US 11,440,905 B2 · Biheterocyclic compound

Abstract

The present invention provides a compound of formula (1) and a pharmaceutical composition comprising the compound useful as a nerve regeneration promoter wherein R1-L- is R1—OC(O)—, or the like, R1 is hydrogen atom, optionally-substituted C1-6 alkyl group, optionally-substituted 3- to 8-membered cycloalkyl group, or the like, R2 is hydrogen atom or the like, Ring A is formula (2) or formula (3) wherein R3 is hydrogen atom, optionally-substituted C1-6 alkyl group, or the like, the part of X, Y, and Z is X═Y—Z, X—Y═Z, or X—Y—Z, X is nitrogen atom, NR4 (R4 is hydrogen atom, optionally-substituted C1-6 alkyl group, or the like), or the like, Y is carbon atom or the like, and Z is carbon atom, nitrogen atom or the like.

A method of preparing a compound of Formula (1B):

wherein
R1-L- is R1—OC(O)— or R1—NHC(O)—;
and
R1 is
(i) hydrogen atom,
(ii) optionally-substituted C1-6 alkyl group,
(iii) optionally-substituted C2-6 alkenyl group,
(iv) optionally-substituted C2-6 alkynyl group,
(v) optionally-substituted 3- to 8-membered cycloalkyl group,
(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,
(vii) optionally-substituted 4- to 8-membered saturated aliphatic heterocyclyl group,
(viii) optionally-substituted 5- to 10-membered unsaturated aliphatic heterocyclyl group,
(ix) optionally-substituted 6- to 10-membered aryl group, or
(x) optionally-substituted 5- to 10-membered heteroaryl group,
wherein the substituent(s) of the (ii) optionally-substituted C1-6 alkyl group is one or more substituents selected independently from the group consisting of hydroxy group, methoxy group, ethoxy group, carboxyl group, carbamoyl group (which may be substituted with one or two the same or different C1-3 alkyl), NR5R6 (wherein R5 and R6 are independently hydrogen atom, C1-3 alkyl group, carboxylmethyl group, 2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3- to 6-membered cycloalkyl group (wherein the substituent(s) of said optionally-substituted 3- to 6-membered cycloalkyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group (wherein the substituent(s) of said optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), and optionally-substituted 5- to 10-membered heteroaryl group (wherein the substituent(s) of said optionally-substituted 5- to 10-membered heteroaryl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), or
the (ii) optionally-substituted C1-6 alkyl group may be any one of the following groups of formulae (4)-(6):
formula (4):
wherein m is 1, 2, 3, 4, or 5, R7 is C1-3 alkoxy group, amino acid group (which binds to C(O) at its N terminus), and peptide consisting of 2-3 amino acid residues (which binds to C(O) at its N terminus),
formula (5):
R8-L2-(CH2CH2O)qCH2CH2 (5)
wherein q is 1, 2, 3, 4, or 5, L2 is single bond or C(O), R8 is hydroxy group, C1-3 alkoxy group, amino group which may be substituted with one or two the same or different C1-3 alkyl, amino acid group (which binds to L2 at its N terminus), or peptide consisting of 2-3 amino acid residues (which binds to L2 at its N terminus),
formula (6):
wherein L3 is CH2 or C(O), and R9 is hydroxy group, C1-3 alkoxy group, amino group which may be substituted with one or two the same or different C1-3 alkyl, amino acid group (which binds to L3 at its N terminus), or peptide consisting of 2-3 amino acid residues (which binds to L3 at its N terminus),
the substituent(s) of the (iii) optionally-substituted C2-6 alkenyl group, and the (iv) optionally-substituted C2-6 alkynyl group are independently one or more substituents selected independently from the group consisting of hydroxy group, methoxy group, ethoxy group, carboxyl group, carbamoyl group (which may be substituted with one or two the same or different C1-3 alkyl), NR5R6 (wherein R5 and R6 are independently hydrogen atom, C1-3 alkyl group, carboxylmethyl group, 2-hydroxyethyl group, or 2-aminoethyl group), optionally-substituted 3- to 6-membered cycloalkyl group (wherein the substituent(s) of said optionally-substituted 3- to 6-membered cycloalkyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, hydroxy group, and carboxyl group), optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group (wherein the substituent(s) of said optionally-substituted 4- to 6-membered saturated aliphatic heterocyclyl group is one or more substituents selected independently from the group consisting of amino group which may be substituted with one or two the same or different C1-3 alkyl, C1-3 alkyl group, hydroxy group, and carboxyl group), and 5- to 10-membered heteroaryl group,
the substituent(s) of the (v) optionally-substituted 3- to 8-membered cycloalkyl group, the (vi) optionally-substituted 4- to 8-membered cycloalkenyl group, the (vii) optionally-substituted 4- to 8-membered saturated aliphatic heterocyclyl group, the (viii) optionally-substituted 5- to 10-membered unsaturated aliphatic heterocyclyl group, the (ix) optionally-substituted 6- to 10-membered aryl group, and the (x) optionally-substituted 5- to 10-membered heteroaryl group are independently one or more substituents selected independently from the group consisting of hydroxy group, methoxy group, ethoxy group, amino group which may be substituted with one or two the same or different C1-3 alkyl, and carboxyl group;
R2 is hydrogen atom, hydroxy group, or carboxyl group;
R3 is
(i) hydrogen atom,
(ii) optionally-substituted C1-6 alkyl group,
(iii) optionally-substituted C2-6 alkenyl group,
(iv) optionally-substituted C2-6 alkynyl group,
(v) optionally-substituted 3- to 8-membered cycloalkyl group,
(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,
(vii) optionally-substituted 4- to 8-membered saturated aliphatic heterocyclyl group,
(viii) optionally-substituted 5- to 10-membered unsaturated aliphatic heterocyclyl group,
(ix) optionally-substituted 6- to 10-membered aryl group, or
(x) optionally-substituted 5- to 10-membered heteroaryl group;
and
X Y Z is X═Y—Z, X—Y═Z, or X—Y—Z,
X is nitrogen atom, or NR4,
R4 is
(i) hydrogen atom,
(ii) optionally-substituted C1-6 alkyl group,
(iii) optionally-substituted C2-6 alkenyl group,
(iv) optionally-substituted C2-6 alkynyl group,
(v) optionally-substituted 3- to 8-membered cycloalkyl group,
(vi) optionally-substituted 4- to 8-membered cycloalkenyl group,
(vii) optionally-substituted 4- to 8-membered saturated aliphatic heterocyclyl group,
(viii) optionally-substituted 5- to 10-membered unsaturated aliphatic heterocyclyl group,
(ix) optionally-substituted 6- to 10-membered aryl group, or
(x) optionally-substituted 5- to 10-membered heteroaryl group,
Y is carbon atom or CH, and
Z is carbon atom, CH, or nitrogen atom, provided that the combination of X, Y, and Z should be any one of chemically-possible selections
or a pharmaceutically acceptable salt thereof;
which comprises the following step:
(step A1) reacting the compound of Formula (1A):
wherein R2, R3, XyZ, X, Y and Z are as defined above, or a pharmaceutically acceptable salt thereof
in the presence of a halogenating agent, followed by reacting with R1NH2 or R1OH to give a compound of formula (1B).

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Biheterocyclic compound

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Biheterocyclic compound

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Abstract

Claims21