Claims
- 1. A modulator of the formula (I) or a salt thereof:
- 2. The modulator of claim 1, where L is —CO—.
- 3. The modulator of claim 2, where X represents from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —OH, —OR1, —C(O)R1, —CO2R1, —O(CO)R1, —OC(O)NR1R2, —SR1, —SOR1, —SO2R1, —NR1R2, —NR1C(O)R2, —NR1C(O)2R2, —NR1(CO)NR1R2, unsubstituted C2-8 alkyl, substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted C3-8 cycloalkyl, unsubstituted or substituted 6- to 10-membered aryl, unsubstituted or substituted 5- or 6-membered heteroaryl, or unsubstituted or substituted 3- to 7-membered heterocyclyl.
- 4. The modulator of claim 2, where at least one X substituent is situated para to the sulfonamido bond as defined in formula (I).
- 5. The modulator of claim 2, where at least one X substituent is situated meta to the sulfonamido bond as defined in formula (I).
- 6. The modulator of claim 2, where at least one X substituent is situated ortho to the sulfonamido bond as defined in formula (I).
- 7. The modulator of claim 2, where at least one X is unsubstituted C2-8 alkyl, unsubstituted C3-8 cycloalkyl, unsubstituted C2-8 alkenyl, or unsubstituted C2-8 alkynyl.
- 8. The modulator of claim 2, where at least one X is substituted C1-8 alkyl, substituted C3-8 cycloalkyl, substituted C2-8 alkenyl, or substituted C2-8 alkynyl, each having from 1 to 5 substituents independently selected from the group consisting of halogen, —OH, —CN, —NO2, ═O, —OC(O)R1, —OR1, —C(O)R1, —CONR1R2, —OC(O)NR1R2, —NR2C(O)R1, —NR1C(O)NR2R3, —CO2R1, —NR1R2, —NR2CO2R1, —SR1, —SOR1, —SO2R1, —SO2NR1R2, —NR1SO2R2, unsubstitute or substituted 6- to 10-membered aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, and unsubstituted or substituted 3- to 10-membered heterocyclyl.
- 9. The modulator of claim 8, where at least one X is substituted C1-8 alkyl, having from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —CN, ═O, —OC(O)R1, —OR1, —C(O)R1, —CONR1R2, —NR2C(O)R1, —CO2R1, —NR1R2, —SO2R1, unsubstituted or substituted phenyl, and unsubstituted or substituted 5- or 6-membered heteroaryl.
- 10. The modulator of claim 2, where at least one X is unsubstituted or substituted 6- to 10-membered aryl, unsubstituted or substituted 5- to 10-membered heteroaryl, or unsubstituted or substituted 3- to 10-membered heterocyclyl, where when X is substituted is has from 1 to 4 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C1-8 alkyl, —CN, —NO2, —OH, —OR1, ═O, —OC(O)R1, —CO2R1, —C(O)R1, —CONR1R2, —OC(O)NR1R2, —NR2C(O)R1, —NR1C(O)NR2R3, —NR1R2, —NR2CO2R1, —SR1, —SOR1, —SO2R1, —SO2NR1R2, and —NR1SO2R2.
- 11. The modulator of claim 10, where at least one X is unsubstituted or substituted phenyl, where when X is substituted it has from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR1, —C(O)R1, —CONR1R2, —NR2C(O)R1, —NR1R2, —SO2R1, and unsubstituted or substituted C1-8 alkyl.
- 12. The modulator of claim 10, where at least one X is unsubstituted or substituted 3- to 7-membered heterocyclyl, where when X is substituted it has from 1 to 3 substituents independently selected from the group consisting of C1-8 alkyl, —OR1, —OH, —OC(O)R1, —CO2R1, —C(O)R1, —CONR1R2, —NR1R2, —SO2R1, and —NR1SO2R2.
- 13. The modulator of claim 10, where at least one X unsubstituted or substituted 5- or 6-membered heteroaryl, where when X is substituted it has from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR1, —C(O)R1, —CONR1R2, —NR2C(O)R1, —NR1R2, —SO2R1, and unsubstituted or substituted C1-8 alkyl.
- 14. The modulator of claim 2, where R1, R2 and R3, when substituted, can have from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR′, —OCOHNR′, —OCONR′2, —SH, —SR′, —SO2NH2, —CONH2, —NHC(O)NH2, NR′C(O)NH2, —CO2H, —CN, —NO2, —NH2, —NHR′ and —NR′2, —S(O)R′, —S(O)2R′, —CO2R′, —CONR′2, —CONHR′, —C(O)R′, —NR′COR′, —NHCOR′, —NR′CO2R′, —NHCO2R′, —CO2R′, —NR′C(O)NR′2, —NHC(O)NR′2, —NR′C(O)NHR′, —NHC(O)NHR′, —NR′SO2R′, —NHSO2R′, —SO2NR′2, and —SO2NHR′, where R′ is C1-6alkyl.
- 15. The modulator of claim 2, where Y represents from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —OR4, —C(O)R4, —SR4,—CF3, —SOR4, and —SO2R4.
- 16. The modulator of claim 15, where Y represents from 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —CF3, and —SO2R4.
- 17. The modulator of claim 15, where at least one Y represents halogen.
- 18. The modulator of claim 2, where Y represents from 1 to 2 substituents, each independently selected from the group consisting of halogen, —CN, —OH, —OR4, —C(O)R4, —CO2R4, —SR4, —SOR4, —SO2R4, and unsubstituted or substituted C1-4 alkyl.
- 19. The modulator of claim 18, where one Y represents a halogen and another substituent selected from the group consisting of halogen, —CN, —OH, —OR4, —C(O)R4, —CO2R4, —SR4, —SOR4, —SO2R4, and unsubstituted or substituted C1-4 alkyl.
- 20. The modulator of claim 18, where at least one Y substituent is located para to the sulfonamide bond as defined in formula (I) and another Y substituent is halogen.
- 21. The modulator of claim 15, where at least one Y is unsubstituted C1-4 alkyl.
- 22. The modulator of claim 15, where at least one Y is substituted C1-4 alkyl, having from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR4, —CN, —NO2, ═O, —OC(O)R4,—CO2R4, —C(O)R4, —CONR4R5, —OC(O)NR4R5, —NR4C(O)R5, —NR4C(O)NR5R6, —NR4R5, —NR4CO2R5, —SR4, —SOR4, —SO2R4, —SO2NR4R5, and —NR4SO2R5,
where R4, R5 and R6 are each independently selected from the group consisting of hydrogen, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C3-6 cycloalkyl, unsubstituted or substituted C2-6 alkenyl, and unsubstituted or substituted C2-6 alkynyl; or where any two of R4, R5 and R6 together with the atom(s) to which they are attached, may form a 5-, 6- or 7-membered ring.
- 23. The modulator of claim 22, where at least one Y is substituted C1-4 alkyl, having from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR4, —CN, —NO2, ═O, —OC(O)R4,—CO2R4, —C(O)R4, —CONR4R5, —NR4C(O)R5, —NR4R5, —NR4, —SR4, —SOR4, —SO2R4, and —NR4SO2R5.
- 24. The modulator of claim 23, where R4, R5 and R6, when substituted, can have from with from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR′, —SH, —SR′, —SO2NH2, —CONH2, 13 NHC(O)NH2, N(C1-6alkyl)C(O)NH2, —CO2H, —CN, —NO2, —NH2, —NHR′, —NR′2, —S(O)R′, —S(O)2R′, —CO2R′, —CONHR′, —CONR′2, and —C(O)R′, where R′ is C1-6alkyl.
- 25. The modulator of claim 2, where Z represents 0 to 3 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C3-8 cycloalkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted C1-8 alkoxy, ═O, —CN, —NO2, —OH, —OR7, 13 OC(O)R7, —CO2R7, —C(O)R7, —CONR7R8, —NR7C(O)R8, —NR7R8, —SR7, —SOR7, —SO2R7, —SO2NR7R8, —NR7SO2R8, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, and unsubstituted or substituted 3- to 7-membered heterocyclyl.
- 26. The modulator of claim 2, where Z represents 0 to 2 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted C1-6 alkoxy, ═O, —CN, —NO2, —OH, —OR7, —C(O)R7, —CONR7R8, —NR7C(O)R8, —NR7R8, —SR7, —SOR7, —SO2R7, —SO2NR7R8, —NR7SO2R8, unsubstituted or substituted phenyl, unsubstituted or substituted 3 to 7-membered heterocycyl, and unsubstituted or substituted 5- or 6-membered heteroaryl.
- 27. The modulator of claim 25, where at least one Z is unsubstituted C1-8 alkyl, unsubstituted C3-8 cycloalkyl, unsubstituted C2-8 alkenyl, unsubstituted C2-8 alkynyl or unsubstituted C1-8 alkoxy, unsubstituted 6- to 10-membered aryl, unsubstituted 3- to 7-membered heterocyclyl, and 3- to 7-membered heteraryl.
- 28. The modulator of claim 25, where at least one Z is substituted C1-8 alkyl, substituted C3-8 cycloalkyl, substituted C2-8 alkenyl, substituted C2-8 alkynyl or substituted C1-8 alkoxy, each having from 1 to 5 substituents independently selected from the group consisting of halogen, —OH, —OR7, —CN, —NO2, ═O, —CN, —NO2, —OC(O)R7, —CO2R7, —C(O)R7, —CONR7R8, —OC(O)NR7R8, —NR7C(O)R8, —NR7C(O)NR8R9, —NR7R8, —NR7CO2R8, —SR7, —SOR7, —SO2R7, —SO2NR7R8, —NR7SO2R8, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, or unsubstituted or substituted 3- to 6-membered heterocyclyl.
- 29. The modulator of claim 25, where each R7, R8 and R9, when substituted, can have from 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —OR′, —OCONHR′, —OCONR′2, —SH, —SR′, —CN, —SO2NH2, —CONH2, —NHC(O)NH2, —NR′C(O)NH2, —CO2H, —NO2, —NH2, —NHR′ and —NR′2, —S(O)R′, —S(O)2R′, —CO2R′, —CONR′2, —CONHR′, —C(O)R′, —NR′COR′, —NHCOR′, —NR′CO2R′, —NHCO2R′, —CO2R′, —NR′C(O)NR′2, —NHC(O)NR′2, —NR′C(O)NHR′, —NHC(O)NHR′, —NR′SO2R′, —NHSO2R′, —SO2NR′2, and —SO2NHR′, where R′ is C1-6alkyl.
- 30. The modulator of claim 3, where Y represents from 1 to 3 substituents, each independently selected from the group consisting of halogen, —CN, —OH, —OR4, —C(O)R4, —CO2R4, —SR4, —SOR4, —SO2R4, and unsubstituted or substituted C1-4 alkyl.
- 31. The modulator of claim 30, where at least one Y is halogen.
- 32. The modulator of claim 25, where Y represents from 1 to 3 substituents, each independently selected from the group consisting of halogen, —CN, —OH, —OR4, —C(O)R4, —CO2R4, —SR4, —SOR4, —SO2R4, and unsubstituted or substituted C1-4 alkyl.
- 33. The modulator of claim 32, where at least one Y is halogen.
- 34. The modulator of claim 15, where Z represents 0 to 3 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C3-8 cycloalkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted C1-8 alkoxy, ═O, —CN, —NO2, —OH, —OR7, —OC(O)R7, —CO2R7, —C(O)R7, —CONR7R8, —NR7C(O)R8, —NR7R8, —SR7, —SOR7, —SO2R7, —SO2NR7R8, —NR7SO2R8, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, and unsubstituted or substituted 3- to 7-membered heterocyclyl.
- 35. The modulator of claim 34, where X is unsubstituted C2-8 alkyl or substituted C1-8 alkyl.
- 36. The modulator of claim 34, where at least one Y is halogen.
- 37. The modulator of claim 30, where Z represents 0 to 3 substituents independently selected from the group consisting of halogen, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C3-8 cycloalkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted C1-8 alkoxy, ═O, —CN, —NO2, —OH, —OR7, —OC(O)R7, —CO2R7, —C(O)R7, —CONR7R8, —NR7C(O)R8, —NR7R8, —SR7, —SOR7, —SO2R7, —SO2NR7R8, —NR7SO2R8, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, and unsubstituted or substituted 3- to 7-membered heterocyclyl.
- 38. The modulator of claim 37, where X is unsubstituted C2-8 alkyl or substituted C1-8 alkyl.
- 39. The modulator of claim 37, where at least one Y is halogen.
- 40. The modulator of claim 1, which has activity in a chemotaxis assay of <10000 nM.
- 41. The modulator of claim 1, which has activity in a chemotaxis assay of <1000 nM.
- 42. The modulator of claim 1, which has activity in a chemotaxis assay of <100 nM.
- 43. The modulator of claim 1, which has activity in a CCR9 chemotaxis assay of <10000 nM.
- 44. The modulator of claim 1, which has activity in a CCR9 chemotaxis assay of <1000 nM.
- 45. The modulator of claim 1, which has activity in a CCR9 chemotaxis assay of <100 nM.
- 46. A modulator of one of the formulae (II) or (III) or a salt thereof:
- 47. The modulator of claim 46, where X′ and X″ are each independently selected from the group consisting of hydrogen, halogen, —CN, —OR1, —C(O)R1, —SO2R1, —NR1R2, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C3-8 cycloalkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted phenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted 5- or 6-membered heterocyclyl, with the proviso that if one of X′ and X″ is hydrogen than the other is not hydrogen or unsubstituted methyl.
- 48. The modulator of claim 46, where X′ and X″ are each independently selected from the group consisting of hydrogen, halogen, —CN, —CF3, —CH═CH2, isoamyl, phenylacetylene, t-butyl, ethyl (Et), i-propyl (iPr), —C(CH3)2CH2CH3, hydroxybutyl, —C(CH3)2CH2CH2OH, —CH2CH2CO2Me, —OCF3, —OMe, —O-iPr, —C(O)Me, —SO2Me, phenyl (Ph), —OEt, pyrazole, thiophene, aminopyridine, oxazole, and morpholinyl, with the proviso that X′ and X″ cannot both be hydrogen simultaneously.
- 49. The modulator of claim 46, where Y′ and Y″ are each independently hydrogen or halogen, with the proviso that one or both are halogen.
- 50. The modulator of claim 46, where Y′ is hydrogen and Y″ is chloro or bromo.
- 51. The modulator of claim 46, where at least one of Y′ or Y″ is a halogen atom and is ortho to the sulfonamide bond in formula (I).
- 52. The modulator of claim 46, where at least one of Y′ or Y″ is a halogen atom and is meta to the sulfonamide bond in formula (I).
- 53. The modulator of claim 46, where at least one of Y′ or Y″ is a halogen atom and is para to the sulfonamide bond in formula (I).
- 54. The modulator of claim 46, where Z′ and Z″ are each independently selected from the group consisting of hydrogen, halogen, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C3-8 cycloalkyl, —CN, —OH, —OR7, —C(O)R7, —CO2R7, —OC(O)R7, —CONR7R8, —NR7R8, —NR7CO2R8, SR7, —SOR7, —SO2R7, —NR7SO2R8, —SO2NR7R8, unsubstituted or substituted phenyl, and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted 3- to 7-membered heterocycyl.
- 55. The modulator of claim 46, where Z′ and Z″ are each independently hydrogen, halogen, —CN, —OR7, —NR7R8, —SR7, —SOR7, and —SO2R7, unsubstituted or substituted C16 alkoxyl, unsubstituted or substituted C1-6 alkyl, unsubstituted or substituted phenyl, or unsubstituted or substituted 5- or 6-membered heterocyclyl.
- 56. The modulator of claim 47, where Y′ and Y″ are each independently hydrogen or halogen, with the proviso that one or both are halogen.
- 57. The modulator of claim 47, where Z′ and Z″ are each independently selected from the group consisting of hydrogen, halogen, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C3-8 cycloalkyl, —CN, —OH, —OR7, —C(O)R7, —CO2R7, —OC(O)R7, —CONR7R8, —NR7R8, —NR7CO2R8, —SR7, —SOR7, —SO2R7, —NR7SO2R8, —SO2NR7R8, unsubstituted or substituted phenyl, and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted 3- to 7-membered heterocycyl.
- 58. The modulator of claim 49, where Z′ and Z″ are each independently selected from the group consisting of hydrogen, halogen, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C1-8 cycloalkyl, —CN, —OH, —OR7, —C(O)R7, —CO2R7, —OC(O)R7, —CONR7R8, —NR7R8, —NR7CO2R8, SR7, —SOR7, —SO2R7, —NR7SO2R8, unsubstituted or substituted 6- to 10-membered aryl, and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted 3- to 7-membered heterocycyl.
- 59. The modulator of claim 56, where Z′ and Z″ are each independently selected from the group consisting of hydrogen, halogen, unsubstituted or substituted C1-8 alkyl, unsubstituted or substituted C3-8 cycloalkyl, —CN, —OH, —OR7, —C(O)R7, —CO2R7, —OC(O)R7, —CONR7R8, —NR7R8, —NR7CO2R8, —SR7, —SOR7, —SO2R7, —NR7SO2R8, —SO2NR7R8, unsubstituted or substituted phenyl, and unsubstituted or substituted 5- or 6-membered heteroaryl, unsubstituted or substituted 3- to 7-membered heterocycyl.
- 60. A composition comprising a pharmaceutically acceptable carrier and a compound of claim 2.
- 61. A method for treating a CCR9-mediated condition or disease comprising administering to a subject a safe and effective amount of The modulator of claim 2.
- 62. The method of claim 61, where the CCR9-mediated disease or condition is an inflammatory condition, an immunoregulatory disorder.
- 63. The method of claim 61, where the CCR9-mediated disease or condition is inflammatory bowel disease, an allergic disease, psoriasis, atopic dermatitis, asthma, fibrotic diseases, graft rejection, immune mediated food allergies, autoimmune diseases, Celiac disease, rheumatoid arthritis, thymoma, thymic carcinoma, leukemia, solid tumor, or acute lymphocytic leukemia.
- 64. The method of claim 61, further comprising administering an anti-inflammatory or analgesic agent.
- 65. The method of claim 61, where the administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.
- 66. The method of claim 61, where the compound is administered in combination with an anti-inflammatory or analgesic agent.
- 67. A method of modulating CCR9 function in a cell, comprising contacting the cell with a CCR9 modulating amount of the modulator of claim 2.
RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional application Serial No. 60/427,670 filed Nov. 18, 2002. The disclosure of the priority application is incorporated by reference herein in its entirety.
Provisional Applications (1)
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Number |
Date |
Country |
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60427670 |
Nov 2002 |
US |