Neurotensinergic agonists and methods of using same preventing or treating pain

A compound of formula (I)

• wherein:
• (i) R1 is H, —CH3, —NH2 or —NH—C(═O)—C(NH2)(aminoalkyl) and R17 is H or CH3;
• or R17 is H, —CH3, —NH2 or —NH—C(═O)—C(NH2)(aminoalkyl);
• and R1 is H or CH3;
• (ii) R3 is a —(C1-C5)aminoalkyl, wherein the aminoalkyl is optionally substituted with one or more substituents, wherein each substituent is independently an halogen, amine, hydroxy, oxo, or a (C1-C5)alkyl;
• or the side chain of a histidine, norleucine, norvaline, glycine or glutamate;
• and R4 is H or —CH3;
• or
• R4 is a —(C1-C5)aminoalkyl, wherein the aminoalkyl is optionally substituted with one or more substituents, wherein each substituent is independently an halogen, amine, hydroxy, oxo, or a (C1-C5)alkyl;
• or the side chain of a histidine, norleucine, norvaline, glycine or glutamate;
• and R3 is H or —CH3;
• (iii) R6 is a —(C1-C5)aminoalkyl, wherein the aminoalkyl is optionally substituted with one or more substituents, wherein each substituent is independently an halogen, amine, hydroxy, oxo, or a (C1-C5)alkyl;
• or the side chain of a histidine, norleucine, norvaline, glycine or glutamate;
• and R7 is H or —CH3;
• or
• R7 is a —(C1-C5)aminoalkyl, wherein aminoalkyl is optionally substituted with one or more substituents, wherein each substituent is independently an halogen, amine, hydroxy, oxo, or a (C1-C5)alkyl;
• or the side chain of a histidine, norleucine, norvaline, glycine or glutamate;
• and R6 is H or —CH3;
• (iv) (a) R10 is H, or —(C1-C5)alkyl, —(CH2)q-(C3-C8)heteroaryl, a —(CH2)q-(C3-C8)aryl, a —(CH2)q-(C3-C8)cycloalkyl, or a —(CH2)q-(C3-C8)heterocycloalkyl, wherein q is 1 to 5, wherein the aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, and wherein the alkyl, heteroaryl, aryl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents, wherein each substituent is independently an halogen, hydroxy, amino, trifluoromethyl, cyano, nitro, or a (C1-C6)alkyl;
• or the side chain of an alanine (cyclopentyl), alanine (cyclohexyl), alanine (cyclobutyl), alanine (cyclopropyl), alanine (bromophenyl), alanine (thienyl), alanine (benzoylphenyl), alanine (anthryl), alanine (styryl), alanine, alanine (pyridyl), alanine (benzothienyl), alanine(naphtyl), biphenylalanine, diphenylalanine, glycine (4-Hydroxyphenyl), alanine (homotyrosine), alanine (furyl), phenylalanine (4-amino), phenylalanine (4-nitro), phenylalanine (4-methyl), phenylalanine (2, 3, 4, 5, 6 pentafluoro), tyrosine, tyrosine (0-acetyl), tryptophan, lysine, m-tyrosine, tyrosine (O-methyl), phenylalanine, phenylalanine (4-fluoro), phenylalanine (4-iodo), phenylalanine (4-tert-butyl), phenylalanine (4-CF3), phenylalanine (3-chloro), phenylalanine (4-chloro), phenylalanine (3-bromo), phenylalanine (4-bromo), phenylalanine (3-iodo) or phenylalanine (4-cyano);
• and R11 is H or —CH3;
• and R9 is as defined in (vi);
• or (b) R11 is H, —(C1-C5)alkyl, —(CH2)q—(C3-C8)heteroaryl, a —(CH2)q—(C3-C8)aryl, a —(CH2)q—(C3-C8)cycloalkyl, or a —(CH2)q—(C3-C8)heterocycloalkyl, wherein q is 1 to 5, wherein the aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, and wherein the alkyl, heteroaryl, aryl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents, wherein each substituent is independently an halogen, hydroxy, amino, trifluoromethyl, cyano, nitro, or a (C1-C6)alkyl;
• or the side chain of a alanine (cyclopentyl), alanine (cyclohexyl), alanine (cyclobutyl), alanine (cyclopropyl), alanine (bromophenyl), alanine (thienyl), alanine (benzoylphenyl), alanine (anthryl), alanine (styryl), alanine, alanine (pyridyl), alanine (benzothienyl), alanine(naphtyl), biphenylalanine, diphenylalanine, glycine (4-Hydroxyphenyl), alanine (homotyrosine), alanine (furyl), phenylalanine (4-amino), phenylalanine (4-nitro), phenylalanine (4-methyl), phenylalanine (2, 3, 4, 5, 6 pentafluoro), tyrosine, tyrosine (0-acetyl), tryptophan, lysine, m-tyrosine, tyrosine (O-methyl), phenylalanine, phenylalanine (4-fluoro), phenylalanine (4-iodo), phenylalanine (4-tert-butyl), phenylalanine (4-CF3), alanine (naphtyl), phenylalanine (3-chloro), phenylalanine (4-chloro), phenylalanine (3-bromo), phenylalanine (4-bromo), phenylalanine (3-iodo) or phenylalanine (4-cyano);
• and R10 is H or —CH3;
• and R9 is as defined in (vi);
• or
• (c) R10 or R11 forms a ring with R9, wherein the ring is a (C3-C8)heterocycloalkyl, optionally fused to a (C3-C8)cycloalkyl, a (C3-C8)heterocycloalkyl, a (C3-C8)aryl or a (C3-C8)heteroaryl, wherein when R9 forms the ring with R10, R11 is H;
• and when R9 forms the ring with R11, R10 is H;
• and wherein the definition of R9 in (vi) does not apply;
• (v) R13 is H or —CH3;
• and R14 is H, —(C1-C5)alkyl, —(CH2)q′—(C3-C8)heteroaryl, a —(CH2)q′—(C3-C8)aryl, —(CH2)q′—(C3-C8)cycloalkyl, or a —(CH2)q′—(C3-C8)heterocycloalkyl, wherein q′ is 1 to 5, wherein the aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, and wherein the alkyl, heteroaryl, aryl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents, wherein each substituent is independently an halogen, hydroxy, alkoxy, or a (C1-C6)alkyl;
• or the side chain of a leucine, tert-leucine, norleucine, norvaline, valine, neopentylglycine, cyclohexylglycine, cyclohexylalanine, phenylalanine, tyrosine (O-methyl), 2, 4, 5-trifluoro phenylalanine, homocyclohexylalanine, cyclopropylalanine, cyclobutylalanine, cyclopentylalanine, cycloheptylalanine or glycine;
• or
• R14 is H or —CH3;
• and R13 is H, —(C1-C5)alkyl, —(CH2)q′—(C3-C8)heteroaryl, a —(CH2)q′—(C3-C8)aryl, —(CH2)q′—(C3-C8)cycloalkyl, or a —(CH2)q′—(C3-C8)heterocycloalkyl, wherein q′ is 1 to 5, wherein the aryl or heteroaryl is optionally fused with one or two (C3-C8)aryl, and wherein the alkyl, heteroaryl, aryl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more substituents, wherein each substituent is independently an halogen, hydroxy, alkoxy, or a (C1-C6)alkyl;
• or the side chain of a leucine, tert-leucine, norleucine, norvaline, valine, neopentylglycine, cyclohexylglycine, cyclohexylalanine, phenylalanine, tyrosine (O-methyl), 2, 4, 5, -trifluoro phenylalanine, homocyclohexylalanine, cyclopropylalanine, cyclobutylalanine, cyclopentylalanine, cycloheptylalanine or glycine;
• (vi) R2, R5, R8, R9, and R12 are each independently H, (C1-12)alkyl, or (C4-C14)aralkyl;
• (vii) R15 is H or —OH;
• (viii) R16 is H or —CH3;
• and
• (ix) X is —(CH2)n, wherein n is 0-4;
• and Y is —(CH2)m-, —CH═CH(CH2)m-, —NR19C(═O)(CH2)m- or —C(═O)NR19(CH2)m-, wherein m is 1-4, wherein Rig is H or (C1-C5)alkyl,
• or a stereoisomer or a mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof.