WO2009046098A1 - Nouveaux inhibiteurs de boronate cycliques de réplication du virus de l'hépatite c - Google Patents

Nouveaux inhibiteurs de boronate cycliques de réplication du virus de l'hépatite c Download PDF

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WO2009046098A1
WO2009046098A1 PCT/US2008/078439 US2008078439W WO2009046098A1 WO 2009046098 A1 WO2009046098 A1 WO 2009046098A1 US 2008078439 W US2008078439 W US 2008078439W WO 2009046098 A1 WO2009046098 A1 WO 2009046098A1
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optionally substituted
fluoro
groups
alkyl
methyl
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PCT/US2008/078439
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English (en)
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Dazhong Fan
Richard Lewis Jarvest
Linos Lazarides
Qun Li
Xianfeng Li
Yang Liu
Liang LIAO
Jacqueline Elizabeth Mordaunt
Zhi-Jie Ni
Jacob Plattner
Xuelei Qian
Martin John Slater
Gemma Victoria White
Yong Kang Zhang
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Smithkline Beecham Corporation
Anacor Pharmaceuticals, Inc.
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Publication of WO2009046098A1 publication Critical patent/WO2009046098A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp

Definitions

  • the present invention relates to novel cyclic boronate compounds useful as anti-viral agents. Specifically, the present invention involves novel inhibitors of Hepatitis C Virus (HCV) replication. BACKGROUND OF THE INVENTION
  • HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants.
  • Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.
  • Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection.
  • adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, (1997) Hepatology, 26 (suppl 1): 71S-77S).
  • HCV non- B hepatitis
  • flaviviruses e g yellow fever virus and Dengue virus types 1-4
  • pestiviruses e g bovine viral diarrhea virus, border disease virus, and classic swine fever virus
  • this RNA Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of ⁇ 3000 amino acids comprising both the structural and nonstructural viral proteins
  • This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice (1996) in B N Fields, D M Knipe and P M Howley (eds) Virology 2 nd Edition, p931-960, Raven Press, N Y )
  • a 3' NTR which roughly consists of three regions an ⁇ 40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyr ⁇ m ⁇ d ⁇ ne tract, and a highly conserved 98 base element also called the "3' X-ta ⁇ l" (Kolykhalov ef al (1996) J Virology, 70, 3363-3371 , Tanaka ef al , (1995) Biochem Bio
  • genotype 1 Although the predominant HCV genotype worldwide is genotype 1, this itself has two main subtypes, denoted 1a and 1b As seen from entries into the Los Alamos HCV database (www hcv lanl gov) (Table 1) there are regional differences in the distribution of these subtypes while genotype 1a is most abundant in the United States, the majority of sequences in Europe and Japan are from genotype 1b The other genotypes with significant are genotypes 2 and 3, each of which also exists in several subtypes
  • the NS3 protein is a 631 amino acid protein, and its first 180 amino acids encode a serine protease of the chymotrypsin family, the NS3-4A protease.
  • Various of the properties of the NS3 protease are summarised in recent reviews by White ef al. (White ef al. (2006) Progress in Medicinal Chemistry, 44, 65-107), Griffith et al. (Griffith et al. (2004) Annual Reports in Medicinal Chemistry, 39, 223-237) and Chen ef al. (Chen et al. (2005) Current Medicinal Chemistry, 12, 2317-1342).
  • the NS3-4A protease is considered to be essential for viral replication (Kolykhalov et al. (2000) Journal of Virology, 74, 2046-2051) and thus inhibition of NS3-4A protease activity is predicted to be useful to treat HCV infection.
  • the present invention involves novel cyclic boronate compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds in treating viral infection, especially HCV infection.
  • R 1 is selected from H; CrC ⁇ alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, Ci-C 6 alkyl and C 2 -C 6 alkenyl, the C 1 -Ce alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; and C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group
  • R A is H or C 1 -C 6 alkyl, optionally substituted with one or more fluoro groups; or R 1 and R 8 together with the two carbon atoms between them form a C 3 -C 7 cycloalkyl group, optionally substituted by one or more groups selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups) and fluoro;
  • R 2 is a group -X-(CH 2 ) m -R 10 , where m is 0, 1 or 2; X is selected from NH, O, O-C(O), S and bond;
  • R 10 is selected from C 6 -ioaryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, each optionally substituted by one or more groups selected from halo, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), OR B , NR B R B , SR B , SO 2 R B , NHSO 2 R 8 , CONHR B , NHCOR 8 , C ⁇ .
  • C 6 .i 0 aryl, 5 to 10-membered heteroaryl and 5 to 10- membered heterocyclyl may itself optionally be substituted by one, two or three groups selected from C 1 -C 6 alkyl, OR B , NR B R B , SR B , SO 2 R B , NHSO 2 R B , CONHR B and NHCOR B ;
  • Each R B is independently selected from H;
  • Ci-C 6 alkyl optionally substituted with one or more groups selected from fluoro, C M0 aryl (optionally substituted with one or more groups selected from halo and C r C 6 alkyl) and 5 to 10-membered heteroaryl (optionally substituted with one or more groups selected from halo and C 1 -C 6 alkyl);
  • C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro, C M0 aryl
  • R 3 is H; or R 2 and R 3 together with the two carbon atoms between them form a C 3 -C 7 cycloalkyl group, wherein the cycloalkyl group is optionally substituted by one or more groups selected independently from C 1 ⁇ alkyl and halo; when X is bond, R 20 is H or OH; otherwise R 20 is H;
  • R 4 is selected from H; C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the C 1 -C 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalky
  • R 4 , R B and the atoms between them form an 8 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH 2 group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds, and which heterocyclic ring may include one or more additional heteroatom groups selected from O, NR A , S, and SO 2 ;
  • Z is selected from -NHR 5 , -OR 5 , -R 5a and ;
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); and C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the C 1 -C 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; R 5a is selected from C 1 -C 8 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C
  • R 4a is selected from H; C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); C 3 - C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the C 1 -C 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloal
  • R 6 is selected from H; C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); and
  • C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the Ci-C 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups;
  • n is 1, 2 or 3; each Y group is selected from C(H) P R 7 , O and NR 9 , with the proviso that no two O or NR 9 groups are adjacent to each other in the ring; p being 1 if the Y group is only single bonded; p being 0 if the Y group is part of an aryl, heteroaryl or heterocyclic ring;
  • R 7 is selected from H; C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups
  • R 3 is selected from H; C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); C 3 -
  • C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the C 1 -C 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups;
  • C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl .group being optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups; C(O)R B ; CO 2 R B ; S(O)R 8 ; and SO 2 R B where R B is independently as defined above;
  • R 8 and R 30 are independently selected from H; C ⁇ Cealkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the C 1 -C 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7
  • 6 membered cyclic ring for example spirocyclopropane; or R 8 and an R 7 together with the atoms between them, or two R 7 groups together with the atoms between them, form a 5, 6 or 7 membered cyclic group which may be aromatic, which may include one or two heteroatom groups selected from O, NR A , S, and SO 2 ; and which may be optionally substituted by one, two or three groups selected from C 1 -C 5 alkyl (optionally substituted with one or more fluoro groups) and fluoro, R 3D is selected from H and Chalky!, or salts thereof.
  • the compounds of the present invention exhibit potency against the replication of HCV and therefore have the potential to achieve therapeutic efficacy in man.
  • a compound of Formula (I) or pharmaceutically acceptable salts thereof for use in human or veterinary medical therapy, particularly in the treatment or prophylaxis of viral infection, particularly flavivirus infection, for example HCV infection.
  • reference herein to therapy and/or treatment includes, but is not limited to prevention, retardation, prophylaxis, therapy and cure of the disease.
  • references herein to treatment or prophylaxis of HCV infection include treatment or prophylaxis of HCV-associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma.
  • a method for the treatment of a human or animal subject with viral infection, particularly HCV infection comprises administering to said human or animal subject an effective amount of a compound of Formula (I) or pharmaceutically acceptable salts thereof.
  • a compound of Formula (I) or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection, particularly HCV infection.
  • the compounds of Formula (I) or salts thereof may contain one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. All of these racemic compounds, enantiomers and diastereoisomers are contemplated to be within the scope of the present invention.
  • Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art.
  • chiral intermediate compounds may be resolved and used to prepare chiral compounds of Formula (I) or salts thereof.
  • the compounds of Formula (I) may exist in different tautomeric forms, i.e. one or more tautomeric forms. All tautomers, and mixtures thereof, are contemplated to be within the scope of the present invention. For example, a claim to 2-hydroxyquinolinyl would also cover its tautomeric form, ⁇ -quinolinonyl.
  • Diastereoisomers of compounds of Formula (I) may be obtained according to methods well known in the literature, for example by preparative HPLC or by chromatographic purifications.
  • R 1 is H or C 1 -C 4 alkyl. In a further aspect of the invention, R 1 is H.
  • R 1 , R 4 , and the atoms between them form a 11- to 17- membered heterocyclic ring (for example a 15-membered ring) which may be optionally substituted with one or more groups selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), fluoro, and a CH 2 group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds.
  • R 1 and R 8 together with the two carbon atoms between them form a C 3 -C 7 cycloalkyl group, optionally substituted by one or more groups selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), C 2 -C 6 alke ⁇ yl (optionally substituted with one or more fluoro groups) and fluoro.
  • R 2 is a group -X-(CH 2 )m-R 10 , where m is 0, 1 or 2. In one aspect of the invention, m is 0.
  • X is -O-, -OC(O)- or a bond. In a further aspect of the invention, X is -O- or -OC(O)-.
  • R 10 is selected from C 6 . 10 aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, each optionally substituted by one, two or three groups selected from halo, Ci-C B aIkyl (optionally substituted with one or more fiuoro groups), OR B , NR B R B , SR B , C 6 . 10 aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, which latter C 6 .
  • R 10 aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl may itself optionally be substituted by one, two or three groups selected from CrC B alkyl, OR B , and NR B R B .
  • R 10 can be for example pyridazone.
  • R 1 ⁇ is selected from 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo, CrCealkyl (optionally substituted with one or more fluoro groups), OR B , NR B R B , SR B , C e .
  • 10 aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl which latter C 6 .
  • 10 aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl may itself optionally be substituted by one, two or three groups selected from Ci-C 6 alkyl, OR B , and NR B R B .
  • R 10 is selected from 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo, OR B and Ci-C 6 alkyl (optionally substituted with one or more fluoro groups).
  • R 10 is selected from 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo and C 1 -Ce alkyl (optionally substituted with one or more fluoro groups). In a further aspect of the invention, R 10 is selected from 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo.
  • R 10 is selected from triazolyl, tetrazolyl, pyridazinyl, quinilinyl, isoquinolinyl or 1,3-dihydro-2H-isoindolyl, all of which may be optionally substituted with one or more groups selected from halo, OR B and C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups).
  • R 10 is selected from quinolinyl, isoquinolinyl or 1 ,3-dihydro-2W-isoindolyl, each of which may be optionally substituted with one or more groups selected from fluoro, chloro, methyl and methoxy.
  • R 1G is selected from triazolyl, tetrazolyl, pyridazinyl, isoquinolinyl or 1,3-dihydro- 2H-isoindolyl, all of which may be optionally substituted with one or more fluoro groups.
  • R 10 is selected from isoquinolinone or 1,3-dihydro-2H- isoindolyl, each of which may be optionally substituted with one or more fluoro groups.
  • R 10 is selected from isoquinolinyl or 1,3-dihydro-2H-isoindolyl, all of which may be optionally substituted with one or more fluoro groups.
  • R 10 is selected from
  • each R B is independently selected from H and C 1 -C 6 alkyl optionally substituted with one or more fluoro groups.
  • R 2 and R 3 together with the two carbon atoms between them form a C 3 . 7 cycloalkyl group, optionally substituted by one or more groups selected from C 1 ⁇ alkyl (for example methyl) and fluoro.
  • R 2 and R 3 together with the two carbon atoms between them form a C 3 . 5 cycloalkyl group, optionally substituted by one or more groups selected from C 1 ⁇ alkyl (for example methyl) and fluoro.
  • R 2 and R 3 together with the two carbon atoms between them form a C 3 cycloalkyl group or a C 5 cycloalkyl group, optionally substituted by one or more groups selected from C 1 ⁇ alkyl (for example methyl) and fluoro.
  • R 2 and R 3 together with the two carbon atoms between them form a dimethyl substituted cyclopropyl ring.
  • R 2 and R 3 together with the two carbon atoms between them form an unsubstituted cyclopentyl ring.
  • R 20 is H.
  • R 4 is selected from C 1 -C 6 alkyl optionally substituted with one or more fluoro groups, C 2 -C 6 alkenyl optionally substituted with one or more fluoro groups and C 3 -C 7 cycloalkyl optionally substituted with one or more fluoro groups. In a further aspect of the invention, R 4 is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl and C 3 -C 7 cycloalkyl. In one aspect of the invention, R 4 is selected from C 1 -C 6 alkyl optionally substituted with one or more fluoro groups and C 3 -C 7 cycloalkyl optionally substituted with one or more fluoro groups.
  • R 4 is selected from C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl. In a further aspect of the invention, R 4 is tert-butyl or cyclohexyl. In a further aspect of the invention, R 4 is tert-butyl.
  • R 4 , R 8 and the atoms between them form an 8 to 17- membered heterocyclic ring which may be optionally substituted with one or more groups selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH 2 group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds, and which heterocyclic ring may include one or more additional heteroatom groups selected from O, NR A , S, and SO 2 .
  • R 4 , R 8 and the atoms between them form an 12 to
  • 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH 2 group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds.
  • Z is In one aspect of the invention, Z is In a further aspect
  • Z is selected from In a further aspect of the invention, Z is selected from -NHR 5 or -OR 5 .
  • Z is selected from -R 5a and
  • R 5 is selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), C 3 -C 7 cycloalkyl (optionally substituted with one or more fluoro groups), and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups). In a further aspect of the invention, R 5 is selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 2 -C 6 alkenyl.
  • R 5 is selected from C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl
  • R 5 is tert-butyl or cyclohexyl
  • R 5 is selected from tert-butyl, cyclopentyl and cyclopentenyl
  • R 5 is selected from tert-butyl and cyclopentyl
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted with one or more fluoro groups
  • R 5a is selected from CrC 6 alkyl optionally substituted with one or more fluoro groups, C3-C 7 cycloalkyl optionally substituted with one or more fluoro groups, Ce 10 aryl optionally substituted by one, two or three groups selected from Ci-Ce alkyl (optionally substituted with one or more fluoro groups), C 1 -C 6 alkoxy (optionally substituted with one or more fluoro groups), hydroxy and halo, and 5 to 10-membered heteroaryl optionally substituted by one, two or three groups selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), C 1 -C 6 alkoxy (optionally substituted with one or more fluoro groups), hydroxy and halo
  • R 5a is tert-butyl or cyclohexyl
  • R 5a is selected from 5 to 10-membered heteroaryl optionally substituted by one, two or three
  • R 4a is selected from Ci-C 6 alkyl optionally substituted with one or more fluoro groups and C 3 -C 7 cycloalkyl optionally substituted with one or more fluoro groups
  • R 4a is tert-butyl or cyclohexyl
  • R 4a is cyclohexyl
  • R 6 is H or C 1 -C 6 alkyl optionally substituted with one or more fluoro groups
  • R 6 is H or C 1 -C 6 alkyl optionally substituted with one or more fluoro groups
  • R 6 is H
  • Y is C(H) P R 7
  • n is 1 and Y is CH 2
  • n is 2 and Y n is CH 2 CH 2
  • n is 3 and Y n is CH 2 CH 2 CH 2 (i e each of the three individual Y groups is CH 2 )
  • R 7 is H or C 1 -C 6 alkyl optionally substituted with one or more fluoro groups In a further aspect of the invention, R 7 is H
  • R 8 is H, C r C 6 alkyl optionally substituted with one or more fluoro groups, C 2 -C 6 alkenyl optionally substituted with one or more fluoro groups, or C 3 -C 7 cycloalkyl optionally substituted with one or more fluoro groups
  • R s is H, methyl, ethyl, isopropyl, propenyl (for example, allyl), ethenyl or cyclopropyl
  • R B is H, ethyl, isopropyl, ethenyl or cyclopropyl
  • R 8 is H or C 1 -C 6 alkyl optionally substituted with one or more fluoro groups
  • R 30 is H, d-C 6 aIkyl optionally substituted with one or more fluoro groups, C 2 -C 6 alkenyl optionally
  • R 30 is H or d-Caalkyl optionally substituted with one or more fluoro groups. In a further aspect of the invention, R 30 is H or methyl. In a further aspect of the invention, R 30 is H.
  • R ⁇ and R 30 together with the carbon atom to which they are attached form a spirocyclopropane ring.
  • R 9 is selected from H, C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro, C(O)R B , and SO 2 R B .
  • n is 1 and Y is C(R 7 ), n is 2 and Y n is C(R 7 JCH 2 , or n is 3 and Y n is C(R 7 JCH 2 CH 2 ; R 7 and R 8 together with the atoms between them (including R 30 ) form a phenyl ring optionally substituted by one, two or three groups selected from C 1 -C 6 alkyl (oprtionally substitutes by one or more fluoro groups) and fluoro.
  • R 1 is H;
  • R 2 is -X-(CH 2 ) m -R 10 ;
  • m is 0;
  • R 1D is selected from 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl each optionally substituted by one, two or three groups selected from halo and Ci-C 6 alkyl (optionally
  • R 1 is H;
  • R 20 is H;
  • R 2 and R 3 together with the two carbon atoms between them form a C 3 . 5 cycloalkyl group, optionally substituted by one or more groups selected from C h alky! (for example methyl) and fluoro;
  • R 4 is selected from C 1 -C 6
  • R 6 is selected from CrC ⁇ alkyl and C 3 -C 7 cycloalkyl
  • R 5a is selected from 5 to 10-membered heteroaryl
  • R 4a is selected from C 1 -C 6 alkyl optionally substituted with one or more fluoro groups and C 3 -C 7 cycloalkyl optionally substituted with one or more fluoro groups
  • R 6 is H; ⁇ is 1 , 2 or 3;
  • Y is C(H) P R 7 ;
  • R 7 is H;
  • R 8 is H, C r C ⁇ aIkyl optionally substituted with one or more fluoro groups, C 2 -C 6 alkenyl optionally substituted with one or more fluoro groups, or C 3 -C 7 cycloalkyl optionally substituted with one or more fluoro groups; and
  • R 30 is H or CrC ⁇
  • R 1 is H;
  • R 2 is -X-(CHz) n -R 10 , m is 0,
  • X is -O- or -OC(O)- and
  • R 10 is selected from
  • R 20 is H; R 4 is tert-butyl or cyclohexyl; Z is selected from -NHR 5 , -OR 5 , -R 5a and pyrazinyl; R 4a is selected from cyclohexyl; R s is H; n is 1 , 2 or 3; Y is C(H) P R 7 ; R 7 is H; R 8 is H, ethyl, ethylene, cyclopropane; and R 30 is H, or salts thereof.
  • R 1 is selected from H; Ci-C 6 aikyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the Ci-C 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; and C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl
  • R A is H or Ci-C 6 alkyl, optionally substituted with one or more fluoro groups; or R 1 and R ⁇ together with the two carbon atoms between them form a C 3 -C 7 cycloalkyl group, optionally substituted by one or more groups selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups) and fluoro;
  • R 2 is a group -X-(CH 2 ) m -R 10 , where m is 0, 1 or 2; X is selected from NH, O, O-C(O), S and bond;
  • R 10 is selected from C ⁇ 10 aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, each optionally substituted by one or more groups selected from d-C 6 alkyl (optionally substituted with one or more fluoro groups), OR B , NR B R B , SR B , SO 2 R B , NHSO 2 R 8 , CONHR B , NHCOR B , C S .
  • each R B is independently selected from H; C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro, Ce- K i ary' (optionally substituted with one or more groups selected from halo and C 1 -C 6 alkyl) and 5 to 10-membered heteroaryl (optionally substituted with one or more groups selected from halo and Ci-C 6 alkyl); C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro, C 6 .
  • R 3 is H; when X is bond, R 20 is H or OH; otherwise R 20 is H;
  • R 4 is selected from H; C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, Ci-C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the C r C 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; and C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalky
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); and C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the Ci-C 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups;
  • R 5a is selected from C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the Ci-C 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl
  • R 4a is selected from H; C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); C 3 - C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the CrC 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalky
  • R 6 is selected from H; C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); and C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the CrC 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; n is 1, 2 or 3; each Y group is selected from C(H) P R 7 , O and NR 9 , with the proviso that no two O or NR 9 groups are adjacent to each other
  • R 9 is selected from H; C f -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group being optionally substituted with one or more groups selected from fluoro, CrC 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups); C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the CrC 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; and C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl, the C 3 -C 7 cycloalkyl group
  • R 1 is H; 20
  • R 2 is a group -X-R 10 ;
  • X is selected from O, O-C(O) and bond
  • R 1 ⁇ is selected from C 6 . 1D aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, each optionally substituted by one or more groups selected from halo, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), OR B and NR B R B ;
  • Each R B is independently selected from H and C 1 -C 6 alkyl optionally substituted with one or 30 more fluoro groups;
  • R 3 is H; or R 2 and R 3 together with the two carbon atoms between them form a C 3 . 7 cycloalkyl group, 35 optionally substituted by one or more groups selected from Ci_ ⁇ alkyl (for example methyl) and fluoro;
  • R 20 is H
  • R 4 is selected from Ci-C 6 alkyl optionally substituted with one or more fluoro groups; C 3 -C 7
  • cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and
  • C 2 -C 6 alkenyl the C 1 -C 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; and C 2 -C 6 alkenyl optionally substituted with one or more fluoro groups; or R 4 , R ⁇ and the atoms between them form an 8 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH 2 group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds, and which heterocyclic ring may include one or more heteroatoms selected from O, NR A , S and SO 2 ;
  • Z is selected from -NHR 5 , -OR 5 , -R 5a and ;
  • R 5 is selected from C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl; and C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups) and C 2 -C 6 alkenyl (optionally substituted with one or more fluoro groups);
  • R 5a is selected from C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl; C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro and C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups); C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl (optionally substituted with one or more fluoro groups); C 6 .i 0 aryl optionally substituted by one, two or three groups selected from Ci-C 6 alkyl (optionally substituted with one or more fluoro groups), OR A , NR A R A and halo; and 5 to 10-membered heteroaryl optionally substituted by one, two or three groups selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), OR A , NR
  • R 4a is selected from H; C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl; C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, Ci-C 6 alkyl (optionally substituted with one or more fluoro groups); and C 2 -C 6 alkenyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl (optionally substituted with one or more fluoro groups).
  • R A is H or C 1 -C 6 alkyl, optionally substituted with one or more fluoro groups
  • R 6 is selected from H; C 1 -C 6 alkyl optionally substituted with one or more fluoro groups; and C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro, C 1 -C 6 alkyl and C 2 -C 6 alkenyl, the CrC 6 alkyl and C 2 -C 6 alkenyl groups being optionally substituted with one or more fluoro groups; n is 1, 2 or 3; each Y group is selected from C(H)R 7 , O and NR 9 , with the proviso that no two O or NR 9 groups are adjacent to each other in the ring;
  • R 7 and R 9 are each independently selected from H and C 1 -C 6 alkyl optionally substituted with one or more fluoro groups;
  • R 8 is selected from H; C 1 -C 6 alkyl optionally substituted with one or more fluoro groups; C 3 -C 7 cycloalkyl optionally substituted with one or more fluroro groups; and C 2 -C 6 alkenyl optionally substituted with one or more fluoro groups; or salts, solvates or esters thereof.
  • R 1 is H;
  • R 2 is a group -X-R 10 ;
  • X is selected from O and O-C(O);
  • R 10 is selected from C ⁇ -io aryl, 5 to 10-membered heteroaryl and 5 to 10-membered heterocyclyl, each optionally substituted by one or more groups selected from halo, C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), OR B and NR B R B ;
  • Each R B is independently selected from H, C 1 -C 6 alkyl optionally substituted with one or more fluoro groups;
  • R 3 is H; or R 2 and R 3 together with the two carbon atoms between them form a C 3 . 7 cycloalkyl group, optionally substituted by one or more groups selected from Ci_ ⁇ alkyl (optionally substituted with one or more fluoro groups) and fluoro;
  • R 20 is H
  • R 4 is selected from CrC 6 alkyl optionally substituted with one or more fluoro groups; C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro and C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups); and C 2 -C 6 alkenyl optionally substituted with one or more fluoro groups; or R 4 , R 8 and the atoms between them form an 12 to 17-membered heterocyclic ring which may be optionally substituted with one or more groups selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), fluoro, oxo, and a CH 2 group bridging two neighbouring carbon atoms to form a cyclopropyl group in the chain, which heterocyclic ring may include one or more double bonds;
  • Z is selected from -NHR 5 , -OR 5 and
  • R 5 is selected from Ci-C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl; and C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro and C 1 -C 5 alkyl (optionally substituted with one or more fluoro groups);
  • R 5a is selected from C$-io aryl optionally substituted by one, two or three groups selected from C- I -C 6 alkyl (optionally substituted with one or more fluoro groups), OR ⁇ , NR A R A and halo; and 5 to 10-membered heteroaryl optionally substituted by one, two or three groups selected from C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups), OR ⁇ , NR A R A and halo;
  • R 4a is selected from H; C 1 -C 6 alkyl optionally substituted with one or more groups selected from fluoro and C 3 -C 7 cycloalkyl; and C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from fluoro and C 1 -C 6 alkyl (optionally substituted with one or more fluoro groups).
  • R A is H or C 1 -C 6 alkyl, optionally substituted with one or more fluoro groups
  • R 6 is selected from H and C 1 -C 6 alkyl optionally substituted with one or more fluoro groups; n is 1 , 2 or 3; each Y group is CH 2 ;
  • R B is selected from H; C 1 -C 6 alkyl optionally substituted with one or more fluoro groups; C 3 -C 7 cycloalkyl optionally substituted with one or more fluroro groups; and C 2 -C 6 alkenyl optionally substituted with one or more fluoro groups; or salts, solvates or esters thereof.
  • a compound of Formula (1a) as defined above, or salts thereof there is provided a compound of Formula (1a) as defined above, or salts thereof.
  • the compound has a structure which is a member selected from-
  • the compound has a structure which is a member selected from
  • R 2 , R 3 , R 4 , R 20 and Z are as described herein.
  • alkyl refers to a hydrocarbon group.
  • the alkyl hydrocarbon group may be linear or branched. Examples of such groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, ⁇ -pentyl, isopentyl, neopentyl or hexyl and the like. If specified herein, the alkyl group may be substituted by one or more substituents.
  • alkenyl refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds.
  • the alkenyl group has from 2 to 6 carbon atoms. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl and the like. If specified herein, the alkenyl group may be substituted by one or more substituents.
  • cycloalkyl refers to a cyclic hydrocarbon group.
  • the hydrocarbon group may be saturated or unsaturated, monocyclic or bridged bicyclic.
  • examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.
  • examples of such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the like.
  • the cycloalkyl group has from 5 to 7 carbon atoms.
  • cycloalkyl moieties are cyclohexenyl, cyclopentenyl and cyclohexyl If specified herein, the cycloalkyl group may be substituted by one or more substituents
  • alkoxy refers to an -O-alkyl group wherein alkyl is as defined herein Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like If specified herein, the alkoxy group may be substituted by one or more substituents
  • aryl refers to an aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems
  • Aryl includes carbocyclic aryl and biaryl groups
  • aryl moieties contain 6-10 carbon atoms
  • aryl may be phenyl If specified herein, the aryl group may be substituted by one or more substituents
  • halogen or “halo” refer to a fluorine, chlorine, bromine or iodine atom References to "fluoro", “chloro”, “bromo” or “iodo” should be construed accordingly
  • heteroaryl refers to a 5-, 6-, 8-, 9- or 10-membered cyclic or bicyclic group with at least one ring having a conjugated pi-electron system and comprising one to four heteroatoms selected from N, O and S
  • heteroaryl moieties are selected from (where applicable) pyridine, pyrazine, thiazole, thiophene, oxadiazole, oxazole, py ⁇ midine, py ⁇ dazine, t ⁇ azole, tetrazole, benzodioxole, benzofuran, benzodioxin, indole, benzimidazole, benzofuran, indole, indazole, isoindole, benzothiophene, benzothiazole, benzoxazole, benzisoxazole, benzisothiazole, benzotriazole, furopy
  • the second ring may be a phenyl ring, such that the overall group is a fused bicyclic heterocycle comprising a 5- or 6- membered heterocycle fused to a phenyl group.
  • heterocyclic moieties are selected from (where applicable) aziridinyl, oxetanyl, oxiranyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxathiolanyl, oxathianyl, diazepanyl, dihydrofuranyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, tetra
  • heterocyclic groups are within the scope of this invention.
  • pinanediol borate refers 2,9,9-trimethyl-3,5-dioxa-4- boratricyclo[6.1.1.0 2l6 ]decane.
  • the present invention provides a compound chosen from the group consisting of:
  • compositions of the present invention are pharmaceutically acceptable salt complexes
  • present invention also covers the pharmaceutically acceptable salts of the compounds of
  • pharmaceutically acceptable salts includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts
  • pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent
  • the invention provides a pharmaceutically acceptable salt of a compound of Formula (I) and embodiments thereof
  • compounds of Formula I may contain an acidic functional group and may therefore be capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable base
  • a pharmaceutically acceptable base addition salt may be formed by reaction of a compound of Formula I with a suitable strong base, optionally in a suitable solvent such as an organic solvent, to give the base addition salt which may be isolated for example by crystallisation and filtration
  • Pharmaceutically acceptable base salts include ammonium salts (for example ammonium or tetraalkylammonium), metal salts, for example alkali-metal or alkaline-earth-metal salts (such as hydroxides, sodium, potassium, calcium or magnesium), organic amines (such as tris [also known as tromethamine or t ⁇ s(hydroxymethyl)am ⁇ nomethane], ethanolamine, diethylamine, t ⁇ ethanolamine, choline, isopropyl
  • a pharmaceutically acceptable acid addition salt of a compound of Formula I is a salt of a strong acid, for example a hydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, perchlorate, phosphate p-tolue ⁇ esulfon ⁇ c, benzenesulfonic or methanesulfonic salt
  • Suitable pharmaceutically acceptable salts of the compounds of Formula (I) include acid salts, for example sodium, potassium, calcium, magnesium and tetraalkylammonium and the like, or mono- or d ⁇ - basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids, organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p- toluenesulfomc acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like
  • Other non-pharmaceutically acceptable salts, for example oxalates may be used, for example in the isolation of compounds of Formula (I), and are included within the scope of this invention
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the
  • the salts of a compound of Formula (I) may be prepared by contacting approp ⁇ ate stoichiometric amounts of the free acid with the appropriate base in a suitable solvent
  • the free acid of a compound of Formula (I) may for example be in solution with the approp ⁇ ate base added as a solid or both the free acid of a compound of Formula (I) and the appropriate acid may independently be in solution
  • Suitable solvents for solubilising a compound of Formula (I) free acid include for example alcohols such as isopropanol, ketones such as acetone, acetonitrile or toluene If the base is to be added as a solution in a solvent, the solvent used may include acetone, methanol or water
  • the salts of a compound of Formula (I) may be isolated in solid form by conventional means from a solution thereof obtained as above
  • a non-crystalline salt may be prepared by precipitation from solution, spray drying or freeze drying of solutions, evaporating a solution to a glass, or
  • the salts of a compound of Formula (I) may be prepared by directly crystallising from a solvent in which the salt has limited solubility, or by triturating or otherwise crystallising a noncrystalline salt
  • organic solvents such as acetone, acetonitrile, butanone, 1- butanol, ethanol, 1-propanol or tetrahydrofuran or mixtures of such solvents may be used
  • An improved yield of the salts may be obtained by the evaporation of some or all of the solvent or by crystallisation at elevated temperature followed by controlled cooling, for example in stages Careful control of the precipitation temperature and seeding may be used to improve the reproducibility of the production process and the particle size distribution and form of the product
  • Salts and solvates of compounds of Formula (I) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable
  • salts and solvates having non-pharmaceutically acceptable counte ⁇ ons or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of Formula (I) or salts, solvates or esters thereof and their pharmaceutically acceptable salts and solvates
  • certain protected derivatives of compounds of Formula (I) which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds defined in the first aspect which are pharmacologically active
  • Such derivatives may therefore be described as "prodrugs" All protected derivatives and prodrugs of compounds defined in the first aspect are included within the scope of the invention Examples of suitable pro-drugs for the compounds of the present invention are descnbed in Drugs
  • the present invention also relates to pharmaceutically acceptable esters of the compounds of Formula (I), for example carboxylic acid esters -COOR, in which R is selected from straight or branched chain alkyl, for example n-propyl, n-butyl, alkoxyalkyl (e g methoxymethyl), aralkyl (e g benzyl), aryloxyalkyl (e g phenoxymethyl), aryl (e g phenyl optionally substituted by halogen, -C 1 4 alkyl or -C 1J( alkoxy or amino), or for example -CH 2 OC(O)R' or - CH 2 OCO 2 R' in which R' is alkyl (e g R' is f-butyl)
  • any alkyl moiety present in such esters preferably contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms Any aryl moiety present in such esters preferably comprises a phenyl group
  • R is
  • the compound of Formula (I) is in the form of parent compound, a salt or a solvate
  • crystalline forms of the compounds of Formula (I) or salts and solvates thereof may exist in one or more polymorphic form, which are included in the present invention
  • pharmaceutically acceptable used in relation to an ingredient (such as an active ingredient, a salt thereof or an excipient) which may be included in a pharmaceutical formulation for administration to a patient, refers to that ingredient being acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical formulation and not being deleterious to the recipient thereof.
  • R 1 , R 6 , R 8 , R 30 , Y and n are as defined above, by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DWIF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DWIF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DWIF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DWIF.
  • a chloroformate such as isobutyl chloroformate
  • a base such as N-methyl morpholine
  • Compounds of Formula (II) may be prepared using standard methods, for example methods described in White ef a/ (2006) and references cited therein.
  • Compounds of Formula (II) in which R 4 , R 8 and the atoms between them form an 8 to 17- membered heterocyclic ring as defined above may be prepared from compounds of Formula (II) in which both R 4 and R 8 contain alkenyl groups by standard ring macrocyclization reaction in the presence of a catalyst, for example Zhan-1 B catalyst ((1 ,3-dimesitylimidazolidin-2-yl)(5- (N,N-dimethylsulfamoyl)-2-isopropoxybenzylidene)ruthenium(V) chloride), in a suitable solvent such as dichloromethane or toluene at certain temperature such as r.t. to 111 0 C.
  • a catalyst for example Zhan-1 B catalyst ((1 ,3-dimesitylimidazolidin-2
  • Compounds of Formula (I) may also be prepared from compounds of Formulae (H) and (IV) wherein R 1 , R ⁇ , R 8 , R 30 , Y and n are as defined above and P and P' are TMS groups, by use of HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • R 1 , R 6 , R 8 , R 30 , Y and n are as defined above and P and P' are suitable protecting groups.
  • compounds of Formula (III) may be prepared from compounds of Formula (Ilia) by treatment with acid, for example aqueous hydrochloric acid or citric acid optionally in combination with a polymer supported phenyl boronic acid in a suitable solvent such as acetonitrile or water or combinations thereof.
  • acid for example aqueous hydrochloric acid or citric acid optionally in combination with a polymer supported phenyl boronic acid in a suitable solvent such as acetonitrile or water or combinations thereof.
  • Compounds of Formula (Ilia) may also be prepared from compounds of Formula (VIb) wherein R 1 , R 6 , R 8 , R 30 , Y and n are as defined above and P, P' and R" are suitable protecting groups, by treatment with acid, for example aqueous hydrochloric acid in a suitable solvent such as 1 ,4-dioxane and optionally hexane.
  • acid for example aqueous hydrochloric acid in a suitable solvent such as 1 ,4-dioxane and optionally hexane.
  • R 1 , R 8 , R 30 , Y, n, P and P' are as defined above and the R groups are selected from H and alkyl, or the two R groups together form a cyclic group, by treatment with acid, for example hydrochloric acid or citric acid optionally in combination with a polymer supported phenyl boronic acid in a suitable solvent such as acetonitrile or water or combinations thereof, or by dehydration preferably at elevated temperature such as 100-200°C, for example using phosphorous oxychloride.
  • acid for example hydrochloric acid or citric acid optionally in combination with a polymer supported phenyl boronic acid in a suitable solvent such as acetonitrile or water or combinations thereof, or by dehydration preferably at elevated temperature such as 100-200°C, for example using phosphorous oxychloride.
  • Compounds of Formula (lllb) may be prepared from compounds of Formula (Ilia) through the removal of the R" protecting group. Compounds of Formula (lllb) may also be prepared from compounds of Formula (V) through the removal of the PP' protecting group;
  • a suitable solvent such as THF
  • R may be interchanged by standard methods.
  • a compound in which R is H can be converted into a compound in which R is alkyl (or the two R groups together form a cyclic group) by addition of an appropriate alcohol.
  • compounds in which R is alkyl (or the two R groups together form a cyclic group) can be converted into a compound in which R is H by reaction with, for example, sodium periodate, optionally in the presence of ammonium acetate, in a suitable solvent, for example aqueous methanol or aqueous acetone.
  • R 6 groups may be interconverted such that a particular R 6 group is provided in a particular required compound (IV).
  • R 1 , R B , R 30 , Y, n, P, P' and R are as defined above (and the two R groups are preferably H) and X is a halide, for example bromide or iodide, in a suitable solvent, for example DMF, DCM or THF, in the presence of a base, for example pyridine, triethylamine or diiospropylamine, optionally with heating.
  • a suitable solvent for example DMF, DCM or THF
  • a base for example pyridine, triethylamine or diiospropylamine, optionally with heating.
  • a suitable base for example pyridine, triethylamine, or diisopropylamine
  • R 1 , R 8 , R 30 , Y, n, P, P' and R are as defined above and R" is a protecting group, for example p-methoxy benzyl, by deprotection of the protecting group R".
  • R" tert-butyldiphenylsilyl
  • deprotection may be achieved using a fluoride source such as tetrabutyl ammonium fluoride, in a suitable solvent, for example THF.
  • Compounds of Formula (Via) may be prepared from compounds of Formula (V) by addition of the protecting group R" to the OH group.
  • Compounds of Formula (VII) may be prepared from compounds of Formula (VlII)
  • Compounds of Formula (VIII) may (VIIId) (VIIId) wherein R B , Y, n, R are as defined above for Formula (VIII), by treatment with a protective reagent, for example TBSCI, and an activating agent, for example imidazole, in a suitable solvent, for example DMF, at a suitable temperature, for example 20°C.
  • a protective reagent for example TBSCI
  • an activating agent for example imidazole
  • Grignard reagents of Formula RO-Y n -CHR 8 - CHR 1 - MgBr may be prepared from the corresponding halides of Formula RO-Y n -CHR 8 - CHR 1 -X where X is a halide, using magnesium, as is well known in the art.
  • Compounds of Formula R'O-Y ⁇ -CHR 8 -CHR 1 -X are well known in the art.
  • Compounds of Formula (VIII) are also very well known in the art and are prepared from compound of Formula (IX)
  • R 8 , Y, n and R" are as defined above, using an alcohol ROH, for example methanol, or a diol, for example pinacol, catechol, pinene diol, (1 R), (2R)-1,2-dicyclohexyl-1 ,2- ethanediol, (1S), (2S)-1 ,2-dicyclohexyl-1 ,2-ethanediol, or ethylene glycol, in a suitable solvent, for example diethylether.
  • ROH for example methanol
  • a diol for example pinacol, catechol, pinene diol, (1 R), (2R)-1,2-dicyclohexyl-1 ,2- ethanediol, (1S), (2S)-1 ,2-dicyclohexyl-1 ,2-ethanediol, or ethylene glycol, in a suitable solvent, for example diethylether.
  • Compounds of Formula (VIII) may also be prepared by treatment of compounds of Formula B(OR) 3 with Grignard reagents of Formula RO-Y n -CHR 8 - MgX in a suitable solvent such as THF.
  • Grignard reagents of Formula RO-Y n -CHR 8 - MgBr may be prepared from the corresponding halides of Formula R'O-Y n -CHR 8 -X where X is a halide, using magnesium, as is well known in the art.
  • Compounds of Formula R'O-Y ⁇ -CHR 8 -X are well known in the art.
  • Compounds of Formula (VIII) may also be prepared by treatment of compounds of Formula (IXa) in which X is a halogen such as chloride, with Grignard reagents of Formula R 1 O-Yn- MgX in a suitable solvent such as THF.
  • Grignard reagents of Formula RO-Y n -MgBr may be prepared from the corresponding halides of Formula RO-Y n -X where X is a halide, using magnesium, as is well known in the art.
  • Compounds of Formula R 1 O-Y n -X are well known in the art.
  • compounds of Formula (I) may be prepared from compounds of Formula (Xl):
  • compounds of Formula (I) may be prepared from compounds of Formula (Xl), by treatment with a boronic acid such as isobutyl boro ⁇ ic acid in the presence of an acid such as hydrochloric acid in a suitable solvent such as methanol or hexanes or combinations thereof.
  • Compounds of Formula (Xl) may be prepared from compounds of Formula (Ilia) by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF. Subsequent deprotectio ⁇ of a protecting group R" according to methods described herein or to methods generally known in the art will produce a compound of Formula (Xl).
  • Compounds of Formula (Xl) may be prepared from compounds of Formula (MIb) by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • Compounds of Formula (Xl) may be prepared from compounds of Formula (V) by deprotection of the amino group (as set out above for the preparation of compounds of Formula (III) from compounds of Formula (IV)) followed by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • compounds of Formula (Xl) may be prepared from compounds of Formula (V) by coupling directly using HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • Compounds of Formula (Xl) may be prepared from compounds of Formula (Vl) by deprotection of the amino group (as set out above for the preparation of compounds of Formula (III) from compounds of Formula (IV)) followed by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • compounds of Formula (Xl) may be prepared from compounds of Formula (Vl) by coupling directly using HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF. Subsequent removal of the leaving group R' (by hydrolysis, for example) according to methods described herein or to methods generally known in the art will produce a compound of Formula (Xl).
  • a base for example pyridine, triethylamine, or diisopropylamine
  • a suitable solvent for example DMF
  • Compounds of Formula (Xl) may be prepared from compounds of Formula (VIb) by deprotection of the amino group (as set out above for the preparation of compounds of Formula (III) from compounds of Formula (IV)) followed by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • compounds of Formula (Xl) may be prepared from compounds of Formula (VIb) by coupling directly using HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF. Subsequent deprotection of a protecting group R" according to methods described herein or to methods generally known in the art will produce a compound of Formula (Xl). Similarly, compounds of Formula (Xl) may be prepared from compounds of Formula (XIa):
  • R 2 , R 20 , R 30 , R 3 , R 4 , Z, R 1 , R 8 , Y, R and n are as defined above and R" is a protecting group, by a process analogous to the process for preparing compound (V) from compound (VIb).
  • R" is a hydroxy protecting group, for example para- methoxybenzyl, by treatment with DDQ (2,3-dichloro-5,6-dicyano-benzoquinone) in a suitable solvent such as dichloromethane and water or combinations thereof, or by treatment with hydrochloric acid in suitable solvent such as dioxane.
  • compounds of Formula (I) may be prepared from compounds of Formula (XIa) in which R" is a para-methoxybenzyl protecting group, by treatment with a boronic acid such as isobutyl boronic acid in the presence of an acid such as hydrochloric acid in a suitable solvent such as methanol or hexanes or combinations thereof, or alternatively using DDQ (2,3-dichloro-5,6-dicyano-benzoquinone) in a suitable solvent such as dichloromethane and water or combinations thereof, or by treatment with hydrochloric acid in suitable solvent such as dioxane, or alternatively in combination of these two deprotection methods.
  • a boronic acid such as isobutyl boronic acid in the presence of an acid such as hydrochloric acid in a suitable solvent such as methanol or hexanes or combinations thereof
  • DDQ 2,3-dichloro-5,6-dicyano-benzoquinone
  • suitable solvent such as
  • Compounds of Formula (XIa) in which R 4 , R ⁇ and the atoms between them form an 8 to 17- membered heterocyclic ring as defined above may be prepared from compounds of Formula (XIa) in which both R 4 and R 8 contain alkenyl groups by standard ring macrocyclization reaction in the presence of a catalyst, for example Zhan-1B catalyst ((1,3- dimesitylimidazolidin-2-yl)(5-(N,N-dimethylsulfamoyl)-2-isopropoxybenzylidene)ruthenium(V) chloride), in a suitable solvent such as dichloromethane or toluene at certain temperature such as r.t. to 111 0 C.
  • a catalyst for example Zhan-1B catalyst ((1,3- dimesitylimidazolidin-2-yl)(5-(N,N-dimethylsulfamoyl)-2-isopropoxybenzylidene)ruthenium(V)
  • Compounds of Formula (XIa) may be prepared from compounds of Formula (Ilia) by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • Compounds of Formula (XIa) may be prepared from compounds of Formula (Vl) by deprotection of the amino group (as set out above for the preparation of compounds of Formula (III) from compounds of Formula (IV)) followed by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DWIF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DWIF.
  • compounds of Formula (XIa) may be prepared from compounds of Formula (Vl) by coupling directly using HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DWIF. Subsequent replacement of the leaving group R' with a protecting group R" according to methods described herein or to methods generally known in the art will produce a compound of Formula (XIa).
  • a base for example pyridine, triethylamine, or diisopropylamine
  • Compounds of Formula (XIa) may be prepared from compounds of Formula (VIb) by deprotection of the amino group (as set out above for the preparation of compounds of Formula (III) from compounds of Formula (IV)) followed by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • compounds of Formula (XIa) may be prepared from compounds of Formula (VIb) by coupling directly using HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • Compounds of Formula (XIb) may be prepared from compounds of Formula (Vl) by deprotection of the amino group (as set out above for the preparation of compounds of Formula (III) from compounds of Formula (IV)) followed by coupling to a compound of Formula (II) by standard coupling methodologies, for example by use of HATU or CDI, optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • compounds of Formula (Xl) may be prepared from compounds of Formula (Vl) by coupling directly using HATU optionally in the presence of a base, for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • a base for example pyridine, triethylamine, or diisopropylamine in a suitable solvent, for example DMF.
  • R 1 , R 6 , R 8 , R 30 , Y and n are as defined above, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (III) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (III) wherein the compound is selected from the group consisting of 3-amino-1 ,2-oxaborinan-2-ol; 3-amino-1 ,2-oxaborepan-2-ol; 3-aminobenzo[d][1 ,2]oxaborol-2(3H)-ol; or a salt thereof.
  • R 1 , R 8 , R, R 30 , Y and n are as defined above, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (HIb) or a salt thereof.
  • a compound of Formula (IMb) wherein the compound is (3R)-3-Amino-3-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0 2 ⁇ ]dec-4-yl]-1- propanol(3R)-3-amino-3-[(1 S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.
  • R 1 , R 6 , R 8 , R 30 , Y and n are as defined above and P and P' are suitable protecting groups as defined herein, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (IV) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (IV) wherein the compound is [2-(Butyloxy)-1,2-oxaborinan-3-yl]bis(trimethylsilyl)amine or a salt thereof.
  • R 1 , R 8 , R 30 , Y, n, P, P' and R are as defined above and R" is a protecting group, as defined herein, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (VIb) or a salt thereof. In a further aspect of the invention, there is provided a compound of Formula (VIb) wherein the compound is selected from the group consisting of
  • X, R 1 , R 8 , R 30 , Y, n and R" are as defined herein and the R groups are alkyl groups, or the two R groups together form a cyclic group, or salts thereof, may be useful as intermediates for the synthesis of compounds of Formula (I). Therefore, in a further aspect of the invention, there is provided a compound of Formula (VII) or a salt thereof.
  • a compound of Formula (VII) wherein the compound is selected from the group consisting of ⁇ [5-Chloro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pentyl]oxy ⁇ (1 ,1- dimethylethyl)dimethylsilane;
  • Methods of making the compounds described herein may be useful to provide compounds, or salts thereof, of a Formula provided herein in a higher yield than with methods currently known in the art. Therefore, in a further aspect of the invention, there is provided a method of making a compound, or a salt thereof, having a Formula provided herein according to a method described herein.
  • a method of making a compound, or a salt thereof which is a member selected from Formulae (I), (II), (III), (Ilia), (1Mb), (IV) 1 (IVb), (IVc), (V), (Vl), (Via), (VIb), (VII), (VIII), (Villa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (IX), (IXa) and (X) according to a method described herein.
  • a method of making a compound, or a salt thereof according to a member selected from Formulae (Xl), (XIa) and (XIb) according to a method described herein.
  • synthesis of compounds of Formula (I) is accomplished by methods analogous to those above.
  • particular protecting groups may be required. Suitable protecting groups can be found, but are not restricted to, those found in T W Greene and P G M Wuts 'Protective Groups in Organic Synthesis', 3 rd Ed (1999), J Wiley and Sons.
  • TBDMS t-butyldimethylsilyloxy TBDPS (or TBS) t-butyldiphenylsilyl
  • the reaction was operated in two batches: To a solution of ⁇ /- ⁇ [(1 ,1- dimethyIethyI)oxy]carbonyI ⁇ -3-methyl-L-valyl-(4R)-4-hydroxy-L-proline 1 (10.5 g, 30.5 mmol) in redistilled DMSO (250 mL) was added potassium t-butoxide (10.3 g). The formed solution was stirred at room temperature for 1 h before addition of 1-chloroisoquinoline (5.0 g, 30.6 mmol). The final solution was left to stir overnight. The two batches were combined and ice water added, then acidified with 1M HCI to pH 4. The mixture was extracted with EtOAc (400 mL x 3).
  • the reaction was operated in two batches: To a solution of ⁇ /-[(cyclopentyloxy)carbonyl]-3- methyl-L-valyl-(4R)-4-hydroxy-L-proline 2 (10 g, 28.1 mmol) in redistilled DMSO (250 mL) was added potassium t-butoxide (9.4 g) at O 0 C. The formed solution was stirred at room temperature for 1 h before addition of 1-chloroisoquinoline (5.0 g, 30.6 mmol). The final solution was stirred at room temperature overnight. The two batches were combined and iced water added, then acidified with 1M HCI to pH 4. The mixture was extracted with EtOAc (150 mL x 3).
  • IZ Compound 16 43 10 g, 0 087 mol
  • NaOH 34 68 g, 0 87 mol
  • Anhydrous DMF 350 mL
  • 6-bromohex-1-ene 13 87 g, 0 085 mol
  • the resulting mixture was stirred at RT for 5m ⁇ n
  • the mixture was decanted into an aqueous solution (3500 mL) containing AcOH (174 mL)
  • the suspension was filtered and washed with water (300 mL*2).
  • Zinc chloride (30.9 mL, 1.0 M in diethyl ether, 30.9 mmol, 1.0 eq) was then added to the reaction mixture at -90°C and then the reaction was allowed to warm to room temperature where it was stirred for 3 h. The reaction was quenched with a saturated solution of ammonium chloride and the phases were separated. The aqueous phase was then extracted with diethyl ether three times and the combined organic extracts were dried over MgSO 4 , filtered and concentrated under reduced pressure. The concentrated material was then diluted in diethyl ether and washed twice with saturated solution of ammonium chloride. The organic layer was then dried over MgSO 4 , filtered and concentrated under reduced pressure to give the title compound.
  • lntermediate B7 (6.0 g, 16.5 mmol, 1.0 eq) in THF (40 mL) was cooled to -78°C under nitrogen.
  • a solution of LHMDS (16.5 mL, 1.0 M in THF, 16.5 mmol, 1.0 eq) was added slowly and the reaction flask was then allowed to warm to room temperature where it was stirred for 2 h.
  • the yellow solution was concentrated under reduced pressure to give an oil. After hexane was added to the oil, a precipitate formed. This was then filtered through Celite and the filtrate concentrated under reduced pressure to give the title compound.
  • the reaction mixture was diluted with diethyl ether (200 mL) and washed with aqueous HCI (0.6 N, 200 mL). The aqueous layer was re-extracted with diethyl ether (2 x 100 mL). The organic layers were combined and concentrated in vacuo. Purification of the crude oil by flash chromatography (5% to 10% ethyl acetate in hexane) gave the title compound.
  • Fresh LDA solution was prepared by adding n-BuLi (2.5 M in hexanes, 17.7 mL, 44.1 mmol) to a solution of di-isopropylamine (6.19 mL, 44.1 mmol) in anhydrous THF (48 mL) under nitrogen at -78 0 C. The mixture was stirred at -78 0 C for 30 min.
  • Intermediate B16 (12.16 g, 36.8 mmol) was mixed with dibromomethane (10.26 mL, 147.2 mmol) in anhydrous THF (58 mL) at -78 0 C.
  • To the borate solution was added the freshly prepared LDA solution through a syringe.
  • Fresh LDA solution was prepared by adding n-BuLi (2.5 M in hexanes, 1.29 mL, 3.23 mmol) to a solution of di-isopropylamine (0.45 mL, 3.23 mmol) in anhydrous THF (1.8 mL) at -78°C and was stirred at -78 0 C under nitrogen for 30 min.
  • Fresh LDA solution was prepared by adding n-BuL ⁇ (1 6M in hexanes, 2 75ml, 44mmol) to a solution of diisopropylamine (445mg, 4 4mmol) in anhydrous THF (3ml) at -78 0 C under nitrogen, and stirred for 30 min
  • the reaction solution was stirred at -78 0 C for 1 h, then Zinc chloride (1 36g, lOmmol) in anhydrous THF (5ml) was added
  • the reaction mixture was allowed to warm up to room temperature and stirred overnight
  • the reaction mixture was diluted with diethyl ether (100ml) and washed with saturated ammonium chloride (100ml)
  • the aqueous layer was re-
  • the reaction mixture was then diluted with petrol (400 mL) and washed with water (5 x 200 mL) before being concentrated under reduced pressure.
  • the residue was dissolved in petrol (250 mL) before being washed again with water (2 x 125 mL).
  • the organic phase was then dried over MgSO 4 filtered and concentrated under reduced pressure.
  • the residue was then passed through a short pad of flash silica (5% diethyl ethe ⁇ petrol) to give the title compound as an oil.
  • the reaction was allowed to reach room temperature slowly and then was heated at 5O 0 C overnight.
  • the reaction mixture was diluted with diethyl ether (200 mL) and extracted with aqueous HCI (0.6 N, 200 mL). The aqueous layer was re-extracted with diethyl ether (2 x 100 mL). The organic layers were combined and concentrated in vacuo. Purification of the crude oil by flash chromatography (5% to 10% ethyl acetate/hexanes) gave the title compound (6.6 g) as a colorless oil.
  • Fresh LDA solution was prepared by adding n-BuLi (2.5 M in hexanes, 0.33 mL, 0.82 mmol) to a solution of di-isopropyllamine (0.11 mL, 0.82 mmol) in anhydrous THF (0.17 mL) at - 78 D C and was stirred at -78°C under nitrogen for 30 min.
  • Intermediate B74 (0.27 g, 0.63 mmol) was mixed with dichloromethane (0.24 mL, 3.76 mmol) in anhydrous THF (1.7 mL) at -78 0 C.
  • dichloromethane 0.24 mL, 3.76 mmol
  • Fresh LDA solution was prepared by adding n-BuLi (2.5 M in hexanes, 0.77 ml_, 1.92 mmol) to a solution of diisopropylamine (0.27 ml_, 1.92 mmol) in anhydrous THF (0.4mL) at -78 0 C and stirred for 30 min.
  • Intermediate B77 (0.55 g, 1.48 mmol) was mixed with dichloromethane (0.57 mL, 8.88 mmol) in anhydrous THF (4 mL) at -78 0 C. To this solution was added the fresh prepared LDA solution through a syringe.

Abstract

L'invention concerne des composés de formule (I) ou un sel de ceux-ci ; dans laquelle R1, R2, R3, R4, R6, R8, R20, R30, Y, Z et n sont tels que définis dans la description. Des utilisations des composés comme médicaments, et dans la fabrication de médicaments pour le traitement d'une infection virale, en particulier une infection par le virus de l'hépatite C sont également décrites. L'invention comprend en outre des procédés de préparation de ces composés et formulations pharmaceutiques de ceux-ci.
PCT/US2008/078439 2007-10-03 2008-10-01 Nouveaux inhibiteurs de boronate cycliques de réplication du virus de l'hépatite c WO2009046098A1 (fr)

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US10206937B2 (en) 2014-07-01 2019-02-19 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
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US10364257B2 (en) 2014-12-19 2019-07-30 Rempex Pharmaceuticals, Inc. Apparatus and continuous flow process for production of boronic acid derivatives
US10385074B2 (en) 2014-05-05 2019-08-20 Rempex Pharmaceuticals, Inc. Synthesis of boronate salts and uses thereof
WO2019204419A1 (fr) 2018-04-20 2019-10-24 The Medicines Company (San Diego), Llc Dérivés d'acide boronique et leurs utilisations thérapeutiques
US10561675B2 (en) 2012-06-06 2020-02-18 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US10618918B2 (en) 2015-03-17 2020-04-14 Qpex Biopharma, Inc. Substituted boronic acids as antimicrobials
US10662205B2 (en) 2014-11-18 2020-05-26 Qpex Biopharma, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
WO2021055612A1 (fr) * 2019-09-17 2021-03-25 BIAL-BioTech Investments, Inc. Imidazole carboxamides substitués et leur utilisation dans le traitement de troubles médicaux
US10966429B2 (en) 2016-03-07 2021-04-06 Agrofresh Inc. Synergistic methods of using benzoxaborole compounds and preservative gases as an antimicrobial for crops
US11008346B2 (en) 2014-06-11 2021-05-18 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US11039617B2 (en) 2013-01-30 2021-06-22 Agrofresh Inc. Large scale methods of uniformly coating packaging surfaces with a volatile antimicrobial to preserve food freshness
US11286270B2 (en) 2017-10-11 2022-03-29 Qpex Biopharma, Inc. Boronic acid derivatives and synthesis thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007016476A2 (fr) * 2005-08-01 2007-02-08 Phenomix Corporation Inhibiteurs de la sérine protéase de l'hépatite c et emploi desdits inhibiteurs
WO2007089618A2 (fr) * 2006-01-27 2007-08-09 Phenomix Corporation Inhibiteurs de la sérine protéase de l'hépatite c et leurs utilisations
WO2008070733A2 (fr) * 2006-12-06 2008-06-12 Phenomix Corporation Inhibiteurs de serine protéase d'hépatite macrocycliques et leurs utilisations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007016476A2 (fr) * 2005-08-01 2007-02-08 Phenomix Corporation Inhibiteurs de la sérine protéase de l'hépatite c et emploi desdits inhibiteurs
WO2007089618A2 (fr) * 2006-01-27 2007-08-09 Phenomix Corporation Inhibiteurs de la sérine protéase de l'hépatite c et leurs utilisations
WO2008070733A2 (fr) * 2006-12-06 2008-06-12 Phenomix Corporation Inhibiteurs de serine protéase d'hépatite macrocycliques et leurs utilisations

Cited By (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103180328B (zh) * 2010-08-10 2016-10-26 莱姆派克斯制药公司 环硼酸酯衍生物及其治疗用途
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EP3666778A1 (fr) 2010-08-10 2020-06-17 Rempex Pharmaceuticals, Inc. Un dérivé cristallin d'ester d'acide boronique cyclique, procédé de préparation et utilisation thérapeutiques
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US8680136B2 (en) 2010-08-10 2014-03-25 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US11684629B2 (en) 2010-08-10 2023-06-27 Melinta Subsidiary Corp. Therapeutic uses of pharmaceutical compositions comprising cyclic boronic acid ester derivatives
JP7227282B2 (ja) 2010-08-10 2023-02-21 レンペックス・ファーマシューティカルズ・インコーポレイテッド 環状ボロン酸エステル誘導体およびその治療的使用
US10639318B2 (en) 2010-08-10 2020-05-05 Rempex Pharmaceuticals, Inc. Therapeutic uses of pharmaceutical compositions comprising cyclic boronic acid ester derivatives
US10004758B2 (en) 2010-08-10 2018-06-26 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and methods of making the same
US10183034B2 (en) 2010-08-10 2019-01-22 Rempex Pharmaceuticals, Inc. Therapeutic uses of pharmaceutical compositions comprising cyclic boronic acid ester derivatives
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US11090319B2 (en) 2010-08-10 2021-08-17 Melinta Subsidiary Corp. Therapeutic uses of pharmaceutical compositions comprising cyclic boronic acid ester derivatives
JP2021073212A (ja) * 2010-08-10 2021-05-13 レンペックス・ファーマシューティカルズ・インコーポレイテッド 環状ボロン酸エステル誘導体およびその治療的使用
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US10172874B2 (en) 2010-08-10 2019-01-08 Rempex Pharmaceuticals, Inc. Pharmaceutical compositions comprising cyclic boronic acid ester derivatives
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WO2012021455A1 (fr) 2010-08-10 2012-02-16 Rempex Pharmaceuticals, Inc. Dérivés cycliques d'esters d'acide boronique et leurs utilisations thérapeutiques
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KR102087313B1 (ko) 2010-08-10 2020-03-11 렘펙스 파머수티클스 인코퍼레이티드 고리형 보론산 에스터 유도체의 제조방법
RU2599791C2 (ru) * 2010-08-10 2016-10-20 Ремпекс Фармасьютикэлз, Инч. Циклические бороновые кислотно-эфирные производные и их использование в терапии
EP3412676A1 (fr) 2010-08-10 2018-12-12 Rempex Pharmaceuticals, Inc. Procédé de préparation des dérivés d'ester d'acide boronique cyclique
US9296763B2 (en) 2010-08-10 2016-03-29 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
JP2017052794A (ja) * 2010-08-10 2017-03-16 レンペックス・ファーマシューティカルズ・インコーポレイテッド 環状ボロン酸エステル誘導体およびその治療的使用
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KR101987091B1 (ko) * 2010-08-10 2019-06-10 렘펙스 파머수티클스 인코퍼레이티드 고리형 보론산 에스터 유도체 및 이의 치료상 용도
US9694025B2 (en) 2010-08-10 2017-07-04 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
JP2014524446A (ja) * 2011-08-17 2014-09-22 グラクソスミスクライン エルエルシー 治療方法
JP2017125010A (ja) * 2011-08-19 2017-07-20 グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ Ｃ型肝炎ウイルス感染の治療のためのベンゾフラン化合物
JP2014527529A (ja) * 2011-08-19 2014-10-16 グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ Ｃ型肝炎ウイルス感染の治療のためのベンゾフラン化合物
US9012491B2 (en) 2011-08-31 2015-04-21 Rempex Pharmaceuticals, Inc. Heterocyclic boronic acid ester derivatives and therapeutic uses thereof
US9382239B2 (en) 2011-11-17 2016-07-05 Dana-Farber Cancer Institute, Inc. Inhibitors of c-Jun-N-terminal kinase (JNK)
US9156858B2 (en) 2012-05-23 2015-10-13 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US10561675B2 (en) 2012-06-06 2020-02-18 Rempex Pharmaceuticals, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US11007206B2 (en) 2012-06-06 2021-05-18 Melinta Subsidiary Corp. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US9132140B2 (en) 2013-01-04 2015-09-15 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9241947B2 (en) 2013-01-04 2016-01-26 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
WO2014107535A1 (fr) 2013-01-04 2014-07-10 Rempex Pharmaceuticals, Inc. Dérivés d'acide boronique et leurs utilisations thérapeutiques
US9101638B2 (en) 2013-01-04 2015-08-11 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US9642869B2 (en) 2013-01-04 2017-05-09 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
WO2014107536A1 (fr) 2013-01-04 2014-07-10 Rempex Pharmaceuticals, Inc. Dérivés d'acide boronique et leurs utilisations thérapeutiques
US11202448B2 (en) 2013-01-30 2021-12-21 Agrofresh Inc. Volatile applications against pathogens
US9138002B2 (en) 2013-01-30 2015-09-22 Agrofresh Inc. Compounds and compositions
US9585396B2 (en) 2013-01-30 2017-03-07 Agrofresh Inc. Volatile applications against pathogens
US9426996B2 (en) 2013-01-30 2016-08-30 Agrofresh Inc. Use of benzoxaboroles as volatile antimicrobial agents on meats, plants, or plant parts
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US11917997B2 (en) 2013-01-30 2024-03-05 Agrofresh Inc. Volatile applications against pathogens
US10070649B2 (en) 2013-01-30 2018-09-11 Agrofresh Inc. Volatile applications against pathogens
US10765117B2 (en) 2013-01-30 2020-09-08 Agrofresh Inc. Volatile applications against pathogens
US10385074B2 (en) 2014-05-05 2019-08-20 Rempex Pharmaceuticals, Inc. Synthesis of boronate salts and uses thereof
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US10669292B2 (en) 2014-05-05 2020-06-02 Rempex Pharmaceuticals, Inc. Synthesis of boronate salts and uses thereof
US9963467B2 (en) 2014-05-19 2018-05-08 Rempex Pharmaceuticals, Inc. Boronic acid derivatives and therapeutic uses thereof
US11008346B2 (en) 2014-06-11 2021-05-18 VenatoRx Pharmaceuticals, Inc. Beta-lactamase inhibitors
US10206937B2 (en) 2014-07-01 2019-02-19 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
US10662205B2 (en) 2014-11-18 2020-05-26 Qpex Biopharma, Inc. Cyclic boronic acid ester derivatives and therapeutic uses thereof
US10364257B2 (en) 2014-12-19 2019-07-30 Rempex Pharmaceuticals, Inc. Apparatus and continuous flow process for production of boronic acid derivatives
DE102016000361A1 (de) 2015-02-13 2016-08-18 Merck Patent Gmbh Verfahren zur Herstellung von Aryl- und Heteroarylalkoholen
US10618918B2 (en) 2015-03-17 2020-04-14 Qpex Biopharma, Inc. Substituted boronic acids as antimicrobials
US10966429B2 (en) 2016-03-07 2021-04-06 Agrofresh Inc. Synergistic methods of using benzoxaborole compounds and preservative gases as an antimicrobial for crops
US10570159B2 (en) 2016-06-30 2020-02-25 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
US11180512B2 (en) 2016-06-30 2021-11-23 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
US10294249B2 (en) 2016-06-30 2019-05-21 Qpex Biopharma, Inc. Boronic acid derivatives and therapeutic uses thereof
WO2018218154A1 (fr) 2017-05-26 2018-11-29 VenatoRx Pharmaceuticals, Inc. Inhibiteurs protéiques de liaison à la pénicilline
US11286270B2 (en) 2017-10-11 2022-03-29 Qpex Biopharma, Inc. Boronic acid derivatives and synthesis thereof
WO2019204419A1 (fr) 2018-04-20 2019-10-24 The Medicines Company (San Diego), Llc Dérivés d'acide boronique et leurs utilisations thérapeutiques
CN109305982A (zh) * 2018-12-23 2019-02-05 沧州普瑞东方科技有限公司 2-丁氧基-1,2-噁硼烷的合成方法
WO2021055612A1 (fr) * 2019-09-17 2021-03-25 BIAL-BioTech Investments, Inc. Imidazole carboxamides substitués et leur utilisation dans le traitement de troubles médicaux

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