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

Patent metadata

Field	Value
Publication number	US-10596163-B2
Application number	US-201816170752-A
Country	US
Kind code	B2
Filing date	Oct 25, 2018
Priority date	Feb 29, 2012
Publication date	Mar 24, 2020
Grant date	Mar 24, 2020

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.

First claim

The invention claimed is:

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 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;
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; and

n is 0, 1, 2 or 3.

6. The compound of claim 5 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; and
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 1 is selected from the group consisting of substituted or unsubstituted C 2-8 alkyl, substituted or unsubstituted C 1-8 alkoxy,

Assignees

• Chemocentryx Inc

Inventors

• Chen Xi
• Fan Junfa
• Fan Pingchen
• Krasinski Antoni
• Li Lianfa
• Lui Rebecca M
• Mcmahon Jeffrey P
• Powers Jay P
• Zeng Yibin
• Zhang Penglie

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P39/06

  Free radical scavengers or antioxidants · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title