Immunomodulating urea azalides

A compound of Formula (1-A1)

• wherein
• Ra, Rb and Rc are each independently H, methyl, ethyl or propyl;
• Rc is methyl, ethyl or propyl;
• R1 is methyl, ethyl, propyl, or isopropyl;
• or R1 is benzyl, —CH2pyridine, —CH2pyrimidine, —CH2pyrazole or —CH2imidazole, wherein each is optionally substituted with at least one R9 substituent;
• R2 and R3 are each independently H, C1-C6alkyl;
• —CH2N(CH3)2, or —CH2CH2N(CH3)2;
• or
• cyclopropyl, C1alkylcyclopropyl, cyclobutyl, C1alkylcyclobutyl, cyclopentyl, C1alkylcyclopentyl, cyclohexyl, C1alkylcyclohexyl, phenyl, C1alkylphenyl, piperadinyl, C1alkylpiperadinyl, C2alkylpiperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrrolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R9 substituent;
• or R2 and R3 taken together with the nitrogen atom to which they are attached form Ring A which is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, indolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally substituted with at least one R10 substituent selected from methyl, ethyl, F, Cl, —CF3— and oxo;
• or Ring A is indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydrobenzooxazinyl, or dihydrobenzothiazinyl optionally substituted with at least one oxo;
• R5 and R6 taken together with the nitrogen atom to which they are attached form Ring B which is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, and wherein each is optionally substituted with at least one R9 substituent;
• and wherein each ring is further optionally fused with Y which is phenyl, pyridinyl or pyrimidinyl;
• and
• R9 is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, cyano, —N(CH3)2, hydroxy, —CHF2, —CF3, —OCHF2, —OCF3 and oxo:
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

A compound is selected from the group consisting of:

• 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((3-morpholinoazetidin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (J-4);
• 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(thiomorpholinomethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (J-11);
• 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (J-13);
• 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((3-(piperidin-1-yl)azetidin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (J-19);
• 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-phenylpiperidin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (J-20);
• and
• 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-(methylsulfonyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (J-21), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

A compound of Formula (1-A3)

• or
• wherein:
• R0 is H, methyl, ethyl or propyl;
• R1 is H or methyl;
• R2 is H, methyl, ethyl, cyclopropyl or phenyl;
• R3 is H, methyl, ethyl or propyl;
• or cyclopropyl, cyclobutyl, phenyl, C1phenyl, piperadinyl, C1-piperadinyl, piperazinyl, morpholinyl or pyridinyl, and wherein each ring is optionally substituted with at least one R9 substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, F, Cl, cyano, —N(CH3)2 and —CF3;
• and
• R7 is H, methyl, ethyl, propyl, isopropyl, t-butyl, —CH2NH2, —CH2NHCH3 or —CH2N(CH3)2;
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.