribute to AD. On the other hand, pathological processing of APP by the proteases β-secretase (also referred to as "β-site of APP cleaving enzyme", memapsin-2 and Aspartyl Protease 2 (Asp2)) followed by γ-secretase cleavage, at sites which are located N-terminal and C-terminal to the a-secretase cleavage site, respectively, produces a very different result than processing at the a site, i.e. the release of
amyloidogenic Αβ peptides, in particular, Αβ 1-42. Processing at the β- and γ-secretase sites can occur in both the endoplasmic reticulum and in the endosomal/lysosomal pathway after reinternalization of cell surface APP. Dysregulation of intracellular pathways for proteolytic processing may be central to the pathophysiology of AD. In the case of amyloid plaque formation, mutations in APP, PS1 or PS2 consistently alter the proteolytic processing of APP so as to enhance Αβ 1-42 formation.
The initial processing of APP by β-secretase results in a soluble N-APP which has recently been implicated in neuronal cell death through a pathway independent of amyloid plaque formation. N-APP is involved in normal pruning of neurons in early development in which relatively unused neurons and their nerve-fiber connections (axons) wither and degenerate. Recently, however, it has been shown that N- APP binds to and activates the apoptotic death receptor 6 (DR6) in vitro which is expressed on axons in response to trophic factor (e.g. nerve growth factor) withdrawal resulting in axonal degeneration. The aging process can lead to a reduction in the levels of growth factors in certain areas of the brain and/or the ability to sense growth factors. This in turn would lead to the release of N-APP fragment by cleavage of APP on neuronal surfaces, activating nearby DR6 receptors to initiate the axonal shrinkage and neuronal degeneration of Alzheimer's.
See also, Rauk, Arvi. "The chemistry of Alzheimer's disease." Chem. Soc. Rev. 38 (2009): p. 2698-2715; Vassar, Robert, Dora M. Kovacs, Riqiang Yan and Philip C. Wong. "The · -Secretase Enzyme BACE in Health and Alzheimer's Disease: Regulation, Cell Biology, Function, and Therapeutic Potential. J.
Neurosci. 29(41) (2009): 12787-12794; and Silvestri, Romano. "Boom in the Development of Non-
Peptidic β-Secretase (BACE1) Inhibitors for the Treatment of Alzheimer's Disease." Medicinal Research Reviews. Vol. 29, No. 2 (2009): p. 295-338.
Since β-secretase cleavage of APP is essential for both amyloid plaque formation and DR6-mediated apoptosis, it is a key target in the search for therapeutic agents for treating AD. SUMMARY OF THE INVENTION
In one aspect of the present invention there is provided novel compounds having the general Formula (I)
Figure imgf000004_0001
I
wherein,
X is CR3 or N;
Y is CR4R4';
Zi and Z2 are independently CR3 or N;
Ri is H, alkyl, carbocyclylalkyl or heterocyclylalkyl wherein said akyl, carbocyclylalkyl and
heterocyclylalkyl are optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl;
R2 and R2' 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; or
R2 and R2' together form a 3 to 6 member carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl;
R3 is H, halogen, amino, hydroxy, 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 and haloalkyl;
R4 and R4' are independently H, 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 and haloalkyl; or
PM and R4' together form a 3 to 6 member carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl; and
m is an integer from 0 to 4.
In another aspect of the present invention there is provided compounds having the general Formula II:
Figure imgf000005_0001
II
and stereoisomers, diastereomers, enantiomers, tautomers and pharmaceutically acceptable salts thereof, wherein X], X2, X3, Re, R7, R7', Rs, R«', and R9 are as defined herein.
In another aspect of the invention, there are provided compositions comprising compounds of the invention I and a carrier, diluent or excipient. In another aspect of the invention, there is provided a method of inhibiting cleavage of APP by β-secretase in a mammal comprising administering to said mammal an effective amount of a compound of the invention.
In another aspect of the invention, there is provided a method for treating a disease or condition mediated by the cleavage of APP by β-secretase in a mammal, comprising administering to said mammal an effective amount of a compound of I.
In another aspect of the invention, there is provided a use of a compound of the invention in the manufacture of a medicament for the treatment of neurodegenerative diseases such as Alzheimer's Disease.
In other aspects of the invention, there are provided processes for preparing compounds of the invention and intermediates therefor. DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
"Acyl" means a carbonyl containing substituent represented by the formula -C(0)-R in which R is H, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein. Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g. benzoyl), and heteroaroyl.
"Alkoxycarbonyl" means the group -C(=0)OR in which R is alkyl. A particular alkoxycarbonyl group is C1-C6 alkoxycarbonyl, wherein the R group is Q-C6 alkyl.
"Alkyl" means a branched or unbranched, saturated or unsaturated (i.e. alkenyl, alkynyl) aliphatic hydrocarbon group, having up to 12 carbon atoms unless otherwise specified. When used as part of another term, for example "alkylamino", the alkyl portion may be a saturated hydrocarbon chain, however also includes unsaturated hydrocarbon carbon chains such as "alkenylamino" and "alkynylamino.
Examples of particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n- heptyl, 3-heptyl, 2-methylhexyl, and the like. The terms "lower alkyl" "C1-C4 alkyl" and "alkyl of 1 to 4 carbon atoms" are synonymous and used interchangeably to mean methyl, ethyl, 1 -propyl, isopropyl, cyclopropyl, 1 -butyl, sec-butyl or t-butyl. In other examples, the alkyl group is Ci-C2, Q-C3, C1-C4, CrC5 or C C6. Unless specified otherwise, substituted alkyl groups contain one, two, three or four substituents which may be the same or different. Alkyl substituents are, unless otherwise specified, halogen, amino, hydroxyl, protected hydroxyl, mercapto, carboxy, alkoxy, nitro, cyano, amidino, guanidino, urea, sulfonyl, sulfinyl, aminosulfonyl, alkylsulfonylamino, arylsulfonylamino, aminocarbonyl, acylamino, alkoxy, acyl, acyloxy, a carbocycle and a heterocycle. Examples of the above substituted alkyl groups include, but are not limited to; cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, carboxyethyl, carboxypropyl, alkyloxycarbonylmethyl,
allyloxycarbonylaminomethyl, carbamoyloxymethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n- butyl), 2-amino(iso-propyl), 2-carbamoyloxyethyl and the like. The alkyl group may also be substituted with a carbocycle group. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl groups, as well as the corresponding -ethyl, -propyl, -butyl, -pentyl, -hexyl groups, etc. Substituted alkyls include substituted methyls e.g. a methyl group substituted by the same substituents as the "substituted Cn-Cm alkyl" group. Examples of the substituted methyl group include groups such as hydroxymethyl, protected hydroxymethyl (e.g. tetrahydropyranyloxymethyl), acetoxymethyl,
carbamoyloxymethyl, trifluoromethyl, chloromethyl, carboxymethyl, bromomethyl and iodomethyl. The terms "alkenyl" and "alkynyl" also include linear or branched-chain radicals of carbon atoms.
"Amidine" means the group -C(NH)-NHR in which R is H, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein. A particular amidine is the group -NH-C(NH)-NH2.
"Amino" means primary (i.e. -NH2) , secondary (i.e. -NRH) and tertiary (i.e. -NRR) amines in which R is H, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein. Particular secondary and tertiary amines are alkylamine, dialkylamine, arylamine, diarylamine, aralkylamine and diaralkylamine wherein the alkyl is as herein defined and optionally substituted. Particular secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine, dipropylamine and disopropylamine.
"Amino-protecting group" as used herein refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group. Particular amino protecting groups are acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc"), benzyloxycarbonyl ("CBz") and 9-fluorenylmethyleneoxycarbonyl ("Fmoc"). Further examples of these groups are found in Greene, T. W. and Wuts, P. G. M. Protective Groups in Organic Synthesis. 2nd ed., John Wiley & Sons, Inc., New York, NY, 1991, chapter 7; E. Haslam, Protective Groups in Organic Chemistry. McOmie, J. G. W. Ed., Plenum Press, New York, NY, 1973, Chapter 5, and Greene, T.W. Protective Groups in Organic Synthesis. 1st ed. New York: John Wiley and Sons, New York, NY, 1981. The term "protected amino" refers to an amino group substituted with one of the above amino-protecting groups. For any protecting group, see also, T. W. Greene, et al. Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006. "Aryl" when used alone or as part of another term means a carbocyclic aromatic group whether or not fused having the number of carbon atoms designated or if no number is designated, up to 14 carbon atoms. Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e.g. Dean, J. A., Lange's Handbook of Chemistry 13th ed. New York: McGraw-Hill, 1985, Table 7- 2). A particular aryl is phenyl. Substituted phenyl or substituted aryl means a phenyl group or aryl group substituted with one, two, three, four or five substituents, for example 1-2, 1-3 or 1-4 substituents chosen, unless otherwise specified, from halogen (F, CI, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (for example CrC6 alkyl), alkoxy (for example CrC6 alkoxy), benzyloxy, carboxy, protected protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, ar lsulfonylamino, arylsulonylaminoalkyl, heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl, or other groups specified. One or more methyne (CH) and/or methylene (C¾) groups in these substituents may in turn be substituted with a similar group as those denoted above. Examples of the term "substituted phenyl" includes but is not limited to a mono- or di(halo)phenyl group such as 2- chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4- dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4- fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4- hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenyl group, for example, 4- cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2- methylphenyl, 4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy- 4-(l-chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3- ethoxy-4-methoxyphenyl and the like; 3- or 4- trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such as 4-carboxyphenyl; a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3 -(protected hydroxymethyl)phenyl or 3,4- di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; a mono- or di(N- (methylsulfonylamino))phenyl such as 3-(N-methylsulfonylamino))phenyl; disubstituted phenyl groups such as 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2- hydroxyphenyl, 3-hydroxy-4-nitrophenyl and 2-hydroxy-4-chlorophenyl; trisubstituted phenyl groups such as 3-methoxy-4-benzyloxy-6-methylsulfonylamino and 3-methoxy-4-benzyloxy-6- phenylsulfonylamino; tetrasubstituted phenyl groups such as 3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. Particular substituted phenyl groups include the 2-chlorophenyl, 2-aminophenyl, 2- bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4- benzyloxyphenyl, 3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(l- chloromethyl)benzyloxy-phenyl, 3-methoxy-4-(l-chloromethyl)benzyloxy -6- methyl sulfonyl aminophenyl groups. Fused aryl rings may also be substituted with any, for example 1, 2 or 3, of the substituents specified herein in the same manner as substituted alkyl groups.
"Carbocyclyl", "carbocyclic", "carbocycle" and "carbocyclo" alone and when used as a moiety in a complex group such as a carbocycloalkyl group, refer to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms, for example 3 to 7 carbon atoms or 3 to 6 carbon atoms, which may be saturated or unsaturated, aromatic or non-aromatic. Particular saturated carbocyclic groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. A particular saturated carbocycle is cyclopropyl. Another particular saturated carbocycle is cyclohexyl. Particular unsaturated carbocycles are aromatic e.g. aryl groups as previously defined, for example phenyl. The terms "substituted carbocyclyl", "carbocycle" and "carbocyclo" mean these groups substituted by the same substituents as the
"substituted alkyl" group.
"Carboxy-protecting group" as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include 4-nitroben2yl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6- trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, alkyl such as t-butyl or t-amyl, trityl, 4- methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t- butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl, beta-(di(n- butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1- (trimethylsilylmethyl)prop-l-en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not to subject a carboxy-protected molecule to strong nucleophilic bases, such as lithium hydroxide or NaOH, or reductive conditions employing highly activated metal hydrides such as LiAlRt. Such harsh removal conditions are also to be avoided when removing amino-protecting groups and hydroxy-protecting groups, discussed below. Particular carboxylic acid protecting groups are the alkyl (e.g. methyl, ethyl, t-butyl), allyl, benzyl and p- nitrobenzyl groups. Further examples of carboxy-protecting groups are found in Greene, T. W. and Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed., New York, John Wiley & Sons, Inc., 1991 , Chapter 5; Haslam, E. Protective Groups in Organic Chemistry. New York, Plenum Press, 1973, Chapter 5; and Greene, T.W. Protective Groups in Organic Synthesis, New York, John Wiley and Sons, 1981, Chapter 5. The term "protected carboxy" refers to a carboxy group substituted with one of the above carboxy-protecting groups. "Comprise" and "comprising" when used herein are non-limiting in scope i.e. are intended to specify the presence of the stated features, integers, components, or steps, but do not preclude the presence or addition such features, integers, components, steps, or groups thereof.
"Guanidine" means the group -NH-C(NH)-NHR in which R is H, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein. A particular guanidine is the group -NH-C(NH)-NH2. "Hydroxy-protecting group" as used herein refers to a derivative of the hydroxy group commonly employed to block or protect the hydroxy group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include tetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silylethers (e.g. TBS, TBDPS) groups. Further examples of these groups are found in Greene, T. W., and Wuts, P. G. M., Protective Groups in Organic Synthesis, 2nd ed., New York, John Wiley & Sons, Inc., 1991, Chapters 2-3; Haslam, E., Protective Groups in Organic Chemistry, New York, Plenum Press, 1973, Chapter 5; and Greene, T.W., Protective Groups in Organic Synthesis, New York, John Wiley and Sons, 1981. The term "protected hydroxy" refers to a hydroxy group substituted with one of the above hydroxy-protecting groups.
"Heterocyclic group", "heterocyclic", "heterocycle", "heterocyclyl", or "heterocyclo" alone and when used as a moiety in a complex group such as a heterocycloalkyl group, are used interchangeably and refer to any mono-, bi-, or tricyclic, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic ring having the number of atoms designated, generally from 5 to about 14 ring atoms, where the ring atoms are carbon and at least one heteroatom (nitrogen, sulfur or oxygen), for example 1 to 4 heteroatoms. The sulfur heteroatoms may optionally be oxidized (e.g. SO, SO2), and any nitrogen heteroatom may optionally be quaternized. Typically, a 5-membered ring has 0 to 2 double bonds and 6- or 7-membered ring has 0 to 3 double bonds. In a particular embodiment, heterocyclic groups are four to seven membered cyclic groups containing one, two or three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Particular non-aromatic heterocycles are morpholinyl (morpholino), pyrrolidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothietanyl, aziridinyl, azetidinyl, 1 -methyl-2-pyrrolyl, piperazinyl and piperidinyl. A
"heterocycloalkyl" group is a heterocycle group as defined above covalently bonded to an alkyl group as defined above. Particular 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, in particular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular l,3,4-thiadiazol-5-yl and l,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as l,3,4-oxadiazol-5-yl, and l,2,4-oxadiazol-5-yl. Particular 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as l,3,4-triazol-5-yl; 1,2,3- triazol-5-yl, l,2,4-triazol-5-yl, and tetrazolyl, such as lH-tetrazol-5-yl. Particular benzo-fused 5- membered heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Particular 6- membered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as l,3,4-triazin-2-yl and l,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2- yl, pyrimid-4-yl, pyridazinyl and the l,3,4-triazin-2-yl groups, are a particular group. Substituents for "optionally substituted heterocycles", and further examples of the 5- and 6-membered ring systems discussed above can be found in W. Druckheimer et al, U.S. Patent No. 4,278,793. In a particular 4,278,793. In a particular embodiment, such optionally substituted heterocycle groups are substituted with hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino and guanidino. "Heteroaryl" alone and when used as a moiety in a complex group such as a heteroaralkyl group, refers to any mono-, bi-, or tricyclic aromatic ring system having the number of atoms designated where at least one ring is a 5-, 6- or 7-membered ring containing from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur, and in a particular embodiment at least one heteroatom is nitrogen (Lange 's Handbook of Chemistry, supra). In a particular embodiment, the heteroaryl is a 5-membered aromatic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulfur. Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to a benzene ring. Particular heteroaryls incorporate a nitrogen or oxygen heteroatom. In a particular embodiment, the heteroaryl is a 5-membered aromatic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulfur. In a particular embodiment, the heteroaryl group is a 6- membered aromatic ring containing one, two or three heteroatoms selected from nitrogen, oxygen and sulfur. The following are examples of the heteroaryl groups (substituted and unsubstituted): thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, tetrazolo[l,5-b]pyridazinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl. In a particular embodiment the heteroaryl group may be: l,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-l,3-thiazol-2-yl, 4- (carboxymethyl)-5-methyl-l,3-thiazol-2-yl sodium salt, l,2,4-thiadiazol-5-yl, 3-methyl-l,2,4-thiadiazol- 5-yl, l,3,4-triazol-5-yl, 2-methyl-l,3,4-triazol-5-yl, 2-hydroxy-l,3,4-triazol-5-yl, 2-carboxy-4-methyl- l,3,4-triazol-5-yl sodium salt, 2-carboxy-4-methyl-l,3,4-triazol-5-yl, l,3-oxazol-2-yl, l,3,4-oxadiazol-5- yl, 2-methyl-l,3,4-oxadiazol-5-yl, 2-(hydroxymethyl)-l,3,4-oxadiazol-5-yl, 1 ,2,4-oxadiazol-5-yl, 1,3,4- thiadiazol-5-yl, 2-thiol-l,3,4-thiadiazol-5-yl, 2-(methylthio)-l,3,4-thiadiazol-5-yl, 2-am ino- 1,3,4- thiadiazol-5-yl, 1 H-tetrazol-5-yl, 1 -methyl- 1 H-tetrazol-5-yl, 1 -( 1 -(dimethylamino)eth-2-yl)- 1 H-tetrazol- 5-yl, l-(carboxymethyl)-lH-tetrazol-5-yl, l-(carboxymethyl)-lH-tetrazol-5-yl sodium salt, 1-
(methylsulfonic acid)-lH-tetrazol-5-yl, l-(methylsulfonic acid)-lH-tetrazol-5-yl sodium salt, 2-methyl- lH-tetrazol-5-yl, l,2,3-triazol-5-yl, 1 -methyl- 1, 2,3 -triazol-5-yl, 2-methyl-l,2,3-triazol-5-yl, 4-methyl- l,2,3-triazol-5-yl, pyrid-2-yl N-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl, 1- methylpyrid-2-yl, 1 -methylpyrid-4-yl, 2-hydroxypyrimid-4-yl, 1 ,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as- triazin-3-yl, 1 ,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy- astriazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2- methyl-astriazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5- yl, 2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-as-triazin-3-yl, 2,5-dihydro-
5- oxo-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl, tetrazolo[l,5-b]pyridazin-
6- yl and 8-aminotetrazolo[l,5-b]-pyridazin-6-yl. An alternative group of "heteroaryl" includes; 4- (carboxymethyl)-5-methyl- 1 ,3-thiazol-2-yl, 4-(carboxymethyl)-5 -methyl- 1 ,3-thiazol-2-yl sodium salt, l ,3,4-triazol-5-yl, 2-methyl-l,3,4-triazol-5-yl, lH-tetrazol-5-yl, 1 -methyl- lH-tetrazol-5-yl, 1-(1-
(dimethylamino)eth-2-yl)- 1 H-tetrazol-5-yl, 1 -(carboxymethyl)- 1 H-tetrazol-5-yl, 1 -(carboxymethyl)- 1 H- tetrazol-5-yl sodium salt, l-(methylsulfonic acid)-lH-tetrazol-5-yl, l-(methylsulfonic acid)-lH-tetrazol-
5- yl sodium salt, l,2,3-triazol-5-yl, l,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, 1,4,5,6- tetrahydro-4-(2-formylmethyl)-5 ,6-dioxo-as-triazin-3 -yl, 2,5 -dihydro-5 -oxo-6-hydroxy-2-methy 1-as- triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, tetrazolo[l,5-b]pyridazin-
6- yl, or 8-aminotetrazolo[l,5-b]pyridazin-6-yl. Heteroaryl groups are optionally substituted as described for heterocycles.
"Inhibitor" means a compound which reduces or prevents the enzymatic cleavage of APP by β-secretase. Alternatively, "inhibitor" means a compound which prevents or slows the formation of beta-amyloid plaques in mammalian brain. Alternatively, "inhibitor" means a compound that prevents or slows the progression of a disease or condition associated with β-secretase enzymatic activity e.g. cleavage of APP. Alternatively, "inhibitor" means a compound which prevents Alzheimer's Disease. Alternatively, "inhibitor" means a compound which slows the progression of Alzheimer's Disease or its symptoms.
"Optionally substituted" unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g. 0, 1, 2, 3 or 4) of the substituents listed for that group in which said substituents may be the same or different. In a particular embodiment, an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents.
"Pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
"Pharmaceutically acceptable salts" include both acid and base addition salts. "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.
"Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N- ethylpiperidine, polyamine resins and the like. Particularly organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine.
"Sulfanyl" means -S-R group in which R is alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein. Particular sulfanyl groups are alkylsulfanyl (i.e. -S(¾-alkyl), for example
methylsulfanyl; arylsulfanyl, for example phenylsulfanyl; aralkylsulfanyl, for example benzylsulfanyl.
"Sulfinyl" means -SO-R group in which R is H, alkyl, a carbocycle, a heterocycle, carbocycle- substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein. Particular sulfonyl groups are alkylsulfinyl (i.e. -SO-alkyl), for example methylsulfinyl; arylsulfinyl, for example phenylsulfinyl; aralkylsulfinyl, for example benzylsulfinyl.
"Sulfonyl" means a -SO2-R group in which R is H, alkyl, a carbocycle, a heterocycle, carbocycle- substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein. Particular sulfonyl groups are alkylsulfonyl (i.e. -S02-alkyl), for example methylsulfonyl; arylsulfonyl, for example phenylsulfonyl; aralkylsulfonyl, for example benzylsulfonyl.
The terms "treat" or "treatment" refer to therapeutic, prophylactic, palliative or preventative measures. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.
The phrases "therapeutically effective amount" or "effective amount" mean an amount of a compound described herein that, when administered to a mammal in need of such treatment, sufficient to (i) treat or prevent the particular disease, condition, or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art. The "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit cleavage of APP by β-secretase, for example by 10% or greater in situ. In a particular embodiment an "effective amount" of the compound inhibits cleavage of APP by β- secretase by 25% or greater in situ. In a particular embodiment the effective amount inhibits cleavage of APP by β-secretase by 50% or greater in situ. In a particular embodiment the effective amount inhibits cleavage of APP by β-secretase by 70% or greater in situ. In a particular embodiment the effective amount inhibits cleavage of APP by β-secretase by 80% or greater in situ. In a particular embodiment the effective amount inhibits cleavage of APP by β-secretase by 90% or greater in situ. Such amount may be below the amount that is toxic to normal cells, or the mammal as a whole. Alternatively, an "effective amount" is the amount of compound necessary to reduce A-beta levels in plasma or cerebrospinal fluid of a mammal, for example, by 10% or greater. In a particular embodiment, an "effective amount" is the amount of compound necessary to reduce A-beta levels in plasma or cerebrospinal fluid of a mammal by 25% or greater. In a particular embodiment, an "effective amount" is the amount of compound necessary to reduce A-beta levels in plasma or cerebrospinal fluid of a mammal by 50% or greater. In a particular embodiment, an "effective amount" is the amount of compound necessary to reduce A-beta levels in plasma or cerebrospinal fluid of a mammal by 75% or greater. Alternatively, an "effective amount" of the compound may be the amount of compound necessary to slow the progression of AD or symptoms thereof.
Abbreviations are sometimes used in conjunction with elemental abbreviations and chemical structures, for example, methanol ("MeOH") or ethanol ("EtOH"). Additional abbreviations used throughout the application may include, for example, benzyl ("Bn"), phenyl ("Ph") and acetate ("Ac").
The present invention provides novel compounds having the general Formula I:
Figure imgf000015_0001
I
wherein X, Y, Z\, Z2, Ri, R2, R2', R3, R4, R4' a d m are as defined herein.
X is CR3 or N. In a particular embodiment, X is N. In a particular embodiment, X is CR3. In a particular embodiment X is CH.
Y is CR4R4' . In a particular embodiment Y is CH2. In a particular embodiment, Y is CR4R4'.
Z] and Z2 are independently CR3 or N. In a particular embodiment, Zj and Z2 are each CR3. In a particular embodiment, Z\ is N and Z2 is CR3. In a particular embodiment, Zj and Z2 are each CR3. In a particular embodiment, Zi is CR3 and Z2 is N. In a particular embodiment, Zi and Z2 are each N. Ri is H, alkyl, carbocyclylalkyl or heterocyclylalkyl wherein said akyl, carbocyclylalkyl and
heterocyclylalkyl are optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl. In an embodiment, R is H, alkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl. In a particular embodiment, Ri is H. In a particular embodiment, Ri is carbocyclylalkyl. In a particular embodiment Ri is benzyl. In a particular embodiment Ri is heterocyclylalkyl optionally substituted with acyl. In a particular embodiment Rj is pyrid-2-ylmethyl. In a particular embodiment, Ri is pyrid-3- ylmethyl. In a particular embodiment, Ri is pyrid-4-ylmethyl. In a particular embodiment Ri is N-acetyl- 4-piperidin-4-ylmethyl. In a particular embodiment, Ri is alkyl. In a particular embodiment, R] is methyl. In a particular embodiment, R] is pyridyl. In a particular embodiment, R] is haloalkyl. In a particular embodiment, Ri is -CH2CF3. In a particular embodiment, Rj is heteroaryl. In a particular embodiment, Ri is 2-pyridyl.
R2 and R2' 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. In an embodiment, R2 and R2' 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 and haloalkyl. In a particular embodiment, R2 and R2' are independently alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl. In a particular embodiment, R2 is alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl and R2' is H. In an embodiment, R2 and R2' are independently alkyl and aralkyl. In an embodiment, R2 is benzyl optionally substituted with halogen, alkoxy and haloalkoxy while R2' is alkyl. In an embodiment, R2 is o- methoxybenzyl while R2' is methyl. In an embodiment, R2 is w-methoxybenzyl while R2' is methyl. In an embodiment, R2 is, /?-methoxybenzyl while R2' is methyl. In an embodiment, R2 is o- difluoromethoxybenzyl while R2' is methyl. In an embodiment, R2 is m-difluoromethoxybenzyl while R2' is methyl. In an embodiment, R2 is 7-difluoromethoxybenzyl while R2' is methyl. In an embodiment, R2 is 3 -fluoro- »-methoxy benzyl while R2' is methyl. In an embodiment, R2 and R2' are independently alkyl and heteroaralkyl. In an embodiment, R2 is pyrid-2-yl while R2' is methyl. In a particular embodiment, R is methyl and R2' is H. In a particular embodiment, R2 is 2-propyl and R2' is H. In a particular embodiment, R2 is t-butyl and R2' is H. In a particular embodiment, R2 is cyclopropyl and R2' is H. In a particular embodiment, R2 is benzyl and R2' is H. In a particular embodiment, R2 is 3-pyridinyl and R2' is H. In a particular embodiment, R2 and R2' are both H. In a particular embodiment, R2 and R2' are both methyl. In a particular embodiment, R2 and R2' are both CH2F.
Alternatively, R2 and R2' together form a 3 to 6 member carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl. In a particular
embodiment, R2 and R2' together form a cycloalkyl ring. In a particular embodiment, R2 and R2' together form a cyclopropyl ring. In a particular embodiment, R2 and R2' together form a cyclobutyl ring. In a particular embodiment, R2 and R2' together form a cyclopentyl ring. In a particular embodiment, R2 and R2' together form a heterocycle. In a particular embodiment, R2 and R2' together form a 4-pyranyl ring. In a particular embodiment, R2 and R2' together form a 4-piperidinyl ring optionally N-substituted with alkyl (e.g. Me) or haloalkyl (e.g. -CH2CHF2).
R3 is H, halogen, amino, hydroxy, 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 and haloalkyl. In an embodiment, R3 is H, 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 halogen, hydroxyl, amino and haloalkyl. In a particular embodiment, R3 is halogen, cyano, alkyl, alkoxy, haloalkyl or haloalkoxy. In a particular embodiment, R3 is F, CI, CN, -CCH, -CF3, -0-CHF2, -OCH3. In a particular embodiment, R3 is CI. In a particular embodiment, R3 is cyano. In a particular embodiment, R3 is -CCH. In a particular
embodiment, R3 is -OCH3. In a particular embodiment, R3 is -0-CHF2. In a particular embodiment, R3 is is -CF3.
R4 and R4' are independently H, 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. In an embodiment, R and R4' are independently H, 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 halogen, hydroxyl, amino and haloalkyl. In an embodiment, R4 and R4' are independently alkyl substituted with a heterocycle optionally substituted with hydroxy, halogen, amino cyano, nitro alkyl, alkoxy, acyl and haloalkyl. In an embodiment, R4 is N-(2,2,2-trifluoroethyl)-piperidin- 4-ylmethyl while R4' is H. In a particular embodiment, R4 and R4' are independently H or alkyl. In a particular embodiment, R4 and R4' are both Me. In a particular embodiment, R and R4' are independently H or halogen. In a particular embodiment, R4 and R4' are both H. In a particular embodiment, R4 and RV are both F. In a particular embodiment, R is F and R4' is H. In a particular embodiment, at least one of R.2, R.2', R , R ' is other than hydrogen.
Alternatively, R4 and R4' together form a 3 to 6 member carbocycle or heterocycle optionally substituted with hydroxyl, halogen, amino and haloalkyl. In a particular embodiment, R and RV together form a carbocycle. In a particular embodiment, R4 and R together form a cycloalkyl ring. In a particular embodiment, R and RV together form a propyl ring. In a particular embodiment, R4 and RV together form a butyl ring. In a particular embodiment, R4 and RV together form a pentyl ring. In a particular embodiment, R4 and RV together form a hexyl ring. In a particular embodiment, R4 and RV together form a heterocycle. In a particular embodiment, R4 and RV together form a 4-pyranyl ring. In a particular embodiment, R4 and RV together form a 4-piperidinyl ring optionally N-substituted with alkyl (e.g. Me) or haloalkyl (e.g. -CH2CHF2).
'm' is an integer from 0 to 4. In an embodiment, m is 0 to 3. In another embodiment, m is 0 to 2. In a particular embodiment, m is 0. In another particular embodiment, m is 1. In another particular embodiment, m is 2. In another particular embodiment, m is 3. In another particular embodiment, m is 4.
In another embodiment of the invention, there are provided compounds of Formula II:
Figure imgf000018_0001
II
wherein,
X] and X2 are independently selected from CRio or N, and X3 is CR5 or N, wherein only one of Xi, X2 or X3 may be N;
R5 is hydrogen or halogen;
R$ is hydrogen, benzyl or C1-C3 alkyl optionally substituted with Ra;
R7 and RT are independently selected from hydrogen, halogen and Ci-Ce alkyl optionally substituted with Rb„ or
R7 and R7< together with the atom to which they are attached form cyclopropyl,
Rg and Rg> are independently selected from hydrogen, C C6 alkyl optionally substituted with Rb, C3-C6 carbocyclyl, 4 to 6 membered heterocyclyl, phenyl, 5 to 6 membered heteroaryl, wherein the carbocyclyl, heterocyclyl, phenyl or heteroaryl are optionally substituted with R(, or
Rg and R together with the atom to which they are attached form a 3 to 6 membered carbocyclyl or heterocyclyl optionally substituted with C1-C3 alkyl optionally substituted with halogen; wherein only one of R7 and R7> or Rg and R may together form a ring;
R is hydrogen, halogen, CN, Ci-Cg alkyl optionally substituted with Rc, Q-Cg alkenyl optionally
substituted with Rc, C]-C3 alkynyl optionally substituted with Rc, CrC8 alkoxy optionally substituted with Rc, phenyl optionally substituted with Rd, a 5-6 membered heteroaryl optionally substituted with Re, a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with Rf, a 3-
6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg, a 9-10 membered bicyclic heteroaryl optionally substituted with ¾, phenylamino, or phenoxy optionally substituted with Rj;
Rio is hydrogen, halogen or methyl;
each Ra is independently selected from OH, OCH3, halogen, a 5-6 membered heteroaryl, and a 3-6
membered heterocyclyl optionally substituted with C1-C3 alkyl optionally substituted with oxo; each ¾ is independently selected from halogen, hydroxyl, methoxy, oxo,
Figure imgf000018_0002
C1-C3 alkyl optionally substituted with halogen or OH, -0(Q-C3 alkyl) optionally substituted with halogen or OH, phenyl, C3-C6 carbocyclyl, a 4 to 6 membered heterocyclyl, a 5 to 6 membered heteroaryl, -O(phenyl) and - S(phenyl), wherein the phenyl, carbocyclyl, heterocyclyl and heteroaryl are optionally substituted with halogen, CN, OH, OCH3, Ci-C6 alkyl and Ci-C6 alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen, OH or OC¾; each Rc is independently selected from halogen, CN, OH, OCH3, Q-C3 alkyl optionally substituted with halogen or OH, -0(CrC3 alkyl) optionally substituted with halogen or OH, C3-Q carbocyclyl and phenyl optionally substituted with halogen, OH or OCH3;
each is independently selected from halogen, CN, cyclopropyl, ORj, SRk, NRiR„„ Q-Cg alkyl
optionally substituted with R„, -0(CrC8 alkyl) optionally substituted with R„, CrC8 alkynyl optionally substituted with ^;
each Re is independently selected from halogen, CN, oxide, NH2, cyclopropyl, ORp, SR^, C C6 alkyl optionally substituted with halogen and ORq, and Q-C6 alkynyl optionally substituted with OR^ each Rf is independently selected from halogen, oxo, Q-Ce alkyl optionally substituted with halogen, and C C6 alkoxycarbonyl;
each Rg is independently selected from halogen, OH, OCH3 and C]-C6 alkyl optionally substituted with halogen;
each Rj, is independently selected from halogen and C1-C6 alkyl;
each Rj is independently selected from halogen and benzyl;
each Rj is independently selected from hydrogen and Q-Ce alkyl optionally substituted with halogen, CN, OH, OCH3 or phenyl;
each Rk is Q-C6 alkyl;
each Ri and n is independently selected from hydrogen and Ci-C6 alkyl;
each R, is independently selected from halogen, OH, OCH3, CN and phenyl;
each R,, is independently selected from halogen and C3-C6 carbocyclyl;
each Rp is independently selected from hydrogen, Q-C alkyl and phenyl;
each R, is halogen;
each Rg is independently selected from halogen and cyclopropyl; and
each Rt is independently selected from halogen, RRm, cyclopropyl, CrC3 alkyl optionally substituted with halogen or OH, and -0(C C3 alkyl) optionally substituted with halogen or OH.
In certain embodiments;
R9 is hydrogen, halogen, CN, CrC8 alkyl optionally substituted with Rc, Ci-C8 alkenyl optionally substituted with Rc, CrC8 alkynyl optionally substituted with R^, phenyl optionally substituted with Rd, a 5-6 membered heteroaryl optionally substituted with R,, a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with Rf, a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg, a 9-10 membered bicyclic heteroaryl optionally substituted with Rj,, phenylamino, or phenoxy optionally substituted with R^;
each Rj, is independently selected from halogen, oxo, NRiRm, C1-C3 alkyl optionally substituted with halogen or OH, -0(CrC3 alkyl) optionally substituted with halogen or OH, phenyl, C3-C¾
carbocyclyl, a 4 to 6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the phenyl, carbocyclyl, heterocyclyl and heteroaryl are optionally substituted with halogen, CN, OH, OCH3 and C C6 alkyl optionally substituted with halogen, OH or OCH3; and
each Re is independently selected from halogen, CN, NH2, cyclopropyl, ORp, SRk, Q-C6 alkyl optionally substituted with halogen and ORq, and Q-Q alkynyl optionally substituted with ORs.
In another embodiment of the invention, there are provided compounds of Formula Ila:
Figure imgf000020_0001
Ila
wherein,
Xi and X2 are independently selected from CR10 or N, wherein only one of X] and X2 may be N;
R5 is hydrogen or halogen;
Re is hydrogen, benzyl or Q-C3 alkyl optionally substituted with Ra;
R7 and RT are independently selected from hydrogen, halogen and methyl, or
R7 and R7- together with the atom to which they are attached form cyclopropyl,
Rg and Rg' are independently selected from hydrogen, cyclopropyl or C1-C6 alkyl optionally substituted with R , or
Rg and Rg- together with the atom to which they are attached form a 3 to 6 membered carbocyclyl or heterocyclyl; wherein only one of R7 and R7' or Rg and Rg- may together form a ring;
R9 is hydrogen, halogen, CN, C Cg alkyl optionally substituted with Rc, Q-Cg alkenyl optionally
substituted with Rc, CrCg 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 Rf, a 3- 6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg, a 9-10 membered bicyclic heteroaryl optionally substituted with Rh, phenylamino, or phenoxy optionally substituted with R;;
Rio is hydrogen, halogen or methyl;
each Ra is independently selected from OH, OCH3 and halogen;
each Rb 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
C6 alkoxy, wherein the alkoxy is optionally substituted with halogen;
each Rc is independently selected from halogen, CN, OH, OCH3, cyclopropyl and phenyl optionally substituted with halogen, OH or OCH3;
each ¾ is independently selected from halogen, CN, cyclopropyl, ORj, SRk, NRR,,,, CrC8 alkyl
optionally substituted with R„, CrCg alkynyl optionally substituted with R,,;
each Re is independently selected from halogen, CN, oxide, NH2, cyclopropyl, ORp, C C6 alkyl optionally substituted with OR,, and Ci-C6 alkynyl optionally substituted with ORs;
each Rf is independently selected from halogen, oxo, Q-Q alkyl, and Ci-C6 alkoxycarbonyl;
each Rg is independently selected from halogen and C C6 alkyl;
each Rh is independently selected from halogen and Q-C6 alkyl;
each Rj is independently selected from halogen and ben2yl;
each Rj is independently selected from hydrogen and C C6 alkyl optionally substituted with halogen or phenyl;
each Rk is C C6 alkyl;
each R) and is independently selected from hydrogen and Q-C6 alkyl;
each R„ is independently selected from halogen, OH, OCH3 and phenyl;
each is independently selected from halogen and C3-C6 carbocyclyl;
each Rp is independently selected from hydrogen, CrC6 alkyl and phenyl;
each Rq is halogen; and
each Rj is independently selected from halogen and cyclopropyl. In certain embodiments:
R9 is hydrogen, halogen, CN, CrC8 alkyl optionally substituted with R^ Q-Cg alkenyl optionally substituted with Rc, C C8 alkynyl optionally substituted with R^ 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 Rf, a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg, a 9-10 membered bicyclic heteroaryl optionally substituted with Rh, phenylamino, or phenoxy optionally substituted with R;
each Rb is independently selected from halogen, phenyl, cyclopropyl and a 4-6 membered heterocyclyl; and
each Re is independently selected from halogen, CN, NH2, cyclopropyl, ORp, CrC6 alkyl optionally substituted with ORq, and C C6 alkynyl optionally substituted with ORs.
In certain embodiments, X] and X2 are independently selected from CR]0 or N, wherein only one of Xi and X2 may be N. In certain embodiments, Xi is N and X2 is CR10. In certain embodiments, X2 is N and Xi is CR10. In certain embodiments, Xi and X2 are CR10. In certain embodiments, Rio is hydrogen, halogen or methyl.
In certain embodiments, X3 is CR5 or N. In certain embodiments, X3 is CR5. In certain embodiments, X3 Only one of Xl5 X2 or X3 may be N. In certain embodiments, Xi is N, X2 is CR)0 and X3 is CR5. In certain embodiments, X2 is N, Xi is CR10 and X3 is CR5. In certain embodiments, X3 is N, and Xi and X2 are CRio. In certain embodiments, Xi and X2 are CR10, and X3 is CR5.
In certain embodiments, X2 is CRio, wherein R10 is halogen. In certain embodiments, X2 is CRio, wherein
In certain embodiments, R5 is hydrogen or halogen. In certain embodiments, R5 is hydrogen or F. In a certain embodiment, R5 is hydrogen.
In certain embodiments, Rf, is selected from hydrogen, benzyl or Ci-C3 alkyl optionally substituted with Ra. In certain embodiments, R$ is selected from benzyl or C C3 alkyl optionally substituted with R^. In certain embodiments, each Ra is independently selected from OH, OCH3, halogen, a 5-6 membered heteroaryl, and a 3-6 membered heterocyclyl optionally substituted with C1-C3 alkyl optionally substituted with oxo. In certain embodiments, Ra is a 5-6 membered heteroaryl, wherein the heteroaryl contains one, two or three heteroatoms selected from oxygen, nitrogen and sulfur. In certain embodiments, Ra is a 5-6 membered heteroaryl, wherein the heteroaryl is pyridinyl. In certain embodiments, Ra is a 3-6 membered heterocyclyl optionally substituted with Ci-C3 alkyl optionally substituted with oxo, wherein the heterocyclyl contains one or two heteroatoms selected from oxygen, nitrogen and sulfur. In certain embodiments, R^ is a 3-6 membered heterocyclyl optionally substituted with Ci-C3 alkyl optionally substituted with oxo, wherein the heterocyclyl is piperdinyl. In certain embodiments, R is selected from hydrogen, benzyl, methyl, ethyl, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2OCH3,
-CH2CH2CH2OCH3,-CH2CF3, pyridin-2-ylmethyl, pyridin-4-ylmethyl and (l-acetylpiperdin-4-yl)methyl. In certain embodiments, Re is selected from benzyl, methyl, ethyl, -CH2CH2OH,
-CH2CH2CH2OH, -CH2CH2OCH3, -CH2CH2CH2OCH3,-CH2CF3, pyridin-2-ylmethyl, pyridin-4-ylmethyl and (l-acetylpiperdin-4-yl)methyl. In certain embodiments, Re is methyl.
In certain embodiments, R6 is selected from hydrogen, benzyl or C C3 alkyl optionally substituted with Ra. In certain embodiments, Ra is OH, OCH3 or halogen. In certain embodiments, R6 is selected from hydrogen, benzyl, methyl, ethyl, -CH2CH2OH,
-CH2CH2CH2OH, -CH2CH2OCH3, -CH2CH2CH2OCH3 and -CH2CF3.
In certain embodiments, Re is hydrogen, alkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl. In a particular embodiment, R« is hydrogen. In a particular embodiment, Rj is alkyl. In a particular embodiment, R¾ is methyl. In a particular embodiment, R is pyridyl. In a particular embodiment, R« is haloalkyl. In a particular embodiment, Re is -CH2CF3. In a particular embodiment, Re is heteroaryl. In a particular embodiment, R^ is 2-pyridyl. In certain embodiments, R7 and R7 are independently selected from hydrogen, halogen and CrC6 alkyl optionally substituted with Rt,. In certain embodiments, each R is independently selected from halogen, oxo, NRjRm, phenyl, cyclopropyl and a 4-6 membered heterocyclyl, wherein the phenyl, cyclopropyl and heterocyclyl are optionally substituted with halogen, CN, OH, OCH3, and Ci-C6 alkyl optionally substituted with halogen, OH or OCH3. In certain embodiments, R7 and R7 are independently selected from hydrogen, F, methyl, and l-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl. In certain embodiments, R7 is selected from hydrogen, F, methyl, and l-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl; and R7 is selected from hydrogen, F and methyl.
In certain embodiments, R7 and RT are independently selected from hydrogen, halogen and methyl. In certain embodiments, R7 and R7> are hydrogen. In certain embodiments, R7 and R7 are methyl. In certain embodiments, R7 and RT are F. In certain embodiments, R7 is F and RT is hydrogen. In certain embodiments, R7 and R7- together with the atom to which they are attached form cyclopropyl. In this embodiment, R7 and R7 form a spirocycle with the carbon atom to which they are attached. In certain embodiments, Rg and R are independently selected from hydrogen, cyclopropyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, -CH2F, -CH2OH, -CH2OCH3, -C(=0)NH2, benzyl, 3-methoxybenzyl, 4- methoxybenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 3-chlorobenzyl, 4- (difluoromethoxy)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, ( 1 H-pyrazol- 1 -yl)methyl, ( 1 H- 1 ,2,4-triazol- l-yl)methyl, (lH-imidazol-l-yl)methyl, -CH20(phenyl), -CH20(3-chlorophenyl) and -CH2S(phenyl).
In certain embodiments, R« and Rg> are independently selected from hydrogen, cyclopropyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, -CH2F, -CH2OH, -C¾OCH3, -C(=0)NH2, benzyl, 3-methoxybenzyl, 4- methoxybenzyl, 4-fluorobenzyl, 3-fluorobenzyl, 2-fluorobenzyl, 3-chlorobenzyl, 4- (difluoromethoxy)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, (1 H-pyrazol- l-yl)methyl, (lH-l,2,4-triazol- l-yl)methyl and (lH-imidazol-l-yl)methyl.
In certain embodiments, Rg and R^ are independently selected from hydrogen, Ci-C6 alkyl optionally substituted with Rb, C3-C6 carbocyclyl, 4 to 6 membered heterocyclyl, phenyl, 5 to 6 membered heteroaryl, wherein the carbocyclyl, heterocyclyl, phenyl or heteroaryl are optionally substituted with R,. In certain embodiments, each Rb is independently selected from halogen, oxo, NRiRm, C C3 alkyl optionally substituted with halogen or OH, -0(C]-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, OCH3, and Ci-C6 alkyl optionally substituted with halogen, OH or OCH3. In certain embodiments, each Rb is independently selected from halogen, oxo, NRjRn,, C1-C3 alkyl optionally substituted with halogen or OH, -0(CrC3 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, OCH3, and C]-C6 alkyl optionally substituted with halogen, OH or OCH3, wherein the heterocyclyl and heteroaryl contain one, two or three heteroatoms selected from oxygen, nitrogen and sulfur. In certain embodiments, each Rb is independently selected from halogen, oxo, NRiR™, C C3 alkyl optionally substituted with halogen or OH, -0(Ci-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, OCH3, and Q-Ce alkyl optionally substituted with halogen, OH or OCH3, wherein the heterocyclyl is tetrahydropyranyl. In certain embodiments, each R< is independently selected from halogen, NRiRm, cyclopropyl, CrC3 alkyl optionally substituted with halogen or OH, and - 0(Ci-C3 alkyl) optionally substituted with halogen or OH. In certain embodiments, Rg and Rg- are independently selected from hydrogen, cyclopropyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, -CH2F, -C(=0)NH2, benzyl, 3-methoxybenzyl, 4-methoxybenzyl, cyclopropylmethyl and (tetrahydropyran-4- yl)methyl.
In certain embodiments, Rg and ¾· are independently selected from hydrogen, cyclopropyl or Ci-C6 alkyl optionally substituted with R¾. In certain embodiments, R¾ is halogen, phenyl, cyclopropyl or a 4-6 membered heterocyclyl. In certain embodiments, R¾ is halogen, phenyl, cyclopropyl or a 4-6 membered heterocyclyl, wherein the heterocyclyl contains one heteroatom selected from oxygen, nitrogen and sulfur. In certain embodiments, R¾ is halogen, phenyl, cyclopropyl or a 4-6 membered heterocyclyl, wherein the heterocyclyl is tetrahydropyranyl. In certain embodiments, Rg and Rg- are independently selected from hydrogen, cyclopropyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, C¾F, benzyl, cyclopropylmethyl and (tetrahydropyran-4-yl)methyl. In certain embodiments, Rg is selected from hydrogen, cyclopropyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, C¾F, benzyl, cyclopropylmethyl and (tetrahydropyran-4-yl)methyl; and R is selected from hydrogen, methyl, ethyl and CH.F. In a particular embodiment, Rg and R ' are independently alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl. In a particular embodiment, Rg is alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl and R# is H. In a particular embodiment, Rg is methyl and Rg' is H. In a particular embodiment, Rg is 2-propyl and Rg is H. In a particular embodiment, Rg is t-butyl and Rg- is H. In a particular embodiment, Rg is cyclopropyl and R ' is H. In a particular embodiment, Rg is benzyl and Rg' is H. In a particular embodiment, Rg is 3- pyridinyl and Rg> is H. In a particular embodiment, Rg and Rg> are both H. In a particular embodiment, Rg and Rg' are both methyl. In a particular embodiment, Rg and Rg' are both C¾F. In certain embodiments, Rg and Rg- are Q-Q alkyl optionally substituted with R¾. In certain
embodiments, each Rb is independently selected from halogen, oxo, NRiRm, C]-C3 alkyl optionally substituted with halogen or OH, -0(C C3 alkyl) optionally substituted with halogen or OH, phenyl, C3-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, OCH3, and Cr Ce alkyl optionally substituted with halogen, OH or OCH3. In certain embodiments, each R¾ is independently selected from halogen, oxo, NRjRm, Q-C3 alkyl optionally substituted with halogen or OH, -0(Ci-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, OCH3, and Ci-C6 alkyl optionally substituted with halogen, OH or OCH3, wherein the heterocyclyl or heteroaryl contain one, two or three heteroatoms selected from oxygen, nitrogen and sulfur. In certain embodiments, each Rj, is independently selected from halogen, oxo, NR^, C1-C3 alkyl optionally substituted with halogen or OH, -Ο(0ι-03 alkyl) optionally substituted with halogen or OH, phenyl, C3-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, OCH3, and C1-C6 alkyl optionally substituted with halogen, OH or OCH3, wherein the heterocyclyl is tetrahydropyranyl. In certain embodiments, Rg and Rg- are
independently selected from methyl, ethyl, isopropyl, tert-butyl, isobutyl, -CH2F, -C(=0)NH2, benzyl, 3- methoxybenzyl, 4-methoxybenzyl, cyclopropylmethyl and (tetrahydropyran-4-yl)methyl.
In certain embodiments, R ' is methyl and Rg is C1-C6 alkyl substituted with Rb. In certain embodiments, Rg' is methyl in the (S)-configuration, and Rg is C C6 alkyl substituted with Rb in the (Reconfiguration. In certain embodiments, Rg' is methyl in the (Reconfiguration, and Rg is Ci-C6 alkyl substituted with Rb in the (S)-configuration. In certain embodiments, Rg- is methyl and Rg is -CH2(Rb). In certain embodiments, Rg is -CH2(Rb). In certain embodiments, ¾ is selected from phenyl, C3-C6 carbocyclyl, a 4 to 6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the phenyl, carbocyclyl, heterocyclyl and heteroaryl are optionally substituted with halogen, CN, OH, OCH3, CrC6 alkyl and C C6 alkoxy, wherein C6 alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen, OH or OCH3. In certain embodiments, ¾ is selected from phenyl, C3-C6 carbocyclyl, a 4-6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the phenyl, carbocyclyl, heterocyclyl and heteroaryl are substituted with at least one substituted selected from halogen, CN, OH, OCH3, CrC¾ alkyl and Ci-C6 alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen, OH or OCH3. In certain embodiments, 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. In certain embodiments, 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, 3-cyanobenzyl and (5-fluoropyridin-2-yl)methyl. In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, Rg- is methyl and Rg is cyclopropylmethyl. In certain embodiments, Rg' is methyl and Rg is (tetrahydropyran-4-yl)methyl. In certain embodiments, 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.
In certain embodiments, Rg' is methyl and Rg is selected from benzyl, 3-methoxybenzyl and 4- methoxybenzyl. In certain embodiments, Rg- is methyl in the (S)-configuration, and Rg is selected from benzyl, 3-methoxybenzyl and 4-methoxybenzyl in the (R)-configuration. In certain embodiments, Rg> is methyl in the (Reconfiguration, and Rg is selected from benzyl, 3-methoxybenzyl and 4-methoxybenzyl in the (S)-configuration.
In certain embodiments, Rg' is methyl and Rg is selected from -CH2OH and -CH2OCH3.
In certain embodiments, Rg' is methyl and Rg is selected from Ci-C6 alkyl optionally substituted with Rj,, wherein Rt, is selected from -O(phenyl) and -S(phenyl), wherein the phenyl is optionally substituted with halogen. In certain embodiments, Rg> is methyl and Rg is selected from
-CH20(phenyl), -CH20(3-chlorophenyl) and -CH2S(phenyl). In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, Rg and R ' together with the atom to which they are attached form a 3 to 6
membered heterocyclyl optionally substituted with C1 -C3 alkyl optionally substituted with halogen. In certain embodiments, Rg and Rg' together with the atom to which they are attached form a 3 to 6
membered heterocyclyl optionally substituted with CrC3 alkyl optionally substituted with halogen, wherein the heterocyclyl contains one heteroatom selected from oxygen, nitrogen and sulfur. In certain embodiments, 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. In certain embodiments, 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.
In certain embodiments, Rg and R ' together with the atom to which they are attached form a 3 to 6 membered carbocyclyl or heterocyclyl. In this embodiment, Rg and Rg' form a spirocycle with the carbon atom to which they are attached. In certain embodiments, Rg and Rg' together with the atom to which they are attached form a 3 to 6 membered carbocyclyl. In certain embodiments, Rg and Rg' together with the atom to which they are attached form a 3 to 6 membered heterocyclyl. In certain embodiments, Rg and Rg- together with the atom to which they are attached form a 3 to 6 membered heterocyclyl, wherein the heterocyclyl contains one heteroatom selected from oxygen, nitrogen and sulfur. In certain embodiments, Rg and R ' together with the atom to which they are attached form a 3 to 6 membered heterocyclyl, wherein the heterocyclyl is tetrahydropyranyl. In certain embodiments, 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. Alternatively, 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. In a particular embodiment, Rg and Rg> together form a cycloalkyl ring. In a particular embodiment, Rg and Rg' together form a cyclopropyl ring. In a particular embodiment, Rg and Rg- together form a cyclobutyl ring. In a particular embodiment, Rg and Rg' together form a cyclopentyl ring. In a particular embodiment, Rg and R ' together form a heterocycle. In a particular embodiment, Rg and Rg' together form a 4-pyranyl ring. In a particular embodiment, Rg and Rg' together form a 4-piperidinyl ring optionally N-substituted with alkyl (e.g. Me) or haloalkyl (e.g. -CH2CHF2). The present invention includes R7 and R7- forming a spirocycle with the carbon atom to which they are attached, and Rg and Rg> forming a spirocycle with the carbon atom to which they are attached. However, the present invention includes that only one of R7 and Rr or ¾ and R# may together form a spirocyclic ring, such that both R7 and R7 and Rg and Rg> may not both independently join together and form spirocyclic rings. Thus, either R7 and Rr 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 R7 and RT or Rg and R may together form a ring.
In certain embodiments, R is hydrogen, halogen, CN, CrCg alkyl optionally substituted with Rc, Q-Cg alkenyl optionally substituted with Rc, CrCg alkynyl optionally substituted with Rc, Q-Cg alkoxy optionally substituted with Rc, phenyl optionally substituted with Rd, a 5-6 membered heteroaryl optionally substituted with Re, a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with Rf, a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg, a 9-10 membered bicyclic heteroaryl optionally substituted with Rh, phenylamino, or phenoxy optionally substituted with R.
In certain embodiments, R9 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 Rf, a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg, a 9-10 membered bicyclic heteroaryl optionally substituted with Rh, phenylamino, or phenoxy optionally substituted with R. In certain embodiments, R9 is Ci-Cg alkyl optionally substituted with Rc, CrCg alkenyl optionally substituted with Rc, Q-Cg alkynyl optionally substituted with Rc, phenyl optionally substituted with Rj, a 5-6 membered heteroaryl optionally substituted with R., a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with Rf, a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg, a 9-10 membered bicyclic heteroaryl optionally substituted with ¾, phenylamino, or phenoxy optionally substituted with R. In certain embodiments, 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 Rf, , a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg, a 9-10 membered bicyclic heteroaryl optionally substituted with Rh, phenylamino, or phenoxy optionally substituted with R;. In certain embodiments, R9 is phenyl optionally substituted with Rd or a 5-6 membered heteroaryl optionally substituted with Re. In certain embodiments, each is independently selected from halogen, CN, OH, OCH3, C1-C3 alkyl optionally substituted with halogen or OH, -0(CrC3 alkyl) optionally substituted with halogen or OH, C3-C6 carbocyclyl and phenyl optionally substituted with halogen, OH or OCH3. In certain embodiments, each Rc is independently selected from halogen, CN, OH, OCH3, cyclopropyl and phenyl optionally substituted with halogen, OH or OCH3.
In certain embodiments, each R<j is independently selected from halogen, CN, cyclopropyl, ORj, SR^, NRiRm, CrC8 alkyl optionally substituted with R„, -0(CrCg alkyl) optionally substituted with R„, Q-Cg alkynyl optionally substituted with Ro. In certain embodiments, each R^ is independently selected from halogen, CN, cyclopropyl, ORj, SR^, NRiR,,,, Q-Cg alkyl optionally substituted with R„, CrC8 alkynyl optionally substituted with Ro.
In certain embodiments, each R» is independently selected from halogen, CN, oxide, NH2, cyclopropyl, ORp, SRk, CrC6 alkyl optionally substituted with halogen and ORq, and Ci-C6 alkynyl optionally substituted with ORs. In certain embodiments, each Re is independently selected from halogen, CN, NH2, cyclopropyl, ORp, Q-C6 alkyl optionally substituted with ORq, and C]-C6 alkynyl optionally substituted
In certain embodiments, each Re is independently selected from halogen, CN, NH2, cyclopropyl, ORp, SRk, C]-C6 alkyl optionally substituted with halogen and ORq, and C]-C6 alkynyl optionally substituted with ORs. In certain embodiments, each R. is independently selected from halogen, CN, NH2,
cyclopropyl, ORp, Ci-C6 alkyl optionally substituted with ORq, and Ci-C6 alkynyl optionally substituted
In certain embodiments, each Rf is independently selected from halogen, oxo, C C6 alkyl optionally substituted with halogen, and Q-C6 alkoxycarbonyl. In certain embodiments, each Rf is independently selected from halogen, oxo, Ci-C6 alkyl, and C C6 alkoxycarbonyl.
In certain embodiments, each Rg is independently selected from halogen, OH, OCH3 and Ci-C6 alkyl optionally substituted with halogen. In certain embodiments, each Rg is independently selected from halogen and Ci-C6 alkyl.
In certain embodiments, each R¾ is independently selected from halogen and Q-C6 alkyl. In certain embodiments, each R; is independently selected from halogen and benzyl.
In certain embodiments, each Rj is independently selected from hydrogen and CrC6 alkyl optionally substituted with halogen, CN, OH, OCH3 and benzyl. In certain embodiments, each Rj is independently selected from hydrogen and C1-C6 alkyl optionally substituted with halogen or phenyl.
In certain embodiments, each ¾ is C -Ce alkyl.
In certain embodiments, each Rj and R™ is independently selected from hydrogen and C C6 alkyl.
In certain embodiments, each R„ is independently selected from halogen, OH, OCH3, CN and phenyl. In certain embodiments, each R„ is independently selected from halogen, OH, OCH3 and phenyl.
In certain embodiments, each RQ is independently selected from halogen and C3-C6 carbocyclyl.
In certain embodiments, each Rp is independently selected from hydrogen, C\-Ce alkyl and phenyl.
In certain embodiments, each Rq is halogen.
In certain embodiments, each Rj is independently selected from halogen and cyclopropyl.
In certain embodiments, R9 is selected from hydrogen, Br, CN, butyl, isobutyl, propyl, isopentyl, -CH2CH2C(CH3)3, -CH2CH2CH2CN, -CH2CH2CH2OCH3, -CH2(phenyl), -CH2CH2(phenyl),
-CH2(3-methoxyphenyl), -CH=CHC(CH3)3, -CH=CHCH2CH(CH3)2, -CH=CHCH2OCH3,
-C≡CCH(CH3)2, -C≡CC(CH3)3, -C≡CCH2CH(CH3)2, -C≡C(cyclopropyl), phenyl, 3 -fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-cyanophenyl (3-benzonitrile), 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-cyclopropylphenyl, 3-(methylthio)phenyl, 3- aminophenyl, 3-(methylamino)phenyl, 3-(3-methylbut-l-ynyl)phenyl, 3-(4-methylpent-l-ynyl)phenyl, 3- (5-methylhex-l-ynyl)phenyl, 3-(cyclopropylethynyl)phenyl, 3-(cyclopentylethynyl)phenyl, 3,5- difluorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5- bis(trifluoromethyl)phenyl, 2-chloro-5-ethoxyphenyl, 3-chloro-2-fluorophenyl, 3-chloro-2-hydroxyphenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3-chloro-5- methoxyphenyl, 3-chloro-5-ethynylphenyl, 5-chloro-2-fluorophenyl, 5-chloro-2 -methoxyphenyl, 5-chloro- 3-cyanophenyl, 2-fluoro-3 -methoxyphenyl, 2-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro-5- methoxyphenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-5-methoxyphenyl, 3-fluoro-5- (trifluoromethyl)phenyl, 3-fluoro-5-(prop-l-ynyl)phenyl, 4-fluoro-3-methoxyphenyl, 4-fluoro-3- (trifluoromethy l)pheny 1, 5 -fluoro-3 -cyanopheny 1, 5-bromo-3 -cyanopheny 1, 3 -cyclopropyl-5 -fluorophenyl, fluorophenyl, 5-cyclopropyl-3-cyanophenyl, 3-ethoxy-2-fluorophenyl, 3-ethoxy-4-fluorophenyl, 3-ethoxy- 5-fluorophenyl, 5-ethoxy-2-fluorophenyl, 5-prop-l-ynyl-3-cyanophenyl, 4-cyanopyridin-2-yl, 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, 5-cyclopropylpyridin-3-yl, 5-bromopyridin-3-yl, 5-chloro-2-methoxypyridin-3-yl, 2-amino-5-chloropyridin-3-yl, 2-methylpyridin-3-yl, 4-methylpyridin-3-yl, 6-methylpyridin-3-yl, 4- chloropyridin-3 -yl, 5 -chloro-2-methy lpyridin-3 -yl, 5 -chloro-6-methylpyridin-3 -y 1, 2-methoxypyridin-3-y 1,
2- (benzyloxy)-5-chloropyridin-3-yl, 2-trifluoromethylpyridin-4-yl, 4-methylpyrimidin-2-yl, pyrimidin-5- yl, 4-methylpyrimidin-5-yl, 4-trifluoromethylpyrimidin-5-yl, pyrazin-2-yl, 6-methylpyrazin-2-yl, 6- chloropyrazin-2-yl, 5-methylpyridzin-3-yl, lH-pyrrol-2-yl, thiophen-2-yl, 4-methylthiophen-2-yl, 5- methylthiophen-2-yl, 4-methoxythiophen-2-yl, thiophen-3-yl, 5-methylfuran-2-yl, isothiazol-5-yl, 2,4- dimethylthiazol-5-yl, 1 -methyl- lH-pyrazol-4-yl, oxazol-5-yl, 1 -methyl- lH-imidazol-5-yl, tetrahydropyran- 4-yl, 5-chloro- 1 -methyl-2-oxo- 1 ,2-dihydropyridin-3-yl, 5-chloro-2-oxo- 1 ,2-dihydropyridin-3-yl, 6-oxo- l,6-dihydropyridin-3-yl, tert-butyl 5,6-dihydropyridine-l(2H)-carboxylate, l,2,5,6-tetrahydropyridin-3-yl, 3,6-dihydro-2H-pyran-4-yl, cyclopentyl, cyclohexyl, (3R,5S)-3,5-dimethylcyclohexyl, 4,4- dimethylcyclohexyl, (3R,5S)-3,5-dimethylcyclohex-l-enyl, 4,4-dimethylcyclohex-l-enyl, 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, quinolin-3-yl, phenylamino, phenoxy and 3-benzyl-5- fluorophenoxy.
In certain embodiments, R9 is selected from hydrogen, Br, CN, butyl, isobutyl, propyl, isopentyl, -CH2CH2C(CH3)3, -CH2CH2CH2CN, -CH2CH2CH2OCH3, cyclohexylmethyl, -CH2(phenyl),
-CH2CH2(phenyl), -CH2(3-methoxyphenyl), -CH=CHC(CH3)3, -CH=CHCH2CH(CH3)2,
-CH2CH2CH2CH=CH2, -CH=CHCH2OCH3, -CH=CH(cyclopropyl), -C≡CCH2CH2CH3,
-C≡CCH(CH3)2, -C≡CC(CH3)3, -C≡CCH2CH(CH3)2, -C≡C(cyclopropyl), phenyl, 3-fluorophenyl, 2- chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 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-cyclopropylphenyl, 3- (methylthio)phenyl, 3-aminophenyl, 3-(methylamino)phenyl, 3-(prop-l-ynyl)phenyl, 3-(3-methylbut-l- ynyl)phenyl, 3-(4-methylpent-l-ynyl)phenyl, 3-(5-methylhex-l-ynyl)phenyl, 3-
(cyclopropylethynyl)phenyl, 3-(cyclopentylethynyl)phenyl, 3-(OCH2CN)phenyl, 3,5-difluorophenyl, 2,3- dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5- bis(trifluoromethyl)phenyl, 2-chloro-5-ethoxyphenyl, 3-chloro-2-fluorophenyl, 3-chloro-2-hydroxyphenyl,
3- chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3-chloro-5- 3-chloro-5-methoxyphenyl, 3-chloro-5-ethynylphenyl, 3-chloro-5-cyclopropylphenyl, 5-chloro-2- fluorophenyl, 5-chloro-2-methoxyphenyl, 5-chloro-3-cyanophenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-3- (trifluoromethyl)phenyl, 2-fluoro-5-methoxyphenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-5- methoxyphenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 3-lluoro-5-(prop-l-ynyl)phenyl, 4-fluoro-3- methoxyphenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 5 -fluoro-3 -cyanophenyl, 2-fluoro-3 -cyanophenyl, 2- fluoro-5-cyanophenyl, 5-bromo-3-cyanophenyl, 5 -methyl-3 -cyanophenyl, 5-difluoromethyl-3- cyanophenyl, 5-methoxy-3-cyanophenyl, 3-cyclopropyl-5-fluorophenyl, 5-cyclopropyl-3-cyanophenyl, 3- ethoxy-2-fluorophenyl, 3-ethoxy-4-fluorophenyl, 3-ethoxy-5-fluorophenyl, 5-ethoxy-2-fluorophenyl, 5- prop-l-ynyl-3-cyanophenyl, 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-fluoropyridin-3-yl, 5-ethynylpyridin-3-yl, 5-(prop-l-ynyl)pyridin-3-yl, 5- (cyclopropylethynyl)pyridin-3-yl, 5-cyanopyridin-3-yl, 5-cyclopropylpyridin-3-yl, 5-bromopyridin-3-yl, 5 (methylthio)pyridin-3-yl, 5-chloro-2-methoxypyridin-3-yl, 2-amino-5-chloropyridin-3-yl, 2-methylpyridin
3- yl, 4-methylpyridin-3-yl, 6-methylpyridin-3-yl, 4-chloropyridin-3-yl, 5-chloro-2-methylpyridin-3-yl, 5- chloro-6-methylpyridin-3-yl, 2-methoxypyridin-3-yl, 2-(benzyloxy)-5-chloropyridin-3-yl, 2- trifluoromethylpyridin-4-yl, 5-(difluoromethyl)pyridin-3-yl, 4-methylpyrimidin-2-yl, pyrimidin-5-yl, 4- methylpyrimidin-5-yl, 4-trifluoromethylpyrimidin-5-yl, pyrazin-2-yl, 6-methylpyrazin-2-yl, 6- chloropyrazin-2-yl, 5-methylpyridzin-3-yl, lH-pyrrol-2-yl, thiophen-2-yl, 4-methylthiophen-2-yl, 5- methylthiophen-2-yl, 4-methoxythiophen-2-yl, thiophen-3-yl, 5-methylfuran-2-yl, isothiazol-5-yl, 2,4- dimethylthiazol-5-yl, 1 -methyl- lH-pyrazol-4-yl, oxazol-5-yl, l-methyl-lH-imidazol-5-yl, tetrahydropyran
4- yl, 5-chloro- 1 -methyl-2-oxo- 1 ,2-dihydropyridin-3-yl, 5-chloro-2-oxo- 1 ,2-dihydropyridin-3-yl, 6-oxo- l,6-dihydropyridin-3-yl, tert-butyl 5,6-dihydropyridine-l(2H)-carboxylate, l,2,5,6-tetrahydropyridin-3-yl, 3,6-dihydro-2H-pyran-4-yl, cyclopentyl, cyclohexyl, (3R,5S)-3,5-dimethylcyclohexyl, 4,4- dimethylcyclohexyl, 3-hydroxycyclohexyl, (3R,5S)-3,5-dimethylcyclohex-l-enyl, 4,4-dimethylcyclohex- 1-enyl, 3-methoxycyclohex-l-enyl, 6-chloroimidazo[ 1 ,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, quinolin-3-yl, phenylamino, phenoxy and 3-benzyl-5-fluorophenoxy.
In certain embodiments, R9 is selected from hydrogen, Br, CN, butyl, isobutyl, propyl, isopentyl, -CH2CH2C(CH3)3, -CH2CH2CH2CN, -CH2CH2CH2OCH3, cyclohexylmethyl, -CH2(phenyl),
-CH2CH2(phenyl), -CH2(3-methoxyphenyl), -CH=CHC(CH3)3, -CH=CHCH2CH(CH3)2,
-CH2CH2CH2CH=CH2, -CH=CHCH2OCH3, -CH=CH(cyclopropyl), -C≡CCH2CH2CH3,
-C≡CCH(CH3)2, -C≡CC(CH3)3, -C≡CCH2CH(CH3)2, -C≡C(cyclopropyl), methoxy, phenyl, 3- fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 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-cyclopropylphenyl, 3- (methylthio)phenyl, 3-aminophenyl, 3-(methylamino)phenyl, 3-(prop-l-ynyl)phenyl, 3-(3-methylbut-l- ynyl)phenyl, 3-(4-methylpent-l-ynyl)phenyl, 3-(5-methylhex-l-ynyl)phenyl, 3-
(cyclopropylethynyl)phenyl, 3-(cyclopentylethynyl)phenyl, 3-(OCH2CN)phenyl, 3,5-difluorophenyl, 2,3- dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5- bis(trifluoromethyl)phenyl, 2-chloro-5-ethoxyphenyl, 3-chloro-2-fluorophenyl, 3-chloro-2-hydroxyphenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3-chloro-5- methoxyphenyl, 3-chloro-5-ethynylphenyl, 3-chloro-5-cyclopropylphenyl, 5-chloro-2-fluorophenyl, 5- chloro-2-methoxyphenyl, 5-chloro-3-cyanophenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-3- (trifluoromethyl)phenyl, 2-fluoro-5-methoxyphenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-5- methoxyphenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-5-(prop-l-ynyl)phenyl, 4-fluoro-3- methoxyphenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 5-fluoro-3-cyanophenyl, 2-fluoro-3-cyanophenyl, 2- fluoro-5-cyanophenyI, 5-bromo-3-cyanophenyl, 5-methyl-3-cyanophenyl, 5-difluoromethyl-3- cyanophenyl, 5-methoxy-3-cyanophenyl, 3-cyclopropyl-5-fluorophenyl, 5-cyclopropyl-3-cyanophenyl, 3- ethoxy-2-fluorophenyl, 3-ethoxy-4-fluorophenyl, 3-ethoxy-5-fluorophenyl, 5-ethoxy-2-fluorophenyl, 5- prop-l-ynyl-3-cyanophenyl, 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-fluoropyridin-3-yl, 5-ethynylpyridin-3-yl, 5-(prop-l-ynyl)pyridin-3-yl, 5- (cyclopropylethynyl)pyridin-3-yl, 5-cyanopyridin-3-yl, 5-cyclopropylpyridin-3-yl, 5-bromopyridin-3-yl, 5- (methylthio)pyridin-3-yl, 5-chloro-2-methoxypyridin-3-yl, 2-amino-5-chloropyridin-3-yl, 2-methylpyridin- 3-yl, 4-methylpyridin-3-yl, 6-methylpyridin-3-yl, 4-chloropyridin-3-yl, 5-chloro-2-methylpyridin-3-yl, 5- chloro-6-methylpyridin-3-yl, 2-methoxypyridin-3-yl, 2-(benzyloxy)-5-chloropyridin-3-yl, 2- trifluoromethylpyridin-4-yl, 5-(difluoromethyl)pyridin-3-yl, 5-chloropyridin-3-yl-l -oxide, 4- methylpyrimidin-2-yl, pyrimidin-5-yl, 4-methylpyrimidin-5-yl, 4-trifluoromethylpyrimidin-5-yl, pyrazin- 2-yl, 6-methylpyrazin-2-yl, 6-chloropyrazin-2-yl, 5-methylpyridzin-3-yl, lH-pyrrol-2-yl, thiophen-2-y], 4- methylthiophen-2-yl, 5-methylthiophen-2-yl, 4-methoxythiophen-2-yl, thiophen-3-yl, 5-methylfuran-2-yl, isothiazol-5-yl, 2,4-dimethylthiazol-5-yl, 1 -methyl- lH-pyrazol-4-yl, oxazol-5-yl, 1 -methyl- lH-imidazol-5- yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, 5-chloro-l-methyl-2-oxo-l,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- 1 (2H)-carboxylate, 1 ,2,5,6-tetrahydropyridin-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl, 3,4-dihydro-2H-pyran-6-yl, cyclopropyl, cyclopentyl, cyclohexyl, (3R,5S)-3,5-dimethylcyclohexyl, 4,4- dimethylcyclohexyl, 3-hydroxycyclohexyl, (3R,5S)-3,5-dimethylcyclohex-l-enyl, 4,4-dimethylcyclohex- 1-enyl, 3-methoxycyclohex-l-enyl, 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, quinolin-3-yl, phenylamino, phenoxy and 3-benzyl-5-fluorophenoxy. In certain embodiments, R9 is selected from cyclohexylmethyl,
Figure imgf000034_0001
-CH=CH(cyclopropyl), -C≡CCH2CH2CH3, 2-(3-phenyl)acetonitrile, 3-(prop-l-ynyl)phenyl, 3- (OCH2CN)phenyl, 3-chloro-5-cyclopropylphenyl, 2-fluoro-3-cyanophenyl, 2-fluoro-5-cyanophenyl, 5- methyl-3-cyanophenyl, 5-difluoromethyl-3-cyanophenyl, 5-methoxy-3-cyanophenyl, 4-methylpyridin-2-yl, 4-fluoropyridin-2-yl, pyridin-3-yl, 2-fluoropyridin-3-yl, 5-(methylthio)pyridin-3-yl, 5- (difluoromethyl)pyridin-3-yl, 3-hydroxycyclohexyl, and 3-methoxycyclohex-l-enyl.
In certain embodiments, R9 is hydrogen. In certain embodiments, R9 is halogen. In certain embodiments, R is Br. In certain embodiments, R9 is CN.
In certain embodiments, R9 is Q-Cg alkyl optionally substituted with Rc. In certain embodiments, each Rc is independently selected from halogen, CN, OH, OCH3, Q-C3 alkyl optionally substituted with halogen or OH, -0(C]-C3 alkyl) optionally substituted with halogen or OH, C3-C6 carbocyclyl and phenyl optionally substituted with halogen, OH or OCH3. In certain embodiments, each Rc is independently selected from CN, OCH3, cyclohexyl and phenyl optionally substituted with OCH3. In certain
embodiments, R9 is selected from butyl, isoburyl, propyl, isopentyl, -CH2CH2C(CH3)3, -CH2CH2CH2CN, - CH2CH2CH2OCH3, cyclohexylmethyl,
-CH2(phenyl), -CH2CH2(phenyl), and -CH2(3-methoxyphenyl).
In certain embodiments, R is Ci-Cg alkyl optionally substituted with Rc. In certain embodiments, each Rc is independently selected from halogen, CN, OH, OCH3, cyclopropyl and phenyl optionally substituted with halogen, OH or OCH3. In certain embodiments, each Rc is independently selected from CN, OCH3 and phenyl optionally substituted with OCH3. In certain embodiments, R9 is selected from butyl, isobutyl, propyl, isopentyl, -CH2CH2C(CH3)3,
-CH2CH2CH2CN, -CH2CH2CH2OCH3, -CH2(phenyl) (benzyl), -CH2CH2(phenyl), and -CH2(3- methoxyphenyl).
In certain embodiments, R9 is CrCg alkenyl optionally substituted with Rc. In certain embodiments, each Rc is independently selected from halogen, CN, OH, OCH3, C1-C3 alkyl optionally substituted with halogen or OH, -0(Ci-C3 alkyl) optionally substituted with halogen or OH, C3-C6 carbocyclyl and phenyl optionally substituted with halogen, OH or OCH3. In certain embodiments, Rc is selected from OCH3 and cyclopropyl. In certain embodiments, R9 is selected from -CH=CHC(CH3)3, -CH=CHCH2CH(CH3)2, - CH2CH2CH2CH=CH2, -CH-CHCH2OCH3,
-CH=CH(cyclopropyl).
In certain embodiments, R9 is Q-Cg alkenyl optionally substituted with R-. In certain embodiments, each Rc is independently selected from halogen, CN, OH, OCH3, cyclopropyl and phenyl optionally substituted with halogen, OH or OCH3. In certain embodiments, Rc is OCH3. In certain embodiments, R9 is selected from -CH=CHC(CH3)3, -CH=CHCH2CH(CH3)2,
-CH=CHCH2OCH3 and -CH=CH(cyclopropyl).
In certain embodiments, R9 is Ci-Cg alkenyl optionally substituted with Rc. In certain embodiments, each Rc is independently selected from halogen, CN, OH, OCH3, cyclopropyl and phenyl optionally substituted with halogen, OH or OCH3. In certain embodiments, R« is OCH3. In certain embodiments, R9 is selected from -CH=CHC(CH3)3, -CH=CHCH2CH(CH3)2, and
-CH=CHCH2OCH3.
In certain embodiments, R9 is Ci-C8 alkynyl optionally substituted with Rc. In certain embodiments, each Rc is independently selected from halogen, CN, OH, OCH3, C1-C3 alkyl optionally substituted with halogen or OH, -0(Ci-C3 alkyl) optionally substituted with halogen or OH, C3-C6 carbocyclyl and phenyl optionally substituted with halogen, OH or OCH3. In certain embodiments, Rc is cyclopropyl. In certain embodiments, R9 is selected from -C≡CCH2CH2CH3, -C≡CCH(CH3)2, -C≡CC(CH3)3, -C≡CCH2CH(CH3)2, and -C≡C(cyclopropyl).
In certain embodiments, R is Ci-C8 alkynyl optionally substituted with Rc. In certain embodiments, each Rc is independently selected from halogen, CN, OH, OCH3, cyclopropyl and phenyl optionally substituted with halogen, OH or OCH3. In certain embodiments, Rc is cyclopropyl. In certain embodiments, R9 is selected from -C≡ CH(CH3)2, -C≡CC(CH3)3,
-C≡CCH2CH(CH3)2, and -C≡C(cyclopropyl). In certain embodiments, R9 is CpCg alkoxy optionally substituted with Rc. In certain embodiments, R9 is methoxy.
In certain embodiments, R9 is phenyl optionally substituted with ¾. In certain embodiments, each ¾ is independently selected from halogen, CN, cyclopropyl, ORj, SRk, NRiR,,,, Q-Cg alkyl optionally substituted with R„, -0(CrCg alkyl) optionally substituted with R„, CrCg alkynyl optionally substituted with Ro. In certain embodiments, each Rj is independently selected from hydrogen and Ci-C6 alkyl optionally substituted with halogen, CN, OH, OCH3 and benzyl. In certain embodiments, each ¾ is independently selected from hydrogen and Ci-C6 alkyl optionally substituted with halogen or phenyl. In certain embodiments, each is CrC6 alkyl. In certain embodiments, each Rj and R„, is independently selected from hydrogen and C C6 alkyl. In certain embodiments, each R„ is independently selected from halogen, OH, OCH3, CN and phenyl. In certain embodiments, each R„ is independently selected from halogen, OCH3 and phenyl. In certain embodiments, each R^ is independently selected from halogen and C3-C6 carbocyclyl. In certain embodiments, each RQ is C3-C6 carbocyclyl. In certain embodiments, 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-cyclopropylphenyl, 3-(methylthio)phenyl, 3-aminophenyl, 3- (methylamino)phenyl, 3-(prop- l-ynyl)phenyl, 3-(3-methylbut-l-ynyl)phenyl, 3-(4-methylpent-l- ynyl)phenyl, 3-(5-methylhex- 1 -ynyl)phenyl, 3-(cyclopropylethynyl)phenyl, 3-(cyclopentylethynyl)phenyl, 3-(OCH2CN)phenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5- dichlorophenyl, 3,5-bis(trifluoromethyl)phenyl, 2-chloro-5-ethoxyphenyl, 3-chloro-2-fluorophenyl, 3- chloro-2-hydroxyphenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-5- (trifluoromethyl)phenyl, 3-chloro-5-methoxyphenyl, 3-chloro-5-ethynylphenyl, 3-chloro-5- cyclopropylphenyl, 5-chloro-2-fluorophenyl, 5-chloro-2-methoxyphenyl, 5-chloro-3-cyanophenyl, 2- fluoro-3-methoxyphenyl, 2-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro-5-methoxyphenyl, 2-fluoro-5- (trifluoromethyl)phenyl, 3 -fluoro-5-methoxyphenyl, 3 -fluoro-5 -(trifluoromethyl)pheny 1, 3 -fluoro-5 -(prop- l-ynyl)phenyl, 4-fluoro-3-methoxyphenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 5-fluoro-3-cyanophenyl, 2- fluoro-3-cyanophenyl (3-(2-fluorobenzonitrile)), 2-fluoro-5-cyanophenyl (3-(4-fluorobenzonitrile)), 5- bromo-3-cyanophenyl, 5-methyl-3-cyanophenyl (3-(5-methylbenzonitrile)), 5-difluoromethyl-3- cyanophenyl (3-(5-(difluoromethyl)benzonitrile)), 5-methoxy-3-cyanophenyl (3-(5-methoxybenzonitrile)), 3-cyclopropyl-5-fIuorophenyl, 5-cyclopropyl-3-cyanophenyl, 3-ethoxy-2-fluorophenyl, 3-ethoxy-4- fluorophenyl, 3-ethoxy-5-fluorophenyl, 5-ethoxy-2-fIuorophenyl, and 5-prop-l-ynyl-3-cyanophenyl.
In certain embodiments, R9 is phenyl optionally substituted with ¾. In certain embodiments, each Rd is independently selected from halogen, CN, cyclopropyl, ORj, SRk, NRiRm, C C8 alkyl optionally substituted with R„, CrC8 alkynyl optionally substituted with R<,. In certain embodiments, each is independently selected from hydrogen and C C6 alkyl optionally substituted with halogen or phenyl. In certain embodiments, each Rk is Q-C6 alkyl. In certain embodiments, each Rj and Rn, is independently selected from hydrogen and Cr e alkyl. In certain embodiments, each R„ is independently selected from halogen, OH, OCH3 and phenyl. In certain embodiments, each R„ is independently selected from halogen, OCH3 and phenyl. In certain embodiments, each RQ is independently selected from halogen and C3-C6 carbocyclyl. In certain embodiments, each RQ is C3-C6 carbocyclyl. In certain embodiments, R is selected from phenyl, 3 -fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-cyanophenyl (3- benzonitrile), 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-cyclopropylphenyl, 3-(methylthio)phenyl, 3-aminophenyl, 3-(methylamino)phenyl, 3-(3-methylbut-l- ynyl)phenyl, 3-(4-methylpent-l-ynyl)phenyl, 3-(5-methylhex-l-ynyl)phenyl, 3-
(cyclopropylethynyl)phenyl, 3-(cyclopentylethynyl)phenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 2,5- dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-bis(trifluoromethyl)phenyl, 2-chloro-5- ethoxyphenyl, 3-chloro-2-fluorophenyl, 3-chloro-2-hydroxyphenyl, 3-chloro-4-fluorophenyl, 3-chloro-5- fluorophenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3-chloro-5-methoxyphenyl, 3-chloro-5-ethynylphenyl, 5-chloro-2-fluorophenyl, 5-chloro-2-methoxyphenyl, 5-chloro-3-cyanophenyl (3-(5-chlorobenzonitrile)),
2- fluoro-3-methoxyphenyl, 2-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro-5-methoxyphenyl, 2-fluoro-5- (trifluoromethyl)phenyl, 3-fluoro-5-methoxyphenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-5-(prop-
1- ynyl)phenyl, 4-fluoro-3-methoxyphenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 5-fluoro-3-cyanophenyl (3- (5-fluorobenzonitrile)), 5-bromo-3-cyanophenyl (3-(5-bromobenzonitrile)), 3-cyclopropyl-5-fluorophenyl, 5 -eye lopropy 1-3 -cyanopheny 1 (3 -(5-cyclopropylbenzonitrile)), 3 -ethoxy-2-fluorophenyl, 3 -ethoxy-4- fluorophenyl, 3 -ethoxy-5 -fluorophenyl, 5-ethoxy-2-fluorophenyl, and 5-prop-l -ynyl-3-cyanophenyl (3-(5- (prop- 1 -ynyl)benzonitrile)).
In certain embodiments, R9 is a 5-6 membered heteroaryl optionally substituted with R<,. In certain embodiments, R9 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. In certain embodiments, R9 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. In certain embodiments, R9 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. In certain embodiments, each R<. is independently selected from halogen, CN, oxide, N¾, cyclopropyl, ORp, SRk, Ci-C6 alkyl optionally substituted with halogen and O q, and CrC6 alkynyl optionally substituted with ORj. In certain embodiments, R9 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-cyclopropylpyridin-3-yl, 5-bromopyridin-3-yl, 5- (methylthio)pyridin-3-yl, 5-chloro-2-methoxypyridin-3-yl, 2-amino-5-chloropyridin-3-yl, 2-methylpyridin-
3- yl, 4-methylpyridin-3-yl, 6-methylpyridin-3-yl, 4-chloropyridin-3-yl, 5-chloro-2-methylpyridin-3-yl, 5- chloro-6-methylpyridin-3-yl, 2-methoxypyridin-3-yl, 2-(benzyloxy)-5-chloropyridin-3-yl, 2- trifluoromethylpyridin-4-yl, 5-(difluoromethyl)pyridin-3-yl, 5-chloropyridin-3-yl-l -oxide, 4- methylpyrimidin-2-yl, pyrimidin-5-yl, 4-methylpyrimidin-5-yl, 4-trifluoromethylpyrimidin-5-yl, pyrazin-
2- yl, 6-methylpyrazin-2-yl, 6-chloropyrazin-2-yl, 5-methylpyridzin-3-yl, lH-pyrrol-2-yl, thiophen-2-yl, 4- thiophen-2-yl, 4-methylthiophen-2-yl, 5-methylthiophen-2-yl, 4-methoxythiophen-2-yl, thiophen-3-yl, 5- methylfuran-2-yl, isothiazol-5-yl, 2,4-dimethylthiazol-5-yl, 1 -methyl- 1 H-pyrazol-4-yl, oxazol-5-yl, and 1- methyl-lH-imidazol-5-yl.
In certain embodiments, R9 is a 5-6 membered heteroaryl optionally substituted with Re. In certain embodiments, R9 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. In certain embodiments, R9 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. In certain embodiments, R9 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. In certain embodiments, each Re is independently selected from halogen, CN, NH2, cyclopropyl, ORp, SR^, C]-C6 alkyl optionally substituted with halogen and ORq, and Q-C6 alkynyl optionally substituted with ORj. In certain embodiments, R9 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-fluoropyridin-3-yl, 5-ethynylpyridin-3-yl, 5-(prop-l-ynyl)pyridin-3-yl, 5-
(cyclopropylethynyl)pyridin-3-yl, 5-cyanopyridin-3-yl, 5-cyclopropylpyridin-3-yl, 5-bromopyridin-3-yl, 5- (methylthio)pyridin-3-yl, 5-chloro-2-methoxypyridin-3-yl, 2-amino-5-chloropyridin-3-yl, 2-methylpyridin- 3-yl, 4-methylpyridin-3-yl, 6-methylpyridin-3-yl, 4-chloropyridin-3-yl, 5-chloro-2-methylpyridin-3-yl, 5- chloro-6-methylpyridin-3-yl, 2-methoxypyridin-3-yl, 2-(benzyloxy)-5-chloropyridin-3-yl, 2- trifluoromethylpyridin-4-yl, 5-(difluoromethyl)pyridin-3-yl, 4-methylpyrimidin-2-yl, pyrimidin-5-yl, 4- methylpyrimidin-5-yl, 4-trifluoromethylpyrimidin-5-yl, pyrazin-2-yl, 6-methylpyrazin-2-yl, 6- chloropyrazin-2-yl, 5-methylpyridzin-3-yl, lH-pyrrol-2-yl, thiophen-2-yl, 4-methylthiophen-2-yl, 5- methylthiophen-2-yl, 4-methoxythiophen-2-yl, thiophen-3-yl, 5-methylfuran-2-yl, isothiazol-5-yl, 2,4- dimethylthiazol-5-yl, 1 -methyl- lH-pyrazol-4-yl, oxazol-5-yl, and 1 -methyl- lH-imidazol-5-yl.
In certain embodiments, R9 is a 5-6 membered heteroaryl optionally substituted with R«. In certain embodiments, R9 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. In certain embodiments, R9 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. In certain embodiments, R9 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. In certain embodiments, each Re is each Re is independently selected from halogen, CN, NH2, cyclopropyl, ORp, Q-C6 alkyl optionally substituted with ORq, and CrC6 alkynyl optionally substituted with ORs. In certain embodiments, 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-3-yl, 2-amino-5-chloropyridin- 3-yl, 2-methylpyridin-3-yl, 4-methylpyridin-3-yl, 6-methylpyridin-3-yl, 4-chloropyridin-3-yl, 5-chloro-2- methylpyridin-3-yl, 5-chloro-6-methylpyridin-3-yl, 2-methoxypyridin-3-yl, 2-(benzyloxy)-5- chloropyridin-3-yl, 2-trifiuoromethylpyridin-4-yl, 4-methylpyrimidin-2-yl, pyrimidin-5-yl, 4- methylpyrimidin-5-yl, 4-trifluoromethylpyrimidin-5-yl, pyrazin-2-yl, 6-methylpyrazin-2-yl, 6- chloropyrazin-2-yl, 5-methylpyridzin-3-yl, 1 H-pyrrol-2-yl, thiophen-2-yl, 4-methylthiophen-2-yl, 5- methylthiophen-2-yl, 4-methoxythiophen-2-yl, thiophen-3-yl, 5-methylfuran-2-yl, isothiazol-5-yl, 2,4- dimethylthiazol-5-yl, 1 -methyl- lH-pyrazol-4-yl, oxazol-5-yl, and 1 -methyl- lH-imidazol-5-yl.
In certain embodiments, R9 is a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with Rf. In certain embodiments, R9 is a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with Rf, wherein the heterocyclyl contains one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain embodiments, 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. In certain embodiments, each Rf is independently selected from halogen, oxo, CrC alkyl, and Q-C6 alkoxycarbonyl. In certain
embodiments, each Rf is independently selected from halogen, oxo, and Q-Ce alkoxycarbonyl. In certain embodiments, each Rf is independently selected from halogen, oxo, and Ci-Ce alkoxycarbonyl. In certain embodiments, Rf is tert-butyl carboxylate. In certain embodiments, R9 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.
In certain embodiments, R9 is a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with Rf. In certain embodiments, R9 is a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with Rf, wherein the heterocyclyl contains one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain embodiments, 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. In certain embodiments, each Rf is independently selected from halogen, oxo, C Ce alkyl, and Ci-C6 alkoxycarbonyl. In certain
embodiments, each Rf is independently selected from halogen, oxo, and C\-C alkoxycarbonyl. In certain embodiments, each Rf is independently selected from halogen, oxo, and Ci-C6 alkoxycarbonyl. In certain embodiments, Rf is tert-butyl carboxylate. In certain embodiments, R9 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. In certain embodiments, R9 is a 5-6 membered saturated heterocyclyl optionally substituted with Rf. In certain embodiments, R9 is a 5-6 membered saturated heterocyclyl optionally substituted with Rf, wherein the heterocyclyl contains one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain embodiments, R9 is a 5-6 membered saturated heterocyclyl optionally substituted with Rf, wherein the heterocyclyl contains one oxygen heteroatom. In certain embodiments, R9 is a 5-6 membered saturated heterocyclyl optionally substituted with Rf, wherein the heterocyclyl is
tetrahydropyranyl. In certain embodiments, each Rf is independently selected from halogen, oxo, Ci-C alkyl, and CpC6 alkoxycarbonyl. In certain embodiments, each Rf is independently selected from halogen, oxo, CrC alkyl, and Ci- 6 alkoxycarbonyl. In certain embodiments, R9 is tetrahydropyran-4-yl.
In certain embodiments, R9 is a 5-6 membered partially unsaturated heterocyclyl optionally substituted with Rf. In certain embodiments, R9 is a 5-6 membered partially unsaturated heterocyclyl optionally substituted with Rf, wherein the heterocyclyl contains one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain embodiments, R9 is a 5-6 membered partially unsaturated heterocyclyl optionally substituted with Rf, wherein the heterocyclyl contains one or two heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. In certain embodiments, R9 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. In certain embodiments, R9 is a 5-6 membered partially unsaturated heterocyclyl optionally substituted with Rf, wherein the heterocyclyl is selected from 1 ,2-dihydropyridinyl, 1 ,6-dihydropyridinyl, 5,6- dihydropyridinyl, 1 ,2,5,6-tetrahydropyridinyl, and 3,6-dihydropyranyl. In certain embodiments, each Rf is independently selected from halogen, oxo, Ci-C6 alkyl, and Ci-C6 alkoxycarbonyl. In certain
embodiments, each Rf is independently selected from halogen, oxo, and CrC alkoxycarbonyl. In certain embodiments, Rf is tert-butyl carboxylate. In certain embodiments, R9 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. In certain embodiments, R9 is a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg. In certain embodiments, each Rg is independently selected from halogen, OH, OCH3 and C C alkyl optionally substituted with halogen. In certain embodiments, each Rg is selected from OCH3 and Q-C6 alkyl. In certain embodiments, R9 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.
In certain embodiments, R9 is a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg. In certain embodiments, each Rg is independently selected from halogen, OH, OCH3 and Ci-C6 alkyl optionally substituted with halogen. In certain embodiments, each Rg is selected from OCH3 and Ci-C6 alkyl. In certain embodiments, R9 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.
In certain embodiments, R9 is a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg. In certain embodiments, each Rg is independently selected from halogen and Ci-C6 alkyl. In certain embodiments, each Rg is CpQ alkyl. In certain embodiments, R9 is selected from cyclopentyl, cyclohexyl, (3R,5S)-3,5-dimethylcyclohexyl, 4,4-dimethylcyclohexyl, (3R,5S)-3,5- dimethylcyclohex-l-enyl and 4,4-dimethylcyclohex- l-enyl.
In certain embodiments, R9 is a 3-6 membered saturated carbocyclyl optionally substituted with Rg. In certain embodiments, each Rg is independently selected from halogen, OH, OCH3 and CrC6 alkyl optionally substituted with halogen. In certain embodiments, each Rg is selected from OH and Q-C6 alkyl. In certain embodiments, R9 is selected from cyclopentyl, cyclohexyl, (3R,5S)-3,5- dimethylcyclohexyl, 4,4-dimethylcyclohexyl, and 3-hydroxycyclohexyl.
In certain embodiments, R9 is a 3-6 membered saturated carbocyclyl optionally substituted with Rg. In certain embodiments, each Rg is independently selected from halogen and Q-C6 alkyl. In certain embodiments, each Rg is Ci-C6 alkyl. In certain embodiments, R9 is selected from cyclopentyl, cyclohexyl, (3R,5S)-3,5-dimethylcyclohexyl, and 4,4-dimethylcyclohexyl.
In certain embodiments, R9 is a 3-6 membered partially unsaturated carbocyclyl optionally substituted with Rg. In certain embodiments, each Rg is independently selected from halogen, OH, OCH3 and C C6 alkyl optionally substituted with halogen. In certain embodiments, each Rg is selected from OCH3 and C C6 alkyl. In certain embodiments, R9 is selected from (3R,5S)-3,5-dimethylcyclohex-l-enyl, 4,4- dimethylcyclohex-l-enyl and 3-methoxycyclohex-l-enyl. In certain embodiments, R is a 3-6 membered partially unsaturated carbocyclyl optionally substituted with Rg. In certain embodiments, each Rg is independently selected from halogen and CpC6 alkyl. In certain embodiments, each Rg is C C6 alkyl. In certain embodiments, R9 is selected from (3R,5S)-3,5- dimethylcyclohex- 1 -enyl and 4,4-dimethylcyclohex- 1 -enyl.
In certain embodiments, R is a 9-10 membered bicyclic heteroaryl optionally substituted with Rh. In certain embodiments, R9 is a 9-10 membered bicyclic heteroaryl optionally substituted with ¾, wherein the heteroaryl contains one, two or three heteroatoms selected from oxygen, nitrogen and sulfur. In certain embodiments, R9 is a 9-10 membered bicyclic heteroaryl optionally substituted with R , wherein the heteroaryl contains one or two nitrogen heteroatoms. In certain embodiments, R9 is a 9-10 membered bicyclic heteroaryl optionally substituted with Rh, wherein the heteroaryl is selected from
imidazopyridinyl, indolyl, pyrrolopyridinyl, isoquinolinyl, and quinolinyl. In certain embodiments, each Rh is independently selected from halogen and C\-C6 alkyl. In certain embodiments, R9 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.
In certain embodiments, R is phenylamino. In certain embodiments, R9 is phenoxy optionally substituted with Rj. In certain embodiments, each Rj is independently selected from halogen and benzyl. In certain embodiments, R9 is selected from phenoxy and 3-benzyl-5-fluorophenoxy.
In certain embodiments, Rio is hydrogen, halogen or methyl. In certain embodiments, Rio is hydrogen, F, CI or methyl. In a certain embodiment, RJ0 is hydrogen. In a certain embodiment, R]0 is F. In a certain embodiment, Ri0 is CI. In a certain embodiment, R]0 is methyl.
In certain embodiments, at least one of R5, R<;, R7, RT, ¾, Rg' and R9 is not hydrogen. In certain embodiments, at least one of R7, RT, R«, ¾· 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. In a particular embodiment, compounds of the invention have the stereochemical orientation represented by Formula Γ or Formula ΙΓ
Figure imgf000043_0001
Γ ΙΓ wherein X, Χ,, Χ2, Υ, Zu Ζ2, R,, R2, R2', R3, Ri, Ri', Rs, Re, R7, R?', Re, Rg', R9, and m are as defined herein.
In particular embodiments, compounds of the invention have the general Formula III - XXXIV:
Figure imgf000043_0002
Figure imgf000043_0003
Figure imgf000044_0001
Figure imgf000045_0001
44
Figure imgf000046_0001
Figure imgf000046_0002
Figure imgf000046_0003
Figure imgf000046_0004

Figure imgf000047_0001
wherein X, Y, Zt, Z2, i, R2, 2', R3, R4,
Figure imgf000047_0002
m, e, R7, R7', Rg, Rg', R9, Rd, Re, and X! are as defined herein.
The invention also encompasses prodrugs of the compounds described above. Suitable prodrugs where applicable 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. In a particular embodiment, 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. One manner of preparing prodrugs is described in USSN 08/843,369 filed April 15, 1997
(corresponding to PCT publication W09846576) the contents of which are incorporated herein by reference in their entirety.
Compounds of the invention may exist as stereoisomers e.g. diastereomers and enantiomers, resonance forms e.g. tautomers, solvates and salts, and all such sterioisomers, resonance forms, solvates and salts are within the scope of the invention herein. SYNTHESIS OF COMPOUNDS
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)).. It will be appreciated that synthetic procedures employed in the preparation of compounds of the invention will depend on the particular substituents present in a compound. In preparing compounds of the invention, protection of remote functionalities (e.g., primary or secondary amines, etc.) of intermediates may be necessary but may not be illustrated in the following general Schemes. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see Greene, T.W., and P.G.M. Wuts. Greene's Protective Groups in Organic Synthesis. 4th ed. New York: Wiley-Interscience, 2006 For illustrative purposes, the Schemes show general methods for preparing the compounds described herein, as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
In a particular general synthetic scheme, compounds of the Formula I may be prepared according to Scheme 1 wherein X, Y, Z Z2, Rj, R2, R2', R3, ¾, R4' and m are as defined herein. Scheme 1
Figure imgf000048_0001
Figure imgf000049_0001
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. In a Suzuki coupling reaction, h is reacted with boronic acid i to give the final compound of Formula I.
In a particular general synthetic scheme, compounds of the Formula II may be prepared according to Scheme 2 wherein Xi, X2, R5, Re, R7, R7', Rg, ¾' and R9, are as defined herein.
Scheme 2
Figure imgf000049_0002
Figure imgf000049_0003
Figure imgf000050_0001
In Scheme 2, l-(5-bromo-2-hydroxyphenyl)ethanone a (or alternatively l-(2-bromo-5-hydroxypyridin-4- yl)ethanone when one of Xi or X2 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 Ri-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. In a Suzuki coupling reaction, h is reacted with boronic acid i to give the final compound of Formula II.
In a particular general synthetic scheme, compounds of the Formula Π may be prepared according to Scheme 2 wherein X2, Re, R7, R7', ¾, Rs' and R9, are as defined herein.
Figure imgf000050_0002
l-(5-Bromo-2-hydroxyphenyl)ethanone a (or alternatively l-(2-bromo-5-hydroxypyridin-4-yl)ethanone when X2 is N) is reacted with the appropriate ketone or aldehyde b to give chromanone c. For compounds where R7 and/or R7> are not hydrogen, Step lb is then necessary. The ketone is then converted to the converted to the corresponding hydantoin (Step 2) to provide spirochroman e. Sprichroman e is reacted with the desired R^-iodide to give f followed by Lawesson's reagent to give thioxospirochroman g, which is converted to amine h by reacting with ammonium and tert-butyl hydroperoxide. Compound h can then be converted to II directly by common transition metal-mediated reactions, or alternatively by first conversion to boronate i, followed by a Suzuki compling to provide Π. Finally, compound a may also be converted to Π by modifying the order of steps by first performing Step 6a, followed by Steps 1-5.
It may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example:
reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art will apply techniques most likely to achieve the desired separation. 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. Enantiomers can also be separated by use of a chiral HPLC column.
A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and S. Wilen. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al. "Chromatographic resolution of enantiomers:
Selective review." J. Chromatogr., 113(3) (1975): pp. 283-302). Racemic mixtures of chiral compounds described herein may be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl- -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid, can result in formation of the diastereomeric salts. Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E., and S. Wilen. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a-
(trifluoromethyl)phenyl acetate (Jacob III, Peyton. "Resolution of (±)-5-Bromonornicotine. Synthesis of (R)- and (S)-Nornicotine of High Enantiomeric Purity." J. Org. Chem. Vol. 47, No. 21 (1982): pp. 4165- 4167), of the racemic mixture, and analyzing the Ή NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/1511 1). By method (3), 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
phenylcarbamates of polysaccharides as a chiral stationary phase." J. of Chromatogr. Vol. 513 (1990): pp. 375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
INDICATIONS
The compounds of the invention inhibit the cleavage of amyloid precursor protein (APP) by β-secretase which is implicated in diseases, in particular, neurodegenerative diseases such as Alzheimer's Disease (AD). In AD, processing of APP by β-secretase produces soluble N-APP which activates extrinsic apoptotic pathways by binding to death receptor 6 (DR6). Furthermore, APP that is processed by β- secretase is subsequently cleaved by γ-secretase thereby producing amyloid beta peptides such as Αβ 1-42 42 that form amyloid plaques which contribute to nerve cell death. Compounds of of the invention inhibit enzymatic cleavage of APP by β-secretase. Accordingly, in an aspect of the invention, there is provided a method of inhibiting cleavage of APP by β-secretase in a mammal comprising administering to said mammal an effective amount of a compound of the invention. In another aspect of the invention, there is provided a method for treating a disease or condition mediated by the cleavage of APP by β-secretase in a mammal, comprising administering to said mammal an effective amount of a compound of the invention. In another aspect, there is provided the use of a compound of the invention, a stereoisomer, diastereomer, enantiomer, tautomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative disease. In an embodiment, the neurodegenerative disease is Alzheimer's Disease. Compounds of the invention may be administered prior to, concomitantly with, or following administration of other therapeutic compounds. Sequential administration of each agent may be close in time or remote in time. The other therapeutic agents may be anti-neurodegenerative with a mechanism of action that is the same as compounds of the invention i.e. inhibit beta-secretase cleavage of APP, or a different mechanism of action, e.g. anti-Αβ antibodies. The compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.
The invention also includes compositions containing the compounds of the invention and a carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions. In a particular embodiment, there is provided a pharmaceutical composition comprising a compound of the invention, or a stereoisomer, diastereomer, enantiomer, tautomer or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient. Typically, the compounds of the invention used in the methods of the invention are formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e. carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range anywhere from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment. In an embodiment, formulations comprising compounds of the invention are sterile. The compounds ordinarily will be stored as a solid composition, although lyophilized formulations or aqueous solutions are acceptable.
Compositions comprising compounds of the invention will be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of administration, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The compounds may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.
Generally, the initial pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg/day, for example about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. Oral unit dosage forms, such as tablets and capsules, may contain from about 25 to about 1000 mg of the compound of the invention. The compound of the invention may be administered by any suitable means, including oral, sublingual, buccal, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. An example of a suitable oral dosage form is a tablet containing about 25mg, 50mg, lOOmg, 250mg, or 500mg of the compound of the invention compounded with about 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution is typically filtered, e.g. using a 0.2 micron filter, to remove impurities and contaminants.
Another formulation may be prepared by mixing a compound described herein and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.
Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.
Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide additives to provide an elegant presentation of the drug (i.e., a compound described herein or
pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
EXAMPLES
The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. For example, the synthesis of non- exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions.
Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds described herein. The identity and purity of compounds were checked by LCMS and 1 H NMR analysis.
Column chromatography was done on a Biotage system (Manufacturer: Dyax Corporation) having a silica gel column or on a silica SepPak cartridge (Waters) (unless otherwise stated). !H NMR spectra were recorded on a Varian instrument operating at 400 MHz. Ή-NMR spectra were obtained as CDC13, CD3OD, D20, (CD3)2SO, (CD3)2CO, C6D6, CD3CN solutions (reported in ppm), using tetramethylsilane (0.00 ppm) or residual solvent (CDC13: 7.26 ppm; CD3OD: 3.31 ppm; D20: 4.79 ppm; (CD3)2SO: 2.50 ppm; (CD3)2CO: 2.05 ppm; C6D6: 7.16 ppm; CD3CN: 1.94 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz).
In the Examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise indicated.
The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Biological Example Cellular BACE1 Inhibition Assay
The BACE inhibition properties of the compounds of the invention may be determined by the following in vitro cellular Amyloidp 1-40 production assay.
Inhibition of Amyloidp 1-40 production was determined by incubating cells with compound for 48 hours and quantifying the level of Amyloidp 1-40 using an HTRF immunoassay.
Materials and Methods: HEK-293 cells stably transfected with a DNA construct containing the coding sequence for the wild type APP695 sequence were grown in DMEM supplemented with 10% fetal bovine serum, penicillin/streptomycin and 150 μg/mL G418. Cells were plated in 96-well plates at 35,000 cells/well and allowed to attach for 8-12 hours. Media was changed to DMEM supplemented with 10% fetal bovine serum, penicillin/streptomycin 15 minutes prior to compound addition. Diluted compounds were then added at a final concentration of 0.5% DMSO. After 48 hours, 4 μΕ of media from each well was added to a corresponding well of a 384 well plate (Perkin Elmer Cat#6008280) containing the HTRF reagents. HTRF reagents were obtained from the CisBio Amyloidp 1-40 peptide assay kit (Cat#
62B40PEC) and were prepared as follows anti-peptide β (l-40)-Cryptate and anti-peptide P (l-40)-XL655 were stored in 2 plate aliquots at -80°C. Diluent and Reconstitution buffer were stored at 4°C. Aliquots of the two antibodies were diluted 1 : 100 with Reconstitution buffer, and this mixture was diluted 1 :2 with Diluent. 12 μΐ^ of the reagent mixture was added to the required wells of the 384 well assay plate. The assay plate was incubated at 4°C for 17 hours and then analyzed for fluorescence at 665 and 620 nm.
The following compounds were tested in the above assay:
Figure imgf000056_0001
Figure imgf000056_0002
Example 326 67.6 Example 368 0.9
Example 333 109 Example 374 2.6
Example 340 68.3 Example 376 5.7
Example 344 39.5 Example 377 5.5
Example 354 206 Example 382 1
Example 366 1.1
Example 1 2'-amino-6-(5-chloropyridin-3-yl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 Ή)- one
Figure imgf000057_0001
Step A: 5'-Bromo-2'-hydroxyacetophenone (21.4 g, 99.5 mmol) was diluted with toluene (400 mL), followed by the addition of propan-2-one (40.2 mL, 498 mmol) and pyrrolidine (8.31 mL, 99.5 mmol). The reaction was heated at reflux for 18 hours. The reaction was allowed to cool, diluted with ethyl acetate and washed with 2N HCl, dried over MgS04, filtered and concentrated. The material was purified on silica gel eluting with 5-30% ethyl acetate/hexanes to yield 6-bromo-2,2-dimethylchroman-4-one (18 g, 70.6 mmol, 70.9% yield) as an oil.
Step B: 6-Bromo-2,2-dimethylchroman-4-one (18.2 g, 71.3 mmol), KCN (9.29 g, 143 mmol) and ammonium carbonate (48.0 g, 499 mmol) were diluted with formamide (200 mL). The reaction was bubbled with argon for 15 minutes, sealed, heated to 70°C and stirred for 24 hours. The reaction was then heated to 1 10°C and stirred for 48 hours. The reaction was allowed to cool and poured into ice water (~1 L). The pH was adjusted to about 5 with concentrated HCl and the reaction was stirred for 1 hour. The precipitate was filtered and rinsed with water. The solid was air dried for 5 hours and placed under vacuum for 15 hours to afford 6-bromo-2,2-dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (21 g, 64.6 mmol, 90.5% yield) as a solid.
Step C: NaH (0.246 g, 6.15 mmol) was diluted with dimethylformamide ("DMF"; 6 mL), followed by the dropwise addition of 6-bromo-2,2-dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (1.0 g, 3.08 mmol; in 8 mL DMF). After stirring for 1 hour, CH3I (0.198 mL, 3.08 mmol) was added, and the reaction was stirred overnight. The reaction was diluted with dichloromethane ("DCM") and washed with IN HCl, water, brine, dried over MgS04, filtered and concentrated. The material was purified on silica gel eluting 5-100% ethyl acetate/hexanes to yield 6-bromo-r,2,2-trimethylspiro[chroman-4,4'-imidazolidine]- 2*,5'-dione (1.03 g, 3.04 mmol, 98.7% yield). Step D: 6-Bromo- ,2,2-trimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (3.0 g, 8.8 mmol) and Lawesson's Reagent (2.1 g, 5.3 mmol) were diluted with toluene (50 mL) and heated under reflux with a condensor and drying tube for 12 hours. The reaction was allowed to cool, diluted with ethyl acetate and washed with 10% aqueous sodium carbonate, water and brine. The organic layer was separated, dried over MgS04, filtered and concentrated. The material was purified on silica gel eluting with 5-50% ethyl acetate/hexanes to yield 6-bromo-r,2,2-trimethyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (2.0 g, 5.6 mmol, 64% yield). 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 NH4OH (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 MgS04, filtered and concentrated. The material was purified on silica gel eluting with 1-10% methanol/DCM with 1%
NH4OH to yield 2'-amino-6-bromo-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (1.5 g, 4.44 mmol, 78.8% yield).
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 μί, 0.74 mmol) was added, and the vial was sealed, heated to 95°C and stirred overnight. The reaction was allowed to cool and loaded onto silica gel eluting with 1-10% MeOH/DCM with 1% NH4OH to yield 2'- amino-6-(5-chloropyridin-3-yl)- ,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (25 mg, 0.067 mmol, 46% yield). Ή NMR (400 MHz, CDC13) δ 8.58 (d, 1H), 8.48 (d, 1H), 7.71 (t, 1H), 7.38 (d, 1H), 6.98 (d, 1H), 6.92 (s, 1H), 3.21 (s, 3H), 2.55 (d, 1H), 1.95 (d, 1H), 1.52 (s, 3H), 1.45 (s, 3H); m/z (APCI- pos) M+l = 371.2.
Example 2 2'-amino-6-(3,5-dichlorophenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one
Figure imgf000058_0001
2'-Amino-6-(3,5-dichlorophenyl)- ,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one was prepared according to the procedures of Example 1 in which 3,5-dichlorophenylboronic acid was used in place of 5-chloropyridin-3-ylboronic acid in Step F. Ή NMR (400 MHz, CDC13) δ 7.35 (dd, 1H), 7.29 (d, 2H), 7.26 (d, IH), 6.92 (d, IH), 6.90 (s, IH), 3.21 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.45 (s, 3H); m/z (APCI-pos) M+l = 404.1.
Example 3 2'-amino-r,2,2-trimethyl-6-(5-(trifluoromethyl)pyridin-3-yl)spiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000059_0001
2'- Amino- 1 ',2,2-trimethyl-6-(5-(trifluoromethyl)pyridin-3-yl)spiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the procedures of Example 1, substituting 5-(trifluoromethyl)pyridin-3-ylboronic acid for 5-chloropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 8.85 (s, IH), 8.80 (s, IH), 7.95 (s, IH), 7.41 (d, IH), 7.00 (d, IH), 6.97 (s,lH), 3.21 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.45 (s, 3H); m/z (APCI-pos) M+l = 405.2.
Example 4 2'-amino-6-(2-fluoro-3-methoxyphenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000059_0002
2'-Amino-6-(2-fluoro-3-methoxyphenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the procedures of Example 1, substituting 2-fluoro-3-methoxyphenylboronic acid for 5-chloropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 7.35-7.40 (m, IH), 7.00-7.10 (m, 2H), 6.85-6.95 (m, 3H), 3.90 (s, 3H), 3.18 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.45 (s, 3H); m/z (APCI-pos) M+l = 384.2.
Example 5 2'-amino-6-(5-methoxypyridin-3-yl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 Ή)- one
Figure imgf000059_0003
2'-Amino-6-(5-methoxypyridin-3-yl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one was prepared according to the procedures of Example 1, substituting 5-methoxypyridin-3-ylboronic acid for 5- chloropyridin-3-ylboronic acid. lU NMR (400 MHz, CDC13) δ 8.32 (s, IH), 8.22 (s, IH), 7.40 (d, IH), 7.21 (s, 1H), 6.95 (s, 1H), 6.90 (d,lH), 3.90 (s, 3H), 3.20 (s, 3H), 2.55 (d, 1H), 1.95 (d, 1H), 1.52 (s, 3H), 1.45 (s, 3H); m/z (APCI-pos) M+l = 367.2.
Example 6 2'-amino-6-(2-fluoro-5-methoxyphenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000060_0001
2'-Amino-6-(2-fluoro-5-methoxyphenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to Example 1, substituting 2-fluoro-5-methoxyphenylboronic acid for 5-chloropyridin- 3-ylboronic acid. 'H NMR (400 MHz, CDC13) δ 7.35 (m, 1H), 7.00 (m, 2H), 6.90 (d, 1H), 6.85 (m, 1H), 6.75 (m, 1H), 3.80 (s, 3H), 3.20 (s, 3H), 3.18 (s, 3H), 2.55 (d, 1H), 1.95 (d, 1H), 1.52 (s, 3H), 1.45 (s, 3H); m/z (APCI-pos) M+l = 384.2.
Example 7 2'-amino-6-(3-ethoxy-2-fluorophenyl)-l',2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000060_0002
2'-Amino-6-(3-ethoxy-2-fluorophenyl)-2,2-dimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the procedures of Example 1, substituting 3-ethoxy-2-fluorophenylboronic acid for 5-chloropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 7.35 (m, 1H), 7.05 (m, 2H), 6.90 (m, 3H), 4.15 (q, 2H), 3.18 (s, 3H), 2.55 (d, 1H), 1.95 (d, 1H), 1.52 (s, 3H), 1.46 (t, 3H), 1.43 (s, 3H); m/z (APCI-pos) M+l = 398.2.
Example 8 2'-amino-6-(3-chloro-5-fluorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000060_0003
2'-Amino-6-(3-chloro-5-fluorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one was prepared according to the procedures of Example 1 , substituting 3-chloro-5-fluorophenylboronic acid for 5-chloropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 7.35 (m, 1H), 7.22 (m, 1H), 7.05 (m, 2H), 6.92 (m, 2H), 3.20 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.43 (s, 3H); m/z (APCI-pos) M+l = 388.1.
Example 9 2'-amino-6-(3-chlorophenyl)-l\2,2 rimethylspiro[chroman-4,4'-imidazol]-5'( H)-one
Figure imgf000061_0001
2'-Amino-6-(3-chlorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( H)-one was prepared according to the procedures of Example 1, substituting 3-chlorophenylboronic acid for 5-chloropyridin-3- ylboronic acid. ¾ NMR (400 MHz, CDC13) δ 7.42 (s, IH), 7.35 (m, IH), 7.30 (m, 2H), 6.92 (m, 2H), 3.20 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.43 (s, 3H); m/z (APCI-pos) M+l = 370.2.
Example 10 2'-amino-6-(5-fluoropyridin-3-yl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)- one
Figure imgf000061_0002
2'-Amino-6-(5-fluoropyridin-3-yl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the procedures of Example 1 , substituting 5-fluoropyridin-3-ylboronic acid for 5- chloropyridin-3-ylboronic acid. *H NMR (400 MHz, CDC13) δ 8.52 (s, IH), 8.39 (d, IH), 7.45 (d, IH), 7.38 (d, IH), 6.95 (m, 2H), 3.20 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.43 (s, 3H); m/z (APCI- pos) M+l = 355.2.
Example 1 1 2'-amino-6-(5-chloro-2-fluorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5*(l'H)-one
Figure imgf000061_0003
2'-Amino-6-(5-chloro-2-fluorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one was prepared according to the procedures of Example 1, substituting 5-chloro-2-fluorophenylboronic acid for 5-chloropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 7.35 (m, IH), 7.30 (m, IH), 7.20 (m, IH), 6.90-7.10 (m, 3H), 3.20 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.43 (s, 3H); m/z (APCI-pos) M+l = 388.1 Example 12 2'-amino-6-(3-chloro-4-fluorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000062_0001
2'-Amino-6-(3-chloro-4-fluorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one prepared according to the procedures of Example 1, substituting 3-chloro-4-fluorophenylboronic acid for 5- chloropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 7.45 (m, IH), 7.25-7.35 (m, 2H), 7.15 (t, lH), 6.92 (d, IH), 6.90 (s, IH), 3.20 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.43 (s, 3H); m/z (APCI-pos) M+l = 388.2.
Example 13 2'-amino-6-(3 -fluorophe [chroman-4,4'-imidazol]-5'( 1 'H)-one
Figure imgf000062_0002
2'- Amino-6-(3 -fluorophenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the procedures of Example 1, substituting 3-fluorophenylboronic acid for 5-chloropyridin-3- ylboronic acid. Ή NMR (400 MHz, (CD3)2SO) δ 7.45 (m, 2H), 7.30 (m, 2H), 7.15 (t,lH), 6.92 (s, IH), 6.85 (d, IH), 3.05 (s, 3H), 2.20 (d, IH), 1.81 (d, IH), 1.42 (s, 3H), 1.39 (s, 3H); m/z (APCI-pos) M+l = 354.2.
Example 14 2'-amino-6-(3,5-difluorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( H)-one
Figure imgf000062_0003
2'-Amino-6-(3,5-difluorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( H)-one was prepared according to the procedures of Example 1, substituting 3,5-difluorophenylboronic acid for 5- chloropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 7.35 (m, IH), 6.90-7.00 (m, 4H), 6.70 (m,lH), 3.20 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.43 (s, 3H); m/z (APCI-pos) M+l = 372.2. Example 15 2'-amino-6-(3-fluoro-5-methoxyphenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000063_0001
2'-Amino-6-(3-fluoro-5-methoxyphenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the procedures of Example 1, substituting 3-fluoro-5-methoxyphenylboronic acid for 5-chloropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 7.35 (m, IH), 6.95 (m, 2H), 6.75 (m,2H), 6.55 (m, IH), 3.82 (s, 3H), 3.20 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.43 (s, 3H); m/z (APCI-pos) M+l = 384.2. Example 16 2'-amino-6-(3-methoxyphenyl)- ,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one
Figure imgf000063_0002
2'-Amino-6-(3-methoxyphenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the procedures of Example 1, substituting 3-methoxyphenylboronic acid for 5-chloropyridin- 3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 7.40 (m, IH), 7.30 (t, IH), 7.00 (m, 3H), 6.90 (d, IH), 6.84 (m, IH), 3.82 (s, 3H), 3.20 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.43 (s, 3H); m/z (APCI- pos) M+l = 366.2.
Example 17 (S)-2'-amino-6-(3-methoxyphenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 Ή)- one
Figure imgf000063_0003
(S)-2,-Amino-6-(3-methoxyphenyl)- ,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( H)-one was prepared according to the procedures of Example 16, followed by a chiral separation. Material was separated using a chiral tech 1 A column (4.6 mm x 250 mm) at 1 mL/min monitoring at 220 nM eluting with diethylamine ("DEA")/isopropyl alcohol ("IPA")/hexanes (0.01/5/95). This compound was the first eluting peak from the separation. Ή NMR (400 MHz, CDC13) δ 7.40 (m, IH), 7.30 (t, IH), 7.00 (m, 3H), 6.90 (d, IH), 6.84 (m, IH), 3.82 (s, 3H), 3.20 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.43 (s, 3H); m/z (APCI-pos) M+l = 366.2. 2'-amino-1^2,2 rimethyl-6-(3-(trifluoromethyl)phenyl)spiro[chroman-4,4'-imidazol]- 5'(l*H)-one
Figure imgf000064_0001
2'-Amino-l 2,2-trimethyl-6-(3-(trifluoromethyl)phenyl)spiro[chroman-4,4'-imidazol]-5^rH)-one was prepared according to the procedures of Example 1, substituting 3-(trifluoromethyl)phenylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 404.2.
Example 19 2'-amino-6-(3-chloro-2-fluorophenyl)- ,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000064_0002
2'-Amino-6-(3-chloro-2-fluorophenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the procedures of Example 1, substituting 3-chloro-2-fluorophenylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 388.2.
Example 20 2'-amino-r,2,2-trimethyl- -m-tolylspiro[chroman-4,4'-imidazol]-5'(rH)-one
Figure imgf000064_0003
2'-Amino-r,2,2-trimethyl-6-m-tolylspiro[chroman-4,4'-imidazol]-5'(rH)-one was prepared according to the procedures of Example 1 substituting m-tolylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 350.2. Example 21 2'-amino-6-(3-ethoxy-5-fluorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000065_0001
2'-Amino-6-(3-ethoxy-5 -fluorophenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to Example 1 , substituting 3-ethoxy-5-fluorophenylboronic acid for 5-chloropyridin-3- ylboronic acid, m/z (APCI-pos) M+l = 398.2.
Example 22 2"-amino-6'-(5-chloropyrid-3-yl)-l"-methyldispiro[cyclohexane-l-2'-chroman-4',4"- imidazol]-5'(l'H)-one
Figure imgf000065_0002
2"-Amino-6'-(5-chloropyrid-3-yl)- '-methyldispiro[cyclohexane-l-2'-chroman-4',4"-imidazol]-5'( H)- one was prepared according to the procedures of Example 1, substituting cyclohexanone for propan-2-one. m/z (APCI-pos) M+l = 41 1.2.
Example 23 2'-amino-6-(3-chlorophenyl)-l'-ethyl-2,2-dimethylspiro[chroman-4,4'-imidazol]-5'( H)- one
Figure imgf000065_0003
2'-Amino-6-(3-chlorophenyl)- 1 '-ethyl-2,2-dimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the procedures of Example 1, substituting CH3CH2I for CH3I, K2C03 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. m/z (APCI-pos) M+l = 384. Example 24 2'-amino-6-(3-chlorophenyl)- 1 '-(2-methoxyethyl)-2,2-dimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000066_0001
2'-Amino-6-(3-chlorophenyl)- 1 '-(2-methoxyethyl)-2,2-dimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the procedures of Example 1 , substituting CH3OCH2CH2Br for CH3I, K2CO3 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. m/z (APCI-pos) M+l = 414.
2'-amino-6-(3-chlorophenyl)- -(3-methoxypropyl)-2,2-dimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000066_0002
2'-Amino-6-(3-chlorophenyl)- 1 '-(3-methoxypropyl)-2,2-dimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the procedures of Example 1, substituting CH3OCH2CH2CH2Br for CH3I, K2C03 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. m/z (APCI-pos) M+l = 428.
Example 26 2'-amino-6-(3-chlorophenyl)- -(2-hydroxyethyl)-2,2-dimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000066_0003
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, K2CO3 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. The crude was purified by preparative TLC (1 mm plate, 5: 1 DCM:MeOH) to give 2'-amino-6-(3-chlorophenyl)-l'-(2- hydroxyethyl)-2,2-dimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one (0.018 g, 0.0450 mmol, 59.3% yield) as a solid, m/z (APCI-pos) M+l = 400.
Example 27 2'-amino-6-(3-chlorophenyl)-r-(3-hydroxypropyl)-2,2-dimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000067_0001
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, K2C03 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. The crude was purified by preparative TLC (0.5 mm plate, 5: 1 DCM:MeOH) to give 2'-amino-6-(3-chlorophenyl)-l'-(3-hydroxypropyl)-2,2- dimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (0.006 g, 0.0145 mmol, 69.6% yield) as a residue, m/z (APCI-pos) M+l = 414. Example 28 (R)-2'-amino-6-(5-chloropyridin-3-yl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000068_0001
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)/C02 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). !H NMR (400 MHz, (CD3)2SO) δ 8.67 (s, 1H), 8.54 (s, 1H), 8.02 (s, 1H), 7.55 (d, 1H), 7.02 (s, 1H), 6.89 (d, 1H), 6.51 (s, 2H), 3.05 (s, 3H), 2.21 (d, 1H), 1.84 (d, 1H), 1.43 (d, 6H); m/z (APCI-pos) M+l = 371.2.
Example 29 2"-amino-6'-(5-chloropyrid-3-yl)-l "-methyldispiro[cyclopropane-l,2'-chroman-4',4"- imidazol -5'(l'H)-one
Figure imgf000068_0002
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
(triphenylphosphoranylidene)acetate (50.5 g, 151 mmol), and benzoic acid (1.84 g, 15.1 mmol) were charged to a round bottom flask. The reaction mixture was heated to 80°C for 18 hours, under N2.
Purified by silica gel chromatography, eluting with DCM to yield methyl 2-cyclopropylideneacetate (5.0 g; 21%).
Step B: A thick- walled pressure tube was charged with methyl 2-cyclopropylideneacetate (5.3 g, 47 mmol), 4-bromophenol (25 g, 142 mmol), dimethylacetamide ("DMA"; 20 mL), and 4A molecular sieves (1 g). The mixture was sparged with N2 for 2 minutess. The mixture was heated to 1 10°C for 18 hours. After cooling to room temperature, the mixture was diluted with diethyl ether (100 mL), and washed with water (50 mL). The aqueous layer was re-extracted with diethyl ether (2 X 50 mL), washed with water (100 mL), brine (100 mL), dried (MgS04), filtered, and concentrated. The crude was purified by Biotage Flash 65 silica gel chromatography, eluting with 25%-40% DCM in hexanes to yield methyl 2-(l-(4- bromophenoxy)cyclopropyl)acetate (5.5 g, 33%). Step C: A IL round bottom flask was charged with with methyl 2-( l-(4- bromophenoxy)cyclopropyl)acetate (5.5 g, 19 mmol), MeOH (20 mL), THF (20 mL), and lithium hydroxide (0.69 g, 29 mmol) dissolved in water (7 mL). The mixture was stirred at room temperature. The starting material had been consumed after stirring for 18 hours. The mixture was concentrated in vacuo. The mixture was diluted with water (50 mL) and extracted organic soluble by-products with diethyl ether (2 X 20 mL). The combined organic phases were extracted with aqueous IN NaOH (20 mL). The aqueous phases were combined and acidified with aqueous 12N HC1 to pH 1. The aqueous phase was then extracted with diethyl ether (3 X 20 mL). These combined organic phases were washed with brine (50 mL), dried (Na2S04), filtered, and concentrated to yield 2-( l-(4- bromophenoxy)cyclopropyl)acetic acid (5.1 g, 73%).
Step D: 2-( 1 -(4-Bromophenoxy)cyclopropyl)acetic acid (5.1 g, 18.8 mmol) and neat thionyl chloride (6.86 mL, 94.1 mmol) were stirred together at room temperature for 4 hours under N2. The reaction mixture was concentrated using toluene (3 X 20 mL) to azeotrope residual thionyl chloride. The product yielded 2-(l-(4-bromophenoxy)cyclopropyl)acetyl chloride (5.5 g, 76%).
Step E: 2-(l -(4-Bromophenoxy)cyclopropyl)acetyl chloride (5.4 g, 19 mmol) as a solution in DCE (15 mL) was added to a stirred suspension of A1C13 (3.0 g, 22 mmol) in dichloroethane ("DCE"; 20 mL) at 0°C. The mixture was removed from the ice bath, and stirred for 30 minutes at room temperature. The reaction was quenched by pouring on to ice (50 mL) and extracting with DCM (3 X 20 mL). The combinded organic phases were dried (Na2S04), filtered, and concentrated. The crude was purified by Biotage Flash 65 silica gel chromatography, eluting with 10% ethyl acetate ("EtOAc")/hexanes to yield 6- bromospiro[chroman-2, l'-cyclopropan]-4-one (2.2 g, 39%). Step F: A Parr reactor (#4749, 23 mL capacity with teflon insert) was charged with absolute EtOH (6 mL) and 6-bromospiro[chroman-2, l'-cyclopropan]-4-one (1.5 g, 5.9 mmol). Ammonium carbonate (2.8 g, 30 mmol) and KCN (0.77 g, 12 mmol) were added. The mixture was heated in the sealed reactor to 130°C for 12 hours with stirring. After cooling to room temperature, the mixture was poured into water (20 mL) and EtOAc (20 mL), and acidified with aqueous 12N HC1 to a pH less than 3. N2 was bubbled through the reaction to sparge excess HCN for 20 minutes in a well-ventilated hood. The product was extracted with EtOAc (3 X 20 mL). The combined organic phases were washed with brine (50 mL), dried (MgS04), filtered, and concentrated to 6'-bromodispiro[cyclopropane-l ,2'-chroman-4',4"-imidazolidine]- 2",5"-dione as a solid (1.7 g, 71%; see Formula 29 f .
Figure imgf000069_0001
29f
Steps G-J: 2"-Amino-6'-(5-chloropyrid-3-yl)-l "-methyldispiro[cyclopropane-l-2'-chroman-4',4"- imidazol]-5'(l'H)-one (7 mg, 25%) was prepared according to the general procedures of Example 1, Steps C-F, substituting 6'-bromodispiro[cyclopropane-l,2'-chroman-4',4"-imidazolidine]-2",5"-dione (Formula 29f) for 6-bromo-2,2-dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione. Ή NMR (400 MHz, CDC13) δ 8.56 (s, 1H), 8.49 (s, 1H), 7.72 (s, 1H), 7.37 (m, 1H), 7.03 (s, 1H), 6.94 (m, 1H), 4.26 (br s, 2H), 3.19 (s, 3H), 2.73 (d, J = 14 Hz, 1H), 1.85 (d, J = 14 Hz, 1H), 1.17 (m, 1H), 0.99 (m, 1H), 0.79 (m, 2H); m/z (APCI-pos) M+l = 369, 371.
Example 30 (3S*,4R*)-2'-amino-6-(5-chloropyridin-3-yl)-3-fluoro-r,2,2-trimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000070_0001
Step A: (E)-N-(6-Bromo-2,2-dimethylchroman-4-ylidene)- 1-phenylethanamine was prepared using methodology described in Pravst, Igor, et al. "Efficient Synthesis of α,α-Difluoro Ketones Using
Selectfluor™ F-TEDA-BF4." Synthesis. 18 (2005): 3140-3146. A 50 mL round bottom flask was charged with 6-bromo-2,2-dimethylchroman-4-one (5.0 g, 20 mmol; prepared according to Example 1, Step A), toluene (20 mL), racemic 1-phenylethanamine (3.6 g, 29 mmol), and lastly 5 drops of trifluoroacetic acid ("TFA"). The mixture was refluxed with azeotropic removal of water using a Dean-Stark apparatus (5 mL capacity) for 2 days under N2, recharging the reaction vessel with toluene as needed. The mixture was cooled to room temperature and concentrated in vacuo. The crude was purified using a silica gel plug (150 mL), eluting with 20% EtOAc/hexanes to yield (E)-N-(6-bromo-2,2-dimethylchroman-4-ylidene)-l- phenylethanamine (7.7 g, 99%). Step B: A thick wall pressure tube was charged with (E)-N-(6-bromo-2,2-dimethylchroman-4-ylidene)- 1 - phenylethanamine (3.0 g, 8.4 mmol), anhydrous MeOH (40 mL), and Selectfluor® (3.3 g, 9.2 mmol; using methodology described in Pravst, Igor, et al. "Efficient Synthesis of α,α-Difluoro Ketones Using
Selectfluor™ F-TEDA-BF4." Synthesis. 18 (2005): 3140-3146). The mixture was heated to 60°C for 15 hours. The mixture was cooled to room temperature, and concentrated aqueous HC1 (5 mL) was added. The suspension was stirred for 15 minutes at room temperature. The mixture was concentrated in vacuo, diluted with DCM (50 mL) and aqueous IN HC1 (50 mL). The phases were separated. The organic phase was washed again with aqueous IN HC1 (50 mL), then with saturated aqueous NaHC03 (50 mL). The organic phase was dried (Na2S04), filtered, and concentrated. Ή NMR indicated a 1 : 1 mixture of mono- fluoro and difluoro-ketones. The products were separated by Biotage Flash 40L silica gel chromatography, eluting with 5% EtOAc/hexanes. The difluoro ketone eluted first. 6-Bromo-3-fluoro- 2,2-dimethylchroman-4-one was prepared (720 mg, 30%).
Step C: (3S*,4R*)-6-bromo-3-fluoro-2,2-dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione was prepared using the general procdure for Example 29, Step F, substituting 6-bromo-3-fluoro-2,2- dimethylchroman-4-one for 6-bromospiro[chroman-2,l'-cyclopropan]-4-one. The heating time was also reduced to 2 hours, instead of 12 hours.
Steps D-G: The remaining synthetic steps toward (3S*,4R*)-2'-amino-6-(5-chloropyridin-3-yl)-3-fluoro- r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (2 mg, 33%) were performed according to the general procedures of Example 1, Steps C-F, substituting (3S*,4R*)-6-bromo-3-fluoro-2,2- dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione for 6-bromo-2,2-dimethylspiro[chroman-4,4'- imidazolidine]-2',5'-dione in Step C. Relative stereochemistry was unconfirmed, m/z (APCI-pos) M+1 = 389.
Example 31 (2R*,4S*)-2'-amino-6-(5-chloropyridin-3-yl)-2-cyclopropyl-r-methylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000071_0001
Step A: A thick wall pressure tube was charged with l-(5-bromo-2-hydroxyphenyl)ethanone (30.8 g, 143 mmol), CH3CN (50 mL), cyclopropanecarbaldehyde (12.0 g, 172 mmol), and then pyrrolidine (12.0 mL, 143 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was concentrated. The mixture was diluted with diethyl ether (200 mL) and aqueous IN HC1 (200 mL). The phases were separated. The organic phase was washed with aqueous IN NaOH (200 mL) and then brine (200 mL). The organic phase was dried (MgS04), filtered, and concentrated to an oil. The crude was purified by Biotage Flash 65 silica gel chromatography, eluting with 5%-10% EtOAc/hexanes to yield 6-bromo-2- cyclopropylchroman-4-one (22 g, 49%).
Step B: 6-Bromo-2-cyclopropylspiro[chroman-4,4'-imidazolidine]-2',5'-dione was prepared using the general procedure for Example 29, Step F, substituting 6-bromo-2-cyclopropylchroman-4-one for 6- bromospiro[chroman-2, 1 '-cyclopropan]-4-one.
Steps C-F: The remaining synthetic steps toward (2R*,4S*)-2'-amino-6-(5-chloropyridin-3-yl)-2- cyclopropyl-r-methylspiro[chroman-4,4'-imidazol]-5'(rH)-one were performed according to the general procedures of Example 1, Steps C-F, substituting 6-bromo-2-cyclopropylspiro[chroman-4,4'- imidazolidine]-2',5'-dione for 6-bromo-2,2-dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione.
Diastereomers of the intermediate 2'-amino-6-bromo-2-cyclopropyl-r-methylspiro[chroman-4,4'- imidazol]-5'(l'H)-one were separated as follows. The diastereomeric, crude mixture 2'-amino-6-bromo-2- cyclopropyl- -methylspiro[chroman-4,4'-imidazol]-5'(rH)-one was triturated with DCM (5 mL) and filtered. The filtered solid was the diastereomer (2S*,4S*)-2'-amino-6-bromo-2-cyclopropyl-r- methylspiro[chroman-4,4'-imidazol]-5'(l'H)-one (792 mg). The mother liquor was purified by Biotage Flash 40L silica gel chromatography, eluting with neat EtOAc, then 5% MeOH in EtOAc to yield (2R*,4S*)-2'-amino-6-bromo-2-cyclopropyl- 1 '-methylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one ( 166 mg, 10%). This product was converted to (2R*,4S*)-2'-amino-6-(5-chloropyridin-3-yl)-2-cyclopropyl-l'- methylspiro[chroman-4,4'-imidazol]-5'( H)-one (8 mg, 28%) according to the general procedure for Example 1, Step F. m/z (APCI-pos) M+l = 382.
Example 32 2'-amino-6-(5-chloropyridin-3-yl)-2-isopropyl- 1 '-methylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000072_0001
Step A: A thick wall pressure tube was charged with l-(5-bromo-2-hydroxyphenyl)ethanone (37.6 g, 175 mmol), toluene (75 mL), isobutyraldehyde (25.2 g, 350 mmol), and then acetic acid (12.6 g, 210 mmol) and pyrrolidine (14.6 mL, 175 mmol). The mixture was heated to 70°C for 18 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The mixture was diluted with diethyl ether (200 mL) and aqueous IN HC1 (200 mL). The phases were separated. The organic phase was washed with aqueous IN NaOH (200 mL), then brine (200 mL). The organic phase was dried (MgS04), filtered, and concentrated to an oil to provide 6-bromo-2-isopropylchroman-4-one (46.3 g, 89%).
(23 g, 55%), 60:40 mixture of diastereomers) was prepared using the general procedure for Example 29, Step F, except substituting 6-bromo-2-isopropylchroman-4-one for 6-bromospiro[chroman-2,l'- cyclopropan]-4-one. The crude was purified by trituration with 1 : 1 diethyl ether/pentane, and filtered to remove colored by-products.
Steps C-F: The remaining synthetic steps toward 2'-amino-6-(5-chloropyridin-3-yl)-2-isopropyl-r- methylspiro[chroman-4,4'-imidazol]-5'(rH)-one (35 mg, 31%), 59:41 mixture of diastereomers) were performed according to the general procedures of Example 1 , Steps C-F, substituting 6-bromo-2- isopropylspiro[chroman-4,4'-imidazolidine]-2',5'-dione for 6-bromo-2,2-dimethylspiro[chroman-4,4'- imidazolidine]-2',5'-dione. m/z (APCI-pos) M+l = 385.
2"-amino-6'-(3-(difluoromethoxy)phenyl)- 1 "-methyldispiro[cyclopropane- 1 -2'-chroman- 4',4"-imidazol]-5'(l'H)-one
Figure imgf000073_0001
2 "-Amino-6'-(3 -(difluoromethoxy)phenyl)- Γ'-^
5'( l'H)-one (8 mg, 26%) was prepared from 2"-amino-6'-bromo-l "-methyldispiro[cyclopropane-l-2'- chroman-4',4"-imidazol]-5'(rH)-one, which was synthesized as described in Example 29, except substituting 3-(difluoromethoxy)phenylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos)
M+l = 400.
Example 34 (2S*,4S*)-2'-amino-2-benzyl-6-(3-chlorophenyl)-r-methylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000073_0002
Step A: A thick wall pressure tube was charged with l-(5-bromo-2-hydroxyphenyl)ethanone (21.5 g, 100 mmol), toluene (100 mL), 2-phenylacetaldehyde (24.0 g, 200 mmol), and then acetic acid (6.86 mL, 120 mmol) and pyrrolidine (8.37 mL, 100 mmol). The mixture was heated to 70°C for 18 hours. The reaction mixture was concentrated in vacuo. The mixture was diluted with diethyl ether (100 mL) and 2N aqueous NaOH ( 100 mL). The phases were separated, and the organic was washed with more 2N aqueous NaOH (100 mL). The combined organic phases were dried (MgS04), filtered and concentrated. The concentrate was purified by Biotage Flash 65 silica gel chromatography, eluting with 3%-10% EtOAc/hexanes to provide 2-benzyl-6-bromochroman-4-one (2.5 g, 7%).
Step B: A thick wall pressure tube was charged with formamide (15.7 mL, 394 mmol) and 2-benzyl-6- bromochroman-4-one (2.5 g, 7.88 mmol). Next, ammonium carbonate (5.30 g, 55.2 mmol) and KCN (1.03 g, 15.8 mmol) were added. The mixture was heated to 70°C while stirring for 18 hours. The reaction mixture was then heated with stirring for 4 days at 90°C. The reaction was poured on to ice and acidified with 2N aqueous HC1 to pH 3. N2 was bubbled through the mixture to purge excess HCN in a well-ventilated hood. The mixture was extracted with EtOAc (2 X 100 mL). The combined organic phases were washed with brine (200 mL), dried (MgS04), filtered, and concentrated. The crude was purified by 2 successive Biotage Flash 65 silica gel columns, eluting with l%-3% MeOH/DCM to provide 2-benzyl-6-bromospiro[chroman-4,4'-imidazolidine]-2',5'-dione (293 mg, 4%).
Steps C-F: The remaining synthetic steps toward (2S*,4S*)-2'-amino-2-benzyl-6-(3-chlorophenyl)-l'- methylspiro[chroman-4,4'-imidazol]-5'( H)-one (1 mg, 32%) were performed according to the general procedures of Example 1, Steps C-F, substituting 2-benzyl-6-bromospiro[chroman-4,4'-imidazolidine]- 2',5'-dione for 6-bromo-2,2-dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione. Diastereomers of the intermediate 2'-amino-2-benzyl-6-bromo- 1 '-methylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one were separated by preparative TLC (0.5 mm thickness, Rf = 0.44), eluting with 10% MeOH/DCM. This product was converted to (2S*,4S*)-2'-amino-2-benzyl-6-(3-chlorophenyl)-l'-methylspiro[chroman-4,4'- imidazol]-5'(l'H)-one according to the general procedure for Example 1, Step F, except substituting 3- chlorophenylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 432, 434.
Example 35 2"-amino-6'-(3-chloro-5-fluorophenyl)-l"-methyldispiro[cyclopropane-l,2'-chroman-4',4" imidazol]-5'(l'H)-one
Figure imgf000074_0001
2"-Amino-6'-(3-chloro-5-fluorophenyl)- '-methyldispiro[cyclopropane-l-2'-chroman-4',4"-imidazol]- 5'(l'H)-one (8 mg, 26%) was prepared from 2"-amino-6'-bromo-l "-methyldispiro[cyclopropane-l-2'- chroman-4',4"-imidazol]-5'(rH)-one, which was synthesized as described in Example 29, above, except substituting 3-chloro-5-fluorophenylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 386, 388.
Example 36 2'-amino-r,2,2-trimethyl-6-(5-methylpyridin-3-yl)spiro[chroman-4,4'-imidazol]-5'(rH)- one
Figure imgf000074_0002
Prepared according to the general procedures of Example 1, substituting 5-methylpyridin-3-ylboronic acid for 5-chloropyridin-3-ylboronic acid. !H NMR (400 MHz, CDC13) δ 8.51 (s, IH), 8.35 (s, IH), 7.55 (s, IH), 7.35 (d, IH), 6.95 (m, 2H), 3.20 (s, 3H), 2.55 (d, IH), 2.35 (s, 3H), 1.95 (d, IH), 1.52 (s, 3H), 1.43 (s, 3H); m/z (APCI-pos) M+l = 351.2. Example 37 2'-amino-6-(5-chloro-2-fluoropyridin-3-yl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000075_0001
Prepared according to the general procedures of Example 1, substituting 5-chloro-2-fluoropyridin-3- ylboronic acid for 5-chloropyridin-3-ylboronic acid. XH NMR (400 MHz, CDC13) δ 8.16 (s, IH), 7.75 (d, IH), 7.35 (d, IH), 6.95 (m, 2H), 3.20 (s, 3H), 2.55 (d, IH), 1.95 (d, IH), 1.52 (s, 3H), 1.43 (s, 3H); m/z (APCI-pos) M+l = 389.1. '-amino-6-(3-chloro-5-methoxyphenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-
Figure imgf000075_0002
Prepared according to the general procedures of Example 1, substituting 3-chloro-5- methoxyphenylboronic acid for 5-chloropyridin-3 -ylboronic acid, m/z (APCI-pos) M+l = 400.2. Example 39 2'-amino-6-(6-chloroimidazo[ 1 ,2-a]pyridin-8-yl)- 1 ',2,2-trimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000075_0003
Step A: 3-Bromo-5-chloro-2-pyridinamine (487 mg, 2.35 mmol) was diluted with ethanol (4 mL), followed by the addition of 2-chloroacetaldehyde (614 ί, 4.69 mmol). The reaction was heated at reflux for 3 hours. The reaction was cooled and loaded onto silica gel eluting with 10-50% ethyl acetate/hexanes to yield 8-bromo-6-chloroimidazo[l,2-a]pyridine (300 mg, 1.30 mmol, 55.2% yield).
Step B: 2'-Amino-r,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; see Example 103, Step A) and 8-bromo-6-chloroimidazo[l,2- ajpyridine (60 mg, 0.26 mmol) were diluted with dioxane (1 mL), followed by the addition of Pd(PPh3)4 (7.5 mg, 0.0065 mmol) and Na2C03 (324 μί, 0.65 mmol). The reaction was sealed, heated to 85°C and stirred for 12 hours. The reaction was loaded directly onto silica gel and eluted with 1-10% methanol/DCM (1% Ν¾ΟΗ) to afford 2'-amino-6-(6-chloroimidazo[l,2-a]pyridin-8-yl)-l',2,2- trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (18 mg, 0.044 mmol, 34% yield), m/z (APCI-pos) M+l = 410.2
Example 40 2-amino-6'-(3-chloro-5-fluorophenyl)-l-methyl-5-oxo-2",3",5",6"-tetrahydro- dispiro[imidazole-4,4'-chroman-2' 4"-pyran]
Figure imgf000076_0001
Prepared according to the general procedures of Example 8, substituting dihydro-2H-pyran-4(3H)-one for propan-2-one. *H NMR (400 MHz, CDC13) δ 7.35 (m, IH), 7.30 (m, IH), 7.21 (m, IH), 7.05 (m, 3H), 4.00 (m, IH), 3.82 (m, IH), 3.75 (m, 2H), 3.20 (s, 3H), 2.55 (m, IH), 1.95 (d, IH), 1.6-1.95 (m, 4H); m/z (APCI-pos) M+l = 430.2.
Example 41 2-amino-6'-(3-chloro-6-fluorophenyl)-l-methyl-5-oxo-2",3",5",6"-tetrahydro- dispiro [imidazole-4,4 ' -chroman-2 ' 4"-pyran]
Figure imgf000076_0002
Prepared according to the general procedures of Example 40, substituting 5-chloro-2-fluorophenylboronic acid for 3-chloro-5-fluorophenylboronic acid. Ή NMR (400 MHz, CDC13) δ 7.35 (m, IH), 7.30 (m, IH), 7.21 (m, IH), 7.05 (m, 2H), 6.90 (m, IH), 4.00 (m, IH), 3.82 (m, IH), 3.75 (m, 2H), 3.20 (s, 3H), 2.55 (m, IH), 1.95 (d, IH), 1.6-1.95 (m, 4H); m/z (APCI-pos) M+l = 430.2.
Example 42 2-amino-6'-(3-chloro-2-fluorophenyI)-l-methyl-5-oxo-2",3",5",6"-tetrahydro- dispiro[imidazole-4,4'-chrom n-2',4"-pyran]
Figure imgf000076_0003
Prepared according to the general procedures of Example 40, substituting 2-fluoro-3-chlorophenylboronic acid for 3-chloro-5-fluorophenylboronic acid, m/z (APCI-pos) M+l = 430.2. Example 43 2-amino-6'-(3-chloro-4-fluorophenyl)- 1 -methyl-5-oxo-2",3",5",6"-tetrahydro- dispiro[imidazole-4,4'-chroman-2',4"-pyran]
Figure imgf000077_0001
Prepared according to the general procedures of Example 40, substituting 3-chloro-4-fluorophenylboronic acid for 3-chloro-5-fluorophenylboronic acid. Ή NMR (400 MHz, CDC13) δ 7.45 (m, 1H), 7.30 (m, 1H), 7.21 (m, 1H), 7.15 (m, 1H), 7.00 (d, 1H), 6.85 (m, 1H), 4.00 (m, 1H), 3.82 (m, 1H), 3.75 (m, 2H), 3.20 (s, 3H), 2.55 (m, 1H), 1.95 (d, 1H), 1.6-1.95 (m, 4H); m/z (APCI-pos) M+l = 430.2.
Example 44 2"-amino-6'-(5-chloropyrid-3-yl)-l"-methyldispiro[cyclopentane-l ,2'-chroman-4',4"- imidazol]-5'(l'H)-one
Figure imgf000077_0002
Prepared according to the general procedures of Example 1, substituting cyclopentanone for propan-2- one. Ή NMR (400 MHz, CDC13) δ 8.55 (s, 1H), 8.45 (s, 1H), 7.70 (s, 1H), 7.35 (m, 1H), 6.95 (m, 2H), 3.20 (s, 3H), 1.6-2.2 (m, 10H); m/z (APCI-pos) M+l = 397.2.
Example 45 2"-amino-6'-(5-trifluoromethylpyrid-3-yl)- '-methyldispiro[cyclopentane-l,2'-chroman- 4',4"-imidazol]-5'(l'H
Figure imgf000077_0003
Prepared according to the general procedured of Example 44, substituting 5-(trifluoromethyl)pyridin-3- ylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 431.2. Example 46 2"-amino-6'-(5-methoxypyrid-3-yl)-l"-methyldispiro[cyclopentane-l,2'-chroman-4',4"- imidazol]-5*(l'H)-one
Figure imgf000078_0001
Prepared according to the general procedures of Example 44, substituting 5-methoxypyridin-3-ylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 393.2.
Example 47 2'-amino-6-(5-chloropyridin-3-yl)-r,3,3-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)- one
Figure imgf000078_0002
Step A: KOtBu (18.5 g, 165 mmol) was added portionwise to a cooled
(-78°C) solution of 6-bromochroman-4-one (7.5 g, 33.0 mmol) and Mel ( 10.3 mL, 165 mmol, d 2.275) in THF (100 mL). The reaction was allowed to warm to ambient temperature overnight. The reaction was poured into a water ether mix and separated. The ether layer was dried over MgSC>4, filtered and concentrated. The material was purified on silica gel eluting with 5-25% ethyl acetate/hexanes to yield 6- bromo-3,3-dimethylchroman-4-one (6.8 g, 26.7 mmol, 80.7% yield).
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 NaHS03 (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 K2C03 (390 mg, 2.82 mmol) and Mel (147 μί, 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. The material was purified on silica gel eluting with 5-50% ethyl acetate/hexanes to yield 6-bromo- ,3,3-trimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (700 mg, 2.06 mmol, 87.7% yield). 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). After refluxing for 12 hours, the reaction was cooled, diluted with ethyl acetate and washed with saturated bicarbonate, water and brine. The organics were dried over MgS04, filtered and concentrated. The material was purified on silica gel eluting with 5-50% ethyl acetate/hexanes to yield 6-bromo-l',3,3- trimethyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (400 mg, 1.13 mmol, 47.7% yield).
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 μΐ,, 15.8 mmol) and NH4OH (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 MgS04, filtered and concentrated. The material was purified on silica gel eluting with 1-10% methanol/DCM with 1% NH4OH to yield 2'- amino-6-bromo-r,3,3-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (250 mg, 0.739 mmol, 70.0% yield).
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(PPh3)4 (8.5 mg, 0.0074 mmol) were combined in a vial and diluted with dioxane (1 mL). Sodium carbonate (222 μί, 0.44 mmol) was added, and the vial was sealed, heated to 95°C and stirred overnight. The reaction was allowed to cool and loaded onto silica gel running a gradient of 1-10% MeOH/DCM with 1% NH4OH 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). Ή NMR (400 MHz, CDC13) δ 8.60 (s, 1H), 8.45 (s, 1H), 7.70 (m, 1H), 7.35 (d, 1H), 7.15 (s, 1H), 7.00 (d, 1H), 4.85 (d, 1H), 3.90 (d, 1H), 3.20 (s, 3H), 1.10 (s, 3H), 0.90 (s, 3H); m/z (APCI-pos) M+l =
371.1.
Example 48 2'-amino-6-(3-methoxyphenyl)-r,3,3-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one
Figure imgf000079_0001
Prepared according to the general procedures of Example 47, substituting 3-methoxyphenylboronic acid for 5-chloropyridin-3-ylboronic acid. Η NMR (400 MHz, CDC13) δ 7.40 (dd, 1H), 7.28 (t, 1H), 7.15 (d, 1H), 7.05 (d, 1H), 6.95 (m, 1H), 6.90 (d, 1H), 6.80 (m, 1H), 4.85 (d, 1H), 3.90 (d, 1H), 3.80 (s, 3H), 3.10 (s, 3H), 1.10 (s, 3H), 0.90 (s, 3H); m/z (APCI-pos) M+l = 366.2. Example 49 2'-amino-6-(5-fluoropyridin-3 -yl)- 1 ',3 ,3 -trimethylspiro[chroman-4,4'-imidazol]-5'( 1 Ή)- one
Figure imgf000080_0001
Prepared according to the general procedures of Example 47, substituting 5-fluoropyridin-3-ylboronic acid for 5-chloropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 8.55 (s, IH), 8.35 (d, IH), 7.45 (m, IH), 7.40 (m, IH), 7.15 (m, IH), 7.00 (d, IH), 4.85 (d, IH), 3.90 (d, IH), 3.10 (s, 3H), 1.10 (s, 3H), 0.90 (s, 3H); m/z (APCI-pos) M+l = 355.2.
Example 50 2'-amino-6-(5-methoxypyridin-3-yl)-r,3,3-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)- one
Figure imgf000080_0002
Prepared according to the general procedures of Example 47, substituting 5-methoxypyridin-3-ylboronic acid for 5-chloropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 8.35 (s, IH), 8.25 (d, IH), 7.40 (m, IH), 7.35 (m, IH), 7.15 (m, IH), 7.00 (d, IH), 4.85 (d, IH), 3.95 (s, 3H), 3.90 (d, IH), 3.10 (s, 3H), 1.10 (s, 3H), 0.90 (s, 3H); m/z (APCI-pos) M+l = 367.2.
Example 51 2'-amino- ,3,3-trimethyl-6- rimidin-5-yl)spiro[chroman-4,4'-imidazol]-5'(rH)-one
Figure imgf000080_0003
Prepared according to the general procedures of Example 47, substituting pyrimidin-5-ylboronic acid for 5-chloropyridin-3-ylboronic acid. JH NMR (400 MHz, CDC13) δ 9.15 (s, IH), 8.85 (s, 2H), 7.40 (m, IH), 7.15 (m, IH), 7.05 (d, IH), 4.85 (d, IH), 3.90 (d, IH), 3.10 (s, 3H), 1.10 (s, 3H), 0.90 (s, 3H); m/z (APCI- pos) M+l = 338.2. Example 52 4-(2'-amino-r,3,3-trimethyl-5'-oxo- ,5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)butanenitrile
Figure imgf000081_0001
2'-Amino-6-bromo-r,3,3-trimethylspiro[chroman-4,4'-imidazol]-5,( H)-one (45 mg, 0.13 mmol) and bis(tributyl phosphine) palladium (68 mg, 0.13 mmol) were diluted with (3-cyanopropyl)zinc(II) bromide (28 mg, 0.13 mmol, 0.5 M solution in THF). The reaction was purged with argon, sealed and heated to 70°C. After stirring for 12 hours, the reaction was allowed to cool and loaded directly onto silica gel. The material was eluted with 1-10% MeOH/DCM (1% NH4OH) to yield 4-(2'-amino-l',3,3-trimethyl-5'- oxo- ,5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)butanenitrile (10 mg, 0.031 mmol, 23% yield). Ή NMR (400 MHz, CDC13) δ 7.00 (m, IH), 6.85 (d, IH), 6.75 (m, IH), 4.80 (d, IH), 3.80 (d, IH), 3.10 (s, 3H), 2.65 (t, 2H), 2.30 (t, 2H), 1.90 (m, 2H), 1.10 (s, 3H), 0.90 (s, 3H); m/z (APCI-pos) M+l = 327.2.
Example 53 2'-amino-6-(3-(difluoromethoxy)phenyl)-r,3,3-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000081_0002
Prepared according to the general procedures of Example 47, substituting 3- (difluoromethoxy)phenylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 402.2. Example 54 2'-amino-6-(3-chlorophen l)- ,3,3-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one
Figure imgf000081_0003
Prepared according to the general procedures of Example 47, substituting 3-chlorophenylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 370.1. Example 55 2'-amino-l\3,3-frimethyl-6-(5-(tri
5'(l'H)-one
Figure imgf000082_0001
Prepared according to the general procedures of Example 47, substituting 5-(trifluoromethyl)pyridin-3- ylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 405.2.
Example 56 2'-amino-6-butyl- 1',3 ,3 -trimeth lspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one
Figure imgf000082_0002
Prepared according to the general procedures of Example 52, substituting butylzinc(II) bromide for (3- cyanopropyl)zinc(II) bromide, m/z (APCI-pos) M+l = 316.2.
Example 57 2'-amino-6-isopentyl- 1 ' 3,3-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one
Figure imgf000082_0003
Prepared according to the general procedures of Example 52, substituting isopentylzinc(II) bromide for (3-cyanopropyl)zinc(II) bromide, m/z (APCI-pos) M+l = 330.2.
Example 58 2'-amino-6-cyclohexyl- 3,3-trimethylspiro[chroman-4,4'-imidazol]-5'( H)-one
Figure imgf000082_0004
Prepared according to the general procedures of Example 52, substituting cyclohexylzinc(II) bromide for (3-cyanopropyl)zinc(II) bromide, m/z (APCI-pos) M+l = 342.2. Example 59 2'-amino-6-(cyclopropylethynyl)- 1 ',3,3-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one
Figure imgf000083_0001
2'-Amino-6-bromo-r,3,3-trimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (100 mg, 0.296 mmol), ethynylcyclopropane (195 mg, 2.96 mmol), Cu(I)I (5.63 mg, 0.0296 mmol) and PdCl2(PPh3)2 (20.8 mg, 0.0296 mmol) were diluted with THF (1 mL), followed by the addition of triethylamine ("TEA"; 82.4 μΐ., 0.591 mmol, d. 0.726). The reaction was sealed and heated to 70°C and stirred for 12 hours. The reaction was loaded onto a plug of silica gel and rinsed with three column volumes of 10%MeOH/DCM (w/1% NH4OH). This was concentrated, and the residue was purified on a gilson prep HPLC (CI 8) eluting with 5-95% water/methanol (0.1% formic acid) to afford 2'-amino-6-(cyclopropylethynyl)-r,3,3- trimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one (3 mg, 0.00928 mmol, 3.14% yield), m/z (APCI-pos) M+l = 324.2.
Example 60 2-(2'-amino-r,2,2-trimethyl-5'-oxo- ,5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)isonicotinonitrile
Figure imgf000083_0002
2-Chloroisonicotinonitrile (0.018 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 rimethyl-6-(4,4,5,5-tetramethyl-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. It was heated in a sealed vial to 100°C for 16 hours. It was cooled to ambient temperature and loaded directly onto a silica gel column. It was purified using a 3-15% methanol with 2% ammonium hydroxide/dichloromethane linear gradient to yield 2-(2'-amino-r,2,2-trimethyl-5'-oxo-l',5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)isonicotinonitrile (0.023 g, 0.064 mmol, 49% yield) as a solid, m/z (APCI-pos) M + 1 = 362.2. Example 61 2'-amino-6-(4-methoxypyridin-2-yl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( H)- one
Figure imgf000084_0001
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. It was heated in a sealed vial to 100°C for 16 hours. It was cooled to ambient temperature and loaded directly onto a silica gel column. It was purified using a 3-15% methanol with 2% ammonium hydroxide/dichloromethane linear gradient to yield 2'-amino-6-(4-methoxypyridin-2-y 1)- 1 ',2,2-trimethy lspiro[chrornan-4,4'-imidazol]- 5'(l'H)-one (0.01 1 g, 0.030 mmol, 23% yield) as a solid, m/z (APCI-pos) M + 1 = 367.2.
Example 62 2'-amino-6-(4-chloropyridin-2-yl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]
one
Figure imgf000084_0002
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. It was heated in a sealed vial to 100°C for 16 hours. It was cooled to ambient temperature and loaded directly onto a silica gel column. It was purified using a 3-15% methanol with 2% ammonium hydroxide/dichloromethane linear gradient to yield 2'-amino-6-(4-chloropyridin-2-yl)- ,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one (0.022 g, 0.059 mmol, 46% yield) as a solid. Ή NMR (400 MHz, CDC13) δ 8.47 (1H), 7.76 (1H), 7.58 (1H), 7.16 (1H), 6.95 (1H), 3.18 (3H), 2.55 (1H), 1.99 (1H), 1.52 (3H), 1.41 (3H); m/z (APCI- neg) M-l = 371.1. Example 63 2'-amino-6-(5-ethynylpyridin-3-yl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 Ή)- one
Figure imgf000085_0001
A 4 mL screw cap glass vial was charged with PdCl2(MeCN)2 (0.350 mg, 0.0014 mmol),
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (1.93 mg, 0.004 mmol), Cs2C03 (87.9 mg, 0.27 mmol), anhydrous acetonitrile (270 μί, 0.135 mmol), and 2'-amino-6-(5-chloropyridin-3-yl)-l',2,2- trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (50 mg, 0.135 mmol). The resulting suspension was sparged with nitrogen for 5 minutes and allowed to stir at room temperature for 30 minutes.
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
temperature, diluted with 10% MeOH/CH2Cl2 (15 mL), and transferred to a round bottom flask. The solvents were removed in vacuo, and the residue obtained was purified by flash chromatography on silica gel (Biotage Flash 12M+) eluting with 30% EtOAc/hexane (100 mL), followed by 5% MeOH/CH2Cl2. 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. Ή NMR (400 MHz, CDC13) δ 8.64 (dd, 2H), 8.44 (br s, IH), 7.83-7.82 (m, IH), 7.43 (dd, IH), 6.99 (d, IH), 6.95 (d, IH), 3.30 (s, 3H), 3.26 (s, IH), 2.56 (d, IH), 2.12 (d, IH), 1.54 (s, 3H), 1.46 (s, 3H). LCMS (APCI+) m/z 361 (M+H)+.
Example 64 2'-amino-r,2,2-trimethyl-6-(5-(prop-l-ynyl)pyridin-3-yl)spiro[chroman-4,4'-imidazol]-
5'(l'H)-one
Figure imgf000085_0002
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(PPh3)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 N2 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 MgS04 and filtered through a pad of Celite®. The filtrate collected was concentrated in vacuo, and the residue obtained was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 10% EtOAc/hexane to provide 3-bromo-5-(prop-l-ynyl)pyridine (681 mg, 79.8% yield) as a solid. Ή NMR (400 MHz, CDC13) δ 8.55 (d, 1H), 8.51 (d, 1H) 7.82-7.80 (m, 1H), 2.08 (s, 3H).
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 Na2C03 (144 μΐ,, 0.27 mmol), and 1,4-dioxane (779 μί, 0.078 mmol). The reaction was sparged with N2 for 5 minutes, sealed with a Teflon screw cap and stirred at 90°C. After 1 hour, the solvents were removed in vacuo, and the resulting residue was purified by C-18 reverse phase HPLC (Gilson UniPoint) eluting with a gradient of 5%-95% CHaCN/water containing 0.5% formic to provide 2'-amino-l',2,2- trimethyl-6-(5-(prop-l-ynyl)pyridin-3-yl)spiro[chroman-4,4'-imidazol]-5'(rH)-one (23 mg, 79% yield) as a solid. Ή NMR (400 MHz, CDC13) δ 8.60 -8.53 (m, 2H), 7.72 (s, 1H), 7.73 (d, 1H), 6.99 (d, 1H), 6.95 (d, 1H), 3.31 (s, 3H), 2.57 (d, 1H), 2.13 (d, 1H), 2.09 (s, 3H), 1.54 (s, 3H), 1.46 (s, 3H). LCMS (APCI+) m/z 375 (M+H)+.
Example 65 2'-amino-6-(3-chloro-5-ethynylphenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-
5'(l'H)-one
Figure imgf000086_0001
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 μί, 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 μί, 1.035 mmol), dichloro[l ,l'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (12.2 mg, 0.0148 mmol) and 1,4- dioxane (2957 μΕ, 0.2957 mmol). The reaction mixture was sparged with N2 for 5 minutes, sealed with a Teflon screw cap and stirred at 90°C for 1 hour. The mixture was allowed to cool to room temperature, then poured on to silica gel column (Biotage Flash 40S+) and eluted with 10% MeOH/CH2Cl2 to provide 2'-amino-6-(3-chloro-5-((trimethylsilyl)ethynyl)phenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one (187 mg, 99% yield) as an oil. MS (APCI+) m/z 466, 468 (M+H)+ with one chlorine. 468 (M+H)+ with one chlorine.
Step B: Solid potassium carbonate (44.2 mg, 0.32 mmol) was added to a solution of 2'-amino-6-(3- chloro-5-((trimethylsilyl)ethynyl)phenyl)-1^2,2-trimethylspiro[chroman-4,4'-imidazol]-5 rH)-one (185 mg, 0.291 mmol) in methanol (5.82 mL, 0.291 mmol), and the mixture was stirred at 50°C for 15 minutes. The solvent was removed, and the resulting residue was purified by C-18 reverse phase HPLC on Gilson UniPoint instrument using a gradient of 5%-95% CH3CN/water containing 0.5% formic to provide 2'- amino-e^S-chloro-S-ethynylpheny -l'^^-trimethylspirofchroman^^'-imidazolj-S rH^one (29 mg, 0.0736 mmol, 25.3% yield) as a solid. Ή NMR (400 MHz, (CD3)2SO) δ 8.19 (s, 1H), 7.55-7.54 (m, 1H), 7.50-7.47 (m, 3H), 6.94 (d, 1H), 6.87 (d, 1H), 4.37 (s, 1H), 3.05 (s, 3H), 2.20 (d, 1H), 1.86 (d, 1H), 1.43 (s, 3H), 1.37 (s, 3H). LCMS (APCI+) m/z 394, 396 (M+H)+ with one CI.
Example 66 2'-amino-6-(3-(cyclopropylethynyl)phenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000087_0001
2'-Amino-6-(3-chlorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (85 mg, 0.23 mmol) and ethynylcyclopropane (25.3 iL, 0.3 mmol) were processed as described in Gelman, Dmitri and Stephen L. Buchwald. "Efficient Palladium-Catalyzed Coupling of Aryl Chlorides and Tosylates with Terminal Alkynes: Use of a Copper Cocatalyst Inhibits the Reaction." Angewandte Chemie International Edition. Vol. 42(48), 2003: 5993-5996, to provide 2'-amino-6-(3-(cyclopropylethynyl)phenyl)-l',2,2- trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (40 mg, 43.6% yield) as a solid. LCMS (APCI+) m/z 401 (M+H)+.
Example 67 2'-amino-6-(5-(cyclopropylethynyl)pyridin-3-yl)-l',2,2-trimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000087_0002
2'-Amino-6-(5-chloropyridin-3-yl)- ,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (50 mg, 0.135 0.135 mmol) and ethynylcyclopropane (89 mg, 1.35 mmol) were processed as described in Gelman, Dmitri and Stephen L. Buchwald. "Efficient Palladium-Catalyzed Coupling of Aryl Chlorides and Tosylates with Terminal Alkynes: Use of a Copper Cocatalyst Inhibits the Reaction." Angewandte Chemie International Edition. Vol. 42(48), 2003: 5993-5996, to provide 2'-amino-6-(5- (cyclopropylethynyl)pyridin-3-yl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (28 mg, 52 yield) as a solid. LCMS (APCI+) m/z 401 (M+H)+.
Example 68 2'-amino-6-(3,5-bis(trifluoromethyl)phenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000088_0001
Prepared according to the general procedures of Example 1 , substituting 3,5- bis(trifluoromethyl)phenylboronic acid for 5-chloropyridin-3-ylboronic acid in Step F. m/z (APCI+) (M+l) = 472. Example 69 2'-amino- 1 ',2,2-trimethyl-6- rimidin-5-yl)spiro[chroman-4,4'-imidazol]-5'( 1 'H)-one
Prepared according to the general procedures of Example 1, substituting pyrimidin-5-ylboronic acid for 5- chloropyridin-3-ylboronic acid in Step F. m/z (APCI+) (M+l) = 338. Example 70 2'-amino-6-(3-chlorophenyl)-2,2-bis(fluoromethyl)- -methylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000088_0003
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 (Na2S04), 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: 2'-Amino-6-(3-chlorophenyl)-2,2-bis(fluoromethyl)- -methylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one was prepared according to the procedures of Example 1 , Steps B-F, substituting 6-bromo-2,2- bis(fluoromethyl)-chroman-4-one for 6-bromo-2,2-dimethylchroman-4-one in Step B, and substituting 3- chlorophenylboronic acid for 5-chloropyridin-3-ylboronic acid in Step F. m/z (APCI+) (M+l) = 406.
Example 71 2'-amino-6-(3-(difluoromethoxy)phenyl)-2,2-bis(fluoromethyl)- -methylspiro[chroman- 4,4'-imidazol]-5'(l'H)-one
Figure imgf000089_0001
Prepared according to the procedures of Example 70 substituting 3-(difluoromethoxy)phenylboronic acid for 3-chlorophenylboronic acid, m/z (APCI+) (M+l) = 438.
2'-amino-6-(5-chloropyridin-3-yl)-2,2-bis(fluoromethyl)- -methylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000089_0002
Prepared according to the procedures of Example 70 substituting 5-chloropyridin-3-ylboronic acid for 3- chlorophenylboronic acid. Ή NMR (400 MHz, (CD3)2SO) δ 8.70 (d, J = 2.0 Hz, 1H),8.56 (d, J = 2.0 Hz, 1H), 8.06 (dd, J = 2.0, 2.0 Hz, 1H), 7.62 (dd, J = 8.6, 2.1 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.62 (br s, 2H), 4.79-4.76 (m, 1H), 4.68-4.64 (m, 1H), 3.07 (s, 3H), 2.56-2.44 (m, 2H), 2.42-2.30 (m, 1H), 1.90 (d, J = 14.5 Hz, 1 H). m/z (APCI+) (M+l) = 407. Example 73 2-amino-6'-(3-chlorophenyl)-l,2',2'-trimethyl-2',3'-dihydrospiro[imidazole-4,4'- pyrano[2,3-c]pyridin]-5(lH)-one
Figure imgf000090_0001
Step A: 2.5M n-BuLi in hexanes (59.7 mL, 149 mmol) was added by syringe to a -78°C solution of diisopropylamine (21.8 mL, 155 mmol) in ether (200 mL). The reaction mixture was stirred for 35 minutes, and then a solution of 6-bromopyridin-3-yl 4-methylbenzene-sulfonate (9.80 g, 29.9 mmol; prepared as described in Serban, Georgeta, Hitoshi Abe, Yasuo Takeuchi, and Takashi Harayama. "A New Approach to the Benzopyridoxepine Core by Metal Mediated Intramolecular Biaryl Ether
Formation." Heterocycles. Vol. 75, Issue 12 (2008): 2949-2958) in ether (450 mL) was added via canula over 50 minutes. The reaction mixture was stirred at -78°C for 2 hours, and then a -78°C solution of N- methoxy-N-methylacetamide (12.7 mL, 1 19 mmol) in ether (20 mL) was added by canula. The reaction mixture was stirred another 1 hour, after which saturated NH4CI (200 mL) was added, and the reaction mixture was removed from the cold bath and allowed to warm to ambient temperature. The mixture was diluted with water and extracted with ether (2 X). The combined extracts were dried (NaaSC^), filtered, and concentrated. The crude was purified on silica gel (5-40% EtOAc in hexanes gradient) to give recovered 6-bromopyridin-3-yl 4-methylbenzenesulfonate (4.4 g, 44.9% yield) as a solid and 4-acet l-6- bromopyridin-3-yl 4-methylbenzene-sulfonate (3.20 g, 28.9% yield) as an oil.
Step B: LiOH-H20 (0.725 g, 17.3 mmol) was added to a 0°C solution of 4-acetyl-6-bromopyridin-3-yl 4- methylbenzenesulfonate (3.20 g, 8.64 mmol) in THF (26 mL) and H20 (13 mL). The reaction mixture was then warmed to ambient temperature and stirred for 4 hours. Saturated NH4CI was added, and the reaction mixture was extracted with EtOAc (2 X). The combined extracts were dried (Na2S04), filtered and concentrated. The crude was purified on silica gel (5-35% EtOAc in hexanes gradient) to give l-(2- bromo-5-hydroxypyridin-4-yl)ethanone (1.34 g, 71.8% yield) as a crystalline solid.
Step C: Acetone (2.28 mL, 31.0 mmol), acetic acid (0.444 mL, 7.75 mmol), and pyrrolidine (0.518 mL, 6.20 mmol) were added successively to a sealable reaction tube containing a solution of l-(2-bromo-5- hydroxypyridin-4-yl)ethanone (2.56 g, 1 1.85 mmol) in toluene (1.5 mL). The tube was sealed, and the reaction mixture was heated in a 70°C sand bath and stirred for 4.5 hours. The reaction mixture was cooled to ambient temperature. The toluene was concentrated in vacuo, and the residue was dissolved in EtOAc (200 mL) and 1M HCl (200 mL). The mixture was extracted with EtOAc (2 X), and the combined extracts were dried (Na2S04), filtered and concentrated. The crude was purified on silica gel (5-40% EtOAc in hexanes gradient) to give 6-bromo-2,2-dimethyl-2H-pyrano[2,3-c]pyridin-4(3H)-one (1.25 g, 41%) as an oil, which solidified on standing. Step D: 2-Amino-6'-(3-chlorophenyl)-l,2^2' rimethyl-2^3'-dihydrospiro[imidazole-4,4'-pyrano[2,3- c]pyridin]-5(lH)-one was prepared according to the procedures of Example 1, Steps B-F, substituting 6- bromo-2,2-dimethyl-2H-pyrano[2,3-c]pyridin-4(3H)-one for 6-bromo-2,2-dimethylchroman-4-one in Step B, and substituting 3-chlorophenylboronic acid for 5-chloropyridin-3-ylboronic acid in Step F. m/z (APCI+) (M+l) = 371.
Example 74 3-(2'-amino-r,2,2-trimethyl-5'-oxo-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6- yl)benzonitrile
Figure imgf000091_0001
Prepared according to the procedures of Example 1, substituting 3-cyanophenylboronic acid for 5- chloropyridin-3-ylboronic acid in Step F. Ή NMR (400 MHz, CDC13) δ 7.71 (s, 1H), 7.66 (d, J = 7.8 H, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.48 (dd, J = 7.6, 7.6 Hz, 1H), 7.38 (dd, J = 8.6, 2.0 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.93 (s, 1H), 3.23 (s, 3H), 2.55 (d, J = 14.1 Hz, 1H), 1.99 (d, J = 14.3 Hz, 1H), 1.53 (s, 3H), 1.44 (s, 3H). m/z (APCI+) (M+1) = 361.
Example 75 5 -(2'-amino- 1 ',2,2-trimethy 1-5 '-οχο- Γ, 5 '-dihydrospiro [chroman-4,4'-imidazole] -6- yl)nicotinonitrile
Figure imgf000091_0002
Prepared according to the procedures of Example 1, substituting 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)nicotinonitrile for 5-chloropyridin-3-ylboronic acid in Step F. Ή NMR (400 MHz, CDC13) δ 8.89 (s, 1H), 8.78 (s, 1H), 7.98 (s, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.0 (d, J = 7.7 Hz, 1H), 6.93 (s, 1H), 3.21 (s, 3H), 2.53 (d, J = 13.9 Hz, 1H), 1.98 (d, J = 13.9 Hz, 1H), 1.53 (s, 3H), 1.44 (s, 3H). m/z (APCI+) (M+l) = 362. Example 76 3-(2'-amino-r,2,2-trimethyl-5'-oxo-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-5- fluorobenzonitrile
Figure imgf000092_0001
2'-Amino-1^2,2 rimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)spiro[chroman-4,4'-imidazol]- 5'(l'H)-one (0.050 g, 0.13 mmol), 3-bromo-5-fluorobenzonitrile (0.052 g, 0.26 mmol), and Pd(PPh3)4
(0.015 g, 0.013 mmol) were combined in dioxane (0.65 mL) and 2M Na2C03 (0.26 mL, 0.52 mmol) (both degassed with nitrogen sparge for 45 minutes prior to use), nitrogen purged headspace, and the reaction vial was capped. The reaction mixture was heated in a 90°C reaction block and stirred for 17 hours. The reaction mixture was then diluted with DCM, Na2S04 was added, and the mixture was stirred 10 minutes. The mixture was filtered through a cotton-plugged pipet topped with Na2S04, rinsed with DCM, and the filtrate was concentrated. The crude was purified by preparative TLC (1 mm plate, 9: 1 DCM:7N
NH3/MeOH) to give 3-(2'-amino- 1 ',2,2-trimethyl-5'-oxo- 1 ',5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)- 5-fluorobenzonitrile (0.020 g, 41% yield) as a powder. Ή NMR (400 MHz, CDC13) δ 7.52 (s, 1H), 7.43- 7.32 (m, 2H), 3.32-7.22 (m, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.91 (s, 1H), 3.23 (s, 3H), 2.53 (d, J = 14.0 Hz, 1H), 1.98 (d, J = 14.0 Hz, 1H), 1.53 (s, 3H), 1.44 (s, 3H). m/z (APCI+) (M+l) = 379.
Example 77 3-(2'-amino-r,2,2-trimethyl-5'-oxo- ,5'-dihydrospiro[chroman-4,4,-imidazole]-6-yl)-5- chlorobenzonitrile
Figure imgf000092_0002
Prepared according to the procedures of Example 76, substituting 3-bromo-5-chlorobenzonitrile for 3- bromo-5-fluorobenzonitrile. Ή NMR (400 MHz, (CD3)2SO) δ 7.94 (d, J = 1.8 Hz, 2H), 7.87 (dd, J = 1.8, 1.8 Hz, 1H), 7.56 (dd, J = 8.6, 2.3 Hz, 1H), 7.05 (s, 1H), 6.89 (d, J = 8.6 Hz, 1H), 3.06 (s, 3H), 2.21 (d, J = 13.9 Hz, 1H), 1.86 (d, J = 13.9 Hz, 1H), 1.43 (s, 3H), 1.39 (s, 3H). m/z (APCI+) (M+l) = 395. Example 78 2'-amino-6-(3-cyclopropyl-5-fluorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-
5*(l'H)-one
Figure imgf000093_0001
Step A: A mixture of l ,3-dibromo-5-fluorobenzene (248 μί, 1.97 mmol), potassium
cyclopropyltrifluoroborate (321 mg, 2.17 mmol), K2CO3 (816.5 mg, 5.91 mmol), PdCl2(dppf)*dcm (32 mg, 0.039 mmol), and toluene/water (3: 1, 8 mL) was sparged with N2 for 5 minutes. The mixture was stirred at 90°C for 18 hours and allowed to cool to room temperature. The reaction mixture was then diluted with EtOAc (50 mL) and washed with brine (3 X 20 mL). The organic layer was separated, dried (MgS04), filtered and concentrated in vacuo. A portion of the crude product obtained was purified by preparative TLC eluting with hexane to provide l-bromo-3-cyclopropyl-5-fluorobenzene as a liquid.
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 Na2C03 (241 μί, 0.45 mmol), and 1 ,4-dioxane (1.3 mL, 0.13 mmol). The reaction mixture was sparged with N2 for 5 minutes, capped, and stirred at 90°C for 90 minutes 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 (MgSC^), filtered and concentrated in vacuo. The residue obtained was passed through a silica plug eluting with 5% MeOH/DCM to provide the semi pure product. This was then purified by preparative TLC eluting with 7% MeOH/DCM. The product isolated was filtered through a 45 μΜ filter and concentrated in vacuo. The residue obtained was crystallized from DCM/Et20 to provide 2'-amino-6-(3-cyclopropyl-5-fluorophenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one (14 mg, 0.036 mmol, 27% yield) as a solid. Ή NMR (400 MHz, CDC13) δ 7.36 (d, J=8.61 Hz, 1H), 6.95 -6.87 (m, 4H), 6.63 (d, J=10.96Hz, 1H), 3.19 (s, 3H), 2.56 (d, J=13.03 Hz, 1H), 1.97 (d, J=14.08Hz, 1H), 1.94-1.88 (m, 1H), 1.52 (s, 3H), 1.41 (s, 3H), 1.02-0.97 (m, 2H), 0.73-0.69 (m, 2H); LCMS (APCI+) m/z 394 (M+H)+. Example 79 3-(2'-amino-1^2,2-trimethyl-5'-oxo-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-5- bromobenzonitrile
Figure imgf000094_0001
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 (50 mg, 0.13 mmol), 3,5-dibromobenzonitrile (34 mg, 0.13 mmol), dichloro[l, -bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (5.3 mg, 0.0065 mmol), 20% aqueous Na2C03 (241 μΐ., 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 (MgS04), 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. The solid formed was filtered, washed with additional EtOAc (2 X 1 mL) to provide 3-(2'-amino-r,2,2-trimethyI-5'-oxo- ,5'- dihydrospiro[chroman-4,4'-imidazole]-6-yl)-5-bromobenzonitrile ( 12 mg, 21% yield) as a solid. 'H NMR (400 MHz, (CD3)2SO) δ 8.05 (s, 1H), 7.97 (s, 2H), 7.54 (d, J=7.04Hsz, 1H), 6.99 (s, 1 H), 6.88 (d,
J=8.61Hz, 1H), 6.52 (br s, 2H), 3.05 (s, 3H), 2.19 (d, J=14.08 Hz, 1H), 1.82 (d, J=14.08 Hz, 1H), 1.43 (s, 3H), 1.39 (s, 3); LCMS (APCI+) m/z 439, 442 (M+H)+. -(2'-amino-l',2,2-trimethyl-5'-oxo- ,5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-5-
Figure imgf000094_0002
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 B: A resealable glass pressure tube was charged with 2'-amino- ,2,2-trimethyl-6-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)spiro[chroman-4,4'-imidazol]-5'(rH)-one (50 mg, 0.13 mmol), 3- bromo-5-cyclopropylbenzonitrile (35 mg, 0.16 mmol), dichloro[l, l'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (5.3 mg, 0.0065 mmol), 20% aqueous Na2C03 (241 0.45 mmol), and 1 ,4-dioxane ( 1.3 mL, 0.13 mmol). The reaction was sparged with N2 for 5 minutes, capped, and stirred at 90°C for 2 hours and allowed to cool to room temperature. The mixture was then diluted with EtOAc, dried with MgS04, filtered, and concentrated in vacuo. The residue obtained was passed through a silica gel column (Biotage Flash 12+) eluting with 3%
MeOH/DCM and then repurified by preparative TLC eluting with 5% MeOH/DCM to provide 3-(2'- amino- 1 ',2,2-trimethyl-5'-oxo- 1 ',5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-5-cyclopropylbenzonitrile (28 mg, 54% yield) as a solid. Ή NMR (400 MHz, CDC13) δ 7.46 (s, IH), 7.35 (m, 2H), 7.21 (s, IH), 6.94 (d, J=8.61 Hz, IH), 6.89 (s, IH), 3.21 (s, 3H), 2.54 (d, J=14.08 Hz, IH), 1.97 (d, J= 14.86Hz, IH), 1.95-1.91 (m, IH), 1.52 (s, 3H), 1.43 (s, 3H), 1.07-1.03 (m, 2H), 0.75-0.72 (m, 2H); LCMS (APCI+) m/z 401 (M+H)+.
Example 81 2'-amino-6-(5-cyclopropylpyridin-3-yl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000095_0001
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 B: 2'-Amino-6-(5-cyclopropylpyridin-3-yl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (27 mg, 55%) yield) was prepared according to the general procedures described in Example 78, Step B, substituting 3-bromo-5-cyclopropylpyridine (31 mg, 0.16 mmol) for l-bromo-3-cyclopropyl-5- fluorobenzene. ¾ NMR (400 MHz, CDC13) δ 8.45 (s, IH), 8.31 (s, IH), 7.36-7.33 (m, 2H), 6.95-6.93 (m, 2H), 3.19 (s, 3H), 2.56 (d, J=14.08 Hz, IH), 1.98 (J=14.08 Hz, IH), 1.94-1.89 (m, IH), 1.52 (s, 3H), 1.42 (s, 3H), 1.03 (d, J=7.04 Hz, 2H), 0.76-0.74 (m, 2H); LCMS (APCI+) m/z 377 (M+H)+.
Example 82 2'-amino-6-(3-cyclopropylphenyl)- ,2,2-trimethylspiro[chroman-4,4'-imidazol]
one
Figure imgf000095_0002
2'-Amino-1^2,2-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 l-bromo-3-cyclopropylbenzene (31 mg, 0.16 mmol) were processed according to the general proceudres described in Example 104 to provide 2'-amino-6-(3- cyclopropylphenyl)-1^2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (15 mg, 31% yield) as a solid. Ή NMR (400 MHz, CDC13) δ 7.38 (d, J= 8.61 Hz, IH), 7.29 (m, IH), 7.22-7.18 (m, IH), 7.15 (s, IH), 6.97 (s, 2H), 6.92 (d, J=8.61 Hz, IH), 3.18 (s, 3H), 2.57 (d, J= 14.08Hz, IH), 1.98 (d, J=14.08 Hz, IH), 1.95-1.88 (m, IH), 1.51 (s, 3H), 1.41 (s, 3H), 1.00-0.95 (m, 2H), 0.76-0.67 (m, 2H); LCMS (APCI+) m/z 376 (M+H)+.
Example 83 3-(2'-amino-r,2,2-trimethyl-5'-oxo-r,5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)-5-
(prop- 1 -ynyl)benzonitrile
Figure imgf000096_0001
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. Ή NMR (400 MHz, CDC13) δ 7.65 (m, IH), 7.58 (s, IH), 7.55 (s, IH), 7.36-7.34 (m, IH), 6.95-6.89 (m, 2H), 3.23 (s, 3H), 2.53 (d, J=14.08Hz, IH), 2.07 (s, 3H), 1.98 (d, J= 14.08 Hz, IH), 1.52 (s, 3H), 1.43 (s, 3H); LCMS (APCI+) m/z 399 (M+H)+.
Example 84 2'-amino-6-(3-fluoro-5-(prop- 1 -ynyl)phenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000096_0002
Step A: l,3-Dibromo-5-fluorobenzene (0.49 mL, 3.94 mmol), copper(I) iodide (0.23 g, 1.18 mmol), Pd(PPh3)4 (0.23 g, 0.199 mmol), tetrabutylammonium fluoride 1M in THF (3.94 mL, 3.94 mmol), and triethylamine (1.8 mL, 13 mmol) were processed according to the general procedures described in Example 64, Step A, to provide l-bromo-3-fluoro-5-(prop-l-ynyl)benzene (681 mg, 62% yield) as an oil. Step B: 2'-Amino-r,2,2-trimethyl-6-(4,4,5,5-tetramethy ^
imidazol]-5'(l'H)-one (50 mg, 0.130 mmol) and l-bromo-3-fluoro-5-(prop-l-ynyl)benzene (33.2 mg, 0.156 mmol) were processed according to the general procedures described in Example 64, Step B, to provide 2'-amino-6-(3-fluoro-5-(prop- 1 -ynyl)phenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one (20 mg, 40% yield) as a solid. Ή NMR (400 MHz, CDC13) δ 7.37-7.34 (m, IH), 7.24 (s, IH), 7.06-7.02 (m, IH), 6.98 (d, J=8.61 Hz, IH), 6.94-6.90 (m, 2H), 3.21 (s, 3H), 2.55 (d, J=14.08 Hz, IH), 2.05 (s, 3H), 1.97 (d, J=14.08Hz, IH), 1.51 (s, 3H), 1.41 (s, 3H); LCMS (APCI+) m/z 392 (M+H)+.
Example 85 2'-amino-6-(5-bromopyridin-3-yl)- ,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( H)- one
Figure imgf000097_0001
In a sealable vial, 2'-amino-r,2,2-trimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)spiro[chroman- 4,4'-imidazol]-5'(l'H)-one (0.025 g, 0.065 mmol), 3,5-dibromopyridine (0.015 g, 0.065 mmol),
PdC12(dppf) dichloromethane adduct (0.0053 g, 0.0065 mmol) in dioxane (1 mL), and 2M Na2C03 (0.13 mL, 0.26 mmol) were added. The reaction solution was degassed with N2 and sealed. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with CH2Cl2/EtOAc. Na2S04 was added to the reaction mixture, which was then filtered and washed with CH2Cl2/EtOAc. The filtrate was concentrated, and the crude product was initially purified by silica gel column chromatography, eluting with CH2C12/7N NH3 in MeOH (10: 1). The product containing fractions were combined, concentrated and repurified on C-l 8 reverse phase HPLC (Gilson Unipoint) eluting with 5-95%
MeOH/water containing 0.1% formic acid gradient to provide 2'-amino-6-(5-bromopyridin-3-yl)- ,2,2- trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (0.01 1 g, 0.026 mmol, 41% yield) as a foamy solid. Ή NMR (400 MHz, (CD3)2SO) δ 8.70 (d, IH), 8.62 (d, IH), 8.13 (t, IH), 7.54 (dd, IH), 7.36 (s, IH), 7.03 (d, IH), 6.89 (d, IH), 3.05 (s, 3H), 2.20 (d, IH), 1.84 (d, IH), 1.43 (s, 3H), 1.39 (s, 3H). m/z (APCI-pos) M+l = 415.1.
2'-amino-6-(3-(difluoromethoxy)phenyl)-l',2,2-trimethylspiro[chroman-4,4'-imidazol] 5'(l'H)-one
Figure imgf000097_0002
2'-Amino-6-(3-(difluoromethoxy)phenyl)-1^2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one was prepared according to the general procedures of Example 1, in which 3-(difluoromethoxy)phenylboronic acid was used in place of 5-chloropyridin-3-ylboronic acid in Step F. Ή NMR (400 MHz, CDC13) δ 7.38 (dd, 1H), 7.36 (t, 1H), 7.28 (d, 1H), 7.18 (s, 1H), 7.04 (d, 1H), 6.95 (s, 1H), 6.93 (d, 1H), 6.53 (t, 1H), 3.19 (s, 3H), 2.56 (d 1H), 1.97 (d, 1H), 1.52 (s, 3H), 1.42 (s, 3H). m/z (APCI-pos) M+l = 402.1.
Example 87 2'-amino-6-cyclohexyl-r,2,2-trimethylspiro[chroman-4,4'-imidazol]
Figure imgf000098_0001
2'-Amino-6-brotno- ,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (50 mg, 0.15 mmol; Example 1, Step E), cyclohexylzinc(II) bromide (0.887 mL, 0.5M in THF) and bis(tri-t-butylphosphine)palladium (0) (7.5 mg, 0.015 mmol) were heated in a small vial to 90°C and stirred overnight. The reaction was allowed to cool and loaded onto silica gel eluting with 1-10% MeOH/DCM with 1% NH4OH to yield 2'- amino-6-cyclohexyl-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one. Ή NMR (400 MHz, CDCI3) δ 7.05 (dd, 1H), 7.76 (d, 1H), 6.61 (d, 1H), 3.20 (s, 3H), 2.53 (d, 1H), 2.34 (m, 1H), 1.94 (d, 1H), 1.75 (m, 5H), 1.48 (s, 3H), 1.35 (s, 3H), 1.27 (m, 5H). m/z (APCI-pos) M+l = 342.2.
Example 88 2-amino-6'-(3,5-dichlorophenyl)-l-methyl-5-oxo-2",3",5",6"-tetrahydro- dispiro [imidazole-4,4 ' -chroman-2 ' ,4"-pyran]
Figure imgf000098_0002
2"-Amino-6'-(3,5-dichlorophenyl)- '-methyldispiro[tetrahydropyran-4-yl-l-2'-chroman-4',4''-imidazol]- 5'(l'H)-one was made according to the general procedure of Example 1, in which dihydro-2H-pyran- 4(3H)-one was used instead of propan-2-one in Step A, and 3,5-dichlorophenylboronic acid was used in place of 5-chloropyridin-3-ylboronic acid in Step F. Ή NMR (400 MHz, CDC13) δ 7.35 (dd, 1H), 7.28 (m, 4H), 7.01 (d, 1H), 4.02 (m, 1H), 3.85 (m, 1H), 3.72 (m, 2H), 3.21 (s, 3H), 2.48 (d, 1H), 1.95 (d, 1H), 1.85 (m, 4 H). m/z (APCI-pos) M+l = 446.1. Example 89 2-amino-6'-(5-chloropyridin-3-yl)-l-methyl-5-oxo-2",3",5",6"-tetrahydro- dispiro [im idazole-4,4 ' -chroman-2 ' 4"-pyran]
Figure imgf000099_0001
2"-Amino-6'-(5-chloropyrid-3-yl)-r'-methyldispiro[tetrahydropyran-4-yl-l-2'-chroman-4 4"-imidazol]- 5'(l'H)-one was made according to the general procedure of Example 88, in which 5-chloropyridin-3- ylboronic acid was used in place of 3,5-dichlorophenylboronic acid in Step F. IH NMR (400 MHz, CDC13) δ 8.57 (s, IH), 8.49 (s, IH), 7.72 (s, IH), 7.39 (d, IH), 7.05 (d, IH), 6.91, (s, IH), 4.02 (m, IH), 3.86 (m, IH), 3.72 (d, 2H), 3.21 (s, 3H), 2.49 (d, IH), 1.95 (d, IH), 1.85 (m, 4H). m/z (APCI-pos) M+l = 413.1.
Example 90 2"-amino-6'-(5-chloropyrid-3-yl)-l"-methyldispiro[cyclobutane-l,2'-chroman-4',4"- imidazol]-5 '( 1 'H)-one
Figure imgf000099_0002
2"-Amino-6'-(5-chloropyrid-3-yl)- '-methyldispiro[cyclobutane-l-2'-chroman-4',4"-imidazol]-5'( rH)- one was made according to the general procedures of Example 1, in which cyclobutanone was used instead of propan-2-one in Step A. Ή NMR (400 MHz, CDC13) δ 8.56 (d, IH), 8.48 (d, IH), 7.70 (t, IH), 7.37 (dd, IH), 7.01 (d, I H), 6.91 (d, IH), 3.21 (s, 3H), 2.52 (m, 2H), 2.22 (m, 2H), 1.98 (m, 2H), 1.75 (m, 2H). m/z (APCI-pos) M+ 1 = 383.1. Example 91 2"-amino-6'-(5-chloropyrid-3-yl)-l"-methyldispiro[cyclopropane-l,3'-chroman-4',4"- imidazol]-5'(l'H)-one
Figure imgf000099_0003
Step A: A mixture of diethyl cyclopropane-l,l-dicarboxylate (14.1 mL, 80.6 mmol) and lithium tri-tert- butoxyaluminohydride (201.4 mL, 201.4 mmol) was heated to reflux in THF for 3 hours. The mixture was cooled down and partitioned between water and EtOAc. The organics were washed with water, brine and dried with Na2S04. This was concentrated down and then purified on a column using 10 to 50% EtOAc:hexanes to give ethyl l-(hydroxymethyl)cyclopropanecarboxylate (1.5 g, 10.4 mmol, 12.9%) as an 12.9%) as an oil.
Step B: A mixture of ethyl l-(hydroxymethyl)cyclopropanecarboxylate (1.9 g, 13.2 mmol),
methanesulfonyl chloride (1.13 mL, 14.5 mmol) and TEA (2.20 mL, 15.81 mmol; d. 0.726) was stirred in DCM (90 mL, 13.2 mmol) for 6 hours at room temperature. The mixture was washed with saturated Na2C03, NaH P04 solution, then brine and dried with Na2S04. This was dried down to give ethyl 1- ((methylsulfonyloxy)methyl)cyclopropanecarboxylate (2.3g, 10.3 mmol, 78%) as an oil.
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 Na2S04. The mixture was purified on a column using 5 to 30% EtOAc:hexanes to give ethyl l-((4- bromophenoxy)methyl)cyclopropanecarboxylate (1.9 g, 6.6 mmol, 71%) as an oil.
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 Na2S04. This was then concentrated down and purified on a column using EtOAc:hexanes (1 :2) to give the l-((4- bromophenoxy)methyl)cyclopropanecarboxylic acid (1.59 g, 5.86 mmol, 88%) as a solid.
Step E: l-((4-Bromophenoxy)methyl)cyclopropanecarboxylic acid (1.59 g, 5.86 mmol) in concentrated H2S04 (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 Na2S04. 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 NaHS03 (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. The solid was filtered off, and the mixture was dried and purifed on a column using 1-10% MeOH/DCM with 1% NH4OH to yield 6'-bromodispiro[cyclopropane-l,3'-chroman-4',4"-imidazolidine]-2",5"-dione (0.63 g, 1.95 mmol, 57 %; see Formula 9 If) as a solid.
Figure imgf000101_0001
91f
Step G: 6'-bromodispiro[cyclopropane-l,3'-chrornan-4',4"-imidazolidine]-2",5"-dione (0.63 g, 1.95 mmol; Formula 9 If), iodomethane (0.122 mL, 1.95 mmol) and K2C03 (0.404 g, 2.92 mmol) in DMF (10 mL, 1.95 mmol) were stirred at room temperature for 4 hours. The mixture was partioned between EtOAc and water. The organics were washed with water four times, followed by brine and dried with Na2S04. This was concentrated down to give 6'-bromo-l "-methyldispiro[cyclopropane-l,3'-chroman-4',4"- imidazolidine]-2",5"-dione (0.635 g, 1.88 mmol 96%; see Formula 91g) as a solid.
Figure imgf000101_0002
91g
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 Na2S04. This was then purified on a column using EtOAc:hexanes to give the 6'-bromo-l "-methyl-2"-thioxodispiro[cyclopropane-l,3'-chroman-4',4"- imidazolidine]-5"-dione (0.31 g, 0.878 mmol 46%; see Formula 91h) as a solid.
Figure imgf000101_0003
91h
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 Ν¾ΟΗ (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. The organics were extracted with DCM, washed with brine and dried with Na2S04. This was concentrated down and purified on a column using 1-10% MeOH/DCM with 1% NH4OH to give 2"-amino-6'-bromo-l"-methyldispiro[cyclopropane-l,3'-chroman- 4',4"-imidazol]-5'(l'H)-one (235 mg, 0.69 mmol, 79%; see Formula 91 i) as a gel.
Figure imgf000102_0001
91i
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(PPh3)4 (0.0137 g, 0.01 19 mmol) and Na2C03 (0.119 mL, 0.238 mmol) in dioxane (9 mL, 0.1 19 mmol) was heated in a sealed vial overnight at 90°C. The mixture was loaded onto a column and purified using 1-10% MeOH/DCM with 1% NH4OH to give 2"-amino-6'-(5- chloropyrid-3-yl)- '-methyldispiro[cyclopropane-l-3'-chroman-4',4"-imidazol]-5'(rH)-one (0.010 g, 0.027 mmol, 23%) as a solid.
Example 92 2-amino-6'-(5-trifluoromethyl-pyridin-3-yl)-l-methyl-5-oxo-2",3",5",6"-tetrahydro- dispiro[imidazole-4,4 ' -chroman-2 ' ,4"-pyran]
Figure imgf000102_0002
2"-Amino-6'-(5-trifluoromethylpyrid-3-yl)-l"-methyldispiro[tetrahydropyran-4-yl-l-2'-chroman-4',4"- imidazol]-5'(l'H)-one was prepared according to the general procedures of Example 88, in which 5- (trifluoromethyl)pyridin-3-ylboronic acid was used in place of 3,5-dichlorophenylboronic acid, m/z (APCI-pos) M+l = 447.1.
Example 93 2"-amino-6'-(pyrimid-5-yl)-l"-methyldispiro[cyclopropane-l ,3'-chroman-4',4"- imidazol]-5'(l'H)-one
Figure imgf000102_0003
2''-Amino-6'-(pyrimid-5-yl)-r'-methyldispiro[cyclopropane-l-3'-chroman-4',4"-imidazol]-5'( H)-one was prepared according to the general procedures of Example 91, in which pyrimidin-5-ylboronic acid was used in place of 3-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine. m/z (APCI-pos) M+l = 336.1. Example 94 (E)-2'-amino-6-(3,3-dimethylbut-l-enyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000103_0001
(E)-2'-Amino-6-(3,3-dimethylbut-l-enyl)-l 2,2-trimethylspiro[chroman-4,4'-imidazol]-5 H)-one was prepared according to the general procedures of Example 1, in which (E)-3,3-dimethylbut-l-enylboronic acid was used in place of 5-chloropyridin-3-ylboronic acid in Step F. m/z (APCI-pos) M+l = 342.2.
Example 95 2"-amino-6'-(5-fluoropyrid-3-yl)-l "-methyldispiro[cyclobutane-l,2'-chroman-4',4"- imidazol]-5'( 1 'H)-one
Figure imgf000103_0002
2"-Amino-6'-(5-fluoropyrid-3-yl)-r'-methyldispiro[cyclobutane-l-2'-chroman-4\4"-imidazol]-5 rH)- one was prepared according to the general procedures of Example 90, in which 5-fluoropyridin-3- ylboronic acid was used in place of 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l =367.1.
Example 96 2-amino-6'-(3-difluoromethoxyphenyl)-l-methyl-5-oxo-2",3",5",6"-tetrahydro- dispiro[imidazole-4,4'-chroman-2',4"-pyran]
Figure imgf000103_0003
2"-Amino-6'-(3-difluoromethoxyphenyl)- '-methyldispiro[tetrahydropyran-4-yl-l-2'-chroman-4',4"- imidazol]-5'(l'H)-one was prepared according to the general procedures of Example 88, in which 3- (difluoromethoxy)phenylboronic acid was used in place of 3,5-dichlorophenylboronic acid, m/z (APCI- pos) M+l =444.2. Example 97 2-amino-6'-(3-trifluoromethylphenyl)-l-rnethyl-5-oxo-2'',3",5'',6''-tetrahydro- dispiro[imidazole-4,4'-chroman-2' 4"-pyran]
Figure imgf000104_0001
2''-Amino-6'-(3-trifluoromethylphenyl)- '-methyld^
imidazol]-5'(l'H)-one was prepared according to the procedure of Example 88, in which 3- (trifluoromethyl)phenylboronic acid was used in place of 3,5-dichlorophenylboronic acid, m/z (APCI- pos) M+1 = 446.2.
Example 98 2-amino-6'-(3-chloromethoxyphenyl)-l-methyl-5-oxo-2",3",5",6"-tetrahydro- dispiro[imidazole-4,4'-chroman-2' 4"-pyran]
Figure imgf000104_0002
2"-Amino-6'-(3-chlorophenyl)-l"-methyldispiro[tetrahydropyran-4-yl-l-2'-chroman-4',4"-imidazol]- 5'(l'H)-one was prepared according to the general procedures of Example 88, in which 3- chlorophenylboronic acid was used in place of 3,5-dichlorophenylboronic acid, m/z (APCI-pos) M+1 = 412.1.
Example 99 2'-amino-6-((3R,5S)-3,5-dimethylcyclohex-l-enyl)- ,2,2-trimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000104_0003
2'-Amino-6-((3R,5S)-3,5-dimethylcyclohex-l-enyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)- one was prepared according to the general procedures of Example 1, in which 2-((3R,5S)-3,5- dimethylcyclohex-l-enyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane was used in place of 5-chloropyridin-3- ylboronic acid, m/z (APCI-pos) M+1 = 368.2. Example 100 2'-amino-6-(3-(methoxymethyl)phenyl)- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000105_0001
2'-Amino-6-(3-(methoxymethyl)phenyl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one was prepared according to the general procedures of Example 1 , in which 3-(methoxymethyl)phenylboronic acid was used in place of 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 380.2.
Example 101 2"-amino-6'-(5-trifluoromethylpyrid-3-yl)- 1 "-methyldispiro[cyclobutane- 1 ,2'-chroman- 4\4"-imidazol]-5'( 1 'H -one
Figure imgf000105_0002
2"-Amino-6'-(5-trifluoromethylpyrid-3-yl)- '-methyldispiro[cyclobutane-l-2'-chroman-4 4"-imidazo^ 5'(l'H)-one was prepared according to the general procedures of Example 90, in which 5- (trifluoromethyl)pyridin-3-ylboronic acid was used in place of 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 417.1.
Example 102 2'-amino- 1 ',2,2-trimethyl-6-(3-methylbut- 1 -ynyl)spiro[chroman-4,4'-imidazol]-5'( 1 'H)-one
Figure imgf000105_0003
A mixture of 2'-amino-6-bromo- ,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (0.10 g, 0.296 mmol) and TEA (0.0824 mL, 0.591 mmol; d. 0.726) in THF (1 mL, 0.296 mmol) was purged with Ar for 5 minutes. 3 -Methyl- 1-butyne (0.0432 mL, 0.444 mmol), PdCl2(PPh3)2 (0.0208 g, 0.0296 mmol) and Cu(I)I (0.00563 g, 0.0296 mmol) was added, and the mixture was heated in a sealed vial overnight at 90°C. The mixture was filtered through Celite®. The filtrate was concentrated down and purified on preparative HPLC to give 2'-amino-r,2,2-trimethyl-6-(3-methylbut-l-ynyl)spiro[chroman-4,4'-imidazol]- 5'(l'H)-one (0.0194 g, 0.0596 mmol, 20%) as a solid, m/z (APCI-pos) M+l = 326.2. Example 103 2'-amino-6-(5-chloro 1 -methyl-2-oxo- 1 ,2-dihydropyridin-3-yl)- 1 ',2,2- trimethy lspiro [chroman-4,4'-imidazol] -5 '( 1 'H)-one
Figure imgf000106_0001
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(PPh3)4
(0.683 g, 0.591 mmol) and Na2C03 (5.91 mL, 11.8 mmol) in dioxane (9 mL, 5.91 mmol) was heated in a sealed vial overnight at 90°C. The mixture was filtered through Celite® and concentrated down. This was then purified on a column using 1-10% MeOH/EtOAc (1% TEA). This gave 2'-amino- ,2,2-trimethyl-6- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)spiro[chroman-4,4'-imidazol]-5'( H)-one (1.65 g, 4.28 mmol, 72%) as a solid.
Step B: A mixture of 2'-amino- ,2,2-trimethyl-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)spiro[chroman-4,4'-imidazol]-5'(rH)-one (0.100 g, 0.260 mmol), 3-bromo-5-chloro-l-methylpyridin- 2(lH)-one, Pd(PPh3)4 (0.0300 g, 0.0260 mmol) and Na2C03 (0.260 mL, 0.519 mmol) in dioxane (1 mL, 0.260 mmol) was heated in a sealed vial overnight at 90°C. The mixture was loaded onto a column and purified using MeOH (1-10%)/DCM (1% NH4OH). This gave 2'-amino-6-(5-chloro-l-methyl-2-oxo-l,2- dihydropyridin-3-yl)-r,2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (0.045 g, 0.1 12 mmol, 43%) as a solid, m/z (APCI-pos) M+l = 401.1. Example 104 2'-amino-6-((3R,5S)-3,5-dimethylcyclohexyl)- ,2,2-trimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one
Figure imgf000106_0002
A solution of 2'-amino-6-((3R,5S)-3,5-dimethylcyclohex-l-enyl)-r,2,2-trimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one (0.005 g, 0.014 mmol) and Pd C (0.0014 g, 0.014 mmol) in MeOH (0.1 mL; d. 0.791) under H2 (1 atm) was stirred to completion, as determined by mass spectroscopy. The mixture was then filtered and concentrated down to give 2'-amino-6-((3R,5S)-3,5-dimethylcyclohexyl)-l',2,2- trimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one (0.0015 g, 0.0041 mmol, 30%). m/z (APCI-pos) M+l = 370.2. Example 105 2'-amino-6-isopenty 1- 1 ',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one
Figure imgf000107_0001
2'-Amino-6-isopentyl-l',2,2-trimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one was prepared according to the general procedures of Example 87, in which isopentylzinc(II) bromide was used in place of cyclohexylzinc(II) bromide, m/z (APCI-pos) M+l = 330.2.
Example 106 2'-amino-6-(5-chloropyridin-3-yl)-r-methylspiro[chroman-4,4'-imidazol]-5'(rH)-one
Figure imgf000107_0002
Step A: Ammonium carbonate (8.46 g, 88.1 mmol), KCN (1.43 g, 22.0 mmol), and NaHS03 (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). The combined organic layers were dried and concentrated to give a foamy solid that was dissolved in DCM/MeOH and purified by flash chromatography, eluting with DCM/MeOH (1-15%) gradient to afford 6-bromospiro[chroman- 4,4'-imidazolidine]-2',5'-dione (0.850 g, 2.86 mmol, 26%).
Step B: K2C03 (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. The residue was purified by flash chromatography, eluting with 10% MeOH DCM to afford 6-bromo-l'- methylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (0.488 g, 1.57 mmol, 93%).
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(¾ and brine. The organic layer was dried and concentrated to give the crude product, which was purified by flash chromatography, eluting with ethyl acetate/hexanes (5-30%) to afford 6-bromo-r-methyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'- one (0.501 g, 1.53 mmol, 97%). Step D: t-Butyl hydroperoxide (70% aq, 3.06 mL, 30.6 mmol) and Ν¾ΟΗ (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
DCM/MeOH (1-10%). 2'-Amino-6-bromo-l'-methylspiro[chroman-4,4'-imidazol]-5'(l'H)-one (0.341 g, 1.10 mmol, 72%) was isolated as an oil that solidified upon standing.
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(PPh3)4 (7.75 mg, 0.00671 mmol), Na2C03 (2.0M solution, 200 μί, 0.402 mmol) in dioxane (671 μί, 0.134 mmol) in a pressure vial was degassed with nitrogen and heated to 90°C for 24 hours. The reaction mixture was loaded directly onto a flash column and eluted with DCM MeOH (2-10% + 1% NH4OH) to afford 2'-amino-6-(5- chloropyridin-3-yl)-r-methylspiro[chroman-4,4'-imidazol]-5'(rH)-one (13 mg, 0.0364 mmol, 27.1% yield), m/z (APCI-pos) M+l = 343.1 (100%), 345.1 (33%).
Example 107 2'-amino-6-(3-chloro-5-fluoro henyl)-r-methylspiro[chroman-4,4'-imidazol]-5'(rH)-one
Figure imgf000108_0001
2'-Amino-6-(3-chloro-5-fluorophenyl)- 1 '-methylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the general procedures of Example 1, Step F, substituting 3-chloro-5-fluorophenylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 360.1 (100%), 362.0 (40%).
Example 108 2'-amino-6-(3-chlorophen l)- -methylspiro[chroman-4,4'-imidazol]-5'(rH)-one
Figure imgf000108_0002
2'-Amino-6-(3-chlorophenyl)- 1 '-methylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the general procedures of Example 1, Step F, substituting 3-chloro-phenylboronic acid for 5- chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 342.1 (100%), 344.1 (35%). Example 109 2'-amino-6-(3-(difluoromethoxy)phenyl)- 1 '-methylspiro[chroman-4,4'-imidazol]-5'( 1 Ή)- one
Figure imgf000109_0001
2'-Amino-6-(3-(difluoromethoxy)phenyl)- 1 '-methylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one was prepared according to the general procedures of Example 1, Step F, substituting 3-(difluoromethoxy)phenylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 374.1.
Example 1 10 2'-amino-6-(3,5-dichloro henyl)-r-methylspiro[chroman-4,4'-imidazol]-5'( H)-one
Figure imgf000109_0002
2'-Amino-6-(3,5-dichlorophenyl)-r-methylspiro[chroman-4,4'-imidazol]-5'( H)-one was prepared according to the general procedures of Example 1, Step F, substituting 3,5-dichlorophenylboronic acid for 5-chloropyridin-3-ylboronic acid, m/z (APCI-pos) M+l = 376.7 (100%), 378.0 (60%).
The following compounds in Table 1 were prepared according to the above procedures using appropriate intermediates.
Table 1
Figure imgf000109_0003
Figure imgf000110_0001
Figure imgf000111_0001
5'(l'H)-one
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
5'(l'H)-one
Figure imgf000124_0001
CF3 U^o^ 5'(l'H)-one
Figure imgf000125_0001
imidazol]-5'(l'H)-one
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
5'(l*H)-one
Figure imgf000132_0001
Figure imgf000133_0001
imidazol]-5'(l'H)-one Example 297 (2S',4R')-2'-amino-6-(5-chloropyridin-3-yl)-2-(3-methoxybenzyl)- 1 ',2- dimethylspiro[chroman-4 4'-imidazol]-5'( H)-one
Figure imgf000134_0001
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). The phases were separated, and then carefully the organic phase was shaken with aqueous saturated NaHCC>3 (100 mL; gas evolution, vent sep funnel cautiously). The organic phase was washed with brine (100 mL), dried (NaHC03), filtered, and concentrated. The crude was purified by Biotage Flash 65 chromatography system, eluting with 10%- 20% EtOAc/hexanes. Yield: 12.1 g (64%) of 6-bromo-2-(3-methoxybenzyl)-2-methylchroman-4-one.
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). N2 was bubbled through the mixture for 30 minutes to sparge HCN. The phases were separated, and the aqueous phase was re-extracted with EtOAc (30 mL). The combined organic phases were washed with brine (50 mL), dried (MgS04), filtered, and concentrated. Yield: 4.0 g (70%) of 6-bromo-2-(3-methoxybenzyl)-2-methylspiro[chroman-4,4'- imidazolidine]-2',5'-dione. Obtained 60:40 ratio of diastereomers by Ή NMR.
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). The combined organic phases were washed with water (100 mL), brine (100 mL), dried (MgS04), filtered, and concentrated. Yield: 3.84 g (81%) of 6-bromo-2-(3-methoxybenzyl)-l',2- dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione. 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 N2. 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(¾ (50 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (20 mL). The combined organic phases were washed with brine (50 mL), dried (MgS04), filtered, and concentrated. Yield: 3.4 g (86%) of 6-bromo-2-(3-methoxybenzyl)-l',2-dimethyl-2'- thioxospiro[chroman-4,4'-imidazolidin]-5'-one.
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 NH4OH (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). The phases were separated. The aqueous was re-extracted with EtOAc (20 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO , filtered, and concentrated. The product was purified by Biotage Flash 65 chromatography system, eluting with neat EtOAc followed by 5% MeOH/EtOAc. The diastereomers were separated. 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(PPh3)4 (13 mg, 0.011 mmol), and 2N aqueous Na2C03 (141 μί, 0.28 mmol). The mixture was sparged with N2 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
NH3)/DCM. Yield: 25 mg (46%) of (2S*,4R')-2'-amino-6-(5-chloropyridin-3-yl)-2-(3-methoxybenzyl)- r,2-dimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one. Ή NMR (400 MHz, CDC13) δ 8.58 (d, J = 2 Hz, 1H), 8.47 (d, J = 2 Hz, 1H), 7.73 (m, 1H), 7.42 (dd, J = 2, 9 Hz, 1H), 7.18 (t, J = 8 Hz, 1H), 7.04 (d, J = 9 Hz, 1H), 6.96 (d, J = 2 Hz, 1H), 6.77 (m, 3H), 4.93 (br s, 2H), 3.77 (s, 3H), 3.33 (d, J = 14 Hz, 1H), 3.15 (s, 3H), 2.82 (d, J = 14 Hz, 1H), 2.52 (d, J = 14 Hz, 1H), 2.09 (d, J = 14 Hz, 1H), 1.33 (s, 3H); m/z (APCI- pos) M+l = 477, 479. Example 298 3-((2S',4R*)-2'-amino-2-(3-methoxybenzyl)- 1 ',2-dimethyl-5'-oxo- 1 ',5'- dihydrospiro[chroman-4 4'-imidazole]-6-yl)benzonitrile
Figure imgf000136_0001
3^(2S^4R 2'-Amino-2-(3-methoxybenzyl)-l',2-dimethyl-5'-oxo-l',5,-dihydrospiro[chroman-4,4'- imidazole]-6-yl)benzonitrile was prepared from (2S',4R')-2'-amino-6-bromo-2-(3-methoxybenzyl)- ,2- dimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (as prepared in Example 297, Step E; 50 mg, 0.1 1 mmol) according to the procedure described for Example 297, Step F, substituting 3-cyanophenylboronic acid for 5-chloropyridin-3-ylboronic acid with. Yield: 27 mg (50%); m/z (APCI-pos) M+l = 467. Example 299 (2R',4R')-2'-amino-6-(3-chlorophenyl)-2-(3-methoxybenzyl)- 1 ',2-dimethylspiro[chroman- 4,4'-imidazol]-5'(l'H -one
Figure imgf000136_0002
(2R',4R')-2'-Amino-6-(3-chlorophenyl)-2-(3-methoxybenzyl)-r,2-dimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one was prepared from (2R',4R')-2'-amino-6-bromo-2-(3-methoxybenzyl)-r,2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (as prepared in Example 297, Step E; 50 mg, 0.1 1 mmol) according to the procedure described for Example 297, Step F, substituting 3-chlorophenylboronic acid for 5-chloropyridin-3-ylboronic acid. Yield: 22 mg (40%); Ή NMR (400 MHz, CDC13) δ 7.39 (s, 1H), 7.37 (dd, J = 2, 9 Hz, 1H), 7.29 (m, 2H), 7.22 (m, 2H), 6.95 (d, J = 9 Hz, 1H), 6.90 (d, J = 2 Hz, 1H), 6.86 (m, 2H), 6.81 (m, 1H), 5.22 (br s, 2H), 3.81 (s, 3H), 3.13 (s, 3H), 3.08 (d, J = 13 Hz, 1H), 2.99 (d, J = 13 Hz, 1H), 2.53 (d, J = 14 Hz, 1H), 1.90 (d, J = 14 Hz, 1H), 1.36 (s, 3H); m/z (APCI-pos) M+l = 476, 478. Example 300 (2R' ,4R' )-2'-amino-6-(5-chloropyridin-3-yl)-2-(3 -methoxybenzyl)- 1 ',2- dimethylspiro[chroman-4 4'-imidazol]-5'(rH)-one
Figure imgf000137_0001
(2R 4R')-2'-Amino-6-(5-chloropyridin-3-yl)-2-(3-methoxybenzyl)-r,2-dimethylspiro[chroman-4,4'- imidazol]-5'( l'H)-one was prepared from (2R',4R')-2'-amino-6-bromo-2-(3 -methoxybenzyl)- 1 ',2- dimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one (as prepared in Example 297, Step E; 50 mg, 0.1 1 mmol) according to the procedure described for Example 297, Step F. Yield: 26 mg (46%). Ή NMR (400 MHz, CDC13) δ 8.53 (s, 1H), 8.45 (s, 1H), 7.69 (s, 1H), 7.35 (d, J = 8 Hz, 1H), 7.22 (t, J = 8 Hz, 1H), 6.99 (d, J = 9 Hz, 1H), 6.85 (m, 4H), 5.07 (br s, 2H), 3.81 (s, 3H), 3.13 (s, 3H), 3.09 (d, J = 14 Hz, 1H), 3.00 (d, J = 14 Hz, 1H), 2.51 (d, J = 14 Hz, 1H), 1.89 (d, J = 14 Hz, 1H), 1.37 (s, 3H); m/z (APCI-pos) M+l = 477, 479.
Example 301 3 -((2R' ,4R')-2'-amino-2-(3 -methoxybenzyl)- 1 ',2-dimethyl-5'-oxo- 1 ',5'- dihydrospiro[chroman-4,4'-imidazole]-6-yl)benzonitrile
Figure imgf000137_0002
3-((2R',4R')-2'-Amino-2-(3-methoxybenzyl)-r,2-dimethyl-5'-oxo-r,5'-dihydrospiro[chroman-4,4'- imidazole]-6-yl)benzonitrile was prepared from (2R',4R')-2'-amino-6-bromo-2-(3-methoxybenzyl)-r,2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (as prepared in Example 297, Step E; 50 mg, 0.1 1 mmol) according to the procedure described for Example 297, Step F, substituting 3-cyanophenylboronic acid for 5-chloropyridin-3-ylboronic acid. Yield: 27 mg (50%). Ή NMR (400 MHz, CDC13) δ 7.68 (s, 1 H), 7.64 (d, J = 9 Hz, 1 H), 7.54 (d, J = 8 Hz, 1H), 7.45 (t, J = 8 Hz, 1H), 7.37 (dd, J = 2, 9 Hz, 1H), 7.22 (t, J = 8 Hz, 1H), 6.98 (d, J = 8 Hz, 1H), 6.85 (m, 4H), 5.07 (br s, 2H), 3.81 (s, 3H), 3.14 (s, 3H), 3.09 (d, J = 13 Hz, 1H), 3.00 (d, J = 13 Hz, 1H), 2.52 (d, J = 14 Hz, 1H), 1.89 (d, J = 14 Hz, 1H), 1.38 (s, 3H); m/z (APCI-pos) M+l = 467. Example 302 (2R',4R')-2'-amino-2-(3-methoxybenzyl)- ,2-dimethyl-6-(pyridin-3-yl)spiro[chroman- 4,4'-imidazol]-5'(l'H -one
Figure imgf000138_0001
(2R',4R')-2'-Amino-2-(3-methoxybenzyl)- ,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-(3-methoxybenzyl)-r,2- dimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (as prepared in Example 297, Step E; 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. Yield: 15 mg (74%). Ή NMR (400 MHz, CDC13) δ 8.67 (s, 1H), 8.51 (d, J = 6 Hz, 1H), 7.71 (d, J = 8 Hz, 1H), 7.39 (m, 1H), 7.29 (m, 1H), 7.22 (t, J = 8 Hz, 1H), 6.99 (d, J = 9 Hz, 1H), 6.94 (s, 1H), 6.86 (m, 2H), 6.82 (m, 1H), 4.67 (br s, 2H), 3.81 (s, 3H), 3.16 (s, 3H), 3.10 (d, J = 13 Hz, 1H), 3.01 (d, J = 13 Hz, 1H), 2.55 (d, J = 14 Hz, 1H), 1.92 (d, J = 14 Hz, 1H), 1.39 (s, 3H); m/z (APCI-pos) M+l = 443.
Example 303 (2R',4R')-2'-amino-6-(2-fluoropyridin-3-yl)-2-(3-methoxybenzyl)-l',2- dimethylspiro[chroman-4,4'-imidazol -5'( 1 'H)-one
Figure imgf000138_0002
(2R',4R')-2'-Amino-6-(2-fluoropyridin-3-yl)-2-(3-methoxybenzyl)-r,2-dimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared from (2R',4R')-2'-amino-6-bromo-2-(3-methoxybenzyl)-r,2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (as prepared in Example 297, Step E; 20 mg, 0.05 mmol) according to the procedure described for Example 297, Step F, substituting 2-fluoropyridin-3- ylboronic acid for 5-chloropyridin-3-ylboronic acid. Yield: 8 mg (38%). Ή NMR (400 MHz, CDC13) δ 8.1 1 (d, J = 5 Hz, 1H), 7.74 (t, J = 8 Hz, 1H), 7.38 (d, J = 9 Hz, 1H), 7.20 (m, 2H), 6.97 (m, 2H), 6.85 (m, 2H), 6.80 (m, 1H), 4.64 (br s, 2H), 3.81 (s, 3H), 3.13 (s, 3H), 3.10 (d, J = 13 Hz, 1H), 3.01 (d, J = 13 Hz, 1H), 2.54 (d, J = 14 Hz, 1H), 1.91 (d, J = 14 Hz, 1H), 1.38 (s, 3H); m/z (APCI-pos) M+l = 461. Example 304 (2R 4R')-2'-amino-2-(3-methoxybenzyl)-r,2-dimethyl-6-(pyrimidin-5-yl)spiro[chroman- 4,4'-imidazol]-5'(l'H -one
Figure imgf000139_0001
(2R\4R' )-2'-Amino-2-(3 -methoxybenzyl)- r,2-dime^
5'(l'H)-one was prepared from (2R',4R')-2'-amino-6-bromo-2-(3-methoxybenzyl)- ,2- dimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (as prepared in Example 297, Step E; 20 mg, 0.05 mmol) according to the procedure described for Example 297, Step F, substituting pyrimidin-5-ylboronic acid for 5-chloropyridin-3-ylboronic acid. Yield: 8 mg (39%). Ή NMR (400 MHz, CDC13) δ 9.12 (s, 1H), 8.80 (s, 2H), 7.39 (d, J = 9 Hz, 1H), 7.23 (t, J = 8 Hz, 1H), 7.03 (d, J = 9 Hz, 1H), 6.92 (s, 1H), 6.86 (m, 3H), 4.62 (br s, 2H), 3.81 (s, 3H), 3.16 (s, 3H), 3.1 1 (d, J = 13 Hz, 1H), 3.01 (d, J = 13 Hz, 1H), 2.53 (d, J = 14 Hz, 1H), 1.90 (d, J = 14 Hz, 1H), 1.40 (s, 3H); m/z (APCI-pos) M+l = 444.
Example 305 (2S',4R')-2'-amino-6-(3-chlorophenyl)-2-(4-methoxybenzyl)-r,2-dimethylspiro[chroman- 4,4'-imidazol]-5'(l'H)-one
Figure imgf000139_0002
(2S 4R')-2'-Amino-6-(3-chlorophenyl)-2-(4-methoxybenzyl)- ,2-dimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one was prepared from (2S',4R')-2'-amino-6-bromo-2-(4-methoxybenzyl)-l',2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-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; 50 mg, 0.1 1 mmol) according to the procedure described for Example 297, Step F, substituting 3-chlorophenylboronic acid for 5-chloropyridin-3- ylboronic acid. Yield: 19 mg (34%); m/z (APCI-pos) M+l = 476, 478. Example 306 (2S ' ,4R' )-2'-amino-6-(5-chloropyridin-3 -yl)-2-(4-methoxybenzy 1)- 1 ',2- dimethylspiro[chroman-4,4'-imidazol -5'(rH)-one
Figure imgf000140_0001
(2S 4R')-2'-Amino-6-(5-chloropyridin-3-yl)-2-(4-methoxybenzyl)- ,2-dimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared from (2S',4R')-2'-amino-6-bromo-2-(4-methoxybenzyl)-r,2- dimethylspiro[chroman-4,4'-imidazol]-5'(l'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; 50 mg, 0.1 1 mmol) according to the procedure described for Example 297, Step F. Yield: 24 mg (42%). Ή NMR (400 MHz, CDC13) δ 8.58 (d, J = 2 Hz, 1 H), 8.47 (d, J = 2 Hz, 1H), 7.73 (t, J = 2 Hz, 1H), 7.41 (m, 1H), 7.09 (d, J = 9 Hz, 2H), 7.03 (d, J = 9 Hz, 1H), 6.96 (d, J = 2 Hz, 1H), 6.81 (d, J = 9 Hz, 2H), 4.74 (br s, 2H), 3.79 (s, 3H), 3.29 (d, J = 13 Hz, 1H), 3.16 (s, 3H), 2.77 (d, J = 14 Hz, 1H), 2.51 (d, J = 14 Hz, 1H), 2.08 (d, J = 14 Hz, 1H), 1.32 (s, 3H); m/z (APCI-pos) M+l = 477, 479.
Example 307 3-((2S',4R')-2'-amino-2-(4-methoxybenzyl)-l',2-dimethyl-5'-oxo-l',5'- dihydrospiro[chroman-4,4'-imidazole]-6-yl)benzonitrile
Figure imgf000140_0002
3-((2S',4R')-2'-Amino-2-(4-methoxybenzyl)-l',2-dimethyl-5'-oxo-l',5'-dihydrospiro[chroman-4,4'- imidazole]-6-yl)benzonitrile was prepared from (2S',4R')-2'-amino-6-bromo-2-(4-methoxybenzyl)-r,2- dimethylspiro[chroman-4,4'-imidazol]-5'(l'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; 50 mg, 0.1 1 mmol) according to the procedure described for Example 297, Step F, substituting 3-cyanophenylboronic acid for 5-chloropyridin-3- ylboronic acid. Yield: 29 mg (54%). 'H NMR (400 MHz, CDC13) δ 7.70 (s, 1H), 7.68 (m, 1H), 7.55 (m, 1H), 7.48 (m, 1H), 7.42 (m, 1H), 7.09 (d, J = 9 Hz, 2H), 7.01 (d, J = 9 Hz, 1H), 6.94 (d, J = 2 Hz, 1H), 6.80 (d, J = 9 Hz, 2H), 5.12 (br s, 2H), 3.78 (s, 3H), 3.29 (d, J = 14 Hz, 1H), 3.15 (s, 3H), 2.77 (d, J = 14 Hz, 1H), 2.50 (d, J = 14 Hz, 1H), 2.07 (d, J = 14 Hz, 1H), 1.31 (s, 3H); m/z (APCI-pos) M+l = 467.
Example 308 (2R',4R')-2'-amino-6-(3-chlorophenyl)-2-(4-methoxybenzyl)-r,2-dimethylspiro[chroman- 4,4'-imidazol]-5'(l'H -one
Figure imgf000141_0001
(2R\4R')-2'-Amino-6-(3-chlorophenyl)-2-(4-methoxy
5'(l'H)-one was prepared from (2R',4R')-2'-amino-6-bromo-2-(4-methoxybenzyl)-r,2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-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; 50 mg, 0.1 1 mmol) according to the procedure described for Example 297, Step F, substituting 3-chlorophenylboronic acid for 5-chloropyridin-3- ylboronic acid. Yield: 15 mg (26%). Ή NMR (400 MHz, CDC13) δ 7.39 (s, 1H), 7.37 (m, 1H), 7.28 (m, 3H), 7.18 (d, J = 8 Hz, 2H), 6.95 (d, J = 9 Hz, 1H), 6.90 (d, J = 2 Hz, 1H), 6.84 (d, J = 9 Hz, 2H), 5.27 (br s, 2H), 3.79 (s, 3H), 3.15 (s, 3H), 3.04 (d, J = 14 Hz, 1H), 2.97 (d, J = 13 Hz, 1H), 2.51 (d, J = 14 Hz, 1H), 1.87 (d, J = 14 Hz, 1H), 1.34 (s, 3H); m/z (APCI-pos) M+l = 476, 478.
Example 309 (2R',4R')-2'-amino-6-(5-chloropyridin-3-yl)-2-(4-methoxybenzyl)-l,,2- dimethylspiro[chroman-4 4'-imidazol]-5'(rH)-one
Figure imgf000141_0002
(2R' ,4R' )-2'-Amino-6-(5-chloropyridin-3 -yl)-2-(4-methoxybenzy 1)- 1 ',2-dimethylspiro[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'(rH)-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; 50 mg, 0.1 1 mmol) according to the procedure described for Example 297, Step F. Yield: 24 mg (44%). Ή NMR (400 MHz, CDC13) δ 8.53 (d, J = 2 Hz, 1H), 8.46 (d, J = 2 Hz, 1H), 7.69 (m, 1H), 7.36 (m, 1H), 7.19 (d, J = 9 Hz, 2H), 6.99 (d, J = 9 Hz, 1H), 1H), 6.89 (d, J = 2 Hz, 1H), 6.84 (d, J = 9 Hz, 2H), 4.99 (br s, 2H), 3.79 (s, 3H), 3.14 (s, 3H), 3.05 (d, J = 13 Hz, 1H), 2.97 (d, J = 13 Hz, 1H), 2.50 (d, J = 14 Hz, 1H), 1.86 (d, J = 14 Hz, 1H), 1.36 (s, 3H); m/z (APCI-pos) M+l = 477, 479.
Example 310 3-((2R',4R')-2,-amino-2-(4-methoxybenzyl)-l',2-dimethyl-5,-oxo-l',5'- dihydrospiro[chroman-4 4'-imidazole]-6-yl)benzonitrile
Figure imgf000142_0001
3-((2R',4R')-2'-Amino-2-(4-methoxybenzyl)- 1 ',2-dimethyl-5'-oxo- 1 ',5'-dihydrospiro[chroman-4,4'- imidazole]-6-yI)benzonitrile was prepared from (2R',4R')-2'-amino-6-bromo-2-(4-methoxybenzyl)- ,2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-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; 50 mg, 0.1 1 mmol) according to the procedure described for Example 297, Step F, substituting 3-cyanophenylboronic acid for 5-chloropyridin-3- ylboronic acid. Yield: 27 mg (51%). Ή NMR (400 MHz, CDC13) δ 7.67 (s, 1H), 7.64 (m, 1H), 7.54 (d, J = 8 Hz, 1H), 7.45 (t, J = 8 Hz, 1H), 7.37 (m, 1H), 7.18 (d, J = 9 Hz, 2H), 6.97 (d, J = 9 Hz, 1H), 6.88 (d, J = 2 Hz, 1H), 6.84 (d, J = 9 Hz, 2H), 5.10 (br s, 2H), 3.79 (s, 3H), 3.14 (s, 3H), 3.04 (d, J = 14 Hz, 1H), 2.97 (d, J = 13 Hz, 1H), 2.50 (d, J = 14 Hz, 1H), 1.86 (d, J = 14 Hz, 1H), 1.36 (s, 3H); m/z (APCI-pos) M+l = 467.
Example 311 (2R',4R')-2'-amino-2-(4-methoxybenzyl)- ,2-dimethyl-6-(pyridin-3-yl)spiro[chroman- 4,4'-imidazol]-5'(rH -one
Figure imgf000142_0002
(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. Yield: 6 mg (30%). Ή NMR (400 MHz, CDC13) δ 8.67 (s, 1H), 8.51 (d, J = 5 Hz, 1H), 7.71 (d, J = 8 Hz, 1H), 7.40 (m, 1H), 7.37 (m, 1H), 7.29 (m, 1H), 7.20 (d, J = 9 Hz, 2H), 6.99 (d, J = 9 Hz, 1H), 6.94 (s, 1H), 6.85 (d, J = 9 Hz, 2H), 4.70 (br s, 2H), 3.80 (s, 3H), 3.16 (s, 3H), 3.06 (d, J = 13 Hz, 1H), 2.98 (d, J = 13 Hz, 1H), 2.53 (d, J = 14 Hz, 1H), 1.88 (d, J = 14 Hz, 1H), 1.37 (s, 3H); m/z (APCI-pos) M+l = 443. ',4R')-2'-amino-6-(2-fluoropyridin-3-yl)-2-(4-methoxybenzyl)-l*,2-
Figure imgf000143_0001
(2R',4R')-2'-Amino-6-(2-fluoropyridin-3-yl)-2-(4-methoxybenzyl)- ,2-dimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared from (2R',4R')-2'-amino-6-bromo-2-(4-methoxybenzyl)-r,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 2-fluoropyridin-3-ylboronic acid for 5-chloropyridin-3- ylboronic acid. Yield: 8 mg (34%). Ή NMR (400 MHz, CDC13) 8 8.1 1 (s, 1H), 7.73 (t, J = 8 Hz, 1H), 7.38 (d, J = 9 Hz, 1H), 7.19 (m, 3H), 6.97 (m, 2H), 6.85 (d, J = 9 Hz, 2H), 4.78 (br s, 2H), 3.79 (s, 3H), 3.13 (s, 3H), 3.05 (d, J = 13 Hz, 1H), 2.98 (d, J = 13 Hz, 1H), 2.52 (d, J = 14 Hz, 1H), 1.87 (d, J = 14 Hz, 1H), 1.36 (s, 3H); m/z (APCI-pos) M+l = 461.
Example 313 (2R' ,4R' )-2'-amino-2-(4-methoxybenzyl)- 1 ',2-dimethyl-6-(pyrimidin-5-yl)spiro[chroman- 4,4'-imidazol]-5'(l'H -one
Figure imgf000143_0002
(2R 4R')-2'-Amino-2-(4-methoxybenzyl)-1^2-dimethyl-6-(pyrimidin-5-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'(rH)-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 pyrimidin-5-ylboronic acid for 5-chloropyridin-3- ylboronic acid. Yield: 7 mg (34%). :H NMR (400 MHz, CDC13) δ 9.12 (s, 1 H), 8.79 (s, 2H), 7.40 (m, 1H), 7.19 (d, J = 9 Hz, 2H), 7.03 (d, J = 9 Hz, 1 H), 6.92 (s, 1 H), 6.85 (d, J = 9 Hz, 2H), 4.62 (br s, 2H), 3.80 (s, 3H), 3.16 (s, 3H), 3.06 (d, J = 13 Hz, 1H), 2.99 (d, J = 13 Hz, 1H), 2.52 (d, J = 14 Hz, 1H), 1.87 (d, J = 14 Hz, 1H), 1.38 (s, 3H); m/z (APCI-pos) M+l = 444.
The following compounds in Table 2 were prepared according to the above procedures using appropriate intermediates.
Table 2
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
imidazol]-5'(l'H)-one
Figure imgf000149_0001
5*(l'H)-one
Figure imgf000150_0001
Figure imgf000151_0001
Example 366 (2R*,4R*)-2'-amino-6-(5-chloropyridin-3-yl)-2-(4-fluorobenzyl)-l ',2- dimethylspiro[chroman-4 4'-imidazol]-5'( 1 'H)-one
Step A: A thick walled, glass pressure tube plus stir bar was charged with 1 -(4-fluorophenyl)propan-2- one (3.8 g, 25 mmol), l-(5-bromo-2-hydroxyphenyl)ethanone (4.5 g, 21 mmol), and toluene (20 mL). Then pyrrolidine ( 1.7 mL, 21 mmol) was added, followed by acetic acid (1.2 mL, 21 mmol). The mixture was heated to 80°C for 18 hours. After cooling to room temperature, the mixture was partioned between EtOAc (50 mL) and aqueous IN HC1 (50 mL). The phases were separated, and then carefully shook organic phase with aqueous saturated NaHC03 (50 mL; gas evolution, vent sep funnel cautiously). The organic phase was washed with brine (50 mL), dried (MgSC^), filtered, and concentrated. Purified by silica gel chromatography on a Biotage Flash 65 system, eluting with 5%-10% EtOAc/hexanes to yield 6- bromo-2-(4-fluorobenzyl)-2-methylchroman-4-one (5.3 g, 66%).
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. Bubbled N2 through the mixture for 30 minutes (back of hood, sashes closed) to sparge HCN. The phases were separated, and the aqueous phase was re-extracted with EtOAc (2 X 50 mL). The combined organic phases were washed with brine (50 mL), dried (MgS04), filtered, and concentrated to yield 6-bromo-2-(4-fluorobenzyl)-2- methylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (4.5 g, 63%). The product was carried forward without purification.
Step C: A round bottomed flask plus stir bar was charged with 6-bromo-2-(4-fluorobenzyl)-2- methylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (4.5 g, 10.7 mmol), DMF (20 mL), potassium carbonate (1.9 g, 14 mmol), and lastly iodomethane (0.60 mL, 9.7 mmol). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was worked up by partioning between EtOAc (50 mL) and water (50 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (50 mL). The combined organic phases were washed with water (2 X 50 mL), brine (50 mL), dried (MgS04), filtered, and concentrated in vacuo to yield 6-bromo-2-(4-fluorobenzyl)-l',2- dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (4.1 g, 51%). The product was carried forward without purification.
Step D: A thick walled, glass pressure tube plus stir bar was charged with 6-bromo-2-(4-fluorobenzyl)- r,2-dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (4.1 g, 9.5 mmol), Lawesson's Reagent (2.3 g, 5.7 mmol), and toluene (20 mL). The mixture was degassed with N2 and heated to 100°C for 15 hours. The mixture was partitioned between EtOAc (50 mL) and saturated aqueous NaHC03 (50 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (20 mL). The combined organic phases were washed with brine (50 mL), dried (MgS04), filtered, and concentrated to yield 6- bromo-2-(4-fluorobenzyl)- ,2-dimethyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (6.0 g, 79%). The product was carried forward without purification. Step E: A round bottomed flask plus stir bar was charged with 6-bromo-2-(4-fluorobenzyl)-r,2-dimethyl- 2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (4.3 g, 9.6 mmol), MeOH (80 mL), 70% aqueous t-butyl hydroperoxide (20 mL, 144 mmol), and 30% aqueous NH4OH (37 mL, 287 mmol). The reaction mixture was stirred for 3 days at room temperature. Water (2 mL) was added and concentrated in vacuo. The mixture was partioned between EtOAc (75 mL) and water (75 mL). The phases were separated, and the aqueous was re-extracted with EtOAc (50 mL). The combined organic phases were washed with brine (50 mL), dried (MgSC^), filtered, and concentrated. Purified crude by silica gel chromatography on a Biotage Flash 65 system, eluting with a gradient of neat EtOAc, followed by 5% MeOH/EtOAc.
Diastereomers were separated to yield (2R*,4R*)-2'-amino-6-bromo-2-(4-fluorobenzyl)-r,2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (360 mg, 8%).
Step F: A 2 dram vial was charged with (2R*,4R*)-2'-amino-6-bromo-2-(4-fluorobenzyl)-r,2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (50 mg, 0.12 mmol), dioxane (0.5 mL), 5- chloropyridin-3-ylboronic acid (20 mg, 0.13 mmol), Pd(PPh3)4 (13 mg, 0.012 mmol), and 2N aqueous Na2C03 (145 μί, 0.29 mmol). The reaction mixture was sparged with N2 for 30 seconds and then heated to 90°C for 15 hours with stirring. After cooling to room temperature, The reaction mixture was loaded directly on to a preparative TLC plate (1 mm thickness, Rf=0.47) and eluted with 10% MeOH (containing 7N NH3)/DCM. Yield of (2R*,4R*)-2'-amino-6-(5-chloropyridin-3-yl)-2-(4-fluorobenzyl)-l',2- dimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one (22 mg, 39%). Ή NMR (400 MHz, CDC13) δ 8.53 (s, 1H), 8.46 (d, J = 2 Hz, 1H), 7.69 (s, 1H), 7.34 (m, 1H), 7.24 (m, 2H), 6.99 (m, 3H), 6.89 (s, 1H), 4.84 (br s, 2H), 3.14 (s, 3H), 3.08 (d, J = 13 Hz, 1H), 2.99 (d, J = 14 Hz, 1 H), 2.48 (d, J = 14 Hz, 1H), 1.85 (d, J = 14 Hz, 1H), 1.36 (s, 3H); m/z (APCI-pos) M+l = 465, 467.
Example 367 (2S*,4R*)-2'-amino-6-(5-chloropyridin-3-yl)-r,2-dimethyl-2-(pyridin-2- ylmethyl)spiro[chroman-4 4'-imidazol]-5'( H)-one
Figure imgf000153_0001
(2S*,4R*)-2'-Amino-6-(5-chloropyridin-3-yl)-r,2-dimethyl-2-(pyridin-2-ylmethyl)spiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared according to the general procedure described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(pyridin-2-yl)propan-2-one. Ή NMR (400 MHz, CDCI3) δ 8.54 (m, 2H), 8.46 (d, J = 2 Hz, 1H), 7.69 (m, 1H), 7.64 (m, 1H), 7.37 (m, 2H), 7.17 (m, 1H), 6.98 (d, J = 9 Hz, 1H), 6.91 (d, J = 2 Hz, 1H), 4.88 (br s, 2H), 3.30 (d, J = 13 Hz, 1H), 3.25 (d, J = 13 Hz, 1H), 3.15 (s, 3H), 2.56 (d, J = 14 Hz, 1H), 2.03 (d, J = 14 Hz, 1H), 1.43 (s, 3H); m/z (APCI-pos) M+l = 448. Example 368 (2S*,4R*)-2'-amino-6-(5-chloropyridin-3-y])-2-((5-fluoropyridin-2-y])methyl)-l',2- dimethylspiro[chroman-4 4'-imidazol]-5'(rH)-one
Figure imgf000154_0001
Step A: Following a procedure similar to that described in WO 2006/094799, a round bottomed flask equipped with a Dean Stark trap and stir bar was charged with 5-fluoropicolinaldehyde (5 g, 40 mmol), toluene (30 mL), and n-butylamine (5.9 mL, 60 mmol). The reaction mixture was heated for 2 hours at reflux to remove water via the Dean Stark trap. The reaction mixture was concentrated in vacuo, and then acetic acid (20 mL) was added followed by nitroethane (4.3 mL, 60 mmol). The residue was heated to 100°C for 2 hours with stirring. The residue was cooled to room temperature, diluted with water (20 mL), and separated phases. The aqueous phase was re-extracted with EtOAc (2 X 20 mL), and the combined organic phases were washed with 5% aqueous NaHC03 (50 mL), dried (Na2S04), filtered, and concentrated to yield (Z)-5-fluoro-2-(2-nitroprop-l-enyl)pyridine (4.9 g, 59%). The product was carried forward without purification at this step.
Step B: Following a procedure similar to that described in WO 2006/094799, a round bottomed flask equipped with water-cooled reflux condenser and stir bar was charged with iron powder (15 g, 269 mmol) and acetic acid (50 mL). (Z)-5-Fluoro-2-(2-nitroprop-l-enyl)pyridine (4.9 g, 27 mmol) dissolved in acetic acid (20 mL) was added to the stirred mixture. The stirring reaction mixture was heated to 120°C for 1 hour. After cooling, the mixture was diluted with water (50 mL), and extracted with DCM (2 X 50 mL). The combined organic phases were washed with brine (50 mL). The organic phases were dried (Na2S04), filtered, concentrated, and a toluene azeotrope (3 x 50 mL) was utilized to remove residual acetic acid. Yield of l-(5-fluoropyridin-2-yl)propan-2-one (4.0 g, 78%). The product was carried forward without purification at this step.
Step C: (2S*,4R*)-2'-Amino-6-(5-chloropyridin-3-yl)-2-((5-fluoropyridin-2-yl)methyl)-l',2- dimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(5- fluoropyridin-2-yl)propan-2-one. Ή NMR (400 MHz, CDC13) δ 8.54 (d, J = 2 Hz, 1H), 8.46 (d, J = 2 Hz, 1H), 8.39 (d, J = 2 Hz, 1H), 7.69 (t, J = 2 Hz, 1H), 7.38 (m, 3H), 6.97 (d, J = 9 Hz, 1H), 6.90 (d, J = 2 Hz, 1H), 4.33 (br s, 2H), 3.28 (d, J = 14 Hz, 1H), 3.23 (d, J = 13 Hz, 1H), 3.15 (s, 3H), 2.51 (d, J = 14 Hz, 1H), 2.00 (d, J = 14 Hz, 1H), 1.43 (s, 3H); m/z (APCI-pos) M+l = 466. Example 369 (2R*,4R*)-2'-amino-2-(3-fluorobenzyl)-1^2-dimethyl-6-(pyrimidin-5-yl)spiro[chroman- 4,4'-imidazol]-5'(l'H -one
Figure imgf000155_0001
Step A: Following a procedure similar to that as described in J. Org. Chem. (1979), 44, 1572, a round bottomed flask plus stir bar under an N2 atmosphere was charged with BF3 etherate (9.7 mL, 75 mmol). While rapidly stirring, the reaction mixture was cooled to -10°C in a NaCl/ice bath. Next, 3-fluoroaniline (5.6 g, 50 mmol) dissolved in DCM (25 mL) was added. t-BuN02 (7.9 mL, 60 mmol) dissolved in DCM (10 mL) was added to this suspension dropwise over a 20 minute period, maintaining the internal temperature between -10°C and -15°C. Following this addition, the temperature of the reaction mixture was maintained at -10°C for 10 minutes, and then the mixture was allowed to warm to 5°C in an ice water bath over a 20 minute period. Pentane (50 mL) was added to the reaction mixture, and the resulting solids were filtered, washed with cold diethyl ether, and dried under high vacuum to yield 3- fluorobenzenediazonium tetrafluoroborate (10.7 g, 99%). The solids were carried forward into the next reaction without purification at this step.
Step B: Following a procedure similar to that as described in J. Org. Chem. (2007), 72, 1856, a round bottomed flask plus stir bar was charged with prop-l-en-2-yl acetate (50 g, 500 mmol), acetonitrile (50 mL) and water (5 mL). Next, a one mL solution of potassium acetate (4.9 g, 50 mmol) dissolved in water (5 mL) was added. Then, 3-fluorobenzenediazonium tetrafluoroborate (10.5 g, 50.0 mmol) as a solid was added in portions over a 10 minute period. Lastly, the rest of the potassium acetate (4.9 g, 50 mmol) in water (5 mL) solution was added over a 45 minute period. There was significant gas evolution during the addition, which was adequately vented. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was partioned between diethyl ether (100 mL) and saturated aqueous NaHC03 (100 mL). The phases were carefully shaken, evolving more gas. The phases were separated, and the organic phase was washed with brine (50 mL), dried (MgSO^, filtered, and concentrated to yield l-(3- fluorophenyl)propan-2-one (7.0 g, 83%). The product was carried forward without purification at this step. Step C: (2R*,4R*)-2'-Amino-2-(3-fluorobenzyl)-1^2-dimethyl-6 pyrimidin-5-yl)spiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(3-fiuorophenyl)propan-2-one, and replacing 5-chloropyridin-3-ylboronic acid in Step F with pyrimidin-5-ylboronic acid. 'LI NMR (400 (400 MHz, CDCI3) δ 9.12 (s, IH), 8.79 (s, 2H), 7.38 (m, IH), 7.27 (m, IH), 7.04 (m, 3H), 6.96 (m, IH), 6.90 (m, IH), 4.88 (br s, 2H), 3.15 (s, 3H), 3.12 (d, J = 13 Hz, IH), 3.02 (d, J = 13 Hz, IH), 2.50 (d, J = 14 Hz, IH), 1.89 (d, J = 14 Hz, IH), 1.39 (s, 3H); m/z (APCI-pos) M+l = 432. Example 370 (2R*,4R*)-2'-amino-2-(4-(difluoromethoxy)benzyl)-r,2-dimethyl-6-(pyrimidin-5- yl)spiro[chroman-4,4'-imidazol -5'(rH)-one
Figure imgf000156_0001
(2R*,4R*)-2'-Amino-2-(4-(difluoromethoxy)benzyl)- ,2-dimethyl-6-(pyrimidin-5-yl)spiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared according to the general procedures described in Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(4-(difluoromethoxy)phenyl)propan-2- one (synthesized from 4-(difluoromethoxy)aniline according to the same preparation described for l-(3- fluorophenyl)propan-2-one, in Example 369, Steps A-B), and replacing 5-chloropyridin-3-ylboronic acid in Step F with pyrimidin-5-ylboronic acid. lH NMR (400 MHz, CDC13) δ 9.12 (s, IH), 8.79 (s, 2H), 7.39 (d, J = 9 Hz, IH), 7.28 (m, 2H), 7.06 (m, 2H), 7.02 (m, IH), 6.91 (s, IH), 6.52 (t, J = 74 Hz, IH), 4.89 (br s, 2H), 3.15 (s, 3H), 3.1 1 (d, J = 14 Hz, IH), 3.02 (d, J = 14 Hz, IH), 2.50 (d, J = 14 Hz, IH), 1.88 (d, J = 14 Hz, IH), 1.39 (s, 3H); m/z (APCI-pos) M+l = 480.
Example 371 (2R* ,4R* )-2'-amino-6-(5 -ch loropyridin-3 -y l)-2-(3 -fluorobenzyl)- Γ,2- dimeth lspiro[chroman-4,4'-imidazol]-5'( H)-one
Figure imgf000156_0002
(2R*,4R*)-2'-Amino-6-(5-chloropyridin-3-yl)-2-(3-fluorobenzyl)-r,2-dimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(3-fluorophenyl)propan-2-one (synthesis described in Example 369, Steps A-B. !H NMR (400 MHz, CDC13) δ 8.54 (s, IH), 8.46 (s, IH), 7.69 (m, IH), 7.35 (m, IH), 7.27 (m, IH), 7.01 (m, 4H), 6.90 (s, IH), 5.07 (br s, 2H), 3.14 (s, 3H), 3.1 1 (d, J = 13 Hz, IH), 3.01 (d, J = 13 Hz, IH), 2.49 (d, J = 14 Hz, IH), 1.89 (d, J = 14 Hz, IH), 1.38 (s, 3H); m/z 3H); m/z (APCI-pos) M+l
Example 372 (2R*,4R*)-2'-amino-2-(3-fluorobenzyl)-6-(2-fluoropyridin-3-yl)-l',2- dimethylspiro[chroman-4 4'-imidazol]-5'(rH)-one
Figure imgf000157_0001
(2R*,4R*)-2'-Amino-2-(3-fluorobenzyl)-6-(2-fluoropyridin-3-yl)- ,2-dimethylspiro[chroman-4,4 imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(3-fluorophenyl)propan-2-one (synthesis described in Example 369, Steps A-B), and replacing 5-chloropyridin-3-ylboronic acid in Step F with 2- fluoropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 8.09 (d, J = 5 Hz, 1H), 7.74 (d, J = 9 Hz, 1H), 7.36 (d, J = 9 Hz, 1H), 7.26 (m, 1H), 7.20 (m, 1H), 6.93-7.06 (m, 5H), 5.11 (br s, 2H), 3.09 (m, 4H), 3.01 (d, J = 13 Hz, 1H), 2.49 (d, J = 14 Hz, 1H), 1.88 (d, J = 14 Hz, 1H), 1.36 (s, 3H); m/z (APCI-pos) M+l = 449.
Example 373 (2R*,4R*)-2'-amino-2-(2-fluorobenzyl)-6-(2-fluoropyridin-3-yl)-l',2- dimethylspiro[chroman-4 4'-imidazol]-5'( H)-one
Figure imgf000157_0002
(2R*,4R*)-2'-Amino-2-(2-fluorobenzyl)-6-(2-fluoropyridin-3-yl)-r,2-dimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing 1 -(4-fluorophenyl)propan-2-one in Step A with commercially available l-(2- fluorophenyl)propan-2-one, and replacing 5-chloropyridin-3-ylboronic acid in Step F with 2- fluoropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 8.10 (m, 1H), 7.72 (m, 1H), 7.36 (m, 2H), 7.21 (m, 2H), 7.10 (t, J = 7 Hz, 1H), 7.03 (t, J = 9 Hz, 1H), 6.96 (d, J = 9 Hz, 2H), 5.35 (br s, 2H), 3.0-3.24 (m, 5H), 2.52 (br d, J = 10 Hz, 1H), 1.94 (br d, J = 11 Hz, 1H), 1.40 (s, 3H); m/z (APCI-pos) M+l = 449. Example 374 (2R*,4R*)-2'-amino-2-(2-fluorobenzyl)-r,2-dimethyl-6-(pyrimidin-5-yl)spiro[chroman- 4,4'-imidazol]-5'(l'H)-one
Figure imgf000158_0001
(2R*,4R*)-2'-Amino-2-(2-fluorobenzyl)-1^2-dimethyl-6-(pyrimidin-5-yl)spiro[chroman-4,4'-imid
5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with commercially available l-(2- fluorophenyl)propan-2-one, and replacing 5-chloropyridin-3-ylboronic acid in Step F with pyrimidin-5- ylboronic acid. Ή NMR (400 MHz, CDC13) δ 9.12 (s, 1H), 8.78 (s, 2H), 7.36 (m, 2H), 7.23 (m, 1H), 7.10 (t, J = 7 Hz, 1H), 7.02 (m, 2H), 6.90 (d, J = 2 Hz, 1 H), 4.84 (br s, 2H), 3.15 (m, 4H), 3.10 (d, J = 14 Hz, 1H), 2.53 (d, J = 14 Hz, 1H), 1.95 (d, J = 14 Hz, 1H), 1.41 (s, 3H); m/z (APCI-pos) M+l = 432.
Example 375 (2R*,4R*)-2'-amino-6-(5-chloropyridin-3-yl)-2-(4-(difluoromethoxy)benzyl)-l,,2- dimethylspiro[chroman-4 4'-imidazol]-5'(rH)-one
Figure imgf000158_0002
(2R*,4R*)-2'-Amino-6-(5-chloropyridin-3-yl)-2-(4-(difluoromethoxy)benzyl)-r,2-dimethylspiro[chroman- 4,4'-imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(4-
(difluoromethoxy)phenyl)propan-2-one (synthesized from 4-(difluoromethoxy)aniline according to the same preparation described for l-(3-fluorophenyl)propan-2-one, in Example 369, Steps A-B). Ή NMR (400 MHz, CDCI3) δ 8.53 (s, 1H), 8.46 (s, 1H), 7.69 (s, 1H), 7.36 (d, J = 9 Hz, 1H), 7.27 (d, J = 6 Hz, 2H), 7.06 (d, J = 9 Hz, 2H), 6.99 (m, 1H), 6.89 (s, 1H), 6.50 (t, J = 74 Hz, 1H), 5.12 (br s, 2H), 3.14 (s, 3H), 3.09 (d, J = 13 Hz, 1H), 3.00 (d, J = 13 Hz, 1H), 2.48 (d, J = 14 Hz, 1H), 1.87 (d, J = 14 Hz, 1H), 1.37 (s, 3H); m/z (APCI-pos) M+l = 513. Example 376 (2R*,4R*)-2'-amino-6-(5-chloropyridin-3-yl)-2-(2-fluorobenzyl)- 1 ',2- dimethy lspiro [chroman-4 4'-im idazol] -5 '( 1 'H)-one
Figure imgf000159_0001
(2R*,4R*)-2'-Amino-6-(5-chloropyridin-3-yl)-2-(2-fluorobenzyl)-1^2-dimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with commercially available l-(2- fluorophenyl)propan-2-one. Ή NMR (400 MHz, CDC13) δ 8.54 (d, J = 2 Hz, 1H), 8.46 (d, J = 2 Hz, 1H), 7.69 (m, 1H), 7.36 (m, 2H), 7.23 (m, 1 H), 7.10 (m, 1H), 7.04 (m, 1H), 6.98 (d, J = 9 Hz, 1H), 6.89 (d, J = 2 Hz, 1H), 4.93 (br s, 2H), 3.15 (s, 3H), 3.13 (d, J = 13 Hz, 1H), 3.09 (d, J = 13 Hz, 1H), 2.53 (d, J = 14 Hz, 1H), 1.94 (d, J = 14 Hz, 1H), 1.40 (s, 3H); m/z (APCI-pos) M+l = 465, 467.
Example 377 (2R*,4R*)-2'-amino-2-(4-fluorobenzyl)-6-(2-fluoropyridin-3-yl)-l',2- dimethylspiro[chroman-4 4'-imidazol]-5'(rH)-one
Figure imgf000159_0002
(2R*,4R*)-2'-Amino-2-(4-fluorobenzyl)-6-(2-fluoropyridin-3-yl)-r,2-dimethylspiro[chroman-4,4'- imidazol]-5'( l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing 5-chloropyridin-3-ylboronic acid in Step F with 2-fluoropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 8.10 (d, J = 4 Hz, 1H), 7.73 (t, J = 9 Hz, 1H), 7.37 (d, J = 9 Hz, 1H), 7.22 (m, 3H), 6.97 (m, 4H), 4.74 (br s, 2H), 3.12 (s, 3H), 3.08 (d, J = 13 Hz, 1H), 3.00 (d, J = 13 Hz, 1H), 2.50 (d, J = 14 Hz, 1 H), 1.87 (d, J = 14 Hz, 1H), 1.36 (s, 3H); m/z (APCI-pos) M+l = 449. Example 378 (2R*,4R*)-2'-amino-2-(4-fluorobenzyl)-r,2-dimethyl-6-(pyrimidin-5-yl)spiro[chroman- 4,4'-imidazol]-5'(l'H)-one
Figure imgf000160_0001
(2R*,4R*)-2'-Amino-2-(4-fluorobenzyl)-r,2-dimethyl-6-(pyrimidin-5-yl)spiro[chroman-4,4'-imidazol]- 5'(l'H)-one was prepared according to the procedures described for Example 366, Steps A-F, replacing 5- chloropyridin-3-ylboronic acid in Step F with pyrimidin-5-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 9.1 1 (s, 1H), 8.78 (s, 2H), 7.38 (d, J = 9 Hz, 1H), 7.24 (m, 2H), 7.00 (m, 3H), 6.91 (s, 1H), 5.01 (br s, 2H), 3.14 (s, 3H), 3.09 (d, J = 13 Hz, 1H), 3.00 (d, J = 14 Hz, 1H), 2.49 (d, J = 13 Hz, 1H), 1.86 (d, J = 13 Hz, 1H), 1.37 (s, 3H); m/z (APCI-pos) M+l = 432.
Example 379 (2R*,4R*)-2'-amino-2-(4-(difluoromethoxy)benzyl)-6-(2-fluoropyridin-3-yl)-r,2- dimethylspiro[chroman-4 4'-imidazol]-5'(rH)-one
Figure imgf000160_0002
(2R*,4R*)-2'-Amino-2-(4-(difluoromethoxy)benzyl)-6-(2-fluoropyridin-3-yl)-1^2-dimethylspiro[chroman- 4,4'-imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(4-
(difluoromethoxy)phenyl)propan-2-one (synthesized from 4-(difluoromethoxy)aniline according to the same preparation described for l-(3-fluorophenyl)propan-2-one, in Example 369, Steps A-B), and replacing 5-chloropyridin-3-ylboronic acid in Step F with 2-fluoropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 8.09 (d, J = 5 Hz, 1H), 7.73 (t, J = 9 Hz, 1H), 7.36 (d, J = 9 Hz, 1H), 7.26 (m, 2H), 7.19 (m, 1H), 7.05 (d, J = 9 Hz, 2H), 6.95 (m, 2H), 6.50 (t, J = 74 Hz, 1H), 5.13 (br s, 2H), 3.09 (s, 3H), 3.08 (d, J = 14 Hz, 1H), 3.00 (d, J = 14 Hz, 1H), 2.48 (d, J = 14 Hz, 1H), 1.87 (d, J = 14 Hz, 1H), 1.36 (s, 3H); m/z (APCI-pos) M+l = 497. Example 380 (2R*,4R*)-2'-amino-2-((5-fluoropyridin-2-yl)methyl)-6-(2-fluoropyridin-3-yl)- 1 ',2- dimethylspiro[chroman-4 4'-imidazol]-5'(rH)-one
Figure imgf000161_0001
(2R*,4R*)-2'-amino-2-((5-fluoropyridin-2-yl)methyl)-6-(2-fluoropyridin-3-yl)-l',2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(5- fluoropyridin-2-yl)propan-2-one (synthesis described in Example 368, Steps A-B), and replacing 5- chloropyridin-3-ylboronic acid in Step F with 2-fluoropyridin-3-ylboronic acid. Ή NMR (400 MHz, CDC13) δ 8.39 (d, J = 3 Hz, IH), 8.1 1 (m, IH), 7.73 (m, IH), 7.38 (m, 3H), 7.20 (m, IH), 6.96 (m, 2H), 4.45 (br s, 2H), 3.28 (d, J = 14 Hz, IH), 3.23 (d, J = 13 Hz, IH), 3.1 1 (s, 3H), 2.52 (d, J = 14 Hz, IH), 2.00 (d, J = 14 Hz, IH), 1.42 (s, 3H); m/z (APCI-pos) M+l = 450.
Example 381 3-((2R*,4R*)-2'-amino-2-(4-(difluoromethoxy)benzyl)- 1 ',2-dimethyl-5'-oxo- 1 ',5 - dihydrospiro[chroman-4 4'-imidazole]-6-yl)benzonitrile
Figure imgf000161_0002
3-((2R*,4R*)-2'-Amino-2-(4-(difluoromethoxy)benzyl)-1^2-dimethyl-5'-oxo-r,5'-dihydrospiro[chroman- 4,4'-imidazole]-6-yl)benzonitrile was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(4- (difluoromethoxy)phenyl)propan-2-one (synthesized from 4-(difiuoromethoxy)aniline according to the same preparation described for l-(3-fluorophenyl)propan-2-one, in Example 369, Steps A-B), and replacing 5-chloropyridin-3-ylboronic acid in Step F with 3-cyanophenylboronic acid. Ή NMR (400 MHz, CDCI3) δ 7.67 (s, IH), 7.64 (d, J = 8 Hz, IH), 7.54 (d, J = 7 Hz, IH), 7.45 (t, J = 7 Hz, IH), 7.35 (d, J = 9 Hz, IH), 7.27 (d, J = 8 Hz, 2H), 7.05 (d, J = 8 Hz, 2H), 6.97 (m, IH), 6.88 (s, IH), 6.50 (t, J = 74 Hz, I H), 5.06 (br s, 2H), 3.14 (s, 3H), 3.08 (d, J = 13 Hz, IH), 3.00 (d, J = 14 Hz, IH), 2.48 (d, J = 14 Hz, IH), 1.86 (d, J = 14 Hz, IH), 1.37 (s, 3H); m/z (APCI-pos) M+l = 503. Example 382 (2S*,4R*)-2'-amino-6-(5-chloropyridin-3-yl)-r,2-dimethyl-2-(pyrimidin-2- ylmethyl)spiro[chroman-4 4'-imidazol]-5'(rH)-one
Figure imgf000162_0001
Step A: Following a procedure similar to that described in J. Org. Chem. (1981), 46, 294, a round bottomed flask plus stir bar was charged with potassium hydride (48.1 g, 360 mmol) and anhydrous THF (500 mL) under an N2 atmosphere. The reaction mixture was cooled in an ice bath, and acetone (17.4 g, 300 mmol) was added. The reaction mixture was stirred for 30 minutes in the ice bath, and then the mixture was removed from the bath and illuminated with two black lights (60 watts) on either side of the flask. 2-Chloropyrimidine (1 1.5 g, 100 mmol) was carefully added as a solid in portions. The reaction mixture was stirred for 30 minutes under illumination of the black lights. The reaction mixture was concentrated in vacuo, and diethyl ether (100 mL) and ice (100 mL) were added. The mixture was acidified with aqueous 3N HCl to pH 1 , then aqueous saturated NaHC03 was added to bring the pH back up to 6. The phases were separated. The product was extracted with DCM (3 X 50 mL). The combined organic phases were dried (Na2S04), filtered, and concentrated. The crude was purified by silica gel chromatography on a Biotage Flash 65 system, eluting with the following gradient: neat hexanes, 25% EtOAc hexanes, 1 : 1 EtOAc/hexanes, and lastly neat EtOAc to fully elute the product. Yield of 1- (pyrimidin-2-yl)propan-2-one (2.6 g, 17%). Step B: (2S*,4R*)-2'-Amino-6-(5-chloropyridin-3-yl)-l',2-dimethyl-2-(pyrimidin-2- ylmethyl)spiro[chroman-4,4'-imidazol]-5'(l'H)-one was prepared according to the procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(pyrimidin-2- yl)propan-2-one. Ή NMR (400 MHz, CDC13) δ 8.72 (d, J = 5 Hz, 2H), 8.56 (d, J = 2 Hz, 1H), 8.47 (d, J = 2 Hz, 1H), 7.71 (t, J = 2 Hz, 1H), 7.38 (dd, J = 2, 9 Hz, 1H), 7.20 (t, J = 5 Hz, iH), 7.02 (d, J = 9 Hz, 1H), 6.93 (d, J = 2 Hz, 1H), 3.49 (m, 2H), 3.20 (s, 3H), 2.81 (br s, 2H), 2.78 (d, J = 15 Hz, 1H), 2.22 (d, J = 15 Hz, 1H), 1.51 (s, 3H); m/z (APCI-pos) M+l = 449. Example 383 (2S*,4R*)-2'-amino-6-(3-chloro-5-fluorophenyl)-r,2-dimethyl-2-(pyrimidin-2- ylmethyl)spiro[chroman-4 4'-imidazol]-5'(rH)-one
Figure imgf000163_0001
(2S*,4R*)-2'-Amino-6-(3-chloro-5-fluorophen^^
4,4'-imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing 1 -(4-fluorophenyl)propan-2-one in Step A with 1 -(pyrimidin-2-yl)propan-2-one (synthesis described in Example 382, Step A), and replacing 5-chloropyridin-3-ylboronic acid in Step F with 3-chloro-5-fluorophenylboronic acid. Ή NMR (400 MHz, CDC13) δ 8.71 (d, J = 5 Hz, 2H), 7.37 (m, 1H), 7.19 (m, 2H), 6.99 (m, 3H), 6.90 (m, 1H), 3.52 (br s, 2H), 3.48 (m, 2H), 3.22 (s, 3H), 2.78 (d, J = 15 Hz, 1H), 2.23 (d, J = 15 Hz, 1H), 1.50 (s, 3H); m/z (APCI-pos) M+l = 466.
Example 384 (2R*,4R*)-2'-amino-2-(3-(difluoromethoxy)benzyl)-6-(2-fluoropyridin-3-yl)-r,2- dimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one
Figure imgf000163_0002
(2R*,4R*)-2'-Amino-2-(3-(difluoromethoxy)benzyl)-6-(2-fluoropyridin-3-yl)- ,2-dimethylspiro[chroman- 4,4'-imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(3-
(difluoromethoxy)phenyl)propan-2-one (synthesized from 3-(difiuoromethoxy)aniline according to the same preparation described for l-(3-fluorophenyl)propan-2-one, in Example 369, Steps A-B), and replacing 5-chloropyridin-3-ylboronic acid in Step F with 2-fluoropyridin-3-ylboronic acid. Ή NMR
(400 MHz, CDC13) δ 8.09 (d, J = 4 Hz, 1H), 7.75 (d, J = 9 Hz, 1H), 7.37 (d, J = 9 Hz, 1H), 7.29 (t, J = 8 Hz, 1H), 7.20 (t, J = 6 Hz, 1H), 7.13 (d, J = 7 Hz, 1H), 7.08 (s, 1H), 7.03 (m, 1H), 6.95 (m, 2H), 6.52 (t, J = 74 Hz, 1H), 5.00 (br s, 2H), 3.1 1 (m, 4H), 3.01 (d, J = 13 Hz, 1H), 2.50 (d, J = 14 Hz, 1H), 1.90 (d, J = 14 Hz, 1H), 1.37 (s, 3H); m/z (APCI-pos) M+l = 497. Examp le 385 (2S*,4R* )-2'-amino-6-(3 -chloro-5 -fluorophenyl)- 1 ',2-dimethyl-2-(pyridin-2- ylmethyl)spiro[chroman-4 4'-imidazol]-5'( H)-one
Figure imgf000164_0001
(2S*,4R*)-2'-Amino-6-(3-chloro-5-fluorophenyl)-r,2-dimethyl-2-(pyridin-2-ylmethyl)spiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with commercially available l-(pyridin-2- yl)propan-2-one, and replacing 5-chloropyridin-3-ylboronic acid in Step F with 3-chloro-5- fluorophenylboronic acid. Ή NMR (400 MHz, CDC13) δ 8.54 (d, J = 5 Hz, 1H), 7.64 (td, J = 2, 8 Hz, 1H), 7.38 (d, J = 8 Hz, 1H), 7.35 (dd, J = 2, 9 Hz, 1H), 7.19 (m, 2H), 7.00 (m, 2H), 6.94 (d, J = 9 Hz, 1H), 6.88 (d, J = 2 Hz, 1H), 5.09 (br s, 2H), 3.29 (d, J = 13 Hz, 1H), 3.24 (d, J = 13 Hz, 1H), 3.15 (s, 3H), 2.55 (d, J = 14 Hz, 1H), 2.03 (d, J = 14 Hz, 1H), 1.42 (s, 3H); m/z (APCI-pos) M+l = 465.
Example 386 (2R*,4R*)-2'-amino-2-(3-(difluoromethoxy)benzyl)-r,2-dimethyl-6-(pyrimidin-5- yl)spiro[chroman-4,4'-imidazol]-5'( H)-one
Figure imgf000164_0002
(2R*,4R*)-2'-amino-2-(3-(difluoromethoxy)benzyl)-r,2-dimethyl-6-(pyrimidin-5-yl)spiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(3-(difluoromethoxy)phenyl)propan-2- one (synthesized from 3-(difluoromethoxy)aniline according to the same preparation described for l-(3- fluorophenyl)propan-2-one, in Example 369, Steps A-B), and replacing 5-chloropyridin-3-ylboronic acid in Step F with pyrimidin-5-ylboronic acid. Ή NMR (400 MHz, CDC¾) δ 9.12 (s, 1H), 8.79 (s, 2H), 7.39 (dd, J = 2, 9 Hz, 1H), 7.30 (t, J = 8 Hz, 1H), 7.13 (d, J = 8 Hz, 1H), 7.09 (m, 1H), 7.02 (d, J = 9 Hz, 2H), 6.90 (d, J = 2 Hz, 1H), 6.53 (t, J = 74 Hz, 1H), 4.77 (br s, 2H), 3.15 (s, 3H), 3.13 (d, J = 13 Hz, 1H), 3.02 (d, J = 13 Hz, 1H), 2.50 (d, J = 14 Hz, 1H), 1.89 (d, J = 14 Hz, 1H), 1.38 (s, 3H); m/z (APCI-pos) M+l = 480. Example 387 (2R*,4R*)-2'-amino-6-(5-chloropyridin-3-yl)-2-(3-fluoro-4-methoxyben2yl)-l',2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one
Figure imgf000165_0001
(2R* ,4R* )-2'- Amino-6-( 5 -ch loropyr idin-3 -y l)-2-(3 -fluoro-4-methoxybenzyl)- 1 ',2-dimethy lspiro[chroman- 4,4'-imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing 1 -(4-fluorophenyl)propan-2-one in Step A with l-(3-fluoro-4- methoxyphenyl)propan-2-one (synthesized from 3-fluoro-4-methoxyaniline according to the same preparation described for l-(3-fluorophenyl)propan-2-one, in Example 369, Steps A-B). 'H NMR (400 MHz, CDC13) δ 8.54 (s, 1H), 8.46 (s, 1H), 7.70 (s, 1H), 7.36 (d, J = 9 Hz, 1H), 7.04 (d, J = 12 Hz, 1H), 6.99 (d, J = 9 Hz, 1H), 6.95 (m, 1H), 6.89 (m, 2H), 5.19 (br s, 2H), 3.87 (s, 3H), 3.15 (s, 3H), 3.03 (d, J = 14 Hz, 1H), 2.95 (d, J = 14 Hz, 1H), 2.47 (br d, J = 13 Hz, 1H), 1.85 (br d, J = 13 Hz, 1H), 1.36 (s, 3H); m/z (APCI-pos) M+l = 495.
Example 388 (2S*,4R*)-2'-amino-6-cyclohexyl-r,2-dimethyl-2-(pyridin-2-ylmethyl)spiro[chroman- 4,4'-imidazol]-5'(l'H)-one
Figure imgf000165_0002
A 2 dram vial was charged with (2S*,4R*)-2'-amino-6-bromo-l',2-dimethyl-2-(pyridin-2- ylmethyl)spiro[chroman-4,4'-imidazol]-5'(rH)-one (52 mg, 0.13 mmol; prepared according to the same procedures used to synthesize (2R*,4R*)-2'-amino-6-bromo-2-(4-fluorobenzyl)-l',2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one in Example 366, Steps A-E, replacing l-(4- fluorophenyl)propan-2-one in Step A with commercially available l-(pyridin-2-yl)propan-2-one) and bis(tri-t-butylphosphine)palladium (0) (13 mg, 0.025 mmol). Next, cyclohexylzinc(II) bromide (0.5M in THF; 751 μί, 0.38 mmol) was added. The mixture was sparged with Ar gas, sealed and heated to 90°C for 18 hours with stirring. After cooling to room temperature, loaded directly on to a preparative TLC plate (0.5 mm thickness, Rf = 0.41), eluting with 10% MeOH (containing 7N NH3)/DCM to yield
(2S*,4R*)-2'-amino-6-cyclohexyl-r,2-dimethyl-2-(pyridin-2-ylmethyl)spiro[chroman-4,4'-imidazol]- 5'(l'H)-one (17 mg, 29%). Ή NMR (400 MHz, CDC13) δ 8.52 (m, 1H), 7.61 (m, 1H), 7.36 (m, 1H), 7.16 (m, 1H), 7.03 (dd, J = 2, 9 Hz, 1H), 6.79 (d, J = 8 Hz, 1H), 6.59 (d, J = 2 Hz, 1H), 4.87 (br s, 2H), 3.26 (d, J = 13 Hz, 1H), 3.21 (d, J = 13 Hz, 1H), 3.16 (s, 3H), 2.53 (d, J = 14 Hz, 1H), 2.33 (m, 1H), 2.01 (d, J = 14 Hz, 1H), 1.68-1.80 (m, 5H), 1.23-1.40 (m, 8H); m/z (APCI-pos) M+l = 419.
Example 389 3-((2R*,4R*)-2'-amino-2-(3-fluoro-4-methoxybenzyl)-l,,2-dimethyl-5'-oxo-l',5'
dihydrospiro[chroman-4,4'-imidazole]-6-yl)benzonitrile
Figure imgf000166_0001
3-((2R*,4R*)-2'-Amino-2-(3-fluoro-4-methoxybenzyl)-r,2-dimethyl-5'-oxo-r,5'-dihydrospiro[chroman- 4,4'-imidazole]-6-yl)benzonitrile was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(3-fluoro-4- methoxyphenyl)propan-2-one (synthesized from 3-fluoro-4-methoxyaniline according to the same preparation described for l -(3-fluorophenyl)propan-2-one, in Example 369, Steps A-B), and replacing 5- chloropyridin-3-ylboronic acid in Step F with 3-cyanophenylboronic acid. Ή NMR (400 MHz, CDC13) δ 7.67 (s, 1H), 7.64 (d, J = 8 Hz, 1H), 7.54 (d, J = 7 Hz, 1H), 7.45 (t, J = 7 Hz, 1H), 7.36 (d, J = 8 Hz, 1H), 7.03 (d, J = 13 Hz, 1H), 6.96 (m, 2H), 6.88 (m, 2H), 5.09 (br s, 2H), 3.87 (s, 3H), 3.14 (s, 3H), 3.02 (d, J = 14 Hz, 1H), 2.94 (d, J = 14 Hz, 1H), 2.46 (d, J = 14 Hz, 1H), 1.86 (d, J = 14 Hz, 1H), 1.36 (s, 3H); m/z (APCI-pos) M+l = 485.
Example 390 (2R*,4R*)-2'-amino-6-(5-chloropyridin-3-yl)-2-(3-(difluoromethoxy)benzyl)-r,2- dimethylspiro[chroman-4 4'-imidazol]-5'( 1 'H)-one
Figure imgf000166_0002
(2R*,4R*)-2'-Amino-6-(5-chloropyridin-3-yl)-2-(3-(difluoromethoxy)benzyl)-r,2-dimethylspiro[chroman- 4,4'-imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing 1 -(4-fluorophenyl)propan-2-one in Step A with l-(3- (difluoromethoxy)phenyl)propan-2-one (synthesized from 3-(difluoromethoxy)aniline according to the same preparation described for l-(3-fluorophenyl)propan-2-one, in Example 369, Steps A-B). Ή NMR (400 MHz, CDC13) δ 8.54 (s, 1H), 8.46 (s, 1H), 7.69 (s, 1H), 7.37 (dd, J = 2, 9 Hz, 1H), 7.31 (d, J = 8 Hz, 1H), 7.29 (t, J = 8 Hz, 1H), 7.08 (s, 1H), 7.02 (d, J = 9 Hz, 1H), 6.98 (d, J = 9 Hz, 1H), 6.89 (d, J = 2 Hz, 1H), 6.52 (t, J = 74 Hz, 1H), 4.88 (br s, 2H), 3.15 (s, 3H), 3.1 1 (d, J = 14 Hz, 1H), 3.01 (d, J = 14 Hz, 1H), 2.50 (d, J = 14 Hz, 1H), 1.89 (d, J = 14 Hz, 1H), 1.37 (s, 3H); m/z (APCI-pos) M+l = 513. Example 391 (2R*,4R*)-2'-amino-2-(3-fluoro-4-methoxybenzyl)- ,2-dimethyl-6-(pyrimidin-5- yl)spiro[chroman-4,4'-imidazol -5'(rH)-one
Figure imgf000167_0001
(2R*,4R*)-2'-Amino-2-(3-fluoro-4-methoxybenzyl)-r,2-dimethyl-6-(pyrimidin-5-yl)spiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(3-fluoro-4-methoxyphenyl)propan-2-one (synthesized from 3-fluoro-4-methoxyaniline according to the same preparation described for l-(3- fluorophenyl)propan-2-one, in Example 369, Steps A-B), and replacing 5-chloropyridin-3-ylboronic acid in Step F with pyrimidin-5-ylboronic acid. Ή NMR (400 MHz, CDC13) 5 9.1 1 (s, 1H), 8.79 (s, 2H), 7.39 (dd, J = 2, 9 Hz, 1H), 7.03 (m, 2H), 6.97 (d, J = 9 Hz, 1H), 6.90 (m, 2H), 4.93 (br s, 2H), 3.88 (s, 3H), 3.15 (s, 3H), 3.03 (d, J = 14 Hz, 1H), 2.96 (d, J = 14 Hz, 1H), 2.48 (d, J = 14 Hz, 1H), 1.86 (d, J = 14 Hz, 1H), 1.37 (s, 3H); m/z (APCI-pos) M+l = 462.
Example 392 3-((2R*,4R*)-2'-amino-2-(3-(difluoromethoxy)benzyl)-l',2-dimethyl-5'-oxo-l',5'- dihydrospiro[chroman-4 4'-imidazole]-6-yl)benzonitrile
Figure imgf000167_0002
3-((2R*,4R*)-2'-Amino-2-(3-(difluoromethoxy)benzyl)- 1 ',2-dimethyl-5'-oxo- 1 ',5'-dihydrospiro[chroman- 4,4'-imidazole]-6-yl)benzonitrile was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-(3- (difluoromethoxy)phenyl)propan-2-one (synthesized from 3-(difluoromethoxy)aniline according to the same preparation described for l-(3-fluorophenyl)propan-2-one, in Example 369, Steps A-B), and replacing 5-chloropyridin-3-ylboronic acid in Step F with 3-cyanophenylboronic acid. Ή NMR (400 MHz, CDC13) δ 7.67 (m, 1H), 7.65 (m, 1H), 7.55 (m, 1H), 7.46 (m, 1H), 7.37 (dd, J = 2, 9 Hz, 1H), 7.29 (t, J = 8 Hz, 1H), 7.12 (d, J = 8 Hz, 1H), 7.08 (m, 1H), 7.02 (m, IH), 6.97 (d, J = 9 Hz, 1 H), 6.88 (d, J = 2 Hz, 1H), 6.52 (t, J = 74 Hz, 1H), 4.83 (br s, 2H), 3.16 (s, 3H), 3.12 (d, J = 14 Hz, 1H), 3.00 (d, J = 14 Hz, 1H), 2.49 (d, J = 14 Hz, 1H), 1.89 (d, J = 14 Hz, 1H), 1.37 (s, 3H); m/z (APCI-pos) M+l = 503. Example 393 (2R*,4R*)-2'-amino-2-benzyl-6-cyclohexyl-r,2-dimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one
Figure imgf000168_0001
Step A: Following a procedure similar to that described in Tetrahedron Letters (2005), 46, 1651, periodic acid (22.8 g, 100 mmol) was added to acetonitrile (500 mL), and the mixture was stirred vigorously at room temperature for 15 minutes. The mixture was then cooled in an ice bath, and l-phenylpropan-2-ol (13.6 g, 100 mmol) was added. A catalytic amount of pyridinium chlorochromate (50 mg, 0.2 mmol) dissolved in acetonitrile (0.2 mL) was added to the stirred suspension. The exothermic reaction was stirred for 30 minutes in the ice bath. The suspension was then diluted with ethyl acetate (500 mL) and washed with 1 : 1 brine:water (500 mL), aqueous saturated Na2S03 solution (500 mL), brine (500 mL), dried (Na2S04), filtered, and concentrated to give l-phenylpropan-2-one (13.1 g, 96%). No purification was performed.
Step B: (2R*,4R*)-2'-Amino-2-benzyl-6-cyclohexyl-l',2-dimethylspiro[chroman-4,4'-imidazol]-5'(rH)- one was prepared following the procedure of Example 388, replacing (2S*,4R*)-2'-amino-6-bromo-l',2- dimethyl-2-(pyridin-2-ylmethyl)spiro[chroman-4,4'-imidazol]-5'( H)-one with (2R*,4R*)-2'-amino-2- benzyl-6-bromo-r,2-dimethylspiro[chroman-4,4'-imidazol]-5'(l'H)-one, which was prepared according to the same procedures used to synthesize (2R*,4R*)-2'-amino-6-bromo-2-(4-fluorobenzyl)-l',2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one in Example 366, Steps A-E, replacing l-(4- fluorophenyl)propan-2-one in Step A with l-phenylpropan-2-one. ]H NMR (400 MHz, CDC13) δ 7.26 (m, 5H), 7.04 (d, J = 9 Hz, 1H), 6.79 (d, J = 9 Hz, 1H), 6.57 (br s, 1H), 5.29 (br s, 2H), 3.15 (s, 3H), 3.07 (d, J = 14 Hz, 1H), 2.99 (d, J = 13 Hz, 1H), 2.51 (d, J = 13 Hz, 1H), 2.32 (m, 1H), 1.7-1.9 (m, 5H), 1.2-1.5 (m, 9H). m/z (APCI-pos) M+l = 418. Example 394 (2R*,4R*)-2'-amino-2-benzyl-6-((E)-2-cyclopropylvinyl)-l',2-dimethylspiro[chroman- 4,4'-imidazol]-5'(l'H -one
Figure imgf000169_0001
(2R*,4R*)-2'-Amino-2-benzyl-6-((E)-2-cyclopropylvinyl)-l 2-dimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one was prepared according to the general procedures described for Example 366, Steps A-F, replacing l-(4-fluorophenyl)propan-2-one in Step A with l-phenylpropan-2-one (synthesized by the procedure described in Example 393, Step A), and replacing 5-chloropyridin-3-ylboronic acid in Step F with (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. Ή NMR (400 MHz, CDC13) δ 7.26 (m, 5H), 7.16 (m, 1H), 6.79 (d, J = 9 Hz, 1H), 6.65 (d, J = 2 Hz, 1H), 6.28 (d, J = 16 Hz, 1H), 5.52 (dd, J = 9, 16 Hz, 1H), 4.76 (br s, 2H), 3.12 (s, 3H), 3.09 (d, J = 13 Hz, 1H), 2.98 (d, J = 13 Hz, 1H), 2.51 (d, J = 14 Hz, 1H), 1.86 (d, J = 14 Hz, 1H), 1.48 (m, 1H), 1.28 (s, 3H), 0.77 (m, 2H), 0.45 (m, 2H); m/z (APCI-pos) M+l = 402.
Example 395 (2R*,4R*)-2'-amino-6-(3-chloro-5-fluorophenyl)-r,2-dimethyl-2-(pyridin-3- ylmethyl)spiro[chroman-4 4'-imidazol]-5'(rH)-one
Figure imgf000169_0002
Step A: A solution of l-(5-bromo-2-hydroxyphenyl)ethanone (4.82 g, 22.4 mmol), l-(pyridin-3- yl)propan-2-one hydrochloride (5.00 g, 29.1 mmol), pyrrolidine (3.68 mL, 44.8 mmol), acetic acid (1.28 mL, 22.4 mmol) and toluene (8 mL) were heated to 120°C for 30 minutes, then 80°C for 15 hours. The reaction was cooled to room temperature, partioned between EtOAc and saturated aqueous NaHCOj and dried over Na2S04. The crude was purified using silica gel chromatography (gradient: 5-50%
EtOAc/hexanes). Purifcation provided 6-bromo-2-methyl-2-(pyridin-3-ylmethyl)chroman-4-one (4.8 g, 64.5% yield) as an oil.
Step B: A solution of 6-bromo-2-methyl-2-(pyridin-3-ylmethyl)chroman-4-one (1.5 g, 4.52 mmol) in ethanol (4.5 mL) was added to a teflon-lined steel pressure vessel containing cyanopotassium (0.588 g, 9.03 mmol), ammonium carbonate (4.34 g, 45.2 mmol) and NaHS03 (0.235 g, 2.26 mmol). The suspension was sealed and heated to 130°C for 15 hours. The reaction was cooled to room temperature and transferred to a flask, rinsing with ethanol. A solution of 6N HC1 was added until the suspension became acidic, and then saturated aqueous NaHC03 was added to return the suspension to slightly basic. The suspension was partitioned between DCM and brine. The organic layer was concentrated, dissolved in DCM, washed with brine, dried over Na2S04 and concentrated to an oil. The crude was purified by silica gel chromatography (gradient: 0-100% (80% DCM: 19% MeOH: 1% NFLOHyDCM). Purification provided 6-bromo-2-methyl-2-(pyridin-3-ylmethyl)spiro[chroman-4,4'-imidazolidine]-2',5'-dione (378 mg, 20.8% yield) as a mixture of diastereomers.
Step C: Under a nitrogen atmosphere, solid NaH (60% dispersion in mineral oil) (37.6 mg, 0.940 mmol) was added to a solution of 6-bromo-2-methyl-2-(pyridin-3-ylmethyl)spiro[chroman-4,4'-imidazolidine]- 2',5'-dione (378 mg, 0.940 mmol) in DMF (5 mL). The suspension was allowed to stir and evolve gas until homogeneous. The solution was cooled to 0°C for 15 minutes, and iodomethane (58.6 μί, 0.940 mmol) was injected. The ice bath was removed, and the reaction was allowed to warm to room temperature. The reaction stirred at room temperature for 15 hours. The reaction was concentrated to a residue and partitioned between EtOAc and half-saturated brine. The organic layer was washed with brine and dried over Na2S04. The work-up provided 6-bromo-l',2-dimethyl-2-(pyridin-3- ylmethyl)spiro[chroman-4,4'-imidazolidine]-2',5'-dione (367 mg, 93.8% yield) as a mixture of diastereomers. The crude was taken to the next step without further purification. Step D: A suspension of 6-bromo-r,2-dimethyl-2-(pyridin-3-ylmethyl)spiro[chroman-4,4'-imidazolidine]- 2',5'-dione (367 mg, 0.882 mmol), Lawesson's Reagent (214 mg, 0.529 mmol) in toluene (5 mL) was heated in a sealed tube for 15 hours. The suspension dissolved upon heating. The reaction was cooled to room temperature and partitioned between EtOAc and saturated aqueous NaHC03. The organic layer was washed with brine and dried over Na2SCy The work-up provided 6-bromo-l',2-dimethyl-2-(pyridin-3- ylmethyl)-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (350 mg, 91.8% yield), which was used directly in the next reaction without further purification.
Step E: A solution of 6-bromo- ,2-dimethyl-2-(pyridin-3-ylmethyl)-2'-thioxospiro[chroman-4,4'- imidazolidin]-5'-one (0.350 g, 0.810 mmol), NH4OH (3.15 mL, 24.3 mmol), 2-hydroperoxy-2- methylpropane (1.68 mL, 12.1 mmol) and methanol (6 mL) were stirred at room temperature for 4 hours. The reaction was treated with water (5 mL) and concentrated to a suspension under vacuum. The suspension was partitioned between 4: 1 DCM/ΓΡΑ and brine. The organic layer was concentrated, and the residue was dissolved in DCM, washed with brine and dried over Na2S04. The crude solid was purified by silica gel chromatography (gradient: 0-100% (80% DCM: 19% MeOH: 1% NH,OH)/DCM), followed by preparative HPLC (column: C-l 8, gradient: 5-95% CH3CN/H20 (both with 0.1% TFA), 20 minutes). The purified TFA salt was partitioned between DCM and saturated aqueous NaHC03. The organic layer was dried over Na2S04 and concentrated to provide (2R*,4R*)-2'-amino-6-bromo-l',2- dimethyl-2-(pyridin-3-ylmethyl)spiro[chroman-4,4'-imidazol]-5'(rH)-one (14 mg, 4.1% yield) and (2S*,4R*)-2'-amino-6-bromo-1^2-dimethyl-2-(pyridin-3-ylmethyl)spiro[chroman-4,4'-im
one (38 mg, 1 1.3% yield). Step F: A solution of (2S*,4R*)-2'-amino-6-bromo-r,2-dimethyl-2-(pyridin-3-ylmethyl)spiro[chroman- 4,4'-imidazol]-5'(l'H)-one (14 mg, 0.034 mmol) and dioxane (170 ί; sparged for 30 minutes with N2) was added to a vial containing 3-chloro-5-fluorophenylboronic acid (8.8 mg, 0.051 mmol) and Pd(PPh3)4 (1.9 mg, 0.0017 mmol). A 2M solution of Na2CC"3 (51 μί, 0.10 mmol) was injected, and the vial was capped and heated to 80°C for 15 hours. The reaction was cooled to room temperature and passed through a plug of silica gel, eluting with a solution of 80% DCM/19% MeOH/1% NH4OH. The crude material was purified by preparative HPLC (column: C-18, gradient 5-95% CH3CN/H20 (both with 0.1% TFA), 20 minutes). The TFA salt was partitioned between DCM and saturated aqueous NaHC03, and the organic layer was dried over Na2S04 and concentrated under vacuum. Purification and conversion to the freebase provided (2S*,4R*)-2'-amino-6-(3-chloro-5-fluorophenyl)-r,2-dimethyl-2-(pyridin-3- ylmethyl)spiro[chroman-4,4'-imidazol]-5'(l'H)-one (5.6 mg, 36% yield) as a powder. Ή NMR (CDC13, 400 MHz) δ 8.64 (d, 2H), 7.45 (m, 3H), 7.23 (s, 1H), 7.14 (d, 1H), 7.04 (t, 2H), 6.91 (s, 1H), 3.19 (s,3H), 2.64 (d, 1H), 2.51 (br.s, 1H), 2.27 (d, 1H), 1.91 (dt, 1H), 0.66 (t, 3H); m/z (APCI-pos) M+l = 465.2.
Example 396 (2R*,4R*)-2'-amino-6-(3-chloro-5-fluorophenyl)-l',2-dimethyl-2-(pyridin-4- ylmethyl)spiro[chroman-4 4'-imidazol]-5'(l'H)-one
Figure imgf000171_0001
(2R*,4R*)-2'-Amino-6-(3-chloro-5-fluorophenyl)-r,2-dimethyl-2-(pyridin-4-ylmethyl)spiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared according to the protocol described in Example 395, where l-(pyridin- 4-yl)propan-2-one was substituted for l-(pyridin-3-yl)propan-2-one hydrochloride in Step A, and the amount of pyrrolidine was decreased by one equivalent. !H NMR (CDC13, 400 MHz) δ 8.47 (m, 2H), 7.52 (d, 1H), 7.41 (d, 1H), 7.22 (m, 2H), 7.03 (m, 3H), 6.91 (s, 1H), 3.45 (d, 1H), 3.23 (s, 3H), 2.86 (d, 1H), 2.55 (d, 1H), 2.06 (d, 1H), 1.31 (s, 3H); m/z (APCI-pos) M+l = 465.1. Example 397 (2S*,4R*)-2'-amino-6-(3-chloro-5-fluorophenyl)-2-(hydroxymethyl)-l',2- dimethylspiro[chroman-4,4'-imidazol]-5'( H)-one
Figure imgf000172_0001
Step A: A solution of l-(5-bromo-2-hydroxyphenyl)ethanone (10 g, 46.5 mmol) and l-(tert- butyldimethylsilyloxy)propan-2-one (1 1.6 mL, 60.5 mmol) in toluene (16 mL) was treated with pyrrolidine (3.82 mL, 46.5 mmol) and acetic acid (2.66 mL, 46.5 mmol). The reaction was heated to 80°C for 3 hours. The reaction was cooled to room temperature and washed with saturated aqueous NH4CI, 1M NaOH and brine, and dried over Na2S04. The crude ketone was purified by silica gel chromatography (gradient: 0-50% EtOAc/hexanes). Purification provided 6-bromo-2-((tert-butyldimethylsilyIoxy)methyl)- 2-methylchroman-4-one (14.1 g, 78.7% yield) as an oil.
Step B: 6-Bromo-2-((tert-butyldimethylsilyloxy)methyl)-2-methylchroman-4-one (3 g, 7.8 mmol) was dissolved in ethanol (8 mL) and added to a teflon-lined steel reaction "bomb" containing ammonium carbonate (7.5 g, 78 mmol), cyanopotassium (1.0 g, 16 mmol) and NaHS03 (0.41 g, 3.9 mmol). The slurry was heated to 130°C for 15 hours. The reaction was cooled to room temperature, and the slurry was transferred to a round bottom flask, rinsing with ethanol. The crude slurry was treated with 6N HC1 until acidic, then with saturated aqueous NaHC03 until basic. The slurry was extracted with DCM. The solvent was removed under vacuum, and the residue was partitioned between DCM and brine, and dried over Na2S04. The crude was purified by silica gel chromatography (gradient: 20-100% EtOAc/hexanes). Purification provided 6-bromo-2-((tert-butyldimethylsilyloxy)methyl)-2-methylspiro[chroman-4,4'- imidazolidine]-2',5'-dione (1.8 g, 51 % yield) as an oil.
Step C: 6-Bromo-2-((tert-butyldimethylsilyloxy)methyl)-2-methylspiro[chroman-4,4'-imidazolidine]-2',5'- dione (1.52 g, 3.34 mmol) was dissolved in DMF (3 mL) and treated with K2C03 (0.461 g, 3.34 mmol) and iodomethane (d 2.275) (0.208 mL, 3.34 mmol). The reaction was capped and stirred for 15 hours at room temperature. The reaction was concentrated under vacuum and partitioned between Et20 and water. The organic layer was washed with brine, dried over Na2S04 and concentrated to provide 6-bromo-2- ((tert-buryldimethylsilyloxy)methyl)-1^2-dimethylspiro[chroman-4,4'-imidazolidine]-2',5'-dione (1.48 g, 94.5%) yield) as a mixture of diastereomers.
Step D: A solution of 6-bromo-2-((tert-butyldimethylsilyloxy)methyl)-r,2-dimethylspiro[chroman-4,4'- imidazolidine]-2',5'-dione (1.48 g, 3.15 mmol) dissolved in anhydrous dioxane (20 mL) was treated with Lawesson's Reagent (0.956 g, 2.36 mmol), sealed in a pressure vessel and heated to 90°C for 15 hours. The reaction was cooled to room temperature and concentrated to a residue. The crude was partitioned between Et20 and water. The organic layer was washed with brine and dried over Na2S04. The organic was concentrated to a crude oil and purified by silica gel chromatography (gradient: 0-20%
EtOAc/hexanes). Purification isolated two diastereomers, (2R*,4R*)-6-bromo-2-((tert- butyldimethylsily]oxy)methyl)-1^2-dimethyl-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (327 mg, 21.4% yield) and (2S*,4R*)-6-bromo-2-((tert-butyldimethylsilyloxy)methyl)-l',2-dimethyl-2'- thioxospiro[chroman-4,4'-imidazolidin]-5'-one (415 mg, 27.1% yield).
Step E: A solution of (2S*,4R*)-6-bromo-2-((tert-butyldimethylsilyloxy)methyl)-l',2-dimethyl-2'- thioxospiro[chroman-4,4'-imidazolidin]-5'-one (189 mg, 0.389 mmol) in THF (2 mL) was treated with 1M TBAF in THF (779 μί, 0.779 mmol) and stirred at room temperature for 15 hours. The reaction was concentrated to a residue and partitioned between DCM and water. The organic was washed with brine and dried over Na2S04. The crude was purified by silica gel chromatography (gradient: 10-100%
EtOAc/hexanes). Purification provided (2S*,4R*)-6-bromo-2-(hydroxymethyl)- ,2-dimethyl-2'- thioxospiro[chroman-4,4'-imidazolidin]-5'-one (101 mg, 69.9% yield).
Step F: A solution of (2S*,4R*)-6-bromo-2-(hydroxymethyl)-l',2-dimethyl-2'-thioxospiro[chroman-4,4'- imidazolidin]-5'-one (76 mg, 0.20 mmol) in methanol (2 mL) was treated with 2-hydroperoxy-2- methylpropane (298 μί, 3.1 mmol) and Ν¾ΟΗ (239 μί, 6.1 mmol), and the reaction was stirred at room temperature for 24 hours. The reaction was treated with water (1 mL) and concentrated under vacuum to a suspension. The thick suspension was extracted with DCM, and the extract was washed with brine and dried over Na2S04. The crude was purified by silica gel chromatography (gradient: 10-100% (80% DCM: 19% MeOH: 1% NHfOHyDCM). Purification provided (2S*,4R*)-2'-amino-6-bromo-2- (hydroxymethyl)- ,2-dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (30 mg, 41% yield) as a powder.
Step G: 2M Sodium carbonate (102 μί, 0.20 mmol) was added to a suspension of (2S*,4R*)-2'-amino-6- bromo-2-(hydroxymethyl)-r,2-dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one (24 mg, 0.068 mmol), 3- chloro-5-fluorophenylboronic acid (18 mg, 0.10 mmol) and Pd(PPh3)4 (3.9 mg, 0.0034 mmol). The reaction was sealed and heated to 80°C for 12 hours. The reaction was cooled to room temperature and concentrated, and the residue was triturated with DCM. The suspension was filtered, and the crude filtrate was concentrated and purified directly by silica gel chromatography (gradient: 0-100% (80% DCM: 19% MeOH: 1% NrLOH)/DCM). Purification provided (2S*,4R*)-2'-amino-6-(3-chloro-5- fluorophenyl)-2-(hydroxymethyl)-l',2-dimethylspiro[chroman-4,4'-imidazol]-5'( H)-one (9.6 mg, 35% yield) as a powder. Ή NMR (CDC13, 400 MHz) δ 7.36 (dd, 1H), 7.21 (s, 1H), 7.02 (m, 2H), 6.95 (d, 1H), 6.92 (s, 1H), 3.83 (d, 1H), 3.59 (d, 1H), 3.21 (s, 3H), 2.75 (d, 1H), 1.87 (d, 1H), 1.42 (s, 3H); m/z (APCI- pos) M+l = 404.1. Example 398 (2S*,4R*)-2'-amino-6-(5-chloropyridin-3-yl)-2-(methoxymethyl)-l',2- dimethylspiro[chroman-4 4'-imidazol]-5'( 1 'H)-one
Figure imgf000174_0001
(2S,4R)-2'-Amino-6-(5-chloropyridin-3-yl)-2-(methoxymethyl)-1^2-dimethylspiro[chroman^
imidazol]-5'(l'H)-one 2,2,2-trifluoroacetate was prepared according to the protocol described in Example 395, where l-methoxypropan-2-one was substituted for l-(pyridin-3-yl)propan-2-one hydrochloride, the amount of pyrrolidine was decreased by 1 equivalent in Step A, and 5-chloropyridin-3-ylboronic acid was substituted for 3-chloro-5-fluorophenylboronic acid in Step F. m/z (APCI-pos) M+l = 401.1. Example 399 3-((2S*,4R*)-2'-amino-2-(methoxymethyl)-l',2-dimethyl-5'-oxo-l',5'- dihydrospiro[chroman-4 4'-imidazole]-6-yl)benzonitrile
Figure imgf000174_0002
3-((2S*,4R*)-2'-Amino-2-(methoxymethyl)-r,2-dimethyl-5'-oxo-r,5'-dihydrospiro[chroman-4,4'- imidazole]-6-yl)benzonitrile 2,2,2-trifluoroacetate was prepared according to the protocol described in Example 395, where 1 -methoxypropan-2-one was substituted for l-(pyridin-3-yl)propan-2-one hydrochloride, the amount of pyrrolidine was decreased by 1 equivalent in Step A, and 3- cyanophenylboronic acid was substituted for 3-chloro-5-fluorophenylboronic acid in Step F. m/z (APCI- pos) M+l = 391.1. Example 400 3-(((2R*,4R*)-2,-amino-6-(3-chloro-5-fluorophenyl)-l',2-dimethyl-5'-oxo-l',5'- dihydrospiro[chroman-4 4'-imidazole]-2-yl)methyl)benzonitrile
Figure imgf000174_0003
Step A: A solution of (2S*,4R*)-2'-amino-6-(3-chloro-5-fluorophenyl)-2-(hydroxymethyl)-l',2- dimethylspiro[chroman-4,4'-imidazol]-5'(l'Fi)-one (200 mg, 0.495 mmol), PPh3 (520 mg, 1.98 mmol), I2 (377 mg, 1.49 mmol), imidazole (135 mg, 1.98 mmol) and THF (2.5 mL) were heated to 90°C for 15 hours. The reaction was cooled to room temperature, concentrated and purified by silica gel chromatography (gradient: 0-25% EtOAc/hexanes). Purification provided (2S*,4R*)-6-(3-chloro-5- fluorophenyl)-2-(iodomethyl)- 1 ',2-dimethyl-2'-[(triphenyl^5-phosphanylidene)amino]- 1 ',2,3,5'- tetrahydrospiro[l-benzopyran-4,4'-imidazole]-5'-one (500 mg, 0.646 mmol, 130% yield) contaminated with PPh30. The material with impurity was used without further purification in Step B.
Step B: A solution of 1M NaHMDS in THF (54 μί, 0.054 mmol) was added to a suspension of (2S*,4R*)-6-(3-chloro-5-fluorophenyl)-2-(iodomethyl)-l',2-dimethyl-2'-[(triphenyl-λ5- phosphanylidene)amino]- ,2,3,5'-tetrahydrospiro[l-benzopyran-4,4'-imidazole]-5'-one (21 mg, 0.027 mmol) prepared in Step A, 3-cyanophenylboronic acid (4.8 mg, 0.033 mmol), nickel(II) iodide (1.7 mg, 0.0054 mmol), (lS,2S)-2-aminocyclohexanol (0.62 mg, 0.0054 mmol) and EPA (136 μί). The contents were sparged for 5 minutes with Ar gas, and the vial was sealed and heated to 60°C for 15 hours. The reaction was cooled to room temperature, concentrated and eluted with a solution of 90% DCM:9% MeOH: 1% NH4OH through a plug of silica gel. The eluent was concentrated and purified by preparative HPLC (column: C- 18; gradient: 5-95% CH3CN/H20 (0.1 % TFA in each); 20 minutes). Purification provided 3-[(2R*,4R*)-6-(3-chloro-5-fluorophenyl)- 1 ',2-dimethyl-5'-oxo-2,-[(triphenyl-λ5- phosphanylidene)amino]- ,2,3,5'-tetrahydrospiro[l-benzopyran-4,4'-imidazole]-2-ylmethyl]benzonitrile 2,2,2-trifluoroacetate (4 mg, 20% yield). Step C: A solution of 3-[(2R*,4R*)-6-(3-chloro-5-fluorophenyl)-l',2-dimethyl-5'-oxo-2'-[(triphenyl^5- phosphanylidene)amino]- ,2,3,5'-tetrahydrospiro[l-benzopyran-4,4'-imidazole]-2-ylmethyl]benzonitrile 2,2,2-trifluoroacetate (3 mg, 0.0035 mmol) was stirred in a solution of ethanol (1 mL) and water (1 mL) with 1 drop IN HCl for 3 hours at room temperature. The reaction was then treated with IN HCl (1 mL) and heated to 80°C for 2 days. The reaction was finally heated to 90°C for an additional 16 hours. The reaction was concentrated and purified by preparative HPLC (column: C-18, gradient: 5-95%
CH3CN/H20 (both w/0.5% TFA), 20 minutes). Purification provided 3-(((2R*,4R*)-2'-amino-6-(3- chloro-5-fluorophenyl)- 1 ',2-dimethyl-5'-oxo- 1 ',5'-dihydrospiro[chroman-4,4'-imidazole]-2- yl)methyl)benzonitrile 2,2,2-trifluoroacetate (1.1 mg, 52% yield) as a powder. TH NMR (CD3OD), 400 MHz) δ 7.68 (m, 1H), 7.67-7.62 (m, 2H), 7.61 (d, 1H), 7.51 (t, 1H), 7.41 (t, 1H), 7.37 (d, 1H), 7.28 (dt, 1H), 7.13 (dt, 1H), 7.06 (d, 1H), 4.10 (dd, 2H), 3.34 (s, 3H), 2.39 (dd, 2H), 1.37 (s, 3H); m/z (APCI/ESI (multimode)-pos) M+l = 489.1. Example 401 (2R*,4R*)-2'-amino-6-(3-chloro-5-fluorophenyl)-2-(3-chlorobenzyl)- 1 ',2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one
Figure imgf000176_0001
(2R*,4R*)-2'-Amino-6-(3-chloro-5-fluorophenyl)-2-(3-chlorobenzyl)-r,2-dimethylspiro[chroman-4,4'- imidazol]-5'(l'H)-one was prepared according to the protocol described in Example 400, where 3- chlorophenylboronic acid was substituted for 3-cyanophenylboronic acid in Step B. m/z (APCI/ESI (multimode)-pos) M+l = 498.1.
Example 402 (2S*,4R*)-2-(( 1 H-pyrazol-1 -yl)methyl)-2'-amino-6-(3-chloro-5-fluorophenyl)- 1 ',2- dimethylspiro[chroman-4 4'-imidazol]-5'(l'H)-one
Figure imgf000176_0002
A suspension of 6-(3-chloro-5-fluorophenyl)-2-(iodomethyl)-r,2-dimethyl-2'-[(triphenyl- - phosphanylidene)amino]- ,2,3,5'-tetrahydrospiro[l-benzopyran-4,4'-imidazole]-5'-one (50 mg, 0.065 mmol), IH-pyrazole (22 mg, 0.32 mmol), Cs2C03 (63 mg, 0.19 mmol) and DMF (325 iL) was sealed in a vial and heated to 120°C for 5 hours. The reaction was cooled to room temperature and partitioned between EtOAc and water. The organic was separated and concentrated under vacuum. The oil residue was dissolved in a solution of ethanol (0.5 mL) and 6N HCl (0.5 mL) and heated to 90°C for 2 hours. The reaction was concentrated under vacuum and purified by preparative HPLC (column: C-18, gradient: 5- 95% CH3CN/H2O (both with 0.1% TFA), 20 minutes). Purification provided (2S,4R)-2-(( 1 H-pyrazol-1 - yl)methyl)-2'-amino-6-(3-chloro-5-fluorophenyl)-r,2-dimethylspiro[chroman-4,4'-imidazol]-5'( H)-one 2,2,2-trifluoroacetate (1.9 mg, 0.0033 mmol, 5.2% yield) as a powder. Ή NMR (CD3OD), 400 MHz): δ
7.75 (d, 1H), 7.64 (dd, 1H), 7.53 (d, 1H), 7.43 (s, 1H), 7.41 (d, 1H), 7.29 (dt, 1H), 7.15 (dt, 1H), 7.1 1 (d, 1H), 6.37 (t, 1H), 4.53 (dd, 2H), 3.34 (s, 3H), 2.36 (dd, 2H), 1.36 (s, 3H); m/z (APCI/ESI (multimode)- pos) M+l = 454.1. Example 403 (2S*,4R*)-2-(( 1 H- 1 ,2,4-triazol- 1 -yl)methyl)-2'-amino-6-(3-chloro-5-fluorophenyl)- 1 ',2- dimethylspiro[chroman-4,4'-imidazol]-5'( 1 'H)-one
Figure imgf000177_0001
(2S*,4R*)-2-(( 1 H- 1 ,2,4-Triazol- 1 -yl)methyl)-2'-amino-6-(3-chloro-5-fluorophenyl)- 1 ',2- dimethylspiro[chroman-4,4'-imidazol]-5'(rH)-one 2,2,2-trifluoroacetate was prepared according to the protocol described in Example 402, where lH-l,2,4-triazole was substituted for lH-pyrazole. Ή NMR (CD3OD), 400 MHz) δ 8.59 (s, 1H), 8.03 (s, 1H), 7.65 (d, 1H), 7.43 (s, 2H), 7.30 (d, 1H), 7.15 (d, 1H), 7.10 (d, 1H), 4.66 (dd, 2H), 3.31 (s, 3H), 2.47 (s, 2H), 1.42 (s, 3H); m/z (APCI-pos) M+l = 455.1. Example 404 3-((2'R*,4R*)-2-amino-2'-(4-fluorobenzyl)-l,2'-dimethyl-5-oxo-l,2,,3',5- tetrahydrospiro[imidazole-4 4'-pyrano[2,3-c]pyridine]-6'-yl)benzonitrile
Figure imgf000177_0002
Step A: A solution of 4-methylbenzene-l-sulfonyl chloride (20.7 g, 109 mmol) in DCM (100 mL) was added to a solution of 6-bromopyridin-3-ol (18.9 g, 109 mmol) and triethylamine (22.6 mL, 163 mmol) in dichloromethane (603 mL, 109 mmol) at 0°C under N2. The reaction mixture was stirred at 0°C for 30 minutes, and then the ice bath was removed and allowed to stir at ambient temperature for 18 hours. The mixture was poured into ice cold saturated NaHC03 solution (100 mL), and the layers were separated. The aqueous layer was extracted with DCM (1 X 30 mL). The organic layers were combined, dried (MgS04), filtered and concentrated in vacuo. The residue obtained was crystallized from EtOAc/hexane to provide 6-bromopyridin-3-yl 4-methylbenzenesulfonate (34.5 g, 96.8% yield) as a solid. LCMS (APCI+) m/z 329 (M+H)+.
Step B: A 500 mL 3 -necked round bottom flask equipped with an N2 inlet, dropping funnel and an internal temperature probe was charged with diisopropylamine (6.424 mL, 45.71 mmol) and THF (50 mL). The solution was cooled to -78°C under N2 and treated dropwise with a solution of n-butyllithium 2.5M in hexanes (18.28 mL, 45.71 mmol) over 30 minutes. The reaction was stirred at -78°C for 10 minutes, and then the cooling bath was replaced with an ice bath. The mixture was stirred at 0°C for 1 hour. Meanwhile, a 1L 3-necked round bottom flask equipped with an N2 inlet, rubber septum, and an internal temperature probe was charged with a solution of 6-bromopyridin-3-yl 4-methylbenzenesulfonate (10 g, 30.5 mmol) in THF (250 mL). The resulting solution was cooled to -78°C under N2 atmosphere. Above prepared LDA solution in THF was then slowly added via a cannula to the pyridine solution at a rate that the internal temperature did not exceed -74°C. The resulting slurry was stirred at -78°C. After 3 hours, N-methoxy-N-methylacetamide (6.5 mL, 61 mmol) was added dropwise maintaining the internal temperature below -75°C. The reaction mixture was allowed to stir at -78°C for 2 more hours. The mixture was then poured into an ice cold saturated NaHC(¾ solution (300 mL). Water (100 mL) was added to the mixture, and it was extracted with EtOAc (3 X 100 mL). The organic layers were combined, dried (MgS0 ), filtered, and concentrated in vacuo. The crude product isolated was purified by flash chromatography on silica gel (Ready Sep 220 g, on Biotage SP1) eluting with 5-40% EtOAc hexane to provide 4-acetyl-6-bromopyridin-3-yl 4-methylbenzenesulfonate (7.9 g, 70% yield). LCMS (APCI+) m/z 370, 371 (M+H)+. Step C: A stirring solution of 4-acetyI-6-bromopyridin-3-yl 4-methylbenzenesulfonate (7.5 g, 20 mmol) in THF (41 mL, 20 mmol) at 0°C was treated with LiOH-H20 (1.7 g, 41 mmol) in H20 (20 mL). The resulting mixture was stirred at 0°C for 30 minutes, and then the ice bath was removed. The mixture was stirred at ambient temperature for 4 hours. The organic solvents were then removed in vacuo. The aqueous residue obtained was diluted with water (50 mL) and made acidic (pH 3) with formic acid. The resulting suspension was extracted into EtOAc (3 X 100 mL). The organic layers were combined, dried (MgS04) and concentrated in vacuo. The crude isolated was purified by flash chromatography on silica gel (Ready Sep 120g on Biotage SP1) eluting with 5-30% EtOAc/hexane gradient to provide l-(2-bromo- 5-hydroxypyridin-4-yl)ethanone (3.4 g, 78% yield) as a solid. LCMS (APCI+) m/z 217 (M+H)+ . Step D: A round bottom flask was charged with l-(2-bromo-5-hydroxypyridin-4-yl)ethanone (4.2 g, 19.44 mmol), l-(4-fluorophenyl)propan-2-one (3.117 mL, 23.33 mmol), toluene (38.88 mL, 19.44 mmol), pyrrolidine (1.623 mL, 19.44 mmol), and acetic acid (1.1 13 mL, 19.44 mmol). The resulting solution was heated at 78°C for 12 hours and allowed to cool to ambient temperature. The mixture was then diluted with EtOAc (100 mL) and washed with 1M NaOH (3 X 20 mL). The organic layer was separated, dried (MgS04) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Ready Sep 220 g on Biotage SP1) eluting with 0-20% EtOAc/hexane gradient to provide 6-bromo-2- (4-fluorobenzyl)-2-methyl-2H-pyrano[2,3-c]pyridin-4(3H)-one (5 g, 55% yield). LCMS (APCI+) m/z 351, 353 (M+H)+. Step E: A metal bomb was charged with a mixture of 6-bromo-2-(4-fluorobenzyl)-2-methyl-2H- pyrano[2,3-c]pyridin-4(3H)-one (4.98 g, 10.7 mmol), ammonium carbonate (1 1.3 g, 1 17 mmol), potassium cyanide (1.74 g, 26.7 mmol) and 200 proof ethanol (10.7 mL, 10.7 mmol). The bomb was sealed and sealed and stirred at 130°C for 20 hours and allowed to cool to room temperature. The contents were suspended in EtOH (20 mL) and transferred to a 1 L Erlenmeyer flask. The resulting suspension was diluted with additional water (100 mL) and slowly acidified to pH 2-3 with 6M HC1. During this time the mixture was sparged with N2. The mixture was allowed to stir at room temperature overnight. The solid formed was filtered, washed with water (3 X 20 mL) and evaporated from C¾CN (3 X 20 mL). The solid isolated was triturated with CH3CN and filtered to provide the first batch of the product. The filtrated collected was concentrated, and the residue was triturated with CL^CN/Et^O to provide the remainder of the product. The combined batches gave 6'-bromo-2'-(4-fluorobenzyl)-2'-methyl-2',3'- dihydrospiro[imidazolidine-4,4'-pyrano[2,3-c]pyridine]-2,5-dione (4.45 g, 98% yield) as a solid. MS (APCI-) m/z 418, 420 (M-HV.
Step F: Potassium carbonate (0.65 g, 4.7 mmol) and iodomethane (0.22 mL, 3.5 mmol) were sequentially added to a solution of 6'-bromo-2'-(4-fluorobenzyl)-2'-methyl-2',3'-dihydrospiro[imidazolidine-4,4'- pyrano[2,3-c]pyridine]-2,5-dione (1.64 g, 3.9 mmol) in DMF (39 mL, 3.9 mmol). The resulting mixture was stirred at ambient temperature for 48 hours and poured into ice water (150 mL). The resulting solid was filtered and washed with additional water. The solid collected was dissolved in EtOAc (100 mL) and washed with brine (20 mL). The organic layer was separated, dried (MgSC^), filtered and concentrated in vacuo. The residue obtained was dried under high vacuum to provide 6'-bromo-2'-(4-fluorobenzyl)-l,2'- dimethyl-2',3'-dihydrospiro[imidazolidine-4,4'-pyrano[2,3-c]pyridine]-2,5-dione (1.8 g, 99.84% yield) as a solid. LCMS (APCI+) m/z 435 (M+H)+.
Step G: A suspension of 6'-bromo-2'-(4-fluorobenzyl)-l,2'-dimethyl-2',3'-dihydrospiro[imidazolidine-4,4'- pyrano[2,3-c]pyridine]-2,5-dione (755 mg, 1.74 mmol) in toluene (6 mL) was stirred at reflux for 1-2 minutes. Then Lawesson's Reagent (387 mg, 0.96 mmol) was added in one portion, and the resulting solution was stirred at 1 10°C for 24 hours. The reaction mixture was concentrated in vacuo, and the residue obtained was purified by flash chromatography on silica gel (Ready Sep, Biotage SP1) eluting with 10-40% EtOAc/hexane gradient to provide 6'-bromo-2'-(4-fluorobenzyl)-l,2'-dimethyl-2-thioxo-2',3'- dihydrospiro[imidazolidine-4,4'-pyrano[2,3-c]pyridin]-5-one. Step H: Ammonia 7M in methanol (17 mL, 120 mmol) and tert butylhydroperoxide 70% in water (8.3 mL, 60 mmol) were sequentially added to a stirred solution of 6'-bromo-2'-(4-fluorobenzyl)-l,2'-dimethyl- 2-thioxo-2',3'-dihydrospiro[imidazolidine-4,4'-pyrano[2,3-c]pyridin]-5-one (1.8 g, 4 mmol) in TUF (8 mL). The mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into brine (30 mL), and the mixture was extracted with EtOAC (3 X 40 mL). The organic layers were combined, dried (MgS04) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with neat EtOAc (500 mL), followed by 2.5% MeOH/EtOAc (500 mL) and 5% MeOH/EtOAc (500 mL) to provide (2'S*,4R*)-2-amino-6'-bromo-2'-(4- bromo-2'-(4-fluorobenzyl)-l,2'-dimethyl-2',3'-dihydrospiro
one and (2'R*,4R*)-2-amino-6'-bromo-2'-(4-fluorobenzyl)- 1 ,2'-dimethyl-2',3'-dihydrospiro[imidazole-4,4'- pyrano[2,3-c]pyridin]-5(lH)-one. Step I: A resealable glass pressure tube was charged with (2'R*,4R*)-2-amino-6'-bromo-2'-(4- fluorobenzyl)-l ,2'-dimethyl-2^3'-dihydrospiro[im^ (30 mg,
0.07 mmol), 3-cyanophenylboronic acid (12 mg, 0.08 mmol), dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (3 mg, 0.004 mmol), 20% aqueous Na2C03 (128 μΙ , 0.24 mmol), and 1,4-dioxane (692 μΙ_., 0.07 mmol). The reaction was sparged with N2 for 5 minutes, capped, and stirred at 90°C for 24 hours and allowed to cool temperature. The mixture was passed through a Ready Sep silica column (12 g) eluting with 5% MeOH/EtOAc. The semi pure product obtained was purified by C-18 reverse phase HPLC (Gilson Unipoint) eluting with 5-95% CH3CN/water containing 0.1% TFA over 25 minutes to provide the TFA salt of 3-((2'R*,4R*)-2-amino-2'- (4-fluorobenzyl)-l,2'-dimethyl-5-oxo-l,2^3^5-tetrahydrospiro[imidazole-4,4'-pyrano[2,3-c]pyridine]-6 - yl)benzonitrile (1 1 mg, 35% yield) as a solid. lH NMR (400 MHz, CD3OD) δ 8.39 (s, IH), 8.33 (s, IH), 8.28 (d, J=7.83 Hz, IH), 7.76 (s, IH), 7.71 (d, J=7.83 Hz, IH), 7.60 (t, J=7.83 Hz, IH), 7.33 (d,d, Jl=5.48 Hz, J2=8.61 Hz, 2H), 7.04 (t, J=8.99 Hz, 2H), 3.3 (s, 3H), 3.2 (d, J=14.09 Hz, IH), 3.12 (d, J=14.09 Hz, IH), 2.49 (d, J=14.87 Hz, I H), 2.38 (d, J= 14.87 Hz, IH), 1.38 (S, 3h); LCMS (APCI+) m/z 456 (M+H)+.
Example 405 (2'R*,4R*)-2-amino-6,-(5-chloropyridin-3-yl)-2'-(4-fluorobenzyl)-l ,2'-dimethyl-2',3'- dihydrospiro[imidazole-4 4'-pyrano[2,3-c]pyridin]-5( 1 H)-one
Figure imgf000180_0001
(2'R*,4R*)-2-Amino-6'-(5-chloropyridin-3-yl)-2,-(4-fluorobenzyl)-l,2,-dimethyl-2',3*- dihydrospiro[imidazole-4,4'-pyrano[2,3-c]pyridin]-5(lH)-one was prepared according to the procedure described for Example 404, Step I, substituting 3-cyanophenylboronic acid with 5-chloropyridin-3- ylboronic acid (13 mg, 0.08 mmol). The title compound (15 mg, 46% yield) was isolated as the HC1 salt by treatment with 4N HC1 in dioxane. Ή NMR (400 MHz, (CD3)2SO) δ 10.8 (s, IH), 9.81 (s, IH), 9.49 (s, IH), 9.22 (s, IH), 8.66 (s, IH), 8.46 (s, IH), 8.45 (s, IH), 8.01 (s, IH), 7.36 (dd, Jl=5.87 Hz, J2= 7.43 Hz, 2H), 7.17 (t, J=8.61 Hz, 2H), 3.23 (s, 3H), 3.19-3.10 (m, 2H), 2.40 (d, J= 14.87 Hz, IH), 2.29 (d, J= 14.87 Hz, IH), 1.36 (s, 3H); LCMS (APCI+) m/z 466 (M+H)+. Example 406 (2'R*,4R*)-2-amino-6'-(3-chlorophenyl)-2'-(4-fluorobenzyl)-l,2,-dimethyl-2',3'- dihydrospiro[imidazole-4 4'-pyrano[2,3-c]pyridin]-5(lH)-one
Figure imgf000181_0001
(2¾*,4R*)-2-Amino-6H3-chlorophenyl)-2'-(4-fluorobenzyl)-l,2'-dimethyl-2^3'-dihydrospiro[imi^ 4,4'-pyrano[2,3-c]pyridin]-5(lH)-one HCl salt (14 mg, 44.1% yield) was prepared according to the procedure described for Example 404, Step I, substituting 3-cyanophenylboronic acid with
chlorophenylboronic acid (13 mg, 0.083 mmol) and then treating with 4N HCl in dioxane. l NMR (400 MHz, (CD3)2SO) S 10.75 (s, 1H), 9.73 (br s, 1H), 9.47 (br s, 1H), 8.41 (s, 1H), 8.04-7.99 (m, 2H), 7.89 (s, 1H), 7.51-7.44 (m, 2H), 7.37-7.33 (tn, 2H), 7.19-7.14 (m, 2H), 3.22 (s, 3H), 3.10 -3.08 (m, 2H), 2.38 (d, J=14.87 Hz, 1H), 2.28 (d, J=14.87 Hz, 1H), 1.36 (s, 3H); LCMS (APCI+) m/z 465 (M+H)+.
Example 407 (2,R*,4R*)-2-amino-6'-(5-chloropyridin-3-yl)-2'-(4-methoxybenzyl)-l,2'-dimethyI-2',3'- dihydrospiro[imidazole-4 4'-pyrano[2,3-c]pyridin]-5(lH)-one
Figure imgf000181_0002
Step A: l-(2-Bromo-5-hydroxypyridin-4-yl)ethanone was processed with l-(4-methoxyphenyl)propan-2- one as described in Example 404, Step D, to provide 2-amino-6'-bromo-2'-(4-methoxybenzyl)-l,2'- dimethyl-2',3'-dihydrospiro[imidazole-4,4'-pyrano[2,3-c]pyridin]-5(lH)-one.
Step B: 2-Amino-6'-bromo-2'-(4-methoxybenzyl)-l,2'-dimethyl-2',3'-dihydrospiro[imidazole-4,4'- pyrano[2,3-c]pyridin]-5(lH)-one was carried forward as in Example 404, Steps G-I, to provide the title compound (5 mg, 9% yield). Ή NMR (400 MHz, CD3OD) δ 8.95 (d, J=1.95 Hz, 1H), 8.50 (d, J=2.35 Hz, 1H), 8.36 (t, J=2.35 Hz, 1H), 8.29 (s, 1H), 7.38 (s, 1H), 7.23-7.21 (m, 2H), 6.87-6.85, m, 2H), 3.77 (s, 3H), 3.16 (s, 3H), 3.05 (d, J=3.5 Hz, 2H), 2.93 (d, J=14.47 Hz, 1H), 1.91 (d, J= 14.08 Hz, 1H), 1.40 (s, 3H); LCMS (APCI+) m/z 478 (M+H)+. Example 408 (2'R*,4R*)-2-amino-6H3-chloro-5-fluorophenyl)-2H4-fluorobenzyl)-l,2'-dimethyl-2',3'- dihydrospiro[imidazole-4 4'-pyrano[2,3-c]pyridin]-5(lH)-one
Figure imgf000182_0001
(2,R*,4R*)-2-Amino-6'-(3-chloro-5-fluorophenyl)-2'-(4-fluorobenzyl)-l,2,-dimethyl-2',3'- dihydrospiro[imidazole-4,4'-pyrano[2,3-c]pyridin]-5(lH)-one (7 mg, 21% yield) was prepared according to the procedure described for Example 404, Step I, substituting 3-cyanophenylboronic acid with 3- chloro-5-fluorophenylboronic acid (14 mg, 0.08 mmol). Ή NMR (400 MHz, CDC13) 5 1 1.59 (br s, IH), 8.60 (br s, IH), 8.42 (s, IH), 7.61 (s, IH), 7.47 (d, J=9.39 Hz, IH), 7.24-7.22 (m, 2H), 7.10-7.01 (m, 5H), 3.36 (s, 3H), 3.1 1 (m, 2H), 2.54 (d, J=14.47Hz, IH), 2.08 (d, J=14.47 Hz, IH), 1.43 (s, 3H); LCMS (APCI+) m/z 483 (M+H)+.
Example 409 (2'R*,4R*)-2-amino-6'-(2-fluoropyridin-3-yl)-2'-(4-methoxybenzyl)-l,2'-dimethyl-2',3'- dihydrospiro[imidazole-4 4'-pyrano[2,3-c]pyridin]-5(lH)-one
Figure imgf000182_0002
(2,R*,4R*)-2-Amino-6,-(2-fluoropyridin-3-yl)-2'-(4-methoxybenzyl)-l,2'-dimethyl-2',3'- dihydrospiro[imidazole-4,4'-pyrano[2,3-c]pyridin]-5(lH)-one (1 1 mg, 21% yield) was prepared from 2- amino-6'-bromo-2'-(4-methoxybenzyl)-l,2'-dimethyl-2',3'-dihydrospiro[imidazole-4,4'-pyrano[2,3- c]pyridin]-5(lH)-one and 2-fluoropyridin-3-ylboronic acid (19 mg, 0.13 mmol) as described for the procedure described for Example 404, Step I. Ή NMR (400 MHz, CD3OD) δ 8.39-8.34 (m, IH), 8.28 (s, IH), 8.18-8.13 (m, IH), 7.42-7.37 (m, IH), 7.25-1.87 (m, 3H), 6.85 (d, J=8.26 Hz, 2H), 3.76 (s, 3H), 3.13 (s, 3H), 3.07-3.01 (m, 2H), 2.40 (d, J=14.86 Hz, IH), 1.91 (d, J=14.08 Hz, IH), 1.39 (s, 3H); LCMS (APCI+) m/z 462 (M+H)+. Example 410 (2¾*,4R*)-2-amino-2H4-fluorobenzyl)-6H2-fluoropyridin-3-yl)-l,2'-dimethyl-2',3'- dihydrospiro[imidazole-4 4'-pyrano[2,3-c]pyridin]-5( 1 H)-one
Figure imgf000183_0001
(2'R*,4R*)-2-amino-2H4-fluorobenzyl)-6'-(2-fluoropyridin-3-yl)-l,2,-dimethyl-2',3'- dihydrospiro[imidazole-4,4'-pyrano[2,3-c]pyridin]-5(lH)-one (16 mg, 51% yield) was prepared according to the procedure described for Example 404, Step I, substituting 3-cyanophenylboronic acid with fluoropyridin-3-ylboronic acid (12 mg, 0.08 mmol). Ή NMR (400 MHz, (CD3)2SO) 5 10.79 (br s, 0.5H), 10.68 (br s, 0.5H), 9.69 (br s, IH), 9.46 (br s, IH), 8.29-8.21 (m, IH), 7.83-7.4 (m, IH), 7.37-7.30 (m, 3H), 7.19-7.13 (m, 3H), 3.15 (s, 3H), 3.14-3.05 (m, 2H), 2.41-2.20 (m, 2H), 1.31 (s, 3H); LCMS (APCI+) m/z 450 (M+H)+.
Example 411 (2,R*,4R*)-2-amino-2'-(4-fluorobenzyl)-l,2'-dimethyl-6,-(pyrimidin-5-yl)-2',3'- dihydrospiro[imidazole-4 4'-pyrano[2,3-c]pyridin]-5(lH)-one
Figure imgf000183_0002
(2'R*,4R*)-2-amino-2'-(4-fluorobenzyl)-l,2'-dimethyl-6'-(pyrimidin-5-yl)-2',3'-dihydrospiro[imidazole- 4,4'-pyrano[2,3-c]pyridin]-5(lH)-one (9 mg, 30% yield) was prepared according to the procedure described for Example 404, Step I, substituting 3-cyanophenylboronic acid with pyrimidin-5-ylboronic acid ( 10 mg, 0.083 mmol). !H NMR (400 MHz, CD3OD) δ 9.34 (s, 2H), 9.14 (s, IH), 8.46 (s, IH), 7.86 (s, IH), 7.36-7.32 (m, 2H), 7.08-7.03 (m, 2H), 3.31 (s, 3H), 3.21 (d, J=14.08 Hz, IH), 3.12 (d, J=14.08 Hz, IH), 2.51 (d, J=14.86 Hz, IH), 2.40 (d, J=14.86 Hz, IH), 1.40 (s, 3H); LCMS (APCI+) m/z 433 (M+H)+. Example 412 (2'R*,4R*)-2-amino-2H4-methoxybenzyl) ,2'-dimethyl-6,-(pyrimidin-5-yl)-2',3'- dihydrospiro[imidazole-4,4'-pyrano[2,3-c]pyridin]-5(lH)-one
Figure imgf000184_0001
(2'R*,4R*)-2-amino-2 4-methoxybenzyl)-l,2'-d^
4,4'-pyrano[2,3-c]pyridin]-5(lH)-one (9 mg, 17% yield) was prepared from 2-amino-6'-bromo-2'-(4- methoxybenzyl)-l,2'-dimethyl-2',3'-dihydrospiro[imidazole-4,4'-pyrano[2,3-c]pyridin]-5(lH)-on and pyrimidin-5-ylboronic acid (17 mg, 0.13 mmol) as described for the procedure described for Example 404, Step I. LCMS (APCI+) m/z 445 (M+H)+. Example 413 2'-amino-7-fluoro-r,2,2-trimethyl-6-(pyrimidin-5-yl)spiro[chroman-4,4'-imidazol]-
5'(l'H)-one
Figure imgf000184_0002
Step A: 4-Bromo-3-fluorophenol (10 g, 52.36 mmol) and triethylamine (8.027 mL, 57.59 mmol) were combined in DCM (0.5M, 105 mL). The solution was cooled to 0°C and treated with acetyl chloride (4.1 mL, 57.6 mmol). The reaction mixture was stirred at 0°C for 15 minutes. The resulting suspension was diluted with diethyl ether (150 mL), and the solids were filtered off. The filtrate was concentrated in vacuo, suspended in ether (150 mL), and the few solids formed were removed via filtration. The filtrate was concentrated in vacuo to afford 4-bromo-3-fluorophenyl acetate (12 g, 98.8% yield) as an oil.
Step B: 4-Bromo-3 -fluorophenyl acetate (4.38 g, 18.8 mmol) was cooled to 0°C and treated with trifluoromethanesulfonic acid (8.316 mL, 93.98 mmol). After 5 minutes, the ice bath was removed, and the reaction was allowed to come to ambient temperature over 15 minutes. The reaction was then heated to 60°C for 75 minutes. The reaction was cooled to 0°C and treated with water (75 mL) with rapid stirring. The resulting suspension was allowed to come to ambient temperature, filtered and washed with water (100 mL), and dried under high vacuum to provide l-(5-bromo-4-fluoro-2-hydroxyphenyl)ethanone (4.16 g, 95% yield) as a solid. Step C: A resealable glass pressure tube was charged with a mixture of l-(5-bromo-4-fluoro-2- hydroxyphenyl)ethanone (1 g, 4.3 mmol), pyrimidin-5-ylboronic acid (0.7 g, 5.6 mmol), 20% sodium carbonate in water (7.96 mL, 15 mmol), PdCl2(dppf)*dcm (0.175 g, 0.215 mmol) and 1,4-dioxane (8.6 mL, 4.3 mmol). The reaction mixture was sparged with N2 for 5 minutes, and then the tube was sealed with a Teflon screw cap and stirred at 85°C for 4 hours. The mixture was cooled to 0°C, diluted with EtOAc (50 mL) and washed with brine (2 X 30 mL). The organic layer was separated, dried (MgS04), filtered and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 40% EtOAc/hexane to provide l-(4-fluoro-2-hydroxy-5- (pyrimidin-5-yl)phenyl)ethanone (705 mg, 70.8% yield) as a solid. LCMS (APCI-) m/z 331 (M-H)- and (APCI+) m/z 333 (M+H)+.
Step D: A mixture of l-(4-fluoro-2-hydroxy-5-(pyrimidin-5-yl)phenyl)ethanone (700 mg, 3 mmol) in toluene (10048 \xL, 3 mmol) was treated with propan-2-one (2213 μί, 30.15 mmol), acetic acid (172.6 Ε, 3.015 mmol) and pyrrolidine (251.6 iL, 3.015 mmol). The mixture was stirred at 85°C for 3 hours and allowed to cool to room temperature, diluted with EtOAc (50 mL), and washed with water (10 mL). The organic layer was separated, dried (MgS04) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 30% EtOAc/hexane and dried under high vacuum to provide 7-fluoro-2,2-dimethyl-6-(pyrimidin-5-yl)chroman-4-one (370 mg, 45% yield) as a solid. LCMS: (APCI+) m/z 273 (M+H)+.
Step E: A metal bomb was charged with a mixture of 7-fluoro-2,2-dimethyl-6-(pyrimidin-5-yl)chroman-4- one (365 mg, 1.34 mmol), ammonium carbonate (1 160 mg, 12 mmol), potassium cyanide (131 mg, 2 mmol) and ethanol (0.75M). The bomb was then sealed and heated at 120°C. After 16 hours, the vessel was cooled to 0°C, and the reaction mixture was transferred to a flask washing with water (about 5 mL) and EtOH (2 mL). The resulting suspension was then carefully acidified with 2M HC1 (pH 2) under a stream of N2 with rapid stirring. The resulting suspension was diluted with water (30 mL) and sparged with N2 for 30 minutes. The solid formed was filtered, washed with additional water (4 X 5 mL) and dried under high vacuum for 24 hours to provide 7-fluoro-2,2-dimethyl-6-(pyrimidin-5-yl)spiro[chroman- 4,4'-imidazolidine]-2',5'-dione (350 mg, 76% yield) as a solid. LCMS (APCI+) m/z 343 (M+H)+.
Step F: Solid potassium carbonate (125 mg, 0.91 mmol) was added to a solution of 7-fIuoro-2,2-dimethyl- 6-(pyrimidin-5-yl)spiro[chroman-4,4'-imidazolidine]-2',5'-dione (345 mg, 1 mmol) in N,N- dimethylformamide (4 mL, 1 mmol) at ambient temperature. The mixture was stirred for 5 minutes and then treated with iodomethane (56.5 μί, 0.91 mmol). The resulting mixture was stirred at room temperature for 15 hours, then poured into water (60 mL) and extracted with EtOAc (2 X 50 mL). The organic layer was washed with water (3 X 20 mL). The EtOAc layer was concentrated in vacuo, and the residue obtained was triturated with EtOAc. The solid formed was collected by filtration and dried under high vacuum to provide 7-fluoro-r,2,2-trimethyl-6-(pyrimidin-5-yl)spiro[chroman-4,4'-imidazolidine]- 2',5'-dione (160 mg, 44.55% yield) as a solid. LCMS (APCI+) m/z 357 (M+H)+. Step G: A suspension of 7-fluoro-r,2,2-trimethyl-6-(pyrimidin-5-yl)spiro[chroman-4,4'-imidazolidine]- 2',5'-dione (150 mg, 0.42 mmol) in toluene (25 mL) was stirred at reflux for 10 minutes. The resulting solution was treated with Lawesson's Reagent (93.6 mg, 0.232 mmol) in 2 portions, and the mixture was stirred at 1 10°C. After 28 hours, toluene was removed in vacuo, and the residue obtained was purified by flash chromatography on silica gel (Biotage Flash 40S+) eluting with 30% EtOAc/hexane to provide 7- fluoro-1^2,2-trimethyl-6-(pyrimidin-5-yl)-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (92 mg, 59% yield) as a solid. MS (APCI+) m/z 373 (M+H)+.
Step H: tert-Butylhydroperoxide 70% in water (491 μΐ^, 3.54 mmol) and ammonia 7M in methanol (1013 μί, 7.09 mmol) were sequentially added to a stirred solution of 7-fluoro-r,2,2-trimethyl-6-(pyrimidin-5- yl)-2'-thioxospiro[chroman-4,4'-imidazolidin]-5'-one (88 mg, 0.24 mmol) in THF (2 mL). The mixture was stirred at ambient temperature for 18 hours, then diluted with EtOAc (75 mL) and washed with water (2 X 20 mL). The organic layer was separated, dried (MgSO^, filtered and concentrated in vacuo. The residue obtained was treated with EtOAc/hexane, and the resulting solid was crystallized form dioxane to provide 2'-amino-7-fluoro-r,2,2-trimethyl-6-(pyrimidin-5-yl)spiro[chroman-4,4'-imidazol]-5'(rH)-one (26 mg, 31% yield) as a solid. MS (APCI+) m/z 356 (M+H)+.
Example 414 2'-amino- ,2,2-trimethyl-6-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4'-imidazol]-
5'(l'H)-one
Figure imgf000186_0001
A solution of 2'-amino-6-(3,4-dihydro-2H-pyran-5-yl)- ,2,2-trimethylspiro[chroman-4,4'-imidazol]- 5'(l'H)-one (6 mg, 0.02 mmol) in methanol (5 mL) was added to a suspension of palladium 10% on activated carbon (1.9 mg, 0.002 mmol) in EtOH (5 mL) under N2 atmosphere. The reaction mixture was purged and backfilled with H2 (3 cycles) and allowed to stir under H2 for 1 hour. The mixture was filtered through a 45 micron filter, and the filtrate was concentrated in vacuo. The residue obtained was evaporated from a mixture of DCM/hexane (1 : 1, 1 mL) and dried under high vacuum for 18 hours to provide 2'-amino-1^2,2 rimethyl-6-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,4'-imidazol]-5'( rH)-one (6 mg, 99% yield) as a solid. LCMS (APCI+) m/z 344 (M+H)+. The following compounds in Table 3 were prepared according to the above procedures using appropriate intermediates.
Table 3
Figure imgf000187_0001
Figure imgf000188_0001
trifluoroacetate
Figure imgf000189_0001
trifluoroacetate
Figure imgf000190_0001
Figure imgf000191_0001
It will be understood that the enumerated embodiments are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the claims. Thus, the foregoing description is considered as illustrative only of the principles of the invention.

Claims

WE CLA :
1. A compound of Formula II
Figure imgf000192_0001
II
wherein,
Xi and X2 are independently selected from CRio or N, and X3 is CR5 or N, wherein only one of
X], X2 or X3 may be N;
R is hydrogen or halogen;
Re is hydrogen, benzyl or C1-C3 alkyl optionally substituted with Ra;
R7 and R7. are independently selected from hydrogen, halogen and C C6 alkyl optionally
substituted with Rb, or
R7 and R7- together with the atom to which they are attached form cyclopropyl,
Rg and Rg. are independently selected from hydrogen, C C6 alkyl optionally substituted with Rb,
C3-C6 carbocyclyl, 4 to 6 membered heterocyclyl, phenyl, 5 to 6 membered heteroaryl, wherein the carbocyclyl, heterocyclyl, phenyl or heteroaryl are optionally substituted with R,, or
Rg and Rg. together with the atom to which they are attached form a 3 to 6 membered carbocyclyl or heterocyclyl optionally substituted with C1-C3 alkyl optionally substituted with halogen; wherein only one of R7 and R7 or Rg and Rg- may together form a ring;
R9 is hydrogen, halogen, CN, C Cg alkyl optionally substituted with Rc, C Cg alkenyl optionally substituted with Rc, C Cg alkynyl optionally substituted with Rc, CrCg alkoxy optionally substituted with Rc, phenyl optionally substituted with Rj, a 5-6 membered heteroaryl optionally substituted with R., a 5-6 membered saturated or partially unsaturated heterocyclyl optionally substituted with Rf, a 3-6 membered saturated or partially unsaturated carbocyclyl optionally substituted with Rg, a 9-10 membered bicyclic heteroaryl optionally substituted with ¾, phenylamino, or phenoxy optionally substituted with R,;
Rio is hydrogen, halogen or methyl;
each Ra is independently selected from OH, OCH3, halogen, a 5-6 membered heteroaryl, and a 3-6 membered heterocyclyl optionally substituted with C C3 alkyl optionally substituted with oxo;
each ¾ is independently selected from halogen, hydroxyl, methoxy, oxo, NRiR„„ Q-C3 alkyl optionally substituted with halogen or OH, -0(CrC3 alkyl) optionally substituted with halogen or OH, phenyl, C3-C6 carbocyclyl, a 3 to 6 membered heterocyclyl, a 5 to 6
membered heteroaryl, -O(phenyl) and -S(phenyl), wherein the phenyl, carbocyclyl, heterocyclyl and heteroaryl are optionally substituted with halogen, CN, OH, OCH3, Ci-C6 alkyl and C C6 alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen, OH or OCH3;
each Rc is independently selected from halogen, CN, OH, OCH3, Q-C3 alkyl optionally
substituted with halogen or OH, -0(C]-C3 alkyl) optionally substituted with halogen or OH, C3-C6 carbocyclyl and phenyl optionally substituted with halogen, OH or OCH3;
each Rj is independently selected from halogen, CN, cyclopropyl, ORj, SRk, NR]R™, CpCg alkyl optionally substituted with R„, -0(Ci-Cg alkyl) optionally substituted with R„, CpCg alkynyl optionally substituted with R,,;
each Re is independently selected from halogen, CN, oxide, NH2, cyclopropyl, ORp, SRk, C]-C6 alkyl optionally substituted with halogen and ORq, and C1-C6 alkynyl optionally substituted with OR,,;
each Rf is independently selected from halogen, oxo, Ci-C6 alkyl optionally substituted with halogen, and C C6 alkoxycarbonyl;
each Rg is independently selected from halogen, OH, OCH3 and C C6 alkyl optionally substituted with halogen;
each Rh is independently selected from halogen and Ci-C6 alkyl;
each R, is independently selected from halogen and benzyl;
each Rj is independently selected from hydrogen and Ci-C6 alkyl optionally substituted with halogen, CN, OH, OCH3 or phenyl;
each Rk is Q-C6 alkyl;
each R| and R™ is independently selected from hydrogen and C1-C6 alkyl;
each R„ is independently selected from halogen, OH, OCH3, CN and phenyl;
each Ro is independently selected from halogen and C3-C carbocyclyl;
each Rp is independently selected from hydrogen, Q-C6 alkyl and phenyl;
each Rq is halogen; and
each Rs is independently selected from halogen and cyclopropyl; and
each Rt is independently selected from halogen, NRjR™, cyclopropyl, C1-C3 alkyl optionally
substituted with halogen or OH, and -0(Ci-C3 alkyl) optionally substituted with halogen or
OH.
The compound of claim 1, wherein Xi and X2 are CR^. The compound of claim 1 , wherein Xj is N and X2 is CRi0.
The compound of claim 1, wherein X2 is N and X] is CRi0.
The compound as claimed in any one of claims 1 to 4, wherein Rio is hydrogen.
The compound as claimed in any one of claims 1 to 4, wherein Rio is F.
The compound as claimed in any one of claims 1 to 6, wherein Re is methyl.
The compound as claimed in any one of claims 1 to 7, wherein Rg and Rg' are independently selected from hydrogen, cyclopropyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, -CH2F, - CH2OH, -CH2OCH3, -C(=0)NH2, benzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4-fluorobenzyl, 3- fluorobenzyl, 2-fluorobenzyl, 3-chlorobenz l, 4-(difluoromethoxy)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, -CH20(phenyl), -CH20(3-chlorophenyl) and - CH2S(phenyl).
The compound as claimed in any one of claims 1 to 8, wherein Rg and Rg- are both methyl.
The compound as claimed in any one of claims 1 to 7, wherein Rg is methyl, Rg is
-CH2(Rb), and Rt, is selected from phenyl, C3-C6 carbocyclyl, a 3 to 6 membered heterocyclyl, and a 5 to 6 membered heteroaryl, wherein the phenyl, carbocyclyl, heterocyclyl and heteroaryl are optionally substituted with halogen, CN, OH, OCH3, CrC6 alkyl and CrC alkoxy, wherein the alkyl and alkoxy are optionally substituted with halogen, OH or OCH3.
The compound as claimed in any one of claims 1 to 10, wherein 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, 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, (l H-imidazol-l -yl)methyl. The compound as claimed in any one of claims 1 to 8, wherein ¾· is methyl and Rg is selected from -CH2OH and -CH2OCH3.
The compound as claimed in any one of claims 1 to 7, wherein Rg and together with the atom to which they are attached form a 3 to 6 membered carbocyclyl or heterocyclyl.
The compound as claimed in any one of claims 1 to 13, wherein R7 and R7- are hydrogen.
The compound as claimed in any one of claims 1 to 14, wherein R9 is selected from hydrogen, Br, CN, butyl, isobutyl, propyl, isopentyl,
-CH2CH2C(CH3)3, -CH2CH2CH2CN, -CH2CH2CH2OCH3, cyclohexylmethyl,
-CH2(phenyl), -CH2CH2(phenyl), -CH2(3-methoxyphenyl), -CH=CHC(CH3)3,
-CH=CHCH2CH(CH3)2, -CH2CH2CH2CH=CH2, -CH=CHCH2OCH3,
-CH=CH(cyclopropyl), -C≡CCH2CH2CH3, -C≡CCH(CH3)2, -C≡CC(CH3)3,
-C≡CCH2CH(CH3)2, -C≡C(cyclopropyl), methoxy, phenyl, 3-fluorophenyl, 2-chlorophenyl, 3- chlorophenyl, 4-chlorophenyl, 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-cyclopropylphenyl,
3- (methylthio)phenyl, 3-aminophenyl, 3-(methylamino)phenyl, 3-(prop-l-ynyl)phenyl, 3-(3- methylbut-l-ynyl)phenyl, 3-(4-methylpent-l-ynyl)phenyl, 3-(5-methylhex-l-ynyl)phenyl, 3- (cyclopropylethynyl)phenyl, 3-(cyclopentylethynyl)phenyl, 3-(OCH2CN)phenyl, 3,5- difluorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,5-bis(trifIuoromethyl)phenyl, 2-chloro-5-ethoxyphenyl, 3-chloro-2-fluorophenyl, 3-chloro-2- hydroxyphenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-chloro-5- (trifluoromethyl)phenyl, 3-chloro-5-methoxyphenyl, 3-chloro-5-ethynylphenyl, 3-chloro-5- cyclopropylphenyl, 5-chloro-2-fluorophenyl, 5-chloro-2-methoxyphenyl, 5-chloro-3-cyanophenyl,
2- fluoro-3-methoxyphenyl, 2-fluoro-3-(trifluoromethyl)phenyl, 2-fluoro-5-methoxyphenyl, 2- fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-5-methoxyphenyl, 3-fluoro-5-(trifluoromethyl)phenyl,
3- fluoro-5-(prop-l-ynyl)phenyl, 4-fluoro-3-methoxyphenyl, 4-fluoro-3-(trifluoromethyl)phenyl, 5- fluoro-3-cyanophenyl, 2-fluoro-3-cyanophenyl, 2-fluoro-5-cyanophenyl, 5-bromo-3-cyanophenyl, 5-methyl-3-cyanophenyl, 5-difluoromethyl-3-cyanophenyl, 5-methoxy-3-cyanophenyl, 3- cyclopropyl-5-fluorophenyl, 5-cyclopropyl-3-cyanophenyl, 3-ethoxy-2-fluorophenyl, 3-ethoxy-4- fluorophenyl, 3-ethoxy-5-fluorophenyl, 5-ethoxy-2-fluorophenyl, 5-prop-l-ynyl-3-cyanophenyl, 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- pyridin-3-y], 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-fluoropyridin-3-yl, 5- ethynylpyridin-3-yl, 5-(prop-l-ynyl)pyridin-3-yl, 5-(cyclopropylethynyl)pyridin-3-yl, 5- cyanopyridin-3-yl, 5-cyclopropylpyridin-3-yl, 5-bromopyridin-3-yl, 5-(methylthio)pyridin-3-yl, 5- chloro-2-methoxypyridin-3-yl, 2-amino-5-chloropyridin-3-yl, 2-methylpyridin-3-yl, 4- methylpyridin-3-yl, 6-methylpyridin-3-yl, 4-chloropyridin-3-yl, 5-chloro-2-methylpyridin-3-yl, 5- chloro-6-methylpyridin-3-yl, 2-methoxypyridin-3-yl, 2-(benzyloxy)-5-chloropyridin-3-yl, 2- trifluoromethylpyridin-4-yl, 5-(difluoromethyl)pyridin-3-yl, 5-chloropyridin-3-yl-l -oxide, 4- methylpyrimidin-2-yl, pyrimidin-5-yl, 4-methylpyrimidin-5-yl, 4-trifluoromethylpyrimidin-5-yl, pyrazin-2-yl, 6-methylpyrazin-2-yl, 6-chloropyrazin-2-yl, 5-methylpyridzin-3-yl, lH-pyrrol-2-yl, thiophen-2-yl, 4-methylthiophen-2-yl, 5-methylthiophen-2-yl, 4-methoxythiophen-2-yl, thiophen- 3-yl, 5-methylfuran-2-yl, isothiazol-5-yl, 2,4-dimethylthiazol-5-yl, 1 -methyl- lH-pyrazol-4-yl, oxazol-5-yl, 1 -methyl- lH-imidazol-5-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, 5-chloro-l- methy 1-2-oxo-l ,2-dihydropyridin-3-yl, 5-chloro-2-oxo-l ,2-dihydropyridin-3-yl, 6-oxo-l ,6- dihydropyridin-3-yl, tert-butyl 5,6-dihydropyridine- 1 (2H)-carboxylate, 1 ,2,5,6-tetrahydropyridin- 3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl, 3,4-dihydro-2H-pyran-6-yl, cyclopropyl, cyclopentyl, cyclohexyl, (3R,5S)-3,5-dimethylcyclohexyl, 4,4-dimethylcyclohexyl, 3 -hydroxy cyclohexyl, (3R,5S)-3,5-dimethylcyclohex-l-enyl, 4,4-dimethylcyclohex-l-enyl, 3- methoxycyclohex-l-enyl, 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, quinolin-3- yl, phenylamino, phenoxy and 3-benzyl-5-fluorophenoxy.
16. A compound of Formula II as claimed in claim 1 and named in Examples 1 to 444. 17. A method of inhibiting cleavage of APP by β-secretase in a mammal comprising administering to said mammal an effective amount of a compound of any one of claims 1 to 16.
18. A method for treating a disease or condition mediated by the cleavage of APP by β-secretase in a mammal, comprising administering to said mammal an effective amount of a compound of any one of claims 1 to 16.
19. The method of claim 18, wherein said disease is Alzheimer's disease.
20. A pharmaceutical composition comprising a compound of any one of claims 1 to 16 and a
pharmaceutically acceptable carrier, diluent or excipient. A compound of Formula (I)
Figure imgf000197_0001
X is CR3 or N;
Y is CR4R4';
Z] and Z2 are independently CR3 or N;
Ri is H, alkyl, carbocyclylalkyl or heterocyclylalkyl wherein said akyl, carbocyclylalkyl and heterocyclylalkyl are optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl;
R2 and R2' 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; or
R2 and R2' together form a 3 to 6 member carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl;
R3 is H, halogen, amino, hydroxy, 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 and haloalkyl;
R4 and R4' are independently H, 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; or
R4 and R4' together form a 3 to 6 member carbocycle or heterocycle optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl; and m is an integer from 0 to 4.
22. The compound of claim 21, wherein X is CH.
23. The compound of any one of claims 21 to 22, wherein Y is CH2.
24. The compound of any one of claims 21 to 23, wherein Z\ and Z2 are both CR3.
25. The compound of any one of claims 21 to 24, wherein Zj is N and Z2 is CR3.
26. The compound of any one of claims 21 to 25, wherein R is Me.
27. The compound of any one of claims 21 to 26, wherein R2 and R2' are both methyl.
28. The compound of any one of claims 21 to 27, wherein R2 and R2' together form a cycloalkyl ring optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl.
29. The compound of any one of claims 21 to 26, wherein R2 and R2' together form a heterocyclic ring optionally substituted with hydroxy, halogen, amino, cyano, nitro, alkyl, alkoxy, acyl and haloalkyl.
30. The compound of any one of claims 21 to 29, wherein R3 is halogen, cyano, alkyl, alkoxy,
haloalkyl or haloalkoxy.
31. The compound of any one of claims 21 to 30, wherein m is 0-2.
PCT/US2010/059553 2009-12-08 2010-12-08 S piro [chroman - 4, 4 ' - imidazol] ones as beta - secretase inhibitors WO2011072064A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US26781009P 2009-12-08 2009-12-08
US26780909P 2009-12-08 2009-12-08
US61/267,809 2009-12-08
US61/267,810 2009-12-08
US30740010P 2010-02-23 2010-02-23
US61/307,400 2010-02-23

Publications (1)

Publication Number Publication Date
WO2011072064A1 true WO2011072064A1 (en) 2011-06-16

Family

ID=44145900

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/059553 WO2011072064A1 (en) 2009-12-08 2010-12-08 S piro [chroman - 4, 4 ' - imidazol] ones as beta - secretase inhibitors

Country Status (1)

Country Link
WO (1) WO2011072064A1 (en)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102796122A (en) * 2011-05-25 2012-11-28 上海药明康德新药开发有限公司 Benzo dihydropyran sulfamide spiro-compound and preparation method thereof
WO2013148851A1 (en) * 2012-03-27 2013-10-03 Array Biopharma Inc. Compounds for treating neurodegenerative diseases
WO2013181202A3 (en) * 2012-05-30 2014-01-30 Astellas Pharma Inc. Chromane compounds
US8729071B2 (en) 2009-10-08 2014-05-20 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
WO2014150344A1 (en) * 2013-03-15 2014-09-25 Merck Sharp & Dohme Corp. C2-azaspiro iminothiazine dioxides as bace inhibitors
US8889703B2 (en) 2010-02-24 2014-11-18 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US8981112B2 (en) 2012-03-05 2015-03-17 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
US9018391B2 (en) 2012-08-27 2015-04-28 Boehringer Ingelheim International Gmbh Inhibitors of beta-secretase
US9126999B2 (en) 2012-05-31 2015-09-08 Eisai R&D Management Co., Ltd. Tetrahydropyrazolopyrimidine compounds
US9145426B2 (en) 2011-04-07 2015-09-29 Merck Sharp & Dohme Corp. Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9181236B2 (en) 2011-08-22 2015-11-10 Merck Sharp & Dohme Corp. 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use
US9212153B2 (en) 2009-03-13 2015-12-15 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US9221839B2 (en) 2011-04-07 2015-12-29 Merck Sharp & Dohme Corp. C5-C6 oxacyclic-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9290477B2 (en) 2012-09-28 2016-03-22 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
WO2017033019A1 (en) 2015-08-26 2017-03-02 Fundación Centro Nacional De Investigaciones Oncológicas Carlos Iii (Cnio) Condensed tricyclic compounds as protein kinase inhibitors
CN106607091A (en) * 2016-10-10 2017-05-03 湘潭大学 Microporous polymer-nano-metal particle catalyst and its preparation method and use
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4278793A (en) 1977-04-02 1981-07-14 Hoechst Aktiengesellschaft Cephem derivative
EP0193415A2 (en) * 1985-03-04 1986-09-03 Sanwa Kagaku Kenkyusho Co., Ltd. Spiro-3-heteroazolidine compounds and salts thereof, their preparation and pharmaceutical agents thereof
WO1993005045A1 (en) * 1991-08-28 1993-03-18 The Upjohn Company Spirocyclic benzopyran imidazolines
WO1996015111A1 (en) 1994-11-15 1996-05-23 Regents Of The University Of Minnesota Method and intermediates for the synthesis of korupensamines
WO1998046576A2 (en) 1997-04-15 1998-10-22 Genentech, Inc. Halo-alkoxycarbonyl prodrugs
WO2002098462A1 (en) * 2001-06-01 2002-12-12 Ono Pharmaceutical Co., Ltd. Remedies containing aldose reductase inhibitor as the active ingredient for demyelinating diseases or diseases associated with demyelination
WO2006094799A2 (en) 2005-03-04 2006-09-14 Glaxo Group Limited Pyridinone derivatives against malaria
WO2007107243A1 (en) 2006-03-18 2007-09-27 Bayer Healthcare Ag Substituted chromanol derivatives and their use
WO2008030412A2 (en) * 2006-09-07 2008-03-13 Merck & Co., Inc. Spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease
WO2010021680A2 (en) * 2008-08-19 2010-02-25 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4278793A (en) 1977-04-02 1981-07-14 Hoechst Aktiengesellschaft Cephem derivative
EP0193415A2 (en) * 1985-03-04 1986-09-03 Sanwa Kagaku Kenkyusho Co., Ltd. Spiro-3-heteroazolidine compounds and salts thereof, their preparation and pharmaceutical agents thereof
WO1993005045A1 (en) * 1991-08-28 1993-03-18 The Upjohn Company Spirocyclic benzopyran imidazolines
WO1996015111A1 (en) 1994-11-15 1996-05-23 Regents Of The University Of Minnesota Method and intermediates for the synthesis of korupensamines
WO1998046576A2 (en) 1997-04-15 1998-10-22 Genentech, Inc. Halo-alkoxycarbonyl prodrugs
WO2002098462A1 (en) * 2001-06-01 2002-12-12 Ono Pharmaceutical Co., Ltd. Remedies containing aldose reductase inhibitor as the active ingredient for demyelinating diseases or diseases associated with demyelination
WO2006094799A2 (en) 2005-03-04 2006-09-14 Glaxo Group Limited Pyridinone derivatives against malaria
WO2007107243A1 (en) 2006-03-18 2007-09-27 Bayer Healthcare Ag Substituted chromanol derivatives and their use
WO2008030412A2 (en) * 2006-09-07 2008-03-13 Merck & Co., Inc. Spiropiperidine beta-secretase inhibitors for the treatment of alzheimer's disease
WO2010021680A2 (en) * 2008-08-19 2010-02-25 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase

Non-Patent Citations (33)

* Cited by examiner, † Cited by third party
Title
"Chiral Liquid Chromatography", 1989, CHAPMAN AND HALL
"Drug Stereochemistry: Analytical Methods and Pharmacology", 1993, MARCEL DEKKER, INC.
ANSEL, HOWARD C. ET AL.: "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems", 2004, WILLIAMS & WILKINS
DEAN, J. A.: "Lange's Handbook of Chemistry", 1985, MCGRAW-HILL
E. HASLAM: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
ELIEL, E.; S. WILEN: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS, INC.
ELIEL, E.; S. WILEN: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS, INC., pages: 322
FIESER, LOUIS F.; MARY FIESER: "Reagents for Organic Synthesis", vol. 1-23, 1967, WILEY
GELMAN, DMITRI; STEPHEN L. BUCHWALD: "Efficient Palladium-Catalyzed Coupling of Aryl Chlorides and Tosylates with Terminal Alkynes: Use of a Copper Cocatalyst Inhibits the Reaction", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 42, no. 48, 2003, pages 5993 - 5996
GENNARO, ALFONSO R. ET AL.: "Remington: The Science and Practice of Pharmacy", 2000, WILLIAMS & WILKINS
GREENE, T. W.; WUTS, P. G. M.: "Protective Groups in Organic Synthesis", 1991, JOHN WILEY & SONS, INC.
GREENE, T. W.; WUTS, P.G.M.: "Protective Groups in Organic Synthesis", 1991, JOHN WILEY & SONS, INC.
GREENE, T.W.: "Protective Groups in Organic Synthesis", 1981, JOHN WILEY AND SONS
GREENE, T.W.; P.G.M. WUTS: "Greene's Protective Groups in Organic Synthesis", 2006, WILEY-INTERSCIENCE
H. CHEN ET AL.: "PARM: A Genetic Evolved Algorithm To Predict Bioactivity", J. CHEM. INF. COMPUT. SCI., vol. 38, no. 2, 23 March 1998 (1998-03-23), pages 243 - 250, XP002624414, ISSN: 0095-2338 *
HASLAM, E.: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
J. ORG. CHEM., vol. 44, 1979, pages 1572
J. ORG. CHEM., vol. 46, 1981, pages 294
J. ORG. CHEM., vol. 72, 2007, pages 1856
JACOB III, PEYTON: "Resolution of (±)-5-Bromonomicotine. Synthesis of (R)- and (S)-Nomicotine of High Enantiomeric Purity", J. ORG. CHEM., vol. 47, no. 21, 1982, pages 4165 - 4167
LOCHMULLER, C. H. ET AL.: "Chromatographic resolution of enantiomers: Selective review", J. CHROMATOGR., vol. 113, no. 3, 1975, pages 283 - 302
OKAMOTO, YOSHIO ET AL.: "Optical resolution of dihydropyridine enantiomers by high-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase", J. OF CHROMATOGR., vol. 513, 1990, pages 375 - 378
PRAVST, IGOR ET AL.: "Efficient Synthesis of ?,?-Difluoro Ketones Using Selectfluor™ F-TEDA-BF4", SYNTHESIS, vol. 18, 2005, pages 3140 - 3146
R. C. GADWOOD ET AL.: "Chiral spirocyclic benzopyran potassium channel openers: evidence for the active conformation of levcromakalim", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 5, no. 18, 1995, pages 2101 - 2104, XP002624416, ISSN: 0960-894X *
R. C. GADWOOD ET AL.: "Synthesis and biological activity of spirocyclic benzopyran imidazolone potassium channel openers", J. MED. CHEM., vol. 36, no. 10, 1993, pages 1480 - 1487, XP000910108 *
RAUK, ARVI: "The chemistry of Alzheimer's disease", CHEM. SOC. REV., vol. 38, 2009, pages 2698 - 2715
ROWE, RAYMOND C: "Handbook of Pharmaceutical Excipients", 2005, PHARMACEUTICAL PRESS
SERBAN, GEORGETA; HITOSHI ABE; YASUO TAKEUCHI; TAKASHI HARAYAMA: "A New Approach to the Benzopyridoxepine Core by Metal Mediated Intramolecular Biaryl Ether Formation", HETEROCYCLES, vol. 75, no. 12, 2008, pages 2949 - 2958
SILVESTRI, ROMANO: "Boom in the Development of Non-Peptidic ?-Secretase (BACEI) Inhibitors for the Treatment of Alzheimer's Disease", MEDICINAL RESEARCH REVIEWS., vol. 29, no. 2, 2009, pages 295 - 338
SU YANG ET AL: "Studies on pharmacophore model of new ATP-sensitive K+ channel opener with pseudo atomic receptor model", JISUANJI-YU-YINGYONG-HUAXUE = COMPUTERS AND APPLIED CHEMISTRY, BEIJING HUAGONG XUEYUAN, BEIJING, CN, vol. 17, no. 1-2, 1 February 1999 (1999-02-01), pages 3 - 7, XP008118885, ISSN: 1001-4160 *
T. W. GREENE ET AL.: "Greene's Protective Groups in Organic Synthesis", 2006, WILEY INTERSCIENCE
TETRAHEDRON LETTERS, vol. 46, 2005, pages 1651
VASSAR, ROBERT; DORA M. KOVACS; RIQIANG YAN; PHILIP C- WONG: "The• -Secretase Enzyme BACE in Health and Alzheimer's Disease: Regulation, Cell Biology, Function, and Therapeutic Potential", J. NEUROSCI., vol. 29, no. 41, 2009, pages 12787 - 12794

Cited By (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9212153B2 (en) 2009-03-13 2015-12-15 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US10336717B2 (en) 2009-03-13 2019-07-02 Vitae Pharmaceuticals, Llc Inhibitors of beta-secretase
US8940748B2 (en) 2009-10-08 2015-01-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US8729071B2 (en) 2009-10-08 2014-05-20 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
US9475785B2 (en) 2009-10-08 2016-10-25 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
US9428475B2 (en) 2009-10-08 2016-08-30 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9687494B2 (en) 2009-10-08 2017-06-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9029362B2 (en) 2009-10-08 2015-05-12 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as brace inhibitors, compositions, and their use
US8889703B2 (en) 2010-02-24 2014-11-18 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US9045500B2 (en) 2010-02-24 2015-06-02 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
US9221839B2 (en) 2011-04-07 2015-12-29 Merck Sharp & Dohme Corp. C5-C6 oxacyclic-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9145426B2 (en) 2011-04-07 2015-09-29 Merck Sharp & Dohme Corp. Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
CN102796122B (en) * 2011-05-25 2015-09-23 上海药明康德新药开发有限公司 Benzo dihydropyran sulfamide sulfamide spiro compound and preparation method
CN102796122A (en) * 2011-05-25 2012-11-28 上海药明康德新药开发有限公司 Benzo dihydropyran sulfamide spiro-compound and preparation method thereof
US9181236B2 (en) 2011-08-22 2015-11-10 Merck Sharp & Dohme Corp. 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use
US8981112B2 (en) 2012-03-05 2015-03-17 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
US9526727B2 (en) 2012-03-05 2016-12-27 Vitae Pharmaceutical, Inc. Inhibitors of beta-secretase
US9949975B2 (en) 2012-03-05 2018-04-24 Vitae Pharmaceuticals, Inc. Inhibitors of beta-secretase
WO2013148851A1 (en) * 2012-03-27 2013-10-03 Array Biopharma Inc. Compounds for treating neurodegenerative diseases
JP2015518048A (en) * 2012-05-30 2015-06-25 コメンティス， インコーポレイテッド Chroman compounds
US8975415B2 (en) 2012-05-30 2015-03-10 Comentis, Inc. Chromane compounds
US9242973B2 (en) 2012-05-30 2016-01-26 Comentis, Inc. Chromane compounds
CN104394862A (en) * 2012-05-30 2015-03-04 科门蒂斯公司 Chromane compounds
WO2013181202A3 (en) * 2012-05-30 2014-01-30 Astellas Pharma Inc. Chromane compounds
EA026380B1 (en) * 2012-05-30 2017-04-28 Коментис, Инк. Chromane compounds
US9850242B2 (en) 2012-05-31 2017-12-26 Eisai R&D Management Co., Ltd Tetrahydropyrazolopyrimidine compounds
US9126999B2 (en) 2012-05-31 2015-09-08 Eisai R&D Management Co., Ltd. Tetrahydropyrazolopyrimidine compounds
US11130758B2 (en) 2012-05-31 2021-09-28 Eisai R&D Management Co., Ltd. Tetrahydropyrazolopyrimidine compounds
US10640500B2 (en) 2012-05-31 2020-05-05 Eisai R&D Management Co., Ltd. Tetrahydropyrazolopyrimidine compounds
US9446046B2 (en) 2012-05-31 2016-09-20 Eisai R&D Management Co., Ltd. Tetrahydropyrazolopyrimidine compounds
US9018391B2 (en) 2012-08-27 2015-04-28 Boehringer Ingelheim International Gmbh Inhibitors of beta-secretase
US9290477B2 (en) 2012-09-28 2016-03-22 Vitae Pharmaceuticals, Inc. Inhibitors of β-secretase
WO2014150344A1 (en) * 2013-03-15 2014-09-25 Merck Sharp & Dohme Corp. C2-azaspiro iminothiazine dioxides as bace inhibitors
US9453034B2 (en) 2013-03-15 2016-09-27 Merck Sharp & Dohme Corp. C2-azaspiro iminothiazine dioxides as BACE inhibitors, compositions, and their use
WO2017033019A1 (en) 2015-08-26 2017-03-02 Fundación Centro Nacional De Investigaciones Oncológicas Carlos Iii (Cnio) Condensed tricyclic compounds as protein kinase inhibitors
CN106607091B (en) * 2016-10-10 2019-03-19 湘潭大学 Microporous polymer-nanometer metal particle catalyst and its preparation method and application
CN106607091A (en) * 2016-10-10 2017-05-03 湘潭大学 Microporous polymer-nano-metal particle catalyst and its preparation method and use
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors

Similar Documents

Publication Publication Date Title
WO2011072064A1 (en) S piro [chroman - 4, 4 &#39; - imidazol] ones as beta - secretase inhibitors
US20120083501A1 (en) Compounds for treating neurodegenerative diseases
US20120065195A1 (en) Compounds for treating neurodegenerative diseases
US20120157448A1 (en) Compounds for treating neurodegenerative diseases
US10231967B2 (en) Compounds and their use as BACE inhibitors
WO2011130741A1 (en) Compounds for treating neurodegenerative diseases
CN108473498B (en) Pyrazolo [1,5a ] pyrimidine derivatives as IRAK4 modulators
KR20210152513A (en) GLP-1R agonists and uses thereof
DK2350090T3 (en) Spiro-oxindole compounds and their use as therapeutic agents
KR20220061087A (en) SHP2 phosphatase allosteric inhibitor
KR20100103702A (en) Condensed aminodihydrothiazine derivative
TW200800908A (en) Novel azacyclyl-substituted aryldihydroisoquinolinones, process for their preparation and their use as medicaments
EP3737680A1 (en) Octahydropyrido[1,2-alpha]pyrazines as magl inhibitors
AU2017286868B2 (en) 5,7-dihydro-pyrrolo-pyridine derivatives for treating neurological and neurodegenerative diseases
KR20240017004A (en) Substituted indole compounds and methods of using them
AU2016325665A1 (en) N-[2-(2-amino-6,6-disubstituted-4, 4a, 5, 6-tetrahydropyrano [3,4-d][1,3] thiazin-8a (8h)-yl) -1, 3-thiazol-4-yl] amides
US20140288091A1 (en) Mono-fluoro beta-secretase inhibitors
US8580962B2 (en) Spiroheterocyclic compounds as mGlu5 antagonists
TW202122092A (en) Alpha-d-galactopyranoside derivatives
JP6480947B2 (en) Spirooxazolone
WO2011087712A2 (en) Tricyclic derivatives and their pharmaceutical use and compositions
CN116332937A (en) Dipeptidyl peptidase I inhibitors and uses thereof
NZ716609B2 (en) Fused piperidine amides as modulators of ion channels

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10796526

Country of ref document: EP

Kind code of ref document: A1

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10796526

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10796526

Country of ref document: EP

Kind code of ref document: A1