US2019031630A1PendingUtilityA1

Cftr regulators and methods of use thereof

45
Assignee: UNIV CALIFORNIAPriority: Dec 24, 2015Filed: Dec 23, 2016Published: Jan 31, 2019
Est. expiryDec 24, 2035(~9.4 yrs left)· nominal 20-yr term from priority
Inventors:Alan S. VerkmanMarc H. LevinOnur Cil
A61P 27/04C07D 417/12A61P 1/10C07D 285/135A61P 11/00A61K 31/433A61P 27/02A61P 1/16A61P 1/00
45
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Claims

Abstract

Provided herein are compounds that activate CFTR and methods for treating constipation, dry eye disorders or other diseases and disorders.

Claims

exact text as granted — not AI-modified
1 . A pharmaceutical composition, comprising a pharmaceutically acceptable excipient, and a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,
 wherein: 
 Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; 
 L 1  and L 2  are independently substituted or unsubstituted C 1 -C 3  alkylene; 
 n1, n2, n3, n4 and n5 are independently an integer from 0 to 4; 
 m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or 2; 
 R 1  is hydrogen, halogen, —CX 1.1   3 , —CHX 1.1   2 , —CH 2 X 1.1 , —CN, —SO n1 R 1A , —SO v1 NR 1B R 1C , —NHNR 1B R 1C , —ONR 1B R 1C , —NHC(O)NHNR 1B R 1C , —NHC(O)NR 1B R 1C , —N(O) m1 , —NR 1B R 1C , —C(O)R 1D , —C(O)OR 1D , —C(O)NR 1B R 1C , —OR 1A , —NR 1B SO 2 R 1A , —NR 1B C(O)R 1D , —NR 1B C(O)OR 1D , —NR 1B OR 1D , —OCX 1.1   3 , —OCHX 1.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  is hydrogen, halogen, —CX 2.1   3 , —CHX 2.1   2 , —CH 2 X 2.1 , —CN, —SO n2 R 2A , —SO v2 NR 2B R 2C , —NHNR 2B R 2C , —ONR 2B R 2C , —NHC(O)NHNR 2B R 2C , —NHC(O)NR 2B R 2C , —N(O) m2 , —NR 2B R 2C , —C(O)R 2D , —C(O)OR 2D , —C(O)NR 2B R 2C , —OR 2A , —NR 2B SO 2 R 2A , —NR 2B C(O)R 2D , —NR 2B C(O)OR 2D , —NR 2B OR 2D , —OCX 2.1   3 , —OCHX 2.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 3  is hydrogen, halogen, —CX 3.1   3 , —CHX 3.1   2 , —CH 2 X 3.1 , —CN, —SO n3 R 3A , —SO v3 NR 3B R 3C , —NHNR 3B R 3C , —ONR 3B R 3C , —NHC(O)NHNR 3B R 3C , —NHC(O)NR 3B R 3C , —N(O) m3 , —NR 3B R 3C , —C(O)R 3D , —C(O)OR 3D , —C(O)NR 3B R 3C , —OR 3A , —NR 3B SO 2 R 3A , —NR 3B C(O)R 3D , —NR 3B C(O)OR 3D , —NR 3B OR 3D , —OCX 3.1   3 , —OCHX 3.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is hydrogen, halogen, —CX 4.1   3 , —CHX 4.1   2 , —CH 2 X 4.1 , —CN, —SO n4 R 4A , —SO v4 NR 4B R 4C , —NHNR 4B R 4C , —ONR 4B R 4C , —NHC(O)NHNR 4B R 4C , —NHC(O)NR 4B R 4C , —N(O) m4 , —NR 4B R 4C , —C(O)R 4D , —C(O)OR 4D , —C(O)NR 4B R 4C , —OR 4A , —NR 4B SO 2 R 4A , —NR 4B C(O)R 4D , —NR 4B C(O)OR 4D , —NR 4B OR 4D , —OCX 4.1   3 , —OCHX 4.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 5  is hydrogen, halogen, —CX 5.1   3 , —CHX 5.1   2 , —CH 2 X 5.1 , —CN, —SO n5 R 5A , —SO v5 NR 5B R 5C , —NHNR 5B R 5C , —ONR 5B R 5C , —NHC(O)NHNR 5B R 5C , —NHC(O)NR 5B R 5C , —N(O) m5 , —NR 5B R 5C , —C(O)R 5D , —C(O)OR 5D , —C(O)NR 5B R 5C , —OR 5A , —NR 5B SO 2 R 5A , —NR 5B C(O)R 5D , —NR 5B C(O)OR 5D , —NR 5B OR 5D , —OCX 5.1   3 , —OCHX 5.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , and R 5D  are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —OCHF 2 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B  and R 5C  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and 
 X 1.1 , X 2.1 , X 3.1 , X 4.1  and X 5.1  are independently —Cl, —Br, —I or —F. 
 
       
     
     
         2 - 6 . (canceled) 
     
     
         7 . A pharmaceutical composition, comprising a pharmaceutically acceptable excipient, and a compound of Formula IA: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,
 wherein: 
 Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; 
 L 1  and L 2  are independently substituted or unsubstituted C 1 -C 3  alkylene; 
 n1, n2, n3, n4, n5, n6, n7, n8, n9 and n10 are independently an integer from 0 to 4; 
 m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9 and v10 are independently 1 or 2; 
 R 1  is hydrogen, halogen, —CX 1.1   3 , —CHX 1.1   2 , —CH 2 X 1.1 , —CN, —SO n1 R 1A , —SO v1 NR 1B R 1C , —NHNR 1B R 1C , —ONR 1B R 1C , —NHC(O)NHNR 1B R 1C , —NHC(O)NR 1B R 1C , —N(O) m1 , —NR 1B R 1C , —C(O)R 1D , —C(O)OR 1D , —C(O)NR 1B R 1C , —OR 1A , —NR 1B SO 2 R 1A , —NR 1B C(O)R 1D , —NR 1B C(O)OR 1D , —NR 1B OR 1D , —OCX 1.1   3 , —OCHX 1.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  is hydrogen, halogen, —CX 2.1   3 , —CHX 2.1   2 , —CH 2 X 2.1 , —CN, —SO n2 R 2A , —SO v2 NR 2B R 2C , —NHNR 2B R 2C , —ONR 2B R 2C , —NHC(O)NHNR 2B R 2C , —NHC(O)NR 2B R 2C , —N(O) m2 , —NR 2B R 2C , —C(O)R 2D , —C(O)OR 2D , —C(O)NR 2B R 2C , —OR 2A , —NR 2B SO 2 R 2A , —NR 2B C(O)R 2D , —NR 2B C(O)OR 2D , —NR 2B OR 2D , —OCX 2.1   3 , —OCHX 2.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 3  is hydrogen, —CX 3.1   3 , —CHX 3.1   2 , —CH 2 X 3.1 , —CN, —SO n3 R 3A , —SO v3 NR 3B R 3C , —NHNR 3B R 3C , —ONR 3B R 3C , —NHC(O)NHNR 3B R 3C , —NHC(O)NR 3B R 3C , —N(O) m3 , —NR 3B R 3C , —C(O)R 3D , —C(O)OR 3D , —C(O)NR 3B R 3C , —OR 3A , —NR 3B SO 2 R 3A , —NR 3B C(O)R 3D , —NR 3B C(O)OR 3D , —NR 3B OR 3D , —OCX 3.1   3 , —OCHX 3.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is hydrogen, halogen, —CX 4.1   3 , —CHX 4.1   2 , —CH 2 X 4.1 , —CN, —SO n4 R 4A , —SO 4 NR 4B R 4C , —NHNR 4B R 4C , —ONR 4B R 4C , —NHC(O)NHNR 4B R 4C , —NHC(O)NR 4B R 4C , —N(O) m4 , —NR 4B R 4C , —C(O)R 4D , —C(O)OR 4D , —C(O)NR 4B R 4C , —OR 4A , —NR 4B SO 2 R 4A , —NR 4B C(O)R 4D , —NR 4B C(O)OR 4D , —NR 4B OR 4D , —OCX 4.1   3 , —OCHX 4.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 5  is hydrogen, halogen, —CX 5.1   3 , —CHX 5.1   2 , —CH 2 X 5.1 , —CN, —SO n5 R 5A , —SO v5 NR 5B R 5C , —NHNR 5B R 5C , —ONR 5B R 5C , —NHC(O)NHNR 5B R 5C , —NHC(O)NR 5B R 5C , —N(O) m5 , —NR 5B R 5C , —C(O)R 5D , —C(O)OR 5D , —C(O)NR 5B R 5C , —OR 5A , —NR 5B SO 2 R 5A , —NR 5B C(O)R 5D , —NR 5B C(O)OR 5D , —NR 5B OR 5D , —OCX 5.1   3 , —OCHX 5.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 6  is hydrogen, halogen, —CX 6.1   3 , —CHX 6.1   2 , —CH 2 X 6.1 , —CN, —SO n6 R 6A , —SO v6 NR 6B R 6C , —NHNR 6B R 6C , —ONR 6B R 6C , —NHC(O)NHNR 6B R 6C , —NHC(O)NR 6B R 6C , —N(O) m6 , —NR 6B R 6C , —C(O)R 6D , —C(O)OR 6D , —C(O)NR 6B R 6C , —OR 6A , —NR 6B SO 2 R 6A , —NR 6B C(O)R 6D , —NR 6B C(O)OR 6D , —NR 6B OR 6D , —OCX 6.1   3 , —OCHX 6.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 7  is hydrogen, halogen, —CX 7.1   3 , —CHX 7.1   2 , —CH 2 X 7.1 , —CN, —SO n7 R 7A , —SO v7 NR 7B R 7C , —NHNR 7B R 7C , —ONR 7B R 7C , —NHC(O)NHNR 7B R 7C , —NHC(O)NR 7B R 7C , —N(O) m7 , —NR 7B R 7C , —C(O)R 7D , —C(O)OR 7D , —C(O)NR 7B R 7C , —OR 7A , —NR 7B SO 2 R 7A , —NR 7A C(O)R 7C , —NR 7B C(O)OR 7D , —NR 7B OR 7D , —OCX 7.8   3 , —OCHX 7.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 8  is hydrogen, halogen, —CX 8.1   3 , —CHX 8.1   2 , —CH 2 X 8.1 , —CN, —SO n8 R 8A , —SO v8 NR 8B R 8C , —NHNR 8B R 8C , —ONR 5B R 8C , —NHC(O)NHNR 5B R 5C , —NHC(O)NR 5B R 5C , —N(O) m5 , —NR 5B R 5C , —C(O)R 8D , —C(O)OR 8D , —C(O)NR 8B R 8C , —OR 8A , —NR 8B SO 2 R 8A , —NR 8B C(O)R 8D , —NR 8B C(O)OR 8D , —NR 8B OR 8D , —OCX 8.1   3 , —OCHX 8.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 9  is hydrogen, halogen, —CX 9.1   3 , —CHX 9.1   2 , —CH 2 X 9.1 , —CN, —SO n9 R 9A , —SO v9 NR 9B R 9C , —NHNR 9B R 9C , —ONR 9B R 9C , —NHC(O)NHNR 9B R 9C , —NHC(O)NR 9B R 9C , —N(O) m9 , —NR 9B R 9C , —C(O)R 9D , —C(O)OR 9D , —C(O)NR 9B R 9C , —OR 9A , —NR 9B SO 2 R 9A , —NR 9B C(O)R 9D , —NR 9B C(O)OR 9D , —NR 9B OR 9D , —OCX 9.1   3 , —OCHX 9.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 10  is hydrogen, halogen, —CX 10.1   3 , —CHX 10.1   2 , —CH 2 X 10.1 , —CN, —SO n10 R 10A , —SO v10 NR 10B R 10C , —NHNR 10B R 10C , —ONR 10B R 10C , —NHC(O)NHNR 10B R 10C , —NHC(O)NR 10B R 10C , —N(O) m1 , —NR 1B R 10C , —C(O)R 10D , —C(O)OR 10D , —C(O)NR 10B R 10C , —OR 10A , —NR 10B SO 2 R 10A , —NR 10B C(O)R 10D , —NR 10B C(O)OR 10D , —NR 10B OR 10D , —OCX 10.1   3 , —OCHX 10.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , R 5D , R 6A , R 6B , R 6C , R 6D , R 7A , R 7B , R 7C , R 7D , R 8A , R 8B , R 8C , R 8D , R 9A , R 9B , R 9C , R 9D , R 10A , R 10B , R 10C  and R 10D  are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —OCHF 2 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B , R 5C , R 6B , R 6C , R 7B , R 7C , R 8B , R 9C , R 9B , R 9C , R 10B  and R 10C  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and 
 X 1.1 , X 2.1 , X 3.1 , X 4.1 , X 5.1 , X 6.1 , X 7.1 , X 1 , X 9.1  and X 10.1  are independently —Cl, —Br, —I or —F, 
 
       
       with proviso that when L 1  and L 2  are independently unsubstituted C 1 -C 3  alkylene, R 2  and R 3  are —OCH 3  and R 7 , R 8 , R 9  and R 10  are hydrogen, then R 6  is not —OCH 3 , or when L 1  and L 2  are independently unsubstituted C 1 -C 3  alkylene, R 2  and R 3  are —OCH 3 , and R 6 , R 8 , R 9  and R 10  are hydrogen, then R 7  is not —OCH 3 . 
     
     
         8 - 14 . (canceled) 
     
     
         15 . A method of treating constipation, comprising administering to a subject in need thereof a therapeutically effective amount a compound of structural Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,
 wherein: 
 Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; 
 L 1  and L 2  are independently substituted or unsubstituted C 1 -C 3  alkylene; 
 n1, n2, n3, n4 and n5 are independently an integer from 0 to 4; 
 m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or 2; 
 R 1  is hydrogen, halogen, —CX 1.1   3 , —CHX 1.1   2 , —CH 2 X 1.1 , —CN, —SO n1 R 1A , —SO v1 NR 1B R 1C , —NHNR 1B R 1C , —ONR 1B R 1C , —NHC(O)NHNR 1B R 1C , —NHC(O)NR 1B R 1C , —N(O) m1 , —NR 1B R 1C , —C(O)R 1D , —C(O)OR 1D , —C(O)NR 1B R 1C , —OR 1A , —NR 1B SO 2 R 1A , —NR 1B C(O)R 1D , —NR 1B C(O)OR 1D , —NR 1B OR 1D , —OCX 1.1   3 , —OCHX 1.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  is hydrogen, halogen, —CX 2.1   3 , —CHX 2.1   2 , —CH 2 X 2.1 , —CN, —SO n2 R 2A , —SO v2 NR 2B R 2C , —NHNR 2B R 2C , —ONR 2B R 2C , —NHC(O)NHNR 2B R 2C , —NHC(O)NR 2B R 2C , —N(O) m2 , —NR 2B R 2C , —C(O)R 2D , —C(O)OR 2D , —C(O)NR 2B R 2C , —OR 2A , —NR 2B SO 2 R 2A , —NR 2B C(O)R 2D , —NR 2B C(O)OR 2D , —NR 2B OR 2D , —OCX 2.1   3 , —OCHX 2.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 3  is hydrogen, halogen, —CX 3.1   3 , —CHX 3.1   2 , —CH 2 X 3.1 , —CN, —SO n3 R 3A , —SO v3 NR 3B R 3C , —NHNR 3B R 3C , —ONR 3B R 3C , —NHC(O)NHNR 3B R 3C , —NHC(O)NR 3B R 3C , —N(O) m3 , —NR 3B R 3C , —C(O)R 3D , —C(O)OR 3D , —C(O)NR 3B R 3C , —OR 3A , —NR 3B SO 2 R 3A , —NR 3B C(O)R 3D D, —NR 3B C(O)OR 3D , —NR 3B OR 3D , —OCX 3.1   3 , —OCHX 3.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is hydrogen, halogen, —CX 4.1   3 , —CHX 4.1   2 , —CH 2 X 4.1 , —CN, —SO n4 R 4A , —SO 4 NR 4B R 4C , —NHNR 4B R 4C , —ONR 4B R 4C , —NHC(O)NHNR 4B R 4C , —NHC(O)NR 4B R 4C , —N(O) m4 , —NR 4B R 4C , —C(O)R 4D , —C(O)OR 4D , —C(O)NR 4B R 4C , —OR 4A , —NR 4B SO 2 R 4A , —NR 4B C(O)R 4D , —NR 4B C(O)OR 4D , —NR 4B OR 4D , —OCX 4.1   3 , —OCHX 4.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 5  is hydrogen, halogen, —CX 5.1   3 , —CHX 5.1   2 , —CH 2 X 5.1 , —CN, —SO n5 R 5A , —SO v5 NR 5B R 5C , —NHNR 5B R 5C , —ONR 5B R 5C , —NHC(O)NHNR 5B R 5C , —NHC(O)NR 5B R 5C , —N(O) m5 , —NR 5B R 5C , —C(O)R 5D , —C(O)OR 5D , —C(O)NR 5B R 5C , —OR 5A , —NR 5B SO 2 R 5A , —NR 5B C(O)R 5D , —NR 5B C(O)OR 5D , —NR 5B OR 5D , —OCX 5.1   3 , —OCHX 5.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C  and R 5D  are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —OCHF 2 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B  and R 5C  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and 
 X 1.1 , X 2.1 , X 3.1 , X 4.1  and X 5.1  are independently —Cl, —Br, —I or —F. 
 
       
     
     
         16 - 19 . (canceled) 
     
     
         20 . A method of treating a dry eye disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structural Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,
 wherein: 
 Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; 
 L 1  and L 2  are independently substituted or unsubstituted C 1 -C 3  alkylene; 
 n1, n2, n3, n4 and n5 are independently an integer from 0 to 4; 
 m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or 2; 
 R 1  is hydrogen, halogen, —CX 1.1   3 , —CHX 1.1   2 , —CH 2 X 1.1 , —CN, —SO n1 R 1A , —SO v1 NR 1B R 1C , —NHNR 1B R 1C , —ONR 1B R 1C , —NHC(O)NHNR 1B R 1C , —NHC(O)NR 1B R 1C , —N(O) m1 , —NR 1B R 1C , —C(O)R 1D , —C(O)OR 1D , —C(O)NR 1B R 1C , —OR 1A , —NR 1B SO 2 R 1A , —NR 1B C(O)R 1D , —NR 1B C(O)OR 1D , —NR 1B OR 1D , —OCX 1.1   3 , —OCHX 1.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  is hydrogen, halogen, —CX 2.1   3 , —CHX 2.1   2 , —CH 2 X 2.1 , —CN, —SO n2 R 2A , —SO v2 NR 2B R 2C , —NHNR 2B R 2C , —ONR 2B R 2C , —NHC(O)NHNR 2B R 2C , —NHC(O)NR 2B R 2C , —N(O) m2 , —NR 2B R 2C , —C(O)R 2D , —C(O)OR 2D , —C(O)NR 2B R 2C , —OR 2A , —NR 2B SO 2 R 2A , —NR 2B C(O)R 2D , —NR 2B C(O)OR 2D , —NR 2B OR 2D , —OCX 2.1   3 , —OCHX 2.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 3  is hydrogen, halogen, —CX 3.1   3 , —CHX 3.1   2 , —CH 2 X 3.1 , —CN, —SO n3 R 3A , —SO v3 NR 3B R 3C , —NHNR 3B R 3C , —ONR 3B R 3C , —NHC(O)NHNR 3B R 3C , —NHC(O)NR 3B R 3C , —N(O) m3 , —NR 3B R 3C , —C(O)R 3D , —C(O)OR 3D , —C(O)NR 3B R 3C , —OR 3A , —NR 3B SO 2 R 3A , —NR 3B C(O)R 3D , —NR 3B C(O)OR 3D , —NR 3B OR 3D , —OCX 3.1   3 , —OCHX 3.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is hydrogen, halogen, —CX 4.1   3 , —CHX 4.1   2 , —CH 2 X 4.1 , —CN, —SO n4 R 4A , —SO v4 NR 4B R 4C , —NHNR 4B R 4C , —ONR 4B R 4C , —NHC(O)NHNR 4B R 4C , —NHC(O)NR 4B R 4C , —N(O) m4 , —NR 4B R 4C , —C(O)R 4D , —C(O)OR 4D , —C(O)NR 4B R 4C , —OR 4A , —NR 4B SO 2 R 4A , —NR 4B C(O)R 4D , —NR 4B C(O)OR 4D , —NR 4B OR 4D , —OCX 4.1   3 , —OCHX 4.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 5  is hydrogen, halogen, —CX 5.1   3 , —CHX 5.1   2 , —CH 2 X 5.1 , —CN, —SO n5 R 5A , —SO v5 NR 5B R 5C , —NHNR 5B R 5C , —ONR 5B R 5C , —NHC(O)NHNR 5B R 5C , —NHC(O)NR 5B R 5C , —N(O) m5 , —NR 5B R 5C , —C(O)R 5D , —C(O)OR 5D , —C(O)NR 5B R 5C , —OR 5A , —NR 5B SO 2 R 5A , —NR 5B C(O)R 5D , —NR 5B C(O)OR 5D , —NR 5B OR 5D , —OCX 5.1   3 , —OCHX 5.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C  and R 5D  are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —OCHF 2 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B  and R 5C  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and 
 X 1.1 , X 2.1 , X 3.1 , X 4.1  and X 5.1  are independently —Cl, —Br, —I or —F. 
 
       
     
     
         21 - 23 . (canceled) 
     
     
         24 . A method of increasing lacrimation, comprising administering to a subject in need thereof a compound of structural Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,
 wherein: 
 Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; 
 L 1  and L 2  are independently substituted or unsubstituted C 1 -C 3  alkylene; 
 n1, n2, n3, n4 and n5 are independently an integer from 0 to 4; 
 m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or 2; 
 R 1  is hydrogen, halogen, —CX 1.1   3 , —CHX 1.1   2 , —CH 2 X 1.1 , —CN, —SO n1 R 1A , —SO v1 NR 1B R 1C , —NHNR 1B R 1C , —ONR 1B R 1C , —NHC(O)NHNR 1B R 1C , —NHC(O)NR 1B R 1C , —N(O) m1 , —NR 1B R 1C , —C(O)R 1D , —C(O)OR 1D , —C(O)NR 1B R 1C , —OR 1A , —NR 1B SO 2 R 1A , —NR 1B C(O)R 1D , —NR 1B C(O)OR 1D , —NR 1B OR 1D , —OCX 1.1   3 , —OCHX 1.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  is hydrogen, halogen, —CX 2.1   3 , —CHX 2.1   2 , —CH 2 X 2.1 , —CN, —SO n2 R 2A , —SO v2 NR 2B R 2C , —NHNR 2B R 2C , —ONR 2B R 2C , —NHC(O)NHNR 2B R 2C , —NHC(O)NR 2B R 2C , —N(O) m2 , —NR 2B R 2C , —C(O)R 2D , —C(O)OR 2D , —C(O)NR 2B R 2C , —OR 2A , —NR 2B SO 2 R 2A , —NR 2B C(O)R 2D , —NR 2B C(O)OR 2D , —NR 2B OR 2D , —OCX 2.1   3 , —OCHX 2.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 3  is hydrogen, halogen, —CX 3.1   3 , —CHX 3.1   2 , —CH 2 X 3.1 , —CN, —SO n3 R 3A , —SO v3 NR 3B R 3C , —NHNR 3B R 3C , —ONR 3B R 3C , —NHC(O)NHNR 3B R 3C , —NHC(O)NR 3B R 3C , —N(O) m3 , —NR 3B R 3C , —C(O)R 3D , —C(O)OR 3D , —C(O)NR 3B R 3C , —OR 3A , —NR 3B SO 2 R 3A , —NR 3B C(O)R 3D , —NR 3B C(O)OR 3D , —NR 3B OR 3D , —OCX 3.1   3 , —OCHX 3.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is hydrogen, halogen, —CX 4.1   3 , —CHX 4.1   2 , —CH 2 X 4.1 , —CN, —SO n4 R 4A , —SO v4 NR 4B R 4C , —NHNR 4B R 4C , —ONR 4B R 4C , —NHC(O)NHNR 4B R 4C , —NHC(O)NR 4B R 4C , —N(O) m4 , —NR 4B R 4C , —C(O)R 4D , —C(O)OR 4D , —C(O)NR 4B R 4C , —OR 4A , —NR 4B SO 2 R 4A , —NR 4B C(O)R 4D , —NR 4B C(O)OR 4D , —NR 4B OR 4D , —OCX 4.1   3 , —OCHX 4.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 5  is hydrogen, halogen, —CX 5.1   3 , —CHX 5.1   2 , —CH 2 X 5.1 , —CN, —SO n5 R 5A , —SO 5v NR 5B R 5C , —NHNR 5B R 5C , —ONR 5B R 5C , —NHC(O)NHNR 5B R 5C , —NHC(O)NR 5B R 5C , —N(O) m5 , —NR 5B R 5C , —C(O)R 5D , —C(O)OR 5D , —C(O)NR 5B R 5C , —OR 5A , —NR 5B SO 2 R 5A , —NR 5B C(O)R 5D , —NR 5B C(O)OR 5D , —NR 5B OR 5D , —OCX 5.1   3 , —OCHX 5.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C  and R 5D  are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —OCHF 2 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B  and R 5C  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and 
 X 1.1 , X 2.1 , X 3.1 , X 4.1  and X 5.1  are independently —Cl, —Br, —I or —F. 
 
       
     
     
         25 . (canceled) 
     
     
         26 . A method of activating Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), comprising contacting CFTR with a compound of structural Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,
 wherein: 
 Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; 
 L 1  and L 2  are independently substituted or unsubstituted C 1 -C 3  alkylene; 
 n1, n2, n3, n4 and n5 are independently an integer from 0 to 4; 
 m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or 2; 
 R 1  is hydrogen, halogen, —CX 1.3 , —CHX 1.1   2 , —CH 2 X 1.1 , —CN, —SO n1 R 1A , —SO v1 NR 1B R 1C , —NHNR 1B R 1C , —ONR 1B R 1C , —NHC(O)NHNR 1B R 1C , —NHC(O)NR 1B R 1C , —N(O) m1 , —NR 1B R 1C , —C(O)R 1D , —C(O)OR 1D , —C(O)NR 1B R 1C , —OR 1A , —NR 1B SO 2 R 1A , —NR 1B C(O)R 1D , —NR 1B C(O)OR 1D , —NR 1B OR 1D , —OCX 1.1   3 , —OCHX 1.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  is hydrogen, halogen, —CX 2.1   3 , —CHX 2.1   2 , —CH 2 X 2.1 , —CN, —SO n2 R 2A , —SO v2 NR 2B R 2C , —NHNR 2B R 2C , —ONR 2B R 2C , —NHC(O)NHNR 2B R 2C , —NHC(O)NR 2B R 2C , —N(O) m2 , —NR 2B R 2C , —C(O)R 2D , —C(O)OR 2D , —C(O)NR 2B R 2C , —OR 2A , —NR 2B SO 2 R 2A , —NR 2B C(O)R 2D , —NR 2B C(O)OR 2D , —NR 2B OR 2D , —OCX 2.1   3 , —OCHX 2.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 3  is hydrogen, halogen, —CX 3.1   3 , —CHX 3.1   2 , —CH 2 X 3.1 , —CN, —SO n3 R 3A , —SO v3 NR 3B R 3C , —NHNR 3B R 3C , —ONR 3B R 3C , —NHC(O)NHNR 3B R 3C , —NHC(O)NR 3B R 3C , —N(O) m3 , —NR 3B R 3C , —C(O)R 3D , —C(O)OR 3D , —C(O)NR 3B R 3C , —OR 3A , —NR 3B SO 2 R 3A , —NR 3B C(O)R 3D , —NR 3B C(O)OR 3D , —NR 3B OR 3D , —OCX 3.1   3 , —OCHX 3.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is hydrogen, halogen, —CX 4.1   3 , —CHX 4.1   2 , —CH 2 X 4.1 , —CN, —SO n4 R 4A , —SO v4 NR 4B R 4C , —NHNR 4B R 4C , —ONR 4B R 4C , —NHC(O)NHNR 4B R 4C , —NHC(O)NR 4B R 4C , —N(O) m4 , —NR 4B R 4C , —C(O)R 4D , —C(O)OR 4D , —C(O)NR 4B R 4C , —OR 4A , —NR 4B SO 2 R 4A , —NR 4B C(O)R 4D , —NR 4B C(O)OR 4D , —NR 4B OR 4D , —OCX 4.1   3 , —OCHX 4.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 5  is hydrogen, halogen, —CX 5.1   3 , —CHX 5.1   2 , —CH 2 X 5.1 , —CN, —SO n5 R 5A , —SO v5 NR 5B R 5C , —NHNR 5B R 5C , —ONR 5B R 5C , —NHC(O)NHNR 5B R 5C , —NHC(O)NR 5B R 5C , —N(O) m5 , —NR 5B R 5C , —C(O)R 5D , —C(O)OR 5D , —C(O)NR 5B R 5C , —OR 5A , —NR 5B SO 2 R 5A , —NR 5B C(O)R 5D , —NR 5B C(O)OR 5D , —NR 5B OR 5D , —OCX 5.1   3 , —OCHX 5.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C  and R 5D  are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —OCHF 2 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B  and R 5C  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and 
 X 1.1 , X 2.1 , X 3.1 , X 4.1  and X 5.1  are independently —Cl, —Br, —I or —F. 
 
       
     
     
         27 . (canceled) 
     
     
         28 . A method of treating a cholestatic liver disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,
 wherein: 
 Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; 
 L 1  and L 2  are independently substituted or unsubstituted C 1 -C 3  alkylene; 
 n1, n2, n3, n4 and n5 are independently an integer from 0 to 4; 
 m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or 2; 
 R 1  is hydrogen, halogen, —CX 1.1   3 , —CHX 1.1   2 , —CH 2 X 1.1 , —CN, —SO n1 R 1A , —SO v1 NR 1B R 1C , —NHNR 1B R 1C , —ONR 1B R 1C , —NHC(O)NHNR 1B R 1C , —NHC(O)NR 1B R 1C , —N(O) m1 , —NR 1B R 1C , —C(O)R 1D , —C(O)OR 1D , —C(O)NR 1B R 1C , —OR 1A , —NR 1B SO 2 R 1A , —NR 1B C(O)R 1D , —NR 1B C(O)OR 1D , —NR 1B OR 1D , —OCX 1.1   3 , —OCHX 1.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  is hydrogen, halogen, —CX 2.1   3 , —CHX 2.1   2 , —CH 2 X 2.1 , —CN, —SO n2 R 2A , —SO v2 NR 2B R 2C , —NHNR 2B R 2C , —ONR 2B R 2C , —NHC(O)NHNR 2B R 2C , —NHC(O)NR 2B R 2C , —N(O) m2 , —NR 2B R 2C , —C(O)R 2D , —C(O)OR 2D , —C(O)NR 2B R 2C , —OR 2A , —NR 2B SO 2 R 2A , —NR 2B C(O)R 2D , —NR 2B C(O)OR 2D , —NR 2B OR 2D , —OCX 2.1   3 , —OCHX 2.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 3  is hydrogen, halogen, —CX 3.1   3 , —CHX 3.1   2 , —CH 2 X 3.1 , —CN, —SO n3 R 3A , —SO v3 NR 3B R 3C , —NHNR 3B R 3C , —ONR 3B R 3C , —NHC(O)NHNR 3B R 3C , —NHC(O)NR 3B R 3C , —N(O) m3 , —NR 3B R 3C , —C(O)R 3D , —C(O)OR 3D , —C(O)NR 3B R 3C , —OR 3A , —NR 3B SO 2 R 3A , —NR 3B C(O)R 3D , —NR 3B C(O)OR 3D , —NR 3B OR 3D , —OCX 3.1   3 , —OCHX 3.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is hydrogen, halogen, —CX 4.1   3 , —CHX 4.1   2 , —CH 2 X 4.1 , —CN, —SO n4 R 4A , —SO v4 NR 4B R 4C , —NHNR 4B R 4C , —ONR 4B R 4C , —NHC(O)NHNR 4B R 4C , —NHC(O)NR 4B R 4C , —N(O) m4 , —NR 4B R 4C , —C(O)R 4D , —C(O)OR 4D , —C(O)NR 4B R 4C , —OR 4A , —NR 4B SO 2 R 4A , —NR 4B C(O)R 4D , —NR 4B C(O)OR 4D , —NR 4B OR 4D , —OCX 4.1   3 , —OCHX 4.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 5  is hydrogen, halogen, —CX 5.1   3 , —CHX 5.1   2 , —CH 2 X 5.1 , —CN, —SO n5 R 5A , —SO v5 NR 5B R 5C , —NHNR 5B R 5C , —ONR 5B R 5C , —NHC(O)NHNR 5B R 5C , —NHC(O)NR 5B R 5C , —N(O) m5 , —NR 5B R 5C , —C(O)R 5D , —C(O)OR 5D , —C(O)NR 5B R 5C , —OR 5A , —NR 5B SO 2 R 5A , —NR 5B C(O)R 5D , —NR 5B C(O)OR 5D , —NR 5B OR 5D , —OCX 5.1   3 , —OCHX 5.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C , and R 5D  are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —OCHF 2 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B  and R 5C  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and 
 X 1.1 , X 2.1 , X 3.1 , X 4.1  and X 5.1  are independently —Cl, —Br, —I or —F. 
 
       
     
     
         29 . (canceled) 
     
     
         30 . A method of treating a pulmonary disease or disorder in a subject in need thereof, the method comprising administrating to the subject an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,
 wherein: 
 Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; 
 L 1  and L 2  are independently substituted or unsubstituted C 1 -C 3  alkylene; 
 n1, n2, n3, n4 and n5 are independently an integer from 0 to 4; 
 m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or 2; 
 R 1  is hydrogen, halogen, —CX 1.1   3 , —CHX 1.1   2 , —CH 2 X 1.1 , —CN, —SO n1 R 1A , —SO v1 NR 1B R 1C , —NHNR 1B R 1C , —ONR 1B R 1C , —NHC(O)NHNR 1B R 1C , —NHC(O)NR 1B R 1C , —N(O) m1 , —NR 1B R 1C , —C(O)R 1D , —C(O)OR 1D , —C(O)NR 1B R 1C , —OR 1A , —NR 1B SO 2 R 1A , —NR 1B C(O)R 1D , —NR 1B C(O)OR 1D , —NR 1B OR 1D , —OCX 1.1   3 , —OCHX 1.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  is hydrogen, halogen, —CX 2.1   3 , —CHX 2.1   2 , —CH 2 X 2.1 , —CN, —SO n2 R 2A , —SO v2 NR 2B R 2C , —NHNR 2B R 2C , —ONR 2B R 2C , —NHC(O)NHNR 2B R 2C , —NHC(O)NR 2B R 2C , —N(O) m2 , —NR 2B R 2C , —C(O)R 2D , —C(O)OR 2D , —C(O)NR 2B R 2C , —OR 2A , —NR 2B SO 2 R 2A , —NR 2B C(O)R 2D , —NR 2B C(O)OR 2D , —NR 2B OR 2D , —OCX 2.1   3 , —OCHX 2.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 3  is hydrogen, halogen, —CX 3.1   3 , —CHX 3.1   2 , —CH 2 X 3.1 , —CN, —SO n3 R 3A , —SO v3 NR 3B R 3C , —NHNR 3B R 3C , —ONR 3B R 3C , —NHC(O)NHNR 3B R 3C , —NHC(O)NR 3B R 3C , —N(O) m3 , —NR 3B R 3C , —C(O)R 3D , —C(O)OR 3D , —C(O)NR 3B R 3C , —OR 3A , —NR 3B SO 2 R 3A , —NR 3B C(O)R 3D , —NR 3B C(O)OR 3D , —NR 3B OR 3D , —OCX 3.1   3 , —OCHX 3.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 4  is hydrogen, halogen, —CX 4.1   3 , —CHX 4.1   2 , —CH 2 X 4.1 , —CN, —SO n4 R 4A , —SO v4 NR 4B R 4C , —NHNR 4B R 4C , —ONR 4B R 4C , —NHC(O)NHNR 4B R 4C , —NHC(O)NR 4B R 4C , —N(O) m4 , —NR 4B R 4C , —C(O)R 4D , —C(O)OR 4D , —C(O)NR 4B R 4C , —OR 4A , —NR 4B SO 2 R 4A , —NR 4B C(O)R 4D , —NR 4B C(O)OR 4D , —NR 4B OR 4D , —OCX 4.1   3 , —OCHX 4.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 5  is hydrogen, halogen, —CX 5.1   3 , —CHX 5.1   2 , —CH 2 X 5.1 , —CN, —SO n5 R 5A , —SO v4 NR 5B R 5C , —NHNR 5B R 5C , —ONR 5B R 5C , —NHC(O)NHNR 5B R 5C , —NHC(O)NR 5B R 5C , —N(O) m5 , —NR 5B R 5C , —C(O)R 5D , —C(O)OR 5D , —C(O)NR 5B R 5C , —OR 5A , —NR 5B SO 2 R 5A , —NR 5B C(O)R 5D , —NR 5B C(O)OR 5D , —NR 5B OR 5D , —OCX 5.1   3 , —OCHX 5.1   2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 5A , R 5B , R 5C  and R 5D  are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —OCHF 2 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1B , R 1C , R 2B , R 2C , R 3B , R 3C , R 4B , R 4C , R 5B  and R c  substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and 
 X 1.1 , X 2.1 , X 3.1 , X 4.1  and X 5.1  are independently —Cl, —Br, —I or —F. 
 
       
     
     
         31 - 44 . (canceled) 
     
     
         45 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof,
 wherein: 
 L 1  and L 2  are —CH 2 —; and 
 R 1 , R 2 , R 3 , R 4  and R 5  are independently hydrogen, —OCH 3  or —OCH 2 CH 3 . 
 
       
     
     
         46 - 48 . (canceled)

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