US 6,649,633 B2 · Nicotinamide biaryl derivatives useful as inhibitors of PDE4 isozymes

Abstract

This application is directed to compounds useful as inhibitors at PDE4 in the treatment of diseases regulated by the activation and degranulation of eosinophils, especially asthma, chronic bronchitis and chronic obstructuive pulmonary disease, of the formula: where j is 0 or 1 provided that when j is 0, n must be 2; k is 0 or 1; m is 0, 1, or 2; n is 1 or 2; W1 is —O—; or —S(═O)t—, where t is 0, 1, or 2; Y is —C(R1a); Q1 is phenyl or substituted phenyl; Q2 is biphenyl or substituted biphenyl; and the remaining variables are defined as set forth in the specification. This application is also directed to pharmaceutical compositions comprising those compounds and to methods of treating diseases regulated by the activation and degranulation of eosinophils, in particular asthma, chronic bronchitis and chronic obstructive pulmonary disease.

A compound of Formula (1.0.0):

wherein
g is 0;
j is 1;
k is 0 or 1
m is 0, 1, or 2;
n is 1 or 2;
W1 is —O—;
or —S(═O)t—, where t is 0, 1, or 2;
Y is ═C(R1a)—, where R1a has the same meaning as defined below;
where
R1a is a member selected from the group consisting of —H;
—F;
—Cl;
—CN;
—NO2;
—(C1-C4) alkyl;
—(C2-C4) alkynyl;
fluorinated-(C1-C3) alkyl;
fluorinated-(C1-C3) alkoxy;
—OR16;
and —C(═O)NR22aR22b;
where
R22a and R22b are each independentiy —H;
—CH3;
—CH2CH3;
—CH2CH2CH3;
—CH2(CH3)2;
—CH2CH2CH2CH3;
—CH(CH3)CH2CH3;
—CH2CH(CH3)2;
—C(CH3)3;
cyclopropyl;
cyclobutyl;
or cyclopentyl;
RA and RB are each a member independently selected from the group consisting of —H;
—F;
—CF3;
—(C1-C4) alkyl;
—(C3-C7) cycloalkyl;
phenyl;
and benzyl;
wherein said cycloalkyl, phenyl, and benzyl moieties are each independently substituted with 0 to 3 substituents R10;
where
R10 is a member selected from the group consisting of phenyl;
—F;
—Cl;
—CF3;
oxo (═O);
—OR16;
—NO2;
—CN;
—C(═O)OR16;
—O—C(═O)R16;
—C(═O)NR16R17;
—O—C(═O)NR16R17;
—NR16R17;
—NR16C(═O)R17;
—NR16C(═O)OR17;
—NR16S(═O)2R17;
and —S(═O)2NR16R17;
where said phenyl is substituted by 0 to 3 R11;
where
R11 is —F;
—Cl;
—CF3;
—CN;
—NO2;
—OH;
—(C1-C3) alkoxy;
—(C1-C3) alkyl;
or —NR16R17;
and
R16 and R17 are each a member independently selected from the group consisting of —H;
—(C1-C4) alkyl;
—(C2-C4) alkenyl;
—(C3-C5) cycloalkyl;
phenyl;
and benzyl;
wherein said alkyl, alkenyl, cycloalkyl, phenyl, and benzyl, is substituted by 0 to 3 substituents selected from the group consisting of —F, —Cl, —CF3, —CN, and —(C1-C3) alkyl;
RC and RD have the same meaning as defined above for RA and RB except that one of them must be —H, and they are selected independently of each other and of RA and RB;
R1 and R2 may individually or together appear on any ring or rings comprising a meaning of the moiety Q2 as defined below;
and R1 and R2 are each a member independently selected from the group consisting of —H;
—F;
—Cl;
—CN;
—NO2;
—(C1-C4) alkyl;
—(C2-C4) alkynyl;
fluorinated-(C1-C3) alkyl;
—OR16;
and —C(═O)NR22aR22b;
where R16, R22a, and R22b have the same meanings as defined above;
R3 is —H;
—(C1-C3) alkyl;
phenyl;
benzyl;
or —OR16, where R16 has the same meaning as defined above;
R4, R5 and R6 may individually or together appear on any ring or rings comprising a meaning of the moiety Q1 as defined below;
and R4, R5 and R6 are each a member independently selected from the group consisting of
the following
(a) —H;
—F;
—Cl;
—(C2-C4) alkynyl;
—R16;
—OR16;
—S(═O)pR16;
—C(═O)R16;
—C(═O)OR16;
—OC(═O)R16;
—CN;
—NO2;
—C(═O)NR16R17;
—OC(═O)NR16R17;
—NR22aC(═O)NR16R17;
—NR22aC(═NR12)NR16R17;
—NR22aC(═NCN)NR16R17;
—NR22aC(═N—NO2)NR16R17;
—C(═NR22a)NR16R17;
—CH2C(═NR22a)NR16R17;
—OC(═NR22a)NR18R17;
—OC(═N—NO2)NR16R17;
—NR16R17;
—CH2NR16R17;
—NR22aC(═O)R16;
—NR22aC(═O)OR18;
═NOR16;
—NR22BS(═O)pR17;
—S(═O)pNR16R17;
and —CH2C(═NR22a)NR16R17;
where
p is 0, 1, or 2;
and R22a, R16, and R17 have the same meanings as defined above;
(b) —(C1-C4) alkyl;
and —(C1-C4) alkoxy in the case where one or more of R4, R5, or R6 has the meaning of —OR16 under (a) above and R16 is defined as —(C1-C4) alkyl;
wherein said alkyl and alkoxy are each independently substituted with 0 to 3 substituents —F or —Cl;
or 0 or 1 substituent (C1-C2) alkoxycarbonyl-;
(C1-C2) alkylcarbonyl-;
or (C1-C2) alkylcarbonyloxy-;
and
(c) an aryl moiety selected from the group consisting of phenyl;
and benzyl;
wherein said aryl moiety is each independently substituted with 0 to 2 substituents R14
where
R14 is a member selected from the group consisting of —(C1-C4) alkyl;
—(C3-C7) cycloalkyl;
phenyl;
and benzyl;
where said alkyl, cycloalkyl, phenyl, and benzyl, is substituted by 0, 1, or 2 substituents —F, —Cl, —CH3, —OR16, —NO2, —CN, or —NR16R17;
and said R14 group further consists of —F;
—Cl;
—CF3;
oxo (═O);
—OR16;
—NO2;
—CN;
—C(═O)OR16;
—O—C(═O)R16;
—C(═O)NR16R17;
—O—C(═O)NR16R17;
—NR16R17;
—NR16C(═O)R17;
—NR16C(═O)OR17;
—NR16S(═O)2R17;
or —S(═O)2NR16R17;
where R16 and R17have the same meanings as defined above;
and further where
R15 is a member independently selected from the group consisting of —H;
—NR16R17;
—C(═O)R16;
—OR16;
—(C1-C4) alkyl-OR16;
—C(═O)OR16;
—(C1-C2) alkyl-C(═O)OR16;
—C(═O)NR16R17;
—(C1-C4) alkyl;
—(C2-C4) alkenyl;
—(CH2)u—(C3-C7) cycloalkyl where u is 0, 1 or 2;
phenyl;
and benzyl;
wherein said alkyl, alkenyl, alkoxy, cycloalkyl, phenyl, and benzyl is substituted with 0 to 3 substituents R12;
where R16 and R17 have the same meanings as defined above;
and
where
R12 is a member independently selected from the group consisting of —F;
—Cl;
—CO2R18;
—OR16;
—CN;
—C(═O)NR18R19;
—NR18R19;
—NR18C(═O)R19;
—NR18C(═O)OR19;
—NR18S(═O)pR19;
—S(═O)pNR18R19, where p is 1 or 2;
—(C1-C4) alkyl;
and —(C1-C4) alkoxy in the case where R12 has the meaning of —OR16 above and R16 is defined as —(C1-C4) alkyl;
wherein said alkyl and alkoxy are each independently substituted with 0 to 3 substituents independently selected from —F;
—Cl;
—(C1-C2) alkoxycarbonyl;
—(C1-C2) alkylcarbonyl;
and —(C1-C2) alkylcarbonyloxy;
where R16 has the same meaning as defined above;
and
where
R18 and R19 are independently selected from the group consisting of —H;
—(C1-C4) alkyl;
and phenyl;
where said alkyl or phenyl is substituted by 0-3 of —F;
or —Cl;
or in the case where Q1 is phenyl
(d) R5 and R6 are taken together to form a moiety which is a member selected from the group consisting of partial Formulas (1.3.1) through (1.3.15):
wherein
R20 and R21 are each a member independently selected from the group consisting of —H;
—F;
—Cl;
—CH3;
—CH2F;
—CHF2;
—CF3;
—OCH3;
and —OCF3;
Q1 is phenyl;
wherein
said phenyl defining Q1 is substituted by R4, R5 and R6, which have the same meaning as defined above;
Q2 is biphenyl;
Z is
wherein
“*” indicates the point of attachment of said partial Formula (1.1.1) to the remaining portion of Formula (1.0.0);
R7A is a member independently selected from the group consisting of
the following
(1) —H;
and
(2) —(C1-C6) alkyl;
—(C2-C6) alkenyl;
or —(C2-C6) alkynyl;
where said alkyl, alkenyl or alkynyl is substituted by 0 to 3 substituents R10, where R10 has the same meaning as defined above;
where
any moiety recited in (1) or (2) above is optionally substituted with respect to (i) any one or more carbon atoms thereof optionally by a substituent R14 where R14 has the same meaning as defined above;
(ii) any one or more nitrogen atoms thereof that is not a point of attachment of said moiety, optionally by a substituent R15 where R15 has the same meaning as defined above, and all tautomer forms thereof;
and (iii) any sulfur atom thereof that is not a point of attachment of said moiety, by 0, 1, or 2 oxygen atoms;
or
a pharmaceutically acceptable salt thereof.

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Nicotinamide biaryl derivatives useful as inhibitors of PDE4 isozymes

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Nicotinamide biaryl derivatives useful as inhibitors of PDE4 isozymes

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Abstract

Claims9