US 10,017,481 B2 · Conformationally constrained, fully synthetic macrocyclic compounds

Abstract

The conformationally restricted, spatially defined macrocyclic ring system of formula (I) is constituted by three distinct molecular parts: Template A, conformation Modulator B and Bridge C. Macrocycles described by this ring system I are readily manufactured by parallel synthesis or combinatorial chemistry in solution or on solid phase. They are designed to interact with a variety of specific biological target classes, examples being agonistic or antagonistic activity on G-protein coupled receptors (GPCRs), inhibitory activity on enzymes or antimicrobial activity. In particular, these macrocycles show inhibitory activity on endothelin converting enzyme of subtype 1 (ECE-1) and/or the cysteine protease cathepsin S (CatS), and/or act as antagonists of the oxytocin (OT) receptor, thyrotropin-releasing hormone (TRH) receptor and/or leukotriene B4 (LTB4) receptor, and/or as agonists of the bombesin 3 (BB3) receptor, and/or show antimicrobial activity against at least one bacterial strain. Thus they are showing great potential as medicaments for a variety of diseases.

A compound consisting of a cyclic arrangement of the building blocks A, B and C and represented by the general formula I

wherein
building block A (“Template”) is represented by
building block B (“Modulator”) is represented by
building block C (“Bridge”) is represented by
which in turn consists of
and wherein
X represents a divalent radical selected from the group of
Z represents a divalent or trivalent radical selected from the group of
forming an integral part of the
Y-Z connectivity which in turn represents a divalent radical selected from the group of
U represents a divalent radical selected from the group of
V and W are representing independently a divalent radical selected from the group of
and wherein
said Template A is a bivalent radical consisting of all possible combinations of structure ABAC
of which AB is selected from the group of
and AC is selected from the group of
wherein Modulator B is a bivalent radical selected from the group of
and Bridge C is a bivalent radical selected from the group of
and wherein further
R1 and R2 are independently defined as H;
F;
Cl;
Br;
I;
CF3;
OCF3;
OCHF2;
NO2;
CN;
C1-24-alkyl;
C2-24-alkenyl;
C2-10-alkynyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—(CR32R33)qOR34;
—(CR32R33)qSR34;
—(CR32R33)qNR7R35;
—(CR32R33)qOCONR7R35;
—(CR32R33)qNR7COOR36;
—(CR32R33)qNR7COR37;
—(CR32R33)qNR7CONR7R35;
—(CR32R33)qNR7SO2R38;
—(CR32R33)qNR7SO2NR7R35;
—(CR32R33)qCOOR36;
—(CR32R33)qCONR7R35;
—(CR32R33)qSO2NR7R35;
—(CR32R33)qCOR37;
—(CR32R33)qSO2R38;
—(CR32R33)qR39;
—(CR32R33)qR40;
—(CR32R33)qR41;
or —(CR32R33)qR44;
R3 and R4 are independently defined as H;
F;
Cl;
CF3;
OCF3;
OCHF2;
NO2;
CN;
C1-24-alkyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
C1-12-alkoxy or aryloxy;
R5 is H;
CF3;
C1-24-alkyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
or heteroaryl-C1-12-alkyl;
R6 is H;
CF3;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—(CR32R33)qOR34;
—(CR32R33)qSR34;
—(CR32R33)qNR7R35;
—(CR32R33)qOCONR7R35;
—(CR32R33)qNR7COOR36;
—(CR32R33)qNR7COR37;
—(CR32R33)qNR7CONR7R35;
—(CR32R33)qNR7SO2R38;
—(CR32R33)qNR7SO2NR7R35;
—(CR32R33)qCOOR36;
—(CR32R33)qCONR7R35;
—(CR32R33)qSO2NR7R35;
—(CR32R33)qCOR37;
—(CR32R33)qSO2R38;
—(CR32R33)qR39;
—(CR32R33)sR40;
or —(CR32R33)qR41;
or —(CR32R33)qR44;
R7 is H;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
or an N-protecting group;
R8 and R9 are independently defined as H;
F;
CF3;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
or heteroaryl-C1-12-alkyl;
R10, R11 and R12 are independently defined as H;
C1-24-alkyl;
or cycloalkyl;
R13 is C1-24-alkyl or cycloalkyl;
R14, R20 and R26 are independently defined as H;
F;
CF3;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—(CR32R33)qOR34;
—(CR32R33)qSR34;
—(CR32R33)qNR7R35;
—(CR32R33)qOCONR7R35;
—(CR32R33)qNR7COOR36;
—(CR32R33)qNR7COR37;
—(CR32R33)qNR7CONR7R35;
—(CR32R33)qNR7SO2R38;
—(CR32R33)qNR7SO2NR7R35;
—(CR32R33)qCOOR36;
—(CR32R33)qCONR7R35;
—(CR32R33)qSO2NR7R35;
—(CR32R33)qCOR37;
—(CR32R33)qSO2R38;
—(CR32R33)qR39;
—(CR32R33)sR40;
—(CR32R33)qR41;
or —(CR32R33)qR44;
R15, R17, R19, R21, R23, R25, R27, R29 and R31 are independently defined as H;
C1-24-alkyl;
cycloalkyl;
or heterocycloalkyl;
R16, R22 and R28 are independently defined as H;
CF3;
C1-24-alkyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
or heteroaryl-C1-12-alkyl;
R18, R24 and R30 are independently defined as H;
F;
CF3;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—(CR32R33)qOR34;
—(CR32R33)qNR7R35;
—(CR32R33)qOCONR7R35;
—(CR32R33)qNR7COOR36;
—(CR32R33)qNR7COR37;
—(CR32R33)qNR7CONR7R35;
—(CR32R33)qNR7SO2R38;
—(CR32R33)qNR7SO2NR7R35;
—(CR32R33)qCOOR36;
—(CR32R33)qCONR7R35;
—(CR32R33)qSO2NR7R35;
—(CR32R33)qCOR37;
or —(CR32R33)qR44;
R32 is H;
F;
CF3;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—(CR51R53)qOR45;
—(CR51R53)qSR45;
—(CR51R53)qNR7R45;
—(CR51R53)qOCONR7R45;
—(CR51R53)qNR74COOR36;
—(CR51R53)qNR7COR37;
—(CR51R53)qNR7CONR7R45;
—(CR51R53)qNR7SO2R38;
—(CR51R53)qNR7SO2NR7R45;
—(CR51R53)qCOOR36;
—(CR51R53)qCONR7R45;
—(CR51R53)qSO2NR7R45;
—(CR51R53)qCOR37;
—(CR51R53)qSO2R38;
—(CR51R53)qR39;
—(CR51R53)sR40;
—(CR51R53)qR41;
or —(CR51R53)qR44;
R33 is H;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
or heteroaryl-C1-12-alkyl;
R34 is H;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—(CR51R53)rOR45;
—(CR51R53)rNR7R45;
—(CR51R53)rOCONR7R35;
—(CR51R53)rNR7COOR36;
—(CR51R53)rNR7COR38;
—(CR51R53)rNR7CONR7R45;
—(CR51R53)rNR7SO2R38;
—(CR51R53)qCOOR36;
—(CR51R53)qCONR7R45;
—(CR51R53)qSO2NR7R45;
—(CR51R53)qCOR38;
—(CR51R53)qSO2R38;
—(CR51R53)qR39;
—(CR51R53)sR40;
—(CR51R53)qR41;
or —(CR51R53)qR44;
R35 is H;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
an N-protecting group;
—(CR32R33)rOR45;
—(CR32R33)rNR7R45;
—(CR32R33)rOCONR7R45;
—(CR32R33)rNR7COOR36;
—(CR32R33)rNR7CONR7R50;
—(CR32R33)rNR7SO2R38;
—(CR32R33)rNR7SO2NR7R50;
—(CR32R33)qCOOR36;
—(CR32R33)rNR7COR37;
—(CR32R33)qCONR7R50;
—(CR32R33)qCOR37;
—(CR32R33)qSO2R38;
—(CR32R33)qSO2NR7R50;
—(CR32R33)qR39;
—(CR32R33)sR40;
—(CR32R33)qR41;
or —(CR32R33)qR44;
R36 is H;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
or an O/S-protecting group;
R37 is C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—(CR51R53)qOR45;
—(CR51R53)qSR45;
—(CR51R53)qNR7R45;
—(CR51R53)qOCONR7R45;
—(CR51R53)qNR7COOR36;
—(CR51R53)qNR7COR38;
—(CR51R53)qNR7CONR7R45;
—(CR51R53)qNR7SO2R38;
—(CR51R53)qNR7SO2NR7R45;
—(CR51R53)qCOOR36;
—(CR51R53)qCONR7R45;
—(CR51R53)qSO2NR7R45;
—(CR51R53)tCOR44;
—(CR51R53)qSO2R38;
—(CR51R53)tR39;
—(CR51R53)uR40;
—(CR51R53)tR41;
or —(CR51R53)tR44;
R38 is C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
or heteroaryl-C1-12-alkyl;
R39 is aryl;
heteroaryl;
—C6H2R3R4R46;
or a group of one of the formulae
R40 is a group of one of the formulae
R41 is a group of one of the formulae
R42 and R43 are independently defined as H;
F;
CF3;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
or heteroaryl-C1-12-alkyl;
R44 is H;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
or a group of one of the formulae
R45 is H;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
an N-protecting group;
—(CR51R53)rOR36;
—(CR51R53)rNR7R57;
—(CR51R53)rOCONR7R57;
—(CR51R53)rNR7CONR7R57;
—(CR51R53)rNR7COR38;
—(CR51R53)rNR7SO2NR7R57;
—(CR51R53)rNR7SO2R38;
—(CR51R53)qCOOR36;
—(CR51R53)qCOR38;
—(CR51R53)qSO2R38;
—(CR51R53)qR39;
—(CR51R53)sR40;
—(CR51R53)qR41;
or —(CR51R53)R44;
R46 is H;
F;
Cl;
CF3;
OCF3;
OCHF2;
NO2;
CN;
C1-24-alkyl;
C2-24-alkenyl;
C2-10-alkynyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—(CR51R53)qOR36;
—(CR51R53)qSR36;
—(CR51R53)q(NR7R57;
—(CR51R53)qOCONR7R57;
—(CR51R53)q(NR7COOR36;
—(CR51R53)q(NR7COR38;
—(CR51R53)q(NR7CONR7R45;
—(CR51R53)q(NR7SO2R38;
—(CR51R53)q(NR7SO2NR7R45;
—(CR51R53)qCOOR36;
—(CR51R53)qCONR7R45;
—(CR51R53)qSO2NR7R45;
—(CR51R53)qCOR38;
—(CR51R53)qSO2R38;
or —(CR51R53)qR44;
R47 is H;
C1-24-alkyl;
C2-24-alkenyl;
C2-10-alkynyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
or —NR7R45;
R48 is H;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
an N-protecting group;
—(CR51R53)rOR45;
—(CR51R53)rSR45;
—(CR51R53)rNR7R45;
—(CR51R53)rOCONR7R45;
—(CR51R53)rNR7COOR36;
—(CR51R53)rNR7COR38;
—(CR51R53)rNR7CONR7R45;
—(CR51R53)rNR7SO2R38;
—(CR51R53)rNR7SO2NR7R45;
—(CR51R53)qCOOR36;
—(CR51R53)qCONR7R45;
—(CR51R53)rSO2NR7R45;
—(CR51R53)qCOR38;
—(CR51R53)qSO2R38;
or —(CR51R53)sR44;
R49 is H;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—(CR51R53)qOR36;
—(CR51R53)qSR36;
—(CR51R53)qNR7R45;
—(CR51R53)qNR7COOR36;
—(CR51R53)qNR7COR38;
—(CR51R53)qNR7SO2R38;
—(CR51R53)qNR7CONR7R45;
—(CR51R53)qCOOR36;
—(CR51R53)qCONR7R45;
—(CR51R53)qCOR38;
or —(CR51R53)qR44;
R50 is H;
C1-24-alkyl;
C2-6-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-6-alkyl;
heteroaryl-C1-6-alkyl;
or an N-protecting group;
R51 and R53 are independently defined as H;
F;
CF3;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—(CR42R43)tOR36;
—(CR42R43)tNR7R57;
—(CR42R43)tCOOR36;
or —(CR42R43)tCONR7R57;
R52 is H;
CF3;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—OR36;
—NR7R57;
—NR7COR38;
—NR7COOR36;
—NR7SO2R38;
—NR7CONR7R57;
—COOR36;
—CONR7R57;
—C(═NR7)NR7R57;
—NR7C(═NR7)NR7R57;
or a group of one of the formulae
R54 is H;
F;
CF3;
OCF3;
OCHF2;
NO2;
CN;
C1-24-alkyl;
C2-24-alkenyl;
C2-10-alkynyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—OR36;
—NR7R57;
—NR7COR38;
—NR7SO2R38;
—NR7CONR7R57;
—COR38;
or —SO2R38;
R55 is H;
CF3;
C1-24-alkyl;
C2-24-alkenyl;
C2-10-alkynyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—COOR36;
or —CONR7R45;
R56 is H;
F;
CF3;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
heterocycloalkyl;
aryl;
heteroaryl;
aryl-C1-12-alkyl;
heteroaryl-C1-12-alkyl;
—(CR42R43)sOR36;
—(CR42R43)sNR7R45;
—(CR42R43)qCOOR36;
or —(CR42R43)qCONR7R45;
R57 is H;
C1-24-alkyl;
C2-24-alkenyl;
cycloalkyl;
aryl;
aryl-C1-12-alkyl;
or an N-protecting group;
taken together (R5 and R6);
(R7 and R14);
(R7 and R16);
(R7 and R18);
(R7 and R20);
(R7 and R22);
(R7 and R24);
(R7 and R26);
(R7 and R28);
(R7 and R30);
(R7 and R35);
(R7 and R45);
(R7 and R57);
(R13 and R13);
(R14 and R16);
(R14 and R18);
(R15 and R51);
(R19 and R51);
(R20 and R22);
(R20 and R24);
(R26 and R28);
(R26 and R30);
(R32 and R33);
(R42 and R43);
or (R51 and R53) can form optionally substituted cycloalkyl or heterocycloalkyl moieties;
and the structural elements —NR7R35;
or —NR44R45 can form one of the groups of the formulae
T is CR54 or N;
Q is O;
S;
or NR35;
M is O;
S;
or NR′;
m is an integer of 0-8;
n is an integer of 0-1;
p is an integer of 0-4;
q is an integer of 0-4;
r is an integer of 2-4;
s is an integer of 1-4;
t is an integer of 0-2;
u is an integer of 1-2;
or a stereoisomer of such a compound;
or a salt, solvate, clathrate, N-oxide, isotopically enriched or enantiomerically enriched version thereof.

618 more elements

Conformationally constrained, fully synthetic macrocyclic compounds

Life of this patent

Conformationally constrained, fully synthetic macrocyclic compounds

Life of this patent

Abstract

Claims15