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WO2022070068A1 - Inhibiteurs de la dihydroorotate déshydrogénase - Google Patents

Inhibiteurs de la dihydroorotate déshydrogénase Download PDF

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Publication number
WO2022070068A1
WO2022070068A1 PCT/IB2021/058904 IB2021058904W WO2022070068A1 WO 2022070068 A1 WO2022070068 A1 WO 2022070068A1 IB 2021058904 W IB2021058904 W IB 2021058904W WO 2022070068 A1 WO2022070068 A1 WO 2022070068A1
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Prior art keywords
fluoro
methyl
isopropyl
tolyl
isoquinolin
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Inventor
Lindsey DERATT
Scott Kuduk
Zhuming Zhang
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Janssen Biotech Inc
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Janssen Biotech Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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

Definitions

  • 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.
  • Retinoic acid targets the promyelocytic leukemia protein (PML)-retinoic acid receptor- ⁇ (RAR- ⁇ ) fusion protein encoded by a t(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).
  • differentiation therapy is successful, it is only applicable to a small population of AML patients. Research efforts have aimed at identifying additional differentiation inducing agents, but with limited success.
  • 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). Since the first observation by Sykes et al.
  • DHODH inhibition drives AML differentiation in vitro, as evidenced by upregulation of the differentiation markers CD11b and CD14, and results in dose dependent anti-leukemic effects, decreased leukemic stem cells and prolonged survival in vivo, additional evidence emerged demonstrating that small molecule DHODH inhibitors mediate antiproliferative activity against AML cells with concomitant cell cycle arrest, upregulation of CD11b and CD14, and induction of apoptosis (Wu D et al.. Haematologica 103: 1472, 2018; Sainas S et al., J Med Chem 61: 6034, 2018; Cao L et al., Mol Cancer Ther, October 23rd Epub ahead of print).
  • 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.
  • 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) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention. DETAILED DESCRIPTION OF THE INVENTION Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in art.
  • 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.
  • 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 - 6cycloalkyl 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 or “halo” 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: .
  • 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: Those skilled in the art will recognize that the species of 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.
  • the term “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. In other words, 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.
  • “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, 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 may comprise the active ingredient in combination with one or more carriers and/or one or more excipients and/or one or more diluents.
  • the term “therapeutically 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 (IC)) 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.
  • 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) 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
  • 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 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.
  • 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.
  • 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.
  • 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 O, 17 O, 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.
  • C n-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.
  • the specific individual substituent assignment to each of such groups is meant to be independently made with respect to the specific individual substituent assignments to the remaining groups.
  • 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.
  • zwitterion zwitterions
  • 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. Sometimes these compounds are referred to by the term “inner salts”.
  • Other sources refer to these compounds as “dipolar ions”, although the latter term is regarded by still other sources as a misnomer.
  • 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. Because there is no need to name each and every embodiment that would be recognized by those of ordinary skill in the art, no structures of the zwitterionic compounds that are associated with the compounds of this invention are given explicitly herein. They are, however, part of the embodiments of this invention.
  • 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 ; Sexample is one of S 1 and S 2 ; Sexample is one of S 1 and S 3 ; Sexample is one of S 2 and S 3 ; Sexample is one of S 1 , S 2 and S 3 ; and S example is any equivalent of each one of these choices.
  • S example is one of S 1 , S 2 , and S 3 ” is accordingly used herein for the sake of brevity, but not by way of limitation.
  • C i -C j 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 ).
  • An additional embodiment of the invention is a compound of Formula (I) wherein X is CH and Y is CH.
  • An additional embodiment of the invention is a compound of Formula (I) wherein X is CH and Y is N.
  • An additional embodiment of the invention is a compound of Formula (I) wherein X is N and Y is CH.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 1 is C 1-4 alkyl.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 1 is CH(CH 3 )2.
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 2 is wherein R a is CH 3 ; and R b is CH 2 OH, CH(OH)CH 3 , or C(OH)(CH 3 ) 2 .
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 2 is
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 2 is
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 2 is
  • An additional embodiment of the invention is a compound of Formula (I) wherein R 2 is An additional embodiment of the invention is a compound of Formula (I) wherein R 2 is An additional embodiment of the invention is a compound of Formula (I) wherein R 2 is 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 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 R 4 is An additional embodiment of the current invention is a compound selected from the compounds shown below in Table 1, and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof: Table 1
  • a further embodiment of the current invention is a compound selected from the group consisting of: 7-Fluoro-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-4-isopropyl-2-(o- tolyl)isoquinolin-1(2H)-one; 7-Fluoro-6-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-isopropyl-2-(o- tolyl)isoquinolin-1(2H)-one; 2-(5-Chloro-3-methyl-1H-pyrazol-4-yl)-7-fluoro-6-(5-(2-hydroxypropan-2-yl)-1-methyl-1H- 1,2,4-triazol-3-yl)-4-isopropylisoquinolin-1(2H)-one; 2-(2-Chloro-4-methylpyridin-3-yl)-7-fluoro
  • An additional embodiment of the invention is a compound of Formula (I) having the Formula (IB): wherein R 2 is , R a is C -alkyl, R b i 4 1 4 s C 1-4 alkyl substituted with one OH member, and R is ; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof.
  • An additional embodiment of the invention is a compound of Formula (I) having the Formula (IC): wherein R 2 is selected from the group consisting of wherein R a is C 1-4 alkyl; R b is C 1-4 alkyl substituted with one OH member; R c is C 1-4 alkyl substituted with one OH member; and R 4 is ; or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof. Also within the scope of the invention are enantiomers and diastereomers of the compounds of Formula (I) (as well as compounds of Formula (IA), (IB), and (IC)).
  • compositions of Formula (I) are also within the scope of the invention.
  • pharmaceutically acceptable salts, N-oxides or solvates of the compounds of Formula (I) are also within the scope of the invention.
  • pharmaceutically acceptable prodrugs of compounds of Formula (I) are also within the scope of the invention, and pharmaceutically acceptable prodrugs of compounds of Formula (I) (as well as compounds of Formula (IA), (IB), and (IC)), and pharmaceutically active metabolites of the compounds of Formula (I) (as well as compounds of Formula (IA), (IB), and (IC)).
  • isotopic variations of compounds of Formula (I) are also as compounds of Formula (IA), (IB), and (IC)), such as, e.g., deuterated compounds of Formula (I).
  • the pharmaceutically acceptable salts, N-oxides or solvates of the isotopic variations of the compounds of Formula (I) (as well as compounds of Formula (IA), (IB), and (IC)).
  • the pharmaceutically acceptable prodrugs of the isotopic variations of the compounds of Formula (I) (as well as compounds of Formula (IA), (IB), and (IC)), and pharmaceutically active metabolites of the isotopic variations of the compounds of Formula (I) (as well as compounds of Formula (IA), (IB), and (IC)).
  • compositions comprising compounds of Formula (I) 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 comprising an effective amount of at least one compound selected from compounds of Formula (I), 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.
  • An additional embodiment of the invention is a pharmaceutical composition
  • 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 1-33), 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.
  • they can be incorporated into a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycols or liquid paraffin.
  • compositions of the present invention can also be injected parenterally, for example, intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally, or intrathecally.
  • compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.
  • a suitable carrier for parenteral administration, the pharmaceutical 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.
  • the pharmaceutical 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 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 ether, benzyl ether, benzyl, sulfonyl, sulfonyl, adiluent, 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) 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, 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) will vary as will the diseases, syndromes, conditions, and disorders being treated.
  • An embodiment of the present invention is directed to a pharmaceutical composition for oral administration, comprising a compound of Formula (I) in an amount of from about 1 mg to about 500 mg.
  • a compound of Formula (I) 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) 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) 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; or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof.
  • 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), 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) to a subject in need thereof.
  • 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 compounds of Formula (IA), (IB), and (IC), such as a compound of Table 1), enantiomers and diastereomers of the compounds of Formula (I) (as well as compounds of Formula (IA), (IB), and (IC) such as a compound of Table 1), isotopic variations of the compounds of Formula (I) (as well as compounds of Formula (IA), (IB), and (IC), such as a compound of Table 1), and pharmaceutical
  • 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 compounds of Formula (IA), (IB), and (IC), 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, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including edema, embolism, fibrosis,
  • 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), 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), 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, lymphomas including but not limited to AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin's lymphoma (NHL), T-non-Hodgkin lymphoma (T-NHL), subtype
  • ALL acute 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), 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), such as a compound shown in Table 1, pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof
  • a pharmaceutical composition comprises an effective amount of a compound of the present invention (e.g., selected from compounds of Formula (I), 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 Formula (I) e.g., selected from compounds of Formula (I), such as a compound shown in Table 1, pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof
  • An additional embodiment of the invention provides the use of a compound of Formula (I), 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 in Table 2: Table 2. PREPARATIVE EXAMPLES Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples to follow.
  • a compound of formula (VII), R a is C 1-6 alkyl or CD 3
  • R a is C 1-6 alkyl or CD 3
  • a base such as Cs 2 CO 3 , K 2 CO 3 , and the like
  • a suitable solvent such as DMF, acetone, DMSO, and the like
  • ethyl 1H- imidazole-2-carboxylate is alkylated employing a base such as Cs 2 CO 3 , K 2 CO 3 , and the like; an alkylating agent such as, CD 3 I, and the like; in a suitable solvent such as DMF, acetone, DMSO and the like; to provide ethyl 1-(methyl-d 3 )-1H-imidazole-2-carboxylate.
  • Ethyl 1-(methyl-d 3 )- 1H-imidazole-2-carboxylate is brominated employing bromination conditions known to one skilled in the art, for example, using a suitable brominating agent such as NBS, and the like; in a suitable solvent such as DMF, to afford a compound of formula (VIII), where R a is CD 3 .
  • a suitable brominating agent such as NBS, and the like
  • a suitable solvent such as DMF
  • a Grignard reagent such as MeMgBr
  • a suitable solvent such as THF, ether, 1,4-dioxane and the like
  • a compound of formula (XI) where R a is C 1-6 alkyl or CD 3 , and Z is CH or N is reacted with a reducing agent such as DIBALH; in a suitable solvent, such as DCM, DCE, and the like; at low temperatures such as -78°C to rt; to provide a compound of formula (XIII).
  • a compound of formula (XIII) is reacted with Grignard reagent, such as MeMgBr, employing conditions previously described to provide a compound of formula (XIV) as a racemic mixture of compounds.
  • the racemic mixture of compounds is separated by SFC to provide the secondary alcohols of formulas (XIVa) and (XIVb) in enantiopure form.
  • methyl 2-bromo-4,5-difluorobenzoate is reacted with 3- methylbutanal; employing a palladium catalyst such as allylpalladium(II) chloride dimer, and the like; a ligand such as XantPhos, and the like; a suitable base such as Cs 2 CO 3 , and the like; in the presence of a water scavenger such as molecular sieves (4A); in a suitable solvent such as 1,4- dioxane; to provide 6,7-difluoro-3-hydroxy-4-isopropylisochroman-1-one.
  • a palladium catalyst such as allylpalladium(II) chloride dimer, and the like
  • a ligand such as XantPhos, and the like
  • a suitable base such as Cs 2 CO 3
  • a water scavenger such as molecular sieves (4A)
  • a suitable solvent such as 1,4- dioxane
  • a compound of formula (XV), where R 4 is as described in claim 1; is reacted with trimethyl aluminum; in a suitable solvent such as dichloromethane, dichloroethane, toluene, or a mixture thereof; the resulting solution is combined with 6,7-difluoro-3-hydroxy-4-isopropylisochroman-1-one, followed by subsequent treatment with acetic acid under heating temperature of 80-100°C for a period of time ranging from 5 to 24 hours; to provide a compound of formula (XVI); where X and Y are CH, R 1 is isopropyl, and R 3 is F.
  • a compound of formula (XV) such as o-toluidine and the like; is directly condensed with 6,7-difluoro-3-hydroxy-4- isopropylisochroman-1-one in acetic acid under heating temperature of 80-100°C for a period of time ranging from 10 to 24 hours; to provide a compound of formula (XVI), where X and Y are CH.
  • a compound of formula (XV), where R 4 is as defined in claim 1; is reacted with a Lewis acid such as AlMe3, AlCl 3 , or the like; in a suitable solvent such as dichloromethane, dichloroethane, toluene, or a mixture thereof; the resulting solution is combined with 6,7-difluoro-3-hydroxy-4- isopropylisochroman-1-one, followed by subsequent treatment with acetic acid under heating temperature of 80-100°C for a period of time ranging from 5 to 24 hours; to provide a compound of formula (XVI); where X and Y are CH, R 1 is isopropyl and R 3 is F.
  • a Lewis acid such as AlMe3, AlCl 3 , or the like
  • a suitable solvent such as dichloromethane, dichloroethane, toluene, or a mixture thereof
  • acetic acid under heating temperature of 80-100°C for a period of time ranging from 5 to 24
  • a compound of formula (XVI) is reacted with benzyl alcohol employing a suitable base such as NaH , and the like; in a suitable solvent such as THF; to provide a compound of formula (XVII); where 6-fluoro group is selectively displaced by a benzyloxy group.
  • a suitable base such as NaH , and the like
  • THF a suitable solvent
  • 6-fluoro group is selectively displaced by a benzyloxy group.
  • the removal of benzyl group in a compound of formula (XVII) is achieved by employing BCl 3 , at a temperature ranging from -78°C to 0°C, in a suitable solvent such as in DCM, DCE, and the like; to afford a compound of formula (XVIII).
  • a compound of formula (XVI) is treated with KOH or NaOH in a suitable solvent such as DMSO under a heating temperature between 80-100°C ; to provide a compound of formula (XVIII) in one step directly.
  • a compound of formula (XVIII) is reacted with a triflating agent such as N- phenylbis(trifluoromethanesufonimide) (TF 2 NPh), a base such as TEA, DIEA, and the like, in a suitable solvent such as DCM, and the like; under room temperature; to provide a triflate compound of formula (XIX), where X is CH, Y is CH, R 3 is F, and R 4 are defined as previously described.
  • a triflating agent such as N- phenylbis(trifluoromethanesufonimide) (TF 2 NPh)
  • TF 2 NPh N- phenylbis(trifluoromethanesufonimide)
  • triflating agents such as trifluoromethanesulfonic anhydride (Tf 2 O), a base such as triethylamine (TEA), pyridine, and the like; may also be used.
  • Tf 2 O trifluoromethanesulfonic anhydride
  • TAA triethylamine
  • pyridine a base
  • SCHEME 8 commercially available or synthetically accessible 4,5- difluorophthalic anhydride is reacted with a hydrazine compound of formula R 4 -NHNH 2 , where R 4 is as defined in claim 1; in acetic acid; at a temperature of 100 °C -125 °C; for a period of 24 h to 48 h; to afford the mixture of a compound of formula (XXa) and a compound of formula (XXb).
  • the mixture can be separated by chromatography, trituration, or precipitation to afford a compound of formula (XXb).
  • a compound of formula (XXb) either in high purity or as a crude mixture with a compound of formula (XXa), with a sulfonate-based leaving group such as trifluoromethanesulfonyl (triflate)
  • a triflating agent such as trifluoromethanesulfonic anhydride (Tf 2 O)
  • Tf 2 O trifluoromethanesulfonic anhydride
  • Tf 2 O trifluoromethanesulfonic anhydride
  • Tf 2 O trifluoromethanesulfonic anhydride
  • Tf 2 O trifluoromethanesulfonic anhydride
  • Tf 2 O trifluoromethanesulfonic anhydride
  • Tf 2 O trifluoromethanesulfonic anhydride
  • Tf 2 O trifluoromethanesulfonic an
  • Milder triflating agents such as N- phenylbis(trifluoromethanesufonimide) (TF 2 NPh), a base such as TEA, DIEA, and the like, in a suitable solvent such as DCM, and the like; may be used.
  • TF 2 NPh N- phenylbis(trifluoromethanesufonimide)
  • a base such as TEA, DIEA, and the like
  • a suitable solvent such as DCM, and the like
  • a commercially available or synthetically accessible boronic acid such as R 1 - B(OH)2, where R 1 is C 2-6 alkenyl or C 2-6 haloalkenyl
  • a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride, and the like
  • a commercially available or synthetically accessible compound of formula (XXV), (which includes compounds of formulas (IX), (X), (XII), (XIV), (XIVa), and (XIVb)); is reacted under Suzuki coupling conditions as previously described, with a compound of formula (XXIV), provides a compound of Formula (I).
  • a compound of formula (XXIV) is reacted with a commercially available or synthetically accessible heteroarylbromide of formula (XXV), where R 2 is optionally substituted imidazolyl, pyrazinyl, pyridinyl, or triazolyl as defined in claim 1; a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride, 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride, XPhos Pd G3, Pd-118, and the like; a suitable base such as Cs 2 CO 3 , Na 2 CO 3 , and the like; in a suitable solvent such as 1,4-dioxane, water, ethanol, or a mixture thereof; employing microwave irradiation or conventional heating; at temperatures ranging from 80 to100°C ; to provide a compound of Formula compound (I).
  • a palladium catalyst such as bis(tri
  • a 1,2,4-triazol-5(4H)-one compound of formula (XXVI), 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 to 85 °C.
  • 2,6-dichloro-5-fluoronicotinic acid is reacted with (COCl)2, a catalytic amount of DMF, in a suitable solvent such as THF, and the like, at temperatures ranging from 0 °C to 25 °C, for a period of 1 h, to provide 2,6-dichloro-5- fluoronicotinoyl chloride.
  • a suitable solvent such as THF, and the like
  • Isopropyl 2,6-dichloro-5-fluoronicotinate is reacted with a commercially available or synthetically accessible nucleophilic compound of formula (XXVI), where PG is benzyl, and R a is C 1-6 alkyl; in the presence of a base such as K 2 CO 3 , Cs 2 CO 3 , NaHCO3, triethylamine, and the like; in a suitable solvent such as dimethylsulfoxide (DMSO), DMF, THF, ACN, and the like; to afford a compound of formula (XXVII).
  • a base such as K 2 CO 3 , Cs 2 CO 3 , NaHCO3, triethylamine, and the like
  • a suitable solvent such as dimethylsulfoxide (DMSO), DMF, THF, ACN, and the like
  • a compound of formula (XXVII) is reacted with 3-methylbutanal; a palladium catalyst such as allylpalladium(II) chloride dimer, and the like; a ligand such as 1,1'- bis(diphenylphosphino)ferrocene (dppf), and the like; a suitable base such as, Cs 2 CO 3 , and the like; in the presence of a water scavenger such as molecular sieves (4A); in a suitable solvent such as 1,4-dioxane; to provide a compound of formula compound (XXIX), where R 1 is isopropyl, R 3 is F, PG is benzyl, and R a is C 1-6 alkyl.
  • a palladium catalyst such as allylpalladium(II) chloride dimer, and the like
  • a ligand such as 1,1'- bis(diphenylphosphino)ferrocene (dppf), and the like
  • a compound of formula (XXX) is prepared by hydration of a compound of formula (XXIX) using a base, such as LiOH, and the like; in a suitable solvent mixture, such as EtOH and water.
  • a base such as LiOH, and the like
  • a suitable solvent mixture such as EtOH and water.
  • a compound of formula (IX), where Z is CH, and R a is C 1-6 alkyl, is reacted with a source of Bu3Sn radical such as hexa ⁇ n ⁇ butylditin; a palladium catalyst such as Pd(PPh3)2Cl 2 , and the like; in a suitable solvent such as toluene; at a temperature of about 100 °C; for a period of 12-18 h; to provide a compound of formula (XXXI), where Z is CH, and R a is C 1-6 alkyl.
  • Bu3Sn radical such as hexa ⁇ n ⁇ butylditin
  • Pd(PPh3)2Cl 2 palladium catalyst
  • a suitable solvent such as toluene
  • a compound of formula (XXXI) is reacted with an alkoxide reagent, preferably MeONa; in a suitable polar solvent such as DMF, DMSO, and the like; to afford a compound of formula (XXXIII). Further reaction of a compound of formula (XXXIII) with a chlorinating reagent such as POCl 3 , and the like; in a suitable polar solvent such as DMF, and the like; at elevated temperatures of about 100 °C; affords a compound of formula (XXXIV).
  • a compound of formula (XXXIV) is reacted with a commercially available or synthetically accessible organostannane compound of formula (XXXII), where Z is CH and R a is C 1-6 alkyl, using a palladium catalyst such as Pd(PPh 3 ) 3 Cl 2 , Pd(dppf)Cl 2 , and the like; in a suitable solvent such as 1,4-dioxane, toluene, and the like; at refluxing temperatures for a period of 2.5 h; to provide a compound of Formula (I), where X is CH, Y is N, R 1 , R 2 , R 3 , R 4 are defined as described in Claim 1.
  • 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).
  • polar solvents including mixtures of polar solvents and aqueous mixtures of polar solvents
  • non-polar solvents including mixtures of non-polar solvents.
  • the compounds according to this invention have at least one chiral center, they 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.
  • the ABPR was set to 100bar to keep the CO 2 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 (MS) 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.
  • Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model AVIII 400 spectrometers.
  • Step A.3-Bromo-1-methyl-1H-1,2,4-triazole-5-carbaldehyde To a mixture of methyl 3-bromo- 1-methyl-1H-1,2,4- triazole-5-carboxylate (10.5 g, 47.7 mmol) in DCM (160 mL) under an atmosphere of nitrogen at -70 °C was added a toluene solution (1 M) of DIBAL-H (95.3 mL, 95.3 mmol) dropwise. The reaction mixture was stirred at -70 °C for 1 h. The reaction mixture was quenched by sat. aq. Rochelle salt (100 mL).
  • Step A 5,6-Difluoro-2-(o-tolylamino)isoindoline-1,3-dione and 6,7-Difluoro-2-(o-tolyl)-2,3- dihydrophthalazine-1,4-dione.
  • the mixture was heated at 80 o C for 0.5 h, and then cooled to -40 o C, followed by the addition of 6,7-difluoro-4-isopropyl-2-(o-tolyl)phthalazin-1(2H)-one (1.8 g, 5.7 mmol) under nitrogen.
  • the reaction mixture was slowly warmed to room temperature and stirred overnight.
  • the mixture was poured into aqueous saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated.
  • Step C 2-(3-Chloro-5-methyl-1H-pyrazol-4-yl)-6,7-difluoro-4-isopropylisoquinolin-1(2H)-one.
  • a mixture of 6,7-difluoro-3-hydroxy-4-isopropylisochroman-1-one (3.2 g, 12.3 mmol) and 3- chloro-5-methyl-1H-pyrazol-4-amine (1.8 g, 13.5 mmol) in AcOH (35 mL) was heated with stirring at 80 °C for overnight. The mixture was cooled to room temperature and concentrated to a small volume ( ⁇ 8 mL). The resulting mixture was triturated with the addition of water (20 mL).
  • benzyl alcohol 8.0 g, 74 mmol
  • THF 10 mL
  • NaH 50% dispersion in mineral oil, 1.6 g, 67 mmol
  • Step B 6-(Benzyloxy)-2-(2-chloro-4-methylpyridin-3-yl)-7-fluoro-4-isopropylisoquinolin- 1(2H)-one.
  • benzyl alcohol 13 g, 118 mmol
  • THF 45 mL
  • NaH 50% dispersion in mineral oil, 4.2 g, 106 mmol
  • Step C 2-(2-Chloro-4-methylpyridin-3-yl)-7-fluoro-6-hydroxy-4-isopropylisoquinolin-1(2H)- one.
  • 6-(benzyloxy)-2-(2-chloro-4-methylpyridin-3-yl)-7-fluoro-4- isopropylisoquinolin-1(2H)-one (5.7 g, 13.1 mmol,) in DCM (80 mL) at -78 °C was added a toluene solution (1 M) of BCl 3 (83 mL, 83 mmol) under nitrogen. The reaction mixture was stirred at -78 °C for 1 h.
  • Step D 2-(2-Chloro-4-methylpyridin-3-yl)-7-fluoro-4-isopropyl-1-oxo-1,2-dihydroisoquinolin- 6-yl trifluoromethanesulfonate.
  • 2-(2-chloro-4-methylpyridin-3-yl)-7-fluoro-6- hydroxy-4-isopropylisoquinolin-1(2H)-one 5.2 g, 15 mmol
  • PhNTf2 (16 g, 45 mmol
  • DMAP (0.91 g, 7.4 mmol
  • TEA 7.6 g, 75 mmol
  • Step E 2-(2-Chloro-4-methylpyridin-3-yl)-7-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoquinolin-1(2H)-one.
  • Step A Ethyl 3-bromo-1-ethyl-1H-1,2,4-triazole-5-carboxylate.
  • ethyl 3-bromo- 1H-1,2,4-triazole-5-carboxylate (0.98 g, 4.5 mmol) and Cs 2 CO 3 (5.8 g, 18 mmol) in anhydrous DMF (20 mL) was added iodoethane dropwise (2.1 g, 13 mmol) at room temperature. Then the resulting reaction mixture was stirred at room temperature for 12 h. The mixture was poured into water (50 mL), extracted with DCM (30 mL ⁇ 2).
  • Step B.3-Bromo-1-(methyl-d3)-1H-1,2,4-triazole-5-carbaldehyde To a mixture of methyl 3- bromo-1-(methyl-d3)-1H-1,2,4-triazole-5-carboxylate (14 g, 62 mmol) in DCM (200 mL) under atmosphere of nitrogen at -70 °C was added a toluene solution (1 M) of DIBAL-H (123 mL, 123 mmol) dropwise. The reaction mixture was stirred at -70 °C for 1 h. The reaction mixture was quenched by the addition of sat. aq. Rochelle salt (100 mL).
  • Step C 2-(4-Bromo-1-(methyl-d3)-1H-imidazol-2-yl)propan-2-ol.
  • ethyl 4,5- dibromo-1-(methyl-d3)-1H-imidazole-2-carboxylate 9 g, 24 mmol
  • THF 70 mL
  • MeMgBr 60 mL, 180 mmol
  • the reaction mixture was stirred at 0 °C for 1 h. Sat. aq. NH 4 Cl (20 mL) was added dropwise to quench the reaction.
  • Step B.7-Fluoro-6-hydroxy-4-isopropyl-2-(2-methoxy-5-methylpyridin-4-yl)isoquinolin-1(2H)- one To a stirred solution of 6,7-difluoro-4-isopropyl-2-(2-methoxy-5-methylpyridin-4- yl)isoquinolin-1(2H)-one (1.4 g, 4.1 mmol) in DMSO (15 mL) was added an aqueous solution (10 M) of KOH (4.1 mL, 41 mmol) at the room temperature. The reaction mixture was stirred at 90 °C overnight. The reaction was cooled to room temperature, adjusted to pH 4 by using aq.
  • Step C.7-Fluoro-4-isopropyl-2-(2-methoxy-5-methylpyridin-4-yl)-1-oxo-1,2- dihydroisoquinolin-6-yl trifluoromethanesulfonate To a solution of 7-fluoro-6-hydroxy-4- isopropyl-2-(2-methoxy-5-methylpyridin-4-yl) isoquinolin-1(2H)-one (1.3 g, 3.8 mmol) in DCM (20 mL) was added PhNTf2 (2.8 g, 7.5 mmol), DMAP (250 mg, 1.9 mmol) and TEA (823 mg, 7.5 mmol) respectively. The reaction mixture was stirred at room temperature overnight.
  • Step B 2-(3-Chloro-6-methylpyridin-2-yl)-7-fluoro-6-hydroxy-4-isopropylisoquinolin-1(2H)- one.
  • 2-(3-chloro-6-methylpyridin-2-yl)-6,7-difluoro-4- isopropylisoquinolin-1(2H) -one (608 mg, 1.7 mmol) in DMSO (10 mL) was added an aqueous solution (10 M) of KOH (1.7 ml, 17 mmol) at the room temperature.
  • the reaction mixture was stirred at 85 °C overnight.
  • the reaction was cooled to room temperature, adjusted to pH 3-4 by using aq.
  • Step C 2-(3-Chloro-6-methylpyridin-2-yl)-7-fluoro-4-isopropyl-1-oxo-1,2-dihydroisoquinolin-6- yl trifluoromethanesulfonate.
  • 2-(3-chloro-6-methylpyridin-2-yl)-7-fluoro-6- hydroxy-4-isopropylisoquinolin -1(2H)-one was added PhNTf 2 (1.8 g, 5.0 mmol), DMAP (100 mg, 0.82 mmol) and TEA (1.2 mL, 8.3 mmol) respectively.
  • Step D 2-(3-Chloro-6-methylpyridin-2-yl)-7-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoquinolin-1(2H)-one.
  • Step B.7-Fluoro-6-hydroxy-4-isopropyl-2-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-4- yl)isoquinolin-1(2H)-one KOH (10 M in H 2 O, 11.3 mL, 113 mmol) was added to a stirred solution of 6,7-difluoro-4-isopropyl-2-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-4- yl)isoquinolin-1(2H)-one (4.2 g, 11.3 mmol) in DMSO (30 mL) at the room temperature, and the mixture was stirred at 90 °C for 2 hours.
  • Step B Isopropyl 2,6-dichloro-5-fluoronicotinate.
  • Step D 2-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-8- isopropyl-5H-pyrano[4,3-b]pyridin-5-one.
  • Step B (5-Cyclopropylpyrazin-2-yl)-7-fluoro-4-isopropyl-2-(o-tolyl)isoquinolin-1(2H)-one.
  • the reaction mixture was sealed in a tube under nitrogen and heated under microwave irradiation at 80 °C for 1 h.
  • the mixture cooled to room temperature and filtered through a short pad of silica gel.
  • the silica gel was washed with ethyl acetate.
  • the combined filtrate was concentrated.
  • the residue was purified by flash column chromatography (SiO 2 , 30-50% ethyl acetate in heptane).
  • Example 2 6-(6-Amino-5-methylpyridin-2-yl)-7-fluoro-4-isopropyl-2-(o-tolyl)isoquinolin- 1(2H)-one.
  • the title compound was prepared in a manner analogous to Example 1, Steps A-B, using 7- fluoro-4-isopropyl-1-oxo-2-(o-tolyl)-1,2-dihydroisoquinolin-6-yl trifluoromethanesulfonate (Intermediate 1) and using 6-bromo-3-methylpyridin-2-amine instead of 2-bromo-5-cyclopropyl- pyrazine in Step B.
  • LCMS (ES-API): mass calcd.
  • Example 3 6-(4-Amino-5-methylpyridin-2-yl)-7-fluoro-4-isopropyl-2-(o-tolyl)isoquinolin- 1(2H)-one.
  • the title compound was prepared in a manner analogous to Example 1, Steps A-B, using 7- fluoro-4-isopropyl-1-oxo-2-(o-tolyl)-1,2-dihydroisoquinolin-6-yl trifluoromethanesulfonate (Intermediate 1) and using 2-bromo-5-methylpyridin-4-amine instead of 2-bromo-5-cyclopropyl- pyrazine in Step B.
  • LCMS (ES-API): mass calcd.
  • Example 4 7-Fluoro-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-4-isopropyl-2- (o-tolyl)isoquinolin-1(2H)-one.
  • Step A 7-Fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(o- tolyl)isoquinolin-1(2H)-one.
  • Step B 7-Fluoro-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-4-isopropyl-2-(o- tolyl)isoquinolin-1(2H)-one.
  • the reaction mixture was sealed in a tube under nitrogen and heated under microwave irradiation at 82 °C for 1 h.
  • the mixture cooled to room temperature and filtered through a short pad of silica gel.
  • the silica gel was washed with ethyl acetate.
  • the combined filtrate was concentrated.
  • the residue was purified by flash column chromatography (SiO 2 , 30-50% ethyl acetate in heptane).
  • Example 5 Racemic 7-Fluoro-6-(5-(1-hydroxyethyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4- isopropyl-2-(o-tolyl)isoquinolin-1(2H)-one.
  • Example 6 6-(5-Acetyl-1-methyl-1H-1,2,4-triazol-3-yl)-7-fluoro-4-isopropyl-2-(o- tolyl)isoquinolin-1(2H)-one.
  • the title compound was prepared in a manner analogous to Example 4, Steps A-B, using 7- fluoro-4-isopropyl-1-oxo-2-(o-tolyl)-1,2-dihydroisoquinolin-6-yl trifluoromethanesulfonate (Intermediate 1) and using 1-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)ethan-1-one instead of 2- (4-bromo-1-methyl-1H-imidazol-2-yl)propan-2-ol (Intermediate 2) in Step B.
  • Example 7 7-Fluoro-6-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-isopropyl- 2-(o-tolyl)isoquinolin-1(2H)-one.
  • 6-(5-acetyl-1-methyl-1H-1,2,4-triazol-3-yl)-7-fluoro-4-isopropyl-2-(o- tolyl)isoquinolin-1(2H)-one (135 mg, 0.32 mmol) in THF (20 mL) at -78 °C was added an ether solution (3 M) of MeMgBr (0.32 mL, 0.97 mmol) dropwise.
  • Example 9 7-Fluoro-6-(5-(hydroxymethyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-isopropyl-2-(o- tolyl)isoquinolin-1(2H)-one.
  • Example 12 (R*)-7-Fluoro-6-(5-(1-hydroxyethyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-isopropyl- 2-(o-tolyl)isoquinolin-1(2H)-one.
  • Example 13 (S*)-7-Fluoro-6-(5-(1-hydroxyethyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-isopropyl- 2-(o-tolyl)isoquinolin-1(2H)-one.
  • Example 14 7-Fluoro-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-4-isopropyl-2- (o-tolyl)phthalazin-1(2H)-one.
  • Example 16 2-(5-Chloro-3-methyl-1H-pyrazol-4-yl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)-1- methyl-1H-imidazol-4-yl)-4-isopropylisoquinolin-1(2H)-one.
  • the reaction mixture was stirred under nitrogen at 60 °C for 12 h.
  • the mixture was diluted with water (2 mL) and then extracted with DCM (2 mL ⁇ 2).
  • the combined organic extract was dried over Na 2 SO 4 , filtered, and concentrated.
  • the residue was purified by flash column chromatography (SiO 2 , gradient elution: 0- 40% ethyl acetate in petroleum ether) to give the title compound as a white solid (34 mg, 27% yield).
  • Example 17 2-(5-Chloro-3-methyl-1H-pyrazol-4-yl)-7-fluoro-6-(5-(2-hydroxypropan-2-yl)-1- methyl-1H-1,2,4-triazol-3-yl)-4-isopropylisoquinolin-1(2H)-one.
  • Example 18 2-(2-Chloro-4-methylpyridin-3-yl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)-1-methyl- 1H-imidazol-4-yl)-4-isopropylisoquinolin-1(2H)-one.
  • the reaction mixture was stirred and heated under nitrogen at 80 °C for 2 h.
  • the mixture was partitioned between ethyl acetate and water.
  • the organic layer was separated, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated.
  • the residue was purified by flash column chromatography (SiO 2 , eluent: 0 – 60% ethyl acetate in petroleum ether) to give the crude product as a light-yellow oil.
  • Example 19 2-(2-Chloro-4-methylpyridin-3-yl)-7-fluoro-6-(5-(2-hydroxypropan-2-yl)-1-methyl- 1H-1,2,4-triazol-3-yl)-4-isopropylisoquinolin-1(2H)-one.
  • Example 20 6-(1-Ethyl-5-(2-hydroxypropan-2-yl)-1H-1,2,4-triazol-3-yl)-7-fluoro-4-isopropyl-2- (o-tolyl)isoquinolin-1(2H)-one.
  • Example 21 (R*)-7-Fluoro-6-(5-(1-hydroxyethyl)-1-(methyl-d 3 )-1H-1,2,4-triazol-3-yl)-4- isopropyl-2-(o-tolyl)isoquinolin-1(2H)-one.
  • Example 22 (S*)-7-Fluoro-6-(5-(1-hydroxyethyl)-1-(methyl-d3)-1H-1,2,4-triazol-3-yl)-4- isopropyl-2-(o-tolyl)isoquinolin-1(2H)-one.
  • Example 23 7-Fluoro-6-(2-(2-hydroxypropan-2-yl)-1-(methyl-d 3 )-1H-imidazol-4-yl)-4 isopropyl-2-(o-tolyl)isoquinolin-1(2H)-one.
  • Example 24 6-(5-Acetyl-1-ethyl-1H-1,2,4-triazol-3-yl)-7-fluoro-4-isopropyl-2-(o- tolyl)isoquinolin-1(2H)-one.
  • Example 25 7-Fluoro-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-4-isopropyl-2- (2-methoxy-5-methylpyridin-4-yl)isoquinolin-1(2H)-one.
  • Example 26 7-Fluoro-6-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-isopropyl- 2-(2-methoxy-5-methylpyridin-4-yl)isoquinolin-1(2H)-one.
  • Example 27 2-(3-Chloro-6-methylpyridin-2-yl)-7-fluoro-6-(2-(2-hydroxypropan-2-yl)-1-methyl- 1H-imidazol-4-yl)-4-isopropylisoquinolin-1(2H)-one.
  • Example 28 6-(1-Ethyl-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl)-7-fluoro-4-isopropyl-2-(o- tolyl)isoquinolin-1(2H)-one.
  • 6-(5-acetyl-1-ethyl-1H-1,2,4-triazol-3-yl)-7-fluoro-4-isopropyl-2-(o- tolyl)isoquinolin-1(2H)-one 200 mg, 0.46 mmol
  • methanol (10 mL) at 0 °C was added NaBH4 (35 mg, 0.93 mmol).
  • Example 29 7-Fluoro-6-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-isopropyl- 2-(o-tolyl)phthalazin-1(2H)-one.
  • Example 30 2-(3-Chloro-6-methylpyridin-2-yl)-7-fluoro-6-(5-(2-hydroxypropan-2-yl)-1-methyl- 1H-1,2,4-triazol-3-yl)-4-isopropylisoquinolin-1(2H)-one.
  • Example 31 7-Fluoro-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-4-isopropyl-2- (3-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoquinolin-1(2H)-one.
  • Example 32 7-Fluoro-6-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-isopropyl- 2-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoquinolin-1(2H)-one.
  • Example 33 3-Fluoro-2-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-imidazol-4-yl)-8-isopropyl-6- (o-tolyl)-1,6-naphthyridin-5(6H)-one.
  • Step A 2-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro-7- hydroxy-8-isopropyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one.
  • Step B 2-(3-((Benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3-fluoro- 8- isopropyl-6-(o-tolyl)-1,6-naphthyridin-5(6H)-one.
  • Step C 3-Fluoro-8-isopropyl-2-methoxy-6-(o-tolyl)-1,6-naphthyridin-5(6H)-one.
  • a mixture of 2-(3-((benzyloxy)methyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-3- fluoro-8- isopropyl-6-(o-tolyl)-1,6-naphthyridin-5(6H)-one (580 mg, 1.1 mmol) and CH 3 ONa (58 mg, 1.1 mmol) was added DMF at 0 °C. The solution was stirred at 0 °C for 1 hour.
  • Step D 2-Chloro-3-fluoro-8-isopropyl-6-(o-tolyl)-1,6-naphthyridin-5(6H)-one.
  • Biological Data DHODH inhibitory activities of the compounds of Examples 1-33 were assessed using the following assays.
  • the half maximal inhibitory concentration values (IC50) are summarized in Table 3.
  • the assay buffer contained 50 nM HEPES, pH 7.5, 150 mM NaCl, 0.5 mM EDTA, and 0.1% Triton X-100 in MilliQ water.
  • Substrate consisting of 20 mM DHO, 5mM CoQ6, and 1mM DCIP in assay buffer, initiates the reaction.
  • the assay is run in end-point mode by quenching the reaction with the potent DHODH inhibitor brequinar. Absorbance measurements were obtained using the BMG Phera Star plate-reading spectrophotomer.
  • Purified human DHODH was purchased from Proteros (cat. No. PR-0044). Chemicals were purchased from Sigma-Aldrich, Teknova, and Avanti Polar Lipids.
  • MOLM-13 Cellular Assay MOLM-13 cells (human acute myeloid leukemia cells) were obtained from DSMZ and were maintained in RPMI 1640 + Glutamax + 25mM HEPES (Invitrogen, catalog number 72400) supplemented with 10% heat inactivated fetal bovine serum (FBS; Invitrogen, catalog number 16140). The day prior to assay set-up, cells were pelleted, resuspended in fresh media, counted, and cells were plated at 0.4 x 10 6 cell/mL in a T150 flask.
  • FBS heat inactivated fetal bovine serum

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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 la DHODH. De tels composés sont représentés par la formule (I) comme suit, dans laquelle R1, R2, R3, R4, X et Y sont tels que définis dans la description.
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Citations (3)

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JP2007015952A (ja) * 2005-07-06 2007-01-25 Shionogi & Co Ltd ナフタレン誘導体
WO2020161663A1 (fr) * 2019-02-07 2020-08-13 Janssen Biotech, Inc. Inhibiteurs de dihydroorotate déshydrogénase
WO2020212897A1 (fr) * 2019-04-17 2020-10-22 Janssen Biotech, Inc. Inhibiteurs de dihydroorotate déshydrogénase

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JP2007015952A (ja) * 2005-07-06 2007-01-25 Shionogi & Co Ltd ナフタレン誘導体
WO2020161663A1 (fr) * 2019-02-07 2020-08-13 Janssen Biotech, Inc. Inhibiteurs de dihydroorotate déshydrogénase
WO2020212897A1 (fr) * 2019-04-17 2020-10-22 Janssen Biotech, Inc. Inhibiteurs de dihydroorotate déshydrogénase

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