WO2023139241A1 - Heterocyclic compounds as ubiquitin specific protease 7 inhibitors - Google Patents

Heterocyclic compounds as ubiquitin specific protease 7 inhibitors Download PDF

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Publication number
WO2023139241A1
WO2023139241A1 PCT/EP2023/051447 EP2023051447W WO2023139241A1 WO 2023139241 A1 WO2023139241 A1 WO 2023139241A1 EP 2023051447 W EP2023051447 W EP 2023051447W WO 2023139241 A1 WO2023139241 A1 WO 2023139241A1
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Prior art keywords
methyl
phenyl
chloro
pyrrolo
pyrimidin
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PCT/EP2023/051447
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English (en)
French (fr)
Inventor
Frank Burkamp
Adam Piotr TREDER
Colin O'dowd
Lauren Emma PROCTOR
James Samuel Shane Rountree
Matthew HELM
Aaron CRANSTON
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Almac Discovery Ltd
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Almac Discovery Ltd
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Priority to US18/729,403 priority Critical patent/US20250122223A1/en
Priority to CN202380027580.0A priority patent/CN118946566A/zh
Priority to EP23701878.3A priority patent/EP4466072A1/en
Priority to JP2024543181A priority patent/JP2025503052A/ja
Publication of WO2023139241A1 publication Critical patent/WO2023139241A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the present invention concerns inhibitors of ubiquitin specific protease 7 (USP7), and methods of use thereof.
  • USP7 ubiquitin specific protease 7
  • the compounds described herein are able to selectively inhibit USP7 activity.
  • the compounds provided herein may therefore be suitable for the treatment and prevention of, for example, cancer and neoplastic conditions.
  • the compounds may be used as monotherapy or as combination therapy with radiation and/or additional therapeutic agents.
  • each R 1 is independently selected from: halo; Ci-Ce alkyl optionally substituted with halo; and C3-C6 cycloalkyl;
  • n is 0, 1 or 2
  • each R 2 is independently selected from optionally substituted Ci-Ce alkyl, optionally substituted C3-C6 cycloalkyl, wherein each of the one or more optional substituents are independently selected from Ci-Ce alkyl, and halo, or wherein “n” is 2 and each R 2 together with the carbon ring atom or atoms to which they are attached combine to form a C3-C6 fused cycloalkyl ring, a C3-C6 spirocyclic cycloalkyl ring, or C3-C4 bridge;
  • R 3 is selected from optionally substituted Ci-Ce alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted C7-C10 arylalkyl, optionally substituted Cs-Cio arylalkenyl, and optionally substituted C3-C6 heteroaryl; wherein each of the one or more optional substituents is independently selected from: halo; Ci-Ce alkyl optionally substituted with halo; and C3-C6 cycloalkyl optionally substituted with methyl or CF3; R 4 is H, Cl, Ci-C 6 alkyl; wherein one of X and Z is O and one of X and Z is NR’, such that the ring comprising X and Z is a morpholine ring, wherein R’ is H or Ci-Ce alkyl, optionally H; or a pharmaceutically acceptable salt or solvate thereof.
  • WO2018/073602 describes a USP7 inhibitor having the structure:
  • the invention includes the combination of all aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.
  • Figure 1 shows electron density maps derived from the crystal structure determination of USP7 in complex with an inhibitor according to the present invention, as described in the Examples below.
  • Figure 1(a) is the initial Fo-Fc difference electron density map of the model (contoured at 3.0 o) resulting from refinement of the initial model prior to modelling of the compound with BUSTER. Shown is the region of the compound binding site in chain B. For clarity, the final refined coordinates are also shown;
  • figure 1(b) is the final 2Fo-Fc electron density map (contoured at 1.5 o) resulting from refinement of the final model with BUSTER. Shown is the region of the compound binding site.
  • Figure 2 shows the overall structure of USP7, in complex with an inhibitor according to the present invention.
  • alkyl group (alone or in combination with another term(s)) means a straight- or branched-chain saturated hydrocarbon substituent typically containing 1 to 15 carbon atoms, such as 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms.
  • a “C n alkyl” group refers to an aliphatic group containing n carbon atoms.
  • a C1-C10 alkyl group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Attachment to the alkyl group occurs through a carbon atom.
  • substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, terf-butyl, pentyl (branched or unbranched), hexyl (branched or unbranched), heptyl (branched or unbranched), octyl (branched or unbranched), nonyl (branched or unbranched), and decyl (branched or unbranched).
  • alkenyl group means a straight- or branched-chain hydrocarbon substituent containing one or more double bonds and typically 2 to 15 carbon atoms; such as 2 to 10, 2 to 8, 2 to 6 or 2 to 4 carbon atoms.
  • substituents include ethenyl (vinyl), 1-propenyl, 3-propenyl, 1 ,4-pentadienyl, 1 ,4- butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl and hexenyl.
  • alkynyl group (alone or in combination with another term(s)) means a straight- or branched-chain hydrocarbon substituent containing one or more triple bonds and typically 2 to 15 carbon atoms; such as 2 to 10, 2 to 8, 2 to 6 or 2 to 4 carbon atoms.
  • substituents include ethynyl, 1-propynyl, 3-propynyl, 1 -butynyl, 3-butynyl and 4-butynyL
  • cycloalkyl group (alone or in combination with another term(s)) means a saturated cyclic hydrocarbon substituent containing 3 to 14 carbon ring atoms.
  • a cycloalkyl may be a single carbon ring, which typically contains 3 to 8 carbon ring atoms and more typically 3 to 6 ring atoms. It is understood that attachment to a cycloalkyl group is via a ring atom of the cycloalkyl group.
  • single-ring cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • a cycloalkyl may alternatively be polycyclic or contain more than one ring.
  • Polycyclic cycloalkyls include bridged, fused, and spirocyclic cycloalkyls.
  • aryl group (alone or in combination with another term(s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms, optionally 6 to 8, 6 to 7, optionally 6 carbon ring atoms.
  • a “C n aryl” group refers to an aromatic group containing n carbon atoms.
  • a Ce-Cwaryl group contains 6, 7, 8, 9 or 10 carbon atoms. Attachment to the aryl group occurs through a carbon atom.
  • An aryl group may be monocyclic or polycyclic (i.e. may contain more than one ring).
  • aryl groups include phenyl, naphthyl, acridinyl, indenyl, indanyl, and tetrahydronapthyl.
  • an aryl group is phenyl.
  • arylalkyl refers to an aryl substituent attached via an alkyl chain.
  • Examples of an arylalkyl substituent include phenylethyl/ethylbenzyl, where the ethyl chain links a phenyl group to the point of attachment.
  • C n includes the carbon atoms in the alkyl chain and in the aryl group.
  • ethylbenzene is a Cs arylalkyl.
  • arylalkenyl refers to an aryl substituent attached via an alkenyl chain.
  • Examples of an arylalkenyl substituent include phenylethenyl/ethenylbenzyl, where the ethenyl chain links to a phenyl group to the point of attachment.
  • C n includes the carbon atoms in the alkyl chain and in the aryl group.
  • phenylethenyl is a Cs arylalkenyl.
  • heteroaryl group (alone or in combination with another term(s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms.
  • a “C n heteroaryl” group refers to an aromatic group containing n carbon atoms and at least one heteroatom.
  • a C2- C10 aryl group contains 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in addition to at least one heteroatom. Attachment to the heteroaryl group occurs through a carbon atom or through a heteroatom.
  • a heteroaryl group may be monocyclic or polycyclic.
  • a heteroaryl may be a single ring or 2 or 3 fused rings.
  • Examples of monocyclic heteroaryl groups include 6- membered rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and 1 ,3,5-, 1 ,2,4- or 1 ,2,3-triazinyl; 5-membered rings such as imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1 ,2,3-, 1 ,2,4-, 1 ,2,5-, or 1 ,3,4-oxadiazolyl and isothiazolyl.
  • Polycyclic heteroaryl groups may be 2 or 3 fused rings.
  • polycyclic heteroaryl groups examples include 6/5-membered fused ring groups such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl, and purinyl; and 6/6-membered fused ring groups such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl.
  • 6/5-membered fused ring groups such as benzothiofuranyl, benzisoxazolyl, benzoxazolyl, and purinyl
  • 6/6-membered fused ring groups such as benzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and benzoxazinyl.
  • polycyclic heteroaryl groups only one ring in the polycyclic system is required to be unsaturated while the remaining ring(s) may be saturated, partially
  • amino group refers to the -NR’R” group.
  • the amino group can be unsubstituted or substituted.
  • R’ and R are hydrogen.
  • R’ and R each independently may be, but are not limited to, hydrogen, an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, sulfonyl, alkenyl, alkanoyl, aryl, arylalkyl, or a heteroaryl group, provided R’ and R” are not both hydrogen.
  • R’ and R may cyclise to form a heterocyclic group including the nitrogen to which they are attached (e.g. a pyrrolidine group).
  • the heterocyclic group formed by R’ and R” may optionally include additional heteroatoms, for example nitrogen or oxygen (e.g. the NR’R” group may form morpholine or piperazine).
  • the heterocyclic group formed by R’ and R” may be monocyclic, polycyclic (e.g. bicyclic), spirocyclic or a bridged ring group (e.g. a diazabicyclo[3.2.1]octane group).
  • Such a cyclic amino group may be optionally substituted, e.g. with an amino group, a methyl group, a hydroxyl group or an oxo group.
  • hydroxyl refers to an -OH group.
  • halo group refers to a group selected from chlorine, fluorine, bromine and iodine.
  • the halo group is selected from chlorine and fluorine.
  • optionally substituted means the group may be substituted with one or more substituents, which can be the same or different, or the group may have no substituents.
  • optionally monosubstituted means the group may have a single substituent or may be unsubstituted.
  • a substituent can be attached through a carbon atom and/or a heteroatom in the alkyl, alkenyl, cycloalkyl, aryl, or group.
  • substituted alkyl or “radical” includes but is not limited to alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halo, hydroxyl, cyano, amino, amido, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, thio, alkanoyl, carboxyl, alkoxycarbonyl, and oxo.
  • the substituent is alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halo, hydroxyl, cyano, amino, amido, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, nitro, thio, alkanoyl, carboxyl, alkoxycarbonyl, and oxo.
  • each of the one or more substituents of any optionally substituted group is independently selected from OH, F, Cl, Br, I, CN, Ci-Ce alkyl, CF3, CHF2, CH2F, CH2OH, C(O)CH 3 , CH 2 NHC(O)OCH 2 CH 3 , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, Ci-Ce alkoxy, amino, Ci-Ce alkylamine, Cs-Ce aryl, C 3 -Ce heteroaryl, benzyl, oxo and amide or two adjacent substituents may together constitute a ring.
  • first substituent may itself be either unsubstituted or substituted.
  • the compounds of the present invention may possess some aspect of stereochemistry.
  • the compounds may possess chiral centres and/or planes and/or axes of symmetry.
  • compounds according to the invention encompass all such stereoisomers.
  • the compounds may be provided as single stereoisomers, single diastereomers, mixtures of stereoisomers or as racemic mixtures, unless otherwise specified.
  • Stereoisomers are known in the art to be molecules that have the same molecular formula and sequence of bonded atoms, but which differ in their spatial orientations of their atoms and I or groups.
  • the compounds of the present invention may exhibit tautomerism. Each tautomeric form is intended to fall within the scope of the invention.
  • the compounds of the present invention may be provided as a pro-drug. Prodrugs are transformed, generally in vivo, from one form to the active forms of the drugs described herein.
  • a hydrogen atom may be 1 H, 2 H (deuterium) or 3 H (tritium).
  • the compounds of the present invention may be provided in the form of their pharmaceutically acceptable salts or as co-crystals.
  • pharmaceutically acceptable salt refers to ionic compounds formed by the addition of an acid to a base.
  • the term refers to such salts that are considered in the art as being suitable for use in contact with a patient, for example in vivo and pharmaceutically acceptable salts are generally chosen for their non-toxic, non-irritant characteristics.
  • co-crystal refers to a multi-component molecular crystal, which may comprise non-ionic interactions.
  • Pharmaceutically acceptable salts and co-crystals may be prepared by ion exchange chromatography or by reacting the free base or acidic form of a compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in one or more suitable solvents, or by mixing the compound with another pharmaceutically acceptable compound capable of forming a co-crystal.
  • Salts known in the art to be generally suitable for use in contact with a patient include salts derived from inorganic and I or organic acids, including the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate and tartrate. These may include cations based on the alkali and alkaline earth metals, such as sodium, potassium, calcium and magnesium, as well as ammonium, tetramethylammonium, tetraethylammonium. Further reference is made to the number of literature sources that survey suitable pharmaceutically acceptable salts, for example the handbook of pharmaceutical salts published by IUPAC. In addition, the compounds of the present invention may sometimes exist as zwitterions, which are considered as part of the invention.
  • each R 1 is independently selected from: halo; Ci-Ce alkyl optionally substituted with halo; and C3-C6 cycloalkyl;
  • n is 0, 1 or 2
  • each R 2 is independently selected from optionally substituted Ci-Ce alkyl, optionally substituted C3-C6 cycloalkyl, wherein each of the one or more optional substituents are independently selected from Ci-Ce alkyl, and halo, or wherein “n” is 2 and each R2 together with the carbon ring atom or atoms to which they are attached combine to form a C3-C6 fused cycloalkyl ring, a C3-C6 spirocyclic cycloalkyl ring, or C3-C4 bridge;
  • R’ is H or Ci-Ce alkyl, optionally H;
  • R 3 is selected from optionally substituted Ci-Ce alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted C7-C10 arylalkyl, optionally substituted C8-C10 arylalkenyl, and optionally substituted C3-C6 heteroaryl; wherein each of the one or more optional substituents is independently selected from: halo; Ci-Ce alkyl optionally substituted with halo; and C3-C6 cycloalkyl optionally substituted with methyl or CF3;
  • R 4 is H, Cl, Ci-C 6 alkyl; wherein one of X and Z is O and one of X and Z is NR’, such that the ring comprising X and Z is a morpholine ring, wherein R’ is H or Ci-Ce alkyl, optionally H; or pharmaceutically acceptable salts or solvates thereof.
  • each R 1 and R 2 when present, may be attached to any of the carbon atoms of their respective rings.
  • each R 1 substituent is independently selected from the recited options and thus may be the same or different from each other.
  • each R 2 substituent is independently selected from the recited options and thus may be the same as or different from each other.
  • R’ is preferably H.
  • X is NR’ and Z is O.
  • “m” is zero or 1. In certain such embodiments “m” is zero - i.e. the phenyl ring is unsubstituted. In certain alternative embodiments, “m” is 1 - i.e. the phenyl ring is monosubstituted.
  • R 1 is selected from: halo; Ci-Ce alkyl optionally substituted with halo; and C3-C6 cycloalkyl.
  • R 1 is selected from fluoro, chloro, C3-C6 cycloalkyl, and Ci-Ce alkyl optionally substituted with fluoro, for example methyl or CFs.
  • R 1 is selected from: Cl; F; and methyl optionally substituted with F, optionally CF3.
  • R 1 is Cl or F.
  • R 1 is methyl optionally substituted with F.
  • R 1 is CF3.
  • R 1 when present as a monosubstituent, is at position 3 of the phenyl ring. That is, preferably the compounds of the invention are according to formula (lb):
  • each R 2 substituent when “n” is 2, each R 2 substituent is at the same position of the morpholinyl ring. Alternatively, when “n” is 2, each R 2 substituent may be at a different position of the morpholinyl ring.
  • the numbering of the ring atoms of a morpholine ring always starts at the oxygen atom.
  • the direction of numbering is such that the point of attachment of the morpholinyl ring to the phenyl ring has the lowest possible number. Therefore, for compounds where Z is NR’ and X is O, the ring atoms are numbered as shown below: whereas, for compounds where Z is O and X is NR’, the ring atoms are numbered as shown below:
  • each R 2 substituent when “n” is 1 or 2, at least one R 2 substituent is at the 6 position of the morpholinyl ring. In preferred such embodiments, each R 2 substituent is at the 6 position of the morpholinyl ring. In certain embodiments, when “n” is 1 or 2, at least one R 2 group is at the 2 position of the morpholinyl ring. In certain preferred such embodiments, each R 2 substituent is at the 2 position of the morpholinyl ring.
  • At least one R 2 group is at the 5 position of the morpholinyl ring. In certain preferred embodiments, each R 2 substituent is at the 5 position of the morpholinyl ring.
  • n is two and each R 2 is attached to the same carbon ring atom. In certain alternative embodiments, “n” is two and each R 2 is attached to different carbon ring atoms, for example adjacent carbon ring atoms.
  • R 2 is independently selected from: methyl optionally substituted with F; ethyl; and cyclopropyl. In certain such embodiments, R 2 is selected from methyl, CHF2, CF3, ethyl, and cyclopropyl. In certain embodiments, R 2 is methyl. In certain embodiments, “n” is two and each R 2 is methyl. In certain such embodiments, each methyl group is attached to the same carbon ring atom. In certain such embodiments, each methyl group is attached at the 6-position of the morpholine ring. Alternatively, each methyl group can be attached to different carbon ring atoms.
  • n is one and R 2 is methyl.
  • the presence of an R 2 substituent results in a chiral centre at the morpholinyl ring carbon to which it is attached.
  • the R 2 substituent is in the R position.
  • the R 2 substituent is in the S position.
  • the invention encompasses compounds according to any of formulae (Ic) 1 , (Ic)", (Ic)"', or (lc) iv :
  • R 2 preferably being independently selected from: methyl, CHF2, CF3, ethyl, and cyclopropyl.
  • R 2 is preferably methyl, ethyl or cyclopropyl.
  • R 2 is methyl.
  • R 2 is ethyl.
  • “n” is 2 and each R 2 together with the carbon ring atom or atoms to which they are attached combine to form a C3-C6 spirocyclic cycloalkyl ring.
  • n is 2 and each R 2 combine to form a C3 or C4 spirocyclic cycloalkyl ring together with the carbon ring atom to which they are attached. In certain preferred such embodiments, “n” is 2 and each R 2 combine to form:
  • Z is NR’ and X is O.
  • X is NR’ and Z is O.
  • “n” is 2 and each R 2 together with the carbon ring atoms to which they are attached combine to form a C3-C6 fused cycloalkyl ring.
  • the two R 2 substituents are on adjacent carbon ring atoms.
  • “n” is 2 and each R 2 combine to form a C3, C5 or Ce fused cycloalkyl ring, together with the carbon ring atoms to which they are attached. In certain such embodiments, each R 2 combine to form a C3 fused cycloalkyl ring. In certain such embodiments, each R 2 combine to form a C5 fused cycloalkyl ring. In certain such embodiments, each R 2 combine to form a Ce fused cycloalkyl ring.
  • n is 2 and each R 2 combine to form:
  • Z is NR’ and X is O.
  • X is NR’ and Z is O.
  • n is 2 and each R 2 combine to form:
  • Z is NR’ and X is O.
  • X is NR’ and Z is O.
  • n is 2 and each R 2 combine to form:
  • Z is NR’ and X is O.
  • X is NR’ and Z is O.
  • n is 2 and each R 2 combine together with the carbon ring atoms to which they are attached to form a C3 or C4 bridged ring. In certain embodiments, “n” is 2 and each R 2 combine together with the carbon ring atoms to which they are attached to form a C4 bridged ring.
  • n is 2 and each R 2 combine together with the carbon ring atoms to which they are attached to form:
  • R 3 is selected from optionally substituted Ci-Ce alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted C7-C10 arylalkyl, optionally substituted Cs-Cw arylalkenyl, and optionally substituted C3-C6 heteroaryl; wherein each of the one or more optional substituents is independently selected from: halo; Ci-Ce alkyl optionally substituted with halo; and C3-C6 cycloalkyl optionally substituted with methyl or CF3.
  • R 3 is selected from optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted C7-C10 arylalkyl, optionally substituted Cs-Cw arylalkenyl, and optionally substituted C3-C6 heteroaryl; wherein each of the one or more optional substituents is independently selected from: halo; Ci-Ce alkyl optionally substituted with halo; and C3-C6 cycloalkyl optionally substituted with methyl or CF 3 .
  • R 3 is optionally substituted C3-C6 cycloalkyl.
  • each of the one or more optional substituents is independently selected from: halo; C1-C2 alkyl optionally substituted with F; and C3-C6 cycloalkyl.
  • R 3 is optionally substituted cyclopropyl.
  • each of the one or more optional substituents is independently selected from methyl, CHF2, CF3, and cyclopropyl.
  • R 3 is optionally substituted cyclopropyl, wherein one of the one or more optional substituents is methyl.
  • R 3 is optionally substituted cyclopropyl, wherein one of the one or more optional substituents is CHF2.
  • R 3 is optionally substituted cyclopropyl, wherein one of the one or more optional substituents is CF3.
  • R 3 is optionally substituted cyclopropyl, wherein one of the one or more optional substituents is cyclopropyl.
  • R 3 is an optionally substituted cyclopropyl group of general formula: wherein R 5 and R 6 are each independently selected from hydrogen, halo; C1-C2 alkyl optionally substituted with F; and C3-C6 cycloalkyl.
  • the compounds of the invention may be according to formula (Id):
  • R 5 and R 6 are substituents as defined above and are each independently selected from hydrogen, halo; C1-C2 alkyl optionally substituted with F; and C3-C6 cycloalkyl. In some embodiments, R 5 and R 6 are each independently selected from hydrogen, methyl, CHF2, CF3 and cyclopropyl.
  • R 5 is selected from hydrogen, methyl, CHF2, and CF3. In some embodiments, R 5 is selected from hydrogen, methyl and CF3. In some embodiments, R 5 is selected from hydrogen and CF3. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is CF3. In some embodiments, R 6 is selected from hydrogen, methyl, CHF2, CF3 and cyclopropyl. In some embodiments, R 6 is selected from methyl and cyclopropyl. In some embodiments, R 6 is methyl.
  • the presence of the R 5 and/or R 6 substituents may result in a chiral centre at the relevant cyclopropyl ring carbon.
  • the R 5 substituent is in the R configuration.
  • the R 5 substituent is in the S configuration.
  • the R 6 substituent is in the R configuration.
  • the R 6 substituent is in the S configuration.
  • the compound may be a compound according to any one of formulae (Id)', (Id)", (Id)"' or (ld)' v :
  • R 3 is optionally substituted phenyl.
  • each of the one or more optional substituents is independently selected from: halo; C1-C2 alkyl optionally substituted with F; and C3-C6 cycloalkyl optionally substituted with methyl or CF3.
  • R 3 is optionally substituted phenyl, wherein each of the one or more optional substituents is independently selected from Cl, F, methyl, CF3, CHF2, and cyclopropyl optionally substituted with methyl or CF3.
  • R 3 is optionally substituted phenyl, wherein one of the one or more optional substituents is Cl.
  • R 3 is optionally substituted phenyl, wherein one of the one or more optional substituents is F.
  • R 3 is optionally substituted phenyl, wherein one of the one or more optional substituents is methyl.
  • R 3 is optionally substituted phenyl, wherein one of the one or more optional substituents is CF3.
  • R 3 is optionally substituted phenyl, wherein one of the one or more optional substituents is CHF2. In certain embodiments R 3 is optionally substituted phenyl, wherein one of the one or more optional substituents is cyclopropyl optionally substituted with methyl. In certain embodiments R 3 is optionally substituted phenyl, wherein one of the one or more optional substituents is cyclopropyl optionally substituted with CF3.
  • R 3 is optionally substituted C7-C10 arylalkyl.
  • each of the one or more optional substituents is independently selected from: halo; Ci-Ce alkyl optionally substituted with halo; and C3-C6 cycloalkyl optionally substituted with methyl or CF3.
  • R 3 is optionally substituted (CH 2 )2-phenyl.
  • each of the one or more optional substituents is independently selected from: halo; Ci-Ce alkyl optionally substituted with halo; and C3-C6 cycloalkyl optionally substituted with methyl or CF3.
  • R 3 is optionally substituted (CH2)2-phenyl, wherein one of the one or more optional substituents is halo.
  • R3 is optionally substituted (CH2)2-phenyl, wherein one of the one or more optional substituents is Ci-Ce alkyl optionally substituted with halo, for example CHF2 of CF3.
  • R 3 is optionally substituted (CH2)2-phenyl, wherein one of the one or more optional substituents is C3-C6 cycloalkyl (e.g. cyclopropyl) optionally substituted with methyl.
  • R 3 is optionally substituted (CH2)2-phenyl, wherein one of the one or more optional substituents is C3-C6 cycloalkyl (e.g. cyclopropyl) optionally substituted CF3.
  • R 3 is optionally substituted (CH2)2-phenyl, wherein one of the one or more optional substituents is on the ethylene chain.
  • the optional substituent on the ethylene chain is selected from: methyl or ethyl, optionally substituted with F.
  • R 3 is optionally substituted (CH2)2-phenyl, wherein one of the one or more optional substituents is on the ethylene chain and is selected from methyl, CHF2 and CF3. In certain such embodiments the optional substituent is CHF2. In certain such embodiments the optional substituent is CF3.
  • R 3 is optionally substituted (CH2)2-phenyl
  • the optional substituent on the ethylene chain is on the second methylene group - i.e. R 3 is: -CH2-CHR-Ph, where “R” is the optional substituent.
  • the substituent on the ethylene chain of R 3 results in a chiral centre at the chain carbon.
  • the compound is the R stereoisomer at this position.
  • the compound is the S stereoisomer at this position.
  • each of the one or more optional substituents of the arylalkyl group is independently selected from F, Cl, methyl, ethyl, CHF2, and CF3.
  • R 4 is selected from H, Cl, and Ci-Ce alkyl.
  • R 4 is chlorine
  • R 4 is H or Ci-Ce alkyl.
  • R 4 can be H or methyl.
  • the chiral centre at morpholinyl ring carbon by which it is attached to the phenyl ring is in the R position
  • embodiments of all aspects including formulae (I), (la), (lb), (Ic) and (Id)
  • the chiral centre at morpholinyl ring carbon by which it is attached to the phenyl ring is in the S position. That is, the invention encompasses compounds of general formula:
  • compounds of the present invention have an IC50 value for USP7 of about 1 nM to about 10,000 nM, more preferably from about 1 nM to about 1000 nM, or from about 100 nM to about 1000 nM, or from about 100 nM to about 500 nM, or from about 100 nM to about 300 nM, or from about 100 nM to about 250 nM.
  • the compounds of the invention have an IC50 value for USP7 of less than 500 nM, most preferably less than 250 nM. A method for determining the IC50 value of a compound for USP7 is described below (see examples).
  • a compound of the invention While it is possible for a compound of the invention to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one USP7 inhibitor as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to any embodiment of the first aspect, for example a compound of formula (I), (la), (lb), (Ic) or (Id), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • compositions may be formulated according to their particular use and purpose by mixing, for example, excipient, binding agent, lubricant, disintegrating agent, coating material, emulsifier, suspending agent, solvent, stabilizer, absorption enhancer and I or ointment base.
  • the composition may be suitable for oral, injectable, rectal, topical buccal, sublingual, transmucosal, transdermal, intranasal, pulmonary, ocular, vaginal or parenteral administration.
  • Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.
  • Suitable pharmaceutically acceptable excipients would therefore be known by the person skilled in the art, for example: fats, water, physiological saline, alcohol (e.g. ethanol), glycerol, polyols, aqueous glucose solution, extending agent, disintegrating agent, binder, lubricant, wetting agent, stabilizer, emulsifier, dispersant, preservative, sweetener, colorant, seasoning agent or aromatizer, concentrating agent, diluent, buffer substance, solvent or solubilizing agent, chemical for achieving storage effect, salt for modifying osmotic pressure, coating agent or antioxidant, saccharides such as lactose or glucose; starch of corn, wheat or rice; fatty acids such as stearic acid; inorganic salts such as magnesium metasilicate aluminate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol; alcohols such as stearyl alcohol or benzyl alcohol;
  • the pharmaceutical composition may be administered orally, such as in the form of tablets, coated tablets, hard or soft gelatine capsules, solutions, emulsions, or suspensions. Administration can also be carried out rectally, for example using suppositories, locally or percutaneously, for example using ointments, creams, gels or solution, or parenterally, for example using injectable solutions.
  • the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
  • carriers e.g., liquid carriers, finely divided solid carrier, etc.
  • the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients.
  • suitable excipients include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof.
  • suitable excipients for use with soft gelatine capsules include, for example, vegetable oils, waxes, fats and semi-solid or liquid polyols.
  • excipients include, for example, water, polyols, saccharose, invert sugar and glucose.
  • excipients include, for example, water, alcohols, polyols, glycerine and vegetable oil.
  • excipients include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.
  • compositions may also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, buffers, coating agents and I or antioxidants.
  • the second drug may be provided in pharmaceutical composition with the present invention or may be provided separately.
  • a pharmaceutical formulation for oral administration may, for example, be granule, tablet, sugar-coated tablet, capsule, pill, suspension or emulsion.
  • a sterile aqueous solution may be provided that may contain other substances including, for example, salts and I or glucose to make the solution isotonic.
  • the anti-cancer agent may also be administered in the form of a suppository or pessary, or may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • the invention provides a compound or pharmaceutical composition according to any embodiment of the first aspect or second aspect for use in therapy, preferably in the treatment and/or prevention of cancer.
  • the invention provides a method of treating or preventing cancer comprising administering to a subject a compound according to any embodiment of the first aspect of the invention or a pharmaceutical composition according to any embodiment of the second aspect of the invention.
  • treatment pertains generally to treatment of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the disorder, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the disorder, amelioration of the disorder, and cure of the disorder.
  • Treatment as a prophylactic measure i.e. , prophylaxis is also included.
  • treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.
  • the subject/patient may be a mammal, a chordate, a vertebrate, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (duck-billed platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset
  • the subject/patient is a human.
  • Cancers or neoplastic conditions suitable to be treated or prevented according to these methods include, for example, prostate cancer, colon cancer, breast cancer, lung cancer, kidney cancer, skin cancers (e.g. melanoma), liver cancers, pancreatic cancer, CNS cancers (e.g. neuroblastomas, glioblastomas), osteosarcoma, haematological malignancies (e.g. leukemia, multiple myeloma and mantle cell lymphoma).
  • the cancer is associated with p53 dysregulation.
  • the cancer is selected from a haematological malignancy (e.g. mantle cell lymphoma, multiple myeloma), prostate cancer, a neuroblastoma, or a glioblastoma.
  • Cancers or neoplastic conditions suitable to be treated with the compounds or compositions according to the invention include, for example: prostate cancer, colon cancer, breast cancer, lung cancer, kidney cancer, skin cancers (e.g. melanoma), liver cancers, pancreatic cancer, CNS cancers (e.g. neuroblastomas, glioblastomas), osteosarcoma, haematological malignancies (e.g. leukemia, multiple myeloma and mantle cell lymphoma).
  • the cancer is associated with p53 dysregulation.
  • the cancer is selected from a haematological malignancy (e.g. mantle cell lymphoma, multiple myeloma), prostate cancer, a neuroblastoma, or a glioblastoma.
  • a method of treating cancer by inhibiting USP7 activity in fibroblasts comprising administering to a subject in need thereof a composition comprising a compound provided herein or a pharmaceutically acceptable salt or solvate thereof.
  • administering treats the cancer by inhibiting USP7 activity in cancer- associated fibroblasts (CAFs).
  • CAFs cancer- associated fibroblasts
  • administration of a compound provided herein or a pharmaceutically acceptable salt or solvate thereof treats the cancer by reducing the level of VEGF in the serum of the subject. In certain embodiments administration of a compound provided herein or a pharmaceutically acceptable salt or solvate thereof treats the cancer by reducing the level of VEGF in the tumour microenvironment.
  • administration of a compound provided herein or a pharmaceutically acceptable salt or solvate thereof treats the cancer by inhibiting production of VEGF by cancer-associated fibroblasts (CAFs).
  • CAFs cancer-associated fibroblasts
  • a method of treating cancer by modulating the tumour immune environment comprising administering to a subject in need thereof a compound provided herein or a pharmaceutically acceptable salt or solvate thereof, wherein administration of the compound modulates the tumour immune environment.
  • a method of treating cancer by increasing tumour infiltrating lymphocytes comprising administering to a subject in need thereof a compound provided herein or a pharmaceutically acceptable salt or solvate thereof, wherein administration of the compound increases the number of TILs, preferably CD8+ TILs.
  • a method of treating cancer by decreasing the proportion of Treg cells relative to CD8+ T cells in the TME comprising administering to a subject in need thereof a compound provided herein or a pharmaceutically acceptable salt or solvate thereof, wherein administration of the compound decreases the proportion of Treg cells relative to CD8+ T cells in the TME.
  • a method of treating cancer by decreasing the number of macrophages in the TME comprising administering to a subject in need thereof a compound provided herein or a pharmaceutically acceptable salt or solvate thereof, wherein administration of the compound decreases the number of macrophages in the TME.
  • a method of treating cancer by administering to a subject in need thereof a combination therapy, the combination therapy comprising a composition comprising a compound provided herein or a pharmaceutically acceptable salt or solvate thereof, and a composition comprising an immune checkpoint inhibitor.
  • a compound provided herein or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating cancer, the method comprising administering to a subject in need thereof a combination therapy, the combination therapy comprising a composition comprising a compound provided herein or a pharmaceutically acceptable salt or solvate thereof, and a composition comprising an immune checkpoint inhibitor.
  • an immune checkpoint inhibitor for use in a method of treating cancer, the method comprising administering to a subject in need thereof a combination therapy, the combination therapy comprising a composition comprising a compound provided herein or a pharmaceutically acceptable salt or solvate thereof, and a composition comprising the immune checkpoint inhibitor.
  • a combination therapy for use in a method of treating cancer comprising administering to a subject in need thereof the combination therapy, the combination therapy comprising a composition comprising a compound provided herein or a pharmaceutically acceptable salt or solvate thereof, and a composition comprising an immune checkpoint inhibitor.
  • administering treats cancer by inhibiting extra-cellular matrix (ECM) remodelling by cancer-associated fibroblasts.
  • ECM extra-cellular matrix
  • the ECM is the ECM of the tumour microenvironment.
  • administration of a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof treats the cancer by inhibiting degradation of the basement membrane, optionally degradation of the tubular basement membrane.
  • administration of a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof treats the cancer by inhibiting angiogenesis, optionally neo-angiogenesis.
  • angiogenesis is inhibited in the tumour microenvironment.
  • administration of a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof treats the cancer by modulation of the tumour immune environment, for example by promoting infiltration of CD8 T cells.
  • the cancer treated is formed of cancer cells, and the cancer cells are resistant to the administered compound (or pharmaceutically acceptable salt or solvate).
  • the cancer treated by the method is formed of cancer cells, and the cancer cells are resistant to the USP7 inhibitor in vitro.
  • the compound or composition of the invention may be used in monotherapy and/or a combination modality.
  • a compound provided herein may be administered in combination with an immune checkpoint inhibitor.
  • the checkpoint inhibitor is selected from an inhibitor of PD1 , PD-L1 , CTLA4, TIGIT, 41 BB, 0X40, GITR.
  • the checkpoint inhibitor is selected from an anti-PD1 antibody, an anti-PD-L1 antibody, an anti- CTLA4 antibody, an anti-41 BB antibody, an anti-OX40 antibody, an anti-GITR antibody, and an anti-ICOS antibody.
  • the checkpoint inhibitor is selected from an anti-PD1 antibody, an anti-PD-L1 antibody, and an anti-CTLA4 antibody.
  • the checkpoint inhibitor is selected from an anti-PD1 antibody and an anti-PD- L1 antibody. In certain embodiments the checkpoint inhibitor is an anti-CTLA4 antibody. In certain embodiments the checkpoint inhibitor is selected from: pembrolizumab (KeytrudaTM), nivolumab (OpdivoTM), cemiplimab (LibtayoTM), Atezolizumab (TecentriqTM), Avelumab (BavencioTM), Durvalumab (ImfinziTM), and Ipilimumab (YervoyTM).
  • Suitable agents that may be used in combination modalities with compounds or compositions according to the invention include one or more of anti-cancer agents, antiinflammatory agents, immuno-modulatory agents, immuno-suppressive agents, neurological agents, anti-diabetic agents, anti-viral agents, anti-bacterial agents and/or radiation therapy.
  • Agents used in combination with the compounds of the present invention may target the same or a similar biological pathway to that targeted by the compounds of the present invention or may act on a different or unrelated pathway.
  • the second active ingredient may include, but is not restricted to: alkylating agents, including cyclophosphamide, ifosfamide, thiotepa, melphalan, chloroethylnitrosourea and bendamustine; platinum derivatives, including cisplatin, oxaliplatin, carboplatin and satraplatin; antimitotic agents, including vinca alkaloids (vincristine, vinorelbine and vinblastine), taxanes (paclitaxel, docetaxel), epothilones and inhibitors of mitotic kinases including aurora and polo kinases; topoisomerase inhibitors, including anthracyclines, epipodophyllotoxins, camptothecin and analogues of camptothecin; antimetabolites, including 5-fluorouracil, capecitabine,
  • alkylating agents including cyclophosphamide, ifosfamide, thiotepa
  • appropriate dosages of the compounds of the invention, and compositions comprising the compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. Dosage for therapeutic effects may differ from the dosage required for diagnostic effects. The selected dosage level will depend on a variety of factors including the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the disorder, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
  • the compounds may be administered to the subject in need of treatment in an “effective amount”.
  • effective amount refers to the amount or dose of a compound which, upon single or multiple dose administration to a subject, provides therapeutic efficacy in the treatment of disease.
  • Therapeutically effective amounts of a compound according to the invention can comprise an amount in the range of from about 0.1 mg/kg to about 20 mg/kg per single dose.
  • a therapeutic effective amount for any individual patient can be determined by the healthcare professional by methods understood by the skilled person.
  • the amount of compound administered at any given time point may be varied so that optimal amounts of the compound, whether employed alone or in combination with any other therapeutic agent, are administered during the course of treatment. It is also contemplated to administer compounds according to the invention, or pharmaceutical compositions comprising such compounds, in combination with any other cancer treatment, as a combination therapy.
  • USP7 inhibitory activities in Table 3a are classified as the following: Table 3b. USP7 inhibition by exemplified compounds.
  • B2Pin2 bis(pinacolato)diboron; Boc: tert-butyloxycarbonyl; BOC2O: di-tert-butyl decarbonate; br: broad; c.a.: catalytic amount; Cu(OTf)2: copper(ll) trifluoromethanesulfonate; DCM: dichloromethane; d: doublet (spectral); DIPEA: diisopropylethylamine; DMAP: 4- dimethylaminopyridine; DMF: A/,A/-dimethylformamide; DMSO: dimethylsulfoxide; dp: datapoint; Pd(dppf)Ch ⁇ CH2CI2: [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane; EDC: A/-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide
  • Microwave experiments were carried out using a Biotage InitiatorTM Eight instrument.
  • the system gives good reproducibility and control at temperature ranges from 60-250°C and pressures of up to a maximum of 20 bar.
  • LCMS Liquid Chromatography Mass Spectrometry experiments to determine retention times (RT) and associated mass ions were performed using the following methods: Method A: The system consisted of an Agilent Technologies 6130 quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LC system with UV diode array detector and autosampler. The spectrometer consisted of an electrospray ionization source operating in positive and negative ion mode. LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Agilent Eclipse Plus C18 RRHD, 1.8 pm, 50 x 2.1 mm maintained at 40 °C. Mobile phases: A) 0.1% (v/v) formic acid in water; B) 0.1% (v/v) formic acid in acetonitrile.
  • Method B The system consisted of an Agilent Technologies 6140 single quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LC system with UV diode array detector and autosampler.
  • the spectrometer consisted of a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode.
  • LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Zorbax Eclipse Plus C18 RRHD, 1.8 pm, 50 x 2.1 mm maintained at 40 °C.
  • Mobile phases A) 0.1 % (v/v) formic acid in water; B) 0.1 % (v/v) formic acid in acetonitrile.
  • Method C The system consisted of either an Agilent Technologies 1100 Series LC/MSD system with UV diode array detector and evaporative light scattering detector (DAD/ELSD) and Agilent LC/MSD VL (G1956A), SL (G1956B) mass spectrometer or an Agilent 1200 Series LC/MSD system with DAD/ELSD and Agilent LC/MSD SL (G6130A), SL (G6140A) mass spectrometer. All of the LCMS data were obtained using the atmospheric pressure chemical ionization mode with positive and negative ion mode switching with a scan range of m/z 80-1000.
  • Method D The system consisted of a Waters QDa mass spectrometer linked to a Waters iCIass UPLC system with TUV detector.
  • the spectrometer consisted of an electrospray ionization source operating in positive and negative ion mode.
  • LCMS experiments were performed on each sample submitted using the following conditions: LC Column: Zorbax Eclipse Plus C18 RRHD, 1 .8 pm, 50 x 2.1 mm maintained at 40 °C. Mobile phases: A) 0.1% (v/v) formic acid in water; B) 0.1 % (v/v) formic acid in acetonitrile.
  • the separation of mixtures of stereoisomers was performed using the following general procedure.
  • the mixture of stereoisomers was dissolved to 66 mg/mL in methanol and purified by HPLC under the stated conditions.
  • Combined fractions of each of stereoisomer were evaporated to near dryness using a rotary evaporator, transferred into final vessels using MeOH, which was removed under a stream of compressed air at 35 °C, before being stored in a vacuum oven at 35 °C and 5 mbar for 16 h.
  • each stereoisomer was analysed to determine chiral purity using the following analytical SFC or HPLC methods under the stated conditions.
  • Example 32, Example 33, Example 62 and Example 66 these are single non- racemic diastereoisomers where the absolute stereochemistry of the morpholine substituents are known however the absolute stereochemistry of the cyclopropyl substituents was unknown. In the case of Example 67 this is a single non-racemic diastereoisomer where the absolute stereochemistry of all three stereocentres was unknown. In the cases of Example 32, Example 33, Example 62, Example 66 and Example 67 the relative stereochemistry of the cyclopropyl substituents was assigned based on NOE experiments.
  • the absolute stereochemistry of the substituents on the cyclopropane ring in Example 62 was subsequently determined, by X-ray analysis of a co-crystal of Example 62 in complex with USP7.
  • the absolute stereochemistry of the substituents on the cyclopropane ring in related Examples 32, 33, 62, 66 and 67 was hence determined via the co-crystal structure of Example 621 USP7 (see Examples, below).
  • the relative stereochemistry of the more active cyclopropane isomer is also consistent with Examples 95 and 96.
  • Example 23 Example 28, Example 29, Example 34, Example 40, Example 41 , Example 70, Example 71 , Example 73, Example 74, Example 76, Example 77, Example 79 and Example 80 these are single enantiomers of unknown absolute configuration in which the stereochemistry has been assigned arbitrarily so may be opposite to that stated.
  • Example 1 Example 2, Example 9 and Example 17 these are racemic diastereoisomers of known relative stereochemistry.
  • Example 10 Example 86 and Example 87 these are each a 1 :1 mixture of two diastereoisomers.
  • Example 53, Example 54 and Example 60 these are unknown mixtures of diastereoisomers.
  • Example 78, Example 81 , Example 82 and Example 85 these are single non- racemic diastereoisomers in which the absolute stereochemistry of the stereocentre in the morpholine ring is unknown and has been assigned arbitrarily so may be opposite to that stated.
  • Example 83 and Example 84 these are 4:4:1 :1 mixtures of diastereoisomers in which the absolute stereochemistry of the stereocentre in the morpholine ring is unknown and has been assigned arbitrarily so may be opposite to that stated.
  • Examples 111 and 112 were named based on their respective activities.
  • the Boc protected amine (1 equiv.) was dissolved in DCM and TFA was added. The reaction was stirred at rt for the stated time before being concentrated under reduced pressure. The remaining residue was dissolved in a mixture of MeOH and DCM and loaded onto a pre-equilibrated SCX-2 cartridge. The cartridge was washed with a 4:1 mixture of DCM/MeOH and the basic compound was eluted using a 4:1 mixture of DCM/7 M NH3 in MeOH. The ammoniacal fractions were concentrated to give the desired product.
  • Epoxide 1 (1-Methylcvclopropyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 4-Methylenepiperidine hydrochloride: A solution of 1-A/-boc-4-methylene-piperidine (1.97 g, 10 mmol) in DCM (10 mL) and 4 M hydrogen chloride in 1 ,4-dioxane (25 mL, 100 mmol) was stirred at rt for 100 min before being concentrated under reduced pressure to give title compound (1.34 g, quant.) as a white solid.
  • Step 2 (1 -Methylcyclopropyl)(4-methylenepiperidin-1 -yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (1.34 g, 10 mmol), 1-methylcyclopropane-1- carboxylic acid (1.00 g, 10 mmol), HATU (3.80 g, 10 mmol), DIPEA (4.18 mL, 30 mmol) and DCM (100 mL) after 1 h gave the title compound (1.69 g, 94%) as a colourless oil.
  • Step 3 (1-Methylcyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using (1-methylcyclopropyl)-(4-methylene-1-piperidyl)methanone (1.69 g, 9.43 mmol) in DCM (47 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (2.54 g, 11.3 mmol) in DCM (47 mL) after 20 h at rt gave the title compound (1.51 g, 82%) as a pale yellow oil.
  • Epoxide 2 (4-Chlorophenyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (4-Chlorophenyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (267 mg, 2.00 mmol), 4-chlorobenzoic acid (313 mg, 2.00 mmol), HATU (760 mg, 2.00 mmol), DIPEA (1.05 mL, 6.00 mmol) and DCM (20 mL) after 1 h gave the title compound (405 mg, 85%) as colourless oil.
  • Step 2 (4-Chlorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using (4-chlorophenyl)-(4-methylene-1-piperidyl)methanone (405 mg, 1.72 mmol) in DCM (8.5 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (462 mg, 2.06 mmol) in DCM (8.5 mL) after 20 h at rt gave the title compound (430 mg, 99%) as colourless oil that solidified upon standing.
  • Step 1 (R)-4,4,4-Trifluoro-1-(4-methylenepiperidin-1-yl)-3-phenylbutan-1-one: General procedure 1 using 4-methylenepiperidine hydrochloride (59.5 mg, 0.445 mmol), (R)-4,4,4- trifluoro-3-phenylbutanoic acid (97.1 mg, 0.445 mmol), HATU (169 mg, 0.445 mmol), DIPEA (0.233 mL, 1.34 mmol) and DCM (4.5 mL) after 1 h at rt gave title compound (129.5 mg, 97%) as a colourless oil.
  • Step 3 (R)-4,4,4-Trifluoro-3-phenyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)butan-1-one: General procedure 2 using (R)-4,4,4-trifluoro-1-(4-methylenepiperidin-1-yl)-3-phenylbutan-1-one (130 mg, 0.436 mmol) in DCM (2.1 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (117 mg, 0.523 mmol) in DCM (2.1 mL) after 20 h at rt gave title compound (143 mg, 94%) as a colourless oil.
  • Step 1 (4-Methylenepiperidin-1-yl)(phenyl)methanone: General procedure 1 using 4- methylenepiperidine hydrochloride (165 mg, 1.23 mmol), benzoic acid (151 mg, 1.23 mmol), HATU (470 mg, 1 .23 mmol), DIPEA (645 pL, 3.70 mmol) and DCM (11 mL) after 30 min gave the title compound (196 mg, 78%) as a white solid.
  • 1 H NMR 500 MHz, Chloroform-d
  • 6 7.56 - 7.29 (m, 5H)
  • 4.80 s, 2H
  • 3.76 (br. s, 2H)
  • 3.40 br. s, 2H
  • 2.33 (br.
  • Step 2 Phenyl(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using (4- methylenepiperidin-1-yl)(phenyl)methanone (196 mg, 0.974 mmol) in DCM (4.5 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (164 mg, 0.733 mmol) in DCM (4.5 mL) after 20 h at rt gave the title compound (163 mg, 77%) as a colourless oil.
  • Epoxide 5 (4-Fluorophenyl)( 1 -oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (4-Fluorophenyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (2.67 g, 20.0 mmol), 4-fluorobenzoic acid (2.80 g, 20.0 mmol), HATU (7.60 g, 20.0 mmol), DIPEA (10.5 mL, 60.0 mmol) and DCM (200 mL) after 30 min gave the title compound (4.31 g, 98%) as a colourless oil.
  • Step 2 (4-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using (4-fluorophenyl)(4-methylenepiperidin-1-yl)methanone (4.31 g, 19.7 mmol) in DCM (98 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (5.29 g, 23.6 mmol) in DCM (98 mL) after 20 h at rt gave the title compound (3.74 g, 80%) as a colourless oil that solidified upon standing.
  • Epoxide 6 (2,4-Difluorophenyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (2,4-Difluorophenyl)(4-methylenepiperidin-1-yl)methanone:
  • General procedure 1 using 4-methylenepiperidine hydrochloride (134 mg, 1.00 mmol), 2,4-difluorobenzoic acid (158 mg, 1.00 mmol), HATU (380 mg, 1.00 mmol), DIPEA (523 pL, 3.00 mmol) and DCM (10 mL) after 75 min gave the title compound (146 mg, 61%) as a viscous colourless oil.
  • Step 2 (2,4-Difluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using (2,4-difluorophenyl)(4-methylenepiperidin-1-yl)methanone (145 mg, 0.611 mmol) in DCM (2.7 mL) at rt and m-CPBA ( ⁇ 77% w/w) (164 mg, 0.733 mmol) in DCM (2.7 mL) after 22 h at rt gave the title compound (150 mg, 97%) as a viscous colourless oil.
  • Epoxide 7 (4-Chloro-2-fluorophenyl)( 1 -oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (4-Chloro-2-fluorophenyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (339 mg, 2.54 mmol), 4-chloro-2-fluorobenzoic acid (443 mg, 2.54 mmol), HATU (965 mg, 2.54 mmol), DIPEA (1.33 mL, 7.61 mmol) and DCM (20 mL) after 19 h gave the title compound (569 mg, 88%) as a colourless gum.
  • Step 2 (4-Chloro-2-fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using (4-chloro-2-fluorophenyl)(4-methylenepiperidin-1-yl)methanone (569 mg, 2.24 mmol in DCM (22 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (603 mg, 2.69 mmol) in DCM (22 mL) after 20 h at rt gave the title compound (574 mg, 94%) as a colourless oil.
  • Epoxide 8 (2-Chlorophenyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (2-Chlorophenyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (339 mg, 2.54 mmol), 2-chlorobenzoic acid (397 mg, 2.54 mmol), HATU (965 mg, 2.54 mmol), DIPEA (1.33 mL, 7.61 mmol) and DCM (20 mL) after 20 h gave the title compound (564 mg, 94%) as a colourless oil.
  • Step 2 (2-Chlorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using (2-chlorophenyl)(4-methylenepiperidin-1-yl)methanone (564 mg, 2.39 mmol) in DCM (22 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (644 mg, 2.87 mmol) in DCM (22 mL) after 20 h at rt gave the title compound (530 mg, 88%) as a colourless oil.
  • Epoxide 9 ((1 S*,2S*)-1-Methyl-2-(trifluoromethyl)cvclopropyl)(1-oxa-6-azaspiro[2.51octan-6- vDmethanone
  • Step 1 4-nitrophenyl (1S,2S)-1-methyl-2-(trifluoromethyl)cyclopropane-1 -carboxylate and 4- nitrophenyl (1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1 -carboxylate:
  • Commercially available 1-methyl-2-(trifluoromethyl)cyclopropane-1 -carboxylic acid (dr 82:18) was purified by flash chromatography (5:95 THF in hexanes) to give the single diastereoisomers. The major was assigned as rac-(1 R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carboxylic acid based on NOE experiments.
  • the first eluted material was arbitrarily assigned as 4-nitrophenyl (1 S*,2S*)-1-methyl-2- (trifluoromethyl)cyclopropane-l -carboxylate (532 mg, 26% recovery).
  • the second eluted material was arbitrarily assigned as 4-nitrophenyl (1 R*,2R*)-1-methyl-2-(trifluoromethyl)cyclopropane- 1 -carboxylate (449 mg, 22% recovery).
  • Step 2 ((1S*,2S*)-1-methyl-2-(trifluoromethyl)cyclopropyl)(4-methylenepiperidin-1- yl)methanone: A mixture of 4-nitrophenyl (1 S*,2S*)-1-methyl-2- (trifluoromethyl)cyclopropane-l -carboxylate (142 mg, 0.491 mmol), 4-methylenepiperidine hydrochloride (98.4 mg, 0.737 mmol), DIPEA (257 pL, 1.47 mmol) and DMF (4.9 mL) was stirred at rt for 70 min.
  • Step 3 ((1S*,2S*)-1-Methyl-2-(trifluoromethyl)cyclopropyl)( 1-oxa-6-azaspiro[2.5]octan-6- yl)methanone:
  • General procedure 2 using ((1 S*,2S*)-1-methyl-2- (trifluoromethyl)cyclopropyl)(4-methylenepiperidin-1-yl)methanone (94.6 mg, 0.383 mmol) in DCM (1.9 mL) at rt and m-CPBA ( ⁇ 77% w/w) (103 mg, 0.459 mmol) in DCM (1.9 mL) after 22 h 30 min at rt gave the title compound (87 mg, 86%) as viscous colourless oil.
  • Epoxide 10 ((1 R*,2R*)-1 -Methyl-2-(trifluoromethyl)cvclopropyl)( 1 -oxa-6-azaspiro[2.51octan- 6-yl)methanone
  • Step 1 ((1R*,2R*)-1-methyl-2-(trifluoromethyl)cyclopropyl)(4-methylenepiperidin-1- yl)methanone: A mixture of 4-nitrophenyl (1R*,2R*)-1-methyl-2- (trifluoromethyl)cyclopropane-l -carboxylate (238 mg, 0.823 mmol), 4-methylenepiperidine hydrochloride (165 mg, 1.23 mmol), DIPEA (430 pL, 2.47 mmol) and DMF (8.2 mL) was stirred at rt for 80 min.
  • Step 2 ((1R*,2R*)-1-Methyl-2-(trifluoromethyl)cyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6- yl)methanone:
  • General procedure 2 using ((1R*,2R*)-1-methyl-2- (trifluoromethyl)cyclopropyl)(4-methylenepiperidin-1-yl)methanone (102 mg, 0.413 mmol) in DCM (2 mL) at rt and m-CPBA ( ⁇ 77% w/w) (111 mg, 0.495 mmol) in DCM (2 mL) after 22 h at rt gave the title compound (107.9 mg, 99%) as a viscous colourless oil.
  • Epoxide 11 (3-Chlorophenyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (3-Chlorophenyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (339 mg, 2.54 mmol), 3-chlorobenzoic acid (397 mg, 2.54 mmol), HATU (965 mg, 2.54 mmol), DIPEA (1.33 mL, 7.61 mmol) and DCM (20 mL) after 20 h gave the title compound (520 mg, 86%) as a colourless oil.
  • Step 2 (3-Chlorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using (3-chlorophenyl)(4-methylenepiperidin-1-yl)methanone (520 mg, 2.21 mmol) in DCM (10 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (593 mg, 2.65 mmol) in DCM (10 mL) after 20 h at rt gave the title compound (445 mg, 80%) as a colourless oil.
  • Epoxide 12 (2-Fluorophenyl)( 1 -oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (2-Fluorophenyl)(4-methylenepiperidin-1-yl)methanone:
  • General procedure 1 using 4-methylenepiperidine hydrochloride (339 mg, 2.54 mmol), 2-fluorobenzoic acid (355 mg, 2.54 mmol), HATU (965 mg, 2.54 mmol), DIPEA (1.33 mL, 7.61 mmol) and DCM (5 mL) after 20 h gave the title compound (501 mg, 90%) as a viscous colourless oil.
  • Step 2 (2-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using (2-fluorophenyl)(4-methylenepiperidin-1-yl)methanone (501 mg, 2.29 mmol) in DCM (10 mL) at rt and m-CPBA ( ⁇ 77% w/w) (615 mg, 2.74 mmol) in DCM (10 mL) after 20 h at rt gave the title compound (501 mg, 93%) as a colourless oil.
  • Epoxide 13 (3,4-Difluorophenyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (3, 4-Difluorophenyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (339 mg, 2.54 mmol), 3,4-difluorobenzoic acid (401 mg, 2.54 mmol), HATU (965 mg, 2.54 mmol), DIPEA (1.33 mL, 7.61 mmol) and DCM (15 mL) after 19 h gave the title compound (533, 88%) as a colourless gum.
  • Step 2 (3,4-Difluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using (3,4-difluorophenyl)(4-methylenepiperidin-1-yl)methanone (533 mg, 2.25 mmol) in DCM (10 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (604 mg, 2.70 mmol) in DCM (10 mL) after 20 h at rt gave the title compound (533 mg, 93%) as a colourless oil.
  • Epoxide 14 (3-Fluorophenyl)( 1 -oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (3-Fluorophenyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (134 mg, 1.00 mmol), 3-fluorobenzoic acid (140 mg, 1 .00 mmol), HATU (380 mg, 1 .00 mmol), DIPEA (523 pL, 3.00 mmol) and DCM (10 mL) after 19 h gave the title compound (178 mg, 81 %) as a viscous colourless oil.
  • Step 2 (3-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using (3-fluorophenyl)(4-methylenepiperidin-1-yl)methanone (178 mg, 0.812 mmol) in DCM (4 mL) at rt and m-CPBA ( ⁇ 77% w/w) (218 mg, 0.974 mmol) in DCM (4 mL) after 18 h at rt gave the title compound (183 mg, 95%) as colourless solid.
  • Epoxide 15 (2,3-Difluorophenyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (2, 3-Difluorophenyl)(4-methylenepiperidin-1-yl)methanone:
  • General procedure 1 using 4-methylenepiperidine hydrochloride (339 mg, 2.54 mmol), 2,3-difluorobenzoic acid (401 mg, 2.54 mmol), HATU (965 mg, 2.54 mmol), DIPEA (1.33 mL, 7.61 mmol) and DCM (15 mL) after 19 h gave the title compound (504 mg, 83%) as a white solid.
  • Step 2 (2,3-Difluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using (2,3-difluorophenyl)(4-methylenepiperidin-1-yl)methanone (504 mg, 2.12 mmol) in DCM (10 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (571 mg, 2.55 mmol) in DCM (10 mL) after 20 h at rt gave the title compound (501 mg, 93%) as a colourless oil.
  • Epoxide 16 [1 ,T-Bi(cvclopropan)1-1-yl(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 [1, 1'-Bi(cyclopropan)]-1-yl(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (267 mg, 2.00 mmol), [1 ,1 '-bi(cyclopropane)]-1- carboxylic acid (252 mg, 2.00 mmol), DIPEA (1.05 mL, 6.00 mmol), HATU (760 mg, 2.00 mmol) and DCM (20 mL) after 19 h at rt gave the title compound (392 mg, 95%) as colourless oil.
  • 1 H NMR 500 MHz, DMSO-d 6 ) 6 4.78 (s, 2H), 3.57 (br.
  • Step 2 [1, 1'-Bi(cyclopropan)]-1-yl(1-oxa-6-azaspiro[2.5]octan-6-yl) methanone:
  • General procedure 2 using [1 ,1'-Bi(cyclopropan)]-1-yl(4-methylenepiperidin-1-yl)methanone (392 mg, 1 .91 mmol) in DCM (9.5 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (514 mg, 2.29 mmol) in DCM (9.5 mL) after 20 h at rt gave title compound (421 mg, 90%) as a colourless oil.
  • Epoxide 17 (1-Oxa-6-azaspiro[2.51octan-6-yl)(p-tolyl)methanone
  • Step 1 (4-methylenepiperidin-1-yl)(p-tolyl)methanone: General procedure 1 using 4- methylenepiperidine hydrochloride (668 mg, 5.00 mmol), 4-methylbenzoic acid (681 mg, 5.00 mmol), HATU (1.90 g, 5.00 mmol), DIPEA (2.61 mL, 15.0 mmol) and DCM (50 mL) after 1 h gave the title compound (940 mg, 87%) as colourless oil.
  • Step 2 (1-Oxa-6-azaspiro[2.5]octan-6-yl)(p-tolyl)methanone:
  • General procedure 2 using (4- methylenepiperidin-1-yl)(p-tolyl)methanone (940 mg, 4.37 mmol) in DCM (22 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (1.17 g, 5.24 mmol) in DCM (22 mL) after 19 h at rt gave the title compound (984 mg, 97%) as a colourless oil that solidified upon standing.
  • Epoxide 18 (1-Oxa-6-azasDiro[2.51octan-6-yl)(4-(trifluoromethyl)ohenyl)methanone
  • Step 1 (4-Methylenepiperidin-1-yl)(4-(trifluoromethyl)phenyl)methanone: General procedure
  • Step 2 (1-Oxa-6-azaspiro[2.5]octan-6-yl)(4-(trifluoromethyl)phenyl)methanone:
  • General procedure 2 using (4-methylenepiperidin-1-yl)(4-(trifluoromethyl)phenyl)methanone (1 .31 g, 4.87 mmol) in DCM (24 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (1.31 g, 5.84 mmol) in DCM (24 mL) after 19 h at rt gave the title compound (1.29 g, 92%) as a white solid.
  • Epoxide 19 (2-Chloro-4-methylphenyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (2-Chloro-4-methylphenyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (668 mg, 5.00 mmol), 2-chloro-4-methylbenzoic acid (853 mg, 5.00 mmol), HATU (1.90 g, 5.00 mmol), DIPEA (2.61 mL, 15.0 mmol) and DCM (50 mL) after 1 h gave the title compound (1.21 g, 96%) as a colourless oil.
  • Step 2 (2-Chloro-4-methylphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using (2-chloro-4-methylphenyl)(4-methylenepiperidin-1-yl)methanone (1.21 g, 4.85 mmol) in DCM (24 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (1.30 g, 5.81 mmol) in DCM (24 mL) after 19 h at rt gave the title compound (1.29 g, 92%) as a white solid.
  • Step 1 (2,4-Dimethylphenyl)(4-methylenepiperidin-1-yl)methanone:
  • General procedure 1 using 4-methylenepiperidine hydrochloride (339 mg, 2.54 mmol), 2,4-dimethylbenzoic acid (401 mg, 2.54 mmol), HATU (965 mg, 2.54 mmol), DIPEA (1.33 mL, 7.61 mmol) and DCM (15 mL) after 19 h gave the title compound (572 mg, 98%) as a white solid.
  • Step 2 (2,4-Dimethylphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using (2,4-dimethylphenyl)(4-methylenepiperidin-1-yl)methanone (572 mg, 2.49 mmol) in DCM (10 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (671 mg, 2.99 mmol) in DCM (10 mL) after 20 h at rt gave the title compound (519 mg, 84%) as a colourless oil.
  • Epoxide 21 6-((4-Nitrophenyl)sulfonyl)-1-oxa-6-azaspiro[2.51octane
  • Step 1 4-Methylene-1-((4-nitrophenyl)sulfonyl)piperidine: A mixture of 4- nitrobenzenesulfonyl chloride (1.12 g, 5.07 mmol), 4-methylenepiperidine hydrochloride (678 mg, 5.074 mmol), DIPEA (2.65 mL, 15.2 mmol) and THF (50 mL) was stirred at rt overnight. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate (100 mL) and extracted with DCM (3 x 100 mL). The combined organic phases were concentrated under reduced pressure and the residue purified by flash chromatography to give the title compound (1.43 mg, 99%) as white solid.
  • Step 2 6-((4-Nitrophenyl)sulfonyl)-1-oxa-6-azaspiro[2.5]octane: General procedure 2 using 4-methylene-1-((4-nitrophenyl)sulfonyl)piperidine (1.43 g, 5.07 mmol) in DCM (50 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (1 .36 g, 6.08 mmol) in DCM (50 mL) after 20 h at rt gave the title compound.
  • LCMS (method B): RT 1.07 min, mass ion not observed.
  • Epoxide 22 (R)-4,4-Difluoro-3-phenyl-1-(1-oxa-6-azaspiro[2.51octan-6-yl)butan-1-one
  • Step 1 (R)-4,4-difluoro-1-(4-methylenepiperidin-1-yl)-3-phenylbutan-1-one: General procedure 1 using 4-methylenepiperidine hydrochloride (138 mg, 1.03 mmol), (R)-4,4- difluoro-3-phenylbutanoic acid (207 mg, 1.03 mmol), HATU (393 mg, 1.03 mmol), DIPEA (0.540 mL, 3.10 mmol) and DCM (10.3 mL) after 3 days gave the title compound (255 mg, 88%) as a colourless oil.
  • Step 2 (R)-4,4-Difluoro-3-phenyl-1 -(1 -oxa-6-azaspiro[2.5]octan-6-yl)butan-1 -one: General procedure 2 using (R)-4,4-difluoro-1-(4-methylenepiperidin-1-yl)-3-phenylbutan-1-one (250 mg, 0.895 mmol) in DCM (4.5 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (241 mg, 1 .074 mmol) in DCM (4.5 mL) after 20 h at rt gave the title compound (245 mg, 92%) as a colourless oil.
  • Epoxide 23 (1 -Methyl-2-(trifluoromethyl)cvclopropyl)( 1 -oxa-6-azaspiro[2.51octan-6- vDmethanone
  • Step 1 (1-Methyl-2-(trifluoromethyl)cyclopropyl)(4-methylenepiperidin-1-yl)methanone: To a stirred solution of 1-methyl-2-(trifluoromethyl)cyclopropane-1 -carboxylic acid (4:1 mixture diastereoisomers, 5.00 g, 29.8 mmol) in DMF (25 mL) at rt were sequentially added HATU (11.3 g, 29.8 mmol) and DIPEA (18.1 mL, 104 mmol).
  • Step 2 (1-Methyl-2-(trifluoromethyl)cyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using (1-Methyl-2-(trifluoromethyl)cyclopropyl)(4-methylenepiperidin-1- yl)methanone (4:1 mixture diastereoisomers, 6.69 g, 27.1 mmol) in DCM (200 mL) at 0 °C and m-CPBA ( ⁇ 70% w/w) (7.84 g, 3.5 mmol) added as solid after 1 h at rt gave the title compound (4.42 g, 62%) as a yellow oil.
  • LCMS (method C): RT 0.95 min, m/z
  • Epoxide 24 (4-Chloro-2-methylphenyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (4-Chloro-2-methylphenyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (356 mg, 2.66 mmol), 4-chloro-2-methylbenzoic acid (455 mg, 2.66 mmol), HATU (1.01 g, 2.66 mmol), DIPEA (1.39 mL, 7.99 mmol) and DCM (20 mL) after 20 h gave the title compound (548 mg, 82%) as a white solid.
  • Step 2 (4-Chloro-2-methylphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using (4-chloro-2-methylphenyl)(4-methylenepiperidin-1-yl)methanone (545 mg, 2.18 mmol) in DCM (10 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (587 mg, 2.62 mmol) in DCM (10 mL) after 20 h at rt gave the title compound (554 mg, 95%) as a colourless oil.
  • Epoxide 25 (4-(Difluoromethyl)phenyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (4-(Difluoromethyl)phenyl)(4-methylenepiperidin-1-yl)methanone: General procedure
  • Step 2 (4-(Difluoromethyl)phenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using (4-(difluoromethyl)phenyl)(4-methylenepiperidin-1-yl)methanone (595 mg, 2.37 mmol) in DCM (10 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (637 mg, 2.84 mmol) in DCM (10 mL) after 20 h at rt gave the title compound (581 mg, 91%) as a colourless oil.
  • Epoxide 26 (4-Cvclopropylphenyl)(1-oxa-6-azaspiro[2.5loctan-6-yl)methanone
  • Step 1 (4-Cyclopropylphenyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (1.00 g, 7.49 mmol), 4-cyclopropylbenzoic acid (1 .26 g, 7.77 mmol), HATU (2.85 g, 7.49 mmol), DIPEA (3.91 mL, 22.5 mmol) and DMF (12 mL) after 20 h gave the title compound (1.33 g, 71%) as a pale yellow oil.
  • Step 2 (4-Cyclopropylphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using (4-cyclopropylphenyl)(4-methylenepiperidin-1-yl)methanone (1.33 g, 5.52 mmol) in DCM (50 mL) at 0 °C and m-CPBA ( ⁇ 70% w/w) (1 .50 g, 6.08 mmol) in DCM (50 mL) after 20 h at rt gave the title compound (653 mg, 46%) as a pale yellow oil.
  • Epoxide 27 (4-(1-Methylcvclopropyl)phenyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (4-(1-Methylcyclopropyl)phenyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (1.63 g, 12.2 mmol), 4-(1- methylcyclopropyl)benzoic acid (2.16 g, 12.2 mmol), HATU (4.64 g, 12.2 mmol), DIPEA (5.10 mL, 36.6 mmol) and DMF (18 mL) after 20 h gave the title compound (2.31 g, 74%) as a pale yellow oil.
  • Step 2 (4-( 1-Methylcyclopropyl)phenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using (4-(1-methylcyclopropyl)phenyl)(4-methylenepiperidin-1- yl)methanone (2.31 g, 9.06 mmol) in DCM (50 mL) at 0 °C and m-CPBA ( ⁇ 70% w/w) (1.50 g, 6.08 mmol) in DCM (50 mL) after 20 h at rt gave the title compound (1.19 g, 49%) as a pale yellow oil.
  • Epoxide 28 ((1 S,2S)-1 ,2-Dimethylcvclopropyl)(1-oxa-6-azaspiro[2.5loctan-6-yl)methanone
  • Step 1 4-Nitrophenyl (1S,2S)-1,2-dimethylcyclopropane-1-carboxylate: To a solution of (1 S,2S)-1 ,2-dimethylcyclopropane-1-carboxylic acid (404 mg, 3.54 mmol) in DMF (10.6 mL) was added EDC (814 mg, 4.25 mmol) and the resulting mixture was stirred at rt for 15 min before 4-nitrophenol (542 mg, 3.89 mmol) and DMAP (43 mg, 0.354 mmol) were added. The resulting mixture was stirred at rt for 19 h before the reaction mixture was diluted with water and extracted with EtOAc (x3).
  • Step 2 ((1S,2S)-1,2-Dimethylcyclopropyl)(4-methylenepiperidin-1-yl)methanone: A solution of 1-A/-boc-4-methylene-piperidine (796 mg, 4.04 mmol) in 4 M HCI in 1 ,4-dioxane (3.36 mL, 13.5 mmol) and DCM (2.3 mL) was stirred at rt for 1 h before being concentrated under reduced pressure.
  • Step 3 ((1 S,2S)-1 ,2-Dimethylcyclopropyl)(1 -oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using ((1 S,2S)-1 ,2-dimethylcyclopropyl)(4-methylenepiperidin-1- yl)methanone (455 mg, 2.35 mmol) in DCM (11.7 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (633 mg, 2.82 mmol) in DCM (11 .7 mL) after 20 h at rt gave the title compound (413 mg, 83%) as a viscous colourless oil.
  • Epoxide 29 ((1 2R)-1 ,2-Dimethylcvclopropyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 4-Nitrophenyl (1R,2R)-1 ,2-dimethylcyclopropane-1-carboxylate: To a solution of (1R,2R)-1 ,2-dimethylcyclopropane-1 -carboxylic acid (598 mg, 5.24 mmol) in DMF (15.7 mL) was added EDC (1 .21 g, 6.29 mmol) and the resulting mixture was stirred at rt for 15 min before 4-nitrophenol (802 mg, 5.76 mmol) and DMAP (64 mg, 0.524 mmol) were added. The resulting mixture was stirred at rt for 19 h before the reaction mixture was diluted with water and extracted with EtOAc (x3).
  • Step 2 ((1R,2R)-1,2-Dimethylcyclopropyl)(4-methylenepiperidin-1-yl)methanone: A solution of 1-A/-boc-4-methylene-piperidine (1.15 g, 5.82 mmol) in 4 M HCI in 1 ,4-dioxane (4.85 mL, 19.4 mmol) and DCM (3.7 mL) was stirred at rt for 1 h before being concentrated under reduced pressure.
  • Step 3 ((1 R, 2R)-1, 2-Dimethylcyclopropyl)(1 -oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using ((1 R,2R)-1 ,2-dimethylcyclopropyl)(4-methylenepiperidin-1- yl)methanone (722 mg, 3.74 mmol) in DCM (18.7 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (1 .00 g, 4.48 mmol) in DCM (18.7 mL) after 20 h at rt gave the title compound (618 mg, 79%) as a viscous colourless oil.
  • Epoxide 30 2,2-Dicvclopropyl-1-(1-oxa-6-azaspiro[2.51octan-6-yl)ethan-1-one
  • Step 1 2,2-Dicyclopropyl-1-(4-methylenepiperidin-1-yl)ethan-1-one: General procedure 1 using 4-methylenepiperidine hydrochloride (159 mg, 1.19 mmol), 2,2-dicyclopropylacetic acid (167 mg, 1.19 mmol), HATU (452 mg, 1.19 mmol), DIPEA (0.622 mL, 3.57 mmol) and DCM (21 mL) after 19 h gave the title compound (180 mg, 69%) as a colourless oil.
  • Step 2 2,2-Dicyclopropyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)ethan-1-one: General procedure 2 using 2,2-dicyclopropyl-1-(4-methylenepiperidin-1-yl)ethan-1-one (180 mg, 0.821 mmol) in DCM (4.1 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (221 mg, 0.985 mmol) in DCM (4.1 mL) after 20 h at rt gave the title compound (187 mg, 97%) as a colourless oil.
  • Epoxide 31 (1-Methylcvclobutyl)(1-oxa-6-azaspiro[2.51octan-6-yl)methanone
  • Step 1 (1-Methylcyclobutyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (97 mg, 0.726 mmol), 1-methylcyclobutane-1- carboxylic acid (83 mg, 0.726 mmol), HATU (276 mg, 0.726 mmol), DIPEA (0.379 mL, 2.18 mmol) and DCM (7.2 mL) after 1 h gave the title compound (131 mg, 93%) as a colourless oil.
  • Step 2 (1-Methylcyclobutyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone:
  • General procedure 2 using (1-methylcyclobutyl)(4-methylenepiperidin-1-yl)methanone (129 mg, 0.667 mmol) in DCM (3.5 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (179 mg, 0.801 mmol) in DCM (3.5 mL) after 22.5 h at rt gave the title compound (133 mg, 95%) as a pale-yellow oil.
  • Step 1 3-Cyclopropyl-1-(4-methylenepiperidin-1-yl)propan-1-one: General procedure 1 using 4-methylenepiperidine hydrochloride (356 mg, 2.66 mmol), 3-cyclopropylpropanoic acid (304 mg, 2.66 mmol), HATU (1.01 g, 2.66 mmol), DIPEA (1.39 mL, 7.99 mmol) and DCM (20 mL) after 19 h gave the title compound (269 mg, 52%) as a colourless gum.
  • Step 2 3-Cyclopropyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)propan-1-one:
  • General procedure 2 using 3-cyclopropyl-1-(4-methylenepiperidin-1-yl)propan-1-one (269 mg, 1.39 mmol) in DCM (6 mL) at 0 °C and m-CPBA ( ⁇ 77% w/w) (374 mg, 1.67 mmol) in DCM (6 mL) after 20 h at rt gave the title compound (200 mg, 68%) as a colourless oil.
  • Epoxide 33 rac-((1R,2R)-2-(Difluoromethyl)-1-methylcvcloDroDyl)(1-oxa-6- azaspiro[2.51octan-6-yl)methanone
  • Step 1 rac-Ethyl (1R,2R)-2-(dimethoxymethyl)-1-methylcyclopropane-1 -carboxylate: To a solution of ethyl 2-(diethoxyphosphoryl)propanoate (6.67 mL, 31.1 mmol) and 2- (dimethoxymethyl)oxirane (5.00 g, 42.3 mmol) in 1 ,2-dimethoxyethane (60 mL) at -78 °C was added dropwise n-butyllithium (2.4 M in hexane, 13 mL, 0.0311 mol). The reaction mixture was allowed to warm up to the rt and stirred for a further 15 min.
  • n-butyllithium 2.4 M in hexane
  • reaction mixture was transferred to an autoclave pressure-reactor and heated at 145 °C for 18 h. Upon cooling to rt the reaction mixture was quenched with saturated aqueous ammonium chloride (200 mL), and the product was extracted with MTBE (3 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (6.80 g, 108%) as a pale-yellow oil. This material was used for next step without purification.
  • Step 2 rac-Ethyl (1 R,2R)-2-formyl-1-methylcyclopropane-1 -carboxylate: To a solution of crude rac-ethyl (1R,2R)-2-(dimethoxymethyl)-1-methylcyclopropane-1 -carboxylate (6.80 g, 31.1 mmol) in THF (100 mL) and water (32 mL) was added concentrated aqueous hydrochloric acid (8 mL). The resulting mixture was stirred at rt for 2 h before the volatiles were removed under reduced pressure. The residue was diluted with brine (200 mL) and the product was extracted into DCM (3 x 100 mL).
  • Step 3 rac-Ethyl (1R,2R)-2-(difluoromethyl)-1-methylcyclopropane-1 -carboxylate: To a stirred solution of crude rac-ethyl (1R,2R)-2-formyl-1-methylcyclopropane-1 -carboxylate (4.60 g, 29.5 mmol) in DCM (80 mL) at 0 °C was added morpholinosulfur trifluoride (7.65 g,
  • Step 4 rac-(1R,2R)-2-(Difluoromethyl)-1-methylcyclopropane-1 -carboxylic acid: To a stirred solution rac-ethyl (1R,2R)-2-(difluoromethyl)-1-methylcyclopropane-1 -carboxylate (5.14 g,
  • reaction mixture was allowed to warm to rt and stirred for a further 2 h before being added via syringe to a stirred solution of 4-methylenepiperidine hydrochloride (802 mg, 6.00 mmol) in DCM (5 mL) under an atmosphere of nitrogen.
  • the resulting solution was cooled to 0 °C and triethylamine (2.09 mL, 15.0 mmol) was added dropwise.
  • the ice-bath was removed, and the reaction mixture was stirred at rt for 1 h before saturated aqueous sodium hydrogen carbonate (60 mL) was added.
  • Step 6 rac-( (1R, 2R)-2-(Difluoromethyl)- 1 -methylcyclopropyl) ( 1 -oxa-6-azaspiro[2.5]octan-6- yl)methanone:
  • General procedure 2 using crude rac-((1R,2R)-2-(difluoromethyl)-1- methylcyclopropyl)(4-methylenepiperidin-1-yl)methanone (1.25 g, 5.00 mmol) in DCM (25 mL) at rt and m-CPBA ( ⁇ 77% w/w) (1 .46 g, 6.50 mmol) in DCM (25 mL) after 19 h at rt gave the title compound (1.16 g, 94% (2 steps)) as a yellow oil.
  • Example 1 /'ac-6-Chloro-3-((4-hvdroxy-1-(1-methylcvclopropane-1-carbonyl)piperidin-4- yl)methyl)-7-(4-((3R,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolo[2,3- dlpyrimidin-4-one
  • Step 1 rac-(2R,5S)-5-(4-Bromophenyl)-2-methylmorpholine:
  • General procedure 8 using 4- bromobenzaldehyde (1.85 g, 10.0 mmol), 2-((tributylstannyl)methoxy)propan-1 -amine (3.78 g, 10.0 mmol), Cu(OTf)2 (3.62 g, 10 mmol), 2,6-dimethylpyridine (1.07 g, 10.0 mmol), HFIP (40 mL), 4A molecular sieves (ca. 1 g) and DCM (160 mL) gave the title compound (1 g, 39%).
  • Step 3 rac-tert-Butyl (2R,5S)-2-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate: General procedure 3 (Work-up A) using rac-tert-butyl (2R,5S)-5-(4-bromophenyl)-2-methylmorpholine-4-carboxylate (600 mg, 1.68 mmol), B2Pin2 (642 mg, 2.53 mmol), Pd(dppf)Ch ⁇ CH2Cl2 (143 mg, 0.168 mmol), KOAc (496 mg, 5.05 mmol) and 1 ,4-dioxane (17 mL) after stirring at 120 °C (microwave irradiation) for 30 min gave the title compound (648 mg, 95%) as a yellow oil.
  • Step 4 rac-tert-Butyl (2R,5S)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate: General procedure 4 (Work-up A) using 4,6-dichloro-7/-/- pyrrolo[2,3-d]pyrimidine (80 mg, 0.426 mmol), rac-tert-butyl (2R,5S)-2-methyl-5-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (343 mg, 0.851 mmol), copper(ll) acetate (155 mg, 0.851 mmol), 1 ,10-phenanthroline (153 mg, 0.851 mmol), boric acid (105 mg, 1.70 mmol) and DMF (8 mL) after 3 days gave the title
  • Step 5 rac-tert-Butyl ( 2R, 5S)-5-(4-( 6-chloro-4-oxo-3, 4-dihydro-7H-pyrrolo[2, 3-d]pyrimidin- 7- yl)phenyl)-2-methylmorpholine-4-carboxylate: General procedure 5 using rac-tert-butyl (2R,5S)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate (98 mg, 0.212 mmol), aqueous sodium hydroxide (4 M, 1.06 mL, 4.23 mmol) and 1 ,4-dioxane (1.1 mL) after 18 h at 100 °C using AcOH for acidification gave the title compound (95 mg, quant.) as a yellow oil.
  • Step 6 rac-tert-Butyl (2R,5S)-5-(4-(6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1- carbonyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate: General procedure 6 using rac-tert-butyl (2R,5S)-5-(4-(6- chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate (94 mg, 0.211 mmol), Epoxide 1 (42 mg, 0.211 mmol), CS2CO3 (207 mg, 0.634 mmol) and DMF (2 mL) after 18 h at 80 °C gave the title compound (31 mg
  • Step 7 rac-6-Chloro-3-((4-hydroxy- 1-(1 -methylcyclopropane- 1 -carbonyl)piperidin-4- yl)methyl)-7-(4-((3R ! 6S)-6-methylmorpholin-3-yl)phenyl)-3 !
  • Example 2 /'ac-6-Chloro-3-((4-hvdroxy-1-(1-methylcvclopropane-1-carbonyl)piperidin-4- yl)methyl)-7-(4-((3R,5S)-5-methylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolo[2,3- dlpyrimidin-4-one
  • Step 1 rac-(3R,5S)-3-(4-Bromophenyl)-5-methylmorpholine:
  • General procedure 8 using 4- bromobenzaldehyde (2.83 g, 15.3 mmol), 1-((tributylstannyl)methoxy)propan-2-amine (5.78 g, 15.3 mmol), Cu(OTf)2 (5.51 g, 15.3 mmol), 2,6-dimethylpyridine (1 .63 g, 15.3 mmol), HFIP (61 mL), 4A molecular sieves (ca. 1 .5 g) and DCM (243 mL) gave the title compound (737 mg, 19%).
  • Step 2 rac-tert-Butyl (3R,5S)-3-(4-bromophenyl)-5-methylmorpholine-4-carboxylate: General procedure 9 using rac-(3R,5S)-3-(4-Bromophenyl)-5-methylmorpholine (737 mg, 2.88 mmol) and BOC2O (754 mg, 3.45 mmol) gave the title compound (820 mg, 80%).
  • LCMS (method C), RT 1 .50 min, 256, 258 [M-Boc+H] + .
  • Step 3 rac-tert-Butyl (3R,5S)-3-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate: General procedure 3 (Work-up A) using rac-tert-butyl (3R,5S)-3-(4-bromophenyl)-5-methylmorpholine-4-carboxylate (600 mg, 1.68 mmol), B2Pin2 (642 mg, 2.53 mmol), Pd(dppf)Ch ⁇ CH2Cl2 (143 mg, 0.168 mmol), KOAc (496 mg, 5.05 mmol) and 1 ,4-dioxane (17 mL) after stirring at 120 °C (microwave irradiation) for 60 min gave the title compound (588 mg, 86%) as a colourless oil.
  • Step 4 rac-tert-Butyl (3R,5S)-3-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5- methylmorpholine-4-carboxylate: General procedure 4 (Work-up A) using 4,6-dichloro-7/-/- pyrrolo[2,3-d]pyrimidine (548 mg, 2.91 mmol), rac-tert-butyl (3R, 5S)-3-methyl-5-(4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (1.76 mg, 4.37 mmol), copper(ll) trifluoroacetate hydrate (1.69 g, 5.83 mmol), 1 ,10-phenanthroline (1.05 g, 5.83 mmol), boric acid (721 mg, 11 .7 mmol) and DMF (55
  • Step 5 rac-tert-Butyl ( 3R, 5S)-3-(4-( 6-chloro-4-oxo-3, 4-dihydro-7H-pyrrolo[2, 3-d]pyrimidin- 7- yl)phenyl)-5-methylmorpholine-4-carboxylate: General procedure 5 using rac-tert-butyl (3R,5S)-3-(4-(4,6-dichloro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4- carboxylate (145 mg, 0.313 mmol), aqueous sodium hydroxide (2 M, 2.35 mL, 4.69 mmol) and 1 ,4-dioxane (2.5 mL) after 18 h at 100 °C gave the title compound (140 mg, quant.) as a white solid.
  • Step 6 rac-tert-Butyl (3R,5S)-3-(4-(6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1- carbonyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5- methylmorpholine-4-carboxylate: General procedure 6 using rac-tert-butyl (3R,5S)-3-(4-(6- chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4- carboxylate (140 mg, 0.315 mmol), Epoxide 1 (62 mg, 0.315 mmol), CS2CO3 (205 mg, 0.629 mmol) and DMF (2.5 mL) after 18 h at 80 °C gave the title compound
  • Step 7 rac-6-Chloro-3-((4-hydroxy- 1-(1 -methylcyclopropane- 1 -carbonyl)piperidin-4- yl)methyl)-7-(4-((3R ! 5S)-5-methylmorpholin-3-yl)phenyl)-3 !
  • Example 3 6-Chloro-3-((4-hvdroxy-1-(1-methylcvclopropane-1-carbonyl)piperidin-4- yl)methyl)-7-(4-(3-methylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolo[2,3- 4-one
  • Step 1 N-(2-(4-Bromophenyl)-1-hydroxypropan-2-yl)-2-chloroacetamide: To a suspension of 2-amino-2-(4-bromophenyl)propan-1-ol hydrochloride (7.25 g, 27.2 mmol) in DCM was added triethylamine (7.96 ml, 57.1 mmol). The resulted solution was cooled to -30 °C and chloroacetyl chloride (2.16 ml, 27.2 mmol) was added dropwise. The resulting mixture was stirred at rt overnight before being diluted with water. The resulting phases were separated and the organic layer was concentrated under reduced pressure.
  • Step 2 5-(4-Bromophenyl)-5-methylmorpholin-3-one: To a solution of A/-(2-(4-bromophenyl)- 1-hydroxypropan-2-yl)-2-chloroacetamide (5.00 g, 16.3 mmol) in THF (100 mL) at 0 °C was added sodium hydride (55% dispersion in mineral oil, 1.53 g, 35.1 mmol). The resulting mixture was stirred at rt for 18 h before saturated aqueous sodium hydrogen carbonate (70 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • A/-(2-(4-bromophenyl)- 1-hydroxypropan-2-yl)-2-chloroacetamide 5.00 g, 16.3 mmol
  • sodium hydride 55% dispersion in mineral oil, 1.53 g,
  • Step 3 3-(4-Bromophenyl)-3-methylmorpholine: To a solution of 5-(4-bromophenyl)-5- methylmorpholin-3-one (3.35 g, 12.4 mmol) in THF (50 mL) at 0 °C under a nitrogen atmosphere was added borane dimethylsulfide complex (5.88 mL, 62.0 mmol). The resulting mixture was allowed to warm to rt and stirred for a further 16 h. To quench the excess borane MeOH (120 mL) was dropwise added and the resulting mixture was stirred at 70°C for 1 h.
  • Step 4 tert-Butyl 3-(4-bromophenyl)-3-methylmorpholine-4-carboxylate: To a solution of 3- (4-bromophenyl)-3-methylmorpholine (700 mg, 2.73 mmol) in THF (10 mL) was added triethylamine (0.457 mL, 3.28 mmol), BOC2O (0.691 mL, 3.01 mmol) and DMAP (c.a.). The resulted solution was stirred at rt for 16 h before BOC2O (0.457 ml, 3.28 mmol) was added. After the starting material was consumed, trifluoroethanol (0.43 mL) was added to decompose an excess of BOC2O.
  • Step 5 tert-Butyl 3-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate: General procedure 3 (Work-up A) using tert-butyl 3-(4- bromophenyl)-3-methylmorpholine-4-carboxylate (180 mg, 0.505 mmol), B2Pin2 (192 mg, 0.758 mmol), Pd(dppf)Cl2 ⁇ CH 2 Cl2 (43 mg, 0.0505 mmol), KOAc (149 mg, 1.52 mmol) and 1 ,4-dioxane (4 mL) after stirring at 120 °C (microwave irradiation) for 30 min gave the title compound (171 mg, 84%) as a yellow oil.
  • Step 6 tert-Butyl 3-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-3- methylmorpholine-4-carboxylate: General procedure 4 (Work-up A) using 4,6-dichloro-7/-/- pyrrolo[2,3-d]pyrimidine (40 mg, 0.213 mmol), tert-butyl 3-methyl-3-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (171 mg, 0.426 mmol), copper(ll) acetate (77.3 mg, 0.426 mmol), 1 ,10-phenanthroline (76.7 mg, 0.426 mmol), boric acid (78.9 mg, 1 .28 mmol) and DMF (2 mL) after 3 days gave the title compound (32 mg, 32%) as a colourless film.
  • Step 4 tert-Butyl 3-(4-( 6-chloro-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin-7-yl)phenyl)-3- methylmorpholine-4-carboxylate: General procedure 5 using tert-butyl 3-(4-(4,6-dichloro-7H- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-3-methylmorpholine-4-carboxylate (32.0 mg, 0.0691 mmol), aqueous sodium hydroxide (2 M, 0.52 mL, 1.04 mmol) and 1 ,4-dioxane (1 mL) after 18 h at 100 °C gave the title compound (31 mg, quant.) as a white solid.
  • Step 7 tert-Butyl 3-(4-( 6-chloro-3-((4-hydroxy- 1-(1 -methylcyclopropane- 1 -carbonyl)piperidin- 4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-3-methylmorpholine- 4-carboxylate: General procedure 6 using tert-butyl 3-(4-(6-chloro-4-oxo-3,4-dihydro-7/-/- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-3-methylmorpholine-4-carboxylate (31 mg, 0.0697 mmol), Epoxide 1 (13.6 mg, 0.0697 mmol), CS2CO3 (45 mg, 0.139 mmol) and DMF (0.7 mL) after 3 days at 80 °C gave the title compound (25.4 mg, 56%) as a white solid.
  • Step 8 6-Chloro-3-((4-hydroxy- 1-(1 -methylcyclopropane- 1 -carbonyl)piperidin-4-yl)methyl)- 7- (4-(3-methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one: General procedure 7 using tert-butyl 3-(4-(6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1- carbonyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-3- methylmorpholine-4-carboxylate (25 mg, 0.0391 mmol), TFA (0.5 mL) and DCM (1 mL) gave, after freeze-drying, the title compound (11.3 mg, 51 %) as an off-white solid.
  • Step 1 (2S,5R)-5-(4-Bromophenyl)-2-methylmorpholine: General procedure 8 using 4- bromobenzaldehyde (1.85 g, 10.0 mmol), (S)-2-((tributylstannyl)methoxy)propan-1-amine (made according to the procedure outlined in Org. Lett. 2014, 16 (4), 1236-1239 starting from (S)-1-aminopropan-2-ol) (3.78 g, 10.0 mmol), Cu(OTf)2 (3.62 g, 10.0 mmol), 2,6- dimethylpyridine (1 .07 g, 10.0 mmol), HFIP (40 mL), 4A molecular sieves (ca.
  • Step 2 tert-Butyl (2S,5R)-5-(4-bromophenyl)-2-methylmorpholine-4-carboxylate: General procedure 9 using (2S,5R)-5-(4-bromophenyl)-2-methylmorpholine (1.37 g, 5.37 mmol) and BOC2O (1.4 g, 6.42 mmol) gave the title compound (1.7 g, 89%).
  • Step 3 tert-Butyl (2S,5R)-2-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate: General procedure 3 (Work-up A) using tert-butyl (2S,5R)-5-(4-bromophenyl)-2-methylmorpholine-4-carboxylate (2 g, 5.61 mmol), B 2 Pin 2 (2.14 g, 8.42 mmol), Pd(dppf)Ch ⁇ CH2CI2 (475 mg, 0.561 mmol), KOAc (1 .65 g, 16.8 mmol) and 1 ,4-dioxane (55 mL) after stirring at 100 °C (thermal) for 2 h gave the title compound (2.10 g, 92%) as pale yellow oil.
  • Step 4 tert-Butyl (2S,5R)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate: General procedure 4 (Work-up A) using 4,6-dichloro-7/-/- pyrrolo[2,3-d]pyrimidine (652 mg, 3.48 mmol), tert-butyl (2S,5R)-2-methyl-5-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (2.10 g, 5.20 mmol), copper(ll) trifluoroacetate hydrate (2.01 g, 6.94 mmol), 1 ,10-phenanthroline (1.25 g, 6.94 mmol), boric acid (858 mg, 13.9 mmol) and DMF (65 mL) after 24
  • Step 5 tert-Butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)-2-methylmorpholine-4-carboxylate: General procedure 5 using tert-butyl (2S,5R)- 5-(4-(4,6-dichloro-7H-pyrrolo[2,3-o(
  • LCMS (method
  • Step 6 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate: General procedure 6 using tert-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (442 mg, 0.994 mmol), Epoxide 2 (375 mg, 1 .49 mmol), CS2CO3 (971 mg, 2.98 mmol) and DMF (10 mL) after 18 h at 80 °C gave the title compound (498 mg, 72%) as
  • Step 7 6-Chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R, 6SJ-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using tert-butyl (2S,5R)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (498 mg, 0.715 mmol), TFA (5 mL) and DCM (10 mL) gave, after freeze-drying, the title compound (385 mg, 90%) as a white solid.
  • Example 5 6-Chloro-3-((1-(4-chlorobenzoyl)-4-hvdroxypiperidin-4-yl)methyl)-7-(3-methyl-4- ((3R,6S)-6-methylmorDholin-3-yl)Dhenyl)-3,7-dihvdro-4/-/-Dyrrolo[2,3- 4-one
  • Step 1 (2S,5R)-5-(4-Bromo-2-methylphenyl)-2-methylmorpholine:
  • General procedure 8 using 4-bromo-2-methylbenzaldehyde (1.99 g, 10.0 mmol), (S)-2- ((tributylstannyl)methoxy)propan-1 -amine (made according to the procedure outlined in Org. Lett.
  • Step 2 tert-Butyl (2S,5R)-5-(4-bromo-2-methylphenyl)-2-methylmorpholine-4-carboxylate: General procedure 9 using (2S,5R)-5-(4-Bromo-2-methylphenyl)-2-methylmorpholine (1.45 g, 5.37 mmol) and BOC2O (1 .4 g, 6.42 mmol) gave the title compound (1 .77 g, 89%).
  • Step 3 tert-butyl (2S,5R)-2-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate: General procedure 3 (Work-up A) using tert-butyl (2S,5R)-5-(4-bromo-2-methylphenyl)-2-methylmorpholine-4-carboxylate (600 mg, 1.62 mmol), B2Pin2 (617 mg, 2.43 mmol), Pd(dppf)Cl2 ⁇ CH2Cl2 (137 mg, 0.162 mmol), KOAc (477 mg, 4.86 mmol) and 1 ,4-dioxane (17 mL) after stirring at 120 °C (microwave irradiation) for 30 min gave the title compound (432 mg, 63%) as pale yellow oil.
  • LCMS (method B): R T 1.83 min, m/z
  • Step 4 tert-Butyl (2S,5R)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- methylphenyl)-2-methylmorpholine-4-carboxylate: General procedure 4 (Work-up A) using 4,6-dichloro-7H-pyrrolo[2,3-o]pyrimidine (97 mg, 0.516 mmol), tert-butyl (2S,5R)-2-methyl-5- (2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (431 mg, 1.03 mmol), copper(ll) acetate (187 mg, 1.03 mmol), 1 ,10-phenanthroline (186 mg, 1 .03 mmol), boric acid (128 mg, 2.06 mmol) and DMF (10 mL) after 6 days at 50 °C gave the
  • Step 5 tert-Butyl ( 2S, 5R)-5-(4-( 6-chloro-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin- 7-yl)- 2-methylphenyl)-2-methylmorpholine-4-carboxylate: General procedure 5 using tert-butyl (2S,5R)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)-2-methylphenyl)-2- methylmorpholine-4-carboxylate (107 mg, 0.224 mmol), aqueous sodium hydroxide (4 M, 1.12 mL, 4.48 mmol) and 1 ,4-dioxane (1.12 mL) after 18 h at 100 °C using AcOH for acidification gave the title compound (104 mg, >100%.) as a yellow glass.
  • Step 7 6-Chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-methyl-4- ( ( 3R, 6S)-6-methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one:
  • General procedure 7 using tert-butyl (2S,5R)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)-2- methylphenyl)-2-methylmorpholine-4-carboxylate (33 mg, 0.0464 mmol), TFA (1 mL) and DCM (2 mL) gave, after freeze-drying, the title compound (26 mg, 91 %)
  • Step 1 4-(tert-Butyl) 3-(4,5,6, 7-tetrachloro-1,3-dioxoisoindolin-2-yl) (2S,3R)-2- methylmorpholine-3,4-dicarboxylate: General procedure 11 using (2S,3R)-4-(tert- butoxycarbonyl)-2-methylmorpholine-3-carboxylic acid (1.11 g, 4.54 mmol), 4, 5,6,7- tetrachloro-2-hydroxyisoindoline-1 , 3-dione (1.37 g, 4.54 mmol), EDC (1.04 g, 5.45 mmol) and DMAP (55 mg, 0.454 mmol) gave the title compound (1.10 g, 46%) as a yellow solid.
  • Step 2 tert-Butyl (2S,3S)-3-(4-bromophenyl)-2-methylmorpholine-4-carboxylate: To 4-(tert- butyl) 3-(4,5,6,7-tetrachloro-1 ,3-dioxoisoindolin-2-yl) (2S,3R)-2-methylmorpholine-3,4- dicarboxylate (363 mg, 0.687 mmol), (4-bromophenyl)boronic acid (414 mg, 2.06 mmol) in a 100 mL RBF under nitrogen was added 1 ,4-dioxane (26 mL).
  • Step 3 tert-Butyl (2S,3S)-2-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate: General procedure 3 (Work-up A) using tert-butyl (2S,3S)-3-(4-bromophenyl)-2-methylmorpholine-4-carboxylate (243 mg, 0.682 mmol), B2Pin2 (346 mg, 1.36 mmol), Pd(dppf)CI 2 ⁇ CH 2 CI 2 (58 mg, 0.0682 mmol), KOAc (201 mg, 2.046 mmol) and 1 ,4-dioxane (7 mL) after stirring at 120 °C (microwave irradiation) for 30 min gave the title compound (133 mg, 48%) as a colourless glass.
  • Step 4 tert-Butyl (2S,3S)-3-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate: General procedure 4 (Work-up A) using 4,6-dichloro-7/-/- pyrrolo[2,3-d]pyrimidine (62 mg, 0.330 mmol), tert-butyl (2S,3S)-2-methyl-3-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (133 mg, 0.330 mmol), copper(ll) acetate (120 mg, 0.660 mmol), 1 ,10-phenanthroline (119 mg, 0.660 mmol), boric acid (82 mg, 1.32 mmol) and DMF (6.2 mL) after 5 days at 50 °C gave the title compound (
  • Step 5 tert-Butyl (2S,3S)-3-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)-2-methylmorpholine-4-carboxylate: General procedure 5 using tert-butyl (2S,3S)- 3-(4-(4,6-dichloro-7H-pyrrolo[2,3-o(
  • Step 7 6-Chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((2S,3S)-2- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (2S,3S)-3-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (14 mg, 0.0201 mmol), TFA (1 mL) and DCM (2 mL) gave, after freeze-drying, the title compound (11 mg, 91%) as a white solid.
  • Example 7 6-Chloro-3-((4-hvdroxy-1-((R)-4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4- yl)methyl)-7-(4-((3R,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolo[2,3- dlDyrimidin-4-one
  • Step 1 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((4-hydroxy-1-((R)-4,4,4-trifluoro-3- phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin- 7- yl)phenyl)-2-methylmorpholine-4-carboxylate: General procedure 6 using tert-butyl (2S,5R
  • Step 2 6-Chloro-3-((4-hydroxy- 1-((R)-4, 4, 4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)- 7-(4-( ( 3R, 6S)-6-methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one:
  • General procedure 7 using tert-butyl (2S,5R)-5-(4-(6-chloro-3-((4-hydroxy-1-((R)-4,4,4- trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3- o(
  • Step 1 4-(tert-Butyl) 3-(4,5,6, 7-tetrachloro-1,3-dioxoisoindolin-2-yl) (2R,3S)-2- methylmorpholine-3,4-dicarboxylate: General procedure 11 using (2R,3S)-4-(tert- butoxycarbonyl)-2-methylmorpholine-3-carboxylic acid (581 mg, 2.37 mmol), 4, 5,6,7- tetrachloro-2-hydroxyisoindoline-1 , 3-dione (713 mg, 2.37 mmol), EDC (546 mg, 2.84 mmol) and DMAP (29 mg, 0.237 mmol) gave the title compound (513 mg, 41%) as a yellow solid.
  • Step 2 tert-Butyl (2R,3R)-3-(4-bromophenyl)-2-methylmorpholine-4-carboxylate: To 4-(tert- butyl) 3-(4,5,6,7-tetrachloro-1 ,3-dioxoisoindolin-2-yl) (2R,3S)-2-methylmorpholine-3,4- dicarboxylate (513 mg, 0.971 mmol), (4-bromophenyl)boronic acid (585 mg, 2.91 mmol) in a 100 mL RBF under nitrogen was added 1 ,4-dioxane (37 mL).
  • the reaction mixture was heated to 75 °C (internal temperature) before triethylamine (1.35 mL, 9.71 mmol) and NiCh ⁇ 6H2O : bathophenanthroline complex in DMF (0.05 M, 3.7 mL, 0.185 mmol, (Angew. Chem. Int. Ed. 2016, 55, 9676-9679)) were sequentially added.
  • the resulting mixture was stirred at 75 °C overnight.
  • EtOAc 40 mL
  • washed with brine The organic layer was dried over MgSC , filtered and concentrated under reduced pressure.
  • Step 3 tert-Butyl (2R,3R)-2-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate: General procedure 3 (Work-up A) using tert-butyl (2R,3R)-3-(4-bromophenyl)-2-methylmorpholine-4-carboxylate (118 mg, 0.331 mmol), B2Pin2 (168 mg, 0.663 mmol), Pd(dppf)CI 2 ⁇ CH 2 CI 2 (28.1 mg, 0.0331 mmol), KOAc (97.5 mg, 0.994 mmol) and 1 ,4-dioxane (4 mL) after stirring at 120 °C (microwave irradiation) for 1 h gave the title compound (65 mg, 48%) as a white solid.
  • Step 4 tert-Butyl (2R,3R)-3-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate: General procedure 4 (Work-up A) using 4,6-dichloro-7/-/- pyrrolo[2,3-d]pyrimidine (30 mg, 0.160 mmol), tert-butyl (2R,3R)-2-methyl-3-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (64.4 mg, 0.160 mmol), copper(ll) acetate (58 mg, 0.319 mmol), 1 ,10-phenanthroline (57.5 mg, 0.319 mmol), boric acid (39.5 mg, 0.638 mmol) and DMF (3 mL) after 6 days at 50 °C gave the title compound
  • Step 5 tert-Butyl (2R,3R)-3-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)-2-methylmorpholine-4-carboxylate: General procedure 5 using tert-butyl (2R,3R)- 3-(4-(4,6-dichloro-7H-pyrrolo[2,3-o(
  • Step 6 tert-Butyl (2R,3R)-3-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate: General procedure 6 using tert-butyl (2R,3R)-3-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (24 mg, 0.0539 mmol), Epoxide 2 (20.4 mg, 0.0809 mmol), CS2CO3 (52.7 mg, 0.162 mmol) and DMF (2 mL) after 18 h at 80 °C gave the title compound (12 mg, 31
  • Step 7 6-Chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((2R,3R)-2- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using tert-butyl (2R,3R)-3-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (12 mg, 0.0172 mmol), TFA (1 mL) and DCM (2 mL) gave, after freeze-drying, the title compound (10 mg, 97%) as an off-white solid.
  • Example 9 rac-6-Chloro-3-((1-(4-chlorobenzoyl)-4-hvdroxypiperidin-4-yl)methyl)-7-(4- ((3R,6R)-6-(trifluoromethyl)morpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolo[2,3-at]pyrimidin-4-
  • Step 1 rac-(2R,5R)-5-(4-Bromophenyl)-2-(trifluoromethyl)morpholine:
  • General procedure 8 using 4-bromobenzaldehyde (5.55 g, 30.0 mmol), 3,3,3-trifluoro-2- ((tributylstannyl)methoxy)propan-1 -amine (made according to the procedure outlined in Org. Lett.
  • Step 2 rac-tert-Butyl (2R,5R)-5-(4-bromophenyl)-2-(trifluoromethyl)morpholine-4- carboxylate: General procedure 10 using rac-(2R,5R)-5-(4-bromophenyl)-2- (trifluoromethyl)morpholine (1 g, 3.9 mmol) and BOC2O (10.9 g, 50 mmol) gave the title compound (150 mg, 1% (2 steps)).
  • LCMS (method C): RT 1.63 min, mass ion not observed. This material was used without further purification.
  • Step 3 rac-tert-Butyl (2R,5R)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2- (trifluoromethyl)morpholine-4-carboxylate: General procedure 3 (Work-up A) using rac-tert- butyl (2R,5R)-5-(4-bromophenyl)-2-(trifluoromethyl)morpholine-4-carboxylate (150 mg, 0.366 mmol), B2Pin2 (139 mg, 0.549 mmol), Pd(dppf)Ch ⁇ CH2Cl2(31 mg, 0.0366 mmol), KOAc (108 mg, 1.10 mmol) and 1 ,4-dioxane (4 mL) after stirring at 120 °C (microwave irradiation) for 1 h gave the title compound (135 mg, 80%) as a colourless glass.
  • LCMS Method B
  • Step 4 rac-tert-Butyl ( 2R, 5R)-5-(4-(4, 6-dichloro- 7H-pyrrolo[2, 3-d]pyrimidin- 7-yl)phenyl)-2- (trifluoromethyl)morpholine-4-carboxylate: General procedure 4 (Work-up A) using 4,6- dichloro-7H-pyrrolo[2,3-o]pyrimidine (55 mg, 0.293 mmol), rac-tert-butyl (2R,5R)-5-(4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-2-(trifluoromethyl)morpholine-4- carboxylate (134 mg, 0.293 mmol), copper(ll) acetate (106 mg, 0.585 mmol), 1 ,10- phenanthroline (105 mg, 0.585 mmol), boric acid (72 mg, 1.17 mmol) and DMF (5.5 m
  • Step 5 rac-tert-Butyl (2R,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)-2-(trifluoromethyl)morpholine-4-carboxylate: General procedure 5 using rac-tert- butyl (2R,5R)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-2- (trifluoromethyl)morpholine-4-carboxylate (17 mg, 0.0329 mmol), aqueous sodium hydroxide (4 M, 0.25 mL, 1.00 mmol) and 1 ,4-dioxane (0.25 mL) after 18 h at 100 °C using AcOH for acidification gave the title compound (17 mg, >100%.) as a yellow glass.
  • Step 6 rac-tert-Butyl (2R,5R)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- (trifluoromethyl)morpholine-4-carboxylate: General procedure 6 using rac-tert-Butyl (2R,5R)- 5-(4-(6-chloro-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- (trifluoromethyl)morpholine-4-carboxylate (17 mg, 0.0341 mmol), Epoxide 2 (12.9 mg, 0.0511 mmol), CS2CO3 (33.3 mg, 0.102 mmol) and DMF (1 mL) after 18 h
  • Step 7 rac-6-Chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6R)-
  • Example 10 6-Chloro-7-(4-((S)-6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hvdroxy-1-((R)- 4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-3,7-dihvdro-4/-/-pyrrolo[2,3-d]pyrimidin- 4-one and 6-chloro-7-(4-((R)-6,6-dimethylmorDholin-3-yl)ohenyl)-3-((4-hvdroxy-1-((R)-4,4,4- trifluoro-3-Dhenylbutanoyl)DiDeridin-4-yl)methyl)-3,7-dihvdro-4/-/-Dyrrolo[2,3-c/lDyrimidin-4-one (I L)
  • Step 1 5-(4-Bromophenyl)-2,2-dimethylmorpholine:
  • General procedure 8 using 4- bromobenzaldehyde (1.85 g, 10.0 mmol), 2-methyl-2-((tributylstannyl)methoxy)propan-1- amine (made according to the procedure outlined in Org. Lett. 2014, 16 (4), 1236-1239 starting from 1-amino-2-methylpropan-2-ol) (3.92 g, 10.0 mmol), Cu(OTf)2 (3.62 g, 10.0 mmol), 2,6-dimethylpyridine (1 .07 g, 10.0 mmol),HFIP (40 mL), 4A molecular sieves (ca.
  • Step 2 tert-Butyl 5-(4-bromophenyl)-2,2-dimethylmorpholine-4-carboxylate: General procedure 9 using 5-(4-bromophenyl)-2,2-dimethylmorpholine (1.74 g, 6.44 mmol) and BOC2O (1.69 g, 7.73 mmol) gave the title compound (2.10 g, 88%).
  • Step 3 tert-Butyl 2,2-dimethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate: General procedure 3 (Work-up A) using 5-(4- bromophenyl)-2,2-dimethylmorpholine (1.40 g, 3.78 mmol), B2Pin2 (1.44 mg, 5.67 mmol), Pd(dppf)Cl2 ⁇ CH2CI2 (320 mg, 0.378 mmol), KOAc (1.11 g, 11 .3 mmol) and 1 ,4-dioxane (36 mL) after stirring at 100 °C (thermal) for 2 h gave the title compound (1.52 g, 96%) as a colourless glass.
  • Step 4 tert-Butyl 5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2- dimethylmorpholine-4-carboxylate: General procedure 4 (Work-up A) using 4,6-dichloro-7/-/- pyrrolo[2,3-d]pyrimidine (457 mg, 2.43 mmol), tert-butyl 2,2-dimethyl-5-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (1.52 g, 3.65 mmol), copper(ll) trifluoroacetate hydrate (1.41 mg, 4.86 mmol), 1 ,10-phenanthroline (876 mg, 4.86 mmol), boric acid (601 mg, 9.72 mmol) and DMF (46 mL) after 4 days at 50 °C gave the title compound (772 mg
  • Step 5 tert-Butyl 5-(4-( 6-chloro-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin-7-yl)phenyl)- 2,2-dimethylmorpholine-4-carboxylate: General procedure 5 using tert-butyl 5-(4-(4,6- dichloro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (97 mg, 0.203 mmol), aqueous sodium hydroxide (4 M, 1 .52 mL, 6.09 mmol) and 1 ,4-dioxane (1.6 mL) after 18 h at 100 °C using AcOH for acidification gave the title compound (94 mg, quant.) as a yellow glass.
  • Step 6 tert-Butyl (S)-5-(4-(6-chloro-3-((4-hydroxy-1-((R)-4,4,4-trifluoro-3- phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin- 7- yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate and tert-butyl (R)-5-(4-(6-chloro-3-((4- hydroxy- 1-((R)-4,4, 4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3, 4-dihydro-7H- pyrrolo[2, 3-d]pyrimidin- 7-yl)phenyl)-2, 2-dimethylmorpholine-4-carboxylate (1:1): General procedure 6 using tert-butyl 5-(
  • Step 7 6-Chloro-7-(4-((S)-6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((R)-4,4,4- trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one and 6-chloro-7-(4-((R)-6, 6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy- 1 -((R)-4, 4, 4- trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (1:1): General procedure 7 using tert-butyl (S)-5-(4-(6-chloro-3-((4-hydroxy-1-((R)-4,4,4- trifluoro
  • Step 1 (2R,5S)-5-(4-Bromophenyl)-2-methylmorpholine: General procedure 8 using 4- bromobenzaldehyde (1.85 g, 10.0 mmol), (R)-2-((tributylstannyl)methoxy)propan-1-amine (made according to the procedure outlined in Org. Lett. 2014, 16 (4), 1236-1239 starting from (R)-1-aminopropan-2-ol) (3.78 g, 10.0 mmol), Cu(OTf)2 (3.62 g, 10.0 mmol), 2,6- dimethylpyridine (1 .07 g, 10.0 mmol), HFIP (40 mL), 4A molecular sieves (ca. 1 g) and DCM (160 mL) gave the title compound (1.10 g, 43%).
  • Step 2 tert-Butyl (2R,5S)-5-(4-bromophenyl)-2-methylmorpholine-4-carboxylate: General procedure 9 using (2R,5S)-5-(4-bromophenyl)-2-methylmorpholine (1.10 g, 4.30 mmol) and BOC2O (1.12 g, 5.15 mmol) gave the title compound (1.4 g, 91%).
  • Step 3 tert-Butyl (2R,5S)-2-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate: General procedure 3 (Work-up A) using tert-butyl (2R,5S)-5-(4-bromophenyl)-2-methylmorpholine-4-carboxylate (600 mg, 1.68 mmol), B2Pin2 (642 mg, 2.53 mmol), Pd(dppf)Ch ⁇ CH2Cl2 (143 mg, 0.168 mmol), KOAc (496 mg, 5.05 mmol) and 1 ,4-dioxane (16.8 mL) after stirring at 120 °C (thermal) for 1 h gave the title compound (541 mg, 79%) as a colourless glass.
  • Step 4 tert-Butyl (2R,5S)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate: General procedure 4 (Work-up A) using 4,6-dichloro-7/-/- pyrrolo[2,3-d]pyrimidine (127 mg, 0.676 mmol), tert-butyl (2R, 5S)-2-methyl-5-(4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (545 mg, 1.35 mmol), copper(ll) acetate (245 mg, 1.35 mmol), 1 ,10-phenanthroline (243 mg, 1.35 mmol), boric acid (167 mg, 2.70 mmol) and DMF (6.8 mL) after 4 days at 50 °C gave the
  • Step 5 tert-Butyl (2R,5S)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)-2-methylmorpholine-4-carboxylate: A solution of tert-butyl (2R,5S)-5-(4-(4,6- dichloro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (100 mg, 0.216 mmol) and aqueous sodium hydroxide (2 M, 1.62 mL, 3.24 mmol) in 1 ,4-dioxane (2 mL) was heated at 100 °C for 18 h.
  • Step 6 tert-Butyl (2R,5S)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate: General procedure 6 using tert-butyl (2R,5S)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (40 mg, 0.0899 mmol), Epoxide 2 (27.1 mg, 0.108 mmol), CS2CO3 (64.4 mg, 0.198 mmol) and DMF (1 mL) after 18 h at 80 °C gave the title compound (20 mg, 31%) as
  • Step 7 6-Chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3S, 6R)-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one:
  • General procedure 7 using tert-butyl (2R,5S)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (20 mg, 0.0287 mmol), TFA (0.35 mL) and DCM (0.7 mL) gave, after freeze-drying, the title compound (8.5 mg, 47%) as a white solid
  • Step 1 (2R,5S)-5-(4-Bromo-2-methylphenyl)-2-methylmorpholine:
  • General procedure 8 using 4-bromo-2-methylbenzaldehyde (1.99 g, 10.0 mmol), (R)-2- ((tributylstannyl)methoxy)propan-1 -amine (made according to the procedure outlined in Org. Lett.
  • Step 2 tert-Butyl (2R,5S)-5-(4-bromo-2-methylphenyl)-2-methylmorpholine-4-carboxylate: General procedure 9 using (2R,5S)-5-(4-Bromo-2-methylphenyl)-2-methylmorpholine (1.73 g, 6.60 mmol) and BOC2O (1 .4 g, 7.92 mmol) gave the title compound (2.25 g, 92%).
  • Step 3 tert-butyl (2R,5S)-2-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate: General procedure 3 (Work-up B) using tert-butyl (2R,5S)-5-(4-bromo-2-methylphenyl)-2-methylmorpholine-4-carboxylate (1.57 g, 4.24 mmol), B 2 Pin 2 (1 .62 g, 6.36 mmol), Pd(dppf)CI 2 ⁇ CH2CI2 (359 mg, 0.424 mmol), KOAc (1 .25 g, 12.7 mmol) and 1 ,4-dioxane (42.4 mL) after stirring at 100 °C (thermal) for 65 min gave the title compound (1.92 g, >100%) as a yellow oil.
  • Step 4 tert-Butyl (2R,5S)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2- methylphenyl)-2-methylmorpholine-4-carboxylate: General procedure 4 (Work-up B) using 4,6-dichloro-7H-pyrrolo[2,3-o]pyrimidine (620 mg, 3.30 mmol), tert-butyl (2R,5S)-2-methyl-5- (2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (1.79 g, 4.29 mmol), copper(ll) trifluoroacetate hydrate (1.91 g, 6.60 mmol), 1 ,10- phenanthroline (1.19 g, 6.60 mmol), boric acid (530 mg, 8.57 mmol) and DMF (33 mL)
  • Step 5 tert-Butyl ( 2R, 5S)-5-(4-( 6-chloro-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin- 7-yl)- 2-methylphenyl)-2-methylmorpholine-4-carboxylate: General procedure 5 using tert-butyl (2R,5S)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)-2-methylphenyl)-2- methylmorpholine-4-carboxylate (968 mg, 2.03 mmol), aqueous sodium hydroxide (4 M, 5.07 mL, 20.3 mmol) and 1 ,4-dioxane (10.1 mL) after 47 h at 100 °C using 2 M aqueous hydrochloric acid for acidification gave the title compound (1.07 g, >100%) as a brown foam.
  • Step 6 tert-Butyl (2R,5S)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylphenyl)-2- methylmorpholine-4-carboxylate: General procedure 6 using tert-butyl (2R,5S)-5-(4-(6- chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)-2-methylphenyl)-2- methylmorpholine-4-carboxylate (150 mg, 0.327 mmol), Epoxide 2 (123 mg, 0.490 mmol), CS2CO3 (213 mg, 0.654 mmol) and DMF (3.3 mL) after 18 h at 80 °C gave the title
  • Step 7 6-Chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-methyl-4- ( ( 3S, 6R)-6-methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one:
  • General procedure 7 using tert-butyl (2R,5S)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)-2- methylphenyl)-2-methylmorpholine-4-carboxylate (119 mg, 0.168 mmol), TFA (2 mL) and DCM (4 mL) gave, after purification by flash chromatography and freeze-drying, the title compound (
  • Example 13 6-Chloro-3-((4-hvdroxy-1-((R)-4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4- yl)methyl)-7-(4-((3S,6R)-6-methylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolo[2,3- dlpyrimidin-4-one
  • Step 1 tert-Butyl (2R,5S)-5-(4-(6-chloro-3-((4-hydroxy-1-((R)-4,4,4-trifluoro-3- phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin- 7- yl)phenyl)-2-methylmorpholine-4-carboxylate: General procedure 6 using tert-butyl (2R,5S)- 5-(4-(6-chloro-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (40 mg, 0.0899 mmol), Epoxide 3 (33.8 mg, 0.108 mmol), CS2CO3 (64.4 mg, 0.198 mmol) and DMF (1 mL) after 18 h at
  • Step 2 6-Chloro-3-((4-hydroxy- 1-((R)-4, 4, 4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)- 7-(4-( ( 3S, 6R)-6-methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using tert-butyl (2R,5S)-5-(4-(6-chloro-3-((4-hydroxy-1-((R)-4,4,4- trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3- o(
  • Example 14 6-Chloro-3-((4-hvdroxy-1-((R)-4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4- yl)methyl)-7-(3-methyl-4-((3S,6R)-6-methylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/- pyrrolo[2,3- 4-one
  • Step 1 tert-Butyl (2R,5S)-5-(4-(6-chloro-3-((4-hydroxy-1-((R)-4,4,4-trifluoro-3- phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin- 7-yl)-2- methylphenyl)-2-methylmorpholine-4-carboxylate: A suspension of tert-butyl (2R,5S)-5-(4-(6- chloro-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylphenyl)-2- methylmorpholine-4-carboxylate (40 mg, 0.0872 mmol), Epoxide 3 (34 mg, 0.109 mmol) and DIPEA (76 pL, 0.436 mmol) in DMF (0.87
  • Step 2 6-Chloro-3-((4-hydroxy- 1-((R)-4, 4, 4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)- 7-(3-methyl-4-((3S,6R)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3- d]pyrimidin-4-one: General procedure 7 using tert-butyl (2R,5S)-5-(4-(6-chloro-3-((4-hydroxy- 1-((R)-4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/- pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylphenyl)-2-methylmorpholine-4-carboxylate (38.6 mg, 0.0500 mmol) TFA (0.25 mL
  • Example 15 6-Chloro-7-(4-(5,5-dimethylmorpholin-3-yl)phenyl)-3-((4-hvdroxy-1-(1- methylcvclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihvdro-4/-/-pyrrolo[2,3- dlpyrimidin-4-one
  • Step 1 5-(4-Bromophenyl)-3,3-dimethylmorpholine: General procedure 8 using 4- bromobenzaldehyde (1.85 g, 10.0 mmol), 2-methyl-1-((tributylstannyl)methoxy)propan-2- amine (Helv. Chim. Acta 2020, 103, e2000179) (3.92 g, 10.0 mmol), Cu(OTf) 2 (3.62 g, 10.0 mmol), 2,6-dimethylpyridine (1 .07 g, 10.0 mmol), HFIP (40 mL), 4A molecular sieves (ca. 1 g) and DCM (160 mL) gave the title compound (360 mg, 13%).
  • Step 2 tert-Butyl 5-(4-bromophenyl)-3,3-dimethylmorpholine-4-carboxylate: General procedure 10 using 5-(4-bromophenyl)-3,3-dimethylmorpholine (360 mg, 1.33 mmol) and Boc 2 O (580 mg, 2.66 mmol) gave the title compound (310 mg, 63%).
  • Step 3 tert-Butyl 3,3-dimethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate: General procedure 3 (Work-up B) using tert-butyl 5-(4- bromophenyl)-3,3-dimethylmorpholine-4-carboxylate (310 mg, 0.8372mmol), B 2 Pin 2 (319 mg, 1.26 mmol), Pd(dppf)CI 2 ⁇ CH 2 CI 2 (70.9 mg, 0.0837 mmol), KOAc (247 mg, 2.51 mmol) and 1 ,4-dioxane (8.4 mL) after stirring at 100 °C (thermal) for 2 h 10 min gave the title compound (390 mg, >100%) as a slightly yellow oil.
  • Step 4 tert-Butyl 5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-3,3- dimethylmorpholine-4-carboxylate: General procedure 4 (Work-up B) using 4,6-dichloro-7/-/- pyrrolo[2,3-d]pyrimidine (130 mg, 0.692 mmol), tert-butyl 3,3-dimethyl-5-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (346 mg, 0.830 mmol), copper(ll) trifluoroacetate hydrate (290 mg, 1.38 mmol), 1 ,10-phenanthroline (249 mg, 1.38 mmol), boric acid (103 mg, 1.66 mmol) and DMF (7 mL) after 4 days at 50 °C gave the title compound (181 mg
  • Step 5 tert-Butyl 5-(4-( 6-chloro-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin-7-yl)phenyl)- 3,3-dimethylmorpholine-4-carboxylate: General procedure 5 using tert-butyl 5-(4-(4,6- dichloro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-3,3-dimethylmorpholine-4-carboxylate (179 mg, 0.375 mmol), aqueous sodium hydroxide (4 M, 937 pL, 3.75 mmol) and 1 ,4-dioxane (1.9 mL) after 18 h 30 min at 100 °C using 2 M aqueous hydrochloric acid for acidification gave the title compound (171.3mg, 99.5%) as yellow solid.
  • Step 6 tert-Butyl 5-(4-( 6-chloro-3-((4-hydroxy- 1-(1 -methylcyclopropane- 1 -carbonyl)piperidin- 4-yl)methyl)-4-oxo-3 ! 4-dihydro-7H-pyrrolo[2 !
  • Example 16 6-Chloro-3-((1-(4-chlorobenzoyl)-4-hvdroxypiperidin-4-yl)methyl)-7-(4-(5,5- dimethylmorDholin-3-yl)Dhenyl)-3,7-dihvdro-4/-/-Dyrrolo[2,3-dlDyrimidin-4-one
  • Step 1 tert-Butyl 5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4- oxo-3, 4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-3,3-dimethylmorpholine-4- carboxylate: General procedure 6 using tert-butyl 5-(4-(6-chloro-4-oxo-3,4-dihydro-7/-/- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-3,3-dimethylmorpholine-4-carboxylate (10 mg, 0.0218 mmol), Epoxide 2 (8.2 mg, 0.0327 mmol), CS2CO3 (14.2 mg, 0.0436 mmol) and DMF (0.44 mL) after 19 h at 80 °C gave the title compound (8.1 mg, 52%) as yellow glass.
  • Step 2 6-Chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-(5,5- dimethylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one: A solution of tert-butyl 5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4- dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-3,3-dimethylmorpholine-4-carboxylate (8.1 mg, 0.0114 mmol) in TFA (0.2 mL) and DCM (0.4 mL) was stirred for 30 min before the reaction mixture was concentrated under reduced pressure.
  • Example 17 /'ac-3-((1-(4-Chlorobenzoyl)-4-hvdroxypiperidin-4-yl)methyl)-7-(4-((3R,6S)-6- m
  • Step 1 rac-tert-Butyl (2R,5S)-5-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate: General procedure 4 (Work-up A) using 4-chloro-7/-/- pyrrolo[2,3-d]pyrimidine (41 mg, 0.267 mmol), rac-tert-butyl (2R,5S)-2-methyl-5-(4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (215 mg, 0.534 mmol), copper(ll) acetate (97 mg, 0.534 mmol), 1 ,10-phenanthroline (96 mg, 0.534 mmol), boric acid (66 mg, 1.07 mmol) and DMF (23 mL) after 5 days at 50 °C gave the
  • Step 2 rac-tert-Butyl (2R,5S)-2-methyl-5-(4-(4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)morpholine-4-carboxylate: A solution of rac-tert-butyl (2R,5S)-5-(4-(4-ch loro-7 H- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (95 mg, 0.222 mmol) and aqueous sodium hydroxide (2 M, 1.66 mL, 3.32 mmol) in 1 ,4-dioxane (2.5 mL) was heated at 100 °C for 18 h.
  • Step 3 rac-tert-Butyl (2R,5S)-5-(4-(3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)- 4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate: General procedure 6 using rac-tert-butyl (2R,5S)-2-methyl-5-(4-(4-oxo-3,4-dihydro-7/-/- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)morpholine-4-carboxylate (90 mg, 0.219 mmol), Epoxide 2 (66 mg, 0.263 mmol), CS2CO3 (157 mg, 0.482 mmol) and DMF (1 .5 mL) after 18 h at 80 °C, after purification by prep-HPLC, gave the
  • Step 4 rac-3-((1-(4-Chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R, 6S)-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using rac-tert-butyl (2R,5S)-5-(4-(3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-o(
  • Step 1 5-(4-Bromophenyl)-4-(4-methoxybenzyl)morpholin-3-one: A solution of 5-(4- bromophenyl)morpholin-3-one (3.30 g, 12.9 mmol) in DMF (129 mL) was cooled down to 0 °C before sodium hydride (60% in mineral oil) (670 mg, 27.9 mmol) was added. The reaction mixture was allowed to warm to rt and stirred for 1 h before 1-(chloromethyl)-4- methoxybenzene (2.22 g, 14.2 mmol) was added slowly. After stirring at rt for 12 h the reaction mixture was diluted with EtOAc before being washed with water and brine.
  • Step 2 5-(4-Bromophenyl)-4-(4-methoxybenzyl)-7-oxa-4-azaspiro[2.5]octane: A solution of ethylmagnesium bromide (3.4 M in THF) (9.15 mL, 31.1 mmol) was added to a solution of titanium(IV) isopropoxide (3.24 g, 11 .4 mmol) in anhydrous THF (55 mL) at -60 °C.
  • Step 4 tert-Butyl 5-(4-bromophenyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate: A solution of 5-(4-bromophenyl)-7-oxa-4-azaspiro[2.5]octane (0.3 g, 1.10 mmol) and BOC2O (0.48 g, 2.2 mmol) in MeCN (2 mL) was stirred at 70 °C overnight. Upon cooling to rt the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography to give the title compound (368 mg, 91 %).
  • Step 5 tert-Butyl 5-(4-(4,4 ! 5 ! 5-tetramethyl-1 ! 3,2-dioxaborolan-2-yl)phenyl)-7-oxa-4- azaspiro[2.5]octane-4-carboxylate: General procedure 3 (Work-up A) using tert-butyl 5-(4-
  • Step 6 tert-Butyl 5-(4-(4.6-dichloro-7H-pyrrolo[2.3-d]pyrimidin-7-yl)phenyl)-7-oxa-4- azaspiro[2.5]octane-4-carboxylate: General procedure 4 (Work-up A) using 4,6-dichloro-7/-/- pyrrolo[2,3-d]pyrimidine (113 mg, 0.601 mmol), ferf-butyl 5-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate (374 mg, 0.902 mmol), copper(ll) trifluoroacetate hydrate (348 mg, 1.20 mmol), 1 ,10-phenanthroline (217 mg, 1.20 mmol), boric acid (149 mg, 2.40 mmol) and DMF (11 .
  • Step 7 tert-Butyl 5-(4-( 6-chloro-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin-7-yl)phenyl)-7- oxa-4-azaspiro[2.5]octane-4-carboxylate: General procedure 5 using ferf-butyl 5-(4-(4,6- dichloro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate (62 mg, 0.130 mmol), aqueous sodium hydroxide (4 M, 0.98 mL, 3.91 mmol) and 1 ,4- dioxane (1 mL) after 18 h at 100 °C using 1 M aqueous potassium bisulfate for acidification gave the title compound (60 mg, quant.) as a yellow glass.
  • Step 8 tert-Butyl 5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4- oxo-3, 4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-7-oxa-4-azaspiro[2.5]octane-4- carboxylate: General procedure 6 using ferf-butyl 5-(4-(6-chloro-4-oxo-3,4-dihydro-7/-/- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate (30 mg, 0.0657 mmol), Epoxide 2 (24.8 mg, 0.0985 mmol), CS2CO3 (64.2 mg, 0.197 mmol) and DMF (1.3 mL) after 18 h at 80 °
  • Step 9 7-(4-(7-Oxa-4-azaspiro[2.5]octan-5-yl)phenyl)-6-chloro-3-((1-(4-chlorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one:
  • General procedure 7 using ferf-butyl 5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(
  • Example 19 7-(4-(7-Oxa-4-azaspirof2.51octan-5-yl)phenyl)-6-chloro-3-((4-hvdroxy-1-(1- methylcvclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihvdro-4/-/-pyrrolo[2,3- dlpyrimidin-4-one
  • Step 1 tert-Butyl 5-(4-( 6-chloro-3-((4-hydroxy- 1-(1 -methylcyclopropane- 1 -carbonyl)piperidin- 4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-7-oxa-4- azaspiro[2.5]octane-4-carboxylate: General procedure 6 using tert-butyl 5-(4-(6-chloro-4- oxo-3, 4-dihydro-7/-/-pyrrolo[2, 3-d]pyrimidin-7-yl)phenyl)-7-oxa-4-azaspiro[2.5]octane-4- carboxylate (30 mg, 0.0657 mmol), Epoxide 1 (19.23 mg, 0.0985 mmol), CS2CO3 (64.2 mg, 0.197 mmol) and DMF (1.3 mL) after
  • Step 2 7-(4-(7-Oxa-4-azaspiro[2.5]octan-5-yl)phenyl)-6-chloro-3-((4-hydroxy-1-( 1- methylcyclopropane- 1 -carbonyl)piperidin-4-yl)methyl)-3, 7-dihydro-4H-pyrrolo[2, 3- d]pyrimidin-4-one: General procedure 7 using tert-butyl 5-(4-(6-chloro-3-((4-hydroxy-1-(1- methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate (25 mg, 0.0383 mmol), TFA (1 mL) and DCM (2 mL) gave, after freeze
  • Example 20 3-((1-Benzoyl-4-hvdroxypiperidin-4-yl)methyl)-6-chloro-7-(4-((3R,6S)-6- methylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolo[2,3-d
  • Step 1 tert-Butyl (2S,5R)-5-(4-(3-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-6-chloro-4-oxo- 3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate: General procedure 6 using ferf-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7/-/- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (40 mg, 0.0899 mmol), Epoxide 4 (29.3 mg, 0.135 mmol), CS2CO3 (88 mg, 0.270 mmol) and DMF (2 mL) after 18 h at 80 °C gave the title compound (40 mg, 67%) as a colour
  • Step 2 3-((1-Benzoyl-4-hydroxypiperidin-4-yl)methyl)-6-chloro-7-(4-((3R, 6SJ-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (2S,5R)-5-(4-(3-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-6- chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate (40 mg, 0.0604 mmol), TFA (1 mL) and DCM (2 mL) gave, after freeze-drying, the title compound (32 mg, 94%) as an off-white solid.
  • Step 1 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate: General procedure 6 using ferf-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (40 mg, 0.0899 mmol), Epoxide 5 (31 .7 mg, 0.135 mmol), CS2CO3 (88 mg, 0.270 mmol) and DMF (2 mL) after 18 h at 80 °C gave the title compound (36 mg,
  • Step 2 6-Chloro-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R, 6SJ-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (2S,5R)-5-(4-(6-chloro-3-((1-(4-fluorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (36 mg, 0.0529 mmol), TFA (1 mL) and DCM (2 mL) gave, after freeze-drying, the title compound (29 mg, 94%) as an off-white solid.
  • Step 1 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((1-(2,4-difluorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate: General procedure 6 using ferf-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (40 mg, 0.0899 mmol), Epoxide 6 (34.2 mg, 0.135 mmol), CS2CO3 (88 mg, 0.270 mmol) and DMF (2 mL) after 18 h at 80 °C gave the title compound (38 mg,
  • Step 2 6-Chloro-3-((1-(2,4-difluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R, 6SJ-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (2S,5R)-5-(4-(6-chloro-3-((1-(2,4-difluorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (38 mg, 0.0544 mmol), TFA (1 mL) and DCM (2 mL) gave, after freeze-drying, the title compound (31 mg, 95%) as a white solid
  • Step 1 tert-Butyl (S)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2- dimethylmorpholine-4-carboxylate and tert-butyl (R)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate: tert-Butyl 5-(4-(4,6-dichloro- 7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (776 mg) was resolved into the single stereoisomers by chiral SFC using a Lux A1 (21 .2 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 25:75 MeOH:CO2.
  • the first eluted material was arbitrarily assigned as tert-butyl (S)-5-(4-(4,6-dichloro-7/-/-pyrrolo[2,3-o(]pyrimidin-7- yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (288 mg, 37% recovery).
  • Chiral purity (method E): RT 1.45 min, 100%ee.
  • the first eluted material was arbitrarily assigned as tertbutyl (R)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-o(
  • Chiral purity (method E): RT 2.25 min, 100%ee.
  • Step 2 tert-Butyl (S)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate: General procedure 5 using tert-butyl (S)-5- (4-(4,6-dichloro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4- carboxylate (288 mg, 0.603 mmol), aqueous sodium hydroxide (4 M, 4.52 mL, 18.1 mmol) and 1 ,4-dioxane (4.5 mL) after 18 h at 100 °C using 1 M aqueous potassium bisulfate for acidification gave the title compound (286 mg, >100%) as a yellow glass.
  • LCMS (method B): RT 1 .40 min, m
  • Step 3 tert-Butyl (S)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)- 4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4- carboxylate: General procedure 6 using tert-butyl (S)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7/-/- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (80 mg, 0.174 mmol), Epoxide 2 (65.8 mg, 0.262 mmol), CS2CO3 (170 mg, 0.523 mmol) and DMF (3 mL) after 18 h at 80 °C gave the title compound (85 mg,
  • Step 4 ( S)-6-Chloro-3-( ( 1 -(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)- 7-(4-( 6, 6- dimethylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (S)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-o(
  • Example 24 3-((1-Benzoyl-4-hvdroxypiperidin-4-yl)methyl)-6-chloro-7-(4-((3S,6R)-6- methylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolor2,3-d
  • Step 1 tert-Butyl (2R,5S)-5-(4-(3-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-6-chloro-4-oxo- 3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate: General procedure 6 using ferf-butyl (2R,5S)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7/-/- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (70 mg, 0.157 mmol), Epoxide 4 (41 mg, 0.189 mmol), CS2CO3 (113 mg, 0.346 mmol) and DMF (1 .5 mL) after 18 h at 80 °C gave, after purification by prep-HPLC, the title compound (
  • Step 2 3-((1-Benzoyl-4-hydroxypiperidin-4-yl)methyl)-6-chloro-7-(4-((3S, 6R)-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one:
  • Step 1 tert-Butyl (2R,5S)-5-(4-(6-chloro-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate: General procedure 6 using tert-butyl (2R,5S)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (70 mg, 0.157 mmol), Epoxide 5 (44.4 mg, 0.189 mmol), CS2CO3 (113 mg, 0.346 mmol) and DMF (1.5 mL) after 18 h at 80 °C gave, after purification by prep-HPLC,
  • Step 2 6-Chloro-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3S, 6R)-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one:
  • General procedure 7 using tert-butyl (2R,5S)-5-(4-(6-chloro-3-((1-(4-fluorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (95.4 mg, 0.140 mmol), TFA (1.5 mL) and DCM (3 mL) gave, after purification by flash chromatography and freeze-drying, the title compound (42.8 mg, 52%) as
  • Step 1 tert-Butyl (3R,5S)-3-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5- methylmorpholine-4-carboxylate and tert-butyl (3S,5R)-3-(4-(4,6-dichloro-7H-pyrrolo[2,3- d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4-carboxylate: rac-tert-Butyl (3R,5S)-3-(4-(4,6- dichloro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4-carboxylate (664.7 mg) was resolved into the single stereoisomers by chiral SFC using a Chiralpak IH (20 mm x 250 mm, 5 pm) column with isocratic solvent conditions: 15:85 MeOH:CO2.
  • the first eluted material was arbitrarily assigned as tert-butyl (3R,5S)-3-(4-(4,6-dichloro-7/-/-pyrrolo[2,3- o(
  • Chiral purity (method F): RT 1.45 min, 100%ee.
  • the first eluted material was arbitrarily assigned as tert-butyl (3S,5R)-3-(4-(4,6-dichloro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-5- methylmorpholine-4-carboxylate (318.8 mg, 47% recovery).
  • Chiral purity (method F): RT 1 .70 min, 99.4%ee.
  • Step 2 tert-Butyl (3R ! 5S)-3-(4-(6-chloro-4-oxo-3 ! 4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)-5-methylmorpholine-4-carboxylate: General procedure 5 using tert-butyl (3R,5S)- 3-(4-(4,6-dichloro-7H-pyrrolo[2,3-o(
  • LCMS (method B): RT 1.32 min, m
  • Step 3 tert-Butyl (3R,5S)-3-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4- carboxylate: General procedure 6 using tert-butyl (3R,5S)-3-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4-carboxylate (80 mg, 0.180 mmol), Epoxide 2 (68 mg, 0.270 mmol), CS2CO3 (176 mg, 0.539 mmol) and DMF (3 mL) after 18 h at 80 °C gave the title compound (69 mg, 55%) as
  • Step 4 6-Chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,5S)-5- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (3R,5S)-3-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-5- methylmorpholine-4-carboxylate (69 mg, 0.0990 mmol), TFA (2 mL) and DCM (4 mL) gave, after freeze-drying, the title compound (54 mg, 91%) as an off-white solid.
  • Example 27 6-Chloro-3-((1-(4-chlorobenzoyl)-4-hvdroxypiperidin-4-yl)methyl)-7-(4-((3S,5R)- 5-methylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolo[2,3-d]pyrimidin-4-one
  • Step 1 tert- Butyl (3S,5R)-3-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)-5-methylmorpholine-4-carboxylate: General procedure 5 using ferf-butyl (3S,5R)- 3-(4-(4,6-dichloro-7H-pyrrolo[2,3-o(
  • LCMS (method B): RT 1.32 min, m
  • Step 2 tert-Butyl (3S,5R)-3-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4- carboxylate: General procedure 6 using ferf-butyl (3S,5R)-3-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4-carboxylate (80 mg, 0.180 mmol), Epoxide 2 (68 mg, 0.270 mmol), CS2CO3 (176 mg, 0.539 mmol) and DMF (3 mL) after 18 h at 80 °C gave the title compound (78 mg, 62%)
  • Step 1 tert-Butyl (S)-5-(4-(6-chloro-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4- oxo-3, 4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4- carboxylate: General procedure 6 using ferf-butyl (S)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7/-/- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (40 mg, 0.0872 mmol), Epoxide 5 (30.8 mg, 0.131 mmol), CS2CO3 (85.2 mg, 0.262 mmol) and DMF (3 mL) after 18 h at 80 °C gave the title compound (45 mg, 74%) as
  • Step 2 (S)-6-Chloro-7-(4-(6,6-dimethylmorpholin-3-yl)phenyl)-3-((1-(4-fluorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (S)-5-(4-(6-chloro-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-tf
  • Step 1 tert-Butyl (R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate: General procedure 5 using tert-butyl (R)-5- (4-(4,6-dichloro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4- carboxylate (321 mg, 0.672 mmol), aqueous sodium hydroxide (4 M, 5.04 mL, 20.2 mmol) and 1 ,4-dioxane (5.1 mL) after 18 h at 100 °C using 1 M aqueous potassium bisulfate for acidification gave the title compound (321 mg, >100%.) as a yellow glass.
  • LCMS (method B): R T 1.40 min, m
  • Step 2 tert-Butyl (R)-5-(4-(6-chloro-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)- 4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4- carboxylate: General procedure 6 using tert-butyl (R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7/-/- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (40 mg, 0.0872 mmol), Epoxide 5 (30.8 mg, 0.131 mmol), CS2CO3 (85.2 mg, 0.262 mmol) and DMF (3 mL) after 18 h at 80 °C gave the title compound (29 mg, 47%) as
  • Step 3 (R)-6-Chloro-7-(4-(6,6-dimethylmorpholin-3-yl)phenyl)-3-((1-(4-fluorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (R)-5-(4-(6-chloro-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-tf
  • Step 1 tert-Butyl ( 2S, 5R)-5-(4-( 6-chloro-3-(( 1 -(4-chloro-2-fluorobenzoyl)-4-hydroxypiperidin- 4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine- 4-carboxylate: General procedure 6 using ferf-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4- dihydro-7H-pyrrolo[2,3-o]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (40 mg, 0.0899 mmol), Epoxide 7 (36.4 mg, 0.135 mmol), CS2CO3 (88 mg, 0.270 mmol) and DMF (2 mL) after 18 h at 80 °C gave the title compound (32 mg,
  • Step 2 6-Chloro-3-((1-(4-chloro-2-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4- ( ( 3R, 6S)-6-methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (2S,5R)-5-(4-(6-chloro-3-((1-(4-chloro-2-fluorobenzoyl)- 4-hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (32 mg, 0.0448 mmol), TFA (1 mL) and DCM (2 mL) gave, after freeze-drying, the title compound (23 mg, 83%) as
  • Step 1 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((1-(2-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate: General procedure 6 using tert-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (40 mg, 0.0899 mmol), Epoxide 8 (34 mg, 0.135 mmol), CS2CO3 (88 mg, 0.270 mmol) and DMF (2 mL) after 18 h at 80 °C gave the title compound (45 mg, 71 %) as
  • Step 2 6-Chloro-3-((1-(2-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R, 6SJ-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using tert-butyl (2S,5R)-5-(4-(6-chloro-3-((1-(2-chlorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (45 mg, 0.0646 mmol), TFA (1 mL) and DCM (2 mL) gave, after freeze-drying, the title compound (33 mg, 85%) as a white solid.
  • Example 32 6-Chloro-3-((4-hvdroxy-1-((1 S,2S)-1-methyl-2-(trifluoromethyl)cvclopropane-1- carbonyl)piperidin-4-yl)methyl)-7-(4-((3/?,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihvdro- 4/-/-pyrrolo[2,3-d
  • Step 1 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((4-hydroxy-1-((1S,2S)-1-methyl-2- (trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H- pyrrolo[2, 3-d]pyrimidin- 7-yl)phenyl)-2-methylmorpholine-4-carboxylate or tert-butyl ( 2S, 5R)- 5-(4-( 6-chloro-3-((4-hydroxy- 1-((1R, 2R)- 1 -methyl-2-(trifluoromethyl)cyclopropane- 1 - carbonyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxy
  • Step 2 6-Chloro-3-((4-hydroxy- 1-((1S, 2S)- 1 -methyl-2-(trifluoromethyl)cyclopropane- 1 - carbonyl)piperidin-4-yl)methyl)-7-(4-((3R,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro- 4H-pyrrolo[2, 3-d]pyrimidin-4-one or 6-chloro-3-( (4-hydroxy- 1-((1R, 2R)- 1 -methyl-2- (trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3R,6S)-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using tert-butyl (2S,5R)-5-(4-(6-chloro-3-(
  • Example 33 6-Chloro-3-((4-hvdroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cvclopropane-1- carbonyl)piperidin-4-yl)methyl)-7-(4-((3R,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihvdro- 4/-/-pyrrolo[2,3-d]pyrimidin-4-one or 6-chloro-3-((4-hvdroxy-1-((1S,2S)-1-methyl-2- (trifluoromethyl)cvcloDroDane-1-carbonyl)Dioeridin-4-yl)methyl)-7-(4-((3R,6S)-6- methylmorDholin-3-yl)Dhenyl)-3,7-dihvdro-4/-/-Dyrrolo[2,3-c/lDyrimidin-4-one
  • Step 1 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((4-hydroxy-1-((1R,2R)-1-methyl-2- (trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H- pyrrolo[2, 3-d]pyrimidin- 7-yl)phenyl)-2-methylmorpholine-4-carboxylate or tert-butyl ( 2S, 5R)- 5-(4-( 6-chloro-3-((4-hydroxy- 1-((1S,2S)-1 -methyl-2-(trifluoromethyl)cyclopropane- 1 - carbonyl)piperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate
  • Step 2 6-Chloro-3-((4-hydroxy- 1-((1R, 2R)- 1 -methyl-2-(trifluoromethyl)cyclopropane- 1 - carbonyl)piperidin-4-yl)methyl)-7-(4-((3R,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro- 4H-pyrrolo[2, 3-d]pyrimidin-4-one or 6-chloro-3-( (4-hydroxy- 1-((1S,2S)-1 -methyl-2- (trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3R,6S)-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (2S,5R)-5-(4-(6-chloro-3-((
  • Step 1 tert-Butyl (R)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)- 4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4- carboxylate: General procedure 6 using ferf-butyl (R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7/-/- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (80 mg, 0.174 mmol), Epoxide 2 (52.7 mg, 0.209 mmol), CS2CO3 (125 mg, 0.384 mmol) and DMF (1.5 mL) after 18 h at 80 °C gave, after purification by prep-HPLC
  • Step 2 (R)-6-Chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-(6,6- dimethylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (R)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-tf
  • Step 1 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((1-(3-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate: General procedure 6 using tert-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (50 mg, 0.112 mmol), Epoxide 11 (34 mg, 0.135 mmol), CS2CO3 (80.6 mg, 0.247 mmol) and DMF (1 mL) after 18 h at 80 °C gave the title compound (55 mg, 70%
  • Step 2 6-Chloro-3-((1-(3-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R, 6S)-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using tert-butyl (2S,5R)-5-(4-(6-chloro-3-((1-(3-chlorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (55 mg, 0.0790 mmol), TFA (0.74 mL) and DCM (1.5 mL) gave, after purification by flash chromatography and freeze-drying, the title compound (35 mg,
  • Example 36 6-Chloro-3-((1-(2-fluorobenzoyl)-4-hvdroxypiperidin-4-yl)methyl)-7-(4-((3 6S)- 6-methylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolo[2,3-d
  • Step 1 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((1-(2-fluorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate: General procedure 6 using tert-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (50 mg, 0.112 mmol), Epoxide 12 (31.7 mg, 0.135 mmol), CS2CO3 (80.6 mg, 0.247 mmol) and DMF (1 mL) after 18 h at 80 °C gave the title compound (42 mg, 54%) as
  • Step 2 6-Chloro-3-((1-(2-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R, 6SJ-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using tert-butyl (2S,5R)-5-(4-(6-chloro-3-((1-(2-fluorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (42 mg, 0.0617 mmol), TFA (0.75 mL) and DCM (1.5 mL) gave, after purification by flash chromatography and freeze-drying, the title compound (30.1 mg, 83%) as
  • Step 1 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((1-(3,4-difluorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate: General procedure 6 using ferf-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (50 mg, 0.112 mmol), Epoxide 13 (34 mg, 0.135 mmol), CS2CO3 (80.6 mg, 0.247 mmol) and DMF (1 mL) after 18 h at 80 °C gave the title compound (50 mg
  • Step 2 6-Chloro-3-((1-(3,4-difluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R, 6SJ-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (2S,5R)-5-(4-(6-chloro-3-((1-(3,4-difluorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (50 mg, 0.0716 mmol), TFA (0.75 mL) and DCM (1.5 mL) gave, after purification by flash chromatography and freeze-drying, the title compound
  • Step 1 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((1-(3-fluorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate: General procedure 6 using ferf-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (40 mg, 0.0899 mmol), Epoxide 14 (25.4 mg, 0.108 mmol), CS2CO3 (64.4 mg, 0.198 mmol) and DMF (1 mL) after 18 h at 80 °C gave the title compound (29.5 mg, 48%) as colour
  • Step 2 6-Chloro-3-((1-(3-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R, 6S)-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (2S,5R)-5-(4-(6-chloro-3-((1-(3-fluorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (29 mg, 0.0426 mmol), TFA (0.75 mL) and DCM (1.5 mL) gave, after freeze-drying, the title compound (18 mg, 72%) as a white solid.
  • Step 1 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((1-(2,3-difluorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate: General procedure 6 using ferf-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (50 mg, 0.112 mmol), Epoxide 15 (34.2 mg, 0.135 mmol), CS2CO3 (80.6 mg, 0.247 mmol) and DMF (1 mL) after 18 h at 80 °C gave the title compound (30 mg,
  • Step 2 6-Chloro-3-((1-(2,3-difluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6S)-6- methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using ferf-butyl (2S,5R)-5-(4-(6-chloro-3-((1-(2,3-difluorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate (30 mg, 0.0430 mmol), TFA (0.75 mL) and DCM (1.5 mL) gave, after purification by flash chromatography and freeze-drying, the title compound (2
  • Example 40 (S)-3-((1-([1 ,1 '-bi(cvclopropane)1-1-carbonyl)-4-hvdroxypiperidin-4-yl)methyl)-6- chloro-7-(4-(6,6-dimethylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolo[2,3-at
  • Step 1 tert-Butyl (S)-5-(4-(3-((1-([1, 1'-bi(cyclopropane)]-1-carbonyl)-4-hydroxypiperidin-4- yl)methyl)-6-chloro-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin- 7-yl)phenyl)-2, 2- dimethylmorpholine-4-carboxylate: General procedure 6 using tert-butyl (S)-5-(4-(6-chloro-4- oxo-3, 4-dihydro-7/-/-pyrrolo[2, 3-d]pyrimidin-7-yl)phenyl)-2, 2-dimethylmorpholine-4- carboxylate (45 mg, 0.0981 mmol), Epoxide 16 (32.6 mg, 0.147 mmol), CS2CO3 (95.8 mg, 0.294 mmol) and DMF (2 mL) after 18 h at 80 °C
  • Step 2 (S)-3-((1-([1, 1'-Bi(cyclopropane)]-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-6- chloro-7-(4-( 6, 6-dimethylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d] pyrimidineone: General procedure 7 using tert-butyl (S)-5-(4-(3-((1-([1 ,1'-bi(cyclopropane)]-1-carbonyl)- 4-hydroxypiperidin-4-yl)methyl)-6-chloro-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7- yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (55 mg, 0.0809 mmol), TFA (1 mL) and DCM (2 mL) gave, after freeze-drying
  • Example 41 (/?)-3-((1-([1 ,1'-bi(cvclopropane)1-1-carbonyl)-4-hvdroxypiperidin-4-yl)methyl)-6- chloro-7-(4-(6,6-dimethylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolo[2,3-at
  • Step 1 tert-Butyl (R)-5-(4-(3-((1-([1, 1'-bi(cyclopropane)]-1-carbonyl)-4-hydroxypiperidin-4- yl)methyl)-6-chloro-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin- 7-yl)phenyl)-2, 2- dimethylmorpholine-4-carboxylate: General procedure 6 using tert-butyl (R)-5-(4-(6-chloro-4- oxo-3, 4-dihydro-7/-/-pyrrolo[2, 3-d]pyrimidin-7-yl)phenyl)-2, 2-dimethylmorpholine-4- carboxylate (45 mg, 0.0981 mmol), Epoxide 16 (32.6 mg, 0.147 mmol), CS2CO3 (95.8 mg, 0.294 mmol) and DMF (2 mL) after 18 h at 80 °C
  • Step 2 (R)-3-((1-([1, 1'-Bi(cyclopropane)]-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-6- chloro-7-(4-( 6, 6-dimethylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d] pyrimidineone: General procedure 7 using tert-butyl (R)-5-(4-(3-((1-([1 ,1'-bi(cyclopropane)]-1-carbonyl)- 4-hydroxypiperidin-4-yl)methyl)-6-chloro-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7- yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (46 mg, 0.0676 mmol), TFA (1 mL) and DCM (2 mL) gave, after freeze-drying
  • Example 42 3-( (1 -([1 , 1 '-Bi(cvclopropane)1-1-carbonyl)-4-hvdroxypiperidin-4-yl)methyl)-6- chloro-7-(4-((3R6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihvdro-4/-/-pyrrolo[2,3-d
  • Step 1 tert-Butyl (2S,5R)-5-(4-(3-((1-([1, 1'-bi(cyclopropane)]-1-carbonyl)-4-hydroxypiperidin- 4-yl)methyl)-6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- methylmorpholine-4-carboxylate: General procedure 6 using tert-butyl (2S,5R)-5-(4-(6- chloro-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4- carboxylate (45 mg, 0.101 mmol), Epoxide 16 (34 mg, 0.152 mmol), CS2CO3 (98.9 mg, 0.303 mmol) and DMF (2 mL) after 18 h at 80 °C gave
  • Step 2 3-((1-([1,1 '-Bi(cyclopropane) ]- 1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-chloro- 7- (4-( ( 3R, 6S)-6-methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one:
  • General procedure 7 using tert-butyl (2S,5R)-5-(4-(3-((1-([1 ,1'-bi(cyclopropane)]-1-carbonyl)- 4-hydroxypiperidin-4-yl)methyl)-6-chloro-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7- yl)phenyl)-2-methylmorpholine-4-carboxylate (47 mg, 0.0705 mmol), TFA (1 mL) and DCM (2 mL)
  • Example 43 7-(4-(5-Oxa-8-azaspiro[3.51nonan-7-yl)phenyl)-3-((1-([1 ,T-bi(cvclopropane)1-1- carbonyl)-4-hvdroxypiperidin-4-yl)methyl)-6-chloro-3,7-dihvdro-4/-/-pyrrolo[2,3-d
  • Step 1 8-(tert-Butyl) 7-(4,5,6, 7-tetrachloro-1,3-dioxoisoindolin-2-yl) 5-oxa-8- azaspiro[3.5]nonane-7,8-dicarboxylate: General procedure 11 using 8-(tert-butoxycarbonyl)- 5-oxa-8-azaspiro[3.5]nonane-7-carboxylic acid (2.60 g, 9.59 mmol), 4,5,6,7-tetrachloro-2- hydroxyisoindoline-1 ,3-dione (2.89 g, 9.59 mmol), EDC (2.21 g, 11.5 mmol) and DMAP (117 mg, 0.959 mmol) gave the title compound (2.34 g, 46%).
  • Step 2 tert-Butyl 7-(4-bromophenyl)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate: To 8-(tert- butyl) 7-(4,5,6,7-tetrachloro-1 ,3-dioxoisoindolin-2-yl) 5-oxa-8-azaspiro[3.5]nonane-7,8- dicarboxylate (710 mg, 1.28 mmol), (4-bromophenyl)boronic acid (772 mg, 3.84 mmol) in a 100 mL RBF under nitrogen was added 1 ,4-dioxane (48.5 mL).
  • the reaction mixture was heated to 75-80 °C (internal temperature) before triethylamine (1.79 mL, 12.8 mmol) and NiCI? ⁇ 6H2O : bathophenanthroline complex in DMF (0.05 M, 4.85 mL, 0.243 mmol, (Angew. Chem. Int. Ed. 2016, 55, 9676-9679)) were sequentially added.
  • the resulting mixture was stirred at 75 °C overnight.
  • EtOAc 250 mL
  • washed with brine The organic layer was dried over MgSC , filtered and concentrated under reduced pressure.
  • Step 3 tert-Butyl 7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-oxa-8- azaspiro[3.5]nonane-8-carboxylate: General procedure 3 (Work-up A) using tert-butyl 7-(4- bromophenyl)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate (415 mg, 1.09 mmol), B2Pin2 (414 mg, 1.63 mmol), Pd(dppf)Ch ⁇ CH2Cl2 (91.9 mg, 0.109 mmol), KOAc (320 mg, 3.26 mmol) and 1 ,4-dioxane (11 mL) after stirring at 100 °C (thermal) for 4 h gave the title compound (460 mg, 98%) as a yellow solid.
  • LCMS (method B): RT 1.84 min, m
  • Step 4 tert-Butyl 7-(4-(4 ! 6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-oxa-8- azaspiro[3.5]nonane-8-carboxylate: General procedure 4 (Work-up A) using 4,6-dichloro-7/7- pyrrolo[2,3-d]pyrimidine (200 mg, 1.06 mmol), ferf-butyl 7-(4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate (457 mg, 1.06 mmol), copper(ll) trifluoroacetate hydrate (616 mg, 2.13 mmol), 1 ,10-phenanthroline (383 mg, 2.13 mmol), boric acid (263 mg, 4.26 mmol) and DMF (20 mL)
  • Step 5 tert-Butyl 7-(4-( 6-chloro-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin-7-yl)phenyl)-5- oxa-8-azaspiro[3.5]nonane-8-carboxylate: General procedure 5 using ferf-butyl 7-(4-(4,6- dichloro-7/7-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate (20 mg, 0.0409 mmol), aqueous sodium hydroxide (4 M, 0.31 mL, 1.23 mmol) and 1 ,4- dioxane (0.3 mL) after 18 h at 100 °C using 1 M aqueous potassium bisulfate for acidification gave the title compound (19 mg, quant.) as a yellow glass.
  • Step 6 tert-Butyl 7-(4-(3-((1-([1, 1'-bi(cyclopropane)]-1-carbonyl)-4-hydroxypiperidin-4- yl)methyl)-6-chloro-4-oxo-3, 4-dihydro- 7H-pyrrolo[2, 3-d]pyrimidin- 7-yl)phenyl)-5-oxa-8- azaspiro[3.5]nonane-8-carboxylate: General procedure 6 using ferf-butyl 7-(4-(6-chloro-4- oxo-3, 4-dihydro-7/-/-pyrrolo[2, 3-d]pyrimidin-7-yl)phenyl)-5-oxa-8-azaspiro[3.5]nonane-8- carboxylate (10 mg, 0.0212 mmol), Epoxide 16 (7.1 mg, 0.0319 mmol), CS2CO3 (20.8 mg, 0.0637 mmol) and DMF (0.5
  • Step 7 7-(4-(5-oxa-8-azaspiro[3.5]nonan-7-yl)phenyl)-3-((1-([1, 1'-bi(cyclopropane)]-1- carbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-chloro-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4- one: General procedure 7 using ferf-butyl 7-(4-(3-((1-([1 ,1'-bi(cyclopropane)]-1-carbonyl)-4- hydroxypiperidin-4-yl)methyl)-6-chloro-4-oxo-3,4-dihydro-7/7-pyrrolo[2,3-o(]pyrimidin-7- yl)phenyl)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate (7.5 mg, 0.0108 mmol), TFA (1 mL)
  • Step 1 tert-Butyl 7-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-4- oxo-3, 4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-oxa-8-azaspiro[3.5]nonane-8- carboxylate: General procedure 6 using tert-butyl 7-(4-(6-chloro-4-oxo-3,4-dihydro-7/7- pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-oxa-8-azaspiro[3.5]nonane-8-carboxylate (10 mg, 0.0212 mmol), Epoxide 2 (8.02 mg, 0.0319 mmol), CS2CO3 (20.8 mg, 0.0637 mmol) and DMF (0.5 mL) after 18 h at 80 °
  • Step 2 7-(4-(5-Oxa-8-azaspiro[3.5]nonan-7-yl)phenyl)-6-chloro-3-((1-(4-chlorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using tert-butyl 7-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7/7-pyrrolo[2,3-o(
  • Step 1 (2S,5R)-5-(4-Bromophenyl)-2-ethylmorpholine:
  • General procedure 8 using 4- bromobenzaldehyde (2.36 g, 12.8 mmol), (S)-2-((tributylstannyl)methoxy)butan-1-amine (made according to the procedure outlined in Org. Lett. 2014, 16 (4), 1236-1239 starting from (S)-1-aminobutan-2-ol) (5.00 g, 12.8 mmol), Cu(OTf) 2 (4.63 g, 12.8 mmol), 2,6- dimethylpyridine (1.37 g, 12.8 mmol), HFIP (51 mL), 4A molecular sieves (ca.
  • Step 2 tert-Butyl (2S,5R)-5-(4-bromophenyl)-2-ethylmorpholine-4-carboxylate: General procedure 9 using (2S,5R)-5-(4-bromophenyl)-2-ethylmorpholine (1.93 g, 7.15 mmol) and BOC 2 O (1.87 g, 8.58 mmol) gave the title compound (1.77 g, 67%).
  • Step 3 tert-Butyl (2S,5R)-2-ethyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)morpholine-4-carboxylate: General procedure 3 (Work-up B) using tert-butyl (2S,5R)-5-(4-bromophenyl)-2-ethylmorpholine-4-carboxylate (741 mg, 2.00 mmol), B 2 Pin 2 (762 mg, 3.00 mmol), Pd(dppf)CI 2 ⁇ CH 2 CI 2 (169 mg, 0.200 mmol), KOAc (589 mg, 6.00 mmol) and 1 ,4-dioxane (20 mL) after stirring at 100 °C (thermal) for 70 min gave the title compound (914 mg, >100%) as a yellow oil.
  • Step 4 tert- Butyl (2S,5R)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2- ethylmorpholine-4-carboxylate: General procedure 4 (Work-up B) using 4,6-dichloro-7/-/- pyrrolo[2,3-d]pyrimidine (289 mg, 1.54 mmol), tert-butyl (2S, 5/?)-2-ethyl-5-(4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)morpholine-4-carboxylate (834 mg, 2.00 mmol), copper(ll) trifluoroacetate hydrate (890 mg, 3.07 mmol), 1 ,10-phenanthroline (554 mg, 3.07 mmol), boric acid (247 mg, 4.00 mmol) and DMF (15.4 mL) after
  • Step 5 tert- Butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)phenyl)-2-ethylmorpholine-4-carboxylate: General procedure 5 using tert-butyl (2S,5R)-5- (4-(4,6-dichloro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)phenyl)-2-ethylmorpholine-4-carboxylate (467 mg, 0.978 mmol), aqueous sodium hydroxide (4 M, 2.45 mL, 9.78 mmol) and 1 ,4- dioxane (4.9 mL) after 26 h 20 min at 100 °C using 2 M aqueous hydrochloric acid for acidification gave the title compound (525 mg, >100%) as a brown solid.
  • Step 6 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-ethylmorpholine-4- carboxylate: General procedure 6 using tert-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-ethylmorpholine-4-carboxylate (60 mg, 0.131 mmol), Epoxide 5 (36.9 mg, 0.157 mmol), CS2CO3 (93.7 mg, 0.288 mmol) and DMF (1 mL) after 18 h at 80 °C gave the title compound
  • Step 1 tert-Butyl (2S,5R)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-ethylmorpholine-4- carboxylate: General procedure 6 using tert-butyl (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro- 7/-/-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-ethylmorpholine-4-carboxylate (60 mg, 0.131 mmol), Epoxide 2 (39.5 mg, 0.157 mmol), CS2CO3 (93.7 mg, 0.288 mmol) and DMF (1 mL) after 18 h at 80 °C gave the title compound (
  • Step 2 6-Chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R, 6SJ-6- ethylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using tert-butyl (2S,5R)-5-(4-(6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(
  • Step 1 tert-Butyl (2R,5S)-5-(4-(6-chloro-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4- yl)methyl)-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylphenyl)-2- methylmorpholine-4-carboxylate: General procedure 6 using tert-butyl (2R,5S)-5-(4-(6- chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylphenyl)-2- methylmorpholine-4-carboxylate (60 mg, 0.131 mmol), Epoxide 5 (36.9 mg, 0.157 mmol), CS2CO3 (93.7 mg, 0.288 mmol) and DMF (1 mL) after 18 h at 80 °C gave the title compound (
  • Step 2 6-Chloro-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(3-methyl-4- ( ( 3S, 6R)-6-methylmorpholin-3-yl)phenyl)-3, 7-dihydro-4H-pyrrolo[2, 3-d]pyrimidin-4-one: General procedure 7 using tert-butyl (2R,5S)-5-(4-(6-chloro-3-((1-(4-fluorobenzoyl)-4- hydroxypiperidin-4-yl)methyl)-4-oxo-3,4-dihydro-7/-/-pyrrolo[2,3-o(]pyrimidin-7-yl)-2- methylphenyl)-2-methylmorpholine-4-carboxylate (57 mg, 0.0821 mmol), TFA (0.75 mL) and DCM (1.5 mL) gave, after purification by flash chromatography and freeze-drying, the title compound (3
  • Example 48 7-(4-((1 2S,5S)-8-Oxa-3-azabicvclo[3.2.11octan-2-yl)phenyl)-6-chloro-3-((1-(4- chlorobenzoyl)-4-hvdroxypiperidin-4-yl)methyl)-3,7-dihvdro-4H-pyrrolo[2,3-d
  • Step 1 (S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)dihydrofuran-2(3H)-one: To (S)-5- (hydroxymethyl)dihydrofuran-2(3/-/)-one (2.90 g, 25.0 mmol) and imidazole (3.40 g, 49.9 mmol) in DMF (29 mL) at 0 °C was added terf-butylchlorodiphenylsilane (8.44 mL, 32.5 mmol). The reaction mixture was allowed to warm to rt and stirred overnight before EtOAc (150 mL) was added.
  • Step 2 (5S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-ol: To a solution of (S)- 5-(((tert-butyldiphenylsilyl)oxy)methyl)dihydrofuran-2(3/-/)-one (7.56 g, 21.3 mmol) dry diethyl ether (100 mL) under nitrogen and at -78 °C was added diisobutylaluminium hydride (1 M in DCM, 32.0 mL, 32.0 mmol). The reaction was stirred at -78 °C for 5 h before being quenched by the addition of MeOH (15 mL).
  • Step 3 (S)-tert-Butyl((2,3-dihydrofuran-2-yl)methoxy)diphenylsilane: To a solution of (5S)-5- (((terf-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-2-ol (7.61 g, 21.3 mmol) in DCM (140 mL) at -50 °C under N2, were added triethylamine (11 .9 mL, 85.4 mmol) followed by methanesulfonyl chloride (2.32 mL, 29.9 mmol).
  • Step 4 (S)-(2,3-Dihydrofuran-2-yl)methyl 4-methylbenzenesulfonate: To (S)-tert-butyl((2,3- dihydrofuran-2-yl)methoxy)diphenylsilane (1.00 g, 2.95 mmol) was added TBAF (1 M in THF, 2.95 mL, 2.95 mmol) and the resulting mixture was stirred at rt for 1 h.
  • Step 5 ( S)-2-( ( 2, 3-Dihydrofuran-2-yl)methyl)isoindoline-1 , 3-dione:
  • Step 6 (S)-(2,3-Dihydrofuran-2-yl)methanamine: To (S)-2-((2,3-dihydrofuran-2- yl)methyl)isoindoline-1 ,3-dione (230 mg, 1.00 mmol) in MeOH (4 mL) was added hydrazine monohydrate (0.19 mL, 6.02 mmol). The reaction mixture was heated at 60 °C for 2h. Upon cooling to rt aqueous sodium hydroxide (2 M, 7.5 mL) was added and the resulting mixture was extracted with DCM (3 x 15 mL).
  • Step 7 (1R,2S,5S)-2-(4-Bromophenyl)-8-oxa-3-azabicyclo[3.2.1]octane: A mixture of (S)- (2,3-dihydrofuran-2-yl)methanamine (100 mg, 1.01 mmol), 4-bromobenzaldehyde (187 mg, 1 .01 mmol) and 3A molecular sieves (200 mg) in DCM (1 mL) was stirred at rt for 19 h. The reaction mixture was filtered through a syringe filter and the volatiles were evaporated under reduced pressure (200 mbar, 40 °C).

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