US 2004O266668A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0266668A1 Nakajima et al. (43) Pub. Date: Dec. 30, 2004
(54) QUINOXALINYL MACROCYCLIC HEPATITIS C SERINE PROTEASE
(I) INHIBITORS (76) Inventors: Suanne Nakajima, Cambridge, MA (US); Miao Zhenwei, Medway, MA (US); Ying Sun, Waltham, MA (US); Datong Tang, Malden, MA (US); Guoyou Xu, Auburndale, MA (US); Brian Porter, Cambridge, MA (US); Yat Sun Or, Watertown, MA (US); Zhe Wang, Hockessin (DE) Correspondence Address: EDWARDS & ANGELL, LLP P.O. BOX 55874 (II) BOSTON, MA 02205 (US) (21) Appl. No.: 10/826,743 (22) Filed: Apr. 16, 2004 Related U.S. Application Data (60) Provisional application No. 60/509,071, filed on Apr. 18, 2003. Publication Classification (51) Int. Cl." ...... A61K 38/12; CO7K 5/12 (52) U.S. Cl...... 514/9; 530/317; 544/405 which inhibit Serine protease activity, particularly the activ ity of hepatitis C virus (HCV) NS3-NS4A protease. Conse quently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful (57) ABSTRACT as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforemen tioned compounds for administration to a Subject Suffering from HCV infection. The invention also relates to methods The present invention relates to compounds of Formula I or of treating an HCV infection in a Subject by administering II, or a pharmaceutically acceptable Salt, ester, or prodrug, a pharmaceutical composition comprising the compounds of thereof: the present invention. US 2004/0266668A1 Dec. 30, 2004
QUINOXALINYL MACROCYCLIC HEPATITIS C replication. Despite the huge number of Viral variants asso SERINE PROTEASE INHIBITORS ciated with HCV infection, the active site of the NS3 protease remains highly conserved thus making its inhibition CROSS-REFERENCE TO RELATED an attractive mode of intervention. Recent SucceSS in the APPLICATIONS treatment of HIV with protease inhibitors supports the concept that the inhibition of NS3 is a key target in the battle 0001. This applications claims benefit of U.S. provisional against HCV. application (conversion of U.S. Ser. No. 10/418, 759) filed Apr. 18, 2003, the entire contents of which is 0007 HCV is a flaviridae type RNA virus. The HCV herein incorporated by reference. genome is enveloped and contains a single Strand RNA molecule composed of circa 9600 base pairs. It encodes a TECHNICAL FIELD polypeptide comprised of approximately 3010 amino acids. 0002 The present invention relates to novel macrocycles 0008. The HCV polyprotein is processed by viral and having activity against the hepatitis C virus (HCV) and host peptidase into 10 discreet peptides which Serve a useful in the treatment of HCV infections. More particularly, variety of functions. There are three Structural proteins, C, the invention relates to macrocyclic compounds, composi E1 and E2. The P7 protein is of unknown function and is tions containing Such compounds and methods for using the comprised of a highly variable Sequence. There are Six Same, as well as processes for making Such compounds. non-structural proteins. NS2 is a zinc-dependent metallo proteinase that functions in conjunction with a portion of the BACKGROUND OF THE INVENTION NS3 protein. NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at 0.003 HCV is the principal cause of non-A, non-B hepa the N-terminal end, which requires NS4A as a cofactor, and titis and is an increasingly Severe public health problem both an ATP-ase-dependent helicase function at the carboxyl in the developed and developing World. It is estimated that terminus. NS4A is a tightly associated but non-covalent the virus infects over 200 million people worldwide, Sur cofactor of the Serine protease. passing the number of individuals infected with the human immunodeficiency virus (HIV) by nearly five fold. HCV 0009. The NS3.4A protease is responsible for cleaving infected patients, due to the high percentage of individuals four sites on the viral polyprotein. The NS3-NS4A cleavage inflicted with chronic infections, are at an elevated risk of is autocatalytic, occurring in cis. The remaining three developing cirrhosis of the liver, Subsequent hepatocellular hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B all occur in trans. NS3 is a Serine protease which is struc carcinoma and terminal liver disease. HCV is the most turally classified as a chymotrypsin-like protease. While the prevalent cause of hepatocellular cancer and cause of NS Serine protease possesses proteolytic activity by itself, patients requiring liver transplantations in the western the HCV protease enzyme is not an efficient enzyme in terms world. of catalyzing polyprotein cleavage. It has been shown that a 0004. There are considerable barriers to the development central hydrophobic region of the NS4A protein is required of anti-HCV therapeutics, which include, but are not limited for this enhancement. The complex formation of the NS3 to, the persistence of the virus, the genetic diversity of the protein with NS4A Seems necessary to the processing Virus during replication in the host, the high incident rate of events, enhancing the proteolytic efficacy at all of the Sites. the Virus developing drug-resistant mutants, and the lack of reproducible infectious culture Systems and Small-animal 0010) A general strategy for the development of antiviral models for HCV replication and pathogenesis. In a majority agents is to inactivate virally encoded enzymes, including of cases, given the mild course of the infection and the NS3, that are essential for the replication of the virus. complex biology of the liver, careful consideration must be Current efforts directed toward the discovery of NS3 pro tease inhibitors were reviewed by S. Tan, A. Pause, Y. Shi, given to antiviral drugs, which are likely to have significant N. Sonenberg, Hepatitis C Therapeutics: Current Status and side effects. Emerging Strategies, Nature Rev. Drug Discov:, 1,867-881 0005. Only two approved therapies for HCV infection are (2002). Other patent disclosures describing the synthesis of currently available. The original treatment regimen gener HCV protease inhibitors are: WO 00/59929 (2000); WO ally involves a 3-12 month course of intravenous inter 99/07733 (1999); WO 00/09543 (2000), WO 99/50230 feron-C. (IFN-O.), while a new approved second-generation (1999); U.S. Pat. No. 5,861,297 (1999); and US2002/ treatment involves co-treatment with IFN-O. and the general 0037998 (2002). antiviral nucleoside mimics like ribavirin. Both of these treatments suffer from interferon related side effects as well SUMMARY OF THE INVENTION as low efficacy against HCV infections. There exists a need for the development of effective antiviral agents for treat 0011. The present invention relates to novel macrocyclic ment of HCV infection due to the poor tolerability and compounds and methods of treating a hepatitis C infection disappointing efficacy of existing therapies. in a Subject in need of Such therapy with Said macrocyclic compounds. The present invention further relates to phar 0006. In a patient population where the majority of maceutical compositions comprising the compounds of the individuals are chronically infected and asymptomatic and present invention, or pharmaceutically acceptable Salts, the prognoses are unknown, an effective drug would desir esters, or prodrugs thereof, in combination with a pharma ably possess Significantly fewer Side effects than the cur ceutically acceptable carrier or excipient. rently available treatments. The hepatitis C non-structural protein-3 (NS3) is a proteolytic enzyme required for pro 0012. In one embodiment of the present invention there cessing of the viral polyprotein and consequently viral are disclosed compounds represented by Formulas I and II, US 2004/0266668A1 Dec. 30, 2004 or pharmaceutically acceptable salts, esters, or prodrugs eroaryl, Substituted heteroaryl, heterocycloalkyl, thereof: substituted heterocycloalkyl, or -NH N=CH(R); (I) 0020 Each R is independently selected from Y. N W-Z hydrogen, C-C alkyl, Substituted C-C alkyl, n C-C alkenyl, Substituted C-C alkenyl, C-C, 2 alkynyl, Substituted C-C alkynyl, C-C2 X N Q cycloalkyl, Substituted C-C cycloalkyl, aryl, Sub stituted aryl, arylalkyl, substituted arylalkyl, het eroaryl, substituted heteroaryl, heteroarylalkyl, Sub O lm O OR stituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl, H N N-. G / 2-Rs ls 0021) Each R is independently selected from A a. O hydrogen, C-C alkyl, C-C alkyl, Substituted R6 C-C alkyl, C-C alkenyl, substituted C-C alk CH enyl, C-C alkynyl, Substituted C-C alkynyl, N- CH2N/ C-C2 cycloalkyl, substituted C-C2 cycloalkyl, H alkylamino, dialkylamino, arylamino, diarylamino, (II) aryl, substituted aryl, arylalkyl, Substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or Sub X N O stituted heterocycloalkyl; 0022. Each R is independently selected from:
0023 (i) -C-C alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally Substituted with one or more Substituent Selected from halogen, aryl, Substituted aryl, heteroaryl, or Substituted heteroaryl, 0024 (ii) -C-C alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent Selected from halogen, aryl, Substituted aryl, heteroaryl, or 0013) Wherein Substituted heteroaryl; 0014) A is independently selected from hydrogen; 0025 (iii)-C-C alkynyl containing 0, 1, 2, or 3 -(C=O)-O-R, -(C=O)-R, -C(=O)- heteroatoms selected from O, S, or N, optionally NH-R, -C(=S)-NH-R, or -S(O)-R; Substituted with one or more substituent Selected from halogen, aryl, Substituted aryl, heteroaryl, or 0015) G is independently selected from -OH, Substituted heteroaryl; 0026 Rs and R are each independently selected from hydrogen or methyl; 0016 L is independently selected from -S-, 0027 j=0, 1, 2, 3, or 4; -SCH-, -SCHCH-, -S(O)-, -S(O)CHCH-, -S(O)-, -S(O)CHCH-, 0028 m=0, 1, or 2; and -O-, -OCH-, -OCHCH-, -(C=O)- CH-, -CH(CH)CH-, -CFHCH-, or 0029) s=0, 1 or 2. -CFCH-; DETAILED DESCRIPTION OF THE 0017 X and Y taken together with the carbon atoms INVENTION to which they are attached form a cyclic moiety selected from aryl, Substituted aryl, heteroaryl, or 0030) A first embodiment of the invention is a compound substituted heteroaryl; represented by Formula I as described above, or a pharma ceutically acceptable salt, ester or prodrug thereof, alone or 0018 W is absent, or independently selected from in combination with a pharmaceutically acceptable carrier or -O-, -S-, -NH-, -C(O)NRI- or excipient. -NR-; 0031) A second embodiment of the invention is a com 0019 Z is independently selected from hydrogen, pound represented by Formula II as described above, or a -CN, -SCN, -NCO, -NCS, -NHNH, -N, pharmaceutically acceptable Salt, ester or prodrug thereof, halogen, -R, -C-C cycloalkyl, Substituted alone or in combination with a pharmaceutically acceptable -C-C, cycloalkyl, aryl, Substituted aryl, het carrier or excipient. US 2004/0266668A1 Dec. 30, 2004
0.032 Representative subgenera of the invention include, 0042 Compound of Formula I, wherein A=tBOC, but are not limited to: G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, 0033) A compound of Formula III: W is absent, Z=2-(formamido)-thiazol-4-yl, j=3, m=S=1, and Rs=Re=hydrogen; (III) 0043 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=ethyl, j=3, m=S=1, and Rs=R= hydrogen; 0044) Compound of Formula I, wherein A=tBOC, O lm O G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, H N W is absent, Z=phenyl, j=3, m=S=1, and Rs=R= N-. G hydrogen; / 2. Rs ls A. a O R6 0045 Compound of Formula I, wherein A=tBOC, CH G=OH, L=absent, X and Y taken together with the N- CH2-NN4 / carbon atoms to which they are attached are phenyl, H W is absent, Z=4-methoxyphenyl, j=3,m=S=1, and Rs=Re=hydrogen; 0046 Compound of Formula I, wherein A=tBOC, 0034) wherein R, and Rs are independently selected from G=OH, L=absent, X and Y taken together with the R; and carbon atoms to which they are attached are phenyl, 0035) A compound of Formula IV: W is absent, Z=4-ethoxyphenyl, ji=3, m=s=1, and Rs=Re=hydrogen; (IV) 0047 Compound of Formula I, wherein A=tBOC, R N W-Z G=OH, L=absent, X and Y taken together with the Nea n carbon atoms to which they are attached are phenyl, W is absent, Z=5-bromothiophen-2-yl, j=3,m=s=1, N 2 R8 N N O and R=R=hydrogen; 0048 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the O lm O carbon atoms to which they are attached are phenyl, W is absent, Z=2-pyrid-3-yl ethylenyl, j=3,m=s=1, H N N G and Rs=Re=hydrogen; / 2-Rs ls A. a. O 0049 Compound of Formula I, wherein A=tBOC, R6 G=OH, L=absent, X and Y taken together with the CH carbon atoms to which they are attached are phenyl, N- CH 2n/ W is absent, Z=3,4-Dimethoxy-phenyl, j=3,m=s=1, H and Rs=Re=hydrogen; 0050 Compound of Formula I, wherein A=tBOC, 0.036 wherein R, and Rs are independently selected from G=OH, L=absent, X and Y taken together with the R; carbon atoms to which they are attached are phenyl, W is absent, Z=2-thiophen-2-yl ethylenyl, j=3,m=s= 0037. A compound of Formula I, II, III, or IV 1, and Rs=Re=hydrogen; wherein W is absent and Z is thiophenyl; 0051) Compound of Formula I, wherein A=tBOC, 0038 A compound of Formula I, II, III or IV G=OH, L=absent, X and Y taken together with the wherein W is -CH=CH- and Z is thiophenyl; carbon atoms to which they are attached are phenyl, 0039. A compound of Formula I, III, or IV wherein Z=indole-2-yl, j=3, m=S=1, and R=R=hydrogen; L is absent, Rs and R are hydrogen, j=3,m=1, and 0.052 Compound of Formula I, wherein A=tBOC, S=1; G=OH, L=absent, X and Y taken together with the 0040 Representative compounds of the invention carbon atoms to which they are attached are phenyl, include, but are not limited to, the following com W is absent, Z=1H-indol-3-yl methyl, ji=3, m=s=1, pounds: and Rs=Re=hydrogen; 0041 Compound of Formula I, wherein A=tBOC, 0053 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, carbon atoms to which they are attached are phenyl, W is absent, Z=thiophen-2-yl, j=3, m =s=1, and W is absent, Z=furan-2-yl, j=3,m=S=1, and Rs=R= Rs=Re=hydrogen; hydrogen; US 2004/0266668A1 Dec. 30, 2004
0054 Compound of Formula I, wherein A=tBOC, carbon atoms to which they are attached are phenyl, G=OH, L=absent, X and Y taken together with the W=-O-, Z=thiophen-3-yl-methyl, j=3, m=s=1, carbon atoms to which they are attached are phenyl, and Rs=Re=hydrogen; W is absent, Z=1H-benzoimidazol-2-yl, j=3,m=S=1, and Rs=Re=hydrogen; 0.066 Compound of Formula I, wherein A=tBOC, 0055 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are carbon atoms to which they are attached are phenyl, W is absent, Z=1H-imidazol-2-ylmethyl, j=3, m=s= 1, and Rs=Re=hydrogen; 0056 Compound of Formula I, wherein A=tBOC, G=OEt, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=chloro, j=3, m=S=1, and Rs=R= hydrogen; 0057 Compound of Formula I, wherein A=tBOC, 0067 W is absent, Z=thiophen-2-yl, j=3, m=S=1, and G=OH, L=absent, X and Y taken together with the R=R=hydrogen; carbon atoms to which they are attached are phenyl, Z=thiophen-3-yl, j=3, m=s=1, and Rs=R=hydro 0068 Compound of Formula I, wherein A=tBOC, gen, G=OH, L=absent, X and Y taken together with the 0.058 Compound of Formula I, wherein A=tBOC, carbon atoms to which they are attached are G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=2-pyrid-3-yl acetylenyl, j=3,m=S=1, and Rs=Re=hydrogen; 0059 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=2,3-dihydrobenzofuran-5-yl, j=3, m=S=1, and Rs=Re=hydrogen; 0069 W is absent, Z=thiophen-2-yl, j=3, m=S=1, and 0060 Compound of Formula I, wherein A=tBOC, R=R=hydrogen; G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, 0070 Compound of Formula I, wherein A=tBOC, W=-NH-, Z=propargyl, j=3, m=S=1, and G=OH, L=absent, X and Y taken together with the Rs=Re=hydrogen; carbon atoms to which they are attached are 0061 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W=-N(ethyl)-, Z=benzyl, j=3, m=s=1, and -O Rs=Re=hydrogen; No 0062) Compound of Formula I, wherein A=tBOC, DC G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W=-NH-, Z=pyrid-3-yl, j=3, m=s=1, and 0071 W is absent, Z=thiophen-2-yl, j=3, m=S=1, and Rs=Re=hydrogen; Rs=Re=hydrogen; 0063 Compound of Formula I, wherein A=tBOC, 0072) Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=tetrazolyl, j=3,m=s=1, and Rs=R= carbon atoms to which they are attached are hydrogen; 0064 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=morpholino, j=3, m=s=1, and R=R=hydrogen; 0065 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the US 2004/0266668A1 Dec. 30, 2004
0.073 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and 0081 W is absent, Z=thiophen-2-yl, j=3, m=S=1, and R=R=hydrogen; R=R=hydrogen; 0074 Compound of Formula I, wherein A=tBOC, 0082 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are carbon atoms to which they are attached are
1.W
0083 W is absent, Z=thiophen-2-yl, j=3, m=S=1, and 0075 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and Rs=Re=hydrogen; Rs=Re=hydrogen; 0084 Compound of Formula I, wherein A=tBOC, 0.076 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are carbon atoms to which they are attached are
21 HO1\/ N
0.077 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and 0085 W is absent, Z=thiophen-2-yl, j=3, m=S=1, and R=R=hydrogen; Rs=Re=hydrogen; 0078 Compound of Formula I, wherein A=tBOC, 0086) Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are carbon atoms to which they are attached are CC HO 0079 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and 0087 W is absent, Z=thiophen-2-yl, j=3, m=S=1, and R=R=hydrogen; R=R=hydrogen; 0080 Compound of Formula I, wherein A=tBOC, 0088 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are carbon atoms to which they are attached are CC US 2004/0266668A1 Dec. 30, 2004
0089 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and Rs=Re=hydrogen; 0090 Compound of Formula I, wherein A=tBOC, HO G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are
0099 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and Rs=Re=hydrogen; 0100 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are 0.091 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and Rs=Re=hydrogen; 0092 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are
HN
0101 W is absent, Z=thiophen-2-yl, j=3, m=S=1, and Rs=Re=hydrogen; 0102) Compound of Formula I, wherein A=tBOC, 0.093 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and G=OH, L=absent, X and Y taken together with the Rs=Re=hydrogen; carbon atoms to which they are attached are 0094) Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are
0.103 W is absent, Z=thiophen-2-yl, j=3, m=S=1, and 0.095 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and Rs=Re=hydrogen; Rs=Re=hydrogen; 0104 Compound of Formula I, wherein A=tBOC, 0096 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are carbon atoms to which they are attached are O
0097 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and 0105 W is absent, Z=thiophen-2-yl, j=3, m=S=1, and R=R=hydrogen; R=R=hydrogen; 0.098 Compound of Formula I, wherein A=tBOC, 0106 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are carbon atoms to which they are attached are US 2004/0266668A1 Dec. 30, 2004 O
0107 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and 0115 W is absent, Z=thiophen-2-yl, j=3, m=S=1, and Rs=Re=hydrogen; Rs=Re=hydrogen; 0108) Compound of Formula I, wherein A=tBOC, 0116 Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are carbon atoms to which they are attached are C
0109 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and Rs=Re=hydrogen; 0117 W is absent, R=R=hydrogen; 0110 Compound of Formula I, wherein A=tBOC, 0118 Compound of Formula I, wherein A=tBOC, G=OEt, L=absent, X and Y taken together with the G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are carbon atoms to which they are attached are
Br
0111) W is absent, Z=thiophen-2-yl, j=3, m=S=1, and Rs=Re=hydrogen; 0119 W is absent, 0112) Compound of Formula I, wherein A=tBOC, Rs=Re=hydrogen; G=OH, L=absent, X and Y taken together with the 0120) Compound of Formula I, wherein carbon atoms to which they are attached are A=-(C=O)-O-R', wherein R'=cyclopentyl, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=thiophen-2-yl, j=3, m=S=1, and ( R=R=hydrogen; N 0121 Compound of Formula I, wherein A=-(C=O)-O-R', wherein R'=cyclobutyl, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=thiophen-2-yl, j=3, m=S=1, and R=R=hydrogen; 0113 W is absent, Z=thiophen-2-yl, j=3, m=s=1, and 0122) Compound of Formula I, wherein Rs=Re=hydrogen; A=-(C=O)-O-R', wherein R'=cyclohexyl, G=OH, L=absent, X and Y taken together with the 0114 Compound of Formula I, wherein A=tBOC, carbon atoms to which they are attached are phenyl, G=OH, L=absent, X and Y taken together with the W is absent, Z=thiophen-2-yl, j=3, m=S=1, and carbon atoms to which they are attached are R=R=hydrogen;
US 2004/0266668A1 Dec. 30, 2004
together with the carbon atoms to which they are 0150. Additional compounds of the invention are those of attached are phenyl, W is absent, Z=thiophen-2-yl, Formula V: ji=3, m=S=1, and Rs=Re=hydrogen; 0.142 Compound of Formula I, wherein A=tBOC, (V) G=OH, L=-O-, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=thiophen-2-yl, j=3,m=s=1, R=me thyl, and Re=hydrogen; 0143 Compound of Formula I, wherein A=tBOC, G=OH, L=-S-, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=thiophen-2-yl, j=3,m=s=1, R=me thyl, and R=hydrogen; 0151 , wherein A and B are as defined in the A-Matrix 0144) Compound of Formula I, wherein A=tBOC, and B-Matrix tables herein. The A-Matrix and B-Matrix G=OH, L=-S(O), X and Y taken together with tables below Set forth Substituents present on the core ring structure shown in formula (V) which when one A substitu the carbon atoms to which they are attached are ent is selected from the A-Matrix and one B Substituent is phenyl, W is absent, Z=thiophen-2-yl, j=3, m=S=1, selected from the B-Matrix an additional compound of the Rs=methyl, and R=hydrogen; invention is described. Compounds are formed by Selecting any element from the A-Matrix with any element from the 0145 Compound of Formula I, wherein A=tBOC, B-matrix to arrive upon an A, B-Substituted macrocycle of G=OH, L=-S(O), X and Y taken together with the formula V. For example,a compound of Formula V, wherein carbon atoms to which they are attached are phenyl, A is element 101 from the A-Matrix and B is element 301 W is absent, Z=thiophen-2-yl, j=3,m=s=1, R=me from the B-Matrix, is designated by the number 101301. thyl, and Re=hydrogen; 0152 Thus, the invention includes compounds of the formula V and the pharmaceutically acceptable Salts thereof, 0146 Compound of Formula I, wherein A=tBOC, wherein A is any element in the A-Matrix and B is any G=OH, L=-SCHCH-, X and Y taken together element of the B-Matrix. with the carbon atoms to which they are attached are 0153 Specific compounds include, but are not limited to, phenyl, W is absent, Z=thiophen-2-yl, j=3, m=S=1, the following: 101301; 101358; 101306; 101302; 101322; Rs=methyl, and Re=hydrogen; 101311; 101325; 101.303; 103304; 101326; 101327; 101330; 101.331; 101.332; 101335; 101336; 101348; 0147 Compound of Formula I, wherein A=tBOC, 101340; 101334; 101348; 101359; 101328; 101360; G=OH, L=CFCH, X and Y taken together with the 101361; 101362; 101329; 105301; 123301; 112301; carbon atoms to which they are attached are phenyl, 124301; 109301; 122301; 111301; 114301; 107301; W is absent, Z=thiophen-2-yl, j=3, m=s=1, and 104301; 101324; 101304; 101355; 101356; 101307; Rs=Re=hydrogen; 101357; 101347; 101352; 110301; 101364; 101308; 101309; 128301; 124301; 113301; 143301; 115301; 0148 Compound of Formula I, wherein A=tBOC, 101367; 101368; 101323; 101317; 108301; 101318; G=OH, L=-CHFCH-, X and Y taken together 101.319; 101351; 101353; 101349; 118301; 120301; with the carbon atoms to which they are attached are 101.333; 101320, 101321; 129301; 121301; 117301; phenyl, W is absent, Z=thiophen-2-yl, j=3, m=S=1, 123352; 101347; 101350; 107365; 101313; 145301; and R=R=hydrogen; and 101366; 101354; 101343; 101314; 10.1339; 101341; 107341; 114341; 106301; 144301; 126301; 127301; 0149 Compound of Formula II, wherein A=tBOC, 130301; 116301; 102301; 140301; 141301; 139301; G=OH, L=absent, X and Y taken together with the 138301; 142301; 137301; 135301; 134301; 133301; carbon atoms to which they are attached are phenyl, 131301; 132301; 136301; 101345; 101344; 101342; W is absent, Z=thiophen-2-yl, j=3, m=s=1, and 105316; 107316; 101315; 101346; 10.1337; 116365; and Rs=Re=hydrogen. 101.338.
A-Matrix > - x Ox x Clux US 2004/0266668A1 Dec. 30, 2004 10
-continued
A-Matrix
101 102 103 104 Clu Ol O Clu t O O 5, N ls N 3. N s', NH s',H H H H H H 105 106 107 1. O8
AuxH Olux Clux N O s',H 2 109 110 111 112
O O S O O N-N, -N-NY, \ * /N-s’, S H N N 21 e S 113 114 115 116
O O O N
121 122 123 124
O O O O ls ls ls N N H 5, N 3. N-1- H H 5, H OH 125 126 127 128 ~%O N-kO N-X-XO O 129 130 131 132
O O O V/
H H H H S us-X-X rxsu cxN -) exle 133 134 135 136 US 2004/0266668A1 Dec. 30, 2004 11
-continued
A-Matrix
O O O S-N'- S-N'- S-N’s S-N- HN H HN H O H H N2 le le N NH
137 138 139
cx N-N-six 21 x > x
141 142 143 144
145
0154)
B-Matrix $1 N $1 N 1 N MeO N S. MeO N S.
2 2 2 CN O or N O MeODOC N O
301 3O2 303 $1 N ?y, \ ( N1's OC N ) O 4N 4N O n N
304 305 306 US 2004/0266668A1 Dec. 30, 2004 12
-continued
B-Matrix
313 315
n N 2 -- 316
N1 N. N
2 N O
319 US 2004/0266668A1 Dec. 30, 2004 13
-continued
B-Matrix
N N
N 2 4. O N N O
orho N 2 O orho
322 323 324 N N su CO CC OCCorho 325 326 327 N. N, N.
2 2 2 CON O CrN O CrN O
328 329 OCC CCC CCorho orho orho 331 332 CrO COr CCC orho oth orho 336
N -- N -- orho
337 338 339 US 2004/0266668A1 Dec. 30, 2004 14
-continued
B-Matrix
N O O N n S els, NN/O) OC NN1 O OC N N S. orho N 2 O N2 O
340 341 342
N -
N O O)S. O J)-S. O N \
OC n4. O N C.4. O N 4. O s S.
343 344 345 l-O - - C’s4. O Cr.4. O Cr4. O
346 347 348 S N N y
n1s1s2 OC N1SN OC N N O 4. O 4. O
349 350 351
21 N N 1S-N O NS 2 N N N1\s N oh-O C O CC 2 O
352 353 354 US 2004/0266668A1 Dec. 30, 2004 15
-continued
B-Matrix
355 356
359
H
-- 362
N-1S S. --
365 366
n 2 --R 368 US 2004/0266668A1 Dec. 30, 2004
O155 According to an alternate embodiment, the phar OCONH-heteroaryl, NHC(O)H, NHC(O)-C-C-alkyl, maceutical compositions of the present invention may fur NHC(O)-aryl, NHC(O)-heteroaryl, NHCO-alkyl, NHCO ther contain other anti-HCV agents. Examples of anti-HCV aryl, NHCO-heteroaryl, NHCONH2, NHCONH-C-C- agents include, but are not limited to, C-interferon, B-inter alkyl, NHCONH-aryl, NHCONH-heteroaryl, SO-C-C- feron, ribavirin, and amantadine. For further details see S. alkyl, SO-aryl, SO-heteroaryl, SONH, SONH-C-C- Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeu alkyl, SONH-aryl, SONH-heteroaryl, C-C-alkyl, tics: Current Status and Emerging Strategies, Nature Rev. C-C-cycloalkyl, CF, CHCF, CHCl, CH-NH2, Drug Discov., 1,867-881 (2002); WO 00/59929 (2000); WO CHSOCH, C-C alkyl, halo alkyl, C-C cycloalkyl, 99/07733 (1999); WO 00/09543 (2000), WO 99/50230 Substituted C-C cycloalkyl, aryl, Substituted aryl, aryla (1999); U.S. Pat. No. 5861297 (1999); and US2002/ lkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, 0037998 (2002) which are herein incorporated by reference benzyloxy, aryloxy, heteroaryloxy, C-C-alkoxy, meth in their entirety. oxymethoxy, methoxyethoxy, amino, benzylamino, ary lamino, heteroarylamino, C-C-alkylamino, di-C-C-alky 0156 According to an additional embodiment, the phar lamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C-C- maceutical compositions of the present invention may fur alkyl-thio, or methylthiomethyl. ther contain other HCV protease inhibitors. O157 According to yet another embodiment, the phar 0165 The terms "C-C alkenyl' or “C-C alkenyl,” as maceutical compositions of the present invention may fur used herein, denote a monovalent group derived from a ther comprise inhibitor(s) of other targets in the HCV life hydrocarbon moiety containing from two to twelve or two to cycle, including, but not limited to, helicase, polymerase, Six carbon atoms having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl metalloprotease, and internal ribosome entry site (IRES). groups include, but are not limited to, for example, ethenyl, 0158 According to a further embodiment, the present propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. invention includes methods of treating hepatitis C infections in a Subject in need of Such treatment by administering to 0166 The term “substituted alkenyl,” as used herein, said subject an anti-HCV virally effective amount or an refers to a "C-C alkenyl' or "C-C alkenyl group inhibitory amount of the pharmaceutical compositions of the Substituted by independent replacement of one, two or three present invention. of the hydrogen atoms thereon with F, Cl, Br, I, OH, NO, CN, C-C-alkyl-OH, C(O)-C-C-alkyl, OCH-C-C- 0159. An additional embodiment of the present invention cycloalkyl, C(O)H, C(O)-aryl, C(O)-heteroaryl, CO-alkyl, includes methods of treating biological Samples by contact CO-aryl, CO-heteroaryl, CONH2, CONH-C-C-alkyl, ing the biological Samples with the compounds of the CONH-aryl, CONH-heteroaryl, OC(O)-C-C-alkyl, present invention. OC(O)-aryl, OC(O)-heteroaryl, OCO-alkyl, OCO-aryl, 0160 Yet a further aspect of the present invention is a OCO-heteroaryl, OCONH, OCONH-C-C-alkyl, process of making any of the compounds delineated herein OCONH-aryl, OCONH-heteroaryl, NHC(O)H, NHC(O)– employing any of the Synthetic means delineated herein. C-C-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO alkyl, NHCO-aryl, NHCO-heteroaryl, NHCONH2, 0161) Definitions NHCONH-C-C-alkyl, NHCONH-aryl, NHCONH-het 0162 Listed below are definitions of various terms used eroaryl, SO-C-C-alkyl, SO-aryl, SO-heteroaryl, to describe this invention. These definitions apply to the SONH, SONH-C-C-alkyl, SONH-aryl, SONH-het terms as they are used throughout this specification and eroaryl, C-C-alkyl, C-C-cycloalkyl, CF, CHCF, claims, unless otherwise limited in Specific instances, either CHCl, CH-NH, CHSOCH, C-C alkyl, halo alkyl, individually or as part of a larger group. C-C2 cycloalkyl, Substituted C-C2 cycloalkyl, aryl, Sub Stituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero 0163 The terms “C-C alkyl,”“C-C alkyl” or “C-C, cycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, alkyl, as used herein, refer to Saturated, Straight- or C-C-alkoxy, methoxymethoxy, methoxyethoxy, amino, branched-chain hydrocarbon radicals containing between benzylamino, arylamino, heteroarylamino, C-C-alky one and three, one and twelve, or one and Six carbon atoms, lamino, di-C-C-alkylamino, thio, aryl-thio, heteroarylthio, respectively. Examples of C-C alkyl radicals include benzyl-thio, C-C-alkyl-thio, or methylthiomethyl. methyl, ethyl, propyl and isopropyl radicals; examples of C-C alkyl radicals include, but are not limited to, methyl, 0.167 The terms “C-C alkynyl' or “C-C alkynyl,” as ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and used herein, denote a monovalent group derived from a n-hexyl radicals, and examples of C-C alkyl radicals hydrocarbon moiety containing from two to twelve or two to include, but are not limited to, ethyl, propyl, isopropyl, Six carbon atoms having at least one carbon-carbon triple n-hexyl, octyl, decyl, dodecyl radicals. bond by the removal of a Single hydrogen atom. Represen tative alkynyl groups include, but are not limited to, for 0164. The term “substituted alkyl,” as used herein, refers example, ethynyl, 1-propynyl, 1-butynyl, and the like. to a “C-C alkyl or “C-C alkyl group Substituted by independent replacement of one, two or three of the hydro 0.168. The term “substituted alkynyl,” as used herein, gen atoms thereon with F, Cl, Br, I, OH, NO, CN, C-C- refers to a "C-C alkynyl' or "C-C alkynyl group alkyl-OH, C(O)-C-C-alkyl, C(O)H, OCH-C-C-cy Substituted by independent replacement of one, two or three cloalkyl, C(O)-aryl, C(O)-heteroaryl, CO-alkyl, CO-aryl, of the hydrogen atoms thereon with F, Cl, Br, I, OH, NO, CO-heteroaryl, CONH, CONH-C-C-alkyl, CONH CN, C-C-alkyl-OH, C(O)-C-C-alkyl, OCH-C-C- aryl, CONH-heteroaryl, OC(O)-C-C-alkyl, OC(O)-aryl, cycloalkyl, C(O)H, C(O)-aryl, C(O)-heteroaryl, CO-alkyl, OC(O)-heteroaryl, OCO-alkyl, OCO-aryl, OCO-het CO-aryl, CO-heteroaryl, CONH2, CONH-C-C-alkyl, eroaryl, OCONH, OCONH-C-C-alkyl, OCONH-aryl, CONH-aryl, CONH-heteroaryl, OC(O)-C-C-alkyl, US 2004/0266668A1 Dec. 30, 2004
OC(O)-aryl, OC(O)-heteroaryl, OCO-alkyl, OCO-aryl, tuted by independent replacement of one, two or three of the OCO-heteroaryl, OCONH, OCONH-C-C-alkyl, hydrogen atoms thereon with F, Cl, Br, I, OH, NO, CN, OCONH-aryl, OCONH-heteroaryl, NHC(O)H, NHC(O)– C-C-alkyl-OH, C(O)-C-C-alkyl, OCH-C-C-cy C-C-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO cloalkyl, C(O)H, C(O)-aryl, C(O)-heteroaryl, CO-alkyl, alkyl, NHCO-aryl, NHCO-heteroaryl, NHCONH2, CO-aryl, CO-heteroaryl, CONH2, CONH-C-C-alkyl, NHCONH-C-C-alkyl, NHCONH-aryl, NHCONH-het CONH-aryl, CONH-heteroaryl, NHC(O)H, OC(O)-C- eroaryl, SO-C-C-alkyl, SO-aryl, SO-heteroaryl, Co-alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO-alkyl, SONH, SONH-C-C-alkyl, SONH-aryl, SONH-het OCO-aryl, OCO-heteroaryl, OCONH, OCONH-C-C- eroaryl, C-C-alkyl, C-C-cycloalkyl, CF, CHCF, alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)-C- CHCl, CH-NH, CHSOCH, C-C alkyl, halo alkyl, C-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO-alkyl, C-C2 cycloalkyl, Substituted C-C2 cycloalkyl, aryl, Sub NHCO-aryl, NHCO-heteroaryl, NHCONH, Stituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero NHCONH-C-C-alkyl, NHCONH-aryl, NHCONH-het cycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, eroaryl, SO-C-C-alkyl, SO-aryl, SO-heteroaryl, C-C-alkoxy, methoxymethoxy, methoxyethoxy, amino, SONH, SONH-C-C-alkyl, SONH-aryl, SONH-het benzylamino, arylamino, heteroarylamino, C-C-alky eroaryl, C-C-alkyl, C-C-cycloalkyl, CF, CHCF, lamino, di-C-C-alkylamino, thio, aryl-thio, heteroarylthio, CHCl, CH-NH, CHSOCH, C-C alkyl, halo alkyl, benzyl-thio, C-C-alkyl-thio, or methylthiomethyl. C-C2 cycloalkyl, Substituted C-C2 cycloalkyl, aryl, Sub Stituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero 0169. The term “C-C alkoxy,” as used herein, refers to cycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, a C-C alkyl group, as previously defined, attached to the C-C-alkoxy, methoxymethoxy, methoxyethoxy, amino, parent molecular moiety through an oxygen atom. Examples benzylamino, arylamino, heteroarylamino, C-C-alky of C-C-alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopen lamino, di-C-C-alkylamino, thio, aryl-thio, heteroarylthio, toxy and n-heXOXy. benzyl-thio, C-C-alkyl-thio, or methylthiomethyl. 0.175. The term "heteroaryl,” as used herein, refers to a 0170 The terms “halo' and “halogen,” as used herein, mono-, bi-, or tri-cyclic aromatic radical or ring having from refer to an atom Selected from fluorine, chlorine, bromine five to ten ring atoms of which one ring atom is Selected and iodine. from S, O and N, Zero, one or two ring atoms are additional 0171 The term “aryl,” as used herein, refers to a mono heteroatoms independently selected from S, O and N; and or bicyclic carbocyclic ring System having one or two the remaining ring atoms are carbon. Heteroaryl includes, aromatic rings including, but not limited to, phenyl, naph but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, thyl, tetrahydronaphthyl, indanyl, idenyl and the like. pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isOOX azolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quino 0172 The term “substituted aryl,” as used herein, refers linyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, qui to an aryl group, as defined herein, Substituted by indepen noxalinyl, and the like. dent replacement of one, two or three of the hydrogen atoms thereon with F, Cl, Br, I, OH, NO, CN, C-C-alkyl-OH, 0176) The term “substituted heteroaryl,” as used herein, C(O)-C-C-alkyl, OCH-C-C-cycloalkyl, C(O)H, refers to a heteroaryl group as defined herein, Substituted by C(O)-aryl, C(O)-heteroaryl, CO-alkyl, CO-aryl, CO-het independent replacement of one, two or three of the hydro eroaryl, CONH, CONH-C-C-alkyl, CONH-aryl, gen atoms thereon with F, Cl, Br, I, OH, NO, CN, C-C- CONH-heteroaryl, OC(O)-C-C-alkyl, OC(O)-aryl, alkyl-OH, C(O)-C-C-alkyl, OCH-C-C-cycloalkyl, OC(O)-heteroaryl, OCO-alkyl, OCO-aryl, OCO-het C(O)H, C(O)-aryl, C(O)-heteroaryl, CO-alkyl, CO-aryl, eroaryl, OCONH, OCONH-C-C-alkyl, OCONH-aryl, CO-heteroaryl, CONH, CONH-C-C-alkyl, CONH OCONH-heteroaryl, NHC(O)H, NHC(O)-C-C-alkyl, aryl, CONH-heteroaryl, OC(O)-C-C-alkyl, OC(O)-aryl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO-alkyl, NHCO OC(O)-heteroaryl, OCO-alkyl, OCO-aryl, OCO-het aryl, NHCO-heteroaryl, NHCONH2, NHCONH-C-C- eroaryl, OCONH, OCONH-C-C-alkyl, OCONH-aryl, alkyl, NHCONH-aryl, NHCONH-heteroaryl, SO-C-C- OCONH-heteroaryl, NHC(O)H, NHC(O)-C-C-alkyl, alkyl, SO-aryl, SO-heteroaryl, SONH, SONH-C-C, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO-alkyl, NHCO alkyl, SONH-aryl, SNH-heteroaryl, C-C-alkyl, C-C- aryl, NHCO-heteroaryl, NHCONH2, NHCONH-C-C- cycloalkyl, CF, CHCF, CHCl, CH-NH, CHSOCH, alkyl, NHCONH-aryl, NHCONH-heteroaryl, SO-C-C- C-C alkyl, halo alkyl, C-C cycloalkyl, Substituted alkyl, SO-aryl, SO-heteroaryl, SONH, SONH-C-C- C-C2 cycloalkyl, aryl, Substituted aryl, arylalkyl, het alkyl, SONH-aryl, SONH-heteroaryl, C-C-alkyl, C.-- eroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzy cycloalkyl, CF, CHCF, CHCl, CH-NH, CHSOCH, loxy, aryloxy, heteroaryloxy, C-C-alkoxy, meth C-C alkyl, halo alkyl, Ca-Cia cycloalkyl, Substituted oxymethoxy, methoxyethoxy, amino, benzylamino, C-C2 cycloalkyl, aryl, Substituted aryl, arylalkyl, het arylamino, heteroarylamino, C-C-alkylamino, di-C-C- eroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzy alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, loxy, aryloxy, heteroaryloxy, C-C-alkoxy, meth C-C-alkyl-thio, or methylthiomethyl. oxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C-C-alkylamino, di-C-C- 0173 The term “arylalkyl,” as used herein, refers to a alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C-C alkyl or C-C alkyl residue attached to an aryl ring. C-C-alkyl-thio, or methylthiomethyl. Examples include, but are not limited to, benzyl, phenethyl 0177. The term "C-C-cycloalkyl” denotes a monova and the like. lent group derived from a monocyclic or bicyclic Saturated 0.174. The term “substituted arylalkyl,” as used herein, carbocyclic ring compound by the removal of a Single refers to an arylalkyl group, as previously defined, Substi hydrogen atom. Examples include, but not limited to, cyclo US 2004/0266668A1 Dec. 30, 2004 propyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo 2.2.1 C-C-alkoxy, methoxymethoxy, methoxyethoxy, amino, heptyl, and bicyclo 2.2.2]octyl. benzylamino, arylamino, heteroarylamino, C-C-alky 0.178 The term “substituted C-C-cycloalkyl,” as used lamino, di-C-C-alkylamino, thio, aryl-thio, heteroarylthio, herein, refers to a C-C-cycloalkyl group as defined benzyl-thio, C-C-alkyl-thio, or methylthiomethyl. herein, Substituted by independent replacement of one, two 0181. The term "heteroarylalkyl,” as used herein, refers or three of the hydrogen atoms thereon with F, Cl, Br, I, OH, to a C-C alkyl or C-C alkyl residue residue attached to NO, CN, C-C-alkyl-OH, C(O)-C-C-alkyl, OCH a heteroaryl ring. Examples include, but are not limited to, C-C-cycloalkyl, C(O)H, C(O)-aryl, C(O)-heteroaryl, pyridinylmethyl, pyrimidinylethyl and the like. CO-alkyl, CO-aryl, CO-heteroaryl, CONH2, CONH C-C-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)-C- 0182. The term “substituted heteroarylalkyl,” as used Co-alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO-alkyl, herein, refers to a heteroarylalkyl group, as previously OCO-aryl, OCO-heteroaryl, OCONH, OCONH-C-C- defined, Substituted by independent replacement or one, two, alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)H, or three of the hydrogen atoms thereon with F, Cl, Br, I, OH, NHC(O)-C-C-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NO, CN, C-C-alkyl-OH, C(O)-C-C-alkyl, OCH NHCO-alkyl, NHCO-aryl, NHCO-heteroaryl, C-C-cycloalkyl, C(O)H, C(O)-aryl, C(O)-heteroaryl, NHCONH, NHCONH-C-C-alkyl, NHCONH-aryl, CO-alkyl, CO-aryl, CO-heteroaryl, CONH, CONH NHCONH-heteroaryl, SO-C-C-alkyl, SO-aryl, SO C-C-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)-C- heteroaryl, SONH, SONH-C-C-alkyl, SONH-aryl, C-alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO-alkyl, SONH-heteroaryl, C-C-alkyl, C-C2-cycloalkyl, CF, OCO-aryl, OCO-heteroaryl, OCONH, OCONH-C-C- CHCF, CHCl, CH-NH, CHSOCH, C-C alkyl, halo alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)H, alkyl, C-C cycloalkyl, Substituted C-C cycloalkyl, aryl, NHC(O)-C-C-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, Substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, het NHCO-alkyl, NHCO-aryl, NHCO-heteroaryl, erocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, NHCONH, NHCONH-C-C-alkyl, NHCONH-aryl, C-C-alkoxy, methoxymethoxy, methoxyethoxy, amino, NHCONH-heteroaryl, SO-C-C-alkyl, SO-aryl, SO benzylamino, arylamino, heteroarylamino, C-C-alky heteroaryl, SONH, SONH-C-C-alkyl, SONH-aryl, lamino, di-C-C-alkylamino, thio, aryl-thio, heteroarylthio, SONH-heteroaryl, C-C-alkyl, C-C2-cycloalkyl, CF, CHCF, CHCl, CH-NH, CHSOCH, C-C alkyl, halo benzyl-thio, C-C-alkyl-thio, or methylthiomethyl. alkyl, C-C cycloalkyl, Substituted C-C cycloalkyl, aryl, 0179 The term “heterocycloalkyl,” as used herein, refers Substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, het to a non-aromatic 5-, 6- or 7-membered ring or a bi- or erocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, tri-cyclic group fused System, where (i) each ring contains C-C-alkoxy, methoxymethoxy, methoxyethoxy, amino, between one and three heteroatoms independently Selected benzylamino, arylamino, heteroarylamino, C-C-alky from oxygen, Sulfur and nitrogen, (ii) each 5-membered ring lamino, di-C-C-alkylamino, thio, aryl-thio, heteroarylthio, has 0 to 1 double bonds and each 6-membered ring has 0 to benzyl-thio, C-C-alkyl-thio, or methylthiomethyl. 2 double bonds, (iii) the nitrogen and Sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom 0183 It shall be understood that any substituted group may optionally be quaternized, and (iv) any of the above defined above (e.g. Substituted C-C alkyl, Substituted rings may be fused to a benzene ring. Representative het C-C alkenyl, Substituted C-C alkynyl, Substituted C-C, erocycloalkyl groups include, but are not limited to, 1.3 cycloalkyl, Substituted aryl, Substituted arylalkyl, Substi dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imida tuted heteroaryl, substituted heteroarylalkyl, or substituted Zolinyl, imidazolidinyl, piperidinyl, piperazinyl, heterocycloalkyl) may also be substituted with the following Oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, suitable substituents: -F, -Cl, -Br, -, -OH, protected hydroxy, aliphatic ethers, aromatic ethers, OXO, -NO, isothiazolidinyl, and tetrahydrofuryl. -CN, -C-C2-alkyl optionally Substituted with halogen 0180. The term “substituted heterocycloalkyl,” as used (Such as perhaloalkyls), C-C2-alkenyl optionally Substi herein, refers to a heterocycloalkyl group, as previously tuted with halogen, -C-C2-alkynyl optionally Substituted defined, Substituted by independent replacement or one, two, with halogen, -NH2, protected amino, -NH-C-C- or three of the hydrogen atoms thereon with F, Cl, Br, I, OH, alkyl, -NH-C-C2-alkenyl, -NH-C-C2-alkenyl, NO, CN, C-C-alkyl-OH, C(O)-C-C-alkyl, OCH -NH-C-C-cycloalkyl, -NH-aryl, -NH-heteroaryl, C-C-cycloalkyl, C(O)H, C(O)-aryl, C(O)-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -di CO-alkyl, CO-aryl, CO-heteroaryl, CONH2, CONH heteroarylamino, -O-C-C2-alkyl, -O-C-C2-alk C-C-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)-C- enyl, -O-C-C-alkynyl, -O-C-C-cycloalkyl, Co-alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO-alkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)H, OCO-aryl, OCO-heteroaryl, OCONH, OCONH-C-C- -C(O)-C-C-alkyl, -C(O)-C-C2-alkenyl, alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)H, -C(O)-C-C2-alkynyl, -C(O)-C-C-cycloalkyl, NHC(O)-C-C-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, -C(O)-aryl, C(O)-heteroaryl, -C(O)-heterocycloalkyl, NHCO-alkyl, NHCO-aryl, NHCO-heteroaryl, -CONH, -CONH-C-C2-alkyl, -CONH-C-C- NHCONH, NHCONH-C-C-alkyl, NHCONH-aryl, alkenyl, -CONH-C-C-alkynyl, -CONH-C-C- NHCONH-heteroaryl, SO-C-C-alkyl, SO-aryl, SO cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH heteroaryl, SONH, SONH-C-C-alkyl, SONH-aryl, heterocycloalkyl, -CO-C-C2-alkyl, -CO-C-C- SONH-heteroaryl, C-C-alkyl, C-C-cycloalkyl, CF, alkenyl, -CO-C-C-alkynyl, -CO-C-C- CHCF, CHCl, CH-NH, CHSOCH, C-C alkyl, halo cycloalkyl, -CO-aryl, -CO-heteroaryl, -CO-hetero alkyl, C-C cycloalkyl, Substituted C-C cycloalkyl, aryl, cycloalkyl, -CO-C-C2-alkyl, -OCO-C-C2-alk Substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, het enyl, -OCO-C-C2-alkynyl, -OCO-C-C-cy erocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, cloalkyl, -OCO-aryl, -OCO-heteroaryl, -OCO US 2004/0266668A1 Dec. 30, 2004 heterocycloalkyl, -OCONH, -OCONH-C-C-alkyl, 0187. The term “diheteroarylamino” refers to a group -OCONH-C-C-alkenyl, -OCONH-C-C-alky having the structure -N(heteroaryl) or -N(substituted nyl, -OCONH-C-C-cycloalkyl, -OCONH-aryl, heteroaryl), where heteroaryl and Substituted heteroaryl is –OCONH-heteroaryl, -OCONH-heterocycloalkyl, as previously defined. Examples of diheteroarylamino are, -NHC(O)H, -NHC(O)-C-C-alkyl, -NHC(O)-C- but not limited to, N,N-difuranylamino, N,N-dithiazolidiny C-alkenyl, -NHC(O)-C-C-alkynyl, -NHC(O)- lamino, N,N-di(imidazole)amino, and the like. C-C-cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, 0188 The compounds described herein contain one or -NHC(O)-heterocycloalkyl, -NHCO-C-C-alkyl, more asymmetric centers and thus give rise to enantiomers, -NHCO-C-C-alkenyl, -NHCO-C-C2-alkynyl, diastereomers, and other Stereoisomeric forms that may be -NHCO-C-C-cycloalkyl, -NHCO-aryl, defined, in terms of absolute Stereochemistry, as (R)- or -NHCO-heteroaryl, -NHCO-heterocycloalkyl, -NH (S)-, or as (D)- or (L)-for amino acids. The present C(O)NH, -NHC(O)NH-C-C-alkyl, -NHC(O)NH invention is meant to include all Such possible isomers, as C-C-alkenyl, -NHC(O)NH-C-C-alkynyl, -NH well as their racemic and optically pure forms. Optical C(O)NH-C-C-cycloalkyl, -NHC(O)NH-aryl, isomerS may be prepared from their respective optically -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, active precursors by the procedures described above, or by NHC(S)NH, -NHC(S)NH-C-C-alkyl, -NHC resolving the racemic mixtures. The resolution can be car (S)NH-C-C-alkenyl, -NHC(S)NH-C-C2-alkynyl, ried out in the presence of a resolving agent, by chroma -NHC(S)NH-C-C-cycloalkyl, -NHC(S)NH-aryl, tography or by repeated crystallization or by Some combi -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, nation of these techniques which are known to those skilled -NHC(NH)NH, -NHC(NH)NH-C-C-alkyl, -NH in the art. Further details regarding resolutions can be found C(NH)NH-C-C-alkenyl, -NHC(NH)NH-C-C- in Jacques, et al., Enantiomers, Racemates, and Resolutions alkynyl, -NHC(NH)NH-C-C-cycloalkyl, -NHC (John Wiley & Sons, 1981). When the compounds described (NH)NH-aryl, -NHC(NH)NH-heteroaryl, herein contain olefinic double bonds or other centers of -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C-C- geometric asymmetry, and unless Specified otherwise, it is alkyl, -NHC(NH)-C-C2-alkenyl, -NHC(NH)-C- intended that the compounds include both E and Z geometric C-alkynyl, -NHC(NH)-C-C-cycloalkyl, -NH isomers. Likewise, all tautomeric forms are also intended to C(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)- be included. The configuration of any carbon-carbon double heterocycloalkyl, -(NH)NH-C-C-alkyl, bond appearing herein is Selected for convenience only and -C(NH)NH-C-C-alkenyl, -(NH)NH-C-C-alky is not intended to designate a particular configuration unless nyl, -C(NH)NH-C-C-cycloalkyl, -C(NH)NH-aryl, the text So States; thus a carbon-carbon double bond depicted -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, arbitrarily herein as trans may be cis, trans, or a mixture of -S(O)-C-C-alkyl, -S(O)-C-C-alkenyl, the two in any proportion. -S(O)-C-C2-alkynyl, -S(O)-C-C-cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, 0189 The term “subject” as used herein refers to a -SONH, -SO2NH-C-C-alkyl, -SONH-C-C- mammal. A Subject therefore refers to, for example, dogs, alkenyl, -SONH-C-C-alkynyl, -SONH-C-C- cats, horses, cows, pigs, guinea pigs, and the like. Preferably cycloalkyl, -SONH-aryl, -SONH-heteroaryl, the Subject is a human. When the Subject is a human, the -SONH-heterocycloalkyl, -NHSO-C-C-alkyl, Subject may be referred to herein as a patient. -NHSO-C-C-alkenyl, -NHSO-C-C-alkynyl, 0190. As used herein, the term “pharmaceutically accept -NHSO-C-C-cycloalkyl, -NHSO-aryl, -NHSO able salt” refers to those salts of the compounds formed by heteroaryl, -NHSO-heterocycloalkyl, -CH-NH, the process of the present invention which are, within the -CHSOCH, -aryl, -arylalkyl, -heteroaryl, -heteroaryla Scope of Sound medical judgment, Suitable for use in contact lkyl, -heterocycloalkyl, -C-C-cycloalkyl, polyalkoxy with the tissues of humans and lower animals without undue alkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, -SH, toxicity, irritation, allergic response and the like, and are -S-C-C-alkyl, -S-C-C2-alkenyl, -S-C-C- commensurate with a reasonable benefit/risk ratio. Pharma alkynyl, -S-C-C-cycloalkyl, -S-aryl, -S-heteroaryl, ceutically acceptable Salts are well known in the art. For -S-heterocycloalkyl, or methylthiomethyl. It is understood example, S. M. Berge, et al. describes pharmaceutically that the aryls, heteroaryls, alkyls and the like can be further acceptable Salts in detail in J. Pharmaceutical Sciences, 66: Substituted. 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, 0184 The term “alkylamino” refers to a group having the or Separately by reacting the free base function with a Structure -NH(C-C alkyl) where C-C alkyl is as Suitable organic acid. Examples of pharmaceutically accept previously defined. able include, but are not limited to, nontoxic acid addition 0185. The term “dialkylamino” refers to a group having Salts are Salts of an amino group formed with inorganic acids the structure -N(C-C alkyl) where C-C alkyl is as Such as hydrochloric acid, hydrobromic acid, phosphoric previously defined. Examples of dialkylamino are, but not acid, Sulfuric acid and perchloric acid or with organic acids limited to, N,N-dimethylamino, N,N-diethylamino, N,N- Such as acetic acid, maleic acid, tartaric acid, citric acid, methylethylamino, and the like. Succinic acid or malonic acid or by using other methods used in the art Such as ion eXchange. Other pharmaceutically 0186 The term “diarylamino” refers to a group having acceptable Salts include, but are not limited to, adipate, the structure -N(aryl) or -N(substituted aryl) where alginate, ascorbate, aspartate, benzeneSulfonate, benzoate, Substituted aryl is as previously defined. Examples of dia bisulfate, borate, butyrate, camphorate, camphorSulfonate, rylamino are, but not limited to, N,N-diphenylamino, N,N- citrate, cyclopentanepropionate, digluconate, dodecylsul dinaphthylamino, N,N-di(toluenyl)amino, and the like. fate, ethaneSulfonate, formate, fumarate, glucoheptonate, US 2004/0266668A1 Dec. 30, 2004 glycerophosphate, gluconate, hemisulfate, heptanoate, heX 0194 The synthesized compounds can be separated from anoate, hydroiodide, 2-hydroxy-ethaneSulfonate, lactobion a reaction mixture and further purified by a method Such as ate, lactate, laurate, lauryl Sulfate, malate, maleate, mal column chromatography, high pressure liquid chromatogra Onate, methaneSulfonate, 2-naphthaleneSulfonate, phy, or recrystallization. AS can be appreciated by the skilled nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec artisan, further methods of Synthesizing the compounds of tinate, perSulfate, 3-phenylpropionate, phosphate, picrate, the formulae herein will be evident to those of ordinary skill pivalate, propionate, Stearate, Succinate, Sulfate, tartrate, in the art. Additionally, the various Synthetic StepS may be thiocyanate, p-toluenesulfonate, undecanoate, Valerate Salts, performed in an alternate Sequence or order to give the and the like. Representative alkali or alkaline earth metal desired compounds. In addition, the Solvents, temperatures, reaction durations, etc. delineated herein are for purposes of Salts include Sodium, lithium, potassium, calcium, magne illustration only and one of ordinary skill in the art will sium, and the like. Further pharmaceutically acceptable Salts recognize that variation of the reaction conditions can pro include, when appropriate, nontoxic ammonium, quaternary duce the desired bridged macrocyclic products of the present ammonium, and amine cations formed using counterions invention. Synthetic chemistry transformations and protect Such as halide, hydroxide, carboxylate, Sulfate, phosphate, ing group methodologies (protection and deprotection) use nitrate, alkyl having from 1 to 6 carbon atoms, Sulfonate and ful in Synthesizing the compounds described herein are aryl Sulfonate. known in the art and include, for example, those Such as 0191 AS used herein, the term “pharmaceutically accept described in R. Larock, Comprehensive Organic Transfor able ester” refers to esters of the compounds formed by the mations, VCH Publishers (1989); T. W. Greene and P. G. M. process of the present invention which hydrolyze in Vivo and Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John include those that break down readily in the human body to Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and leave the parent compound or a Salt thereof. Suitable ester Fieser's Reagents for Organic Synthesis, John Wiley and groups include, for example, those derived from pharma Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents ceutically acceptable aliphatic carboxylic acids, particularly for Organic Synthesis, John Wiley and Sons (1995). alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in 0.195 The compounds of this invention may be modified which each alkyl or alkenyl moiety advantageously has not by appending various functionalities via any Synthetic more than 6 carbon atoms. Examples of particular esters means delineated herein to enhance Selective biological include, but are not limited to, formates, acetates, propi properties. Such modifications are known in the art and onates, butyrates, acrylates and ethylsuccinates. include those which increase biological penetration into a 0.192 The term “pharmaceutically acceptable prodrugs” given biological System (e.g., blood, lymphatic System, as used herein refers to those prodrugs of the compounds central nervous System), increase oral availability, increase formed by the process of the present invention which are, Solubility to allow administration by injection, alter metabo within the Scope of Sound medical judgment, Suitable for use lism and alter rate of excretion. in contact with the tissueS of humans and lower animals with 0196) Pharmaceutical Compositions undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and 0197) The pharmaceutical compositions of the present effective for their intended use, as well as the Zwitterionic invention comprise a therapeutically effective amount of a forms, where possible, of the compounds of the present compound of the present invention formulated together with invention. "Prodrug, as used herein means a compound one or more pharmaceutically acceptable carriers. AS used which is convertible in vivo by metabolic means (e.g. by herein, the term "pharmaceutically acceptable carrier' hydrolysis) to afford any compound delineated by the for means a non-toxic, inert Solid, Semi-Solid or liquid filler, mulae of the instant invention. Various forms of prodrugs are diluent, encapsulating material or formulation auxiliary of known in the art, for example, as discussed in Bundgaard, any type. Some examples of materials which can Serve as (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. pharmaceutically acceptable carriers are SugarS Such as (ed.), Methods in Enzymology, Vol. 4, Academic Press lactose, glucose and Sucrose, Starches Such as corn Starch (1985); Krogsgaard-Larsen, et al., (ed). “Design and Appli and potato Starch, cellulose and its derivatives Such as cation of Prodrugs, Textbook of Drug Design and Develop Sodium carboxymethyl cellulose, ethyl cellulose and cellu ment, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal lose acetate; powdered tragacanth; malt, gelatin; talc, excipi of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of ents Such as cocoa butter and Suppository waxes, oils Such Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and as peanut oil, cottonseed oil; Safflower oil, Sesame oil, olive Stella (eds.) Prodrugs as Novel Drug Delivery Systems, oil; corn oil and Soybean oil; glycols, Such a propylene American Chemical Society (1975); and Bernard Testa & glycol, esterS Such as ethyl oleate and ethyl laurate; agar, Joachim Mayer, “Hydrolysis. In Drug And Prodrug Metabo buffering agents Such as magnesium hydroxide and alumi lism: Chemistry, Biochemistry And Enzymology,” John num hydroxide, alginic acid; pyrogen-free water, isotonic Wiley and Sons, Ltd. (2002). Saline, Ringer's Solution; ethyl alcohol, and phosphate buffer Solutions, as well as other non-toxic compatible 0193 Combinations of substituents and variables envi lubricants Such as Sodium lauryl Sulfate and magnesium Sioned by this invention are only those that result in the Stearate, as well as coloring agents, releasing agents, coating formation of stable compounds. The term “stable', as used agents, Sweetening, flavoring and perfuming agents, preser herein, refers to compounds which possess Stability Suffi Vatives and antioxidants can also be present in the compo cient to allow manufacture and which maintains the integrity Sition, according to the judgment of the formulator. The of the compound for a sufficient period of time to be useful pharmaceutical compositions of this invention can be for the purposes detailed herein (e.g., therapeutic or prophy administered to humans and other animals orally, rectally, lactic administration to a Subject). parenterally, intracisternally, intravaginally, intraperito US 2004/0266668A1 Dec. 30, 2004 neally, topically (as by powders, ointments, or drops), buc ambient temperature but liquid at body temperature and cally, or as an oral or nasal Spray. therefore melt in the rectum or vaginal cavity and release the 0198 Liquid dosage forms for oral administration active compound. include pharmaceutically acceptable emulsions, microemul 0203 Solid compositions of a similar type may also be Sions, Solutions, Suspensions, SyrupS and elixirs. In addition employed as fillers in Soft and hard-filled gelatin capsules to the active compounds, the liquid dosage forms may using Such excipients as lactose or milk Sugar as well as high contain inert diluents commonly used in the art Such as, for molecular weight polyethylene glycols and the like. example, water or other Solvents, Solubilizing agents and emulsifierS Such as ethyl alcohol, isopropyl alcohol, ethyl 0204. The active compounds can also be in micro-encap carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Sulated form with one or more excipients as noted above. propylene glycol, 1,3-butylene glycol, dimethylformamide, The Solid dosage forms of tablets, dragees, capsules, pills, oils (in particular, cottonseed, groundnut, corn, germ, olive, and granules can be prepared with coatings and shells Such castor, and Sesame oils), glycerol, tetrahydrofurfuryl alco as enteric coatings, release controlling coatings and other hol, polyethylene glycols and fatty acid esters of Sorbitan, coatings well known in the pharmaceutical formulating art. and mixtures thereof. Besides inert diluents, the oral com In Such Solid dosage forms the active compound may be positions can also include adjuvants Such as wetting agents, admixed with at least one inert diluent Such as Sucrose, emulsifying and Suspending agents, Sweetening, flavoring, lactose or Starch. Such dosage forms may also comprise, as and perfuming agents. is normal practice, additional Substances other than inert diluents, e.g., tableting lubricants and other tableting aids 0199 Injectable preparations, for example, sterile inject Such a magnesium Stearate and microcrystalline cellulose. In able aqueous or oleaginous Suspensions may be formulated the case of capsules, tablets and pills, the dosage forms may according to the known art using Suitable dispersing or also comprise buffering agents. They may optionally contain wetting agents and Suspending agents. The Sterile injectable opacifying agents and can also be of a composition that they preparation may also be a Sterile injectable Solution, Sus release the active ingredient(s) only, or preferentially, in a pension or emulsion in a nontoxic parenterally acceptable certain part of the intestinal tract, optionally, in a delayed diluent or Solvent, for example, as a Solution in 1,3-butane manner. Examples of embedding compositions which can be diol. Among the acceptable vehicles and Solvents that may be employed are water, Ringer's Solution, U.S.P. and iso used include polymeric Substances and waxes. tonic Sodium chloride Solution. In addition, Sterile, fixed oils 0205 Dosage forms for topical or transdermal adminis are conventionally employed as a Solvent or Suspending tration of a compound of this invention include ointments, medium. For this purpose any bland fixed oil can be pastes, creams, lotions, gels, powders, Solutions, SprayS, employed including Synthetic mono- or diglycerides. In inhalants or patches. The active component is admixed addition, fatty acids Such as oleic acid are used in the under Sterile conditions with a pharmaceutically acceptable preparation of injectables. carrier and any needed preservatives or buffers as may be 0200. The injectable formulations can be sterilized, for required. Ophthalmic formulation, ear drops, eye ointments, example, by filtration through a bacterial-retaining filter, or powders and Solutions are also contemplated as being within by incorporating Sterilizing agents in the form of Sterile Solid the Scope of this invention. compositions which can be dissolved or dispersed in Sterile 0206. The ointments, pastes, creams and gels may con water or other Sterile injectable medium prior to use. tain, in addition to an active compound of this invention, 0201 In order to prolong the effect of a drug, it is often excipients Such as animal and vegetable fats, oils, waxes, desirable to slow the absorption of the drug from Subcuta paraffins, Starch, tragacanth, cellulose derivatives, polyeth neous or intramuscular injection. This may be accomplished ylene glycols, Silicones, bentonites, Silicic acid, talc and Zinc by the use of a liquid Suspension of crystalline or amorphous oxide, or mixtures thereof. material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in 0207 Powders and sprays can contain, in addition to the turn, may depend upon crystal size and crystalline form. compounds of this invention, excipients Such as lactose, talc, Alternatively, delayed absorption of a parenterally admin Silicic acid, aluminum hydroxide, calcium Silicates and istered drug form is accomplished by dissolving or Suspend polyamide powder, or mixtures of these Substances. SprayS ing the drug in an oil vehicle. Injectable depot forms are can additionally contain customary propellants Such as chlo made by forming microencapsule matrices of the drug in rofluorohydrocarbons. biodegradable polymerS Such as polylactide-polyglycolide. 0208 Transdermal patches have the added advantage of Depending upon the ratio of drug to polymer and the nature providing controlled delivery of a compound to the body. of the particular polymer employed, the rate of drug release Such dosage forms can be made by dissolving or dispensing can be controlled. Examples of other biodegradable poly the compound in the proper medium. Absorption enhancers mers include poly(orthoesters) and poly(anhydrides). Depot can also be used to increase the flux of the compound acroSS injectable formulations are also prepared by entrapping the the skin. The rate can be controlled by either providing a rate drug in liposomes or microemulsions which are compatible controlling membrane or by dispersing the compound in a with body tissues. polymer matrix or gel. 0202 Compositions for rectal or vaginal administration 0209 Antiviral Activity are preferably Suppositories which can be prepared by mixing the compounds of this invention with Suitable non 0210. An inhibitory amount or dose of the compounds of irritating excipients or carrierS Such as cocoa butter, poly the present invention may range from about 0.1 mg/Kg to ethylene glycol or a Suppository wax which are Solid at about 500 mg/Kg, alternatively from about 1 to about 50 US 2004/0266668A1 Dec. 30, 2004 22 mg/Kg. Inhibitory amounts or doses will also vary depend coincidental with the Specific compound employed; and like ing on route of administration, as well as the possibility of factors well known in the medical arts. co-usage with other agents. 0216) The total daily inhibitory dose of the compounds of 0211. According to the methods of treatment of the this invention administered to a Subject in Single or in present invention, Viral infections are treated or prevented in divided doses can be in amounts, for example, from 0.01 to a Subject Such as a human or lower mammal by adminis 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg tering to the Subject an anti-hepatitis C virally effective body weight. Single dose compositions may contain Such amount or an inhibitory amount of a compound of the amounts or Submultiples thereof to make up the daily dose. present invention, in Such amounts and for Such time as is In general, treatment regimens according to the present necessary to achieve the desired result. An additional invention comprise administration to a patient in need of method of the present invention is the treatment of biologi such treatment from about 10 mg to about 1000 mg of the cal Samples with an inhibitory amount of a compound of compound(s) of this invention per day in Single or multiple composition of the present invention in Such amounts and doses. for Such time as is necessary to achieve the desired result. 0217. Unless otherwise defined, all technical and scien 0212. The term “anti-hepatitis C virally effective tific terms used herein are accorded the meaning commonly amount of a compound of the invention, as used herein, known to one with ordinary skill in the art. All publications, mean a Sufficient amount of the compound So as to decrease patents, published patent applications, and other references the Viral load in a biological Sample or in a Subject. AS well mentioned herein are hereby incorporated by reference in understood in the medical arts, an anti-hepatitis C virally their entirety. effective amount of a compound of this invention will be at a reasonable benefit/risk ratio applicable to any medical 0218. Abbreviations treatment. 0219. Abbreviations which have been used in the descrip 0213 The term “inhibitory amount” of a compound of tions of the Schemes and the examples that follow are: the present invention means a Sufficient amount to decrease 0220 ACN for acetonitrile; the hepatitis C viral load in a biological Sample or a Subject. 0221 BME for 2-mercaptoethanol; It is understood that when said inhibitory amount of a compound of the present invention is administered to a 0222 BOP for benzotriazol-1-yloxy-tris(dimethy Subject it will be at a reasonable benefit/risk ratio applicable lamino)phosphonium hexafluorophosphate; to any medical treatment as determined by a physician. The 0223 COD for cyclooctadiene; term “biological sample(s), as used herein, means a Sub stance of biological origin intended for administration to a 0224) DAST for diethylaminosulfur trifluoride; Subject. Examples of biological Samples include, but are not 0225 DABCYL for 6-(N-4'-carboxy-4-(dimethy limited to, blood and components thereof Such as plasma, lamino)azobenzene)-aminohexyl-1-O-(2-cyanoet platelets, Subpopulations of blood cells and the like; organs hyl)-(N,N-diisopropyl)-phosphoramidite; Such as kidney, liver, heart, lung, and the like; Sperm and 0226 DCM for dichloromethane; ova, bone marrow and components thereof, or Stem cells. Thus, another embodiment of the present invention is a 0227 DIAD for diisopropyl azodicarboxylate; method of treating a biological Sample by contacting Said 0228 DIBAL-H for diisobutylaluminum hydride; biological Sample with an inhibitory amount of a compound 0229 DIEA for diisopropyl ethylamine; or pharmaceutical composition of the present invention. 0230 DMAP for N,N-dimethylaminopyridine; 0214. Upon improvement of a subject's condition, a 0231. DME for ethylene glycol dimethyl ether; maintenance dose of a compound, composition or combi nation of this invention may be administered, if necessary. 0232) DMEM for Dulbecco's Modified Eagles Subsequently, the dosage or frequency of administration, or Media; both, may be reduced, as a function of the Symptoms, to a 0233 DMF for N,N-dimethyl formamide; level at which the improved condition is retained when the 0234) DMSO for dimethylsulfoxide; Symptoms have been alleviated to the desired level, treat ment should cease. The Subject may, however, require 0235 DUPHOS for intermittent treatment on a long-term basis upon any recur rence of disease Symptoms. 0215. It will be understood, however, that the total daily usage of the compounds and compositions of the present / invention will be decided by the attending physician within the Scope of Sound medical judgment. The Specific inhibi tory dose for any particular patient will depend upon a s variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific SN compound employed; the Specific composition employed; C the age, body weight, general health, SeX and diet of the patient; the time of administration, route of administration, and rate of excretion of the Specific compound employed; N-- the duration of the treatment; drugs used in combination or US 2004/0266668A1 Dec. 30, 2004 23
0236 EDANS for 5-(2-Amino-ethylamino)-naph 0247 RT for reverse transcription; thalene-1-Sulfonic acid; 0248 RT-PCR for reverse transcription-polymerase 0237 EDCI or EDC for 1-(3-diethylaminopropyl)- chain reaction; 3-ethylcarbodiimide hydrochloride; 0238 EtOAc for ethyl acetate; 0249 TEA for triethyl amine; 0239). HATU for O(7-AZabenzotriazole-1-yl)-N,N, 0250 TFA for trifluoroacetic acid; N',N'-tetramethyluronium hexafluorophosphate; 0251 THF for tetrahydrofuran; 0240 Hoveyda’s Cat. for Dichloro(o-isopro poxyphenylmethylene) (tricyclohexylphosphine)ru 0252) TLC for thin layer chromatography; thenium(II); 0253) TPP or PPhs for triphenylphosphine; 0241 KHMDS is potassium bis(trimethylsilyl) 0254 teOC or Boc for tert-butyloxy carbonyl; and amide; 0255 Xantphos for 4.5-Bis-diphenylphosphanyl-9, 0242. Ms for mesyl; 9-dimethyl-9H-xanthene. 0243 NMM for N-4-methylmorpholine 0244 PyBrOP for Bromo-tri-pyrolidino-phospho 0256 Synthetic Methods nium hexafluorophosphate, 0257 The compounds and processes of the present inven tion will be better understood in connection with the fol 0245 Ph for phenyl; lowing synthetic schemes which illustrate the methods by 0246 RCM for ring-closing metathesis; which the compounds of the invention may be prepared. US 2004/0266668A1 Dec. 30, 2004 24 HON HOO HOOHOHO US 2004/0266668A1 Dec. 30, 2004 25
0258 All of the quinoxaline analogs were prepared from another peptide coupling with cyclopropyl amine (1-4) the common intermediate If. The Synthesis of compound yielded the tri-peptide (1-5). Finally, ring closure methathe (1-6) is outlined in Scheme 1. Commercially available sis with a Ruthenium-based catalyst gave the desired key boc-hydroxyproline (1-1) is treated with HCl in dioxane and intermediate (1-6) (for further details on ring closing met is further coupled with acid (1-2) using HATU to afford athesis see recent reviews: Grubbs et al., Acc. Chem. Res., intermediate (1-3). Other amino acid derivatives containing 1995, 28, 446; Shrock et al., Tetrahedron 1999, 55, 8141; a terminal alkene may be used in place of (1-2) in order to Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012; Tmka et create varied macrocyclic structures (for further details see al., Acc. Chem. Res. 2001, 34, 18; and Hoveyda et al., Chem. WO/0059929). Hydrolysis of (1-3) with LiOH followed by Eur: J. 2001, 7,945).
1. DIAD/PPh3 He 2. LiOH.H2O
1-6
2-2
N HN HN 21 On
O
2-3 2-4 2-5 US 2004/0266668A1 Dec. 30, 2004 26
0259. The quinoxaline analogs of the present invention were prepared via Several different Synthetic routes. The Simplest method, shown in Scheme 2, is to condense com Scheme 4 mercially available 1H-quinoxalin-2-one analogs including, O NO O A. but not limited to, compounds 2-1-2-5 with key intermediate 1. DCC 1-6 by using Mitsunobu conditions followed by hydrolysis -- R4 HeDME HO rt, 5h with LiOH. The existing literature predicts Mistonobu prod NH uct formation at the 1 position nitrogen, however attachment 2 O at the carbonyl oxygen was observed to form compound 2-2. 4-1 4-2 A detailed discussion of the identification and characteriza O NO 1 2 B tion of the unexpected oxo Mitosunobu addition product H2/Pd/C He appears in the examples herein. For further details on the MeOH Mitsunobu reaction, see O. Mitsunobu, Synthesis 1981, NH O rt, 5h 1-28; D. L. Hughes, Org. React. 29, 1-162 (1983); D. L. Hughes, Organic Preparations and Procedures Int. 28, 127-164 (1996); and J. A. Dodge, S. A. Jones, Recent Res. O R4 Dev. Org. Chem. 1, 273-283 (1997). 4-3
Scheme 3 -O C O NH2 R4 O H 4-4 --- R-i- -- anh. MeOH 21 Room Temp. OC NH2 EO O -90% 3-1 3-2 0261) 3.6 substituted quinoxalin-2-ones of formula (4-4), E= C1-C6 alkyl wherein R is previously defined, can be made in a regiose lective manner to favor the 6-position Substitution beginning with the amide coupling of 4-methoxy-2-nitro aniline (4-1) R. i. and Substituted gloxylic acid (4-2) to yield compound (4-3). OC2 N CO The 3,6-Substituted quinoxalin-2-one (4-4) is created via H catalytic reduction of the nitro of compound (4-3) followed 3-3 by condensation to the 3,6-Substituted quinoxalin-2-one (4-4). Other substituents may be introduced into (4-4) 0260 Various quinoxaline derivatives of formula (3-3) through the use of other 2-nitroanilines. Examples of keto can be made with phenyl diamines of formula (3-1), wherein acids Suitable for the reaction described in Scheme 4 R is previously defined, and keto acids or esters of formula include, but are not limited to, benzoylformic acid, phe (3-2), wherein R is previously defined, in anhydrous metha nylpyruvic acid, indole-3-glyoxylic acid, indole-3-pyruvic nol at room temperature (see Bekerman et al., J. Heterocycl. acid, nitrophenylpyruvic acid, (2-furyl)glyoxylic acid, and Chem. 1992, 29, 129-133 for further details of this reaction). the like. Examples of 2-nitro anilines Suitable for the reac Examples of phenyl diamines Suitable for creating quinoxa tion described in Scheme 4 include, but are not limited to, line derivatives of formula (3-3) include, but are not limited 4-ethoxy-2-nitroaniline, 4-amino-3-nitrobenzotrifluoride, to, 1,2-diamino-4-nitrobenze, o-phenylenediamine, 3,4-di 4,5-dimethyl-2-nitroaniline, 4-fluoro-2-nitroaniline, aminotoluene, 4-chloro-1,2-phenylenediamine, methyl-3,4- 4-chloro-2-nitroaniline, 4-amino-3-nitromethylbenzoate, diaminobenzoate, benzo1,3dioxole-5,6-diamine, 1,2-di 4-benzoyl-2-nitroaniline, 3-bromo-4-methoxy-2-nitroa amino-4,5-methylene dioxybenzene, 4-chloro-5- niline, 3'-amino-4'-methyl-2-nitroacetophenone, 5-ethoxy (trifluoromethyl)-1,2-benzenediamine, and the like. 4-fluoro-2-nitroaniline, 4-bromo-2-nitroaniline, 4-(trifluo Examples of keto acids Suitable for the reaction described in romethoxy)-2-nitroaniline, ethyl-4-amino3-nitrobenzoate, Scheme 3 include, but are not limited to, benzoylformic 4-bromo-2-methyl-6-nitroaniline, 4-propoxy-2-nitroaniline, acid, phenylpyruvic acid, indole-3-glyoxylic acid, indole-3- 5-(propylthio)-2-nitroaniline, and the like. pyruvic acid, nitrophenylpyruvic acid, (2-furyl)glyoxylic acid, and the like. Examples of keto esterS Suitable for the reaction described in Scheme 3 include, but are not limited Scheme 5 to ethyl thiophene-2-glyoxylate, ethyl 2-OXO-4-phenylbu tyrate, ethyl 2-(formylamino)-4-thiazolylglyoxylate, ethyl A. 2-amino-4-thiozolyl glyoxylate, ethyl-2-oxo-4-phenylbu N NH2 tyrate, ethyl-(5-bromothien-2-yl)glyoxylate, ethyl-3- indolylglyoxylate, ethyl-2-methylbenzoyl formate, ethyl-3- R-i -- ethylbenzoyl formate, ethyl-3-ethylbenzoyl formate, ethyl 2 NH2 4-cyano-2-oxobutyrate, methyl(1-methylindolyl)-3- 3-1 glyoxylate, and the like. US 2004/0266668A1 Dec. 30, 2004 27
-continued -continued
O N1 O 1N HeMeOH Room Temperature O 5-1
R4 R4 N N
2 NH SOCI 21 N 140 HN (DMF:toluene) HN O Cl
O O 5-6 5-2 5-3
B
Stille
Suzuki Coupling
Reaction Coupling -- o1N R4-B(OH)2Pd(PPh.) CsCO/CsF dioxane DME
5-7 5-5
0262 A. A key intermediate, 3-chloro-1H-quinoxalin-2- one (5-3), can be synthesized from phenyl diamines of formula (3-1), as previously defined, and Oxalic acid diethyl Sonogashira ester (5-1) to yield 1,4-dihydro-quinoxaline-2,3-dione (5-2) Reaction under Similar conditions as discussed in Scheme 3 (see H-E-R Pd(II), 5% eq Bekerman et al., J. Heterocycl. Chem. 1992, 29, 129-133) 1N Cul followed by treatment with SOCl (1.37 equiv.) in (1:40 TEA, MeCN DMF:toluene) (see Loev et al., J. Med Chem. (1985), 28, reflux 12h 363-366 for further details). 0263 B. The key 3-chloro-quinoxalin-2-one (5-3) is added to the macrocyclic precursor (1-6) via Mitsunobu 5-4 conditions, adding via the carbonyl oxygen, rather than the expected 1-position nitrogen, to give the key macrocylic US 2004/0266668A1 Dec. 30, 2004 28 intermediate of formula (5-4). This intermediate facilitates the introduction of various substituents at the 3-position of -continued the quinoxaline. 0264 Suzuki Coupling 0265 Compounds of formula (5-5), wherein R is previ ously defined, can be Synthesized via Suzuki coupling reaction with an aryl, Substituted aryl, heteroaryl, or Substi tuted heteroaryl boronic acid in DME in the presence of Pd(PPh3), and CsCO. For further details concerning the Suzuki coupling reaction See A. Suzuki, Pure Appl. Chem. 63, 419-422 (1991) and A. R. Martin, Y. Yang, Acta Chem. Scand. 47, 221-230 (1993). Examples of boronic acids Suitable for Suzuki coupling to macrocyclic key intermedi ate (5-5) include, but are not limited to, 2-bromo thiophene, phenylboronic acid, 5-bromothiophene-3-boronic acid, 4-cyanophenylboronic acid, 4-trifluorimethoxyphenylbo ronic acid, and the like. 6-1 0266 Sonogashira Reaction 0267 Compounds of formula (5-6), wherein R is as previously defined, can be Synthesized via Sonagashira reaction with the macrocyclic key intermediate a terminal alkyne in acetonitrile in the presence triethylamine, PdCl(PPh), and Cul at 90° C. for 12 hours. For further details of the Sonogashira reaction See Sonogashira, Com prehensive Organic Synthesis, Volume 3, Chapters 2.4 and O KCO2-u2 Sonogashira, Synthesis 1977,777. Terminal alkenes suitable DMF for the Sonogashira reaction with macrocyclic key interme N room temp diate (5-5) include, but are not limited to, ethynylbenzene, f 1N to reflux 4-cyano-ethynylbenzene, propargylbenzene, and the like. F 12-24 hours 0268 Stille Coupling 0269 Compounds of formula (5-7), wherein R is previ ously defined, can be Synthesized via Stille coupling reac tion with key macrocyclic intermediate of formula (5-4) and aryl stannanes in dioxane in the presence of Pd(PPh). For further details of the Stille Coupling reaction see J. K. Stille, Angew. Chem. Int. Ed. 25,508-524 (1986), M. Pereyre et al., Tin in Organic Synthesis (Butterworths, Boston, 1987) pp 185-207 passim, and a review of synthetic applications in T. N. Mitchell, Synthesis 1992, 803-815. Organostannanes Suitable for Stille coupling with key macrocyclic interme diate (5-4) include, but are not limited to, tributyltin cyanide, allyl-tri-n-butyltin, 2-tributyltin-pyridine, 2-tri-n-butyltin furan, 2-tri-n-butyltin thiophene, 2,3-dihydron-5-(tri-n-bu tyltin)benzofuran, and the like.
6-2
HNRR4, HS-R4, KsCOs K2CO2 Her He DMF DMF room temp room temp to reflux to reflux 12-24 hours
5-4 5-4 US 2004/0266668A1 Dec. 30, 2004 29
HNRR (1.2 equiv.), and stirring the resulting reaction -continued mixture at room temperature for 5-12 hours. Amines Suitable for these conditions include, but are not limited to, ethyl amine, 2-phenyl ethylamine, cyclohexylamine, ethylmethy lamine, diisopropyl amine, benzylethyl amine, 4-pentenyl amine, propargyl amine and the like. 0272 For amines wherein R is hydrogen and R is aryl, Substituted aryl, heteroaryl, or Substituted heteroaryl, a dif ferent Set of conditions must be used to arrive on compound (6-1). Adding of NaH (2 equiv.) and HNRR (1.2 equiv.) to a 0.1M Solution of the macrocyclic quinoxalinyl intermedi ate (5-4) in THF and stirring the resulting reaction mixture for 5-12 hours affords the aniline substituted compound (6-1). Amines Suitable for the instant conditions are aniline, 6-3 4-methoxy aniline, 2-amino-pyridine, and the like. 0273 Introduction of ethers to the 2 position of the 0270 Via the key macrocyclic 3-chloro-quinoxalinyl quinoxaline ring, can be achieved through treating a 0.1M intermediate (5-4), three additional classes of Substituents Solution of macrocyclic quinoxalinyl intermediate (5-4) in may be introduced at the 3 position of the quinoxaline ring. DMF with KCO (2 equiv.) and HOR (1.2 equiv.), wherein Among the various groups that may be introduced are R is previously defined. The resulting reaction mixture can mono-Substituted amino, di-Substituted amino, ethers, and then be stirred for 5-12 hours at room temperature to arrive thio-ethers. at the desired ether moiety at the 3 postion. Alcohols suitable 0271 The amino-Substituted quinoxaline (6-1), wherein for these conditions include, but are not limited to, ethanol, R, and Ra are as previously defined, can be formed through propanol, isobutanol, trifluoromethanol, phenol, 4-methoX adding to a 0.1M Solution of macrocyclic quinoxalinyl yphenol, pyridin-3-ol, and the like. Thioesters can be made intermediate (5-4) in 10 ml DMF, KCO (2 equiv.) and via the same procedure.
Scheme 7 Z.
N NH2 W. O N1 NN W-Z Her Br -- anh, MeOH Br 2 21 NH2 RO O N O H 7-1 3-2 7-2 y/
N n Br - Suzuki N Coupling
7-3
Sonogashira Reaction 7-4 \s Chemistry US 2004/0266668A1 Dec. 30, 2004 30
-continued
Stille Coupling
7-5
7-6
0274) Derivation of the benzo portion of the quinoxaline undergo Suzuki coupling reactions, Sonogashira reactions, ring may be achieved through the halogen-Substituted qui or Stille couplings at the position occupied by the chloro. noxaline of formula (7-2). Quinoxaline of formula (7-2) can See previous discussion of Suzuki couplings, Sonogashira be formed with chloro-substituted phenyldiamine (7-1) with reactions, and Stille couplings for further details. The Buch diketo compound of formula (7-2), wherein W, Z, and R are wald reaction allows for the Substitution with amines, both as previously defined, in anhydrous methanol as previously primary and Secondary, as well as 1H-nitrogen heterocycles detailed. Intermediate (7-3) is formed under Mitsunobu at the aryl bromide. For further details of the Buchwald conditions with macrocyclic precursor (7-6) and chloroSub reaction see J. F. Hartwig, Angew. Chem. Int. Ed. 37, stituted quinoxaline (7-2). Intermediate (7-3) may then 2046-2067 (1998).
Scheme 8 O O O 1n NH2 O 1n N14 N14 O R. MeOH O Lio HO -- 4 -> Ho HO rt MeOH NH2 O O O 8-1 8-2 8-3 8-4
O O O MeO N - R4 N. R R N. R YN n DCC HO n1''' DCC 'NN sn1 NHRA H M -e-(MeO)MeNHHCI -- e N O EtN, DCM, rt N1 No EtsN, DCM, N O H H rt H 8-5 8-4 8-7 US 2004/0266668A1 Dec. 30, 2004 31
-continued O
N R4 R C N O H 0275 The 3&stabstituted 2-Oxo-1,2-dihydro-quinoxaline 6-carboxylic acid intermediate (8-4) can be formed via -continued condensation of ethyl 3,4-diaminobenzoate (8-1) and oxo acetic acid of formula (8–2), wherein R is previously defined, via the method described previously in Scheme 3 HN (see Bekerman et al., J. Heterocycl. Chem. 1992, 29, 129 133 for further details). The resulting ethyl ester (8-3) is then hydrolyzed with LiOH in MeOH at room temperature to yield carboxylic acid intermediate (8–4). 0276 Carboxylic acid (8-4) then may be converted to substituted ketone (8-6) via Weinreb's amide (8-5) and Subsequent treatment with various Grignard Reagents (see Weinreb et al. Tetrahedron Lett. 1977, 4171; Weinreb et al, Synth. Commun. 1982, 12,989 for details of the formation and use of Weinreb's amide; and see B. S. Furniss, A. J. Hannaford, P. W. G. Smith, A. R. Tatchell, Vogel's Textbook of Practical Organic Chemistry, 5" ed., Longman, 1989). NH2 The addition is performed in an inert Solvent, generally at HO low temperatures. Suitable Solvents include, but are not limited to, tetrahydrofuran, diethylether, 1,4-dioxane, 1,2- NH dimethoxyethane, and hexanes. Preferably the solvent is tetrahydrofuran or diethylether. Preferably the reaction is 9-6 run at -78° C. to O. C. DMSO HO Her 0277. In the alternative, carboxylic acid (8-4) may be (COCl)2 used to form various amides of formula (8-7), wherein R and R are previously defined, in a manner generally described in Scheme 8. All of the various quinoxalin-2-one 9-7 compounds described in Scheme 8 are further coupled to the N R4 macrocyclic precursor via the Mitsunobu conditions described above Scheme 9 r NDC O H A. 9-8 O N R4 NH O N(R), NaCNBH 2 -as O1 R4 MeOH ACN, HOAc HO rt r N CO H NH2 O 9-8 9-1 9-2 Rin N R4 N N R4 N O O1 H2NNH2-H2O H --- Pd/C, MeOH, reflux N CO H 9-3 0278. Further 6-substituted quinoxalin-2-one compounds HN N R4 can be made Via the procedures Set forth generally in Scheme 9. O N CO 0279 A. Reduction of 6-nitro and Amide Formation H 9-4 0280 6-nitro-1H-quinoxalin-2-one (9-3) can be formed in the manner previously described from the 3,4-diamino US 2004/0266668A1 Dec. 30, 2004 32 nitrobenzene and the oxo acetic acid of formula (9-2), wherein R is previously described. Reduction of the nitro -continued group at the 6-position can be achieved via Pd/C with 21 2^ W-Z HNNH.HO in refluxing MeOH. The 6-position amine R-i- (9-4) then can be treated with a wide array of acid chlorides to arrive upon various amides of formula (9-5). N-n-n
0281 B. Oxidation of Benzyl Alcohol and Reductive Amination 0282 Quinoxalin-2-one of formula (9-7) can be formed via the condensation of 3,4-diaminobenzyl alcohol and various OXO acetic acids of formula (9-2), wherein R is as previously defined as elucidated in previous Schemes. The resulting benzyl alcohol (9-7) may then be oxidized under Swern conditions, or any other oxidation conditionsto arrive (10-1) on aldehyde of formula (9-8). For further details concerning the Swern reaction see A. J. Mancuso, D. Swern, Synthesis 1981, 165-185 passim; T. T. Tidwell, Org. React. 39, 297 0283 Reduction of the preceding quinoxalinyl macrocy 572 passim (1990). For other oxidation conditions see B. S. clic compounds is performed by treating a Solution of the Furniss, A. J. Hannaford, P. W. G. Smith, A. R. Tatchell, ethyl ester (7-4) in THF/MeOH/HO with LiOH.HO to Vogel's Textbook of Practical Organic Chemistry, 5" ed., afford the corresponding free acid. Longman, 1989. Subsequent reductive amination with pri 0284 All references cited herein, whether in print, elec mary or secondary amines in the presence of NaCNBH and tronic, computer readable Storage media or other form, are acetic acid can yield compounds of formula (9-9). expressly incorporated by reference in their entirety, includ ing but not limited to, abstracts, articles, journals, publica tions, texts, treatises, internet web sites, databases, patents, and patent publications. EXAMPLES 0285) The compounds and processes of the present inven tion will be better understood in connection with the fol LiOH.H2O lowing examples, which are intended as an illustration only --- and not to limit the Scope of the invention. Various changes THF/MeOHA and modifications to the disclosed embodiments will be H2O apparent to those skilled in the art and Such changes and modifications including, without limitation, those relating to OEt the chemical Structures, Substituents, derivatives, formula tions and/or methods of the invention may be made without departing from the Spirit of the invention and the Scope of the appended claims Example 1 (7-4) Synthesis of the Cyclic Peptide Precursor 0286)
OH OH
A. Boc OH Ho HATU, 1.2 eq O N HN DIEA, 4 eq 21 HCI OMe DMF OMe
Boc n N O H 1a 1b 1c
le
1N LOH Bp-dioxane r.t, 3 h. US 2004/0266668A1 Dec. 30, 2004
-continued OH OH OH
D O C O N OH se- se Hoveyda's Cat. Boc HATU, 1.2 eq Boc O DCM DIEA, 4 eq reflux, 4-12 h. DMF
e 1. 1f 1d
0287) 1A. To a solution of Boc-L-2-amino-8-nonenoic after removal of the elution solvents (1.24 g., 87%), identi acid 1a (1.36 g., 5 mol) and the commercially available fied by HPLC (Retention time=7.84 min, 30-70%, 90% B), cis-L-hydroxyproline methyl ester 1b (1.09 g, 6 mmol) in 15 and MS (found 516.28, M+Na"). For further details of the ml DMF, DIEA (4 ml, 4 eq) and HATU (4g, 2 eq) were Synthetic methods employed to produce the cyclic peptide added. The coupling is carried out at 0°C. over a period of 1 hour. The reaction mixture is diluted with 100 mL EtOAc, precursor 1, see WO 00/059929 (2000). and followed by washing with 5% citric acid 2x20 ml, water 2x20 ml, 1M NaHCO 4x20 ml and brine 2x10 ml, respec Example 2 tively. The organic phase is dried over anhydrous Na2SO and then is evaporated, affording the dipeptide 1c (1.91 g, Compound of Formula I, Wherein A=tBOC, 95.8%) that is identified by HPLC (Retention time=8.9 min, G=OH, L=Absent, X and Y Taken Together with 30-70%, 90% B), and MS (found 421.37, M+Nat). the Carbon Atoms to which they are Attached are 0288) 1B. The dipeptide 1c (1.91 g) is dissolved in 15 mL phenyl, W is Absent, Z=thiophen-2-yl, j=3,m=S=1, of dioxane and 15 mL of 1 N LiOH acqueous solution and the and Rs=Re=hydrogen hydrolysis reaction is carried out at room temperature for 4 0291 Step 2A. hours. The reaction mixture is acidified by 5% citric acid and extracted with 100 mL EtOAc, and followed by washing with water 2x20 ml, 1M NaHCO 2x20 ml and brine 2x20 ml, respectively. The organic phase is dried over anhydrous Na2SO and then removed in Vacuum, yielding the free OH carboxylic acid compound 1d (1.79 g, 97%), which is used for next Step Synthesis without need for further purification. 0289 1C. To a solution of the free acid obtained above (1.77, 4.64 mmol) in 5 ml DMF, D-f-vinyl cyclopropane --DIAD (2 eq), PPh3 (2 eq) amino acid ethyl ester 1e (0.95 g, 5 mmol), DIEA (4 ml, THF 4eq.) and HATU (4 g, 2 eq) were added. The coupling is carried out at 0° C. over a period of 5 hour. The reaction mixture is diluted with 80 mL EtOAc, and followed by washing with 5% citric acid 2x20 ml, water 2x20 ml, 1M NaHCO, 4x20 ml and brine 2x10 ml, respectively. The organic phase is dried over anhydrous Na2SO and then evaporated. The residue is purified by Silica gel flash chro matography using different ratioS of hexanes: EtOAC as elution phase (5:1->3:1-> 1:1-> 1:2->1:5). The linear tripep tide 1 f is isolated as an oil after removal of the elution solvents (1.59 g, 65.4%), identified by HPLC (Retention time=11.43 min) and MS (found 544.84, M+Na"). 0290) 1D. Ring Closing Metathesis (RCM). A solution of the linear tripeptide 1f (1.51 g, 2.89 mmol) in 200 ml dry DCM is deoxygenated by bubbling N. Hoveyda’s 1 gen eration catalyst (5 mol % eq) is then added as solid. The reaction is refluxed under N atmosphere 12 hours. The Solvent is evaporated and the residue is purified by Silica gel 0292 To a cooled mixture of macrocyclic precursor flash chromatography using different ratioS of hexanes: E 1,3-(thiophen-2-yl)-1H-quinoxalin-2-one 2a (1.1 equiv.), tOAc as elution phase (9:1->5:1->3:1-> 1:1->1:2-> 1:5). and triphenylphosphine (2 equiv.) in THF was added DIAD The cyclic peptide precursor 1 is isolated as a white powder (2 equiv.) dropwise at 0°C. The resulting mixture was held US 2004/0266668A1 Dec. 30, 2004 34 at 0° C. for 15 min. before being warmed to room tempera 4.75 (1H), 4.23 (1H), 4.12 (1H), 2.65-2.75 (2H), 2.52 (1H), ture. After 18 hours, the mixture was concentrated under 2.21 (1H), 1.97 (1H), 1.80 (1H), 1.62 (2H), 1.54 (1H), 1.47 Vacuum and the residue was purified by chromatography (2H), 1.44 (2H), 1.41 (2H), 1.09 (9H). eluting with 60% ethyl acetate-hexane to give 2b as a clear oil (35 mg, 99%). 0297) 'C-NMRCDOD, 8 (ppm): 176.2, 1741, 1734, 0293 MS (found): 7044 (M+H). Hi-NMR CDC1, 8 156.0, 152.9, 1410, 139.6, 138.9, 138.6, 131.5, 130.6, (ppm): 8.6 (d. 1H), 8.0 (d. 1H), 7.8 (d. 1H), 7.6 (m, 2H), 7.5 130.0, 129.3, 128.1, 127.8, 127.1, 126.6, 78.6, 76.1, 59.8, (d. 2H), 7.2 (t, 1H), 7.0 (brs, 1H), 6.0 (brt, 1H), 5.5 (m, 1H), 53.3, 52.3, 41.4, 34.5, 32.3, 30.0, 27.5, 27.4, 27.2 (3C), 26.1, 5.3 (brd, 1H), 5.2 (t, 1H), 5.0 (m. 1H), 4.6 (brt, 1H), 4.1-4.3 22.6, 22.4. (m, 3H), 3.1 (m, 1H), 5.3 (m, 1H), 2.1-2.3 (m, 2H), 1.3 (brs, 9H), 1.2 (t, 3H). Example 3 0294 Step 2B. Compound of Formula I, Wherein A=tBOC, G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are phenyl, W is Absent, Z=2-(formamido)-thiazol-4-yl, ji=3, m=S=1, and Rs=Re=hydrogen 0298 Step 3A. g Ho NH2
--
OEt No NH2 3a
S /so O /NNH EtOH N He
1n O 3b
S /so N ANNH
No N O H 3c 0295) A solution of compound 2b and lithium hydroxide (10 equiv.) in THF/MeOH/HO (2:1:0.5) was stirred at room temperature for 20 hours. The exceSS Solvents were evapo 0299 Commercially available 4-Methoxy-benzene-1,2- rated in vacuo, the resulting residue was diluted with water, diamine 3a (3.6 mmol) and (2-Formylamino-thiazol-4-yl)- followed by acidification to pH -5. The mixture was oxo-acetic acid ethyl ester 3b (1 equiv.) in ethanol (40 mL) extracted 2 times with ethyl acetate. The combined organic was heated to reflux for 5 hours. After the mixture was extracts were washed once with brine, dried (MgSO4), filtered and concentrated in vacuo to give an oily residue, cooled to room temperature, the exceSS ethanol was evapo which was purified by column chromatography eluting with rated in vacuo, and the residue was placed under high Vacuum for 2 hours to give compound 3c as a greenish 2-10% methanol-chloroform (87%). yellow powder. 0296) MS (found): 676.3 H-NMR (CDOD, 8 (ppm): 8.14 (1H), 7.96 (1H), 7.86 (1H), 7.65 (1H), 7.62 (1H), 7.59 0300 MS (found): 303.1 (M+H). Hi-NMR (DMSO-d, 8 (1H), 7.19 (1H), 6.07 (1H), 5.53 (1H), 5.52(1H), 4.81 (1H), (ppm): 8.7 (s, 1H), 8.6 (m, 2H), 7.2-7.3 (m, 4H), 3.8 (s.3H). US 2004/0266668A1 Dec. 30, 2004 35
0301 Step 3B.
S /so OH N ANNH OC n N O No N O H OEt X DIAD (2 eq), PPhs (2 eq)THF
S
No CCCs O
OEt
3d
0302) To a cooled mixture of 1, quinoxalin-2-one 3c (1.1 Example 4 equiv.), triphenylphosphine (2 equiv.) in THF was added DIAD (2 equiv.) dropwise at 0°C. The resulting mixture was Compound of Formula I, Wherein A=tBOC, kept at 0°C. for 15 min. before warming to room tempera G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are ture. After 18 hours, the mixture was concentrated in vacuo phenyl, W is Absent, Z=ethyl, j=3, m=S=1, and and the residue was purified by chromatography eluting with R=R=hydrogen 80-100% ethyl acetate-hexane to give 3d as a yellow oil. 0307 The title compound is prepared with 3-ethyl-1H 0303 MS (found): 778.5 (M+H). quinoxalin-2-one and the title compound from Example 1 under the Mitsunobu conditions described in Example 2, 0304) Step 3C. followed by the reduction of the ethyl ester via treatment 0305) A solution of 3d and lithium hydroxide (10 equiv.) with LiOH as elucidated in Example 2. in THF/MeOH/HO (2:1:0.5) was stirred at room tempera ture for 20 hours. The excess solvent was evaporated in Example 5 vacuo, the residue was diluted with water and followed by Compound of Formula I, Wherein A=tBOC, acidification to pH -5. The mixture was extracted 2 times G=OH, L=Absent, X and Y Taken Together with with ethyl acetate. The combined organic extracts were the Carbon Atoms to which they are Attached are washed once with brine, dried (MgSO4), filtered and con phenyl, W is Absent, Z=phenyl, j=3, m=S=1, and centrated in vacuo to give a Solid residue which was purified R=R=hydrogen by HPLC to give. 0308 The title compound is prepared with 3-phenyl-1H 0306 MS (found): 750.4 (M+H). MS (found): 722.4 quinoxalin-2-one and the title compound from Example 1 (M+H). under the Mitsunobu conditions described in Example 2, US 2004/0266668A1 Dec. 30, 2004 36 followed by the reduction of the ethyl ester via treatment title compound from Example 1 under the Mitsunobu con with LiOH as elucidated in Example 2. ditions described in Example 2, followed by the reduction of the ethyl ester via treatment with LiOH as elucidated in Example 6 Example 2. Compound of Formula I, Wherein A=tBOC, Example 11 G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are Compound of Formula I, Wherein A=tBOC, phenyl W is Absent, Z=4-methoxyphenyl, j=3, G=OH, L=Absent, X and Y Taken Together with m=S=1, and Rs =R=hydrogen the Carbon Atoms to which they are Attached are 0309 The title compound is prepared with 3-(4-methox phenyl, W is Absent, Z=2-thiophen-2-yl ethylenyl, yphenyl)-1H-quinoxalin-2-one and the title compound from j=3, m=S=1, and Rs=R=hydrogen Example 1 under the Mitsunobu conditions described in 0314. The title compound is prepared with 3-2-thiophen Example 2, followed by the reduction of the ethyl ester via 2-yl-Vinyl)-1H-quinoxalin-2-one and the title compound treatment with LiOH as elucidated in Example 2. from Example 1 under the Mitsunobu conditions described Example 7 in Example 2, followed by the reduction of the ethyl ester via treatment with LiOH as elucidated in Example 2. Compound of Formula I, Wherein A=tBOC, G=OH, L=Absent, X and Y Taken Together with Example 12 the Carbon Atoms to which they are Attached are phenyl, W is Absent, Z=4-ethoxyphenyl, j=3, Compound of Formula I, Wherein A=tBOC, m=S=1, and Rs=Re=hydrogen G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are 0310 The title compound is prepared with 3-(4-ethox phenyl, Z=indole-2-yl, j=3, m=S=1, and yphenyl)-1H-quinoxalin-2-one and the title compound from Rs=Re=hydrogen Example 1 under the Mitsunobu conditions described in Example 2, followed by the reduction of the ethyl ester via Preparation of treatment with LiOH as elucidated in Example 2. 3-(1H-Indol-3-yl)-1H-quinoxalin-2-one Example 8 0315. The quinoxalin-2-one of the present example is prepared by heating the commercially available phenyl-1,2- Compound of Formula I, Wherein A=tBOC, diamine (3.6 mmol) and indole-3-glyoxylic acid (1 equiv.) in G=OH, L=Absent, X and Y Taken Together with ethanol (40 mL) to reflux for 5 hours. After the mixture is the Carbon Atoms to which they are Attached are cooled to room temperature, the exceSS ethanol was evapo phenyl, W is Absent, Z=5-bromothiophen-2-yl, j=3, rated in vacuo, and the residue is placed under high Vacuum m=S=1, and Rs=Re=hydrogen for 2 hours to give 3-(1H-Indol-3-yl)-1H-quinoxalin-2-one. 0311. The title compound is prepared with 3-(5-bromo thiophen-2-yl)-1H-quinoxalin-2-one and the title compound 0316 Mitsunobu Coupling to Macrocycle from Example 1 under the Mitsunobu conditions described 0317. The title compound is prepared with 3-(1H-Indol in Example 2, followed by the reduction of the ethyl ester via 3-yl)-1H-quinoxalin-2-one and the title compound from treatment with LiOH as elucidated in Example 2. Example 1 under the Mitsunobu conditions described in Example 2, followed by the reduction of the ethyl ester via Example 9 treatment with LiOH as elucidated in Example 2. Compound of Formula I, Wherein A=tBOC, G=OH, L=Absent X and Y Taken Together with Example 13 the Carbon Atoms to which they are Attached are phenyl, W is Absent, Z=2-pyrid-3-yl ethylenyl j=3, Compound of Formula I, Wherein A=tBOC, m=S=1, and R=R=hydrogen G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are 0312 The title compound is prepared with 3-2-(pyrid phenyl, W is absent, Z=1H-indol-3-yl methyl, j=3, 3-yl)-Vinyl)-1H-quinoxalin-2-one and the title compound m=S=1, and Rs=Re=hydrogen from Example 1 under the Mitsunobu conditions described in Example 2, followed by the reduction of the ethyl ester via Preparation of treatment with LiOH as elucidated in Example 2. 3-(1H-Indol-3-ylmethyl)-1H-quinoxalin-2-one Example 10 0318. The quinoxalin-2-one of the present example is prepared with phenyl-1,2-diamine and indole-3-pyruvic acid Compound of Formula I, Wherein A=tBOC, via the method described in Example 12 to afford 3-(1H G=OH, L=Absent, X and Y Taken Together with Indol-3-ylmethyl)-1H-quinoxalin-2-one. the Carbon Atoms to which they are Attached are phenyl, W is Absent, Z=3,4-Dimethoxy-phenyl, 0319 Mitsunobu Coupling to Macrocycle ji=3, m=S=1, and Rs=Re=hydrogen 0320 The title compound is prepared with 3-(1H-Indol 0313 The title compound is prepared with 3-2-(3,4- 3-ylmethyl)-1H-quinoxalin-2-one and the title compound Dimethoxy-phenyl)-vinyl)-1H-quinoxalin-2-one and the from Example 1 under the Mitsunobu conditions described US 2004/0266668A1 Dec. 30, 2004 37 in Example 2, followed by the reduction of the ethyl ester via 0328 Mitsunobu Coupling to Macrocycle treatment with LiOH as elucidated in Example 2. 0329. The title compound is prepared with 3-(1H-Imida Example 14 Zol-2-ylmethyl)-1H-quinoxalin-2-one and the title com pound from Example 1 under the Mitsunobu conditions Compound of Formula I, Wherein A=tBOC, described in Example 2, followed by the reduction of the G=OH, L=Absent, X and Y Taken Together with ethyl ester via treatment with LiOH as elucidated in the Carbon Atoms to which they are Attached are Example 2. phenyl, W is Absent, Z=furan-2-yl, ji=3, m=S=1, and Rs=Re=hydrogen Example 17 Compound of Formula I, Wherein A=tBOC, Preparation of 3-(furan-2-yl)-1H-quinoxalin-2-one G=OEt, L=Absent, X and Y Taken Together with 0321) The quinoxalin-2-one of the present example is the Carbon Atoms to which they are Attached are prepared with phenyl-1,2-diamine and furan-2-ylglyoxylic phenyl, W is Absent, Z=chloro, j=3,m=S=1, and acid via the method described in Example 12 to afford Rs=Re=hydrogen 3-(furan-2-yl)-1H-quinoxalin-2-one. Preparation of 3-chloro-1H-quinoxalin-2-one 0322 Mitsunobu Coupling to Macrocycle 0330. The quinoxalin-2-one of the present example is 0323 The title compound is prepared with 3-(furan-2- prepared with phenyl-1,2-diamine and Oxalic acid via the yl)-1H-quinoxalin-2-one and the title compound from method described in Example 12 to afford the 1,4-Dihydro Example 1 under the Mitsunobu conditions described in quinoaxline-2,3-dione. The 1,4-Dihydro quinoaxline-2,3-di Example 2, followed by the reduction of the ethyl ester via one is then treated with SOCl in 2.5% DMF:toluene, heated treatment with LiOH as elucidated in Example 2. to 130 C., stirred for 2 h, filtered and concentrated to afford the 3-chloro-1H-quinoxalin-2-one in crude form. Example 15 0331 Mitsunobu Coupling to Macrocycle Compound of Formula I, Wherein A=tBOC, 0332 The title compound is prepared with 3-chloro-1H G=OH, L=Absent, X and Y Taken Together with quinoxalin-2-one and the title compound from Example 1 the Carbon Atoms to which they are Attached are under the Mitsunobu conditions described in Example 2. phenyl, W is Absent, Z=1H-benzoimidazol-2-yl, j=3, m=S=1, and R=R=hydrogen Example 18 Preparation of 3-(1H-benzoimidazol-2-yl)-1-H-qui Compound of Formula I, Wherein A=tBOC, noXalin-2-one G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are 0324. The quinoxalin-2-one of the present example is phenyl, Z=thiophen-3-yl, j=3, m=S=1, and prepared with phenyl-1,2-diamine and (1H-benzoimidazol Rs=Re=hydrogen 2-yl) oxo-acetic acid via the method described in Example 12 to afford 3-(1H-benzoimidazol-2-yl)-1H-quinoxalin-2- 0333) To a mixture of the title compound of Example 17 (0.055 mmol), 3-thiophene boronic acid (0.28 mmol), Oc. cesium carbonate (0.22 mmol), potassium fluoride mono 0325 Mitsunobu Coupling to Macrocycle hydrate (0.44 mmol) is placed in a round bottom flask and 0326 The title compound is prepared with 3-(1H-ben is flushed twice with nitrogen. To this mixture is added DME Zoimidazol-2-yl)-1H-quinoxalin-2-one and the title com and the resulting Solution is flushed again with nitrogen pound from Example 1 under the Mitsunobu conditions before palladium tetrakis(triphenylphopshine) (10 mol%) is described in Example 2, followed by the reduction of the added. After flushing two more times with nitrogen, the ethyl ester via treatment with LiOH as elucidated in mixture is heated to reflux for 20 hours. The mixture is then Example 2. cooled and then diluted with water and extracted three times with EtOAc. The combined EtOAc layers are washed once Example 16 with brine, dried (MgSO), filtered and concentrated in vacuo. The residue is purified by column chromatography Compound of Formula I, Wherein A=tBOC, eluting with 20-40%. EtOAc-hexane to yield the ethyl ester G=OH, L=Absent, X and Y Taken Together with precursor of the title compound. The ethyl ester is then the Carbon Atoms to which they are Attached are hydrolyzed to the free acid via treatment with LiOH as phenyl W is Absent, Z=1H-imidazol-2-ylmethyl, elucidated in Example 2 to arrive at the title compound. j=3, m=S=1, and R=R=hydrogen Example 19 Preparation of Compound of Formula I, Wherein A=tBOC, 3-(1H-Imidazol-2-ylmethyl)-1H-quinoxalin-2-one G=OH, L=Absent, X and Y Taken Together with 0327. The quinoxalin-2-one of the present example is the Carbon Atoms to which they are Attached are prepared with phenyl-1,2-diamine and (1H-benzoimidazol phenyl, W is Absent, Z=2-pyrid-3-yl acetylenyl, 2-yl) oxo-acetic acid via the method described in Example ji=3, m=S=1, and Rs=Re=hydrogen 12 to afford 3-(1H-Imidazol-2-ylmethyl)-1H-quinoxalin-2- 0334. The title compound is prepared by reaction of a Oc. degassed Solution of the title compound from Example 17 (4 US 2004/0266668A1 Dec. 30, 2004 38 mmol), 2-pyrid-3-yl acetylene (4 mmol), and 1 ml of tri pound. The ethyl ester is then hydrolyzed to the free acid via ethylamine and 10 ml of acetonitrile with PdCl2(PPh3) (0.2 treatment with LiOH to arrive upon the title compound. mmol) and Cul (0.1 mmol). The resulting reaction mixture is degassed and Stirred for 5 minutes at room temperature. Example 23 The reaction is then heated to 90° C. and stirred for 12 hours. Compound of Formula I, Wherein A=tBOC, Subsequently, the reaction mixture is concentrated in vacuo G=OH, L=Absent, X and Y Taken Together with and purified by silica column to afford the ethyl ester of the the Carbon Atoms to which they are Attached are title compound. The ethyl ester is then hydrolyzed to the free phenyl, W=-NH-, Z=pyrid-3-yl, j=3, m=s=1, acid via treatment with LiOH as elucidated in Example 2 to and Rs=Re=hydrogen arrive at the title compound. 0338. The title compound is formed by reacting a 0.1M Example 20 solution of the title compound from Example 17 in DMF with 3-aminopyridine (1.2 equiv.) in the presence of K2CO Compound of Formula I, Wherein A=tBOC, (2 equiv.) at room temperature for 5-12 hours. The resulting G=OH, L=Absent, X and Y Taken Together with reaction mixture is then extracted with EtOAc, washed with the Carbon Atoms to which they are Attached are NaHCO, water, and brine, and the washed extract is con phenyl, W is Absent, centrated in vacuo. The residue is then purified by Silica Z=2,3-dihydrobenzofuran-5-yl, j=3,m=s=1, and chromatography to yield the ethyl ester of the title com Rs=Re=hydrogen pound. The ethyl ester is then hydrolyzed to the free acid via treatment with LiOH to arrive upon the title compound. 0335) To a degassed solution of the title compound of Example 17 (1 mmol) and 2,3-dihydrobenzofuran-5-yl stan Example 24 nane (2 mmol) is added Pd(PPh) (10 mol%). The mixture is degassed with nitrogen two additional times and heated to Compound of Formula I, Wherein A=tBOC, 100° C. for 3 hours. The cooled mixture is concentrated in G=OH, L=Absent, X and Y Taken Together with vacuo and the residue is purified by column chromatography the Carbon Atoms to which they are Attached are (30% EtOAc/Hexane) to give the ethyl ester of the title phenyl, W is Absent, Z=tetrazolyl, j=3, m=s=1, and compound. The ethyl ester is then hydrolyzed via treatment Rs=Re=hydrogen with LiOH as elucidated in Example 2 to give the title 0339. The title compound is formed by reacting a 0.1M compound. solution of the title compound from Example 17 in DMF with tetrazole (1.2 equiv.) in the presence of KCO (2 Example 21 equiv.) at room temperature for 5-12 hours. The resulting reaction mixture is then extracted with EtOAc, washed with Compound of Formula I, Wherein A=tBOC, NaHCO, water, and brine, and the washed extract is con G=OH, L=Absent, X and Y Taken Together with centrated in vacuo. The residue is then purified by Silica the Carbon Atoms to which they are Attached are chromatography to yield the ethyl ester of the title com phenyl, W=-NH-, Z=propargyl, ji=3, m=S=1, pound. The ethyl ester is then hydrolyzed to the free acid via and Rs=Re=hydrogen treatment with LiOH to arrive upon the title compound. 0336. The title compound is formed by reacting a 0.1M Example 25 solution of the title compound from Example 17 in DMF with propargylamine (1.2 equiv.) in the presence of K2CO Compound of Formula I, Wherein A=tBOC, (2 equiv.) at room temperature for 5-12 hours. The resulting G=OH, L=Absent, X and Y Taken Together with reaction mixture is then extracted with EtOAc, washed with the Carbon Atoms to which they are Attached are NaHCO, water, and brine, and the washed extract is con phenyl, W is Absent, Z=morpholino, ji=3, m=s=1, centrated in vacuo. The residue is then purified by Silica and Rs=R=hydrogen chromatography to yield the ethyl ester of the title com 0340. The title compound is formed by reacting a 0.1M pound. The ethyl ester is then hydrolyzed to the free acid via solution of the title compound from Example 17 in DMF treatment with LiOH to arrive upon the title compound. with morpholine (1.2 equiv.) in the presence of KCO (2 equiv.) at room temperature for 5-12 hours. The resulting Example 22 reaction mixture is then extracted with EtOAc, washed with NaHCO, water, and brine, and the washed extract is con Compound of Formula I, Wherein A=tBOC, centrated in vacuo. The residue is then purified by Silica G=OH, L=Absent, X and Y Taken Together with chromatography to yield the ethyl ester of the title com the Carbon Atoms to which they are Attached are pound. The ethyl ester is then hydrolyzed to the free acid via phenyl, W=-N(ethyl)-, Z=benzyl, j=3, m=s=1, treatment with LiOH to arrive upon the title compound. and Rs=R=hydrogen Example 26 0337 The title compound is formed by reacting a 0.1M solution of the title compound from Example 17 in DMF Compound of Formula I, Wherein A=tBOC, with benzylethylamine (1.2 equiv.) in the presence of KCOs G=OH, L=Absent, X and Y Taken Together with (2 equiv.) at room temperature for 5-12 hours. The resulting the Carbon Atoms to which they are Attached are reaction mixture is then extracted with EtOAc, washed with phenyl, W=-O-, Z=thiophen-3-yl-methyl, j=3, NaHCO, water, and brine, and the washed extract is con m=S=1, and Rs=Re=hydrogen centrated in vacuo. The residue is then purified by Silica 0341 The title compound is formed by reacting a 0.1M chromatography to yield the ethyl ester of the title com solution of the title compound from Example 17 in DMF US 2004/0266668A1 Dec. 30, 2004 39 with thiophen-3-yl methanol (1.2 equiv.) in the presence of 2-(thiophen-2-yl) oxoacetic acid (1 equiv.) in DMF in the KCO (2 equiv.) at room temperature for 5-12 hours. The presence of DCC at room temperature to 80 C. to arrive at resulting reaction mixture is then extracted with EtOAc, the precursor 2-nitro amide (N-(4-Methoxy-2-nitro-phenyl)- washed with NaHCO, water, and brine, and the washed 2-oxo-2-thiophen-2-yl-acetamide). The precursor 2-nitro extract is concentrated in vacuo. The residue is then purified amide is Subjected to catalytic hydrogenation conditions by silica chromatography to yield the ethyl ester of the title (H/Pd/C in MeOH) forming the amine followed by ring compound. The ethyl ester is then hydrolyzed to the free acid closure to form 6-Methoxy-3-thiophen-2-yl-1H-quinoxalin via treatment with LiOH to arrive upon the title compound. 2-one. Example 27 0350 Mitsunobu Coupling to Macrocycle 0351. The title compound is prepared with 6-Methoxy Compound of Formula I, Wherein A=tBOC, 3-thiophen-2-yl-1H-quinoxalin-2-one and the title com G=OH, L=Absent, X and Y Taken Together with pound from Example 1 under the Mitsunobu conditions the Carbon Atoms to which they are Attached are described in Example 2, followed by the reduction of the ethyl ester via treatment with LiOH as elucidated in 0342 Example 2. Example 29 Compound of Formula I, Wherein A=tBOC, G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are O352 0343 W is Absent, Z=thiophen-2-yl, j=3, m=S=1, and Rs=Re=hydrogen Preparation of No s 7-Methoxy-3-thiophen-2-yl-1H-quinoxalin-2-one 0344) The quinoxalin-2-one of the present example is 0353 W is Absent, Z=thiophen-2-yl, j=3, m=S=1, and prepared with 4-Methoxy-benzene-1,2-diamine and R=R=hydrogen (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 7-Methoxy-3-thiophen-2-yl-1H-qui Preparation of noXalin-2-one. 6,7-Methoxy-3-thiophen-2-yl-1-H-quinoxalin-2-one 0354) The quinoxalin-2-one of the present example is 0345 Mitsunobu Coupling to Macrocycle prepared with 4,5-Dimethoxy-benzene-1,2-diamine and 0346) The title compound is prepared with 7-Methoxy (thiophen-2-yl) oxo-acetic acid via the method described in 3-thiophen-2-yl-1H-quinoxalin-2-one and the title com Example 12 to afford 6,7-Methoxy-3-thiophen-2-yl-1H-qui pound from Example 1 under the Mitsunobu conditions noxalin-2-one. described in Example 2, followed by the reduction of the ethyl ester via treatment with LiOH as elucidated in 0355 Mitsunobu Coupling to Macrocycle Example 2. 0356. The title compound is prepared with 6,7-Methoxy 3-thiophen-2-yl-1H-quinoxalin-2-one and the title com Example 28 pound from Example 1 under the Mitsunobu conditions described in Example 2, followed by the reduction of the Compound of Formula I, Wherein A=tBOC, ethyl ester via treatment with LiOH as elucidated in G=OH, L=Absent, X and Y Taken Together with Example 2. the Carbon Atoms to which they are Attached are 0347) Example 30 Compound of Formula I, Wherein A=tBOC, -O G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are 0357) 0348 W is Absent, Z=thiophen-2-yl, j=3, m=S=1, and Rs=Re=hydrogen N Preparation of 7-Methoxy-3-thiophen-2-yl-1H-quinoxalin-2-one 0349 The 2-nitro amide precursor of the present example is prepared with 4-Methoxy-2-nitroaniline (1 equiv.) and US 2004/0266668A1 Dec. 30, 2004 40
W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and Example 32 R=R=hydrogen Compound of Formula I, Wherein A=tBOC, Preparation of G=OH, L=Absent, X and Y Taken Together with 6-cyano-3-thiophen-2-yl-1H-quinoxalin-2-one the Carbon Atoms to which they are Attached are 0358. The quinoxalin-2-one of the present example is 0365) prepared with 4-cyano-benzene-1,2-diamine and (thiophen 2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-cyano-3-thiophen-2-yl-1H-quinoxalin-2-one. 21 0359 Mitsunobu Coupling to Macrocycle N 0360 The title compound is prepared with 6-cyano-3- thiophen-2-yl-1H-quinoxalin-2-one and the title compound from Example 1 under the Mitsunobu conditions described in Example 2, followed by the reduction of the ethyl ester via W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and treatment with LiOH as elucidated in Example 2. Rs=Re=hydrogen Example 31 Preparation of 2-Thiophen-2-yl-4H-pyrido 2,3-bipyrazin-3-one Compound of Formula I, Wherein A=tBOC, G=OH, L=Absent, X and Y Taken Together with 0366 The quinoxalin-2-one of the present example is the Carbon Atoms to which they are Attached are prepared with 2,3-diamino pyridine and (thiophen-2-yl) OXO-acetic acid via the method described in Example 12 to 0361) afford 2-thiophen-2-yl-4H-pyrido 2,3-bipyrazin-3-one. 0367 Mitsunobu Coupling to Macrocycle 0368. The title compound is prepared with 2-thiophen 2-yl-4H-pyrido2,3-bipyrazin-3-one and the title compound from Example 1 under the Mitsunobu conditions described in Example 2, followed by the reduction of the ethyl ester via treatment with LiOH as elucidated in Example 2. Example 33 Compound of Formula I, Wherein A=tBOC, G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are 0369) W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and Rs=Re=hydrogen Preparation of 6-tetrazol-5-yl-3-thiophen-2-yl-1H quinoxalin-2-one 0362. The quinoxalin-2-one of the present example is prepared with 4-cyano-benzene-1,2-diamine and (thiophen 2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-cyano-3-thiophen-2-yl-1H-quinoxalin-2-one. W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and The cyano compound is then treated with NaNs (5 eqiv.), R=R=hydrogen EtN (3 equiv.), in Xylenes in a sealed tube and heated to 140° C. and stirred 12 hours to afford the 6-tetrazol-5-yl-3- Preparation of 7-Thiophen-2-yl-5H-1,3-dioxa-5,8- thiophen-2-yl-1H-quinoxalin-2-one after extraction and diaza-cyclopentablnaphthalen-6-one purification. 0370. The quinoxalin-2-one of the present example is 0363 Mitsunobu Coupling to Macrocycle prepared with Benzo1,3dioxole-5,6-diamine and (thiophen-2-yl) oxo-acetic acid via the method described in 0364. The title compound is prepared withó-tetrazol-5- Example 12 to afford 7-thiophen-2-yl-5H-1,3-dioxa-5,8- yl-3-thiophen-2-yl-1H-quinoxalin-2-one and the title com diaza-cyclopentablnaphthalen-6-one. pound from Example 1 under the Mitsunobu conditions described in Example 2, followed by the reduction of the 0371 Mitsunobu Coupling to Macrocycle ethyl ester via treatment with LiOH as elucidated in 0372 The title compound is prepared with 7-thiophen Example 2. 2-yl-5H-1,3-dioxa-5,8-diaza-cyclopentablnaphthalen-6- US 2004/0266668A1 Dec. 30, 2004 one and the title compound from Example 1 under the (thiophen-2-yl) oxo-acetic acid via the method described in Mitsunobu conditions described in Example 2, followed by Example 12 to afford 6-Methanesulfonyl-3-thiophen-2-yl the reduction of the ethyl ester via treatment with LiOH as 1H-quinoxalin-2-one. elucidated in Example 2. 0379 Mitsunobu Coupling to Macrocycle Example 34 0380 The title compound is prepared with 6-Methane sulfonyl-3-thiophen-2-yl-1H-quinoxalin-2-one and the title Compound of Formula I, Wherein A=tBOC, compound from Example 1 under the Mitsunobu conditions G=OH, L=Absent, X and Y Taken Together with described in Example 2, followed by the reduction of the the Carbon Atoms to which they are Attached are ethyl ester via treatment with LiOH as elucidated in Example 2. 0373) Example 36 Compound of Formula I, Wherein A=tBOC, G=OH, L=Wbsent, X and Y Taken Together with the Carbon Atoms to which they are Attached are CC 0381)
W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and R=R=hydrogen Preparation of 3-Thiophen-2-yl-1H-benzogquinoxalin-2-one 0374. The quinoxalin-2-one of the present example is prepared with napthylene-2,3-diamine and (thiophen-2-yl) OXO-acetic acid via the method described in Example 12 to W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and afford 3-Thiophen-2-yl-1H-benzogquinoxalin-2-one. R=R=hydrogen 0375 Mitsunobu Coupling to Macrocycle Preparation of 2-Oxo-3-thiophen-2-yl-1,2-dihydro 0376 The title compound is prepared with 3-Thiophen quinoxaline-6-sulfonic acid 2-yl-1H-benzogquinoxalin-2-one and the title compound 0382. The quinoxalin-2-one of the present example is from Example 1 under the Mitsunobu conditions described prepared with 3,4-Diamino-benzeneSulfonic acid and in Example 2, followed by the reduction of the ethyl ester via (thiophen-2-yl) oxo-acetic acid via the method described in treatment with LiOH as elucidated in Example 2. Example 12 to afford 2-Oxo-3-thiophen-2-yl-1,2-dihydro quinoxaline-6-sulfonic acid. Example 35 0383 Mitsunobu Coupling to Macrocycle Compound of Formula I, Wherein A=tBOC, 0384. The title compound is prepared with 2-Oxo-3- G=OH, L=Absent, X and Y Taken Together with thiophen-2-yl-1,2-dihydro-quinoxaline-6-sulfonic acid and the Carbon Atoms to which they are Attached are the title compound from Example 1 under the Mitsunobu conditions described in Example 2, followed by the reduc 0377) tion of the ethyl ester via treatment with LiOH as elucidated in Example 2. Example 37 Compound of Formula I, Wherein A=tBOC, G=OH, L=Absent X and Y Taken Together with the Carbon Atoms to which they are Attached are 0385) W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and R=R=hydrogen HO Preparation of 6-Methanesulfonyl-3-thiophen-2-yl-1H-quinoxalin-2-one 0378. The quinoxalin-2-one of the present example is prepared with 4-MethaneSulfonyl-benzene-1,2-diamine and US 2004/0266668A1 Dec. 30, 2004 42
W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and Example 39 R=R=hydrogen Compound of Formula I, Wherein A=tBOC, Preparation of G=OH, L=Absent, X and Y Taken Together with 6-Hydroxymethyl-3-thiophen-2-yl-1H-quinoxalin-2-one the Carbon Atoms to which they are Attached are 0386 The quinoxalin-2-one of the present example is 0393) prepared with (3,4-Diamino-phenyl)-methanol and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 6-Hydroxymethyl-3-thiophen-2-yl 1H-quinoxalin-2-one. 0387 Mitsunobu Coupling to Macrocycle 0388. The title compound is prepared with 6-Hydroxym ethyl-3-thiophen-2-yl-1H-quinoxalin-2-one and the title compound from Example 1 under the Mitsunobu conditions described in Example 2, followed by the reduction of the W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and ethyl ester via treatment with LiOH as elucidated in R=R=hydrogen Example 2. Preparation of Example 38 6-Nitro-3-thiophen-2-yl-1H-quinoxalin-2-one 0394. The quinoxalin-2-one of the present example is Compound of Formula I, Wherein A=tBOC, prepared with 4-Nitro-benzene-1,2-diamine and (thiophen G=OH, L=Absent, X and Y Taken Together with 2-yl) oxo-acetic acid via the method described in Example the Carbon Atoms to which they are Attached are 12 to afford 6-Nitro-3-thiophen-2-yl-1H-quinoxalin-2-one. 0389) 0395 Mitsunobu Coupling to Macrocycle 0396 The title compound is prepared with 6-Nitro-3- thiophen-2-yl-1H-quinoxalin-2-one and the title compound from Example 1 under the Mitsunobu conditions described in Example 2, followed by the reduction of the ethyl ester via treatment with LiOH as elucidated in Example 2. Example 40 Compound of Formula I, Wherein A=tBOC, G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and 0397) Rs=Re=hydrogen
Preparation of 6-Piperidin-1-ylmethyl-3-thiophen-2- HN y1-1H-quinoxalin-2-one 0390 The quinoxalin-2-one of the present example is prepared first via Swern oxidation with DMSO and (COCl). of 6-Hydroxymethyl-3-thiophen-2-yl-1H-quinoxalin-2-one to form 2-Oxo-3-thiophen-2-yl-1,2-dihydro-quinoxaline-6- carbaldehyde. The 6-carboxaldehyde compound then under W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and goes reductive amination with piperidine in acetonitrile in Rs=Re=hydrogen the presence of NaCNBH and acetic acid to afford, after an aqueous workup and purification, 6-Piperidin-1-ylmethyl-3- Preparation of thiophen-2-yl-1H-quinoxalin-2-one. 6-amino-3-thiophen-2-yl-1H-quinoxalin-2-one 0391 Mitsunobu Coupling to Macrocycle 0398. The quinoxalin-2-one of the present example is prepared by reducing 6-nitro-3-thiophen-2-yl-1H-quinoxa 0392 The title compound is prepared with 6-Piperidin lin-2-one of Example 39 with HNNH.HO in the presence 1-ylmethyl-3-thiophen-2-yl-1H-quinoxalin-2-one and the of Pd/C in refluxing MeOH. title compound from Example 1 under the Mitsunobu con ditions described in Example 2, followed by the reduction of 0399 Mitsunobu Coupling to Macrocycle the ethyl ester via treatment with LiOH as elucidated in 0400. The title compound is prepared with 6-amino-3- Example 2. thiophen-2-yl-1H-quinoxalin-2-one and the title compound US 2004/0266668A1 Dec. 30, 2004 43 from Example 1 under the Mitsunobu conditions described 04.07 Mitsunobu Coupling to Macrocycle in Example 2, followed by the reduction of the ethyl ester via 0408. The title compound is prepared with 6-Nitro-3- treatment with LiOH as elucidated in Example 2. thiophen-2-yl-1H-quinoxalin-2-one and the title compound from Example 1 under the Mitsunobu conditions described Example 41 in Example 2, followed by the reduction of the ethyl ester via treatment with LiOH as elucidated in Example 2. Compound of Formula I, Wherein A=tBOC, G=OH, L=Absent, X and Y Taken Together with Example 43 the Carbon Atoms to which they are Attached are Compound of Formula I, Wherein A=tBOC, 0401) G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are 04.09 HO
W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and R=R=hydrogen Rs=Re=hydrogen Preparation of Preparation of N-(2-Oxo-3-thiophen-2-yl-1,2-dihy 6-hydroxy-3-thiophen-2-yl-1H-quinoxalin-2-one dro-quinoxalin-6-yl)-2-phenyl-acetamide 0410 The quinoxalin-2-one of the present example is 0402. The quinoxalin-2-one of the present example is prepared with 3,4-diaminophenol (which is prepared by prepared by treating 6-amino-3-thiophen-2-yl-1H-quinoxa treating 3,4-dinitrophenol with HNNH.HO, Pd/C lin-2-one of Example 40 with phenethyl acid chloride to refluxed in MeOH), and (thiophen-2-yl) oxo-acetic acid via afford, after workup and purification, N-(2-Oxo-3-thiophen the method described in Example 12 to afford 6-hydroxy 2-yl-1,2-dihydro-quinoxalin-6-yl)-2-phenyl-acetamide. 3-thiophen-2-yl-1H-quinoxalin-2-one. 0403 Mitsunobu Coupling to Macrocycle 0411 Mitsunobu Coupling to Macrocycle 0412. The title compound is prepared with 6-hydroxy-3- 04.04 The title compound is prepared with N-(2-Oxo-3- thiophen-2-yl-1H-quinoxalin-2-one and the title compound thiophen-2-yl-1,2-dihydro-quinoxalin-6-yl)-2-phenyl-aceta from Example 1 under the Mitsunobu conditions described mide and the title compound from Example 1 under the in Example 2, followed by the reduction of the ethyl ester via Mitsunobu conditions described in Example 2, followed by treatment with LiOH as elucidated in Example 2. the reduction of the ethyl ester via treatment with LiOH as elucidated in Example 2. Example 44 Example 42 Compound of Formula I, Wherein A=tBOC, G=OH, L=Absent, X and Y Taken Together with Compound of Formula I, Wherein A=tBOC, the Carbon Atoms to which they are Attached are G=OH, L=Absent, X and Y Taken Together with 0413) the Carbon Atoms to which they are Attached are 0405
W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and R=R=hydrogen W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and Preparation of Rs=Re=hydrogen 6-Benzyloxy-3-thiophen-2-yl-1H-quinoxalin-2-one Preparation of 0414. The quinoxalin-2-one of the present example is 6-Nitro-3-thiophen-2-yl-1H-quinoxalin-2-one prepared treating 6-hydroxy-3-thiophen-2-yl-1H-quinoxa lin-2-one from Example 43 in DMF with bromomethyl 0406. The quinoxalin-2-one of the present example is benzene in the presence of KCO at a temperature between prepared with 4-Nitro-benzene-1,2-diamine and (thiophen 25 C. to 80°C. The resulting reaction mixture, after workup 2-yl) oxo-acetic acid via the method described in Example and purification, affords 6-benzyloxy-3-thiophen-2-yl-1H 12 to afford 6-Nitro-3-thiophen-2-yl-1H-quinoxalin-2-one. quinoxalin-2-one. US 2004/0266668A1 Dec. 30, 2004 44
0415 Mitsunobu Coupling to Macrocycle line-6-carboxylic acid ethyl ester from Example 45 via the 0416) The title compound is prepared with 6-benzyloxy hydrolysis of the ethyl ester according to the procedure of 3-thiophen-2-yl-1H-quinoxalin-2-one and the title com Example 2 to afford the carboxylic acid. pound from Example 1 under the Mitsunobu conditions 0424) Step 40b described in Example 2, followed by the reduction of the ethyl ester via treatment with LiOH as elucidated in 0425 The carboxylic acid is then dissolved in DMF in Example 2. the presence of DCC and triethylamine and to the resulting reaction mixture is added (MeO)NHMe to form Weinreb's Example 45 amide. The Weinreb's amide is then treated with magnesium benzyl bromide in THF at -75 C. to afford, after extraction Compound of Formula I, Wherein A=tBOC, and purification, the 6-Phenylacetyl-3-thiophen-2-yl-1H G=OH, L=Absent, X and Y Taken Together with quinoxalin-2-one. the Carbon Atoms to which they are Attached are 0426 Mitsunobu Coupling to Macrocycle 0417 0427. The title compound is prepared with 6-Pheny lacetyl-3-thiophen-2-yl-1H-quinoxalin-2-one and the title HO compound from Example 1 under the Mitsunobu conditions described in Example 2, followed by the reduction of the ethyl esters via treatment with LiOH as elucidated in Example 2. W is Absent, Z =thiophen-2-yl, j=3, m=S=1, and Example 47 Rs=Re=hydrogen Compound of Formula I, Wherein A=tBOC, Preparation of 2-Oxo-3-thiophen-2-yl-1,2-dihydro G=OH, L=Absent, X and Y Taken Together with quinoxaline-6-carboxylic acid ethyl ester the Carbon Atoms to which they are Attached are 0418. The quinoxalin-2-one of the present example is 0428 prepared with 3,4-Diamino-benzoic acid ethyl ester and (thiophen-2-yl) oxo-acetic acid via the method described in Example 12 to afford 2-Oxo-3-thiophen-2-yl-1,2-dihydro quinoxaline-6-carboxylic acid ethyl ester. 0419 Mitsunobu Coupling to Macrocycle 0420. The title compound is prepared with 2-Oxo-3- thiophen-2-yl-1,2-dihydro-quinoxaline-6-carboxylic acid ethyl ester and the title compound from Example 1 under the Mitsunobu conditions described in Example 2, followed by the reduction of the ethyl esters via treatment with LiOH as elucidated in Example 2. W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and R=R=hydrogen Example 46 Preparation of 2-Oxo-3-thiophen-2-yl-1,2-dihydro Compound of Formula I, Wherein A=tBOC, quinoxaline-6-carboxylic acid benzylamide G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are 0429 Step 41a 0421) 0430. The quinoxalin-2-one of the present example is prepared with 2-OXO-3-thiophen-2-yl-1,2-dihydro-quinoxa line-6-carboxylic acid benzylamide from Example 45 via the hydrolysis of the ethyl ester according to the procedure of Example 2 to afford the carboxylic acid. 0431 Step 41b 0432. The carboxylic acid is then dissolved in DMF in the presence of DCC and triethylamine and to the resulting W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and reaction mixture is added benzyl amine to afford, after Rs=Re=hydrogen extraction and purification, 2-OXO-3-thiophen-2-yl-1,2-di Preparation of hydro-quinoxaline-6-carboxylic acid benzylamide. 6-Phenylacetyl-3-thiophen-2-yl-1H-quinoxalin-2-one 0433 Mitsunobu Coupling to Macrocycle 0422) Step 40a 0434. The title compound is prepared with 2-Oxo-3- 0423. The quinoxalin-2-one of the present example is thiophen-2-yl-1,2-dihydro-quinoxaline-6-carboxylic acid prepared with 2-OXO-3-thiophen-2-yl-1,2-dihydro-quinoxa benzylamide and the title compound from Example 1 under US 2004/0266668A1 Dec. 30, 2004 45 the Mitsunobu conditions described in Example 2, followed OXO-acetic acid via the method described in Example 12 to by the reduction of the ethyl esters via treatment with LiOH afford 6-bromo-3-thiophen-2-yl-1H-quinoxalin-2-one. as elucidated in Example 2. 0441 Mitsunobu Coupling to Macrocycle Example 48 0442. The title compound is prepared with 6-bromo-3- thiophen-2-yl-1H-quinoxalin-2-one and the title compound Compound of Formula I, Wherein A=tBOC, from Example 1 under the Mitsunobu conditions described G=OH, L=Absent, X and Y Taken Together with in Example 2 to afford the title compound. the Carbon Atoms to which they are Attached are Example 50 0435) Compound of Formula I, Wherein A=tBOC, G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are 0443) C ( N W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and R=R=hydrogen Preparation of 6-Phenethyl-3-thiophen-2-yl-1H-quinoxalin-2-one W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and 0436 The quinoxalin-2-one of the present example is Rs=Re=hydrogen prepared with 6-Phenylacetyl-3-thiophen-2-yl-1H-quinoxa lin-2-one from Example 46 via treatment with H2/Pd-C in 0444 To a degassed solution of the title compound of the presence of acetic acid to form the 6-phenethyl com Example 49 (1 mmol) and thiazol-2yl stannane (2 mmol) is pound. added Pd(PPh3), (10 mol%). The mixture is degassed with nitrogen two additional times and heated to 100° C. for 3 0437 Mitsunobu Coupling to Macrocycle hours. The cooled mixture is concentrated in vacuo and the 0438. The title compound is prepared with 6-Phenethyl residue is purified by column chromatography (30% EtOAc/ 3-thiophen-2-yl-1H-quinoxalin-2-one and the title com Hexane) to give the ethyl ester of the title compound. The pound from Example 1 under the Mitsunobu conditions ethyl ester is then hydrolyzed via treatment with LiOH as described in Example 2, followed by the reduction of the elucidated in Example 2 to give the title compound. ethyl esters via treatment with LiOH as elucidated in Example 2. Example 51 Compound of Formula I, Wherein A=tBOC, Example 49 G=OH, L=Absent, X and Y Taken Together with Compound of Formula I, Wherein A=tBOC, the Carbon Atoms to which they are Attached are G=OEt, L=Absent, X and Y Taken Together with 0445) the Carbon Atoms to which they are Attached are 0439) Br Oc
W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and R=R=hydrogen R=R=hydrogen 0446. To a mixture of the title compound of Example 49 Preparation of (0.055 mmol), phenyl boronic acid (0.28 mmol), cesium 6-bromo-3-thiophen-2-yl-1H-quinoxalin-2-one carbonate (0.22 mmol), potassium fluoride monohydrate (0.44 mmol) is placed in a round bottom flask and is flushed 0440 The quinoxalin-2-one of the present example is twice with nitrogen. To this mixture is added DME and the prepared with 4-bromo-2-nitroaniline and (thiophen-2-yl) resulting Solution is flushed again with nitrogen before US 2004/0266668A1 Dec. 30, 2004 46 palladium tetrakis(triphenylphopshine) (10 mol%) is added. W is Absent, Z=thiophen-2-yl, j=3,m=s=1, After flushing two more times with nitrogen, the mixture is Rs=Re=hydrogen heated to reflux for 20 hours. The mixture is then cooled and 0450. The title compound is prepared by adding to a dry then diluted with water and extracted three times with mixture of the title compound from Example 49 (0.068 EtOAc. The combined EtOAc layers are washed once with mmol), imidazole (2 eq.), CSCO (3 eq.), Xantphos (30 mol brine, dried (MgSO), filtered and concentrated in vacuo. %), and Pd(OAc) under nitrogen dioxane. The reaction The residue is purified by column chromatography eluting mixture is then degassed and stirred at 75 C. for 18 hours. with 20-40%. EtOAc-hexane to yield the ethyl ester precur Upon completion of the reaction, monitored via TLC, the sor of the title compound. The ethyl ester is then hydrolyzed reaction mixture is diluted with DCM, filtered, and concen to the free acid via treatment with LiOH as elucidated in trated in vacuo. The reaction mixture is then purified via Example 2 to arrive at the title compound. silica column chromatography with 5% MeOH/CHCl to afford the ethyl ester of the title compound. The ethyl ester Example 52 is then hydrolyzed by the conditions set forth in Example 2 to afford the title compound. Compound of Formula I, Wherein A=tBOC, G=OH, L=Absent, X and Y Taken Together with Example 54 the Carbon Atoms to which they are Attached are Compound of Formula I, Wherein A=-(C=O)- 0447) O-R', Wherein R'=cyclopentyl, G=OH, L=Ab sent, X and Y Taken Together with the Carbon Atoms to which they are Attached are phenyl, W is Absent, Z=thiophen-2-yl, j=3, m=S=1, and Rs=Re= hydrogen 0451 54a-Amine Deprotection. 0452 0.041 mmol of the title compound of Example 2 is dissolved in 4 ml of a 4M Solution of HCl in dioxane and Stirred for 1 hour. The reaction residue 54a is concentrated in vacuo. 0453 54b-Chloroformate Reagent 0454. The chloroformate reagent 54b is prepared by W is Absent, Z=thiophen-2-yl, j=3,m=s=1, dissolving 0.045 mmol of cyclopentanol in THF (3 Rs=Re=hydrogen ml) and adding 0.09 mmol of phosgene in toluene 0448. The title compound is prepared by reaction of a (20%). The resulting reaction mixture is stirred at degassed Solution of the title compound from Example 49 (4 room temperature for 2 hours and the Solvent is mmol), 2-pyrid-3-yl acetylene (4 mmol), and 1 ml of tri removed in vacuo. To the residue is added DCM and ethylamine and 10 ml of acetonitrile with PdCl2(PPh3) (0.2 Subsequently concentrated to dryneSS twice in vacuo mmol) and Cul (0.1 mmol). The resulting reaction mixture yielding chloroformate reagent 54b. is degassed and Stirred for 5 minutes at room temperature. 0455 54c-Carbamate Formation The reaction is then heated to 90° C. and stirred for 12 hours. 0456. The title carbamate is prepared by dissolving Subsequently, the reaction mixture is concentrated in vacuo residue 54a in 1 ml of THF, adding 0.045 mmol of and purified by silica column to afford the ethyl ester of the TEA, and cooling the resulting reaction mixture to 0 title compound. The ethyl ester is then hydrolyzed to the free C. To this O C. reaction mixture is added chloro acid via treatment with LiOH as elucidated in Example 2 to formate reagent 54b in 3 ml of THF. The resulting arrive at the title compound. reaction mixture is reacted for 2 hours at 0° C., extracted with EtOAc, washed by 1M sodium bicar Example 53 bonate, water and brine, dried over MgSO, and concentrated in vacuo to dryneSS. The crude com Compound of Formula I, Wherein A=tBOC, pound is purified by Silica column and the ethyl ester G=OH, L=Absent, X and Y Taken Together with is Subsequently hydrolyzed by the procedure Set the Carbon Atoms to which they are Attached are forth in Example 2. 0449) Example 55 Compound of Formula I, Wherein A=-(C=O)- O-R', Wherein R'=cyclobutyl, G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are phenyl, W is Absent, Z=thiophen-2-yl, j=3, m=S=1, and Rs=R=hydro gen 0457. The title compound is prepared by the method described in Example 54 with the title compound of Example 2 and cyclobutanol. US 2004/0266668A1 Dec. 30, 2004 47
Example 56 Example 59 Compound of Formula I, Wherein A=-(C=O)- Compound of Formula I, Wherein A=-(C=O)- O-R', wherein R'=cyclohexyl, G=OH, L=Absent, O-R', Wherein R'= X and Y Taken Together with the Carbon Atoms to which they are Attached are phenyl, W is Absent, 0463) Z=thiophen-2-yl, j=3,m=s=1, and Rs=R'-hydro gen 0458) The title compound is prepared by the method described in Example 54 with the title compound of Example 2 and cyclohexanol. Example 57 Compound of Formula I, Wherein A=-(C=O)- O-R', Wherein R'= 0459) G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are phenyl, W is Absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=R=hydrogen 0464) The title compound is prepared by the method M2. described in Example 54 with the title compound of Example 2 and
G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are phenyl, W is Absent, Z=thiophen-2-yl, j=3, m=s=1, and Rs=Re=hydrogen
0460) The title compound is prepared by the method OH. described in Example 54 with the title compound of Example 2 and (R)-3-hydroxytetrahydrofuran. Example 58 Compound of Formula I, Wherein A=-(C=O)- Example 60 O-R', Wherein R'= Compound of Formula I, Wherein A=-(C=O)-R', Wherein R'=cyclopentyl, 0461) G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are phenyl, W is Absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=Re=hydrogen 0465. The title compound is prepared with the title com pound from Example 2 in 4 ml of a 4M solution of HCl in dioxane and stirring the reaction mixture for 1 hour. The reaction residue is concentrated in vacuo. To this residue, 4 ml of THF and 0.045 mmol of TEA is added, the mixture is G=OH, L=Absent, X and Y Taken Together with cooled to 0° C., to which is added 0.045 mmol of the the Carbon Atoms to which they are Attached are cyclopentyl acid chloride. The resulting reaction mixture is phenyl, W is Absent, Z=thiophen-2-yl, j=3,m=s=1, Stirred for 2 hours at 0° C. The reaction mixture is then and Rs=Re=hydrogen extracted with EtOAc, washed with 1M sodium bicarbonate, Water and brine, dried over MgSO and concentrated to 0462. The title compound is prepared by the method dryness in vacuo. The crude compound is purified by silica described in Example 54 with the title compound of column and the ethyl ester is Subsequently hydrolyzed by the Example 2 and (S)-3-hydroxytetrahydrofuran. procedure set forth in Example 2. US 2004/0266668A1 Dec. 30, 2004 48
Example 61 compound is purified by Silica column and the ethyl ester is Subsequently hydrolyzed by the procedure set forth in Compound of Formula I, Wherein A=-(C=O)- NH-R', Wherein R'=cyclooentyl, G=OH, L=ab Example 2. sent, X and Y Taken Together with the Carbon Atoms to which they are Attached are phenyl, W is Example 64 Absent, Z=thiophen-2-yl, j=3, m=s=1, and Rs=Rs= Compound of Formula I, Wherein A=-(C=O)- hydrogen O-R', R'=cyclopentyl, G=-O-phenethyl, L=Ab 0466. The title compound is prepared with the title com sent, X and Y Taken Together with the Carbon pound from Example 2 in 4 ml of a 4M solution of HCl in Atoms to which they are Attached are phenyl, W is dioxane and stirring for 1 hour. The resulting reaction Absent, Z=thiophen-2-yl, j=3, m=s=1 and R=R= residue is concentrated in vacuo, dissolved in 4 ml THF, and hydrogen cooled to 0°C. To the 0° C. solution is added 0.045 mmol of cyclopentylisocyanate and the resulting reaction mixture 0469) is stirred at room temperature for 4 hours. The solution is then extracted with EtOAc, washed with 1% HCl, water and brine, dried over MgSO, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the pro cedure set forth in Example 2.
Example 62 PyBrOP
Compound of Formula I, Wherein A=-(C=S)- DIEA NH-R', Wherein R'=cyclopentyl G=OH, L=Ab sent, X and Y Taken Together with the Carbon Atoms to which they are Attached are phenyl, W is Absent, Z=thiophen-2-yl, j=3, m=s=1, and R=R= hydrogen DCM 0467. The title compound is prepared with the title com pound from Example 2 in 4 ml of a 4M solution of HCl in dioxane and stirring for 1 hour. The resulting reaction residue is concentrated in vacuo, dissolved in 4 ml THF, and cooled to 0°C. To the 0° C. solution is added 0.045 mmol of cyclopentyl isothiocyanate and the resulting reaction mixture is stirred at room temperature for 4 hours. The Solution is then extracted with EtOAc, washed with 1% HCl, water and brine, dried over MgSO, and concentrated in vacuo to dryness. The crude compound is purified by silica column and the ethyl ester is subsequently hydrolyzed by the procedure set forth in Example 2. Example 63 Compound of Formula I, Wherein A=-S(O)-R', Wherein R'=cyclopentyl, G=OH, L=Absent, X and Y Taken Together with the Carbon Atoms to which they are Attached are phenyl, W is Absent, Z=thiophen-2-yl, j=3, m=s=1, and Rs=R=hydro gen 0468. The title compound is prepared with the title com 0470 The title compound is prepared by adding to a pound from Example 2 in 4 ml of a 4M solution of HCl in Solution of the title compound of Example 54 and phenethyl dioxane and stirring for 1 hour. To the resulting concentrated alcohol 64a in 0.5 ml DCM, is added 1.2 eq. PyBrOP, 4 eq. reaction residue, which has been dissolved in 4 ml THF, is DIEA, and catalytic amount of DMAP at 0C. The resulting added 0.045 mmol of TEA, and cooled to 0°C. To the 0° C. reaction mixture is stirred for 1 hour at 0° C. and then Solution is added 0.045 mmol of cyclopentyl sulfonyl chlo Warmed to room temperature over a period of 4-12 hours. ride and the resulting reaction mixture is stirred at 0°C. for The reaction mixture is purified by silica gel flash chroma 2 hours. The Solution is then extracted with EtOAc, washed tography using different ratios of hexanes: EtOAc as elution with 1M Sodium bicarbonate, water and brine, dried over phase (9:1->5:1->3:1-> 1:1) to afford the title compound MgSO4, and concentrated in vacuo to dryness. The crude isolated phenethyl ester 64b. US 2004/0266668A1 Dec. 30, 2004 49
0471 Other esters can be made using the same proce Example 66 dures. Compound of Formula I, Wherein A=-(C=O)- Example 65 O-R', R'=cyclopentyl, G=-NHS(O)-phenethyl L=Absent, X and Y Taken Together with the Car Compound of Formula I, Wherein A=-(C=O)- bon Atoms to which they are Attached are phenyl, O-R', R'=cyclopentyl, G=-NH-phenethyl, W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and L=Absent, X and Y Taken Together with the Car Rs=Re=hydrogen bon Atoms to which they are Attached are phenyl, W is Absent, Z=thiophen-2-yl, j=3,m=S=1, and 0474) Rs=Re=hydrogen 0472)
PyBrOP DMAP
DEA
EDC DEA
OH HN --O
0475. The title compound is prepared by adding to a solution of the title compound of Example 54 and C-tolu enesulfonamide 66a (10 mg) in 0.5 ml DCM, is added 1.2 eq. PyBrOP, 4 eq. DIEA, and catalytic amount of DMAP at O C. The resulting reaction mixture is stirred for 1 hour and 65b. then allowed to warm to room temperature over a period of 4-12 hours. The reaction mixture is purified by Silica gel flash chromatography using different ratioS of hexanes: E tOAc as elution phase (9:1->5:1->3:1-> 1:1) to afford the title compound sulfonamide 66b. Other sulfonamides can be 0473. The title compound is prepared by adding to a made via the Same procedure. solution of the title compound of Example 54 and phen ethylamine 65a (0.05 ml) in 0.5 ml DMF, EDC (1.2 eq.) and Example 67 DIEA (4 eq) at 0 C. The resulting reaction mixture is Stirred at 1 hour. Subsequently, the reaction is warmed to Compound of Formula I, Wherein A=-(C=O)- room temperature over a period of 4-12 hours. The reaction O-R', R'=cyclopentyl G=-(C=O)-OH, L=Ab mixture is purified by Silica gel flash chromatography using sent, X and Y Taken Together with the Carbon different ratios of hexanes: EtOAc as elution phase (9:1-> Atoms to which they are Attached are phenyl, W is 5:1->3:1-> 1:1) to afford title compound phenethyl amide Absent, Z=thiophen-2-yl, j=3 m=S=1, and Rs=R= 65b. Other amides can be made via the same procedure. hydrogen US 2004/0266668A1 Dec. 30, 2004 50
0476)
1) HONH2 EDCI DMF He
2) DIBAL-H
OH
54 67a
1) 2) HCI HO X CN dioxaneH2O
TFA
0477 The title compound is prepared by adding to a crude form. The crude compound 67b undergoes a DeSS solution of the title compound of Example 54 in 0.5 ml Martin oxidation in THF (0.5 ml), providing the C-carbonyl DMF, EDC (1.2 eq.) and DIEA (4 eq) at O C. The resulting compound 67.c in crude form. The crude 67c is purified by reaction mixture is stirred at 1 hour. Subsequently, the Silica gel flash chromatography using different ratios of reaction is warmed to room temperature over a period of hexanes: EtOAc as elution phase (9:1->5:1->3:1-> 1:1) to 4-12 hours. The reaction mixture is purified by Silica gel afford the title compound isolated keto acid 67c. flash chromatography to afford hydroxyamide. The hydroya mide is then treated with DIBAL-H at -78° C. in THF for Example 68 2 hours. The reaction mixture is then diluted with 8 ml Compound of Formula I, Wherein A=-(C=O)- EtOAc, washed with water and brine, dried over NaSO, O-R', R'=cyclopentyl, G=-(C=O)-O-phen and concentrated in vacuo to yield aldehyde 67a. To a ethyl, L=Absent, X and Y Taken Together with the solution of aldehyde 67a in 0.5 ml THF, is added C-hydroxy Carbon Atoms to which they are Attached are phe C.-methyl-propionitrile (0.1 ml) and catalytic amount TFA at nyl, W is Absent, Z=thiophen-2-yl, j=3,m=S=1, OC. The resulting reaction mixture is warmed from O C. to and Rs=R=hydrogen room temperature over a period of 4-12 hours followed by hydrolysis with concentrated hydrochloric acid in dioxane. 0478. The title compound is prepared with the title com The reaction is then extracted with EtOAc, and washed with pound keto acid of Example 67 and phenethanol according water and brine to yield C.-hydroxy compound 67b in its to the procedure set forth in Example 64. US 2004/0266668A1 Dec. 30, 2004 51
Example 69 Synthesis of (2S)-N-Boc-amino-5-oxo-non-8-enoic acid Compound of Formula I, Wherein A=-(C=O)- O-R, R =cyclopentyl, G=-(C=O)-NH-phen 0482) 71A. The aforementioned amino acid is prepared ethyl, L=Absent, X and Y Taken Together with the by adding to a Solution of monoallyl ester of malonic acid in Carbon Atoms to which they are Attached are phe dry THF under N at -78. C., n-Bu-Mg dropwise over a nyl, W is Absent, Z=thiophen-2-yl, j=3, m=S=1, period of 5 min. The resulting Suspension is then Stirred at and Rs=R=hydrogen room temperature for 1 hour and evaporated to dryneSS. 0479. The title compound is prepared with the title com Solid Mg salt 71b, is dried under vacuum. pound keto acid of Example 67 and phenethylamine accord 0483 Glutamic acid derivative 71a is first mixed with ing to the procedure Set forth in Example 65. 1,1'-carbonyldiimidazole in anhydrous THF and the mixture is Stirred at room temperature for 1 hour to activate the free Example 70 acid moiety. Subsequently, the activated glutamic acid derivative is cannulated into a solution of Mg salt 49b and Compound of Formula I, Wherein A=-(C=O)- the reaction mixture obtained is stirred at room temperature O-R', R'=cyclopentyl, G=-(C=O)-NH for 16 hours. The mixture then is diluted with ethyl acetate S(O)-benzyl, L=Absent, X and Y Taken Together and the organic solution is washed with 0.5 NHCl (at 0°C.) with the Carbon Atoms to which they are Attached and brine, dried and evaporated. The residue obtained is are phenyl, W is Absent, Z=thiophen-2-yl, j=3, resolved via silica chromatography with a 35-40% ethyl m=S=1, and Rs=Re=hydrogen acetate in hexanes eluent System to yield diester 71c. 0480. The title compound is prepared with the title com 0484 71B. To a stirred solution of tetrakis (triph pound keto acid of Example 67 and C-toluenesulfonamide enylphosphine) Pd(0) in dry DMF is added the diester in according to the procedure Set forth in Example 66. DMF. The mixture is stirred at room temperature for 3.5 hours. The DMF is evaporated under reduced pressure and Example 71 the residue diluted with EtOAc. The EtOAc Solution is washed with 0.5N 0° C. HCl, brine, dried and evaporated. Compound of Formula I, Wherein A=tBOC, The residue is chromatographed on Silica gel using 15% to G=OH, L=-(C=O)CH-, X and Y Taken 20% EtOAc in hexane as eluent to afford the methyl ester Together with the Carbon Atoms to which they are intermediate. Attached are phenyl, W is Absent, Z=thiophen-2-yl, 0485 The methyl ester intermediate is then diluted with ji=3, m=S=1, and Rs=Re=hydrogen THF and water, LiOH.HO is added and the resulting 0481) mixture is stirred at room temperature for 25 hours, wherein
O
tEOcNH OCH A. tEOcNH susOCH3
O OH 71b. N-O 71a US 2004/0266668A1 Dec. 30, 2004 52 the completion of the hydrolysis is monitored by TLC. The Synthesis of (2S,5R)-N-Boc-2-amino-5-methyl reaction mixture is concentrated under Vacuum to remove a non-8-enoic acid (72h) majority of the THF and further diluted with methylene 0490) 72A. To solid ethyl 2-acetamidomalonate 72b is chloride. The resulting solution is washed with 1 NHCl, added (R)-(+)-citronellal 72a in a solution of pyridine over dried with anhydrous NaSO and concentrated under 1 min. The resulting solution is cooled in a 10° C. bath and vacuum. To remove minor impurities and excess Boc-O, the acetic anhydride is added over 4 min. The resulting Solution crude product is purified via flash chromatography using a is stirred for 3 hours at room temperature and another solvent gradient from 100% hexane ->100% EtOAc as the portion of ethyl 2-acetamidomalonate 72a is added. The eluent. (2S)-N-Boc-amino-5-oxo-non-8-enoic acid 71d is resulting mixture is stirred at room temperature for an obtained. For further details of the preceding amino acid additional 11 hours. Ice is then added and the Solution is synthesis may be found in T. Tsuda et al., J. Am. Chem. Soc., stirred for 1.5 hours, then the mixture is diluted with 250 ml 1980, 102, 6381-6384 and WOOO/59929. water and extracted with two portions of ether. The organic 0486 71C. Synthesis of Modified Cyclic Peptide Precur phase is washed with 1N HCl, sat. NaHCO, dried NaSO, sor Mesylate concentrated and purified by flash chromatography (40% 0487. The modified cyclic peptide precursor mesylate is EtOAc/hexane) to afford compound 72c. prepared using the Synthetic route detailed in Example 1 0491 72B. To a degassed solution of 72c in dry ethanol using (2S)-N-Boc-amino-5-oxo-non-8-enoic acid 71d in is added (S,S)-Et-DUPHOS Rh(COD)OTf. The mixture is place of Boc-L-2-amino-8-nonenoic acid la followed by subjected to 30 psi of hydrogen and stirred on a Parr shaker conversion to the corresponding meSylate via the method for 2 hours. The resulting mixture is evaporated to dryneSS described in Example 2. to obtain the crude compound 72d, which is used in the Subsequent Step without purification. 0488 The title compound is prepared with the modified cyclic peptide precursor meSylate formed in 71C and 0492 72C. Compound 72d is dissolved in a mixture of 3-(thiophen-2-yl)-1H-quinoxylin-2-one by the Mitsunobu teuOH/acetone/HO (1:1:1) and placed in an ice bath (0 conditions elucidated in Example 2 followed by hydrolysis C.). NMMO and OsO is consecutively added and the of the ethyl ester via the method set forth in Example 2. reaction mixture is stirred at room temperature for 4 hours. A majority of the acetone is removed by evaporation under Example 72 Vacuum and then the mixture is extracted with ethyl acetate. The organic layer is further washed with water and brine, Compound of Formula I, Wherein A=tBOC, dried over anhydrous MgSO and evaporated to dryneSS. G=OH, L=-CH(CH)CH-, X and Y Taken The diol 72e is obtained in high purity after flash column Together with the Carbon Atoms to which they are chromatography using 1% ethanol in ethyl acetate as the Attached are phenyl, W is Absent, Z=thiophen-2-yl, eluent. ji=3, m=S=1, and Rs=Re=hydrogen 0493) 72D. To a solution of diol 72e in THF/HO (1:1) at 0489 0° C., NalO is added and the reaction mixture is stirred at
CH CH A. NHAc -e-
H3CN 2 29 on-on HC COOEt CH col CH 72a 72c N
COOEt
US 2004/0266668A1 Dec. 30, 2004 53 room temperature for 3.5 hours. A majority of the THF Example 73 Solvent is Subsequently removed by evaporation under Vacuum and the remaining mixture is extracted with EtOAc. Compound of Formula I, Wherein A=tBOC, The combined organic layers are further washed with 5% G=OH, L=-O-, X and Y Taken Together with the Carbon Atoms to which they are Attached are aqueous citric acid Solution, 5% aq. NaHCOs and brine, then phenyl, W is Absent, Z=thiophen-2-yl, 3, m=s=1, the organic phase is dried over MgSO and evaporated to Rs=methyl, and Re=hydrogen dryneSS under vacuum. Aldehyde intermediate 72f is used in the following Step in its crude form. 0499) 0494 72E. To a solution of PhPCHBr in anhydrous toluene, KHMDS is added forming a suspension which is OH O OH O stirred at room temperature for 30 min. under N. After - A - - B - Stirring, the Suspension is cooled to 0 C., a Solution of OH -N1.1. aldehyde intermediate 72f in THF is added, the mixture is NHEOc NHtBoc warmed to room temperature, and Stirred for 1 hour. A majority of the THF is evaporated under vacuum, EtOAc is 73a 73b added to the mixture and the organic phase is washed with 21 21 water, 5% aq. NaHCO and brine. The organic phase is then dried over MgSO and evaporated to dryneSS under vacuum. O O C O O Pure compound 72g is isolated after purification via flash He chromatography on Silica gel, using hexane:EtOAc (3:2) as the eluent. ----- OH NHEOc NHEOc 0495 72F. To a solution of crude 72g in THF, Boc-O, and 73c 73d DMAP is added and the reaction mixture is heated to reflux for 2.5 hours. Subsequently, a majority of the THF is evaporated, the crude mixture is diluted with methylene Synthesis of N-Boc-O-allyl-(L)-threonine (73d) chloride and washed with 1N HCl to remove DMAP. The 0500) 73A. Boc-(L)-threonine 73a is partially dissolved organic layer is further extracted with Saturated aq. in methylene chloride/methanol at 0° C. A solution of NaHCO, dried with anyhrous NaSO and concentrated diazomethane in diethyl ether is added until yellow, indi under vacuum. The crude product is then diluted with THF cating the presence of diazomethane. Upon evaporation of and water, LiOH.HO is added and the resulting mixture is the solvents, crude methyl ester 73b is obtained. stirred at room temperature for 25 hours, wherein the 0501) 73B. Intermediate 73b is dissolved in anhydrous completion of the hydrolysis is monitored by TLC. The diethyl ether, AgO is added and freshly activated 4 A reaction mixture is concentrated under Vacuum to remove a molecular Sieves. Finally, allyl iodide is added to the reac majority of the THF and further diluted with methylene tion mixture and is Stirred at reflux. Two additional portions chloride. The resulting solution is washed with 1N HCl, of allyl iodide are added to the reaction mixture after a dried with anhydrous NaSO and concentrated under period of 20 hours and 30 hours and stirring is continued for a total of 36 hours. The mixture is then filtered through celite Vacuum. To remove minor impurities and exceSS Boc-O, the and purified by flash chromatography on Silica gel, using crude product is purified via flash chromatography using a EtOAc/hexane (1:4) as the eluent, to afford compound 73c. solvent gradient from 100% hexane ->100% EtOAc as the eluent. (2S, 5R)-N-Boc-2-amino-5-methyl-non-8-enoic 0502 73C. Compound 73c is dissolved in a mixture of THF/MeOH/HO (2:1:1) and LiOH.HO is added. The acid 72 h is obtained. For further details of the preceding Solution is stirred at room temperature for 2 hours, and is amino acid synthesis see WO 00/59929. acidified with 1 NHCl to pH -3 before the solvents are removed under Vacuum. The resulting crude compound 73d 0496 Synthesis of Modified Cyclic Peptide Precursor is obtained. For further details of the preceding Synthesis See Mesylate WO 00/59929, which is herein incorporated by reference in 0497. The modified cyclic peptide precursor mesylate is its entirety. prepared using the Synthetic route detailed in Example 1 0503) 73D. Synthesis of Modified Cyclic Peptide Precur using ((2S, 5R)-N-Boc-2-amino-5-methyl-non-8-enoic sor Mesylate acid 72h in place of Boc-L-2-amino-8-nonenoic acid la 0504. The modified cyclic peptide precursor mesylate is followed by conversion to the corresponding meSylate via prepared using the Synthetic route detailed in Example 1 the method described in Example 2. using N-Boc-O-allyl-(L)-threonine 73d in place of Boc-L- 0498. The title compound is prepared with the modified 2-amino-8-nonenoic acid 1a followed by conversion to the cyclic peptide precursor meSylate formed in 72G and corresponding meSylate via the method described in 3-(thiophen-2-yl)-1H-quinoxylin-2-one by the Mitsunobu Example 2. conditions elucidated in Example 2 followed by hydrolysis 0505) The title compound is prepared with the modified of the ethyl ester via the method set forth in Example 2. cyclic peptide precursor meSylate formed in 73D and US 2004/0266668A1 Dec. 30, 2004 54
3-(thiophen-2-yl)-1H-quinoxylin-2-one by the Mitsunobu 0509) 74C. To a solution of thioester 74c is HO/EtOH conditions elucidated in Example 2 followed by hydrolysis (3:5 ratio) and aqueous solution of 0.2M NaOH is added and of the ethyl ester via the method set forth in Example 2. the mixture is Stirred at room temperature for 1.5 hours. Allyl iodide is then added and Stirring is continued at room Example 74 temperature for an additional 30 min. The reaction mixture is concentrated to half of its original Volume and then Compound of Formula I, Wherein A=tBOC, extracted with EtOAc. The aqueous layer is acidified to pH G=OH, L=-S-, X and Y Taken Together with ~3 with cold, aqueous 0.5N HCl and re-extracted with the Carbon Atoms to which they are Attached are EtOAc. The combined organic layers are washed with brine, phenyl, W is Absent, Z=thiophen-2-yl, j=3, m=S 1, dried over anhydrous MgSO and evaporated to dryness Rs=methyl, and Re=hydrogen under Vacuum. The crude reaction mixture contains at least 0506) four products, all of the products are isolated after flash sinus O E sinus OH He-A. o1 Net, On f 1n N HO CH O HC
74a 74b
O
sinus OH
Synthesis of (2S,3S)-N-Boc-2 chromatography on Silica gel, using hexane/EtOAc (gradient amino-3(mercaptoallyl)butanoic acid (74e) from 9:1 to 3:1). The desired product 74d is the least polar compound. 0507 74A. Compound 74a is dissolved in pyridine and 0510) 74D. A solution of compound 74d in MeOH/HO the solution is cooled to 0°C. in an ice bath, tosyl chloride (3:1) is mixed with aqueous NaOH (0.3 N) for 24 hours at is added in Small portions and the reaction mixture is room temperature and for 1 hour at 40 C. The reaction partitioned between diethyl ether and H2O. The ether layer mixture is acidified with cold aqueous 0.5 NHCl, the MeOH is further washed with 0.2 N HCl and brine, dried over is removed under vacuum and the remaining aqueous mix anhydrous MgSO, filtered and concentrated to dryneSS ture is extracted with EtOAc. The organic phase is dried over under vacuum. Purification of the crude material by flash MgSO and evaporated to dryness in order to obtain com chromatography on Silica gel, using hexane/EtOAc (gradient pound 74e. For further details of the synthesis of amino acid from 8:2 to 7:3 ratio) as the eluent, leads to isolation of tosyl 74e, see WO 00/59929, which is herein incorporated by derivative 74b. reference in its entirety. 0508) 74B. To a solution of tosyl derivative 74b in 0511 74E. Synthesis of Modified Cyclic Peptide Precur anhydrous DMF, potassium thioacetate is added and the sor Mesylate reaction mixture is stirred at room temperature for 24 hours. A majority of the DMF is then evaporated under vacuum and 0512. The modified cyclic peptide precursor mesylate is the remaining mixture is partitioned between EtOAC and prepared using the Synthetic route detailed in Example 1 HO. The aqueous layer is re-extracted with EtOAc, the using (2S, 3S)-N-Boc-2 amino-3(mercaptoallyl)butanoic combined organic layers are washed with brine, dried over acid 74e in place of Boc-L-2-amino-8-nonenoic acid 1 a anhydrous MgSO and evaporated to dryness. Purification of followed by conversion to the corresponding meSylate via the crude material by flash chromatography on Silica gel the method described in Example 2. using hexane/EtOAC (4:1 ratio) as the eluent, affords 0513. The title compound is prepared with the modified thioester 74c. cyclic peptide precursor meSylate formed in 74E and US 2004/0266668A1 Dec. 30, 2004 55
3-(thiophen-2-yl)-1H-quinoxylin-2-one by the Mitsunobu Example 76 conditions elucidated in Example 2 followed by hydrolysis Compound of Formula I, Wherein A=tBOC, of the ethyl ester via the method set forth in Example 2. G=OH, L=-S(O), X and Y Taken Together with the Carbon Atoms to which they are Attached are Example 75 phenyl, W is Absent, Z=thiophen-2-yl, j=3,m=S=1, Rs=methyl, and Re=hydrogen Compound of Formula I, Wherein A=tBOC, 0519 Formation of Modified Amino Acid G=OH, L=-S(O), X and Y Taken Together with the Carbon Atoms to which they are Attached are (76a) phenyl, W is Absent, Z=thiophen-2-yl, j=3, m=S=1, O Rs=methyl, and Re=hydrogen sinus OH O 0514 Formation of Modified Amino Acid M HC /S \ .
(75a) 0520) 76A. The modified amino acid is prepared by O dissolving Sodium metaperiodate (1.1 eq.) in water and cooled to 0°C. in an ice bath followed by adding dropwise a Solution of compound 76d in dioxane. The resulting sinus OH reaction mixture is stirred for one hour at 0° C. and 4 hours at 40 C. The reaction mixture is concentrated, water is added, and the mixture is extracted with methylene chloride twice. The combined organic layers are washed with water, brine, dried with anhydrous MgSO and concentrated in vacuo. The methyl ester is then reduced via the method set forth in Example 74D to arrive upon the modified amino acid 76a. For further details concerning the sulfur oxidation 0515 75A. The modified amino acid is prepared by reaction, see S. A. Burrage et al., Tett. Lett., 1998, 39, dissolving Sodium metaperiodate (1.1 eq.) in water and 2831-2834. cooled to 0°C. in an ice bath followed by adding dropwise 0521 76B. Synthesis of Modified Cyclic Peptide Precur a Solution of compound 75d in dioxane. The resulting sor Mesylate reaction mixture is stirred for one hour at 0° C. and 4 hours 0522 The modified cyclic peptide precursor mesylate is at 40 C. The reaction mixture is concentrated, water is prepared using the Synthetic route detailed in Example 1 added, and the mixture is extracted with methylene chloride using the modified amino acid 76a in place of Boc-L-2- twice. The combined organic layers are washed with water, amino-8-nonenoic acid 1a followed by conversion to the corresponding meSylate via the method described in brine, dried with anhydrous MgSO and concentrated in Example 2. vacuo. The methyl ester is then reduced via the method set 0523 The title compound is prepared with the modified forth in Example 74D to arrive upon the modified amino cyclic peptide precursor meSylate formed in 76B and acid 75a. For further details concerning the Sulfur oxidation 3-(thiophen-2-yl)-1H-quinoxylin-2-one by the Mitsunobu reaction, see S. A. Burrage et al., Tett. Lett., 1998, 39, conditions elucidated in Example 2 followed by hydrolysis 2831-2834, which is herein incorporated by reference in its entirety. of the ethyl ester via the method set forth in Example 2. Example 77 0516 75B. Synthesis of Modified Cyclic Peptide Precur Compound of Formula I, Wherein A=tBOC, sor Mesylate G=OH, L=-SCHCH-, X=Y=thiophen-3-yl, Z=hydrogen, j=0, m=S=1, and Rs=R=CH 0517. The modified cyclic peptide precursor mesylate is 0524) prepared using the Synthetic route detailed in Example 1
using the modified amino acid 75a in place of Boc-L-2- amino-8-nonenoic acid 1a followed by conversion to the corresponding meSylate via the method described in Example 2. 0518. The title compound is prepared with the modified COOH A. cyclic peptide precursor meSylate formed in 75B and 3-(thiophen-2-yl)-1H-quinoxylin-2-one by the Mitsunobu conditions elucidated in Example 2 followed by hydrolysis of the ethyl ester via the method set forth in Example 2. US 2004/0266668A1 Dec. 30, 2004 56
0525) 77A. Synthesis of (S)-N-Boc-2-amino-3-methyl 3(1-mercapto-4-butenyl)butanoic acid (77b) -continued 0526 L-Penicillamine 77a is dissolved in DMF/DMSO (5:1), Subsequently, 4-bromopentene and CSOH.H2O are added to the mixture and Stirring is continued for an addi tional 12 hours. The DMF is subsequently removed in vacuo, the remaining mixture is diluted with 0.5 NHCl (at 0° C) to adjust the pH to ~4-5 and then extracted with 2 portions of EtOAc. The organic phase is washed with brine (2x), dried over MgSO and evaporated to dryness to afford 78b. the crude carboxylic acid 77a. 0527 77B. Synthesis of Modified Cyclic Peptide Precur sor Mesylate 0528. The Modified Cyclic peptide precursor mesylate is prepared using the Synthetic route detailed in Example 1 Synthesis of (2S)-N-Boc-amino-5-difluoro-non-8- using the modified amino acid 77a in place of Boc-L-2- enoic acid (78b) amino-8-nonenoic acid 1a followed by conversion to the 0531 78A. To a solution of the ketone compound 71d corresponding meSylate via the method described in (0.30 g, 1 mmol) in 5 ml DCM, DAST (Diethylaminosul Example 2. furtrifluoride, 0.2g, 1.2 eq) is added. The reaction is kept at 0529. The title compound is prepared with the modified room temperature over a period of 2-3 days. The Solvent is cyclic peptide precursor meSylate formed in 77B and evaporated and the residue is purified by Silica gel flash 3-(thiophen-2-yl)-1H-quinoxylin-2-one by the Mitsunobu chromatography using different ratios of hexanes: EtOAC as conditions elucidated in Example 2 followed by hydrolysis eluent (9:1->5:1->3:1-> 1:1), providing the isolated methyl of the ethyl ester via the method set forth in Example 2. ester 78a. For further details concerning the preceding Synthesis, see Tius, Marcus A et al., Tetrahedron, 1993, 49, Example 78 16; 3291-3304, which is herein incorporated by reference in its entirety. Compound of Formula I, Wherein A=tBOC, G=OH, L=CFCH., X and Y Taken Together with 0532 78B. Methyl ester 78a is dissolved in THF/MeOH/ the Carbon Atoms to which they are Attached are phenyl, W is Absent, Z=thiophen-2-yl, j=3, m=S=1, HO (2:1:1) and LiOH.H2O is added. The solution is stirred and Rs=Re=hydrogen at room temperature for 2 hours, and is then acidified with 1N HCl to pH -3 before the solvents are removed in vacuo O530) to afford the crude (2S)-N-Boc-amino-5-difluoro-non-8- enoic acid 78b. 0533 78C. Synthesis of Modified Cyclic Peptide Precur O sor Mesylate 0534. The modified cyclic peptide precursor mesylate is Boc1 4. OMe A. Her prepared using the Synthetic route detailed in Example 1 DAST DCM using crude (2S)-N-Boc-amino-5-difluoro-non-8-enoic RT, 2–3 d acid 78b in place of Boc-L-2-amino-8-nonenoic acid 1 a followed by conversion to the corresponding meSylate via O the method described in Example 2. 71d 0535 The title compound is prepared with the modified cyclic peptide precursor meSylate formed in 78C and 3-(thiophen-2-yl)-1H-quinoxylin-2-one by the Mitsunobu O conditions elucidated in Example 2 followed by hydrolysis of the ethyl ester via the method set forth in Example 2. Boc1 OMe B He Example 79 Compound of Formula I, Wherein A=tBOC, F 2 G=OH, L=-CHFCH-, X and Y Taken Together F with the Carbon Atoms to which they are Attached 78a. are phenyl, W is Absent, Z=thiophen-2-yl, j=3, m=S=1 and Rs=R=hydrogen US 2004/0266668A1 Dec. 30, 2004
0536)
O O O
Boc1 OMe A. Boc1 OMe B Boc1 OMe Ho- --- DAST DCM RT, 2–3 d O 21 HO 21 H 2 F 71d 79a 79b /6 O
Boc1 N4.OH
H 2 F 79c
Synthesis of (2S)-N-Boc-amino-5-fluoro-non-8- 0542. The title compound is prepared with the modified enoic acid (79c) cyclic peptide precursor meSylate formed in 79C and 0537) 79A. To a solution of the ketone compound 71d in 3-(thiophen-2-yl)-1H-quinoxylin-2-one by the Mitsunobu 5 ml methanol, NaBH (2.2 eq) is added. The reaction conditions elucidated in Example 2 followed by hydrolysis mixture is stirred at room temperature over a period of 2-6 of the ethyl ester via the method set forth in Example 2. hours, and then quenched by 1M ammonium chloride and extracted with EtOAc (30 ml). The solvent is evaporated and Example 80 the crude hydroxy compound 79a is obtained. Compound of Formula II, Wherein A=tBOC, 0538 79B. The hydroxy compound 79a is dissolved in 5 G=OH, L=Absent, X and Y Taken Together with ml DCM to which DAST (0.2g, 1.2 eq) is added and stirred the Carbon Atoms to which they are Attached are at -45 C. for 1 hour. The reaction mixture is then warmed phenyl, W is Absent, Z=thiophen-2-yl, j=3,m=S=1, to room temperature and Stirred over a period of 2-3 dayS. and Rs=Re=hydrogen The Solvent is evaporated and the residue is purified by Silica gel flash chromatography using different ratioS of heX 0543 80A. The saturated cyclic peptide precursor is anes:EtOAc as eluent (9:1->5:1->3:1-> 1:1), providing the prepared by catalytic reduction of the cyclic peptide precur isolated monofluoro compound methyl ester 79b. For further sor of Example 1 with Pd/C in MeOH in the presence of H. details concerning the preceding reaction, See Buist, Peter H 0544 The title compound is prepared with the saturated et al., Tetrahedron Lett., 1987, 28, 3891-3894, which is cyclic peptide precursor meSylate formed in 80A and herein incorporated by reference in its entirety. 3-(thiophen-2-yl)-1H-quinoxylin-2-one by the Mitsunobu 0539 79C. Methyl ester 79b is dissolved in THF/MeOH/ conditions elucidated in Example 2 followed by hydrolysis HO (2:1:1) and LiOH.HO is added. The solution is stirred of the ethyl ester via the method set forth in Example 2. at room temperature for 2 hours, and is then acidified with 0545. The compounds of the present invention exhibit 1N HCl to pH -3 before the solvents are removed in vacuo potent inhibitory properties against the HCV NS3 protease. to afford the crude (2S)-N-Boc-amino-5-difluoro-non-8- The following examples elucidate assays in which the enoic acid 79c. compounds of the present invention are tested for anti-HCV 0540 79D. Synthesis of Modified Cyclic Peptide Precur effects. sor Mesylate 0541. The modified cyclic peptide precursor mesylate is Example 81 prepared using the Synthetic route detailed in Example 1 NS3/NS4a Protease Enzyme Assay using crude (2S)-N-Boc-amino-5-monofluoro-non-8-enoic acid 79b in place of Boc-L-2-amino-8-nonenoic acid 1 a 0546) HCV protease activity and inhibition is assayed followed by conversion to the corresponding meSylate via using an internally quenched fluorogenic Substrate. ADAB the method described in Example 2. CYL and an EDANS group are attached to opposite ends of US 2004/0266668A1 Dec. 30, 2004 58 a short peptide. Quenching of the EDANS fluorescence by the amplification plot crosses a defined fluorescence thresh the DABCYL group is relieved upon proteolytic cleavage. old. Comparison of the threshold cycles of the sample with Fluorescence was measured with a Molecular Devices Fluo a known Standard provides a highly Sensitive measure of romax (or equivalent) using an excitation wavelength of 355 relative template concentration in different samples (ABI nm and an emission wavelength of 485 nm. User Bulletin #2 Dec. 11, 1997). The data is analyzed using the ABI SDS program version 1.7. The relative template 0547 The assay is run in Corning white half-area 96-well concentration can be converted to RNA copy numbers by plates (VWR 29444-312 Corning 3693) with full-length employing a standard curve of HCV RNA standards with NS3 HCV protease 1b tethered with NS4A cofactor (final known copy number (ABI User Bulletin #2 Dec. 11, 1997). enzyme concentration 1 to 15 nM). The assay buffer is complemented with 10 uM NS4A cofactor Pep 4A(Anaspec 0553) The RT-PCR product was detected using the fol 25336 or in-house, MW 1424.8). RET S1 (Ac-Asp-Glu lowing labeled probe: Asp(EDANS)-Glu-Glu-Abu-COOAla-Ser-Lys-(DAB CYL)-NH2, AnaSpec 22991, MW 1548.6) is used as the fluorogenic peptide substrate. The assay buffer contained 50 5' FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA mM Hepes at pH 7.5, 30 mM NaCl and 10 mMBME. The enzyme reaction is followed over a 30 minutes time course 0554 FAM=Fluorescence reporter dye. at room temperature in the absence and presence of inhibi torS. 0555 TAMRA:=Quencher dye. 0548. The peptide inhibitors HCV Inh 1 (Anaspec 25345, 0556. The RT reaction is performed at 48° C. for 30 MW 796.8) Ac-Asp-Glu-Met-Glu-Glu-Cys-OH, -20° C. minutes followed by PCR. Thermal cycler parameters used and HCV Inh 2 (Anaspec 25346, MW 913.1) Ac-Asp-Glu for the PCR reaction on the ABI Prism 7700 Sequence Dif-Cha-Cys-OH, were used as reference compounds. Detection System were: one cycle at 95 C., 10 minutes followed by 35 cycles each of which included one incuba 0549 IC50 values were calculated using XLFit in Activi tion at 95 C. for 15 seconds and a second incubation for 60 tyBase (IDBS) using equation 205: y=A+((B-A)/(1+((C/x) C. for 1 minute. 0557. To normalize the data to an internal control mol Example 82 ecule within the cellular RNA, RT-PCR is performed on the cellular messenger RNA glyceraldehydes-3-phosphate Cell-Based Replicon Assay dehydrogenase (GAPDH). The GAPDH copy number is very stable in the cell lines used. GAPDH RT-PCR is 0550 Quantification of HCV Replicon RNA in Cell performed on the same exact RNA sample from which the Lines (HCV Cell Based Assay) HCV copy number is determined. The GAPDH primers and probes, as well as the Standards with which to determine 0551 Cell lines, including Huh-11-7 or Huh 9-13, har copy number, are contained in the ABI Pre-Developed boring HCV replicons (Lohmann, et al Science 285:110 TaqMan Assay Kit (catalog no. 431 0884E). The ratio of 113, 1999) are seeded at 5x10 cells/well in 96 well plates HCV/GAPDH RNA is used to calculate the activity of and fed media containing DMEM (high glucose), 10% fetal compounds evaluated for inhibition of HCV RNA replica calf Serum, penicillin-Streptomycin and non-essential amino tion. acids. Cells are incubated in a 5% CO incubator at 37 C. At the end of the incubation period, total RNA is extracted 0558 Activity of Compounds as Inhibitors of HCV Rep and purified from cells using Qiagen Rneasy 96 Kit (Catalog lication (Cell Based Assay) in Replicon Containing Huh-7 No. 74182). To amplify the HCV RNA so that sufficient Cell Lines material can be detected by an HCV specific probe (below), 0559 The effect of a specific anti-viral compound on primers specific for HCV (below) mediate both the reverse HCV replicon RNA levels in Huh-11-7 or 9-13 cells was transcription of the HCV RNA and the amplification of the determined by comparing the amount of HCV RNA nor cDNA by polymerase chain reaction (PCR) using the Taq malized to GAPDH (e.g. the ratio of HCV/GAPDH) in the Man One-Step RT-PCR Master Mix Kit (Applied Biosys cells exposed to compound verSuS cells exposed to the 0% tems catalog no. 4309169). The nucleotide sequences of the inhibition and the 100% inhibition controls. Specifically, RT-PCR primers, which are located in the NS5B region of cells were seeded at 5x10 cells/well in a 96 well plate and the HCV genome, are the following: were incubated either with: 1) media containing 1% DMSO (0% inhibition control), 2) 100 international units, IU/ml HCV Forward primer RBNS5bfor " Interferon-alpha 2b in media/1% DMSO or 3) media/1% 5' GCTGCGGCCTGTCGAGCT DMSO containing a fixed concentration of compound. 96 well plates as described above were then incubated at 37 C. HCV Reverse primer 'RBNS5Brev": for 3 days (primary Screening assay) or 4 days (IC50 5' CAAGGTCGTCTCCGCATAC determination). Percent inhibition was defined as: 0552) Detection of the RT-PCR product was accom 0560 % Inhibition=100-((S-C2)/C1-C2)))x100 plished using the Applied Biosystems (ABI) Prism 7700 Sequence Detection System (SDS) that detects the fluores 0561 where cence that is emitted when the probe, which is labeled with 0562 S=the ratio of HCV RNA copy number/ a fluorescence reporter dye and a quencher dye, is processed GAPDH RNA copy number in the sample; during the PCR reaction. The increase in the amount of fluorescence is measured during each cycle of PCR and 0563 C1=the ratio of HCV RNA copy number/ reflects the increasing amount of RT-PCR product. Specifi GAPDH RNA copy number in the 0% inhibition cally, quantification is based on the threshold cycle, where control (media/1% DMSO); and US 2004/0266668A1 Dec. 30, 2004 59
0564 C2=the ratio of HCV RNA copy number/ G is independently selected from -OH, -O-(C-C, GAPDH RNA copy number in the 100% inhibi alkyl), -NHS(O)-R,-(C=O)-Ra;-(C=O) tion control (100 IU/ml Interferon-alpha 2b). O-R, or -(C=O)-NH-R; 0565. The dose-response curve of the inhibitor was gen L is independently selected from -S-, -SCH erated by adding compound in Serial, three-fold dilutions over three logs to Wells Starting with the highest concentra tion of a Specific compound at 10 uM and ending with the lowest concentration of 0.01 uM. Further dilution series (1 uM to 0.001 uM for example) was performed if the IC50 -CH(CH)CH-, -CFHCH-, or -CFCH-; value was not in the linear range of the curve. IC50 was X and Y taken together with the carbon atoms to which determined based on the IDBS Activity Base program using they are attached form a cyclic moiety Selected from Microsoft Excel “XL Fit” in which A=100% inhibition value aryl, Substituted aryl, heteroaryl, or Substituted het (100 IU/ml Interferon-alpha 2b), B=0% inhibition control eroaryl; value (media/1% DMSO) and C=midpoint of the curve as defined as C=(B-A/2)+A. A, B and C values are expressed W is absent, or independently selected from -O-, as the ratio of HCV RNA/GAPDH RNA as determined for -S-, -NH-, -C(O)NRI- or -NR-; each sample in each well of a 96 well plate as described above. For each plate the average of 4 wells were used to Z is independently selected from hydrogen; -CN, define the 100% and 0% inhibition values. -SCN, -NCO, -NCS, -NHNH, -N, halogen, -R, -C-C cycloalkyl, Substituted -C-C- 0566 Although the invention has been described with cycloalkyl, aryl, Substituted aryl, heteroaryl, Substituted respect to various preferred embodiments, it is not intended heteroaryl, heterocycloalkyl, Substituted heterocy to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made cloalkyl, and -NH-N=CH(R); therein which are within the spirit of the invention and the Each R is independently Selected from hydrogen, C-C, Scope of the appended claims. alkyl, Substituted C-C alkyl, C-C alkenyl, Substi tuted C-C alkenyl, C-C alkynyl, Substituted C-C, What is claimed: alkynyl, C-C cycloalkyl, Substituted C-C2 1. A compound of Formula I or II: cycloalkyl, aryl, Substituted aryl, arylalkyl, Substituted arylalkyl, heteroaryl, Substituted heteroaryl, heteroary lalkyl, Substituted heteroarylalkyl, heterocycloalkyl, or
(I) Substituted heterocycloalkyl, Each R is independently selected from hydrogen, C-C, alkyl, C-C alkyl, Substituted C-C alkyl, C-C alk enyl, Substituted C-C alkenyl, C-C alkynyl, Substi tuted C-C alkynyl, C-C cycloalkyl, Substituted C-C2 cycloalkyl, alkylamino, dialkylamino, ary lamino, diarylamino, aryl, Substituted aryl, arylalkyl, O Substituted arylalkyl, heteroaryl, Substituted heteroaryl, heteroarylalkyl, Substituted heteroarylalkyl, heterocy cloalkyl, or Substituted heterocycloalkyl, Each R is independently selected from: (i) -C-C alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with (II) one or more Substituent Selected from halogen, aryl, Substituted aryl, heteroaryl, or Substituted heteroaryl; (ii) -C-C alkenyl containing 0, 1, 2, or 3 heteroat oms selected from O, S, or N, optionally substituted with one or more Substituent Selected from halogen, aryl, Substituted aryl, heteroaryl, or Substituted het eroaryl; or (iii)-C-C alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more Substituent Selected from halogen, aryl, Substituted aryl, heteroaryl, or Substituted heteroaryl; Rs and R are each independently selected from hydrogen or methyl; j=0, 1, 2, 3, or 4, A is independently selected from hydrogen; -(C=O)- O-R, (C=O)-R, C(=O)-NH-R, m=0, 1, or 2, and C(=S)-NH-R, or -S(O)-R; S=0, 1 or 2. US 2004/0266668A1 Dec. 30, 2004 60
2. The compound of claim 1, wherein the compound is of atoms to which they are attached are phenyl, W is Formula III: absent, Z=ethyl, j=3, m=S=1, and Rs=R=hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon (III) atoms to which they are attached are phenyl, W is absent, Z=phenyl, j=3,m=S=1, and Rs=R=hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=4-methoxyphenyl, j=3,m=S=1, and Rs=Re= O hydrogen; N H H N Compound of Formula I, wherein A=tBOC, G=OH, N-. G / 2-Rs ls L=absent, X and Y taken together with the carbon A. O atoms to which they are attached are phenyl, W is R6 CH absent, Z=4-ethoxyphenyl, j=3, m=S=1, and Rs=R= N- CH2 N4N / hydrogen; H Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon wherein R, and Rs are independently Selected from R as atoms to which they are attached are phenyl, W is defined in claim 1. absent, Z=5-bromothiophen-2-yl, j=3, m=S=1, and 3. The compound of claim 1, wherein the compound is of Rs=Re=hydrogen; Formula IV: Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon (IV) atoms to which they are attached are phenyl, W is R N W-Z absent, Z=2-pyrid-3-yl ethylenyl, j=3, m=S=1, and 7 nea n Rs=R=hydrogen; Sa 2 Compound of Formula I, wherein A=tBOC, G=OH, R8 N N O L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=3,4-Dimethoxy-phenyl, j=3, m=S=1, and O lm O Rs=Re=hydrogen; H N N-. G Compound of Formula I, wherein A=tBOC, G=OH, / 2-Rs ls L=absent, X and Y taken together with the carbon A. a. O atoms to which they are attached are phenyl, W is R6 CH absent, Z=2-thiophen-2-yl ethylenyl, j=3, m=S=1, and N- CH n/ Rs=Re=hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon wherein R, and Rs are independently Selected from R as atoms to which they are attached are phenyl, Z=indole defined in claim 1. 2-yl, j=3, m=S=1, and Rs=Re=hydrogen; 4. A compound according to any one of claims 1-3, wherein W is absent and Z is thiophenyl. Compound of Formula I, wherein A=tBOC, G=OH, 5. A compound according to any one of claims 1-3, L=absent, X and Y taken together with the carbon wherein W is -CH=CH- and Z is thiophenyl. atoms to which they are attached are phenyl, W is 6. A compound according to claim 1 which is Selected absent, Z=1H-indol-3-yl methyl, j=3, m=S=1, and from: Rs=Re=hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is atoms to which they are attached are phenyl, W is absent, Z=thiophen-2-yl, j=3, m=S=1, and Rs=Re= absent, Z=furan-2-yl, j=3,m=S=1, and Rs=R=hydro hydrogen; gen, Compound of Formula I, wherein A=tBOC, G=OH, Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is atoms to which they are attached are phenyl, W is absent, Z=2-(formamido)-thiazol-4-yl, j=3,m=S=1, and absent, Z=1H-benzoimidazol-2-yl, j=3, m=S=1, and Rs=Re=hydrogen; Rs=Re=hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon L=absent, X and Y taken together with the carbon US 2004/0266668A1 Dec. 30, 2004
atoms to which they are attached are phenyl, W is absent, Z=1H-imidazol-2-ylmethyl, j=3, m=S=1, and Rs=Re=hydrogen; Compound of Formula I, wherein A=tBOC, G=OEt, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=chloro, ji=3, m=S=1, and Rs=R=hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, W is absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=R= L=absent, X and Y taken together with the carbon hydrogen; atoms to which they are attached are phenyl, Compound of Formula I, wherein A=tBOC, G=OH, Z=thiophen-3-yl, j=3, m=S=1, and Rs=R=hydrogen; L=absent, X and Y taken together with the carbon Compound of Formula I, wherein A=tBOC, G=OH, atoms to which they are attached are L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=2-pyrid-3-yl acetylenyl, j=3, m=S=1, and Rs=Re=hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=2,3-dihydrobenzofuran-5-yl, j=3, m=S=1, W is absent, Z=thiophen-2-yl, j=3,m=s=1, and R=R= and Rs=R=hydrogen; hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, atoms to which they are attached are W=-NH-, Z=propargyl, j=3,m=s=1, and R=R= hydrogen; -O Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, No W=-N(ethyl)-, Z=benzyl, j=3,m=s=1, and Rs=R= DC hydrogen; W is absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=R= Compound of Formula I, wherein A=tBOC, G=OH, hydrogen; L=absent, X and Y taken together with the carbon Compound of Formula I, wherein A=tBOC, G=OH, atoms to which they are attached are phenyl, L=absent, X and Y taken together with the carbon W=-NH-, Z=pyrid-3-yl, j=3,m=s=1, and R=R= atoms to which they are attached are hydrogen; n Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=tetrazolyl, j=3, m=S=1, and Rs=R=hydro c gen, W is absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=R= Compound of Formula I, wherein A=tBOC, G=OH, hydrogen; L=absent, X and Y taken together with the carbon Compound of Formula I, wherein A=tBOC, G=OH, atoms to which they are attached are phenyl, W is L=absent, X and Y taken together with the carbon absent, Z=morpholino, j=3, m=S=1, and Rs=Re=hy atoms to which they are attached are drogen; Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W=-O-, Z=thiophen-3-yl-methyl, j=3,m=S=1, and Rs=Re=hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are US 2004/0266668A1 Dec. 30, 2004 62
W is absent, Z=thiophen-2-yl, j=3,m=S=1, and Rs=R= hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are
21 W is absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=R= hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, W is absent, Z=thiophen-2-yl, j=3,m=S=1, and Rs=R= L=absent, X and Y taken together with the carbon hydrogen; atoms to which they are attached are Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are HO
W is absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=R= hydrogen; W is absent, Z=thiophen-2-yl, j=3,m=S=1, and Rs=R= hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon Compound of Formula I, wherein A=tBOC, G=OH, atoms to which they are attached are L=absent, X and Y taken together with the carbon atoms to which they are attached are
W is absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=R= W is absent, Z=thiophen-2-yl, j=3,m=S=1, and Rs=R= hydrogen; hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon L=absent, X and Y taken together with the carbon atoms to which they are attached are atoms to which they are attached are
O N
W is absent, Z=thiophen-2-yl, j=3,m=S=1, and Rs=R= W is absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=R= hydrogen; hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon L=absent, X and Y taken together with the carbon atoms to which they are attached are atoms to which they are attached are US 2004/0266668A1 Dec. 30, 2004 63
HN
W is absent, Z=thiophen-2-yl, j=3,m=s=1, and R=R= hydrogen; W is absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=R= hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon L=absent, X and Y taken together with the carbon atoms to which they are attached are atoms to which they are attached are
W is absent, Z=thiophen-2-yl, j=3,m=s=1, and R=R= hydrogen; W is absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=R= hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are atoms to which they are attached are
W is absent, Z=thiophen-2-yl, j=3,m=s=1, and R=R= W is absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=R= hydrogen; hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon L=absent, X and Y taken together with the carbon atoms to which they are attached are atoms to which they are attached are
HO
W is absent, Z=thiophen-2-yl, j=3,m=S=1, and Rs=R= W is absent, Z=thiophen-2-yl, j=3,m=s=1, and Rs=R= hydrogen; hydrogen; Compound of Formula I, wherein A=tBOC, G=OH, Compound of Formula I, wherein A=tBOC, G=OH, L=absent, X and Y taken together with the carbon L=absent, X and Y taken together with the carbon atoms to which they are attached are atoms to which they are attached are US 2004/0266668A1 Dec. 30, 2004 64 C-d W is absent, Z=thiophen-2-yl, j=3,m=S=1, and Rs=Re= hydrogen; W is absent, Z=thiophen-2-yl, j=3, m=S=1, R=R= Compound of Formula I, wherein A=tEOC, G=OEt, hydrogen; L=absent, X and Y taken together with the carbon Compound of Formula I, wherein A=tEOC, G=OH, atoms to which they are attached are L=absent, X and Y taken together with the carbon atoms to which they are attached are
W is absent, Z=thiophen-2-yl, j=3,m=S=1, and Rs=Re= hydrogen; W is absent, Z=thiophen-2-yl, j=3, m=S=1, Rs=Re= Compound of Formula I, wherein A=tBOC, G=OH, hydrogen; L=absent, X and Y taken together with the carbon atoms to which they are attached are Compound of Formula I, wherein A=-(C=O)-O-R', wherein R'=cyclopentyl, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=thiophen-2-yl, j=3, m=s=1, and Rs=Re=hydrogen; Compound of Formula I, wherein A=-(C=O)-O-R', wherein R'=cyclobutyl, G=OH, L=absent, X and Y taken together with the carbon atoms to which they are attached are phenyl, W is absent, Z=thiophen-2-yl,j=3, m=s=1, and Rs=Re=hydrogen; Compound of Formula I, wherein A=-(C=O)-O-R', W is absent, Z=thiophen-2-yl, j=3,m=S=1, and Rs=Re= wherein R'=cyclohexyl, G=OH, L=absent, X and Y hydrogen; taken together with the carbon atoms to which they are Compound of Formula I, wherein A=tBOC, G=OH, attached are phenyl, W is absent, Z=thiophen-2-yl, j=3, L=absent, X and Y taken together with the carbon m=s=1, and Rs=R=hydrogen; atoms to which they are attached are Compound of Formula I, wherein A=-(C=O)-O-R', wherein R'= () Old s G=OH, L=absent, X and Y taken together with the carbon W is absent, Z=thiophen-2-yl, j=3,m=S=1, and Rs=Re= atoms to which they are attached are phenyl, W is hydrogen; absent, Z=thiophen-2-yl, j=3, m=S=1, and Rs=Re= Compound of Formula I, wherein A=tBOC, G=OH, hydrogen; L=absent, X and Y taken together with the carbon Compound of Formula I, wherein A=-(C=O)-O-R', atoms to which they are attached are wherein R'=
US 2004/0266668A1 Dec. 30, 2004 66
Compound of Formula I, wherein A=tBOC, G=OH, 101309; 128301; 124301; 113301; 143301; 115301; L=CFCH., X and Y taken together with the carbon 101367; 101368; 101323; 101317; 108301; 101318; atoms to which they are attached are phenyl, W is 101.319; 101351; 101353; 101349; 118301; 120301; absent, Z=thiophen-2-yl, j=3, m=S=1, and Rs=R= 101.333; 101320; 101321; 129301; 121301; 117301; hydrogen; and 123352; 101347; 101350; 107365; 101313; 145301; 101366; 101354; 101343; 101314; 101339; 101341; Compound of Formula I, wherein A=tBOC, G=OH, 107341; 114341; 106301; 144301; 126301; 127301; L=-CHFCH-, X and Y taken together with the 130301; 116301; 102301; 140301; 141301; 139301; carbon atoms to which they are attached are phenyl, W 138301; 142301; 137301; 135301; 134301; 133301; is absent, Z=thiophen-2-yl, j=3, m=S=1, and Rs=Re= 131301; 132301; 136301; 101345; 101344; 101342; hydrogen. 105316; 107316; 101315; 101346; 10.1337; 116365; or 7. A compound of Formula V: 101.338. 9. A pharmaceutical composition comprising an inhibitory amount of a compound according to claim 1 or 7 alone or in (V) combination with a pharmaceutically acceptable carrier or excipient. 10. A method of treating a hepatitis C viral infection in a Subject, comprising administering to the Subject an inhibi tory amount of a pharmaceutical composition according to claim 9. 11. A method of inhibiting the replication of hepatitis C Virus, the method comprising Supplying a hepatitis C viral NS3 protease inhibitory amount of the pharmaceutical com position of claim 9. 12. The method of claim 10 further comprising adminis wherein A and B are as defined in the A-Matrix and tering concurrently an additional anti-hepatitis C virus B-Matrix tables. agent. 8. A compound of claim 8 Selected from compound 13. The method of claim 12, wherein said additional numbers: 101301; 101358; 101306; 101302; 101322; anti-hepatitis C Virus agent is Selected from the group 101311; 101325; 101.303; 103304; 101326; 101327; consisting of C-interferon, B-interferon, ribavarin, and ada 101330; 101.331; 101.332; 101.335; 101336; 101348; mantine. 101340; 101334; 101348; 101359; 101328; 101360; 14. The method of claim 12, wherein said additional 101361; 101362; 101329; 105301; 123301; 112301; anti-hepatitis C virus agent is an inhibitor of hepatitis C virus 124301; 109301; 122301; 111301; 114301; 107301; helicase, polymerase, metalloprotease, or IRES. 104301; 101324; 101304; 101355; 101356; 101307; 101357; 101347; 101352; 110301; 101364; 101308; k k k k k