US2020197386A1PendingUtilityA1
Aza-Aryl 1H-Pyrazol-yl Benzene Sulfonamides
Est. expiryFeb 29, 2032(~5.6 yrs left)· nominal 20-yr term from priority
Inventors:Xi ChenJunfa FanPingchen FanAntoni KrasinskiLianfa LiRebecca M. LuiJeffrey P. McmahonJay P. PowersYibin ZengPenglie Zhang
A61P 11/06A61P 31/18A61P 1/04A61P 19/02A61P 37/00C07D 403/10A61P 37/06C07D 401/04C07D 401/06C07D 403/04C07D 401/10A61K 45/06C07D 405/14A61P 35/00A61K 31/517C07D 231/42A61P 9/10A61P 11/02A61P 39/06A61K 31/4725A61K 31/502A61P 17/00A61P 17/04A61K 31/415A61K 31/5377A61P 27/02A61P 1/16A61P 25/28A61P 31/00A61K 31/4709A61P 1/00A61P 35/02A61P 3/10A61P 11/00A61P 29/00A61P 37/08A61P 13/12A61P 19/00A61P 15/02A61P 17/06A61P 43/00A61P 37/02
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Claims
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
exact text as granted — not AI-modified1 . A compound or salt thereof 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, 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 , 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 6 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; and
the compound is not 3,4-dimethoxy-N-(3-methyl-1-(4,6,8-trimethylquinolin-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide, N-(1-(4,8-dimethylquinolin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3,4-dimethoxybenzenesulfonamide, 3,4-dimethoxy-N-(3-methyl-1-(4-methylquinolin-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide, 3,4-dimethoxy-N-(3-methyl-1-(quinolin-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide, 2,3-dihydro-N-[3-methyl-1-(4-methyl-2-quinolinyl)-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide, 2,3-dihydro-N-[3-methyl-1-(4,8-dimethyl-2-quinolinyl)-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide, 3,4-dimethoxy-N-(1-(8-methoxy-4-methylquinolin-2-yl)-3-methyl-1H-pyrazol-5-yl)benzenesulfonamide, 2,3-dihydro-N-[3-methyl-1-(2-quinolinyl)-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide, 2,3-dihydro-N-[1-(8-methoxy-4-methyl-2-quinolinyl)-3-methyl-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide, or 2,3-dihydro-N-[3-methyl-1-(4,6,8-trimethyl-2-quinolinyl)-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide.
2 . The compound claim 1 or salt thereof, wherein the compound or salt thereof is 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 ;
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 selected from the group consisting of
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 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 3 or salt thereof, wherein R 1 is —C(CH 3 ) 3 .
6 . 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 .
7 . 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, 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 , 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 1 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; and
the compound is not 3,4-dimethoxy-N-(3-methyl-1-(4,6,8-trimethylquinolin-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide, N-(1-(4,8-dimethylquinolin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3,4-dimethoxybenzenesulfonamide, 3,4-dimethoxy-N-(3-methyl-1-(4-methylquinolin-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide, 3,4-dimethoxy-N-(3-methyl-1-(quinolin-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide, 2,3-dihydro-N-[3-methyl-1-(4-methyl-2-quinolinyl)-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide, 2,3-dihydro-N-[3-methyl-1-(4,8-dimethyl-2-quinolinyl)-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide, 3,4-dimethoxy-N-(1-(8-methoxy-4-methylquinolin-2-yl)-3-methyl-1H-pyrazol-5-yl)benzenesulfonamide, 2,3-dihydro-N-[3-methyl-1-(2-quinolinyl)-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide, 2,3-dihydro-N-[1-(8-methoxy-4-methyl-2-quinolinyl)-3-methyl-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide, or 2,3-dihydro-N-[3-methyl-1-(4,6,8-trimethyl-2-quinolinyl)-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide.
8 . The composition of claim 7 , wherein the compound or salt thereof is 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 ;
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 selected from the group consisting of
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 .
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 or salt thereof.
12 . A method for treating a CCR(9)-mediated condition or disease comprising administering to a subject an effective amount of a compound or salt thereof 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, 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 , 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 6 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; and
the compound is not 3,4-dimethoxy-N-(3-methyl-1-(4,6,8-trimethylquinolin-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide, N-(1-(4,8-dimethylquinolin-2-yl)-3-methyl-1H-pyrazol-5-yl)-3,4-dimethoxybenzenesulfonamide, 3,4-dimethoxy-N-(3-methyl-1-(4-methylquinolin-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide, 3,4-dimethoxy-N-(3-methyl-1-(quinolin-2-yl)-1H-pyrazol-5-yl)benzenesulfonamide, 2,3-dihydro-N-[3-methyl-1-(4-methyl-2-quinolinyl)-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide, 2,3-dihydro-N-[3-methyl-1-(4,8-dimethyl-2-quinolinyl)-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide, 3,4-dimethoxy-N-(1-(8-methoxy-4-methylquinolin-2-yl)-3-methyl-1H-pyrazol-5-yl)benzenesulfonamide, 2,3-dihydro-N-[3-methyl-1-(2-quinolinyl)-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide, 2,3-dihydro-N-[1-(8-methoxy-4-methyl-2-quinolinyl)-3-methyl-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide, or 2,3-dihydro-N-[3-methyl-1-(4,6,8-trimethyl-2-quinolinyl)-1H-pyrazol-5-yl]-2-oxo-6-benzoxazolesulfonamide.
13 . The method of claim 12 , wherein the compound or salt thereof is 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 ;
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 selected from the group consisting of
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.
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, an allergic disease, psoriasis, atopic dermatitis, asthma, a fibrotic disease, graft rejection, a graft-v-host disease, an immune mediated food allergy, an autoimmune disease, Celiac disease, rheumatoid arthritis, thymoma, thymic carcinoma, leukemia, solid tumor, acute lymphocytic leukemia, melanoma, primary sclerosing cholangitis, hepatitis, inflammatory hepatic disease, or post-operative ileus.
17 . 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.
18 . The method of claim 12 , wherein the CCR(9)-mediated disease or condition is asthma.
19 . The method of claim 12 , wherein the CCR(9)-mediated disease is graft-v-host disease.
20 . The method of claim 12 , further comprising administering an anti-inflammatory or analgesic agent.Cited by (0)
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