Claims for Patent: 7,288,657

Summary for Patent: 7,288,657

Title:	Biphenyl compounds useful as muscarinic receptor antagonists
Abstract:	This invention provides compounds of formula I: wherein a, b, c, d, m, n, p, s, t, W, Ar1, R1, R2, R3, R4, R6, R7, and R8 are as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.
Inventor(s):	Mathai Mammen, Yu-Hua Ji, YongQi Mu, Craig Husfeld, Li Li
Assignee:	Theravance Biopharma R&D IP LLC
Application Number:	US11/077,433
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,288,657
Patent Claims:	1. A compound of formula I: wherein: a is 0 or an integer of from 1 to 5; each R1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR1a, —C(O)OR1b, —SR1c, —S(O)R1d, —S(O)2R1e, —NR1fR1g, —NR1hS(O)2R1i, and —NR1jC(O)R1k; where each of R1a, R1b, R1c, R1d, R1e, R1f, R1g, R1h, R1i, R1j, and R1k is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl; b is 0 or an integer of from 1 to 4; each R2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR2a, —C(O)OR2b, —SR2c, —S(O)R2d, —S(O)2R2e, —NR2fR2g, —NR2hS(O)2R2i, and —NR2jC(O)R2k; where each of R2a, R2b, R2c, R2d, R2e, R2f, R2g, R2h, R2i, R2j, and R2k is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl; W represents O or NWa, where Wa is hydrogen or (1-4C)alkyl; c is 0 or an integer from 1 to 5; each R3 independently represents (1-4C)alkyl or two R3 groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl; m is 0 or 1; R4 is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl; s is 0, 1 or 2; Ar1 represents a phenylene group or a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur; wherein the phenylene or heteroarylene group is substituted with (R5)q where q is 0 or an integer from 1 to 4 and each R5 is independently selected from halo, hydroxy, (1-4C)alkyl or (1-4C)alkoxy; t is 0, 1 or 2; n is 0 or an integer from 1 to 3; d is 0 or an integer from 1 to 4; each R6 independently represents fluoro or (1-4C)alkyl; p is 0 or 1; and R7 and R8 are independently hydrogen or (1-4C)alkyl; wherein each alkyl and alkoxy group in R1, R1a-1k, R2, R2a-2k, R3, R5, R6, R7, and R8 is optionally substituted with 1 to 5 fluoro substituents; or a pharmaceutically acceptable salt or stereoisomer thereof. 2. The compound of claim 1, wherein a, b and c each represent 0. 3. The compound of claim 1, wherein W represents O. 4. The compound of claim 1, wherein m is 0, s is 0 and t is 1. 5. The compound of claim 1, wherein the —CONR7R8 group is in the para position, d is 0 and n is 2. 6. The compound of claim 1, wherein Ar1 represents phen-1,3-ylene, phen-1,4-ylene, 2,4-thienylene or 2,5-thienylene; wherein the phenylene or thienylene group is optionally substituted with one or two R5 substituents. 7. The compound of claim 6, wherein Ar1 represents phen-1,4-ylene or 2,4-thienylene, optionally substituted with one or two R5 substituents. 8. The compound of any one of claims 1 to 6, wherein R4 is selected from hydrogen, methyl and ethyl. 9. The compound of any one of claims 1 to 6, wherein R7 is selected from hydrogen, methyl, ethyl, n-propyl and isopropyl; and R8 is hydrogen. 10. The compound of any one of claims 1 to 6, wherein R7 and R8 are ethyl. 11. The compound of claim 1 wherein a, b and c each represent 0; W represents O; m is 0; s is 0; t is 1; Ar1 represents phen-1,4-ylene optionally substituted with one or two R5 substituents; d is 0; n is 2, the —CONR7R8 group is in the para position; and R8 is hydrogen. 12. The compound of claim 11, wherein R5 is independently selected from halo, (1-4C)alkyl or (1-4C)alkoxy, wherein each alkyl and alkoxy group is optionally substituted with from 1 to 3 fluoro substituents. 13. A compound selected from: biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]ethylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{methyl-[4-(4-methylcarbamoylpiperidin-1-ylmethyl)benzoyl]amino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-ethylcarbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{methyl-[4-(4-propylcarbamoylpiperidin-1-ylmethyl)benzoyl]amino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-isopropylcarbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(4-carbamoylpiperidin-1-ylmethyl)-2-fluorobenzoylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[2,5-dibromo-4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)-2-fluorobenzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)-2-fluorobenzoylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)-2-fluorobenzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(3-(S)-diethylcarbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[4-(2-carbamoyl-piperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[4-(4-carbamoyl-piperidin-1-ylmethyl)-2-methoxybenzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)thiophene-2-carbonyl]amino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)thiophene-2-carbonyl]amino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)-1H-pyrrole-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)-1H-pyrrole-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)furan-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-diethylcarbamoyl-piperidin-1-ylmethyl)furan-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)furan-2-carbonyl]-amino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)furan-2-carbonyl]amino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-[2-({3-[4-(3-carbamoylpiperidin-1-ylmethyl)phenyl]propionyl}methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-[2-({3-[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]propionyl}methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{3-[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{3-[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{3-[4-(3-diethylcarbamoylpiperidin-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(4-carbamoylpiperidin-1-ylmethyl)benzoylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)-2-chloro-benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)-2-chloro-5-methoxybenzoyl]methylamino}ethyl)piperidin-4-yl ester; and biphenyl-2-ylcarbamic acid 1-[2-({2-[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]acetyl}methylamino)ethyl]piperidin-4-yl ester; or a pharmaceutically acceptable salt or solvate thereof. 14. Biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable salt thereof. 15. A process for preparing a compound of any one of claims 1, 13 or 14, the process comprising: (a) reacting a compound of formula II: or a salt thereof, with a compound of formula III: wherein Z1 represents a leaving group; or (b) coupling a compound of formula IV: with a compound of formula V: or; (c) reacting a compound of formula VI: wherein Z2 represents a leaving group; with a compound of formula VII: or (d) reacting a compound of formula II with a compound of formula VIII: in the presence of a reducing agent; or (e) reacting a compound of formula IX: with a compound of formula VII in the presence of a reducing agent; or (f) reacting a compound of formula XVIII: where R′ is H, —CH3 or —CH2CH3, with a compound of formula XIX: NHR7R8 XIX to provide a compound of formula I. 16. The process of claim 15, which further comprises forming a pharmaceutically acceptable salt of the compound of formula I. 17. The product prepared by the process of claim 15. 18. The product prepared by the process of claim 16.