US 11,883,387 B2
PqsR inverse agonists
Ahmed S. A. Ahmed, Braunschweig (DE); Martin Empting, Braunschweig (DE); Mostafa Hamed, Braunschweig (DE); Rolf W. Hartmann, Braunschweig (DE); Jörg Haupenthal, Braunschweig (DE); Thomas Hesterkamp, Braunschweig (DE); Ahmed A. M. Kamal, Braunschweig (DE); Christine K. Maurer, Braunschweig (DE); Teresa Röhrig, Braunschweig (DE); Christian Schütz, Braunschweig (DE); Samir Yahiaoui, Braunschweig (DE); and Michael Zender, Braunschweig (DE)
Assigned to Helmholtz-Zentrum Für Infektionsforschung GmbH, Braunschweig (DE)
Appl. No. 17/257,804
Filed by HELMHOLTZ-ZENTRUM FÜR INFEKTIONSFORSCHUNG GMBH, Braunschweig (DE)
PCT Filed Jul. 3, 2019, PCT No. PCT/EP2019/067899
§ 371(c)(1), (2) Date Jan. 4, 2021,
PCT Pub. No. WO2020/007938, PCT Pub. Date Jan. 9, 2020.
Claims priority of application No. 18181475 (EP), filed on Jul. 3, 2018.
Prior Publication US 2021/0353606 A1, Nov. 18, 2021
Int. Cl. A61K 31/4439 (2006.01); A61P 31/04 (2006.01); A61K 31/444 (2006.01); A61K 31/506 (2006.01); A61K 45/06 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 403/12 (2006.01); C07D 405/14 (2006.01); C07D 413/12 (2006.01); C07D 417/12 (2006.01); C07D 417/14 (2006.01); C07D 471/04 (2006.01)
CPC A61K 31/4439 (2013.01) [A61K 31/444 (2013.01); A61K 31/506 (2013.01); A61K 45/06 (2013.01); A61P 31/04 (2018.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 403/12 (2013.01); C07D 405/14 (2013.01); C07D 413/12 (2013.01); C07D 417/12 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01)] 17 Claims
 
1. A compound having the formula (I):

OG Complex Work Unit Chemistry
or a pharmacologically acceptable salt thereof,
wherein
A represents a group:

OG Complex Work Unit Chemistry
wherein
said group A is as defined in (i) or (ii):
(i) A1 is CH; A2 is N;
A3 is N or C—RA3,
RA3 represents a hydrogen atom, a halogen atom, CF3, CN, C(═O)NH2, C(═O)OH, CH2OH, CH2NH2, OH, OMe, or NH2; and
RA represents CF3, CN, Cl, NO2 or F; or
(ii) A1 is N; A2 is N; A3 is C—NH2; and RA represents CF3, CN, Cl, NO2 or F;
L is a group represented by formula (L-1) or (L-2):

OG Complex Work Unit Chemistry
wherein
X1 is NH or S;
ring B is a partially unsaturated or aromatic, 5-membered heterocyclic ring represented by formula (B-1) or 6-membered heterocyclic ring represented by formula (B-2):

OG Complex Work Unit Chemistry
wherein
the ring represented by formula (B-1) is:
(i) a ring, wherein M1 is CH; M2 is C or N; and each of M3 and M4, independently of one another, is N or NH; or
(ii) a ring, wherein M1 is S; M2 is C; M3 is N; and M4 is CH;
M11, M12, M13, and M14 each, independently of one another, represents CH or N;
at least one of M11, M12, M13, and M14 being a group with a heteroatom as defined above;
U1 and U2 each, independently of one another, represents N or C(R′);
R1, at each occasion independently, represents a hydrogen atom, a halogen atom, OH, CN, CF3, CH2—OH, OCH3, OCF3; or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclo-alkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group;
each “custom character”, independently of one another, represents a single bond or a double bond, wherein at least one “custom character” in each of the rings of formulae (L-1), (B-1) and (B-2) is a double bond;

OG Complex Work Unit Chemistry
wherein
X2 is NH, O or S;
Y1 represents N, NH, S or O;
Y2 represents N or C(R11);
Y3 represents N or NH;
R11 represents a hydrogen atom, a halogen atom, OH, CN, CF3, CH2—OH, OCH3, OCF3; or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group;
each “custom character” independently of one another, represents a single bond or a double bond, wherein at least one “custom character” in the ring of formula (L-2) is a double bond;
T is R2 or a group: —Y—R3, wherein
R2 is a hydrogen atom, a halogen atom, CN, CF3, CH2—OH; NRT1RT2; or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, all of which groups may optionally be substituted;
RT1 and RT2 each, independently of one another, represents a hydrogen atom or a (C1-C3)alkyl group, which may be substituted by one or more, identical or different, group(s) selected from a halogen atom, OH, ═O, and NH2;
Y is —O— or —S—; and
R3 is a hydrogen atom; or an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclo-alkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, all of which groups may optionally be substituted.