CFTR regulators and methods of use thereof

A method of treating a dry eye disorder in a subject in need thereof, comprising administering to the subject an effective amount a compound of Formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• X is —O—, —NH— or —S—;
• n1, n2, n6, n7, n8, and n9 are independently an integer from 0 to 4;
• m1, m6, m7, m8, m9, v1, v6, v7, v8, and v9 are each independently 1 or 2;
• R1 is hydrogen, halogen, —CX1.13, —CHX1.12, —CH2X1.1, —CN, —SOn1R1A, —SOv1NR1BR1C, —NHNR1BR1C, —ONR1BR1C, —NHC(O)NHNR1BR1C, —NHC(O)NR1BR1C, —N(O)m1, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —NR1BSO2R1A, —NR1BC(O)R1D, —NR1BC(O)OR1D, —NR1BOR1D, —OCX1.13, —OCHX1.12, 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;
• R2 is hydrogen, —CX2.13, CHX2.12, —(CH2)n2CX2.13, —OR2A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or haloalkyl;
• R3 is hydrogen, —C(O)R3D, —C(O)NHNR3BR3C, —C(O)OR3D, —SO2R3A, C(O)NR3BR3C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
• R4 is hydrogen, —C(O)R4D, —C(O)NHNR4BR4C, —C(O)OR4D, —SO2R4A, C(O)NR4BR4C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R3 and R4 may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein R3 and R4 are optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R5 is hydrogen, —C(O)R5D, —C(O)NHNR5BR5C, —C(O)OR5D, —SO2R5A, C(O)NR5BR5C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R3 and R4 may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• R6 is hydrogen, halogen, —CX6.13, —CHX6.12, —CH2X6.1, —CN, —SOn6R6A, —SOv6NR6BR6C, —NHNR6BR6C, —ONR6BR6C, —NHC(O)NHNR6BR6C, —NHC(O)NR6BR6C, —N(O)m6, —NR6BR6C, —C(O)R6D, —C(O)OR6D, —C(O)NR6BR6C, —OR6A, —NR6BSO2R6A, —NR6BC(O)R6D, —NR6BC(O)OR6D, —NR6BOR6D, —OCX6.13, —OCHX6.12, 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;
• R7 is hydrogen, halogen, —CX7.13, —CHX7.12, —CH2X7.1, —CN, —SOn7R7A, —SOv7NR7BR7C, —NHNR7BR7C, —ONR7BR7C, —NHC(O)NHNR7BR7C, —NHC(O)NR7BR7C, —N(O)m7, —NR7BR7C, —C(O)R7D, —C(O)OR7D, —C(O)NR7BR7C, —OR7A, —NR7BSO2R7A, —NR7AC(O)R7C, —NR7BC(O)OR7D, —NR7BOR7D, —OCX7.13, —OCHX7.12, 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;
• R8 is hydrogen, halogen, —CX8.13, —CHX8.12, —CH2X8.1, —CN, —SOn8R8A, —SOv8NR8BR8C, —NHNR8BR8C, —ONR8BR8C, —NHC(O)NHNR8BR8C, —NHC(O)NR8BR8C, —N(O)m8, —NR8BR8C, —C(O)R8D, —C(O)OR8D, —C(O)NR8BR8C, —OR8A, —NR8BSO2R8A, —NR8BC(O)R8D, —NR8BC(O)OR8D, —NR8BOR8D, —OCX8.13, —OCHX8.12, 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;
• R9 is hydrogen, halogen, —CX9.13, —CHX9.12, —CH2X9.1, —CN, —SOn9R9A, —SOv9NR9BR9C, —NHNR9BR9C, —ONR9BR9C, —NHC(O)NHNR9BR9C, —NHC(O)NR9BR9C, —N(O)m9, —NR9BR9C, —C(O)R9D, —C(O)OR9D, —C(O)NR9BR9C, —OR9A, —NR9BSO2R9A, —NR9BC(O)R9D, —NR9BC(O)OR9D, —NR9BOR9D, —OCX9.13, —OCHX9.12, 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;
• R1 and R6, R6 and R7, R1 and R9, or R8, and R9 are optionally joined to form, together with the atoms to which they are attached, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R8A, R8B, R8C, R8D, R9A, R9B, R9C and R9D are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, 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;
• R1B, R1C, R2B, R2C, R3B, R3C, R4B, R4C, R5B, R5C, R6B, R6C, R7B, R7C, R8B, R8C, R9B and R9C substituents bonded to the same nitrogen atom may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• and
• X1.1, X2.1, X6.1, X7.1, X8.1 and X9.1 are independently —Cl, —Br, —I or —F;
• with the proviso that when X is —O—;
• R2 is —(CH2)n2CX2.13;
• n2 is 1;
• X2.1 is fluorine;
• R3 is hydrogen;
• and R4 is substituted or unsubstituted C1-C3 alkyl, then R6 is not —NO2;
• and when X is —O—;
• R2 is —(CH2)n2CX2.13;
• n2 is 1;
• X2.1 is fluorine;
• R3 is hydrogen;
• and R4 is substituted or unsubstituted C1-C3 alkyl, then R9 is not —NO2.

A method of increasing lacrimation in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• X is —O—, —NH— or —S—;
• n1, n2, n6, n7, n8, and n9 are independently an integer from 0 to 4;
• m1, m6, m7, m8, m9, v1, v6, v7, v8, and v9 are each independently 1 or 2;
• R1 is hydrogen, halogen, —CX1.13, —CHX1.12, —CH2X1.1, —CN, —SOn1R1A, —SOv1NR1BR1C, —NHNR1BR1C, —ONR1BR1C, —NHC(O)NHNR1BR1C, —NHC(O)NR1BR1C, —N(O)m1, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —NR1BSO2R1A, —NR1BC(O)R1D, —NR1BC(O)OR1D, —NR1BOR1D, —OCX1.13, —OCHX1.12, 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;
• R2 is hydrogen, —CX2.13, CHX2.12, —(CH2)n2CX2.13, —OR2A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or haloalkyl;
• R3 is hydrogen, —C(O)R3D, —C(O)NHNR3BR3C, —C(O)OR3D, —SO2R3A, C(O)NR3BR3C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
• R4 is hydrogen, —C(O)R4D, —C(O)NHNR4BR4C, —C(O)OR4D, —SO2R4A, C(O)NR4BR4C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R3 and R4 may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein R3 and R4 are optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R5 is hydrogen, —C(O)R5D, —C(O)NHNR5BR5C, —C(O)OR5D, —SO2R5A, C(O)NR5BR5C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R3 and R4 may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• R6 is hydrogen, halogen, —CX6.13, —CHX6.12, —CH2X6.1, —CN, —SOn6R6A, —SOv6NR6BR6C, —NHNR6BR6C, —ONR6BR6C, —NHC(O)NHNR6BR6C, —NHC(O)NR6BR6C, —N(O)m6, —NR6BR6C, —C(O)R6D, —C(O)OR6D, —C(O)NR6BR6C, —OR6A, —NR6BSO2R6A, —NR6BC(O)R6D, —NR6BC(O)OR6D, —NR6BOR6D, —OCX6.13, —OCHX6.12, 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;
• R7 is hydrogen, halogen, —CX7.13, —CHX7.12, —CH2X7.1, —CN, —SOn7R7A, —SOv7NR7BR7C, —NHNR7BR7C, —ONR7BR7C, —NHC(O)NHNR7BR7C, —NHC(O)NR7BR7C, —N(O)m7, —NR7BR7C, —C(O)R7D, —C(O)OR7D, —C(O)NR7BR7C, —OR7A, —NR7BSO2R7A, —NR7AC(O)R7C, —NR7BC(O)OR7D, —NR7BOR7D, —OCX7.13, —OCHX7.12, 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;
• R8 is hydrogen, halogen, —CX8.13, —CHX8.12, —CH2X8.1, —CN, —SOn8R8A, —SOv8NR8BR8C, —NHNR8BR8C, —ONR8BR8C, —NHC(O)NHNR8BR8C, —NHC(O)NR8BR8C, —N(O)m8, —NR8BR8C, —C(O)R8D, —C(O)OR8D, —C(O)NR8BR8C, —OR8A, —NR8BSO2R8A, —NR8BC(O)R8D, —NR8BC(O)OR8D, —NR8BOR8D, —OCX8.13, —OCHX8.12, 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;
• R9 is hydrogen, halogen, —CX9.13, —CHX9.12, —CH2X9.1, —CN, —SOn9R9A, —SOv9NR9BR9C, —NHNR9BR9C, —ONR9BR9C, —NHC(O)NHNR9BR9C, —NHC(O)NR9BR9C, —N(O)m9, —NR9BR9C, —C(O)R9D, —C(O)OR9D, —C(O)NR9BR9C, —OR9A, —NR9BSO2R9A, —NR9BC(O)R9D, —NR9BC(O)OR9D, —NR9BOR9D, —OCX9.13, —OCHX9.12, 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;
• R1 and R6, R6 and R7, R1 and R9, or R8, and R9 are optionally joined to form, together with the atoms to which they are attached, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R8A, R8B, R8C, R8D, R9A, R9B, R9C and R9D are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, 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;
• R1B, R1C, R2B, R2C, R3B, R3C, R4B, R4C, R5B, R5C, R6B, R6C, R7B, R7C, R8B, R8C, R9B and R9C substituents bonded to the same nitrogen atom may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• and
• X1.1, X2.1, X6.1, X7.1, X8.1 and X9.1 are independently —Cl, —Br, —I or —F;
• with the proviso that when X is —O—;
• R2 is —(CH2)n2CX2.13;
• n2 is 1;
• X2.1 is fluorine;
• R3 is hydrogen;
• and R4 is substituted or unsubstituted C1-C3 alkyl, then R6 is not —NO2;
• and when X is —O—;
• R2 is —(CH2)n2CX2.13;
• n2 is 1;
• X2.1 is fluorine;
• R3 is hydrogen;
• and R4 is substituted or unsubstituted C1-C3 alkyl, then R9 is not —NO2.

A method of activating a Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), comprising contacting the CFTR with an effective amount of a compound of Formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• X is —O—, —NH— or —S—;
• n1, n2, n6, n7, n8, and n9 are independently an integer from 0 to 4;
• m1, m6, m7, m8, m9, v1, v6, v7, v8, and v9 are each independently 1 or 2;
• R1 is hydrogen, halogen, —CX1.13, —CHX1.12, —CH2X1.1, —CN, —SOn1R1A, —SOv1NR1BR1C, —NHNR1BR1C, —ONR1BR1C, —NHC(O)NHNR1BR1C, —NHC(O)NR1BR1C, —N(O)m1, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —NR1BSO2R1A, —NR1BC(O)R1D, —NR1BC(O)OR1D, —NRBOR1D, —OCX1.13, —OCHX1.12, 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;
• R2 is hydrogen, —CX2.13, CHX2.12, —(CH2)n2CX2.13, —OR2A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or haloalkyl;
• R3 is hydrogen, —C(O)R3D, —C(O)NHNR3BR3C, —C(O)OR3D, —SO2R3A, C(O)NR3BR3C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
• R4 is hydrogen, —C(O)R4D, —C(O)NHNR4BR4C, —C(O)OR4D, —SO2R4A, C(O)NR4BR4C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R3 and R4 may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein R3 and R4 are optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R5 is hydrogen, —C(O)R5D, —C(O)NHNR5BR5C, —C(O)OR5D, —SO2R5A, C(O)NR5BR5C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R3 and R4 may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• R6 is hydrogen, halogen, —CX6.13, —CHX6.12, —CH2X6.1, —CN, —SOn6R6A, —SOv6NR6BR6C, —NHNR6BR6C, —ONR6BR6C, —NHC(O)NHNR6BR6C, —NHC(O)NR6BR6C, —N(O)m6, —NR6BR6C, —C(O)R6D, —C(O)OR6D, —C(O)NR6BR6C, —OR6A, —NR6BSO2R6A, —NR6BC(O)R6D, —NR6BC(O)OR6D, —NR6BOR6D, —OCX6.13, —OCHX6.12, 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;
• R7 is hydrogen, halogen, —CX7.13, —CHX7.12, —CH2X7.1, —CN, —SOn7R7A, —SOv7NR7BR7C, —NHNR7BR7C, —ONR7BR7C, —NHC(O)NHNR7BR7C, —NHC(O)NR7BR7C, —N(O)m7, —NR7BR7C, —C(O)R7D, —C(O)OR7D, —C(O)NR7BR7C, —OR7A, —NR7BSO2R7A, —NR7AC(O)R7C, —NR7BC(O)OR7D, —NR7BOR7D, —OCX7.13, —OCHX7.12, 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;
• R8 is hydrogen, halogen, —CX8.13, —CHX8.12, —CH2X8.1, —CN, —SOn8R8A, —SOv8NR8BR8C, —NHNR8BR8C, —ONR8BR8C, —NHC(O)NHNR8BR8C, —NHC(O)NR8BR8C, —N(O)m8, —NR8BR8C, —C(O)R8D, —C(O)OR8D, —C(O)NR8BR8C, —OR8A, —NR8BSO2R8A, —NR8BC(O)R8D, —NR8BC(O)OR8D, —NR8BOR8D, —OCX8.13, —OCHX8.12, 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;
• R9 is hydrogen, halogen, —CX9.13, —CHX9.12, —CH2X9.1, —CN, —SOn9R9A, —SOv9NR9BR9C, —NHNR9BR9C, —ONR9BR9C, —NHC(O)NHNR9BR9C, —NHC(O)NR9BR9C, —N(O)m9, —NR9BR9C, —C(O)R9D, —C(O)OR9D, —C(O)NR9BR9C, —OR9A, —NR9BSO2R9A, —NR9BC(O)R9D, —NR9BC(O)OR9D, —NR9BOR9D, —OCX9.13, —OCHX9.12, 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;
• R1 and R6, R6 and R7, R1 and R9, or R8, and R9 are optionally joined to form, together with the atoms to which they are attached, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R8A, R8B, R8C, R8D, R9A, R9B, R9C and R9D are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, 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;
• R1B, R1C, R2B, R2C, R3B, R3C, R4B, R4C, R5B, R5C, R6B, R6C, R7B, R7C, R8B, R8C, R9B and R9C substituents bonded to the same nitrogen atom may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• and
• X1.1, X2.1, X6.1, X7.1, X8.1 and X9.1 are independently —Cl, —Br, —I or —F;
• with the proviso that when X is —O—;
• R2 is —(CH2)n2CX2.13;
• n2 is 1;
• X2.1 is fluorine;
• R3 is hydrogen;
• and R4 is substituted or unsubstituted C1-C3 alkyl, then R6 is not —NO2;
• and when X is —O—;
• R2 is —(CH2)n2CX2.13;
• n2 is 1;
• X2.1 is fluorine;
• R3 is hydrogen;
• and R4 is substituted or unsubstituted C1-C3 alkyl, then R9 is not —NO2.

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:
• X is —O—, —NH— or —S—;
• n1, n2, n6, n7, n8, and n9 are independently an integer from 0 to 4;
• m1, m6, m7, m8, m9, v1, v6, v7, v8, and v9 are each independently 1 or 2;
• R1 is hydrogen, halogen, —CX1.13, —CHX1.12, —CH2X1.1, —CN, —SOn1R1A, —SOv1NR1BR1C, —NHNR1BR1C, —ONR1BR1C, —NHC(O)NHNR1BR1C, —NHC(O)NR1BR1C, —N(O)m1, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —NR1BSO2R1A, —NR1BC(O)R1D, —NR1BC(O)OR1D, —NR1BOR1D, —OCX1.13, —OCHX1.12, 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;
• R2 is hydrogen, —CX2.13, CHX2.12, —(CH2)n2CX2.13, —OR2A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or haloalkyl;
• R3 is hydrogen, —C(O)R3D, —C(O)NHNR3BR3C, —C(O)OR3D, —SO2R3A, C(O)NR3BR3C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
• R4 is hydrogen, —C(O)R4D, —C(O)NHNR4BR4C, —C(O)OR4D, —SO2R4A, C(O)NR4BR4C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R3 and R4 may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein R3 and R4 are optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R5 is hydrogen, —C(O)R5D, —C(O)NHNR5BR5C, —C(O)OR5D, —SO2R5A, C(O)NR5BR5C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R3 and R4 may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• R6 is hydrogen, halogen, —CX6.13, —CHX6.12, —CH2X6.1, —CN, —SOn6R6A, —SOv6NR6BR6C, —NHNR6BR6C, —ONR6BR6C, —NHC(O)NHNR6BR6C, —NHC(O)NR6BR6C, —N(O)m6, —NR6BR6C, —C(O)R6D, —C(O)OR6D, —C(O)NR6BR6C, —OR6A, —NR6BSO2R6A, —NR6BC(O)R6D, —NR6BC(O)OR6D, —NR6BOR6D, —OCX6.13, —OCHX6.12, 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;
• R7 is hydrogen, halogen, —CX7.13, —CHX7.12, —CH2X7.1, —CN, —SOn7R7A, —SOv7NR7BR7C, —NHNR7BR7C, —ONR7BR7C, —NHC(O)NHNR7BR7C, —NHC(O)NR7BR7C, —N(O)m7, —NR7BR7C, —C(O)R7D, —C(O)OR7D, —C(O)NR7BR7C, —OR7A, —NR7BSO2R7A, —NR7AC(O)R7C, —NR7BC(O)OR7D, —NR7BOR7D, —OCX7.13, —OCHX7.12, 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;
• R8 is hydrogen, halogen, —CX8.13, —CHX8.12, —CH2X8.1, —CN, —SOn8R8A, —SOv8NR8BR8C, —NHNR8BR8C, —ONR8BR8C, —NHC(O)NHNR8BR8C, —NHC(O)NR8BR8C, —N(O)m8, —NR8BR8C, —C(O)R8D, —C(O)OR8D, —C(O)NR8BR8C, —OR8A, —NR8BSO2R8A, —NR8BC(O)R8D, —NR8BC(O)OR8D, —NR8BOR8D, —OCX8.13, —OCHX8.12, 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;
• R9 is hydrogen, halogen, —CX9.13, —CHX9.12, —CH2X9.1, —CN, —SOn9R9A, —SOv9NR9BR9C, —NHNR9BR9C, —ONR9BR9C, —NHC(O)NHNR9BR9C, —NHC(O)NR9BR9C, —N(O)m9, —NR9BR9C, —C(O)R9D, —C(O)OR9D, —C(O)NR9BR9C, —OR9A, —NR9BSO2R9A, —NR9BC(O)R9D, —NR9BC(O)OR9D, —NR9BOR9D, —OCX9.13, —OCHX9.12, 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;
• R1 and R6, R6 and R7, R1 and R9, or R8, and R9 are optionally joined to form, together with the atoms to which they are attached, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R8A, R8B, R8C, R8D, R9A, R9B, R9C and R9D are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, 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;
• R1B, R1C, R2B, R2C, R3B, R3C, R4B, R4C, R5B, R5C, R6B, R6C, R7B, R7C, R8B, R8C, R9B and R9C substituents bonded to the same nitrogen atom may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• and
• X1.1, X2.1, X6.1, X7.1, X8.1 and X9.1 are independently —Cl, —Br, —I or —F;
• with the proviso that when X is —O—;
• R2 is —(CH2)n2CX2.13;
• n2 is 1;
• X2.1 is fluorine;
• R3 is hydrogen;
• and R4 is —CH3, then R6 is not —NO2;
• and when X is —O—;
• R2 is —(CH2)n2CX2.13;
• n2 is 1;
• X2.1 is fluorine;
• R3 is hydrogen;
• and R4 is —CH3, then R9 is not —NO2.

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:
• X is —O—, —NH— or —S—;
• n1, n2, n6, n7, n8, and n9 are independently an integer from 0 to 4;
• m1, m6, m7, m8, m9, v1, v6, v7, v8, and v9 are each independently 1 or 2;
• R1 is hydrogen, halogen, —CX1.13, —CHX1.12, —CH2X1.1, —CN, —SOn1R1A, —SOv1NR1BR1C, —NHNR1BR1C, —ONR1BR1C, —NHC(O)NHNR1BR1C, —NHC(O)NR1BR1C, —N(O)m1, —NR1BR1C, —C(O)R1D, —C(O)OR1D, —C(O)NR1BR1C, —OR1A, —NR1BSO2R1A, —NR1BC(O)R1D, —NR1BC(O)OR1D, —NR1BOR1D, —OCX1.13, —OCHX1.12, 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;
• R2 is hydrogen, —CX2.13, CHX2.12, —(CH2)n2CX2.13, —OR2A, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or haloalkyl;
• R3 is hydrogen, —C(O)R3D, —C(O)NHNR3BR3C, —C(O)OR3D, —SO2R3A, C(O)NR3BR3C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
• R4 is hydrogen, —C(O)R4D, —C(O)NHNR4BR4C, —C(O)OR4D, —SO2R4A, C(O)NR4BR4C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R3 and R4 may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl, wherein R3 and R4 are optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R5 is hydrogen, —C(O)R5D, —C(O)NHNR5BR5C, —C(O)OR5D, —SO2R5A, C(O)NR5BR5C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, wherein R3 and R4 may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• R6 is hydrogen, halogen, —CX6.13, —CHX6.12, —CH2X6.1, —CN, —SOn6R6A, —SOv6NR6BR6C, —NHNR6BR6C, —ONR6BR6C, —NHC(O)NHNR6BR6C, —NHC(O)NR6BR6C, —N(O)m6, —NR6BR6C, —C(O)R6D, —C(O)OR6D, —C(O)NR6BR6C, —OR6A, —NR6BSO2R6A, —NR6BC(O)R6D, —NR6BC(O)OR6D, —NR6BOR6D, —OCX6.13, —OCHX6.12, 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;
• R7 is hydrogen, halogen, —CX7.13, —CHX7.12, —CH2X7.1, —CN, —SOn7R7A, —SOv7NR7BR7C, —NHNR7BR7C, —ONR7BR7C, —NHC(O)NHNR7BR7C, —NHC(O)NR7BR7C, —N(O)m7, —NR7BR7C, —C(O)R7D, —C(O)OR7D, —C(O)NR7BR7C, —OR7A, —NR7BSO2R7A, —NR7AC(O)R7C, —NR7BC(O)OR7D, —NR7BOR7D, —OCX7.13, —OCHX7.12, 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;
• R8 is hydrogen, halogen, —CX8.13, —CHX8.12, —CH2X8.1, —CN, —SOn8R8A, —SOv8NR8BR8C, —NHNR8BR8C, —ONR8BR8C, —NHC(O)NHNR8BR8C, —NHC(O)NR8BR8C, —N(O)m8, —NR8BR8C, —C(O)R8D, —C(O)OR8D, —C(O)NR8BR8C, —OR8A, —NR8BSO2R8A, —NR8BC(O)R8D, —NR8BC(O)OR8D, —NR8BOR8D, —OCX8.13, —OCHX8.12, 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;
• R9 is hydrogen, halogen, —CX9.13, —CHX9.12, —CH2X9.1, —CN, —SOn9R9A, —SOv9NR9BR9C, —NHNR9BR9C, —ONR9BR9C, —NHC(O)NHNR9BR9C, —NHC(O)NR9BR9C, —N(O)m9, —NR9BR9C, —C(O)R9D, —C(O)OR9D, —C(O)NR9BR9C, —OR9A, —NR9BSO2R9A, —NR9BC(O)R9D, —NR9BC(O)OR9D, —NR9BOR9D, —OCX9.13, —OCHX9.12, 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;
• R1 and R6, R6 and R7, R1 and R9, or R8, and R9 are optionally joined to form, together with the atoms to which they are attached, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
• R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R8A, R8B, R8C, R8D, R9A, R9B, R9C and R9D are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF3, —OCCl3, —OCBr3, —OCI3, —OCHF2, —OCHCl2, —OCHBr2, —OCHI2, 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;
• R1B, R1C, R2B, R2C, R3B, R3C, R4B, R4C, R5B, R5C, R6B, R6C, R7B, R7C, R8B, R8C, R9B and R9C substituents bonded to the same nitrogen atom may optionally be joined to form, together with the atoms to which they are attached, a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
• and
• X1.1, X2.1, X6.1, X7.1, X8.1 and X9.1 are independently —Cl, —Br, —I or —F;
• with the proviso that when X is —O—;
• R2 is —(CH2)n2CX2.13;
• n2 is 1;
• X2.1 is fluorine;
• R3 is hydrogen;
• and R4 is —CH3, then R6 is not —NO2;
• and when X is —O—;
• R2 is —(CH2)n2CX2.13;
• n2 is 1;
• X2.1 is fluorine;
• R3 is hydrogen;
• and R4 is —CH3, then R9 is not —NO2.