Epothilone derivatives

Abstract

The present invention relates to compounds of the formula in which the variables G, W, Q, X, Y, B 1 , B 2 , Z 1 , Z 2 , and R 1 –R 7 are as defined herein, methods for the preparation of the derivatives and intermediates thereof.

1. A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein: 
       
         
           
           
               
               
           
         
         G is selected from the group consisting of alkyl; substituted alkyl; substituted aryl; a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; 
       
       
         
           
           
               
               
           
         
          and a 1-methyl-2-(substituted R′) ethenyl group, wherein R′ is a monocyclic group selected from the group consisting of pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetraydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahyro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl; or a bicyclic heterocyclic group selected from the group consisting of benzothiazolyl, benzoxazoyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl], furo[2,3-b]pyridinyl, dihydroisoindolyl, dihydroquinazolinyl, 3,4-dihydro-4-oxo-quinazolinyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, and thienothienyl; wherein the R′ substituents are selected from alkyl, hydroxyalkyl, and oxo; 
         W is O or NR 15 ; NH;  
         X is O or H, H; 
         Y is selected from the group consisting of O; H, OR 16 ; OR 17 , OR 17 ; NOR 18 ; H, NHOR 19 ; H, NR 20 R 21 ; H, H; and CHR 22 ; wherein OR 17 , OR 17  can be a cyclic ketal; 
         Z 1  and Z 2  are independently CH 2 ; 
         B 1  and B 2  are independently selected from the group consisting of OR 24 , OCOR 25 , and O—C(═O)—NR 26 R 27 , and when B 1  is OH and Y is OH, H they can form a six-membered ring ketal or acetal; 
         B 1  is selected from the group consisting of OR 24 , OCOR 25 , and O—C(═O)—NR 26 R 27 ; 
         B 2  is selected from the group consisting of OH, OCOR 25 , and O—C(═O)—NR 26 R 27 ; 
         R 1  and R 2  are both hydrogen; 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 13 , R 14 , R 18 , R 19 , R 20 , R 21 , R 22 , R 26 , and R 27  are selected from the group consisting of H, alkyl, substituted alkyl, and aryl, and when R 1  and R 2  are alky, they can be joined to form a cycloalkyl; ; and when R 3  and R 4  are alkyl they can be joined to 
         form a cycloalkyl; 
         R 6  is methyl; 
         R 16 , R 17 , R 24 , and R 25  are selected from the group consisting of H, alkyl, and substituted alkyl; 
         R 11 , R 12 , R 32 , and R 33  are selected from the group consisting of H; alkyl; substituted alkyl; aryl; substituted aryl; cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C 3 –C 7  carbocyclic ring; and a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; 
         R 8  is hydrogen or methyl; 
         R 15  is selected from the group consisting of H; alkyl; substituted alkyl; aryl; substituted aryl; cycloalkyl containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C 3 –C 7  carbocyclic ring; a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic saturated or unsaturated ring system having between 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; 
       
       R 32 C═O, R 33 SO2, hydroxy, O-alkyl or O-substituted alkyl;
 or a pharmaceutically acceptable salt thereof; 
 
       with the proviso that compounds wherein
 W and X are both O; and 
 R 1 , R 2  and R 7  are is H; and 
 R 3  and R 4  are methyl; and 
 G is 1-methyl-2-(substituted)-4-thiazolyl-ethenyl; 
 
       are excluded. 
     
     
       2. The compound of  claim 1 , wherein: X is O and Y is O; or a pharmaceutically
 acceptable salt thereof. 
 
     
     
       3. The compound of  claim 2 , wherein: B 1  is OH and B 2  is OH; or a pharmaceutically acceptable salt thereof. 
     
     
       4. The compound of  claim 3 , wherein W is O; or a pharmaceutically acceptable salt thereof. 
     
     
       5. The compound of  claim 4 , wherein:
 R 1 , R 2 , and R 7  are is H; and 
 R 3 , R 4 , and R 5  are methyl; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       6. The compound of  claim 5 , wherein G is: 
       
         
           
           
               
               
           
         
         a 1-methyl-2-(substituted R′) ethenyl group; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       7. The compound of  claim 6 , wherein R 11  is a 4 to 7 membered monocyclic saturated or unsaturated ring system having from 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R′ is a monocyclic group selected from the group consisting of pyrrolidinyl, pyrrol, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl; or a pharmaceutically acceptable salt thereof. 
     
     
       8. The compound of  claim 3 , wherein W is NR 15  NH; or a pharmaceutically acceptable salt thereof. 
     
     
       9. The compound of  claim 8 , wherein:
 R 1 , R 2 , and R 7  are is H; and 
 R 3 , R 4 , and R 5  are methyl; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       10. The compound of  claim 9 , wherein G is: 
       
         
           
           
               
               
           
         
         a 1-methyl-2-(substituted R′) ethenyl group;  
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       11. The compound of  claim 10 , wherein R 11  is a 4 to 7 membered monocyclic saturated or unsaturated ring system having from 1 and 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R′ is a monocyclic group selected from the group consisting of pyrrolidinyl, pyrrol, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl; or a pharmaceutically acceptable salt thereof. 
     
     
       12. The compound of  claim 11 , wherein R 15  is H; or a pharmaceutically acceptable salt thereof. 
     
     
       13. A pharmaceutical composition comprising the compound of  claim 1  or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable vehicle or diluent.