Compounds useful in inhibiting human trefoil factor 3

Patent metadata

Field	Value
Publication number	US-11141402-B2
Application number	US-201816619218-A
Country	US
Kind code	B2
Filing date	Jun 5, 2018
Priority date	Jun 5, 2017
Publication date	Oct 12, 2021
Grant date	Oct 12, 2021

Abstract

Disclosed herein are compounds of Formula I,

wherein A, R 1 to R 6 , and x to z have the meanings given in the description.

First claim

The invention claimed is:

1. A compound of formula I:

wherein:
R 1 represents CN or Het a , which latter group is unsubstituted or substituted by halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, which latter four groups are unsubstituted or substituted by one or more substituents selected from halo, OH and NH 2 ;
R 2 and R 3 independently represent H, C(O)R 7 , S(O) x′ R 7′ , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, which latter four groups are unsubstituted or substituted by one or more substituents selected from halo, OH and NH 2 ; or
R 1 and R 2 and/or R 3 , together with the atoms they are attached to, form a heterocyclic or heteroaromatic ring system having from 9 to 10 atoms in the ring system, which ring system is unsubstituted or substituted by one or more groups selected from ═S, ═O, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, or Het b , which latter six groups are unsubstituted or substituted by one or more substituents selected from halo, OR 8 and NR 9 R 10 ;
each R 4 independently represents halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, (which latter four groups are unsubstituted or substituted by one or more substituents selected from halo, OH and NH 2 ), OR 11 , or NR 12 R 13 ,
each R 5 independently represents halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, (which latter four groups are unsubstituted or substituted by one or more substituents selected from halo, OH and NH 2 ), OR 14 , or NR 15 R 16 ;
each R 6 independently represents halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, (which latter four groups are unsubstituted or substituted by one or more substituents selected from halo, OH, NH 2 , and ═O), OR 17 , or NR 18 R 19 ;
R 7 and R 7′ independently represent Het c , aryl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, which latter five groups are unsubstituted or substituted by one or more substituents selected from aryl (which group is unsubstituted or substituted by one or more of C 1-6 alkyl, alkoxy, halo, NO 2 , OH and NH 2 ), alkoxy, C 1-3 alkyl, Het d , halo, OH and NH 2 ;
R 8 , R 11 , R 14 and R 17 each independently represent at each occurrence thereof H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, which latter four groups are unsubstituted or substituted by one or more substituents selected from halo, alkoxy, OH and NH 2 ;
R 9 , R 10 , R 12 , R 13 , R 15 , R 16 , R 18 , and R 19 each independently represent at each occurrence thereof H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, which latter four groups are unsubstituted or substituted by one or more substituents selected from halo, alkoxy, OH and NH 2 ;
Het a to Het d independently represent, at each occurrence, a 5- or 6-membered heterocyclic or heteroaromatic groups containing one or more heteroatoms selected from O, S and N, which heterocyclic groups are optionally substituted by one or more substituents selected from ═O, ═S, halo, OH, C 1-4 alkyl and C 1-4 alkoxy, which latter two groups are optionally substituted by one or more substituents selected from halo, OH and NH 2 ;
A represents a 5- to 13-membered carbocyclic or heterocyclic ring system that is aromatic and/or non-aromatic;
x is from 0 to 4;
x′ is from 1 to 2;
y is from 0 to 5; and
z is from 0 to 5,

or a pharmaceutically acceptable salt or solvate, or a deuteriated compound of the Formula I thereof;
with the proviso that a compound of formula I excludes the following compounds:

2. The compound of claim 1 , wherein R 1 represents CN or Het a , which latter group is unsubstituted or substituted by halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, which latter four groups are unsubstituted or substituted by one or more substituents selected from halo, OH and NH 2 .

3. The compound of claim 1 , wherein R 2 and R 3 independently represent H, C(O)R 7 , S(O) x′ R 7′ , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, which latter four groups are unsubstituted or substituted by one or more substituents selected from halo, OH and NH 2 .

4. The compound of claim 3 , wherein R 2 and R 3 independently represent H, C(O)R 7 and S(O) 2 R 7′ .

5. The compound of claim 1 , wherein Het a to Het d independently represent, at each occurrence, a 5- or 6-membered heteroaromatic group containing one or more heteroatoms selected from 0 and N, which heterocyclic groups are unsubstituted or substituted by one or more substituents selected from ═O, halo, OH, C 1-4 alkyl and C 1-4 alkoxy, which latter two groups are optionally substituted by one or more substituents selected from halo, OH and NH 2 .

6. The compound of claim 1 , wherein A represents a 6- to 10-membered aromatic or heterocyclic ring system, optionally wherein A represents a 6-membered aromatic or heterocyclic ring system.

7. The compound of claim 1 , wherein:
x is from 0 to 2; and/or
x′, when present, is 2; and/or
y is from 1 to 3; and/or
z is from 1 to 3.

8. The compound of claim 1 , wherein:
R 1 represents CN or Het a , which latter group is unsubstituted or substituted by halo, C 1-6 alkyl, which latter four group is unsubstituted or substituted by one or more substituents selected from halo, OH and NH 2 ;
R 2 and R 3 independently represent H, C(O)R 7 , S(O) x′ R 7′ , C 1-6 alkyl, which latter group is unsubstituted or substituted by one or more substituents selected from halo, OH and NH 2 ;
each R 4 independently represents halo, C 1-6 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from halo, OH and NH 2 ), OR 11 , or NR 12 R 13 ,
each R 5 independently represents halo, C 1-6 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from halo, OH and NH 2 ), OR 14 , or NR 15 R 16 ;
each R 6 independently represents halo, C 1-6 alkyl (which latter group is unsubstituted or substituted by one or more substituents selected from halo, OH and NH 2 ), OR 17 , or NR 18 R 19 ;
R 7 and R 7′ independently represent Het c , aryl, C 1-6 alkyl, which latter two groups are unsubstituted or substituted by one or more substituents selected from aryl (which group is unsubstituted or substituted by one or more of C 1-6 alkyl, alkoxy, halo, NO 2 , OH and NH 2 ), alkoxy, C 1-3 alkyl, Het d , halo, OH and NH 2 ;
R 11 , R 14 and R 17 each independently represent at each occurrence thereof H, C 1-6 alkyl, C 2 -6 alkenyl, C 2-6 alkynyl, or C 3-6 cycloalkyl, which latter four groups are unsubstituted or substituted by one or more substituents selected from halo, alkoxy, OH and NH 2 ;
R 12 , R 13 , R 15 , R 16 , R 18 , and R 19 each independently represent at each occurrence thereof H, C 1-6 alkyl, which latter group is unsubstituted or substituted by one or more substituents selected from halo, alkoxy, OH and NH 2 ;
Het a , Het c and Het d independently represent, at each occurrence, a 5- or 6-membered heterocyclic or heteroaromatic group containing one or more heteroatoms selected from O, S and N, which heterocyclic groups are optionally substituted by one or more substituents selected from ═O, ═S, halo, OH, C 1-4 alkyl and C 1-4 alkoxy, which latter two groups are optionally substituted by one or more substituents selected from halo, OH and NH 2 ;
A represents a 5- to 13-membered carbocyclic or heterocyclic ring system that is aroma

Assignees

• Nat Univ Singapore
• Univ Of Mysore
• Bangalore Univ

Inventors

• Lobie Peter Edward
• Pandey Vijay Kumar
• Kanchugarakoppal Subbegowda Rangappa
• Basappa
• Chakrabhavi Dhananjaya Mohan
• RANGAPPA Shobith

Classifications

• C07D493/04 Primary

  Ortho-condensed systems · CPC title

• C07D491/22

  in which the condensed system contains four or more hetero rings · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title