Macrocylic inhibitors of hepatitis c virus

Abstract

Inhibitors of HCV replication of formula (I), the N-oxides, salts, and stereochemically isomeric forms thereof, wherein each dashed line (represented by represents an optional double bond; X is N, CH and where X bears a double bond it is C; R 1 is aryl or a saturated, a partially unsaturated or completely unsaturated 5 or 6 membered monocyclic or 9 to 12 membered bicyclic heterocyclic ring system wherein said ring system contains one nitrogen, and optionally one to three additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining ring members are carbon atoms; wherein said ring system may be optionally substituted on any carbon or nitrogen ring atom with one, two, three, or four substituents; L is a direct bond, —O—, —O—C 1-4 alkanediyl-, —O—C(═O)—, —O—C(═O)—NR 4a — or —O—C(═O)—NR 4a C 1-4 alkanediyl-; R 2 is hydrogen, —OR 5 , —C(O)OR 5 , —C(═O)R 6 , —C(═O)NR 4a R 4b , —C(═O)NHR 4c , —NR 4a R 4b , —NHR 4c , —NR 4a SO p NR 4a R 4b , —NR 4a SO p R 7 , or B(OR 5 ) 2 ; R 3 is hydrogen, and where X is C or CH, R 3 may also be C 1-6 alkyl; n is 3, 4, 5, or 6; p is 1 or 2; aryl is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydronaphthyl, each of which may be optionally substituted with one, two or three substituents; Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with a benzene ring, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents; pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

1 . A compound having the formula 
     
       
         
         
             
             
         
       
       the N-oxides, addition salts, and stereochemically isomeric forms thereof, wherein each dashed line (represented by   represents an optional double bond; 
       X is N, CH and where X bears a double bond it is C; 
       R 1  is aryl or a saturated, a partially unsaturated or completely unsaturated 5 or 6 membered monocyclic or 9 to 12 membered bicyclic heterocyclic ring system wherein said ring system contains one nitrogen, and optionally one to three additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining ring members are carbon atoms; wherein said ring system may be optionally substituted on any carbon or nitrogen ring atom with one, two, three, or four substituents each independently selected from C 3-7 cycloalkyl aryl, Het, —C(═O)—NR 4a R 4b , —C(═O)OR 6 , —C(═O)OR 5a , and C 1-6 alkyl optionally —NR 4a C(═O)R 6 , —NR 4a SO p R 7 , —SO p R 7 , —SO p NR 4a R 4b , —NR 4a R 4b , —C(═O)R 6 , substituted with C 3-7 cycloalkyl, aryl, Het, —C(═O)NR 4a R 4b , —NR 4a R 4b , —C(═O)R 6 , —NR 4a C(═)R 6 , —NR 4a SO p R 7 , —SO p R 7 , —SO p NR 4a R 4b , —C(═O)OR 5 , or —NR 4a C(O)OR 5a ; and wherein the substituents on any carbon atom of the heterocyclic ring may also be selected from —OR 8 , —SR 8 , halo, polyhalo-C 1-6 alkyl, oxo, thio, cyano, nitro, azido, —NR 4a R 4b , —NR 4a C(═O)R 6 , —NR 4a SO p R 7 , —SO p R 7 , —SO p NR 4a R 4b , —C(═O)OH, and —NR 4a C(═O)OR 5a ; 
       L is a direct bond, —O—, —O—C 1-4 alkanediyl-, —O—C(O)NR 4a — or —O—C(O)NR 4a C 1-4 alkanediyl-; 
       R 2  represents hydrogen, —OR 5 , —C(═O)OR 5 , —C(═O)R 6 , —C(═O) NR 4a R 4b , —((═O)NHR 4c , —NR 4a R 4b , —NHR 4c , —NR 4a SO p NR 4a R 4b , —NR 4a SO p R 7 , or B(OR 5 ) 2 ; 
       R 3  is hydrogen, and where X is C or CH, R 3  may also be C 1-6 alkyl; 
       n is 3, 4, 5, or 6; 
       p is 1 or 2; 
       each R 4a  and R 4b  are, independently, hydrogen, C 3-7 cycloalkyl, aryl, Het, C 1-6 alkyl optionally substituted with halo, C 1-4 alkoxy, cyano, polyhaloC 1-4 alkoxy, C 3-7 cycloalkyl, aryl, or with Het; or R 4a  and R 4b  taken together with the nitrogen atom to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6  alkylpiperazinyl, 4-C 1-6  alkylcarbonyl-piperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or with two C 1-6 alkyl radicals; 
       R 4c  is C 3-7 cycloalkyl, aryl, Het, —O—C 3-7 cycloalkyl, —O-aryl, —O-Het, C 1-6 alkyl, or 
       C 1-6 alkoxy, wherein said C 1-6 alkyl, or C 1-6 alkoxy may be each optionally substituted with —C(═O)OR 5 , C 3-7 cycloalkyl, aryl, or Het; 
       R 5  is hydrogen; C 2-6 alkenyl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or Het; 
       R 5a  is C 2-6 alkenyl, C 3-7 cycloalkyl, Het, or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or Het; 
       R 6  is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, or aryl; 
       R 7  is hydrogen; polyhaloC 1-6 alkyl; aryl; Het; C 3-7 cycloalkyl optionally substituted with C 1-6 alkyl; or C 1-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or Het; 
       aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydronaphthyl, each of which may be optionally substituted with one, two or three substituents selected from halo, C 1-6 alkyl, polyhaloC 1-4 alkyl, hydroxy, C 1-6 alkoxy, polyhaloC 1-6  alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-6  alkylcarbonyl, C 1-6 alkoxycarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, aminocarbonyl, mono- or diC 1-6 alkylaminocarbonyl, azido, mercapto, C 3-7 cycloalkyl, phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or with two C 1-6 alkyl radicals; and the phenyl, pyridyl, thiazolyl, pyrazolyl groups may be optionally substituted with 1, 2 or 3 substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, halo, amino, mono- or diC 1-6 alkylamino; 
       Het as a group or part of a group is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally condensed with a benzene ring, and wherein the group Het as a whole may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo, C 1-6 alkyl, polyhalo-C 1-6 alkyl, hydroxy, C 1-6 alkoxy, polyhaloC 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkyl, carboxyl, C 1-4 alkylcarbonyl, C 1-6 alkoxycarbonyl, cyano, nitro, amino, mono- or diC 1-6 alkylamino, aminocarbonyl, mono- or diC 1-6 alkylaminocarbonyl, C 3-7 cycloalkyl, phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl, 4-C 1-6 alkylcarbonyl-piperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or with two C 1-6 alkyl radicals; and the phenyl, pyridyl, thiazolyl, pyrazolyl groups may be optionally substituted with 1, 2 or 3 substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, halo, amino, mono- or diC 1-6 alkylamino. 
     
   
   
       2 . A compound according to  claim 1  wherein the compound has the formula (I-b): 
     
       
         
         
             
             
         
       
     
   
   
       3 . A compound according to any one of  claims 1 - 2 , wherein the compound has the formula (I-c) or (I-d): 
     
       
         
         
             
             
         
       
     
   
   
       4 . A compound according to any one of  claims 1 - 2 , wherein L is —O—, —O—CO— or a direct bond. 
   
   
       5 . A compound according to  claim 3  or  4  wherein L is —O— and R 1  is (d-1) a radical of formula 
     
       
         
         
             
             
         
       
       (d-2) a radical of formula 
     
     
       
         
         
             
             
         
       
       (d-3) a radical of formula 
     
     
       
         
         
             
             
         
       
       (d-4) a radical of formula 
     
     
       
         
         
             
             
         
       
       or in particular, (d-4-a) a radical of formula 
     
     
       
         
         
             
             
         
       
       (d-5) a radical of formula 
     
     
       
         
         
             
             
         
       
       wherein in radicals (d-1)-(d-5), as well as in (d-4-a) and (d-5-a): 
       R 1a , R 1b , R 1b′ , R 1d , R 1d′ , R 1e , R 1f  are independently any of the substituents selected from those mentioned as possible substituents on the monocyclic or bicyclic ring systems of R 1 , as specified in  claim 1 . 
     
   
   
       6 . A compound according to  claim 3  or  4  wherein L is —O— and R 1  is a radical of formula 
     
       
         
         
             
             
         
       
       wherein R 1f  is hydrogen, C 1-6 alkyl, amino, mono- or diC 1-6 alkylamino, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkylpiperazinyl (in particular 4-methylpiperazinyl), or morpholinyl. 
     
   
   
       7 . A compound according to any one of  claims 1 - 6 , wherein
 (f) R 2  is NHR 4c , where R 4c  is C 1-6 alkyl, aryl, Het, C 1-6 alkoxy, —O-aryl, or —O-Het; or   (g) R 2  is —OR 5 , where R 5  is methyl, ethyl, tert-butyl, or hydrogen; or   (h) R 2  is —NHS(═O) 2 R 7 , where R 7  is methyl, cyclopropyl, methylcyclopropyl, or phenyl; or   (j) R 2  is —C(═O)OR 5 , —C(═O)R 6 , —C(═O)NR 4a R 4b , or —C(═O)NHR 4c , wherein R 4a , R 4b , R 4c , R 5 , or R 6  are as defined are as defined in any one of  claims 1 - 4 , and where R 4c  is cyclopropyl; or   (j) R 2  is —NHS(═O) 2 NR 4a R 4b  where R 4a  and R 4b  are, each independently, hydrogen, C 3-7 cycloalkyl or C 1-6 alkyl.   
   
   
       8 . A compound according to any one of  claims 1 - 7  wherein n is 4 or 5. 
   
   
       9 . A compound according to any one of  claims 1 - 8  wherein X is N. 
   
   
       10 . A compound according to any one of  claims 1 - 8  wherein X is CH and the bond between X and the carbon atom bearing R 3  is a single bond. 
   
   
       11 . A compound according to any one of  claims 1 - 9  wherein R 3  is hydrogen. 
   
   
       12 . A compound according to any of  claims 1 - 11  other than an N-oxide, or salt. 
   
   
       13 . A combination comprising
 (a) a compound as defined in any one of  claims 1  to  12  or a pharmaceutically acceptable salt thereof; and   (b) ritonavir, or a pharmaceutically acceptable salt thereof.   
   
   
       14 . A pharmaceutical composition comprising a carrier, and as active ingredient an anti-virally effective amount of a compound as claimed in any one of  claims 1 - 12  or a combination according to  claim 13 . 
   
   
       15 . A compound according to any of  claims 1 - 12  or a combination according to  claim 13 , for use as a medicament. 
   
   
       16 . Use of a compound according to any of  claims 1 - 12  or a combination according to  claim 13 , for the manufacture of a medicament for inhibiting HCV replication. 
   
   
       17 . A method of inhibiting HCV replication in a warm-blooded animal said method comprising the administration of an effective amount of a compound according to any of  claims 1 - 12  or an effective amount of each component of the combination according to  claim 13 . 
   
   
       18 . A process for preparing a compound as claimed in any of  claims 1 - 12 , wherein said process comprises:
 (a) preparing a compound of formula (I) wherein the bond between C 7  and C 8  is a double bond, which is a compound of formula (I-i), by forming a double bond between C 7  and C 8 , in particular via an olefin metathesis reaction, with concomitant cyclization to the macrocycle as outlined in the following reaction scheme:   
     
       
         
         
             
             
         
       
       (b) converting a compound of formula (I-d) to a compound of formula (I) wherein the link between C7 and C8 in the macrocycle is a single bond, i.e. a compound of formula (I-j): 
     
     
       
         
         
             
             
         
       
       by a reduction of the C 7 -C 8  double bond in the compound of formula (I-i); 
       (c) preparing a compound of formula (I) wherein R 2  represents NR 5a R 5b , —NHR 5c , —NHSO p NR 5a R 5b , —NR 5a SO p R 8 , these groups being collectively represented by —NR 2-a R 2-b ), said compound being represented by formula (I-d-1), by forming an amide bond between an intermediate (III) and an amine H—NR 2-a R 2-b , (IV-a), or preparing a compound of formula (I) wherein R 2  represents —OR 6 , i.e. a compound (I-d-2), by forming an ester bond between an intermediate (III) and an alcohol (IV-b) as outlined in the following scheme wherein G represents a group: 
     
     
       
         
         
             
             
         
       
       (d) preparing a compound of formula (I) wherein R 2  represents hydrogen, i.e. a compound (I-d-3), from an ester (I-d-2-a), which is an intermediate of formula (I-d-2) wherein R 6  is C 1-4 alkyl, by a reduction reaction to a corresponding alcohol (I-d-3), followed by an oxidation reaction with a mild oxidant: 
     
     
       
         
         
             
             
         
       
       (e) reacting an intermediate (V) with intermediates (4b), (4c), (4d), (4e) or (41) as outlined in the following reaction scheme wherein the various radicals have the meanings specified above and C 1-4 Alk represents C 1-4 alkanediyl: 
     
     
       
         
         
             
             
         
       
       and wherein Y in (4b) represents hydroxy or a leaving group; which reaction in particular is an O-arylation reaction where Y represents a leaving group, or a Mitsunobu reaction, where Y is hydroxy; 
       (f) preparing a compound of formula (I) wherein L is a urethane group (L is —O—C(═O)—NR 5a —) by reacting an intermediate (4a) with an amine (4c) or (4d) in the presence of a carbonyl introducing agent, the latter in particular comprising phosgene or a phosgene derivative; 
       (g) preparing compounds of formula (I) wherein L is —O—C(═O)— by reacting an alcohol (4a) with an acid (4e) or active derivative thereof, such as a corresponding acylating agent, in particular an acid anhydride or acid halide; 
       (h) preparing compounds of formula (I) wherein L is —O—C 1-4 alkanediyl- by an ether forming reaction between (4a) and (4f); 
       (i) converting compounds of formula (I) into each other by a functional group transformation reaction; or 
       (j) preparing a salt form by reacting the free form of a compound of formula (I) with an acid or a base.