Modulators of pharmacokinetic properties of therapeutics

Abstract

The present application provides for a compound of Formula I, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, compositions containing such compounds, therapeutic methods that include the administration of such compounds, and therapeutic methods and include the administration of such compounds with at least one additional therapeutic agent.

What is claimed: 
     
         1 . A method for improving the pharmacokinetics of a drug which is metabolized by cytochrome P450 monooxygenase, comprising administering to a patient treated with the drug a therapeutically effective amount of a compound of formula IID, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 L 1  is selected from the group consisting of —C(R 6 ) 2 —, —C(O)—, —S(O 2 )—, —N(R 7 )—C(O)—, and —O—C(O)—; 
 each L 3  is independently a covalent bond, alkylene, or substituted alkylene; 
 each L 4  is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, —O—, —CH 2 —O—, and —NH—; 
 each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl,
 with the proviso that when A is H, p is 0; 
 
 Z 1  and Z 2  are each independently —O— or —N(R 7 )—; 
 Y and X are each independently selected from the group consisting of heterocyclyl and heterocyclylalkyl; 
 each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 R 1 , R 3 , and R 5  are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl; 
 R 2  is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxyalkyl, hydroxyalkyl, arylheteroalkyl, substituted arylheteroalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -alkylene-C(O)—OH, -alkylene-C(O)—Oalkyl, -alkylene-C(O)amino, and -alkylene-C(O)-alkyl; 
 R 4  and R 6  are each independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl; 
 each R 7  is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; 
 R 8  and R 9  are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN; and 
 each p is independently 0 or 1. 
 
     
     
         2 . The method of  claim 1 , wherein:
 L 1  is —C(R 6 ) 2 —;   each L 3  is alkylene;   each A is aryl or substituted aryl;   X and Y are each heterocyclylalkyl;   Z 1  is —N(R 7 )—; and   Z 2  is —O—.   
     
     
         3 . The method of  claim 1 , wherein a therapeutically effective amount of a combination comprising the drug and the compound of Formula IID or the pharmaceutically acceptable salt of the compound of Formula IID is administered to the patient. 
     
     
         4 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The method of  claim 1 , wherein the drug metabolized by cytochrome P450 is an HIV protease inhibiting compound, HIV non-nucleoside inhibitor of reverse transcriptase, HIV nucleoside inhibitor of reverse transcriptase, HIV nucleotide inhibitor of reverse transcriptase, HIV integrase inhibitor, gp41 inhibitor, CXCR4 inhibitor, gp120 inhibitor, CCR5 inhibitor, capsid polymerization inhibitor, other drug for treating HIV, interferon, ribavirin, ribavirin analog, NS3 protease inhibitor, alpha-glucosidase 1 inhibitor, hepatoprotectant, non-nucleoside inhibitor of HCV, NS5a inhibitor, NS5b polymerase inhibitor, other drug for treating HCV, or a mixture thereof. 
     
     
         6 . The method of  claim 1 , wherein the drug and the compound or salt thereof is administered as a single composition to the patient. 
     
     
         7 . A method for increasing blood plasma levels of a drug which is metabolized by cytochrome P450 monooxygenase, comprising administering to a patient treated with the drug a therapeutically effective amount of a compound of formula IID, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 L 1  is selected from the group consisting of —C(R 6 ) 2 —, —C(O)—, —S(O 2 )—, —N(R 2 )—C(O)—, and —O—C(O)—; 
 each L 3  is independently a covalent bond, alkylene, or substituted alkylene; 
 each L 4  is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, —O—, —CH 2 —O—, and —NH—; 
 each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl,
 with the proviso that when A is H, p is 0; 
 
 Z 1  and Z 2  are each independently —O— or —N(R 7 )—; 
 Y and X are each independently selected from the group consisting of heterocyclyl and heterocyclylalkyl; 
 each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 R 1 , R 3 , and R 5  are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl; 
 R 2  is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxyalkyl, hydroxyalkyl, arylheteroalkyl, substituted arylheteroalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -alkylene-C(O)—OH, -alkylene-C(O)—Oalkyl, -alkylene-C(O)amino, and -alkylene-C(O)-alkyl; 
 R 4  and R 6  are each independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl; 
 each R 7  is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; 
 R 8  and R 9  are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN; and 
 each p is independently 0 or 1. 
 
     
     
         8 . The method of  claim 7 , wherein:
 L 1  is —C(R 6 ) 2 —;   each L 3  is alkylene;   each A is aryl or substituted aryl;   X and Y are each heterocyclylalkyl;   Z 1  is —N(R 7 )—; and   Z 2  is —O—.   
     
     
         9 . The method of  claim 7 , wherein a therapeutically effective amount of a combination comprising the drug and the compound of Formula IID or the pharmaceutically acceptable salt of the compound of Formula IID is administered to the patient. 
     
     
         10 . A method for inhibiting cytochrome P450 monooxygenase in a patient, comprising administering to a patient in need thereof an amount a compound of formula IID, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, effective to inhibit cytochrome P450 monooxygenase, wherein,
 L 1  is selected from the group consisting of —C(R 6 ) 2 —, —C(O)—, —S(O 2 )—, —N(R 7 )—C(O)—, and —O—C(O)—; 
 each L 3  is independently a covalent bond, alkylene, or substituted alkylene; 
 each L 4  is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, —O—, —CH 2 —O—, and —NH—; 
 each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl,
 with the proviso that when A is H, p is 0; 
 
 Z 1  and Z 2  are each independently —O— or —N(R 7 )—; 
 Y and X are each independently selected from the group consisting of heterocyclyl and heterocyclylalkyl; 
 each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 R 1 , R 3 , and R 5  are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl; 
 R 2  is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxyalkyl, hydroxyalkyl, arylheteroalkyl, substituted arylheteroalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -alkylene-C(O)—OH, -alkylene-C(O)—Oalkyl, -alkylene-C(O)amino, and -alkylene-C(O)-alkyl; 
 R 4  and R 6  are each independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl; 
 each R 7  is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; 
 R 8  and R 9  are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN; and 
 each p is independently 0 or 1. 
 
     
     
         11 . The method of  claim 10 , wherein:
 L 1  is —C(R 6 ) 2 —;   each L 3  is alkylene;   each A is aryl or substituted aryl;   X and Y are each heterocyclylalkyl;   Z 1  is —N(R 7 )—; and   Z 2  is —O—.   
     
     
         12 . The method of  claim 10 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A method for treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula IID, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 L 1  is selected from the group consisting of —C(R 6 ) 2 —, —C(O)—, —S(O 2 )—, —N(R 7 )—C(O)—, and —O—C(O)—; 
 each L 3  is independently a covalent bond, alkylene, or substituted alkylene; 
 each L 4  is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, —O—, —CH 2 —O—, and —NH—; 
 each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl,
 with the proviso that when A is H, p is 0; 
 
 Z 1  and Z 2  are each independently —O— or —N(R 2 )—; 
 Y and X are each independently selected from the group consisting of heterocyclyl and heterocyclylalkyl; 
 each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 R 1 , R 3 , and R 5  are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl; 
 R 2  is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxyalkyl, hydroxyalkyl, arylheteroalkyl, substituted arylheteroalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -alkylene-C(O)—OH, -alkylene-C(O)—Oalkyl, -alkylene-C(O)amino, and -alkylene-C(O)-alkyl; 
 R 4  and R 6  are each independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl; 
 each R 7  is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; 
 R 8  and R 9  are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN; and 
 each p is independently 0 or 1, 
 
       in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, and mixtures thereof. 
     
     
         14 . The method of  claim 13 , wherein:
 L 1  is —C(R 6 ) 2 —;   each L 3  is alkylene;   each A is aryl or substituted aryl;   X and Y are each heterocyclylalkyl;   Z 1  is —N(R 7 )—; and   Z 2  is —O—.   
     
     
         15 . The method of  claim 13 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 13 , wherein:
 (1) the HIV protease inhibiting compounds are selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859;   (2) the HIV non-nucleoside inhibitors of reverse transcriptase are selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC-120, TMC-278 (rilpivirene), efavirenz, BILR 355 BS, VRX 840773, UK-453061, and RDEA806;   (3) the HIV nucleoside inhibitors of reverse transcriptase are selected from the group consisting of zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, racivir (±-FTC), D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, and fosalvudine tidoxil (formerly HDP 99.0003);   (4) the HIV nucleotide inhibitors of reverse transcriptase are selected from the group consisting of tenofovir and adefovir;   (5) the HIV integrase inhibitors are selected from the group consisting of curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, S-1360, zintevir (AR-177), L-870812, and L-870810, MK-0518 (raltegravir), BMS-538158, GSK364735C, BMS-707035, MK-2048, and BA 011;   (6) the gp41 inhibitor are selected from the group consisting of enfuvirtide, sifuvirtide, FB006M, and TRI-1144;   (7) the CXCR4 inhibitor is AMD-070;   (8) the entry inhibitor is SP01A;   (9) the gp120 inhibitor is BMS-488043 or BlockAide/CR;   (10) the G6PD and NADH-oxidase inhibitor is immunitin;   (11) the CCR5 inhibitors are selected from the group consisting of aplaviroc, vicriviroc, maraviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5mAb004;   (12) the other drugs for treating HIV are selected from the group consisting of BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), Ampligen, HRG214, Cytolin, VGX-410, KD-247, AMZ 0026, CYT 99007A-221 HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040).   
     
     
         17 . A method for treating an HCV infection comprising administering to a patient in need thereof a therapeutically effective amount a compound of formula IID, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 L 1  is selected from the group consisting of —C(R 6 ) 2 —, —C(O)—, —S(O 2 )—, —N(R 7 )—C(O)—, and —O—C(O)—; 
 each L 3  is independently a covalent bond, alkylene, or substituted alkylene; 
 each L 4  is independently selected from the group consisting of a covalent bond, alkylene, substituted alkylene, —O—, —CH 2 —O—, and —NH—; 
 each A is independently selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl,
 with the proviso that when A is H, p is 0; 
 
 Z 1  and Z 2  are each independently —O— or —N(R 7 )—; 
 Y and X are each independently selected from the group consisting of heterocyclyl and heterocyclylalkyl; 
 each Ar is independently selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 R 1 , R 3 , and R 5  are each independently selected from the group consisting of H, alkyl, substituted alkyl, arylalkyl, and substituted arylalkyl; 
 R 2  is independently selected from the group consisting of H, alkyl, substituted alkyl, alkoxyalkyl, hydroxyalkyl, arylheteroalkyl, substituted arylheteroalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aminoalkyl, substituted aminoalkyl, -alkylene-C(O)—OH, -alkylene-C(O)—Oalkyl, -alkylene-C(O)amino, and -alkylene-C(O)-alkyl; 
 R 4  and R 6  are each independently selected from the group consisting of H, alkyl, substituted alkyl, and heteroalkyl; 
 each R 7  is independently selected from the group consisting of H, alkyl, substituted alkyl, heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, and substituted heterocyclyl; 
 R 8  and R 9  are each one or more substituents independently selected from the group consisting of H, alkyl, substituted alkyl, halogen, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, and —CN; and 
 each p is independently 0 or 1, 
 
       in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of interferons, ribavirin, ribavirin analogs, NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, other drugs for treating HCV, and mixtures thereof. 
     
     
         18 . The method of  claim 17 , wherein:
 L 1  is —C(R 6 ) 2 —;   each L 3  is alkylene;   each A is aryl or substituted aryl;   X and Y are each heterocyclylalkyl;   Z 1  is —N(R 7 )—; and   Z 2  is —O—.   
     
     
         19 . The method of  claim 17 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
     
     
         20 . The method of  claim 17 , wherein:
 (1) the interferons are selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, rIFN-alpha 2a, consensus IFN alpha (infergen), feron, reaferon, intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega with DUROS, albuferon, locteron, Rebif, oral interferon alpha, IFNalpha-2b XL, AVI-005, PEG-Infergen, and Pegylated IFN-beta;   (2) the ribavirin analog is viramidine (taribavirin);   (3) the NS5b polymerase inhibitors are selected from the group consisting of NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554, and GSK625433;   (4) the NS3 protease inhibitor are selected from the group consisting of SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339, and ITMN-191;   (5) the alpha-glucosidase 1 inhibitors are selected from the group consisting of MX-3253 (celgosivir) and UT-231B;   (6) the hepatoprotectants are selected from the group consisting of IDN-6556, ME 3738, LB-84451, and MitoQ;   (7) the non-nucleoside inhibitors of HCV are selected from the group consisting of benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, phenylalanine derivatives, A-831, and A-689; and   (8) the other drugs for treating HCV are selected from the group consisting of zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, Oglufanide, and VX-497 (merimepodib).