CYCLIC UREA COMPOUNDS AS TROPOMYOSIN-RELATED KINASE (TRK) iNHIBITORS

A method of treating pain in a patient in need thereof comprising administering to the patient a compound according to Formula (I):

• wherein:
• p is 0, 1 or 2;
• R and R1, which may be identical or different, are O or NH;
• R2 and R3, which may be identical or different, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl that are optionally substituted, or R2 and R3 taken together with the carbon atom to which they are attached form 3- to 10-membered carbocyclyl that is optionally being substituted or 3- to 10-membered heterocyclyl containing one or more hetero atoms chosen from O, S, N and NR7 that is optionally being substituted;
• A1 is single bond, alkyl, alkenyl or alkynyl;
• Y and Y1, which may be identical or different, are such that one of Y and Y1 is —OCF3, —O—F2—CHF2, —O—CHF2, —O—CH2—CF3, —SO2NR5R6, —SF5 and —S(O)n-alkyl and the other of Y and Y1 is —OCF3, —O—F2—CHF2, —O—CHF2, —O—CH2—CF3, SO2NR5R6, —SF5, —S(O)n-alkyl, hydrogen, halogen, hydroxyl, alkoxy, nitro, —CN, —NR5R6, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, —CF3, —O-alkenyl, —O-alkynyl, —O-cycloalkyl, —S(O)n-alkenyl, —S(O)n-alkynyl, —S(O)n-cycloalkyl, —CONR5R6, or free, salified or esterified carboxyl, or the
• that is optionally substituted with one or more alkyl that are optionally substituted, wherein
• q is 2, 3 or 4;
• R5 and R6, which may be identical or different, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl, or R5 and R6 taken together with the nitrogen atom to which they are attached form 3- to 10-membered heterocyclyl containing one or more hetero atoms chosen from O, S, N and NR7 that is optionally being substituted;
• A2, which may be identical to or different from A1, is defined as A1 or is CO or SO2,
• B2 is saturated or unsaturated, 3- to 10-membered monocyclic or bicyclic heterocyclyl containing one or more hetero atoms chosen from O, S, N and NR7 that is optionally substituted with one or more identical or different substituents defined as Y2, wherein
• R7 is hydrogen, alkyl, cycloalkyl, phenyl, acyl, —S(O)2Alk, —S(O)2Aryl, —S(O)2heteroaryl or —S(O)2NR5R6,
• Y2 is hydrogen, halogen, hydroxyl, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O-alkenyl, —O-alkynyl, —O-cycloalkyl, —S(O)n-alkyl, —S(O)n-alkenyl, —S(O)n-alkynyl, —S(O)n-cycloalkyl, —COOR13, —OCOR13, NR5R6, CONR5R6, —S(O)n—NR5R6, —NR10—CO—R13, —NR10—SO2—R13, NH—SO2—NR5R6, —NR10—CO—NR5R6, —NR10—CS—NR5R6 or —NR10—COOR13, all of which are optionally substituted;
• all the alkyl, alkenyl, alkynyl and alkoxy above are linear or branched and contain not more than 6 carbon atoms,
• all the cycloalkyl and heterocyclyl above contain not more than 7 carbon atoms,
• all the aryl and heteroaryl above contain not more than 10 carbon atoms,
• all the carbocyclyl, heterocyclyl, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl above, and also the ring formed by R5 and R6 with the nitrogen atom to which they are attached, are optionally substituted with one or more substituents, which may be identical or different, selected from the group consisting of halogen, cyano, hydroxyl, alkoxy, —CF3, nitro, aryl, heteroaryl, —C(═O)—OR9, —C(═O)—R8, —NR11R12, —C(═O)—NR11R12, —N(R10)—C(═O)—R8, —N(R10)—C(═O)—OR9, —N(R10)—C(═O)—NR11R12, —N(R10)—S(O)n—R8, —S(O)n—R8, —N(R10)—S(O)n—NR11R12 and —S(O)n—NR11R12,
• all the aryl and heteroaryl above are optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy and alkylenedioxy,
• all the cyclic radicals above, and also the ring formed by R5 and R6 with the nitrogen atom to which they are attached, are optionally substituted with one or more substituents selected from the group consisting of oxo and thioxo,
• n is 0 to 2, and wherein
• R8 is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl,
• R9 is defined as R8 or is hydrogen,
• R10 is hydrogen or alkyl,
• R11 and R12, which may be identical or different, are hydrogen, C3-C6 cycloalkyl, C1-C4 alkyl or phenyl, optionally substituted with one or more substituents, which may be identical or different, selected from the group consisting of halogen, cyano, hydroxyl, alkoxy, —CF3, nitro, phenyl, and free, salified, esterified or amidated carboxyl, or R11 and R12 taken together with the nitrogen atom to which they are attached form 5- to 7-membered cyclic radical containing one or more hetero atoms chosen from O, S, N and NR7, preferably a cyclic amine, and
• R13, which may be identical to or different to R5 or R6, is defined as R5 or R6, or a racemic, enantiomeric or diastereoisomeric isomer form of the compound of Formula (I), addition salt with mineral or organic acid or with mineral or organic base thereof, with the proviso:
• a) when p is 0, R and R1 are oxygen, A1 is single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —OCF3 or —S-alk, A2 is single bond or alkyl and B2 is an optionally substituted heterocyclyl, then R2 and R3 are not one hydrogen and the other imidazolylalkyl;
• b) when p is 0, R and R1 are oxygen, A1 is single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —OCF3, —SO-Alk, —S(O)2-alk or —SO2NH2, A2 is CH2 and B2 is an optionally substituted heterocyclyl, then R2 and R3 are not one hydrogen and the other alkyl optionally interrupted with O, S or N-alk;
• always substituted with a hydroxamate (—CO—NHOH);
• c) when p is 0, R and R1 are oxygen, A1 is a single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —S(O)n-alk, A2 is single bond and B2 is an optionally substituted 5- or 6-membered aromatic heterocyclyl, then R2 and R3 are not selected from the group consisting of hydrogen, alkyl, arylalkyl, aryl and heteroaryl;
• or
• d) when p is 0 to 2, R and R1 are oxygen, A1 is single bond, Y and Y1, which may be identical or different, are one is —SO2Alk or SO2NH2 and the other is NR5R6, A2 is single bond or alkylene and B2 is optionally substituted 5- to 10-membered heterocyclyl, then R2 and R3 are not both hydrogen.

A method of inhibiting a tropomyosin-receptor kinase in a patient comprising administering to the patient a compound according to Formula (I):

• wherein:
• p is 0, 1 or 2;
• R and R1, which may be identical or different, are O or NH;
• R2 and R3, which may be identical or different, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl that are optionally substituted, or R2 and R3 taken together with the carbon atom to which they are attached form 3- to 10-membered carbocyclyl that is optionally being substituted or 3- to 10-membered heterocyclyl containing one or more hetero atoms chosen from O, S, N and NR7 that is optionally being substituted;
• A1 is single bond, alkyl, alkenyl or alkynyl;
• Y and Y1, which may be identical or different, are such that one of Y and Y1 is —OCF3, —O—F2—CHF2, —O—CHF2, —O—CH2—CF3, —SO2NR5R6, —SF5 and —S(O)n-alkyl and the other of Y and Y1 is —OCF3, —O—F2—CHF2, —O—CHF2, —O—CH2—CF3, SO2NR5R6, —SF5, —S(O)n-alkyl, hydrogen, halogen, hydroxyl, alkoxy, nitro, —CN, —NR5R6, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, —CF3, —O-alkenyl, —O-alkynyl, —O-cycloalkyl, —S(O)n-alkenyl, —S(O)n-alkynyl, —S(O)n-cycloalkyl, —CONR5R6, or free, salified or esterified carboxyl, or the
• that is optionally substituted with one or more alkyl that are optionally substituted, wherein
• q is 2, 3 or 4;
• R5 and R6, which may be identical or different, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl, or R5 and R6 taken together with the nitrogen atom to which they are attached form 3- to 10-membered heterocyclyl containing one or more hetero atoms chosen from O, S, N and NR7 that is optionally being substituted;
• A2, which may be identical to or different from A1, is defined as A1 or is CO or SO2,
• B2 is saturated or unsaturated, 3- to 10-membered monocyclic or bicyclic heterocyclyl containing one or more hetero atoms chosen from O, S, N and NR7 that is optionally substituted with one or more identical or different substituents defined as Y2, wherein
• R7 is hydrogen, alkyl, cycloalkyl, phenyl, acyl, —S(O)2Alk, —S(O)2Aryl, —S(O)2heteroaryl or —S(O)2NR5R6,
• Y2 is hydrogen, halogen, hydroxyl, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —O-alkenyl, —O-alkynyl, —O-cycloalkyl, —S(O)n-alkyl, —S(O)n-alkenyl, —S(O)n-alkynyl, —S(O)n-cycloalkyl, —COOR13, —OCOR13, NR5R6, CONR5R6, —S(O)n—NR5R6, —NR10—CO—R13, —NR10—SO2—R13, NH—SO2—NR5R6, —NR10—CO—NR5R6, —NR1—CS—NR5R6 or —NR10—COOR13, all of which are optionally substituted;
• all the alkyl, alkenyl, alkynyl and alkoxy above are linear or branched and contain not more than 6 carbon atoms,
• all the cycloalkyl and heterocyclyl above contain not more than 7 carbon atoms,
• all the aryl and heteroaryl above contain not more than 10 carbon atoms,
• all the carbocyclyl, heterocyclyl, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl above, and also the ring formed by R5 and R6 with the nitrogen atom to which they are attached, are optionally substituted with one or more substituents, which may be identical or different, selected from the group consisting of halogen, cyano, hydroxyl, alkoxy, —CF3, nitro, aryl, heteroaryl, —C(═O)—OR9, —C(═O)—R8, —NR11R12, —C(═O)NR11R12, —N(R10)—C(═O)—R8, —N(R10)—C(═O)—OR9, —N(R10)—C(═O)—NR11R12, —N(R10)—S(O)n—R8, —S(O)n—R8, —N(R10)—S(O)n—NR11R12 and —S(O)n—NR11R12,
• all the aryl and heteroaryl above are optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy and alkylenedioxy,
• all the cyclic radicals above, and also the ring formed by R5 and R6 with the nitrogen atom to which they are attached, are optionally substituted with one or more substituents selected from the group consisting of oxo and thioxo,
• n is 0 to 2, and wherein
• R8 is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl,
• R9 is defined as R8 or is hydrogen,
• R10 is hydrogen or alkyl,
• R11 and R12, which may be identical or different, are hydrogen, C3-C6 cycloalkyl, C1-C4 alkyl or phenyl, optionally substituted with one or more substituents, which may be identical or different, selected from the group consisting of halogen, cyano, hydroxyl, alkoxy, —CF3, nitro, phenyl, and free, salified, esterified or amidated carboxyl, or R11 and R12 taken together with the nitrogen atom to which they are attached form 5- to 7-membered cyclic radical containing one or more hetero atoms chosen from O, S, N and NR7, preferably a cyclic amine, and
• R13, which may be identical to or different to R5 or R6, is defined as R5 or R6, or a racemic, enantiomeric or diastereoisomeric isomer form of the compound of Formula (I), addition salt with mineral or organic acid or with mineral or organic base thereof, with the proviso:
• a) when p is 0, R and R1 are oxygen, A1 is single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —OCF3 or —S-alk, A2 is single bond or alkyl and B2 is an optionally substituted heterocyclyl, then R2 and R3 are not one hydrogen and the other imidazolylalkyl;
• b) when p is 0, R and R1 are oxygen, A1 is single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —OCF3, —SO-Alk, —S(O)2-alk or —SO2NH2, A2 is CH2 and B2 is an optionally substituted heterocyclyl, then R2 and R3 are not one hydrogen and the other alkyl optionally interrupted with O, S or N-alk;
• always substituted with a hydroxamate (—CO—NHOH);
• c) when p is 0, R and R1 are oxygen, A1 is a single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —S(O)n-alk, A2 is single bond and B2 is an optionally substituted 5- or 6-membered aromatic heterocyclyl, then R2 and R3 are not selected from the group consisting of hydrogen, alkyl, arylalkyl, aryl and heteroaryl;
• or
• d) when p is 0 to 2, R and R1 are oxygen, A1 is single bond, Y and Y1, which may be identical or different, are one is —SO2Alk or SO2NH2 and the other is NR5R6, A2 is single bond or alkylene and B2 is optionally substituted 5- to 10-membered heterocyclyl, then R2 and R3 are not both hydrogen.