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WO2025076017A1 - Carbamates destinés à être utilisés comme inhibiteurs de sarm1 - Google Patents

Carbamates destinés à être utilisés comme inhibiteurs de sarm1 Download PDF

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Publication number
WO2025076017A1
WO2025076017A1 PCT/US2024/049501 US2024049501W WO2025076017A1 WO 2025076017 A1 WO2025076017 A1 WO 2025076017A1 US 2024049501 W US2024049501 W US 2024049501W WO 2025076017 A1 WO2025076017 A1 WO 2025076017A1
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compound
pharmaceutically acceptable
acceptable salt
formula
mmol
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PCT/US2024/049501
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English (en)
Inventor
Mingshuo ZENG
Bing-Yan Zhu
Bryan Ka Ip CHAN
Matthew L. DEL BEL
Lewis J. Gazzard
Jessica Marie GRANDNER
Samantha Alyson GREEN
Jun Liang
Russell Tyler SMITH
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Genentech, Inc.
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Publication of WO2025076017A1 publication Critical patent/WO2025076017A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • Axonal degeneration is a hallmark of several neurological disorders including peripheral neuropathy, traumatic brain injury, and neurodegenerative diseases (See, for example, Gerdts et al., SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science 3482016, pp.453-457 and Krauss et al., (2020) Trends Pharmacol. Sci.41, 281, each of which is hereby incorporated by reference in its entirety). Neurodegenerative diseases and injuries are devastating to both patients and caregivers. Costs associated with these diseases currently exceed several hundred billion dollars annually in the Unites States alone. Since the incidence of many of these diseases and disorders increases with age, their incidence is rapidly increasing as demographics change.
  • the present disclosure is directed to a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 1 is CR 7 or N; X 2 is CR 4 , CHR 4 , or N; X 3 is absent, CH, CH 2 , NH, or S; X 4 is N, CH 2 , CH, NH, O, or S; X 5 is CR 8 ; Y is absent, CR 5 R 6 , or CH 2 CH 2 , wherein R 5 and R 6 are independently H, OH, CN, halo, C 1-6 alkyl, or C 1-6 cycloalkyl, or R 5 and R 6 , taken together with the carbon to which they are bonded, form a C 3-6 cycloalkyl; Z is CH or N; one of Q 1 and Q 2 is N and the other is CR 4 ; one of Q 3 and Q 4 is N and the other is CR 4 ; or Q 3 and Q 4 are CR 4 ; R 1a is H
  • the alkyl radical is C 1-12 , C 1-10 , C 1-8 , C 1-6 , C 1-5 , C 1-4 , or C 1-3 .
  • alkyl groups include methyl (Me, –CH 3 ), ethyl (Et, –CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, –CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, – CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, –CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, – CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, –CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, – C(CH 3 ) 3
  • hydroxy alkyl refers to alkyl substituted with one hydroxy substituent.
  • spirocycloalkyl examples include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro [2.5] octane and spiro [4.5] decane.
  • a heteroaryl group is attached at a carbon atom of the heteroaryl group.
  • carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quino
  • “Fused” refers to any ring structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with an existing ring structure in the compounds of the invention.
  • a s used herein a wavy line “ ” that intersects a bond in a chemical structure indicate the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule.
  • a s used herein, “ ” represents a single or double bond in a chemical structure.
  • divalent groups are described generically without specific bonding configurations. It is understood that the generic description is meant to include both bonding configurations, unless specified otherwise.
  • stereoisomers refer to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another.
  • optically active compounds i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane- polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another.
  • one aspect of the invention includes a compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: X 1 is CR 7 or N; X 2 is CR 4 , CHR 4 , or N; X 3 is absent, CH, CH 2 , NH, or S; X 4 is N, CH 2 , CH, NH, O, or S; X 5 is CR 8 ; Y is absent, CR 5 R 6 , or CH 2 CH 2 , wherein R 5 and R 6 are independently H, OH, CN, halo, C 1-6 alkyl, or C 1-6 cycloalkyl, or R 5 and R 6 , taken together with the carbon to which they are bonded, form a C 3-6 cycloalkyl; Z is CH or N; one of Q 1 and Q 2 is N and the other is CR 4 ; one of Q 3 and Q 4 is N and the other is CR 4 , or Q 3 and Q 4 are CR 4 ; R 1a is H or
  • R 4 is H.
  • Ring A is selected from wherein X 1 , X 2 , X 3 , X 4 , Q 1 , Q 2 , Q 3 and Q 4 are as defined above.
  • X 1 is C or N
  • X 2 is CR 4 or N
  • X 3 is CH, NH, or S
  • X 4 is N, CH, NH, or S.
  • Q1 is N and Q 2 , Q 3 and Q 4 are CR 4 .
  • R 4 is H.
  • X 1 is C; X 2 is CR 4 ; X 3 is NH; and X 4 is N, wherein R 4 is as defined for Formula (I).
  • R 4 is H.
  • X 1 is N; X 2 is CR 4 ; X 3 is CH; and X 4 is N, wherein R 4 is as defined for Formula (I). In one such embodiment, R 4 is H.
  • X 1 is C; X 2 is CR 4 ; X 3 is S; and X 4 is N, wherein R 4 is as defined for Formula (I). In one such embodiment, R 4 is H.
  • X 1 is N; X 2 is N; X 3 is CH; and X 4 is N.
  • X 1 is C; X 2 is N; X 3 is S; and X 4 is N.
  • X 1 is C; X 2 is N; X 3 is NH; and X 4 is CH.
  • Ring A is selected from for Formula (I).
  • R 4 is H, halo, or C 1-6 hydroxyalkyl. In one such embodiment, R 4 is H.
  • the compound has Formula (IIb): wherein Z, Y, R 1a , R 1b , R 2 , and R 3 are as defined for Formula (I).
  • the compound has Formula (IIc): wherein Z, Y, R 1a , R 1b , R 2 , and R 3 are as defined for Formula (I).
  • the compound has Formula (V) wherein Z, Y, Q 1 , Q 2 , Q 3 , Q 4 , R 1a , R 1b , R 2 , and R 3 are as defined herein.
  • the compound has Formula (Va) wherein Z, Y, Q 3 , Q 4 , R 1a , R 1b , R 2 , and R 3 are as defined herein.
  • Z is N.
  • Z is CH.
  • the compound has Formula (IIIa) or Formula (IIIb): wherein R 6 is H, OH, or CN, and R 1a and R 1b are as defined for Formula (I).
  • R 1a is H and R 1b is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, and C 1-6 haloalkyl, wherein each aryl or heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from C 1-6 alkyl, halo, and C 1-6 haloalkyl.
  • the compound of Formula (I), Formula (II), Formula (IIb), or a pharmaceutically acceptable salt thereof has Formula (IIb-1), Formula (IIb- 2), Formula (IIb-3), Formula (IIb-4), Formula (IIb-5), or Formula (IIb-6):
  • R 1a and R 1b are as defined for Formula (I).
  • the compound of Formula (I), Formula (II), Formula (III), Formula (IV), or a pharmaceutically acceptable salt thereof is selected from the compounds in Table 1, shown below, or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds of the present disclosure. Salts of such compounds are also contemplated. See the Examples section for preparation of such compounds. Compounds that do not have preparation details explicitly described in the Examples may be prepared by modifying the preparation details for other compounds provided herein, using methods generally known in the art.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • Embodiments of the present invention include all manner of rotamers and conformationally restricted states of a compound of the invention.
  • Atropisomers which are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers, are also included.
  • certain compounds of the invention may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer.
  • the compound of Formula (I), Formula (II), Formula (III), or Formula (IV) is a mixture of atropisomers.
  • the starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds.) Pergamon, Oxford 1984, vol.
  • the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about ⁇ 78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature, or, about 20 °C.
  • a reaction temperature range of from about ⁇ 78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature, or, about 20 °C.
  • such uses may include therapeutic and/or diagnostic uses. Alternatively, in some embodiments such uses may include research, production, and/or other technological uses.
  • the present disclosure provides methods comprising administering one or more compounds of Formula (I) to an individual, e.g., to treat, prevent, or reduce the risk of developing one or more conditions characterized by axonal degeneration.
  • the compound of Formula (I) is a SARM1 inhibitor.
  • one or more compounds and/or pharmaceutical compositions as described herein are useful as stabilizing agents to promote in vitro neuronal survival.
  • the compounds and/or pharmaceutical compositions of the present disclosure inhibit NADase activity of SARM1.
  • the compounds or pharmaceutical compositions of the present disclosure alleviate one or more attributes of neurodegeneration.
  • the present disclosure provides methods of treating a neurodegenerative disease or disorder comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • changes in biomarkers can be detected systemically or with a sample of CSF, plasma, serum, and/or tissue from a subject.
  • one or more compounds and/or compositions can be used to affect a change in the concentration of NF-L and/or NF-H contained the CSF of a subject.
  • one or more compounds and/or pharmaceutical compositions as described herein can affect constitutive NAD and/or cADPR levels in neurons and/or axons.
  • an epothilone is ixabepilone.
  • a taxane is paclitaxel or docetaxel.
  • a vinca alkaloid is vinblastine, vinorelbine, vincristine, or vindesine.
  • a proteasome inhibitor is bortezomib.
  • a platinum-based drug is cisplatin, oxaliplatin, or carboplatin.
  • an auristatin is conjugated monomethyl auristatin E.
  • a neurodegenerative disease or disorder comprises a chronic disease or disorder of the PNS.
  • a metabolic disease or disorder comprises diabetes mellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders of lipid/glycolipid metabolism, a nutritional deficiency, a vitamin deficiency, or a mitochondrial disorder.
  • a neurodegenerative disease or disorder comprises an acute disease or disorder of the CNS.
  • an acute disease or disorder of the CNS comprises an ischemia, a traumatic CNS injury, injury from a chemical agent, thermal injury, or viral encephalitis.
  • an ischemia comprises cerebral ischemia, hypoxic demyelination, ischemic demyelination, ischemic optic neuropathy, or non-arteritic anterior ischemic optic neuropathy.
  • a neuropathy or axonopathy is associated with axonal degeneration, including, but not limited to Parkinson’s disease, non-Parkinson’s disease, Alzheimer's disease, Herpes infection, diabetes, amyotrophic lateral sclerosis, a demyelinating disease, ischemia or stroke, chemical injury, thermal injury, and AIDS.
  • one or more compounds or pharmaceutical compositions as described herein is characterized that, when administered to a population of subjects, reduces one or more symptoms or features of neurodegeneration.
  • a relevant symptom or feature may be selected from extent, rate, and/or timing of neuronal disruption.
  • the present disclosure provides inhibitors of SARM1 activity for treatment of neurodegenerative or neurological diseases or disorders that involve axon degeneration or axonopathy.
  • the present disclosure also provides methods of using inhibitors of SARM1 activity to treat, prevent or ameliorate axonal degeneration, axonopathies and neurodegenerative or neurological diseases or disorders that involve axonal degeneration.
  • the present disclosure provides methods of treating neurodegenerative or neurological diseases or disorders related to axonal degeneration, axonal damage, axonopathies, demyelinating diseases, central pontine myelinolysis, nerve injury diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage resulting from a leukoencephalopathy or a leukodystrophy.
  • neuropathies and axonopathies include any disease or condition involving neurons and/or supporting cells, such as for example, glia, muscle cells or fibroblasts, and, in particular, those diseases or conditions involving axonal damage.
  • Axonal damage can be caused by traumatic injury or by non-mechanical injury due to diseases, conditions, or exposure to toxic molecules or drugs. The result of such damage can be degeneration or dysfunction of the axon and loss of functional neuronal activity. Disease and conditions producing or associated with such axonal damage are among a large number of neuropathic diseases and conditions.
  • Such neuropathies can include peripheral neuropathies, central neuropathies, and combinations thereof.
  • peripheral neuropathic manifestations can be produced by diseases focused primarily in the central nervous systems and central nervous system manifestations can be produced by essentially peripheral or systemic diseases.
  • a peripheral neuropathy can involve damage to the peripheral nerves, and/or can be caused by diseases of the nerves or as the result of systemic illnesses.
  • Some such diseases can include diabetes, uremia, infectious diseases such as AIDs or leprosy, nutritional deficiencies, vascular or collagen disorders such as atherosclerosis, and autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa.
  • peripheral nerve degeneration results from traumatic (mechanical) damage to nerves as well as chemical or thermal damage to nerves.
  • Such conditions that injure peripheral nerves include compression or entrapment injuries such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injuries, contusions, fracture or dislocated bones; pressure involving superficial nerves (ulna, radial, or peroneal) which can result from prolonged use of crutches or staying in one position for too long, or from a tumor; intraneural hemorrhage; ischemia; exposure to cold or radiation or certain medicines or toxic substances such as herbicides or pesticides.
  • the nerve damage can result from chemical injury due to a cytotoxic anticancer agent such as, for example, taxol, cisplatinin, a proteasome inhibitor, or a vinca alkaloid such as vincristine.
  • peripheral neuropathies Typical symptoms of such peripheral neuropathies include weakness, numbness, paresthesia (abnormal sensations such as burning, tickling, pricking or tingling) and pain in the arms, hands, legs and/or feet.
  • a neuropathy is associated with mitochondrial dysfunction. Such neuropathies can exhibit decreased energy levels, i.e., decreased levels of NAD and ATP.
  • peripheral neuropathy is a metabolic and endocrine neuropathy which includes a wide spectrum of peripheral nerve disorders associated with systemic diseases of metabolic origin.
  • Ischemic optic neuropathies also include non-arteritic anterior ischemic optic neuropathy.
  • neurodegenerative diseases that are associated with neuropathy or axonopathy in the central nervous system include a variety of diseases. Such diseases include those involving progressive dementia such as, for example, Alzheimer’s disease, senile dementia, Pick’s disease, and Huntington’s disease; central nervous system diseases affecting muscle function such as, for example, Parkinson’s disease, motor neuron diseases and progressive ataxias such as amyotrophic lateral sclerosis; demyelinating diseases such as, for example multiple sclerosis; viral encephalitides such as, for example, those caused by enteroviruses, arboviruses, and herpes simplex virus; and prion diseases.
  • progressive dementia such as, for example, Alzheimer’s disease, senile dementia, Pick’s disease, and Huntington’s disease
  • central nervous system diseases affecting muscle function such as, for example, Parkinson’s disease, motor neuron diseases and progressive ataxias such
  • a neuropathy or axonopathy associated with axonal degeneration can be any of a number of neuropathies or axonopathies such as, for example, those that are hereditary or congenital or associated with Parkinson’s disease, Alzheimer's disease, Herpes infection, diabetes, amyotrophic lateral sclerosis, a demyelinating disease, ischemia or stroke, chemical injury, thermal injury, and AIDS.
  • neurodegenerative diseases not mentioned above as well as a subset of the above-mentioned diseases can also be treated with the methods of the present disclosure. Such subsets of diseases can include Parkinson’s disease or non-Parkinson’s diseases, or Alzheimer’s disease.
  • compounds and/or pharmaceutical compositions as described herein are administered to individuals suffering from or susceptible to a disease, disorder or condition as described herein; in some embodiments, such a disease, disorder or condition is characterized by axonal degeneration, such as one of the conditions mentioned herein.
  • axonal degeneration such as one of the conditions mentioned herein.
  • an individual to whom a compound or pharmaceutical composition is administered as described herein exhibits one or more signs or symptoms associated with axonal degeneration; in some embodiments, the subject does not exhibit any signs or symptoms of neurodegeneration.
  • provided methods comprise administering a compound of Formula (I) to an individual in need thereof. In some such embodiments, the individual is at risk of developing a condition characterized by axonal degeneration.
  • the individual is identified as being at risk of axonal degeneration, e.g., based on the individual’s genotype, a diagnosis of a condition associated with axonal degeneration, and/or exposure to an agent and/or a condition that induces axonal degeneration.
  • the individual is at risk of developing a neurodegenerative disorder.
  • the individual is elderly.
  • the individual is known to have a genetic risk factor for neurodegeneration.
  • the individual has a family history of neurodegenerative disease.
  • the individual expresses one or more copies of a known genetic risk factor for neurodegeneration.
  • the individual is drawn from a population with a high incidence of neurodegeneration.
  • chemotherapeutic agents include, but not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).
  • provided methods comprise administering a pharmaceutical composition as described herein to an individual or population of individuals based on the presence or absence of one or more biomarkers.
  • provided methods further comprise monitoring the level of a biomarker in an individual or population of individuals and adjusting the dosing regimen accordingly.
  • DOSAGE AND ADMINISTRATION The present invention provides pharmaceutical compositions or medicaments containing a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof and at least one therapeutically inert excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.
  • An embodiment therefore, includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention, or a pharmaceutically acceptable salt thereof may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the severity of the disorder, the particular patient being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the “therapeutically effective amount” of the compound of the present invention, or a pharmaceutically acceptable salt thereof to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit SARM1 activity.
  • the pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug.
  • an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
  • suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
  • the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
  • the container may have deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
  • sustained-release matrices include polyesters, hydrogels (for example, poly(2- hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid- glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.
  • polyesters for example, poly(2- hydroxyethyl-methacrylate), or poly(vinylalcohol)
  • polylactides copolymers of L-glutamic acid and gamma-ethyl-L-glutamate
  • non-degradable ethylene-vinyl acetate non-degradable ethylene-viny
  • soft capsules contain one or more active compound that is dissolved or suspended in a suitable liquid.
  • suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol.
  • stabilizers are optionally added.
  • therapeutically effective amounts of at least one of the compounds described herein are formulated for buccal or sublingual administration.
  • Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels.
  • the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion.
  • formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers.
  • useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
  • multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or excipients useful herein.
  • organic solvents such as N-methylpyrrolidone are also employed.
  • the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days.
  • Suitable containers include, for example, bottles, vials, syringes, blister pack, etc.
  • the container may be formed from a variety of materials such as glass or plastic.
  • the container may hold a compound of the present invention, or a pharmaceutically acceptable salt thereof or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • kits An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. EXAMPLES The following examples illustrate the preparation and biological evaluation of compounds within the scope of the invention. These examples and preparations which follow are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.
  • the gradient started at 2 % MPB and ended at 98% MPB over 7 min and held at 98% MPB for 1.5 min following an equilibration for 1.5 min.
  • LC column temperature was 40 o C. UV absorbance was collected by a DAD detector and mass spec full scan was applied to all experiments.
  • Thermo qE 30-min The samples were analyzed on a Dionex Ultimate 3000 coupled with Thermo Scientific Q Exactive HRMS using ESI as ionization source.
  • the LC separation was done on an Agilent Zorbax Eclipse XDB-C18, 3.5 um, 100 ⁇ 3.0 mm column at a flow rate of 0.7 ml/minute.
  • MPA mobile phase A
  • MPB mobile phase B
  • the gradient started at 2% MPB and ended at 98% MPB over 25.5 min and held at 98%B for 2.5 min following equilibration for 1.5 min.
  • LC column temperature was 40 o C. UV absorbance was collected by a DAD detector and mass spec full scan was applied to all experiments.
  • Step 2 Synthesis of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (INT-1) To a mixture of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (200 g, 562 mmol), pyridin-4-ylboronic acid (75.9 g, 617 mmol) and K 2 CO 3 (233 g, 1.68 mol) in dioxane (1000 mL) and H 2 O (400 mL) was added Pd(dppf)Cl 2 (20.6 g, 28.1 mmol). The reaction mixture was stirred at 100 °C for 45 min under nitrogen atmosphere.
  • the reaction mixture was concentrated, and the residue was dissolved in MeOH (50 mL).
  • the mixture was filtered and the filtrate was concentrated.
  • the residue was diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • reaction mixture was stirred at room temperature for 3 hrs and then 100 o C for 16 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 4 — 7 Synthesis of 3-(3-(Pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3- yl)-1,3-oxazinan-2-one 3-(3-(Pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2- one was prepared using the general procedure described for the preparation of 1a/1b by replacing 3- amino-1-(4-chloro-3-fluoro-phenyl)propan-1-ol with 3-amino-1-(6-(trifluoromethyl)pyridin-3- yl)propan-1-ol in Step 1.
  • reaction mixture was stirred at 70 o C for 2 hours, and then NaBH(OAc) 3 (2 g, 31.7 mmol) was added.
  • the reaction was stirred at 70 o C for 2 hours.
  • the reaction was quenched with saturated NaHCO 3 solution (100 mL) and extrated with ethyl acetate (200 mL).
  • the organic layer was washed withbrine (100 mL), dried over anhydrous Na 2 SO 4 filtered and concentrated under reduced pressure.
  • the reaction was stirred at room temperature for 1 hour.
  • the reaction was quenched with water (150 mL) and extrated with ethyl acetate (150 mL).
  • the organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • reaction mixture was concentrated, and the residue was re-dissolved in ethyl acetate (20 mL) and washed with NaHCO 3 solution (20 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filterated and concentrated under reduced pressure.
  • Step 2 Synthesis of 6-(3,4-difluorophenyl)-1,3-oxazinan-2-one
  • tert-butyl (3-(3,4-difluorophenyl)-3-hydroxypropyl)carbamate (1.72 g, 5.99 mmol) at 0 o C under nitrogen atmosphere.
  • the mixture was warmed to room temperature for 2 hours.
  • the reaction mixture was quenched with saturated NH 4 Cl solution (10 mL) and concentrated.
  • Step 3 Synthesis of 6-(3,4-difluorophenyl)-3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-
  • 6-(3,4-difluorophenyl)-1,3-oxazinan-2-one 670 mg, 3.1 mmol
  • 4-(5-bromo- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine 1.3 g, 3.8 mol
  • 1,4-dioxane 15 mL
  • DMEDA 0.1 mL, 0.6 mmol
  • K 2 CO 3 1. g, 10.1 mmol
  • CuI 120 mg, 0.6 mmol
  • reaction was stirred at room temperature for 1 hours, then heated stirred at 100 o C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 5 Chiral separation of 6-(6-Chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)- 1,3-oxazinan-2-one
  • 6-(6-Chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (200 mg) was separated by chiral SFC (Chiralpak IC (250 mm x 30 mm, 5 um), Supercritical CO 2 / EtOH + 0.1% NH 4 OH 50/50; 50 mL/min) to afford 6-(6-chloro-5-fluoropyridin-3-yl)-3-(3-(pyridin- 4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one (Ex 12a, peak
  • Step 2 Synthesis of 6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one
  • tert-butyl (3-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)propyl)carbamate 800 mg, 2.5 mmol
  • NaH 50% in mineral oil, 150 mg, 3.8 mmol
  • the mixture was stirred at room temperature for 2 hours.
  • the reaction was quenched with saturated aqueous NH 4 Cl solution (10 mL) and extracted with ethyl acetate (10 mL x 2).
  • Step 3 Synthesis of 3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one
  • 6-(6-(trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one 290 mg, 1.2 mmol
  • 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine 459 mg, 1.3 mmol
  • 1,4-dioxane 6 mL
  • DMEDA 0.04 mL, 0.4 mmol
  • K 2 CO 3 488 mg, 3.5 mmol
  • CuI 67 mg, 0.4 mmol
  • Step 4 Synthesis of 3-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)-1,3- oxazinan-2-one
  • a solution of 3-(3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-6-(6- (trifluoromethyl)pyridin-3-yl)-1,3-oxazinan-2-one (220 mg, 0.4 mmol) in 5% TFA / HFIP (5 mL) was stirred at room temperature for 16 hours.
  • Step 2 Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1-((2- To a mixture of 6-(4-chloro-3-fluorophenyl)-1,3-oxazinan-2-one (355 mg, 1.55 mmol) and 4- (5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridazine (500 mg, 1.41 mmol) in 1,4-dioxane (10 mL) was added DMEDA (0.03 mL, 0.28 mmol), CuI (54 mg, 0.28 mmol) and K 2 CO 3 (583 mg, 4.22 mmol).
  • Step 3 Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan- 2-one
  • a solution of 6-(4-chloro-3-fluorophenyl)-3-(3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1,3-oxazinan-2-one 300 mg, 0.60 mmol) in 5% TFA/HFIP (21 mL) at room temperature for 8 h.
  • the mixture was stirred at -78 o C for 30 min under nitrogen atmosphere, and then the mixture was warmed up to room temperature and stirred for 16 hrs.
  • the mixture was quenched with saturated Rochelle salt solution (50 mL), diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3).
  • the combined organic phase was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 3 Synthesis of 3,5-dibromo-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-((2-
  • reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3) and. The combined organic phases were washed with brine (30 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , 20% ethyl acetate in petroleum ether) to afford 3,5-dibromo-4-(((tert- butyldimethylsilyl)oxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (7.2 g, 95% yield) as a yellow oil.
  • Step 2 Synthesis of 4-(5-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3- yl)pyridine
  • 3,5-dibromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole 1.3 g, 3.5 mmol
  • pyridin-4-ylboronic acid 431 mg, 3.5 mmol
  • 1,4-dioxane 15 mL
  • water 3 mL
  • K 2 CO 3 1.5 g, 10.5 mmol
  • Pd(dppf)Cl 2 256 mg, 0.35 mmol
  • Step 5 Chiral Separation of 6-(4-Chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5- yl)-1,3-oxazinan-2-one
  • 6-(4-Chloro-3-fluorophenyl)-3-(4-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-1,3-oxazinan-2- one 140 mg, 0.37 mmol
  • Step 2 Synthesis of 6-(4-chloro-3-fluorophenyl)-3-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)-1,3-oxazinan-2- one
  • DMEDA 0.2 mL, 0.17 mmol
  • CuI 33 mg, 0.17 mmol
  • K 3 PO 4 555 mg, 2.61 mmol
  • Step 1 Synthesis of 3-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propan-1-amine
  • 3-amino-1-(4-chloro-3-fluoro-phenyl)propan-1-ol 4.4 g, 21.6 mmol
  • imidazole 4.4 g, 64.8 mmol
  • TBSCl 4.9 g, 32.4 mmol
  • Step 2 Synthesis of N-(3-((tert-butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propyl)-3- (pyridin-4-yl)isothiazol-5-amine
  • 5-bromo-3-(4-pyridyl)isothiazole 260 mg, 1.08 mmol
  • 3-((tert- butyldimethylsilyl)oxy)-3-(4-chloro-3-fluorophenyl)propan-1-amine 514 mg, 1.62 mmol
  • 2- methyl-2-butanol 16 mL
  • Cs 2 CO 3 (1.05 g, 3.24 mmol
  • Brettphos Pd G3 98 mg, 0.11 mmol
  • Step 5 Synthesis of 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-3-(3-(pyridin-4-yl)-1-((2- To a solution of 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)pyridine (230 mg, 0.65 mmol), 6-(4-chloro-3-fluorophenyl)-5,5-difluoro-1,3-oxazinan-2-one (241 mg, 0.91 mmol) in 1,4-dioxane (10 mL) was added K 3 PO 4 (276 mg, 1.3 mmol) and tBuBrettPhos Pd G3 (56 mg, 0.06 mmol).
  • Step 2 Synthesis of 1-(4-chloro-3-fluorophenyl)-3-((3-(pyridin-4-yl)bicyclo[1.1.1]pentan-1-
  • MeOH MeOH
  • NaBH4 1.0 g, 27.07 mmol
  • Recombinant full-length SARM1(E26-T274) with a final concentration of 7.5 nM was pre- incubated with the respective compound at 1% DMSO final assay concentration for 15 min at room temperature.
  • the reaction was initiated by addition of 20 ⁇ M NAD and 20 ⁇ M NMN, final concentrations. After a 45 min room temperature incubation, the reaction was terminated by addition of 60 ⁇ L methanol. Samples were diluted in water (4 ⁇ L samples + 80 ⁇ L water) and nicotinamide concentrations were analyzed by liquid chromatography mass spectrometry using a Waters Acquity UPLC coupled to a AB Sciex 4500 triple quadropole mass spectrometer.
  • Incubations are performed at 1 ⁇ M drug concentration and 0.5 million cells mL -1 at 37°C with 5% CO 2 .
  • Hepatocytes are prepared manually by thawing in INVITROGRO HT media and diluted to 1 million cells mL -1 with DMEM buffer.
  • Compound dilution, incubation, and various liquid handling procedures are carried out using a Tecan Fluent liquid handling system.
  • the automated assay is composed of two separately coded protocols. The first protocol is the compound dilution protocol where test compounds are diluted from stock vials and aliquoted to the incubation plates.
  • the second protocol is the incubation protocol, which adds the hepatocytes, incubates the plates, and quenches the plates at their respective timepoints.
  • One plate is allocated for each timepoint (i.e., 0 min, 60 min, 120 min, 180 min, 240 min) being taken during the time course.
  • 50 ⁇ L of 1 million cells mL -1 is added to each well of each plate using wide-bore tips (Tecan Pure, Gurnnedorf, Switzerland).
  • the hepatocytes are placed on an INHECO Thermoshake RM on-deck shaking incubator set at 37°C and 650 rpm to keep the cells in suspension until they are added to each plate.
  • Cells were maintained in Dulbecco’s Modified Eagle Medium supplemented with 10% fetal bovine serum, pen-strep, puromycin and plasmocin before seeding on Millipore Millicell-24 well plates at 2.5 x 10 5 cells/mL and allowed to grow for 5 days.
  • Dulbecco Modified Eagle Medium supplemented with 10% fetal bovine serum, pen-strep, puromycin and plasmocin before seeding on Millipore Millicell-24 well plates at 2.5 x 10 5 cells/mL and allowed to grow for 5 days.
  • transport buffer Hank’s Balanced Salt Solution with 10 mM HEPES, pH 7.4
  • Test compound dose solutions were prepared at 1 ⁇ M in transport buffer containing the monolayer integrity marker lucifer yellow (100 ⁇ M). The dose solutions were added to the donor chambers and transport buffer was added to all receiver chambers.
  • the permeability was examined in the apical to basolateral (A:B) and basolateral to apical (B:A) directions.
  • the receiver chambers were sampled at 60, 120, and 180 min and were replenished with fresh transport buffer. Lucifer yellow was measured using a fluorescence plate reader (ex: 425 nm; em: 530 nm) and compound concentrations in the donor and receiving compartments were determined by LC-MS/MS analysis.

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Abstract

La présente invention concerne des composés carbamate de formule (I), tels que décrits plus en détail dans la description, qui sont utilisés pour inhiber des protéines SARM1, ainsi que des compositions contenant ces composés et des méthodes de traitement comprenant leur administration.
PCT/US2024/049501 2023-10-05 2024-10-02 Carbamates destinés à être utilisés comme inhibiteurs de sarm1 WO2025076017A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022031736A1 (fr) * 2020-08-04 2022-02-10 Nura Bio, Inc. Dérivés de pyridine substitués utiles comme inhibiteurs de sarm1
US20220056013A1 (en) * 2020-08-24 2022-02-24 Disarm Therapeutics, Inc. Inhibitors of SARM1
WO2024123967A1 (fr) * 2022-12-08 2024-06-13 Senya Pharmaceuticals, Inc. Inhibiteurs de sarm1, compositions pharmaceutiques et applications thérapeutiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022031736A1 (fr) * 2020-08-04 2022-02-10 Nura Bio, Inc. Dérivés de pyridine substitués utiles comme inhibiteurs de sarm1
US20220056013A1 (en) * 2020-08-24 2022-02-24 Disarm Therapeutics, Inc. Inhibitors of SARM1
WO2024123967A1 (fr) * 2022-12-08 2024-06-13 Senya Pharmaceuticals, Inc. Inhibiteurs de sarm1, compositions pharmaceutiques et applications thérapeutiques

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Title
"Comprehensive Heterocyclic Chemistry II", vol. 1-11, 1996, PERGAMON
"Comprehensive Organic Synthesis", vol. 1-40, 1991, WILEY & SONS
"Lang's Handbook of Chemistry", 1985
"McGraw-Hill Dictionary of Chemical Terms", vol. 1-9, 1984, MCGRAW-HILL BOOK COMPANY
ANSEL, H.C.: "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems", 2004, LIPPINCOTT, WILLIAMS & WILKINS
ELIEL, E.WILEN, S.: "Stereochemistry of Organic Compounds", 1994, JOHN WILEY & SONS, INC.
GENNARO, ALFONSO R. ET AL.: "Remington: The Science and", 2000, LIPPINCOTT, WILLIAMS & WILKINS
GERDTS ET AL.: "SARM1 activation triggers axon degeneration locally via NAD(+) destruction", SCIENCE, vol. 3482016, pages 453 - 457
KRAUSS ET AL., TRENDS PHARMACOL. SCI., vol. 41, 2020, pages 281
R. C. LAROCK: "Fieser's Reagents for Organic Synthesis", vol. 1-21, 1999, WILEY & SONS
ROWE, R. C.: "Handbook of Pharmaceutical Excipients", 2005, PHARMACEUTICAL PRESS

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