IP Library › Granted Patent US 10,596,163

Granted Patent B2

US 10,596,163 · App. 16/170,752 · Granted Mar 24, 2020

Aza-aryl 1H-pyrazol-1-yl benzene sulfonamides

Inventors: Xi Chen (E. Palo Alto, CA); Junfa Fan (Foster City, CA); Pingchen Fan (Fremont, CA); Antoni Krasinski (San Jose, CA); Lianfa Li (San Jose, CA); Rebecca M. Lui (Santa Clara, CA); Jeffrey P. McMahon (San Francisco, CA); Jay P. Powers (Pacifica, CA); Yibin Zeng (Foster City, CA); Penglie Zhang (Foster City, CA)

Assignee: ChemoCentryx, Inc.

A61K31/4709 A61K31/415 A61K31/4725 A61K31/502 A61K31/517 A61K31/5377 A61K45/06 C07D231/42 C07D401/04 C07D401/06 C07D401/10 C07D403/04 C07D403/10 C07D405/14

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Quick Facts

Patent No.: US 10,596,163
App. No.: 16/170,752
Granted: Mar 24, 2020
Kind: B2

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Abstract

Compounds are provided that act as potent antagonists of the CCR(9) receptor. Animal testing demonstrates that these compounds are useful for treating inflammation, a hallmark disease for CCR(9). The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR(9)-mediated diseases, and as controls in assays for the identification of CCR(9) antagonists.

Claims (143)

1. A compound or salt thereof of formula (II):

wherein:

R 1 is selected from the group consisting of substituted or unsubstituted C 2-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, unsubstituted C 1-8 alkylamino, and substituted or unsubstituted C 3-10 heterocyclyl; and

R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy; or

R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring;

R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or halo;

R 4 is H or F;

R 5 is H, F, Cl, or —CH 3 ; and

R 6 is H, halo, —CN, —CO 2 R a , —CONH 2 , —NH 2 , unsubstituted C 1-8 aminoalkyl, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted C 1-8 alkoxy, wherein R a is H or substituted or unsubstituted C 1-8 alkyl; or

R 5 and R 6 together with the carbon atoms to which they are attached form a carbocyclic ring;

L is a bond, —CH 2 —, or —CH(CH 3 )—;

Z is selected from the group consisting of

and N-oxides thereof;

the Z group is unsubstituted or substituted with 1 to 3 independently selected R 8 substituents;

each R 8 is independently selected from the group consisting of H, halo, —CN, —OH, oxo, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, —NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

R 20 and R 21 are each independently H or substituted or unsubstituted C 1-8 alkyl,

wherein substituents for substituted alkyl including the alkyl portions of aminoalkyl, alkylamino, and alkoxy are independently selected from: halogen, —CN, —CO 2 R′, —C(O)R′, —C(O)NR′R″, oxo (═O or —O − ), —OR′, —OC(O)R′, —OC(O)NR′R″, —NO 2 , —NR′C(O)R″, —NR′″C(O)NR′R″, —NR′R″, —NR′CO 2 R″, —NR'S(O)R″, —NR'S(O) 2 R′″, —NR′″S(O)NR′R″, —NR′″S(O) 2 NR′R″, —SR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NR′—C(NHR″)═NR′″, —SiR′R″R′″, —OSiR′R″R′″, —N 3 , unsubstituted C 6-10 aryl, unsubstituted 5- to 10-membered heteroaryl, and unsubstituted 3- to 10-membered heterocyclyl;

wherein the number of substituents is from zero to (2m′+1), where m′ is the total number of carbon atoms in the alkyl, alkenyl, and alkynyl group;

wherein substituents for substituted aryl, heterocyclyl, and heteroaryl are independently selected from halogen, —CN, —CO 2 R′, —C(O)R′, —C(O)NR′R″, oxo (═O or —O − ), —OR′, —OSiR′R″R′″, —OC(O)R′, —OC(O)NR′R″, —NO 2 , —NR′C(O)R″, —NR′″C(O)NR′R″, —NR′R″, —NR′CO 2 R″, —NR'S(O)R″, —NR'S(O) 2 R″, —NR′″S(O)NR′R″, —NR′″S(O) 2 NR′R″, —SR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NR′—C(NHR″)═NR′″, —SiR′R″R′″, —N 3 , unsubstituted C 1-8 alkyl, unsubstituted C 2-8 alkenyl, unsubstituted C 2-8 alkynyl, unsubstituted C 6-10 aryl, unsubstituted 5- to 10-membered heteroaryl, and unsubstituted 3- to 10-membered heterocyclyl;

wherein the number of possible substituents to substituted aryl, heterocyclyl, and heteroaryl is from 0 to the total number of open valences on the ring system; and

wherein R′, R″ and R′″ are each independently hydrogen, unsubstituted C 1-8 alkyl, unsubstituted C 2-8 alkenyl, or unsubstituted C 2-8 alkynyl.

2. The compound claim 1 or salt thereof, wherein

Z is

wherein the Z group is unsubstituted or substituted with 1 to 3 independently selected R 8 substituents.

3. The compound of claim 2 or salt thereof, wherein

R 1 is selected from the group consisting of: —CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —C(CH 3 ) 2 CH 2 CH 3 , —C(CH 2 CH 2 )CN, —C(OH)(CH 3 ) 2 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OC(CH 3 ) 3 , —OCH 2 CH(CH 3 ) 2 , —OCF 3 , and morpholino;

R 2 is H, F, or Cl; or

R 3 is H, —CH 3 , or —OCH 3 ;

R 4 is H or F;

R 5 is H;

R 6 is H, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C 3 H 7 , —CH 2 F, —CHF 2 , —CF 2 CH 3 , —CF 3 , —CH 2 OCH 3 , —CH 2 OH, —CH 2 CN, —CN, or —CONH 2 ; and

each R 8 is independently selected from the group consisting of H, F, Cl, Br, —CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —NH 2 , —N(CH 3 ) 2 , and —CN.

4. The compound of claim 2 or salt thereof, wherein

R 1 is —C(CH 3 ) 3 ;

R 2 is H or F;

R 3 is H;

R 4 is H;

R 5 is H; and

R 6 is —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 .

5. The compound of claim 1 or salt thereof, of formula (IIIa) or (IIIb):

wherein:

R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy; or

R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring;

R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or halo;

R 4 is H or F;

R 5 is H, F, Cl, or —CH 3 ; and

R 5 and R 6 together with the carbon atoms to which they are attached form a carbocyclic ring;

R 20 and R 21 are each independently H or substituted or unsubstituted C 1-8 alkyl; and

n is 0, 1, 2 or 3.

6. The compound of claim 5 or salt thereof, wherein

R 2 is H, F, or C 1 ; or

R 1 and R 2 together form —OC(CH 3 ) 2 CH 2 — or —C(CH 3 ) 2 CH 2 CH 2 —;

R 3 is H, —CH 3 , or —OCH 3 ;

R 4 is H or F;

R 5 is H;

R 6 is H, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —C 3 H 7 , —CH 2 F, —CHF 2 , —CF 2 CH 3 , —CF 3 , —CH 2 OCH 3 , —CH 2 OH, —CH 2 CN, —CN, or —CONH 2 ; and

each R 8 is independently selected from the group consisting of H, F, Cl, Br, —CH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —NH 2 , —N(CH 3 ) 2 , and —CN.

7. The compound of claim 5 or salt thereof, wherein R 1 is —C(CH 3 ) 3 .

8. The compound of claim 5 or salt thereof, wherein

R 2 is H or F;

R 3 is H;

R 4 is H; and

R 6 is —CH 3 , —CH 2 F, —CHF 2 , or —CF 3 .

9. A composition comprising a pharmaceutically acceptable carrier and a compound or salt of formula (I):

wherein:

R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy; or

R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring;

R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or halo;

R 4 is H or F;

R 5 is H, F, Cl, or —CH 3 ; and

R 6 is H, halo, —CN, —CO 2 R a , —CONH 2 , —NH 2 , substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or unsubstituted C 1-8 aminoalkyl, wherein R a is H or substituted or unsubstituted C 1-8 alkyl; or

R 5 and R 6 together with the carbon atoms to which they are attached form a carbocyclic ring;

L is a bond, —CH 2 —, or —CH(CH 3 )—;

each of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are independently selected from the group consisting of N, N—O, and —CR 8 —; wherein at least one and not more than two of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 are N or N—O;

R 8 is each independently selected from the group consisting of H, halo, —CN, —OH, oxo, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, —NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;

R 20 and R 21 are each independently H or substituted or unsubstituted C 1-8 alkyl,

wherein substituents for substituted alkyl including the alkyl portions of aminoalkyl, alkylamino, and alkoxy are independently selected from: halogen, —CN, —CO 2 R′, —C(O)R′, —C(O)NR′R″, oxo (═O or —O—), —OR′, —OC(O)R′, —OC(O)NR′R″, —NO 2 , —NR′C(O)R″, —NR′″C(O)NR′R″, —NR′R″, —NR′CO 2 R″, —NR'S(O)R″, —NR'S(O) 2 R′″, —NR′″S(O)NR′R″, —NR′″S(O) 2 NR′R″, —SR′, —S(O)R′, —S(O) 2 R′, —S(O) 2 NR′R″, —NR′—C(NHR″)═NR′″, —SiR′R″R′″, —OSiR′R″R′″, —N 3 , unsubstituted C 6-10 aryl, unsubstituted 5- to 10-membered heteroaryl, and unsubstituted 3- to 10-membered heterocyclyl;

wherein the number of substituents is from zero to (2m′+1), where m′ is the total number of carbon atoms in the alkyl, alkenyl, and alkynyl group;

wherein the number of possible substituents to substituted aryl, heterocyclyl, and heteroaryl is from 0 to the total number of open valences on the ring system; and

wherein R′, R″ and R′″ are each independently hydrogen, unsubstituted C 1-8 alkyl, unsubstituted C 2-8 alkenyl, or unsubstituted C 2-8 alkynyl.

10. The composition of claim 9 , wherein the compound or salt thereof is of formula (II):

wherein:

R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy; or

R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring;

R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or halo;

R 4 is H or F;

R 5 is H, F, C 1 , or —CH 3 ;

R 6 is H, halo, —CN, —CO 2 R a , —CONH 2 , —NH 2 , unsubstituted C 1-8 aminoalkyl, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted C 1-8 alkoxy;

R a is H or substituted or unsubstituted C 1-8 alkyl;

L is a bond; and

Z is

wherein the Z group is unsubstituted or substituted with 1 to 3 independently selected R 8 substituents;

R 20 and R 21 are each independently H or substituted or unsubstituted C 1-8 alkyl.

11. A method of modulating CCR(9) function in a cell, comprising contacting the cell with a CCR(9) modulating amount of the compound of claim 1 .

12. A method for treating a CCR(9)-mediated condition or disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound or salt thereof of formula (I):

wherein:

R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy; or

R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring;

R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or halo;

R 4 is H or F;

R 5 is H, F, Cl, or —CH 3 ; and

R 5 and R 6 together with the carbon atoms to which they are attached form a carbocyclic ring;

L is a bond, —CH 2 —, or —CH(CH 3 )—;

R 20 and R 21 are each independently H or substituted or unsubstituted C 1-8 alkyl,

wherein the number of substituents is from zero to (2m′+1), where m′ is the total number of carbon atoms in the alkyl, alkenyl, and alkynyl group;

wherein the number of possible substituents to substituted aryl, heterocyclyl, and heteroaryl is from 0 to the total number of open valences on the ring system;

wherein R′, R″ and R′″ are each independently hydrogen, unsubstituted C 1-8 alkyl, unsubstituted C 2-8 alkenyl, or unsubstituted C 2-8 alkynyl; and

wherein the CCR(9)-mediated disease or condition is selected from the group consisting of ulcerative colitis, Crohn's disease, inflammatory bowel disease, asthma, graft rejection, immune mediated food allergies, celiac disease, primary sclerosing cholangitis, and graft-v-host disease.

13. The method of claim 12 , wherein the compound or salt thereof is of formula (II):

wherein:

R 2 is H, F, Cl, or substituted or unsubstituted C 1-8 alkoxy; or

R 1 and R 2 together with the carbon atoms to which they are attached form a non-aromatic carbocyclic ring or a heterocyclic ring;

R 3 is H, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, or halo;

R 4 is H or F;

R 5 is H, F, Cl, or —CH 3 ;

R 6 is H, halo, —CN, —CO 2 R a , —CONH 2 , —NH 2 , unsubstituted C 1-8 aminoalkyl, substituted or unsubstituted C 1-8 alkyl, or substituted or unsubstituted C 1-8 alkoxy;

R a is H or substituted or unsubstituted C 1-8 alkyl;

L is a bond;

Z is

wherein the Z group is unsubstituted or substituted with 1 to 3 independently selected R 8 substituents;

R 20 and R 21 are each independently H or substituted or unsubstituted C 1-8 alkyl.

14. The method of claim 12 , wherein the subject is a human.

15. The method of claim 12 , wherein the administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.

16. The method of claim 12 , wherein the CCR(9)-mediated disease or condition is an inflammatory bowel disease selected from Crohn's disease or ulcerative colitis.

17. The method of claim 12 , wherein the CCR(9)-mediated disease or condition is asthma.

18. The method of claim 12 , wherein the CCR(9)-mediated disease is graft-v-host disease.

19. The method of claim 12 , further comprising administering an anti-inflammatory or analgesic agent.

Assignments (2)

ASSIGNEE CHANGE OF ADDRESS Recorded Jun 27, 2023

From: CHEMOCENTRYX, INC.

To: CHEMOCENTRYX, INC.

Reel/Frame 064144/0685 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 14, 2022

From: CHEN, XI; FAN, JUNFA; FAN, PINGCHEN; KRASINSKI, ANTONI; LUI, REBECCA M.; MCMAHON, JEFFREY P.; POWERS, JAY P.; ZENG, YIBIN; ZHANG, PENGLIE; LI, LIANFA

To: CHEMOCENTRYX, INC.

Reel/Frame 060505/0129 →

Continuity (4)

Continuation 14541637 · Nov 14, 2014

Continuation 13781412 · Feb 28, 2013

Provisional Application 61604998 · Feb 29, 2012

Related Publication 20190060304A1 · Feb 28, 2019

Cited By (2)

US 12,486,247 US 12,611,404