US20200270303A1 - Macrocyclic proline derived hcv serine protease inhibitors - Google Patents

Macrocyclic proline derived hcv serine protease inhibitors Download PDF

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US20200270303A1
US20200270303A1 US16/724,677 US201916724677A US2020270303A1 US 20200270303 A1 US20200270303 A1 US 20200270303A1 US 201916724677 A US201916724677 A US 201916724677A US 2020270303 A1 US2020270303 A1 US 2020270303A1
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substituted
cycloalkenyl
cycloalkyl
alkenyl
alkyl
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Yat Sun Or
Jun Ma
Guoqiang Wang
Jiang Long
Bin Wang
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Enanta Pharmaceuticals Inc
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Enanta Pharmaceuticals Inc
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    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
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Definitions

  • the present invention relates to novel hepatitis C virus (HCV) protease inhibitor compounds, methods for using the same to treat HCV infection, as well as processes for making such compounds.
  • HCV hepatitis C virus
  • HCV is the principal cause of non-A, non-B hepatitis and is an increasingly severe public health problem both in the developed and developing world. It is estimated that the virus infects over 200 million people worldwide, surpassing the number of individuals infected with the human immunodeficiency virus (HIV) by nearly five fold. HCV infected patients, due to the high percentage of individuals inflicted with chronic infections, are at an elevated risk of developing cirrhosis of the liver, subsequent hepatocellular carcinoma and terminal liver disease. HCV is the most prevalent cause of hepatocellular cancer and cause of patients requiring liver transplantations in the western world.
  • HIV human immunodeficiency virus
  • anti-HCV therapeutics There are considerable barriers to the development of anti-HCV therapeutics, which include, but are not limited to, the persistence of the virus, the genetic diversity of the virus during replication in the host, the high incident rate of the virus developing drug-resistant mutants, and the lack of reproducible infectious culture systems and small-animal models for HCV replication and pathogenesis. In a majority of cases, given the mild course of the infection and the complex biology of the liver, careful consideration must be given to antiviral drugs, which are likely to have significant side effects.
  • NS3 hepatitis C non-structural protein-3
  • HCV is a flaviridae type RNA virus.
  • the HCV genome is enveloped and contains a single strand RNA molecule composed of circa 9600 base pairs. It encodes a polypeptide comprised of approximately 3010 amino acids.
  • the HCV polyprotein is processed by viral and host peptidase into 10 discreet peptides which serve a variety of functions.
  • the P7 protein is of unknown function and is comprised of a highly variable sequence.
  • NS2 is a zinc-dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein.
  • NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus.
  • NS4A is a tightly associated but non-covalent cofactor of the serine protease.
  • the NS3/4A protease is responsible for cleaving four sites on the viral polyprotein.
  • the NS3-NS4A cleavage is autocatalytic, occurring in cis.
  • the remaining three hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B all occur in trans.
  • NS3 is a serine protease which is structurally classified as a chymotrypsin-like protease. While the NS serine protease possesses proteolytic activity by itself, the HCV protease enzyme is not an efficient enzyme in terms of catalyzing polyprotein cleavage. It has been shown that a central hydrophobic region of the NS4A protein is required for this enhancement. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficacy at all of the sites.
  • a general strategy for the development of antiviral agents is to inactivate virally encoded enzymes, including NS3, that are essential for the replication of the virus.
  • Current efforts directed toward the discovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov. 1, 867-881 (2002).
  • the invention provides compounds represented by Formula I, or pharmaceutically acceptable salts, esters, or prodrugs thereof:
  • A is absent, —(C ⁇ O)—, —S(O) 2 —, —C( ⁇ N—OR 1 )— or —C( ⁇ N—CN)—;
  • —C 3 -C 12 cycloalkyl is selected from —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted —C 3 -C 12 heterocycloalkyl; or
  • R 7 and R 8 are each independently C 1 -C 8 alkyl or C 2 -C 8 alkenyl and are each independently optionally substituted with one or more halo;
  • —C 3 -C 12 cycloalkyl is selected from —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted —C 3 -C 12 heterocycloalkyl.
  • X and Y taken together with the carbon atoms to which they are attached, form a cyclic moiety selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocylic, more preferably aryl, substituted aryl, heteroaryl or substituted heteroaryl.
  • X and Y taken together with the carbon atoms to which they are attached, form a benzo or substituted benzo ring.
  • the present invention features pharmaceutical compositions comprising a compound of the invention (e.g., Formula I), or a pharmaceutically acceptable salt, ester or prodrug thereof.
  • pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention (e.g., Formula I), or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • a first embodiment of the invention is a compound represented by Formula I as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • X 1 -X 4 are independently selected from —CR 6 and N, wherein each R 6 is independently selected from:
  • A is absent, —(C ⁇ O)—, —S(O) 2 —, —C( ⁇ N—OR 1 )— or —C( ⁇ N—CN)—;
  • —C 3 -C 12 cycloalkyl substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted —C 3 -C 12 heterocycloalkyl;
  • R 7 and R 8 are each independently C 1 -C 8 alkyl or C 2 -C 8 alkenyl and are each independently optionally substituted with one or more halo;
  • each Y 1 and Y 2 are independently selected from CR 6 and N, and each Y 3 is independently selected from NR 6 , S and O;
  • each R 6 is independently selected from:
  • A is absent, —(C ⁇ O)—, —S(O) 2 —, —C( ⁇ N—OR 1 )— or —C( ⁇ N—CN)—;
  • _ is selected from —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted —C 3 -C 12 heterocycloalkyl;
  • R 7 and R 8 are each independently C 1 -C 8 alkyl or C 2 -C 8 alkenyl and are each independently optionally substituted with one or more halo;
  • X 1 -X 4 are independently selected from —CR 6 and N, wherein each R 6 is independently selected from:
  • A is absent, —(C ⁇ O)—, —S(O) 2 —, —C( ⁇ N—OR 1 )— or —C( ⁇ N—CN)—;
  • —C 3 -C 12 cycloalkyl substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted —C 3 -C 12 heterocycloalkyl;
  • R 7 and R 8 are each independently C 1 -C 8 alkyl or C 2 -C 8 alkenyl and are each independently optionally substituted with one or more halo;
  • X 1 -X 4 are independently selected from —CR 6 and N, wherein each R 6 is independently selected from:
  • —C 3 -C 12 cycloalkyl substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted —C 3 -C 12 heterocycloalkyl;
  • R 7 and R 8 are each independently C 1 -C 8 alkyl or C 2 -C 8 alkenyl and are each independently optionally substituted with one or more halo;
  • the present invention also features compounds of Formula VII and pharmaceutically acceptable salts, esters, and prodrugs thereof:
  • R 1′ , R 2′ , R 3′ and R 4′ are each independently R 6 , or R′ and R 2′ , R 2′ and R 3′ , or R 3′ and R 4′ taken together with the carbon atoms to which each is attached, form an aromatic, heteroaromatic, cyclic or heterocyclic ring;
  • —C 3 -C 12 cycloalkyl substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted —C 3 -C 12 heterocycloalkyl;
  • R 7 and R 8 are each independently C 1 -C 8 alkyl or C 2 -C 8 alkenyl and are each independently optionally substituted with one or more halo;
  • —C 3 -C 12 cycloalkyl substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted —C 3 -C 12 heterocycloalkyl;
  • Formulas I-VII is C 3 -C 12 carbocycle or 4- to 6-membered heterocycle and is optionally substituted with one or more substituents independently selected from halo, C 1 -C 8 alkyl or C 2 -C 8 alkenyl.
  • substituents independently selected from halo, C 1 -C 8 alkyl or C 2 -C 8 alkenyl.
  • C 3 -C 6 carbocycle can be a non-aromatic C 3 -C 6 carbocycle or a non-aromatic 4- to 6-membered heterocycle and is optionally substituted with one or more substituents independently selected from halo, C 1 -C 6 alkyl or C 2 -C 6 alkenyl. More preferably,
  • C 4 -C 6 carbocycle is saturated C 4 -C 6 carbocycle or saturated 4- to 6-membered heterocycle and is optionally substituted with one or more substituents independently selected from halo, C 1 -C 8 alkyl or C 2 -C 8 alkenyl.
  • R 1′ , R 2′ , R 3′ and R 4′ are hydrogen. Also preferably, R 1′ and R 4′ are hydrogen; and one of R 2′ and R 3′ is hydrogen, and the other is selected from halo, methyl optionally substituted with one or more halo, or —O-methyl optionally substituted with one or more halo.
  • R 1′ and R 2′ , or R 2′ and R 3′ , or R 3′ and R 4′ taken together with the carbon atoms to which they are attached, form a 5- or 6-membered carbocycle or heterocycle (e.g., phenyl), and the rest of R 1′ , R 2′ , R 3′ and R 4′ preferably are hydrogen.
  • R 3 is
  • R′ is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R is N
  • the present invention features compounds of Formula VII or pharmaceutically acceptable salts thereof, wherein
  • R′ is vinyl
  • the present invention features compounds of Formula VII or pharmaceutically acceptable salts thereof, wherein
  • R′ is vinyl
  • R 3′ is —O-methyl optionally substituted with one or more halo, and R 1′ , R 2′ , and R 4′ are hydrogen.
  • the present invention features compounds of Formula VII or pharmaceutically acceptable salts thereof, wherein
  • R′ is vinyl
  • R, R 2′ , R 3′ and R 4′ are hydrogen.
  • the present invention features compounds of Formula VII or pharmaceutically acceptable salts thereof, wherein
  • R′ is vinyl
  • R 3′ is halo (e.g, F), and R 1′ , R 2′ , and R 4′ are hydrogen.
  • the present invention features compounds of Formula VII or pharmaceutically acceptable salts thereof, wherein
  • R′ is vinyl
  • R 3′ and R 4′ taken together with carbon atoms to which they are attached form phenyl, and R′ and R 2′ are hydrogen.
  • the invention provides a compound of Formula VIII:
  • A is absent, or selected from —(C ⁇ O)—, —S(O) 2 —, —C( ⁇ N—OR 1 )— and —C( ⁇ N—CN)—;
  • —C 3 -C 12 cycloalkyl substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, substituted —C 3 -C 12 cycloalkenyl; —C 3 -C 12 heterocycloalkyl, and substituted —C 3 -C 12 heterocycloalkyl;
  • Representative compounds of the invention include, but are not limited to, the following compounds (example 1 to example 256 in Table 1) according to Formula VIII wherein R, -L 2 -W-L 1 -,
  • R′ and G are delineated for each example in Table 1.
  • Representative compounds of the invention also include, but are not limited to, the following compounds (example 257 to example 264 in Table 2) according to Formula IX wherein R, -L 2 -W-L 1 -,
  • R′ and G are delineated for each example in Table 2.
  • Representative compounds of the invention also include, but are not limited to, the following compounds (example 265 to example 272 in Table 3) according to Formula X wherein R, -L 2 -W-L 1 -,
  • R′ and G are delineated for each example in Table 3.
  • representative compounds of the invention also include, but are not limited to, the following compounds (example 273 to example 299 in Table 4) according to Formula XI, wherein R,
  • R′ and G are delineated for each example in Table 4.
  • the present invention also features pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof.
  • the present invention features pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.
  • the invention features methods of treating a hepatitis C infection in a subject in need of such treatment with said pharmaceutical composition.
  • the present invention features methods of using compounds of the present invention or pharmaceutically acceptable salts thereof to treat HCV infection.
  • the methods comprise administering to an HCV patient in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the compound is a compound having Formula VII as described above.
  • HCV genotype 1 and 3 variants e.g., genotype 1a R 155 K, D168E or D168V variants, genotype 1b R 155 K or D168V variants, or genotype 3a S138T, A166T or Q168R variants.
  • Clinical trials and replicon cell assays have identified HCV variants that are resistant to many known protease inhibitors. For instance, the R 155 K variants have been shown to confer low-level resistance to telaprevir and boceprevir and confer high-level resistance to BILN 2061 and danoprevir (ITMN-191).
  • the compounds of the present invention enable an effective and broad-spectrum treatment for HCV infections.
  • the present invention features methods of treating HCV variants.
  • the methods comprise administering to patients infected with or harboring such variants an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. These patients can be treatment-na ⁇ ve patients or treatment-experienced patients.
  • the patient receiving treatment according to this aspect of the invention harbors a variant selected from genotype 1a R 155 K, D168E or D168V variants, genotype 1b R 155 K or D168V variants, or genotype 3a A166T or Q168R variants.
  • the patient harbors an HCV variant selected from genotype 1 R 155 K or D168V variants or genotype 3 Q168R variants.
  • the patient can harbor a variant selected from genotype 1a R 155 K or D168V variants, genotype 1b R 155 K or D168V variants, or genotype 3s Q168R variants.
  • the patient harbors a variant selected from genotype 1 R 155 K or D168V variants, e.g., genotype 1a R 155 K or D168V variants or genotype 1b R 155 K or D168V variants.
  • the patient harbors a genotype 1 R 155 K variant (e.g., a genotype 1a or 1b R 155 K variant).
  • the patient harbors a genotype 1 D168V variant (e.g., a genotype 1a or 1b D168V variant).
  • the patients treated according to this aspect of the invention may have previously received but failed a treatment regimen containing another HCV protease inhibitor.
  • the other HCV protease inhibitor(s) used in the prior treatment can be selected from, for example and without limitation, telaprevir, boceprevir, danoprevir, vaniprevir, narlaprevir, TMC-435 (Tibotec), BILN 2061 (Boehringer Ingelheim), BI-201335 (Boehringer Ingelheim), BMS-650032 (BMS), or a combination thereof.
  • the compound employed in this aspect of the invention is a compound having Formula VII as described above or a pharmaceutically acceptable salt thereof. More preferably, the compound employed in this aspect of the invention is selected from compounds of Examples 1, 2, 4, 5, 6, 8, 34, 36, 40, 65, 89, 90, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, or 297, or pharmaceutically acceptable salts thereof. Highly preferably, the compound employed in this aspect of the invention is selected from compounds of Examples 5, 6, 275, 276, 287, 288, 289, 294, 296 or 297, or pharmaceutically acceptable salts thereof.
  • the present invention features methods of treating HCV patients who have previously received a treatment regimen containing another HCV protease inhibitor.
  • the methods comprise administering to said patients an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • these treatment-experienced patients may harbor resistant variants or be prone to HCV mutations and, as a result, be less responsive to other protease inhibitors (e.g., telaprevir, boceprevir, danoprevir, vaniprevir, narlaprevir, TMC-435 (Tibotec), BILN 2061 (Boehringer Ingelheim), BI-201335 (Boehringer Ingelheim), BMS-650032 (BMS), or a combination thereof).
  • protease inhibitors e.g., telaprevir, boceprevir, danoprevir, vaniprevir, narlaprevir, TMC-435 (Tibotec), BILN 2061 (Boehringer Ingelheim
  • the compound employed in this aspect of the invention is a compound having Formula VII as described above or a pharmaceutically acceptable salt thereof. More preferably, the compound employed in this aspect of the invention is selected from compounds of Examples 1, 2, 4, 5, 6, 8, 34, 36, 40, 65, 89, 90, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298 or 299, or pharmaceutically acceptable salts thereof. Highly preferably, the compound employed in this aspect of the invention can be selected from compounds of Examples 5, 6, 275, 276, 287, 288, 289, 294, 296 or 297, or pharmaceutically acceptable salts thereof.
  • the present invention features methods of treating HCV patients infected with genotype 3 HCV viruses. These methods are based on the unexpected finding that the compounds of the invention are effective in inhibiting HCV genotype 3 viruses including certain variants (e.g., A166T, Q168R or S138T variants). These methods comprise administering to said patients an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the compound employed in this aspect of the invention is a compound having Formula VII as described above or a pharmaceutically acceptable salt thereof.
  • the compound employed in this aspect of the invention is selected from compounds of Examples 1, 2, 4, 5, 6, 8, 34, 36, 40, 65, 89, 90, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298 or 299, or pharmaceutically acceptable salts thereof.
  • the compound employed in this aspect of the invention can be selected from compounds of Examples 5, 6, 275, 276, 287, 288, 289, 294, 296 or 297, or pharmaceutically acceptable salts thereof.
  • the present invention also features the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medication for the treatment of HCV variants.
  • the patients being treated may be infected with or harbor a variant selected from genotype 1a R 155 K, D168E or D168V variants, genotype 1b R 155 K or D168V variants, or genotype 3a A166T or Q168R variants.
  • the present invention features the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medication for the treatment of treatment-experienced HCV patients who have previously received but failed a treatment containing another HCV protease inhibitor (e.g., telaprevir, boceprevir, danoprevir, vaniprevir, narlaprevir, TMC-435 (Tibotec), BILN 2061 (Boehringer Ingelheim), BI-201335 (Boehringer Ingelheim), BMS-650032 (BMS), or a combination thereof).
  • another HCV protease inhibitor e.g., telaprevir, boceprevir, danoprevir, vaniprevir, narlaprevir, TMC-435 (Tibotec), BILN 2061 (Boehringer Ingelheim), BI-201335 (Boehringer Ingelheim), BMS-650032 (BMS), or a combination thereof.
  • the present invention contemplates the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medication for the treatment of HCV patients infected with genotype 3 HCV (including genotype 3 variants, such as genotype 3s A166T, Q168R or S138T variants).
  • a compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone, or in combination with one or more other anti-HCV agents, such as HCV polymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors, CD81 inhibitors, cyclophilin inhibitors, internal ribosome entry site (IRES) inhibitors or any combinations thereof.
  • Interferon, ribavirin or both can also be included in the treatment.
  • the methods described herein can further comprise administering to the patient peginterferon-alpha and ribavirin. Different agents can be administered simultaneously or sequentially.
  • the dosing frequency of each agent in a treatment regimen can be the same or different.
  • a compound of the invention can be dosed once daily and ribavirin can be dosed twice daily.
  • Compounds of the present invention can be administered as the sole active pharmaceutical agent, or used in combination with one or more agents to treat or prevent hepatitis C infections or the symptoms associated with HCV infection.
  • Other agents to be administered in combination with a compound or combination of compounds of the invention include therapies for disease caused by HCV infection that suppresses HCV viral replication by direct or indirect mechanisms.
  • agents such as host immune modulators (for example, interferon-alpha, pegylated interferon-alpha, interferon-beta, interferon-gamma, CpG oligonucleotides and the like), cyclophilins (e.g., Debio 025), or antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase (for example, ribavirin and the like). Also included are cytokines that modulate immune function. Also included are vaccines comprising HCV antigens or antigen adjuvant combinations directed against HCV.
  • host immune modulators for example, interferon-alpha, pegylated interferon-alpha, interferon-beta, interferon-gamma, CpG oligonucleotides and the like
  • cyclophilins e.g., Debio 025
  • antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenas
  • IRS internal ribosome entry site
  • Other agents to be administered in combination with a compound of the present invention include any agent or combination of agents that inhibit the replication of HCV by targeting proteins of the viral genome involved in the viral replication. These agents include but are not limited to other inhibitors of HCV RNA dependent RNA polymerase such as, for example, nucleoside type polymerase inhibitors described in WO0190121(A2), or U.S. Pat. No.
  • 6,348,587B1 or WO0160315 or WO00132153 or non-nucleoside inhibitors such as, for example, benzimidazole polymerase inhibitors described in EP 1162196A1 or WO00204425 or inhibitors of HCV protease such as, for example, peptidomimetic type inhibitors such as BILN2061 and the like or inhibitors of HCV helicase.
  • agents to be administered in combination with a compound of the present invention include any agent or combination of agents that inhibit the replication of other viruses for co-infected individuals. These agents include but are not limited to therapies for disease caused by hepatitis B (HBV) infection or therapies for disease caused by human immunodeficiency virus (HIV) infection.
  • HBV hepatitis B
  • HAV human immunodeficiency virus
  • one aspect of the invention is directed to a method for treating or preventing an infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof.
  • Examples of the host immune modulator are, but not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamrna, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • a further aspect of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment an agent or combination of agents that treat or alleviate symptoms of HCV infection including cirrhosis and inflammation of the liver, with a therapeutically effective amount of a compound or combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof.
  • Yet another aspect of the invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof.
  • An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but not limited thereto, L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof.
  • Example of the RNA-containing virus includes, but not limited to, hepatitis C virus (HCV).
  • Another aspect of the invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof.
  • HIV human immunodeficiency virus
  • An example of the RNA-containing virus includes, but not limited to, hepatitis C virus (HCV).
  • the present invention provides the use of a compound or a combination of compounds of the invention, or a therapeutically acceptable salt form, stereoisomer, or tautomer, prodrug, salt of a prodrug, or combination thereof, and one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, particularly hepatitis C virus.
  • Examples of the host immune modulator are, but not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • combination of compound or compounds of the invention, together with one or more agents as defined herein above can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form, prodrug, salt of a prodrug, or combination thereof.
  • combination of therapeutic agents can be administered as a pharmaceutical composition containing a therapeutically effective amount of the compound or combination of compounds of interest, or their pharmaceutically acceptable salt form, prodrugs, or salts of the prodrug, in combination with one or more agents as defined hereinabove, and a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions can be used for inhibiting the replication of an RNA-containing virus, particularly Hepatitis C virus (HCV), by contacting said virus with said pharmaceutical composition.
  • such compositions are useful for the treatment or prevention of an infection caused by an RNA-containing virus, particularly Hepatitis C virus (HCV).
  • further aspect of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus, particularly a hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a compound or combination of compounds of the invention or a pharmaceutically acceptable salt, stereoisomer, or tautomer, prodrug, salt of a prodrug, or combination thereof, one or more agents as defined hereinabove, and a pharmaceutically acceptable carrier.
  • HCV hepatitis C virus
  • the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or within a predetermined period of time, or the therapeutic agents can be given as a single unit dosage form.
  • Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to, agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal.
  • agents can be selected from another anti-HCV agent; an HIV inhibitor; an HAV inhibitor; and an HBV inhibitor.
  • anti-HCV agents include those agents that are effective for diminishing or preventing the progression of hepatitis C related symptoms or disease. Such agents include but are not limited to immunomodulatory agents, inhibitors of HCV NS3 protease, other inhibitors of HCV polymerase, inhibitors of another target in the HCV life cycle and other anti-HCV agents, including but not limited to, ribavirin, amantadine, levovirin and viramidine.
  • Immunomodulatory agents include those agents (compounds or biologicals) that are effective to enhance or potentiate the immune system response in a mammal.
  • Immunomodulatory agents include, but are not limited to, inosine monophosphate dehydrogenase inhibitors such as VX-497 (merimepodib, Vertex Pharmaceuticals), class I interferons, class II interferons, consensus interferons, asialo-interferons pegylated interferons and conjugated interferons, including but not limited to, interferons conjugated with other proteins including but not limited to, human albumin.
  • Class I interferons are a group of interferons that all bind to receptor type I, including both naturally and synthetically produced class I interferons, while class II interferons all bind to receptor type II.
  • Examples of class I interferons include, but are not limited to, [alpha]-, [beta]-, [delta]-, [omega]-, and [tau]-interferons, while examples of class II interferons include, but are not limited to, [gamma]-interferons.
  • Inhibitors of HCV NS3 protease include agents (compounds or biologicals) that are effective to inhibit the function of HCV NS3 protease in a mammal.
  • Inhibitors of HCV NS3 protease include, but are not limited to, those compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO 2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO 2004/101605, WO 2004/103996, WO 2005/028501, WO 2005/070955, WO 2006/000085, WO 2006/007700 and WO 2006/007708 (all by Boehringer Ingelheim), WO 02/060926, WO 03/053349, WO03/099274, WO 03/
  • Inhibitors of HCV polymerase include agents (compounds or biologicals) that are effective to inhibit the function of an HCV polymerase.
  • Such inhibitors include, but are not limited to, non-nucleoside and nucleoside inhibitors of HCV NS5B polymerase.
  • inhibitors of HCV polymerase include but are not limited to those compounds described in: WO 02/04425, WO 03/007945, WO 03/010140, WO 03/010141, WO 2004/064925, WO 2004/065367, WO 2005/080388 and WO 2006/007693 (all by Boehringer Ingelheim), WO 2005/049622 (Japan Tobacco), WO 2005/014543 (Japan Tobacco), WO 2005/012288 (Genelabs), WO 2004/087714 (IRBM), WO 03/101993 (Neogenesis), WO 03/026587 (BMS), WO 03/000254 (Japan Tobacco), and WO 01/47883 (Japan Tobacco), and the clinical candidates XTL-2125, HCV 796, R-1626 and NM 283.
  • Inhibitors of another target in the HCV life cycle include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of HCV other than by inhibiting the function of the HCV NS3 protease. Such agents may interfere with either host or HCV viral mechanisms necessary for the formation and/or replication of HCV.
  • Inhibitors of another target in the HCV life cycle include, but are not limited to, entry inhibitors, agents that inhibit a target selected from a helicase, a NS2/3 protease and an internal ribosome entry site (IRES) and agents that interfere with the function of other viral targets including but not limited to, an NS5A protein and an NS4B protein.
  • a patient may be co-infected with hepatitis C virus and one or more other viruses, including but not limited to, human immunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis B virus (HBV).
  • HAV human immunodeficiency virus
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • combination therapy to treat such co-infections by co-administering a compound according to the present invention with at least one of an HIV inhibitor, an HAV inhibitor and an HBV inhibitor.
  • compositions of the present invention may further comprise inhibitor(s) of other targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • inhibitor(s) of other targets in the HCV life cycle including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • compositions of the present invention may further comprise another anti-viral, anti-bacterial, anti-fungal or anti-cancer agent, or an immune modulator, or another therapeutic agent.
  • the present invention includes methods of treating viral infection such as, but not limited to, hepatitis C infections in a subject in need of such treatment by administering to said subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • the present invention includes methods of treating hepatitis C infections in a subject in need of such treatment by administering to said subject an anti-HCV virally effective amount or an inhibitory amount of a pharmaceutical composition of the present invention.
  • An additional embodiment of the present invention includes methods of treating biological samples by contacting the biological samples with the compounds of the present invention.
  • Yet a further aspect of the present invention is a process of making any of the compounds delineated herein employing any of the synthetic means delineated herein.
  • viral infection refers to the introduction of a virus into cells or tissues, e.g., hepatitis C virus (HCV). In general, the introduction of a virus is also associated with replication.
  • HCV hepatitis C virus
  • Viral infection may be determined by measuring virus antibody titer in samples of a biological fluid, such as blood, using, e.g., enzyme immunoassay.
  • a biological fluid such as blood
  • Other suitable diagnostic methods include molecular based techniques, such as RT-PCR, direct hybrid capture assay, nucleic acid sequence based amplification, and the like.
  • a virus may infect an organ, e.g., liver, and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease and hepatocellular carcinoma.
  • anti-cancer agent refers to a compound or drug capable of preventing or inhibiting the advancement of cancer.
  • examples of such agents include cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine, cyclosporin A, phenothiazines or thioxantheres.
  • anti-fungal agent shall used to describe a compound which may be used to treat a fungus infection other than 3-AP, 3-AMP or prodrugs of 3-AP and 3-AMP according to the present invention.
  • Anti-fungal agents according to the present invention include, for example, terbinafine, fluconazole, itraconazole, posaconazole, clotrimazole, griseofulvin, nystatin, tolnaftate, caspofungin, amphotericin B, liposomal amphotericin B, and amphotericin B lipid complex.
  • antibacterial agent refers to both naturally occurring antibiotics produced by microorganisms to suppress the growth of other microorganisms, and agents synthesized or modified in the laboratory which have either bactericidal or bacteriostatic activity, e.g., ⁇ -lactam antibacterial agents, glycopeptides, macrolides, quinolones, tetracyclines, and aminoglycosides.
  • bacteriostatic it means that the agent essentially stops bacterial cell growth (but does not kill the bacteria); if the agent is bacteriocidal, it means that the agent kills the bacterial cells (and may stop growth before killing the bacteria).
  • immune modulator refers to any substance meant to alter the working of the humoral or cellular immune system of a subject.
  • immune modulators include inhibitors of mast cell-mediated inflammation, interferons, interleukins, prostaglandins, steroids, cortico-steroids, colony-stimulating factors, chemotactic factors, etc.
  • C 1 -C 6 alkyl or “C 1 -C 8 alkyl,” as used herein, refer to saturated, straight- or branched-chain hydrocarbon radicals containing between one and six, or one and eight carbon atoms, respectively.
  • C 1 -C 6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl radicals; and examples of C 1 -C 8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals.
  • C 2 -C 6 alkenyl or “C 2 -C 8 alkenyl,” as used herein, denote a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety has at least one carbon-carbon double bond and contains from two to six, or two to eight carbon atoms, respectively.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.
  • C 2 -C 6 alkynyl or “C 2 -C 8 alkynyl,” as used herein, denote a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety has at least one carbon-carbon triple bond and contains from two to six, or two to eight carbon atoms, respectively.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • carbocycle refers to a saturated (e.g., “cycloalkyl”), partially saturated (e.g., “cycloalkenyl” or “cycloalkynyl”) or completely unsaturated (e.g., “aryl”) ring system containing zero heteroatom ring atom.
  • Ring atoms or “ring members” are the atoms bound together to form the ring or rings.
  • a carbocycle group is a divalent moiety linking two other elements in a depicted chemical structure (such as Z in Formula IA)
  • the carbocycle group can be attached to the two other elements through any two substitutable ring atoms.
  • a C 4 -C 6 carbocycle has 4-6 ring atoms.
  • C 3 -C 8 -cycloalkyl denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom where the saturated carbocyclic ring compound has from 3 to 8, or from 3 to 12, ring atoms, respectively.
  • C 3 -C 8 -cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C 3 -C 12 -cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
  • C 3 -C 8 -cycloalkenyl or “C 3 -C 12 -cycloalkenyl” as used herein, denote a monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond by the removal of a single hydrogen atom where the carbocyclic ring compound has from 3 to 8, or from 3 to 12, ring atoms, respectively.
  • C 3 -C 8 -cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples of C 3 -C 12 -cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.
  • arylalkyl refers to a C 1 -C 3 alkyl or C 1 -C 6 alkyl residue attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl and the like.
  • heteroaryl refers to a mono-, bi-, or tri-cyclic aromatic radical or ring having from five to ten ring atoms of which at least one ring atom is selected from S, O and N; wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.
  • heteroarylalkyl refers to a C 1 -C 3 alkyl or C 1 -C 6 alkyl residue residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like.
  • substituted refers to independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to, —F, —Cl, —Br, —I, —OH, protected hydroxy, —NO 2 , —CN, —NH 2 , N 3 , protected amino, alkoxy, thioalkoxy, oxo, -halo-C 1 -C 12 -alkyl, -halo-C 2 -C 12 -alkenyl, -halo-C 2 -C 12 -alkynyl, -halo-C 3 -C 12 -cycloalkyl, —NH—C 1 -C 12 -alkyl, —NH—C 2 -C 12 -alkenyl, —NH—C 2 -C 12 -alkynyl, —NH—C 3 -C 12 -cycloalkyl,
  • each substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from —F, —Cl, —Br, —I, —OH, —NO 2 , —CN, or —NH 2 .
  • any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein, can be any aromatic group.
  • Aromatic groups can be substituted or unsubstituted.
  • any alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl moiety described herein can also be an aliphatic group, an alicyclic group or a heterocyclic group.
  • An “aliphatic group” is non-aromatic moiety that may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contain one or more units of unsaturation, e.g., double and/or triple bonds.
  • An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is understood that aliphatic groups may be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups described herein.
  • alicyclic denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be further substituted.
  • heterocycloalkyl and “heterocyclic” can be used interchangeably and refer to a non-aromatic 3-, 4-, 5-, 6- or 7-membered ring or a bi- or tri-cyclic group fused system, where: (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to a benzene ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted.
  • heterocycloalkyl groups include, but are not limited to, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl.
  • Such heterocyclic groups may be further substituted to give substituted heterocyclic.
  • alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl are intended to be monovalent or divalent.
  • alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene, cycloalkynylene, arylalkylene, hetoerarylalkylene and heterocycloalkylene groups are to be included in the above definitions, and are applicable to provide the formulas herein with proper valency.
  • hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxy group so that it will depart during synthetic procedures such as in a substitution or elimination reactions.
  • hydroxy activating group include, but not limited to, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate and the like.
  • activated hydroxy refers to a hydroxy group activated with a hydroxy activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups.
  • halo and “halogen,” as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques, which are known to those skilled in the art.
  • subject refers to a mammal.
  • a subject therefore refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like.
  • the subject is a human.
  • the subject may be referred to herein as a patient.
  • pharmaceutically acceptable salt refers to those salts of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxy group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the are described generally in T. H. Greene and P. G., S. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).
  • hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphen
  • Preferred hydroxy protecting groups for the present invention are acetyl (Ac or —C(O)CH 3 ), benzoyl (Bz or —C(O)C 6 H5), and trimethylsilyl (TMS or —Si(CH 3 ) 3 ).
  • acetyl Ac or —C(O)CH 3
  • benzoyl Bz or —C(O)C 6 H5
  • trimethylsilyl TMS or —Si(CH 3 ) 3
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • salts include, but are not limited to, nontoxic acid addition salts e.g., salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • nontoxic acid addition salts e.g., salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed.
  • Amino protecting groups as known in the are described generally in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.
  • ester refers to esters of the compounds formed by the process of the present invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.
  • Prodrug as used herein means a compound, which is convertible in vivo by metabolic means (e.g. by hydrolysis) to afford any compound delineated by the formulae of the instant invention.
  • prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs , Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology , Vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design and Application of Prodrugs, Textbook of Drug Design and Development , Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series , John Wiley & Sons, N Y, 1986.
  • protogenic organic solvent or “protic solvent” as used herein, refer to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series , John Wiley & Sons, N Y, 1986.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and variation of the reaction conditions can produce the desired bridged macrocyclic products of the present invention.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M.
  • the compounds of this invention may be modified by appending various functionalities via synthetic means delineated herein to enhance selective biological properties.
  • modifications include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulf
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, e
  • sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • An inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
  • viral infections are treated or prevented in a subject such as a human or lower mammal by administering to the subject an anti-hepatitis C virally effective amount or an inhibitory amount of a compound of the present invention, in such amounts and for such time as is necessary to achieve the desired result.
  • An additional method of the present invention is the treatment of biological samples with an inhibitory amount of a compound of composition of the present invention in such amounts and for such time as is necessary to achieve the desired result.
  • anti-hepatitis C virally effective amount of a compound of the invention, as used herein, mean a sufficient amount of the compound so as to decrease the viral load in a biological sample or in a subject (e.g., resulting in at least 10%, preferably at least 50%, more preferably at least 80%, and most preferably at least 90% or 95%, reduction in viral load).
  • an anti-hepatitis C virally effective amount of a compound of this invention will be at a reasonable benefit/risk ratio applicable to any medical treatment.
  • inhibitory amount of a compound of the present invention means a sufficient amount to decrease the hepatitis C viral load in a biological sample or a subject (e.g., resulting in at least 10%, preferably at least 50%, more preferably at least 80%, and most preferably at least 90% or 95%, reduction in viral load). It is understood that when said inhibitory amount of a compound of the present invention is administered to a subject it will be at a reasonable benefit/risk ratio applicable to any medical treatment as determined by a physician.
  • biological sample(s),” as used herein, means a substance of biological origin intended for administration to a subject.
  • biological samples include, but are not limited to, blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, and the like; sperm and ova; bone marrow and components thereof; or stem cells.
  • another embodiment of the present invention is a method of treating a biological sample by contacting said biological sample with an inhibitory amount of a compound or pharmaceutical composition of the present invention.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease.
  • the subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • 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 inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; 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; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the total daily inhibitory dose of the compounds of this invention administered to a subject in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • the coupling reagent can be selected from, but not limited to, HATU/DIPEA, DCC/DMAP, for further details on peptide coupling reagents see: Christian A. G. N. Montalbetti et al., Tetrahedron 2005, 61, 10827) to afford the diene 1-4.
  • Ring-closing metathesis of diene 1-4 with a ruthenium-based catalyst gives the desired macrocyclic alkene 1-5 (for further details on ring-closing metathesis see recent reviews: Grubbs et al., Acc. Chem. Res., 1995, 28, 446; Shrock et al., Tetrahedron 1999, 55, 8141; Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012; Trnka et al., Acc. Chem. Res. 2001, 34, 18, and Hoveyda et al., Chem. Eur. J. 2001, 7, 945).
  • the hydrolysis of the macrocyclic ester 1-5 to the corresponding acid 1-6 could be effected with inorganic base, such as, but not limited to LiOH, NaOH, KOH.
  • the resulted acid 1-6 is coupled with amine 1-7 employing amide coupling reagent (the coupling reagent can be selected from, but not limited to, HATU, DCC and HOBT in the presence of organic base such as, but not limited to, DIEPA, TEA, DMAP; for further details on amide formation see recent review: Christian A. G. N. Montalbetti et al., Tetrahedron 2005, 61, 10827) to afford amide 1-8 or 1-9.
  • amide coupling reagent can be selected from, but not limited to, HATU, DCC and HOBT in the presence of organic base such as, but not limited to, DIEPA, TEA, DMAP; for further details on amide formation see recent review: Christian A. G. N. Montalbetti et al.,
  • amide 1-8 can be prepared from the acid 1-10, which is synthesized from the hydrolysis of the ester 1-8.
  • the acid 1-9 was activated with CDI and followed by coupling with sulfonamide 1-11 in presence of organic base such as, but not limited to DBU to provide the title compound 1-8.
  • the synthesis of quinoxaline derivative 1-1 is exemplified in Scheme 2.
  • the bromide 2-2 was coupled with aldehyde 2-1 employing metal such as, but not limited to In, Zn, Mg or Cr to afford the hydroxyl ester 2-3, which was further oxidized to give the ketone ester 2-4 with oxidation reagent such a, but not limited to TPAP/NMO.
  • the synthesis of ketone ester 2-4 could be effected through lithium halogen exchange of bromide 2-2 followed by coupling with ester 2-5 (this precedure could also be applied to acid chloride 2-6 or the Weinreb amide 2-7) to afford the ketone ester 2-4.
  • bromide 2-2 was treated with metal such as, but not limited to In, Zn or Mg and then reacted with acid chloride 2-6 or ester 2-5 or Weinreb amide 2-7 to give the ketone ester 2-4.
  • the ketone ester 2-4 was condensed with diamine 2-8 to afford the quinoxaline 2-9.
  • the hydroxyl quinoxaline 2-9 was converted into chloroquinoxaline 3-3 utilizing chlorination reagent such as but not limited to, POCl 3 , which was coupled with commercially available N-Boc-trans-4-hydroxy-L-proline 2-11 and followed by esterification to give the quinoxaline derivative 1-1.
  • compound 1-1 could be synthesized from the Mitsunobu reaction of commercially available alcohol 2-12 with quinoxaline 2-9.
  • Mitsunobu reaction see O. Mitsunobu, Synthesis 1981, 1-28; D. L. Hughes, Org. React. 1983, 29, 1; D. L. Hughes, Organic Preparations and Procedures Int. 1996, 28, 127; and J. A. Dodge, S. A. Jones, Recent Res. Dev. Org. Chem. 1997, 1, 273; K. C. Kumara Swamy et. al., Chem. Rev. 2009, 109, 2551.
  • the synthesis of acid 1-3 commenced with acylation of the racemic diol 3-1 to afford the diacetate 3-2 (for hydroxyl acylation see: T. W. Greene, Protective Groups in Organic Synthesis , Fourth Edition, John Wiley and Sons, 2006).
  • the kinetic resolution of the diacetate 3-2 was achieved by partial deacetylation with enzyme such as, but not limited to, Amano lipase to give the mono acetate 3-3 (M. P. Schneider et al., J. Chem. Soc., Chem. Commun., 1991, 49; for further information on kinetic resolution see: H. Pellissier, Tetrahedron, 2008, 64, 1563).
  • allyl ether 3-4 which was hydrolyzed with inorganic base such as, but not limited to, LiOH, NaOH to afford the alcohol 3-5.
  • inorganic base such as, but not limited to, LiOH, NaOH to afford the alcohol 3-5.
  • inorganic base such as, but not limited to, LiOH, NaOH to afford the alcohol 3-5.
  • the chloroformation by treating alcohol 3-5 with COCl 2 followed by coupling with amino acid 3-6 to provide the acid 1-3.
  • the allyl ether 3-5 could also be obtained when optical pure diol 3-1 was deprotonated with NaH followed by coupling with allyl bromide.
  • This alcohol 5-1 was treated with phosgene (or some other reagent such as, but not limited to triphosgene, diphosgene, carbonyldiimidazole) followed by coupling with amino acid 3-6 in the present of base such as, but not limited to LiOH or NaOH.
  • phosgene or some other reagent such as, but not limited to triphosgene, diphosgene, carbonyldiimidazole
  • amino acid 3-6 in the present of base such as, but not limited to LiOH or NaOH.
  • the Boc group in compound 7-1 was removed under acidic condition and the resulted amine was treated with phosgene or other reagent such as, but not limited to triphosgene or diphosgene or carbonyldi-imidazole in the presence of base such as, but not limited to pyridine or DMAP to afford the isocyanate 7-2.
  • This isocyanate 7-2 was coupled with diol 7-3 in the presence of organic base such as, but not limited to DBU to provide the mono alcohol 7-4.
  • Cross metathesis of alkene 7-4 and protected diol 7-5 in the presence of catalyst provides the alcohol 4-2 (for further details on cross metathesis see: Grubbs et al. J. Am. Chem. Soc. 2003, 125, 11360; R. Raju et al. Org. Lett. 2006, 8, 2139; Y. Schrodi et al. Aldrichimica Acta 2007, 40, 45).
  • quinoxalinyl derivative 4-4 has been exemplified in Scheme 8.
  • the alcohol 3-5 is treated with phosgene or other reagent such as, but not limited to triphosgene or diphosgene or carbonyldi-imidazole and then coupled with amine 8-1 in the presence of base such as, but not limited to NaOH to afford the alkene 8-2, which will undergo cross metathesis with quinoxalinyl derivative 2-10 to provide the t-butyl ester 8-3 (for further details on cross metathesis see: Grubbs et al. J. Am. Chem. Soc. 2003, 125, 11360; R. Raju et al. Org. Lett. 2006, 8, 2139; Y.
  • (+)-cyclopentane-1,2-diol 3-1a (10.02 g, 97.159 mmol) in DCM (20 ml) and pyridine (150 ml) was added acetic anhydride (36.7 ml, 388.63 mmol) and DMAP (593 mg) portionwise.
  • acetic anhydride (36.7 ml, 388.63 mmol)
  • DMAP 593 mg
  • the resulted solution was stirred for 21 h, and solvent was removed in vacuo.
  • the residue was dissolved in EtOAc, and the resulted solution was washed with 1N HCl, water, NaHCO 3 , water and brine.
  • the organic layer was dried and concentrated in vacuo.
  • the residue was purified by flash chromatography on CombiFlash with Hexane to 15% acetone in hexane to afford the diacetate 3-2a (17.1 g, 94%).
  • the acid 1-6a (crude product from step 1i) was dissolved in DCM (70 ml), and to this solution was added sulfonamide 1-7a (702 mg, 2.404 mmol), HATU (1.045 g, 2.748 mmol) and DIPEA (0.60 ml, 3.435 mmol). The mixture was stirred for 3 h, and then diluted with DCM. The organic layer was washed with 1 N HCl, water, brine, dried and concentrated in vacuo. The residue was first purified by flash chromatography on CombiFlash with Hexane to 50% EtOAc in hexane and then further purified by HPLC to afford the title compound (1.126 g, 60%). MS-ESI m/z 801.40 (M+H) + .
  • the acid 1-6a (21 mg, 0.0356 mmol) was dissolved in DCM (1.5 ml), and to this solution was added sulfonamide 1-7c (12.4 mg, 0.0463 mmol), HATU (17.6 mg, 0.0462 mmol) and DIPEA (12.4 ul, 0.0712 mmol). The mixture was stirred for 3 h, and then diluted with DCM. The organic layer was washed with 1 N HCl, water, brine, dried and concentrated in vacuo. The residue was purified by HPLC to afford the title compound. MS-ESI m/z 803.25 (M+H) + .
  • the acid 1-6-1 (9.8 mg, 0.0166 mmol) was dissolved in DCM (1.0 mL), and to this solution was added sulfonamide 1-7a (6.2 mg, 0.0216 mmol), HATU (9.5 mg, 0.0216 mmol) and DIPEA (5.8 ⁇ L, 0.0249 mmol). The mixture was stirred for 3 h, and then diluted with DCM. The organic layer was washed with with 10% citric acid, sat. NaHCO 3 , brine, dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by preparative TLC 50% EtOAc in hexane afford the title compound (2.0 mg, 20%). MS-ESI m/z 815.30 (M+H) + .
  • the acid 1-6-1 (crude product from step 266d) was dissolved in DCM (1 mL), and to this solution was added sulfonamide 1-7b (10.2 mg, 0.035 mmol), HATU (13.3 mg, 0.035 mmol) and DIPEA (12.2 ⁇ L, 0.07 mmol). The mixture was stirred for 3 h, and then diluted with DCM. The organic layer was washed with with 10% citric acid, sat. NaHCO 3 , brine, dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by preparative TLC 50% EtOAc in hexane afford the title compound (3 mg, 30%). MS-ESI m/z 839.38 (M+H) + .
  • the acid 1-6-1 was dissolved in DCM (1 mL), and to this solution was added sulfonamide 1-7c (12.4 mg, 0.0463 mmol), HATU (17.6 mg, 0.0462 mmol) and DIPEA (12.4 uL, 0.0712 mmol). The mixture was stirred for 3 h, and then diluted with DCM. The organic layer was washed with 10% citric acid, sat. NaHCO 3 , brine, dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by preparative TLC 50% EtOAc in hexane afford the title compound (2.6 mg, 25%). MS-ESI m/z 816.91 (M+H) + .
  • the compound 1-4a-1 was prepared by following the procedure described in the preparation of example 1 (step 1g). MS-ESI m/z 715.3 (M+H) + .
  • the compound 1-5a-1 was prepared by following the procedure described in the preparation of example 1 (step 1h). MS-ESI m/z 687.4 (M+H) + .
  • the compound 1-6a-1 was prepared by following the procedure described in the preparation of example 1 (step 1i). MS-ESI m/z 673.3 (M+H) + .
  • the compound of example 273 was prepared by following the procedure described in the preparation of example 1 (step 1j). MS-ESI m/z 923.4 (M+H) + .
  • the compound of example 280 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 847.4 (M+H) + .
  • the compounds of the present invention exhibit potent inhibitory properties against the HCV NS3 protease.
  • the following examples describe assays in which the compounds of the present invention can be tested for anti-HCV effects.
  • Each compound's anti-HCV activity can be determined by measuring the activity of the luciferase reporter gene in the replicon in the presence of 5% FBS.
  • the luciferase reporter gene, and selectable marker gene for replicons stably maintained in cell lines, is placed under the translational control of the poliovirus IRES instead of the HCV IRES, and HuH-7 cells are used to support the replication of the replicon.
  • the inhibitory activities of the compounds of the present invention can be evaluated using a variety of assays known in the art.
  • stable subgenomic replicon cell lines can be used for compound characterization in cell culture, including those derived from genotypes 1a-H77, 1b-N and 1b-Con1, obtained from University of Texas Medical Branch, Galveston, Tex. (1a-H77 and 1b-N) or Apath, LLC, St. Louis, Mo. (1b-Con1).
  • Chimeric replicons using the genotype 1a or 1b replicons with insertion of NS3 genes from isolates from humans infected with genotypes 1a or 1b can be used to measure inhibitory activity against a panel of the target protein from natural isolates.
  • Chimeric replicons using the genotype 1a or 1b replicons with insertion of NS3 genes from isolates from humans infected with genotypes 3a, 4 or 6 can be used to measure inhibitory activity against representatives of those genotypes.
  • the genotype 1a replicon construct contains the NS3-NS5B coding region derived from the H77 strain of HCV (1a-H77).
  • the replicon also has a firefly luciferase reporter and a neomycin phosphotransferase (Neo) selectable marker.
  • These two coding regions comprise the first cistron of the bicistronic replicon construct, with the second cistron containing the NS3-NS5B coding region with addition of adaptive mutations E1202G, K1691R, K2040R and S22041.
  • the 1b-Con1 and 1b-N replicon constructs are identical to the 1a-H77 replicon, except that the HCV 5′ UTR, 3′ UTR, and NS3-NS5B coding region are derived from the 1b-Con1 or 1b-N strain, and the adaptive mutations are K1609E, K1846T and Y3005C for 1b-Con1 or A1098T, E1202G, and S22041 for 1b-N.
  • the 1b-Con1 replicon construct contains a poliovirus IRES between the HCV IRES and the luciferase gene.
  • Replicon cell lines can be maintained in Dulbecco's modified Eagles medium (DMEM) containing 10% (v/v) fetal bovine serum (FBS), 100 IU/ml penicillin, 100 mg/ml streptomycin (Invitrogen), and 200 mg/ml G418 (Invitrogen).
  • DMEM Dulbecco's modified Eagles medium
  • FBS fetal bovine serum
  • penicillin 100 IU/ml bovine serum
  • streptomycin Invitrogen
  • G418 Invitrogen
  • the inhibitory effects of the compounds of the invention on HCV replication can also be determined by measuring activity of the luciferase reporter gene encoded by subgenomic replicons not containing the Neo selectable marker, that are transiently expressed in cells.
  • the adaptive mutations encoded by the 1a-H77, 1b-N and 1b-Con-1 replicons are the same as listed above.
  • the 1b-Con1 replicon used for these transient assays contains the NS2-NS5B coding region rather than the NS3-5B coding region.
  • These replicons may encode target NS3 genes as described for stable subgenomic replicons or they may encode amino acid variants that confer varying degrees of susceptibility to the drug.
  • variants could include R 155 K, D168E or D168V in a genotype 1a NS3 gene; R 155 K or D168V in a genotype 1b NS3 gene; S138T, A166T or Q168R in a genotype 3a NS3 gene.
  • cells can be transfected with the replicon by electroporation and seeded into 96 well plates at a density of 5000 cells per well in 100 ⁇ l DMEM containing 5% FBS.
  • compounds of Examples 275, 276, 283, 290, 294, 295, and 296 showed EC 50 values of less than 1 nM; and compounds of Examples 1, 2, 4, 5, 6, 8, 34, 36, 40, 65, 89, 90, 273, 274, 279, 280, 281, 284, 285, 287, 288, 289, 291, 292, 293, 297, 298, and 299 showed EC 50 values of from 1 to 10 nM.
  • compounds of Examples 1, 2, 5, 6, 275, 276, 280, 287, 288, 289, 290, 291, 294, and 296 showed EC 50 values of less than 10 nM; compounds of Examples 281, 282, 283, 284, 292, 293, 295, and 297 showed EC 50 values of from 10 to 100 nM; and compounds of Examples 273, 274, 277, 278, and 279 showed EC 50 values of from 100 nM to 1 ⁇ M.
  • compounds of Examples 2, 5, 6, 275, 276, 280, 283, 289, and 291 showed EC 50 values of less than 10 nM; compounds of Examples 1, 4, 8, 281, 282, 284, 285, and 293 showed EC 50 values of from 10 to 100 nM; and compounds of Examples 65, 90, 277, and 286 showed EC 50 values of from 100 nM to 1 ⁇ M.
  • compounds of Examples 2, 5, and 6 When tested using genotype 3a A166T transient replicon assays, compounds of Examples 2, 5, and 6 showed EC 50 values of less than 100 nM; and compounds of Examples 1, 4, and 8 showed EC 50 values of from 100 to 500 nM.
  • compounds of Examples 5 and 6 When tested using genotype 3a S138T transient replicon assays, compounds of Examples 5 and 6 showed EC 50 values of less than 100 nM; and compounds of Examples 1, 2, 4, 8, and 65 showed EC 50 values of from 100 nM to 1 ⁇ M.

Abstract

The present invention discloses compounds of Formula I or pharmaceutically acceptable salts, esters, or prodrugs thereof:
Figure US20200270303A1-20200827-C00001
which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

Description

    RELATED APPLICATIONS
  • This application is a is a continuation application of U.S. application Ser. No. 16/142,087, filed on Sep. 26, 2018, which is a continuation application of U.S. application Ser. No. 15/839,249, filed Dec. 12, 2017, now abandoned, which is a continuation application of U.S. application Ser. No. 15/287,042, filed on Oct. 6, 2016, now abandoned, which is a continuation application of U.S. application Ser. No. 14/946,866, filed Nov. 20, 2015, now abandoned, which is a continuation application of U.S. application Ser. No. 14/146,161, filed Jan. 2, 2014, now U.S. Pat. No. 9,220,748, issued on Dec. 29, 2015, which is a continuation application of U.S. application Ser. No. 13/237,120, filed on Sep. 20, 2011, now U.S. Pat. No. 8,648,037, issued on Feb. 11, 2014, which claims the benefit of U.S. Provisional Application No. 61/385,058, filed on Sep. 21, 2010, U.S. Provisional Application No. 61/499,994, filed on Jun. 22, 2011, and U.S. Provisional Application No. 61/504,616, filed on Jul. 5, 2011. The entire teachings of the above applications are incorporated herein by reference.
    • JOINT RESEARCH AGREEMENT
  • Inventions described in this application were made by or on behalf of Enanta Pharmaceuticals, Inc. and Abbott Laboratories who are parties to a joint research agreement, that was in effect on or before the date such inventions were made and such inventions were made as a result of activities undertaken within the scope of the joint research agreement.
    • TECHNICAL FIELD
  • The present invention relates to novel hepatitis C virus (HCV) protease inhibitor compounds, methods for using the same to treat HCV infection, as well as processes for making such compounds.
    • BACKGROUND OF THE INVENTION
  • HCV is the principal cause of non-A, non-B hepatitis and is an increasingly severe public health problem both in the developed and developing world. It is estimated that the virus infects over 200 million people worldwide, surpassing the number of individuals infected with the human immunodeficiency virus (HIV) by nearly five fold. HCV infected patients, due to the high percentage of individuals inflicted with chronic infections, are at an elevated risk of developing cirrhosis of the liver, subsequent hepatocellular carcinoma and terminal liver disease. HCV is the most prevalent cause of hepatocellular cancer and cause of patients requiring liver transplantations in the western world.
  • There are considerable barriers to the development of anti-HCV therapeutics, which include, but are not limited to, the persistence of the virus, the genetic diversity of the virus during replication in the host, the high incident rate of the virus developing drug-resistant mutants, and the lack of reproducible infectious culture systems and small-animal models for HCV replication and pathogenesis. In a majority of cases, given the mild course of the infection and the complex biology of the liver, careful consideration must be given to antiviral drugs, which are likely to have significant side effects.
  • Only two approved therapies for HCV infection are currently available. The original treatment regimen generally involves a 3-12 month course of intravenous interferon-α (IFN-α), while a new approved second-generation treatment involves co-treatment with IFN-α and the general antiviral nucleoside mimics like ribavirin. Both of these treatments suffer from interferon related side effects as well as low efficacy against HCV infections. There exists a need for the development of effective antiviral agents for treatment of HCV infection due to the poor tolerability and disappointing efficacy of existing therapies.
  • In a patient population where the majority of individuals are chronically infected and asymptomatic and the prognoses are unknown, an effective drug would desirably possess significantly fewer side effects than the currently available treatments. The hepatitis C non-structural protein-3 (NS3) is a proteolytic enzyme required for processing of the viral polyprotein and consequently viral replication. Despite the huge number of viral variants associated with HCV infection, the active site of the NS3 protease remains highly conserved thus making its inhibition an attractive mode of intervention. Recent success in the treatment of HIV with protease inhibitors supports the concept that the inhibition of NS3 is a key target in the battle against HCV.
  • HCV is a flaviridae type RNA virus. The HCV genome is enveloped and contains a single strand RNA molecule composed of circa 9600 base pairs. It encodes a polypeptide comprised of approximately 3010 amino acids.
  • The HCV polyprotein is processed by viral and host peptidase into 10 discreet peptides which serve a variety of functions. There are three structural proteins, C, E1 and E2. The P7 protein is of unknown function and is comprised of a highly variable sequence. There are six non-structural proteins. NS2 is a zinc-dependent metalloproteinase that functions in conjunction with a portion of the NS3 protein. NS3 incorporates two catalytic functions (separate from its association with NS2): a serine protease at the N-terminal end, which requires NS4A as a cofactor, and an ATP-ase-dependent helicase function at the carboxyl terminus. NS4A is a tightly associated but non-covalent cofactor of the serine protease.
  • The NS3/4A protease is responsible for cleaving four sites on the viral polyprotein. The NS3-NS4A cleavage is autocatalytic, occurring in cis. The remaining three hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B all occur in trans. NS3 is a serine protease which is structurally classified as a chymotrypsin-like protease. While the NS serine protease possesses proteolytic activity by itself, the HCV protease enzyme is not an efficient enzyme in terms of catalyzing polyprotein cleavage. It has been shown that a central hydrophobic region of the NS4A protein is required for this enhancement. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficacy at all of the sites.
  • A general strategy for the development of antiviral agents is to inactivate virally encoded enzymes, including NS3, that are essential for the replication of the virus. Current efforts directed toward the discovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov. 1, 867-881 (2002).
    • SUMMARY OF THE INVENTION
  • In one aspect, the invention provides compounds represented by Formula I, or pharmaceutically acceptable salts, esters, or prodrugs thereof:
  • Figure US20200270303A1-20200827-C00002
  • wherein:
  • A is absent, —(C═O)—, —S(O)2—, —C(═N—OR1)— or —C(═N—CN)—;
  • Figure US20200270303A1-20200827-C00003
  • is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl;
    or
  • Figure US20200270303A1-20200827-C00004
  • wherein R7 and R8 are each independently C1-C8 alkyl or C2-C8 alkenyl and are each independently optionally substituted with one or more halo;
      • M1 and M2 are each independently selected from O and NR1;
      • each R1 is independently selected at each occurrence from the group consisting of:
      • (i) hydrogen;
      • (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
      • (iii) heterocycloalkyl; substituted heterocycloalkyl; and
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • L1 and L2 are each independently selected from —C1-C8 alkylene, —C2-C8 alkenylene, or —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkylene, substituted —C2-C8 alkenylene, or substituted —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkylene, or substituted —C3-C12 cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkenylene, or substituted —C3-C12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
      • W is absent, —O—, —S—, —NH—, —N(Me)-, —C(O)NH—, or —C(O)N(Me)-;
      • X and Y, taken together with the carbon atoms to which they are attached, form a cyclic moiety selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocylic, carbocyclic and substituted carbocyclic;
      • X′ is N or —C(R2)—, where R2 is selected from the group consisting of:
      • (i) hydrogen, halogen, CN, CF3, NO2, OR3, SR3, —NHS(O)2—R3, —NH(SO2)NR4R5, NR4R5, CO2R3, COR3, CONR4R5, N(R1)COR3; aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • (ii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • each R3 is independently selected from C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; and —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • each R4 and R5 are independently selected from H and R3, or R4 and R5 together with the nitrogen atom to which they are attached form a heterocyclic ring;
      • R and R′ are each independently selected from the group consisting of:
      • (i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, substituted —C4-C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl;
      • (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) hydrogen or deuterium;
      • G is selected from —OH, —NHS(O)2—R3, —NH(SO2)NR4R5, and NR4R5; and
      • R″ is selected from hydrogen, methyl, ethyl, and allyl.
  • In one embodiment,
  • Figure US20200270303A1-20200827-C00005
  • is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl.
  • In one embodiment of the invention,
  • Figure US20200270303A1-20200827-C00006
  • is selected from, but not limited to, the group of rings consisting of:
  • Figure US20200270303A1-20200827-C00007
  • Preferably, X and Y, taken together with the carbon atoms to which they are attached, form a cyclic moiety selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocylic, more preferably aryl, substituted aryl, heteroaryl or substituted heteroaryl. Most preferably, X and Y, taken together with the carbon atoms to which they are attached, form a benzo or substituted benzo ring.
  • In another embodiment, the present invention features pharmaceutical compositions comprising a compound of the invention (e.g., Formula I), or a pharmaceutically acceptable salt, ester or prodrug thereof. In still another embodiment of the present invention there are disclosed pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention (e.g., Formula I), or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient. In yet another embodiment of the invention are methods of treating a hepatitis C infection in a subject in need of such treatment with said compound of the invention (e.g., Formula I), or said pharmaceutical compositions.
  • Other features, objects, and advantages of the present invention are apparent in the detailed description that follows. It should be understood, however, that the detailed description, while indicating preferred embodiments of the invention, are given by way of illustration only, not limitation. Various changes and modifications within the scope of the invention will become apparent to those skilled in the art from the detailed description.
    • DETAILED DESCRIPTION OF THE INVENTION
  • A first embodiment of the invention is a compound represented by Formula I as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • Another embodiment of the invention is a compound represented by Formula II:
  • Figure US20200270303A1-20200827-C00008
  • or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, where X1-X4 are independently selected from —CR6 and N, wherein each R6 is independently selected from:
      • (i) hydrogen; halogen; —NO2; —CN; or N3;
      • (ii) -M-R3, wherein M is O, S, or NH;
      • (iii) NR4R5;
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and
      • (vi) heterocycloalkyl or substituted heterocycloalkyl;
  • A is absent, —(C═O)—, —S(O)2—, —C(═N—OR1)— or —C(═N—CN)—;
  • Figure US20200270303A1-20200827-C00009
  • is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl;
      • or
  • Figure US20200270303A1-20200827-C00010
  • wherein R7 and R8 are each independently C1-C8 alkyl or C2-C8 alkenyl and are each independently optionally substituted with one or more halo;
      • M1 and M2 are each independently selected from O and NR1;
      • each R1 is independently selected at each occurrence from the group consisting of:
      • (i) hydrogen;
      • (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • L1 and L2 are each independently selected from —C1-C8 alkylene, —C2-C8 alkenylene, or —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkylene, substituted —C2-C8 alkenylene, or substituted —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkylene, or substituted —C3-C12 cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkenylene or substituted —C3-C12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
      • W is absent, —O—, —S—, —NH—, —N(Me)-, —C(O)NH—, or —C(O)N(Me)-;
      • X′ is N or —C(R2)—, where R2 is selected from the group consisting of:
      • (i) hydrogen, halogen, CN, CF3, NO2, OR3, SR3, —NHS(O)2—R3, —NH(SO2)NR4R5, NR4R5, CO2R3, COR3, CONR4R5, N(R1)COR3; aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • (ii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • each R3 is independently selected from C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl;
      • each R4 and R5 are independently selected from H and R3, or R4 and R5 combined together with the N they are attached to form a heterocyclic ring;
      • R and R′ are each independently selected from the group consisting of:
      • (i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, substituted —C4-C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl;
      • (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) hydrogen; deuterium;
      • G is selected from —OH, —NHS(O)2—R3, —NH(SO2)NR4R5, and NR4R5; and
      • R″ is selected from hydrogen, methyl, ethyl, and allyl.
  • Another embodiment of the invention is a compound represented by Formula III or IV:
  • Figure US20200270303A1-20200827-C00011
  • or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, where each Y1 and Y2 are independently selected from CR6 and N, and each Y3 is independently selected from NR6, S and O;
  • each R6 is independently selected from:
      • (i) hydrogen; halogen; —NO2; —CN; or N3;
      • (ii) -M-R3, wherein M is O, S, or NH;
      • (iii) NR4R5;
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and
      • (vi) heterocycloalkyl or substituted heterocycloalkyl;
  • A is absent, —(C═O)—, —S(O)2—, —C(═N—OR1)— or —C(═N—CN)—;
  • Figure US20200270303A1-20200827-C00012
  • _is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl;
      • or
  • Figure US20200270303A1-20200827-C00013
  • wherein R7 and R8 are each independently C1-C8 alkyl or C2-C8 alkenyl and are each independently optionally substituted with one or more halo;
      • M1 and M2 are each independently selected from O and NR1;
      • each R1 is independently selected at each occurrence from the group consisting of:
      • (i) hydrogen;
      • (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • L1 and L2 are each independently selected from —C1-C8 alkylene, —C2-C8 alkenylene, or —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkylene, substituted —C2-C8 alkenylene, or substituted —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkylene, or substituted —C3-C12 cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkenylene, or substituted —C3-C12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
      • W is absent, —O—, —S—, —NH—, —N(Me)-, —C(O)NH—, or —C(O)N(Me)-;
      • X′ is N or —C(R2)—, where R2 is selected from the group consisting of:
      • (i) hydrogen, halogen, CN, CF3, NO2, OR3, SR3, —NHS(O)2—R3, —NH(SO2)NR4R5, NR4R5, CO2R3, COR3, CONR4R5, N(R1)COR3; aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • (ii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • each R3 is independently selected from C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl;
      • each R4 and R5 are independently selected from H and R3, or R4 and R5 combined together with the N they are attached to form a heterocyclic ring;
      • R and R′ are each independently selected from the group consisting of:
      • (i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, substituted —C4-C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl;
      • (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) hydrogen or deuterium;
      • G is selected from —OH, —NHS(O)2—R3, —NH(SO2)NR4R5, and NR4R5; and
      • R″ is selected from hydrogen, methyl, ethyl, and allyl.
  • Another embodiment of the invention is a compound represented by Formula V:
  • Figure US20200270303A1-20200827-C00014
  • or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, wherein
  • X1-X4 are independently selected from —CR6 and N, wherein each R6 is independently selected from:
      • (i) hydrogen; halogen; —NO2; —CN; or N3;
      • (ii) -M-R3, where M is O, S, or NH;
      • (iii) NR4R5;
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and
      • (vi) heterocycloalkyl or substituted heterocycloalkyl;
  • A is absent, —(C═O)—, —S(O)2—, —C(═N—OR1)— or —C(═N—CN)—;
  • Figure US20200270303A1-20200827-C00015
  • is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl;
      • or
  • Figure US20200270303A1-20200827-C00016
  • wherein R7 and R8 are each independently C1-C8 alkyl or C2-C8 alkenyl and are each independently optionally substituted with one or more halo;
      • M1 and M2 are each independently selected from O and NR1;
      • each R1 is independently selected at each occurrence from the group consisting of:
      • (i) hydrogen;
      • (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • X′ is N or —C(R2)—, where R2 is selected from the group consisting of:
      • (i) hydrogen, halogen, CN, CF3, NO2, OR3, SR3, —NHS(O)2—R3, —NH(SO2)NR4R5, NR4R5, CO2R3, COR3, CONR4R5, N(R1)COR3; aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • (ii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • each R3 is independently selected from C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl;
      • each R4 and R5 are independently selected from H and R3, or R4 and R5 combined together with the N they are attached to form a heterocyclic ring;
      • R and R′ are each independently selected from the group consisting of:
      • (i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, substituted —C4-C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl;
      • (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) hydrogen; or deuterium;
      • G is selected from —OH, —NHS(O)2—R3, —NH(SO2)NR4R5, and NR4R5; and
      • R″ is selected from hydrogen, methyl, ethyl, and allyl.
  • Another embodiment of the invention is a compound represented by Formula VI:
  • Figure US20200270303A1-20200827-C00017
  • or a pharmaceutically acceptable salt, ester or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier or excipient, wherein:
  • X1-X4 are independently selected from —CR6 and N, wherein each R6 is independently selected from:
      • (i) hydrogen; halogen; —NO2; —CN; or N3;
      • (ii) -M-R3, wherein M is O, S, or NH;
      • (iii) NR4R5;
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and
      • (vi) heterocycloalkyl or substituted heterocycloalkyl;
  • Figure US20200270303A1-20200827-C00018
  • is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl;
      • or
  • Figure US20200270303A1-20200827-C00019
  • wherein R7 and R8 are each independently C1-C8 alkyl or C2-C8 alkenyl and are each independently optionally substituted with one or more halo;
      • M1 and M2 are each independently selected from O and NR1;
      • each R1 is independently selected at each occurrence from the group consisting of:
      • (i) hydrogen;
      • (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • each R3 is independently selected from C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl;
      • each R4 and R5 are independently selected from H and R3, or R4 and R5 combined together with the N they are attached to form a heterocyclic ring;
      • R and R′ are each independently selected from the group consisting of:
      • (i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, substituted —C4-C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl;
      • (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) hydrogen; or deuterium;
      • G is selected from —OH, —NHS(O)2—R3, —NH(SO2)NR4R5, and NR4R5; and
      • R″ is selected from hydrogen, methyl, ethyl, and allyl.
  • The present invention also features compounds of Formula VII and pharmaceutically acceptable salts, esters, and prodrugs thereof:
  • Figure US20200270303A1-20200827-C00020
  • wherein R1′, R2′, R3′ and R4′ are each independently R6, or R′ and R2′, R2′ and R3′, or R3′ and R4′ taken together with the carbon atoms to which each is attached, form an aromatic, heteroaromatic, cyclic or heterocyclic ring;
  • Figure US20200270303A1-20200827-C00021
  • is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl;
      • or
  • Figure US20200270303A1-20200827-C00022
  • wherein R7 and R8 are each independently C1-C8 alkyl or C2-C8 alkenyl and are each independently optionally substituted with one or more halo;
      • each R6 is independently selected from:
      • (i) hydrogen; halogen; —NO2; —CN; or N3;
      • (ii) -M-R3, wherein M is O, S, or NH;
      • (iii) NR4R5;
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • (v) aryl; substituted aryl; heteroaryl; or substituted heteroaryl; and
      • (vi) heterocycloalkyl or substituted heterocycloalkyl;
      • R3 is independently selected from C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic; aryl; substituted aryl; heteroaryl; and substituted heteroaryl;
      • each R4 and R5 are independently selected from H and R3, or R4 and R5 combined together with the N they are attached to form a heterocyclic ring;
      • R and R′ are each independently selected from the group consisting of:
      • (i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, substituted —C4-C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl;
      • (ii) aryl; substituted aryl; heteroaryl; or substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) hydrogen; or deuterium;
      • R″ is selected from hydrogen, methyl, ethyl, and allyl.
  • In certain embodiments of the compounds of Formulas I-VII,
  • Figure US20200270303A1-20200827-C00023
  • is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl;
  • In certain embodiments,
  • Figure US20200270303A1-20200827-C00024
  • in Formulas I-VII is C3-C12 carbocycle or 4- to 6-membered heterocycle and is optionally substituted with one or more substituents independently selected from halo, C1-C8 alkyl or C2-C8 alkenyl. For instance,
  • Figure US20200270303A1-20200827-C00025
  • can be a non-aromatic C3-C6 carbocycle or a non-aromatic 4- to 6-membered heterocycle and is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl or C2-C6 alkenyl. More preferably,
  • Figure US20200270303A1-20200827-C00026
  • is saturated C4-C6 carbocycle or saturated 4- to 6-membered heterocycle and is optionally substituted with one or more substituents independently selected from halo, C1-C8 alkyl or C2-C8 alkenyl.
  • In certain embodiments of the compounds of Formulas I to VII,
  • Figure US20200270303A1-20200827-C00027
  • is selected from the group consisting of:
  • Figure US20200270303A1-20200827-C00028
  • Highly preferably,
  • Figure US20200270303A1-20200827-C00029
  • is selected from the group below:
  • Figure US20200270303A1-20200827-C00030
  • Preferably, R1′, R2′, R3′ and R4′ are hydrogen. Also preferably, R1′ and R4′ are hydrogen; and one of R2′ and R3′ is hydrogen, and the other is selected from halo, methyl optionally substituted with one or more halo, or —O-methyl optionally substituted with one or more halo.
  • Also, preferably R1′ and R2′, or R2′ and R3′, or R3′ and R4′, taken together with the carbon atoms to which they are attached, form a 5- or 6-membered carbocycle or heterocycle (e.g., phenyl), and the rest of R1′, R2′, R3′ and R4′ preferably are hydrogen.
  • Preferably, R3 is
  • Figure US20200270303A1-20200827-C00031
  • Preferably, R′ is
  • Figure US20200270303A1-20200827-C00032
  • more preferably
  • Figure US20200270303A1-20200827-C00033
  • Preferably, R is
  • Figure US20200270303A1-20200827-C00034
  • more preferably
  • Figure US20200270303A1-20200827-C00035
  • In one embodiment, the present invention features compounds of Formula VII or pharmaceutically acceptable salts thereof, wherein
  • Figure US20200270303A1-20200827-C00036
  • R′ is vinyl
  • Figure US20200270303A1-20200827-C00037
  • or difluoromethyl
  • Figure US20200270303A1-20200827-C00038
    • R3 is
  • Figure US20200270303A1-20200827-C00039
    • and R is
  • Figure US20200270303A1-20200827-C00040
  • In another embodiment, the present invention features compounds of Formula VII or pharmaceutically acceptable salts thereof, wherein
  • Figure US20200270303A1-20200827-C00041
  • R′ is vinyl
  • Figure US20200270303A1-20200827-C00042
  • or difluoromethyl
  • Figure US20200270303A1-20200827-C00043
    • R3 is
  • Figure US20200270303A1-20200827-C00044
    • and R is
  • Figure US20200270303A1-20200827-C00045
  • R3′ is —O-methyl optionally substituted with one or more halo, and R1′, R2′, and R4′ are hydrogen.
  • In yet another embodiment, the present invention features compounds of Formula VII or pharmaceutically acceptable salts thereof, wherein
  • Figure US20200270303A1-20200827-C00046
  • R′ is vinyl
  • Figure US20200270303A1-20200827-C00047
  • or difluoromethyl
  • Figure US20200270303A1-20200827-C00048
    • R3 is
  • Figure US20200270303A1-20200827-C00049
    • and R is
  • Figure US20200270303A1-20200827-C00050
  • and R, R2′, R3′ and R4′ are hydrogen.
  • In another embodiment, the present invention features compounds of Formula VII or pharmaceutically acceptable salts thereof, wherein
  • Figure US20200270303A1-20200827-C00051
  • R′ is vinyl
  • Figure US20200270303A1-20200827-C00052
  • or difluoromethyl
  • Figure US20200270303A1-20200827-C00053
    • R3 is
  • Figure US20200270303A1-20200827-C00054
    • and R is
  • Figure US20200270303A1-20200827-C00055
  • R3′ is halo (e.g, F), and R1′, R2′, and R4′ are hydrogen.
  • In still another embodiment, the present invention features compounds of Formula VII or pharmaceutically acceptable salts thereof, wherein
  • Figure US20200270303A1-20200827-C00056
  • R′ is vinyl
  • Figure US20200270303A1-20200827-C00057
  • or difluoromethyl
  • Figure US20200270303A1-20200827-C00058
    • R3 is
  • Figure US20200270303A1-20200827-C00059
    • and R is
  • Figure US20200270303A1-20200827-C00060
  • R3′ and R4′ taken together with carbon atoms to which they are attached form phenyl, and R′ and R2′ are hydrogen.
  • In another aspect, the invention provides a compound of Formula VIII:
  • Figure US20200270303A1-20200827-C00061
  • wherein:
  • A is absent, or selected from —(C═O)—, —S(O)2—, —C(═N—OR1)— and —C(═N—CN)—;
  • Figure US20200270303A1-20200827-C00062
  • is selected from —C3-C12 cycloalkyl, substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, substituted —C3-C12 cycloalkenyl; —C3-C12 heterocycloalkyl, and substituted —C3-C12 heterocycloalkyl;
      • M1 and M2 are selected from O and NR1; wherein R1 is selected at each occurrence from the group consisting of:
      • (i) hydrogen;
      • (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • L1 and L2 are independently selected from —C1-C8 alkylene, —C2-C8 alkenylene, or —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; substituted —C1-C8 alkylene, substituted —C2-C8 alkenylene, or substituted —C2-C8 alkynylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkylene, or substituted —C3-C12 cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkenylene, or substituted —C3-C12 cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
      • W is absent, or selected from —O—, —S—, —NH—, —N(Me)-, —C(O)NH—, and —C(O)N(Me)-;
      • X and Y, taken together with the carbon atoms to which they are attached, form a cyclic moiety selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocylic;
      • X′ is selected from N and —C(R2)—, where R2 is selected from the group consisting of:
      • (i) hydrogen, halogen, CN, CF3, NO2, OR1, SR1, —NHS(O)2—R2, —NH(SO2)NR3R4, NR3R4, CO2R1, COR1, CONR1R2, N(R1)COR2;
      • (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
      • R and R′ are each independently selected from the group consisting of:
      • (i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C4-C12 alkylcycloalkyl, or substituted —C4-C12 alkylcycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; —C4-C12 alkylcycloalkenyl, or substituted —C4-C12 alkylcycloalkenyl;
      • (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl; and
      • (iv) hydrogen; deuterium;
      • G is selected from —OH, —NHS(O)2—R3, —NH(SO2)NR4R5, and NR4R5;
      • R3 is selected from:
      • (i) aryl; substituted aryl; heteroaryl; substituted heteroaryl
      • (ii) heterocycloalkyl; substituted heterocycloalkyl; and
      • (iii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; heterocylic; substituted heterocyclic;
      • R4 and R5 are independently selected from:
      • (i) hydrogen;
      • (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
      • (iii) heterocycloalkyl or substituted heterocycloalkyl;
      • (iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms independently selected from O, S and N; substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C3-C12 cycloalkyl, or substituted —C3-C12cycloalkyl; —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl; heterocyclic, or substituted heterocyclic;
  • and
      • R″ is selected from hydrogen, methyl, ethyl and allyl.
  • Representative compounds of the invention include, but are not limited to, the following compounds (example 1 to example 256 in Table 1) according to Formula VIII wherein R, -L2-W-L1-,
  • Figure US20200270303A1-20200827-C00063
  • R′ and G are delineated for each example in Table 1.
  • Figure US20200270303A1-20200827-C00064
  • TABLE 1
    Example # R —L2—W—L1—
    Figure US20200270303A1-20200827-C00065
         		R′ G
    1.
    Figure US20200270303A1-20200827-C00066
    Figure US20200270303A1-20200827-C00067
    Figure US20200270303A1-20200827-C00068
    Figure US20200270303A1-20200827-C00069
    Figure US20200270303A1-20200827-C00070
    2.
    Figure US20200270303A1-20200827-C00071
    Figure US20200270303A1-20200827-C00072
    Figure US20200270303A1-20200827-C00073
    Figure US20200270303A1-20200827-C00074
    Figure US20200270303A1-20200827-C00075
    3.
    Figure US20200270303A1-20200827-C00076
    Figure US20200270303A1-20200827-C00077
    Figure US20200270303A1-20200827-C00078
    Figure US20200270303A1-20200827-C00079
    Figure US20200270303A1-20200827-C00080
    4.
    Figure US20200270303A1-20200827-C00081
    Figure US20200270303A1-20200827-C00082
    Figure US20200270303A1-20200827-C00083
    Figure US20200270303A1-20200827-C00084
    Figure US20200270303A1-20200827-C00085
    5.
    Figure US20200270303A1-20200827-C00086
    Figure US20200270303A1-20200827-C00087
    Figure US20200270303A1-20200827-C00088
    Figure US20200270303A1-20200827-C00089
    Figure US20200270303A1-20200827-C00090
    6.
    Figure US20200270303A1-20200827-C00091
    Figure US20200270303A1-20200827-C00092
    Figure US20200270303A1-20200827-C00093
    Figure US20200270303A1-20200827-C00094
    Figure US20200270303A1-20200827-C00095
    7.
    Figure US20200270303A1-20200827-C00096
    Figure US20200270303A1-20200827-C00097
    Figure US20200270303A1-20200827-C00098
    Figure US20200270303A1-20200827-C00099
    Figure US20200270303A1-20200827-C00100
    8.
    Figure US20200270303A1-20200827-C00101
    Figure US20200270303A1-20200827-C00102
    Figure US20200270303A1-20200827-C00103
    Figure US20200270303A1-20200827-C00104
    Figure US20200270303A1-20200827-C00105
    9.
    Figure US20200270303A1-20200827-C00106
    Figure US20200270303A1-20200827-C00107
    Figure US20200270303A1-20200827-C00108
    Figure US20200270303A1-20200827-C00109
    Figure US20200270303A1-20200827-C00110
    10.
    Figure US20200270303A1-20200827-C00111
    Figure US20200270303A1-20200827-C00112
    Figure US20200270303A1-20200827-C00113
    Figure US20200270303A1-20200827-C00114
    Figure US20200270303A1-20200827-C00115
    11.
    Figure US20200270303A1-20200827-C00116
    Figure US20200270303A1-20200827-C00117
    Figure US20200270303A1-20200827-C00118
    Figure US20200270303A1-20200827-C00119
    Figure US20200270303A1-20200827-C00120
    12.
    Figure US20200270303A1-20200827-C00121
    Figure US20200270303A1-20200827-C00122
    Figure US20200270303A1-20200827-C00123
    Figure US20200270303A1-20200827-C00124
    Figure US20200270303A1-20200827-C00125
    13.
    Figure US20200270303A1-20200827-C00126
    Figure US20200270303A1-20200827-C00127
    Figure US20200270303A1-20200827-C00128
    Figure US20200270303A1-20200827-C00129
    Figure US20200270303A1-20200827-C00130
    14.
    Figure US20200270303A1-20200827-C00131
    Figure US20200270303A1-20200827-C00132
    Figure US20200270303A1-20200827-C00133
    Figure US20200270303A1-20200827-C00134
    Figure US20200270303A1-20200827-C00135
    15.
    Figure US20200270303A1-20200827-C00136
    Figure US20200270303A1-20200827-C00137
    Figure US20200270303A1-20200827-C00138
    Figure US20200270303A1-20200827-C00139
    Figure US20200270303A1-20200827-C00140
    16.
    Figure US20200270303A1-20200827-C00141
    Figure US20200270303A1-20200827-C00142
    Figure US20200270303A1-20200827-C00143
    Figure US20200270303A1-20200827-C00144
    Figure US20200270303A1-20200827-C00145
    17.
    Figure US20200270303A1-20200827-C00146
    Figure US20200270303A1-20200827-C00147
    Figure US20200270303A1-20200827-C00148
    Figure US20200270303A1-20200827-C00149
    Figure US20200270303A1-20200827-C00150
    18.
    Figure US20200270303A1-20200827-C00151
    Figure US20200270303A1-20200827-C00152
    Figure US20200270303A1-20200827-C00153
    Figure US20200270303A1-20200827-C00154
    Figure US20200270303A1-20200827-C00155
    19.
    Figure US20200270303A1-20200827-C00156
    Figure US20200270303A1-20200827-C00157
    Figure US20200270303A1-20200827-C00158
    Figure US20200270303A1-20200827-C00159
    Figure US20200270303A1-20200827-C00160
    20.
    Figure US20200270303A1-20200827-C00161
    Figure US20200270303A1-20200827-C00162
    Figure US20200270303A1-20200827-C00163
    Figure US20200270303A1-20200827-C00164
    Figure US20200270303A1-20200827-C00165
    21.
    Figure US20200270303A1-20200827-C00166
    Figure US20200270303A1-20200827-C00167
    Figure US20200270303A1-20200827-C00168
    Figure US20200270303A1-20200827-C00169
    Figure US20200270303A1-20200827-C00170
    22.
    Figure US20200270303A1-20200827-C00171
    Figure US20200270303A1-20200827-C00172
    Figure US20200270303A1-20200827-C00173
    Figure US20200270303A1-20200827-C00174
    Figure US20200270303A1-20200827-C00175
    23.
    Figure US20200270303A1-20200827-C00176
    Figure US20200270303A1-20200827-C00177
    Figure US20200270303A1-20200827-C00178
    Figure US20200270303A1-20200827-C00179
    Figure US20200270303A1-20200827-C00180
    24.
    Figure US20200270303A1-20200827-C00181
    Figure US20200270303A1-20200827-C00182
    Figure US20200270303A1-20200827-C00183
    Figure US20200270303A1-20200827-C00184
    Figure US20200270303A1-20200827-C00185
    25.
    Figure US20200270303A1-20200827-C00186
    Figure US20200270303A1-20200827-C00187
    Figure US20200270303A1-20200827-C00188
    Figure US20200270303A1-20200827-C00189
    Figure US20200270303A1-20200827-C00190
    26.
    Figure US20200270303A1-20200827-C00191
    Figure US20200270303A1-20200827-C00192
    Figure US20200270303A1-20200827-C00193
    Figure US20200270303A1-20200827-C00194
    Figure US20200270303A1-20200827-C00195
    27.
    Figure US20200270303A1-20200827-C00196
    Figure US20200270303A1-20200827-C00197
    Figure US20200270303A1-20200827-C00198
    Figure US20200270303A1-20200827-C00199
    Figure US20200270303A1-20200827-C00200
    28.
    Figure US20200270303A1-20200827-C00201
    Figure US20200270303A1-20200827-C00202
    Figure US20200270303A1-20200827-C00203
    Figure US20200270303A1-20200827-C00204
    Figure US20200270303A1-20200827-C00205
    29.
    Figure US20200270303A1-20200827-C00206
    Figure US20200270303A1-20200827-C00207
    Figure US20200270303A1-20200827-C00208
    Figure US20200270303A1-20200827-C00209
    Figure US20200270303A1-20200827-C00210
    30.
    Figure US20200270303A1-20200827-C00211
    Figure US20200270303A1-20200827-C00212
    Figure US20200270303A1-20200827-C00213
    Figure US20200270303A1-20200827-C00214
    Figure US20200270303A1-20200827-C00215
    31.
    Figure US20200270303A1-20200827-C00216
    Figure US20200270303A1-20200827-C00217
    Figure US20200270303A1-20200827-C00218
    Figure US20200270303A1-20200827-C00219
    Figure US20200270303A1-20200827-C00220
    32.
    Figure US20200270303A1-20200827-C00221
    Figure US20200270303A1-20200827-C00222
    Figure US20200270303A1-20200827-C00223
    Figure US20200270303A1-20200827-C00224
    Figure US20200270303A1-20200827-C00225
    33.
    Figure US20200270303A1-20200827-C00226
    Figure US20200270303A1-20200827-C00227
    Figure US20200270303A1-20200827-C00228
    Figure US20200270303A1-20200827-C00229
    Figure US20200270303A1-20200827-C00230
    34.
    Figure US20200270303A1-20200827-C00231
    Figure US20200270303A1-20200827-C00232
    Figure US20200270303A1-20200827-C00233
    Figure US20200270303A1-20200827-C00234
    Figure US20200270303A1-20200827-C00235
    35.
    Figure US20200270303A1-20200827-C00236
    Figure US20200270303A1-20200827-C00237
    Figure US20200270303A1-20200827-C00238
    Figure US20200270303A1-20200827-C00239
    Figure US20200270303A1-20200827-C00240
    36.
    Figure US20200270303A1-20200827-C00241
    Figure US20200270303A1-20200827-C00242
    Figure US20200270303A1-20200827-C00243
    Figure US20200270303A1-20200827-C00244
    Figure US20200270303A1-20200827-C00245
    37.
    Figure US20200270303A1-20200827-C00246
    Figure US20200270303A1-20200827-C00247
    Figure US20200270303A1-20200827-C00248
    Figure US20200270303A1-20200827-C00249
    Figure US20200270303A1-20200827-C00250
    38.
    Figure US20200270303A1-20200827-C00251
    Figure US20200270303A1-20200827-C00252
    Figure US20200270303A1-20200827-C00253
    Figure US20200270303A1-20200827-C00254
    Figure US20200270303A1-20200827-C00255
    39.
    Figure US20200270303A1-20200827-C00256
    Figure US20200270303A1-20200827-C00257
    Figure US20200270303A1-20200827-C00258
    Figure US20200270303A1-20200827-C00259
    Figure US20200270303A1-20200827-C00260
    40.
    Figure US20200270303A1-20200827-C00261
    Figure US20200270303A1-20200827-C00262
    Figure US20200270303A1-20200827-C00263
    Figure US20200270303A1-20200827-C00264
    Figure US20200270303A1-20200827-C00265
    41.
    Figure US20200270303A1-20200827-C00266
    Figure US20200270303A1-20200827-C00267
    Figure US20200270303A1-20200827-C00268
    Figure US20200270303A1-20200827-C00269
    Figure US20200270303A1-20200827-C00270
    42.
    Figure US20200270303A1-20200827-C00271
    Figure US20200270303A1-20200827-C00272
    Figure US20200270303A1-20200827-C00273
    Figure US20200270303A1-20200827-C00274
    Figure US20200270303A1-20200827-C00275
    43.
    Figure US20200270303A1-20200827-C00276
    Figure US20200270303A1-20200827-C00277
    Figure US20200270303A1-20200827-C00278
    Figure US20200270303A1-20200827-C00279
    Figure US20200270303A1-20200827-C00280
    44.
    Figure US20200270303A1-20200827-C00281
    Figure US20200270303A1-20200827-C00282
    Figure US20200270303A1-20200827-C00283
    Figure US20200270303A1-20200827-C00284
    Figure US20200270303A1-20200827-C00285
    45.
    Figure US20200270303A1-20200827-C00286
    Figure US20200270303A1-20200827-C00287
    Figure US20200270303A1-20200827-C00288
    Figure US20200270303A1-20200827-C00289
    Figure US20200270303A1-20200827-C00290
    46.
    Figure US20200270303A1-20200827-C00291
    Figure US20200270303A1-20200827-C00292
    Figure US20200270303A1-20200827-C00293
    Figure US20200270303A1-20200827-C00294
    Figure US20200270303A1-20200827-C00295
    47.
    Figure US20200270303A1-20200827-C00296
    Figure US20200270303A1-20200827-C00297
    Figure US20200270303A1-20200827-C00298
    Figure US20200270303A1-20200827-C00299
    Figure US20200270303A1-20200827-C00300
    48.
    Figure US20200270303A1-20200827-C00301
    Figure US20200270303A1-20200827-C00302
    Figure US20200270303A1-20200827-C00303
    Figure US20200270303A1-20200827-C00304
    Figure US20200270303A1-20200827-C00305
    49.
    Figure US20200270303A1-20200827-C00306
    Figure US20200270303A1-20200827-C00307
    Figure US20200270303A1-20200827-C00308
    Figure US20200270303A1-20200827-C00309
    Figure US20200270303A1-20200827-C00310
    50.
    Figure US20200270303A1-20200827-C00311
    Figure US20200270303A1-20200827-C00312
    Figure US20200270303A1-20200827-C00313
    Figure US20200270303A1-20200827-C00314
    Figure US20200270303A1-20200827-C00315
    51.
    Figure US20200270303A1-20200827-C00316
    Figure US20200270303A1-20200827-C00317
    Figure US20200270303A1-20200827-C00318
    Figure US20200270303A1-20200827-C00319
    Figure US20200270303A1-20200827-C00320
    52.
    Figure US20200270303A1-20200827-C00321
    Figure US20200270303A1-20200827-C00322
    Figure US20200270303A1-20200827-C00323
    Figure US20200270303A1-20200827-C00324
    Figure US20200270303A1-20200827-C00325
    53.
    Figure US20200270303A1-20200827-C00326
    Figure US20200270303A1-20200827-C00327
    Figure US20200270303A1-20200827-C00328
    Figure US20200270303A1-20200827-C00329
    Figure US20200270303A1-20200827-C00330
    54.
    Figure US20200270303A1-20200827-C00331
    Figure US20200270303A1-20200827-C00332
    Figure US20200270303A1-20200827-C00333
    Figure US20200270303A1-20200827-C00334
    Figure US20200270303A1-20200827-C00335
    55.
    Figure US20200270303A1-20200827-C00336
    Figure US20200270303A1-20200827-C00337
    Figure US20200270303A1-20200827-C00338
    Figure US20200270303A1-20200827-C00339
    Figure US20200270303A1-20200827-C00340
    56.
    Figure US20200270303A1-20200827-C00341
    Figure US20200270303A1-20200827-C00342
    Figure US20200270303A1-20200827-C00343
    Figure US20200270303A1-20200827-C00344
    Figure US20200270303A1-20200827-C00345
    57.
    Figure US20200270303A1-20200827-C00346
    Figure US20200270303A1-20200827-C00347
    Figure US20200270303A1-20200827-C00348
    Figure US20200270303A1-20200827-C00349
    Figure US20200270303A1-20200827-C00350
    58.
    Figure US20200270303A1-20200827-C00351
    Figure US20200270303A1-20200827-C00352
    Figure US20200270303A1-20200827-C00353
    Figure US20200270303A1-20200827-C00354
    Figure US20200270303A1-20200827-C00355
    59.
    Figure US20200270303A1-20200827-C00356
    Figure US20200270303A1-20200827-C00357
    Figure US20200270303A1-20200827-C00358
    Figure US20200270303A1-20200827-C00359
    Figure US20200270303A1-20200827-C00360
    60.
    Figure US20200270303A1-20200827-C00361
    Figure US20200270303A1-20200827-C00362
    Figure US20200270303A1-20200827-C00363
    Figure US20200270303A1-20200827-C00364
    Figure US20200270303A1-20200827-C00365
    61.
    Figure US20200270303A1-20200827-C00366
    Figure US20200270303A1-20200827-C00367
    Figure US20200270303A1-20200827-C00368
    Figure US20200270303A1-20200827-C00369
    Figure US20200270303A1-20200827-C00370
    62.
    Figure US20200270303A1-20200827-C00371
    Figure US20200270303A1-20200827-C00372
    Figure US20200270303A1-20200827-C00373
    Figure US20200270303A1-20200827-C00374
    Figure US20200270303A1-20200827-C00375
    63.
    Figure US20200270303A1-20200827-C00376
    Figure US20200270303A1-20200827-C00377
    Figure US20200270303A1-20200827-C00378
    Figure US20200270303A1-20200827-C00379
    Figure US20200270303A1-20200827-C00380
    64.
    Figure US20200270303A1-20200827-C00381
    Figure US20200270303A1-20200827-C00382
    Figure US20200270303A1-20200827-C00383
    Figure US20200270303A1-20200827-C00384
    Figure US20200270303A1-20200827-C00385
    65.
    Figure US20200270303A1-20200827-C00386
    Figure US20200270303A1-20200827-C00387
    Figure US20200270303A1-20200827-C00388
    Figure US20200270303A1-20200827-C00389
    Figure US20200270303A1-20200827-C00390
    66.
    Figure US20200270303A1-20200827-C00391
    Figure US20200270303A1-20200827-C00392
    Figure US20200270303A1-20200827-C00393
    Figure US20200270303A1-20200827-C00394
    Figure US20200270303A1-20200827-C00395
    67.
    Figure US20200270303A1-20200827-C00396
    Figure US20200270303A1-20200827-C00397
    Figure US20200270303A1-20200827-C00398
    Figure US20200270303A1-20200827-C00399
    Figure US20200270303A1-20200827-C00400
    68.
    Figure US20200270303A1-20200827-C00401
    Figure US20200270303A1-20200827-C00402
    Figure US20200270303A1-20200827-C00403
    Figure US20200270303A1-20200827-C00404
    Figure US20200270303A1-20200827-C00405
    69.
    Figure US20200270303A1-20200827-C00406
    Figure US20200270303A1-20200827-C00407
    Figure US20200270303A1-20200827-C00408
    Figure US20200270303A1-20200827-C00409
    Figure US20200270303A1-20200827-C00410
    70.
    Figure US20200270303A1-20200827-C00411
    Figure US20200270303A1-20200827-C00412
    Figure US20200270303A1-20200827-C00413
    Figure US20200270303A1-20200827-C00414
    Figure US20200270303A1-20200827-C00415
    71.
    Figure US20200270303A1-20200827-C00416
    Figure US20200270303A1-20200827-C00417
    Figure US20200270303A1-20200827-C00418
    Figure US20200270303A1-20200827-C00419
    Figure US20200270303A1-20200827-C00420
    72.
    Figure US20200270303A1-20200827-C00421
    Figure US20200270303A1-20200827-C00422
    Figure US20200270303A1-20200827-C00423
    Figure US20200270303A1-20200827-C00424
    Figure US20200270303A1-20200827-C00425
    73.
    Figure US20200270303A1-20200827-C00426
    Figure US20200270303A1-20200827-C00427
    Figure US20200270303A1-20200827-C00428
    Figure US20200270303A1-20200827-C00429
    Figure US20200270303A1-20200827-C00430
    74.
    Figure US20200270303A1-20200827-C00431
    Figure US20200270303A1-20200827-C00432
    Figure US20200270303A1-20200827-C00433
    Figure US20200270303A1-20200827-C00434
    Figure US20200270303A1-20200827-C00435
    75.
    Figure US20200270303A1-20200827-C00436
    Figure US20200270303A1-20200827-C00437
    Figure US20200270303A1-20200827-C00438
    Figure US20200270303A1-20200827-C00439
    Figure US20200270303A1-20200827-C00440
    76.
    Figure US20200270303A1-20200827-C00441
    Figure US20200270303A1-20200827-C00442
    Figure US20200270303A1-20200827-C00443
    Figure US20200270303A1-20200827-C00444
    Figure US20200270303A1-20200827-C00445
    77.
    Figure US20200270303A1-20200827-C00446
    Figure US20200270303A1-20200827-C00447
    Figure US20200270303A1-20200827-C00448
    Figure US20200270303A1-20200827-C00449
    Figure US20200270303A1-20200827-C00450
    78.
    Figure US20200270303A1-20200827-C00451
    Figure US20200270303A1-20200827-C00452
    Figure US20200270303A1-20200827-C00453
    Figure US20200270303A1-20200827-C00454
    Figure US20200270303A1-20200827-C00455
    79.
    Figure US20200270303A1-20200827-C00456
    Figure US20200270303A1-20200827-C00457
    Figure US20200270303A1-20200827-C00458
    Figure US20200270303A1-20200827-C00459
    Figure US20200270303A1-20200827-C00460
    80.
    Figure US20200270303A1-20200827-C00461
    Figure US20200270303A1-20200827-C00462
    Figure US20200270303A1-20200827-C00463
    Figure US20200270303A1-20200827-C00464
    Figure US20200270303A1-20200827-C00465
    81.
    Figure US20200270303A1-20200827-C00466
    Figure US20200270303A1-20200827-C00467
    Figure US20200270303A1-20200827-C00468
    Figure US20200270303A1-20200827-C00469
    Figure US20200270303A1-20200827-C00470
    82.
    Figure US20200270303A1-20200827-C00471
    Figure US20200270303A1-20200827-C00472
    Figure US20200270303A1-20200827-C00473
    Figure US20200270303A1-20200827-C00474
    Figure US20200270303A1-20200827-C00475
    83.
    Figure US20200270303A1-20200827-C00476
    Figure US20200270303A1-20200827-C00477
    Figure US20200270303A1-20200827-C00478
    Figure US20200270303A1-20200827-C00479
    Figure US20200270303A1-20200827-C00480
    84.
    Figure US20200270303A1-20200827-C00481
    Figure US20200270303A1-20200827-C00482
    Figure US20200270303A1-20200827-C00483
    Figure US20200270303A1-20200827-C00484
    Figure US20200270303A1-20200827-C00485
    85.
    Figure US20200270303A1-20200827-C00486
    Figure US20200270303A1-20200827-C00487
    Figure US20200270303A1-20200827-C00488
    Figure US20200270303A1-20200827-C00489
    Figure US20200270303A1-20200827-C00490
    86.
    Figure US20200270303A1-20200827-C00491
    Figure US20200270303A1-20200827-C00492
    Figure US20200270303A1-20200827-C00493
    Figure US20200270303A1-20200827-C00494
    Figure US20200270303A1-20200827-C00495
    87.
    Figure US20200270303A1-20200827-C00496
    Figure US20200270303A1-20200827-C00497
    Figure US20200270303A1-20200827-C00498
    Figure US20200270303A1-20200827-C00499
    Figure US20200270303A1-20200827-C00500
    88.
    Figure US20200270303A1-20200827-C00501
    Figure US20200270303A1-20200827-C00502
    Figure US20200270303A1-20200827-C00503
    Figure US20200270303A1-20200827-C00504
    Figure US20200270303A1-20200827-C00505
    89.
    Figure US20200270303A1-20200827-C00506
    Figure US20200270303A1-20200827-C00507
    Figure US20200270303A1-20200827-C00508
    Figure US20200270303A1-20200827-C00509
    Figure US20200270303A1-20200827-C00510
    90.
    Figure US20200270303A1-20200827-C00511
    Figure US20200270303A1-20200827-C00512
    Figure US20200270303A1-20200827-C00513
    Figure US20200270303A1-20200827-C00514
    Figure US20200270303A1-20200827-C00515
    91.
    Figure US20200270303A1-20200827-C00516
    Figure US20200270303A1-20200827-C00517
    Figure US20200270303A1-20200827-C00518
    Figure US20200270303A1-20200827-C00519
    Figure US20200270303A1-20200827-C00520
    92.
    Figure US20200270303A1-20200827-C00521
    Figure US20200270303A1-20200827-C00522
    Figure US20200270303A1-20200827-C00523
    Figure US20200270303A1-20200827-C00524
    Figure US20200270303A1-20200827-C00525
    93.
    Figure US20200270303A1-20200827-C00526
    Figure US20200270303A1-20200827-C00527
    Figure US20200270303A1-20200827-C00528
    Figure US20200270303A1-20200827-C00529
    Figure US20200270303A1-20200827-C00530
    94.
    Figure US20200270303A1-20200827-C00531
    Figure US20200270303A1-20200827-C00532
    Figure US20200270303A1-20200827-C00533
    Figure US20200270303A1-20200827-C00534
    Figure US20200270303A1-20200827-C00535
    95.
    Figure US20200270303A1-20200827-C00536
    Figure US20200270303A1-20200827-C00537
    Figure US20200270303A1-20200827-C00538
    Figure US20200270303A1-20200827-C00539
    Figure US20200270303A1-20200827-C00540
    96.
    Figure US20200270303A1-20200827-C00541
    Figure US20200270303A1-20200827-C00542
    Figure US20200270303A1-20200827-C00543
    Figure US20200270303A1-20200827-C00544
    Figure US20200270303A1-20200827-C00545
    97.
    Figure US20200270303A1-20200827-C00546
    Figure US20200270303A1-20200827-C00547
    Figure US20200270303A1-20200827-C00548
    Figure US20200270303A1-20200827-C00549
    Figure US20200270303A1-20200827-C00550
    98.
    Figure US20200270303A1-20200827-C00551
    Figure US20200270303A1-20200827-C00552
    Figure US20200270303A1-20200827-C00553
    Figure US20200270303A1-20200827-C00554
    Figure US20200270303A1-20200827-C00555
    99.
    Figure US20200270303A1-20200827-C00556
    Figure US20200270303A1-20200827-C00557
    Figure US20200270303A1-20200827-C00558
    Figure US20200270303A1-20200827-C00559
    Figure US20200270303A1-20200827-C00560
    100.
    Figure US20200270303A1-20200827-C00561
    Figure US20200270303A1-20200827-C00562
    Figure US20200270303A1-20200827-C00563
    Figure US20200270303A1-20200827-C00564
    Figure US20200270303A1-20200827-C00565
    101.
    Figure US20200270303A1-20200827-C00566
    Figure US20200270303A1-20200827-C00567
    Figure US20200270303A1-20200827-C00568
    Figure US20200270303A1-20200827-C00569
    Figure US20200270303A1-20200827-C00570
    102.
    Figure US20200270303A1-20200827-C00571
    Figure US20200270303A1-20200827-C00572
    Figure US20200270303A1-20200827-C00573
    Figure US20200270303A1-20200827-C00574
    Figure US20200270303A1-20200827-C00575
    103.
    Figure US20200270303A1-20200827-C00576
    Figure US20200270303A1-20200827-C00577
    Figure US20200270303A1-20200827-C00578
    Figure US20200270303A1-20200827-C00579
    Figure US20200270303A1-20200827-C00580
    104.
    Figure US20200270303A1-20200827-C00581
    Figure US20200270303A1-20200827-C00582
    Figure US20200270303A1-20200827-C00583
    Figure US20200270303A1-20200827-C00584
    Figure US20200270303A1-20200827-C00585
    105.
    Figure US20200270303A1-20200827-C00586
    Figure US20200270303A1-20200827-C00587
    Figure US20200270303A1-20200827-C00588
    Figure US20200270303A1-20200827-C00589
    Figure US20200270303A1-20200827-C00590
    106.
    Figure US20200270303A1-20200827-C00591
    Figure US20200270303A1-20200827-C00592
    Figure US20200270303A1-20200827-C00593
    Figure US20200270303A1-20200827-C00594
    Figure US20200270303A1-20200827-C00595
    107.
    Figure US20200270303A1-20200827-C00596
    Figure US20200270303A1-20200827-C00597
    Figure US20200270303A1-20200827-C00598
    Figure US20200270303A1-20200827-C00599
    Figure US20200270303A1-20200827-C00600
    108.
    Figure US20200270303A1-20200827-C00601
    Figure US20200270303A1-20200827-C00602
    Figure US20200270303A1-20200827-C00603
    Figure US20200270303A1-20200827-C00604
    Figure US20200270303A1-20200827-C00605
    109.
    Figure US20200270303A1-20200827-C00606
    Figure US20200270303A1-20200827-C00607
    Figure US20200270303A1-20200827-C00608
    Figure US20200270303A1-20200827-C00609
    Figure US20200270303A1-20200827-C00610
    110.
    Figure US20200270303A1-20200827-C00611
    Figure US20200270303A1-20200827-C00612
    Figure US20200270303A1-20200827-C00613
    Figure US20200270303A1-20200827-C00614
    Figure US20200270303A1-20200827-C00615
    111.
    Figure US20200270303A1-20200827-C00616
    Figure US20200270303A1-20200827-C00617
    Figure US20200270303A1-20200827-C00618
    Figure US20200270303A1-20200827-C00619
    Figure US20200270303A1-20200827-C00620
    112.
    Figure US20200270303A1-20200827-C00621
    Figure US20200270303A1-20200827-C00622
    Figure US20200270303A1-20200827-C00623
    Figure US20200270303A1-20200827-C00624
    Figure US20200270303A1-20200827-C00625
    113.
    Figure US20200270303A1-20200827-C00626
    Figure US20200270303A1-20200827-C00627
    Figure US20200270303A1-20200827-C00628
    Figure US20200270303A1-20200827-C00629
    Figure US20200270303A1-20200827-C00630
    114.
    Figure US20200270303A1-20200827-C00631
    Figure US20200270303A1-20200827-C00632
    Figure US20200270303A1-20200827-C00633
    Figure US20200270303A1-20200827-C00634
    Figure US20200270303A1-20200827-C00635
    115.
    Figure US20200270303A1-20200827-C00636
    Figure US20200270303A1-20200827-C00637
    Figure US20200270303A1-20200827-C00638
    Figure US20200270303A1-20200827-C00639
    Figure US20200270303A1-20200827-C00640
    116.
    Figure US20200270303A1-20200827-C00641
    Figure US20200270303A1-20200827-C00642
    Figure US20200270303A1-20200827-C00643
    Figure US20200270303A1-20200827-C00644
    Figure US20200270303A1-20200827-C00645
    117.
    Figure US20200270303A1-20200827-C00646
    Figure US20200270303A1-20200827-C00647
    Figure US20200270303A1-20200827-C00648
    Figure US20200270303A1-20200827-C00649
    Figure US20200270303A1-20200827-C00650
    118.
    Figure US20200270303A1-20200827-C00651
    Figure US20200270303A1-20200827-C00652
    Figure US20200270303A1-20200827-C00653
    Figure US20200270303A1-20200827-C00654
    Figure US20200270303A1-20200827-C00655
    119.
    Figure US20200270303A1-20200827-C00656
    Figure US20200270303A1-20200827-C00657
    Figure US20200270303A1-20200827-C00658
    Figure US20200270303A1-20200827-C00659
    Figure US20200270303A1-20200827-C00660
    120.
    Figure US20200270303A1-20200827-C00661
    Figure US20200270303A1-20200827-C00662
    Figure US20200270303A1-20200827-C00663
    Figure US20200270303A1-20200827-C00664
    Figure US20200270303A1-20200827-C00665
    121.
    Figure US20200270303A1-20200827-C00666
    Figure US20200270303A1-20200827-C00667
    Figure US20200270303A1-20200827-C00668
    Figure US20200270303A1-20200827-C00669
    Figure US20200270303A1-20200827-C00670
    122.
    Figure US20200270303A1-20200827-C00671
    Figure US20200270303A1-20200827-C00672
    Figure US20200270303A1-20200827-C00673
    Figure US20200270303A1-20200827-C00674
    Figure US20200270303A1-20200827-C00675
    123.
    Figure US20200270303A1-20200827-C00676
    Figure US20200270303A1-20200827-C00677
    Figure US20200270303A1-20200827-C00678
    Figure US20200270303A1-20200827-C00679
    Figure US20200270303A1-20200827-C00680
    124.
    Figure US20200270303A1-20200827-C00681
    Figure US20200270303A1-20200827-C00682
    Figure US20200270303A1-20200827-C00683
    Figure US20200270303A1-20200827-C00684
    Figure US20200270303A1-20200827-C00685
    125.
    Figure US20200270303A1-20200827-C00686
    Figure US20200270303A1-20200827-C00687
    Figure US20200270303A1-20200827-C00688
    Figure US20200270303A1-20200827-C00689
    Figure US20200270303A1-20200827-C00690
    126.
    Figure US20200270303A1-20200827-C00691
    Figure US20200270303A1-20200827-C00692
    Figure US20200270303A1-20200827-C00693
    Figure US20200270303A1-20200827-C00694
    Figure US20200270303A1-20200827-C00695
    127.
    Figure US20200270303A1-20200827-C00696
    Figure US20200270303A1-20200827-C00697
    Figure US20200270303A1-20200827-C00698
    Figure US20200270303A1-20200827-C00699
    Figure US20200270303A1-20200827-C00700
    128.
    Figure US20200270303A1-20200827-C00701
    Figure US20200270303A1-20200827-C00702
    Figure US20200270303A1-20200827-C00703
    Figure US20200270303A1-20200827-C00704
    Figure US20200270303A1-20200827-C00705
    129.
    Figure US20200270303A1-20200827-C00706
    Figure US20200270303A1-20200827-C00707
    Figure US20200270303A1-20200827-C00708
    Figure US20200270303A1-20200827-C00709
    Figure US20200270303A1-20200827-C00710
    130.
    Figure US20200270303A1-20200827-C00711
    Figure US20200270303A1-20200827-C00712
    Figure US20200270303A1-20200827-C00713
    Figure US20200270303A1-20200827-C00714
    Figure US20200270303A1-20200827-C00715
    131.
    Figure US20200270303A1-20200827-C00716
    Figure US20200270303A1-20200827-C00717
    Figure US20200270303A1-20200827-C00718
    Figure US20200270303A1-20200827-C00719
    Figure US20200270303A1-20200827-C00720
    132.
    Figure US20200270303A1-20200827-C00721
    Figure US20200270303A1-20200827-C00722
    Figure US20200270303A1-20200827-C00723
    Figure US20200270303A1-20200827-C00724
    Figure US20200270303A1-20200827-C00725
    133.
    Figure US20200270303A1-20200827-C00726
    Figure US20200270303A1-20200827-C00727
    Figure US20200270303A1-20200827-C00728
    Figure US20200270303A1-20200827-C00729
    Figure US20200270303A1-20200827-C00730
    134.
    Figure US20200270303A1-20200827-C00731
    Figure US20200270303A1-20200827-C00732
    Figure US20200270303A1-20200827-C00733
    Figure US20200270303A1-20200827-C00734
    Figure US20200270303A1-20200827-C00735
    135.
    Figure US20200270303A1-20200827-C00736
    Figure US20200270303A1-20200827-C00737
    Figure US20200270303A1-20200827-C00738
    Figure US20200270303A1-20200827-C00739
    Figure US20200270303A1-20200827-C00740
    136.
    Figure US20200270303A1-20200827-C00741
    Figure US20200270303A1-20200827-C00742
    Figure US20200270303A1-20200827-C00743
    Figure US20200270303A1-20200827-C00744
    Figure US20200270303A1-20200827-C00745
    137.
    Figure US20200270303A1-20200827-C00746
    Figure US20200270303A1-20200827-C00747
    Figure US20200270303A1-20200827-C00748
    Figure US20200270303A1-20200827-C00749
    Figure US20200270303A1-20200827-C00750
    138.
    Figure US20200270303A1-20200827-C00751
    Figure US20200270303A1-20200827-C00752
    Figure US20200270303A1-20200827-C00753
    Figure US20200270303A1-20200827-C00754
    Figure US20200270303A1-20200827-C00755
    139.
    Figure US20200270303A1-20200827-C00756
    Figure US20200270303A1-20200827-C00757
    Figure US20200270303A1-20200827-C00758
    Figure US20200270303A1-20200827-C00759
    Figure US20200270303A1-20200827-C00760
    140.
    Figure US20200270303A1-20200827-C00761
    Figure US20200270303A1-20200827-C00762
    Figure US20200270303A1-20200827-C00763
    Figure US20200270303A1-20200827-C00764
    Figure US20200270303A1-20200827-C00765
    141.
    Figure US20200270303A1-20200827-C00766
    Figure US20200270303A1-20200827-C00767
    Figure US20200270303A1-20200827-C00768
    Figure US20200270303A1-20200827-C00769
    Figure US20200270303A1-20200827-C00770
    142.
    Figure US20200270303A1-20200827-C00771
    Figure US20200270303A1-20200827-C00772
    Figure US20200270303A1-20200827-C00773
    Figure US20200270303A1-20200827-C00774
    Figure US20200270303A1-20200827-C00775
    143.
    Figure US20200270303A1-20200827-C00776
    Figure US20200270303A1-20200827-C00777
    Figure US20200270303A1-20200827-C00778
    Figure US20200270303A1-20200827-C00779
    Figure US20200270303A1-20200827-C00780
    144.
    Figure US20200270303A1-20200827-C00781
    Figure US20200270303A1-20200827-C00782
    Figure US20200270303A1-20200827-C00783
    Figure US20200270303A1-20200827-C00784
    Figure US20200270303A1-20200827-C00785
    145.
    Figure US20200270303A1-20200827-C00786
    Figure US20200270303A1-20200827-C00787
    Figure US20200270303A1-20200827-C00788
    Figure US20200270303A1-20200827-C00789
    Figure US20200270303A1-20200827-C00790
    146.
    Figure US20200270303A1-20200827-C00791
    Figure US20200270303A1-20200827-C00792
    Figure US20200270303A1-20200827-C00793
    Figure US20200270303A1-20200827-C00794
    Figure US20200270303A1-20200827-C00795
    147.
    Figure US20200270303A1-20200827-C00796
    Figure US20200270303A1-20200827-C00797
    Figure US20200270303A1-20200827-C00798
    Figure US20200270303A1-20200827-C00799
    Figure US20200270303A1-20200827-C00800
    148.
    Figure US20200270303A1-20200827-C00801
    Figure US20200270303A1-20200827-C00802
    Figure US20200270303A1-20200827-C00803
    Figure US20200270303A1-20200827-C00804
    Figure US20200270303A1-20200827-C00805
    149.
    Figure US20200270303A1-20200827-C00806
    Figure US20200270303A1-20200827-C00807
    Figure US20200270303A1-20200827-C00808
    Figure US20200270303A1-20200827-C00809
    Figure US20200270303A1-20200827-C00810
    150.
    Figure US20200270303A1-20200827-C00811
    Figure US20200270303A1-20200827-C00812
    Figure US20200270303A1-20200827-C00813
    Figure US20200270303A1-20200827-C00814
    Figure US20200270303A1-20200827-C00815
    151.
    Figure US20200270303A1-20200827-C00816
    Figure US20200270303A1-20200827-C00817
    Figure US20200270303A1-20200827-C00818
    Figure US20200270303A1-20200827-C00819
    Figure US20200270303A1-20200827-C00820
    152.
    Figure US20200270303A1-20200827-C00821
    Figure US20200270303A1-20200827-C00822
    Figure US20200270303A1-20200827-C00823
    Figure US20200270303A1-20200827-C00824
    Figure US20200270303A1-20200827-C00825
    153.
    Figure US20200270303A1-20200827-C00826
    Figure US20200270303A1-20200827-C00827
    Figure US20200270303A1-20200827-C00828
    Figure US20200270303A1-20200827-C00829
    Figure US20200270303A1-20200827-C00830
    154.
    Figure US20200270303A1-20200827-C00831
    Figure US20200270303A1-20200827-C00832
    Figure US20200270303A1-20200827-C00833
    Figure US20200270303A1-20200827-C00834
    Figure US20200270303A1-20200827-C00835
    155.
    Figure US20200270303A1-20200827-C00836
    Figure US20200270303A1-20200827-C00837
    Figure US20200270303A1-20200827-C00838
    Figure US20200270303A1-20200827-C00839
    Figure US20200270303A1-20200827-C00840
    156.
    Figure US20200270303A1-20200827-C00841
    Figure US20200270303A1-20200827-C00842
    Figure US20200270303A1-20200827-C00843
    Figure US20200270303A1-20200827-C00844
    Figure US20200270303A1-20200827-C00845
    157.
    Figure US20200270303A1-20200827-C00846
    Figure US20200270303A1-20200827-C00847
    Figure US20200270303A1-20200827-C00848
    Figure US20200270303A1-20200827-C00849
    Figure US20200270303A1-20200827-C00850
    158.
    Figure US20200270303A1-20200827-C00851
    Figure US20200270303A1-20200827-C00852
    Figure US20200270303A1-20200827-C00853
    Figure US20200270303A1-20200827-C00854
    Figure US20200270303A1-20200827-C00855
    159.
    Figure US20200270303A1-20200827-C00856
    Figure US20200270303A1-20200827-C00857
    Figure US20200270303A1-20200827-C00858
    Figure US20200270303A1-20200827-C00859
    Figure US20200270303A1-20200827-C00860
    160.
    Figure US20200270303A1-20200827-C00861
    Figure US20200270303A1-20200827-C00862
    Figure US20200270303A1-20200827-C00863
    Figure US20200270303A1-20200827-C00864
    Figure US20200270303A1-20200827-C00865
    161.
    Figure US20200270303A1-20200827-C00866
    Figure US20200270303A1-20200827-C00867
    Figure US20200270303A1-20200827-C00868
    Figure US20200270303A1-20200827-C00869
    Figure US20200270303A1-20200827-C00870
    162.
    Figure US20200270303A1-20200827-C00871
    Figure US20200270303A1-20200827-C00872
    Figure US20200270303A1-20200827-C00873
    Figure US20200270303A1-20200827-C00874
    Figure US20200270303A1-20200827-C00875
    163.
    Figure US20200270303A1-20200827-C00876
    Figure US20200270303A1-20200827-C00877
    Figure US20200270303A1-20200827-C00878
    Figure US20200270303A1-20200827-C00879
    Figure US20200270303A1-20200827-C00880
    164.
    Figure US20200270303A1-20200827-C00881
    Figure US20200270303A1-20200827-C00882
    Figure US20200270303A1-20200827-C00883
    Figure US20200270303A1-20200827-C00884
    Figure US20200270303A1-20200827-C00885
    165.
    Figure US20200270303A1-20200827-C00886
    Figure US20200270303A1-20200827-C00887
    Figure US20200270303A1-20200827-C00888
    Figure US20200270303A1-20200827-C00889
    Figure US20200270303A1-20200827-C00890
    166.
    Figure US20200270303A1-20200827-C00891
    Figure US20200270303A1-20200827-C00892
    Figure US20200270303A1-20200827-C00893
    Figure US20200270303A1-20200827-C00894
    Figure US20200270303A1-20200827-C00895
    167.
    Figure US20200270303A1-20200827-C00896
    Figure US20200270303A1-20200827-C00897
    Figure US20200270303A1-20200827-C00898
    Figure US20200270303A1-20200827-C00899
    Figure US20200270303A1-20200827-C00900
    168.
    Figure US20200270303A1-20200827-C00901
    Figure US20200270303A1-20200827-C00902
    Figure US20200270303A1-20200827-C00903
    Figure US20200270303A1-20200827-C00904
    Figure US20200270303A1-20200827-C00905
    169.
    Figure US20200270303A1-20200827-C00906
    Figure US20200270303A1-20200827-C00907
    Figure US20200270303A1-20200827-C00908
    Figure US20200270303A1-20200827-C00909
    Figure US20200270303A1-20200827-C00910
    170.
    Figure US20200270303A1-20200827-C00911
    Figure US20200270303A1-20200827-C00912
    Figure US20200270303A1-20200827-C00913
    Figure US20200270303A1-20200827-C00914
    Figure US20200270303A1-20200827-C00915
    171.
    Figure US20200270303A1-20200827-C00916
    Figure US20200270303A1-20200827-C00917
    Figure US20200270303A1-20200827-C00918
    Figure US20200270303A1-20200827-C00919
    Figure US20200270303A1-20200827-C00920
    172.
    Figure US20200270303A1-20200827-C00921
    Figure US20200270303A1-20200827-C00922
    Figure US20200270303A1-20200827-C00923
    Figure US20200270303A1-20200827-C00924
    Figure US20200270303A1-20200827-C00925
    173.
    Figure US20200270303A1-20200827-C00926
    Figure US20200270303A1-20200827-C00927
    Figure US20200270303A1-20200827-C00928
    Figure US20200270303A1-20200827-C00929
    Figure US20200270303A1-20200827-C00930
    174.
    Figure US20200270303A1-20200827-C00931
    Figure US20200270303A1-20200827-C00932
    Figure US20200270303A1-20200827-C00933
    Figure US20200270303A1-20200827-C00934
    Figure US20200270303A1-20200827-C00935
    175.
    Figure US20200270303A1-20200827-C00936
    Figure US20200270303A1-20200827-C00937
    Figure US20200270303A1-20200827-C00938
    Figure US20200270303A1-20200827-C00939
    Figure US20200270303A1-20200827-C00940
    176.
    Figure US20200270303A1-20200827-C00941
    Figure US20200270303A1-20200827-C00942
    Figure US20200270303A1-20200827-C00943
    Figure US20200270303A1-20200827-C00944
    Figure US20200270303A1-20200827-C00945
    177.
    Figure US20200270303A1-20200827-C00946
    Figure US20200270303A1-20200827-C00947
    Figure US20200270303A1-20200827-C00948
    Figure US20200270303A1-20200827-C00949
    Figure US20200270303A1-20200827-C00950
    178.
    Figure US20200270303A1-20200827-C00951
    Figure US20200270303A1-20200827-C00952
    Figure US20200270303A1-20200827-C00953
    Figure US20200270303A1-20200827-C00954
    Figure US20200270303A1-20200827-C00955
    179.
    Figure US20200270303A1-20200827-C00956
    Figure US20200270303A1-20200827-C00957
    Figure US20200270303A1-20200827-C00958
    Figure US20200270303A1-20200827-C00959
    Figure US20200270303A1-20200827-C00960
    180.
    Figure US20200270303A1-20200827-C00961
    Figure US20200270303A1-20200827-C00962
    Figure US20200270303A1-20200827-C00963
    Figure US20200270303A1-20200827-C00964
    Figure US20200270303A1-20200827-C00965
    181.
    Figure US20200270303A1-20200827-C00966
    Figure US20200270303A1-20200827-C00967
    Figure US20200270303A1-20200827-C00968
    Figure US20200270303A1-20200827-C00969
    Figure US20200270303A1-20200827-C00970
    182.
    Figure US20200270303A1-20200827-C00971
    Figure US20200270303A1-20200827-C00972
    Figure US20200270303A1-20200827-C00973
    Figure US20200270303A1-20200827-C00974
    Figure US20200270303A1-20200827-C00975
    183.
    Figure US20200270303A1-20200827-C00976
    Figure US20200270303A1-20200827-C00977
    Figure US20200270303A1-20200827-C00978
    Figure US20200270303A1-20200827-C00979
    Figure US20200270303A1-20200827-C00980
    184.
    Figure US20200270303A1-20200827-C00981
    Figure US20200270303A1-20200827-C00982
    Figure US20200270303A1-20200827-C00983
    Figure US20200270303A1-20200827-C00984
    Figure US20200270303A1-20200827-C00985
    185.
    Figure US20200270303A1-20200827-C00986
    Figure US20200270303A1-20200827-C00987
    Figure US20200270303A1-20200827-C00988
    Figure US20200270303A1-20200827-C00989
    Figure US20200270303A1-20200827-C00990
    186.
    Figure US20200270303A1-20200827-C00991
    Figure US20200270303A1-20200827-C00992
    Figure US20200270303A1-20200827-C00993
    Figure US20200270303A1-20200827-C00994
    Figure US20200270303A1-20200827-C00995
    187.
    Figure US20200270303A1-20200827-C00996
    Figure US20200270303A1-20200827-C00997
    Figure US20200270303A1-20200827-C00998
    Figure US20200270303A1-20200827-C00999
    Figure US20200270303A1-20200827-C01000
    188.
    Figure US20200270303A1-20200827-C01001
    Figure US20200270303A1-20200827-C01002
    Figure US20200270303A1-20200827-C01003
    Figure US20200270303A1-20200827-C01004
    Figure US20200270303A1-20200827-C01005
    189.
    Figure US20200270303A1-20200827-C01006
    Figure US20200270303A1-20200827-C01007
    Figure US20200270303A1-20200827-C01008
    Figure US20200270303A1-20200827-C01009
    Figure US20200270303A1-20200827-C01010
    190.
    Figure US20200270303A1-20200827-C01011
    Figure US20200270303A1-20200827-C01012
    Figure US20200270303A1-20200827-C01013
    Figure US20200270303A1-20200827-C01014
    Figure US20200270303A1-20200827-C01015
    191.
    Figure US20200270303A1-20200827-C01016
    Figure US20200270303A1-20200827-C01017
    Figure US20200270303A1-20200827-C01018
    Figure US20200270303A1-20200827-C01019
    Figure US20200270303A1-20200827-C01020
    192.
    Figure US20200270303A1-20200827-C01021
    Figure US20200270303A1-20200827-C01022
    Figure US20200270303A1-20200827-C01023
    Figure US20200270303A1-20200827-C01024
    Figure US20200270303A1-20200827-C01025
    193.
    Figure US20200270303A1-20200827-C01026
    Figure US20200270303A1-20200827-C01027
    Figure US20200270303A1-20200827-C01028
    Figure US20200270303A1-20200827-C01029
    Figure US20200270303A1-20200827-C01030
    194.
    Figure US20200270303A1-20200827-C01031
    Figure US20200270303A1-20200827-C01032
    Figure US20200270303A1-20200827-C01033
    Figure US20200270303A1-20200827-C01034
    Figure US20200270303A1-20200827-C01035
    195.
    Figure US20200270303A1-20200827-C01036
    Figure US20200270303A1-20200827-C01037
    Figure US20200270303A1-20200827-C01038
    Figure US20200270303A1-20200827-C01039
    Figure US20200270303A1-20200827-C01040
    196.
    Figure US20200270303A1-20200827-C01041
    Figure US20200270303A1-20200827-C01042
    Figure US20200270303A1-20200827-C01043
    Figure US20200270303A1-20200827-C01044
    Figure US20200270303A1-20200827-C01045
    197.
    Figure US20200270303A1-20200827-C01046
    Figure US20200270303A1-20200827-C01047
    Figure US20200270303A1-20200827-C01048
    Figure US20200270303A1-20200827-C01049
    Figure US20200270303A1-20200827-C01050
    198.
    Figure US20200270303A1-20200827-C01051
    Figure US20200270303A1-20200827-C01052
    Figure US20200270303A1-20200827-C01053
    Figure US20200270303A1-20200827-C01054
    Figure US20200270303A1-20200827-C01055
    199.
    Figure US20200270303A1-20200827-C01056
    Figure US20200270303A1-20200827-C01057
    Figure US20200270303A1-20200827-C01058
    Figure US20200270303A1-20200827-C01059
    Figure US20200270303A1-20200827-C01060
    200.
    Figure US20200270303A1-20200827-C01061
    Figure US20200270303A1-20200827-C01062
    Figure US20200270303A1-20200827-C01063
    Figure US20200270303A1-20200827-C01064
    Figure US20200270303A1-20200827-C01065
    201.
    Figure US20200270303A1-20200827-C01066
    Figure US20200270303A1-20200827-C01067
    Figure US20200270303A1-20200827-C01068
    Figure US20200270303A1-20200827-C01069
    Figure US20200270303A1-20200827-C01070
    202.
    Figure US20200270303A1-20200827-C01071
    Figure US20200270303A1-20200827-C01072
    Figure US20200270303A1-20200827-C01073
    Figure US20200270303A1-20200827-C01074
    Figure US20200270303A1-20200827-C01075
    203.
    Figure US20200270303A1-20200827-C01076
    Figure US20200270303A1-20200827-C01077
    Figure US20200270303A1-20200827-C01078
    Figure US20200270303A1-20200827-C01079
    Figure US20200270303A1-20200827-C01080
    204.
    Figure US20200270303A1-20200827-C01081
    Figure US20200270303A1-20200827-C01082
    Figure US20200270303A1-20200827-C01083
    Figure US20200270303A1-20200827-C01084
    Figure US20200270303A1-20200827-C01085
    205.
    Figure US20200270303A1-20200827-C01086
    Figure US20200270303A1-20200827-C01087
    Figure US20200270303A1-20200827-C01088
    Figure US20200270303A1-20200827-C01089
    Figure US20200270303A1-20200827-C01090
    206.
    Figure US20200270303A1-20200827-C01091
    Figure US20200270303A1-20200827-C01092
    Figure US20200270303A1-20200827-C01093
    Figure US20200270303A1-20200827-C01094
    Figure US20200270303A1-20200827-C01095
    207.
    Figure US20200270303A1-20200827-C01096
    Figure US20200270303A1-20200827-C01097
    Figure US20200270303A1-20200827-C01098
    Figure US20200270303A1-20200827-C01099
    Figure US20200270303A1-20200827-C01100
    208.
    Figure US20200270303A1-20200827-C01101
    Figure US20200270303A1-20200827-C01102
    Figure US20200270303A1-20200827-C01103
    Figure US20200270303A1-20200827-C01104
    Figure US20200270303A1-20200827-C01105
    209.
    Figure US20200270303A1-20200827-C01106
    Figure US20200270303A1-20200827-C01107
    Figure US20200270303A1-20200827-C01108
    Figure US20200270303A1-20200827-C01109
    Figure US20200270303A1-20200827-C01110
    210.
    Figure US20200270303A1-20200827-C01111
    Figure US20200270303A1-20200827-C01112
    Figure US20200270303A1-20200827-C01113
    Figure US20200270303A1-20200827-C01114
    Figure US20200270303A1-20200827-C01115
    211.
    Figure US20200270303A1-20200827-C01116
    Figure US20200270303A1-20200827-C01117
    Figure US20200270303A1-20200827-C01118
    Figure US20200270303A1-20200827-C01119
    Figure US20200270303A1-20200827-C01120
    212.
    Figure US20200270303A1-20200827-C01121
    Figure US20200270303A1-20200827-C01122
    Figure US20200270303A1-20200827-C01123
    Figure US20200270303A1-20200827-C01124
    Figure US20200270303A1-20200827-C01125
    213.
    Figure US20200270303A1-20200827-C01126
    Figure US20200270303A1-20200827-C01127
    Figure US20200270303A1-20200827-C01128
    Figure US20200270303A1-20200827-C01129
    Figure US20200270303A1-20200827-C01130
    214.
    Figure US20200270303A1-20200827-C01131
    Figure US20200270303A1-20200827-C01132
    Figure US20200270303A1-20200827-C01133
    Figure US20200270303A1-20200827-C01134
    Figure US20200270303A1-20200827-C01135
    215.
    Figure US20200270303A1-20200827-C01136
    Figure US20200270303A1-20200827-C01137
    Figure US20200270303A1-20200827-C01138
    Figure US20200270303A1-20200827-C01139
    Figure US20200270303A1-20200827-C01140
    216.
    Figure US20200270303A1-20200827-C01141
    Figure US20200270303A1-20200827-C01142
    Figure US20200270303A1-20200827-C01143
    Figure US20200270303A1-20200827-C01144
    Figure US20200270303A1-20200827-C01145
    217.
    Figure US20200270303A1-20200827-C01146
    Figure US20200270303A1-20200827-C01147
    Figure US20200270303A1-20200827-C01148
    Figure US20200270303A1-20200827-C01149
    Figure US20200270303A1-20200827-C01150
    218.
    Figure US20200270303A1-20200827-C01151
    Figure US20200270303A1-20200827-C01152
    Figure US20200270303A1-20200827-C01153
    Figure US20200270303A1-20200827-C01154
    Figure US20200270303A1-20200827-C01155
    219.
    Figure US20200270303A1-20200827-C01156
    Figure US20200270303A1-20200827-C01157
    Figure US20200270303A1-20200827-C01158
    Figure US20200270303A1-20200827-C01159
    Figure US20200270303A1-20200827-C01160
    220.
    Figure US20200270303A1-20200827-C01161
    Figure US20200270303A1-20200827-C01162
    Figure US20200270303A1-20200827-C01163
    Figure US20200270303A1-20200827-C01164
    Figure US20200270303A1-20200827-C01165
    221.
    Figure US20200270303A1-20200827-C01166
    Figure US20200270303A1-20200827-C01167
    Figure US20200270303A1-20200827-C01168
    Figure US20200270303A1-20200827-C01169
    Figure US20200270303A1-20200827-C01170
    222.
    Figure US20200270303A1-20200827-C01171
    Figure US20200270303A1-20200827-C01172
    Figure US20200270303A1-20200827-C01173
    Figure US20200270303A1-20200827-C01174
    Figure US20200270303A1-20200827-C01175
    223.
    Figure US20200270303A1-20200827-C01176
    Figure US20200270303A1-20200827-C01177
    Figure US20200270303A1-20200827-C01178
    Figure US20200270303A1-20200827-C01179
    Figure US20200270303A1-20200827-C01180
    224.
    Figure US20200270303A1-20200827-C01181
    Figure US20200270303A1-20200827-C01182
    Figure US20200270303A1-20200827-C01183
    Figure US20200270303A1-20200827-C01184
    Figure US20200270303A1-20200827-C01185
    225.
    Figure US20200270303A1-20200827-C01186
    Figure US20200270303A1-20200827-C01187
    Figure US20200270303A1-20200827-C01188
    Figure US20200270303A1-20200827-C01189
    Figure US20200270303A1-20200827-C01190
    226.
    Figure US20200270303A1-20200827-C01191
    Figure US20200270303A1-20200827-C01192
    Figure US20200270303A1-20200827-C01193
    Figure US20200270303A1-20200827-C01194
    Figure US20200270303A1-20200827-C01195
    227.
    Figure US20200270303A1-20200827-C01196
    Figure US20200270303A1-20200827-C01197
    Figure US20200270303A1-20200827-C01198
    Figure US20200270303A1-20200827-C01199
    Figure US20200270303A1-20200827-C01200
    228.
    Figure US20200270303A1-20200827-C01201
    Figure US20200270303A1-20200827-C01202
    Figure US20200270303A1-20200827-C01203
    Figure US20200270303A1-20200827-C01204
    Figure US20200270303A1-20200827-C01205
    229.
    Figure US20200270303A1-20200827-C01206
    Figure US20200270303A1-20200827-C01207
    Figure US20200270303A1-20200827-C01208
    Figure US20200270303A1-20200827-C01209
    Figure US20200270303A1-20200827-C01210
    230.
    Figure US20200270303A1-20200827-C01211
    Figure US20200270303A1-20200827-C01212
    Figure US20200270303A1-20200827-C01213
    Figure US20200270303A1-20200827-C01214
    Figure US20200270303A1-20200827-C01215
    231.
    Figure US20200270303A1-20200827-C01216
    Figure US20200270303A1-20200827-C01217
    Figure US20200270303A1-20200827-C01218
    Figure US20200270303A1-20200827-C01219
    Figure US20200270303A1-20200827-C01220
    232.
    Figure US20200270303A1-20200827-C01221
    Figure US20200270303A1-20200827-C01222
    Figure US20200270303A1-20200827-C01223
    Figure US20200270303A1-20200827-C01224
    Figure US20200270303A1-20200827-C01225
    233.
    Figure US20200270303A1-20200827-C01226
    Figure US20200270303A1-20200827-C01227
    Figure US20200270303A1-20200827-C01228
    Figure US20200270303A1-20200827-C01229
    Figure US20200270303A1-20200827-C01230
    234.
    Figure US20200270303A1-20200827-C01231
    Figure US20200270303A1-20200827-C01232
    Figure US20200270303A1-20200827-C01233
    Figure US20200270303A1-20200827-C01234
    Figure US20200270303A1-20200827-C01235
    235.
    Figure US20200270303A1-20200827-C01236
    Figure US20200270303A1-20200827-C01237
    Figure US20200270303A1-20200827-C01238
    Figure US20200270303A1-20200827-C01239
    Figure US20200270303A1-20200827-C01240
    236.
    Figure US20200270303A1-20200827-C01241
    Figure US20200270303A1-20200827-C01242
    Figure US20200270303A1-20200827-C01243
    Figure US20200270303A1-20200827-C01244
    Figure US20200270303A1-20200827-C01245
    237.
    Figure US20200270303A1-20200827-C01246
    Figure US20200270303A1-20200827-C01247
    Figure US20200270303A1-20200827-C01248
    Figure US20200270303A1-20200827-C01249
    Figure US20200270303A1-20200827-C01250
    238.
    Figure US20200270303A1-20200827-C01251
    Figure US20200270303A1-20200827-C01252
    Figure US20200270303A1-20200827-C01253
    Figure US20200270303A1-20200827-C01254
    Figure US20200270303A1-20200827-C01255
    239.
    Figure US20200270303A1-20200827-C01256
    Figure US20200270303A1-20200827-C01257
    Figure US20200270303A1-20200827-C01258
    Figure US20200270303A1-20200827-C01259
    Figure US20200270303A1-20200827-C01260
    240.
    Figure US20200270303A1-20200827-C01261
    Figure US20200270303A1-20200827-C01262
    Figure US20200270303A1-20200827-C01263
    Figure US20200270303A1-20200827-C01264
    Figure US20200270303A1-20200827-C01265
    241.
    Figure US20200270303A1-20200827-C01266
    Figure US20200270303A1-20200827-C01267
    Figure US20200270303A1-20200827-C01268
    Figure US20200270303A1-20200827-C01269
    Figure US20200270303A1-20200827-C01270
    242.
    Figure US20200270303A1-20200827-C01271
    Figure US20200270303A1-20200827-C01272
    Figure US20200270303A1-20200827-C01273
    Figure US20200270303A1-20200827-C01274
    Figure US20200270303A1-20200827-C01275
    243.
    Figure US20200270303A1-20200827-C01276
    Figure US20200270303A1-20200827-C01277
    Figure US20200270303A1-20200827-C01278
    Figure US20200270303A1-20200827-C01279
    Figure US20200270303A1-20200827-C01280
    244.
    Figure US20200270303A1-20200827-C01281
    Figure US20200270303A1-20200827-C01282
    Figure US20200270303A1-20200827-C01283
    Figure US20200270303A1-20200827-C01284
    Figure US20200270303A1-20200827-C01285
    245.
    Figure US20200270303A1-20200827-C01286
    Figure US20200270303A1-20200827-C01287
    Figure US20200270303A1-20200827-C01288
    Figure US20200270303A1-20200827-C01289
    Figure US20200270303A1-20200827-C01290
    246.
    Figure US20200270303A1-20200827-C01291
    Figure US20200270303A1-20200827-C01292
    Figure US20200270303A1-20200827-C01293
    Figure US20200270303A1-20200827-C01294
    Figure US20200270303A1-20200827-C01295
    247.
    Figure US20200270303A1-20200827-C01296
    Figure US20200270303A1-20200827-C01297
    Figure US20200270303A1-20200827-C01298
    Figure US20200270303A1-20200827-C01299
    Figure US20200270303A1-20200827-C01300
    248.
    Figure US20200270303A1-20200827-C01301
    Figure US20200270303A1-20200827-C01302
    Figure US20200270303A1-20200827-C01303
    Figure US20200270303A1-20200827-C01304
    Figure US20200270303A1-20200827-C01305
    249.
    Figure US20200270303A1-20200827-C01306
    Figure US20200270303A1-20200827-C01307
    Figure US20200270303A1-20200827-C01308
    Figure US20200270303A1-20200827-C01309
    Figure US20200270303A1-20200827-C01310
    250.
    Figure US20200270303A1-20200827-C01311
    Figure US20200270303A1-20200827-C01312
    Figure US20200270303A1-20200827-C01313
    Figure US20200270303A1-20200827-C01314
    Figure US20200270303A1-20200827-C01315
    251.
    Figure US20200270303A1-20200827-C01316
    Figure US20200270303A1-20200827-C01317
    Figure US20200270303A1-20200827-C01318
    Figure US20200270303A1-20200827-C01319
    Figure US20200270303A1-20200827-C01320
    252.
    Figure US20200270303A1-20200827-C01321
    Figure US20200270303A1-20200827-C01322
    Figure US20200270303A1-20200827-C01323
    Figure US20200270303A1-20200827-C01324
    Figure US20200270303A1-20200827-C01325
    253.
    Figure US20200270303A1-20200827-C01326
    Figure US20200270303A1-20200827-C01327
    Figure US20200270303A1-20200827-C01328
    Figure US20200270303A1-20200827-C01329
    Figure US20200270303A1-20200827-C01330
    254.
    Figure US20200270303A1-20200827-C01331
    Figure US20200270303A1-20200827-C01332
    Figure US20200270303A1-20200827-C01333
    Figure US20200270303A1-20200827-C01334
    Figure US20200270303A1-20200827-C01335
    255.
    Figure US20200270303A1-20200827-C01336
    Figure US20200270303A1-20200827-C01337
    Figure US20200270303A1-20200827-C01338
    Figure US20200270303A1-20200827-C01339
    Figure US20200270303A1-20200827-C01340
    256.
    Figure US20200270303A1-20200827-C01341
    Figure US20200270303A1-20200827-C01342
    Figure US20200270303A1-20200827-C01343
    Figure US20200270303A1-20200827-C01344
    Figure US20200270303A1-20200827-C01345
  • Representative compounds of the invention also include, but are not limited to, the following compounds (example 257 to example 264 in Table 2) according to Formula IX wherein R, -L2-W-L1-,
  • Figure US20200270303A1-20200827-C01346
  • R′ and G are delineated for each example in Table 2.
  • Figure US20200270303A1-20200827-C01347
  • TABLE 2
    Example # R —L2—W—L1—
    Figure US20200270303A1-20200827-C01348
         		R′ G
    257.
    Figure US20200270303A1-20200827-C01349
    Figure US20200270303A1-20200827-C01350
    Figure US20200270303A1-20200827-C01351
    Figure US20200270303A1-20200827-C01352
    Figure US20200270303A1-20200827-C01353
    258.
    Figure US20200270303A1-20200827-C01354
    Figure US20200270303A1-20200827-C01355
    Figure US20200270303A1-20200827-C01356
    Figure US20200270303A1-20200827-C01357
    Figure US20200270303A1-20200827-C01358
    259.
    Figure US20200270303A1-20200827-C01359
    Figure US20200270303A1-20200827-C01360
    Figure US20200270303A1-20200827-C01361
    Figure US20200270303A1-20200827-C01362
    Figure US20200270303A1-20200827-C01363
    260.
    Figure US20200270303A1-20200827-C01364
    Figure US20200270303A1-20200827-C01365
    Figure US20200270303A1-20200827-C01366
    Figure US20200270303A1-20200827-C01367
    Figure US20200270303A1-20200827-C01368
    261.
    Figure US20200270303A1-20200827-C01369
    Figure US20200270303A1-20200827-C01370
    Figure US20200270303A1-20200827-C01371
    Figure US20200270303A1-20200827-C01372
    Figure US20200270303A1-20200827-C01373
    262.
    Figure US20200270303A1-20200827-C01374
    Figure US20200270303A1-20200827-C01375
    Figure US20200270303A1-20200827-C01376
    Figure US20200270303A1-20200827-C01377
    Figure US20200270303A1-20200827-C01378
    263.
    Figure US20200270303A1-20200827-C01379
    Figure US20200270303A1-20200827-C01380
    Figure US20200270303A1-20200827-C01381
    Figure US20200270303A1-20200827-C01382
    Figure US20200270303A1-20200827-C01383
    264.
    Figure US20200270303A1-20200827-C01384
    Figure US20200270303A1-20200827-C01385
    Figure US20200270303A1-20200827-C01386
    Figure US20200270303A1-20200827-C01387
    Figure US20200270303A1-20200827-C01388
  • Representative compounds of the invention also include, but are not limited to, the following compounds (example 265 to example 272 in Table 3) according to Formula X wherein R, -L2-W-L1-,
  • Figure US20200270303A1-20200827-C01389
  • R′ and G are delineated for each example in Table 3.
  • Figure US20200270303A1-20200827-C01390
  • TABLE 3
    Example # R —L2—W—L1—
    Figure US20200270303A1-20200827-C01391
         		R′ G
    265.
    Figure US20200270303A1-20200827-C01392
    Figure US20200270303A1-20200827-C01393
    Figure US20200270303A1-20200827-C01394
    Figure US20200270303A1-20200827-C01395
    Figure US20200270303A1-20200827-C01396
    266.
    Figure US20200270303A1-20200827-C01397
    Figure US20200270303A1-20200827-C01398
    Figure US20200270303A1-20200827-C01399
    Figure US20200270303A1-20200827-C01400
    Figure US20200270303A1-20200827-C01401
    267.
    Figure US20200270303A1-20200827-C01402
    Figure US20200270303A1-20200827-C01403
    Figure US20200270303A1-20200827-C01404
    Figure US20200270303A1-20200827-C01405
    Figure US20200270303A1-20200827-C01406
    268.
    Figure US20200270303A1-20200827-C01407
    Figure US20200270303A1-20200827-C01408
    Figure US20200270303A1-20200827-C01409
    Figure US20200270303A1-20200827-C01410
    Figure US20200270303A1-20200827-C01411
    269.
    Figure US20200270303A1-20200827-C01412
    Figure US20200270303A1-20200827-C01413
    Figure US20200270303A1-20200827-C01414
    Figure US20200270303A1-20200827-C01415
    Figure US20200270303A1-20200827-C01416
    270.
    Figure US20200270303A1-20200827-C01417
    Figure US20200270303A1-20200827-C01418
    Figure US20200270303A1-20200827-C01419
    Figure US20200270303A1-20200827-C01420
    Figure US20200270303A1-20200827-C01421
    271.
    Figure US20200270303A1-20200827-C01422
    Figure US20200270303A1-20200827-C01423
    Figure US20200270303A1-20200827-C01424
    Figure US20200270303A1-20200827-C01425
    Figure US20200270303A1-20200827-C01426
    272.
    Figure US20200270303A1-20200827-C01427
    Figure US20200270303A1-20200827-C01428
    Figure US20200270303A1-20200827-C01429
    Figure US20200270303A1-20200827-C01430
    Figure US20200270303A1-20200827-C01431
  • In addition, representative compounds of the invention also include, but are not limited to, the following compounds (example 273 to example 299 in Table 4) according to Formula XI, wherein R,
  • Figure US20200270303A1-20200827-C01432
  • R′ and G are delineated for each example in Table 4.
  • Figure US20200270303A1-20200827-C01433
  • TABLE 4
    Exaaws mple# R
    Figure US20200270303A1-20200827-C01434
    Figure US20200270303A1-20200827-C01435
         		R′ G
    273.
    Figure US20200270303A1-20200827-C01436
    Figure US20200270303A1-20200827-C01437
    Figure US20200270303A1-20200827-C01438
    Figure US20200270303A1-20200827-C01439
    Figure US20200270303A1-20200827-C01440
    274.
    Figure US20200270303A1-20200827-C01441
    Figure US20200270303A1-20200827-C01442
    Figure US20200270303A1-20200827-C01443
    Figure US20200270303A1-20200827-C01444
    Figure US20200270303A1-20200827-C01445
    275.
    Figure US20200270303A1-20200827-C01446
    Figure US20200270303A1-20200827-C01447
    Figure US20200270303A1-20200827-C01448
    Figure US20200270303A1-20200827-C01449
    Figure US20200270303A1-20200827-C01450
    276.
    Figure US20200270303A1-20200827-C01451
    Figure US20200270303A1-20200827-C01452
    Figure US20200270303A1-20200827-C01453
    Figure US20200270303A1-20200827-C01454
    Figure US20200270303A1-20200827-C01455
    277.
    Figure US20200270303A1-20200827-C01456
    Figure US20200270303A1-20200827-C01457
    Figure US20200270303A1-20200827-C01458
    Figure US20200270303A1-20200827-C01459
    Figure US20200270303A1-20200827-C01460
    278.
    Figure US20200270303A1-20200827-C01461
    Figure US20200270303A1-20200827-C01462
    Figure US20200270303A1-20200827-C01463
    Figure US20200270303A1-20200827-C01464
    Figure US20200270303A1-20200827-C01465
    279.
    Figure US20200270303A1-20200827-C01466
    Figure US20200270303A1-20200827-C01467
    Figure US20200270303A1-20200827-C01468
    Figure US20200270303A1-20200827-C01469
    Figure US20200270303A1-20200827-C01470
    280.
    Figure US20200270303A1-20200827-C01471
    Figure US20200270303A1-20200827-C01472
    Figure US20200270303A1-20200827-C01473
    Figure US20200270303A1-20200827-C01474
    Figure US20200270303A1-20200827-C01475
    281.
    Figure US20200270303A1-20200827-C01476
    Figure US20200270303A1-20200827-C01477
    Figure US20200270303A1-20200827-C01478
    Figure US20200270303A1-20200827-C01479
    Figure US20200270303A1-20200827-C01480
    282.
    Figure US20200270303A1-20200827-C01481
    Figure US20200270303A1-20200827-C01482
    Figure US20200270303A1-20200827-C01483
    Figure US20200270303A1-20200827-C01484
    Figure US20200270303A1-20200827-C01485
    283.
    Figure US20200270303A1-20200827-C01486
    Figure US20200270303A1-20200827-C01487
    Figure US20200270303A1-20200827-C01488
    Figure US20200270303A1-20200827-C01489
    Figure US20200270303A1-20200827-C01490
    284.
    Figure US20200270303A1-20200827-C01491
    Figure US20200270303A1-20200827-C01492
    Figure US20200270303A1-20200827-C01493
    Figure US20200270303A1-20200827-C01494
    Figure US20200270303A1-20200827-C01495
    285.
    Figure US20200270303A1-20200827-C01496
    Figure US20200270303A1-20200827-C01497
    Figure US20200270303A1-20200827-C01498
    Figure US20200270303A1-20200827-C01499
    Figure US20200270303A1-20200827-C01500
    286.
    Figure US20200270303A1-20200827-C01501
    Figure US20200270303A1-20200827-C01502
    Figure US20200270303A1-20200827-C01503
    Figure US20200270303A1-20200827-C01504
    Figure US20200270303A1-20200827-C01505
    287.
    Figure US20200270303A1-20200827-C01506
    Figure US20200270303A1-20200827-C01507
    Figure US20200270303A1-20200827-C01508
    Figure US20200270303A1-20200827-C01509
    Figure US20200270303A1-20200827-C01510
    288.
    Figure US20200270303A1-20200827-C01511
    Figure US20200270303A1-20200827-C01512
    Figure US20200270303A1-20200827-C01513
    Figure US20200270303A1-20200827-C01514
    Figure US20200270303A1-20200827-C01515
    289.
    Figure US20200270303A1-20200827-C01516
    Figure US20200270303A1-20200827-C01517
    Figure US20200270303A1-20200827-C01518
    Figure US20200270303A1-20200827-C01519
    Figure US20200270303A1-20200827-C01520
    290.
    Figure US20200270303A1-20200827-C01521
    Figure US20200270303A1-20200827-C01522
    Figure US20200270303A1-20200827-C01523
    Figure US20200270303A1-20200827-C01524
    Figure US20200270303A1-20200827-C01525
    291.
    Figure US20200270303A1-20200827-C01526
    Figure US20200270303A1-20200827-C01527
    Figure US20200270303A1-20200827-C01528
    Figure US20200270303A1-20200827-C01529
    Figure US20200270303A1-20200827-C01530
    292.
    Figure US20200270303A1-20200827-C01531
    Figure US20200270303A1-20200827-C01532
    Figure US20200270303A1-20200827-C01533
    Figure US20200270303A1-20200827-C01534
    Figure US20200270303A1-20200827-C01535
    293.
    Figure US20200270303A1-20200827-C01536
    Figure US20200270303A1-20200827-C01537
    Figure US20200270303A1-20200827-C01538
    Figure US20200270303A1-20200827-C01539
    Figure US20200270303A1-20200827-C01540
    294.
    Figure US20200270303A1-20200827-C01541
    Figure US20200270303A1-20200827-C01542
    Figure US20200270303A1-20200827-C01543
    Figure US20200270303A1-20200827-C01544
    Figure US20200270303A1-20200827-C01545
    295.
    Figure US20200270303A1-20200827-C01546
    Figure US20200270303A1-20200827-C01547
    Figure US20200270303A1-20200827-C01548
    Figure US20200270303A1-20200827-C01549
    Figure US20200270303A1-20200827-C01550
    296.
    Figure US20200270303A1-20200827-C01551
    Figure US20200270303A1-20200827-C01552
    Figure US20200270303A1-20200827-C01553
    Figure US20200270303A1-20200827-C01554
    Figure US20200270303A1-20200827-C01555
    297.
    Figure US20200270303A1-20200827-C01556
    Figure US20200270303A1-20200827-C01557
    Figure US20200270303A1-20200827-C01558
    Figure US20200270303A1-20200827-C01559
    Figure US20200270303A1-20200827-C01560
    298.
    Figure US20200270303A1-20200827-C01561
    Figure US20200270303A1-20200827-C01562
    Figure US20200270303A1-20200827-C01563
    Figure US20200270303A1-20200827-C01564
    Figure US20200270303A1-20200827-C01565
    299.
    Figure US20200270303A1-20200827-C01566
    Figure US20200270303A1-20200827-C01567
    Figure US20200270303A1-20200827-C01568
    Figure US20200270303A1-20200827-C01569
    Figure US20200270303A1-20200827-C01570
  • The present invention also features pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof. In one embodiment, the present invention features pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient. In another embodiment, the invention features methods of treating a hepatitis C infection in a subject in need of such treatment with said pharmaceutical composition.
  • In addition, the present invention features methods of using compounds of the present invention or pharmaceutically acceptable salts thereof to treat HCV infection. The methods comprise administering to an HCV patient in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • Preferably, the compound is a compound having Formula VII as described above.
  • It was unexpectedly discovered that the compounds of the invention can significantly inhibit or suppress certain HCV genotype 1 and 3 variants (e.g., genotype 1a R155K, D168E or D168V variants, genotype 1b R155K or D168V variants, or genotype 3a S138T, A166T or Q168R variants). Clinical trials and replicon cell assays have identified HCV variants that are resistant to many known protease inhibitors. For instance, the R155K variants have been shown to confer low-level resistance to telaprevir and boceprevir and confer high-level resistance to BILN 2061 and danoprevir (ITMN-191). See Bartels et al., THE JOURNAL OF INFECTIOUS DISEASES 198:800-807 (2008). See also Lu et al., ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 48:2260-2266 (2004); and Zhou et al., THE JOURNAL OF BIOLOGICAL CHEMISTRY, 282:22619-22628 (2007). Viral load rebound, which often indicates treatment failure, has been observed in patients receiving treatment with danoprevir after the R155K variants emerge. See www.natap.org/2010/AASLD/AASLD_84.htm (61th Annual Meeting of the American Association for the Study of Liver Diseases, Boston, Mass., Oct. 30-Nov. 3, 2010). Likewise, viral load rebound has been reported in patients receiving treatment with vaniprevir (MK-7009). R155K or D168V variants have been detected in these patients, suggesting resistance or reduced susceptibility of these variants to vaniprevir. See www.natap.org/2009/EASL/EASL_27.htm (EASL 44th Annual Meeting, April 2009, Copenhagen, Denmark). Moreover, HCV variants harboring R155K have been detected as the predominant quasispecies in some treatment-naïve patients. See Salloum et al., ANTIVIRAL RESEARCH 87:272-275 (2010). Accordingly, with significantly improved inhibitory activities against wild-type as well as variants, the compounds of the present invention enable an effective and broad-spectrum treatment for HCV infections.
  • In one aspect, the present invention features methods of treating HCV variants. The methods comprise administering to patients infected with or harboring such variants an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. These patients can be treatment-naïve patients or treatment-experienced patients. In one embodiment, the patient receiving treatment according to this aspect of the invention harbors a variant selected from genotype 1a R155K, D168E or D168V variants, genotype 1b R155K or D168V variants, or genotype 3a A166T or Q168R variants. In another embodiment, the patient harbors an HCV variant selected from genotype 1 R155K or D168V variants or genotype 3 Q168R variants. For example, the patient can harbor a variant selected from genotype 1a R155K or D168V variants, genotype 1b R155K or D168V variants, or genotype 3s Q168R variants. In yet another embodiment, the patient harbors a variant selected from genotype 1 R155K or D168V variants, e.g., genotype 1a R155K or D168V variants or genotype 1b R155K or D168V variants. In one example, the patient harbors a genotype 1 R155K variant (e.g., a genotype 1a or 1b R155K variant). In another example, the patient harbors a genotype 1 D168V variant (e.g., a genotype 1a or 1b D168V variant).
  • The patients treated according to this aspect of the invention may have previously received but failed a treatment regimen containing another HCV protease inhibitor. The other HCV protease inhibitor(s) used in the prior treatment can be selected from, for example and without limitation, telaprevir, boceprevir, danoprevir, vaniprevir, narlaprevir, TMC-435 (Tibotec), BILN 2061 (Boehringer Ingelheim), BI-201335 (Boehringer Ingelheim), BMS-650032 (BMS), or a combination thereof.
  • Preferably, the compound employed in this aspect of the invention is a compound having Formula VII as described above or a pharmaceutically acceptable salt thereof. More preferably, the compound employed in this aspect of the invention is selected from compounds of Examples 1, 2, 4, 5, 6, 8, 34, 36, 40, 65, 89, 90, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, or 297, or pharmaceutically acceptable salts thereof. Highly preferably, the compound employed in this aspect of the invention is selected from compounds of Examples 5, 6, 275, 276, 287, 288, 289, 294, 296 or 297, or pharmaceutically acceptable salts thereof.
  • In another aspect, the present invention features methods of treating HCV patients who have previously received a treatment regimen containing another HCV protease inhibitor. The methods comprise administering to said patients an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. Without limiting the present invention to any particular theory, these treatment-experienced patients may harbor resistant variants or be prone to HCV mutations and, as a result, be less responsive to other protease inhibitors (e.g., telaprevir, boceprevir, danoprevir, vaniprevir, narlaprevir, TMC-435 (Tibotec), BILN 2061 (Boehringer Ingelheim), BI-201335 (Boehringer Ingelheim), BMS-650032 (BMS), or a combination thereof). Preferably, the compound employed in this aspect of the invention is a compound having Formula VII as described above or a pharmaceutically acceptable salt thereof. More preferably, the compound employed in this aspect of the invention is selected from compounds of Examples 1, 2, 4, 5, 6, 8, 34, 36, 40, 65, 89, 90, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298 or 299, or pharmaceutically acceptable salts thereof. Highly preferably, the compound employed in this aspect of the invention can be selected from compounds of Examples 5, 6, 275, 276, 287, 288, 289, 294, 296 or 297, or pharmaceutically acceptable salts thereof.
  • Moreover, the present invention features methods of treating HCV patients infected with genotype 3 HCV viruses. These methods are based on the unexpected finding that the compounds of the invention are effective in inhibiting HCV genotype 3 viruses including certain variants (e.g., A166T, Q168R or S138T variants). These methods comprise administering to said patients an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. Preferably, the compound employed in this aspect of the invention is a compound having Formula VII as described above or a pharmaceutically acceptable salt thereof. More preferably, the compound employed in this aspect of the invention is selected from compounds of Examples 1, 2, 4, 5, 6, 8, 34, 36, 40, 65, 89, 90, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298 or 299, or pharmaceutically acceptable salts thereof. Highly preferably, the compound employed in this aspect of the invention can be selected from compounds of Examples 5, 6, 275, 276, 287, 288, 289, 294, 296 or 297, or pharmaceutically acceptable salts thereof.
  • The present invention also features the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medication for the treatment of HCV variants. For instance, the patients being treated may be infected with or harbor a variant selected from genotype 1a R155K, D168E or D168V variants, genotype 1b R155K or D168V variants, or genotype 3a A166T or Q168R variants. In addition, the present invention features the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medication for the treatment of treatment-experienced HCV patients who have previously received but failed a treatment containing another HCV protease inhibitor (e.g., telaprevir, boceprevir, danoprevir, vaniprevir, narlaprevir, TMC-435 (Tibotec), BILN 2061 (Boehringer Ingelheim), BI-201335 (Boehringer Ingelheim), BMS-650032 (BMS), or a combination thereof). Furthermore, the present invention contemplates the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medication for the treatment of HCV patients infected with genotype 3 HCV (including genotype 3 variants, such as genotype 3s A166T, Q168R or S138T variants).
  • In the methods described herein, a compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone, or in combination with one or more other anti-HCV agents, such as HCV polymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors, CD81 inhibitors, cyclophilin inhibitors, internal ribosome entry site (IRES) inhibitors or any combinations thereof. Interferon, ribavirin or both can also be included in the treatment. For example, the methods described herein can further comprise administering to the patient peginterferon-alpha and ribavirin. Different agents can be administered simultaneously or sequentially. The dosing frequency of each agent in a treatment regimen can be the same or different. For instance, a compound of the invention can be dosed once daily and ribavirin can be dosed twice daily.
  • Compounds of the present invention can be administered as the sole active pharmaceutical agent, or used in combination with one or more agents to treat or prevent hepatitis C infections or the symptoms associated with HCV infection. Other agents to be administered in combination with a compound or combination of compounds of the invention include therapies for disease caused by HCV infection that suppresses HCV viral replication by direct or indirect mechanisms. These include agents such as host immune modulators (for example, interferon-alpha, pegylated interferon-alpha, interferon-beta, interferon-gamma, CpG oligonucleotides and the like), cyclophilins (e.g., Debio 025), or antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase (for example, ribavirin and the like). Also included are cytokines that modulate immune function. Also included are vaccines comprising HCV antigens or antigen adjuvant combinations directed against HCV. Also included are agents that interact with host cellular components to block viral protein synthesis by inhibiting the internal ribosome entry site (IRES) initiated translation step of HCV viral replication or to block viral particle maturation and release with agents targeted toward the viroporin family of membrane proteins such as, for example, HCV P7 and the like. Other agents to be administered in combination with a compound of the present invention include any agent or combination of agents that inhibit the replication of HCV by targeting proteins of the viral genome involved in the viral replication. These agents include but are not limited to other inhibitors of HCV RNA dependent RNA polymerase such as, for example, nucleoside type polymerase inhibitors described in WO0190121(A2), or U.S. Pat. No. 6,348,587B1 or WO0160315 or WO00132153 or non-nucleoside inhibitors such as, for example, benzimidazole polymerase inhibitors described in EP 1162196A1 or WO00204425 or inhibitors of HCV protease such as, for example, peptidomimetic type inhibitors such as BILN2061 and the like or inhibitors of HCV helicase.
  • Other agents to be administered in combination with a compound of the present invention include any agent or combination of agents that inhibit the replication of other viruses for co-infected individuals. These agents include but are not limited to therapies for disease caused by hepatitis B (HBV) infection or therapies for disease caused by human immunodeficiency virus (HIV) infection.
  • Accordingly, one aspect of the invention is directed to a method for treating or preventing an infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof. Examples of the host immune modulator are, but not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamrna, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • A further aspect of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment an agent or combination of agents that treat or alleviate symptoms of HCV infection including cirrhosis and inflammation of the liver, with a therapeutically effective amount of a compound or combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof. Yet another aspect of the invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof. An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but not limited thereto, L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof. Example of the RNA-containing virus includes, but not limited to, hepatitis C virus (HCV).
  • Another aspect of the invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, or combination thereof. An example of the RNA-containing virus includes, but not limited to, hepatitis C virus (HCV). In addition, the present invention provides the use of a compound or a combination of compounds of the invention, or a therapeutically acceptable salt form, stereoisomer, or tautomer, prodrug, salt of a prodrug, or combination thereof, and one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, particularly hepatitis C virus. Examples of the host immune modulator are, but not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • When used in the above or other treatments, combination of compound or compounds of the invention, together with one or more agents as defined herein above, can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form, prodrug, salt of a prodrug, or combination thereof. Alternatively, such combination of therapeutic agents can be administered as a pharmaceutical composition containing a therapeutically effective amount of the compound or combination of compounds of interest, or their pharmaceutically acceptable salt form, prodrugs, or salts of the prodrug, in combination with one or more agents as defined hereinabove, and a pharmaceutically acceptable carrier. Such pharmaceutical compositions can be used for inhibiting the replication of an RNA-containing virus, particularly Hepatitis C virus (HCV), by contacting said virus with said pharmaceutical composition. In addition, such compositions are useful for the treatment or prevention of an infection caused by an RNA-containing virus, particularly Hepatitis C virus (HCV).
  • Hence, further aspect of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus, particularly a hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a compound or combination of compounds of the invention or a pharmaceutically acceptable salt, stereoisomer, or tautomer, prodrug, salt of a prodrug, or combination thereof, one or more agents as defined hereinabove, and a pharmaceutically acceptable carrier.
  • When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or within a predetermined period of time, or the therapeutic agents can be given as a single unit dosage form.
  • Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to, agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal. Such agents can be selected from another anti-HCV agent; an HIV inhibitor; an HAV inhibitor; and an HBV inhibitor.
  • Other anti-HCV agents include those agents that are effective for diminishing or preventing the progression of hepatitis C related symptoms or disease. Such agents include but are not limited to immunomodulatory agents, inhibitors of HCV NS3 protease, other inhibitors of HCV polymerase, inhibitors of another target in the HCV life cycle and other anti-HCV agents, including but not limited to, ribavirin, amantadine, levovirin and viramidine.
  • Immunomodulatory agents include those agents (compounds or biologicals) that are effective to enhance or potentiate the immune system response in a mammal. Immunomodulatory agents include, but are not limited to, inosine monophosphate dehydrogenase inhibitors such as VX-497 (merimepodib, Vertex Pharmaceuticals), class I interferons, class II interferons, consensus interferons, asialo-interferons pegylated interferons and conjugated interferons, including but not limited to, interferons conjugated with other proteins including but not limited to, human albumin. Class I interferons are a group of interferons that all bind to receptor type I, including both naturally and synthetically produced class I interferons, while class II interferons all bind to receptor type II. Examples of class I interferons include, but are not limited to, [alpha]-, [beta]-, [delta]-, [omega]-, and [tau]-interferons, while examples of class II interferons include, but are not limited to, [gamma]-interferons.
  • Inhibitors of HCV NS3 protease include agents (compounds or biologicals) that are effective to inhibit the function of HCV NS3 protease in a mammal. Inhibitors of HCV NS3 protease include, but are not limited to, those compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO 2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO 2004/101605, WO 2004/103996, WO 2005/028501, WO 2005/070955, WO 2006/000085, WO 2006/007700 and WO 2006/007708 (all by Boehringer Ingelheim), WO 02/060926, WO 03/053349, WO03/099274, WO 03/099316, WO 2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712, WO 2005/051410, WO 2005/054430 (all by BMS), WO 2004/072243, WO 2004/093798, WO 2004/113365, WO 2005/010029 (all by Enanta), WO 2005/037214 (Intermune) and WO 2005/051980 (Schering), and the candidates identified as VX-950, ITMN-191 and SCH 503034.
  • Inhibitors of HCV polymerase include agents (compounds or biologicals) that are effective to inhibit the function of an HCV polymerase. Such inhibitors include, but are not limited to, non-nucleoside and nucleoside inhibitors of HCV NS5B polymerase. Examples of inhibitors of HCV polymerase include but are not limited to those compounds described in: WO 02/04425, WO 03/007945, WO 03/010140, WO 03/010141, WO 2004/064925, WO 2004/065367, WO 2005/080388 and WO 2006/007693 (all by Boehringer Ingelheim), WO 2005/049622 (Japan Tobacco), WO 2005/014543 (Japan Tobacco), WO 2005/012288 (Genelabs), WO 2004/087714 (IRBM), WO 03/101993 (Neogenesis), WO 03/026587 (BMS), WO 03/000254 (Japan Tobacco), and WO 01/47883 (Japan Tobacco), and the clinical candidates XTL-2125, HCV 796, R-1626 and NM 283.
  • Inhibitors of another target in the HCV life cycle include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of HCV other than by inhibiting the function of the HCV NS3 protease. Such agents may interfere with either host or HCV viral mechanisms necessary for the formation and/or replication of HCV. Inhibitors of another target in the HCV life cycle include, but are not limited to, entry inhibitors, agents that inhibit a target selected from a helicase, a NS2/3 protease and an internal ribosome entry site (IRES) and agents that interfere with the function of other viral targets including but not limited to, an NS5A protein and an NS4B protein.
  • It can occur that a patient may be co-infected with hepatitis C virus and one or more other viruses, including but not limited to, human immunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis B virus (HBV). Thus, also contemplated is combination therapy to treat such co-infections by co-administering a compound according to the present invention with at least one of an HIV inhibitor, an HAV inhibitor and an HBV inhibitor.
  • According to yet another embodiment, the pharmaceutical compositions of the present invention may further comprise inhibitor(s) of other targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, and internal ribosome entry site (IRES).
  • According to another embodiment, the pharmaceutical compositions of the present invention may further comprise another anti-viral, anti-bacterial, anti-fungal or anti-cancer agent, or an immune modulator, or another therapeutic agent.
  • According to still another embodiment, the present invention includes methods of treating viral infection such as, but not limited to, hepatitis C infections in a subject in need of such treatment by administering to said subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • According to a further embodiment, the present invention includes methods of treating hepatitis C infections in a subject in need of such treatment by administering to said subject an anti-HCV virally effective amount or an inhibitory amount of a pharmaceutical composition of the present invention.
  • An additional embodiment of the present invention includes methods of treating biological samples by contacting the biological samples with the compounds of the present invention.
  • Yet a further aspect of the present invention is a process of making any of the compounds delineated herein employing any of the synthetic means delineated herein.
    • Definitions
  • Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.
  • The term “viral infection” refers to the introduction of a virus into cells or tissues, e.g., hepatitis C virus (HCV). In general, the introduction of a virus is also associated with replication.
  • Viral infection may be determined by measuring virus antibody titer in samples of a biological fluid, such as blood, using, e.g., enzyme immunoassay. Other suitable diagnostic methods include molecular based techniques, such as RT-PCR, direct hybrid capture assay, nucleic acid sequence based amplification, and the like. A virus may infect an organ, e.g., liver, and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease and hepatocellular carcinoma.
  • The term “anti-cancer agent” refers to a compound or drug capable of preventing or inhibiting the advancement of cancer. Examples of such agents include cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine, cyclosporin A, phenothiazines or thioxantheres.
  • The term “anti-fungal agent” shall used to describe a compound which may be used to treat a fungus infection other than 3-AP, 3-AMP or prodrugs of 3-AP and 3-AMP according to the present invention. Anti-fungal agents according to the present invention include, for example, terbinafine, fluconazole, itraconazole, posaconazole, clotrimazole, griseofulvin, nystatin, tolnaftate, caspofungin, amphotericin B, liposomal amphotericin B, and amphotericin B lipid complex.
  • The term “antibacterial agent” refers to both naturally occurring antibiotics produced by microorganisms to suppress the growth of other microorganisms, and agents synthesized or modified in the laboratory which have either bactericidal or bacteriostatic activity, e.g., β-lactam antibacterial agents, glycopeptides, macrolides, quinolones, tetracyclines, and aminoglycosides. In general, if an antibacterial agent is bacteriostatic, it means that the agent essentially stops bacterial cell growth (but does not kill the bacteria); if the agent is bacteriocidal, it means that the agent kills the bacterial cells (and may stop growth before killing the bacteria).
  • The term “immune modulator” refers to any substance meant to alter the working of the humoral or cellular immune system of a subject. Such immune modulators include inhibitors of mast cell-mediated inflammation, interferons, interleukins, prostaglandins, steroids, cortico-steroids, colony-stimulating factors, chemotactic factors, etc.
  • The term “C1-C6 alkyl,” or “C1-C8 alkyl,” as used herein, refer to saturated, straight- or branched-chain hydrocarbon radicals containing between one and six, or one and eight carbon atoms, respectively. Examples of C1-C6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl radicals; and examples of C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals.
  • The term “C2-C6 alkenyl,” or “C2-C8 alkenyl,” as used herein, denote a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety has at least one carbon-carbon double bond and contains from two to six, or two to eight carbon atoms, respectively. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl and the like.
  • The term “C2-C6 alkynyl,” or “C2-C8 alkynyl,” as used herein, denote a monovalent group derived from a hydrocarbon moiety by the removal of a single hydrogen atom wherein the hydrocarbon moiety has at least one carbon-carbon triple bond and contains from two to six, or two to eight carbon atoms, respectively. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • The term “carbocycle” refers to a saturated (e.g., “cycloalkyl”), partially saturated (e.g., “cycloalkenyl” or “cycloalkynyl”) or completely unsaturated (e.g., “aryl”) ring system containing zero heteroatom ring atom. “Ring atoms” or “ring members” are the atoms bound together to form the ring or rings. Where a carbocycle group is a divalent moiety linking two other elements in a depicted chemical structure (such as Z in Formula IA), the carbocycle group can be attached to the two other elements through any two substitutable ring atoms. A C4-C6 carbocycle has 4-6 ring atoms.
  • The term “C3-C8-cycloalkyl”, or “C3-C12-cycloalkyl,” as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom where the saturated carbocyclic ring compound has from 3 to 8, or from 3 to 12, ring atoms, respectively. Examples of C3-C8-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C3-C12-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl.
  • The term “C3-C8-cycloalkenyl”, or “C3-C12-cycloalkenyl” as used herein, denote a monovalent group derived from a monocyclic or polycyclic carbocyclic ring compound having at least one carbon-carbon double bond by the removal of a single hydrogen atom where the carbocyclic ring compound has from 3 to 8, or from 3 to 12, ring atoms, respectively. Examples of C3-C8-cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples of C3-C12-cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.
  • The term “aryl,” as used herein, refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.
  • The term “arylalkyl,” as used herein, refers to a C1-C3 alkyl or C1-C6 alkyl residue attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl and the like.
  • The term “heteroaryl,” as used herein, refers to a mono-, bi-, or tri-cyclic aromatic radical or ring having from five to ten ring atoms of which at least one ring atom is selected from S, O and N; wherein any N or S contained within the ring may be optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.
  • The term “heteroarylalkyl,” as used herein, refers to a C1-C3 alkyl or C1-C6 alkyl residue residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like.
  • The term “substituted” as used herein, refers to independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to, —F, —Cl, —Br, —I, —OH, protected hydroxy, —NO2, —CN, —NH2, N3, protected amino, alkoxy, thioalkoxy, oxo, -halo-C1-C12-alkyl, -halo-C2-C12-alkenyl, -halo-C2-C12-alkynyl, -halo-C3-C12-cycloalkyl, —NH—C1-C12-alkyl, —NH—C2-C12-alkenyl, —NH—C2-C12-alkynyl, —NH—C3-C12-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, —O—C1-C12-alkyl, —O—C2-C12-alkenyl, —O—C2-C12-alkynyl, —O—C3-C12-cycloalkyl, —O-aryl, —O— heteroaryl, —O-heterocycloalkyl, —C(O)— C1-C12-alkyl, —C(O)— C2-C12-alkenyl, —C(O)— C2-C12-alkynyl, —C(O)—C3-C12-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH2, —CONH— C1-C12-alkyl, —CONH— C2-C12-alkenyl, —CONH— C2-C12-alkynyl, —CONH—C3-C12-cycloalkyl, —CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO2— C1-C12-alkyl, —OCO2— C2-C12-alkenyl, —OCO2— C2-C12-alkynyl, —OCO2—C3-C12-cycloalkyl, —OCO2-aryl, —OCO2-heteroaryl, —OCO2-heterocycloalkyl, —OCONH2, —OCONH— C1-C12-alkyl, —OCONH— C2-C12-alkenyl, —OCONH— C2-C12-alkynyl, —OCONH— C3-C12-cycloalkyl, —OCONH— aryl, —OCONH— heteroaryl, —OCONH— heterocycloalkyl, —NHC(O)— C1-C12-alkyl, —NHC(O)—C2-C12-alkenyl, —NHC(O)—C2-C12-alkynyl, —NHC(O)—C3-C12-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO2— C1-C12-alkyl, —NHCO2— C2-C12-alkenyl, —NHCO2— C2-C12-alkynyl, —NHCO2— C3-C12-cycloalkyl, —NHCO2— aryl, —NHCO2— heteroaryl, —NHCO2— heterocycloalkyl, —NHC(O)NH2, —NHC(O)NH— C1-C12-alkyl, —NHC(O)NH—C2-C12-alkenyl, —NHC(O)NH—C2-C12-alkynyl, —NHC(O)NH—C3-C12-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH— heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH2, —NHC(S)NH— C1-C12-alkyl, —NHC(S)NH—C2-C12-alkenyl, —NHC(S)NH—C2-C12-alkynyl, —NHC(S)NH—C3-C12-cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH2, —NHC(NH)NH—C1-C12-alkyl, —NHC(NH)NH—C2-C12-alkenyl, —NHC(NH)NH—C2-C12-alkynyl, —NHC(NH)NH—C3-C12-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C1-C12-alkyl, —NHC(NH)—C2-C12-alkenyl, —NHC(NH)—C2-C12-alkynyl, —NHC(NH)—C3-C12-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)— heteroaryl, —NHC(NH)-heterocycloalkyl, —C(NH)NH—C1-C12-alkyl, —C(NH)NH—C2-C12-alkenyl, —C(NH)NH—C2-C12-alkynyl, —C(NH)NH—C3-C12-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH— heteroaryl, —C(NH)NH-heterocycloalkyl, —S(O)—C1-C12-alkyl, —S(O)—C2-C12-alkenyl, —S(O)—C2-C12-alkynyl, —S(O)—C3-C12-cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO2NH2, —SO2NH—C1-C12-alkyl, —SO2NH—C2-C12-alkenyl, —SO2NH—C2-C12-alkynyl, —SO2NH—C3-C12-cycloalkyl, —SO2NH-aryl, —SO2NH-heteroaryl, —SO2NH-heterocycloalkyl, —NHSO2—C1—C12-alkyl, —NHSO2—C2-C12-alkenyl, —NHSO2—C2-C12-alkynyl, —NHSO2—C3-C12-cycloalkyl, —NHSO2-aryl, —NHSO2-heteroaryl, —NHSO2-heterocycloalkyl, —CH2NH2, —CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C3-C12-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S—C1-C12-alkyl, —S—C2-C12-alkenyl, —S—C2-C12-alkynyl, —S—C3-C12-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, methylthiomethyl, or -L′-R′, wherein L′ is C1-C6alkylene, C2-C6alkenylene or C2-C6alkynylene, and R′ is aryl, heteroaryl, heterocyclic, C3-C12cycloalkyl or C3-C12cycloalkenyl. It is understood that the aryls, heteroaryls, alkyls, and the like can be further substituted. In some cases, each substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from —F, —Cl, —Br, —I, —OH, —NO2, —CN, or —NH2.
  • In accordance with the invention, any of the aryls, substituted aryls, heteroaryls and substituted heteroaryls described herein, can be any aromatic group. Aromatic groups can be substituted or unsubstituted.
  • It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl moiety described herein can also be an aliphatic group, an alicyclic group or a heterocyclic group. An “aliphatic group” is non-aromatic moiety that may contain any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contain one or more units of unsaturation, e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is understood that aliphatic groups may be used in place of the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylene groups described herein.
  • The term “alicyclic,” as used herein, denotes a monovalent group derived from a monocyclic or polycyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be further substituted.
  • The term “heterocycloalkyl” and “heterocyclic” can be used interchangeably and refer to a non-aromatic 3-, 4-, 5-, 6- or 7-membered ring or a bi- or tri-cyclic group fused system, where: (i) each ring contains between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to a benzene ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted. Representative heterocycloalkyl groups include, but are not limited to, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted to give substituted heterocyclic.
  • It will be apparent that in various embodiments of the invention, the substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl are intended to be monovalent or divalent. Thus, alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene, cycloalkynylene, arylalkylene, hetoerarylalkylene and heterocycloalkylene groups are to be included in the above definitions, and are applicable to provide the formulas herein with proper valency.
  • The term “hydroxy activating group”, as used herein, refers to a labile chemical moiety which is known in the art to activate a hydroxy group so that it will depart during synthetic procedures such as in a substitution or elimination reactions. Examples of hydroxy activating group include, but not limited to, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate and the like.
  • The term “activated hydroxy”, as used herein, refers to a hydroxy group activated with a hydroxy activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.
  • The term “protected hydroxy,” as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups.
  • The terms “halo” and “halogen,” as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques, which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
  • The term “subject” as used herein refers to a mammal. A subject therefore refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like. Preferably the subject is a human. When the subject is a human, the subject may be referred to herein as a patient. As used herein, the term “pharmaceutically acceptable salt” refers to those salts of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.
  • The term “hydroxy protecting group,” as used herein, refers to a labile chemical moiety which is known in the art to protect a hydroxy group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the are described generally in T. H. Greene and P. G., S. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl, 2-(trimethyl silyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like. Preferred hydroxy protecting groups for the present invention are acetyl (Ac or —C(O)CH3), benzoyl (Bz or —C(O)C6H5), and trimethylsilyl (TMS or —Si(CH3)3). Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts e.g., salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • The term “amino protecting group,” as used herein, refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the are described generally in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.
  • As used herein, the term “pharmaceutically acceptable ester” refers to esters of the compounds formed by the process of the present invention which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • The term “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds formed by the process of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention. “Prodrug”, as used herein means a compound, which is convertible in vivo by metabolic means (e.g. by hydrolysis) to afford any compound delineated by the formulae of the instant invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).
  • The term “aprotic solvent,” as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, N Y, 1986.
  • The terms “protogenic organic solvent” or “protic solvent” as used herein, refer to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, N Y, 1986.
  • Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable”, as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and variation of the reaction conditions can produce the desired bridged macrocyclic products of the present invention. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).
  • The compounds of this invention may be modified by appending various functionalities via synthetic means delineated herein to enhance selective biological properties. Such modifications include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
    • Pharmaceutical Compositions
  • The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term “pharmaceutically acceptable carrier” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.
  • The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
  • The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
    • Antiviral Activity
  • An inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
  • According to the methods of treatment of the present invention, viral infections are treated or prevented in a subject such as a human or lower mammal by administering to the subject an anti-hepatitis C virally effective amount or an inhibitory amount of a compound of the present invention, in such amounts and for such time as is necessary to achieve the desired result. An additional method of the present invention is the treatment of biological samples with an inhibitory amount of a compound of composition of the present invention in such amounts and for such time as is necessary to achieve the desired result.
  • The term “anti-hepatitis C virally effective amount” of a compound of the invention, as used herein, mean a sufficient amount of the compound so as to decrease the viral load in a biological sample or in a subject (e.g., resulting in at least 10%, preferably at least 50%, more preferably at least 80%, and most preferably at least 90% or 95%, reduction in viral load). As well understood in the medical arts, an anti-hepatitis C virally effective amount of a compound of this invention will be at a reasonable benefit/risk ratio applicable to any medical treatment.
  • The term “inhibitory amount” of a compound of the present invention means a sufficient amount to decrease the hepatitis C viral load in a biological sample or a subject (e.g., resulting in at least 10%, preferably at least 50%, more preferably at least 80%, and most preferably at least 90% or 95%, reduction in viral load). It is understood that when said inhibitory amount of a compound of the present invention is administered to a subject it will be at a reasonable benefit/risk ratio applicable to any medical treatment as determined by a physician. The term “biological sample(s),” as used herein, means a substance of biological origin intended for administration to a subject. Examples of biological samples include, but are not limited to, blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, and the like; sperm and ova; bone marrow and components thereof; or stem cells. Thus, another embodiment of the present invention is a method of treating a biological sample by contacting said biological sample with an inhibitory amount of a compound or pharmaceutical composition of the present invention.
  • Upon improvement of a subject's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. The subject may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • 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 inhibitory dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; 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; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • The total daily inhibitory dose of the compounds of this invention administered to a subject in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art. All publications, patents, published patent applications, and other references mentioned herein are hereby incorporated by reference in their entirety.
    • Abbreviations
  • Abbreviations which have been used in the descriptions of the schemes and the examples that follow are:
      • ACN for acetonitrile;
      • BME for 2-mercaptoethanol;
      • BOP for benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate;
      • CDI for carbonyldiimidazole;
      • COD for cyclooctadiene;
      • DAST for diethylaminosulfur trifluoride;
      • DABCYL for 6-(N-4′-carboxy-4-(dimethylamino)azobenzene)-aminohexyl-1-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite;
      • DBU for 1,8-Diazabicycloundec-7-ene;
      • DCC for N, N′-dicyclohexylcarbodiimide;
      • DCM for dichloromethane;
      • DIAD for diisopropyl azodicarboxylate;
      • DIBAL-H for diisobutylaluminum hydride;
      • DIPEA for diisopropyl ethylamine;
      • DMAP for N,N-dimethylaminopyridine;
      • DME for ethylene glycol dimethyl ether;
      • DMEM for Dulbecco's Modified Eagles Media;
      • DMF for N,N-dimethyl formamide;
      • DMSO for dimethylsulfoxide;
      • DSC for N, N′-disuccinimidyl carbonate;
      • DUPHOS for
  • Figure US20200270303A1-20200827-C01571
      • EDANS for 5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid;
      • EDCI or EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride;
      • EtOAc for ethyl acetate;
      • EtOH for ethyl alcohol;
      • HATU for O (7-Azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate;
      • HCl for hydrochloric acid;
      • Hoveyda's Cat. for Dichloro(o-isopropoxyphenylmethylene) (tricyclohexylphosphine)ruthenium(II);
      • In for indium;
      • KHMDS is potassium bis(trimethylsilyl) amide;
      • Ms for mesyl;
      • NMM for N-4-methylmorpholine;
      • NMO for N-4-methylmorpholine-N-Oxide;
      • PyBrOP for Bromo-tri-pyrolidino-phosphonium hexafluorophosphate;
      • Ph for phenyl;
      • RCM for ring-closing metathesis;
      • RT for reverse transcription;
      • RT-PCR for reverse transcription-polymerase chain reaction;
      • TBME for tert-butyl methyl ether;
      • TEA for triethyl amine;
      • TFA for trifluoroacetic acid;
      • THF for tetrahydrofuran;
      • TLC for thin layer chromatography;
      • TPAP tetrapropylammonium perruthenate;
      • TPP or PPh3 for triphenylphosphine;
      • tBOC or Boc for tert-butyloxy carbonyl;
      • Xantphos for 4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene; and
      • Zhan 1 B for
  • Figure US20200270303A1-20200827-C01572
  • Synthetic Methods
  • The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes that illustrate the methods by which the compounds of the invention may be prepared, which are intended as an illustration only and not to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.
  • The preparation of quinoxalinyl macrocyclic compounds is exemplified in Scheme 1. The Boc group of quinoxaline derivative 1-1 (see Scheme 2 for preparation) was deprotected under acidic condition at room temperature (the acid can be selected from, but not limited to, HCl in dioxane or HCl in ethyl acetate or TFA. For further details on deprotection of Boc group see: T. W. Greene, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley and Sons, 2006) to give the amine 1-2, which is coupled with acid 1-3 employing peptide coupling reagent (the coupling reagent can be selected from, but not limited to, HATU/DIPEA, DCC/DMAP, for further details on peptide coupling reagents see: Christian A. G. N. Montalbetti et al., Tetrahedron 2005, 61, 10827) to afford the diene 1-4. Ring-closing metathesis of diene 1-4 with a ruthenium-based catalyst gives the desired macrocyclic alkene 1-5 (for further details on ring-closing metathesis see recent reviews: Grubbs et al., Acc. Chem. Res., 1995, 28, 446; Shrock et al., Tetrahedron 1999, 55, 8141; Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012; Trnka et al., Acc. Chem. Res. 2001, 34, 18, and Hoveyda et al., Chem. Eur. J. 2001, 7, 945).
  • Figure US20200270303A1-20200827-C01573
    • Wherein R′, R, G and
  • Figure US20200270303A1-20200827-C01574
  • are previously defined as in Formula I.
  • The hydrolysis of the macrocyclic ester 1-5 to the corresponding acid 1-6 could be effected with inorganic base, such as, but not limited to LiOH, NaOH, KOH. The resulted acid 1-6 is coupled with amine 1-7 employing amide coupling reagent (the coupling reagent can be selected from, but not limited to, HATU, DCC and HOBT in the presence of organic base such as, but not limited to, DIEPA, TEA, DMAP; for further details on amide formation see recent review: Christian A. G. N. Montalbetti et al., Tetrahedron 2005, 61, 10827) to afford amide 1-8 or 1-9. Alternatively, amide 1-8 can be prepared from the acid 1-10, which is synthesized from the hydrolysis of the ester 1-8. The acid 1-9 was activated with CDI and followed by coupling with sulfonamide 1-11 in presence of organic base such as, but not limited to DBU to provide the title compound 1-8.
  • Figure US20200270303A1-20200827-C01575
  • The synthesis of quinoxaline derivative 1-1 is exemplified in Scheme 2. The bromide 2-2 was coupled with aldehyde 2-1 employing metal such as, but not limited to In, Zn, Mg or Cr to afford the hydroxyl ester 2-3, which was further oxidized to give the ketone ester 2-4 with oxidation reagent such a, but not limited to TPAP/NMO. Alternatively, the synthesis of ketone ester 2-4 could be effected through lithium halogen exchange of bromide 2-2 followed by coupling with ester 2-5 (this precedure could also be applied to acid chloride 2-6 or the Weinreb amide 2-7) to afford the ketone ester 2-4. Yet another alternative procedure is that the bromide 2-2 was treated with metal such as, but not limited to In, Zn or Mg and then reacted with acid chloride 2-6 or ester 2-5 or Weinreb amide 2-7 to give the ketone ester 2-4. The ketone ester 2-4 was condensed with diamine 2-8 to afford the quinoxaline 2-9. The hydroxyl quinoxaline 2-9 was converted into chloroquinoxaline 3-3 utilizing chlorination reagent such as but not limited to, POCl3, which was coupled with commercially available N-Boc-trans-4-hydroxy-L-proline 2-11 and followed by esterification to give the quinoxaline derivative 1-1. Alternatively, compound 1-1 could be synthesized from the Mitsunobu reaction of commercially available alcohol 2-12 with quinoxaline 2-9. For further details on the Mitsunobu reaction, see O. Mitsunobu, Synthesis 1981, 1-28; D. L. Hughes, Org. React. 1983, 29, 1; D. L. Hughes, Organic Preparations and Procedures Int. 1996, 28, 127; and J. A. Dodge, S. A. Jones, Recent Res. Dev. Org. Chem. 1997, 1, 273; K. C. Kumara Swamy et. al., Chem. Rev. 2009, 109, 2551.
  • Figure US20200270303A1-20200827-C01576
  • wherein
  • Figure US20200270303A1-20200827-C01577
  • is previously defined as in Formula I.
  • The synthesis of acid 1-3 commenced with acylation of the racemic diol 3-1 to afford the diacetate 3-2 (for hydroxyl acylation see: T. W. Greene, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley and Sons, 2006). The kinetic resolution of the diacetate 3-2 was achieved by partial deacetylation with enzyme such as, but not limited to, Amano lipase to give the mono acetate 3-3 (M. P. Schneider et al., J. Chem. Soc., Chem. Commun., 1991, 49; for further information on kinetic resolution see: H. Pellissier, Tetrahedron, 2008, 64, 1563).
  • Allylation of monoacetate compound 3-3 affords allyl ether 3-4, which was hydrolyzed with inorganic base such as, but not limited to, LiOH, NaOH to afford the alcohol 3-5. Upon the chloroformation by treating alcohol 3-5 with COCl2, followed by coupling with amino acid 3-6 to provide the acid 1-3. Moreover, the allyl ether 3-5 could also be obtained when optical pure diol 3-1 was deprotonated with NaH followed by coupling with allyl bromide.
  • Figure US20200270303A1-20200827-C01578
  • wherein R′ and
  • Figure US20200270303A1-20200827-C01579
  • are previously defined as in Formula I.
  • The alternative routes for synthesis of macrocyclic ester 1-5 have been exemplified in Scheme 4. There are many other synthetic routes to this intermediate 1-5, some precursors are shown in Scheme 4. For example, the macrocyclic ester 1-5 could be obtained via the amide bond formation in acid 4-1 (for further details on amide bond formation see recent review: Christian A. G. N. Montalbetti et al., Tetrahedron 2005, 61, 10827); Pd catalyzed intramolecular allylation in allylic Boc derivative 4-2 (Guoqiang Wang et al., Org. Lett., 2004, 6, 4455); the deprotection of Boc group (for carbamate deprotection see: T. W. Greene, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley and Sons, 2006) followed by carbamate formation in succinimidyl carbonate 4-3 (J. V. Eycken, J. Org. Chem., 2007, 72, 5514); base catalyzed ether formation in alcohol 4-4 and Mitsunobu type ether formation in hydroxyl quinoxaline 4-5 (for further details on the Mitsunobu reaction, see O. Mitsunobu, Synthesis 1981, 1-28; D. L. Hughes, Org. React. 1983, 29, 1; D. L. Hughes, Organic Preparations and Procedures Int. 1996, 28, 127; and J. A. Dodge, S. A. Jones, Recent Res. Dev. Org. Chem. 1997, 1, 273; K. C. Kumara Swamy et. al., Chem. Rev. 2009, 109, 2551).
  • Figure US20200270303A1-20200827-C01580
  • wherein
  • Figure US20200270303A1-20200827-C01581
  • is previously defined as in Formula I.
  • The synthesis of acid 4-1 has been exemplified in Scheme 5. The cross-metathesis of quinoxaline derivative 1-1 and allyl ether 3-5 leads to the alcohol 5-1 (for further details on cross metathesis see: Grubbs et al. J. Am. Chem. Soc. 2003, 125, 11360; R. Raju et al. Org. Lett. 2006, 8, 2139; Y. Schrodi et al. Aldrichimica Acta 2007, 40, 45). This alcohol 5-1 was treated with phosgene (or some other reagent such as, but not limited to triphosgene, diphosgene, carbonyldiimidazole) followed by coupling with amino acid 3-6 in the present of base such as, but not limited to LiOH or NaOH. The deprotection of Boc group in acid 5-2 (for carbamate deprotection see: T. W. Greene, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley and Sons, 2006) affords the acid 4-1.
  • Figure US20200270303A1-20200827-C01582
  • wherein R, R″ and
  • Figure US20200270303A1-20200827-C01583
  • are previously defined as in Formula I.
  • The synthesis of quinoxalinyl derivative 4-3 has been exemplified in Scheme 6. The deprotection of Boc group (T. W. Greene, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley and Sons, 2006) in ester 5-1 provides the corresponding amine, which is coupled with amino acid 6-1 utilizing peptide coupling reagent such as, but not limited to HATU, or DCC or BOP (for further details on peptide coupling see: Christian A. G. N. Montalbetti et al., Tetrahedron 2005, 61, 10827) to afford the alcohol 6-2. The activation of hydroxyl group in alcohol 6-2 is achieved when treated with DSC/TEA to afford the succinimidyl carbonate 4-3 (for application of DSC in carbamate formation see: J. V. Eycken, J. Org. Chem., 2007, 72, 5514).
  • Figure US20200270303A1-20200827-C01584
  • wherein R, R″ and
  • Figure US20200270303A1-20200827-C01585
  • are previously defined as in Formula I.
  • The synthesis of quinoxalinyl derivative 4-2 has been exemplified in Scheme 7. The deprotection of Boc group (T. W. Greene, Protective Groups in Organic Synthesis, Fourth Edition, John Wiley and Sons, 2006) of ester compound 1-1 provides the corresponding acid, which is coupled with amino acid 6-1 utilizing peptide coupling reagent such as, but not limited to HATU, or DCC or BOP (for further details on peptide coupling see: Christian A. G. N. Montalbetti et al., Tetrahedron 2005, 61, 10827) to afford the alcohol 7-1. The Boc group in compound 7-1 was removed under acidic condition and the resulted amine was treated with phosgene or other reagent such as, but not limited to triphosgene or diphosgene or carbonyldi-imidazole in the presence of base such as, but not limited to pyridine or DMAP to afford the isocyanate 7-2. This isocyanate 7-2 was coupled with diol 7-3 in the presence of organic base such as, but not limited to DBU to provide the mono alcohol 7-4. Cross metathesis of alkene 7-4 and protected diol 7-5 in the presence of catalyst provides the alcohol 4-2 (for further details on cross metathesis see: Grubbs et al. J. Am. Chem. Soc. 2003, 125, 11360; R. Raju et al. Org. Lett. 2006, 8, 2139; Y. Schrodi et al. Aldrichimica Acta 2007, 40, 45).
  • Figure US20200270303A1-20200827-C01586
  • wherein R, R″ and
  • Figure US20200270303A1-20200827-C01587
  • are previously defined as in Formula I.
  • The synthesis of quinoxalinyl derivative 4-4 has been exemplified in Scheme 8. The alcohol 3-5 is treated with phosgene or other reagent such as, but not limited to triphosgene or diphosgene or carbonyldi-imidazole and then coupled with amine 8-1 in the presence of base such as, but not limited to NaOH to afford the alkene 8-2, which will undergo cross metathesis with quinoxalinyl derivative 2-10 to provide the t-butyl ester 8-3 (for further details on cross metathesis see: Grubbs et al. J. Am. Chem. Soc. 2003, 125, 11360; R. Raju et al. Org. Lett. 2006, 8, 2139; Y. Schrodi et al. Aldrichimica Acta 2007, 40, 45). The t-butyl group in compound 8-3 was deprotected under acidic condition (the acid is selected from, but not limited to HCl or TFA) and this is followed by coupling with amine 8-4 utilizing peptide coupling reagents (for further details on peptide coupling see: Christian A. G. N. Montalbetti et al., Tetrahedron 2005, 61, 10827) to afford the quinoxalinyl compound 4-4.
  • Figure US20200270303A1-20200827-C01588
  • wherein R and
  • Figure US20200270303A1-20200827-C01589
  • is previously defined as in Formula I.
  • The synthesis of quinoxalinyl derivative 4-5 has been exemplified in Scheme 9. Analogous to the synthesis of intermediate 8-3, the cross metathesis of t-butyl ester 8-2 and quinoxalinyl derivative 2-9 provides the t-butyl ester 9-1. The removal of t-butyl group in 9-1 could be achieved under acidic condition (HCl) to afford the acid 9-2, which undergoes coupling with amine 9-3 employing peptide coupling reagent such as, but not limited to HATU/DIPEA to provide the intermediate 4-5.
    • EXAMPLES
  • The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations 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
  • Compound of Formula VIII, wherein
  • Figure US20200270303A1-20200827-C01590
    • Step 1a
  • Figure US20200270303A1-20200827-C01591
  • To the solution of 3-bromo-3,3-difluoroprop-1-ene 2-2 (5.61 g, 35.74 mmol) and ethyl glyoxalate 2-1 (6.52 ml, 42.9 mmol, 50% in toluene) in DMF (80 ml) and water (20 ml) was added Indium powder. The resulted mixture was stirred vigorously for 6 h, and then diluted with TBME, the mixture was filtered and washed with water, brine, dried and concentrated in vacuo to afford the crude product 2-3 (6.21 g). This material was used directly to next step without further purification.
  • To the crude ethyl 3,3-difluoro-2-hydroxypent-4-enoate 2-3 (4.9 g, 27.20 mmol) in DCM (150 ml) was added TPAP (240 mg, 0.68 mmol) and NMO (11.03 g, 81.61 mmol). The suspension was stirred at rt for 5h, and then diluted with DCM, washed with water, brine, dried and concentrated in vacuo to afford the crude ketone ester 2-4. This material was used directly to next step without further purification.
    • Step 1b
  • Figure US20200270303A1-20200827-C01592
  • To the solution of crude ethyl 3,3-difluoro-2-oxopent-4-enoate 2-4 (prepared from 35.74 mmol of 3-bromo-3,3-difluoroprop-1-ene) in EtOH (200 ml) was added o-benzene-1,2-diamine 2-8 (4.64 g, 42.89 mmol). The resulted mixture was heated to reflux for 14 h and then cool down to rt, the solid was collected by filtration and washed with cold EtOH to give quinoxaline 2-9 (2.81 g) after drying. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on CombiFlash with Hexane to 30% acetone in hexane to afford another portion of quinoxaline 2-9 (0.43 g). MS (ESI): m/z=223.09 [M+H].
    • Step 1c
  • Figure US20200270303A1-20200827-C01593
  • To 3-(1,1-difluoroallyl)quinoxalin-2-ol 2-9 (2.31 g, 10.40 mmol) was added POCl3 (10.8 ml) and DMF (1.1 ml), the resulted mixture was heated to 65° C. for 2 h. The mixture was diluted with ethyl acetate and then slowly poured into ice. After partition the organic layer was washed with water, NaHCO3 solution and brine to give the desired product 2-10 (2.45 g). This material was used directly to next step without further purification. MS (ESI): m/z=241.01 [M+H].
    • Step 1d
  • Figure US20200270303A1-20200827-C01594
  • To a solution of N-Boc-trans-4-hydroxy-L-proline 2-11 (2.404 g, 10.396 mmol) in DMF (14 ml) and THF (60 ml) at 0° C. was added t-BuONa (3.0 g, 31.189 mmol) portionwise. The reaction mixture was allowed to warm up to rt. After stirring for 1 h, the mixture was cooled down to 0° C. and 2-chloro-3-(1,1-difluoroallyl)quinoxaline 2-10 (2.45 g, -10.396 mmol) was added and warmed up to rt. After stirring for 4 h, the reaction mixture was quenched with 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (3×), and the organic layer was combined, washed with water, brine, dried and concentrated in vacuo. To the residue in DCM (50 ml) and MeOH (10 ml) was added TMSCHN2 (10.4 ml, 20.792 mmol, 2.0 M in Hexane). The solution was stirred at rt for 30 min then concentrated in vacuo. The residue was purified by flash chromatography on CombiFlash with Hexane to 30% ethyl acetate in hexane to afford desired product 1-1 (3.84 g, 82%). MS (ESI): m/z=450.24 [M+H].
    • Step 1e
  • Figure US20200270303A1-20200827-C01595
  • To a solution of (+)-cyclopentane-1,2-diol 3-1a (10.02 g, 97.159 mmol) in DCM (20 ml) and pyridine (150 ml) was added acetic anhydride (36.7 ml, 388.63 mmol) and DMAP (593 mg) portionwise. The resulted solution was stirred for 21 h, and solvent was removed in vacuo. The residue was dissolved in EtOAc, and the resulted solution was washed with 1N HCl, water, NaHCO3, water and brine. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography on CombiFlash with Hexane to 15% acetone in hexane to afford the diacetate 3-2a (17.1 g, 94%).
  • To the suspension of (+)-cyclopentane-1,2-diyl diacetate 3-2a (17.0 g, 91.3 mmol) in buffer (pH=7, 140 ml) was added Amano Lipase PS (from Burkholderia cepacia, Aldrich, 1.81 g). The resulted mixture was vigorously stirred and 1 N NaOH (65 ml) was added via an addition funnel over 18 h to keep the pH at 7. The mixture was diluted with EtOAc and water, filtered and the aqueous layer was extracted with EtOAc. The organic layer was combined, washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on CombiFlash with Hexane to 35% acetone in hexane to afford desired product 3-3a (4.6 g, 35%).
  • To a solution of (1R,2R)-2-hydroxycyclopentyl acetate 3-3a (3.42 g, 23.715 mmol) in DMF (80 ml) at 0° C. was added NaH (1.04 g, 26.087 mmol, 60% dispersion in mineral oil). The resulted mixture was warmed up to rt and stirred for 30 min, and it was cooled down to 0° C. and allyl bromide (2.2 ml, 26.087 mmol) was added. The mixture was stirred at rt for 1.5 h and quenched with NH4Cl solution at 0° C. The mixture was extracted with EtOAc (3×), and the organic layer was combined, washed with water, brine, dried (Na2SO4) and concentrated in vacuo. To the residue in MeOH (47 ml) and THF (94 ml) was added 1 N LiOH solution (47.4 ml, 47.43 mmol). The mixture was stirred for 30 min and the mixture was extracted with EtOAc (3×), and the organic layer was combined, washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on CombiFlash with Hexane to 25% acetone in hexane to afford alcohol 3-5a (1.36 g, 40%, 95.8% ee by HPLC).
    • Step 1f
  • Figure US20200270303A1-20200827-C01596
  • To a solution of (1R,2R)-2-(allyloxy)cyclopentanol 3-5a (2.20 g, 15.50 mmol) in THF (150 ml) was added phosgene solution (16.3 ml, 30.9 mmol, 20% in toluene). The resulted solution was stirred for 14 h, and concentrated in vacuo. To the residue in dioxane (50 ml) was added L-tert-leucine 3-6a (2.237 g, 17.05 mmol) in dioxane (100 ml) and 1 N NaOH (18.6 ml, 18.6 mmol). The mixture was stirred for 5 h, and acidified with 1N HCl. The mixture was extracted with EtOAc (3×), and the organic layer was combined, washed with water, brine, dried and concentrated in vacuo to afford the acid 1-3a (4.32 g). This material was used directly to next step without further purification.
    • Step 1g
  • Figure US20200270303A1-20200827-C01597
  • To a solution of quinoxaline derivative 1-1 (3.02 g, 6.719 mmol) in DCM (20 ml) was added 4 N HCl (20 ml, in dioxane). The resulted solution was stirred for 2 h and solvent was removed in vacuo. To the residue in DMF (67 ml) was added acid 1-3a (1.849 g, 8.063 mmol), HATU (3.321 g, 8.735 mmol) and DIPEA (2.33 ml, 13.438 mmol). The mixture was stirred for 3 h and concentrated in vacuo. The residue was dissolved in EtOAc and washed with 1 N HCl (2×), water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on CombiFlash with Hexane to 35% EtOAc in hexane to afford diene 1-4a (2.48 g, 59%). MS-ESI m/z 631.43 (M+H)+.
    • Step 1h
  • Figure US20200270303A1-20200827-C01598
  • To a solution of the diene 1-4a (1.38 g, 2.188 mmol) in toluene under nitrogen atmosphere at 110° C. was added Zhan 1B catalyst (128 mg, 0.140 mmol) and the resulted solution was stirred at 110° C. for 37 h. Zhan 1B catalyst (70 mg×2) was added in two portions and the reaction was stopped until the disappearance of starting material by MS. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on CombiFlash with Hexane to 40% EtOAc in hexane to afford the alkene 1-5a (0.768 g, 59%). MS-ESI m/z 603.20 (M+H)+.
    • Step 1i
  • Figure US20200270303A1-20200827-C01599
  • To a solution of the ester 1-5a (1.38 g, 2.29 mmol) in MeOH (23 ml) and THF (46 ml) was added LiOH solution (22.9 ml, 1 N). The resulted mixture was stirred for 16 h and quenched with 1 N HCl. The mixture was extracted with DCM (3×), and the organic layer was combined, washed with brine, dried (Na2SO4) and concentrated in vacuo to afford the acid 1-6a. The acid was used to the next step without further purification.
    • Step 1j
  • Figure US20200270303A1-20200827-C01600
  • The acid 1-6a (crude product from step 1i) was dissolved in DCM (70 ml), and to this solution was added sulfonamide 1-7a (702 mg, 2.404 mmol), HATU (1.045 g, 2.748 mmol) and DIPEA (0.60 ml, 3.435 mmol). The mixture was stirred for 3 h, and then diluted with DCM. The organic layer was washed with 1 N HCl, water, brine, dried and concentrated in vacuo. The residue was first purified by flash chromatography on CombiFlash with Hexane to 50% EtOAc in hexane and then further purified by HPLC to afford the title compound (1.126 g, 60%). MS-ESI m/z 801.40 (M+H)+.
    • Example 2
  • Compound of Formula VIII, wherein
  • Figure US20200270303A1-20200827-C01601
    • Step 2a
  • Figure US20200270303A1-20200827-C01602
  • The acid 1-6a (19.5 mg, 0.0332 mmol) was dissolved in DCM (1.0 ml), and to this solution was added sulfonamide 1-7b (13.2 mg, 0.0432 mmol), HATU (18.9 mg, 0.0498 mmol) and DIPEA (11.5 ul, 0.0664 mmol). The mixture was stirred for 3 h, and then diluted with DCM. The organic layer was washed with 1 N HCl, water, brine, dried and concentrated in vacuo. The residue was purified by HPLC to afford the title compound. MS-ESI m/z 825.39 (M+H)+.
    • Example 4
  • Compound of Formula VIII, wherein
  • Figure US20200270303A1-20200827-C01603
    • Step 4a
  • Figure US20200270303A1-20200827-C01604
  • The acid 1-6a (21 mg, 0.0356 mmol) was dissolved in DCM (1.5 ml), and to this solution was added sulfonamide 1-7c (12.4 mg, 0.0463 mmol), HATU (17.6 mg, 0.0462 mmol) and DIPEA (12.4 ul, 0.0712 mmol). The mixture was stirred for 3 h, and then diluted with DCM. The organic layer was washed with 1 N HCl, water, brine, dried and concentrated in vacuo. The residue was purified by HPLC to afford the title compound. MS-ESI m/z 803.25 (M+H)+.
    • Example 5
  • Compound of Formula VIII, wherein
  • Figure US20200270303A1-20200827-C01605
    • Step 5a
  • Figure US20200270303A1-20200827-C01606
  • The acid 1-6a (19.5 mg, 0.0332 mmol) was dissolved in DMF (0.5 ml) and DCM (0.5 ml), and to this solution was added sulfonamide 1-7d (13.8 mg, 0.0465 mmol), HATU (18.9 mg, 0.0498 mmol) and DIPEA (11.5 ul, 0.0664 mmol). The mixture was stirred for 2 h and the solvent was removed in vacuo, the residue was purified by HPLC to afford the title compound. MS-ESI m/z 815.38 (M+H)+.
    • Example 6
  • Compound of Formula VIII, wherein
  • Figure US20200270303A1-20200827-C01607
    • Step 6a
  • Figure US20200270303A1-20200827-C01608
  • The acid 1-6a (21 mg, 0.0356 mmol) was dissolved in DCM (1.5 ml), and to this solution was added sulfonamide 1-7e (13.0 mg, 0.0463 mmol), HATU (17.6 mg, 0.0462 mmol) and DIPEA (12.4 ul, 0.0712 mmol). The mixture was stirred for 3 h, and then diluted with DCM. The organic layer was washed with 1 N HCl, water, brine, dried and concentrated in vacuo. The residue was purified by HPLC to afford the title compound. MS-ESI m/z 839.41 (M+H)+.
    • Example 8
  • Compound of Formula VIII, wherein
  • Figure US20200270303A1-20200827-C01609
    • Step 8a
  • Figure US20200270303A1-20200827-C01610
  • The acid 1-6a (19.5 mg, 0.0332 mmol) was dissolved in DMF (0.5 ml) and DCM (0.5 ml), and to this solution was added sulfonamide 1-7f (13.8 mg, 0.0465 mmol), HATU (18.9 mg, 0.0498 mmol) and DIPEA (11.5 ul, 0.0664 mmol). The mixture was stirred for 2 h and the solvent was removed in vacuo, the residue was purified by HPLC to afford the title compound. MS-ESI m/z 817.37 (M+H)+.
    • Example 34
  • Compound of Formula VIII, wherein
  • Figure US20200270303A1-20200827-C01611
    • Step 34a
  • Figure US20200270303A1-20200827-C01612
  • A mixture of compound 34a-1 (2.0 g, 8.678 mol), Pd/C (458 mg, 0.434 mmol, 10% wet) and THF (100 ml) was hydrogenated under 60 PSI for 15 h, and another portion of Pd/C (458 mg) was added, the mixture was stirred for another 20 h until the disappearance of starting material. The mixture was filtered, washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on CombiFlash with Hexane to 60% EtOAc in hexane to afford the diol 34a-2 (315 mg, 41%).
  • To the solution of diol 34a-2 (400 mg, 4.545 mmol) in DMF (8 ml) at 0° C. was added NaH (200 mg, 5.0 mmol, 60% dispersion in mineral oil). The resulted mixture was warmed up to rt and stirred for 40 min, the allyl bromide (0.42 ml, 5.0 mmol) was added. The mixture was stirred for 2 h, and quenched with NH4Cl solution. The mixture was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on CombiFlash with Hexane to 25% acetone in hexane to afford the alcohol 34a-3 (132 mg).
  • To the solution of alcohol 34a-3 (132 mg, 1.031 mmol), PPh3 (810.9 mg, 3.092 mmol) and 4-nitrobenzoic acid (586 mg, 3.505 mmol) in THF (10 ml) was added DIAD (0.61 ml, 3.092 mmol). The resulted solution was stirred for 11 h, and the solvent was removed in vacuo. The residue was purified by flash chromatography on CombiFlash with Hexane to 40% EtOAc in hexane to afford the ester 34a-4 (161 mg, 56%).
  • To the solution of alcohol 34a-4 (161 mg, 0.581 mmol) in THF (4 ml) and MeOH (2 ml) was added LiOH (2 ml, 1 N). The mixture was stirred for 2.5 h and the mixture was extracted with EtOAc (3×). The organic layer was combined, washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford the alcohol 34a-5 (58 mg). This material was used directly to the next step without further purification.
    • Step 34b
  • Figure US20200270303A1-20200827-C01613
  • To a solution of (1R,2R)-2-(allyloxy)cyclobutanol 34a-5 (58 mg, 0.453 mmol) in THF (2 ml) was added phosgene solution (0.48 ml, 0.906 mmol, 20% in toluene). The resulted solution was stirred for 4 h, and concentrated in vacuo. To the residue in dioxane (5 ml) was added L-tert-leucine 3-6a (71 mg, 0.544 mmol) and 1 N NaOH (0.59 ml, 0.59 mmol). The mixture was stirred for 14 h, and acidified with 1N HCl. The mixture was extracted with EtOAc (3×), and the organic layer was combined, washed with water, brine, dried and concentrated in vacuo to afford the acid 1-3b (117 mg). This material was used directly to next step without further purification.
    • Step 34c
  • Figure US20200270303A1-20200827-C01614
  • To a solution of quinoxaline derivative 1-1 (224 mg, 0.498 mmol) in DCM (2 ml) was added HCl (3 ml, 4 N in dioxane). The resulted solution was stirred for 1.5 h and solvent was removed in vacuo. To the residue in DCM (8 ml) was added acid 1-3b (120 mg, 0.453 mmol), HATU (258 mg, 0.680 mmol) and DIPEA (0.17 ml, 0.996 mmol). The mixture was stirred for 3 h and concentrated in vacuo. The residue was dissolved in EtOAc and washed with 1 N HCl (2×), water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on CombiFlash with Hexane to 35% EtOAc in hexane to afford diene 1-4b (115 mg). MS-ESI m/z 617.3 (M+H)+.
    • Step 34d
  • Figure US20200270303A1-20200827-C01615
  • To a solution of the diene 1-4b (115 mg, 0.186 mmol) in toluene under nitrogen atmosphere at 110° C. was added Zhan 1B catalyst (14 mg, 0.0186 mmol) and the resulted solution was stirred at 110° C. for 19 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on CombiFlash with Hexane to 35% EtOAc in hexane to afford the alkene 1-5b (38 mg). MS-ESI m/z 589.25 (M+H)+.
    • Step 34e
  • Figure US20200270303A1-20200827-C01616
  • To a solution of the ester 1-5b (38 mg, 0.0646 mmol) in MeOH (1 ml) and THF (2 ml) was added LiOH solution (1 ml, 1 N). The resulted mixture was stirred for 14 h and quenched with 1 N HCl. The mixture was extracted with ethyl acetate (3×), and the organic layer was combined, washed with brine, dried (Na2SO4) and concentrated in vacuo to afford the acid 1-6b. The acid was used to the next step without further purification. MS-ESI m/z 575.27 (M+H)+.
    • Step 34f
  • Figure US20200270303A1-20200827-C01617
  • Following procedure described in the preparation of example 2 (step 2a), acid 1-6b was converted to compound example 34. MS-ESI m/z 833.40 (M+H)+.
    • Example 36
  • Compound of Formula VIII, wherein
  • Figure US20200270303A1-20200827-C01618
  • Following procedure described in the preparation of example 4 (step 4a), acid 1-6b was converted to compound example 36. MS-ESI m/z 789.45 (M+H)+.
    • Example 40
  • Compound of Formula VIII, wherein
  • Figure US20200270303A1-20200827-C01619
  • Following procedure described in the preparation of example 8 (step 8a), acid 1-6b was converted to compound example 40. MS-ESI m/z 803.47 (M+H)+.
    • Example 265
  • Compound of Formula X, wherein
  • Figure US20200270303A1-20200827-C01620
    • Step 265a
  • Figure US20200270303A1-20200827-C01621
  • To a suspension of NaH (49 mg, 1.22 mmol, 60% in mineral oil) in THF was added a solution of 2-1-1 (0.1 g, 0.489 mmol) in THF (1.5 mL) at 0° C. After stirred at 0° C. for 45 min, a solution of 2-chloro-3-(1,1-difluoroallyl)quinoxaline 2-10 in THF (1 mL) was added and then the reaction mixture was heated at 60° C. for 3 h. Cooled to 0° C. and quenched with 2 N HCl at 0° C. The aqueous layer was extracted with DCM (3×), and the organic layer was combined, washed with water, brine, dried and concentrated in vacuo. To the residue in MeOH (5 ml) was added TMSCHN2 (2 mL, 4 mmol, 2.0 M in Hexane) and the solution was stirred at rt for 30 min. Concentrated in vacuo. The residue was purified by flash chromatography with Hexane to 40% ethyl acetate in hexane to afford desired product 1-1-1 (82 mg, 43%). MS (ESI): m/z=464.21 [M+H].
    • Step 265b
  • Figure US20200270303A1-20200827-C01622
  • To a solution of quinoxaline derivative 1-1-1 (82 mg, 0.18 mmol) in DCM (3 mL) was added 4 N HCl (12 mL, in dioxane). The resulted solution was stirred for 2 h at 0° C. and solvent was removed in vacuo. To the residue in DCM (2 mL) was added acid 1-3a (69 mg, 0.23 mmol), HATU (133.8 mg, 0.352 mmol) and DIPEA (122.6 μL, 0.704 mmol). The mixture was diluted in DCM and washed with 10% citric acid, sat. NaHCO3, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography with Hexane to 40% EtOAc in hexane to afford diene 1-4-1 (129.5 mg, >99%). MS-ESI m/z 645.33 (M+H)+.
    • Step 265c
  • Figure US20200270303A1-20200827-C01623
  • To a solution of the diene 1-4-1 (110 mg, 0.17 mmol) in toluene under nitrogen atmosphere at 110° C. was added Zhan 1B catalyst (17.9 mg, 0.026 mmol) and the resulted solution was stirred at 110° C. for 5 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography with Hexane to 40% EtOAc in hexane to afford the alkene 1-5-1 (38 mg, 36%). MS-ESI m/z 617.32 (M+H)+.
    • Step 265d
  • Figure US20200270303A1-20200827-C01624
  • To a solution of the ester 1-5-1 (38 mg, 0.062 mmol) in MeOH (3 mL) and THF (6 mL) was added LiOH solution (3 mL, 1 N). The resulted mixture was stirred for 9 h at 0° C.˜rt and quenched with 1 N HCl at 0° C. The mixture was extracted with DCM (3×), and the organic layer was combined, washed with brine, dried (Na2SO4) and concentrated in vacuo to afford the acid 1-6-1. The acid was used to the next step without further purification.
    • Step 265e
  • Figure US20200270303A1-20200827-C01625
  • The acid 1-6-1 (9.8 mg, 0.0166 mmol) was dissolved in DCM (1.0 mL), and to this solution was added sulfonamide 1-7a (6.2 mg, 0.0216 mmol), HATU (9.5 mg, 0.0216 mmol) and DIPEA (5.8 μL, 0.0249 mmol). The mixture was stirred for 3 h, and then diluted with DCM. The organic layer was washed with with 10% citric acid, sat. NaHCO3, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC 50% EtOAc in hexane afford the title compound (2.0 mg, 20%). MS-ESI m/z 815.30 (M+H)+.
    • Example 266
  • Compound of Formula X, wherein
  • Figure US20200270303A1-20200827-C01626
    • Step 266a
  • Figure US20200270303A1-20200827-C01627
  • The acid 1-6-1 (crude product from step 266d) was dissolved in DCM (1 mL), and to this solution was added sulfonamide 1-7b (10.2 mg, 0.035 mmol), HATU (13.3 mg, 0.035 mmol) and DIPEA (12.2 μL, 0.07 mmol). The mixture was stirred for 3 h, and then diluted with DCM. The organic layer was washed with with 10% citric acid, sat. NaHCO3, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC 50% EtOAc in hexane afford the title compound (3 mg, 30%). MS-ESI m/z 839.38 (M+H)+.
    • Example 268
  • Compound of Formula X, wherein
  • Figure US20200270303A1-20200827-C01628
    • Step 268a
  • Figure US20200270303A1-20200827-C01629
  • The acid 1-6-1 was dissolved in DCM (1 mL), and to this solution was added sulfonamide 1-7c (12.4 mg, 0.0463 mmol), HATU (17.6 mg, 0.0462 mmol) and DIPEA (12.4 uL, 0.0712 mmol). The mixture was stirred for 3 h, and then diluted with DCM. The organic layer was washed with 10% citric acid, sat. NaHCO3, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC 50% EtOAc in hexane afford the title compound (2.6 mg, 25%). MS-ESI m/z 816.91 (M+H)+.
    • Example 273
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01630
    • Step 273a
  • Figure US20200270303A1-20200827-C01631
  • To the solution of ethyl 3,3-difluoro-2-oxopent-4-enoate 2-4 (0.417 g, 2.34 mmol) in EtOH (12 ml) was added 2-amino-4-(trifluoromethoxy)aniline 2-8-1 0.54 g, 2.81 mmol). The resulted mixture was heated to reflux for 14 h and then cool down to rt, the mixture was diluted by ethyl acetate, washed by 1M HCl, water, and brine. The solvent was removed and the crude product was purified by combiflash (12 g silica gel, 0-50% EA in Hexanes) to give 2-9-1 (0.228 g, 0.745 mmol, 31.8% yield) and 2-9-2 (0.358 g, 1.169 mmol, 49.9% yield).
    • Step 273b
  • Figure US20200270303A1-20200827-C01632
  • To the solution of 2-9-2 (0.228 g, 0.745 mmol), (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (0.219 g, 0.894 mmol) and Triphenylphosphine (0.293 g, 1.117 mmol) in THF (3.72 ml), the Diisopropyl azodicarboxylate (0.217 ml, 1.117 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was concentrated. The crude product was purified by combiflash (25 g silica gel, 0-40% ethyl acetate in Hexanes) to give 1-1-1 (0.320 g, 0.600 mmol, 81% yield). MS-ESI, m/z=534.45 (M+1)+.
    • Step 273c
  • Figure US20200270303A1-20200827-C01633
  • The compound 1-4a-1 was prepared by following the procedure described in the preparation of example 1 (step 1g). MS-ESI m/z 715.3 (M+H)+.
    • Step 273d
  • Figure US20200270303A1-20200827-C01634
  • The compound 1-5a-1 was prepared by following the procedure described in the preparation of example 1 (step 1h). MS-ESI m/z 687.4 (M+H)+.
    • Step 273e
  • Figure US20200270303A1-20200827-C01635
  • The compound 1-6a-1 was prepared by following the procedure described in the preparation of example 1 (step 1i). MS-ESI m/z 673.3 (M+H)+.
    • Step 273f
  • Figure US20200270303A1-20200827-C01636
  • The compound of example 273 was prepared by following the procedure described in the preparation of example 1 (step 1j). MS-ESI m/z 923.4 (M+H)+.
    • Example 274
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01637
  • The compound of example 274 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 899.3 (M+H)+.
    • Example 275
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01638
  • The compound of example 275 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 923.4 (M+H)+.
    • Example 276
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01639
  • The compound of example 276 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 899.3 (M+H)+.
    • Example 277
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01640
  • The compound of example 277 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 833.4 (M+H)+.
    • Example 278
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01641
  • The compound of example 278 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 831.4 (M+H)+.
    • Example 279
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01642
  • The compound of example 279 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 855.4 (M+H)+.
    • Example 280
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01643
  • The compound of example 280 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 847.4 (M+H)+.
    • Example 281
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01644
  • The compound of example 281 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 845.4 (M+H)+.
    • Example 282
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01645
  • The compound of example 282 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 869.4 (M+H)+.
    • Example 283
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01646
  • The compound of example 283 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 906.3 (M+H)+.
    • Example 284
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01647
  • The compound of example 284 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 883.4 (M+H)+.
    • Example 285
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01648
  • The compound of example 285 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 893.3 (M+H)+.
    • Example 286
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01649
  • The compound of example 286 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 883.4 (M+H)+.
    • Example 287
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01650
  • The compound of example 287 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 868.4 (M+H)+.
    • Example 288
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01651
  • The compound of example 288 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 831.4 (M+H)+.
    • Example 289. Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01652
  • The compound of example 289 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 845.4 (M+H)+.
    • Example 290
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01653
  • The compound of example 290 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 889.4 (M+H)+.
    • Example 291
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01654
  • The compound of example 291 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 865.4 (M+H)+.
    • Example 292
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01655
  • The compound of example 292 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 889.4 (M+H)+.
    • Example 293
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01656
  • The compound of example 293 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 865.4 (M+H)+.
    • Example 294
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01657
  • The compound of example 294 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 833.4 (M+H)+.
    • Example 295
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01658
  • The compound of example 295 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 833.4 (M+H)+.
    • Example 296
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01659
  • The compound of example 296 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 857.3 (M+H)+.
    • Example 297
  • Compound of Formula XI, wherein
  • Figure US20200270303A1-20200827-C01660
  • The compound of example 297 was prepared by following the procedure described in the preparation of example 273. MS-ESI m/z 843.3 (M+H)+.
  • The compounds of the present invention exhibit potent inhibitory properties against the HCV NS3 protease. The following examples describe assays in which the compounds of the present invention can be tested for anti-HCV effects.
    • Example 301. Biological Assays
  • Each compound's anti-HCV activity can be determined by measuring the activity of the luciferase reporter gene in the replicon in the presence of 5% FBS. The luciferase reporter gene, and selectable marker gene for replicons stably maintained in cell lines, is placed under the translational control of the poliovirus IRES instead of the HCV IRES, and HuH-7 cells are used to support the replication of the replicon.
  • The inhibitory activities of the compounds of the present invention can be evaluated using a variety of assays known in the art. For instance, stable subgenomic replicon cell lines can be used for compound characterization in cell culture, including those derived from genotypes 1a-H77, 1b-N and 1b-Con1, obtained from University of Texas Medical Branch, Galveston, Tex. (1a-H77 and 1b-N) or Apath, LLC, St. Louis, Mo. (1b-Con1). Chimeric replicons using the genotype 1a or 1b replicons with insertion of NS3 genes from isolates from humans infected with genotypes 1a or 1b can be used to measure inhibitory activity against a panel of the target protein from natural isolates. Chimeric replicons using the genotype 1a or 1b replicons with insertion of NS3 genes from isolates from humans infected with genotypes 3a, 4 or 6 can be used to measure inhibitory activity against representatives of those genotypes. The genotype 1a replicon construct contains the NS3-NS5B coding region derived from the H77 strain of HCV (1a-H77). The replicon also has a firefly luciferase reporter and a neomycin phosphotransferase (Neo) selectable marker. These two coding regions, separated by the FMDV 2a protease, comprise the first cistron of the bicistronic replicon construct, with the second cistron containing the NS3-NS5B coding region with addition of adaptive mutations E1202G, K1691R, K2040R and S22041. The 1b-Con1 and 1b-N replicon constructs are identical to the 1a-H77 replicon, except that the HCV 5′ UTR, 3′ UTR, and NS3-NS5B coding region are derived from the 1b-Con1 or 1b-N strain, and the adaptive mutations are K1609E, K1846T and Y3005C for 1b-Con1 or A1098T, E1202G, and S22041 for 1b-N. In addition, the 1b-Con1 replicon construct contains a poliovirus IRES between the HCV IRES and the luciferase gene. Replicon cell lines can be maintained in Dulbecco's modified Eagles medium (DMEM) containing 10% (v/v) fetal bovine serum (FBS), 100 IU/ml penicillin, 100 mg/ml streptomycin (Invitrogen), and 200 mg/ml G418 (Invitrogen).
  • The inhibitory effects of the compounds of the invention on HCV replication can also be determined by measuring activity of the luciferase reporter gene encoded by subgenomic replicons not containing the Neo selectable marker, that are transiently expressed in cells. The adaptive mutations encoded by the 1a-H77, 1b-N and 1b-Con-1 replicons are the same as listed above. The 1b-Con1 replicon used for these transient assays contains the NS2-NS5B coding region rather than the NS3-5B coding region. These replicons may encode target NS3 genes as described for stable subgenomic replicons or they may encode amino acid variants that confer varying degrees of susceptibility to the drug. For example, variants could include R155K, D168E or D168V in a genotype 1a NS3 gene; R155K or D168V in a genotype 1b NS3 gene; S138T, A166T or Q168R in a genotype 3a NS3 gene. For example, cells can be transfected with the replicon by electroporation and seeded into 96 well plates at a density of 5000 cells per well in 100 μl DMEM containing 5% FBS. Compounds diluted in dimethyl sulfoxide (DMSO) to generate a 200x stock in a series of eight half-log dilutions can then be further diluted 100-fold in the medium containing 5% FBS and added to the cell culture plates already containing 100 μl of DMEM with 5% FBS. After an incubation period of either 3 or 4 days, 30 μl of Passive Lysis buffer (Promega) can be added to each well, with incubation for 15 minutes with rocking to lyse the cells. Luciferin solution (100 al, Promega) can be added to each well, and luciferase activity can be measured with a luminometer. The percent inhibition of HCV RNA replication can be calculated for each compound concentration and the EC50 value can be calculated using nonlinear regression curve fitting to the 4-parameter logistic equation and GraphPad Prism 4 software.
  • When tested using genotype 1a Huh-7 stable replicon assays, compounds of Examples 1, 4, 5, 6, 8, 275, 276, 283, 284, 287, 288, 289, 290, 291, 294, 295, 296, and 297 showed EC50 values of less than 1 nM; compounds of Examples 2, 36, 40, 65, 89, 90, 273, 274, 280, 285, 292, 293, 298, and 299 showed EC50 values of from 1 to 10 nM; and compounds of Example 34 showed EC50 values of from 10 to 100 nM.
  • When tested using genotype 1b Con1 stable replicon assays, compounds of Examples 275, 276, 283, 290, 294, 295, and 296 showed EC50 values of less than 1 nM; and compounds of Examples 1, 2, 4, 5, 6, 8, 34, 36, 40, 65, 89, 90, 273, 274, 279, 280, 281, 284, 285, 287, 288, 289, 291, 292, 293, 297, 298, and 299 showed EC50 values of from 1 to 10 nM.
  • When tested using genotype 1a wild-type transient replicon assays, compounds of Examples 5, 6, 275, 276, 283, 284, 287, 288, 289, 291, 294, 295, and 297 showed EC50 values of less than 0.1 nM; compounds of Examples 1, 2, 4, 8, 277, 280, 281, 282, 285, 286, 292, 293, 296, 298, and 299 showed EC50 values of from 0.1 to 1 nM; and compounds of Examples 34, 36, and 40 showed EC50 values of from 1 to 10 nM.
  • When tested using genotype 1a R155K transient replicon assays, compounds of Examples 2, 5, 6, 8, 275, 276, 281, 283, 284, 287, 288, 289, 291, 294, 295, 296, and 297 showed EC50 values of less than 0.1 nM; compounds of Examples 1, 4, 277, 280, 282, 285, 286, 292, 293, and 299 showed EC50 values of from 0.1 to 1 nM; and compounds of Examples 34, 40, 36, and 298 showed EC50 values of from 1 to 10 nM.
  • When tested using genotype 1a D168E transient replicon assays, compounds of Examples 1, 2, 4, 5, 6, and 8 showed EC50 values of less than 1 nM; and compounds of Examples 40, 298, and 299 showed EC50 values of from 1 to 100 nM.
  • When tested using genotype 1a D168V transient replicon assays, compounds of Examples 2, 5, 6, 276, 281, 287, 288, 289, 291, 292, 295, 296, and 297 showed EC50 values of less than 1 nM; compounds of Examples 1, 8, 275, 280, 282, 283, 284, and 293 showed EC50 values of from 1 to 10 nM; and compounds of Examples 4, 36, 40, 277, 285, 286, 298, and 299 showed EC50 values of from 10 nM to 1 μM.
  • When tested using genotype 1b wild-type transient replicon assays, compounds of Examples 1, 2, 4, 5, 6, 8, 275, 276, 281, 282, 283, 284, 285, 286, 287, 288, 289, 291, 292, 293, 294, 295, 296, and 297 showed EC50 values of less than 1 nM; and compounds of Examples 34, 36, 40, 277, 280, 298, and 299 showed EC50 values of from 1 to 10 nM.
  • When tested using genotype 1b R155K transient replicon assays, compounds of Examples 1, 2, 4, 5, 6, and 8 showed EC50 values of less than 1 nM; and compounds of Examples 34, 36, 40, 298, and 299 showed EC50 values of from 1 to 10 nM.
  • When tested using genotype 1b D168V transient replicon assays, compounds of Examples 1, 5, 6, 275, 276, and 282 showed EC50 values of less than 1 nM; and compounds of Examples 2, 4, 8, 34, 36, 40, 280, 298, and 299 showed EC50 values of from 1 to 100 nM.
  • When tested using genotype 3a wild-type stable replicon assays, compounds of Examples 1, 2, 5, 6, 275, 276, 280, 287, 288, 289, 290, 291, 294, and 296 showed EC50 values of less than 10 nM; compounds of Examples 281, 282, 283, 284, 292, 293, 295, and 297 showed EC50 values of from 10 to 100 nM; and compounds of Examples 273, 274, 277, 278, and 279 showed EC50 values of from 100 nM to 1 μM.
  • When tested using genotype 3a wild-type transient replicon assays, compounds of Examples 2, 5, 6, 275, 276, 280, 283, 289, and 291 showed EC50 values of less than 10 nM; compounds of Examples 1, 4, 8, 281, 282, 284, 285, and 293 showed EC50 values of from 10 to 100 nM; and compounds of Examples 65, 90, 277, and 286 showed EC50 values of from 100 nM to 1 μM.
  • When tested using genotype 3a A166T transient replicon assays, compounds of Examples 2, 5, and 6 showed EC50 values of less than 100 nM; and compounds of Examples 1, 4, and 8 showed EC50 values of from 100 to 500 nM.
  • When tested using genotype 3a Q168R transient replicon assays, compounds of Examples 5, 6, 275, 276, 280, 281, 282, 283, 289, 291, and 293 showed EC50 values of less than 100 nM; and compounds of Examples 1, 2, 4, 8, 90, 277, 284, 285, and 286 showed EC50 values of from 100 nM to 1 μM.
  • When tested using genotype 3a S138T transient replicon assays, compounds of Examples 5 and 6 showed EC50 values of less than 100 nM; and compounds of Examples 1, 2, 4, 8, and 65 showed EC50 values of from 100 nM to 1 μM.
  • The foregoing description of the present invention provides illustration and description, but is not intended to be exhaustive or to limit the invention to the precise one disclosed. Modifications and variations are possible in light of the above teachings or may be acquired from practice of the invention. Thus, it is noted that the scope of the invention is defined by the claims and their equivalents.
  • While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims (5)

1-26. (canceled)
27. A compound selected from the group consisting of:
Figure US20200270303A1-20200827-C01661
28. The compound of claim 1, wherein the compound is:
Figure US20200270303A1-20200827-C01662
29. The compound of claim 1, wherein the compound is:
Figure US20200270303A1-20200827-C01663
30. The compound of claim 1, wherein the compound is:
Figure US20200270303A1-20200827-C01664
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