US 8,895,585 B2 · Nicotinamide derivative or salt thereof

Abstract

An object of the present invention is to provide to a compound and a pharmaceutical composition, which have excellent Syk-inhibitory activity. The present invention provides a nicotinamide derivative represented by the following formula (I) (wherein R1 represents a halogen atom; R2 represents a C1-12 alkyl group, a C2-12 alkenyl group, a C2-12 alkynyl group, a C3-8 cycloalkyl group, an aryl group, an ar-C1-6 alkyl group or a heterocyclic group, each optionally having at least one substituent; R3 represents an aryl group or a heterocyclic group each optionally having at least one substituent; and R4 and R5 each independently represent a hydrogen atom; and R2 and R4 may form a cyclic amino group optionally having at least one substituent together with the nitrogen atom to which they bind) or a salt thereof, and a pharmaceutical composition for use in the treatment of a Syk-related disease which comprises the nicotinamide derivative or a salt thereof.

A nicotinamide derivative represented by the following formula (I) or a salt thereof:

wherein
R1 represents a halogen atom;
R2 represents a C1-12 alkyl group optionally having at least one substituent, a C2-12 alkenyl group optionally having at least one substituent, a C2-12 alkynyl group optionally having at least one substituent, a C3-8 cycloalkyl group optionally having at least one substituent, an aryl group optionally having at least one substituent, an ar-C1-6 alkyl group optionally having at least one substituent or a heterocyclic group optionally having at least one substituent;
R3 represents an aryl group optionally having at least one substituent or a heterocyclic group optionally having at least one substituent;
and
R4 and R5 each independently represent a hydrogen atom, a C1-12 alkyl group, a C2-12 alkenyl group, or a C2-12 alkynyl group;
wherein the substituent optionally possessed by the C1-12 alkyl group, C2-12 alkenyl group, C2-12 alkynyl group, C3-8 cycloalkyl group, aryl group, ar-C1-6 alkyl group or heterocyclic group, represented by R2, is selected from the following substituent group α1-2, wherein
the substituent group α1-2 consists of a halogen atom;
a cyano group;
a nitro group;
an oxo group;
an optionally protected carboxyl group;
an optionally protected hydroxyl group;
an optionally protected amino group;
a C1-6 alkyl group optionally having at least one substituent selected from the following substituent group β1-1;
a C2-6 alkenyl group optionally having at least one substituent selected from the following substituent group β1-1;
a C2-6 alkynyl group optionally having at least one substituent selected from the following substituent group β1-1;
a C3-8 cycloalkyl group optionally having at least one substituent selected from the following substituent group β1-1;
an aryl group optionally having at least one substituent selected from the following substituent group β1-1;
a C1-6 alkoxy group optionally having at least one substituent selected from the following substituent group β1-1;
an aryloxy group optionally having at least one substituent selected from the following substituent group β1-1;
an acyl group optionally having at least one substituent selected from the following substituent group β1-1;
a C1-6 alkylsulfonyl group optionally having at least one substituent selected from the following substituent group β1-1;
an arylsulfonyl group optionally having at least one substituent selected from the following substituent group β1-1;
a heterocyclic group optionally having at least one substituent selected from the following substituent group β1-1;
and a group represented by the formula -Q1-Q2-NR6R7 (wherein R6 and R7 each independently represent a hydrogen atom, an amino-protecting group, a C1-6 alkyl group optionally having at least one substituent, a C2-6 alkenyl group optionally having at least one substituent, a C2-6 alkynyl group optionally having at least one substituent, a C3-8 cycloalkyl group optionally having at least one substituent, a C1-6 alkoxy group optionally having at least one substituent, an aryl group optionally having at least one substituent, or a heterocyclic group optionally having at least one substituent, or R6 and R7 may form a cyclic amino group optionally having at least one substituent, together with the nitrogen atom to which they bind;
Q1 represents —NH—, a C1-6 alkylene group optionally having at least one substituent, a C2-6 alkenylene group optionally having at least one substituent, a C2-6 alkynylene group optionally having at least one substituent, or a bond;
Q2 represents a group represented by —C(═X7)— (wherein X7 represents an oxygen atom, a sulfur atom, or a group represented by ═NR29 (wherein R29 represents a hydrogen atom, a C1-12 alkyl group optionally having at least one substituent, a C2-12 alkenyl group optionally having at least one substituent, a C2-12 alkynyl group optionally having at least one substituent, a C3-8 cycloalkyl group optionally having at least one substituent or a C1-6 alkoxy group optionally having at least one substituent)), a C1-6 alkylene group, or a bond),
wherein the substituent group β1-1 consists of a halogen atom, a cyano group, a nitro group, an oxo group, an optionally protected carboxyl group, an optionally protected hydroxyl group, an optionally protected amino group, a C1-6 alkyl group optionally having at least one halogen atom, a C3-8 cycloalkyl group optionally having at least one halogen atom, a C1-6 alkoxy group optionally having at least one halogen atom, an aryl group optionally having at least one halogen atom, and a heterocyclic group optionally having at least one halogen atom;
wherein the substituent optionally possessed by the aryl or heterocyclic group represented by R3 is selected from the following substituent group α2-2,
wherein the substituent group α2-2 consists of a halogen atom;
a cyano group;
a nitro group;
an oxo group;
an optionally protected carboxyl group;
an optionally protected hydroxyl group;
an optionally protected amino group;
a C1-6 alkyl group optionally having at least one substituent selected from the following substituent group β2-1;
a C2-6 alkenyl group optionally having at least one substituent selected from the following substituent group β2-1;
a C2-6 alkynyl group optionally having at least one substituent selected from the following substituent group β2-1;
a C3-8 cycloalkyl group optionally having at least one substituent selected from the following substituent group β2-1;
an aryl group optionally having at least one substituent selected from the following substituent group β2-1;
a C1-6 alkoxy group optionally having at least one substituent selected from the following substituent group β2-1;
an aryloxy group optionally having at least one substituent selected from the following substituent group β2-1;
an acyl group optionally having at least one substituent selected from the following substituent group β2-1;
a C1-6 alkylsulfonyl group optionally having at least one substituent selected from the following substituent group β2-1;
an arylsulfonyl group optionally having at least one substituent selected from the following substituent group β2-1;
a heterocyclic group optionally having at least one substituent selected from the following substituent group β2-1;
and a group represented by the formula -Q3-Q4-NR24R25 (wherein R24 and R25 each independently represent a hydrogen atom, an amino-protecting group, a C1-6 alkyl group optionally having at least one substituent, a C2-6 alkenyl group optionally having at least one substituent, a C2-6 alkynyl group optionally having at least one substituent, a C3-8 cycloalkyl group optionally having at least one substituent, a C1-6 alkoxy group optionally having at least one substituent, an ar-C1-6 alkyl group optionally having at least one substituent, an aryl group optionally having at least one substituent, a heterocyclic group optionally having at least one substituent, or R24 and R25 may form a cyclic amino group optionally having at least one substituent, together with the nitrogen atom to which they bind;
Q3represents —NH—, a C1-6 alkylene group optionally having at least one substituent, a C2-6 alkenylene group optionally having at least one substituent, a C2-6 alkynylene group optionally having at least one substituent, or a bond;
and Q4 represents —C(═O)—, a C1-6 alkylene group, or a bond);
wherein the substituent group β2-1 consists of a halogen atom, a cyano group, a nitro group, an oxo group, an optionally protected carboxyl group, an optionally protected hydroxyl group, an optionally protected amino group, a C1-6 alkyl group optionally having at least one halogen atom, a C3-8 cycloalkyl group optionally having at least one halogen atom, a C1-6 alkoxy group optionally having at least one halogen atom, an ar-C1-6 alkyl group optionally having at least one halogen atom, an aryl group optionally having at least one halogen atom, and a heterocyclic group optionally having at least one halogen atom;
wherein the heterocyclic group is selected from the group consisting of azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidyl, tetrahydropyridyl, pyridyl, homopiperidinyl, octahydroazocinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, homopiperazinyl, triazolyl, tetrazolyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, morpholinyl, thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxide-thiomorpholinyl, 1,1-dioxide-thiomorpholinyl, indolinyl, indolyl, isoindolinyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, tetrahydroquinolinyl, quinolyl, tetrahydroisoquinolinyl, isoquinolinyl, quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, pyrrolopyridyl, imidazopyridyl, indolidinyl, dihydrocyclopentapyridyl, triazolopyridyl, pyrazolopyridyl, pyridopyrazyl, purinyl, pteridinyl, quinuclidinyl, 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodioxanyl, 1,4-benzodioxanyl, 2,3-dihydrobenzothienyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzomorpholinyl, dihydropyranopyridyl, dihydrodioxinopyridyl, 1,3-dioxolopyridyl, dihydropyridooxazinyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl and thiazolopyridyl;
and
wherein the acyl group is a formyl group, a succinyl group, a glutaryl group, a maleoyl group, a phthaloyl group, a C2-12 alkanoyl group, an aroyl group, or an (α-substituted) amino acetyl group.

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Nicotinamide derivative or salt thereof

Life of this patent

Nicotinamide derivative or salt thereof

Life of this patent

Abstract

Claims29