US 12,583,861 B2 · Derivatives of imidazo[4,5-d]pyridazine, their preparation and their therapeutic application

Abstract

The present invention relates to a compound of formula (I) wherein R1 represents H, (C1-C6)alkyl-; hydroxy-(C1-C6)alkyl-; NH2—(C1-C6)alkyl-; NH—(C1-C6)alkyl-(C1-C6)alkyl-; N((C1-C6)alkyl)2-(C1-C6)alkyl-; (C2-C6)alkenyl-; (C2-C6)alkynyl-; phenyl(C1-C6)alkyl-; (C3-C10)cycloalkyl(C1-C6)alkyl-; (C3-C10)membered heterocycloalkyl(C1-C6)alkyl-; (C5-C10)membered heteroaryl(C1-C6)alkyl-; (C3-C10)membered heterocycloalkyl-NH—(C1-C16)alkyl-; and (C3-C10)membered heterocycloalkyl-N(C(O)—(C1-C6)alkyl)-(C1-C16)alkyl-; R2 represents a halogen atom, a (C1-C6)alkyl- group or other well defined groups; and R3 represents a deuterium atom; H, (C1-C6)alkyl-; (C2-C6)alkenyl-; (C2-C6)alkynyl-; (C1-C6)alkylthio-; —OR6; —NR7R8; (C3-C10)membered heterocycloalkyl-; (C5-C10)membered heteroaryl-; —(C6-C10)membered aryl; and (C3-C10)cycloalkyl-. The present invention further relates to intermediates of these compounds, processes for their preparation, a medicament and a pharmaceutical composition comprising them, and their therapeutic uses, in particular as TLR7 and/or TLR8 agonists, as well as their use in a vaccine.

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:
R1 represents:
a hydrogen atom, or
a group selected from:
a)
a (C1-C6)alkyl- group;
a hydroxy-(C1-C6)alkyl- group;
a NH2—(C1-C6)alkyl- group;
a NH—(C1-C6)alkyl-(C1-C6)alkyl- group;
a N((C1-C6)alkyl) 2-(C1-C6)alkyl- group;
a (C2-C6)alkenyl- group;
a (C2-C6)alkynyl- group;
b)
a phenyl (C1-C6)alkyl- group being unsubstituted or substituted by at least one substituent selected from:
b1)—a (C1-C6)alkoxy- group;
b2)—a hydroxyl group;
b3) a —C(O)—H group;
and
b4)—a (C1-C6)alkyl- group being unsubstituted or substituted by at least one substituent selected from:
b4.1)—a hydroxyl group;
and
b4.2)—a —NR4R5 group wherein R4 and R5, being independently from each other selected from:
b4.2.1)—a hydrogen atom;
b4.2.2)—a (C1-C16)alkyl- group;
b4.2.3)—a CH3—[O—(CH2)2]n— group with n being an integer from 1 to 30, a (C1-C6)alkoxy(C1-C6)alkyl- group, or a (C1-C6)alkoxy(C1-C6)alkoxy(C1-C6)alkyl- group;
b4.2.4)—a (C1-C6)alkyl-S(O2)— group;
b4.2.5)—a (C1-C6)alkyl-NH—C(O)— group;
b4.2.6)—a (C1-C16)alkyl-C(O)— group;
b4.2.7)—a (C1-C16)alkyl-O—C(O)— group;
b4.2.8)—a CH3—[O—(CH2)2]n—C(O)— group with n being an integer from 1 to 30;
b4.2.9)—a (C3-C10)cycloalkyl- group being unsubstituted or substituted by at least one substituent selected from:
a hydroxyl group;
and
a (C1-C6)alkyl- group;
or
b4.2.10)—a (C3-C10) membered heterocycloalkyl- group comprising from one to four heteroatoms selected from oxygen, nitrogen, sulfur, —S(O)— and —SO2—;
b4.2.11)—a phenyl-C(O)— group;
b4.2.12)—a (C1-C6)alkoxy-phenyl-(C1-C6)alkyl-O—C(O)— group;
b4.2.13)—a (C1-C16)alkyl-C(O)—NH-phenyl-(C1-C6)alkyl-O—C(O)— group;
b4.2.14)—a (C1-C16)alkyl-O—C(O)—(C1-C6)alkyl- group;
or R4 and R5 form together with the nitrogen atom to which they are attached a (C3-C10) membered heterocycloalkyl- group comprising one to four heteroatoms selected from oxygen, nitrogen and sulfur, said (C3-C10) membered heterocycloalkyl- group being unsubstituted or substituted by at least one substituent selected from a (C1-C6)alkyl- group, and a CH3—[O—(CH2)2]n— group with n being an integer from 1 to 30;
c)—a (C3-C10)cycloalkyl (C1-C6)alkyl- group being unsubstituted or substituted by at least one substituent selected from-NH2 and a NH2—(C1-C6)alkyl- group;
d)—a (C3-C10)membered heterocycloalkyl(C1-C6)alkyl- group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur,
said heterocycloalkyl group being unsubstituted or substituted by at least one substituent selected from a (C1-C6)alkyl- group and a CH3—[O—(CH2)2]n— group with n being an integer from 1 to 30;
and
e)—a (C5-C10) membered heteroaryl (C1-C6)alkyl- group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur,
said heteroaryl being unsubstituted or substituted by at least one substituent selected from:
a (C1-C6)alkyl- group;
a NH2—(C1-C6)alkyl- group and
a cyano group;
f)—a (C3-C10) membered heterocycloalkyl-NH—(C1-C16)alkyl- group, said heterocycloalkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, S(O), SO2 and sulfur;
g)—a (C3-C10) membered heterocycloalkyl-N(C(O)—(C1-C6)alkyl)-(C1-C16)alkyl- group, said heterocycloalkyl group comprising one to four heteroatoms selected from oxygen, nitrogen, S(O), SO2 and sulfur;
R2 represents a halogen atom,
or a group selected from:
a (C1-C6)alkyl- group;
a (C2-C6)alkenyl- group;
a (C2-C6)alkynyl- group;
a (C1-C6)alkylthio- group;
a (C1-C6)alkylthio (C1-C6)alkyl- group;
a (C1-C6)alkyl-S(O)— group;
a (C1-C6)alkyl-S(O2)— group;
a (C1-C6)alkyl-S(O)—(C1-C6)alkyl- group;
a (C1-C6)alkyl-S(O2)—(C1-C6)alkyl- group;
a (C1-C6)alkoxy- group;
a (C1-C6)alkoxy(C1-C6)alkyl- group;
a (C1-C6)haloalkoxy(C1-C6)alkyl- group;
a (C3-C5)cycloalkyl-O—(C1-C6)alkyl- group;
a (C1-C6)alkyl-NH—(C1-C6)alkyl- group;
a ((C1-C6)alkyl)2-N—(C1-C6)alkyl- group;
a (C1-C6)alkyl-NH— group;
and
a ((C1-C6)alkyl)2N— group;
R3 represents:
a deuterium atom;
a hydrogen atom
or a group selected from:
a)
a (C1-C6)alkyl- group;
a (C2-C6)alkenyl- group;
a (C2-C6)alkynyl- group;
and
a (C1-C6)alkylthio- group;
b)
a —OR6 group wherein R6 is selected from:
a hydrogen atom;
a (C1-C6)alkyl- group;
a CH3—[O—(CH2)2]n— group with n being an integer from 1 to 30;
a (C2-C6)alkenyl- group;
a (C2-C6)alkynyl- group;
a (C3-C10)cycloalkyl- group;
a phenyl group;
a phenyl (C1-C6)alkyl- group;
and
a (C3-C10) membered heterocycloalkyl- group comprising one to four heteroatoms selected from oxygen, nitrogen, sulfur, —S(═O)— and —S(═O)2—;
c)
a —NR7R8 group wherein R7 and R8 being, independently from each other, selected from:
a hydrogen atom;
a CH3—[O—(CH2)2]n— with n being an integer from 1 to 30;
a (C1-C6)alkyl- group unsubstituted or substituted by
a (C5-C10) membered heteroaryl group comprising one to four heteroatoms selected from oxygen, nitrogen and sulfur;
or
a phenyl group being unsubstituted or substituted by at least one substituent selected from:
a cyano group and
a NR9R10—(C1-C6)alkyl- group wherein:
R9 and R10 being, independently from each other, selected from:
a hydrogen atom;
a (C1-C6)alkyl- group;
a CH3—[O—(CH2)2]n— with n being an integer from 1 to 30, or
R9 and R10 together form with the nitrogen atom to which they are attached a (C3-C10) membered heterocycloalkyl- group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur,
said (C3-C10) membered heterocycloalkyl group being unsubstituted or substituted by at least one substituent selected from a (C1-C6)alkyl- group, and a CH3—[O—(CH2)2]n— group with n being an integer from 1 to 30;
or R7 and R8 form together with the nitrogen atom to which they are attached a (C3-C10) membered heterocycloalkyl- group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur,
said heterocycloalkyl group being unsubstituted or substituted by at least one substituent selected from:
a phenyl group and
a hydroxy (C1-C6)alkyl-phenyl- group;
d)
a (C3-C10) membered heterocycloalkyl- group comprising one to four heteroatoms selected from oxygen, nitrogen and sulfur;
e)
a (C5-C10) membered heteroaryl- group comprising one to four heteroatoms selected from oxygen, nitrogen, and sulfur,
said (C5-C10) membered heteroaryl- group being unsubstituted or substituted by at least one (C1-C6)alkyl- group;
f)
a —(C6-C10) membered aryl group;
and
g)
a (C3-C10)cycloalkyl- group.

121 more elements

Derivatives of imidazo[4,5-d]pyridazine, their preparation and their therapeutic application

Life of this patent

Derivatives of imidazo[4,5-d]pyridazine, their preparation and their therapeutic application

Life of this patent

Abstract

Claims18