Claims
- 1. A compound according to formula (I),
- 2. A compound according to claim 1, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein:
G is a bond; Ar is an aryl or heteroaryl substituted with one to three R1; R1 is selected from alkyl, substituted alkyl, halogen, cyano, nitro, OR10, NR10R11, C(═O)R10, CO2R10, C(═O)NR10R11, NR10C(═O)R11, NR10C(═O)OR11, SR10, S(O)oR10a, NR10SO2R10a, NHCH(alkyl)CO2R10, SO2NR10R11, cycloalkyl, heterocyclo, aryl, and heteroaryl; R10 and R11 (i) are selected independently of each other from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo; or (ii) R10 is taken together with R11 to form a heteroaryl or heterocyclo; R10a is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo; and o is 1 or 2.
- 3. A compound according to claim 1, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
J is selected from —O—, —S—, —S(═O)—, —SO2—, or —NHSO2—; or J is C1-3alkylene, C2-3alkenylene, or C1-2 heteroalkylene optionally substituted with one to two R9; R9 is -A1-Q-A2-R16; A1 is a bond, C1-2alkylene, or C2-3alkenylene; Q is a bond, —C(═O)—, —C(═O)NR17—, —C(═S)NR17—, —SO2—, —SO2NR17-, —CO2—, or —NR17CO2—; A2 is a bond, C1-3alkylene, C2-3alkenylene, —C1-4alkylene-NR17—, —C1-4alkylene-NR17C(═O)—, —C1-4alkylene-S—, —C1-4alkylene-SO2—, or —C1-4alkylene-O—, wherein said A2 alkylene groups are branched or straight chain and optionally substituted with a group selected from —CO2H, —CO2(C1-4alkyl), —S(C1-4alkyl), NH2, —NH(C1-4alkyl), or —N(C1-4alkyl)2; R16 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo; and R17 is hydrogen or alkyl.
- 4. A compound according to claim 3, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
R16 is selected from cycloalkyl, heterocyclo, aryl or heteroaryl optionally substituted with one to three R18; R18 is selected from C1-6alkyl, substituted C1-6alkyl, halogen, cyano, nitro, OR20, NR20R21, C(═O)R20, CO2R20, C(═O)NR20R21, C(═O)NR20SO2R20a, NR20C(═O)R21, NR20C(═O)OR21, SR20, S(O)uR20a, NR20SO2R20a, NHCH(alkyl)CO2R20, SO2NR20R21, C3-7cycloalkyl, phenyl, four to seven membered heterocyclo, or five or six membered heteroaryl, said C3-7cycloalkyl, phenyl, four to seven membered heterocyclo, or five or six membered heteroaryl groups in turn being optionally substituted with one to two R22; R20 and R21 are selected from hydrogen, alkyl, alkenyl, C3-7cycloalkyl, phenyl, benzyl, phenylethyl, napthyl, a four to seven membered heterocylo, or a five to six membered heteroaryl, or when attached to the same nitrogen atom may join to form a heterocyclo or heteroaryl; wherein each of R20 and R21 in turn is optionally substituted with one to two R22; R20a is selected from hydrogen, alkyl, alkenyl, CO2H, CO2(alkyl), C3-7cycloalkyl, phenyl, benzyl, phenylethyl, napthyl, a four to seven membered heterocyclo, or a five to six membered heteroaryl; wherein each R20a in turn is optionally substituted with one to two R22; and R22 is selected from the group consisting of (C1-4)alkyl, (C2-4)alkenyl, hydroxy, cyano, CF3, O(C1-4alkyl), OCF3, C(═O)H, C(═O)(C1-4alkyl), CO2H, CO2(C1-4alkyl), NHCO2(C1-4alkyl), —S(C1-4alkyl), —NH2, —NH(C1-4alkyl), N(C1-4alkyl)2, N(CH3)3+, SO2(C1-4alkyl), C(═O)(C1-4alkylene)NH2, C(═O)(C1-4alkylene)NH(alkyl), and C(═O)(C1-4alkylene)N(C1-4alkyl)2.
- 5. A compound according to claim 4, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
Ar is 397T1 and M1 are selected from —N— and —CH—, and T2 and M2 are selected from O, S, NH, S(═O), SO2, NHSO2, —C(═O)— and —CH2—; J is a —C2-3alkylene optionally substituted with one to two R9, —(CH2)y—NH—, or —(CH2)y—NR9—; R1a and R1b are independently selected from halogen, C1-4alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO2H, —C(═O)H, —CO2alkyl, —C(═O)alkyl, —C(═O)NH(CH2)1-4CO2H, —C(═O)NH(CH2)1-4CO2(alkyl), and S(O)2alkyl; or from phenyl, benzyl, phenyloxy, benzyloxy and heteroaryl in turn optionally substituted with halogen, C1-4alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO2H, —C(═O)H, —CO2alkyl, and/or —C(═O)alkyl; or alternatively, two R1b groups join together with each other or one R1b joins together with R1a to form a fused benzo ring; R4a and R4c are selected from halogen, alkyl, cyano, haloalkyl, haloalkoxy, nitro, aryloxy, and arylthio; R4b is hydrogen, halogen, alkyl, substituted alkyl, nitro, cyano, hydroxy, alkoxy, haloalkoxy, phenyloxy, —CO2H, —C(═O)H, —NH(alkyl), —N(alkyl)2, —CO2alkyl, —C(═O)alkyl, alkylthio, —C(═O)NH(CH2)1-4CO2H, —C(═O)NH(CH2)1-4CO2(alkyl), aryl, heteroaryl, or heterocyclo, wherein each of the aryl, heteroaryl, and heterocyclo groups are optionally substituted with one to two halogen, C1-4alkyl, OMe, CF3, CN, OCF3, CO2H, C(═O)H, CO2alkyl, and/or C(═O)alkyl; n is 0, 1, or 2; and y is 0, 1 or 2.
- 6. A compound according to claim 1, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, having the formula:
- 7. A compound according to claim 6, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which R1a is halogen or cyano, and R4a and R4c are independently selected from halogen, alkyl, cyano, trifluoromethyl, and nitro.
- 8. A compound according to claim 3, having the formula (Ie),
- 9. A compound according to claim 8, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
R1a is halogen, cyano, nitro, trifluoromethyl, OCF3, aryl or heteroaryl; R1b is halogen, C1-4alkyl, cyano, nitro, —CO2H, —C(═O)H, —CO2alkyl, or —C(═O)alkyl; R2 is hydrogen, C1-6alkyl, or C1-6alkyl substituted with CO2H or CO2(C1-4alkyl); R9 is selected from hydrogen, C1-10alkyl, substituted C1-10alkyl, C2-10alkenyl, substituted C2-10alkenyl, C3-6cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, —(CH2)sphenyl, —(CH2)stetrazolyl, —(CH2)spyridyl, —(CH2)sthienyl, —(CH2)scarbazolyl, —(CH2)sindolyl, —(CH2)sfuryl, —(CH2)squinolyl, —(CH2)sC3-6cycloalkyl, —(CH2)sthiazolyl, —(CH2)spyrrolyl, —(CH2)simidazolyl, —(CH2)sisoxazolyl, —(CH2)sbenzofuryl, —(CH2)spyrazolyl, —C(═O)H, —C(═O)(alkyl), —C(═O)C1-10alkyl, —C(═O)phenyl, —C(═O)piperidyl, —C(═O)morpholinyl, —C(═O)C3-6cycloalkyl, —C(═O)pyrrolidinyl, —C(═O)quinolyl, —C(═O)imidazolyl, —C(═O)pyrazolyl, —C(═O)thiazolyl, —C(═O)quinoxalinyl, —C(═O)pyridyl, —C(═O)-1,2,5,6-tetrahydropyridyl, —C(═O)benzothiazolyl, —C(═O)benzotriazolyl, —C(═O)benzodioxanyl, —C(═O)benzooxadiazolyl, —C(═O)1,2,3,4-tetrahydroquinolyl, —C(═O)thienopyrazolyl, —C(═O)(CH2)stetrazolyl, —C(═O)(CH2)spyridyl, —C(═O)(CH2)sphenyl, —C(═O)(CH2)spyrrolidinyl, —C(═O)(CH2)spiperidyl, —C(═O)CH═CH(phenyl), —C(═O)CH═CH(pyridyl), —C(═O)CH2O(alkyl), —C(═O)CH2S(alkyl), —C(═O)CH2S(pyridyl), —C(═O)CH2SO2(alkyl), —C(═O)CH2SO2(phenyl), —C(═O)CH2NH(phenyl), —C(═O)CH2NH(benzyl), —C(═O)CH2NH(thiazolyl), —C(═O)CH2NHC(═O)pyridyl, —C(═O)CH2NHC(═O)phenyl, —(CH2)tSO2(alkyl), —(CH2)tSO2(phenyl), —(CH2)tSO2(thienyl), —(CH2)tSO2(imidazolyl), —(CH2)tSO2(furyl), (CH2)tSO2(pyrrolyl), SO2NH(phenyl), —C(═S)NH2, —C(═S)NH(alkyl), —C(═S)NH(phenyl), —(CH2)C(═O)pyrrolidinyl, —(CH2)C(═O)piperidyl, —(CH2)C(═O)piperazinyl, —CO2(alkyl), —CO2(phenyl), —CO2(benzyl), NHCO2(alkyl), —(CH2)tC(═O)NH(phenyl), —(CH2)tC(═O)NH(piperidyl), —(CH2)tC(═O)NH(thienyl), —(CH2)tC(═O)NH(thiazolyl), —(CH2)tC(═O)NH(cyclopentyl), —(CH2)tC(═O)NH(cyclopentenyl), —(CH2)tC(═O)NH(benzyl), —(CH2)tC(═O)NH(pyrrolidinyl), —(CH2)tC(═O)NH(piperazinyl), —(CH2)tC(═O)NH2, —(CH2)tC(═O)NH(alkyl), —(CH2)tC(═O)N(alkyl)2, —(CH2)tC(═O)N(C1-4alkyl)(phenyl), —(CH2)tC(═O)N(C1-4alkyl)(thienyl), —(CH2)tC(═O)N(C1-4alkyl) (thiazolyl), —(CH2)tC(═O)N(C1-4alkyl)(benzyl), —(CH2)tC(═O)N(C1-4alkyl)CO2(alkyl), wherein each R9 is optionally substituted with one to two R18; R18 is selected from —(CH2)qhalogen, —(CH2)qnitro, —(CH2)qcyano, —(CH2)qhaloalkyl, —(CH2)qhaloalkoxy, —(CH2)qSR24, C3-7cycloalkyl, —SO2R24, —OR24, —(CH2)qCO2R24, —(CH2)qNR24R25, —(CH2)qNHCO2R24, —C(═O)NH—SO2R24, —C(═O)(CH2)qNR24R25, —O(CH2)rNR24R25, —C(═O)R24, —(CH2)qR24 and —C1-4alkyl or —C2-4alkenyl optionally substituted with CO2R24; R24 is selected from hydrogen, alkyl, phenyl, benzyl, C3-7cycloalkyl, five or six membered heteroaryl, and four to seven membered heterocyclo, in turn optionally substituted with one to two C1-4alkyl, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, —CO2H, CO2C1-4alkyl, C1-4alkoxy, —S(C1-4alkyl), amino, and/or aminoC1-4alkyl, provided that when R24 is attached to a sulfonyl group as in —SO2R24, then R24 is not hydrogen; R25 is selected from hydrogen and alkyl; and n is 0, 1, or 2; p is 1 or 2; q is 0, 1, 2, 3, or 4; r is 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; and t is 1, 2, 3, or 4.
- 10. A compound according to claim 1, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein J is selected from:
- 11. A compound according to claim 1, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein Z is CR4b.
- 12. A compound according to claim 3, having the formula,
- 13. A compound according to claim 1, having the formula,
- 14. A compound according to claim 1, having the formula,
- 15. A compound having the formula,
- 16. A compound according to claim 15, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein R4a and R4c are chloro.
- 17. A compound according to claim 15, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein R1a is cyano or halogen.
- 18. A compound according to claim 15, having the formula,
- 19. A compound according to claim 18, or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:
R2 is selected from hydrogen, C1-6alkyl, and C1-6alkyl substituted with amino, NH(C1-4alkyl), N(alkyl)2, C(═O)H, C(═O)C1-4alkyl, CO2H, CO2(C1-4alkyl), SO2C1-4alkyl, SO3H, and/or PO(OH)2; R4a and R4b are selected from halogen, C1-4alkyl, cyano, halo C1-4alkyl, and haloC1-4alkoxy; J is —(CHR9c)x— or —(CH2)y—NR9c—; R9c is A1-Q-A2-R16; R16 is selected from (a) hydrogen and C1-6alkyl or C2-6alkenyl optionally substituted with one to two of OH, O(C1-4alkyl), —CO2H, —CO2(C1-4alkyl), NH2, —NH(C1-4alkyl), and/or N(C1-4alkyl)2, or from (b) furanyl, indolyl, carbazolyl, pyrazolyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, benzofuranyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, phenyl, piperidyl, pyrrolidinyl, pyridazinyl, C3-7cycloalkyl, piperazinyl, thiazolyl, morpholinyl, 1,2,5,6-tetrahydropyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, benzodioxanyl, benzooxadiazolyl, thienopyrazolyl, tetrahydroquinolinyl, and quinolinyl, wherein each of said cyclic R16 groups in turn is optionally substituted with up to three R18; R17 is hydrogen or alkyl; and R18 is selected from hydrogen, (C1-6)alkyl, (C2-6)alkenyl, CO2H, CO2(C1-6alkyl), C(═O)H, C(═O)(C1-6alkyl), halogen, cyano, hydroxy, (C1-4)alkoxy, (C1-4)haloalkyl, (C1-4)haloalkoxy, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, N(C1-4alkyl)3+, —C(═O)(CH2)NH2, —NHCO2(C1-4alkyl), SO2(C1-4alkyl), phenyl, C3-7cycloalkyl, five to six membered heteroaryl, and four to seven membered heterocyclo, wherein each group R18 in turn is optionally substituted with one to two of (C1-4) alkyl, (C2-4) alkenyl, CO2H, CO2(C1-4alkyl), C(═O)H, C(═O)(C1-4alkyl), halogen, cyano, hydroxy, (C1-4)alkoxy, trifluoromethyl, trifluoromethoxy, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, N(C1-4alkyl)3+, —C(═O)(CH2)NH2, —NHCO2(C1-4alkyl), and/or SO2(C1-4alkyl).
- 20. A compound according to claim 19, having the formula,
- 21. A compound according to claim 19, having the formula,
- 22. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.
- 23. A pharmaceutical composition comprising at least one compound according to claim 15 and a pharmaceutically acceptable carrier or diluent.
- 24. A method of inhibiting an LFA-1/ICAM-associated condition in a mammal comprising administering to the mammal a therapeutically-effective amount of a compound according to claim 1.
- 25. The method of claim 24 in which LFA-1/ICAM-associated condition is selected from acute or chronic graft vs host reactions, acute or chronic transplant rejection, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, osteoporosis, diabetes, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, Alzheimer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatis, multiple organ injury syndrome, myocardial infarction, atherosclerosis, stroke, reperfusion injury, acute glomerulonephritis, vasculitis, thermal injury, necrotizing enterocolitis, granulocyte transfusion associated syndrome, Sjogren's syndrome, eczema, atopic dermatitis, contact dermatitis, urticaria, schleroderma, psoriasis, asthma, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), hepatitis B, hepatitis C, organ-tissue autoimmune disease, autoimmune thyroiditis, uveitis, systemic lupus erythematosis, Addison's disease, autoimmune polyglandular disease, and Grave's disease.
- 26. A method of treating an inflammatory or immune disease in a mammal animal comprising administering to the mammal in need of such treatment a therapeutically-effective amount of a pharmaceutical composition according to claim 22.
- 27. The method of claim 26 in which the inflammatory or immune disease is selected from acute or chronic transplant rejection, rheumatoid arthritis, osteoarthritis, diabetes, asthma, inflammatory bowel disease, and chronic obstructive pulmonary disease.
- 28. An intermediate useful for preparing a compound having therapeutic activity, the intermediate having the formula:
- 29. The intermediate according to claim 28, selected from one of:
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 60/326,361, filed Oct. 1, 2001, U.S. Provisional Application No. 60/354,113, filed Feb. 4, 2002, and U.S. Provisional Application No. 60/400,259, filed Aug. 1, 2002, each of which is incorporated herein by reference.
Provisional Applications (3)
|
Number |
Date |
Country |
|
60326361 |
Oct 2001 |
US |
|
60354113 |
Feb 2002 |
US |
|
60400259 |
Aug 2002 |
US |