IP Library › Granted Patent US 11,384,064

Granted Patent B2

US 11,384,064 · App. 16/859,896 · Granted Jul 12, 2022

Chemokine receptor modulators and uses thereof

Inventors: Jeffrey J. Jackson (San Bruno, CA); John Michael Ketcham (San Mateo, CA); Akinori Okano (San Mateo, CA); Maureen Kay Reilly (San Francisco, CA); Omar Robles-Resendiz (Redwood City, CA); Jacob Bradley Schwarz (San Ramon, CA); Parcharee Tivitmahaisoon (San Francisco, CA); David Juergen Wustrow (Los Gatos, CA); Ashkaan Younai (Daly City, CA); Mikhail Zibinsky (Redwood City, CA)

Assignee: RAPT Therapeutics, Inc.

C07D401/14 A61P11/06 A61P17/00 A61P29/00 A61P35/00 C07D495/04

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Quick Facts

Patent No.: US 11,384,064
App. No.: 16/859,896
Granted: Jul 12, 2022
Kind: B2

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Abstract

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

Claims (135)

1. A method of treating or preventing inflammation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of structural Formula (IIb):

or a pharmaceutically acceptable salt thereof, wherein:

X 2 is CR 9 ;

n1, n2, n3.2, n3.3, n4, n7, and n9, are independently an integer from 0 to 4;

m1, m2, m3.2, m3.3, m4, m7, m9, v1, v2, v3.2, v3.3, v4, v7, and v9, v10, and are independently 1 or 2;

z4 is 1;

L 7 is a bond, —O—, —S—, —NR 7.2B —, —C(O)—, —C(O)O—, —S(O)—, —S(O) 2 —, R 41 -substituted or unsubstituted C 1 -C 8 alkylene or R 41 -substituted or unsubstituted C 3 -C 8 cycloalkylene;

R 41 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, R 42 -substituted or unsubstituted C 1 -C 8 alkyl, R 42 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 42 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 42 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 42 -substituted or unsubstituted C 6 -C 10 aryl, or R 42 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 42 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, R 43 -substituted or unsubstituted C 1 -C 8 alkyl, R 43 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 4 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 43 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 43 -substituted or unsubstituted C 6 -C 10 aryl, or R 43 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 43 is independently hydrogen, oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted C 6 -C 10 aryl, or unsubstituted 5 to 6 membered heteroaryl;

R 1 is hydrogen, halogen, —CX 1.1 3 , —CHX 1.1 2 , —CH 2 X 1.1 , —CN, —N 3 , —SO n1 R 1A , —SO v1 NR 1B R 1C , —NHNR 1B R 1C , —ONR 1B R 1C , —NHC(O)NHNR 1B R 1C , —NHC(O)NR 1B R 1C , —N(O) m1 , —NR 1B R 1C , —C(O)R 1D , —C(O)OR 1D , —C(O)NR 1B R 1C , —OR 1A , —NR 1B SO 2 R 1A , —NR 1B C(O)R 1D , —NR 1B C(O)OR 1D , —NR 1B OR 1D , —OCX 1.1 3 , —OCHX 1.1 2 , —OCH 2 X 1.1 , R 11 -substituted or unsubstituted C 1 -C 8 alkyl, R 11 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 11 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 11 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 11 -substituted or unsubstituted C 6 -C 10 aryl, or R 11 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 11 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, R 12 -substituted or unsubstituted C 1 -C 8 alkyl, R 12 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 12 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 12 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 12 -substituted or unsubstituted C 6 -C 10 aryl, or R 12 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 12 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, R 13 -substituted or unsubstituted C 1 -C 8 alkyl, R 13 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 13 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 13 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 13 -substituted or unsubstituted C 6 -C 10 aryl, or R 13 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 13 is independently hydrogen, oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted C 6 -C 10 aryl, or unsubstituted 5 to 6 membered heteroaryl;

R 2 is hydrogen, halogen, —CX 2.1 3 , —CHX 2.1 2 , —CH 2 X 2.1 , —CN, —N 3 , —SO n2 R 2A , —SO v2 NR 2B R 2C , —NNR 2B R 2C , —ONR 2B R 2C , —NHC(O)NHNR 2B R 2C , —NHC(O)NR 2B R 2C , —N(O) m2 , —NR 2B R 2C , —C(O)R 2D , —C(O)OR 2D , —C(O)NR 2B R 2C , —OR 2A , —NR 2B SO 2 R 2A , —NR 2B C(O)R 2D , —NR 2B C(O)OR 2D , —NR 2B OR 2D , —OCX 2.1 3 , —OCHX 2.1 2 , —OCH 2 X 2.1 , R 14 -substituted or unsubstituted C 1 -C 8 alkyl, R 14 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 14 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 14 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 14 -substituted or unsubstituted C 6 -C 10 aryl, or R 14 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 14 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, R 15 -substituted or unsubstituted C 1 -C 8 alkyl, R 15 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 15 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 15 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 15 -substituted or unsubstituted C 6 -C 10 aryl, or R 15 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 15 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, R 16 -substituted or unsubstituted C 1 -C 8 alkyl, R 16 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 16 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 16 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 16 -substituted or unsubstituted C 6 -C 10 aryl, or R 16 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 16 is independently hydrogen, oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted C 6 -C 10 aryl, or unsubstituted 5 to 6 membered heteroaryl;

R 3.2 is hydrogen, halogen or —SO n3.2 R 3.2A ;

R 3.3 is hydrogen, halogen, or —SO n3.2 R 3.3A ;

R 4 is hydrogen, halogen, —CX 4.1 3 , —CHX 4.1 2 , —CH 2 X 4.1 , —CN, —N 3 , —SO n4 R 4A , —SO v4 NR 4B R 4C , —NHNR 4B R 4C , —ONR 4B R 4C , —NHC(O)NHNR 4B R 4C , —NHC(O)NR 4B R 4C , —N(O) m4 , —NR 4B R 4C , —C(O)R 4D , —C(O)OR 4D , —C(O)NR 4B R 4C , —OR 4A , —NR 4B SO 2 R 4A , —NR 4B C(O)R 4D , —NR 4B C(O)OR 4D , —NR 4B OR 4D , —OCX 4.1 3 , —OCHX 4.1 2 , —OCH 2 X 4.1 , R 20 -substituted or unsubstituted C 1 -C 8 alkyl, R 20 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 20 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 20 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 20 -substituted or unsubstituted C 6 -C 10 aryl, or R 20 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 20 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, R 21 -substituted or unsubstituted C 1 -C 8 alkyl, R 21 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 21 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 21 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 21 -substituted or unsubstituted C 6 -C 10 aryl, or R 21 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 21 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, R 22 -substituted or unsubstituted C 1 -C 8 alkyl, R 22 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 22 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 22 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 22 -substituted or unsubstituted C 6 -C 10 aryl, or R 22 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 22 is independently hydrogen, oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted C 6 -C 10 aryl, or unsubstituted 5 to 6 membered heteroaryl;

R 7 is hydrogen, halogen, —CX 7.1 3 , —CHX 7.1 2 , —CH 2 X 7.1 , —CN, —N 3 , —SO n7 R 7A , —SO v7 NR 7B R 7C , —NHNR 7B R 7C , —ONR 7B R 7C , —NHC(O)NHNR 7B R 7C , —NHC(O)NR 7B R 7C , —N(O) m7 , —NR 7B R 7C , —C(O)R 7D , —C(O)OR 7D , —C(O)NR 7B R 7C , —OR 7A , —NR 7B SO 2 R 7A , —NR 7B C(O)R 7D , —NR 7B C(O)OR 7D , —NR 7B OR 7D , —OCX 7.1 3 , —OCHX 7.1 2 , —OCH 2 X 7.1 , R 29 -substituted or unsubstituted C 1 -C 8 alkyl, R 29 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 29 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 29 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 29 -substituted or unsubstituted C 6 -C 10 aryl, or R 29 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 29 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, R 30 -substituted or unsubstituted C 1 -C 8 alkyl, R 30 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 30 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 30 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 30 -substituted or unsubstituted C 6 -C 10 aryl, or R 30 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 30 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I—OCH 2 F, R 31 -substituted or unsubstituted C1-C 8 alkyl, R 31 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 31 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 31 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 31 -substituted or unsubstituted C 6 -C 10 aryl, or R 31 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 31 is independently hydrogen, oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted C 6 -C 10 aryl, or unsubstituted 5 to 6 membered heteroaryl;

R 9 is hydrogen, halogen, —CX 9.1 3 , —CHX 9.1 2 , —CH 2 X 9.1 , —CN, —N 3 , —SO n9 R 9A , —SO v9 NR 9B R 9C , —NHNR 9B R 9C , —ONR 9B R 9C , —NHC(O)NHNR 9B R 9C , —NHC(O)NR 9B R 9C , —N(O) m9 , —NR 9B R 9C , —C(O)R 9D , —C(O)OR 9D , —C(O)NR 9B R 9C , —OR 9A , —NR 9B SO 2 R 9A , —NR 9B C(O)R 9D , —NR 9B C(O)OR 9D , —NR 9B OR 9D , —OCX 9.1 3 , —OCHX 9.1 2 , —OCH 2 X 9.1 , R 35 -substituted or unsubstituted C 1 -C 8 alkyl, R 35 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 35 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 35 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 35 -substituted or unsubstituted aryl, or R 35 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 35 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, R 36 -substituted or unsubstituted C 1 -C 8 alkyl, R 36 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 36 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 36 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 36 -substituted or unsubstituted C 6 -C 10 aryl, or R 36 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 36 is independently oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, R 37 -substituted or unsubstituted C 1 -C 8 alkyl, R 37 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 37 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 37 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 37 -substituted or unsubstituted C 6 -C 10 aryl, or R 37 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 37 is independently hydrogen, oxo, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCF 3 , —OCBr 3 , —OCI 3 , —OCHCl 2 , —OCHBr 2 , —OCHI 2 , —OCHF 2 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 I, —OCH 2 F, unsubstituted C 1 -C 8 alkyl, unsubstituted 2 to 8 membered heteroalkyl, unsubstituted C 3 -C 8 cycloalkyl, unsubstituted 3 to 8 membered heterocycloalkyl, unsubstituted C 6 -C 10 aryl, or unsubstituted 5 to 6 membered heteroaryl;

R 44 is hydrogen;

R 1A , R 1B , R 1C , R 1D , and R 7.2B are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —COOH, —CONH 2 , R 11 -substituted or unsubstituted C 1 -C 8 alkyl, R 11 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 11 -substituted or unsubstituted C3-C 8 cycloalkyl, R 11 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 11 -substituted or unsubstituted C 6 -C 10 aryl, or R 11 -substituted or unsubstituted 5 to 6 membered heteroaryl; R 1B and R 1C substituents bonded to the same nitrogen atom may optionally be joined to form a R 11 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl or R 11 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 2A , R 2B , R 2C , and R 2D are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —COOH, —CONH 2 , R 14 -substituted or unsubstituted C 1 -C 8 alkyl, R 14 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 14 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 14 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 14 -substituted or unsubstituted C 6 -C 10 aryl, or R 14 -substituted or unsubstituted 5 to 6 membered heteroaryl; R 2B and R 2C substituents bonded to the same nitrogen atom may optionally be joined to form a R 14 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl or R 14 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 4A , R 4B , R 4C , and R 4D are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —COOH, —CONH 2 , R 20 -substituted or unsubstituted C 1 -C 8 alkyl, R 20 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 20 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 20 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 20 -substituted or unsubstituted C 6 -C 10 aryl, or R 20 -substituted or unsubstituted 5 to 10 membered heteroaryl; R 4B and R 4C substituents bonded to the same nitrogen atom may optionally be joined to form a R 20 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl or R 20 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 7A , R 7B , R 7C , and R 7D are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —COOH, —CONH 2 , R 29 -substituted or unsubstituted C 1 -C 8 alkyl, R 29 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 29 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 29 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 29 -substituted or unsubstituted C 6 -C 10 aryl, or R 29 -substituted or unsubstituted 5 to 6 membered heteroaryl; R 7B and R 7C substituents bonded to the same nitrogen atom may optionally be joined to form a R 29 substituted or unsubstituted 3 to 8 membered heterocycloalkyl or R 29 -substituted or unsubstituted 5 to 6 membered heteroaryl;

R 9A , R 9B , R 9C , and R 9D are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —COOH, —CONH 2 , R 35 -substituted or unsubstituted C 1 -C 8 alkyl, R 35 -substituted or unsubstituted 2 to 8 membered heteroalkyl, R 35 -substituted or unsubstituted C 3 -C 8 cycloalkyl, R 35 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl, R 35 -substituted or unsubstituted C 6 -C 10 aryl, or R 35 -substituted or unsubstituted 5 to 6 membered heteroaryl: R 9B and R 9C substituents bonded to the same nitrogen atom may optionally be joined to form a R 35 -substituted or unsubstituted 3 to 8 membered heterocycloalkyl or R 35 -substituted or unsubstituted 5 to 6 membered heteroaryl; and

X 1.1 , X 2.1 , X 4.1 , X 7.1 , and X 9.1 , are independently —Cl, —Br, —I or —F;

wherein:

each substituted or unsubstituted 2 to 8 membered heteroalkyl contains at least one carbon atom and at least one heteroatom;

each substituted or unsubstituted 3 to 8 membered heterocycloalkyl contains at least one carbon atom and at least one heteroatom;

each substituted or unsubstituted 5 to 6 membered heteroaryl contains at least one carbon atom and at least one heteroatom; and

each heteroatom is selected from oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

2. A method of inhibiting C—C chemokine receptor type 4 (CCR4), comprising contacting CCR4 with a compound of structural Formula (IIb):

or a pharmaceutically acceptable salt thereof, wherein:

X 2 is CR 9 ;

n1, n2, 3.2, n3.3, n4, n7, and n9, are independently an integer from 0 to 4;

m1, m2, m3.2, m3.3, m4, m7, m9, v1, v2, v3.2, v3.3, v4, v7, and v9, v10, and are independently 1 or 2;

z1 is an integer from 0 to 5;

z4 is 1;

R 3.2 is hydrogen, halogen or —SO n3.2 R 3.2A ;

R 3.3 is hydrogen, halogen, or —SO n3.2 R 3.3A ;

R 44 is hydrogen;

X 1.1 , X 2.1 , X 4.1 , X 7.1 , and X 9.1 , are independently —Cl, —Br, —I or —F

wherein:

each substituted or unsubstituted 2 to 8 membered heteroalkyl contains at least one carbon atom and at least one heteroatom;

each substituted or unsubstituted 3 to 8 membered heterocycloalkyl contains at least one carbon atom and at least one heteroatom;

each substituted or unsubstituted 5 to 6 membered heteroaryl contains at least one carbon atom and at least one heteroatom; and

each heteroatom is selected from oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

3. The method of claim 1 , further comprising co-administering an anti-inflammatory agent to the subject.

4. The method of claim 3 , wherein the anti-inflammatory agent is a thalidomide derivative, a retinoid, a non-steroidal anti-inflammatory agent (NSAID), a cyclo-oxygenase inhibiting nitric oxide donor (CINOD), a glucocorticosteroid, an analgesic, a hyaluronic acid derivative, or a nutritional supplement.

5. The method of claim 1 , wherein the inflammation is asthma, urticaria, rhinitis or dermatitis.

6. The method of claim 5 , wherein the inflammation is allergic asthma, autoimmune urticaria, allergic rhinitis or contact dermatitis.

7. The method of claim 4 , wherein the anti-inflammatory agent is thalidomide, dithranol, calcipotriol, methotrexate, leflunomide, hydroxychloroquine, d-penicillamine, auranofin, or diacerein.

8. The method of claim 1 , comprising administering a therapeutically effective amount of a pharmaceutical composition comprising the compound of formula (IIb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. The method of claim 1 or 2 , wherein the compound has the formula: