WO2022053010A1 - Dérivés de pyrimidone à cycles fusionnés destinés à être utilisés dans le traitement d'une infection par le virus de l'hépatite b ou de maladies induites par le virus de l'hépatite b - Google Patents

Dérivés de pyrimidone à cycles fusionnés destinés à être utilisés dans le traitement d'une infection par le virus de l'hépatite b ou de maladies induites par le virus de l'hépatite b Download PDF

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Publication number
WO2022053010A1
WO2022053010A1 PCT/CN2021/117601 CN2021117601W WO2022053010A1 WO 2022053010 A1 WO2022053010 A1 WO 2022053010A1 CN 2021117601 W CN2021117601 W CN 2021117601W WO 2022053010 A1 WO2022053010 A1 WO 2022053010A1
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WIPO (PCT)
Prior art keywords
alkyl
group
nhc
halo
substituted
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PCT/CN2021/117601
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English (en)
Inventor
Lianzhu LIU
Gang Deng
Chunliang Lu
Zhiguo Liu
Sandrine Céline GROSSE
Koen Vandyck
Edgar Jacoby
Tim Hugo Maria Jonckers
Pierre Jean-Marie Bernard Raboisson
Stefaan Julien Last
Serge Maria Aloysius Pieters
Mathieu Perrier
Wim Gaston Verschueren
Carolina Martinez Lamenca
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Janssen Sciences Ireland Unlimited Company
Johnson & Johnson (China) Investment Ltd.
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Application filed by Janssen Sciences Ireland Unlimited Company, Johnson & Johnson (China) Investment Ltd. filed Critical Janssen Sciences Ireland Unlimited Company
Publication of WO2022053010A1 publication Critical patent/WO2022053010A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • This invention relates to fused ring pyrimidone derivatives, processes for their preparation, pharmaceutical compositions, and their use in treating chronic hepatitis B virus (HBV) infection.
  • HBV chronic hepatitis B virus
  • HBV infection chronic hepatitis B virus (HBV) infection is a significant global health problem, affecting over 5%of the world population (over 350 million people worldwide and 1.25 million individuals in the U.S. ) .
  • HBV human immunodeficiency virus
  • Current treatments do not provide a cure and are limited to only two classes of agents (interferon alpha and nucleoside analogues/inhibitors of the viral polymerase) ; drug resistance, low efficacy, and tolerability issues limit their impact.
  • the low cure rates of HBV are attributed at least in part to the fact that complete suppression of virus production is difficult to achieve with a single antiviral agent.
  • persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma.
  • Current therapy goals for HBV-infected patients are directed to reducing serum HBV DNA to low or undetectable levels, and to ultimately reducing or preventing the development of cirrhosis and hepatocellular carcinoma.
  • HBV capsid protein plays essential functions during the viral life cycle.
  • HBV capsid/core proteins form metastable viral particles or protein shells that protect the viral genome during intercellular passage, and also play a central role in viral replication processes, including genome encapsidation, genome replication, and virion morphogenesis and egress.
  • Capsid structures also respond to environmental cues to allow un-coating after viral entry.
  • the present invention relates to compounds that are capable of capsid assembly modulation.
  • the compounds of the present invention may provide a beneficial balance of properties with respect to prior art compounds. In particular, they may display favourable metabolic properties, tissue distribution, safety and/or pharmaceutical profile.
  • R 1a is hydrogen; R 1b is halo; R 1c is halo, CF 3 or CHF 2 ; and R 1d is halo or C 1-4 alkyl; or
  • R 1a is halo;
  • R 1b is halo;
  • R 1c is halo, CF 3 or CHF 2 ; and
  • R 1d is hydrogen;
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl, phenyl, or 5-to 6-membered heteroaryl; wherein the C 1- 6 alkyl is optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; and wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • R 1a is Cl and R 1b is CF 3 or CHF 2 ; or
  • R 1a is Br and R 1b is selected from the group consisting of Cl, CF 3 and CHF 2 ;
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl, phenyl, or 5-to 6-membered heteroaryl; wherein the C 1- 6 alkyl is optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; and wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , CF 2 CH 3 , and -CN;
  • R 1d is hydrogen, halo or C 1-4 alkyl
  • R 2 is selected from the group consisting of
  • n 2 , n 3 , n 4 , n 5 , n 6 , and n 7 independently represent 0 or 1;
  • ring A represents a phenyl or a 5-or 6-membered heteroaryl ring, wherein Q is a carbon or a heteroatom, and x represents 1, 2 or 3;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl, phenyl, or 5-to 6-membered heteroaryl; wherein the C 1- 6 alkyl is optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; and wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 3-6 cycloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CH 3 , CN, and -C ⁇ CH; with the proviso that one of R 1a , R 1b or R 1c is -C ⁇ CH;
  • R 1d is selected from the group consisting of hydrogen, halo, and C 1-4 alkyl
  • R 2 is selected from the group consisting of
  • n 2 , n 3 , n 4 , n 5 , n 6 , n 7 and n 8 independently represent 0 or 1;
  • Het is selected from the group consisting of 1H-pyrazolyl and 1, 3, 4-oxadiazolyl, each being optionally substituted with methyl;
  • ring A represents a phenyl or 5-or 6-membered heteroaryl ring, wherein Q is a carbon or a heteroatom, and x represents 1, 2 or 3;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl, phenyl, or 5-to 6-membered heteroaryl; wherein the C 1- 6 alkyl is optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; and wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • R 1a and R 1c are each independently selected from the group consisting of hydrogen, halo, and CN;
  • R 1b is CF 3 or CHF 2 ;
  • R 1d are each independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, in particular methyl, and CN;
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl, phenyl, or 5-to 6-membered heteroaryl; wherein the C 1- 6 alkyl is optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; and wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , CF 2 CH 3 , CN, and -C ⁇ CH; with the proviso that at least one of R 1a , R 1b and R 1c is halo or CF 3 ;
  • R 1d is hydrogen, C 1-4 alkyl or halo
  • Het is selected from the group consisting of 1H-pyrazolyl and 1, 3, 4-oxadiazolyl, each being optionally substituted with methyl;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl, phenyl, or 5-to 6-membered heteroaryl; wherein the C 1- 6 alkyl is optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; and wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , CF 2 CH 3 , CN, and -C ⁇ CH; with the proviso that at least one of R 1a , R 1b and R 1c is halo or CF 3 ;
  • R 1d is hydrogen, halo or C 1-4 alkyl
  • R 2 is selected from the group consisting of
  • ring A represents a phenyl or a 5-or 6-membered heteroaryl ring, wherein Q is a carbon or a heteroatom, and x represents 1, 2 or 3;
  • R 3 represents C 3-6 cycloalkyl or C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of C 3-6 cycloalkyl, OH, halo, phenyl or 5-to 6-membered heteroaryl, in particular pyridyl or pyrazinyl, wherein the phenyl or 5-or 6-membered heteroaryl, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1- 4 alkyl, and OC 3-6 cycloalkyl;
  • a method of treating or preventing HBV infection or an HBV-induced disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of any of Formulae (I-1) to (I-7) as described herein or a pharmaceutically acceptable salt thereof.
  • the invention also relates to a pharmaceutical composition, which comprises at least one compound or a pharmaceutically acceptable salt thereof as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) , and which further comprises at least one pharmaceutically acceptable carrier.
  • a pharmaceutical composition which comprises at least one compound or a pharmaceutically acceptable salt thereof as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) , and which further comprises at least one pharmaceutically acceptable carrier.
  • the application pertains to the compound or pharmaceutically acceptable salt thereof as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) or the pharmaceutical composition as defined herein, for use as a medicament.
  • the application pertains to the compound or pharmaceutically acceptable salt thereof as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) , or the pharmaceutical composition as defined herein, for use in the prevention or treatment of an HBV infection or of an HBV-induced disease in mammal in need thereof.
  • a pharmaceutically acceptable salt thereof e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof
  • the pharmaceutical composition as defined herein for use in the prevention or treatment of an HBV infection or of an HBV-induced disease in mammal in need thereof.
  • the application pertains to the compound or pharmaceutically acceptable salt thereof as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) , or the pharmaceutical composition as defined herein, for use in the prevention or treatment of chronic Hepatitis B.
  • HBV-induced disease or condition includes progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Additionally, HBV acts as a helper virus to hepatitis delta virus (HDV) , and it is estimated that more than 15 million people may be HBV/HDV co-infected worldwide, with an increased risk of rapid progression to cirrhosis and increased hepatic decompensation, than patients suffering from HBV alone (Hughes, S.A. et al. Lancet 2011, 378, 73-85) . HDV, infects therefore subjects suffering from HBV infection.
  • HDV hepatitis delta virus
  • the compounds of the invention may be used in the treatment and/or prophylaxis of HBV/HDV co-infection, or diseases associated with HBV/HDV co infection. Therefore, in a particular embodiment, the HBV infection is in particular HBV/HDV co-infection, and the mammal, in particular the human, may be HBV/HDV co-infected, or be at risk of HBV/HDV co infection.
  • the application pertains to the compound or pharmaceutically acceptable salt thereof as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) , or the pharmaceutical composition as defined herein, for use in the prevention or treatment of liver fibrosis, liver inflammation, liver necrosis, cirrhosis, end-stage liver disease or hepatocellular carcinoma.
  • a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof
  • the pharmaceutical composition as defined herein for use in the prevention or treatment of liver fibrosis, liver inflammation, liver necrosis, cirrhosis, end-stage liver disease or hepatocellular carcinoma.
  • the application pertains to a product comprising a first compound and a second compound as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of an HBV infection or of an HBV-induced disease in mammal in need thereof, wherein said first compound is different from said second compound, wherein said first compound is the compound or pharmaceutically acceptable salt thereof as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) or the pharmaceutical composition as defined herein, and wherein said second compound is another HBV inhibitor which is selected from the group consisting of: therapeutic agents selected from HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors,
  • HBV inhibitor
  • compounds e.g., the compounds of any of Formulae (I-1) to (I-7) , or pharmaceutically acceptable salts thereof, which are notably useful in the treatment or prevention of HBV infection or of an HBV-associated (or HBV-induced) condition or disease in a subject in need thereof.
  • the compounds provided herein e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof
  • have antiviral activity and are believed to exhibit favorable metabolic properties, tissue distribution, safety and pharmaceutical profiles, and to be suitable for use in humans.
  • Disclosed compounds may modulate (e.g., accelerate, delay, inhibit, disrupt or reduce) normal viral capsid assembly or disassembly, bind to HBV core protein and capsid or alter metabolism of cellular polyproteins and precursors. The modulation may occur during the assembly process, when the capsid protein is mature, or during viral infectivity.
  • Disclosed compounds can be used in methods of modulating the activity or properties of HBV cccDNA, or the generation or release of HBV RNA particles from within an infected cell.
  • a compound of the application may accelerate the kinetics of HBV capsid assembly, thereby preventing or competing with the encapsidation of the Pol-pgRNA complex and thus blocking the reverse transcription of the pgRNA.
  • the compounds described herein may be suitable for monotherapy and are effective against natural or native HBV strains and against HBV strains resistant to currently known drugs.
  • the compounds described herein e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof
  • the articles “a” and “an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • use of the term “including” as well as other forms, such as “include” , “includes, ” and “included, ” is not limiting.
  • the term “comprising” which is synonymous with “including” or “containing” , is open-ended, and does not exclude additional, unrecited element (s) , ingredient (s) or method step (s) , whereas the term “consisting of” is a closed term, which excludes any additional element, step, or ingredient which is not explicitly recited.
  • the term “essentially consisting of” is a partially open term, which does not exclude additional, unrecited element (s) , step (s) , or ingredient (s) , as long as these additional element (s) , step (s) or ingredient (s) do not materially affect the basic and novel properties of the invention.
  • the term “comprising” (or “comprise (s) ” ) hence includes the term “consisting of” ( “consist (s) of” ) , as well as the term “essentially consisting of” ( “essentially consist (s) of” ) . Accordingly, the term “comprising” (or “comprise (s) ” ) is, in the present application, meant as more particularly encompassing the term “consisting of” ( “consist (s) of” ) , and the term “essentially consisting of” ( “essentially consist (s) of” ) .
  • the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20%or ⁇ 10%, including ⁇ 5%, ⁇ 1%, and ⁇ 0.1%from the specified value, as such variations are appropriate to perform the disclosed methods.
  • capsid assembly modulator refers to a compound that disrupts or accelerates or inhibits or hinders or delays or reduces or modifies normal capsid assembly (e.g., during maturation) or normal capsid disassembly (e.g., during infectivity) or perturbs capsid stability, thereby inducing aberrant capsid morphology and function.
  • a capsid assembly modulator accelerates capsid assembly or disassembly, thereby inducing aberrant capsid morphology.
  • a capsid assembly modulator interacts (e.g.
  • a capsid assembly modulator causes a perturbation in structure or function of CA (e.g., ability of CA to assemble, disassemble, bind to a substrate, fold into a suitable conformation, or the like) , which attenuates viral infectivity or is lethal to the virus.
  • treatment is defined as the application or administration of a therapeutic agent, i.e., a disclosed compound (alone or in combination with another pharmaceutical agent) , to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications) , who has an HBV infection, a symptom of HBV infection or the potential to develop an HBV infection, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the HBV infection, the symptoms of HBV infection, or the potential to develop an HBV infection.
  • Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
  • prevent means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.
  • the term “patient, ” “individual” or “subject” refers to a human or a non-human mammal.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals.
  • the patient, subject, or individual is human.
  • the terms “effective amount, ” “pharmaceutically effective amount, ” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977) , each of which is incorporated herein by reference in its entirety.
  • composition refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA) , which is incorporated herein by reference.
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C 1 -C 3 alkyl or C 1-3 alkyl means an alkyl having one to three carbon atoms, C 1 -C 4 alkyl or C 1-4 alkyl means an alkyl having one to four carbon) and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. Embodiments of alkyl generally include, but are not limited to, C 1 -C 6 alkyl, such as C 1 -C 4 alkyl.
  • halo or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
  • cycloalkyl refers to a monocyclic saturated radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom.
  • C 3-6 cycloalkyl includes groups having 3 to 6 ring atoms and include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • heterocycloalkyl refers to a monocyclic saturated radical comprising one or more heteroatoms, more in particular, one, two or three, even more in particular, one or two, and most particular, one.
  • Said ring heteroatoms are each selected from O, S, and N.
  • each heterocyclic group has from 3 to 7 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • the heterocyclic group can be attached to the remainder of the molecule, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure. If indicated, the heterocycle can be partially saturated.
  • heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, and oxazepanyl.
  • An example of a 3-membered heterocyclic group includes, and is not limited to, aziridine.
  • Examples of 4-membered heterocyclic groups include, and are not limited to, azetidine.
  • Examples of 5-membered heterocyclic groups include, and are not limited to, pyrrolidine, oxazolidine, tetrahydrofuran and thiazolidine.
  • Examples of 6-membered heterocycloalkyl groups include, and are not limited to, piperidine, morpholine, and piperazine.
  • Examples of 7-membered heterocycloalkyl groups include, and are not limited to, azepanyl, and oxazepanyl, e.g. 1, 4-oxazepanyl.
  • heterocyclic groups include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, tetrahydrofuran, thiophene, piperidine, piperazine, morpholine, thiomorpholine.
  • unsaturated or “non saturated” [ring] refers to the presence of double bonds between the atoms forming the ring.
  • An unsaturated ring may be aromatic or non-aromatic.
  • saturated refers to the presence of single bonds between the atoms forming the ring.
  • aromatic refers to a ring or a ring system comprising one or more cycles, wherein each of the one or more cycles is polyunsaturated and has aromatic character, i.e., has (4n + 2) delocalized ⁇ (pi) electrons, where n is an integer.
  • heteroaryl or “heteroaromatic” refers to a heterocycle having aromatic character.
  • aromatic character the skilled person is aware of the customary limitations to the number of ring atoms.
  • heteroaryl rings or ring systems may be referred to ring size by the total number of atoms (including heteroatoms) in the ring or ring system, e.g. 5-membered, 6-membered if monocyclic, 9-membered, 10-membered if bicyclic, and so forth.
  • heteroaryls include pyridyl, pyrazinyl, pyrimidinyl (including, e.g., 2-and 4-pyrimidinyl) , pyridazinyl, thienyl, furyl, pyrrolyl (including, e.g., 2-pyrrolyl) , imidazolyl, thiazolyl, oxazolyl, pyrazolyl (including, e.g., 3-and 5-pyrazolyl) , isothiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 3, 4-triazolyl, tetrazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 3-oxadiazolyl, 1, 3, 4-thiadiazolyl and 1, 3, 4-oxadiazolyl. More particular examples of heteroaryls include pyridyl, pyrazinyl, pyridazinyl.
  • spirocycloalkyl refers to a radical that comprises a twisted structure of two or three rings, in particular at most two rings, that are linked together by one common atom, in particular a carbon atom.
  • spiro bicyclic systems are cyclic systems wherein two cycles are joined at a single atom.
  • a spirocycloalkyl in relation to the application is a C 5-12 spirocycloalkyl, more particularly a C 6-10 spirocycloalkyl, more particularly a C 7-9 spirocycloalkyl, more particularly a C 7 spirocycloalkyl, more particularly spiro [3.3] heptyl.
  • a spirocycloalkyl may also contain at least one, in particular at most one, heteroatom, in particular N, more particularly 2-azaspiro [3.3] heptyl.
  • spirocycloalkyl groups can be in particular spirocarbobicyclic or spiroheterobicyclic.
  • Fused bicyclic groups are two cycles that share two atoms and the bond between these atoms.
  • substituted means that the specified group or moiety bears one or more, in particular one, two or three, more in particular one or two, substituents.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.
  • Lines (such as “--- “) drawn into a particular ring of a ring system indicate that the bond may be attached to any of the suitable ring atoms.
  • the expression “Nitrogen atom to which it is attached” with respect to R 2 means the Nitrogen atom of the 5, 6, 7, 8-tetrahydropyrido [3, 4-d] pyrimidin-4 (3H) -one, to which the R 2 substituent is attached.
  • the half maximal effective concentration (EC 50 ) is intended in accordance with its general meaning in the field. It may more particularly refer to the concentration of a compound which induces a response halfway between the baseline and maximum, typically after a specified exposure time.
  • the EC 50 value is commonly used as a measure of a compound's potency, with a lower value generally indicating a higher potency.
  • the disclosed compounds may possess one or more stereocenters, and each stereocenter may exist independently in either R or S configuration.
  • the stereochemical configuration may be assigned at indicated centers as (*R) , (*S) , (R*) or (S*) when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically/diastereomerically pure.
  • Compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
  • a stereoisomeric form of a compound refers to all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable.
  • Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a mixture of one or more isomers can be utilized as the disclosed compound described herein.
  • Compounds described herein may contain one or more chiral centers. These compounds can be prepared by any means, including stereoselective synthesis, enantioselective synthesis or separation of a mixture of enantiomers or diastereomers. Resolution of compounds and isomers thereof can be achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
  • the disclosed compounds may exist as tautomers.
  • a “tautomer” refers to a proton-shift from one atom of the molecule to another atom of the same molecule. All tautomers are included within the scope of the compounds presented herein, although they may not be explicitly indicated in the above any of Formulae (I-1) to (I-7) .
  • the compounds of the invention may also exist in unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • Compounds described herein also include isotopically-labeled compounds wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S.
  • Isotopically-labeled compounds can be useful in drug or substrate tissue distribution studies. Substitution with heavier isotopes such as deuterium may afford greater metabolic stability (which may lead to for example, increased in vivo half-life or reduced dosage requirements) .
  • Isotopically-labeled compounds can be prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • the compounds described herein may be labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the invention relates to a compound of Formula (I-1) as defined herein,
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl or phenyl; wherein the C 1-6 alkyl is optionally substituted with a substituent selected from the group consisting of C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; and wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3- 6 cycloalkyl.
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of C 3-6 cycloalkyl, phenyl, pyridyl, pyrazinyl; and phenyl; wherein each of the phenyl, pyridyl or pyrazinyl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1- 4 alkyl, and OC 3-6 cycloalkyl.
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of C 3-6 cycloalkyl, phenyl, pyridyl or pyrazinyl; and phenyl; wherein each of the phenyl, pyridyl or pyrazinyl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , OCF 3 , and OCHF 2 .
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of cyclopropyl, phenyl, pyridyl or pyrazinyl; and phenyl; wherein each of the phenyl, pyridyl or pyrazinyl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , OCF 3 , and OCHF 2 .
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • R 1a is hydrogen; R 1b is halo; R 1c is CF 3 or CHF 2 ; and R 1d is halo or methyl; or
  • R 1a is halo; R 1b is halo; R 1c is CF 3 or CHF 2 ; and R 1d is hydrogen.
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • R 2a’ represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; and R 2c’ is selected from the group consisting of hydrogen, halo, C 1-4 alkyl and CHF 2 .
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • R 1a is hydrogen; R 1b is halo; R 1c is halo, CF 3 or CHF 2 ; and R 1d is halo or methyl; or
  • R 1a is halo;
  • R 1b is halo;
  • R 1c is halo, CF 3 or CHF 2 ; and
  • R 1d is hydrogen;
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl or 5-to 6-membered heteroaryl; phenyl; or 5-to 6-membered heteroaryl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3- 6 cycloalkyl;
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • R 2 is (f) , (g) , or (h) :
  • R 2a’ represents C 1-4 alkyl, in particular methyl
  • R 2c’ is selected from the group consisting of hydrogen, halo, C 1-4 alkyl and CHF 2
  • X is CH or N.
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • R 1a is hydrogen; R 1b is halo; R 1c is halo, CF 3 or CHF 2 ; and R 1d is halo or methyl; or
  • R 1a is halo;
  • R 1b is halo;
  • R 1c is halo, CF 3 or CHF 2 ; and
  • R 1d is hydrogen;
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl or 5-to 6-membered heteroaryl; phenyl; or 5-to 6-membered heteroaryl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3- 6 cycloalkyl.
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • R 2 is (a) , (b) , (c) , (d) , (e) , (f) or (g) :
  • each R 2a independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; each R 2b independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; and each R 2c is independently selected from the group consisting of hydrogen, halo, C 1- 4 alkyl, C 3-6 cycloalkyl, and CHF 2 , in particular selected from the group consisting of hydrogen, halo and C 1-4 alkyl. In a particular embodiment, R 2c is halo or C 1-4 alkyl.
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • R 2 is (a) , (b) , (c) , (d) , (e) , (f) or (g) , wherein each R 2a independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; each R 2b independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; and each R 2c is independently selected from the group consisting of halo, C 1-4 alkyl, C 3-6 cycloalkyl, and CHF 2 , in particular selected from the group consisting of halo and C 1-4 alkyl.
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • R 2 is (a) , (b) , (c) , (d) or (e) :
  • each R 2a independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; each R 2b independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; and each R 2c is independently selected from the group consisting of hydrogen, halo, C 1- 4 alkyl, C 3-6 cycloalkyl, and CHF 2 , in particular selected from the group consisting of hydrogen, halo and C 1-4 alkyl. In a particular embodiment, R 2c is halo or C 1-4 alkyl.
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • R 2 is (a) , (b) , (c) , (d) or (e) , wherein each R 2a independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; each R 2b independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; and each R 2c is independently selected from the group consisting of halo, C 1-4 alkyl, C 3-6 cycloalkyl, and CHF 2 , in particular selected from the group consisting of halo and C 1-4 alkyl.
  • the invention relates to a compound of Formula (I-1) as described herein, wherein
  • the invention relates to a compound of Formula (I-2) as defined herein, wherein
  • R 1a is Cl and R 1b is CF 3 or CHF 2 ; or
  • R 1a is Br and R 1b is selected from the group consisting of Cl, CF 3 and CHF 2 ;
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; or phenyl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-2) as defined herein, wherein
  • R 1a is Cl and R 1b is CF 3 or CHF 2 ; or
  • R 1a is Br and R 1b is selected from the group consisting of Cl, CF 3 and CHF 2 ;
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl or phenyl
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; or phenyl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 1a is Cl and R 1b is CF 3 or CHF 2 ;
  • R 1a is Br and R 1b is selected from the group consisting of Cl, CF 3 and CHF 2 ;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; or phenyl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 1a is Cl and R 1b is CF 3 or CHF 2 ; or
  • R 1a is Br and R 1b is selected from the group consisting of Cl, CF 3 and CHF 2 ;
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; or phenyl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 1a is Cl and R 1b is CF 3 or CHF 2 ; or
  • R 1a is Br and R 1b is selected from the group consisting of Cl, CF 3 and CHF 2 ;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; or phenyl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 2 is (a) , (b) , (c) , (d) , (e) , (f) or (g) :
  • each R 2a independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; each R 2b independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; and each R 2c is independently selected from the group consisting of hydrogen, halo, C 1- 4 alkyl, C 3-6 cycloalkyl, and CHF 2 , in particular selected from the group consisting of hydrogen, halo and C 1-4 alkyl. In a particular embodiment, R 2c is halo or C 1-4 alkyl.
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 2 is (a) , (b) , (c) , (d) or (e) :
  • each R 2a independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; each R 2b independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; and each R 2c is independently selected from the group consisting of hydrogen, halo, C 1- 4 alkyl, C 3-6 cycloalkyl, and CHF 2 , in particular selected from the group consisting of hydrogen, halo and C 1-4 alkyl. In a particular embodiment, R 2c is halo or C 1-4 alkyl.
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 2 is (a) , (b) , (c) , (d) , (e) , (f) or (g) :
  • each R 2a independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; each R 2b independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; and each R 2c is independently selected from the group consisting of halo, C 1-4 alkyl, C 3- 6 cycloalkyl, and CHF 2 , in particular selected from the group consisting of halo and C 1- 4 alkyl.
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 2 is (a) , (b) , (c) , (d) or (e) :
  • each R 2a independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; each R 2b independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl, more in particular methyl; and each R 2c is independently selected from the group consisting of halo, C 1-4 alkyl, C 3-6 cycloalkyl, and CHF 2 , in particular selected from the group consisting of halo and C 1-4 alkyl.
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 1a is Cl and R 1b is CF 3 or CHF 2 ; or
  • R 1a is Br and R 1b is selected from the group consisting of Cl, CF 3 and CHF 2 ;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; or phenyl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 2 is (h) , (i) , or (j) :
  • R 2a’ represents C 1-4 alkyl, in particular methyl
  • R 2c’ is selected from the group consisting of hydrogen, halo, C 1-4 alkyl and CHF 2
  • X is CH or N.
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 1a is Cl and R 1b is CF 3 or CHF 2 ;
  • R 2 is selected from the group consisting of
  • R 1a is Br and R 1b is selected from the group consisting of Cl, CF 3 and CHF 2 ;
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; or phenyl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl.
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 2 is a 5-membered heteroaryl selected from the group consisting of
  • each R 2a independently represents C 1-4 alkyl or C 3-6 cycloalkyl, in particular methyl or cyclopropyl; and each R 2b independently represents C 1-4 alkyl, in particular methyl;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; or phenyl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl.
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of C 3-6 cycloalkyl, phenyl, and 5-to 6-membered heteroaryl; or phenyl; wherein each of the phenyl or 5-or 6-membered heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of C 3-6 cycloalkyl, phenyl, pyridyl, and pyrazinyl; or phenyl; wherein each of the phenyl, pyridyl or pyrazinyl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl.
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of C 3-6 cycloalkyl, phenyl, pyridyl and pyrazinyl; or phenyl; wherein each of the phenyl, pyridyl or pyrazinyl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , OCF 3 , and OCHF 2 .
  • the invention relates to a compound of Formula (I-2) as described herein, wherein
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of cyclopropyl, phenyl, pyridyl or pyrazinyl; or phenyl; wherein each of the phenyl, pyridyl or pyrazinyl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , OCF 3 , and OCHF 2 .
  • the invention relates to a compound of Formula (I-2) as described herein, wherein R 1a is Cl and R 1b is CF 3 or CHF 2 ; herein referred to as a compound of Formula (I-2A) .
  • the invention relates to a compound of Formula (I-2) as described herein, wherein R 1a is Br and R 1b is selected from the group consisting of Cl, CF 3 and CHF 2 ; herein referred to as a compound of Formula (I-2B) .
  • the invention relates to a compound of Formula (I-2B) , wherein
  • R 1a is Br and R 1b is selected from the group consisting of Cl, CF 3 and CHF 2 ;
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; or phenyl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-2B) as described herein, wherein
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of C 3-6 cycloalkyl, phenyl, and 5-to 6-membered heteroaryl; or phenyl; wherein each of the phenyl or 5-or 6-membered heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-2B) as described herein, wherein
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of cyclopropyl, phenyl, pyridyl, pyrazinyl; or phenyl; wherein each of the phenyl, pyridyl or pyrazinyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3- 6 cycloalkyl;
  • R 2 is a 5-membered heteroaryl selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl and isoxazoly
  • R 2 is a 6-membered heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl
  • the invention relates to a compound of Formula (I-2) or (I-2B) as described herein, wherein
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of cyclopropyl, phenyl, pyridyl, pyrazinyl; or phenyl; wherein each of the phenyl, pyridyl or pyrazinyl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3- 6 cycloalkyl.
  • the invention relates to a compound of Formula (I-2) or (I-2B) as described herein, wherein
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl or phenyl.
  • the present invention provides compounds of Formula (I-3) .
  • the invention relates to a compound of Formula (I-3) as defined herein, wherein
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , CF 2 CH 3 , and -CN;
  • R 1d is hydrogen, halo or C 1-4 alkyl
  • R 2 is selected from the group consisting of
  • n 2 , n 3 , n 4 , n 5 , n 6 , and n 7 independently represent 0 or 1;
  • ring A represents a phenyl or a 5-or 6-membered heteroaryl ring, wherein Q is a carbon or a heteroatom, and x represents 1, 2 or 3;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; phenyl; or 5-to 6-membered heteroaryl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3- 6 cycloalkyl;
  • the invention relates to a compound of Formula (I-3) as defined herein, wherein at least one of R 1a , R 1b and R 1c is halo or CF 3 .
  • the invention relates to a compound of Formula (I-3) as defined herein, wherein
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , and -CN; with the proviso that at least one of R 1a , R 1b and R 1c is halo or CF 3 ;
  • R 1d is hydrogen or halo
  • R 2 is selected from the group consisting of
  • n 6 represents 0 or 1, and optionally further substituted with one or two substituents each independently selected from the group consisting of halo, C 1-4 alkyl, CH 2 F, CHF 2 , CF 3 , and OH;
  • n 7 represents 0 or 1;
  • ring A represents a phenyl ring and x represents 2 or 3; or A represents a 5-or 6-membered heteroaryl ring, and x represents 1, 2 or 3; in particular wherein ring A represents a phenyl ring or a 5-or a 6-membered heteroaryl ring, and x represents 2 or 3; and wherein Q is a carbon or a heteroatom;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a OH substituent; phenyl; or 5-to 6-membered heteroaryl; wherein each of the phenyl or 5-or 6-membered heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl.
  • the invention relates to a compound of Formula (I-3) as defined herein, wherein
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , and -CN; with the proviso that at least one of R 1a , R 1b and R 1c is halo or CF 3 ;
  • R 1d is hydrogen or halo
  • R 2 is selected from the group consisting of
  • ring A represents a 5-or 6-membered heteroaryl ring, wherein Q is a carbon or a heteroatom, and x represents 1, 2 or 3;
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl; phenyl; or 5-to 6-membered heteroaryl;
  • the invention relates to a compound of Formula (I-3) as defined herein, wherein
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , and -CN; with the proviso that at least one of R 1a , R 1b and R 1c is halo or CF 3 ;
  • R 1d is hydrogen or halo
  • R 2 is selected from the group consisting of
  • ring A represents a 5-or 6-membered heteroaryl ring, wherein Q is a carbon or a heteroatom, and x represents 1, 2 or 3;
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl; phenyl; or 5-to 6-membered heteroaryl.
  • the invention relates to a compound of Formula (I-3) as defined herein, wherein R 1a and R 1d are hydrogen; R 1b is halo; and R 1c is CF 3 .
  • the invention relates to a compound of Formula (I-3) as defined herein, wherein Q is carbon or nitrogen.
  • the invention relates to a compound of Formula (I-3) as defined herein, wherein (a) is
  • R4 when R4 can be 5-or 6-membered heteroaryl, it can be selected from pyridyl and pyrazinyl.
  • C 5-12 spiroheterocycloalkyl is selected from azaspiro [3.3] heptane.
  • the invention relates to a compound of Formula (I-4) as defined herein, wherein
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , CF 2 CH 3 , CN, and -C ⁇ CH; with the proviso that one of R 1a , R 1b or R 1c is -C ⁇ CH;
  • R 1d is hydrogen, halo or C 1-4 alkyl
  • R 2 is selected from the group consisting of
  • n 2 , n 3 , n 4 , n 5 , n 6 , n 7 and n 8 independently represent 0 or 1;
  • ring A represents a 5-or 6-membered heteroaryl ring, wherein Q is a carbon or a heteroatom, and x represents 1, 2 or 3;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, phenyl and 5-to 6-membered heteroaryl; phenyl; or 5-to 6-membered heteroaryl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-4) as defined herein, wherein
  • R 2 is selected from the group consisting of
  • n 1 , n 2 , n 3 , n 4 , n 5 , and n 6 independently represent 0 or 1;
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with phenyl or 5-to 6-membered heteroaryl
  • the invention relates to a compound of Formula (I-4) as defined herein, having the formula (I-4-a)
  • R 1a and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , CF 2 CH 3 , and CN;
  • R 1d is hydrogen or halo
  • R 2 is selected from the group consisting of
  • n 1 , n 2 , n 3 , n 4 , n 5 , n 6 and n 7 independently represent 0 or 1;
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with phenyl or 5-to 6-membered heteroaryl
  • the invention relates to a compound of Formula (I-4) as defined herein, having the formula (I-4-a)
  • R 1a and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , and CF 3 ;
  • R 1d is hydrogen or halo
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl optionally substituted with phenyl or 5-to 6-membered heteroaryl
  • the invention relates to a compound of Formula (I-4-a) as defined herein, wherein R 1a is CHF 2 or CF 3 and R 1c is halo; and R 1d is hydrogen or halo.
  • the invention relates to a compound of Formula (I-4) or (I-4-a) as defined herein, wherein R 3 represents hydrogen or C 1-6 alkyl; and R 4 represents C 1-6 alkyl optionally substituted with phenyl, pyridyl or pyrazinyl, more in particular C 1-6 alkyl.
  • the invention relates to a compound of Formula (I-5) as defined herein, wherein
  • R 1a is hydrogen
  • R 1b is CF 3 or CHF 2 ; and R 1c is bromo; or
  • R 1b is CF 3 ; and R 1c is fluoro;
  • R 1d is hydrogen
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; phenyl; or 5-to 6-membered heteroaryl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3- 6 cycloalkyl;
  • the invention relates to a compound of Formula (I-5) as defined herein, wherein
  • the invention relates to a compound of Formula (I-5) as defined herein, wherein
  • the invention relates to a compound of Formula (I-5) as defined herein, wherein
  • the invention relates to a compound of Formula (I-5) as defined herein, wherein
  • R 1a and R 1c are each independently selected from the group consisting of hydrogen, halo, and CN;
  • R 1b is CF 3 or CHF 2 ;
  • R 1d are each independently selected from the group consisting of hydrogen, halo, methyl and CN;
  • R 2 is selected from the group consisting of
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, C 3-6 cycloalkyl, phenyl and 5-to 6-membered heteroaryl; phenyl; or 5-to 6-membered heteroaryl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3- 6 cycloalkyl;
  • the invention relates to a compound of Formula (I-5) as defined herein, wherein
  • R 1a is hydrogen
  • R 1b is CF 3 or CHF 2 ; and R 1c is bromo; or
  • R 1b is CF 3 ; and R 1c is fluoro;
  • R 1d is hydrogen
  • R 2 is selected from the group consisting of
  • the invention relates to a compound of Formula (I-5) as defined herein, wherein
  • R 3 represents hydrogen or C 1-6 alkyl
  • R 4 represents C 1-6 alkyl or phenyl.
  • the invention relates to a compound of Formula (I-6) as defined herein, wherein
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , CF 2 CH 3 , CN, and -C ⁇ CH; with the proviso that at least one of R 1a , R 1b and R 1c is halo or CF 3 ;
  • R 1d is hydrogen, C 1-4 alkyl or halo
  • Het is selected from the group consisting of 1H-pyrazolyl and 1, 3, 4-oxadiazolyl, each being optionally substituted with methyl;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, phenyl and 5-to 6-membered heteroaryl; phenyl; or 5-to 6-membered heteroaryl; wherein each of the phenyl or 5-or 6-membered heteroaryl in each instance, may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-6) as defined herein, wherein
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , CF 2 CH 3 , CN, and -C ⁇ CH; with the proviso that at least one of R 1a , R 1b and R 1c is halo or CF 3 ;
  • R 1d is hydrogen or halo
  • Het is selected from the group consisting of 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, and 1, 3, 4-oxadiazol-2-yl, each being optionally substituted with methyl;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a OH; phenyl; or 5-to 6- membered heteroaryl; wherein the phenyl or 5-or 6-membered heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-6) as defined herein, wherein
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , CF 2 CH 3 , CN, and -C ⁇ CH; with the proviso that at least one of R 1a , R 1b and R 1c is halo or CF 3 ;
  • R 1d is hydrogen or halo
  • Het is selected from the group consisting of 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, and 1, 3, 4-oxadiazol-2-yl, each being optionally substituted with methyl;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a OH; phenyl; or 5-to 6-membered heteroaryl; wherein the phenyl or 5-or 6-membered heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-6) as defined herein, wherein
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , CF 2 CH 3 , CN, and -C ⁇ CH; with the proviso that at least one of R 1a , R 1b and R 1c is halo or CF 3 ;
  • R 1d is hydrogen or halo
  • a cyclohexyl substituted with a –C ( O) NHC 2-4 alkyl substituent, and is optionally further substituted with a substituent selected from the group consisting of halo and OH;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a OH; phenyl; or 5-to 6-membered heteroaryl; wherein the phenyl or 5-or 6-membered heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl;
  • the invention relates to a compound of Formula (I-6) as defined herein, wherein
  • R 1a and R 1d are hydrogen; and R 1b is Br and R 1c is Cl, CHF 2 , or CF 3 ; or R 1a and R 1b are each independently halo; R 1c is CHF 2 or CF 3 ; and R 1d is hydrogen;
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with a OH; phenyl; or 5-to 6-membered heteroaryl; wherein the phenyl or 5-or 6-membered heteroaryl may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, CF 3 , CHF 2 , CH 2 F, C 1-4 alkyl, C 3-6 cycloalkyl, CN, OH, OCF 3 , OCHF 2 , OCH 2 F, OC 1-4 alkyl, and OC 3-6 cycloalkyl.
  • the invention relates to a compound of Formula (I-6) as defined herein, wherein
  • R 3 represents hydrogen or C 1-6 alkyl optionally substituted with OH
  • R 4 represents C 1-6 alkyl optionally substituted with OH.
  • the invention relates to a compound of Formula (I-6) as defined herein, wherein NR 3 R 4 is selected from the group consisting of NH (iso-propyl) or N (ethyl) 2 .
  • the invention relates to a compound of Formula (I-6) as defined herein, wherein R 3 and R 4 are each independently selected from C 1-6 alkyl optionally substituted with OH.
  • the invention relates to a compound of Formula (I-6) as defined herein, wherein NR 3 R 4 is N (ethyl) 2 .
  • the invention relates to a compound of Formula (I-7) as defined herein, wherein
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , and -C ⁇ CH; with the proviso that at least one of R 1a , R 1b and R 1c is halo or CF 3 ;
  • R 1d is hydrogen, halo or C 1-4 alkyl
  • R 2 is selected from the group consisting of
  • n 1 , n 2 , n 3 , n 4 , n 5 , n 6 and n 7 independently represent 0 or 1;
  • R 3 represents C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of OH, phenyl or 5-to 6-membered heteroaryl, in particular pyridyl or pyrazinyl; or C 3-6 cycloalkyl optionally substituted with one or more substituents each independently selected from OH or halo;
  • the invention relates to a compound of Formula (I-7) as defined herein,
  • R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen, halo, CH 2 F, CHF 2 , CF 3 , and -C ⁇ CH; with the proviso that at least one of R 1a , R 1b and R 1c is halo or CF 3 ;
  • R 1d is hydrogen or halo
  • R 2 is selected from the group consisting of
  • R 3 represents C 1-6 alkyl optionally substituted with OH; or C 3-6 cycloalkyl optionally substituted with one or more substituents each independently selected from OH or halo;
  • the invention relates to a compound of Formula (I-7) as defined herein, wherein Q is carbon or nitrogen.
  • the invention relates to a compound of Formula (I-7) as defined herein, wherein (a) is
  • the heteroaryl when in R 4 reference is made to 5-or 6-membered heteroaryl, can be selected from pyridyl and pyrazinyl.
  • C 5-12 spiroheterocycloalkyl is selected from azaspiro [3.3] heptane.
  • the invention relates to a compound of Formula (I-7) as defined herein, wherein
  • R 2 is selected from the group consisting of
  • the invention relates to a compound of Formula (I-7) as defined herein, wherein
  • R 2 is selected from the group consisting of
  • the invention relates to a compound of Formula (I-7) as defined herein, wherein R 3 represents C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of OH, phenyl or 5-to 6-membered heteroaryl, in particular pyridyl or pyrazinyl; or C 3-6 cycloalkyl optionally substituted with one or more substituents each independently selected from OH or halo.
  • the invention relates to a compound of Formula (I-7) as defined herein, wherein R 3 represents C 1-6 alkyl optionally substituted with OH; or C 3-6 cycloalkyl optionally substituted with one or more substituents each independently selected from halo.
  • the invention relates to a compound of Formula (I-7) as defined herein, wherein R 3 represents iso-propyl, iso-butyl, 1-hydroxy-2-methylpropan-1-yl, or 2, 2-difluorocyclopropyl.
  • the compounds of the application can be useful for simultaneous, separate or sequential use in the treatment of chronic Hepatitis B or of HBV-induced diseases.
  • HBV-induced diseases can be selected from the group consisting of liver fibrosis, liver inflammation, liver necrosis, cirrhosis, end-stage liver disease, and hepatocellular carcinoma.
  • the application pertains to a method of treatment or prevention of a subject in need thereof, comprising administering to a subject in need thereof with a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) or the pharmaceutical composition as defined herein.
  • a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof as defined herein e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof
  • the application pertains to a method of treating or preventing an HBV infection or of an HBV-induced disease in a mammal, said method comprising administering to said mammal a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) , or the pharmaceutical composition as defined herein.
  • a compound or pharmaceutically acceptable salt thereof as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) , or the pharmaceutical composition as defined herein.
  • the application pertains to a method of treating or preventing chronic Hepatitis B in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) , or the pharmaceutical composition as defined herein.
  • a compound or pharmaceutically acceptable salt thereof as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) , or the pharmaceutical composition as defined herein.
  • the application pertains to a method of treating or preventing HBV-induced disease Hepatitis B in a subject, said method comprising administering to said subject a compound or pharmaceutically acceptable salt as defined herein (e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof) , or the pharmaceutical composition as defined herein, wherein the HBV-induced disease is selected from the group consisting of liver fibrosis, liver inflammation, liver necrosis, cirrhosis, end-stage liver disease, and hepatocellular carcinoma.
  • a compound or pharmaceutically acceptable salt as defined herein e.g., a compound of any of Formulae (I-1) to (I-7) or a pharmaceutically acceptable salt thereof
  • the HBV-induced disease is selected from the group consisting of liver fibrosis, liver inflammation, liver necrosis, cirrhosis, end-stage liver disease, and hepatocellular carcinoma.
  • the application relates to such a compound or pharmaceutically acceptable salt thereof, or to such a pharmaceutical composition, for use in the prevention, the prevention of aggravation, the amelioration or the treatment of an HBV-induced disease or condition.
  • the application relates to such a compound or pharmaceutically acceptable salt, or to such a pharmaceutical composition, for any of the above-mentioned uses, more particularly for use in the prevention, the prevention of aggravation, the amelioration, or the treatment of one or more of the following items:
  • chronic hepatis infection more particularly chronic hepatis B infection (ie, preventing that the hepatitis (B) infection becomes chronic) ;
  • a hepatitis-associated or hepatitis-induced (chronic) disease or condition more particularly of a hepatitis B-associated or hepatitis B-induced (chronic) disease or condition;
  • the amelioration (reduction) of the fibrosis progression rate of a (chronic) hepatitis infection more particularly the prevention of cirrhosis in a subject having a (chronic) hepatitis infection, more particularly by a (chronic) hepatitis B infection (e.g., preventing that the subject reaches the cirrhotic stage of fibrosis) .
  • the application pertains to a method of treating or preventing an HBV infection or of an HBV-induced disease in a mammal, said method comprising administering to said mammal a product comprising a first compound and a second compound as a combined preparation for simultaneous, separate or sequential use, wherein said first compound is different from said second compound, wherein said first compound is the compound or pharmaceutically acceptable salt as defined herein or the pharmaceutical composition as defined herein, and wherein said second compound is another HBV inhibitor which is selected from the group consisting of: therapeutic agents selected from HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonu
  • composition comprising at least one disclosed compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
  • the compounds of the present invention may be administered as crystalline or amorphous products. They may be obtained for example as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs. Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • excipient is used herein to describe any ingredient other than the compound (s) of the invention. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions of the present invention may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, for example, for oral, rectal, or percutaneous administration.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. Also included are solid form preparations that can be converted, shortly before use, to liquid forms.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • the compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
  • the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • the effective amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • the effective amount ranges mentioned herein are therefore only guidelines and are not intended to limit the scope or use of the invention to any extent.
  • an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets) , capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a disclosed compound for the treatment of HBV infection in a patient.
  • compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • pharmaceutical compositions of the invention comprise a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
  • the dose of a disclosed compound is from about 1 mg to about 2, 500 mg. In some embodiments, a dose of a disclosed compound used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.
  • a dose of a second compound is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
  • the present invention is directed to a packaged pharmaceutical composition
  • a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a disclosed compound, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of HBV infection in a patient.
  • routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
  • the compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans) buccal, (trans) urethral, vaginal (e.g., trans-and perivaginally) , (intra) nasal and (trans) rectal) , intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion.
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used.
  • the terms and phrases “simultaneous use” , “separate use” or “sequential use” in the context of the administration of two or more therapies or components to a subject refers to administration of two or more therapies or components, for example a compound according to any of Formulae (I-1) to (I-7) and at least one other compound.
  • “simultaneous use” can be administration of the two or more components at essentially the same moment in time.
  • the two or more components can be administered in one composition or in multiple, in particular separate, compositions. More particularly, during simultaneous use, when the two or more components are administered in multiple compositions, said compositions may be administered via the same or via a different route.
  • the two or more components when they are for “sequential use” , they can be administered in multiple, in particular separate, compositions sequentially within a short time period, such as within 24, 20, 16, 12, 8 or 4 hours, within 1 hour, within 45, 30, 20, 15, 10, 5, 4, 3, or 2 minutes, or within 1 minute.
  • a first therapy or component e.g. a first compound according to any of Formulae (I-1) to (I-7)
  • a second therapy or component e.g., a second compound according to any of Formulae (I-1) to (I-7)
  • a first therapy or component e.g. a first therapy or component
  • a first compound according to any of Formulae (I-1) to (I-7) ) and a second therapy or component (e.g, a second compound according to any of Formulae (I-1) to (I-7) ) are administered in the same composition.
  • a first therapy or component e.g. a first compound according to any of Formulae (I-1) to (I-7)
  • a second therapy or component e.g., a second compound according to any of Formulae (I-1) to (I-7)
  • Exemplary compounds of the present invention include the following compounds, or a stereoisomeric form or a tautomeric form thereof,
  • the solids were filtrated out and the filter cake was washed with i-PrOH (1x5 L) .
  • the filtrate was concentrated under reduced pressure.
  • the resulting mixture was diluted with CH 2 Cl 2 (7 L) and water (7 L) .
  • the mixture was basified to pH 8 with NaOH (4 N, aq. ) .
  • the resulting mixture was extracted with CH 2 Cl 2 (2x4 L) .
  • the combined organic layers were washed with brine (1x6 L) , dried over anhydrous Na 2 SO 4 .
  • N- (4-chloro-3- (trifluoromethyl) phenyl) pivalamide 6-3 10 g, 90 %purity, 32.2 mmol
  • anhydrous tetrahydrofuran 100 mL
  • 2.5 M n-butyllithium in hexane 31 mL, 77.5 mmol
  • the reaction mixture was cooled to -78 °C, followed by addition of iodomethane (3 mL, 48.2 mmol) in tetrahydrofuran (10 mL) .

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Abstract

La présente invention concerne des composés selon l'une quelconque des formules (I-1) à (I-7), des compositions pharmaceutiques comprenant au moins l'un desdits composés, leur utilisation en tant que médicament, et leur utilisation dans le traitement d'une infection par le virus de l'hépatite B (HBV) chronique. L'invention concerne également des procédés de préparation de composés selon l'une quelconque des formules (I-1) à (I-7).
PCT/CN2021/117601 2020-09-11 2021-09-10 Dérivés de pyrimidone à cycles fusionnés destinés à être utilisés dans le traitement d'une infection par le virus de l'hépatite b ou de maladies induites par le virus de l'hépatite b WO2022053010A1 (fr)

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CNPCT/CN2020/114911 2020-09-11
CNPCT/CN2020/114915 2020-09-11
CN2020114913 2020-09-11
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CNPCT/CN2020/114916 2020-09-11
CNPCT/CN2020/114912 2020-09-11
CN2020114911 2020-09-11
CN2020114912 2020-09-11
CNPCT/CN2020/114914 2020-09-11
US202063106644P 2020-10-28 2020-10-28
US202063106573P 2020-10-28 2020-10-28
US202063106653P 2020-10-28 2020-10-28
US202063106610P 2020-10-28 2020-10-28
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US202063106593P 2020-10-28 2020-10-28
US63/106,644 2020-10-28
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WO2023205645A1 (fr) * 2022-04-20 2023-10-26 Aligos Therapeutics, Inc. Composés bicycliques
WO2023205653A1 (fr) * 2022-04-20 2023-10-26 Aligos Therapeutics, Inc. Composés bicycliques
WO2024073559A1 (fr) * 2022-09-30 2024-04-04 Aligos Therapeutics, Inc. Composés bicycliques
US11952374B2 (en) 2020-10-21 2024-04-09 Aligos Therapeutics, Inc. Bicyclic compounds

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US11952374B2 (en) 2020-10-21 2024-04-09 Aligos Therapeutics, Inc. Bicyclic compounds
WO2022266193A1 (fr) * 2021-06-18 2022-12-22 Aligos Therapeutics, Inc. Composés bicycliques
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WO2023205645A1 (fr) * 2022-04-20 2023-10-26 Aligos Therapeutics, Inc. Composés bicycliques
WO2023205653A1 (fr) * 2022-04-20 2023-10-26 Aligos Therapeutics, Inc. Composés bicycliques
WO2024073559A1 (fr) * 2022-09-30 2024-04-04 Aligos Therapeutics, Inc. Composés bicycliques

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