WO2012022707A1 - Substituted heteroaryl spiropyrrolidine mdm2 antagonists - Google Patents

Substituted heteroaryl spiropyrrolidine mdm2 antagonists Download PDF

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WO2012022707A1
WO2012022707A1 PCT/EP2011/064015 EP2011064015W WO2012022707A1 WO 2012022707 A1 WO2012022707 A1 WO 2012022707A1 EP 2011064015 W EP2011064015 W EP 2011064015W WO 2012022707 A1 WO2012022707 A1 WO 2012022707A1
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Prior art keywords
chloro
pyrrolidine
neopentyl
oxo
dihydrospiro
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PCT/EP2011/064015
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French (fr)
Inventor
David Joseph Bartkovitz
Xin-Jie Chu
Qingjie Ding
Prabha Saba Karnachi
Jin-Jun Liu
Sung-Sau So
Jing Zhang
Zhuming Zhang
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F. Hoffmann-La Roche Ag
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Publication of WO2012022707A1 publication Critical patent/WO2012022707A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Definitions

  • the present invention relates to heteroaryl spiropyrrolidine derivatives which act as inhibitors of MDM2-p53 interactions and are useful in the amelioration or treatment of cancer, in particular solid tumors.
  • p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis.
  • p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis.
  • p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop.
  • MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes.
  • MDM2 mediates the ubiquitin- dependent degradation of p53.
  • p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells.
  • MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation.
  • MDM2 to p53 The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the pl6INK4/pl9ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g.
  • MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells.
  • the present invention relates to heteroaryl spiropyrrolidines of formula I which act as antagonists of MDM2 interactions and hence are useful as potent and selective anticancer agents.
  • R5 is selected from the group consisting of H, F, CI, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy;
  • R 6 is selected from the group consisting of H, F, CI, methyl
  • R 7 is selected from the group consisting of H, F, CI, methyl
  • R 8 is selected from the group consisting of H, F, CI, methyl
  • Ri and R 2 are independently selected from the group consisting of lower alkyl,
  • R 3 and R4 are selected from the group consisting of (CH 2 ) n -R ⁇ (CH 2 ) n -NR'R", (CH 2 ) n - NR'COR", (CH 2 ) n -NR'S0 2 R", (CH 2 ) n -COOH, (CH 2 ) n -COOR ⁇ (CH 2 ) n -CONR'R", (CH 2 ) n -OR', (CH 2 ) n -SR', (CH 2 ) n -SOR', (CH 2 ) n -S0 2 R ⁇ (CH 2 ) n -COR', (
  • R' and R' ' are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, hetereoaryl, substituted hetereoaryl, hetereocycle or substituted hetereocycle or R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or
  • n and p are independently 0 to 6; or
  • Another embodiment of the invention relates to compounds of formula I having a stereochemical structure shown as formula II
  • R5 is selected from the group consisting of H, F, CI, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy;
  • R 6 is selected from the group consisting of H, F, CI and methyl
  • R 7 is selected from the group consisting of H, F, CI and methyl
  • R 8 is selected from the group consisting of H, F, CI and methyl
  • Ri and R 2 are independently selected from the group consisting of lower alkyl,
  • substituted lower alkyl lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
  • R 3 and R 4 are selected from the group consisting of (CH 2 ) n -R ⁇ (CH 2 ) n -NR'R", (CH 2 ) n -
  • R' and R' ' are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, hetereoaryl, substituted hetereoaryl, hetereocycle or substituted hetereocycle or R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or
  • n and p are independently 0 to 6: or
  • R 2 is selected from the group consisting of aryl substitued with CI , F or Brand heteroaryl optionally substituted with H, F , CI or Br.
  • R9 and Rio are both methyl, or alternatively, R9 and Rio together with the carbon to which they are attached form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or
  • R11 is (CH 2 ) q -Ri 2 , where q is 0, 1 or 2 and Ri 2 is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle and substituted heterocycle.
  • R 3 and R 4 are hydrogen, and the other (CH 2 ) n -R ⁇ n is 0 or 1 and R' is aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle.
  • R' is aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle.
  • R5 is selected from F, CI or Br
  • R 6 , R7, R 8 are hydrogen
  • R 2 is selected from the group consisting of aryl, aryl substitued with CI or F or Br, and heteroaryl optionally substituted with H, F , CI or Br;
  • Ri is a substituted lower alkyl of the formula
  • R9 and Rio are both methyl, or alternatively, R9 and Rio together with the carbon to which they are attached form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl;
  • R 11 is (CH 2 ) q -Ri 2, where q is 0, 1 or 2;
  • R 12 is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle and substituted heterocycle;
  • R 3 and R 4 are hydrogen, and the other is (CH 2 ) n -R' ;
  • n 0 or 1 ;
  • R' is selected from aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle.
  • R5 is selected from F, CI or Br
  • R 6 , R 7, Rg are hydrogen
  • R 2 is selected from the group consisting of
  • Ri 3 is F, CI or Br
  • Ri 4 is H or F
  • Ri is a substituted lower alkyl of the formula
  • R9 and Rio are both methyl, or alternatively, R9 and Rio together with the carbon to which they are attached form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl;
  • R 11 is (CH 2 ) q -Ri 2 , where q is 0, 1 or 2;
  • R 12 is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle and substituted heterocycle;
  • R 3 and R 4 are hydrogen, and the other is (CH 2 ) n -R';
  • n 0 or 1 ;
  • R' is selected from aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle; or
  • alkyl refers to straight- or branched-chain saturated hydrocarbon groups having from 1 to about 12 carbon atoms, including groups having from 1 to about 7 carbon atoms.
  • alkyl substituents may be "lower” alkyl substituents.
  • lower alkyl refers to alkyl groups having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
  • alkenyl as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing at least one double bond and having 2 to 6, preferably 2 to 4 carbon atoms.
  • alkenyl substituents may be “lower” alkenyl substituents.
  • lower alkenyl refers to alkenyl groups having from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms.
  • alkenyl examples are vinyl, ethenyl, allyl, isopropenyl, 1- propenyl, 2-methyl- l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-l-butenyl, 3-methyl-2- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
  • Alkoxy, alkoxyl or lower alkoxy refers to any of the above “alkyl” or “lower alkyl” groups which is attached to the remainder of the molecule by an oxygen atom (RO-).
  • Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like.
  • multiple alkoxy side chains e.g. ethoxy ethoxy, methoxy ethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy side chains, e.g., dimethylamino ethoxy, diethylamino ethoxy, dimethoxy-phosphoryl methoxy and the like.
  • alkynyl as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one triple bond and having 2 to 6, preferably 2 to 4 carbon atoms.
  • alkynyl group examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl and 5-hexynyl.
  • Amino means the group -NH 2 .
  • Aryl means a monovalent, monocyclic or bicyclic, aromatic carboxylic hydrocarbon radical, preferably a 6-10 member aromatic ring system.
  • Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
  • cycloalkyl as used herein means any stable monocyclic or polycyclic system which consists of carbon atoms only, any ring of which being saturated.
  • said cycloalkyl contains from 3 to 12, more preferably from 3 to 10, carbon atoms.
  • cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds.
  • bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane
  • bicyclononanes such as [4.3.0]bicyclononane
  • bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or
  • cycloalkenyl is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, with at least one ring thereof being partially unsaturated.
  • said cycloalkenyl contains from 3 to 12, more preferably from 3 to 10, and especially preferred from 5 to 10 carbon atoms.
  • Examples of cycloalkenyls include, but are not limited to, cyclopentenyl or cyclohexenyl.
  • halogen as used herein means fluorine, chlorine, bromine, or iodine, preferably fluorine and chlorine.
  • Heteroaryl means an aryl as defined above wherein at least one carbon atom, preferably 1 to 4 carbon atoms, is/are replaced by a heteroatom independently selected from nitrogen, oxygen or sulfur.
  • Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole substituted or unsubstituted triazolyl and substituted or unsubstituted tetrazolyl.
  • aryl or heteroaryl which are bicyclic it should be understood that one ring may be aryl while the other is heteroaryl and both being substituted or unsubstituted.
  • Heteroatom means an atom selected from N, O and S.
  • Heterocycle or “heterocyclic ring” means a substituted or unsubstituted 5 to 8 membered, mono- or bicyclic, non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom.
  • Examples include pyrrolidin-2-yl; pyrrolidin-3-yl; piperidinyl; morpholin-4-yl and the like which in turn can be substituted.
  • IC50 refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC 50 can be measured, inter alia, as is described subsequently in the Example providing biological data.
  • Ni means -N0 2 .
  • “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
  • “Pharmaceutically acceptable ester” refers to a conventionally esterified compound of formula I having a carboxyl group, which esters retain the biological effectiveness and properties of the compounds of formula I and are cleaved in vivo (in the organism) to the corresponding active carboxylic acid. Information concerning esters and the use of esters for the delivery of pharmaceutical compounds is available in Design of Prodrugs. Bundgaard H ed. (Elsevier, 1985). See also, H. Ansel et ah, Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 108-109; Krogsgaard-Larsen, et ah, Textbook of Drug Design and Development (2d Ed. 1996) at pp. 152-191.
  • “Pharmaceutically acceptable salt” refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, trifluoro acetic acid and the like.
  • Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide.
  • Chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel et ah , Pharmaceutical Dosage Forms and Drug Delivery Systems (1995) at pgs. 456-457.
  • substituted as in substituted alkyl, means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution site are independently selected from the specified options.
  • optionally substituted refers to the fact that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be, but does not necessarily have to be, substituted with another substituent.
  • the various groups may be substituted by 1-5 or, preferably, 1-3 substituents independently selected from the group consisting of lower alkyl, lower-alkenyl, lower-alkynyl, dioxo-lower-alkylene (forming e.g.
  • a benzodioxyl group halogen, hydroxy, CN, CF 3 , NH 2 , N(H, lower-alkyl), N(lower-alkyl)2, aminocarbonyl, carboxy, N0 2 , lower-alkoxy, thio-lower-alkoxy, lower-alkylsufonyl, amino sulfonyl, lower-alkylcarbonyl, lower- alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower-alkyl, fluoro- lower-alkoxy, lower- alkoxy-carbonyl-lower-alkoxy, carboxy-lower-alkoxy, carbamoyl-lower- alkoxy, hydroxy-lower-alkoxy, NH 2 -lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower- alkyl) 2 -low
  • Preferred substituents for the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle rings are halogen, lower alkoxy, lower alkyl, hydroxycarbonyl, carboxy, carboxy lower alkoxy, oxo and CN.
  • Preferred substituents for alkyl are alkoxy and N(lower alkyl) 2 .
  • the present compounds as well as their salts that have at least one asymmetric carbon atom may be present as racemic mixtures or different stereoisomers.
  • the various isomers can be isolated by known separation methods, e.g., chromatography.
  • the compounds of the present invention may be useful in the treatment or control of cell proliferative disorders, in particular oncological disorders, more particularly solid tumors, such as, for example, breast, colon, lung and prostate tumors.
  • the present compounds preferably the compounds of formula (II), for use as medicament, in particular for use as medicament in the treatment of solid tumors, preferably breast, colon, lung and prostate tumors.
  • the present invention provides pharmaceutical preparations comprising the compounds according to the present invention, preferably the compounds of formula (II), together with a pharmaceutically acceptably carrier or excipient.
  • a “therapeutically effective amount” of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
  • the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, as well as the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a formula I compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the present invention provides novel methods for the synthesis of heteroaryl spiropyrrolidines of formula I or II.
  • Compounds of this invention can be synthesized according to the following general schemes. Suitable processes for synthesizing these compounds are provided in the examples.
  • An intermediate III can be made from a base-catalyzed condensation reaction of appropriately selected substituted 4- or 5- or 6- or 7-aza-2-oxindole I and appropriate substituted aldehyde II in methanol (Scheme 1).
  • the choice of bases includes but is not limited to pyrrolidine or piperidine.
  • the reaction generates III as a mixture of Z- and E-isomers with E-isomer as major product.
  • intermediates V or VII can be made from a acid-catalyzed condensation reaction of appropriately selected substituted 5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one IV or 4,6-dihydro- thieno[3,2-b]pyrrol-5-one VI and aldehyde II in hydrochloric and actic aicd (M. Cheung et al, Tetrahedron Lett. 2001, 42, 999) (Scheme 2).
  • Racemic synthesis of compounds in formula I and II can be achieved as outlined in Scheme 4.
  • Amine NHRsRj can be reacted with N-protected glycine like N-Boc glycine by using a coupling reagent like EDCI or HATU to give intermediate VIII.
  • Intermediate VIII can be treated with trifluoroacetic acid or HC1 at room temperature to remove protective Boc group and give intermediate IX.
  • Apropriatedly selected aldehyde RiCHO can react with IX to give the imine X.
  • selected aldehyde RiCHO can be reacted with glycine tert-butyl ester to generate imine XIV.
  • the racemic mixture of intermediate XV and XV can be made from intermediates XIV and VII by LiOH mediated cyclization reaction.
  • the mixture of XVI and XVI' can be subsequently converted to a racemic mixture of acid XVII and XVII' by using trifluoroacetic acid.
  • Amide formation with various amine by using diphenylphsphinic chloride as the coupling reagent can lead to the racemic mixture of compounds Xlla and Xlla' in formula II.
  • chiral separation by chiral Super Fluid Chromatography (SFC) or chiral HPLC gives oprically pure or enriched chiral compounds Xlla in formula II.
  • Step a A mixture of methyl 4-aminobenzoate (Aldrich, 5.00 g, 32.4 mmol), tert- butoxycarbonylamino-acetic acid (9.44 g, 53.4 mmol, Aldrich) and l-(3-dimetgylaminopropyl)-
  • Step b A solution of methyl 4-(2-(tert-butoxycarbonylamino)acetamido)-benzoate (5.25 g, 17.0 mmol) in CH 2 CI 2 (40 mL) at 0 C was treated with TFA (20 mL) and the mixture was stirred at rt for 4 h. The solvent was then removed under reduced pressure. The residue was further dried in vacuum overnight to give methyl 4-(2-aminoacetamido)benzoate as a TFA salt (5.82 g, 99%).
  • Step c To a suspension of the above methyl 4-(2-aminoacetamido)benzoate TFA salt (4.95 g, 15.4 mmol) in t-butyl methyl ether (160 mL) at rt was added TRIETHYLAMINE (1.74 g, 2.40 ml, 17.2 mmol) and the mixture was stirred for 30 min. 3,3-Dimethylbutanal (1.69 g, 16.9 mmol) in t-butyl methyl ether (5 mL) was added and the reaction mixture was allowed to stir at rt overnight. t-Butyl methyl ether (100 mL) was added and stirred for 20 min.
  • Step a To a solution of tert-butyl 2-aminoacetate (Aldrich, 1.00 g, 7.62 mmol) in CH 2 C1 2 (30 mL) was added 3,3-dimethylbutanal (Aldrich, 1.00 g, 9.98 mmol). The mixture was stirred at rt for 4 h. Water added and organic layer separated. The aqueous layer was extracted with CH 2 CI 2 . The combined organic extracts were washed with water and concentrated to give (E)-tert-butyl 2-(3,3-dimethylbutylideneamino)acetate as a colorless oil (1.52 g, 93%).
  • Step b A suspension of 3-(3-chloro-2-fluorobenzylidene)-lH-pyrrolo[3,2-c]pyridin-2(3H)-one (60 mg, 0.218 mmol, Example 4) in CH 2 CI 2 (8 mL) was treated with triethylamine (133 mg, 1.31 mmol).
  • (E)-tert-butyl 2-(3,3-dimethylbutylideneamino)acetate 69 mg, 0.325 mmol
  • silver(I) fluoride Aldrich, 47 mg, 0.370 mmol
  • the reaction mixture was partition between EtOAc and water, washed with brine and dried over Na 2 S0 4 and concentrated to dryness.
  • the residue was dissolved in t-BuOH (8 mL) and 2,3,4,6,7, 8, 9, 10-octahydropyrimido[l,2-a]azepine (DBU) (Aldrich, 266 mg, 1.75 mmol) and heated at 120 C for 2 h.
  • DBU 2,3,4,6,7, 8, 9, 10-octahydropyrimido[l,2-a]azepine
  • reaction mixture was allowed to stir at 40 °C for 23 h.
  • the mixture was diluted with EtOAc, washed with water and concentrated to a small volume. MeOH was added slowly (-15 mL) and the mixture was stirred in cold bath for -20 min.
  • reaction mixture was allowed to stir at 40 °C for 20 h, giving a clear reaction mixture.
  • the mixture was diluted with EtOAc (100 mL), washed with water (2x20 mL) and concentrated to a small volume. MeOH was added slowly (-10 mL) and the mixture was stirred in cold bath for -20 min.
  • Step a A mixture of 3-methoxy-4-nitrobenzoic acid (Acros, 10 g, 51 mmol) in thionyl chloride (36 g) was heated at reflux for 2 h. The mixture was concentrated. To the residue was added a methanolic solution (7 N) of ammonia. The reaction mixture was stirred at room temperature for 72 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The precipitate between the two layers was filtered and collected to give 3-methoxy-4- nitrobenzamide as a light yellow solid (8 g, 81%).
  • Step b To a solution of 3-methoxy-4-nitrobenzamide (8 g, 41 mmol) in dioxane (300 mL) was added pyridine (32 g, 408 mmol), followed by dropwise addition of trifluoroacetic anhydride (43 g, 204 mmol). The reaction mixture was stirred at room temperature for 5 h . Water was added to quench the reaction. The mixture was concentrated, then the residue was partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, aqueous saturated CuS0 4 solution, brine, dried over MgS0 4 , and concentrated to give 3-methoxy-4-nitrobenzonitrile as a off white solid (6.5 g, 90%)
  • Step c To the suspension of 3-methoxy-4-nitrobenzonitrile (11.4 g, 64 mmol) in ethyl acetate (60 mL) was added 10% Pd/C (1 g). The reaction mixture was vigorously shaken in a Parr under an atmosphere of hydrogen (50 psi) at room temperature for 45 min . The mixture was filtered through a short pad of celite, and the filtrate was concentrated to give 4-amino-3-methoxy- benzonitrile as a yellow oil, which solidified at stand (9.5 g, 95%)
  • Step d To a solution of 2-(tert-butoxycarbonylamino)acetic acid (Advanced Chemical, 3.9 g, 22.3 mmol) and Nl-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine
  • Step e To a solution of tert-butyl 2-(4-cyano-2-methoxyphenylamino)-2-oxoethylcarbamate (1.5 g, 4.9 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 1 h, then concentrated.
  • Step f To a mixture of 2-amino-N-(4-cyano-2-methoxyphenyl)acetamide trifluoroacetic acid (1.7 g, 5.4 mmol) in methyl tert-butyl ether (20 mL) was added triethylamine (0.78 mL, 5.7 mmol). The mixture was stirred at room temperature for 30 min.
  • the reaction mixture was stirred at 40 °C for 18 h.
  • the mixture was cooled to room temperature and filtered.
  • the rsulting precipitate was collected, washed with ethyl acetate, and dried to give the first batch of desired product.
  • the filtrate was concentrated, and the residue was purified by chromatography (5-10% EtOAc in dichlormethane) to give the second batch of desired product.
  • Step b To a solution of 3-methoxy-4-nitrophenol (1 g, 5.9 mmol) in anhydrous DMF (25 mL) were added K 2 C0 3 (2.45 g, 17.7 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.7 g, 7.1 mmol) sequentially. The reaction mixture was heated at 70 °C for 20 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgS0 4 , and concentrated.
  • Step c To a solution of tert-butyl-[2-(3-methoxy-4-nitro-phenoxy)-ethoxy]-dimethyl-silane (4 g, 12.2 mmol) in THF (50 mL) was added an aqueous HC1 solution (1 N, 20 mL, 20 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHC0 3 solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate.
  • Step e A suspension of 2-(3-methoxy-4-nitrophenoxy)ethyl acetate (2.4 g, 9.4 mmol) and Pd/C (Aldrich, 10%, 0.4 g) in ethyl acetate (30 mL) was vigorously shaken in a Parr under atmosphere of 3 ⁇ 4 (50 psi) for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give acetic acid 2-(4-amino-3-methoxy-phenoxy)-ethyl ester as a light brown oil (2 g, 94%).
  • Step f To a solution of 2-(tert-butoxycarbonylamino)acetic acid (Advanced Chemical, 2.57 g, 14.7 mmol) and EDCI (Aldrich, 2.81 g, 14.7 mmol) in dichloromethane (20 mL) was added 2- (4-amino-3-methoxy-phenoxy)-ethyl ester (2 g, 8.9 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated, and the residue was partitioned between dichloromethane and saturated aqueous NH 4 C1 solution . The organic layer was separated, and aqueous layer was extracted with dichloromethane twice.
  • 2-(tert-butoxycarbonylamino)acetic acid Advanced Chemical, 2.57 g, 14.7 mmol
  • EDCI Aldrich, 2.81 g, 14.7 mmol
  • 2- (4-amino-3-methoxy-phenoxy)-ethyl ester (2 g, 8.
  • Step g A solution of 2-(4-(2-(tert-butoxycarbonylamino)acetamido)-3-methoxyphenoxy)ethyl acetate (1 g, 2.6 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was then triturated with hexanes, concentrated, dried in vacuo to give 2-(4-(2-aminoacetamido)-3- methoxyphenoxy)ethyl acetate trifluoroacetic acid as an off white foam (0.8 g, 77%).
  • Step h To a mixture of 2-(4-(2-aminoacetamido)-3-methoxyphenoxy)ethyl acetate
  • N-(4-cyano-2-methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (Example 61, 0.24 g, 0.85 mmol) was added in one portion.
  • the reaction mixture was stirred at 40 °C for 1 h.
  • the mixture was cooled to room temperature and filtered through a short pad of silica gel.
  • the silica gel was washed with ethyl acetate. The filtrate was concentrated.
  • the reaction mixture was stirred at 40 °C for 24 h.
  • the mixture was cooled to room temperature and filtered.
  • the rsulting precipitate was collected, washed with ethyl acetate, and dried to give the first batch of desired product.
  • the filtrate was concentrated, and the residue was purified by chromatography (5-10% EtOAc in dichlormethane) to give the second batch of desired product.
  • Example 70 (Example 70, 0.28 g, 0.77 mmol) prepared in was added in one portion.
  • the reaction mixture was stirred at 40 °C for 3 h.
  • an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) was added, and the reaction mixture was stirred at 40 °C for 1 h.
  • the mixture was poured into water, and extracted with ethyl acetate three time. The combined extract was washed with water, brine, dried over MgS0 4 , and concentrated.
  • Step a To a solution of 2,5-dichlorothiophene (Aldrich, 21 g, 137 mmol) in concentrated H 2 S0 4 (59 niL) at 0 °C was added a fine powder form of NaN0 3 (28 g, 412 mmol) in one portion. The reaction mixture was stirred at 0 °C for 2 min when a brown fume began to appear. The reaction mixture was poured into the mixture of ice-water and ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgS0 4 , and concentrated. The residue was purified by chromatography (1% EtOAc in hexanes) to give 2,5-dichloro-3-nitrothiophene as a yellow oil (17 g, 63%).
  • Step b To a solution of tert-butyl ethyl malonate (Alfa, 16.2 g, 86 mmol) in anhydrous DMSO (50 mL) were added NaH (Aldrich, 60%, 5.15 g, 129 mmol). The mixture was heated at 100 °C for 1 h, the cooled to room temperature. 2,5-Dichloro-3-nitrothiophene (17 g, 86 mmol) was added in one portion. The reaction mixture was heated at 60 °C for 2 h. The mixture was cooled to room temperature, and water and dilute aqueous HCl solution were slowly added. The mixture was extracted with ethyl acetate twice times.
  • Step c To a solution of ethyl 2-(5-chloro-3-nitrothiophen-2-yl)acetate (10 g, 40 mmol) in methanol (200 mL) was added an aqueous solution (40 mL) of NH 4 C1 (17 g, 320 mmol), followed by activated Zinc (Aldrich, 15.7 g, 240 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered through a short pad of celite. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate.
  • Step d To a flask charged with ethyl 2-(3-amino-5-chlorothiophen-2-yl)acetate (6.7 g, 31 mmol) was added anhydrous toluene (30 mL). The mixture was evaporated to dryness. The process was repeated three times.
  • the reaction mixture was stirred at room temperature for 18 h.
  • the "pH" of the mixture was adjusted to 3-6 by aqueous HC1 solution.
  • the mixture was concentrated to a small volume, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice.
  • Example 98 136 mg, 0.71 mmol
  • HOBt 96 mg, 0.71 mmol
  • NH 4 C1 188 mg, 3.55 mmol
  • triethylamine 72 mg, 0.71 mmol
  • the reaction mixture was heated at 68 °C for 1 h.
  • the mixture was cooled to room temperature, then partitioned bewteen ethyl acetate and water.
  • the organic layer was separated, and aqueous layer was extracted with ethyl acetate twice.
  • the combined organic extract was washed with water, brine, dried over MgS0 4 , and
  • Example 100 (Example 100, 0.17 g) was separated by chiral SFC chromatography to provide chiral
  • N-(4-cyano-2- methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (Example 61, 0.23 g, 0.79 mmol) was added in one portion.
  • the reaction mixture was stirred at 40 °C for 1 h.
  • the mixture was cooled to room temperature and filtered through a short pad of silica gel.
  • the silica gel was washed with ethyl acetate. The filtrate was concentrated.
  • the reaction mixture was stirred at 40 °C for 66 h.
  • the mixture was cooled to room temperature and filtered through a short pad of silica gel.
  • the silica gel was washed with ethyl acetate. The filtrate was concentrated.
  • Example XI was reacted with anhydrous LiOH (14 mg, 0.585 mmol) and (E)-methyl 4-(2-(3,3- dimethylbutylideneamino)acetamido)-3-methoxybenzoate (329 mg, 1.03 mmol, Example 3) at 40 °C for 23 h to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methoxy-2- neopentyl-2'-oxo-1 ⁇ 2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate as a white solid (188 mg, 30%). MS (ES + ) m/z [(M+H) + ]: 625
  • Example 112 was reacted with anhydrous LiOH (17.5 mg, 0.73 mmol) and (E)-methyl 4-(2- (3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate (405 mg, 1.26 mmol, Example 3) at 40 °C for 23 h to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-hydroxy-2- neopentyl-2'-oxo-1 ⁇ 2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate as a white solid (253 mg, 32%).
  • Example 114 Example 114
  • the ability of the compounds to inhibit the interaction between p53 and MDM2 proteins was measured by an HTRF (homogeneous time-resolved fluorescence) assay in which recombinant GST-tagged MDM2 binds to a peptide that resembles the MDM2-interacting region of p53. Binding of GST-MDM2 protein and p53-peptide (biotinylated on its N-terminal end) is registered by the FRET (fluorescence resonance energy transfer) between Europium (Eu)-labeled anti-GST antibody and streptavidin-conjugated Allophycocyanin (APC).
  • FRET fluorescence resonance energy transfer
  • Test is performed in black flat-bottom 384-well plates (Costar) in a total volume of 40 uL containing:90 nM biotinylate peptide, 160 ng/ml GST-MDM2, 20 nM streptavidin-APC (PerkinElmerWallac), 2 nM Eu-labeled anti- GST- antibody (PerkinElmerWallac), 0.2% bovine serum albumin (BSA), 1 mM dithiothreitol (DTT) and 20 mM Tris-borate saline (TBS) buffer as follows: Add 10 uL of GST-MDM2 (640 ng/ml working solution) in reaction buffer to each well.
  • BSA bovine serum albumin
  • DTT dithiothreitol
  • TBS Tris-borate saline
  • Activity data for some of the Example compounds expressed as IC50: bsa: 0.02%' are as follows ampl Number IC50: bsa: 0.02%

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Abstract

There are provided compounds of the general formula (I) wherein A, B, V, W, R1, R2, R3, R3, and R4, are as described herein, enantiomers and pharmaceutically acceptable salts thereof, as well as methods for making said compounds and pharmaceutical compositions containing them. The present compounds are useful as anticancer agents, in particular as agents in the therapeutic and/or prophylactic treatment of solid tumors such as for example breast, colon, lung and prostate tumors.

Description

SUBSTITUTED HETEROARYL SPIROPYRROLIDINE MDM2 ANTAGONISTS
The present invention relates to heteroaryl spiropyrrolidine derivatives which act as inhibitors of MDM2-p53 interactions and are useful in the amelioration or treatment of cancer, in particular solid tumors. p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes. In addition, MDM2 mediates the ubiquitin- dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells. MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation.
The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the pl6INK4/pl9ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g.
antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells. The present invention relates to heteroaryl spiropyrrolidines of formula I which act as antagonists of MDM2 interactions and hence are useful as potent and selective anticancer agents.
In one embodiment, there are provided compounds of the formula
Figure imgf000004_0001
wherein in the case of (f) A is a bond;
R5 is selected from the group consisting of H, F, CI, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy;
R6 is selected from the group consisting of H, F, CI, methyl;
R7 is selected from the group consisting of H, F, CI, methyl;
R8 is selected from the group consisting of H, F, CI, methyl;
Ri and R2 are independently selected from the group consisting of lower alkyl,
substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl; R3 and R4 are selected from the group consisting of (CH2)n-R\ (CH2)n-NR'R", (CH2)n- NR'COR", (CH2)n-NR'S02R", (CH2)n-COOH, (CH2)n-COOR\ (CH2)n-CONR'R", (CH2)n-OR', (CH2)n-SR', (CH2)n-SOR', (CH2)n-S02R\ (CH2)n-COR', (CH2)n-S03H, (CH2)n-SONR'R", (CH2)n-S02NR'R", (CH2CH20)m-(CH2)n-R\ (CH2CH20)m-(CH2)n-OH, (CH2CH20)m-(CH2)n- OR', (CH2CH20)m-(CH2)n-NR'R", (CH2CH20)m-(CH2)n-NR'COR", (CH2CH20)m-(CH2)n- NR'S02R", (CH2CH20)m-(CH2)n-COOH, (CH2CH20)m-(CH2)n-COOR\ (CH2CH20)m-(CH2)n- CONR'R", (CH2CH20)m-(CH2)n-S02R', (CH2CH20)m-(CH2)n-COR', (CH2CH20)m-(CH2)n- SONR'R", (CH2CH20)m-(CH2)n-S02NR'R", (CH2)p-(CH2CH20)m-(CH2)n-R' , (CH2)P- (CH2CH20)m-(CH2)n-OH, (CH2)p-(CH2CH20)m-(CH2)n-OR' , (CH2)p-(CH2CH20)m-(CH2)n- NR'R", (CH2)p-(CH2CH20)m-(CH2)n-NR'COR", (CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", (CH2)p-(CH2CH20)m-(CH2)n-COOH, (CH2)p-(CH2CH20)m-(CH2)n-COOR' , (CH2)P- (CH2CH20)m-(CH2)n-CONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02R', (CH2)p-(CH2CH20)m- (CH2)n-COR', (CH2)p-(CH2CH20)m-(CH2)n-SONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COR', -SOR' and S02R'
wherein R' and R' ' are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, hetereoaryl, substituted hetereoaryl, hetereocycle or substituted hetereocycle or R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or
unsubstituted heterocycle;
m, n and p are independently 0 to 6; or
a pharmaceutically acceptable salt thereof. Another embodiment of the invention relates to compounds of formula I having a stereochemical structure shown as formula II
Figure imgf000005_0001
wherein
Figure imgf000006_0001
Figure imgf000006_0002
wherein in the case of (f) A is a bond;
R5 is selected from the group consisting of H, F, CI, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy;
R6 is selected from the group consisting of H, F, CI and methyl;
R7 is selected from the group consisting of H, F, CI and methyl;
R8 is selected from the group consisting of H, F, CI and methyl;
Ri and R2 are independently selected from the group consisting of lower alkyl,
substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R3 and R4 are selected from the group consisting of (CH2)n-R\ (CH2)n-NR'R", (CH2)n-
NR'COR", (CH2)n-NR'S02R", (CH2)n-COOH, (CH2)n-COOR\ (CH2)n-CONR'R", (CH2)n-OR\ (CH2)n-SR\ (CH2)n-SOR\ (CH2)n-S02R\ (CH2)n-COR\ (CH2)n-S03H, (CH2)n-SONR'R", (CH2)n-S02NR'R", (CH2CH20)m-(CH2)n-R', (CH2CH20)m-(CH2)n-OH, (CH2CH20)m-(CH2)n- OR', (CH2CH20)m-(CH2)n-NR'R", (CH2CH20)m-(CH2)n-NR'COR", (CH2CH20)m-(CH2)n- NR'S02R", (CH2CH20)m-(CH2)n-COOH, (CH2CH20)m-(CH2)n-COOR', (CH2CH20)m-(CH2)n- CONR'R", (CH2CH20)m-(CH2)n-S02R\ (CH2CH20)m-(CH2)n-COR', (CH2CH20)m-(CH2)n- SONR'R", (CH2CH20)m-(CH2)n-S02NR'R", (CH2)p-(CH2CH20)m-(CH2)n-R' , (CH2)P- (CH2CH20)m-(CH2)n-OH, (CH2)p-(CH2CH20)m-(CH2)n-OR' , (CH2)p-(CH2CH20)m-(CH2)n- NR'R", (CH2)p-(CH2CH20)m-(CH2)n-NR'COR", (CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", (CH2)p-(CH2CH20)m-(CH2)n-COOH, (CH2)p-(CH2CH20)m-(CH2)n-COOR', (CH2)P-
(CH2CH20)m-(CH2)n-CONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02R\ (CH2)p-(CH2CH20)m- (CH2)n-COR', (CH2)p-(CH2CH20)m-(CH2)n-SONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COR', -SOR' and S02R'
wherein R' and R' ' are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, hetereoaryl, substituted hetereoaryl, hetereocycle or substituted hetereocycle or R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or
unsubstituted heterocycle;
m, n and p are independently 0 to 6: or
a pharmaceutically acceptable salt thereof.
Preferred are compounds of Formula I, including compounds of Formula II, or a
pharmaceutically acceptable salt thereof wherein R5 is F, CI or Br.
Preferred are compounds of Formula I, including compounds of Formula II, or a
pharmaceutically acceptable salt thereof wherein R6 , R7i Rg are all hydrogen.
Preferred are compounds of Formula I, including compounds of Formula II, or a
pharmaceutically acceptable salt thereof wherein R2 is selected from the group consisting of aryl substitued with CI , F or Brand heteroaryl optionally substituted with H, F , CI or Br.
Preferred are compounds of Formula I, including compounds of Formula II, or a
pharmaceutically acceptable salt thereof wherein Ri is a substituted lower alkyl of the formula
Figure imgf000007_0001
where R9 and Rio are both methyl, or alternatively, R9 and Rio together with the carbon to which they are attached form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or
acyclohexyl ;
R11 is (CH2)q-Ri2, where q is 0, 1 or 2 and Ri2 is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle and substituted heterocycle.
Preferred are compounds of Formula I, including compounds of Formula II or a
pharmaceutically acceptable salt thereof wherein one of R3 and R4 is hydrogen, and the other (CH2)n-R\ n is 0 or 1 and R' is aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle. Preferred are compounds of Formula I, including compounds of Formula II, or a
pharmaceutically acceptable salt thereof, wherein
R5 is selected from F, CI or Br;
R6 , R7, R8 are hydrogen;
R2 is selected from the group consisting of aryl, aryl substitued with CI or F or Br, and heteroaryl optionally substituted with H, F , CI or Br;
Ri is a substituted lower alkyl of the formula
Figure imgf000008_0001
where R9 and Rio are both methyl, or alternatively, R9 and Rio together with the carbon to which they are attached form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl; R11 is (CH2)q-Ri2, where q is 0, 1 or 2;
R12 is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle and substituted heterocycle;
one of R3 and R4 is hydrogen, and the other is (CH2)n-R' ;
n is 0 or 1 ; and
R' is selected from aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle.
Further preferred are compounds of Formula II
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000009_0003
R5 is selected from F, CI or Br;
R6 , R7, Rg are hydrogen;
R2 is selected from the group consisting
Figure imgf000009_0004
wherein
Ri3 is F, CI or Br;
Ri4 is H or F;
Ri is a substituted lower alkyl of the formula
Figure imgf000010_0001
where R9 and Rio are both methyl, or alternatively, R9 and Rio together with the carbon to which they are attached form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl; R11 is (CH2)q-Ri2, where q is 0, 1 or 2;
R12 is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle and substituted heterocycle;
one of R3 and R4 is hydrogen, and the other is (CH2)n-R';
n is 0 or 1 ;
R' is selected from aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle; or
a pharmaceutically acceptable salt thereof.
Especially preferred are compounds of the formula
methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide;
methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate; rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid; rac-(2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide;
methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l,,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoate;
rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoic acid;
methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate; rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid; rac-(2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-carboxamide;
methyl rac-4-((2S ,3 S ,4S ,5R)-4-(3 -chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- Γ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide; methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate;
rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoic acid;
methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoate;
rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoic acid;
methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3R,4S,5R)-6,-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2,-oxo-l,,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]py acid; chiral methyl 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; chiral 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; chiral (2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide; methyl rac-4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; methyl rac-4-((2S,3S,4S,5R)-5'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-5'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; chiral methyl 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; chiral methyl 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; chiral 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; chiral (2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2-fluorophenyl)- 2-neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide; chiral 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; chiral (2R,3S,4R,5S)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2-fluorophenyl)- 2-neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide; chiral 4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]py acid; chiral 4-((2R,3R,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- di ydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; chiral methyl 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate;
chiral methyl 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate;
methyl rac-4-{ (2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate; rac-4- { (2S ,3S ,4R,5R)-6'-chloro-4-(3 -chlorophenyl)-2-neopentyl-2'-oxo- Γ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoic acid; rac-(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-N-(4-cyano-2-methoxyphenyl)- 2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide;
rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chlorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; methyl rac-4-{ (2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate; methyl rac-4-{ (2S,3R,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate; rac-4- { (2S ,3S ,4S ,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2-neopentyl-2'-oxo- Γ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoic acid; rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-N-(4-cyano-2-methoxyphenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; rac-2-(4-((2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxyphenoxy)ethyl acetate;
rac-(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]- 5-carboxamide; rac-(2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-
5-carboxamide;
chiral (2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]- 5-carboxamide;
methyl rac-4-((2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; rac-(2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2- neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]- 5-carboxamide; rac-(2S,3S,4S,5R)-6'-bromo-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; rac-(2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine] 5-carboxamide;
methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-fluoro-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-fluoro-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; rac-(2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-6'-fluoro-2- neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6'-fluoro-2- neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; rac-(2S,3S,4S,5R)- 4-(3-chloro-2-fluorophenyl)-N-[4-(2-hydroxyethoxy)-2-methoxyphenyl]-6'- fluoro-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5- carboxamide;
rac-(2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-[4-(2-hydroxyethoxy)-2- methoxyphenyl]-2-neopentyl-6'-oxo-6',7'-dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3- d] pyrimidine] - 5 -carboxamide ;
methyl rac-4-{ (2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6'-oxo-6',7'- dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoate; methyl rac-4-{ (2S,3S,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6'-oxo-6',7'- dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-m
rac-4-{(2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6'-oxo-6',7'- dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]py
acid;
rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-6'-oxo-6^7'-dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-carboxamide; methyl rac-4-((2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate; methyl rac-4-((2S,3S,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-{(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid; chiral 4-{(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid; rac-(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide;
chiral (2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2-fluorophenyl)- 2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide; rac-(2S,3S,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2- neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide;
rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide;
rac-(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- carboxamide,
chiral (2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- carboxamide,
methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methoxy-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methoxy-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid, methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-hydroxy-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-hydroxy-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid, rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6'-methoxy- 2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide, rac-2-(4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3- methoxyphenoxy)ethyl acetate,
rac-(2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]- 5-carboxamide,
methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid , rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide, methyl rac-4-((2S,3S,4S,5R)-7'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, rac-4-((2S,3S,4S,5R)-7'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid and
rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-carboxamide.
As used herein, the following terms shall have the following definitions. The term "alkyl" refers to straight- or branched-chain saturated hydrocarbon groups having from 1 to about 12 carbon atoms, including groups having from 1 to about 7 carbon atoms. In certain embodiments, alkyl substituents may be "lower" alkyl substituents. The term "lower alkyl" refers to alkyl groups having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.
The term "alkenyl" as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing at least one double bond and having 2 to 6, preferably 2 to 4 carbon atoms. In certain embodiments, alkenyl substituents may be "lower" alkenyl substituents. The term "lower alkenyl" refers to alkenyl groups having from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms. Examples of "alkenyl" are vinyl, ethenyl, allyl, isopropenyl, 1- propenyl, 2-methyl- l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-l-butenyl, 3-methyl-2- butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl.
"Alkoxy, alkoxyl or lower alkoxy" refers to any of the above "alkyl" or "lower alkyl" groups which is attached to the remainder of the molecule by an oxygen atom (RO-). Typical lower alkoxy groups include methoxy, ethoxy, isopropoxy or propoxy, butyloxy and the like. Further included within the meaning of alkoxy are multiple alkoxy side chains, e.g. ethoxy ethoxy, methoxy ethoxy, methoxy ethoxy ethoxy and the like and substituted alkoxy side chains, e.g., dimethylamino ethoxy, diethylamino ethoxy, dimethoxy-phosphoryl methoxy and the like. The term "alkynyl" as used herein means an unsaturated straight-chain or branched aliphatic hydrocarbon group containing one triple bond and having 2 to 6, preferably 2 to 4 carbon atoms. Examples of such "alkynyl group" are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3- butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl and 5-hexynyl.
"Amino" means the group -NH2.
"Aryl" means a monovalent, monocyclic or bicyclic, aromatic carboxylic hydrocarbon radical, preferably a 6-10 member aromatic ring system. Preferred aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl.
The term "cycloalkyl" as used herein means any stable monocyclic or polycyclic system which consists of carbon atoms only, any ring of which being saturated. Preferably, said cycloalkyl contains from 3 to 12, more preferably from 3 to 10, carbon atoms. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicycloalkyls, including bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds.
The term "cycloalkenyl" is intended to refer to any stable monocyclic or polycyclic system which consists of carbon atoms only, with at least one ring thereof being partially unsaturated. Preferably, said cycloalkenyl contains from 3 to 12, more preferably from 3 to 10, and especially preferred from 5 to 10 carbon atoms. Examples of cycloalkenyls include, but are not limited to, cyclopentenyl or cyclohexenyl.
The term "halogen" as used herein means fluorine, chlorine, bromine, or iodine, preferably fluorine and chlorine. "Heteroaryl" means an aryl as defined above wherein at least one carbon atom, preferably 1 to 4 carbon atoms, is/are replaced by a heteroatom independently selected from nitrogen, oxygen or sulfur. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazole substituted or unsubstituted triazolyl and substituted or unsubstituted tetrazolyl.
In the case of aryl or heteroaryl which are bicyclic it should be understood that one ring may be aryl while the other is heteroaryl and both being substituted or unsubstituted.
"Heteroatom" means an atom selected from N, O and S.
"Heterocycle" or "heterocyclic ring" means a substituted or unsubstituted 5 to 8 membered, mono- or bicyclic, non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms are replaced by a hetero atom selected from nitrogen, oxygen or sulfur atom. Examples include pyrrolidin-2-yl; pyrrolidin-3-yl; piperidinyl; morpholin-4-yl and the like which in turn can be substituted.
Hydroxy or hydroxyl is a prefix indicating the presence of a monovalent -OH group. "IC50" refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC50 can be measured, inter alia, as is described subsequently in the Example providing biological data. "Nitro" means -N02.
Oxo means the group =0.
"Pharmaceutically acceptable," such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
"Pharmaceutically acceptable ester" refers to a conventionally esterified compound of formula I having a carboxyl group, which esters retain the biological effectiveness and properties of the compounds of formula I and are cleaved in vivo (in the organism) to the corresponding active carboxylic acid. Information concerning esters and the use of esters for the delivery of pharmaceutical compounds is available in Design of Prodrugs. Bundgaard H ed. (Elsevier, 1985). See also, H. Ansel et ah, Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 108-109; Krogsgaard-Larsen, et ah, Textbook of Drug Design and Development (2d Ed. 1996) at pp. 152-191.
"Pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, trifluoro acetic acid and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., Ansel et ah , Pharmaceutical Dosage Forms and Drug Delivery Systems (1995) at pgs. 456-457.
"Substituted," as in substituted alkyl, means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution site are independently selected from the specified options. The term "optionally substituted" refers to the fact that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be, but does not necessarily have to be, substituted with another substituent. In the specification where indicated the various groups may be substituted by 1-5 or, preferably, 1-3 substituents independently selected from the group consisting of lower alkyl, lower-alkenyl, lower-alkynyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen, hydroxy, CN, CF3, NH2, N(H, lower-alkyl), N(lower-alkyl)2, aminocarbonyl, carboxy, N02, lower-alkoxy, thio-lower-alkoxy, lower-alkylsufonyl, amino sulfonyl, lower-alkylcarbonyl, lower- alkylcarbonyloxy, lower-alkoxycarbonyl, lower-alkyl-carbonyl-NH, fluoro-lower-alkyl, fluoro- lower-alkoxy, lower- alkoxy-carbonyl-lower-alkoxy, carboxy-lower-alkoxy, carbamoyl-lower- alkoxy, hydroxy-lower-alkoxy, NH2-lower-alkoxy, N(H, lower-alkyl)-lower-alkoxy, N(lower- alkyl)2-lower-alkoxy, lower-alkyl- 1 -oxiranyl-lower-alkoxy-lower- alkyl, 2-oxo-pyrrolidin- 1 -yl, (l, l-dioxo)-2-isothiazolidine, 3-lower-alkyl sulfinyl, a substituted or unsubstituted heterocyclic ring, a substituted or unsubstituted aryl ring, a substituted or unsubstituted heteroaryl ring, trifluoro-lower-alkylsulfonylamino-aryl, lower-alkyl sulfonylaminocarbonyl, lower-alkyl sulfonylaminocarbonyl-aryl, hydroxycarbamoyl-phenyl, benzyloxy-lower-alkoxy, mono- or di- lower alkyl substituted amino- sulfonyl and lower-alkyl which can optionally be substituted with halogen, hydroxy, NH2, N(H, lower-alkyl) or N(lower-alkyl)2.. Preferred substituents for the cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle rings are halogen, lower alkoxy, lower alkyl, hydroxycarbonyl, carboxy, carboxy lower alkoxy, oxo and CN. Preferred substituents for alkyl are alkoxy and N(lower alkyl)2.
The present compounds as well as their salts that have at least one asymmetric carbon atom may be present as racemic mixtures or different stereoisomers. The various isomers can be isolated by known separation methods, e.g., chromatography.
Compounds disclosed herein and covered by formula I and II above may exhibit tautomerism or structural isomerism. It is intended that the invention encompasses any tautomeric or structural isomeric form of these compounds, or mixtures of such forms, and is not limited to any one tautomeric or structural isomeric form depicted in the formulas above.
The compounds of the present invention, in particular compounds of formula (II), may be useful in the treatment or control of cell proliferative disorders, in particular oncological disorders, more particularly solid tumors, such as, for example, breast, colon, lung and prostate tumors.
Therefore, in a further embodiment of the present invention there are provided the present compounds, preferably the compounds of formula (II), for use as medicament, in particular for use as medicament in the treatment of solid tumors, preferably breast, colon, lung and prostate tumors.
In yet another embodiment, the present invention provides pharmaceutical preparations comprising the compounds according to the present invention, preferably the compounds of formula (II), together with a pharmaceutically acceptably carrier or excipient.
A "therapeutically effective amount" of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, as well as the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of a formula I compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, sachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste. Synthetic Methods
The present invention provides novel methods for the synthesis of heteroaryl spiropyrrolidines of formula I or II. Compounds of this invention can be synthesized according to the following general schemes. Suitable processes for synthesizing these compounds are provided in the examples.
An intermediate III can be made from a base-catalyzed condensation reaction of appropriately selected substituted 4- or 5- or 6- or 7-aza-2-oxindole I and appropriate substituted aldehyde II in methanol (Scheme 1). The choice of bases includes but is not limited to pyrrolidine or piperidine. The reaction generates III as a mixture of Z- and E-isomers with E-isomer as major product.
Scheme 1
Figure imgf000023_0001
m=0-3
Reagents and conditions: pyrrolidine or piperidine, MeOH, 50 °C, 3 h
Similarly, intermediates V or VII can be made from a acid-catalyzed condensation reaction of appropriately selected substituted 5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one IV or 4,6-dihydro- thieno[3,2-b]pyrrol-5-one VI and aldehyde II in hydrochloric and actic aicd (M. Cheung et al, Tetrahedron Lett. 2001, 42, 999) (Scheme 2).
Scheme 2
Figure imgf000023_0002
m is 0-2
Reagents and conditions: acetic acid and concentrated HC1, room temperature, 18 h; Preparation of starting material Via is described in Scheme 3 to exemplify the synthesis of intermediate VI in Scheme 2. 2,5-dichlorothiophene can be treated with sodium nitrate in concentrated sulfuric acid to give 2,5-dichlorothiphene-3-nitrothiophene. Nucleophilic substitution of 5-chloro group with tert-butyl ethyl malonate mono-sodium salt and treatment with trifluoroacetic acid lead to methyl 2-(5-chloro-3-nitrothiophen-2-yl)acetate
(WO2008132139). Reduction of nitro group with Zinc and ammonium chloride and cyclizing reaction to form amide promoted by trimathylaluminum afford intermediate Via (S. Hu, et al, J. Heterocyclic. Chem. 2005, 42, 661).
Scheme 3
Figure imgf000024_0001
Via
Reagents and conditions:
a) NaN03, cone, sulfuric acid, 0 °C, 3 min;
b) tert-butyl ethyl malonate, NaH, DMSO, 60 °C, 3 h;
c) TFA, CH2C12, room temperature, 18 h;
d) Zinc, NH4C1, MeOH/H20, room temperature, 1 h;
e) AlMe3, toluene, 0-10 °C, 0.5 h;
Racemic synthesis of compounds in formula I and II can be achieved as outlined in Scheme 4. Amine NHRsRj can be reacted with N-protected glycine like N-Boc glycine by using a coupling reagent like EDCI or HATU to give intermediate VIII. Intermediate VIII can be treated with trifluoroacetic acid or HC1 at room temperature to remove protective Boc group and give intermediate IX. Apropriatedly selected aldehyde RiCHO can react with IX to give the imine X. The cylcoaddition reaction between intermediates X and intermediate III or V or VII mediated by LiOH or LiCl/DABCO gives a racemic and diastereomeric mixture of compounds XI in formula I together with other isomers. Compounds XI can be purified by flash chromatography followed by chiral separation by chiral Super Fluid Chromatography (SFC) or chiral HPLC to give oprically pure or enriched chiral compounds XII in formula II.
Scheme 4
Figure imgf000025_0001
X III or V or VII XI XII
Reagents and conditions:
a. EDCI, or HATU/iPr2NEt, CH2C12 , rt, 4 h;
b. TFA or HC1, CH2C12, rt, 1 h;
c. NEt3, tert-butyl methyl ether, rt, 18 h
d. LiOH, 40 °C, 24 h;
e. Flash chromatography and Chiral SFC separation
Similarly, compounds in formula I and II can be prepared as outlined in Scheme 5. Intermediate III or V or VII can be protected with Boc group to give intermediate XIII. The cylcoaddition reaction between intermediates X and XIII mediated by LiOH or LiCl/DABCO follow by reaction to remove Boc group by trfluroacetic aicd give compounds XI in formula I. Compounds XI can be subsequently separated into oprically pure or enriched chiral compounds XII in formula II.
Scheme 5
Figure imgf000026_0001
XIII
Reagents and conditions:
a. Boc20, DAMP, CH2C12 , rt, 3 h;
b. LiOH, 40 °C, 24 h;
c. TFA, CH2C12, rt, 1 h;
e. Flash chromatography and Chiral SFC separation
Alternative synthesis of compounds Xlla in formula II can be achieved. As illustrated in
Scheme 6, selected aldehyde RiCHO can be reacted with glycine tert-butyl ester to generate imine XIV. The racemic mixture of intermediate XV and XV can be made from intermediates XIV and VII by LiOH mediated cyclization reaction. The mixture of XVI and XVI' can be subsequently converted to a racemic mixture of acid XVII and XVII' by using trifluoroacetic acid. Amide formation with various amine
Figure imgf000026_0002
by using diphenylphsphinic chloride as the coupling reagent can lead to the racemic mixture of compounds Xlla and Xlla' in formula II. Finally chiral separation by chiral Super Fluid Chromatography (SFC) or chiral HPLC gives oprically pure or enriched chiral compounds Xlla in formula II.
Scheme 6
Figure imgf000027_0001
Reagents and conditions:
a. CH2C12 , rt, 4 h;
b. LiOH, 40 °C, 24 h;
c. TFA or HC1, CH2C1,, rt, 18 h;
d. NHR3R4, iPr2NEt, Ph2P(=0)Cl, CH2C12, rt, 18 h; e. Chiral SFC separation
Examples
The compounds of the present invention may be synthesized according to novel techniques. The following examples and references are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims.
Example 1
Preparation of intermediate (E -methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)benzoate
Figure imgf000028_0001
M. W. 290.37 C16H22N2O3
Step a: A mixture of methyl 4-aminobenzoate (Aldrich, 5.00 g, 32.4 mmol), tert- butoxycarbonylamino-acetic acid (9.44 g, 53.4 mmol, Aldrich) and l-(3-dimetgylaminopropyl)-
3- ethylcarbodiimide hydrochloride (Chem-Impex, 10.16 g, 53.1 mmol) in CH2CI2 (60 mL) was stirred vigorously at rt for 2 h. The reaction mixture was then concentrated in vacuum and the residue was dissolved in EtOAc (150 mL), washed successively with water (120 mL), sat. NH4C1 (20 mL), sat. NaHC03 (50 mL), water (50 mL) and brine (20 mL), dried over Na2S04 and concentrated in vacuum. The white solid was further dried in vacuum overnight to give methyl
4- (2-(tert-butoxycarbonylamino)acetamido)- benzoate (11.28 g). Step b: A solution of methyl 4-(2-(tert-butoxycarbonylamino)acetamido)-benzoate (5.25 g, 17.0 mmol) in CH2CI2 (40 mL) at 0 C was treated with TFA (20 mL) and the mixture was stirred at rt for 4 h. The solvent was then removed under reduced pressure. The residue was further dried in vacuum overnight to give methyl 4-(2-aminoacetamido)benzoate as a TFA salt (5.82 g, 99%). Step c: To a suspension of the above methyl 4-(2-aminoacetamido)benzoate TFA salt (4.95 g, 15.4 mmol) in t-butyl methyl ether (160 mL) at rt was added TRIETHYLAMINE (1.74 g, 2.40 ml, 17.2 mmol) and the mixture was stirred for 30 min. 3,3-Dimethylbutanal (1.69 g, 16.9 mmol) in t-butyl methyl ether (5 mL) was added and the reaction mixture was allowed to stir at rt overnight. t-Butyl methyl ether (100 mL) was added and stirred for 20 min. The solid was filtrated off and the filtrate was washed with water, brine, dried over Na2S04 and concentrated to give (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-benzoate as a white solid (3.25 g, 72%). MS (ES+) m/z [(M+H)+]: 291
Example 2
Preparation of intermediate 4-{2-[3,3-Dimethyl-but-(E)-ylideneamino]-acetylamino}-2- methoxybenzoic acid methyl ester
Figure imgf000029_0001
M. W. 320.39 Ci7H24N204
To a suspension of methyl 4-(2-aminoacetamido)-2-methoxybenzoate hydrochloride (prepared in a similar manner as described in Example 1 (0.50 g, 1.82 mmol) in t-butyl methyl ether (8 mL) at rt, was added triethylamine (203 mg, 2.01 mmol) and the mixture was stirred for 30 min. 3,3- Dimethylbutanal (0.24g, 0.30 mL, 2.27 mmol, Aldrich) in t-butyl methyl ether (2 mL) was added and the reaction mixture was allowed to stir at rt overnight. t-Butyl methyl ether (50 mL) was added and stirred for 20 min. The solid was filtrated off and the filtrate was washed with water, brine, dried over Na2S04 and concentrated to give 4-{2-[3,3-dimethyl-but-(E)-ylideneamino]- acetylamino}-2-methoxybenzoic acid methyl ester as a white solid (353 mg, 60%). MS (ES+) m/z [(M+H)+]: 320
Example 3
Preparation of intermediate (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3- methoxybenzoate
Figure imgf000029_0002
M. W. 320.39 Ci7H24N204
(E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate was prepared in a manner similar to the method described in Example 1. MS (ES+) m/z [(M+H)+]: 320 Example 4
Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-l,3-dihydro- pyrrolo[3,2c]pyridin-2-one
Figure imgf000030_0001
M. W. 274.68 Ci4H8ClFN20
To a suspension of lH-pyrrolo[3,2-c]pyridin-2(3H)-one (1.00 g, 7.46 mmol, prepared according to the method described in J. Org. Chem, 1991, 56, 4805-4808) in MeOH (55 mL) in a 100-mL round-bottomed flask, was added 3-chloro-2-fluorobenzaldehyde (Oakwood Products, 3.55 g, 22.40 mmol), giving a clear solution. Piperidine (Lancaster, 2.66 g, 31.20 mmol) was added slowly. After stirred for 10 min, the reaction mixture was heated at 50 °C for 3 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-l,3- dihydro-pyrrolo[3,2-c]pyridin-2-one as a light yellow crystalline solid (1.38 g, 67%). MS (ES+) m/z [(M+H)+]: 275
Example 5
Preparation of intermediate rac-(2S,3S,4S,5R)-tert-butyl 4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro rrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxylate
Figure imgf000030_0002
M. W. 488.01 C26H3iClFN303
Step a: To a solution of tert-butyl 2-aminoacetate (Aldrich, 1.00 g, 7.62 mmol) in CH2C12 (30 mL) was added 3,3-dimethylbutanal (Aldrich, 1.00 g, 9.98 mmol). The mixture was stirred at rt for 4 h. Water added and organic layer separated. The aqueous layer was extracted with CH2CI2. The combined organic extracts were washed with water and concentrated to give (E)-tert-butyl 2-(3,3-dimethylbutylideneamino)acetate as a colorless oil (1.52 g, 93%). Step b: A suspension of 3-(3-chloro-2-fluorobenzylidene)-lH-pyrrolo[3,2-c]pyridin-2(3H)-one (60 mg, 0.218 mmol, Example 4) in CH2CI2 (8 mL) was treated with triethylamine (133 mg, 1.31 mmol). (E)-tert-butyl 2-(3,3-dimethylbutylideneamino)acetate (69 mg, 0.325 mmol) was added followed by silver(I) fluoride (Aldrich, 47 mg, 0.370 mmol) and the mixture was stirred at rt for for 24 h. The reaction mixture was partition between EtOAc and water, washed with brine and dried over Na2S04 and concentrated to dryness. The residue was dissolved in t-BuOH (8 mL) and 2,3,4,6,7, 8, 9, 10-octahydropyrimido[l,2-a]azepine (DBU) (Aldrich, 266 mg, 1.75 mmol) and heated at 120 C for 2 h. The reaction mixture was then cooled to rt and partitioned between EtOAc and water, washed with water, brine and concentrated. The crude material was purified by flash chromatography (EtOAc/CH2Cl2: 5/95 to 40/60) to give rac-(2S,3S,4S,5R)-tert-butyl 4- (3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- c]pyridine]-5-carboxylate (10.2 mg, 8.6%) as a white solid. MS (ES+) m/z [(M+H)+]: 488
Example 6
Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate
Figure imgf000031_0001
M. W.595.08 C3iH32ClFN405
To a suspension of 3-(3-chloro-2-fluorobenzylidene)-lH-pyrrolo[3,2-c]pyridin-2(3H)-one (450 mg, 1.64 mmol, Example 4) in anhydrous THF (25 mL) at 40 °C, was added anhydrous LiOH (19 mg, 0.82 mmol) and the suspension was stirred at 40 °C for 10 min before (E)-methyl 4-(2- (3,3-dimethylbutylideneamino)-acetamido)-3-methoxybenzoate (551 mg, 1.72 mmol, Example 3) was added in one portion. The reaction mixture was allowed to stir at 40 °C for 23 h. The mixture was diluted with EtOAc (100 mL), washed with water (2x20 mL) and concentrated to a small volume. MeOH was added slowly (-15 mL) and the mixture was stirred in cold bath for 20 min. The resulting precipitate was filtered, washed with cold MeOH and dried in vacuum overnight to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white powder (556 mg, 56%). MS (ES+) m/z [(M+H)+]: 595
Example 7
Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid
Figure imgf000032_0001
M. W. 581.05 C3oH3oClFN405
To a solution of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (151 mg, 0.254 mmol, Example 6) in THF (8 mL) was added a solution of LiOH hydrate (63 mg, 1.50 mmol) in water (4 mL). The reaction mixture was stirred at rt for 20 h before it was treated with IN HC1 to silghtly acidic. The mixture was partitioned between CH2CI2 (30 mL) and water (10 mL), extracted with CH2CI2 (3x30 mL). The combined organic extracts were washed with water, dried over Na2S04, concentrated and lyophized to give rac-4-((2S,3R,4S,5R)-4-(3-chloro- 2-fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]- 5-ylcarboxamido)-3-methoxybenzoic acid as a white powder (145 mg, 95%). MS (ES+) m/z
[(M+H)+]: 581
Example 8
Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- carboxamide
Figure imgf000033_0001
M. W. 580.06 C3oH3iClFN504
A mixture of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- Γ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxyb acid (51 mg, 0.087 mmol, Example 7) and 1,1 -carbonyldiimidazole (Aldrich, 28 mg, 0.174 mmol) in THF (3 mL) was stirred at rt for 17 h. Ammonium hydroxide (180 mg, 5.14 mmol) was added and the mixture was stirred for 20 min. The mixture was partitioned between EtOAc (75 mL) and water (10 mL), washed with sat. NaHC03 (10 mL), water (10 mL) then sat. NH4C1 (10 mL). The organic layer was dried over Na2S04 and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography (ethanol/ CH2C12, 0.5/99.5 to 3/97) to give rac- (2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (25 mg, 50%). MS (ES+) m z [(M+H)+]: 580
Example 9
Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2- methoxybenzoate
Figure imgf000033_0002
M. W. 595.08 C3iH32ClFN405
To a solution of E/Z-(E)-3-(3-chloro-2-fluorobenzylidene)-lH-pyrrolo[3,2-c]pyridin-2(3H)-one (173 mg, 0.63 mmol, Example 4) in anhydrous THF (12 mL) was added anhydrous LiOH (11 mg, 0.43 mmol) and the mixture was stirred at 40 °C for 10 min. (E)-methyl 4-(2-(3,3- dimethylbutylideneamino)acetamido)-2-methoxybenzoate (220 mg, 0.68 mmol, Example 2) was added in one portion. The reaction mixture was allowed to stir at 40 °C overnight, giving a clear reaction mixture. This mixture was diluted with EtOAc and washed with water, brine and dried over Na2S04 and concentrated. The crude product was purified on flash chromatography (EtOAc/CH2Cl2, 3/97 to 60/40) to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5- ylcarboxamido)-2-methoxybenzoate as a white solid (119 mg, 32%). MS (ES+) m/z [(M+H)+]: 595
Example 10
Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- Γ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid
Figure imgf000034_0001
M. W. 581.05 C3oH30ClFN405
To a suspension of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2- methoxybenzoate (107 mg, 0.181 mmol, Example 9) in THF (10 mL) was added a solution of LiOH hydrate (61 mg, 1.47 mmol) in water (5 mL). The reaction mixture was stirred at rt overnight until the reaction was complete. The reaction mixture was then treated with IN HCl to slightly acidic, diluted with ethyl acetate (100 mL), washed with water (10 mL), dried with Na2S04 and concentrated to give rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrr^
2-methoxybenzoic acid as a white solid (89 mg, 85%). MS (ES+) m/z [(M+H)+]: 581
Example 11
Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- carboxamide
Figure imgf000035_0001
M. W. 580.06 C3oH3iClFN504
A mixture of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)- 2-methoxybenzoic acid (30 mg, 0.052 mmol, Example 10) and 1,1 -carbonyldiimidazole (Aldrich, 37 mg, 0.22 mmol) in THF (3 mL) was stirred at rt for 17 hr. Ammonium hydroxide (180 mg, 5.14 mmol) was added and the mixture was stirred for 20 min. The mixture was partitioned between EtOAc (75 mL) and water (10 mL), washed with sat. NaHC03 (10 mL), water (10 mL) then sat. NH4C1 (10 mL). The organic layer was dried over Na2S04 and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography (ethanol/CH2Cl2, 0.5/99.5 to 3/97) to give rac- (2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (27 mg, 89%). MS (ES+) m/z [(M+H)+]: 580 Example 12
Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-l,3-dihydro- pyrrolo[2,3b]pyridin-2-one
Figure imgf000036_0001
M. W. 274.68 Ci4H8ClFN20
To a suspension of lH-pyrrolo[2,3-b]pyridin-2(3H)-one (Chemgenx, 926 mg, 6.91 mmol) in MeOH (55 mL), was added 3-chloro-2-fluorobenzaldehyde (Oakwood Products, 3.29 g, 20.70 mmol). Piperidine (Lancaster, 2.41 g, 2.8 mL, 28.30 mmol) was added slowly. After stirring a few minutes, the reaction mixture was heated at 50 °C for 3 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[2,3- b]pyridin-2-one as a light yellow crystalline solid (1.18 g, 62%). MS (ES+) m/z [(M+H)+]: 275 Example 13
Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000036_0002
M. W. 595.08 C3iH32ClFN405 To a suspension of E/Z-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[2,3-b]pyridin-2- one (401 mg, 1.46 mmol, Example 12) in anhydrous THF (25 mL) at 40 °C was added anhydrous LiOH (17 mg, 0.73 mmol) and the suspension was stirred at 40 °C for 10 min before (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate (490 mg, 1.53 mmol, Example 3) was added in one portion. The reaction mixture was allowed to stir at 40 °C for 23 h. The mixture was diluted with EtOAc, washed with water and concentrated to a small volume. MeOH was added slowly (-15 mL) and the mixture was stirred in cold bath for -20 min. The resulting precipitate was filtered, washed with cold MeOH and dried overnight in vacuum to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (543 mg, 62%). MS (ES+) m/z [(M+H)+]: 595
Example 14
Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid
Figure imgf000037_0001
M. W. 581.05 C3oH3oClFN405
To a solution of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate (154 mg, 0.26 mmol, Example 13) in THF (8 mL) was added a solution of LiOH hydrate (77 mg, 1.84 mmol) in water (4 mL). The reaction mixture was stirred at rt for 20 h before it was treated with IN HC1 to slightly acidic. The mixture was partitioned between CH2CI2 (30 mL) and water (10 ml), extracted with CH2CI2. The combined organic extracts were washed with water, dried over Na2S04, concentrated and lyophized to give rac-4-
((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine- 3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (150 mg, 97%). MS (ES+) m/z [(M+H)+]: 581
Example 15
Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoate
Figure imgf000038_0001
M. W. 565.03 C3oH3oClFN404
To a suspension of 3-(3-chloro-2-fluorobenzylidene)-lH-pyrrolo[2,3-b]pyridin-2(3H)-one (102 mg, 0.372 mmol, Example 12) in anhydrous THF (25 mL) at 40 °C was added hydrous LiOH (5 mg, 0.21 mmol) and the suspension was stirred at 40 °C for 10 min before (E)-methyl 4-(2-(3,3- dimethylbutylideneamino)acetamido)benzoate (114 mg, 0.391 mmol, Example 1) was added in one portion. The reaction mixture was allowed to stir at 40 °C for 23 h. The mixture was diluted with EtOAc (100 mL) and washed with water (2x20 mL), concentrated to a small volume (~5 mL). MeOH was added (2 mL) and the solution was stirred in cold bath until precipitate started to form. The precipitate was filtered and washed with cold MeOH, dried overnight in vacuum to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoate as (47.6 mg, 23%) a white powder. MS (ES+) m/z [(M+H)+]: 565.
Example 16
Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoic acid
Figure imgf000039_0001
M. W. 551.01 C29H28C1FN404
To a solution of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoate (45 mg, 0.079 mmol, Example 15) in THF (4 mL) was added a solution of LiOH hydrate (23 mg, 0.55 mmol) in water (2 mL). The reaction mixture was stirred at rt for 24 hrs before it was treated with IN HCl to slightly acidic. The mixture was partitioned between water (10 mL) and CH2C12 (30 mL), extracted with CH2C12. The combined organic extracts were washed with water, dried over Na2S04, concentrated and lyophized to give rac-4-((2S,3R,4S,5R)-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5- ylcarboxamido)benzoic acid as a white solid (25 mg, 59%). MS (ES+) m/z [(M+H)+]: 551
Example 17
Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2- methoxybenzoate
Figure imgf000039_0002
M. W. 595.08 C3iH32ClFN405 To a solution of E/Z-3-(3-chloro-2-fluorobenzylidene)-lH-pyrrolo[2,3-b]pyridin-2(3H)-one (99 mg, 0.36 mmol, Example 12) in anhydrous THF (9 mL) was added anhydrous LiOH (6 mg, 0.26 mmol) and the mixture was stirred at 40 °C for 10 min. (E)-Methyl 4-(2-(3,3- dimethylbutylideneamino)acetamido)-2-methoxybenzoate (123 mg, 0.385 mmol, Example 2) was added in one portion. The reaction mixture was allowed to stir at 40 °C overnight, giving a clear reaction mixture. This mixture was diluted with EtOAc (100 mL) and washed with water, brine and dried over Na2S04 and concentrated. The crude product was purified by flash chromatography (EtOAc/CH2Cl2, 3/97 to 60/40) to give methyl rac-4-((2S,3R,4S,5R)-4-(3- chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3- b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate as a white solid (128 mg, 60%). MS (ES+) m/z [(M+H)+]: 595
Example 18
Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- Γ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b] ridine]-5-ylcarboxamido)-2-methoxybenzoic acid
Figure imgf000040_0001
M. W. 581.05 C3oH3oClFN405
To a suspension of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2- methoxybenzoate (116 mg, 0.196 mmol, Example 17) in THF (10 mL) was added a solution of LiOH hydrate (66 mg, 1.57 mmol) in water (5 mL). The reaction mixture was stirred at rt overnight and was then treated with IN HC1 to slightly acidic, diluted with ethyl acetate (100 mL), washed with water (10 mL), dried with Na2S04 and concentrated to give rac-4- ((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'-dihydrospiro[pyrrolidine- 3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid as a white solid (103 mg, 91%). MS (ES+) m/z [(M+H)+]: 581 Example 19
Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5- carboxamide
Figure imgf000041_0001
M. W. 580.06 C3oH3iClFN504
A mixture of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid (29 mg, 0.051 mmol, Example 18) and 1,1 -carbonyldiimidazole (Aldrich, 35 mg, 0.217 mmol) in THF (3 mL) was stirred at rt for 17 h. Ammonium hydroxide (180 mg, 5.14 mmol) was added and the mixture was stirred for 20 min. The mixture was partitioned between EtOAc (75 mL) and water (10 mL), washed with sat. NaHC03 (10 mL), water (10 mL) then sat. NH4C1 (10 mL). The organic layer was dried over Na2S04 and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography (ethanol/CH2Cl2, 0.5/99.5 to 5/95) to give rac- (2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-carboxamide as a white solid (23 mg, 78%). MS (ES+) m/z [(M+H)+]: 580
Example 20
Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-l,3-dihydro- pyrrolo[3,2-b]pyridin-2-one
Figure imgf000042_0001
M. W. 274.68 Ci4H8ClFN20
To a suspension of lH-pyrrolo[3,2-b]pyridin-2(3H)-one (Sinova. 933 mg, 6.96 mmol) in MeOH (35 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 3.58 g, 22.6 mmol) giving a clear solution. Piperidine (Lancaster, 2.58 g, 30.30 mmol) was added slowly. After stirred for a few minutes, the reaction mixture was heated at 50 °C for 3 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[3,2-b]pyridin-2- one as a light yellow crystalline solid (1.22 g, 64%). MS (ES+) m/z [(M+H)+]: 275 Example 21
Preparation of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000042_0002
M. W. 595.08 C3iH32ClFN405 To a solution of E/Z-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 20, 301 mg, 1.10 mmol) in anhydrous THF (22 mL) at 40 °C was added anhydrous LiOH (13 mg, 0.54 mmol) and the mixture was stirred at 40 °C for 10 min before (E)-methyl 4- (2-(3,3-dimethylbutylideneamino)-acetamido)-3-methoxybenzoate (Example 3, 367 mg, 1.15 mmol) was added in one portion. The reaction mixture was allowed to stir at 40 °C for 20 h, giving a white precipitate. The resulting precipitate was filtered, washed with cold MeOH and dried overnight in vacuum to give methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate as a white solid (242 mg, 37%). MS (ES+) m/z [(M+H)+]: 595
Example 22
Preparation of rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid
Figure imgf000043_0001
M. W. 581.05 C3oH3oClFN405
To a suspension of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate (Example 21, 124 mg, 0.21 mmol) in THF (8 mL) was added a solution of LiOH hydrate (69 mg, 1.66 mmol) in water (4 mL). The reaction mixture was stirred at 40 °C for 24 h until the reaction was complete. The reaction mixture was treated with IN HC1 to slightly acidic and the precipitate was filtered and washed with cold MeOH and dried overnight to give rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- diJiydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (114 mg, 94%). MS (ES+) m/z [(M+H)+]: 581 Example 23
Preparation of intermediate E/Z-6-Chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro- pyrrolo[3,2-c]pyridin-2-one
Figure imgf000044_0001
M. W. 309.13 Ci4H7Cl2FN20
To a suspension of 6-chloro-lH-pyrrolo[3,2-c]pyridin-2(3H)-one (Sinova, 689 mg, 4.09 mmol) in MeOH (50 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 1.89 g, 11.9 mmol). Piperidine (1.46 g, 17.2 mmol) was added slowly, giving a clear brown solution. After stirred for a few minutes, the reaction mixture was heated at 50 °C for 5 h, resulting in a yellow
precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3- dihydro-pyrrolo[3,2-c]pyridin-2-one as a light brown solid (1.07 g, 85%). MS (ES+) m/z
[(M+H)+]: 309
Example 24
Preparation of methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-
2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000044_0002
M. W. 629.52 C3iH3iCl2FN405 A suspension of E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[3,2- c]pyridin-2-one (Example 23, 240 mg, 0.78 mmol) in anhydrous THF (25 mL) was mildly warmed to a clear solution and then cooled down to 40 °C. Anhydrous LiOH (8.7 mg, 0.367 mmol) was added and the mixture was stirred at 40 °C for 10 min. (E)-methyl 4-(2-(3,3- dimethylbutylideneamino)-acetamido)-3-methoxybenzoate (Example 3, 235 mg, 0.733 mmol) was added in one portion. The reaction mixture was allowed to stir at 40 °C for 20 h, giving a clear reaction mixture. This mixture was diluted with EtOAc (100 mL) and washed with water, brine and dried over Na2S04 and concentrated. The crude product was purified on flash chromatography (THF/hexane, 5/95 to 50/50) to give methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4- (3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (210 mg, 45%). MS (ES+) m/z [(M+H)+]: 629
Example 25
Preparation of rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid
Figure imgf000045_0001
M. W. 615.49 C3oH29Cl2FN405
To a suspension of methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate (Example 24, 48 mg, 0.076 mmol) in THF (4 mL) was added a solution of liOH hydrate (25 mg, 0.60 mmol) in water (2 mL) and the reaction mixture was stirred at rt overnight. The mixture was treated with IN HC1 to slightly acidic, diluted with ethyl acetate (200 mL), washed with water (15 mL), dried with Na2S04 and concentrated to give rac-4- ((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- di ydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-met^^ acid as a white solid (38 mg, 82%). MS (ES+) m/z [(M+H)+]: 615
Example 26
Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- carboxamide
Figure imgf000046_0001
M. W. 614.51 C3oH3oCl2FN504
A mixture of rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- 1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (Example 25, 19 mg, 0.031 mmol), N,N-diisopropylethylamine (30 mg, 0.23 mmol) and O- (7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (Chem- Impex, 22 mg, 0.057 mmol) in DMF (4 mL) was stirred for 2 min before a solution of ammonia in isopropanol (Aldrich, 2 M, 0.08 mL, 0.16 mmol) was added. The mixture was stirred for 0.5 h and poured into EtOAc (70 mL), washed with water (10 mL), brine (15 mL) and concentrated. The crude product was purified by flash chromatography (EtOH/CH2Ci2, 0.5/99.5 to 5/95) to give rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- carboxamide as a white solid (7.6 mg, 37%). MS (ES+) m/z [(M+H)+]: 614
Example 27
Preparation of methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate
Figure imgf000047_0001
M. W. 599.49 C3oH29Cl2FN404
A suspension of E/Z-6-chloro-3-(3-chloro-2-fluorobenzylidene)-lH-pyrrolo[3,2-c]pyridin- 2(3H)-one (Example 23, 258 mg, 0.83 mmol) in anhydrous THF (20 mL) was warmed to a clear solution and then cooled down to 40 °C. Anhydrous LiOH (10 mg, 0.42 mmol) was added and the mixture was stirred at 40 °C for 10 min. (E)-Methyl 4-(2-(3,3- dimethylbutylideneamino)acetamido)benzoate (Example 1, 247 mg, 0.85 mmol) was added in one portion. The reaction mixture was allowed to stir at 40 °C for 20 h, giving a clear reaction mixture. This mixture was diluted with EtOAc (100 mL) and washed with water, brine and dried over Na2S04 and concentrated. The crude product was purified on flash chromatography (THF/hexane, 5/95 to 50/50) to give methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- ylcarboxamido)benzoate as a white solid (148 mg, 29%). MS (ES+) m/z [(M+H)+]: 599
Example 28
Preparation of rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- 1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoic acid
Figure imgf000047_0002
M. W. 585.47 C29H27C12FN404 To a suspension of methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- ylcarboxamido)benzoate (Example 27, 22 mg, 0.036 mmol) in THF (4 mL) was added a solution of LiOH hydrate (25 mg, 0.61 mmol) in water (2 mL) and the reaction mixture was stirred at rt overnight. The reaction mixture was treated with IN HC1 to slightly acidic, diluted with ethyl acetate (100 mL), washed with water (15 mL), dried with Na2S04 and concentrated to give rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoic acid as a white solid (20 mg, 93%). MS (ES+) m/z [(M+H)+]: 585
Example 29
Preparation of intermediate E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-methyl-l,3-dihydro- pyrrolo[3,2-b]pyridin-2-one
Figure imgf000048_0001
M. W. 288.71 Ci5Hi0ClFN2O
To a suspension of 6-methyl-lH-pyrrolo[3,2-b]pyridin-2(3H)-one (Sinova, 500 mg, 3.37 mmol) in MeOH (20 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 1.60 g, 10.1 mmol) giving a clear solution. Piperidine (Lancaster, 1.2 g, 14.1 mmol) was added slowly. After stirred for a few minutes, the reaction mixture was heated at 50 °C for 4 h, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-methyl-l,3- dihydro-pyrrolo[3,2-b]pyridin-2-one as a light yellow crystalline solid (946 mg, 97%). MS (ES+) m/z [(M+H)+]: 289 Example 30
Preparation of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-
2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000049_0001
M. W. 609.09 C32H34C1FN405
To a suspension of E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-methyl-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 29, 300 mg, 1.04 mmol) in anhydrous THF (20 mL) at 40 °C was added anhydrous LiOH (13 mg, 0.55 mmol) and the mixture was stirred at 40 °C for 10 min before (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate
(Example 3, 364 mg, 1.14 mmol) was added in one portion. The reaction mixture was allowed to stir at 40 °C for 23 h, giving a white precipitate. The resulting precipitate was filtered, washed with cold THF and dried overnight in vacuum to give methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro- 2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (305 mg, 48%). MS (ES+) m/z [(M+H)+]: 609
Example 31
Preparation of rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo- 1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid
Figure imgf000049_0002
M. W. 595.06 C3iH32ClFN405
To a suspension of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate (Example 30, 288.8 mg, 0.474 mmol) in THF (16 mL) was added a solution of LiOH hydrate (159 mg, 3.79 mmol) in water (8 mL). The reaction mixture was heated at 45 °C for 22 h. After cooled to rt, the mixture was treated with IN HC1 to slightly acidic. The resulting precipitate was filtered, washed with cold water and then THF, dried overnight to give rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (265 mg, 94%). MS (ES+) m/z [(M+H)+]: 595
Example 32
Preparation of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl- 2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoate
Figure imgf000050_0001
M. W. 579.06 C3iH32ClFN404
To a suspension of E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-methyl-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 29, 201 mg, 0.69 mmol) in anhydrous THF (15 mL) at 40 °C was added LiOH (9.5 mg, 0.397 mmol) and the mixture was stirred at 40 °C for 10 min before methyl 4-(2-(3,3-dimethylbutylideneamino)-acetamido)benzoate (Example 1, 215 mg, 0.740 mmol) was added in one portion. The reaction mixture was allowed to stir at 40 °C for 21 h, giving a white precipitate. The resulting precipitate was filtered, washed with cold THF and dried overnight in vacuum to give methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2- neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5- ylcarboxamido)benzoate as a white solid (135 mg, 33%). MS (ES+) m/z [(M+H)+]: 579
Example 33
Preparation of rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'- 1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoic acid
Figure imgf000051_0001
M. W. 565.03 C3oH3oClFN404
To a suspension of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2- neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5- ylcarboxamido)benzoate (Example 32, 109 mg, 0.19 mmol) in THF (12 mL) was added a solution of LiOH hydrate (63 mg, 1.51 mmol) in water (6 mL). The suspension was warmed at 45 °C for 20 h. After cooled to rt, the mixture was treated with IN HC1 to slightly acidic. The resulting precipitate was filtered and washed with cold water and then THF, dried overnight to give rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoic acid (110 mg, 90%). MS (ES+) m/z [(M+H)+]: 565
Example 34
Preparation of intermediate E/Z- 6-Chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro- pyrrolo[2,3-b]pyridin-2-one
Figure imgf000051_0002
M. W. 309.13 Ci4H7Cl2FN20
To a suspension of 6-chloro-l,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (Sinova, 501.5 mg, 2.83 mmol) in MeOH (25 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 1.35 g, 8.51 mmol). Piperidine (Aldrich, 1.03 g, 12.0 mmol) was added slowly, giving a clear brown solution. After stirred for a few minutes, the reaction mixture was heated at 50 °C overnight, resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z- 6-chloro-3-(3-chloro-2-fluoro-benzylidene)- l,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as a grey solid (457 mg, 52%). MS (ES+) m/z
[(M+H)+]: 309 Example 35
Preparation of methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-
2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000052_0001
M. W. 629.52 C3iH3iCl2FN405
To a solution of E/Z- 6-chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[2,3- b]pyridin-2-one (Example 34, 151 mg, 0.49 mmol) in anhydrous THF (12 mL) was added anhydrous LiOH (9 mg, 0.38 mmol) and the mixture was stirred at 40 °C for 10 min. (E)-methyl 4-(2-(3,3-dimethylbutylideneamino)-acetamido)-3-methoxybenzoate (Example 3, 169 mg, 0.53 mmol) was added in one portion. The reaction mixture was allowed to stir at 40 °C overnight, giving a clear reaction mixture. This mixture was diluted with EtOAc (100 mL) and washed with water, brine and dried over Na2S04 and concentrated. The crude product was purified by flash chromatography (EtOAc/CH2Cl2, 1/99 to 50/50) to give methyl rac-4-((2S,3R,4S,5R)-6'-chloro- 4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3- b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (34 mg, 11%). MS (ES+) m/z [(M+H)+]: 629
Example 36
Preparation of rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid
Figure imgf000053_0001
M. W. 615.49 C3oH29Cl2FN405
To a suspension of methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fl
neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido) 3-methoxybenzoate (Example 35, 29 mg, 0.046 mmol) in THF (2 mL) was added a solution of LiOH hydrate (16 mg, 0.39 mmol) in water (2 mL). The reaction mixture was stirred at rt overnight until the reaction was complete. The reaction mixture was treated with IN HC1 to slightly acidic, diluted with ethyl acetate (100 mL), washed with water (10 mL), dried with Na2S04 and concentrated to give rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)- 3-methoxybenzoic acid as a white solid (26 mg, 92%). MS (ES+) m/z [(M+H)+]: 615
Example 37
Preparation of chiral methyl 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate (A)
and chiral methyl 4-((2R,3S,4R,5S)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate(B)
Figure imgf000053_0002
M. W. 595.08 C3iH32ClFN405
Methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b^
(310 mg, Example 6) was separated by SFC(Waters/Thar Multi-Gram II, Kromasil 5-CelluCoat OD 3x25 cm., 35°C at 100 bar, eluting with 40% MeOH in carbon dioxide) to give chiral methyl 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoate, MS (ES+) m/z [(M+H)+]: 595, and chiral methyl 4-((2R,3S,4R,5S)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3- methoxybenzoate. MS (ES+) m/z [(M+H)+]: 595
Example 38
Preparation of chiral 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'- rrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid
Chiral
Figure imgf000054_0001
MW 581.05, C3oH30ClFN405
To a solution of chiral methyl 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3- methoxybenzoate (Example 37, 83 mg, 0.140 mol) in THF (8 mL) was added a solution of LiOH hydrate (47 mg, 1.14 mmol) in water (4 mL). The reaction mixture was stirred at rt overnight before it was treated with IN HC1 to slightly acidic. The mixture was partitioned between water (10 mL) and EtOAc (100 mL), washed with water, brine and dried over Na2S04, concentrated and lyophized to give chiral 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)- 3-methoxybenzoic acid as a white powder (53 mg, 66%). MS (ES+) m/z [(M+H)+]: 581 Example 39
Preparation of chiral (2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- carboxamide
Figure imgf000055_0001
M. W. 580.06 C3oH3iClFN504
A mixture of chiral 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (Example 38, 40 mg, 0.069 mmol) and 1,1 -carbonyldiimidazole (Aldrich, 27.6 mg, 0.170 mmol) in THF (3 mL) was stirred at rt for 17 h. Ammonium hydroxide (Aldrich, 153 mg, 4.37 mmol) was added and the mixture was stirred for 20 min. The mixture was partitioned between EtOAc (75 mL) and water (10 mL), washed with sat. NaHC03 (10 mL), water (10 mL) then sat. NH4C1 (10 mL). The organic layer was dried over Na2S04 and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography (ethanol/CH2Cl2, 0.5/99.5 to 3/97) to give chiral (2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (37 mg, 92%). MS (ES+) m/z [(M+H)+]: 580
Example 40
Preparation of intermediate E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydr( pyrrolo[3,2-b]pyridin-2-one
Figure imgf000055_0002
M. W. 309.13 Ci4H7Cl2FN20
To a mixture of 6-chloro-4-aza-2-oxindole (Sinova, 1.5 g, 8.9 mmol) and 3-chloro-2- fluorobenzaldehyde (Oakwood, 1.4 g, 8.9 mmol) in methanol (65 mL) was added piperidine (Aldrich, 0.76 g, 8.9 mmol) dropwise. The reaction mixture was heated at 50 °C and stirred for 3 h. Then the mixture was cooled to room temperature and filtered. The resulting precipitate was collected and dried to give E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro- pyrrolo[3,2-b]pyridin-2-one as a yellow solid (1.8 g, 65 %).
Example 41
Preparation of intermediate rac-(2S,3S,4S,5R)-tert-butyl 6'-chloro-4-(3-chloro-2-fluorophenyl)- 2-neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxylate
Figure imgf000056_0001
M. W. 522.45 C26H3oCl2FN303
To a suspension of E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 40, 623 mg, 2.02 mmol) in anhydrous THF (20 mL) were added 1,4- diazabicyclo [2,2,2] octane (249 mg, 2.22 mmol, Aldrich) and anhydrous LiCl (Aldrich, 101 mg, 2.38 mmol) under N2. The suspension was warmed at 40 °C for a few minutes before (E)-tert- butyl 2-(3,3-dimethylbutylideneamino)acetate (Example 5, Step a, 522 mg, 2.45 mmol) in CH- 2C12 (5 mL) was added. The reaction mixture was allowed to stir at 40 °C for 19 h. The reaction mixture was partitioned between CH2C12 and water. The organic layer was separated and the aqueous layer was extracted with CH2C12 twice. The combined extracts were washed with water, brine and evaporated. The crude product was purified by flash chromatography (EtOAc/hexane, 20/80 to 50/50) to give rac-(2S,3S,4S,5R)-tert-butyl 6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxylate as a light yellow solid (261 mg, 25%). MS (ES+) m/z [(M+H)+]: 522 Example 42
Preparation of methyl rac-4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-
2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000057_0001
M. W. 629.52 C3iH3iCl2FN405
To a solution of E/Z-6-chloro-3-(3-chloro-2-fluorobenzylidene)-lH-pyrrolo[3,2-b]pyridin- 2(3H)-one (Example 40, 90 mg, 0.29 mmol) in anhydrous THF (8 mL) was added anhydrous LiOH (5 mg, 0.20 mmol) and the mixture was stirred at 40 °C for 10 min. (E)-Methyl 4-(2-(3,3- dimethylbutylideneamino)acetamido)-3-methoxybenzoate (99 mg, 0.31 mmol) was added in one portion. The reaction mixture was allowed to stir at 40 °C overnight giving a white precipitate. The resulting precipitate was filtered, washed with cold THF and dried overnight in vacuum to give methyl rac-4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate as a white solid (33 mg, 18%). MS (ES+) m/z [(M+H)+]: 629
Example 43
Preparation of rac-4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid
Figure imgf000058_0001
M. W. 615.49 C3oH29Cl2FN405
To a suspension of methyl rac-4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate (Example 42, 62 mg, 0.10 mmol) in THF (5 mL) was added a solution of LiOH hydrate (34 mg, 0.82 mmol) in water (2.5 mL). The reaction mixture was stirred at rt overnight until the reaction was complete. The mixture was then treated with IN HCl to slightly acidic, diluted with ethyl acetate (100 mL), washed with water (10 mL), dried with Na2S04 and concentrated to give rac-4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoic acid as a white solid (57 mg, 94%). MS (ES+) m/z [(M+H)+]: 615
Example 44
Preparation of rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5- carboxamide
Figure imgf000058_0002
M. W. 614.51 C30H3oCl2FN504
A mixture of rac-4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (Example 43, 30 mg, 0.050 mmol,), N,N-disiopropylethylamine (51.9 mg, 0.402 mmol) and 0(7-azabenzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluorohposphate (HATU) (Chem-Impex, 30 mg, 0.080 mmol) in DMF (4 mL) was stirred for 20 min before NH4C1 (7.6 mg, 0.13 mmol) was added. The mixture was stirred for 4 h and poured into EtOAc (120 mL), washed with water (10 mL), sat NH4C1 (10 mL), sat NaHC03 (10 mL), and brine (15 mL) and concentrated. The crude product was purified by RP-HPLC (40% to 100% MeCN in H20) to give rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5- carboxamide as a white solid (7 mg, 25%). MS (ES+) m/z [(M+H)+]: 614
Example 45
Preparation of intermediate E/Z-5-chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro- pyrrolo[3,2-b]pyridin-2-one
Figure imgf000059_0001
M. W. 309.13 Ci4H7Cl2FN20
To a suspension of 5-chloro-lH-pyrrolo[3,2-b]pyridin-2(3H)-one (Sinova, 815.5 mg, 4.84 mmol) in MeOH (45 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 2.3 g, 14.5 mmol). Piperidine (Aldrich, 1.63 g, 19.2 mmol) was added slowly. After stirring a few minutes, the mixture was heated at 50 °C for 6 h resulting in a yellow precipitation. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-5-chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a light brown solid (1.38 g, 92%). MS (ES+) m/z [(M+H)+]: 309
Example 46
Preparation of methyl rac-4-((2S,3S,4S,5R)-5'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000060_0001
M. W. 629.52 C3iH3iCl2FN405
A suspension of E/Z-5-chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 45, 331.2 mg, 1.07 mmol) in anhydrous THF (25 mL) was warmed to a clear solution and then cooled down to 40 C. LiOH (18 mg, 0.70 mmol) was added and the mixture was stirred at 40 °C for 10 min. (E)-Methyl 4-(2-(3,3- dimethylbutylideneamino)acetamido)-3-methoxybenzoate (Example 3, 360.9 mg, 1.13 mmol) was added in one portion. The reaction mixture was allowed to stir at 40 °C for 20 h, giving a clear reaction mixture. The mixture was diluted with EtOAc (100 mL), washed with water (2x20 mL) and concentrated to a small volume. MeOH was added slowly (-10 mL) and the mixture was stirred in cold bath for -20 min. The resulting precipitate was filtered, washed with cold MeOH and dried overnight in vacuum to give methyl rac-4-((2S,3S,4S,5R)-5'-chloro-4-(3- chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (420 mg, 76%). MS (ES+) m/z [(M+H)+]: 629
Example 47
Preparation of rac-4-((2S,3S,4S,5R)-5'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid
Figure imgf000060_0002
M. W. 615.49 C3oH29Cl2FN405
To a suspension of methyl rac-4-((2S,3S,4S,5R)-5'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate (Example 46, 111 mg, 0.17 mmol) in THF (10 mL) was added a solution of LiOH hydrate (61 mg, 1.46 mmol) in water (5 mL). The reaction mixture was stirred at rt overnight before it was treated with IN HC1 to slightly acidic, diluted with ethyl acetate (200 mL), washed with water (15 mL), dried with Na2S04 and concentrated to give rac-4- ((2S ,3S ,4S ,5R)-5'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- 1 ',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (107 mg, 98%). MS (ES+) m/z [(M+H)+]: 615
Example 48
Preparation of intermediate E/Z-3-(3-chloro-2-fluoro-benzylidene)-7-methyl-l,3-dihydro- pyrrolo[3,2-b]pyridin-2-one
Figure imgf000061_0001
M. W. 288.71 Ci5H10ClFN2O
To a suspension of 7-methyl-lH-pyrrolo[3,2-b]pyridin-2(3H)-one (Sinova, 818.0 mg, 5.52 mmol) in MeOH (30 mL) was added 3-chloro-2-fluorobenzaldehyde (Oakwood, 2.60 g, 16.4 mmol) in MeOH (2 mL) to give a clear solution. Piperidine (Aldrich, 1.89 g, 22.2 mmol) was added slowly and a light yellow precipitation started to form shortly. After stirring a few minutes, the reaction mixture was heated at 50 °C for 12 h. The reaction mixture was cooled and the precipitate was filtered, washed with cold MeOH and dried in vacuum to give E/Z-3-(3-chloro-2-fluoro- benzylidene)-7-methyl-l,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a light brown solid (939 mg, 58%). MS (ES+) m/z [(M+H)+]: 288 Example 49
Preparation of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7'-methyl-2-neopentyl-
2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000062_0001
M. W. 609.10 C32H34C1FN405
To a suspension of E/Z-3-(3-chloro-2-fluoro-benzylidene)-7-methyl-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 48, 318 mg, 1.10 mmol) in anhydrous THF (25 mL) was added LiOH (20 mg, 0.85 mmol) and the mixture was stirred at 40 °C for 10 min. (E)-Methyl 4-(2-(3,3- dimethylbutylideneamino)acetamido)-3-methoxybenzoate (Example 3, 371 mg, 1.16 mmol) was added in one portion. The reaction mixture was allowed to stir at 40 °C for 20 h. The mixture was diluted with EtOAc (100 mL) and washed with water, brine and dried over Na2S04 and concentrated. The crude product was purified on flash chromatography (EtOAc/CH2Cl2, 3/97 to 20/20) to give methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7'-methyl-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate as a white solid (171 mg, 26%). MS (ES+) m/z [(M+H)+]: 609
Example 50
Preparation of rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7'-methyl-2-neopentyl-2'-oxo- 1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid
Figure imgf000063_0001
M. W. 595.08 C3iH32ClFN405
To a suspension of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7'-methyl-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate (Example 49, 150 mg, 0.246 mmol) in THF (14 mL) was added LiOH monohydrate (83 mg, 1.98 mmol) in water (5 mL). The mixture was stirred at rt overnight. The mixture was then treated with IN HC1 to slightly acidic, diluted with ethyl acetate (100 mL), washed with water (10 mL), dried with Na2S04 and concentrated to give rac-4-((2S,3S,4S,5R)-4- (3-chloro-2-fluorophenyl)-7'-methyl-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (110 mg, 75%). MS (ES+) m/z [(M+H)+]: 595
Example 51
Preparation of chiral methyl 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate(A)
and
chiral methyl 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate(B)
Figure imgf000064_0001
M. W. 629.52 C3iH3iCl2FN405
Methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 24) was separated by SFC Chromatography (Waters/Thar Multi-Gram II, Kromasil 5- CelluCoat OD 3x25 cm., 35°C at 100 bar, eluting with 40% ethanol in carbon dioxide) to give chiral methyl 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, MS (ES+) m/z [(M+H)+]: 629, and chiral methyl 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- ylcarboxamido)-3-methoxybenzoate. MS (ES+) m/z [(M+H)+]: 629
Example 52
Preparation of chiral 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3- methoxybenzoic acid
Figure imgf000064_0002
M. W. 615.49 C3oH29Cl2FN405
To a solution of chiral methyl 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate (Example 51, 56 mg, 0.090 mmol,) in THF (6 mL) was added a solution of LiOH hydrate (31 mg, 0.74 mmol) in water (3 mL). The reaction mixture was stirred at rt overnight before it was treated with IN HC1 to slightly acidic. The mixture was partitioned between EtOAc (100 mL) and water (10 mL), washed with water, brine and dried over Na2S04, concentrated and lyophized to give chiral 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- ylcarboxamido)-3-methoxybenzoic acid as a white powder (46 mg, 84%). MS (ES+) m/z
[(M+H)+]: 615 Example 53
Preparation of chiral (2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- carboxamide
Figure imgf000065_0001
M. W. 614.51 C30H30Cl2FN5O4
A mixture of chiral 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- 1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (Example 52, 26 mg, 0.043 mmol) and 1,1 -carbonyldiimidazole (Aldrich, 26 mg, 0.16 mmol) in THF (3 mL) was stirred at rt for 17 hrs. Ammonium hydeoxide (180 mg, 5.14 mmol) was added and the mixture was stirred for 20 min. The mixture was partitioned between EtOAc (75 mL) and water (10 mL), washed with sat. NaHC03 (10 mL), water (10 mL) then sat. NH4C1 (10 mL). The organic layer was dried over Na2S04 and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography (ethanol/CH2Cl2, 0.5/99.5 to 3/97) to give chiral (2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- carboxamide as a white solid (21 mg, 79%). MS (ES+) m/z [(M+H)+]: 614 Example 54
Preparation of chiral 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3- methoxybenzoic acid
Chiral
Figure imgf000066_0001
MW 615.49, C3oH29Cl2FN405
To a solution of chiral methyl 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate (62 mg, 0.099 mmol, Example 51) in THF (6 mL) was added a solution of LiOH hydrate (34 mg, 0.82 mmol) in water (3 mL). The reaction mixture was stirred at rt overnight before it was treated with IN HC1 to slightly acidic. The mixture was partitioned between EtOAc (100 mL) and water (10 mL), washed with water, brine and dried over Na2S04, concentrated and lyophized to give chiral 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- ylcarboxamido)-3-methoxybenzoic acid as a white powder (50 mg, 81%). MS (ES+) m/z
[(M+H)+]: 615
Example 55
Preparation of chiral (2R,3S,4R,5S)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- carboxamide
Figure imgf000067_0001
M. W. 614.51 C3oH3oCl2FN504
A mixture of chiral 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (Example 54, 29 mg, 0.047 mmol) and 1,1 -carbonyldiimidazole (Aldrich, 23 mg, 0.14 mmol) in THF (3 mL) was stirred at rt for 17 h. Ammonium hydroxide (180 mg, 5.14 mmol) was added and the mixture was stirred for 20 min. The mixture was partitioned between EtOAc (75 mL) and water (10 mL), washed with sat. NaHC03 (10 mL), water (10 mL) then sat. NH4C1 (10 mL). The organic layer was dried over Na2S04 and concentrated in vacuo onto silica gel. The crude material was purified by flash chromatography (ethanol/CH2Cl2, 0.5/99.5 to 3/97) to give chiral
(2R,3S,4R,5S)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (20 mg, 70%). MS (ES+) m/z [(M+H)+]: 614
Example 56
Preparation of chiral 4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoic acid(A)
and chiral 4-((2R,3R,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid(B)
Figure imgf000068_0001
M. W. 615.49 C3oH29Cl2FN405
A rac-4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluoro
dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxyben^ acid (Example 43) was separated by SFC Chromatography SFC(Waters/Thar Multi-Gram II, Chiral Technologies, Diacel OD, 3x25 cm., 35°C at 100 bar, eluting with 35% Ethanol in carbon dioxide) to give chiral 4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoic acid, MS (ES+) m/z [(M+H)+]: 615, and chiral 4-((2R,3R,4R,5S)-6'-chloro-4-(3- chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid. MS (ES+) m/z [(M+H)+]: 615
Example 57
Preparation of chiral methyl 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- ylcarboxamido)benzoate(A)
and chiral methyl 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- 1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate(B)
Figure imgf000069_0001
M. W. 599.49 C3oH29Cl2FN404
Rac-methyl 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate (Example 27) was separated by SFC (Waters/Thar Multi-Gram II, Chiral Technologies, Diacel IA, 3x25 cm., 35 °C at 100 bar, eluting with 35% ethanol in carbon dioxide) to give chiral methyl 4- ((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate, MS (ES+) m/z [(M+H)+]: 599, and chiral methyl 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5- ylcarboxamido)benzoate. MS (ES+) m/z [(M+H)+]: 599
Example 58
Preparation of intermediate E/Z-6-chloro-3-(3-chloro-benzylidene)-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one
Figure imgf000069_0002
M. W. 291.19 Ci4H8Cl2N20
To the mixture of 6-chloro-4-aza-2-oxindole (Sinova, 1 g, 5.9 mmol,) and 3-chloro- benzaldehyde (Aldrich, 0.83 g, 5.9 mmol) in methanol (50 mL) was added piperidine (Aldrich, 0.5 g, 5.9 mmol) dropwise. The reaction mixture was heated at 80 °C and stirred for 1 h. Then the mixture was cooled to room temperature and filtered. The resulting precipitate was collected and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (0-25% EtOAc in dichlormethane) to give the second batch of product. The two batches were combined to give E/Z-6-chloro-3-(3-chloro-benzylidene)-l,3- dihydro-pyrrolo[3,2-b]pyridin-2-one as an orange solid (0.9 g, 52 %).
Example 59
Preparation of methyl rac-4-{(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3- methoxybenzoate
Figure imgf000070_0001
M. W. 611.52 C3iH32Cl2N405
To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-l,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 58, 0.25 g, 0.86 mmol) in tetrahydrofuran (2 mL) was added anhydrous LiOH (41 mg, 1.72 mmol). The mixture was warmed to 40 °C and stirred for 10 min. 4-{2-[3,3-dimethyl-but- (E)-ylideneamino]-acetylamino}-3-methoxy-benzoic acid methyl ester (Example 3, 0.27 g, 0.86 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 2 h. The mixture was cooled to room temperature and filtered. The rsulting precipitate was collected, washed with ethyl acetate, and dried to give methyl rac-4-{(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}- 3-methoxybenzoate as an off-white solid (0.15 g, 29%). MS (ES+) m/z Calcd for
C3iH32Cl2N405+ H [(M+H)+]: 611, found: 611.
Example 60
Preparation of rac-4-{(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoic acid
Figure imgf000071_0001
M. W. 597.50 C3oH3oCl2N405
To a solution of methyl rac-4-{(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3- methoxybenzoate (Example 59, 70 mg, 0.11 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (1 N) of NaOH (1.1 mL, 1.1 mmol). The reaction mixture was stirred at room temperature for 5 h. The "pH" of the mixture was adjusted to 5 by aqueous HC1 solution, then concentrated to a small volume. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgS04, and concentrated to give rac-4-{(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-2-neopentyl-2'-oxo- 1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoic acid as an off-white solid (58 mg, 85%). MS (ES+) m/z Calcd for C3oH30Cl2N405+ H [(M+H)+]: 597, found: 597.
Example 61
Preparation of intermediate N-(4-cyano-2-methoxy-phenyl)-2-[3,3-dimethyl-but-(E)- ylideneamino] -acetamide
Figure imgf000071_0002
M. W. 287.36 Ci6H21N302
Step a: A mixture of 3-methoxy-4-nitrobenzoic acid (Acros, 10 g, 51 mmol) in thionyl chloride (36 g) was heated at reflux for 2 h. The mixture was concentrated. To the residue was added a methanolic solution (7 N) of ammonia. The reaction mixture was stirred at room temperature for 72 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The precipitate between the two layers was filtered and collected to give 3-methoxy-4- nitrobenzamide as a light yellow solid (8 g, 81%).
Step b: To a solution of 3-methoxy-4-nitrobenzamide (8 g, 41 mmol) in dioxane (300 mL) was added pyridine (32 g, 408 mmol), followed by dropwise addition of trifluoroacetic anhydride (43 g, 204 mmol). The reaction mixture was stirred at room temperature for 5 h . Water was added to quench the reaction. The mixture was concentrated, then the residue was partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, aqueous saturated CuS04 solution, brine, dried over MgS04, and concentrated to give 3-methoxy-4-nitrobenzonitrile as a off white solid (6.5 g, 90%)
Step c: To the suspension of 3-methoxy-4-nitrobenzonitrile (11.4 g, 64 mmol) in ethyl acetate (60 mL) was added 10% Pd/C (1 g). The reaction mixture was vigorously shaken in a Parr under an atmosphere of hydrogen (50 psi) at room temperature for 45 min . The mixture was filtered through a short pad of celite, and the filtrate was concentrated to give 4-amino-3-methoxy- benzonitrile as a yellow oil, which solidified at stand (9.5 g, 95%)
Step d: To a solution of 2-(tert-butoxycarbonylamino)acetic acid (Advanced Chemical, 3.9 g, 22.3 mmol) and Nl-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine
hydrochloride (EDCI) (Aldrich, 4.27 g, 22.3 mmol) in dichloromethane (20 mL) was added 4- amino-3-methoxy-benzonitrile (2 g, 13.5 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous NH4C1 solution . The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (0-15%EtOAc in dichlormethane) to give tert-butyl 2- (4-cyano-2-methoxyphenylamino)-2-oxoethylcarbamate as a white solid (3.3 g, 80%). Step e: To a solution of tert-butyl 2-(4-cyano-2-methoxyphenylamino)-2-oxoethylcarbamate (1.5 g, 4.9 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was then triturated with hexanes, concentrated, dried in vacuo to give 2-amino-N-(4-cyano-2- methoxyphenyl)acetamide trifluoroacetic acid as a yellow solid (1.2 g, 77%). Step f: To a mixture of 2-amino-N-(4-cyano-2-methoxyphenyl)acetamide trifluoroacetic acid (1.7 g, 5.4 mmol) in methyl tert-butyl ether (20 mL) was added triethylamine (0.78 mL, 5.7 mmol). The mixture was stirred at room temperature for 30 min. Then 3,3-dimethyl- butyraldehyde (Aldrich, 0.57 g, 5.7 mmol) was added. The reaction mixture was stirred at room temperature for 3.5 h.. The mixture was filtered, and the filtrate was concentrated. The residue was partitioned between dichloromethane and water . The organic layer was separated, and aqueous layer was extracted with dichlormethane. The combined organic extract was washed with water, dried over MgS04, and concentrated to give N-(4-cyano-2-methoxy-phenyl)-2-[3,3- dimethyl-but-(E)-ylideneamino]-acetamide (1.2 g, 77%) as a yellow foam which was used in the next step without further purification.
Example 62
Preparation of rac-(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-N-(4-cyano-2-methoxyphenyl)- 2-neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide
Figure imgf000073_0001
M. W. 578.50 C30H29CI2N5O3
To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-l,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 58, 0.1 g, 0.34 mmol) in tetrahydrofuran (2 mL) was added anhydrous LiOH (16.5 mg, 0.69 mmol). The mixture was warmed to 40 °C and stirred for 10 min. N-(4-cyano-2-methoxy- phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (Example 61, 0.15 g, 0.52 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 2 h. The mixture was cooled to room temperature and filtered. The resulting precipitate was collected, washed with ethyl acetate, and dried to give rac-(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-N-(4-cyano-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]- 5-carboxamide as a white solid (33 mg, 17%). MS (ES+) m/z Calcd for C30H29CI2N5O3+ H
[(M+H)+]: 578, found: 578.
Example 63
Preparation of rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3- chlorophenyl)-2-neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5- carboxamide
Figure imgf000074_0001
M. W. 596.51 C3oH3iCl2N504
To the solution of rac-(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-N-(4-cyano-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-
5-carboxamide (Example 62, 26 mg, 0.045 mmol) in DMSO (0.2 mL) at 0 °C was added an aqueous solution (30%) of H2O2 (Aldrich, 0.076 mg, 0.67 mmol) , followed by the addition of aqueous solution (1 N) of NaOH (0.23 mL, 0.23 mmol). The reaction mixture was stirred at 0 °C for 1 h. The mixture was partitioned bewteen ethyl acetate and saturated aqueous Na2S03 solution.. The organic layer was separated, washed with water, brine, dried over MgS04, and concentrated to give rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3- chlorophenyl)-2-neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5- carboxamide as an off-white solid (24 mg, 90%). MS (ES+) m/z Calcd for C3oH3iCl2N504+ H [(M+H)+]: 596, found: 596.
Example 64
Preparation of intermediate E/Z-3-(3-bromo-2-fluoro-benzylidene)-6-chloro-l,3-dihyd:
pyrrolo[3,2-b]pyridin-2-one
Figure imgf000075_0001
M. W. 353.58 Ci4H7BrClFN20
To the mixture of 6-chloro-4-aza-2-oxindole (Sinova, 1 g, 5.9 mmol) and 3-bromo-2- fluorobenzaldehyde (Aldrich, 1.6 g, 7.9 mmol) in methanol (30 mL) was added piperidine (Aldrich, 2 g, 24 mmol) dropwise. The reaction mixture was heated at 50 °C and stirred for 3 h. Then the mixture was cooled to room temperature and filtered. The resulting precipitate was collected and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (25-50% EtOAc in hexanes) to give the second batch of product. The two batches were combined to give E/Z-3-(3-bromo-2-fluoro- benzylidene)-6-chloro-l,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a yellow solid (1.6 g, 76 %).
Example 65
Preparation of methyl rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3- methoxybenzoate
Figure imgf000075_0002
M. W. 673.96 C3iH3iBrClFN405
To a solution of E/Z-3-(3-bromo-2-fluoro-benzylidene)-6-chloro-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 64, 0.3 g, 0.85 mmol) in tetrahydrofuran (10 mL) was added anhydrous LiOH (41 mg, 1.7 mmol). The mixture was warmed to 40 °C and stirred for 10 min. 4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-benzoic acid methyl ester (Example 3, 0.27 g, 0.85 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 18 h. The mixture was cooled to room temperature and filtered. The rsulting precipitate was collected, washed with ethyl acetate, and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (5-10% EtOAc in dichlormethane) to give the second batch of desired product. The two batches were combined to give methyl rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3- methoxybenzoate as a white solid (0.17 g, 30%). MS (ES+) m/z Calcd for C3iH3iBrClFN405+ H [(M+H)+]:673, found: 673.
Example 66
Preparation of methyl rac-4-{(2S,3R,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2-neopentyl-
2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3- methoxybenzoate
Figure imgf000076_0001
M. W. 673.96 C3iH31BrClFN405
In the preparation of rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3- methoxybenzoate as described in Example 65, methyl rac-4-{(2S,3R,4S,5R)-4-(3-bromo-2- fluorophenyl)-6'-chloro-2-neopentyl-2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate was obtained as another product by chromatography (5-10% EtOAc in dichlormethane): 50 mg, 9%, off white solid. MS (ES+) m/z Calcd for C3iH3iBrClFN405+ H [(M+H)+]:673, found: 673. Example 67
Preparation of rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-meth^ acid
Figure imgf000077_0001
M. W. 659.94 C3oH29BrClFN405
To a solution of methyl rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}- 3-methoxybenzoate (Example 65, 120 mg, 0.18 mmol) in tetrahydrofuran (8 mL) was added an aqueous solution (1 N) of NaOH (1 mL, 1 mmol). The reaction mixture was stirred at room temperature for 18 h. The "pH" of the mixture was adjusted to 3 by aqueous HCl solution, then concentrated to a small volume. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgS04, and concentrated to give rac-4-{(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3- methoxybenzoic acid as a white solid (80 mg, 68%). MS (ES+) m/z Calcd for
C30H29BrClFN4O5+ H [(M+H)+]: 659, found: 659.
Example 68
Preparation of rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-N-(4-cyano-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-
5-carboxamide
Figure imgf000078_0001
M. W. 640.94 C3oH28BrClFN504
To a solution of E/Z-3-(3-bromo-2-fluoro-benzylidene)-6-chloro-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 64, 0.1 g, 0.28 mmol) in tetrahydrofuran (1 mL) was added
anhydrous LiOH (13.5 mg, 0.57 mmol). The mixture was warmed to 40 °C and stirred for 10 min. N-(4-cyano-2-methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (Example 61, 0.12 g, 0.42 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 1 h. The mixture was cooled to room temperature and filtered. The resulting precipitate was collected, washed with ethyl acetate, and dried to give rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'- chloro-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-b]pyridine]-5-carboxamide as a white solid (40 mg, 22%). MS (ES+) m/z Calcd for C3oH28BrClFN504+ H [(M+H)+]: 640, found: 640.
Example 69
Preparation of rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-N-(4-carbamoyl-2- methoxyphenyl)-6'-chloro-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2b]pyridine]-5-carboxamide
Figure imgf000078_0002
M. W. 658.95 C3oH3oBrClFN504
To a solution of rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-N-(4-cyano-2- methoxyphenyl)-2-neopentyl-2'-oxo- 1 \2'-dih^
5-carboxamide (Example 68, 32 mg, 0.05 mmol) in DMSO (0.2 mL) at 0 °C was added an aqueous solution (30%) of H2O2 (Aldrich, 0.085 mg, 0.75 mmol) , followed by the addition of aqueous solution (1 N) of NaOH (0.25 mL, 0.25 mmol). The reaction mixture was stirred at 0 °C for 1 h. The mixture was partitioned bewteen ethyl acetate and saturated aqueous Na2S03 solution.. The organic layer was separated, washed with water, brine, dried over MgS04, and concentrated to give rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-N-(4-carbamoyl-2- methoxyphenyl)-6'-chloro-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- b]pyridine] -5-carboxamide as a off white solid (29 mg, 88%). MS (ES+) m/z Calcd for
C30H3oBrClFN504+ H [(M+H)+]: 658, found: 658.
Example 70
Preparation of intermediate acetic acid 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]- acetylamino}-3-methoxy-phenoxy)-ethyl ester
Figure imgf000079_0001
M. W. 364.45 Ci9H28N205 Step a: To a solution of 4-fluoro-2-methoxy- 1 -nitrobenzene (Combi-blocks, 3.4 g, 19.9 mmol) in DMSO (40 mL) was added an aqueous solution (1 N) of NaOH (40 mL, 40 mmol). The reaction mixture was heated at 80 °C for 20 h. The mixture was cooled to room temperature, and the "pH" of the solution was adjusted to 5 by aqueous HC1 solution. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgS04, and concentrated to give 3-methoxy-4-nitrophenol as a light yellow solid (3.2 g, 95%).
Step b: To a solution of 3-methoxy-4-nitrophenol (1 g, 5.9 mmol) in anhydrous DMF (25 mL) were added K2C03 (2.45 g, 17.7 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.7 g, 7.1 mmol) sequentially. The reaction mixture was heated at 70 °C for 20 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (0-20% EtOAc in hexanes) to give tert-butyl-[2-(3-methoxy-4-nitro-phenoxy)-ethoxy]-dimethyl-silane as a light yellow oil (1.0 g, 52%).
Step c: To a solution of tert-butyl-[2-(3-methoxy-4-nitro-phenoxy)-ethoxy]-dimethyl-silane (4 g, 12.2 mmol) in THF (50 mL) was added an aqueous HC1 solution (1 N, 20 mL, 20 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHC03 solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgS04, and concentrated to give 2-(3- methoxy-4-nitrophenoxy)ethanol as an off white solid (2.1 g, 81%). Step d: To a solution of 2-(3-methoxy-4-nitrophenoxy)ethanol (2.1 g, 9.9 mmol) and pyridine (0.9 g, 11.4 mmol) in THF (50 mL) at 0 °C was acetyl chloride (0.89 g, 11.4 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, saturated aqueous CuS04 solution, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (0-40% EtOAc in dichloromethane) to give 2-(3- methoxy-4-nitrophenoxy)ethyl acetate as a yellow foam (2.4 g, 95%).
Step e: A suspension of 2-(3-methoxy-4-nitrophenoxy)ethyl acetate (2.4 g, 9.4 mmol) and Pd/C (Aldrich, 10%, 0.4 g) in ethyl acetate (30 mL) was vigorously shaken in a Parr under atmosphere of ¾ (50 psi) for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give acetic acid 2-(4-amino-3-methoxy-phenoxy)-ethyl ester as a light brown oil (2 g, 94%). Step f: To a solution of 2-(tert-butoxycarbonylamino)acetic acid (Advanced Chemical, 2.57 g, 14.7 mmol) and EDCI (Aldrich, 2.81 g, 14.7 mmol) in dichloromethane (20 mL) was added 2- (4-amino-3-methoxy-phenoxy)-ethyl ester (2 g, 8.9 mmol). The reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated, and the residue was partitioned between dichloromethane and saturated aqueous NH4C1 solution . The organic layer was separated, and aqueous layer was extracted with dichloromethane twice. The combined organic extract was washed with saturated aqueous NaHC03 solution, brine, dried over MgS04, and concentrated to give 2-(4-(2-(tert-butoxycarbonylamino)acetamido)-3-methoxyphenoxy)ethyl acetate as a light brown oil (3.3 g, 97%).
Step g: A solution of 2-(4-(2-(tert-butoxycarbonylamino)acetamido)-3-methoxyphenoxy)ethyl acetate (1 g, 2.6 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was then triturated with hexanes, concentrated, dried in vacuo to give 2-(4-(2-aminoacetamido)-3- methoxyphenoxy)ethyl acetate trifluoroacetic acid as an off white foam (0.8 g, 77%).
Step h: To a mixture of 2-(4-(2-aminoacetamido)-3-methoxyphenoxy)ethyl acetate
trifluoroacetic acid (1 g, 2.5 mmol) in methyl tert-butyl ether (12 mL) was added triethylamine (0.53 mL, 3.8 mmol). The mixture was stirred at room temperature for 30 min. Then 3,3- dimethyl-butyraldehyde (Aldrich, 0.33 g, 2.7 mmol) was added. The reaction mixture was stirred at room temperature for 20 h.. The mixture was filtered, and the filtrate was concentrated. The residue was partitioned between dichloromethane and water . The organic layer was separated, and aqueous layer was extracted with dichlormethane. The combined organic extract was washed with water, dried over MgS04, and concentrated to give acetic acid 2-(4-{2-[3,3-dimethyl-but- (E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester as a yellow oil (0.9 g, 98%) which was used in the next step without further purification.
Example 71
Preparation of rac-2-(4-((2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-2-neopentyl-2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxyphenoxy)ethyl acetate
Figure imgf000082_0001
M. W. 655.58 C33H36C12N406
To a solution of E/Z-6-chloro-3-(3-chloro-benzylidene)-l,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (Example 58, 0.14 g, 0.48 mmol) in tetrahydrofuran (3 mL) was added anhydrous LiOH (23 mg, 0.96 mmol). The mixture was warmed to 40 °C and stirred for 10 min. 2-(4-{2-[3,3-dimethyl- but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester (Example 70, 0.18 g, 0.48 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 2 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated, and the residue was purified by chromatography (0-20% EtOAc in dichloromethane) to give rac-2-(4-((2S,3S,4R,5R)-6'-chloro- 4-(3-chlorophenyl)-2-neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- b]pyridine]-5-ylcarboxamido)-3-methoxyphenoxy)ethyl acetate as an off white solid (0.1 g, 32%). Example 72
Preparation of rac-(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-
5-carboxamide
Figure imgf000083_0001
M. W. 613.54 C3iH34Cl2N405
To a solution of rac-2-(4-((2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxyphenoxy)ethyl acetate (Example 71, 0.1 g, 0.15 mmol) in tetrahydrofuran (2 mL) was added an aqueous solution (1 N) of NaOH (2 mL, 2 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHC03 solution.. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgS04, and concentrated. The residue was recrystallized in methanol to give rac-(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]- 5-carboxamide as a white solid (11 mg, 12%). MS (ES+) m/z Calcd for C3iH34Cl2N405+ H
[(M+H)+]: 613, found: 613.
Example 73
Preparation of rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-N-(4-(2- hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-b]pyridine]-5-carboxamide
Figure imgf000084_0001
M. W. 675.98 C3iH33BrClFN405
To a solution of E/Z-3-(3-bromo-2-fluoro-benzylidene)-6-chloro-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 64, 0.1 g, 0.28 mmol) in tetrahydrofuran (1 mL) was added anhydrous LiOH (14 mg, 0.57 mmol). The mixture was warmed to 40 °C and stirred for 10 min. 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester (Example 70, 0.16 g, 0.42 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 3 h. Then an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) was added, and the reaction mixture was stirred at 40 °C for 1 h. The mixture was poured into water, and extracted with ethyl acetate three time. The combined extract was washed with water, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (0-100% EtOAc in dichloromethane) to give rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-N-(4-(2- hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-b]pyridine]-5-carboxamide as a light yellow solid (40 mg, 21%).
MS (ES+) m z Calcd for C3iH33BrClFN405+ H [(M+H)+]: 675, found: 675.
Example 74
Preparation of rac-(2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2- hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-b]pyridine]-5-carboxamide
Figure imgf000085_0001
M. W. 631.53 C3iH33Cl2FN405
To a solution of E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 40, 0.15 g, 0.49 mmol) in tetrahydrofuran (1.5 mL) was added anhydrous LiOH (23 mg, 0.97 mmol). The mixture was warmed to 40 °C and stirred for 10 min. 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester (Example 70, 0.27 g, 0.73 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 2 h. Then an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) was added, and the reaction mixture was stirred at 40 °C for 1 h. The mixture was poured into water, and extracted with ethyl acetate three time. The combined extract was washed with water, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (0-100% EtOAc in dichloromethane) to give rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-N-(4-(2- hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-b]pyridine]-5-carboxamide as a yellow solid (51 mg, 17%). MS (ES+) m/z Calcd for C3iH33Cl2FN405+ H [(M+H)+]: 631, found: 631.
Example 75
Preparation of chiral (2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2- hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-b]pyridine]-5-carboxamide
Figure imgf000086_0001
M. W. 631.53 C3iH33Cl2FN405
Rac-(2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridm^ 5-carboxamide (Example 74, 0.11 g) was separated by chiral SFC chromatography to provide chiral (2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]- 5-carboxamide as a off white solid (10 mg, 9%) and chiral (2R,3R,4R,5S)-6'-chloro-4-(3-chloro- 2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide as an off white solid (12 mg, 11%).
MS (ES+) m z Calcd for C3iH33Cl2FN405+ H [(M+H)+]: 631, found: 631.
Example 76
Preparation of intermediate E/Z- 6-bromo-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydr( pyrrolo[3,2-b]pyridin-2-one
Figure imgf000086_0002
M. W. 353.58 Ci4H7BrClFN20
To the mixture of 6-bromo-4-aza-2-oxindole (Sinova, 0.3 g, 1.4 mmol) and 3-chloro-2- fluorobenzaldehyde (Oakwood, 0.45 g, 2.8 mmol) in methanol (20 mL) was added piperidine
(Aldrich, 0.36 g, 4.2 mmol) dropwise. The reaction mixture was heated at 50 °C and stirred for 3 h. Then the mixture was cooled to room temperature and filtered. The resulting precipitate was collected and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (25-50% EtOAc in hexanes) to give the second batch of product. The two batches were combined to give E/Z- 6-bromo-3-(3-chloro-2-fluoro- benzylidene)-l,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a yellow solid (0.35 g, 70 %).
Example 77
Preparation of methyl rac-4-((2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000087_0001
M. W. 673.96 C3iH3iBrClFN405
To a solution of E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 76, 0.16 g, 0.45 mmol) in tetrahydrofuran (10 mL) was added anhydrous LiOH (11 mg, 0.45 mmol). The mixture was warmed to 40 °C and stirred for 10 min. 4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-benzoic acid methyl ester (Example 3, 0.15 g, 0.48 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 18 h. The mixture was cooled to room temperature and filtered. The rsulting precipitate was collected, washed with ethyl acetate, and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (5-10% EtOAc in dichlormethane) to give the second batch of desired product. The two batches were combined to give methyl rac-4-((2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate as a white solid (32 mg, 10%).
MS (ES+) m/z Calcd for C3iH3iBrClFN405+ H [(M+H)+]: 673, found: 673. Example 78
Preparation of rac-4-((2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fl
l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3^
acid
Figure imgf000088_0001
M. W. 659.94 C3oH29BrClFN405
To a solution of methyl rac-4-((2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate (Example 77, 25 mg, 0.037 mmol) in tetrahydrofuran (6 mL) was added an aqueous solution (1 N) of NaOH (2 mL, 2 mmol). The reaction mixture was stirred at room temperature for 20 h. The "pH" of the mixture was adjusted to 3 by aqueous HCl solution, then concentrated to a small volume. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgS04, and concentrated to give rac-4-((2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoic acid as a white solid (19 mg, 78%).
MS (ES+) m/z Calcd for C3oH29BrClFN405+ H [(M+H)+]: 659, found: 659.
Example 79
Preparation of rac-(2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-
5-carboxamide
Figure imgf000089_0001
M. W. 640.94 CsoHssBrClFNsOs
To a solution of E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 76, 0.2 g, 0.57 mmol) in tetrahydrofuran (2 mL) was added anhydrous LiOH (27 mg, 1.1 mmol). The mixture was warmed to 40 °C and stirred for 10 min. N-(4-cyano-2-methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (Example 61, 0.24 g, 0.85 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 1 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated. The resulting precipitate was filtered and collected to give rac-(2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-N-(4- cyano-2-methoxyphenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- b]pyridine]-5-carboxamide as a yellow solid (80 mg, 22%). MS (ES+) m/z Calcd for
C30H28BrClFN5O3+ H [(M+H)+]: 640, found: 640.
Example 80
Preparation of rac-(2S,3S,4S,5R)-6'-bromo-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5- carboxamide
Figure imgf000089_0002
M. W. 658.95 C3oH3oBrClFN504
To a solution of rac-(2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2- methoxyphenyl)-2-neopentyl-2'-oxo- 1 \2'-dih^
5-carboxamide (Example 79, 70 mg, 0.11 mmol) in DMSO (0.5 mL) at 0 °C was added an aqueous solution (30%) of H2O2 (Aldrich, 0.19 g, 1.6 mmol), followed by the addition of aqueous solution (1 N) of NaOH (0.54 mL, 0.54 mmol). The reaction mixture was stirred at 0 °C for 1 h. The mixture was partitioned bewteen ethyl acetate and saturated aqueous Na2S03 solution.. The organic layer was separated, washed with water, brine, dried over MgS04, and concentrated to give rac-(2S,3S,4S,5R)-6'-bromo-N-(4-carbamoyl-2-methoxyphenyl)-4-(3- chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- b]pyridine] -5-carboxamide as a off white solid (56 mg, 78%). MS (ES+) m/z Calcd for
C30H3oBrClFN504+ H [(M+H)+]: 658, found: 658.
Example 81
Preparation of rac-(2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-(2- hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-b]pyridine]-5-carboxamide
Figure imgf000090_0001
M. W. 675.98 C3iH33BrClFN405
To a solution of E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 76, 0.2 g, 0.57 mmol) in tetrahydrofuran (2 mL) was added anhydrous LiOH (27 mg, 1.1 mmol). The mixture was warmed to 40 °C and stirred for 10 min. 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester (Example 70, 0.31 g, 0.85 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 3 h. Then an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) was added, and the reaction mixture was stirred at 40 °C for 1 h. The mixture was poured into water, and extracted with ethyl acetate three time. The combined extract was washed with water, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (0-100% EtOAc in dichloromethane) to give rac-(2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-(2- hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-b]pyridine]-5-carboxamide as a light yellow solid (65 mg, 17%).
MS (ES+) m/z Calcd for C3iH33BrClFN405+ H [(M+H)+]: 675, found: 675.
Example 82
Preparation of intermediate E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-fluoro-l,3-dihydro- pyrrolo[3,2-b]pyridin-2-one
Figure imgf000091_0001
M. W. 292.67 Ci4H7ClF2N20
To the mixture of 6-fluoro-4-aza-2-oxindole (Sinova, 1 g, 4.6 mmol) and 3-chloro-2- fluorobenzaldehyde (Oakwood Products, 1.2 g, 7.6 mmol) in methanol (50 mL) was added piperidine (Aldrich, 2 g, 24 mmol) dropwise. The reaction mixture was stirred at room temperature for 10 h. Then the mixture was filtered. The resulting precipitate was collected to give the first batch of desired product. The filtrate was concentrated. The residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second btach of desire product. The two batches were combined to give E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-fluoro-l,3-dihydro- pyrrolo[3,2-b]pyridin-2-one as a yellow solid (Yield 1.1 g, 82%).
Example 83
Preparation of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-fluoro-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000092_0001
M. W. 613.058 C3iH3iClF2N405
To a solution of E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-fluoro-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 82, 0.3 g, 1 mmol) in tetrahydrofuran (10 niL) was added anhydrous LiOH (25 mg, 1 mmol). The mixture was warmed to 40 °C and stirred for 10 min. 4-{2-[3,3- dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-benzoic acid methyl ester (Example 3, 0.33 g, 1 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 24 h. The mixture was cooled to room temperature and filtered. The rsulting precipitate was collected, washed with ethyl acetate, and dried to give the first batch of desired product. The filtrate was concentrated, and the residue was purified by chromatography (5-10% EtOAc in dichlormethane) to give the second batch of desired product. The two batches were combined to give methyl rac- 4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-fluoro-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate as a white solid (0.21g, 33%). MS (ES+) m/z Calcd for C3IH3IC1F2N405+ H [(M+H)+]: 613, found: 613.
Example 84
Preparation of rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-fluoro-2-neopentyl-2'-oxo- 1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid
Figure imgf000093_0001
M. W. 599.03 C3oH29ClF2N405
To a solution of methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-fluoro-2-neopentyl- 2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate (Example 83, 0.21 g, 0.34 mmol) in tetrahydrofuran (8 mL) was added an aqueous solution (1 N) of NaOH (2 mL, 2 mmol). The reaction mixture was stirred at 60 °C for 24 h. The "pH" of the mixture was adjusted to 3 by aqueous HCl solution, then concentrated to a small volume. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgS04, and concentrated to give rac-4- ((2S ,3S ,4S ,5R)-4-(3-chloro-2-fluorophenyl)-6'-fluoro-2-neopentyl-2'-oxo- Γ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (0.19 g, 93%). MS (ES+) m/z Calcd for C30H29ClF2N4O5+ H [(M+H)+]: 599, found: 599.
Example 85
Preparation of rac-(2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-
6'-fluoro-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5- carboxamide
Figure imgf000094_0001
C30H28CIF2N5O3
To a solution of E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-fluoro-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 82, 0.18 g, 0.62 mmol) in tetrahydrofuran (2 mL) was added anhydrous LiOH (30 mg, 1.2 mmol). The mixture was warmed to 40 °C and stirred for 10 min. N-(4-cyano-2-methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (Example 61, 0.27 g, 0.92 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 1 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated. The resulting precipitate was filtered and collected to give rac-(2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2- methoxyphenyl)-6'-fluoro-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- b]pyridine]-5-carboxamide as a white solid (40 mg, 11%). MS (ES+) m/z Calcd for
C30H28CIF2N5O3+ H [(M+H)+]: 580, found: 580.
Example 86
Preparation of rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2- fluorophenyl)-6'-fluoro-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2b]pyridine]-5-carboxamide
Figure imgf000094_0002
M. W. 598.05 C3oH3oClF2N504
To a solution of rac-(2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)- 6'-fluoro-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5- carboxamide (Example 85, 30 mg, 0.52 mmol) in DMSO (0.3 mL) at 0 °C was added an aqueous solution (30%) of H202 (Aldrich, 0.088 g, 0.78 mmol) , followed by the addition of aqueous solution (1 N) of NaOH (0.26 mL, 0.26 mmol). The reaction mixture was stirred at 0 °C for 1 h. The mixture was partitioned bewteen ethyl acetate and saturated aqueous Na2S03 solution. The organic layer was separated, washed with water, brine, dried over MgS04, and concentrated to give rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2- fluorophenyl)-6'-fluoro-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- b]pyridine]-5-carboxamide as an off white solid (24 mg, 78%). MS (ES+) m/z Calcd for
C3oH30ClF2N504+ H [(M+H)+]: 598, found: 598.
Example 87
Preparation of rac-(2S,3S,4S,5R)- 4-(3-chloro-2-fluorophenyl)-N-[4-(2-hydroxyethoxy)-2- methoxyphenyl]-6'-fluoro-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2b]pyridine]-5-carboxamide
Figure imgf000095_0001
M. W. 615.07 C3iH33ClF2N405
To a solution of E/Z-3-(3-chloro-2-fluoro-benzylidene)-6-fluoro-l,3-dihydro-pyrrolo[3,2- b]pyridin-2-one (Example 82, 0.15 g, 0.51 mmol) in tetrahydrofuran (2 mL) was added anhydrous LiOH (25 mg, 1 mmol). The mixture was warmed to 40 °C and stirred for 10 min. 2- (4- { 2- [3 ,3-dimethyl-but-(E)-ylideneamino] -acetylamino } -3-methoxy-phenoxy)-ethyl ester
(Example 70, 0.28 g, 0.77 mmol) prepared in was added in one portion. The reaction mixture was stirred at 40 °C for 3 h. Then an aqueous solution (1 N) of NaOH (1 mL, 1 mmol) was added, and the reaction mixture was stirred at 40 °C for 1 h. The mixture was poured into water, and extracted with ethyl acetate three time. The combined extract was washed with water, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (0-100% EtOAc in dichloromethane) to give rac-(2S,3S,4S,5R)- 4-(3-chloro-2-fluorophenyl)-N-[4-(2- hydroxyethoxy)-2-methoxyphenyl]-6'-fluoro-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine- 3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide as a light yellow solid (55 mg, 17%). MS (ES+) m/z Calcd for C3iH33ClF2N4C>5+ H [(M+H)+]: 615, found: 615.
Example 88
Preparation of intermediate E/Z-2-chloro-5-(3-chloro-2-fluoro-benzylidene)-5,7-dihydr( pyrrolo[2,3-d]pyrimidin-6-one
Figure imgf000096_0001
M. W. 310.12 C13H6CI2FN3O
To a mixture of 2-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (Molbridge, 0.5 g, 3.0 mmol) in acetic acid (8 mL) and aqueous concentrated HC1 solution (37%, 2 mL) was added 3-chloro-2- fluorobenzaldehyde (Oakwood, 0.9 g, 5.7 mmol). The reaction mixture was stirred at room temperature for 24 h. The mixture was neutralized to "pH" 7-8 by aqueous saturated NaHC03 solution, then extracted with ethyl acetate several times. The combined organic extract was washed with water, brine, dried over MgS04, and concentrated to a small volume. The resulting precipitate was collected and dried to give the first batch of desired product. The filtrate was concentrated, and residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desired product. The two batches were combined to give E/Z-2-chloro-5-(3- chloro-2-fluoro-benzylidene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one as a yellow solid (0.51 g, 56 %). Example 89
Preparation of rac-(2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-[4-(2- hydroxyethoxy)-2-methoxyphenyl]-2-neopentyl-6'-oxo-6',7'-dihydrospiro[pyrrolidine-3,5'- pyrrolo[2,3-d]pyrimidine]-5-carboxamide
Figure imgf000097_0001
M. W. 632.52 C3oH32Cl2FN505
To a solution of E/Z-2-chloro-5-(3-chloro-2-fluoro-benzylidene)-5,7-dihydro-pyrrolo[2,3- d]pyrimidin-6-one (Example 88, 0.3 g, 0.97 mmol) in tetrahydrofuran (3 mL) was added anhydrous LiOH (23 mg, 0.97 mmol). The mixture was warmed to 40 °C and stirred for 10 min. 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)-ethyl ester (Example 70, 0.53 g, 1.5 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 2 h. Then an aqueous solution (1 N) of NaOH (1.5 mL, 1.5 mmol) was added, and the reaction mixture was stirred at 40 °C for 1 h. The mixture was poured into water, and extracted with ethyl acetate three time. The combined extract was washed with water, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (0-80% EtOAc in dichloromethane) to give rac-(2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-[4-(2- hydroxyethoxy)-2-methoxyphenyl]-2-neopentyl-6'-oxo-6',7'-dihydrospiro[pyrrolidine-3,5'- pyrrolo[2,3-d]pyrimidine]-5-carboxamide as a yellow solid (25 mg, 4%). MS (ES+) m/z Calcd for C30H32Cl2FN5O5+ H [(M+H)+] : 632, found: 632.
Example 90
Preparation of methyl rac-4-{(2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 6'-oxo-6\7'-dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3- methoxybenzoate
Figure imgf000098_0001
M. W. 630.50 C30H30CI2FN5O5
To a solution of E/Z-2-chloro-5-(3-chloro-2-fluoro-benzylidene)-5,7-dihydro-pyrrolo[2,3- d]pyrimidin-6-one (Example 88, 0.2 g, 0.65 mmol) in tetrahydrofuran (15 mL) was added anhydrous LiOH (15 mg, 0.65 mmol). The mixture was warmed to 40 °C and stirred for 10 min. 4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-benzoic acid methyl ester (Example 3, 0.22 g, 0.68 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 5 h. The mixture was cooled to room temperature and concentrated. The residue was purified by chromatography (5-10% EtOAc in dichlormethane) to give methyl rac-4- {(2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6'-oxo-6',7'- dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoate as a white solid (0.12 g, 28%). MS (ES+) m/z Calcd for C30H30CI2FN5O5+ H [(M+H)+]: 630, found: 630. Example 91
Preparation of methyl rac-4-{(2S,3S,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 6'-oxo-6\7'-dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3- methoxybenzoate
Figure imgf000098_0002
M. W. 630.50 C30H30CI2FN5O5
In the preparation of methyl rac-4-{ (2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-6'-oxo-6^7'-dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5- ylcarboxamido}-3-methoxybenzoate as described in Example 90, methyl rac-4- {(2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6'-oxo-6',7'- dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoate was obtained as another product by chromatography (5-10% EtOAc in dichlormethane): Yield 45 mg, 11%, a white solid. MS (ES+) m/z Calcd for C30H30CI2FN5O5+ H [(M+H)+]: 630, found: 630.
Example 92
Preparation of rac-4-{ (2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6'-oxo- 6',7'-dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3- methoxybenzoic acid
Figure imgf000099_0001
M. W. 616.47 C29H28CI2FN5O5
To a solution of methyl rac-4-{(2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-6'-oxo-6',7'-dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5- ylcarboxamido}-3-methoxybenzoate (Example 90, 98 mg, 0.16 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (I N) of NaOH (1 mL, 1 mmol). The reaction mixture was stirred at 60 °C for 24 h. The "pH" of the mixture was adjusted to 3 by aqueous HC1 solution, then concentrated to a small volume. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgS04, and concentrated to give rac-4-{(2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 6'-oxo-6\7'-dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3- methoxybenzoic acid as a white solid (90 mg, 94%). MS (ES+) m/z Calcd for C29H28CI2FN5O5+ H [(M+H)+]: 616, found: 616.
Example 93
Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-6'-oxo-6\7'-dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]- 5-carboxamide
Figure imgf000100_0001
M. W. 615.49 C29H29Cl2FN604
To a solution of rac-4-{(2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6'- oxo-6^7'-dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3- methoxybenzoic acid (Example 92, 90 mg, 0.15 mmol) in anhydrous DMF (2 mL) were added EDCI (56 mg, 0.29 mmol), HOBt (39 mg, 0.29 mmol), NH4C1 (77 mg, 1.5 mmol), and
triethylamine (30 mg, 0.29 mmol) sequentially. The reaction mixture was heated at 68 °C for 1 h. The mixture was partitioned bewteen ethyl acetate and water.. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgS04, and concentrated. The residu was purified by chromatography (25-100% EtOAc in dichloromethane) to give rac-(2S,3R,4S,5R)-N-(4- carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6'-oxo-6',7'- dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-carboxamide as a light yellow solid (67 mg, 75%). MS (ES+) m/z Calcd for C29H29CI2FN6C + H [(M+H)+]: 615, found: 615.
Example 94
Preparation of intermediate 2-chloro-4, -dihydro-thieno[3,2-b]pyrrol-5-one
Figure imgf000100_0002
M. W. 173.62 C4H4C1N0S
Step a: To a solution of 2,5-dichlorothiophene (Aldrich, 21 g, 137 mmol) in concentrated H2S04 (59 niL) at 0 °C was added a fine powder form of NaN03 (28 g, 412 mmol) in one portion. The reaction mixture was stirred at 0 °C for 2 min when a brown fume began to appear. The reaction mixture was poured into the mixture of ice-water and ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (1% EtOAc in hexanes) to give 2,5-dichloro-3-nitrothiophene as a yellow oil (17 g, 63%).
Step b: To a solution of tert-butyl ethyl malonate (Alfa, 16.2 g, 86 mmol) in anhydrous DMSO (50 mL) were added NaH (Aldrich, 60%, 5.15 g, 129 mmol). The mixture was heated at 100 °C for 1 h, the cooled to room temperature. 2,5-Dichloro-3-nitrothiophene (17 g, 86 mmol) was added in one portion. The reaction mixture was heated at 60 °C for 2 h. The mixture was cooled to room temperature, and water and dilute aqueous HCl solution were slowly added. The mixture was extracted with ethyl acetate twice times. The combined organic extract was washed with water, brine, dried over MgS04, and concentrated. Trifluoroacetic acid (50 mL) was added. The reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and saturated aqueous NaHC03 solution. The organic layer was separated, washed with water, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (0-20% EtOAc in hexanes) to give ethyl 2-(5-chloro-3- nitrothiophen-2-yl)acetate as a brown oil (10 g, 61%).
Step c: To a solution of ethyl 2-(5-chloro-3-nitrothiophen-2-yl)acetate (10 g, 40 mmol) in methanol (200 mL) was added an aqueous solution (40 mL) of NH4C1 (17 g, 320 mmol), followed by activated Zinc (Aldrich, 15.7 g, 240 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered through a short pad of celite. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgS04, and concentrated. The residue was purified by chromatography (20-50% EtOAc in hexanes) to give ethyl 2-(3-amino-5- chlorothiophen-2-yl) acetate as a yellow oil (7 g, 80%). Step d: To a flask charged with ethyl 2-(3-amino-5-chlorothiophen-2-yl)acetate (6.7 g, 31 mmol) was added anhydrous toluene (30 mL). The mixture was evaporated to dryness. The process was repeated three times. To the residue was added toluene (300 mL), and the temperature of the solution was lowered to 0 °C. A toluene solution (2 N) of trimethylaluminum (38 mL, 76 mmol) was added. The reaction mixture was stirred at 10 °C for 0.5 h, then quenched by methanol (10 mL) slowly. The mixture was poured into saturated aqueous NH4C1 solution, and extracted with ethyl acetate twice. The combined organic extract was dried over MgS04 and concentrated to give warmed to room temperature and stirred for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, saturated aqueous CuS04 solution, brine, dried over MgS04, and concentrated to give crude 2- chloro-4,6-dihydro-thieno[3,2-b]pyrrol-5-one as a black solid (5.4 g, 75%).
Example 95
Preparation of intermediate E/Z-2-chloro-6-(3-chloro-2-fluorobenzylidene)-4H-thieno[3,2- b]pyrrol-5(6H)-one
Figure imgf000102_0001
M. W. 314.17 Ci3H6Cl2FNOS
To a mixture of 2-chloro-4,6-dihydro-thieno[3,2-b]pyrrol-5-one (Example 94, 4.2 g, 24 mmol) in acetic acid (60 mL) and aqueous concentrated HC1 solution (37%, 15 mL) was added 3- chloro-2-fluorobenzaldehyde (Oakwood, 7.5 g, 47 mmol). The reaction mixture was stirred at room temperature for 24 h. The mixture was filtered, and the resulting precipitate was collected, washed with ethyl acetate, and dried to give the first batch of desire product. The filtrate was concentrated, and the residue was neutralized to "pH" 7-8 by aqueous saturated NaHC03 solution, then extracted with ethyl acetate several times. The combined organic extract was washed with water, brine, dried over MgS04, and concentrated and residue was purified by chromatography (20-40% EtOAc in hexanes) to give the second batch of desired product. The two batches were combined to give E/Z-2-chloro-6-(3-chloro-2-fluorobenzylidene)-4H- thieno[3,2-b]pyrrol-5(6H)-one as a brown solid (5.1 g, 69 %). Example 96
Preparation of methyl rac-4-((2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-
5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000103_0001
M. W. 634.55 C30H30CI2FN3O5S
To a solution of E/Z-2-chloro-6-(3-chloro-2-fluorobenzylidene)-4H-thieno[3,2-b]pyrrol-5(6H)- one (Example 95, 0.37 g, 1.2 mmol) in tetrahydrofuran (10 mL) was added anhydrous LiOH (28 mg, 1.2 mmol). The mixture was warmed to 40 °C and stirred for 10 min. 4-{2-[3,3-dimethyl- but-(E)-ylideneamino]-acetylamino}-3-methoxy-benzoic acid methyl ester (Example 3, 0.4 g, 1.3 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 60 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated. The residue was purified by chromatography (5-10% EtOAc in dichlormethane) to give methyl rac-4-((2S,3R,4R,5R)-2'- chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'- thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate as a brown solid (90 mg, 12%). MS (ES+) m/z Calcd for C30H30CI2FN3O5S + H [(M+H)+]: 634, found: 634.
Example 97
Preparation of methyl rac-4-((2S,3S,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-
5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000104_0001
M. W. 634.55 C30H30CI2FN3O5S
In the preparation of methyl rac-4-((2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-5'-oxo-4^5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3- methoxybenzoate as described in Example 96, methyl rac-4-((2S,3S,4R,5R)-2'-chloro-4-(3- chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2- b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate was obtained as another product by chromatography (5-10% EtOAc in dichlormethane): Yield 30 mg, 4%, a brown solid. MS (ES+) m/z Calcd for C30H30CI2FN3O5S + H [(M+H)+]: 634, found: 634.
Example 98
Preparation of rac-4-{ (2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo- 4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido}- 3-methoxybenzoic acid
Figure imgf000104_0002
M. W. 620.53 C29H28CI2FN3O5S
To a solution of methyl rac-4-{(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3- methoxybenzoate (Example 96, 90 mg, 0.14 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (1 niL, 1 mmol) and methanol (1 mL). The reaction mixture was stirred at room temperature for 18 h. The "pH" of the mixture was adjusted to 3-6 by aqueous HC1 solution. The mixture was concentrated to a small volume, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic extracts were combined, washed with water, brine, dried over MgS04, and concentrated to give rac-4-{(2S,3R,4R,5R)-2'-chloro-4-(3-chloro- 2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- ylcarboxamido}-3-methoxybenzoic acid as a off white solid (75 mg, 85%). MS (ES+) m/z Calcd for C29H28CI2FN3O5S + H [(M+H)+]: 620, found: 620.
Example 99
Preparation of chiral 4-{(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'- oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3- methoxybenzoic acid
Figure imgf000105_0001
M. W. 620.53 C29H28CI2FN3O5S
Rac-4-{(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid (Example 98, 0.15 g) was separated by chiral SFC chromatography to provide chiral 4- {(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid as a yellow solid (39 mg, 24%) and chiral 4-{(2R,3S,4S,5S)-2'-chloro-4-(3-chloro-2-fluorophenyl)-
2- neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-
3- methoxybenzoic acid as an off white solid (41 mg, 25%). MS (ES+) m/z Calcd for
C29H28CI2FN3O5S+H [(M+H)+] : 620, found: 620. Example 100
Preparation of rac-(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-5'-oxo-4\5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- carboxamide
Figure imgf000106_0001
M. W. 619.54 C29H29C12FN404S
To a solution of rac-4-{(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'- oxo-4^5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3- methoxybenzoic acid (220 mg, 0.36 mmol) in anhydrous DMF (2 niL) were added EDCI
(Example 98, 136 mg, 0.71 mmol), HOBt (96 mg, 0.71 mmol), NH4C1 (188 mg, 3.55 mmol), and triethylamine (72 mg, 0.71 mmol) sequentially. The reaction mixture was heated at 68 °C for 1 h. The mixture was cooled to room temperature, then partitioned bewteen ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgS04, and
concentrated. The residu was purified by chromatography (25-100% EtOAc in dichloromethane) to give rac-(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- carboxamide as a light brown solid (170 mg, 77%). MS (ES+) m/z Calcd for C29H29C12FN404S+ H [(M+H)+]: 619, found: 619.
Example 101
Preparation of chiral (2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- carboxamide
Figure imgf000107_0001
M. W. 619.54 C29H29C12FN404S
Rac-(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-5'-oxo-4^5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide
(Example 100, 0.17 g) was separated by chiral SFC chromatography to provide chiral
(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide as a light yellow solid (70 mg, 41%) and chiral (2R,3S,4S,5S)-N-(4-carbamoyl-2-methoxyphenyl)-2'- chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'- thieno[3,2-b]pyrrole]-5-carboxamide as a light yellow solid (68 mg, 40%). MS (ES+) m/z Calcd for C29H29C12FN404S + H [(M+H)+]: 619, found: 619.
Example 102
Preparation of rac-(2S,3S,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2- methoxyphenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- carboxamide
Figure imgf000107_0002
M. W. 601.53 C29H27C12FN403S To a solution of E/Z-2-chloro-6-(3-chloro-2-fluorobenzylidene)-4H-thieno[3,2-b]pyrrol-5(6H)- one (Example 95, 0.15 g, 0.48 mmol) in tetrahydrofuran (1 mL) was added anhydrous LiOH (23 mg, 0.96 mmol). The mixture was warmed to 40 °C and stirred for 10 min. N-(4-cyano-2- methoxy-phenyl)-2-[3,3-dimethyl-but-(E)-ylideneamino]-acetamide (Example 61, 0.23 g, 0.79 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 1 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated. The residue was purified by chromatography (0-20% EtOAc in dichlormethane) to give rac-(2S,3S,4R,5R)-2'-chloro-4-(3- chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide as a purple solid (40 mg, 14%). MS (ES+) m/z Calcd for CigHiTCliFN^S + H [(M+H)+]: 601, found: 601.
Example 103
Preparation of rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- carboxamide
Figure imgf000108_0001
M. W. 619.54 C29H29C12FN404S
To a solution of rac-(2S,3S,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2- methoxyphenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- carboxamide (Example 102, 28 mg, 0.47 mmol) in DMSO (0.2 mL) at 0 °C was added an aqueous solution (30% Aldrich) of H2O2 (0.079 g, 0.7 mmol) , followed by the addition of aqueous solution (1 N) of NaOH (0.23 mL, 0.23 mmol). The reaction mixture was stirred at 0 °C for 1 h. The mixture was partitioned bewteen ethyl acetate and saturated aqueous Na2S03 solution.. The organic layer was separated, washed with water, brine, dried over MgS04, and concentrated to give rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3- chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4\5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2- b]pyrrole]-5-carboxamide as a purple solid (Yield 25 mg, 87%). MS (ES+) m/z Calcd for C29H29C12FN404S+ H [(M+H)+]: 619, found: 619. Example 104
Preparation of intermediate rac-(2S,3R,4R,5R)-tert-butyl 2'-chloro-4-(3-chloro-2-fluorophenyl)- 2-neopentyl-5'-oxo-4^5'-dihydrospiro[ rrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxylate
Figure imgf000109_0001
M. W. 527.49 C25H29C12FN203S
To a solution of E/Z-2-chloro-6-(3-chloro-2-fluorobenzylidene)-4H-thieno[3,2-b]pyrrol-5(6H)- one (Example 95, 0.9 g, 2.9 mmol) in tetrahydrofuran (20 mL) was added anhydrous LiOH (97 mg, 4.1 mmol). The mixture was warmed to 40 °C and stirred for 10 min. [3,3-dimethyl-but-(E)- ylideneamino] -acetic acid tert-butyl ester (Example 5, Step a, 1.8 g, 8.4 mmol) was added in one portion. The reaction mixture was stirred at 40 °C for 66 h. The mixture was cooled to room temperature and filtered through a short pad of silica gel. The silica gel was washed with ethyl acetate. The filtrate was concentrated. The residue was purified by chromatography (10-33% EtOAc in dichlormethane) to give rac-(2S,3R,4R,5R)-tert-butyl 2'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- carboxylate as a white solid (0.18 g, 12%).
Example 105
Preparation of intermediate rac-(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxylic acid trifluoroacetic acid
Figure imgf000110_0001
M. W. 471.38 C21H21CI2FN2O3S.C2HF3O2
A solution of rac-(2S,3R,4R,5R)-tert-butyl 2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'- oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxylate (Example 104, 64 mg, 0.12 mmol) in dichloromethane (2 mL) was added trifluoroacetic aicd (3 mL). The reaction mixture was stirred at room temperature for 24 h, then concentrated. The residue was then triturated with ethyl ether and hexanes, concentrated, dried in vacuo to give rac-(2S,3R,4R,5R)- 2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'- thieno[3,2-b]pyrrole]-5-carboxylic acid trifluoroacetic acid as an off white solid (71 mg, 100%).
Example 106
Preparation of intermediate 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-2-methoxy- phenylamine
Figure imgf000110_0002
M. W. 297.47 C15H27NO3S1
A suspension of tert-butyl-[2-(3-methoxy-4-nitro-phenoxy)-ethoxy] -dimethyl- silane (Example 70, Step b, 1 g, 3.05 mmol) and Pd/C (Aldrich, 10%, 0.1 g) in ethyl acetate (25 mL) was vigorously shaken in a Parr under atmosphere of ¾ (50 psi) for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 4-[2-(tert-butyl-dimethyl- silanyloxy)-ethoxy]-2-methoxy-phenylamine as a light yellow oil (0.9 g, 99%).
Example 107
Preparation of rac-(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2- hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'- thieno[3,2-b]pyrrole]-5-carboxamide
Figure imgf000111_0001
M. W. 636.57 C30H32CI2FN3O5S
To a solution of rac-(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo- 4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxylic acid trifluoroacetic acid (Example 105, 0.18 g, 0.31 mmol) in dichloromethane (5 niL) was added diisopropylethylamine (0.2 g, 1.5 mmol), diphenylphosphinic chloride (Aldrich, 0.15 g, 0.61 mmol) respectively. The mixture was stirred at room temperature for 8 min, then 4-(2-(tert- butyldimethylsilyloxy)ethoxy)-2-methoxyaniline (0.14 g, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 3 h.The mixture was concentrated. The residue was dissolved into tetrahydrofuran (5 mL), and an aqueous solution (I N) of HC1 ( 1 mL, 1 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over Na2S04, then concentrated. The residue was purified by
chromatography (10-100% of EtOAc in CH2C12) to give rac-(2S,3R,4R,5R)-2'-chloro-4-(3- chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide as a yellow solid (0.1 g, 51%). HRMS (ES+) m/z Calcd for C30H32CI2FN3O5S + H [(M+H)+]: 636, found: 636. Example 108
Preparation of chiral (2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2- hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'- thieno[3,2-b]pyrrole]-5-carboxamide
Figure imgf000112_0001
M. W. 636.57 C30H32CI2FN3O5S
Rac-(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-5'-oxo-4\5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- carboxamide (Example 107, 93 mg) was separated by chiral SFC chromatography to provide chiral (2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- carboxamide as a off white solid (25 mg, 27%) and chiral (2R,3S,4S,5S)-2'-chloro-4-(3-chloro-2- fluorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide as an off white solid (33 mg, 36%). MS (ES+) m/z Calcd for C30H32CI2FN3O5S + H [(M+H)+]: 637, found: 637.
Example 109
Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-methoxy-l,3-dihydro- pyrrolo[3,2-c]pyridin-2-one
Figure imgf000112_0002
M.W. 304.71 C15H10C1FN2O2
In a manner similar to the method described in Example 12, 6-methoxy-lH-pyrrolo[3,2- c]pyridin-2(3H)-one (Sinova, 489 mg, 2.98 mmol) was reacted with 3-chloro-2- fluorobenzaldehyde (Oakwood Products, 1.42 g, 8.94 mmol) and piperidine (Lancaster, 1.03 g, 1.2 mL, 12.1 mmol) in methanol (20 mL) to give E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6- - I l l - methoxy-l,3-dihydro-pyrrolo[3,2-c]pyridin-2-one as a light yellow solid (835 mg, 92%). MS (ES+) m/z [(M+H)+]: 305
Example 110
Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methoxy-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-
3-methoxybenzoate
Figure imgf000113_0001
M.W. 625.10 C32H34C1FN406
In a manner similar to the method described in Example 13, E/Z-3-(3-Chloro-2-fluoro- benzylidene)-6-methoxy-l,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (300 mg, 0.985 mmol,
Example XI) was reacted with anhydrous LiOH (14 mg, 0.585 mmol) and (E)-methyl 4-(2-(3,3- dimethylbutylideneamino)acetamido)-3-methoxybenzoate (329 mg, 1.03 mmol, Example 3) at 40 °C for 23 h to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methoxy-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate as a white solid (188 mg, 30%). MS (ES+) m/z [(M+H)+]: 625
Example 111
Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methoxy-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3- methoxybenzoic acid
Figure imgf000114_0001
M.W. 611.08 C31H32C1FN406
In a manner similar to the method described in Example 14, methyl rac-4-((2S,3R,4S,5R)-4-(3- chloro-2-fluorophenyl)-6'-methoxy-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 110, 86 mg, 0.14 mmole) was reacted with LiOH hydrate (57 mg, 1.36 mmol) in water to give rac-4- ((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methoxy-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (76 mg, 98%). MS (ES+) m/z [(M+H)+]: 611
Example 112
Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-hydroxy-l,3-dihydro- pyrrolo[3,2-c]pyridin-2-one
Figure imgf000114_0002
M.W. 290.68 C14H8C1FN202
In a manner similar to the method described in Example 12, 6-hydroxy-lH-pyrrolo[3,2- c]pyridin-2(3H)-one (Sinova, 700 mg, 4.66 mmol) was reacted with 3-chloro-2- fluorobenzaldehyde (Oakwood Products, 2.20 g, 13.9 mmol) and piperidine (Lancaster, 1.59 g, 18.7 mmol) to give E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-hydroxy-l,3-dihydro-pyrrolo[3,2- c]pyridin-2-one as a light brown solid (683 mg, 50%). MS (ES+) m/z [(M+H)+]: 291 Example 113
Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-hydroxy-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-
3-methox benzoate
Figure imgf000115_0001
M.W. 611.08 C31H32C1FN406
In a manner similar to the method described in Example 13, E/Z-3-(3-Chloro-2-fluoro- benzylidene)-6-hydroxy-l,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (300 mg, 0.985 mmol,
Example 112) was reacted with anhydrous LiOH (17.5 mg, 0.73 mmol) and (E)-methyl 4-(2- (3,3-dimethylbutylideneamino)acetamido)-3-methoxybenzoate (405 mg, 1.26 mmol, Example 3) at 40 °C for 23 h to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-hydroxy-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate as a white solid (253 mg, 32%). MS (ES+) m/z [(M+H)+]: 611 Example 114
Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-hydroxy-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3- methox benzoic acid
Figure imgf000115_0002
M.W. 597.05 C30H30C1FN4O6 In a manner similar to the method described in Example 14, methyl rac-4-((2S,3R,4S,5R)-4-(3- chloro-2-fluorophenyl)-6'-methoxy-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 113, 99 mg, 0.16 mmole) was reacted with LiOH hydrate (62 mg, 1.49 mmol) in water to give rac-4- ((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-hydroxy-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (87 mg, 90%). MS (ES+) m/z [(M+H)+]: 597
Example 115
Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2- fluorophenyl)-6'-methoxy-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- c] ridine]-5-carboxamide
Figure imgf000116_0001
M.W. 610.09 C31H33C1FN505
In a manner similar to the method described in Example 19, rac-4-((2S,3R,4S,5R)-4-(3-chloro- 2-fluorophenyl)-6'-methoxy-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (40 mg, 0.065 mmol, Example 111) was reacted with 1,1 -carbonyldiimidazole (Aldrich, 52 mg, 0.32 mmol) in THF (3 mL) followed by work-up with ammonium hydroxide (310 mg, 8.84 mmol) to give rac-(2S,3R,4S,5R)-N-(4- carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6'-methoxy-2-neopentyl-2'-oxo- ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (11 mg, 26%). MS (ES+) m/z [(M+H)+]: 610
Example 116
Preparation of rac-2-(4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3- methoxyphenoxy)ethyl acetate
Figure imgf000117_0001
M.W. 673.57 C33H35C12FN406
In a manner similar to the method described in Example 71, E/Z-6-Chloro-3-(3-chloro-2-fluoro- benzylidene)-l,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (Example 23, 245 mg, 0.795 mmole) was reacted with 2-(4-{2-[3,3-dimethyl-but-(E)-ylideneamino]-acetylamino}-3-methoxy-phenoxy)- ethyl ester (Example 70, 316 mg, 0.867 mmol) and anhydrous LiOH (14 mg, 0.60 mmol) to give rac-2-(4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3- methoxyphenoxy)ethyl acetate as an off-white solid. MS (ES+) m/z [(M+H)+]: 655
Example 117
Preparation of rac-(2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2- hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-c]pyridine]-5-carboxamide
^OH M.W. 631.54 C31H33C12FN405
In a manner similar to the method described in Example 72, rac-2-(4-((2S,3R,4S,5R)-6'-chloro- 4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- c]pyridine]-5-ylcarboxamido)-3-methoxyphenoxy)ethyl acetate was reacted with aqueous NaOH in THF to give rac-(2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2- hydroxyethoxy)-2-methoxyphenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solide. MS (ES+) m/z [(M+H)+]: 631.
Example 118
Preparation of intermediate E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-methyl-l,3-dihyd:
pyrrolo[3,2-c]pyridin-2-one
Figure imgf000118_0001
M.W. 288.71 C15H10C1FN2O
In a manner similar to the method described in Example 12, 6-methyl-lH-pyrrolo[3,2-c]pyridin- 2(3H)-one (Sinova, 750 mg, 5.06 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (Oakwood Products, 2.40 g, 15.1 mmol) and piperidine (Lancaster, 172 g, 20.2 mmol) to give E/Z-3-(3-Chloro-2-fluoro-benzylidene)-6-methyl-l,3-dihydro-pyrrolo[3,2-c]pyridin-2-one as a light brown solid (623 mg, 41%). MS (ES+) m/z [(M+H)+]: 289
Example 119
Preparation of methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000119_0001
M.W. 609.10 C32H34C1FN405
In a manner similar to the method described in Example 13, E/Z-3-(3-Chloro-2-fluoro- benzylidene)-6-methyl-l,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (318 mg, 1.10 mmol, Example 118) was reacted with anhydrous LiOH (19 mg, 0.81 mmol) and (E)-methyl 4-(2-(3,3- dimethylbutylideneamino)acetamido)-3-methoxybenzoate (393 mg, 1.23 mmol, Example 3) at 40 °C for 23 h to give methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate as a white solid (146 mg, 21%). MS (ES+) m/z [(M+H)+]: 609
Example 120
Preparation of rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo- l 2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic
Figure imgf000119_0002
M.W. 595.08 C31H32C1FN405
In a manner similar to the method described in Example 14, methyl rac-4-((2S,3R,4S,5R)-4-(3- chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example Xll, 136 mg, 0.22 mmole) was reacted with LiOH hydrate (78 mg, 1.87 mmol) in water to give rac-4- ((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-meth^ acid as a white solid (118 mg, 88%). MS (ES+) m/z [(M+H)+]: 595 Example 121
Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2- fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- c] ridine]-5-carboxamide
Figure imgf000120_0001
M.W. 594.09 C31H33C1FN504
In a manner similar to the method described in Example 19, rac-4-((2S,3R,4S,5R)-4-(3-chloro- 2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (21 mg, 0.034 mmol, Example 120) was reacted with 1,1 -carbonyldiimidazole (Aldrich, 27 mg, 0.165 mmol) in THF (3 mL) followed by work-up with ammonium hydroxide (0.18 mL mg, 4.62 mmol) to give rac-(2S,3R,4S,5R)-N-(4- carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo- ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide as a white solid (20 mg, 97%). MS (ES+) m/z [(M+H)+]: 594
Example 122
Preparation of intermediate E/Z- 7-Chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro- pyrrolo[3,2-b]pyridin-2-one
Figure imgf000121_0001
M.W. 309.13 C14H7C12FN20
In a manner similar to the method described in Example 12, 7-chloro-lH-pyrrolo[3,2-b]pyridin- 2(3H)-one (Sinova, 500 mg, 2.97 mmol) was reacted with 3-chloro-2-fluorobenzaldehyde (Oakwood Products, 1.010 g, 8.9 mmol) and piperidine (Lancaster, 1.01 g, 11.9 mmol) to give E/Z- 7-Chloro-3-(3-chloro-2-fluoro-benzylidene)-l,3-dihydro-pyrrolo[3,2-b]pyridin-2-one as a light brown solid (615 mg, 67%). MS (ES+) m/z [(M+H)+]: 309
Example 123
Preparation of methyl rac-4-((2S,3S,4S,5R)-7'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxybenzoate
Figure imgf000121_0002
M.W. 629.52 C31H31C12FN405
In a manner similar to the method described in Example 13, E/Z- 7-Chloro-3-(3-chloro-2-fluoro- benzylidene)-l,3-dihydro-pyrrolo[3,2-b]pyridin-2-one (301 mg, 0.974 mmol, Example 122) was reacted with anhydrous LiOH (17 mg, 0.697 mmol) and (E)-methyl 4-(2-(3,3- dimethylbutylideneamino)acetamido)-3-methoxybenzoate (326 mg, 1.02 mmol, Example 3) at 40 °C for 23 h to give methyl rac-4-((2S,3S,4S,5R)-7'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)- 3-methoxybenzoate as a white solid (38 mg, 6%). MS (ES+) m/z [(M+H)+]: 629
Example 124
Preparation of rac-4-((2S,3S,4S,5R)-7'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid
Figure imgf000122_0001
M.W. 615.49 C30H29C12FN4O5
In a manner similar to the method described in Example 14, methyl rac-4-((2S,3S,4S,5R)-7'- chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'- pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate (Example 123, 32 mg, 0.052 mmole) was reacted with LiOH hydrate (17 mg, 0.42 mmol) in water to give rac-4- ((2S ,3S ,4S ,5R)-7'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- 1 ',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid as a white solid (30 mg, 95%). MS (ES+) m/z [(M+H)+]: 615
Example 125
Preparation of rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2- fluorophenyl)-2-neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5- carboxamide
Figure imgf000123_0001
M.W. 614.51 C30H30C12FN5O4
In a manner similar to the method described in Example 19, rac-4-((2S,3S,4S,5R)-7'-chloro-4- (3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2- b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid (16 mg, 0.026 mmol, Example 124) was reacted with 1,1 -carbonyldiimidazole (Aldrich, 19 mg, 0.115 mmol) in THF (3 mL) followed by work-up with ammonium hydroxide (126 mg, 3.6 mmol) to give rac-(2S,3R,4S,5R)-N-(4- carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-carboxamide as a white solid (11 mg, 65%). MS (ES+) m/z [(M+H)+]: 614
Example 126
: V SU' Aci h ,V-s y
The ability of the compounds to inhibit the interaction between p53 and MDM2 proteins was measured by an HTRF (homogeneous time-resolved fluorescence) assay in which recombinant GST-tagged MDM2 binds to a peptide that resembles the MDM2-interacting region of p53. Binding of GST-MDM2 protein and p53-peptide (biotinylated on its N-terminal end) is registered by the FRET (fluorescence resonance energy transfer) between Europium (Eu)-labeled anti-GST antibody and streptavidin-conjugated Allophycocyanin (APC).
Test is performed in black flat-bottom 384-well plates (Costar) in a total volume of 40 uL containing:90 nM biotinylate peptide, 160 ng/ml GST-MDM2, 20 nM streptavidin-APC (PerkinElmerWallac), 2 nM Eu-labeled anti- GST- antibody (PerkinElmerWallac), 0.2% bovine serum albumin (BSA), 1 mM dithiothreitol (DTT) and 20 mM Tris-borate saline (TBS) buffer as follows: Add 10 uL of GST-MDM2 (640 ng/ml working solution) in reaction buffer to each well. Add 10 uL diluted compounds (1:5 dilution in reaction buffer) to each well, mix by shaking. Add 20 uL biotinylated p53 peptide (180 nM working solution) in reaction buffer to each well and mix on shaker. Incubate at 37°C for 1 h. Add 20 uL streptavidin-APC and Eu- anti-GST antibody mixture (6 nM Eu-anti-GST and 60 nM streptavidin-APC working solution) in TBS buffer with 0.2% BSA, shake at room temperature for 30 minutes and read using a TRF capable plate reader at
665 and 615 nm (Victor 5, Perkin ElmerWallac). if not specified, the reagents were purchased from Sigma Chemical Co.
Activity data for some of the Example compounds expressed as IC50: bsa: 0.02%' are as follows ampl Number IC50: bsa: 0.02%
6 0.0324
13 0.0303
28 0.0105
35 0.0145
39 0.0084
47 0.0345
52 0.0050
56A 0.0050
63 0.0146
66 1.8332
69 0.0129
75 0.0064
83 0.0195
86 0.0187
101 0.0046
89 0.0117
91 0.0107
96 0.0227
99 0.0054
110 0.0136
111 0.007
113 >10
114 >10 115 0.127
116 0.012
117 0.014
119 0.0116
120 0.012
121 0.0118
123 6.253
124 1.013
126 0.005

Claims

Claims
1. A compound of the formula
Figure imgf000126_0001
wherein in the case of (f) A is a bond;
R5 is selected from the group consisting of H, F, CI, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy;
R6 is selected from the group consisting of H, F, CI, methyl;
R7 is selected from the group consisting of H, F, CI, methyl;
R8 is selected from the group consisting of H, F, CI, methyl;
Ri and R2 are independently selected from the group consisting of lower alkyl,
substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;
R3 and R4 are selected from the group consisting of (CH2)n-R\ (CH2)n-NR'R", (CH2)n-
NR'COR", (CH2)n-NR'S02R", (CH2)n-COOH, (CH2)n-COOR\ (CH2)n-CONR'R", (CH2)n-OR\ (CH2)„-SR\ (CH2)n-SOR', (CH2)n-S02R', (CH2)n-COR', (CH2)n-S03H, (CH2)n-SONR'R", (CH2)n-S02NR'R", (CH2CH20)m-(CH2)n-R', (CH2CH20)m-(CH2)n-OH, (CH2CH20)m-(CH2)n- OR\ (CH2CH20)m-(CH2)n-NR'R", (CH2CH20)m-(CH2)n-NR'COR", (CH2CH20)m-(CH2)n- NR'S02R", (CH2CH20)m-(CH2)n-COOH, (CH2CH20)m-(CH2)n-COOR', (CH2CH20)m-(CH2)n- CONR'R", (CH2CH20)m-(CH2)n-S02R\ (CH2CH20)m-(CH2)n-COR', (CH2CH20)m-(CH2)n- SONR'R", (CH2CH20)m-(CH2)n-S02NR'R", (CH2)p-(CH2CH20)m-(CH2)n-R' , (CH2)p- (CH2CH20)m-(CH2)n-OH, (CH2)p-(CH2CH20)m-(CH2)n-OR' , (CH2)p-(CH2CH20)m-(CH2)n- NR'R", (CH2)p-(CH2CH20)m-(CH2)„-NR'COR", (CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", (CH2)p-(CH2CH20)m-(CH2)n-COOH, (CH2)p-(CH2CH20)m-(CH2)n-COOR' , (CH2)p- (CH2CH20)m-(CH2)n-CONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02R', (CH2)p-(CH2CH20)m-
(CH2)n-COR', (CH2)p-(CH2CH20)m-(CH2)n-SONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COR', -SOR' and S02R'
wherein R' and R' ' are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, hetereoaryl, substituted hetereoaryl, hetereocycle or substituted hetereocycle or R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or
unsubstituted heterocycle;
m, n and p are independently 0 to 6; or
a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, with the specific configuration shown in formula II
Figure imgf000127_0001
wherein
Figure imgf000128_0001
s selected from the group consisting of
Figure imgf000128_0002
wherein in the case of (f) A is a bond;
R5 is selected from the group consisting of H, F, CI, Br, I, cyano, nitro, ethynyl, cyclopropyl, methyl, ethyl, isopropyl, vinyl and methoxy;
R6 is selected from the group consisting of H, F, CI and methyl;
R7 is selected from the group consisting of H, F, CI and methyl;
R8 is selected from the group consisting of H, F, CI and methyl;
Ri and R2 are independently selected from the group consisting of lower alkyl,
substituted lower alkyl, lower alkenyl, substituted lower alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl, substituted cycloalkyl, cycloalkenyl and substituted cycloalkenyl;
R3 and R4 are selected from the group consisting of (CH2)n-R\ (CH2)n-NR'R", (CH2)n-
NR'COR", (CH2)n-NR'S02R", (CH2)n-COOH, (CH2)n-COOR\ (CH2)n-CONR'R", (CH2)n-OR\ (CH2)n-SR\ (CH2)n-SOR\ (CH2)n-S02R\ (CH2)n-COR\ (CH2)n-S03H, (CH2)n-SONR'R", (CH2)n-S02NR'R", (CH2CH20)m-(CH2)n-R\ (CH2CH20)m-(CH2)n-OH, (CH2CH20)m-(CH2)n- OR', (CH2CH20)m-(CH2)n-NR'R", (CH2CH20)m-(CH2)n-NR'COR", (CH2CH20)m-(CH2)n- NR'S02R", (CH2CH20)m-(CH2)n-COOH, (CH2CH20)m-(CH2)n-COOR\ (CH2CH20)m-(CH2)n- CONR'R", (CH2CH20)m-(CH2)n-S02R', (CH2CH20)m-(CH2)n-COR', (CH2CH20)m-(CH2)n- SONR'R", (CH2CH20)m-(CH2)n-S02NR'R", (CH2)p-(CH2CH20)m-(CH2)n-R' , (CH2)P- (CH2CH20)m-(CH2)n-OH, (CH2)p-(CH2CH20)m-(CH2)n-OR' , (CH2)p-(CH2CH20)m-(CH2)n- NR'R", (CH2)p-(CH2CH20)m-(CH2)n-NR'COR", (CH2)p-(CH2CH20)m-(CH2)n-NR'S02R", (CH2)p-(CH2CH20)m-(CH2)n-COOH, (CH2)p-(CH2CH20)m-(CH2)n-COOR', (CH2)P-
(CH2CH20)m-(CH2)n-CONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02R', (CH2)p-(CH2CH20)m- (CH2)n-COR' , (CH2)p-(CH2CH20)m-(CH2)n-SONR'R", (CH2)p-(CH2CH20)m-(CH2)n-S02NR'R", -COR', -SOR' and S02R'
wherein R' and R' ' are independently selected from H, lower alkyl, substituted lower alkyl, lower cycloalkyl, substituted lower cycloalkyl, lower alkenyl, substituted lower alkenyl, lower cycloalkenyl, substituted lower cycloalkenyl, aryl, substituted aryl, hetereoaryl, substituted hetereoaryl, hetereocycle or substituted hetereocycle or R and R may independently link to form a cyclic structure selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl or substituted or
unsubstituted heterocycle;
m, n and p are independently 0 to 6; or
a pharmaceutically acceptable salt thereof.
3. The compound of claims 1 or 2 wherein R5 is F, CI or Br. 4. The compound of claims 1 or 2 wherein R6 , R7, R8 are all hydrogen.
5. The compound of claims 1 or 2 wherein R2 is selected from the group consisting of aryl, aryl substitued with CI, F or Br, and heteroaryl optionally substituted with H, F, CI or Br. 6. The compound of claims 1 or 2 wherein Ri is a substituted lower alkyl of the formula
Figure imgf000129_0001
where
R9 and Rio are both methyl; or alternatively,
R9 and Rio together with the carbon to which they are attached form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl ;
R11 is (CH2)q-Ri2i where q is 0, 1 or 2; and
Ri2 is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle and substituted heterocycle.
7. The compound of claims 1 or 2, wherein
one of R3 and R4 is hydrogen, and the other is (CH2)n-R' ;
R' is aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle; and
n is 0 or 1.
8. The compound of claims 1 and 2 wherein
R5 is selected from F, CI or Br;
R6 , R7, R8 are hydrogen;
R2 is selected from the group consisting of aryl, aryl substitued with CI or F or Br, and heteroaryl optionally substituted with H, F or CI or Br;
Ri is a substituted lower alkyl of the formula
Figure imgf000130_0001
where
R9 and Rio are both methyl; or alternatively
R9 and Rio together with the carbon to which they are attached form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl;
R11 is (CH2)q-Ri2, where q is 0, 1 or 2;
R12 is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle and substituted heterocycle;
one of R3 and R4 is hydrogen, and the other is (CH2)n-R' ;
R' is selected from aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle; and
n is 0 or 1.
. A compound of the formula
Figure imgf000131_0001
wherein
R5 is selected from F, CI or Br;
R6 , R7, Rg are hydrogen; and
R2 is selected from the group consisting
Figure imgf000131_0002
wherein
Ri3 is F, CI or Br;
Ri4 is H or F; and
Ri is a substituted lower alkyl of the formula
Figure imgf000132_0001
R9 and Rio are both methyl; or alternatively
R9 and Rio together with the carbon to which they are attached form a ring selected from cyclopropyl, cyclobutyl, cyclopentyl or acyclohexyl;
R11 is (CH2)q-Ri2, where q is 0, 1 or 2;
R12 is selected from the group consisting of hydrogen, hydroxyl, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle and substituted heterocycle;
one of R3 and R4 is hydrogen, and the other is (CH2)n-R';
R' is selected from aryl, substituted aryl, hetereoaryl, substituted heteroaryl, hetereocycle or substituted heterocycle; and
n is 0 or 1 ; or
a pharmaceutically acceptable salt thereof.
10. A compound of claim 2 selected from the group consisting of
methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide;
methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate; rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid; rac-(2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide;
methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- di ydrospiro[pyrrolidine-3,3'-pyrroto acid; methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l,,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoate;
rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)benzoic acid;
methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoate and rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-2-methoxybenzoic acid.
11. A compound of claim 2 selected from the group consisting of
rac-(2S,3R,4S,5R)-N-(4-carbamoyl-3-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2-neopentyl- 2'-oxo-r,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-carboxamide;
methyl rac-4-((2S ,3 S ,4S ,5R)-4-(3 -chloro-2-fluorophenyl)-2-neopentyl-2'-oxo- Γ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide; methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate;
rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoic acid;
methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoate and rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'- di ydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)benzoic acid.
12. A compound of claim 2 selected from the group consisting of
methyl rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; chiral methyl 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; chiral 4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; chiral (2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide; methyl rac-4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; methyl rac-4-((2S,3S,4S,5R)-5'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-5'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-7'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid and
chiral methyl 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate.
A compound of claim 2 selected from the group consisting of chiral methyl 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]py
chiral 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; chiral (2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2-fluorophenyl)- 2-neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide; chiral 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; chiral (2R,3S,4R,5S)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2-fluorophenyl)- 2-neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide; chiral 4-((2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; chiral 4-((2R,3R,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid; chiral methyl 4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate;
chiral methyl 4-((2R,3S,4R,5S)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)benzoate;
methyl rac-4-{ (2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate; rac-4- { (2S ,3S ,4R,5R)-6'-chloro-4-(3 -chlorophenyl)-2-neopentyl-2'-oxo- Γ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoic acid; rac-(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-N-(4-cyano-2-methoxyphenyl)- 2-neopentyl-2'- oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide and
rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chlorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide.
14. A compound of claim 2 selected from the group consisting of
methyl rac-4-{ (2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate; methyl rac-4-{ (2S,3R,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoate; rac-4- { (2S ,3S ,4S ,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-2-neopentyl-2'-oxo- Γ,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido}-3-methoxybenzoic acid; rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-N-(4-cyano-2-methoxyphenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; rac-2-(4-((2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3- methoxyphenoxy)ethyl acetate;
rac-(2S,3S,4R,5R)-6'-chloro-4-(3-chlorophenyl)-N-(4-(2-hydroxyethoxy)-2-methoxyphenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; rac-(2S,3S,4S,5R)-4-(3-bromo-2-fluorophenyl)-6'-chloro-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]- 5-carboxamide;
rac-(2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]- 5-carboxamide;
chiral (2S,3S,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-
5-carboxamide;
methyl rac-4-((2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid and
rac-(2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2- neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]- 5-carboxamide.
15. A compound of claim 2 selected from the group consisting of
rac-(2S,3S,4S,5R)-6'-bromo-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; rac-(2S,3S,4S,5R)-6'-bromo-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]- 5-carboxamide;
methyl rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-fluoro-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-((2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-fluoro-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]^ acid; rac-(2S,3S,4S,5R)-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-6'-fluoro-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; rac-(2S,3S,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6'-fluoro-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-carboxamide; rac-(2S,3S,4S,5R)- 4-(3-chloro-2-fluorophenyl)-N-[4-(2-hydroxyethoxy)-2-methoxyphenyl]-6'- fluoro-2-neopentyl-2'-oxo- ,2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5- carboxamide;
rac-(2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-[4-(2-hydroxyethoxy)-2- methoxyphenyl]-2-neopentyl-6'-oxo-6',7'-dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3- d]pyrimidine]-5-carboxamide;
methyl rac-4-{ (2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6'-oxo-6',7'- dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxyb methyl rac-4-{ (2S,3S,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6'-oxo-6',7'- dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoate; rac-4-{(2S,3R,4S,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-6'-oxo-6',7'- dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-ylcarboxamido}-3-methoxybenzoic acid;
rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-6'-oxo-6',7'-dihydrospiro[pyrrolidine-3,5'-pyrrolo[2,3-d]pyrimidine]-5-carboxamide and
methyl rac-4-((2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate.
16. A compound of claim 2 selected from the group consisting of
methyl rac-4-((2S,3S,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido)-3-methoxybenzoate; rac-4-{(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid; chiral 4-{(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-5'-oxo-4',5'- dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-ylcarboxamido}-3-methoxybenzoic acid; rac-(2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-5'-oxo-4',5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide; chiral (2S,3R,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2-fluorophenyl)- 2-neopentyl-5'-oxo-4^5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide; rac-(2S,3S,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-cyano-2-methoxyphenyl)-2- neopentyl-5'-oxo-4^5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide;
rac-(2S,3S,4R,5R)-N-(4-carbamoyl-2-methoxyphenyl)-2'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-5'-oxo-4^5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5-carboxamide;
rac-(2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-5'-oxo-4\5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5- carboxamide and
chiral (2S,3R,4R,5R)-2'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-5'-oxo-4\5'-dihydrospiro[pyrrolidine-3,6'-thieno[3,2-b]pyrrole]-5^ carboxamide.
17. A compound of claim 2 selected from the group consisting of
methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methoxy-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methoxy-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid, methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-hydroxy-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-hydroxy-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid, rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6'-methoxy- 2-neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide, rac-2-(4-((2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3- methoxyphenoxy)ethyl acetate,
rac-(2S,3R,4S,5R)-6'-chloro-4-(3-chloro-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-2- methoxyphenyl)-2-neopentyl-2'-oxo-l\2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]- 5-carboxamide,
methyl rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, rac-4-((2S,3R,4S,5R)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2-neopentyl-2'-oxo-l',2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid , rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-4-(3-chloro-2-fluorophenyl)-6'-methyl-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-c]pyridine]-5-carboxamide methyl rac-4-((2S,3S,4S,5R)-7'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoate, rac-4-((2S,3S,4S,5R)-7'-chloro-4-(3-chloro-2-fluorophenyl)-2-neopentyl-2'-oxo-r,2'- dihydrospiro[pyrrolidine-3,3'-pyrrolo[3,2-b]pyridine]-5-ylcarboxamido)-3-methoxybenzoic acid and
rac-(2S,3R,4S,5R)-N-(4-carbamoyl-2-methoxyphenyl)-6'-chloro-4-(3-chloro-2-fluorophenyl)-2- neopentyl-2'-oxo-1^2'-dihydrospiro[pyrrolidine-3,3'-pyrrolo[2,3-b]pyridine]-5-carboxamide.
18. A pharmaceutical composition comprising a compound of claim 2, or a pharmaceutically acceptable salt thereof, as an active ingredient together with a pharmaceutically acceptable carrier or excipient. 19. A compound according to any one of claims 1 to 17 for use as medicament.
20. A compound according to any one of claims 1 to 17 for use as medicament for the therapeutic and/or prophylactic treatment of solid tumors, in particular breast, colon, lung and prostate tumors.
21. The use of a compound according to any one of claims 1 to 17 for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of solid tumors, in particular breast, colon, lung and prostate tumors. 22. A method of treating or ameliorating cancer comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any of claims 1-16.
23. The novel compounds, processes, methods and uses substantially as described
hereinabove.
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8629133B2 (en) 2011-03-10 2014-01-14 Daiichi Sankyo Company, Limited Dispiropyrrolidine derivatives
WO2014128094A1 (en) 2013-02-21 2014-08-28 F. Hoffmann-La Roche Ag Asymmetric synthesis of a substituted pyrrolidine-2-carboxamide
US8846657B2 (en) 2012-12-20 2014-09-30 Merck Sharp & Dohme Corp. Substituted imidazopyridines as HDM2 inhibitors
WO2016001376A1 (en) 2014-07-03 2016-01-07 Boehringer Ingelheim International Gmbh New spiro[3h-indole-3,2´-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors
JP2016510028A (en) * 2013-02-28 2016-04-04 アムジエン・インコーポレーテツド Benzoic acid derivative MDM2 inhibitors for the treatment of cancer
US9359368B2 (en) 2012-09-06 2016-06-07 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
WO2017060431A1 (en) 2015-10-09 2017-04-13 Boehringer Ingelheim International Gmbh Spiro[3h-indole-3,2´-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors
WO2017201449A1 (en) 2016-05-20 2017-11-23 Genentech, Inc. Protac antibody conjugates and methods of use
WO2018027477A1 (en) 2016-08-08 2018-02-15 肖飞 Spirocyclic indolone polyethylene glycol carbonate compound, composition, preparation method and use thereof
CN112707846A (en) * 2019-10-25 2021-04-27 成都伊诺达博医药科技有限公司 Preparation method of dacomitinib key intermediate
WO2023056069A1 (en) 2021-09-30 2023-04-06 Angiex, Inc. Degrader-antibody conjugates and methods of using same

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011060049A2 (en) 2009-11-12 2011-05-19 The Regents Of The University Of Michigan Spiro-oxindole mdm2 antagonists
UA109464C2 (en) 2010-11-12 2015-08-25 Дзе Ріджентс Оф Дзе Юніверсіті Оф Мічіган Spiro-oxindoles as mdm2 antagonists
CA2835422C (en) 2011-05-11 2016-10-11 The Regents Of The University Of Michigan Spiro-oxindole mdm2 antagonists
US9745314B2 (en) 2014-04-17 2017-08-29 The Regents Of The University Of Michigan MDM2 inhibitors and therapeutic methods using the same
CA2958193C (en) 2014-08-18 2024-02-27 Hudson Biopharma Inc. Spiropyrrolidines as mdm2 inhibitors
CN108299438B (en) * 2017-01-13 2022-05-17 国家纳米科学中心 PH-responsive near-infrared fluorescent probe compound and preparation method and application thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006091646A2 (en) * 2005-02-22 2006-08-31 The Regents Of The University Of Michigan Small molecule inhibitors of mdm2 and uses thereof
WO2008132139A2 (en) 2007-04-27 2008-11-06 Ucb Pharma S.A. New heterocyclic derivatives useful for the treatment of cns disorders
WO2010031713A1 (en) * 2008-09-18 2010-03-25 F. Hoffmann-La Roche Ag Substituted pyrrolidine-2-carboxamides
WO2011061139A1 (en) * 2009-11-17 2011-05-26 F. Hoffmann-La Roche Ag Substituted pyrrolidine-2-carboxamides
WO2011067185A1 (en) * 2009-12-02 2011-06-09 F. Hoffmann-La Roche Ag Spiroindolinone pyrrolidines

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006091646A2 (en) * 2005-02-22 2006-08-31 The Regents Of The University Of Michigan Small molecule inhibitors of mdm2 and uses thereof
WO2008132139A2 (en) 2007-04-27 2008-11-06 Ucb Pharma S.A. New heterocyclic derivatives useful for the treatment of cns disorders
WO2010031713A1 (en) * 2008-09-18 2010-03-25 F. Hoffmann-La Roche Ag Substituted pyrrolidine-2-carboxamides
WO2011061139A1 (en) * 2009-11-17 2011-05-26 F. Hoffmann-La Roche Ag Substituted pyrrolidine-2-carboxamides
WO2011067185A1 (en) * 2009-12-02 2011-06-09 F. Hoffmann-La Roche Ag Spiroindolinone pyrrolidines

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Design of Prodrugs", 1985, ELSEVIER
ANSEL ET AL., PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS, 1995, pages 456 - 457
H. ANSEL ET AL.: "Pharmaceutical Dosage Forms and Drug Delivery Systems", 1995, pages: 108 - 109
J. ORG. CHEM, vol. 56, 1991, pages 4805 - 4808
KROGSGAARD-LARSEN ET AL.: "Textbook of Drug Design and Development", 1996, pages: 152 - 191
M. CHEUNG ET AL., TETRAHEDRON LETT., vol. 42, 2001, pages 999
S. HU ET AL., J. HETEROCYCLIC. CHEM., vol. 42, 2005, pages 661

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8629133B2 (en) 2011-03-10 2014-01-14 Daiichi Sankyo Company, Limited Dispiropyrrolidine derivatives
US9884871B2 (en) 2012-09-06 2018-02-06 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US10023578B2 (en) 2012-09-06 2018-07-17 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US9745315B2 (en) 2012-09-06 2017-08-29 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US9718830B2 (en) 2012-09-06 2017-08-01 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US9359368B2 (en) 2012-09-06 2016-06-07 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US9540386B2 (en) 2012-09-06 2017-01-10 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US10030030B2 (en) 2012-09-06 2018-07-24 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US9718831B2 (en) 2012-09-06 2017-08-01 Daiichi Sankyo Company, Limited Crystals of dispiropyrrolidine derivatives
US8846657B2 (en) 2012-12-20 2014-09-30 Merck Sharp & Dohme Corp. Substituted imidazopyridines as HDM2 inhibitors
WO2014128094A1 (en) 2013-02-21 2014-08-28 F. Hoffmann-La Roche Ag Asymmetric synthesis of a substituted pyrrolidine-2-carboxamide
JP2016510028A (en) * 2013-02-28 2016-04-04 アムジエン・インコーポレーテツド Benzoic acid derivative MDM2 inhibitors for the treatment of cancer
WO2016001376A1 (en) 2014-07-03 2016-01-07 Boehringer Ingelheim International Gmbh New spiro[3h-indole-3,2´-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors
WO2017060431A1 (en) 2015-10-09 2017-04-13 Boehringer Ingelheim International Gmbh Spiro[3h-indole-3,2´-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors
WO2017201449A1 (en) 2016-05-20 2017-11-23 Genentech, Inc. Protac antibody conjugates and methods of use
WO2018027477A1 (en) 2016-08-08 2018-02-15 肖飞 Spirocyclic indolone polyethylene glycol carbonate compound, composition, preparation method and use thereof
CN112707846B (en) * 2019-10-25 2023-04-21 成都伊诺达博医药科技有限公司 Preparation method of dacatinib key intermediate
CN112707846A (en) * 2019-10-25 2021-04-27 成都伊诺达博医药科技有限公司 Preparation method of dacomitinib key intermediate
WO2023056069A1 (en) 2021-09-30 2023-04-06 Angiex, Inc. Degrader-antibody conjugates and methods of using same

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