NZ526782A

Cannabinoid receptor ligands

Abstract

Disclosed are compounds of formula (I), wherein: R1 is H, alkyl, halo-alkyl, cycloalkyl, cycloalkylNH-, arylalkyl, heterocycloalkyl, heteroaryl, N(R2)2, or NR2aryl, or optionally substituted aryl, R2 is independently selected from H and alkyl, R3 is H, alkyl, Cl, F, CF3, OCF2H, OCF3, OH or alkoxy, R4 is H, alkyl, alkoxy, cycloalkyl, alkenyl, aryl, benzyl, heteroaryl, heterocycloalkyl, arylNH-, heteroarylNH-, cycloalkylNH-, N(R2)2, or NR2aryl, the alkyl, alkoxy, cycloalkyl, alkenyl, phenyl or heteroaryl being optionally substituted, R5 is H or alkyl, R6 is H or alkyl, or R5 and R6 are taken together to form a carbonyl group, and the remaining substituents are defined herein. The compounds are used in the manufacture of medicaments to stimulate cannabinoid CB2 receptors in a mammal.

NZ526782A, drawing sheet 1 — Sheet 1 of 139

Term

Term ended

Projected expiry passed 7 February 2022, 4.6 years ago.

57 claims: 10 independent, 47 dependent

1
We claim:or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound;wherein: R1 is H, alkyl, haloC-t-Ce alkyl, cycloaikyl, cycloalkyINH-, arylalkyl, heterocycloalkyl, heteroaryl, N(R2)2, or NR2aryl, unsubstituted aryl or aryl substituted with one to three X;R2 is the same or different in each occurrence and is independently selected from H or CrCe alkyl;R3 is H, CrC6 alkyl, Cl, F, CF3, OCF2H, OCF3, OH or CrC6 alkoxy;R4 is H, Ci-C6 alkyl, Ο^-Οβ alkoxy, cycloaikyl, alkenyl, aryl, benzyl, heteroaryl, heterocycloalkyl, aryINH-, heteroaryINH-, cycloalkyINH-, N(R2)2, or NR2aryl, said alkyl, alkoxy, cycloaikyl, alkenyl, phenyl or heteroaryl optionally substituted with one to three R5 is H or CrC6 alkyl;R6 is H or CrC6 alkyl;or R5and R6 taken together with the carbon atom form a carbonyl group;L1 is CrC6 alkylene, C2-C6alkenylene, C(R2)2, O X., CHOR2-, NOR5-, -SO2-, -SO-, -S-, -0-, -NR2-, -C(0)NR2-, -NR2C(O>, -CHCF3- or-CF2~;O L2 is a covalent bond, CrC6 alkylene, -C (R2)2-, , -CHOR2-, -C(R2)OH, NOR5-, -SOa-, -NR2SO2-, -SO-, -S-, -0-, -SO2NR2-, -N(R2)-, -C(O)NR2- or -NR2C(0)-;WO 02/062750 PCT/US02/03672 -104X is the same or different, and is independently selected from H, halogen, CF3, CN, OCF2H, OCF2CF3, OCF3i OR2, Ci-C3 alkyl, cycloalkyl, cycloalkoxy, C1-C6 alkoxy, alkoxyCi-Ce alkoxy, O-cycloalkyl, cycloalkylamino, cycloalkylalkoxy, heteroalkyi, OSO2R2, -COOR2, -CON(R2)2, NHR2, aryINH-, N(R2)2, or NR2 aryl;Y is a covalent bond, -CH2-, -SO2-, or Z is a covalent bond, -CH2-, -SO2- or X. t Y, R1, Z and R2 can be taken together with the nitrogen atom to form a heterocycloalkyl;with the proviso that if Y is a covalent bond, R1 cannot form a N-N bond with the nitrogen atom;and n is an integer of 0 to 4.
6
The compound according to Claim 1 of the formula 106- or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound; 5 wherein Xand R4are as shown in the table below:intellectual property office OF N.Z. ·' 7 mar 2005 RECEIVED WO 02/062750 PCT/US02/03672 -107- WO 02/062750 PCT/US02/03672 -108- WO 02/062750 PCT/US02/03672 -109-
9
10. The compound according to Claim 1 of the formula, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound;wherein X Is OCF2H and R1 is CH3. The
10
11. The compound according to Claim 1 of the formula, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound;wherein X is CH3 and R1 is CH3.
40
42. A composition for treating rheumatoid arthritis which comprises a compound selected from the class consisting of COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, an anti-TNF-α compound or other classes of compounds indicated for the treatment of rheumatoid arthritis and a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound, as defined In any one of claims 1 to 6. 323763_1.DOC - 126
41
43. A composition for treating rheumatoid arthritis which comprises a compound selected from the class consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, an anti-TNF-α compound or other classes of compounds indicated for the treatment of rheumatoid arthritis and a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound, as defined in any one of claims 7 to 29.
46
48. A composition for treating multiple sclerosis which comprises a compound selected from interferon beta-1 a, interferon beta-1 b, glatiramer acetate or other compounds indicated for the treatment of multiple sclerosis and a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound as defined in any one of claims 1 to 6. r-_________ WlfcLLfcClUAL PROPERTY OFFICE OF N2. ? MAR 2005 RECEIVED 323763 1.DOC - 127
47
49. A composition for treating multiple sclerosis which comprises a compound selected from interferon beta-1 a, interferon beta-1 b, glatiramer acetate or other compounds indicated for the treatment of multiple sclerosis and a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound as defined in any one of claims 7 to 29.
52
54. A composition for treating psoriasis which comprises a compound selected from the class consisting of an immunosuppressive, a steroid, an anti-TNF-α compound or other classes of compounds indicated for the treatment of psoriasis and a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound, as defined in any one of Claims 1 to 6. 7 MAR 2005 -RECEIVED 323763_1.DOC - 128
53
55. A composition for treating psoriasis which comprises a compound selected from the class consisting of an immunosuppressive, a steroid, an anti-TNF-α compound or other classes of compounds indicated for the treatment of psoriasis and a compound, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound as defined in any one of Claims 7 to 29. i

Independent claims10

894 paragraphs in 251 sections, as filed

BACKGROUND OF THE INVENTION

This invention relates to cannabinoid receptor ligands and, more particularly, to compounds that bind to cannabinoid (CB2) receptors. Compounds according to the present invention generally exhibit anti-inflammatory and immunomodulatory activity and are useful in treating conditions characterized by inflammation and immunomodulatory irregularities. Examples of conditions which may be treated include, but are not limited to, rheumatoid arthritis, asthma, allergy, psoriasis, Crohn’s disease, systemic lupus erythematosus, multiple sclerosis, diabetes, cancer, glaucoma, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, and nephritis. The invention also relates to pharmaceutical compositions containing said compounds.

Cannabinoid receptors belong to the superfamily of G-protein coupled receptors. They are classified into the predominantly neuronal CB1 receptors and the predominantly peripheral CB2 receptors. While the effects of CB1 receptors are principally associated with the central nervous system, CB2 receptors are believed to have peripheral effects related to bronchial constriction, immunomodulation and inflammation. As such, a selective CB2 receptor binding agent is expected to have therapeutic utility in the control of diseases associated with inflammation, immunomodulation and bronchial constriction such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, inflammatory disorders ofthe lungs and gastrointestinal tract, and respiratory tract disorders such as reversible airway obstruction, chronic asthma and bronchitis (see, e.g., R.G. Pertwee, Curr. Med. Chem. 6(8), (1999),635).

Various compounds have reportedly been developed which interact with CB2 receptors and/or which have, inter alia, anti-inflammatory activity associated with cannabinoid receptors. See, e.g., U.S. Pat. Nos. 5,338,753, 5,462,960, 5,532,237, 5,925,768, 5,948,777, 5,990,170, 6,013,648 and 6,017,919.

WO 02/062750

PCT/US02/03672

-2SUMMARY OF THE INVENTION

This invention relates to compounds of formula I:

a prodrug thereof, or a pharmaceutically acceptable salt, solvate or stereoisomer of the compound or of said prodrug; wherein:

R1 is H, alkyl, haloCrC6 alkyl, cycloalkyl; cycloalkyINH-, arylalkyl, heterocycloalkyl, heteroaryl, N(R2)2, or NR2aryl, unsubstituted aryl or aryl substituted with one to three X;

R2 is the same or different in each occurrence and is independently selected from H or Ci-C6 alkyl;

R3 is H, Ci-C6 alkyl, Cl, F, CF3, OCF2H, OCF3, OH or Ci-C6 alkoxy;

R4 is H, Ci-Ce alkyl, C-i-Ce alkoxy, cycloalkyl, alkenyl, aryl, benzyl, heteroaryl, heterocycloalkyl, aryINH-, heteroaryINH-, cycloalkyINH-, N(R2)2, or NR2aryl, said alkyl, alkoxy, cycloalkyl, alkenyl, phenyl or heteroaryl optionally substituted with one to three X;

R5 is H or C1-C6 alkyl;

R6 is H or C1-C6 alkyl; or

R5 and R6 taken together with the carbon atom form a carbonyl group;

O

L1 is Ci-C6 alkylene, C2-C6alkenylene, C(R2)2, , -CHOR2-, NOR5-, -SO2-,

-SO-, -S-, -O-, -NR2-, -C(O)NR2-, -NR2C(O)-, -CHCF3- or -CF2-;

WO 02/062750

PCT/US02/03672

L2 is a covalent bond, Ο-ι-Οθ alkylene, -C (R2)2-, , -CHOR2-, -C(R2)OH,

X is the same or different, and is independently selected from H, halogen, CF3, CN, OCF2H, OCF2CF3, OCF3, OR2, Ci-C6 alkyl, cycloaikyl, cycloalkoxy, C-i-Ce alkoxy, alkoxyCrCe alkoxy, O-cycloalkyl, cycloalkylamino, cycloalkylalkoxy, heteroalkyl, OSO2R2, -COOR2, -CON(R2)2, NHR2, arylNH-, N(R2)2, or NR2 aryl;

Y is a covalent bond, -CH2-, -SO2-, or

O

O

Z is a covalent bond, -CH2-, -SO2- or ; or

Y, R1, Z and R2 can be taken together with the nitrogen atom to form a heterocycloalkyl; with the proviso that if Y is a covalent bond, R1 cannot form a N-N bond with the nitrogen atom; and n is an integer of 0 to 4.

Cannabinoid receptor ligands according to the present invention have antiinflammatory activity and/or immunomodulatory activity and are useful in the treatment of various medical conditions including, e.g., cutaneous T cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, glaucoma, diabetes, osteoporosis, renal ischemia, myocardial infarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, Crohn’s disease, inflammatory bowel disease, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) or bronchitis. It is contemplated that a compound of this invention may be useful in treating more than one of the diseases listed.

- 4(followed by page 4a) indomethacin, ibuprofen and the like; COX-2 selective inhibitors such as Vioxx® (rofecoxib) and Celebrex® (celecoxib); COX-1 inhibitors such as Feldene (piroxicam); immunosuppressives such as steroids, cyclosporine, Tacrolimus, rapamycin, muromonab-CD3 (0KT3), Basilixmab and the like; biological response modifiers (BRMs) such as Enbrel (etanercept), Remicade (infliximab), IL-1 antagonists, anti-CD40, anti-CD28, IL-10, anti-adhesion molecules and the like; and other anti-inflammatory agents such as p38 kinase inhibitors, PDE4 inhibitors, TACE * inhibitors, chemokine receptor antagonists, Thalidomide arid other small molecule inhibitors of pro-inflammatory cytokine production. They may also be co-administered with or used in combination with H1 antagonists such as Claritin, Clarinex, Zyrtec, Allegra, Benadryl, and other H1 antagonists. Other drugs that the compounds of the invention may be co-administered or used in combination with include Anaprox,

Arava, Arthrotec, Azulfidine, Aspirin, Cataflam, Celestone Soluspan, Clinoril, Cortone Acetate, Cuprimine, Daypro, Decadron, Depen, Depo-Medrol, Disalcid, Dolobid, Naprosyn, Gengraf, Hydrocortone, Imuran, Indocin, Lodine, Motrin, Myochrysine, Nalfon, Naprelan, Neoral, Orudis, Oruvail, Pediapred, Plaquenil, Prelone, Relafen, Solu-Medrol, Tolectin, Trilisate and Volataren. These include any formulations of the above-named drugs.

For the treatment of multiple sclerosis, the compounds of tiie invention may be co-administered or used in combination with Avonex (interferon beta-1 a),

Betaseron (interferon beta-1 b), Rebif (interferon beta-1 a) and Copaxone (glatiramer acetate).

These include any formulations of the above-named drugs.

For the treatment of psoriasis, the compounds of the invention may be coadministered or used in combination with steroids, methotrexate, cyclosporin, Xanelin, Amivere, Vitamin D analogs, topical retinoids, anti-TNF-α compounds and other drugs indicated’for this condition. These include any formulations of the above-named drugs.

For the treatment of asthma, the compounds of the invention may be coadministered or used in combination with Singulair, Accolate, Albuterol, and other

OF N.Z.

323763_1.DOC 7 MAR 2005 .RECEIVED

- 4a (followed by page 5) drugs indicated for this disease. These include any formulations of the above-named drugs.

For the treatment of inflammatory bowel disease or Crohn’s disease, the compounds of the invention may be co-administered or used in combination with sulfasalazine, budesonide, mesalamine and other drugs indicated for these diseases. These include any formulations ofthe above-named drugs.

INTELLECTUAL PROPERTY OFFICE OF N.Z.

; 7 MAR 2005 RECEIVED

323763_1.DOC

WO 02/062750

PCT/US02/03672

-5ln another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

Unless otherwise defined, the following definitions shall apply throughout the specification and claims.

When any variable (e.g., R2) occurs more than one time in any constituent, its definition in each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

“Aiky!” means straight or branched alkyl chains of 1 to 12 carbon atoms. The term includes the isomers thereof such as isopropyl, isobutyl, sec-butyl, etc.

“Haloalkyl” means alkyl having 1 or more halo atoms.

“Heteroalkyl” means straight or branched alkyl chain comprised of from 1 to 12 carbon atoms and 1 or more heteroatoms independently selected from the group consisting of Ν, O and S.

“Cyeloalkyl” as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including, but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantyl among others.

“Heterocycloalkyl” means cyeloalkyl containing one or more heteroatoms.

“Aryl” means an aromatic monocyclic or multicyclic ring system comprising from 6 to 14 carbon atoms. Non-limiting examples include phenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl.

“Arylalkyl” means a group in which the aryl and alkyl are as previously desecribed. Non-limiting examples of suitable arylalkyl groups include benzyl, 2phenethyl and naphthlenylmethyl. The bond to the parent moiety is through the alkyl.

“Heteroaryl” means a single ring or benzofused heteroaromatic group of 5 to 10 atoms comprised of 1 to 9 carbon atoms and 1 or more heteroatoms independently selected from the group consisting of Ν, O and S. N-oxides of the ring nitrogens are also included, as well as compounds wherein a ring nitrogen is substituted by a Ci-C6 alkyl group to form a quaternary amine. Examples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl,

INIBXECrUAL PROPERTY OFFICE •1FN2 ' J MAR 2005

-®- RECEIVED tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazinyl, pyrimidyi, pyridazinyl and triazolyl. Examples of benzofused heteroaryl groups are indolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl (i.e., thionaphthenyi), benzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. All positional isomers are contemplated, e.g., 25 pyridyl, 3-pyridyl and 4-pyridyl.

“Alkoxy” means an alkyl radical attached by an oxygen, i.e., alkoxy groups having 1 to 9 carbon atoms.

“Alkenyl” means straight or branched chains of carbon atoms having one or more double bonds in the chain, conjugated or unconjugated.

“Oxime” means a CH(:NOH) radical containing moiety.

► “Halogen”, “halogenated” or “halo” refers to fluorine, chlorine, bromine or iodine radicals.

·»*

The term prodrug, as used but not claimed herein, represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

Linker groups such as L1, L2, Y and Z are divalent.·

In a preferred group of compounds of formula I, 0 = L1 is -SO2-, -CH2-, -CHCH3-, , -C=NOR2-, -C(CH3)2-, -CHOH-, -O-, -S- or-S=O;

θ ~»~

L2 is -SOr,, -CH2-, -CH(CH3)-,-C(CH3)2-, ’ CH2 , -NH-, -0-, CH3 _C— ι

NHSO2-, -NHC(0> or OH ;

R1 is H, -CH3NH2, -CH2CF3, -NHC3H7, -NHC2H6, -NHC4H9, CrC6 alkyl, -CF3, -CH(CH3)2, thiophenyl, morpholinyl, cyclopropanyl, benzyl, naphthyl, C(CH3)3, NHphenyl, 3,5-difluorophenyl, phenyl, N-cyclopentyl or N(CH3)2,·

WO 02/062750

PCT/US02/03672

-7R2isHorCH3;

R4 is furanyl, pyridyl, pyrimidyl, thiophenyl, quinolyl, t-butoxy, alkoxyl, cyclohexyl, phenyl, tolyl, C3H7, dimethylpyrimdyl, trifluoromethoxyphenyl, morpholinylphenyl or CH3; with the proviso that when R4 is t-butoxy, L2 must be

Q ~H~ , -CH2-, -CHCH3-,-C(CH3)2-or CH2 (all of the above optionally substituted with one to three substituents, which are the same or different and are independently selected from X;

R5 and R6 are independently H or CH3:

X is H, Cl, CF3, OCH3, OCF3i OCF2H, CH3 or CrC6 cycloalkyl;

O

Y is-SO2-or;

Z is a covalent bond; or

R1, Y, R2 and Z taken together with the nitrogen atom form a morpholinyl group.

In a more preferred embodiment ofthe invention,

L1 is -SO2- or -CH2-;

L2 is -SO2-;

R1 is CH3 or CF3: and

R4 is phenyl, pyrimidyl or pyridyl, said phenyl, pyrimidyl or pyridyl groups optionally substituted with one to three substituents independently selected from the group consisting of Ci-C6 alkyl, C1-C6 alkoxy, OH, CF3 and halogen.

More preferably, the phenyl is substituted with OCH3 or halogen selected from fluorine and chlorine.

Compounds ofthe invention may have at ieast one asymmetrical carbon atom and therefore all isomers, including diastereomers and rotational isomers are contemplated as being part of this invention. The invention includes (+)- and (-)isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optionally pure or optically enriched starting materials or by separating isomers of a compound of

WO 02/062750

PCT/US02/03672

-8formula I. Those skilled in the art will appreciate that for some compounds of formula l, one isomer may show greater pharmacological activity that other isomers.

Compounds of formula I can exist in unsolvated and solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of this invention.

Compounds of the invention with a basic group can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium bicarbonate. The free base form differs from its respective salt form somewhat in certain physical properties, such as solubility in polar solvents, but the salt is otherwise equivalent to its respective free base forms for purposes of the invention.

Certain compounds of the invention are acidic (e.g., compounds where R2 is a hydrogen covalently bonded to N). Acidic compounds according to the present invention can form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, magnesium, zinc, lithium, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkyiamines, N-methyiglucamine, piperazines and other amines.

Compounds of the present invention are generally prepared by processes known in the art, for example by the processes described below.

The following abbreviations are used in the procedures and schemes: aqueous (aq), anhydrous (anhyd), n-butyliithium (η-BuLi), dibromodimethylhydantoin (DBDMH), diisopropylethylamine (DIPEA), diethyl ether (Et2O), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), 1-(3-dimethyIaminopropyl)-3-ethyicarbodiimide hydrochloride (EDCI), ethanol (EtOH), ethyl acetate (EtOAc), 2-propanol (IPA), leaving group (LG), lithium hexamethyidisilazide (LHMDS), meta-chloroperoxybenzoic acid (MCPBA), methanesulfonic acid (MsOH), methanesulfonyl chloride (MsCI),

WO 02/062750

PCT/US02/03672

-9N-iodosuccinamide (NIS), preparative thin layer chromatography on Merck- silica plates (PTLC), phenyl (Ph), pyridinium chlorochromate (PCC), pyridine (Py), trifluoroacetic anhydride (TFAA), triflic’anhydride (Tf2O), tetrahydrofuran (THF), silica gel chromatography (sgc), thin layer chromatography (TLC), room temperature (rt), hours (h), minutes (min), molar (M), pounds per square inch (psi), and saturated aqueous sodium chloride solution (brine).

WO 02/062750

PCT/US02/03672

-10General Scheme I

Preparation of Aryl-Bis-Sulfone Compounds

Reaction Conditions are shown to fine left of all vertical and angled arrows.

CC

Conditions A 1) CH3Li/THF/-78°C _ 2) n-BuLi R5vr6Q 3) (X-PhS)2 ^Y^NA;F34>MCPBA.CH2C|2 2) DBDMH or

MftOH R3

Conditions A NH2 1.0 M LiOH

-N^R!

R4-L2 0 0

Conditions A Ligand/Aryl-Br Base/Soivent/Pd(0) or

Conditions B NaBH(OAc)3 Carbonyl compound'

Conditions B

1) CH3Li/THF/-78°C

2) n-BuLi

3) X-PhSO2F n_BuLj, 2.1 eq

THF.-78 “C 2) R4-L2-LG • Rs Re O NACF3 or JLxJ

Conditions Β f

O O

Dioxane

K2CO3/MeOH/H2O R^L2

1) n-BuLi, 2.1 eq THF,-78 °C

2) l2

R4-L2-H

Base

Solvent

R2-Y-LG

Rb/R6

Conditions A

Base/Solvent

Nucleophile/Pd(0)

Ligand or

Conditions B'

Base/Solvent'

Nucleophile

R5R6

hfRi

R4-L20 °

Description of Reactions-General Scheme I ln step 1, trifluoroacetic anhydride is dissolved in a suitable inert solvent such as methylene chloride and reacted with a benzyl amine at room temperature for 1-5 hr. MsOH (2 eq) is added followed by DBDMH and the reaction mixture is stirred

WO 02/062750

PCT/US02/03672

-11overnight at room temperature and subjected to aqueous work up. The crude product is recrystallized from a mixture of Et2O and hexanes or purified via chromatography.

In step 2, the product of step 1 is dissolved in THF, cooled in a dry ice/IPA bath and treated with methyllithium then η-BuLi. The resulting dianion may be trapped with a sulfonyl fluoride or a disulfide. If a disulfide is the trapping agent, the resulting product is oxidized with MCPBA in CH2CI2 at room temperature for 1-6 h. The product may be purified via chromatography or crystallization.

In step 3, the product of step 2 is dissolved in THF and treated with η-BuLi at 78 °C to form a dianion that is trapped with a suitable electrophile.

Alternatively, in step 3 the product of step 2 is dissolved in THF treated with nBuLi at -78 °C to form a dianion which is trapped with iodine to provide the iodo substituted product. The product may be purified via sgc or crystallization. The iodo product can be converted to a similar product by nucleophilic aromatic substitution with a variety of nucleophiles, including amines, alcohols, and thiols.

In step 4, the product of step 3 is dissolved in a suitable solvent such as dioxane, ethanol, methanol or THF and an alkali metal hydroxide or carbonate such as lithium hydroxide or potassium carbonate is added either as an aqueous solution or as a solid. The reaction mixture is stirred at room temperature for 0.5-24 h. The product may be purified via sgc or crystallization.

In step 5, a combination of the product of step 4 and a tertiary amine base was dissolved in a suitable solvent such as CH2CI2 or dioxane, at room temperature, cooled, and a suitable electrophile is added. The reaction mixture is stirred between 78 °C and 100 °C for 0.5 to 48 h. The product may be purified via sgc or crystallization.

In step 6, the product of step 5 is dissolved in a suitable inert solvent such as THF or CH2CI2 and treated with a suitable base such as NaH or triethylamine. An electrophile is added and the reaction mixture is stirred between 0 °C and 100°C for 0.5 to 48 h. The product may be purified via sgc or crystallization.

WO 02/062750

PCT/US02/03672

General Scheme II

Preparation of Methylene Linked Compounds

Description of reactions-General Scheme II

In step 1, trifluoroacetic anhydride is dissolved in a suitable inert solvent such as methylene chloride and treated with a benzyl amine at ambient temperature, then stirred for 1-5 h. Methanesulfonic acid (2 eq) is added followed by dibromodimethylhydantoin and the reaction mixture is stirred overnight at rt and subjected to aqueous work up. The product may be purified by chromatography or crystallization.

In step 2, the product of step 1 is dissolved in THF, cooled in a dry ice/acetone bath (-78°C) and treated with methyllithium, then η-BuLi. The dianion is then treated with a THF solution containing the aldehyde (i). The resulting mixture is warmed to rt and stirred for 10 h. The product is purified by chromatography.

In step 3, the alcohol product from step 2 is dissolved in methylene chloride and treated with ten fold excess of triethylsilane followed by a slight excess of boron trifluoride etherate. The resulting mixture is stirred at room temperature for 4h, and purified by chromatography.

In step 4, the product of step 3 is dissolved in a suitable solvent such as dioxane, ethanol, or THF and an alkali metal hydroxide such as lithium hydroxide is

WO 02/062750

PCT/US02/03672

-13added either as an aqueous solution or as a solid. The reaction mixture is stirred at rt for 0.5-24 h.

in step 5, the product of step 4 is dissolved in a mixture of a suitable inert solvent such as CH2CI2 or dioxane and a tertiary amine base, and a suitable electrophile is added. The reaction mixture is stirred between -78 °C and 100 °C for 0.5 to 48 h.

The aldehyde (i) used in step 2 was prepared by one of the following two procedures: 1) Regioselective ortho lithiation of a 4-substituted benzaldehyde, and quenching with a substituted phenyl disulfide followed by oxidation with metachloroperoxybenzoic acid to the sulfone. 2) Base promoted displacement of fluoride from an ortho-fluorobenzaidehyde by a thiophenol, phenol, or aniline.

General Scheme III

Preparation of Ketone and Olefin Linked Compounds

LHDMS

1. LIOH, 1,4 dioxane

2. Base, R1-Y-LG

NHYR1

Description of reactions-General Scheme Hl in step 1 the secondary alcohol, the product of Step 2 in Scheme ll is oxidized with PCC, in a suitable inert solvent such as CH2CI2i to the carbonyl by stirring at rt for 18 h. In step 2, the ketone is treated with the ylide obtained by base treatment of dried methyltriphenylphosphonium bromide, providing the exo methylene product. In

WO 02/062750

PCT/US02/03672

-14step 3 the trifluoroacetamide group can be hydrolyzed with base and reacted with a variety of acylating, sulfonylating, alkylating and other electrophilic reagents.

The ketone product can be treated with hydroxylamine hydrochloride in pyridine and heated at 80°C for 24 h. The mixture was cooled to room temperature and the solvent removed under reduced pressure. Upon workup and purification, the oxime is obtained.

General Scheme IV

Preparation of Oxygen Linked Compounds

1) CH3Li/THF/-78°C

2) n-BuLi

3) R4-L2-LG

Description of reactions-General Scheme IV 5 In step 1, 2-bromo-4-chlorophenol and a 4-fluorobenzonitrile are dissolved in a polar aprotic solvent such as DMA in the presence of a suitable base such as potassium hydroxide. The reaction mixture is heated for 0.5-7 days. Preferred temperatures are greater than 60 °C. The reaction mixture is diluted with a suitable extraction solvent such as diethyl ether and washed with water. The solvents are removed and the product is purified via sgc.

WO 02/062750

PCT/US02/03672

-15ln step 2, the product of step 1 is dissolved in a solution of diborane in THF. The reaction is stirred at reflux for 1 -24 h then quenched with water and partitioned between EtOAc and aq NaOH. The solvents are evaporated and the product is purified by formation of the HCI salt in diethyl ether.

In step 3, the product of step 2 is suspended in CH2CI2 and a suitable base such as triethylamine is added. The reaction mixture is cooled, and TFAA is added. The reaction mixture is stirred from 0.5 to 8 h, then subjected to aqueous workup.

The crude product is purified by sgc.

in step 4, the product of step 3 is dissolved in THF and treated with methyl lithium, then η-BuLi at -78 °C to form a dianion that is trapped with a suitable electrophile. The reaction mixture is quenched with a suitable proton source such as aq NH4CI or phosphate buffer then extracted with EtOAc. The product may be purified via sgc or crystallization.

In step 5, the product of step 4 is dissolved in a suitable solvent such as dioxane, ethanol, or THF and an alkali metal hydroxide such as lithium hydroxide is added either as an aqueous solution or as a solid. The reaction mixture is stirred at rt for 0.5-24 h.

In step 6, the product of step 5 is dissolved in a mixture of a suitable inert solvent such as CH2CI2 or dioxane and a tertiary amine base, and a suitable electrophile is added. The reaction mixture is stirred between -78°C and 100 °C for 0.5to 48 h.

In step 7, the product of step 6 is dissolved in a suitable inert solvent such as THF or CH2CI2 and treated with a suitable base such as NaH or triethylamine. An electrophile is added and the reaction mixture is stirred between 0°C and 100°C for 0.5 to 48 h.

WO 02/062750

PCT/US02/03672

-16General Scheme V Preparation of Amide Compounds

Description of Reactions-General Scheme V

In step 1,1-chloro-4-fluorobenzene is dissolved in anhyd THF and treated with n-BuLi at -78 °C to form an anion that is trapped with a suitable electrophile. The product may be purified via sgc or crystallization.

In step 2, the product of step 1 is dissolved in a suitable polar solvent such as acetonitrile or DMA. A benzoic acid containing a nucleophilic moiety such as an OH, NHR, or SH is added, and two or more equivalents of a suitable base such as potassium hydroxide or sodium hydride is added. The reaction mixture may be stirred for 1-24 h at temperatures ranging between 0°C and 150°C. The reaction mixture is partitioned between water and a suitable solvent such as EtOAc. The product may be purified via sgc or crystallization.

In step 3, the product of step 2 is dissolved in CH2CI2. Pentafluorophenol and

EDCI are added. The reaction mixture is stirred at rt for 0.5-24 h then partitioned between water and CH2CI2. The solvents are evaporated. The product may be purified via sgc or crystallization.

In step 4, the product of step 3 is dissolved in a suitable solvent such as CH2CI2. An amine base such as DIPEA or triethylamine is added, followed by a primary or secondary amine. The reaction mixture may be stirred for 1-24 h at rt. The reaction mixture is then subjected to aqueous workup and isolation and the product is purified via sgc.

WO 02/062750

PCT/US02/03672

-17ln step 5, if the nucleophilic moiety in step 2 contains oxidizable functionality, the product of step 4 is dissolved in a suitable solvent such as CH2CI2 and MCPBA is added. The reaction mixture may be stirred for 0.5-48 h then partitioned between a suitable solvent such as CH2CI2 or EtOAc and an aqueous base such as Na2CO3. The solvent is evaporated and the product is purified via sgc.

General Scheme VI

C-Ring Addition Elimination Chemistry

I'

Rs Rr

LJl Nl

NH,

,)TFAWCH2CI2 2) MsOH/NIS

Y'N'^CFs

LIOH

F3 -OifflSDS.

KF/acetone/H20

1) NaNQ2/AcOH/HCI

2) CuCI/AcOH/SO2

Triflic Anhydride Et3N/CH2CI2

R4SH/NaH dioxane/Δ

Description of Reactions-General Scheme VI

In step 1, trifluoroacetic anhydride is dissolved in a suitable inert solvent such as methylene chloride and reacted with a benzyl amine at rt for 1-5 h. Methanesulfonic acid (2 eq) is added followed by N-iodosuccinamide. The reaction mixture is stirred overnight at rt, then subjected to aqueous work up. The crude product is recrystallized from isopropanol and water.

In step 2, CuCI is dissolved in glacial acetic acid. The flask is cooled to 0 °C and SO2 gas is bubbled in with stirring for 40 min. in a separate flask 2-fluoro-4chloroaniline is dissolved in glacial acetic acid and concentrated HCI. The resulting

WO 02/062750

PCT/US02/03672

-18solution is cooled to 0 °C and treated with an aqueous solution of NaNO2. The reaction mixture is stirred for 30 min at 0 °C and the contents are added to the flask containing the SO2 solution causing vigorous gas evolution. The reaction is then allowed to warm to rt. The product is isolated by pouring the reaction mixture onto chipped ice, then filtering the resulting solid.

In step 3, the product of step 2 is dissolved in acetone. An aqueous solution of KF (2 eq) is added and the reaction mixture is stirred for 12-24 h at rt. The reaction mixture is extracted with a suitable solvent such as CH2Cl2 or Et2O and the solvent is evaporated to afford the product.

In step 4, the product of step 1 is dissolved in THF and TMEDA is added. The flask is placed under N2 blanket, and cooled to 0 °C. A solution of isopropyl magnesium chloride in THF is added and the reaction mixture is stirred for 1-4 h. The resulting solution is added to a flask containing the product of step 3 that was cooled with an ice-water bath. The reaction mixture is stirred for 1-3 h. The reaction is quenched with aqueous NH4CI and extracted with EtOAc. After evaporation of the solvent, the crude product is purified via sgc.

In step 6, the product of step 5 is dissolved in a suitable inert solvent such as CH2CI2 or acetonitrile and a tertiary amine base, and a triflic anhydride is added. The reaction mixture is stirred between -78°C and rt for 0.5 to 48 h. The product may be purified via sgc or crystallization.

In step 7, the product of step 6 is dissolved in a suitable inert solvent such as dioxane and a thiol is added. A base such as sodium hydride, sodium hydroxide, or NaHMDS is added and the reaction mixture is stirred at a suitable temperature between 50 °C and 100 °C for 4-24 h. The reaction mixture is quenched with water and extracted with a suitable solvent. The solvents are evaporated and the crude product is purified via sgc.

In step 8, the product of step 7 is dissolved in a suitable inert solvent such as

CH2CI2. Na2HPO4 and urea hydrogen peroxide complex is added, followed by TFAA.

WO 02/062750

PCT/US02/03672

-19The reaction mixture is refluxed for 4-16 h, then partitioned between water and

CH2CI2. The solvents are evaporated and the crude product is purified via sgc.

Those skilled in the art will appreciate that similar reactions to those described 5 in the above schemes may be carried out on other compounds of formula I as long as substituents present would not be susceptible to the reaction conditions described. Starting materials for the above processes are either commercially available, known in the art, or prepared by procedures well known in the art. Exemplary compounds of formula 1 are set forth below in Table I. CB means covalent bond.

TABLE I

<td> D</td><td> ch3</td><td> H</td><td> H</td><td> t-butoxy</td><td></td><td> H</td><td> ch3</td><td> so2</td><td> co</td><td> och3</td><td> so2</td><td> CB</td>

WO 02/062750

PCT/US02/03672

<td> K</td><td> ch3</td><td> H</td><td> H</td><td> t-butoxy</td><td></td><td> H</td><td> ch3</td><td> so2</td><td> CZSLSSQ</td><td> ocf2h</td><td> so2</td><td> CB</td>

WO 02/062750

PCT/US02/03672

WO 02/062750

PCT/US02/03672

WO 02/062750

PCT/US02/03672

WO 02/062750

PCT/US02/03672

WO 02/062750

PCT/US02/03672

<td> CZ</td><td> CFa</td><td> H</td><td> H</td><td> XY</td><td> H</td><td> CHa</td><td> SO2</td><td> SOa</td><td> OCFaH</td><td> C=O</td><td> CB</td>

<td> DA</td><td> CHa</td><td> H</td><td> H</td><td> .XX</td><td> H</td><td> CHa</td><td> SO2</td><td> SOa</td><td> OCFaH</td><td> SOa</td><td> CB</td>

WO 02/062750

PCT/US02/03672

WO 02/062750

PCT/US02/03672

WO 02/062750

PCT/US02/03672

<td> FA</td><td> CF,</td><td> H</td><td> H</td><td></td><td> σ</td><td> Η</td><td> CH,</td><td> C=O</td><td> NHSOa</td><td> H</td><td> C=O</td><td> CB</td>

WO 02/062750

PCT/US02/03672

<td> FJ</td><td> *R\ Y. Z and R2 combine to form morpholinyl</td><td> *</td><td> H</td><td> a,</td><td></td><td> 0 II</td><td> s</td><td> SOz</td><td> a</td><td> *</td><td> *</td>

<td> FM</td><td> *R’, Y. Z and R2 combine to form morpholinyl</td><td> *</td><td> H</td><td> a</td><td></td><td> 0 II</td><td> so2</td><td> SOz</td><td> Cl</td><td> *</td><td> *</td>

WO 02/062750

PCT/US02/03672

<td> GF</td><td> NHCaHe</td><td> H</td><td> H</td><td> a</td><td> H</td><td> CH3</td><td> CHa</td><td> SOj</td><td> ocf3</td><td> SOa</td><td> CB</td>

WO 02/062750

PCT/US02/03672

CB is a covalent bond

- means that the substituent is not present

In a preferred embodiment, there are disclosed compounds of the formula

a prodrug thereof, or a pharmaceutically acceptable salt of the compound or of said prodrug; wherein X, R1 and R4 are as shown in the table below:

<td> Example</td><td> X</td><td> R1</td><td> R4</td>

WO 02/062750

PCT/US02/03672

<td> Example</td><td> X</td><td> R1</td><td> R4</td>

WO 02/062750

PCT/US02/03672

<td> Example</td><td> X</td><td> R1</td><td> -R*</td>

<td> XXXII</td><td> CN</td><td> CFs</td><td> aF</td>

<td> XXXIII</td><td> nh2</td><td> CFs</td><td> aF</td>

<td> XXXIV</td><td> H xZ</td><td> CFs</td><td> aF</td>

<td> XXXVI</td><td> Cl</td><td> CFs</td><td> CC0</td>

<td> XXXVII</td><td> yy</td><td> CF3</td><td> a</td>

<td> XXXVIII</td><td> CN</td><td> CFs</td><td> O'</td>

<td> XXXIX</td><td> -conh2</td><td> CFs</td><td> a</td>

WO 02/062750

PCT/US02/03672

<td> Example</td><td> X</td><td> R1</td><td> R*</td>

<td> XXXXI</td><td> -OH</td><td> CFs</td><td> a</td>

<td> XXXXII</td><td> yy</td><td> CFs</td><td> Οζ</td>

<td> XXXXIII</td><td></td><td> CFs</td><td> a.</td>

<td> XXXXIV</td><td> h3c^o^</td><td> CFs</td><td> a</td>

<td> xxxxv</td><td></td><td> CFs</td><td> a</td>

<td> xxxxxv</td><td> OCHa</td><td> CFs</td><td> a</td>

<td> XXXXXVI</td><td> o</td><td> CHs</td><td> a</td>

ln another preferred embodiment, there are disclosed compounds of the formula

a prodrug thereof, or a pharmaceutically acceptable salt of the compound or of said prodrug; wherein X, Y-R1 and R4 are as shown in the table below:

WO 02/062750

PCT/US02/03672

<td> Example</td><td> X</td><td> Y-R1</td><td> r*</td>

<td> XXXXVI</td><td> X</td><td> ch3 A,</td><td> a</td>

<td> XXXXVII</td><td> X</td><td> P</td><td> a</td>

<td> XXXXVIII</td><td> X.</td><td> P</td><td> a</td>

<td> XXXXIX</td><td> X</td><td> X</td><td> a</td>

<td> XXXXXI</td><td> -OCH3</td><td> ch3 A,</td><td> aF</td>

<td> XXXXXII</td><td> -och3</td><td> XX h3c</td><td> a</td>

<td> XXXXXI 11</td><td> -OCH3</td><td> Ό</td><td> Οζ</td>

Compound A: 1h NMR (300 MHz, CDCI3) 1.54 (d, J = 6.9Hz 3H), 2.67 (s, 3H), 4.72 (q, J = 5Hz 1H), 4.86 (br. d, J = 5Hz,1H, NH), 7.08-8.42 (m, 11H).

Compound C : 1H NMR (400 MHz, CDCI3) 1.51 (d, J = 7.2Hz 3H), 2.67 (s, 3H), 4.702 (q, J = 6.8Hz 1H), 5.05 (br. d, J = 6.4Hz,1H, NH), 6.71 (t, J = 71.6 Hz, CF2H) 7.078.47 (m, 11H).

Compound G : 1H NMR (300 MHz, CDCI3) 8.43-8.41 (m, 1H), 8.36 (d, 8Hz, 1H), 8.2810 8.22 (m, 1H), 7.96-7.92 (m, 2H), 7.69-7.60 (m, 2H), 7.52-7.47 (m, 2H), 7.43-7.37 (m,

1H), 7.13-7.06 (m, 1H), 4.76-4.70 (m, 2H), 2.68 (s, 3H), 2.59 (s, 3H), 1.41 (d, 7 Hz, 3H).

Compound L : 1H NMR (300 MHz, CDCI3) 8.61-5.97 (m, 2H), 8.40 (d, 8 Hz, 1H),

8.24-8.21 (m, 1H), 7.96 (d, 8 Hz, 2H), 7.86-7.83 (m, 1H), 7.70-7.63 (m, 1H), 7.52 (d, 8

WO 02/062750

PCT/US02/03672

-36Hz, 2H), 7.46-7.40 (m, 1H), 7.18-7.12 (m, 1H), 4.80-4.70 (m, 1H), 2.71 (s, 3H), 1.56 (d, 7Hz, 3H).

Compound R; 1H NMR (300 MHz, CDCI3) 8.89-8.87 (m, 1H), 8.58 (d, 8Hz, 1H), 8.328.25 (m, 1H), 8.15-8.11 (m, 1H), 8.03-7.98 (m, 2H), 7.71-7.63 (m, 1H), 7.52-7.48 (m, 2H), 7.47-7.41 (m, 1H), 7.16-7.09 (m, 1H), 5.62 (d, 8 Hz, 1H), 4.90-4.80 (m, 1H), 1.63 (d, 7 Hz, 3H).

Compound S : 1H NMR (300 MHz, CDCI3) 8.61-8.59 (m, 1H), 8.39 (d, 8 Hz, 1H),

8.29- 8.24 (m, 1H), 7.99 (d, 8 Hz, 2H), 7.86-7.82 (m, 1H), 7.67-7.62 (m, 1H), 7.49 (d, 8Hz, 1H), 7.46-7.40 (m, 1H), 7.16-7.10 (m, 1H), 4.89-4.84 (m, 1H), 1.65 (d, 6 Hz, 1H).

Compound AB : 1H NMR (300 MHz, CDCI3) 8.88-8.86 (m, 1H), 8.62-8.59 (m, 1H),

8.30- 8.29 (m, 1H), 8.15-8.11 (m, 1H), 8.00-7.96 (m, 2H), 7.71-7.63 (m, 1H), 7.56-7.52 (m, 2H), 7.47-7.41 (m, 1H), 7.16-7.09 (m, 1H), 4.99-4.84 (m, 1H), 4.80-4.70 (m, 1H), 2.71 (s,3H), 1.54 (d, 7Hz, 3H).

Compound AT: 1H NMR (300 MHz, CDCI3) 8.51 (br s 1H), 8.39 (d, 8 Hz, 2H), 7.99 (d, 8 Hz, 2H), 7.86-7.83 (m, 1H), 7.61-7.50 (m, 1H), 7.49 (d, 8 Hz), 7.05-6.99 (m, 1H), 4.70-4.50 (m, 2H), 2.83 (s, 3H), 2.57 (s, 3H), 1.50 (d, 7 Hz, 3H).

Compound BA : 1h NMR (300 MHz, CDCI3) 1.54 (d, J = 6.9 Hz 3H), 2.7 (s, 3H), 4.72 (q, J = 5.5Hz 1H), 5.05 (br. d, J = 5Hz,1 H, NH), 7.1 -8.55 (m, 11H).

Compound BD : 1H NMR (300 MHz, CDCI3) 8.51 (d, 9 Hz, 1H), 8.47-8.45 (m, 1H), 8.01-7.97 (m, 2H), 7.71-7.63 (m, 2H), 7.52-7.41 (m, 3H), 7.17-7.10 (m, 1H), 5.51 (d, 8 Hz, 1H), 4.90-4.80 (m, 1H), 1.64 (d, 7 Hz, 3H).

Compound BZ: 1H NMR (300 MHz, CDCI3) 8.43 (brs, 1H), 8.32 (d, 8 Hz, 1H), 8.288.22 (m, 1H), 7.94 (d, 8 Hz, 2H), 7.68-7.58 (m, 2H), 7.47-7.37 (m, 3H), 7.12-7.06 (m,

1H), 5.72 (d, 8 Hz, 1H), 4.86-4.70 (m, 1H), 2.59 (s, 3H), 1.60 (d, 7 Hz, 3H).

Compound CD : 1H NMR (300 MHz, CDCI3): 8.82-8.78 (m, 1H), 8.23 (d, 7 Hz, 2H), 8.21-8.07 (m, 1H), 7.81-7.77 (m, 2H), 7.63-7.57 (m, 1H), 7.55 (d, 7 Hz, 2H), 7.40-7.32 (m, 1H), 7.20-7.16 (m, 1H), 4.8-4.7 (m, 2H), 2.67 (s, 3H), 1.55 (d, 7 Hz, 2H).

Compound FS ; 1H NMR (300 MHz, CDCi3) 8.66-8.62 (m, 1H), 8.51-8.47 (m, 1H), 8.29-8.24 (m, 1H), 7.99-7.95 (m, 2H), 7.93-7.89 (m, 2H), 7.67-7.53 (m, 1H), 7.50-7.44 (m, 2H), 7.42-7.39 (m, 1H), 7.13-7.07 (m, 1H), 4.78-4.73 (m, 1H), 4.61-4.59 (m, 1H), 2.70 (s, 3H), 1.56 (d, 7 Hz, 3H).

Compound FY; 1H NMR (300 MHz, CDCI3) 8.66-8.63 (m, 1H), 8.49-8.46 (m, 1H),

8.28-8.25 (m, 1H), 8.01 (d, 8 Hz, 2H), 7.93-7.89 (m, 2H), 7.65-7.58 (m, 1H), 7.56 (d, 8

Hz, 2H), 7.47-7.41 (m, 1H), 7.13-7.07 (m, 1H), 5.18 (d, 6 Hz, 1H), 4.90-4.80 (m, 1H),

1.66 (d, 7 Hz, 3H).

WO 02/062750

PCT/US02/03672

-37Compound GG : 1H NMR (300 MHz, CDCI3): 8.88 (d, 1.2 Hz, 1H), 8.51-8.56 (m, 2H), 8.31 (dd, 8 Hz, 1Hz, 1H), 8.18 (dd, 8 Hz, 1 Hz, 1H), 8.08-7.96 (m, 3H), 7.62-7.48 (m, 3H), 5.51 (d, 9 Hz, 1H), 4.90-4.70 (m, 1H), 1.62 (d, 7 Hz, 3H).

Compound GH : 1H NMR (300 MHz, CDCI3): 8.63 (d, 2 Hz), 8.58-8.55 (m, 1H), 8.348.28 (m, 2H), 8.07-7.98 (m, 3H), 8.35 (dd, 8 Hz, 2 Hz, 1H), 7.55-7.46 (m, 3H), 5.34 (d, 8 Hz, 1H), 4.9-4.8 (m, 1H), 1.64 (d, 6 Hz, 3H).

Compound GQ/XXiX,: 1H NMR (300 MHz, CDCI3): δ 8.56-8.52 (m, 1H), 8.32-8.21 (m, 3H), 8.02-7.92 (m, 4H), 5.42 (d, 9 Hz, 1H), 8.02-7.92 (m, 4H), 5.42 (d, 1H, 9 Hz), 4.844.78 (m, 1H), 2.16-2.06 (m, 1H), 1.60 (d, 7Hz, 3H), 1.20-1.17 (m, 2H), 0.97-0.89 (m, 1H).

Compound GR/XXX,: 1H NMR (300 MHz, CDCI3): δ 8.33-8.22 (m, 3H), 8.00-7.94 (m, 2H), 7.66-7.58 (m, 1H), 7.53-7.37 (m, 4H), 7.16-7.05 (m, 1H), 5.160 (d, 9 Hz, 1H), 4.88-4.83 (m, 1H), 2.17-2.06 (m, 1H), 1.65 (d, 7 Hz, 3H), 1.28-1.20 (m, 2H), 0.97-0.90 (m, 2H).

Compound GS/XXXI,: 1H NMR (300 MHz, CDCI3); δ 8.38-8.29 (m, 2H), 8.17 (d, 8 Hz, 1H), 8.07-8.02 (m, 1H), 7.91-7.85 (m, 2H), 7.56-7.36 (m, 5H), 6.11 (d, 8 Hz, 1H), 4.844.78 (m, 1H), 2.12-2.01 (m, 1H), 1.57 (d, 7Hz, 3H), 1.21-1.12 (m, 2H), 0.92-0.86 (m, 2H).

Compound GW/XXXVI, : 1H NMR (300 MHz, CDCI3): δ 10.19 (d, 7.8 Hz, 1H), 8.278.42 (m, 4H), 8.13 (dd, 7.8 Hz, 2.1 Hz, 1H), 7.93 (d, 8.4 Hz, 2H), 7.78-7.63 (m, 2H), 7.59 (d, 8.4 Hz, 2H), 4.80 (m, 1H), 1.44 (d, 6.9 Hz, 3H).

Compound HO/XXXXXV, : 1H NMR (300 MHz, CDCI3): δ 8.56 (d, 3.9 Hz, 1H), 8.318.22 (m, 2H), 8.124 (d, 2.7 Hz, 1H), 8.05-7.95 (m, 1H), 7.92 (d, 8.4 Hz, 2H), .750-7.45 (m, 1H), 7.92 (d, 8.4 Hz, 2H), 7.27-7.23 (m, 2H), 5.8 (d, NH, 1H), 4.85-4.75 (m, 1H), 3.99 (s, 3H), 1.58 (d, 7.2 Hz, 3H).

Compound HP/XXXXXVI,: 1H NMR (300 MHz, CDCI3): δ 8.56-8.52 (m, 1H), 8.31-8.23 (m, 3H), 8.02-7.90 (Μ, 4H), 4.87-4.78 (d, 7 Hz, 1H), 4.69 (m, 1 H), 2.66 (s, 3H), 2.162.06 (m, 1H), 1.51 (d, 7 Hz, 3H), 1.27 -1.17 (m, 2H), 0.96-0.90 (m, 2H).

The compounds of the present invention exhibit anti-inflammatory and/or immunomodulatory activity and are useful in the treatment of various medical conditions including, e.g., rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, glaucoma, diabetes, osteoporosis, renal ischemia, cerebral stroke, cerebral ischemia, nephritis, psoriasis, allergy, inflammatory disorders ofthe lungs and gastrointestinal tract such as Crohn’s disease, and respiratory tract disorders such as reversible airway obstruction, asthma, chronic obstructive pulmonary disease (COPD)

WO 02/062750

PCT/US02/03672

-38and bronchitis. This utility is manifested as demonstrated by activity in the following assay.

Potential cannabinoid receptor ligands were screened for the ability to compete with [3H] CP-55,940 for binding to recombinant cannabinoid receptors. Test compounds were serially diluted in Diluent Buffer (50 mM Tris pH 7.1,1 mM EDTA, 3 mM MgCI2i 0.1% BSA, 10% DMSO, 0.36% methyl cellulose (Sigma M-6385)) from stocks prepared in 100% DMSO. Aliquots (10 ul) were transferred into 96-well microtiter plates. Membrane preparations of recombinant human cannabinoid CB2 receptor (Receptor Biology #RB-HCB2) or recombinant human cannabinoid CB1 receptor (Receptor Biology #RB-HCB1) were diluted to 0.3 mg/ml in Binding Buffer (50 mM Tris pH 7.2,1 mM EDTA, 3 mM MgCI2f 0.1% BSA). Aliquots (50 ul) were added to each well of the microtiter plate. The binding reactions were initiated by addition of [3HJ CP-55,940 (New England Nuclear # NET 1051; specific activity =180 Ci/mmol) to each well of the microtiter plate. Each 100 ul reaction mixture contained 0.48 nM [3H] CP-55,940,15 ug membrane protein in binding buffer containing 1% DMSO and 0.036 % methyl cellulose. Following incubation for 2 hours at room temperature, the reactions were filtered through 0.5% polyethylenimine-coated GF/C filter plates (UniFilter-96, Packard) with a TomTec Mark 3U Harvester (Hamden, CT). The filter plate was washed 5 times with binding buffer, rotated 180°, then re-washed 5 times with binding buffer. Bound radioactivity was quantitated following addition of 30 ul of Packard Microscint 20 scintillant in a Packard TopCount NXT microplate scintillation counter. Non-linear regression analysis of the resulting data was performed using Prism 2.0b (GraphPad, San Diego, CA).

WO 02/062750

PCT/US02/03672

-39bronchitis. It is contemplated that a compound of this invention may be useful in treating more than one of the diseases listed.

Additionally, a compound of the present invention may be co-administered or used in combination with disease-modifying antirheumatic drugs (DMARDS) such as methotrexate, azathioptrine leflunomide, pencillinamine, gold salts, mycophenolate mofetil, cyclophosphamide and other similar drugs. They may also be coadministered with or used in combination with NSAIDS such as piroxicam, naproxen, indomethacin, ibuprofen and the like; COX-2 selective inhibitors such as Vioxx® and Celebrex®; COX-1 inhibitors such as Feldene; immunosuppressives such as steroids, cyclosporine, Tacrolimus, rapamycin and the like; biological response modifiers (BRMs) such as Enbrel, Remicade, IL-1 antagonists, anti-CD40, anti-CD28, IL-10, anti-adhesion molecules and the like; and other anti-inflammatory agents such as p38 kinase inhibitors, PDE4 inhibitors, TACE inhibitors, chemokine receptor antagonists, Thalidomide and other small molecule inhibitors of pro-inflammatory cytokine production. Other drugs that the compounds of the invention may be co-administered or used in combination with include Anaprox, Arava, Arthrotec, Azulfidine, Aspirin, Cataflam, Celestone Soluspan, Clinoril, Cortone Acetate, Cuprimine, Daypro, Decadron, Depen, Depo-Medrol, Disalcid, Dolobid, Naprosyn, Gengraf, Hydrocortone, Imuran, Indocin, Lodine, Motrin, Myochrysine, Nalfon, Naprelan, Neoral, Orudis, Oruvail, Pediapred, Plaquenil, Prelone, Relafen, Solu-Medrol, Tolectin, Trilisate and Volataren. These include any formulation of the abovenamed drugs.

For the treatment of multiple sclerosis, the compounds of the invention may be co-administered or used in combination with Avonex, Betaseron and Copaxone.

For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.

The present invention also relates to a pharmaceutical composition comprising a compound of formula I of this invention and a pharmaceutically acceptable carrier. The compounds of formula I can be administered in any conventional dosage form known to those skilled in the art. Pharmaceutical compositions containing the compounds of formula I can be prepared using conventional pharmaceutically acceptable excipients and additives and conventional techniques. Such

WO 02/062750

PCT/US02/03672

-40pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like. Ail routes of administration are contemplated including, but not limited to, parenteral, transdermal, subcutaneous, intramuscular, sublingual, inhalation, rectal and topical.

Thus, appropriate unit forms of administration include oral forms such as tablets, capsules, powders, cachets, granules and solutions or suspensions, sublingual and buccal forms of administration, aerosols, implants, subcutaneous, intramuscular, intravenous, intranasal, intraoccular or rectal forms of administration.

When a solid composition is prepared in the form of tablets, e.g., a wetting agent such as sodium lauryl sulfate can be added to micronized or non-micronized compounds of formula I and mixed with a pharmaceutical vehicle such as silica, gelatin starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, various polymers, or other appropriate substances. Tablets can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously or at predetermined intervals, e.g., by using ionic resins and the like.

A preparation in the form of gelatin capsules may be obtained, e.g., by mixing the active principle with a diluent, such as a glycol or a glycerol ester, and incorporating the resulting mixture into soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir can contain the active principle together, e.g., with a sweetener, methylparaben and propylparaben as antiseptics, flavoring agents and an appropriate color.

Water-dispersible powders or granules can contain the active principle mixed, e.g., with dispersants, wetting agents or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners and/or other flavoring agents.

Rectal administration may be provided by using suppositories which may be prepared, e.g., with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.

Parenteral, intranasal or intraocular administration may be provided by using, e.g., aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing pharmacologically compatible dispersants and/or solubilizers, for example, propylene glycol or polyethylene glycol.

WO 02/062750

PCT/US02/03672

-41 Thus, to prepare an aqueous solution for intravenous injection, it is possible to use a co-solvent, e.g., an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as Tween® 80. An oily solution injectable intramuscularly can be prepared, e.g., by solubilizing the active principle with a triglyceride or a glycerol ester.

Topical administration can be provided by using, e.g., creams, ointments or gels.

Transdermal administration can be provided by using patches in the form of a multilaminate, or with a reservoir, containing the active principle and an appropriate solvent.

Administration by inhalation can be provided by using, e.g., an aerosol containing sorbitan trioleate or oleic acid, for example, together with trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas; it is also possible to use a system containing the active principle, by itself or associated with an excipient, in powder form.

The active principle can also be formulated as microcapsules or microspheres, e.g., liposomes, optionally with one or more carriers or additives.

Implants are among the prolonged release forms which can be used in the case of chronic treatments. They can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.

The daily dose of a compound of formula I for treatment of a disease or condition cited above is about 0.001 to about 100 mg/kg of body weight per day, preferably about 0.001 to about 10 mg/kg. For an average body weight of 70 kg, the dosage level is therefore from about 0.1 to about 700 mg of drug per day, given in a single dose or 2-4 divided doses. The exact dose, however, is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.

WO 02/062750

PCT/US02/03672

-42EXAMPLEI

Compound 1

Compound 1. TFAA (67 mL, 0.474 moi) was dissolved in CH2CI2 (300 mL) and cooled in an ice water bath. A solution of (S)-a-methylbenzylamine (56.4 g, 0.465 mol) dissolved in CH2CI2 (100 mL) was added and the ice bath was removed. The reaction mixture was stirred at rt for 3 h. The reaction mixture was cooled in an ice bath and MsOH (80 mL, 1.23 mol) was added followed by DBDMH (65 g, 0.227 mol). The reaction mixture was left stirring overnight at rt then quenched with 1M aq NaHSO3. The organic layer was washed with water and brine, dried with MgSO4, and concentrated to give 130 g of white solid. The crude product was recrystallized from Et2O and hexanes giving 46 g (32%) of intermediate Compound 1 as a solid.

Compound 2. In a flame dried flask under N2 blanket, Compound 1 (12.35 g, 41.2 mmol) was dissolved in dry THF (165 mL) and cooled to -78°C. Methyllithium (1.4 M in Et2O, 30 mL, 42 mmol) was added and the reaction mixture was stirred for 5 min. η-BuLi (1.6 M in hexanes, 26 mL, 42 mmol) was added followed after 10 min by p-methoxybenzenesulfonyl fluoride (8.64 g, 45.4 mmol) which was prepared by standard methods. The cold bath was removed after 10 min and the reaction mixture was allowed to warm to rt over 45 min then quenched with pH 7 sodium phosphate buffer (1 M, 100 mL, 100 mmol). The reaction mixture was extracted with EtOAc and the resulting organic layer was washed with brine and dried with MgSO4. After evaporation ofthe solvent, the crude product was purified by sgc (20%-50% EtOAc/hexanes gradient) to give 10.39 g (65%) of Compound 2 as a solid.

WO 02/062750

PCT/US02/03672

-43h3c

CH3

Compound 3

Compound 3. In a flame dried flask under N2 blanket, Compound 2 (11.09 g, 28.6 mmol) was dissolved in anhyd THF (100 mL) and cooled to -78°C. A solution of n-BuLi (2.5 M in hexanes, 24 mL, 60 mmol) was added and the reaction mixture was stirred for 40 min. Bis-4-methoxyphenyl disulfide (8.76 g / 31.5 mmol) was added and the reaction mixture was stirred at -78 °C for 40 min then between -15 °C and -30 °C for 5 h then quenched with pH 7.0 sodium phosphate buffer (1.0 M, 120 mL). The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with additional EtOAc. The combined organic layer was washed with aq Na2CO3 and brine, then dried with MgSO4 and concentrated to dryness. The crude product (13.8 g yellow foam) was dissolved in CH2Cl2 (120 mL) and cooled to 0°C. MCPBA (18.5 g, ca 107 mmol) was added, followed by additional CH2CI2 (40 mL). The ice bath was removed and the reaction mixture was stirred at rt for overnight. Aqueous NaHCO3 (200 mL) and CH2CI2 were added and the layers were separated. The organic layer was washed with aq NaHSO3, NaHCO3, H2O, and brine then dried with MgSO4. The crude product was purified by sgc (30% to 50% EtOAc/hexanes gradient) to give 7.21 g (45%) of Compound 3.

CH3

H;

Compound 4

WO 02/062750

PCT/US02/03672

-44Compound 4. Compound 3 (4.47 g, 8.02 mmol) was dissolved In p-dioxane (16 mL) and cooled to 0 °C. LiOH (1.0 M aq, 10 mL, 10 mmol) was added and the ice bath was removed. The reaction mixture was stirred at rt for 6 h then concentrated. CH2CI2 (100 mL) and NaOH (1.0 M aq, 10 mL) were added and the layers were separated. The aqueous layer was extracted with additional CH2CI2 and the combined organic layer was dried with MgSO4 and concentrated. The crude product was purified by sgc (2%-10% MeOH (NH3)/CH2CI2 gradient mobile phase) to give 3.23 g (87%) of Compound 4.

.X

Compound I

Compound I. Compound 4 (3.08 g, 6.67 mmol) was dissolved in CH2CI2 (33 mL) and triethylamine (1.40 mL, 10.0 mmol) then cooled to 0 °C. MsCI (569 pL, 7.34 mmol) was added and the reaction mixture was stirred at 0 °C for 1 h and 15 min. Citric acid (0.5 M, 40 mL) and additional CH2CI2 were added and the layers were separated. The organic layer was washed with citric acid, NaHCO3, and brine then dried with MgSO4. The solvent was evaporated and the crude product was purified by sgc (40%-70% EtOAc/hexanes gradient) to give 3.44 g (96%) of Compound I as a solid.

Compound II

WO 02/062750

PCT/US02/03672

-45Compound II. Compound 4 (27.5 mg, 0.0595 mmol) was dissolved in methylene chloride (226 μ!_) and DIPEA (12 μΙ_). A solution of propionyl chloride dissolved in 1,2-dichloroethane (1 M, 75 μΙ_, 0.075 mmol) was added and the reaction mixture was shaken at room temperature overnight. Tris(2-aminoethyl)amine polystyrene (4.1 mmol N/g, ca 60 mg) was added to the reaction mixture. The reaction mixture was shaken for an additional hour at rt. The crude product was concentrated, then dissolved in EtOAc and filtered through a silica-gel SepPak (Waters Corp.). The resulting filtrate was concentrated to give 9 mg (29%) of Compound II.

h3cz

Compound III

Compound III. Compound 4 (25 mg, 0.054 mmol) was dissolved in CH2CI2 (270 μ!_). A solution of phenyl isocyanate dissolved in toluene (1.0 M, 65 mL, 0.065 mmol) was added and the reaction mixture was shaken at rt overnight. Tris (2-aminoethyl) amine polystyrene (4.1 mmol N/g, ca 60 mg) was added to the reaction mixture and the reaction mixture was shaken for an additional 40 min at rt. EtOAc was added and the reaction mixture was filtered through a silica gel SepPak (Waters Corp.). The resulting filtrate was concentrated to give 18 mg (57%) of Compound III.

EXAMPLE 11

CI

O

Compound 5

Compound 5. In a 3-necked flame-dried flask under N2 blanket Compound 1 (40.0 g, 134 mmol) was dissolved in anhyd THF (535 mL) and cooled to -75 °C

WO 02/062750

PCT/US02/03672

-46(internal temperature). A solution of methyllithium (1.4 M in diethyl ether, 105 mL, 147 mmol) was added at a rate that kept the internal temperature below -60 °C. The reaction was stirred for 15 min and a solution of η-BuLi (2.5 M in hexanes, 62 mL, 155 mmoi) was added at a rate that maintained the internal temperature of the reaction below -65 °C. The reaction mixture was stirred for 40 min. and a solution of bis(4chlorophenyl) disulfide (42 g, 146 mmol) dissolved in anhyd THF (90 mL) was added via addition funnel over 1 h. The reaction mixture was stirred for 3 h then quenched with HCI (1 M aqueous, 200 mL, 200 mmol). EtOAc (500 mL) was added and the layers were separated. The aqueous layer was extracted with 500 mL EtOAc, and the combined organic layer was washed with 1 M aq KOH, water, and brine. After drying with MgSO4, the solvent was evaporated to give 54.1 g of a solid. The crude product (52.3 g) was dissolved in CH2CI2 (750 mL) and cooled to 2 °C (internal temp).

MCPBA (60%, 184 g) was added in portions over 1 hr and 20 min keeping the internal temperature below 15 °C. The reaction mixture was stirred an additional 2 h. NaOH (1 M aq, 500 mL) and CH2CI2 were added and the layers were separated. The aqueous layer was extracted with an additional 300 mL of CK2CI2. The combined organic layer was washed with 1M aqueous NaOH, water, and brine, then dried with MgSO4. After evaporation of the solvent, a solid (65 g) was obtained. The crude product was partially purified by trituration from Et2O/hexanes to give 33.3 g of a solid which was subsequently purified via sgc (20%-25% EtOAc/hexanes) to give 30 g (57%) of Compound 5 as a solid.

Compound 6. In a flame dried 3-necked flask under N2 blanket Compound 5 (44 g, 112 mmol) was dissolved in anhyd THF (450 mL) and cooled in a dry ice/IPA bath. A solution of n-butyl lithium (2.5 M in hexanes, 92 mL, 230 mmol) was added at a rate that maintained the internal reaction temperature below -60 °C, and the reaction mixture was stirred for 1 h. A solution of 2-fluorobenzenesuifonyI fluoride (22.3 g, 125 mmol) dissolved in anhyd THF (20 mL) was added and the reaction

WO 02/062750

PCT/US02/03672

-47mixture was left stirring overnight and allowed to warm to rt. The reaction mixture was cooled to 0 °C and quenched with saturated aq ammonium chloride (300 mL). EtOAc (600 mL) and brine (25 mL) were added and the layers were separated. The organic layer was washed with water and brine, then dried with MgSO4. The solvents were evaporated giving a foam (62 g). The product was purified by sgc (20%-25% EtOAc/hexanes mobile phase) giving 9.1 g (15%) of Compound 6.

Compound 7. Compound 6 (6.77 g, 12.3 mmol) was dissolved in dioxane (15 mL) and cooled in an ice bath. Aqueous lithium hydroxide (1 M, 15 mL, 15 mmol) was added and the reaction mixture was left stirring overnight. The reaction mixture was concentrated, then partitioned between CH2CI2 and water. The aqueous layer was extracted with additional CH2CI2 and the combined organic layer was dried with MgSO4. Evaporation of the solvent afforded 5.66 g of a foam which was purified by sgc (10% MeOH (NH3)/CH2CI2) to give 4.27 g of Compound 7 (77%).

Compound IV. Compound 7 (2.66 g, 5.86 mmol) was dissolved in CH2CI2 (28 mL) and triethylamine (0.98 mL) and cooled to 0°C. MsCI (0.499 mL, 6.45 mmol) was added and the reaction mixture was stirred at 0 °C for 6 h. The reaction mixture was partitioned between water and CH2CI2. The aqueous layer was extracted with

WO 02/062750

PCT/US02/03672

-48additional CH2CI2 and the combined organic layer was dried with MgSO4. Evaporation of the solvent afforded 3.0 g of a foam which was purified by sgc (40%-50% EtOAc/hexanes gradient) to give 2.77 g (89%) of Compound IV.

Compound IV: 1H NMR (300 MHz, CDCI3) 8.61-5.97 (m, 2H), 8.40 (d, 8 Hz, 1H), 8.24-8.21 (m, 1H), 7.96 (d, 8 Hz, 2H), 7.86-7.83 (m, 1H), 7.70-7.63 (m, 1H), 7.52 (d, 8 Hz, 2H), 7.46-7.40 (m, 1H), 7.18-7.12 (m, 1H), 4.80-4.70 (m, 1H), 2.71 (s, 3H), 1.56 (d, 7Hz, 3H).

Compound V. Compound 7 (26.1 g, 57.4 mmol) was dissolved in CH2CI2 (200ml_) and triethylamine (20 mL) and cooled to -78°C. Triflic anhydride (10.45 mL, 62.1 mmol) was added and the reaction mixture was stirred for 3 h. The reaction was quenched with water and the layers were separated. The organic layer was washed with water and brine, then dried with MgSO4. The solvent was evaporated to give 42 g of a foam. The crude product was purified via sgc (33%-50% EtOAc/hexanes gradient) to give 29.7 g (88%) of Compound V.

Compound V : 1H NMR (300 MHz, CDCI3) 8.61-8.59 (m, 1H), 8.39 (d, 8 Hz, 1H), 8.29-8.24 (m, 1H), 7.99 (d, 8 Hz, 2H), 7.86-7.82 (m, 1H), 7.67-7.62 (m, 1H), 7.49 (d, 8Hz, 1H), 7.46-7.40 (m, 1H), 7.16-7.10 (m, 1H), 4.89-4.84 (m, 1H), 1.65 (d, 6 Hz, 1H).

WO 02/062750

PCT/US02/03672

Compound VI

Compound VI. Compound V (300 mg, 0.512 mmol) was dissolved in methanol (60 mL). Sodium bicarbonate (720 mg, 8.57 mmol) and 5% palladium on carbon (480 mg) were added. The reaction mixture was shaken on a Parr apparatus under 52 psi of hydrogen gas overnight. The reaction mixture was filtered and the solvent was evaporated. The resulting material was partitioned between EtOAc and aq NaHCO3. The organic layer was dried with MgSO4 and the solvents were evaporated. The crude product was purified via sgc (33% EtOAc/hexanes) to give 257 mg (91%) of Compound VI.

EXAMPLE III

O

Compound 8

Compound 8. In a flame dried 3-necked flask under N2 blanket Compound 5 (35.7 g, 91 mmol) was dissolved in anhyd THF (360 mL) and cooled in a dry ice/lPA bath. A solution of η-BuLi (2.5 M in hexanes, 76 mL, 190 mmol) was added at a rate that maintained the internal temperature below -60 °C. The reaction mixture was stirred for 1 h. A solution of 2,6-difluorobenzenesulfonyl fluoride (19.47 g, 99.28 mmol) dissolved in anhyd THF (60 mL) was added. The reaction mixture was stirred for 2.5 h, then quenched with saturated aq NH4Ci (400 mL). EtOAc (500 mL) was added and the layers were separated. The aq layer was extracted with EtOAc and the

WO 02/062750

PCT/US02/03672

-50combined organic layer was washed with brine and dried with MgSO4. The solvent was evaporated to give 60.7 g of an oil which was purified by sgc (15%-40% EtOAc/hexanes gradient) giving 14.4 g (28%) of Compound 8.

Compound 9. Compound 8 (21.1 g, 37.2 mmol) was dissolved in dioxane (47 mL) and aq lithium hydroxide (1.0 M, 41 mL, 41 mmol) was added. After 5.5 h, additional LiOH (20 mL) was added and the reaction mixture was stirred overnight. The reaction mixture was extracted with CH2CI2, and partitioned between CH2CI2 and water. The aq layer was extracted with additional CH2CI2 and the combined organic layer was dried with MgSO4. The solvents were evaporated to give 17.6 g of a foam and the crude product was purified by sgc (1 %-3% MeOH (NH3)/CH2Ci2 gradient) to give 12.2 g (69%) of Compound 9.

Compound VII

Compound VII. Compound 9 (10.7 g, 22.6 mmol) was dissolved in a mixture of CH2CI2 (90 mL) and triethylamine (8mL) and cooled to -78 °C. Triflic anhydride (3.80 mL, 22.6 mmol) was added and the reaction mixture was stirred for 2 h. The reaction was quenched with saturated aq NaHCO3 and the layers were separated. The aqueous layer was extracted with CH2CI2. The combined organic layer was

WO 02/062750

PCT/US02/03672

-51 washed with brine and dried with MgSO4. The solvents were evaporated and the crude product was purified by sgc to give 9.88 g (73%) of Compound Vii.

EXAMPLE IV

Compound 5. In a flame dried flask under N2 blanket Compound 1 (39.2 g,

132 mmol) was dissolved in anhyd THF (1 L) and cooled in a dry ice/acetone bath. A solution of methyllithium (1.6 M in Et2O, 82.7 mL, 132 mmol) was added followed by a solution of n-BuLi (2.5 M in hexanes, 53 mL, 133 mmol). The reaction mixture was stirred for 25 min and a solution of bis(4-trifluoromethylphenyl) disulfide (46.9 g,132 mmol) dissolved in THF (200 mL) was added. The reaction mixture was stirred for 2 h then allowed to warm to rt overnight. The reaction was quenched with water and concentrated. The resulting mixture was diluted with EtOAc, washed with water, and dried with Na2SO4. The solvent was evaporated and the crude product was purified via sgc (20% EtOAc/hexanes) to give 49.2 g (95%) of a solid. This material (49.2 g) was dissolved in CH2Cl2 (1.2 L) and cooled in an ice bath. MCPBA (60%, 90 g) was added in small portions. After 1 h, the ice bath was removed and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between CH2CI2 and 10% aqueous NaHCO3. The combined organic layer was washed with water and dried with Na2SO4. The solvent was evaporated and the crude product was purified by sgc (25% EtOAc/hexanes) to give 46.3 g (85%) of Compound 5.

Compound 10. In a flame dried flask under N2 blanket, Compound 5 (21.55 g,

50.7 mmol) was dissolved in anhyd THF (300 mL) and cooled in a dry ice/IPA bath. A solution of methyllithium (1.6 M in Et20,32 mL, 51 mmol) was added, followed by nBuLi (2.5 M in hexanes, 20.3 mL, 50.7 mmol) and the reaction mixture was stirred for

WO 02/062750

PCT/US02/03672

-5210 min. A solution of bis-(2-fiuorophenyl) disulfide (14.2 g, 55.7 mmol) dissolved in THF was added and the reaction mixture was stirred for 2 h at -78°C. The ice bath was removed and the reaction mixture was allowed to warm to rt and left stirring overnight. The reaction mixture was quenched with saturated aqueous NH4CI and extracted with EtOAc. The organic layer was dried with Na2SO4 and the solvents were evaporated. The crude product was purified via sgc (25% EtOAc/hexanes) to give 23.2 g of a solid. This materiai was dissolved in CH2Cl2 (400 mL) and cooled in an ice bath. MCPBA (60%, 30.3 g) was added in several portions and the reaction mixture was stirred for 1 h. The ice bath was removed and the reaction mixture was left stirring overnight. The reaction mixture was partitioned between CH2CI2 and 5% aq Na2CO3. The organic layer was washed with water and dried with Na2SO4. The solvents were evaporated and the crude product was purified via sgc (25%EtOAc/hexanes) to give 10.84 g (44%) of Compound 10.

Compound 11. Compound 10 (11.88 g, 20.36 mmol) was dissolved in dioxane (200 mL) and aq lithium hydroxide (1.0 M, 400 mL) was added. The reaction mixture was stirred for 3 h then and partitioned between CH2CI2 and water. The organic layer was dried with Na2SO4 and concentrated to give 9.34 g (99%) of Compound 11.

Compound VIII. Compound 11 (0.63 g, 1.29 mmol) was dissolved in a mixture of CH2CI2 (60mL) and triethylamine (0.27 mL) and cooled in an ice bath. Triflic

WO 02/062750

PCT/US02/03672

-53anhydride (0.55 g, 1.95 mmoi) was added and the reaction mixture was stirred for 1 h. The ice bath was removed, and the reaction mixture was stirred an additional 3 h.

The reaction was partitioned between water and CH2CI2. The organic layer was washed with water and dried with Na2SO4. The solvent was evaporated and the crude product was purified by sgc (20% EtOAc/hexanes) to give 0.53 g (66%) of Compound VIII.

Compound VIII: 1H NMR (300 MHz, CDCI3) 8.89-8.87 (m, 1H), 8.58 (d, 8Hz, 1H), 8.32-8.25 (m, 1H), 8.15-8.11 (m, 1H), 8.03-7.98 (m, 2H), 7.71-7.63 (m, 1H), 7.52-7.48 (m, 2H), 7.47-7.41 (m, 1H), 7.16-7.09 (m, 1H), 5.62 (d, 8 Hz, 1H), 4.90-4.80 (m, 1H), 1.63 (d, 7 Hz, 3H).

EXAMPLE V

Potassium hydroxide (3.1 g, 55.2 mmol), 2-bromo-4-chlorophenol (9.52 g, 45.9 mmol), and 4-fluorobenzonitrile (5.73 g, 47.3 mmol) were added to DMA (25 mL) and the reaction mixture was stirred between 100 °C and 110 °C for one week. The reaction mixture was stirred at rt an additional two days. The solvents were partially removed on the rotary evaporator and the resulting mixture was partitioned between water and a 3:1 Et2O/hexanes solution. The organic layer was washed with water and brine, then dried with MgSO4. The solvents were evaporated and the crude product was purified by sgc (20%-30% CH2CI2/hexanes) to give 11.96 g (81%) of an oil.

Compound 12

Compound 12. The product of the above step (5.90 g, 19.1 mmol) was placed under N2 atmosphere and a solution of borane in THF (1.0 M, 21 mL, 21 mmol) was

WO 02/062750

PCT/US02/03672

-54added causing an exotherm. Once the reaction mixture had returned to rt, it was heated to reflux and stirred at reflux overnight. Additional borane in THF (1.0 M, mL, 20 mmol) was added and the reaction mixture was stirred at reflux for an additional 26 h then allowed to cool to rt. Water (55 mL) was added and the reaction mixture was partially concentrated. The resulting mixture was partitioned between EtOAc and aq NaOH (1.0 M). The organic layer was dried with MgSO4 and concentrated to give 6.2 g of an oil. This material was dissolved in Et2O and a solution of HCI in Et2O was added causing Compound 12 (5.2 g, 78%) to precipitate as a solid.

O

Compound 13

Compound 13. Compound 12 (5.13 g, 16.6 mmol) was suspended in a mixture of CH2CI2 (40 mL) and triethylamine (7.5 mL). The mixture was cooled in an ice-water bath and TFAA (2.35 mL, 16.6 mmol) was added. The reaction mixture was stirred for 1 h and 20 min and the ice bath was removed. The reaction mixture was stirred for an additional 1 h and 20 min at rt. The reaction mixture was diluted with CH2CI2 (100 mL) and washed with aq citric acid (0.5 M), saturated aq NaHCO3, water, and brine, then dried with MgSO4. The solvents were evaporated and the crude product (5.22 g) was purified via sgc (10%-20% EtOAc/hexanes gradient) to give Compound 13.

O

Compound 14

WO 02/062750

PCT/US02/03672

-55Compound 14. Ina flame dried flask under N2 blanket, Compound 13 (1.00 g, 2.47 mmol) was dissolved in anhyd THF (13 mL) and cooled in a dry ice/IPA bath. Methyllithium (1.4 M in Et20,2.3 mL, 3.22 mmol) was added, followed by η-BuLi (2.5 M in hexanes, 1.3 mL, 3.25 mmol). The reaction mixture was stirred for 1 h at -78 °C. A solution of 2,6-difluorobenzenesulfonyl fluoride (1.10 g, 5.60 mmol) dissolved in THF was added and the reaction mixture was stirred for 4 h. The reaction mixture was quenched with pH 7 sodium phosphate buffer (1.0 M) and EtOAc was added.

The layers were separated and the aqueous layer was extracted with additional EtOAc. The combined organic layer was washed with brine and dried with MgSO4. The solvents were evaporated and the crude product was purified via sgc (20%-33% EtOAc/hexanes) gradient to give 76 mg of Compound 14.

Compound 15. Compound 14 (59 mg, 0.12 mmol) was dissolved in 700 pL of dioxane and LiOH (1.0 M, 300 pL, 0.3 mmol) was added. The reaction mixture was stirred at rt for 24 h then partitioned between CH2CI2 and 1.0 M aq NaOH. The organic layer was dried with MgSO4 and concentrated. The crude product was purified via PTLC (Merck- silica plates, 3% (MeOH/NH3)/CH2CI2) to give the desired Compound 15. (21 mg, 45%).

Compound IX

WO 02/062750

PCT/US02/03672

-56Compound IX. Compound 15 (17 mg, 0.042 mmol) was dissolved in CH2CI2 (166 pL) and DIPEA (20 pL). The flask was cooled in an ice/water bath and MsCi (12 pL, 0.15 mmol) was added. The reaction mixture was stirred at 0 °C for 1 h and 30 min. The resulting mixture was partitioned between water and CH2CI2. The organic layer was washed with water and brine, then dried with MgSO4. The crude product was purified via PTLC (50 % EtOAc/hexanes) to give 10 mg (50%) Compound IX.

EXAMPLE VI

Compound 16 (0.116 g, 0.22 mmoles) was dissolved in CH2C]2 (4 mL) and cooled to 0 °C. BBr3 solution (1.0 M in CH2Cl2,0.66 mL) was added and the ice bath was removed. The reaction mixture was stirred at rt for 48 h and then quenched with water at -78 °C. The reaction mixture was diluted with CH2CI2 and the resulting organic layer was washed with aqueous NaHCO3, H2O (3X5 mL), and brine. The organics were dried over Na2SO4 and the solvent was removed under vacuum to give 0.09 g of crude product. The product was isolated by PTLC (5% CH3OH / CH2CI2) to provide Compound X (0.01 g, 8.8%).

WO 02/062750

PCT/US02/03672

Compound 16 :1 h NMR (300 MHz, CDCI3) 1.54 (d, J = 6.9Hz 3H), 2.67 (s, 3H), 4.72 (q, J = 5Hz 1H), 4.86 (br. d, J = 5Hz,1H, NH), 7.08-8.42 (m, 11H).

-575

EXAMPLE VII

Compound 17 was converted to Compound 18 using the procedure in example VI.

Compound 18

WO 02/062750

PCT/US02/03672

Compound 18 (0.34 g, 0.64 mmoles) was dissolved in DMF (11 mL), cesium carbonate (0.84 g, 2.58 mmoi) was added and the reaction mixture was cooled to 15 °C. Dry bromodifluoromethane gas was introduced into the solution and bubbled for 15-20 min. Progress of the reaction was monitored by TLC and upon completion the reaction mixture was diluted with EtOAc (20 mL), washed with water (4X10 mL), and brine. The organics were dried over Na2SO4 and concentrated under reduced pressure to give 0.36 g of an oil. The crude product was purified by PTLC (50% EtOAc/hexanes) to provide 0.31 g (83%) of Compound 19.

Compound 19 was converted to Compound XI using the procedure in example II.

Compound XI: 1h NMR (400 MHz, CDCI3) 1.51 (d, J = 7.2Hz 3H), 2.67 (s, 3H), 4.702 (q, J = 6.8Hz 1H), 5.05 (br. d, J = 6.4Hz,1H, NH), 6.71 (t, J = 71.6 Hz, CF2H) 7.078.47 (m, 11H).

WO 02/062750

PCT/US02/03672

-59EXAMPLE VIII

O

CH3O

A

Compound 20

Compound 20. To a solution of Compound 2 (5.00 g, 12.9 mmol) in anhyd THF (75 mL) at -78 °C was added η-BuLi (13 mL, 2.5 M in hexanes, 32 mmol) dropwise over 10 min. The reaction mixture was stirred for 30 min. A solution of di-fbutyl dicarbonate (3.10 g, 14.2 mmol) in anhyd THF (25 mL) was added in one portion via cannula. The reaction was allowed to proceed for 4 h at -78 °C. The reaction mixture was then diluted with EtOAc (~250 mL) and washed successively with saturated aq NaHSO4 (-100 mL), water (-100 mL), and brine (-100 mL). The organic layer was dried over anhyd MgSO4, filtered, and concentrated under reduced pressure to yield a solid. Further purification of the solid by sgc (25% EtOAc/hexanes) gave 5.32 g (84%) of Compound 20 as a solid.

Compound XII

Compound XII. Compound 20 (2.06 g, 4.23 mmol) was dissolved in methanol (40 mL) and a solution of potassium carbonate (2.92 g, 21.1 mmol) in water (10 mL) was added. The reaction was allowed to proceed for 18 h. The solvent was then removed by evaporation under reduced pressure. The resulting white solid was partitioned between water (-100 mL) and EtOAc (-400 mL). The aqueous layer was extracted further with EtOAc (-100 mL). The combined organic layers were washed with brine (-500 mL), then dried over anhyd MgSO4 and filtered. Evaporation of the

WO 02/062750

PCT/US02/03672

-60solvent gave 1.22 g (74%) of f-butyl 2-((4-(1 (S)-aminoethyl)phenyl]sulfonyl-5methoxybenzoate, an oil, which was used in the next step without further purification. MsCI (242 pL, 357 mg, 3.12 mmol) was added dropwise to a solution of crude f-butyl 2-((4-(1 (S)-aminoethyl)phenyl]suifonyl-5-methoxybenzoate (1.22 g, 3.12 mmol) and triethylamine (522 pL, 379 mg, 3.75 mmol) in anhyd CH2CI2 (3.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 5 min, then allowed to warm to rt, and subsequently stirred for 3 h. The reaction mixture was diluted with CH2CI2 (-50 mL) and washed successively with 1 M HCI (~50 mL), water (3 x -50 mL) and brine (-50 mL). The organic solution was dried over anhyd MgSO4, filtered, and concentrated to yield a solid. Subsequent purification ofthe crude product by sgc (25% EtOAc/hexanes) gave 1.41 g (96%) of Compound XII as a solid.

EXAMPLE IX

O

Compound 21

Compound 21. In a flame dried flask under N2 blanket, Compound 5 (400 mg, 1.0 mmol) was dissolved in dry THF (5 mL) and cooled to -78 °C. A solution of n-BuLi (1.0 M in hexanes, 1.9 mL, 1.9 mmol) was added and the reaction mixture was stirred for 30 min. 2-Fluorobenzaldehyde (200 mg, 1.6 mmol) was added and the reaction mixture was stirred at -78 °C for 3 h. The reaction mixture was then quenched with saturated aq NH4CI (20 mL). Methylene chloride (30 mL) was added and the layers were separated. The organic layer was washed with brine, then dried over Na2SO4, and concentrated to dryness. The crude product was purified via sgc (25% EtOAc/hexanes) to give 330 mg (62%) of Compound 21 as a powder.

WO 02/062750

PCT/US02/03672

-61 Ο

Compound 22

Compound 22. Compound 21 (10 mg) was dissolved in CH2CI2 (10 mL).

Triethylsilane (40 pL, 0.25 mmol) was added followed by BF3*Et2O (20 pL, 0.16 mmol). The reaction mixture was stirred at rt overnight. After removing the solvent, the crude product was purified via PTLC (25% EtOAc/hexanes) to give 6.0 mg (62%) Compound 22 as an oil.

Compound XIII

Compound XIII. Compound 22 (12 mg) was dissolved in methanol (2 mL) at rt.

NaOH (1.0 M, 2 mL, 2.0 mmol) was added and the mixture was stirred at rt for 2 h.

The solvent was removed, CH2Cl2 (15 mL) and brine (15 mL) were added, and the layers were separated. The aqueous layer was extracted with additional CH2CI2 (15 mL) and the combined organic layers were dried over Na2SO4 and concentrated to dryness. The crude product was then dissolved in CH2CI2 (10 mL) and cooled to 0 °C.

MsCI (14 pL, 0.18 mmol) was added followed by addition of pyridine (30 pL, 0.37 mmol). The reaction mixture was slowly warmed to rt and stirred overnight. Brine (15 mL) was added and extracted. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude product was purified via PTLC (25% EtOAc/hexanes) to give 10 mg (86%) of Compound XIII as an oil.

WO 02/062750

PCT/US02/03672

-62EXAMPLE X

Λ.

cf3

Compound 23

Compound 23. Compound 21 (330 mg, 0.64 mmol) was dissolved in CH2CI2 (20 mL) at rt. Celite (450 mg) was added followed by addition of PCC (450 mg, 2.1 mmol). The mixture was stirred at rt overnight. The solid was removed by filtration and the organic layer was washed with aq. NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude product was purified via sgc (33% EtOAc/hexanes) to give 310 mg (94%) of Compound 23 as a powder.

Compound XIV

Compound XIV. Compound 23 (15 mg) was dissolved in methanol (2 mL) at rt. NaOH (1.0 M, 2 mL, 2.0 mmol) was added and the mixture was stirred at rt for 2 h.

The solvent was removed and CH2CI2 (15 mL) and brine (15 mL) were added and the layers separated. The aq layer was extracted with additional CH2CI2 (15 mL) and the combined organic layer was dried over Na2SO4 and concentrated to dryness. The crude product was then dissolved in CH2CI2 (10 mL) and cooled to 0 °C. MsCI (15 pL, 0.19 mmol) was added followed by addition of pyridine (30 μί, 0.37 mmol). The reaction mixture was slowly warmed to rt and stirred overnight. Brine (15 mL) was added and extracted. The organic layer was dried over Na2SO4 and concentrated to

WO 02/062750

PCT/US02/03672

-63dryness. The crude product was purified via PTLC (33% EtOAc/hexanes) to give 9 mg (62%) of Compound XIV as an oil.

O

Compound 24

Compound 24. Oven dried methyltriphenylphosphonium bromide (430 mg, 1.2 mmol) and LHDMS (1.0 M in hexanes, 1.8 mL, 1.8 mmol) were stirred in dry THF (5 ml) at 0 °C for 20 min., then warmed to rt and stirred for 10 min. A solution of Compound 23 (300 mg, 0.58 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at rt overnight. EtOAc (20 ml) was added and the organic solution was washed with brine. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude product was purified via PTLC (25% EtOAc/hexanes) to give 260 mg (87%) of Compound 24 as an oil.

Compound XV

Compound XV. Compound 24 (200 mg, 0.39 mmol) was dissolved in methanol (3 mL) at rt. NaOH (1.0 M, 3 mL, 3.0 mmol) was added and the mixture was stirred at 50 °C for 2 h. The solvent was removed, CH2CI2 (20 mL) and brine (20 mL) were added, and the layers were separated. The aqueous layer was extracted with additional CH2CI2 (15 mL) and the combined organic layers were dried over Na2SO4 and concentrated to dryness. The crude product was then dissolved in CH2CI2

WO 02/062750

PCT/US02/03672

-64(15 mL) and cooled to 0 °C. MsCI (200 pL, 2.5 mmol) was added followed by addition of pyridine (400 pL, 4.9 mmol). The reaction mixture was slowly warmed to rt and stirred overnight. Brine (15 mL) was added and the organic layer separated, dried over Na2SO4 and concentrated to dryness. The crude product was purified via PTLC (50% EtOAc/hexanes) to give 160 mg (82%) of Compound XV as an oil.

EXAMPLE XI

Compound 25

F

Compound 26

Compound 26. Compound 25 (1.3 g, 2.7 mmol) was stirred at rt with a mixture of CH2Ci2/TFA (2:1,30 mL) for 3 h. The reaction mixture was then poured into brine (40 mL). The layers were separated. The aq layer was extracted with CH2CI2 (3 X 30 mL) and the combined organic layers were dried over Na2SO4 and concentrated to dryness. The crude product was dissolved in CH2CI2 (30 mL). EDCI (0.75 g, 3.9 mmol) and pentafluorophenol (0.73 g, 4.0 mmol) were added and the mixture was stirred at rt overnight. The reaction mixture was extracted with diluted aq NaOH and washed with brine. The organic layer was then dried over Na2SO4 and concentrated

WO 02/062750

PCT/US02/03672

-65to dryness. The crude product was purified via sgc (33% EtOAc/hexanes) to give 1.15 g (72%) of Compound 26 as a foam.

Compound XVI

Compound XVI. Compound 26 (50 mg) was dissolved in CH2CI2 (2 mL). 1Adamantanamine (21 mg, 0.14 mmol) was added followed by addition of DIPEA (0.05 mL, 0.29 mmol). The reaction mixture was shaken overnight. The reaction mixture was then subjected to Amberiyst 15 resin (300 mg, loading 4.1 mmol/g), and was again shaken overnight. The resin was removed by filtration. The filtrate was subjected to MP carbonate resin (Argonaut Technologies) (100 mg, loading 2.64 mmoi/g) for 4 h. The resin was removed by filtration and the filtrate concentrated to give 33 mg (70%) of Compound XVI as a powder.

EXAMPLE XII

Compound 27

Compound 27. Compound 5 (500 mg, 1.3 mmol) was dissolved in dry THF (6 mL) at rt. NaH (53 mg, 60%, 1.3 mmol) was added, and the reaction mixture was stirred at rt for 1 h. The reaction mixture was then cooled to -78 °C, and η-BuLi (1.0

WO 02/062750

PCT/US02/03672

-66M in hexanes, 1.5 mL, 1.5 mmol) was added dropwise under N2 atmosphere. The reaction was stirred at -78 °C for 40 min. A solution of l2 {390 mg, 1.5 mmol) in THF (2 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 3 h, then quenched with saturated aq NH4CI (20 mL). EtOAc (30 mL) was added and the layers were separated. The organic layer was washed with brine, then dried over Na2SO4, and concentrated to dryness. The crude product (640 mg) was used without further purification. The crude product (60 mg) was dissolved in toluene (2 mL) and Pd(OAc)2 (2 mg), PfBu3 (1 drop), NaOfeu (14 mg, 0.15 mmol) and p-Chloroaniline (13 mg, 0.11 mmol) were added. The mixture was kept in a sealed tube and heated to 120 °C for 20 h. After cooling, methylene chloride (30 mL) and brine (20 mL) were added and the layers were separated. The organic layer was washed with brine, then dried over Na2SO4, and concentrated to dryness. The crude product was purified with via PTLC (20% EtOAc/hexanes) to give 18 mg (30 %) of Compound 27 as a powder.

Compound XVII

Compound XVH. Compound 27 (12 mg) was dissolved in methanol (2 mL) at rt. NaOH (1.0 M, 2 mL, 2.0 mmol) was added and the mixture was stirred at rt for 3 h. The solvent was removed, CH2Ci2 (20 mL) and brine (20 mL) were added, and the layers were separated. The aq layer was extracted with additional CH2CI2 (15 mL) and the combined organic layers were dried over Na2SO4 and concentrated to dryness. The crude product was then dissolved in CH2CI2 (15mL) and cooled to 0 °C. MsCI (15 pL, 0.19 mmol) and pyridine (30 pL, 0.37 mmol) were added. The reaction mixture was slowly warmed up to rt and stirred overnight. Brine (15 mL) was added and the reaction mixture was extracted with CH2CI2. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude product was purified via PTLC (33% EtOAc/hexanes) to give 6.0 mg (52%) of Compound XVII as an oil.

WO 02/062750

PCT/US02/03672

Compound 28

Compound 28. Compound 5 (500 mg, 1.3 mmol) was dissolved in dry THF (6 mL) at rt. NaH (53 mg, 60%, 1.3 mmol) was added, and the mixture was stirred at rt for 1 h. The reaction mixture was cooled to -78 °C, and η-BuLi (1.0 M, 1.5 mL, 1.5 mmol) was added dropwise under N2 atmosphere, and the temperature was maintained at -78 °C for 40 min. A solution of i2 (390 mg, 1.5 mmol) in THF (2 mL) was added dropwise. The reaction was stirred at -78 °C for 3 h. The reaction mixture was quenched with saturated aq NH4CI (20 mL). EtOAc (30 mL) was added and the layers were separated. The organic layer was washed with brine, then dried over Na2SO4, and concentrated to dryness. The crude product (640 mg) was used without further purification. The crude product (60 mg) was dissolved in toluene (2 mL) and

NaH (5 mg, 60%, 0.12 mmol), CuBr*Me2S (34 mg, 0.17 mmol) and p-chlorophenol (15 mg, 0.12 mmol) were added. The reaction mixture was kept in a sealed tube and heated to 120 °C overnight. After cooling, CH2CI2 (30 mL) and brine (20 mL) were added and the layers were separated. The organic layer was washed with brine, then dried over Na2SO4, and concentrated to dryness. The crude product was purified via

PTLC (20% EtOAc/hexanes) to give 19 mg (31 %) of Compound 28 as a powder.

Compound XVIII

WO 02/062750

PCT/US02/03672

-68Compound XVIII. Compound 28 (15 mg, 29 pmol) was dissolved in methanol (2 mL) at rt. NaOH (1.0 M, 2 mL, 2.0 mmol) was added and the mixture was stirred at rt for 2 h. The solvent was removed and CH2CI2 (20 mL) and brine (20 mL) was added and the layers were separated. The aq layer was extracted with additional CH2CI2 (15 mL) and the combined organic layer was dried over Na2SO4 and concentrated to dryness. The crude product was then dissolved in CH2CI2 (15mL) and cooled to 0 °C. MsCI (20 pL, 0.25 mmol) was added followed by addition of pyridine (20 pL, 0.25 mmoi). The reaction mixture was slowly warmed up to rt and stirred overnight. Brine (15 mL) was added and extracted with CH2CI2. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude product was purified via PTLC (50% EtOAc/hexanes) to give 7.0 mg (48%) of Compound XVII as an oil.

EXAMPLE XIII

Compound 29

Compound 29. To a solution of Ν,Ν,Ν-Trimethylethylenediamine (1.2 mL, 8.6 mmol) in THF (8 mL) at -20 °C was added η-BuLi (1.6 M, 5.4 mL, 8.6 mmol) dropwise. After 15 min 4-trifluoromethoxybenzaldehyde (1.5 g, 7.8 mmol) in THF (8 mL) was added. The mixture was stirred for 15 minutes and additional η-BuLi (1.6M, 14.6 mL, 23 mmol) was added. The reaction mixture was stirred at -20 °C for 1h, then placed in the freezer at -20°C for 20 h. The mixture was cooled to -40 °C, and a solution of bis(2-fluorophenyl)disulfide (4. 0 g, 15.7 mmoles) in 30 mL THF was added. The reaction mixture was stirred at -35 °C for 3 h. The reaction mixture was poured into 0.5 N HCI and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to an oil. Purification by sgc (3 % EtOAc / hexanes) gave 1.55 g (62 %) of Compound 29 as a solid..

WO 02/062750

PCT/US02/03672

Compound 30. Methyllithium (3.25 mL, 5 mmol, 1.4 M ether) was added to a solution of Compound 1 (1.22 g, 4 mmol) at -70°C. After 10 min n-BuLi (1.6 M in hexanes, 2.83 mL, 5 mmol) was added and stirred for 30 min. A solution of Compound 29 (1.44g, 4.55mmoles), dissolved in THF (15mL) was added. The resulting mixture was stirred at -70 °C for 2.5 h, quenched with water, warmed to 0 °C and then extracted with 2 X 50 mL EtOAc. The organic layer was washed with water, dried (Na2SO4), filtered and concentrated to an oil. Purification by sgc (EtOAc : hexanes ) gave Compound 30 (1.4 g, 58%) as a gum.

Compound 31. Triethylsilane (3.5 mL, 22.5 mmol) was added to a solution of Compound 30 (0.6 g ,1.125 mmol) in CH2CI2 (30 mL), followed by addition of boron trifluoride etherate (0.32 mL, 1.94 mmol). After stirring at rt for 15 min the reaction mixture was diluted with 50 mL CH2CI2, washed with water, dried over Na2SO4, filtered, and concentrated to give a solid. Purification via PTLC (25%EtOAc/hexanes (1:3) gave Compound 31 (0.47 g, 89 %) as a solid.

WO 02/062750

PCT/US02/03672

Compound 32. MCPBA (1.56 g (56%), 5.09 mmol) was added to a solution of

Compound 31 (0.47 g, 0.9 mmol) in CH2CI2 (30 mL) at rt. After stirring for 16 h the reaction was washed with 5% aq NaHSO3, aq NaHCO3, and water. The organics were dried over Na2SO4, filtered, and concentrated to give Compound 31 (0.4 g, 82%) as a solid.

Compound 33. 1 M aq LiOH (9.7 mL, 9.7 mmol) was added to a solution of

Compound 32 (1.78 g, 3.2 mmol) in 1,4-dioxane (15 mL). The resulting mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was dissolved in 50 mL CH2CI2 and washed with 10 mL brine. The organics were dried over Na2SO4, filtered and concentrated to an oil, which was used in the next step without additional purification.

WO 02/062750

PCT/US02/03672

Compound 34

Compound 34. Triethylamine (0.28 mL, 2 mmol) was added to a solution of

Compound 33 (0.18 g, 0.4 mmol) in CH2CI2 at rt, followed by addition of MsCI (0.061 mL, 7.9 mmoi) in 0.2 mL CH2CI2. The mixture was stirred overnight, then washed with 2 X 10 mL water, dried over Na2SO4, filtered, and concentrated to give an oil. The oil was purified via PTLC using EtOAc : hexanes (1:1) as the solvent to give Compound

34 (0.137g, 65%) as a solid.

Compound XIX

Compound XIX. Triethylamine (0.296 mL, 2.1 mmol) was added to a solution of Compound 33 (0.4 g, 0.9 mmol) in 8 mL ofCH2CI2, cooled to 0°C, followed by addition of a solution of trifluoromethanesulfonic anhydride (0. 54 g, 1.9 mmol) in CH2CI2 (5 mL). The mixture was stirred at 0 °C for 3 h, washed with water, dried over

Na2SO4, filtered, concentrated under reduced pressure to give crude Compound XIX. The crude product was purified via PTLC using 33% EtOAc: hexanes to give Compound XIX as a solid (0.32 g, 62%).

WO 02/062750

PCT/US02/03672

-72EXAMPLE XIV

Compound XX. Triethylamine (0.018 mL, 0.129 mmol) was added to a solution of Compound 33 (0.05 g, 0.11 mmol) in CH2CI2 (1.5 mL) followed by addition of 4-(trifluoromethoxy)benzenesulfonyl chloride (0.02 mL, 0.118 mmol) in CH2CI2 at rt. The stirring was continued for 10 h. The reaction mixture was diluted with 50 mL CH2CI2, washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by PTLC (33%EtOAc: hexanes to give Compound XX as a solid (0.048 g, 65%).

Compound XXI. Triethylamine (0.012 mL, 0.086 mmol) was added to a solution of Compound 33 (0.033 g, 0.073 mmol) in CH2CI2 (1 mL) at -5 °C. A solution of acetyl chloride (0.0057 mL, 0.08 mmol) in 0.5 mL CH2CI2 was added. The mixture was stirred overnight at rt. The organics were washed with water, and then dried over Na2SO4, filtered, and then concentrated under reduced pressure. The resulting crude was purified by PTLC (EtOAc) to provide Compound XXI as a solid (0.009 g, 25%).

WO 02/062750

PCT/US02/03672

Compound XXII. Cyclopentyl isocyanate (0.0135 g, 0.12 mmol) was added as a CH2CI2 solution (0.5 mL) to a solution of Compound 33 (0.05 g, 0.11 mmol) in CH2CI2 (1 mL). The reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the crude product was subjected to PTLC (EtOAc/hexanes 1:2) to provide Compound XXII (0.04 g, 65%).

EXAMPLE XV

Compound XXIII

Compound XXIII. N-Boc-piperazine (0.5 g, 2.68 mmol) was added to a solution of Compound XIX (0.2 g, 0.34 mmol) in CH3CN (10 mL). The reaction was heated at 80°C for 72 h. Additional N-Boc-piperazine (0.25 g, 1.34 mmol) was added and heated at 80 °C for another 16 h. The solvent was removed under reduced pressure and the crude product was purified via PTLC (50%EtOAc:hexanes) to provide Compound XXIII as a solid, (0.096 g, 37%).

WO 02/062750

PCT/US02/03672

-74EXAMPLE XVI

Compound 35

Compound 35. Pyridinium chlorochromate (0.194 g, 0.899 mmol) was added to a mixture of Compound 30 (0.4 g, 0.75 mmol) and Celite (0.4 g) in CH2CI2 (10 mL) at rt. The mixture was stirred for 18 h, filtered through Celite and concentrated. The crude material was purified via PTLC using 33% EtOAc:hexanes to obtain Compound 35 (0.4 g, 100%).

Compound 36. MCPBA (1.29 g (56%), 4.18 mmol) was added to a solution of Compound 35 (0.4 g, 0.75 mmol) in CH2CI2 (20 mL) and stirred at rt for 18 h. The reaction was washed with 5% aq NaHSO3, 5% NaHCO3, and water. The organics were dried over Na2SO4, filtered and concentrated. The crude product was purified via PTLC using EtOAc:hexanes (1:1) to provide Compound 36 (0.34 g, 80%).

WO 02/062750

PCT/US02/03672

Compound 37. Compound 36 was converted to Compound 37 using a procedure similar to that described in example II.

Compound 38. LHMDS (0.9 mL, 1M solution THF, 0.896 mmol) was added to a suspension of methyltriphenylphosphonium bromide (0.215 g, 0.6 mmol) in anhydrous THF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 20 min, then for

10 minutes at rt. A solution of Compound 36 (0.17 g, 0.3 mmol) in THF (8mL) was added and stirring continued for 10 h at rt. The mixture was diluted with EtOAc and washed with water. The organics were dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified via PTLC using EtOAc:hexanes (1:3) to provide Compound 38 as a solid. (0.09 g, 54%).

WO 02/062750

PCT/US02/03672

Compound XXIV

Compound XXIV. Compound 38 was converted to Compound XXIV using a procedure similar to that described in example II.

Compound XXV

Compound XXV. Hydroxylamine hydrochloride (0.076 g, 1.09 mmol) was added to a solution of Compound 37 (0.03 g, 0.055 mmol) in pyridine (0.5 mL). The mixture was heated at 80 °C for 24 h. The mixture was cooled to rt and the solvent was removed under reduced pressure. The residue was dissolved in 50 mL CH2CI2 and washed with water and brine. The organics were dried over Na2SO4, filtered and concentrated to provide crude Compound XXV, which was purified via PTLC (EtOAc/hexanes, 1:3) to afford Compound XXV as a solid (0.01 g, 33%).

WO 02/062750

PCT/US02/03672

-77EXAMPLE XVII

Compound 39

Compound 39. In a flame dried flask under N2 blanket, Compound 2 (4.00 g,

10.32 mmol) was dissolved in anhyd THF (41 mL) and cooled to -78°C. A solution of η-BuLi (2.5 M in hexanes, 8.25 mL, 20.6 mmol) was added and the reaction mixture was stirred for 25 min. Bis-4-chlorophenyl disulfide (3.10 g/10.8 mmol) was added and the reaction mixture was stirred at -78°C for 3 h then between -78 °C and -10°C for 3 h. The reaction mixture was quenched with pH 7.0 sodium phosphate buffer (1.0 M, 50 mL). The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, then dried with Na2SO4 and concentrated to dryness. The crude product (5.44 g foam) was dissolved in CH2CI2 (120 mL) and cooled to 0°C. MCPBA (7.24 g) was added. The ice bath was removed and the reaction mixture was stirred at rt overnight. Aqueous NaHCO3 and CH2CI2 were added and the layers were separated. The organic layer was washed with aq NaHSO3, NaHCO3, H2O, and brine then dried with MgSO4. The crude product was purified by sgc (35%-40% EtOAc/hexanes gradient) to give 1.86 g (32%) of Compound 39.

Compound 40

WO 02/062750

PCT/US02/03672

-78Compound 40. Compound 39 (1.52 g, 2.70 mmol) was dissolved in dioxane (9 mL) and cooled to 0°C. LiOH (1.0 M aq, 3 mL, 3 mmol) was added and the reaction mixture was left stirring overnight, during which time it warmed to rt. The solvents were evaporated. CH2CI2 and aq NaOH were added and the layers were separated. The aqueous layer was extracted with additional CH2CI2 and the combined organic layer was dried with Na2SO4 and concentrated to give 0.85 g (68%) of Compound 40.

Compound XXVI. Compound 40 (143 mg, 0.307 mmol) was dissolved in dioxane and sulfamide (0.128,1.33 mmol) was added. The reaction mixture was stirred at reflux for 24 h then allowed to cool to rt and concentrated. The reaction mixture was purified via PTLC (5% MeOH/CH2CI2) giving 54 mg (32%) of Compound XXVI.

Compound 41

Compound 41. in a flame dried flask under N2 blanket, 1-chloro-4fiuorobenzene (7.36 g, 56.4 mmol) was dissolved in anhyd THF and cooled in a dry ice/acetone bath. η-BuLi (2.5 M in hexanes, 22.5 mL, 56.3 mmol) was added and toe

WO 02/062750

PCT/US02/03672

-79reaction was stirred for 50 min. 2-Fluorobenzene sulfonyl fluoride (10.3 g, 57.8 mmol) was added and the reaction mixture was left stirring overnight, during which time it warmed to rt. Saturated aq NH4CI (100 mL) was added, followed by EtOAc (100 mL) and the layers were separated. The organic layer was washed with water and brine, then dried with MgSO4. The solvents were evaporated and the crude product was purified via sgc (10% EtOAc/hexanes) to afford Compound 41 (2.55 g, 16%) as a solid.

O

Compound 42

Compound 42. 4-Mercaptobenzoic acid (0.54 g, 3.50 mmol) was dissolved in

DMA (10 mL) and cooled in an ice bath. Sodium hydride (60% suspension in oil, 0.30 g, 7.5 mmol) was added and the reaction mixture was stirred for 20 min. The ice bath was removed and the reaction mixture was stirred for 1 h. The flask was cooled to 0°C again and compound 41 (1.0 g, 3.46 mmol) dissolved in DMA (5 mL) was added. The reaction mixture was stirred at 0 °C for 30 min, then allowed to warm to rt and stirred overnight. The reaction mixture was diluted with CH2CI2 and washed with 5% aq HCI, water, and brine. The organic layer was dried with Na2SO4 and the solvents were evaporated. The crude product was purified via sgc (5% MeOH/CH2CI2) to give Coompound 42 as a solid (1.04 g, 71 %).

WO 02/062750

PCT/US02/03672

80O

F

Compound 43

Compound 43. Pentafluorophenol (0.91 g, 4.94 mmol) and Compound 42 (1.04 g, 2.46 mmol) were dissolved in 30 mL of CH2CI2 and EDCI was added. The reaction was stirred overnight and diluted with water and CH2CI2. The layers were separated and the organic layer was washed with water and dried with Na2SO4. The crude product was purified via sgc (5% EtOAc/hexanes) to give 0.9 g (62%) of Compound 43 as a solid.

Compound XXVII

Compound XXVII. Compound 43 (0.15 g, 0.25 mmol) was dissolved in CH2CI2 (5 mL). Morpholine (44 mg, 0.51 mmoi) and DIPEA (49 mg, 0.38 mmol) were added and the reaction mixture was stirred at rt for 2h. The reaction mixture was diluted with EtOAc and washed with 5% aq NaHCO3, water and brine. The organic layer was dried with Na2SO4 and the solvents were evaporated. The crude product was purified via sgc (50% EtOAc/hexanes) to give 98 mg (77%) of Compound XXVii.

WO 02/062750

PCT/US02/03672

-81 Ο

F

Compound XXVIII

Compound XXVIII. Compound XXXVII (72 mg, 0.146 mmol) was dissolved in CH2CI2 (3 mL) and MCPBA (ca 50%, 0.11 g, ca 0.36 mmol) was added. The reaction mixture was stirred overnight then diluted with CH2CI2, The reaction mixture was washed with aq Na2CO3 and water then dried with Na2SO4. The solvents were evaporated and the crude product was purified via sgc (60% EtOAc/hexanes) to give 61 mg (79%) of Compound XXXVIil as a solid.

Example XIX

Compound 44

Compound 44. Cyclopropyl benzene (48.5 g, 410 mmol), glacial acetic acid (510 mL), and sodium acetate (38.9 g, 474 mmol) were added to a roundbottomed flask. The flask was cooled in an ice-water bath. A solution of bromine (66.3 g, 414 mmol) dissolved in 105 mL of acetic acid was added dropwise over 90 min. The reaction mixture was stirred at temperatures between 0 °C and 10 °C for 5 h. The reaction was then allowed to warm to rt overnight. Hexanes (1300 mL) and water (250 mL) were added. Aqueous NaHSO3 (1M) was added until the reaction mixture changed from yellow to clear. The layers were separated. The organic layer was washed with water, 1M aq Na2CO3, and brine, then dried with Na2SO4. The solvent was evaporated and the crude product was purified via sgc using hexanes as the mobile phase to give 17 g of p-cyclopropylbromobenzene (21%) (Compound 44).

WO 02/062750

PCT/US02/03672

SO2CI

Compound 45

Compound 45. A flask was flame dried under N2 blanket Compound 44 (10.0 g, 50.7 mmol) was added, followed by dry THF (100 mL). The resulting solution was cooled to -78 °C. A solution of n-butyl lithium in hexanes (2.27 M, 22.35 mL, 50.7 mmol) was added dropwise via syringe. The reaction mixture was stirred for 10 min. SO2 gas was bubbled into the reaction mixture until the pH of a reaction mixture sample was <1 when mixed with water. The reaction mixture was stirred for 30 min at -78 °C. The ice bath was removed and the reaction mixture was allowed to warm to rt. The reaction mixture was stirred for an additional 30 min at rt. The reaction mixture was concentrated to afford a solid. CH2Ci2 (500 mL) and Nchlorosuccinamide (10.2 g, 76 mmol) were added and the reaction mixture was stirred for 4 hrs at rt. Water and CH2CI2 were added and the layers were separated. The organic layer was washed with water and brine, then dried with MgSO4. The solution was filtered and the solvents were evaporated to give 13.3 g of crude p-cyclopropylbenzenesulfonyl chloride (Compound 45).

Compound 46

Compound 46. Crude compound 45 (13.3 g) was dissolved in 200 mL of acetone and 60 mL of water. Potassium fluoride (7.12 g, 122 mmol) was added and the reaction mixture was stirred overnight at rt. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried with Na2SO4, filtered, and

WO 02/062750

PCT/US02/03672

-83concentrated to dryness to give 9.80 g (97%) of crude p-cyclopropyl benzenesulfonyl fluoride (Compound 46).

Compound 47

Compound 47. A flask was flame dried under N2 blanket. Compound 1 (44.29 g, 150 mmol) was added, followed by 500 mL of anhydrous THF. The flask was cooled to -78 °C and a solution of n-butyl lithium in hexanes (1.77 M, 154 mL, 272 mmol) was added over 40 min. The reaction mixture was stirred for 1.5 h at -78 °C, then transferred via cannula into a solution of crude p-cyclopropyl benzenesulfonyl fluoride (27.2 g, 135 mmol) dissolved in 200 mL of anhydrous THF over 1.5 h. The reaction mixture was stirred for 1h. Water was added, followed by EtOAc. The layers were separated and the organic layer was washed with aq NH4CI, water, and brine, then dried with Na2SO4. The solvents were evaporated, and the crude product was purified by sgc (25%-33% EtOAc/Hexanes gradient mobile phase) to give 24.5 g (45%) of compound 47.

Compound 48

Compound 48. A flask was flame dried under N2 blanket. Compound 47 (16.33 g, 41.1 mmol) was dissolved in 400 mL of anhydrous THF and cooled to -78

WO 02/062750

PCT/US02/03672

-84°C. A solution of n-butyi lithium in hexanes (2.3 M, 35.7 mL, 82.1 mmol) was added dropwise via syringe. The reaction mixture was stirred for 1.5 h at -78 °C. A solution of 2, 2-dithiodipyridine (8.89 g, 41.1 mmol) dissolved in 40 mL of THF was added and the reaction mixture was stirred for 2 h. The cold bath was removed, and the reaction mixture was allowed to warm to rt overnight. The reaction mixture was cooled with an ice-water bath and the reaction was quenched with 10 mL of water. The reaction mixture was diluted with EtOAc and washed with saturated aq NH4CI, water, and brine. The organic layer was dried with Na2SO4 and concentrated. The crude product was purified via sgc using 1:2 EtOAc/Hexanes as the mobile phase giving 15.49 g (74%) of Compound 48.

Compound 49

Compound 49. Compound 48 (15.49 g, 30.6 mmoi) was dissolved in 1 L of CH2CI2 and the flask was placed in a rt water bath. MCPBA (22.0 g, ca 74 mmol) was added in portions and the reaction mixture was left stirring overnight at rt. The reaction mixture was diluted with CH2CI2 and washed with 10% aq NaHCO3, water, and brine, then dried with Na2SO4. The solvent was evaporated and the crude product was purified via sgc using a 20%-50% EtOAc/Hexanes gradient as the mobile phase. Compound 49 (9.4 g, 57%) was isolated as a solid.

WO 02/062750

PCT/US02/03672

- 85 Compound 50

Compound 50. Compound 49 (10.16 g, 18.87 mmol) was dissolved in 300 mL of p-dioxane and 300 mL of 1.0 M aq LiOH was added. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with CH2CI2. The layers were separated, and the organic layer was washed with water and brine, then dried with

Na2SO4. The solvents were evaporated to give 9.0 g of crude Compound 50.

Compound XXIX. Crude compound 50 (7.74 g, 17.5 mmol) was dissolved in CH2CI2 (250 mL). Diisopropylethylamine (2.71 g, 21 mmol) was added and the flask was cooled to-78 °C. A solution of triflic anhydride (5.97 g, 21.1 mmol) dissolved in CH2CI2 (50mL) was added dropwise over 1h. The reaction mixture was stirred for 2 h at -78 °C. The cold bath was removed, and the reaction mixture was allowed to warm to rt overnight. The reaction mixture was diluted with CH2CI2 and washed with water and brine. The organic layer was dried with Na2SO4 and the solvents were evaporated. The crude product was purified via sgc using 1:2 EtOAc/Hexanes as the mobile phase to give 8.61 g (85%) of Compound XXIX.

Compound XXIX: 1H NMR (300 MHz, CDCI3): δ 8.56-8.52 (m, 1H), 8.32-8.21 (m, 3H), 8.02-7.92 (m, 4H), 5.42 (d, 9 Hz, 1H), 8.02-7.92 (m, 4H), 5.42 (d, 1H, 9 Hz), 4.84-4.78 (m, 1H), 2.16-2.06 (m, 1H), 1.60 (d, 7Hz, 3H), 1.20-1.17 (m, 2H), 0.97-0.89 (m, 1H).

WO 02/062750

PCT/US02/03672

Compound XXX

Compound XXX. Compound XXX was prepared from compound 47 using the procedures in example II.

Compound XXX: 1H NMR (300 MHz, CDCI3): δ 8.33-8.22 (m, 3H), 8.00-7.94 (m, 2H), 7.66-7.58 (m, 1H), 7.53-7.37 (m, 4H), 7.16-7.05 (m, 1H), 5.160 (d, 9 Hz, 1H), 4.884.83 (m, 1H), 2.17-2.06 (m, 1H), 1.65 (d, 7 Hz, 3H), 1.28-1.20 (m, 2H), 0.97-0.90 (m, 2H).

Compound XXXI. The potassium salt of compound XXIX (56 mg, 0.09 mmoi) was dissolved in CH2CI2 (5 mL) and Na2HPO4 (0.13 g, 0.91 mmol), and ureahydrogen peroxide complex (85 mg, 0.90 mmol) were added. Trifluoroacetic acid was added (47 mg, 0.22 mmol) and the reaction mixture was refluxed for 4 h then left stirring overnight at rt. Additional urea-hydrogen peroxide complex (85 mg, 0.9 mmol) and TFAA (0.56 mmol) were added and the reaction mixture was refluxed for 6h. The reaction mixture was allowed to cool to rt and diluted with CH2CI2 and water. The layers were separated and the organic layer was washed with water, dried with Na2SO4, and concentrated. The crude product was purified v/a PTLC on silica using EtOAc as the mobile phase to give 34 mg (64%) of compound XXXI.

WO 02/062750

PCT/US02/03672

-87Compound XXXI: 1H NMR (300 MHz, CDCl3): δ 8.38-8.29 (m, 2H), 8.17 (d, 8 Hz, 1H), 8.07-8.02 (m, 1H), 7.91-7.85 (m, 2H), 7.56-7.36 (m, 5H), 6.11 (d, 8 Hz, 1H), 4.84-4.78 (m, 1H), 2.12-2.01 (m, 1H), 1.57 (d, 7Hz, 3H), 1.21-1.12 (m, 2H), 0.92-0.86 (m, 2H).

Compound XXXII. Compound V (0.50 g, 0.85 mmol), zinc (II) cyanide (65 mg, 0.55 mmol), zinc dust (11 mg, 0.17 mmol), 1,1’-Bis(diphenylphosphino)ferrocene (21 mg, 0.04 mmol), and tris(dibenzylidineacetone) dipalladium (17 mg, 0.129 mmol) were added to a 25 mL flask. Dimethylacetamide was added and the reaction mixture was placed under N2 blanket and heated to 110 °C. The reaction mixture was stirred at 110 °C for 4 h, then partitioned between EtOAc and water. The organic layer was washed with 2M ammonium hydroxide, water, and brine, then dried with MgSO4. Evaporation of the solvent afforded 0.49 g of an oil that was purified via sgc using a 20%-25% EtOAc/Hexanes gradient mobile phase to afford compound XXXII (0.20 g).

Compound XXXIII. Compound V (0.51 g, 0.87 mmoi), tris(dibenzylidineacetone) dipalladium (40 mg, 0.04 mmol), 2-(dicyclohexylphosphino)WO 02/062750

PCT/US02/03672

-88biphenyl (36 mg, 0.103 mmol), and sodium tert-butoxide (204 mg, 2.12 mmol) were added to a Schlenck flask under N2 blanket. Toluene (2.5 mL) was added, followed by benzophenone imine (210 mg, 1.15 mmol). The reaction mixture was stirred overnight at 70 °C under N2. The reaction mixture was allowed to cool to rt and 1 M aq HCI was added. The reaction mixture was diluted with EtOAc and the layers were separated. The organic layer was washed with water and brine, then dried with MgSOzf. The resulting material was filtered and concentrated to give 0.37 g of an oil. The crude product was purified via sgc using a 25%-50% EtOAc/Hexanes gradient mobile phase, followed by a 5%MeOH/45%EtOAc/50%Hexanes mobile phase to give

0.11 g of an oil as product.

Compound XXXIV

Compound XXXIV. Compound V (264 mg, 0.45 mmol), sodium tert-butoxide (103 mg, 1.07 mmol), tris(dibenzylideneacetone) dipalladium (107 mg, 0.116 mmol), and 2-(di-tert-butyl-phosphino)biphenyl (61 mg, 0.20 mmoi) were added to a Schlenck flask under N2. THF (1.5 mL) and cyclopropylamine (0.6 g, 10.5 mmol) were added and the reaction mixture was stirred for 24 h at rt. EtOAc and 1 M aq HCI were added and the layers were separated. The organic layer was washed with 1 M aq HCI, water, and brine, then dried with MgSO4. Filtration and evaporation of the solvents gave an oil which was purified via sgc using 25% EtOAc/Hexanes as the mobile phase. Compound XXIV (109 mg) was obtained as a foam.

WO 02/062750

PCT/US02/03672

Compound XXXV

Compound XXXV. Compound XXXV was prepared from compound 5 according to the procedures in Example XIX.

Compound XXXV: 1H NMR (300 MHz, CDCI3): δ 8.88 (d, 1.2 Hz, 1H), 8.51-8.56 (m, 2H), 8.31 (dd, 8 Hz, 1 Hz, 1H), 8.18 (dd, 8 Hz, 1 Hz, 1H), 8.08-7.96 (m, 3H), 7.62-7.48 (m, 3H), 5.51 (d, 9Hz, 1H), 4.90-4.70 (m, 1H), 1.62 (d, 7 Hz, 3H).

Compound XXXVI. Compound XXXVI was prepared from compound XXXV according to the procedure in Example XIX.

Compound XXXVI: 1H NMR (300 MHz, CDCI3): δ 10.19 (d, 7.8 Hz, 1H), 8.27-8.42 (m, 4H), 8.13 (dd, 7.8 Hz, 2.1 Hz, 1H), 7.93 (d, 8.4 Hz, 2H), 7.78-7.63 (m, 2H), 7.59 (d, 8.4 Hz, 2H), 4.80 (m, 1H), 1.44 (d, 6.9 Hz, 3H).

WO 02/062750

PCT/US02/03672

-90Compound XXXVII

Compound XXXVII. Compound XXXV (0.312 g, 0.548 mmol) was dissolved in

2 propanol (20 mL) and 1.0 M aq NaOH was added (10 mL). The reaction mixture was stirred at temperatures between 80 °C to 84 °C for six days. The reaction mixture was allowed to cool to rt and partially concentrated. EtOAc was added and the layers were separated. The aqueous layer was acidified with 1 M aq H2SO4 and extracted with EtOAc. The combined organic layer was dried with MgSO4 and concentrated to give 0.29 g of an oil. The crude product was purified via sgc using a 25%-33% EtOAc/Hexanes gradient as the mobile phase. The fraction containing Compound XXVll was repurified via sgc using 3% MeOH/CHaCh as the mobile phase to give 0.05 g (15%) of Compound XXXVII as a solid.

Compound XXXVIII. Compound XXXVIII was prepared from compound XXXV according to the procedure used to prepare compound XXXII.

WO 02/062750

PCT/US02/03672

-91 Compound XXXIX. Compound XXXII (0.10 g, 0.17 mmol) was dissolved in acetone (1.5 mL) and water (1 mL). Potassium carbonate (3 mg, 0.022 mmol) and urea-hydrogen peroxide complex (0.16 g, 1.70 mmol) were added and the reaction mixture was stirred overnight at rt. The reaction mixture was diluted with EtOAc and washed with water. The solvents were evaporated and the crude product was purified via PTLC on SiO2 using 50% EtOAc/Hexanes as the mobile phase to afford Compound XXXIX (75 mg, 73%) as a solid.

Compound XXXX. Compound XXXX was prepared from compound 2 according to the procedures in Example II.

Compound XXXXI. Compound XXXXI was prepared from compound XXXX according to the procedure used to convert compound 16 to compound X.

WO 02/062750

PCT/US02/03672

Compound XXXXII

Compound XXXXII. Compound XXXXI (0.15 g, 0.264 mmoi) was dissolved in DMA (5 mL). Potassium iodide (0.22 g, 1.30 mmol), cesium carbonate (0.19 g, 0.58 mmol), and 2-bromopropane (49 mg, 0.398 mmol) were added and the reaction mixture was left stirring at rt over the weekend. EtOAc was added and the reaction mixture was washed with satd. aq NH4CI and water. The organic layer was dried with Na2SO4 and concentrated. The crude product was purified via sgc using 3% Et2O/CH2CI2 as the mobile phase to give 83 mg (51%) of Compound XXXXII.

Compound XXXXIII. Compound XXXXI (0.10 g, 0.176 mmol) was dissolved in DMF (2 mL). Sodium hydride (7 mg, ca 1.2 eq) and bromomethylcyclopropane (26 mg, 0.19 mmol) were added and the reaction was stirred at 50 °C for 4 hr then allowed to cool to rt. EtOAc and water were added, and the layers were separated. The organic layer was washed with water and dried with Na2SO4. The solvent was

WO 02/062750

PCT/US02/03672

-93evaporated and the crude product was purified via sgc using 33% EtOAc/Hexanes as the mobile phase to give 15 mg (14%) of Compound XXXXIII.

Compound XXXXIV. Compound XXXXIV was prepared according to the 10 procedure used for Compound XXXXIII using ethyl iodide as the electrophile and stirring the reaction at rt overnight before workup.

Compound XXXXV. Compound XXXXI (0.40 g, 0.70 mmol) was dissolved in DMF (8 mL) and NaH (62 mg, ca 2.2 eq) was added. The reaction mixture was stirred for 30 min. Sodium iodide (0.52 g, 3.46 mmol) and 2-chloroethyl methyl ether (80 mg, 0.85 mmol) were added. The reaction mixture was stirred for 1 h at rt then 5 h at 110 °C. The reaction mixture was allowed to cool to rt. EtOAc and satd aq NH4CI were added and the layers were separated. The organic layer was washed with water and dried with Na2SO4. Evaporation of the solvent, followed by sgc using 50%

EtOAc/Hexanes as the mobile phase, afforded 0.21 g (48%) of Compound XXXXV.

WO 02/062750

PCT/US02/03672

Compound XXXXVI

Compound XXXXVI. Compound 50 (50 mg, 0.11 mmol) was dissolved in • CH2CI2 (3 mL) and acetic acid (7 mg). Acetone (6 mg, 0.13 mmol), and NaBH(OAc)3 (36 mg, 0.169) were added, and the reaction mixture was left stirring at rt overnight. EtOAc was added and the reaction mixture was washed with 10% Na2CO3 and water. The solvents were evaporated and the crude product was purified via PTLC on SiO2 using EtOAc as the mobile phase. The resulting product was dissolved in EtOAc and HCI in Et2O was added causing a white precipitate to form. The solvent was removed and the precipitate was washed with Et2O and dried in vacuo to give 32 mg (49%) of compound XXXXVI as a solid.

Compound XXXXVII

Compound XXXXVII. Compound XXXXVII was prepared according to the procedure used for compound XXXXVI using cyclopentanone as the carbonyl source.

WO 02/062750

PCT/US02/03672

Compound XXXXVIII. Compound XXXXVIII was prepared according to the procedure used for compound XXXXVI using cyclohexanone as the carbonyl source.

Compound XXXXIX. Compound XXXXIX was prepared according to the procedure used for compound XXXXVI using cyclopropanecarboxaldehyde as the carbonyl source.

WO 02/062750

PCT/US02/03672

-96Compound XXXXX. Compound XXVIII (0.10 g, 0.197 mmol) was dissolved in a solution of borane in THF (1.0 M, 1.0 mL, 1.0 mmol). The reaction mixture was refluxed for 4 h then allowed to cool to rt. The solution was concentrated. Methanol (5 mL) and 1 M aq HCl (5 mL) were added and the resulting solution was stirred for 5 h at rt. The reaction mixture was concentrated and EtOAc was added. The resulting solution was washed with aq NaOH and water, then dried with Na2SO4. The solvent was evaporated and the crude product was purified via PTLC using 40% EtOAc/Hexanes as the mobile phase. The product isolated from this step was dissolved in EtOAC, and HCI in Et2O was added causing a precipitate to form. The solvent was removed and the precipitate was washed with Et2O and dried in vacuo to give 22 mg (21 %) of Compound XXXXX as a solid.

.0.

Compound 51

Compound 51 was prepared from Compound 2 according to the procedures in Example 11.

Compound XXXXXI

Compound XXXXXI. Compound XXXXXI was prepared from compound 51 according to the procedure used to prepare compound XXXXVI.

WO 02/062750

PCT/US02/03672

Compound XXXXXII

Compound XXXXXII. Compound XXXXXII was prepared from compound 51 according to the procedure used to prepare compound XXXXVI using 3-methyl-2thiophenecarboxaldehyde as the carbonyl source.

Compound XXXXXIII. Compound XXXXXIII was prepared from compound 51 according to the procedure used to prepare compound XXXXVI using benzaldehyde as the carbonyl source.

Compound 52

WO 02/062750

PCT/US02/03672

-98Compound 52. Compound 52 was prepared from compound 2 using the procedures in Example II with benzenesulfonyl fluoride as the initial electrophile.

Compound XXXXXIV

Compound XXXXXIV. Compound 52 (0.29 g, 0.67 mmol), cesium carbonate (0.44 g, 1.35 mmol), tris(dibenzylideneacetone) dipalladium (31 mg, 0.034 mmol), dppp (28 mg, 0.068 mmoi), and 2-bromopyridine (0.16 g, 1.01 mmol) were dissolved in 11 mL of toluene under N2 blanket. The reaction mixture was stirred at 80 °C overnight under N2, then allowed to cool to rt. CH2CI2 was added and the reaction mixture was washed with 2M aq NaHCO3, water, and brine. The organic layer was dried with Na2SO4and the solvent was evaporated. The crude product was purified via sgc using EtOAc as the mobile phase. The resulting material was dissolved in EtOAc and a solution of HCl/Et2O was added. The solvents were evaporated to give 145 mg (42%) of Compound XXXXXIV as a solid.

Compound XXXXXV

WO 02/062750

PCT/US02/03672

-99Compound XXXXXV. Compound XXXV (0.92 g, 1.67 mmol), was dissolved in methanol (40 mL) and 1.0 M aq NaOH was added (20 mL). The reaction mixture was stirred at 70 °C for 21 h. The reaction mixture was concentrated and extracted with EtOAc. The organic layer was washed with 1 M aq HCI, water, and brine, then dried with MgSO4. The solvent was evaporated and the crude product was purified via sgc using 25%-33% EtOAc/Hexanes as the mobile phase. Compound XXXXXV (0.82 g, 90%) was isolated as an oil.

Compound XXXXV: 1H NMR (300 MHz, CDCI3): δ 8.56 (d, 3.9 Hz, 1H), 8.31-8.22 (m, 2H), 8.124 (d, 2.7 Hz, 1H), 8.05-7.95 (m, 1H), 7.92 (d, 8.4 Hz, 2H), .750-7.45 (m, 1H), 7.92 (d, 8.4 Hz, 2H), 7.27-7.23 (m, 2H), 5.8 (d, NH, 1H), 4.85-4.75 (m, 1H), 3.99 (s, 3H), 1.58 (d, 7.2 Hz, 3H).

Compound XXXXXVI

Compound XXXXXVI. Compound 50 was converted to compound XXXXXVI according to the procedure in Example II.

Compound XXXXXVI: 1H NMR (300 MHz, CDCI3): δ 8.56-8.52 (m, 1H), 8.31-8.23 (m, 3H), 8.02-7.90 (Μ, 4H), 4.87-4.78 (d, 7 Hz, 1H), 4.69 (m, 1 H), 2.66 (s, 3H), 2.16-2.06 (m, 1H), 1.51 (d, 7 Hz, 3H), 1.27 -1.17 (m, 2H), 0.96-0.90 (m, 2H).

Cl ‘0

Compound 53

Compound 53. 2-fluoro-4-chloroaniline (22.90 g, 151 mmol) was dissolved in 120 mL of AcOH and 80 mL of concentrated HCI was added with stirring. The

WO 02/062750

PCT/US02/03672

-100reaction mixture was cooled to 0 °C and a solution of NaNO2 (27.2 g, 0.4 mol) dissolved in 40 mL of H2O was added over 10 min. The reaction mixture was stirred for 30 min at 0 °C. In a separate flask, 500 mg of CuCI was dissolved in 200 mL of AcOH. The flask was cooled to 0 °C and SO2 gas was bubbled into the solution for 40 minutes. The contents ofthe aniline” flask were added to the contents ofthe second flask over 20 minutes causing a vigorous evolution of gas. After the addition was complete, the ice bath was removed, and the reaction mixture was allowed to warm to rt. The reaction mixture was poured into 500 g of chipped ice and the resulting solids were collected, washed and dried to give 26.1 g (73%) of compound 53.

Compound 54

Compound 54. Compound 53 (4.0 g, 17.5 mmol) was dissolved in acetone (80 mL) and a solution of potassium fluoride (2.03 g, 35 mmol) in water (40 mL) was added. The reaction mixture was stirred at rt overnight. It was partially concentrated on the rotovap, then partitioned between CH2CI2 and water. Evaporation of the solvent afforded Compound 54 (2.60 g, 70%) as an oil.

Compound 55

Compound 55. Compound 55 was prepared from α-methyi benzylamine using a procedure similar to that used to prepare compound 1. N-lodosuccinamide was substituted for DBDMH and the product was recrystallized from isopropanol/water.

WO 02/062750

PCT/US02/03672

-101 Ο

CI

Compound 56

Compound 56. Compound 55 (4.33g, 12.5 mmol) was dissolved in THF (50 mL) and TMEDA (5.6 mL, 37 mmol) was added. The flask was placed under N2 blanket and cooled to 0 °C. A solution of isopropyl magnesium chloride (2.0 M in THF, 15 mL, 30 mmol) was added via syringe over 6 min. The reaction mixture was stirred at 0 °C for 1 h. The resulting solution was transferred via cannula into a flask containing compound 53 (15 mmol) in an ice-water bath over 15 min. The reaction mixture was left stirring at 0 °C for 1.5 h. Aq NH4CI was added and the reaction mixture was extracted with EtOAc. The combined organic layer was washed with brine and dried with MgSO4. The solvents were evaporated and the crude product was purified via sgc using 1:4 EtOAc/Hexanes as the mobile phase. Solid compound 56 (3.5 g, 68%) was obtained.

Compound 57

Compound 57. Compound 56 was converted to compound 57 using hydrolysis and sulfonylation procedures similar to those described in Example II.

Compound 58

WO 02/062750

PCT/US02/03672

-102Compound 58. Compound 57 (0.1 Og, 0.22 mmol) was dissolved in 1 mL of dioxane and 2-mercaptoimidazole was added (28 mg, 0.28 mmol). Sodium hydride (60% dispersion in mineral oil, 18 mg) was added and the reaction mixture was stirred at 100 °C for 8 h. The reaction mixture was quenched with ice and extracted with

EtOAc. The organic layer was dried with MgSO4 and the solvents were evaporated. The crude product was purified via sgc using a 5:95 MeOH/CH2Cl2 mobile phase to give 18 mg (15%) of compound 58 as product.

Compound XXXXXVII

Compound XXXXXVII. Compound 57 was oxidized to compound XXXXXVII 15 using a procedure similar to that used to oxidize Compound XIX to compound XXI.

It will be understood that various modifications may be made to the embodiments and examples disclosed herein. Therefore, the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. Those skilled in the art will envision various modifications within the pe and spirit of the claims appended hereto.

I

Contents251

12 priority claims, no other members on record

This recordMember, by publication datePriority claim

Priority claims12

Priority claims
Document	Office	Kind	Date
26737501	United States of America	P	2001-02-08
26737501	United States of America	P	2001-02-08
29260001	United States of America	P	2001-05-22
29260001	United States of America	P	2001-05-22
0203672	United States of America	W	2002-02-07
0203672	United States of America	W	2002-02-07
01267375	–	–	–
01292600	–	–	–
PCTUS0203672	–	–	–
US20010267375P	–	–	–
US20010292600P	–	–	–
WO2002US03672	–	–	–

2 legal events, as the office reported them to INPADOC

Over the term

Point at a mark for the event

Events

Legal events, newest first
	Event	Code
2006-01-27	Renewal (renewal fees accepted)RENW	RENW
2005-09-30	Patent sealedPSEA	PSEA