Claims for Patent: 7,745,460

Summary for Patent: 7,745,460

Title:	Modulators of cellular adhesion
Abstract:	The present invention provides compounds having formula (I): and pharmaceutically acceptable derivatives thereof, wherein R1-R4, n, p, A, B, D, E, L and AR1 are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of disorders mediated by the CD11/CD18 family of cellular adhesion molecules (e.g., LFA-1).
Inventor(s):	Wang Shen, Kenneth Barr, Johan D. Oslob, Min Zhong
Assignee:	Bausch and Lomb Ireland Ltd
Application Number:	US11/978,388
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,745,460
Patent Claims:	1. A compound of the structure (I): or pharmaceutically acceptable salts thereof; R1 and R2 are each independently hydrogen, —(CH2)mOH, —(CH2)maryl, —(CH2)mheteroaryl, wherein m is 0-6, —CH(R1A)(OR1B), —CH(R1A)(NHR1B), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q, wherein U is absent, —O—, —S(O)0-2—, —SO2N(R1A), —N(R1A)—, —N(R1A)C(═O)—, —N(R1A)C(═O)—O—, —N(R1A)C(═O)—N(R1B)—, —N(R1A)—SO2—, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R1A)—, —OC(═O)N(R1A)—, —C(═N—R1E)—, —C(═N—R1E)—O—, —C(═N—R1E)—N(R1A)—, —O—C(═N—R1E)—N(R1A)—, —N(R1A)C(═N—R1E)—, —N(R1A)C(═N—R1E)—O—, —N(R1A)C(═N—R1E)—N(R1B)—, —P(═O)(OR1A)—O—, or —P(═O)(R1A)—O—; T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and Q is hydrogen, halogen, cyano, isocyanate, —OR1B; —SR1B; —N(R1B)2, —NHC(═O)OR1B, —NHC(═O)N(R1B)2, —NHC(═O)R1B, —NHSO2R1B, NHSO2N(R1B)2, —NHSO2NHC(═O)OR1B, —NHC(═O)NHSO2R1B, —C(═O)NHC(═O)OR1B, C(═O)NHC(═O)R1B, —C(═O)NHC(═O)N(R1B)2, —C(═O)NHSO2R1B, —C(═O)NHSO2N(R1B)2, C(═S)N(R1B)2, —SO2R1B, —SO2OR1B, —SO2N(R1B)2, —SO2—NHC(═O)OR1B, —OC(═O)—N(R1B)2, —OC(═O)R1B, —OC(═O)NHC(═O)R1B, —OC(═O)NHSO2R1B, —OSO2R1B, or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R1 and R2 taken together are an alicyclic or heterocyclic moiety; wherein each occurrence of R1A and R1B is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R1C, or —C(═O)NR1CR1D; wherein each occurrence of R1C and R1D is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R1E is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR1C, —NR1CR1D or —SO2R1C; R3 is —C(═O)OR3A, —C(═O)H, —CH2OR3A, —CH2OC(═O)-alkyl, —C(═O)NH(R3A), or —CH2X0; wherein each occurrence of R3A is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R3A, taken together with R1 and R2, forms a heterocyclic moiety; wherein X0 is a halogen selected from F, Br or I; R4 for each occurrence, is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GRG1 wherein G is —O—, —S—, NRG2—, —CO—, —SO—, —SO2—, C(═O)O—, —C(═O)NRG2—, C(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; n is an integer from 0-4; AR1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; A, B, D and E are connected by single bonds; wherein D is N; each occurrence of A, B, and E is CHRi wherein each occurrence of Ri is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2, —CO—, —SO—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or any two adjacent occurrences of taken together, represent an alicyclic, heteroalicyclic, aryl, or heteroaryl moiety; p is an integer from 0-4; and, L is a substituted or unsubstituted C1-6 alkylidene or C2-6 alkenylidine chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O). 2. The compound of claim 1, wherein R3 is carboxyl or protected carboxyl, wherein R3 is C(═O)R3A, wherein R3A is hydroxy, alkoxy, cycloalkoxy, aralkoxy, arcycloalkoxy, aryloxy, alkylcarbonyloxyalkyloxy, alkoxycarbonyloxyalkyloxy, alkoxycarbonylalkyloxy, cycloalkylcarbonyloxyalkyloxy, cycloalkoxycarbonyloxyalkyloxy, cycloalkoxycarbonylalkyloxy, arylcarbonyloxyalkyloxy, aryloxycarbonyloxyalkyloxy, alkoxyalkylcarbonyloxyalkyloxy, or one of the structures: 3. The compound of claim 1 wherein the compound has the structure: wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and RB1, RB2 and RE are independently hydrogen or substituted or unsubstituted lower alkyl. 4. The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 is a moiety having the following structure: wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and RS is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, or is -G0RG1 wherein G0 is —O—, —S— or —NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety. 5. The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 is a moiety having the following structure: wherein R1A is Ar2, SR1B or NR1BR1C; or an alkyl or heteroalkyl moiety; and Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; wherein R1B and R1C are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or R1B and R1C, taken together with the nitrogen atom to which they are attached, form a heterocylic or heteroaryl moiety. 6. The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 is a moiety having the following structure: wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and R2A is hydrogen, C1-6alkyl, C2-6alkenyl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A, taken together with a substituent on Ar2, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety. 7. The compound of claim 4, 5, or 6, wherein R3A is independently hydrogen, lower alkyl, phenyl or benzyl. 8. The compound of claim 4 or 6 wherein Ar2 is one of the following structures: wherein s is an integer from 0-2; and each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —ORG1, —SRG1, —NRG1RG2—, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is independently lower alkyl, or when Y is ORP5 may also be hydrogen; each occurrence of RP2 is independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; RP3 is lower alkyl or —N(RP2)2; and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety. 9. The compound of claim 8 wherein Ar2 is one of the following structures: 10. The compound of claim 4 or 6 wherein Ar2 is one of the following structures: wherein RP3 is lower alkyl and RG1 is hydrogen or lower alkyl. 11. The compound of claim 5 wherein R1A is —NH2 or a moiety having the structure: wherein RP1 is independently hydrogen, hydroxyl, lower alkyl or lower heteroalkyl; and each occurrence of RP2 is independently hydrogen or lower alkyl. 12. The compound of claim 11 wherein R1A is —NH2 or a moiety having the structure: wherein RP1 is hydrogen or lower alkyl. 13. The compound of claim 5 wherein R1A is a moiety having one of the structures: wherein s is an integer between 0 and 2; and each occurrence of RP1 is independently lower alkyl or is -GRG1 wherein G is —O— or —NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence of RP2 is independently hydrogen, lower alkyl, aryl or heteroaryl. 14. The compound of claim 13 wherein R1A is a moiety having one of the structures: wherein G is —O— or —NRG2—, and RG1 and RG2 are independently hydrogen or lower alkyl. 15. The compound of claim 6, wherein —NH(R2A)Ar2 is one of the following structures: wherein X1 is N or CRP1; s is an integer from 0-5; and each occurrence of RP1 is independently hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is —RG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and RP3 is alkyl, heteroalkyl, aryl or heteroaryl. 16. The compound of claim 15, wherein —NH(R2A)Ar2 has the following structure: wherein RP1 is hydrogen, halogen or lower alkyl. 17. The compound of any one of claims 4, 5, and 6, wherein Ar2 is one of the following structures: wherein each occurrence of s is an integer from 0-6; X1, is CHRP1; X2 and X3 are independently CHRP1, NRP2, CHSO2RP3, or NSO2RP3; X5 is O, S or NRP2; each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —P(═O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is ORP5 may also be hydrogen; each occurrence of RP2 is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent occurrences of RP1 and RP2, taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and each occurrence of RP3 is independently alkyl, aryl, heteroaryl or —N(RP2)2. 18. The compound of claim 17 wherein Ar2 is one of the following structures: wherein X1 is N or CRP1; s is an integer from 0-6; each occurrence of RP1 is independently hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is —RG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and RP3 is independently lower alkyl or aryl. 19. The compound of claim 1, wherein L is a moiety having the structure: 20. The compound of claim 1, wherein AR1 is one of the following structures: wherein each occurrence of r is an integer from 0-6; X1, X2, X3 and X4 are independently N or CRQ1; X5 is O, S or NRQ2; AR3 is a heterocyclic, aryl or heteroaryl moiety; each occurrence of RQ1 is independently hydrogen, ORQ3, OCF3, SRQ3, halogen, CN, isocyanate, NO2, CF3, NRQ3QRQ4, —SO2RQ3, alkyl-NRQ3RQ4—, alkyl-C(═O)—NRQ3RQ4, alkyl-C(═O)RQ3, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, wherein each occurrence of RQ3 and RQ4 is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety; and RQ2 is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group. 21. The compound of claim 20, wherein AR1 is one of the following structures: wherein X0 is F or Cl; X2 is N or CRQ1; X5 is CH, O, S or NH; and RQ1 is hydrogen, methyl, —CF3, —OH, —OCH3, —OCF3 or halogen. 22. The compound of claim 21, wherein AR1 is one of the following structures: 23. The compound of claim 22, wherein AR1 is one of the following structures: 24. The compound of claim 1, wherein AR1-L- is one of the following structures: 25. The compound of claim 8 wherein Ar2 is: 26. The compound of claim 1 having the structure: 27. The compound of claim 1 having the structure: 28. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent, and optionally further comprising an additional therapeutic agent. 29. The pharmaceutical composition of claim 28, wherein the compound is present in an amount effective to modulate adhesion between intracellular adhesion molecules and the leukocyte integrin family of receptors. 30. The pharmaceutical composition of claim 28, wherein the intracellular adhesion molecules are selected from ICAM-1, ICAM-2 and ICAM-3. 31. The pharmaceutical composition of claim 28, wherein the compound is present in an amount effective to antagonize CD11/CD18 receptors associated with leukocytes. 32. The pharmaceutical composition of claim 28, wherein the compound is present in an amount effective to antagonize Mac-1 and/or LFA-1. 33. A method of treating an immune or inflammatory disorder in a subject mediated through the CD11/CD18 family of cellular adhesion molecules, the method comprising administering to a subject a therapeutically effective amount of a compound of claim 1, wherein the disorder is selected from psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, dermatitis, meningitis, uveitis, eczema, asthma, poison ivy, poison oak, Sjorgen's syndrome, pulmonary fibrosis and rheumatoid arthritis. 34. The method of claim 33, wherein the CD11/CD18 family of cellular adhesion molecules is LFA-1. 35. A method of treating an immune or inflammatory disorder in a subject comprising administering to a subject in need thereof a compound of claim 1, wherein the disorder is selected from psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, dermatitis, meningitis, uveitis, eczema, asthma, poison ivy, poison oak, Sjorgen's syndrome, pulmonary fibrosis and rheumatoid arthritis. 36. The compound of claim 1, wherein AR1 is: wherein r is an integer from 0-6; each occurrence of RQ1 is independently hydrogen, ORQ3, OCF3, SRQ3, halogen, CN, isocyanate, NO2, CF3, NRQ3QRQ4, —SO2RQ3, alkyl-NRQ3RQ4—, alkyl-C(═O)—NRQ3RQ4, alkyl-C(═O)RQ3, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, wherein each occurrence of RQ3 and RQ4 is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety; L is a moiety having the structure: —C(═O)NHC(R1)(R2)R3 is a moiety having the following structure: wherein RS is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, or is -G0RG1 wherein G0 is —O—, —S— or —NRG2—; RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety; R3A is hydrogen, a protecting group, a pharmaceutically acceptable salt or ester; Ar2 has the following structure: wherein s is an integer from 0-6; each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —P(═O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—. 37. The compound of claim 36, wherein RS is hydrogen.