WO2001010798A1 - Solid phase synthesis of oxa- and thiazoles - Google Patents

Solid phase synthesis of oxa- and thiazoles Download PDF

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Publication number
WO2001010798A1
WO2001010798A1 PCT/US2000/021051 US0021051W WO0110798A1 WO 2001010798 A1 WO2001010798 A1 WO 2001010798A1 US 0021051 W US0021051 W US 0021051W WO 0110798 A1 WO0110798 A1 WO 0110798A1
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Prior art keywords
alkyl
aryl
formula
hetero
hydrogen
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PCT/US2000/021051
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French (fr)
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Barry A. Bunin
Steven P. Tushup
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Chemrx Advanced Technologies, Inc.
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Priority to AU63966/00A priority Critical patent/AU6396600A/en
Publication of WO2001010798A1 publication Critical patent/WO2001010798A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the present invention relates to solid phase and combinato ⁇ al synthesis of oxazole and thiazole de ⁇ vatives.
  • Organic compounds of potential therapeutic interest are traditionally synthesized and evaluated one at a time, thus dramatically limiting the number of de ⁇ vatives that can be synthesized and screened against a specific receptor or enzyme.
  • Oxazoles and thiazoles are a class of heterocychc compounds having potential use as pharmaceuticals. There is thus a continuing need for processes that facilitate the synthesis of a large number of compounds in a relatively short period of time.
  • the present invention provides a
  • X' is O or S
  • R 1 is -R 3 , -NR 3 R 4 , -NR 3 C(NR 4 )NR 3 R 4 or -NR 3 C(O)NR 3 R 4 wherein R 3 is
  • R 4 is hydrogen or (C 1-6 )alkyl, wherein any aromatic moiety comprising R 1 optionally is substituted with 1 to 3 substituents independently selected from halo, nitro, cyano, (C ]-6 )alkyl, halo-substituted(d_ 6 )alkyl, -OR 5 , -C(O)R 5 , -C(O)OR 5 , -C(O)NR 5 R 5 , -S(O) 2 NR 5 R 5 , - X 3 NR 5 R 5
  • R 2 is -CH 2 OH, -C(O)NR 9 R 10 or -C(O)OR n , wherein R 9 , R 10 and R n independently are hydrogen, (C ⁇ . 6 )alkyl, (C 3 _ ⁇ )cycloalkyl(C ⁇ _ 3 )alkyl, hetero(C 3 - ⁇ 2 )cycloalkyl(C i -3 )alkyl , (C 6 _ x 2 )aryl(C 0 - 6 )alkyl , hetero(C 5 .
  • R 8 is (i) hydrogen, (ii) (C ⁇ _ 6 )alkyl optionally substituted with -OR 17 , -SR 17 , - S(O)R 17 , -S(O) 2 R 17 , -C(O)R 17 , -C(O)OR 17 , -C(O)NR 17 R 18 , -NR 17 R 18 , -NR 18 C(O)R 17 , -NR 18 C(O)OR 17 ,-NR I8 C(O)NR 17 R 18 or -NR 18 C(NR 18 )NR 17 R 18 , wherein R 17 is (C j - 6 )alkyl , (C i .
  • R 1 , X 1 and X 2 are as defined above and "SS" represents a solid support
  • Another aspect of the preferred invention provides a process for synthesizing a compound or an array of compounds of Formula ⁇ ,
  • X 1 is O or S;
  • R 1 is -R 3 , -NR 3 R 4 , -NR 3 C(NR 4 )NR 3 R 4 or -NR 3 C(O)NR 3 R 4 wherein R 3 is
  • R 4 is hydrogen or (C ⁇ _ 6 )alkyl, wherein any aromatic moiety comprising R optionally is substituted with 1 to 3 substituents independently selected from halo, nitro, cyano, (C ⁇ -6 )alkyl, halo-substituted(C,- 6 )alkyl, -OR 5 , -C(O)R 5 , -C(O)OR 5 , -C(O)NR 5 R 5 , -S(O) 2 NR 5 R 5 , - X 3 NR 5 R 5 , -X 3 NR 5 C(O)R 5 , -X 3 NR 5 C(O)OR 5 , -X 3 NR 5 C(O)NR 5 R 5 and - X 3 NR 3 C(NR 5 )NR 5 R 5 , wherein X 3 is
  • R 2 is -CH 2 OH, -C(O)NR 9 R 10 or -C(O)OR ⁇ , wherein R 9 , R 10 and R n independently are hydrogen, (C ⁇ _ 6 )alkyl, (C 3- ⁇ 2 )cycloalkyl(C ⁇ . 3 )alkyl, hetero(C 3 .
  • R 12 is -OR 13 or -NR 13 R 14 , wherein R 13 and R 14 are independently hydrogen, (C ⁇ -6 )alkyl, (C 6 - ⁇ 2 )aryl(C 0 - 6 )alkyl, polycyclo(C 6 _ ⁇ 2 )aryl(C 0 .
  • R 1 and X 1 are as defined above and "SS" represents a solid support
  • step (i) comprises treating a compound of Formula A with a compound of Formula B in the presence of a coupling agent selected from DIC, PyBOP or HATU and an acylation catalyst selected from DMAP or 4-pyrrolidinopyridine.
  • a coupling agent selected from DIC, PyBOP or HATU
  • an acylation catalyst selected from DMAP or 4-pyrrolidinopyridine.
  • a preferred embodiment is a process wherein step (1) comprises treating a compound of Formula D with a compound of Formula B in the presence of a coupling agent selected from DIC, PyBOP or HATU and an acylation catalyst selected from DMAP or 4-pyrrolidinopyridine.
  • a coupling agent selected from DIC, PyBOP or HATU
  • an acylation catalyst selected from DMAP or 4-pyrrolidinopyridine.
  • a further preferred process of the present invention is one wherein steps (i) and (1) are carried out in the presence of an inert solvent selected from DCM, THF and chloroform and at a temperature ranging from about 15°C to about 35°C.
  • an inert solvent selected from DCM, THF and chloroform
  • step (ii) and (2) are selected from THF, methylene chloride, DCM, ethyl acetate, DMF, dioxane, chloroform and DMSO; and the reactions are carried out at a temperature ranging from about -30°C to about 35°C.
  • a further preferred embodiment of the present invention is where the reducing agent in steps (ii)(a) and (2)(a) is LiBrL;. Preferred is a process wherein steps (ii)(b) and (2)(b) are carried out at a temperature ranging from about 10°C to about 50°C.
  • Another aspect of the present invention provides an array of compounds synthesized by the processes of the present invention.
  • Yet another aspect of the present invention provides a process for synthesizing a compound or an array of compounds of Formula C.
  • Preferred is a process for synthesizing a compound or an array of compounds of Formula E.
  • a compound of Formula B (1 equivalent) and a coupling agent, preferably DIC (1 equivalent), are dissolved in an inert solvent (e.g., DCM; 15 mL/g of Formula B). The resulting solution is allowed to stand for 5 to 15 minutes.
  • the compound of Formula A (1-10 equivalents) is swelled in a suitable inert solvent (e.g., DCM at lOmL/g of Formula A) and added to the mixture of Formula B, DIC and DCM.
  • An acylation catalyst e.g., DMAP; 0.4-1.2 equivalents
  • the mixture is agitated, with frequent venting, at a temperature between about 10°C and about 40°C for about 10 to about 24 hours.
  • the resin is isolated from solvents and washed free of contaminants and dried to yield purified compound of Formula C.
  • the resin is typically washed in succession with: 1:1 DCM:THF (xl); DCM (x2); MeOH (x2); and dioxane (x3); and dried under reduced pressure.
  • Compounds of Formula I where R" is CH 2 OH, are prepared by treating compounds of Formula C with a reducing agent (alkaline borohydrides e.g., NaBfLi or LiBFL t ).
  • a reducing agent alkaline borohydrides e.g., NaBfLi or LiBFL t .
  • the reaction typically is carried out by mixing an inert solvent suspension of the compound of Formula C with a reducing agent, preferably LiBFLi, in a suitable solvent (e.g., THF). This mixture is agitated for about 10 to about 24 hours at a temperature of from about -30°C to about 35°C.
  • This reaction mixture is filtered and the filter is washed through with a suitable solvent (e.g., dioxane).
  • the combined filtrate is lyophilized to yield compounds of Formula I in relatively pure form.
  • Compounds of Formula I can be purified further, as necessary, using the solid supported liquid-liquid extraction (SLE) procedure
  • Compounds of Formula I where R 2 is C(O)NR 9 R 10 , are prepared by treating a suspension of a compound of Formula C with a solution of an amine of formula R 9 R 10 NH. Typically, the reaction is carried out in an inert solvent (e.g., dioxane, DCM, THF, preferably dioxane). The resulting mixture is gently agitated for about 10 to about 24 hours at temperatures between about 10°C and about 40°C. The reaction mixture then is filtered and the filter washed through with dioxane. The combined filtrate is collected and lyophilized to obtain compounds of Formula I in relatively pure form.
  • Compounds of Formula I can be purified further by performing a solid supported liquid-liquid extraction (SLE) as described by Johnson et al. in Tetrahedron 54 (1998) 4097-4106.
  • SLE solid supported liquid-liquid extraction
  • Compounds of Formula I, where R" is C(O)OR ⁇ are prepared by treating a suspension of a compound of Formula C with a compound of Formula R ⁇ OH.
  • the reaction mixture is gently agitated for about 10 to about 24 hours at temperatures between about 30°C and about 50°C.
  • the reaction mixture then is filtered and the filter washed through with a suitable solvent (e.g., dioxane, DCM, THF, preferable dioxane).
  • the reaction is carried out in the presence of a non-nucleophilic base (e.g., triethylamine (TEA), trimethylamine or pyridine, preferably TEA) and in a suitable inert solvent (e.g., dioxane, DCM, THF, preferably dioxane).
  • a non-nucleophilic base e.g., triethylamine (TEA), trimethylamine or pyridine, preferably TEA
  • a suitable inert solvent e.g., dioxane, DCM, THF, preferably dioxane.
  • a suitable solvent preferably DMF
  • a coupling agent preferably DIC (typically 1 equivalent)
  • the resultant complex is added to the thiophenol resm from above and an acylation catalyst (e.g., DMAP; 0.1 equivalents) and the resulting mixture is agitated for 10 to 24 hours at ambient temperatures
  • the resm is isolated from solvents, washed free of contaminants and d ⁇ ed to yield a resin protected compound of Formula A.
  • the resin is typically washed in succession with 1:1 DCM.THF (xl), DCM (x3) and MeOH (x3)
  • the protective group is then removed by, for example, hydrolysis of the resin with a suitable acid (preferably TFA; lOmL g of resin) in the presence of an inert solvent (preferably DCM) for about one hour.
  • a suitable acid preferably TFA; lOmL g of resin
  • an inert solvent preferably DCM
  • the resin is isolated from solvents and washed free of contaminants to yield compounds of Formula A
  • the resin is typically washed in succession with DCM (x2), 15% (v:v) TEA in DCM (x2), MeOH (x2) and DCM (x2).
  • Carboxyhc acids comp ⁇ sing a Boc protected amino group e.g. Boc-nipecotic acid or Boc-4-ammomethylbenzo ⁇ c
  • Boc-nipecotic acid or Boc-4-ammomethylbenzo ⁇ c may be obtained commercially (e.g., Novabiochem) or may be synthesized by the process desc ⁇ bed in Bodanszky and Bodanszky, The Practice ofpeptide Synthesis- Sp ⁇ nger-Verlag: New York, 1984.
  • Compounds of Formula B may be prepared by Hantsch condensations of ethylbromopyruvate with thioureas and thioamides. A detailed procedure is described by Chucholowski et al., (Chimia, 50, 1996, 525-530) and Hantsch, A., (Ber. 1890, 23, 1474).
  • Compounds of Formula B may be prepared from serine or threonine methyl esters as described by Wipf and Miller (Tetrahedron Letters, Vol. 33, No. 7, pp. 907-910, 1992) and Williams et al. (Tetrahedron Letters, Vol. 38, pp. 331-334, 1997).
  • Another aspect of the present invention provides a process for synthesizing compounds of Formula ⁇ .
  • the novel process is described in Scheme B, below:
  • a compound of Formula B (1 equivalent) and a coupling agent, preferably DIC (1 equivalent), are dissolved in an inert solvent (e.g., DCM; 15 mL/g of Formula B). The resulting solution is allowed to stand for 5 to 15 minutes.
  • the compound of Formula D (1-10 equivalents) is swelled in a suitable inert solvent (e.g., DCM at lOmL g of Formula D) and added to the mixture of Formula B, DIC and DCM.
  • An acylation catalyst e.g., DMAP; 0.4-1.2 equivalents
  • the mixture is agitated, with frequent venting, at a temperature between about 10°C and about 40°C for about 10 to 24 hours.
  • the resin is isolated from solvents, washed free of contaminants and d ⁇ ed to yield a compound of Formula E.
  • the resm is typically washed m succession with 1:1 DCM:THF (xl), DCM (x2), MeOH (x2) and dioxane (x3).
  • Compounds of Formula ⁇ , where R" is CH 2 OH are prepared by treating compounds of Formula E with a reducing agent (alkaline borohyd ⁇ des e.g., NaBFLi or L1BH 4 .
  • a reducing agent alkaline borohyd ⁇ des e.g., NaBFLi or L1BH 4 .
  • the reaction is typically earned out by mixing an inert solvent suspension of the compound of Formula E with a reducing agent, preferably L1BH 4 , m a suitable solvent (e.g., THF). This resulting mixture is agitated for about 10 to about 24 hours at a temperature of from about 5°C to about 35°C.
  • This reaction mixture is filtered and the filter is washed through with a suitable solvent (e.g., dioxane).
  • the combined filtrate is lyophilized to yield compounds of Formula II in relatively pure form.
  • Compounds of Formula ⁇ where R 2 is C(O)NR 9 R 10 , are prepared by treating a suspension of a compound of Formula E with a solution of an amine of formula R 9 R I0 NH. Typically the reaction is carried out in an inert solvent (e.g., dioxane, DCM, THF, preferably dioxane). The resulting mixture is agitated for 10 to 24 hours at temperatures between about 10°C and about 40°C. The reaction mixture then is filtered and the filter washed through with dioxane. The combined filtrate is lyophilized to obtain compounds of Formula TJ in relatively pure form. Compounds of Formula TJ can be purified further by performing a solid supported liquid-liquid extraction (SLE) described by Johnson et al., in Tetrahedron 54 (1998) 4097-4106.
  • SLE solid supported liquid-liquid extraction
  • Compounds of Formula ⁇ , where R 2 is C(O)OR ⁇ are prepared by treating a suspension of a compound of Formula E with a compound of formula R n OH.
  • a non-nucleophilic base e.g., triethylamine (TEA), trimethylamine or pyridine, preferably TEA
  • a suitable inert solvent e.g., dioxane, DCM, THF, preferably dioxane.
  • the reaction mixture is agitated for 10 to 24 hours at temperatures between about 30°C and about 50°C.
  • the reaction mixture is then filtered and the filter washed through with suitable solvents (e.g., dioxane).
  • suitable solvents e.g., dioxane
  • Compounds of Formula D and Formula B can be prepared by synthetic methods known to one skilled in the art. Compounds of Formula B are prepared as discussed for Scheme A, above. An illustrative method to prepare a compound of Formula D is discussed below.
  • a solution of sodium methoxide (typically about 1.387 mol in a suitable solvent, preferable DMF) is cooled to about 0°C and then heated with 4- hydroxythiophenol (typically 1 equivalent).
  • This mixture is agitated for up to 2 hours at ambient temperature and then combined with a suitable solid support, e.g., Merrifield resin (Midwest Biotech) in DMF.
  • a suitable solid support e.g., Merrifield resin (Midwest Biotech) in DMF.
  • the resulting mixture is agitated for up to 60 hours at a temperature of about 60°C.
  • the resin is isolated from solvents and washed free from contaminants with suitable inert solvents to yield a compound of Formula D.
  • the resin is washed up to three times in succession with DMF, MeOH, AcOH, IN HChAcOH (5% v:v), DCM, MeOH and Et 2 O.
  • novel process of the present invention can also be used to prepare an array of compounds of Formula I or Formula U.
  • the following description is the general procedure to accomplish such a synthetic array.
  • the resin-supported compounds of Formula C or Formula E are suspended in dioxane (40ml) and partitioned into PolyfiltronicsTM plates (2.7 ⁇ m). The plates are placed in Hydra clamps and the Hydra is then used to dispense in to each well, either (i) 800 ⁇ L of 0.5M R 9 R 10 NH in dioxane, (ii) 800 ⁇ L of dioxane:TEA:R n OH (8: 1 : 1), or (iii) 800 ⁇ L of 2M L1BH4 in THF diluted 1:3 in dioxane to each well. The wells are covered with a TeflonTM sheet and clamped.
  • the LiBFLi cleavage plates are shaken for 10 to 24 hours at temperatures between 5°C and 35°C.
  • the amine (R 9 R 10 NH) cleavage plates are shaken for 10 to 24 hours at temperatures between 10°C and 40°C.
  • the alcohol (R n OH) cleavage plates are placed in the HydraTM rotisserie oven on the rocker table apparatus for 10 to 24 hours at temperatures between 30°C and 50°C.
  • the Formula I or Formula TJ products are collected by gravity filtration and minor N positive pressure into 2mL BeckmanTM plates. The resin in each well is then washed with 400 ⁇ L of dioxane and the filtrate is collected.
  • the plates are frozen at -78°C and then lyophilized at 5°C for a 24 hour period on the VirtisTM tray lyophilizer.
  • the cleaved residues are then taken up in 800 ⁇ L of DCM and shaken orbitally for 20 minutes.
  • the compounds of Formula I or Formula II are then extracted through the SLE material (pre-primed with 2N HC1 (350 ⁇ L) or H 2 0
  • a compound of Formula A in which X 2 is a group of Formula (c) wherein R 7 is hydrogen and R 8 is benzyl and SS is Merrifield resin (3.2g) was swelled in DCM (32mL). This swelled compound was added to a mixture of 2-p-tolyl-oxazole-4- carboxylic acid (7.8g, 38.4mmol), DIC (6mL; 38.4mmol) and DCM (117 mL). The resulting solution was allowed to stand for 5 to 15 minutes. DMAP (140mg; 1.15mmol) was added and the resulting mixture was agitated, with frequent venting, at a temperature of about 25°C for about 15 hours.
  • the resulting resin was isolated and washed in succession with 1: 1 DCMTHF (lxlOOmL), DCM (2xl00mL), MeOH (2xl00mL) and dioxane (3xl00mL) and dried under reduced pressure to yield the corresponding compound of Formula C in which X 1 is oxygen, R 1 is of 2- -tolyl and X 2 is a group of Formula (c) wherein R 7 is hydrogen and R 8 is benzyl.
  • the compound of Formula C was suspended in a minimal amount of dioxane and treated with 0.5M butylamine in dioxane (50 mL). The resulting mixture was agitated for 10 to 24 hours at a temperature of 25°C.
  • the resin of Formula C is suspended in a minimal amount of dioxane and then treated with an 8: 1 : 1 mixture of dioxane:TEA:Pent-2-yn-l-ol (50 mL). The resulting mixture was gently agitated for 10 to 24 hours at a temperature of 40°C. The mixture was then filtered and the residue washed with dioxane. The combined filtrate was collected and lyophilized to obtain 2-( ⁇ 2-[3-benzyl-3-(2-methoxy-phenyl)-ureido]-thiazole-4-carbonyl ⁇ -amino) -3- benzylsulfanyl-propionic acid pent-2-ynyl ester (standard 6).
  • the resulting resin was isolated and washed in succession with 1: 1 DCMTHF (lxlOOmL), DCM (2xl00mL), MeOH (2xl00mL) and dioxane (3xl00mL) and dried under reduced pressure to yield the corresponding compound of Formula E in which R 1 is 4-hexyloxy-phenyl and X 1 is O.
  • the compound of Formula E was suspended in a minimal amount of dioxane and then treated with 0.5M l-benzyl-piperidin-4-ylamine in dioxane (50 mL). The resulting mixture was gently agitated for 10 to 24 hours at a temperature of 25°C. The mixture was then filtered and the filter washed with dioxane.
  • Acetonitrile ACN
  • Acetic Acid AcOH
  • t-butyloxycarbonyl Boc
  • dichloromethane DCM
  • 2,3-Dichloro-5,6-dicyano-l,4- benzoquinone DDQ
  • diisopropylcarbodiimide DIC
  • 4-Dimethylamino-pyridine DMAP
  • electrospray ionization ESI
  • Diethyl Ether Et 2 O
  • Ethyl acetate Ethyl acetate
  • HPLC Liquid Chromatography/Mass Spectroscopy
  • Alkyl indicated alone means a straight or branched, saturated or unsaturated aliphatic radical having the number of carbon atoms indicated (e.g., (C ⁇ _ )alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, etc.).
  • Alkyl indicated as part of a larger radical means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when 0 atoms are indicated means a bond (e.g., (C 0-3 )alkyl of (C 3 _ ⁇ 2 )cycloalkyl(C 0 - 3 )alkyl means a bond, methylene, ethylene, trimethylene, 1-methylethylene, etc.).
  • Alkylene means a saturated or unsaturated, branched or unbranched, hydrocarbon divalent radical having the number of carbon atoms indicated and any ketone, thioketone, iminoketone and substituted derivative thereof (e.g., (C ⁇ _ )alkylene includes methylene (-C ⁇ 2 -), ethylene (-CH 2 CH 2 -), methylethylene, vinylene, ethynylene, trimethylene (-CH 2 CH 2 CH 2 -), 2-oxotrimethylene (-CH 2 C(O)CH 2 -), 2-thiatrimethylene (-CH 2 C(S)CH 2 -), 2-iminotrimethylene (-CH 2 C( ⁇ H)CH 2 -), propenylene (-CH 2 CH-CH- or -CH-CHCH 2 -), propanylylidene (-CHCH 2 CH 2 -), propendiylene (-CHCH-CH-), 1-aminotetramethylene, pentamethylene, etc.).
  • Alkyloxy means the radical -OR, wherein R is alkyl as defined above, having the number of carbon atoms indicated (e.g., (C ⁇ _ 6 )alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, and the like).
  • Array of compounds is defined as a collection of independent (individual) compounds that are synthesized by the process of the present invention. Generally, the term 'array of compounds' indicates a collection of compounds distinct from one another. Also included in the array of compounds is a mixture of individual compounds.
  • Aryl means an aromatic monocyclic, polycyclic or fused polycyclic ring system containing the number of annular carbon atoms indicated, wherein each ring contained therein is comprised of 6 annular members (e.g., (C 6 - ]2 )aryl includes phenyl, naphthalenyl, and biphenylyl).
  • Computer Synthesis is defined as an ordered strategy for parallel synthesis of arrays of single compounds or mixtures, by sequential addition of reagents.
  • Coupling Agent is intended to represent an additive that facilitates the course of a reaction but does not get incorporated in to the final product.
  • Illustrative examples of coupling agents are diisopropylcarbodiimide (DIC), N- hydroxybenzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HO At) and N- hydroxysuccinimide.
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic ring, bicyclic ring assembly (directly linked by a single bond or fused) or bridged polycyclic ring assembly containing the number of annular carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C 3- i 2 )cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthalenyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1
  • Halo means fluoro, chloro, bromo or iodo.
  • t )aryl includes thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxaxolyl, indolyl, benzo[b]thienyl, isobenzofuranyl, purinyl, isoquinolyl, pterdinyl, perimidinyl, imidazolyl, 1-methylimidazolyl, 1-benzylimidazolyl, pyridyl, pyrazolyl, pyrazinyl, quinolyl, [2,4]bipyridinylyl, 2-phenylpyridyl, 4-thiazol-4-ylphenyl, lH-imidazol-1-ylphenyl, and the like).
  • Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like.
  • ⁇ eterocycloalkyl means cycloalkyl, as defined herein, provided that one or more of the annular carbon atoms indicated is replaced by heteroatom moiety selected from -N-, -NR-, -O- or -S-, wherein R is hydrogen, (C ⁇ _ 6 )alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term heterocyclo(C 5 -i )alkyl includes piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, [l,4 bipiperidinylyl, l' ⁇ '-dihydro ⁇ H-fl ⁇ lbipyridinylyl, l-morpholin-4-ylpiperidinyl, etc.).
  • Suitable protecting groups include tert-butoxycarbonyl, benzyloxy
  • Iminoketone derivative means a derivative containing the moiety -C(NR)-, wherein R is hydrogen or (C ⁇ - 6 )alkyl.
  • inert solvents as used herein represents solvents that do not react with the reagents dissolved therein.
  • Illustrative examples of inert solvents are tetrahydrofuran (T ⁇ F), methylene chloride, dichloromethane (DCM), ethyl acetate (ETOAc), dimethyl formamide (DMF), dioxane, chloroform and dimethylsulfoxide (DMSO).
  • Ketone derivative means a derivative containing the moiety -C(O)-
  • Niro means the radical -NO
  • Polycycloaryl means a bicyclic ⁇ ng assembly (directly linked by a single bond or fused) containing the number of annular carbon atoms indicated, wherein at least one, but not all, of the fused ⁇ ngs comp ⁇ sing the radical is aromatic, and any carbocyclic ketone, thioketone or iminoketone de ⁇ vative thereof (e.g., polycyclo(C 9 ⁇ )aryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2-d ⁇ hydronaphthalenyl, cyclohexylphenyl, phenylcyclohexyl,
  • Solid support or (SS) signifies polyme ⁇ c mate ⁇ al for supported synthesis.
  • linker molecule and solid support can be found in The Comb ato ⁇ al Index, B. A. Bunin, 1998, which is incorporated herein by reference.
  • Thioketone de ⁇ vative means a de ⁇ vative containing the moiety -C(S)-.

Abstract

Thia- and oxazole-4-carboxylic acid derivatives are prepared by solid phase synthesis, using intermediates of formula (α) where SS is a solid support and n is 0 or 1.

Description

SOLID PHASE SYNTHESIS OF OXA-AND THIAZOLES
FIELD OF INVENTION
The present invention relates to solid phase and combinatoπal synthesis of oxazole and thiazole deπvatives.
BACKGROUND OF THE INVENTION
Organic compounds of potential therapeutic interest are traditionally synthesized and evaluated one at a time, thus dramatically limiting the number of deπvatives that can be synthesized and screened against a specific receptor or enzyme.
It is therefore desirable to develop new synthetic methodology for synthesizing a large number (library) of compounds of potential therapeutic interest, such as small heterocychc compounds. Oxazoles and thiazoles are a class of heterocychc compounds having potential use as pharmaceuticals. There is thus a continuing need for processes that facilitate the synthesis of a large number of compounds in a relatively short period of time. ,
The realization of known synthetic reactions on a solid support may not always be possible and may require careful optimization of the reaction conditions. For example, liquid phase reaction conditions may not be amenable with some types of supports or liquid phase reactions may require precise temperature adjustment in arrays of reactors for solid phase synthesis. Additionally, the classical tools for the quality control of intermediates (infrared spectroscopy, nuclear magnetic resonance spectroscopy and mass spectroscopy) may only be of limited use in solid phase synthesis. For these reasons, the implementation of known liquid phase reactions to a solid support may often require a major effort and time investment. However, solid phase synthesis, once implemented and optimized, offers many advantages if compared to synthesis in liquid phase. The advantages of the present invention are the production of a large number of diverse oxazole and thiazole compounds, synthesized by a time and cost efficient process. Further advantages of the present invention will become apparent from a consideration of the ensuing descπption SUMMARY OF THE INVENTION
Keeping the above-discussed needs in mind, the present invention provides a
Figure imgf000003_0001
process for the synthesis of a compound or an array of compounds represented by Formula I in which:
X' is O or S;
R1 is -R3, -NR3R4, -NR3C(NR4)NR3R4 or -NR3C(O)NR3R4 wherein R3 is
Figure imgf000003_0002
(Cι-ιo)alkyl, (C6-ι2)aryl(C0-3)alkyl, polycyclo(C6-ι2)aryl(C0-3)alkyl, hetero(C5_i2)aryl(C0- 3)alkyl or heteropolycyclo(C6-ι )aryl(C0-3)alkyl and R4 is hydrogen or (C1-6)alkyl, wherein any aromatic moiety comprising R1 optionally is substituted with 1 to 3 substituents independently selected from halo, nitro, cyano, (C]-6)alkyl, halo-substituted(d_6)alkyl, -OR5, -C(O)R5, -C(O)OR5, -C(O)NR5R5, -S(O)2NR5R5, - X3NR5R5, -X3NR5C(O)R5, -X3NR5C(O)OR5, -X3NR5C(O)NR5R5 and - X3NR5C(NR5)NR5R5, wherein X3 is a bond or methylene and R5 at each occurrence independently is hydrogen or (C].6)alkyl; X is a group selected from Formulae (a), (b), (c) and (d):
R2 is -CH2OH, -C(O)NR9R10 or -C(O)ORn, wherein R9, R10 and Rn independently are hydrogen, (Cι.6)alkyl, (C3_ι )cycloalkyl(Cι_3)alkyl, hetero(C3-ι 2)cycloalkyl(C i -3)alkyl , (C6_ x 2)aryl(C0-6)alkyl , hetero(C5. j 2)aryl (C0-6)alkyl, polycyclo(C6.ι2)aryl(Co-6)alkyl, heteropolycyclo(C6-ι2)aryl(Co-6)alkyl or -X4R12, wherein X4 is (C1-4)alkylene and R12 is -OR13 or -NR13R14, wherein R13 and R14 are independently hydrogen, (Cι_6)alkyl, (C6_ι )aryl(C0-6)alkyl, polycyclo(C6-ι2)aryl(Co-6)alkyl, hetero(C5-ι2)aryl(C0-6)alkyl, heteropolycyclo(C6_ι2)aryl(Co-6)alkyl, -XOR10 or -X^NR^R10, wherein X4 is as defined above and R , 16 at each occurrence independently is hydrogen or (Cι-2)alkyl, wherein any aromatic moieties comprising R9, R10 or Rn optionally independently are substituted with 1 to 3 substituents independently selected from halo, nitro, cyano, (Cι_6)alkyl, halo-substituted(Cι.6)alkyl, -OR5, -C(O)R5, -C(O)OR5, -C(O)NR5R5, - S(O)2NR5R5, -X4NR5R5, -X4NR5C(O)R5, -X4NR5C(O)OR5, -X4NR5C(O)NR5R5 and - X4NR5C(NR5)NR5R5, wherein X4 and R5 are as defined above, or R9 and R10 together with the nitrogen atom to which R9 and R10 are attached form hetero(C5_7)cycloalkyl optionally substituted with -X4R12, wherein X4 and R12 are as defined above; R7 is hydrogen or (Cι-4)alkyl; and
R8 is (i) hydrogen, (ii) (Cι_6)alkyl optionally substituted with -OR17, -SR17, - S(O)R17, -S(O)2R17, -C(O)R17, -C(O)OR17, -C(O)NR17R18, -NR17R18, -NR18C(O)R17, -NR18C(O)OR17,-NRI8C(O)NR17R18 or -NR18C(NR18)NR17R18, wherein R17 is (C j -6)alkyl , (C i .6)alkanoylaminomethyl , (C3.12)cycloalkyl(C0_3)alkyl , hetero(C3-12)cycloalkyl(C0-3)alkyl, (C6-i2)aryl(C0-3)alkyl, (C6_ι2)arylsulfonyl, hetero(C5_j2)aryl(Co-3)alkyl, (C9-ι2)polycycloaryl(Co_3)alkyl or hetero(C8-ι )polycycloaryl(Co-3)alkyl and R18 at each occurrence independently is hydrogen or (Cι_6)alkyl, or (iii) (C3-ι2)cycloalkyl(Cι-3)alkyl, hetero(C3.12)cycloalkyl(Cι.3)alkyl, (C6„ι2)aryl(Cι_3)alkyl, hetero(C5_12)aryl(C1-3)alkyl, (C9_ι2)polycycloaryl(Co-3)alkyl or hetero(C8-ι )polycycloaryl(C]_3)alkyl; said process comprising:
(i) treating a compound of Formula A:
Figure imgf000004_0001
Formula A with a compound of Formula B:
Figure imgf000005_0001
Formula B
in the presence of a coupling agent and optionally an acylation catalyst, to yield a compound of Formula C:
Figure imgf000005_0002
Formula C
where R1, X1 and X2 are as defined above and "SS" represents a solid support; and
(ii) treating a compound or an array of compounds of Formula C with (a) a reducing agent to yield a compound or an array of compounds of Formula I where R2 is CH2OH, or (b) a compound of formula R9R10NH or RuOH to yield a compound or an array of compounds of Formula I where R2 is -C(O)NR9R10 or -C(O)ORπ, respectively.
Another aspect of the preferred invention provides a process for synthesizing a compound or an array of compounds of Formula π,
Figure imgf000006_0001
Formula TJ
in which:
X1 is O or S; R1 is -R3, -NR3R4, -NR3C(NR4)NR3R4 or -NR3C(O)NR3R4 wherein R3 is
(Cι.ιo)alkyl, (C6-ι2)aryl(C0-3)alkyl, polycyclo(C6-ι2)aryl(C0_3)alkyl, hetero(C5.12)aryl(C0. 3)alkyl or heteropolycyclo(C6-ι2)aryl(C0-3)alkyl and R4 is hydrogen or (Cι_6)alkyl, wherein any aromatic moiety comprising R optionally is substituted with 1 to 3 substituents independently selected from halo, nitro, cyano, (Cι-6)alkyl, halo-substituted(C,-6)alkyl, -OR5, -C(O)R5, -C(O)OR5, -C(O)NR5R5, -S(O)2NR5R5, - X3NR5R5, -X3NR5C(O)R5, -X3NR5C(O)OR5, -X3NR5C(O)NR5R5 and - X3NR3C(NR5)NR5R5, wherein X3 is a bond or methylene and R5 at each occurrence independently is hydrogen or (Cι.6)alkyl;
R2 is -CH2OH, -C(O)NR9R10 or -C(O)ORπ, wherein R9, R10 and Rn independently are hydrogen, (Cι_6)alkyl, (C3-ι2)cycloalkyl(Cι.3)alkyl, hetero(C3.12)cycloalkyl (C i _3)alkyl , (C6_ι 2)aryl (C0-6)alkyl , hetero(C5-ι 2)aryl(C0-6)alkyl , polycyclo(C6_ι )aryl(Co-6)alkyl, heteropolycyclo(C6_ι )aryl(Co-6)alkyl or -X4R12, wherein X4 is (C,.4)alkylene and R12 is -OR13 or -NR13R14, wherein R13 and R14 are independently hydrogen, (Cι-6)alkyl, (C6-ι2)aryl(C0-6)alkyl, polycyclo(C6_ι2)aryl(C0.6)alkyl, hetero(C5,ι2)aryl(C0-6)alkyl, heteropolycyclo(C6.ι2)aryl(C0_6)alkyl, -X4OR16 or -X4NR16R16, wherein X4 is (Cι_ )alkylene and R1 at each occurrence independently is hydrogen or (Cj.2)alkyl, wherein any aromatic moieties comprising R , R or R optionally independently are substituted with 1 to 3 substituents independently selected from halo, nitro, cyano, (C,_6)alkyl, halo-substιtuted(C,.6)alkyl, -OR5, -C(O)R5, -C(O)OR5, -C(O)NR5R5, - S(O)2NR5R5, -X4NR5R5, -X4NR5C(O)R5, -X4NR5C(O)OR5, -X4NR5C(O)NR5R5 and - X4NR5C(NR5)NR5R5, wherein X4 and R5 are as defined above, or R9 and R10 together with the nitrogen atom to which R and R are attached form hetero(C5_ )cycloalkyl optionally substituted with -X4R12, wherein X4 and R12 are as defined above;
said process comprising: (1) treating a compound of Formula D:
Figure imgf000007_0001
Formula D with a compound of Formula B:
Figure imgf000007_0002
Formula B
in the presence of a coupling agent and optionally an acylation catalyst, to yield a compound of Formula E:
Figure imgf000007_0003
Formula E
where R1 and X1 are as defined above and "SS" represents a solid support; and
(2) treating a compound or an array of compounds of Formula E with (a) a reducing agent to yield a compound or an array of compounds of Formula II, where R2 is CH2OH, or (b) a compound of formula R9R10NH or RπOH to yield a compound or an array of compounds of Formula II where R2 is -C(O)NR9R10 or -C(O)ORn, respectively.
DETAILED DESCRIPTION OF THE INVENTION
While the broadest definition of this invention is set forth in the Summary of the Invention, certain aspects of the invention are preferred.
For example, preferred is a process wherein step (i) comprises treating a compound of Formula A with a compound of Formula B in the presence of a coupling agent selected from DIC, PyBOP or HATU and an acylation catalyst selected from DMAP or 4-pyrrolidinopyridine.
A preferred embodiment is a process wherein step (1) comprises treating a compound of Formula D with a compound of Formula B in the presence of a coupling agent selected from DIC, PyBOP or HATU and an acylation catalyst selected from DMAP or 4-pyrrolidinopyridine.
A further preferred process of the present invention is one wherein steps (i) and (1) are carried out in the presence of an inert solvent selected from DCM, THF and chloroform and at a temperature ranging from about 15°C to about 35°C.
Preferred is a process wherein the inert solvent in steps (ii) and (2) are selected from THF, methylene chloride, DCM, ethyl acetate, DMF, dioxane, chloroform and DMSO; and the reactions are carried out at a temperature ranging from about -30°C to about 35°C.
A further preferred embodiment of the present invention is where the reducing agent in steps (ii)(a) and (2)(a) is LiBrL;. Preferred is a process wherein steps (ii)(b) and (2)(b) are carried out at a temperature ranging from about 10°C to about 50°C.
Another aspect of the present invention provides an array of compounds synthesized by the processes of the present invention.
Yet another aspect of the present invention provides a process for synthesizing a compound or an array of compounds of Formula C.
Preferred is a process for synthesizing a compound or an array of compounds of Formula E.
EXPERIMENTAL DETAILS
The novel process of the present invention to synthesize compounds of
Formula I is described in Scheme A, below:
Scheme A
Figure imgf000009_0001
Formula A
Figure imgf000009_0002
Figure imgf000009_0003
Formula C
Figure imgf000009_0004
Formula I or C(0)OR' General Synthetic procedure
The novel process outlined in Scheme A above can be used to synthesize compounds of Formula I wherein X1, X2, R1 R2, R9, R10 and R11 are as described in the Summary of the Invention. The general description of each step of this process is discussed below.
Synthesis of Compounds of Formula C (Step (i))
A compound of Formula B (1 equivalent) and a coupling agent, preferably DIC (1 equivalent), are dissolved in an inert solvent (e.g., DCM; 15 mL/g of Formula B). The resulting solution is allowed to stand for 5 to 15 minutes. The compound of Formula A (1-10 equivalents) is swelled in a suitable inert solvent (e.g., DCM at lOmL/g of Formula A) and added to the mixture of Formula B, DIC and DCM. An acylation catalyst (e.g., DMAP; 0.4-1.2 equivalents), may be added to the reaction mixture. The mixture is agitated, with frequent venting, at a temperature between about 10°C and about 40°C for about 10 to about 24 hours. The resin is isolated from solvents and washed free of contaminants and dried to yield purified compound of Formula C. For example, the resin is typically washed in succession with: 1:1 DCM:THF (xl); DCM (x2); MeOH (x2); and dioxane (x3); and dried under reduced pressure.
Synthesis of Compounds of Formula I (Step (ii)(aT)
Compounds of Formula I, where R" is CH2OH, are prepared by treating compounds of Formula C with a reducing agent (alkaline borohydrides e.g., NaBfLi or LiBFLt). The reaction typically is carried out by mixing an inert solvent suspension of the compound of Formula C with a reducing agent, preferably LiBFLi, in a suitable solvent (e.g., THF). This mixture is agitated for about 10 to about 24 hours at a temperature of from about -30°C to about 35°C. This reaction mixture is filtered and the filter is washed through with a suitable solvent (e.g., dioxane). The combined filtrate is lyophilized to yield compounds of Formula I in relatively pure form. Compounds of Formula I can be purified further, as necessary, using the solid supported liquid-liquid extraction (SLE) procedure of Johnson et al. as described in Tetrahedron 54 (1998) 4097-4106.
Synthesis of Compounds of Formula I (Step (ii)(b))
Compounds of Formula I, where R2 is C(O)NR9R10, are prepared by treating a suspension of a compound of Formula C with a solution of an amine of formula R9R10NH. Typically, the reaction is carried out in an inert solvent (e.g., dioxane, DCM, THF, preferably dioxane). The resulting mixture is gently agitated for about 10 to about 24 hours at temperatures between about 10°C and about 40°C. The reaction mixture then is filtered and the filter washed through with dioxane. The combined filtrate is collected and lyophilized to obtain compounds of Formula I in relatively pure form. Compounds of Formula I can be purified further by performing a solid supported liquid-liquid extraction (SLE) as described by Johnson et al. in Tetrahedron 54 (1998) 4097-4106.
Compounds of Formula I, where R" is C(O)ORπ, are prepared by treating a suspension of a compound of Formula C with a compound of Formula RπOH. The reaction mixture is gently agitated for about 10 to about 24 hours at temperatures between about 30°C and about 50°C. The reaction mixture then is filtered and the filter washed through with a suitable solvent (e.g., dioxane, DCM, THF, preferable dioxane). Typically, the reaction is carried out in the presence of a non-nucleophilic base (e.g., triethylamine (TEA), trimethylamine or pyridine, preferably TEA) and in a suitable inert solvent (e.g., dioxane, DCM, THF, preferably dioxane). The combined filtrate is lyophilized to yield compounds of Formula I.
Starting Materials Compounds of Formula A and Formula B can be prepared by synthetic methods known to one skilled in the art. Illustrative methods to prepare compounds of Formula A and Formula B are discussed below.
Preparation of a compound of Formula A A solution of sodium methoxide in a suitable solvent, preferably DMF, is cooled to about 0°C and then heated with 4-hydroxythiophenol (typically 1 equivalent) This mixture is agitated for up to 2 hours at ambient temperature and then combined with a suitable solid support, e g., Merπfield resm (Midwest Biotech), m DMF. The resulting mixture is agitated for up to 60 hours at a temperature of about 60°C The resm is isolated from solvents and washed free from contaminants with suitable inert solvents. For example, resin is washed up to three times m succession with DMF, MeOH, AcOH, IN HCl:AcOH (5% v:v), DCM, MeOH and Et2O to yield a thiophenol resm.
A carboxyhc acid compπsing a protected ammo group (1 equivalent), solvated in an inert solvent (e.g., dioxane, DCM, THF, preferably DCM), is mixed with a coupling agent, preferably DIC (typically 1 equivalent), and allowed to stand for 5 to 15 minutes. The resultant complex is added to the thiophenol resm from above and an acylation catalyst (e.g., DMAP; 0.1 equivalents) and the resulting mixture is agitated for 10 to 24 hours at ambient temperatures The resm is isolated from solvents, washed free of contaminants and dπed to yield a resin protected compound of Formula A. For example, the resin is typically washed in succession with 1:1 DCM.THF (xl), DCM (x3) and MeOH (x3) The protective group is then removed by, for example, hydrolysis of the resin with a suitable acid (preferably TFA; lOmL g of resin) in the presence of an inert solvent (preferably DCM) for about one hour. The resin is isolated from solvents and washed free of contaminants to yield compounds of Formula A For example, the resin is typically washed in succession with DCM (x2), 15% (v:v) TEA in DCM (x2), MeOH (x2) and DCM (x2).
Carboxyhc acids compπsing a Boc protected amino group, e.g. Boc-nipecotic acid or Boc-4-ammomethylbenzoιc, may be obtained commercially (e.g., Novabiochem) or may be synthesized by the process descπbed in Bodanszky and Bodanszky, The Practice ofpeptide Synthesis- Spπnger-Verlag: New York, 1984. Preparation of a compound of Formula B
Compounds of Formula B (wherein X - I' i •s, sulfur) may be prepared by Hantsch condensations of ethylbromopyruvate with thioureas and thioamides. A detailed procedure is described by Chucholowski et al., (Chimia, 50, 1996, 525-530) and Hantsch, A., (Ber. 1890, 23, 1474).
Compounds of Formula B (wherein X1 is oxygen) may be prepared from serine or threonine methyl esters as described by Wipf and Miller (Tetrahedron Letters, Vol. 33, No. 7, pp. 907-910, 1992) and Williams et al. (Tetrahedron Letters, Vol. 38, pp. 331-334, 1997).
Another aspect of the present invention provides a process for synthesizing compounds of Formula π. The novel process is described in Scheme B, below:
Scheme B
Figure imgf000013_0001
Formula D
Figure imgf000013_0002
Formula II or C(0)OR' General Synthetic procedure
The novel process outlined in Scheme B above can be used to synthesize compounds of Formula II wherein X1, R1 R2, R9, R10 and R11 are as descπbed in the Summary of the Invention. The general descπption of each step of this process is as given below.
Synthesis of Compounds of Formula E (Step (1))
A compound of Formula B (1 equivalent) and a coupling agent, preferably DIC (1 equivalent), are dissolved in an inert solvent (e.g., DCM; 15 mL/g of Formula B). The resulting solution is allowed to stand for 5 to 15 minutes. The compound of Formula D (1-10 equivalents) is swelled in a suitable inert solvent (e.g., DCM at lOmL g of Formula D) and added to the mixture of Formula B, DIC and DCM. An acylation catalyst (e.g., DMAP; 0.4-1.2 equivalents) may be added to the reaction mixture. The mixture is agitated, with frequent venting, at a temperature between about 10°C and about 40°C for about 10 to 24 hours. The resin is isolated from solvents, washed free of contaminants and dπed to yield a compound of Formula E. For example, the resm is typically washed m succession with 1:1 DCM:THF (xl), DCM (x2), MeOH (x2) and dioxane (x3).
Synthesis of Compounds of Formula U (Step (2)(a))
Compounds of Formula π, where R" is CH2OH, are prepared by treating compounds of Formula E with a reducing agent (alkaline borohydπdes e.g., NaBFLi or L1BH4. The reaction is typically earned out by mixing an inert solvent suspension of the compound of Formula E with a reducing agent, preferably L1BH4, m a suitable solvent (e.g., THF). This resulting mixture is agitated for about 10 to about 24 hours at a temperature of from about 5°C to about 35°C. This reaction mixture is filtered and the filter is washed through with a suitable solvent (e.g., dioxane). The combined filtrate is lyophilized to yield compounds of Formula II in relatively pure form. Compounds of Formula II can be puπfied further, as necessary, using the solid supported liquid-liquid extraction (SLE) procedure of Johnson et al. as descπbed in Tetrahedron 54 (1998) 4097-4106. Synthesis of Compounds of Formula II (Step (2)(b))
Compounds of Formula π, where R2 is C(O)NR9R10, are prepared by treating a suspension of a compound of Formula E with a solution of an amine of formula R9RI0NH. Typically the reaction is carried out in an inert solvent (e.g., dioxane, DCM, THF, preferably dioxane). The resulting mixture is agitated for 10 to 24 hours at temperatures between about 10°C and about 40°C. The reaction mixture then is filtered and the filter washed through with dioxane. The combined filtrate is lyophilized to obtain compounds of Formula TJ in relatively pure form. Compounds of Formula TJ can be purified further by performing a solid supported liquid-liquid extraction (SLE) described by Johnson et al., in Tetrahedron 54 (1998) 4097-4106.
Compounds of Formula π, where R2 is C(O)ORπ, are prepared by treating a suspension of a compound of Formula E with a compound of formula RnOH. Typically the reaction is carried out in the presence of a non-nucleophilic base (e.g., triethylamine (TEA), trimethylamine or pyridine, preferably TEA) and in a suitable inert solvent (e.g., dioxane, DCM, THF, preferably dioxane). The reaction mixture is agitated for 10 to 24 hours at temperatures between about 30°C and about 50°C. The reaction mixture is then filtered and the filter washed through with suitable solvents (e.g., dioxane). The combined filtrate is lyophilized to yield compounds of Formula π.
Preparation of Compounds of Formula D and Formula B
Compounds of Formula D and Formula B can be prepared by synthetic methods known to one skilled in the art. Compounds of Formula B are prepared as discussed for Scheme A, above. An illustrative method to prepare a compound of Formula D is discussed below.
Preparation of a compound of Formula D:
A solution of sodium methoxide (typically about 1.387 mol in a suitable solvent, preferable DMF) is cooled to about 0°C and then heated with 4- hydroxythiophenol (typically 1 equivalent). This mixture is agitated for up to 2 hours at ambient temperature and then combined with a suitable solid support, e.g., Merrifield resin (Midwest Biotech) in DMF. The resulting mixture is agitated for up to 60 hours at a temperature of about 60°C. The resin is isolated from solvents and washed free from contaminants with suitable inert solvents to yield a compound of Formula D. For example, typically the resin is washed up to three times in succession with DMF, MeOH, AcOH, IN HChAcOH (5% v:v), DCM, MeOH and Et2O.
Synthesis of an Array of Compounds of Formula I or Formula TJ
The novel process of the present invention can also be used to prepare an array of compounds of Formula I or Formula U. The following description is the general procedure to accomplish such a synthetic array.
The resin-supported compounds of Formula C or Formula E are suspended in dioxane (40ml) and partitioned into Polyfiltronics™ plates (2.7μm). The plates are placed in Hydra clamps and the Hydra is then used to dispense in to each well, either (i) 800 μL of 0.5M R9R10NH in dioxane, (ii) 800 μL of dioxane:TEA:RnOH (8: 1 : 1), or (iii) 800 μL of 2M L1BH4 in THF diluted 1:3 in dioxane to each well. The wells are covered with a Teflon™ sheet and clamped. The LiBFLi cleavage plates are shaken for 10 to 24 hours at temperatures between 5°C and 35°C. The amine (R9R10NH) cleavage plates are shaken for 10 to 24 hours at temperatures between 10°C and 40°C. The alcohol (RnOH) cleavage plates are placed in the Hydra™ rotisserie oven on the rocker table apparatus for 10 to 24 hours at temperatures between 30°C and 50°C. The Formula I or Formula TJ products are collected by gravity filtration and minor N positive pressure into 2mL Beckman™ plates. The resin in each well is then washed with 400 μL of dioxane and the filtrate is collected. The plates are frozen at -78°C and then lyophilized at 5°C for a 24 hour period on the Virtis™ tray lyophilizer. The cleaved residues are then taken up in 800 μL of DCM and shaken orbitally for 20 minutes. The compounds of Formula I or Formula II are then extracted through the SLE material (pre-primed with 2N HC1 (350 μL) or H20
(350 μL)) using the Tecan Genesis RSP 200 Series (Tecan, AG). The 2 mL Beckman™ product plates are then concentrated using the Savant™ Speedvac. All of the plates are then put in a large dessicator and vacuum dried for 10 to 24 hours. Representative Compounds of Formula I
2-p-Tolyl-oxazole-4-carboxylic acid ri-butylcarbamoyl-2-phenyl-ethyll-amide
(Standard 1):
A compound of Formula A in which X2 is a group of Formula (c) wherein R7 is hydrogen and R8 is benzyl and SS is Merrifield resin (3.2g) was swelled in DCM (32mL). This swelled compound was added to a mixture of 2-p-tolyl-oxazole-4- carboxylic acid (7.8g, 38.4mmol), DIC (6mL; 38.4mmol) and DCM (117 mL). The resulting solution was allowed to stand for 5 to 15 minutes. DMAP (140mg; 1.15mmol) was added and the resulting mixture was agitated, with frequent venting, at a temperature of about 25°C for about 15 hours. The resulting resin was isolated and washed in succession with 1: 1 DCMTHF (lxlOOmL), DCM (2xl00mL), MeOH (2xl00mL) and dioxane (3xl00mL) and dried under reduced pressure to yield the corresponding compound of Formula C in which X1 is oxygen, R1 is of 2- -tolyl and X2 is a group of Formula (c) wherein R7 is hydrogen and R8 is benzyl. The compound of Formula C was suspended in a minimal amount of dioxane and treated with 0.5M butylamine in dioxane (50 mL). The resulting mixture was agitated for 10 to 24 hours at a temperature of 25°C. The mixture was then filtered and the residue washed with dioxane (50 mL). The combined filtrate was collected and lyophilized to obtain 2-p- tolyl-oxazole-4-carboxylic acid (l-butylcarbamoyl-2-phenyl-ethyl)-amide (standard 1).
2-(j2-r3-Benzyl-3-(2-methoxy-phenyl)-ureidol-thiazole-4-carbonylj-amino) -3- benzylsulfanyl-propionic acid pent-2-ynyl ester (Standard 6):
2-[3-Benzyl-3-(2-methoxy-phenyl)-ureido]-thiazole-4-carboxylic acid ( 14.7g, 38.4mmol) and DIC (6mL; 38.4mmol) were dissolved in DCM (221 mL). The resulting solution was allowed to stand for 5 to 15 minutes. A compound of Formula A in which X2 is a group of Formula (c) wherein R7 is hydrogen and R8 is 4- benzylsulfanylmethyl and SS is Merrifield resin (3.2g) was swelled in DCM (32 mL) and added to the thiazole-4-carboxylic acid mixture. To this reaction mixture was added DMAP (140mg; 1.15mmol), and the mixture was agitated, with frequent venting, at a temperature of about 25°C for about 10 to 24 hours. The resulting resin was isolated and washed in succession with 1 : 1 DCMTHF (lxlOOmL), DCM (2xl00mL), MeOH (2xl00mL) and dioxane (3xl00mL) and dried under reduced pressure to yield the corresponding compound of Formula C in which X1 is S, R1 is 3- benzyl-3-(2-methoxy-phenyl)-ureido and X2 is a group of Formula (c) wherein R7 is hydrogen and R is 4-benzylsulfanylmethyl. The resin of Formula C is suspended in a minimal amount of dioxane and then treated with an 8: 1 : 1 mixture of dioxane:TEA:Pent-2-yn-l-ol (50 mL). The resulting mixture was gently agitated for 10 to 24 hours at a temperature of 40°C. The mixture was then filtered and the residue washed with dioxane. The combined filtrate was collected and lyophilized to obtain 2-({2-[3-benzyl-3-(2-methoxy-phenyl)-ureido]-thiazole-4-carbonyl}-amino) -3- benzylsulfanyl-propionic acid pent-2-ynyl ester (standard 6).
Representative Compounds of Formula TJ 2-(4-Hexyloxy-phenyl)-oxazole-5-carboxyIic acid (l-benzyl-piperidin-4-yl)-amide (Standard 7):
2-(4-Hexyloxy-phenyl)-oxazole-5-carboxylic acid (11. lg, 38.4mmol) and DIC (6mL; 38.4mmol) were dissolved in DCM (166 mL). The resulting solution was allowed to stand for 5 to 15 minutes. A compound of Formula D in which SS is Merrifield resin (3.2g) was swelled in DCM (32 mL) and added to the Formula B, DIC and DCM mixture. To this reaction mixture was then added DMAP (140mg; 1.15mmol), and the mixture was agitated, with frequent venting, at a temperature of about 25°C for about 10 to 24 hours. The resulting resin was isolated and washed in succession with 1: 1 DCMTHF (lxlOOmL), DCM (2xl00mL), MeOH (2xl00mL) and dioxane (3xl00mL) and dried under reduced pressure to yield the corresponding compound of Formula E in which R1 is 4-hexyloxy-phenyl and X1 is O. The compound of Formula E was suspended in a minimal amount of dioxane and then treated with 0.5M l-benzyl-piperidin-4-ylamine in dioxane (50 mL). The resulting mixture was gently agitated for 10 to 24 hours at a temperature of 25°C. The mixture was then filtered and the filter washed with dioxane. The combined filtrate was collected and lyophilized to obtain 2-(4-hexyloxy-phenyl)-oxazole-5-carboxylic acid (l-benzyl-piperidin-4-yl)-amide (standard 7). Synthesis of Specific Compounds (Standards)
The following standard compounds of Formula I were prepared using the novel process of the present invention:
Figure imgf000019_0001
STANDARD 1 STANDARD 2
Figure imgf000019_0002
The following standard compound of Formula II was prepared using the novel process of the present invention:
Figure imgf000020_0001
STANDARD 7
Characterization data for the above standards are as follows:
Standard 1: Exact mass 405.2; (MH+) m/z= 406.1
Standard 2: Exact mass 303.1; (MH+) m z= 303.9
Standard 3: Exact mass 499.2; (MrT) m/z= 500.2
Standard 4: Exact mass 443.2; (MH+) m/z= 444.1
Standard 5: Exact mass 513.3; (MH+) m z= 514.3
Standard 6: Exact mass 642.2; (MH+) m/z= 643.2
Standard 7: Exact mass 461.3 ; (MH+) m/z= 462.2
Analysis Procedure
A. Chromatography: All validation samples are analyzed on a Hewlett Packard HPl lOO HPLC employing a Zorbax 4.6 mm x 7.5 cm SP-C18 column with a guard column. Samples are monitored at UV settings of 214 and 254 nm. The column is heated at 40°C and the flow rate is 0.800 mL per minute for all runs. Gradient elution is performed using water with 0.05% TFA (solvent A) and acetonitrile containing 0.05% TFA (solvent B) as mobile phases. Most samples are prepared as dilute solutions in acetonitrile, methanol or mixtures thereof.
HPLC Gradient:
Time (minutes) % Solvent B 0.00 0.00 5.00 100 8.00 100.0 9.50 0.00
B. Mass Spectrometry: Identity of peaks observed by HPLC are determined by electrospray (ESI) LC/MS analysis on a Finnigan TSQ 7000 mass spectrometer with a Hewlett Packard HP1050 HPLC. Alternatively, purified compounds or relatively pure mixtures are analyzed with a Hewlett Packard 5989 particle beam mass spectrometer and Hewlett Packard 59980 LC/MS interface in either CI or El mode, with a Hewlett Packard HP1050 HPLC using methanol as mobile phase for direct injection of samples. Most samples are prepared as dilute solutions in acetonitrile or methanol. For analysis of both the test library and production library, direct injection MS analysis is performed on the Sciex 150 MCA, Shimadzu LC-10 HPLC, according to the following conditions:
LC/MS Assay: Mobile A: Water (containing 0.05% AcOH and 1.0% MeOH) Mobile B: Methanol (containing 0.05% AcOH and 1.0% water) Flow Rate: 0.3 mL/min Sample volume: 10.0 μL Column: Zorbax 3.0 x 50.0 mm column with inline filter Temp.: 40°C Gradient: 0 to 100% B in 6.0 min, 100% B for 1.0 min, 0% B for
2.0 min.
Detection: UV monitoring at 214, 254, 280, and 320 nm DEFINITIONS
Abbreviations used: Acetonitrile (ACN); Acetic Acid (AcOH); t- butyloxycarbonyl (Boc); dichloromethane (DCM); 2,3-Dichloro-5,6-dicyano-l,4- benzoquinone (DDQ); diisopropylcarbodiimide (DIC); 4-Dimethylamino-pyridine (DMAP); electrospray ionization (ESI); Diethyl Ether (Et2O); Ethyl acetate (EtOAc); High performance liquid chromatography (HPLC); Liquid Chromatography/Mass Spectroscopy (LC/MS); Methanol (MeOH); triethylamine (TEA); Tetrahydrofuran (THF); Trifluoroacetic Acid (TFA); tetrapyrrolidinophosphonium hexafluorophosphate (PyBOP); N-{(dimethylamino)(lH-l,2,3-triazole[4,5-b]pyridin- l-yl)-methylene}-N-methylmethan-aminium hexafluorophosphate N-oxide (ΗATU); 4-Dimethylamino-pyridine (DMAP).
"Alkyl" indicated alone means a straight or branched, saturated or unsaturated aliphatic radical having the number of carbon atoms indicated (e.g., (Cι_ )alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, etc.). Alkyl indicated as part of a larger radical (e.g., as in arylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when 0 atoms are indicated means a bond (e.g., (C0-3)alkyl of (C3_ι2)cycloalkyl(C0-3)alkyl means a bond, methylene, ethylene, trimethylene, 1-methylethylene, etc.).
"Alkylene" means a saturated or unsaturated, branched or unbranched, hydrocarbon divalent radical having the number of carbon atoms indicated and any ketone, thioketone, iminoketone and substituted derivative thereof (e.g., (Cι_ )alkylene includes methylene (-CΗ2-), ethylene (-CH2CH2-), methylethylene, vinylene, ethynylene, trimethylene (-CH2CH2CH2-), 2-oxotrimethylene (-CH2C(O)CH2-), 2-thiatrimethylene (-CH2C(S)CH2-), 2-iminotrimethylene (-CH2C(ΝH)CH2-), propenylene (-CH2CH-CH- or -CH-CHCH2-), propanylylidene (-CHCH2CH2-), propendiylene (-CHCH-CH-), 1-aminotetramethylene, pentamethylene, etc.). When no carbon atoms are indicated (e.g., as in (Co)alkylene), a bond is intended.
"Alkyloxy" means the radical -OR, wherein R is alkyl as defined above, having the number of carbon atoms indicated (e.g., (Cι_6)alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, 1-propynyloxy, 2-propynyloxy, and the like).
"Array of compounds" is defined as a collection of independent (individual) compounds that are synthesized by the process of the present invention. Generally, the term 'array of compounds' indicates a collection of compounds distinct from one another. Also included in the array of compounds is a mixture of individual compounds.
Aryl means an aromatic monocyclic, polycyclic or fused polycyclic ring system containing the number of annular carbon atoms indicated, wherein each ring contained therein is comprised of 6 annular members (e.g., (C6-]2)aryl includes phenyl, naphthalenyl, and biphenylyl).
"Burgess Reagent" is the name given to the compound (CH3CH2)3N+S(O)2N" C(O)OCH3.
"Combinatorial Synthesis" is defined as an ordered strategy for parallel synthesis of arrays of single compounds or mixtures, by sequential addition of reagents.
"Coupling Agent" is intended to represent an additive that facilitates the course of a reaction but does not get incorporated in to the final product. Illustrative examples of coupling agents are diisopropylcarbodiimide (DIC), N- hydroxybenzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HO At) and N- hydroxysuccinimide.
"Cycloalkyl" means a saturated or partially unsaturated, monocyclic ring, bicyclic ring assembly (directly linked by a single bond or fused) or bridged polycyclic ring assembly containing the number of annular carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., (C3-i2)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclohexylyl, cyclopentylcyclohexyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthalenyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-l-yl, etc.).
"Halo" means fluoro, chloro, bromo or iodo.
"Heteroaryl" means aryl, as defined herein, provided that one or more of the annular carbon atoms indicated, is replaced by heteroatom moiety selected from -Ν=, - NR-, -O- or -S-, wherein R is hydrogen, (Cj_6)alkyl or a protecting group, and each ring contained therein is comprised of 5 to 6 annular members (e.g., hetero(C5.t )aryl includes thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxaxolyl, indolyl, benzo[b]thienyl, isobenzofuranyl, purinyl, isoquinolyl, pterdinyl, perimidinyl, imidazolyl, 1-methylimidazolyl, 1-benzylimidazolyl, pyridyl, pyrazolyl, pyrazinyl, quinolyl, [2,4]bipyridinylyl, 2-phenylpyridyl, 4-thiazol-4-ylphenyl, lH-imidazol-1-ylphenyl, and the like). Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like.
"Ηeterocycloalkyl" means cycloalkyl, as defined herein, provided that one or more of the annular carbon atoms indicated is replaced by heteroatom moiety selected from -N-, -NR-, -O- or -S-, wherein R is hydrogen, (Cι_6)alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term heterocyclo(C5-i )alkyl includes piperidyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, quinuclidinyl, morpholinyl, [l,4 bipiperidinylyl, l'^'-dihydro^H-fl^lbipyridinylyl, l-morpholin-4-ylpiperidinyl, etc.). Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the like.
"Ηeteropolycycloaryl" means polycycloaryl, as defined herein, except one or more of the annular carbon atoms indicated are replaced by a heteroatom moiety selected from -N=, -NR-, -O- or -S-, wherein R is hydrogen, (Cι_ )alkyl or a protecting group, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., heteropolycyclo(C8_ι2)aryl includes 3,4-dihydro-2H-quinolinyl,
5,6,7, 8-tetrahydroquinolinyl, 3,4-dihydro-2H-[l,8]naphthyridinyl, morpholinylpyridyl, piperidinylphenyl, l,2,3,4,5,6-hexahydro-[2,2T]bipyridinylyl,
2,4-dioxo-3,4-dihydro-2H-quinazolinyl, 3-oxo-2,3-dihydrobenzo[l,4]oxazinyl, and the like).
"Iminoketone derivative" means a derivative containing the moiety -C(NR)-, wherein R is hydrogen or (Cι-6)alkyl.
"Inert solvents" as used herein represents solvents that do not react with the reagents dissolved therein. Illustrative examples of inert solvents are tetrahydrofuran (TΗF), methylene chloride, dichloromethane (DCM), ethyl acetate (ETOAc), dimethyl formamide (DMF), dioxane, chloroform and dimethylsulfoxide (DMSO).
"Ketone derivative" means a derivative containing the moiety -C(O)-
"Nitro" means the radical -NO
"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase "any 1 to 3 annular atoms of any aromatic ring with available valences compπsing R6 optionally independently is substitutedO means that the aromatic πng referred to may or may not be substituted in order to fall within the scope of the invention.
"Polycycloaryl" means a bicyclic πng assembly (directly linked by a single bond or fused) containing the number of annular carbon atoms indicated, wherein at least one, but not all, of the fused πngs compπsing the radical is aromatic, and any carbocyclic ketone, thioketone or iminoketone deπvative thereof (e.g., polycyclo(C9 ι )aryl includes indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2-dιhydronaphthalenyl, cyclohexylphenyl, phenylcyclohexyl,
2,4-dιoxo-l,2,3,4-tetrahydro-naphthalenyl, or the like).
"Solid support or (SS)", as used in the present invention, signifies polymeπc mateπal for supported synthesis. A detailed descπption of the terms linker molecule, and solid support can be found in The Comb atoπal Index, B. A. Bunin, 1998, which is incorporated herein by reference.
"Thioketone deπvative" means a deπvative containing the moiety -C(S)-.

Claims

WE CLAIM:We Claim:
1. A process for synthesizing a compound or an array of compounds of Formula I:
Figure imgf000027_0001
in which:
X' is O or S;
R1 is -R3, -NR R4, -NR3C(NR4)NR3R4 or -NR3C(O)NR3R4 wherein R3 is (Cι_ιo)alkyl, (C6-ι2)aryl(C0-3)alkyl, polycyclo(C6.12)aryl(C0-3)alkyl, hetero(C5.ι2)aryl(C0- 3)alkyl or heteropolycyclo(C6_i2)aryl(Co-3)alkyl and R4 is hydrogen or (Cι_6)alkyl, wherein any aromatic moiety comprising R1 optionally is substituted with 1 to 3 substituents independently selected from halo, nitro, cyano, (Cι.6)alkyl, halo-substituted(C1-6)alkyl, -OR5, -C(O)R5, -C(O)OR5, -C(O)NR5R5, -S(O)2NR5R5, - X3NR5R5, -X3NR5C(O)R5, -X3NR5C(O)OR5, -X3NR5C(O)NR5R5 and - X3NR5C(NR5)NR5R5, wherein X3 is a bond or methylene and R5 at each occurrence independently is hydrogen or (Cι-6)alkyl; X2 is a group selected from Formulae (a), (b), (c) and (d):
Figure imgf000027_0002
R2 is -CH2OH, -C(O)NR9R'° or -C(O)ORn, wherein R9, R10 and R11 independently are hydrogen,
Figure imgf000027_0003
(C3-ι2)cycloalkyl(Cι_3)alkyl, hetero(C3.12)cycloal kyl (C i _3)alkyl , (C6-] 2)aryl (C0-6)alkyl , hetero(C5.12)aryl (C0-6)alkyl, polycyclo(C6_ι2)aryl(Co-6)alkyl, heteropolycyclo(C6.]2)aryl(Co-6)alkyl or -X4R12, wherein X is (C,_4)alkylene and R , 112 is -OR 113J or -NR , 113JRr> 14 , wherein R . 113J and R14 are independently hydrogen, (C1 6)alkyl, (C6 12)aryl(Co 6)alkyl, polycyclo(C6 ι2)aryl(C0 6)alkyl, hetero(C5.ι2)aryl(C0 6)alkyl, heteropolycyclo(C6 12)aryl(Co 6)alkyl, -XOR 1160 or -X4NR , 1'6°rR) 1160, wherein X4 is as defined above and R , 16 at each occurrence independently is hydrogen or (Cj 2)alkyl, wherein any aromatic moieties compπsing R9, R10 or R! 1 optionally independently are substituted with 1 to 3 substituents independently selected from halo, nitro, cyano, (Cj 6)alkyl, halo-substιtuted(Cι-6)alkyl, -OR5, -C(O)R5, -C(O)OR5, -C(O)NR5R5, -
S(O)2NR ) 5TτT> 5, -X NR » 53rR>5D, -X4NR3C(O)R3, -X4NR3C(O)OR\ -X^NR OMT 5Rr> 53 and
X4NR3C(NR NR > 53nR5D, wherein X and R3 are as defined above, or R' and R 1ι0υ together with the nitrogen atom to which R and R 10 are attached form hetero(C5 )cycloalkyl optionally substituted with -X4R12, wherein X4 and R12 are as defined above;
R7 is hydrogen or (Cι- )alkyl; and
R8 is (l) hydrogen, (π) (Ci ό)alkyl optionally substituted with -OR17, -SR17, - S(O)R17, -S(O)2R17, -C(O)R17, -C(O)OR17, -C(O)NR17R!8, -NR17R18, -NR18C(O)R17, -NRlδC(O)OR , 1"7,-NR,δC(O)NR , 117,τR> l,δ or -NRlδC(NR,δ)NR 1"7rRι l,8δ, wherein R , 17
IS
(Cj ό)alkyl, (Cι_ )alkanoylamιnomethyl, (C3 ι2)cycloalkyl(C0 3)alkyl, hetero(C3 12)cycloalkyl(C0 3)alkyl, (C6.ι2)aryl(C0 3)alkyl, (C6.ι2)arylsulfonyl, hetero(C5 ι )aryl(Co-3)alkyl, (C9 12)polycycloaryl(C0 3)alkyl or hetero(C8_ι2)polycycloaryl(Co 3)alkyl and R18 at each occurrence independently is hydrogen or (Cι.6)alkyl, or (in) (C3.ι2)cycloalkyl(Cι-3)alkyl, hetero(C3 ι2)cycloalkyl(Cι.3)alkyl, (C6-ι2)aryl(C1 3)alkyl, hetero(C5 ι2)aryl(C] 3)alkyl, (C9 ι2)polycycloaryl(Co-3)alkyl or hetero(C8 ι2)polycycloaryl(Cι_3)alkyl;
said process compπsing: (l) treating a compound of Formula A:
Figure imgf000028_0001
Formula A with a compound of Formula B:
Figure imgf000029_0001
Formula B
in the presence of a coupling agent and optionally an acylation catalyst, to yield a compound of Formula C:
Figure imgf000029_0002
Formula C
where R1, X1 and X2 are as defined above and "SS" represents a solid support; and
(ii) treating a compound or an array of compounds of Formula C with (a) a reducing agent to yield a compound or an array of compounds of Formula I where R2 is CH2OH, or (b) a compound of formula R9R10NH or RnOH to yield a compound or an array of compounds of Formula I where R2 is -C(O)NR9R10 or -C(O)ORn, respectively.
2. A process for synthesizing a compound or an array of compounds of
Formul aa T TJT-:
Figure imgf000030_0001
Formula TJ
in which: X' is O or S;
R1 is -R3, -NR3R4, -NR3C(NR4)NR3R4 or -NR3C(O)NR3R4 wherein R3 is (Cι-ιo)alkyl, (C6.ι2)aryl(C0.3)alkyl, polycyclo(C6-ι2)aryl(C0-3)alkyl, hetero(C5-ι2)aryl(Co- 3)alkyl or heteropolycyclo(C6-i2)aryl(Co-3)alkyl and R4 is hydrogen or (C).6)alkyl, wherein any aromatic moiety comprising R optionally is substituted with 1 to 3 substituents independently selected from halo, nitro, cyano, (Cι_6)alkyl, halo-substituted(Cι_6)alkyl, -OR5, -C(O)R5, -C(O)OR5, -C(O)NR5R5, -S(O)2NR5R5, - X3NR5R5, -X3NR5C(O)R5, -X3NR5C(O)OR5, -X3NR5C(O)NR5R5 and - X3NR5C(NR5)NR5R5, wherein X3 is a bond or methylene and R5 at each occurrence independently is hydrogen or (Cι-6)alkyl; R2 is -CH2OH, -C(O)NR9R10 or -C(O)ORπ, wherein R9, R10 and R11 independently are hydrogen, (Cι-6)alkyl, (C3-12)cycloalkyl(Cι.3)alkyl, hetero(C3_ι2)cycloalkyl(Cι_3)alkyl, (C6-ι2)aryl(Co.6)alkyl, hetero(C5_]2)aryl(C0-6)alkyl, polycyclo(C6-ι2)aryl(Co-6)alkyl, heteropolycyclo(C6.ι2)aryl(C0-6)alkyl or -X4R12, wherein X4 is (C]-4)alkylene and R12 is -OR13 or -NR13R14, wherein R13 and R14 are independently hydrogen, (Cι.6)alkyl, (C6-i2)aryl(C0-6)alkyl, polycyclo(C6.]2)aryl(C0.6)alkyl, hetero(C5.ι2)aryl(C0-6)alkyl, heteropolycyclo(C6.i2)aryl(C0-6)alkyl, -X4OR16 or -X4NR16R16, wherein X4 is (Cι_ )alkylene and R16 at each occurrence independently is hydrogen or (Cι_2)alkyl, wherein any aromatic moieties comprising R , R or R11 optionally independently are substituted with 1 to 3 substituents independently selected from halo, nitro, cyano, (Cj-f alkyl, halo-substituted(Cj.6)alkyl, -OR5, -C(O)R5, -C(O)OR5, -C(O)NR5R5, - S(O)2NR5R5, -X4NR5R5, -X4NR5C(O)R5, -X4NR5C(O)OR5, -X4NR5C(O)NR5R5 and - X4NR5C(NR5)NR5R5, wherein X4 and R5 are as defined above, or R9 and R10 together with the nitrogen atom to which R9 and R10 are attached form hetero(C5-7)cycloalkyl optionally substituted with -X4R12, wherein X4 and R12 are as defined above;
said process comprising: (1) treating a compound of Formula D:
Figure imgf000031_0001
Formula D with a compound of Formula B:
Figure imgf000031_0002
Formula B
in the presence of a coupling agent and optionally an acylation catalyst, to yield a compound of Formula E:
Figure imgf000031_0003
Formula E
where R1 and X1 are as defined above and "•" represents a solid support; and (2) treating a compound or an array of compounds of Formula E with (a) a reducing agent to yield a compound or an array of compounds of Formula U, where R2 is CH2OH, or (b) a compound of formula R9R10NH or RπOH to yield a compound or an array of compounds of Formula II where R2 is -C(O)NR9R10 or -C(O)ORn, respectively.
3. The process of claim 1 in which: X' is O or S;
R1 is -R3, -NR3R4 or -NR3C(O)NR3R4 wherein R3 is (C1-10)alkyl, (C6-i2)aryl(Co-3)alkyl, hetero(C5-ι2)aryl(C0_3)alkyl or heteropolycyclo(C6-ι2)aryl(Co-
3 )alkyl and R is hydrogen or (Cι-6)alkyl, wherein any aromatic moiety comprising R optionally is substituted with 1 to 3 substituents independently selected from halo, nitro, (Cι_6)alkyl, halo-substituted(Cι_6)alkyl or -OR5 wherein R5 at each occurrence independently is hydrogen or (Cι-6)alkyl; X2 is a group selected from Formulae (a), (b), (c) and (d):
Figure imgf000032_0001
R2 is -CH2OH, -C(O)NR9R10 or -C(O)ORπ, wherein R9, R10 and R11 independently are hydrogen, (Cι_6)alkyl, (C3_ι2)cycloalkyl(Cι-3)alkyl, hetero(C3.12)cycloalkyl(C j -3)alkyl , (C6. j 2)aryl (C0-6)alkyl , hetero(C5- 12)aryl(C0-6)alkyl, polycyclo(C6-ι2)aryl(C0-6)alkyl, heteropolycyclo(C6_i )aryl(Co.6)alkyl or -X4R12, wherein X4 is (Cι_4)alkylene and R12 is -OR13 or -NR13R14, wherein R13 and R14 are independently hydrogen, (Cι-6)alkyl, (C6.!2)aryl(Co-6)alkyl, polycyclo(C6.ι2)aryl(C0_6)alkyl, hetero(C5.ι2)aryl(C0-6)alkyl, heteropolycyclo(C6.12)aryl(C0-6)alkyl, -X4OR16 or -X4NR16R16, wherein X4 is as defined above and R16 at each occurrence independently is hydrogen or (C]_2)alkyl, wherein any aromatic moiety comprising R9, R10 or R11 optionally is substituted with 1 to 3 substituents independently selected from halo, nitro, cyano, (Cι_6)alkyl, halo-substituted(Cι-6)alkyl, -OR5, -C(O)R5, -C(O)OR5, -C(O)NR3R5, -S(O)2NR5R5, - X4NR5R5, -X NR5C(O)R5, -X4NR5C(O)OR5, -X4NR5C(O)NR5R5 and - X4NR5C(NR5)NR5R5, wherein X4 and R5 are as defined above, or R9 and R10 together with the nitrogen atom to which R9 and R1 are attached form hetero(C5.7)cycloalkyl optionally substituted with -X4R12, wherein X and R12 are as defined above;
R7 is hydrogen or (Cι- )alkyl; and
R8 is (i) hydrogen, (ii) (Cι_6)alkyl optionally substituted with -OR17, -SR17, - S(O)R17, -S(O)2R17, -NR18C(O)OR17, or -NR18C(NR18)NR17R18, wherein R17 is (Cι_6)alkyl, (Cι-6)alkanoylaminomethyl or (C3_ι2)cycloalkyl(C0_3)alkyl and R18 at each occurrence independently is hydrogen or (C]-6)alkyl.
4. The process of claim 2 wherein: X1 is O or S; R1 is -R3, -NR3R4 or -NR3C(O)NR3R4 wherein R3 is (Chalky!, (C6-ι2)aryl(Co-3)alkyl, hetero(C5.i2)aryl(C0-3)alkyl or heteropolycyclo(C6-i2)aryl(C0_ )alkyl and R4 is hydrogen or (Cι.6)alkyl, wherein any aromatic moiety comprising R1 optionally is substituted with 1 to 3 substituents independently selected from halo, nitro, (Ci_6)alkyl, halo-substituted(Cι_ )alkyl or -OR5 wherein R5 at each occurrence independently is hydrogen or (Cι-6)alkyl; R2 is -CH2OH, -C(O)NR9R10 or -C(O)ORπ, wherein R9, R10 and R11 independently are hydrogen, (Cι-6)alkyl, (C3_ι2)cycloalkyl(Cι.3)alkyl, hetero(C3_ι2)cycloalkyl(Cι_3)alkyl, (C6.12)aryl(C0-6)alkyl, hetero(C5,ι2)aryl(C0_6)alkyl, polycyclo(C6-ι )aryl(Co-ό)alkyl, heteropolycyclo(C6-ι )aryl(Co-6)alkyl or -X4R12, wherein X4 is (C,.4)alkylene and R12 is -OR13 or -NR13R14, wherein R13 and R14 are independently hydrogen, (Cι.6)alkyl, (C6-ι2)aryl(C0-6)alkyl, polycyclo(C6_12)aryl(C0-6)alkyl, hetero(C5.i2)aryl(Co-6)alkyl, heteropolycyclo(C6.ι2)aryl(Co-6)alkyl, -X4OR16 or -X4NR16R16, wherein X4 is as described above and R16 at each occurrence independently is hydrogen or (Cι-2)alkyl, wherein any aromatic moiety comprising R9, R10 or R11 optionally is substituted with 1 to 3 substituents independently selected from halo, nitro, cyano, (Cj.6)alkyl, halo-substιtuted(C]_6)alkyl, -OR5, -C(O)R5, -C(O)OR5, -C(O)NR5R5, -S(O)2NR5R5, - X4NR5R5, -X4NR5C(O)R5, -X4NR5C(O)OR5, -X4NR5C(O)NR5R5 and - X4NR5C(NR5)NR5R5, wherein X4 and R5 are as defined above, or R9 and R10 together with the nitrogen atom to which R9 and R10 are attached form hetero(C5_7)cycloalkyl optionally substituted with -X4R12, wherein X4 and R12 are as defined above.
5. The process of claim 3 wherein step (i) comprises treating a compound of Formula A with a compound of Formula B in the presence of a coupling agent selected from DIC, PyBOP, and HATU, and a catalyst selected from DMAP and 4- pyrrolidinopyridine.
6. The process of claim 5 wherein step (i) is carried out in the presence of an inert solvent selected from DCM, THF, and chloroform at a temperature ranging from about 15°C to about 35°C.
7. The process of claim 6 wherein the reducing agent in step (i)(a) is LiBH
8. The process of claim 7 wherein the inert solvent in step (ii) is selected from THF, methylene chloride, DCM, ethyl acetate, DMF, dioxane, chloroform and DMSO, and step (ii)(a) is carried out at a temperature ranging from about -30°C to about 35°C.
9. The process of claim 8 wherein step (ii)(b) is carried out at a temperature ranging from about 10°C to about 50°C.
10. An array of compounds synthesized by the process of Claim 1.
11. The process of claim 4 wherein step (1) comprises treating a compound of Formula D with a compound of Formula B in the presence of a coupling agent selected from DIC, PyBOP, and HATU, and a catalyst selected from DMAP and 4- pyrrolidinopyridine.
12. The process of claim 11 wherein step (1) is carried out in the presence of an inert solvent selected from DCM, THF and chloroform, and at a temperature ranging from about 15°C to about 35°C.
13. The process of claim 12 wherein the reducing agent in step (2)(a) is LiBH
14. The process of claim 13 wherein the inert solvent in step (2) is selected from THF, methylene chloride, DCM, ethyl acetate, DMF, dioxane, chloroform and DMSO, and step (2)(a) is carried out at a temperature ranging from about -30°C to about 35°C.
15. The process of claim 14 wherein step (2)(b) is carried out at a temperature ranging from about 10°C to about 50°C.
16. An array of compounds synthesized by the process of claim 2.
17. A process for synthesizing a compound or an array of compounds of Formula C:
Figure imgf000035_0001
Formula C
in which:
X1 is O or S;
R1 is -R3, -NR3R4, -NR3C(NR4)NR3R4 or -NR3C(O)NR R4 wherein R3 is
(Cι_ιo)alkyl, (C6-i2)aryl(C0- )alkyl, polycyclo(C6-ι2)aryl(C0-3)alkyl, hetero(C5_ι2)aryl(C0- 3)alkyl or heteropolycyclo(C6.ι2)aryl(Co-3)alkyl and R4 is hydrogen or (Cι_6)alkyl, wherein any aromatic moiety comprising R1 optionally is substituted with 1 to 3 substituents selected independently from halo, nitro, cyano, (Cι.6)alkyl, halo-substituted(C1_6)alkyl, -OR5, -C(O)R5, -C(O)OR5, -C(O)NR5R5, -S(O)2NR5R5, - X3NR5R5, -X3NR5C(O)R5, -X3NR5C(O)OR5, -X3NR C(O)NR5R5 and - X3NR3C(NR5)NR5R5, wherein X3 is a bond or methylene and R5 at each occurrence independently is hydrogen or (Cι,6)alkyl;
X r2 i ■s a group selected from Formulae (a), (b), (c) and (d):
Figure imgf000036_0001
R .7 i •s hydrogen or (Cι-4)alkyl; and R8 is (i) hydrogen, (ii) (C1.6)alkyl optionally substituted with -OR17, -SR17, - S(O)R17, -S(O)2R17, -C(O)R17, -C(O)OR17, -C(O)NR17R18, -NR17R18, -NR18C(O)R17,
NR'δC(O)OR , 1,7/,-NRlδC(O)NR , 1,7/rR> 1i8δ or -NR'δC(NR,δ)NR 1"7Rπ l f , wherein R , 17
Figure imgf000036_0002
(Cj_6)alkyl, (Cι-6)alkanoylaminomethyl, (C3_i2)cycloalkyl(Co-3)alkyl, hetero(C3.i2)cycloalkyl(C0-3)alkyl, (C6-i2)aryl(Co-3)alkyl, (C6-i2)arylsulfonyl, hetero(C5.12)aryl(Co-3)alkyl, (C9_]2)polycycloaryl(C0-3)alkyl or hetero(C8-i2)polycycloaryl(Co-3)alkyl and R at each occurrence independently is hydrogen or (Cj-6)alkyl, or (iii) (C3-i2)cycloalkyl(Cι.3)alkyl, hetero(C3_ι2)cycloalkyl(Cι_3)alkyl, (C6-i2)aryl(Cι_3)alkyl, hetero(C5.ι2)aryl(Cι.3)alkyl, (C _i2)polycycloaryl(Co-3)alkyl or hetero(C8_ι2)polycycloaryl(Cι_3)alkyl;
said process comprising:
(i) treating a compound of Formula A:
Figure imgf000036_0003
Formula A with a compound of Formula B:
Figure imgf000037_0001
Formula B
in the presence of a coupling agent and optionally an acylation catalyst, to yield a compound of Formula C:
Figure imgf000037_0002
Formula C
where R1, X1 and X2 are as defined above and "SS" represents a solid support.
18. A process for synthesizing a compound or an array of compounds of Formula E:
Figure imgf000037_0003
Formula E in which:
X1 is O or S;
R1 is -R3, -NR3R4, -NR3C(NR4)NR3R4 or -NR3C(O)NR3R4 wherein R3 is (Cj.ιo)alkyl, (C6.]2)aryl(Co-3)alkyl, polycyclo(C6.ι2)aryl(C0-3)alkyl, hetero(C5.ι2)aryl(Co- )alkyl or heteropolycyclo(C6-i2)ary](C0-3)alkyl and R is hydrogen or (Cι_6)alkyl, wherein any aromatic moiety comprising R1 optionally is substituted with 1 to 3 substituents selected independently from halo, nitro, cyano, (Cj_6)alkyl, halo-substituted(Cι_6)alkyl, -OR5, -C(O)R5, -C(O)OR5, -C(O)NR5R5, -S(O)2NR5R5, - X3NR5R5, -X3NR5C(O)R5, -X3NR5C(O)OR5, -X3NR5C(O)NR5R5 and - X3NR5C(NR5)NR5R5, wherein X3 is a bond or methylene and R5 at each occurrence independently is hydrogen or (Cι_6)alkyl;
said process comprising treating a compound of Formula D:
Figure imgf000038_0001
Formula D
with at least a compound of Formula B:
Figure imgf000038_0002
Formula B in the presence of a coupling agent and optionally an acylation catalyst, to yield a compound of Formula E:
Figure imgf000039_0001
Formula E
where R and X are as defined above and "SS" represents a solid support.
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