EP4100124A1 - Composés hétérocycliques utilisés en tant qu'inhibiteurs de la dihydroorotate déshydrogénase - Google Patents

Composés hétérocycliques utilisés en tant qu'inhibiteurs de la dihydroorotate déshydrogénase

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Publication number
EP4100124A1
EP4100124A1 EP21704615.0A EP21704615A EP4100124A1 EP 4100124 A1 EP4100124 A1 EP 4100124A1 EP 21704615 A EP21704615 A EP 21704615A EP 4100124 A1 EP4100124 A1 EP 4100124A1
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EP
European Patent Office
Prior art keywords
oxy
ethyl
triazol
trifluoropropan
hydroxymethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP21704615.0A
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German (de)
English (en)
Inventor
Scott Kuduk
Xuqing Zhang
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Janssen Biotech Inc
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Janssen Biotech Inc
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Publication of EP4100124A1 publication Critical patent/EP4100124A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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

Definitions

  • the present invention relates to novel compounds that are dihydroorotate dehydrogenase (DHODH) inhibitors. These compounds may be useful for the treatment of a disease, disorder, or medical condition where there is an advantage in inhibiting DHODH.
  • the invention also relates to pharmaceutical compositions comprising one or more of such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the method of treatment of cancer, and autoimmune and inflammatory diseases, syndromes, and disorders.
  • DHODH dihydroorotate dehydrogenase
  • Acute myelogenous leukemia is a clonal disease of the blood and bone marrow resulting from mutations that occur in normal hematopoietic stem cells.
  • AML is a heterogenous disease in that it presents with a range of cytogenetic, morphological and immunophenotypic features, and is characterized by an accumulation of clonal, abnormal myeloid progenitor cells, known as myeloblasts. These cells demonstrate disruption of normal myeloid differentiation and excessive proliferation, resulting in the decreased formation of hematopoietic cells.
  • AML represents an unmet medical need with >20,000 new cases per year in the US with 5 -year overall survival below 30% (Stein ET et al., Health Qual Life Outcomes 16: 193, 2018).
  • Differentiation therapy is considered an attractive approach to AML treatment based on the knowledge that differentiation and loss of stem cell self-renewal are coupled in normal cells.
  • Treatment of acute promyelocytic leukemia, which represents 10-15% of all AML, with all-trans retinoic acid is the paradigm for differentiation therapy.
  • Retinoic acid targets the promyelocytic leukemia protein (PML)-retinoic acid receptor- ⁇ (RAR- ⁇ ) fusion protein encoded by at(15,17) chromosomal translocation.
  • PML-RAR specifically lifts the transcriptionally mediated differentiation block induced by the fusion protein and early clinical trials with single agent ATRA demonstrated complete hematologic remission in all treated patients (McCulloch D et al. Onco Targets Ther 2017; 10: 1585-1601; Nowak D et al. Blood 113: 3655, 2009).
  • DHODH dihydroorotate dehydrogenase
  • DHODH is a flavin mononucleotide (FMN) flavoprotein located in the inner mitochondrial membrane that catalyzes the oxidation of dihydroorotate to orotate, the fourth step in the de novo pyrimidine biosynthesis pathway. Inhibition of DHODH leads to decreased pyrimidine synthesis important precursors for nucleotide synthesis, but also glycoprotein and phospholipid biosynthesis (Reis RAG et al., Archives Biochem Biophysics 632: 175, 2017; Vyas VK et al., Mini Rev Med Chem 11: 1039, 2011).
  • FMN flavin mononucleotide
  • DHODH is a validated target for the treatment of autoimmune diseases with the FDA approved small molecule DHODH inhibitors leflunomide and teriflunomide for rheumatoid arthritis and multiple sclerosis, respectively (Lolli ML et al., Recent patents on Anti-Cancer Drug Discovery 13: 86, 2018).
  • DHODH inhibitors that provide a therapeutic benefit to patients suffering from cancer and/or inflammatory and immunological diseases.
  • Embodiments of the present invention relate to compounds, pharmaceutical compositions containing them, methods of making and purifying them, methods of using them as inhibitors of DHODH enzymatic activity and methods for using them in the treatment of a subject suffering from or diagnosed with a disease, disorder, or medical condition such as autoimmune or inflammatory disorders, or diseases such as cancer.
  • Embodiments of this invention are compounds of Formula (I),
  • X 1 and X 2 are each independently CH or N;
  • Y is O, NH or S
  • R 1 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 2-6 alkenyl; C 1-6 haloalkyl; C 1-6 haloalkyl substitu ted with OH, or OCH 3 ; C 3-6 Cyeloalkyl; C 3-6 heterocycloalkyl; and phenyl; wherein R b is C 1-6 alkyl substituted with a member selected from the group consisting of:
  • R c is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 Cyeloalkyl;
  • Embodiments of this invention are compounds of Formula (II), wherein X 3 and X 4 are each independently CH or N; wherein when X 3 is N, X 4 is CH and wherein when X 3 is CH, X 4 is N;
  • Z is O, S, or NH
  • R 5 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; and C 3-6 Cyeloalkyl; wherein
  • the present invention further provides methods for treating or ameliorating a disease, syndrome, condition, or disorder in a subject, including a mammal and/or human in which the disease, syndrome, condition, or disorder is affected by the inhibition of DHODH enzymatic activity, including but not limited to, cancer and/or inflammatory or immunological diseases, using a compound of Formula (I) (as well as a compound of Formula (II)) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.
  • a compound of Formula (I) as well as a compound of Formula (II)
  • a pharmaceutically acceptable salt isotope, N-oxide, solvate, or stereoisomer thereof.
  • substituted means that the specified group or moiety bears one or more 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.
  • alkyl refers to a straight- or branched-chain alkyl group having from 1 to 8 carbon atoms in the chain.
  • alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • C 1-6 alkyl refers to straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain.
  • C 1-4 alkyl refers to straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain.
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.).
  • alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain).
  • cycloalkyl refers to a saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle.
  • C 3-6 Cycloalkyl refers to a carbocycle having from 3 to 6 ring atoms per carbocycle.
  • Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:
  • halogen represents chlorine, fluorine, bromine, or iodine.
  • haloalkyl refers to a straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain optionally substituting hydrogens with halogens.
  • C 1-6 haloalkyl refers to a straight- or branched-chain alkyl group having from 1 to 6 carbon atoms in the chain, optionally substituting hydrogens with halogens.
  • C 1-4 haloalkyl refers to a straight- or branched-chain alkyl group having from 1 to 4 carbon atoms in the chain, optionally substituting hydrogens with halogens.
  • haloalkyl groups include trifluoromethyl (CF 3 ), difluoromethyl (CF 2 H), monofluoromethyl (CH 2 F), pentafluoroethyl (CF 2 CF 3 ), tetrafluoroethyl (CHFCF 3 ), monofluoroethyl (CH 2 CH 2 F), trifluoroethyl (CH 2 CF 3 ), tetrafluorotrifluoromethylethyl (CF(CF 3 ) 2 ), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • aryl refers to a monocyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) having 6 atoms per ring. (Carbon atoms in the aryl groups are sp2 hybridized.)
  • phenyl represents the following moiety:
  • heterocycloalkyl and “4- to 6-membered heterocycloalkyl” mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present and not excluded otherwise, a nitrogen atom.
  • heterocycloalkyl groups include the following entities, in the form of properly bonded moieties:
  • tetrahydro-2H-thiopyran 1,1 -dioxide represents the following moiety
  • tetrahydrofuranyl represents the following moiety:
  • tetrahydropyranyl represents the following moiety:
  • heteroaryl refers to a monocyclic or fused bicyclic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 9 ring atoms per heterocycle.
  • heteroaryl groups include the following entities, in the form of properly bonded moieties:
  • heterocycloalkyl, cycloalkyl, heteroaryl and aryl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.
  • tautomeric or " tautomeric form " refers to structural isomers of different energies that are interconvertible through low energy barriers.
  • proton tautomers also known as proton tautomers
  • the valence tautomers include interconversions by restructuring some bond electrons.
  • hydroxypyridine or the tautomeric pyridone is represented below.
  • variable point of attachment means that a group is allowed to be attached at more than one alternative position in a structure.
  • the attachment will always replace a hydrogen atom on one of the ring atoms.
  • all permutations of bonding are represented by the single diagram, as shown in the illustrations below.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the term “treat”, “treating”, or “treatment” of any disease, condition, syndrome or disorder refers, in one embodiment, to ameliorating the disease, condition, syndrome or disorder (i.e. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating”, or “treatment” refers to alleviating or ameliorating at least one physiological or biochemical parameter associated with or causative of the disease, condition, syndrome or disorder, including those which may not be discernible by the patient.
  • “treat”, “treating”, or “treatment” refers to modulating the disease, condition, syndrome or disorder either physically (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both.
  • “treat”, “treating”, or “treatment” refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome or disorder.
  • subject and “patient” are used interchangeably herein and may refer to an animal, preferably a mammal, most preferably a human.
  • active compound As used herein, the terms active compound, pharmaceutical agent and active ingredient are used interchangeably to refer to a pharmaceutically active compound.
  • Other ingredients in a drug composition such as carriers, diluents or excipients, may be substantially or completely pharmaceutically inert.
  • a pharmaceutical composition (also referred to herein as a composition or formulation) may comprise the active ingredient in combination with one or more carriers and/or one or more excipients and/or one or more diluents.
  • terapéuticaally effective amount refers to an amount (e.g., of an active compound or pharmaceutical agent, such as a compound of the present invention), which elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, including reduction or inhibition of an enzyme or a protein activity, or ameliorating symptoms, alleviating conditions, slowing or delaying disease progression, or preventing a disease.
  • therapeutically effective amount may refer to an amount that, when administered to a particular subject, achieves a therapeutic effect by inhibiting, alleviating or curing a disease, condition, syndrome or disorder in the subject or by prophylactically inhibiting, preventing or delaying the onset of a disease, condition, syndrome or disorder, or symptom(s) thereof.
  • a therapeutically effective amount may be an amount which relieves to some extent one or more symptoms of a disease, condition, syndrome or disorder in a subject; and/or returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease, condition, syndrome or disorder; and/or reduces the likelihood of the onset of the disease, condition, syndrome or disorder, or symptom(s) thereof.
  • “Pharmaceutically acceptable” means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of an acid or base of a compound represented by Formula (I) (as well as compounds of Formula (IA), (IB) and (II)) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al, “Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts,
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
  • Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates
  • a compound of Formula (I) (as well as a compound of Formula (II)) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Compounds of Formula (I) may contain at least one nitrogen of basic character, so desired pharmaceutically acceptable salts may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid,
  • an inorganic acid such as hydrochlor
  • Compounds of Formula (I) may contain a carboxylic acid moiety, a desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine, piperazine, N-methyl-glucamine and tromethamine and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • amino acids such as glycine and arginine
  • ammonia carbonates, bicarbonates, primary, secondary, and tertiary amines
  • cyclic amines such as benzylamines, pyrrolidines, piperidine, morpholine, piperazine, N-methyl-glucamine and tromethamine
  • inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of such formula.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual ( R )- or (S)-stereoisomers or as mixtures thereof.
  • any formula given herein is intended to represent a racemate, one or more of its enantiomeric forms, one or more of its diastereomeric forms, and mixtures thereof.
  • any formula given herein is intended to refer also to any one of: hydrates, solvates, polymorphs and of such compounds, and mixtures thereof, even if such forms are not listed explicitly.
  • the term “R” at a stereocenter designates that the stereocenter is purely of the R-configuration as defined in the art; likewise, the term “S” means that the stereocenter is purely of the S-configuration, As used herein, the term “RS” refers to a stereocenter that exists as a mixture of the R- and S-configurations,
  • Compounds containing one stereocenter drawn without a stereo bond designation are a mixture of 2 enantiomers.
  • Compounds containing 2 stereocenters both drawn without stereo bond designations are a mixture of 4 diastereomers.
  • Compounds with 2 stereocenters both labeled “RS” and drawn with stereo bond designations are a 2-component mixture with relative stereochemistry as drawn.
  • Unlabeled stereocenters drawn without stereo bond designations are a mixture of the R- and S-configurations. For unlabeled stereocenters drawn with stereo bond designations, the absolute stereochemistry is as depicted.
  • references to a compound herein stands for a reference to any one of: (a) the recited form of such compound, and (b) any of the forms of such compound in the medium in which the compound is being considered when named.
  • reference herein to a compound such as R-COOH encompasses reference to any one of: for example, R-COOH(s), R-COOH(sol), and R-COO-(sol).
  • R- COOH(s) refers to the solid compound, as it could be for example in a tablet or some other solid pharmaceutical composition or preparation
  • R-COOH(sol) refers to the undissociated form of the compound in a solvent
  • R-COO-(sol) refers to the dissociated form of the compound in a solvent, such as the dissociated form of the compound in an aqueous environment, whether such dissociated form derives from R- COOH, from a salt thereof, or from any other entity that yields R-COO- upon dissociation in the medium being considered.
  • an expression such as “exposing an entity to compound of formula R-COOH” refers to the exposure of such entity to the form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such exposure takes place.
  • an expression such as “reacting an entity with a compound of formula R-COOH” refers to the reacting of (a) such entity in the chemically relevant form, or forms, of such entity that exists, or exist, in the medium in which such reacting takes place, with (b) the chemically relevant form, or forms, of the compound R-COOH that exists, or exist, in the medium in which such reacting takes place.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number in an enriched form.
  • isotopes that can be incorporated into compounds of the invention in a form that exceeds natural abundances include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H (or chemical symbol D), 3 H (or chemical symbol T), 11 C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 I, respectively.
  • Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H, or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of this invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • Cn-m alkyl refers to an aliphatic chain, whether straight or branched, with a total number N of carbon members in the chain that satisfies n ⁇ N ⁇ m, with m > n.
  • each of groups Q and R can be H or F
  • the choice of H or F for Q is made independently of the choice of H or F for R, so the choice of assignment for Q does not determine or condition the choice of assignment for R, or vice-versa, unless it is expressly indicated otherwise.
  • Illustrative claim recitation in this regard would read as “each of Q and R is independently H or F”, or “each of Q and R is independently selected from the group consisting of H and F”.
  • a zwitterionic compound would be encompassed herein by referring to a compound that is known to form a zwitterion, even if it is not explicitly named in its zwitterionic form.
  • Terms such as zwitterion, zwitterions, and their synonyms zwitterionic compound(s) are standard IUPAC-endorsed names that are well known and part of standard sets of defined scientific names.
  • the name zwitterion is assigned the name identification CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities.
  • a zwitterion or zwitterionic compound is a neutral compound that has formal unit charges of opposite sign.
  • aminoethanoic acid (the amino acid glycine) has the formula H 2 NCH 2 COOH, and it exists in some media (in this case in neutral media) in the form of the zwitterion + H 3 NCH 2 COO-.
  • Zwitterions, zwitterionic compounds, inner salts and dipolar ions in the known and well-established meanings of these terms are within the scope of this invention, as would in any case be so appreciated by those of ordinary skill in the art.
  • embodiments of this invention comprise the various groupings that can be made from the listed assignments, taken independently, and equivalents thereof.
  • substituent S example is one of S 1 , S 2 , and S 3
  • this listing refers to embodiments of this invention for which S example is S 1 ; S example is S 2 ; S example is S 3 , S example is one of S 1 and S 2 ; S example is one of S 1 and S 3 ; S example is one of S 2 and S 3 ; S example is one of S 1 , S 2 and S 3 ; and S example is any equivalent of each one of these choices.
  • C i -C j when applied herein to a class of substituents, is meant to refer to embodiments of this invention for which each and every one of the number of carbon members, from i to j including i and j, is independently realized.
  • the term C 1 -C 3 refers independently to embodiments that have one carbon member ( C 1 ), embodiments that have two carbon members (C 2 ), and embodiments that have three carbon members (C 3 ).
  • Embodiments of this invention include compounds of Formula (I),
  • X 1 and X 2 are each independently CH or N;
  • Y is O, NH or S
  • R 1 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 2-6 alkenyl; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; C 3-6 Cyeloalkyl; C 3-6 heterocycloalkyl; and phenyl; wherein
  • R b is C 1-6 alkyl substituted with a member selected from the group consisting of: OH, halo, CN, OC 1-6 alkyl, OC 1-6 haloalkyl and OC 3-6 Cyeloalkyl;
  • R c is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 Cyeloalkyl;
  • R 3 is H, Cl or F
  • R 4 is selected from the group consisting of: (a) C 1-6 alkyl; C 1-6 alkyl substituted with one or two substituents each independently selected from the group consisting of OH and OCH 3 ; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH 3 ; cyclohexyl substituted with CH 3 ; and tetrahydro-2H-thiopyran 1,1 -dioxide; and
  • An additional embodiment of the invention is a compound of Formula (I) wherein X 1 is CH.
  • An additional embodiment of the invention is a compound of Formula (I) wherein X 1 is N.
  • An additional embodiment of the invention is a compound of Formula (I) wherein X 2 is CH.
  • An additional embodiment of the invention is a compound of Formula (I) wherein X 2 is N.
  • An additional embodiment of the invention is a compound of Formula (I) wherein Y is O.
  • An additional embodiment of the invention is a compound of Formula (I) wherein Y is NH.
  • An additional embodiment of the invention is a compound of Formula (I) wherein Y is S.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 1 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 2-6 alkenyl; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; C 3-6 cycloalkyl; tetrahydropyran-4-yl; and phenyl.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 1 is C 1-4 alkyl; C 1-4 alkyl substituted with OH, or OCH 3 ; C 1-4 haloalkyl; C 1- 4 haloalkyl substituted with OH, or OCH 3 ; tetrahydropyran-4-yl; or C 3-6 Cyeloalkyl.
  • An additional embodiment of the invention is a compound of Formula (I) wherein Y is O and R 1 is CH(CH 3 ) 2 , CH(CH 3 )(CF 3 ), cyclopropyl, cyclobutyl, or tetrahydropyranyl .
  • An additional embodiment of the invention is a compound of Formula (I) wherein Y is O and R 1 is CH(CH 3 ) 2 or CH(CH 3 )(CF 3 ).
  • An additional embodiment of the invention is a compound of Formula (I) wherein
  • An additional embodiment of the invention is a compound of Formula (I) wherein An additional embodiment of the invention is a compound of Formula (I) wherein ; wherein
  • R b is C 1-4 alkyl substituted with OH, halo, CN, OC 1-4 alkyl, OC 1-4 haloalkyl or OC 3-6 cycloalkyl; and R c is C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl.
  • An additional embodiment of the invention is a compound of Formula (I) wherein
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 3 is H.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 3 is Cl.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 3 is F.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 4 is
  • R e is selected from the group consisting of: Cl, F, CH 3 , and OCH 3 ; and n is 1 or 2.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 4 is
  • An additional embodiment of the invention is a compound of Formula (I) wherein
  • An additional embodiment of the invention is a compound of Formula (I) wherein wherein
  • R d is independently selected from the group consisting of: H, Cl, CH 3 , OH and OCH 3 ; R e is F, Cl, or CH 3 ; and n is 1 or 2.
  • An additional embodiment of the invention is a compound of Formula (I) wherein
  • An additional embodiment of the invention is a compound of Formula (I) wherein n is 1.
  • An additional embodiment of the invention is a compound of Formula (I) wherein n is 2.
  • An additional embodiment of the invention is a compound of Formula (I) wherein Y is NH and R 4 is
  • An additional embodiment of the invention is a compound of Formula (I) wherein Y is S and R 4 is Further embodiments of the current invention include compounds as shown below in Table 1, and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof.
  • Additional embodiments of the invention include a compound of Formula (I) having the Formula (IA), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof: Y is O, NH or S;
  • R 1 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 2-6 alkenyl; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; C 3-6 cycloalkyl; C 3-6 heterocycloalkyl; and phenyl; R b is C 1-6 alkyl substituted with a member selected from the group consisting of:
  • R c is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;
  • R e is selected from the group consisting of: halo, C 1-6 alkyl, and OC 1-6 alkyl; and n is 1 or 2.
  • Additional embodiments of the invention include compounds of Formula (I) having the Formula (IB), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof: wherein
  • X 1 is CH or N
  • Y is O or NH
  • R 1 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 2-6 alkenyl; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; C 3-6 cycloalkyl; C 3-6 heterocycloalkyl; and phenyl;
  • R 2 is wherein
  • R b is C 1-6 alkyl substituted with a member selected from the group consisting of:
  • R c is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 Cyeloalkyl;
  • R 3 is H or F
  • R 4 is selected from the group consisting of: R d is independently selected from the group consisting of: H, Cl, and F; R e is selected from the group consisting of: F, CH 3 , and OCH 3 ; and n is 1 or 2.
  • An additional embodiment of the invention is a compound of Formula (I) having the Formula (IA), wherein Y is O.
  • An additional embodiment of the invention is a compound of Formula (I) having the Formula (IA), wherein R 1 is C 1-6 alkyl or C 1-6 haloalkyl.
  • An additional embodiment of the invention is a compound of Formula (I) having the Formula (IB), wherein Y is N.
  • An additional embodiment of the invention is a compound of Formula (I) having the Formula (IB), wherein Y is O.
  • Embodiments of this invention also include compounds of Formula (II) and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, wherein
  • X 3 and X 4 are each independently CH or N; wherein when X 3 is N, X 4 is CH and wherein when X 3 is CH, X 4 is N;
  • Z is O, S, or NH;
  • R 5 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or
  • R g is selected from the group consisting of: halo, C 1-6 alkyl and OC 1-6 alkyl; and m is 1 or 2.
  • An additional embodiment of the invention is a compound of Formula (II) wherein X 3 is N, X 4 is CH.
  • An additional embodiment of the invention is a compound of Formula (II) wherein X 3 is CH, X 4 is N.
  • An additional embodiment of the invention is a compound of Formula (II) wherein Z is O.
  • An additional embodiment of the invention is a compound of Formula (II) wherein R 5 is C 1-6 alkyl or C 1-6 haloalkyl.
  • An additional embodiment of the invention is a compound of Formula (II) wherein R 7 is H.
  • An additional embodiment of the invention is a compound of Formula (I) wherein
  • Formula (I) ((as well as Formulas (IA), (IB), and (II)), such as, e.g., deuterated compounds of Formula (I).
  • pharmaceutically acceptable salts, N-oxides or solvates of the isotopic variations of the compounds of Formula (I) (as well as Formulas (IA), (IB), and (II)).
  • compositions of Formula (I) are also within the scope of the invention.
  • pharmaceutically acceptable prodrugs of the isotopic variations of the compounds of Formula (I) as well as Formulas (IA), (IB), and (II)
  • pharmaceutically active metabolites of the isotopic variations of the compounds of Formula (I) as well as Formulas (IA), (IB), and (II)).
  • compositions comprising compounds of Formula (I) (as well as compounds of Formula (II)) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or pharmaceutically acceptable diluent.
  • the compounds of Formula (I) may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), and combinations thereof.
  • An embodiment of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of at least one compound selected from compounds of Formula (I) (as well as compounds of Formula (II)), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, in accordance with any embodiment described herein; and at least one pharmaceutically acceptable excipient.
  • Y is O, NH or S
  • R 1 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 2-6 alkenyl; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; C 3-6 cycloalkyl; C 3-6 heterocycloalkyl; and phenyl; wherein
  • R b is C 1-6 alkyl substituted with a member selected from the group consisting of:
  • R c is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;
  • R 3 is H, Cl orF
  • R 4 is selected from the group consisting of:
  • R e is selected from the group consisting of: halo; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; OC 1-6 alkyl; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; and n is 1 or 2; or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers of a compound of Formula (I); and (B) at least one pharmaceutically acceptable excipient.
  • Z is O, S, or NH
  • R 5 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; and C 3-6 cycloalkyl;
  • R 7 is H or F
  • R g is selected from the group consisting of: halo, C 1-6 alkyl and OC 1-6 alkyl; and m is 1 or 2; or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers of a compound of Formula (II); and (B) at least one pharmaceutically acceptable excipient.
  • An additional embodiment of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound shown in Table 1 (e.g., a compound selected from Examples 1-78), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer of the compound of Table 1, a pharmaceutically acceptable prodrug of the compound of Table 1, or a pharmaceutically active metabolite of the compound of Table 1 ; and at least one pharmaceutically acceptable excipient.
  • Solid oral dosage forms such as, tablets or capsules, containing one or more compounds of the present invention may be administered in at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
  • Additional oral forms in which the present inventive compounds may be administered include elixirs, solutions, syrups, and suspensions; each optionally containing flavoring agents and coloring agents.
  • one or more compounds of Formula (I) can be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • inhalation intratracheal or intranasal
  • a suppository or pessary or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • they can be incorporated into a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycols or liquid paraffin.
  • An alternative means of administration includes transdermal administration by using a skin or transdermal patch.
  • compositions of the present invention can also be injected parenterally, for example, intracavemosally, intravenously, intramuscularly, subcutaneously, intradermally, or intrathecally.
  • the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.
  • compositions of the present invention are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood.
  • compositions of the present invention may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.
  • compositions containing at least one of the compounds of Formula (I) (as well as compounds of Formula (II)) as the active ingredient can be prepared by mixing the compound(s) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques.
  • a pharmaceutically acceptable carrier e.g., benzyl alcohol, benzyl ether, benzyl sulfonate, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques.
  • the carrier, excipient, and diluent may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral, etc.).
  • suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations also may be optionally coated with substances such as, sugars, or be enterically coated so as to modulate the major site of absorption and disintegration.
  • the carrier, excipient and diluent will usually include sterile water, and other ingredients may be added to increase solubility and preservation of the composition.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives such as, solubilizers and preservatives.
  • a therapeutically effective amount of a compound of Formula (I) (as well as compounds of Formula (II)) or a pharmaceutical composition thereof may comprise a dose range from about 0.1 mg to about 3000 mg, or any particular amount or range therein, in particular from about 1 mg to about 1000 mg, or any particular amount or range therein, or, more particularly, from about 10 mg to about 500 mg, or any particular amount or range therein, of active ingredient in a regimen of about 1 to about (4x) per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for a compound of Formula (I) (as well as compounds of Formula (II)) will vary as will the diseases, syndromes, conditions, and disorders being treated.
  • a pharmaceutical composition may be provided in the form of one or more tablets containing about 1.0, about 10, about 50, about 100, about 150, about 200, about 250, or about 500 milligrams of a compound of Formula (I).
  • An embodiment of the present invention is directed to a pharmaceutical composition for oral administration, comprising a compound of Formula (I) (as well as compounds of Formula (II)) in an amount of from about 1 mg to about 500 mg.
  • a compound of Formula (I) (as well as compounds of Formula (II)) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three and (4x) daily.
  • Optimal dosages of a compound of Formula (I) (as well as compounds of Formula (II)) to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease, syndrome, condition or disorder.
  • factors associated with the particular subject being treated including subject gender, age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level and desired therapeutic effect.
  • the above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Compounds of Formula (I) may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a compound of Formula (I) (as well as compounds of Formula (II)) is administered to a subject in need thereof.
  • one or more compounds of Formula (I) are useful in methods for treating, ameliorating and / or preventing a disease, a syndrome, a condition or a disorder that is affected by the inhibition of DHODH enzymatic activity.
  • An additional embodiment of the invention relates to the use of compounds of Formula (I), e.g., by inhibiting dihydroorotate oxygenase enzyme activity, in treating disorders like inflammatory disorders, autoimmune disorders, or cancer;
  • X 1 and X 2 are each independently CH or N;
  • Y is O, NH or S
  • R 1 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 2-6 alkenyl; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; C 3-6 Cyeloalkyl; C 3-6 heterocycloalkyl; and phenyl; wherein
  • R b is C 1-6 alkyl substituted with a member selected from the group consisting of: OH, halo, CN, OC 1-6 alkyl, OC 1-6 haloalkyl and OC 3-6 Cyeloalkyl;
  • R c is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 Cyeloalkyl;
  • R 3 is H, Cl or F
  • R 4 is selected from the group consisting of: (a) C 1-6 alkyl; C 1-6 alkyl substituted with one or two substituents each independently selected from the group consisting of OH and OCH 3 ; tetrahydro-2H-pyran-4-yl; tetrahydro-2H-pyran-4-yl substituted with OCH 3 ; cyclohexyl substituted with CH 3 ; and tetrahydro-2H-thiopyran 1,1 -dioxide; and
  • R d is independently selected from the group consisting of: H; halo; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH,
  • C 1-6 haloalkyl; C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 CN; OH; CO 2 H; N(CH 3 ) 2 ; (C O)NH-CH 2 CH 2 OH; NHSO 2 CH 3 ; OC 1-6 alkyl; and OC 1-6 alkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; is selected from the group consisting of: halo; C 1-6 alkyl; C 1-6 alkyl substituted with a member selected from the group consisting of: OH, OCH 3 , SCH 3 , and OCF 3 ; OC 1-6 alkyl; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with a member selected from the group consisting of: OH, and OCH 3 ; and n is 1 or 2; or pharmaceutically
  • An additional embodiment of the invention relates to the use of compounds of Formula (II), e.g., by inhibiting dihydroorotate oxygenase enzyme activity, in treating disorders like inflammatory disorders, autoimmune disorders, or cancer; wherein
  • X 3 and X 4 are each independently CH or N; wherein when X 3 is N, X 4 is CH and wherein when X 3 is CH, X 4 is N;
  • Z is O, S, or NH;
  • R 5 is selected from the group consisting of: C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; and C 3-6 cycloalkyl;
  • R 7 is H or F
  • R g is selected from the group consisting of: halo, C 1-6 alkyl and OC 1-6 alkyl; and m is 1 or 2; or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof.
  • DHODH Dihydroorotate Dehydrogenase
  • the present invention provides a method for inhibiting or altering Dihydroorotate Dehydrogenase (DHODH) enzymatic activity, the method comprising contacting DHODH with any compound of Formula (I) (as well as compounds of Formula (II)), aspect or embodiment disclosed herein, thereby inhibiting or otherwise altering DHODH enzymatic activity.
  • DHODH Dihydroorotate Dehydrogenase
  • An additional embodiment of the present invention provides methods for treating diseases, disorders, or medical conditions mediated or otherwise affected by dihydroorotate dehydrogenase (DHODH) enzyme activity comprising administering a compound of Formula (I) (as well as compounds of Formula (II)) to a subject in need thereof.
  • DHODH dihydroorotate dehydrogenase
  • DHODH inhibitor may refer to an agent that inhibits or reduces DHODH activity.
  • the term “therapeutically effective amount” refers to the amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent, and/ or ameliorate a condition, or a disorder or a disease (i) mediated by DHODH enzymatic activity; or (ii) associated with DHODH enzymatic activity; or (iii) characterized by activity (normal or abnormal) of DHODH enzyme; or (2) reduce or inhibit the activity of DHODH enzyme; or (3) reduce or inhibit the expression of DHODH; or (4) modify the protein levels of DHODH.
  • DHODH inhibitors are believed to act by inhibiting nucleic acid synthesis, cell cycle arrest or altering post-translational glycosylation of proteins involved in regulating myeloid differentiation within progenitor tumor cells.
  • An additional embodiment of the invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated or otherwise affected by DHODH enzymatic activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from: compounds of Formula (I) (as well as Formulas (IA), (IB), and (II) such as a compound of Table 1), enantiomers and diastereomers of the compounds of Formula (I) (as well as Formulas (IA), (IB), and (II) such as a compound of Table 1), isotopic variations of the compounds of Formula (I) (as well as Formulas (IA), (IB), and (II) such as a compound of Table 1), and pharmaceutically acceptable salts of all of the foregoing.
  • compounds of Formula (I) as well as Formulas (IA), (IB), and (II) such as a compound of Table 1
  • a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition, such as cancer comprises administering to the subject an effective amount of at least one compound selected from: compounds of Formula (I) (as well as Formulas (IA), (IB), and (II) such as a compound of Table 1), and pharmaceutically acceptable salts of all the foregoing (e.g., by inhibiting or otherwise altering dihydroorotate oxygenase enzyme activity in the subject).
  • inhibitors of DHODH of the present invention may be used for the treatment of immunological diseases including, but not limited to, autoimmune and inflammatory disorders, e.g. arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus- host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjogren’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune -complex vasculitides, allergic disorders, asthma, bronchi
  • the term “affect” or “affected” when referring to a disease, disorder, or medical condition that is affected by the inhibition or alteration of DHODH enzymatic activity) includes a reduction in the frequency and / or severity of one or more symptoms or manifestations of said disease, syndrome, condition or disorder; and / or includes the prevention of the development of one or more symptoms or manifestations of said disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.
  • An additional embodiment of the invention provides a method of treatment of cancer comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of Formula (I) (as well as compounds of Formula (II)), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.
  • the cancer is selected from but not limited to, lymphomas, leukemias, carcinomas, and sarcomas.
  • An additional embodiment of the invention provides the use of a compound of Formula (I) (as well as compounds of Formula (II)), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, for the treatment of one or more cancer types.
  • the uses and methods of treatment described herein are directed to the treatment of cancer, wherein the cancer is selected from but not limited to: leukemias including but not limited to acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), (acute) T-cell leukemia, acute monocytic leukemia, acute promyelocytic leukemia (APL), bisphenotypic B myelomonocytic leukemia, chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), large granular lymphocytic leukemia, plasma cell leukemia, and also myelodysplastic syndrome (MDS), which can develop into an acute myeloid leukemia,
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • APL acute promyelocytic leukemia
  • CML chronic myeloid leukemia
  • CMML chronic myelomonocytic leukemia
  • lymphomas including but not limited to AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtypes of NHL such as Diffuse Large Cell Lymphoma (DLBCL), activated B-cell DLBCL, germinal center B-cell DLBCL, double-hit lymphoma and double-expressor lymphoma; anaplastic large cell lymphoma, marginal B cell lymphoma and primary mediastinal B-cell lymphoma, immunoblastic large cell lymphoma, Burkitt lymphoma, follicular lymphoma, hairy cell leukemia, Hodgkin's disease, mantle cell lymphoma (MCL), lymphoplasmatic lymphoma, precursor B -lymphoblastic lymphoma, lymphoma of the central nervous system, small lymphocytic lymphoma (SLL) and chronic lymph
  • cancers that may benefit from a treatment with inhibitors of DHODH of the present invention include, but are not limited to, lymphomas, leukemias, carcinomas, and sarcomas, e.g. non-Hodgkin’s lymphoma, diffuse large B- cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, brain (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head & neck cancer, testicular
  • the compounds of the present invention may be employed in combination with one or more other medicinal agents, more particularly with one or more anti-cancer agents, e.g. chemotherapeutic, anti- proliferative or immunomodulating agents, or with adjuvants in cancer therapy, e.g. immunosuppressive or anti-inflammatory agents.
  • anti-cancer agents e.g. chemotherapeutic, anti- proliferative or immunomodulating agents, or with adjuvants in cancer therapy, e.g. immunosuppressive or anti-inflammatory agents.
  • Additional non-limiting examples of anti-cancer agents that may be administered in combination with a compound of the present invention include biologic compounds, such as monoclonal antibodies (e.g., that mediate effector function upon binding to cancer cell-associated antigens, or block interaction of a receptor expressed on cancer cells with a soluble or cell bound ligand), bispecific antibodies that mediate immune cell redirection, etc.
  • a method of treating cancer comprises administering an effective amount of a compound of the present invention (e.g., selected from compounds of Formula (I) (as well as compounds of Formula (II)), such as a compound shown in Table 1, pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof) and an effective amount of one or more additional anti-cancer agents, wherein the method comprises administering the compound of the present invention and the additional anti -cancer agent(s) either simultaneously (e.g., as part of the same pharmaceutical composition) or sequentially.
  • a compound of the present invention e.g., selected from compounds of Formula (I) (as well as compounds of Formula (II)
  • additional anti-cancer agents such as a compound shown in Table 1, pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof
  • the method comprises administering the compound of the present invention and the additional anti -cancer agent(s) either simultaneously (e
  • a pharmaceutical composition comprises an effective amount of a compound of the present invention (e.g., selected from compounds of Formula (I) (as well as compounds of Formula (II)), such as a compound shown in Table 1, pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof), an effective amount of one or more additional anti -cancer agents, and optionally one or more excipients.
  • a compound of the present invention e.g., selected from compounds of Formula (I) (as well as compounds of Formula (II)
  • an effective amount of one or more additional anti -cancer agents e.g., selected from compounds of Formula (I) (as well as compounds of Formula (II)
  • an effective amount of one or more additional anti -cancer agents e.g., selected from compounds of Formula (I) (as well as compounds of Formula (II)
  • An additional embodiment of the invention provides the use of a compound of Formula (I) (as well as compounds of Formula (II)), or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof, as part of chemotherapeutic regimens for the treatment of cancers, lymphomas and leukemias alone or in combination with classic antitumoral compounds well known by the one skilled in the art.
  • Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0 °C and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent. Abbreviations used in the instant specification, particularly the schemes and examples, are as follows:
  • TBDPS tert-Butyldiphenylchlorosilane
  • TBS tert-Butyldimethylsilyl TES triethylsilane
  • TIPS triisopropylsilane
  • a 1,2,4-triazol-5(4H)-one compound of formula (V), where PG is Bn is prepared from ethyl 2-(benzyloxy)acetate in three steps.
  • 2-(benzyloxy)acetohydrazide is prepared by the reaction of ethyl 2- (benzyloxy)acetate with hydrazine hydrate, in a suitable solvent such as EtOH, and the like; at temperatures ranging from 70-85 °C.
  • Reaction of the hydrazide with an isocyanate of formula R c -NCO, where R c is C 1-6 alkyl, in a suitable solvent such as water, and the like provides the corresponding semicarbazide.
  • Subsequent cyclization of the semicarbazide with a suitable base such as NaOH, in a suitable solvent such as water provides a compound of formula (V), where PG is Bn.
  • Protecting group exchange of a compound of formula (V), where PG is Bn to a compound of formula (V) where PG is TBDPS is achieved in two steps employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999.
  • deprotection of benzyl group is achieved under hydrogenolytic conditions known to one skilled in the art provides the alcohol.
  • deprotection is achieved employing a palladium catalyst such Pd/C, and the like; under H 2 ; in a suitable solvent such as EtOH, MeOH, EtOAc, or a mixture thereof, preferably EtOH; with or without the presence HCl; for a period of 4 to 72 hrs.
  • a palladium catalyst such Pd/C, and the like
  • a suitable solvent such as EtOH, MeOH, EtOAc, or a mixture thereof, preferably EtOH
  • EtOH preferably EtOH
  • a second step protection of the corresponding alcohol as the silyl ether, is achieved with tert-butyldimethylsilyl chloride, a suitable base such as imidazole, dimethylaminopyridine, pyridine, and the like; in a solvent such as DMF, DCM, and the like; at temperatures ranging from 0 °C to room temperature; affords a compound of formula (V) where PG is TBDPS.
  • R 1 is C 1-6 alkyl; C 1-6 alkyl substituted with OH, or OCH 3 ; C 2-6 alkenyl; C 1-6 haloalkyl; C 1-6 haloalkyl substituted with OH, or OCH 3 ; C 3-6 cycloalkyl; C 3-6 heterocycloalkyl; and phenyl; in the presence of a suitable base such as NaH, and the like; in an aprotic solvent such as DMF, and the like; at temperatures ranging from 0 °C to 100 °C, preferably 30 °C; to provide a compound of formula (VI).
  • a compound of formula (VI) is oxidized with a suitable oxidant such as MnO 2 , DDQ and the like; in a suitable solvent such as dioxane, toluene and the like; at temperatures ranging from 60 °C to 120 °C, preferably 100 °C; to afford a compound of formula (VII).
  • a suitable oxidant such as MnO 2 , DDQ and the like
  • a suitable solvent such as dioxane, toluene and the like
  • a compound of formula (VII) is coupled with a commercially available or synthetically accessible compound of formula (VIII), where R b is C 1-6 alkyl substituted with O-PG, where PG is a suitable alcohol protecting group such as Bn, allyl, p-methoxy-Bn (PMB), TBDMS, methoxymethyl (MOM), 2- methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl (SEM); under Ullman N-arylation conditions; with a suitable catalyst such as Cul, Cu(acac) 2 , CuO, and the like; a suitable base such a K 3 PO 4 , Cs 2 CO 3 , t-BuOK and the like; with or without a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane- 1,2-diamine, dimethylglycine and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; at
  • a compound of formula (XIII) is prepared in two steps from a compound of formula (XII).
  • a compound of formula (XII) is hydrolyzed with a suitable oxidant such as H 2 O 2 , NaCIO and the like; with a suitable base such a K 2 CO 3 , Cs 2 CO 3 and the like; in a solvent such as DMSO, dioxane, THF and the like; at temperatures ranging from 0 to 60 °C.
  • a suitable oxidant such as H 2 O 2 , NaCIO and the like
  • a suitable base such as K 2 CO 3 , Cs 2 CO 3 and the like
  • a solvent such as DMSO, dioxane, THF and the like
  • a compound of formula (XIII) is treated with a suitable base such as NaH, t- BuOK, LiHMDS and the like; in an aprotic solvent such as THF, dioxane and the like; at temperatures ranging from 0 °C to about 80 °C; to afford a compound of formula (XIV).
  • a compound of formula (XIV) is reacted with a chlorinating agent such as POCl 3 , SOCl 2 and the like; at temperatures ranging from 60 °C to about 100 °C; to afford a compound of formula (XV).
  • a compound of formula (XIX) is reacted with a commercially available or synthetically accessible compound of formula (VIII); under Ullman N-arylation conditions; employing a suitable catalyst such as Cul, Cu(acac) 2 , CuO, and the like; a suitable base such a K 3 PO 4 , Cs 2 CO 3 , t-BuOK and the like; with or without a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane-1,2- diamine, dimethylglycine and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; to afford a compound of formula (XX).
  • a compound of formula (XX) is reacted with a chlorinating agent employing methods previously described to afford a compound of formula (XXI).
  • a compound of formula (VII) is reacted with a chlorinating agent employing conditions previously described to afford a compound of formula (XXII).
  • a compound of formula (XXII) is reacted a commercially available or synthetically accessible compound of formula R 4 -Y 1 , where R 4 is a suitably substituted aryl or five or six membered heteroaryl ring and Y 1 is OH, SH, or NH 2 ; under nucleophilic substitution conditions, with a suitable base such a KOH, Cs 2 CO 3 , t- BuOK and the like; without or in a suitable solvent such as NMP, DMF, DMSO, and the like; to provide a compound of formula (XXIII).
  • a compound of formula compound (XXIII) was reacted with diphenylmethanimine under Buchwald-Hartwig amination conditions, in the presence of a suitable catalyst such as Pd(Ph 3 P) 4 , Pd 2 (dba) 3 , PdCl 2 (Ph 3 P) 2 , and the like; with a suitable base such a K 3 PO 4 , Cs 2 CO 3 , t-BuOK and the like; with a suitable ligand such as Xantphos (4,5-bis(diphenylphosphino)-9,9- dimethylxanthene), CPhos (2-dicyclohexylphosphino-2',6'-bis( N,N- dimethylamino)biphenyl), BINAP and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; at temperatures ranging from 60 °C to about 120 °C; to provide a compound of formula compound (XXIV).
  • a compound of formula (XXIV) is deprotected with an acidic agent such as TFA, HCl and H 2 SO 4 the like; in a suitable solvent such as dioxane, THF, DCM, and the like; at temperatures ranging from 0 °C to about 80 °C; to provide a compound of formula (XXV).
  • an acidic agent such as TFA, HCl and H 2 SO 4 the like
  • a suitable solvent such as dioxane, THF, DCM, and the like
  • a compound of formula compound (XXV) is reacted with phenyl carbonochloridate; a suitable base such a TEA, DIPEA, pyridine and the like; in a suitable solvent such as dioxane, THF, DCM, and the like; at temperatures ranging from 0 °C to about 60 °C, to provide a compound of formula compound (XXVI).
  • SCHEME 7 According to SCHEME 7, commercially available 2-amino-4-bromo-6- fluorobenzonitrile is hydrolyzed to under a base such as K 2 CO 3 , and the like; in a protonic solvent such as water, and the like; at temperatures ranging from 80 °C to aboutl60 °C; employing conventional heating or microwave irradiation; to afford 2- amino-4-bromo-6-fluorobenzamide.
  • a base such as K 2 CO 3 , and the like
  • a protonic solvent such as water, and the like
  • 2-Amino-4-bromo-6-fluorobenzamide is treated with a formylating agent such as DMF, and the like; in the presence of an acid such as pTSA, MSA and the like; at temperatures ranging from 60 °C to about 140 °C; to afford 7 -bromo-5 -fluoroquinazolin-4(3H)-one .
  • 7-Bromo-5 -fluoroquinazolin-4(3H)-one is coupled with a commercially available or synthetically accessible alcohol of formula R 1 OH: employing conditions previously described to afford a compound of formula (XXVII).
  • a compound of formula (XXVII) is reacted with a commercially available or synthetically accessible compound of formula (VIII); under Ullman N-arylation conditions, under a suitable catalyst such as Cul, Cu(acac) 2 , CuO, and the like; with a suitable base such a K 3 PO 4 , Cs 2 CO 3 , t-BuOK and the like; with or without a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane- 1,2-diamine, dimethylglycine and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; to afford a compound of formula (XXVIII).
  • a compound of formula (XXVIII) is reacted with a chlorinating agent such as POCl 3 , SOCl 2 and the like; employing conditions previously described to provide a compound of formula (XXIX).
  • a compound of formula (XXXI) is annulated employing a suitable catalyst such as Pd(OAc) 2 , Pd 2 (dba) 3 , and the like; with a suitable base such a K 3 PO 4 , Cs 2 CO 3 , K 2 CO 3 and the like; with a suitable electrophile such as 1,2-employing conventional heating or under micro wave irradiation; at temperatures ranging from 100 °C to about 160 °C, to afford a compound of formula (XXXII).
  • a suitable catalyst such as Pd(OAc) 2 , Pd 2 (dba) 3 , and the like
  • a suitable base such as K 3 PO 4 , Cs 2 CO 3 , K 2 CO 3 and the like
  • a suitable electrophile such as 1,2-employing conventional heating or under micro wave irradiation
  • a compound of formula (XXXII) is reacted halogenated with a bromine source such as NBS, Bn, and the like; with a suitable radical initiator such as BPO, AIBN and the like; in a suitable solvent such as DCE, CCl 4 , and the like; at temperatures ranging from 70 °C to about 120 °C, to afford a compound of formula (XXXIII).
  • a compound of formula (XXXIII) is reacted with hydrazine in a suitable solvent such as EtOH, dioxane, and the like; at temperatures ranging from 80 °C to about 120 °C, to afford a compound of formula (XXXIV).
  • a compound of formula (XXXIV) is reacted with a chlorinating agent according to methods previously described to afford a compound of formula (XXXV).
  • 4,6-Dichloro-7-fluoro-1-hydroxyfuro[3,4-c]pyridin-3(1H)-one is reacted with hydrazine in a suitable solvent such as THF, MeOH, EtOH and the like; at temperatures ranging from 20 °C to about 80 °C; to afford 5,7-dichloro-8- fluoropyrido [3 ,4-d]pyridazin-4(3H)-one .
  • SCHEME 10 According to SCHEME 10, commercially available 2,6-dichloro-5- fluoronicotinic acid is treated with a suitable base such as LDA, LiHMDS, and the like; in a solvent such as THF, ether, and the like; at temperatures ranging from -78 °C to about 0 °C, for example at about -40 °C, followed by reaction with a bromine source such as NBS, 1,2-dibromo-1,1,2,2-tetrachloroethane and the like to afford 4-bromo-2,6- dichloro-5-fluoronicotinic acid.
  • a suitable base such as LDA, LiHMDS, and the like
  • a solvent such as THF, ether, and the like
  • a bromine source such as NBS, 1,2-dibromo-1,1,2,2-tetrachloroethane and the like to afford 4-bromo-2,6- dichloro-5-fluoronicotinic acid.
  • 4-Bromo-2,6-dichloro-5-fluoronicotinic acid is reacted with a chloro source such as oxalyl chloride, thionyl chloride, and the like; in a suitable solvent such as DCM, THF, ether and the like; at temperatures ranging from 0 °C to about 80 °C, followed by reaction with t-butyl amine; in a suitable base such as TEA, DIPEA, and the like; to afford 4-bromo-N-(tert-butyl)-2,6-dichloro-5- fluoronicotinamide.
  • a chloro source such as oxalyl chloride, thionyl chloride, and the like
  • a suitable solvent such as DCM, THF, ether and the like
  • a suitable base such as TEA, DIPEA, and the like
  • (E)-N-(tert-Butyl)-2,6-dichloro-4-(2-ethoxyvinyl)-5- fluoronicotinamide is annulated intramolecularly in a suitable acid such as TFA, formic acid, and the like; in a suitable solvent such as DCM, THF, ether and the like; at temperatures ranging from 20 °C to about 80 °C; to afford 6,8-dichloro-5-fluoro-2,7- naphthyridin-1(2H)-one.
  • 6,8-Dichloro-5-fluoro-2,7-naphthyridin-1(2H)-one is coupled with a commercially available or synthetically accessible alcohol of formula R 1 OH: employing conditions previously described to provide a compound of formula (XXXIX).
  • a compound of formula (XXXIX) is reacted with a commercially available or synthetically accessible compound of formula (VIII); under Ullman N-arylation conditions, employing conditions previously described to provide a compound of formula (XL).
  • a compound of formula (XXXXVIII) is reacted with a chlorinating agent such as POCl 3 , SOCl 2 and the like; employing conditions previously described to provide a compound of formula (XLI).
  • a compound of formula (XLII) which includes compounds of formulas (X), (XV), (XVII), (XXXVIII), and (XLI); is reacted with a commercially available or synthetically accessible compound of formula R 4 -Y 1 .
  • R 4 is C 1-6 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of OH and OCH 3 , C 3-6 cycloalkyl substituted with C 1- 3 alkyl, a suitably substituted aryl, a five or six membered heteroaryl ring, or an optionally substituted six membered heterocycloalkyl; and Y 1 is OH, SH, or NH 2 ; under nucleophilic substitution conditions, with a suitable base such a NaH, KOH, Cs 2 CO 3 , t- BuOK, DBU, and the like; without or in a suitable solvent such as NMP, DMF, DMSO, dioxane, and the like; at temperatures ranging from 0 °C to 150 °C; employing conventional or microwave heating.
  • a suitable base such as NaH, KOH, Cs 2 CO 3 , t- BuOK, DBU, and the like
  • a suitable solvent such as NMP, DMF,
  • the CO 2 H functional group can be further coupled with an amine such as 2-aminoethan-1-ol, under conventional amide bond forming techniques known to one skilled in the art; for example where the acid is activated with an appropriate activating reagent, for example a carbodiimide, such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI) optionally in the presence of hydroxybenzotriazole (HOBt) and/or a catalyst such as 4-dimethylaminopyridine (DMAP); a halotrisaminophosphonium salt such as (benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP ®
  • Coupling reactions are conducted in a suitable solvent such as DCM, THF, DMF and the like, optionally in the presence of a tertiary amine such as N-methylmorpholine, N-ethyldiisopropylamine (DIEA, DIPEA), or triethylamine (TEA), at a temperature ranging from about 0 °C to rt.
  • a suitable solvent such as DCM, THF, DMF and the like
  • a tertiary amine such as N-methylmorpholine, N-ethyldiisopropylamine (DIEA, DIPEA), or triethylamine (TEA)
  • the CO 2 H functional group is further transformed to aNH 2 group by the treatment with diphenylphosphoryl azide (DPPA) and an organic base such as TEA or DIPEA, in a suitable alcohol solvent such as t-BuOH at a temperature of 60- 100°C; followed by hydrolysis in an acidic solvent such as HCl/dioxane solution at a temperature of 20-30°C; the amino group is alkylated to provide the dimethylamino group (NMe 2 ) employing formaldehyde, an acid such as acetic acid and a reducing agent such as NaBH 3 CN. in a suitable solvent such as MeOH or THF, at a temperature of about 0-50°C.
  • the amino group is also reacted with methane sulfonyl chloride to provide a compound where the amine is substituted with SO 2 CH 3 .
  • a compound of formula (XLII) is reacted a commercially available or synthetically accessible compound of formula R 4 -Y 1 .
  • R 4 is a suitably substituted aryl or five or six membered heteroaryl ring and Y 1 is OH, SH, or NH 2 ; under Ullman arylation conditions; employing a suitable catalyst such as Cul,
  • Cu(acac) 2 , CuO, and the like a suitable base such a K 3 PO 4 , Cs 2 CO 3 , t-BuOK and the like; with or without a suitable ligand such as picolinic acid, trans-N,N- dimethylcyclohexane- 1,2-diamine, dimethylglycine and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; at temperatures ranging from 80 °C to about 120 °C.
  • a suitable base such as K 3 PO 4 , Cs 2 CO 3 , t-BuOK and the like
  • a suitable ligand such as picolinic acid, trans-N,N- dimethylcyclohexane- 1,2-diamine, dimethylglycine and the like
  • a suitable solvent such as dioxane, DMF, DMSO, and the like
  • Deprotection of PG is achieved according to procedures known to one skilled in the art and employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999.
  • deprotection is achieved employing Pd/C; under an H 2 ; in a suitable solvent such as EtOH, MeOH, EtOAc, or a mixture thereof, preferably EtOH; with or without the presence HCl, preferably 0.75 equiv for 4 to 72 hrs, to provide a compound of Formula (I).
  • PG is benzyl
  • deprotection can be employed using trifluoroacetic acid as solvent; or by treatment with BCl 3 ; in a suitable solvent such as DCM, toluene, and the like; at reduced temperatures ranging from -78 °C to rt; for a period of about 1 to 4 hrs.
  • PG is TBDPS
  • a compound of formula (XLIII) (which includes compounds of formulas (XXI), and (XXIX)), where R 5 is C 1-6 alkyl or C 1-6 haloalkyl, R 7 is H or F, X 3 is CH or N, and X 4 is CH or N; is reacted a commercially available or synthetically accessible compound of formula R 8 -Z, where R 8 is a suitably substituted aryl or five or six membered heteroaryl ring and Z is OH, SH, or NH 2 ; under nucleophilic substitution conditions, with a suitable base such a KOH, Cs 2 CO 3 , t-BuOK and the like; without or in a suitable solvent such as NMP, DMF, DMSO, and the like.
  • a compound of formula (XLIII) is reacted a commercially available or synthetically accessible compound of formula R 8 -Z, where R 8 is a suitably substituted aryl or five or six membered heteroaryl ring and Z is OH, SH, or NH 2 ; under Ullman arylation conditions; employing a suitable catalyst such as Cul, Cu(acac) 2 ,
  • a suitable base such as K 3 PO 4 , Cs 2 CO 3 , t-BuOK and the like; with or without a suitable ligand such as picolinic acid, trans-N,N-dimethylcyclohexane- 1,2- diamine, dimethylglycine and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; at temperatures ranging from 80 °C to about 120 °C.
  • Deprotection of PG is achieved according to procedures known to one skilled in the art and employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999.
  • deprotection is achieved employing Pd/C; under an H 2 ; in a suitable solvent such as EtOH, MeOH, EtOAc, or a mixture thereof, preferably EtOH; with or without the presence HCl, preferably 0.75 equiv for 4 to 72 hrs, to provide a compound of Formula (II).
  • PG is benzyl
  • deprotection can be employed using trifluoroacetic acid as solvent.
  • PG is TBDPS, is deprotected employing conditions known to one skilled in the art, preferably with TBAF in a suitable solvent such as THF, and the like; to afford a compound of Formula (II).
  • N-methylethanamine is reacted with a compound of formula (XXVI), employing a suitable base such as TEA or DIPEA and the like; in a suitable solvent such as DCM, THF, and the like at a temperature ranging from 0-30 to provide a compound of Formula (I), where R 2 is and R 3 is H.
  • a compound of formula (XXXV) is reacted with a commercially available or synthetically accessible compound of formula R 4 -Y 1 , where R 4 is C 1-6 alkyl optionally substituted with one or two substituents each independently selected from the group consisting of OH and OCH 3 C 3-6 cycloalkyl substituted with C 1 - 3alkyl; suitably substituted aryl; a five or six membered heteroaryl ring; or an optionally substituted six membered heterocycloalkyl; and Y 1 is OH, SH, or ME; under nucleophilic substitution conditions, with a suitable base such aNaH, KOH, Cs 2 CO 3 , t- BuOK, DBU, and the like; without or in a suitable solvent such as NMP, DMF, DMSO, dioxane, and the like; at temperatures ranging from 0 °C to 150 °C; employing conventional or microwave heating.
  • R 4 is C 1-6 alkyl optionally substitute
  • a compound of formula (XLIV) is coupled with a commercially available or synthetically accessible compound of formula (VIII), where R b is C 1-6 alkyl substituted with O-PG, where PG is a suitable alcohol protecting group as previously described; under Ullman N-arylation conditions; with a suitable catalyst such as Cul, Cu(acac) 2 , CuO, and the like; a suitable base such a K 3 PO 4 , Cs 2 CO 3 , t- BuOK and the like; with or without a suitable ligand such as picolinic acid, trans-N,N- dimethylcyclohexane- 1,2-diamine, dimethylglycine and the like; in a suitable solvent such as dioxane, DMF, DMSO, and the like; at temperatures ranging from 80 °C to about 120 °C; to provide a compound of formula (XLV).
  • VIII commercially available or synthetically accessible compound of formula (VIII)
  • R b is C 1-6 alkyl substituted
  • Deprotection of PG is achieved according to procedures known to one skilled in the art and employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999.
  • deprotection is achieved employing Pd/C; under an H 2 ; in a suitable solvent such as EtOH, MeOH, EtOAc, or a mixture thereof, preferably EtOH; with or without the presence HCl, preferably 0.75 equiv for 4 to 72 hrs, to provide a compound of Formula (II).
  • PG is benzyl
  • deprotection can be employed using trifluoroacetic acid as solvent.
  • PG is TBDPS, is deprotected employing conditions known to one skilled in the art, preferably with TBAF in a suitable solvent such as THF, and the like; to afford a compound of Formula (I).
  • Compounds of Formula (I) may be converted to their corresponding salts using methods known to one of ordinary skill in the art.
  • an amine of Formula (I) is treated with trifluoroacetic acid, HCl, or citric acid in a solvent such as Et 2 O, CH 2 Cl 2 , THF, MeOH, chloroform, or isopropanol to provide the corresponding salt form.
  • trifluoroacetic acid or formic acid salts are obtained as a result of reverse phase HPLC purification conditions.
  • Crystalline forms of pharmaceutically acceptable salts of compounds of Formula (I) may be obtained in crystalline form by recrystallization from polar solvents (including mixtures of polar solvents and aqueous mixtures of polar solvents) or from non-polar solvents (including mixtures of non-polar solvents).
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • Compounds prepared according to the schemes described above may be obtained as single forms, such as single enantiomers, by form-specific synthesis, or by resolution. Compounds prepared according to the schemes above may alternately be obtained as mixtures of various forms, such as racemic (1:1) or non-racemic (not 1:1) mixtures. Where racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers may be isolated using conventional separation methods known to one of ordinary skill in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation. Where regioisomeric or diastereomeric mixtures are obtained, as applicable, single isomers may be separated using conventional methods such as chromatography or crystallization.
  • reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where solutions were “dried,” they were generally dried over a drying agent such asNa 2 SO 4 or MgSO 4 . Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure.
  • METHOD B A Gilson GX-281 semi-prep-HPLC with Phenomenex Synergi C18(10 ⁇ m, 150 x 25mm) , or Boston Green ODS C18 (5 ⁇ m, 150 x 30mm) , and mobile phase of 5-99% ACN in water(0.1%TFA) over 10 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min. or
  • METHOD C A Gilson GX-281 semi-prep-HPLC with Phenomenex Synergi C18(10 ⁇ m, 150 x 25mm), or Boston Green ODS C18 (5 ⁇ m, 150 x 30mm) , and mobile phase of 5-99% ACN in water(0.05%HCl) over 10 min and then hold at 100% ACN for 2 min, at a flow rate of 25 mL/min. or METHOD D.
  • Preparative supercritical fluid high performance liquid chromatography was performed either on a Thar 80 Prep-SFC system, or Waters 80Q Prep-SFC system from Waters.
  • the ABPR was set to 100bar to keep the CO2 in SF conditions, and the flow rate may verify according to the compound characteristics, with a flow rate ranging from 50g/min to 70g/min.
  • the column temperature was ambient temperature
  • Mass spectra were obtained on a SHIMADZU LCMS-2020 MSD or Agilent 1200 ⁇ G6110A MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass.
  • NMR Nuclear magnetic resonance
  • Step B 2-Chloro-6-fluoro-3-(2-methoxyethoxy)benzaldehyde.
  • 2- chloro-4-fluoro-1-(2-methoxyethoxy)benzene (2 g, 9.70 mmol) in THF (20 mL) was added n-BuLi (2.5 M in hexane, 4.65 mL) slowly at -78°C.
  • n-BuLi 2.5 M in hexane, 4.65 mL
  • the reaction mixture was stirred at -78°C for 1 hr, and then DMF (1.06 g, 14.54 mmol, 1.12 mL) was added to the mixture.
  • reaction mixture was stirred at -78 °C for 1 hr, then warmed to 10 °C for 2 hrs, and then stirred at 15°C for 12 hrs.
  • Step C 2-Chloro-6-fluoro-3-(2-methoxyethoxy)phenyl formate.
  • Step D 2-Chloro-6-fluoro-3-(2-methoxyethoxy)phenol.
  • 2-Chloro-6-fluoro-3-(2- methoxyethoxy)phenyl formate (2.1 g) was dissolved in MeOH (30 mL). Then aq.
  • Step A 3-Chloro-1-methyl-1H-pyrazole-4-carbaldehyde.
  • DMF 4.47 g, 61.16 mmol, 4.71 mL
  • POCl 3 21.88 g, 142.71 mmol, 13.26 mL
  • 1-Methylpyrazol-3-ol 2.0 g, 20.39 mmol
  • H 2 O 80 ml
  • the mixture was basified with 1 N NaOH solution to pH 8.
  • Step B 3-Chloro-1-methyl-1H-t)yrazol-4-ol.
  • m-CPBA 1.40 g, 6.92 mmol, 85% purity
  • Step B 2-Chloro-5-methylpyridin-4-ol.
  • DCE 1,2-dichloroethane
  • BBr 3 28.61 g, 114.22 mmol, 11.01 mL
  • the mixture was stirred at 80 °C for 12 hours.
  • Step D 3-Chloro-2-methoxy-5-methylpyridin-4-ol.
  • NMP N-methyl-2-pyrrolidone
  • Step B 5-Chloro-3-methyl- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazolc-4- carbaldehyde.
  • NaH 719.36 mg, 17.99 mmol, 60% purity
  • THF 13 mL
  • 5-chloro-3-methyl-1H-pyrazole-4-carbaldehyde 1.3 g, 8.99 mmol
  • the resulting suspension was stirred at 25 °C for 1 h.
  • Step C 5-Chloro-3-methyl- 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazol-4-ol.
  • Step A 2.5-Dimethylpyridin-4-ol.
  • Step B 3-Chloro-6-methoxynyridin-2( I H)-one.
  • 5-chloro-2-methoxy-1- oxido-pyridin-1-ium 1.3 g, 7.50 mmol
  • THF triethylamine
  • TFAA trifluoroacetic anhydride
  • Step B 4-Bromo-N-(tert-butyl)-2.6-dichloro-5-fluoronicotinamide.
  • 4-Bromo-2.6- dichloro-5-fluoronicotinic acid 300 mg, 1.04 mmol
  • thionyl chloride 2 mL
  • the solvent was cooled down and removed in vacuum.
  • the residue was re-dissolved in DCM (5 mL) was treated with triethylamine (0.3 mL, 2.08 mmol) followed by t-butylamine (0.13 mL, 1.25 mmol) at 0 °C.
  • the reaction was slowly warmed to room temperature over 2 hours.
  • the solution was partitioned between DCM and water.
  • Step C (E)-N-(tert -Butyl)-2.6-dichloro-4-(2-ethoxyv inyl)-5-fluoronicotinamide. 4- Bromo-N-(tert-butyl)-2,6-dichloro-5-fluoronicotinamide (200 mg, 0.58 mmol), Pd 2 (dba) 3 (53 mg, 0.058 mmol), tricyclohexylphosphine (16 mg, 0.058 mmol), (E)-2- (2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (172 mg, 0.87 mmol), sodium carbonate (184 mg, 1.74 mmol) in dioxane (10 mL) and water (1 mL) were heated at 100 °C for 2 hours.
  • Step D 6.8-Dichloro-5-fluoro-2.7-naphthyridin-1(2H)-one.
  • Step A 4.6-Dichloro-7-fluoro-1-hydroxyfuro[3.4-clpyridin-3( 1H)-one.
  • THF 50 mL
  • n-BuLi 2.5 M in THF, 42.86 mL
  • the mixture was stirred at -78 °C for 1 hr.
  • Step B 5.7-Dichloro-8-fluoropyridor3.4-dlpyridazin-4-ol.
  • Step C 7-Chloro-8-fluoro-5-(( 1.1.1 -trifluoropropan-2-yl)oxy)pyrido
  • NaH 500 mg, 12.5 mmol, 60% purity
  • Step A 3-((Benzyloxy)methyl)-4-ethyl-1-(8-fluoro-4-hydroxy-5-((1,1,1- trifluoropropan-2-yl)oxylpyrido 13.4-dlpyridazin-7 -yl)- 1H- 1.2.4-triazol-5(4H)-one .
  • Step B 3-((Benzyloxy)methyl)- 1 -(4-chloro-8-fluoro-5-(( 1.1.1 -trifluoropropan-2- yl)oxylpyrido 13.4-dlpyridazin-7 -yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one .
  • Step A (S)-3-((Benzyloxy)methyl)-4-ethyl- 1-(8-fluorc)-4-hydro ⁇ y-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyrido [ 3.4-d]pyridazin-7 -y l)- 1H- 1.2.4-triazol-5(4H)-one .
  • the title compound was prepared in a manner analogous to Intermediate 17, Step A, using (S)-7-chloro-8-fluoro-5-((1,1,1-trifluoropropan-2-yl)oxy)pyrido[3,4-d]pyridazin-4-ol (Intermediate 16).
  • Step B (S)-3-((Benzyloxy)methyl)- 1 -(4-chloro-8-fluoro-5-(( 1.1.1 -trifluoropropan-2- yl)oxy)pyridol3.4-dlpyridazin-7-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)-one.
  • Intermediate 19 5-((Benzyloxy)methyl)-2-(8-chloro-4-fluoro-1-((l.1, 1-trifluoropropan-
  • Step A 6-(3-( (Benzyloxy)methyl)-4-ethyl-5 -oxo-4.5 -dihydro- 1H- 1.2.4-triazol- 1 -ylI-5 - fluoro-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)-2.7-naphthyridin- 1(2H)-one.
  • Step B 5-((Benzyloxy)methyl)-2-(8-chloro-4-fluoro- 1 -(( 1 , 1 , 1 -trifluoropropan-2- yl)oxyl-2.7-naphthyridin-3-yl)-4-ethyl-24-dihydro-3H-1.2.4-triazol-3-one.
  • the title compound was prepared in a manner analogous to Intermediate 17, Step B.
  • Step C 6-Bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)isoauinolin-1(2H)-one.
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • Step D 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1-yl)- 8-111 , 1 , 1 -trifluoropropan-2-yl)oxylisoquinolin- 1 (2H)-one .
  • Step E 5-((Benzyloxy)methyl)-2-( 1-chloro-8-(( 1, 1, 1 -trifluoropropan-2-yl)oxy) isoqiiinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2,4-triazol-3-one.
  • Step A (S)-6-Bromo-8-(( 1, 1.1 -trifluoropropan-2-yl)oxy)-3.4-dihydroisoquinolin- 1 (2H)- one.
  • (2S)- 1.1. 1 -trifluoropropan-2-ol (490.74 mg, 4.30 mmol) in DMF (15 mL) was added NaH (183.54 mg, 4.59 mmol, 60% purity) at 0 °C.
  • the reaction mixture was stirred at 0 °C for 0.5 hours.
  • 6-bromo-8-fluoro-3,4- dihydroisoquinolin- l(2H)-one the product from Int.
  • Step B (S)-6-Bromo-8-(( 1, 1.1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 (2H)-one.
  • DDQ DDQ
  • Step C (S)-6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1- yl)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 (2H)-one .
  • Step D (S)-3-((Benzyloxy)methyl)-1-(1-chloro-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one.
  • Step A 6-Bromo-8-isopropoxy-3.4-dihydroisoauinolin- 1 (2H)-one.
  • iso- propanol (0.174 mL, 2.27 mmol) in DMF (5 mL) was added sodium hydride (60%, 90 mg, 2.27 mmol) portion wise, at 0 °C in 10 min. After the addition was complete, the mixture was stirred for another 30 min.
  • 6-bromo-8- fluoro-3,4-dihydroisoquinolin-1(2H)-one 185 mg, 0.758 mmol
  • the reaction mixture was then warmed to room temperature over 2 hours.
  • Step B 3-((Benzyloxy)methyl)-1-(1-chloro-8-isopropoxyisoquinolin-6-yl)-4-ethyl-1H-
  • Step A 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1 ,2.4-triazol- 1 -yl)-2- chloro-4-methylnicotinonitrile .
  • Step B 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1 ,2.4-triazol- 1 -yl)-4- methyl -2-1 ( 1, 1.1 -trifluoropropan-2-yl)oxy)nicotinonitri 1 e
  • sodium hydride 60%, 31 mg, 0.782 mmol
  • Step C 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1-yl)-4- methyl-2-( (1.1.1 -trifluoropropan-2-yl)oxy)nicotinamide .
  • Step D 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1-yl)-N- ((dimethylamino)methylene)-4-methyl-2-((1,1,1-trifluoropropan-2-yl)oxy)nicotinamide.
  • Step E 6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1.2.4-triazol- l-yl)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)-2.7 -naphthyridin- 1 ( 2H) -one .
  • Step F 3-((Benzyloxy)methyl)- 1 -(8-chloro- 1 -(( 1 , 1 , 1 -trifluoropropan-2-yl)oxy )-2.7- naphthyridin-3-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Intermediate 20, Step C.
  • Step B 7-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1 ,2.4-triazol- 1 -yl )-5 (( 1.1.1 -trifluoropropan-2-yl)oxy)p ⁇ Tidol 3.4-d
  • Step C 3-((Benzyloxy)methyl)-1-(4-chloro-5-((1,1,1-trifluoropropan-2- yl)oxy)pyrido[3.4-d]pyridazin-7-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Intermediate 20, Step E.
  • Step B (S)-4-Bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoic acid.
  • Methyl (S)-4- bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoate (84 mg, 0.23 mmol) in dioxane (1.0 mL) and 1M NaOH (1.5 mL) was stirred at room temperature for 2 h. The mixture was diluted with water and EtOAc and acidified with IN HCl. The organics were extracted, washed with brine, dried over sodium sulfate, filtered and concentrated to provide the title compound as a white solid which was used without further purification.
  • Step C (S)-5-Bromo-7-((1,1,1-trifluoropropan-2-yl)oxylisobenzofuran-1(3H)-one.
  • (S)- 4-Bromo-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoic acid 31 mg, 0.1 mmol
  • palladium acetate 2.2 mg, 0.01 mmol
  • potassium bicarbonate 25 mg, 0.25 mmol
  • dibromomethane 0.4 mL, 6.0 mmol
  • Step D (S)-3.5-Dibromo-7-((1,1,1-trifluoropropan-2-yl)oxy)isobenzofuran-1(3H)-one.
  • a vial was charged with (S)-5-bromo-7-((1,1,1-trifluoropropan-2-yl)oxy)isobenzofuran- l(3H)-one (540 mg, 1.661 mmol), N-bromosuccinimide (NBS) (325 mg, 1.8 mmol), 2,2'-azobis(2-methylpropionitrile) (14 mg, 0.08 mmol) and 1,2-dichloroethane (DCE) (10.8 mL).
  • NBS N-bromosuccinimide
  • DCE 1,2-dichloroethane
  • Step E (S)-6-Bromo-8-(( 1, 1, 1 -trifluoropropan-2-yl)oxy)phthalazin- 1 (2H)-one.
  • (Sl-3.5- Dibromo-7-((1,1,1-trifluoropropan-2-yl)oxy)isobenzofuran-1(3H)-one (670 mg, 1.6 mmol) was dissolved in EtOH (6.5 mL) and hydrazine hydrate (0.41 mL, 1.027 g/mL, 8.3 mmol) was added then heated to 80 °C for 5 h. The mixture was concentrated then taken up in EtO Ac and water. The organics were extracted with EtO Ac (2 x).
  • Step F (S)-6-Bromo- 1 -chloro-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)phthalazinc.
  • (S)-6- Bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)phthalazin-1(2H)-one (73 mg, 0.22 mmol) was stirred in POCl 3 (1.46 mL, 1.65 g/mL, 15.7 mmol) at 100 °C for 2 h. The reaction was cooled down and then concentrated under reduced pressure and placed under vacuum overnight ( ⁇ 80 mg). The crude product was not purified further.
  • Step A 4-Ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1.2.4-triazol-3-one .
  • Step B 5-(((tert-Butyldiphenylsilyl)oxy)methyl)-4-ethyl-2.4-dihydro-3H- 1 ,2.4-triazol- 3 -one.
  • Step A 7-Chloro-8-fluoro-5-isopropoxYPYridol3.4-d
  • iso-propanol 0.4 mL, 6.92 mmol
  • sodium hydride 60%, 56 mg, 1.4 mmol
  • the mixture was stirred for another 30 min.
  • 5,7-dichloropyrido[3,4-d]pyridazin-4(3H)-one 300 mg, 1.4 mmol
  • Step B 7-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1-yl)-8- fluoro-5 -isopropoxypyrido[3.4-d]pyridazin-4(3H)-one .
  • 7-chloro-8-fluoro-5- isopropoxypyrido[3,4-d]pyridazin-4(3H)-one (200 mg, 0.78 mmol) and Cs 2 CO 3 (253 mg, 0.78 mmol) in DMF (2 mL) was heated at 80 °C overnight. The reaction solution was partitioned between ethyl acetate and saturated ammonium chloride solution.
  • Step C 5-((Benzyloxy)methyl)-2-(4-chloro-8-fluoro-5-isopropoxypyridol3.4- dlpyridazin-7-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • the title compound was prepared in a manner analogous to Intermediate 20, Step E.
  • Example 1 2-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one.
  • Step A 5-((Benzyloxy)methyl)-2-(1-(2-chloro-6-fluorophenoxy)-8-(( 1 , 1, 1- trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Step B 2-(1-(2-Chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy)iso quinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2 4-dihydro-3H- 1 ,2.4-triazol-3-one.
  • Example 2 (S)-2-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3- one.
  • Step A (S)-5 -( (Benzyloxy)methyl)-2-( 1 -(2-chloro-6-fluorophenoxy)-8-( (1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H-L2.4-triazol-3-one.
  • Step B (S)-2-( l-(2-Chloro-6-fluorophenoxy)-8-((1.1.1 -trifluoropropan-2-yl)oxyl isoqiiinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3-one.
  • Example 3 2-( 1 -((2-Chloro-6-fluorophenyl)amino)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1.2.4-triazol-3- one.
  • Step A 7-(3-( (Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H- 1 ,2.4-triazol- 1 -yl)-3 - (2-chloro-6-fluorophenyl)-6-fluoro- l-isopropyl-2.2-dimethyl-2.3-dihydroquinazolin- 4(1H)- one.
  • Step B 3-(2-Chloro-6-fluorophenyl)-7-(4-ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro- 1H- 1 ,2,4-triazol- 1 -yl)-6-fluoro- 1 -isopropyl -2.2-dimethyl -2.3 -dihydroquinazolin-4( 1H)- one.
  • Example 4 2-(1-((2-Chloro-6-fluorot)henyl)thio)-8-(( 1,1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one.
  • Step A 5-((Benzyloxy)methyl)-2-(1-((2-chloro-6-fluorophenyl)thio)-8-((1,1,1- ixv)isoquinolin-6-vl)-4-ethvl-2.4-dihvdro-3H-1.2.4-triazol-3-one.
  • Step B 2-(1-((2-Chloro-6-fluorophenyl)thio)-8-((1.1.1-trifluoropropan-2-yl) oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • the title compound was prepared according to the procedure of Example 1, Step B.
  • Example 5 4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro-1H- 1,2.4-triazol- 1 - yl)-8-(( 1, 1, 1 -trifluoropropan-2-yl)oxy)isoauinolin- 1 -yl)oxy)-3.5-difluorobenzonitrile.
  • Step A 4-((6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1- yl)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3.5-difluorobenzonitrile.
  • Step B 4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro-1H- 1.2.4-triazol- l-yl)-8- ((1,1.1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-3.5 -difluorobenzonitrile .
  • the title compound was prepared in a manner analogous to Example 1, Step B.
  • Example 6 2-( 1 -(2.6-Difluoro-4-(bydroxymethyl)phenoxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 , 2.4-triazol -3- one.
  • Step A 4-((6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1.2.4-triazol- 1 - yl)-8-(( 1.1.1 -tnfluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-3.5-difluorobenzaldchydc.
  • Step C 2-(1-(2.6-Difluoro-4-(hydroxymethyl)phenoxy)-8-(( 1.1.1 -trifluoropropan-2- yl )oxy) isoq uinolin-6-yl )-4-ethyl-5 -(hydroxymethyl)-2.4-dih ydro-3H- 1 ,2.4-triazol-3- one.
  • the title compound was prepared in a manner analogous to Example 1, Step B.
  • Example 7 4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro- 1H- 1.2.4-triazol- 1 - yl)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-3.5-dif1uorobenzoic acid.
  • Step B 4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro- 1H- 1.2.4-triazol- 1-yl)-8- ((1,1.1 -trifluoropropan-2-yl)oxylisoauinolin- 1 -yl)oxy)-3.5-difluorobenzoic acid.
  • the title compound was prepared according to Example 1, Step B to yield a white solid.
  • Example 8 4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1- yl)-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3.5-difluoro-N-(2- hydroxyethyl)benzamide .
  • Step A 4-((6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1 ,2.4-triazol- 1 - yl)-8-(( 1, 1, 1 -trifluoropropan-2-yl)oxy)isoquinolin- 1 -yl)oxy)-3.5-difluoro-N-(2- hydroxyethyl ) benzamide .
  • Step B 4-((6-(4-Ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1-yl)-8- ((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1-yl)oxy)-3.5-difluoro-N-(2-hydroxyethyl) benzamide.
  • Example 9 2-( 1 -(2-Chloro-4,6-difluorophenoxy)-8-(( 1,1,1 -trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyD-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Step A 5-((Benzyloxy)methyl)-2-( 1 -(2-chloro-4.6-difluorophenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxylisoauinolin-6-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Step B 2-(1-(2-Chloro-4,6-difluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy) isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Example 11 (S)-2-( 1 -((4-Chloropyridin-3-yl)oxy)-8-(( 1 , 1, 1 -trifluoropropan-2-yl) oxy)isoauinolin-6-ylt-4-ethyl-5-(bydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Step A (S)-5-((Benzyloxy)methyD-2-(T-((4-chloropyridin-3-yl)oxy)-8-((1- 1, 1- trifluoropropan-2-yl)oxylisoauinolin-6-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step B (S)-2-(1-((4-Chloropyridin-3-yl)oxy)-8-(( 1.1 , 1-trifluorporopan-2-yl) oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Example 12 (S)-2-( 1 -((2-Chloropyridin-3-yl)oxy)-8-(( 1, 1, 1-trifluoropropan-2-yl) isoaiimolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3-one.
  • Step A (S)-5-((Benzyloxy)methyD-2-(1-((2-chloropyridin-3-yl)oxy)-8-((1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol-3-one.
  • Step B (S)-2-(1-((2-Chloropyridin-3-yl)oxy)-8-((1,1,1-trifluoropropan-2-yl) oxy)isoq u inol in -6-yl)-4-ethyl -5 -(hydroxymethyl )-2.4-dihydro-3H- 1 ,2.4-triazol-3-one.
  • Step A (S)-5-((Benzyloxy)methyl)-2-(1-((2-chloro-4-methylpyridin-3-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol- 3 -one.
  • Step B (S)-2-(1-((2-Chloro-4-methylpyridin-3-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Example 14 (S)-2-( 1 -((2.4-Dimethylpyridin-3-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3- one.
  • Step A (S)-5-((Benzyloxy)methyl)-2-( 1 -((2.4-dimethylpyridin-3-yl)oxy)-8-(( 1, 1, 1- trifluoropropan-2-yl) isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol-3-one.
  • Step B (S)-2-(1-((2.4-Dimethylpyridin-3-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3- one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Example 15 (S)-4-Ethyl-5-(hydroxymethyl)-2-(1-((4-methylpyridin-3-yl)oxy)-8- ((1,1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H- 1 ,2.4-triazol-3 -one .
  • Step A (S)-5-((Benzyloxy)methyl)-4-ethyl-2-(1-((4-methylpyridin-3-yl)oxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Step B (S)-4-Ethyl-5-(hydroxymethyl)-2-(1-((4-methylpyridin-3-yl)oxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Example 16 (S)-2-(1-(2-Chloro-5-methylphenoxy)-8-((l.1. l-trifluoropropan-2-yl) oxy)isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Step A (S)-5-((Benzyloxy)methyl)-2-( 1 -(2-chloro-5-methylphenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol-3-one.
  • Step B (S)-2-(1-(2-Chloro-5-methylphenoxy)-8-(( 1, 1, 1 -trifluoropropan-2-yl) oxylisoauinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Step A (S)-5-((Benzyloxy)methyl)-2-( 1 -((4-chloro-2-methylpyridin-3-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol- 3 -one.
  • Step B (S)- 1 -( 1 -((4-Chloro-2-methyl Dy ridin-3-yl)oxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Example 18 (S)- 1 -( 1 -((3-Chloropyridin-2-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy) isoqiiinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2.4-triazol-5(4H)-one. . (S)-3-((Benzyloxy)methyl)- ,1,1- trifluoro propan-2 -yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)-one.
  • Step B (S)-1-(1-((3-Chloropyridin-2-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy) iso quinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)-one.
  • Example 19 (S)- 1 -( 1 -((3.5-Dimethylisoxazol-4-yl)oxy)-8-(( 1, 1, 1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • Step A (S)-5-((Benzyloxy)methyl)-2-(T-((3.5-dimethylisoxazol-4-yl)oxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one.
  • Example 20 2-(8-(2-Chloro-6-fluorophenoxy)- 1 -(( 1. 1.1 -trifluoropropan-2-yl)oxy)-2.7- naphthyridin-3-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Example 21 2-(4-(2-Chloro-6-fluorophenoxy)-5-(( 1.1.1 -trifluoropropan-2-yl)oxy ) pyridol3.4-dlpyridazin-7-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-
  • Example 22 2-(4-(2-Chloro-6-fluorophenoxY)-5-(( 1.1.1 -trifluoropropan-2-yl)oxy)- 1.6- naphthyridin-7-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1.2.4-triazol-3-one.
  • Example 23 (S)-3-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy) isoquinolin-6-yl)- 1 -ethyl- 1 -methylurea.
  • Step A (S)-6-Bromo-1-chloro-8-((1.1,1-trifluoropropan-2-yl)oxyfisoauinoline.
  • a solution of (S)-6-bromo-8-((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-1(2H)-one (Intermediate 21, product from Step B, 200 mg, 595.05 ⁇ mol) in POCl 3 (4 mL) was heated to 110 °C for 2 hours. The mixture was cooled and then concentrated under reduced pressure. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL X2).
  • Step D (S)- 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy) iso quinolin-6-amine .
  • Step E (S)-Phenyl (1-(2-chloro-6-fluorophenoxy)-8-((1.1.1 -trifluoropropan-2-yl)oxy) isoquinolin-6-yl)carbamate.
  • Step F (S)-3-(1-(2-Chloro-6-fluorophenoxy)-8-((1,1,1-trifluoropropan-2-yl)oxy) iso quinolin-6-yl)- 1 -ethyl- 1 -methylurea.
  • Example 24 (S)-2-(4-(2-Chloro-6-fluorophenoxy)-5-(( 1.1.1 -trifluoropropan-2-yl) qiiinazolin-7-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3-one.
  • Step A 2-Amino-4-bromo-6-fluorobenzamide.
  • a solution of 2-amino-4-bromo-6- fluorobenzonitrile (536 mg, 2.5 mmol), K 2 CO 3 (137.8 mg, 1.0 mmol) and water (10 mL) was heated at 150 °C for 45 minutes employing microwave irradiation.
  • the reaction mixture was extracted with EtOAc.
  • the combined organics layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a tan solid.
  • the crude product was used without further purification in the subsequent step.
  • Step B 7-Bromo-5-fluoroqiiinazolin-4(3H)-one.
  • 2-amino-4-bromo-6- fluorobenzamide (415 mg, 1.8 mmol) in DMF (10 mL) was added p-toluenesulfonic acid monohydrate (677 mg, 3.6 mmol).
  • p-toluenesulfonic acid monohydrate (677 mg, 3.6 mmol) was added and the reaction was continued at 120 °C for another 2 h.
  • Step C (S)-7-Bromo-5-((1,1,1-trifluoropropan-2-yl)oxy)quinazolin-4(3H)-one.
  • Step E (S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-(4-(2-chloro-6-fluorophenoxy)- 5-111,1.1-trifluoropropan-2-yl)oxylauinazolin-7-yl)-4-ethyl-2.4-dihydro-3H- 1,2.4- triazol-3-one.
  • Step F (S)-2-(4-(2-Chloro-6-fluorophenoxy)-5-(( 1.1.1 -trifluoropropan-2-yl)oxy) quinazolin-7-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Example 25 (S)-2-( 1 -(2-Chloro-6-fluorophenoxy)-8-(( 1, 1, 1 -trifluoropropan-2- ylIoxyk)hthalazin-6-ylI-4-ethyl-5-(hydroxymethylI-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Step A (S)-6-Bromo-1-(2-chloro-6-fluorophenoxy)-8-((1.1.1-trifluoropropan-2- yl)oxy )phthalazinc .
  • 2-Chloro-6-fluoronhenol 159 mg, 1.1 mmol was added to (S)-6- bromo-1-chloro-8-((1,1,1-trifluoropropan-2-yl)oxy)phthalazine (Intermediate 25, 80 mg, 0.225 mmol) followed by dioxane (1.0 mL).
  • Step B (S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-( 1 -(2-chloro-6-fluorophenoxy)- 8-1(1. l-1-trifluoropropan-2-yr)oxy)phthalazin-6-yl)-4-ethyl-2.4-dihydro-3H- 1,2.4- triazol-3-one.
  • Example 26 (S)-1-(1-((2.5-Dichloropyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxylisoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4Hl-one.
  • Step A (S)-3-((Benzyloxy)methyD-1-(1-((2.5-dichloropyridin-4-yl)oxy)-8-((l ⁇ 1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one .
  • Step B (S)- 1 -(1-((2.5-Dichloropyridin-4-yl)oxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Example 27 (S)-2-( 1 -((5-chloro-2-methylpyridin-4-yl)oxy)-8-(( 1.1. 1-trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1 ,2.4-triazol-3- one.
  • Step B (S)-1-(5-Chloro-1-((5-chloro-2-methylpyridin-4-yl)oxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol- 5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Step A (S)-5-((Benzyloxy (methyl )-2-( 1 -((5-chloro-2-methoxypyridin-4-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol- 3 -one.
  • Step B (S)-1-(1-((5-Chloro-2-methoxypyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxylisoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4II)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Step A (S)-3-((Benzyloxy)methyl)- 1 -(5-chloro- 1 -((5-chloro-2-methoxYpyridin-4- yl)oxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2.4-triazol- 5(4H)-one.
  • Step B (S)- 1 -(5-Chloro- 1 -((5-chloro-2-methoxyDyridin-4-yl)oxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol- 5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Example 30 (S)- 1 -( 1 -((5-Chloro-2-hydroxypyridin-4-yl)oxy)-8-(( 1.1.1 -trifluoropropan- 2-yl)oxy)isoqiiinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)-one.
  • Step A (S)-3-((Benzyloxy)methyl)- 1 -( 1 -((5-chloro-2-hydroxypyridin-4-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one .
  • Step B (S)-1-( l-((5-Chloro-2-hydroxypyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Example 31 (S)- 1 -( 1 -(( 1.3-Dimethyl-1H-pyrazol-4-yl)oxy)-8-(( 1. l.l-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • Step A (S)-3-((Benzyloxy)methyD-1-(1-((1.3-dimethyl-1H-pyrazol-4-yl)oxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one .
  • Step B (S)-1-(1-((1.3-Dimethyl-1H-pyrazol-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Step A (S)-3-((Benzyloxy)methyl)-4-ethyl- 1 -(1-(2-fluoro-5-methylphenoxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 1H- 1.2.4-triazol-5(4H)-one .
  • Step B (S)-4-Ethyl-1-(1-(2-fluoro-5-methylphenoxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Example 33 (S)- 1 -( 1 -(2-Chloro-6-fluoro-3-(2-methoxycthoxy)phenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2.4-triazol- 5(4H)-one.
  • Step A (S)-3-((Benzyloxy)methyl)- 1 -( 1 -(2-chloro-6-fluoro-3-(2- methoxycthoxy)phenoxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one.
  • Step B (S)-1-(1-(2-Chloro-6-fluoro-3-(2-methoxyethoxy)phenoxy)-8-((1,1,1- trifluoroDroDan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2,4-triazol- 5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step
  • Example 34b (S)- 1 -( 1 -(2-Chloro-6-fluoro-3-hydroxyphenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2.4-triazol-
  • Example 35 (S)-1-(1-(2.5-Dimethylphenoxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3 -(hydroxymethyl)- 1H-1.2.4-triazol-5(4H)-one.
  • Step B (S)- 1 -(1-(2.5-Dimeth ⁇ lphenoxy)-8-(( 1 , 1, 1 -trifluoropropan-2- yl)oxylisoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4Hl-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Example 36 (S)-1-(1-((3-Chloro-1-methyl-1H-pyrazol-4-yl)oxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-
  • Step A (S)-3-((Benzyloxy)methyl)- 1 -( 1 -((3-chloro- 1 -methyl- 1H-Dyrazol-4-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one .
  • Step B (S)-1-(1-((3-Chloro-1-methyl-1H-pyrazol-4-yl)oxy)-8-((1,1,1-trifluoropropan- 2-yl)oxy)isoqiiinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Step A (S)-Methyl 3-((6-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4- triazol- 1 -yl)-8-( (1.1.1 -trifluoropropan-2-yl)oxylisoquinolin- 1 -yl)oxy)-2-chloro-4- fluorobenzoate.
  • Step B (S)-3-((6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro- 1H- 1.2.4-triazol-
  • Step C (S)-1-(1-(3-Amino-2-chloro-6-fluorophenoxy)-8-((1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-3-((benzyloxy)methyl)-4-ethyl-1H-1.2.4-triazol-5(4H)-one.
  • Step D (S)-N-(3-((6-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4- triazol- 1 -yl)-8-( (1.1.1 -trifluoropropan-2-yl)oxylisoquinolin- 1 -yl)oxyl-2-chloro-4- fluorophenyl)methanesulfonamide .
  • Step E (S)-N-(2-Chloro-3-((6-(4-ethyl-3-(hydroxymethyl)-5-oxo-4.5-dihydro-1H- 1.2.4-triazol- 1 -yl)-8-(( 1.1.1 -trifluoropropan-2-yl)oxylisoquinolin- 1-yl)oxyl-4- fl uo ro ph e n yl ) m e th an c s ul fo n am i dc .
  • Example 38 (S)- 1 -( 1 -(2-Chloro-3-(dimethYlamino)-6-fluorophenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyD- 1H- 1.2.4-triazol-
  • Step A (S)-3-((Benzyloxy)methyl)- 1 -( 1 -(2-chloro-3-(dimethylamino)-6- fluorophenoxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoauinolin-6- ⁇ l)-4-ethyl- 1H- 1,2,4- triazol-5(4H)-one.
  • Step B (S)-1-(1-(2-Chloro-3-(dimethylamino)-6-fluorophenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2.4-triazol- 5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Example 39 (S)-1-(1-((3.6-Dichloropyridin-2-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydro ⁇ ymethyl)- 1H- 1 ,2.4-triazol-5(4H)-one.
  • Step A (S)-3-((Benzyloxy)methyl)- 1 -( l-((3.6-dichloropyridin-2-yl)oxy)-8-(( 1, 1.1 - trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one .
  • Step B (S)- 1 -(1-((3.6-Dichloropyridin-2-yl)oxy)-8-(( 1. 1. 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • Step A (S)-3-((Benzyloxy)methyl)-1-(1-(2-chloro-6-fluoro-3-methoxyphenoxy)-8- ((1.1.1 -trifluoropropan-2-yl) isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one ,
  • Step B (S)- 1 -( l-(2-Chloro-6-fluoro-3-methoxyphenoxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Example 41 (S)-1-(1-((3-Chloro-2-methoxy-5-methylpyridin-4-yl)oxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(bydroxymethyl)- 1H- 1.2.4-triazol- 5(4H)-one.
  • Step A (S)-3-((Benzyloxy)methyl)- 1 -( 1 -((3-chloro-2-methoxY-5-methylpYridin-4- yl)oxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1 ,2.4-triazol- 5(4H)-one.
  • Step B (S)- 1 -( 1 -((3-Chloro-2-methoxy-5-methyl Dy ridin-4-yl)oxy)-8-(( 1, 1, 1- trifluoroDroDan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-3-(bydroxymethyl)- 1H- 1.2,4-triazol- 5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Step B (S)- 1 -( 1 -((3-Chloro-2-methoxy Dy ridin-4-yl)oxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 2, Step B.
  • Step A (S)-3-((Benzyloxy)methyl)- 1 -( 1 -((5-chloro-3-methyl- 1 -(42- (trimethylsilyl)ethoxylmethyl)- 1H-pyrazol-4-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one.
  • Step B (S)- 1 -( 1 -((5-Chloro-3-methyl- 1H-pyrazol-4-ylk>xy)-8-(( 1, 1, 1-trifluoropropan- 2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3 -(hydroxymethyl)- 1H- 1 ,2.4-triazol-5 (4H)-one .
  • Step A (S)-3-((Benzyloxy)methyl)- 1 -( 1 -((3-chloro-2.5-dimethylpyridin-4-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one .
  • Step B (S)-3-((Benzyloxy)methyl)-1-(1-((3-chloro-2.5-dimethylpyridin-4-yl)oxy)-8- ((1,1,1-trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)-one
  • Example 45 (S)-2-(4-((3-Chloro-5-fluoro-2-methoxypyridin-4-yl)oxyl-8-fluoro-5- (( 1.1.1 -trifluoropropan-2-yl)oxy)pyridol 3.4-dlpyridazin-7-yl)-4-ethyl-5- (hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Step A (,S)-3-((Benzyloxy)methyl)- 1 -(4-((3-chloro-5-fluoro-2-methoxypyridin-4- yl)oxy)-8-fluoro-5-(( 1.1.1 -trifluoropropan-2-yl)oxy)pyrido
  • Step B (, S') -4-Ethyl- 1 -(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyridol 3.4-d]lpyridazin-7-yl)-3-(hydroxymethyl)- 1H- 1.2.4- triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 63, Step B as an off-white solid.
  • Example 46 (S)-4-Ethyl-3-(hydroxymethyl)-1-(1-((l-methyl-1H-pyrazol-5-yl)oxy)-8- ((1,1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 1H- 1 ,2.4-triazol-5 (4H)-one .
  • Step A (S)-3-((Benzyloxy)methyl)-4-ethyl- 1-( 1 -(( 1 -methyl- 1H-pyrazol-5-yl )oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoauinolin-6-yl)- 1H- 1.2.4-triazol-5(4H)-one .
  • Step B (S)-4-Ethyl-3-(hydroxymethyl)-1-(1-((1-methyl-1H-pyrazol-5-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 1H- 1.2.4-triazol-5(4H)-one .
  • the title compound was prepared in a manner analogous to Example 18, Step B.
  • 1 H NMR 400 MHz,
  • Step A (S)-3-((Benzyloxy)methyD-1-(1-((3-chloro-6-methoxypyridin-2-yl)oxy)-8 - ((1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl- 1H- 1.2.4-triazol-5(4H)-one .
  • Step B (S)-1-(1-((3-Chloro-6-methoxypyridin-2-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 18, Step B.
  • Example 48 (S)- 1 -( 1 -(( 1.3 -Dimethyl- 1H-pyrazol-5 -yl)oxy)-8-( (1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • Step A (S)-3 -( (benzyloxylmethyl)- 1-11-1(1 ,3 -dimethyl- 1H-pyrazol-5 -yl)oxyl-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)-one ,
  • the title compound was prepared in a manner analogous to Example 18, Step A by coupling 1,3- dimethyl- 1H-pyrazol-5-ol with (S)-3-((benzyloxy)methyl)- 1 -( 1 -chloro-8-(( 1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Intermediate 21).
  • Step B (S)- 1 -( 1 -(( 1.3-Dimethyl- 1H- Dy razol-5-yl)oxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydro ⁇ ymethyl)- 1H- 1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 18, Step B.
  • Example 49 (S)-1-(1-((2-Chloro-5-fluoropyridin-4-yl)oxy)-8-((l.1. l-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1.2.4-triazol-5(4H)-one.
  • Step B (S)-1-(1-((2-Chloro-5-fluoropyridin-4-yl)oxy)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 18, Step B.
  • Step A (S)-3-((Benzyloxy)methyl)-4-ethyl- 1 -( l-((tetrahydro-2H-pyran-4-yl)oxy)-8- ((1.1.1 -trifluoropropan-2-yl)oxylisoquinolin-6-yl)- 1H- 1 ,2.4-triazol-5(4H)-one , NaH (27.62 mg, 690.47 ⁇ mol , 60% purity) was added to tetrahydropyran-4-ol (2.04 g, 19.97 mmol, 2 mL) at 0 °C under N 2 .
  • Step B (S)-4-Ethyl-3 -(hydroxymethyl!- 1 -( 1 -( (tetrahydro-2H-pyran-4-yl)oxy)-8-(( 1,1.1- trif1uoropropan-2-yl)oxy)isoauinolin-6-yl)- 1H- 1 ,2.4-triazol-5(4H)-one.
  • Example 51 (S)-4-Ethyl-3-(hydroxymethyl)- 1 -( 1 -(pentan-3-yloxy)-8-(( 1.1.1- trifluoropropan-2-yl) isoquinolin-6-yl)- 1H- 1.2.4-triazol-5(4H)-one.
  • Step A (S)-5-((benzyloxy)methyl)-4-ethyl-2-(T-(pentan-3-yloxy)-8-((l.l.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Step B (S)-4-Ethyl-3-(hydroxymethyl)-1-(1-(pentan-3-yloxy)-8-((1,1,1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 50, Step B as a white solid.
  • Example 52 (S)- 1 -( 1 -(( 1.3-Dimethoxypropan-2-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • Step A (S)-5-((benzyloxy)methyl)-2-( 1 -(( 1.3-dimethoxypropan-2-yl)oxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2,4-triazol-3-one.
  • Step B (S)- 1-( 1 -(( 1.3-Dimethoxypropan-2-yl)oxy)-8-(( 1, 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • Step A 5-((benzyloxy)methyl)-4-ethyl-2-( !-((( 1 R.2R)-2-methylcyclohc ⁇ yl)oxy)-8- (((S)-1.l.l -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H- 1 ,2.4-triazol-3 - one.
  • Step B 4-Ethyl-3-(hydroxymethyD-1-(1-trans-2-methylcyclohexyl)oxy) -8-(((S)- 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 50, Step B as a white solid.
  • Example 54 (S)- 1 -( 1 -(( 1.3-Dihydroxypropan-2-yl)oxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • Step A (S)-5-((benzyloxy)methyl)-2-( 1 -(( 1.3-bis(benzyloxy)propan-2-yl)oxy)-8-
  • Step B (S)- 1 -( 1 -(( 1.3-Dihydroxypropan-2-yl)oxy)-8-(( 1 , 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3 -(hydroxymethyl)- 1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 50, Step B as a white solid.
  • Example 55 (S)-4-Ethyl-3-(hydro ⁇ ymethyl)- 1-( 1 -isobutoxy-8-(( 1.1.1 -trifluoropropan- 2.4-triazol-5(4H)-one.
  • Step A (S)-5-((benzyloxy)methyl)-4-ethyl-2-(1-isobutoxy-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Step B (S)-4-Ethyl-3-(hydroxymethyl)- 1 -( 1 -isobutoxy-8-(( 1 , 1, 1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 50, Step B as a white solid.
  • Example 56 (S)-4-Ethyl-3-(hydro ⁇ ymethyl)- 1-( 1 -(2-methoxyethoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoauinolin-6-yl)- 1H- 1.2.4-triazol-5(4H)-one.
  • Step B (S)-4-Ethyl-3-(liydroxymethyl)-1-(T-(2-methoxyethoxy)-8-(( 1-1-1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 50, Step B as a white solid.
  • Example 57 4-Ethyl-3-(hydroxymethyl)-1-(1-((3-methoxytetrahydro-2H-pyran-4- yl)oxy)-8-(((S)- 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 1H- 1.2.4-triazol-
  • Step A 5-((Benzyloxy)methyl)-4-ethyl-2-( 1 -((3-methoxytctrahydro-2H- Dy ran-4- yl)oxy)-8-(((S)- 1.1 , 1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-2.4-dihydro-3H- 1.2.4- triazol-3-one.
  • Step B 4-Ethyl-3-(hydroxymethyl)-1-(1-((3-methoxytetrahydro-2H-pyran-4-yl)oxy)-8- (((S)-1.l.l -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)- 1H- 1 ,2.4-triazol-5 (4H)-one .
  • the title compound was prepared in a manner analogous to Example 50, Step B as a white solid.
  • Example 58 4-Ethyl- 1 -(1-(( 1 -hydroxy-3-methoxypropan-2-yl)oxy)-8-(((S)- 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-3-(hydroxymethyl)- 1H- 1.2.4-triazol-5(4H)- one.
  • Step A 2-(1-(( 1 -(benzyloxy)-3-methoxypropan-2-yl)oxy)-8-(((S)- 1.1. 1-trifluoropropan-
  • Step B 4-Ethyl- 1 -( 1 -(( 1 -hydroxy-3-methoxypropan-2-yl)oxy)-8-(((S)- 1. 1.1- trifluoropropan-2-yl)oxy)isoauinohn-6-yl)-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)- one.
  • the title compound was prepared in a manner analogous to Example 50, Step B as a white solid.
  • Example 59 (SM-(1-((Tetrahydro-2H-thiopyran 1.1 -dioxide)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)- 1H- 1 ,2.4-triazol- 5(4H)-one.
  • Step A ( S)-5-((Benzyloxy)methyl)-2-( 1 -(( 1.1 -dioxidotetrahydro-2H-thiopyran-4- yl)oxy)-8-(( 1.1.1 -trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1 ,2.4-triazol-3 -one .
  • Step B (S)-l-(1-((Tetrahydro-2H-thiopyran l.l-dioxide)-8-((1,1,1-trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-3-(hydroxymethyl)-1H-1.2.4-triazol-5(4H)-one.
  • the title compound was prepared in a manner analogous to Example 50, Step B as a white solid.
  • Example 60 2-( 1 -(6-Chloro-2-fluoro-3-methoxyphenoxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy) isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one.
  • Step A 5-((Benzyloxy)methyl)-2-( 1 -(6-chloro-2-fluoro-3-methoxyphenoxy)-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoauinolin-6-yl)-4-ethyl-2.4-dihydro-3H- 1.2.4-triazol-3-one.
  • Step B 2- ⁇ 1 -(6-Chloro-2-fluoro-3-methoxyphenoxy)-8-(( 1.1.1 -trifluoropropan-2- yl)oxy) isoquinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one.
  • the title compound was prepared in a manner analogous to Example 1, Step B as a white solid.
  • Example 61 2-( 1 -(2-Chloro-6-fluorophenoxy)-4-fluoro-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoauinolin-6-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H- 1.2.4-triazol-3- one.
  • Step A 6-(3-((BenzyloxyfmethyD-4-ethyl-5-oxo-4.5-dihydro-1H-1.2.4-triazol-1-ylf-4- fluoro-3 -methoxy-8-( (1.1.1 -trifluoropropan-2-yl)oxyl-3.4-dihydroisoauinolin- 1 (2H)- one.
  • Step B 5-((Benzyloxy)methyl)-2-( 1 -chloro-4-fluoro-3-methoxy-8-(( 1.1.1- trifluoropropan-2-yl)oxyf-3.4-dihydroisoauinolin-6-ylV4-ethyl-2 4-dihydro-3H-1.2.4- triazol-3 -one .
  • Step C 5-((Benzyloxy)methyl)-2-( 1 -chloro-4-fluoro-8-(( 1.1.1 -trifluoropropan-2- yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Step D 5-((Benzyloxy)methyl)-2-(1-(2-chloro-6-fluorot)henoxy)-4-fluoro-8-(( 1.1.1- trifluoropropan-2-yl)oxy)isoquinolin-6-yl)-4-ethyl-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Example 62 2-(4-(2-Chloro-6-fluorophenoxyf-8-fluoro-5-((1,1,1-trifluoropropan-2- yl!oxy!pyrido 13.4-d]pyrida zin -7 -yl!-4-ethyl-5 -(hydroxymethyl) -2.4-dihydro-3H- 1,2.4- triazol-3-one.
  • Step A 3-((Benzyloxy)methyl)-1-(4-(2-chloro-6-fluorophenoxy)-8-fluoro-5-((1,1,1- trifluoropropan-2-yl) pyrido[3.4-d]pyridazin-7-yl)-4-ethyl- 1H- 1 ,2.4-triazol-5(4H)- one.
  • Step B 1-(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl)oxylpyrido 13.4-dlpyridazin-7 -yl)-4-ethyl-3 -(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)- one.
  • the title compound was prepared in a manner analogous to Example 1, Step B.
  • 1 H NMR (400 MHz, CDCl 3 ) ⁇ 9.59 (s, 1H), 7.34 - 7.30 (m, 1H), 7.26 - 7.21 (m, 1H),
  • Example 63 (S)- 1 -(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-(( 1, 1, 1 -trifluoropropan-2- yl)oxylpyrido 13.4-dlpyridazin-7 -yl)-4-ethyl-3 -(hydroxymethyl)- 1H- 1 ,2.4-triazol-5(4H)- one.
  • Step A (S)-3-((Benzyloxy)methyl)- 1 -(4-(2-chloro-6-fluorophenoxy)-8-fluoro-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyridol3.4-dlpyridazin-7-yl)-4-ethyl-1H-1.2.4-triazol-5(4H)- one.
  • NaH 50% purity, 418 mg, 10.44 mmol
  • 2- chloro-6-fluorophenol (6.12 g, 41.76 mmol) in DMF (5 mL) at room temperature. After addition, the mixture was heated to 70 °C for 0.5 hour.
  • Step B (S)-1-(4-(2-Chloro-6-fluorophenoxy)-8-fluoro-5-((1,1,1-trifluoropropan-2- yl!oxy!pyrido 13.4-dlpyridazin-7 -yl)-4-ethyl-3 -(hydroxymethyl )- 1H- 1 ,2.4-triazol-5(4H)- one.
  • Example 64 4-Ethyl-1-(8-fluoro-4-((3-methoxytetrahydro-2H-pyran-4-yl)oxy)-5-(((Sl- 1.1.1 -trifluoropropan-2-yl)oxy)pyrido G 3.4-dlpyridazin-7 -yl)-3 -(hydroxymethyl )- 1H- 1 ,2.4-triazol-5(4H)-one.
  • Step A 3-((Benzyloxy)methyl)-4-cth ⁇ 1- 1-(8-fluoro-4-((3-methoxytctrahydro-2H-p ⁇ Tan- 4-yl)oxy)-5-(((S)- 1.1.1 -trifluoropropan-2-yl)oxy)pyridol 3.4-d
  • Step B 4-Ethyl- 1 -(8-fluoro-4-((3 -methoxytetrahydro-2H-pyran-4-yl)oxy)-5 -(((SI- 1.1.1- trifluoropropan-2-yl)oxy)pyrido 13.4-dlpyridazin-7 -yl)-3 -(hydroxymethyl)- 1H- 1.2.4- triazol-5(4H)-one.
  • 1 H NMR (400MHz, CDCl 3 ) ⁇ 9.53 - 9.40 (m, 1H), 6.37 - 5.70 (m,
  • Example 65 2-(8-(2-Chloro-6-fluorophenoxy)-4-fluoro-1-((1,1,1-trifluoropropan-2- yl)oxy)-2.7-naphthyridin-3-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4- triazol-3-one.
  • Step A 5-((Benzyloxy)methyl)-2-(8-(2-chloro-6-fluorophenoxy)-4-fluoro- 1 -(( 1.1.1 - trifluoropropan-2-yl)oxy)-2.7-naphthyridin-3-yl)-4-ethyl-2.4-dihydro-3H- 1 .2.4-triazol-
  • Step B 2-( 8-(2-Chloro-6-fluorophenoxy)-4-fluoro- 1 -(( 1.1.1 -trifluoropropan-2-yl)oxy)- 2.7-naphthyridin-3-yl)-4-ethyl-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3-one.
  • Example 66 (S)-4-ethyl-2-(8-fluoro-4-(o-tolyloxy)-5-((1,1,1-trifluoropropan-2- yl)oxy)pyridol3.4-dlpyridazin-7-yl)-5-(hydroxymethyl)-2.4-dihydro-3H-1.2.4-triazol-3- one.
  • Step B (,S')-4-Ethyl- 1 -(8-fluoro-4-(o-tolyloxy)-5-(( 1.1.1 -trifluoropropan-2- yl)oxy)pyrido
  • Example 67 (S)-4-Ethyl-2-(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-((1,1,1- trifluoropropan-2-yl) pyrido[3.4-d]pyridazin-7-yl)-5-(hydroxymethyl)-2.4-dihydro- 3H-1.2.4-triazol-3-one. 5-((1,1,1-trifluoropropan-2-yl)oxy)pyridol3.4-anpyridazin-7-yl)-1i7-1.2.4-triazol-5(4H)- one.
  • Step B (,V)-4-Ethyl- 1 -(8-fluoro-4-(4-fluoro-2-methylphenoxy)-5-(( 1.1.1- trifluoropropan-2-yl)oxy)pyridol 3.4-J
  • the title compound was prepared in a manner analogous to Example 63, Step B.
  • Step A (,S')-3-((benzyloxy)methyl)-4-ethyl- 1 -(8-fluoro-4-(5-fluoro-2-methylphenoxy)- 5-111.1. l-trifluoropropan-2-yl)oxy)pyridol3.4-anpyridazin-7-yl)-1i7-1.2.4-triazol-5(4Ef)- one.
  • Step B (,S')-4-ethyl- 1 -(8-fluoro-4-(5 -fluoro-2-methylphenoxy)-5-(( 1.1.1 -trifluoropropa n-2-yl)oxy)pyridor3.4- ⁇ 71pyridazin-7-yl)-3-(hydroxymethyl)- 177-1, 2.4-triazol-5(47/)-one
  • Example 69 (S)-2-(4-(2-Chloro-4.6-difluorophenoxy)-8-fluoro-5-((1,1,1- trifluoropropan-2-yl)oxylpyrido 13.4-dlpyridazin-7 -yl)-4-ethyl-5 -(hydroxymethyl)-2.4- dihydro-3H- 1.2.4-triazol-3 -one .

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Abstract

L'invention concerne des composés, des compositions et des procédés pour traiter des maladies, des troubles ou des états médicaux qui sont affectés par la modulation de DHODH. Des modes de réalisation de ces composés sont représentés par la formule (I) et la formule (II) comme suit : et où R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, X3, X4, Y et Z sont tels que définis dans la description.
EP21704615.0A 2020-02-04 2021-02-04 Composés hétérocycliques utilisés en tant qu'inhibiteurs de la dihydroorotate déshydrogénase Withdrawn EP4100124A1 (fr)

Applications Claiming Priority (2)

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US202062969688P 2020-02-04 2020-02-04
PCT/IB2021/050908 WO2021156787A1 (fr) 2020-02-04 2021-02-04 Composés hétérocycliques utilisés en tant qu'inhibiteurs de la dihydroorotate déshydrogénase

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CA3170111A1 (fr) 2021-08-12
AU2021216714A1 (en) 2022-09-29
MX2022009535A (es) 2022-11-14
WO2021156787A1 (fr) 2021-08-12
KR20220137709A (ko) 2022-10-12

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