Heterocyclic compounds as ubiquitin-specific protease 7 inhibitors

Abstract

The present invention relates to inhibitors of ubiquitin-specific protease 7 (USP7) and methods of using same. Specifically, the present invention relates to inhibitors of formula (I), including stereoisomers: JPEG2025503052000200.jpg6773 [In formula: "m" is 0, 1, or 2, and each R 1 are independently halo; C optionally substituted with halo 1 -C 6 Alkyl; and C 3 -C 6 cycloalkyl; "n" is 0, 1, or 2, and each R 2 each independently represents an optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 6 cycloalkyl, where each of the one or more optional substituents is independently selected from C 1 -C 6 selected from alkyl and halo; or where "n" is 2 and each R 2 Together with one or more carbon ring atoms to which they are attached, they form a C 3 -C 6 Fused cycloalkyl ring, C 3 -C 6 Spirocyclic cycloalkyl ring or C 3 -C 4 Forming bridges; R 3 is an optionally substituted C 1 -C 6 Alkyl, optionally substituted C 3 -C 6 Cycloalkyl, optionally substituted phenyl, optionally substituted C 7 -C 10 Arylalkyl, optionally substituted C 8 -C 10 Arylalkenyl and optionally substituted C 3 -C 6heteroaryl; wherein each of the one or more optional substituents is independently selected from halo; C optionally substituted with halo 1 -C 6 alkyl; and optionally methyl or CF 3 C replaced with 3 -C 6 cycloalkyl; R 4 H, Cl, C 1 -C 6 is alkyl; wherein X and Z are morpholine rings, one of X and Z is O, and one of X and Z is NR′, where R′ is H or C. 1 -C 6 alkyl, optionally H. or a pharma- ceutically acceptable salt or solvate thereof.

Description

[Technical Field]

[0001] This application claims priority to GB application 2200753.8, filed January 21, 2022, the contents and elements of which are incorporated herein by reference for all purposes.

[0002] FIELD OF THE INVENTION The present invention relates to inhibitors of ubiquitin-specific protease 7 (USP7) and methods of use thereof. [Background technology]

[0003] Background of the Invention Over the past 30 years, protein ubiquitination has emerged as an important post-translational modification with roles in numerous cellular processes, including protein degradation, gene expression, DNA repair, immune response, metabolism, and cell cycle control. Dysregulation of the ubiquitin-proteasome system (UPS) has been implicated in cancer (Hoeller et al., Nat. Rev. Cancer (2006), 6, 776-788), viral infection (Gao et al., Can. J. Physiol. Pharmacol. (2006), 84, 5-14), metabolic or neurodegenerative disorders (Loosdregt et al., Immunity (2013), 39, 259-271; Rubinsztein et al., Nature (2006), 443, 780-786), and immune and inflammatory-related conditions (Wang et al., Cell Mol. Immunol. (2006), 3, 255-261; Corn J. et al., Nat. Struct. Mol. Biol. (2014), 21, 297-300; Nicholson et al., Cell Biochem. Biophys. (2011), 60, 61-68).

[0004] The established and growing interrelationship between USP7 and numerous proteins involved in human disease suggests that small molecule inhibitors of USP7 may have beneficial and broad therapeutic applications in human health. Small molecule USP7 inhibitors are described in the following patent applications: US2008 / 0103149A1, WO2010 / 114881A1, WO2010 / 081783A1, WO2011 / 086178A1, WO2013 / 030218A1, EP2565186A1, EP1749822A1, WO2016 / 109 515A1, WO2016 / 109480A1, WO2016 / 126929A1, WO2016 / 126926A1, WO2016 / 126935A1, WO2016 / 150800A1, WO2017 / 158381, WO2017 / 158388, WO2018 / 073602 and WO2021 / 161047. Summary of the Invention [Problem to be solved by the invention]

[0005] Nevertheless, there remains a need for improved USP7 inhibitors, for example, those with improved inhibitory activity, improved solubility, improved in vivo stability, improved pharmacokinetics, or an improved combination of some or all of these properties. The present invention addresses this need. [Means for solving the problem]

[0006] Summary of the Invention The compounds described herein can selectively inhibit USP7 activity. Therefore, the compounds provided herein may be suitable for the treatment and prevention of, for example, cancer and neoplastic conditions. The compounds may be used in monotherapy or in combination with radiation and / or additional therapeutic agents.

[0007] Therefore, in a first aspect, the present invention provides a compound of formula (I) including stereoisomers. [ka] [During the ceremony: "m" is 0, 1, or 2, and each R 1 is independently selected from halo; C1-C6 alkyl optionally substituted with halo; and C3-C6 cycloalkyl; "n" is 0, 1, or 2, and each R 2 are independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, wherein each of the one or more optional substituents is independently selected from C1-C6 alkyl and halo; or where "n" is 2 and each R 2 together with one or more carbon ring atoms to which they are attached form a C3-C6 fused cycloalkyl ring, a C3-C6 spirocyclic cycloalkyl ring, or a C3-C4 bridge; R 3 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted C7-C 10 Arylalkyl, optionally substituted C-C 10 arylalkenyl and optionally substituted C3-C6 heteroaryl; wherein each of the one or more optional substituents is independently selected from halo; C1-C6 alkyl optionally substituted with halo; and C3-C6 cycloalkyl optionally substituted with methyl or CF3; R 4 is H, Cl, C1-C6 alkyl; wherein one of X and Z is O and one of X and Z is NR′, where R′ is H or C1-C6 alkyl, optionally H, such that X and Z are morpholine rings. or a pharmaceutically acceptable salt or solvate thereof.

[0008] In certain embodiments, the compounds of formula (Ia), including stereoisomers, [ka] [During the ceremony: "m", "n", R 1 ~R 4 and R' is as defined for formula (I). or a pharmaceutically acceptable salt or solvate thereof.

[0009] The compounds of the present invention are particularly advantageous as they exhibit improved properties compared to USP7 inhibitors described in the literature.

[0010] WO2018 / 073602 discloses a compound having the structure: [ka] (Comparative Example - Example 226 of WO2018 / 073602).

[0011] The compounds of the present invention differ from this comparative example at least in that the side chain morpholinyl ring in formula (I) is C-linked rather than N-linked, and is attached to the phenyl at the 4 (para) position rather than the 3 (meta) position.

[0012] Compared to Comparative Example 226, compounds of the present invention exhibit improved inhibition of USP7, which is particularly evident when USP7 inhibition is determined using binding of USP7 as the cellular target (Table 1). [Table 1]

[0013] The compounds of the present invention also exhibit improved solubility and microsomal stability compared to prior art USP7 compounds (Table 2). [Table 2]

[0014] The present invention therefore provides novel USP7 inhibitor compounds with improved properties compared to those described in the prior art.

[0015] The present invention includes all combinations of the described embodiments and preferred features except where such combinations are expressly not permitted or expressly avoided.

[0016] Embodiments and experiments illustrating the construction of the present invention will now be described with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0017] [Figure 1]

[0023] Figures 1(a) and 1(b) show electron density maps derived from the crystal structure determination of USP7 in complex with an inhibitor of the invention, as described in the Examples below. Figure 1(a) shows the initial Fo-Fc difference electron density map (contoured at 3.0σ) of the model, derived from refinement of the initial model prior to modeling of the compound in BUSTER. The region of the compound binding site in chain B is indicated. For clarity, the final refinement coordinates are also shown; Figure 1(b) shows the final 2Fo-Fc electron density map (contoured at 1.5σ) derived from refinement of the final model in BUSTER. The region of the compound binding site is indicated.

[0018] [Figure 2] 1 shows the overall structure of USP7 complexed with an inhibitor of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0019] Detailed Description Aspects and embodiments of the present invention are described below with reference to the accompanying drawings. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned herein are incorporated by reference.

[0020] Unless otherwise specified herein, scientific and technical terms used in connection with the present invention shall have meanings commonly understood by those of ordinary skill in the art. However, in the event of any potential ambiguity, the definitions provided herein shall take precedence over any dictionary or external definitions in order to clarify the meaning and scope of the terms.

[0021] As used in this specification and the appended claims, unless otherwise indicated to the contrary, the following terms have the meanings indicated: The term "alkyl group" (alone or in combination with other terms) means a straight-chain or branched-chain saturated hydrocarbon substituent, typically containing 1 to 15 carbon atoms, e.g., 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. n An "alkyl" group refers to an aliphatic group containing n carbon atoms. For example, C1-C 10 The alkyl group contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Attachment to the alkyl group is through a carbon atom. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-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).

[0022] The term "alkenyl group" (alone or in combination with other terms) includes straight-chain or branched-chain hydrocarbon substituents containing one or more double bonds and typically 2 to 15 carbon atoms; for example, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples of such substituents include ethenyl (vinyl), 1-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, and hexenyl.

[0023] The term "alkynyl group" (alone or in combination with other terms) means a straight- or branched-chain hydrocarbon substituent containing one or more triple bonds and typically 2 to 15 carbon atoms; for example, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples of such substituents include ethynyl, 1-propynyl, 3-propynyl, 1-butynyl, 3-butynyl, and 4-butynyl.

[0024] The term "cycloalkyl group" (alone or in combination with other terms) means a saturated cyclic hydrocarbon substituent containing 3 to 14 carbon ring atoms. Cycloalkyls can be a single carbon ring, typically containing 3 to 8 carbon ring atoms and more typically 3 to 6 ring atoms. It is understood that attachment to a cycloalkyl group is through a ring atom of the cycloalkyl group. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyls can alternatively be polycyclic or contain more than one ring. Polycyclic cycloalkyls include bridged, fused, and spirocyclic cycloalkyls.

[0025] The term "aryl group" (alone or in combination with other terms) means an aromatic carbocyclyl containing 6 to 14 carbon ring atoms, optionally 6 to 8, 6 to 7, and optionally 6 carbon ring atoms. n An "aryl" group refers to an aromatic group containing n carbon atoms. For example, C6-C 10 The aryl group contains 6, 7, 8, 9, or 10 carbon atoms. The bond to the aryl group is via a carbon atom. The aryl group can be monocyclic or polycyclic (i.e., it can contain more than one ring). In the case of a polycyclic aromatic ring, only one ring in the polycyclic ring system need be unsaturated, while the remaining rings can be saturated, partially saturated, or unsaturated. The bond to the aryl group is via a carbon atom contained in the ring. Examples of aryl groups include phenyl, naphthyl, acridinyl, indenyl, indanyl, and tetrahydronaphthyl. Preferably, the aryl group is phenyl.

[0026] The term "arylalkyl" refers to an aryl substituent attached via an alkyl chain. Examples of arylalkyl substituents include phenylethyl / ethylbenzyl (where an ethyl chain connects the phenyl group to the point of attachment). n " In arylalkyl, C n contains the carbon atoms of the alkyl chain and the aryl group. For example, ethylbenzene is a C8 arylalkyl.

[0027] The term "arylalkenyl" refers to an aryl substituent attached via an alkenyl chain. Examples of arylalkenyl substituents include phenylethenyl / ethenylbenzyl (where the ethenyl chain connects the phenyl group to the point of attachment). n " In arylalkyl, C n includes the carbon atoms of the alkyl chain and the aryl group. For example, phenylethenyl is a C8 arylalkenyl.

[0028] The term "heteroaryl group" (alone or in combination with other terms) means an aromatic heterocyclyl containing 5 to 14 ring atoms. n A "heteroaryl" group refers to an aromatic group containing n carbon atoms and at least one heteroatom. For example, C-C 10 Aryl groups contain 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, in addition to at least one heteroatom. Bonding to the heteroaryl group can occur through a carbon atom or a heteroatom. Heteroaryl groups can be monocyclic or polycyclic. Heteroaryls can be monocyclic or have two or three condensed rings. Examples of monocyclic heteroaryl groups include six-membered rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4-, or 1,2,3-triazinyl; and five-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 can have two or three condensed rings. Examples of polycyclic heteroaryl groups 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. In the case of polycyclic heteroaryl groups, only one ring in the polycyclic ring system need be unsaturated, while the remaining rings can be saturated, partially saturated, or unsaturated.

[0029] The term "amino group" refers to the group -NR'R" . An amino group can be unsubstituted or substituted. In an unsubstituted amino group, R' and R" are hydrogen. In a substituted amino group, R' and R" can, independently of each other, be, but are not limited to, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, sulfonyl, alkenyl, alkanoyl, aryl, arylalkyl, or heteroaryl, with the proviso that R' and R" are not both simultaneously hydrogen. In a substituted amino group, R' and R" can cyclize to form a heterocyclic group containing the nitrogen to which they are attached (e.g., a pyrrolidine group). The heterocyclic group formed by R' and R" can optionally contain additional heteroatoms, such as nitrogen or oxygen (e.g., an NR'R" group can form morpholine or piperazine). The heterocyclic group formed by R' and R" can be monocyclic, polycyclic (e.g., bicyclic), spirocyclic, or bridged (e.g., diazabicyclo[3.2.1]octane) groups. Such cyclic amino groups can be optionally substituted, for example, with amino, methyl, hydroxyl, or oxo groups.

[0030] The term "hydroxyl group" refers to an --OH group.

[0031] The term "oxo group" refers to a (=O) group, i.e., a substituent oxygen atom attached to another atom by a double bond. For example, a carbonyl group (-C(=O)-) is a carbon atom attached to an oxygen atom by a double bond, i.e., an oxo group attached to a carbon atom.

[0032] The term "halo group" refers to a group selected from chlorine, fluorine, bromine and iodine. Preferably, halo groups are selected from chlorine and fluorine.

[0033] The term "optionally substituted" means that the group may be substituted with one or more substituents, which may be the same or different, or that the group may have no substituents. The term "optionally monosubstituted" means that the group may have a single substituent or may be unsubstituted.

[0034] Substituents can be attached via a carbon atom and / or heteroatom in the alkyl, alkenyl, cycloalkyl, aryl, or group. The term "substituent" (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.

[0035] In certain embodiments, the substituents are 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.

[0036] In certain embodiments, each of the one or more substituents of any optionally substituted group is independently OH, F, Cl, Br, I, CN, C1-C6 alkyl, CF3, CHF2, CH2F, CH2OH, C(O)CH3, CH2NHC(O)OCH2CH 3、 and selected from C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, amino, C1-C6 alkylamine, C5-C6 aryl, C3-C6 heteroaryl, benzyl, oxo, and amido, or two adjacent substituents may be joined together to form a ring.

[0037] If a group is substituted with a further optionally substituted group, it is understood that the initial substituent may itself be unsubstituted or substituted.

[0038] For completeness, it is also noted that certain chemical formulas used herein define delocalized systems. This definition is also known in the art as the definition of aromaticity and may refer, for example, to the presence of planar monocyclic, bicyclic, or tricyclic ring systems containing (4n+2) electrons, where n is an integer. In other words, these systems may exhibit Hückel aromaticity.

[0039] In any embodiment, the compounds of the present invention may have certain stereochemical aspects. For example, the compounds may have chiral centers and / or planes and / or axes of symmetry. Unless otherwise specified, the compounds of the present invention encompass all such stereoisomers. That is, the compounds may be provided as single stereoisomers, single diastereomers, mixtures of stereoisomers, or racemic mixtures, unless otherwise specified. Stereoisomers are known in the art as molecules that have the same molecular formula and arrangement of bonded atoms, but differ in the spatial orientation of the atoms and / or groups.

[0040] Furthermore, compounds of the invention may exhibit tautomerism, and each tautomeric form is intended to be within the scope of the invention.

[0041] Additionally, the compounds of the present invention are provided as prodrugs, which are converted, generally in vivo, from one form to the active form of the drug described herein.

[0042] Additionally, it is understood that the elements described herein may be common isotopes or isotopes other than common isotopes. For example, hydrogen atoms are 1 H, 2 H (deuterium) or 3 H (tritium).

[0043] Additionally, the compounds of the present invention may be provided in the form of a pharmaceutically acceptable salt or co-crystal.

[0044] The term "pharmaceutically acceptable salt" refers to an ionic compound formed by the addition of an acid to a base. This term refers to salts that are considered in the art to be suitable for use, for example, in vivo in contact with a patient; pharmaceutically acceptable salts are generally chosen for their non-toxic and non-irritating characteristics.

[0045] The term "co-crystal" refers to a multi-component molecule that may involve non-ionic interactions.

[0046] Pharmaceutically acceptable salts and co-crystals can be prepared by ion exchange chromatography or by reacting the free base or acid form of the compound with a stoichiometric amount or an excess of one or more desired salt-forming inorganic or organic acids or bases in a suitable solvent, or by mixing with other pharmaceutically acceptable compounds capable of forming co-crystals with the present compounds.

[0047] Salts known in the art to be generally suitable for use in contact with patients include salts derived from inorganic and / or organic acids, including hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, and tartrate. These may contain cations based on alkali and alkaline earth metals, such as sodium, potassium, calcium, and magnesium, as well as ammonium, tetramethylammonium, and tetraethylammonium. For further information on suitable pharmaceutically acceptable salts, see the Handbook of Pharmaceutical Salts published by IUPAC.

[0048] Additionally, compounds of the present invention may exist as zwitterions and are considered as part of this invention.

[0049] Thus, in a first aspect of the present invention, there is provided a compound of formula (I), including stereoisomers: [ka] [During the ceremony: "m" is 0, 1, or 2, and each R 1 is independently selected from halo; C1-C6 alkyl optionally substituted with halo; and C3-C6 cycloalkyl; "n" is 0, 1, or 2, and each R 2 are independently selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, wherein each of the one or more optional substituents is independently selected from C1-C6 alkyl and halo; or where "n" is 2 and each R2, together with the one or more carbon ring atoms to which they are attached, form a C3-C6 fused cycloalkyl ring, a C3-C6 spirocyclic cycloalkyl ring, or a C3-C4 bridge; R' is H or C1-C6 alkyl, optionally H; R 3 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted C7-C 10 Arylalkyl, optionally substituted C-C 10 arylalkenyl and optionally substituted C3-C6 heteroaryl; wherein each of the one or more optional substituents is independently selected from halo; C1-C6 alkyl optionally substituted with halo; and C3-C6 cycloalkyl optionally substituted with methyl or CF3; R 4 is H, Cl, C1-C6 alkyl; wherein one of X and Z is O and one of X and Z is NR′, where R′ is H or C1-C6 alkyl, optionally H, such that X and Z are morpholine rings; or a pharmaceutically acceptable salt or solvate thereof.

[0050] According to formula (I), each R 1 and R 2 When present, may be attached to any carbon atom of each ring.

[0051] According to formula (I), when "m" is 2, each R 1 The substituents are independently selected from the listed options and can therefore be the same or different from one another. Similarly, when "n" is 2, each R 2 The substituents are independently selected from the listed options and, therefore, may be the same or different from one another.

[0052] In a preferred embodiment, the compound of formula (Ia), including stereoisomers: [ka] [During the ceremony: "m", "n", R 1 ~R 4 and R' is as defined above in relation to formula (I). or a pharmaceutically acceptable salt or solvate thereof.

[0053] In certain embodiments of formula (I) or (Ia), R' is preferably H.

[0054] In another embodiment of Formula (I), X is NR' and Z is O.

[0055] In certain preferred embodiments of Formula (I) or (Ia), "m" is 0 or 1. In certain such embodiments, "m" is 0 - i.e., the phenyl ring is unsubstituted. In certain other embodiments, "m" is 1 - i.e., the phenyl ring is monosubstituted.

[0056] In these embodiments where "m" is 1, R 1 is selected from halo; C-C alkyl optionally substituted with halo; and C-C cycloalkyl. In some such embodiments, R 1 is selected from fluoro, chloro, C3-C6 cycloalkyl and C1-C6 alkyl optionally substituted with fluoro, e.g., methyl or CF3. In certain preferred embodiments, R1 is selected from Cl; F; and methyl optionally substituted with F, optionally CF. In certain preferred embodiments, R 1 is Cl or F. In one preferred embodiment, R 1 is methyl optionally substituted with F. In one preferred embodiment, R 1 is CF3.

[0057] In one preferred embodiment, R 1 When present as a substituent, is at the 3-position of the phenyl ring. Thus, preferably the compounds of the present invention have the formula (Ib): [ka] wherein "m" is 0 or 1, and the remaining integers are as defined in relation to formula (I). It is of the type.

[0058] In certain embodiments, preferred features of formulas (Ia) and (Ib) include when Z is NH, X is O, and R 1 When present as a substituent, it is attached at the 3-position of the phenyl ring. That is, some preferred compounds of the present invention have the formula (Ic): [ka] wherein "m" is 0 or 1, and the remaining integers are as defined in relation to formula (I). It is of the type.

[0059] In certain preferred embodiments of all aspects (including Formulas (I), (Ia), (Ib), (Ic), and (Id)), "n" is 1 or 2. Alternatively, in certain embodiments, "n" is 0 and the morpholine ring is R 2 It has no substituents. In some preferred embodiments, "n" is 1. In some preferred embodiments, "n" is 2.

[0060] In some embodiments, when "n" is 2, each R2 The substituents are in the same position on the morpholinyl ring. Alternatively, when "n" is 2, each R 2 The substituents may be at different positions on the morpholinyl ring.

[0061] As will be appreciated by those skilled in the art and in accordance with IUPAC convention, the numbering of ring atoms in a morpholine ring always begins with the oxygen atom. In the numbering used herein, the numbering method is such that the point of attachment of the morpholinyl ring to the phenyl ring is the lowest possible number. Therefore, for compounds where Z is NR' and X is O, the ring atoms are numbered as follows: [ka] On the other hand, for compounds where Z is O and X is NR', the ring atoms are numbered as follows: [ka]

[0062] Depictions herein of substituents at certain positions on the morpholinyl ring are to be construed accordingly.

[0063] In certain preferred embodiments, when "n" is 1 or 2, at least one R 2 The substituent is at the 6-position of the morpholinyl ring. In preferred such embodiments, each R 2 The substituent is at the 6-position of the morpholinyl ring.

[0064] In some embodiments, when "n" is 1 or 2, at least one R 2 The group is at the 2-position of the morpholinyl ring. In certain preferred such embodiments, each R 2 The substituent is at the 2-position of the morpholinyl ring.

[0065] In some embodiments, when "n" is 1 or 2, at least one R 2 The group is at the 5-position of the morpholinyl ring. In certain preferred embodiments, each R2 The substituent is at the 5-position of the morpholinyl ring.

[0066] In some embodiments, "n" is 2 and each R 2 are attached to the same carbon ring atom. In some other embodiments, "n" is 2 and each R 2 are attached to different carbon ring atoms, for example adjacent carbon ring atoms.

[0067] In certain preferred embodiments of all aspects, R 2 is independently selected from methyl optionally substituted with F; ethyl; and cyclopropyl. In some such embodiments, R 2 is selected from methyl, CHF2, CF3, ethyl, and cyclopropyl. 2 is methyl. In some embodiments, "n" is 2 and each R 2 is methyl. In some such embodiments, each methyl group is attached to the same carbon ring atom. In some such embodiments, each methyl group is attached to the 6-position of the morpholine ring. Alternatively, each methyl group can be attached to a different carbon ring atom.

[0068] Alternatively, in some embodiments, "n" is 1 and R 2 is methyl.

[0069] In certain embodiments of all aspects (including Formulas (I), (Ia), (Ib), (Ic) and (Id)), R 2 The presence of the substituent provides a chiral center at the morpholinyl ring carbon to which it is attached. In certain preferred such embodiments, R 2 The substituent is at the R position. In an alternative and equally preferred embodiment, R 2 The substituent is in the S position.

[0070] For example, n is 1 and R 2 In certain embodiments of Formula (Ic), wherein is at the 6-position of the morpholine ring, the present invention provides a compound of Formula (Ic): I ,(I C) ii ,(I C) iiior (Ic) iv : [ka] [In the formula, m, R 1 , R 2 , R 3 and R 4 is as defined in relation to formula (Ic); R 2 are preferably independently selected from methyl, CHF2, CF3, ethyl and cyclopropyl. In some such embodiments, R 2 is preferably methyl, ethyl, or cyclopropyl. In some such embodiments, R 2 is methyl. In some such embodiments, R 2 is ethyl.

[0071] In some embodiments, "n" is 2 and each R 2 together with one or more carbon ring atoms to which they are attached, form a C-C spirocyclic cycloalkyl ring. In one preferred embodiment, "n" is 2 and each R 2 together with the carbon ring atoms to which they are attached form a C3 or C4 spirocyclic cycloalkyl ring. In one preferred such embodiment, "n" is 2 and each R 2 together: [ka] Form.

[0072] In some such embodiments, Z is NR' and X is O. Alternatively, X is NR' and Z is O.

[0073] In one preferred embodiment, "n" is 2 and each R 2 taken together with the carbon ring atoms to which they are attached form a C3-C6 fused cycloalkyl ring.

[0074] In some such embodiments, two R 2 The substituents are on adjacent carbon ring atoms.

[0075] In some embodiments, "n" is 2 and each R 2 together with the carbon ring atoms to which they are attached form a C3, C5, or C6 fused cycloalkyl ring. 2 are taken together to form a C3 fused cycloalkyl ring. In some such embodiments, each R 2 are taken together to form a C5 fused cycloalkyl ring. In some such embodiments, each R 2 together form a C6 fused cycloalkyl ring.

[0076] In some embodiments, "n" is 2 and each R 2 together: [ka] Form.

[0077] In some such embodiments, Z is NR' and X is O. Alternatively, X is NR' and Z is O.

[0078] In some embodiments, "n" is 2 and each R 2 together: [ka] Form.

[0079] In some such embodiments, Z is NR' and X is O. Alternatively, X is NR' and Z is O.

[0080] In some embodiments, "n" is 2 and each R 2 together: [ka] Form.

[0081] In some such embodiments, Z is NR' and X is O. Alternatively, X is NR' and Z is O.

[0082] In some embodiments, "n" is 2 and each R 2 together with the carbon ring atoms to which they are attached form a C3 or C4 bridged ring. In some embodiments, "n" is 2 and each R 2 together with the carbon ring atoms to which they are attached form a C4 bridged ring.

[0083] In some embodiments, "n" is 2 and each R 2 together with the carbon ring atoms to which they are attached: [ka] Form.

[0084] In all embodiments (including formulas (I), (Ia), (Ib), (Ic) and (Id)), R 3 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted C7-C 10 Arylalkyl, optionally substituted C-C 10 arylalkenyl and optionally substituted C3-C6 heteroaryl; wherein each of the one or more optional substituents is independently selected from halo; C1-C6 alkyl optionally substituted with halo; and C3-C6 cycloalkyl optionally substituted with methyl or CF3.

[0085] In some embodiments (including Formulas (I), (Ia), (Ib), (Ic) and (Id)), R 3 is an optionally substituted C3-C6 cycloalkyl, an optionally substituted phenyl, an optionally substituted C7-C 10Arylalkyl, optionally substituted C-C 10 arylalkenyl and optionally substituted C3-C6 heteroaryl; wherein each of the one or more optional substituents is independently selected from halo; C1-C6 alkyl optionally substituted with halo; and C3-C6 cycloalkyl optionally substituted with methyl or CF3.

[0086] In some embodiments, R 3 is an optionally substituted C3-C6 cycloalkyl. In some such embodiments, each of the one or more optional substituents is independently selected from halo; C1-C2 alkyl optionally substituted with F; and C3-C6 cycloalkyl.

[0087] In some embodiments, R 3 is an optionally substituted cyclopropyl. In some such embodiments, each of the one or more optional substituents is independently selected from methyl, CHF, CF, and cyclopropyl. In some embodiments, R 3 is an optionally substituted cyclopropyl, wherein one of the one or more optional substituents is methyl. In certain embodiments, R 3 is an optionally substituted cyclopropyl, wherein one of the one or more optional substituents is CHF. In certain embodiments, R 3 is an optionally substituted cyclopropyl, wherein one of the one or more optional substituents is CF. In certain embodiments, R 3 is an optionally substituted cyclopropyl, where one of the one or more optional substituents is cyclopropyl.

[0088] In some embodiments, R 3 is the general formula: [ka] [In the formula, R 5 and R 6are each independently selected from hydrogen, halo; C1-C2 alkyl optionally substituted with F; and C3-C6 cycloalkyl. is an optionally substituted cyclopropyl group of the formula:

[0089] That is, in one embodiment, the compounds of the present invention have the formula (Id): [ka] [In the formula, R 5 and R 6 is as defined herein, and the remaining integers are as defined in relation to formula (I), (Ia), (Ib) or (Ic). It can be of the following type.

[0090] R 5 and R 6 is a substituent as defined above and is independently selected from hydrogen, halo; C1-C2 alkyl optionally substituted with F; and C3-C6 cycloalkyl. In certain embodiments, R 5 and R 6 are each independently selected from hydrogen, methyl, CHF2, CF3, and cyclopropyl.

[0091] In some embodiments, R 5 is selected from hydrogen, methyl, CHF2, and CF3. In some embodiments, R 5 is selected from hydrogen, methyl, and CF. In some embodiments, R 5 is selected from hydrogen and CF. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is CF3.

[0092] In some embodiments, R 6 is selected from hydrogen, methyl, CHF2, CF3, and cyclopropyl. 6 is selected from methyl and cyclopropyl. 6 is methyl.

[0093] In the compound of formula (Id), R 5 and / or R 6 The presence of the substituents provides a chiral center at the relevant cyclopropyl ring carbon. 5 The substituents are in the R configuration. In certain other embodiments, R 5 The substituent is in the S configuration. In some such embodiments, R 6 The substituents are in the R configuration. In certain other embodiments, R 6 The substituent is in the S configuration.

[0094] For example, in certain embodiments of Formula (Id), the compound has the formula (Id): i , (Id) ii , (Id) iii or (Id) iv : [ka] It can be either of the following.

[0095] In certain other embodiments (i.e., formula (I), (Ia), (Ib) or (Ic)), R 3 is an optionally substituted phenyl. In some such embodiments, each of the one or more optional substituents is independently selected from halo; C-C alkyl optionally substituted with F; and C-C cycloalkyl optionally substituted with methyl or CF.

[0096] In some embodiments, R 3 is an optionally substituted phenyl, wherein each of the one or more optional substituents is independently selected from Cl, F, methyl, CF, CHF, and cyclopropyl optionally substituted with methyl or CF. In certain embodiments, R 3 is an optionally substituted phenyl, wherein one of the one or more optional substituents is Cl. In certain embodiments, R 3is an optionally substituted phenyl, wherein one of the one or more optional substituents is F. In certain embodiments, R 3 is an optionally substituted phenyl, wherein one of the one or more optional substituents is methyl. In certain embodiments, R 3 is an optionally substituted phenyl, wherein one of the one or more optional substituents is CF. In certain embodiments, R 3 is an optionally substituted phenyl, wherein one of the one or more optional substituents is CHF. In certain embodiments, R 3 is an optionally substituted phenyl, where one of the one or more optional substituents is cyclopropyl optionally substituted with methyl. In certain embodiments, R 3 is an optionally substituted phenyl, where one of the one or more optional substituents is cyclopropyl optionally substituted with CF3.

[0097] In some embodiments, R 3 is an optionally substituted C7-C 10 In some such embodiments, each of the one or more optional substituents is independently selected from halo; C-C alkyl optionally substituted with halo; and C-C cycloalkyl optionally substituted with methyl or CF.

[0098] In some embodiments, R 3 is an optionally substituted (CH)-phenyl. In some such embodiments, each of the one or more optional substituents is independently selected from halo; C-C alkyl optionally substituted with halo; and C-C cycloalkyl optionally substituted with methyl or CF. In some embodiments, R 3 is an optionally substituted (CH)-phenyl, where one of the one or more optional substituents is halo. In certain embodiments, R 3is an optionally substituted (CH)-phenyl, where one of the one or more optional substituents is C-C alkyl optionally substituted with halo, e.g., CHF or CF. In certain embodiments, R 3 is an optionally substituted (CH)-phenyl, where one of the one or more optional substituents is a C-C cycloalkyl (e.g., cyclopropyl) optionally substituted with methyl. In certain embodiments, R 3 is an optionally substituted (CH2)2-phenyl, where one of the one or more optional substituents is a C3-C6 cycloalkyl (e.g., cyclopropyl) optionally substituted with CF3.

[0099] In some embodiments, R 3 is an optionally substituted (CH)-phenyl, where one of the one or more optional substituents is on the ethylene chain. In some such embodiments, the optional substituents on the ethylene chain are selected from methyl or ethyl, optionally substituted with F.

[0100] In some embodiments, R 3 is an optionally substituted (CH)-phenyl, where one of the one or more optional substituents is on the ethylene chain and is selected from methyl, CHF, and CF. In some such embodiments, the optional substituent is CHF. In some such embodiments, the optional substituent is CF.

[0101] In one preferred embodiment, R 3 When R is an optionally substituted (CH)-phenyl, the optional substituent on the ethylene chain is on the second methylene group - i.e., R 3 is —CH—CHR-Ph, where “R” is an optional substituent.

[0102] In some such embodiments, R 3The substituents on the ethylene chain result in a chiral center at the chain carbon. In certain preferred embodiments, the compound is the R stereoisomer at this position. In certain other preferred embodiments, the compound is the S stereoisomer at this position.

[0103] Preferably, R 3 When is an arylalkyl group, each of the one or more optional substituents on the arylalkyl group is independently selected from F, Cl, methyl, ethyl, CHF2, and CF3.

[0104] According to all embodiments (including formulas (I), (Ia), (Ib), (Ic) and (Id)), R 4 is selected from H, Cl and C1-C6 alkyl.

[0105] In some embodiments, R 4 is chlorine.

[0106] In certain other embodiments, R 4 is H or C1-C6 alkyl. For example, R 4 can be H or methyl.

[0107] In certain embodiments of all aspects (including formulae (I), (Ia), (Ib), (Ic), and (Id)), the chiral center at the morpholinyl ring carbon attached to the phenyl ring is at the R position. In certain embodiments of all aspects (including formulae (I), (Ia), (Ib), (Ic), and (Id)), the chiral center at the morpholinyl ring carbon attached to the phenyl ring is at the S position. That is, the present invention provides compounds of the general formula: [ka] This includes compounds of the formula:

[0108] Also provided in a first aspect is the following compound (or a pharmaceutically acceptable salt or solvate thereof): rac-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3R,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, rac-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3R,5S)-5-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 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, 6-chloro-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, 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, 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, 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, 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, rac-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6R)-6-(trifluoromethyl)morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 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, 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, 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, 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, 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, 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, 6-chloro-7-(4-(5,5-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 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, 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, 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, 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, 3-((1-benzoyl-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, 6-chloro-3-((1-(4-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, 6-chloro-3-((1-(2,4-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, (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, 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, 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, 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, 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3S,5R)-5-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (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, (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, 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, 6-chloro-3-((1-(2-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, 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, 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, (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, 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, 6-chloro-3-((1-(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, 6-chloro-3-((1-(3,4-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, 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, 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, (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]pyrimidin-4-one, (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]pyrimidin-4-one, 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, 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, 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, 6-chloro-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 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, 7-(4-((1R,2S,5S)-8-oxa-3-azabicyclo[3.2.1]octan-2-yl)phenyl)-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 7-(4-((1R,2S,5S)-8-oxa-3-azabicyclo[3.2.1]octan-2-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, 6-chloro-3-((1-(4-chloro-2-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, 6-chloro-3-((1-(3-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, 6-chloro-3-((1-(2-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, 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-(octahydro-2H-benzo[b][1,4]oxazin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-(octahydrocyclopenta[b][1,4]oxazin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-(4-methylbenzoyl)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, 6-chloro-3-((4-hydroxy-1-(4-(trifluoromethyl)benzoyl)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, 6-chloro-3-((1-(2-chloro-4-methylbenzoyl)-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, 6-chloro-3-((1-(2,4-dimethylbenzoyl)-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, 6-chloro-3-((1-(2,4-dimethylbenzoyl)-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, 7-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-4-yl)phenyl)-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3S,6R)-6-cyclopropylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-((1S,2S)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)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, 6-chloro-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)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, 6-chloro-3-((1-cinnamoyl-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, 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6S)-6-cyclopropylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)methyl)-7-(4-((3R,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((1S,2S)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-7-(4-((R)-6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((1S,2S)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-7-(4-((S)-6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((1S,2S)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-7-(4-((R)-6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-7-(4-((S)-6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3S,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6R)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (S)-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (R)-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-7-(3-fluoro-4-(morpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (S)-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(3-methyl-4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (R)-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(3-methyl-4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-(4-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (S)-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (R)-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-((R)-4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-7-(4-((S)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (S)-3-((1-([1,1'-bi(cyclopropane)]-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-chloro-7-(4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (R)-3-((1-([1,1'-bi(cyclopropane)]-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-chloro-7-(4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-((R)-4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-7-(4-((R)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((1-((R)-4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((S)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-(1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((S)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-(1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((R)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((1-((R)-4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((R)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-7-(3-chloro-4-((S)-morpholin-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, 6-chloro-7-(3-chloro-4-((R)-morpholin-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, 6-chloro-3-((4-hydroxy-1-((R)-4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-7-(4-((S)-morpholin-3-yl)-3-(trifluoromethyl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-((R)-4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-7-(4-((R)-morpholin-3-yl)-3-(trifluoromethyl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-(morpholin-2-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((1-(4-chloro-2-methylbenzoyl)-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, 6-chloro-3-((1-(4-chloro-2-methylbenzoyl)-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, 6-chloro-3-((1-(4-(difluoromethyl)benzoyl)-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, 6-chloro-3-((1-(4-(difluoromethyl)benzoyl)-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, 6-chloro-3-((1-(4-cyclopropylbenzoyl)-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, 6-chloro-3-((4-hydroxy-1-(4-(1-methylcyclopropyl)benzoyl)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, 6-chloro-3-((1-((1S,2S)-1,2-dimethylcyclopropane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((1-((1R,2R)-1,2-dimethylcyclopropane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 7-(4-((1S,2R,5R)-8-oxa-3-azabicyclo[3.2.1]octan-2-yl)phenyl)-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (R)-6-chloro-7-(4-(6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, (S)-6-chloro-7-(4-(6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((1-(2,2-dicyclopropylacetyl)-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, 6-chloro-7-(4-((3R,6S)-6-cyclopropylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-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, 6-chloro-3-((4-hydroxy-1-(1-methylcyclobutane-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, 6-chloro-3-((1-(3-cyclopropylpropanoyl)-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, 6-chloro-7-(4-((3S,6R)-6-cyclopropylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-7-(4-((3S,6R)-6-ethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3S,6R)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3S,6R)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-((1S,2S)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3S,6R)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((S)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((R)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 6-chloro-3-((1-((1S,2S)-2-(difluoromethyl)-1-methylcyclopropane-1-carbonyl)-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, and 6-chloro-3-((1-((1R,2R)-2-(difluoromethyl)-1-methylcyclopropane-1-carbonyl)-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.

[0109] In certain embodiments, the compounds of the present invention have an IC50 of about 1 nM to about 10,000 nM against USP7, more preferably about 1 nM to about 1000 nM, or about 100 nM to about 1000 nM, or about 100 nM to about 500 nM, or about 100 nM to about 300 nM, or about 100 nM to about 250 nM. 50In certain preferred embodiments, compounds of the present invention have IC values ​​of less than 500 nM, most preferably less than 250 nM, against USP7. 50 The compound has an IC value against USP7. 50 The method for determining the value is as follows (see Examples).

[0110] In certain embodiments, there is provided a compound of Formula (I), (Ia), (Ib), (Ic) or (Id) of the first aspect or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.

[0111] While it is possible for the compounds of the present invention to be administered alone, they are preferably provided as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one USP7 inhibitor described herein together with one or more other pharmaceutically acceptable ingredients known to those of skill in the art, including pharmaceutically acceptable carriers, diluents, additives, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweetening agents. The formulation may further comprise other active agents, e.g., other therapeutic or prophylactic agents.

[0112] In a second aspect, therefore, the present invention provides a pharmaceutical composition comprising a compound of any embodiment of the first aspect, such as a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0113] Pharmaceutical compositions may be formulated by mixing, for example, additives, binders, lubricants, disintegrants, coating agents, emulsifiers, suspending agents, solvents, stabilizers, absorption enhancers, and / or ointment bases depending on the particular use and purpose. The compositions may be suitable for oral, injectable, rectal, topical buccal, sublingual, transmucosal, transdermal, intranasal, pulmonary, ocular, vaginal, or parenteral administration.

[0114] Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical reference books, e.g. Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; Handbook of Pharmaceutical Excipients , 5th edition, 2005.

[0115] Suitable pharmaceutically acceptable additives are therefore known to those skilled in the art, for example: fats, water, saline, alcohols (e.g. ethanol), glycerol, polyols, aqueous glucose solutions, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings or fragrances, thickeners, diluents, buffer substances, solvents or solubilizers, chemicals achieving a preservative effect, salts for modifying the osmotic pressure, coating agents or antioxidants, sugars such as lactose or glucose; corn, wheat or rice starch; fatty acids such as stearic acid; inorganic salts such as magnesium aluminometasilicate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycols; alcohols such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives such as methylcellulose, carboxymethylcellulose, ethylcellulose or hydroxypropylmethylcellulose; and other customary additives such as gelatin, talc, vegetable oils and gum arabic.

[0116] For example, the pharmaceutical compositions may be administered orally in the form of tablets, coated tablets, hard or soft gelatin capsules, solutions, emulsions or suspensions, etc. Administration may also be carried out rectally, e.g., using suppositories, topically or transdermally, e.g., using ointments, creams, gels or solutions, or parenterally, e.g., using injectable solutions.

[0117] The formulation can be prepared by any method known in the pharmaceutical art. Such methods include the step of combining the compound with a carrier that constitutes one or more accessory ingredients. Generally, the formulation is prepared by uniformly and intimately combining the compound with a carrier (e.g., a liquid carrier, a finely divided solid carrier, etc.), and then, if necessary, shaping the product.

[0118] For the preparation of tablets, coated tablets or hard gelatin capsules, the compounds of the present invention can be mixed with pharmaceutically inert, inorganic or organic additives.Examples of suitable additives include lactose, maize starch or its derivatives, talc or stearic acid or its salts.Suitable additives for use in soft gelatin capsules include, for example, vegetable oils, waxes, fats and semi-solid or liquid polyols.

[0119] For the production of solutions and syrups, additives include, for example, water, polyols, sucrose, invert sugar and glucose.

[0120] For injectable solutions, additives include, for example, water, alcohols, polyols, glycerin and vegetable oils.

[0121] For suppositories and topical and transdermal applications, excipients include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.

[0122] The pharmaceutical compositions may also include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, odorants, buffers, coating agents, and / or antioxidants.

[0123] For combination therapy, the second drug may be provided in a pharmaceutical composition together with the present invention or may be provided separately.

[0124] Thus, pharmaceutical preparations for oral administration may be, for example, granules, tablets, sugar-coated tablets, capsules, pills, suspensions, or emulsions. For parenteral injection, for example, for intravenous, intramuscular, or subcutaneous use, sterile aqueous solutions may be provided, which may contain other substances, including, for example, salts and / or glucose to make the solution isotonic. Anticancer agents may also be administered in the form of suppositories or pessaries, or may be applied topically in the form of lotions, solutions, creams, ointments, or dusting powders.

[0125] In a third aspect, the present invention provides a compound or pharmaceutical composition according to any embodiment of the first or second aspect for use in therapy, preferably in the treatment and / or prophylaxis of cancer.

[0126] In a fourth aspect, the present invention provides a method of treating or preventing cancer, comprising administering to a subject a compound of any embodiment of the first aspect of the invention or a pharmaceutical composition of any embodiment of the second aspect of the invention.

[0127] The term "treatment," as used herein in describing treating a disorder, generally refers to the treatment of humans or animals (e.g., in veterinary applications) to achieve a desired therapeutic effect, such as inhibiting the progression of the disorder, including reducing the rate of progression, stopping progression, alleviating symptoms of the disorder, ameliorating the disorder, and curing the disorder. Treatment as a prophylactic (i.e., preventative) measure is also included. For example, use in patients who have not yet developed the disorder but are at risk of developing the disorder is included in the term "treatment." For example, treatment includes preventing cancer, reducing the incidence of cancer, alleviating symptoms of cancer, etc.

[0128] The subject / patient can be a mammal, chordate, vertebrate, placental mammal, marsupial (e.g., kangaroo, wombat), monotreme (platypus), rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (e.g., pig), ovine (e.g., sheep), bovine (e.g., cow), primate, ape (e.g., monkey or ape), simian (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or human. Furthermore, the subject / patient can be in any of its developmental forms, for example, a fetus.

[0129] In a preferred embodiment, the subject / patient is a human.

[0130] Suitable cancers or neoplastic conditions to be treated or prevented by these methods include, for example, prostate cancer, colon cancer, breast cancer, lung cancer, kidney cancer, skin cancer (e.g., melanoma), liver cancer, pancreatic cancer, CNS cancer (e.g., neuroblastoma, glioblastoma), osteosarcoma, and hematological malignancies (e.g., leukemia, multiple myeloma, and mantle cell lymphoma). In a preferred embodiment, the cancer is associated with p53 dysregulation. In a preferred embodiment, the cancer is selected from hematological malignancies (e.g., mantle cell lymphoma, multiple myeloma), prostate cancer, neuroblastoma, or glioblastoma.

[0131] The cancer or neoplastic condition suitable for treatment with the compound or composition of the present invention includes, for example, prostate cancer, colon cancer, breast cancer, lung cancer, kidney cancer, skin cancer (e.g., melanoma), liver cancer, pancreatic cancer, CNS cancer (e.g., neuroblastoma, glioblastoma), osteosarcoma, hematological malignancies (e.g., leukemia, multiple myeloma and mantle cell lymphoma).In some preferred embodiments, cancer is associated with p53 dysregulation.In some preferred embodiments, cancer is selected from hematological malignancies (e.g., mantle cell lymphoma, multiple myeloma), prostate cancer, neuroblastoma or glioblastoma.

[0132] WO2021 / 161047 shows that USP7 inhibitors can treat cancer by acting on the tumor microenvironment (TME), for example, by inhibiting USP7 in fibroblasts. The contents and disclosure of WO2021 / 161047 are expressly incorporated herein by reference.

[0133] Accordingly, provided herein is a method for 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.

[0134] In certain embodiments, administration of a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, treats cancer by inhibiting USP7 activity in cancer-associated fibroblasts (CAFs).

[0135] In some embodiments, administration of a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, treats cancer by reducing the level of VEGF in the serum of a subject. In some embodiments, administration of a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, treats cancer by reducing the level of VEGF in the tumor microenvironment.

[0136] In certain embodiments, administration of a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, treats cancer by inhibiting the production of VEGF by cancer-associated fibroblasts (CAFs).

[0137] In a further aspect, a method of treating cancer by modulating the tumor immune environment is provided, 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 tumor immune environment.

[0138] In a further embodiment, provided is a method of treating cancer by increasing tumor infiltrating lymphocytes (TILs), 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.

[0139] In a further embodiment, provided is a method of treating cancer by reducing 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 reduces the ratio of Treg cells to CD8+ T cells in the TME.

[0140] In a further aspect, provided is a method of treating cancer by reducing 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 reduces the number of macrophages in the TME.

[0141] WO2021 / 161047 also shows that USP7 inhibitors used in combination with immune checkpoint inhibitors exhibit beneficial efficacy (e.g., synergistic efficacy) in the treatment of cancer. The contents and disclosure of WO2021 / 161047 are expressly incorporated herein by reference.

[0142] In a further aspect, provided is a method of treating cancer by administering a combination therapy to a subject in need thereof, wherein the combination therapy comprises a composition comprising a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, and a composition comprising an immune checkpoint inhibitor.

[0143] In a further aspect, there is provided 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.

[0144] In a further aspect, an immune checkpoint inhibitor for use in a method of treating cancer is provided, 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.

[0145] In a further aspect, a combination therapy for use in a method of treating cancer is provided, the method comprising administering a combination therapy to a subject in need thereof, wherein the combination therapy comprises a composition comprising a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, and a composition comprising an immune checkpoint inhibitor.

[0146] In some embodiments, administration of a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, treats cancer by inhibiting extracellular matrix (ECM) remodeling by cancer-associated fibroblasts. In such embodiments, the ECM is the ECM of the tumor microenvironment.

[0147] In certain embodiments, administration of a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, treats cancer by inhibiting basement membrane degradation, optionally renal tubular basement membrane degradation.

[0148] In certain embodiments, administration of a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, treats cancer by inhibiting angiogenesis, and optionally, neovascularization. In such embodiments, angiogenesis is inhibited in the tumor microenvironment.

[0149] In certain embodiments, administration of a compound provided herein, or a pharmaceutically acceptable salt or solvate thereof, treats cancer by modulating the tumor immune environment, e.g., promoting the infiltration of CD8 T cells.

[0150] In some embodiments, the cancer to be treated is formed from cancer cells, and the cancer cells are resistant to the administered compound (or a pharmaceutically acceptable salt or solvate). In some embodiments, the cancer to be treated by the method is formed from cancer cells, and the cancer cells are resistant to the USP7 inhibitor in vitro.

[0151] The compounds or compositions of the present invention may be used in monotherapy and / or in combination modalities.

[0152] As previously described, in certain embodiments, a compound provided herein (or a pharmaceutically acceptable salt or solvate thereof) may be administered in combination with an immune checkpoint inhibitor. In certain embodiments, the checkpoint inhibitor is selected from an inhibitor of PD1, PD-L1, CTLA4, TIGIT, 41BB, OX40, or GITR. In certain embodiments, the checkpoint inhibitor is selected from an anti-PD1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, an anti-41BB antibody, an anti-OX40 antibody, an anti-GITR antibody, and an anti-ICOS antibody. In certain embodiments, the checkpoint inhibitor is selected from an anti-PD1 antibody, an anti-PD-L1 antibody, and an anti-CTLA4 antibody. In certain embodiments, 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 pembrolizumab (Keytruda TM ), nivolumab (Opdivo TM ), cemiplimab (libtayo TM ), atezolizumab (Tecentriq TM ), avelumab (Bavencio TM ), durvalumab (Imfinzi) TM ) and ipilimumab (Yervoy TM ) is selected.

[0153] Other suitable agents that may be combined with the compounds or compositions of the invention in a combination modality include one or more of an anti-cancer agent, an anti-inflammatory agent, an immunomodulatory agent, an immunosuppressant, an agent for neurological disorders, an anti-diabetic agent, an antiviral agent, an antibacterial agent, and / or radiation therapy.

[0154] Agents used in combination with compounds of the present invention may target the same or similar biological pathways as those targeted by compounds of the present invention, or may act on different or unrelated pathways.

[0155] Depending on the disease to be treated, various combination partners may be co-administered with the compounds of the present invention. The second active ingredient may be an alkylating agent, including cyclophosphamide, ifosfamide, thiotepa, melphalan, chloroethylnitrosourea, and bendamustine; a platinum derivative, including cisplatin, oxaliplatin, carboplatin, and satraplatin; a mitotic inhibitor, including vinca alkaloids (vincristine, vinorelbine, and vinblastine), taxanes (paclitaxel, docetaxel), epothilones, and inhibitors of mitotic kinases, including aurora and polo kinase; a topoisomerase inhibitor, including anthracyclines, epipodophyllotoxins, camptothecin, and camptothecin analogs; an antimetabolite, including 5-fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, 6-thioguanine, fludarabine, methotrexate, and pemetrexed. protein kinase inhibitors including imatinib, gefitinib, sorafenib, sunitinib, erlotinib, dasatinib, and lapatinib; proteosome inhibitors including bortezomib; histone deacetylase inhibitors including baroproate and SAHA; anti-angiogenic drugs including bevacizumab; monoclonal antibodies including trastuzumab, rituximab, alemtuzumab, tositumomab, cetuximab, panitumumab; monoclonal antibody conjugates including gemtuzumab ozogamicin, ibritumomab tiuxetan; and hormone therapy agents including antiestrogens (tamoxifen, raloxifene, anastrozole, letrozole, exemestane), antiandrogens (flutamide, bicalutamide), and progesterone analogs or antagonists.

[0156] Those skilled in the art will recognize that the appropriate dosage of the compounds of the present invention and compositions containing such compounds will vary from patient to patient. Determining the optimal dosage generally involves balancing the level of therapeutic benefit against any risk or harmful side effects. The dosage required for therapeutic efficacy may differ from the dosage required for diagnostic efficacy. 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 compound excretion, the duration of treatment, other drugs, compounds, and / or substances used in combination, the severity of the disorder, and the patient's species, sex, age, weight, condition, general health, and medical history. The amount of compound and the route of administration are ultimately at the discretion of the physician, veterinarian, or clinician, but generally the dosage will be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial dangerous or harmful side effects.

[0157] Administration can be once, continuously, or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment.Methods for determining the most effective means and dosage of administration are well known to those skilled in the art and vary depending on the formulation used for treatment, the purpose of treatment, the target cells being treated, and the subject being treated.Single or multiple administrations can be carried out, with the dose level and pattern selected by the treating physician, veterinarian, or clinician.

[0158] With respect to aspects of the present invention relating to therapeutic uses of the compounds of the present invention, the compounds may be administered to a subject in need of treatment in an "effective amount." The term "effective amount" refers to an amount or dose of a compound that, upon single or multiple administration to a subject, provides therapeutic efficacy in treating a disease. A therapeutically effective amount of a compound of the present invention may include an amount ranging from about 0.1 mg / kg to about 20 mg / kg per administration. The therapeutically effective amount for a given patient can be determined by a medical professional in a manner understood by those skilled in the art. The amount of compound administered at any given time may vary so that an optimal amount of compound, either alone or in combination with any other therapeutic agent, is administered during the course of treatment. It is also contemplated that the compounds of the present invention or pharmaceutical compositions containing such compounds may be administered in combination with any other cancer treatment as a combination therapy.

[0159] The features disclosed in the foregoing description or the following claims or the accompanying drawings, whether expressed in a particular form or function disclosed or as a method or process for obtaining a disclosed result, may, insofar as appropriate, be utilized individually or in any combination of such features to realize the invention in its various forms.

[0160] While the invention has been described in conjunction with the above embodiments, many equivalent modifications and variations will be apparent to those skilled in the art in light of this disclosure. Accordingly, the exemplary embodiments of the invention set forth above should be considered illustrative and not restrictive. Various changes to the described embodiments can be made without departing from the spirit and scope of the invention.

[0161] To avoid any misunderstanding, any theoretical explanations provided herein are provided with the intention of enhancing the reader's understanding, and the inventors do not wish to be bound by any of these theoretical explanations.

[0162] Any section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0163] Throughout this specification, including the claims which follow, unless the context requires otherwise, the terms "comprise" and "include" and variations thereof such as "comprises," "including," and "comprises" will be understood to imply the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps.

[0164] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" encompass the plural forms unless the context clearly dictates otherwise. Ranges may be expressed as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations by use of the prefix "about," it will be understood that the particular value forms another embodiment. The term "about" in connection with numerical values ​​is arbitrary and means, for example, ±10%. [Example]

[0165] The invention will now be described in connection with several examples.

[0166] The following example compounds were synthesized by the methods described below. Biochemical Inhibitory IC 50 The values ​​were determined as follows and are shown in the following table.

[0167] [Table 3] [Table 4] USP7 inhibitory activity in Table 3a is classified as follows: [Table 5]

[0168] [Table 6] [Table 7]

[0169] Experimental Section Abbreviations and Acronyms B2Pin2: bis(pinacolato)diboron; Boc: tert-butyloxycarbonyl; Boc2O: di-tert-butyl dicarbonate; br: broad; ca: catalytic amount; Cu(OTf)2: copper(II) trifluoromethanesulfonate; DCM: dichloromethane; d: doublet (spectral); DIPEA: diisopropylethylamine; DMAP: 4-dimethylaminopyridine; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; dp: data point; Pd(dppf)Cl2·C H2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane; EDC: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; ee: enantiomeric excess; equiv.: equivalent; EtOAc: ethyl acetate; Ex.: example; h: hour; HATU: N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; hept: septuplet (spectrum); HFIP: hexafluoroisopropanol; HPLC: high-performance liquid chromatography; IPA: 2-propanol; KOAc: potassium acetate; LC: liquid chromatography; LCMS: liquid chromatography mass spectrometry; M: molar concentration; m / z: mass-to-charge ratio; m-CPBA: 3-chloroperbenzoic acid; MeCN: acetonitrile; MeOH: methanol; min: minutes; MS: mass spectrometry; m: multiplet (spectrum); MTBE: methyl tert-butyl ether; NMR: nuclear magnetic resonance; p: quintuplet (spectrum); Ph: phenyl; ppm: parts per million; prep: preparative; q: quartet (spectrum); quint: quintuplet (spectrum); RBF: round-bottom flask; R T : retention time; rt: room temperature; s: singlet; TFA: trifluoroacetic acid; THF: tetrahydrofuran; t: triplet (spectrum); UV: ultraviolet; v / v: volume / unit volume; w / w: weight / unit weight.

[0170] General experimental conditions Solvents and Reagents Common organic solvents used in the reactions (e.g., THF, DMF, DCM, and MeOH) were purchased from Sigma-Aldrich (登録商標) From Sure / Seal TM Bottles were purchased anhydrous and handled appropriately under nitrogen. Water was deionized using an Elga PURELAB Option-Q. All other solvents used (i.e., workup and purification) were generally HPLC grade and were supplied as received from various commercial sources. Unless otherwise noted, all starting materials used were purchased from commercial sources and used as received.

[0171] Microwave synthesis Microwave operation is performed using Biotage Initiator TM The experiment was carried out using the Eight instrument, which provides good reproducibility and control of temperatures ranging from 60 to 250°C and pressures up to 20 bar.

[0172] Flash chromatography Unless otherwise stated, purification of compounds by flash chromatography was performed by Biotage (登録商標) Sfaer Silica D Duo 60μm Cartridge Column (10~340g), Grace GraceResolv Cartridge Column (4~330g), SILICYCLE SiliaSep TM This was achieved using a Biotage Isolera Four system using either 4-12 g cartridge columns or 25-40 g SILICYCLE SiliaSep PREMIUM cartridge columns. Appropriate gradients of cyclohexane, EtOAc, DCM, and MeOH were used depending on the polarity of the compounds. For more polar and basic compounds, Biotage® Sfaer KP-Amino D cartridge columns (11-28 g) were used.

[0173] NMR spectroscopy 1H NMR spectra were recorded at ambient temperature using a Bruker Avance (300 MHz), Bruker Avance III (400 MHz), or Bruker Ascend (500 MHz) spectrometer. All chemical shifts (δ) are expressed in ppm. The residual solvent signal was used as an internal standard, and characteristic solvent peaks were corrected against the reference data outlined in J. Org. Chem., 1997, 62, pp. 7512-7515; in other cases, the NMR solvent included tetramethylsilane, which was used as an internal standard.

[0174] Liquid Chromatography Mass Spectrometry (LCMS) Retention time (R T Liquid chromatography mass spectrometry (LCMS) studies to determine ) and related mass ions were performed using the following method: Method A The system consisted of an Agilent Technologies 6130 quadrupole mass spectrometer coupled to an Agilent Technologies 1290 Infinity LC system equipped with a UV diode array detector and autosampler. The spectrometer consisted of an electrospray ionization source operating in positive and negative ion mode. LCMS tests were performed on each provided sample using the following conditions: LC column: Agilent Eclipse Plus C18 RRHD, 1.8 μm, 50 × 2.1 mm, maintained at 40 °C. Mobile phase: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in acetonitrile. [Table 8]

[0175] Method BThe system consisted of an Agilent Technologies 6140 single quadrupole mass spectrometer coupled to an Agilent Technologies 1290 Infinity LC system equipped with a UV diode array detector and autosampler. The spectrometer consisted of a multimode ionization source (electrospray and atmospheric pressure chemical ionization) operated in positive and negative ion modes. LCMS tests were performed on each provided sample using the following conditions: LC column: Zorbax Eclipse Plus C18 RRHD, 1.8 μm, 50 × 2.1 mm, maintained at 40 °C. Mobile phase: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in acetonitrile. [Table 9]

[0176] Method C The system consisted of an Agilent Technologies 1100 Series LC / MSD system with a UV diode array detector and evaporative light scattering detector (DAD / ELSD) and an Agilent LC / MSD VL (G1956A) or SL (G1956B) mass spectrometer or an Agilent 1200 Series LC / MSD system with a DAD / ELSD and an Agilent LC / MSD SL (G6130A) or SL (G6140A) mass spectrometer. All LC / MS data were acquired using atmospheric pressure chemical ionization (ACI) with positive and negative ion mode switching over a scan range of m / z 80–1000. LC / MS experiments were performed on each provided sample using the following conditions: LC column: Zorbax SB-C18 RRHD, 1.8 μm, 4.6 × 15 mm. Mobile phase: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in acetonitrile. [Table 10]

[0177] Method DThe system consisted of a Waters iClass UPLC system and a Waters QDa mass spectrometer coupled to a TUV detector. The spectrometer consisted of an electrospray ionization source operating in positive and negative ion mode. LCMS studies were performed on each provided sample using the following conditions: LC column: Zorbax Eclipse Plus C18 RRHD, 1.8 μm, 50 × 2.1 mm, maintained at 40 °C. Mobile phase: A) 0.1% (v / v) formic acid in water; B) 0.1% (v / v) formic acid in acetonitrile. [Table 11]

[0178] Preparative high-performance liquid chromatography Basic conditions :LC column:Waters XBridge TM Prep C18 5μm OBD TM On a 19 x 50 mm column at rt using a gradient of mobile phase: A) 0.1% (v / v) ammonium hydroxide in 95:5 acetonitrile / water solution; B) 0.1% (v / v) ammonium hydroxide in water.

[0179] Chiral separation of stereoisomers by bicritical fluid chromatography (SFC) Separation of stereoisomeric mixtures was carried out using the following general method: the stereoisomeric mixture was dissolved in methanol to 50 mg / mL and purified by SFC under the conditions described. The combined fractions of each stereoisomer were evaporated to near dryness using a rotary evaporator and transferred to a final vessel using DCM, which was stripped under a stream of compressed air at 40°C, and then stored in a vacuum oven at 40°C and 5 mbar for 16 hours.

[0180] Chiral separation of stereoisomers by HPLC Separation of stereoisomeric mixtures was carried out using the following general method: The stereoisomeric mixture was dissolved in methanol to 66 mg / mL and purified by HPLC under the conditions described. The combined fractions of each stereoisomer were evaporated to near dryness using a rotary evaporator and transferred to a final container using MeOH, which was removed under a stream of compressed air at 35°C, and then stored in a vacuum oven at 35°C and 5 mbar for 16 hours.

[0181] Chiral Purity Analysis After separation of the chiral stereoisomeric mixture, each stereoisomer was analyzed using the following analytical SFC or HPLC method under the conditions described to determine chiral purity.

[0182] Method A (HPLC) : [Table 12]

[0183] Method B (HPLC) : [Table 13]

[0184] Method C (SFC) : [Table 14]

[0185] Method D (HPLC) : [Table 15]

[0186] Method E (SFC) : [Table 16]

[0187] Method F (SFC) : [Table 17]

[0188] Method G(SFC) : [Table 18]

[0189] Method H(SFC) : [Table 19]

[0190] Method I (SFC) : [Table 20]

[0191] Method J(SFC) : [Table 21]

[0192] Method K (SFC) : [Table 22]

[0193] Method L(SFC) : [Table 23]

[0194] Nomenclature and stereochemistry Unless otherwise noted, the names of the structures were determined using the 'Convert Structure to Name' function in ChemDraw Professional 20.1 (CambridgeSoft / PerkinElmer). The relative stereochemistry of the morpholine substituents was assigned based on literature methods (Org. Lett. 2014, 16, 1236-1239; J. Am. Chem. Soc. 2019, 141, 9739-9745) and NMR studies. In the case of Examples 26, 27, 61, 64, 68, and 69, these are single non-racemic diastereoisomers of known relative stereochemistry, but the absolute stereochemistry is unknown and arbitrarily assigned, and therefore may be the opposite of that shown.

[0195] In the cases of Examples 32, 33, 62, and 66, these are single non-racemic diastereoisomers in which the absolute stereochemistry of the morpholine substituents was known, but the absolute stereochemistry of the cyclopropyl substituents was unknown. In the case of Example 67, this is a single non-racemic diastereoisomer in which the absolute stereochemistry of all three stereocenters was unknown. In the cases of Examples 32, 33, 62, 66, and 67, the relative stereochemistry of the cyclopropyl substituents was assigned based on NOE experiments. The absolute stereochemistry of the substituents on the cyclopropane ring of Example 62 was subsequently determined by X-ray analysis of a cocrystal of Example 62 in complex with USP7. The absolute stereochemistry of the substituents on the cyclopropane ring of the related Examples 32, 33, 62, 66, and 67 was therefore determined from the Example 62 / USP7 cocrystal structure (see Examples below). The relative stereochemistry of the more active cyclopropane isomer also matches Examples 95 and 96. The stereochemistry of Examples 108, 109, and 110 in the same series was determined similarly. In the case of Examples 23, 28, 29, 34, 40, 41, 70, 71, 73, 74, 76, 77, 79, and 80, the stereochemistry has been arbitrarily assigned and is therefore a single enantiomer of unknown absolute configuration, which may be the opposite of that described. In the case of Examples 1, 2, 9, and 17, they are racemic diastereoisomers of known relative stereochemistry. In the case of Examples 10, 86, and 87, they are each a 1:1 mixture of two diastereoisomers. In the case of Examples 53, 54, and 60, they are unknown mixtures of diastereoisomers. In the case of Examples 78, 81, 82, and 85, these are single non-racemic diastereoisomers in which the absolute stereochemistry of the stereocenters on the morpholine ring is unknown and arbitrarily assigned, and thus may be the opposite of that described. In the case of Examples 83 and 84, these are 4:4:1:1 mixtures of diastereoisomers in which the absolute stereochemistry of the stereocenters on the morpholine ring is unknown and arbitrarily assigned, and thus may be the opposite of that described. Examples 111 and 112 are named based on their respective activities.

[0196] General Procedure General Procedure 1: HATU Coupling The appropriate amine or amine hydrochloride (1 equivalent), carboxylic acid (1 equivalent), and HATU (1 equivalent) were dissolved in DCM, followed by the addition of DIPEA (3 equivalents). The reaction was stirred for the indicated time and then quenched by the addition of saturated aqueous sodium bicarbonate. The resulting mixture was extracted with DCM (x3) using an ISOLUTE® separator. The combined organic phases were concentrated under reduced pressure, and the remaining residue was purified by flash chromatography to give the product.

[0197] General Procedure 2: m-CPBA Oxidation A solution of m-CPBA (<77% w / w) (1.2 equiv.) in DCM (0.2 M) was added dropwise via syringe or addition funnel to a stirring solution of alkene (1 equiv.) in DCM (0.2 M) at rt or 0°C. After the addition was complete, the reaction mixture was stirred at rt for the indicated time. Excess m-CPBA was quenched by the addition of saturated aqueous sodium thiosulfate (approximately 0.4 mL / g m-CPBA), after which the resulting mixture was transferred to a separatory funnel containing saturated aqueous sodium bicarbonate. The resulting biphasic mixture was extracted with DCM (×3), and the combined organic layers were passed through an ISOLUTE® Phase Separator and concentrated under reduced pressure. The remaining residue was purified by flash chromatography to give the product.

[0198] General Procedure 3: Miyaura boronation A suspension of the appropriate aryl bromide (1 equiv.), B2Pin2 (1.5 equiv.), Pd(dppf)Cl2·CHCl2 (0.1 equiv.), and KOAc (3 equiv.) in 1,4-dioxane (0.1 M) was heated and stirred as described for the time indicated. Workup A: After cooling to rt, the reaction mixture was filtered through Celite, and the solid was washed with EtOAc. The resulting solution was concentrated under reduced pressure, and the residue was purified by flash chromatography to give the product. Workup B: After cooling to rt, the reaction mixture was concentrated under reduced pressure, and the residue was suspended in DCM. The resulting suspension was filtered through Celite, washing the solid with DCM, and the combined filtrates were then concentrated under reduced pressure. The resulting residue was purified by flash chromatography to give the product.

[0199] General Procedure 4: Chan-Lam Coupling A suspension of the appropriate NH-heterocycle (1–1.5 equiv.), the appropriate arylboronate (1–2 equiv.), the appropriate copper(II) salt (2 equiv.), 1,10-phenanthroline (2 equiv.), and boric acid (2–4 equiv.) in DMF was stirred at the indicated temperature under air for the indicated time. Workup A: After cooling to rt, the reaction mixture was diluted with 1:1 brine / water and extracted with EtOAc. The organic layer was washed with 1:1 brine / water, dried (MgSO), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the product. Workup B: After cooling to rt, the reaction mixture was diluted with 10% aqueous ammonium hydroxide, and the resulting suspension was extracted with DCM (×3) using an ISOLUTE® separator. The combined organic phases were concentrated under reduced pressure, and the residue was purified by flash chromatography to give the product.

[0200] General Procedure 5: Hydrolysis of Chloropyrimidines A mixture of chloropyrimidine (1 equiv.), aqueous sodium hydroxide (10-20 equiv.), and 1,4-dioxane was heated at 100°C for the indicated time. After cooling to rt, the reaction mixture was acidified to approximately pH 4-5 by the addition of the indicated acid, and the product was extracted with DCM (x3). The resulting solution was passed through an ISOLUTE® separator and concentrated under reduced pressure to give the product, which was used in the next step without further purification.

[0201] General Procedure 6: Epoxide Ring Opening with Pyrimidinones The appropriate pyrimidinone (1 equiv.), epoxide (1–1.5 equiv.), and CsCO (1–3 equiv.) were suspended in DMF, and the reaction mixture was heated at 80 °C for the indicated time. The reaction was cooled to rt, saturated aqueous ammonium chloride or water was added, and the resulting mixture was extracted with DCM or EtOAc (×3). The combined organic phases were dried (ISOLUTE® Phase Separator or MgSO) and concentrated under reduced pressure, and the remaining residue was purified by flash chromatography to give the product.

[0202] General Procedure 7: Boc Deprotection to the Free Base The Boc-protected amine (1 equiv.) was dissolved in DCM and TFA was added. The reaction was stirred at rt for the indicated time and then 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 basic compounds were eluted using a 4:1 mixture of DCM / 7M NH3 in MeOH. The ammoniacal fraction was concentrated to give the desired product.

[0203] General Procedure 8: Synthesis of saturated heterocycles using SnAP reagents To a solution of SnAP reagent (1 equiv.) in DCM was added the corresponding aldehyde (1 equiv.) and 4 Å molecular sieves (approximately 100 mg / mmol) at rt. The reaction mixture was stirred at rt for 2 h and filtered through a short layer of Celite. The filtrate was concentrated under reduced pressure to give the imine.

[0204] Separately, 2,6-dimethylpyridine (1 equiv.) was added in one portion to a suspension of HFIP (0.25 M) and anhydrous Cu(OTf) (1 equiv.). The resulting mixture was stirred at rt for 1 h, during which time a homogeneous suspension formed. A solution of the imine (1 equiv.) in DCM (0.0625 M) was added in one portion, and the resulting mixture was stirred at rt for 12 h. The reaction was quenched at rt with 10% aqueous ammonium hydroxide solution and stirred vigorously for 15 min. The layers were separated, and the aqueous layer was extracted with DCM (×3). The combined organic layers were washed with water (×3) and brine, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the product.

[0205] General Procedure 9: Boc Protection To a solution of the substituted morpholine (1 equiv.) in DCM was added Boc2O (1.2 equiv.) After stirring at rt for 18 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography to give the desired product.

[0206] General Procedure 10: Boc Protection To a solution of the substituted morpholine (1 equiv.) in MeCN was added Boc2O (2 equiv.). After stirring at rt for 18 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography to give the desired product.

[0207] General Procedure 11: EDC Coupling To a solution of the corresponding carboxylic acid (1 equiv.) in DCM (0.1 M) was added EDC (1.2 equiv.), and the resulting mixture was stirred at rt for 15 min, followed by the addition of 4,5,6,7-tetrachloroisoindoline-1,3-dione (1 equiv.) and DMAP (0.1 equiv.). The resulting mixture was stirred at rt for 18 h, after which the reaction mixture was directly purified by flash chromatography to give the desired product.

[0208] Epoxide 1: (1-methylcyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] Step 1: 4-Methylenepiperidine hydrochloride: A solution of 1-N-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, then concentrated under reduced pressure to give the title compound (1.34 g, quantitative) as a white solid. 1 H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 2H), 4.86 (s, 2H), 3.05 (t, J = 6.1 Hz, 4H), 2.41 (t, J = 6.1 Hz, 4H).

[0209] 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) afforded the title compound (1.69 g, 94%) as a colorless oil after 1 h. 1 H NMR (500 MHz, DMSO-d6) δ 4.77 (s, 2H), 3.53 (t, J = 6.0 Hz, 4H), 2.15 (t, J = 5.9 Hz, 4H), 1.23 (s, 3H), 0.85 - 0.75 (m, 2H), 0.59 - 0.49 (m, 2H).

[0210] Step 3: (1-Methylcyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (1-methylcyclopropyl)-(4-methylene-1-piperidyl)methanone (1.69 g, 9.43 mmol) in DCM (47 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (2.54 g, 11.3 mmol) in DCM (47 mL) afforded the title compound (1.51 g, 82%) as a pale yellow oil after 20 h at rt. 1H NMR (500 MHz, DMSO-d6) δ 3.78 - 3.68 (m, 2H), 3.62 - 3.47 (m, 2H), 2.68 (s, 2H), 1.69 (ddd, J = 13.1, 8.6, 4.2 Hz, 2H), 1.43 (ddd, J = 13.3, 6.5, 3.9 Hz, 2H), 1.23 (s, 3H), 0.83 - 0.77 (m, 2H), 0.58 - 0.50 (m, 2H).

[0211] Epoxide 2: (4-chlorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (405 mg, 85%) as a colorless oil after 1 hour. LCMS (Method A): R T = 1.41 min, m / z = 236, 238 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.54 - 7.48 (m, 2H), 7.46 - 7.41 (m, 2H), 4.79 (s, 2H), 3.60 (br. s, 2H), 3.34 (br. s, 2H (signal overlap with HDO)), 2.20 (br. s, 4H).

[0212] Step 2: (4-Chlorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (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) afforded, after 20 h at rt, the title compound (430 mg, 99%) as a colorless oil that solidified upon standing. LCMS (Method A): R T = 0.99 min, m / z = 252, 254 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.54 - 7.48 (m, 2H), 7.48 - 7.42 (m, 2H), 3.85 (br. s, 1H), 3.58 (br. s, 1H), 3.42 (br. s, 2H), 2.69 (s, 2H), 1.76 (br. s, 2H), 1.47 (br. s, 2H).

[0213] Epoxide 3: (R)-4,4,4-trifluoro-3-phenyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)butan-1-one [ka] 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) afforded the title compound (129.5 mg, 97%) as a colorless oil after 1 h at rt. LCMS (Method A): R T = 1.54 min, m / z = 298 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 7.45 - 7.39 (m, 2H), 7.38 - 7.29 (m, 3H), 4.75 (s, 1H), 4.73 (s, 1H), 4.16 - 4.07 (m, 1H), 3.54 - 3.42 (m, 2H), 3.42 - 3.33 (m, 2H), 3.20 (dd, J = 16.4, 9.4 Hz, 1H), 2.98 (dd, J = 16.4, 4.2 Hz, 1H), 2.20 - 2.13 (m, 1H), 2.08 - 2.00 (m, 2H), 1.98 - 1.91 (m, 1H).

[0214] 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 a solution of (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 a solution of m-CPBA (<77% w / w) (117 mg, 0.523 mmol) in DCM (2.1 mL) afforded the title compound (143 mg, 94%) as a colorless oil after 20 h at rt. LCMS (Method A): R T = 1.23 min, m / z = 314 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.46 - 7.40 (m, 2H), 7.40 - 7.29 (m, 3H), 4.18 - 4.07 (m, 1H), 3.70 - 3.49 (m, 3H), 3.44 - 3.34 (m, 1H), 3.21 (dd, J = 16.4, 9.4 Hz, 1H), 3.00 (dd, J = 16.4, 4.2 Hz, 1H), 2.70 - 2.59 (m, 2H), 1.76 - 1.68 (m, 0.5H), 1.62 - 1.52 (m, 1H), 1.50 - 1.41 (m, 1H), 1.36 - 1.29 (m, 1H), 1.27 - 1.21 (m, 0.5H).

[0215] Epoxide 4: Phenyl(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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 μL, 3.70 mmol) and DCM (11 mL) afforded the title compound (196 mg, 78%) as a white solid after 30 min. 1 H NMR (500 MHz, chloroform-d) δ 7.56 - 7.29 (m, 5H), 4.80 (s, 2H), 3.76 (br. s, 2H), 3.40 (br. s, 2H), 2.33 (br. s, 2H), 2.18 (br. s, 2H).

[0216] Step 2: Phenyl(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (4-methylenepiperidin-1-yl)(phenyl)methanone (196 mg, 0.974 mmol) in DCM (4.5 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (164 mg, 0.733 mmol) in DCM (4.5 mL) afforded the title compound (163 mg, 77%) as a colorless oil after 20 h at rt. 1 H NMR (500 MHz, chloroform-d) δ 7.54–7.32 (m, 5H), 4.25 (br. s, 1H), 3.76–3.42 (br. m, 3H), 2.73 (s, 2H), 2.08–1.79 (br. m, 2H), 1.68–1.30 (br. m, 2H (signal overlap with HDO)).

[0217] Epoxide 5: (4-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (4.31 g, 98%) as a colorless oil after 30 min. LCMS (Method A): R T = 1.25 min, m / z = 220 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.51 - 7.45 (m, 2H), 7.31 - 7.24 (m, 2H), 4.79 (s, 2H), 3.59 (br. s, 2H), 3.33 (br. s, 2H (signal overlap with HDO)), 2.20 (br. s, 4H).

[0218] Step 2: (4-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (4-fluorophenyl)(4-methylenepiperidin-1-yl)methanone (4.31 g, 19.7 mmol) in DCM (98 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (5.29 g, 23.6 mmol) in DCM (98 mL) afforded, after 20 h at rt, the title compound (3.74 g, 80%) as a colorless oil that solidified upon standing. LCMS (Method A): R T = 0.82 min, m / z = 236 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.55 - 7.45 (m, 2H), 7.31 - 7.24 (m, 2H), 3.85 (br. s, 1H), 3.70 - 3.33 (br. m, 3H), 2.69 (s, 2H), 1.76 (br. s, 2H), 1.47 (br. s, 2H).

[0219] Epoxide 6: (2,4-difluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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 μL, 3.00 mmol) and DCM (10 mL) afforded the title compound (146 mg, 61%) as a viscous colorless oil after 75 min. LCMS (Method A): R T = 1.31 min, m / z = 238 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.54 - 7.46 (m, 1H), 7.40 - 7.31 (m, 1H), 7.22 - 7.14 (m, 1H), 4.81 (s, 1H), 4.78 (s, 1H), 3.64 (br. s, 2H), 3.26 - 3.15 (m, 2H), 2.30 - 2.19 (m, 2H), 2.18 - 2.06 (m, 2H).

[0220] Step 2: (2,4-Difluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (2,4-difluorophenyl)(4-methylenepiperidin-1-yl)methanone (145 mg, 0.611 mmol) in DCM (2.7 mL) at rt and a solution of m-CPBA (<77% w / w) (164 mg, 0.733 mmol) in DCM (2.7 mL) afforded the title compound (150 mg, 97%) as a viscous colorless oil after 22 h at rt. LCMS (Method A): R T = 0.89 min, m / z = 254 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 7.58 - 7.48 (m, 1H), 7.41 - 7.32 (m, 1H), 7.24 - 7.14 (m, 1H), 3.98 - 3.83 (m, 1H), 3.69 - 3.56 (m, 1H), 3.40 - 3.31 (m, 2H), 2.71 (d, J = 4.8 Hz, 1H), 2.68 (d, J = 4.8 Hz, 1H), 1.86 - 1.73 (m, 1H), 1.73 - 1.62 (m, 1H), 1.58 - 1.47 (m, 1H), 1.47 - 1.34 (m, 1H).

[0221] Epoxide 7: (4-chloro-2-fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (569 mg, 88%) as a colorless gum after 19 h. LCMS (Method A): R T = 1.46 min, m / z = 254, 256 [M+H] + .

[0222] Step 2: (4-chloro-2-fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (4-chloro-2-fluorophenyl)(4-methylenepiperidin-1-yl)methanone (569 mg, 2.24 mmol) in DCM (22 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (603 mg, 2.69 mmol) in DCM (22 mL) afforded the title compound (574 mg, 94%) as a colorless oil after 20 h at rt. LCMS (Method B): R T= 1.06 min, m / z = 270, 272 [M+H] + .

[0223] Epoxide 8: (2-chlorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (564 mg, 94%) as a colorless oil after 20 h. LCMS (Method A): R T = 1.34 min, m / z = 236, 238 [M+H] + .

[0224] Step 2: (2-Chlorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (2-chlorophenyl)(4-methylenepiperidin-1-yl)methanone (564 mg, 2.39 mmol) in DCM (22 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (644 mg, 2.87 mmol) in DCM (22 mL) afforded the title compound (530 mg, 88%) as a colorless oil after 20 h at rt. LCMS (Method B): R T = 0.85 min, m / z = 252, 254 [M+H] + .

[0225] Epoxide 9: ((1S*,2S*)-1-Methyl-2-(trifluoromethyl)cyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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 afford a single diastereoisomer. Based on NOE experiments, the major one was assigned as rac-(1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carboxylic acid. To a solution of rac-(1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carboxylic acid (10 g, 59.5 mmol) in DMF (178.5 mL) was added EDC (13.7 g, 71.4 mmol), and the resulting mixture was stirred at RT for 15 min. Then, 4-nitrophenol (9.93 g, 71.4 mmol) and DMAP (73 mg, 0.595 mmol) were added. The resulting mixture was stirred at RT for 19 h. The reaction mixture was then diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0–20% EtOAc in hexanes) to give rac-4-nitrophenyl (1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carboxylate (12.7 g, 74%). rac-4-Nitrophenyl (1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carboxylate (2 g) was resolved into single stereoisomers by semi-preparative chiral HPLC using a Chiralpak AS-H (4.6 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 95:5 hexane (0.1% v / v TFA) / IPA. The first-eluting material was arbitrarily assigned as 4-nitrophenyl (1S*,2S*)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carboxylate (532 mg, 26% recovery). Chiral purity (Method A): R T = 17.06 min, 100% ee. [α] D 20= +44.72 (c 0.25, MeOH). The second eluting material was arbitrarily assigned as 4-nitrophenyl (1R*,2R*)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carboxylate (449 mg, 22% recovery). Chiral purity (Method A): R T = 18.41 min, 97.7% ee. [α] D 20 = -43.92(c 0.25, MeOH).

[0226] Step 2: ((1S*,2S*)-1-Methyl-2-(trifluoromethyl)cyclopropyl)(4-methylenepiperidin-1-yl)methanone: A mixture of 4-nitrophenyl (1S*,2S*)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carboxylate (142 mg, 0.491 mmol), 4-methylenepiperidine hydrochloride (98.4 mg, 0.737 mmol), DIPEA (257 μL, 1.47 mmol), and DMF (4.9 mL) was stirred at rt for 70 min. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with DCM (3×20 mL) using an ISOLUTE® separator. The combined organic phases were concentrated under reduced pressure, and the residue was purified by flash chromatography to give the title compound (94.6 mg, 77%) as a viscous colorless oil. 1 H NMR (500 MHz, DMSO-d6) δ 4.79 (s, 2H), 3.50 (br. s, 4H), 2.34 - 2.06 (m, 5H), 1.44 - 1.38 (m, 1H), 1.38 - 1.32 (m, 3H), 1.16 - 1.10 (m, 1H).

[0227] Step 3: ((1S*,2S*)-1-Methyl-2-(trifluoromethyl)cyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of ((1S*,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 a solution of m-CPBA (<77% w / w) (103 mg, 0.459 mmol) in DCM (1.9 mL) afforded the title compound (87 mg, 86%) as a viscous colorless oil after 22 h 30 min at rt. LCMS (Method A, 220 nm): R T = 0.99 min, m / z = 264 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 3.78 - 3.64 (m, 2H), 3.52 (br. s, 2H), 2.69 (s, 2H), 2.20 - 2.10 (m, 1H), 1.72 (br. s, 2H), 1.53 - 1.39 (m, 3H), 1.38 - 1.35 (m, 3H), 1.13 (t, J = 5.8 Hz, 1H).

[0228] Epoxide 10: ((1R*,2R*)-1-Methyl-2-(trifluoromethyl)cyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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-1-carboxylate (238 mg, 0.823 mmol), 4-methylenepiperidine hydrochloride (165 mg, 1.23 mmol), DIPEA (430 μL, 2.47 mmol), and DMF (8.2 mL) was stirred at rt for 80 min. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with DCM (3×20 mL) using an ISOLUTE® Phase Separator. The combined organic phases were concentrated under reduced pressure, and the residue was purified by flash chromatography to give the title compound (103 mg, 50%) as a viscous colorless oil. 1 H NMR (500 MHz, DMSO-d6) δ 4.79 (s, 2H), 3.50 (s, 4H), 2.29 - 2.06 (m, 5H), 1.40 (dd, J = 9.5, 5.5 Hz, 1H), 1.38 - 1.32 (m, 3H), 1.13 (t, J = 5.9 Hz, 1H).

[0229] Step 2: ((1R*,2R*)-1-Methyl-2-(trifluoromethyl)cyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of ((1R*,2R*)-1-methyl-2-(trifluoromethyl)cyclopropyl)(4-methylenepiperidin-1-yl)methanone (102 mg, 0.413 mmol) in DCM (2 mL) at rt and a solution of m-CPBA (<77% w / w) (111 mg, 0.495 mmol) in DCM (2 mL) afforded the title compound (107.9 mg, 99%) as a viscous colorless oil after 22 h at rt. LCMS (Method A, 220 nm): R T = 1.00 min (220 nm), m / z = 264 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 3.78 - 3.64 (m, 2H), 3.53 (br. s, 2H), 2.69 (s, 2H), 2.20 - 2.10 (m, 1H), 1.72 (br. s, 2H), 1.56 - 1.38 (m, 3H), 1.38 - 1.31 (m, 3H), 1.13 (t, J = 5.9 Hz, 1H).

[0230] Epoxide 11: (3-chlorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (520 mg, 86%) as a colorless oil after 20 h. LCMS (Method B): R T = 1.41 min, m / z = 236, 238 [M+H] + .

[0231] Step 2: (3-chlorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (3-chlorophenyl)(4-methylenepiperidin-1-yl)methanone (520 mg, 2.21 mmol) in DCM (10 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (593 mg, 2.65 mmol) in DCM (10 mL) afforded the title compound (445 mg, 80%) as a colorless oil after 20 h at rt. LCMS (Method B): R T = 0.98 min, m / z = 252, 254 [M+H] + .

[0232] Epoxide 12: (2-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (501 mg, 90%) as a viscous colorless oil after 20 h. LCMS (Method A): R T = 1.24 min, m / z = 220 [M+H] + .

[0233] Step 2: (2-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (2-fluorophenyl)(4-methylenepiperidin-1-yl)methanone (501 mg, 2.29 mmol) in DCM (10 mL) at rt and a solution of m-CPBA (<77% w / w) (615 mg, 2.74 mmol) in DCM (10 mL) afforded the title compound (501 mg, 93%) as a colorless oil after 20 h at rt. LCMS (Method A): R T = 0.80 min, m / z = 236 [M+H] + .

[0234] Epoxide 13: (3,4-difluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (533, 88%) as a colorless gum after 19 h. LCMS (Method A): R T = 1.32 min, m / z = 238 [M+H] + .

[0235] Step 2: (3,4-Difluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (3,4-difluorophenyl)(4-methylenepiperidin-1-yl)methanone (533 mg, 2.25 mmol) in DCM (10 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (604 mg, 2.70 mmol) in DCM (10 mL) afforded the title compound (533 mg, 93%) as a colorless oil after 20 h at rt. LCMS (Method B): R T = 0.91 min, m / z = 254 [M+H] + .

[0236] Epoxide 14: (3-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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 μL, 3.00 mmol) and DCM (10 mL) afforded the title compound (178 mg, 81%) as a viscous colorless oil after 19 hours. LCMS (Method A): R T = 1.27 min, m / z = 220 [M+H] + .

[0237] Step 2: (3-Fluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (3-fluorophenyl)(4-methylenepiperidin-1-yl)methanone (178 mg, 0.812 mmol) in DCM (4 mL) at rt and a solution of m-CPBA (<77% w / w) (218 mg, 0.974 mmol) in DCM (4 mL) afforded the title compound (183 mg, 95%) as a colorless solid after 18 h at rt. LCMS (Method A): R T = 0.85 min, m / z = 236 [M+H] +. 1 H NMR (500 MHz, DMSO-d6) δ 7.54 - 7.45 (m, 1H), 7.41 - 7.09 (m, 3H), 3.87 (br. s, 1H), 3.59 (br. s, 1H), 3.40 (br. s, 2H), 2.69 (s, 2H), 1.77 (br. s, 2H), 1.50 (br. s, 1H), 1.43 (br. s, 1H).

[0238] Epoxide 15: (2,3-Difluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (504 mg, 83%) as a white solid after 19 h. LCMS (Method A): R T = 1.31 min, m / z = 238 [M+H] + .

[0239] Step 2: (2,3-Difluorophenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (2,3-difluorophenyl)(4-methylenepiperidin-1-yl)methanone (504 mg, 2.12 mmol) in DCM (10 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (571 mg, 2.55 mmol) in DCM (10 mL) afforded the title compound (501 mg, 93%) as a colorless oil after 20 h at rt. LCMS (Method B): R T = 0.89 min, m / z = 254 [M+H] + .

[0240] Epoxide 16: [1,1'-Bi(cyclopropane)]-1-yl(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] Step 1: [1,1′-Bi(cyclopropane)]-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) afforded the title compound (392 mg, 95%) as a colorless oil after 19 h at rt. 1 H NMR (500 MHz, DMSO-d6) δ 4.78 (s, 2H), 3.57 (br. s, 4H), 1.16 (tt, J = 8.3, 5.1 Hz, 1H), 2.25 - 2.07 (m, 4H), 0.73 - 0.65 (m, 2H), 0.52 - 0.42 (m, 2H), 0.42 - 0.34 (m, 2H), 0.15 - 0.05 (m, 2H).

[0241] Step 2: [1,1'-Bi(cyclopropane)]-1-yl(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of [1,1'-bi(cyclopropane)]-1-yl(4-methylenepiperidin-1-yl)methanone (392 mg, 1.91 mmol) in DCM (9.5 mL) at 0°C and a solution of m-CPBA (<77% w / w) (514 mg, 2.29 mmol) in DCM (9.5 mL) afforded the title compound (421 mg, 90%) as a colorless oil after 20 h at rt. LCMS (Method A): R T = 0.79 min, m / z = 222 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 3.78 (br. s, 2H), 3.59 (br. s, 2H), 2.68 (s, 2H), 1.80 - 1.60 (m, 2H), 1.51 - 1.38 (m, 2H), 1.20 - 1.13 (m, 1H), 0.74 - 0.69 (m, 2H), 0.50 - 0.44 (m, 2H), 0.43 - 0.35 (m, 2H), 0.17 - 0.08 (m, 2H).

[0242] Epoxide 17: (1-oxa-6-azaspiro[2.5]octan-6-yl)(p-tolyl)methanone [ka] 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) afforded the title compound (940 mg, 87%) as a colorless oil after 1 hour. LCMS (Method A): R T = 1.36 min, m / z = 216 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.30 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.8 Hz, 2H), 4.78 (s, 2H), 3.58 (br. s, 2H), 3.34 (br. s, 2H (signal overlap with HDO)), 2.34 (s, 3H), 2.19 (br. s, 4H).

[0243] Step 2: (1-Oxa-6-azaspiro[2.5]octan-6-yl)(p-tolyl)methanone: General procedure 2 using a solution of (4-methylenepiperidin-1-yl)(p-tolyl)methanone (940 mg, 4.37 mmol) in DCM (22 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (1.17 g, 5.24 mmol) in DCM (22 mL) afforded, after 19 h at rt, the title compound (984 mg, 97%) as a colorless oil that solidified upon standing. LCMS (Method A): R T = 0.93 min, m / z = 232 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.33 - 7.30 (m, 2H), 7.25 (d, J = 7.8 Hz, 2H), 3.98 - 3.33 (br. m, 4H), 2.68 (s, 2H), 2.34 (s, 3H), 1.73 (br. s, 2H), 1.46 (br. s, 2H).

[0244] Epoxide 18: (1-oxa-6-azaspiro[2.5]octan-6-yl)(4-(trifluoromethyl)phenyl)methanone [ka] Step 1: (4-Methylenepiperidin-1-yl)(4-(trifluoromethyl)phenyl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (668 mg, 5.00 mmol), 4-(trifluoromethyl)benzoic acid (951 mg, 5.00 mmol), HATU (1.90 g, 5.00 mmol), DIPEA (2.61 mL, 15.0 mmol) and DCM (50 mL) afforded the title compound (1.31 g, 97%) as a crystalline white solid after 1 hour. LCMS (Method A): R T = 1.48 min, m / z = 270 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 7.82 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 4.86 - 4.73 (m, 2H), 3.64 (s, 2H), 3.26 (s, 2H), 2.27 (s, 2H), 2.16 (s, 2H).

[0245] Step 2: (1-Oxa-6-azaspiro[2.5]octan-6-yl)(4-(trifluoromethyl)phenyl)methanone: General procedure 2 using a solution of (4-methylenepiperidin-1-yl)(4-(trifluoromethyl)phenyl)methanone (1.31 g, 4.87 mmol) in DCM (24 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (1.31 g, 5.84 mmol) in DCM (24 mL) afforded the title compound (1.29 g, 92%) as a white solid after 19 h at rt. LCMS (Method A): R T = 1.12 min, m / z = 286 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.82 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 7.9 Hz, 2H), 3.99 - 3.82 (m, 1H), 3.69 - 3.53 (m, 1H), 3.37 (s, 2H), 2.76 - 2.65 (m, 2H), 1.90 - 1.78 (m, 1H), 1.78 - 1.67 (m, 1H), 1.60 - 1.48 (m, 1H), 1.48 - 1.35 (m, 1H).

[0246] Epoxide 19: (2-chloro-4-methylphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (1.21 g, 96%) as a colorless oil after 1 hour. LCMS (Method A): R T = 1.48 min, m / z = 250, 252 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.37 - 7.35 (m, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.22 (ddd, J = 7.8, 1.5, 0.7 Hz, 1H), 4.83 - 4.79 (m, 1H), 4.78 - 4.74 (m, 1H), 3.73 - 3.66 (m, 1H), 3.65 - 3.54 (m, 1H), 3.18 - 3.08 (m, 2H), 2.33 (s, 3H), 2.28 - 2.19 (m, 2H), 2.19 - 2.04 (m, 2H).

[0247] Step 2: (2-chloro-4-methylphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (2-chloro-4-methylphenyl)(4-methylenepiperidin-1-yl)methanone (1.21 g, 4.85 mmol) in DCM (24 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (1.30 g, 5.81 mmol) in DCM (24 mL) afforded the title compound (1.29 g, 92%) as a white solid after 19 h at rt. LCMS (Method A): R T = 1.16 min, m / z = 266, 268 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 7.36 (s, 1H), 7.29 (t, J = 7.1 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 3.97 - 3.89 (m, 0.5H), 3.89 - 3.81 (m, 0.5H), 3.67 (ddd, J = 13.0, 8.5, 4.0 Hz, 0.5H), 3.58 (ddd, J = 12.8, 8.9, 3.8 Hz, 0.5H), 3.30 - 3.16 (m, 2H), 2.74 - 2.68 (m, 1H), 2.68 - 2.62 (m, 1H), 2.33 (s, 3H), 1.83 (ddd, J = 13.4, 8.8, 4.1 Hz, 0.5H), 1.78 - 1.63 (m, 1.5H), 1.58 - 1.51 (m, 0.5H), 1.51 - 1.34 (m, 1.5H).

[0248] Epoxide 20: (2,4-dimethylphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (572 mg, 98%) as a white solid after 19 h. LCMS (Method B): R T = 1.31 min, m / z = 230 [M+H] + .

[0249] Step 2: (2,4-dimethylphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (2,4-dimethylphenyl)(4-methylenepiperidin-1-yl)methanone (572 mg, 2.49 mmol) in DCM (10 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (671 mg, 2.99 mmol) in DCM (10 mL) afforded the title compound (519 mg, 84%) as a colorless oil after 20 h at rt. LCMS (Method A): R T = 1.00 min, m / z = 246 [M+H] + .

[0250] Epoxide 21: 6-((4-nitrophenyl)sulfonyl)-1-oxa-6-azaspiro[2.5]octane [ka] 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 bicarbonate (100 mL) and extracted with DCM (3 x 100 mL). The combined organic phases were concentrated under reduced pressure, and the residue was purified by flash chromatography to give the title compound (1.43 mg, 99%) as a white solid. LCMS (Method B): R T = 1.34 min, no mass ions observed. 1 H NMR (500 MHz, chloroform-d) δ 8.43–8.32 (m, 2H), 8.00–7.88 (m, 2H), 4.80–4.69 (m, 2H), 3.20–3.06 (m, 4H), 2.39–2.26 (m, 4H).

[0251] Step 2: 6-((4-nitrophenyl)sulfonyl)-1-oxa-6-azaspiro[2.5]octane: General procedure 2 using a solution of 4-methylene-1-((4-nitrophenyl)sulfonyl)piperidine (1.43 g, 5.07 mmol) in DCM (50 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (1.36 g, 6.08 mmol) in DCM (50 mL) afforded the title compound after 20 h at rt. LCMS (Method B): R T = 1.07 min, no mass ions observed. 1 H NMR (500 MHz, chloroform-d) δ 8.48 - 8.34 (m, 2H), 8.04 - 7.91 (m, 2H), 3.72 - 3.57 (m, 2H), 2.92 (td, J = 11.3, 3.2 Hz, 2H), 2.68 (s, 2H), 2.17 - 2.01 (m, 2H), 1.51 - 1.41 (m, 2H).

[0252] Epoxide 22: (R)-4,4-difluoro-3-phenyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)butan-1-one [ka] 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) afforded the title compound (255 mg, 88%) as a colorless oil after 3 days. LCMS (Method A): R T = 1.46 min, m / z = 280 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 7.36 - 7.24 (m, 5H), 6.24 (td, J = 56.5, 3.9 H, 1H), 4.74 (d, J = 6.2 Hz, 2H), 3.71 - 3.59 (m, 1H), 3.47 - 3.33 (m, 4H), 2.95 (dd, J = 16.2, 8.2 Hz, 1H), 2.87 (dd, J = 16.2, 5.8 Hz, 1H), 2.18 - 2.10 (m, 1H), 2.09 - 1.92 (m, 3H).

[0253] 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 a solution of (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 a solution of m-CPBA (<77% w / w) (241 mg, 1.074 mmol) in DCM (4.5 mL) afforded the title compound (245 mg, 92%) as a colorless oil after 20 h at rt. LCMS (Method A): R T = 1.08 min, m / z = 296 [M+H] + .

[0254] Epoxide 23: (1-methyl-2-(trifluoromethyl)cyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] Step 1: (1-Methyl-2-(trifluoromethyl)cyclopropyl)(4-methylenepiperidin-1-yl)methanone: To a stirring solution of 1-methyl-2-(trifluoromethyl)cyclopropane-1-carboxylic acid (4:1 mixture of diastereoisomers, 5.00 g, 29.8 mmol) in DMF (25 mL) at rt, HATU (11.3 g, 29.8 mmol) and DIPEA (18.1 mL, 104 mmol) were added sequentially. After stirring at rt for 3 min, 4-methylenepiperidine hydrochloride (3.97 g, 29.8 mmol) was added in one portion, and the resulting mixture was stirred at rt overnight. The reaction mixture was poured into 150 mL of water, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure, and the product was dried (0.1 mbar / 50°C for 5 hours) to give the title compound (6.69 g, 91%), which was used in the next step without further purification.

[0255] Step 2: (1-Methyl-2-(trifluoromethyl)cyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (1-methyl-2-(trifluoromethyl)cyclopropyl)(4-methylenepiperidin-1-yl)methanone (4:1 mixture of 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 a solid afforded the title compound (4.42 g, 62%) as a yellow oil after 1 h at rt. LCMS (Method C): T = 0.95 min, m / z = 264 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 1.08 (t, J = 5.9 Hz, 1H), 1.40–1.54 (m, 6H), 1.79–1.93 (m, 3H), 2.72 (s, 2H), 3.27–3.74 (m, 2H), 3.89–4.09 (m, 2H).

[0256] Epoxide 24: (4-chloro-2-methylphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (548 mg, 82%) as a white solid after 20 h. LCMS (Method A): R T = 1.34 min, m / z = 250, 252 [M+H] + .

[0257] Step 2: (4-chloro-2-methylphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (4-chloro-2-methylphenyl)(4-methylenepiperidin-1-yl)methanone (545 mg, 2.18 mmol) in DCM (10 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (587 mg, 2.62 mmol) in DCM (10 mL) afforded the title compound (554 mg, 95%) as a colorless oil after 20 h at rt. LCMS (Method B): R T = 1.04 min, m / z = 266, 268 [M+H] + .

[0258] Epoxide 25: (4-(difluoromethyl)phenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] Step 1: (4-(Difluoromethyl)phenyl)(4-methylenepiperidin-1-yl)methanone: General procedure 1 using 4-methylenepiperidine hydrochloride (372 mg, 2.78 mmol), 4-(difluoromethyl)benzoic acid (479 mg, 2.78 mmol), HATU (1.06 g, 2.78 mmol), DIPEA (1.45 mL, 8.35 mmol) and DCM (20 mL) afforded the title compound (595 mg, 85%) as a white solid after 20 h. LCMS (Method A): R T = 1.20 min, m / z = 252 [M+H] + .

[0259] Step 2: (4-(Difluoromethyl)phenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (4-(difluoromethyl)phenyl)(4-methylenepiperidin-1-yl)methanone (595 mg, 2.37 mmol) in DCM (10 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (637 mg, 2.84 mmol) in DCM (10 mL) afforded the title compound (581 mg, 91%) as a colorless oil after 20 h at rt. LCMS (Method B): R T = 0.91 min, m / z = 268 [M+H] + .

[0260] Epoxide 26: (4-cyclopropylphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (1.33 g, 71%) as a pale yellow oil after 20 h. LCMS (Method C): R T = 1.26 min, m / z = 242 [M+H] + .1 H NMR (400 MHz, chloroform-d) δ 7.31 (d, J = 7.4 Hz, 2H), 7.09 (d, J = 7.2 Hz, 2H), 4.79 (s, 2H), 3.72 (br. s, 2H), 3.45 (br. s, 2H), 2.25 (br. s, 4H), 1.91 (tt, J = 8.6, 4.9 Hz, 1H), 1.09 - 0.93 (m, 2H), 0.81 - 0.61 (m, 2H).

[0261] Step 2: (4-Cyclopropylphenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (4-cyclopropylphenyl)(4-methylenepiperidin-1-yl)methanone (1.33 g, 5.52 mmol) in DCM (50 mL) at 0° C. and a solution of m-CPBA (<70% w / w) (1.50 g, 6.08 mmol) in DCM (50 mL) afforded the title compound (653 mg, 46%) as a pale yellow oil after 20 h at rt. LCMS (Method C): R T = 1.21 min, m / z = 258 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.32 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H), 4.35 - 4.07 (m, 1H), 3.81 - 3.45 (m, 3H), 2.73 (s, 2H), 2.07 - 1.76 (m, 3H), 1.53 - 1.32 (m, 2H), 1.08 - 0.91 (m, 2H), 0.79 - 0.62 (m, 2H).

[0262] Epoxide 27: (4-(1-methylcyclopropyl)phenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (2.31 g, 74%) as a pale yellow oil after 20 h. LCMS (Method C): R T = 1.34 min, m / z = 256 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.33 (d, J = 7.9 Hz, 2H), 7.26 (d, J = 7.7 Hz, 2H), 4.79 (s, 2H), 3.68 (br. s, 2H), 3.49 (br. s, 2H), 2.25 (br. s, 4H), 1.41 (s, 3H), 0.99 - 0.82 (m, 2H), 0.82 - 0.63 (m, 2H).

[0263] Step 2: (4-(1-methylcyclopropyl)phenyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (4-(1-methylcyclopropyl)phenyl)(4-methylenepiperidin-1-yl)methanone (2.31 g, 9.06 mmol) in DCM (50 mL) at 0° C. and a solution of m-CPBA (<70% w / w) (1.50 g, 6.08 mmol) in DCM (50 mL) afforded the title compound (1.19 g, 49%) as a pale yellow oil after 20 h at rt. LCMS (Method C): R T = 1.16 min, m / z = 272 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.31 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 4.35 - 4.04 (m, 1H), 3.79 - 3.46 (m, 3H), 2.71 (s, 2H), 2.03 - 1.72 (m, 2H), 1.62 - 1.32 (m, 5H), 0.90 - 0.83 (m, 2H), 0.78 - 0.72 (m, 2H). 1 H NMR (400 MHz, chloroform-d) δ 7.34 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 4.22 (br. s, 1H), 3.65 (br. s, 1H), 3.60 - 3.36 (m, 2H), 2.73 (s, 2H), 1.89 (br. s, 2H), 1.49 (br. s, 2H), 1.41 (s, 3H), 0.99 - 0.83 (m, 2H), 0.83 - 0.65 (m, 2H).

[0264] Epoxide 28: ((1S,2S)-1,2-dimethylcyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] Step 1: 4-Nitrophenyl (1S,2S)-1,2-dimethylcyclopropane-1-carboxylate: To a solution of (1S,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, followed by the addition of 4-nitrophenol (542 mg, 3.89 mmol) and DMAP (43 mg, 0.354 mmol). The resulting mixture was stirred at rt for 19 h, after which the reaction mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0–20% EtOAc in hexanes) to afford the title compound (633 mg, 76%) as a pale yellow oil. 1H NMR (500 MHz, chloroform-d) δ 8.26 (d, J = 9.1 Hz, 2H), 7.25 (d, J = 9.1 Hz, 2H), 1.76 - 1.66 (m, 1H), 1.61 (dd, J = 9.3, 4.1 Hz, 1H), 1.40 (s, 3H), 1.22 (d, J = 6.3 Hz, 3H), 0.58 (dd, J = 6.9, 4.1 Hz, 1H).

[0265] Step 2: ((1S,2S)-1,2-Dimethylcyclopropyl)(4-methylenepiperidin-1-yl)methanone: A solution of 1-N-boc-4-methylene-piperidine (796 mg, 4.04 mmol) in 4 M HCl in 1,4-dioxane (3.36 mL, 13.5 mmol) and DCM (2.3 mL) was stirred at rt for 1 h and then concentrated under reduced pressure. To the resulting solid was added a solution of 4-nitrophenyl (1S,2S)-1,2-dimethylcyclopropane-1-carboxylate (633 mg, 2.69 mmol) in DMF (15.6 mL) and DIPEA (1.41 mL, 8.07 mmol). The resulting mixture was stirred at rt for 90 min and then diluted with saturated aqueous sodium bicarbonate (30 mL). The resulting mixture was extracted with EtOAc (x3) and the combined organic layers were washed with 1:1 water / brine (x4), passed through a phase separator and concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound (456 mg, 87%) as a yellow oil. LCMS (Method B): R T = 1.12 min (220 nm), m / z = 194 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 4.78 (s, 2H), 3.61 - 3.51 (m, 4H), 2.21 (t, J = 5.8 Hz, 4H), 1.25 (s, 3H), 1.17 - 1.05 (m, 5H), 0.19 (dd, J = 5.4, ​​4.4 Hz, 1H).

[0266] Step 3: ((1S,2S)-1,2-Dimethylcyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of ((1S,2S)-1,2-dimethylcyclopropyl)(4-methylenepiperidin-1-yl)methanone (455 mg, 2.35 mmol) in DCM (11.7 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (633 mg, 2.82 mmol) in DCM (11.7 mL) afforded the title compound (413 mg, 83%) as a viscous colorless oil after 20 h at rt. LCMS (Method B): R T = 0.79 min (220 nm), m / z = 210 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 1 H NMR (500 MHz, chloroform-d) δ 4.01 - 3.86 (m, 2H), 3.61 - 3.42 (m, 2H), 2.72 (s, 2H), 1.84 (ddd, J = 14.0, 9.8, 4.5 Hz, 2H), 1.49 (ddd, J = 5.2, 3.6, 1.3 Hz, 1H), 1.46 (ddd, J = 5.1, 3.8, 1.4 Hz, 1H), 1.26 (s, 3H), 1.19 - 1.05 (m, 5H), 0.21 (t, J = 4.8 Hz, 1H).

[0267] Epoxide 29: ((1R,2R)-1,2-dimethylcyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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). The resulting mixture was stirred at rt for 15 min, after which 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, after which the reaction mixture was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0–20% EtOAc in hexanes) to afford the title compound (912 mg, 74%) as a pale yellow oil. 1 H NMR (500 MHz, chloroform-d) δ 8.26 (d, J = 9.1 Hz, 2H), 7.25 (d, J = 9.1 Hz, 2H), 1.76 - 1.66 (m, 1H), 1.61 (dd, J = 9.3, 4.1 Hz, 1H), 1.40 (s, 3H), 1.22 (d, J = 6.3 Hz, 3H), 0.58 (dd, J = 6.9, 4.1 Hz, 1H).

[0268] Step 2: ((1R,2R)-1,2-Dimethylcyclopropyl)(4-methylenepiperidin-1-yl)methanone: A solution of 1-N-boc-4-methylene-piperidine (1.15 g, 5.82 mmol) in 4 M HCl in 1,4-dioxane (4.85 mL, 19.4 mmol) and DCM (3.7 mL) was stirred at rt for 1 h and then concentrated under reduced pressure. To the resulting solid was added a solution of 4-nitrophenyl (1R,2R)-1,2-dimethylcyclopropane-1-carboxylate (912 mg, 3.88 mmol) in DMF (22.5 mL) and DIPEA (2.03 mL, 11.6 mmol). The resulting mixture was stirred at rt for 90 min and then diluted with saturated aqueous sodium bicarbonate (30 mL). The resulting mixture was extracted with EtOAc (x3), and the combined organic layers were washed with 1:1 water / brine (x4), passed through a phase separator, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound (722 mg, 96%) as a yellow oil. LCMS (Method B): R T = 1.12 min (220 nm), m / z = 194 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 4.78 (s, 2H), 3.61 - 3.51 (m, 4H), 2.21 (t, J = 5.8 Hz, 4H), 1.25 (s, 3H), 1.17 - 1.05 (m, 5H), 0.19 (dd, J = 5.4, ​​4.4 Hz, 1H).

[0269] Step 3: ((1R,2R)-1,2-Dimethylcyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of ((1R,2R)-1,2-dimethylcyclopropyl)(4-methylenepiperidin-1-yl)methanone (722 mg, 3.74 mmol) in DCM (18.7 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (1.00 g, 4.48 mmol) in DCM (18.7 mL) afforded the title compound (618 mg, 79%) as a viscous colorless oil after 20 h at rt. LCMS (Method B): R T= 0.79 min (220 nm), m / z = 210 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 1 H NMR (500 MHz, chloroform-d) δ 4.01 - 3.86 (m, 2H), 3.61 - 3.42 (m, 2H), 2.72 (s, 2H), 1.84 (ddd, J = 14.0, 9.8, 4.5 Hz, 2H), 1.49 (ddd, J = 5.2, 3.6, 1.3 Hz, 1H), 1.46 (ddd, J = 5.1, 3.8, 1.4 Hz, 1H), 1.26 (s, 3H), 1.19 - 1.05 (m, 5H), 0.21 (t, J = 4.8 Hz, 1H).

[0270] Epoxide 30: 2,2-Dicyclopropyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)ethan-1-one [ka] 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) afforded the title compound (180 mg, 69%) as a colorless oil after 19 hours. LCMS (Method B): R T = 1.22 min, m / z = 220 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 4.77 (s, 2H), 3.49 (br s, 2H), 3.42 (br s, 2H), 2.11 (br s, 4H), 1.70 (t, J = 8.8 Hz, 1H), 1.07 - 0.98 (m, 2H), 0.49 - 0.42 (m, 2H), 0.35 - 0.23 (m, 4H), 0.11 - 0.04 (m, 2H).

[0271] Step 2: 2,2-Dicyclopropyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)ethan-1-one: General procedure 2 using a solution of 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 a solution of m-CPBA (<77% w / w) (221 mg, 0.985 mmol) in DCM (4.1 mL) afforded the title compound (187 mg, 97%) as a colorless oil after 20 h at rt. LCMS (Method B): R T = 0.90 min, m / z = 236 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 3.77 - 3.64 (m, 1H), 3.64 - 3.54 (m, 1H), 3.54 - 3.45 (m, 2H), 2.67 (s, 2H), 1.71 (t, J = 8.8 Hz, 1H), 1.68 - 1.58 (m, 2H), 1.44 - 1.33 (m, 2H), 1.08 - 0.98 (m, 2H), 0.50 - 0.41 (m, 2H), 0.37 - 0.23 (m, 4H), 0.13 - 0.03 (m, 2H).

[0272] Epoxide 31: (1-methylcyclobutyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) afforded the title compound (131 mg, 93%) as a colorless oil after 1 h. 1H NMR (500 MHz, DMSO-d6) δ 4.76 (s, 2H), 3.54 - 3.33 (m, 2H), 3.28 - 3.12 (m, 2H), 2.46 - 2.37 (m, 2H), 2.21 - 2.04 (m, 4H), 1.98 - 1.85 (m, 1H), 1.83 - 1.73 (m, 2H), 1.69 - 1.55 (m, 1H), 1.35 (s, 3H).

[0273] Step 2: (1-Methylcyclobutyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of (1-methylcyclobutyl)(4-methylenepiperidin-1-yl)methanone (129 mg, 0.667 mmol) in DCM (3.5 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (179 mg, 0.801 mmol) in DCM (3.5 mL) afforded the title compound (133 mg, 95%) as a pale yellow oil after 22.5 h at rt. 1 H NMR (500 MHz, DMSO-d6) δ 3.74 - 3.59 (m, 1H), 3.48 - 3.32 (m, 3H), 2.67 (s, 2H), 2.46 - 2.38 (m, 2H), 1.97 - 1.86 (m, 1H), 1.83 - 1.76 (m, 2H), 1.74 - 1.57 (m, 3H), 1.46 - 1.37 (m, 2H), 1.36 (s, 3H).

[0274] Epoxide 32: 3-Cyclopropyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)propan-1-one [ka] 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) afforded the title compound (269 mg, 52%) as a colorless gum after 19 h. 1 H NMR (500 MHz, chloroform-d) δ 4.79 - 4.76 (m, 2H), 3.60 (t, J = 5.9 Hz, 2H), 3.50 - 3.44 (m, 2H), 2.50 - 2.42 (m, 2H), 2.22 (dt, J = 16.3, 5.9 Hz, 4H), 1.58 - 1.50 (m, 2H), 0.78 - 0.67 (m, 1H), 0.49 - 0.38 (m, 2H), 0.11 - 0.02 (m, 2H).

[0275] Step 2: 3-Cyclopropyl-1-(1-oxa-6-azaspiro[2.5]octan-6-yl)propan-1-one: General procedure 2 using a solution of 3-cyclopropyl-1-(4-methylenepiperidin-1-yl)propan-1-one (269 mg, 1.39 mmol) in DCM (6 mL) at 0° C. and a solution of m-CPBA (<77% w / w) (374 mg, 1.67 mmol) in DCM (6 mL) afforded the title compound (200 mg, 68%) as a colorless oil after 20 h at rt. 1H NMR (500 MHz, chloroform-d) δ 4.15 - 4.07 (m, 1H), 3.75 - 3.67 (m, 1H), 3.56 (ddd, J = 13.5, 9.9, 3.5 Hz, 1H), 3.42 (ddd, J = 13.4, 9.9, 3.6 Hz, 1H), 2.72 (s, 2H), 2.53 - 2.41 (m, 2H), 1.90 - 1.79 (m, 2H), 1.58 - 1.52 (m, 2H), 1.52 - 1.41 (m, 2H), 0.78 - 0.68 (m, 1H), 0.49 - 0.39 (m, 2H), 0.12 - 0.03 (m, 2H).

[0276] Epoxide 33: rac-((1R,2R)-2-(difluoromethyl)-1-methylcyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone [ka] 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) was added n-butyllithium (2.4 M in hexane, 13 mL, 0.0311 mol) dropwise at -78 °C. The reaction mixture was warmed to rt and stirred for an additional 15 min. The reaction mixture was transferred to an autoclave pressure vessel and heated at 145 °C for 18 h. After cooling to rt, the reaction mixture was quenched with saturated aqueous ammonium chloride (200 mL), and the product was extracted with MTBE (3 × 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, which was used in the next step without further purification. 1H NMR (400 MHz, chloroform-d) δ 4.28 (d, J = 7.1 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.39 (s, 6H), 1.84 (dt, J = 9.5, 6.8 Hz, 1H), 1.41 (dd, J = 9.5, 4.2 Hz, 1H), 1.33 (s, 3H), 1.28 - 1.11 (m, 3H), 0.74 (dd, J = 6.6, 4.3 Hz, 1H).

[0277] Step 2: rac-Ethyl (1R,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, after which the volatiles were removed under reduced pressure. The residue was diluted with brine (200 mL), and the product was extracted with DCM (3 × 100 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (4.60 g, 94% (2 steps)) as a yellow oil. This material was used without further purification. 1 H NMR (500 MHz, chloroform-d) δ 9.51 (d, J = 4.3 Hz, 1H), 4.18–4.11 (m, 2H), 2.55–2.48 (m, 1H), 1.72 (dd, J = 8.7, 4.4 Hz, 1H), 1.53–1.48 (m, 1H), 1.44 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H).

[0278] Step 3: rac-Ethyl (1R,2R)-2-(difluoromethyl)-1-methylcyclopropane-1-carboxylate: To a stirring 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, 43.7 mmol). The reaction was stirred at rt for 19 h and then slowly poured into a vigorously stirring mixture of saturated aqueous sodium bicarbonate and ice blocks. Once the ice had melted, the resulting mixture was transferred to a separatory funnel, the layers were separated, and the aqueous layer was further extracted with DCM (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (5.14 g, 97%) as a yellow oil. This material was used without further purification. 1 H NMR (500 MHz, chloroform-d) δ 5.60 (td, J = 55.9, 6.1 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.07–1.97 (m, 1H), 1.54–1.48 (m, 1H), 1.39 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 0.94–0.88 (m, 1H). 19 F NMR (proton decoupled, 376 MHz, chloroform-d) δ -109.20 (d, 2 J F-F = 289.2 Hz), -113.89 (d, 2 J F-F = 289.2 Hz).

[0279] Step 4: rac-(1R,2R)-2-(difluoromethyl)-1-methylcyclopropane-1-carboxylic acid: To a stirring solution of rac-ethyl (1R,2R)-2-(difluoromethyl)-1-methylcyclopropane-1-carboxylate (5.14 g, 28.8 mmol) in MeOH (40 mL) was added a solution of sodium hydroxide (2.62 g, 0.0655 mmol) in water (10 mL). The resulting mixture was stirred at rt for 19 h, after which the volatiles were removed under reduced pressure. The residue was diluted with water (100 mL), and the mixture was acidified to pH 3-4 by the addition of concentrated aqueous hydrochloric acid, after which the product was extracted with DCM (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by flash chromatography (SiO, 2-5% THF in hexanes) to afford the title compound (1.77 g, 40%) as a pale gray crystalline solid. 1 H NMR (600 MHz, chloroform-d) δ 11.38 (br. s, 1H), 5.63 (td, J = 55.8, 5.8 Hz, 1H), 2.15–2.05 (m, 1H), 1.62–1.55 (m, 1H), 1.41 (s, 3H), 1.06–0.99 (m, 1H). 19 F NMR (protons decoupled, 376 MHz, chloroform-d) δ -109.84 (d, J = 289.7 Hz), -114.24 (d, J = 289.7 Hz). The product was identified as rac-(1R,2R)-2-(difluoromethyl)-1-methylcyclopropane-1-carboxylic acid based on NOE studies.

[0280] Step 5: rac-((1R,2R)-2-(difluoromethyl)-1-methylcyclopropyl)(4-methylenepiperidin-1-yl)methanone: To a stirring solution of rac-(1R,2R)-2-(difluoromethyl)-1-methylcyclopropane-1-carboxylic acid (751 mg, 5.00 mmol) and DMF (19.36 μL, 0.250 mmol) in DCM (5 mL) was added dropwise at 0° C. under a nitrogen atmosphere, oxalyl chloride (2 M in DCM, 3.00 mL, 6.00 mmol). The reaction mixture was warmed to rt and stirred for an additional 2 h, after which it was added via syringe to a stirring solution of 4-methylenepiperidine hydrochloride (802 mg, 6.00 mmol) in DCM (5 mL) under a nitrogen atmosphere. The resulting solution was cooled to 0 °C and triethylamine (2.09 mL, 15.0 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at rt for 1 h, after which saturated aqueous sodium bicarbonate (60 mL) was added. The resulting mixture was extracted with DCM (3 × 20 mL) using a phase separator, and the combined organic layers were concentrated under reduced pressure to afford the title compound (1.25 g, 109%) as a yellow oil. This material was used without further purification. 1 H NMR (500 MHz, DMSO-d6) δ 5.94 (ddd, J = 56.2, 54.5, 7.2 Hz, 1H), 4.81 - 4.73 (m, 2H), 3.70 - 3.36 (m, 4H), 2.26 - 2.07 (m, 4H), 1.72 - 1.61 (m, 1H), 1.33 (s, 3H), 1.25 - 1.18 (m, 1H), 0.95 - 0.91 (m, 1H).

[0281] Step 6: rac-((1R,2R)-2-(difluoromethyl)-1-methylcyclopropyl)(1-oxa-6-azaspiro[2.5]octan-6-yl)methanone: General procedure 2 using a solution of 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) afforded the title compound (1.16 g, 94% (2 steps)) as a yellow oil after 19 h at rt. 1 H NMR (500 MHz, DMSO-d6) δ 5.94 (ddd, J = 56.2, 54.6, 7.2 Hz, 1H), 3.94 - 3.63 (m, 2H), 3.53 (br. s, 2H), 2.71 - 2.65 (m, 2H), 1.83 - 1.61 (m, 3H), 1.54 - 1.38 (m, 2H), 1.34 (s, 3H), 1.25 - 1.20 (m, 1H), 0.96 - 0.90 (m, 1H).

[0282] Example 1: rac-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3R,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one [ka] 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) (3.62 g, 10 mmol), 2,6-dimethylpyridine (1.07 g, 10.0 mmol), HFIP (40 mL), 4 Å molecular sieves (approximately 1 g), and DCM (160 mL) gave the title compound (1 g, 39%). 1H NMR (400 MHz, chloroform-d) δ 7.43 (d, J = 8.4 Hz, 2H), 7.34 - 7.18 (m, 2H), 3.92 - 3.73 (m, 2H), 3.65 (ddd, J = 10.2, 6.2, 2.4 Hz, 1H), 3.37 (t, J = 9.8 Hz, 1H), 3.01 (dd, J = 11.7, 2.4 Hz, 1H), 2.70 (dd, J = 11.6, 10.1 Hz, 1H), 1.17 (d, J = 6.2 Hz, 3H).

[0283] Step 2: rac-tert-butyl (2R,5S)-5-(4-bromophenyl)-2-methylmorpholine-4-carboxylate: General procedure 9 using rac-(2R,5S)-5-(4-bromophenyl)-2-methylmorpholine (1 g, 3.90 mmol) and BocO (1.02 g, 4.68 mmol) gave the title compound (1.39 g, quantitative). LCMS (Method C), R T = 1.47 min, m / z = 256, 258 [M-Boc+H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.46 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 4.77 (t, J = 5.4 Hz, 1H), 4.02 (dd, J = 12.3, 4.6 Hz, 1H), 3.99 - 3.92 (m, 1H), 3.72 (dd, J = 12.3, 5.8 Hz, 1H), 3.51 (dd, J = 13.5, 4.0 Hz, 1H), 3.37 (dd, J = 13.5, 4.8 Hz, 1H), 1.35 (s, 9H), 1.29 (d, J = 6.5 Hz, 3H).

[0284] 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 (Workup 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)Cl.CHCl (143 mg, 0.168 mmol), KOAc (496 mg, 5.05 mmol), and 1,4-dioxane (17 mL) afforded the title compound (648 mg, 95%) as a yellow oil after stirring at 120 °C (microwave irradiation) for 30 min. LCMS (Method A): R T = 1.97 min, m / z = 404 [M+H] + .

[0285] 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: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.426 mmol), rac-tert-butyl General procedure 4 (Workup A) using (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(II) 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) afforded the title compound (98 mg, 49%) as a colorless glass after 3 days. LCMS (Method A): R T = 1.90 min, m / z = 463, 465 [M+H] + .

[0286] 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-d]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) afforded the title compound (95 mg, quantitative) as a yellow oil after acidification with AcOH for 18 h at 100° C. LCMS (Method B): R T = 1.22 min, m / z = 445 [M+H] + .

[0287] 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: rac-tert-butyl General procedure 6 using (2R,5S)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (94 mg, 0.211 mmol), epoxide 1 (42 mg, 0.211 mmol), CsCO (207 mg, 0.634 mmol) and DMF (2 mL) afforded the title compound (31 mg, 22%) as a colorless glass after 18 h at 80 °C. LCMS (Method A): R T = 1.42 min, m / z = 640, 642 [M+H] + .

[0288] 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)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one: rac-tert-butyl General procedure 7 using (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 (31 mg, 0.0484 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (14 mg, 53%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.71 min, m / z = 540, 542 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H), 4.91 (s, 1H), 4.01 (s, 2H), 3.99 - 3.90 (m, 2H), 3.85 (dd, J = 10.0, 3.2 Hz, 1H), 3.81 (dd, J = 10.6, 3.2 Hz, 1H), 3.61 - 3.51 (m, 1H), 3.26 (t, J = 10.3 Hz, 1H), 3.16 (s, 2H), 2.96 (dd, J = 11.7, 2.3 Hz, 1H), 2.94 - 2.85 (m, 1H), 2.58 - 2.54 (m, 1H), 1.59 - 1.36 (m, 4H), 1.21 (s, 3H), 1.10 (d, J = 6.2 Hz, 3H), 0.80 - 0.73 (m, 2H), 0.55 - 0.49 (m, 2H).

[0289] Example 2: rac-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3R,5S)-5-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one [ka] 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) (5.51 g, 15.3 mmol), 2,6-dimethylpyridine (1.63 g, 15.3 mmol), HFIP (61 mL), 4 Å molecular sieves (approximately 1.5 g), and DCM (243 mL) gave the title compound (737 mg, 19%). LCMS (Method C): R T = 0.68 min, m / z = 256, 258 [M+H] + .

[0290] 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 BocO (754 mg, 3.45 mmol) gave the title compound (820 mg, 80%). LCMS (Method C), R T = 1.50 minutes, 256, 258 [M-Boc+H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.48 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 5.07 (d, J = 3.9 Hz, 1H), 4.54 - 4.46 (m, 1H), 4.11 (dt, J = 7.1, 2.5 Hz, 1H), 3.77 (dd, J = 12.2, 4.0 Hz, 1H), 3.71 (d, J = 2.5 Hz, 2H), 1.50 (s, 9H), 0.91 (d, J = 7.1 Hz, 3H).

[0291] 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 (Workup 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)Cl.CHCl (143 mg, 0.168 mmol), KOAc (496 mg, 5.05 mmol), and 1,4-dioxane (17 mL) afforded the title compound (588 mg, 86%) as a colorless oil after stirring at 120 °C (microwave irradiation) for 60 min. LCMS (Method B): R T = 1.74 min, m / z = 304 [M-Boc+H] + .

[0292] 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: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (548 mg, 2.91 mmol), rac-tert-butyl General procedure 4 (Workup A) using (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(II) 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 mL) afforded the title compound (882 mg, 65%) as a colorless glass after 3 days. LCMS (Method B): R T = 1.69 min, m / z = 463, 465 [M+H] + . 1H NMR (500 MHz, chloroform-d) δ 8.62 (s, 1H), 7.89 - 7.77 (m, 2H), 7.41 - 7.33 (m, 2H), 6.74 (s, 1H), 5.22 (d, J = 3.6 Hz, 1H), 4.59 (dd, J = 12.3, 1.2 Hz, 1H), 4.23 - 4.14 (m, 1H), 3.85 (dd, J = 12.3, 4.0 Hz, 1H), 3.80 - 3.74 (m, 2H), 1.53 (s, 9H), 1.01 (d, J = 7.1 Hz, 3H).

[0293] 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-d]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) afforded the title compound (140 mg, quantitative) as a white solid after 18 h at 100° C. LCMS (Method B): R T = 1.22 min, m / z = 445, 446 [M+H] + .

[0294] 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: rac-tert-butyl General procedure 6 using (3R,5S)-3-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4-carboxylate (140 mg, 0.315 mmol), epoxide 1 (62 mg, 0.315 mmol), CsCO (205 mg, 0.629 mmol) and DMF (2.5 mL) afforded the title compound (120 mg, 59%) as a white solid after 18 h at 80° C. LCMS (Method B): R T = 1.33 min, m / z = 584, 586 [M-butene + H] + , 540, 542 [M-Boc+H] + .

[0295] 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)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one: rac-tert-butyl General procedure 7 using (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 (10 mg, 0.0156 mmol), TFA (0.25 mL) and DCM (0.5 mL) afforded the title compound (7.1 mg, 78%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.68 min, m / z = 540, 542 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.9 Hz, 2H), 6.81 (s, 1H), 4.91 (s, 1H), 4.01 (s, 2H), 3.95 (dt, J = 13.0, 4.6 Hz, 3H), 3.75 (dd, J = 36.0, 10.4 Hz, 2H), 3.25 - 3.07 (m, 3H), 2.97 (s, 3H), 1.50 (d, J = 12.0 Hz, 2H), 1.39 (d, J = 13.3 Hz, 2H), 1.21 (s, 3H), 0.96 (d, J = 5.9 Hz, 3H), 0.77 (q, J = 4.1 Hz, 2H), 0.53 - 0.50 (m, 2H).

[0296] Example 3: 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 [ka] 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 resulting 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 and then diluted with water. The resulting phases were separated and the organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound (5.00 g, 60%). LCMS (Method C): R T = 1.12 min, m / z = 306, 308 [M+H] + . 1H NMR (500 MHz, chloroform-d) δ 7.47 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.13 (br. s, 1H), 4.06 (d, J = 2.3 Hz, 2H), 3.87 (d, J = 11.8 Hz, 1H), 3.68 (d, J = 11.8 Hz, 1H), 3.45 (br. s, 1H), 1.68 (s, 3H).

[0297] Step 2: 5-(4-Bromophenyl)-5-methylmorpholin-3-one: To a solution of N-(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, after which saturated aqueous sodium bicarbonate (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. The crude product was purified by flash chromatography to give the title compound (3.35 g, 76%). LCMS (Method C): R T = 1.11 min, m / z = 270, 272 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.49 (d, J = 7.2 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 4.17 (s, 2H), 3.78 (d, J = 11.9 Hz, 1H), 3.69 (d, J = 11.9 Hz, 1H), 1.62 (s, 3H), 0.84 (br. s, 1H).

[0298] 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) was added borane dimethyl sulfide complex (5.88 mL, 62.0 mmol) at 0 °C under a nitrogen atmosphere. The resulting mixture was warmed to rt and stirred for an additional 16 h. To quench excess borane, MeOH (120 mL) was added dropwise, and the resulting mixture was stirred at 70 °C for 1 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure, and 5% aqueous hydrochloric acid was added to the residue. The resulting pH 1 mixture was extracted with EtOAc (2 × 30 mL) to remove by-products. The pH of the aqueous layer was adjusted to pH 10 by the addition of Na2CO3, and the product was then extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (700 mg, 22%). LCMS (Method C): T = 1.36 min, m / z = 256, 258 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.49 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 4.06 (d, J = 11.9 Hz, 1H), 3.69 (m, 2H), 3.55 (d, J = 11.9 Hz, 1H), 2.88 (m, 1H), 2.80 (m, 1H), 1.67 (br. s, 1H), 1.34 (s, 3H).

[0299] 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), BocO (0.691 mL, 3.01 mmol), and DMAP (ca). The resulting solution was stirred at rt for 16 h, after which BocO (0.457 mL, 3.28 mmol) was added. After consumption of the starting material, trifluoroethanol (0.43 mL) was added to destroy excess BocO. After 5 h, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography to give the title compound (800 mg, 82%). LCMS (Method C): R T = 1.61 min, m / z = 300, 302 [M-butene + H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.43 (d, J = 7.2 Hz, 2H), 7.26 (d, J = 7.2 Hz, 2H), 4.02 (m, 1H), 3.74 (m, 2H), 3.43 (m, 3H), 1.70 (s, 3H), 1.14 (s, 9H).

[0300] 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 (Workup A) using tert-butyl 3-(4-bromophenyl)-3-methylmorpholine-4-carboxylate (180 mg, 0.505 mmol), B2Pin2 (192 mg, 0.758 mmol), Pd(dppf)Cl.CH2Cl2 (43 mg, 0.0505 mmol), KOAc (149 mg, 1.52 mmol), and 1,4-dioxane (4 mL) afforded the title compound (171 mg, 84%) as a yellow oil after stirring at 120 °C (microwave irradiation) for 30 min. LCMS (Method A): R T = 1.97 min, m / z = 404, 406 [M+H] + .

[0301] Step 6: tert-butyl 3-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-3-methylmorpholine-4-carboxylate: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (40 mg, 0.213 mmol), tert-butyl General procedure 4 (Workup A) was followed using 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(II) 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) to give the title compound (32 mg, 32%) as a colorless film after 3 days. LCMS (Method B): R T = 1.65 min, m / z = 463, 465 [M+H] + .

[0302] 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) afforded the title compound (31 mg, quantitative) as a white solid after 18 h at 100° C. LCMS (Method B): R T = 1.19 min, m / z = 445, 447 [M+H] + .

[0303] 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: tert-butyl General procedure 6 using 3-(4-(6-chloro-4-oxo-3,4-dihydro-7H-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), CsCO (45 mg, 0.139 mmol) and DMF (0.7 mL) afforded the title compound (25.4 mg, 56%) as a white solid after 3 days at 80° C. LCMS (Method B): R T = 1.30 min, m / z = 584, 586 [M-butene + H] + ; 540, 542 [M-Boc+H] + .

[0304] 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: tert-butyl General procedure 7 using 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 (25 mg, 0.0391 mmol), TFA (0.5 mL) and DCM (1 mL) afforded the title compound (11.3 mg, 51%) as an off-white solid after freeze-drying. LCMS (Method B): R T = 0.674 min, m / z = 540, 542 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.76 - 7.72 (m, 2H), 7.41 (d, J = 8.5 Hz, 2H), 6.81 (s, 1H), 4.91 (s, 1H), 4.08 (d, J = 11.3 Hz, 1H), 4.01 (s, 2H), 3.95 (dt, J = 12.9, 4.2 Hz, 2H), 3.58 - 3.49 (m, 3H), 3.16 (br. s, 2H), 2.71 (dd, J = 53.7, 7.1 Hz, 3H), 1.50 (d, J = 12.7 Hz, 2H), 1.40 (d, J = 13.4 Hz, 2H), 1.27 (s, 3H), 1.21 (s, 3H), 0.77 (q, J = 4.1 Hz, 2H), 0.53 - 0.50 (m, 2H).

[0305] Example 4: 6-chloro-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 [ka] 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 (prepared starting from (S)-1-aminopropan-2-ol according to the procedure outlined in Org. Lett. 2014, 16 (4), 1236-1239) (3.78 g, 10.0 mmol), Cu(OTf) (3.62 g, 10.0 mmol), 2,6-dimethylpyridine (1.07 g, 10.0 mmol), HFIP (40 mL), 4 Å molecular sieves (approximately 1 g), and DCM (160 mL) gave the title compound (1.37 g, 53%). LCMS (Method C): R T = 0.63 min, m / z = 256, 258 [M+H] + . 1H NMR (500 MHz, chloroform-d) δ 7.58 - 7.39 (m, 2H), 7.32 - 7.19 (m, 2H), 3.94 - 3.76 (m, 2H), 3.66 (td, J = 7.4, 6.8, 3.3 Hz, 1H), 3.38 (t, J = 10.1 Hz, 1H), 3.02 (dd, J = 11.7, 2.6 Hz, 1H), 2.71 (t, J = 10.8 Hz, 1H), 1.92 (s, 1H), 1.18 (d, J = 6.2 Hz, 3H).

[0306] 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 BocO (1.4 g, 6.42 mmol) gave the title compound (1.7 g, 89%). LCMS (Method C): T = 1.32 min, m / z = 256, 258 [M-Boc+H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.45 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 4.76 (t, J = 5.2 Hz, 1H), 4.01 (dd, J = 12.3, 4.6 Hz, 1H), 3.98 - 3.92 (m, 1H), 3.71 (dd, J = 12.3, 5.8 Hz, 1H), 3.51 (dd, J = 13.5, 3.8 Hz, 1H), 3.36 (dd, J = 13.5, 4.8 Hz, 1H), 1.34 (s, 9H), 1.28 (d, J = 6.4 Hz, 3H). Chiral purity (Method B): R T = 11.32 min, >98%ee.

[0307] 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 (Workup A) using tert-butyl (2S,5R)-5-(4-bromophenyl)-2-methylmorpholine-4-carboxylate (2 g, 5.61 mmol), B2Pin2 (2.14 g, 8.42 mmol), Pd(dppf)Cl.CHCl (475 mg, 0.561 mmol), KOAc (1.65 g, 16.8 mmol), and 1,4-dioxane (55 mL) afforded the title compound (2.10 g, 92%) as a pale yellow oil after stirring at 100 °C (thermal) for 2 h. LCMS (Method B): R T = 1.71 min, m / z = 304 [M-Boc+H] + .

[0308] Step 4: tert-butyl (2S,5R)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (652 mg, 3.48 mmol), tert-butyl General procedure 4 (Workup A) using (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(II) 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) afforded the title compound (1.07 g, 66%) as a colorless glass after 24 h at 75-80° C. LCMS (Method B): R T = 1.68 min, m / z = 463, 465 [M+H] + .

[0309] 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-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (1.07 g, 2.30 mmol), aqueous sodium hydroxide (4 M, 17.2 mL, 69.0 mmol) and 1,4-dioxane (17.3 mL) afforded the title compound (1.08 g, >100%) as a yellow glass after acidification with 1 M aqueous potassium bisulfate at 100° C. for 18 hours. LCMS (Method B): R T = 1.30 min, m / z = 445, 447 [M+H] + .

[0310] 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: tert-butyl General procedure 6 using (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), CsCO (971 mg, 2.98 mmol) and DMF (10 mL) afforded the title compound (498 mg, 72%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T = 1.50 min, m / z = 640, 642 [M-butene + H] + .

[0311] Step 7: 6-chloro-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: tert-butyl General procedure 7 using (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 (498 mg, 0.715 mmol), TFA (5 mL) and DCM (10 mL) afforded the title compound (385 mg, 90%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.83 min, m / z = 596, 598 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.65 - 7.55 (m, 2H), 7.55 - 7.48 (m, 2H), 7.47 - 7.34 (m, 4H), 6.79 (s, 1H), 4.95 (s, 1H), 4.31 - 4.08 (m, 1H), 4.02 (s, 2H), 3.85 (dd, J = 10.1, 3.3 Hz, 1H), 3.80 (dd, J = 10.6, 3.2 Hz, 1H), 3.62 - 3.49 (m, 1H), 3.48 - 3.33 (m, 1H), 3.29 - 3.20 (m, 2H), 3.20 - 3.05 (m, 1H), 3.04 - 2.77 (m, 2H), 2.58 - 2.52 (m, 1H), 1.69 - 1.53 (m, 2H), 1.53 - 1.25 (m, 2H), 1.09 (d, J = 6.2 Hz, 3H). Chiral purity (Method C): R T = 2.98 min, 99.8% ee.

[0312] Example 5: 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 [ka] Step 1: (2S,5R)-5-(4-bromo-2-methylphenyl)-2-methylmorpholine: 4-bromo-2-methylbenzaldehyde (1.99 g, 10.0 mmol), (S)-2-((tributylstannyl)methoxy)propan-1-amine (Org. Lett. 2014, 16 (4), General procedure 8 using (prepared according to the procedure outlined in 1236-1239, starting from (S)-1-aminopropan-2-ol) (3.78 g, 10.0 mmol), Cu(OTf) (3.62 g, 10.0 mmol), 2,6-dimethylpyridine (1.07 g, 10.0 mmol), HFIP (40 mL), 4 Å molecular sieves (approximately 1 g) and DCM (160 mL) gave the title compound (1.45 g, 53%). LCMS (Method C): R T = 0.63 min, m / z = 270, 272 [M+H] + .

[0313] 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 BocO (1.4 g, 6.42 mmol) gave the title compound (1.77 g, 89%). LCMS (Method C, 5 min gradient): R T = 3.54 min, m / z = 270, 272 [M-Boc+H] + . 1H NMR (500 MHz, chloroform-d) δ 7.36 - 7.12 (m, 3H), 4.72 (dd, J = 9.1, 4.9 Hz, 1H), 3.92 (td, J = 7.2, 6.8, 4.1 Hz, 1H), 3.84 (dd, J = 12.3, 4.7 Hz, 1H), 3.76 (dd, J = 13.5, 3.8 Hz, 1H), 3.45 (dd, J = 12.3, 8.8 Hz, 1H), 3.23 (dd, J = 13.5, 6.5 Hz, 1H), 2.31 (s, 3H), 1.25 (d, J = 5.9 Hz, 3H), 1.19 (s, 9H). Chiral purity (Method D): R T = 5.371 min, >98%ee.

[0314] 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 (Workup 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)Cl.CHCl (137 mg, 0.162 mmol), KOAc (477 mg, 4.86 mmol), and 1,4-dioxane (17 mL) afforded the title compound (432 mg, 63%) as a pale yellow oil after stirring at 120 °C (microwave irradiation) for 30 min. LCMS (Method B): R T = 1.83 min, m / z = 318 [M-Boc+H] + .

[0315] 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: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (97 mg, 0.516 mmol), tert-butyl General procedure 4 (Workup A) using (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(II) 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) afforded the title compound (107 mg, 43%) as a colorless glass after 6 days at 50° C. LCMS (Method B): R T = 1.76 min, m / z = 477, 479 [M+H] + .

[0316] 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-d]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) for 18 h at 100° C. to afford the title compound (104 mg, >100%) as a yellow glass after acidification with AcOH. LCMS (Method B): R T = 1.28 min, m / z = 459, 461 [M+H] + .

[0317] 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)-2-methylphenyl)-2-methylmorpholine-4-carboxylate: tert-butyl General procedure 6 using (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 (52 mg, 0.113 mmol), epoxide 2 (42.8 mg, 0.170 mmol), CsCO (111 mg, 0.340 mmol) and DMF (2 mL) afforded the title compound (33 mg, 41%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T = 1.55 min, m / z = 654, 656 [M-butene + H] + .

[0318] 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: tert-butyl General procedure 7 using (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)-2-methylphenyl)-2-methylmorpholine-4-carboxylate (33 mg, 0.0464 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (26 mg, 91%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.87 min, m / z = 610, 612 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.27 - 7.19 (m, 2H), 6.77 (s, 1H), 4.95 (s, 1H), 4.22 - 4.09 (m, 1H), 4.01 (s, 2H), 3.98 (dd, J = 10.0, 3.0 Hz, 1H), 3.79 (dd, J = 10.9, 3.0 Hz, 1H), 3.61 - 3.53 (m, 1H), 3.43 - 3.33 (m, 1H), 3.28 - 3.07 (m, 3H), 2.97 (dd, J = 11.6, 2.3 Hz, 1H), 2.84 - 2.71 (m, 1H), 2.61 - 2.52 (m, 1H), 2.41 (s, 3H), 1.68 - 1.52 (m, 2H), 1.52 - 1.29 (m, 2H), 1.10 (d, J = 6.2 Hz, 3H).

[0319] Example 6: 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 [ka] 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) afforded the title compound (1.10 g, 46%) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 4.60–4.15 (m, 2H), 3.95–3.86 (m, 1H), 3.73–3.61 (m, 1H), 3.60–3.35 (m, 2H), 1.61–1.43 (m, 12H).

[0320] 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). The reaction mixture was heated to 75 °C (internal temperature), followed by the sequential addition of triethylamine (958 μL, 6.87 mmol) and a DMF solution of NiCl 6H O:bathophenanthroline complex (0.05 M, 2.6 mL, 0.130 mmol (Angew. Chem. Int. Ed. 2016, 55, 9676-9679)). The resulting mixture was stirred at 75 °C overnight. After cooling to rt, the reaction mixture was diluted with EtOAc (40 mL) and washed with brine. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound (103 mg, 42%) as a colorless glass. LCMS (Method B): R T = 1.61 min, m / z = 256, 258 [M-Boc+H] + .

[0321] 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 (Workup 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)Cl.CHCl (58 mg, 0.0682 mmol), KOAc (201 mg, 2.046 mmol), and 1,4-dioxane (7 mL) afforded the title compound (133 mg, 48%) as a colorless glass after stirring at 120 °C (microwave irradiation) for 30 min. LCMS (Method B): R T = 1.73 min, m / z = 304 [M-Boc+H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.81 - 7.74 (m, 2H), 7.46 - 7.38 (m, 2H), 4.68 (d, J = 4.1 Hz, 1H), 4.29 - 4.16 (m, 1H), 3.97 (td, J = 10.9, 4.1 Hz, 1H), 3.84 - 3.75 (m, 1H), 3.74 - 3.62 (m, 1H), 3.34 - 3.19 (m, 1H), 1.38 (s, 9H), 1.34 (s, 12H), 1.31 (d , J = 6.4 Hz, 3H).

[0322] Step 4: tert-butyl (2S,3S)-3-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (62 mg, 0.330 mmol), tert-butyl General procedure 4 (Workup A) using (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(II) 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) afforded the title compound (40 mg, 26%) as a colorless glass after 5 days at 50° C. LCMS (Method B): R T = 1.68 min, m / z = 463, 465 [M+H] + .

[0323] 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-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (40 mg, 0.0863 mmol), aqueous sodium hydroxide (4 M, 0.43 mL, 1.73 mmol) and 1,4-dioxane (0.43 mL) afforded the title compound (38 mg, 98%) as a yellow glass after acidification with AcOH for 18 h at 100° C. LCMS (Method B): R T = 1.22 min, m / z = 445, 447 [M+H] + .

[0324] Step 6: tert-butyl (2S,3S)-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: tert-butyl General procedure 6 using (2S,3S)-3-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (39 mg, 0.0877 mmol), epoxide 2 (33.1 mg, 0.132 mmol), CsCO (85.7 mg, 0.263 mmol) and DMF (2 mL) afforded the title compound (14 mg, 22%) as a colorless glass after 18 h at 80° C. LCMS (Method B): R T = 1.48 min, m / z = 640, 642 [M-butene + H] + .

[0325] 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: tert-butyl General procedure 7 using (2S,3S)-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 (14 mg, 0.0201 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (11 mg, 91%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.85 min, m / z = 596, 598 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.61 - 7.54 (m, 2H), 7.54 - 7.48 (m, 2H), 7.45 - 7.41 (m, 2H), 7.41 - 7.36 (m, 2H), 6.79 (s, 1H), 4.95 (s, 1H), 4.22 - 4.11 (m, 1H), 4.02 (s, 2H), 3.80 (dd, J = 10.7, 1.9 Hz, 1H), 3.62 (td, J = 11.0, 3.0 Hz, 1H), 3.44 (d, J = 8.7 Hz, 1H), 3.39 (dq, J = 8.6, 6.0 Hz, 2H), 3.28 - 3.21 (m, 1H), 3.19 - 3.07 (m, 1H), 2.93 - 2.75 (m, 3H), 1.67 - 1.52 (m, 2H), 1.52 - 1.27 (m, 2H), 0.86 (d, J = 6.0 Hz, 3H).

[0326] Example 7: 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 [ka] 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: tert-butyl General procedure 6 using (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (41 mg, 0.0922 mmol), epoxide 3 (43.3 mg, 0.138 mmol), CsCO (90.1 mg, 0.277 mmol) and DMF (2 mL) afforded the title compound (15 mg, 21%) as a colorless glass after 18 h at 80° C. LCMS (Method B): R T= 1.58 min, m / z = 702, 704 [M-butene + H] + .

[0327] 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-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (15 mg, 0.0198 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (12 mg, 92%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.89 min, m / z = 658, 660 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 0.5H), 8.03 (s, 0.5H), 7.64 - 7.56 (m, 2H), 7.46 - 7.26 (m, 7H), 6.79 (s, 0.5H), 6.79 (s, 0.5H), 4.88 (s, 1H), 4.18 - 4.04 (m, 1H), 4.03 - 3.68 (m, 6H), 3.62 - 3.50 (m, 1H), 3.30 - 3.09 (m, 3H), 3.01 - 2.78 (m, 3H), 2.57 - 2.52 (m, 2H), 1.68 - 1.16 (m, 4H), 1.09 (d, J = 6.2 Hz, 3H).

[0328] Example 8: 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 [ka] 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) afforded the title compound (513 mg, 41%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 4.60–4.15 (m, 2H), 3.95–3.86 (m, 1H), 3.73–3.61 (m, 1H), 3.60–3.35 (m, 2H), 1.61–1.43 (m, 12H).

[0329] 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), followed by the sequential addition of triethylamine (1.35 mL, 9.71 mmol) and a DMF solution of NiCl 6H O:bathophenanthroline complex (0.05 M, 3.7 mL, 0.185 mmol, (Angew. Chem. Int. Ed. 2016, 55, 9676-9679)). The resulting mixture was stirred at 75 °C overnight. After cooling to rt, the reaction mixture was diluted with EtOAc (40 mL) and washed with brine. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound (118 mg, 34%) as a colorless glass. LCMS (Method B): R T = 1.61 min, m / z = 256, 258 [M-Boc+H] + .

[0330] 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 (Workup 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)Cl.CHCl (28.1 mg, 0.0331 mmol), KOAc (97.5 mg, 0.994 mmol), and 1,4-dioxane (4 mL) afforded the title compound (65 mg, 48%) as a white solid after stirring at 120 °C (microwave irradiation) for 1 h. LCMS (Method B): R T= 1.76 min, m / z = 304 [M-Boc+H] + .

[0331] Step 4: tert-butyl (2R,3R)-3-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (30 mg, 0.160 mmol), tert-butyl General procedure 4 (Workup A) using (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(II) 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) afforded the title compound (24 mg, 32%) as a colorless glass after 6 days at 50° C. LCMS (Method A): R T = 1.89 min, m / z = 463, 465 [M+H] + .

[0332] 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-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (24 mg, 0.0518 mmol), aqueous sodium hydroxide (4 M, 0.39 mL, 1.55 mmol) and 1,4-dioxane (0.4 mL) afforded the title compound (24 mg, >100%) as a yellow glass after acidification with AcOH for 18 h at 100° C. LCMS (Method B): R T = 1.22 min, m / z = 445, 447 [M+H] + .

[0333] 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: tert-butyl General procedure 6 using (2R,3R)-3-(4-(6-chloro-4-oxo-3,4-dihydro-7H-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), CsCO (52.7 mg, 0.162 mmol) and DMF (2 mL) afforded the title compound (12 mg, 31%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T = 1.48 min, m / z = 640, 642 [M-butene + H] + .

[0334] 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: tert-butyl General procedure 7 using (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 (12 mg, 0.0172 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (10 mg, 97%) as an off-white solid after freeze-drying. LCMS (Method B): R T = 0.94 min, m / z = 596, 598 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.63 - 7.55 (m, 2H), 7.56 - 7.48 (m, 2H), 7.46 - 7.35 (m, 4H), 6.80 (s, 1H), 4.96 (s, 1H), 4.28 - 4.09 (m, 1H), 4.03 (s, 2H), 3.88 - 3.72 (m, 1H), 3.63 (td, J = 11.0, 3.0 Hz, 1H), 3.45 (d, J = 8.7 Hz, 1H), 3.40 (dq, J = 8.7, 6.0Hz, 2H), 3.30 - 3.20 (m, 1H), 3.20 - 3.05 (m, 1H), 2.93 - 2.75 (m, 3H), 1.75 - 1.54 (m, 2H), 1.53 - 1.25 (m, 2H), 0.86 (d, J = 6.0 Hz, 3H).

[0335] Example 9: rac-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6R)-6-(trifluoromethyl)morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one [ka] Step 1: rac-(2R,5R)-5-(4-bromophenyl)-2-(trifluoromethyl)morpholine: 4-bromobenzaldehyde (5.55 g, 30.0 mmol), 3,3,3-trifluoro-2-((tributylstannyl)methoxy)propan-1-amine (Org. Lett. 2014, 16 (4), General procedure 8 using Cu(OTf) (10.9 g, 30.0 mmol), 2,6-dimethylpyridine (3.21 g, 30.0 mmol), HFIP (120 mL), 4 Å molecular sieves (approximately 3 g), and DCM (480 mL) following the procedures outlined in [1236-1239] and starting from 3-amino-1,1,1-trifluoropropan-2-ol (13.0 g, 30.0 mmol), Cu(OTf) (10.9 g, 30.0 mmol), 2,6-dimethylpyridine (3.21 g, 30.0 mmol), HFIP (120 mL), 4 Å molecular sieves (approximately 3 g), and DCM (480 mL) gave the title compound, which was used in the next step without further purification.

[0336] 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 BocO (10.9 g, 50 mmol) afforded the title compound (150 mg, 1% (2 steps)). LCMS (Method C): T = 1.63 min, no mass ion observed. This material was used without further purification.

[0337] 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: rac-tert-butyl General procedure 3 (Workup A) using (2R,5R)-5-(4-bromophenyl)-2-(trifluoromethyl)morpholine-4-carboxylate (150 mg, 0.366 mmol), B2Pin2 (139 mg, 0.549 mmol), Pd(dppf)Cl.CH2Cl2 (31 mg, 0.0366 mmol), KOAc (108 mg, 1.10 mmol), and 1,4-dioxane (4 mL) afforded the title compound (135 mg, 80%) as a colorless glass after stirring at 120 °C (microwave irradiation) for 1 h. LCMS (Method B): R T = 1.75 min, m / z = 402 [M-butene + H] + .

[0338] 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: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (55 mg, 0.293 mmol), rac-tert-butyl General procedure 4 (Workup A) using (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(II) 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 mL) afforded the title compound (17 mg, 11%) as a colorless glass after 6 days at 50° C. LCMS (Method A): R T = 1.71 min, m / z = 517, 519 [M+H] + .

[0339] 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-d]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) afforded the title compound (17 mg, >100%) as a yellow glass after 18 h at 100° C. and acidification with AcOH. LCMS (Method B): R T = 1.33 min, m / z = 499, 501 [M+H] + .

[0340] 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: rac-tert-butyl General procedure 6 using (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 (17 mg, 0.0341 mmol), epoxide 2 (12.9 mg, 0.0511 mmol), CsCO (33.3 mg, 0.102 mmol) and DMF (1 mL) afforded the title compound (12 mg, 46%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T = 1.55 min, m / z = 694, 696 [M-butene + H] + .

[0341] Step 7: rac-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6R)-6-(trifluoromethyl)morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one: rac-tert-butyl General procedure 7 using (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 (12 mg, 0.0160 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (7 mg, 67%) as an off-white solid after freeze-drying. LCMS (Method B): R T = 1.00 min, m / z = 650, 652 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.54 - 7.49 (m, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.45 - 7.39 (m, 2H), 6.81 (s, 1H), 4.96 (s, 1H), 4.31 - 4.12 (m, 2H), 4.14 - 3.92 (m, 4H), 3.59 - 3.45 (m, 1H), 3.45 - 3.34 (m, 2H), 3.29 - 3.04 (m, 3H), 3.03 - 2.83 (m, 1H), 1.69 - 1.27 (m, 4H).

[0342] Example 10: 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) [ka] 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 (prepared from 1-amino-2-methylpropan-2-ol according to the procedure outlined in Org. Lett. 2014, 16 (4), 1236-1239) (3.92 g, 10.0 mmol), Cu(OTf) (3.62 g, 10.0 mmol), 2,6-dimethylpyridine (1.07 g, 10.0 mmol), HFIP (40 mL), 4 Å molecular sieves (approximately 1 g), and DCM (160 mL) gave the title compound (1.74 g, 64%). LCMS (Method C): R T = 0.75 min, m / z = 270, 272 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.45 (d, J = 7.6 Hz, 2H), 7.30 (d, J = 7.6 Hz, 2H), 3.86 - 3.76 (m, 1H), 3.64 - 3.51 (m, 2H), 2.90 - 2.79 (m, 2H), 1.43 (s, 3H), 1.22 (s, 3H).

[0343] 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 BocO (1.69 g, 7.73 mmol) gave the title compound (2.10 g, 88%). LCMS (Method C): T = 1.64 min, m / z = 270, 272 [M-Boc+H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.46 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 5.04 (s, 1H), 4.14 - 3.96 (m, 2H), 3.65 (d, J = 13.6 Hz, 1H), 2.79 (d, J = 13.6 Hz, 1H), 1.46 (s, 9H), 1.27 (s, 3H), 1.17 (s, 3H).

[0344] 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 (Workup A) using 5-(4-bromophenyl)-2,2-dimethylmorpholine (1.40 g, 3.78 mmol), B2Pin2 (1.44 mg, 5.67 mmol), Pd(dppf)Cl.CH2Cl2 (320 mg, 0.378 mmol), KOAc (1.11 g, 11.3 mmol), and 1,4-dioxane (36 mL) afforded the title compound (1.52 g, 96%) as a colorless glass after stirring at 100 °C (thermal) for 2 h. LCMS (Method B): R T = 1.78 min, m / z = 318 [M-Boc+H] + .

[0345] Step 4: tert-butyl 5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (457 mg, 2.43 mmol), tert-butyl General procedure 4 (Workup A) using 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(II) 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) afforded the title compound (772 mg, 66%) as a colorless glass after 4 days at 50° C. LCMS (Method B): R T = 1.74 min, m / z = 477, 479 [M+H] + .

[0346] 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-d]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) afforded the title compound (94 mg, quantitative) as a yellow glass after acidification with AcOH after 18 h at 100° C. LCMS (Method B): R T = 1.30 min, m / z = 459,461 [M+H] + .

[0347] 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): tert-butyl General procedure 6 using 5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (47 mg, 0.102 mmol), epoxide 3 (48.1 mg, 0.154 mmol), CsCO (100 mg, 0.307 mmol) and DMF (3 mL) afforded the title compound (27 mg, 34%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T = 1.62 min, m / z = 716, 718 [M-butene + H] + .

[0348] 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): 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 General procedure 7 using (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) (27 mg, 0.0350 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (23 mg, 97%) as an off-white solid after freeze-drying. LCMS (Method B): R T = 0.94 min, m / z = 672, 674 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 0.5H), 8.03 (s, 0.5H), 7.68 - 7.61 (m, 2H), 7.47 - 7.27 (m, 7H), 6.80 (s, 0.5 H), 6.80 (s, 0.5H), 4.88 (s, 1H), 4.17 - 4.05 (m, 1H), 4.03 - 3.80 (m, 4H), 3.80 - 3.71 (m, 1H), 3.62 - 3.55 (m, 1H), 3.55 - 3.44 (m, 1H), 3.28 - 3.11 (m, 2H), 3.00 - 2.66 (m, 5H), 1.63 - 1.56 (m, 0.5H), 1.46 - 1.26 (m, 3H), 1.36 (s, 3H), 1.25 - 1.16 (m, 0.5H), 1.14 (s, 3H).

[0349] Example 11: 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 [ka] 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 (prepared from (R)-1-aminopropan-2-ol according to the procedure outlined in Org. Lett. 2014, 16 (4), 1236-1239) (3.78 g, 10.0 mmol), Cu(OTf) (3.62 g, 10.0 mmol), 2,6-dimethylpyridine (1.07 g, 10.0 mmol), HFIP (40 mL), 4 Å molecular sieves (approximately 1 g), and DCM (160 mL) gave the title compound (1.10 g, 43%). LCMS (Method C): R T = 0.81 min, m / z = 256, 258 [M+H] + .

[0350] 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 BocO (1.12 g, 5.15 mmol) gave the title compound (1.4 g, 91%). LCMS (Method C): T = 1.60 min, m / z = 256, 258 [M-Boc+H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.45 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 4.76 (t, J = 5.2 Hz, 1H), 4.01 (dd, J = 12.3, 4.6 Hz, 1H), 3.98 - 3.92 (m, 1H), 3.71 (dd, J = 12.3, 5.8 Hz, 1H), 3.51 (dd, J = 13.5, 3.8 Hz, 1H), 3.36 (dd, J = 13.5, 4.8 Hz, 1H), 1.34 (s, 9H), 1.28 (d, J = 6.4 Hz, 3H). Chiral purity (Method B): R T = 10.61 min, >99%ee.

[0351] 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 (Workup 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)Cl.CHCl (143 mg, 0.168 mmol), KOAc (496 mg, 5.05 mmol), and 1,4-dioxane (16.8 mL) afforded the title compound (541 mg, 79%) as a colorless glass after stirring at 120 °C (thermal) for 1 h. LCMS (Method B): R T= 1.77 min, m / z = 348 [M-butene + H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.64 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 4.76 (t, J = 5.4 Hz, 1H), 3.97 - 3.88 (m, 2H), 3.66 (q, J = 6.1 Hz, 1H), 3.46 (dd, J = 13.6, 4.1 Hz, 1H), 3.34 (dd, J = 13.5, 4.5 Hz, 1H), 1.28 (s, 12H), 1.27 (s, 9H), 1.17 (s, 3H).

[0352] Step 4: tert-butyl (2R,5S)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (127 mg, 0.676 mmol), tert-butyl General procedure 4 (Workup A) using (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(II) 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) afforded the title compound (122 mg, 38%) as a colorless glass after 4 days at 50° C. LCMS (Method A): R T = 1.69 min, m / z = 463, 465 [M+H] + .

[0353] 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-d]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. After cooling to rt, water was added and the aqueous phase was extracted with DCM (3×15 mL). The combined organic phases were concentrated under reduced pressure to give the title compound (96 mg, quantitative) as a white solid. LCMS (Method B): T = 1.24 min, m / z = 445, 447 [M+H] + .

[0354] 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: tert-butyl General procedure 6 using (2R,5S)-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 2 (27.1 mg, 0.108 mmol), CsCO (64.4 mg, 0.198 mmol) and DMF (1 mL) afforded the title compound (20 mg, 31%) as a white solid after 18 h at 80 °C. LCMS (Method B): R T = 1.49 min, m / z = 640, 642 [M-butene + H] + .

[0355] 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: tert-butyl General procedure 7 using (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 (20 mg, 0.0287 mmol), TFA (0.35 mL) and DCM (0.7 mL) afforded the title compound (8.5 mg, 47%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.97 min, m / z = 596, 598 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.62 - 7.58 (m, 2H), 7.52 - 7.48 (m, 2H), 7.44 - 7.37 (m, 4H), 6.79 (s, 1H), 4.95 (s, 1H), 4.22 - 4.12 (m, 1H), 4.02 (s, 2H), 3.87 - 3.78 (m, 2H), 3.60 - 3.50 (m, 1H), 3.42 - 3.33 (m, 1H), 3.29 - 3.21 (m, 2H), 3.17 - 3.08 (m, 1H), 2.95 (dd, J = 11.7, 2.3 Hz, 1H), 2.93 - 2.84 (m, 1H), 2.57 - 2.53 (m, 1H), 1.68 - 1.53 (m, 2H), 1.51 - 1.41 (m, 1H), 1.38 - 1.27 (m, 1H), 1.09 (d, J = 6.2 Hz, 3H). Chiral purity (Method C): R T = 3.96 min, 100% ee.

[0356] Example 12: 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 [ka] 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 (prepared from (R)-1-aminopropan-2-ol according to the procedure outlined in Org. Lett. 2014, 16 (4), 1236-1239) (3.78 g, 10.0 mmol), Cu(OTf) (3.62 g, 10.0 mmol), 2,6-dimethylpyridine (1.07 g, 10.0 mmol), HFIP (40 mL), 4 Å molecular sieves (approximately 1 g), and DCM (160 mL) gave the title compound (1.73 g, 66%). LCMS (Method C): R T = 0.88 min, m / z = 270, 272 [M+H] + .

[0357] 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 BocO (1.4 g, 7.92 mmol) gave the title compound (2.25 g, 92%). LCMS (Method C): R T = 1.69 min, m / z = 270, 272 [M-Boc+H] + . 1H NMR (500 MHz, chloroform-d) δ 7.36 - 7.12 (m, 3H), 4.72 (dd, J = 9.1, 4.9 Hz, 1H), 3.92 (td, J = 7.2, 6.8, 4.1 Hz, 1H), 3.84 (dd, J = 12.3, 4.7 Hz, 1H), 3.76 (dd, J = 13.5, 3.8 Hz, 1H), 3.45 (dd, J = 12.3, 8.8 Hz, 1H), 3.23 (dd, J = 13.5, 6.5 Hz, 1H), 2.31 (s, 3H), 1.25 (d, J = 5.9 Hz, 3H), 1.19 (s, 9H). Chiral purity (Method D): R T = 4.742 min, >99%ee.

[0358] 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: tert-butyl General procedure 3 (Workup B) using (2R,5S)-5-(4-bromo-2-methylphenyl)-2-methylmorpholine-4-carboxylate (1.57 g, 4.24 mmol), B2Pin2 (1.62 g, 6.36 mmol), Pd(dppf)Cl CHCl (359 mg, 0.424 mmol), KOAc (1.25 g, 12.7 mmol), and 1,4-dioxane (42.4 mL) afforded the title compound (1.92 g, >100%) as a yellow oil after stirring at 100 °C (thermal) for 65 min. LCMS (Method A): R T = 2.03 min, m / z = 362 [M-butene + H] + .

[0359] 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: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (620 mg, 3.30 mmol), tert-butyl General procedure 4 (Workup B) using (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(II) 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) afforded the title compound (970 mg, 61%) as a white foam after 5 days at 50° C. LCMS (Method A): R T = 1.99 min, m / z = 477, 479 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.08 (s, 1H), 4.81 (dd, J = 8.9, 5.0 Hz, 1H), 4.03 - 3.97 (m, 1H), 3.95 (dd, J = 12.1, 5.0 Hz, 1H), 3.81 (dd, J = 13.4, 4.0 Hz, 1H), 3.52 (dd, J = 12.1, 9.0 Hz, 1H), 3.23 (dd, J = 13.5, 6.5 Hz, 1H), 2.40 (s, 3H), 1.22 - 1.16 (m, 12H).

[0360] 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-d]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) for 47 hours at 100° C. to afford the title compound (1.07 g, >100%) as a brown foam after acidification using 2 M aqueous hydrochloric acid. LCMS (Method A): R T = 1.36 min, m / z = 459, 461 [M+H] + .1H NMR (500 MHz, DMSO-d6) δ 12.16 (br. s, 1H), 7.84 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.25 - 7.19 (m, 2H), 6.69 (s, 1H), 4.80 (dd, J = 8.9, 5.1 Hz, 1H), 4.04 - 3.95 (m, 1H), 3.93 (dd, J = 12.1, 5.1 Hz, 1H), 3.79 (dd, J = 13.5, 4.0 Hz, 1H), 3.50 (dd, J = 12.1, 9.0 Hz, 1H), 3.23 (dd, J = 13.5, 6.3 Hz, 1H), 2.38 (s, 3H), 1.20 - 1.16 (m, 12H).

[0361] 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: tert-butyl General procedure 6 using (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 (150 mg, 0.327 mmol), epoxide 2 (123 mg, 0.490 mmol), CsCO (213 mg, 0.654 mmol) and DMF (3.3 mL) afforded the title compound (119 mg, 52%) as an orange glass after 18 h at 80° C. LCMS (Method B): R T = 1.54 min, m / z = 654, 656 [M-butene + H] + .

[0362] 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: tert-butyl General procedure 7 using (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 (119 mg, 0.168 mmol), TFA (2 mL) and DCM (4 mL) afforded the title compound (66 mg, 64%) as a white solid after purification by flash chromatography and freeze-drying. LCMS (Method B): R T = 0.85 min, m / z = 610, 612 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.56 - 7.48 (m, 2H), 7.49 - 7.38 (m, 2H), 7.23 (s, 2H), 6.78 (s, 1H), 4.96 (s, 1H), 4.17 (s, 1H), 4.00 (d, J = 21.0 Hz, 3H), 3.80 (dd, J = 10.9, 3.0 Hz, 1H), 3.46 - 3.33 (m, 1H), 3.30 - 3.08 (m, 3H), 3.02 - 2.92 (m, 1H), 2.83 - 2.71 (m, 1H), 2.58 (t, J = 10.7 Hz, 1H), 2.42 (s, 3H), 1.71 - 1.26 (m, 4H), 1.10 (d, J = 6.2 Hz, 3H).

[0363] Example 13: 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 [ka] 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: tert-butyl General procedure 6 using (2R,5S)-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 3 (33.8 mg, 0.108 mmol), CsCO (64.4 mg, 0.198 mmol) and DMF (1 mL) afforded the title compound (18.5 mg, 27%) as a colorless glass after 18 h at 80° C. LCMS (Method B): R T = 1.57 min, m / z = 702, 704 [M-butene + H] + .

[0364] 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: tert-butyl General procedure 7 using (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 (18.5 mg, 0.0244 mmol), TFA (0.35 mL) and DCM (0.7 mL) afforded the title compound (7.4 mg, 43%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.89 min, m / z = 658, 660 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 0.5H), 8.03 (s, 0.5H), 7.76 - 7.13 (m, 9H), 6.79 (s, 0.5H), 6.79 (s, 0.5H), 4.88 (s, 1H), 4.17 - 3.69 (m, 7H), 3.60 - 3.51 (m, 1H), 3.29 - 3.10 (m, 3H), 3.06 - 2.72 (m, 4H), 2.57 - 2.52 (m, 1H), 1.64 - 1.55 (m, 0.5H), 1.49 - 1.27 (m, 3H), 1.22 - 1.17 (m, 0.5H), 1.09 (d, J = 6.2 Hz, 3H).

[0365] Example 14: 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 [ka] 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 tert-butyl A suspension of (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 (40 mg, 0.0872 mmol), epoxide 3 (34 mg, 0.109 mmol), and DIPEA (76 μL, 0.436 mmol) in DMF (0.87 mL) was stirred at 100° C. for 20 h. After cooling to rt, the reaction mixture was diluted with saturated aqueous sodium bicarbonate (15 mL), and the resulting suspension was extracted with DCM (3×10 mL) using an ISOLUTE® Phase Separator. The combined organic phases were concentrated under reduced pressure, and the residue was purified by flash chromatography to give the title compound (38.6 mg, 57%) as a white solid. LCMS (Method A): R T = 1.61 min, m / z = 716, 718 [M-butene + H] + .

[0366] 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: tert-butyl General procedure 7 using (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 (38.6 mg, 0.0500 mmol), TFA (0.25 mL) and DCM (0.5 mL) afforded the title compound (31.3 mg, 91%) as an off-white solid after freeze-drying. LCMS (Method B): R T = 0.96 min, m / z = 672, 674 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 0.5H), 8.02 (s, 0.5H), 7.73 (d, J = 8.0 Hz, 1H), 7.51 - 7.28 (m, 5H), 7.28 - 7.11 (m, 2H), 6.78 (s, 1H), 4.88 (s, 1H), 4.17 - 4.04 (m, 1H), 4.05 - 3.85 (m, 4H), 3.84 - 3.71 (m, 2H), 3.58 (ddd, J = 8.9, 6.3, 2.3 Hz, 1H), 3.29 - 3.10 (m, 3H), 3.04 - 2.67 (m, 4H), 2.58 (t, J = 10.9 Hz, 1H), 2.41 (s, 3H), 1.63 - 1.56 (m, 0.5H), 1.45 - 1.27 (m, 3H), 1.23 - 1.17 (m, 0.5H), 1.10 (d, J = 6.2 Hz, 3H).

[0367] Example 15: 6-chloro-7-(4-(5,5-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one [ka] 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) (3.62 g, 10.0 mmol), 2,6-dimethylpyridine (1.07 g, 10.0 mmol), HFIP (40 mL), 4 Å molecular sieves (approximately 1 g), and DCM (160 mL) gave the title compound (360 mg, 13%). LCMS (Method C): R T = 0.78 min, m / z = 270, 272 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.44 (d, J = 8.9 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 4.19 (dd, J = 10.5, 3.6 Hz, 1H), 3.82 (dd, J = 10.9, 3.6 Hz, 1H), 3.52 (d, J = 10.8 Hz, 1H), 3.28 (d, J = 10.9 Hz, 2H), 3.16 (d, J = 10.6 Hz, 1H), 1.35 (s, 3H), 1.06 (s, 3H).

[0368] 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 BocO (580 mg, 2.66 mmol) gave the title compound (310 mg, 63%). LCMS (Method C): T = 1.60 min, m / z = 270, 272 [M-Boc+H] + . 1H NMR (500 MHz, chloroform-d) δ 7.44 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.4 Hz, 2H), 4.92 (t, J = 4.7 Hz, 1H), 4.12 - 4.03 (m, 2H), 3.48 (d, J = 11.6 Hz, 1H), 3.31 (d, J = 11.7 Hz, 1H), 1.47 (s, 3H), 1.37 (d, J = 3.2 Hz, 12H).

[0369] 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 (Workup B) using tert-butyl 5-(4-bromophenyl)-3,3-dimethylmorpholine-4-carboxylate (310 mg, 0.8372 mmol), B2Pin2 (319 mg, 1.26 mmol), Pd(dppf)Cl.CHCl (70.9 mg, 0.0837 mmol), KOAc (247 mg, 2.51 mmol), and 1,4-dioxane (8.4 mL) afforded the title compound (390 mg, >100%) as a slightly yellow oil after stirring at 100 °C (thermal) for 2 h 10 min. LCMS (Method A): R T = 2.09 min, m / z = 418 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.64 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H), 4.89 (t, J = 4.6 Hz, 1H), 4.02 (d, J = 4.6 Hz, 2H), 3.36 (d, J = 11.7 Hz, 1H), 3.30 (d, J = 11.8 Hz, 1H (signal overlap with HDO)), 1.13-1.49 (m, 27H).

[0370] Step 4: tert-Butyl 5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-3,3-dimethylmorpholine-4-carboxylate: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (130 mg, 0.692 mmol), tert-butyl General procedure 4 (final procedure B) using 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(II) 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) afforded the title compound (181 mg, 54%) as an off-white foam after 4 days at 50° C. LCMS (Method B): R T = 1.77 min, m / z = 477, 479 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.58 - 7.53 (m, 2H), 7.53 - 7.48 (m, 2H), 7.10 (s, 1H), 4.96 (t, J = 4.9 Hz, 1H), 4.11 (dd, J = 11.8, 4.8 Hz, 1H), 4.03 (dd, J = 11.7, 5.1 Hz, 1H), 3.46 (d, J = 11.7 Hz, 1H), 3.40 (d, J = 11.6 Hz, 1H), 1.44 (s, 3H), 1.42 (s, 3H), 1.30 (s, 9H).

[0371] 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-d]pyrimidin-7-yl)phenyl)-3,3-dimethylmorpholine-4-carboxylate (179 mg, 0.375 mmol), aqueous sodium hydroxide (4 M, 937 μL, 3.75 mmol) and 1,4-dioxane (1.9 mL) afforded the title compound (171.3 mg, 99.5%) as a yellow solid after acidification using 2 M aqueous hydrochloric acid at 100° C. for 18 hours 30 minutes. LCMS (Method A): R T = 1.43 min, m / z = 459, 461 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 12.16 (br. s, 1H), 7.84 (s, 1H), 7.52 - 7.47 (m, 2H), 7.42 - 7.37 (m, 2H), 6.68 (s, 1H), 4.94 (t, J = 4.8 Hz, 1H), 4.10 (dd, J = 11.7, 4.8 Hz, 1H), 4.04 (dd, J = 11.7, 5.0 Hz, 1H), 3.45 (d, J = 11.7 Hz, 1H), 3.38 (d, J = 11.6 Hz, 1H), 1.43 (s, 3H), 1.41 (s, 3H), 1.30 (s, 9H).

[0372] 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[2,3-d]pyrimidin-7-yl)phenyl)-3,3-dimethylmorpholine-4-carboxylate: tert-butyl General procedure 6 using 5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-3,3-dimethylmorpholine-4-carboxylate (10 mg, 0.0218 mmol), epoxide 1 (6.4 mg, 0.0327 mmol), CsCO (14.2 mg, 0.0436 mmol) and DMF (0.44 mL) afforded the title compound (8 mg, 56%) as a yellow glass after 19 h at 80° C. LCMS (Method A): R T = 1.55 min, m / z = 654, 656 [M+H] + .

[0373] Step 7: 6-Chloro-7-(4-(5,5-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one: A solution of 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)-3,3-dimethylmorpholine-4-carboxylate (8 mg, 0.0122 mmol) in TFA (0.2 mL) and DCM (0.4 mL) was stirred for 30 minutes, after which the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 1:1 DCM / triethylamine (1 mL) and the resulting solution was purified by flash chromatography (Biotage (登録商標)Purification on an Sfaer KP-Amino D 11 g cartridge (0-100% DCM in cyclohexane, then 0-10% MeOH in DCM) gave the title compound (6.6 mg, 94%) as a white solid after lyophilization. LCMS (Method B): T = 0.71 min, m / z = 554, 556 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.66 - 7.58 (m, 2H), 7.42 - 7.34 (m, 2H), 6.80 (s, 1H), 4.91 (s, 1H), 4.22 (dd, J = 10.5, 3.4 Hz, 1H), 4.00 (s, 2H), 3.95 (dt, J = 13.2, 4.1 Hz, 2H), 3.84 (dd, J = 10.5, 3.5 Hz, 1H), 3.46 (d, J = 10.6 Hz, 1H), 3.22 - 2.98 (m, 4H), 2.43 (s, 1H), 1.57 - 1.45 (m, 2H), 1.43 - 1.35 (m, 2H), 1.28 (s, 3H), 1.21 (s, 3H), 1.02 (s, 3H), 0.81 - 0.72 (m, 2H), 0.57 - 0.45 (m, 2H).

[0374] Example 16: 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 [ka] 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: tert-butyl General procedure 6 using 5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-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), CsCO (14.2 mg, 0.0436 mmol) and DMF (0.44 mL) afforded the title compound (8.1 mg, 52%) as a yellow glass after 19 h at 80° C. LCMS (Method A): R T = 1.74 min, m / z = 710, 712 [M+H] + .

[0375] 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 minutes, after which the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 1:1 DCM / triethylamine (1 mL) and the resulting solution was purified by flash chromatography (Biotage (登録商標) Purification on an Sfaer KP-Amino D 11 g cartridge (0-100% DCM in cyclohexane, then 0-10% MeOH in DCM) gave the title compound (7.1 mg, 94%) as a white solid after lyophilization. LCMS (Method B): T= 0.84 min, m / z = 610, 612 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.66 - 7.59 (m, 2H), 7.53 - 7.47 (m, 2H), 7.44 - 7.40 (m, 2H), 7.40 - 7.35 (m, 2H), 6.79 (s, 1H), 4.95 (s, 1H), 4.25 - 4.19 (m, 1H), 4.16 (br. s, 1H), 4.02 (s, 2H), 3.84 (dd, J = 10.6, 3.4 Hz, 1H), 3.46 (d, J = 10.6 Hz, 1H), 3.41 - 3.03 (m, 5H (signal overlap with HDO)), 2.42 (br. s, 1H), 1.60 (br. s, 2H), 1.46 (br. s, 1H), 1.33 (br. s, 1H), 1.27 (s, 3H), 1.02 (s, 3H).

[0376] Example 17: 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 [ka] Step 1: rac-tert-butyl (2R,5S)-5-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate: 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (41 mg, 0.267 mmol), rac-tert-butyl General procedure 4 (Workup A) using (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(II) 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) afforded the title compound (95 mg, 83%) as a colorless glass after 5 days at 50° C. LCMS (Method B): R T= 1.57 min, m / z = 429, 431 [M+H] + .

[0377] 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-chloro-7H-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. After cooling to rt, water was added and the resulting mixture was extracted with DCM (3×15 mL). The combined organic phases were concentrated under reduced pressure to give the title compound (90.3 mg, 99%) as a white solid. LCMS (Method B): T = 1.14 min, m / z = 411 [M+H] + .

[0378] 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: rac-tert-butyl General procedure 6 using (2R,5S)-2-methyl-5-(4-(4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)morpholine-4-carboxylate (90 mg, 0.219 mmol), epoxide 2 (66 mg, 0.263 mmol), CsCO (157 mg, 0.482 mmol) and DMF (1.5 mL) afforded the title compound (73.1 mg, 50%) as a white solid after 18 h at 80 °C and purification by preparative HPLC. LCMS (Method B): R T = 1.40 min, m / z = 606, 608 [M-butene + H] + .

[0379] 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: rac-tert-butyl General procedure 7 using (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 (73 mg, 0.110 mmol), TFA (0.25 mL) and DCM (0.25 mL) afforded the title compound (61 mg, 97%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.77 min, m / z = 562, 564 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.80 - 7.64 (m, 2H), 7.64 - 7.54 (m, 2H), 7.54 - 7.45 (m, 3H), 7.45 - 7.35 (m, 2H), 6.74 - 6.65 (m, 1H), 4.96 (s, 1H), 4.17 (br. s, 1H), 4.05 (br. s, 3H), 3.87 (br. s, 1H), 3.69 (br. s, 1H), 3.62 - 3.20 (m, 3H (signal overlap with HDO)), 3.13 (br. s, 3H), 2.69 (br. s, 1H), 1.61 (br. s, 2H), 1.48 (br. s, 1H), 1.34 (br. s, 1H), 1.13 (br. s, 3H).

[0380] Example 18: 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 [ka] 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 to 0 °C, after which sodium hydride (60% in mineral oil) (670 mg, 27.9 mmol) was added. The reaction mixture was warmed to rt and stirred for 1 h, after which 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 and then washed with water and brine. The organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound (3.9 g, 80%). LCMS (Method C): R T = 1.36, m / z = 376, 378 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.52 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 5.48 (d, J = 14.6 Hz, 1H), 4.41 (d, J = 16.4 Hz, 1H), 4.31 (dd, J = 16.8, 1.6 Hz, 1H), 4.28 - 4.23 (m, 1H), 3.91 (ddd, J = 12.0, 3.9, 1.6 Hz, 1H), 3.80 (s, 3H), 3.78 - 3.73 (m, 1H), 3.35 (d, J = 14.3 Hz, 1H).

[0381] 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. A solution of 5-(4-bromophenyl)-4-(4-methoxybenzyl)morpholin-3-one (3.90 g, 10.4 mmol) in THF (10 mL) was added dropwise, and the mixture was stirred at −60° C. for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride / water, and the volatiles were removed under reduced pressure. The residue was diluted with water and washed with EtOAc. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (0.9 g, 22%). LCMS (Method C): R T =1.58, m / z = 388, 390 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.33 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.04 (dd, J = 11.9, 3.5 Hz, 1H), 3.95 (dd, J = 11.9, 5.6 Hz, 1H), 3.81 - 3.76 (m, 4H), 3.74 - 3.70 (m, 1H), 3.66 (d, J = 11.2 Hz, 1H), 3.54 - 3.45 (m, 2H), 0.36 - 0.28 (m, 2H), 0.68 - 0.60 (m, 1H), 0.43 - 0.36 (m, 1H).

[0382] Step 3: 5-(4-Bromophenyl)-7-oxa-4-azaspiro[2.5]octane: A solution of 5-(4-bromophenyl)-4-(4-methoxybenzyl)-7-oxa-4-azaspiro[2.5]octane (0.9 g, 2.32 mmol) in TFA (10 mL) was heated at 70° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography to give the title compound (0.3 g, 47%). LCMS (Method C): R T = 0.72, m / z = 268, 270 [M+H] + . 1 H NMR (500 MHz, chloroform-d) δ 7.44 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 4.08 (dd, J = 10.3, 3.2 Hz, 1H), 3.97 - 3.90 (m, 2H), 3.35 (d, J = 11.3 Hz, 1H), 3.16 (d, J = 11.2 Hz, 1H), 0.79 - 0.69 (m, 1H), 0.67 - 0.53 (m, 3H).

[0383] 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 BocO (0.48 g, 2.2 mmol) in MeCN (2 mL) was stirred at 70 °C overnight. After 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%). LCMS (Method C): R T 1.50 min, m / z = 268, 270 [M-Boc+H] + . 1H NMR (500 MHz, chloroform-d) δ 7.59 - 7.35 (m, 4H), 5.29 - 5.20 (m, 1H), 4.37 (dd, J = 12.3, 2.2 Hz, 1H), 4.05 (dd, J = 11.0, 2.2 Hz, 1H), 3.91(dd, J = 12.2, 4.2 Hz, 1H), 3.00(d, J = 11.0 Hz, 1H), 1.50(s, 9H), 1.23(dt, J = 10.0, 7.1 Hz, 1H), 0.65(dt, J = 9.9, 6.8 Hz, 1H), 0.38(ddd, J = 10.0, 7.2, 5.2 Hz, 1H), -0.03(ddd, J = 10.9, 7.7, 5.4 Hz, 1H).

[0384] 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 (workup A) using tert-butyl 5-(4-bromophenyl)-7-oxa-4-azaspiro[2.5]octane-4-carboxylate (385 mg, 1.05 mmol), B2Pin2 (398 mg, 1.57 mmol), Pd(dppf)Cl2·CHCl2 (88.5 mg, 0.105 mmol), KOAc (308 mg, 3.14 mmol), and 1,4-dioxane (11 mL) afforded the title compound (374 mg, 85%) as a slightly yellow oil after stirring at 100 °C (microwave) for 1 h. LCMS (Method B): R T = 1.74 min, m / z = 316 [M-Boc+H] + .

[0385] 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: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (113 mg, 0.601 mmol), tert-butyl General procedure 4 (Workup A) using 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(II) trifluoroacetate hydrate (348 mg, 1.20 mmol), 1,10-phenanthroline (217 mg, 1.20 mmol), boric acid (149 mg, 2.40 mmol) and DMF (11.3 mL) afforded the title compound (62 mg, 21%) as a colorless glass after 1 day at 65° C. and 12 hours at 80° C. LCMS (Method B): R T = 1.74 min, m / z = 475, 477 [M+H] + .

[0386] 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 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 (62 mg, 0.130 mmol), aqueous sodium hydroxide (4 M, 0.98 mL, 3.91 mmol) and 1,4-dioxane (1 mL) to afford the title compound (60 mg, quantitative) as a yellow glass after acidification with 1 M aqueous potassium bisulfate at 100° C. for 18 hours. LCMS (Method B): R T = 1.29 min, m / z = 457, 459 [M+H] + .

[0387] 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: tert-butyl General procedure 6 using 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 (30 mg, 0.0657 mmol), epoxide 2 (24.8 mg, 0.0985 mmol), CsCO (64.2 mg, 0.197 mmol) and DMF (1.3 mL) afforded the title compound (24 mg, 51%) as a colorless glass after 18 h at 80° C. LCMS (Method B): R T = 1.54 min, m / z = 652, 654 [M-butene + H] + .

[0388] 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: tert-butyl General procedure 7 using 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 (24 mg, 0.0339 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (20 mg, 97%) as an off-white solid after freeze-drying. LCMS (Method B): R T = 0.83 min, m / z = 608, 610 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.64 - 7.56 (m, 2H), 7.54 - 7.46 (m, 2H), 7.46 - 7.40 (m, 2H), 7.40 - 7.35 (m, 2H), 6.79 (s, 1H), 4.95 (s, 1H), 4.28 - 4.10 (m, 1H), 4.09 - 4.03 (m, 1H), 4.02 (s, 2H), 3.91 (dd, J = 10.7, 3.2 Hz, 1H), 3.88 - 3.82 (m, 1H), 3.44 - 3.33 (m, 1H), 3.30 - 3.20 (m, 2H), 3.20 - 3.03 (m, 2H), 2.83 - 2.68 (m, 1H), 1.70 - 1.25 (m, 4H), 0.64 - 0.45 (m, 4H).

[0389] Example 19: 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 [ka] 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: tert-butyl General procedure 6 using 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 (30 mg, 0.0657 mmol), epoxide 1 (19.23 mg, 0.0985 mmol), CsCO (64.2 mg, 0.197 mmol) and DMF (1.3 mL) afforded the title compound (25 mg, 58%) as a colorless glass after 18 h at 80° C. LCMS (Method B): R T = 1.39 min, m / z = 596, 598 [M-butene + H] + .

[0390] 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: tert-butyl General procedure 7 using 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 (25 mg, 0.0383 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (21 mg, 99%) as an off-white solid after freeze-drying. LCMS (Method B): R T = 0.70 min, m / z = 552, 554 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.67 - 7.54 (m, 2H), 7.45 - 7.30 (m, 2H), 6.80 (s, 1H), 4.91 (s, 1H), 4.10 - 4.03 (m, 1H), 4.00 (s, 2H), 3.98 - 3.88 (m, 3H), 3.88 - 3.82 (m, 1H), 3.30 - 3.02 (m, 4H), 2.76 (d, J = 6.2 Hz, 1H), 1.62 - 1.32 (m, 4H), 1.21 (s, 3H), 0.81 - 0.72 (m, 2H), 0.61 - 0.44 (m, 6H).

[0391] Example 20: 3-((1-benzoyl-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 [ka] 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: tert-butyl General procedure 6 using (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 4 (29.3 mg, 0.135 mmol), CsCO (88 mg, 0.270 mmol) and DMF (2 mL) afforded the title compound (40 mg, 67%) as a colorless glass after 18 h at 80 °C. LCMS (Method A): R T = 1.51 min, m / z = 606, 608 [M-butene + H] + .

[0392] Step 2: 3-((1-Benzoyl-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-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 (40 mg, 0.0604 mmol), TFA (1 mL) and DCM (2 mL) to afford the title compound (32 mg, 94%) as an off-white solid after freeze-drying. LCMS (Method B): R T = 0.75 min, m / z = 562, 564 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.65 - 7.56 (m, 2H), 7.49 - 7.42 (m, 3H), 7.42 - 7.33 (m, 4H), 6.80 (s, 1H), 4.95 (s, 1H), 4.32 - 4.11 (m, 1H), 4.03 (s, 2H), 3.91 - 3.75 (m, 2H), 3.63 - 3.49 (m, 1H), 3.47 - 3.34 (m, 1H), 3.30 - 3.21 (m, 2H), 3.21 - 3.07 (m, 1H), 3.04 - 2.81 (m, 2H), 2.60 - 2.53 (m, 1H), 1.74 - 1.22 (m, 4H), 1.10 (d, J = 6.2 Hz, 3H).

[0393] Example 21: 6-chloro-3-((1-(4-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 [ka] 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: tert-butyl General procedure 6 using (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 5 (31.7 mg, 0.135 mmol), CsCO (88 mg, 0.270 mmol) and DMF (2 mL) afforded the title compound (36 mg, 58%) as a colorless glass after 18 h at 80° C. LCMS (Method B): R T = 1.42 min, m / z = 624, 626 [M-butene + H] + .

[0394] Step 2: 6-chloro-3-((1-(4-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: tert-butyl General procedure 7 using (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 (36 mg, 0.0529 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (29 mg, 94%) as an off-white solid after freeze-drying. LCMS (Method B): R T = 0.77 min, m / z = 580, 582 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.63 - 7.58 (m, 2H), 7.51 - 7.43 (m, 2H), 7.43 - 7.36 (m, 2H), 7.32 - 7.23 (m, 2H), 6.80 (s, 1H), 4.96 (s, 1H), 4.32 - 4.07 (m, 1H), 4.03 (s, 2H), 3.88 - 3.78 (m, 2H), 3.61 - 3.50 (m, 1H), 3.49 - 3.35 (m, 1H), 3.30 - 3.22 (m, 2H), 3.22 - 3.03 (m, 1H), 2.99 - 2.93 (m, 1H), 2.93 - 2.84 (m, 1H), 2.60 - 2.53 (m, 1H), 1.76 - 1.25 (m, 4H), 1.10 (d, J = 6.2 Hz, 3H).

[0395] Example 22: 6-chloro-3-((1-(2,4-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 [ka] 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: tert-butyl General procedure 6 using (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 6 (34.2 mg, 0.135 mmol), CsCO (88 mg, 0.270 mmol) and DMF (2 mL) afforded the title compound (38 mg, 60%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T = 1.44 min, m / z = 642, 644 [M-butene + H] + .

[0396] Step 2: 6-chloro-3-((1-(2,4-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: tert-butyl General procedure 7 using (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 (38 mg, 0.0544 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (31 mg, 95%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.79 min, m / z = 598, 600 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.64 - 7.58 (m, 2H), 7.55 - 7.44 (m, 1H), 7.43 - 7.31 (m, 3H), 7.18 (td, J = 8.4, 2.4 Hz, 1H), 6.80 (s, 1H), 4.99 (s, 1H), 4.28 - 4.16 (m, 1H), 4.13 - 3.91 (m, 2H), 3.91 - 3.76 (m, 2H), 3.61 - 3.50 (m, 1H), 3.30 - 3.20 (m, 3H), 3.19 - 3.11 (m, 1H), 3.04 - 2.81 (m, 2H), 2.59 - 2.53 (m, 1H), 1.68 - 1.44 (m, 3H), 1.42 - 1.28 (m, 1H), 1.10 (d, J = 6.2 Hz, 3H).

[0397] Example 23: (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 [ka] 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-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (776 mg) was resolved into single stereoisomers by chiral SFC using a Lux A1 (21.2 mm x 250 mm, 5 μm) column with isocratic solvent conditions: 25:75 MeOH:CO. The first eluting material was arbitrarily assigned as tert-butyl (S)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (288 mg, 37% recovery). Chiral purity (Method E): R T= 1.45 min, 100% ee. The first material to elute as an off-white solid was assigned as tert-butyl (R)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2,2-dimethylmorpholine-4-carboxylate (320.9 mg, 41% recovery). Chiral purity (Method E): R T = 2.25 min, 100% ee.

[0398] 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-d]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) afforded the title compound (286 mg, >100%) as a yellow glass after 18 h at 100° C. and acidification using 1 M aqueous potassium bisulfate. LCMS (Method B): R T = 1.40 min, m / z = 459, 461 [M+H] + .

[0399] 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: tert-butyl General procedure 6 using (S)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-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), CsCO (170 mg, 0.523 mmol) and DMF (3 mL) afforded the title compound (85 mg, 68%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T = 1.77 min, m / z = 654, 656 [M-butene + H] + .

[0400] 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 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 (85 mg, 0.120 mmol), TFA (2 mL) and DCM (4 mL) to afford the title compound (69 mg, 94%) as an off-white solid after freeze-drying. LCMS (Method B): R T = 0.86 min, m / z = 610, 612 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.69 - 7.60 (m, 2H), 7.54 - 7.47 (m, 2H), 7.47 - 7.34 (m, 4H), 6.80 (s, 1H), 4.96 (s, 1H), 4.32 - 4.09 (m, 1H), 4.03 (s, 2H), 3.81 (dd, J = 10.3, 3.5 Hz, 1H), 3.58 (dd, J = 11.1, 3.6 Hz, 1H), 3.47 (t, J = 10.7 Hz, 1H), 3.43 - 3.33 (m, 1H), 3.30 - 2.98 (m, 2H), 2.90 - 2.72 (m, 2H), 2.68 (d, J = 11.5 Hz, 1H), 1.75 - 1.23 (m, 7H), 1.14 (s, 3H).

[0401] Example 24: 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 [ka] 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: tert-butyl General procedure 6 using (2R,5S)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (70 mg, 0.157 mmol), epoxide 4 (41 mg, 0.189 mmol), CsCO (113 mg, 0.346 mmol) and DMF (1.5 mL) afforded the title compound (64 mg, 61%) as a white solid after 18 h at 80 °C and purification by preparative HPLC. LCMS (Method B): R T = 1.39 min, m / z = 606, 608 [M-butene + H] + .

[0402] 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: General procedure 7 using 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 (64 mg, 0.0967 mmol), TFA (1 mL) and DCM (2 mL) to afford the title compound (29.1 mg, 53%) as a white solid after purification by flash chromatography and freeze-drying. LCMS (Method B): R T = 0.74 min, m / z = 562, 564 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.62 - 7.57 (m, 2H), 7.46 - 7.41 (m, 3H), 7.38 (td, J = 7.6, 7.0, 2.8 Hz, 4H), 6.79 (s, 1H), 4.95 (s, 1H), 4.17 (s, 1H), 4.02 (s, 2H), 3.82 (ddd, J = 19.5, 10.3, 3.2 Hz, 2H), 3.58 - 3.51 (m, 1H), 3.39 (s, 1H), 3.29 - 3.05 (m, 3H), 2.99 - 2.82 (m, 2H), 2.57 - 2.52 (m, 1H), 1.69 - 1.25 (m, 4H), 1.09 (d, J = 6.2 Hz, 3H).

[0403] Example 25: 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 [ka] 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: tert-butyl General procedure 6 using (2R,5S)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-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), CsCO (113 mg, 0.346 mmol) and DMF (1.5 mL) afforded the title compound (91.4 mg, 85%) as a white solid after 18 h at 80 °C and purification by preparative HPLC. LCMS (Method B): R T = 1.42 min, m / z = 624, 626 [M-butene + H] + .

[0404] 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: tert-butyl General procedure 7 using (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 (95.4 mg, 0.140 mmol), TFA (1.5 mL) and DCM (3 mL) afforded the title compound (42.8 mg, 52%) as a white solid after purification by flash chromatography and freeze-drying. LCMS (Method B): R T = 0.73 min, m / z = 580, 582 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.62 - 7.57 (m, 2H), 7.48 - 7.43 (m, 2H), 7.41 - 7.36 (m, 2H), 7.29 - 7.23 (m, 2H), 6.79 (s, 1H), 4.95 (s, 1H), 4.16 (s, 1H), 4.02 (s, 2H), 3.82 (ddd, J = 19.6, 10.3, 3.3 Hz, 2H), 3.55 (dqd, J = 12.4, 6.1, 2.1 Hz, 1H), 3.39 (s, 1H), 3.28 - 3.04 (m, 3H), 2.99 - 2.82 (m, 2H), 2.57 - 2.52 (m, 1H), 1.53 (d, J = 72.6 Hz, 4H), 1.09 (d, J = 6.2 Hz, 3H).

[0405] Example 26: 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 [ka] 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-d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4-carboxylate (664.7 mg) was purified by elution on a Chiralpak IH (20 mm x 250 mm, 5 μm) column under isocratic conditions: 15:85 Resolution into single stereoisomers was achieved by chiral SFC using MeOH:CO. The first eluting material was arbitrarily assigned as tert-butyl (3R,5S)-3-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4-carboxylate (309 mg, 46% recovery). Chiral purity (Method F): RT = 1.45 min, 100% ee. The first eluting material was arbitrarily assigned as tert-butyl (3S,5R)-3-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4-carboxylate (318.8 mg, 47% recovery). Chiral purity (Method F): R T = 1.70 min, 99.4% ee.

[0406] 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-d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4-carboxylate (309 mg, 0.667 mmol), aqueous sodium hydroxide (4 M, 5 mL, 20.0 mmol), and 1,4-dioxane (5 mL) afforded the title compound (337 mg, >100%) as a yellow glass after 18 h at 100° C. and acidification using 1 M aqueous potassium bisulfate. LCMS (Method B): R T = 1.32 min, m / z = 445, 447 [M+H] + .

[0407] 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: tert-butyl General procedure 6 using (3R,5S)-3-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4-carboxylate (80 mg, 0.180 mmol), epoxide 2 (68 mg, 0.270 mmol), CsCO (176 mg, 0.539 mmol) and DMF (3 mL) afforded the title compound (69 mg, 55%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T = 1.50 min, m / z = 640, 642 [M-butene + H] + .

[0408] 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: tert-butyl General procedure 7 using (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 (69 mg, 0.0990 mmol), TFA (2 mL) and DCM (4 mL) afforded the title compound (54 mg, 91%) as an off-white solid after freeze-drying. LCMS (Method A): R T = 0.76 min, m / z = 596, 598 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.64 - 7.60 (m, 2H), 7.54 - 7.48 (m, 2H), 7.46 - 7.37 (m, 4H), 6.80 (s, 1H), 4.96 (s, 1H), 4.29 - 4.09 (m, 1H), 4.03 (s, 2H), 4.00 - 3.88 (m, 1H), 3.85 - 3.64 (m, 2H), 3.49 - 3.34 (m, 1H), 3.31 - 3.20 (m, 1H), 3.21 - 3.07 (m, 2H), 3.08 - 2.78 (m, 3H), 1.76 - 1.27 (m, 4H), 0.97 (d, J = 6.0 Hz, 3H).

[0409] Example 27: 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3S,5R)-5-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one [ka] 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 tert-butyl (3S,5R)-3-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4-carboxylate (319 mg, 0.688 mmol), aqueous sodium hydroxide (4 M, 5.16 mL, 20.7 mmol), and 1,4-dioxane (5.2 mL) afforded the title compound (360 mg, >100%) as a yellow glass after 18 h at 100° C. and acidification using 1 M aqueous potassium bisulfate. LCMS (Method B): R T = 1.32 min, m / z = 445, 447 [M+H] + .

[0410] 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: tert-butyl General procedure 6 using (3S,5R)-3-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-5-methylmorpholine-4-carboxylate (80 mg, 0.180 mmol), epoxide 2 (68 mg, 0.270 mmol), CsCO (176 mg, 0.539 mmol) and DMF (3 mL) afforded the title compound (78 mg, 62%) as a colorless glass after 18 h at 80 °C. LCMS (Method A): R T = 1.64 min, m / z = 696, 698 [M+H] + .

[0411] Step 3: 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3S,5R)-5-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one: tert-butyl General procedure 7 using (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 (69 mg, 0.0990 mmol), TFA (2 mL) and DCM (4 mL) afforded the title compound (59 mg, 99%) as a white solid after freeze-drying. LCMS (Method B): R T = 1.08 min, m / z = 596, 598 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.64 - 7.60 (m, 2H), 7.53 - 7.47 (m, 2H), 7.44 - 7.36 (m, 4H), 6.79 (s, 1H), 4.95 (s, 1H), 4.25 - 4.08 (m, 1H), 4.02 (s, 2H), 3.96 (dd, J = 10.2, 3.1 Hz, 1H), 3.78 (dd, J = 10.5, 3.2 Hz, 1H), 3.71 (dd, J = 10.3, 2.6 Hz, 1H), 3.44 - 3.32 (m, 1H), 3.30 - 3.19 (m, 1H), 3.19 - 3.06 (m, 2H), 3.05 - 2.83 (m, 3H), 1.73 - 1.26 (m, 4H), 0.95 (d, J = 6.0 Hz, 3H).

[0412] Example 28: (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 [ka] 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: tert-butyl General procedure 6 using (S)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-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), CsCO (85.2 mg, 0.262 mmol) and DMF (3 mL) afforded the title compound (45 mg, 74%) as a colorless glass after 18 h at 80° C. LCMS (Method A): R T = 1.61 min, m / z = 638, 640 [M-butene + H] + .

[0413] 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 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 (45 mg, 0.0648 mmol), TFA (1 mL) and DCM (2 mL) to afford the title compound (38 mg, 98%) as a white solid after freeze-drying. LCMS (Method A): R T = 0.74 min, m / z = 594, 596 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.67 - 7.59 (m, 2H), 7.49 - 7.43 (m, 2H), 7.43 - 7.37 (m, 2H), 7.30 - 7.23 (m, 2H), 6.79 (s, 1H), 4.95 (s, 1H), 4.33 - 4.07 (m, 1H), 4.02 (s, 2H), 3.80 (dd, J = 10.3, 3.6 Hz, 1H), 3.57 (dd, J = 11.1, 3.6 Hz, 1H), 3.46 (t, J = 10.7Hz, 1H), 3.43 - 3.33 (m, 1H), 3.30 - 2.97 (m, 2H), 2.93 - 2.72 (m, 2H), 2.68 (d, J = 11.6 Hz, 1H), 1.74 - 1.25 (m, 7H), 1.13 (s, 3H).

[0414] Example 29: (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 [ka] 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-d]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) afforded the title compound (321 mg, >100%) as a yellow glass after 18 h at 100° C. and acidification using 1 M aqueous potassium bisulfate. LCMS (Method B): R T = 1.40 min, m / z = 459, 461 [M+H] + .

[0415] 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: tert-butyl General procedure 6 using (R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-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), CsCO (85.2 mg, 0.262 mmol) and DMF (3 mL) afforded the title compound (29 mg, 47%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T = 1.64 min, m / z = 638, 640 [M-butene + H] + .

[0416] 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 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 (29 mg, 0.0418 mmol), TFA (1 mL) and DCM (2 mL) to afford the title compound (24 mg, 96%) as a white solid after freeze-drying. LCMS (Method A): R T = 0.75 min, m / z = 594, 596 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.67 - 7.59 (m, 2H), 7.51 - 7.42 (m, 2H), 7.42 - 7.37 (m, 2H), 7.31 - 7.21 (m, 2H), 6.79 (s, 1H), 4.95 (s, 1H), 4.30 - 4.08 (m, 1H), 4.02 (s, 2H), 3.80 (dd, J = 10.3, 3.6 Hz, 1H), 3.57 (dd, J = 11.1, 3.6 Hz, 1H), 3.51 - 3.43 (m, 1H), 3.43 - 3.33 (m, 1H), 3.29 - 3.01 (m, 2H), 2.96 - 2.72 (m, 2H), 2.68 (d, J = 11.6 Hz, 1H), 1.72 - 1.26 (m, 7H), 1.13 (s, 3H).

[0417] Example 30: 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 [ka] 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: tert-butyl General procedure 6 using (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 7 (36.4 mg, 0.135 mmol), CsCO (88 mg, 0.270 mmol) and DMF (2 mL) afforded the title compound (32 mg, 49%) as a colorless glass after 18 h at 80 °C. LCMS (Method A): R T = 1.69 min, m / z = 658, 660 [M-butene + H] + .

[0418] 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: tert-butyl General procedure 7 using (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 (32 mg, 0.0448 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (23 mg, 83%) as a white solid after freeze-drying. LCMS (Method A): R T = 0.79 min, m / z = 614, 616 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.63 - 7.58 (m, 2H), 7.57 - 7.53 (m, 1H), 7.50 - 7.42 (m, 1H), 7.41 - 7.34 (m, 3H), 6.79 (s, 1H), 4.98 (s, 1H), 4.26 - 4.15 (m, 1H), 4.11 - 3.95 (m, 2H), 3.89 - 3.75 (m, 2H), 3.61 - 3.49 (m, 1H), 3.30 - 3.19 (m, 4H), 3.19 - 3.10 (m, 1H), 3.00 - 2.91 (m, 1H), 2.58 - 2.52 (m, 1H), 1.69 - 1.42 (m, 3H), 1.37 - 1.29 (m, 1H), 1.09 (d, J = 6.2 Hz, 3H).

[0419] Example 31: 6-chloro-3-((1-(2-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 [ka] 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: tert-butyl General procedure 6 using (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), CsCO (88 mg, 0.270 mmol) and DMF (2 mL) afforded the title compound (45 mg, 71%) as a colorless glass after 18 h at 80° C. LCMS (Method A): R T = 1.62 min, m / z = 640, 642 [M-butene + H] + .

[0420] Step 2: 6-chloro-3-((1-(2-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: tert-butyl General procedure 7 using (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 (45 mg, 0.0646 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (33 mg, 85%) as a white solid after freeze-drying. LCMS (Method A): R T = 0.71 min, m / z = 596, 598 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (d, J = 1.8 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.56 - 7.48 (m, 1H), 7.47 - 7.27 (m, 5H), 6.78 (d, J = 2.2 Hz, 1H), 4.97 (d, J = 2.3 Hz, 1H), 4.28 - 4.17 (m, 1H), 4.10 - 3.92 (m, 2H), 3.87 - 3.75 (m, 2H), 3.60 - 3.48 (m, 1H), 3.29 - 3.03 (m, 4H), 3.01 - 2.81 (m, 2H), 2.59 - 2.52 (m, 1H), 1.72 - 1.43 (m, 3H), 1.37 - 1.27 (m, 1H), 1.09 (d, J = 6.2 Hz, 3H).

[0421] Example 32: 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 [ka] 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-carboxylate: tert-butyl General procedure 6 using (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (100 mg, 0.225 mmol), epoxide 9 (71 mg, 0.270 mmol), CsCO (161 mg, 0.495 mmol) and DMF (2 mL) for 18 h at 80° C. and purified by preparative HPLC to give the title compound (72.9 mg, 45%) as a white solid. LCMS (Method B): R T = 1.48 min, m / z = 652, 654 [M-butene + H] + .

[0422] 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: 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 General procedure 7 using (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 (72.9 mg, 0.103 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (45.6 mg, 72%) as a white solid after purification by flash chromatography and freeze-drying. LCMS (Method A): R T = 0.69 min, m / z = 608, 610 [M+H] + . 11H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.63 - 7.56 (m, 2H), 7.42 - 7.36 (m, 2H), 6.81 (s, 1H), 4.93 (s, 1H), 4.08 - 3.77 (m, 6H), 3.60 - 3.50 (m, 1H), 3.48 - 3.33 (m, 1H), 3.25 (t, J = 10.3 Hz, 1H), 3.12 - 2.76 (m, 3H), 2.57 - 2.52 (m, 1H), 2.19 - 2.03 (m, 1H), 1.74 - 1.35 (m, 5H), 1.34 (s, 3H), 1.15 - 1.11 (m, 1H), 1.09 (d, J = 6.3 Hz, 3H).

[0423] Example 33: 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

Chem.

[0424] 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: 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 General procedure 7 using (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 (111 mg, 0.157 mmol), TFA (1.5 mL) and DCM (3 mL) afforded the title compound (73 mg, 75%) as a very pale yellow solid after purification by flash chromatography and freeze-drying. LCMS (Method A): R T = 0.71 min, m / z = 608, 610 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.63 - 7.58 (m, 2H), 7.41 - 7.36 (m, 2H), 6.81 (s, 1H), 4.93 (s, 1H), 4.06 - 3.78 (m, 6H), 3.59 - 3.51 (m, 1H), 3.47 - 3.33 (m, 1H), 3.25 (t, J = 10.3 Hz, 1H), 3.08 - 2.79 (m, 3H), 2.57 - 2.52 (m, 1H), 2.18 - 2.05 (m, 1H), 1.73 - 1.36 (m, 5H), 1.34 (s, 3H), 1.14 - 1.10 (m, 1H), 1.09 (d, J = 6.3 Hz, 3H).

[0425] Example 34: (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 [ka] 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: tert-butyl General procedure 6 using (R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-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), CsCO (125 mg, 0.384 mmol) and DMF (1.5 mL) for 18 h at 80° C. and purified by preparative HPLC to give the title compound (87 mg, 70%) as a white solid. LCMS (Method B): R T = 1.55 min, m / z = 654, 656 [M-butene + H] + .

[0426] 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: tert-butyl General procedure 7 using (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 (87 mg, 0.122 mmol), TFA (1.5 mL) and DCM (3 mL) afforded the title compound (45.8 mg, 61%) as an off-white solid after purification by flash chromatography and freeze-drying. LCMS (Method B): R T = 0.78 min, m / z = 610, 612 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.66 - 7.61 (m, 2H), 7.53 - 7.47 (m, 2H), 7.45 - 7.37 (m, 4H), 6.79 (s, 1H), 4.95 (s, 1H), 4.25 - 4.09 (m, 1H), 4.02 (s, 2H), 3.80 (dd, J = 10.3, 3.6 Hz, 1H), 3.57 (dd, J = 11.1, 3.6 Hz, 1H), 3.46 (t, J = 10.7 Hz, 1H), 3.40 - 3.33 (m, 1H), 3.30 - 3.20 (m, 1H), 3.19 - 3.07 (m, 1H), 2.80 (s, 1H), 2.77 (d, J = 11.6 Hz, 1H), 2.68 (d, J = 11.6 Hz, 1H), 1.68 - 1.55 (m, 2H), 1.52 - 1.41 (m, 1H), 1.40 - 1.27 (m, 1H), 1.35 (s, 3H), 1.13 (s, 3H).

[0427] Example 35: 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 [ka] 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: tert-butyl General procedure 6 using (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (50 mg, 0.112 mmol), epoxide 11 (34 mg, 0.135 mmol), CsCO (80.6 mg, 0.247 mmol) and DMF (1 mL) afforded the title compound (55 mg, 70%) as a colorless gum after 18 h at 80° C. LCMS (Method A): R T = 1.61 min, m / z = 640, 642 [M-butene + H] + .

[0428] 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: tert-butyl General procedure 7 using (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 (55 mg, 0.0790 mmol), TFA (0.74 mL) and DCM (1.5 mL) afforded the title compound (35 mg, 73%) as a white solid after purification by flash chromatography and freeze-drying. LCMS (Method B): R T = 0.73 min, m / z = 596, 598 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.63 - 7.57 (m, 2H), 7.53 - 7.44 (m, 3H), 7.41 - 7.37 (m, 2H), 7.37 - 7.32 (m, 1H), 6.79 (s, 1H), 4.95 (s, 1H), 4.23 - 4.12 (m, 1H), 4.07 - 3.96 (m, 2H), 3.87 - 3.77 (m, 2H), 3.60 - 3.51 (m, 1H), 3.39 - 3.20 (m, 3H) (Signal overlap with HDO)), 3.17 - 3.07 (m, 1H), 3.00 - 2.92 (m, 1H), 2.89 (s, 1H), 2.58 - 2.53 (m, 1H), 1.69 - 1.56 (m, 2H), 1.51 - 1.41 (m, 1H), 1.37 - 1.29 (m, 1H), 1.09 (d, J = 6.2 Hz, 3H).

[0429] Example 36: 6-chloro-3-((1-(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 [ka] 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: tert-butyl General procedure 6 using (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-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), CsCO (80.6 mg, 0.247 mmol) and DMF (1 mL) afforded the title compound (42 mg, 54%) as a colorless gum after 18 h at 80° C. LCMS (Method A): R T = 1.52 min, m / z = 624, 626 [M-butene + H] + .

[0430] Step 2: 6-chloro-3-((1-(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: tert-butyl General procedure 7 using (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 (42 mg, 0.0617 mmol), TFA (0.75 mL) and DCM (1.5 mL) afforded the title compound (30.1 mg, 83%) as a white solid after purification by flash chromatography and freeze-drying. LCMS (Method A): R T = 0.66 min, m / z = 580, 582 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.63 - 7.57 (m, 2H), 7.52 - 7.46 (m, 1H), 7.44 - 7.35 (m, 3H), 7.32 - 7.25 (m, 2H), 6.79 (s, 1H), 4.98 (s, 1H), 4.22 (dt, J = 12.6, 4.0 Hz, 1H), 4.10 - 3.94 (m, 2H), 3.87 - 3.77 (m, 2H), 3.55 (dqd, J = 12.5, 6.1, 2.2 Hz, 1H), 3.29 - 3.19 (m, 3H), 3.19 - 3.11 (m, 1H), 2.99 - 2.92 (m, 1H), 2.89 (s, 1H), 2.57 - 2.52 (m, 1H), 1.67 - 1.45 (m, 3H), 1.38 - 1.29 (m, 1H), 1.09 (d, J = 6.2 Hz, 3H).

[0431] Example 37: 6-chloro-3-((1-(3,4-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 [ka] 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: tert-butyl General procedure 6 using (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (50 mg, 0.112 mmol), epoxide 13 (34 mg, 0.135 mmol), CsCO (80.6 mg, 0.247 mmol) and DMF (1 mL) afforded the title compound (50 mg, 63%) as a colorless gum after 18 h at 80° C. LCMS (Method A): R T = 1.57 min, m / z = 642, 644 [M-butene + H] + .

[0432] Step 2: 6-chloro-3-((1-(3,4-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: tert-butyl General procedure 7 using (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 (50 mg, 0.0716 mmol), TFA (0.75 mL) and DCM (1.5 mL) afforded the title compound (35 mg, 80%) as a white solid after purification by flash chromatography and freeze-drying. LCMS (Method B): R T = 0.72 min, m / z = 598, 600 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.63 - 7.57 (m, 2H), 7.57 - 7.46 (m, 2H), 7.42 - 7.35 (m, 2H), 7.30 - 7.23 (m, 1H), 6.79 (s, 1H), 4.95 (s, 1H), 4.15 (br. s, 1H), 4.09 - 3.90 (m, 2H), 3.89 - 3.77 (m, 2H), 3.55 (dqd, J = 12.5, 6.1, 2.2 Hz, 1H), 3.36 (br. s, 1H), 3.25 (t, J = 10.3 Hz, 2H), 3.12 (br. s, 1H), 3.00 - 2.92 (m, 1H), 2.89 (br. s, 1H), 2.58 - 2.52 (m, 1H), 1.70 - 1.56 (m, 2H), 1.51 - 1.27 (m, 2H), 1.09 (d, J = 6.2 Hz, 3H).

[0433] Example 38: 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 [ka] 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: tert-butyl General procedure 6 using (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 14 (25.4 mg, 0.108 mmol), CsCO (64.4 mg, 0.198 mmol) and DMF (1 mL) afforded the title compound (29.5 mg, 48%) as a colorless gum after 18 h at 80° C. LCMS (Method A): R T = 1.53 min, m / z = 624, 626 [M-butene + H]+ .

[0434] 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: tert-butyl General procedure 7 using (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 (29 mg, 0.0426 mmol), TFA (0.75 mL) and DCM (1.5 mL) afforded the title compound (18 mg, 72%) as a white solid after freeze-drying. LCMS (Method A): R T = 0.69 min, m / z = 580, 582 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.64 - 7.56 (m, 2H), 7.49 (td, J = 7.9, 5.8 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.31 - 7.19 (m, 3H), 6.79 (s, 1H), 4.95 (s, 1H), 4.17 (s, 1H), 4.10 - 3.95 (m, 2H), 3.82 (ddd, J = 19.6, 10.3, 3.2 Hz, 2H), 3.55 (dqd, J = 12.4, 6.1, 2.2 Hz, 1H), 3.25 (t, J = 10.3 Hz, 3H (signal overlap with HDO)), 3.12 (t, J = 14.9 Hz, 1H), 2.99 - 2.79 (m, 2H), 2.54 (d, J = 11.1 Hz, 1H), 1.61 (s, 2H), 1.47 (s, 1H), 1.33 (s, 1H), 1.09 (d, J = 6.2 Hz, 3H).

[0435] Example 39: 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 [ka] 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: tert-butyl General procedure 6 using (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-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), CsCO (80.6 mg, 0.247 mmol) and DMF (1 mL) afforded the title compound (30 mg, 38%) as a white solid after 18 h at 80 °C. LCMS (Method B): R T = 1.56 min, m / z = 642, 644 [M-butene + H] + .

[0436] 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: tert-butyl General procedure 7 using (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 (30 mg, 0.0430 mmol), TFA (0.75 mL) and DCM (1.5 mL) afforded the title compound (22.3 mg, 86%) as a white solid after purification by flash chromatography and freeze-drying. LCMS (Method B): R T = 0.79 min, m / z = 598, 600 [M+H] + .1 H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.56 - 7.46 (m, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.34 - 7.26 (m, 1H), 7.26 - 7.15 (m, 1H), 6.79 (s, 1H), 4.99 (s, 1H), 4.22 (dt, J = 13.3, 4.2 Hz, 1H), 4.10 - 3.94 (m, 2H), 3.89 - 3.75 (m, 2H), 3.55 (dqd, J = 12.5, 6.1, 2.2 Hz, 1H), 3.28 - 3.21 (m, 3H), 3.21 - 3.12 (m, 1H), 2.98 - 2.92 (m, 1H), 2.89 (s, 1H), 2.58 - 2.53 (m, 1H), 1.67 - 1.45 (m, 3H), 1.40 - 1.30 (m, 1H), 1.09 (d, J = 6.2 Hz, 3H).

[0437] Example 40: (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]pyrimidin-4-one [ka] 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: tert-butyl General procedure 6 using (S)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-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), CsCO (95.8 mg, 0.294 mmol) and DMF (2 mL) afforded the title compound (55 mg, 82%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T= 1.47 min, m / z = 624, 626 [M-butene + H] + .

[0438] 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]pyrimidin-4-one: tert-butyl General procedure 7 using (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 (55 mg, 0.0809 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (40 mg, 85%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.78 min, m / z = 580, 582 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.67 - 7.60 (m, 2H), 7.44 - 7.35 (m, 2H), 6.81 (s, 1H), 4.92 (s, 1H), 4.19 - 3.89 (m, 4H), 3.81 (dd, J = 10.4, 3.5 Hz, 1H), 3.57 (dd, J = 11.1, 3.6 Hz, 1H), 3.46 (t, J = 10.7 Hz, 1H), 3.38 - 2.89 (m, 2H), 2.88 - 2.65 (m, 3H), 1.69 - 1.38 (m, 4H), 1.36 (s, 3H), 1.17 - 1.09 (m, 4H), 0.73 - 0.64 (m, 2H), 0.52 - 0.42 (m, 2H), 0.42 - 0.33 (m, 2H), 0.14 - 0.05 (m, 2H).

[0439] Example 41: (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]pyrimidin-4-one [ka] 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: tert-butyl General procedure 6 using (R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-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), CsCO (95.8 mg, 0.294 mmol) and DMF (2 mL) afforded the title compound (46 mg, 69%) as a colorless solid after 18 h at 80 °C. LCMS (Method B): R T = 1.47 min, m / z = 624, 626 [M-butene + H] + .

[0440] 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]pyrimidin-4-one: tert-butyl General procedure 7 using (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 (46 mg, 0.0676 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (37 mg, 94%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.77 min, m / z = 580, 582 [M+H] + .1 H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.68 - 7.60 (m, 2H), 7.44 - 7.37 (m, 2H), 6.81 (s, 1H), 4.92 (s, 1H), 4.08 - 3.93 (m, 4H), 3.81 (dd, J = 10.3, 3.5 Hz, 1H), 3.57 (dd, J = 11.1, 3.6 Hz, 1H), 3.46 (t, J = 10.7 Hz, 1H), 3.37 - 2.91 (m, 2H), 2.89 - 2.65 (m, 3H), 1.66 - 1.38 (m, 4H), 1.36 (s, 3H), 1.20 - 1.03 (m, 4H), 0.72 - 0.62 (m, 2H), 0.50 - 0.43 (m, 2H), 0.42 - 0.32 (m, 2H), 0.15 - 0.04 (m, 2H).

[0441] Example 42: 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 [ka] 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: tert-butyl General procedure 6 using (2S,5R)-5-(4-(6-chloro-4-oxo-3,4-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylmorpholine-4-carboxylate (45 mg, 0.101 mmol), epoxide 16 (34 mg, 0.152 mmol), CsCO (98.9 mg, 0.303 mmol) and DMF (2 mL) afforded the title compound (47 mg, 69%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T = 1.41 min, m / z = 610, 612 [M-butene + H] + .

[0442] 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: tert-butyl General procedure 7 using (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 (47 mg, 0.0705 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (36 mg, 90%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.76 min, m / z = 566, 568 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.64 - 7.57 (m, 2H), 7.43 - 7.36 (m, 2H), 6.80 (s, 1H), 4.91 (s, 1H), 4.12 - 3.91 (m, 4H), 3.90 - 3.77 (m, 2H), 3.61 - 3.51 (m, 1H), 3.46 - 2.75 (m, 5H (signal overlap with HDO)), 2.59 - 2.53 (m, 1H), 1.62 - 1.46 (m, 2H), 1.46 - 1.35 (m, 2H), 1.17 - 1.11 (m, 1H), 1.09 (d, J = 6.2 Hz, 3H), 0.71 - 0.62 (m, 2H), 0.50 - 0.41 (m, 2H), 0.41 - 0.34 (m, 2H), 0.13 - 0.04 (m, 2H).

[0443] Example 43: 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 [ka] 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%). 1 H NMR (500 MHz, chloroform-d) δ 5.11 - 4.62 (m, 1H), 4.34 - 4.18 (m, 1H), 4.05 - 3.81 (m, 2H), 3.24 - 3.02 (m, 1H), 2.23 - 2.05 (m, 2H), 2.04 - 1.90 (m, 2H), 1.89 - 1.79 (m, 1H), 1.70 - 1.61 (m, 1H), 1.58 - 1.40 (m, 9H).

[0444] 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), followed by the sequential addition of triethylamine (1.79 mL, 12.8 mmol) and a DMF solution of NiCl2·6H2O:bathophenanthroline complex (0.05 M, 4.85 mL, 0.243 mmol, (Angew. Chem. Int. Ed. 2016, 55, 9676-9679)). The resulting mixture was stirred at 75 °C overnight. After cooling to rt, the reaction mixture was diluted with EtOAc (250 mL) and washed with brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give the title compound (366 mg, 74%) as a colorless glass. LCMS (Method B): R T = 1.75 min, m / z = 282, 284 [M-Boc+H] + This material was used without further purification.

[0445] 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 (workup 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)Cl2·CHCl2 (91.9 mg, 0.109 mmol), KOAc (320 mg, 3.26 mmol), and 1,4-dioxane (11 mL) afforded the title compound (460 mg, 98%) as a yellow solid after stirring at 100 °C (thermal) for 4 h. LCMS (Method B): R T = 1.84 min, m / z = 330 [M-Boc+H] + This material was used without further purification.

[0446] 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: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.06 mmol), tert-butyl General procedure 4 (Workup A) using 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(II) 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) afforded the title compound (127 mg, 24%) as a colorless glass after 3 days at 50° C. LCMS (Method B): R T = 1.80 min, m / z = 489, 491 [M+H] + .

[0447] 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 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 (20 mg, 0.0409 mmol), aqueous sodium hydroxide (4 M, 0.31 mL, 1.23 mmol) and 1,4-dioxane (0.3 mL) afforded the title compound (19 mg, quantitative) as a yellow glass after 18 h at 100° C. and acidification using 1 M aqueous potassium bisulfate. LCMS (Method B): R T = 1.38 min, m / z = 471, 473 [M+H] + .

[0448] 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: tert-butyl General procedure 6 using 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 (10 mg, 0.0212 mmol), epoxide 16 (7.1 mg, 0.0319 mmol), CsCO (20.8 mg, 0.0637 mmol) and DMF (0.5 mL) afforded the title compound (7.5 mg, 51%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T = 1.54 min, m / z = 636, 638 [M-butene + H] + .

[0449] 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: tert-butyl General procedure 7 using 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 (7.5 mg, 0.0108 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (6 mg, 93%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.81 min, m / z = 592, 594 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.67 - 7.56 (m, 2H), 7.45 - 7.33 (m, 2H), 6.80 (s, 1H), 4.91 (s, 1H), 4.12 - 3.93 (m, 4H), 3.84 (dd, J = 10.1, 3.2 Hz, 1H), 3.60 (dd, J = 10.9, 3.3 Hz, 1H), 3.47 - 2.75 (m, 5H), 2.70 (dd, J = 11.7, 1.9 Hz, 1H), 2.35 - 2.27 (m, 1H), 2.08 - 1.69 (m, 4H), 1.70 - 1.32 (m, 5H), 1.18 - 1.08 (m, 1H), 0.67 (s, 2H), 0.52 - 0.41 (m, 2H), 0.41 - 0.32 (m, 2H), 0.12 - 0.07 (m, 1H).

[0450] Example 44: 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 [ka] 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: tert-butyl General procedure 6 using 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 (10 mg, 0.0212 mmol), epoxide 2 (8.02 mg, 0.0319 mmol), CsCO (20.8 mg, 0.0637 mmol) and DMF (0.5 mL) afforded the title compound (6 mg, 39%) as a colorless glass after 18 h at 80 °C. LCMS (Method B): R T = 1.61 min, m / z = 666, 668 [M-butene + H] + .

[0451] 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: tert-butyl General procedure 7 using 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 (6 mg, 0.0083 mmol), TFA (1 mL) and DCM (2 mL) afforded the title compound (5 mg, 96%) as a white solid after freeze-drying. LCMS (Method B): R T = 0.88 min, m / z = 622, 624 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.63 - 7.57 (m, 2H), 7.53 - 7.47 (m, 2H), 7.46 - 7.36 (m, 4H), 6.79 (s, 1H), 4.95 (s, 1H), 4.27 - 4.07 (m, 1H), 4.02 (s, 2H), 3.84 (dd, J = 10.2, 3.2 Hz, 1H), 3.59 (dd, J = 10.9, 3.3 Hz, 1H), 3.42 - 3.33 (m, 1H), 3.29 - 2.96 (m, 4H), 2.96 - 2.76 (m, 1H), 2.70 (dd, J = 11.7, 1.9 Hz, 1H), 2.35 - 2.22 (m, 1H), 2.01 - 1.70 (m, 4H), 1.69 - 1.27 (m, 5H).

[0452] Example 45: 6-chloro-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one [ka] 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 (prepared 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) (4.63 g, 12.8 mmol), 2,6-dimethylpyridine (1.37 g, 12.8 mmol), HFIP (51 mL), 4 Å molecular sieves (approximately 1.28 g), and DCM (205 mL) gave the title compound (1.93 g, 56%). LCMS (Method C): R T = 0.93 min, m / z = 270, 272 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 0.97 (t, J = 7.5 Hz, 3H), 1.40 - 1.66 (m, 2H), 2.72 (dd, J = 11.5, 10.2 Hz, 1H), 3.08 (dd, J = 11.5, 2.3 Hz, 1H), 3.33 - 3.50 (m, 2H), 3.76 - 3.93 (m, 2H), 6.96 (d, J = 7.7 Hz, 2H), 7.46 (d, J = 7.7 Hz, 2H).

[0453] 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 BocO (1.87 g, 8.58 mmol) gave the title compound (1.77 g, 67%). LCMS (Method C): R T = 1.40 min, m / z = 270, 272 [M-Boc+H] + . 1 H NMR (400 MHz, chloroform-d) δ 0.95 (t, J = 7.4 Hz, 3H), 1.35 (s, 9H), 1.48 - 1.61 (m, 1H), 1.65 - 1.79 (m, 1H), 3.38 - 3.52 (m, 2H), 3.58 - 3.67 (m, 1H), 3.73 (dd, J = 12.3, 5.4 Hz, 1H), 3.96 (dd, J = 12.2, 4.5 Hz, 1H), 4.79 (t, J = 5.1 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H).

[0454] 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 (Workup B) using tert-butyl (2S,5R)-5-(4-bromophenyl)-2-ethylmorpholine-4-carboxylate (741 mg, 2.00 mmol), B2Pin2 (762 mg, 3.00 mmol), Pd(dppf)Cl.CHCl (169 mg, 0.200 mmol), KOAc (589 mg, 6.00 mmol), and 1,4-dioxane (20 mL) afforded the title compound (914 mg, >100%) as a yellow oil after stirring at 100 °C (thermal) for 70 min. LCMS (Method A): R T = 2.07 min, m / z = 362 [M-butene + H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.65 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 4.80 (t, J = 5.4 Hz, 1H), 3.91 (dd, J = 12.2, 4.9 Hz, 1H), 3.69 (dd, J = 12.2, 6.0 Hz, 1H), 3.66 - 3.60 (m, 1H), 3.49 (dd, J = 13.7, 3.8 Hz, 1H), 3.41 (dd, J = 13.7, 4.4 Hz, 1H), 1.65 - 1.55 (m, 1H), 1.53 - 1.44 (m, 1H), 1.29 (s, 9H), 1.28 (s, 6H), 1.17 (s, 6H), 0.88 (t, J = 7.4 Hz, 3H). This material was used without further purification.

[0455] Step 4: tert-butyl (2S,5R)-5-(4-(4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-ethylmorpholine-4-carboxylate: 4,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (289 mg, 1.54 mmol), tert-butyl General procedure 4 (Workup B) using (2S,5R)-2-ethyl-5-(4-(4,4,5,5-tetram...

Claims

1. Compounds of formula (I), including stereoisomers: 【Chemistry 1】 [In the ceremony: "m" is 0, 1, or 2, and each R １ is independently halo; C optionally substituted with halo １ -C ６ Alkyl; and C ３ -C ６ cycloalkyl; "n" is 0, 1, or 2, and each R ２ is independently an optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ cycloalkyl, where each of the one or more optional substituents is independently selected from C １ -C ６ selected from alkyl and halo; or where "n" is 2 and each R ２ together with the carbon ring atom or atoms to which they are attached, C ３ -C ６ Fused cycloalkyl ring, C ３ -C ６ Spirocyclic cycloalkyl ring or C ３ -C ４ Forming crosslinks; R ３ is an optionally substituted C １ -C ６ Alkyl, optionally substituted C ３ -C ６ Cycloalkyl, optionally substituted phenyl, optionally substituted C ７ -C １０ Arylalkyl, optionally substituted C ８ -C １０ Arylalkenyl and optionally substituted C ３ -C ６ heteroaryl; wherein each of the one or more optional substituents is independently selected from halo; C optionally substituted with halo １ -C ６ alkyl; and optionally methyl or CF ３ C substituted with ３ -C ６ cycloalkyl; R ４ is H, Cl, C １ -C ６ is alkyl; wherein one of X and Z is O and one of X and Z is NR′, where R′ is H or C, such that X and Z are morpholine rings. １ -C ６ alkyl, optionally H. or a pharma- ceutically acceptable salt or solvate thereof.

2. Compounds of formula (Ia), including stereoisomers: 【Chemistry 2】 [In the ceremony: "m", "n", R １ ~R ４ and R' is as defined in claim 1. or a pharma- ceutically acceptable salt or solvate thereof.

3. Compounds of formula (Ic), including stereoisomers: 【Chemistry 3】 [In the ceremony: "m", "n", R １ ~R ４ and R' is as defined in claim 1. or a pharma- ceutically acceptable salt or solvate thereof.

4. 2. The compound of claim 1, wherein X is NR' and Z is O, or a pharma- ceutically acceptable salt or solvate thereof.

5. The compound of any one of claims 1 to 4, wherein "m" is 0 or 1, or a pharma- ceutically acceptable salt or solvate thereof.

6. The compound of any one of claims 1 to 5, wherein "m" is 0, or a pharma- ceutically acceptable salt or solvate thereof.

7. The compound of any one of claims 1 to 6, wherein "n" is 1 or 2, or a pharma- ceutically acceptable salt or solvate thereof.

8. Each R １ are independently Cl; F; methyl optionally substituted with F, optionally CF ３ 8. The compound of any one of claims 1 to 7, or a pharma- ceutically acceptable salt or solvate thereof, wherein R is selected from ethyl, propyl and cyclopropyl, optionally substituted with F.

9. Each R １ is independently methyl optionally substituted with F, or a pharma- ceutically acceptable salt or solvate thereof.

10. Each R ２ 10. The compound of any one of claims 1 to 9, or a pharma- ceutically acceptable salt or solvate thereof, wherein: is independently selected from methyl optionally substituted with F; ethyl; and cyclopropyl.

11. Each R ２ 11. The compound of any one of claims 1 to 10, or a pharma- ceutically acceptable salt or solvate thereof, wherein is independently selected from methyl; ethyl; and cyclopropyl.

12. Each R ２ 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt or solvate thereof, wherein is independently selected from methyl or ethyl.

13. "n" is 1 and R ２ The compound of any one of claims 1 to 12, or a pharma- ceutically acceptable salt or solvate thereof, wherein is methyl.

14. "n" is 2, and each R ２ The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt or solvate thereof, wherein is methyl.

15. "n" is 2, and each R ２ together with the carbon ring atoms to which they are attached, ３ Or C ４ 14. The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt or solvate thereof, which forms a spirocyclic cycloalkyl ring.

16. "n" is 2, and each R ２ together with the carbon ring atoms to which they are attached, ３ -C ６ A fused cycloalkyl ring, optionally ３ , C ５ Or C ６ 14. The compound of any one of claims 1 to 13, or a pharma- ceutically acceptable salt or solvate thereof, which forms a fused cycloalkyl ring.

17. "n" is 2, and each R ２ together with the carbon ring atoms to which they are attached, ４ 14. The compound according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt or solvate thereof, which forms a bridge.

18. 13. The compound of any one of claims 1 to 12, or a pharma- ceutically acceptable salt or solvate thereof, wherein "n" is 1.

19. At least one R ２ group is at the 6-position of the morpholinyl ring, and optionally each R ２ 19. The compound of any one of claims 1 to 18, or a pharma- ceutically acceptable salt or solvate thereof, wherein the substituent is at the 6-position of the morpholinyl ring.

20. At least one R ２ group is at the 2-position of the morpholinyl ring, and optionally each R ２ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt or solvate thereof, wherein the substituent is at the 2-position of the morpholinyl ring.

21. At least one R ２ group is at the 5-position of the morpholinyl ring, and optionally each R ２ 21. The compound of any one of claims 1 to 20, or a pharma- ceutically acceptable salt or solvate thereof, wherein the substituent is at the 5-position of the morpholinyl ring.

22. R ４ 22. The compound of any one of claims 1 to 21, or a pharma- ceutically acceptable salt or solvate thereof, wherein is chlorine.

23. R ４ is H or C １ -C ６ 22. The compound of any one of claims 1 to 21, or a pharma- ceutically acceptable salt or solvate thereof, wherein: R is an alkyl group;

24. R ４ is H or methyl, or a pharma- ceutically acceptable salt or solvate thereof.

25. R ３ is optionally substituted C ３ -C ６ Cycloalkyl (wherein each of the one or more optional substituents is independently halo); C optionally substituted with F １ -C ２ Alkyl; and C ３ -C ６ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt or solvate thereof, selected from cycloalkyl.

26. R ３ is an optionally substituted cyclopropyl, wherein each of the one or more optional substituents is independently methyl, CHF ２ , C.F. ３ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt or solvate thereof, wherein said compound is selected from:

27. R ３ is of the general formula: 【Chemistry 4】 [In the formula, R ５ and R ６ each independently represents hydrogen, halo; C optionally substituted with F １ -C ２ Alkyl; and C ３ -C ６ cycloalkyl.

26. The compound of any one of claims 1 to 25, wherein:

28. R ５ and R ６ are each independently hydrogen, methyl, or CHF ２ , C.F. ３ and cyclopropyl, preferably R ５ are independently hydrogen and CF ３ is selected from R ６ 28. The compound of claim 27, wherein is independently selected from methyl and cyclopropyl.

29. R ３ is optionally substituted phenyl, wherein each of the one or more optional substituents is independently halo, C optionally substituted with F. １ -C ２ Alkyl and optionally methyl or CF ３ C substituted with ３ -C ６ 29. The compound of any one of claims 1 to 28, or a pharma- ceutically acceptable salt or solvate thereof, selected from: cycloalkyl.

30. R ３ is an optionally substituted phenyl, wherein each of the one or more optional substituents is independently Cl, F, methyl, CF ３ , C.H.F. ２ and optionally methyl or CF ３ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt or solvate thereof, wherein the compound is selected from cyclopropyl substituted with cyclopropyl.

31. R ３ is optionally substituted C ７ -C １０ arylalkyl, where each of the one or more optional substituents is independently halo; C optionally substituted with halo １ -C ６ alkyl; and optionally methyl or CF ３ C substituted with ３ -C ６ Cycloalkyl 32, or a pharma- ceutically acceptable salt or solvate thereof.

32. R ３ is optionally substituted (CH ２ ) ２ -phenyl, where each of the one or more optional substituents is independently halo; C optionally substituted with halo １ -C ６ alkyl; and optionally methyl or CF ３ C substituted with ３ -C ６ 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt or solvate thereof, selected from cycloalkyl.

33. R ３ When is an arylalkyl group, each of the one or more optional substituents of the arylalkyl group is independently halo, methyl, ethyl, CHF ２ and C.F. ３ 33. The compound of any one of claims 1 to 32, selected from the group consisting of:

34. 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, selected from the following: rac-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3R,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one rac-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3R,5S)-5-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 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 6-chloro-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 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 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 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 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 rac-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6R)-6-(trifluoromethyl)morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 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 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 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 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 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 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 6-chloro-7-(4-(5,5-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 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 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 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 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 3-((1-benzoyl-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 6-chloro-3-((1-(4-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 6-chloro-3-((1-(2,4-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 (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 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 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 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 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3S,5R)-5-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (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 (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 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 6-chloro-3-((1-(2-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 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 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 (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 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 6-chloro-3-((1-(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 6-chloro-3-((1-(3,4-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 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 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 (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]pyrimidin-4-one (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]pyrimidin-4-one 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 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 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 6-chloro-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3-((1-(4-fluorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 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 7-(4-((1R,2S,5S)-8-oxa-3-azabicyclo[3.2.1]octan-2-yl)phenyl)-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 7-(4-((1R,2S,5S)-8-oxa-3-azabicyclo[3.2.1]octan-2-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 6-chloro-3-((1-(4-chloro-2-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 6-chloro-3-((1-(3-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 6-chloro-3-((1-(2-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 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-(octahydro-2H-benzo[b][1,4]oxazin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-(octahydrocyclopenta[b][1,4]oxazin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-(4-methylbenzoyl)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 6-chloro-3-((4-hydroxy-1-(4-(trifluoromethyl)benzoyl)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 6-chloro-3-((1-(2-chloro-4-methylbenzoyl)-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 6-chloro-3-((1-(2,4-dimethylbenzoyl)-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 6-chloro-3-((1-(2,4-dimethylbenzoyl)-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 7-(4-(2-oxa-5-azabicyclo[4.1.0]heptan-4-yl)phenyl)-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3S,6R)-6-cyclopropylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-((1S,2S)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)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 6-chloro-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)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 6-chloro-3-((1-cinnamoyl-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 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6S)-6-cyclopropylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)methyl)-7-(4-((3R,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((1S,2S)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-7-(4-((R)-6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((1S,2S)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-7-(4-((S)-6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((1S,2S)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-7-(4-((R)-6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-7-(4-((S)-6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3S,6S)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6R)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (S)-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (R)-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-7-(3-fluoro-4-(morpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (S)-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(3-methyl-4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (R)-6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(3-methyl-4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-(4-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (S)-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (R)-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-((R)-4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-7-(4-((S)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (S)-3-((1-([1,1'-bi(cyclopropane)]-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-chloro-7-(4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (R)-3-((1-([1,1'-bi(cyclopropane)]-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-6-chloro-7-(4-(morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-((R)-4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-7-(4-((R)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((1-((R)-4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((S)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-(1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((S)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-(1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((R)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((1-((R)-4,4-difluoro-3-phenylbutanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((R)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-7-(3-chloro-4-((S)-morpholin-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 6-chloro-7-(3-chloro-4-((R)-morpholin-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 6-chloro-3-((4-hydroxy-1-((R)-4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-7-(4-((S)-morpholin-3-yl)-3-(trifluoromethyl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-((R)-4,4,4-trifluoro-3-phenylbutanoyl)piperidin-4-yl)methyl)-7-(4-((R)-morpholin-3-yl)-3-(trifluoromethyl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-Chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-(morpholin-2-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one. 6-chloro-3-((1-(4-chloro-2-methylbenzoyl)-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 6-chloro-3-((1-(4-chloro-2-methylbenzoyl)-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 6-chloro-3-((1-(4-(difluoromethyl)benzoyl)-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 6-chloro-3-((1-(4-(difluoromethyl)benzoyl)-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 6-chloro-3-((1-(4-cyclopropylbenzoyl)-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 6-chloro-3-((4-hydroxy-1-(4-(1-methylcyclopropyl)benzoyl)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 6-chloro-3-((1-((1S,2S)-1,2-dimethylcyclopropane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((1-((1R,2R)-1,2-dimethylcyclopropane-1-carbonyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 7-(4-((1S,2R,5R)-8-oxa-3-azabicyclo[3.2.1]octan-2-yl)phenyl)-6-chloro-3-((1-(4-chlorobenzoyl)-4-hydroxypiperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (R)-6-chloro-7-(4-(6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (S)-6-chloro-7-(4-(6,6-dimethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((1-(2,2-dicyclopropylacetyl)-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 6-chloro-7-(4-((3R,6S)-6-cyclopropylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-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 6-chloro-3-((4-hydroxy-1-(1-methylcyclobutane-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 6-chloro-3-((1-(3-cyclopropylpropanoyl)-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 6-chloro-7-(4-((3S,6R)-6-cyclopropylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-7-(4-((3S,6R)-6-ethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-7-(4-((3R,6S)-6-ethylmorpholin-3-yl)phenyl)-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3S,6R)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3S,6R)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-((1S,2S)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((3S,6R)-6-methylmorpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((S)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((4-hydroxy-1-((1R,2R)-1-methyl-2-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)-7-(4-((R)-morpholin-3-yl)phenyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one 6-chloro-3-((1-((1S,2S)-2-(difluoromethyl)-1-methylcyclopropane-1-carbonyl)-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 and 6-chloro-3-((1-((1R,2R)-2-(difluoromethyl)-1-methylcyclopropane-1-carbonyl)-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.

35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34, or a pharma- ceutically acceptable salt or solvate thereof.

36. A compound of any one of claims 1 to 34, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 35, for use in therapy.

37. 36. A compound of any of claims 1 to 34, or a pharma- ceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 35, for use in a method for treating cancer.

38. 37. Use of a compound of any of claims 1 to 34, or a pharma- ceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 35, in the manufacture of a medicament for use in a method of treating cancer.

39. A method of treating cancer in a subject, comprising administering to the subject an effective amount of a compound of any of claims 1 to 34, or a pharma- ceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 35.

40. 40. The compound or pharmaceutical composition for use of claim 38 or the method of claim 39 or the use of claim 36 or claim 37, wherein the method comprises administration of a further therapeutic agent.

41. 40. The compound or pharmaceutical composition for use of claim 38 or the method of claim 39 or the use of claim 36 or claim 37, wherein the method comprises administration of an immune checkpoint inhibitor.

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