Aza-aryl 1H-pyrazol-1-yl benzene sulfonamides
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.
1 . A compound or salt 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, and substituted or unsubstituted C 3-10 heterocyclyl, and;
R 2 is H, F, or Cl; 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 1-2 alkyl, substituted or unsubstituted C 1-2 alkoxy, or halo;
R 4 is H or F;
R 5 is H or F;
R 6 is H, —CN, —CONH 2 , or substituted or unsubstituted C 1-8 alkyl;
where R 5 and R 6 may together form a carbocyclic ring;
L is a bond, —CH 2 —, or —CH(CH 3 )—;
Z is selected from the group consisting of
wherein the Z group is unsubstituted or substituted with 1 to 3 independently selected R 8 substituents;
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, and —NR 20 R 21 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl; and
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:
R 1 is selected from the group consisting of substituted or unsubstituted C 2-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, and substituted or unsubstituted C 3-10 heterocyclyl; and
R 2 is H, F, or Cl; 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 1-2 alkyl, substituted or unsubstituted C 1-2 alkoxy, or halo;
R 4 is H or F;
R 5 is H or F;
R 6 is H, —CN, —CONH 2 , or substituted or unsubstituted C 1-8 alkyl;
R a is H or substituted or unsubstituted C 1-8 alkyl;
L is a bond;
wherein 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; and
R 20 and R 21 are each independently H or substituted or unsubstituted C 1-8 alkyl.
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 3 or salt thereof, wherein R 1 is —C(CH 3 ) 3 .
5 . The compound of claim 4 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 .
6 . 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 .
7 . A composition comprising a pharmaceutically acceptable carrier and a compound or salt 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, and substituted or unsubstituted C 3-10 heterocyclyl; and
R 2 is H, F, or Cl; 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 1-2 alkyl, substituted or unsubstituted C 1-2 alkoxy, or halo;
R 4 is H or F;
R 5 is H or F; and
R 6 is H, —CN, —CONH 2 , 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
wherein the Z group is unsubstituted or substituted with 1 to 3 independently selected R& substituents;
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 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.
8 . The composition of claim 7 ,
wherein:
R 1 is selected from the group consisting of substituted or unsubstituted C 2-8 alkyl, substituted or unsubstituted C 1-8 alkoxy, and substituted or unsubstituted C 3-10 heterocyclyl; and
R 2 is H, F, or Cl; 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 1-2 alkyl, substituted or unsubstituted C 1-2 alkoxy, or halo;
R 4 is H or F;
R 5 is H or F;
R 6 is H, —CN, —CONH 2 , or substituted or unsubstituted C 1-8 alkyl;
L is a bond;
wherein 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; and
R 20 and R 21 are each independently H or substituted or unsubstituted C 1-8 alkyl.
9 . The composition of claim 8 , 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.
10 . The composition of claim 8 , 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 .