Applications of biased ligands of the serotonin 5-ht7 receptor for the treatment of pain, multiple sclerosis and the control of thermoregulation

A compound having the following formula (I-1)

• wherein:
• R and R′ are, independently from each other, H or (C1-C6)alkyl groups, or form together with the carbon atoms carrying them a (C6-C10)aryl group;
• said aryl group being optionally substituted with one or several substituents, said substituents being in particular selected from the group consisting of:
• halogen;
• (C1-C6)alkyl;
• OH;
• (C1-C6)alkoxy;
• —NRdRe, Rd and Re, independently from each other, being H or a (C1-C6)alkyl group;
• aryl;
• heteroaryl;
• halo(C1-C6)alkyl group, such as CF3;
• —C(═O)—NRfRg, Rf and Rg, independently from each other, being H or a (C1-C6)alkyl group;
• and
• —C(═O)—Rh, Rh being a (C1-C6)alkyl group;
• R2 is selected from the group consisting of:
• H;
• (C1-C6)alkyl group;
• halo(C1-C6)alkyl group;
• aryl;
• and
• heteroaryl;
• A1 is a linker having the following formula (II):
• wherein:
• n is an integer varying from 1 to 7;
• and
• A2 is a bond or a C2 divalent radical, possibly substituted with at least one substituent selected from the group consisting of:
• (C1-C6)alkyl, (C3-C7)cycloalkyl, and hetero(C1-C6)alkyl, wherein possibly at least one carbon atom of A2 or A1 is replaced with a heteroatom such as —O—, —S— or —NRa—, Ra being H or a (C1-C6)alkyl group;
• and wherein A1 is possibly substituted with at least one substituent selected from the group consisting of:
• (C1-C6)alkyl, (C3-C7)cycloalkyl, and hetero(C1-C6)alkyl;
• R″ is a group having the following formula (A-1):
• wherein:
• the bonds “a” and “b” form a 4- to 10-membered saturated heterocycloalkyl group with the nitrogen atoms carrying them, said heterocycloalkyl group being optionally substituted for example with at least one substituent selected from (C1-C6)alkyl groups, and being selected from the monocyclic groups, bicyclic groups, fused bicycles and spiro-type rings;
• and
• R4 is selected from the optionally substituted heteroaryl groups;
• or its pharmaceutically acceptable salts, racemates, diastereomers or enantiomers.

A compound having the formula (I-3):

• wherein:
• R2 is selected from the group consisting of:
• H;
• (C1-C6)alkyl group;
• halo(C1-C6)alkyl group;
• aryl;
• and
• heteroaryl;
• A1 is a linker having the following formula (II):
• wherein:
• n is an integer varying from 1 to 7;
• and
• A2 is a bond or a C2 divalent radical, possibly substituted with at least one substituent selected from the group consisting of:
• (C1-C6)alkyl, (C3-C7)cycloalkyl, and hetero(C1-C6)alkyl, wherein possibly at least one carbon atom of A2 or A1 is replaced with a heteroatom such as —O—, —S— or —NRa—, Ra being H or a (C1-C6)alkyl group;
• and wherein A1 is possibly substituted with at least one substituent selected from the group consisting of:
• (C1-C6)alkyl, (C3-C7)cycloalkyl, and hetero(C1-C6)alkyl;
• R6 is selected from the group consisting of:
• —OH, (C1-C6)alkoxy, (C1-C6)alkyl, halogen, and thio(C1-C6)alkyl, and
• R7 is halogen;
• or its pharmaceutically acceptable salts, racemates, diastereomers or enantiomers.

A compound having the following formula (I-4):

• wherein:
• A1 is a linker having the following formula (II):
• wherein:
• n is an integer varying from 1 to 7;
• and
• A2 is a bond or a C2 divalent radical, possibly substituted with at least one substituent selected from the group consisting of:
• (C1-C6)alkyl, (C3-C7)cycloalkyl, and hetero(C1-C6)alkyl, wherein possibly at least one carbon atom of A2 or A1 is replaced with a heteroatom such as —O—, —S— or —NRa—, Ra being H or a (C1-C6)alkyl group;
• and wherein A1 is possibly substituted with at least one substituent selected from the group consisting of:
• (C1-C6)alkyl, (C3-C7)cycloalkyl, and hetero(C1-C6)alkyl;
• the bonds “a” and “b” form a 4- to 10-membered saturated heterocycloalkyl group with the nitrogen atoms carrying them, said heterocycloalkyl group being optionally substituted for example with at least one substituent selected from (C1-C6)alkyl groups, and being selected from the monocyclic groups, bicyclic groups, fused bicycles and spiro-type rings;
• and
• R4 is selected from the optionally substituted (C6-C10)aryl and heteroaryl groups;
• or its pharmaceutically acceptable salts, racemates, diastereomers or enantiomers.

A compound having the following formula (I-5):

• wherein:
• A1 is a linker comprising from 3 to 10 carbon atoms, wherein possibly at least one carbon atom of A1 is replaced with a heteroatom such as —O—, —S— or —NRa—, Ra being H or a (C1-C6)alkyl group;
• and wherein A1 is possibly substituted with at least one substituent selected from the group consisting of:
• (C1-C6)alkyl, (C3-C7)cycloalkyl, and hetero(C1-C6)alkyl;
• the bonds “a” and “b” form a 4- to 10-membered saturated heterocycloalkyl group with the nitrogen atoms carrying them, said heterocycloalkyl group being optionally substituted for example with at least one substituent selected from (C1-C6)alkyl groups, and being selected from the monocyclic groups, bicyclic groups, fused bicycles and spiro-type rings;
• and
• R4 is selected from the optionally substituted (C6-C10)aryl and heteroaryl groups;
• or its pharmaceutically acceptable salts, racemates, diastereomers or enantiomers.

A compound having the following formula (I-6):

• wherein:
• A1 is a linker having the following formula (II):
• wherein:
• n is an integer varying from 1 to 7;
• and
• A2 is a bond or a C2 divalent radical, possibly substituted with at least one substituent selected from the group consisting of:
• (C1-C6)alkyl, (C3-C7)cycloalkyl, and hetero(C1-C6)alkyl, wherein possibly at least one carbon atom of A2 or A1 is replaced with a heteroatom such as —O—, —S— or —NRa—, Ra being H or a (C1-C6)alkyl group;
• and wherein A1 is possibly substituted with at least one substituent selected from the group consisting of:
• (C1-C6)alkyl, (C3-C7)cycloalkyl, and hetero(C1-C6)alkyl;
• R4 is selected from the optionally substituted (C6-C10)aryl and heteroaryl groups;
• or its pharmaceutically acceptable salts, racemates, diastereomers or enantiomers.