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1. (WO2018022992) CHEMOKINE RECEPTOR MODULATORS AND USES THEREOF
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

WHAT IS CLAIMED IS:

1. A compound havin structural Formula I :


(I),

or a pharmaceutically acceptable salt thereof, wherein:

X1 is CR8 or N;

X2 is CR9 or N;

X3 is CR10 or N;

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;

z1 is an integer from 0 to 5;

z2 is an integer from 0 to 2;

z3 is an integer from 0 to 11;

z4 is an integer from 0 to 2;

L7 is a bond,–O–,–S–,–NR7.2B–,–C(O)–, -C(O)O–,–S(O)–,–S(O)2–, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R1 is hydrogen, halogen,–CX1.1

3, -CHX1.1

2, -CH2X1.1,–CN,–N3,–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,–OCX1.1

3,–OCHX1.1

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;

R2 is hydrogen, halogen,–CX2.1

3, -CHX2.1

2, -CH2X2.1,–CN,–N3,–SOn2R2A,

–SOv2NR2BR2C, -NHNR2BR2C, ^ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C,– N(O)m2,–NR2BR2C,–C(O)R2D,–C(O)OR2D,–C(O)NR2BR2C,–OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D,–NR2BOR2D,–OCX2.1

3,–OCHX2.1

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;

R3 is independently hydrogen, halogen,–CX3.1

3, -CHX3.1

2, -CH2X3.1,–CN,–N3, –SOn3R3A,–SOv3NR3BR3C, -NHNR3BR3C, ^ONR3BR3C, -NHC(O)NHNR3BR3C,

-NHC(O)NR3BR3C,–N(O)m3,–NR3BR3C,–C(O)R3D,–C(O)OR3D,–C(O)NR3BR3C,–OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D,–NR3BOR3D,–OCX3.1

3,–OCHX3.1

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;

R4 is hydrogen, halogen,–CX4.1

3, -CHX4.1

2, -CH2X4.1,–CN,–N3,–SOn4R4A, –SOv4NR4BR4C, -NHNR4BR4C, ^ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C,– N(O)m4,–NR4BR4C,–C(O)R4D,–C(O)OR4D,–C(O)NR4BR4C,–OR4A, -NR4BSO2R4A, -NR4BC(O)R4D, -NR4BC(O)OR4D,–NR4BOR4D,–OCX4.1

3,–OCHX4.1

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;

R5 is independently hydrogen, halogen, oxo,–CX5.1

3, -CHX5.1

2, -CH2X5.1,–CN, –N3,–SOn5R5A,–SOv5NR5BR5C, -NHNR5BR5C, ^ONR5BR5C, -NHC(O)NHNR5BR5C,

-NHC(O)NR5BR5C,–N(O)m5,–NR5BR5C,–C(O)R5D,–C(O)OR5D,–C(O)NR5BR5C,–OR5A, -NR5BSO2R5A, -NR5BC(O)R5D, -NR5BC(O)OR5D,–NR5BOR5D,–OCX5.1

3,–OCHX5.1

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;

R6 is independently hydrogen, halogen, oxo,–CX6.1

3, -CHX6.1

2, -CH2X6.1,–CN,– N3,–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,–OCX6.1

3,–OCHX6.1

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;

R7 is hydrogen, halogen,–CX7.1

3, -CHX7.1

2, -CH2X7.1,–CN,–N3,–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, -NR7BC(O)R7D, -NR7BC(O)OR7D,–NR7BOR7D,–OCX7.1

3,–OCHX7.1

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;

R8 is hydrogen, halogen,–CX8.1

3, -CHX8.1

2, -CH2X8.1,–CN,–N3,–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,–OCX8.1

3,–OCHX8.1

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;

R9 is hydrogen, halogen,–CX9.1

3, -CHX9.1

2, -CH2X9.1,–CN,–N3,–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,–OCX9.1

3,–OCHX9.1

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;

R10 is hydrogen, halogen,–CX10.1

3, -CHX10.1

2, -CH2X10.1,–CN,–N3,–SOn10R10A, –SOv10NR10BR10C, -NHNR10BR10C, ^ONR10BR10C, -NHC(O)NHNR10BR10C,

-NHC(O)NR10BR10C,–N(O)m10,–NR10BR10C,–C(O)R10D,–C(O)OR10D,–C(O)NR10BR10C,– OR10A, -NR10BSO2R10A, -NR10BC(O)R10D, -NR10BC(O)OR10D,–NR10BOR10D,–OCX10.1

3,– OCHX10.1

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;

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, R7.2B, R8A, R8B, R8C, R8D, R9A, R9B, R9C, R9D, R10A, R10B, R10C and R10D are independently hydrogen, halogen,–CF3,–CCl3,–CBr3,–CI3,– COOH,–CONH2, 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, R9C, R10B and R10C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted

heterocycloalkyl or substituted or unsubstituted heteroaryl; and

X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X7.1, X8.1, X9.1 and X10.1 are independently–Cl,– Br,–I or–F,

wherein at least one of X1, X2 and X3 is N.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

z1 is 2;

z2 is 0;

z4 is 1; and

R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -F, -OH, CH2OH, -(CH2)2OH, -(CH2)3OH, -C(CH3)2OH, -CH2SO2NH2,–(CH2)2SO2NH2, -CH2C(O)NH2, -(CH2)2C(O)NH2, -(CH2)3C(O)NH2, -CH2NHSO2CF3, -(CH2)2NHSO2CF3, -(CH2)3NHSO2CF3, -CH2NHSO2CH3, -(CH2)2NHSO2CH3, -(CH2)3NHSO2CH3, -CH2SO2CH3,–(CH2)2SO2CH3, -CH2SO2NH2 or–(CH2)2SO2NH2.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has structural Formula (II):

wherein:

n3.2, and n3.3 are independently an integer from 0 to 4;

m3.2, m3.3, v3.2 and v3.3 are independently 1 or 2

R4 is hydrogen,–CX4.1

3,–CN,–C(O)NR4BR4C, 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;

R3.2 is hydrogen, halogen,–CX3.2

3, -CHX3.2

2, -CH2X3.2,–CN,–N3,–SOn3.2R3.2A, –SOv3.2NR3.2BR3.2C, -NHNR3.2BR3.2C, ^ONR3.2BR3.2C, -NHC(O)NHNR3.2BR3.2C,

-NHC(O)NR3.2BR3.2C,–N(O)m3.2,–NR3.2BR3.2C,–C(O)R3.2D,–C(O)OR3.2D,–C(O)NR3.2BR3.2C,– OR3.2A, -NR3.2BSO2R3.2A, -NR3.2BC(O)R3.2D, -NR3.2BC(O)OR3.2D,–NR3.2BOR3.2D,–OCX3.2

3,– OCHX3.22, 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;

R3.3 is hydrogen, halogen,–CX3.3

3, -CHX3.3

2, -CH2X3.3,–CN,–N3,–SOn3.3R3.3A, –SOv3.3NR3.3BR3.3C, -NHNR3.3BR3.3C, ^ONR3.3BR3.3C, -NHC(O)NHNR3.3BR3.3C,

-NHC(O)NR3.3BR3.3C,–N(O)m3.3,–NR3.3BR3.3C,–C(O)R3.3D,–C(O)OR3.3D,–C(O)NR3.3BR3.3C,– OR3.3A, -NR3.3BSO2R3.3A, -NR3.3BC(O)R3.3D, -NR3.3BC(O)OR3.3D,–NR3.3BOR3.3D,–OCX3.3

3,– OCHX3.3

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;

R3.2A, R3.2B, R3.2C, R3.2D, R3.3A, R3.3B, R3.3C and R3.3D are independently hydrogen, halogen,–CF3,–CCl3,–CBr3,–CI3,–COOH,–CONH2, 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; R3.2B, R3.2C, R3.3B and R3.3C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and

X3.2 and X3.3 are independently–Cl,–Br,–I or–F.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound has structural Formula (IIa):

6. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound has structural Formula (IIb):


(IIb).

7. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein the compound has structural Formula (IIc):

8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein the compound has structural Formula (IId):

9. The compound of claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein z4 is 1.

10. The compound of claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R2 is substituted or unsubstituted alkyl.

13. The compound of claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen,–CN, -C(O)NH2,–CX4.1

3 or substituted or unsubstituted alkyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R4 is–CN,–C(O)NH2, -CF3 or–CH3.

15. The compound of claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein R3.2 and R3.3 are independently halogen.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R3.2 and R3.3 are independently chlorine.

17. The compound of claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein R7 is–OR7A,–C(O)R7D,–C(O)OR7D,–C(O)NR7BR7C,–SOn7R7A,–

SOv7NR7BR7C, 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.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein L7 is a bond or substituted or unsubstituted alkylene.

19. The compound of claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein:

L7 is a bond; and

R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -(CH2)2OH, -CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2OH,–(CH2)2SO2NH2,–(CH2)3SO2NH2, -(CH2)2CONH2, -(CH2)3CONH2 -(CH2)3CON(H)Me, -(CH2)3CON(Me)2, -(CH2)2SO2Me, -(CH2)3SO2Me, -CH2CH(OH)Me, -CH2CO2H, -(CH2)2CO2H, -CH(CH3)CH2CO2H, -(CH2)3CO2H, -(CH2)2SO2NHCH3, -(CH2)2SO2N(CH3)2, -(CH2)2SO2-(N-morpholinyl), -(CH2)2NHCOCH3, -(CH2)3NHCOCH3, -(CH2)2NHCOCH(CH3)2, -(CH2)2NHSO2CH3, -(CH2)2NHSO2CF3, -(CH2)2NHSO2NHCH(CH3)2, -CH2CH(CH3)CH2OH (R and S), -CH(CH3)(CH2)2OH, -CH2-(2-imidazoyl), -CH2-(4-imidazoyl),-CH2-(3-pyrazoyl), 4-tetrahydropyranyl, 3-oxetanyl, -(CH2)2NHCO2Me, -(CH2)3NHCO2Me.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has structural Formula (III):

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has structural Formula (IV):

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has structural Formula (V):


(V).

23. The compound of any one of claims 20 to 22, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

24. The compound of any one of claims 20 to 22, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

25. The compound of any one of claims 20 to 22, or a pharmaceutically acceptable salt thereof, wherein R1 is–CH3.

26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:

,




,


,

,

27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:


,


,


,


,


28. A pharmaceutical composition, comprising a compound having structural Formula (I) and a pharmaceuticall acce table exci ient:


(I),

or a pharmaceutically acceptable salt thereof, wherein:

X1 is CR8 or N;

X2 is CR9 or N;

X3 is CR10 or N;

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;

z1 is an integer from 0 to 5;

z2 is an integer from 0 to 2;

z3 is an integer from 0 to 11;

z4 is an integer from 0 to 2;

L7 is a bond,–O–,–S–,–NR7.2B–,–C(O)–, -C(O)O–,–S(O)–,–S(O)2–, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R1 is hydrogen, halogen,–CX1.1

3, -CHX1.1

2, -CH2X1.1,–CN,–N3,–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,–OCX1.1

3,–OCHX1.1

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;

R2 is hydrogen, halogen,–CX2.1

3, -CHX2.1

2, -CH2X2.1,–CN,–N3,–SOn2R2A, –SOv2NR2BR2C, -NHNR2BR2C, ^ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C,– N(O)m2,–NR2BR2C,–C(O)R2D,–C(O)OR2D,–C(O)NR2BR2C,–OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D,–NR2BOR2D,–OCX2.1

3,–OCHX2.1

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;

R3 is independently hydrogen, halogen,–CX3.1

3, -CHX3.1

2, -CH2X3.1,–CN,–N3,

–SOn3R3A,–SOv3NR3BR3C, -NHNR3BR3C, ^ONR3BR3C, -NHC(O)NHNR3BR3C,

-NHC(O)NR3BR3C,–N(O)m3,–NR3BR3C,–C(O)R3D,–C(O)OR3D,–C(O)NR3BR3C,–OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D,–NR3BOR3D,–OCX3.1

3,–OCHX3.1

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;

R4 is hydrogen, halogen,–CX4.1

3, -CHX4.1

2, -CH2X4.1,–CN,–N3,–SOn4R4A, –SOv4NR4BR4C, -NHNR4BR4C, ^ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C,– N(O)m4,–NR4BR4C,–C(O)R4D,–C(O)OR4D,–C(O)NR4BR4C,–OR4A, -NR4BSO2R4A, -NR4BC(O)R4D, -NR4BC(O)OR4D,–NR4BOR4D,–OCX4.1

3,–OCHX4.1

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;

R5 is independently hydrogen, halogen, oxo,–CX5.1

3, -CHX5.1

2, -CH2X5.1,–CN, –N3,–SOn5R5A,–SOv5NR5BR5C, -NHNR5BR5C, ^ONR5BR5C, -NHC(O)NHNR5BR5C,

-NHC(O)NR5BR5C,–N(O)m5,–NR5BR5C,–C(O)R5D,–C(O)OR5D,–C(O)NR5BR5C,–OR5A, -NR5BSO2R5A, -NR5BC(O)R5D, -NR5BC(O)OR5D,–NR5BOR5D,–OCX5.1

3,–OCHX5.1

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;

R6 is independently hydrogen, halogen, oxo,–CX6.1

3, -CHX6.1

2, -CH2X6.1,–CN,– N3,–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,–OCX6.1

3,–OCHX6.1

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;

R7 is hydrogen, halogen,–CX7.1

3, -CHX7.1

2, -CH2X7.1,–CN,–N3,–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, -NR7BC(O)R7D, -NR7BC(O)OR7D,–NR7BOR7D,–OCX7.1

3,–OCHX7.1

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;

R8 is hydrogen, halogen,–CX8.1

3, -CHX8.1

2, -CH2X8.1,–CN,–N3,–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,–OCX8.1

3,–OCHX8.1

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;

R9 is hydrogen, halogen,–CX9.1

3, -CHX9.1

2, -CH2X9.1,–CN,–N3,–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,–OCX9.1

3,–OCHX9.1

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;

R10 is hydrogen, halogen,–CX10.1

3, -CHX10.1

2, -CH2X10.1,–CN,–N3,–SOn10R10A, –SOv10NR10BR10C, -NHNR10BR10C, ^ONR10BR10C, -NHC(O)NHNR10BR10C,

-NHC(O)NR10BR10C,–N(O)m10,–NR10BR10C,–C(O)R10D,–C(O)OR10D,–C(O)NR10BR10C,– OR10A, -NR10BSO2R10A, -NR10BC(O)R10D, -NR10BC(O)OR10D,–NR10BOR10D,–OCX10.1

3,– OCHX10.1

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;

R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A,
R9B, R9C, R9D, R10A, R10B, R10C and R10D are independently hydrogen, halogen,–CF3,–CCl3,–CBr3,–CI3,– COOH,–CONH2, 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, R9C, R10B and R10C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and

X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X7.1, X8.1, X9.1 and X10.1 are independently–Cl,– Br,–I or–F,

wherein at least one of X1, X2 and X3 is N.

29. A method of treating or preventing a disease or disorder mediated by CCR4, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 28.

30. A method of inhibiting C-C chemokine receptor type 4 (CCR4), comprising contacting CCR4 with a com ound havin structural Formula I :


(I),

or a pharmaceutically acceptable salt thereof, wherein:

X1 is CR8 or N;

X2 is CR9 or N;

X3 is CR10 or N;

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;

z1 is an integer from 0 to 5;

z2 is an integer from 0 to 2;

z3 is an integer from 0 to 11;

z4 is an integer from 0 to 2;

L7 is a bond,–O–,–S–,–NR7.2B–,–C(O)–, -C(O)O–,–S(O)–,–S(O)2–, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R1 is hydrogen, halogen,–CX1.1

3, -CHX1.1

2, -CH2X1.1,–CN,–N3,–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,–OCX1.1

3,–OCHX1.1

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;

R2 is hydrogen, halogen,–CX2.1

3, -CHX2.1

2, -CH2X2.1,–CN,–N3,–SOn2R2A, –SOv2NR2BR2C, -NHNR2BR2C, ^ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C,– N(O)m2,–NR2BR2C,–C(O)R2D,–C(O)OR2D,–C(O)NR2BR2C,–OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D,–NR2BOR2D,–OCX2.1

3,–OCHX2.1

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;

R3 is independently hydrogen, halogen,–CX3.1

3, -CHX3.1

2, -CH2X3.1,–CN,–N3, –SOn3R3A,–SOv3NR3BR3C, -NHNR3BR3C, ^ONR3BR3C, -NHC(O)NHNR3BR3C,

-NHC(O)NR3BR3C,–N(O)m3,–NR3BR3C,–C(O)R3D,–C(O)OR3D,–C(O)NR3BR3C,–OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D,–NR3BOR3D,–OCX3.1

3,–OCHX3.1

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;

R4 is hydrogen, halogen,–CX4.1

3, -CHX4.1

2, -CH2X4.1,–CN,–N3,–SOn4R4A, –SOv4NR4BR4C, -NHNR4BR4C, ^ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C,– N(O)m4,–NR4BR4C,–C(O)R4D,–C(O)OR4D,–C(O)NR4BR4C,–OR4A, -NR4BSO2R4A, -NR4BC(O)R4D, -NR4BC(O)OR4D,–NR4BOR4D,–OCX4.1

3,–OCHX4.1

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;

R5 is independently hydrogen, halogen, oxo,–CX5.1

3, -CHX5.1

2, -CH2X5.1,–CN,

–N3,–SOn5R5A,–SOv5NR5BR5C, -NHNR5BR5C, ^ONR5BR5C, -NHC(O)NHNR5BR5C, -NHC(O)NR5BR5C,–N(O)m5,–NR5BR5C,–C(O)R5D,–C(O)OR5D,–C(O)NR5BR5C,–OR5A, -NR5BSO2R5A, -NR5BC(O)R5D, -NR5BC(O)OR5D,–NR5BOR5D,–OCX5.1

3,–OCHX5.1

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;

R6 is independently hydrogen, halogen, oxo,–CX6.1

3, -CHX6.1

2, -CH2X6.1,–CN,– N3,–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,–OCX6.1

3,–OCHX6.1

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;

R7 is hydrogen, halogen,–CX7.1

3, -CHX7.1

2, -CH2X7.1,–CN,–N3,–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, -NR7BC(O)R7D, -NR7BC(O)OR7D,–NR7BOR7D,–OCX7.1

3,–OCHX7.1

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;

R8 is hydrogen, halogen,–CX8.1

3, -CHX8.1

2, -CH2X8.1,–CN,–N3,–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,–OCX8.1

3,–OCHX8.1

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;

R9 is hydrogen, halogen,–CX9.1

3, -CHX9.1

2, -CH2X9.1,–CN,–N3,–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,–OCX9.1

3,–OCHX9.1

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;

R10 is hydrogen, halogen,–CX10.1

3, -CHX10.1

2, -CH2X10.1,–CN,–N3,–SOn10R10A, –SOv10NR10BR10C, -NHNR10BR10C, ^ONR10BR10C, -NHC(O)NHNR10BR10C,

-NHC(O)NR10BR10C,–N(O)m10,–NR10BR10C,–C(O)R10D,–C(O)OR10D,–C(O)NR10BR10C,– OR10A, -NR10BSO2R10A, -NR10BC(O)R10D, -NR10BC(O)OR10D,–NR10BOR10D,–OCX10.1

3,– OCHX10.1

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;

R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R7.2B, R8A, R8B, R8C, R8D, R9A, R9B, R9C, R9D, R10A, R10B, R10C and R10D are independently hydrogen, halogen,–CF3,–CCl3,–CBr3,–CI3,– COOH,–CONH2, 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, R9C, R10B and R10C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted

heterocycloalkyl or substituted or unsubstituted heteroaryl; and

X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X7.1, X8.1, X9.1 and X10.1 are independently–Cl,– Br,–I or–F,

wherein at least one of X1, X2 and X3 is N.

31. A method of treating or preventing a disease or disorder mediated by CCR4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having structural Formula I :


(I),

or a pharmaceutically acceptable salt thereof, wherein:

X1 is CR8 or N;

X2 is CR9 or N;

X3 is CR10 or N;

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;

z1 is an integer from 0 to 5;

z2 is an integer from 0 to 2;

z3 is an integer from 0 to 11;

z4 is an integer from 0 to 2;

L7 is a bond,–O–,–S–,–NR7.2B–,–C(O)–, -C(O)O–,–S(O)–,–S(O)2–, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R1 is hydrogen, halogen,–CX1.1

3, -CHX1.1

2, -CH2X1.1,–CN,–N3,–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,–OCX1.1

3,–OCHX1.1

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;

R2 is hydrogen, halogen,–CX2.1

3, -CHX2.1

2, -CH2X2.1,–CN,–N3,–SOn2R2A, –SOv2NR2BR2C, -NHNR2BR2C, ^ONR2BR2C, -NHC(O)NHNR2BR2C, -NHC(O)NR2BR2C,– N(O)m2,–NR2BR2C,–C(O)R2D,–C(O)OR2D,–C(O)NR2BR2C,–OR2A, -NR2BSO2R2A, -NR2BC(O)R2D, -NR2BC(O)OR2D,–NR2BOR2D,–OCX2.1

3,–OCHX2.1

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;

R3 is independently hydrogen, halogen,–CX3.1

3, -CHX3.1

2, -CH2X3.1,–CN,–N3,

–SOn3R3A,–SOv3NR3BR3C, -NHNR3BR3C, ^ONR3BR3C, -NHC(O)NHNR3BR3C,

-NHC(O)NR3BR3C,–N(O)m3,–NR3BR3C,–C(O)R3D,–C(O)OR3D,–C(O)NR3BR3C,–OR3A, -NR3BSO2R3A, -NR3BC(O)R3D, -NR3BC(O)OR3D,–NR3BOR3D,–OCX3.1

3,–OCHX3.1

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;

R4 is hydrogen, halogen,–CX4.1

3, -CHX4.1

2, -CH2X4.1,–CN,–N3,–SOn4R4A, –SOv4NR4BR4C, -NHNR4BR4C, ^ONR4BR4C, -NHC(O)NHNR4BR4C, -NHC(O)NR4BR4C,– N(O)m4,–NR4BR4C,–C(O)R4D,–C(O)OR4D,–C(O)NR4BR4C,–OR4A, -NR4BSO2R4A, -NR4BC(O)R4D, -NR4BC(O)OR4D,–NR4BOR4D,–OCX4.1

3,–OCHX4.1

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;

R5 is independently hydrogen, halogen, oxo,–CX5.1

3, -CHX5.1

2, -CH2X5.1,–CN, –N3,–SOn5R5A,–SOv5NR5BR5C, -NHNR5BR5C, ^ONR5BR5C, -NHC(O)NHNR5BR5C,

-NHC(O)NR5BR5C,–N(O)m5,–NR5BR5C,–C(O)R5D,–C(O)OR5D,–C(O)NR5BR5C,–OR5A, -NR5BSO2R5A, -NR5BC(O)R5D, -NR5BC(O)OR5D,–NR5BOR5D,–OCX5.1

3,–OCHX5.1

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;

R6 is independently hydrogen, halogen, oxo,–CX6.1

3, -CHX6.1

2, -CH2X6.1,–CN,– N3,–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,–OCX6.1

3,–OCHX6.1

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;

R7 is hydrogen, halogen,–CX7.1

3, -CHX7.1

2, -CH2X7.1,–CN,–N3,–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, -NR7BC(O)R7D, -NR7BC(O)OR7D,–NR7BOR7D,–OCX7.1

3,–OCHX7.1

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;

R8 is hydrogen, halogen,–CX8.1

3, -CHX8.1

2, -CH2X8.1,–CN,–N3,–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,–OCX8.1

3,–OCHX8.1

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;

R9 is hydrogen, halogen,–CX9.1

3, -CHX9.1

2, -CH2X9.1,–CN,–N3,–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,–OCX9.1

3,–OCHX9.1

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;

R10 is hydrogen, halogen,–CX10.1

3, -CHX10.1

2, -CH2X10.1,–CN,–N3,–SOn10R10A, –SOv10NR10BR10C, -NHNR10BR10C, ^ONR10BR10C, -NHC(O)NHNR10BR10C,

-NHC(O)NR10BR10C,–N(O)m10,–NR10BR10C,–C(O)R10D,–C(O)OR10D,–C(O)NR10BR10C,– OR10A, -NR10BSO2R10A, -NR10BC(O)R10D, -NR10BC(O)OR10D,–NR10BOR10D,–OCX10.1

3,– OCHX10.1

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;

R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R7.2B, R8A, R8B, R8C, R8D, R9A, R9B, R9C, R9D, R10A, R10B, R10C and R10D are independently hydrogen, halogen,–CF3,–CCl3,–CBr3,–CI3,– COOH,–CONH2, 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, R9C, R10B and R10C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and

X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X7.1, X8.1, X9.1 and X10.1 are independently–Cl,– Br,–I or–F,

wherein at least one of X1, X2 and X3 is N.

32. The method of claim 31, wherein:

z1 is 2;

z2 is 0;

z4 is 1; and

R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -F, -OH, CH2OH, -(CH2)2OH, -(CH2)3OH, -C(CH3)2OH, -CH2SO2NH2,–(CH2)2SO2NH2, -CH2C(O)NH2, -(CH2)2C(O)NH2, -(CH2)3C(O)NH2, -CH2NHSO2CF3, -(CH2)2NHSO2CF3, -(CH2)3NHSO2CF3, -CH2NHSO2CH3, -(CH2)2NHSO2CH3, -(CH2)3NHSO2CH3, -CH2SO2CH3,–(CH2)2SO2CH3, -CH2SO2NH2 or–(CH2)2SO2NH2.

33. The method of claim 32, wherein R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.

34. The method of claim 31, wherein the compound has structural Formula (II):


(II),

or a pharmaceutically acceptable salt thereof,wherein:

n3.2, and n3.3 are independently an integer from 0 to 4;

m3.2, m3.3, v3.2 and v3.3 are independently 1 or 2

R4 is hydrogen,–CX4.1

3,–CN,–C(O)NR4BR4C, 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;

R3.2 is hydrogen, halogen,–CX3.2

3, -CHX3.2

2, -CH2X3.2,–CN,–N3,

–SOv3.2NR3.2BR3.2C, -NHNR3.2BR3.2C, ^ONR3.2BR3.2C, -NHC(O)NHNR3.2BR3.2C,

-NHC(O)NR3.2BR3.2C,–N(O)m3.2,–NR3.2BR3.2C,–C(O)R3.2D,–C(O)OR3.2D,–C(O)NR3.2BR3.2C,– OR3.2A, -NR3.2BSO2R3.2A, -NR3.2BC(O)R3.2D, -NR3.2BC(O)OR3.2D,–NR3.2BOR3.2D,–OCX3.2

3,– OCHX3.2

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;

R3.3 is hydrogen, halogen,–CX3.3

3, -CHX3.3

2, -CH2X3.3,–CN,–N3,–SOn3.3R3.3A, –SOv3.3NR3.3BR3.3C, -NHNR3.3BR3.3C, ^ONR3.3BR3.3C, -NHC(O)NHNR3.3BR3.3C,

-NHC(O)NR3.3BR3.3C,–N(O) .3D

m3.3,–NR3.3BR3.3C,–C(O)R3 ,–C(O)OR3.3D,–C(O)NR3.3BR3.3C,– OR3.3A, -NR3.3BSO2R3.3A, -NR3.3BC(O)R3.3D, -NR3.3BC(O)OR3.3D,–NR3.3BOR3.3D,–OCX3.3

3,– OCHX3.3

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;

R3.2A, R3.2B, R3.2C, R3.2D, R3.3A, R3.3B, R3.3C and R3.3D are independently hydrogen, halogen,–CF3,–CCl3,–CBr3,–CI3,–COOH,–CONH2, 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; R3.2B, R3.2C, R3.2B and R3.2C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and

X3.2 and X3.3 are independently–Cl,–Br,–I or–F.

35. The method of claim 34, wherein the compound has structural Formula (IIa):


(IIa) or a pharmaceutically acceptable salt thereof.

36. The method of claim 34, wherein the compound has structural Formula (IIb):


(IIb) or a pharmaceutically acceptable salt thereof.

37. The method of claim 35, wherein the compound has structural Formula (IIc):


(IIc) or a pharmaceutically acceptable salt thereof.

38. The method of claim 36, wherein the compound has structural Formula (IId):


(IId) or a pharmaceutically acceptable salt thereof.

39. The method of claim 37 or 38, wherein z4 is 1.

40. The method of claim 37 or 38, wherein R1 and R2 are independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.

41. The method of claim 40, wherein R1 is hydrogen.

42. The method of claim 40, wherein R2 is substituted or unsubstituted alkyl.

43. The method of claim 37 or 38, wherein R4 is hydrogen,–CN, -C(O)NH2,– CX4.1

3 or substituted or unsubstituted alkyl.

44. The method of claim 43, wherein R4 is–CN, -C(O)NH2, -CF3 or–CH3.

45. The method of claim 37 or 38, wherein R3.2 and R3.3 are independently halogen.

46. The method of claim 45, wherein R3.2 and R3.3 are independently chlorine. 47. The method of claim 37 or 38, wherein R7 is–OR7A,–C(O)R7D,–

C(O)OR7D,–C(O)NR7BR7C,–SOn7R7A,–SOv7NR7BR7C, 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.

48. The method of claim 47, wherein L7 is a bond or substituted or unsubstituted alkylene.

49. The method of claim 37 or 38, wherein:

L7 is a bond; and

R7 is hydrogen, substituted or unsubstituted alkyl, phenyl, -(CH2)2OH, -CH2C(CH3)2OH, -(CH2)3OH, -(CH2)2CH(CH3)2OH,–(CH2)2SO2NH2,–(CH2)3SO2NH2, -(CH2)2CONH2, -(CH2)3CONH2 -(CH2)3CON(H)Me, -(CH2)3CON(Me)2, -(CH2)2SO2Me, -(CH2)3SO2Me, -CH2CH(OH)Me, -CH2CO2H, -(CH2)2CO2H, -CH(CH3)CH2CO2H, -(CH2)3CO2H, -(CH2)2SO2NHCH3, -(CH2)2SO2N(CH3)2, -(CH2)2SO2-(N-morpholinyl), -(CH2)2NHCOCH3, -(CH2)3NHCOCH3, -(CH2)2NHCOCH(CH3)2, -(CH2)2NHSO2CH3, -(CH2)2NHSO2CF3, -(CH2)2NHSO2NHCH(CH3)2, -CH2CH(CH3)CH2OH (R and S), -CH(CH3)(CH2)2OH, -CH2-(2-imidazoyl), -CH2-(4-imidazoyl),-CH2-(3-pyrazoyl), 4-tetrahydropyranyl, 3-oxetanyl, -(CH2)2NHCO2Me, -(CH2)3NHCO2Me.

50. The method of claim 31, wherein the compound has structural Formula (III):


(III) or a pharmaceutically acceptable salt thereof.

51. The method of claim 31, wherein the compound has structural Formula (IV):


(IV) or a pharmaceutically acceptable salt thereof.

52. The method of claim 31, wherein the compound has structural Formula (V):


(V) or a pharmaceutically acceptable salt thereof.

53. The method of any one of claims 50 to 52, wherein R2 is hydrogen.

54. The method of any one of claims 50 to 52, wherein R1 is hydrogen.

55. The method of any one of claims 25 to 52, wherein R1 is–CH3.

56. The method of claim 31, wherein the compound has the structure:

,


,


,

,

,


,


57. The method of claim 31, wherein the disease or disorder is an immune or inflammatory disease or disorder.

58. The method of claim 57, further comprising co-administering an anti-inflammatory agent in combination with a compound of structural Formula (I) or a

pharmaceutically acceptable salt thereof.

59. The method of claim 58, wherein the anti-inflammatory is thalidomide or a derivative thereof, a retinoid, dithranol, calcipotriol, a non-steroidal anti-inflammatory agent (NSAID), a cyclo-oxygenase inhibiting nitric oxide donor (CINOD), a glucocorticosteroid, methotrexate, leflunomide, hydroxychloroquine, d-penicillamine, auranofin, ananalgesic, a diacerein, hyaluronic acid derivative, or a nutritional supplement.

60. The method of claim 31, wherein the disease or disorder is a cardiovascular or metabolic disease or disorder.

61. The method of claim 60, further comprising co-administering a cardiovascular agent or a metabolic disorder agent in combination with a compound of structural Formula (I).

62. The method of claim 61, wherein the cardiovascular agent is a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist, a lipid lowering agent, a modulator of blood cell morphology, a thrombolytic or an anticoagulant.

63. The method of claim 31, wherein the disease or disorder is cancer.

64. The method of claim 63, further comprising co-administering a chemotherapeutic agent or anticancer agent in combination with a compound of structural Formula (I).

65. The method of claim 64, wherein the chemotherapeutic agent or anticancer agent is an antiproliferative/antineoplastic drug, an antimetabolite, an antitumour antibiotic, an antimitotic agent, a topoisomerase inhibitor, a cytostatic agent, an oestrogen receptor down regulator, an antiandrogen, a LHRH antagonist or LHRH agonist, a progestogen, an aromatase inhibitor, an inhibitor of 5.alpha.-reductase, an agent which inhibits cancer cell invasion, an inhibitor of growth factor function, a farnesyl transferase inhibitor, a tyrosine kinase inhibitor, a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family, an inhibitor of the platelet-derived growth factor family, an inhibitor of the hepatocyte growth factor family; an antiangiogenic agent, a vascular damaging agent, an agent used in antisense therapy, an anti-ras antisense, an agent used in a gene therapy, an immunotherapeutic agent, or an antibody.

66. The method of claim 65, further comprising co-administering a therapeutically effective amount of at least two of: a CCR4 inhibitor, an inhibitor of the PD-L1/PD-1 pathway, an inhibitor of CTLA-4 or an agonistic antibody of CD137 (4-1BB).

67. The method of claim 65, further comprising co-administering a therapeutically effective amount of at least two of: a CCR4 inhibitor, an an immune modulator agent or an agent from Table 1, or any combination thereof.

68. The method of any one of claims 63 to 67, wherein the cancer is colon cancer or pancreatic cancer.