# US 10,246,462 B2 · Chemokine receptor modulators and uses thereof

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- Number: US 10,246,462 B2
- Document ID: US10246462B2
- Status: Granted
- Kind: B2
- Application number: 15/700,040
- Filed: 2017-09-08
- Published: 2018-03-15
- Granted: 2019-04-02
- Earliest claimed: 2016-09-09
- Assignees: FLX Bio, Inc.
- Applicants: FLX Bio, Inc.
- Inventors: Hilary Plake Beck; Berenger Biannic; Minna Hue Thanh Bui; Dennis X. Hu; Jeffrey J. Jackson; John Michael Ketcham; Jay Patrick Powers; Maureen Kay Reilly; Omar Robles-Resendiz; Hunter Paul Shunatona; James Ross Walker; David Juergen Wustrow; Ashkaan Younai; Mikhail Zibinsky
- Web page: https://patentgrep.com/patent/US10246462B2

## CPC

- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed herein, inter alia, are compounds and methods of use thereof for the modulation of chemokine receptor activity.

## Claims

### Claim 1

A compound having structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is a substituted or unsubstituted heterocycloalkyl;
X1 is N;
X2 is N;
X3 is CR10;
X4 is C, CR11 or N;
z1 is an integer from 0 to 5;
z2 is an integer from 0 to 13;
z3 is an integer from 0 to 12;
z4 is an integer from 0 to 3;
is a single bond or double bond, wherein if is a single bond, then X4 is CR11 or N, and if is a double bond, then X4 is C;
L7 is a bond, —O—, —S—, —NR7B—, —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; wherein each substituted alkylene, substituted heteroalkylene, substituted cycoalkylene, substituted heterocycloalkylene, substituted arylene, or substituted heteroarylene is substituted with at least one substituent group;
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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R2 is hydrogen, halogen, —CX2.13, —CHX2.12, —CH2X2.1, —CN, —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, —OCX2.13, —OCHX2.12, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R3 is independently hydrogen, halogen, —CX3.13, —CHX3.12, —CH2X3.1, —CN, —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, —OCX3.13, —OCHX3.12, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least on substituent group;
R4 is hydrogen, halogen, —CX4.13, —CHX4.12, —CH2X4.1, —CN, —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, —OCX4.13, —OCHX4.12, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R5 is independently hydrogen, halogen, oxo, —CX5.13, —CHX5.12, —CH2X5.1, —CN, —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, —OCX5.13, —OCHX5.12, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted hetercycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R6 is independently hydrogen, halogen, oxo, —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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R10 is hydrogen, halogen, —CX10.13, —CHX10.12, —CH2X10.1, —CN, —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, —OCX10.13, —OCHX10.12, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R11 is hydrogen, halogen, —CX11.13, —CHX11.12, —CH2X11.1, —CN, —SOn1R11A,
—SOv11NR11BR11C, —NHNR11BR11C, —ONR11BR11C, —NHC(O)NHNR11BR11C, —NHC(O)NR11BR11C, —N(O)m11, —NR11BR11C, —C(O)R11D, —C(O)OR11D, —C(O)NR11BR11C, —OR11A, —NR11BSO2R11A, —NR11BC(O)R11D, —NR11BC(O)OR11D, —NR11BOR11D, —OCX11.13, —OCHX11.12, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R3A, R3B, R3C, R3D, R4A, R4B, R4C, R4D, R5A, R5B, R5C, R5D, R6A, R6B, R6C, R6D, R7B, R10A, R10B, R10C, R10D, R11A, R11B, R11C and R11D 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 and R1C, R2B and R2C, R3B and R3C, R4B and R4C, R5B and R5C, R6B and R6C, R10B and R10C, R11B and R11C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
n1, n2, n3, n4, n5, n6, n10 and n11 are independently an integer from 0 to 4;
m1, m2, m3, m4, m5, m6, m10, m11, v1, v2, v3, v4, v5, v6, v10, and v11 are independently 1 or 2; and
X1.1, X2.1, X3.1, X4.1, X5.1, X6.1, X10.1, and X11.1 are independently —Cl, —Br, —I or —F.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound has structural Formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
X5 is —CR12 or —N;
X6 is —CR13, —CR13R14, —N or —NR15;
z3 is an integer from 0 to 12;
z5 is an integer from 0 to 3;
R12 is hydrogen, halogen, —CX12.13, —CHX12.12, —CH2X12.1, —CN, —SOn12R12A, —SOv12NR12BR12C, —NHNR12BR12C, —ONR12BR12C, —NHC(O)NHNR12BR12C, —NHC(O)NR12BR12C, —N(O)m12, —NR12BR12C, —C(O)R12D, —C(O)OR12D, —C(O)NR12BR12C, —OR12A, —NR12BSO2R12A, —NR12BC(O)R12D, —NR12BC(O)OR12D, —NR12BOR12D, —OCX12.13, —OCHX12.12, 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; herein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R13 is hydrogen, halogen, —CX13.13, —CHX13.12, —CH2X13.1, —CN, —SOn13R13A, —SOv13NR13BR13C, —NHNR13BR13C, —ONR13BR13C, —NHC(O)NHNR13BR13C, —NHC(O)NR13BR13C, —N(O)m13, —NR13BR13C, —C(O)R13D, —C(O)OR13D, —C(O)NR13BR13C, —OR13A, —NR13BSO2R13A, —NR13BC(O)R13D, —NR13BC(O)OR13D, —NR13BOR13D, —OCX13.13, —OCHX13.12, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycoloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R14 is hydrogen, halogen, —CX14.13, —CHX14.12, —CH2X14.1, —CN, —SOn14R14A, —SOv14NR14BR14C, —NHNR14BR14C, —ONR14BR14C, —NHC(O)NHNR14BR14C, —NHC(O)NR14BR14C, —N(O)m14, —NR14BR14C, —C(O)R14D, —C(O)OR14D, —C(O)NR14BR14C, —OR14A, —NR14BSO2R14A, —NR14BC(O)R14D, —NR14BC(O)OR14D, —NR14BOR14D, —OCX14.13, —OCHX14.12, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, ort substituted heteroaryl is substituted with at least one substituent group;
R15 is hydrogen, halogen, —CX15.13, —CHX15.12, —CH2X15.1, —CN, —SOn15R15A, —SOv15NR15BR15C, —NHNR15BR15C, —ONR15BR15C, —NHC(O)NHNR15BR15C, —NHC(O)NR15BR15C, —N(O)m15, —NR15BR15C, —C(O)R15D, —C(O)OR15D, —C(O)NR15BR15C, —OR15A, —NR15BSO2R15A, —NR15BC(O)R15D, —NR15BC(O)OR15D, —NR15BOR15D, —OCX15.13, —OCHX15.12, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R12A, R12B, R12C, R12D, R13A, R13B, R13C, R13D, R14A, R14B, R14C, R14D, R15A, R15B, R15C and R15D 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; R12B and R12C, R13B and R13C, R14B and R14C and R15B and R15C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or subsitituted heteroaryl is substituted with at least on substituent group;
n12, n13, n14, and n15 are independently an integer from 0 to 4;
m12, m13, m14, m15, v12, v13, v14, and v15 are independently 1 or 2;
is a single bond or double bond, wherein if is a single bond, then X6 is CR13R14 or NR15, and if is a double bond, then X6 is N or CR13; and
X12.1, X13.1, X14.1 and X15.1 are independently —Cl, —Br, —I or —F.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the compound has structural Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
R4 is hydrogen, —CX4.13, —CN, —C(O)R4D, —C(O)OR4D, —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, —CX3.23, —CHX3.22, —CH2X3.2, —CN, —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, —OCX3.23, —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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R3.3 is hydrogen, halogen, —CX3.33, —CHX3.32, —CH2X3.3, —CN, —SOn3.3R3.3A, —SOv3.3NR3.3BR3.3C, —NHNR3.3BR3.3C, —ONR3.3BR33C, —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, —OCX3.33, —OCHX3.32, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one subtituent group;
R3.2A, R3.2B, R3.2C, R3.2D, R3.3C and R3.3D are independently hydrogen, halogen, —CF3, —CCl3, —CBr3, —CI3, —COOH, —CONH2, substituted or unsubstituted alkyl, substituted or unsubtituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3.2B and 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 unsusbtituted heteroaryl; wherein each substituted alkyl, substituted heteroalkyl, substititued cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
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; and
X3.2 and X3.3 are independently —Cl, —Br, —I or —F.

### Claim 4 (depends on 3)

The compound of claim 3, wherein the compound has structural Formula (IV):
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 3)

The compound of claim 3, wherein the compound has structural Formula (VI):
or a pharmaceutically acceptable salt thereof, wherein:
R5.2 is hydrogen, halogen, —CX5.63, —CHX5.62, —CH2X5.6, —CN, —SOn5.2R5.6A, —SOv5.2NR5.6BR5.6C, NHNR5.6BR5.6C, —ONR5.6BR5.6C, NHC(O)NHNR5.6BR5.6C, —NHC(O)NR5.6BR5.6C, —N(O)m5.2, —NR5.6BR5.6C, —C(O)R5.6D, —C(O)OR5.6D, —C(O)NR5.6BR5.6C, —OR5.6A, —NR5.6BSO2R5.6A, —NR5.6BC(O)R5.6D, —NR5.6BC(O)OR5.6D, —NR5.6BOR5.6D, —OCX5.63, —OCHX5.62, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R5.3 is hydrogen, halogen, —CX5.73, —CHX5.72, —CH2X5.7, —CN, —SOn5.3R5.7A, —SOv5.3NR5.7BR5.7C, —NHNR5.7BR5.7C, —ONR5.7BR5.7C, —NHC(O)NHNR5.7BR5.7C, —NHC(O)NR5.7BR5.7C, —N(O)m5.3, —NR5.7BR5.7C, —C(O)R5.7D, —C(O)OR5.7D, —C(O)NR5.7BR5.7C, —OR5.7A, —NR5.7BSO2R5.7A, —NR5.7BC(O)R5.7D, —NR5.7BC(O)OR5.7D, —NR5.7BOR5.7D, —OCX5.73, —OCHX5.72, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R5.4 is hydrogen, halogen, —CX5.83, —CHX5.82, —CH2X5.8, —CN, —SOn5.4R5.8A, —SOv5.4NR5.8BR5.8C, —NHNR5.8BR5.8C, —ONR5.8BR5.8C, NHC(O)NHNR5.8BR5.8C, —NHC(O)NR5.8BR5.8C, —N(O)m5.4, —NR5.8BR5.8C, —C(O)R5.8D, —C(O)OR5.8D, —C(O)NR5.8BR5.8C, —OR5.8A, —NR5.8BSO2R5.8A, —NR5.8BC(O)R5.8D, —NR5.8BC(O)OR5.8D, —NR5.8BOR5.8D, —OCX5.83, —OCHX5.82, 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; wherein each substituted alkyl, substituted heteroalykl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R5.5 is hydrogen, halogen, —CX5.93, —CHX5.92, —CH2X5.9, —CN, —SOn5.5R5.9A, —SOv5.5NR5.9BR5.9C, NHNR5.9BR5.9C, —ONR5.9BR5.9C, NHC(O)NHNR5.9BR5.9C, —NHC(O)NR5.9BR5.9C, —N(O)m5.5, —NR5.9BR5.9C, —C(O)R5.9D, —C(O)OR5.9D, —C(O)NR5.9BR5.9C, —OR5.9A, —NR5.9BSO2R5.9A, —NR5.9BC(O)R5.9D, —NR5.9BC(O)OR5.9D, —NR5.9BOR5.9D, —OCX5.93, —OCHX5.92, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R5.6A, R5.6B, R5.6C, R5.6D, R5.7A, R5.7B, R5.7C, R5.7D, R5.8A, R5.8B, R5.8C, R5.8D, R5.9A, R5.9B, R5.9C and R5.9D 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; R5.6B and R5.6C, R5.7B and R5.7C, R5.8B and R5.8C, R5.9B and R5.9C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
n5.2, n5.3, n5.4, and n5.5 are independently an integer from 0 to 4;
m5.2, m5.3, m5.4, m5.5, v5.2, v5.3, v5.4, and v5.5 are independently are independently 1 or 2; and
X5.6, X5.7, X5.8 and X5.9 are independently —Cl, —Br, —I or —F.

### Claim 6 (depends on 5)

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

### Claim 7 (depends on 5)

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

### Claim 8 (depends on 5)

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

### Claim 9 (depends on 5)

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

### Claim 10 (depends on 5)

The compound of claim 5, wherein the compound has structural Formula (IX):
or a pharmaceutically acceptable salt thereof, wherein:
R6.2 is hydrogen, halogen, —CX6.63, —CHX6.62, —CH2X6.6, —CN, —SOn6.2R6.6A, —SOv6.2NR6.6BR6.6C, —NHNR6.6BR6.6C, —ONR6.6BR6.6C, —NHC(O)NHNR6.6BR6.6C, —NHC(O)NR6.6BR6.6C, —N(O)m6.2, —NR6.6BR6.6C, —C(O)R6.6D, —C(O)OR6.6D, —C(O)NR6.6BR6.6C, —OR6.6A, —NR6.6BSO2R6.6A, —NR6.6BC(O)R6.6D, —NR6.6BC(O)OR6.6D, —NR6.6BOR6.6D, —OCX6.63, —OCHX6.62, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R6.3 is hydrogen, halogen, —CX6.73, —CHX6.72, —CH2X6.7, —CN, —SOn6.3R6.7A, —SOv6.3NR6.7BR6.7C, —NHNR6.7BR6.7C, —ONR6.7BR6.7C, —NHC(O)NHNR6.7BR6.7C, —NHC(O)NR6.7BR6.7C, —N(O)m6.3, —NR6.7BR6.7C, —C(O)R6.7D, —C(O)OR6.7D, —C(O)NR6.7BR6.7C, —OR6.7A, —NR6.7BSO2R6.7A, —NR6.7BC(O)R6.7D, —NR6.7BC(O)OR6.7D, —NR6.7BOR6.7D, —OCX6.73, —OCHX6.72, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R6.4 is hydrogen, halogen, —CX6.83, —CHX6.82, —CH2X6.8, —CN, —SOn6.4R6.8A, —SOv6.4NR6.8BR6.8C, —NHNR6.8BR6.8C, —ONR6.8BR6.8C, —NHC(O)NHNR6.8BR6.8C, —NHC(O)NR6.8BR6.8C, —N(O)m6.4, —NR6.8BR6.8C, —C(O)R6.8D, —C(O)OR6.8D, —C(O)NR6.8BR6.8C, —OR6.8A, —NR6.8BSO2R6.8A, —NR6.8BC(O)R6.8D, —NR6.8BC(O)OR6.8D, —NR6.8BOR6.8D, —OCX6.83, —OCHX6.82, 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; wherein each substituted alkyl, substituded heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituded heteroaryl is substituted with at least one substituent group;
R6.5 is hydrogen, halogen, —CX6.93, —CHX6.92, —CH2X6.9, —CN, —SOn6.5R6.9A, —SOv6.5NR6.9BR6.9C, —NHNR6.9BR6.9C, —ONR6.9BR6.9C, —NHC(O)NHNR6.9BR6.9C, —NHC(O)NR6.9BR6.9C, —N(O)m6.5, —NR6.9BR6.9C, —C(O)R6.9D, —C(O)OR6.9D, —C(O)NR6.9BR6.9C, —OR6.9A, —NR6.9BSO2R6.9A, —NR6.9BC(O)R6.9D, —NR6.9BC(O)OR6.9D, —NR6.9BOR6.9D, —OCX6.93, —OCHX6.92, 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; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
R6.6A, R6.6B, R6.6C, R6.6D, R6.7A, R6.7B, R6.7C, R6.7D, R6.8A, R6.8B, R6.8C, R6.8D, R6.9A, R6.9B, R6.9C and R6.9D 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; R6.6B and R6.6C, R6.7B and R6.7C, R6.8B and R6.8C, R6.9B and R6.9C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; wherein each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl is substituted with at least one substituent group;
n6.2, n6.3, n6.4, and n6.5 are independently an integer from 0 to 4;
m6.2, m6.3, m6.4, m6.5, v6.2, v6.3, v6.4, and v6.5 are independently 1 or 2; and
X6.6, X6.7, X6.8 and X6.9 are independently —Cl, —Br, —I or —F.

### Claim 11 (depends on 2)

The compound of claim 2, wherein the compound has structural Formula (X):
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

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

### Claim 13 (depends on 11)

The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 1)

A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

### Claim 16 (depends on 1)

A method of treating a disease or disorder mediated by CCR4, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the CCR4 mediated disease or disorder is cancer, an immune disease or disorder, or an imflammatory disease or disorder.

### Claim 17 (depends on 16)

The method of claim 16, wherein the disease or disorder is an immune or inflammatory disease or disorder selected from asthma, dermatitis, infection, chronic inflammation, rheumatoid arthritis, and systemic Lupus Erythematosus.

### Claim 18 (depends on 16)

The method of claim 16, wherein the disease or disorder is cancer selected from carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, solid cancer and lymphoid cancer.

### Claim 19 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a 4-membered to 8-membered substituted or unsubstituted heterocycloalkyl.

### Claim 20 (depends on 2)

The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein:
z1 is 2; and
z4 is 1.

### Claim 21 (depends on 2)

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.

### Claim 22 (depends on 3)

The compound of claim 3, wherein the compound has structural Formula (III):
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 22)

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

### Claim 24 (depends on 22)

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

### Claim 25 (depends on 4)

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

### Claim 26 (depends on 25)

The compound of claim 25, wherein the compound has structural Formula (Va):
or a pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 25)

The compound of claim 25, wherein the compound has structural Formula (Vb):
or a pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen, —CN, —CX4.13, —C(O)R4D, —C(O)OR4D, —C(O)NR4BR4C, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.

### Claim 29 (depends on 28)

The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein R4 is —CN, —CF3, —C(O)NH2, —CH3 or —C(CH3)2OH.

### Claim 30 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R3.2 and R3.3 are independently halogen, —CN, —CF3 or unsubstituted alkyl.

### Claim 31 (depends on 30)

The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R3.2 and R3.3 are independently —F, —Cl, —CN, —CF3 or unsubstituted alkyl .

### Claim 32 (depends on 30)

The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein R3.2 and R3.3 are independently halogen, —CN, —CF3 or —CH3.

### Claim 33 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen or unsubstituted alkyl.

### Claim 34 (depends on 33)

The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R1 is —CH3 or —CH2CH3.

### Claim 35 (depends on 33)

The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R2 is —CH3 or —CH2CH3.

### Claim 36 (depends on 33)

The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

### Claim 37 (depends on 33)

The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

### Claim 38 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X2 is N.

### Claim 39 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X3 is N.

### Claim 40 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein z2 and z3 are independently an integer from 0 to 2.

### Claim 41 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen, —F, —CN, —CH3, —CF3, —(CH2)2OH, —CO2NH2 or —CO2CH2CH3.

### Claim 42 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen, —OH, —CH3, —CH2OH, —(CH2)2OH, —(CH2)3OH, —CH2NH2, —(CH2)2NH2, —(CH2)3NH2, —CH2CO2CH2CH3, —(CH2)2CO2CH2CH3, —(CH2)3CO2CH2CH3, —CH2CO2H, —(CH2)2CO2H, —(CH2)3CO2H, —(CH2)CO2NH2, —(CH2)2CONH2, —(CH2)3CO2 NH2, —(CH2)CHFCO2H, —(CH2)2CHFCO2H, —(CH2)CF2CO2H, —(CH2)2CF2CO2H,

### Claim 43 (depends on 6)

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

### Claim 44 (depends on 6)

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

### Claim 45 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein X1 and X3 are independently N.

### Claim 46 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently N.

### Claim 47 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R4 is —CN, —C(O)NH2, —CF3, —CH3 or —C(CH3)2OH.

### Claim 48 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R3.2 and R3.3 are independently halogen, —CN, —CF3 or unsubstituted alkyl.

### Claim 49 (depends on 48)

The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R3.2 and R3.3 are independently —F, —Cl, —CN, —CF3 or unsubstituted alkyl.

### Claim 50 (depends on 48)

The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R3.2 and R3.3 are independently halogen, —CN, —CF3 or —CH3.

### Claim 51 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen or unsubstituted alkyl.

### Claim 52 (depends on 51)

The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein R1 is —CH3 or —CH2CH3.

### Claim 53 (depends on 51)

The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein R2 is —CH3 or —CH2CH3.

### Claim 54 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen.

### Claim 55 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

### Claim 56 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein z3 is an integer from 0 to 2.

### Claim 57 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R5.2,R5.3, R5.4, R5.5 are independently hydrogen, —F, —CN, —CF3, —(CH2)2OH, —CO2NH2 or —CO2CH2CH3.

### Claim 58 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen, —OH, —CH3, —CH2OH, —(CH2)2OH, —(CH2)3OH, —CH2NH2, —(CH2)2NH2, —(CH2)3NH2, —CH2CO2CH2CH3, —(CH2)2CO2CH2CH3, —(CH2)3CO2CH2CH3, —CH2CO2H, —(CH2)2CO2H, —(CH2)3CO2H, —(CH2)CO2NH2, —(CH2)2CONH2, —(CH2)3CO2NH2, —(CH2)CHFCO2H, —(CH2)2CHFCO2H, —(CH2)CF2CO2H, —(CH2)2CF2CO2H,

### Claim 59 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein z5 is 1.

### Claim 60 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein z5 is 0.

### Claim 61 (depends on 54)

The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein z3 and z5 are independently 1.

### Claim 62 (depends on 54)

The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein R6 is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.

### Claim 63 (depends on 10)

The compound of claim 10, wherein the compound has structural Formula (IXa):
or a pharmaceutically acceptable salt thereof.

### Claim 64 (depends on 10)

The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently N.

### Claim 65 (depends on 10)

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

### Claim 66 (depends on 10)

The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R3.2 and R3.3 are independently halogen, —CN, —CF3 or unsubstituted alkyl.

### Claim 67 (depends on 10)

The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R4 is —CN, —C(O)NH2, —CF3, —CH3 or —C(CH3)2OH.

### Claim 68 (depends on 10)

The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R5.4 and R5.5 are independently hydrogen, fluorine, —CN, —CH3, —CH2CH3,—CF3, —(CH2)OH, —(CH2)2OH, —(CH3)2OH, —CO2H, —CO2NH2 or —CO2CH2CH3.

### Claim 69 (depends on 10)

The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R6.2 is hydrogen, —CH3, —CH2OH, —(CH2)2OH, —(CH2)3OH, —CH2NH2, —(CH2)2NH2, —(CH2)3NH2, —CH2CO2CH2CH3, —(CH2)2CO2CH2CH3, —(CH2)3CO2CH2CH3, —CH2CO2H, —(CH2)2CO2H, —(CH2)3CO2H, —(CH2)CO2NH2, —(CH2)2CONH2, —(CH2)3CO2NH2, —(CH2)CHFCO2H, —(CH2)2CHFCO2H, —(CH2)CF2CO2H, —(CH2)2CF2CO2H,

### Claim 70 (depends on 10)

The compound of claim 10, wherein the compound has structural Formula (IXb):
or a pharmaceutically acceptable salt thereof.

### Claim 71 (depends on 70)

The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently N.

### Claim 72 (depends on 70)

The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently hydrogen or unsubstituted alkyl.

### Claim 73 (depends on 70)

The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein R3.2 and R3.3 are independently halogen, —CN, —CF3 or unsubstituted alkyl.

### Claim 74 (depends on 70)

The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein R4 is —CN, —C(O)NH2, —CF3, —CH3 or —C(CH3)2OH.

### Claim 75 (depends on 70)

The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein R5.2 and R5.5 are independently hydrogen, fluorine, —CN, —CH3, —CH2CH3, —CF3, —(CH2)OH, —(CH2)2OH, —(CH3)2OH, —CO2H, —CO2NH2 or —CO2CH2CH3.

### Claim 76 (depends on 70)

The compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein R6.2 is hydrogen, —OH, —CH3, —CH2OH, —(CH2)2OH, —(CH2)3OH, —CH2NH2, —(CH2)2NH2, —(CH2)3NH2, —CH2CO2CH2CH3, —(CH2)2CO2CH2CH3, —(CH2)3CO2CH2CH3, —CH2CO2H, —(CH2)2CO2H, —(CH2)3CO2H, —(CH2)CO2NH2, —(CH2)2CONH2, —(CH2)3CO2NH2, —(CH2)CHFCO2H, —(CH2)2CHFCO2H, —(CH2)CF2CO2H, —(CH2)2CF2CO2H,

### Claim 77 (depends on 18)

The method of claim 18, wherein the cancer is kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophagus cancer, liver cancer, hepatocarcinoma, B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas, Burkitt's, Small Cell, and Large Cell lymphomas, Hodgkin's lymphoma, MDS, AML, ALL, ATLL, CML, multiple myeloma, glioblastoma, neuroblastoma, colorectal cancer, cervical cancer, gastric cancer, cancer of the thyroid, cancer of the endocrine system, non-small cell lung cancer, melanoma, mesothelioma, Medulloblastoma, colorectal cancer, thyroid carcinoma, cholangiocarcinoma, pancreatic adenocarcinoma, skin cutaneous melanoma, colon adenocarcinoma, rectum adenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioblastoma multiforme, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.