Ketolide compounds

Abstract

The invention relates to ketolide compounds of Formula (1) and their pharmaceutically acceptable salts, solvates, hydrates, polymorphs and stereoisomers having antimicrobial activity. The invention also provides pharmaceutical compositions containing the compounds of invention and methods of treating or preventing microbial infections with the compounds of invention, wherein, T is —C*H(R 1 )—P-Q; R, is hydrogen; unsubstituted or substituted lower alkyl, cycloalkyl or aryl; P is heteroaryl ring; Q is unsubstituted or substituted aryl or heteroaryl ring; and P is attached to Q via carbon-carbon link; and R 3 is hydrogen or fluorine, With the provision that when R, is hydrogen, R 3 is fluorine.

1 - 42 . (canceled) 
     
     
         43 . A compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, 
       
         
           
           
               
               
           
         
         wherein, 
         T is —C*H(R 1 )—P-Q; 
         R 1  is hydrogen; unsubstituted or substituted lower alkyl, cycloalkyl or aryl; 
         P is heteroaryl ring; 
         Q is unsubstituted or substituted aryl or heteroaryl ring; and 
         P is attached to Q via carbon-carbon link; and 
         R 3  is hydrogen or fluorine, 
         With the provision that when R 1  is hydrogen, R 3  is fluorine. 
       
     
     
         44 . A compound as claimed in  claim 43 , wherein:
 T is —C*H(R 1 )—P-Q;   R 1  is hydrogen;   R 3  is fluorine,   P is 5 or 6-membered heteroaryl ring with up to three heteroatoms;   Q is unsubstituted or substituted aryl or 5 or 6-membered heteroaryl ring; and   P is attached to Q via carbon-carbon link.   
     
     
         45 . A compound as claimed in  claim 43 , wherein:
 T is —C*H(R 1 )—P-Q;   R 1  is hydrogen;   R 3  is fluorine,   P is 5 or 6-membered heteroaryl ring with up to three heteroatoms;   Q is unsubstituted or substituted aryl or 5 or 6-membered heteroaryl ring with up to two nitrogens; and   P is attached to Q via carbon-carbon link.   
     
     
         46 . A compound as claimed in  claim 43 , wherein:
 T is —C*H(R 1 )—P-Q;   R 1  is hydrogen;   R 3  is fluorine,   P is 5-membered heteroaryl ring;   Q is unsubstituted or substituted aryl or 6-membered heteroaryl ring with up to two nitrogens; and   P is attached to Q via carbon-carbon link.   
     
     
         47 . A compound as claimed in  claim 43 , wherein:
 T is —C*H(R 1 )—P-Q;   R 1  is hydrogen;   R 3  is fluorine,   P is 6-membered heteroaryl ring;   Q is unsubstituted or substituted aryl or 5 or 6-membered heteroaryl ring with up to two heteroatoms; and   P is attached to Q via carbon-carbon link.   
     
     
         48 . A compound as claimed in  claim 43 , wherein:
 T is —C*H(R 1 )—P-Q;   R 1  is hydrogen;   R 3  is fluorine,   P is 5-membered heteroaryl ring;   Q is unsubstituted or substituted pyridine or pyrimidine; and   P is attached to Q via carbon-carbon link.   
     
     
         49 . A compound as claimed in  claim 43 , wherein:
 T is —C*H(R 1 )—P-Q;   R 1  is unsubstituted or substituted lower alkyl, cycloalkyls, or aryl;   P is heteroaryl ring;   Q is unsubstituted or substituted aryl or heteroaryl ring; and   P is attached to Q via carbon-carbon link; and   R 3  is hydrogen or fluorine.   
     
     
         50 . A compound as claimed in  claim 43 , wherein:
 T is —C*H(R 1 )—P-Q;   R 1  is unsubstituted or substituted lower alkyl;   P is heteroaryl ring;   Q is unsubstituted or substituted aryl or heteroaryl ring; and   P is attached to Q via carbon-carbon link; and   R 3  is hydrogen or fluorine   
     
     
         51 . A compound as claimed in  claim 43 , wherein:
 T is —C*H(R 1 )—P-Q;   R 1  is unsubstituted or substituted lower alkyl;   P is 5-membered heteroaryl ring with up to three heteroatoms;   Q is unsubstituted or substituted aryl or heteroaryl ring; and   P is attached to Q via carbon-carbon link; and   R 3  is hydrogen or fluorine   
     
     
         52 . A compound as claimed in  claim 43 , wherein:
 T is —C*H(R 1 )—P-Q;   R 1  is methyl;   P is 5-membered heteroaryl ring with up to three heteroatoms;   Q is unsubstituted or substituted aryl or heteroaryl ring with up to two nitrogens; and   P is attached to Q via carbon-carbon link; and   R 3  is hydrogen or fluorine.   
     
     
         53 . A compound as claimed in  claim 43 , wherein:
 T is —C*H(R 1 )—P-Q;   R 1  is methyl;   P is 5-membered heteroaryl ring;   Q is pyridine or pyrimidine; and   P is attached to Q via carbon-carbon link; and   R 3  is hydrogen or fluorine.   
     
     
         54 . A compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, selected from:
 a compound of formula (I) wherein T is [3-(pyrimidin-2-yl)-isoxazol-5-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [5-(isoxazol-3-yl)-pyrimidin-2-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [5-(pyrimidin-2-yl)-isoxazol-3-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [5-(2-amino-pyridin-6-yl)-isoxazol-3-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [5-(pyridin-2-yl)-isoxazol-3-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [2-(2-amino-pyridin-6-yl)-1,3,4-thiadiazol-5-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [2-(pyrimidin-2-yl)-1,3,4-thiadiazol-5-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [2-(2-amino-pyridin-5-yl)-1,3,4-thiadiazol-5-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [5-(pyrazin-2-yl)-isoxazol-3-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [2-(6-amino-pyrimidin-2-yl)-1,3,4-thiadiazol-5-yl]-CH 2  and R 3  is F—;   a compound of formula (I) wherein T is [2-(3-amino-phenyl)-1,3,4-thiadiazol-5-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [2-(2-amino-pyridin-6-yl)-pyridin-6-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [5-(6-amino-pyrimidin-2-yl)-isoxazol-3-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is (RS)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (R)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (RS)-[3-(pyridin-2-yl)-isoxazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (R)-[3-(pyridin-2-yl)-isoxazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[3-(pyridin-2-yl)-isoxazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (RS)-[5-(pyrimidin-2-yl)-isoxazol-3-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (R)-[5-(pyrimidin-2-yl)-isoxazol-3-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[5-(pyrimidin-2-yl)-isoxazol-3-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (R)-[5-(pyridin-2-yl)-isoxazol-3-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[5-(pyridin-2-yl)-isoxazol-3-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (R)-[5-(pyridin-2-yl)-isoxazol-3-yl]-CH(C 2 H 5 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[5-(pyridin-2-yl)-isoxazol-3-yl]-CH(C 2 H 5 )— and R 3  is H;   a compound of formula (I) wherein T is (RS)-[2-(pyrimidin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (R)-[2-(pyrimidin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(pyrimidin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(2-amino-pyridin-6-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (R)-[2-(2-amino-pyridin-6-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (RS)-[2-(2-amino-pyridin-5-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(2-amino-pyridin-5-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (R)-[2-(2-amino-pyridin-5-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (RS)-[2-(pyrazin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R3 is H;   a compound of formula (I) wherein T is (R)-[2-(pyrazin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(pyrazin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (RS)-[2-(pyridin-2-yl)-1,3,4-oxadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(3-aminophenyl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and 3 is H;   a compound of formula (I) wherein T is (S)-[2-(2-hydroxy-pyridin-6-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[5-(isoxazol-3-yl)-pyrimidin-2-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[5-(2-amino-pyridin-6-yl)-isoxazol-3-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(4-hydroxy-pyridin-6-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (R)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 2 OH)— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 2 OH)— and R 3  is H;   a compound of formula (I) wherein T is (RS)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(C 2 H 5 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(C 2 H 5 )— and R 3  is H;   a compound of formula (I) wherein T is (R)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(C 2 H 5 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (R)-[2-(2-amino-pyridin-6-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (S)-[2-(2-amino-pyridin-6-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (S)-[2-(pyrimidin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (S)-[2-(pyrazin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (S)-[5-(pyrimidin-2-yl)-isoxazol-3-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (S)-[2-(3-aminophenyl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (S)-[5-(pyridin-2-yl)-isoxazol-3-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (S)-[5-(isoxazol-3-yl)-pyrimidin-2-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (R)-[5-(isoxazol-3-yl)-pyrimidin-2-yl]-CH(CH 3 )— and R 3  is F; and   a compound of formula (I) wherein T is (S)-[5-(2-amino-pyridin-6-yl)-isoxazol-3-yl]-CH(CH 3 )— and R 3  is F.   
     
     
         55 . A compound or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof, selected from:
 a compound of formula (I) wherein T is [5-(isoxazol-3-yl)-pyrimidin-2-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is [2-(pyrimidin-2-yl)-1,3,4-thiadiazol-5-yl]-CH 2 — and R 3  is F;   a compound of formula (I) wherein T is (S)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(pyrimidin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(2-amino-pyridin-6-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(2-amino-pyridin-5-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[5-(isoxazol-3-yl)-pyrimidin-2-yl]-CH(CH 3 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 2 OH)— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(C 2 H 5 )— and R 3  is H;   a compound of formula (I) wherein T is (S)-[2-(pyridin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (S)-[2-(2-amino-pyridin-6-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (S)-[2-(pyrimidin-2-yl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (S)-[2-(3-aminophenyl)-1,3,4-thiadiazol-5-yl]-CH(CH 3 )— and R 3  is F;   a compound of formula (I) wherein T is (S)-[5-(isoxazol-3-yl)-pyrimidin-2-yl]-CH(CH 3 )— and R 3  is F; and   a compound of formula (I) wherein T is (S)-[5-(2-amino-pyridin-6-yl)-isoxazol-3-yl]-CH(CH 3 )— and R 3  is F.   
     
     
         56 . A pharmaceutical composition comprising therapeutically effective amount of a compound of formula (I) according to  claim 43  or a pharmaceutically acceptable salt, solvate, polymorph or stereoisomer thereof, optionally, with one or more pharmaceutically acceptable excipient. 
     
     
         57 . A pharmaceutical composition of  claim 56  wherein the composition is administered parenterally or orally. 
     
     
         58 . A method of treating infection caused by a microorganism in a subject, comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (I) according to  claim 43  or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof. 
     
     
         59 . A method for prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by microorganism, a prophylactically effective amount of a compound of formula (I) according to  claim 43  or a pharmaceutically acceptable salt, solvate, hydrate, polymorph or stereoisomer thereof 
     
     
         60 . A method of treating infection caused by a microorganism in a subject, comprising administering to the subject in need thereof, a pharmaceutical composition according to  claim 56 . 
     
     
         61 . A method for prophylactic treatment of a subject, comprising administering to a subject at risk of infection caused by microorganism, a pharmaceutical composition according to  claim 56 . 
     
     
         62 . A method according to any one of  claims 58 - 61 , wherein the microorganism is at least one microorganism selected from a bacteria, fungi, protozoa, yeast, mold, or mildew.