WO2023200441A1 - Composés hétérocycliques antiviraux - Google Patents

Composés hétérocycliques antiviraux Download PDF

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Publication number
WO2023200441A1
WO2023200441A1 PCT/US2022/024663 US2022024663W WO2023200441A1 WO 2023200441 A1 WO2023200441 A1 WO 2023200441A1 US 2022024663 W US2022024663 W US 2022024663W WO 2023200441 A1 WO2023200441 A1 WO 2023200441A1
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WIPO (PCT)
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mmol
compound
esi
afford
purified
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PCT/US2022/024663
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English (en)
Inventor
Adam SZYMANIAK
Jianming Yu
Kevin Mcgrath
Xiben LI
Tyler J. MANN
Robert Leon
In Jong Kim
Yat Sun Or
Long Nguyen
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Enanta Pharmaceuticals, Inc.
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Priority to PCT/US2022/024663 priority Critical patent/WO2023200441A1/fr
Publication of WO2023200441A1 publication Critical patent/WO2023200441A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates generally to compounds and pharmaceutical compositions useful as Respiratory Syncytial Virus (RSV) inhibitors and Human Metapneumovirus (HMPV) inhibitors.
  • RSV Respiratory Syncytial Virus
  • HMPV Human Metapneumovirus
  • HRSV Human respiratory syncytial virus
  • N nucleocapsid protein
  • L RNA polymerase protein
  • P phosphoprotein
  • M2-1 transcription anti -termination factor
  • RNP ribonucleoprotein
  • F fusion protein
  • HRSV acute lower respiratory infections
  • patient populations at high risk during HRSV infections include the elderly, immunocompromised, children up to the age of two and patients with chronic obstructive pulmonary disorder (COPD) or chronic heart failure (CHF).
  • COPD chronic obstructive pulmonary disorder
  • CHF chronic heart failure
  • HRSV was found over four years to cause 177,500 hospital admissions and 14,000 deaths in the U.S. elderly population. It is well-known that almost all children will be infected with HRSV in the first 3 years after birth and HRSV infection is more severe in premature infants. In fact, HRSV is the most common cause of bronchiolitis and pneumonia in infants under the age of one in the U.S. It is estimated that approximately 3.2 million hospitalizations and 66,000 deaths worldwide in children less than 5 years old are due to HRSV. HRSV has been associated with more deaths of infants below one year old and more infant hospitalizations than influenza.
  • HRSV infection can also affect healthy individuals and repeated HRSV infections even over the course of two months can occur. Symptoms are similar to colds in healthy individuals, however fever, wheezing, rapid and difficult breathing, and cyanosis occur in more severe cases.
  • Palivizumab is a monoclonal antibody that is approved for prophylactic use, but its use is limited due to its high price. Palivizumab is generally only used for high risk infants, such as premature infants or those with cardiac/lung disease, but has been only 60% effective in reducing hospitalizations. Ribavirin is approved as an inhalation treatment option, but its effectiveness is limited and there are safety concerns associated with it. Taking into account the treatment options, and the consistent seasonality of the HRSV epidemic, the development of new therapeutic agents for the treatment of HRSV is desirable.
  • RSV fusion inhibitors that have been disclosed in the following publications: W02010/103306, WO2012/068622, WO2013/096681, W02014/060411, WO2013/186995, WO2013/186334, WO 2013/186332, WO 2012 080451, WO 2012/080450, WO2012/080449, WO 2012/080447, WO 2012/080446, WO 2015/110446, WO 2017/009316, J. Med. Chem. 2015, 58, 1630-1643, Bioorg. Med. Chem. Lett., 2015, 25, 976-981 and Ato. Commun., 2017, 8, 167.
  • N-protein inhibitors for treatment of HRSV have been disclosed in the following publications: WO 2004/026843, J. Med. Chem. 2006, 49, 2311-2319, and J. Med. Chem. 2007, 50, 1685-1692.
  • L-protein inhibitors for HRSV have been disclosed in the following publications: WO 2011/005842, WO 2005/042530, Antiviral Res. 2005, 65, 125-131, and Bioorg. Med. Chem. Lett. 2013, 23, 6789-6793.
  • nucleosides/polymerase inhibitors examples include WO 2011/ 005842, WO 2013/242525, WO 2014/031784, WO 2015/026792, WO 2016/ 0055791, WO 2016/138158 and J. Med. Chem. 2015, 58, 1862-1878.
  • HMPV human metapneumovirus
  • ARTI acute lower respiratory tract infections
  • HMPV infection In healthy adults over the age of 65 years, the annual incidence rate of HMPV infection is 1.2/1,000, and 38% of disease (e.g., COPD), and individuals are twice as likely to have symptomatic disease and requirement for medical care. In immunocompromised individuals, HMPV is responsible for 6% of total respiratory infections in lung transplants and 3% of lower respiratory infections associated with stem cell transplant. HMPV infection is also thought to be associated with acute graft rejection.
  • HMPV L protein sequence is homologous to HRSV L protein.
  • HMPV infection is the second most common cause of lower respiratory tract infection in children (behind HRSV) and also problematic for the elderly population. There are 4 subtypes of HMPV found in clinical isolates (Al, A2, Bl and B2). Reinfection occurs throughout childhood following initial infection. No therapeutics are currently available for HMPV infection.
  • the present invention has identified compounds that are heterocyclic molecules that are potent against HRSV-A/B and HMPV.
  • the invention includes methods to prepare these molecules, methods for the RSV cell-based assay, the HMPV-GFP cell-based assay, the HMPV- TN/1501/A1 cell-based assay, and small-molecules that have potential to treat HRSV/HMPV infection.
  • the present invention provides compounds represented by Formula (I), and pharmaceutically acceptable salts, esters and prodrugs thereof that can be used to treat or prevent viral (particularly HRSV or HMPV) infection: wherein:
  • A is selected from the group consisting of:
  • Ri and R2 are each independently selected from the group consisting of:
  • Ri and R2 are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 6- membered ring;
  • Z is selected from the group consisting of:
  • W is selected from the group consisting of:
  • G is selected from the group consisting of:
  • n is 1, 2 or 3; preferably n is 1 or 2;
  • Y is O, S(O) 2 , orNR 14 ;
  • E is selected from the group consisting of:
  • R 3 is hydroxy or fluorine;
  • R 4 is selected from the group consisting of:
  • R 11 at each occurrence is independently selected from the group consisting of:
  • R 12 at each occurrence is independently selected from the group consisting of:
  • R 11 and R 12 are taken together with the nitrogen atom to which they are attached to form a 3- to 12- membered heterocyclic ring, preferably the said 3- to 12- membered heterocyclic ring is, but not limited to morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, and, azetidine; R 13 at each occurrence is independently selected from the group consisting of:
  • R 14 is selected from:
  • Y is O.
  • Y is O, and n is 1 or 2.
  • R 1 is hydrogen or F.
  • R2 is hydrogen or F.
  • Z is hydrogen, Cl or F.
  • R 1 is hydrogen
  • R2 is hydrogen
  • Z is hydrogen
  • W is optionally substituted methyl, optionally substituted ethyl, or optionally substituted cyclopropyl.
  • W is cyclopropyl, ethyl, - CH 3 , -CH 2 F, -CHF 2 , or -CF 3 .
  • R 3 is -OH.
  • R 4 is optionally substituted methyl or optionally substituted cyclopropyl.
  • R 3 is OH
  • R 4 is CF 3 or cyclopropyl.
  • R 1 is hydrogen
  • R2 is hydrogen
  • R 3 is OH
  • R 4 is CF 3 .
  • G is-C(0)NR 11 R 12 . In certain embodiments, G is -C(0)NH 2 . In certain embodiments of the compounds of Formula (I), G is -CH 2 NHR 13 , -
  • G is -CH 2 C(O)NH 2 .
  • A is selected from one of wherein each of these groups is optionally substituted.
  • A is selected from the groups set forth below,
  • A is selected from the
  • A is wherein Ra is hydrogen, halogen, -CN, -NO2, -OR 11 , -NR 11 R 12 , -
  • NR 11 C(O)R 12 -NR 11 S(O) 2 R 12 , -S(O) 2 R 12 , -S(O) 2 NR 11 R 12 , -NR 11 C(O)NR 11 R 12 , -C(O)R 11 , -C(O)OR 11 , -C(0)NR 11 R 12 , optionally substituted -C 1 -C 6 alkyl, optionally substituted - C 3 -C 8 -cycloalkyl.
  • Rb and Rb’ are each independently selected from hydrogen, halogen, -OR 11 , -NR 11 R 12 , optionally substituted -C 1 -C 6 alkyl, optionally substituted -C 3 -C 8 cycloalkyl. optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.
  • Rb and Rb’ are taken together with the carbon atoms to which they are attached to form a 4- to 7- membered ring fused with the phenyl ring.
  • E is optionally substituted aryl, preferably optionally substituted phenyl. In certain embodiments of the compounds of Formula (I), E is selected from one of the following by removal of a hydrogen atom:
  • E is selected from the groups set forth below,
  • E is selected from the groups set forth below,
  • the compound of Formula (I) is represented by Formula (la) or Formula (lb), or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein A, Ri, R2, Z, W, G, n, Y, E, R 3 , and R 4 are as previously defined.
  • the compound of Formula (I) has the stereochemistry shown in Formula (lb).
  • the compound of Formula (I) is represented by Formula (II), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein A, Ri, R2, W, G, n, E, R 3 , and R 4 are as previously defined.
  • the compound of Formula (I) is represented by Formula (III) or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein A, W, G, n, Y, E, R 3 , and R 4 are as previously defined.
  • the compound of Formula (I) is represented by one of Formulae (IV- 1) ⁇ (IV-2), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein A, W, G, Y, E, R 3 , and R 4 are as previously defined.
  • the compound of Formula (I) is represented by one of Formulae (V-l) ⁇ (V-4), or a pharmaceutically acceptable salt, ester, or wherein A, W, G, E, R 14 , R 3 , and R 4 are as previously defined.
  • the compound of Formula (I) is represented by one of Formulae (VI-1) ⁇ (VI-4), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein A, W, G, E, R 14 , R 3 , and R 4 are as previously defined.
  • W is optionally substituted methyl; more preferably, W is -CH 3 or -CF 3 .
  • the compound of Formula (I) is represented by one of Formulae (VII- 1) ⁇ (VII- 12), or a pharmaceutically acceptable salt, ester, or prodrug thereof:
  • W is cyclopropyl, ethyl, -CH 3 , -CH 2 F, -CHF 2 , or -CF 3 ; more preferably, W is -CH 3 or -CF 3 .
  • the compound of Formula (I) is represented by one of Formulae (VIII-1) ⁇ (VIII-12), or a pharmaceutically acceptable salt, ester, or prodrug thereof:
  • W is cyclopropyl, ethyl, -CH 3 , -CH 2 F, -CHF 2 , or -CF 3 ; more preferably, W is -CH 3 or -CF 3 .
  • the compound of Formula (I) is represented by one of Formulae (IX-1) ⁇ (IX-4), or a pharmaceutically acceptable salt, ester, or prodrug thereof:
  • each R 21 is independently optionally substituted methyl, halo, -CN, -OR 11 , or -
  • each R 21 is independently halo or optionally substituted methyl, and m is 1 or 2. More preferably, each R 21 is independently -F, -Cl, -CN, -CF 3 , -CH 2 F or -CHF 2 , and m is 1 or 2.
  • the compound of Formula (I) is represented by one of Formulae (X-l) ⁇ (X-4), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein R 21 , m, A, W, G, R 14 , R 3 , and R 4 are as previously defined.
  • each R 21 is independently halo or optionally substituted methyl, and m is 1 or 2.
  • the compound of Formula (I) is represented by one of Formulae (XII- 1) ⁇ (XII- 12), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein m’ is 0, 1, or 2.
  • A, R 3 , R 4 , R 21 , R 11 , R 12 , and R 13 are as previously defined.
  • m is 2.
  • the compound of Formula (I) is represented by one of Formulae (XIII-1) ⁇ (XIII-12), or a pharmaceutically acceptable salt, ester, or prodrug thereof:
  • R 21 , m , A, R 3 , R 4 , R 11 , R 12 , and R 13 are as previously defined.
  • m is 2.
  • the compound of Formula (I) is represented by one of Formulae (XIV-1) ⁇ (XIV-6), or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein each R 22 is independently halo; -CN; -NO2, -OR 11 ; -NR 11 R 12 ; -NR 11 C(0)R 12 ; -
  • R 21 is halogen
  • R 3 is -OH
  • R 4 is -CH 3 , -CF 3 , or cyclopropyl
  • W is cyclopropyl, ethyl, -CH 3 , -CH 2 F, -CHF 2 , or -CF 3 .
  • two adjacent R 22 groups are taken together with the carbon atoms to which they are attached to form a 4- to 12- membered carbocyclic or heterocyclic, and which said 4- to 12- membered carbocyclic or heterocyclic is fused with the phenyl or quinolinyl.
  • the compound of Formula (I) is represented by one of Formulae (XV-1) ⁇ (XV-6), or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein W, m , R 3 , R 4 , R 21 , R 22 , R 11 , and R 12 are as previously defined.
  • R 21 is halogen
  • R 3 is -OH
  • R 4 is -CH 3 , -CF 3 , or cyclopropyl
  • W is cyclopropyl, ethyl, -CH 3 , - CH 2 F, -CHF 2 , or -CF 3 .
  • two adjacent R 22 groups are taken together with the carbon atoms to which they are attached to form a 4- to 12- membered carbocyclic or heterocyclic ring, and which said 4- to 12- membered carbocyclic or heterocyclic is fused with the phenyl or quinolinyl.
  • the compound of Formula (I) is represented by one of Formulae (XVI-1) ⁇ (XVI-12), or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • R 23 is hydrogen; halo; -CN; -NO2, -OR 11 ; -NR 11 R 12 ; -NR 11 C(0)R 12 ; -NR 11 S(O)2R 12 ; -S(O) 2 R 12 ; -S(O) 2 NR 11 R 12 , -NR 11 C(O)NR 11 R 12 ; -C(O)R 11 , -C(O)OR 11 ; -C(O)NR 11 R 12 ; optionally substituted -C 1 -C 6 alkyl; optionally substituted -C 3 -C 8 cycloalkyl; optionally substituted 3- to 8-membered heterocyclic; optionally substituted aryl; or optionally substituted heteroaryl; and W, R 21 , R 22 , m , R 3 , R 4 , R 11 , and R 12 are as previously defined.
  • R 21 is halogen
  • R 3 is -OH
  • R 4 is -CH 3 , -CF 3 , or cyclopropyl
  • W is cyclopropyl, ethyl, -CH 3 , -CH 2 F, -CHF 2 , or -CF 3 .
  • the compound of Formula (I) is represented by one of Formulae (XVII- 1) ⁇ (XVII- 12), or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • R 21 is halogen
  • R 3 is -OH
  • R 4 is -CH 3 , -CF 3 , or cyclopropyl
  • W is cyclopropyl, ethyl, -CH 3 , -
  • the compound of Formula (I) is represented by one of Formulae (XVIII-1) ⁇ (XVIII- 14), or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • R 14 , R 21 , and R 22 are as previously defined.
  • the compound of Formula (I) is represented by one of Formulae (XIX-1) ⁇ (XIX- 14), or a pharmaceutically acceptable salt, ester, or prodrug thereof:
  • R 14 , R 21 , and R 22 are as previously defined.
  • the compound of Formula (I) is represented by one of Formulae (XX-1) ⁇ (XX-20), or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • each R 3 1 is independently optionally substituted -C 1 -C 3 alkyl or halo;
  • R 3 2 is independently halo, -OR 11 , -NR 11 R 12 , -NR 11 C(0)R 12 , -C(0)NR 11 R 12 , -C(O)R 11 , optionally substituted -C 1 -C 6 alkyl, or optionally substituted -C 3 -C 8 cycloalkyl; and R 11 , R 12 , and R 14 are as previously defined.
  • R 31 is halo
  • R 32 is halo, -NH 2 , optionally substituted methyl, optionally substituted cyclopropyl
  • R 14 is optionally substituted cyclopropyl.
  • the compound of Formula (I) is represented by one of Formulae (XXI-1) ⁇ (XXI-20), or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • R 3 1, R 3 2, R 11 , R 12 , and R 14 is as previously defined.
  • R 3 1 is halo
  • R 3 2 is halo
  • -NH 2 optionally substituted methyl
  • R 14 is optionally substituted cyclopropyl.
  • the compound of Formula (I) is represented by one of Formulae (XXII- 1) ⁇ (XXII- 14), or a pharmaceutically acceptable salt, ester or prodrug thereof.
  • R 24 is hydrogen or R 22 ; and W, R 4 , Ri4, R 21 , and R 22 are as previously defined.
  • R 4 is optionally substituted -C 3 -C 6 cycloalkyl. More preferably, R 4 is optionally substituted cyclopropyl or optionally substituted cyclobutyl.
  • the compound of Formula (I) is represented by one of Formulae (XXIII-1) ⁇ (XXIII-14), or a pharmaceutically acceptable salt, ester or prodrug thereof:
  • R 4 is optionally substituted -C 3 -C 6 cycloalkyl. More preferably, R 4 is optionally substituted cyclopropyl or optionally substituted cyclobutyl, and W is optionally substituted methyl.
  • the compound of Formula (I) is represented by Formula (XXIV), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein A, E, R 3 , and R 4 are each as previously defined.
  • the compound of Formula (I) is represented by Formula (XXIV), or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein R 3 is -OH; R 4 is optionally substituted methyl or optionally substituted -C 3 - C 6 cycloalkyl;
  • A is selected from:
  • the compound of Formula (I) is represented by Formula (XXV), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein each R 41 , R 42 , R 43 , R 44 , and R 45 are each independently selected form hydrogen, halogen, optionally substituted methyl, optionally substituted methoxyl or -CN.
  • R 3 , R 4 , R 14 , and R24 are as previously defined.
  • R 3 is -OH;
  • R 4 is optionally substituted methyl or optionally substituted -C 3 -C 6 cycloalkyl;
  • R 14 is optionally substituted -C 3 -C 6 cycloalkyl or optionally substituted methyl;
  • R 24 is optionally substituted methoxyl or halogen.
  • the compound of Formula (I) is represented by one Formulae (XXVI-1) ⁇ (XXVI-3), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein R 3 , R 14 , R24, R 41 , R 42 , R 43 , R 44 , and R 45 are as previously defined.
  • the compound of Formula (I) is represented by Formula (XXVII), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein R 14 , R24, R 41 , R 42 , R 43 , R 44 , and R 45 are as previously defined.
  • the compound of Formula (I) is represented by Formula (XXVIII), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein R 14 , R24, R 41 , R 42 , R 43 , R 44 , and R 45 are as previously defined.
  • the compound of Formula (I) is represented by one of Formula (XXIV), Formula (XXV), Formulae (XXVI-1) ⁇ (XXVI-3), Formula (XXVII), or Formula (XXVIII), or a pharmaceutically acceptable salt, ester or prodrug, wherein R 14 is optionally substituted -C 3 -C 6 cycloalkyl or optionally substituted methyl; R24 is optionally substituted methoxyl or halogen; and each R 41 , R 42 , R 43 , R 44 , and R 45 are each independently selected from hydrogen, -F, -Cl, -CH 3 , -CF 3 , -OCH 3 , or -OCF 3 .
  • the compound of Formula (I) is represented by Formula (XXIV), Formula (XXV), Formulae (XXVI-1) ⁇ (XXVI-3), Formula (XXVII), or Formula (XXVIII), or a pharmaceutically acceptable salt, ester or prodrug, wherein R 14 is -CHF 2 , ; R 24 is -F, -Cl, or -OCH 3 ; and selected from:
  • the compound of Formula (I) is represented by Formulae (XXIX-1) ⁇ (XXIX-3), or a pharmaceutically acceptable salt, ester, or prodrug thereof: wherein R 4 6 is substituted methyl or optionally substituted cyclopropyl; R 47 is hydrogen, Cl, F, or optionally substituted methoxyl, R 41 , R 42 , R 43 , R 44 , and R 45 are as previously defined.
  • R 46 is cyclopropyl, 1 -fluorocyclopropyl or difluoromethyl.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.
  • the present invention provides a method for the prevention or treatment of RSV activities and for treating RSV infection in a subject in need thereof.
  • the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I).
  • the present invention also provides the use of a compound of formula (I) for the preparation of a medicament for the prevention or treatment of RSV.
  • a compound of formula (I), or pharmaceutically acceptable salt thereof is combined with a steroid anti-inflammatory compound, for example budesonide or fluticasone.
  • a steroid anti-inflammatory compound for example budesonide or fluticasone.
  • the steroid is administered in low doses to minimize immuno- suppressant effects.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof is combined with a non-steroid anti-inflammatory compound, for example leukotriene antagonists such as Singulair (Merck) or Accolate (Astra Zeneca), phosphodiesterase 4 inhibitors such as roflumilast (Altana), TNF alpha inhibitors such as Enbrel (Amgen), Remicade (Centocor), Humira (Abbot) or CDP870 (Celltech) or NSAIDS.
  • a compound of formula (I) is combined with interleukin 8 or interleukin 9 inhibitors.
  • the present invention thus also relates to a product containing a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anti-inflammatory compound for simultaneous, separate or sequential use in the treatment of RSV.
  • the present invention also relates to a combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, with an anti-influenza compound and the use of such a combination in the treatment of concomitant RSV and influenza infections.
  • the present invention thus also relates to a product containing a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an anti-influenza compound for simultaneous, separate or sequential use in the treatment of concomitant RSV and influenza infections.
  • the compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
  • the compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrastemally, transdermally or by infusion techniques.
  • the compounds may also be administered as suppositories.
  • the compounds of the invention are administered by intranasal or intrabronchial administration.
  • the present invention also provides an inhaler or nebulizer containing a medicament which comprises (a) a derivative of the formula (I), as defined above, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a pharmaceutical composition containing such a benzodiazepine derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, cellulose, com starch or potato starch; lubricants, e.g., silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g., starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g., starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, nontoxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • diluents e.g., lactose, dextrose, saccharose,
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
  • the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • the present invention also relates to the novel compounds, as defined above; or a pharmaceutically acceptable salt thereof, for use in a method of treating the human or animal body.
  • the present invention also relates to a pharmaceutical composition comprising a novel compound as defined above and a pharmaceutically acceptable diluant or carrier.
  • the pharmaceutical composition comprises a pharmaceutically acceptable salt of a novel compound as defined above.
  • a pharmaceutically acceptable salt is as defined above.
  • the novel compounds of the invention are typically administered in the manner defined above and the compounds are typically formulated for administration in the manner defined above.
  • the pharmaceutical compositions comprise optically active isomers of the novel compounds of the invention.
  • preferred novel compounds of the invention containing only one chiral center include an R enantiomer in substantially pure form, an S enantiomer in substantially pure form and enantiomeric mixtures which contain an excess of the R enantiomer or an excess of the S enantiomer.
  • pharmaceutical contains a compound of the invention which is a substantially pure optical isomer.
  • the novel compounds of the invention can, if desired, be used in the form of solvates.
  • 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.
  • aryl refers to a mono-, bi-, or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl.
  • a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
  • Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
  • heteroaryl refers to a mono-, bi-, or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, 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, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl.
  • a polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.
  • aromatic groups can be substituted or unsubstituted.
  • bicyclic aryl or “bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic; and the two rings can be fused or covalently attached.
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals.
  • C 1 -C 3 alkyl refers to alkyl groups containing from one to three, one to six, one to ten carbon atoms, 2 to 4 and 3 to 6 carbon atoms respectively.
  • 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 and octyl radicals.
  • alkenyl refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • C 2 -C 10 alkenyl refers to alkenyl groups containing from two to ten, two to eight, two to four or three to six 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.
  • alkynyl refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • C 2 -C 10 alkynyl refers to alkynyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • cycloalkyl refers to a monocyclic or polycyclic saturated carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system, and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond.
  • Preferred cycloalkyl groups include C 3 -C 12 cycloalkyl, C 3 -C 6 cycloalkyl, C 3 -C 8 cycloalkyl and C 4 -C 7 cycloalkyl.
  • C 3 -C 12 cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3- methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like.
  • cycloalkenyl refers to monocyclic or polycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridged or spiro system having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond.
  • Preferred cycloalkenyl groups include C 3 -C 12 cycloalkenyl, C 3 -C 8 cycloalkenyl or C 5 -C 7 cycloalkenyl groups.
  • C 3 -C 12 cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept- 2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl, bicyclo[4.2.1]non-3-en-9-yl, and the like.
  • arylalkyl means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -CEECEE-phenyl.
  • substituted arylalkyl means an arylalkyl functional group in which the aryl group is substituted.
  • heteroarylalkyl means a functional group wherein an alkylene chain is attached to a heteroaryl group.
  • substituted heteroarylalkyl means a heteroarylalkyl functional group in which the heteroaryl group is substituted.
  • alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1 -propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
  • Preferred alkoxy are (C 1 -C 3 ) alkoxy.
  • any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.
  • An “aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds.
  • aliphatic groups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH, NH 2 , C(O), S(O)2, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH 2 , S(O) 2 NH, S(O) 2 NH 2 , NHC(O)NH 2 , NHC(O)C(O)NH, NHS(O) 2 NH, NHS(O) 2 NH 2 , C(O)NHS(O) 2 , C(O)NHS(O) 2 NH or C(O)NHS(O) 2 NH 2 , and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group.
  • groups comprising one or more functional groups, non-aro
  • Carbon atoms of an aliphatic group can be optionally oxo-substituted.
  • An aliphatic group may be straight chained, branched, cyclic, or a combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted.
  • Carbocycle or “carbocyclic” refers to a saturated, partially unsaturated or aromatic cyclic group in which each atom within the ring is carbon.
  • cabocyclics include cycloalkyl, cycloalkenyl and aryl groups.
  • heterocyclic or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quatemized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted or optionally substituted with exocyclic olefinic, iminic or oximic double bond.
  • heterocycloalkyl groups include, but are not limited to, 1,3-di oxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5- azaspiro[2.5]octyl, l-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl.
  • heterocyclic groups may be further substituted.
  • Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible). It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s).
  • One of skill in the art can readily determine the valence of any such group from the context in which it occurs.
  • substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, -C 1 -C 12 -alkyl; -C 2 -C 12 -alkenyl, -C 2 -C 12 -alkynyl, -C 3 -C 12 -cycloalkyl, protected hydroxy, -NO2, -N 3 , -CN, -NH 2 , protected amino, oxo, thioxo, -NH -C 1 -C 12 -alkyl, -NH-C 2 -C 8 - alkenyl, -NH-C 2 -C 8 -alkynyl, -NH-C 3 -C 12 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH- hetero
  • the substituents are independently selected from halo, preferably Cl and F; -C 1 -C 4 -alkyl, preferably methyl and ethyl; halo-C 1 -C 4 -alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C 2 - C 4 -alkenyl; halo-C 2 -C 4 -alkenyl; C 3 -C 6 - cycloalkyl, such as cyclopropyl; -C 1 -C 4 -alkoxy, such as methoxy and ethoxy; halo-C 1 -C 4 - alkoxy, such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy, -CN; -OH; NH 2 ; -C 1 -C 4 -alkylamino; di(-C 1 -C 4 -alkyl)amino; and NO 2 .
  • each substituent in a substituted moiety is additionally optionally substituted when possible with one or more groups, each group being independently selected from -C 1 -C 4 -alkyl; -CF 3 , -OCH 3 , -OCF 3 , -F, -Cl, -Br, -I, - OH, -NO 2 , -CN, and -NH 2 .
  • a substituted alkyl, alkenyl or alkoxy group is substituted with one or more halogen atoms, preferably fluorine or chlorine atoms.
  • Such substituted alkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.
  • Such substituted alkoxy groups include fluoromethoxy, difluoromethoxy and trifluoromethoxy.
  • halo or halogen alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.
  • the term “optionally substituted”, as used herein, means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.
  • the term “hydrogen” includes hydrogen and deuterium. In addition, the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.
  • the compounds of each formula herein are defined to include isotopically labelled compounds.
  • An “isotopically labelled compound” is a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level which is significantly greater than the natural abundance of that isotope.
  • one or more hydrogen atom positions in a compound can be enriched with deuterium to a level which is significantly greater than the natural abundance of deuterium, for example, enrichment to a level of at least 1%, preferably at least 20% or at least 50%.
  • Such a deuterated compound may, for example, be metabolized more slowly than its nondeuterated analog, and therefore exhibit a longer half-life when administered to a subject.
  • Such compounds can synthesize using methods known in the art, for example by employing deuterated starting materials.
  • isotopically labelled compounds are pharmaceutically acceptable.
  • hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction.
  • hydroxyl activating group include, but are not limited to, mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate and the like.
  • activated hydroxyl refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p- nitrobenzoate, phosphonate groups, for example.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl 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 art 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).
  • hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxy carbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxy carbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenyl- methyl (trityl), methoxy methyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)- ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
  • hydroxy prodrug group refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan, Prodrugs. Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992) and in “Prodrugs of Alcohols and Phenols” by S. S. Dhareshwar and V. J. Stella, in Prodrugs Challenges and Rewards Part-2. (Biotechnology: Pharmaceutical Aspects), edited by V. J. Stella, et al, Springer and AAPSPress, 2007, pp 31-99.
  • 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 art 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, methoxy carbonyl, t-butoxy carbonyl, 9-fluorenyl- methoxy carbonyl, benzyloxy carbonyl, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • leaving group means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • 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.
  • protic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • alcohol for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that 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.
  • 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.
  • a method such as column chromatography, high pressure liquid chromatography, or recrystallization.
  • further methods of synthesizing the compounds of the Formula herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, 2 nd Ed. Wiley-VCH (1999); T.W. Greene and P.G.M.
  • subject refers to an animal.
  • the animal is a mammal. More preferably, the mammal is a human.
  • a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and may 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.
  • 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.
  • 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 or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
  • Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of these compounds and mixtures thereof.
  • the term "pharmaceutically acceptable salt,” refers to those salts 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. For example, S. M. 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.
  • nontoxic acid addition salts are 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, cyclopentane-propionate, 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, pam
  • 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.
  • Pharmaceutically acceptable salts can also be prepared by deprotonation of the parent compound with a suitable base, thereby forming the anionic conjugate base of the parent compound.
  • the counter ion is a cation.
  • Suitable cations include ammonium and metal cations, such as alkali metal cations, including Li + , Na + , K + and Cs + , and alkaline earth metal cations, such as Mg 2+ and Ca 2+ .
  • the term "pharmaceutically acceptable ester” refers to esters 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, esters of -C 1 Ce-alkanoic acids, such as acetate, propionate, butyrate and pivalate esters.
  • the invention provides pharmaceutically acceptable prodrugs of the compounds disclosed herein.
  • pharmaceutically acceptable 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.
  • prodrugs can be derivatized as amides or alkyl esters.
  • Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, ethyl succinate, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • a compound of the invention can incorporate two or more groups that are metabolically removed in vivo to yield the active parent compound.
  • treating means relieving, lessening, reducing, eliminating, modulating, or ameliorating, i.e., causing regression of the disease state or condition. Treating can also include inhibiting, i.e., arresting the development, of an existing disease state or condition, and relieving or ameliorating, i.e., causing regression of an existing disease state or condition, for example when the disease state or condition may already be present.
  • preventing means, to completely or almost completely stop a disease state or condition, from occurring in a patient or subject, especially when the patient or subject is predisposed to such or at risk of contracting a disease state or condition.
  • the compounds of the present invention can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • hydrates include monohydrates, dihydrates, etc.
  • solvates include ethanol solvates, acetone solvates, etc.
  • Solidvates means solvent addition forms that contain either stoichiometric or nonstoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrate.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
  • an analog is a compound that is similar to or comparable in function and appearance to the reference compound.
  • 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 com 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; com 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
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, 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, intrastemal, 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, com, 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,
  • 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.
  • DPPA for diphenylphosphoryl azide or diphenyl phosphorylazidate
  • dppf for l,l'-Bis(diphenylphosphino)ferrocene
  • Ts or tosyl for p-CH 3 C 6 H 4 SO 2 -; tBOC or Boc for tert-butyloxy carbonyl; and
  • a leaving group such as but not limited to, tosyl and methanlsulfonyl
  • Intramolecular epoxide opening mediated by base such as but not limited to, LDA, produces compound 5. Hydroxy group compound 5 is protected with proper protecting group such as but not limited to, TBDPS and TBS, affords compound 6. Trifluomethyl ketone 7 is obtained from iodine-magnesium exchange of compound 6 followed by addition of ester such as but not limited to, ethyl 2,2,2-trifluoroacetate.
  • Trifluoromethyl ketone 7 in cross-coupled with various metal coupling partners 8 but not limited to, boronic acids, boronic esters, organotin reagents, organozinc reagents, organomagnesium reagents, organo silicon reagents or the like catalyzed by appropriate Pd, Ni, Cu or the like catalyst to afford compound 9.
  • Nitromethane addition in the presence of base such as but not limited to, K 2 CO 3 and Cs 2 CO 3 ,to compound 9 affords compound 10.
  • Reduction of nitro group with reducing reagents such as but not limited to, zinc and acetic acid, produces key intermediate 11.
  • Scheme 5 illustrates another method to prepare a compound of formula 11, wherein Ar is E; P is a hydroxy protecting group; n is 1, 2 or 3; and E is as previously defined.
  • Ketone 9 is converted to compound of formula 26 via olefination.
  • 26 is obtained from; 1) 6 via cross-coupling with metal coupling partner 6-1, which can be, but is not limited to, a boronic acid, a boronic ester, an organotin reagent, an organozinc reagent, an organomagnesium reagent, an organosilicon reagent or the like catalyzed by appropriate Pd, Ni, Cu or the like catalyst to afford compound 25; 2) compound 25 is converted to compound 26 as previously described method in scheme 1.
  • Compounds of formula 27 are prepared by dihydroxylation followed by epoxide formation. Epoxide opening of compound 27 with amine equivalent such as but not limited to, NH 4 OH and NH 3 , provides compounds of formula 11.
  • Ari is A; Ar is E; R’ is -C 1 -C 6 alkyl, -C 3 -C 6 cycloalkyl, aryl, or heteroaryl; n is 1, 2 or 3; and A and E are as previously defined.
  • Amine 11 is protected with a protecting group such as but not limited to, Boc and Cbz. After deprotection of hydroxy protecting group, subsequent oxidations provide acid 30.
  • Compound 30 is coupled with various amines to provide amide 31. Deprotection of amine protecting group followed by subsequent amide formation affords compounds of formula 23.
  • Scheme 7 illustrates an additional route for the synthesis of the desired compounds.
  • Example 1 step b A solution of the compound from step a (250 mg, 0.98 mmol), Pd(dppf)Cl 2 (142 mg, 0.19 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (425 mg, 1.94 mmol), H 2 O (0.1 mL) and Cs 2 CO 3 (950 mg, 2.91 mmol) in dioxane (3 mL) was stirred for 2 hours at 90°C under N 2 atmosphere. The resulting solution was purified by reverse phase C18 column chromatography (MeOH/0.1% FA in H 2 O) to afford the desired product as a white solid (180 mg, 68%). ESI-MS m/z: 270.15 [M+H] + .
  • step b 125 mg, 0.333 mmol.
  • the solid was dissolved in DMF and cooled to 0°C.
  • DIPEA 407 pl, 2.332 mmol
  • 1-methylcyclopropan-l -amine hydrochloride 124 mg, 1.148 mmol
  • PyBOP 260 mg, 0.500 mmol was then added in one portion, the reaction stirred for 10 minutes, warmed to room temperature and monitored by LCMS (1.5 hr).
  • the reaction diluted was with EtOAc and quenched with water.
  • the aqueous layer was extracted with EtOAc, with a phase separator cartridge, and the combined organics were concentrated.
  • Example 2 step c To a 20 mL vial containing Example 2 step c (9 mg, 0.312 mmol) was added a stir bar. The compound was dissolved in MeOH, THF and Water (0.2 M, 2: 1 : 1). Lithium hydroxide hydrate (62 mg, 1.56 mmol) was added, the reaction stirred at room temperature and monitored by LCMS. The stir bar was removed, and the vial cooled to 0°C. The reaction was acidified with 2 M HC1, and the pH brought to around 4-5 (used IM NaOH if too acidic). The product was extracted 3x with 10% MeOH/DCM with a phase separator and concentrated. Dried on high vacuum to afford the title compound (45 mg, 50%). ESI-MS m/z: 202.0 [M+H] + .
  • Example 2 The following example was prepared using the same procedures as Example 1 step c, with the corresponding acid from step d and amine HC1 salt (25 mg) coupling partners. The residue was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the title compound (8 mg, 20%) ESI-MS m/z: 682.2.
  • step a the compound from step a (400 mg, 1.337 mmol) was suspended in THF (5.35 ml) and Lawesson's reagent (595 mg, 1.471 mmol) was added. The reaction was heated to 65°C overnight. The reaction was allowed to cool to room temperature and stand before concentrating. Crude reaction mixture purified by silica gel chromatography eluting with 0- 50% EtOAc/Hexanes to give the title compound (400 mg, 1.27 mmol, 95%).
  • step a 500 mg, 1.872 mol
  • step a 500 mg, 1.872 mol
  • step a 500 mg, 1.872 mol
  • step a 500 mg, 1.872 mol
  • step a 500 mg, 1.872 mol
  • step a BBr 3 (3.74 mL, 3.74 mmol)
  • the resulting mixture was stirred at rt for 20hrs and then quenched with water (2 mL). After diluted with DCM (50 mL), the organic layer was separated, dried and evaporated.
  • the residue was purified by Gilson prep-HPLC (20-90%, MeCN/Water, 25 min) to afford the desired product (40 mg, 8.44%) as a brown foam.
  • step b 40 mg, 0.158 mmol from step b in DMF (2 mL) were added K 2 CO 3 (43.7 mg, 0.316 mmol) and 2,2-difluoroethyl 4-methylbenzenesulfonate (187 mg, 0.79 mmol).
  • K 2 CO 3 43.7 mg, 0.316 mmol
  • 2,2-difluoroethyl 4-methylbenzenesulfonate 187 mg, 0.79 mmol.
  • the resulting mixture was heated at 60°C in a sealed vessel for 20hrs. After evaporated the solvent, the residue was purified by Combiflash eluting with 0-30% EtOAc/hexanes to obtain the desired product (35 mg, 85%) as a pale-yellow foam.
  • step c The compound from step c (3.80 g, 14.84 mmol) and aminocyclopropane (1.27 g, 22.26 mmol) in toluene (50 mL) were treated with molecular sieves. The reaction was stirred at room temperature for 2 hours, then heated at reflux for overnight. After cooling to room temperature, the mixture was filtered over celite and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford the desired product (2.4 g, 60%) as a brown oil. ESI-MS m/z: 267.05 [M+H] + .
  • step a Into a 100 mL round-bottom flask were added the compound from step a (280 mg, 1.48 mmol), KOH (1.25 g, 22.28 mmol), EtOH (21 mL) and H 2 O (7 mL) at room temperature. The resulting mixture was stirred for overnight at 80°C. The resulting mixture was concentrated under reduced pressure. The residue was acidified to pH 5 with HC1 (2 M aq.). The product was collected by filtration and washed with water to afford the title compound (263 mg) ESI-MS m/z: 209.15 [M+H] + .
  • step e Into a 30 mL pressure tank reactor were added the compound form step e (400 mg, 1.5 mmol), Pd(AcO)2 (101 mg, 0.45 mmol), DPPP (371 mg, 0.9 mmol), EtOH (4 mL), Et 3 N (1 mL) and DMF (4 mL) at room temperature. The resulting mixture was stirred for overnight at 100°C under CO atmosphere at 10 atm. The reaction was monitored by TLC. The resulting mixture was filtered, the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure.
  • step f Into a 50 mL round-bottom flask were added the compound form step f (360 mg, 1.4 mmol), LiOH (166 mg, 7 mmol), MeOH (5 mL) and H 2 O (1 mL) at room temperature. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was acidified to pH 6 with HC1 (aq). The resulting mixture was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with water (3x3 mL) to afford the desired compound (280 mg, 87%) as off-white solid. ESI-MS m/z: 233.00 [M+H] + .
  • step c To a solution of the compound from step c (2.6 g, 6.47 mmol) in DMF (10 mL), H 2 O (10 mL) and TEA (2.5 mL) was added DPPP (1 g, 2.59 mmol) and Pd(OAc) 2 (0.29 g, 1.29 mmol) in a pressure tank. The mixture was pressurized to 15 atm with carbon monoxide and stirred at 100°C for 2 days. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under reduced pressure.
  • step a (0.083 g, 0.430 mmol) in THF (5 ml) was treated with potassium tnmethylsilanolate (0.276 g, 2.148 mmol) and stirred at room temperature.
  • Step a (37mg, 0.179 mmol) was dissolved in DCM (1 ml) and DAST (83 pl, 0.625 mmol) was added at 0 °C. The reaction mixture was allowed to stir at 0 °C for 2 h. The reaction mixture was diluted with ethyl acetate and poured into IN HC1 solution. The aqueous layer was extracted with ethyl acetate for 3 times. The combined organic layers were dried and purified by flash chromatography to give the title compound. (15mg, 36.6% yield). ESI-MS m/z: 230.00 [M+H] + .
  • Step b (193mg, 0.216 mmol) was dissolved in Ethyl acetate (2.159 ml) in a 40 mL vial. The vial was flushed with nitrogen gas three times, palladium on carbon (22.98 mg, 0.022 mmol) was added in one portion. The vial was flushed with hydrogen balloon and the reaction mixture was allowed to stir at 25°C for 2h. The hydrogen gas was removed and flushed with nitrogen. The solution was filtered through celite and the residue was concentrated and purified by HPLC. ESI-MS m/z: 714.13 [M+H] + .
  • Example 4 step a (38mg, 0.061 mmol) was dissolved in tBuOH and water. 2-methyl-2- butene (129 pl, 1.213 mmol) and sodium dihydrogen phosphate (72.8 mg, 0.606 mmol) were added at rt. Then sodium chlorite (68.6 mg, 0.606 mmol) was added. The reaction mixture was allowed to stir at rt for 30min. The reaction was quenched by adding 15% Na2S20s solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried and purified by HPLC to give the title compound (14 mg, 0.022 mmol, 35.9% yield). ESI-MS m/z: 643.15 [M+H] + .
  • a 20 mL vial was charged with a 20 mL vial was charged with step a (250 mg, 1.13 mmol) cesium carbonate (736 mg, 2.26 mmol) DMF (2.3 ml) then Mel (212 pl, 3.39 mmol) was added. The mixture was stirred for 16 h. The mixture was then diluted with 5 mL water, and 5 mL dichloromethane. The layers were separated, and the aqueous layer was washed 5 x 5 mL with dichloromethane.
  • the vial was placed under a balloon of CO, and the mixture was heated to 80°C for 16 h. Additional palladium(II) acetate (12 mg, 0.054 mmol) was added and the mixture heated to 100°C for 4 h.
  • the reaction vessel was degassed by sparging with N 2 , then the mixture was concentrated and purified by automated silica gel chromatography to afford the title compound as a yellow oil (35 mg, 28%).
  • Example 1 Into a 100 mL round-bottom flask were added Example 1, step b (3.80 g, 10.27 mmol), acetone (100 mL), the solution was cooled to 0°C, and then Jones reagent (1.9-2.2 M, 10 mL) was added dropwise (with internal temperature monitoring). The reaction was warmed to room temperature and monitored by LCMS (3 hr). The reaction was cooled to 0°C, quenched with 'PrOH and stirred for 15 minutes. The reaction was diluted with EtOAc and water. The aqueous was extracted, the combined organics were dried and concentrated under reduced pressure to get the crude product as ayellow solid (3.95 g, 99%). ESI-MS m/z: 383.80 [M+H] + .
  • step b Into a 100 mL round-bottom flask were added the compound from step a (3.95 g, 10.28 mmol), NH4CI (1.10 g, 20.57 mmol) and the solids dissolved in DMF (20 mL). Hunig’s base (5.27 mL, 30.84 mmol) was added, the reaction was cooled to 0°C, and HATU (7.82 g, 20.56 mmol) was added. The reaction was warmed to room temperature and monitored by LCMS (1 hr). The reaction was diluted with EtOAc and water. The aqueous was extracted, the combined organics were dried and concentrated.
  • step b Into a 100 mL round-bottom flask were added the compound from step b (3.00 g, 7.83 mmol), 3,3,3-trifhroroprop-1-en-2-ylboronic acid (2.19 g, 15.65 mmol), Pd(dppf)Ch (1.15 g, 1.56 mmol), and the material dissolved in dioxane (40 mL) and H 2 O (5 mL). K 2 CO 3 (3.25 g, 23.50 mmol) was then added and the resulting mixture was stirred for 1 h at 90°C under nitrogen atmosphere. The mixture was cooled to room temperature, poured into water, extracted with EtOAc and the combined organics were concentrated under reduced pressure.
  • step c 5.00 g, 14.24 mmol
  • 3-chloro-4-fluorophenylboronic acid 3.72 g, 21.33 mmol
  • THF 80 mL
  • Na 2 CO 3 3.32 g, 31.33 mmol
  • H 2 O 20 mL
  • Pd(PPh 3 ) 2 Cl 2 1.00 g, 1.42 mmol
  • the resulting mixture was stirred for 1 h at 70°C under nitrogen atmosphere.
  • the reaction was monitored by TLC and LCMS.
  • the resulting mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried, and concentrated under reduced pressure.
  • AD-mix- 33.82 g, 43.41 mmol
  • methanesulfonamide 1.38 g, 14.47 mmol
  • the solids were dissolved in tBuOH (60 mL) and H 2 O (100 mL), and the flask cooled to 0°C and the compound from step d (5.80 g, 14.47 mmol) was added slowly as a solution of tBuOH (40 mL).
  • the reaction was allowed to warm to room temperature naturally and stirred for 16 hrs.
  • the reaction was quenched with the addition of sodium sulfite (0.25 g per g AD-mix), diluted with water and EtOAc.
  • step e Into a 250 mL round-bottom flask were added the compound from step e (4.70 g, 10.81 mmol) and DCM (80 mL) at room temperature. The solution was cooled to 0°C, and DMAP (264 mg, 2.16 mmol), TEA (3.28 g, 32.43 mmol and TsCl (2.47 g, 12.97 mmol) were then sequentially added. The resulting mixture was stirred for 1 h at 0°C. The mixture was acidified to pH 4 with 2 M HC1, and the aqueous extracted with DCM.
  • step a To a 20 mL vial containing step a (483 mg, 1.081 mmol) was added and stir bar, and the material was dissolved in THF/MeOH, and Water (1:1:1, 0.25 M). Lithium hydroxide hydrate (113 mg, 2.70 mmol) was added, the reaction stirred at room temperature and monitored by LCMS.
  • Example 1 step c The compounds in Table 1 were prepared by a method similar to that of Example 1 step c (PyBOP or HATU). The majority of compounds were purified by Gilson prep-HPLC, and some were purified by automated column chromatography (silica gel). Many of the aryl acid coupling partners were prepared according to Intermediates 1-38, or analogous procedures. In certain cases the aryl acid coupling partners were commercially available or prepared by previously described methods.
  • step a 143 mg, 0.613 mmol
  • the solid was dissolved in DCM.
  • POCh 114 pl, 1.226 mmol
  • the reaction was diluted with DCM and quenched with water and saturated sodium bicarbonate.
  • DCM and DCM/MeOH extraction with a phase separator cartridge, and the organics were concentrated. The reside was purified by automated column chromatography (silica gel, 0-90% EtOAc in hexanes) to afford the desired compound (102 mg, 66%).
  • Example 233
  • step b Into a 50 mL round-bottom flask were added the compound from step b (2.12 g, 5.12 mmol), followed by di chloromethane (21 mL) then 2,6-lutidine (890 ⁇ L, 7.68 mmol). The mixture was cooled to -78 °C, then triflic anhydride (1 M solution in dichloromethane, 5.63 mL 5.63 mmoL) was added dropwise over 10 min. The mixture was allowed to stir at -78 °C for 30 min and monitored by LCMS. The mixture was warmed to 0 °C and was then diluted with water and dichloromethane.
  • step a 393.9 mg, 0.908 mmol was added a stir bar and ammonia (3890 pl, 27.2 mmol) was added. The reaction was heated to 45°C and monitoted by LCMS (1.5 hr complete). The stir bar was removed, and the reaction concentrated. The material was frittered with DCM to afford a light brown solid as the desired product (360 mg, 96%).
  • Example 2 contains examples that were prepared with the similar method to Example 1 step c (PyBOP or HATU).
  • the amine coupling partners were prepared according to Intermediates 44-46 or by analogous procedures as a mixture of diastereomers. The majority of compounds were purified by Gilson prep-HPLC. If depicted as a single diasteromer, the diastereomers were separated on Gilson prep-HPLC.
  • the aryl acid coupling partners were prepared according to Intermediates 1-46 or by analogous procedures with slight modifications, and also prepared according to procedures found in US patent application no. 16/930,622.
  • Table 3 contains examples that were prepared with the similar method to Example 1 step c (PyBOP or HATU). The majority of compounds were purified by Gilson prep-HPLC, and some were purified by automated column chromatography (silica gel). The aryl acid coupling partners were prepared according to Intermediates 1-43, or by analogous procedures with slight modifications and also prepared according to procedures found in US patent application no. 16/930,622. Table 3
  • Table 4 contains examples that were prepared with the similar method to Example 1 step c (PyBOP or HATU). The majority of compounds were purified by Gilson prep-HPLC, and some were purified by automated column chromatography (silica gel). The aryl acid coupling partners were commercially available. Table 4
  • step e Into a 250 mL round-bottom flask containing step d (1.6 g, 3.04 mmol) were added NH 3 (68 mL, 156 eq, 7N in MeOH) at room temperature. The resulting mixture was stirred for 20 hr at room temperature and monitored by LCMS. The solvent was removed, and the crude mixture was dissolved in EtOAc. The organics were washed 3x with sat. sodium bicarbonate, and the organics were concentrated. The crude material was triturated with DCM to afford the desired product (590.9 mg, 52%) as an off-white solid. ESI-MS m/z: 372.15 [M+H] + .
  • the compound from step a (1.4 g, 4.08 mmol), (4-fluorophenyl)boronic acid (0.685 g, 4.90 mmol), PdCl 2 (dppf) DCM (0.200 g, 0.245 mmol), and K 2 CO 3 (1.692 g, 12.24 mmol) were dissolved in 1,4-Dioxane (16.32 ml) and Water (4.08 ml). The reaction was sparged with N 2 and sealed. The reaction was heated to 90 °C. After 4 hours, the reaction was cooled to RT and water was added. The aqueous layer was washed with EtOAc.
  • the above compound was prepared in an analogous fashion to Intermediate 36 with the corresponding aryl boronic acid pinacol ester.
  • the aryl boronic acid pinacol ester was prepared from the corresponding bromide by Pd-catalyzed borylation.
  • the crude material was purified by prep-TLC (silica gel, 6% MeOH in DCM with NH 3 ) to afford the desired product (355 mg, 67%) as a white solid.
  • step a 90 mg, 0.357 mmol
  • 2N NaOH 1 mL
  • the mixture was neutralized to pH- 3 by adding IN HC1.
  • the solid was precipitated out.
  • the desired product 85 mg, 100 %) was obtained.
  • ESI-MS m/z: 239.20 [M+H] + .
  • step b To the compound from step b (1.5 g, 6.2 mmol) was added to a 50% aqueous solution of fluoroboric acid (9.8 mL) at room temperature and stirred for 5 min. The mixture was cooled in an ice bath for 10 min and an aqueous solution of NaNO 2 (900 mg, 13.04 mmol) in 1.7 mL H 2 O was added to the mixture. The reaction mixture was stirred at 10°C for 30 min, during which the product precipitated. The cooled reaction mixture was filtered through a Buchner funnel and the solid product washed with small amounts of H 2 O, MeOH and Et 2 O, and dried under high vacuum to obtain the crude product as a brown solid. ESI-MS m/z: 253.00 [M+H] + .
  • step b Into a 250 mL round-bottom flask were added the compound from step b (1.82 g, 7.18 mmol) and a solution of NaOAc (21.83 g, 266.09 mmol) in MeOH (90 mL) and THF (90 mL) was treated with SnCl 2 (18.19 g, 94.92 mmol) and stirred for 16 hrs at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure.
  • step c To a 250 mL round-bottom flask containing Intermediate 36 step c (5.09 g, 14.50 mmol) was added THF (24.16 mL), Acetone (24.16 mL) and Water (24.16 mL). The flask was cooled to 0°C, and NMO (4.25 g, 36.2 mmol) was added followed by potassium osmate dihydrate (0.230 g, 0.623 mmol). The reaction was stirred for 10 minutes, warmed to room temperature and allowed to stir overnight for 20 hr. Sodium sulfite was added, the mixture diluted with water and the reaction stirred for 20 minutes. The mixture was diluted with EtOAc and the aqueous layer was extracted.
  • step a To a 250 mL round-bottom flask containing step a (4.118 g, 10.69 mmol) was added DCM (36 mL, 0.3 M). DMAP (0.065 g, 0.535 mmol) was added followed by TEA (4.47 ml, 32.1 mmol). The flask was cooled to 0°C, and TsCl (2.242 g, 11.76 mmol) was added, stirred for 10 minutes, warmed to room temperature and monitored by LCMS (1 hr).
  • step b To a 500 mL round-bottom flask containing step b (3.92 g, 10.70 mmol) was added ammonia (239 mL, 1670 mmol, 7N in MeOH) at 0°C. The reaction was stirred for 10 minutes, warmed to room temperature and monitored by LCMS (3.5 hr). The stir was then removed and the reaction concentrated. The crude material was dissolved in EtOAc and the organics were washed 3x with saturated sodium bicarbonate. The organics were concentrated, and the crude material was triturated with DCM/hexanes to afford a white solid (2.41 g, 59%) as a mixture of diastereomers. ESI-MS m/z: 384.21 [M+H] + .
  • step c 1.000 g, 2.60 mmol
  • 2-cyclopropyl-7-methoxy-2H-indazole-5-carboxylic acid 0.05 g, 2.60 mmol
  • the solids were dissolved in N,N-Dimethylformamide (13.02 mL, 0.2 M), and DIPEA (0.909 mL, 5.21 mmol) was added.
  • the vial was cooled to 0°C, and PyBOP (1.626 g, 3.12 mmol) was added.
  • the reaction was stirred for 10 minutes, warmed to room temperature and monitored by LCMS (1 hr). The reaction was quenched with sat.
  • Example 891 was purified by prep-HPLC (ACN/H 2 O, 20-90%, 25 min) from Example 891 as a white solid (3 mg, 6%).
  • Table 6 contains examples that were prepared with a similar method to Example 891 using Example 890. If necessary to push conversion, more palladium and boronic acid were added. The majority of compounds were purified and the diastereomers were separated by prep-HPLC (ACN/H 2 O, 20-90%, 25 min). If reported as a mixture of diastereomers, they were likely not separable by HPLC. Table 6
  • Table 7 contains examples that were prepared with the similar method to Example 1 step c (PyBOP or HATU). The majority of compounds were purified by prep- HPLC (ACN/H 2 O, 20-90%, 25 min). If depicted as a single diastereomer, they were separated during prep-HPLC purification.
  • the amine coupling partners were prepared in analogous fashion to Intermediates 45 & 46.
  • the aryl acid coupling partners were prepared according to Intermediates 1-95, or by analogous procedures with slight modifications and also prepared according to procedures found in US patent application no. 16/930,622. Table 7
  • Table 9 contains examples that were prepared with a similar method to Example 891 using Example 890 and Intermediate 115. If necessary to push conversion, more palladium and boronic acid were added. The majority of compounds were purified and the diastereomers were separated by prep-HPLC (ACN/H 2 O, 20-90%, 25 min). If reported as a mixture of diastereomers, they were likely not separable by HPLC.
  • Example 1228 (15 mg, 0.024 mmol) was dissolved in EtOH (0.5 mL) and MeOH (0.5 mL) and palladium on carbon (10% wt., 0.8 mg, 0.00075 mmol) was added. The air in the headspace of the reaction vessel was replaced with H 2 from a balloon, and the mixture was allowed to stir under H 2 for 24 hours. The reaction mixture was then filtered through a short pad of celite, and the filtrate concentrated to afford the product. (14 mg, 93%). ESI-MS m/z: 638.29 [M+H] + .
  • Example 890 (30 mg, 0.05 mmol) was dissolved in DMF (1 mL). Morpholine (44 mg, 0.5 mmol) and K 2 CO 3 (69 mg, 0.5 mmol) were added and the vial was sealed and heated to 100°C for 24 h. The reaction was cooled to room temperature and diluted with H 2 O (1 mL). The aqueous layer was washed with EtOAc and the combined organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by by prep-HPLC (ACN/H 2 O, 20-90%, 25 min) to give the title compound (5 mg, 16%). ESI-MS m/z: 605.27 [M+H] + .
  • Example 1271 The following example was prepared in an analogous fashion to Example 1269. ESI-MS m/z: 639.20 [M+H] + .
  • Example 1271
  • Example 10 The following example was prepared in an analogous fashion to Example 1269. ESI-MS m/z: 639.20 [M+H] + .
  • Table 10 contains examples that were prepared with the similar method to Example 1 step c (PyBOP or HATU) and Example 891 using Example 890 and Intermediate 115. The majority of compounds were purified by prep-HPLC (ACN/H 2 O, 20- 90%, 25 min), and some were purified by automated column chromatography (silica gel). The aryl acid and amine coupling partners were prepared according to Intermediates 1-113, or by analogous procedures with slight modifications, and also prepared according to procedures found in US patent application no. 16/930,622.
  • Hep-2 cells (originally derived from tumors grown in irradiated-cortisonised weanling rats that had been injected with epidermoid carcinoma tissue from the larynx of a 56 year old male, but later found to be indistinguishable from HeLa cells by PCR DNA analysis), were used for the culturing of genotype A, “Long” strain RSV. Flasks were inoculated with RSV and viral stocks were collected once cytopathic effect (CPE) was greater than 90%. Viral stocks in 25% sucrose media were snap frozen using liquid nitrogen to increase viral stability.
  • CPE cytopathic effect
  • Viral stock titers were quantified by tissue culture infectious dose 50% (TCID 50 ) using 8,000 cells per well and 3-fold viral dilutions across a 96-well plate, cultured for 4 days. Viral stock titers were also quantified by a plaque forming unit assay, as described elsewhere.
  • Hep-2 cells are seeded into the inner 60 wells of a 96-well plate at 8,000 cells per well in a volume of 50 ⁇ L using Growth Media (DMEM without phenol red, 1% L-Glut, 1% Penn/Strep, 1% nonessential amino acids, 10% heat-inactivated FBS). 2-fold serial dilutions of control and test compounds are added to the wells in duplicate in a total volume of 25 ⁇ L. Viral stock is then added to the wells at a multiplicity of infection (MOI) of 0.1 in a volume of 25 ⁇ L, bringing the total volume of each well to 100 ⁇ L.
  • MOI multiplicity of infection
  • Each 96-well plate has a control column of 6 wells with cells and virus but no compound (negative control, max CPE), a column with cells but no compound or virus (positive control, minimum CPE), and a column with no cells or virus or compound (background plate/reagent control).
  • the control wells with cells but no virus are given an additional 25 ⁇ L of growth media containing an equal quantity of sucrose as those wells receiving the viral stock in order to keep consistent in media and volume conditions.
  • the outer wells of the plate are filled with 125 ⁇ L of moat media (DMEM, 1% Penn/Strep) to act as athermal and evaporative moat around the test wells.
  • DMEM moat media
  • EC 50 each compound (Table 12). EC 50 ranges are as follows: A ⁇ 0.2 ⁇ M; B > 0.2 ⁇ M.
  • HMPV antiviral activity was evaluated using a recombinant version of HMPV CAN97-83 engineered to contain the coding sequence for enhanced green fluorescence protein (eGFP) in the 3’ end of the virus genome (MPV-GFP1, ViraTree).
  • eGFP enhanced green fluorescence protein
  • MPV-GFP1 ViraTree
  • Vero E6 cells ATCC # CCL-7
  • EMEM serum-free Eagle’s Modified Essential Medium
  • SF-EMEM penicillin-streptomycin
  • SF-EMEM serum-free OptiMEM (Invitrogen, Cat No.) (SF-OptiMEM) containing 0.5 pg/mL TPCK-Trypsin (VENDOR) and 1% penicillin-streptomycin was added to the cells at 50 ⁇ L/well.
  • SF-OptiMEM serum-free OptiMEM
  • VENDOR TPCK-Trypsin
  • penicillin-streptomycin was added to the cells at 50 ⁇ L/well.
  • Compounds were added into the 96-well plates using a JANUS automated liquid handling system (VENDOR). Compounds were initially diluted 1:50 into an intermediate 96-well plate containing SF- OptiMEM prior to transfer to the assay plate (25 ⁇ L/well).
  • Virus infection was performed by preparing a working stock of MPV-GFP1 at a multiplicity of infection (MOI) equal to 0.05/25 ⁇ L and aliquoting 25 ⁇ L of virus inoculum to the compound and positive control wells.
  • MOI multiplicity of infection
  • SF-OptiMEM was added (25 ⁇ L/well) to the appropriate wells to serve as a virus-free negative control for the assay.
  • the final DMSO concentration of all wells is 0.5%. Plates were incubated at 32°C, 5% CO 2 for 5 days.
  • A is the minimum y value
  • B is the maximum y value
  • C is the logEC 50 value
  • D is the slope factor.
  • TN/1501/A1 virus infections were performed in-suspension with LLC-MK 2 cells.
  • the cells were washed twice with PBS and removed from the cell-culture flask with 0.25% trypsin- EDTA (Thermo Fisher Scientific, MA).
  • the trypsin-EDTA was inactivated by resuspending in 2% fetal bovine serum (FBS) and OptiMEM (ThermoFisher Scientific, MA) containing 1% penicillin-streptomycin.
  • FBS fetal bovine serum
  • OptiMEM ThermoFisher Scientific, MA
  • TPCK-Trypsin serum-free (SF)-OptiMEM containing 4 pg/mL TPCK-Trypsin (Sigma Aldrich, MO), 1% penicillin-streptomycin (ThermoFisher Scientific, MA) and 100 pg/mL CaCh. Cells were counted and seeded at a density of 5,000 cells/well, 12.5 ⁇ L/well.
  • Virus infections were done at a multiplicity of infection (MOI) of 0.014 with 12.5 ⁇ L added per well.
  • MOI multiplicity of infection
  • SF-OptiMEM 12.5 ⁇ L/well, was added to the appropriate wells to serve as a virus-free negative control for the assay.
  • the final concentration of TPCK-trypsin was 2 ⁇ g/mL. Plates were incubated at 37°C, 5% CO 2 for 6 days.

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Abstract

La présente invention divulgue des composés de formule (I) ou des sels, esters ou promédicaments pharmaceutiquement acceptables de ceux-ci : Formule (I) qui inhibent le virus respiratoire syncytial humain (VRS) ou les inhibiteurs du métapneumovirus humain (MPVh). La présente invention concerne en outre des compositions pharmaceutiques comprenant les composés susmentionnés destinées à être administrées à un patient souffrant d'une infection à VRS ou MPVh. L'invention concerne également des méthodes de traitement d'une infection à VRS ou MPVh chez un patient par l'administration d'une composition pharmaceutique comprenant les composés de la présente invention.
PCT/US2022/024663 2022-04-13 2022-04-13 Composés hétérocycliques antiviraux WO2023200441A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9617289B2 (en) * 2012-10-16 2017-04-11 Janssen Sciences Ireland Uc RSV antiviral compounds
WO2021066922A1 (fr) * 2019-10-04 2021-04-08 Enanta Pharmaceuticals, Inc. Composés hétérocycliques antiviraux
US20210238188A1 (en) * 2020-01-24 2021-08-05 Enanta Pharmaceuticals, Inc. Heterocyclic compounds as anti-viral agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9617289B2 (en) * 2012-10-16 2017-04-11 Janssen Sciences Ireland Uc RSV antiviral compounds
WO2021066922A1 (fr) * 2019-10-04 2021-04-08 Enanta Pharmaceuticals, Inc. Composés hétérocycliques antiviraux
US20210238188A1 (en) * 2020-01-24 2021-08-05 Enanta Pharmaceuticals, Inc. Heterocyclic compounds as anti-viral agents

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