IP Library › Patent Application 16807891

Patent Application

App. No. 16/807,891

Aza-Aryl 1H-Pyrazol-yl Benzene Sulfonamides

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Patent No.: US None
App. No.: 16/807,891

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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 (134)

1 . 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 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 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; and

8 . The composition of claim 7 , 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; 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;

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 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 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; and

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; 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;

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.