However, grafts or organ transplants between two genetically dissimilar individuals generally do not succeed without immunosuppressive drug therapies.

A number of drugs are currently being used or investigated for their immunosuppressive properties.

Among these drugs, the most commonly used immunosuppressant is cyclosporin A. However, usage of cyclosporin has numerous side effects such as nephrotoxicity, hepatotoxicity and other central nervous system disorders. Thus, there is presently a need to investigate new immunosuppressive agents that are less toxic but equally as effective as those currently available.

There are a number of autoimmune disease states for which present treatments are inadequate. Examples include asthma, psoriasis, insulin dependent diabetes mellitus, ulcerative colitis, rheumatoid arthritis, multiple sclerosis and lupus erythematosus.

Consequently, there is a need for new drugs which can treat these autoimmune disorders.

SUMMARY OF THE INVENTION One embodiment of the present invention is a method of suppressing the immune system in a subject in need of immune system suppression. The method comprises administering to the subject an effective amount of a compound represented by Structural Formula (I), (II), (III) or (IV):

and physiologically acceptable salts amd esters thereof.

Ring A, Ring B and Ring C are substituted or unsubstituted.

Ring B has one or two nitrogen atoms. The"dotted line"in Ring B indicates the presence or absence of a double bond.

Ring D is a substituted or unsubstituted aromatic group.

Ring D is substituted on adjacent ring carbon atoms (ortho, carbon atoms if Ring D is a phenyl ring) with the carboxylic acid and amide group.

Arl and Ar, are independently an aromatic group or a substituted aromatic group.

Ar2 and Ar3 are independently an aromatic group, substituted aromatic group, a cycloalkyl group, a substituted cycloalkyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group.

Xi is a covalent bond,-CH2-,-CH2CH2-,-CH=CH-or a cycloalkyl group to which Arl and Ar2 are both fused. <BR> <BR> <BR> <P> X2 is a covalent bond,-C (O)-,-CH2-,-CH (R2)-,<BR> <BR> <BR> <BR> <BR> -CH2-CH(R2)-or-CH2-C (R3) (R2)-.<BR> <BR> <BR> <BR> <BR> <P> X3 is a covalent bond or-CH2-,-CH (R2)-,-NH-, and -N(R2).

X4 is-O-,-S-,-OCH2-or-CH2CH2-.

R1 is an aliphatic or substituted aliphatic group.

R2 and R3 are independently-H, a C1-C3 alkyl or halogenated alkyl group, or wherein R2 and R3, taken together with the carbon atom to which they are attached, are a C3-C6 cycloalkyl group.

The invention also includes pharmaceutical compositions comprising one or more of the compounds or small organic molecules which have been identified herein as immune system suppressants and a suitable pharmaceutical carrier. The invention further relates to novel compounds which can be used to suppress the immune system in a subject in need of immune system suppression.

The method of the present invention can be used to treat subjects having an autoimmune disease, such as asthma, psoriasis, insulin dependent diabetes mellitus, ulcerative colitis, rheumatoid arthritis, multiple sclerosis and lupus erythematosus. It is expected that

the methods disclosed herein will not cause the undesirable side effects associated with other immunosuppressive drugs such as cyclosporin. In another embodiment, the method of the present invention can be used to treat tumors in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION In a preferred embodiment, the compound is represented by Structural Formula (V):

R1 is an aliphatic group such as a C1-C3 aliphatic group or a substituted C1-C3 aliphatic group. More preferably, R1 is a C1-C3 alkyl group or a C1-C3 halogenated alkyl group.

Xi is a covalent bond or-CH2-.

Ring A, Arl and Ar2 are as defined for Structural Formula (I).

In another preferred embodiment, the compound is represented by Structural Formula (VI):

X1 is a covalent bond or"CH-.

Ring A, Arl and Ar2 are as defined for Structural Formula (I).

In another preferred embodiment, the compound is represented by Structural Formula (VII):

Xi is a covalent bond,-CH2-,-CH2CH2-,-CH=CH-or a cyclpentyl group to which Arl and Ar2 are both fused.

Preferably, X1 is a covalent bond or-CH2-.

Ring A, Arl and Ar2 are as defined for Structural Formula (I).

In another preferred embodiment, the compound is represented by Structural Formula (VIII):

Ring A, Ri, X2 and Ar3 are as defined above for Structural Formula (II). Ri in Structural Formula (VIII) is preferably-H, a C1-C3 alkyl group or a halogenated Cl-C3 alkyl group, more preferably,-H, methyl or ethyl.

X2 in Structural Formula (VIII) is preferably-CH2-. Ar3 is preferably a substituted or unsubstituted aromatic group.

In another preferred embodiment, the compound is represented by Structural Formula (IX):

In Structural Formula (IX), Ring D, R2 and Ar3 are as defined in Structural Formula (III). R2 is preferably -H, methyl or ethyl.

In another preferred embodiment, the compound is represented by Structural Formula (X):

In Structural Formula (X), Ring D, R2 and Ar3 are as defined in Structural Formula (III). R2 is preferably -H or methyl. Ring D is preferably a carbocyclic aromatic ring.

In another preferred embodiment, the compound is represented by Structural Formula (XI):

Ar3 in Structural Formula (XI) is as defined in Structural Formula (III).

In another preferred embodiment, the compound is represented by Structural Formulas (XII) or (XIII):

Arg in Structural Formulas (XII) and (XIII) are as defined in Structural Formula (IV). Ar4 is preferably a substituted or unsubstituted carbocyclic aromatic group.

Another embodiment of the present invention is a method of suppressing the immune system in a subject in need of immune system suppression. The method comprises administering an effective amount of a compound represented by Structural Formula (XIV): Ring A is substituted or unsubstitued.

Arl, Ar2 and Xi are as defined above for Structural Formula (I). Preferably, X1 is a covalent bond or-CH2-.

Also included in the present invention are physiologically acceptable salts of the compounds represented by Structural Formulas (I) through (XIV).

Salts of compounds containing an amine or other basic group can be obtained, for example, by reacting with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid and the like. Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base, for example, a hydroxide base. Salts of acidic functional groups contain a countercation such as sodium, potassium and the like.

As used herein, aliphatic groups include straight chained, branched or cyclic C1-C8 hydrocarbons which are completely saturated or which contain one or more units of unsaturation. An"alkyl"group is a saturated aliphatic group.

Aromatic groups include carbocyclic aromatic groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl, and heterocyclic aromatic groups such as N- imidazolyl, 2-imidazolyl, 2-thienyl, 3-thienyl, 2- furanyl, 3-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidy, 4-pyrimidyl, 2-pyranyl, 3-pyranyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4- oxazolyl and 5-oxazolyl.

Aromatic groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples include 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2- benzothiazole, 2-benzooxazole, 2-benzimidazole, 2-

quinolinyl, 3-quinolinyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, and acridintyl.

Non-aromatic heterocyclic rings are non-aromatic carbocyclic rings which include one or more heteroatoms such as nitrogen, oxygen or sulfur in the ring. The ring can be five, six, seven or eight-membered.

Examples include 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahyrothiophenyl, 3-tetrahyrothiophenyl, 2-morpholino, 3-morpholino, 4- morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2- pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2- piperazinyl, 1-piperidinyl, 2-piperidinyl, 3- piperidinyl, 4-piperidinyl and 4-thiazolidinyl.

Suitable substituents on an alkyl, aliphatic, aromatic or non-aromatic heterocyclic ring include, for example, -OH, one or more halogens (-Br,-C1,-I and-F), -O (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group),-CN,- NO2,-COOH,-NH2,-NH (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group),-N (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, <BR> <BR> <BR> aromatic or substituted aromatic group) 2,-COO (aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group),-CONH2, -CONH (aliphatic, substituted aliphatic group, benzyl, substituted benzyl, aromatic or substituted aromatic group)),-SH,-S (aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) and-NH-C (=NH)-NH2. A substituted non- aromatic heterocyclic ring, or aromatic group can also have an aliphatic or substituted aliphatic group as a substituent. In addition, a substituted aromatic or non-aromatic heterocyclic group can have another

aromatic group, substituted aromatic group, non-aromatic heterocyclic group or substituted non-aromatic heterocyclic group as a substituent. A substituted alkyl or aliphatic group can also have a non-aromatic heterocyclic ring, benzyl, substituted benzyl, aromatic or substituted aromatic group as a substituent. A substituted non-aromatic heterocyclic ring (for example, Ring B in Structural Formula (I) can also have =O, =S, =NH or =N (aliphatic, aromatic or substituted aromatic group) as a substituent. A substituted aliphatic, substituted aromatic or substituted non-aromatic heterocyclic ring can have more than one substituent.

Subjects in need of treatment to suppress the immune system include subjects with an autoimmune disease. Examples of autoimmune diseases include insulin dependent diabetes mellitus, asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, multiple sclerosis and lupus erythematosus. Subjects with an organ transplant are also in need of treatment to suppress the immune system in order to suppress or prevent organ transplant rejection. An"organ transplant"refers to transferring or"transplanting"an internal organ (e. g. heart, lung, kidney, liver, pancreas, stomach, large intestine and small intestine) or external organ (e. g. skin) from a donor to a recipient, wherein the donor is genetically distinct from the individual or animal who has received the transplant. An"organ transplant"also includes cross species transplants.

"An effective amount"is the dosage of compound required to achieve the desired therapeutic and/or prophylactic effect, for example the dosage of the compound which results in suppression of an immune response in the individual or animal, or which results in suppression of an organ transplant rejection in the subject. A"desired therapeutic effect and/or

prophylactic effect"includes, for example, increasing the life span or ameliorating the symptoms of an individual or animal having or likely to have an autoimmune disease such as asthma, psoriasis, insulin dependent diabetes mellitus, ulcerative colitis, rheuma- toid arthritis, multiple sclerosis and lupus erythematosus. Examples of symptoms which can be ameliorated include hyperglycemia in diabetes, joint pain, stiffness and immobility in rheumatoid arthritis, paralysis in multiple sclerosis and rash and skin lesion in lupus erythematosus. With respect to insulin dependent diabetes mellitus, a"desired therapeutic or prophylactic effect"includes mitigating or preventing secondary complications resulting from the disease, such as vascular disorders, arise. Suitable dosages can be determined by methods known in the art and can be dependent, for example, upon the individual's age, weight, sensitivity, tolerance and overall well-being.

For example, dosages can be from about 10 mg/kg/day to about 1000 mg/kg/day. An effective amount of the compound can be administered by an appropriate route in a single dose or multiple doses.

A"subject"is preferably a mammal, such as a human, but can also be an animal in need of veterinary treatment, e. g., domestic animals (e. g., dogs, cats, and the like), farm animals (e. g., cows, sheep, pigs, horses, chickens and the like) and laboratory animals (e. g., rats, mice, guinea pigs, and the like).

The compound can be administered alone or in conjunction with other pharmacologically active agents, e. g., together with other immunosuppressive agents or together with antibiotics and/or antiviral agents.

Compounds that can be coadministered include steroids, (e. g. methyl prednisolone acetate), NSAIDS and other known immunosuppressants such as azathioprine, 15- deoxyspergualin, cyclosporin, mizoribine, mycophenolate

mofetil, brequinar sodium, leflunomide, FK-506, rapamycin and related compounds. Dosages of these drugs will also vary depending upon the condition and individual to be treated.

A variety of routes of administration are possible including, but not necessarily limited to parenteral (e. g., intravenous, intraarterial, intramuscular, subcutaneous injection), oral (e. g., dietary), nasal, slow releasing microcarriers, topical or rectal, depending on the disease or condition to be treated.

Oral, parenteral and intravenous administration are preferred modes of administration. Formulation of the compound to be administered will vary according to the route of administration selected (e. g., solution, emulsion, gels, creams, ointments, oils, aerosoles, capsule). An appropriate composition comprising the compound to be administered can be prepared in a physiologically acceptable vehicle or carrier. For solutions or emulsions, suitable carriers include, for example, aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Intravenous vehicles can include various additives, preservatives, or fluid, nutrient or electrolyte replenishers (See, generally, Remington's Pharmaceutical Science, 16th Edition, Mack, Ed. (1980)). To avoid systemic exposure, the compound can be applied topically as a cream, ointment or gel.

The invention is illustrated by the following examples which are not intended to be limiting in any way.

EXEMPLIFICATION Example 1-Preparation of exemplary compounds of the present invention Trifluoromethylphenyl) phenyl]-4-carboxy-1 (2H) isoquinolinone (I) A) 4- (4-Bromophenyl) aminomethylene homophthalic anhydride Homophthalic anhydride (6.48 g), triethylorthoformate (30 ml), 4-bromoaniline (6.88 g) and 1,4-dioxane (25 ml) were mixed and refluxed for 30 min. The reaction mixture was cooled to room temperature. The resulting precipitate was collected by filtration and washed with a small amount of dioxane. The filtrate was stirred at room temperature for 48 more hours, with collection of the precipitate by filtration every 24 hour. The combined precipitate was dried over in vacuo and 7.68 g of pale yellow solid was obtained. 1H-nmr (DMSO-d6/CDCl3,250MHz): 8.92 (t, 1H), 8.16 (d, 1H), 8.02 (d, 1H), 7.75-7.58 (m, 5H), 7.33 (t, 2H).

B) 2- (4-Bromophenyl)-4-carboxy-1 (2H) isoquinolinone: 4- (4-Bromophenyl) aminomethylene homophthalic anhydride (7.68 g), with NaOH (4.0 g), was suspended in the solution of EtOH (300 ml) and H20 (15 ml), and stirred at room temperature for 3 hours. Solvent was removed in vacuo and the residue was suspended in ice-water (100 ml), acidified with 36% HC1 (8 ml) to pH 2. The suspension was filtered and the collected white solid was washed with water, dried over in vacuo overnight.

The given crude product (5.9 g) was subject to

recrystallization by refluxing in AcOH (100 ml), cooling to room temperature and adding of water (100 ml). 3.54 g of fine powder was afforded after collected by filtration, washed with water and dried in vacuo.

1H-nmr (DMSO-d6,250 MHZ): 8.85 (d, 1H), 8.31 (d, 1H), 8.18 (s, 1H), 7.86 (t, 1H), 7.75 (q, 2H), 7.62 (t, 1H), 7.53 (q, 2H).

C) 2- [4- (3-Trifluoromethylphenyl) phenyl]-4- carboxy-1 (2H) isoquinolinone: The mixture of 2- (4-Bromophenyl)-4-carboxy-1 (2H) isoquinolinone (690 mg), 3-trifluoromethylphenylboronic acid (600 mg), tetrakis (triphenylphosphine)-palladium (o) (80 mg), 2 M Na2CO3 solution (4 ml) and toluene (6 ml) was refluxed under argon for 16 hours. The reaction mixture was quenched with 2N HCl (20 ml) at room temperature, extracted with EtOAc (500 ml), washed with 0.5 N HC1 (3x200 ml). The organic layer was dried with anhydrous Na2SO4, filtered. Solvent was removed from the filtrate.

The resulted residue was subject to silica gel flash column purification, with elution by chloroform: acetic acid (99.5: 0.5 to 98: 2). 360 mg of title product was afforded upon solvent was removed from the pure fraction <BR> <BR> <BR> and dried in vacuo overnight. 1H-nmr (DMSO-d6,250MHz) : 8.88 (d, 1H), 8.34 (d, 1H), 8.23 (s, 1H), 8.06 (m, 2H), 7.96-7.83 (m, 3H), 7.77-7.60 (m, 5H). The acid product was suspended in MeOH (25 ml) and neutralized with 1.00 N NaOH (0.88 ml) at room temperature for 2 hours. Solvent was removed from the resulted solution under reduced pressure and 380 mg of sodium salt was given after dried in vacuo overnight. MS (FAB-): m/z 408 (M-Na+).

Sodium 2- (3'methoxy-1, 1'-biphenyl-4-yl)-6-fluoro- quinazoline-4-carboxylate (II) A) 2- (4-bromophenyl)-6-fluoro-quinazoline-4-carboxylate: A mixture of 4-fluoroaniline (7.40 mL, 0.067 mmol), p-bromobenzoyl chloride (14.53g, 0.067 and diisopropylethylamine (11.6 mL, 0.067 mmol) in THF (100 mL) was stirred at rt. for 4 h. The solvent was removed to dryness and ethanol (200 mL) added. The mixture was filtered, the solid washed with ethanol (3 X 25 mL) and then dried under vacuum overnight. The solid was suspended in SOCS2 (40 mL) and the mixture refluxed for 2 h. The solvent was removed to dryness and the solid dried under vacuum for 1 h. The solid was redissolved in 1,2-dichlorobenzene (30 mL) and ethylcyanoformate (6.2 mL, 0.063 mmol) added. A solution of SnCl4 (7.6 mL, 0.65 mmol) in 1,2-dichlorobenzene (20 mL) was added dropwise over a period of lh. The mixture was placed in a preheated bath (135 °C) for 15 min. The mixture was cooled down to rt. and poured slowly into a cold (0 °C) solution of NaOH (1M, 100 mL). The mixture was extracted with EtOAc (3 X 200 mL). The solvent was dried over MgSO4, filtered and the solvent removed to dryness. The mixture was purified by column chromatography using 2% EtOAc/hexane. The product was suspended in a 6/1 solution of EtOH/NaOH (20%) and the mixture refluxed for 2h. The mixture was filtered and the solid washed with EtOH (3 X 20 mL). Crude yield 4.53 g (20.7 %, more than 95 % pure by HPLC). A small sample was purified by column chromatography using first EtOAc and then 1/1 EtOAc/hexane 1% HOAC. CHN calculated (found) for C15HBN202BrF: C, 51.82 (51.82); H, 2.32 N, 8.07 (7.93).

B) Sodium 2- (3'methoxy-l, l'-biphenyl-4-yl)-6-fluoro- quinazoline-4-carboxylate: Pd (PPh3) 4 (0. 9540,0.76 mmol) was added to a degassed solution of A (1.0478,2.84 mmol) and 3-methoxyphenylboronic acid (1.0212 g, 6.72 mmol) in a suspension of THF (100 mL)/Na2CO3 (2 M, 10 ml). The mixture was refluxed for 2 days, the solvent was removed to dryness and HC1 (1M, 100 mL) added. The mixture was filtered and the solid redissolved in EtOAc (400 mL), dried over MgSO4, filtered and the solvent removed to dryness. The mixture was purified by column chromatography using EtOAc until the boronic acid was eluted and then 1/1 EtOAc/hexane 1% HOAc. The product (0.5316 g, 1.432 mmol, 50% yield) was suspended in 3/1 EtOH/H2O (40 mL) and a solution of NaOH (1.370 mL, 1.036M) was added. The mixture was heated to reflux for 30 min, cooled down to rt., filtered and the solvent removed to dryness. CHN calculated (found) for C22H1403FN22H2O: C, 61.11 (60.97); H, 4.20 (3.81); N, 6.48 (6.22).

Sodium 6-fluoro-2- (4-fluorobenzyloxy) quinoline-4- carboxylate (III) A) 5-fluoro-1-acetylisatin: A mixture of 5-fluoroisatin (4.00 g, 24.2 mmol) in acetic anhydride (8 mL) was heated to reflux for 1.5 h. The mixture was cooled down to rt. and let stand for 12 h. The mixture was filtered and the solid washed with acetic anhydride and then dried under high vacuum to yield 1.8 g. The filtrate was concentrated to dryness and the mixture purified by column chromatography using 1/1 EtOAc/hexane to yield an extra 1.1 g. Total yield 2.9 g (57 %).

B) 4-carboxy-6-fluoroquinolin-2-one: A mixture of A (2.00 g, 9.65 mmol) in NaOH (20 %, 40 mL) was refluxed for lh, cooled down and the pH was adjusted to 2 with HC1 (1M). The mixture was filtered and the solid washed with water and then cold acetone to give 1.2 g (60 % yield) of crude material. The solid was dried under vacuum and used without purification in the next step.

C) 2-chloro-4-carboxy-6-fluoroquinoline: A suspension of B (1.00 g, 4.98 mmol) in PORC13 (5 mL) was refluxed for 2 h. The mixture was cooled down to rt., and poured slowly into iced-water. The solid was filtered, suspended in NaOH (1M, 50 mL) and the mixture stirred at rt. overnight. The pH was adjusted back to 3 with HC1 (1M) and the mixture filtered. The solid was dried under high vacuum overnight. Yield 1.037 g (95%).

D) sodium 6-fluoro-2- (4-fluorobenzyloxy) quinoline- 4-carboxylate: 4-fluorobenzyl alcohol (0.29 mL, 2.67 mmol) was added to a cooled (0 °C) suspension of NaH (320 mg, 13.4 mmol, 60 % in mineral oil). The mixture was stirred for 10 min. and C (600 mg, 2.67 mmol) was added and stirred to rt. and for 5 h. The solvent was removed to dryness and the mixture partitioned between HCl/EtOAc (1M, 50 mL/150 mL). The aqueous layer was extracted with EtOAc (3 X 50 ml), the organic layer was dried over MgSO4, filtered and the solvent removed to dryness. The product was purified by column chromatography using 3/1 Hexane/EtOAc 1 % HOAc. Yield; 0.5884 g (70 %). The acid was dissolved in EtOH (10 mL) and NaOH (1.803 mL, 1.036 N) added. The mixture was filtered and the solvent removed to dryness. CHN

calculated (found) for C17Hl0NF203Na 11/2 H2O: C, 56.05 (56.37); H, 3.60 (3.53); N, 3.85 (3.68).

N- (2-carboxyphenyl)-N'- [2-methyl-4- (2'-methylphenyl)] phe nyl urea (PRO 8644) (IV) To a cooled (-78° C) solution of 4-amino-3,2'-dimethylbiphenyl (200mg; lmmol), diisopropylethylamine (262mL; 1.5mmol) and methylene chloride (5mL) was added phenyl chloroformate (138 mL; 1. lmmol) and the resulting mixture was allowed to slowly warm to room temperature. After 3h, tlc analysis [hexane/EtOAc (4: 1)] indicated complete reaction. The mixture was extracted with 1N HC1 (2X), water (1X), dried (K2CO3) and concentrated affording the crude carbamate as a solid. The solid was washed with hexane to afford the carbamate (316mg ; quant.) which was used directly without further purification. The solid carbamate was taken up in N, N-dimethylacetamide (5mL); anthranilic acid (137mg ; lmmol) and dimethylaminopyridine (pinch) were added sequentially and the resulting mixture was heated to 100° C for 2h.

The solution was then cooled to room temperature and treated with 1N HC1 (50mL), generating a white precipitate. The solid was filtered, washed with water and dried. Purification by silica gel flash chromatography, eluting with CHCl3 followed by CHCL3/MeOH/HOAc (10: 1: 0.1) afforded the desired urea (143mg ; 400) as a white solid. 1H NMR (DMSO-d6) d 10.30 (s, 1H, exch.), 9.05 (s, 1H, exch), 8.33 (d, 1H, J = 9.0Hz), 7.93 (dd, 1H, J = 7.6-7.4 (m, 2H), 7.3-7.1 (m, 6H), 7.03 (td, 1H, J = 2.30 (s, 3H), 2.25 (s, 3H). FAB-MS: 359 [M-H].

PRO 8658 (V) A) 4- (l-naphthyl) phenylacetic acid: To a solution of 4-bromophenylacetic acid (323mg ; 1.5mmol) and tetrakis (triphenylphosphine)-palladium (0) (52mg ; 0.045mmol) in dimethoxyethane (5mL) was added 1-naphthaleneboronic acid (284mg ; 1.65mmol) followed by a 1M aqueous solution of sodium bicarbonate (4.5mL; 4.5mmol) and the resultant mixture was refluxed. After 3h, tlc analysis [hexane/EtOAc (3: 2) + 1% HOAc] indicated complete reaction. The solution was cooled to room temperature, acidified with 1N HC1 and extracted with EtOAc (3X). The combined organic solution was extracted with 1N aqueous NaOH (3X) and the aqueous extract was back-extracted once with EtOAc. The aqueous phase was then acidified with 1N HC1 and extracted with EtOAc (3X). The combined organic extracts were then dried (MgSO4) and concentrated under reduced pressure affording a yellow oil. The oil was taken up in a mixture of hexane/EtOAc (3: 2) and passed through a plug of silica gel, then further eluted with hexane/EtOAc/HOAc (75: 50: 0.25). Concentration of the combined eluents afforded the desired biaryl acetic acid (343mg; 87%) as a light yellow foam. 1H NMR (CDCl3) d 8.0-7.8 (m, 3H), 7.6-7.4 (m, 8H), 3.78 (s, 2H).

B) 4- (l-naphthyl) phenylacetyl anthranilamide (PRO 8568): A solution of 4- (l-naphthyl) phenylacetic acid (340mg; 1.3mmol), thionyl chloride (300mL) and toluene (5mL) was refluxed for 2.5h, at which time IR analysis indicated complete conversion to the acid chloride (1798cm~1). The solution was then concentrated under vacuum to afford the crude acid chloride as a straw-colored syrup. This

residue was taken up in acetonitrile (5mL), anthranilic acid (162mg; 1.18mmol) was added and the mixture was refluxed for 2h, then kept warm overnight. The solution was cooled in an ice bath, and the resulting precipitate was then filtered, washed with cold acetonitrile and dried, affording the pure amide product (368mg ; 82%) as an off-white solid. 1H NMR (DMSO-d6) d 11.23 (s, lH, exch.), 8.52 (d, lH. J= 8.6Hz), 8.1-7.9 (m, 3H), 7.82 (br. d, 1H, J = 8.0 Hz), 7.7-7.4 (m, 9H), 7.16 (br. t, 1H, J = 8.0Hz), 3.88 (s, 2H). FAB-MS: 380 [M-H].

3-Biphenyl carbonyl amino-2-thiophene carboxylic acid (VI) 370 mg of methyl 3-amino-2-thiophene carboxylate in 3 ml of Pyridine was added cat. amount of DMAP followed by 765 mg of biphenyl carbonyl chloride. After stirring at room temp. for 18 hours, the mixture was concentrated down to dryness. The residue was dissolved in CH2Cl2 and washed with 1N HC1 followed by sat. NaHCO3 then brine.

The organic phase was then dried over MgSO4 and concentrated to dryness under vacuum. 500 mg of the resulting materiel was dissolved in 15 ml of mixture solvent of MeOH: H20 : THF (1: 1: 1). The mixture was added 50 mg of KOH and heated to 55C for 3 hours. After cooling down to room temp, the mixture was adjusted to pH=1, extracted with CH2Cl2. The organic phase was concentrated under vacuum to give the essentially pure title compound as a solid. The total yield for two steps was 78%. 1H-NMR (CDCl3): 7.40-7.55 (3H, m), 7.70 (2H, brd, J=8.20), 7.90 (2H, d, J=10.0), 7.93 (1H, d, J=6.27), 8.10 (2H, d, J=10.0), 8.15 (1H, d, J=6.27).

FAB-MS: (M-H)-=322

4-hydroxy-2-oxo-2,5-dihydro-furan-3-carboxylic acid-4-trifluoromethylthiophenylamide (VII) <BR> <BR> <BR> <BR> <BR> <BR> <BR> Tetronic acid (1.00 g, 10 mmoles), triethylamine ( 1.01 g, 10 mmoles), and DMAP (1.22 g, 10 mmoles) in anhydrous chloroform (30 ml) was stirred at room temperature for 30 minutes.

Trifluoromethylthiophenyl isocyanate (2.20 g, 10.05 mmoles) was dropwise added over 20 minutes. The solution was continuously stirred at room temperature for 48 hours. Ice-chilled 1N HC1 aqueous solution (30 ml) was added. The mixture was extracted with solution of EtOAc: MeOH (19 : 1, 500 ml) and washed with 2N HC1 solution for four times (200 ml each). The organic layer then was dried with anhydrous Na2SO4, filtered. Solvent was removed from the filtrate in vacuo. The residue was subject to silica gel flash column purification, with elution by EtOAc: AcOH (99.5 : 0.5 to 98.5 : 1.5). 690 mg of the product was given from the pure fraction. 1H-NMR (DMSO-d6): 7.73 (d, 2H), 7.57 (d, 2H), 4.26 (s, 2H); MS (FAB-): m/z 318 (M-H+ ).

Example 2-Biological Data The compounds of the present invention were tested by an enzyme assay, an MLR assay and an in vivo GvH model according to a modification of procedures disclosed in Copeland et al., Arch. Biochem. Biophys.

323: 79-86 (1995), Colligan et al., Current Protocils in Immunology 1994,1 and Ford et al., Transplantation 10: 258. The entire teachings of these references are incorporated herein by reference. The results are reported in the Table. id IMOLSTRUCTURE F enz ic50 Imir ic50 in vivo , : 7749 14 nom 12 uM : i !' .- ! 7750vS160 nM i 9 uM I m . w i i I 7831 < 5 nM l 8 uM ° ì i i i 7851 15 nM 3 uM 785 1 lazzi i i j i'ED50-80 mg/kg 7854 C, ., 30 nM 3 uM i p. o. in GvH I p. c. in GvH I ; i i 7871 50 nM 13 uM Y' I i inactive n. a. 8537 I.,. , 8538 o I 140 nM 18 uM 15. i8 G Hkg i _ i i 8539 S < 37 nM 13 uM.0, !Ymg/kgp. o. in GvH ; a 04 8634 @ inactive 4 X | ° , - i .ia.. 8637 1. 2 uM 17 um _ _ wu 6^00" 1, 00 8651'. 7 nM 6 um 0 me/kg p. c. in GvH _ I r x 86-52 150 nM 31 uM i ! v i 1. < 1 1. 6 nM 0.48 uM 1 i ; i 'I !-X'" 8889 7 nM 0.36 uM i ' I ; i 5.5 nM 11 uM 11 um 8677 i o "°r I 8679 La67s ---------- '°, r° jP 0 r ! 8680 I","Y ; i i i s6al i C, ÇYe I I id jMOLSTRUCTURE i enz icãO (uM) mir ic50 (uM) in vivo 7371 ' ED50-40 mpk p. o. 0. 019 U. 1 14 GvH ' 7708.' ! . 0.14 0.52 7809'r" 7708+1 o>"so 0. 14 0. 52 7809 t H : t 3. 6 x _/\4 3.6 X I 78101 1. 6 10 7346 : 3. 4 78471 Y,, i 78471 fy 0. 058 1.6 I 0. 82 z 0.82 11 i 0 78559 0. 82|1 18507 j 0>, 0- 0.02 0.46 EDãO 20-40 mpk p. o. GvH 0. ., 0. 043 2 8609 ! , : ?-c a. 19%) @80mpk p. o. GvH I i 8 6 1 0 » M 0 0 9 1. 1 %, I 80 1 o. :, >do' v ici. MOL_ ñUCTURE enz ic_O (uM) mir icãO (uM) in vivo 774ãt_|0. 51 | 2 9ji \0. 5 ãj > co7745-' 74"1. 5 51 29 z 7709 zou . 7-174 77751 "0 /O/ 0. 51 2 4 0 z f) T1751 0. 49 24 "0 7776 2. 6 15 7780 . 8. 8 36 7806 G 1. 2 2 5 ,. 7807- ; - . 7808 i 1 B 1 1 1 l l i -^. ^-0. 4 q 2 0. 48 7gaa /P1, w.- s 02_A7AaMt t3í3-i7853 0.() 13 1 2 i po GvH 7875a 7875 0.012 4 L 7895 w 0.011 zozo r i 8002; "; 8002012 I., I i lie I i 0. 049 4 I i 8004: QYO' 0. 16 I 3, 25% 80 mpk 0.16 3 .. po po GvH 8005i 805i',; 38% @ 80 mpk 0. 07 5 ! 85301 qe i, ! 0.0. 11 17.2 j ; r I 8531'o !- I 'TYI 0. 0014 5. 9 ° @80mpkpo n 8532 0,-w 1. 3 x N y w 19 1 iL8533 : :-- . k W 84a Y. = g54ga* 2. 26 8547 e 0. 57 20 N C d 8565 °"j o i x i 8500 °q> ~ I,', I 0. 003 4. 8 i- < 0. 009 2.6 i ! 8601ooH i i i a'I 0. 007 16. S i 8608' 0.89 1. 6 i 3. 1 0.003 8627 0. 002 8628 0. 016 4 '86281 0-r : I 0. 016 4 I 8629jj t »-l Fm 0. 062 2 0% @40mpkpc . 8630 Y-^ I i 'Y'0025 4 @''00mpk po GvH 8633 8633v--'* po Gvh 8642 24°, a 100 mpk 0.031 2 po GvH OS °, o G Su mek ;. c 0 '" o 1 17 " : y z 868 a nez I 86531 0. 214 33 \H I i 8654i oyoH I I 865a4CzOH, 9eNtOJSO. O 05 5 | 1 4214 330. 86541 8655-°' 86551 0.344 27 Iy 8656, oyat \ 086 18 I aS8657 ; F 0.024 14 f id MOLSTRUCTURE i enz ic50 (uMt | mir icãO (uM) in vivo 5462 c, 5462 N, ru o 7 HO 0. 034 0. 034 j g , I 7856, cH,, o I I 0. 018 2 I F : 7857 KO 0. 016 1. 5 l9 mpk p. o. GvH ' 7894'. j i 0. 022 I >fi0 a 7904 0. 001 29% I C 80 0. 052 ^'i mpk p. o. GvH 7907 I inactive n. t. i I 80060 c., cH, t. 4 7 a if eoos inactive n. t. a 8009 0. 17 11 xi 8010 0 or. N N 0.; 0. 052 801o. Gvh 8011 cy' 0. 013 g J 0'' 8509 i o aH __ _ __. i N N a 0. 01 1 7. 4'12% I C 100 0. ° o. Gvh 3570! o" 8570 ! 0. 04 2 0 8571 I W 8571 i o oH I ; i 'I o; I y \ I 0.016; 1 4 8572 0. 011 4. 3 85731 i 8573 0. 001 0. 2 8585 06 y 8585: o or, 0. 01 15 /0/Br i 8586 0 0. 005 d.9 0/o I Q 100 w8580< t0. 005 0 5g | °%| @100mpk mpk p. o. Gvh ! 8587 0 0-*% inact u 8602°t N i noi7 8603 0. 217 I 8603 intact 0 ' ° 8604 a CH y inact "ale 0 8605 , W Y 0. 0014 8606 ; i j HS i i j' ssfl7; - I inact 0 8617'o C*4 t 09 9 0. 057 3. 4 8618, ou, « I 1 @ 80 3 ; fi | mpk p. o. Gvh i 8619)i OCM 00 0.77 >60 8638'rvaq 0.038 0. 16 8644 ; as4a. W,, I o I Q. 001 0.018 8645' 0. 3 5 xi ° 0. 3 5 I 8050 061 5 8659. sus p. ! i 18°, o I Q 80 i ! 18% f@30 i 8607^ 0.3 0. 009 \ 4. Amices i 85, 1 09e0H 0.016 14 'I'C 'ut 8614i CHI I F i | 0. 13 1 13 I I 8615i Ci 0. 17 14 I I as35 o 0.021 23 o w I I I 8636 ! ooH ) 019 17% 1 @ 100 16 mpk p. o. Gvh i o i i 8658 ! 8658. « ' " I I o 0.034 n I mpk p. o. Gvh I id MOLSTRUCTURE í enz ic50 (uM)'rnir ic50 (uM) in vivo . \, 7832 0.9 21 c/o @ 20 mpk p. o. GvH t !- 7849 < O. 5 5 2 1 C, « . 7852 0. 82 51 - 7862 0.53 27 . . _ j's 7882 0. 53 31 "0 MMOLSTRUCTUREenz ic50 (uM) ! mtr ic50 (uM) invivo i OH , 15 >35 6789 F 35 also i i 3 2 \ | am i ° 67901 ! = jCkl J" O. a9 1 6 77231 7723 II \ a __ 7722 5 49 j o 0 cl 6%% I Q 80 mpk p. o. GvH a 7763 oui' 78341 0.11 is vs lift7 /l _-_ _ 0. 3'I 33 0, 7834, ^ _- 0. 25 27 7850 0. 71 7870 0. 7i r 787C ',, 0. 14 3 0 , r h a 78960.6 7 I du 7898' / 0. 18 2 0. 18 0 7899 " 2 I >60 °

EQUIVALENTS While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the claims.