Heterocyclic compounds as ccr5 antagonists

Abstract

The present invention relates to compounds of formula (I), or pharmaceutically acceptable derivatives thereof, useful in the treatment of CCR5-related diseases and disorders, for example, useful in the inhibition of HIV replication, the prevention or treatment of an HIV infection, and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).

1 . A compound of formula (I) 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable derivative thereof, wherein:
 X is a C 1-5  alkylene chain, wherein said X is optionally substituted by one or more ═O, ═S, —S(O) t —, alkyl, or halogen; 
 Ring A is a piperidine; 
 Ring B has an oxygen atom in addition to the depicted nitrogen; 
 R 1  is phenyl optionally substituted by one or more R 6 ; 
 each R 2  is independently selected from the group consisting of —OR 0 , —C(O)—R 0 , —S(O) 2 —R 0 , —C(O)—N(R 0 ) 2 , —S(O) 2 —N(R 0 ) 2 , —(CH 2 ) a —N(R 0 )(—V b —R + ), —(CH 2 ) a —(—V b —R + ), halogen, alkyl optionally substituted by one or more R 7 , alkenyl optionally substituted by one or more R 7 , alkynyl optionally substituted by one or more R 7 , aryl optionally substituted by one or more R 6 , heteroaryl optionally substituted by one or more R 6 , cycloalkyl optionally substituted by one or more R 8 , and heterocyclyl optionally substituted by one or more R 8 ; and two adjacent R 2 s on Ring A are optionally taken together to form a fused, saturated, partially saturated or aromatic 5-6 membered ring having 0-3 heteroatoms selected from oxygen, phosphorus, sulfur, or nitrogen; or two geminal R 2 s are optionally taken together to form a spiro, saturated, partially saturated or aromatic 5-6 membered ring having 0-3 heteroatoms selected from oxygen, phosphorus, sulfur, or nitrogen, said fused or spiro ring being optionally substituted by one or more R 8 ; 
 each a independently is 0-3; 
 each b independently is 0 or 1; 
 V is —C(O)—, —C(O)O—, —S(O) 2 —, or —C(O)—N(R 0 )—; 
 R +  is alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, or heterocyclyl, wherein said R +  is optionally substituted by one or more R 8 ; 
 m is 1; 
 n is 0-5; 
 R 3  is H, —N(R 0 ) 2 , —N(R 0 )C(O)R 0 , —CN, halogen, CF 3 , alkyl optionally substituted by one or more groups selected from R 7  or —S-aryl optionally substituted by —(CH 2 ) 1-6 —N(R 0 )SO 2 (R 0 ), alkenyl optionally substituted by one or more groups selected from R 7  or —S-aryl optionally substituted by —(CH 2 ) 1-6 —N(R 0 )SO 2 (R 0 ), alkynyl optionally substituted by one or more groups selected from R 7  or —S-aryl optionally substituted by —(CH 2 ) 1-6 —N(R 0 )SO 2 (R 0 ), cycloalkyl or carbocyclyl optionally substituted by one or more R 8 , aryl optionally substituted by one or more R 6 , heteroaryl optionally substituted by one or more R 6 , or heterocyclyl optionally substituted by one or more R 8 ; 
 Y is —C(O)—, 
 each t independently is 1 or 2; 
 each R 6  is independently selected from the group consisting of halogen, —CF 3 , —OCF 3 , —OR 0 , —(CH 2 ) 1-6 —OR 0 , —SR 0 , —(CH 2 ) 1-6 —SR 0 , —SCF 3 , —R 0 , methylenedioxy, ethylenedioxy, —NO 2 , —CN, —(CH 2 ) 1-6 —CN, —N(R 0 ) 2 , —(CH 2 ) 1-6 —N(R 0 ) 2 , —NR 0 C(O)R 0 , —NR 0 (CN), —NR 0 C(O)N(R 0 ) 2 , —NR 0 C(S)N(R 0 ) 2 , —NR 0 °CO 2 R 0 , —NR 0 NR 0 C(O)R 0 , —NR 0 NR 0 C(O)N(R 0 ) 2 , —NR 0 NR 0 CO 2 R 0 , —C(O)C(O)R 0 , —C(O)CH 2 C(O)R 0 , —(CH 2 ) 0-6 CO 2 R 0 , —O—C(O)R 0 , —C(O)R 0 , —C(O)N(R 0 )N(R 0 ) 2 , —C(O)N(R 0 ) 2 , —C(O)N(R 0 )OH, —C(O)N(R 0 )SO 2 R 0 , —OC(O)N(R 0 ) 2 , —S(O) t R 0 , —S(O) t —OR 0 , —S(O) t N(R 0 )C(O)R 0 , —S(O) t N(R 0 )OR 0 , —NR 0 SO 2 N(R 0 ) 2 , —NR 0 SO 2 R 0 , —C(═S)N(R 0 ) 2 , —C(═NH)—N(R 0 ) 2 , —(CH 2 ) 1-6 —C(O)R 0 , —C(═N—OR 0 )—N(R 0 ) 2 , —O—(CH 2 ) 0-6 —SO 2 N(R 0 ) 2 , —(CH 2 ) 1-6 NHC(O)R 0 , and —SO 2 N(R 0 ) 2  wherein the two R 0 s on the same nitrogen are optionally taken together to form a 5-8 membered saturated, partially saturated, or aromatic ring having additional 0-4 heteroatoms selected from oxygen, phosphorus, nitrogen, or sulfur; 
 each R 7  is independently selected from the group consisting of halogen, —CF 3 , —R 0 , —OR 0 , —OCF 3 , —(CH 2 ) 1-6 —OR 0 , —SR 0 , —SCF 3 , —(CH 2 ) 1-6 —SR 0 , aryl optionally substituted by R 6 , methylenedioxy, ethylenedioxy, —NO 2 , —CN, —(CH 2 ) 1-6 —CN, —N(R 0 ) 2 , —(CH 2 ) 1-6 —N(R 0 ) 2 , —NR 0 C(O)R 0 , —NR 0 (CN), —NR 0 C(O)N(R 0 ) 2 , —N(R 0 )C(S)N(R 0 ) 2 , —NR 0 CO 2 R 0 , —NR 0 NR 0 C(O)R 0 , —NR 0 NR 0 C(O)N(R 0 ) 2 , —NR 0 NR 0 CO 2 R 0 , —C(O)C(O)R 0 , —C(O)CH 2 C(O)R 0 , —(CH 2 ) 0-6 —CO 2 R 0 , —C(O)R 0 , —C(O)N(R 0 )N(R 0 ) 2 , —C(O)N(R 0 ) 2 , —C(O)N(R 0 )OH, —OC(O)R 0 , —C(O)N(R 0 )SO 2 R 0 , —OC(O)N(R 0 ) 2 , —S(O) t R 0 , —S(O) t —OR 0 , —S(O) t N(R 0 )C(O)R 0 , —S(O) t N(R 0 )OR 0 , —NR 0 SO 2 N(R 0 ) 2 , —NR 0 SO 2 R 0 , —C(═S)N(R 0 ) 2 , —C(═NH)—N(R 0 ) 2 , —(CH 2 ) 1-6 —C(O)R 0 , —C(═N—OR 0 )—N(R 0 ) 2 , —O—(CH 2 ) 0-6 —SO 2 N(R 0 ) 2 , —(CH 2 ) 1-6 —NHC(O)R 0 , and —SO 2 N(R 0 ) 2  wherein the two R 0 s on the same nitrogen are optionally taken together to form a 5-8 membered saturated, partially saturated, or aromatic ring having additional 0-4 heteroatoms selected from oxygen, phosphorus, nitrogen, or sulfur; 
 each R 8  is independently selected from R 7 , ═O, ═S, ═N(R 0 ), and ═N(CN); 
 each R 0  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, wherein each member of R 0  except H is optionally substituted by one or more R*, OR*, N(R*) 2 , ═O, ═S, halo, CF 3 , NO 2 , CN, —C(O)R*, —CO 2 R*, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-aralkyl, —S(O) t -aryl, —S(O) t -heteroaryl, —NR*SO 2 R*, —NR*C(O)R*, —NR*C(O)N(R*) 2 , —N(R*)C(S)N(R*) 2 , —NR*CO 2 R*, —NR*NR*C(O)R*, —NR*NR*C(O)N(R*) 2 , —NR*NR*CO 2 R*, —C(O)C(O)R*, —C(O)CH 2 C(O)R*, —C(O)N(R*)N(R*) 2 , —C(O)N(R*) 2 , —C(O)NR*SO 2 R*, —OC(O)N(R*) 2 , —S(O) t R*, —NR*SO 2 N(R*) 2 , and —SO 2 N(R*) 2  wherein the two R*s on the same nitrogen are optionally taken together to form a 5-8 membered saturated, partially saturated or aromatic ring having additional 0-4 heteroatoms selected from oxygen, phosphorus, nitrogen or sulfur; and 
 each R* is independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl. 
 
   
   
       2 . The compound of  claim 1  wherein R 1  is phenyl mono- or di-substituted with halogen. 
   
   
       3 . The compound of  claim 2  wherein R 1  is phenyl di-substituted with Cl. 
   
   
       4 . The compound of  claim 1  wherein —(Y) m —R 3  is 
     
       
         
         
             
             
         
       
     
   
   
       5 . The compound of  claim 1  wherein —(Y) m —R 3  is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       6 . The compound of  claim 1  wherein m is 1, Y is —C(O)—, and R 3  is either aryl or heteroaryl wherein either is optionally substituted, optionally substituted alkyl, or optionally substituted cycloalkyl. 
   
   
       7 . The compound of  claim 1  where X is —(CH 2 )—, —(CH 2 —CH 2 )—, or —(CH 2 —CH 2 —CH 2 )—. 
   
   
       8 . The compound of  claim 7  wherein X is optionally substituted by one or more halogen or oxo. 
   
   
       9 . The compound of  claim 8  wherein X is disubstituted with halogen. 
   
   
       10 . The compound of  claim 9  wherein X is disubstituted with fluoro. 
   
   
       11 . The compound of  claim 10  wherein X is —(CF 2 —CH 2 )—. 
   
   
       12 . The compound of  claim 1  wherein the A ring is selected from the following, where the asterisk (*) indicates the preferred, but not limiting, point(s) of substitution: 
     
       
         
         
             
             
         
       
     
   
   
       13 . The compound of  claim 12  wherein each R 2 , with an asterisk indicating a point of substitution from ring A, independently is selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       14 . The compound of  claim 1  wherein the A ring, with two geminal R 2 s, is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       15 . The compound of  claim 1  wherein the A ring is piperidine, either optionally substituted with one or more R 2 . 
   
   
       16 . The compound of  claim 15  wherein the A ring in combination with R 2  is 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       17 . The compound of  claim 1  wherein ring B is selected from the group consisting of 
     
       
         
         
             
             
         
       
     
   
   
       18 . The compound according to  claim 1  selected from the group consisting of: 
     6-(2-{4-[5-(4-chlorophenyl)-1H-pyrazol-3-yl]piperidin-1-yl}ethyl)-3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinane 
     
       
         
         
             
             
         
       
     
     2-benzyl-8-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}-2,8-diazaspiro[4.5]decan-1-one 
     
       
         
         
             
             
         
       
     
     3-(2,2-dimethylpropanoyl)-6-{2-[4-(2-naphthyl)piperidin-1-yl]ethyl}-6-phenyl-1,3-oxazinane 
     
       
         
         
             
             
         
       
     
     6-chloro-N-[(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)methyl]-1,3-benzothiazol-2-amine 
     
       
         
         
             
             
         
       
     
     1-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-1H-indole 
     
       
         
         
             
             
         
       
     
     4-nitrobenzyl allyl(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)carbamate 
     
       
         
         
             
             
         
       
     
     N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-N-ethyl-2-(4-nitrophenyl)acetamide 
     
       
         
         
             
             
         
       
     
     5-chloro-1-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one 
     
       
         
         
             
             
         
       
     
     N-allyl-N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-2-phenylacetamide 
     
       
         
         
             
             
         
       
     
     N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)-N-ethyl-2-(4-fluorophenyl)acetamide 
     
       
         
         
             
             
         
       
     
     4-{2-[(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)(ethyl)amino]-2-oxoethyl}benzamide 
     
       
         
         
             
             
         
       
     
     N-[(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)methyl]-N-methylnaphthalene-1-sulfonamide 
     
       
         
         
             
             
         
       
     
     N-[(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)methyl]naphthalene-2-sulfonamide 
     
       
         
         
             
             
         
       
     
     N-(cyclopropyl methyl)-N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)pyrimidin-2-amine 
     
       
         
         
             
             
         
       
     
     N-allyl-N-(1-{2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethyl}piperidin-4-yl)pyridin-2-amine 
     
       
         
         
             
             
         
       
     
   
   
       19 . A method of treatment of a viral infection in a human comprising administering to said human an antiviral effective amount of a compound according to  claim 1 . 
   
   
       20 . A method according to  claim 18  wherein the viral infection is an HIV infection. 
   
   
       21 . A method of treatment of a bacterial infection in a human comprising administering to said human an effective amount of a compound according to  claim 1 . 
   
   
       22 . A method according to  claim 20  wherein the bacterium is  Yersinia pestis.    
   
   
       23 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to  claim 1  together with a pharmaceutically acceptable carrier. 
   
   
       24 . The pharmaceutical composition according to  claim 22  in the form of a tablet or capsule. 
   
   
       25 . The pharmaceutical composition according to  claim 22  in the form of a liquid. 
   
   
       26 . A method of treatment or prevention of a viral infection in a human comprising administering to said human a composition comprising a compound according to  claim 1  and another therapeutic agent. 
   
   
       27 . A method according to  claim 25 , wherein said composition comprises another therapeutic agent selected from the group consisting of (1-alpha, 2-beta, 3-alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(−)BHCG, SQ-34514, lobucavir], 9-[(2R,3R,4S)-3,4-bis(hydroxymethyl)-2-oxetanosyl]adenine (oxetanocin-G), acyclic nucleosides, acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir, acyclic nucleoside phosphonates, (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC), [[[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]phosphinylidene]bis(oxymethylene)-2,2-dimethylpropanoic acid (bis-POM PMEA, adefovir dipivoxil), [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid (tenofovir), (R)-[[2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid bis-(isopropoxycarbonyloxymethyl)ester (bis-POC-PMPA), ribonucleotide reductase inhibitors, 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl) thiocarbonohydrazone and hydroxyurea, nucleoside reverse transcriptase inhibitors, 3′-azido-3′-deoxythymidine (AZT, zidovudine), 2′,3′-dideoxycytidine (ddC, zalcitabine), 2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine (ddI, didanosine), 2′,3′-didehydrothymidine (d4T, stavudine), (−)-beta-D-2,6-diaminopurine dioxolane (DAPD), 3′-azido-2′,3′-dideoxythymidine-5′-H-phosphosphonate (phosphonovir), 2′-deoxy-5-iodo-uridine (idoxuridine), (−)- cis -1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine),  cis -1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC), 3′-deoxy-3′-fluorothymidine, 5-chloro-2′,3′-dideoxy-3′-fluorouridine, (−)-cis-4-[2-amino-6-(cyclopropylamino)-9 H -purin-9-yl]-2-cyclopentene-1-methanol (abacavir), 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G), ABT-606 (2HM-H2G) ribavirin, protease inhibitors, indinavir, ritonavir, nelfinavir, amprenavir, saquinavir, fosamprenavir, (R)—N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N—[(R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthiopropanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide (KNI-272), 4R-(4alpha,5alpha,6beta)]-1,3-bis[(3-aminophenyl)methyl]hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one dimethanesulfonate (mozenavir), 3-[1-[3-[2-(5-trifluoromethylpyridinyl)-sulfonylamino]phenyl]propyl]-4-hydroxy-6alpha-phenethyl-6beta-propyl-5,6-dihydro-2-pyranone (tipranavir), N′-[2(S)-Hydroxy-3(S)—[N-(methoxycarbonyl)-I-tert-leucylamino]-4-phenylbutyl-N alpha-(methoxycarbonyl)-N′-[4-(2-pyridyl)benzyl]-L-tert-leucylhydrazide (BMS-232632), 3-(2(S)-Hydroxy-3(S)-(3-hydroxy-2-methylbenzamido)-4-phenylbutanoyl)-5,5-dimethyl-N-(2-methylbenzyl)thiazolidine-4(R)-carboxamide (AG-1776), N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenyl-methyl-4(S)-hydroxy-5-(1-(1-(4-benzo[b]furanylmethyl)-2(S)—N′-(tert-butylcarboxamido)piperazinyl)pentanamide (MK-944A), interferons, α-interferon, renal excretion inhibitors, probenecid, nucleoside transport inhibitors, dipyridamole, pentoxifylline, N-acetylcysteine (NAC), Procysteine, α-trichosanthin, phosphonoformic acid, immunomodulators, interleukin II, thymosin, granulocyte macrophage colony stimulating factors, erythropoetin, soluble CD 4  and genetically engineered derivatives thereof, non-nucleoside reverse transcriptase inhibitors (NNRTIs), nevirapine (BI-RG-587), alpha-((2-acetyl-5-methylphenyl)amino)-2,6-dichloro-benzeneacetamide (loviride), 1-[3-(isopropylamino)-2-pyridyl]-4-[5-(methanesulfonamido)-1H-indol-2-ylcarbonyl]piperazine monomethanesulfonate (delavirdine), (10R,11S,12S)-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-benzo(1,2-b:3,4-b′:5,6-b″)tripyran-2-one ((+) calanolide A), (4S)-6-Chloro-4-[1E)-cyclopropylethenyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (DPC-083), (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one (efavirenz, DMP 266), 1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-2,4(1H,3H)-pyrimidinedione (MKC-442), and 5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethyl carbamate (capravirine), glycoprotein 120 antagonists, PRO-2000, PRO-542, 1,4-bis[3-[(2,4-dichlorophenyl)carbonylamino]-2-oxo-5,8-disodiumsulfanyl]naphthalyl-2,5-dimethoxyphenyl-1,4-dihydrazone (FP-21399), cytokine antagonists, reticulose (Product-R), 1,1′-azobis-formamide (ADA), 1,11-(1,4-phenylenebis(methylene))bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD-3100), integrase inhibitors, and fusion inhibitors. 
   
   
       28 . A method of treatment of a viral infection in a mammal comprising administering to said mammal a composition comprising a compound according to  claim 1  and ritonavir.