Nicotinamide acids, amides, and their mimetics active as inhibitors of PDE4 isozymes

A compound of Formula (1.0.0):

• 278
• —wherein—
• 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;
• A has the following meanings:
• (a) a member selected from the group consisting of partial Formulas (1.1.1) through (1.1.5):
• 279
• —wherein—
• “*” indicates the point of attachment of each partial Formula (1.1.1) through (1.1.5) to the remaining portion of Formula (1.0.0);
• q is 1, 2, or 3, provided that where q is 2 or 3, R9 has the meaning of —H in at least one instance, or two instances, respectively;
• v 0 or 1;
• W3 is —O—;
• —N(R9)—, where R9 has the same meaning as defined below;
• or —OC(═O)—;
• R7 is a member independently selected from the group consisting of
• —the following:—
• (1) —H;
• (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 is a member selected from the group consisting of phenyl;
• pyridyl;
• —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 or pyridyl is substituted by 0 to 3 R12;
• —where—
• R12 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-C6)cycloalkyl;
• phenyl;
• benzyl;
• and pyridyl;
• wherein said alkyl, alkenyl, cycloalkyl, phenyl, benzyl, or pyridyl is substituted by 0 to 3 substituents selected from the group consisting of —F, —Cl, —CF3, —CN, and —(C1-C3)alkyl;
• (3) —(CH2)u—(C3-C7)cycloalkyl where u is 0, 1 or 2;
• and further where said (C3-C7)cycloalkyl is substituted by 0 to 3 substituents R10 where R10 has the same meaning as defined above;
• —and—
• (4) phenyl or benzyl, where said phenyl or benzyl is independently substituted by 0 to 3 substituents R10 where R10 has the same meaning as defined above;
• R8 is a member independently selected from the group consisting of
• —the following:—
• (1) tetrazol-5-yl;
• 1,2,4-triazol-3-yl;
• 1,2,4-triazol-3-on-5-yl;
• 1,2,3-triazol-5-yl;
• imidazol-2-yl;
• imidazol-4-yl;
• imidazolidin-2-on-4-yl;
• 1,2,4-oxadiazol-3-yl;
• 1,2,4-oxadiazol-5-on-3-yl;
• 1,2,4-oxadiazol-5-yl;
• 1,2,4-oxadiazol-3-on-5-yl;
• 1,3,4-oxadiazolyl;
• 1,3,4-oxadiazol-2-on-5-yl;
• oxazolyl;
• isoxazolyl;
• pyrrolyl;
• pyrazolyl;
• succinimidyl;
• glutarimidyl;
• pyrrolidonyl;
• 2-piperidonyl;
• 2-pyridonyl;
• 4-pyridonyl;
• pyridazin-3-onyl;
• thiazolyl;
• isothiazolyl;
• thiadiazolyl;
• morpholinyl;
• parathiazinyl;
• pyridyl;
• pyrimidinyl;
• pyrazinyl;
• pyridazinyl;
• —and—
• (2) indolyl;
• indolinyl;
• isoindolinyl;
• benzo[b]furanyl;
• 2,3-dihydrobenzofuranyl;
• 1,3-dihydroisobenzofuranyl;
• 2H-1-benzopyranyl;
• 2-H-chromenyl;
• chromanyl;
• benzothienyl;
• 1H-indazolyl;
• benzimidazolyl;
• benzoxazolyl;
• benzisoxazolyl;
• benzothiazolyl;
• benzotriazolyl;
• benzotriazinyl;
• phthalazinyl;
• 1,8-naphthyridinyl;
• quinolinyl;
• isoquinolinyl;
• quinazolinyl;
• quinoxalinyl;
• pyrazolo[3,4-d]pyrimidinyl;
• pyrimido[4,5-d]pyrimidinyl;
• imidazo[1,2-a]pyridinyl;
• pyridopyridinyl;
• pteridinyl;
• and 1H-purinyl;
• —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 below;
• (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 below, and all tautomer forms, and optionally N-oxide 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;
• —and further where—
• R14 is a member selected from the group consisting of —(C1-C4)alkyl;
• —(C3-C7)cycloalkyl;
• phenyl;
• benzyl;
• pyridyl;
• and quinolinyl;
• where said alkyl, cycloalkyl, phenyl, benzyl, pyridyl, or quinolinyl 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;
• and —S(═O)2NR16R17;
• —and still 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;
• benzyl;
• pyridyl;
• and quinolinyl;
• wherein said alkyl, alkenyl, alkoxy, cycloalkyl, phenyl, benzyl, pyridyl or quinolinyl is substituted with 0 to 3 substituents R11;
• where R16 and R17 have the same meanings as defined above;
• and
• —where—
• R11 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;
• where R11 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—
• R18 and R19 are independently selected from the group consisting of —H;
• —(C1-C4)alkyl;
• and phenyl;
• R9 is a member selected from the group consisting of —H;
• —(C1-C4)alkyl;
• —(C3-C7)cycloalkyl;
• phenyl;
• benzyl;
• pyridyl;
• —C(═O)OR18;
• —C(═O)R18;
• —OR18;
• —(C1-C2)alkyl-OR18;
• and —(C1-C2)alkyl-C(═O)OR18;
• where R18 has the same meaning as defined above;
• —or A has the meaning—
• (b) a moiety comprising a member selected from the group consisting of —O—P(═O)(OH)2 (phosphoric);
• —PH(═O)OH (phosphinic);
• —P(═O)(OH)2 (phosphonic);
• —[P(═O)(OH)—O(C1-C4)alkyl](alkylphosphono);
• —P(═O)(OH)—O(C1-C4)alkyl)(alkylphosphinyl);
• —P(═O)(OH)NH2 (phosphoramido);
• —P(═O)(OH)NH(C1-C4)alkyl and —P(═O)(OH)NHR25 (substituted phosphoramido);
• —O—S(═O)2OH (sulfuric);
• —S(═O)2OH (sulfonic);
• —S(═O)2NHR25 (arylsulfonamido);
• —S(═O)2NHR12;
• and acylsulfonamido selected from the group consisting of —C(═O)NHS(═O)2R26;
• —C(═O)NHS(═O)2NH2;
• —C(═O)NHS(═O)2(C1-C4)alkyl;
• —C(═O)NHS(═O)2NH(C1-C4)alkyl;
• —C(═O)NHS(═O)2N[(C1-C4)alkyl]2;
• —S(═O)2NHC(═O)(C1-C4)alkyl;
• —S(═O)2NHC(═O)NH2;
• —S(═O)2NHC(═O)NH(C1-C4)alkyl;
• —S(═O)2NHC(═O)N[(C1-C4)alkyl]2;
• —S(═O)2NHC(═O)R25;
• —S(═O)2NHCN;
• —S(═O)2NHC(═S)NH2;
• —S(═O)2NHC(═S)N H(C1-C4)alkyl;
• —S(═O)2NHC(═S)N[(C1-C4)alkyl]2;
• and —S(═O)2NHS(═O)2R25;
• —where—
• R25 is —H;
• —(C1-C4)alkyl;
• phenyl;
• or —OR18;
• W is —O—;
• —S(═O)t—, where t is 0, 1, or 2;
• or —N(R3)— where R3 has the same meaning as defined below;
• Y is ═C(R1a)—, where R1a has the same meaning as defined below;
• or —[N(O)k]— where k is 0 or 1;
• —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)NR12aR12b;
• —where—
• R12aand R12b are each independently —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 has the same meaning as defined above;
• —or—
• RA and RB are taken together, but only in the case where m is 1, to form a spiro moiety of Formula (1.2.0):
• 280
• —where—
• r and s are independently 0 to 4 provided that the sum of r+s is at least 1 but not greater than 5;
• —and—
• XA is —CH2—, —CHR12—, or —C(R12)2— where each R12 is selected independently of the other and each has the same meaning as defined above;
• —NR 15—, where R15 has the same meaning as defined above;
• —O—;
• or —S(═O)t, where t is 0, 1, or 2;
• and said spiro moiety is substituted as to any one or more carbon atoms thereof by 0 to 3 substituents R14, as to a nitrogen atom thereof by 0 or 1 substituent R15, and as to a sulfur atom thereof by 0 or 2 oxygen atoms;
• 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 B2 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)NR12aR12b;
• where R12a and R12b 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 B1 as defined below, and R4, R5 and R6 are each a member independently selected from the group consisting of
• —the following:—
• (a) —H;
• provided that R5 and R6 are not both —H at the same time;
• —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;
• —NR12aC(═O)NR16R17;
• —NR12aC(═NR12)NR16R17;
• —NR12aC(═NCN)NR16R17;
• —NR12aC(═N—NO2)NR16R17;
• —C(═NR12a)NR16R17;
• —CH2C(═NR12a)NR16R17;
• —OC(═NR12a)NR16R17;
• —OC(═N—NO2)NR16R17;
• —NR16R17;
• —CH2NR16R17;
• —NR12aC(═O)R16;
• —NR12aC(═O)OR16;
• ═NOR16;
• —NR12aS(═O)pR17—S(═O)pNR16R17;
• and —CH2C(═NR 12a)NR16R17;
• —where—
• p is 0, 1, or 2;
• and R12a, R16, and R17 have the same meanings as defined above;
• (b) —(C1-C4)alkyl;
• and —(C1-C4)alkoxy, where 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 or heterocyclyl moiety selected from the group consisting of phenyl;
• benzyl;
• furanyl;
• tetrahydrofuranyl;
• oxetanyl;
• thienyl;
• tetrahydrothienyl;
• pyrrolyl;
• pyrrolidinyl;
• oxazolyl;
• oxazolidinyl;
• isoxazolyl;
• isoxazolidinyl;
• thiazolyl;
• thiazolidinyl;
• isothiazolyl;
• isothiazolidinyl;
• pyrazolyl;
• pyrazolidinyl;
• oxadiazolyl;
• thiadiazolyl;
• imidazolyl;
• imidazolidinyl;
• pyridinyl;
• pyrazinyl;
• pyrimidinyl;
• pyridazinyl;
• piperidinyl;
• piperazinyl;
• triazolyl;
• triazinyl;
• tetrazolyl;
• pyranyl;
• azetidinyl;
• morpholinyl, parathiazinyl;
• indolyl;
• indolinyl;
• benzo[b]furanyl;
• 2,3-dihydrobenzofuranyl;
• 2-H-chromenyl;
• chromanyl;
• benzothienyl;
• 1-H-indazolyl;
• benzimidazolyl;
• benzoxazolyl;
• benzisoxazolyl;
• benzthiazolyl;
• quinolinyl;
• isoquinolinyl;
• phthalazinyl;
• quinazolinyl;
• quinoxalinyl;
• and purinyl;
• wherein said aryl and heterocyclyl moieties are each independently substituted with 0 to 2 substituents R14 where R14 has the same meaning as defined above;
• —or in the case where B1 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):
• 281 282
• —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;
• R23 and R24 are each independently —H;
• —CH3;
• —OCH3;
• —CH2CH3;
• —OCH2CH3;
• —CH2CH2CH3;
• —CH2(CH3)2;
• —CH2CH2CH2CH3;
• —CH(CH3)CH2CH3;
• —CH2CH(CH3)2;
• —(CH3)3;or absent, in which case the dashed line ---- represents a double bond, provided that in partial Formula (1.3.1 1) R23 and R24 may not both be absent at the same time;
• B1 is a moiety comprising a saturated or unsaturated carbon ring system that is 3- to 7-membered monocyclic, or that is 7- to 12-membered, fused or discontinuous, polycyclic;
• wherein optionally one carbon atom thereof may be replaced by a heteroatom selected from N, O, and S;
• and where N is selected, optionally a second carbon atom thereof may be replaced by a heteroatom selected from N, O, or S;
• —wherein—
• said moiety defining B1 is substituted on any ring or rings thereof by R4, R5 and R6, which have the same meaning as defined above;
• B2 is a moiety comprising a saturated or unsaturated carbon ring system that is 3- to 7-membered monocyclic, or that is 7- to 12-membered, fused or discontinuous, polycyclic;
• wherein optionally one carbon atom thereof may be replaced by a heteroatom selected from N, O, and S;
• and where N is selected, optionally a second carbon atom thereof may be replaced by a heteroatom selected from N, O, or S;
• —wherein—
• said moiety defining B2 is substituted on any ring or rings thereof by R1 and R2, which have the same meaning as defined above;
• —or—
• a pharmaceutically acceptable salt thereof.