Pyrimidine carboxamides useful as inhibitors of pde4 isozymes

A compound of Formula (1.0.0):

• 155
• or a pharmaceutically acceptable salt thereof;
• wherein
• 4 -j is 0 or 1;
• -k is 0 or 1;
• -m is 0 or 1;
• -n is 1 or 2;
• -W is —O—;
• —S(═O)t—, where t is 0, 1, or 2;
• or —N(R3)—;
• where
• R3 is —H;
• —(C1-C3)alkyl;
• —OR12;
• phenyl;
• or benzyl;
• RA and RB are each a member independently selected from the group consisting of —H;
• —F;
• —CF3;
• —(C1-C4)alkyl;
• —(C3-C7)cycloalkyl;
• phenyl;
• or benzyl;
• wherein said alkyl, cycloalkyl, phenyl, or benzyl moiety is each independently substituted with 0 to 3 substituents R10;
• provided that
• for the above and all other applicable meanings of RA and RB when R10 as a substituent of RA or RB has the meaning of —OR12, —OC(═O)R12, or —OC(═O)NR12R13, the positional relationship of said —OR12, —OC(═O)R12, or OC(═O)NR12R13 to —OR12 as a meaning of E, is other than a vicinal one;
• where
• R10 is a member selected from the group consisting of —F;
• —Cl;
• —CF3;
• —CN;
• —OR12;
• (C1-C2)alkyl;
• hydroxy(C1-C2)alkyl;
• —O—C(═O)R13;
• —O—C(═O)NR12R13;
• —NR12R13;
• —NR12C(═O)R13;
• —NR12C(═O)OR13;
• —NR12S(═O)2R13;
• and —S(═O)2NR12R13;
• where
• R12 and R13 are each a member independently selected from the group consisting of —H;
• —(C1-C4)alkyl;
• phenyl;
• or benzyl;
• wherein said alkyl, phenyl, or benzyl is substituted by 0 to 3 substituents selected from the group consisting of F and Cl;
• or
• RA and RB are taken together, provided that m is 1, to form a spiro moiety of Formula (1.1.0):
• 156
• 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
• QA is selected from the group consisting of —CH2—, —CHF, —CF2, —N(R3)—, —O—;
• and —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, including the carbon atom of the group —CH2— defining QA, by 0 to 3 substituents R10, where R3 and R10 have the same meanings as defined above;
• provided that
• for the above and all other applicable meanings of RA and RB, when R10 as a substituent of RA or RB has the meaning of —OR12, —OC(═O)R12, or —OC(═O)NR12R13, the positional relationship of said —OR12, —OC(═O)R12, or —OC(═O)NR12R13 to —OR12 as a meaning of E, is other than a vicinal one;
• RC and RD have the same meaning as defined above for RA and RB, except that at least one of RC and RD must be —H, and they are selected independently of each other and of RA and RB;
• ZA is a member independently selected from the group consisting of
• the following
• (a) a saturated or unsaturated cyclic or bicyclic (C3-C9) heterocyclic group which is a member selected from the group consisting of furanyl;
• thienyl;
• pyrrolyl;
• oxazolyl;
• isoxazolyl;
• thiazolyl;
• isothiazolyl;
• pyrazolyl;
• oxadiazolyl;
• thiadiazolyl;
• imidazolyl;
• pyrazinyl;
• pyrimidinyl;
• pyridazinyl;
• triazolyl;
• tetrazolyl;
• 2,3-benzofuranyl;
• 2,3-dihydrobenzo-furanyl;
• 1,3-dihydroiso-benzofuranyl;
• benzo[b]thienyl;
• indolyl;
• indolinyl;
• isoindolinyl;
• 2H-1-benzopyranyl;
• 4H-1-benzopyranyl;
• 1H-2-benzopyranyl;
• chromanyl;
• isochromanyl;
• quinolinyl;
• isoquinolinyl;
• 1,2,3,4-tetrahydro-quinolinyl;
• 1,2,3,4-tetrahydro-isoquinolinyl;
• 1,3-benzodioxolyl;
• 3H-2,1-benzoxathiolyl;
• benzoxazolyl;
• 1,2-benzisoxazolyl;
• 2,1-benzisoxazolyl;
• 1,2-benzodithiolyl;
• 1,3-benzodithiolyl;
• benzothiazolyl;
• 1,2-benzisothiazolyl;
• benzimidazolyl;
• indazolyl;
• 1,4-benzodioxanyl;
• 4H-3,1-benzoxazinyl;
• 2H-1,4-benzoxazinyl;
• 1,4-benzothiazinyl;
• 1,2-benzothiazinyl;
• quinazolinyl;
• quinoxalinyl;
• phthalazinyl;
• cinnolinyl;
• 1,2,3-benzothiadiazolyl;
• 2H-1,2,4-benzo-thiadiazinyl;
• 2H-1,2,4-benzo-oxadiazinyl;
• benzoxtriazinyl;
• 1,2,3-benzotriazinyl;
• 1,2,4-benzotriazinyl;
• and benzotetrazinyl;
• wherein said heterocyclic group is substituted as to any one or more nitrogen atoms thereof by 0 or 1 R9 substitutent, where
• R9 is independently selected from the group consisting of —H;
• and —(C1-C4)alkyl;
• further wherein said heterocyclic group is substituted as to any one or more carbon atoms thereof by 0-3 R16 substitutents, where
• R16 is independently selected from the group consisting of —F;
• —Cl;
• —CN;
• —OR12;
• (C1-C4)alkyl;
• (C3-C7)cycloalkyl;
• —CF3;
• —C(═O)OR12;
• —NO2;
• —NR12R13;
• hydroxy(C1-C4)alkylamino;
• phenyl;
• and benzyl;
• where R12 and R13 have the same meaning as defined above;
• and where said alkyl, alkoxy or cycloalkyl is each independently substituted by 0-3 R18 substituents,
• where
• R18 is independently selected from the group consisting of —F;
• —Cl;
• —CN;
• —OR12;
• —CF3;
• —NR12R13;
• and phenyl;
• where R12 and R13 have the same meanings as defined above;
• and further ZA
• (b) is (C3-C7)cycloalkyl independently substituted by 0-3 R16 substituents where R16 has the same meaning as defined above;
• and still further ZA
• (c) is phenyl or pyridyl substituted by 0 to 3 substituents R4,
• where
• R4 is a member independently selected from the group consisting of
• the following
• (1) —F;
• —Cl;
• —CN;
• —OR12;
• —S(═O)pR12;
• —C(═O)OR12, —OC(═O)R12;
• —NO2;
• —C(═O)NR12R13;
• —OC(═O)NR12R13;
• —NR12R13;
• —NR14C(═O)R12;
• —NR14C(═O)OR12;
• —NR14S(═O)pR12;
• and —S(═O)pNR12R13;
• where p is 0, 1, or 2;
• and R12 and R13 have the same meaning as defined above;
• where
• R14 is selected from the group consisting of —H;
• —CH3;
• and —CH2CH3;
• and further R4
• (2) is independently —(C1-C4)alkyl;
• or —(C1-C4)alkoxy where R12 of —OR12 in the above definition of R4 has the meaning of —(C1-C4)alkyl;
• wherein said alkyl or 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 still further R4
• (3) is independently phenyl;
• benzyl;
• or a heterocyclyl moiety selected from the group consisting of 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 phenyl, benzyl, or heterocyclyl moiety is each independently substituted with 0 to 2 substituents R10 where R10 has the same meaning as defined above;
• or
• R4 on adjacent carbon atoms, where ZA is selected as phenyl, are taken together with the carbon atoms to which they are attached and the phenyl ring of which they are a part, to form a benzofused heterocyclyl moiety comprising a member selected from the group consisting of 2,3-benzofuranyl;
• 2,3-dihydrobenzofuranyl;
• 1,3-dihydroisobenzofuranyl;
• benzo[b]thienyl;
• indolyl;
• indolinyl;
• isoindolinyl;
• 2H-1-benzopyranyl;
• 4H-1-benzopyranyl;
• 1H-benzopyranyl;
• chromanyl;
• isochromanyl;
• quinolinyl;
• isoquinolinyl;
• 1,2,3,4-tetrahydroquinolinyl;
• 1,2,3,4-tetrahydroisoquinolinyl;
• 1,3-benzodioxolyl;
• 3H-2,1-benzoxathiolyl;
• benzoxazolyl;
• 1,2-benzisoxazolyl;
• 2,1-benzisoxazolyl;
• 1,2-benzodithiolyl;
• 1,3-benzodithiolyl;
• benzothiazolyl;
• 1,2-benzisothiazolyl;
• benzimidazolyl;
• indazolyl;
• 1,4-benzodioxanyl;
• 4H-3,1-benzoxazinyl;
• 2H-1,4-benzoxazinyl;
• 1,4-benzothiazinyl;
• 1,2-benzothiazinyl;
• quinazolinyl;
• quinoxalinyl;
• phthalazinyl;
• cinnolinyl;
• 1,2,3-benzothiadiazolyl;
• 2H-1,2,4benzothiadiazinyl;
• 2H-1,2,4-benzoxadiazinyl;
• benzoxtriazinyl;
• 1,2,3-benzotriazinyl;
• 1,2,4-benzotriazinyl;
• and benzotetrazinyl;
• ZB is phenyl;
• pyridyl;
• pyrimidinyl;
• imidazolyl;
• cyclopentyl;
• cyclohexyl;
• cyclopentenyl, cyclohexenyl, norbornanyl, norbornenyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.1]octanyl, bicyclo[3.3.0]octanyl, bicyclo[2.2.2]oct-5-enyl, bicyclo[2.2.2]oct-7-enyl, bicyclo[3.3.1]nonanyl, or adamantanyl;
• R1 and R2 are each a member independently selected from the group consisting of —H;
• —F;
• —Cl;
• —OR12;
• —S(═O)pR12;
• —C(═O)OR12;
• —OC(═O)R12;
• —CN;
• —NO2;
• —C(═O)NR12R13;
• —NR12R13;
• and —S(═O)pNR12R13;
• where p is 0, 1, or 2;
• and R12 and R13 have the same meanings as defined above;
• E is selected from the group consisting of —H;
• —F;
• —Cl;
• —CN;
• —OR12;
• (C1-C4)alkyl;
• hydroxy(C1-C4)alkyl;
• —CF3;
• —NO2;
• —N12R13;
• —NR12S(═O)2R13;
• and —S(═O)2NR12R13;
• where R12 and R13 have the same meanings as defined above;
• and
• R7 and R8 are each independently selected from the group consisting of —H;
• —F;
• —Cl;
• —OR12;
• (C1-C4)alkyl;
• hydroxy(C1-C4)alkyl;
• —CF3;
• —C(═O)OR12;
• —NR12R13;
• hydroxy(C1-C4)alkylamino;
• phenyl;
• benzyl;
• or a heterocyclyl moiety selected from the group consisting of pyrrolyl;
• oxazolyl;
• thiazolyl;
• oxadiazolyl;
• thiadiazolyl;
• imidazolyl;
• pyridinyl;
• tetrazolyl;
• indolyl;
• and benzimidazolyl;
• wherein said phenyl, benzyl, or heterocyclyl moiety is each independently substituted with 0 to 2 substituents R10 where R10 has the same meaning as defined above;
• in the event that
• j or k is 1, or both j and k are 1 at the same time, a compound of Formula (1.0.0) is in the form of a N-oxide.