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WO2025076632A1 - Composés et leurs utilisations - Google Patents

Composés et leurs utilisations Download PDF

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Publication number
WO2025076632A1
WO2025076632A1 PCT/CA2024/051349 CA2024051349W WO2025076632A1 WO 2025076632 A1 WO2025076632 A1 WO 2025076632A1 CA 2024051349 W CA2024051349 W CA 2024051349W WO 2025076632 A1 WO2025076632 A1 WO 2025076632A1
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Prior art keywords
compound
formula
optionally substituted
mmol
pharmaceutically acceptable
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Inventor
Agnès JONCOUR
Rhalid Akkari
Bertrand Heckmann
Hélène JARY
Virginie Roques
Frank BREBION
Béranger DUTHION
Elodie ROUSSEAU
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Fibrocor Therapeutics Inc
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Fibrocor Therapeutics Inc
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    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • 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
    • C07D403/14—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 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention features compositions and methods for treating DDR-mediated diseases and disorders.
  • DDR1-null mice have been valuable in understating the role of these receptors in various diseases, including cancer, atherosclerosis, lung and liver fibrosis, renal injury, and osteoarthritis.
  • DDR1 can confer resistance to chemotherapy and mediate prosurvival signals in breast cancer and lymphoma cell lines (see, e.g., Cader et al., Blood 122(26): p. 4237-45 (2013); Ongusaha et al., The EMBO journal 22(6): p. 1289-301 (2003)) and may be involved in the recurrence of certain types of cancer (see, e.g., Dian et al., Medical oncology 29(5): p. 3077-82 (2012)). Screening of non-small cell lung carcinoma (NSCLC) tissue samples showed that DDR1 is significantly upregulated in these patients and that expression of DDR1 is significantly associated with overall and disease-free survival. Multivariate analysis revealed that expression of DDR1 is independent of tumor differentiation, stage, histology, and patient age.
  • NSCLC non-small cell lung carcinoma
  • DDR1 is implicated in modulation of inflammation and fibrosis.
  • DDR1-deficient mice show reduced bleomycin-induced pulmonary injury characterized by reduced collagen and tenascin-C levels (see, e.g., Avivi-Green et al., American journal of respiratory and critical care medicine 174(4): p. 420-7 (2006)).
  • DDR1 expression is elevated in patients with lupus nephritis and Goodpasture's syndrome as well as in a mouse model of crescentic glomerulonephritis (see, e.g., Kerroch et al., FASEB journal 26(10): p. 4079-91 (2012)).
  • p is 0, 1, or 2. In some embodiments, q is 1 or 2.
  • X 1 is N. In some embodiments, X 1 is CR 3 . In some embodiments, X 2 is N. In some embodiments, X 2 is CR 3 . In some embodiments, X 3 is N. In some embodiments, X 3 is CR 3 . In some embodiments, X 4 is N. In some embodiments, X 4 is CR 3 . In some embodiments, X 3 and X 4 are each CR 3 .
  • the compound of Formula I has the structure of Formula VI:
  • p is 2. In some embodiments, p is 3. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3.
  • the compound of Formula lllb is selected from the compounds of
  • the compound of Formula I has the structure of Formula IVa
  • the compound of Formula IVb is selected from the compounds of
  • the compound of Formula Vlb is selected from the compounds of Table 4a:
  • the compound of Formula IVc is selected from the compounds of
  • Table 5b Table 5b.
  • the compound of Formula IVd is selected from the compounds of Table 6a:
  • the compound of Formula IVd is selected from the compounds of Table 6b:
  • the compound of Formula I has the structure of Formula Vc In some embodiments, the compound of Formula Vc is selected from the compounds of Table
  • the compound of Formula Vc is selected from the compounds of Table 7b: Table 7b.
  • the compound of Formula I has the structure of Formula Vd
  • the compound of Formula Vd is selected from the compounds of Table 8a:
  • the compound of Formula Vd is selected from the compounds of
  • the compound of Formula I has the structure of Formula Vila:
  • the compound of Formula Vila is selected from the compounds of
  • the compound of Formula Vila is selected from the compounds of Table 9b: Table 9b.
  • the compound of Formula I has the structure of Formula VI lb:
  • the compound of Formula VI lb is selected from the compounds of
  • Table 10a Table 10a.
  • the compound of Formula VI lb is selected from the compounds of Table 10b:
  • the compound of Formula I has the structure of Formula Villa:
  • the compound of Formula I has the structure of Formula VI I lb:
  • the compound of Formula VI I lb is selected from the compounds of
  • the compound of Formula I has the structure of Formula IXb:
  • the compound of Formula IXb is selected from the compounds of Table 12:
  • the compound of Formula I has the structure of Formula Xa: In some embodiments, the compound of Formula I has the structure of Formula Xb:
  • the compound of Formula Xb is selected from the compounds of Table 13a:
  • the compound of Formula Xb is selected from the compounds of Table 13b:
  • R 2 is optionally substituted Ce-C-io aryl. In some embodiments, R 2 is optionally substituted 3- to 11-membered heteroaryl. In some embodiments, R 2 is: wherein
  • X 5 and X 6 are each, independently, N or CH;
  • R 8 and R 9 are each, independently, H, optionally substituted amino, optionally substituted Ci-
  • R 2 is
  • R 10 is halo, cyano, or optionally substituted CI-CB alkyl; and m is 0, 1 , 2, 3, or 4
  • R 1 is optionally substituted CI-CB heteroalkyl.
  • R 3 is halo. In some embodiments, R 3 is Br. In some embodiments, R 3 is F. In some embodiments, R 3 is Cl. In some embodiments, R 3 is C1-C4 alkyl. In some embodiments, R 3 is cyano. In some embodiments, R 3 is C1-C4 alkoxy.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.
  • the DDR-mediated disease or disorder is a fibrotic disease. In some embodiments, the DDR-mediated disease or disorder is an inflammatory disease. In some embodiments, the DDR-mediated disease or disorder is cancer. In some embodiments, the DDR- mediated disease or disorder is a metabolic bone disease. In some embodiments, the DDR-mediated disease or disorder is a cardiovascular disease. In some embodiments, the DDR-mediated disease or disorder is a central nervous system disorder.
  • the term “subject” refers to any mammal (e.g., a human, a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig). In some embodiments, the subject is a human.
  • the term “pharmaceutical composition” refers to an active compound, formulated together with one or more pharmaceutically acceptable carriers.
  • the active compound is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • a “pharmaceutically acceptable excipient,” as used herein, refers any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and non-inflammatory in a subject.
  • Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration.
  • terapéuticaally effective amount means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, and/or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, and/or condition.
  • a therapeutically effective amount is one that reduces the incidence and/or severity of, and/or delays onset of, one or more symptoms of the disease, disorder, and/or condition.
  • therapeutically effective amount does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment.
  • the term "treat” or “treatment” includes administration of a compound to a subject, e.g., by any route, e.g., orally, topically, by inhalation, by ex-vivo contact with one or more cells of the subject.
  • the subject e.g., a patient
  • Treatment is not limited to curing or complete healing, but can result in one or more of alleviating, relieving, altering, partially remedying, ameliorating, improving or affecting the disorder, reducing one or more symptoms of the disorder or the predisposition toward the disorder.
  • substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges.
  • the term “Ci-Ce alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl, and hexyl.
  • the present disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual subcombination of members at each position.
  • alkyl refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms).
  • an alkyl group is unbranched (i.e. , is linear); in some embodiments, an alkyl group is branched.
  • Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like.
  • amino represents -N(R N1 )2, wherein each R N1 is, independently, H, OH, NO 2 , N(R N2 ) 2 , SO 2 OR N2 , SO 2 R N2 , SOR N2 , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein each of these recited R N1 groups can be optionally substituted, as defined herein for each group; or two R N1 combine to form a heterocyclyl, and wherein each R N2 is, independently, H, alkyl, or aryl.
  • amino groups of the invention can be an unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R N1 )2).
  • amino is -NH2 or -NHR N1 , wherein R N1 is, independently, OH, NO2, NH2, NR N2 2, SO2OR N2 , SO2R N2 , SOR N2 , alkyl, or aryl, and each R N2 can be H, alkyl or aryl.
  • aryl refers to an aromatic mono- or polycyclic radical of 6 to 16 carbon atoms. Examples of such groups include, but are not limited to, phenyl, naphthyl, and 1/-/-indenyl, anthracenyl, and phenanthryl.
  • aryloxy refers to a radical having the structure aryl-O-, wherein aryl is as defined herein.
  • cycloalkyl refers to a saturated, non-aromatic, monovalent mono- or polycyclic radical of three to ten carbons atoms (e.g., three to eight atoms or three to six carbon atoms).
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.
  • cycloalkylene refers to a divalent radical derived by removing a hydrogen atom from a cycloalkyl group, as defined herein.
  • cycloalkyloxy refers to a radical having the structure cycloalkyl-O-, wherein cycloalkyl is as defined herein.
  • cycloalkenyl refers to an unsaturated, non-aromatic, monovalent mono- or polycyclic radical of four to ten carbons atoms (e.g., four to eight atoms or three to six carbon atoms) including at least one carbon-carbon double bond.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptentyl, and cyclooctenyl.
  • cycloalkenyloxy refers to a radical having the structure cycloalkenyl-O-, wherein cycloalkyl is as defined herein.
  • heteroalkylene refers to a divalent radical derived by removing a hydrogen atom from a heteroalkyl group, as defined herein.
  • heteroalkenyl refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms, excluding those forming a carbon-carbon double bond, have been replaced by oxygen or sulfur.
  • heteroalkynyl refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms, excluding those forming a carbon-carbon triple bond, have been replaced by oxygen or sulfur.
  • heteroaryl refers to an aromatic mono- or polycyclic radical of five to twelve atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, and S, with the remaining ring atoms being C. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group.
  • heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.
  • heteroaryloxy refers to a radical having the structure heteroaryl- O-, wherein heteroaryl is as defined herein.
  • heterocyclyl denotes a mono- or polycyclic radical having three to twelve atoms (e.g., five atoms, six atoms, or seven atoms) having at least one ring containing one, two, three, or four ring heteroatoms selected from N, O, or S, wherein no ring is aromatic.
  • heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1 ,3-dioxanyl.
  • heterocyclyloxy refers to a radical having the structure heterocyclyl-O-, wherein heterocyclyl is as defined herein.
  • thiol represents an -SH group.
  • a phrase of the form “optionally substituted X” is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g. alkyl) per se is optional.
  • a substitution is required by a given structure, and optionally substituted refers to one or more additional substituents. For example, in moiety -L 2 -R 4 when L 2 is an alkyl the moiety describes an alkyl “L 2 ” that is substituted by group R 4 .
  • optionally substituted X means that X may be optionally substituted with one or more (e.g. , 1, 2, 3, 4, 5, or 6) substituents, which may independently be any of the substituents as described herein. In some embodiments, a substituent can be further substituted as described herein.
  • alkyl, alkenyl, alky nyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyloxy, cycloalkenyloxy, heterocyclyloxy, aryloxy, and heteroaryloxy groups may be substituted with cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl, halo, OH, amino, ON, NO2, thiol, Ns, SO2 a , wherein R a is alkyl or aryl, SO2N b c , wherein each of R b and R c is, independently, H, alkyl, or aryl, SOR d , wherein R d is H, alkyl, or aryl, or SiR e R f , R e and R f is, independently, H or alky
  • Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon.
  • Racemate or “racemic mixture” means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e. , they do not rotate the plane of polarized light.
  • Geometric isomer means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system.
  • Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration.
  • "R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule.
  • Certain of the disclosed compounds may exist in atropisomeric forms.
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • the stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9%) by weight relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure.
  • the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure.
  • each of X 1 , X 2 , X 3 , and X 4 is, independently, N or CR 3 ;
  • R 1 is H, -N(R 4 )(R 5 ), -OR 6 , optionally substituted 3- to 11-membered heteroaryl, optionally substituted CB-C-IO aryl, optionally substituted CI-CB alkyl, optionally substituted CI-CB heteroalkyl, optionally substituted 3- to 11-membered heterocyclyl, or optionally substituted C3-C10 cycloalkyl;
  • the compound is selective for DDR1 over DDR2. In some embodiments, the compound inhibits DDR1 with an IC50 that is at least 25 times greater than the IC50 at which the compound inhibits DDR2 as measured by a biochemical DDR assay, such as one described in the Examples section, below.
  • the compounds of the invention are preferably formulated into pharmaceutical compositions for administration to a mammal, preferably, a human, in a biologically compatible form suitable for administration in vivo. Accordingly, in an aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.
  • the compounds of the invention may be used in the form of the free base and in the form of salts. All forms are within the scope of the invention.
  • the described compounds or salts thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.
  • a compound of the invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • a compound of the invention may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers.
  • a compound of the invention may also be administered parenterally.
  • the dosage of the compounds of the invention, and/or compositions comprising a compound of the invention can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • the compounds of the invention may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds of the invention are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form).
  • Dose ranges include, for example, between 10-1000 mg (e.g., 50- 800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.
  • the dosage amount can be calculated using the body weight of the patient.
  • the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1-50 mg/kg (e.g., 0.25-25 mg/kg).
  • the compounds of the invention can be useful for the treatment of DDR-mediated diseases and conditions, including, without limitation, fibrotic disease (e.g., liver fibrosis, kidney fibrosis, lung fibrosis, skin scar), inflammatory disease (e.g., atherosclerosis), and cancer.
  • fibrotic disease e.g., liver fibrosis, kidney fibrosis, lung fibrosis, skin scar
  • inflammatory disease e.g., atherosclerosis
  • cancer e.g., atherosclerosis
  • diseases include, but are not limited to, renal conditions, liver conditions, inflammatory conditions, vascular conditions, cardiovascular conditions, and acute and chronic organ transplant rejection.
  • the compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Wuts & Greene 2014).
  • a compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. All reagents are of commercial grade and are used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents are used for reactions conducted under inert atmosphere. Reagent grade solvents are used in all other cases, unless otherwise specified. Column chromatography is performed on silica gel 60 (35-70 pm) or with Biotage® SNAP KP-NH, Biotage® SNAP Ultra, or Interchim® PuriFlash® Si HC flash chromatography cartridges.
  • Electrospray MS spectra are obtained on a Waters Acquity H-Class UPLC system coupled to a UV PDA detector and to a Waters SQD or SQD2 mass spectrometer.
  • Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using Waters XBRIDGE BEH C18 OBD 30 mm ID x 100/150 mm L columns and ACN/H2O gradients with either 0.1% formic acid in both mobile phases, 0.1% diethylamine in both mobile phases, 0.1% formic acid in H2O, or 10 mM NH4HCO3 in H2O (adjusted to pH 10 with ammonia). Microwave heating is performed with a Biotage® Initiator.
  • the various starting materials, intermediates, and compounds may be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification. Salts may be prepared from compounds by known salt-forming procedures.
  • reaction mixture After 20min at 35°C, the reaction mixture had become a solution. It was quenched by addition of water (3.2L, 8 V) and NaOH aq 2M (0.8L, 2 V). The aqueous phase was extracted with EtOAc (3.2L/8 V, then 1.6L/4 V). The organic phases were combined, washed with brine (1.2L, 3 V) and concentrated under vacuum to around 2 V. The resulting solution was added dropwise to MTBE (3.2L, 8 V), under stirring. Crystallization instantly occurred along the addition. After the addition, the suspension was stirred for a further hour at room temperature, then filtered.
  • reaction mixture was concentrated in vacuo and the residue dissolved in dimethyl sulfoxide and neutralized with ammonia in methanol.
  • the resulting solution was purified by preparative HPLC to afford a solid which was triturated with diethyl ether and diisopropyl ether to afford a white powder (26.4 mg, 0.054 mmol).
  • indolin-2-one 600 mg, 4,51 mmol was dissolved in dry tetrahydrofuran (12 ml_) and HMPA (1 ,2 ml_, 6,90 mmol) was added. The resulting mixture was cooled to -78°C, n-BuLi 2.5 M in hexanes (3,97 ml_, 9,91 mmol) was added and the reaction was stirred at -78°C for 2.5 h, ⁇ [(1 ,3- dibromopropan-2-yl)oxy]methyl ⁇ benzene (1388 mg, 4,51 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched carefully with water and extracted with DCM (3x).
  • Oxalylchloride (1.1 ml_, 13 mmol) was added dropwise at 0°C to a solution of 3- ((tertbutyldiphenylsilyl)oxy)cyclobutanecarboxylic acid (3.6 g, 10 mmol) in N,N-dimethylformamide (40 ja.L, 0.517 mmol) and tetrahydrofuran (90 ml_) under nitrogen atmosphere. The ice bath was removed and the solution was allowed to warm to room temperature. After 45 minutes, the solvent was evaporated under reduced pressure and dried at 40°C in vacuo for an extra 2 hours.
  • N-(2-bromo-3-pyridy l)-3-[tert-buty l(diphenyl)sily l]oxy-N-[(4- ethoxyphenyl)methyl]cyclobutanecarboxamide (3.61 g, 5.73 mmol) was dissolved in dry toluene (70 ml_). Nitrogen was bubbled through the solution for 5 minutes.
  • Trifluoromethanesulfonic acid (3.5 ml_, 38 mmol) was added to a stirred solution of 3-[tert- butyl(diphenyl)silyl]oxy-1'-[(4-methoxyphenyl)methyl]spiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-2'- one (2.04 g, 3.72 mmol) in dichloromethane (25 ml_) and trifluoroacetic acid (25 ml_). The reaction mixture was stirred at ambient temperature overnight.
  • Potassium tert-butoxide (5.7 g, 50 mmol) was added portionwise at room temperature to a stirring suspension of tert-butyl 2-(3-hydroxy-2'-oxo-spiro[cyclobutane-1 ,3'-pyrrolo[3,2-b]pyridine]-1'- yl)acetate (6.05 g, 19.9 mmol) and 5-chloro-2-tritylpyrazolo[4,3-b]pyridine (8.7 g, 22 mmol) in dimethyl sulfoxide (70ml_). After 1 hour the solution was diluted with water (700 ml_) and acidified with HCI 2N (20 ml_) to pH 4.
  • the aqueous phase was extracted with ethyl acetate (2 x 250 ml_).
  • the combined organic phases were washed with a saturated aqueous solution of NaCI (700 ml_).
  • the organic phase was dried over sodium sulfate, filtered, and evaporated under reduced pressure.
  • the yellowish residue was dissolved in a minimum of ethyl acetate (150 ml_) and vigorously stirred.
  • n-Heptane (1 L) was added gradually and stirring at room temperature was continued for 1 hour. The precipitate was filtered, washed with n-heptane and dried at 50°C under reduced pressure.
  • the solution was stirred at room temperature for 30 minutes.
  • the solution was poured on to iced water (200 ml_).
  • the aqueous phase was extracted with ethyl acetate (100 ml_).
  • the organic phase was washed with a saturated aqueous solution of NaCI (200 ml_).
  • the organic phase was dried over sodium sulfate, filtered, and evaporated under reduced pressure.
  • the crude sample was purified by flash column chromatography eluting with DCM/MeOH from 1/0 to 96/4.
  • the obtained solid was dissolved in dichloromethane (40 ml_) and trifluoroacetic acid (5 ml_, 66.13 mmol) was added.
  • the solution was stirred at room temperature for 2.5 hours.
  • the resulting solution was diluted with DCM (20 ml_) and vigorously stirred. A saturated aqueous solution of NaHCOs (50 ml_) was carefully added, followed by solid Na2COs till the aqueous phase reached a basic pH. The organic phase was separated, dried over sodium sulfate, filtered, and evaporated under reduced pressure.
  • the crude sample was purified by flash column chromatography eluting with DCM/MeOH from 1/0 to 94/6. The collected compound was dried at 40°C under nitrogen flow to give a white solid which was dissolved in a minimum of acetonitrile and a large amount of water was added while heating. The mixture was refluxed in an open vessel for 10 minutes without condenser. The resulting mixture was allowed to cool to ambient temperature. The liquid phase was removed and the solid remaining was washed with water. The solid was then dried under reduced pressure at 40°C affording a white solid.
  • reaction mixture was heated to 40°C and stirring was continued for another hour.
  • the reaction mixture was filtered over celite and rinsed with ethanol, then DIPEA (30 mL) was added and the mixture was concentrated under reduced pressure.
  • the crude was redissolved in EtOAc (500 mL) and washed with water (200 mL), 1 M HCI aq. (200 mL) and brine (200 mL), dried over Na2SO4, filtered and the solvent was removed under reduced pressure.
  • the compounds of the invention were tested for their ability to inhibit DDR1 and DDR2 in vitro using an ADP-Glo assay.
  • Methods of carrying out a DDR1 and DDR2 ADP-Glo assay are shown, for example in WO 2022/128850 (see Example 3) and WO 2022/008383 (see Example 3). This disclosure of each of these applications is incorporated herein by reference.

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Abstract

L'invention concerne des composés de formule I, et des compositions pharmaceutiques de ceux-ci, aptes à inhiber des protéines DDR (par exemple, DDR1 et/ou DDR2), et leurs utilisations dans le traitement de maladies ou de troubles médiés par DDR (par exemple, une maladie fibrotique, une maladie inflammatoire, un cancer, une maladie osseuse métabolique, une maladie cardiovasculaire et des troubles du SNC).
PCT/CA2024/051349 2023-10-13 2024-10-11 Composés et leurs utilisations Pending WO2025076632A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009061676A2 (fr) * 2007-11-06 2009-05-14 Amira Pharmaceuticals, Inc. Antagonistes de récepteurs pgd2
WO2009124692A1 (fr) * 2008-04-11 2009-10-15 Almirall, S.A. Nouveaux dérivés substitués de spiro[cycloalkyl-1,3’-indol]-2’(1’h)-one et leur utilisation en tant qu’inhibiteurs de la kinase activée par le mitogène p38
US8450341B2 (en) * 2008-04-28 2013-05-28 Almirall, S.A. Substituted indolin-2-one derivatives and their use as P38 mitogen-activated kinase inhibitors
WO2018038667A1 (fr) * 2016-08-25 2018-03-01 Medivir Ab Inhibiteurs du virus respiratoire syncytial
WO2018038668A1 (fr) * 2016-08-25 2018-03-01 Medivir Ab Inhibiteurs du virus respiratoire syncytial
WO2018069732A1 (fr) * 2016-10-14 2018-04-19 Heptares Therapeutics Limited Composés hétérocycliques ayant une activité en tant que modulateurs des récepteurs muscariniques m1 et/ou m4 dans le traitement de maladies et de douleurs du système nerveux central
CN114907254A (zh) * 2021-12-15 2022-08-16 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) 一种3-碳环螺羟吲哚类化合物的制备方法
CN115650902A (zh) * 2021-05-12 2023-01-31 苏州恩华生物医药科技有限公司 1′,2′-二氢-3′h-螺[环丁烷1,4′-异喹啉]-3′-酮衍生物的盐及其应用

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009061676A2 (fr) * 2007-11-06 2009-05-14 Amira Pharmaceuticals, Inc. Antagonistes de récepteurs pgd2
WO2009124692A1 (fr) * 2008-04-11 2009-10-15 Almirall, S.A. Nouveaux dérivés substitués de spiro[cycloalkyl-1,3’-indol]-2’(1’h)-one et leur utilisation en tant qu’inhibiteurs de la kinase activée par le mitogène p38
US8450341B2 (en) * 2008-04-28 2013-05-28 Almirall, S.A. Substituted indolin-2-one derivatives and their use as P38 mitogen-activated kinase inhibitors
WO2018038667A1 (fr) * 2016-08-25 2018-03-01 Medivir Ab Inhibiteurs du virus respiratoire syncytial
WO2018038668A1 (fr) * 2016-08-25 2018-03-01 Medivir Ab Inhibiteurs du virus respiratoire syncytial
WO2018069732A1 (fr) * 2016-10-14 2018-04-19 Heptares Therapeutics Limited Composés hétérocycliques ayant une activité en tant que modulateurs des récepteurs muscariniques m1 et/ou m4 dans le traitement de maladies et de douleurs du système nerveux central
CN115650902A (zh) * 2021-05-12 2023-01-31 苏州恩华生物医药科技有限公司 1′,2′-二氢-3′h-螺[环丁烷1,4′-异喹啉]-3′-酮衍生物的盐及其应用
CN114907254A (zh) * 2021-12-15 2022-08-16 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) 一种3-碳环螺羟吲哚类化合物的制备方法

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