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WO2025190888A1 - Inhibiteurs macrocycliques de kif18a et leur utilisation - Google Patents

Inhibiteurs macrocycliques de kif18a et leur utilisation

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Publication number
WO2025190888A1
WO2025190888A1 PCT/EP2025/056508 EP2025056508W WO2025190888A1 WO 2025190888 A1 WO2025190888 A1 WO 2025190888A1 EP 2025056508 W EP2025056508 W EP 2025056508W WO 2025190888 A1 WO2025190888 A1 WO 2025190888A1
Authority
WO
WIPO (PCT)
Prior art keywords
hexaen
nonacosa
oxo
ethanesulfonamide
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/056508
Other languages
English (en)
Inventor
Dong DING
Chungen Liang
Kun MIAO
Jianping Wang
Kuan Wang
Yao Wu
Zhengyuan XIN
Hongying Yun
Ge Zou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Original Assignee
F Hoffmann La Roche AG
Hoffmann La Roche Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Hoffmann La Roche Inc filed Critical F Hoffmann La Roche AG
Publication of WO2025190888A1 publication Critical patent/WO2025190888A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • 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
    • C07D471/22—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 systems contains four or more hetero 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
    • C07D498/12—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 three hetero rings
    • C07D498/18—Bridged systems
    • 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
    • C07D498/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/18—Bridged systems

Definitions

  • the present invention relates to organic compounds, in particular to KIF18A (Kinesin Family Member 18A) inhibitors, useful for treatment of cancers in a mammal.
  • KIF18A Kinesin Family Member 18A
  • the present invention relates to macrocyclic compounds that have KIF18A inhibition activity, as well as their manufacture, pharmaceutical compositions containing them and their potential use as medicaments.
  • BACKGROUND OF THE INVENTION KIF18A is a mitotic kinesin possessing an ATPase activity. It is thought to regulate dynamics at the plus end of kinetochore microtubules for proper chromosome positioning during cell mitosis (Rath and Kozielsky. Nat. Rev.
  • KIF18A plays dual roles in chromosome alignment and microtubule depolymerization/ stabilization. Depletion of KIF18A leads to aberrant spindles, misaligned chromosomes and activation of spindle assembly checkpoint (SAC). KIF18A depolymerizes longer microtubules more quickly than shorter ones. Genetic ablation of KIF18A results in long microtubules (Mayr et al.
  • KIF18A is a synthetic lethal partner with different forms of genomic instability, such as whole-genome doubling (WGD), aneuploidy and chromosomal instability (CIN) (Quinton et al. Nature.2021, 590(7846); Cohen-Sharir et al. Nature.2021, 590(7846); Marquis et al. Nat. Commun.2021, 12(1)).
  • WGD whole-genome doubling
  • CIN chromosomal instability
  • Objects of the present invention are novel compounds of formula (I), their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) as KIF18A inhibitors for the treatment of cancers.
  • the compounds of formula (I) show superior KIF18A inhibition activity, in particular, time dependent inhibition.
  • the compounds of formula (I) also show good safety and good PK profiles, e.g., good microsome stability, solubility, hepatic clearance and safety margin.
  • Another aspect of the invention pertains to a process for the preparation of a compound of formula (I), as well as a compound of formula (I) or a pharmaceutically acceptable salt thereof when manufactured according to the process.
  • Another aspect of the invention pertains to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Another aspect of the invention pertains to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as therapeutically active substance.
  • Another aspect of the invention pertains to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.
  • Another aspect of the invention pertains to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of cancer.
  • Another aspect of the invention pertains to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the inhibition of KIF18A. Another aspect of the invention pertains to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of cancer. Another aspect of the invention pertains to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the inhibition of KIF18A. Another aspect of the invention pertains to a method for the treatment of cancer, which method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • substituted denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule.
  • C 1-6 aalkyl alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 2 to 6 or 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
  • Particular “C 1- 6 alkyl” groups are methyl, ethyl, propyl, isopropyl, and isopentyl.
  • C 1-6 aalkoxy denotes C 1-6 aalkyl-O-.
  • C 3-10 cycloalkyl denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. Bicyclic means consisting of two saturated carbocycles having one or more carbon atoms in common. Examples for monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • bicyclic cycloalkyl examples include bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.
  • halogen or “halo” denotes fluoro, chloro, bromo, or iodo.
  • haloC 1-6 aalkyl denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by same or different halogen atoms, particularly fluoro atoms.
  • haloC 1-6 alkyl examples include monochloro-, difluoro-or trifluoro-methyl, -ethyl or -propyl, for example difluoromethyl.
  • pharmaceutically acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
  • Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, trifluoroacetic acid, formic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
  • Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide.
  • the chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et al., Organic Process Research & Development 2000, 4, 427-435. Particular are the sodium salts of the compounds of formula (I).
  • therapeutically effective amount denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
  • composition denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.
  • pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.
  • R a is H, halogen, or C 1-6 alkyl;
  • a further embodiment of present invention is (ii) a compound according to embodiment (i), wherein A 1 is N or CH; A2 is N or CH; A 3 is N or CR a , wherein R a is H, fluoro, or methyl.
  • a further embodiment of present invention is (iii) a compound according to embodiment (i) or embodiment (ii), wherein each of A1 and A2 is CH, A3 is CR a , wherein R a is H or methyl.
  • a further embodiment of present invention is (iv) a compound according to any one of embodiments (i) - (iii), wherein R 1 is NR b1 SO2R b2 or , R b1 is H, R b2 is C 1-6 aalkyl optionally substituted with OH.
  • a further embodiment of present invention is (v) a compound according to any one of embodiments (i) - (iv), wherein R 1 is NR b1 SO 2 R b2 , R b1 is H, R b2 is selected from methyl, ethyl, and hydroxyethyl.
  • a further embodiment of present invention is (vi) a compound according to any one of embodiments (i) - (v), wherein L 1 is selected from CONH, NHCO, and a .
  • a further embodiment of present invention is (vii) a compound according to any one of embodiments (i) - (vi), wherein R 2 is selected from H, fluoro, methyl, and methoxy.
  • a further embodiment of present invention is (viii) a compound according to any one of embodiments (i) - (v), wherein B1 is N or CH, B2 is N , B 3 is N or CR 2 , R 2 is H or C 1-6 alkyl.
  • a further embodiment of present invention is (ix) a compound according to any one of embodiments (i) - (viii), wherein R 2 is H or methyl.
  • a further embodiment of present invention is (x) a compound according to any one of embodiments (i) - (ix), wherein m 1 is 1 or 2, m 2 is 0 or 1, R c occurs once or twice and each R c is independently selected from H, fluoro, and difluoromethyl, R d is H, methyl, or difluoroethyl.
  • a further embodiment of present invention is (xi) a compound according to any one of embodiments (i) - (ix), wherein L 2 is c , ( ) m2 R c ( ) m1 Y is N, Z 1 is C(R c )2, Z2 is CH, m 1 is 1 or 2, m 2 is 0 or 1, each R c is independently selected from H and halogen.
  • a further embodiment of present invention is (xii) a compound according to any one of embodiments (i) - (ix), wherein L 2 is c , ( ) m2 R c ( ) m1 Y is N, Z 1 is C(R c ) 2 , Z2 is CH, m 1 is 1 or 2, m 2 is 0 or 1; R c is H or fluoro.
  • a further embodiment of present invention is (xiii) a compound according to any one of embodiments (i) - (xii), wherein L3 is (CH2)q1, (CH2)q2NH, or -(CH2)r-O-(CH2)s-, optionally substituted by R e , q1 is 3, 4, 5, or 6, q 2 is 2, r is 0, s is 2, R e is fluoro or methyl.
  • a further embodiment of present invention is (xiv) a compound according to any one of embodiments (i) - (xii), wherein L3 is (CH2)q1 or -(CH2)r-O-(CH2)s-, q 1 is 3, r is 0, s is 2.
  • a further embodiment of present invention is (xv) a compound according to any one of embodiments (i) - (xiv), wherein each of n1 and n2 is 1.
  • a further embodiment of present invention is (xvi) a compound according to any one of embodiments (i) - (xv), wherein R 3 is absent or selected from fluoro, methyl, ethyl, difluoromethyl, and trifluoromethyl.
  • a further embodiment of present invention is (xvii) a compound according to embodiment (i), wherein, each of A1 and A2 is CH, A3 is CR a , wherein R a is H or C 1-6 aalkyl; R 1 is NR b1 SO 2 R b2 , R b1 is H, R b2 is hydroxyC 1-6 aalkyl; L1 is NHCO , B 1 is N or CH; B 2 is N; B3 is N or CR 2 ; R 2 is H or C 1-6 aalkyl; L2 is c , ( ) m2 R c ( ) m1 Y is N, Z1 is C(R c )2, Z 2 is CH, m 1 is 1 or 2, m2 is 0 or 1, each R c is independently selected from H and halogen; L 3 is (CH2)q1 or -(CH2)r-O-(CH2)s-, q1 is 3, r is 0, s is 2; each of
  • a further embodiment of present invention is (xviii) a compound according to embodiment (xvii), wherein each of A1 and A2 is CH, A 3 is CR a , wherein R a is H or methyl; R 1 is NR b1 SO2R b2 , R b1 is H, R b2 is hydroxyethyl; L1 is NHCO , B 1 is N or CH; B 2 is N; B3 is N or CR 2 ; R 2 is H or methyl; L 2 is c , ( ) m2 R c ( ) m1 Y is N, Z 1 is C(R c ) 2 , Z 2 is CH, m1 is 1 or 2, m 2 is 0 or 1, R c is H or fluoro; L3 is (CH2)q1 or -(CH2)r-O-(CH2)s-, q1 is 3, r is 0, s is 2; each of n1 and n2 is 1; R 3 is absent or selected from
  • a further embodiment of present invention is (xix) a compound selected from: 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide, N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 15,18 .1 2,6 .0 9,14 ]nonacosa- 2(29),3,5,9,11,13-he
  • a further embodiment of present invention is (xxi) a compound or a pharmaceutically acceptable salt thereof according to any one of embodiments (i) to (xix), when manufactured according to the process of embodiment (xx).
  • PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.
  • compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
  • a compound of formula (I) is formulated in an acetate buffer, at pH 5.
  • the compounds of formula (I) are sterile.
  • the compound 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 particular mammal 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 “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit KIF18A. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.
  • the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01 to 100mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • oral unit dosage forms such as tablets and capsules, preferably contain from about 1 to about 100 (e.g., 25 to 100) mg of the compound of the invention.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • An example of a suitable oral dosage form is a tablet containing about 1 to 1000 mg (e.g., 25mg, 50mg, 100mg, 250mg, or 500mg) of the compound of the invention compounded with about 1 to 1000 (e.g., 90-30) mg anhydrous lactose, about 1 to 1000 (e.g., 5-40) mg sodium croscarmellose, about 1 to 1000 (e.g., 5-30) mg polyvinylpyrrolidone (PVP) K30, and about 1 to 1000 (e.g., 1-10) mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • an aerosol formulation can be prepared by dissolving the compound of the invention, for example 1 to 1000 (e.g., 5-400 mg), in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired.
  • a suitable buffer solution e.g. a phosphate buffer
  • a tonicifier e.g. a salt such sodium chloride
  • the solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.
  • An embodiment therefore, includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof.
  • compositions comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • pharmaceutical composition comprising a compound of formula (I) for use in the treatment of cancer.
  • the following embodiments illustrate typical compositions of the present invention, but serve merely as representative thereof.
  • Composition A A compound of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Composition B A compound of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg INDICATIONS AND METHODS OF TREATMENT The compounds of the invention trap KIF18A in a microtubule-bound state thus inhibiting KIF18A ATPase activity.
  • the compounds of the invention are useful for inducing mitotic arrest, micronucleus formation and apoptosis in particular cancer cells.
  • Compounds of the invention are useful for triggering synthetic lethal vulnerability in cancer cells that possess high levels of chromosomal instability, e.g., high grade serous ovarian cancer, triple negative breast cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, colorectal cancer, bladder cancer, head and neck cancer and endometrial cancer.
  • Another embodiment includes a method of treating cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
  • Cancer includes but is not limited to, ovarian cancer (e.g., high grade serous ovarian cancer), breast cancer (e.g., triple negative breast cancer), lung cancer (e.g., non-small cell lung cancer), gastric cancer, esophageal cancer, colorectal cancer, bladder cancer, head and neck cancer and endometrial cancer.
  • a further embodiment of present invention is (xxiii) a compound of the invention for use as therapeutically active substance.
  • a further embodiment of present invention is (xxiv) a compound of the invention for use in the treatment or cancer.
  • a further embodiment of present invention is (xxv) the use of a compound of the invention for the treatment of cancer.
  • a further embodiment of present invention is (xxvi) the use of a compound of the invention for the inhibition of KIF18A.
  • a further embodiment of present invention is (xxvii) the use of a compound of the invention for the preparation of a medicament for the treatment of cancer.
  • a further embodiment of present invention is (xxviii) the use of a compound of the invention for the preparation of a medicament for the inhibition of KIF18A.
  • a further embodiment of present invention is (xxix) a method for the treatment of cancer, which method comprises administering an effective amount of a compound of the invention.
  • a further embodiment of present invention is (xxx) the use of according to any one of embodiments (xxv) to (xxviii), or the method according to embodiment (xxix), wherein the cancer is ovarian cancer (e.g., high grade serous ovarian cancer), breast cancer (e.g., triple negative breast cancer), lung cancer (e.g., non-small cell lung cancer), gastric cancer, esophageal cancer, colorectal cancer, bladder cancer, head and neck cancer, or endometrial cancer.
  • ovarian cancer e.g., high grade serous ovarian cancer
  • breast cancer e.g., triple negative breast cancer
  • lung cancer e.g., non-small cell lung cancer
  • gastric cancer e.g., esophageal cancer, colorectal cancer, bladder cancer, head and neck cancer, or endometrial cancer.
  • esophageal cancer colorectal cancer
  • bladder cancer bladder cancer
  • head and neck cancer or endometrial cancer.
  • compound of formula V V can be prepared by a substitution reaction of compound of formula X with compound of formula IX, in the presence of base (such as, TEA, DIPEA or K 2 CO 3 ) in a solvent such as (DMF, DMSO, dioxane or CH3CN); b) compound of formula V V can be prepared by amidation reaction of compound of formula VI with compound of formula VIIIa in the presence of NMI/TCFH, EDCI/Pyridine, or HATU/DIPEA in a solvent (such as DMF, CH3CN, THF, DCM, or pyridine), Alternatively, compound of formula V can also be obtained by the crossing coupling reaction of compound of formula VII with compound of formulation VIIIb in the presence of Pd catalyst (such as Pd2dba3/xantphos) with base (such as TEA, DIPEA or Cs2CO3) in a solvent (such as DMF, CH3CN, THF, DCM, pyridine, or 1,4-dioxan
  • Compound of formula IIb can be prepared by a coupling reaction of using compound of formula IIa with ClSO2CH2COOEt, in the presence of an organic base (such TEA, DIEPA or DMAP), in a solvent such as (THF, EtOAc, DMF or DCM);
  • Compound of formula Ib can be prepared by reduction reaction of compound of formula IIb in the presence of a reducing agent (such as LiAlH4 or LiBH4) in a solvent (such as DCM or THF).
  • a reducing agent such as LiAlH4 or LiBH4
  • Scheme 2 XIa a wherein PG is H, or a protected group such as Boc or Cbz, X is Cl or Br.
  • Compound of formula Va can be prepared by a substitution reaction of compound of formula X with compound of formula XIa, in the presence of a base (such as TEA, DIPEA or K2CO3), in a solvent (such as DMF, DMSO, Dioxane or CH3CN).
  • a base such as TEA, DIPEA or K2CO3
  • a solvent such as DMF, DMSO, Dioxane or CH3CN.
  • compound of formula XIVb can be prepared by a substitution reaction of compound of formula XIb with compound of formula XVa, in the presence of a base (such as TEA or DIPEA), in a solvent such as (DMF, DMSO, dioxane or CH 3 CN);
  • a base such as TEA or DIPEA
  • compound of formula XIII can be prepared by cross coupling reaction of compound of formula XIVb with compound of formula XVb in the presence of Pd catalyst (such as Pd2dba3/xantphos or Pd-PEPPSi-Ipent), with an inorganic base (such as Cs2CO3 or K2CO3) in a solvent (such as 1, 4-dioxane or t-BuOH);
  • Pd catalyst such as Pd2dba3/xantphos or Pd-PEPPSi-Ipent
  • an inorganic base such as Cs2CO3 or K2CO3
  • solvent such as 1, 4-di
  • Compound of formula Vc can be prepared by a substitution reaction of compound of formula XIc with compound of formula XVc, in the presence of a base (such as TEA or DIPEA), in a solvent (such as DMF, DMSO, dioxane, or CH3CN) under microwave irradiation, b) Compound of formula IIc can be prepared by the intramolecule Mitsunobu reaction of compound of formula Vc in the presence of CMBP in a solvent (such as THF, Toluene, or mixture of solvent THF and Toluene); c) Compound of formula Ic can be prepared by the reaction of compound of formula IIc with amine NH2SO2R b2 in the presence of CuI and MNPMO in organic solvent (such as DMF, DMSO) using inorganic base (such as potassium triphosphate).
  • a base such as TEA or DIPEA
  • a solvent such as DMF, DMSO, dioxane, or CH3CN
  • Compound of formula Id can be prepared according to the synthetic route outlined in scheme 4: d) Compound of formula IId IId can be prepared by Mitsunobu reaction of compound of formula IIc with SO2R b2 OH in the presence of CMBP in a solvent (such as THF, Toluene, or mixture of solvent THF and Toluene); e) Compound of formula Id can be prepared by the reaction of compound of formula IId with NH2SO2R b2 in the presence of CuI and MNPMO in organic solvent (such as DMF or DMSO) using inorganic base (such as potassium triphosphate).
  • a solvent such as THF, Toluene, or mixture of solvent THF and Toluene
  • e) Compound of formula Id can be prepared by the reaction of compound of formula IId with NH2SO2R b2 in the presence of CuI and MNPMO in organic solvent (such as DMF or DMSO) using inorganic base (such as potassium triphosphat
  • Silica gel brand and pore size i) KP-SIL 60 ⁇ , particle size: 40-60 ⁇ m; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400.
  • LC/MS spectra of compounds were obtained using a LC/MS (Waters TM Alliance 2795- Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ), LC/MS conditions were as follows (running time 3 or 1.5 mins): Acidic condition I: A: 0.1% TFA in H 2 O; B: 0.1% TFA in acetonitrile; Acidic condition II: A: 0.0375% TFA in H 2 O; B: 0.01875% TFA in acetonitrile; Basic condition I: A: 0.1% NH3 ⁇ H2O in H2O; B: acetonitrile; Basic condition II: A: 0.025% NH 3 ⁇ H 2 O in H 2 O; B: acetonitrile; Neutral condition: A: H 2 O; B: acetonitrile.
  • Mass spectra generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (MH) + .
  • NMR Spectra were obtained using Bruker Avance 400 MHz. The microwave assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.
  • imidazole 8.06 g, 118.33 mmol
  • triphenylphosphine 27.78 g, 105.91 mmol
  • iodine 27.78 g, 109.44 mmol
  • N-BOC-piperidine-4-carboxylic acid methyl ester 3.77 g, 15.49 mmol
  • LDA 8.39 mL, 16.78 mmol
  • Int-1e A mixture of 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-1-tert-butoxycarbonyl- piperidine-4-carboxylic acid ( Int-1d , 3.00 g, 6.14 mmol), AgNO 3 (1.59 g, 9.36 mmol), Selectfluor (4.35 g, 12.28 mmol) (CAS: 140681-55-6, PharmaBlock) in Acetone (40 mL) and water (40 mL) was degassed under N2 three times.
  • tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro- piperidine-1-carboxylate (Int-1e, 2.40 g, 5.19 mmol) in EtOAc (100 mL) was degassed under N 2 three times, then to the mixture was added Pd/C (600.0 mg, 10% loaded on active carbon) under N2.
  • tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-formyl- piperidine-1-carboxylate Int-2a, 2.40 g, 5.08 mmol
  • BAST 3.37 g, 15.23 mmol
  • Int-2 Tert-butyl 4-(difluoromethyl)-4-[3-(4-piperidyl)propyl]piperidine-1-carboxylate (Int-2) was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4-[3-(1- benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate (Int-1e) with tert- butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-(difluoromethyl)piperidine-1-carboxylate (Int-2b).
  • THF a solution of (methoxymethyl)triphenylphosphonium chloride (20.51 g, 59.83 mmol) in THF (60 mL) were added the solution of t-BuOK (70.39 mL, 70.39 mmol) dropwise under N2 balloon, and the reaction mixture was stirred at 25 °C for 30 min, followed by addition of the solution of tert-butyl 4-formyl-4-methyl-piperidine-1-carboxylate ( Int-3a , 8.0 g, 35.2 mmol) in THF (20 mL).
  • a solution of tert-butyl 4-[(Z)-2-methoxyvinyl]-4-methyl-piperidine-1-carboxylate (Int- 3b, 6.8 g, 26.63 mmol) in acetone (50 mL) was added the solution of TsOH (13.76 g, 79.89 mmol) in water (25 mL).
  • the reaction mixture was stirred at 25 °C for 16 hrs.
  • the reaction mixture was diluted with H2O (50 mL), extracted with EA (100 mL) three times.
  • a mixture of dimethyl (1-diazo-2-oxopropyl)phosphonate (5.73 g, 29.83 mmol), K2CO3 (10.31 g, 74.59 mmol) and tert-butyl 4-methyl-4-(2-oxoethyl)piperidine-1-carboxylate (Int-3c, 6.0g, 24.86 mmol) in methanol (50 mL) was stirred at 25 °C for 12 hrs under N2. The mixture was concentrated in vacuo.
  • Int-3 A solution of tert-butyl 4-methyl-4-[3-(4-pyridyl)prop-2-ynyl]piperidine-1-carboxylate (Int-3e, 3.1 g, 9.86 mmol) and HOAc (710.45 mg, 11.83 mmol) in IPA (20 mL) and THF (20 mL) was stirred at 20 °C until becoming clear solution.
  • tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-formyl- piperidine-1-carboxylate Int-4a, 2.40 g, 5.08 mmol
  • BAST 3.37 g, 15.23 mmol
  • Int-4 A solution of tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4- (difluoromethyl)piperidine-1-carboxylate (Int-4b, 900.0 mg.1.82 mmol) in TFA (2.0 mL) and DCM (10 mL) was stirred at 20 °C for 2 hrs. The mixture was poured into sat. NaHCO 3 (100 mL), extracted with EA (100 mL) three times.
  • a solution of 4-(trifluoromethyl)piperidin-4-amine (Int-5a, 3.355 g, 11.89 mmol) in THF (20 mL) was added a solution of K 2 CO 3 (6572.32 mg, 47.56 mmol) in water (20 mL), then N- (benzyloxycarbonyloxy)succinimide (2963.01 mg, 11.89 mmol) was added to the mixture.
  • Tert-butyl 4-[2-[[4-(trifluoromethyl)-4-piperidyl]amino]ethyl]piperidine-1-carboxylate was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4-[3-(1- benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate ( Int-1e ) with benzyl 4-[2-(1-tert-butoxycarbonyl-4-piperidyl)ethylamino]-4-(trifluoromethyl)piperidine-1-carboxylate (Int-5d).
  • reaction mixture was stirred at 25 °C for 30 min, followed by addition of the solution of tert- butyl 4-formyl-4-methyl-piperidine-1-carboxylate (10.0 g, 43.99 mmol) in THF (60 mL) dropwise at 0 °C. After being stirred at 25 °C for 12 hrs, the mixture was diluted with H2O (200 mL), extracted with EA (300 mL) three times. The combined organic layers was washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered. The filtrate was concentrated in vacuo.
  • a solution of tert-butyl 4-[(E)-3-methoxy-3-oxo-prop-1-enyl]-4-methyl-piperidine-1- carboxylate ( Int-7a, 10.0 g, 35.29 mmol) in methanol (100 mL) was added Pd/C (5.0 g, 10% loaded on active carbon) under N 2 .
  • the suspension was degassed in vacuo and purged with H 2 three times.
  • the reaction mixture was stirred at 25 °C for 2 hrs under H2 balloon.
  • a solution of tert-butyl 4-(3-methoxy-3-oxo-propyl)-4-methyl-piperidine-1-carboxylate (Int-7b, 7.0 g, 24.53 mmol) in THF (70 mL) was added LiAlH4 (1.86 g, 49.06 mmol) at 0 °C.
  • the reaction mixture was stirred at 25 °C for 2 hrs under N 2 balloon.
  • the suspension was quenched with Na 2 SO 4 . 10H 2 O (10 g) in portions at 0 o C.
  • imidazole 2.01 g, 29.58 mmol
  • triphenylphosphine 6.94 g, 26.48 mmol
  • iodine 6.94 g, 27.36 mmol
  • N-Cbz-4-piperidinecarboxylic acid methyl ester 3.17 g, 11.44 mmol
  • LiHMDS 12.87 mL, 12.87 mmol, 1.0 M in THF
  • Int-7f A mixture of O1-benzyl O4-methyl 4-[3-(1-tert-butoxycarbonyl-4-methyl-4- piperidyl)propyl]piperidine-1,4-dicarboxylate (Int-7e, 1.50 g, 2.9 mmol), NaOH (1.16 g, 29.03 mmol) in Ethanol (20 mL) and water (20 mL) was stirred at 70 °C for 6 hrs.
  • Int-7g A mixture of 1-benzyloxycarbonyl-4-[3-(1-tert-butoxycarbonyl-4-methyl-4- piperidyl)propyl]piperidine-4-carboxylic acid (Int-7f, 1.20 g, 2.39 mmol), AgNO3 (811.08 mg, 4.77 mmol), Selectfluor (2018.05 mg, 5.7 mmol) in Acetone (10 mL) and water (10 mL) was degassed and purged with N2 three times.
  • Int-15 Tert-butyl 4,4-difluoro-3-[3-(4-piperidyl)propyl]piperidine-1-carboxylate
  • Int-15 was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4-[3-(1- benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate (Int-1e) with tert- butyl 3-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4,4-difluoro-piperidine-1-carboxylate (Int- 15c).
  • the mixture was evacuated and backfilled with N 2 three times. After being stirred for 2 hrs at 25 °C under N2, the mixture was poured into sat. NH4Cl (150 mL), extracted with EA (150 mL) three times. The combined organic phase was washed with brine (400 mL) twice, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo.
  • Int-16 tert-butyl 4,4-difluoro-3-[2-(4-piperidyl)ethoxy]piperidine-1-carboxylate (Int-16) was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4-[3-(1- benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate (Int-1e) with tert- butyl 3-[2-(1-benzyloxycarbonyl-4-piperidyl)ethoxy]-4,4-difluoro-piperidine-1-carboxylate (Int- 16b).
  • NMP NMP
  • NaH 401.4 mg, 10.03 mmol
  • Int-17 Tert-butyl 3,3-difluoro-4-[2-(4-piperidyl)ethoxy]pyrrolidine-1-carboxylate ( Int-17 , 610.0 mg, 1.82 mmol) was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4- [3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate (Int-1e) with benzyl 4-[2-(1-tert-butoxycarbonyl-4,4-difluoro-pyrrolidin-3-yl)oxyethyl]piperidine-1- carboxylate (Int-17b).
  • BAST 50.66 g, 228.98 mmol
  • the mixture was heated to 45°C and stirred at 4 °C for 2 hrs.
  • Solution A (tert-butyl 3-allyl-4,4-difluoro-piperidine-1-carboxylate (Int-18b, 2.2g), THF (10V, 22mL)
  • Solution B BH 3 .
  • Solution C H 2 O 2 (3 eq., 50%, 0.4 g) and NaOH (3eq., 3M,9mL)
  • EA 150 mL
  • Int-19 Tert-butyl 3-[3-[4-(difluoromethyl)-4-piperidyl]propyl]-4,4-difluoro-piperidine-1- carboxylate (Int-19, 127.0 mg, 0.32 mmol) was prepared in analogy to intermediate 1 in step (f) by replacing tert-butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1- carboxylate (Int-1e) with tert-butyl 3-[3-[1-benzyloxycarbonyl-4-(difluoromethyl)-4- piperidyl]propyl]-4,4-difluoro-piperidine-1-carboxy
  • the reaction mixture was stirred at 90 °C for 12 hrs under N 2 .
  • the crude mixture was filtered through a pad celit, and the filtrate was concentrated in vacuo.
  • the mixture was diluted with EA (160 mL), washed with water (90 mL) and brine (60 mL) three times, dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo.
  • the residue was purified by prep-HPLC (Column: Phenomenex luna C18150*40mm* 15um; Condition: water (TFA)-ACN; B%: 60-90%; FlowRate (mL/min): 60). The fraction was adjusted with sat. aq.
  • Int-20 Tert-butyl 6,6-difluoro-1-[3-(4-piperidyl)propyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • tert-butyl 2-[1-hydroxy-3-(4-pyridyl)prop-2-ynyl]morpholine-4- carboxylate (Int-21b, 1.3 g, 4.08 mmol) in DCM (13 mL) was added 1,1'- thiocarbonyldiimidazole (873.22 mg, 4.9 mmol). After being stirred for 16 hrs at 25 °C, the mixture was concentrated in vacuo.
  • Int-21d 200.0 mg, 0.66 mmol
  • THF 20 mL
  • Step (d): benzyl 4-(3-methoxy-3- oxo -propyl)-4-methyl-piperidine-1-carboxylate Int-22d A solution of CbzOSu (3120.8 mg, 12.52 mmol), methyl 3-(4-methyl-4- piperidyl)propanoate (Int-22c, 2.32 g, 12.52 mmol) in methanol (50 mL) was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated in vacuo. The oil was diluted with water (50 mL), extracted with EA (50 mL) four times.
  • Int-22e NaBH4 (604.05 mg, 15.97 mmol) was added to the solution of benzyl 4-(3-methoxy-3-oxo- propyl)-4-methyl-piperidine-1-carboxylate (Int-22d, 3.4 g, 7.98 mmol) in ethanol (35 mL) at 0°C, then stirred at 25°C for 1 hr. The reaction mixture was quenched with water (120 mL), extracted with EA (40 mL) four times.
  • Step (f): benzyl 4-(3-iodopropyl)-4-methyl-piperidine-1-carboxylate Int-22f A mixture of imidazole (479.27 mg, 7.04 mmol), molecular iodine (1.65 g, 6.5 mmol), PPh 3 (1.66 g, 6.34 mmol) in DCM (12 mL) was stirred at 25 °C for 0.5 hr. Then benzyl 4-(3- hydroxypropyl)-4-methyl-piperidine-1-carboxylate (Int-22e, 1.58 g, 5.42 mmol) in DCM (10 mL) was added to the mixture and then stirred at 25 °C for 12 hrs.
  • Tert-butyl 4,4-difluoro-3-[3-(4-methyl-4-piperidyl)propyl]piperidine-1-carboxylate (Int 22, 524.0 mg, 1.45 mmol ) was prepared in analogy to intermediate 1 in step (f) by replacing tert- butyl 4-[3-(1-benzyloxycarbonyl-4-piperidyl)propyl]-4-fluoro-piperidine-1-carboxylate (Int-1e) with tert-butyl 3-[3-(1-benzyloxycarbonyl-4-methyl-4-piperidyl) propyl]-4,4-difluoro- piperidine-1-carboxylate ( Int-22 ).
  • benzyl 4-(2-hydroxyethyl)-4-methyl-piperidine-1-carboxylate 3.2 g, 11.54 mmol, Int-23a
  • TEA 2.3 g, 17.88 mmol
  • p-toluenesulfonyl chloride 3.3g, 17.31 mmol
  • tert-butyl 3-[2-(1-benzyloxycarbonyl-4-methyl-4-piperidyl)ethoxy]-4,4- difluoro-piperidine-1-carboxylate 1.0 g, 2.01 mmol, Int-23c
  • Pd/C 0.1 g, 10% purity on charcoal
  • Pd(OH)2/C 0.1 g, 10% purity on charcoal
  • methyltriphenylphosphonium bromide 50.6 g, 141.64 mmol
  • t-BuOK 21.56 g, 141.64 mmol
  • the mixture was stirred at 40°C for 1 hr
  • a solution of benzyl 4-ethyl-4-formyl-piperidine-1-carboxylate 13.0 g, 47.21 mmol, Int-24a
  • THF 50 mL
  • the intermediate 24c was obtained by flower chemistry as follows: Solution 1: benzyl 4-ethyl-4-vinyl-piperidine-1-carboxylate, 1 eq, 10 g in THF, 100 mL
  • the solution 1 was pumped by Pump 1 S1, P1, 7.667 mL/min to flow reactor 1 FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 64.115 mL, 25 °C
  • the solution 2 was pumped by Pump 2 S2, P2, 5.156 mL/min to flow reactor 1
  • Int-24f Tert-butyl 3-[2-(1-benzyloxycarbonyl-4-ethyl-4-piperidyl)ethoxy]-4,4-difluoro-piperidine- 1-carboxylate (1030.0 mg, 2.02 mmol, Int-24f) was prepared in analogy to Intermediate 23, by replacing benzyl 4-methyl-4-[2-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate (Int-23b) with benzyl 4-ethyl-4-[2-(p-tolylsulfonyloxy)ethyl]piperidine-1-carboxylate (1070.49 mg, 2.4 mmol, Int-24e ).
  • 6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxylic acid Int-31a, 1500.0 mg, 4.29 mmol
  • methanol (20 mL) di-t-butyldicarbonate (936.86 mg, 4.29 mmol). The mixture was stirred for 2 hrs at 20 °C.
  • Int-39a 4-[4-[3-(1-tert-butoxycarbonyl-4-fluoro-4-piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine- 3-carboxylic acid (Int-39a, 910 mg, 1.95 mmol) was prepared in analogy to Intermediate 31, by replacing 2, 6-difluoronicotinic acid with 4, 6-difluoropyridine-3-carboxylic acid. MS obsd. (ESI + )[(M+H) + ]: 468.2.
  • Int-39 Tert-butyl 4-[3-[1-(5-carbamoyl-2-fluoro-4-pyridyl)-4-piperidyl]propyl]-4-fluoro- piperidine-1-carboxylate (Int-39, 850 mg, 1.85 mmol) was prepared in analogy to Int-32, by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]-6-fluoro-pyridine-3- carboxylic acid ( Int-31) with 4-[4-[3-(1-tert-butoxycarbonyl-4-fluoro-4-piperidyl)propyl]
  • 4-methylpyridine 4.36 mL, 44.84 mmol
  • THF 110 mL
  • n- BuLi 17.93 mL, 44.84 mmol
  • a solution of tert-butyl 4-[2-oxo-3-(4-pyridyl)propyl]piperidine-1-carboxylate (Int-40b, 9.2 g, 28.89 mmol) in methanol (90 mL) was stirred at 20°C until becoming clear solution. Adjust the H2 back pressure regulator to 2.5 MPa, the flow rate of H2 to 30 ml/min, heated the fixed bed (10%Ru/SiO 2,5g) to 100°C.
  • Int-40d A solution of tert-butyl 4-[2-oxo-3-(4-piperidyl)propyl]piperidine-1-carboxylate (Int-40c, 1650.0 mg, 5.09 mmol) in MeCN (100 mL) was added N-(benzyloxycarbonyloxy)succinimide (2661.49 mg, 10.68 mmol) and stirred for 12 hrs at 20 °C. The mixture was concentrated in vacuo.
  • DCM 20 mL
  • DAST 0.52 mL, 3.91 mmol
  • CAS 38078-09-0, Shanghai Haohong Pharmaceutical Co.,Ltd
  • reaction mixture was stirred at 25 °C for 3 hrs under H 2 balloon.
  • the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to afford tert-butyl 4-[2-fluoro-3-(4-piperidyl)propyl]piperidine-1-carboxylate (Int-40f, 500.0 mg, 1.52 mmol), which was used in next step directly without further purification.
  • 2-[4-[3-(1-Tert-butoxycarbonyl-4-piperidyl)-2-fluoro-propyl]-1-piperidyl]-6-fluoro- pyridine-3-carboxylic acid ( Int-40g ) was prepared in analogy to Intermediate 31 , by replacing 4-[3-(4-piperidyl)propyl]piperidine with tert-butyl 4-[2-fluoro-3-(4-piperidyl)propyl]piperidine- 1-carboxylate (Int-40f, 360 mg).
  • Int-46 Tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro-phenyl)-4-piperidyl]ethoxy]-4,4-difluoro- piperidine-1-carboxylate (620.0 mg, 1.21 mmol, Int-46) was prepared in analogy to Intermediate 32 , by replacing 2-[4-[3-(1-tert-butoxycarbonyl-4-piperidyl)propyl]-1-piperidyl]- 6-fluoro-pyridine-3-carboxylic acid (Int-31) with tert-butyl 3-[2-[1-(2-carbamoyl-5-nitro- phenyl)-4-piperidyl]ethoxy]-4,
  • the reaction mixture was stirred at 110 °C for 12 hrs.
  • the mixture was purified by reverse flash (120g Flash Column Welch Ultimate XB_C1820-40 ⁇ m; 120 A, water (0.1% FA)-ACN, 80%, 80 mL/min).
  • the solution 2 was pumped by Pump 2 (Solution 2, Pump 2, 10 mL/min) to flow reactor 1 (flow reactor 1, Glass (GL), Continues stirred tank reactor (CSTRs), 150 mL, 80 °C), and flow reactor 2 (flow reactor 2, Glass (GL), Continues stirred tank reactor (CSTRs), 150 mL, 80 °C).
  • the residence time of flow reactor 1 was 5 min.
  • the residence time of flow reactor 2 was 5.000 min.
  • the mixture was collected with a bottle.
  • the Pump 1 and Pump 2 was started at the same time.
  • the reaction mixture was collected after running 10 min. Take a sample for analysis after 10 min. Stop collecting the reaction mixture after 40 min.
  • N-(2-chloropyrimidin-4-yl)-2-fluoro-4-nitro-benzamide (Int-53 , 1.20 g, 4.05 mmol ) was prepared in analogy to Intermediate 52, by replacing 2,6-dichloropyridine and 2,6-difluoro-4- nitro-benzamide (Int-52c) with 2,4-dichloropyrimidine and 2-fluoro-4-nitro-benzamide (Int- 53a ).
  • 2-chloro-6-ethynyl-pyridine Int-57
  • 2-chloro-6-ethynyl-pyridine Int-57
  • 2-chloro-6-ethynyl-pyridine Int-57
  • 2-chloro-6-ethynyl-pyridine 3407.73 mg, 24.77 mmol
  • a solution of tert-butyl 4-allyl-4-fluoro-piperidine-1-carboxylate (1.0 g, 4.11 mmol) in DCM (3 mL) and TFA (1.0 mL, 4.11 mmol) was stirred at 25 °C for 1 hr.
  • the mixture was concentrated in vacuo to afford 4-allyl-4-fluoro-piperidine (Int-70, 1.00 g, 3.89 mmol).
  • tert-butyl 4-fluoro-4-formyl-piperidine-1-carboxylate Int-70a, 14.5 g, 62.7 mmol
  • MeCN MeCN
  • DBU dimethyltriphenylphosphonium bromide
  • tert-butyl 4-allyl-3,3-difluoro-pyrrolidine-1-carboxylate (Int-73a, 1.60 g, 6.47 mmol) in TFA (4.0 mL) and DCM (10 mL) was stirred at 25 °C for 1 hr. The mixture was concentrated in vacuo to afford 4-allyl-3,3-difluoro-pyrrolidine (1.30 g, 4.98 mmol).
  • Example 1 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: E DCI, Py TFA, DCM Int-31 1.1 1.2 Cs 2 CO 3 , Dioxane Cs 2 CO 3 , DMSO 1 .3
  • tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]- 4-piperidyl]propyl]piperidine-1-carboxylate compound 1.1 , 800.0 mg, 1.43 mmol
  • DCM 6 mL
  • TFA 0.74 mL, 9.65 mmol
  • compound 1.2 N-(6-chloro-2-pyridyl)-6-fluoro-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]pyridine-3-carboxamide
  • t-BuONa 100.35 mg, 1.05 mmol
  • 1,4-Dioxane 40 mL
  • PEPPSI-Pd 40.0 mg
  • reaction mixture was taken up in EA (50 ml) and the organic phase was washed with water (50 mL) twice, sat.aq. brine (50 mL). The organic layers was separated and dried over anhydrous Na 2 SO 4 , concentrated in vacuo.
  • Example 2 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM x Padnt(pdhboas, o 2 ) dixane 3 Int-32 2.1 2.2 PEPPSI-Pd Cs 2 CO 3 , Dioxane Cs 2 CO 3 , DMSO 2.3
  • Example 3 N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 15,18 .1 2,6 .0 9,14 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 15,18 .1 2,6 .0 9,14 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 3) was prepared in analogy to Example 2 , by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d).
  • Example 4 15,18 2,6 9,14 N-(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13- hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: K3PO4, CuI EDCI, Py N,N'-Dimethyl-1,2-cyclohexanediamine DMF I nt_43 4.1 PEPPSI-Pd TFA, DCM Cs 2 CO 3 , dioxane 4 .2 4.3
  • the mixture was evacuated and back-filled with nitrogen three times.
  • the reaction vessel was sealed and heated in microwave at 130 °C for 5 hrs.
  • the mixture was poured into water (50 mL), then extracted with EA (50 mL) three times.
  • the combined organic phase was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo.
  • compound 4.3 N-(6-chloro-2-pyridyl)-4-(ethylsulfonylamino)-2-[4-[3-(4-piperidyl)propyl]-1- piperidyl]benzamide (compound 4.3) was prepared in analogy to Example 1, by replacing tert- butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[2-[(6-chloro
  • Example 5 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,4,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM x Padn 2t(pdhboas), 3 Int-32 5.1 5.2 PEPPSI-Pd Cs 2 CO 3 , dioxane Cs 2 CO 3 , DMSO 5 .3
  • Example 6 15,18 2,6 9,14 N-(8-oxo-1,4,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide 15,18 2,6 9,14 N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 6) was prepared in analogy to Example 5 , by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d).
  • Example 7 15,18 2,6 9,14 2-hydroxy- N -(8- oxo -1,3,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM P Cds 2 2 (CdOba 3 ,) 2 d,io Xxaanntpehos Int-36 7.1 7.2 PEPPSI-Pd Cs 2 CO 3 , dioxane DMSO, Cs 2 CO 3 7.3
  • Example 8 15,18 2,6 9,14 N-(8- oxo -1,3,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide 15,18 2,6 9,14 N-(8-oxo-1,3,7,13,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 8) was prepared in analogy to Example 7, by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d).
  • Example 9 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9(14),10,12-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM TCFH, NMI MeCN Int-35 9.1 9.2 Cs 2 CO 3 , dixoane Cs 2 CO 3 , DMSO 9 .3
  • Example 10 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,4,7,11,15,29-hexazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM NaH, THF Int-36 10.1 10.2 PEPPSI-Pd dioxane, Cs 2 CO 3 Cs 2 CO 3 , DMSO 10.3
  • Example 11 N-(8-oxo-1,4,7,11,15,29-hexazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide N-(8-oxo-1,4,7,11,15,29-hexazapentacyclo[20.2.2.215,18.12,6.09,14]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide ( Example 11 ) was prepared in analogy to Example 10, by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d).
  • Example 12 15,18 2,6 9,14 N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide 15,18 2,6 9,14 N-(8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 12) was prepared in analogy to Example 1, by replacing 2-hydroxyethanesulfonamide with ethanesulfonamide in step (d).
  • Example 13 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,11,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme:
  • Example 14 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,10,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9(14),10,12-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM TCFH, NMI MeCN, Int-37 14.1 14.2 PEPPSI-Pd Cs 2 CO 3 , dioxane Cs 2 CO 3 , DMSO 1 4.3
  • Example 15 15,18 2,6 9,14 N-(20-fluoro-8-oxo-1,7,13,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM Pd 2 (dba) 2 , Xantphos Cs 2 CO 3 , dioxane Int-40 15.1 15.2 PEPPSI-Pd Cs 2 CO 3 , dioxane Cs 2 CO 3 , DMSO 1 5.3
  • Example 20 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TCFH, NMI TFA, DCM MeCN 20.1 20.2 Int-33 PEPPSI-Pd B 2 (OH) 4 , 4,4 ' -bipyridine TEA, DCM dioxane DMF 2 0.3 20.4 20.5 LAH, THF
  • Example 21 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,4,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: PEPPSI-Pd DIEA, DMSO Cs 2 CO 3 , dioxane Int-54 21.1 21.2 B 2 (OH) 4,4 ' -bipyrid 4 ine DMF TEA, DCM LAH, THF 21.3 21.4
  • Example 22 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,3,7,15,29-pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM Pd 2 (dba), Xantphos Cs 2 CO 3 , 2 dioxane Int-34 22.1 22.2 PEPPSI-Pd 4,4 B '-2b ( iO pH y r ) i 4dine TEA, DCM Cs DMF o 2 CO dixane 3 22.3 22.4 22.5 LAH, THF
  • Example 23 15,18 2,6 9,14 2-hydroxy- N -(8- oxo -1,3,7,15-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: PEPPSI-Pd DIEA, DMSO dioxane, Cs 2 CO 3 Int-55 23.1 23.2 B ' 2 (OH) 4,4-bipyridine LAH, THF D MF TEA, DCM 23.3 23.4
  • Example 24 2-hydroxy-N-(3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM TCFH, NMI MeCN Int-33 24.1 24.2 B PEPPSI-Pd 4,4 ' -b 2 (OH) ipyrid 4 ine d C i s o 2x C an O e 3 DMF TEA, DCM 2 4.3 24.4 24.5 LAH THF
  • Example 24 2-Hydroxy-N-(3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl)ethanesulfonamide
  • Example 24 was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 methyl 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0
  • Example 25 15,18 2,6 9,14 N-(10-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: Cs 2 CO 3 , PEPPSI-Pd DIEA, DMSO 1,4-dioxane Int-54 25.1 25.2 B(OH , 2 4 ' ) 4 -bip 4 yridine LAH DMF TEA, DCM THF 25.3 25.4
  • 2-Chloro-6-[1-[2-[4-[3-(4-fluoro-4-piperidyl)propyl]-1-piperidyl]-4-nitro-phenyl]triazol-4- yl]pyridine was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 4-[3-[1-[2-[4-(6-chloro-2-pyri
  • Example 27 N-(22-fluoro-18-methyl-8-oxo-1,7,15,29- tetrazapentacyclo[20.2.2.2 15,18 .1 2,6 .0 9,14 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: Int-7 TFA DIEA, DMSO DCM Int-50 27.1 27.2 PEPPSI-Pd B 4,4 ' - 2 (OH) bipyri 4 dine Cs 2 CO DMF TEA, DCM dioxane 3 27.3 27.4 27.5 LAH, THF
  • a solution of benzyl 4-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4-methyl- 4-piperidyl]propyl]-4-fluoro-piperidine-1-carboxylate (compound 27.1, 580.0 mg, 0.89 mmol) in TFA (5.0 mL, 0.89 mmol) was stirred at 80 °C for 1 hrs.
  • Methyl 2-[[8-oxo-18-(trifluoromethyl)-1,7,15,19,29- 15,18 2,6 9,14 pentazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1,7
  • Example 29 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: Int-1 TFA, DCM DIEA, DMSO Int-50 29.1 29.2 B PEPPSI-Pd 4,4 ' - 2 (OH) bipyri 4 dine Cs 2 CO DMF TEA, DCM dioxane 3 29.3 29.4 29.5 LAH, THF
  • a mixture of N-(22-fluoro-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)propane-1- sulfonamide compound 30.1, 60.0 mg, 0.1 mmol
  • K2CO3 43.03 mg, 0.31 mmol
  • Example 31 15,18 2,6 9,14 N-(22-fluoro-8- oxo -1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TEA, DCM c ompound 29.4
  • Example 31 15,18 2,6 9,14 N-(22-fluoro-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 31) was prepared in analogy to 15,18 2,6 9,14 Example 20, by replacing 12-amino-1,
  • Example 32 15,18 2,6 9,14 N-[18-(difluoromethyl)-8-oxo-1,7,15,29-tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy-ethanesulfonamide
  • Example 29 was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.
  • 4-Amino-18,18-difluoro-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-8-one (compound 33.4) was prepared in analogy to Example 20, by replacing 12-nitro-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-8-one
  • Methyl 2-[(18,18-difluoro-8-oxo-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)sulfamoyl]acetate was prepared in analogy to Example 20, by replacing 15,18
  • Example 33 N-(18,18-difluoro-8-oxo-20-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy- ethanesulfonamide (Example 33) was prepared in analogy to Example 20, by replacing methyl 15,18 2,6 9,14 2-[(8-oxo-1,7,15,29-t
  • Example 34 15,18 2,6 9,14 2-hydroxy-N-(8-oxo-1,7,15-triazapentacyclo[20.2.2.2 .1 .0 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: PEPPSI-Pd DIEA, DMSO Cs dio 2 CO xane 3 Int-56 34.1 34.2 B 4,4 ' - 2 (OH) bipyri 4 dine LAH, THF DMF TEA, DCM 34.3 34.4
  • Example 35 10,14 15,19 2,7 N-(18,18-difluoro-8- oxo -1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: Int-15 TFA, DCM DIEA, DMSO Int-50 35.1 35.2 PEPPSI-Pd B 2 (OH) 4 Cs 2 CO 4,4 ' -bipyridine dioxane 3 DMF TEA, DCM 35.3 35.4 35.5 LAH, THF
  • Example 35A and Example 35b 2-hydroxy-N-[(19S)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy-N-[(19R)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide (Example 35A and Example 35B)
  • Example 35A and Example 35B Separation of compound of Example 35 by SFC afforded Example 35A (faster eluting, 19.59 mg) and
  • Example 36 N-[22-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl]-2-hydroxy- ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: Int-2 TFA, DCM DIEA, DMSO Int-50 36.1 36.2 PEPPSI-Pd B 4,4 ' - 2 (OH) bipyri 4 dine Cs dio 2 CO xane 3 DMF TEA, DCM 36.3 36.4 36.5 LAH, THF
  • Methyl 2-[[22-(difluoromethyl)-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12- yl]sulfamoyl]acetate was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1
  • Example 37 N-(17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide
  • Example 37 was prepared in analogy to Example 20 , by replacing methyl 15,18 2,6 9,14 2-[(8-oxo-1,7,15,29
  • Example 37A and Example 37B 2-hydroxy-N-[(18S)-17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy- N -[(18 R )-17,17-difluoro-8-oxo-19-oxa-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28)-hexaen-4- yl]ethanesulfonamide (Example 37A and Example 37B)
  • Example 37A and Example 37B Separation of compound of Example 37 by SFC afforded Example 37A (faster eluting, 34.08 mg) and Example 37B (slower eluting, 37.72 mg) with column DAICEL CHIRALPAK IG (250mm*30mm, 10um), CO 2 -EtOH (0.1%NH 3 H 2 O), 40%, 150ml/min).
  • Example 37A (faster eluting): 34.08 mg, 0.06 mmol. MS obsd. (ESI + ) [(M+H) + ]: 552.4. 1 H NMR (400 MHz, DMSO-d6) ⁇ 11.35 (br.
  • Example 39 N-(18,18-difluoro-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM DIEA, DMSO Int-42 3 9.1 39.2 B PEPPSI-Pd 2 (OH) 4,4 ' -bipyri 4 dine CsCO dio 2 xane 3 DMF TEA, DCM 39.3 39.4 39.5 LAH, THF
  • Methyl 2-[(18,18-difluoro-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 12-amino-1
  • Example 40 N-(18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM Pd 2(dba 3), Xantphos Cs 2 CO, 2 dioxane Int-42 40.1 40.2 PEPPSI-Pd B 4,4 ' - 2 (OH) bipyri 4 dine Cs dio 2 CO xane 3 DMF TEA, DCM 4 0.3 40.4 40.5 LAH, THF
  • Example 40 N-(18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 40) was prepared in analogy to Example 20 , by replacing 15,18 2,6 9,14 methyl 2-[(8-oxo-1,7,15,29-tetraza
  • Example 40A and Example 40B 2-hydroxy- N -[(19 S )-18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy- N -[(19 R )-18,18-difluoro-12-methyl-8-oxo-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide (Example 40A and Example 40B)
  • Example 40A and Example 40B Separation of Example 40 by SFC afforded Example 40A (faster e
  • Example 40A (faster eluting): MS obsd. (ESI + ) [(M+H) + ]: 579.2.
  • Example 40B (slower eluting): MS obsd. (ESI + ) [(M+H) + ]: 579.2.
  • Example 41 2-hydroxy-N-(18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: Int-18 TFA, DCM DIEA, DMSO Int-50 41.1 41.2 PEPPSI-Pd B 4,4 ' - 2 (OH) bipyrid 4 ine CsC dio 2 O xane 3 DMF TEA, DCM 41.3 41.4 41.5 LAH, THF
  • Example 41A and example 41B 2-hydroxy- N -[(19 S )-18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy- N -[(19 R )-18,18,23-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide (Example 41A and Example 41B)
  • Example 41A and Example 41B Separation of Example 41 by SFC afforded Example 41A (faster eluting,
  • Example 42 N-[23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl]-2- hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: Int-19 TFA, DCM DIEA, DMSO Int-50 42.1 42.2 B 2 (OH) PEPPSI-Pd 4,4 ' -bipyri 4 dine Cs dio 2 CO xane 3 DMF TEA, DCM 42.3 42..4 42..5 LAH, THF
  • N-(6-chloro-2-pyridyl)-2-[4-(difluoromethyl)-4-[3-(4,4-difluoro-3-piperidyl)propyl]-1- piperidyl]-4-nitro-benzamide (compound 42.2) was prepared in analogy to Example 1, by replacing tert-butyl 4-[3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4- piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[2-[(
  • Example 42A and Example 42B 2-hydroxy-N-[(19S)-23-(difluoromethyl)-18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy- N -[(19 R )-23-(difluoromethyl)-18,18-difluoro-8-oxo- 10,14 15,19 2,7 1,9,15,29-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide (Example 42A and Example 42B)
  • Example 42A and Example 42B Separation of Example 42 by
  • Example 42A faster eluting: MS obsd. (ESI + ) [(M+H) + ]: 614.2.
  • Example 42B (slower eluting): MS obsd. (ESI + ) [(M+H) + ]: 614.2.
  • Example 44 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,5,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2(7),3,5,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM Pd 2 (dba), Xantphos CsCO 2 2 3 , dioxane Int-46 44.1 44.2 PEPPSI-Pd Cs dio 2 CO xane 3 Cs 2 CO 3 , DMSO 44.3
  • Example 45 N-[23-(difluoromethyl)-18,18-difluoro-8- oxo -1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl]-2- hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM Pd 2 (dba) 2 , Xantphos Cs 2 CO 3 , dioxane Int-45 45.1 45.2 PEPPSI-Pd Cs dio 2 CO xane 3 Cs 2 CO 3 , DMSO 45.3
  • 23-(Difluoromethyl)-4,18,18-trifluoro-1,5,9,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-8-one ( compound 45.3) was prepared in analogy to Example 1, by replacing N-(6-chloro-2-pyridyl)-6-fluoro-2-[4- [3-(4-piperidyl)propyl]-1-piperidyl]pyridine-3-carboxamide (compound 1.2)
  • Example 46 N-(18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide
  • Example 46 was prepared in analogy to Example 20 , by replacing methyl 15,18 2,6 9,14 2-[(8-oxo-1,7,15,29-tetraza
  • Example 46A and Example 46B 2-hydroxy-N-[(19S)-18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy- N -[(19 R )-18,18-difluoro-23-methyl-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide (Example 46A and Example 46B)
  • Example 46A and Example 46B Separation of compound of Example 46 by SFC afforded Example 46A (faster
  • Example 47 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,9,13,15-tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10(29),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme:
  • N-(2-chloro-4-pyridyl)-2-[4-[3-(4,4-difluoro-3-piperidyl)propyl]-1-piperidyl]-4-nitro- benzamide (compound 47.2) was prepared in analogy to Example 1, by replacing tert-butyl 4- [3-[1-[3-[(6-chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1- carboxylate (compound 1.1) with tert-butyl 3-[3-[1-[2-[(2-chloro-4-pyridyl)carbam
  • Example 48 10,14 15,19 2,7 N-(18,18-difluoro-8- oxo -1,3,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide 10,14 15,19 2,7 N-(18,18-difluoro-8-oxo-1,3,9,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa- 2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide was prepared in analogy to Example 44, by replacing tert-butyl 4-[3-[1-(5-carbamoyl-2-methyl-4-pyridyl)-4- piperidyl]propyl]piperidine-1-carboxy
  • Example 49 2-hydroxy-N-(13,18,18-trifluoro-8-oxo-1,9,15,29- tetrazapentacyclo[21.2.2.1 10,14 .1 15,19 .0 2,7 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: Int-15 TFA, DCM DIEA, DMSO Int-58 49.1 49.2 PEPPSI-Pd B 2 (OH) 4 , 4,4 ' -bipyridine Cs dio 2 CO xane 3 DMF TEA, DCM 49.3 49.4 49..5 LAH, THF
  • Methyl 2-[(13,18,18-trifluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl)sulfamoyl]acetate was prepared in analogy to Example 20, by replacing 12- 15,18 2,6 9,14
  • Example 49 2-hydroxy-N-(13,18,18-trifluoro-8-oxo-1,9,15,29- tetrazapentacyclo[21.2.2.1 10,14 .1 15,19 .0 2,7 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4- yl)ethanesulfonamide
  • Example 49 was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 methyl 2-[(8-oxo-1,7,15,29-tetrazapentacyclo[20.2
  • Example 50 N-(18,18-difluoro-8- oxo -1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: I nt-20 TFA, DCM Int-50 5 0.1 50.2 PEPPSI-Pd 2 3 B xane 2 (OH) 4 , 4,4 ' -bipyridine CsCO, dio DMF TEA, DCM 50.3 50..4 50..5 LAH, THF
  • Methyl 2-[(18,18-difluoro-8-oxo-1,9,15,29- 10,14 15,19 2,7 17,19 tetrazahexacyclo[21.2.2.1 .1 .0 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)sulfamoyl]acetate was prepared in analogy to Example 20, by replacing 12- 15,18
  • Example 51 2-hydroxy-N-(8-oxo-18-oxa-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10(29),11,13-hexaen-4- yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: I nt-21 TFA, DCM Int-50 51.1 51.2 PEPPSI-Pd B 2 (OH) 4 , 4,4 ' -bipyridine C di s o 2 x C a O ne 3 DMF TEA, DCM 5 1.3 51..4 51..5 LAH, THF
  • N-(6-chloro-2-pyridyl)-2-[4-(3-morpholin-2-ylpropyl)-1-piperidyl]-4-nitro-benzamide was prepared in analogy to Example 1, by replacing tert-butyl 4-[3-[1-[3-[(6- chloro-2-pyridyl)carbamoyl]-6-fluoro-2-pyridyl]-4-piperidyl]propyl]piperidine-1-carboxylate (compound 1.1) with tert-butyl 2-[3-[1-[2-[(6-chloro-2-pyridyl)carbamoyl]-5-nitro-phenyl]-4- piperidyl]prop
  • Example 52 N-(18,18-difluoro-13-methoxy-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: Int-15 TFA, DCM NaH, THF, Int-51 52.1 52.2 PEPPSI-Pd B 2 (OH) 4 , 4,4 ' -bipyridine C s2 CO 3 , Dioxane DMF TEA, DMF 5 2.3 52..4 52..5 LAH, THF
  • Example 52 N-(18,18-difluoro-13-methoxy-8-oxo-1,9,15,29- 10,14 15,19 2,7 tetrazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2(7),3,5,10(29),11,13-hexaen-4-yl)-2- hydroxy-ethanesulfonamide (Example 52) was prepared in analogy to Example 20, by replacing 15,18 2,6 9,14 methyl 2-[(8-oxo-1,7,15,29,29
  • To a solution of N-[6-(4-allyl-3,3-difluoro-pyrrolidin-1-yl)-2-pyridyl]-4-nitro-2-(4-vinyl-1- piperidyl)benzamide (compound 60.2, 400.0 mg, 0.8 mmol) in DCM (4.0 L) was added Grabs' 2nd (136.51 mg, 0.16 mmol) (CAS: 246047-72-3, Sinocompound) at 20 °C.
  • To a solution of (20Z)-17,17-difluoro-4-nitro-1,9,15,28- 10,14 15,18 2,7 tetrazapentacyclo[20.2.2.1 .1 .0 ]octacosa-2,4,6,10,12,14(28),20-heptaen-8-one compound 60.3, 150.0 mg, 0.32 mmol
  • Pd/C 50.0 mg, 10% loaded on active carbon
  • Example 60 N-(17,17-difluoro-8-oxo-1,9,15,28-tetrazapentacyclo[20.2.2.1 10,14 .1 15,18 .0 2,7 ]octacosa- 2,4,6,10,12,14(28)-hexaen-4-yl)-2-hydroxy-ethanesulfonamide
  • Example 60 was prepared in analogy to Example 20 , by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo
  • Example 61 N-(18,22-difluoro-8- oxo -1,3,7,15,29-pentazapentacyclo[20.2.2.2 15,18 .1 2,6 .0 9,14 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: Int-70 Int-71 Grubbs-II DIEA, DMSO DIEA, NMP DCM Int-53 61.1 61.2 B(OH) 4,4 ' - 2 bipyri 4 dine DMF TEA, DCM 61.3 61.4 61.5 LAH, THF
  • compound 61.2 N-[2-(4-allyl-4-fluoro-1-piperidyl)pyrimidin-4-yl]-2-(4-fluoro-4-vinyl-1-piperidyl)-4-nitro- benzamide (compound 61.2) was prepared in analogy to Example 21, by replacing N-(6- chloropyrazin-2-yl)-2-fluoro-4-nitro-benzamide (Int-54) and 4-[3-(4-piperidyl)propyl]piperidine with N-[2-(4-allyl-4-fluoro-1-piperidyl)pyrimidin-4-yl]-2-fluoro-4-nitro-benzamide ( compound 61.1) and 4-fluoro-4-vinyl-piperidine (Int-7
  • Example 62 N-(18,22-difluoro-3-methoxy-8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,11,13-hexaen-12-yl)-2-hydroxy- ethanesulfonamide (Example 62) was prepared in analogy to Example 20, by replacing methyl 15,18 2,6 9,14 2-[(8-oxo-1,7,15,29-te
  • Example 65 2-hydroxy-N-(7-oxo-1,8,15,29-tetrazapentacyclo[20.2.2.2 15,18 .1 2,6 .0 9,14 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme:
  • a solution of tert-butyl 4-[3-[1-[5-[(2,4-dimethoxyphenyl)methylamino]-2-nitro-phenyl]- 4-piperidyl]propyl]piperidine-1-carboxylate compound 65.3 , 700.0 mg, 1.17 mmol
  • DMSO DMSO
  • 4,4’-bipyridine 9.16 mg, 0.06 mmol
  • a mixture of N-[4-amino-2-[4-[3-(4-piperidyl)propyl]-1-piperidyl]phenyl]-6-chloro- pyridine-2-carboxamide compound 65.6 , 350.0 mg, 0.77 mmol), Cs 2 CO 3 (750.19 mg, 2.3 mmol) and PEPPSI-Pd (65.82 mg, 0.08 mmol) in 1,4-Dioxane (300 mL) was degassed under N 2 for three times.
  • Example 65 2-hydroxy-N-(7-oxo-1,8,15,29-tetrazapentacyclo[20.2.2.2 15,18 .1 2,6 .0 9,14 ]nonacosa- 2(29),3,5,9,11,13-hexaen-12-yl)ethanesulfonamide (Example 65) was prepared in analogy to Example 20, by replacing methyl 2-[(8-oxo-1,7,15,29- 15,18 2,6 9,14 tetrazapentacyclo[20.2.2.2 .1 .0 ]nonacosa-2(29),3,5,9,
  • 4-bromo-2-[4-(4-hydroxybutyl)-1-piperidyl]-N-(3- sulfamoylphenyl)benzamide compound 70.1, 200 mg, 391.82 ⁇ mol
  • CMBP 4.11.15 ⁇ L, 1.57 mmol
  • DMSO DMSO
  • ethanesulfonamide 53.2 mg, 487.38 ⁇ mol
  • MNPMO 20.7 mg, 64.98 ⁇ mol
  • copper (I) iodide (6.19 mg, 32.49 ⁇ mol)
  • Example 71 N-(8,15,15-trioxo-15 ⁇ 6-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)methanesulfonamide (Example 71, 13 mg) was prepared in analogy to Example 70 , by replacing ethanesulfonamide with methanesulfonamide in the step (c). MS obsd. (ESI + ) [(M+H) + ]: 507.4.
  • Example 72 N-(8,15,15-trioxo-15 ⁇ 6-thia-1,9,16-triazatetracyclo[20.2.2.110,14.02,7]heptacosa- 2(7),3,5,10(27),11,13-hexaen-4-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: CMBP DIEA, MeCN toluene I nt-59 72.1 72.2 CuI, MNPMO K 3 PO 4 , DMSO E xample 72 N-(8,15,15-trioxo-15 ⁇ 6-thia-1,9,16-triazatetracyclo[20.2.2.110,14.02,7]heptacosa- 2(7),3,5,10(27),11,13-hexaen-4-yl)ethanesulfonamide ( Example 72 , 8.0 mg) was prepared in analogy to the Example 70, by replacing 4-(4-piperidyl
  • Example 73 N-(17-methyl-8,15,15-trioxo-15 ⁇ 6-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: CMBP DIEA, MeCN Toluene I nt-59 73.1 73.2 CuI, MNPMO K 3 PO 4 , DMSO E xample 73 N-(17-methyl-8,15,15-trioxo-15 ⁇ 6-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide (Example 73, 11.2 mg) was prepared in analogy to Example 70
  • Example 74 N-(21-methyl-8,15,15-trioxo-15 ⁇ 6-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: CMBP DIEA, MeCN Toluene I nt-59 74.1 74.2 CuI, MNPMO K 3 PO 4 , DMSO E xample 74 N-(21-methyl-8,15,15-trioxo-15 ⁇ 6-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide (Example 74, 18.4 mg) was prepared in analogy to Example 70
  • Example 75 N-[16-(2,2-difluoroethyl)-8,15,15-trioxo-15 ⁇ 6-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl]ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: CuI, MNPMO CMBP, toluene/THF K 3 PO 4 , DMSO 70.2 75.1
  • 4-bromo-16-(2,2-difluoroethyl)-15,15-dioxo-15 ⁇ 6-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-8-one compound 75.1 , 100 mg, 179.71 ⁇ mol) in DMSO (1.29 mL) was added ethanesulfonamide (58.85 mg, 539.12 ⁇ mol), MNPMO (57.2
  • Example 76 N-(16-methyl-8,15,15-trioxo-15 ⁇ 6-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4- yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: MeOH CuI, MNPMO CMBP, toluene/THF K 3 PO 4 , DMSO 7 0.2 76.1
  • Example 76 N-(16-methyl-8,15,15-trioxo-15 ⁇ 6-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7]hexacosa- 2(7),3,5,10(26),11,13-hexaen-4-yl)ethanesulfonamide ( Example 76 , 15 mg) was prepared in analogy to Example 75 by replacing 2,2-difluoro
  • Example 77 N-(16,21-dimethyl-8,15,15-trioxo-15 ⁇ 6-thia-1,9,16- triazatetracyclo[19.2.2.110,14.02,7]hexacosa-2(7),3,5,10(26),11,13-hexaen-4-yl)-2-hydroxy- ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: MeOH CuI, MNPMO CMBP, toluene/THF K 3 PO 4 , DMSO 7 4.2 77.1
  • Example 77 N-(16,21-dimethyl-8,15,15-trioxo-15 ⁇ 6-thia-1,9,16-triazatetracyclo[19.2.2.110,14.02,7] hexacosa-2(7),3,5,10(26),11,13-hexaen-4-yl)-2-hydroxy-ethanesulfonamide (Example 77, 2 mg)
  • Example 78 10,14 2,7 2-hydroxy-N-(8-oxo-15-oxa-1,9,27-triazatetracyclo[20.2.2.1 .0 ]heptacosa- 2(7),3,5,10,12,14(27)-hexaen-4-yl)ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: 78.1 K 2 CO 3 Grubbs-II HATU/DIEPA DMSO 7 8.2 78.3 Pd/H 2 K3PO4, CuI DMF N,N'-Dimethyl-1,2 -cyclohexanediamine 7 8.4 78.5 78
  • (20Z)-4-bromo-15-oxa-1,9,27-triazatetracyclo[20.2.2.1 .0 ]heptacosa- 2(7),3,5,10,12,14(27),20-heptaen-8-one compound 78.4, 50 mg, 109.56 ⁇ mol
  • potassium phosphate 69.77 mg, 328.67 ⁇ mol
  • N,N-dimethylformamide 3 mL
  • Example 79 N-(18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2- hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM Pd 2 2 (dba 3), Xantphos CsCO, 2 dioxane Int-46 79.1 79.2 PEPPSI-Pd B(OH) 4,4 ' - 2 bipyri 4 dine Cs dio 2 CO xane 3 DMF TEA, DCM 79.3 79.4 79.5 LAH, THF
  • Example 79A and Example 79B 2-hydroxy-N-[(19S)-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy-N-[(19R)-18,18-difluoro-12-methyl-8-oxo-20-oxa- 10,14 15,19 2,7 1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide
  • Example 79A and Example 79B Separat
  • Example 79A (faster eluting): MS obsd. (ESI + ): 581.3 [(M+H) + ].
  • Example 80 N-(18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2- hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM P Cds 2 2 (CdOba 3,) 2 d,i Xoxaanntpehos Int-47 80.1 80.2 PEPPSI-Pd 4,4 B ' - 2 b(iOpHyr)i 4 dine C diso 2 xCaOne 3 DMF TEA, DCM 8 0.3 80.4 80.5 LAH, THF
  • Example 80 N-(18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2-hydroxy- ethanesulfonamide ( Example 80 , 57.9 mg) was prepared in analogy to Example 40 , by replacing tert-but
  • Example 80A and Example 80B 2-hydroxy-N-[(19S)-18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy-N-[(19R)-18,18-difluoro-12,23-dimethyl-8-oxo-20-oxa- 10,14 15,19 2,7 1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide
  • Example 80A and Example 80B Separation of Example 80 by SFC afforded
  • Example 80A (faster eluting): MS obsd. (ESI + ) [(M+H) + ]: 595.2.
  • Example 81 N-(23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2- hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM Pd 2 (dba) 2 , Xantphos Cs 2 CO 3 , dioxane Int-48 81.1 81.2 PEPPSI-Pd B 4,4 ' - 2 (OH) bipyri 4 dine Cs dio 2 CO xane 3 DMF TEA, DCM 8 1.3 81.4 81.5 LAH, THF
  • Example 81 N-(23-ethyl-18,18-difluoro-12-methyl-8-ox
  • Example 81A and Example 81B 2-hydroxy-N-[(19S)-23-ethyl-18,18-difluoro-12-methyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy-N-[(19R)-23-ethyl-18,18-difluoro-12-methyl-8-oxo-20- 10,14 15,19 2,7 oxa-1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)- hexaen-4-yl]ethanesulfonamide
  • Example 81A and Example 81B Separation of Example
  • Example 81B (slower eluting): MS obsd. (ESI + ): 609.2 [(M+H) + ].
  • Example 82 N-(18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4-yl)-2- hydroxy-ethanesulfonamide
  • the titled compound was synthesized according to the following scheme: TFA, DCM Pd 2 2 (dba 3), Xantphos CsCO, 2 dioxane Int-49 82.1 82.2 PEPPSI-Pd B(OH) 4,4 ' - 2 bipyri 4 dine Cs dio 2 CO xane 3 DMF TEA, DCM 82.3 82.4 82.5 LAH, THF
  • Example 82 N-(18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,
  • Example 82A and Example 82B 2-hydroxy-N-[(19S)-18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa-1,9,13,15,29- 10,14 15,19 2,7 pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide and 2-hydroxy-N-[(19R)-18,18-difluoro-6,12-dimethyl-8-oxo-20-oxa- 10,14 15,19 2,7 1,9,13,15,29-pentazapentacyclo[21.2.2.1 .1 .0 ]nonacosa-2,4,6,10,12,14(29)-hexaen-4- yl]ethanesulfonamide
  • Example 82B 2-hydroxy-N-[(19S)-18,18-difluor
  • This assay determined the potency of compounds in inhibiting KIF18A ATPase in the presence of microtubules (MT).
  • Recombinant human KIF18A (1-355) protein was expressed in E. coli with an N-terminal GST tag. The protein was purified sequentially on a GST Bestarose FF column, a Mono S 10/100 GL column and a Superdex200 gel filtration column. The entire assay was conducted at RT.
  • KIF18A at a concentration of 8nM was pre- incubated with a three-fold dilution of the test compound or DMSO for 15 minutes in an assay buffer consisting of 15mM Tris pH 7.5, 10mM MgCl 2 , 0.01% Pluronic F-68, 1 ⁇ M Taxol, and 50 ⁇ g/ml microtubules (MT).52 ⁇ M ATP was added to initiate the enzymatic reaction. At 30 minutes, the ADP-Glo reagent was added to terminate the reaction. Following a 40-minute incubation, the detection reagent (Promega#V913A) was added, and luminescence was measured using a PHERAstar FSX reader (BMG).
  • an assay buffer consisting of 15mM Tris pH 7.5, 10mM MgCl 2 , 0.01% Pluronic F-68, 1 ⁇ M Taxol, and 50 ⁇ g/ml microtubules (MT).52 ⁇ M ATP was added to initiate the
  • % Inhibition 100 - (Signal compound- Signal positive control) / (Signal vehicle control - Signal positive control) ⁇ 100.
  • the positive control represented the group without KIF18A, while the vehicle control was the DMSO group.
  • IC50 4-parameter nonlinear regression equation with a variable slope was used, and the analysis was performed using GraphPad Prism 9.0.
  • Table 1 The activities of the compounds of the present invention in Kif18A motor assay Example B2 The anti-proliferation activity of KIF18A was studied using a Cell Titer Glo assay (promega). This assay determined the potency of compounds in inhibiting cell growth.
  • HT-29 (ATCC) 1800 cells/well, 90 ⁇ l of McCoy’s 5A media supplemented with 10% FBS.
  • Test compounds were added to cells in a 10x dilution scheme by adding 10 ⁇ l of serially diluted compound to the plate, and the treated cells were incubated in a 37°C, 5% CO 2 incubator. After 3 days incubation, the media and compounds were refreshed with 90 ⁇ l media and 10 ⁇ l 10x compounds accordingly, and the treated cells were incubated for additional 3 days in a 37°C, 5% CO2 incubator. The cells were treated for 6 days in total, and cell viability determined via the Promega Cell Titre-Glo® Assay kit.
  • Luminescence units were used to calculate %Inhibition. %Inhibition was calculated for each well as: ([max - min] - [test - min]/[max – min]. EC50 values were calculated from concentration vs. %Inhibition data via a four-parameter variable slope model. Table 2: The activities of the compounds of the present invention in HT29 Cell Titer Glo assay

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Abstract

La présente invention concerne de nouveaux composés de formule générale (I) dans laquelle L1, L2, L3, R1, R2, R3, A1, A2, A3, B1, B2, B3, n1 et n2 sont tels que décrits dans la description, ou un sel pharmaceutiquement acceptable de ceux-ci, des compositions comprenant les composés et des procédés d'utilisation des composés.
PCT/EP2025/056508 2024-03-12 2025-03-11 Inhibiteurs macrocycliques de kif18a et leur utilisation Pending WO2025190888A1 (fr)

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WO2020132649A1 (fr) * 2018-12-20 2020-06-25 Amgen Inc. Amides d'hétéroaryle utiles en tant qu'inhibiteurs de kif18a
WO2021026099A1 (fr) * 2019-08-02 2021-02-11 Amgen Inc. Inhibiteurs de kif18a
US20220289724A1 (en) * 2019-08-02 2022-09-15 Amgen Inc. Kif18a inhibitors
US20220372018A1 (en) * 2019-08-02 2022-11-24 Amgen Inc. Kif18a inhibitors
WO2023088441A1 (fr) * 2021-11-19 2023-05-25 微境生物医药科技(上海)有限公司 Inhibiteur de kif18a
WO2024153217A1 (fr) * 2023-01-20 2024-07-25 Insilico Medicine Ip Limited Inhibiteurs de kif18a et leurs utilisations
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WO2020132649A1 (fr) * 2018-12-20 2020-06-25 Amgen Inc. Amides d'hétéroaryle utiles en tant qu'inhibiteurs de kif18a
WO2021026099A1 (fr) * 2019-08-02 2021-02-11 Amgen Inc. Inhibiteurs de kif18a
US20220289724A1 (en) * 2019-08-02 2022-09-15 Amgen Inc. Kif18a inhibitors
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WO2023088441A1 (fr) * 2021-11-19 2023-05-25 微境生物医药科技(上海)有限公司 Inhibiteur de kif18a
WO2024153217A1 (fr) * 2023-01-20 2024-07-25 Insilico Medicine Ip Limited Inhibiteurs de kif18a et leurs utilisations
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