Claims for Patent: 7,973,038

Summary for Patent: 7,973,038

Title:	Modulators of ATP-binding cassette transporters
Abstract:	Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.
Inventor(s):	Sara S. Hadida Ruah, Matthew Hamilton, Mark T. Miller, Peter D. J. Grootenhuis, Brian Richard Bear, Jason McCartney, Jinglan Zhou
Assignee:	Vertex Pharmaceuticals Inc
Application Number:	US12/768,894
Patent Claims:	1. A method of modulating CFTR transporter activity comprising the step of contacting said ABC transporter with a compound of formula (I): wherein: each R1 is an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C3-10 cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R1 is an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl attached to the 5- or 6-position of the pyridyl ring; each R2 is hydrogen, an optionally substituted C1-6 aliphatic, an optionally substituted C3-6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl; each R3 and R′3 together with the carbon atom to which they are attached form an optionally substituted C3-7 cycloaliphatic or an optionally substituted heterocycloaliphatic; each R4 is an optionally substituted aryl or an optionally substituted heteroaryl; and each n is 1-4. 2. A method of treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, hereditary emphysema, or COPD, said method comprising the step of administering to said patient an effective amount of a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: Each R1 is an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted C3-10 cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy, provided that at least one R1 is an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl attached to the 5- or 6- position of the pyridyl ring; Each R2 is hydrogen, an optionally substituted C1-6 aliphatic, an optionally substituted C3-6 cycloaliphatic, an optionally substituted phenyl, or an optionally substituted heteroaryl; Each R3 and R′3 together with the carbon atom to which they are attached form an optionally substituted C3-7 cycloaliphatic or an optionally substituted heterocycloaliphatic; Each R4 is an optionally substituted aryl or an optionally substituted heteroaryl; and Each n is 1, 2, 3 or 4. 3. The method according to claim 2, wherein one R1 that is attached to 5- or 6-position of the pyridyl ring is aryl or heteroaryl, each optionally substituted with 1, 2, or 3 of RD; wherein RD is —ZDR9; wherein each ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by —CO—, —CS—, —CONRE—, —CONRENRE—, —CO2—, —OCO—, —NRECO2—, —O—, —NRECONRE—, —OCONRE—, —NRENRE—, —NRECO—, —S—, —SO—, —SO2—, —NRE—, —SO2NRE—, —NRESO2—, or —NRESO2NRE—; each R9 is independently RE, halo, —OH, —NH2, —NO2, —CN, —CF3, or —OCF3; and each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 4. The method according to claim 3, wherein the one R1 attached to the 5- or 6-position of the pyridyl ring is phenyl optionally substituted with 1, 2, or 3 of RD. 5. The method according to claim 3, wherein the one R1 attached to the 5- or 6-position of the pyridyl ring is heteroaryl optionally substituted with 1, 2, or 3 of RD. 6. The method according to claim 3, wherein one R1 attached to the 5- or 6-position of the pyridyl ring is a 5 or 6 membered heteroaryl having 1, 2, or 3 heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, wherein the heteroaryl is substituted with 1 of RD, wherein RD is —ZDR9; each ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by —O—, —NHC(O)—, —C(O)NRE—, —SO2—, —NHSO2—, —NHC(O)—, —NRESO2—, —SO2NH—, —SO2NRE—, —NH—, or —C(O)O—. 7. The method according to claim 6, wherein one carbon unit of ZD is replaced by —O—, —NHC(O)—, —C(O)NRE—, —SO2—, —NHSO2—, —NHC(O)—, —SO—, —NRESO2—, —SO2NH—, —SO2NRE—, —NH—, or —C(O)O—. 8. The method according to claim 3, wherein R9 is independently an optionally substituted aliphatic, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl, H, or halo. 9. The method according to claim 2, wherein one R1 that is attached to the 5- or 6-position of the pyridyl ring is cycloaliphatic or heterocycloaliphatic, each optionally substituted with 1, 2, or 3 of RD. 10. The method according to claim 9, wherein one R1 that is attached to the 5- or 6-position of the pyridyl ring is an optionally substituted C3-C8 cycloalkyl or an optionally substituted C3-C8 cycloalkenyl. 11. The method according to claim 2, wherein the one R1 attached to the 5- or 6-position of the pyridyl ring is selected from the group consisting of 12. The method according to claim 2, wherein R2 is hydrogen. 13. The method according to claim 2, wherein R3 and R′3 together with the carbon atom to which they are attached form an unsubstituted C3-7 cycloaliphatic or an unsubstituted heterocycloaliphatic. 14. The method according to claim 13, wherein R3 and R′3 together with the carbon atom to which they are attached form an unsubstituted cyclopropyl, an unsubstituted cyclopentyl, or an unsubstituted cyclohexyl. 15. The method according to claim 2, wherein R4 is an aryl or heteroaryl optionally substituted with 1, 2, or 3 of —ZCR8, wherein each ZC is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZC are optionally and independently replaced by —CO—, —CS—, —CONRC—, —CONRCNRC—, —CO2—, —OCO—-, —NRCCO2—, —O—, —NRCCONRC—, —OCONRC—, —NRCNRC—, —NRCCO—, —S—, —SO—, —SO2—, —NRC—, —SO2NRC—, —NRCSO2—, or —NRCSO2NRC—; each R8 is independently RC, halo, —OH, —NH2, —NO2, —CN, or —OCF3; and each RC is independently an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 16. The method according to claim 15, wherein R4 is an aryl optionally substituted with 1, 2, or 3 of —ZCR8. 17. The method according to claim 16, wherein R4 is an optionally substituted phenyl. 18. The method according to claim 15, wherein R4 is a heteroaryl optionally substituted with 1, 2, or 3 of —ZC 8. 19. The method according to claim 15, wherein R4 is one selected from 20. The method according to claim 2, wherein said compound has formula (IV): or a pharmaceutically acceptable salt thereof, wherein RD is —ZDR9, wherein each ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by —CO—, —CS—, —CONRE—, —CONRENRE—, —CO2—, —OCO—, —NRECO2—, —O—, —NRECONRE—, —OCONRE—, —NRENRE—, —NRECO—, —S—, —SO—, —SO2—, —NRE—, —SO2NRE—, —NRESO2—, or —NRESO2NRE—; R9 is independently RE, halo, —OH, —NH2, —NO2, —CN, —CF3, or —OCF3; Each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; R2 is C1-4 aliphatic, C3-6 cycloaliphatic, phenyl, or heteroaryl, each of which is optionally substituted, or R2 is hydrogen; R3 and R′3 together with the carbon atom to which they are attached form a C3-7 cycloaliphatic or a C3-7 heterocycloaliphatic, each of which is optionally substituted with 1, 2, or 3 of —ZBR7, wherein each ZB is independently a bond, or an optionally substituted branched or straight C1-4 aliphatic chain wherein up to two carbon units of ZB are optionally and independently replaced by —CO—, —CS—, —CONRB—, —CONRBNRB—, —CO2—, —OCO—, —NRBCO2—, —O—, —NRBCONRB—, —OCONRB—, —NRBNRB—, —NRBCO—, —S—, —SO—, —SO2—, —NRB—, —SO2NRB—, —NRBSO2—, or —NRBSO2NRB—; Each R7 is independently RB, halo, —OH, —NH2, —NO2, —CN, —CF3, or —OCF3; Each RB is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl; Each R4 is an aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 of —ZCR8, wherein each ZC is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZC are optionally and independently replaced by —CO—, —CS—, —CONRC—, —CONRCNRC—, —CO2—, —OCO—, —NRCCO2-, —O—, —NRCCONRC—, —OCONRC—, —NRCNRC—, —NRCCO—, —S—, —SO—, —SO2—, —NRC—, —SO2NRC—, —NRCSO2—, or —NRCSO2NRC—; Each R8 is independently RC, halo, —OH, —NH2, —NO2, —CN, —CF3, or —OCF3; and Each RC is independently an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 21. The method according to claim 20, wherein said compound has formula V-A or formula V-B: or a pharmaceutically acceptable salt thereof, wherein: T is an optionally substituted C1-2 aliphatic chain, wherein each of the carbon units is optionally and independently replaced by —CO—, —CS—, —COCO—, —SO2—, —B(OH)—, or —B(O(C1-6 alkyl))—; Each of R1′ and R1″ is an optionally substituted C1-6 aliphatic, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted 3 to 10 membered cycloaliphatic, an optionally substituted 3 to 10 membered heterocycloaliphatic, carboxy, amido, amino, halo, or hydroxy; RD1 is attached to carbon number 3″ or 4″; each RD1 and RD2 is —ZDR9, wherein each ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein up to two carbon units of ZD are optionally and independently replaced by —CO—, —CS—, —CONRE—, —CONRENRE—, —CO2—, —OCO—, —NRECO2—, —O—, —NRECONRE—, —OCONRE—, —NRENRE—, —NRECO—, —S—, —SO—, —SO2—, —NRE—, —SO2NRE—, —NRESO2—, or —NRESO2NRE—; R9 is independently RE, halo, —OH, —NH2, —NO2, —CN, —CF3, or —OCF3; or RD1 and RD2, taken together with atoms to which they are attached, form a 3-8 membered saturated, partially unsaturated, or aromatic ring with up to 3 ring members independently selected from the group consisting of O, NH, NRE, and S; and each RE is independently hydrogen, an optionally substituted C1-8 aliphatic group, an optionally substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally substituted aryl, or an optionally substituted heteroaryl. 22. The method according to claim 21, wherein up to two methylene units of T are independently and optionally replaced by —CO—, —CS—, —B(OH), or —B(O(C1-6 alkyl). 23. The method according to claim 21, wherein T is an optionally substituted chain selected from the group consisting of —CH2— and —CH2CH2—. 24. The method according to claim 21, wherein T is optionally substituted by F, Cl, C1-6 alkyl, C3-8 cycloalkyl, phenyl, naphthyl, —O—(C1-6 alkyl), —O—(C3-8 cycloalkyl), —O-phenyl, or C3-8 spiroaliphatic. 25. The method according to claim 21, wherein T is selected from the group consisting of —CH2—, —CH2CH2—, —CF2—, —C(CH3)2—, —C(O)—, —C(Phenyl)2—, —B(OH)—, and —CH(OEt)-. 26. The method according to claim 25, wherein T is selected from the group consisting of —CH2—, —CF2—, and —C(CH3)2—. 27. The method according to claim 21, wherein ZD is independently a bond or an optionally substituted branched or straight C1-6 aliphatic chain wherein one carbon unit of ZD is optionally replaced by —CO—, —SO—, —SO2—, —COO—, —OCO—, —CONRE—, —NRECO—, NRECO2—, —O—, —NRESO2—, or —SO2NRE—. 28. The method according to claim 21, wherein RD1 is —ZDR9, wherein R9 is halo, —OH, —NH2, —CN, —CF3, —OCF3, or an optionally substituted group selected from the group consisting of C1-6 aliphatic, C3-8 cycloaliphatic, 3-8 membered heterocycloaliphatic, C6-10 aryl, and 5-10 membered heteroaryl. 29. The method according to claim 28, wherein R9 is F, Cl, —OH, —CN, —CF3, or —OCF3. 30. The method according to claim 28, wherein R9 is selected from the group consisting of C1-6 straight or branched alkyl or C2-6 straight or branched alkenyl; wherein said alkyl or alkenyl is optionally substituted by 1 or 2 substituents independently selected from the group consisting of RE, oxo, halo, —OH, —NRERE, —ORE, —COORE, and —CONRERE. 31. The method according to claim 28, wherein R9 is C3-8 cycloaliphatic optionally substituted by 1 or 2 substituents independently selected from the group consisting of RE, oxo, halo, —OH, —NRERE, —ORE, —COORE, and —CONRERE. 32. The method according to claim 31, wherein R9 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. 33. The method according to claim 28, wherein R9 is a 3-8 membered heterocyclic with 1 or 2 heteroatoms independently selected from the group consisting of O, NH, NRE, and S; wherein said heterocyclic is optionally substituted by 1 or 2 substituents independently selected from the group RE, oxo, halo, —OH, —NRERE, —ORE, —COORE, and —CONRERE. 34. The method according to claim 33, wherein R9 is an optionally substituted 3-8 membered heterocyclic is 35. The method according to claim 33, wherein R9 is optionally substituted by 1 or 2 substituents independently selected from the group consisting of oxo, F, Cl, methyl, ethyl, i-propyl, t-butyl, —CH2OH, —CH2CH2OH, —C(O)OH, —C(O)NH2, —CH2O(C1-6 alkyl), —CH2CH2O(C1-6 alkyl), and —C(O)(C1-6 alkyl). 36. The method according to claim 28, wherein R9 is 5-8 membered heteroaryl with 1 or two ring atom independently selected from the group consisting of O, S, and NRE; wherein said heteroaryl is optionally substituted by 1 or 2 substituents independently selected from the group RE, oxo, halo, —OH, —NRERE, —ORE, —COORE, and —CONRERE. 37. The method according to claim 36, wherein R9 is 38. The method according to claim 36, wherein R9 is optionally substituted by 1 or 2 substituents independently selected from the group consisting of F, Cl, methyl, ethyl, i-propyl, t-butyl, —CH2OH, —CH2CH2OH, —C(O)OH, —C(O)NH2, —CH2O(C1-6 alkyl), —CH2CH2O(C1-6 alkyl), and —C(O)(C1-6 alkyl). 39. The method according to claim 21, wherein RD1 and RD2, taken together with carbons to which they are attached, form an optionally substituted 3-8 membered saturated, partially unsaturated, or aromatic ring with 0-2 ring atoms independently selected from the group consisting of O, NH, NRE, and S. 40. The method according to claim 39, wherein RD1 and RD2, taken together with phenyl containing carbon atoms 3″ and 4″, is 41. The method according to claim 39, wherein RD1 and RD2, taken together with phenyl containing carbon atoms 3″ and 4″, is optionally substituted by 1 or 2 substituents independently selected from the group consisting of RE, oxo, halo, —OH, —NRERE, —ORE, —COORE, and —CONRERE. 42. The method according to claim 21, wherein RD2 is selected from the group consisting of H, C1-6 aliphatic, halo, —CN, —NH2, —CH2NH2, —OH, —O(C1-6 aliphatic), —CH2OH, —SO2(C1-6 aliphatic), —NH—SO2(C1-6 aliphatic), —C(O)O(C1-6 aliphatic), —C(O)OH, —NHC(O)(C1-6 aliphatic), —C(O)NH2, —C(O)NH(C1-6 aliphatic), and —C(O)N(C1-6 aliphatic)2. 43. The method according to claim 21, wherein R1″ is hydrogen. 44. The method according to claim 21, wherein R1′ and R1″ are both hydrogen. 45. The method according to claim 2, wherein the compound is selected from